Data Collection Forms in Clinical Trials [1 ed.] 0881677590

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Data Collection Forms i n Clinical Trials BERT SPILKER

J O H N SCHOENFELDER

Raven Press Otsuka America P h i . . MOCK

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Data Collection Forms i n Clinical Trials

Data Collection Forms in Clinical Trials

Bert Spilker, Ph.D., M.D. Director, Project Coordination, Burroughs Wellcome Co. Research Triangle Park, North Carolina Adjunct Professor of Pharmacology and Adjunct Professor of Medicine University of North Carolina School of Medicine Clinical Professor of Pharmacy University of North Carolina School of Pharmacy Chapel Hill, North Carolina

John Schoenfelder, Ph.D. Associate Director, Biostatistics, Adria Laboratories Columbus, Ohio Adjunct Assistant Professor of Biostatistics University of North Carolina School of Public Health Chapel Hill, North Carolina

RAVEN PRESS >

NEW YORK

Raven Press, Ltd., 1185 Avenue of the Americas, New York, New York 10036

© 1991 by Raven Press, Ltd. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronical, mechanical, photocopying, or recording, or otherwise, without the prior written permission of the publisher. Made in the United States of America Library of Congress Cataloging-in-Publication Data

Spilker, Bert. Data collection forms in clinical trials / by Bert Spilker, John Schoenfelder. p. cm. Includes bibliographical references and index. ISBN 0-88167-759-0 1. Clinical trials— Forms. 2. Health surveys— Forms. I. Schoenfelder, John. II. Title. [DNLM: 1. Clinical Trials.—Forms. 2. Data Collection —forms. QV 771 S756d] R853.C55S63 1991 616'.072—dc20 DNLM/DLC for Library of Congress 91-7863 C1P The material contained in this volume was submitted as previously unpublished material, except in the instances in which credit has been given to the source from which some of the illustrative material was derived. Great care has been taken to maintain the accuracy of the information contained in the volume. However, neither Raven Press nor the authors can be held responsible for errors or for any consequences arising from the use of the information contained herein. Materials appearing in this book prepared by individuals as part of their official duties as U.S. Government employees are not covered by the abovementioned copyright. 987654321

To the many people whose efforts and creativity have contributed to designing the data collection forms in this book

v

Contents Preface, xi Acknowledgments, xii Terminology, xiii List of Tables and Figures, xiv PART I CREATING DATA COLLECTION FORMS 1

An Overall Approach: Building a Library of Forms

2 Types of Data Collection Forms

1 3

9

Background Considerations, 9 Three Levels of Viewing Data Collection Forms, 10

3 Choosing Modules and Designing Forms: Guidelines, Pointers, and Pitfalls

12

Background, 12 Guidelines, 13 Pointers, 19 Pitfalls, 26

4 Preparing the Data Collection Form Package

30

Items Often Included in a Data Collection Form Package, 30 Methods Used to Organize Pages, 32

5 Reproducing and Assembling Forms

34

6 Remote Data Entry Forms

37

vii

CONTENTS

7

Data Processing and Storage of Completed Forms

8 Selected Issues PART II

EXAMPLES OF DATA COLLECTION FORMS

Introduction to Part II

44 47 51 53

Organization of Part II, 53 Page Numbering System Used in Part II, 54

A Background of a Clinical Trial

55

General Pointers and Comments, 55 Specific Pointers and Comments on Individual Forms, 56

Al

Instructions for Completing Data Collection Forms

59

A2 Time-and-Events Schedules

71

A3 Demographics

79

A4 General Medical History

87

A5 Specific Types of Medical Histories A6

Medication History

A7 Inclusion and Exclusion Criteria

B Physical and Other Examinations

109 153 163

179

General Pointers and Comments, 179 Specific Pointers and Comments on Individual Forms, 179

Bl

Physical Examinations

181

B2

Vital Signs

225

B3 Neurological Examinations

viii

243

CONTENTS

C

B4 Ophthalmological Examinations

263

B5

Psychological and Psychiatric Tests

277

B6 Other Specialized Physical Examinations

281

Laboratory Tests and Evaluations

297

General Pointers and Comments, 297 Specific Pointers and Comments on Individual Forms, 297

Cl

D

Clinical Chemistry and Hematology Tests

301

C2 Radiology and Pathology Reports

327

C3 Electrocardiograms

345

C4

Urine Tests

359

C5

Microbiology Tests

373

C6

Virology Tests

383

C7

Neurology Tests

389

C8

Endocrinology and Immunology Tests

397

C9

Other Laboratory Tests

403

Adverse Events (Experiences)

427

General Pointers and Comments, 427 Specific Pointers and Comments on Individual Forms, 427

E

Medicines and Assays of Biological Levels General Pointers and Comments, 473 Specific Pointers and Comments on Individual Forms, 473

473

CONTENTS

El

Dosing and Dispensing Records

475

E2 Concomitant Medications

521

E3 Pharmacokinetic Samples to Assay

535

F Efficacy

551

General Pointers and Comments, 551 Specific Pointers and Comments on Individual Forms, 551

Fl

G

Efficacy Evaluations

553

F2 Compliance

593

F3 Patient Diaries

601

Patient Termination and Miscellaneous Forms

607

General Pointers and Comments, 607 Specific Pointers and Comments on Individual Forms, 608

X

G1 Termination and Premature Patient Discontinuation

611

G2 Global Clinical Impressions

647

G3 Additional and Unscheduled Patient Visits

653

G4 Comment Log and Investigator Verification Forms

657

References

662

Subject Index

663

Preface Obtaining complete and accurate data is essential to achieving the scientific and medical objectives of all clinical trials. The primary purpose of this book is to aid researchers in completing protocols at as high a standard as possible. We originally wrote the text and assembled the library of forms for academic and other investigators who do not readily have access to high-quality data collection forms. Given the importance of data collection and the lack of published sources of many data collection forms, it seemed that this book would address a great need. We still believe this to be true. In addition, numerous conversations have recently convinced us that many sponsors within the pharmaceutical industry and government also need and would benefit from a library of data collection forms that could be easily modified for specific clinical trials. This book provides many examples of well-designed data collection forms. Examples of poorly designed forms are not included. Although we considered providing samples of poorly designed forms and critiquing them for the reader, it seemed preferable to focus on the positive aspects of well-designed forms. Bert Spilker, Ph.D., M.D. John Schoenfelder, Ph.D.

Acknowledgments We greatly appreciate the help of Dr. Imogene McCanless and Ms. Suzanne Bryan, who reviewed the manuscript and made many helpful suggestions. Valuable discussions were also held with Kate Esch, Brenda Bruni, Nancy Bauer, and Melissa Beaman. The library of data collection forms in Part II of this book consists of actual forms sent to us by several pharmaceutical companies. This book would not have been possible without the cooperation of the following people, whose generosity is sincerely appreciated: Drs. William M. Wardell and Edward M. Hughes, Boehringer-Ingelheim Pharmaceuticals Inc. Dr. Gilbert H . Mayor and Mr. Steve Mayo, Boots Company (USA) Inc. Drs. John J . Donahue and Kenneth M. Given, Bristol-Myers Squibb Co. Dr. George Maha and Ms. Melissa Beaman, Burroughs Wellcome Co. Dr. Ronald Kartzinel and Mr. Lawrence Fabrizio Jr., Ciba-Geigy Corporation Drs. David Lee and M. Mak, Duphar B.V. Dr. Imogene McCanless (currently with Cato Research Ltd.), Glaxo Inc. Dr. Archie Andrew and Ms. Barbara K. Kennedy, R. W. Johnson Pharmaceutical Research Institute Dr. W. Leigh Thompson, Ms. Jane Chavers, Ms. Roberta J . Smithey, and Ms. Candice P. Lange, Lilly Research Laboratories Dr. Zofia Dziewanowska and Mr. Jay D. Miller, Roche Pharmaceuticals Dr. Hubert Peltier and Ms. Frances Kavanaugh, Sterling Drug, Inc. Dr. George H . Ishler and Mr. John K. Coombs, The Upjohn Company Dr. Alfred S. C . Ling and Ms. Frances M. Rink, Wyeth-Ayerst Laboratories. We thank them for their vision in appreciating the potential value of this reference. Dr. Robert Vogel of Onsite Systems (Berkeley, California) generously created the remote data forms from hard-copy forms. This enables the reader to appreciate readily how current hard-copy forms may be modified for use as computer screens. Forms from two cooperative cancer study groups, the National Surgical Adjunct Breast and Bowel Group and the Cancer and Leukemia Group B, are included. We are grateful to them and the National Cancer Institute. We thank Oxford University Press for permission to use information from “Clinical Trials Design, Conduct, and Analysis” by C . L . Meinert and S. Tonascia ( 1986) in tables shown in Part I, Chapters 3 to 5. We appreciate the insights and suggestions for organizing Part II of this book provided by Dr. Graham Lees and Ms. Isabel Stein of Raven Press. The authors particularly thank Ms. Thomasine Cozart and Ms. Janice Wilson for their help in preparing this manuscript. The authors would like to thank Ms. Elizabeth Majors for her help with the artwork.

xii

Terminology Case report form. Synonym used widely in the pharmaceutical industry for data

collection form. Also called a case record form. Data collection form. A single sheet used in a clinical trial in order to collect data,

assist in monitoring, and provide the data used in data processing. It may contain one, less than one, or more data modules; conversely, a data module may be presented on one or more data collection forms. Data collection form package. The booklet containing the entire set of data collection forms for a single patient in a specific clinical trial. It may also be referred to as a case record. Data module. The series of questions used to collect data on one particular topic

in data collection forms. Examples include modules for demographics, vital signs, laboratory tests, termination records and adverse events. Modules range in size from a fraction of a single data collection form to many forms. Modules are often repeated at each clinic visit in a single clinical trial, but the length of the module may vary (e.g., a full examination versus an abbreviated examination). Level 1 data collection forms. General data collection forms that are suitable for almost any clinical trial, although most forms would require at least minimal modification prior to use. Each form may contain one or more data modules. Level 2 data collection forms. General data collection forms modified from level

1 that only relate to a specific disease, medicine, or therapeutic area. These forms are designed to measure either safety or efficacy variables. Level 3 data collection forms. Data collection forms modified from level 2 for a specific clinical trial. These forms could rarely be used unaltered in another clinical trial. Library of data collection forms. A collection of data collection forms at either

level 1 or level 2.

xiii

List of Tables and Figures CHAPTER 1

Table 1. 1

Basic questions to pose when creating data collection forms .................................................................................

5

Table 1.2

Benefits of maintaining a standardized library of forms . . .

6

Table 1.3

Representative types of data collection form modules . . . .

7

Representative examples of data collection forms used for the three levels of specificity ............................................

11

Table 3.1

General guidelines for creating useful data collection forms

13

Table 3.2

General guidelines for item construction .............................

16

Table 3.3

Guidelines relating to language and terminology ..................

16

Table 3.4

Guidelines relating to using items from other clinical trials

17

Table 3.5

Guidelines relating to response checklists ...........................

17

Table 3.6

Guidelines relating to measurement and calculation items

18

Table 3.7

Guidelines providing directions on how to proceed from item to item ......................................................................

18

Table 3.8

Guidelines for time and date items .....................................

18

Table 3.9

Guidelines for designing the layout of data collection forms

19

CHAPTER 2

Table 2. 1

CHAPTER 3

Table 3.10 Guidelines for arranging items on data collection forms . . .

20

Table 3.11 General pointers for creating data collection forms ...........

20

Table 3.12 Methods for avoiding errors of omission .............................

21

Table 3.13 Methods for avoiding errors of commission ........................

21

LIST OF TABLES

Table 3.14 Considerations used when selecting questions for inclusion on data collection forms for the Coronary Drug Project

22

Table 3.15 Factors to consider when choosing between open and closed systems .................................................................

23

Table 3.16 Pitfalls to avoid in designing data collection forms .............

27

CHAPTER 4

Considerations for locating instructional materials in the data collection form package ............................................

31

Table 5.1

Considerations of paper used for data collection forms . . .

35

Table 5.2

Considerations of type style used for data collection forms

35

Table 5.3

Considerations of duplicating data collection forms ...........

35

Table 5.4

Considerations for physically assembling the data collection form package ....................................................

36

Models of data flow and verification using remote data entry ...................................................................................

39

Risk factors to contrast medium: traditional data collection form ...................................................................................

40

Risk factors to contrast medium: remote study monitoring computer screen design ....................................................

41

Risk factors to contrast medium (continued): remote study monitoring computer screen design .................................

42

Comparison of traditional data collection forms, remote trial monitoring workbooks, and remote trial monitoring data forms ..........................................................................

43

Frequently encountered errors relating to the degree that data collection forms are filled in accurately and completely ........................................................................

45

Frequently encountered errors relating to consistency and logic found on data collection forms ...............................

45

Table 4.1

CHAPTER 5

CHAPTER 6

Fig. 6.1 Fig. 6.2 Fig. 6.3 Fig. 6.4 Table 6.1

CHAPTER 7

Table 7.1

Table 7.2

XV

PARTI

Creating Data Collection Forms

1 An Overall Approach: Building a Library of Forms Introduction Prior to the 1980s almost every clinical trial had data collection forms designed specifically for it. Data collection forms from similar clinical trials were often redesigned based either on experiences from previous trials or on theoretical considerations. Many people regarded data collection forms as artistic creations of how best to collect data. Most people wanted to add their own personal touch or imprint on the forms, even if the protocol was similar or identical to another for which adequate forms were already available. As a result, the investigational staff usually required more time to complete the forms and the data processors more time to orient themselves to the new forms than necessary. New computer programs had to be written to enter the data into the computer. Many questions had to be recoded. Statisticians had to write new programs to analyze the data. During the 1980s it became more common to use identical data collection forms across multiple clinical trials. This practice improved both the speed and accuracy of data collection, data processing, and data analysis. At the present time, the use of a library of standard forms enables efficient collection and processing of data. Remote data entry, described briefly in Chapter 6, is leading us into a future where more and more data will travel via telephone lines, computer disk, and eventually satellite transmission. This will have an impact on the design of data collection forms to a degree but not as drastically as might be guessed. Chapter 6 shows how paper data collection forms can be modified for remote data entry. A substantial expenditure of time and energy is required to create a coherent and well-designed protocol for a clinical trial. Major contributors to that process usually include a team of physicians, experienced clinical trial study coordinators, monitors, statisticians, and others (e.g., dispensing pharmacists and laboratory personnel). If the clinical trial is sponsored, then additional personnel from the sponsor’s site are also involved. After intensely reviewing all relevant information about the test medicine(s) or other treatment(s) and the indication being evaluated, the researchers write an initial draft of the protocol and disseminate it for peer review. After a series of appropriate revisions, the protocol is finalized and submitted to one or more Ethics Committee/Institutional Review Board (IRB) for approval. A discussion of issues relating to protocol development may be found in Spilker (1991). Once the protocol is finalized, and prior to submission to the

3

A N O V E R A L L A P P R O A C H : BUILDING A LIBRARY O F F O R M S

Ethics Committee/IRB, attention is focused on creating the data collection forms (i.e., the pages or computer screens used to collect and record the data). Feinstein (1970a,/?) presents a broader view of collecting data than we present in this book. For example, he discusses unstructured as well as structured formats. H e also discusses many of the principles underlying data collection and describes nuances that would be of interest to students of the art of data collection.

Problems of Hastily Developed Data Collection Forms Given the time and attention usually devoted to protocol development, it is paradoxical that data collection forms are often hastily constructed at the end of that process. This often transpires just prior to beginning the clinical trial. Haste often occurs in order to meet a preselected clinical trial initiation date. As a result, often comparatively little thought is given to the organization and design of the data collection forms. Moreover, few data collection forms are available in library reference books to assist investigators or others who are assembling data collection forms de novo. There are many reasons for the haste described above. The explanation given most often is that data collection forms cannot be developed until a protocol is finalized and the researchers know what specific data will be collected and when. While it is true that data collection forms cannot be finalized prior to completing a protocol, usually most of the variables on which data will be collected are known early in protocol development. Therefore the process of designing the forms can be started prior to protocol completion. Moreover, the process of designing a data collection form may identify attributes of a protocol that are inappropriate or infeasible, requiring additional protocol development. One way to minimize this problem is to develop a protocol and its data collection forms simultaneously. A second explanation for the rushed preparation time is that those who construct data collection forms often are not the same people who develop the protocols. This comes about in part because constructing data collection forms is often mistakenly viewed as a clerical rather than a scientific task. On the other hand, academicians who conduct relatively small clinical trials often create their own data collection forms. Given that data are the primary “output” of a clinical trial, the quality of a trial is limited by the quality of the data produced. It is imperative that those who develop the forms to collect data either be intimately involved in the protocol development process, or work closely with those who are. This collaboration will allow those constructing the forms to understand the clinical trial’s objectives and to appreciate the relative importance of collecting data on the many variables being assessed. As a result, better trials are developed. This occurs not only through the collection of more appropriate data, but often through the design of a better protocol. By being forced to think about how data on each variable are collected, analyzed, and interpreted, the protocol developer becomes more critical about what data are collected, when they are collected, and how they are collected (e.g., whether to use a visual analogue scale or a five-point rating scale). A third explanation for the lack of attention given to data collection forms is the lack of understanding of the benefits to be gained from having and using good forms (i.e., those that are clear and well organized, provide direction, are straightforward to complete, and are formatted to accommodate the needs of the data entry process). Good forms facilitate each stage of data collection and processing. They make it easier for the investigator to record the data; for the sponsor (if any) to monitor the trial; for the data processing personnel to edit, clean, enter, and validate the data; for the statistician to analyze the data; and ultimately for the clinician to interpret the data. As a result, better data are generated, with better clinical trial results. The unfortunate result of thoughtless, poorly con-

4

A N O V E R A L L A P P R O A C H : B U I L D I N G A L I B R A R Y O F FORMS

structed data collection forms is poor-quality or unreliable data. Such data can lead to confusing or misdirected results, loss of patients for analysis purposes, and loss of statistical power, or data artifacts. The optimal data collection form for data capture will generally differ from the optimal form for monitoring and from the optimal form for data entry. As a result, a compromise is usually reached that balances different interests. Data capture should be the first priority in almost all cases.

Starting Point for Creating Data Collection Forms The construction of data collection forms should begin with the development of a library of standardized forms. Too often the development of forms is regarded as a protocol-specific task. The process of developing data collection forms by beginning with a series of blank pages each time a new protocol is written is highly inefficient and interferes with the advancement of a clinical trial program. Worse yet, previously made and identified mistakes in forms are repeated. The best mechanism for avoiding these problems is to develop a library of standardized data collection forms. It is important that the development of the library draw on the resources of several team members in order to ensure that the forms are logical and clear from a variety of perspectives. That library, then, could be consulted to assist in designing data collection forms for any protocol. It could also be consulted during the development of the protocol for the specific clinical trial element. Modifications to library forms are necessary for any specific clinical trial, and investigators must take care to ensure that all required modifications get made. The forms that comprise Part 11 of this book can serve as prototypes for clinical investigators who do not have a set of their own. Table 1.1 lists a series of basic questions to pose in creating data collection forms.

Benefits of Developing and Using a Library of Standardized Forms Maintaining a library of standardized forms provides several benefits to investigators and sponsors. First, it facilitates and expedites the process of constructing data collection forms for a specific trial. Second, the process of consulting a library of forms encourages attention to identifying how the data will be collected. Third, it fosters standardization in the actual collection process. When the same variables are collected at multiple clinic visits, it is important that those variables be collected and recorded in an identical fashion at each visit. Thus, the process of

TABLE 1.1 Basic questions to pose when creating data collection forms 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.

What categories of data must be collected? How much data is needed to address the objectives? How detailed must each module be? How often must the data be collected? What methods should be used to collect the data? What format will facilitate collecting the data as well as monitoring and processing it? Are any questions on the forms inappropriately asking for an interpretation of data in lieu of collecting raw data? Are too many modules being placed on a single page? Are unrelated modules being placed on a single page? Is the order of the questions the same or different on forms that collect the same data? Could shading (i.e., using gray tones to indicate a portion of the form that is not to be completed) be used to distinguish between full and abbreviated forms?

5

A N OVERALL APPROACH: BUILDING A LIBRARY OF FORMS

using standardized forms facilitates internal (visit-to-visit) as well as external (trialto-trial) consistency. Another major advantage is that form libraries generally are the product of contributions from a variety of team members, and hence reflect the joint expertise of scientists from several therapeutic areas. Forms developed solely by one team tend to be more limited. Standardization assists the investigator in completing the forms because the familiarity with the forms that is achieved over time facilitates their usefulness. Moreover, this familiarity also increases the accuracy of the data entered on the forms. The use of the same forms at each visit also assists a trial monitor or auditor in reviewing the forms. After the clinical trial is completed and the forms are beginning to be processed, standardization greatly assists the data entry process. Use of standardized pages simplifies the task for the data entry programmer of writing the data entry program. Standardization also allows data entry operators to develop more rapidly a familiarity with the physical layout of the pages. The operators’ enhanced familiarity with the forms results in faster and more accurate data entry. Advantages carry through to the statisticians analyzing the data; their programming tasks will be simplified, and they will often be able to reuse previously developed programs. The overall benefit associated with building, maintaining, and continually updating a standardized library of data collection forms is that experience gained in the past may be systematically incorporated into future trials. The forms derived by accumulating improvements from a diverse group of clinical trial scientists are generally superior to those resulting from the efforts of a single team for a single protocol. Problems encountered with completing or processing previously used data collection forms should not be repeated in the future. Table 1 .2 provides several specific practical benefits associated with standardization.

Three Levels of Data Collection Forms In practice there are three levels of data collection forms. The first and most general level is the global standardized library of data collection forms. This library contains forms that are appropriate for all types of clinical trials and treatments (e.g., demographic forms and adverse event forms). Forms provided in Part II of this book are primarily of this type. The second level of data collection forms consists of forms that are specific to a particular type of treatment, medicine, therapeutic area, or trial (e.g., forms appropriate for analgesic studies). This level of forms constitute the library for that treatment, medicine, therapeutic area, or type of trial. Finally, the third level is made up of the forms which are specific to a particular clinical trial (e.g., forms for a one-day trial of antihistamines in seasonal allergic rhinitis).

TABLE 1.2 Benefits of maintaining a standardized library of formsa 1. 2. 3. 4. 5. 6. 7. 8. 9.

Decreases time spent in form design and development Minimizes cost of constructing and printing forms Increases uniformity of content and form across trials Simplifies the completion of data collection forms Simplifies the editing of completed forms Minimizes errors in coding and data entry Increases the accuracy and speed of data processing Simplifies computer programming for data entry, retrieval, and statistical analysis Increases efficiency of generating data listings and graphic displays a

6

Modified from Cato and Cook (1984).

A N OVERALL APPROACH: BUILDING A LIBRARY OF FORMS

Types of Data Collection Forms For any clinical trial, many types of data collection forms must be used; these include forms for screening (e.g., admission criteria assessments or patient demographic and background characteristics), dosing, compliance, efficacy, vital signs, adverse experiences, clinical laboratory tests, and trial termination. Although the specific variables assessed and data collected on these and other forms often vary from trial to trial, similar trials generally collect similar data. Thus as an example, the demographic, safety, and study termination forms should be almost interchangeable across most clinical trials, though greater or lesser amounts of data may be collected. Each individual protocol assessing efficacy has its own specific efficacy objective. Hence, efficacy forms often differ substantially from trial to trial. However, trials on the same treatment(s), conducted by one investigator or by a single group of investigators with similar efficacy objectives, should use generally similar efficacy forms. It is usually important to collect and record data on efficacy variables in an identical fashion at each clinic visit within a single trial.

Modules For each patient who completes a clinical trial, the completed data package may be thought of as being made up of modules. Each module consists of a group of data collection forms (sometimes referred to as case report forms or case record forms) that contain similar data and are used together for a single visit. Each module collects a specific type of data (e.g., demographic data, physical examination data). Some modules are contained on a single data collection form, whereas other modules require two or more data collection forms. Table 1.3 identifies some representative types of modules.

Who Creates and Reviews Data Collection Forms? There is no ideal answer to this question, but the spectrum of developers and reviewers of data collection forms ranges from a single individual (e.g., investigator, monitor, trial coordinator, data collection form specialist) to a formal team of individuals. If a team is assembled, its purpose is primarily to allow each member to review each unique form (i.e. , page) of the data collection form package from the member’s own perspective. Even if a form has been used successfully in other clinical trials, it is important to review its suitability for the present trial. A team that could review data collection forms includes in addition to the designer, the following individuals: (1) investigator; (2) statistician; (3) clinical monitor; (4) trial coordinator; (5) database administrator; (6) data-processing editor; (7) data entry operator or coordinator; (8) data-processing programmer; and (9) physician. Differences of opinions often exist, and compromises must be reached. For example, investigators often want data collection forms to be condensed into

TABLE 1.3 Representative types of data collection form modules 1. 2. 3. 4. 5. 6. 7.

Physical examinations Laboratory tests Medicine dosages Efficacy measures Additional patient visit Adverse events Comment log

8. 9. 10. 11. 12. 13.

Medical and surgical history Baseline signs and symptoms Concurrent medications Concurrent conditions Patient disposition and termination Death during trial

7

A N O V E R A L L A P P R O A C H : B U I L D I N G A LIBRARY O F F O R M S

approximately 10 pages, whereas data processors want perhaps 100 pages to facilitate the accuracy and speed of the data entry process. On the other hand, data processors also want to create tables from data present on a single page and do not like to work with several pages. Correcting table errors is much more difficult on a multipage form. Use of jargon on forms is another area in which strong feelings exist. Creating Options t o Answer Specific Questions

Medical textbooks may appear to be a good source of information for identifying alternative answers to each question. However, it is preferable to ask a group of practicing physicians to describe an event, or to describe how they would answer a specific question. How they approach and answer the question can serve as the basis for data collection form design. At the same time it would be useful to ask these physicians preferable ways to state each specific question that requires data collection. Having examined some of the issues inherent in building a library of data collection forms, we turn now to a look at the types of data collection forms.

8

2 Types of Data Collection Forms BACKGROUND CONSIDERATIONS One relatively common way of classifying data collection forms is whether they are to be used for a single trial or many clinical trials. In practice, however, this distinction is often blurred because many single clinical trials are actually specific sites of multicenter trials where each center uses the same protocol and data collection forms. Many investigators who conduct single-site clinical trials conduct numerous trials in sequence or simultaneously. In each of these cases, consulting a library of standardized forms would be helpful in developing data collection forms. Purposes o f Collecting Data The physical layout of each data collection form must accomplish three basic purposes. The first is data capture, the collecting of raw data. For that purpose the forms should be clear, provide necessary instructions, and be easy for the investigator or staff to complete. Second, data must be collected in such a way as to facilitate monitoring or auditing. Third, forms should be designed to expedite the steps of data processing: reviewing, editing, and entering data into a computer. T o accomplish this, the format must provide data in an easy-to-extract form for entering into a computerized database or for hand tabulation; this in turn will facilitate the eventual statistical analysis and clinical interpretation. These three purposes of data forms — data capture, data monitoring, and data processing— are sometimes at odds with each other. When compromises are necessary, the investigator’s requirements for collecting and recording data should take precedence over data monitoring or data processing requirements. Internal Standardization When considering forms for a single clinical trial conducted at a single site, internal standardization of repeatedly used forms (i.e., consistency from clinic visit to clinic visit) is a major focus of the standardization process. When the same information is collected at multiple visits, practical considerations dictate that the physical appearance of repeated data collection forms be the same (or nearly the

9

TYPES OF DATA COLLECTION FORMS

same) at all visits. This simple consideration, which surprisingly is often not followed, is of substantial benefit to both the investigator or staff completing the forms and to the data management personnel processing the completed forms. Both groups can become extremely proficient at quickly locating specific data items on the individual pages, when the page format is constant for each type of form.

External Standardization When considering forms for multiple clinical trials or for a single trial conducted at multiple sites, standardization across trials becomes as important as internal standardization. While such external standardization may seem to be of little practical value to investigators who are only conducting a single sponsored trial, it is extremely important to the sponsor’s data processors and data management personnel. When data processors are required to continually learn and familiarize themselves with differently formatted forms, their productivity suffers in terms of both accuracy and speed. The larger the number of formats and the greater the differences among them, the more pronounced is the negative effect.

Modules Regardless of whether one is considering data collection forms for a single trial or multiple trials, one can group the data collected into distinct modules, for example, demographic variables, medical history variables, or trial-specific efficacy variables. Some modules can easily be standardized (1) across all trials for al treatments, (2) within a particular therapeutic area, or (3) within a particular treatment or project. Some modules must be almost entirely trial-specific (e.g., certain efficacy parameters).

THREE LEVELS OF VIEWING DATA COLLECTION FORMS Level 1 Data Collection Forms: Forms Suitable for All Clinical Trials The major section of a centralized library of standardized data collection forms (which we have defined as level 1 data collection forms) is composed of those modules that can be essentially standardized across all clinical trials. This encompasses virtually all modules except those that collect efficacy data. A few specific examples include modules that (1) verify inclusion and exclusion criteria, (2) collect basic demographic data, (3) collect medical history and physical examination information, (4) collect baseline signs and symptoms, and (5) collect postbaseline adverse event information. It is almost imperative to develop a universal form for collecting adverse events. This will help monitors and investigators ensure that all the information required by regulatory authorities is collected. In addition, a universal adverse events form will greatly facilitate the investigation, detection, and interpretation of any untoward effects that may be associated with a clinical trial.

Level 2 Data Collection Forms: Forms Used for a Specific Project or Medicine Each therapeutic area or specific project may have special forms designed and placed in a section of a centralized library. That section would contain only mod10

TYPES OF D A T A COLLECTION FORMS

ules that can be standardized only across clinical trials within a specific area or project. These forms include efficacy parameters and detailed medical history questions and safety evaluations that focus on a specific disease or group of diseases. One example would be an asthma section, which would contain modules that collect asthma-targeted information (e.g., various pulmonary variables, asthmatic history); another would be an anticonvulsant section, which would contain modules that collect specialized information (e.g., seizure history, diaries for seizure count) required when studying anticonvulsant medicines.

Level 3 Data Collection Forms: Forms to Be Used in a Specific Clinical Trial When constructing data collection forms for a specific clinical trial, one should begin by searching the centralized library for standardized forms on levels 1 or 2 that can be used. If none of the standardized forms are acceptable as is or with minor revisions, for a specific purpose then trial-specific forms must be designed. For example, for the baseline evaluation in most clinical trials, a relatively brief, standardized physical examination form is sufficient. In many trials, however, a specific component of the physical examination (e.g., the gastrointestinal system) will need a more extensive evaluation. This can be accommodated by designing a detailed assessment form to be used in conjunction with the standardized form. When it is necessary to create trial-specific forms, those forms should be modified (if possible) from an existing form in the standardized library. That modified form, or a completely new form if an existing form could not be modified, should then be added to the library at levels 1 or 2 for future use. Forms should be designed to be as similar in format as other forms in the library that are used in the clinical trial of interest. The principles of designing forms are described in the following chapter. A comparison of representative examples of data collection forms for all three levels is presented in Table 2.1.

TABLE 2.1

Representative examples of data collection forms used for the three levels of specificity

1. Medical history form Level 1—General medical history Level 2—History of seizures Level 3—History of seizures modified to focus on the week prior to entry into the specific clinical trial 2. Physical examination form Level 1—General physical examination Level 2— Evaluation of all peripheral pulses Level 3—Evaluation of all peripheral pulses modified to be obtained before and after a 10-minute walk in a specific clinical trial 3. Laboratory clinical chemistry form Level 1—General clinical chemistry form Level 2—Specific tests required to evaluate ovarian function (e.g., FSH LH) a Level 3— Times when each of these tests are to be obtained relative to each patient’s menstrual cycle a

FSH = follicle stimulating hormone; LH = luteinizing hormone.

11

3 Choosing Modules and Designing Forms: Guidelines, Pointers, and Pitfalls BACKGROUND The design of data collection forms for any clinical trial is not straightforward. It is, however, a basic precept of this book that good, carefully designed forms are an absolute necessity if the objectives of a clinical protocol are to be successfully met. Cato and Cook (1984) state that well-designed forms have become a necessity in clinical research to serve the following purposes: (1) check the logistics, design, and practicality of the protocol; (2) expeditiously and accurately process, analyze, and interpret the data; (3) check protocol adherence and/or investigator compliance; and (4) fulfill regulatory requirements. The design of data collection forms has a large impact on both the quantity and the quality of the resulting data. Forms should be developed by personnel who are experienced in form construction, familiar with the methods to be used for both data collection and data processing, and aware of the primary goals and objectives of the clinical trial. The development process can be facilitated by a review of the data collection forms used in other clinical trials, especially trials similar to the one in question. Another means of facilitating the development of data collection forms is to consult a library of standardized forms as described in Chapters 1 and 2. The sample forms in Part II of this book provide a starting point for that review. Standardization of data collection forms across multiple clinical trials is highly desirable, and standardization of the methods used for collecting and recording data within a single trial is critical. When considering the proper focus for the optimal construction of a data collection form, the first step is to determine the specific goal for the particular form. Because data collection forms are used for multiple purposes (e.g., to capture data, to monitor a clinical trial, and to extract data for processing), a form that is optimal for data capture may not facilitate monitoring or be easy to use for data extraction. Since some features of a form that facilitate one purpose may conflict with features desired for the other two purposes, the choices made in designing each form should result from a decision of which specific interests take priority on which forms. General guidelines that are primarily directed at the easy, accurate capture of data on data collection forms are listed in Table 3.1 and discussed in the following 12

CHOOSING MODULES AND DESIGNING FORMS: GUIDELINES, POINTERS, AND PlTFALLS

TABLE 3.1 General guidelines for creating useful data collection forms 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

Use forced responses (i.e., closed-system choices rather than open ones) Avoid blank items Use consistent codes and questions Make each form self-contained Collect data at different visits on separate forms® Include extra forms to accommodate additional or unscheduled patient visits or other occasions when data are collected Do not allow data collection forms to dictate what is included in a protocol Include sufficient information in a clinical trial protocol to design data collection forms Test data collection forms for clarity and ease of completion by conducting practice runs with staff. Correct any problems noted during these practice runs Avoidmodifying forms during a clinical trial

8 Exceptions may be made for clinical laboratory examinations, dosage dispensing, or other data where it is important to evaluate visit-by-visit trends.

section. It should be understood that no set of guidelines can be all-encompassing and address all concerns associated with the design of data collection forms. For example, guidelines can never determine the content of the forms. Adopting and systematically adhering to a standardized approach, however, will result in higherquality forms and consequently higher-quality data.

GUIDELINES Guideline 1: Use Forced (i.e., Closed-System) Responses The first guideline is to use forced responses. Questions presented on a data collection form should be constructed so that a response is required. This means avoiding questions such as “Check if present,” since the absence of a response would then be assumed to be a negative response. Information can be missing on a form for a variety of reasons, one of which is an oversight. T o accommodate the possibility of an oversight and to be able to detect it, a good practice is always to require a written response and never to assume that the absence of a response is a datum. Another component of forcing a response is controlling the format of that response. Instead of providing a blank line with a request for a date or a numeric field that could have a variety of formats, it is generally preferable to use boxes or partial boxes and to identify where the month, day, year, or other specific data should be placed. Consistent formats within a single form aid the collection of consistent information at the data collection site and also greatly aid the speed and accuracy of data entry. At the entry stage, even clearly written dates take more time to read and enter when different formats are used on different forms or at different locations on the same form. A corollary to this guideline is that all responses must be placed in designated areas or spaces and not in the margins or on the backs of forms. Forms should usually occur on one side of the page only.

Guideline 2: Avoid Blank Items Instructions should explicitly indicate that all items on the form are to be filled in. If an item does not apply or if a requested evaluation is not performed, then N A (“not applicable” or “not available”), ND (“not done”), or Unk (“unknown”) should be recorded in the space provided. A blank space could indicate an NA, ND, Unk response or that the question was overlooked. T o ensure that

13

C H O O S I N G M O D U L E S AND DESIGNING F O R M S : G U I D E L I N E S , P O I N T E R S , AND P l T F A L L S

the item has not been overlooked, a notation that a response is not given should be required.

Guideline 3: Use Consistent Codes and Questions It is important to use consistent logic throughout a form. Alternating between coded responses for which abnormal = yes and normal = yes fosters errors. Questions should be asked in the same manner on all forms. For example, if an investigator is asked to score a condition (1 to 5) as 1 = mild and 5 = severe on one form, at one evaluation, then that same investigator should not be asked to score the same, or even a different, condition as 1 = severe and 5 = mild on another form. If an investigator is asked, “ H a s the patient’s condition improved since the last visit?” at one evaluation, then he or she should not be asked, “Has the patient’s condition deteriorated since the last visit?” at a subsequent evaluation. A range of codes from 1 to 5 for one question on a form should not be followed by a code range of 0 to 5 or 0 to 4 for possible answers on subsequent questions and/or forms.

Guideline 4: Make Each Form Self-contained Self-contained forms are vital. When algorithms or charts (e.g., nomograms) are needed for classifying subjects or determining data, it is important to include that information either on the data collection form itself or in the data collection form package. Although the information may exist in the protocol or investigator brochure, those documents are often not readily available when needed and should not have to be referred to by the investigator. It is important to also provide the information in the form.

Guideline 5: Collect Data at Different Visits on Separate Forms Separate the data collected at different clinic visits as much as possible. This enables the data to be recorded with minimum time spent searching for the correct form to use. True, it is usually easier for monitors to scan data collection forms and identify trends when data are placed next to each other. For example, if all clinical laboratory results have visit and date designations to identify when the measurements were taken, it is easier to scan the data when they are on the same form than on separate sheets. Nonetheless, collecting information from multiple patient visits on the same page fosters errors. Severe problems can arise when measurements are not taken at one of the scheduled visits. It is thus important to consider the issue of where to record the next values, assuming that they are correctly taken. In many clinical trials it is useful to use a combination approach of separating most but not all data from multiple visits. Doses dispensed (or laboratory results) are often placed in side-by-side columns from subsequent visits.

Guideline 6: Include Extra Forms to Accommodate Additional or Unscheduled Patient Visits or Other Occasions When Data Are Collected It is generally a good idea to ensure that forms are available for unscheduled visits or other events that are not planned. If this is not done, then unexpected or

14

CHOOSING MODULES AND DESIGNING FORMS: GUIDELINES, POINTERS, AND PlTFALLS

unpJanned-for information will be recorded in the margins or in a space originally designed for another purpose. This information may be inadvertently misused or misinterpreted. It is important for most clinical trials that forms for these purposes be included when the full set is printed; the extra forms can be separated from the rest of the forms by a tab divider labeled “Optional Visit,” “Makeup Visit,” or “Additional Visit.”

Guideline 7: Do Not Allow Data Collection Forms to Dictate What Is Included in a Protocol If the forms were to state what type of laboratory analytes could be collected, that might influence the protocol. Also, a data collection form focuses on details because of its nature; if these details have not yet been addressed by the protocol, important components of the trial would then be specified by the data forms. It is important to prevent this kind of influence from occurring in designing data collection forms.

Guideline 8: Include Sufficient Information in a Clinical Trial Protocol to Design Data Collection Forms The amount of data to collect, as well as their type and frequency, should be specified in the protocol. Although much of this information is given in the timeand-events schedule, discussions between the protocol author and the designer of the data collection forms are usually necessary to ensure that all details are addressed. The specific wording of pertinent questions should be discussed and identified both in the protocol and in the data collection forms. The wording of a question greatly influences the responses obtained. For example, in collecting adverse event data it is possible to ask “How do you feel?,” “Have you had any adverse feelings?,” or “ H a s anything unusual occurred in your health since we last spoke?”

Guideline 9: Test and Improve Data Collection Forms by Conducting Practice Runs with Staff You can improve forms by conducting dry runs with the actual staff who complete the forms using make-believe patients at first. Later, this exercise should be repeated with real patients. This exercise will help ensure that questions of both content and format are clear and unambiguous.

Guideline 10: Avoid Modifying Forms During a Clinical Trial The data collection forms used in a clinical trial often appear to be less than ideal. Various improvements will occur to the investigator, staff, or monitors that would enhance their usefulness. The urge to modify the forms should be resisted, unless the original forms contain errors, or a protocol modification requires one or more changes in the forms. Making changes to the forms under other conditions usually results in different data being collected at different times or for different patients. Even if the data collected do not differ, the different forms will tend to confuse data entry personnel. Utilizing a run-through process before the trial begins minimizes the chances of having problems with the forms.

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C H O O S I N G M O D U L E S AND DESIGNING F O R M S : G U I DELI N ES , POINTERS, AND P1TFALLS

TABLE 3.2 General guidelines for item construction3 1.

Every item should require a response. Allowing a blank or unanswered item to indicate the absence of a condition or event can cause confusion and inaccuracy in both monitoring and data processing The circumstances under which an item is to be skipped should either be part of the item or be clearly stated in the instructions for the item Items or sections on a form that may be skipped in certain instances should be preceded by items that document the presence of those instances. For example, a form should include an item for recording the patient’s age immediately preceding parts of the form that are to be skipped for patients in a specific age group The physical layout of the form should enable items to be easily completed and reviewed Ensure that no two items collect the same information (i.e., the same data should not be recorded in two places). For example, medications used to treat an adverse experience may be recorded in a special place, or they may be recorded with concomitant medications used during a trial. Both options, however, should not be used in the same trial When using open-form items, consider indicating the format of the response (e.g., lines such as • _ k g ” to record weight to the nearest 10th of a kilogram) The order of questions for a given test or examination should mirror the usual order followed by the physician

2. 3.

4. 5.

6. 7. a

Points 1 to 3 are modified from Meinert and Tonascia (1986) with permission.

TABLE 3.3

Guidelines relating to language and terminology3

1. Use simple, uncomplicated language 2. Avoid esoteric terminology and abbreviations 3. Avoid terms that may have different meanings to different people 4. Avoid slang and jargon 5. Use language that is familiar to personnel completing the forms 6. Provide necessary definitions of all relevant terms on the forms 7. Use simple uncomplicated sentences when constructing items and instructional material 8. Avoid unnecessary words 9. Avoid double negatives 10. Items soliciting an affirmative or negative response are confusing when the affirmative reply represents the absence of a condition 11. Avoid compound questions by dividing them into a series of specific questions 12. Items requiring a comparative judgment should indicate the basis for the comparison 13. Language research suggests that positive terms (e.g., better, bigger, more) are less subject to interpretation error than negative terms (e.g., worse, smaller, less) 14. The time point or interval to be used in answering an item should be explicitly stated in the item 15. Avoid variation in the direction of the response from question to question. (That is, do not state some questions that require a comparative assessment in positive terms and others in negative terms) 16. Avoid leading questions (such as ‘‘Did you have a headache yesterday?”) 17. Avoid ambiguous questions. (For example, “Did the patient complete the trial as specified in the protocol” could be asking either “Did the patient withdraw prematurely?” or “Did the patient deviate from the protocol-specified conduct?”) 18. Questions should be spelled out in sufficient detail to be understood without having to resort either to the protocol or to the investigator’s brochure 19. Lists and other alternatives to prose paragraphs are sometimes easier to understand 20. Questions and answers need to be self-explanatory ___ a

16

Points 1 to 14 are modified from Meinert and Tonascia (1986) with permission.

CHOOSING MODULES AND DESIGNING FORMS: GUIDELINES, POINTERS, AND PlTFALLS

TABLE 3.4 Guidelines relating to using items from other clinical trials3 1. Do not use an item just because it has been used previously in other clinical trials. Have a definite reason relating to the protocol for including every item that is used 2. Do not produce an item de novo if a suitable version of the item is known to exist, has been used in other trials, and has produced seemingly reliable information 3. Do not use an entire form or section of a form that has been copyrighted without the approval of the copyright holder 4. Do not reproduce an entire form or section of a form used in another trial without permission from those who conducted the trial, even if the form has not been copyrighted 5. Do not assume that an item is acceptable for use and has been validated merely because it has been used in other clinical trials a

Points 1 to 4 are modified from Meinert and Tonascia (1986) with permission.

Specific Guidelines for Constructing Forms General guidelines for constructing the individual items on the data collection forms are given i n Table 3.2. Guidelines and suggestions relating to other factors of form construction are given i n Tables 3.3 to 3. 10. These factors include language and terminology (Table 3.3), the use of items from other trials (Table 3.4), response checklists (Table 3.5), measurement and calculation items (Table 3.6), instructional items (Table 3.7), time and date items (Table 3.8), the general layout o f the

TABLE 3.5 Guidelines relating to response checklists3 1. Vertical checklists are easier to use, and are subject to less confusion with regard to the location of appropriate check spaces than are horizontal checklists 2. A response checklist that is not exhaustive should include an “other (specify)” category that can be used to record responses that are not specified in the response list 3. If the possible responses are not mutually exclusive, an instruction to “check all that apply” should be included 4. Adequate space should be provided on each form to write out and identify responses that fall into the “other" category. The amount of space provided generally influences the amount and legibility of the information recorded 5. Frequent use of an “other” category will increase the time required for completing the item and for coding and processing the information generated by it. If this occurs, one should alter the response list when designing forms for future clinical trials 6. A condition is more likely to be recorded as present if it appears in a checklist than if it does not 7. Checklists should be infrequently used for collecting adverse event data in Phase II and Phase III trials. In Phase I trials in which it may be more serious to miss events than to have overreporting, checklists may be a useful tool 8. It is sometimes helpful to include a summary check position at the beginning or end of a list. The summary position may be used in lieu of checking each individual entry in the list 9. If there is a natural ordering among the responses (e.g., “condition worsened," “no change,” “condition improved”), the responses should be listed in that logical order 10. When asking respondents to make selections among choices, it is preferable to have the respondent indicate the choices that apply instead of asking him to delete the choices that do not apply 11. Questions requiring a check mark to indicate the appropriate reply are preferable than those in which the respondent reads a list of items associated with the question and records the code number of the item selected. The latter choice is only appropriate when the same list of responses applies to several questions on the form or when the list of possible responses is inordinately long 12. Use of lists that are not part of the form, or that are located elsewhere in the data collection package, will increase the time needed to complete the form 3

All points except point 3 are modified from Meinert and Tonascia (1986) with permission.

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CHOOSING M O D U L E S AND DESIGNING F O R M S : G U I D E L I N E S , POINTERS, AND P i l l ALLS

TABLE 3.6

1. 2. 3. 4. 5. 6. 7.

8. 9. 10.

a

Guidelines relating to measurement and calculation items3

The unit of measurement should be specified on the form Measurements should be made and recorded in units familiar to the personnel responsible for making them. Use of unconventional or unfamiliar units may lead to data collection and recording errors Whenever feasible, all recordings of a specified variable should be made using the same units of measurement When it is impractical to specify the units of measurement in advance, space should be provided on the form for the units to be written in by the personnel completing the forms Numerical variables, such as age, height, and blood pressure should not be recorded in categorical form The precision and number of significant figures required for a measurement should be clearly specified on the form The raw data used to make summary calculations should be recorded on the form. For example, if an “official” measurement is the mean of three actual measurements, then the actual measurements should also be recorded on the form Forms should be constructed to minimize the number of arithmetic calculations required during a patient visit or when data are entered on the form Items that do require a series of arithmetic operations during the completion of a form should be arranged in a format that facilitates those operations. For example, numbers that must be added or subtracted should be arranged vertically If a variable may be measured in more than one way (e.g„ temperature measured orally or rectally; blood pressure measured with the patient erect, supine, or sitting), then the form should clearly indicate the manner in which the measurement should be made Points 1 to 9 are modified from Meinert and Tonascia (1986) with permission.

TABLE 3.7

Guidelines providing directions on how to proceed from item to item3

1. Instructions should be clear and conveniently located with respect to the items to which they apply 2. Instructions should be brief and to the point 3. A stop item is used to indicate conditions that, when encountered during a patient visit, require clinic personnel to temporarily or permanently halt some procedure or process 4. Stop items on any given form should be placed so that the respondent terminates all work on the form as soon as a stop is indicated 5. A common use of stop items during the prerandomization period is to indicate conditions that exclude a patient from the clinical trial 6. Prerandomization stop procedures should be arranged in ascending order with regard to the risk or discomfort they entail for patients 7. A skip item is used whenever there is an item or group of items that can be skipped depending on the answer to the skip item 8. A skip item should indicate the conditions under which the skip can occur and the item or items to be skipped 3

Points 3 to 8 are modified from Meinert and Tonascia (1986) with permission.

TABLE 3.8

1.

Times should not be recorded on a 24-hour clock unless personnel responsible for the recordings are thoroughly familiar with 24-hour timing schemes Items requiring a clock time using a 12-hour clock should indicate whether the time recordings are for AM or PM The use of AM and PM may cause confusion for recording 12 noon and 12 midnight, unless instructions on the form indicate how these times are to be recorded Explicit guidance should be given as to the order of day and month, especially if international comparisons may be made. The most common orderings are “month-day-year” in the United States and “day-month-year” in Europe Instructions should indicate that, if at all possible, complete dates should be recorded. Recording only the year or just the month and year is often insufficient

2. 3. 4. 5. 3

18

Guidelines for time and date items3

Points 1 to 4 are modified from Meinert and Tonascia (1986) with permission.

CHOOSING MODULES AND DESIGNING FORMS! GUIDELINES, POINTERS, AND PlTFALLS

TABLE 3.9 Guidelines for designing the layout of data collection forms3 1. Layout should be as clear and attractive as possible (i.e., aesthetically balanced) 2. Avoid overcramping forms — do not be afraid to use blank space appropriately 3. Choose a layout that permits use of a single page size for all forms 4. Use a layout in which all forms in a package are oriented in the same way (either vertically or horizontally) 5. Use a layout that is uncluttered and that facilitates use of the forms by both clinic and data-processing personnel 6. The layout chosen should be compatible with data entry needs. However, if clinical needs and data entry needs are in conflict, the clinical needs should take precedence 7. Choose between a full page or two-column layout 8. Two-column layouts are generally more space-efficient than full-page layouts 9. Do not scatter throughout the page boxes that need to be checked or filled in. Align them on the left or right margin, preferably being consistent throughout the data collection form package 10. The space between a question and the place for its answer should be kept as small as possible 11. Standardizing the location of check positions within and across forms facilitates completion of the forms and reduces the time and errors involved in keying the data from them 12. Items should be arranged to minimize the number that are split across columns or pages 13. Forms should be printed, copied, or typed on only one side. The reverse side may be used to print instructional material or left blank 14. The respondent should see a “path" from question to question through the form 15. Layout should be designed to help the respondent identify items or sections that may be skipped under specified conditions. This may be done by setting key words or phrases in boldface type, in boxes, or by use of special instructions or other aids to direct the respondent to applicable items or sections 45 16. Blank space should reflect meaningful groupings of the material. Space between subparts of an item (e.g., response categories in a checklist) should be less than the space between items 17. Space separating items should be uniform unless variation in spacing has operational significance 18. The space separating one part or section of a form from another should be the same and should be greater than the space separating individual items 19. Righthand justification of typed or printed text should be avoided if it results in a noticeable variation in the spacing between words. Spacing between words should be uniform, even if this results in uneven right-sided margin. 20. Similarity of formats across questions will help the respondent and reduce the number of accompanying instructions and notes 21. Spacing between lines should facilitate reading 22. Use lowercase letters for text instead of all capitals a b

Points 3 to 13 and 15 to 19 are modified from Meinert and Tonascia (1986) with permission. See Table 3.7.

form (Table 3.9), and the ordering of items on the form (Table 3.10). In general, care should be taken to make the forms as clear, unambiguous, uncrowded, short, and simple as possible.

POINTERS Pointers differ from guidelines. Whereas guidelines are basic principles to follow whenever possible in creating data collection forms, pointers refer to issues to consider to assess whether the point is relevant to a particular clinical trial. A summary of all the pointers discussed in this section are listed in Table 3.11. 19

CHOOSING MODULES AND DESIGNING FORMS! GUIDELINES, POINTERS, AND PlTFALLS

TABLE 3.10 Guidelines for arranging items on data collection forms3 1. 2. 3. 4.

5.

6. 7. 8. 9. 10. a

Arrange items to correspond with the order in which the information will become available to the respondent Place items calling for a particular frame of reference next to one another The nature, quality, and quantity of information obtained may be influenced by the order of the items on the form The order of procedures should remain fixed over the duration of a trial, especially if there is a chance that one procedure would affect the results of another procedure. A fixed order does not eliminate this problem, but it can control the effect over time and across treatment groups Arrangement of items within a form should be compatible with the preparation required for a particular examination. For example, all items collected from patients i n a fasting state should precede items that can be collected after the patients have eaten Group items into sections with headings indicating the general content of the sections. Use a different type font to facilitate identification of section headings Numbering and identification schemes should be designed to facilitate the identification of items and their subparts Use different spacing t o indicate transition from one item to another and from one section to another Create a numbering system to identify relevant items on a data collection form. Number items sequentially either within a section or over an entire group of forms Place confidential information on separate forms of a data collection form package, so that it may be removed and stored separately from the rest of the package Points 2 to 8 are modified from Meinert and Tonascia (1986) with permission.

Pointer 1: Consider Carefully the Amount of Data to Collect per Visit, per Event, and Overall in Every Clinical Trial A major decision i n developing data collection forms is the determination o f h o w much information to collect at each clinic visit. The process used for this step should be designed to protect against both errors o f omission (not collecting enough data) and errors o f commission (collecting too much data). Details are provided b y Spilker (1984, 1987). Haste i n preparing forms is probably the most common cause o f errors o f omission, and a desire to obtain all data that are easy to obtain i s an important contributor to errors o f commission. Tables 3.12 and 3.13 identify a number o f methods for avoiding errors o f omission and commission, respectively.

TABLE 3.11 General pointers for creating data collection forms 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

20

Consider carefully the amount of data to collect per visit, per event, and overall in every clinical trial Avoid crowding the questions Consider the use of closed versus open systems Use consistent units of measurement Avoid requiring the respondent to make calculations whenever possible Avoid “change assessment” questions Avoid mixing time frames on a single page Consider placing an administrative information section on data collection forms Evaluate the use of specialized terms and jargon Evaluate the placement of instructions on data collection forms Provide anatomical drawings or other helpful figures to assist completion of data collection forms Considerthe consequences of creating incomplete or inadequate data collection forms Ensure that patient diagnoses are correctly made Collect relevant information to address clinical trial objectives at the time of the trial Differentiate between unknown, uncertain, and missing data instead of using the phrase “not available”

CHOOSING MODULES AND DESIGNING FORMS: GUIDELINES, POINTERS, AND PlTFALLS

TABLE 3.12 Methods for avoiding errors of omission3

1. Allow adequate time for developing and testing the forms 2. Solicit content advice and input from persons who are not directly involved in the development process before creating the forms to be used 3. Review the data collection forms that were used or are being used in similar clinical trials 4. Ask colleagues not directly involved in the development process to review the proposed forms after they are created 5. Test the forms under approximate study conditions before using them in the clinical trial. For example, collect data on several “test” patients prior to initiating the trial a

Modified from Meinert and Tonascia (1986) with permission.

The consequences of collecting too little or too much data are potentially serious. At one extreme is the clinical trial where investigators collect too little data and collect it in a haphazard manner, often on various pieces of paper they have quickly assembled without considering (and preparing) appropriate forms required for data collection. In this situation, results of some tests may be adequately documented but relevant data generated in other tests may be inadequate for appropriate statistical analysis. The worst-case scenario occurs when the clinical trial’s objectives are inadequately addressed because of insufficient data collection. The other extreme occurs when substantially more data are collected than are required to address the objectives. A vast amount of data generated and collected may threaten the actual conduct of a clinical trial as well as its analysis. The conduct of a trial could be affected if trial personnel were required to spend excessive time with patients to generate the data. The amount of paperwork in a trial influences the enthusiasm with which an investigator recruits patients. Likewise, the quality of the responses will deteriorate if too much is asked of busy clinicians. The investigator, research coordinator, and other personnel may grumble at the redundant work; the patients may feel hassled by excessive demands and testing; the individuals who monitor and enter the data into computers may feel burdened; and the statisticians and clinicians who analyze and interpret the data may only utilize part of the data collected in an attempt to avoid being “swamped” by irrelevant information or, worse yet, be accused of merely conducting a “fishing expedition.” Once collected, irrelevant data must be addressed, especially if the results appear to conflict with those obtained using planned analyses. T o avoid both of these extremes (which we believe to be rather common), the individual responsible for designing and assembling the data collection forms must analyze the overall approach to data collection as well as each data collection form used, adding important measurements and questions and eliminating extraneous ones. Each potential item could be categorized as providing information that falls into one of three groups: (1) it is necessary for the statistical analysis addressing the (primary) objectives of the study; (2) it is supportive; (3) it is potentially useful depending on the results obtained (i.e. , it would be nice but not necessary to know). All items in group 1 must be included on the form. Some supportive items (group 2) may be expendable and should not be included; these TABLE 3.13 Methods for avoiding errors of commission3

1 . Distinguish between data needed for patient care and data needed to address the objectives of the clinical trial. Only collect the latter type of data 2. Make certain each datum scheduled for collection is of direct relevance to achieving a stated aim or objective of the clinical trial 3. Establish an appropriate set of review and approval procedures in order for new items to be added to existing forms 3

Modified from Meinert and Tonascia (1986) with permission.

21

CHOOSING MODULES AND DESIGNING FORMS! G u i D E L INES, POINTERS, AND PlTEALLS

items should be carefully scrutinized before a final decision is made. Items in the third category of information should be eliminated. There are several questions for determining the amount of data to collect: (1) How necessary are the data for addressing the objectives of the protocol? (2) How will the data fit with data collected from other trials (if they may be combined at some point into a meta-analysis or into a regulatory submission)? (3) How will the data be treated in the reports generated from the trial? Discussions among investigators, sponsors (if any), statisticians, and others should be able to resolve these issues. Table 3.14 lists considerations used by the Coronary Drug Project in selecting questions to be included on their data collection forms.

Pointer 2: Avoid Crowding the Questions Attempting to save space on data collection forms can be counterproductive. Placing unrelated modules on the same page, placing questions relating to different times on the same page, and other similar decisions can lead to omissions, unnecessary page flipping, and confusion. Ensure that questions are placed in a sensible order, and that pages are constructed with particular concepts in focus. Moving questions from one page to another to save space can be dangerous. Space can be used to highlight critical components of data. For example, in a Phase 1 trial, the start time and stop time of an infusion is critical. The information requires very little space to record, but if the question is crowded into an illogical place, it may be easily missed.

Pointer 3: Consider the Use of Closed Versus Open Systems Data collection forms range from using a closed system, which consists of almost 100% preprinted multiple-choice responses, to an open system, where the questions are followed by spaces or lines for entering the responses. In the former case, data entry and statistical analysis are immeasureably simplified, all investigators will presumably complete the forms in the same or similar manner, and the data obtained may be more easily combined with data from other studies. Closed systems tend to structure information. However, there is a chance that meaningful data may not be collected in a totally closed system, and some investigators will undoubtedly resent and even resist this regimented approach. In the totally open system, different investigators will probably complete the form differently, but some of the observations and comments collected on the forms may provide valuable insights about the patients and their responses.

TABLE 3.14 Considerations used when selecting questions for3inclusion on data collection forms for the Coronary Drug Project

1. Is there a need to determine whether the experimental treatment may have an effect — either beneficial or adverse— with respect to this item? 2. Is the baseline observation for this item likely to be highly correlated with the primary response variable for the study, thus making it a useful variable for assessing comparability of treatment groups at baseline? 3. Is there another item similar to this one and probably highly correlated with it that has already been selected for inclusion on the form? 4. Does the anticipated quality (i.e., validity and reliability) of the information obtained for this data item warrant its inclusion? 5. Is there likely to be any harm to patients in asking the question or making the measurement? 6. Is the cost of measuring and processing this item commensurate with its anticipated worth to this study? a

22

Modified from Knatterud et al. (1983), with permission.

CHOOSING MODULES AND DESIGNING FORMS: GUIDELINES, POINTERS, AND PlTFALLS

An important goal in designing data collection forms is to have a minimum number of write-in answers or responses. One essential write-in area is the “investigator’s comment,” located either in one central place or on several of the forms in the data collection form package. A list of alternative answers should probably be provided for questions on many of the other forms with instructions to check, cross out, circle, or otherwise indicate the specific response. An additional space or spaces for “other” responses should always be considered; if these are adopted, additional space should be provided to specify what that other response actually is. In recording data from laboratory tests, some individuals prefer indicating the actual number of digits on the form that is to be used in the answer (e.g. , hematocrit ), because ) rather than using a single line (e.g., hematocrit = = this latter method may elicit a different number of digits in some written responses. Furthermore, when solid lines are used, there is a tendency for investigators to record extraneous material and for data entry personnel to improperly left- or right-justify the responses. For closed-system questions, investigators should use a response of NA (“not applicable”) or a similar term to avoid having certain boxes or lines left blank on the data collection forms. Blank responses are undesirable, since they are ambiguous: (1) the patient may have shown no response to the variable in the question and so the investigator left the response blank intentionally; (2) the investigator may not have assessed that question; (3) the question may have been found to be irrelevant at that site; (4) the investigator may have forgotten to enter the response on the form; (5) any of several other possibilities. Additional factors to consider when deciding between open and closed systems are given in Table 3.15.

Pointer 4: Use Consistent Units of Measurement In multicenter trials, the units of measurement used at each site must be compared for each test to ensure that all laboratories are using the same system of units. This is especially relevant if studies are being conducted in two or more countries, since only some countries utilize standard international units, and several systems exist for expressing results of certain laboratory parameters. If the units of meabetween open and closed TABLE 3.15 Factors to consider when choosing a,b systems

1. Open forms should be used when it is difficult to anticipate some or many of the different responses that may be given 2. Open forms should be used if there is a desire to avoid leading the respondent by providing a list of permissible responses 3. Open forms should be considered when collecting numeric data. Open forms may sometimes be used even if the data are to be subsequently tabulated into predesignated categories (e.g., age less than 20, between 20 and 60, greater than 60). The opportunity to categorize data in different ways would be lost if the actual ages were not collected. The open form, however, should partially force the format of the response (e.g., indicate age to nearest year) 4. Closed-system items, with a predefined list of response options, should be used whenever there is a need to structure or limit the responses obtained 5. The time required to code and process information from closed-system items is usually less than for open-system items 6. A closed-system item will not facilitate coding and processing if most of the responses fall into a general catchall category, such as the “other (specify)” category, which is often included at the end of a response list a

An open system means that blank boxes, lines, or areas on the form are filled in without forcing the person completing the form to use preselected responses. b Feinstein (1970a, b) discusses unstructured (open) formats in detail.

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CHOOSING MODULES AND DESIGNING FORMS: GUIDELINES, POINTERS, AND P1TFALLS

surement differ, it may be necessary to include conversion factors in the data collection form package or to use conversion factors on selected data after the forms have been completed and the data entered in a computer. It is also important to be consistent in using metric versus English units (e.g., kilograms versus pounds, and degrees Celsius versus degrees Fahrenheit) throughout a data collection form package. Pointer 5: Avoid Requiring the Respondent to Make Calculations Whenever Possible Calculations should not be requested on forms. There will be errors that will require investigator involvement to correct. The assessment values should be recorded, and the calculations should be done by the computer. If a calculated result is needed for action in the trial (e.g., if a sum of symptom scores above a specified threshold requires a particular action), provide a worksheet on a facing page (in a style similar to that of some tax forms from government revenue collectors). The markings on these worksheets would not be entered into the database; hence the worksheets would not require cleanup but would be available for supporting documentation if needed. Pointer 6: Avoid ''Change Assessment" Questions Questions that are framed in terms of assessing the current status of the patient are preferable to those requiring the respondent to assess whether improvement or deterioration from a baseline has occurred. The computer is better than staff at forming differences of scores. Requiring a change assessment often depends on the memory of the investigator and requires flipping back through the data collection form to get the baseline status. Scoring disease status at the moment (a “snapshot”) avoids these potential sources of bias and error. On the other hand, there are some occasions when a single status rating scale is too coarse to pick up subtle but important clinical changes. Under these conditions a change assessment question or index should be considered. Pointer 7: Avoid Mixing Timeframes on a Single Page It is recommended that timeframes be consistent on the same page. For example, it is wise to avoid placing medical history and concurrent medication on the same form; it is preferable to have “Medical History” and “Medication History” on one page and “Concurrent Conditions” and “Concurrent Medications” on a separate page. Also, data collected at visit 1 should be on a separate page from data collected at visit 2. Pointer 8: Consider Placing an Administrative Information Section o n Data Collection Forms Each form in the data collection form package should have a standardized section in which spaces are provided for the patient’s initials, clinical trial number, and specific data relevant to the information on that form. Other standard information often included on each form includes the title of the trial, the name of the sponsor (if any), the page number, the title of the information on that form (e.g., Electrocardiogram, Medical History, or Vital Signs), and relevant information about the sponsor or treatment [e.g., Investigational New Drug Application (IND) number, department organizing the trial, code number of the treatment being inves24

CHOOSING MODULES AND DESIGNING FORMS: GUIDELINES, POINTERS, AND PlTFALLS

tigated]. To identify the contents of any form at a glance, it is helpful to print the title of the information contained in that form at the top of the page in much larger, bolder type than that used for the rest of the page. Pointer 9: Evaluate the Use of Specialized Terms and Jargon Developing data collection forms often requires the use of medical jargon and specialized terminology that will be familiar and suitable for the physician and other clinical personnel completing the forms. Precoded synonyms or codes for many of these terms are useful for data entry and analysis. Those codes, however, should not be printed on the form if doing so will make the form more difficult to complete. Appropriate precoding of various responses should be considered as a means of facilitating data entry and analysis at the end of the trial. Discussing the forms with the personnel who will process them after the data have been collected will provide important information on this point. When deciding how to phrase questions, one should keep in mind who will be completing the forms. Items that will be completed by the investigator or staff may be phrased differently than items to be completed by patients. Even when the investigator will be completing a form, one should consider if the patient will be present when the form is being filled in. Pointer 10: Evaluate the Placement of Instructions o n Data Collection Forms To present instructions for completing a data collection form, they may be placed in several possible locations: 1. On adjoining facing pages. Instructions are usually on the lefthand page and the data collection form on the right. The instructions may be written in prose at the top of the left page, or they may be written opposite the question(s) to which they refer. 2. On top of the page to which they refer. 3. Written throughout the page to which they refer. 4. Written on a page in the front of the data collection forms for each visit. 5. Written on the back of the page to which they refer. (This approach is not recommended.) The more complex the instructions, the more preferable is method 1 mentioned above, with instructions facing the question they relate to. For simple instructions, method 2 is preferable. Use the fewest and most concise instructions possible. Many people do not read or follow instructions in completing forms. Questions should indicate where any instructions are located, and this information should often be printed in bold type. Include all information on the form that is required to answer any question. Reminders of protocol points may be placed in the data collection form package, particularly when presenting the investigator with a memory aid or when the dose is to be changed or a different procedure is to be followed. Definitions that are important, along with a time-and-events schedule, may be placed in the front of each package of data collection forms. A long code list could be placed on the facing list for reference as in method 1. Pointer 11: Provide Anatomical Drawings or Other Helpful Figures to Assist Completion of Data Collection Forms In many clinical trials a drawing of the relevant anatomical area allows staff to indicate the extent or the severity of a lesion, disease, or symptom. This may facilitate data collection and interpretation (e.g., location and extent of pain).

25

CHOOSING MODULES AND DESIGNING FORMS: GUIDELINES, POINTERS, AND PlTFALLS

Pointer 12: Consider the Consequences of Creating Incomplete or Inadequate Data Collection Forms Incomplete or inadequate data collection forms may result in implausible or lost and unretrievable data. In such cases the data may either be correctable (e.g., by reference to a laboratory slip) or not. In addition to losing some data, it is likely that the ability to include some patients in an analysis of efficacy will be lost. It is certain that a significant amount of money will be lost, and possibly the entire trial’s value.

Pointer 13: Ensure That Patient Diagnoses Are Correctly Made For clinical trials where patients and not volunteers are enrolled, include a form to ensure that patients meet the criteria for the disease. Diagnostic criteria to establish the presence of a disease must sometimes be completed after the time of enrollment (e.g., for bacteriological culture results or for enzyme support of a diagnosis of myocardial infarction). Special care should be taken to ensure that the inclusion criteria listed on the data collection form agree exactly with those in the protocol. It has been our experience that this seemingly simple agreement is often lacking. This problem may result from last-minute protocol changes.

Pointer 14: Collect Relevant Information to Address Trial Objectives at the Time of the Trial There is sometimes a temptation to collect additional data after a clinical trial is completed. The additional data may be of interest if the results of a clinical trial are unacceptable or unanticipated. Data collection forms should never be designed with the idea of possibly collecting additional data at a later date.

Pointer 15: Differentiate between Unknown, Uncertain, and Missing Data Instead of Using the Phrase "Not Available" Utilize the most precise terms possible for completing the data collection forms. Relevant forms should indicate acceptable terms. The phrase “not available” is ambiguous and should be avoided. A preferable choice of terms is “unknown,” “uncertain,” or “missing.” Permissible terms should be determined in advance and indicated on the forms.

PITFALLS Table 3.16 lists several of the common pitfalls to be avoided when constructing data collection forms. A few additional pitfalls are as follows: 1.

2.

26

Asking for a diagnosis of a disease without giving criteria for diagnosis. The following question might be found in some data collection forms: Is disease X present? Yes No The problem is that each investigator may use different criteria to diagnose disease X , and possibly not the official criteria. Numerous problems of interpretation could be created, if specific criteria for diagnosing the disease are not presented. Collecting excessive demographic data. A great deal of demographic data may be collected that has no relation to the clinical trial’s objectives. These data usually include marital status, social status, economic status, education,

CHOOSING MODULES AND DESIGNING FORMS’. GUIDELINES, POINTERS, AND P1TFALLS TABLE 3.16

Pitfalls to avoid in designing data collection forms8

1. Requesting information without providing adequate instructions on the data collection forms (or elsewhere) regarding how to complete the forms 2. Using two or more pages for a single category of information that could easily fit one page 3. Requesting an excessive amount of information to be put on a single page, which crowds the page and makes monitoring, editing, and data entry difficult 4. Using jargon unfamiliar to the person filling out the form. Some individuals advocate eliminating all jargon from data collection forms; however, jargon that is widely accepted may facilitate data collection and improve its quality 5. Using a check-off system to obtain responses to a question, but not including all possibilities or an “other (specify)’’ category, where different responses may be listed 6. Collecting all or almost all data in the form of write-ins, so that it is difficult or impossible to rapidly combine or condense data obtained from many patients 7. Using codes on the form that are only relevant to data processors and make the forms difficult for investigators or their staff to complete 8. Not combining or attaching all of the forms in the data collection package for each patient in a manner that is easy to use, store, and retrieve 9. Using abbreviations or acronyms that are unknown or may have multiple definitions. Only the most universally understood abbreviations or acronyms should be used 10. Combining two questions into one that leads to confusion, or creating questions that have more than one interpretation 11. Using relative questions without providing the reference point (e.g., “compared to baseline,” “since the last visit," “over the last 24 hours") 12. Using confusing language (e.g., “Is there no history of . . .”) a

3.

4.

5.

6.

7.

Modified from Spilker (1987) with permission.

and position i n a household. These data generally slow data processing and statistical analyses. This principle could extend to virtually any category of data that are unnecessary. Collecting all data listed on standard data collection forms. Some categories of data on a standard library page given i n Part I I may be relevant early i n a medicine’s development, but not after sufficient data are collected to show that the parameters are not affected by the medicine. A t that stage the data should no longer be collected. Even if it is relevant to collect the data at some patient visits, i t may be possible to alter the forms i n such a way as to prevent data from being collected for other patient visits: by shading the area or by deleting the category or entire module. Printing ranges for analytes on the data collection forms. Unless one is certain that all analytes indicated will be collected and that the ranges are correct, avoid stating analyte ranges explicitly. Also, do not include analytes supplied by the laboratory (e.g., all of those i n a SMA-35) that are not of interest to the clinical trial, as this generates excessive data. Printing and punching holes in data collection forms in one country for shipment to another. The binders that are purchased i n one country may have rings that do not accommodate forms where holes were punched i n another country. Understand cultural differences in how forms are perceived. Shading of boxes or questions that investigators are not to fill i n is a commonly used technique i n the United States. The fact that this approach upsets clinical investigators in some European countries should be considered. Undated forms. Date-stamp all data collection form packages when they arrive at a sponsor or when they are totally completed at the investigator’s site for an unsponsored trial. This practice establishes a time that may be important to refer to at a later time to determine whether the forms were received as a completed package or i n a piecemeal manner; and, also if they were received before or after a certain time point.

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CHOOSING MODULES AND DESIGNING FORMS.' GUIDELINES, POINTERS, AND PlTFALLS

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

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Placing more than one adverse event per line on any form. If nausea and vomiting are both placed on a single line, it could lead to difficulties in describing the various characteristics if they differ between the two symptoms. Placing more than a single adverse event on one line will also complicate the assignment of standard dictionary (e.g., COSTART) terms during data processing. Identifying a problem by a single name. If a patient’s problem has many components, then each should be listed. For example, for a patient with fatigue, runny nose, cough, and sneezing, these symptoms should be listed and not simply “cold.” It is rarely 100% certain that each of these symptoms results from a cold. Colds should be listed as a comment and not as a separate event. Confusing disease symptoms with adverse events. If all adverse events are assiduously collected, then those symptoms associated with the disease being treated will be listed on data collection forms as adverse events. This is potentially a serious problem for diseases that are complex and replete with adverse events. Collecting data on the onset and intensity of abnormalities unassociated with the clinical trial (e.g., physical problems). This is usually unwarranted. Moreover, these data are often unobtainable or are clinically insignificant for the clinical trial. Unclear timeframes. Ensure that the timeframe of reference to be considered in answering every question is understood. The best way to do this is to state the timeframe on the form itself (e.g., “over the last 24 hours . . . , ” “since your last clinic visit . . . ” ) . Conducting trials with different kinds of equipment. In multicenter trials ensure that all sites have and use identical equipment. If differences exist, which they invariably do, then confirm that no changes in forms are required (e.g., for different electrocardiogram machines), or modify forms if relevant (e.g., for various respiratory ventilators). Rating the clinical significance of various events without specifying the identity and the perspective of the rater. An abnormality for the patient (e.g., urinary tract infection) is clinically significant for the patient, but if it preceded the trial, it is not clinically significant for the trial or for the medicine being evaluated. An adverse event that occurs during the clinical trial may be clinically significant for the patient but not for the medicine, so that an investigator in a sponsored trial should be instructed on how clinical significance is rated for the patient. Moreover, a definition of the term should be presented. Forgetting to ensure that causality of medicine and each adverse event is assessed. Evaluating the causality of medicine and adverse event (i.e., did the medicine cause the adverse event?) may be determined by the investigator or the sponsor. This evaluation should be made at a standardized point for all abnormalities assessed. Determination of causality could occur at the time of (1) the incident, (2) the patient’s completion, (3) the trial’s completion, or (4) whenever the investigator feels comfortable in reaching a decision. Ignoring visual appearance of the form from viewpoint of the respondent. In placing questions and codes on the form it is necessary to consider visual appeal as well as the logical flow of the form. Leaving the form of negative responses up to the respondent. Negative responses can be reported in many ways and it is usually desirable to indicate which of the following are desired if a simple check (e.g., “ y e s , ” “ n o , ” or “unknown”) is not used. Possible negative responses include “none,” “nil,” “not seen,” ‘ W N L ” (i.e., within normal limits), “absent,” “ 0 , ” “zero,” “negative,” “neg.,” “ — , ” and “ N . ”

CHOOSING MODULES AND DESIGNING FORMS! GUIDELINES, POINTERS, AND PlTFALLS

18. Allowing the respondent to determine appropriate ways to describe patient termination. It is often difficult to create suitable options for describing reasons for patient termination. Some reasons are specific to the disease or patient population (e.g., the teacher refused to allow the child to leave the class to take his or her medicine). The issue is to determine how much data are really needed. 19. Omitting a question to assess the quality of each patient’s participation, when relevant. It is often relevant to include a question on the patient termination form requesting the investigator’s assessment of the patient’s participation in the clinical trial (e.g., patient participated as planned, with minor irregularities or with major irregularities). All significant irregularities should be identified. In this chapter we looked at issues to consider when designing forms —guidelines of what to include and pitfalls to avoid. Next we turn to the question of assembling the forms into a data collection form package.

29

Preparing the Data Collection Form Package After the content, format, and physical layout of the individual data collection forms for a clinical trial have been finalized, it is necessary to put the forms together. After the individual forms are arranged into a coherent order, additional materials are often added to assist the investigator and staff as they record data onto the forms. The completed packet (i.e., the ordered forms along with all accompanying materials) is referred to as a data collection form package. Each patient enrolled in a clinical trial has his or her data recorded in such a package. ITEMS OFTEN INCLUDED IN A DATA COLLECTION FORM PACKAGE In addition to the individual data collection forms, materials explaining the trial design and directions for completing the forms are often included in the data collection form package. Specific items usually included are a diagram of the clinical trial design, a time-and-events schedule, general instructions, various checklists, and section dividers. These items are discussed below. Diagram of the Clinical Trial Design When decisions are being made regarding additional materials to include in the data collection form package, it is important to remember that in many instances the personnel completing the data collection forms will not have been involved in developing either the clinical trial’s protocol or the forms. For this reason, a diagrammatic representation of the trial design can prove to be invaluable. It provides the investigator and staff with a pictorial schematic that informs them when the patient was last seen and when the patient will be seen again. In addition, the staff becomes familiar with the projected flow of patients through the trial in terms of clinic visits. Prototypes of schematic diagrams of clinical trial designs may be found in Presentation of Clinical Data by Spilker and Schoenfelder (1990). Time-and-Events Schedule The time-and-events schedule serves as a flowchart during a clinical trial’s conduct. One or more time-and-events schedules provide exact details as to what

30

PREPARING THE DATA COLLECTION FORM PACKAGE

evaluations are to be performed at each visit or time of day. This important information should be placed at the beginning of the package where it can be readily located. Several examples of time-and-events schedules are included in Part II, category A. 2.

General Instructions Since it is easy for investigators and staff to forget or ignore instructions, it is a good idea to provide that information on the forms rather than on accompanying documents. It is not sufficient to assume that the investigator or staff will consult the protocol for instructions while completing the data collection forms. Thus, general instructions to facilitate completion of the forms, in addition to those printed on the individual forms, should also be included in the data collection form package. For sponsored trials a telephone number should be included that provides access to someone, such as a clinician, nurse, or trial coordinator, who can address questions that arise. Instructional information should be either interspersed throughout the data collection form package in appropriate places or kept at the beginning of the package. Considerations for deciding on where to place the instructional material are listed in Table 4.1. Specific examples of instructional materials are given in Part II, category A . l .

Checklists and Section Dividers A checklist of forms to be completed at each clinic visit or at each specified time point during a short-term clinical trial may be included in the packet. This would serve as a helpful guide that could be placed at the start of that section of the

TABLE 4.1 Considerations for locating instructional materials in the data 3 collection form package

1. Instructional material should be placed where the personnel completing the forms most need it and can easily locate it 2. Instructional material on the first page of the form should indicate when the package is to be initially used (e.g., after the patient completes the screen and signs the informed consent) 3. Instructional material relating to specific items or sections of a form should be located next to those items or sections 4. Instructional material that is too extensive for inclusion next to the item or section to which it pertains should be placed either in a separate booklet or on the back side of the page adjacent to the page in question 5. All instructions needed for completing a form should be included on the form. It is unwise to rely on the protocol or other documents for information relating to completing the forms 6. Instructions should be clear, concise, and simple 7. Instructional material should be readily identified with a title plus special type font, or by some other method 8. Items with a list of permissible responses that are not mutually exclusive must contain an instruction to indicate whether the respondent may select more than one response 9. Items that include “unknown,” “do not know," or “uncertain” as response options should include instructional notes to indicate whether any special procedures are required before these categories are checked 10. Key definitions needed for completion of an item should appear on the form (e.g., definitions of the categories for evaluating the relationship of a reported adverse event to study medication) 11. There should be an instruction at the end of each data collection form package that indicates where the package is to be sent after completion a

Points 2 to 11 are modified from Meinert and Tonascia (1986) with permission.

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PREPARING THE D A T A COLLECTION FORM PACKAGE

data collection forms. A few examples are given in Part II (e.g., A. 1.7, A. 1.8). Section dividers with tabs may be inserted to facilitate the location of specific clinic visit forms or a specific type of form. These dividers may be printed on heavy colored paper.

METHODS USED TO ORGANIZE PAGES There are two basic ordering schemes used to assemble data collection form packages. One scheme is to group forms according to the type of data being collected, and the other is to group forms by visit.

Data Collection Forms Organized by Type of Form This approach would keep all vital signs forms together, all primary efficacy variable forms together, all adverse event forms together, and so forth. This grouping does not facilitate the process of actually entering data onto the forms because data from a single clinic visit must be entered in each section of the data collection form package. This approach, however, is often helpful when checking the data’s internal consistency. When this approach is used, data of one type may be entered on either a single page (e.g., using one column per visit) or on separate pages (e.g., one page per visit). If data are entered on a single page, the investigator or monitor can immediately see all the measurements on any one variable and may readily detect any noteworthy trends or inconsistencies. For example, a systolic blood pressure reading of 160 mmHg at visit 5 of a clinical trial would not, by itself, be a questionable value. However, if a reviewer noted that systolic pressure values were 120 mmHg or less at visits 1 to 4, the reviewer might immediately question the accuracy and significance of the visit 5 reading. Another advantage of organizing the package by type of form is that by watching the data accrue visit by visit, one can more easily detect subtle trends in the data. For example, consider a specific laboratory analyte. Two examples of readily detectable trends when data are arranged in adjoining columns are (1) consistent movement (upwards or downwards) that does not leave the reference range, and (2) movement where initially abnormal values gradually become more abnormal. This approach is particularly useful in an intensive care unit or in any trial where certain types of data are collected on a very frequent basis. The more time that lapses between periods of data collection, the less need there is for using this approach for most types of data collection. Although it facilitates data review, grouping the data collection forms by type of data collected may actually hinder data collection itself. At any clinic visit, the investigator or staff would have to record data in each of many sections of the book containing the forms. It would be necessary to record data insertions on efficacy, vital signs, and so forth. This jumping around within the data collection form package introduces many opportunities for error (e.g., turning to the wrong page, or writing information on a notepad to record later and then discarding or losing the note prior to recording the data).

Data Collection Forms Organized on a Visit-by-Visit Basis From a practical standpoint, data collection is facilitated by grouping the individual forms according to clinic visit (i.e., creating a separate section for all forms to be completed at each visit). Thus, at each clinic visit, all information for a patient would be recorded within a single section (e.g., visit 4) of the data col-

32

PREPARING THE D A T A COLLECTION FORM PACKAGE

lection form package. The identity of clinic visits could be expressed in terms of length of time on the clinical treatment (e.g., month 5), number of the clinic visit (e.g., visit 6), or by exact date of the visit (e.g., March 15) for certain trials. This last approach is not recommended because of the possibility of postponing or changing the starting date for a trial or exact date of a visit. Strict adherence to grouping data collection forms according to specific clinic visit numbers or months may provide information that is hard to interpret. For example, this grouping can cause problems for variables such as adverse events and concomitant medications. For example, if the same adverse event is recorded at consecutive visits, it may be unclear if it represents two occurrences of the same event or one occurrence with a relatively long duration. Similarly, if the same concomitant medication is recorded at consecutive visits, the duration of its usage may be unclear.

Combination Approach A reasonable compromise (which we recommend) for most clinical trials utilizing multiple clinic visits is to organize most forms on a visit-by-visit basis. These forms may be divided either according to the number of the clinic visit or by the duration of time in the trial at the time of the clinic visit (e.g., week 8). However, forms for recording data such as adverse events that reflect information that may be continuing between visits (or from visit to visit) may be grouped together at the beginning (or end) of the data collection form package. Within the section of the package corresponding to each clinic visit, there should appear a reminder for the investigator or staff to also complete the additional form(s). An entry should be made within the visit-by-visit section confirming that relevant data from that visit is being recorded in each appropriate section of the package. Forms that are commonly organized in this manner, apart from the adverse events and concomitant medicines, include patient dosing charts and clinical laboratory examination data. The same data should only be recorded in one location within a single package (i.e., identical data should not be entered in a visit-by-visit section and also in a special combined visit section). The section containing forms organized in the combination approach described may all be printed in a different color from the other sections, or the section divider may be printed in a different color. If this option is used, then an easyto-read-through color should be chosen. We turn next in Chapter 5 to the mechanics of reproducing and assembling the forms in the data collection form package.

33

5 Reproducing and Assembling Forms After one has settled on an appropriate organization for the data collection form package, the individual forms must be copied and assembled. For sponsored trials it is also necessary to distribute the forms to individual clinical trial sites. Sufficient time must be allowed to ensure that the packages arrive at the site and that a dry run is conducted before any patients are enrolled in the study. It is usually preferable to also conduct a pretrial round-table meeting at which all pertinent forms are discussed with investigators and with the trial coordinators who will help run the trial.

Copying Data Collection Forms Decisions must be made in regard to (1) the size, weight, and color of the pages and section dividers; (2) the type style and size; and (3) the method of reproduction (i.e., photocopying vs. printing). Some important considerations in making those decisions are listed in Tables 5. 1 to 5.3, respectively. When a data collection form package is to be filed or could be filed with a patient’s medical records, it would be useful if the overall size of the package were similar or identical to that of the medical records.

Assembling the Data Collection Form Package After the contents of the data collection form package have been finalized and the individual forms and accompanying materials have been copied, it is time to put the forms together physically. Important considerations relating to this task are given in Table 5.4. Regardless of how it is put together, the package should be convenient to handle. It should be of a standard size and shape and of sufficient quality that it will not inadvertently fall apart during the course of the trial. Most packages are placed into three- (or other number) ring binders for ease of adding or removing pages.

34

REPRODUCING AND ASSEMBLING FORMS

TABLE 5.1 Considerations of paper used for data collection formsa 1. The same-size paper should be used for all forms and for all additional material included in the data collection form package 2. A paper size of 8.5 by 11 inches is preferable to other sizes in the United States, especially when forms are to be photocopied and filed using standard office equipment. Forms in most European countries are 8.25 by 11.75 inches (21 by 30 cm) 3. Good-quality paper should be used to avoid bleeding from ink or felt-tip pens, which are sometimes used to complete the forms 4. Paper must have sufficient weight and strength to withstand frequent handling 5. Any color coding scheme should be simple, logical, and easy to remember 13 6. Color coding should never be the sole means of identifying a form or its uses (also use a title plus page number) 13 7. Colors utilized should be limited to only a few distinct shades that are easy to recognize and differentiate13 8. A particular color should have the same meaning throughout the package 13 9. As a general rule, forms printed on pastel-colored paper are easier to read and will produce better photocopies than forms printed on dark-colored paper. It is wise to avoid red colors because they photocopy poorly 10. The legibility of photocopies produced from pages using the proposed colors should be investigated before final color selections are made 13 11. Carbonless duplication paper used to make several copies at one time is not recommended because of difficulties in making changes, retaining colors (if used) in photocopying, and the quality of thin paper usually used0 a

Some points are modified from Meinert and Tonascia (1986) with permission. Color pages may not photocopy well; moreover, they will not retain their color. 0 If carbonless duplication paper is used, enclose a piece of cardboard in the cover of the data collection form package; this cardboard can be placed between sheets when making corrections. b

TABLE 5.2 Considerations of type style used for data collection formsa 1. 2. 3. 4.

Make the print or type font large and crisp enough to allow for clear photocopying Use a print or type font at least the size of newsprint Use lowercase lettering for all text. Do not capitalize long phrases or sentences Use a different print or type font for emphasizing specific words, phrases, and headings, and also for distinguishing instructional material and other notes from data collection items 5. Vary the boldness of type to emphasize important questions 6. Make sure the spacing between words is uniform, even though this does not yield forms with a right-justified margin (i.e., an even righthand margin) a

6 5 2 4

Some points are modified from Meinert and Tonascia (1986) with permission.

TABLE 5.3 Considerations of duplicating data collection forms3 _______ 1. Use printed forms, which are generally easier to read and are aesthetically more pleasing than are typewritten forms 2. Forms may be photo-reproduced from either typed or professionally printed masters 3. Consider printing over photocopying in the following cases: (1) for forms that are to be used in large numbers; (2) for forms that are difficult to photocopy because of their size; and (3) for forms that are difficult to photocopy because of the way in which the data collection forms package is assembled 4. Do not print forms until they have been thoroughly tested and are no longer subject to revision 5. Use a well-known and respected printer 6. Confirm that there are no missing pages __________________________ a

Some points are modified from Meinert and Tonascia (1986) with permission.

35

REPRODUCING AND ASSEMBLING FORMS TABLE 5.4

Considerations for physically assembling the data collection form package 11

1. The data collection form package may be supplied to clinics with the individual forms collated and bound, collated and unbound, or uncollated 2. Uncollated forms are preferable when the number of pages making up the package varies depending on the patient or examination 3. Collated, unbound forms are preferable if it is likely that they will have to be disassembled for completion and/or photocopying 4. Collated, bound forms are preferable in most situations. Binding with a three-ring binder is often preferable to a glued binding because additional pages may be added as necessary and the forms may be separated during the trial for ease of completion 5. Paper clips or similar kinds of fasteners are unacceptable for securing the individual forms of a completed data collection form package 6. The individual data collection forms of a package should be sequentially numbered using numbers that are to be assigned to patients (e.g., A4302.701) 7. Clearly delineated section dividers should be used to separate individual sections 8. Including a transparent or opaque holder for storing EKGs or other physiological records in the front or back of the data collection form package should be considered “Some points are modified from Meinert and Tonascia (1986) with permission.

36

6 Remote Data Entry Forms Remote data entry refers to data collected in sponsored trials and means that the initial process of entering data into a computer occurs at the investigational site rather than at a sponsor’s home office or at a contractor’s office. The computerized data are then transferred to the sponsor by modem (i.e. , telephone) or by disk or data tape. Future technological advances may enable satellite transmission on a frequent basis. The initial reaction of some investigators and staff to the term “remote data entry” is that data collection forms have become obsolete. Their belief is that it will no longer be necessary to spend many hours designing, revising, printing, assembling, and entering data on those forms. However, this is not generally true; even if data are collected in a patient’s chart and transferred to a computer without a hard-copy data collection form package, most of the previously mentioned functions still must take place in order to design screens that appear on the computer monitor and serve to prompt the person entering data. Because these screens are analogous to individual data collection forms and because most personnel who enter data at investigational sites are not trained as data entry operators, the clarity of the screens and their ease of use are of paramount importance. The task of designing these screens replaces the task of constructing paper data collection forms; however, the steps involved in these two tasks are essentially the same.

Computer- Assisted Data Collection Form Design This is a useful practice as long as the software does not dictate what is to go into the data collection forms. Usually the computer is biased to create a form that is 100% appropriate for data entry, whereas data collection often requires or prefers different designs or approaches. The criteria of a data entry operator in judging a form are primarily based on the speed of data transmission into the computer. Investigators judge a data collection form by the ease of use and accuracy of the data they enter (e.g., having laboratory analytes listed on a form in the same order as on the report slip).

Entering Data at the Investigator's Site There are many ways in which the actual data entry process can take place. One way is to have the data recorded on pseudo data collection forms (sometimes called clinical trial workbooks) that are later entered into a computer. Each workbook is a virtual duplicate of all the screens used in the entry process. Another

37

R E M O T E D A T A E N T R Y FORMS

method is to enter the data directly into a computer. This may be done either by entering data directly from the patient’s medical charts or by first copying information from a machine or direct observation onto “scraps” of paper that are then discarded after the data have been entered. Using and discarding scraps of paper should be discouraged. Data may also be entered directly into a computer (e.g., laptop) while the patient is being examined (i.e. , without any data collection form hard copy). Regardless of the method used for data entry, when requested data are unavailable, an “ M ” or another specifically defined character may be placed on computer screens for missing. This prevents the sponsor from calling frequently for information believed to have been forgotten or unentered. Some data can be entered electronically, directly from the medical instruments making the measurements. One example of this is in laboratory examinations where the machine analyzing the samples has the capability of electronically storing the results. Other examples include heart monitoring equipment and machines recording ambulatory blood pressure measurements.

Transferring Data from the Investigational Site to the Sponsor Just as there are many ways of entering clinical trial data into a computer at an investigational site, there are numerous ways of transferring those data from an investigational site to the trial’s sponsor. One method is have the investigational site download the data onto floppy diskettes at prespecified intervals and then to send those diskettes via mail or courier service to the sponsor. Another method is have the computer at the investigator’s site “talk” to a computer at the sponsor’s location and electronically transfer the data. Electronic transfer may occur at night, so that each morning the sponsor’s database would be current with the investigator’s database. Still another method is to give personnel at the investigational site dial-in privileges to the sponsor’s computer system. The data could then be directly entered into the sponsor’s system from the investigational site. Figure 6.1, taken from Spilker (1990), depicts three models of data flow using remote data entry. In model A, both electronic and paper copies of the data are available, whereas only the electronic copy exists in model B. Model C differs from the other two models in that the personnel who transmit the data from the site to the sponsor are not part of the investigator’s staff. Rather, they are employees either of the sponsor or of an independent contracting organization.

Comparison of a Traditional and Remote Trial Monitoring Workbook Data Collection Form Differences between a traditional hard-copy data collection form (Fig. 6.2) and a monitoring workbook page (Figs. 6.3 and 6.4) are illustrated by the six points indicated in the figures. Corresponding explanations of these circled numbers are as follows: ®

®

38

Only one box is used for the Yes/No question in the remote trial monitoring workbook because it is easier to enter a “ Y ” or “ N ” than it is to position the cursor on the appropriate box and enter an “ X ” . This decision is standard for all mutually exclusive multiple-choice data items. There are no two- or three-character identifiers printed next to the risk factors in the remote trial monitoring workbook. They were printed in the traditional form to help the professional in-house data enterer key in the correct code. It is impractical to expect the investigator’s data entry personnel to execute such a task accurately on a computer. The data entry system must be programmed to generate these identifiers automatically in the records that get

REMOTE D A T A E N T R Y FORMS

Investigator Interacts With Patient

Data Transmitted by Staff to Sponsor via Computer

DCF Filled in by Investigator or Staff

Sponsor Edits Data

Data Processed & Analyzed

Monitor Verifies Data

Investigator Interacts With Patient

Data Transmitted by Staff to Sponsor via Computer

Sponsor Edits Data

Data Processed & Analyzed

Monitor Verifies Data

Investigator Interacts With Patient

Data Edited by Sponsor's Monitor at Site

DCF Filled in by Investigator or Staff

Data Transmitted by Monitor from Investigator's Site

Data Processed & Analyzed

Monitor Verifies Data

Three models of how data flow and verification may be organized using remote data entry. From Spilker (1990).

FIG. 6.1

®

sent to the mainframe computer at the sponsor’s site or at the data coordinating center. The investigator’s name, clinical trial site, patient’s first name, middle initial, last initials, and trial number are not printed in the remote trial monitoring workbook. There are several reasons for this: •

•

•

®

The traditional data collection form package has these items on every page to help in-house personnel to identify a page if it became separated from the rest of the pages. The investigator’s site does not need to know the investigator’s name or trial site to help them do that. The remote trial monitoring system should automatically display this information on each data entry screen, rather than having the data enterer key this information in repeatedly. This will reduce the chance of misidentification of a page. The remote trial monitoring system can print this information at the top of each page of the final remote trial monitoring data collection form without requiring that it be entered by a data enterer on each page.

The remote trial monitoring workbook does not contain the instruction to “List most recent first.” This instruction was given to help the investigator, staff, and in-house sponsor’s staff review the reactions once these have been

39

REMOTE D A T A E N T R Y FORMS

Investigator Name

Date (M/D/Y)

Study Site

Patient’s First Name

Ml

LI

Patient’s Study Number

ASSOCIATED RISK FACTORS TO CONTRAST MEDIUM No

Yes

In addition to Liver Disease, does the patient have a known history of any of the following? If yes, check appropriate box(es). Yes

Yes

E J Previous Reaction to Contrast Medium®

HAS

1 I Hypoalbuminemia

A70

O

Age > 70 Years

PRO

□

DM

□

Diabetes Mellitus

SCD

L U Sickle Cell Disease

HYP

E D Hypertension

TD

□

Thyroid Dysfunction

CHF

□

Congestive Heart Failure

PC

□

Pheochromocytoma

Rl

□

Renal Insufficiency

LtD

□

Liver Disease

PCM

RD MM

Proteinuria

E J Renal Disease

VAO

1 I Vascular Disease

1 1 Multiple Myeloma

ASM

1 I Asthma

MS

1 I Multiple Sclerosis

HF

HG

□

DA

Hyperuricemia/Gout

FA a

] Hay Fever □

Drug Allergy* ] Food Allergy*

If yes, complete bottom of page.

* If yes, list on page 2

PREVIOUS REACTION T O CONTRAST MEDIUM *Date (M/D/Y)

Type of Examination

Contrast Medium

Reaction

Severity

Treatment

_ ZL—. f

— /— /— * List most recent first and indicate “Unk" for any incomplete information

A sample data collection form for identifying risk factors to contrast medium as well as previous reactions to contrast medium. Reproduced courtesy of Onsite Systems, Berkeley, Calif.

FIG. 6.2

®

40

recorded on the data collection forms. However, the remote trial monitoring system can and probably should be programmed to automatically sort these reactions by date after the data entry screen has been filled out. This sorted listing will be displayed for future review and printed on the remote trial monitoring data collection form. The remote trial monitoring workbook does not contain the instruction to “indicate U N K for any incomplete information.” Since data are transferred to the sponsor’s site continuously during the clinical trial, a remote trial monitoring project requires a more formal mechanism to help the sponsor’s in-

R E M O T E D A T A E N T R Y FORMS

ASSOCIATED RISK FACTORS TO CONTRAST MEDIUM Date

/ mm

/ dd

yy

In addition to Liver Disease, does the patient have a known history of any of the following? (Y)es/(N)o

u®

If YES, check appropriate box(es) on the following form.

® ® FIG. 6.3 The first of three sample computer screens designed for remote study monitoring to collect data on part of the data collection form illustrated in Fig. 6.2. The circled numbers 1, 3, and 6 refer to points discussed in the text. Reproduced courtesy of Onsite Systems, Berkeley, Calif.

house personnel determine whether a missing item is missing because it was neglected by the data enterer, or because the datum is truly “lost” forever. One way to implement this mechanism is through a data-lost character. The data enterer can key this character into any field, to indicate that that field value will never be available. (Afield is a portion of a screen that receives data in the form of letters and/or numbers; each screen is made up of several fields.) Since this mechanism is applicable for all fields, it is unnecessary to include instructions specific to certain fields on how to indicate incomplete information in those fields. ® The remote trial monitoring workbook places the Yes/No question on one screen image and the list of risk factors on the next screen image. This is because the data entry system is programmed to skip the list of risk factors completely if the Yes/No question is answered “No.” This skipping mechanism is implemented as a “conditional screen execution,” thus requiring separate screens for these two groups of information. Data Management In addition to getting entered into the computer and transferred to the sponsor, the data must also be retrieved from the computer. Clinical trials using remote data entry often create paper data collection forms, which we refer to as remote trial monitoring data forms. Those forms are usually printed from the database after the trial data are transmitted. The design of the printed forms is extremely important, particularly because these forms are usually exact copies of the data entry screens. For clinical trials submitted to the Food and Drug Administration in support of a regulatory application, the regulatory reviewers often want to see a subset of the printed forms. Thus, the printed forms must be easy to read and organized 41

REMOTE D A T A E N T R Y FORMS

ASSOCIATED RIS>K FA(DTORS TO CONTRAST 1VIEDILI M Continued) Yes (X)

Yes (X) Previous Reaction to Contrast Medium + Age > 70 Years

Proteinuria

Diabetes Mellitus

Sickle Cell Disease

Hypertension

Thyroid Dysfunction

Congestive Heart Failure

Pheochromocytoma

Renal Insufficiency

Liver Disease

Hypoalbuminemia

Renal Disease

Vascular Disease

Multiple Myeloma

Asthma

Multiple Sclerosis

Hay Fever

Hyperuricemia/Gout

Drug Allergy + + Food Allergy + +

+ ++

A

lf YES, complete the following form. lf YES, list on Patient Histor y

ASSOCIATED RISK FACTORS T O CONTRAST M E D I U M (Continued)

PREVIOUS REACTION TO CONTRAST M E D I U M Date (m/d/y)

/

/

/

/

/

/

Type of Examination

Contrast Medium

Reaction

Severity

Treatment

B FIG. 6.4 A: The second computer screen designed to collect data for remote study monitoring on part of the data collection form illustrated in Fig. 6.2. Number 2 is discussed in the text. B : The third of three computer screens designed to collect data for remote study monitoring using the data collection form in Fig. 6.2 as a model. Numbers 4 and 5 are discussed in the text. Reproduced courtesy of Onsite Systems, Berkeley, Calif.

42

R E M O T E D A T A E N T R Y FORMS

in a consistent manner; they should also be similar to data collection forms designed to be completed during the trial if remote data entry is not used. Table 6.1 itemizes the characteristics of the two kinds of data forms used with remote trial monitoring discussed in this chapter, along with traditional data forms. The next chapter details how the forms are processed once the data have been entered, transferred, and edited. TABLE 6.1 Comparison of traditional data collection forms, remote trial monitoring workbooks, and remote trial monitoring data forms3 Remote trial Remote trial monitoring monitoring Traditional data forms workbooks data forms Design automatically generates data entry system Role in clinical trial Filled with data Used for data collection Multipart forms Signed by investigator Copied to sponsor Computer generated Used for data entry Submitted to a regulatory authority a b

No

Yes

Yes

Required6 During trial Yes Yes Yes Yes No Yes Yes

Optional During trial Sometimes No No No No Yes No

Required6 At end of trial No No Yes Yes Yes No Yes

Reproduced courtesy of Onsite Systems, Berkeley, Calif. One or the other is required, although both may be produced.

43

7 Data Processing and Storage of Completed Forms After data collection forms have been completed and edited, they are ready for processing. For unsponsored clinical trials, that processing is done at the investigational site. For sponsored trials the forms are usually sent to the sponsor’s location for processing; however, copies of all forms are kept at the investigator’s site. The first steps in the data-processing process are the review, entry, validation, and correction of the data recorded in data collection forms. If it has not been done during the clinical trial, the first step in the process is to check the adverse event forms for the presence of any serious adverse events. Following this important check, the forms may be processed in any appropriate manner consistent with the institution’s standard operating procedures. More groups are using bar codes on individual data collection form sheets so that loose pages may be more readily tracked as parts of a package become separated. Dismantling of the package can occur for many legitimate reasons (e.g., blood analysis for medicine levels sent to special laboratories are accompanied by the relevant forms). Types of Errors During the monitoring and later during processing, the data collection forms should be reviewed for legibility. Illegible entries should be investigated and rewritten prior to sending the forms to data entry operators. Forms should also be reviewed for completeness, consistency, and logic. Missing and incorrect values should be corrected, and borderline values (e.g., a recorded pulse of 40 beats per minute) should be identified and investigated for accuracy. Frequently encountered types of errors are listed in Tables 7.1 and 7.2. Correcting Errors As errors are uncovered and the correct responses are identified, the data collection forms need to be updated to reflect the correct responses. In most cases, corrections to the forms should be made by drawing a line through the incorrect entry and then writing the correct response above or adjacent to the original entry. The correction should be initialed and dated by the person making the correction. Other options exist to correct forms. For example, a separate errata sheet may

44

DATA PROCESSING AND STORAGE OF COMPLETED FORMS

TABLE 7.1 Frequently encountered errors relating to the degree that data collection forms are filled in accurately and completely 1. 2. 3. 4. 5. 6. 7.

Date fields either are not filled in or are incomplete. For example, only the year or only the month and year are recorded on the form Fields for recording evaluations that were not done are not filled in. An entry of ND (“not done’’), NA (“not applicable”), or something similar should be made Entire forms or sections of a form are sometimes inadvertently skipped Requested source documents (e.g., laboratory reports or ECG tracings) are not attached to the form as requested Investigator’s signature (or initials) is missing Measurements are recorded, but the units of measurement are not reported Reasons or explanations requested in the forms are not provided, nor are any explanations given for the missing reasons

be used for each patient’s data collection form to avoid having to initial and date every change where it occurs in the package. The errata sheet could have columns for patient number, page, item changed, original value, new value, comment, date, and initials of the person making the change. For sponsored studies it is important that changes posted to forms at the sponsor’s location also be reflected in the forms maintained at the investigator’s site. A good way of ensuring that the sponsor’s and investigator’s forms agree is to have a copy of the corrected data collection forms sent to the investigator to replace the copy that was made prior to sending the forms to the sponsor. For practical reasons, this exercise is usually performed only after all data collection forms for a clinical trial have been edited and validated.

Maintenance of Data Collection Forms for Unsponsored Clinical Trials Many medical schools and other institutions either have or are developing policies that address this question. Readers should consult the policies of their institution in this regard. It is common for institutions to request or to require their professional staff to retain original data for a five-year period after its publication.

TABLE 7.2 Frequently encountered errors relating to consistency and logic found on data collection forms 1. Respiration-rate and heart-rate measurements are interchanged 2. Checklists with mutually exclusive responses have more than one response checked 3. Information indicated on the adverse event form is not documented elsewhere. For example, an adverse event form indicates that an event required drug treatment, but no concomitant medication is indicated anywhere; or, the adverse event form indicates that an event required the discontinuation of trial medication, but the patient disposition form does not indicate that the patient discontinued treatment because of an adverse event 4. Screening data fails t o confirm inclusion criteria on the checklist. For example, the checklist may indicate that patients must be at least 18 years old, but the patient’s age is given as 16 years on the screening form 5. Unsolicited comments are made in the margins of the forms. These comments need t o be evaluated with the result that either they need to be “moved” to an appropriate location or the form needs to be annotated to indicate that they should not be entered 6. Unrequested data are collected and “forced” into existing items on the form that were designed for other data 7. Forms indicate that measurements are to be made in specified units, but other units are used instead (e.g., for laboratory tests) 8. Times are listed in terms of AM or PM instead of using a 24-hour clock 9. Measurement units are not used consistently (e.g., weight is recorded in pounds for some patients and in kilograms for others)

45

DATA PROCESSING AND STORAGE OF COMPLETED FORMS

Maintenance of Data Collection Forms for Sponsored Clinical Trials After all of the forms have been processed and the clinical trial data have been analyzed, reported, and interpreted, the data collection forms must still be maintained. For clinical trials being submitted to the Food and Drug Administration (FDA) as part of a New Drug Application (NDA), the forms must be kept for two years after the medicine has been approved or after the submission has been withdrawn. At any time during that period the FDA can request to see the paper forms. Additionally, companies are required to provide the FDA with copies of the data collection forms for all patients who either died during the study or who were prematurely discontinued from the study because of an adverse event. If an NDA is not submitted, federal regulations dictate that copies of the forms must be maintained by the investigator for five years after the study is completed. Most if not all pharmaceutical companies have rigorously enforced standard operating procedures that define who is responsible for maintaining the forms. Those standard procedures also dictate how the forms will be maintained. In many instances, the forms are kept indefinitely on microfiche or optical disk and not just for the period of time specified by governmental regulations.

46

8 Selected Issues Inherent Conflicts Among the Four Groups with Vested Interests in Data Collection Forms There are four groups with vested interests in how data collection forms are designed: (1) investigators; (2) monitors and auditors; (3) data processors; and (4) statisticians. Their goals are overlapping, and compromises must often be reached in designing the best forms. A few examples of inherent conflicts follow. 1. Ordering the laboratory analytes on the data collection form. Investigators want the ordering of analytes to be identical to that on the form they receive from their laboratory. Data processors, however, want the order to be the same at all sites in a multicenter trial since having a different order at each site makes it more difficult to enter the data into a computer. 2. Number of laboratory analytes reported on the data collection form. This issue is similar to the previous one. The investigator prefers to see all the analyzed and reported analytes listed on the data collection form to avoid having to pick out only those requested by the sponsor from a larger list. The data processing personnel, statisticians, and clinical sponsors, on the other hand, do not want different analytes reported from each site. 3. Organizing data collection forms on a visit-by-visit basis versus grouping all data of one type in adjoining columns. Monitors find it easier to monitor data placed in adjoining columns to spot trends in abnormalities. Investigators generally prefer visit-by-visit forms, and especially dislike having to enter some data o h a visit-by-visit basis and other data from multiple visits on the same page.

Who Should Control Data Collection Form Design? Of the four major groups (i.e., the investigator, the monitor, the data processor, and the statistician) who should influence data collection form design? Ideally none should have the decisive influence. The ultimate design should be a compromise among the needs of all of these groups. Some sponsors establish a priority in favor of one particular group, but we believe that an overall discussion and compromise creates more effective data collection forms.

47

SELECTED ISSUES

Changing Data Collection Forms During a Clinical Trial Although this practice is not condoned, there are times when it is necessary. It may be needed during a clinical trial when the basic method used or endpoints measured are changed for regulatory, ethical, scientific, safety, or medical reasons. This is most likely to occur during long-term clinical trials, particularly in diseases where knowledge is evolving (e.g., AIDS) or where new information on a medicine has forced changes to occur in a protocol. Another factor that may change is the frequency with which data are collected.

Collecting Partially Completed Data Collection Forms From Clinical Trial Sites If an extremely important clinical trial is being conducted, it may not be possible to wait for all clinic visits for any given patient to be completed before part(s) of the data collection forms are collected. The process of partial form collection must be carefully thought through in advance; it may be desirable to collect certain forms (e.g., modules) from each clinic visit or the entire set of forms for specific clinic visits. Usually placing data side by side on a single form is inappropriate if partially completed forms are to be collected while the clinical trial is in progress.

Who Completes the Data Collection Forms? The form completion process can range from having all forms completed by a single person to having each form completed by a different person. It is important to identify who is completing each type of form. This could be particularly useful for answering questions, understanding the reasons for intrasite differences (i.e., the same form was filled in by a different person at two clinic visits), or intersite differences. Regulatory or sponsor auditors also might wish to evaluate these data. If certain data are filled in by inexperienced or unqualified individuals, then it is important to obtain and document that information.

Improving Designs of Data Collection Forms in the Future T o retain the most important lessons and information learned from forms that were not optimally designed, it is important to understand the rationale behind the structure of items used on each page. Reasons certain features did or did not work should be identified, as well as the reasons for leaving certain aspects intact. Although this effort would require a detailed explanation of why certain questions or formats were not useful, this information is important for facilitating interactions between investigators or monitors and the staff who are asked to make changes to the forms, and also for training others as data collection form designers.

Discussing the Completion of Data Collection Forms with Investigators and Staff Discussions among investigators and staff about the process of completing data collection forms may take place on a one-by-one basis for either a single-site or a multicenter trial. In a multicenter trial the sponsor would visit each investigator to review the process for completing forms. This may also occur at a pretrial roundtable meeting. At either time a set of completed forms could be prepared and used to illustrate the correct way of completing the forms. Incorrect form 48

SELECTED ISSUES

completion may also be shown; however, consider this approach carefully before choosing it, since incorrect methods often persist in some people’s minds, and it may be extremely difficult to break bad habits. Regardless of the approach(es) used, it is important to review the quality and correctness of the data form completion after the first one to three patients have entered a clinical trial.

Patients Who Do Not Want to Complete Relevant Data Collection Forms Many clinical trials include tests (e.g., profile of mood) that are completed by the patient. Many patients resist completing relevant data collection forms themselves but are content to answer the same questions when they are posed by others. This may be a reflection of illiteracy, which occurs with some frequency in many geographical areas. Suspicion of this problem should lead to nonthreatening questions such as, “Would you feel more comfortable if 1 read these questions to you?” Alternatives may often be found to obtain the required data, but considerations should be given to possible biases introduced by this method. It cannot be assumed that the data obtained by asking a patient to complete a form privately would be the same as the data derived from interviewing the patient.

Evaluating the Data Collection Forms After the data collection forms for a clinical trial have been finalized, and prior to actually printing and duplicating them, it is a good exercise for the designers or one of their peers to pose as a test patient and complete the forms. This exercise often exposes hidden defects in the forms. Deficiencies discovered at this time can be easily corrected before they impact on the conduct of the trial. The eight chapters in Part I provide many of the technical details and caveats necessary to consider in preparing data collection forms. A library of actual forms, prepared by 15 different organizations, is shown in Part II. Although many are not perfect, they illustrate the range of forms that may be prepared.

49

PART II

Examples of Data Collection Forms

Introduction to Part II Part II of this book is a library of data collection forms that have been used primarily within the pharmaceutical industry. Specific companies and government groups that provided forms are acknowledged at the beginning of this book. Neither the company nor the medicine being investigated is included in the forms themselves, however. These forms may be used as the starting point in developing forms for clinical researchers who do not have their own library of standardized forms. It is our hope that these researchers can find forms that require only minor modifications and can then use these to begin building their own libraries. Even researchers with access to a library of forms should find these examples useful. These forms can be used to supplement their own library, they can be modified to become additions to that library, or they can provide new ideas for incorporation into new forms for future clinical trials. The data collection forms in Part II are mainly level 1 (i.e. , general) forms. They can be modified for a specific therapeutic area or medicine (level 2) or for a specific clinical trial (level 3). Some examples of levels 2 and 3 forms are also included, but forms are not individually identified according to their level. Investigators should be able to use most of these forms for their clinical trials with only minor modifications. Even if major modifications are required, these forms can serve as models for those persons charged with designing the specific data collection forms. Many poorly designed forms exist and are widely used in large clinical trials. We have intentionally excluded examples of poorly designed forms from this book. Numerous forms present difficulties for entering and extracting data. We felt it better to include only those forms we consider to be good to excellent. On the other hand, several styles of the included forms may appear overly cumbersome or complex. These may be more appropriate for specific clinical trials; that is, although too cumbersome to be standardized forms (level 1), they are acceptable as level 3 forms.

ORGANIZATION OF PART II The data collection forms presented in Part II are partitioned into seven lettered categories: A. B. C. D. E. F. G.

Background of a Clinical Trial Physical and Other Examinations Laboratory Tests and Evaluations Adverse Events (Experiences) Medicines and Assays of Biological Levels Efficacy Patient Termination and Miscellaneous Forms

53

INTRODUCTION TO PART I I

Within each category the forms are further organized into subcategories based on the specific type of data collected. The major categories identified above and their subcategories are listed in the Contents in the front of the book. In addition, each category of Part II is headed by a detailed table of contents. A number of comments are also given in each category introduction that are specific to that type of form. There is no significance to the ordering of the forms within the individual subcategories. Some of the presented data collection forms contain two or more modules on a single form. This situation occurs commonly in data collection forms, because various modules required for collecting specific data do not require an entire page at each visit. Combining modules onto a single form, therefore, saves both space and paper. This practice of placing related modules on a single data collection form makes sense, as long as care is taken to avoid cramming too many modules onto a single page.

PAGE NUMBERING SYSTEM USED I N PART II Two numbers appear on each page in Part II of this book. One number is the sequential page number, which is a continuation of the page numbers used in Part I. The second number is the data collection form identification number, which consists of a letter followed by two numerals separated by periods. The letter and the first numeral identify the form’s category and subcategory, respectively, as listed in the contents and discussed above. The second numeral gives the order of the form within its subcategory. For example, A. 2. 1 is the first form in category A, subcategory 2; B.4.9 is the ninth form in category B, subcategory 4; and so forth. Some forms are too long to be presented on only one page. When that happens, an additional numeral has been added to the data collection form identification number to count the pages within a multipage form. Thus, if form B.3.17 were presented on two pages, those pages would be identified As B.3. 17.1 and B.3. 17.2. In a few situations where the original form occupies less than a full page, we have chosen to reproduce two or more separate forms on a single page to save space. Because different modules are often placed on one page by those preparing forms, readers are advised to consult the index of this book for a complete list of modules in an area of interest. In this case the separate forms are distinguished by lower case letters added to the form numbers. For example, A.3. l a , A. 3. l b , and A.3.1c are similar forms from different clinical investigations, reproduced here on the same page.

54

A. BACKGROUND OF A CLINICAL TRIAL Title 1. Instructions for Completing Data Collection Forms 2. Time-and-Events Schedules 3. Demographics 4. General Medical History 5. Specific Types of Medical Histories 6. Medication History 7. Inclusion and Exclusion Criteria

Form Numbers

Page Numbers

A.l.la-A.1.11

59-69

A.2.1-A.2.7.2 A.3.1a-A.3.7 A.4.1-A.4.20 A.5.1.1— A.5.36

71-78 79-85 87-108 109-151

A.6.1a-A.6.9 A.7.1a-A.7.12

153-162 163-177

GENERAL POINTERS AND COMMENTS • All instructions must be unambiguous (A.l). • Time-and-events schedules may be placed only in the protocol and not in data collection forms (A.2). • Multiple time-and-events schedules may be created for different levels of an activity (A.2). • Care must be taken to distinguish between categories of races and those of ethnic or national groups and to request data desired (A.3). • Ask patients for their birth dates rather than their ages (A.3). • Avoid collecting excessive detail on general medical history forms (A.4). • Because general medical history data are usually listed and not analyzed, it may be acceptable to use a more open than closed system (A.4). • Avoid collecting specific medical history data that have also been collected on the general medical history form (A.5). • All inclusion/exclusion criteria should be listed on the data collection form — not only the most important criteria (A.7). • Use the exact same wording for inclusion/exclusion criteria on the data collection form as is used in the protocol (A.7). • Avoid shading in a “No” box for inclusion criteria that should be answered yes, and a “Yes” box for exclusion criteria that should be answered no (A.7).

55

BACKGROUND O F A C L I N I C A L T R I A L

•

Avoid using double negatives or other awkward sentence structures in order to force the creation of criteria that have a yes answer (A. 7).

SPECIFIC POINTERS AND COMMENTS ON INDIVIDUAL FORMS A.l Instructions for Completing Data Collection Forms • Two separate forms are combined on A. 1.1. ® Instructions on A. 1.2 refer to A. 1.3. • •

Instructions given may be quite general (A. 1.1) or pertain to a specific page (A. 1.5). Instructions for adverse event forms may include an algorithm (A. 1.5).

•

Adverse event forms (Section D), sometimes called medical event forms or adverse experience forms, are often complex and require specific instructions (A. 1.4 and A. 1.6).

•

A table of contents for each visit is useful and may have check-off boxes (A. 1.7) or form numbers listed (A. 1.8). Documentation of informed consents may be included (A. 1.9). Sensitive or personal patient information, including identifications that could be used for follow-up, may be collected (A. 1.10 and A. 1.11) and stored separately from the rest of the data collection forms.

• •

A.2 Time-and-Events Schedules • • • •

A time-and-e vents form may be included for general information (A. 2.5) or it may have boxes to be checked (A. 2. 4). A dosing schedule and requests for other data may be illustrated as a schematic (A. 2.1) or in a table format (most others). Separating treatment and posttreatment periods may add focus to differences (AAA). A series of two or more schedules may describe different levels of detail (A.2.7.1 and A.2.7.2).

A.3 Demographics •

Multiple forms per page are given on A.3.1, and multiple modules per page on A.3. 2.

•

“Other” categories in a checklist should include both a line and the term “specify” to obtain data (A.3. la). Weight and height are often included in this form for convenience (A.3.1 and AAA). Aspects of medical history are often combined on the same page with demographics (e.g., history of allergies in AAA, smoking history in A.3.5, previous neurological disease in AAA).

• •

A.4 General Medical History

56

•

Multiple modules per page are shown on AAA. 1 to AAA A, A. 4.8, and AAA.

•

A general patient identifier may be used (A.4. 1).

BACKGROUND OF A CLINICAL TRIAL

• •

Data on prior clinical trial experience may be collected (A. 4. 2). Background information may be collected on various work status, insurance, economic status, and related categories (A.4.3). These data are not commonly needed.

•

Past and present history may appear on separate parts of the form (A.4.4) or combined in the same module (A. 4.6).

•

The lack of lines and connectors from the “description and date” column in A.4.4 may make it difficult to identify which row a particular response is associated with.

•

Specific diagnoses may be sought (A.4.8 and A.4.9), or the form may simply ask for descriptions of abnormalities (A.4.7).

• •

The date of onset of a problem may also be collected (A. 4.9). Recruitment data may be collected (A.4. 11).

•

Medical history may be extremely superficial (A.4. 20).

A. 5 Specific Types of Medical Histories • •

Breast cancer history may be specific (A.5. 1.1 and A.5. 1.2). Menstrual history may be simple (A.5.9), intermediate (A.5. 1.1), or detailed (A.5.8.1).

•

Obstetrical and gynecological history may be simple or detailed (A.5.8. 2 and A.5. 10) and may request information on labor and delivery (A.5.11) or exposure to chemicals (A.5. 13). • Psychiatric history is given in A.5. 15. • Epileptic history forms may be general or detailed (A.5. 16 to A.5. 19). » Cardiovascular history forms are shown on A.5. 20.1 to A.5. 26. • Pulmonary history data are collected on A.5. 27 to A.5. 29. • Infectious disease history forms are shown in A.5. 28 and A.5. 30 to A.5.34. 2. • Checklists should include all possibilities. There is no space to record exactly 0.1 ml for “penetrating wound, estimated volume injected” in A.5. 33. • A joint evaluation history is presented in A.5. 35.1 and A.5.35. 2. • A preoperative history form is shown in A.5. 36.

A.6 Medication History •

Multiple forms per page are given on A.6.1 to A.6. 3.

•

It is sometimes relevant to request specific time data on medicine (A.6.4, A.6.6.1, and A.6.6. 2). Specific medicines or classes may be specifically inquired about (A.6.5).

•

A.7 Inclusion and Exclusion Criteria • • •

Multiple forms per page are given on A.7.1. General questions are indicated in A.7.1 that may be posed at relevant visits. Form A.7.2 requires both yes and no answers for patients to be admitted, but all questions may be phrased to elicit only a single answer for eligible patients.

•

Form A.7. 4 provides data that must be examined to determine the patient’s eligibility. Form A.7.9. 1 and A.7.9. 2 dramatically indicate the only acceptable responses. Alternatively, a box may be placed around unacceptable responses. Multiple pages per form occur in A.7. 10.1 and A.7. 10.2.

• •

57

Al

INSTRUCTIONS FOR COMPLETING DATA COLLECTION FORMS

GENERAL INSTRUCTIONS FOR COMPLETING THIS CASE REPORT FORM

•

Use only black ink. Other colors will not copy correctly.

•

The principal investigator must sign and date the Summary Report form, certifying the accuracy and completeness of the data. This should be done as soon as possible after the patient has completed the study.

•

All pages must be filled out. If a question does not apply, write NA; i f a test is not done, write ND; i f the result is 0, enter 0.

•

Do not use white-out. I f an error is made, draw a single line through the error, write the correct entry in the adjacent space, and initial the correction.

•

Informed consent is required at the beginning of the study. The signed consent form must be attached to the case report form.

A.l.la

PRE-TREATMENT PROCEDURES Protocol

Inv. No.

Pt. No.

Pt. Initials (Tint. Middle. iMt)

Date o f Enrol ment Month

No

INVESTIGATOR CHECKLIST 1.

Was informed consent obtained and a copy attached t o CRF?

2.

Were laboratory tests conducted and results recorded o n pages 33 and 34?

3.

Was a skin lesion biopsy obtained for culture o f B. burgdorferi (page 8)?

4.

Was serum collected for Lyme disease serologies?

5.

Was a n 8-12 day during-therapy appointment made?

□ □ □ □

D«y

Year

Yes

I I I I I I I I I. I

A.l.lb 59

DIRECTIONS FOR COMPLETING PRENATAL EXPOSURE FOLLOW-UP QUESTIONNAIRE

INQUIRY MEDICATION 1.

Source of Information Name, specialty or type (patient, doctor, dentist, etc.), address, city, and state. Leave blank: Mfr. Control No./Contact No.

2.

Patient identification

3.

Date of birth or age

4.

Sex

5.

Weight

6.

Mother’s identification -

7.

LMP

8.

Estimated date of delivery

9.

Age of mother

10.

Age of father

11.

Outcome - Check all appropriate boxes. If a congenital anomaly or perinatal problems occurred, describe fully using attachments, if necessary.

12.

APGAR Scores at one minute and five minutes, if performed.

13.

Diagnostic studies

-

Avoid abbreviations. Indicate, if abnormal.

14.

Medication History

-

Dose, frequency (e.g. 2 tablets 3x/day tor 10 days).

15.

Pertinent family medical history

16.

Pregnancy history of mother

17.

Other comments

18.

Reason for C a e s a r e a n Section Caesarean Section in some hospitals is required after a certain time of labor, and not required for a medical problem. In other cases an infant/mother problem is the reason Caesarean was performed (e.g. toxemia, fetal distress, cephalopelvic disproportion, etc.)

19.

Void

-

-

-

Name or initials of patient, or chart number.

Note weight and indicate units, either k g or lb. Name, initials or chart number.

Date of last menstrual period for mother.

-

-

Reporting Health Professional's assessment of causality, smoking, drug, family history, etc.

Only if there was: 1. 2. 3.

60

PRODUCT/PRODUCTS REPORTED BY SOURCE

No event No patient Patient has not been o n a is unknown.

product or generic of a

20.

Signature of reporter or subsidiary representative completing the form.

21.

Date of report.

A.1.2

product where the manufacturer

PRENATAL EXPOSURE FOLLOW-UP INQUIRY MEDICATION: MFR. CONTROL NO.

CONTACT NO.

SEX

KG LB

M

------ /

/ ------

F

yrs.

yrs.

12

Normal Infant Congenital Abnormality: Describe Perinatal Problems: Describe Still Birth Elective Abortion Spontaneous Abortion Date of Death: Deceased

1 Min.:

5 Min.:

Cause: / MO

»3

DIAGNOSTIC STUDIES

(AMNIOCENTESIS. ETC )

DIAGNOSTIC PROCEDURE / TEST

14

Studies Attached DATE

RESULTS

LIST OF MATERNAL MEDICATIONS DURING OR IMMEDIATELY PRECEDING PREGNANCY.

MEDICATIQN(S)

INDICATION/CONDITIQN TREATED

ROUTE

DOSE-FREQ.

START - STOP DATES

HISTORY • FAMILY / GENETIC / PREGNANCY / TOXIC EXPOSURE

Gravida: Para: Abortions: 1B

Yes

d No

If Yes, Indicate Reason for C.S.

i9

VOID IF

20

21

SIGNATURE

Inquiry Only / N o Event N o Patient Not _____Drug

DATEOFREPORT

_________ / _________ / _________ M O _________D A Y _________Y R

PATIENT IDENTIFICATION IS KEPT I N CONFIDENCE.

A.1.3

61

INSTRUCTIONS FOR COMPLETING ADVERSE EVENTS FORM For each adverse event, please record the following: •

Description of the adverse event.

•

Frequency o f the event as single episode, intermittent, continuous.

•

Severity as mild, moderate or severe. The severity of an adverse event is a relative estimate of severity made by the clinical investigator, and is based upon a comparison with the most severe case encountered i n past training and clinical experience. The maximum severity reported during the evaluation period should b e checked.

•

Date o f onset (month/day/year).

•

Time t o onset since last dose. Indicate units of seconds, minutes, hours or days.

•

Outcome of the adverse event as resolved, improved, unchanged, worse or fatal.

•

Date o f resolution i f resolved (month/day/year)

•

I f resolved, duration of the event i f less than 24 hours. Indicate units of seconds, minutes or hours.

•

Action taken as none, drug discontinued due t o adverse event, drug dosage adjusted, drug stopped/restarted, medication required, hospitalization required or hospitalization prolonged. I f medication is required t o treat the adverse event, record specifics o n the concurrent medications page.

•

Was the event serious? (no/yes) Serious means the experience was fatal or life-threatening (see definition below), resuited i n hospitalization, prolonged an existing hospitalization, resulted i n permanent disability, is a congenital anomaly, cancer or overdose.

•

Was the event life-threatening? (no/yes) Life-threatening means the patient was in,the view of the investigator, at immediate risk of death from the reaction as i t occurred. It does not include a reaction that, had i t occurred i n a more serious form, might have caused death.

•

Causality assessment as unrelated, unlikely, possibly, probably or almost certainly related to either the study drug or the patient's original condition/other illness. Possibly related means that there is a reasonable possibility that the experience may have been caused by the drug. Any of the following types of adverse events must be reported t o the Study Monitor w i t h i n 24 hours. The ------ Study Monitor must report such events i n writing t o the Drug Surveillance Department within 24 hours. A Serious Adverse Event Form must be completed, signed by the investigator and returned t o the Study Monitor within 48 hours. The Study Monitor must provide a copy t o the Drug Surveillance Department within 24 hours. 1. death or any life-threatening event 2. any event which is permanently disabling or incapacitating 3. any event which requires hospitalization or prolongs hospitalization 4. any event which is a congenital anomaly or cancer 5. any overdose which results i n an adverse event regardless of severity.

A.1.4

62

INSTRUCTIONS FOR COMPLETING PAGE B PATIENT IDENTIFICATION:

Repeat data from previous page.

SIDE EFFECTS DURING STUDY:

NO: Check appropriate box. YES: Check appropriate box; complete rest of page as Instructed below.

SIDE EFFECTS:

List all side effects experienced by patient during the course of this study.

SEVERITY:

Record severity for each side effect listed.

DURATION:

Record duration In appropriate units of time.

STUDY DRUG RELATED:

Refer to Algorithm below.

COURSE O F SIDE EFFECT:

Indicate course, if other is checked, specify in comments section.

SYMPTOMATIC TREATMENT: Indicate and specify any symptomatic treatment.

ALGORITHM FOR ESTABLISHING CAUSAL RELATIONSHIP BETWEEN DRUG AND EVENT

Does event have p reasonable temporal association with use of the drug?

No

Causal relationship considered remote .

Yes Was there a dechallengo from the drug?

No

Is the event likely due to an existing clinical condition?

No

Causal relationship considered possible .

Yes Did the observed event abate upon dechallenge ?

No

Yes

Yes Was there a rechallenge ?

No

Could the event be due to an existing clinical condition?

N o ____>

Causal relationship considered probable .

Yes Did the reaction or event reappear upon rectwllenge ? Yes Causal relationship considered highly probable .

No

Is the event likely due to an existing clinical condition?

Causal relationship considered possible .

Yes

Causal relationship considered remote .

63

INSTRUCTIONS FOR MEDICAL EVENT FORM (MEF) GENERAL INSTRUCTIONS • If no medical event has occurred, check the No box near the top of the page and proceed to the next page. • Enter only medical events that occur after the subject has qualified for entry into the study.

DEFINITION O F A MEDICAL EVENT A medical event is any medical experience associated with the use of investigational medication (all protocolrequired medications) in humans, whether or not it is considered medication related. This includes the following: 1) all suspected adverse medication reactions; 2) all reactions from medication overdose, abuse, withdrawal, sensitivity, toxicity, or failure of a medication's expected pharmacologic actions; and 3) all other medical events such as injury, surgery, or accidents, as well as unrelated illnesses, extensions of symptomatology, or significantly abnormal clinical laboratory, physiological testing, or physical examination findings.

SPECIFIC INSTRUCTIONS A. Medical Event When a set of symptoms constitute a syndrome, list only the syndrome (eg, runny nose, sore throat, headache, fever, and aching muscles could be reported as viral illness). When no syndrome exists, each individual symptom should be reported. Be sure to include any medical events identified on the Laboratory Report form or other safety forms (eg, Physical exam, ECG, Ophthalmologic, X-ray). Date and time (using a 24-hour clock) of the first appearance of this event during Start date and time this study. The first date and time this medical event was no longer present. If the event is Stop date and time still ongoing, draw a line through the stop date; eg, Nature of event 1 = Episodic Sometimes present and sometimes not present. 2 = Constant! Present continuously from the start date to the stop date. single event 3 = Chronic Not expected to resolve and not caused b y investigational medication. (NOTE: chronic events must be reported again if there is a change in intensity and/or relationship to investigational medication) Maximum intensity Does not interfere with subject’s usual function. 1 — Mild Interferes to some extent with subject’s usual function. 2 — Moderate Interferes significantly with subject’s usual function. 3 = Severe B. Outcome to date Indicate the status of the medical event as of the date at the top of this form. Event no longer present and no residual effects observed. 0 = Recovered, no residual effects Event no longer present, but residual effects (ie, functional or physical 1 = Recovered, residual effects disability) are observed. Describe residual effects under COMMENTS. Event is still ongoing. Describe any disability due to event under COMMENTS. 2 — Continues Subject died. Details are required on the Medical Event Form - Supplemental Information 3 — Death (MEFSI) form. C. Was the event serious? A serious medical event is one that is fatal or life-threatening (i.e., subject a t immediate risk of death), is permanently disabling, requires or prolongs inpatient hospitalization, or is a congenital anomaly, cancer, or medication overdose. Also to be included is any other event the investigator judges to be serious. Severe is a measure of intensity; thus, a severe reaction is not necessarily serious. For example, nausea that persists for several hours may be considered severe, but would not be a serious medical event unless it met one of the criteria listed in the previous paragraph. If a serious medical event occurs, immediately notify by telephone the Clinical Monitor whose name appears on the cover page of y o u r protocol. Complete the MEDICAL EVENT FORM (MEF) through this question ("Was event serious”) a n d then also complete a MEDICAL EVENT FORM SUPPLEMENTAL INFORMATION (MEFSI) form.

D. Is there a reasonable possibility that the event was caused by the investigational medication? Enter the appropriate response (0 = No, 1 = Yes). E. Action taken with investigational medication because of this event 0 = None 1 = Discontinued 2 = Reduced 3 = Interrupted 4 — Increased

F.

64

Investigational medication was unchanged Investigational medication was permanently stopped (subject dropped) Dose of investigational medication was lowered Investigational medication was temporarily stopped Dose of investigational medication was increased (for withdrawal symptoms) Treatment for medical event!s) Record all treatment given for medical events on the form used to report NON-INVESTIGATIONAL MEDICATION. Enter medical event as the Reason for Use of Medication. A.1.6

SCREEN CHECKLIST Check when completed Admission Criteria Informed Consent (Place in record) Pregnancy Waiver (If Applicable; place in record) Medical History Seizure History Physical Exam Neurological Exam Vital Signs ECG EEG (Attach copy of interpretation) Laboratory: Hematology Blood Chemistry Urinalysis

use integrated forms

Pregnancy Test (If Applicable) AED Plasma Levels Pill Count Side Effects Dosage Record Seizure Record

use integrated forms

Additional Tests Performed (If Any) AED Doses RX Neurologists Comment Log (Optional) Form to Central Reviewer Patients Given their General Instructions Form

65

PROTOCOL 0 1 9 BASELINE SECTION

This section SF1901 -

t o be performed w i t h i n

1 4 days p r i o r

to entry.

SCREENING

F F 0 1 0 0 - TEAR OFF SHEET SF1905 - BASELINE EVALUATION FF0504 - MICRO-NEURO DEMOGRAPHICS

[Required for a l l

F F 0 5 0 5 - MICRO-NEURO HISTORY AND E X M

patients at baseline]

[ R e q u i r e d for a l l

patients at baseline]

FF0801 - HEMATOLOGY H g b , WBC w / d l f f e r e n t l a i , p l a t e l e t s , MCV FF0802 - URINALYSIS [ M i c r o s c o p i c n o t r e q u i r e d ] FF0803 - CHEMISTRY/LFT'S Serum C r e a t i n i n e ,

T. Bilirubin,

SGPT

FF0902 - H I V VIRUS L A B , SEROLOGY HIV ELISA FF0903 - H I V VIRUS L A B , P 2 4 ANTIBODY FF1001 -

IMMUNOLOGIC STUDIES, LYMPHOCYTE SUBSETS

F F 3 0 0 0 - VIROLOGY CULTURE/D I RECT P 2 4 ASSAY SPECIMEN P24 Antigen S F 1 9 0 9 - SERUM

LEVEL

Optional

patient

forms for

subset

Identified

for

HIV cultures

a n d serum B 1 2

F F 0 8 0 4 - OTHER CHEMISTRIES Serum B 1 2 FF3000 - VIROLOGY CULTURE/D I RECT P 2 4 ASSAY SPECIMEN HIV Culture

* S F 1 9 0 4 - STUDY DRUG TERMINATION FORM * F F 2 5 0 0 - PO DRUG DISPENSING RECORD F F 1 6 0 0 - OFF STUDY ***SF1909 -

LEVELS ( 3 )

*These forms a r e l o c a t e d I n t h e s e c t i o n l a b e l e d " M e d i c a t i o n " T h i s f o r m i s l o c a t e d I n t h e s e c t i o n l a b e l e d "Wrap-up" These a d d i t i o n a l forms a r e l o c a t e d I n t h e s e c t i o n l a b e l e d "Pharmacokinetics"

66

A.1.8

INFORMED CONSENT COMPLETE THIS FORM FOR EACH PATIENT. ATTACH A COPY OF THE SIGNED INFORMED CONSENT DOCUMENT.

Patient Initials Middle

First

Date Patient Signed Consent

/

I Mo

Last

Day

Yr

The above patient (or legally authorized representative of the Patient) on the above date signed an informed consent document that: (1)

(2)

Conforms to and was obtained in accordance with the applicable FDA requirements which include requirement for prior IRB approval of the consent document used (e.g., 21 CRF §50.20 through §50.27, Informed Consent of Human Subjects); and Contains the informed consent information supplied by in the study protocol or otherwise in conformance with the applicable instructions received from

/ Physician Investigator's Signature

Mo

/ ____ Yr Day

A.1.9

67

S E N S I T I V E DATA — PLACE I N SECURE AREA

FOLLOW-UP FORM 1 — TEAR OFF SHEET

Patient

ID Center

Pat lent

Check

No. Pat ient

Name

Patient

Address

__________

Digit

________________

City

State

Phone Number :

Study

(

Z i p Code

) -

ID: Protocol No.

Drug No.

Check Digit

S u b u n i t Code:

S E N S I T I V E DATA — TEAR OFF AND PLACE I N SECURE AREA

Protocol No. : Subject Initials:

Subject No.:

CONFIDENTIAL SUBJECT FOLLOW-UP INVESTIGATOR Name Address

City

State

Zip Code

City

State

Zip Code

State

Zip Code

Telephone Number

INSTITUTION Name of Institution Address Telephone Number

SUBJECT IDENTIFICATION Parent or Guardian

Subject's Full Name Address Telephone Number

City Sex

Social Security Number

Birthdate (M/D/Y)

Hospital Number

PERSON TO BE NOTIFIED IN AN EMERGENCY OR IF ABOVE CANNOT BE LOCATED Relationship

Full Name Address

City

State

Zip Code

Telephone Number

Data

Sifnaturt i Initials

A.1.11

69

A 2 TIME-AND-EVENTS SCHEDULES

Inv. No.

Protocol No.

Subject’s Initials

Subject No.

Date

Month

(First, Middle, Last)

Day

Year

STUDY SCHEDULE: TREATMENT PERIOD 1 Study Day One Insert Catheter Report to site 10pm

6am

B r e a k '

an s t Sam

L u n £

D i n "

e r

Noon

4pm

8pm

B r e a k f a s 7am t 8am

6am

12

4am

6am

M

BS

Study Day Two

4am

AEI

AEI

M AEI

12

D

L u n c h

j

n n e r

III I I I I I M AEI

8pm

4pm

Noon

I I

I III I l l i

I I I Illi

I

AEI

AEI

M

BS

BS

Study Day Three

B r e a k f a s 7am t 8am

M

D

L u n c h

n n

e r 4pm

Noon

8pm

12

4am

Sam

AEI

AEI

M BS BS BS BS BS BS BS BS BS BS BS BS BS BS BS BS BS BS BS BS BS BS BS BS BS

M = Medication BS = Blood Sample AEI = Adverse Event Interview: “How do you feel”? All adverse events must be recorded in adverse event section .

A.2.1

71

STUDY SCHEDULE

Patient's Initials

Visit

____________J

Patient N o l_______I ______I ______|

Initial

Screening Period

1

2

3

4

5

6

7

Follow-up

0

7-14

14*2

14*2

14*2

14*2

14*2

14*2

14*2

7-10

Date Days F r o m Previous Visit

REMINDER. OBTAIN THE FOLLOWING DATA— SEE CASE REPORT FORM FOR DETAILS Tests

Initial

Screening Period

1

2

3

4

5

6

7

Follow-up "if necessary)

HISTORY

•

PHYSICAL

0

•

CHEMISTRIES

•

•

•

HEMATOLOGY

•

•

•

URINALYSIS

•

•

•

CHEST X-RAY

• a

ECG (12-LEAD)

•

•

BASELINE PET

•

•

•

•

•

VITAL SIGNS

•

•

•

•

•

REVERSIBILITY

• b

PFT-

•

•

•

•

STUDY DRUG

•

•

•

•

•

•

•

•

•

•

•

DIARY CARDS ISSUED

•

PEAK FLOW METER ISSUED

•

DRUG RECONCILIATION

«

—To b e done

* At specified times

a —If not performed within previous 12 months b —See directions o n back of page 4

A.2.2

72

©

•

•

•

•

•

•

•

STUDY SCHEDULE Treatment

Activity

Day 1 (Baseline)

Post-Treatment

Day 8 (Visit 2)

Day 15 (Visit 3)

Day 29 (Visit 4)

Medical History

•

Physical Examination

•

Pregnancy Test

0

Clinical Assessment

•

•

•

•

Direct Microscopic Examination

•

•

e

o

•

•

e

Efficacy Evaluations Fungal Culture

•

Fungal Identification

•

Drug Dispensed

•

• •

Drug Returned • o

•

To be done If applicable

A.2.3

73

Compd. # DO IND #

STUDY EVENTS SCHEDULE

Pro). # NDA #

NOT

Dosing Period 1

FILL Protocol #

Study #

IN

Exam Date: _ _ _/ _ _ _/ _ _ _ M D Y

-14 to -10

Theoretical Clock Time Completed (24-hour clock) (x/)

...

-1

0 .5 1

— ...... ____

2

3

—

4

8

—

10

— —

12 24

If volunteer does not complete the study:

74

□ □ □ □ □ □ □ □ □ □ □ □ □ □ □ □ □ □ □ □ □ □ □ □ □ □ □ □ □

□□□□□□□

Study Hour

Vol. Init: ____________ F M L

a

Vol. #:

Dept.

Sec.

Event Clinical Laboratory Analysis (Drug Urine Screen Only) Physical Exam./Body Weight (exclude genitourinary and rectal systems) Vital Signs Abbreviated Neurological Examination Snack Admission Criteria/Concomitant Meds Clinical Laboratory Analysis (hematology, clinical chem., and urinalysis) Vital Signs EKG (12 Lead) Adverse Experiences Checklist Profile of Mood States Give 6 capsules of Investigational Drug prescribed for this Dosing Period. Vital Signs Vital Signs Adverse Experience Checklist Vital Signs EKG (lead II) Adverse Experiences Checklist Vital Signs Vital Signs Adverse Experiences Checklist Profile of Mood States Lunch Vital Signs Adverse Experiences Checklist Profile of Mood States Dinner Vital Signs Adverse Experiences Checklist Clinical Laboratory Analysis (hematology, clinical chem., and urinalysis) Physical Exam/Body Weight (exclude genitourinary and rectal systems) Vital Signs EKG (12 Lead) Abbreviated Neurological Exam Adverse Experiences Checklist Profile of Mood States

Complete Study Discontinuation Record

A.2.4

Schedule of Evaluations (Revised Protocol) 6 4 68 7 2 7 6 8 0 8 4 8 8 92 9 6 100 104

56

60

Brief Symptoms (Follow-up Form 29)

X

X

X

X

X

X

X

X

X

X

X

X

X

Vital Signs (Follow-up Form 7-Section 1)

X

X

X

X

X

X

X

X

X

X

X

X

X

Follow-up Status Report (Study Form 2)

X

X

X

X

X

X

X

X

X

X

X

X

X

Follow-up Medication History (Study Form 3)

X

X

X

X

X

X

X

X

X

X

X

X

X

DAYS:

Brief Physical Exam (Follow-up Form 7-Section 6)

X

X

Micro-Neuro History & Exam (Follow-up Form 5-Section 5)

X

X

X

X

X

Toxicity Report (Follow-up Form 28)

X

X

X

X

X

X

X

X

X

X

X

X

X

Hematology (Follow-up Form 8-Section 1)

X

X

X

X

X

X

X

X

X

X

X

X

X

Chemistries/BUN, Creatinine/ Liver Function Tests (Follow-up Form 8-Section 3)

X

X

X

X

X

X

X

X

X

X

X

X

X

Other Chemistries/CPK (Follow-up Form 8-Section 4)

X

X

X

X

X

X

X

X

X

X

X

X

X

Chest X-ray (Follow-up Form 8-Section 8)

X

HIV Virus Lab/P24 Antibody (Follow-up Form 10-Section 1)

X

X

X

X

Immunologic Studies (Follow-up Form 10-Section 1)

X

X

X

X

Merieux Skin Tests (Follow-up Form 11)

X

X

X

X

X X

X X

X X

HIV Culture P24 Antigen (Follow-up Form 30) Levels of _________ (Study Form 9)

X

A.2.5

X

75

76

X

X

|

X X

X

X

X

X X

CM X

V*

in X X X X

X X

X X

X X X

X X

X

XXX X X

X

X X X X

X

Snacks are allowed after the 1 0 hour meat.

co X

to b e determined i n dosing Periods 4-9 only.

X

X

b

Dinner

O vX

a

X

X

Lunch

X

Juice permitted

X (12 lead)

X

Discontinuation Record

j

co

Snack

XXX

Meals b _____________

Abbrev.

XX

Profile of Mood States

X

X

Adverse Experiences Checklist

X

X

a

Complete

X

X(12lead)

X

Plasma Drug Samp'e

X

I X (lei

X

Laboratory Tests: Hematology Clinical Chem. Urinalysis Urine Screen

X

X(12iead)

xr

X (12 lead)

co

EKG

CM

Ophthalmological Exam

Abbrev.

£

Complete

Q.

Neurological Exam.

xr CM

Vital Signs

o

Physical Exam (& wt.) ___________________

o

Dose of Drug

g ® u cn Q co CO CD

Informed Consent

-14 t o -10 T

Admission Criteria

Event ___________

Dosing Period (hrs.)

□i 5 X

X

X

X X X

V-

X

o

(S|

o

(SI

o

X X X X X

X

X

X

JO X

X X

X

X X

X

JO

X

X X X

X

X

X

X

X

X X

X X X

X X X

_Q X X

X

X X

X X X

X X X

X X

m

X X

X X X

X X X

_Q X

X X

co

X X

LL

un

X

X X

X X X

X X X

X

A.2.7.1

Posttreatment Phased

X

X

X

Adverse Experience Assessment a Volunteers will be screened as outpatients within 2 weeks prior t o the start of the Treatment Phase. b Volunteers will be admitted t o the treatment unit by 1300 hours on Day 0. Volunteers will fast from midnight on Day Oto 1300 hours o n Day 1 (Treatments A, C, and E only), d Posttreatment Phase assessments will be performed after completion of Dosing Period 4.

(V)

Blood Collection for Assay

X

ECG-lnterval Rhythm i Strip

DAY

Dosing Period 4

X

I ECG Telemetry

(SI

X

I Compliance Interview ICTM Administration

DAY

Dosing Period 3

o

X

| Hematology

DAY

Dosing Period 2

(SI

X

I Urinalysis | Unit Admission

DAY

Dosing Period 1

X

1Vita! Signs 1Urine Drug Screen I Serum Chemistry

I Informed Consent X

I Inclusion/ Exclusion I | Medical History | Physical Examination 112-lead ECG

Screening/ Baseline Phase®

X

1

Event

Treatment Phase

TABLE 2: OVERALL SCHEDULE OF TIME AND EVENTS

X X

2.00 2.50 3.00

1000 1030 1100 1200

12.00 13.00 16.00

1800 2000 2100 2400

Vital Signs

X X X X X X X

ECGInterval Rhythm Strips Blood Collection

Mealsb

a

“D X X X X X X X X X X X X

X X X X X X X

— X

X

o o

Z'L'Z'N

For PR, QRS a n d QT i n t e r v a l measurement. b B = breakfast, L = lunch, D - d i n n e r a n d S = snack. c T r e a t m e n t Groups B, D , a n d F o n l y . d B l o o d sample w i l l b e d r a w n i m m e d i a t e l y p r i o r t o a d m i n i s t r a t i o n o f CTM e Lunch served 5 h o u r s post-dose a t a p p r o x i m a t e l y 1300 hours.

00

o o o

1600

1400

1.50

0930

o o

1300

1.00

0830

-0.25

CTM ECG A d m i n i s t r a t i o n Telemetry

X

OOS

a

-1.00

0745

0730

0700

o o 00 o o o

0060

r—

o LD O OSO

Day

Study Time (hours)

co

00 0

78 Clock Time (hours)

TABLE 3 : TIMETABLE OF MEASUREMENTS A N D ACTIVITIES FOR STUDY DAYS 1-3 OF EACH DOSING PERIOD

X

X

I ( 2 5 - 2 6 ) I Type o f B i o p s y : II I I I II I II II 1 I I 3 = Excisional I 1 = Needle (tru-cut) -----1-----1 Y r s . I 1-----1-----1 1-----1-----1 1-----1-----1 1 -------1 I 2 = Needle Aspiration 4 = Incisional YR DAY MO I (46) I D a t e o f Mastectomy I i ------1-------1 -i------1 IMaximum C l i n i c a l I -, ------,-------, , -------, ------, , -------, ------, I I II I I I Tumor S i z e (cm) I I II I II I II I .-------1-------> -, ------1------. -i------1-------1 ( 2 7 - 3 2 ) I ( f r o m mammogram, i f d o n e ) 1------1------- -------‘ ( 4 7 - 4 9 ) 1 ( 5 0 ) -i------i l I M i c r o s c o p i c Tumor I Date of Axillary Dissection | ,-------,-------, !-------,-------, ,-------,-------, -' ------' I I Diagnosis: ( 5 1 - 5 2 ) -.’ ------: ------: ! I I No. o f Nodes H i s t o l o g i c a l l y P o s i t i v e L.... .... .•.. 1 I -I ------> I I I Proposed Date of First Treatment | -, ------!-------, -, ------,-------, -, ------, ------, | I I I Type of Mastectomy I I I II I II I I I 1 = Lumpectomy + A.D. 1-------1 ( 3 9 ) I 1 -------1------1 1........1...- ...1 .... u -..... 1 ( 5 3 - 5 8 ) l I 2 = Modified Radical I I APPROVED I I IER/PR LAB I I I ll(fmol) I I I I l(fmol) I 1 , I -J- - 1 I - ‘ — ' 1 ( 6 3 - 6 6 ) '........1 ‘ I ( 5 9 - 6 2 ) L-1 -i------1-------.-------1 -> ------1 I B . S . A . -i------1-------1-------1 -f ------1 (WEIGHT (HEIGHT I! I I I I I I I I I I I I I (kg) I I I I I I (cm) 1 -------'-------'------- -------' 1 ( 7 5 - 7 7 ) 1------ ------- u- ----’ I ' ■ - .... ‘. .. .. -------' 1 ( 7 1 - 7 4 ) 1(67-70) ( 7 8 - 8 2 ) i ------1-------1-------1-------1------->1 IM.D. R e s p o n s i b l e f o r C h e m o t h e r a p y

(83-87) r

IM. I). R e s p o n s i b l e f o r F o l l o w - U p

I I I -: ------: I I I I I I I I |

The a s s i g n e d t r e a t m e n t a n d d r u g d o s a g e s w i l l be p r o v i d e d t o you by t h e Randomization Office at the time of randomization: A s s i g n e d T r e a t m e n t ( W r i t e c o d e number i n box a n d r e c o r d d r u g d o s a g e s b e l o w . )

(88) 1 = S t a n d a r d AC T h e r a p y 2 = Cyclophosphamide Intensification 3 = Cyclophosphamide Intensification

I ADRIAMYCIN I |

|

a n d I n c r e a s e d T o t a l Dose

. |

I mg. e v e r y 21 d a y s f o r 4 c y c l e s I I I !-------i-------1-------1 ( 8 9 - 9 1 ) ,-------,-------,-------,-------,

I I I I I CYCLOPHOSPHAMIDE I 1 ------J-------'------J -------‘ I i-------1-------1 I I I I I TAMOXIFEN ( i f a g e 50+) i _________________ ______________'■■ ■ ' .... ‘

cycles mg. e v e r y 2 1 d a y s f o r (92-95) mg., b.i.d. for 5 years beginning on Day 1 o f C y c l e 1 ( 9 6 - 9 7 ) _______________________

A.5.2

111

STUDY NUMBER Yes

No

1

2D

Has the patient signed the consent form? (98)

1

2

Is the patient pregnant?

iC

20

Tumor fixed to chest wall, pectoral muscle, or skin on clinical examination?

lD

2D

Any clinical indication of skin edema, ulceration, erythema, skin infiltration, or peau d’orange of the ipsilateral breast? Any clinical indication of satellite nodules on the skin around the tumor? • If yes, microscopic tumor diagnosis of the nodules

Yes PHYSICAL EXAM

2D

1

,

(99-111)

Ipsilateral axillary nodes palpable?

No (119-127)

PATIENT HISTORY, CONT.

Has the patient received any therapy for this breast cancer?

1

20

1

2 D Is the patient receiving any hormonal therapy?

1

2D

1

20

iD

2D

• If yes, will these be discontinued while patient is on protocol (until first recurrence)?

lD

2D

Any non-malignant systemic disease which would contra-indicate any of the protocol therapies?

I I

• If yes, will this be discontinued while patient is on protocol (until first recurrence)? Is the patient taking birth control pills?

specify:

lD

20

Any non-malignant systemic disease which would interfere with long-term follow-up?

lD

20

Psychiatric or addictive disorder which would preclude obtaining informed consent?

1

2D

lD

20

10

20

Any edema of the arm?

PRE-ENTRY STUDIES

1

20

Mass in opposite breast? • If yes, microscopic tumor diagnosis of the mass:

20

Any palpable nodes in the supraclavicular or infraclavicular area or in the opposite axilla? • If yes, microscopic diagnosis of these nodules:

Diastolic blood pressure (Must be 100 or less) (128-130) (131) Chest X-RAY REPORT 1 — Negative for metastasis 2 — Suspicious for metastasis 3 — Positive for metastasis

20

_

1

• If yes, were they movable in relation to the chest wall and nerves? • Is the largest axillary node larger than 2.0 cm?

PATIENT HISTORY

(112-118)

Has the patient had: 1

2D

• A myocardial infarction?

1

2D

• Congestive heart failure? Does the patient have:

1

20

• Angina pectoris which requires anti-anginal medication?

1

2D

• Cardiac valvular disease with documented cardiac function compromise?

lD

2D

Has the patient had a radiological oophorectomy?

1

2D

Has the patient had any other malignancies? • If yes, specify: (The only acceptable cancers are: squamous or basal cell carcinoma of the skin which has been effectively treated and carcinoma in situ of the cervix treated operatively only).

|—1 I—I

IF ADRIAMYCIN/CYCLOPHOSPHAMIDE PROTOCOL PACKS ARE TO BE ORDERED FROM SECTION AND REPORT AT RANDOMIZATION:

Chest X-RAY REPORT

(132)

1 — No cardiomegaly 2 — Cardiomegaly (133) EKG REPORT 1 — No cardiomegaly 2 — Ventricular hypertrophy (134) BONE SCAN REPORT 1 — Negative for metastasis 2 — Suspicious for metastasis 3 — Positive for metastasis WBC (X1000) [4.0 or more]

(135-137)

Platelets (x1000) [100 or more]

(138-140)

Bilirubin (mg°/o) [1.5 or less]

(141-143)

SGOT (I.U./ml) [60 or less]

(144-146)

SERUM CREATININE (mg%) [1.5 or less]

(147-148)

VIA NSABP, COMPLETE THE FOLLOWING

PARTY RESPONSIBLE FOR DRUG PAYMENT/DISTRIBUTION ACCT #:

NAME:

__

ADDRESS: TELEPHONE:

112

A.5.3

HABITS

Average Daily Consumption (Weekly total divided by seven) 0 = None L = Less than one 1,2,3, etc = whole numbers ONLY

Smoking Number of years (past or current) patient has smoked Does the patient currently smoke?.............................................................

1 = Yes 2 = No

If yes, enter average daily consumption Number of cigarettes Number of cigars Number of pipesful Alcohol Does the patient currently consume alcohol?

1 = Yes 2 = No

If yes, enter average daily consumption Number of 12 oz beers or wine coolers

.

Number of 4 - 6 oz glasses of wine Number of ounces of distilled spirits Caffeinated Beverages Does the patient currently consume caffeinated beverages?

1 = Yes 2 = No

If yes, enter average daily consumption Number of 8 oz cups of coffee Number of 8 oz cups of tea Number of 12 oz colas

A.5.4

113

■

Clinical Report Form Drug Identification Indication

Visit ? Page 1 of ?

ADMISSION RECORD OF EVENTS List all current signs, symptoms, and acute illnesses, other than which are EXPECTED T O ABATE during this study If none, enter a n "X" here Describe event concisely. Use cosTART term to classify. Event number will be used as the Indication For Use (IFU) for drugs listed o n the Current Drug Therapy page. Event

1

-------------------------------------------------------------------------------------------------------------...

__

CLASS FICA"PION Term ----------------------------------------------------------------------------------------------------Diagnos is D a g

. , ______ / ______/ ______ Mo Day Yr

Severity

1 = Mild 2 = Moderate 3 = Severe

Event

2

CLASSIFICA1PION T e r m _______________________________________________________________ Diagnos is Dat e

, , ______ / ______/ ______ Mo Day Yr

Severity

1 = Mild 2 = Moderate 3 = Severe

Event

3

________________________________________________________________________

CLASSIFICATION T e r m Diagnosis Date

/ Mo

/ Day}

Severity Yr

1 = Mild _ .. , 2 = Moderate 3 = Severe

Event

4

-------------------------------------------------------------------------------------------------------------------------

CLASSIFICATION T e r m Diagnosis Date

I Mo

I Day

Severity

1 = Mild

Yr 2 = Moderate

___________________________________________

A.5.5 114

3 = Severe

Clinical Report Form Drug Identification Indication Visit ? Page 1 of

7

CHRONIC ILLNESSES List all other illnesses, other than which are EXPECTED TO CONTINUE for the duration of the study

,

If none, enter an "X" here

Illness 70

_______ _

_______________________________________________________

CLASSIFICATION Term Diagnosis Date

i Mo

I Day

Severity 1 = Mild Yr 2 = Moderate 3 = Severe

Illness 71

___________ _ _ ___________________________________________________

CLASSIFICATION Term Diagnosis Date

/ Mo

/ Day

Severity 1 = Mild Yr 2 = Moderate 3 = Severe

Illness 72

___________

_ _ _— ----------------------------------------------------------------------------

CLASSIFICATION Term Diagnosis Date

________

/ Mo

/ Day

Severity 1 = Mild Yr 2 = Moderate 3 = Severe

Illness 73

_______.— _ —

-------------------------------------------------------------------------------—

CLASSIFICATION Term ---------------------------------------------------------------------------------------------Diagnosis Date Mo

/----------! --------Day Yr

Severity 1 = Mild 2 = Moderate 3 = Severe

A.5.6

115

Clinical Report Form Drug Identification Indication

Visit ? Page 1 of ?

SIGNIFICANT HISTORICAL DIAGNOSES List all clinically significant historical diagnoses that are N O LONGER PRESENT. If none, enter an ’’X" here If the patient's record contains a significant surgery, list the surgery as the diagnosis, "surgical procedure" as the classification term, and surgery date as date recovered. List each episode of a significant illness separately.

Diagnosis -----------------------------------------------------------------------------------------------------------------------CLASSIFICATION Term Date Recovered ----------! ----------1----------

Yr

Day

Mo

Diagnosis CLASSIFICATION Term I

/

Date Recovered

Yr

Day

Mo

Diagnosis CLASSIFICATION Term /

/

Date Recovered

Mo

Day

Yr

Diagnosis __________________________________________________________________ _____ CLASSIFICATION Term Date Recovered ----------1----------1----------

Mo

116

Day

Yr

A.5.7

Protocol No. Subject Initials:! Date of Visit:

I

/ Month

1

|

Subject No.:|

I

Investigator’s No.:|

|

|

|

Admission

' ------Day

| Page

Year

DATE OF BIRTH Month

2

I

ETHNIC GROUP

Dav

D 1 WHITE

Year

0 2 BLACK

D 3 ORIENTAL

O 4 OTHER _______________

3

DOES SUBJECT SMOKE?

1 . NO

O 2 YES. NUMBER OF CIGARETTES/ DAY

MENSTRUAL HISTORY 4

AGE AT MENARCHE

5 NUMBER OF DAYS I N CYCLE (RANGE!

TO

DAYS

6 NUMBER OF FLOW DAYS (RANGE!

TO

DAYS

7 AMOUNT OF FLOW

1. LIGHT

0 2. AVERAGE

( 1 2 padt /day I

3. HEAVY

(3-4 padi/dayl

0 4. VARIABLE

(B* padi/day)

MENSTRUAL PROBLEMS - INDICATE FREQUENCY* AND SEVERITY 8

DYSMENORRHEA ■ FREQUENCY

9

DYSMENORRHEA • SEVERITY

10 PREMENSTRUAL TENSION • FREQUENCY

1. NEVER □ 1 NONE 1. NEVER 0 1 . NONE

2. SOMETIMES 0 2. MILD 0 2. SOMETIMES 0 2 MILD

0 3. OFTEN 3 MODERATE 0 3. OFTEN 3 MODERATE

11

PREMENSTRUAL TENSION • SEVERITY

12

AMENORRHEA

1. NEVER

2.S0METIMES

O 3. OFTEN

13

OLIGOMENORRHEA

1. NEVER

2.S0METIMES

1 OFTEN

14 HYPERMENORRHEA

1. NEVER

0 2.S0METIMES

D 3. OFTEN

15 BREAKTHROUGH BLEEDING

1. NEVER

0 2. SOMETIMES

O 3. OFTEN

04

ALWAYS

04

SEVERE

D 4 ALWAYS 0 4 SEVERE

• SOMETIMES ■ LESS THAN 50% OF THE TIME OFTEN - GREATER THAN 50% OF THE TIME DATE

INVEST IGATQA SIGNATURE

A.5.8.1

117

Protocol No. Subject No.:

Subject Initials:

Investigator’s No.:

Date of Visit:--------/--------/ ------Month Day Year

Admission

Page

O B / G Y N HISTORY

16

TOTAL NUMBER OF PREGNANCIES

17

NUMBER OF DELIVERIES

18

NUMBER OF ABORTIONS

19

NUMBER STILLBORN

20

NUMBER OF CHILDREN WITH DEFORMITIES

Describe

NUMBER OF CHILDREN OVER 9 LB. AT BIRTH

Specify weightlt)

21 22 23

If ”0" Skip to Question 26

Induced

NAUSEA AND VOMITING WITH PREGNANCY

1.NONE

Spontaneout

D 2. SLIGHT

Ectopic

3. MODERATE

4. SEVERE

DATE FIRST PREGNANCY TERMINATED llricluPe Delivery)

24

DATE LAST PREGNANCY TERMINATED IlncluOe Delivery!

25

HISTORY OF CERVICAL/VAGlNAL DISORDERS

Month

Da

Year

Month

Da

Year

2. YES

D1.NO

If YES. Check All That Apply

CERVICITIS

HERPES SIMPLEX VIRUS-II

CANDIDA

CERVICAL EROSION

TRICHOMONAS

HEMOPHILUS

N. GONORRHEA

OTHER BACTERIAL VAGINITIS OTH ER ____________ _______________________________ ____

26

MOST RECENT HORMONAL CONTRACEPTIVE

1 . NONE. SKIP TO PAGE 3 2. PRODUCT (Brand end Dote)

IF YES DURATION OF THERAPY (MontM

DATE OF LAST ACTIVE PiU Month Dev DISCONTINUATION DUE TO MEDICALLY RELATED REASON? SPOTTING

Year Di. NO

2. YES

O WEIGHT GAIN

I F YES. REASON DISCONTINUED „ BREAKTHROUGH BLEEDING

(CHECK A L L THAT APPLY)

HEADACHES

HYPERTENSION

AMENORRHEA

NAUSEA

OTHER INVESTIGATOR SIGNATURE

118

NERVOUSNESS

___

.......................................................

foATE

A.5.8.2

PATIENT NUMBER:

MENOPAUSAL STATUS Page 1 of 1

month

FRAME SIZE:

day

FIRST 3 LETTERS OF LAST NAME:

year

.......................................................................................................................................

month DATE OF LAST MENSTRUAL PERIOD: MENOPAUSE:

....................

year

I I I I I I

1 . Natural (If < 5 Years, Indicate FSH and LH Levels): FSH

I i I I mIU/ml

LH

Illi

mIU/ml

2. Surgical 3. Radiation 4. Other: ____________________ _ (Specify)

A.5.9

119

Form 2 Maternal History Patient Initials

Date Enrolled

Patient Study #

Mo /

Day

/ Yr

Protocol

F

M

L

Location

Study Center #

Mother's Age

Gravida

Para:

Marital Status

Abortions:

Q [3 ["I Cervical Swabs for HSV:

None

Date of Swab M o / Day / Yr

HSV+

Married Divorced Single______ None

Oral Swabs for HSV: Date of Swab M o / Day / Yr

HSV-

HSV+

HSV-

I 1 1 Maternal VD History:

Prior To This Pregnancy:

No Maternal History Herpes Labials Genital Herpes Intra-Oral Herpes

Check If Not Present

□ □ □

D

Gonorrhea

If Present, Date of last occurrence Mo / Yr

During This Pregnancy:

Check If Present, Date of Last If Not Number of Occurrence Present Occurrences Month/ Day/ Year

||||~ Illi IIII

L L..I. 1 1

r~r..i i “i

Syphilis Present Pregnancy Normal

No Yes Not Present

If No, please describe below:

Present, Not Herpes Related

Present, Herpes Related

Present, Cause Unknown

Presence Unknown

Date of Occurrence M o / Day / Yr

1 1 1 1 1 1

Fever Genital pain Genital vesicles Genital ulcer Positive cytology for HSV Lymphadenopathy

Does sexual partner have a history of Genital Herpes?

Yes Possibly No Could Not Determine

120

A.5.10

p H I M A R Y

R E c U R R E N T

Form 3 Labor and Delivery Date Enrolled Patient Initials

Patient Study # Protocol

F

M

L

Study Center#

Apgar Score

Head

Birth Date M o / Day ' Yr

Birth Weight

Location

Circumference 1 min. lbs. OR

in. OR cm

grams Gestational Age

5 min.

Dubowitz Fetal Scalp Monitor Used?

weeks

|

||

Yes No Do Not Know

weeks

Labor and Delivery Normal? Yes

If No, please describe below:

No Yes

Do Not Know

No

Traumatic Delivery Meconium Staining Prolonged Labor Multiple Birth Resuscitation at Birth Breech Delivery Maternal HSV Lesions At Delivery Caesarean Section Reason for C-Section, if performed Herpes Prolonged Labor Abnormal Presentation Q

Duration of Ruptured Membrane:

Prolapsed Cord Prior C-Section Other:

|

Specify

Yes

I

mm.

Estimated Duration of Labor: |

Breast Feeding:

hrs

.

|

| hrs.

|

|

| mm.

No

Baby Normal A t Birth? Yes No

If No, please describe below: Yes Microcephaly Purpura Skin Vesicles Intrauterine Growth Retardation Positive Eye Findings: Describe Other:

No

Do Not Know

O

Specify

A.5.11

121

Form 4 Patient's History Date Enrolled Patient | Initials F

M

Patient Study r | #

Protocol

L

Symptom

Study Center#

Location

Is Symptom Due to

Check if

Duration (Days) of

Herpes’

Symptom Is

Symptom if Present Prior

Present a t

To Study But Not Present At Enrollment into Study

Date of Onset Yes

No

Enrollment

Skin Vesicles

Lethargy

Fever

Conjunctivitis

Seizures

Disseminated Intravascular Coagulation

Pneumonia

Other: Other:

Please estimate Time of

| |

No

Onset of Herpetic Disease

I I

Yes

relative t o Birth:

EZU Do Not Know

| |

Did patient require respiratory assistance’

Present at birth

1 1

< 2 4 hours after birth

□

1-2 days after birth

□ I I

Did patient require respirator’

| |

No

3-5 days after birth

I I O

Yes Yes, positive end expiratory pressure (PEEP)

> 5 days after birth

□

Did not know

Date patient first placed on respirator. Month/ Day/ Year

IIIIIII 122

A.5.12

Duration (days) on respirator:

LU

Page

Cm od # / N a m e

Proj #

NDA *

EXPOSURE TO DURING PREGNANCY

Protocol #

Inv. A

NOTE: Please use BLACK i n k .

Pt. A

HISTORY OF THIS PREGNANCY (CONT.) Occupational Exposure Occupation:

Job title

Industry

Partner's job title

Industry

During the 6 months prior to conception throughout the pregnancy was this patient exposed to any of the following ? YES*

(/)

Dates of Exposure (M/D/Y) First Exposure

Last Exposure

NO (✓)

UNKNOWN (/)

Radiation Benzene Petrochemicals Insecticides Anesthetic Gases Other (specify)

•Describe in detail below. Com m en ts _______________________ __________________________________ _____________________________

A.5.13

123

PATIENT HISTORY Inv. No.

Protocol

Pt. Initials

Pt. No.

(f test. M»ddle. Last)

Enrollment Date

|

j Month

| O«y

| Ve*r

Medical Record N o . : (optional)

BACKGROUND INFORMATION Date o f Birth

|

| Month

Sex:

Weight Day

Z J Male

Race:

Z ) Female Age:

|

|

|

|

| lbs

Height

ins.

Year

| years

EZI White E U Black

Z ] American I n d i a n

O Hispanic

Z ) Other

FERTILITY (Female patients only) Yes Does the patient have childbearing potential? I f N O , answer the following: Reason for lack o f childbearing potential? Prior hysterectomy Prior tubal ligation Post-menopausal Pre-pubertal Other (Explain:

)

I f YES, answer the following: Was a pregnancy test performed? Was the result negative? If N O t o either o f the above, the patient is NOT eligible for the study. If YES, answer the following: Is contraception adequate for the period o f d r u g treatment?

[

I f NO the patient is NOT eligible for the study. I f YES, method o f contraception (only the following are acceptable):

124

Not sexually active

[

Oral contraceptives

[

IUD

[

Diaphragm

[

A.5.14

PATIENT NUMBER:

PATIENT PERSONAL PSYCHIATRIC HISTORY

FIRST 3 LETTERS OF LAST NAME:

Page 1 of 1 month DATE:

day

year

I II I I I I I

PRIMARY PSYCHIATRIC DIAGNOSIS: DURATION OF PRESENT EPISODE:

I

I

I weeks

(If More Than One Year, Enter " 5 3 " )

NUMBER OF PREVIOUS EPISODES REQUIRING THERAPY: 0 . None

1 . Single

AGE AT FIRST EPISODE REQUIRING THERAPY:

|— .— , I I I years

2. Multiple

LIST ANY SECONDARY PSYCHIATRIC DIAGNOSIS ACCORDING TO THE DSM III (If "None, ” Circle) :

SIGNIFICANT PAST PSYCHIATRIC HISTORY (If "None, " Circle) :

NONE

LIST ANY PREVIOUS PSYCHIATRIC MEDICATION(S) (If "None, " Circle) :

NONE

DRUG

MONTHS

Signature:

A.5.15

NONE

EFFICACY

1I I

1. Satisfactory 2. Unsatisfactory 3. Equivocal

III

1. Satisfactory 2. Unsatisfactory 3. Equivocal

111

1. Satisfactory 2. Unsatisfactory 3. Equivocal

111

1. Satisfactory 2. Unsatisfactory 3. Equivocal

1I I

1.. Satisfactory 2. Unsatisfactory 3. Equivocal

_ _______________________

125

Page 2 Date (m/d/y)

Visit

Day

Investigator

Patient Identification' 1

Screen

-84

2

13

1

?

i2

Medication Code

:3

i!

.

’For Patient Identification use first 3 letters of first name then first 3 letters of last name

Sex

For Female Patients

M

1.

Menopausal at least 1 year

F

2.

Premenopausal & surgically incapable of bearing children

3.

Pregnancy Test

Date of onset: _____/ _____/ _____

(serum B ■ subunit HCG RIA)

Date of Birth (m/d/y)

FSH level __________

LH level

procedure: _________________________________ date: _____/ _____/ _____ negative

positive, if positive, do not enter patient into study.

Race

Date of Written Consent (m/d/y)

White

Oriental

Black

Other: _ _________________________ ________________ _ _

American Indian

EPILEPTIC SEIZURE HISTORY Classification'

Age at Onset

Description of Seizure

Frequency in Past 6 Months

Etiology

1

2

3

4

'Classification of seizure type: SP ■ simple partial; CP ■ complex partial; PE - partial evolving to secondarily generalized; CL • cluster

For

______________________

___I ___I ___

_________________Initials __________________________Date (m/d/y)

USE BLACK BALLPOINT PEN — PRINT LEGIBLY

126

A.5.16

Use Only

EFFICACY AND SAFETY STUDY—PARTIAL SEIZURES

SEIZURE HISTORY PATIENT'S INITIALS: ________ F M L

PATIENT# _______________

DATE _ _ / _ _ / _ _ M D Y

Cmpd*

Proj. #

IND*

NDA It

Protocol No.:

Study No.:

Dept:

Section:

For Each Seizure Type Complete the Following (Use a separate form for each Seizure Type). _________— __ Circle Correct Entry. Clinical Seizure Type Described below: CODE GENERAL INFORMATION times per day,

1. Average frequency of this type of seizure over past 6 months: week, month 2. Seizure frequency has:

increased, decreased, remained unchanged during past year.

3. Do seizures follow any cycle? N o Yes. If so, indicate period and associated factors (if any). 4. Are there seizure precipitants? No Yes. Specify

------------------

_—-------------

ICTAL EVENTS 1. Objective Clinical Manifestations (check, and specify side of body): Focal Motor without March Focal Motor with March (Jacksonian) Versive (generally contraversive) Postural Phonatory (Vocalization on arrest of speech) No Yes Other _ specify Yes 2. Automatisms Describe Clinical Manifestation.

Edited by

Yes

No

O

No

._____________ M.D.

Date -----------Date

A.5.17.1

Investigator's Signature

127

EFFICACY AND SAFETY STUDY—PARTIAL SEIZURES

SEIZURE HISTORY PATIENT'S INITIALS: ________ F M L

DATE _ _ / _ _ / _ _ M D Y

PATIENT # _______________

Cmpd*

Proj. #

IND*

NDA #

Protocol No.:

Study No.:

Dept:

Section:

ICTAL EVENTS (CONTINUED) 3. Other manifestations (Sensory, Psychic) Describe: 4. Usual duration of seizures: 5. Seizures occur during:

sec, min

to

Waking, Sleeping, Both

6. Consciousness impaired: Always, Never, Sometimes 7. If so, consciousness is impaired: Immediately, Gradually (from seizure onset) and it occurs: Before, Simultaneously, After objective clinical manifestations? 8. Secondary generalized seizures occur:

Always, Never, Sometimes

9. Partial seizures evolve to generalized: Tonic, Clonic, Tonic-Clonic, Atonic, Myoclonic, seizures?

POST-ICTAL EVENTS 1. Rate of mental clearing post-seizure is: Immediate (Less than 30 sec), Short (30 sec to 10 min), Delayed (More than 10 min) 2. Describe feelings after an attack: Tired, Anxious, Headaches. Muscle Soreness, Confusion. Other (Describe) 3. Patient is amnesic for ictal event: Always, Never, Sometimes

Reviewers Comment o n Classification:

Edited by

Classification is acceptable If no, the following changes are required:

Yes

No

This seizure meets entrance criteria

Yes

No

Date

128

M.D.

...........

Date ------------

A.5.17.2

Investigator's Signature

Compd*

Pro). #

IND*

NDA #

Protocol No.:

Study No.:

Dept:

Section:

LONG TERM EFFICACY AND SAFETY STUDY

SEIZURE HISTORY SCREEN

’atient's Initials: ___/ - / ML F

...

Patient //

Date:

M

/ — / -Y D

SEIZURE CLASSIFICATION

Clinical Seizure Type(s):*

Average No. in Past Code 8 Weeks (per wk)

Controlled

Uncontrolled

Average No. in Baseline Prior to Original Study (per wk)

:

CN CO I D CD

HISTORY OF SEIZURES Unknown

1 . Etiology (if known): 2. Family history of epilepsy. Parent □ ,

3. Age at first seizure:

Sibling □ ,

Other

-----------------------------------------------------

years

Unk No 4. Has patient ever had status epilepticus? Yes If so, seizure type(s) of status: tonic-clonic □ , other □ , specify: ----------------------------------------— How often has status epilepticus occured during the previous 3 years? --------------------5. CT scan or other radiological data pertinent to epilepsy: Yes

No

Unk —-— ——- --------------------

If yes, specify

'Use Revised International Classification of Epileptic Seizures (See Seizure Code)

M.D. Edited by

Date

Investigator s Signature

Date

A.5.18

129

SEIZURE HISTORY SCREEN

3

atient s Initials:

F

... / — — Patisnt ft . M L

...................... Data. ..... ./ MOV

_™__

Compd*

Proj. ft

IND*

NDA tt

Protocol No.:

Study No.:

Dept:

Section:

For Each Seizure Type Complete the Following (Use a separate form for each Seizure Type). Circle Correct Entry. Clinical Seizure Type Described below:

CODE: 1 . Average frequency of this type of seizure over past 6 months: times per day week month 2. Do seizures follow any cycle: No, Yes. If so, indicate period and associated factors (if any). ---------------------------------------------------------------------------------------------------------------------3. Are there seizure precipitants?

No,

Yes. Specify

4. Objective Clinical Manifestations (check, and specify side of body):

5. Automatisms

Yes

6. Other manifestations

Sensory,

No. Describe

7. Usual duration of seizures: 8. Seizures occur during: 9. Consciousness impaired:

Yes D N o . Describe

Psychic to

sec,

Waking,

Sleeping,

Always,

If so, consciousness is impaired:

Never,

Immediately,

min

Both Sometimes Gradually (from seizure onset)

10. Rate of mental clearing post-seizure is: Immediate (Less than 3 0 sec ), to 10 min), Delayed (More than 10 min), NA 11. Patient is amnesic for ictal event:

Always,

Never,

Short (30 sec

Sometimes

N.A. = Not applicable

Edited by

_______________

_

Date

Date

_____________________

Investigator's Signature

A.5.19 130

_________________________ M . D .

Cmpd. #/Name

Page

CARDIOVASCULAR MEDICAL HISTORY

Proj. #

IND #

NDA #

Screen/Baseline Protocol # — Study #

NOTE: Please use BLACK ink. Patient's Initials

_________ _____ _ F M L

Exam Date

Patient # ____________

_ _ _ _ __ M

_

Sec.

Dept.

Check the appropriate box(es) for each category. (/) A. Previous Ischemic Heart Disease

B. Previous Diagnosed Myocardial Infarction C. Previous Angioplasty

YES

NO

SUS UNK

If YES, provide details as specified. If SUSPECT, provide details i f available. Chest Pain: rjYES

NO YES

If YES:

Noncardiac Atypical Possibly Angina Angina Stable Unstable

Date:

Date:

D

Y

_______ ___ M D Y

Specify Artery: LAD □Diagonal

Circumflex

□Circumflex

Obtuse Marginal

Obtuse Marginal

RCAorRPDA

RCAorRPDA

LMCA

LMCA

Q1

D2

Approximate Duration: Manifestations:

E. Valvular Dysfunction

_______ ___ M D Y

LAD Diagonal

NYHACIass:

4

Date: ___ _______ M D Y

Specify Artery:

D. Congestive Heart Failure

NYHA Class 01 2 3

Recurrence Date: M

NO 0

Q3

Q4

_________years

Dyspnea PND Orthopnea

□Fatigue Peripheral Edema Other (specify) _______

Tricuspid Stenosis

Mitral Stenosis

Tricuspid Regurgitation Pulmonic Stenosis

Mitral Regurgitation Aortic Stenosis

Pulmonic Regurgitation

Aortic Regurgitation

A.5.20.1 131

Page

Cmpd. WName

CARDIOVASCULAR MEDICAL HISTORY (Cont.)

IND #

Proj. #

NDA #

Screen/Baseline Protocol # — Study #

NOTE: Please use BLACK ink. Patient's Initials

_ ___ ___, _______ F (VI L

Patient # _ _

_____

Exam Date

____ __________ (VI 0 Y

Dept.

Sec.

Check the appropriate box(es) for each category. (/) F. History of Arrhythmias

G. Conduction Abnormality

H. Peripheral Vascular Disease 1.

Cerebrovascular Disease

J.

Other

YES

NO

SUS UNK

If YES, provide details as specified. If SUSPECT, provide details i f available. Atrial Asymptomatic Symptomatic Palpitations Syncope Presyncope Cardiac Arrest

Ventricular

1 Premature Ectopic i Beats 'Tachycardia | Nonsustained J Sustained I Bradycardia 1 Flutter 1 Fibrillation

1st0 AV Block 2nd0, Mobitz 1 2nd0, Mobitz 2 3rd0 AV Block Left Anterior Hemiblock Left Posterior Hemiblock

Intermittent Claudication

Left Bundle Branch Block Right Bundle Branch Block Accessory Pathway (WPW) Sick Sinus Syndrome □Other _________________

QYES

QNO

Transient Cerebral Ischemic Attack Other (specify) _____________________________________

Check all that apply: Stokes-Adams Pulmonary Embolus Pericarditis Deep Vein Thrombosis

Congenital Heart Disease Family History of Ischemic Heart Disease □Pacemaker

COMMENTS _____; ________________________________________________________________________

132

A.5.20.2

PATIENT NUMBER:

CORONARY ARTERY DISEASE HISTORY Page 1 of 2 DATE:

month

day

FIRST 3 LETTERS OF LAST NAME: year

I I I I I I I I I

H A S THE PATIENT UNDERGONE:

1. No

2. Yes

1. No

2. Yes

CORONARY ANGIOGRAPHY?:

1. No

2. Yes

IF "YES, " W A S THERE 6 0 % NARROWING OF A M A J O R CORONARY ARTERY?:

1. No

2. Yes

1. No

2. Yes

W A S A REVERSIBLE THALLIUM DEFECT PRESENT?:

1 . No

2. Yes

D I D THE PATIENT DEVELOP A T LEAST 1 M M OF S T DEPRESSION?:

1. No

2. Yes

S T A N D A R D STRESS TEST?:

1. No

2. Yes

1. No

2. Yes

CORONARY ARTERY BYPASS SURGERY?: month DATE(S): (List Most Recent First)

day

year

1 1- 1 I I I n month

day

i

year

1I 1I I I I I ( month

day

year

111I I I I I I

CORONARY ANGIOPLASTY?: month

DATE(S): (List Most Recent First)

day

year

111I I I | | | 1 1 1 □J month

month

day

day

year

I I I year

111I I I I I I

month DATE: (If More Than One, List Only Most Recent)

day

year

I 11 I I I LU

THALLIUM STRESS TEST?: month DATE: (If More Than One, List Only Most Recent)

year

111I I I I I I

month DATE: (If More Than One, List Only Most Recent)

day

day

year

I I I I I I I I I

D I D THE PATIENT DEVELOP A T LEAST 1 M M OF S T DEPRESSION?:

A.5.21.1

133

PATIENT NUMBER:

CORONARY ARTERY DISEASE HISTORY

FIRST 3 LETTERS OF LAST NAME:

Page 2 of 2 month DATE:

day

year

I 11 I I I I 11

DOES THE PATIENT HAVE A HISTORY OF: ANGINA PECTORIS?: month ONSET DATE:

2. Yes

1. No

2. Yes

year

I I I I I I

MYOCARDIAL INFARCTION?: month DATE(S): (List Most Recent First)

1 . No

111 month

day

m

day

year

111 year

1 1 1 rn 1 1 1 month

111

day

m

year

111

OTHER MANIFESTATIONS OF CORONARY ARTERY DISEASE?: DIAGNOSIS

1 . No

2. Yes (If "Yes, " Specify Below) ONSET DATE

month

year

I I I month

month

Signature:

A.5.21.2

134

year

m

year

CHF Symptoms Patient's Response Question How Short Of Breath Are You At Rest? How Short Of Breath Are You Walking O n Level Ground? H o w Short Of Breath Are You Walking U p Stairs? How Many Times D o You Awaken Breathless At Night? (Paroxysmal Nocturnal Dyspnea)

O n How Many Pillows D o You Sleep? (Orthopnea)

How Fatigued (Tired) Are You At Rest? How Fatigued (Tired) Are You Walking On Level Ground? How Fatigued (Tired) Are You Walking Up Stairs? Overall, What Is Your Sense Of Well-being?

Response

Q Q

(Check Only One)

None

Di

Severe

MM

Dl

Very Severe

D

Moderate

Di

None

Di

Severe

□

Mild

Di

Very Severe

□

Moderate

Dj

None

D i Severe

□

Mild

Di

Moderate

Dl Very Severe Di Not Applicable

Di

None

□

1-2 Times

Comment

D i 3 or More Times Di

None

D i 1 Pillow D i 2 Pillows Q None Q Mild

D i 3 Pillows D i > 3 Pillows Di

Severe

Di

Very Severe

Di

Moderate

Qi

None

D i Severe

□

Mild

Ql

Dl

Moderate

□

None

Very Severe

D l Severe

D l Very Severe Q Mild Dl Moderate Q l Not Applicable Poor D i Very Good D i Very Poor d Good D i Fair

Clinician’s Response What Is The Clinician's □ View Of The Patient's Overall Well-being?

d Q

Very Good Good

D| Poor Di Very Poor

Fair

A .5.22

135

VISIT 1 PATIENT SCREENING (cont'd) HYPERTENSION HISTORY dd’e. l a s t )

Month

DOES THE PATIENT HAVE A HISTORY OF: |__| 0 =

1. U n e q u i v o c a l l y p o s i t i v e t h a l l i u m 2 0 1 stress test?

Yr

Day

Mo I f yes, list d a t e o f m o s t r e c e n t : L o c a t i o n o f reversible p e r f u s i o n defect(s)?

| _ _| 0 =

2. U n e q u i v o c a l l y p o s i t i v e t e c h n e t i u m stress test? Mo

Day

Mo

Yr

Yr

I f yes, list d a t e o f m o s t r e c e n t : ATTACH A COPY OF THE TEST REPORT 3. D i a b e t e s m e l l i t u s ? I f yes, list d a t e o f o n s e t : IF DIABETES IS UNCONTROLLED OR BRITTLE, PATIENT IS INELIGIBLE FOR STUDY. 4. H y p e r t e n s i o n ? Mo

Yr

I f yes, list d a t e o f o n s e t : IF HYPERTENSION IS UNCONTROLLED, PATIENT IS INELIGIBLE FOR STUDY. 5. P e r i p h e r a l vascular disease? Mo

Yr

I f yes, list d a t e o f o n s e t :

6. Congestive h e a r t f a i l u r e ?

|_] 0 = N o

I

Mo

Yr

I1

I f yes, list d a t e o f o n s e t : □

N Y H A F u n c t i o n a l Class (check o n e ) :

A.5.25 138

3 = III

Ddy

Year

ul

BASELINE

Protocol

Date

Pt. No.

Pt. nitials

Inv. No.

(First. Middle, Last)

' CONCURRENT 1. Diabetes m e l l i t u s ?

f

Mo

/;

* *’ T ? *>

Year

01

2 0 0 rng/ml) 2 . Hypertension?

I

10 = N o I

I 1 = Yes Mo

Yr

I f yes, list d a t e o f diagnosis: IF HYPERTENSION IS UNCONTROLLED, PATIENT IS INELIGIBLE FOR STUDY. BP > 170/100 1 = Yes

0 = No

3 . Peripheral vascular disease?

Mo

Yr

I f yes, list d a t e o f diagnosis: IF THIS CONDITION W I L L INTERFERE W I T H THE ETT, THE PATIENT SHOULD BE EXCLUDED. 4. Congestive heart f a i l u r e ?

I

I 0 = No Mo

I ] 1=Yes Yr

I f yes, list date o f diagnosis: N Y H A Functional Class (check o n e ) :

IF N Y H A CLASS I I OR GREATER, PATIENT IS INELIGIBLE FOR THE STUDY. None

List a n y a d d i t i o n a l c o n c u r r e n t disorders.

A.5.26 139

ASTHMA REPORT Visit 0

Patient's Initials (First, Middle, Last)

Patient Number

till

Date of Visit (Mo/Day/Yr) _____/_ _ _ _ !_ _____

Yes

No

Will inhaled steroids b e used concurrently w i t h study medication?

duration:

dose:

If yes, specify drug:

N O OTHER ASTHMA MEDICATIONS SHOULD BE TAKEN WITH THE STUDY MEDICATIONS

Other medication (specify all non-asthma medication currently receiving) 1.

____________________________ _ _

2.

4.

___________________________ _ _ _ _

5.

Duration of Asthma O

___________ _

_

Skin Test Results

1 year

Positive

1 - 5 years

____________6. __________, ________________________

Classification of Asthma O Intrinsic

O Negative

0 ► 5 years

__________________________________

__________________________________3.

Extrinsic

Not Tested

Mixed

Symptoms Experienced During Past Two Weeks Mild = present but causing little or no discomfort.

Moderate = annoying but not interfering with daily routine or sleep. None

Severe = causing marked discomfort and some interference with daily routine or sleep.

Mild

Unbearable = disabling, interferes considerably with daily routine or sleep.

Severe

Moderate

Unbearable

Wheeze Breathlessness

O

Tightness of Chest Cough

O __

Further details

___________________________________

Auscultation N o wheezing

Wheeze o n inspiration and expiration

Wheeze o n forced expiration

Wheeze audible without stethoscope

Wheeze w i t h normal expiration

Dyspnea plus wheeze audible without stethoscope

Pulmonary Function Tests (best of 3 readings) Has patient received oral bronchodilator i n past 12 hours?

No

Yes

Has patient received aerosol bronchodilator i n past 12 hours?

No

Yes

No

O Yes

Date

of

Reversibility

Test Medication _______

Has patient received long-acting theophylline i n the past 24 hours? FEV-|(l/sec)

% Reversibility

Predicted: Before bronchodilator (baseline): After bronchodilator: Reversibility must b e at least 1 5 % of predicted t o qualify for the study.

140

A.5.27

FEF

25-75

FVC(I)

PATIENT HISTORY Inv. No.

Protocol

Pt. No.

Pt. Initials (First. Middle. L«M)

Date o f Enrol ment Month

Oay

HISTORY OF ALLERGIES (Check one) Does the patient have a history of: Asthma o r Atopy

No

Yes, specify reaction

________________________________.

Cephalosporin Allergy

□No

Yes, specify reaction

_ _______________________________

Penicillin Allergy

□No

Yes, specify reaction

_______________________________

Other d r u g allergies

DNo

Yes, specify drug -----------------------------------------------------------specify reaction _ _______________________________

MEDICAL AND SURGICAL HISTORY EXCEPT LYME DISEASE History o f significant medical o r surgical illness? | | N o

|

Medical

2) 3)

If yes, complete below. Surgical

■

1)

|Yes

__________________: ____________________

4)

D

-----------------------------------------------------------------

2)

-----------------------------------------------------------------

3)

-----------------------------------------------------------------

4)

-----------------------------------------------------------------

LYME DISEASE HISTORY No

Has the patient had Lyme disease previously?

Yes

I f yes, complete below: Date o f diagnosis:

Month

D i d the patient's disease resolve completely?

CXay

Year Yes

No

If No, patient should not b e entered i n this study. I f Yes, date o f resolution: Month

O«y

Year

Comment o n clinical course and treatment:

A.5.28

141

Inv. No.

Protocol

Patient's Initials

Pt. No.

Date Month

Day

Year

VISIT 1 PRE-TREATMENT ASTHMA HISTORY

ANSWER THE FOLLOWING FOR ALL FEMALES

A g e a t first diagnosis o f asthma

PREGNANCY INFORMATION

Previous use o f medications for 0 = no, 1 = yes asthma?

Has patient h a d a t least one menstrual period? 0 = no, 1 ~ yes

IF YES, LIST FOUR USED BEGINNING WITH THE MOST RECENT MEDICATION:

IF YES, COMPLETE THE FOLLOWING:

# 1 ________________________________ Date Stopped

Day

Year

_______________________________

Date Stopped #3

Date o f last menses: Month

Month

Day

Year

Month

Day

Year

___________

Date Stopped

Date Stopped Month

Day

Average n u m b e r o f asthma attacks per month d u r i n g t h e last three months?

Pregnancy Test Performed: 0 = n o , 1 = yes Results o f Test: 0 = negative, 1 = positive 2 = not d o n e

Year

0 = none/not applicable, 1 = o r a l contraceptives, 2 - IUD, 3 = diaphragm a n d f o a m , 4 = condoms a n d foam, 5 = surgically sterile, 8 = other IF OTHER, SPECIFY BELOW:

Number o f days since the last asthma attack? Number o f hospitalizations d u e t o asthma w i t h i n the last year? Does t h e patient have any o f the f o l l o w i n g between asthma attacks? 0 = no, 1 = yes

Shortness o f breath 0 = n o , 1 = yes Cough

0 = n o , 1 = yes

Chest tightness

0 = n o , 1 = yes

A.5.29

142

Year

Primary Method o f Contraception

# 4 ___________—

Wheeze

Day

L_1_J L_1_J Month

#2

—

DAY 1 BASELINE EVALUATION Inv. No.

Pt. No.

Patient's Initials (First, Middle, Last)

Primary Diagnosis of Skin Infection O Tinea versicolor D Disease Status: O Acute

D

Date of Visit _____/ / Mo. Day Yr.

Other, specify

D

Chronic

Duration of current condition: _ _ _ _ _ _ ______ weeks

Recurrent

Check appropriate sltefs) below:

On the sketch below: Shade all areas affected with t. versicolor

Site(s)

Body Area

Circle site(s) selected for KOH preparation

Site{s)

Affected Treated

The same site must be sampled at each visit 4 %

Face Neck Trunk

9%

>

Arms

9%

t

Legs

4/2%

Buttocks 4’/2%

9%

9%

Other, specify:

IT Estimate: % Body Surface Area

9% A 9% 9%

9%

Affected

.%

% Body Surface Area Treated

.%

BACK

FRONT

Clinical Assessment (Circle appropriate scores.) Absent Scaling 0.0 Erythema

0.0

0.5

Mild 1.0

1.5

Moderate 2.0

2.5

Severe 3.0

0.5

1.0

1.5

2.0

2.5

3.0

Total score: ______ _____ _

KOH Preparation:

Mycological Assessment Date culture read: . _____/ Comments:

Culture Result: .. / _

Negative

Positive

No Growth

Growth Organism Identification: ___ __________

________________________________________________

A.5.30 143

VISIT 1 : PATIENT HISTORY Inv. No.

Protocol

Pt. Initials

Pt. No.

(First, Middle, last)

Has patient received any antimicrobial medica tion (antivirals, topicals) i n the 7 days prior t o enrollment i n t his study?

PREVIOUS ANTIMICROBIAL MEDICATIONS

0 = No, 1 = Yes NOTE:

Use of any systemic antibacterial medication i n the previous 7 days w i l l exclude the patient from t h e study.

Medication (Enter one per line)

Unit Dose (mg)

Times per day

TOP Date Started IV IM Yr PO M o Day

I I I I I

I 1I I I n

™ TT T

-

III!]

A.5.31

144

If yes, specify below

Date Stopped Mo

Day

Yr

Indications for use

PATIENT HISTORY Inv. No.

Protocol

Pt. No.

Date o f Enrol ment

Pt. Initials

Month

(Firvt, Middle, list)

Day

Year

PREVIOUS ANTIMICROBIALS (Include antibacterials, antivirals, antifungals) Has patient received antimicrobial therapy i n the past 10 days?

ONo

Oves

I f yes, give details: Medication Please Print

Unit Dose (mg)

Times per day

TOP Date Started IV IM Yr PO M o Day

□

CURRENT BACKGROUND DISORDERS

No

Date Stopped Mo

|

Day

| Yes

Yr

Indication For Use

I f yes, complete

Comment Alcoholism Diabetes Mellitus Heart Disease Pulmonary Disease Neoplasia Impaired Renal Function Liver Disease G l Disease Osteomyelitis Rheumatologic Disease Neurologic Disease Other

If yes, one per line:

A.5.32

145

Page

Cmpd. #/Name

Prop #

H I V EXPOSURE DATA IND #

NOTE: Please use BLACK ink. Patient's Initials

Protocol # — Study #

Patient # F

M

___________

Dept.

Sec.

L

Time:

Date of Exposure: -fi/T ~D Type of Inoculum:

NDA #

(0-2359)

Y~

Blood

Serum

Plasma

□Other

Complete chart below concerning exposure. (/)

Type of Exposure Penetrating Wound

Provide details as specified Needlestick Cut w i t h contaminated sharp object

Specify:

Estimated Volume Injected: 0.1 ml Note: Splash onto Abraded Skin

Specify:

A needlestick without infusion of blood is estimated to be approximately 0.001 ml. Open wound (cut, wound, scratch, etc.) Dermatitis (acne, rash, infections, cracks due to excessive drying, or trauma, etc.)

Duration of Exposure: < 1 min. 1-15min. > 15 min. Estimated Surface Area Covered: < 1 cm 2 1-10cm2 > 1 0 c m2 Splash onto Mucous Membranes

Specify Membrane:

Mouth Nasal Conjunctival

Estimated Volume of Inoculum: 0.1-1.0 m l >1.0 ml Duration of Exposure: < 1 min. 1-15 min. >15min. Was inoculum ingested? QYes

146

A.5.33

DNo

Protocol STUDY

FORM 2 - ADVANCED ARC/AIDS DIAGNOSIS

P a t i e n t Number:

Date o f P a t i e n t v i s i t :

Study ID:

Subunit Code:

Study Week:

Key Operator Code:

Instructions:

Page 1 Of 3

/ / (dd/nwm/yy)

T h i s form must be completed a t each scheduled protocol v i s i t w h i l e t h e p a t i e n t i s on study therapy and a t each r e q u i r e d f o l l o w - u p I n t e r v a l a f t e r study therapy has been d i s c o n t i n u e d . Answer each q u e s t i o n . I f a s p e c i f i c d i a g n o s i s o r Item has been reported a t an e a r l i e r v i s i t , respond by e n t e r i n g t h e l e t t e r ' P ' t o I n d i c a t e t h a t t h i s Item was reported p r e v i o u s l y .

Y

N

a . Were you a b l e t o contact t h e p a t i e n t for f o l l o w - u p ....................................................................................... Y t h i s month?

N

1 . Has the p a t i e n t been permanently d i s c o n t i n u e d from study drug? I f Yes,

I f Yes, a1 .

I n d i c a t e t h e source o f f o l l o w - u p data and complete the remainder o f t h i s form

i—
10 l b s o r 10% o f body w e i g h t w i t h i n a s i x month I n t e r v a l ?

Y

N

P

b ) Fever > 3 8 . 5 C ° w i t h o r w i t h o u t n i g h t sweats, w i t h o u t known cause, p e r s i s t i n g for > 1 4 c o n s e c u t i v e days o r a t o t a l o f > 1 5 days w i t h i n a 30 day I n t e r v a l ?

Y

N

P

c ) D i a r r h e a d e f i n e d as 3 o r more l i q u i d s t o o l s per d a y , p e r s i s t i n g for > 30 days w i t h o u t d e f i n a b l e cause?

Y

N

P

d ) Recurrent o r a l c a n d i d i a s i s ?

Y

N

P

e ) Mui t l-dermatomal Herpes z o s t e r ?

Y

N

P

f) Oral hairy leukoplakia?

Y

N

P

ENTER THE TWO MOST RECENT CD4 COUNTS: CD4 ( T 4 ) COUNT*’*' a) b)

.

SPECIMEN DATE /

/

/

/

**Be sure t o e n t e r CD4 counts o n LYMPHOCYTE SUBSET FORMS (FF1001)

Once t h e d i a g n o s i s o f ADVANCED ARC I s e s t a b l i s h e d , t h e p a t i e n t must b e t e r m i n a t e d from s t u d y t h e r a p y . Complete STUDY DRUG TERMINATION (SF1904) and f o l l o w a t r e g u l a r I n t e r v a l s for HIV d i s e a s e p r o g r e s s i o n and s u r v i v a l u s i n g e x t r a c o p i e s o f t h i s form.

A.5.34.2

148

PATIENT NUMBER:

JOINT EVALUATION Page 1 of 2

year

day

month

ETJ

CD

DATE:

FIRST 3 LETTERS OF LAST NAME:

EE UPPER EXTREMITIES - UPPER BODY

SCALE

0 - None

1 - Mild

2 = Moderate

3 = Severe

8 = Injected Joint

9 = Non-respondable Joint

LEFT SIDE

RIGHT SIDE JOINTS

TENDERNESS

SWELLING

TENDERNESS

SWELLING

TEMPOROMANDIBULAR: STERNOCLAVICULAR: ACROMIOCLAVICULAR: SHOULDER: ELBOW: WRIST: METACARPOPHALANGEAL

FIRST Sthumb) : SECOND: THIRD: FOURTH: FIFTH: PROXIMAL INTERPHALANGEAL

INTERPHALANGEAL tthumb) : INDEX: MIDDLE: RING: LITTLE: DISTAL INTERPHALANGEAL

INDEX: MIDDLE: RING. LITTLE:

A.5.35.1

149

PATIENT NUMBER:

JOINT EVALUATION Page 2 of 2 DATE:

month

I

I

I

FIRST 3 LETTERS OF LAST NAME:

day

I

I

year

I

I

I

I LOWER EXTREMITIES - LOWER BODY

SCALE

0 - None

1 = Mild

2 = Moderate

3 = Severe

8 = Injected Joint

9 = Non-respondable Joint

LEFT SIDE

RIGHT SIDE JOINTS

TENDERNESS

SWELLING

TENDERNESS

SWELLING

HIP: KNEE: ANKLE

MORTISE: TARSUS: METATARSOPHALANGEAL

FIRST: SECOND: THIRD: FOURTH: FIFTH: INTERPHALANGEAL (distal and/or proximal)

FIRST: SECOND: THIRD: FOURTH: FIFTH:

Signature: _______

A.5.35.2 150

______________________________ _________

PRE-OPERATIVE EVALUATION Inv. No.

Protocol

Pt. No.

Pt. Initials (first, Middle. Last)

0 = NO , 1 = YES

RISK FACTOR EVALUATION

|

|

Does this patient have diabetes mellitus? Is this patient obese (>30% above ideal body weight)?

|

Has this patient recently lost >20% of their body weight?

| *

Has this patient received corticosteroid therapy? * i f yes, specify Drug Name Dosage Duration of Therapy Has this patient been hospitalized > 5 days prior to surgery?

__

Is this patient malnourished (serum albumin . 1 0 0 lbs?

3.

—

12 years o f age?

—

..... —

—

—

—

Is the patient m a l e o r non-pregnant, non-lactating female practicing adequate contraception?

4.

Does the patient have erythema m i g r a n s (EM)?

5.

Is the patient a n outpatient?

6.

Has the study been explained t o the patient a n d has the patient consent form been signed a n d d a t e d ? *

— —

—

r—

—

—

—

A L L O F THE ABOVE QUESTIONS M U S T BE ANSWERED YES FOR THE PATIENT TO BE ENROLLED ‘Attach a copy o f the patient consent t o the case report form.

NO

EXCLUSION CRITERIA (Check one) 1.

Does the patient have a history o f a n i m m e d i a t e hypersensitivity reaction t o p e n i c i l l i n o r o f any serious adverse reaction t o a n y cephalosporin o r tetracycline d r u g ?

2.

Has the patient received any systemic antibiotic therapy w i t h i n the past 10 days known t o b e active against B. burgdorferi?

3.

Does the patient have a history o f a gastrointestinal disorder that m a y diminish antibiotic absorption ( e . g . , malabsorption, inflammatory bowel syndrome, chronic diarrhea, o r c o l o n i c surgery within 3 months prior t o enrollment i n the study)?

4.

Does this patient have a s i g n i f i c a n t u n d e r l y i n g disease as specified i n the protocol?

5.

Has this patient been involved i n a n investigational d r u g study w i t h i n o n e month prior t o enrollment?

6.

Has this patient been entered i n this study before?

7.

Does this patient have a condition o r appointment record which makes i t h i g h l y u n l i k e l y that the course o f treatment o r follow-up w i l l b e completed?

A L L O F THE ABOVE QUESTIONS M U S T BE ANSWERED N O FOR THE PATIENT T O BE ENROLLED

A.7.11

176

YES

PROTOCOL

Pt. No.

Inv. No.

Pt. Initials 1 i

Date 1 i 1 i

MO.

DAY

Visit No.

01

1

YR.

EXCLUSION CRITERIA

Does the patient have any of the following: 1.

hypertension secondary to renovascular disease, pheochromocytoma, or primary aldosteronism, or hypertension which requires surgical intervention?

»□ »□

,□

2.

systolic blood pressure > 220 mmHg?

3.

uncontrolled diabetes mellitus?

4.

severe cardiac diseases other than hypertension; i.e. unstable angina pectoris or recent myocardial infarction less than six months old, heart block of greater than first degree, other major conduction abnormalities or severe arrhythmia, congestive heart failure not controlled by conventional treatment, bradycardia of less than 50 beats per minute?

0

5.

a cerebrovascular accident within the last six months?

(P

6.

bronchial asthma, bronchospastic COPD requiring chronic treatment with bronchodilators (theophylline, albuterol, etc.)?

0

7.

clinically significant hepatic or renal disease?

0°

8.

history of intolerance to beta-blockers?

9.

treatment with guanethidine or rauwolfia agents within two weeks prior to entering the study?

10.

11.

12.

13.

YES*

NO

1DI

1 DJ

any other medical condition which would endanger the patient if he or she participated in the trial? an infirmity, disability, or geographical location which seems likely to prevent regular attendance for follow-up patient visits? a recent history of alcoholism, drug abuse, psychosis, antagonistic personality or poor motivation, emotional or intellectual problems likely to limit validity of consent to participate in the study? treatment within one month before the study with another investigational drug?

(P 0

(P

1□

1□

1

(P

,□

0

1

* If the answer to any of the above questions is yes, please do not enroll this patient in the study.

A.7.12

177

B. PHYSICAL AND OTHER EXAMINATIONS Title 1. 2. 3. 4. 5.

Physical Examinations Vital Signs Neurological Examinations Ophthalmological Examinations Psychological and Psychiatric Tests 6. Other Specialized Physical Examinations

Form Numbers

Page Numbers

B.1.1— B.1.43 B.2. 1.1— B.2.16 B.3. 1—B.3. 12 B.4.1— B.4.11.3 B.5.1-B.5.2.2

181-223 225-241 243-262 263-275 277-279

B.6.1— B.6.15

281-296

GENERAL POINTERS AND COMMENTS •

Request information on height only at screen (B.l).

•

Request information on abnormalities of body systems at posttreatment in terms of changes from baseline (B.l). Indicate the patient’s desired position (seated, standing, or supine) for vital signs and the length of time the patient should be in that position (if relevant) before the measurement (B.2).

•

•

Neurological posttreatment forms should identify whether findings were present at baseline or emerged during treatment (B.3).

•

Ophthalmological posttreatment forms should identify whether findings were present at baseline or emerged during treatment (B.4).

» Ensure that only validated scales are used to collect data, except in unusual circumstances (B.5); for example, if no validated scales exist.

SPECIFIC POINTERS AND COMMENTS ON INDIVIDUAL FORMS B.l Physical Examinations • Multiple modules per page are shown on B . l . 24. ® The “ n o change” column in B . l . 4 should indicate the reference point for comparison (e.g., last week, last visit, baseline). 179

PHYSICAL AND OTHER EXAMINATIONS

•

Inconsistently ordering the same responses (e.g., “ y e s ” or “ n o ” ) in different questions is confusing and liable to result in errors (B.1.12).

B.2 Vital Signs •

Some forms allow a sequence of values (many per day and/or many days’ worth) to be observed with a rapid scan of columns (B.2.2 to B.2.6 and others).

•

Forms B.2. 1. 1 and B.2. 1.2 could be combined on a single page to save paper.

B.3 Neurological Examinations •

• •

These forms illustrate a wide variation in detail and focus of the examination. This depends to some degree on the patients treated and the nature of the treatment. Many specific tests could be illustrated as for other types of physical examinations. Results from four separate examinations are presented side by side on B.3.9.

B.4 Ophthalmological Examinations •

Two forms are presented on B.4.9.

B.5 Psychological and Psychiatric Tests •

Forms B.5.1 and B.5. 2 provide different approaches for recording data, i.e., filling in a number and circling a number. Other forms in this library provide additional approaches to presenting data.

B.6 Other Specialized Physical Examinations •

180

Selected forms are presented for a variety of specialized examinations. Some collect highly specific numeric data (B.6.4), while others are extremely general (abdominal examination in B.6. 13).

Bl

PHYSICAL EXAMINATIONS

PHYSICAL EXAMINATION PATIENT INITIALS (3)

Drug ID PATIENT NUMBER

VISIT

DATE OF PHYSICAL EXAM (month/day/year) 1

It is preferred that the same person conduct both the pre-study and post-study physical examination. Examiner’s Initials: WEIGHT

HEIGHT

SEATED BLOOD PRESSURE (after 2 minute rest) (systolic/diastolic) /

lb

in

mm Hg

PULSE beats/min

(0) NORMAL (1) OTHER, describe: Head

11

I I

Eyes

11

I

Ears

11

n

Nose

11

i i

Throat

11

i i

Neck

1

i i

Chest Wall

1

i i

Lungs

□

i i i i

Heart

Abdomen

11

□

Extremities

n

D

Other Clinically Significant Findings

oEi None

B.1.1

181

DURING-TREATMENT ASSESSMENT ( D A Y 8 - 1 2 ) Inv. No.

Protocol

Pt. Initials

Pt. No.

—

...... .........

( f m t . Middle. last)

Date o f Enrollment Month

Day

Date

SIGNS AND SYMPTOMS

□No

Is erythema migrans (EM) present?

Size o f largest lesion:

If YES, number o f lesions I L L l

Dves X

Site o f lesion(s) _________________________ □No

Are systemic manifestations present? No

Mild

Moderate Severe

Splenomegaly Radiculopathy Lymphadenopathy: _ regional diffuse Malaise Irritability Fatigue Jaw pain Chills Headache Stiff neck Parathesia Myalgia Arthralgia Arthritis Pleuritis Backache Nausea Vomiting Diarrhea Sore throat * Fever Temperature

1 °F

Oral CZ

Other, one per line:

* > 1 0 0 0°F (oral) or > J 00.6 °F (rectal)

182

Year

B.1.2

Dyes Comment

mm

DAY 1 PATIENT HISTORY/PHYSICAL EXAM Inv. No.

Age (Yrs.)

Patient's Initials (First, Middle, Last)

Sax Male Female

Pt. No.

Origin Caucasian Black

Oriental Hispanic

Date of Visit ____ / / Mo. Day Yr.

American Indian Other (Specify)

_________

Female Patients Only Childbearing Status (Check One) Premenstrual

Pregnancy Test

Post-Menopausal

Sterile

Date tested: _____/ / __ Mo. Day Yr.

Childbearing potential*— indicate method of contraception: Not sexually active IUD Result: Oral contraceptives D Diaphragm Other, specify _________________________________________________ ( ‘ A l l patients i n this category must have a pregnancy test) Significant Medical History

Allergies

None

None

Neg. Pos. NA

Yes, specify below:

Yes, specify below:

Drug/Compound

Type of Reaction

Physical Examination Anatomy

Check N = Normal. A = Abnormal (give pertinent details)

Eyes

N

A

Ears

N

A

Nose

N

A

Mouth and Throat

N

A

Neck

N

A

Chest

N

A

Heart

N

A

Abdomen

N

A

Extremities

N

A

Nervous System

N

A

Skin (excluding study infection)

N

A

Lymph Nodes

N

A

Genitalia

N

□

Comments:

A

1 ......................

B.1.3

183

Page

PHYSICAL EXAMINATION

Cmpd. #/Name

IND #

_________________ F M L

HEIGHT

NDA #

Protocol # — Study #

NOTE: Please use BLACK ink. Patient's Initials

Proj. #

Patient #

(cm)

____________

WEIGHT

Exam Date

_________________ M D Y

(kg)

Dept.

Sec.

BODY SURFACE AREA

(m2)

KARNOFSKY PERFORMANCE SCORE BODY REGIONS/SYSTEMS CHECK Body Region Code #

Body Region/System

Nor.

Abn.

Not (/) if ExamNo i n e d Change

Body Region Code #

Body Region/System

1

M e n t a l Status

9

Abdomen

2

Neurological

10

Liver

3

Skin

11

Spleen

4

Head & Neck

12

Genitalia

5

Eyes

13

Rectal

6

Chest & Back

14

Extremities

7

Lungs

15

Lymph Nodes

8

Ca rdiovascular

16

O t h e r : _____________

Nor.

Abn.

Not (✓) i f ExamNo ined Change

ABNORMAL PHYSICAL FINDINGS Specify all abnormal physical findings in the chart below. Indicate the body region(s) or system(s) affected by the abnormality by recording the appropriate code number(s) in the column provided. Body Region Code #(s)

Abnormal Physical Finding

HEPATOMEGALY? If YES, complete below.

Yes

No

Body Region Code #(s)

Abnormal Physical Finding

SPLENOMEGALY? Yes If YES, complete below.

QNO

Below xiphoid:

cm

Below Midline:

cm

Below RCM:

cm

Below LCM:

cm

NOTE: Record all symptoms on the "Symptoms/Toxicities/Adverse Experiences" pages of this DCF (pp. ).

184

B.1.4

Page

GENERAL PHYSICAL EXAMINATION NOTE: Please use BLACK ink

00

Pt./Vol. # Initials

Investigator’s Name

Pt./ Vol. #

M

Proj. #

IND #

NDA #

NOT FILL

~F

of Cmpd. #/Name

Protocol# — Study#

IN

L~~

Dept. M

Sec.

Y

Exam Date

SEX:

C Male

RACE:

White

Female

BIRTHDATE: _ _ _ M

Black

Other, Specify

BODY WEIGHT: ________

kgs.

lbs.

BODY HEIGHT:

cms.

ins.

Medium

Large

BODY FRAME:

Small

VITAL SIGNS:

GENERAL EXAMINATION:

(/) Head/Neck EENT

Y

_________ _________

Systol ic/Diastolic

Blood Pressure (sitting) __________ / (mm Hg) Temperature (oral)

_ _ ____

D

DC

_______ 0

Pulse Rate (beats/min.) ____________ _ _ _ _ (at rest)

F°

Resp. Rate (breaths/min.) _______________

Are there CLINICALLY SIGNIFICANT abnormalities? If yes, please provide details below.

Yes

No

Nor. A b n .

Chest

Heart Lungs Abdomen Liver Spleen Pelvic Genital Rectal Extremities Skin Neurological Pulses OTHER (specify)

investigator's Signature

B.1.5

M

~TF~

“

185

STUDY TITLE

PHYSICAL EXAMINATION 94-1603-10

DO NOT WRITE IN SHADED AREAS

4/90

PRINCIPAL M O N I T O R

PRINCIPAL INVESTIGATOR

INVESTIGATOR'S N O .

SUBJECT'S INITIALS

SUBJECT N O .

MONITOR NAME PROTOCOL N O .

STUDY PERIOD

DATE OF EVALUATION

M/0000/0000 WEIGHT

,cm [ 3 2 inches

ORAL TEMPERATURE

„

SUPINE BLOOD PRESSURE

_ ’

Dikg 2 pounds

PULSE

i Regular

,°c _____________________

n

2

°F

________ / m i n

2

Irregular

_____/ _ _ _

mm Hg

SYS._________DIAS.

RESPIRATION RATE

___ _ _ / m i n

General Appearance: INSTRUCTIONS:

Check appropriate box to indicate current physical findings. Describe any abnormalities, indicating left or right where applicable.

HEAD A N D NECK

-n

P H Y S I C A L

IF A B N O R M A L , BRIEFLY DESCRIBE

1 In Normal 1 1, Abnormal EENT/MOUTH

IF A B N O R M A L , BRIEFLY DESCRIBE

1 l n Normal O , Abnormal CHEST/LUNGS

IF A B N O R M A L , BRIEFLY DESCRIBE

EZZ] 0 Normal I I , Abnormal HEART 1—1

IF A B N O R M A L , BRIEFLY DESCRIBE

1—1

| _| 0 Normal | _((Abnormal

ABDOMEN

IF A B N O R M A L , BRIEFLY DESCRIBE

CJoNormal □ ,

Abnormal

lAClZ-

oz-

EXTREMITIES

IF A B N O R M A L , BRIEFLY DESCRIBE

1 In Normal 1 L Abnormal SKIN

IF A B N O R M A L , BRIEFLY DESCRIBE

1 In Normal 1 1, Abnormal MENTATION

IF A B N O R M A L , BRIEFLY DESCRIBE

0 Normal E J , Abnormal OTHER A B N O R M A L PHYSICAL FINDINGS? DoNo

EL

IF YES, BRIEFLY DESCRIBE

Yes

COMMENTS:

INITIALS/SIGNATURE:

186

DAY c

HEIGHT

-----------

MO.

B.1.6

Clinical Report Form Drug Identification Indication

Visit ? Page 1 of ?

DO NOT WRITE IN THIS SPACE (FOR USE IN COMPILING DATA)

Date Received at

WEIGHT Measure to the nearest tenth with shoes off. Weight Unit of Measure

1 = kg

Reviewed

HEIGHT

Audit

2 = lb

Measure to the nearest tenth with shoes off.

Date

Height Unit of Measure

1 = cm

Initials

2 = in

Initials

Date Keyed

PHYSICAL EXAMINATION CONFIRMATION A physical exam was performed per protocol and any abnormalities that were found have been listed on the appropriate pages of the clinical report form (i.e., Historical Diagnoses, Chronic Illnesses, or Admission Record of Events)

1 = Yes

Date Venfied

2 = No

B.1.7

187

Form 4 Enrollment/History/P.E.

Date Enrolled

Patient Study #

Patient Initials

Protocol

[ Study Center #

Location

PATIENT'S HISTORY Symptom due t o Herpes Symptom

Yes

No

Date o f Onset

Check i f Present at

Duration (days) of Symptom i f Present

Enrollment

Prior t o Study b u t n o t a t Enrollment

Skin Vesicles Lethargy Fever _______ Conjunctivitis Other PHYSICAL EXAM AT ENROLLMENT Age a t Enrollment

Sex

Female

Ethnic Group:

LZ1 Male

Caucasian Hispanic Black

iys

Oriental Weight a t Enrollment

H T a t Enrollment

Other:

Temperature

cm. Specify Skin:

Number Vesicles a t Enrollment Mo

Eyes: /

Day

/

Normal

Yr

Abnormal

Date o f Onset o f Lesions I f Abnormal: Onset o f Disease Relative t o Birth:

Conjunctivitis

Present a t Birth < 2 4 hours after birth 1-2 days after birth

Chorioretinitis Other: Specify

3-5 days after birth > 5 days after birth Site 1st Vesicle (s) Site 2nd Vesicle(s) Eyes Head Arms Trunk Perineum Legs Mouth None Unknown GENERAL EXAMINATION Please V

Normal

Abnormal

Please provide details of any abnormalities

Head/Neck ENT Chest Heart Lungs Abdomen Liver Spleen Extremities Neuro

188

B.1.8

Form 5 Physical Evaluation During Hospitalization Patient Initials I F

Patient Study #

I

|

M

|

|

|

|

Protocol

|

|

L

Study Center#

Location

PHYSICAL EXAMINATION AT COMPLETION OF IV THERAPY Mo ||

Date of Enrollment

/

Day

/ )!|

Yr Date ot examination

|

Mo |

/ 1

1

Weight

■ 1

1

1

k

g

Age

days

|

Eyes:

Yes

—

Hearing:

No

1 _ _1

If yes, number

Normal . A. Abnormal

| _ _|-----1 _ _|

If Abnormal:

start date

Conjunctivitis Chorioretinitis

Yr

r11 .

°C

_ ______ _ Mo

1— 1

/

Temperature

Starting Oral Drug Dosage :

Skin: Vesicles still present?

Day

/

1

Day

mg/dose /

1

Yr

—

Other _______________ Specify

_ _ Normal

*lf abnormal J

Abnormal

[

Right

_ _ Left

‘Attach Report

GENERAL EXAMINATION Please V

Normal

Abnormal

Please provide details of any abnormalities

Head/Neck ENT Chest Heart Lungs Abdomen Liver Spleen Extremities Neuro.

B.1.9

189

Form 40 Patient Follow-Up Date Enrolled Patient Study #

Patient Initials

Protocol [ F

M

|

L Study Center#

Follow-up Date Mo / Day / Yr

Follow-up Interval:

1 month 2 months 3 months 4 months

12 months 24 months 36 months 48 months Sick Visit Other: ________Specify interval_____

5 months 6 months Functional Assessment:

Patient is developing normally

Patient is institutionalized

Patient is impaired - please describe:

Patient died

Cause of Death:

Date of Death: |

Autopsy performed?

No

Yes:

Location

Autopsy Report:

It/lo

/

Day

I

I

I

/ I

Attached

Yr I

I

Not available

Sick Visit: Specify Reason

__

Plasma drug level obtained: Yes

No

Drug Stopped:

Yes

No

Date

Drug restarted

Date

PHYSICAL EXAM AT FOLLOW UP

Head Circumference

Weight! I I ' I I I kg For Age (percentile) 80% 20-50% Drug Dosage: mg/dose Current _________ increase to

190

Eye:

Normal

If Abnormal: Conjunctivitis Dendritic lesions Blindness Other: Specify

Yes

Abnormal

No

Unknown

Skin:

Hearing: Normal Abnormal If Abnormal,* Right Left ‘Attach Report

Recurrent skin vesicles? Yes

No

If Yes: 1st recurrence 2nd recurrence Other # recurrences since patient was last seen

□□

Was CSF obtained if 1st or 2nd recurrence? Yes No

B.1.10

Form 12 Clinical Evaluation Continued P a t i e n t Initials

P a t i e n t Study # J" |

Protocol

[

I

Location

Study Center # 14

T r e a t m e n t Day D a t e (Month/Day/Year)

21

n i i i i i1 1

28

1_ 1 1 1 1 1

1 1 1 1 11 1 1 1 1

SECTION A : OBSERVATIONS IF PATIENT IS EVALUABLE, COMPLETE SECTION B, OTHERWISE GO TO SECTION B.

o

□ naan

□□

p □

o

□ □

□□

□ o

o□□

□ o

□

o □□□□

o

CNE’

□

□□□□□

NO

□□□□□

YES

□

Visual Field Loss. Personality Change

CNE’

□□□□

□

H e a r i n g Loss

NO

o

oo

o

--------- ------

Person

YES

□□o o

CNE’

NO

□

YES

□□□□

CNE*

□□

n

n

NO

□

Place .. ---------

r ' | o

YES

□□

..................... ............................... D i .t s a Time

Not Evaluable

O

o□

□

□□

□

□□□ □

□□

□oo□

□□

□ooo

□□

B.1.11

□□

□o□ o

□ □ □

o □ □

o o □ □oo□

Could Not Evaluate

No 1 1 res

T—MBS

Attached Not available

□□ □□□

*CNE

If YES.

SRSKSU ■asm oO □

Yr

□1

Day /

. .......... .. ..... ....

□□ □□□

I f patient died, w a s autopsy performed:

1

O

/

□o□

Mo

□

|

I f patient died, please enter date o f d e a t h :

0 0

o

Frequent ( > 5 / d a y ) Cutaneous herpetic lesions

□

Infrequent ( < 5 / d a y )

□o

s

oo

Prolonged ( > 2 0 m m . )

□□

a

□

□

Brief ( < 5 m i n u t e s ) I n t e r m e d i a t e (5-20 m i n . )

□□

z u

□o

Focal Generalized

oo

S

□□

o

Spasticity

0

□o

□

o □□□

□

Hemiparesis

□□□□

Dysphasia - A p h a s i c

□□□□

Papilledema

BirnWUHW

Ataxia U n e q u a l Pupils

□

SECTION B: PHYSICAL EXAMINATION

Form 3 8 Patient F o l l o w - u p C o n t i n u e d Patient Initials

Patient Study # Protocol r ”

F

M

]

L

I

I

I

Study Center# GENERAL EXAMINATION

Please V

Normal

Please provide details of any abnormalities

Abnormal

Head/Neck ENT Chest Heart Lungs Abdomen Liver Spleen Extremities Neuro.

NEUROLOGICAL TESTS: Was an EEG performed at this follow-up? No Yes If Yes, were the results within normal limits? Yes No Was a CAT Scan performed at this follow-up? (To Be Done at 3,6, 12 Months as medically indicated) No Yes If Yes, were the results within normal limits? Yes No Send above reports to Central Unit

Psychological Assessment Done:

Yes

No

Send reports t o Central Unit

HSV Serum Antibody: To be sent to Central Unit at 6 months Serum obtained No Yes Send serum to Central Unit

Was CSF obtained at this follow-up? (To Be Obtained with the First Two Skin Recurrences*) Yes No If yes, were the results within normal limits? Yes No

*Send fluid sample to Central Unit

C o m m e n t s a n d O t h e r Findings:

192

B.1.12

Location

Form 5 Enrollment and P.E.

DISEASE CLASSIFICATION CNSOnly: H Disseminated O n l y : ~ CNS 8 Disseminated: LZ Patient Initials

D a t e Enrolled

P a t i e n t Study # Protocol

F

M

L

Study C e n t e r #

Date of Enrollment

Age at

I n t o Study

Enrollment

Sex

Location

Ethnic G r o u p : O

M o n t h / Day / Year 1

1

1

1

1

1

1

1

1

1

Idays

1__1

Male

|

Female

j

Caucasian

1 1 Hispanic Negro |

|

Oriental Other: Specify

W e i g h t a t Enrollment

Head Circumference

Pulse/min.

Temperature

a t Enrollment lbs

___ ___

i i i.i i i

0R

0R

_

kg

i n ■o

cm

I

I

I . I

I °C.

PHYSICAL E X A M AT ENROLLMENT SKIN N u m b e r o f Skin Vesicles

Site o f

Site o f

First Vesicle(s)

Secondary Vesicle(s)

□□□□□□□

a t Enrollment Head

m

Arms Trunk Perineum Legs Unknown None

EYES:

LUNGS:

Normal

□□□□□□□

Right

Left

Conjunctivitis Chorioretinitis

—

O t h e r : ____________ Specify ABDOMEN: [_J I

I

n

Normal Hepatomegaly

l~~l Splenomegaly

liver I |

|

[

| cm

spleen I |

|

|

| cm.

Normal Rales Tachypnea Retractions Decreased Breathing N o Breathing Sounds Other: SPECIFY

Necrotizing Enterocolitis Other:

O t h e r Findings a t E n r o l l m e n t :

(SPECitiv)

I

I

I

I

Hepatitis (As diagnosed by f enzymes, f direct bilirubin) Microcephaly Other:

B.1.13

(SPECIFY)

193

Form 31 Patient Follow-up

Date Enrolled

Patient Study #

Patient Initials

Protocol F

M

L Study Center #

Location

Follow-up Interval:

Follow-up Date Mo / Day / Yr

6 mo. 12 mo. 24 mo. 36 mo. 48 mo.

Functional Assessment: Patient is developing normally Patient is impaired — please describe:

Patient is institutionalized Patient died Date of Death Mo / Day / Yr

Cause of Death:

Autopsy performed? No Yes

Autopsy Report: Attached Not available

PHYSICAL EXAM AT FOLLOW UP Weight for Age (percentile)

Height for Age (percentile)

o

?□□□□ Z o Q

£□□□□

Normal Conjunctivitis Dendritic lesions Blindness Other: Specify

!□□□□

Skin:

□□□□□

□□□□□ Eye:

80% Hearing:

Normal Abnormal

Recurrent skin vesicles? No Yes # recurrences since patient was last seen

Comments and other findings:

194

80%

B.1.14

If Abnormal, Right Left

PLEASE ATTACH INTERIM SUMMARY REPORT OF PATIENT’S VISIT

PATIENT NUMBER: (7-9)

FINAL VISIT REPORT

FIRST 3 LETTERS OF LAST NAME: (10-12)

Page 1 of 1 DATE:

(13-20)

(2 1 - 2 6 )

HAS PATIENT DROPPED OUT OR DISCONTINUED THERAPY ?: (27)

1. No

2. Yes (If "Yes," Complete The Remainder Of This Visit And Study Termination Sheet) PHYSICAL EXAMINATION

1. pounds Or 2. kilograms

WEIGHT: (dO-Od)

L..1 I I •

SITTING BLOOD PRESSURE:

I systolic I I |/ I diastolic I I I

(33 -38 )

PULSE: (39 -41 )

______ FT I I

/minute

WERE THERE ANY SIGNIFICANT FINDINGS SINCE THE LAST EXAMINATION ?: (42)

1. No

2. Yes (If “Yes," Specify Below)

F ~|

(44-49)

(50-55)

STOOL EXAMINATION

HEMOCCULT TEST: (56)

NUMBER OF TABLETS RETURNED:

1. Negative

2. Positive

Bottle A : (57 -59 )

L_J_J_J

Bottle B: (60-62 )

I

i

I

I

(IF NOT RETURNED, INSERT DASHES ABOVE AND EXPLAIN):

WAS AIMS QUESTIONNAIRE ADMINISTERED ?:

1. No

2. Yes

(6 3 )

WILL PATIENT BE ENROLLED INTO THE HUMANITARIAN EXTENSION ?: (64)

1. No

DOSAGE INSTRUCTIONS:

2. Yes (If "Yes," Dispense Medication For Humanitarian Extension)

1. 50 mg b.i.d.

(65)*

COMMENTS: _________________________________________________________ _

__________________

Signature: .

B.1.15

195

PATIENT NUMBER:

INTERIM OR FINAL EXAMINATION

FIRST 3 LETTERS OF LAST NAME:

Page 1 of 1

month DATE:

I

I

I

day I

I

year I

I

I

H A S PATIENT DROPPED OUT OR DISCONTINUED THERAPY?:

1- No

WEIGHT:

III

BLOOD PRESSURE:

2. Yes Uf “ Y e s , ” Complete This Visit And Study Termination Sheet/

pounds

POSITION

RESPIRATIONS:

1

1

1 /min.

LLJ:LU I I I ■I I I

1. Supine 2. Standing

I I hl I I

diastolic

I I I hl I I systolic diastolic III l/l I I systolic

3. Sitting

°C

II

TIME (24 hr. clock)

systolic L E G E N D

CORE TEMPERATURE:

diastolic

I I I J / .I..J.. . .. I. ..I

PULSE:

Illi

/minute

PULSE:

Illi

/minute

PULSE:

I I I I

/minute

PHYSICAL EXAMINATION

H.E.E.N.T.:

1. Negative

2. Positive

MUSCULOSKELETAL:

1. Negative

2. Positive

PULMONARY:

1. Negative

2. Positive

NEUROLOGICAL:

1. Negative

2. Positive

CARDIOVASCULAR:

1. Negative

2. Positive

DERMATOLOGIC:

1. Negative

2. Positive

GASTROINTESTINAL:

1. Negative

2. Positive

CHEST X-RAY:

1. Negative

2. Positive

GENITO-URINARY:

1. Negative

2. Positive

E.K.G.:

1. Negative

2. Positive

IF THERE ARE ANY CHANGES FROM PREVIOUS PHYSICAL EXAMINATION OTHER THAN NEGATIVE FINDINGS, CIRCLE POSITIVE AND DESCRIBE BELOW:

46687

Signature:

196

B.1.16

____________________________________

PATIENT NUMBER:

HISTORY AND PHYSICAL EXAMINATION

FIRST 3 LETTERS OF LAST NAME:

Page 1 of 1

DATE OF BIRTH:

month

day

year

I I I LL] I I

DATE:

1. White

ORIGIN:

month

day

year

111I i I I I ! 1. Male

SEX:

2. Female

3. Oriental OCCUPATION: ________________________

4. Other: _ _ _ _ _

2. Black

(Specify)

HEIGHT:

I I I inches

WEIGHT:

Illi

pounds

TEMPERATURE:

Illi

. I

I °F

MEDICAL HISTORY

DRUG ABUSE:

1. Negative

2. Positive (Specify):..

HYPERSENSITIVITY:

1. Negative

2. Positive (Specify): _

H.E.E.N.T.:

1. Negative

2. Positive (Specify): _

PULMONARY:

1. Negative

2. Positive (Specify): _

CARDIOVASCULAR:

1. Negative

2. Positive (Specify):.

GASTROINTESTINAL:

1. Negative

2. Positive (Specify): _

HEPATIC:

1. Negative

2. Positive (Specify):.

RENAL:

1. Negative

2. Positive (Specify):.

MUSCULOSKELETAL:

1. Negative

2. Positive (Specify):.

NEUROLOGIC:

1. Negative

2. Positive (Specify): _

DERMATOLOGIC:

1. Negative

2. Positive (Specify): -

METABOLIC:

1. Negative

2. Positive (Specify):.

FAMILIAL DISEASE:

1. Negative

2. Positive (Specify):.

BLOOD PRESSURE:

L E G E N D

POSITION

TIME 124 hr. clock)

systolic

diastolic

systolic

diastolic

systolic

diastolic

PULSE:

1. Supine 2. Standing

PULSE:

/minute

PULSE:

/minute

3. Sitting

PHYSICAL EXAMINATION

H.E.E.N.T.:

1. Negative

2. Positive (Specify):

PULMONARY:

1. Negative

2. Positive (Specify):

CARDIOVASCULAR:

1. Negative

2. Positive (Specify):

GASTROINTESTINAL:

1. Negative

2. Positive (Specify):

______________________________________

GENITOURINARY:

1. Negative

2. Positive (Specify):

___

MUSCULOSKELETAL:

1. Negative

2. Positive (Specify):

NEUROLOGIC:

1. Negative

2. Positive (Specify):

_ _ _ _ __

DERMATOLOGIC:

1. Negative

2. Positive (Specify):

...................

CHEST X-RAY:

1. Negative

2. Positive (Specify):

___ _____

E.K.G.:

1. Negative

2. Positive (Specify):

____ ____

__

___

23088

Signature:

B.1.17

—

------------------------

197

PATIENT NUMBER:

PHYSICAL EXAMINATION

FIRST 3 LETTERS OF LAST NAME:

Page 1 of 1

month DATE:

HEIGHT:

day

year

I I I I I I I I I I I inches

WEIGHT:

Illi

LIST A N Y SIGNIFICANT FINDINGS BELOW (If "None," Circle):

pounds

NONE

H A S PATIENT USED ALCOHOL OR CAFFEINE I N THE PAST 7 2 HOURS?:

1. N o

2. Yes

W A S URINE D R U G SCREEN CONDUCTED?:

1. N o

2. Yes

I S SYSTOLIC BLOOD PRESSURE AT LEAST 110 m m H g A N D DIASTOLIC BLOOD PRESSURE AT LEAST 7 0 m m H g I N SUPINE, SITTING A N D ERECT POSITIONS?: 1. N o

2. Yes

DOES BLOOD PRESSURE DECREASE M O R E T H A N 2 0 m m H g SYSTOLIC Oft 1 0 m m H g DIASTOLIC I N ASSUMING THE ERECT POSITION F R O M THE SUPINE A N D DOES THE PATIENT HAVE SYMPTOMS O F ORTHOSTATIC HYPOTENSION?: 1. N o

2. Yes

40888

Signature:

B.1.18

198

____________________

Clinical Assessment Present

Sign Jugular Venous Distension

Yes

No

Q

Q

Comment

Ifyes,__4_

Distension

Centimeters' (at 4 5 degree angle)

Hepatojugular Reflux

Q

Point of Maximal Impulse

Q

FJ

Fl "anS

Fl i®sS

Pedal Edema

Q

Q

Q

Q

Q

Sacral Edema

Q

Q

Q

Q

Q

(location i n relation t o intercostal space)

Murmurs „

., hLsoands)

(S4)

Rates

Hepatomegaly

1 _ _ _Total liver span

E y e s ------------

Centimeters (at Right M.C.L)

NYHA Functional Class

Qi

□nsQnMQiliQlV

B.1.19

199

Physical Examination System

Comment

Finding

(Required for positive finding)

’ositive Negative

Dermatological

□

□

HEENT

□

□

Respiratory

□

□

Cardiovascular

□

□

Abdominal

□

□

Genital

□

Anorectal

□

J

Locomotor

□

□

Lymphatic

□

□

Neurological

□

□

OR □

Not Assessed

OR □

Not Assessed

B.1.20

200

PAGE 9 OF 25 ABSENCE O F ENTRY INDICATES TEST WAS NOT DONE (RANGES, AS ENTRIES, ARE NOT ACCEPTABLE)

PLEASE TYPE O R USE BLACK INK

____________________________ D O NOT WRITE I N SCREENED AREAS _________ PROJECT NO. STUDY EDP NO. AT. EDP NO. PATIENT IDENTIFICATION

INVESTIGATOR

INITIALS

1 1 1

I.D. NO.

PRE-STUDY OTHER MO. 1 DAY 1 YR. MO. 1 DAY YR. 1 1 1 1 1 1 1 1 t

SAFETY PANEL LABORATORY DATA (Date specimen collected) WRITE I N LABORATORY NAME

TIME SPECIMEN COLLECTED

A.M. PM.

:

A M. RM.

PRE-STUDY PHYSICAL EXAMINATION WEIGHT (lbs.) DATE MO. 1 DAY 1 YR. 1 1 1 1 1 1 RESR PULSE

TEMP (°F)

B.P.

: / NORM.

NOT DONE

SKIN

1

0 2

3

HEAD

1

2

3

EYES

C)1

D2

Q3

FUNDUSCOPIC

Q1

02

03

EARS

CJ1

D2

D3

NOSE

1

2

3

THROAT

1

2

3

1

MOUTH

0 2

3

NECK

01

0 2

0 3

LUNGS

D1

D2

03

HEART

1

BREASTS

1

ABDOMEN

1

LYMPH NODES

Qi

EXTREMITIES

1

2

3

2

0 3

E)2

0 3

2

3

02

3

NEUROLOGICAL

Di

D2

CJ3

GENITALIA

Di

0 2

Q3

PELVIC

1

2

3

RECTAL

1

0 2

3

CHEST X-RAY

Qi

COMMENTS (Data and sign all comments)

INtTlALS OF REVIEWER

ABNORM.

D2

D3

CHECK IF NONE

(Check one)

DATE STAMP

ACTION NOT NEEDED

B.1.21

ACTION NEEDED (See attached document tor action taken)

201

Page Investigator Name

Date (M/D/Y)

Study Site

Ml

Subject’s First Name

LI

VITAL SIGNS

Systolic BP

______ _______

mm Hg (supine)

Diastolic BP

______ _______

mm Hg (supine)

Pulse

______ _______

BPM (supine)

Temperature

______ _______

Respiration

______ _______

(If abnormal, describe)

NOR ABN PEHEAD

["""""1 1 1

PEEYES -

[ 1 1 1

PEEARS

l~l

PENOSE

1 1 1 1

PEORAL

1 1 1 1

PEPHAR

l~]

PELUNG

1 1 1 1

PEHART

D

PEABDN

1 1 1 1

PEXTM

1 1 1 1

PESKtN

1 1 1 1

PENEUR

1 1 [~l

Neurologic

1 1 1 1

Other (specify)

1 1

Head Eyes Ears Nose Oral Cavity Pharynx

1 1

Lungs Heart Abdomen Extremities Skin

B.1.22

202

°C RPM

Subject’s Study Number

Page 21 Visit

Day

Baseline

0

Date (m/d/y)

Investigator 1

Patient Identification* 2 I 2 3

1

i

Medication Code 3

i 'For Patient Identification use first 3 letters of first name then first 3 letters of last name

FOLLOW-UP PHYSICAL EXAMINATION No Change

Changed

Not

From Baseline

From Baseline

Examined

Comment if changed from baseline

General Appearance Skin HEENT Neck Heart Lung Abdomen

n

Genitourinary Extremities

Neurological Findings (Record on Day 0 Neurological Examination)

r .■ . A u Other significant findings:

Non

e

MD 1736

For

Use Only

J Initials

Date (m/d/y)

USE BLACK BALLPOINT PEN — PRINT LEGIBLY

B.1.23

203

PAGE 7 OF 25

HISTORY RECORD

(Significant operations, illnesses or trauma)

A

VITAL SIGNS DATE MO. 1 DAY 1 YR. 1 1 1 1

RESPIRATION

PULSE

TEMPERATURE

BLOOD PRESSURE /

VITAL SIGNS DATE MO. 1 DAY 1 YR. 1 1 1 1

TIME

DATE MO. 1 DAY 1 YR. 1 1 1 1

TIME

PULSE

TEMPERATURE

RESPIRATION

BLOOD PRESSURE

A.M. RM. /

:

VITAL SIGNS WEIGHT

TEMP

RESPIRATION

PULSE

/

DATE MO. I DAY I YR. I I I I

PHYSICAL EXAMINATION

(Check one for each category)

SKIN

B.R

A.M. RM.

NOT ABNORM. NORM. DONE Q3 2 1

NOT ABNORM. NORM. DONE 2 1 3

MOUTH

EXTREMITIES

NOT ABNORM. NORM. DONE 3 2 1

1

2

3

NEUROLOGICAL

1

2

3

HEAD

1

2

3

EYES

1

2

3

LUNGS

1

2

3

GENITALIA

1

2

3

FUNDUSCOPIC

1

2

3

HEART

1

2

3

PELVIC

1

2

3

EARS

1

2

3

BREASTS

1

2

3

RECTAL

1

2

3

NOSE

1

2

3

ABDOMEN

1

2

3

OTHER (Specify)

1

2

3

THROAT

1

2

3

LYMPH NODES

1

2

3

NECK

DESCRIBE ANY ABNORMAL FINDINGS

CHECK IF NONE

PHYSICAL EXAMINATION (Describe significant abnormal findings)

DATE OF EXAMINATION MO. I DAY I YR.

I I DESCRIBE METHOD OF BIRTH CONTROL (If applicable)

204

B.1.24

I I

NEGATIVE PREGNANCY TEST

PATIENT NUMBER:

PHYSICAL EXAMINATION

FIRST 3 LETTERS OF LAST NAME.

Page 1 of 1

month DATE:

day

year

I I I I I I I _I

WEIGHT;

I I I I pounds TIME

POST-DOSING HOUR

(24 Hour Clock)

0-1

| | |:| | |

LIST ANY SIGNIFICANT FINDINGS (If "None,” Circle):

NONE

4-8

I I |:| I I

LIST ANY SIGNIFICANT FINDINGS (If "None," Circle):

NONE

24

I I |:| I I

LIST ANY SIGNIFICANT FINDINGS (If "None," Circle):

NONE

OTHER

I I |:| I I

LIST ANY SIGNIFICANT FINDINGS (If "None," Circle):

NONE

lilllSliSlOlSlililiSSlllISSliSllO

WERE LABORATORY SPECIMENS DRAWN AT THIS VISIT?:

1. No

2. Yes

(Labs Required At Visits 1, 2, 2 4 Hours Post First Dose, O-Hour Pre-Second Dose, 2 4 Hours Post Second Dose, and Visit 5 (Discharge))

B.1.25

205

PATIENT NUMBER:

INTERIM OR FINAL EXAMINATION

FIRST 3 LETTERS OF LAST NAME:

Page 1 of 1

month

day

year

I I I I I I I I I

DATE:

H A S THE PATIENT DROPPED O U T OR DISCONTINUED THERAPY?:

1. No

WEIGHT:

I __

2. Yes (If "Yes," Complete This Visit And Study Termination Sheet)

1 1 pounds

BLOOD PRESSURE:

RESPIRATIONS:

POSITION

L

J _1 /minute

TEMPERATURE:

1I

1. 1 1 ° F

TIME (24 hr. dock)

systolic

diastolic

1 1 1 l/l 1 1 1

1. Supine

systolic

1 1 1 l/l

2. Standing

systolic

3. Sitting

PULSE:

I I I I /minute

PULSE:

I I I I /minute

PULSE:

Illi

diastolic diastolic

LL U/L 1 1 1

/minute

PHYSICAL EXAMINATION

H.E.E.N.T.:

1. Negative

2. Positive

MUSCULOSKELETAL:

1. Negative

2. Positive

PULMONARY:

1. Negative

2. Positive

NEUROLOGICAL:

1. Negative

2. Positive

CARDIOVASCULAR:

1. Negative

2. Positive

DERMATOLOGIC:

1. Negative

2. Positive

GASTROINTESTINAL:

1. Negative

2. Positive

CHEST X-RAY:

1. Negative

2. Positive

GENITOURINARY:

1. Negative

2. Positive

E.K.G.:

1. Negative

2. Positive

IF THERE ARE A N Y CHANGES F R O M PREVIOUS PHYSICAL EXAMINATION OTHER T H A N NEGATIVE FINDINGS, CIRCLE POSITIVE A N D DESCRIBE BELOW:

23688

Signature:

206

B.1.26

PATIENT NUMBER:

PRETREATMENT EVALUATION

FIRST 3 LETTERS O F LAST N A M E :

Page 2 of 3 month DATE:

day

year

I I I I I I I I systolic

BLOOD PRESSURE:

diastolic

I I I l/l I I I

SURFACE AREA:

Illi

PULSE:

□ . I I I m2

I I I . [~1 °C

TEMPERATURE:

WEIGHT SIX M O N T H S AGO:

/minute

PRESENT WEIGHT:

kilograms

PRETREATMENT WEIGHT LOSS:

DOSE TO BE ADMINISTERED:

I I I I I mg/m2

10-EdAM (Days 1 And 8 O f Each Course):

mg

CISPLATIN (Day 1 O f Each Course):

mg

CYCLOPHOSPHAMIDE (Day 1 O f Each Course):

mg

ZUBROD PERFORMANCE STATUS (Circle One Response Below): DEFINITIONS

SCALE

0

ASYMPTOMATIC

1

SYMPTOMATIC, FULLY AMBULATORY

2

SYMPTOMATIC, I N BED LESS T H A N 5 0 % OF DAY

3

SYMPTOMATIC, I N BED MORE T H A N 5 0 % O F DAY, BUT NOT BEDRIDDEN

4

BEDRIDDEN PHYSICAL EXAMINATION

NONE

LIST A N Y SIGNIFICANT FINDINGS (If "None," Circle): (Including Evaluable Clinical ParameterlsJ)

BA.ll

207

PATIENT NUMBER:

PHYSICAL EXAMINATION

FIRST 3 LETTERS OF LAST N A M E :

Page 1 of 1

month

day

year

I I I I I I LI ..

DATE:

hours WEIGHT:

minutes

TIME POST DOSE:

HEIGHT: TIME BLOOD PRESSURE

POSITION

(minutes)

uZmOmr

systolic 1. Sitting 2. Standing 3. Supine

LIST A N Y SIGNIFICANT FINDINGS (If "None," Circle):

PULSE:

Illi

/minute

PULSE:

Illi

/minute

PULSE:

Illi

/minute

PULSE:

Illi

/minute

NONE

__________

COMMENTS:

B.1.28

208

diastolic

PATIENT NUMBER:

INTERIM PHYSICAL EXAMINATION Page 1 of 1 DATE:

month I

I

FIRST 3 LETTERS OF LAST NAME:

day

I

I

I

year I

I

I

HAS PATIENT DROPPED OUT OR DISCONTINUED THERAPY?:

1. No

2. Yes (If “ Y e s , " Complete Final Visit Report Forms And Study Termination Sheet) PRE-DOSE PHYSICAL EXAMINATION

WEIGHT:

I

I

I~1 pounds

systolic SUPINE BLOOD PRESSURE:

diastolic

1 1 1 1/ITI systolic

SITTING BLOOD PRESSURE:

1 1 1 1/1 systolic

| /minute*

PULSE:

| _ _L

1 1 1

PULSE:

1 _ _L 1 1 /minute

PULSE:

I _ _1 1 1 /minute

diastolic 1/1

STANDING BLOOD PRESSURE:

j

1

diastolic

1 1 1

LIST ANY SIGNIFICANT FINDINGS SINCE THE LAST EXAMINATION (If " N o n e , " Circle None) :

NONE

2-HOUR PHYSICAL EXAMINATION

WEIGHT:

III

I pounds systolic

diastolic

SUPINE BLOOD PRESSURE:

l/l systolic

1 1

1

1/1 1 1 1

SITTING BLOOD PRESSURE:

sysfo/Zc

| _ _L 1 1 /minute

PULSE:

I _ _L 1 1 /minute

diastolic

] / LI..1 . .1

STANDING BLOOD PRESSURE:

PULSE:

diastolic

PULSE:

_ _1

1 1 /minute

LIST ANY SIGNIFICANT FINDINGS SINCE THE LAST EXAMINATION (If "None, " Circle None) :

NONE

24-HOUR PHYSICAL EXAMINATION

WEIGHT:

Illi

pounds systolic

SUPINE BLOOD PRESSURE:

1

diastolic

1 1 1/1

l/l

SITTING BLOOD PRESSURE:

1 1 1

PULSE:

I _ _L 1

PULSE:

I _ _L 1 1 /minute

PULSE:

| _ _1

1 /minute

1 1 1 diastolic

systolic STANDING BLOOD PRESSURE:

1 1 1 diastolic

systolic

l/l

1 1 1

1 1 /minute

LIST ANY SIGNIFICANT FINDINGS SINCE THE LAST EXAMINATION (If "None, " Circle None) :

Signature:

B.1.29

NONE

........ .......................

209

PATIENT NUMBER:

I N T E R I M VISIT REPORT

FIRST 3 LETTERS OF LAST NAME:

Page 1 of 1

month

day

year

I I ..I I I. I I I

DATE:

H A S PATIENT DROPPED OUT OR DISCONTINUED THERAPY?:

2. Yes (If "Yes," Complete Forms At This Visit Where Appropriate And Study Termination Sheet)

1. No

PHYSICAL EXAMINATION

WEIGHT:

Illi

pounds

TIME

TIME

(Hours)

(24 Hour Clock)

SITTING BLOOD PRESSURE

systolic

0

diastolic

1 1 1 l/l 1 1 1 systolic

2

diastolic

l/l 1 1 1 systolic

4

diastolic

l/l 1 1 1 systolic

8

diastolic

l/L 1 1. .1 systolic

12

diastolic

J/LLU

LIST A N Y SIGNIFICANT FINDINGS SINCE THE LAST EXAMINATION (If "None," Circle):

DRUG DISPENSING

CIRCLE ONLY ONE CHOICE:

1. Aspirin 325 mg 20 mg

2.

3. Aspirin 325 mg

+

2 0 mg

B.1.30

210

PULSE

(/minute)

NONE

FOLLOW-UP FORM 29 - BRIEF SYMPTOMS P a t i e n t Number:

Date o f Pat l e n t V i s i t :

Study I D :

S u b u n i t Code:

Study week:

Key O p e r a t o r Code:

Instructions:

Enter Karnofsky Score.

Page 1 o f 2 ___/ /_ (dd/mmm/yy)

E n t e r a - 1 i f t h e K a r n o f s k y Score was n o t p e r f o r m e d .

( R e f e r t o Appendix 6 f o r s c o r e d e s c r i p t i o n s )

1.

KARNOFSKY SCORE:

2.

Has t h e p a t i e n t had any symptoms s i n c e l a s t v i s i t ? (AT BASELINE: Has t h e p a t i e n t had any symptoms w i t h i n t h e l a s t 30 days o r w i t h i n a p r o t o c o l - s p e c i f i e d t i m e l i m i t ? ) .......................................... Y

N

E n t e r a - 1 I n t h e Symptom Code f i e l d f o l l o w i n g t h e l a s t e n t r y . I F YES, COMPLETE SECTION Symptom Code 1

Descr I p t i o n o f Symptom

# Days P r e s e n t 2

Sever I t y G r a d i n g3

a. b. c. d. e. f. gh. I. j. k.

Symptom Code: 2

R e f e r t o Appendix 8 f o r a p p l i c a b l e symptom c o d e s .

At B a s e l i n e :

Number o f days p r e s e n t w i t h i n l a s t 30 days o r w i t h i n a protocol-specified time limit. At Regular V l s i t s / C o n t a c t / F o l low-up: Number o f days p r e s e n t s i n c e l a s t v i s I t / c o n t a c t / f o l low-up S e v e r i t y Score Code:

1 2 » 34 9 »

M i l d , a b l e t o c a r r y o n normal a c t i v i t i e s Moderate and i m p a c t s o n normal a c t i v i t i e s Severe and u n a b l e t o p e r f o r m d a l l y a c t i v i t i e s L i fe-threatening, requi r Ing hospl ta I I zat ion Not a p p l i c a b l e

B.1.31

211

POST TREATMENT PHYSICAL EXAM FORM

PROTOCOL

Inv. No.

Visit No.

Date

Pt. Initials

Pt. No.

MO

DAY

YR.

PHYSICAL EXAM

Weight I

I

i-----1 lbs.

Fundoscopy: Grade KW (circle one)

NORMAL

ABNORMAL

0

12

3

Check appropriate box and describe any abnormalities. Comment on any changes since pretreatment physical exam.

Eyes ooooooooooc

□□□□□□□□□□a

Ears Nose Mouth Throat Glands Lungs Heart Abdomen Liver Lymph Nodes Extremities Genitalia Other, specify

B.1.32

212

4

INTERIM PHYSICAL EXAM Inv. No.

Protocol

Pt. nitials

Date

Pt. No. Month

Day

Visit No. Year

02

Please conduct a physical examination o n t h e patient, t h e n answer t h e question below. W e r e there any significant findings since t h e previous examination? I~~|Q = N o

Q 1 = Yes (If yes, specify below)

B.1.33

213

Inv. No.

Protocol

Patient's Initials

Patient No.

(Firjt. Middle. L*$t)

CLINICAL SYMPTOMS A t the pre-therapy assessment please check the box indicating the presence or absence of symptoms appropriate t o the patient's diagnosis. For subsequent assessments indicate progress by recording the corresponding number: 0 = not applicable/not evaluable 1 = unchanged 2 = improved 3 = worse 4 = disappeared Pre-therapy

Interim

Interim

Interim

Posttherapy

Follow-up

Date Present

Absent

—

—

'

■

Pneumonia cough

—

—

—

dyspnea

— —

chest pain sputum production Septicemia

—

—

—

—

malaise

:::::::

myalgia

....

abdominal pain guarding rebound UTI

—

—

—

—

—

flank pain hematuria

—

dysuria frequency

B.1.34

214

—

DURING TREATMENT ASSESSMENT - D A Y 3 - 5 Inv. No.

Protocol

Specify:

°F

TEMPERATURE:

Pt. Initials

Pt. No.

|

Present

SYMPTOMS (Check one)

Irritable, fussy Lethargy Otalgia, ear p u l l i n g Anorexia Vomiting Impaired hearing Insomnia

|

[Rectal

[Axillary

Absent

nnnnnnnm

mnrmnnn

Temperature a t h o m e £ 100. 4°F (37.9°C)

I

|Oral

Date

Otorrhea

OTOSCOPIC FINDINGS (Check o n e for each ear) Right ear Absent

Present

Left ear Present

Absent

I

Erythema Opacification

I

Distorted or Obscured Landmarks Distorted or Obscured Light Reflex

_I

Impaired M o b i l i t y Fullness, b u l g i n g Perforation Otorrhea

I

Effusion

ADDITIONAL PHYSICAL FINDINGS (check one) W e r e there any n e w significant physical findings since t h e last visit? D

No

Yes _

I f yes, what?

_____

Date: ____________________________________________________________._______ _ _ __ _ _—

B.1.35

215

PATIENT SCREENING (cont'd) IDENTIFICATION

: Inv. No.

Protocol

Pt. Initials

Month

(firu. Middle, lajl)

>

4

Height I

I ins.

I

Date

Pt. No.

D*y

PRE-TREATMENT PHYSICAL E X A M Weight

lbs.

Fundoscopy K-W Grade (Circle one) 3

12

4

NORMAL Eyes Ears Nose Mouth Throat Lungs Heart Abdomen Liver Extremities Genitalia Musculoskeletal Neurologic Dermal Lymph nodes Other (specify)

titititjtjtjtititjtit]tititit)tii2

0

Check appropriate box and describe any abnormalities.

B.1.36

216

Year

PATIENT NUMBER:

INTERIM VISIT REPORT

FIRST 3 LETTERS OF LAST NAME:

Page 1 of 1

month

year

day

DATE: H A S PATIENT DROPPED OUT?:

1. No

WEIGHT:

2. Yes (If "Yes," Complete Final Visit Report Forms And Study Termination Sheet)

1

1

DOSAGE: DOSE ADMINISTERED: FUNDUSCOPY:

1

_J • 1 _1 kg L 1. 1 1 1 mg/'m? 1 1.1 1 1 1 Imo 1

SURFACE AREA: TIME START INFUSION: TIME END INFUSION:

[Z1.1. 1 M | _ _1 J • 1_I-..1 (24 Hour Clock) 1 1 J • 1 1 1 (24 Hour Clock)

RIGHT

1. Normal

2. Abnormal (Specify Below)

3. Not Required

LEFT

1. Normal

2. Abnormal (Specify Below)

3. Not Required

PHYSICAL EXAMINATION

LIST ANY SIGNIFICANT FINDINGS SINCE THE LAST EXAMINATION (If "None," Circle):

NONE

(Including Evaluable Clinical Parameter(sl)

PERFORMANCE SCALE (Circle One):

0

Normal activity; asymptomatic

1

Symptomatic; fully ambulatory

2

Symptomatic; in bed < 50% of time

3

Symptomatic; in bed 50% of time; not bedridden

4

100% bedridden

5

Dead

B.1.37

217

PATIENT NUMBER:

INTERIM VISIT REPORT

FIRST 3 LETTERS OF LAST NAME:

r Illi

Page 1 of 1 month DATE:

day

year

I I I I I I IT I

H A S PATIENT DROPPED O U T OR DISCONTINUED THERAPY?: 1. N o

2. Yes (If "Yes," Complete Final Visit Report Forms A n d Study Termination Sheet!

INDICATE THE TOTAL NUMBER OF TABLETS/CAPSULES RETURNED:

IIII Illi

BOTTLE A: BOTTLE B:

tablets capsules

PHYSICAL EXAMINATION

WEIGHT:

Illi.I I

kg

systolic BLOOD PRESSURE:

diastolic

I I I I/1 II 1

PULSE:

LIST A N Y SIGNIFICANT FINDINGS SINCE THE LAST EXAMINATION Uf "None," Circle):

PERFORMANCE SCALE (ECOG) (Circle One):

Illi

/minute

NONE

0 . Fully Active (Karnofsky 90-100) 1. Restricted I n Physically Strenuous Activities, But Ambulatory (Karnofsky 70-80) 2 . Ambulatory, Capable O f Self-Care, Unable To Work, U p M o r e T h a n 5 0 % O f Waking Hours (Karnofsky 50-60) 3 . Limited Self-Care, Confined To Bed Or Chair M o r e Than 5 0 % O f Waking Hours (Karnofsky 30-40) 4 . Completely Disabled, N o Self-Care (Karnofsky 10-20)

B.1.38

218

T

,

PHYSICAL EXAMINATION REPORT FORM (Pretreatment) Visit 0

Patient's Initials (First, Middle, Last)

Patient Number 1 _ _ _1 1 1

Date of Visit (Mo/Day/Yr) _____/ _____/ _ _ _ _ Weight

Height

_______lbs.

______ ins.

Sitting Blood Pressure

Sitting Pulse 1

1

1

Ibeat s/min.

1

1

1 _l / l

1

1

Imm Hg

Check N == Normal, A = Abnormal (give pertinent details)'

Anatomy Eyes'

N

A

Ears

N

A

Nose

N

A

Mouth and Throat

N

A

Neck

N

A

Chest"

N

A

Heart

N

A

Abdomen

N

A

Extremities

N

A

N

A

Skin

N

A

Lymph Nodes

N

A

Other _______________________

N

A

N

A

o

Nervous System

n

Other _ ___________ . __________ ‘Excluding Corrective Lenses “Excluding Asthma

Chest X-Ray (specify date, if not done, enter N.D. ________)

Comment if Abnormal: ___________________________ Date ________

ECG (12-Lead) Date (specify date; attach copy of _____ ___ tracings to this Case Report Form.)

N

A

_______________________________________________ Comment if Abnormal: ____________________________

N

A

___________ . ___________________________ _ __ _ _-

COMMENTS

B.1.39

219

PROT. NO.

PATIENT INITIALS

ALLOC. NO.

please print or write clearly

HISTORY Allergy: Cardiovascular system: Pulmonary disease: Neurologic/CNS disorder: Gastro-intestinal disorder: Renal disease: Diabetes: Liver disease: Skin disorder: Musculo-skeletal disorder: Other:

PHYSICAL EXAM General appearance: Lymphatic: HEENT: Neck: Chest: Heart: Liver: Spleen: Abdomen: Skin: Extremities: Neurologic: Genitals: _Other:

220

B.1.40

|

EFFICACY AND SAFETY STUDY—PARTIAL SEIZURES

INVESTIGATOR’S ASSESSMENT

Cmpd*

Pro). #

IND*

NDA #

Protocol No.:

Study No.:

Dept:

Section:

WEEK 2

PATIENT’S INITIALS:

_______

PATIENT# -------------------------

DATE — — / — M D Y

F M L

Relationship of Abnormality to AED Therapy

Comment on all abnormalities.

YES

1. Gen'l Behavior:

NT

Norm

Abn.............. ..........

2. Gait:

NT

Norm

Abn.............. ..........

3. Speech:

NT

Norm

Abn.............. ..........

4. Coordination:

NT

Norm

Abn.......................

5. Nystagmus:

NT

No

Yes ......................

6. Pupillary Reflex;

NT

Norm

Abn........................

7. Mental Status:

NT

Norm

Abn.............. ..........

8. Cardiovascular:

NT

Norm

Abn.............. ..........

9. Level of Alertness:

NT

Norm

Abn.............. ..........

Possibly

No

Link.

(NT-Not Testable) Comments (Please refer to item number for each comment):

Edited by

M.D.

Date Date

B.1.41

Investigator’s Signature

221

PATIENT NUMBER:

INITIAL PHYSICAL EXAMINATION Page 1 of 1

month

FIRST 3 LETTERS OF LAST NAME:

day

year

DATE: PHYSICAL EXAMINATION

HEIGHT:

inches

WEIGHT:

systolic

diastolic

SUPINE BLOOD PRESSURE:

systolic

PULSE:

/minute

PULSE:

/minute

PULSE:

/minute

diastolic

SITTING BLOOD PRESSURE:

systolic

pounds

diastolic

STANDING BLOOD PRESSURE:

LIST A N Y SIGNIFICANT FINDINGS BELOW (If "None, " Circle None) :

NONE

32188

Signature:

222

B.1.42

______________________________________

FORM 5 - BASELINE EVALUATION

STUDY Patient

Number:

Page 4 of

4

L I M I T E D PHYSICAL EXAM

12. V i t a l Signs: a) Temperature: (Cent Igrade)

(Fahrenheit)

b ) Respiratory Rate: (excurs lons/mln) c ) Radial Pulse ( S i t t i n g a f t e r 3 m l n . ) : d) Blood Pressure (mmHg) (Sitting after 3 mln.)

13. Weight:

lbs

OR

14. H e i g h t :

I nches

OR

Dlastol l c :

Systolic:

kg

•

cm

15. Does the p a t i e n t have s i g n i f i c a n t lymphadenopathy d e f i n e d as lymph nodes >1.0 cm diameter I n two o r more non-cont Iguous e x t r a - l n g u l n a I s i t e s ? ...........................................................................................................................

Y

N

D i d the p a t i e n t have a normal baseline physical exam ( e v a l u a t i o n ) ? . . . .

Y

N

16.

I f No, record c l i n i c a l signs o f disease, p h y s i c i a n observations o r abnormal p h y s i c a l f i n d i n g s :

17. Baseline Karnofsky Performance Score: (See Appendix 6 for Performance s c a l e )

B.1.43

223

B2

VITAL S I G N S

Clinical Report Form Drug Identification Indication

Visit ? Page 1 of ?

VITAL SIGNS: TEMPERATURE

If not obtained, enter an "X" here UNITS

METHOD

1 = Fahrenheit 2 = Centigrade

TEMPERATURE

UNITS

1 = Orally 2 = Rectally 99 = Other

METHOD

B.2.1.1

225

Clinical Report Form Drug Identification Indication

Visit ? Page 1 of ?

VITAL SIGNS: BLOOD PRESSURE

If not obtained, enter an "X" here POSITION r- W CO

= Sitting = Standing = Supine

POSITION

BLOOD PRESSURE (MM Hg)

HEART RATE (per minute)

SYSTOLIC / DIASTOLIC / / /

B.2.1.2

226

Clinical Report Form Drug Identification Indication

Visit ? Page 1 of ?

VITAL SIGNS If none, enter an "X" here

DATE MO DAY YR

TIME

SITTING BLOOD PRESSURE SYS / DIA mm Hg

I I

I I

I I

I

I I

I

I

I

I

HEART RATE min ' 1

RESPIRATIONS min -1

I I I I

I

I

II II

I

I

I

I

I

I

I

I

I

I I

I

B.2.2

227

Clinical Report Form Drug Identification Indication

Visit ? Page 1 of ?

| PULSE, BLOOD PRESSURE AND TEMPERATURE DATA | If none, enter an "X" here 1 = Fahrenheit

Temperature Recorded in

2 = Centigrade DATE

TIME Yr

Day

MO

PULSE SUPINE BPM

BLOOD PRESSURE TEMPERATURE SUPINE Degrees mm Hg I

I

I

I

I

I

I I

I

I

I

I

I

I

I

I

I I

I I

I

I

I

I

I

I

I

I

I

I I

I

I

I

I

I

I

I

I

I

I

I

I

I I I

I

B.2.3

228

DO

VITAL SIGNS

Compd. #

Proj. #

IND #

NDA K

NOT

Days 1-4

FILL Protocol #

Study #

IN

Vol. Init: ________________ Vol. # ____________ F M L

Dept.

Sec.

Note: Shaded areas are not to be completed. Actual Clock Study Scheduled Time Day Clock (24 Hour) Time 1

Supinet Blood Pressure Systolic/Diastohc

Pulse Rate Resp Rale Beats/Min. CountsMn

Standing! Blood Pressure SystohcCiastolic

Pulse Rate Beats/Min.

□ Comment and significant

07:00 . ... • W:

08:00

• :

■' ? .

I««

10:00

S;S' 1/day r e q u i r e s i n d w e l l i n g F o l e y o r Texas not e l I c i t e d not a p p l I c a b l e /

Date o f onset o f motor symptoms BEHAVIOR /MOOD I.

Mood 0 1 2 3 4 8 9

256

-

.

...................................................

normal s p i r i t s , n o d e p r e s s i o n depressed about I l l n e s s but d o e s n ' t I n t r u d e o n f u n c t i o n f r e q u e n t l y f e e l s depressed, I n t e r f e r e s w i t h f u n c t i o n i n g v e r y depressed, r e q u i r i n g m e d i c a t i o n o r r e g u l a r t h e r a p y severe d e p r e s s i o n , r e q u i r e s s u i c i d e p r e c a u t i o n s not e l ( c i t e d not a p p l i c a b l e

B.3.I1.3

/

FOLLOW-UP FORM 5 M I C R O NEURO -

Pat lent Number :

SECTION 5

H I S T O R Y AND EXAM

1

Page 4 of 8

Neurological Physical ( c o n t . )

J.

Social apathy/wl thdrawal 0 - normal s o c i a l i z a t i o n 1 - less i n t e r e s t but continues w i t h normal a c t i v i t i e s 2 - a c t i v i t i e s reduced because o f lack o f I n t e r e s t but maintains most contacts 3 - marked loss of i n t e r e s t I n f r i e n d s and normal s o c i a l a c t i v i t i e s , doesn't seek s o c i a l contact 4 - l i t t l e o r no meaningful s o c i a l I z a t Ion 8 - not e l I c i ted 9 - not appl icable

K.

Emotional l a b i 1 1 t y / a g i t a t Ion 0 - normal 1 - more a g i t a t e d or e a s i l y e x c i t e d , but doesn't a l t e r s o c i a l ability 2 - c l e a r l y l a b i l e o r hyperactive so t h a t social I n t e r a c t i o n s are a l t e r e d (Inappropriate I n s u l t s , hypomanlc behavior) 3 - maintained I n a s t a t e o f constant h y p e r a c t i v i t y or a g i t a t i o n , may experience h a l l u c i n a t i o n s 4 - frank d e l i r i u m 8 - not e l i c l t e d 9 - not appl Icable

Date o f Onset of HIV-related Behavioral Symptoms

/

/

HEADACHE ( w i t h i n l a s t 4 weeks) 0 - none o r occ. as before 1 1 Iness 1 - m i l d , occasional (1/week) 2 - moderate (nearly d a l l y , r e q u i r i n g repeated nonnarcotic ana I ges I cs 3 - severe ( d a l l y , r e q u i r i n g n a r c o t i c analgesics) 8 - not e l i c l t e d 9 - not appl Icable SEIZURES ( w i t h i n l a s t 4 weeks) 0 1 2 3 8 9

-

none s i n g l e p a r t i a l seizure repeated p a r t i a l or grand mal seizures frequent ( > 4/wk) p a r t i a l or generalized seizures not e l i c l t e d not appl Icable B.3.11.4

257

FOLLOW-UP FORM 5 MICRO NEURO -

SECTION 5

H I S T O R Y AND EXAM

P a t i e n t Number:

Page 5 of

Neurological Physical (cont.) SENSATION P a r e s t h e s i a s ( t i n g l i n g o r numbness) o r p a i n due t o n e u r o p a t h y none mi I d d i s t a l s e n s a t i o n s moderate d i s t a l s e n s a t i o n s t o a n k l e s o r w r i s t s severe d i s t u r b i n g s e n s a t i o n s i n t e r f e r i n g w i t h normal funct ion Ing 8 - not e l I c l t e d 9 - not a p p l I c a b l e 0 1 2 3

-

Comment :

MICRO NEUROLOGICAL EXAMINATIONS

LEVEL OF CONSC I OUSNESS/ AROUSAL 0 1 2 3 4 5 6 7 8 9

-

normal del irlous agitated anxious slow l e t h a r g i c but r e a d i l y a r o u s a b l e l e t h a r g i c , r e q u i r i n g frequent a r o u s a l stuporous, unresponsive to verbal s t i m u l i persistent vegetative state coma

Comment : MICRO MENTAL STATUS Or i e n t a t i o n T i m e : y e a r , season, d a t e , d a y , month ( 0 - 5 ; score 1 f o r each correct)

A t t e n t i o n and C o n c e n t r a t i o n S p e l l " w o r l d " , " h o r s e " , " b l a c k " , " c a t c h " o r "bread" backwards. ( 1 - 5 ; number l e t t e r s c o r r e c t b e f o r e 1 s t e r r o r ) F o l l o w a 3-stage command "Touch your l e f t e a r w i t h your r i g h t thumb and s t i c k out your tongue" l e f t e a r , r i g h t thumb, ( 1 - 3 ; s c o r e 1 f o r each c o r r e c t a c t i o n ; tongue)

258

B.3.11.5

8

FOLLOW-UP FORM 5 - SECTION 5 MICRO NEURO - HISTORY AND EX/M P a t i e n t Number :

Page 6 o f 8

Neurological Physical (cont.) MOTOR S t r e n g t h ( w o r s t muscle g r o u p ) R Leg 0 1 2 3 8 9

normal ml I d weakness ( 4 / 5 ) moderate weakness ( 3 / 5 ) severe weakness ( 2 / 5 o r w o r s e ) not t e s t e d c o u l d not assess

-

L L e g . ..................................................................................................................... 0 - normal 1 - ml I d weakness ( 4 / 5 ) 2 - moderate weakness ( 3 / 5 ) 3 - severe weakness ( 2 / 5 o r w o r s e ) 8 - not t e s t e d 9 - c o u l d not assess ( S c r e e n l e g b y t e s t i n g toe & h e e l w a l k i n g , and deep-knee bend) R arm 0 1 2 3 8 9

normal m i l d weakness ( 4 / 5 ) moderate weakness ( 3 / 5 ) severe weakness ( 2 / 5 o r worse) not t e s t e d c o u l d not assess

-

L Arm

CM CO CO O>

0 - normal 1 - ml I d weakness ( 4 / 5 ) - moderate weakness ( 3 / 5 ) - severe weakness ( 2 / 5 o r w o r s e ) - not tested - c o u l d not assess ( S c r e e n arms b y t e s t i n g d e l t o i d s , b i c e p s , g r i p & f i n g e r s p r e a d )

Comment :

B .3.11.6

259

FOLLOW-UP FORM 5 M I C R O NEURO -

SECTION 5

H I S T O R Y AND EXAM

Patient Number:

Page 7 of

Neurological Physical ( c o n t . ) COORDINATION Ga i t Coordlnat Ion 0 1 2 3 4 7 8 9

-

norma I g a i t ml I d Impairment (evident only on r a p i d turns or tandem) moderate impairment (clear d i f f i c u l t y of unassisted g a i t ) severe Impairment (walking o n l y w i t h assistance) non-ambulatory weakness precludes assessment o f g a i t coordination not tested could not assess

Limb Coordlnat Ion ( r a p i d f Inger-oppos i t Ion, w r i s t r o t a t i o n or foot-tapping) 0 - normal 1 - ml I d slowness or clumsiness (compared to examiner the movement I s s l i g h t l y slower, fatigues o r breaks down e a r l i e r ) 2 - moderate slowness o r clumsiness (notably slowed and d y s a r t h r i c , r e a d i l y appreciated even a t s t a r t o f task) 3 - severe slowness or clumsiness 7 - weakness precludes t e s t i n g 8 - not tested 9 - cannot judge Comment : REFLEXES Deep Tendon Reflexes 0 1 2 3

-

normal Increased I n legs only generalized Increase general decrease (most notably d i s t a l l y ) Increased proximally & depressed d i s t a l l y Increased on one s i d e other not tested cannot judge

Comment :

260

B.3.11.7

8

FOLLOW-UP FORM 5 M I C R O NEURO -

SECTION 5

H I S T O R Y AND EXAM

P a t i e n t Number:

Neurological History

Page 8 o f 8

(cont.)

SENSATION Loss d u e t o n e u r o p a t h y 0 - normal 1 - mild Impairment (Increased threshold to position, vibration In great toes) 2 - moderate Impairment (decrease I n p o s i t i o n or v i b r a t i o n , p i n or cold to ankle) 3 - severe I m p a i r m e n t ( l o s s o f s e n s a t i o n i n l e g s t o knees o r w r i s t s 8 - d i d n o t assess 9 - c o u l d n o t assess Corrment :

_____________________________________________ MICRO NEUROPSYCHOLOGICAL EXAMINATION

D I G I T - S Y k B O L SUBTEST OF THE WAIS-R (WISC-R c o d i n g B f o r 1 2 - 1 6 y e a r o l d s ) ENTER NUMBER OF CORRECT RESPONSES

Impairment If

Age ( y e a r s )

Total » Correct < < <
9 0 seconds -

etc.,

-

score as 9 8 ;

score as 9 0 . )

261

4 3 2 1

COMMENTS:

OPENING

EYES

1

spontaneously t o shout to pain n o response

< 1 YEAR

PEDIATRIC C O M A SCALE

Best M o t o r Response

Eyes O p e n i n g

Entry

MoZ D a y / Yr

F

L

P a t i e n t Study # Protocol

r

J Study Center #

Location

I

RESPONSE

1

M o / Day/ Yr

Localizes p a i n Flexion A b n o r m a l Flexion-abnormal (Decorticate Rigidity) Extension (Decerebrate Rigitiy) N o Response

< 1 YEA R

M o / Day/ Yr

MOTOR

BEST

M o / Day/ Yr

RESPONSE

VERBAL

BEST

M o / Day/ Yr

B.3.12

M o / D a y / Yr

TREATMENT DAY

Smiles, coos, cries, a p p r o p r i a t e l y Cries I n a p p r o p r i a t e c r y i n g a n d / o r screaming Grunts N o response

0-23 MONTHS

M o / D a y / Yr

O n each t r e a t m e n t d a y i n d i c a t e d b e l o w , please select t h e m o s t a p p r o p r i a t e p a t i e n t response u n d e r each o f t h e t h r e e m a i n categories. E n t e r t h e n u m b e r o f p o i n t s corresponding t o t h e selected response in t h e a p p r o p r i a t e b o x f o r t h e t r e a t m e n t day. T h e n s u m t h e p o i n t s f o r each t r e a t m e n t d a y a n d e n t e r t h e t o t a l p o i n t s i n t h e a p p r o p r i a t e boxes.

IVI

P a t i e n t Initials

Form 10 Pediatric Coma Scale

9

262 LT> CC CsJ V-

B4

OPHTHALMOLOGICAL EXAMINATIONS

Compd. # DO IND #

OPHTHALMOLOGICAL EXAMINATION Screen

Proj. # NDA #

NOT FILL Protocol #

Study #

IN

Exam Date: _ _ _/ _ _ _/ _ _ _ M D Y

Vol. Init: _____________ F M L

Dept.

Vol. #: ____________

Sec.

INTRAOCULAR PRESSURE

O.D.

Goldmann applanation (mmHg)

O.S.

. ---------------------

---------------

SLIT LAMP EXAMINATION

Arcus Old inactive opacities Active inflammation Other (describe below)

□□□□°

Cornea, Conjunctiva and Sclera

□□□□§

Check ( V ) all abnormalities and comment below:

Anterior Chamber

O.D. O.S.

Cells or Flare Keratitic Precipitates Stain with 1% Rose Bengal Exudate Synechiae Other (describe below)

Lamellar separation Vacuoles Other (describe below)

COMMENTS:

No comment

□□□□□

Water clefts Opacities

□ □□□□

Lens

Comment but not significant

Comment and significant

B.4.1

263

OPHTHALMOLOGICAL EXAM SCREEN

Patient's Initials: _ _ _/ _ _ _ / ------ Patient # ----------------F

1. 2. 3. 4.

Does subject Visual acuity Visual acuity Visual acuity

M

M

L

D

Compd*

Proj. #

IND*

NDA tt

Protocol No.:

Study No.:

Dept:

Section:

Y

Yes

wear glasses or contact lenses? __________________ with glasses — right eye (Leave blank if not applicable) with glasses — left eye (Leave blank if not applicable) without glasses — right eye _____________________

No

COMMENTS

5. Visual acuity without glasses — left eye ______________________ 6. Tonometry (mm Hg) — right eye _____________________________ 7. Tonometry (mm Hg) — left eye ______________________________ 8. Gonioscopy — right eye (Open Angle. Narrow Angle or Closed) _ _ _ 9. Gonioscopy — left eye (Open Angle. Narrow Angle or Closed) _____ 10. Is near vision accommodation normal for this patient? ___________ 11. Has there been a clinically significant change in any of the above items since Screen? (Prot. tt 30) ____________________________

d Yes_____________

12. Slit Lamp: If abnormal, check ( V ) the following items if applicable a — Cornea — right eye b — Cornea — left eye c — Iris — right eye d — Iris — left eye e — Lens — right eye f — Lens — left eye

F l Normal

Yes

No

N.A.

d Abnormal Comments

______________________________ ______________________________ ______________________________

13. Funduscopic Examination: If abnormal, check (>/ ) the following items if applicable a — Disc — right eye b — Disc — left eye c — Macula — right eye d — Macula — left eye e — Vessels — right eye f — Vessels — left eye

d Normal

d Abnormal Comments

d d d

_________________ ______________________________

d d d

______________________________ ______________________________ ______________________________

14. Patient shows evidence of progressive ophthalmologic disease?

Comment on all Abnormal Findings:

No ______________

d Yes

d No

- _______________________________ _____________________________________

_______

M.D. Edited by

264

Date

Investigator’s Signature

Date

B.4.2

Investigator

Date (m/d/y)

Medication Code

Patient Identification* 1

2

3

1

2

3

•For Patient Identification use first 3 tetters of first name then first 3 letters of last name

Date of Examination (m/d/y)

Ophthalmologist’s Name

OPHTHALMOLOGIC EXAMINATION RIGHT EYE

Normal

LEFT EYE

Abnormal, specify

Normal

Cornea

Cornea

Anterior Chamber Depth

Anterior Chamber Depth

Anterior Chamber Activity

■< -J

Iris

Iris

Pupillary Light Reflex

Pupillary Light Reflex

Accommodation Reflex

Accommodation Reflex

_______ __ _____ _______ _______

Lens Posterior Chamber Foveal Reflex Macula kJ

_____ _ _____ _______ _______

Lens Posterior Chamber Foveal Reflex Macula

Disk

Disk

Q

Pigmentation

Pigmentation

LL

Retinal Vessels

Retinal Vessels

Extraocular Movements

Extraocular Movements

if)

_______

Anterior Chamber Activity ___________

CL

Abnormal, specify

Color Perception

_______

Color Perception

_______

Vertical Phoria

_______ _______

Vertical Phoria

_______ ____

Horizontal Phoria Visual Acuity

Horizontal Phoria

Tonometry By Indentation or Applanation

Tonometry By Indentation or Applanation

Other Findings _ None

Other Findings C None

This was (Check one)

20/

Visual Acuity

20/

initial study examination. followup examination with no significant change from initial study examination. followup examination with the following significant change(s) from initial study examination. Specify defect and probable cause.

MD-1237 (010189)

For

_______________________

Use Only

_I _ _I ___

____________________Initials _________________________ Date (m/d/y)

U S E B L A C K B A L L P O I N T P E N — P R I N T LEGIBLY

B.4.3

265

Protocol No.

Date of Exam

Month

Investigator's No.:

Subject No.:

Subject Initials:

' _ _ _ _' Year Day

BASELINE

OPHTHALMOLOGY EXAMINATION RESULTS 1 . FUNDUSCOPY

LEFT EYE

RIGHT EYE ABNORMAL

NORMAL

NORMAL

□

j ABNORMAL

DESCRIBE ABNORMALITY:

2 . TONOMETRY

_____ _ __mm Hg

________mm Hg

DESCRIBE ABNORMALITY:

3. SLIT LAMP

QNORMAL

ABNORMAL

NORMAL

WITH CORR. 20

WITHOUT CORR. 20'

□

ABNORMAL

DESCRIBE ABNORMALITY:

4 . VISUAL ACUITY

WITHOUT CORR. 20

WITH CORR. 20

DESCRIBE ABNORMALITY:

DATE ____________________ _ _ _

OPHTHALMOLOGISTS SIGNATURE

DATE

INVESTIGATOR SIGNATURE

266

B.4.4

PATIENT NUMBER:

OCULAR PROBLEM(S) Page 1 of 1 month DATE:

day

FIRST 3 LETTERS OF LAST NAME: year

I I I I I

LIST ANY N E W OR CONTINUING OCULAR PROBLEMIS) SINCE THE LAST VISIT THAT WERE NOT PRESENT AT THE INITIAL VISIT (If "None, " Circle Below):

%%%%%%%

(Codes For Reference Only) STUDY DRUG

SEVERITY

1 = Mild 2 = Moderate 3 = Severe

REGARDING

RELATIONSHIP

1 = Concomitant Illness — Not Study Drug Related 2 = Remote 3 = Possible 4 = Probable 5 = Definite

%%%%%

ACTION TAKEN

TREATMENT

PATIENT OUTCOME

REQUIRED

TO DATE

STUDY DRUG

1 = None 2 = Study Drug Dosage Changed 3 = Study Drug Temporarily Interrupted 4 = Patient Discontinued

1 2 3 4 5

= = = = =

None OTC Prescription Drug Hospitalization Non-Drug Therapy

1 = Recovered 2 = Medical Problem(s) Still Present 3 = Alive With Sequelae 4 = Death

O N S E T DATE (month/da y/yea r} nmwnn> inn,n i ........ rr ifvrfiir

STUDY

ACTION TAKEN

DRUG

REGARDING

SEVERITY

RELAT.

STUDY DRUG

REQUIRED

T O DATE

(Use O n e

(Use O n e

(Use One o r

(Use O n e o r

(Use O n e

C o d e Only)

M o r e Codets)]

M o r e Codelsil

C o d e Only)

(If “Continuing," OCULAR PROBLEM

Circle Below} aaaataaa

(Use Precise Medical

E N D DATE

Terminology}

ata—a-

(month/day/year)

C o d e Only}

PATIENT TREATMENT

OUTCOME

*********«*»*»*«*******e

NONE

.•.•.•.•.W.'.'.W'.W'.W.'.'.W*.

1. OD 2. OS

_ _ CONTINUING ___

1. OD 2. OS

_ _ CONTINUING ___

1. OD 2. OS

_ _ CONTINUING ___

1. OD 2. OS

CONTINUING ___

1. OD 2. OS

CONTINUING ___

1. OD 2. OS

_ _ CONTINUING ___

1. OD 2. OS

_ _ CONTINUING ___

15686

Signature:

B.4.5

— —

267

PATIENT NUMBER:

OPHTHALMOLOGIC EXAMINATION

FIRST 3 LETTERS OF LAST N A M E :

Paga 1 of 1 CORNEAL ENDOTHELIAL CELL COUNTS VISIT NUMBER

1

month day year CORNEAL THICKNESS: 0.1 I I mm

i' r if i i m

CELL COUNT:

10

I I I I I I I I" I

I I I I I /mm2

month day year CORNEAL THICKNESS: O.LLJ mm

mi

i im

CELL COUNT:

monf/> 22

I I I I I /mm2

month day year CORNEAL THICKNESS: O.l I I mm CELL COUNT:

16

LEFT EYE

RIGHT EVE

DATE

I I I I I /mm2

day year CORNEAL THICKNESS: O.l I I mm

i r ii r u n

CELL COUNT:

I I I I I /mm2

CORNEAL THICKNESS: CELL COUNT:

I I I I I /mm2

CORNEAL THICKNESS: CELL COUNT:

O.l I I mm

I I I I I /mm2

CORNEAL THICKNESS: CELL COUNT:

O.l I I mm

I I I I I /mm2

CORNEAL THICKNESS: CELL COUNT:

O.l I I mm

O.l I I mm

I I III

/mm2

28286

Signature: B.4.6

268

_________________

PATIENT NUMBER:

OPHTHALMOLOGIC EXAMINATION Page 1 of 1 DATE:

month

day

FIRST 3 LETTERS OF LAST NAME: year

I I I F I I I...I 2. Left

1. Right

TREATED EYE (Circle One! : CORTICAL CATARACT.

1. No

2. Yes

NUCLEAR SCLEROTIC CATARACT:

2. Yes

ANTERIOR SUBCAPSULAR CATARACT:

1. No 1. No

2. Yes

POSTERIOR SUBCAPSULAR CATARACT:

1. No

2. Yes

MORGAGNIAN CATARACT:

1. No

2. Yes

BEST CORRECTED VISUAL ACUITY (Complete One For Treated Eye) PUPILLARY DIAMETER

20/

i— |— |— | Illi

OD:

1

1

COUNTING i— |— | FINGERS: 1 1 1 feet

OS:

1 mm

NORMAL

SLIT LAMP (Treated Eye)

LIGHT PERCEPTION:

I

I

I

ABNORMAL

LID:

1

2

CONJUNCTIVA:

1

2

CORNEA:

1

2

ANTERIOR CHAMBER:

1

2 2

IRIS:

1

LENS:

1

2

POSTERIOR CHAMBER:

1

2

OD:

I

I

________

OS:

I mmHg

NORMAL

FUNDUSCOPY (Treated Eye)

2. Yes

mm

IF ABNORMAL, DESCRIBE:

GOLDMANN TONOMETRY

1 . No

I

I

I mmHg

ABNORMAL

NON-VISIBLE

DISC:

1

2

3

VESSELS:

1

2

3

MACULA:

1

2

3

IF ABNORMAL, DESCRIBE: _____________________________________________ _ _ ________

41487

Signature:

________________________- - ------------ --------

B.4.7

269

PATIENT NUMBER:

INITIAL OPHTHALMOLOGIC EXAMINATION

FIRST 3 LETTERS OF LAST NAME:

Page 1 of 1 month DATE:

I

I

I

day

. Year

II

m

RIGHT EYE I— |— |— |

COUNTING FINGERS:

BEST CORRECTED OR MANIFEST VISUAL ACUITY (Complete One For Each Eye)

LIGHT PERCEPTION:

PUPILLARY DIAMETER

OD:

SLIT L A M P

GOLDMANN TONOMETRY

20/

Illi

I

I

|— |— | I I I feet

1. No

2. Yes

COUNTING FINGERS:

Illi

LIGHT PERCEPTION:

I

I

|— |— | I I I feet

1 . No

2. Yes

NORMAL

ABNORMAL

2

I mm

NORMAL

ABNORMAL

LID:

1

2

LID:

1

ANTERIOR CHAMBER:

1

2

ANTERIOR CHAMBER:

1

2

LENS:

1

2

LENS:

1

2

VITREOUS:

1

2

VITREOUS:

1

2

IF ABNORMAL, DESCRIBE: __________________________________

IF ABNORMAL, DESCRIBE: __________________________________

OD:

OS:

I

I

I mmHg

I

I

I mmHg

IF GREA TER THAN 2 4 mmHg, PA TIENT C A N N O T ENTER STUD Y.

ABNORMAL

NONVISIBLE

NORMAL

ABNORMAL

NONVISIBLE

DISC:

1

2

3

DISC:

1

2

3

VESSELS:

1

2

3

VESSELS:

1

2

3

MACULA:

1

2

3

MACULA:

1

2

3

IF ABNORMAL, DESCRIBE: __________________________________

14388

Signature:

B.4.8

270

I— |— |— | 20/

OS:

I mm

NORMAL

FUNDUSCOPY

LEFT EYE

IF ABNORMAL, DESCRIBE: __________________________________

PATIENT NUMBER:

OPHTHALMOLOGIC EXAMINATION Page 1 of 1 DATE:

month

r--r— p

FIRST 3 LETTERS OF LAST NAME:

day

Illi

,

year

I I I I I..I I I I

H A S PATIENT DROPPED OUT OR DISCONTINUED STUDY DRUG THERAPY?: 1 . No

2. Yes (If "Yes, " Complete Final Visit Report Forms And Study Termination Sheet!

H A S PATIENT ADMINISTERED STUDY DRUG PROPERLY SINCE THE LAST VISIT?: 1 , No (If "No, " Describe Below)

2 . Yes

LEFT EYE

RIGHT EYE BEST CORRECTED OR MANIFEST VISUAL ACUITY (Complete One For Each Eye)

LIGHT PERCEPTION:

GOLDMANN TONOMETRY

OD:

20/

.— |— |— | Illi

I

I

COUNTING FINGERS:

|— |— r 1 1 1 feet

1 . No

2. Yes

20/

COUNTING FINGERS:

LIGHT PERCEPTION:

OS:

I mmHg

I— |— |— | Illi

I

I

|— |— | I I I feet

1 . No

2. Yes

I mmHg

B.4.9a

PATIENT NUMBER:

OPHTHALMOLOGIC EXAMINATION

FIRST 3 LETTERS OF LAST NAME:

Page 1 of 1 month DATE:

day

year

I 11 I I I I I I LEFT EYE

RIGHT EYE 1. Full

1 . Full

2 . Generalized Constriction

2 . Generalized Constriction

3 . Nasal Step

3 . Nasal Step VISUAL FIELDS

4 . Paracentral Scotomalsl

4 . Paracentral Scotoma(s)

5. Bjerrum Scotoma(s)

5. Bjerrum Scotoma(s)

6 . Split Fixation

6 . Split Fixation

7. Central and Temporal Islands

7. Central and Temporal Islands

8 . Temporal Island

8 . Temporal Island

CUP/DISC RATIO:

FUNDUSCOPY

PERIPHERAL FUNDUS:

D

1. Normal

CUP/DISC RATIO:

. 0

2 . Abnormal

DESCRIBE: __________________________________

PERIPHERAL FUNDUS:

D

1. Normal

. G

2 . Abnormal

DESCRIBE: __________________________________

14588

Signature:

B.4.9b

--------------

271

PATIENT NUMBER:

OPHTHALMOLOGIC EXAMINATION Page 1 of 1 DATE:

month

FIRST 3 LETTERS O F LAST N A M E :

year

day

I I I I 11 I I

H A S PATIENT DROPPED OUT OR DISCONTINUED THERAPY?:

2. Yes (If " Y e s , " Complete Final Visit Report Forms And Study Termination Sheet)

1 . No

LEFT EYE

RIGHT EYE

UNCORRECTED: 2 0 /

UNCORRECTED: 2 0 /

CORRECTED: 2 0 /

CORRECTED: 20/ SPECTACLE CORRECTION:

SPECTACLE CORRECTION: VISUAL ACUITY

AXIS

CYLINDER

SPHERE

(Distance) MANIFEST ACUITY: 2 0 /

I I _LI AXIS

CYLINDER

I

Fl

I

VISUAL ACUITY

CYLINDER

(Near) MANIFEST ACUITY: 20/

I I I I

CYLINDER

AXIS

Illi I I I I

SPECTACLE CORRECTION: AXIS

+ CYLINDER

+SPHERE

AXIS

n . m n . m rr

MANIFEST ACUITY: 20/

Illi

MANIFEST REFRACTION:

MANIFEST REFRACTION: SPHERE

AXIS

I I I I

CYLINDER

SPHERE

CORRECTED: 20/

SPECTACLE CORRECTION: SPHERE

MANIFEST ACUITY: 20/

UNCORRECTED: 2 0 /

UNCORRECTED: 20/ I l l i CORRECTED: 20/

CYLINDER

SPHERE

MANIFEST REFRACTION:

MANIFEST REFRACTION: SPHERE

I I I I

AXIS

CYLINDER

SPHERE

ACCOMMODATIVE AMPLITUDE

OD:

CORNEAL ANESTHESIOMETRY

OD: I

I

I mm

OS: I

I

I mm

PUPILLARY DIAMETER

OD: I

I

I mm

OS: I

I

I mm

GOLDMANN TONOMETRY

OD: I

I

I mmHg

OS: I

I

I mmHg

AXIS

14688

Signature:

272

B.4.10

_____________

DO NOT WRITE IN THIS SPACE (FOR USE I N COMPILING DATA)

PLEASE TYPE OR PRINT LEGIBL Y WITH BLACK BALL POINT PEN | OPHTHALMOLOGIST'S REPORT |

*Please

explain _

/

/ Mo

"X" in this

If eye examination was not performed, enter

I

I

Day

abnormal answers or Ophthalmologist's

| Left Eye | 20/ ____ 1 | 20/ ____ 1

| | 1 | 1

| RIGHT I II 4-

|

LEFT |

|

Report of abnormalities.

________ __________________ I I I 1

Date examined

Yr

| Right Eye 1 2 0 / _____ 1 1 2 0 / ____ 1

box.

Enter month, day, and year If patient was examined. m o n t h a n d d a y a r e unknown e n t e r d a s h e s ( - • ’ ) . ___________

Visual Acuity: (Corrected) } If vision is not corrected. I E n t e r d a s h e s ( - - ) . ____________

(Uncorrected)

| Enter the appropriate I for each test. 1 = Normal | 2 - Abnormal |

4-

result! | | |

EXTERNAL EYE: I ______________I I I ______________I ____________ | I ____________ I ______________| | | I

I , _______________________________ L i d _________________________________________ | C o n j u n c t i v a _____________________________________________________________________ S c l e r a __________________________ ________________________________ _____________ ________| | External Ocular Muscles S L I T LAMP:

_________J ________________________________________ C o r n e a ___________ 1 ______________I ____________ | I I ______________I ______________| __________ S t r o m a I __________________________________________ I ____________ I ______________| __________~ E n d o t h e l i u m I I ______________| _____________J __________ E p i t h e l i u m ________ I ____________________________________________ _______ Anterior Chamber I ______________| _____________ | I ! ______________| ______________| __________ F l a r e ( A b s e n t = N o r m a l )____________________________________________ I I ______________| ______________| __________ C e l l s ( A b s e n t = N o r m a l ) ______________________________________ _| Iris I ______________I ___________ I I P u p i l l a r y L i g h t R e s p o n s e _____ _ _ _ _ I ______________I ______________| I L e n s - ( A p h a k i c = A b n o r m a l ) _______ ________________________________________ I ______________I____________ | I ___________________ ( A b s e n t = N o r m a l ) _______ I ______________I ____________ j __________- C o r t i c a l C a t a r a c t ______ I I ______________|____________ | __________~ N u c l e a r C a t a r a c t ( A b s e n t = N o r m a l ) __________________________ | - Subcapsular Cataract (Absent = Normal) | | I FUNDUSCOPIC: I I I I I I I I I

| ______________I _______ ______________I ______________| ______________I ___________ | ______________I ____________ | ______________|_____________ | ______________( ______________| ______________| ___________ | __________I ___________ | ______________| ____________ |

_____________________ ___________,______________ Retina M a c u l a ____________________________________ P e r i p h e r y _________ V e s s e l s __________________________________ E x u d a t e s ( A b s e n t = N o r m a l )_________ _______________________________ Microaneurysms (Absent = Normal) H e m o r r h a g e ( A b s e n t = N o r m a l ) _____ ____________________________ N e r v e H e a d ____________ . ___________________ V i t r e o u s ________________________________

I —J I I J

I _________

I I I

TONOMETRIC:

1 ______1 mmHg 1 ______1 mmHg

1 ______1 M e t h o d U s e d

E n t e r t h e v a l u e s a n d t h e c o d e f o r m e t h o d u s e d i n the a p p r o p r i a t e | boxes. | 1 = Applanation | 2 = Schiotz | 3 = Electronic | _ _________________________________ I _____________________________________________

B.4.11.1

273

DO NOT WRITE IN THIS SPACE {FOR USE I N COMPILING DATA)

PLEASE TYPE O R PRINT LEGIBL Y WITH BLACK BALL POINT PEN I OPHTHALMOLOGIST'S REPORT (con’d.) | | I

Right | |

| |

mm

Left | |

| Enter the appropriate result. I 1 = Normal I 2 = Abnormal

| |

____ | | I

_| Enter the code for method used. I Attach a copy of the results. I 1 - Tangent Screen | 2 = Goldman | 3 = Automated Perimeter | ( e.g. ,Humphrey ,Field Master) I 9 9 = Other -(Note in I Ophthalmologist's Report of | abnormalities.)

| I I | I | | | |

Distance between patient and tangent screen

Ophthalmologist's Report of Abnormalities Specify details including description, location, severity, progression and recommendations.

Ophthalmologist's Signature

___________________________

____

_________

Date• Mo

Investigator's Signature

_ ______

__________

Date:

I Mo

B.4.11.2

/ / Day Yr I Day

Yr

OP - OPHTHALMOLOGIST’S REPORT These g r a p h i c s w i l l b e a v a i l a b l e f o r t h e second page o f t h i s module.

8

|1O

I S i l O l ___s

hs

B.4.11.3

275

B5

PSYCHOLOGICAL A N D PSYCHIATRIC TESTS Form 28 Mini Mental State

Patient Initialt

Patient Study # Protocol

F

[

|

L

M

Study Center A

Location

M I N I MENTAL STATE Maximum Score

Score ORIENTATION

5

(

)

What is the (year) (season) (date) (day) (month)?

5

(

)

Where are we: (state) (county) (town) (hospital) (floor)? REGISTRATION

3

(

)

Name 3 objects: 1 second to say each. Then ask the patient all 3 after you have said them. Give 1 point for each correct answer. Then repeat them until he learns all 3. Count trials and record. ATTENTION A N O CALCULATION

S

(

)

Serial 7's. 1 pent for each correct. Stop after 5 answers. Alternative spell 'world" backwards. RECALL

3

(

)

Ask for 3 objects repeated above. Give 1 point for each correct. LANGUAGE

9

(

)

Name a pencil, and watch: (2 points) Repeat the following, ' N o ifs, ands or buts.’ (1 point) Follow a 3-stage command: 'Take a paper in your right hand, fold it in half, and put i t on the floor.' (3 points) Read and obey the following: 'Close your eyes.* (1 point) Write a sentence. (1 point)

“““

TOTAL SCORE

(

)

ASSESS level o f consciousness along a continuum.

I Alert

Drowsy

B.5.1

Stupor

Coma ■

PATIENT NUMBER:

HAMILTON PSYCHIATRIC RATING SCALE FOR DEPRESSION Page 1 of 2

month

day

FIRST 3 LETTERS OF LAST NAME:

.— >— Illi

year

DATE: For each item, circle the number identifying the response which best characterizes the patient. 1. DEPRESSED MOOD (sadness, hopeless, helpless, worthless)

2 . FEELINGS OF GUILT

3 . SUICIDE

4 . INSOMNIA EARLY

5 . INSOMNIA MIDDLE

6. INSOMNIA LATE

7 . WORK AND ACTIVITIES

8 . RETARDATION Islowness o f thought & speech; impaired ability to concentrate: decreased motor activity) 9. AGITATION

10. ANXIETY PSYCHIC

278

0 . Absent 1. These feeling states indicated only on questioning 2. These feeling states spontaneously reported verbally 3 . Communicates feeling states non-verbally, i.e., through facial expression, posture, voice, and tendency to weep 4. Patient reports virtually only these feeling states in his spontaneous verbal and nonverbal communication 0. Absent 1. Self-reproach, feels he has let people d o w n 2. Ideas of guilt or rumination over past erros or sinful deeds 3. Present illness is a punishment, delusions of guilt 4. Hears accusatory or denunciatory voices and/or experiences threatening visual hallucinations 0 . Absent 1. Feels life is not worth living 2. Wishes he were dead or any thoughts of possible death to self 3. Suicide ideas or gesture 4. Attempts at suicide (any serious attempt rates 4) 0 . No difficulty falling asleep 1. Complains of occasional difficulty falling asleep, i.e., more than '/: hour 2 . Complains of nightly difficulty falling asleep 0 . No difficulty 1. Patient complains of being restless and disturbed during the night 2. Waking during the night — any getting out of bed rates 2 (except for purpose of voiding) 0 . No difficulty 1. Waking in early hours of the morning but goes back to sleep 2. Unable to fall asleep again if gets out of bed 0. No difficulty 1. Thoughts and feelings of incapacity, fatigue or weakness related to activities, work or hobbies 2. Loss of interest in activity; hobbies or work — either directly reported by patient, or indirectly in listlessness, indecision and vacillation (feels he has to push self to work or activities) 3. Decrease in actual time spent in activities or decrease in productivity. In hospital, rate 3 if patient does not spend at least three hours a day in activities (hospital job or hobbies) exclusive of ward chores 4. Stopped working because of present illness. In hospital, rate 4 if patient engages in no activities except ward chores, or if patient fails to perform ward chores unassisted 0 . Normal speech and thought 1. Slight retardation at interview 2. Obvious retardation at interview 3. Interview difficult 4 . Complete stupor

0 . None 1. "Playing w i t h " hands, hair. etc. 2. Hand-wringing, nail-biting, hair-pulling, biting of lips, etc. 0. No difficulty 1. Subjective tension and irritability 2. Worrying about minor matters 3. Apprehensive attitude apparent in face or speech 4. Fears, expressed without questioning

B .5.2.1

PATIENT NUMBER:

HAMILTON PSYCHIATRIC RATING SCALE FOR DEPRESSION Page 2 of 2 DATE:

month

day

FIRST 3 LETTERS OF LAST NAME: year

1. 1 I I I I I I I

11. ANXIETY SOMATIC

12. SOMATIC SYMPTOMS GASTRO-INTESTINAL

13. SOMATIC SYMPTOMS GENERAL

14. GENITAL SYMPTOMS

15. HYPOCHONDRIASIS

16. WEIGHT CHANGE (complete either A or Bl

0. Absent 1. Mild 2. Moderate 1 3. Severe ff 4. Incapacitating J

f 1 1 v

Physiological concomitants of anxiety, such as: Gastro-intestinal— dry mouth, wind, indigestion, diarrhea, cramps, belching cardio-vascular — palpitations, headaches respiratory — hyperventilation, sighing urinary frequency sweating

0. None 1. Loss of appetite but eating without staff encouragement. Heavy feelings in abdomen 2. Difficulty eating without staff urging, requests or requires laxatives or medication for bowels or medication for G.l. symptoms 0. None 1. Heaviness in limbs, back or head. Backaches, headache, muscle aches, loss of energy and fatigability 2. Any clear-cut symptom rates 2 0. Absent 1. Mild 2. Severe 3. Not ascertained

Symptoms such as: Loss of libido Menstrual disturbances

0 . Not present 1. Self-absorption (bodily) 2. Preoccupation with health 3. Frequent complaints, requests for help, etc. 4. Hypochondrical delusions A. When rating by history (pre-treatment): 0 . No weight loss or weight gain 1. Probable weight loss associated with present illness — 2. Definite (according to patient) weight loss 8. On weekly ratings by ward psychiatrist, when actual weight changes are measured: 0 . Less than 1 lb. weight loss or weight gain in one week 1. One to 2 lb. weight loss in one week 2. Greater than 2 lb. weight loss in week

17. INSIGHT

18. DIURNAL VARIATION

19. DEPERSONALIZATION AND DEREALIZATION

20. PARANOID SYMPTOMS

21. OBSESSIONAL AND COMPULSIVE SYMPTOMS

0. Acknowledges being depressed and ill 1. Acknowledges illness but attributes cause to bad food, climate, overwork, virus, need of rest, etc. 2. Denies being ill at all 0. Absent (no variation in symptoms a.m./p.m.) 1. Mild (minimal variation in symptoms a.m./p.m.) 2. Severe (significant variation in symptoms a.m./p.m.) 0. Absent 1. Mild 2. Moderate 3. Severe 4. Incapacitating

Such as: Feelings of unreality Nihilistic ideas

0. None 1. Suspicious 2. Ideas of reference 3. Delusions of reference and persecution 4. Persecutory hallucinations 0. Absent 1. Mild 2. Severe

61478 Signature:

B .5.2.2

.......— ________. _ _ _——------ -

279

B6

O T H E R SPECIALIZED PHYSICAL EXAMINATIONS

PATIENT NUMBER:

PRETREATMENT EVALUATION

FIRST 3 LETTERS OF LAST NAME:

Page 3 of 3

month

day

year

SITE OF FIRST METASTASES:

ANATOMIC SITE !Skm, Liver, Brain) month DATE OF FIRST METASTASES:

year

day

I I I I I I I I I

OTHER TUMORS:

1. No

SKIN:

2. Yes

if "Yes," Has Patient Been Disease Free For Five Years?:

PAST HISTORY O F THESE TUMORS: PROSTATE:

1. No

2. Yes

1. No

2. Yes

UTERINE/CERVICAL:

1. No

2. Yes

1. No

2. Yes

COLON:

1. No

2. Yes

1. No

2. Yes

H E A D A N D NECK:

1. No

2. Yes

1. No

2. Yes

EVALUATION O F PATIENT'S GENERAL CONDITION AT START OF STUDY DRUG THERAPY:

(Circle One For Each Category) PHYSICIAN:

1. Very Good

2. Good

3. Fair

4. Poor

PATIENT:

1. Very Good

2. Good

3. Fair

4. Poor

COMMENTS:

B.6.1

281

PATIENT NUMBER:

DIAGNOSIS AND EXTENT OF THE CANCER

FIRST 3 LETTERS OF LAST NAME:

Page 1 of 1 year

day

month DATE:

______________________________________________________________________ _______

PRIMARY SITE OF CANCER:

__________________________________________________________________________________________

HISTOLOGY:

month DATE OF DIAGNOSIS:

month

year

I I I I I I

DATE OF FIRST RECURRENCE:

I I I I I I

INDICATE DISEASE-FREE INTERVAL:

1. No Disease-Free Interval (i.e., Presenting With Stage IV Disease) 2. < 2 Years 3. > 2 Years INDICATE THE SITE OF THE BULK OF CURRENT DISEASE I N THIS PATIENT:

1. Soft Tissue le.g., Skin, Superficial Lymph Nodes) 2. Bone 3. Visceral (Liver, Lung, Peritoneum, Pleura) ER STATUS:

1. Positive ( > 5 fm/mg protein)

2. Unknown

3. Negative

PR STATUS:

1. Positive

2. Unknown

3. Negative

AROMATASE:

1. Positive

2. Unknown

3. Negative

B.6.2

282

year

PATIENT NUMBER:

DIAGNOSIS A N D EXTENSION OF THE CANCER

FIRST 3 LETTERS OF LAST N A M E :

Page 1 of 1

month

day

year

DATE: DIAGNOSIS

1. No

2. Yes

ADENOCARCINOMA:

1. Illb

2. IV

LARGE CELL:

1. Illb

2. IV

EPIDERMOID/SQUAMOUS:

1. Illb

2. I V

NON-SMALL CELL LUNG CANCER: HISTOLOGIC TYPE -

MEASURABLE DISEASE: DISEASE SITE

METHOD OF EVALUATION

MEASUREMENTS

(physical exam, x-ray, scan, etc.)

(perpendicular diameters in cm)

DATE

day

month

year

1.

/

2.

/

3.

/

m m III m m m m m

4.

/

I I II I II I I

m

EVALUABLE DISEASE: DISEASE SITE

DATE

METHOD OF EVALUATION

(physical exam, x-ray, scan, etc.)

month

day

year

2.

mmm

4.

IF AVAILABLE, PLEASE ATTACH COPIES OF REPORTS ON ALL TESTS TAKEN.

Signature:

B.6.3

...........— -------------— --------

283

PATIENT NUMBER:

CANCER MEASUREMENTS

FIRST 3 LETTERS OF LAST NAME:

Page 1 of 1

year

day

month DATE:

M E T H O D OF EVALUATION:

ADDITIONAL MEASUREMENT

(Specify) DATE:

I

I

I

year

day

month I

I

I

I

I

I

2. Abnormal

1. Normal

NON-MEASURABLE MEASURABLE iCircle One)

SITE

SIZE (cm)

1

2

I I l . l Ixl I I. I I

1

2

LLJ.UxLJJ.U

1

2

I I l.l LI I l.l I

1

2

I I I. I Ixl I l . l

METHOD OF EVALUATION:

ADDITIONAL MEASUREMENT

(Specify) month

day

year

1. Normal

DATE:

2. Abnormal

NON-MEASURABLE MEASURABLE (Circle One)

SITE

SIZE (cm)

X ADDITIONAL MEASUREMENT

METHOD OF EVALUATION:

(Specify) month

day

year

1. Normal

DATE:

SITE

2. Abnormal

NON-MEASURABLE MEASURABLE (Circle One)

SUBMIT COPIES OF ALL REPORTS

284

B.6.4

SIZE (cm)

FORM F

FOLLOW-UP FORM INSTITUTION

PROTOCOL STUDY NUMBER

MIDDLE INITIAL

FIRST

PATIENT'S LAST NAME

DATE FORM COMPLETED

EXAMINING PHYSICIAN - NAME AND ADDRESS

ASSIGNED TREATMENT ARM

METHOD O F PATIENT CONTACT

DATE PATIENT LAST SEEN OR CONTACTED

] TELEPHONE CONTACT TO PATIENT OR PHYSICIAN

|— | SEEN IN HOSPITAL I I OR CLINIC (Specify)

|— | OTHER I I (Specify)

DATE OF PHYSICAL EXAM

PHYSICAL FINDINGS SIDE OF MASTECTOMY

CHEST WALL

BREAST

SCAR SUSP.

NEG.

POS.

NEG.

SUSP.

NEG.

SUSP.

POS

NEG

SUSP

POS.

SUSP

POS

I NEG. I COMMENTS:

SUSP

POS

SUPRACLAVICULAR NODES

AXILLARY NODES

PARASTERNAL NODULES

NEG.

POS.

SUSP.

POS.

SUSP

POS

NEG

POS

SUSP

SKIN

OPPOSITE SIDE PARASTERNAL NODULES

CHEST WALL

BREAST NEG.

SUSP

POS.

NEG

SUSP.

NEG.

SUSP

POS

NEG.

SUSP

POS

POS

SKIN

SUPRACLAVICULAR NODES

AXILLARY NODES I NEG. I COMMENTS:

NEG.

POS.

OTHER PHYSICAL FINDINGS:

MANAGEMENT O F PATIENTS (FOR SUSPICIOUS OR POSITIVE FINDINGS, SUBMIT DOCUMENTATION) Date(s) Performed

Biopsy

Findings

Site:

NEG

SUSP.

Site:

NEG

SUSP

Chest X-ray/Lung Tomogram

NEG

SUSP

POS

NEG

SUSP

POS

NEG

1 _ _1 SUSP

NEG

o

susp

POS

NEG

C

SUSP

POS

Bone Survey/Scan

. 11

SiteSite:

.

.

. _ .

_

_

.

_

1___1 POS.

Liver Scan

NEG

SUSP

POS

Brain Scan

NEG.

SUSP

POS.

Mammogram or Xeroradiogram

NEG

SUSP

POS

EKG

NORMAL

Other, Specify:

ABNORMAL

1___1 POS

NEG

1___1 SUSP

NEG

G

SUSP

G

POS

NEG

G

SUSP

G

PCS

* N O T ACCEPTABLE TREATMENT FAILURE CRITERIA

B.6.5.1

285

SECOND PRIMARY (Include copies of all test results, operative reports and pathology reports along with slides/blocks.) MO [. ~_I J

Date of Diagnosis

vn I

OA* L. -I. .]

I _ _j

Method of Detection Cell Type

Site

__

CHEMISTRIES

_______________________________j DATE PERFORMED

BUN |MG‘«|

CREATININE (MG%)

ALK. PHOS (UNITS)

GGTP (UNITS)

SGOT iUNITS)

SGPT (UNITS)

CALCIUM (MG%)

BILIRUBIN

DATE PERFORMED

wee

NEUTROPHILS

LYMPHOCYTES

MONOCYTES

BASOPHILS

EOS

BANDS

HGB

HCT

PLATELETS

OTHER (SPECIFY)

HEMATOLOGY

ADVERSE REACTIONS/TOXICITIES (eg.. leukemia, blood dyscrasias. pulmonary embolism, deep vein phlebitis, cardiovascular dysfunction, etc ) GIVE DATE AND ATTACH ANY CLINICAL REPORTS.

ADDITIONAL THERAPY (SUBMIT TREATMENT SHEETS. FLOW SHEETS. PATHOLOGY REPORTS) Inclusive Dates of Treatment CHEMOTHERAPY (Specify agents and dose)

ENDOCRINE (Specify agents and dose)

RADIATION THERAPY (Specify sites and dose)

ABLATIVE OR SURGICAL TREATMENT

OTHER (Specify)

PATIENT STATUS IS PATIENT LIVING 9 YES

UNDERLYING CAUSE OF DEATH - SUBMIT COPY OF DEATH CERTIFICATE

NO

O

1_ _1 UNKNOWN

1.

IF DEAD DATE OF DEATH MO 1

1

1

DAY 1

1

I

YR 1

1

PLACE OF DEATH

1

2. 3.

EVIDENCE OF TREATMENT FAILURE AT DEATH — | YES. BOTH CLINICAL |— j . ;— | L J AND AUTOPSY L J YES. AUTOPSY L_J YES. CLINICAL WAS AUTOPSY PERFORMED (IF "YES". SUBMIT COPY OF FINAL AUTOPSY REPORT) G

YES.

C

NO

G

UNKNOWN

ADDITIONAL COMMENTS

286

B .6.5.2

i— j L J NO

i— i 1— i UNKNOWN

FORM OR1

OPERATIVE REPORT FORM INSTRUCTIONS: Part 1: Information should be completed by Institution Data Coordinator at the time patient is randomized. Part II: Information should be completed by surgeon responsible for case immediately after operation. Submit top page and DICT ATED OPERATIVE REPORT to Biostatistical Center within 14 days after surgery.

PART I. TO BE COMPLETED BY INSTITUTION DATA COORDINATOR Patient's Last Name

First

Ml

FOB HEADQUARTERS USE ONLY Initials o f Person Completing F o r m :

Name of institution

H-2)

j

(70-73)

STUDY NUMBER (3-11)

(74-76)

(77-80)

3 3

—

TYPE O F BIOPSY

DATE OF BIOPSY MO

(First positive pathology diagnosis, includes aspiration)

DAY

YEAR

(12-17)

1

Needle (tru-cut)

ZZ

2

Excisional ZZ

3

N e e d l e Aspiration

i_

4

Incisional

(18-21)

28

MO

DAY

YEAR

MO

DAY

YEAR

(29-34)

DATE FORM COMPLETED BY SURGEON

SURGEON RESPONSIBLE FOR CASE MO

DATE OF MASTECTOMY

DAY

YEAR

D A T E O F AXILLARY D I S S E C T I O N

(22-27)

(35-40)

PART II: TO BE COMPLETED BY SURGEON RESPONSIBLE FOR CASE 3

4

FOR SEGMENTAL MASTECTOMY ONLY

TYPE O F MASTECTOMY PERFORMED Segmental ZZ i Total + A x . Dis. (Modified Radical) ZZ 2 Radical Mastectomy ZZ 3 Other ZZ 4

W a s t h e axillary dissection performed using: a separate incision? s a m e incision a s M X ?

Specify:

3

4

t o fascia?

Were s e g m e n t a l margins c h e c k e d b y pathologist intraoperatively:

—

PECTORAL MUSCLES

W a s t u m o r fixed and/or attached to skin?

Yes C

No L

Y e s ZZ N o ZZ

__J

13

.........

14

Frozen Sections? Gross Exam? W a s nipple removed?

W a s t h e pectoral fascia removed?

Yes ZZ N o I.2

_ _ _ J 15

W a s t h e pectoralis minor c u t ?

Yes ZZ N o ZZ

__J

removed? If removed, reason for removal:

Yes C

No C

...................................

N o ZZ

Yes C

No

_ _ _ _ 17

__J

W a s breast drain used?

4

No C

33

Yes ZZ N o ZZ

AXILLARY D I S S E C T I O N

34

------Y e s ZZ N o ZZ

35

A N A T O M I C A L L I M I T S O F T H E AXILLARY DISSECTION: M E D I A L : D i d dissection reach n o d e s b e h i n d pectoralis m in or ?

cm

L A T E R A L : latissimus dorsi

24-25

N o zZ

Yes [j

_____ 20

cm

W e r e n o d e s other t h a n axillary nodes removed?

31

19

_ _ _ _ 21

22-23

No C

1—------

— -----

If m u s c l e only partially removed, h o w m u c h ?

Yes ZZ

Yes ZZZ N o ZZ

32

W a s breast parenchyma reconstructed or approximated?

W a s a n axillary dissection performed? removed?

N o ZZ

16

3 Yes L

Yes ZZ

If yes, reason:

1ft

W a s the pectoralis major c u t ?

29

(Check one) ZZ

:

Yes Z

r=

N o ZZ

S U P E R I O R : axillary vein

Yes ZZ N o ZZ

L I S T N E R V E S IDENTIFIED: nerve to serratus anterior?

Yes ZZ N o ZZ

26

if yes, w h i c h o n e s a n d why?

Yes ZZ N o ZZ

36

37

— —

38

39

27

3

4

FOR TOTAL MASTECTOMY ONLY

W a s prosthetic or m u s c l e flap reconstruction d o n e at time of mastectomy?

Yes ZZ

N o ZZ

nerve t o latissimus dorsi?

Yes :Z

nerve t o pectoralis major?

Yes ZZ N o ZZ

28

SUCTION CATHETERS USED?

Yes ZZ N o

..

40 41

—

42

Signature of S u r g e o n Responsible for C a s e

B.6.6

287

PATIENT NUMBER: FIRST 3 LETTERS OF LAST NAME:

BONE PAIN A N D NARCOTIC SCORES Page 1 of 1 month DATE:

I

I

day

I

I

I

year I

I _ _I

ENTER THE APPROPRIATE SCORE FOR EACH EVALUATION. PAIN SCORE

SCORE ENTER PATIENT'S ASSESSMENT OF SEVERITY OF BONE PAIN USING THE FOLLOWING SCALE: 0 = None 1 = Mild 2 = Moderate 3 = Severe

I

I

I

I

ENTER PATIENT'S FREQUENCY OF BONE PAIN USING THE FOLLOWING SCALE: 0 = None 1 = Occasional (Less Than Daily) 2 = Intermittent (At Least Once Daily) 3 = Constant (Most Of The Time) ENTER PATIENT'S TOTAL BONE PAIN SCORE (Severity Score X Frequency Score):

O

NARCOTIC SCORE

SCORE ENTER TYPE OF MEDICATION USING THE FOLLOWING SCALE: 0 = None 1 = Mild Analgesic (Aspirin, Any OTC Component, Or Propoxyphene) 2 = Mild Narcotic (30 MG Codeine, Oxycodone, Or Meperidine, etc.) 3 = Strong Narcotic (60 MG Or More Codeine, Morphine, Or Hydromorphone, etc.) ENTER FREQUENCY OF MEDICATION USING THE FOLLOWING SCALE: 0 = None 1 = Occasional (Less Than Daily) 2 = Once Daily 3 = More Than Once Daily ENTER PATIENT'S TOTAL NARCOTIC SCORE (Type Of Medication Score X Frequency Score):

288

B.6.7

SCREENING PERIOD Patient's Initials (First, Middle, Last)

DF NO.

SYMPTOM SCORES-

FIRST WEEK ( No. of attacks

if none enter 0

Date (Mo/Day/Yr)

Card No.

Visit 0

Pt. No.

LL_L _J

I

I

to

I ___)

Peak Flow Reading (Best of 3)

A.M. P.M. A.M. P.M. A.M. P.M. A.M. P.M. A.M. P.M. A.M. P.M. A.M. P.M. SECOND WEEK (

I

I

to

a. At each stated time interval, enter symptom scores and number of attacks for the previous 12 hours using the following definitions. If symptom is absent enter 0. 1

Mild = present but causing little or no discomfort. 3

Severe = causing marked discomfort and some interference with daily routinelsleep.

2 Moderate = annoying but not interfering with daily routine! sleep. 4

Unbearable = disabling, interferes considerably with daily routinelsleep.

B.6.8

289

Dr No.

Patient Number

Patient's Initials (First, Middle, Last)

Visit 1

I I _ _ _I___I STUDY DAY 1 (VISIT 1)

Date of Visit (Mo/Day/Yr) _____/ _____1_____

Symptoms Experienced During Past Two Weeks Mild = present but causing little or no discomfort.

Moderate = annoying but not interfering with daily routine or sleep. None

Mild

Severe = causing marked discomfort and some interference with daily routine or sleep. Moderate

Unbearable =.disabling, interferes considerably with daily routine or sleep.

Severe

Unbearable

Wheeze Breathlessness Tightness of Chest Cough Further details _____

Auscultation Wheeze on inspiration and expiration

No wheezing Wheeze on forced expiration

Wheeze audible without stethoscope

Wheeze with normal expiration

Dyspnea plus wheeze audible without stethoscope

Time of Study Drug i— i i— i i— i i— i Administration: I _ _I I _ _I : I _ _I I _ _I

AM PM

ECG (12-LEAD) One hour after study drug administration, obtain a 12-lead electrocardiogram. Attach copy of tracings to this case report form. Check N = Normal. A = Abnormal (give pertinent details) N

290

A

B.6.9

Form 14 Skin Evaluation Patient Initials F

M

L

Patient Study #

I I I I1

Protocol Study Center #

Study Day/ Date (M/D/Y)

New Skin Vesicles Yes

No

Location

Number of New Skin Vesicles

F ntry 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

B.6.10

291

Protocol No. Investigator’s No.:

Subject No.:

Subject Initials:

Admission

Page

DATE O F EXAM Month

Day

Year

GYN EXAMINATION Normal 1

Abnormal 2

Describe Abnormality

10. VULVA 11.

Appearance

12.

Bartholin Glands

13.

Skene Glands

14.

Other:

20. VAGINA 21.

Appearance

22.

Discharge

23.

Bladder/Urethra

30. CERVIX 31.

Appearance

32.

Discharge

33.

Other:

40. UTERUS 41.

Size

42.

Consistency

43.

Position

44.

Mobility

45.

Other:

50. OVARIES 60. TUBES 70. ANORECTAL

PAP SMEAR TAKEN

1. YES

2. NO (PREVIOUS SMEAR MUST BE WITHIN THE PAST 60 DAYS)

Record pretherapy Pap Smear data on Control Cycle Report, Question Number 14. Comments:

DATE

INVESTIGATOR SIGNATURE

292

B.6.11

Page

Prop #

Cmpd .f/Name

ABNORMAL INVOLUNTARY MOVEMENT SCALE (AIMS)

IND #

NDA #

Screen/Baseline Protocol # — Study #

NOTE: Please use BLACK ink. Patient's Initials

______________ L M F

Patient #

___________

Exam ________________ Y D M Date

Dept.

Sec.

INSTRUCTIONS: Complete examination procedure before making ratings. MOVEMENT RATINGS:

Rate highest severity observed. Rate movements that occur upon activation one LESS than those observed spontaneously. Rating 1.

Muscles of Facial Expression, e.g., movements of forehead, eyebrows, periorbital area, cheeks; include frowning, blinking, smiling, grimacing.

2.

Lips and Perioral Area, e.g., puckering, pouting, smacking.

3.

Jaw, e.g., biting, clenching, chewing, mouth opening, lateral movement.

4.

Tongue - Rate only increase in movement in and out of mouth, NOT inability to sustain movement.

5.

Upper (arms, wrists, hands, fingers) - Include choreic movements (i.e., rapid, objectively purposeless, irregular, spontaneous) athetoid movements (i.e., slow, irregular complex serpentine). Do NOT include tremor (i.e., repetitive, regular, rhythmic).

6.

Lower (legs, knees, ankles, toes), e.g., lateral knee movement, foot tapping, heel dropping, foot squirming, inversion and eversion of foot.

TRUNK MOVEMENTS

7.

Neck, Shoulders, Hips, e.g., rocking, twisting, squirming, pelvic gyrations.

GLOBAL JUDGMENTS

8.

Severity of abnormal movements.

9.

Incapacitation due to abnormal movements.

FACIALAND ORAL MOVEMENTS

EXTREMITY MOVEMENTS

DENTAL STATUS

Code 0 1 2 3 4

= = = = =

None Minimal Mild Moderate Severe

0 1 2 3 4

= = = = =

None, normal Minimal Mild Moderate Severe

No awareness Aware, no distress Aware, mild distress Aware, moderate distress 4 = Aware, severe distress

10. Patient's awareness of abnormal movements (rate only patient's report).

0 = 1= 2= 3=

1 1. Current problems with teeth and/or dentures.

0 = No 1 = Yes

12. Does patient usually wear dentures?

TOTAL SCORE

B.6.12

293

Protocol No. : Subject Initials: L_J__ .. Date of Exam m/o/Y):

/

Subject No.: /

POST THERAPY / EARLY TERMINATION ABDOMINAL EXAMINATION

VITAL SIGNS AND WEIGHT

JUST PRIOR TO SURGERY

Pulse Rate ________/min.

Abdominal Distention

Bowel Sounds Symptoms

Absent

Blood Pressure _____ / _____ mm Hg systolic

diastolic

Weight ________lb.

Rebound Tenderness Direct Tenderness Guarding Rigidity Nonsurgical Abdominal Pain

Abdominal Pain

,

□.

IMPROVED

294

B.6.13

□a □a

Da

Present

........

a

Vomiting

a

. ...: , . o’o

□ , ' LOST TO FOLLOW-UP _

Date

Signature / Initials

□a

a

□ . NOT IMPROVED

Diminished

□s

Nausea

CLINICAL RESPONSE BASED ON SIGNS AND SYMPTOMS l oCURE l

Present

............

Absent

□

Signs

□ □ o' □' □' □' □'

Temp _________°F

Clinical Report Form Drug Identification Indication Visit ? Page 1 of ?

CARDIOVASCULAR DISEASE DIAGNOSIS If not done, enter an "X" here

Date of Onset for CHF

Mo

Date of Onset for current NYHA CHF Classification

Congenital Ischemic Hypertensive Rheumatic Infectious/Parasitic Systemic Disease Pulmonary Disease Cardiac Tumor Cardiac Trauma Toxic Drug Induced Alcohol Other (Specify on Comments Page) Idiopathic

ANATOMICAL (Cont'd)

Coronary Artery Disease Anginal Symptoms Electrocardiographic Findings Echocardiographic Findings Ventricular Aneurysm ... Infarct < 2 wks Infarct > 2 wks to 6 months Infarct > 6 months to 12 months Infarct > 12 months Aortic Aneurysm Valvular

ANATOMICAL

Cardiomyopathy Acute myocarditis Dilated Hypertrophic Restrictive

_ C--------->------Yr Day Mo

1 = Absent 2 = Present 3 = Not Known

Enter appropriate numerical code ETIOLOGICAL

/----------/ ------Yr Day

Mitral Stenosis Mitral Incompetence Tricuspid Stenosis Tricuspid Incompetence Aortic Stenosis Aortic Incompetence Pulmonary Stenosis Pulmonary Incompetence Other Valvular . Other (Specify on Comments Page)

FUNCTIONAL

Long QT Syndrome Conduction Defect AV - First Degree AV - Second Degree AV - Third Degree LBBB RBBB LAHB LPHB Permanent Pacemaker. Arrhythmia Supraventricular Fibrillation Flutter PAT PAC Junctional Pre-Excitation Ventricular VPD Unsustained VT Sustained VT VF Congestive Heart Failure Class I Class II Class III Class IV

B.6.14

295

296

_______________ F M L

Patient #

___________

Dept.

IND #

NDA #

Fick

Thermodilution

Dye Dilution

‘Recommended but not required.

Cardiac Output* (liters/min)

RAPm * (mm Hg)

PCWPm * (mm Hg)

PAPd * (mm Hg)

PAPS* (mm Hg)

SAPd (mm Hg)

SAPs (mm Hg)

Heart Rate (beats/minute)

Body Temperature (°C)

Time (0-2359)

Date (M/D/Y)

B.6.15

Prop#

Protocol # — Study #

Cmpd. #/Name

Record body temperature and hemodynamic measurements every 4 hours during the Treatment Period. Record cardiac output every 8 hours during the Treatment Period.

Patient's Initials

NOTE: Please use BLACK ink.

Treatment Period

BODY TEMPERATURE/HEMODYNAMIC MEASUREMENTS/CARDIAC OUTPUT

Page

CO

C. LABORATORY TESTS AND EVALUATIONS Title 1. Clinical Chemistry and Hematology Tests 2. Radiology and Pathology Reports 3. Electrocardiograms 4. Urine Tests 5. Microbiology Tests 6. Virology Tests 7. Neurology Tests 8. Endocrinology and Immunology Tests 9. Other Laboratory Tests

Form Numbers

Page Numbers

C.l.1-C. 1.26

301-326

C.2.1— C.2.16

327-344

C.3. la—C.3. 13 C.4.1—C.4.14 C.5.1-C.5.9 C.6.1-C.6.6 C.7.1-C.7.8 C.S.lb— C.8.6

345-357 359-372 373-381 383-388 389-396 397-402

C.9.1-C.9.20.2

403-425

GENERAL POINTERS AND COMMENTS • List laboratory tests in the same order they appear on laboratory reports for single-site trials. • List laboratory tests in the same order for all sites in a multicenter trial. • Consider having common units of measurements at all sites, but if this is not practical, ensure that conversion of data occurs at an appropriate time. • Have actual counts of platelets measured, whenever possible (C.l). 8 EKG abnormalities should be listed individually for checking. Merely checking a box for an abnormal EKG and requesting a list of abnormalities (sometimes on one line) creates problems for data entry (C.3). SPECIFIC POINTERS AND COMMENTS ON INDIVIDUAL FORMS C.l Clinical Chemistry and Hematology Tests Variations in the examples in this subcategory indicate decisions that form designers have to make about whether to:

LABORATORY TESTS AND EVALUATIONS

® • ® •

Include hematology and blood chemistries on the same form (C.1.1). Include check-off boxes for abnormal values (C. 1.1). List reference range values on the form (C.1.9). Use the specific order of tests reported by the laboratory or by other sites in the trial. • Use a separate box or space for each digit in a test’s value (C.1.2, C.1.5, and others). • Include a check-off space or box for clinical significance (C.1.1 and C . 1 .3). ® Include multiple visits on a single page (C.1.6, C.1.7, and others). • Include other laboratory tests on the same page (C.1.8). « Include units of measurements (C.1.9). • Have the respondent leave unreported or missing results blank or marked appropriately (C.1.10). ® Code individual tests (C.1.11 and C.1.13). • ® ® ® •

Allow for comments (C.1.12). Evaluate clinical significance with a code (C.1.15). Include relationship of an abnormality to therapy (C.1.16). Include optional visits (C. 1.20). Include the time of sample collection (C.1.6, C.1.22, and others).

C.2 Radiology and Pathology Reports •

Codes may be used on forms (C.2. 1).

•

Forms may be designed individually for data collection from a specific test (C.2. 2) or for multiple radiological tests (C.2. 12.1 to C.2. 12.3). • Chest x-rays and other tests may be open-ended (C.2.9), highly specific using forced responses (C.2. 10), or general in form (C.2. 16). ® Forms may include instructions (C.2. 11). •

Other neurological test forms are also shown in Section C.7.

C.3 Electrocardiograms ® Multiple forms per page are given on C.3.1. • Detailed instructions are given on many forms (C.3.4, C.3.5, and C.3. 10).

C.4 Urine Tests ® Multiple forms are presented on page C.4.4. •

Providing the codes on the forms is helpful to the personnel entering data (C.4.1). » For urine collection data the time of collection is important (C.4. 3), as is total volume (C.4. 4a).

•

Data may be collected for many visits on one form; nine visits are shown in C.4.11. ® Urine creatinine clearance data are shown in C.4. 13 and C.4. 14. ® Urine screens for illicit drugs are shown in section C.9.

298

LABORATORY TESTS AND EVALUATIONS

C.5 Microbiology Tests • Culture data forms may be open ended (C.5.1 and C.5.2) or highly detailed (C.5.5). ® Multiple modules are listed in form C.5.1. C.6 Virology Tests • These forms may be modified (if desired) in similar ways to other laboratory forms to create numerous additional forms. C.7 Neurology Tests • Cerebrospinal fluid may be assessed for many parameters (C.7.1) or for one (C.7.2). • EEG reports may be simple, moderately detailed (C.7.4), or highly detailed (C.7.5). • Other neurological test forms are also shown in section C.2. C.8 Endocrinology and Immunology Tests • Multiple forms are presented on C.8.1. C.9 Other Laboratory Tests • Forms may be general (C.9.1 and C.9.2) or focus on any item of interest. • Specific tests illustrated include: Fecal collections (C.9.3) Pulmonary function tests (C.9.4 to C.9.6) Coagulation tests (C.9.7) Audiometric tests (C.9.8 and C.9.9) Saliva collection (C.9. 10) Osmolality data (C.9. 11) Urine drug screens (C.9. 12) Serum creatinine (C.9. 14) Blood gas (C.9. 15) Specimens (C.9. 16) Stress test (C.9.17 and C.9.18) Echocardiogram (C.9. 19.1 to C.9. 19.3). • Check-off forms ask the investigator to confirm that certain laboratory activities have been performed (C.9.7 and C.9.9). • Forms may collect only specific laboratory values (C.9. 13). • Flow sheets are commonly used in some trials to combine all laboratory and radiology data for the trial on the same sheets (C.9.20.1 and C.9. 20.2).

299

Cl

CLINICAL CHEMISTRY A N D HEMATOLOGY T E S T S

Drug ID

LABORATORY TESTS PATIENT INITIALS (3)

VISIT

DATE SPECIMEN COLLECTED _____(month/day/year) _____

PATIENT NUMBER

List below all laboratory findings. Indicate those values that are outside normal range and comment on those which are clinically significant. Attach laboratory report to this page. Time Specimens Obtained: ______________ (24-hour clocktime)

ACTUAL VALUE

OUTSIDE NORMAL RANGE IF OUTSIDE NORMAL RANGE, IS IT CLINICALLY SIGNIFICANT? (D

HEMATOLOGY _____ BLOOD CHEMISTRY

(0) NO

(1) YES - comment:

O

I

Hemoglobin Hematocrit

I I

O

O

White Blood Count

I I

Q

D

Neutrophils

I I

n

Lymphocytes

I I

D

Monocytes

I I

Eosinophils

I I

Basophils

I I

Q I

o I

Platelet Count

I

Total Bilirubin

I I

n

o

Alkaline Phosphatase

I I

n

SGOT

I I

o I I

BUN

I

n

i i

Creatinine

I

D

Albumin Calcium

I I l~J .

Phosphorus

I I

Glucose

I

LDH

I I

Total Protein Uric Acid

o Q FASTED 1 D UNFASTED

n

n

Q

Q I I

Qi

n

I C.1.1 301

PLEASE PRINT LEGIBLY __________ PATIENT NUMBER PATIENT INITIALS SUBJECT NUMBER SUBJECT INITIALS

LABORATORY RECORD USE BLACK BALL-POINT PEN STUDY PHASE

________DO NOT WRITE I N SHADED AREAS NAME OF LABORATORY:

Please record any clinically significant changes f r o m BASELINE LABORATORY VALUES regarded t o b e adverse events o n the STUDY EVENT RECORD (FORM )__________________________________________ DATE SPECIMEN COLLECTED

DATE SPECIMEN COLLECTED HEMOGLOBIN HEMATOCRIT

WBC

|

|

|

|

|

|

| | | | | I I II I I

I I I I

|....|

| ....|

PLATED

|....|

|

|....1

Indicate patient’s status at the time of blood

|

NONFASTING

CHLORIDE CARBON DIOXIDE

- OR ~ HCO 3

EOSINOPHILS

GLUCOSE

MONOCYTES

BLOOD CHEMISTRY

CELL COUNT DIFFERENTIAL

FASTING

2

POTASSIUM

LYMPHOCYTES

HEMATOLOGY

1

SODIUM

NEUTROPHILS

BASOPHILS ATYPICAL LYMPHOCYTES OTHER WBC (Specify value & type)

□ Q

type:

type:

BUN / UREA CREATININE CALCIUM PHOSPHORUS URIC ACID BILIRUBIN, TOTAL TOTAL PROTEIN ALBUMIN

PLATELETS (Estimate) LDH

DATE SPECIMEN COLLECTED

/ / ' D~7 v T "

CHOLESTEROL

11 1

1

1

1

SGOT / AST

OSMOLALITY

1

1

1

1

SGPT / ALT

PH

LU

“

SPECIFIC GRAVITY

- OR 1

ALKALINE PHOSPHATASE

PROTEIN/ALBUMIN

TRIGLYCERIDES

SIS

GLUCOSE/SUGAR KETONES/ACETONE

< z

HEMOGLOBIN/BLOOD

MICROSCOPIC EXAMINATION OF SEDIMENT RBC (per high power field) WBC (per high power field) OTHER MICROSCOPIC FINDINGS - INCLUDE BACTERIA, CASTS AND CRYSTALS (Include number & type of positive findings only)

INVESTIGATOR'S INITIALS PAGE NO.

BOOKLET NO.

302

C.1.2

Page ___________ of ___________ Cmpd. #/Name

CLINICAL CHEMISTRY/HEMATOLOGY NOTE: Please use BLACK ink

DO IND #

Pt./Vol. # Initials

Investigator's Name

Pt./Vol.#

M

NDA If

NOt FILI

~F

L~

Protocol# — Study#

IN

Dept. D

M

Proj. #

Sec.

Y

Exam Date Clinical Chemistry

Normal Range

Unit of Measure

Value

Comment Clinically Significant Only

(7) CS**

Calcium(s) Phosphorous (s) Glucose(s) Bun(s) Uric Acid(s) Cholesterol, Total (s) Protein, Total (s) Albumin(s) Bilirubin, Total (s) Aik. Phosphatase(s) LDH(s) SGOT OTHER (specify) HEMATOLOGY Hemoglobin Hematocrit RBC Platelet Estimate WBC Neutrophils Lymphocytes Monocytes Eosinophils Basophils OTHER (specify)

Excluded from study because of clinically significant abnormalities *(s) = Serum “ C S = Clinically significant abnormality

CO0102

Yes

Investigator s Signature

C.1.3

No

M

L>

Y

303

LABORATORY REPORT FORM (Pretreatment) Dr.

Visit 0

Date Specimen Obtained

Patient Number

Patient's Initials (First, Middle, Last)

1_____1 ____ (Mo/Day/Yr) __ 1 _____I _____

Repeat Date Specimen Obtained

'Check all values outside normal range Blood Chemistry

Normal Range/Units

(Mo/Day/Yr) _ _/ _ _ _1_ _ _ _ _

Repeat (if necessary) Value

•

Code

Normal Range/Units

Value

•

Code

Glucose Urea Nitrogen Creatinine Uric Acid Calcium Potassium Sodium Alkaline Phosphatase Bilirubin, Total SGOT SGPT Protein, Total Albumin Hematology WBC (x103) RBC (x106) Hemoglobin Hematocrit Neutrophils Lymphocytes Monocytes Eosinophils Basophils Bands Urinalysis pH Protein (Albumin) Sugar Acetone (Ketones) WBC RBC Casts Please comment on all abnormal labs:

304

_ _——

C.1.4

PATIENT NUMBER:

LABORATORY REPORT

FIRST 3 LETTERS OF LAST NAME:

Page 1 of 1 month

day

year

I I I I I I I I

DATE:

HEMATOLOGY

HEMOGLOBIN, gm/dL:

MEAN CORPUSCULAR HEMOGLOBIN, PG:

HEMATOCRIT, % :

MEAN CORPUSCULAR VOLUME, FL: X 1000/mmd

TOTAL W.B.C.:

MEAN CORPUSCULAR HEMOGLOBIN CONC.,

LYMPHOCYTES, % :

PROTHROMBIN TIME, seconds:

NEUTROPHILS, %:

PARTIAL THROMBOPLASTIN TIME, seconds:

MONOCYTES, % :

TOTAL RBC, millions/mm3

EOSINOPHILS, % : BASOPHILS, OTHER: (Specify) PLATELET COUNT:

I

I

i

I X 1000/mm3 BLOOD CHEMISTRY

(To Be Completed At Each Tumor Evaluation Visit) SGPT, units/L: (Every Visit)

CALCIUM, mg/dl:

LDH, units/L:

PHOSPHORUS, mg/dl: GLUCOSE, mg/dl:

1. Fasting 2. N o n Fasting

URIC ACID, mg/dl:

BLOOD UREA NITROGEN, mg/dl:

CREATININE, mg/dl: (Every Visit)

TOTAL BILIRUBIN, mg/dl:

SODIUM, mEq/L:

ALBUMIN, gm/dl:

POTASSIUM, mEq/L:

TOTAL PROTEIN, gm/dl:

CHLORIDE, mEq/L:

ALKALINE PHOSPHATASE, units/L:

CARBON DIOXIDE, mmoL/L:

SGOT, units/L: URINALYSIS

MICROSCOPIC

(To Be Completed At Each Tumor Evaluation Visit)

(To Be Completed At Each Tumor Evaluation Visit) MICRO-CODE: 0 Iper HPF) 1 - 5 6 - 20

SPECIFIC GRAVITY:

= 0 = +1 = +2

21 - 50 OVER 5 0

= +3 = +4

PROTEIN:

0

+1

+2

+3

+4

GLUCOSE:

0

+1

+2

+3

+4

R.B.C.:

0

+1

+2

+3

+4

ACETONE:

0

+1

+2

+3

+4

W.B.C.:

0

+1

+2

+3

+4

CASTS:

0

+1

+2

+3

+4

+2

+3

+4

OTHER: _______ (specify) 0

+1

ENTER "N/A" FOR ANY LAB VALUE WHICH WAS NOT OBTAINED.

C.1.5

305

PATIENT NUMBER:

LABORATORY

FIRST 3 LETTERS OF LAST NAME:

Page 1 of 2 month

day

year

[_. L. .J L U D Z

DATE:

Illi

STUDY DAY:

month

day

Illi year

day

month

year

day

month

11! 1

Illi

Illi year

month

day

year

month

day

DATE:

LULUUJ | | || | || | | I I II HI H I I II I II I I □ U f f l

TIME SPECIMENS TAKEN (24 Hour Clock):

| | |: I | I

| | | : | | | I I I : | Il

I L I •I I I

year

| | |;[ i i

HEMATOLOGY

HEMOGLOBIN, gm: HEMATOCRIT, %:

m.n rn m

1111

W.B.C. X 1000: NEUTROPHILS, % : LYMPHOCYTES, % :

LJJ

EOSINOPHILS, %.

m

MONOCYTES, % :

UJU

LU

BASOPHILS, % : OTHER (specify):

11

OTHER (specify):

I I I

I I I

I I I

111

PLATELET COUNT x 1000: or

2. Inadequate

2. Inadequate

2. Inadequate

1. Adequate

1. Adequate

1. Adequate

1. Adequate

1. Adequate

PLATELET ESTIMATE:

2. Inadequate

2. Inadequate

URINALYSIS

APPEARANCE (specify): SPECIFIC GRAVITY:

H

. lol

I

I

H

.

I° I I I

0.0U

[7} . | o |

0 +1 +2 + 3 + 4

0 +1 +2 + 3 + 4

0 +1 +2 + 3 + 4

H

.

l° I I I

| _ _|

pH: PROTEIN:

0 +1 + 2 + 3 +4

0 +1 +2 + 3 + 4

GLUCOSE:

0 +1 + 2 + 3 + 4

0 +1 + 2 + 3 + 4

0 +1 + 2 + 3 + 4

0 +1 + 2 + 3 + 4

0 +1 + 2 + 3 +4

ACETONE:

0 +1 + 2 + 3 + 4

0 +1 + 2 + 3 + 4

0 +1 + 2 + 3 + 4

0 +1 + 2 + 3 + 4

0 +1 +2 + 3 + 4

CODE (PER HPF):

0 0 = 1 - 5 = +1

6 - 20 = +2 21 - 50 = + 3

Over 5 0 = + 4

MICROSCOPIC

R.B.C.:

0 +1 + 2 + 3 + 4

0 +1 +2 + 3 + 4

0 +1 + 2 + 3 + 4

0 +1 + 2 + 3 + 4

0 +1 + 2 + 3 + 4

W.B.C.:

0 +1 + 2 + 3 + 4

0 +1 + 2 + 3 + 4

0 +1 + 2 + 3 + 4

0 +1 + 2 + 3 +4

0 +1 +2 + 3 +4

CASTS:

0 +1 + 2 + 3 + 4

0 +1 +2 + 3 + 4

0 +1 + 2 + 3 + 4

0 +1 + 2 + 3 + 4

0 +1 + 2 + 3 +4

CRYSTALS:

0 +1 + 2 + 3 + 4

0 +1 + 2 + 3 + 4

0 +1 +2 +3 + 4

0 +1 +2 + 3 + 4

0 +1 + 2 + 3 +4

CELLS:

0 +1 + 2 + 3 + 4

0 +1 +2 + 3 + 4

0 +1 + 2 + 3 + 4

0 +1 +2 +3 + 4

0 +1 + 2 + 3 +4 0 * 1 + 2 + 3 +4

0 +1 + 2 + 3 +4

BACTERIA:

0 +1 + 2 + 3 +4

0 +1 +2 + 3 + 4

0 +1 + 2 + 3 + 4

0 +1 + 2 + 3 +4

0 +1 + 2 + 3 + 4

0 +1 + 2 + 3 + 4

0 +1 + 2 +3 + 4

0 +1 + 2 + 3 + 4

OTHER (specify):

306

C.1.6

Form 1 8 Laboratory Follow-Up P a t i e n t Initials

Patient Study # Location

Study C e n t e r #

HEMATOLOGY Normal Range

T r e a t m e n t D a y 21

Treatment Day 28

D A T E (Mo/Day/Yr) Hemoglobin gm % Hematocrit % W3C x 10* D F F 6 ft e IM T 1 A L

I

Polys/Bands % — Lymphs %

H

m

m

Monos % Eos%

III

Bas%

I

Platelets x 10* I

Retie. C o u n t %

I

I

]

1

| | | |

1

1

1

I

I

URINALYSIS Normal Range

Treatment D a y 2 1

Treatment Day 2 8

DATE (Mo/Day/Yr) QUANTITY REPORTED

0

Tr S m M d L g

0

Tr S m M d L g

0

Tr S m M d L g

0

Tr S m M d L g

0

Tr S m M d L g

-

1- 2-3-4-

-

1- 2-3-4-

-

1-2-3-4*

-

1 - 2* 3- 4-

-

1 - 2- 3- 4-

□□□

Albumin Sugar

0 □□□

□□□

0

Ketones

0

Bile PH

c

c

WBC/hpf RBC/hpf Other Abnormalities

CHEMISTRIES Normal Range

Treatment Day 28

Treatment D a y 2 1

1

I

DATE (Mo/Oay/Yr) BUN mg % Creatinine m g % B i l i r u b i n Total m g %

——

B i l i r u b i n Direct m g % SGOT I U SGPT I U

— ——

LDH % ■—— Uric Acid mg/dl

_

A l k a l i n e Phos. I U

C.1.7

307

Protocol No. Subject Initials:]

|

|

|

Subject No.:

J Date Samplei Taken:_____/ VMr Month Day

___________

Investigator's N o .

BASELINE

LABORATORY RESULTS CBC AUTOMATED

T 3 UPTAKE

WBC

T 4 RIA

RBC

Free T 4 C A L C

HEMOGLOBIN HEMATOCRIT PLATELET COUNT

LIPO, CHOLFRACT

POLYS

TRIGLYCERIDES

LYMPHOCYTES

CHOLESTEROL

MONOCYTES

LDL-CHOLESTEROL

EOSINOPHILS

HDL-CHOLESTEROL

BASOPHILS

URINALYSIS

CHEM PANEL

COLOR

BUN

APPEARANCE

CALCIUM URIC ACID

SPECIFIC GRAVITY PH PROTEIN

PROTEIN TOTAL

GLUCOSE

SGOT

KETONE

SGPT

ALBUMIN

BLOOD

ALKALINE PHOSPT.

WBC

PHOSPHORUS

RBC

GLUCOSE

HYALINE CASTS

BILIRUBIN TOTAL

FINELY GRANULAR

SODIUM

COARSE GRANULAR

POTASSIUM

EPITHELIAL CELLS

CHLORIDE

BACTERIA MUCOUS CALCIUM OXALATE URIC ACID AMORPHOUS TRIP.PHOS YEAST

308

I

I Page

THYROID PANEL

INVESTIGATOR

I

SIGNATURE

DATE

C.1.8

I

I

Sompd. #

Proj. #

IND #

NDA #

FILL Protocol #

Study #

DO

CLINICAL CHEMISTRY/HEMATOLOGY Screen

NOT IN

Vol. #: ____________

Vol. Init: _____________ L M F

Exam Date: _ _ _/ _ _ _/ _ _ _ Y D M

Dept.

Sec.

Enter N D under value column if teat could not be performed. Normal Range

Unit of Measure

Glucose

60-115

mg %

Clinical Chemistry

Value

Sodium

136-148

Potassium

3.5-5.5

mEq/L mEq/L

Chloride

96-110

mEq/L

Urea Nitrogen

6-23

mg %

Creatinine

.7-1.7

mg %

•

U r i c Acid

3.0-8.5

mg %

•

Calcium

8.5-11.0

mg %

Phosphorous

2.5-4.5

mg %

Alkaline Phosphatase

30-115

U/L

Total Bilirubin

.1-1.2

mg %

0-41

U/L

SGOT LDH

•

• • •

60-225

U/L

Cholesterol

150-300

mg %

Total Protein

6.0-8.0

gm %

•

3.5-5.5

gm %

•

Hemoglobin

11.9-17.0

gm %

•

Hematocrit

36-50

%

•

4.0-5.8

106/ m m3

• •

Albumin

Comment Only On Clinically Significant Values

CS*’

OTHER (specify)

HEMATOLOGY

Total RBC Reticulocytes

.5-2.0

Plateiet Estimate

Adequate

Total WBC

4.0-10.8

Neutrophils Bands Lymphocytes Monocytes Eosinophils Basophils

%

ADEQUATE NOT ADEQUATE

103/ m m3

39.9-73.6

%

—

%

18.6-47.7

%

0-10

%

0-6.7

% %

0-1.5

•

* * C S = Clinically significant abnormality Excluded from study because of clinically significant abnormalities

Yes

No

INVESTIGATOR’S INIT.

C.1.9

309

Form 12 Laboratory (Continued) Patient Initials

Patient Study # Protocol

M

Study Center #

Location

5 Month

6 Month

HEMATOLOGY ORAL THERAPY Normal Range

2 Month

3 Month

4 Month

DATE (Mo/Day/Yr)

□

Hemoglobin g m % Hematocrit % WBC x 103

Dt

Polys/Bands % Lymphs % Monos % Eos %

%

Bas %

Platelets x 10 3 Retie. Count %

CHEMISTRIES ORAL THERAPY Normal Range

2 Month

3 Month

4 Month

5 Month

6 Month

DATE (Mo/Day/Yr) BUN m g % Creatinine m g % Bilirubin Total m g % Bilirubin Direct m g % SGOT IU Uric Acid mg/dl

line through boxes for unreported lab results. DO NOT put 0 for unreported lab results. t Differential should total 100.

310

C.1.10

Filling in Instructions:

Use black pen. Start with the right -hand box. Encircle pre-filled boxes. Fill M for missing answers. Study day: Screening 7

LABORATORY TESTS Blood screen

. Patient no.

The blood sample should be taken in the morning, before breakfast

3 4-8

0

0

0

0

Date of blood sample

9-12 15-20

day

year

month

HAEMATOLOGY Red blood cells

x 101 2/l

Haemoglobin

g/cH

PCV (haematocrit)

23-25

1 1

26-28

%

1

29-31

x 109/l

1

White cell count

32-34

Neutrophils

%

Lymphocytes

%

Monocytes

%

51-52

Eosinophils

%

54-55

Basophils

%

57-58

Others

%

60-61

Platelets

x 109 /l

63-65

45-46 48-49

BIOCHEMISTRY Glucose (fasting)

mmol/1

23-25*

Creatinine

p.mol/1

26-28

Blood urea

mmol/1

Sodium

mmol/1

Potassium

mmol/1

1

35-36

Calcium

mmol/1

I

37-39

Chloride

mmol/1

4042

Alkaline phosphatase

IU/1

43-45

Total bilirubin

pmol/1

4647

SGOT (AST)

IU/1

48-50

SGPT (ALT)

IU/1

Total protein

g/1

Albumin Cholesterol

g/1 mmol/1

Triglycerides

mmol/1

* For the punchtypist: new card

8

3; repeat column 4-20

C.1.11

K1

29-31 32-34

51-53 54-55 56-57 1

58-61

1

62-65

Initials 311

PAGE 25 OF 25 PLEASE TYPE O R U S E BLACK INK NAME AND ADDRESS OF LABORATORY

D O NOT WRITE I N SCREENED AREAS PROJECT NO.

NORMAL RANGES OF LABORATORY DATA NUMERIC NORMAL RANGE UNITS

TEST MINIMUM

ALLOWABLE TERMS

MAXIMUM

MALES HEMOGLOBIN (gm/100ml) FEMALES

K E M A T 0 L 0 G Y

MALES HEMATOCRIT (%) FEMALES WBC NEUTROPHILS (%) LYMPHOCYTES (%) MONOCYTES (%) EOSINOPHILS (%) BASOPHILS (%) CREATININE CALCIUM PHOSPHORUS

B L 0 0 D C H E M 1 S T R Y

BUN URIC ACID TOTAL PROTEIN ALBUMIN ALKALINE PHOSPHATASE SGO-T SGP-T BILIRUBIN (TOTAL) BLOOD SUGAR LDH CHOLESTEROL PLEASE DATE AND SIGN ALL COMMENTS

CHECK IF NONE

C 0 M M E N T S

INVESTIGATOR'S SIGNATURE

312

C.1.12

DATE MO. I DAY I YR. I I I I

Page Visit

Investigator Name

Study Site

Screen Subject’s First Name

Ml

LI

Subject’s Study Number

LABORATORY PARAMETERS (Within 14 Days Pre-Dosing) PARAMETERS HEMATOLOGY;

CHEMISTRY:

HWBC

WBC (thou/cmm)

CGLU

Glucose (mg/dL)

HRBC

RBC (mil/CMM)

ONA

Sodium (meq/L)

HHGB

Hemoglobin (gm/dL)

HHCT

Hematocrit (%)

COL

Chloride (meq/L)

HPLTC

Platelets (K/CMM)

CC02

Carbon Dioxide (mm/L)

Potassium (,meq/L)

BUN (mg/dL)

DIFFERENTIAL: HBAND

Bands (%)

WBrli

Creatinine (mg/dL)

HPOLY

Seg. Neutros. (%)

icPROil

Total Protein (gm/dL)

HLYM

Lymphocytes (%)

HMONO

Monocytes (%)

CCHOL

HEOS

Eosinophils (%)

WAltt

HBASO

Basophils (%)

H

Other (

) (%) ___________

URINALYSIS: USPGR

Specific Gravity

UGLU

Glucose

UPROT

Protein

UPH

pH URINE MICROSCOPY:

Albumin (gm/dL) Cholesterol (mg/dL) Calcium (mg/dL)

CPHUS

Phosphorus (mg/dL)

CUA

Uric Acid (mg/dL) Total Bilirubin (mg/dL)

CBtLT :

LDH (IU/L) AST/SGOT (IU/L)

CALKP

:

Aik. Phosph. (IU/L)

Wliiii

:

ALT/SGPT (IU?L) OTHER TESTS:

CALT ;

G-6PD

URBC

RBC/HPF

UWBC

WBC/HPF

HG6PD

VDRL

UCST

Casts-Type

OVDRL

Hepatitis B Surface Antigen

U ____

Quantity/LPF

OHBSA

UCRYST

Crystals-Type

U ____

Quantity

No

Yes

I I

| |

Were there any clinically significant abnormal findings? If yes, explain below. Were there any missing values? If yes, explain below.

C.1.13

313

LABORATORY TEST RESULTS (If unit* or normal ranges differ from those previously supplied, new units end ranges MUST be submitted on a new lab ... •■ ..... HEMATOLOGY

RESULTS

BLOOD CHEMISTRY

Hemoglobin (g/dl)

Total Protein (g/dl)

Hematocrit (%)

Albumin (g/dl)

WBC (/mm 3)

Total Cholesterol (mg/dl)

Bands (%)

Urea Nitrogen (mg/dl)

Neutrophils (%)

Uric Acid (mg/dl)

Lymphocytes (%)

Total Bilirubin (mg/dl)

Monocytes (%)

Alkaline Phosphatase (mU/ml)

Eosinophils (%)

LDH (MU/ml)

Basophils (%)

ASAT (SGOT) (I.U./L)

Platelets (/mm 3)

ALAT (SGPT) (I.U./L) Glucose (mg/dl)

URINALYSIS

Calcium (mg/dl)

Specific Gravity

Phosphorus (mg/dl)

pH

Sodium (mEq/L)

Protein (0,trace,1,2,3,4)

Potassium (mEq/L)

Glucose (0,1,2,3,4)

Chloride (mEq/L)

Casts/hpf

Creatinine (mg/dl)

Crystals/hpf

Bicarbonate (mEq/L)

RBC/hpf

WBC/hpf Epithelial Cells/hpf Bacterial Cells/hpf Other Cells/hpf Ketones (0,1, 2, 3, 4) (If required) Quantitative Urine Protein (mg/24 hrs.)

C.1.14

314

RESULTS

CLINICAL LABORATORY D A T A REPORT Inv. No.

Protocol

Pt. I n i t i a l s

Visit No.

Date

Pt. N o .

1 (First, Middle. Last)

Fasting:

Date of Collection: Day

Month

Complete Blood Count R.B.C. (x106)

H E M A T 0 L O G Y

Value

‘Code

mi ii

Glycosylated Hemoglobin(%)

r i i.i i

Hematocrit

LU-LJJ i i i in I I I.I I I I l I.I I I I I I.I I I

3

Platelets (x10 ) W.B.C. (x103) Neutrophils (%)

Lymphocytes (%) Eosinophils (%) Monocytes (%) Basophils (%)

*

Yes

Year

01

No

Year

Hemoglobin

Comment i f abnormal

!

I I I.I I I I I I.I" I I I I I.I I I

m.m I I [ I I l

HDL Cholesterol LDL Cholesterol CHD Risk

Day

LU.LU

Bands (%)

L I P I D S

Month

rri.i i i

Code all abnormals: 1 = not clinically significant 2 = significant but not study drug related 3 = significant and of unknown study drug relationship 4 = significant and study drug related

Principal Investigator's signature Please attach a copy of the report to the case report form.

C.1.15

315

Protocol No. : Subject No.:

Subject Initials:

HEMATOLOGY ADMISSION

POST THERAPY/ EARLY TERMINATION

REPEAT/ FOLLOW-UP

___/ ___ ! ___

___ ! ___ ! ___

REPEAT/ FOLLOW-UP

REPEAT/ FOLLOW-UP

Date Sample Taken: (MontWD>y/Yeir)

_ _/ _ _/ _ _

/ _ _/ _ _

___/„__! ___

RELATIONSHIP TO DRUG* R E M 0 T E 1

'

P 0 s s 1 B L E 2

P R 0 B A B L E 3

N 0 N E 4

HEMOGLOBIN WBC D 1 F F E R E N T 1 A L

NEUTROPHILS BANDS LYMPHOCYTES MONOCYTES EOSINOPHILS BASOPHILS Other:

PLATELET COUNT Other:

•COMMENT ON AND FOLLOW-UP ANY MARKEDLY ABNORMAL VALUE APPEARING AFTER ADMISSION LABORATORY WORK. (SEE DEFINITIONS):

Data

Signature 1Initial*

316

C.1.16

Protocol No. : Subject No.:

Subject Initials:

BLOOD CHEMISTRY ADMISSION

POST THERAPY/ EARLY TERMINATION

REPEAT/ FOLLOW-UP

REPEAT/ FOLLOW-UP

REPEAT / FOLLOW-UP

RELATIONSHIP TO DRUG*

_ _/ _ _/ _ _

_ _/ _ _/ _ _

_ _/ _ _/ _ _

R E M 0 T E

Date Sample Taken: (Morrth/Day/Year)

_ _/ _ _/ _ _

_ _/ _ _/ _ _

..

1

P 0 s s 1 B L E 2

P R 0 B A B L E 3

H 0 N E 4

GLUCOSE CREATININE BUN TOTAL BILIRUBIN ALK. PHOSPHATASE SGOT

‘COMMENT ON AND FOLLOW-UP ANY MARKEDLY ABNORMAL VALUE APPEARING AFTER ADMISSION LABORATORY WORK. (SEE DEFINITIONS):

___________________________

Date

Signature / Inhiait

C.1.17

317

Page

CLINICAL LABORATORY EXAMS Course 1

Cmpd. Marne

IND ff

Prop ff

NDA #

Protocol If — Study ft

NOTE: Please use BLACK ink. Patient's ________________ L Ml F Initials

Patient #

__________

HEMATOLOGY Scheduled Time

Pre-Treatment

Date (M/D/Y) Time of Collection (0-2359) Hemoglobin (g/dL) Hematocrit (%) WBC (x 103/mm3) D 1 I t R e N 1 1 A L

Total of Bands + Segs (%) Lymphocytes (%) Monocytes (%) Eosinophils (%) Basophils (%) Remaining Cells (%)

Platelets (x 1O3/mm3) PT (sec)*

Patient Control

PTT (sec)* Patient Control Other Other Other-

Name of Lab

‘Required only if clinically indicated.

C.1.18

318

Dept.

Sec.

Pt. Allocation No.

3dH/O0H ddH/OSM ddH/SlSVO 3SOOM9 Niwnanv

Idas ±09S

asooms 3NINL1V38O Nna

(e o i x ) i 3 3 3 i \ n d

3IHdONISO3 3JLAOONOH 31AOOHdlNA~l saNva siiHdouinaN

(c o i x ) o a M NI3CH9CM3H 1IHOO±VW3H

Date Mo/Day/Yr

HEMATOLOGY

UHdOSVS

C.1.19

BLOOD CHEMISTRY

Niarms

Protocol

Inv. No.

'SOHd X I V

Record any drug related abnormal values on the adverse events page (page 9).

S3NO13X

319

320 SCREEN

No □

Yes □

MDY

BASELINE Week 4 Week 1

No O Yes O

_ /_/_ MDY No □

Yes □

_/_ /_ MDY

Week 12 Week 15

No □ YesD

_/_ /_ MD Y 1

No □

Yes □

MDY

Optional

|

Study No.: Section:

Dept:

O

O

O

o

o

O

Edited by __________ Date

C.1.20

Date

. _. _ ...

Proj. #

Protocol No.:

.L. IND’

No □

Investigators Signature

___________________________ M.D.

cs

Yes c

MDY

Optional

•

NOTE: COMMENT O N CLINICALLY SIGNIFICANT ABNORMALITIES O N LAST PAGE OF SECTION—"LABORATORY EXAMINATION(ABNORMAL RESULTS)”

Platelet Est.

RBC Morph.

Eosinophils

Monocytes

Lymphs

Basophils

Neutrophils

MCHC

MCH

MCV

HCT

HGB

RBC

WBC

Yes □

MDY

............. -

1

PATIENT # ________________

Are clinically significant abnormal values present? No □ If yes. check ( them in Normal column “CS"

PATIENT'S INITIALS: ________ F M L

SCREEN, BASELINE (A), TREATMENT (A)

HEMATOLOGY

EFFICACY AND SAFETY STUDY—PARTIAL SEIZURES

ip E O

< o z

them in Normal Range

No □ Yes □

No □ Yes □

MDY No □ Yes □

MDY

Week 7

'NoC

Yes □

MDY

Week 12

No □ Yes □

MDY

Week 15

No □

Yes □

___ MDY

Optional

O

O

O

O

O

O

No □

Yes □

_ /_/_ MDY

Optional

Edited by

C.1.21

________________________ M.D. Investigator’s Signature

_

Section:

Study No.:

Protocol No.: Dept:

NDA #

Proj. #

IND*

Cmpd'

NOTE: COMMENT O N CLINICALLY SIGNIFICANT ABNORMALITIES O N LAST PAGE OF SECTION—"LABORATORY EXAMINATION— (ABNORMAL RESULTS)"

SGOT

LACTIC DEHYD.

ALKALINE PHOS.

BILIRUBIN (TOT.)

CREATININE

URIC ACID

ALBUMIN

PROTEIN (TOT.)

UREA NIT. (BUN)

GLUCOSE

CHLORIDE

POTASSIUM

SODIUM

I f yes, check column “CS"

MDY

BASELINE Week 4

PATIENT #---------------------------

SCREEN

________ F M L

Are clinically significant abnormal values present?

PATIENT'S INITIALS:

SCREEN, BASELINE (A), TREATMENT (A)

BLOOD CHEMISTRY

EFFICACY AND SAFETY STUDY—PARTIAL SEIZURES

O

321

PATIENT NUMBER:

LABORATORY

FIRST 3 LETTERS OF LAST NAME:

Page 2 of 2 month

day

year

I I I I I I I LJ

DATE:

STUDY DAY:

Illi month

day

year

month

day

I I I I

iiii

Illi year

month

day

year

I I 11 I 11 I I X X L X

DATE: TIME SPECIMENS TAKEN (24 Hour Clock): BLOOD CHEMISTRY

2. Non-Fasting

day

year

month

day

year

I I II I II I I I I II I II I I

| | |:| | | | | |;| | | | | |;|

1 r 1: 1 "1 1 X C D 1. Fasting

month

IIII

1. Fasting

1. Fasting

2. Non-Fasting

2. Non-Fasting

1. Fasting 2. Non-Fasting

1. Fasting 2. Non-Fasting

GLUCOSE, mg, %:

IIII

BUN, mg, %:

XJ.D

UU.D

CREATININE, mg, %: TOTAL PROTEIN, gm, %: ALBUMIN, gm, %: TOTAL BILIRUBIN, mg, %:

i i.n

L±j.n

CHOLESTEROL, mg, %: SGOT, units: SGPT, units: LDH, units: CPK, units:

cm.

ALK. PHOSPHATASE, units: URIC ACID, mg, %: SODIUM, mEq/L: CHLORIDE, mEq/L: POTASSIUM, mEq/L: OTHER VALUES

25988

Signature: _____ _________________________________________

322

C.1.22

Page

CLINICAL LABORATORY EXAMS (Cont.) Course 1

Cmpd. #/Name

IND //

PlOJ. //

NDA //

Protocol ft — Study #

NOTE: Please use BLACK ink. Patient's Initials

_________________ F M L

Patient #

___________

Dept.

Sec.

CLINICAL CHEMISTRY Scheduled Time

Pre-treatment

Date (M/D/Y) Time of Collection (0-2359) BUN (mg/dL) Creatinine (mg/dL) SGOT (AST. U/mL) SGPT (ALT. U/mL) Alkaline Phosphatase (U/L) Total Bilirubin (mg/dL) LDH (U/mL) Total Protein (g/dL) Albumin (mg/dL) Other Other Other

Name of Lab

C.1.23

323

CLINICAL LABORATORY DATA REPORT Protocol

Pt. I n i t i a s

Inv. N o .

Date

Pt. N o .

Visit NQ

----—........... . . . .... ........ ...... ......... (First. Middle. Last)

Date o f Collection: L _ L_J L_JLJ Month

Chemistries

Day

Value

Month

Fasting:

‘Code

Phosphorus (inorganic) Sodium Potassium Chloride LDH

AST(SGOT) Total Bilirubin GGT ALT(SGPT) Alkaline Phosphatase Cholesterol Triglycerides Total Protein Globulin Albumin A/G Ratio BUN Creatinine Uric Acid Glucose Iron *

Codeallabnormals: 1 = not clinically significant 2 = significant but not study drug related 3 = significant and of unknown study drug relationship 4 = significant and study drug related

Principal Investigator's signature Please attach a copy of the report to the case report form.

324

Yes

Year

Calcium

C H E M I S T R Y

Day

C.1.24

Comment i f significant

No

Year

U1

LABORATORY TESTS AND RESULTS

(Reference Laboratory Value)

Test

mrri mo

HEMATOLOGY Hb Hematocrit ESR (Wintrobe) RBC WBC Platelets

(| | |.| (I l l i

i day

Date

Date

Date yr

i mo

day

yr

mo

day

yr

( r~T~i to n ~ i 9/dL ) (m to m %) ( I I I to | | | mm/1st h. ) to million/ ) | to | | |» | | thousand// ) to | | | |

thousand/ L )

Other (specify) .

CHEMISTRY BUN Creatinine Creatinine Clearance

■■■I ( L□ • □ ( L□ • □

Uric Acid Calcium Plasma Electrolytes Na + K+

er Total Bilirubin SGOT SGPT LDH CPK y-Glutamyl-transpeptidase Alkaline phosphatase Total Proteins Albumin Globulin Glucose Cholesterol Triglycerides Other (specify)

URINALYSIS Leucocytes Hematuria Albuminuria

to 1 1 to 1 1

(1 1 1 1 to | (i i»r~~] to | (i i i 1 to | ( L□ • □ to m (L i i i1 to | (L i i i1 to | (L i i i1 to | (i i n to

•

mg/dL )

•

mg/dL )

| 1 1 mtq/L ) | » | | mEq/L) | 1 1 mtq/L ) . mg/dL ) | 1 1 1 IU/L ) | 1 1 1 IU/L ) | 1 1..1 IU/L ) c 1 1 1 IU/L )

■■■■ ■■■■ ■■■■

( | | | to | | | KA units ) (□□•□to (□•□to (□•□to

□□•□9/dL) □•□ g/dL) □•□g/dL)

(Illi to I I I. . .I mg/dL ) ( I I I I I to I I I I I mg/dL ) ( < I I I I I mg/dL )

_________________________— —

= No ( 1 = No ( 1 = No

d

Other (specify)

Mi ■■■■ ■■■■

—

2 = Yes ) 2 = Yes) 2 = Yes )

.... ................... .

OTHER LABORATORY TESTS (specify)

C.1.25

325

STUDY TITLE

LABORATORY REPORT - Hematology & Chemistries 94-1603-12

D O N O T WRITE I N SHADED AREAS

4/90

INVESTIGATOR'S N O .

PRINCIPAL INVESTIGATOR

PRINCIPAL M O N I T O R

SUBJECT'S INITIALS

SUBJECT N O .

MONITOR NAME STUDY PERIOD

PROTOCOL N O .

DATE SPECIMENS TAKEN

M/0000/0000 VALUE

Codt

ASSAY

Hematocrit (Het) ( % )

A l b u m i n (g/dl)

H e m o g l o b i n (Hgb) (g/dl)

A l k a l i n e Phosphatase (U/L)

Platelet c o u n t (x10 3 / m m 3)

ALT (SGPT) (U/L)

WBC(x10 3 / m m 3 )

AST (SGOT) (U/L) Electronic Differential ( f r o m cell counter)

,

YR.

VALUE

Code

Bilirubin, t o t a l (mg/dl)

Granulocytes ( % )

BUN (Urea n i t r o g e n ) (mq/dl)

Total lymphocytes ( % )

Calcium (mg/dl)

Monocytes ( % )

Chloride (mEq/L)

If differential performed manually, Enter results below:

Creatine kinase (U/L) If elevated: ________ Creatine kinase-MB ( C K - M B ) ( % o f total)

Manual Differential

g S

Total Neutrophils ( % )

DAY

CHECK BOX IF TEST NOT DONE

CHECK BOX IF TEST NOT DONE

ASSAY

MO.

Creatinine (mg/dl) Glucose (mg/dl)

Total Lymphocytes ( % )

□ , Random □

2

Fasting

Monocytes ( % ) LDH (U/L) Eosinophils ( % ) M a g n e s i u m (mg/dl) Basophils ( % )

Phosphorous, inorganic (mg/dl) _______________

Other ( % ) Other

Potassium (mEq/L) DESCRIBE:

Protein, t o t a l (g/dl) Sodium (mEq/L)

P r o t h r o m b i n Time (PT) Subject (sec) ______________ Prothrombin Time (PT) Control (sec) ______________ P r o t h r o m b i n Time (PT) % o f Control ______________ Partial Thromboplastin Time (aPTT) Subject (sec) ________ Partial Thromboplastin Time (aPTT) Control (sec)

N R S T X

= = = = =

Partial Thromboplastin Time (aPTT) % o f Control

* * If clinically significant, EXPLAIN BELOW

COMMENTS:

INITIALS/SIGNATURE:

326

place ONE o f t h e f o l l o w i n g codes i n t h e space provided. N o t clinically significant Related t o underlying disease o r current condition Clinically significant * * Results unavailable d u e t o technical error Other, explain below

* Abnormal Values -

C.1.26

C2

RADIOLOGY A N D PATHOLOGY REPORTS

Page Investigator Name

Date (M/D/Y)

Study Site

Ml

Patient’s First Name

LI

Patient’s Study Number

ASSOCIATED RISK FACTORS TO CONTRAST MEDIUM No

Yes

In addition to Liver Disease, does the patient have a known history of any of the following? If yes, check appropriate box(es). Yes

Yes PCM

1 1 Previous Reaction to Contrast Medium®

HAS

1 1 Hypoalbuminemia

A70

1 1 Age > 70 Years

PRO

E J Proteinuria

DM

□

Diabetes Mellitus

SCD

□

HYP

□

Hypertension

TD

EZ] Thyroid Dysfunction

CHF

□

Congestive Heart Failure

R1

□

Renal Insufficiency

RD

1 1 Renal Disease

MM

1 1 Multiple Myeloma

MS

1 1 Multiple Sclerosis

HG

□

□ LID

Sickle Cell Disease

Pheochromocytoma

1 1 Liver Disease 1 1 Vascular Disease

:||ASM||| HF

1 1 Asthma I | Hay Fever 1 1 Drug Allergy*

Hyperuricemia/Gout

| | Food Allergy* a

If yes, complete bottom of page.

* If yes, list on page 2

PREVIOUS REACTION TO CONTRAST MEDIUM *Date (M/D/Y)

/

■. ..-

Type of Examination

Contrast Medium

Reaction

Severity

Treatment

/- _

X.._

* List most recent first and indicate “Unk” for any incomplete information

C.2.1

327

Investigator Name

Date (M/D/Y)

Study Site

Patient’s First Name

LI

Ml

Patient’s Study Number

MRI EFFICACY AND DIAGNOSIS: OPEN EVALUATION (On-Site Investigator) No

Yes

1. Was there contrast enhancement as a result of the injection of S-095? If yes, indicate which pulse sequence(s) showed best contrast enhancement: 2. Did post S-095 scans provide more diagnostic information than pre S-095 scans?

_J !

If yes, was the additional information of I help in determining the diagnosis.

I

Parameter

Prior to S - 0 9 5 Injection Spin Echo

Grading of Quality of Delineation (select one)1

poor Adequate EZZJ Excellent

P

P Poor P Poor L J Adequate L J Adequate Excellent D Excellent

O

Spin Echo T1

Poor Adequate O

Poor Adequate

Poor P Poor Adequate L_J Adequate CZ Excellent Excellent

P

xr m

O

m

CM CO

'

3

4 5 >5

□□□

0 1 2

□□□□

st to m

3

CM CO

3

4 5 I >5

1-

I

0 1 I 2 I

O

4 5 >5

Gradient Echo

Poor Adequate

□□□

0 1 2

O Poor Adequate

O

□□□□

Discrete Space-Filling Lesion(s) present, complete page 13.

Poor Adequate

O

I significant Post S - 0 9 5 Injection

Gradient Echo

T2

T1

Pulse Sequence

Abnormal Structures or Lesions

| moderate |

I marginal |

Signal to Noise Ratio (SNR) ROI Intensities

Pixels

IntenIntensity sity Pixels Pixels

IntenIntenIntensity sity Pixels sity Pixels

Region 1 Region 2 Region 3 Region 4

MRI Diagnosis: -------------------------------------------------------------------------------------------------------------O Confirmatory Information If yes, was information from

No CT

Yes Biopsy

Surgery

Was final diagnosis different than MR diagnosis? | | No I I Yes

I I Other (Specify): If yes, explain:

MRI QUALITY OF DELINEATION - Details not well delineated, insufficient information for diagnosis Poor Adequate - Details adequately delineated, sufficient information for diagnosis Excellent - Details finely delineated, more than sufficient information for diagnosis

328

C.2.2

Page Investigator Name

Date (M/D/Y)

Study Site

Patient’s First Name

Ml

LI

Patient’s Study Number

BLINDED MRI EFFICACY EVALUATION (Off-Site Investigator) Image Code Number: 1.

2.

________________________

Were Discrete Space-Filling Lesions observed? ED

No

EZI

Yes

Number of Lesions: I I 1

I I 2

I I 3

I I 4

If yes, complete question 2. I I 5

I I

>5

Confidence Level Lesion

3.

Possible

Probable

Definite

Size ED mm ________ cm

Location

1

I I

I I

I I

2

[~l

I I

I I

3

I I

I I

l~]

ED mm ________ ED cm

4

I "I

I I

I I

ED mm

5

I I

I I

I I

________ □

________

mm cm

cm

mm ________ED cm

Was Extra Lepatic Disease Observed? ED I |

No Yes

If yes, describe:

_____________________

ON-SITE INVESTIGATOR USE ONLY Number of false positives:

I I 0

Number of false negatives: I I 0 Comments:

I I

1

I I 1

I I 2

ED

I I 3

I I 4

I I 5

3

[~~l 4

I I 5

2

_______________________________________________________________________________

C.2.3

329

Form 10 Magnetic Resonance Imaging Form (MRI) Patient Initials

Patient Study # Protocol [

| Study Center #

Location

Exam Date M

D

Y H e a d M R I Scan

RESULTS:

Normal Abnormal Grade: Equivocal

(1 = Mild, 2 = Moderate, 3 = Severe)

Please Check Interval Completion / Completion of IV Tx. 3 months As medically 6 months r~] 12 months indicated

ATTACH XEROX COPY OF MRI REPORT TO THIS FORM. (Form to be completed at Central Unit) LOCATION OF ABNORMALITY: (Check all that apply) Right

Left

Frontal Lobes Parietal Lobes Occipital Lobes Cerebellum Mesencephalon Pons Medulla Basal Ganglia Periventricular Optic Nerve 1

Code Location as:

1 = Gray matter 2 = White matter 3 = Both

RADIOGRAPHIC DIAGNOSIS: (Check all that apply) Demyelination Cortical atrophy Infarction Ventricular enlargement Tumor Other, specify Other mass COMMENTS:

330

C.2.4

Location 1

PATIENT NUMBER:

CHEST X-RAY REPORT

FIRST 3 LETTERS OF

LAST

NAME:

Page 1 of 1

month DATE:

day

year

I I I I I I III month

DATE X-RAY WAS TAKEN:

day

year

I I I I l_l I I. I

OVERALL RESULTS:

1. Normal /Attach Report) 2. Abnormality Clinically Insignificant — Patient Will Continue In The Study (Specify Below And Attach Report) 3. Abnormality Clinically Significant Which May Interfere With The Study — Patient Will Not Continue In The Study (Specify Below And Attach Report) LIST A N Y SIGNIFICANT FINDINGS SINCE THE LAST CHEST X-RAY EXAMINATION (If "None," Circle):

C.2.5

NONE

331

FURTHER INVESTIGATIONS Inv. No.

Protocol

Pt. Initials

Pt. Allocation No.

X-RAY / BONE SCAN / GALLIUM SCAN

TEST

Date

Normal

Abnormal

Results

L O W E R EXTREMITY V A S C U L A R E V A L U A T I O N Pedal P u l s e s (Use the key below to report results)

0=0 +=1 ++ = 2 +++ = 3 ++++ = 4

Post Tibial

Dorsal Pedal

Key

Popliteal

Right

Left

D o p p l e r P r e s s u r e s - Systolic mg/Hg Brachial

Thigh

Post Tibial

Dorsal Pedal

Right

Left

T c PO2 (mmHg) Below the Knee

Above the Knee

Chest

Right

Left

332

C.2.6

Foot

PROT. NO

PATIENT INITIALS

ALLOC NO.

please print or write clearly

X-RAYS DATE

NORMAL

ABNORMAL

DESCRIPTION

OTHER PROCEDURE RESULTS (e.g. CT, ultrasound, L.P., blood gases, viral or fungal cultures, etc.) DATE

TEST

RESULTS

C.2.7

333

Inv. No.

Protocol

Patient's Initials I Patient No.

CHEST X-RAY RESULTS

Date Mo

Day

Year

Interpre -tation

Comments

p R E T X

III

D U R 1 N G T R E A T M E N T

P O s T T R E A T M E N T F O L t O W u p

334

C.2.8

Interpretation 1 «= unchanged 2 = improved 3 = worse

PRETREATMENT REPORT FORM Inv. No.

PROTOCOL

Pt. No.

Pt. Initials Illi MO

Date 1 1 1 DAY

Visit No.

01

YR

DEMOGRAPHICS Age

I

i

Sex (circle one)

1 years (must be >60)

Race (circle one)

1 = female

1 = Caucasian

2 = male

2 = negro 3 = hispanic 4 = oriental 5 = other _________

DURATION OF HYPERTENSION I-----i-----1yrs. I-----1-----1 months or

O

newly diagnosed

CHEST X-RAY REPORT

Date X-Ray Performed: J

I—I—I—I—I—l—I MO

DAY

YR

Comments on results:

Attach copy of X-Ray Report

■ ......... '.........' ........... "..........’ ................................ -. . . .

. . ... .

..............' ......................... I

ELECTROCARDIOGRAM --------------------------- ... -..... - -- -------------- - -—

Date ECG Performed:

I

I MO

I

....... -............................ - --------

I DAY

I

I

- . .— .-. .-. .. ... - . ..- . . . —

| . . .- -------------------- -- . .—

. -... . -... i

I

YR

Comments on results:

Attach copy of 12 lead ECG

C.2.9

335

Form 6 Chest X-Ray

Patient Initials

Patient Study # f

Protocol L

M

F

Study Center #

X RavDate

Month /Pay / Year 1 1 1 1 1 1 1

Location

X-Ray Normal i—i —

if Abnormal, please describe below:

X Ray Abnormal

ATTACH XEROX COPY OF X-RAY TO THIS FORM. FORM TO BE COMPLETED AT CENTRAL UNIT.

For each lung, indicate the presence of an abnormality by checking the appropriate location of the abnormality within each lung showing evidence of involvement. LEFT LUNG

RIGHT LUNG DIFFUSE Upper

Middle

Reticulogranular Infiltrate Interstitial Infiltrate Consolidation Hyperinflation Decreased Volume Edema Pleural Fluid Atelectasis Pneumothorax "HSV Pneumonia" "Bacterial Pneumonia" Hyaline Membrane Disease Aspiration Hemorrhage Diaphragmatic Hernia Other:

336

o

C.2.10

Lower

Upper

Middle

Lower

0 0 NOT WHITE IN THIS SPACE i r o n u s e IN COMPILING DATA)

PLEASE TYPE OR PRINT LEGIBL Y WITH BLACK BALL POINT PEN I CHEST X-RAY | I

Mo

| If Chest X-Ray was not performed, enter "X" in this box.

/ / Day Yr

Date of X-Ray

I Enter month, day, and year I that X-Ray was taken.

| I

Cm. Thoracic Diameter from PA film

I Enter thoracic diameter I in centimeters from PA film.

I |

Cm. Heart Diameter from PA film

I Enter heart diameter in I centimeters from PA film.

| I

Pleural Fluid

1 = Present 2 = Absent

I I | | I | I I

| Enter appropriate code. | If pleural fluid is present and associated with a n illness,| enter the diagnosed illness o n | | the appropriate page (e.g., HISTORICAL DIAGNOSIS, CHRONIC | | ILLNESS, or RECORD O F EVENTS I pages).

Pleural Congestion

I = Present 2 = Absent

I | | I I I I I

J Enter appropriate code. | If pleural congestion is present and associated with an | | illness, enter the diagnosed illness on the appropriate page| | (e.g. , HISTORICAL DIAGNOSIS, CHRONIC ILLNESS, or RECORD OF | | EVENTS pages).

1 = Normal 2 = Abnormal

| I Enter appropriate code. If | abnormal describe in COMMENTS. |

Chest X-Ray

C.2.11

337

PATIENT NUMBER:

CANCER MEASUREMENTS

□zo

FIRST 3 LETTERS OF LAST NAME:

Page 1 of 3 month DATE:

day

year

I I I I 11 I I

CHEST X-RAY:

1. Not Done

month DATE:

I

I

day

I

I

I

year I

I

I

I

month I

I

I

I

1

1

2

1

2

1

2

1

2

I

I

1. Normal

1

1

I

I

LOCATION OF LESIONS

I i I I

I. 0 i. o I. 0 I.

2. Abnormal NON-MEASURABLE

1

2

SIZE /cm)

1

2

1

2

1

2

I I I . I lx I I I . 0 I I I . I lx I I 1. 0 I I 1. 1 lx 1 1 1. 0 1 1 1. 0 x 1 1 1. 0

2. Done /Complete Remainder Of This Section)

I

1. Normal MEASURABLE

2. Abnormal NON-MEASURABLE

/Circle One) 1

2

1

2

1

2

1

2

SUBMIT COPIES OF ALL REPORTS

338

I . I lx I i . r~ix i I . I lx I I . I lx I

year

day 1

I i I I

/Circle One)

1. Not Done

1

I i I I

2. Done /Complete Remainder Of This Section)

MEASURABLE

BONE SCAN:

DATE:

SIZE (cm)

year I

SITE

month

NON-MEASURABLE

1

1. Not Done day

I

2. Abnormal

/Circle One)

CHEST CAT SCAN:

I

1. Normal MEASURABLE

SITE

DATE:

2. Done /Complete Remainder Of This Section)

C.2.12.1

SIZE fem)

m.UxLu.n i. .n . i. ixi i i . 0 00.0x00.0 Il l-llxl 1 l.l 1

PATIENT NUMBER:

CANCER MEASUREMENTS

FIRST 3 LETTERS OF LAST N A M E :

Page 2 of 3

month DATE:

day

year

I I I I I I I I 1. Not Done

X-RAY (SUSPICIOUS AREAS) OR BONE SURVEY:

month DATE:

day

year

I I I I I I I I I

month I

I

I

MIXED

1

2

3

1

2

I I I . O x I I I. I I

1

2

3

1

2

I I I.

1

2

3

1

2

r i i . i ix i i i .

1

2

3

1

2

I I I.

I

I

I

I

day I

I

I

1. Normal MEASURABLE

2. Abnormal NON-MEASURABLE

SIZE tern)

(Circle One) 1

2

I I I. O x I I I.

1

2

I I I . I Ixl I I .

1

2

I I I . I Ixl I I .

1

2

I I I . I Ixl I I .

2. Done (Complete Remainder Of This Section}

year I

FILLING DEFECTS

42088

XI I I.

2. Done (Complete Remainder Of This Section!

1. Not Done

I

XI I I .

year

LIVER SCAN:

month

SIZE (cm)

(Circle One)

BLASTIC

1. Not Done

day I

NONMEASURABLE

LYTIC

AREAS OF INVOLVEMENT

DATE:

2. Abnormal

MEASURABLE

A B D O M I N A L CAT SCAN:

I

1. Normal TYPE (Circle One)

SITE

DATE:

2. Done (Complete Remainder Of This Section)

I

I

1. Normal MEASURABLE

2. Abnormal NON-MEASURABLE

SIZE (cm)

(Circle One) 1

2

I I I . I lx I I I .

1

2

I I I.

1

2

I I I. O x I I I ■o

1

2

I I I. O XI I I. O

X I I ...I .

SUBMIT COPIES OF ALL REPORTS C.2.12.2

339

PATIENT NUMBER.

CANCER MEASUREMENTS

FIRST 3 LETTERS OF LAST NAME:

Page 3 of 3

month DATE:

day

year

I I I I I I I. I

SUPERFICIAL/PALPABLE LESIONS (INCLUDING LYMPH NODES):

month DATE:

day

1. Not Present

2. Present (Complete Remainder Of This Section)

year

I I I I I I I I I MEASURABLE

DESCRIPTION

SITE

NON-MEASURABLE

SIZE (cm)

(Circle One) 1

2

I I I. G x I I I. G

1

2

I I I. G x I I I. G

1

2

I I I . I lx I I . G

1

2

GC.Gxm.G

ATTACH PHOTOGRAPH 1. Not Done

BRAIN CT:

month DATE:

day

2. Done (Complete Remainder Of This Section)

year

I I I I I I I I I

1. Normal

2. Abnormal

MEASURABLE

SITE

NON-MEASURABLE

SIZE (cm)

(Circle One) 1

2

oiGGiD

1

2

i i i.rixi i i . G

1

2

m.rixi

1

2

1 1 1. 1 1x1 1 1. G

i i.n

S U B M I T COPY OF REPORT MAGNETIC RESONANCE IMAGING:

month DATE:

day

340

2. Done (Complete Remainder Of This Section)

year

I I I I I I I I I SITE

1. Not Done

1. Normal MEASURABLE

2. Abnormal NON-MEASURABLE

SIZE (cm)

(Circle One) 1

2

I .I.. I .

1

2

I I I. Q x I I I. G

1

2

I I I. G xI I I. G

1

2

I I I. G x I I I. G

C.2.12.3

XI I I. G

P A T H O L O G Y REPORT

Submit within 30 days following operation Answer all questions. Leave n o blanks. When information unknown, so state.

INSTITUTION

4- 1 2

PROTOCOL

MIDDLE i N l i lAL

FIRS T

PATIENT S LAST NAME

HOSPITAL N O

(16) BREAST INVOLVED

(18-23) DATE OF MASTECTOMY

1 E ] HIGHT (24-29) DATE OF BIOPSY

FORM D-1

DATE THIS FORM COMPLETED

(3-11) STUDY N O.................................................. .. . (12-15) REVIEW N O

1(17) TYPE OF BIOPSY 2OI.EFT

NEEDLE 1 (30-49) PATHOLOGY N O

EXCISIONAL

2O

ASPIRATION

3

(50) TYPE OF MASTECTOMY I—. TOTAL + AX DIS 1 L I SEGMENTAL + AX DIS __________________________2 L J hcd Hnd'caii

r—■ 3 L J RADICAL MASTECTOMY

GROSS CHARACTERISTICS OF THE TUMOR (57-59) MAX SUPERIOR-INFERIOR DIAMETER

(54-56) MAX ANTEROPOSTERIOR DIAMETER

(51-53) MAX TRANSVERSE DIAMETER

CM

CM

lOvES

2ONO

m iL—IYES QUADRANT OF PRIMARY

pOnO

I64| O U l - ( o'.) Rhythm: o D Sinus i D Other; describe: ____________________ _________________________ ________________ _ PR interval:

0.

sec.

QRS interval: 0 . _ _ ____________sec.

Q T interval.\

0.

sec.

RR interval:........................ _______sec.

Are there any clinically significant abnormal E C G findings? o Q N O (no comment required)

1

D YES (please describe) __________________ __________________________________________________________________

D o E C G findings exclude this patient from participation in this clinical trial? oQ NO 1

YES - Enter reason o n the Enrollment Log.

Mount tracings o n p a g e provided or provide 8 1 /2 x 11 ECG tracing report a n d attach to this p a g e . Record Patient Number, Patient Initials, Visit Number and Date of Tracing o n all attachments.

C.3.4

348

Clinical Report Form Drug Identification Indication

Visit Page 1 of ?

ELECTROCARDIOGRAM RECORD

If none, enter an "X" here

Complete the Electrocardiogram Record in chronological order by date and time. Include one ECG per envelope, matching the ECG number on the envelope with the number listed below.

ECG Number 1

Date Mo

Day

I

I

Yr

Time

2

C.3.5

349

Page Investigator Name

Date (M/D/Y)

Study Site

__——----

__

Ml

Patient’s First Name

LI

Patient’s Study Number

ELECTROCARDIOGRAM 1. Was the ECG normal immediately prior to the MRI Procedure? If no, provide interpretation:

2. Was there any clinically relevant change during the angiocardiographic procedure for the following parameters? If yes, comment including onset time, duration, description, etc. No I

I

Yes P-R Interval

________________________________________________ _ _ _

QRS Complex

Q-T Interval

T-Wave

3. Were there any clinically relevant episodes of ventricular ectopic beats following the contrast medium administration? If yes, comment:

4. Were there any other clinically relevant changes in the ECG during the angiocardiographic procedure? If yes, comment:

ECG was recorded:

Immediately prior to injection Immediately after injection 1 Hour 24 Hour ______ _______

Other: (specify)

350

C3.6

PATIENT NUMBER:

ELECTROCARDIOGRAPHIC EXAMINATION

FIRST 3 LETTERS OF LAST NAME:

Page 1 of 1 month

day

year

'/.-I HOUR POST-DOSING

TIME ECG WAS TAKEN:

I

I

I

:

I

I

I (24 Hour Clock!

OVERALL RESULTS: 1. Normal (Attach Copy! 2. Abnormality Clinically Insignificant — Patient Will Continue In The Study (Specify Below And Attach Copy) 3. Abnormality Clinically Significant Which May Interfere With The Study — Patient Will Not Continue In The Study (Specify Below And Attach Copy) LIST ANY SIGNIFICANT FINDINGS SINCE THE LAST ECG EXAMINATION (If "None," Circle):

NONE

4-8 HOURS POST-DOSING

TIME ECG WAS TAKEN:

I

I

I

:

I

I

I (24 Hour Clock)

OVERALL RESULTS: 1. Normal (Attach Copy) 2. Abnormality Clinically Insignificant — Patient Will Continue In The Study (Specify Below And Attach Copy) 3. Abnormality Clinically Significant Which May Interfere With The Study — Patient Will Not Continue In The Study (Specify Below And Attach Copy) LIST ANY SIGNIFICANT FINDINGS SINCE THE LAST ECG EXAMINATION (If "None," Circle):

C.3.7

NONE

351

PATIENT NUMBER:

ELECTROCARDIOGRAPHIC EXAMINATION

FIRST 3 LETTERS OF LAST NAME:

Page 1 of 1

month DATE:

I

I

day

I

I

I

year I

I

I

month DATE ECG W A S TAKEN:

I

I

day I

I

I

year I

I

I

I

TIME:

F

I

I : I

I

I (24 Hour Clock)

OVERALL RESULTS:

1. Normal — Patient May Enter Study (Attach Copy) 2. Abnormality Clinically Insignificant — Patient May Enter Study (Specify Below And Attach Copy) 3. Abnormality Clinically Insignificant — Patient May Not Enter Study (Specify Below And Attach Copy) 4. Abnormality Clinically Significant — Patient May Not Enter Study (Specify Below And Attach Copy) LIST A N Y CHANGE SINCE PREVIOUS ECG EXAMINATION:

1. No Change 2. ECG Change Is Probably Due To The Study Drug 3. ECG Change Is Probably Not Due To The Study Drug

Signature:

352

C.3.8

_________

Compd. # DO IND #

ELECTROCARDIOGRAM

Proj. # NDA #

NOT

Screen

FILL Protocol #

Study #

IN

Exam Date: ___/ _ _ _/ __ _ v M D

Vol. Init: ____________ F M L

Dept.

Vol. #:

Sec.

12 LEAD ATTACH COPY OF THE TRACING AND REPORT Heart Rate: ECG:

/min. Normal

PR Interval:

sec.

QRS Duration:

sec.

QT Interval:

sec.

Axis

Abnormal. If abnormal, complete each section below.

I. List and Describe each abnormality below. Discuss in terms of rhythm, wave morphology and conduction. NOTE: If any abnormality is clinically significant, a cardiologist must be consulted and a copy of his/her report attached.

II. Assess the abnormality below. NOTE: ALL PREVIOUS TRACINGS MUST BE AVAILABLE TO THE CARDIOLOGIST FOR EVALUATION. 1

. Assess relationship of abnormality to study drug: Unlikely

Probable

Unknown

2. Is this the first cardiac abnormality detected in the study for this volunteer? (Comment on relationship to previous tracings below): Yes

No

INVESTIGATOR’S INIT.

C.3.9

353

CLINICAL REPORT FORM DRUG NAME OR NUMBER FREE TEXT TO IDENTIFY THE STUDY FROM OTHER STUDIES

D O N O T WRITE I N THIS S P A C E (FOR USE I N COMPILING DATA)

Visit Page 1 of

PLEASE TYPE OR PRINT LEGIBLY WITH BLACK BALL POINT PEN I HOLTER TAPE TRANSMITTALI Patient Initials

| Enter first, middle, and last initials. If the| | patient has no middle initial, enter a dash (— ). I

First Middle Last

Mo

I I Day Yr

Date Recorded

___________________| Enter month, day, and year hotter tape was applied.!

Start Time

I Enter the 24-hour clock time Holter started.! I (Eg.: 1:30 PM = 1330.) . I

REVIEWED

Stop Time

AUDIT

Diary Entries

/ Mo

DATE

| Enter the 24-hour clock time| | Holter stopped. |

I Day

1 = No Entry 2 = All on Record of Events 3 = At Least One Event Is Chronic and is Not on Record of Events. 99 = Other

Date of Last Dose

I | | |

Enter appropriate code for diary entries obtained from patient’s diary. If other, specify on CRF comments page.

| Enter the month, day, and year that the last dose | | of study drug was taken prior to this Holter. |

Yr

1 Enter the 24-hour clock time that last dose of 1 study drug was taken prior to this Holter.

Time of Last Dose

1 = Yes 2 “ No

Additional Profile

1 = Yes 2 = No

Special Instructions

I Enter the appropriate code. I

1 = Yes 2 = No

| Enter the appropriate code. | I If yes, enter instructions below.| | If no, leave instructions blank. {

SPECIAL INSTRUCTIONS FOR CARDIO DATA:

Recorder Number | Enter the five-digit recorder number.| Pacemaker

1 = Yes 2 = No

| Enter the appropriate code.|

***NOTE***

354

| |

I Enter appropriate code. If yes, enter the| | name of profile; if no, enter a dash (-). I

Name of Profile Report Generated

| | | |

THIS SECTION IS FOR USE BY CDS ONLY:

Date Received

j

j

|

|

|

|

|

Date Processed

I

I

}

I

I

I

I

C.3.10

Analyst code

|

|

I

I

_J

_l

I

Clinical Report Form Drug Identification Indication

Visit ? Page 1 of ?

ELECTROCARDIOGRAM

If none, enter an "X" here

Date Electrocardiogram performed

Electrocardiogram is

............ + 120

MORPHOLOGY:

Normal Atrium: Ventricle:

NA MYOCARDIAL INFARCTION: NA ST SEGMENT:

ILBBB

Artifical pacemaker Bigeminy Other

IVCD Other

Indeterminate QRS < - 3 0 Biatrial

RAH RVH High Lateral I, AVL Anterior V3, V4 Extensive Anterior 1, L, V1-V6 Other

Absent Septal V1, V2, (V3) Lateral 1, L, V5, V6 Inferior (2), 3, F

Antero Septal V1-V4 Antero Lateral V3-V6

Abnormal (Describe below)

Normal Depressed

1 V1

2 V2

3 V3

R V4

L V5

F V6

Elevated

1 V1

2 V2

3 V3

R V4

L V5

F V6

Low to Flat

1 V1

2 V2

3 V3

R V4

L V5

F V6

Biphasic

1 V1

«s

R V4

L V5

F V6

Inverted

1 V1

2 V2

3 V3

R V4

L V5

F V6

Peaked

1 V1

2 V2

3 V3

R V4

Positive

1 V1

2 V2

3 V3

R V4

L V5

F V6

Negative

1 V1

2 V2

3 V3

R V4

L V5

F V6

L_1 N A

Abnormal (Describe below)

Normal

I

T WAVES:

IRBBB

□ □□

RHYTHM:

>

□

INTERVALS:

u_ £

L V5

□ □

Abnormal (Describe below)

Normal

__

________________________________________________________

/

INTERPRETED BY Mo.

356

□ □

Comments

□ □

U WAVES:

□d

NA

C.3.12

/ Day

Yr.

C m p d . # / Name

Page

ELECTROCARDIOGRAM Screen

Proj. #

NDA # NA

IND #

Protocol # — Study #

NOTE: Please use Black ink. Patient's initials

Exam

Patient # F

M

uate

L

Dept. M

D

Sec.

Y

Check (>x) if ECG done previously (within 14 days of Treatment Day 1). Heart Rate: _____ _____/min.

PR Interval: _ _ ________sec.

QT Interval: __________sec

Axis ________ _ _(degrees)

ECG:

Normal

Abnormal

QRS Duration: __________sec.

If ABNORMAL, indicate the specific abnormality(ies) by recording the appropriate code number(s) from the list below.

Abnormalities A. RHYTHM ABNORMALITIES 1-Sinus Tachycardia 2-Sinus Bradycardia 3-Premature Ectopic Atrial Beats 4-Escape Ectopic Atrial Beats 5-Artrial Tachycardia Without Block 6-Atrial Tachycardia With Block 7-Atrial Flutter 8-Atrial Fibrillation 9-Premature Ectopic Junctional Beats 10-Escape Ectopic Junctional Beats 11-Escape Junctional Rhythm (2000 mg%

WBC, RBC, Casts

0 = Negative, none seen 1 = Rare, 1-2 hpf 2 = Occasional, few, 3-5 hpf 3 = Moderate, 6-10 hpf 4 = Many, 1 1-50 hpf 5 = TNTC, TMTC (too numerous/many t o count), > 5 0 , loaded

(type not necessary)

Interpretation Code Numbers: 0 = W i t h i n normal limits 1 = Abnormality not related t o study drug

2 = Abnormality possibly or probably related t o study drug 3 = Cause not determined

C.4.1 359

Protocol No. : Subject No.:

Subject Initials:

URINALYSIS ADMISSION

POST THERAPY / EARLY TERMINATION

Date Sample Taken: _ _J ___/ ___

(Month/Oay/Year)

_ _/ _ _/ _ _

■ . ■ ■

REPEAT/ FOLLOW-UP _ _/ _ _/ _ _

REPEAT / FOLLOW-UP

REPEAT / FOLLOW-UP

___! __J ___

___I ___! ___

■ .

RELATIONSHIP TO DRUG* R E M 0 T E 1

P 0 S S 1 B L E 2

P R 0 B A B L E 3

N 0 N E 4

pH SPECIFIC GRAVITY M 1 C R 0 S C 0 p 1 c

RBC WBC NONAMORPHOUS CRYSTALS Other:

‘COMMENT ON AND FOLLOW-UP ANY MARKEDLY ABNORMAL VALUE APPEARING AFTER ADMISSION LABORATORY WORK. (SEE DEFINITIONS):

INVESTIGATOR

360

______________________ _

DATE

SIGNATURE

C.4.2

Page Study Site

Investigator Name

Ml

Subject’s First Name

Date of Test Drug Administration

LI

Subject’s Study Number

Time of Test Drug Administration ____________________MT

M

D

Y

URINE COLLECTION LOG COLLECTlOh ID NO. O1H

STUDY TIME (Hours)

CLOCKTIME COLLECTION DATE COLLECTION COMPLETED (M/D/Y) COMPLETED (MT)

COMMENT

PH

Control at Baseline -12-0

02H

0-6

03H

6-12

04H

12-24

05H

24-48

06H

48-72

__/ _ f . ./

Refrigerate samples immediately upon collection

Shipping Date:

Z

Z

Collections were processed as per protocol (unless otherwise noted in comments).

Signature of Site Technician

Copy Distribution:

White & Yellow Pink Hard

-

Monitor Return with Samples Retained in Investigator’s File

C.4.3

361

PATIENT NUMBER:

URINE COLLECTIONS Page 1 of 1

month

FIRST 3 LETTERS OF LAST NAME:

day

year

I I I I I I I I

DATE:

TIME RELATIVE TO DOSE

month DATE:

day

TOTAL VOLUME

FRACTIONAL COLLECTION

TIME VOIDED ________pH

year

I I II I II I I 1 1 1:1 1 1

0 - 2 4 HOURS

month DATE:

CLOCK TIME 124 hr. clock)

day

—

year

I I I _LJ I I I

24-48 HOURS

C.4.4a

Drug ID VISIT

PATIENT INITIALS (3)

PATIENT NUMBER

List below all abnormal laboratory findings and comment on those which are clinically significant. Attach centralized laboratory report to this page. TEST NAME

ABNORMAL IF OUTSIDE NORMAL RANGE, IS IT CLINICALLY SIGNIFICANT? VALUE

(0) NO (1) YES -

please comment

Specific Gravity

D

Glucose Protein MICROSCOPIC

____________URINALYSIS

PH

RBC Casts WBC Bacteria

Serologic Pregnancy Test (females only)

362

02) O

o D Performed 1

Not Performed

C.4.4b

STUDY TITLE

LABORATORY REPORT - Urinalysis D O N O T WRITE I N SHADED AREAS

4/90

INVESTIGATOR'S N O .

PRINCIPAL INVESTIGATOR

PRINCIPAL M O N I T O R

SUBJECT'S INITIALS

SUBJECT N O .

MONITOR NAME STUDY PERIOD

PROTOCOL N O .

DATE SPECIMEN TAKEN

M/0000/0000 VALUE

/

DAY

C

CHECK BOX IF TEST NOT DONE

CHECK BOX IF TEST NOT DONE

ASSAY

MO,

Code

VALUE

ASSAY □

0

Code *

0, Negative

O , 1 + , Small □ Glucose (sugar)

u R N A L Y S I S

□

o

0, Negative

□

T

T, Trace, 100 mg/dl C/,0 gm/dl)

Blood (hemoglobin)

□

o

0, Negative

□

T

T, Trace

□ , 1 + , 250 mg/dl ( ’ /4 gm/dl) □ 2 2 + , 500 mg/dl (V 2 gm/dl)

□ 2 2 + , Moderate, 50 RBC/pl □ 3 3 + , Large, 250 RBC/pl

□

o

0, Negative

□

T

T, Trace, 1 5 mg/dl

□ „ 4 + , > 2 5 0 RBC/yl

Are any results from the urine microscopic analysis considered clinically significant?

□ , 1 + , 30 mg/dl □ 2 2 + , 100 mg/dl □ 3 3 + , 300 mg/dl

□

□ 4 4 + , >2000 mg/dl Ketones

2 + , Moderate

□ , 1 + , Small, 5-10 RBC/pl

□ 3 3 + , 1000 mg/dl (1 gm/dl) □ a 4 + , >2000 mg/dl ( > 2 gm/dl) Protein (albumin)

2

□ 3 3 + , Large

□

0

0, Negative

□

T

T, Trace, 5 mg/dl

0

If YES, please list below:

No

□ r Yes

0 1 1 + , Small, 1 5 mg/dl □ 2 2 + , Moderate, 40 mg/dl □

3

3 + , Large, 80-160 mg/dl

□ a 4 + , > 1 6 0 mg/dl

* Abnormal Values - place ONE o f the f o l l o w i n g codes i n t h e space provided. N = Not clinically significant R = Related t o underlying disease or current condition S = Clinically significant * * T = Results unavailable due t o technical error X = Other, explain below * * If clinically significant, EXPLAIN BELOW COMMENTS:

INITIALS/SIGNATURE:

C.4.5

363

PATIENT NUMBER:

URINE SAMPLING

FIRST 3 LETTERS OF LAST NAME:

Page 1 of 1

month DATE:

day

year

I I I I I I I I I

DOSE GIVEN:

Illi

COLLECTION INTERVAL

.I l l i

mg

TIME DRUG GIVEN:

END OF COLLECTION PERIOD

(24 Hour Clock)

URINE VOLUME

CONTROL

Hour(s) Hour(s) Hourts) Hourls) Hour(s) Hour(s) Hour(s) Hour(s) Hourts) Hourls) Hourts) Hourls) Hourts) Hourts)

C.4.6

364

I I I ! I I I (24 Hour Clock)

URINE pH

COMMENT

PATIENT NUMBER:

URINE SAMPLING Page 1 of 1

DATE:

FIRST 3 LETTERS OF LAST NAME:

month day year U I I I L

DOSE GIVEN:

Q

.

I I I mg

URINE SAMPLING TIME PROM DRUG ADMINISTRATION

I I I Hour I I I Hour I I ! Hour I I I Hour I I I Hour I I I Hour I I I Hour I I I Hour I I I Hour I I I Hour

TIME DRUG GIVEN:

ACTUAL TIME

(24 Hour Clock) | | |;| | | | | |;| | | |;| | | | | |;| | |

URINE VOLUME

I I I ■'I I I (24 Hour Clock) URINE pH

| [ |;| | | | :| J ] | [ ]. | | | [ | |;| [ ] [ | ]: [ | | | ; | [~[

C.4.7

365

PATIENT NUMBER:

URINE COLLECTIONS

FIRST 3 LETTERS OF LAST NAME:

Page 1 of 1 month DATE:

day

I I I I I I I I STUDY DATE

month

year

day

VOLUME Iml)

TIME POST DOSING year 0 HOUR

month

day

year 0

month

day

2 HOURS

year 2 - 4 HOURS

4

6 HOURS

6 - 8 HOURS

8 - 12 HOURS

I LI I

12 - 2 4 HOURS month

day

year 2 4 - 4 8 HOURS

C.4.8

366

TIME !24 Hour Clocks

Compd. # DO IND #

Proj. # NDA #

NOT

URINALYSIS

FILL Protocol #

Screen

Study #

IN

Exam Date: ___/ _ _ _1 _ _ M D Y

Vol. Init: ____________ F M L

Vol. #: ___________

Dept.

Sec.

Enter ND under value column if test could not be performed. MACROSCOPIC Valuet

Observation/Measurement

(V) OS*

Comment Only On Clinically Significant Values

Color/Appearance

•

pH Specific Gravity

•

Protein Glucose Acetone Occult Blood OTHER (specify) MICROSCOPIC WBC/hpf RBC/hpf Casts Crystals OTHER (specify)

Excluded from study because of clinically significant abnormalities

Yes

No

*CS = Clinically aigniflcant abnormality

tNOTE: Please enter the CODES below in the Value column of the specific test/measurement where applicable Protein, Glucose, Acetone, Occult blood Epithelial Cells, crystals, WBC, RBC, Casts 0 0.5 1 2 3 4

= = = = = =

none or negative trace or positive (qualitative) + or 1 + h or 2 + + •< + -i>- + or 3 + -;- -ir + + or 4 +

0 0.5 1 2 3 4

= = = = = =

Bacteria

none or negative 0 = none or negative rare, occasional, few, present, trace (1-5) 0.5 = rare, trace, occasional, few. several (1-10) several, mild (6-10) 1 = mild (11-50) 2 = moderate (51-75) moderate (11-25) 3 = many, numerous (76-100) many, much (26-50) 4 = loaded, severe (>100) loaded, severe (>50)

INVESTIGATOR’S INIT.

C.4.9

367

URINE ASSAY/WITHDRAWALS AND DROPOUTS Inv. No.

Protocol

Pt. No.

Pt. Initials _________ (First, Middle, Last)

URINE BIOASSAY Record t h e results o f t h e assay as: A = antibiotic absent P = antibiotic present DAY 3-7

WITHDRAWALS AND DROPOUTS Did t h e p a t i e n t complete 10 days o f treatment? Did t h e p a t i e n t complete t h e study?

0 = No, 1 = Yes

0 = No, 1 = Yes

If n o , please indicate t h e category as defined b e l o w : (Check one)

I I I I I

I Treatment Failure I Adverse Event I Unable t o Take Medication I Did n o t r e t u r n I Other (specify below):

Date o f w i t h d r a w a l : Month

Day

Year

C.4.10

368

No □

Yes □

Yes □

No □

Yes □

o

Yes □

No □

Yes □

MDY

Baseline B Week 20

2 = moderate (11-25) 3 ~ many (26-50) 4 = loaded, severe (over 50)

No □

MDY

Week 15

No □

Yes □

MDY

Week 23

o

o

o

o

N o L_ Yes

MDY

Week 31

_____________

C.4.11

Date

Yes O

No □

Investigator's Signature

Yes □

MDY

Optional

Section:

Study No.:

NDA #

Proj. #

___________________________ M.D.

o

_____________

No □

—/_ MDY

Follow-Up Week 36

o

Edited by __________ Date

NOTE: COMMENT ON CLINICALLY SIGNIFICANT ABNORMALITIES ON LAST PAGE OF SECTION—"LABORATORY EXAMINATION— (ABNORMAL RESULTS)"

No □

MDY

Week 7

o

0 = none or negative 0.5 = rare, occasional, few, trace (1-5) 1 = several, mild (6-10)

*WBC, RBC, casts and crystals:

PREGNANCY TEST

OTHER

’CRYSTALS

•CASTS

OSH.

’WBC

SEDIMENT:

KETONES

BILE

GLUCOSE

PROTEIN (Alb)

pH

SPECIFIC GRAV.

COLOR

them in Normal

MDY

Baseline A Week 4

Dept:

□

If yes. check column "CS"

Are clinically significant abnormal values present?

MDY

SCREEN

PATIENT # _______________

IND -

Cmpd*

i o

PATIENT'S INITIALS: ________ F M L

SCREEN TO WEEK 36

URINALYSIS—SPECIAL TESTS

EFFICACY AND SAFETY STUDY—PARTIAL SEIZURES

6 z

O

|

370

Sample No.*

-

L

Dosing Day j

0-8

0-8

Date (M/D/Y)

Date (IWD/Y)

Time (0-2400)

T o b e o b t a i n e d o n t h e f i r s t dose o f d r u g o n d o s i n g days 7 , 1 4 , 21, a n d 24.

Time (0-2400)

End of Collection

Protocol

Form 1 7 URINE DRUG CONCENTRATION

Start of Collection

Patient Study #

Time (Hours)

Scheduled Collection Time

M

co o

* Sample No. = X for sample not taken.

F

Patient Initials

rCO o

Total Volume (ml)

Concentration of

To be completed at

Results

Study Center #

in pg,'ml

Location

M

L

|||

Time (Hours)

-

Date (M/D/Y) Time (0-2400)

Start of Collection

f

1 ,73 _ _ _ _ Body Surface Area

C.4.13

Weight

x

!

Serum Creatinine

Results

Study C e n t e r #

Urine Creatinine

Weight

Volume (ml/min)

Time (0-2400)

Total Volume (ml)

Height

x

Date (IWD/Y)

End of Collection

I

Height

Creatinine clearance calculations): Urine Creatinine (mq/dl) Serum Creatinine (mg/dl)

Day 1

Protocol

24-HOUR URINE CREATININE CLEARANCE

Form 18 Laboratory Follow-Up

1 Baseline t o be done concomitant w i t h t h e initiation of therapy Others as medically indicated

|

Patient Study #

Scheduled Collection Time

| _ _ _ |_

Dosing Day

|

-

Sample No*

F

Patient Initials

o

371

Creatinine Clearance

Location

PATIENT NUMBER:

RENAL EVALUATION

FIRST 3 LETTERS OF LAST NAME:

Page 1 of 1

month

day

year

DATE:

START TIME:

—

—

0=No 1=Yes

Was Treatment Required For The Event? i (circle one)

0=No 1=Yes

o

—

0=No 1=Yes

Relationship To Study Drug t=reiated i 2=not related [ 3=unknown

460

ADVERSE EVENT FORM

0

Seventy Adverse Event

* 1 = serious 2 a nonserious

Yes

Date of Onset Mo

Dav

Yr.

Duration

Time of Event (circle a m. or p.m.)

Hours

Mm$

Pattern 1 = continuous 2 = intermittent 3 = isolated

Relationship To Study Drug 1 = related 2 =■ not related 3 = ununowo

if 22 < 0.

if

0«NO 1 = Yes 0 « No 1 = Yes 0 = NO i«Yes

M II O V-

if if

An adverse event is considered: SERIOUS: if i t is life-threatening: requires emergency treatment, requires or prolongs inpatient hospitalization. Cancer and overdose are always considered serious.

‘1 II o

if

2222222 2222222 — ———

if

3222222 3222 222 ———— —— 2 222 222 Comments, give details of follow-up care and treatment (if required).

Treatment Required? (circle one) Explain under comments

ON a 0

Did the patient experience any adverse events? If yes, specify below

0 = No 1 = Yes

INVESTIGATOR: Complete Items 1-39, except 2 and 25. MONITOR: Complete Items 2, 25, 30, 33b, 34b, 40-48.

MEDICAL EVENT REPORTING FORM (FOR SERious EVENT ONLY) - See protocol f o r definition of SERIOUS

(Refer t o instructions f o r completing form.) 3. PATIENT STUDY NO.

1. INVESTIGATOR NAME (PRINT OR TYPE)

6. PATIENT INITIALS

4. PROTOCOL NO.

:OUNTRY

11. WEIGHT

10. HEIGHT

DATE OF BIRTH

49. DATABASE NO.

UNITED STATES

M/0000/0000 YEARS □

CANCER

□

□

OVERDOSE

OTHER

14(a). Is this a follow-up t o a previous written ortelephone report?

(b). If Yes, date of initial report: tie. If death, state cause:

is MEDICAL EVENT (describe)

DAY

MO.

19. EVENT STATUS 5

?

£ > ? 5 -o a s 5

j22 TEST/LABORATORY i CONFIRMATION?

20. TREATMENT FOR EVENT _ _ ______I 21. OUTCOME OF THIS MEDICAL EVENT None

□

Completed?

Qves

5 -K f

F l No

Event not yet resolved

□

l~~l Resolved, n o sequelae Duration: __________________

.—> 1—> □ LJYes LJNo

1


—. . IZATION REQUIRED □ L J Y e s L I NO OR PROLONGED?

Yes

□

No

(If Yes, attach report)

23. Patient dropped from study due to event?

EVENT RESULTED IN CHRONIC CONDITION. SEVERE AND/OR PERMANENT DISABILITY

1

i *

1 H S It|h

Prescription d r u g therapy required?

□

DECEASED (Complete items 16-18) Outcome unknown (lost t o follow-up)

□

Yes

□

No

DRUG/THERAPY ASSOCIATED W I T H EVENT ( * DO NOT BREAK CODE - See instructions. Monitor will complete in INVESTIGATOR-BLINDED studies) ____________________ 26. TREATMENT INDICATION FOR THIS DRUG/THERAPY

p?

28. ROUTE OF i 29. REGIMEN (btd.tid, ADMIN.(oral, etc.) i IV.etc.)

30. TOTAL DAILY DOSE (amount/ type of units)

31 DATE STARTED (Mo./ Day / Y r . )

32. DATE STOPPED (Mo./ Day / Y r . )

□

Yes

g

[□Yes

□

Yes

£

□

No

33c. THERAPY DISCONTINUED DUE TO EVENT? □

>

□

o

Oves □

1

□

Yes

QNO □

□

QNO QNo

[j □ Y e s

No

de therapy USED TO TREAT THE EVENT. Forms specified in study protocol should be completed for therapy used t o treat the event.)

* O N° 1

SOA□

D No O Yes

1 Ohio DYes □ No n v e s _______________1_______________ QYes QNo ! QNO OYes QNo OYes

ONQ S0AO

CD

* □ No F l Yes

□

□ No □Yes

f ONO QYes

□

□

35. DRUG NAME DRUG/THERAPY DECHALLENGE-RECHALLENGE Did medical event: □ Yes □ No a. abate after discontinuing drug? b. reappear after re-introducing drug? □ Yes □ No 33. INVESTIGATOR'S

SIGNATURE:

J MONITOR COMMENT:

37. DRUG NAME

36. DRUG NAME

□ Yes □ No O v e s O No

□ Yes □ No □ Yes □ No

/ / SIGNED: - B r o -'-T5y r / - 7 R-

1 39. DATE

4o. Monitor 43.Dispensation protocol? D Y e s L2JND#: 41.NDA#: received date: 44. Type of study: D D M A clinical □Epidemiology/post marketing surveillance □Consumer Products Vft. □investigator IND □Literature n p R & D 45.Type of report: □Prelim □init/Final 116. Monitor name: 217. MONITOR/ □ Follow-up: 1VIRA/MRC SIGN.: database # if known

“ MoV bAY

1

o

□ NO QYes

> □

cd 34(a) OTHER RELEVANT HISTORY (e. g., diagnoses, allergies, pregnancy with LMP, etc.)

34(b) INVESTIGATOR COMMENT:

|

o

□

o N0

nves □

in< u

o

(D O

O

NO

J b. MONITOR

□

ITH EVE

□ □

MSOGATED

a. INVESTIGATOR □

, ________1________ 1 1

24

(D

J

s £

□ □ □ □ □

(2)

STOP

TIME DATE ( M / D / Y ) (24-hr clock)

J ajQAeg o

(1)

I

DATE TIME ( M / D / Y ) (24-hr clock)

cu

o z

e Bjepop

* £

ACTION TAKEN

STUDY DRUG RELATIONSHIP

CC 14-1

1

_ c

START

£

□

NONE

Please record start date and time; stop date and time . __________

□

□

DATES AND TIMES OF OCCURRENCE I N STUDY

pm

I

5

I

! £ &

I

I

Specify any negative event t h a t the

i CONDITION i EXISTED JF YES, PRIOR T O IS IT : STUDY ENTRY WORSE?

LU w

STUDY EVENT

ADVERSE EVENTS Inv. No.

Protocol

Date of Assessment

Pt. No.

Day

Month

Did the patient experience any adverse event(s) during the study period?

0Q

Yes, please complete details below.

No

C=No l=Yes

iJOiiittfl ro o = 4 Units

____ (29)

INFECTION

Mild

Moderate

Severe

Life-threatening

____ (30)

NAUSEA

Able to eat

Decrease intake

No intake

—

VOMITING

1 q. 24 hrs.

2-5 q. 24 hrs.

6-10 q. 24 hrs.

Parenteral support

— J (32)

DIARRHEA

+ 2-3 q. 24 hrs.

+ 4-6 q. 24 hrs. Moderate

+ 7-9 q. 24 hr. Severe

10+ q. 24 hrs: bloody: support.

____ (33)

STOMATITIS

Mild

Ulcers

Cannot eat

Support req.

____ (34)

HEMATURIA

Micro

N o clots

Gross + Clots

Transfusion

____ (35)

ALOPECIA

Mild

Pronounced

Total

—

____ (36)

PULMONARY

Asympt. w/ abn. PFTs

Exertion dyspnea

Normal activity dyspnea

Rest dyspnea

____ (37)

PHLEBITIS/PULM. EMB.

Superficial

Deep Vein Thrombosis w/o hosp.

DVT w/ Hospitalization

Pulm. Emb.

____ (38)

CARDIAC DYSRHYTHM.

Transient

Recurrent

Rx. req.

Monitoring

____ (39)

CARDIAC FUNCTION

Asympt: < 2 0 % Deer, in Lt. V.F.

> 2 0 % Deer, in Lt. V.F.

Mild C.H.F.

Severe C.H.F

____ (40)

CARDIAC ISCHEMIA

Flat T-wave

Addn. EKG Changes

Angina

M.l.

____ (41)

CARDIAC PERICARDIAL

Asympt.

Pericarditis

Drainage

Tamponade

____ (42)

HYPERTENSION

Transient

2 0 + Inor. diastolic

Rx. req.

Crisis

____ (43)

HYPOTENSION

No. Rx.

Outpt fluids required

Rx. req./ hosp.

Rx/Hosp req. > 48 Hrs.

—J

(31)

‘GRADE 5 = DEATH “ G R A D E 3, 4, or 5 = Complete Reverse Side

470

D.37.2

ENTER HIGHEST GRADE**

CRITERIA

____ (44)

NEURO-SENSORY

____ (45)

NEURO-MOTOR

____ (46)

NEURO-CORTICAL

_ _ _ (47)

TOXICITY GRADE*

NEURO-CEREBELLAR

1

2

3

4

Mild

Moderate

Severe

—

Subjective

Mild objective

Impaired function

Paralysis

Mild

Moderate

Severe

Coma/Seizures

Slight incoord.

Tremor, slurred speech, nystagmus

Ataxia

Necrosis

Suicidal

____ (48)

NEURO-MOOD

Mild

Moderate

Severe

—J

NEURO-HEADACHE

Mild

Moderate

Unrelenting

____ (50)

NEURO-CONSTIPATION

Mild

Moderate

Severe

Ileus > 96 Hrs.

□

NEURO-HEARING

Loss on audiometry

Tinnitus

Impaired function

Deafness

NEURO-VISION

Transient

Asympt, measurable change

Subtotal loss

Blindness

____ (53)

SKIN

Eruption

Eruption w/pruritis

Gen’lized eruption

Ulcerative dermatitis

------ (54)

ALLERGY

Rash

Urticaria

Rx. req.

Anaphylaxis

< 38°C

28-40°C

>40°C

With hypotension

Pain

Pain w/inflam.

Ulceration

Surgery

(49)

(51)

_ _ _ (52)

_ _ _ (55)

— ------- (56)

FEVER

LOCAL COMPLICATION OR EXTRAVASATION

(57)

OTHER, Describe

_ _ _ (58)

OTHER, Describe

OVER

‘GRADE 5 = DEATH “GRADE 3, 4, or 5 = Complete Reverse Side

D.37.3

471

E. MEDICINES AND ASSAYS OF BIOLOGICAL LEVELS Title

Form Numbers

Page Numbers

1.

Dosing and Dispensing Records

E. 1.1— E.l.45

475-519

2.

Concomitant Medications

E.2. 1— E.2. 13

521-533

3.

Pharmacokinetic Samples t o Assay

E.3. 1— E.3. 16

535-550

GENERAL POINTERS A N D COMMENTS •

Generic names should be used for recording concomitant prescription medicines, and brand names should be used for recording over-the-counter medicines (E.2). It is desirable to utilize only a single concomitant medicine form for the entire trial rather than to have one for each clinic visit (E.2).

• •

• •

Identify all medicines and nonfood substances (e.g., vitamins) used on the concomitant medicine form, even if they are not used to treat the focus disease of the trial (E.2). For recording elapsed time, utilize minutes up to approximately 180, hours up to approximately 72, and days after that (E.3). Provide a blank space to indicate the actual time each sample is collected (E.3).

SPECIFIC POINTERS A N D COMMENTS O N INDIVIDUAL FORMS E.l

Dosing and Dispensing Records

•

Details of dosing administration, particularly for infusions, may be collected (E.1.1).

•

Both theoretical and actual times are important to know ( E . l . 2).

473

MEDICINES AND ASSAYS O F BIOLOGICAL LEVELS

Identifying who administered each dose may be important (E. 1 .4 and E. 1 .22). Collecting medication labels from containers used is often done (E.1.5). Information on all dosing dispensed and used for a trial may be collected on one page (E. 1 .6). • Collecting information on medication returned is often done (E.1.10 and E.1.11). • Collecting information on noninvestigational medicines is important (E.1.14 and E. 1 .15). • A chemotherapeutic flow sheet often collects data on many topics on a single page (E. 1.16). • A form to collect data on medication deviations from protocol may be useful (E. 1 .21). • Titration doses may be separated from maintenance doses (E. 1 .23). « Calculations used in preparing medication may be captured on a form (E. 1 .29). • Mealtimes may be identified (E. 1 .30). • Forms may include a place for peel-off or tear-off labels from medicine dispensed (E. 1 .39, E.1.30, E . 1.31, and E.1.40 to E.1.45).

• • •

E.2 Concomitant Medications • • • • • •

Concomitant medicine may be referred to by other phrasing, such as “all medications other than study drug taken since the last visit” (E.2. 1). Information on previously used medicine may be relevant (E.2. 2). Showing how to fill in a form may be useful (E.2. 4). Medicines given as part of the procedure may be collected (E.2.6). Information on concomitant medicines that were discontinued or in which the dosage was changed may be collected (E.2. 10). Information collected may be highly detailed (E.2. 13) or general.

E.3 Pharmacokinetic Samples to Analyze • • • •

474

Forms may include space in which to enter concentration values (E.3. 2 and others). Scheduled and actual times of sample collection as well as details of dosing are important (E.3. 2 and others). The initials of the sample collector may be requested (E.3.9, E.3.11, and E.3. 14). A box may be used to separate information reported by the investigator and by laboratory personnel (E.3. 15— left side completed by investigator and right side completed by laboratory personnel).

El

DOSING AND DISPENSING RECORDS

PATIENT NUMBER:

STUDY DRUG DOSAGE SCHEDULE

I

I

FIRST 3 LETTERS

,— ,—

OF LAST NAME:

L_L_

Page 1 of 1

month DATE:

I. I

I

day

year

I 1J

L I

I

ROUTE /Circle One):

1. P.O.

2. I.M.

3. I.V.

4. sub-q

5. Duodenal Infusion

6. Other

DOSAGE FORM (Circle One):

1. Capsules INDIVIDUAL DOSE:

3. Suspension

2. Tablets O

XI

I

I

I

Illi

NUMBER OF DOSES/DAY (Circle One): NUMBER OF DAYS:

I

I

mg 1. Single

4. Liquid Solution

.5. Transdermal

(Indicate Number Of Multiple Dosage Units, If Greater Than 1) 2. Multiple:

I

I

I

TIME INFUSION STARTED:

1 I

+ AIR BUBBLE TRAVEL TIME (min.):

I

:

1 1 1 (24 Hour Clock)

:

1 1 1

= TIME DRUG REACHES INFUSION SITE:

1 1 1 '• 1 1 1 (24 Hour Clock)

TIME INFUSION STOPPED:

1

+ AIR BUBBLE TRAVEL TIME (min.):

COMMENTS:

1....1 : 1 1 1 (24 Hour Clock) :

1 1 1

= TIME DRUG DELIVERY ENDS:

1 1 1 : 1 1 1 (24 Hour Clock)

FLUID SAMPLE TIME:

1 1 1 : .1 ... 1....1 (24 Hour Clock)

FLUID pH:

1 1 1.

COLOR: _______________________________

E.1.1

475

PATIENT NUMBER:

DATA COLLECTION FORM

FIRST 3 LETTERS OF LAST NAME:

,— >— r I I I

Page 1 of 1 month

DATE:

I

T

l

REQUIREMENTS:

DOSE:

day

I

I

year

I

I

I

I

PA T/ENT WILL F A S T FROM 8 P.M. THE D A Y BEFORE THE MORNING DOSE A T AROUND 8 A . M . A N D CONTINUE TO F A S T UNTIL FOUR HOURS POST-DOSE. 1 . GIVE

ICircle One Dose) 2.

SOLUTION 5 0 m g I N BUFFERED WATER SOLUTION Qp POTASSIUM 5 0 m g TABLET W I T H 2 0 0 m l OF WATER

TIME: INITIALS: TIME

THEORETICAL TIME

ACTUAL TIME

. _______________________ INITIALS

PREDOSE POST-DOSE 5 Imin)

_______________________

________________

_______________________

_____________________

10 15

________________________

20 25 30 40 50 1 . 0 (hr) 1.25 1.5 2.0 2.5 3.0 4.0*

_____________ ;

5.0 6.0

_________ ___

8.0

._________________

'RESUME NORMAL EATING HABITS AFTER BLOOD SAMPLE IS DRAWN.

Signature: ____ ______________________________________________

476

E.1.2

PATIENT NUMBER:

STUDY DRUG DOSAGE SCHEDULE

FIRST 3 LETTERS OF LAST NAME:

Page 1 of 1 month DATE:

day

year

I _I _I U _I I _L_

ROUTE (Circle One):

1. P.O,

DOSAGE FORM (Circle One):

1. Capsules

2. I.M.

3. I.V.

2. Tablets

3. Suspension

INDIVIDUAL DOSE:

4. sub-q 4. Liquid Solution

5, Other 5. Transdermal

(Indicate Number Of Multiple Dosage Units, If Greater Than 1)

NUMBER OF DOSES/DAY (Circle One):

1. Single

2. Multiple: E U

AM

PM

TIME OF DOSE (24 Hour Clock): NUMBER OF DAYS:

COMMENTS:

— — .........................

....................

....................................................

E.1.3

477

DO

Multiple Dose Tolerance and Pharmacokinetic Study

MEDICATION RECORD

Compd. #

Prop #

IND #

NDA #

NOT FILL Protocol #

Study #

IN

Vol. Init: _________________ Vol. # _____________ F M L

Theoretical Time’

mg

Dept.

Initials’ ’

Day 6 Dose 1

07:00

Dose 2

12:00

Dose 3

17:00

Dose 4

22:00

Dose 1

07:00

Dose 2

12:00

Dose 3

17:00

Dose 4

22:00

Dose 1

07:00

Dose 2

12:00

Day 7

Day 8

Dose 3

17:00

Dose 4

22:00

Dose 1

07:00

Dose 2

12.00

Day 9

Dose 3

17:00

Dose 4

22:00

Day 10 Dose 1

07:00

* l f receiving three doses, theoretical times are 07:00, 13:00 and 19:00 “ I n i t i a l s of the individual who provided doses to the volunteer EXPLAIN IN DETAIL ANY CHANGE O F DOSE DUE TO ADVERSE REACTIONS OR REASONS NOT ACCORDING TO PROTOCOL I N THE COMMENT LOG.

E.1.4

478

Sec.

DO

MEDICATION RECORD

Compd tt

Proj #

IND #

NDA #

NOT FILL Protocol #

Study H

IN

Vol. Init: _________________ Vol. # ____________ F M L

Dept

Sec

Attach Medication Labels here:

Day 1

Day 2

Day 3

Day 4

Day 5

Day 6

Day 7

Day 8

Day 9

Day 10

Day 11

Day 12

E.1.5

479

Compd*

Proj. a

IND’

NDA #

Protocol No.:

Study No.:

Dept:

Section:

LONG TERM EFFICACY AND SAFETY STUDY

DOSAGE RECORD YEAR 1: MONTH 1 2

Patient's Initials: ___ F

_ _/ _ _ _ Patient # _____________ Date: — __ / _ __ / _ _ _ ML ________________________________M D Y

Enter the total daily dose (mg) prescribed of all antiepileptic drugs using codes below.

( ) = Number of doses not taken during week WEEK 7 1 rr MUI 9 '

-T,

(Date of last visit!

_________ _ ( ‘ ( '

)

_

~

(

)

(

)

(

)

( )

( )

(

3 4 5

( ) ( ) ( )

( )

( )

(

( ) ( )

( )

(

6

1

)

(

(

)

( I

8

( )

9 10

( )

(

.( )

/

( )

( )

(

( ) ( )

( ) ( )

( ) ( )

( (

11

( )

( )

( )

(

12

(1

(

(

)

(

13 14

( ) 1 )

( ) ( )

( )

(

15

( )

( )

( )

(

16

( )

( )

( )

(

17

( )

( )

( )

(

18 19

( ) ___ (I

( ) ( 1

( )

(

20

________ ( )

------------- ( )

7

________

_ _

Etho=ethosuximide VPA=valproic acid Meth=methsuximide

)

)

Phsx=phensuximide Clon=clonazepam PHT=phenytoin

_ I

___

________

_____

_ I

__ 1

)

)

_ ----------- ( )

(

_ _ ------------

(

CBZ=carbamazepine PR primidone PB phenobarbital

Reasons for Change in Rx Dose (include dates Rx changed):

General Compliance:

91-100%D

81 - 90%

7 0 - 80%

Less than 70% _______________________ M.D.

Edited by

480

Date

Date

Investigator's Signature

E.1.6

EFFICACY AND SAFETY STUDY—PARTIAL SEIZURES

DOSAGE RECORD TREATMENT A: WEEKS 5-8 PATIENT'S INITIALS:

PATIENT #

Cmpd“

Pro). #

IND*

NDA #

Protocol No.:

Study No.:

Dept:

Section:

F M L

Enter the total daily dose(mg) of all antiepileptic drugs.

* IrxTZZ

R x .........

Day 1 (_ 2

WEEK

*

* Rx

Study Drug

*

Rx Z Z Z

Taken

Taken

Taken

-------

-------

-------

-------

--------

-------

Taken

5 6 7

1 2 3

WEEK

/

)

-------

4

5 6 7

*Etho=ethosuximide VPA=valproic acid Meth =methsux imide

Phsx=phensuximide Clon=clonazepam PHT =phenytoin

CBZ=carbamazepine PR =primidone PB=phenobarbital

Reasons for Change in Rx Dose (include dates Rx changed):

Edited by:

Date:

Date

E.1.7

Investigator's Signature

481

DRUG ADMINISTRATION Protocol

Inv. No.

Pt. No.

Pt. Initials (first. Middle, last)

Date of Enrollment Month

Q*y

year

CONCOMITANT ANTIMICROBIAL(S) (Include antibacterials, antivirals, antifungals administered during the entire study period except study drugs) No

Yes

I f yes, please specify (one per line) Medication Please Print

Unit Dose (mg)

Times per day

TOP Date Started IV IM PO M o Day Yr

THIS PAGE MAY BE PHOTOCOPIED IF ADDITIONAL SPACE IS REQUIRED

482

E.1.8

Date Stopped Mo

Day

Yr

Indication For Use

Inv. No.

Protocol

Patient's Initials

Patient No.

(F i n t . M t d d l e . L a s t )

Randomized t o :

was metronidazole added?

No

E D Yes

STUDY DRUG ADMINISTRATION

Study Drug(s)

Study Drug(s)

Unit dose (mg)

Length o f Infusion (mins.)

Times per day

1= IM 2 = IV

Date Started Year Day Month

Was Duration Changed? No Yes

11

New Duration (mins.)

Date Stopped Year Day Month

Reason for change

11

[~~l 1 1 [~]

11

C o n d i t i o n o f p a t i e n t u p o n discontinuation o f study drugs: good

Ofair

serious

E.1.9

483

MEDICATIONS Protocol

Inv. No.

Pt. No.

Pt. Initials

DRUG ADMINISTRATION Assigned Group Date o f first dose Month

Day

Year

Month

Day

Year

Date of last dose

Total number of doses Were any doses missed?

No

Yes

If yes, h o w many? Explain:

No Was the medication container returned? Was the container empty? If no, amount remaining:

AFFIX TEAR OFF PORTION O F PATIENT'S M E D I C A T I O N LABEL HERE

484

E.1.10

Yes

Page Visit

Date (m/d/y)

1

2

3

2

1

H

Medication Code

Patient Identification’

Investigator

3

'For Patient Identification use first 3 letters of first name then first 3 letters of last name

STUDY MEDICATION RETURN DATA

Date study medication card returned (if different from date at top of page):

I

I

Medication Label (Bottle Letter/Control Number)

Medication Label (Bottle Letter/Control Number)

Medication Code (if different from top of page):

Medication Code (if different from top of page):

Number of tablets DISPENSED:

Number of tablets DISPENSED:

Number of tablets RETURNED: (verify by count):

Number of tablets RETURNED: (verify by count):

II

DIFFERENCE (dispensed minus returned):

□

DIFFERENCE (dispensed minus returned):

0

Number of tablets REPORTED AS TAKEN (by “Patient Diary/lnterview"):

0

Number of tablets REPORTED AS TAKEN (by “Patient Diary/lnterview’’):

Comment on differences between E l and 0 instructions

as well as deviation from prescribing

___________________________________________________________

Comment on differences between E l and 0

as well as deviation from prescribing

instructions

STUDY MEDICATION DISPENSE DATA

Dispense Study Medication Card: _____________

Number of tablets dispensed: ___________

Dispense Study Medication Card: _____________

Number of tablets dispensed: ___________

Attach Medication Label Here Number Side Up Tape edges only; do not cover printing Do Not Staple

Attach Medication Label Here Number Side Up Tape edges only; do not cover printing Do Not Staple

For ___________________________________________

Use Only

_____I _____ I _____

___________________Initials __________________________Date (m/d/y)

USE BLACK BALLPOINT PEN — PRINT LEGIBLY

E.1.11

485

Page Visit

Date (m/d/y)

Investigator

Patient Identification’ 1

2

3

2

1

Medication Code 3

‘ F o r Patient identification use first 3 letters of first name then first 3 letters of last ■•ame

STUDY MEDICATION DOSAGE RECORD Has the patient taken study medication as instructed at the last visit? □

Yes (complete " N E W PRESCRIBING INFORMATION” section)

□

No (complete "DOSAGE CHANGE SINCE LAST VISIT" section) DOSAGE CHANGE SINCE LAST VISIT

Stop Date (m/d/y) of Previous Dose (if applicable)

□

Number of Tablets Per Dose

Start Date (m/d/y) of New Dose

No Change

Number of Doses Per Day

Reason for Change

NEW PRESCRIBING INFORMATION OF STUDY MEDICATION

Instruct the patient to take: ,

New dose to begin on:

/

/

at

pm

For

______________________ ___I ___I ___ _____________________Initials _________________

Date (m/d/y)

USE BLACK BALLPOINT PEN - PRINT LEGIBLY

486

E.1.12

Use Only

G

STUDY TITLE

MEDICAL EVENT FORM - SUPPLEMENTAL INFORMATION (MEFSI) (USE TO SUPPLEMENT MEDICAL EVENT FORM (MEF) FOR SERIOUS EVENTS ONLY)

D O NOT WRITE I N SHADED AREAS

INVESTIGATOR'S NO.

PRINCIPAL INVESTIGATOR

PRINCIPAL MONITOR

SUBJECT'S INITIALS

SUBJECT NO.

MONITOR N A M E STUDY PERIOD

PROTOCOL NO.

Mo

EVALUATION

VR

DAY

-

'

M/0000/0000 DATABASE NO.

IS THIS A FOLLOW-UP REPORT?

COUNTRY

□

UNITED STATES

C L Yes

0 No

Reason Event is Serious

Dropped from study due t o this event?

Medical Event (USE SAME TERMINOLOGY USED ON MEF)

□

0

d,

(CHECK ALL THAT APPLY) LZJ , |

L i f e Threatening

|

]

Permanently Disabling

|

|

Required or Prolonged Hospitalization

|

|

|

1 6 Cancer

|

]

Overdose

|

|

O t h e r Clinical Judgment

4

IF SUBJECT DIED, SPECIFY:

n

1 L Report Attached

0 = None

INVESTIGATIONAL MEDICATION

1 =

(Enter "study drug", if this is a blinded study) D a t e Stopped (Mo./Day/Yr.)

DOSIN G REGIM EN Amount

Units

Freq.

Route of Admin.

Discontinued

Is t h e r e a reasonable possibility t h a t the event was caused b y t h i s medication?

2 = Reduced 3 =

D a t e Started (Mo./Day/Yr.)

N o t done

o

1 1 1 Report Available

Action Taken

M e d i c a t i o n Trade Name

______

_____ _ 1

Probable Cause: ____________ AUTOPSY

Congenital A n o m a l y

YR.

I

DAY

i

MO.

Date ____ I

|

No Yes

Fatal

Reason f o r Use ( M a j o r Diagnosis)

0 = No 1 = Yes

Interrupted

t Mon1 itor's I Opinion

4 = Increased

Did event abate after stopping medication?

Did event reappear after reintroducing medication?

0 = No 1 = Yes 2 = NA

0 = No 1 = Yes 2 = NA

1. 1 /

/

/

/

—

/

/

/

/

—

—

—

—

-------

2. - ------ ]

A c t i o n Taken 0 = None

RELEVANT NON-INVESTIGATIONAL MEDICATION

1 =

Discontinued

Is t h e r e a reasonable possibility t h a t the event was caused b y t h i s medication?

2 a Reduced 3 = M e d i c a t i o n Trade Name

D a t e Started (Mo./Day/Yr.)

D a t e Stopped (Mo./Day/Yr.)

DOSING REGIM EN Amount

Units

Freq.

Route of Admin.

Reason f o r Use ( M a j o r Diagnosis)

--------

0 = No 1 = Yes

Interrupted

I MonI itor's I Opinion

4 = Increased

Did event abate after stopping medication?

Did event reappear after reintroducing medication?

0 = No 1 = Yes 2 = NA

0 = No 1 = Yes 2 = NA

1. /

/

/

/

—

/

/

/

/

—

____ l

____

—

—

—

—

2.

OTHER RELEVANT HISTORY (e.g., diagnoses, allergies, pregnancy w i t h LMP etc.)

--------

1

--------

RELEVANT TESTS / LAB D A T A

INVESTIGATOR COMMENT:

MO.

DAY

i

YR.

I

INVESTIGATOR'S SIGNATURE: TYPE OF REPORT

MONITOR COMMENT:

□ 1 Preliminary O

3

Follow-up, enter Database No. at top

1 1, Initial / Final MO.

Received d a t e :

MONITOR'S SIGNATURE:

E.1.13

i

/

DAY

1

YR.

/

487

NON-INVESTIGATIONAL M E D I C A T I O N PRINCIPAL MONITOR

INVESTIGATOR'S NO.

PRINCIPAL INVESTIGATOR

SUBJECT'S INITIALS

SUBJECT NO.

MONITOR NAME PROTOCOL NO.

STUDY PERIOD

DATE OF EVALUATION

M/0000/0000

MO.

DAY

C

Have there been any CHANGES since the last report? No If No, check box and skip this page. If Yes, complete this page. ACTION TAKEN

MEDICATION TRADE NAME

Zl, START ZZI2 STOP a CHANGE IN DOSE 4 SINGLE DOSE

EXAMPLE

I

DATE OF ACTION

(0001-2400)

0 8 / 0 4 /88_

-l-L-L-L

2

STOP

—

l~~1a CHANGE IN DOSE 4 SINGLE DOSE I

|

1

START

2

sroP

—

| | 3 CHANGE IN DOSE 0 4 SINGLE DOSE

I

3.

I ! START

I I? STOP EH, CHANGE IN DOSE I h SINGLE

___ / ___ / ___

---------™_

DOSE

|

4.

1 1 START

ELsiOP I

-----------

h CHANGE IN DOSE

0 4 SINGLE DOSE

I I. START 5.

2

STOP

I la CHANGE IN DOSE I h SINGLE

___ / ___ / ___

—

___

-----------

DOSE

6.

0 1 START I la STOP I la CHANGE IN DOSE IZh SINGLE DOSE I

7.

I , START 2 SI OP

I la CHANGE

—

I N DOSE

E h SINGLE DOSE I I. START 8.

2 STOP

I la CHANGE IN DOSE 0 4 SINGLE

— ---------

DOSE

INITIALS/SIGNATURE:

488

UNITS

FREQ.

ROUTE OF ADMIN.

mg

q8hr

IV

DOSING REGIMEN AMOUNT

I , START

1.

2.

TIME OF ACTION

(MO/DAY'YR|

E.1.14

REASON FOR ACTION (MAJOR DIAGNOSIS)

NON-INVESTIGATIONAL MEDICATION PRINCIPAL MONITOR

INVESTIGATOR'S NO.

PRINCIPAL INVESTIGATOR

SUBJECT'S INITIALS

SUBJECT NO.

MONITOR NAME PROTOCOL NO.

STUDY PERIOD

DATE OF EVALUATION

M/0000/0000

MO.

DAV

,

YR.

Has subject taken any medication during the past 30 days? If No, check box and skip this page. If Yes, complete this page. MEDICATION TRADE NAME

DATE &TIME STARTED (MO/DAY/YR)

TOBE CONTINUED?

(0001-2400)

07 /23 /88 [SJoNO

1.

2.

3.

□

(YES

□

0

□

1 YES

□

0

, YES

□

0

□

l YES

□

□ □

8.

□

0

(YES

□

0

□

lYES

__L_L_

NO

NO

£3

□

10.

PO

o

--LJ—.

QID

NO

□

□

9.

—LJ—

mg

(MAJOR DIAGNOSIS)

t3

□

7.

0_ 9_ 0_ 0_

FREQ.

o

—LJ—

□

6.

08 /20 /88

UNITS

REASON FOR USE OF MEDICATION

NO

o £ z > ©

5.

AMOUNT

ROUTE OF ADMIN.

NO

□

□

4.

DOSING REGIMEN

5

o_ J L / L L

(MO/DAY/YR) (0001-2400)

£

EXAMPLE

IF NO, DATE SflME STOPPED

□

0

□

1 YES

NO

INITIALS/SIGNATURE:

E.1.15

489

NAME

CHEMOTHERAPY FLOW SHEET / / DATE ----CYCLE No DAY OF TREATMENT / / HEMATOLOGY WBC HEMOGLOBIN PLATELETS ---Weight HEIGHT ---Surface Area

/

/

/

/

/

/ /

II

/

/

/

/

—

—

/

/

/

CHEMO Drug Dose Route Q 1 — — 2. 3. 4. 5. 6. OTHER DRUGS (eg antiemetics, analgesics or anxiolytics) Drug Dose Route

TOXICITY (WHO grade) Oral Nausea/Vomiting Diarrhea Cutaneous Hair Neurotoxicity Other Creat. Clearance EVALUABLE LESIONS 1. 2. 3. 4. 5. 6. PERF STATUS RESPONSE CLINICIAN'S INIT.

E.1.16

490

—

—

—

—

—

—

TREATMENT Inv. No.

Protocol

Pt Initials

Pt. No.

. .....I. . . . . . . (First. Middle, last)

STUDY DRUG ADMINISTRATION

Was study drug administered according to protocol?

0 = No, 1 = Yes

If no, specify why not: Date (mo/day/yr)

Time (24 hour clock)

-------- -------- --------

-------- ---- ----

Time Dose 1 Time Dose 2 Time Dose 3 Time Dose 4 Time Dose 5 Time Dose 6 Time Dose 7 Time Dose 8 Time Dose 9 Time Dose 10

ADDITIONAL ANTIMICROBIAL MEDICATIONS

Were additional antibiotics required? TOP

Medication (Enter one per line)

Unit Times per Dose day (mg)

If yes, specify below

0 = No, 1 = Yes IV IM PO

Date Started Mo

Day

Yr

Date Stopped Mo

Day

Indication for use

Yr

I I 1 I 1

1 I 1 'I' l'L ] 'JJ r l

[ | f E.1.17

491

Page

EXPERIMENTAL DRUGS/DOSAGE NOTE: Please use BLACK ink

DO IND #

Pt./Vol. # Initials

Investigator's Name

Pt./Vol.#

Drug Name

M

~

NDA #

Protocol # -

Study #

IN Sec.

Dept.

Period

Dosage Constants

Proj. #

NOT FILL

■?

of Cmpd. #/Name

,

DATES OF ADMINISTRATION Est. Average Total Daily Dose

Container # Start

-------------

End

EST. DAILY DOSE RANGE Low

High

*Est. # Missed Doses ( / = none)

State Reasons for deviation(s) from scheduled dosage regimen

—

— — — ------- — —

—

—

— - -----

—

-■--------------

------- — — —

—

—

—

—

—

--------------

—

---------.— -— .—- — —

—

—

™-------------

• Est. = Estimated

* Missed days are included in calculations of the estimated average total daily dose and estimated daily dose range.

(✓) If no significant deviations from dosage schedule Investigator’s Signature

492

E.1.18

M

D

V

Cmpd. #/Name

EXPERIMENTAL DRUGS/DOSAGE NOTE: Please use BLACK ink

DO IND #

Pt./Vol. # Initials

Investigator’s Name

Pt./ Vol.#

Drug Name

M

I

(/) A P Hour Min. M M

Dept.

Period

Sec.

_____________

ACTUAL DOSE ADMINISTRATION

SCHEDULED DOSE ADMINISTRATION Time

Protocol# — Study#

IN

,

Dosage Constants

D a

NDA #

NOT FILL

~F

Proj. #

D 0 s e #

Amount

Unit of Meas.

Container #

Date

Time

(J) A P Hour Min. M M

D 0 s Amount e #

Unit of Meas.

State Reason(s) for deviation from scheduled dosage regimen

□ ( 7 ) If no significant deviations from dosage schedule Investigator's Signature

E.1.19

M

D

Y

493

Cmpd. #/Name

EXPERIMENTAL DRUGS/DOSAGE NOTE: Please use BLACK ink

DO IND #

Pt./Vol. # Initials

Investigator's Name

Pt./Vol. tt

M

Protocol# — Study#

IN

Dept.

Drug Name ________________________________ Period ___________ Dosage Constants

NDA #

NOT FILL

”F

Proj. #

Sec.

__________________ ____

DATES O F ADMINISTRATION

Container # Start

Unit Dose

End

—

—

—

—

—------------ — _

—

—

—

—

DAILY DOSE ADMINISTRATION

Frequency

Total Daily Dose

Unit of Meas.

State Reason(s) for deviation(s) from scheduled dosage regimen

—

— — ------ —

— --------- ---- ---------

—

—

—

—

—

—

—

—

—

—

—

— .— .—

NOTE: Any change in the unit dose, frequency ortotal daily dose requires a new line entry. Missed days of drug administration are recorded by giving dates and entering a zero in the Total Daily Dose column. □ ( ✓) If no significant deviations from dosage schedule Investigator’s Signature

494

E.1.20

M

D

Y

Form A

MEDICATION CHANGES (WORK SHEET) Patient Study #

Patient Initials

|

Protocol | | F

M

L

____ || Location

Study Center #

Document only medication deviations from protocol specified administration including the dosing interval and/or dosage of drug and if drug is stopped before Day 14. Study Day Date

1

2

3

4

5

6

7

3

9

10

X X X X X X X X X X

E.1.21

495

Protocol No. Subject Initials:

Investigator’s No. : | J

Subject No.:

RECORD OF STUDY DRUG Blisterpak

Date Dispensed

Drug Dispensed By

Number

(Mo/Day/Year)

(Initials)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

INVESTIGATOR

496

DATE

SIGNATURE

E.1.22

1111

STUDY DRUG ADMINISTRATION RECORD

Protocol

Inv. No.

Pt. nitials

Date

Pt. No.

first. Middle. Last)

Month

Day

Year

TITRATION DOSES

TIME (MILITARY)

DOSE (mgs)

■■■■- _ _ _ _■ - .

MAINTENANCE DOSES

TIME (MILITARY)

DOSE (mgs)

... .....

E.1.23

497

PROT. NO.

PATIENT INITIALS

ALLOC. NO.

please print or write clearly

Date of enrollment Age

Sex: Male Female

Date of birth ____/ ____/ ____

- ------- years — months

Height ______. inches

Weight _____ lbs.

black

Ethnic origin: Caucasian

oriental

other

...... —

Primary Study Diagnoses: -------------------------------------------------------------------------------------------------------------------("FUO” if not known)

Date of onset: ----------------------------------------------------------------------------------

Underlying diagnosis: Date diagnosed:

________________________________________________________ ........................................................................................................................................ dates

INDUCTION REGIMEN

drugs 1st

from

.

to .—...............

— ..

2nd

—...............................

3rd

................................. . ............................. dates

MAINTENANCE CHEMOTHERAPY REGIMEN

drugs

from

dates

RADIATION THERAPY

SURGICAL THERAPY

body sites

rads

procedure

date

E.1.24

498

to

from

to

indication

BASELINE Inv. No.

Protocol

Pt. nitials (First, Middle, Last)

Month

Yrs. (Must b e 21 t o 80)

J

I Female

[D

2

Male

Day

Visit

No. ft4 U l

Year

Race

Sex

Age

Date

Pt. No.

,□

Caucasian

J I Black J—

J D ] Hispanic

..ED Other, specify _______________

aE D Oriental

....; Diagnosed within last year?

o = No

Di

* 2 SINCE VISIT 4, THE PATIENT MUST BE DISCONTINUED FROM STUDY. COMPLETE THE FINAL VISIT REPORT FORMS AND THE STUDY TERMINATION SHEET. ALSO, IF EITHER ASSESSMENT > 8 , THE PATIENT MUST BE DISCONTINUED FROM STUDY. COMPLETE THE FINAL VISIT REPORT FORMS AND THE STUDY TERMINATION SHEET. PATIENT'S RATING OF JOINT PAIN AGGRAVATED BY WALKING AT THIS VISIT: (Circle Appropriate Number)

No Pain

I-------------|-------------|-------------|-------------|-------------|-------------|-------------|-------------|-------------1-------------1 0123456789

10

sx Pain

IS THE PATIENT ABLE TO WALK 5 0 FEET?: 2. Yes (If " Y e s , " Specify Time Below)

1 . N o (If "No, " Specify Below)

TIME:

I _ _I

I

I seconds

WAS A WALKING AID USED?:

1. N o

2. Yes (If " Y e s , " Describe Below)

STOOL EXAMINATION

HEMOCCULT TEST:

1 . Negative

2. Positive

Signa tore:

F.1.5

____________________________

557

ASSESSMENTS Protocol No.

Inv. No.

Pt. No.

Pt. Initials

(First, Middle, Last)

Date

Month

Day

Year

CLINICAL ASSESSMENT — PREVENTION O F LATE LYME DISEASE (Check one) □ Clinical Success: Patient remains free of symptoms and signs of late Lyme disease throughout the 1-year follow-up period. □ Clinical Improvement: Patient develops symptoms of late Lyme disease but presents no objective evidence of active disease during the 1-year post-treatment follow-up period. □ Clinical Failure: Patient develops signs and symptoms of late Lyme disease, including serological confirmation of B. burgdorferi infection, during the 1-year post-treatment follow-up period. □ Clinically Unevaluable: Patient is lost to follow-up or develops signs and symptoms of early Lyme disease due to recurrence or reinfection during the 1-year post-treatment follow-up period.

F.1.6

558

ASSESSMENTS Protocol No.

Inv. No.

Pt. No.

Date

Pt. Initials

(First, Middle, Last)

Month

Day

Year

EFFICACY ASSESSMENTS (Check one) Please specify the category as defined below: □

Clinical Cure: Resolution of clinical symptoms and signs of infection during treatment with a continued asymptomatic state through the 2 week post-treatment follow-up visit and resolution of middle ear effusion at least by the 2 week posttreatment visit.

□

Clinical Improvement: Resolution of clinical symptoms and signs of infection during treatment with a continued asymptomatic state through the 2 week post-treatment follow-up visit and persistence of middle ear effusion at the 2 week post-treatment follow-up visit.

□

Clinical Failure: (Specify) □

Persistence of clinical signs and symptoms of acute infection despite treatment for at least 72 hours, or,

□

Treatment discontinued due to adverse event.

□

Recurrence: Initial diminution of clinical symptoms and signs of acute infection during treatment, but with recurrence (based on clinical and otoscopic findings) within the 2 week post-treatment period.

□

Unevaluable: (Specify) □

Concurrent administration of NON-STUDY antimicrobial drug

□

Patient failed to complete both post-treatment visits.

□

Patient received study drug for less than 72 hours for reasons not related to an adverse event.

□

Evidence of poor compliance with therapy as defined by lack of antibacterial levels in intratreatment urine specimen.

□

Patient withdraws from the study for reasons not related to an adverse event.

559

ASSESSMENTS Protocol No.

Inv. No.

Pt. No.

Pt. Initials

(First, Middle, Last)

Date

Month

Day

BACTERIOLOGICAL EFFICACY (Check one) Please specify the category as defined below: □

Bacteriological Cure: Initial pathogen eradicated from subsequent cultures taken during the post-treatment follow-up period.

□

Presumed Bacteriological Cure: In the absence of any subsequent cultures, the isolate will be considered to have been eradicated if there are no clinical symptoms or signs of acute infection (with or without persistence of middle ear effusion) at both post-treatment visits.

□

Bacteriological Failure: Initial pathogen not eradicated from a culture obtained after at least 72 hours of study therapy.

□

Presumed Bacteriological Failure: No subsequent cultures obtained but signs and symptoms of acute infection persist after at least 72 hours of study therapy.

□

Bacteriological Cure with Reinfection: Bacteriological cure (as defined above) plus the isolation of one or more new pathogens during the study period which are associated with signs and symptoms of acute infection which require continued or alternate antimicrobial therapy.

□

Recurrence: Bacteriological cure (as defined above) plus the reisolation of the initial pathogen during the 2 week posttreatment follow-up period.

□

Bacteriologically Unevaluable: (Specify) □

Inability to culture and identify a pathogen from pre-treatment samples.

□

Isolation of a pathogen from a pre-treatment culture which is resistant in vitro to either of the study drugs or is not tested for in vitro susceptibility.

□

Concurrent administration of any non-study antibiotic unrelated to the treatment of otitis media.

□

Duration of study therapy less than 72 hours.

□

Evidence of poor compliance with therapy as defined by lack of antibacterial levels in intratreatment urine specimen.

F.1.8

560

PATIENT NUMBER:

STRESS TEST STANDARD BRUCE PROTOCOL Page 1 of 1

month

FIRST 3 LETTERS O F LAST N A M E :

day

year

I I I I I I I I I

DATE:

TIME O F START OF TEST:

I. I . I I I I. I (24 hr dock) 1. No (If “No, " Give Reason):

ARE S T S E G M E N T S ANALYZABLE?:

________________

2. Yes LEAD U S E D FOR S T S E G M E N T A N A L Y S I S :

BLOOD PRESSURE

MINUTES

HEART RATE

systolic / diastolic

(Circle + or — )

'—

L-—— »

1

E

— .

BASELINE

S T SEGMENT DEVIATION FROM ISOELECTRIC LINE

L — -J ***.

L——1

4

■—

U_— i

3

9

2

9

STAGE

.. —

5

M I N . & SEC.

ONSET OF ANGINA Development O f Moderately Severe Angina

/min.

ONSET OF 1 m m Increase I n S T Depression Termination Of Test

REASON FOR T E R M I N A T I O N O F TEST:

/mm.

mm

1. Moderately Severe Angina 2. Other:

______________________ /speedy)

38688

Signature:

F.1.9

561

Treadmill Test Was Treadmill Test performed at this visit? If required but not performed, document reason in comment section on next page. Has patient recently experienced significant factors that may affect today's exercise? If yes, provide comment on the next page. Time Test Started:

Date Of Testing: MM

EO

Stage

DD

Speed (MPH)

Time of Last Dose of Study Medication: 24 Hr, Clock

YY

Grade (%)

Blood Pressure (mmHg) Systolic ________Diastolic

0

0

1

1.0

0

2

1.5

0

3

2.0

3.5

4

2.0

7.0

5

2.0

10.5

6

3.0

7.5

7

3.0

10.0

8

3.0

12.5

9

3.0

15.0

10

3.4

14.0

0

0

REST

5 Minute Recovery

F.1.10 562

Duration of Exercise:

24 Hr. Clock

YY

Date of Last Dose of Study Medication: MM

Q

Heart Rate (bpm)

Borg Scale Rating

Exercise Evaluation

UNREMARKABLE

ECG FINDINGS DURING TEST AND RECOVERY PERIOD [J

PVC's

Q|

OTHER (specify below)

COMMENTS FOR ECG FINDINGS:

REASONS FOR STOPPING: ( C h e c k those which are applicable)

□ □ □

DYSPNEA FATIGUE specify If treadmill test is stopped for reasons not including dyspnea and/or fatigue, test must be repeated within allowed time frame or patient must be discontinued.

Comment: ___________________

—

F.l.ll 563

PATIENT NUMBER:

APPLICATION SITE EVALUATION

FIRST 3 LETTERS OF LAST NAME:

i— i— r I

I I

Page 1 of 1

day

month DATE:

year

I I I I I I I I I MODIFIED DRAIZE RATING SCALE

SITE:

ERYTHEMA AND ESCHAR FORMATION:

0. No erythema 1. Very slight erythema (barely perceptible) 2. Well-defined erythema 3. Moderate to severe erythema 4. Severe erythema (beet redness) to slight eschar formations (injuries in depth)

SITE:

EDEMA FORMATION:

0 . No edema 1. Very slight edema (barely perceptible) 2. Slight edema (edges of area well defined by definite raising) 3. Moderate (raised approximately 1 mm) 4. Severe edema (raised more than 1 mm and extending beyond the area of exposure)

47387

Signature:

564

F.1.12

_____

CLINICAL EVALUATION Protocol

Day

Date

Local Swelling

(Mo/Day/Vr)

0=None 1=Mild 2=Mod 3=Sev.

Inv. No.

Local Local Drainage Heat Erythema 0=None 1=Mild 2=Mod 3=Sev.

0=None 1 =Mild 2=Mod 3=Sev.

0=None 1=Mild 2=Mod 3=Sev.

Pt. Initials

Fever

Foul Size of Odor Ulcer

0= 38°C 0=No 1=38-39°C 1=Yes 2= 39°C

Pt. Allocation No.

Comments

(mm)

PreTreatment 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 PostTreatment

F.1.13

565

Page

LESION MEASUREMENTS/ EFFICACY EVALUATION

Cmpd. Marne

IND #

Pro/. »

NDA #

Protocol # — Study #

NOTE: Please use BLACK ink. Patient #

Patient's ________________ L M F Initials

___________

Sec.

Dept.

LESION MEASUREMENTS Scheduled Time

Date (M/D/Y)

Lesion #3

Lesion #2

Lesion # 1 Size (cm x cm)

Total Area (cm )

Size (cm x cm)

Total Area (cm 2 )

Size (cm x cm)

Pretherapy During Therapy Week 1 Week 2 Week 3 Week 4 Post Therapy 1.5 Months 3 Months 6 Months 12 Months EFFICACY EVALUATION Scheduled Time

Date (M/D/Y)

Clinical Cure

Response to Therapy ( / ) Failure Parasitologic Complete Cure Cure

End of Therapy Post Therapy 1.5 Months 3 Months 6 Months 12 Months

REINFESTATION Did the patient experience reinfestation during the study? If YES, date diagnosed: ~M~ " D

566

Y~ F.1.14

QYes

No

Relapse

Total Area (cm2)

TREATMENT EVALUATIONS Inv. No.

Patient’s Initials (First, Middle, Last)

pt. No.

Day 15

Day 8 / Date of Visit

/

/

Mo.

Day

0.0 0.5 1.0 1.5 2.0 2.5 3.0

Absent

Mb.

Yr.

Day 29

/ Day

/ Yr.

/

Mo.

Day

0.0 0.5 1.0 1.5 2.0 2.5 3.0

Absent

Yr.

Clinical Assessment Scaling

Erythema

0.0 0.5 1.0 1.5 D 2.0 2.5 3.0

Total severity score at baseline (From page 5) Global Response to Therapy as compared to Baseline

Mild Moderate Severe

Mycologlcal Results KOH Preparation (See instructions on opposite page)

0.0 0.5 1.0 1.5 2.0 2.5 3.0

Absent Mild Moderate Severe

Cleared Excellent Good Fair Poor Unchanged Worse

(See instructions on opposite page)

0.0 O 0.5 1.0 1.5 2.0 2.5 3.0

Pos

Absent Mild Moderate Severe Absent Mild Moderate Severe

Cleared Excellent Good Fair Poor Unchanged O Worse Pos

Neg

0.0 0.5 1.0 1.5 2.0 2.5 3.0

§ € 3 X* z o 3 q*

Mild Moderate Severe Absent Mild Moderate Severe

Cleared Excellent Good Fair Poor Unchanged Worse

B 3 s.

Neg

Pos

Neg

Mycologlcal Response Cure Failure Non-evaluable Specify reason below

Cure Failure Non-evaluable Specify reason below

Patient 1 = Patient completed visit Status 2 = Patient will continue in the study 3 = Treatment stopped— adverse event 4 = Patient failed to return for visit (explain) 5 = Other (explain below)

1 2 3 4 5

1 2 3 4 5

Adverse Events (If yes, complete page 7)

No

Yes

No

Yes

No

Yes

No

Yes

No

Yes

No No

Yes Yes

(See instructions on opposite page)

Changes i n Concurrent Medication Did patient treat test site during post-treatment period? (If yes, specify below)

Medication

Single Dose Amt. Units

Times per Day

Route IV IM PO etc.

Date Date Started Stopped M/D/Y M/D/Y /

/

/

/

/

/

/

/

/

/

/

/

1 1

/

/

Comments: (Indicate Date)

Cure Failure Non-evaluable Specify reason below 1 NA 3 4 5

Diagnosis

- —— ----------------

Drug dispensing and patient compliance data (pages 9 and 10) must be completed at each visit.

F.1.15

567

HOSPITALIZATION If the patient has not been hospitalized during this interval, enter an "X" here Hospitalization Status

1 = Hospitalization continues from previous visit. (Stop Here). 2 = Hospitalization began and ended during this visit interval. (Complete entire page). 3 = Hospitalization began during this visit interval and continues. (Complete entire page. Enter dash (-) for the discharge date). 4 = Hospitalization ended during this visit interval. (Enter only discharge date. Enter dash (-) for admission date).

Admission Date

/ Mo

Discharge Date

/ Mo

Reason for Hospitalization

/ Day

Yr

/ Day

Yr

1 = Because of the event listed in the RECORD OF EVENTS section. (NOTIFY IMMEDIATELY). 2 = Required or optional for protocol tests. 99 = Other (include details on Comments page). (NOTIFY IMMEDIATELY).

If reason for hospitalization is 1, enter the Event number from the RECORDS OF EVENTS section which necessitated the hospitalization

F.1.16

568

CLINICAL CASE REPORT FORM (DRUG NAME) PROJECT TITLE (FREE TEXT) D O NOT WRITE I N THIS SPACE (FOR USE IN COMPILING DATA)

PLEASE TYPE OR PRINT LEGIBLY WITH BLACK BALL POINT PEN I INPATIENT HOSPITALIZATION DATA |

Patient's hospital chart number

. Enter the patient's chart . number obtained at this admission. Please, record I the name and address of the | hospital o n the COMMENTS I page.

I / Date of Hospital Admission • - - - —- - Day Yr

. ------ , Enter month, day, and year _____

/ / Date of Hospital Discharge ■ -- - - -- - ° Day Yr

------

F.1.17

. | | | |

.. , , Enter month, day, and year

569

DO NOT WRITE IN THIS SPACE (FOR USE IN COMPILING DATA)

PLEASE TYPE OR PRINT LEGIBLY WITH BLACK BALL POINT PEN

DATE RECEIVED AT

| INTERIM SUMMARY | IF PATIENT DISCONTINUES AIL STUDY DRUG THERAPY, D O NOT COMPLETE AN INTERIM SUMMARY. INSTEAD, COMPLETE THE STUDY SUMMARY.

Patient Initials

Date of Therapy Period Change

Therapy Period Ended 1 = Double Blind Extension 2 = Double Blind Therapy 3 ~ Post Therapy (No Drug) Reason For Ending This Therapy Period

Therapy Period Being Started 1 = Double Blind Extension 3 = Post-Therapy ( N o Drug) 4 = Open Label Extension

I

I Enter the month, day, and year the patient | changed therapy periods.

| I

_____________________________ | Enter the numeric code for the therapy | period. ______

I I

| Enter the numeric code for the reason why | this therapy period is being ended.

| I

| Enter the numeric code for the therapy being | | started. I

F.1.18

570

I (").___________ ____________

1 = Schedule by the protocol 2 = Lack of Efficacy 4 = Patient decision other than an unwanted effect of study drug, (describe in Comments section). 5 = Physician's decision other than an unwanted effect of study drug, (describe in Comments section). 9 ~ Primary event necessitating discontinuation— form RECORD OF EVENTS section. If #9, enter EVENT NUMBER from the RECORD O F EVENTS section of this visit. 11 = Patient relapsed

U A I E VERIFIED __________________INHIALS

DA7E KEYED _____________________INITIALS

DATE _________ A UDIT _________

REVIEWED

/ / Mo Day Year

| Enter first, middle, and last initial. If | | patient has no middle initial, enter dashes |

INTERIM VISIT MODULE

HAS PATIENT DROPPED OUT OR DISCONTINUED THERAPY?:

1. No

2. Yes (If " Y e s , " Complete Final Visit Report Forms And Study Termination Sheet)

OR

HAS PATIENT DROPPED OUT OR DISCONTINUED THERAPY?:

1. No

2. Yes (If "Yes, " Complete This Visit And Study Termination Sheet)

INTERIM/FINAL PHYSICAL EXAMINATION MODULE

PHYSICAL EXAMINATION

WEIGHT:

Illi

pounds systolic

SITTING BLOOD PRESSURE:

Illi

diastolic / Illi

PULSE:

I

I

I

I /minute

LIST ANY SIGNIFICANT FINDINGS SINCE THE LAST EXAMINATION? (If "None, " Circle) :

NONE

F.1.19

571

572

CLINICAL OBSERVATIONS

|

•p c

£

Inv. No.

Protocol

Pt. No.

(First, Middle, Last)

|

WOUND AND DRAIN ASSESSMENT 0 = No, 1 = Yes, 2 = Not Done (enter appropriate response i n each box) Observation

PO Day 1 X. Q o

Date

PO Day 2

PO Day 3

PO Day 4

PO Day 5

PO Day 6

PO Day 7

PO Day 8

PO Day 9

PO PO PO PO PO Day 10 Day 11 Day 12 Day 13 Day 14

| Mo Day Yr || M o Day Yr || M o Day Yr | j M o Day Yr || M o Day Yr || M o Day Yr || M o Day Yr || M o Day Yr || M o Day Yr || M o Day Yr j| M o Day Yr || M o Day Yr || M o Day Yr I

Inflammation Edema Erythema Formation of Abscesses

Local Purulence

Comments:

F.1.20

Page

Cmpd. #/Name

Proj. #

LESION EVALUATION IND #

NDA#

Protocol # — Study #

NOTE: Please use BLACK ink. Patient #

___________

£

_______________ L M F

a. Q

Patient's Initials

1. To be completed daily for the first five days, o n day 7, and o n day 14.

Date M/D/Y

Time (0-2359)

Severity of Pain* (0-3)

Stage of Primary Lesion (see explanation of stages o n the facing page) (25% Increments)

Size (mm)** Length

Width

Prodrome

Macule

Papules

. ...

missm:

Y r.....

.. ........

I:-:-:-.-’-:--:-::-:'

.....

* Definitions of codes o n facing page. **Size of primary lesion to be assessed o n days 1 and 4. Lesion size should include erythema.

Complete items 2 and 3 on final day of the study: 2. Was this recurrence □ the same as usual? □ worse than usual? □ better than usual? 3.

Did the patient's lesion disseminate?

□ Yes

□ No

573

F.1.21

Vesicles

Soft Crust

Hard Crust

Residual Swelling

Healed

aweiwpdixo

0

DISEASE ASSESSMENT F O R M (Skin Lesions)

# ■fojd

574

Page

NDA# Protocol # — Study #

NOTE: Please use black i n k . ___ F

___ _ _ L M

Patient# __________

Dept.

Hi — i— >— ■ Illi

Page 1 of 1 month

day

year

DATE:

CIRCLE ONE NUMBER FOR EACH EVALUATION ACCORDING TO YOUR MOST RECENT ASSESSMENT OF THE PATIENT. ACTIVITY: During the last month, the patient 2. has been working or studying full-time, or nearly so, in usual occupation; or managing own household: or participating in unpaid or voluntary activities, whether retired or not. 1. has been working or studying in usual occupation or managing own household or participating in unpaid or voluntary activities; but requiring major assistance or a significant reduction in hours worked or a sheltered situation or was on sick leave. 0. has not been working or studying in any capacity and not managing own household. DAILY LIVING: During the last month, the patient 2. has been self-reliant in eating, washing, toiletting and dressing, using public transport or driving own car. 1. has been requiring assistance (another person or special equipment) for daily activities and transport but performing light tasks. 0. has not been managing personal care nor light tasks and/or not leaving own home or institution at all. HEALTH: During the last month, the patient 2. has been appearing to feel well or reporting feeling "great" most of the time. 1. has been lacking energy or not feeling entirely " u p to par" more than just occasionally. 0. has been feeling very ill or "lousy," seeming weak and washed out most of the time or was unconscious. SUPPORT: During the last month, 2. the patient has been having good relationships with others and receiving strong support from at least one family member and/or friend. 1. support received or perceived has been limited from family and friends and/or by the patient's condition. 0. support from family and friends occurred infrequently or only when absolutely necessary or patient was unconscious. OUTLOOK: During the last month, the patient 2. has usually been appearing calm and positive in outlook, accepting and in control of personal circumstances, including surroundings. 1. has sometimes been troubled because not fully in control of personal circumstances or has been having periods of obvious anxiety. 0. has been seriously confused or very frightened or consistently anxious and depressed or unconscious.

F.1.26

579

Form 29 Illness Cost Patient Initials

Patient Study # Protocol

F

M

L

Study Center #

P ease check follow-up interval:

ILLNESS COST Follow-up Date Mo

Location

/ Day /

11

Yr

□

6 months

□

12 months

□

1

□

Since the onset o f this illness, the patient has spent:

24 months 36 months

days at home days in Intermediate Care or Nursing Home days in Hospital

Comments and Other Findings:

580

F.1.27

Inv No.

Protocol

Patient's Initials

Patient No.

(f tr$t. Middle. Last)

POST TREATMENT CLINICAL EVALUATION (24-48 hours after therapy) PNEUMONIA Cure Improvement 1__1 Failure

UTI WITH SEPTI- (“I CEMIA (5-9 days) L - 1

1 _1 Cure

1 _1 Cure

1 _1 Cure

1 1 Improvement

1 1 Improvement

1 1 Improvement

1 _1 Failure

I _I Failure

1 1 Failure

PNEUMONIA WITH SEPTICEMIA

1 _1 Cure Improvement 1 _1 Failure

f- ] -

UTI (5-9 days)

SEPTICEMIA

L J

HI

m

Unassessable, specify w h y : ............................................................................................

.....

FOLLOW-UP CLINICAL EVALUATION (4-6 weeks after therapy) PNEUMONIA

PNEUMONIA WITH SEPTICEMIA

SEPTICEMIA 1__1 Cure

cure

Cure 1 _1 Improvement

1__1 Improvement

Improvement

1__1 Failure

Failure

Failure

Relapse

Relapse

Relapse 1 1

Fl L J ~

UTI

uTi wiTH SEPTICEMIA

1 _1 Cure

1 _1 Cure

1 _I Improvement

1 _1 Improvement

L_1 Failure Relapse

r~i

Failure Relapse ||

o

Unassessable, specify w h y :

_________ __________________________

BACTERIOLOGIC EVALUATION (4-6 weeks after therapy) PNEUMONIA Cleared

SEPTICEMIA Cleared

PNEUMONIA WITH SEPTICEMIA Cleared

UTI

UTI WITH SEPTICEMIA Cleared

Cleared

1__1 Failure

1 _I Failure

1__I Failure

1 _I Failure

I__| Failure

1__1 Relapse

1 _1 Relapse

1__1 Relapse

1 _1 Cleared w i t h superinfection

1 _I Cleared w i t h superinfection

Colonization

Colonization

Colonization

Re-infection

Re-infection

Re-infection

Superinfection

Superinfection

Superinfection

Persistence w i t h superinfection

Persistence w i t h superinfection

Relapse

Relapse

Re-infection E3

Q

Unassessable, specify w h y :

f~|

1 _1 Re-infection

n ___________________________________________________________

F.1.28

581

PATIENT NUMBER:

SURVIVAL DATA

FIRST 3 LETTERS OF LAST NAME:

Page 1 of 1 DATE OF FOLLOW UP:

month

day

year

EVERY EFFORT MUST BE M A D E TO DETERMINE THE PATIENT'S CURRENT STATUS. AS O F THIS DATE, INDICATE THE STATUS OF THIS PATIENT: 1. PATIENT DIED (Complete Below): month

day

year

DATE OF DEATH:

I I I I I I I _I I

PRIMARY CAUSE OF DEATH:

1. Cancer Related 2. Non-Cancer Related: _________ (Specify)

2 . DATE OF LAST CONTACT W I T H PATIENT: TYPE O F CONTACT:

month

day

year

I I I I I I I I I 1. Clinic/Office Visit 2. Telephone 3. Mail Contact 4 . Other: _________________ (Specify)

3 . PATIENT IS:

1. Continuing To Be Seen A t This O f f i c e 2 . Lost To Follow-Up (No Further Information Available) 3 . Moved (Complete Below): Where: (Specify City/State) Name of N e w Physician:

Address:

_______________

Telephone:

F.1.29

582

D E R I V E D DATA F O R M

Protocol No.

Inv. No.

Pt. No.

Pt. Initials

Month

(First, Middle, Last)

DERIVED MEASUREMENT

WHEN ELEVATED BP DEVELOPS

Date

10-30 MINUTES AFTER FINAL TITRATION DOSE

Day

Year

JUST PRIOR TO END OF MAINTENANCE PERIOD

Cl MAP SVR MPAP PVR SI LVSW RVSW LCW RCW CaO2 CmvO2 CcO2 AVDO2 O2AV O2ER VO2 QsQt

F.1.30

583

Page

SEIZURE RECORD

Cmpd. #/Name

IND If

Proj. *

NDA #

Protocol # — Study #

NOTE: Please use BLACK ink. Patient's Initials

______________ L M F

Patient #

___________

Dept.

Sec

INSTRUCTIONS: Enter total daily counts for each uncontrolled seizure type experienced. Enter 'O' i f NO SEIZURES occurred o n a given day. Enter 'NR' i f the seizures are a type t h a t requires an observer and NO OBSERVER WAS PRESENT o n a given day. Major Seizure Type (Enter Code From Page B, i.e., A, B, or C) Study Week

Study Day

Date (M/D/Y)

1.

2.

3.

1

2

3

1

4

5

6

7

8

9

10

2

11

12

13

14

F.1.31 584

4.

5.

6.

Compd*

Proj. #

IND*

NDA #

Protocol No.:

Study No.:

Dept:

Section:

LONG TERM EFFICACY A N D SAFETY STUDY

SEIZURE RECORD YEAR 1: M O N T H 1 2

Patient's Initials: _ _ _/ _ _ _/ _ _ _ Patient # F

M

L

_____________ Date: ------/ ------/ -----M

D

Y

For all seizure types (specify name and code in the spaces provided), enter the total weekly seizure frequencies for each week of the study. Enter "0" for seizure-free weeks. All weeks must be accounted for. For the last week of the 4 month period, indicate the number of days in parentheses that seizures were counted. Include all seizures that were not controlled upon entry into original

study plus any emergent seizures.

Type: Int. Code:

-------

-------

-------

WEEK 1

M

DY

2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

(

)

19 20

( (

) )

_______ M.D. Edited by

Date

Date

Investigator's Signature

F.1.32

585

EFFICACY AND SAFETY STUDY—PARTIAL SEIZURES

SEIZURE RECORD TREATMENT A: WEEKS 5-8 PATIENT'S INITIALS: ________ F M L

PATIENT # _______________

Cmpd*

Proj. #

IND*

NDA #

Protocol No.:

Study No.:

Dept:

Section:

For all seizure types (specify name and code i n the spaces provided), enter the total daily seizure frequencies for each day of the study. Enter “0” for seizure-free days. All days must be accounted for. Type: Code: Day (

/

-----------------------

-------------------------

-------------------------

-----------------

)1 2

WEEK

3

-------

-------

—

—

-------

7 Weekly Total: Day ( — / — ) 1 2 WEEK 3

—

—

■—

6 6 7 Weekly Total: Day ( _ _ /__) WEEK

3

4

7—

5

Day (

/— ) 1 2

6 7 Weekly Total:

WEEK

8

3

7

Weekly Total:

Edited by:

586

Date:

MD Date

F.1.33

Investigator's Signature

MODIFIED NYU SCALE DAY 8

Project No.

IND No :

Compound No.:

Product Name:

Protocol No .

Study No.:

Section:

Dept.:

USE BLACK INK Patient's Initials: _ _ _ / _ _ _ / ___ L M F

Patient #

____________

Date: ___ / _ _ _ / ----Y D M

FOR EACH ITEM, CHECK ONLY ONE BOX EVALUATION OF DISEASE STATE 1. STAGE OF DISEASE (Hoehn & Yahr Scale) STAGE I Mild, unilateral disease. STAGE 2 Bilateral involvement. STAGE 3 Mild gait disturbances - mild to moderate disability. STAGE 4 Severe disability, able to walk or stand unassisted but markedly incapacitated. STAGE 5 Confined to bed or wheelchair.

ON/OFF STATUS AT TIME OF ASSESSMENT (check one):

ON

POFF

2. DISABILITY EVALUATION (New York University Parkinson Disease Scale) a. Rigidity (Judged on passive movement of major joints with patient relaxed in sitting position; cogwheeling to be ignored) 0 Absent. 1 Minimal. 2 Moderate, definitely abnormal. 3 Marked; but full range of motion easily achieved. 4 Very marked; full range of motion achieved with difficulty. RIGHT UPPER LIMB

LEFT UPPER LIMB

NECK

□ □□□□

no

1 2

1 0 2

3 4

03

1 2

1 2

0

4

03 0-4

D3 4

LEFT LOWER LIMB Qo

Do

Do

0

RIGHT LOWER LIMB

0

TOTAL RIGIDITY SCORE

1 2

03 4

b. Tremor 0 1

Absent. Minimal, barely seen.

2 3 4

Moderate in amplitude; easily observable. Marked. Very marked in amplitude.

RIGHT UPPER LIMB

LEFT UPPER LIMB

NECK

RIGHT LOWER LIMB 0 1 2 3 4

LEFT LOWER LIMB 0 1 2 3 4

TOTAL TREMOR SCORE

(Continued)

___________________________________M.D. INVESTIGATOR’S INITIALS

F.l.34.1

587

MODIFIED NYU SCALE

Project N o

IND No.

Compound N o .

Product Name:

Protocol No.:

Study N o

Section.

Dept.:

DAY 8

USE BLACK INK

Patient's Initials.

/ F

Patient #

/ M

D t . ___ I M

L

— —..... I

D

Y

c. Bradykinesia (Combining both slowness and poverty of movement in general) 0 1 2 3 O 4

None. Minimal slowness giving movement a deliberate character, could be normal for some persons. Mild degree of slowness and poverty of movement which is definitely abnormal. Moderate slowness with occasional hesitation on initiating movement and arrests of on-going movement. Marked slowness and poverty of movement, with frequent freezing and long delays in initiation movement.

d. Gait 0 1 2 3 4

Freely ambulatory, good stepping, turns readily. Walks slowly, may shuttle with short steps but no festination or propulsion. Walks with great difficulty with festination, short steps, freezing and propulsions but requires little or no assistance. Severe disturbance of gait requiring frequent assistance. Cannot walk at all, even with help.

e. Postural Stability (If Romberg is normal, judge response to sudden posterior displacement produced by a push on sternum) 0 1 2 3 4

Normal. Retropulsion but recovers unaided. Absence of postural response, would fall if not caught by examiner. Very unstable, tends to fall spontaneously with both feet together. Unable to stand without assistance.

TOTAL SCORE MODIFIED NYU SCALE

M.D. INVESTIGATOR'S INITIALS

588

F.l.34.2

NORTHWESTERN DISABILITY TEST

Project No.

IND No

Compound No.:

Product Name:

Protocol No.:

Study No.:

Section

Dept.:

DAY 8

USE BLACK INK

Patient's Initials: ___ / ___ / ___ L M F

Patient #

___________

Date: ----- / ___ / ----Y D M

FOR EACH ITEM, CHECK ONLY ONE BOX I EVALUATION OF DISEASE STATE"] 1. WALKING a. Always Walks Alone □ 0 Normal. □ 1 Gait differs only slightly from normal in quality and speed, turning is the most difficult task, posture is essentially normal. □ 2 Quality of gait is poor and slow, posture moderately affected, may be tendency toward mild propulsion, turning is difficult. □ 3 Gait is extremely abnormal; very slow and shuffling, posture grossly affected, there may be propulsion. b. Sometimes Walks Alone □ 4 Walks short distances with ease, walking outdoors is difficult but often done without help, rarely walks longer distances alone. □ 5 Walks from room to room with only moderate difficulty, may occasionally walk outdoors without assistance. □ 6 Walks from room to room without assistance, but moves slowly and uses external support, never walks alone outdoors. c. Never Walks Alone □ 7 □ 8 □ 9 □ 10

Requires potential help indoors, active help outdoors. Requires moderate help indoors, walks outdoors with considerable help. Needs considerable help even for short distances, cannot walk outdoors with help. Cannot walk at all, even with maximum assistance.

2. DRESSING a. Complete Self Help □ 0 Normal. Q 1 Dresses self completely with only slightly more time and effort than normal. □ 2 Dresses self completely but slowly and with great effort. b. Requires Partial Assistance □ O □ Q

3 4 5 6

Does all dressing alone except fine activities (tie, buttons). Performs more than half of dressing activities alone, with considerable effort and slowness. Performs about half of dressing activities independently. Performs only gross dressing activities alone (hat, coat).

c. Requires Complete Assistance O 7 Gives considerable help through bodily movements. □ 8 Can give some help through bodily movements. □ 9 Movements of patient neither help nor hinder assistant. Q 10 Patient is a hindrance rather than help to assistant. (Continued)

_________ ____________________M.D. _ INVESTIGATOR’S INITIALS

F.l.35.1

589

NORTHWESTERN DISABILITY TEST DAY 8

Project No.

IND No.:

Compound No.:

Product Name:

Protocol No.:

Study No.:

Section:

Dept.:

USE BLACK INK

Patient's Initials: ___ 1 ___ / ___ L M F

3. EATING D 0 □ 1 □ 2 D 3 □ 4 □ 5

Patient #

___________

Date: ___ / ----- / ----Y D M

Normal. Follows a normal diet, but chewing and swallowing are labored. Eats some hard food routinely, but requires time and effort. Handles liquids and soft foods with ease, hard food occasionally eaten, but requires great effort and much time. Eats only liquid and soft food, these are consumed very slowly. Eating so impaired that a hospital setting is required to get adequate nutrition.

4. FEEDING □ 0 Normal. C l 1 Feeds self fully more slowly than normal with rare accidents. □ 2 Handles all tending tasks alone with moderate slowness, still may get help in specific situations, accidents are not infrequent. □ 3 Performs most feeding tasks alone moderately slowly, still may get help in specific tasks. □ 4 Performs only a few feeding tasks independently. E ] 5 Requires complete assistance. 5. HYGIENE a. Complete Self Help □ 0 Normal. □ 1 Hygiene maintained normally but slowly. □ 2 Hygiene activities moderately time consuming, no substitute methods, few accidents. □ 3 Hygiene maintained independently, but with effort and slowness, accidents not infrequent, may use substitute methods. b. Requires Partial Assistance □ 4 Manages most of personal needs alone, has substituted methods for accomplishing difficult tasks. □ 5 Requires aid for some tasks not difficult in terms of coordination. □ 6 Requires assistance for half of toilet needs. □ 7 Performs a few tasks alone with assistance nearby. c. Requires Complete Assistance Q 8 Hygiene maintained well, gives aid to assistant. G 9 Reasonably good hygiene with assistance, but does not give assistant significant help. □ 10 Unable to maintain proper hygiene even with maximum help. (Continued)

. ...................................... INVESTIGATOR’S INITIALS

F .1.35.2

590

___..... M.D.

NORTHWESTERN DISABILITY TEST DAY 8

Project No.

IND No.:

Compound No.:

Product Name:

Protocol No.:

Study No.:

Section:

Dept.:

USE BLACK INK

Patient's Initials: ___ / ___ / ___ L M F

Patient #

___________

Date: ___ / ___ / ___ Y D M

6. SPEECH EZ] □ □ □ □ □ □

0 1 2 3 4 5 6

□

7

[3 8 □ 9 □ 10

Normal. Speech entirely adequate, minor voice disturbances present. Speech easily understood, but voice or speech rhythm may be disturbed. Communication accomplished with ease, although speech impairment detracts from content. Speech can always be understood if listener pays close attention, both articulation and voice may be defective. Speech always employed for communication, but articulation is still very poor, usually uses complete sentences. Uses speech for most communication but articulation is highly unintelligible, may have occasional difficulty in initiating speech, usually speaks in single words or short phrases. Attempts to use speech for communication, but has difficulty in initiating vocalization, may stop in middle of phrase and be unable to continue. Vocalizes to call attention to self. Vocalizes, but rarely for communicative purposes. Does not vocalize at all.

TOTAL SCORE NORTHWESTERN DISABILITY SCALE

_______________________ _______M.D. ____ INVESTIGATOR’S INITIALS

F.l.35.3

591

COMPLIANCE

F2

VISIT 6 (OPTIONAL) Pt. Initials

Inv. No.

Protocol No.

Date

Pt. No.

Month

(First, Middle, Last)

Day

Year

ADDITIONAL LABORATORIES Were any additional laboratory tests necessary since last visit? No Yes If yes, complete additional laboratory form.

MEDICATION COMPLIANCE Study Tablets returned this visit: Circle which bottle returned:

Placebo

Bottle D

Bottle B

Bottle E

Bottle C Study Tablets dispensed this visit: No

Yes

Placebo

No

Yes

Active Bottle B

C

DRUG ISSUED THIS VISIT

AFFIX TEAR-OFF DRUG LABEL(S) HERE

F.2.1

593

LEAD-IN PHASE Pt. Initials

Inv. No.

Protocol

Visit No.

Date

Pt. No.

Month

(First, Middle, Last)

Day

02

Year

ADVERSE EVENTS/ILLNESSES & MEDICATION COMPLIANCE Has the patient been queried on adverse events and concurrent illness? 0 = No

1 = Yes

Please record any new events or changes in existing conditions on page 34. Remember to follow-up on stop dates for events continuing over more than one visit. No. capsules returned: Time and date of last dose: (military time)

Month

Day

Year

IF MEDICATION TAKEN THIS AM, RESCHEDULE VISIT AND INSTRUCT PATIENT NOT TO TAKE MEDICATION PRIOR TO VISIT. CONCOMITANT MEDICATION CHANGES List any changes in concurrent drugs and indicate if they were added, discontinued or adjusted since last visit (More than one may be checked). Include the dates for all changes.

□

□

Added Date

□

!

!

□

Date

!

!

□

Dosage adjusted Date

!

□

Discontinued Date

!

!

□ !

!

Dosage adjusted Date

!

>

/

INTERIM PHYSICAL EXAM HEART RATE

BLOOD PRESSURE Average Supine

mmHg

Average Standing

mmHg

Were there any significant findings since the previous examination? 0 = No

594

1 = Yes (If yes, specify below)

F.2.2

!

Daily Dose

Discontinued Date

!

!

!

Added Date

!

Date

!

4. Drug

Daily Dose

Added

!

Dosage adjusted

Discontinued Date

!

□

Added Date

! □

2. Drug

□

!

Discontinued Date

□

□

Dosage adjusted Date

!

Daily Dose

3. Drug

Daily Dose

1. Drug

Weight

lbs

!

CASE REPORT FORM PROTOCOL NO. Page 54 of 59

— INVESTIGATOR NO.

(OPTIONAL) STUDY WEEK

PATIENT NO.

MO.

INITIALS

RECORD O F MEDICATION FOR THE PRECEDING hours have elapsed since last dose

DY.

YR.

WEEKS

Randomization No. (if post-randomization)

Number of tablets were dispensed on MO.

DY.

YR.

MO.

DY.

YR.

Number of tablets were returned on

Number of tablets ingested over

days

If 24 + 3 hours have not elapsed since last dose, reschedule patient. Was the patient rescheduled?

Yes

2d

No

Please record any adverse event and/or any change in concomitant medication on pages 56-59. If treatment is discontinued, please complete physical examination and study status on pages 51-52. VITAL SIGNS

kg. lb.

Weight

2. SUPINE (after seated & after 5 min. rest) HEART RATE (per min.)

1. SEATED (after 5 min. rest) HEART RATE (per min.)

BLOOD PRESSURE (mmHg)

BLOOD PRESSURE (mmHg) Measured within a 5 min. period

3. STANDING (immediately after supine) HEART RATE (per min.)

BLOOD PRESSURE (mmHg)

Total BP AVERAGE SEATED BLOOD PRESSURE (mmHg)

(after 2 min.) 2.

F.2.3

595

SUMMARY REPORT FORM Patient Number

Protocol Number

Patient’s Initials (First, Middle, Last)

Overall Clinical Evaluation of response to therapy Check clinical response (refer to frequency and severity of all asthma symptoms) Improved Comments

No change

Worse

______

Not evaluable (explain briefly below) . ________________________________________________________

Compliance How many visits did the patient complete? Did patient complete the study according to the protocol?

No

Yes

If no, check as appropriate and give details: Patient failed to return

i ____________

Poor compliance

______________________________________________________________________

Adverse Events

_______________________________________________________________________

Required medical intervention (oral steroids, epinephrine, etc.)

Other

_ _ ________________________

I confirm that the information given in this case report form is accurate and complete.

Principal Investigator’s Signature

Date

Sponsor’s Evaluation Evaluable Not Evaluable

596

F.2.4

;_______________

PATIENT NUMBER:

INTERIM VISIT REPORT Page 1 of 1 DATE:

FIRST 3 LETTERS OF LAST NAME:

month I

I

da y

year

I

HAS PATIENT DROPPED OUT OR DISCONTINUED THERAPY?:

1 . No

2. Yes (If "Yes, " Complete Final Visit Report Forms And Study Termination Sheet)

HAS PATIENT TAKEN MORNING DOSE OF STUDY MEDICATION?:

1. No

2. Yes

NUMBER OF TABLETS RETURNED FROM LAST VISIT: BOTTLE A: I l l i

BOTTLE B: I l l i

(If Not Returned, Insert Dashes Above and Explain) :

COMMENTS:

_

16787

Signature:

F.2.5

_______

597

Cmpd*

Proj. #

IND"

NDA #

Protocol No.:

Study No.:

Dept:

Section:

EFFICACY AND SAFETY STUDY—PARTIAL SEIZURES

PILL COUNTS WEEK 2

PATIENT'S INITIALS:

________ F M L

PATIENT# ________________ DATE _ _ / _ _ /_.„. . M D Y

No. Rx per day

Study Drug

X

No. Days Since last visit *

=

Total Expected Use

X

2. ( -----------— )

X

3. ( -------------- )

X

+

No. Refilled (If any)

Actual No. In Bottle

+ + +

X

1. ( -----------— )

Pill Count at last visit

—

Actual No. Used

— —

* C o u n t entire day of last visit. D o not count today's visit date.

Study Drug:

Actual Use

_ _ _ __ ___________

____________________________ X 100 = _____% Compliance Expected Use ________________ Actual Use 1. ( _ ------------ )

____________________________ X100= _____ % Compliance Expected Use ___ ____________ Actual Use

2. ( -------------- )

_________________

_________________

___________________________ X 100 = _____ % Compliance Expected Use ________________ Actual Use ____ _ ___________

3. ( ----------_ )

____________________________ X 100 = _____ % Compliance Expected Use ________________

Comment on all % Compliance < 9 0 % o r > 110%

Edited by

. ____________ M.D.

Date ----------------- ----Date

598

F.2.6

Investigator's Signature

Date (m/d/y)

Visit

Investigator

Patient Identification’ 1

3

2

1

2

Medication Code 3

-------------- ------------------------------

f-or r a t i e n i identification use first 3 letters of first name then first 3 letters of last name

DRUG RETURN DATA Phenytoin

None

Carbamazepine

None _______________ Number DISPENSED:

Number DISPENSED:

Number RETURNED:

Number RETURNED:

(verify by count):

(verify by count):

D DIFFERENCE (dispensed minus returned):

E l DIFFERENCE (dispensed minus returned):

E l Number REPORTED AS TAKEN

B

(by "Patient Diary/lnterview”): Comment on differences between E l and Q as well as deviation from prescribing instructions

____________________________________________________________

Number REPORTED AS TAKEN (by “Patient Diary/lnterview"):

Comment on differences between D

as well as deviation from prescribing

Phenobarbital

Number DISPENSED:

Number DISPENSED:

Number RETURNED:

Number RETURNED:

(verify by count):

B

_________________________________. __________________________

instructions

None

None _______________________Valproic Acid

and

(verify by count):

E l DIFFERENCE (dispensed minus returned):

E l DIFFERENCE (dispensed minus returned):

B

B

1

Number REPORTED AS TAKEN (by "Patient Diary/lnterview"):

Comment on differences between E l and instructions

B

as well as deviation from prescribing

____________________________________________________________

Number REPORTED AS TAKEN (by "Patient Diary/lnterview”):

Comment on differences between E l and instructions

B

as well as deviation from prescribing

____________________________________________________________

Primidone

L i None Number DISPENSED: Number RETURNED: (verify by count):

E l DIFFERENCE (dispensed minus returned): Q Number REPORTED AS TAKEN (by "Patient Diary/lnterview”): Comment on differences between E l and instructions

B

as well as deviation from prescribing

____________________________________________________________

PRESCRIBING INFORMATION FOR CONCOMITANT ANTICONVULSANT MEDICATION FOR NEXT PERIOD No. Dispensed

The patient has been instructed to take:

Carbamazepine Phenytoin Valproic Acid Phenobarbital Primidone

For

__________________________

Use Only

___/ _ _ _I ___

__________________ Initials __________________________Date (m/d/y)

USE BLACK

BALLPOINT

PEN — PRINT LEGIBLY

F.2.7

599

F3

PATIENT DIARIES

PATIENT NUMBER:

SUBJECT DIARY CARD Page 1 of 1 DATE:

month I

I

I

day I

I

FIRST 3 LETTERS OF LAST NAME:

year I

ILl

PLEASE LIST CONTENT OF EVENING MEAL PRIOR TO THE DAY OF STUDY DRUG ADMINISTRATION.

NOTE: EVENING MEAL SHOULD BE LIMITED IN FAT CONTENT. month

day

year

DATE OF MEAL:

I I I I I I l....._L3

TIME OF MEAL:

I I I : I I I p.m.

CONTENT OF MEAL:

28488

Signature:

,

F.3.1

601

INTERIM VISIT FORM Protocol

Inv. No.

Pt. nitials

Date

Pt. No.

Visit NO. A3

(First. M i d d l e . Last)

Month

Day

Year

ANGINA DIARY SUMMARY CONCOMITANT MEDICATION CHANGES N o . a n g i n a episodes: (since last visit)

——— ———

N o . sublingual NTG tabs consumed: (since last visit) Was t h e r e a change i n level o f activity o r e m o t i o n a l stress since last visit? 0 = No 1 = Yes

List any changes i n concurrent drugs and indicate i f they were added ordiscontinued since last visit. (Both may b e checked.) Daily Dose

1. Drug ZJ Added □ Discontinued 2. Drug

Daily Dose

□ Added □ Discontinued

I f yes, please explain.

□ Added □ Discontinued 4. Drug

No. tabs returned this visit:

DRUGS ISSUED THIS VISIT

AFFIX

□ Dosage adjusted

Daily Dose

□ Added □ Discontinued

No. tabs dispensed this visit:

□ Dosage adjusted

Daily Dose

3. Drug

MEDICATION COMPLIANCE

□ Dosage adjusted

□ Dosage adjusted

ADVERSE EVENTS/ILLNESSES Has t h e patient experienced any adverse events or intercurrent illnesses since t h e last visit?

TEAR-OFF □ 0 = No

DRUG LABEL HERE

DlxYes

(Visit 3) If yes, complete adverse event/illness f o r m .

F.3.2 602

LEAD-IN PHASE Protocol

Inv. No.

Pt. Initials

Pt. No.

(First, Middle, Last)

Date

Month

Visit No.

Day

Year

02

DIARY INFORMATION RECORD ALL ANGINA ATTACKS SINCE THE LAST VISIT No. of Episodes

Date

Nitroglycerin

Day 1

Day 2

Day 3

Day 4

Day 5

Day 6

Day 7

Was there a change in level of activity or emotional stress since last visit?

No

Yes

Comments:

NO. O F ANGINA EPISODES:

NO. OF SUBLINGUAL NTG TABS CONSUMED: (SINCE LAST VISIT)

(SINCE LAST VISIT)

F.3.3

603

DIARY INFORMATION Date

Pt. No.

Pt. nitials

Inv. No.

Protocol

first. Middle. Last)

Month

Day

Visit Year

RECORD ALL ANGINA ATTACKS SINCE THE LAST VISIT

Time (dock time)

Date

: Month

Day

: Day

Year

; Month

Day

Year

Day

Year

(Circle A M or PM)

L_L_J

| :

L_L— J

: Day

Year

L__L_

J

: Day

Year

; Year

L_L—

(Circle A M or P M ) :

Year

(Circle A M or PM) :

Day

Year

Year

□ 1 - Mild 0 2 - Moderate 0 3 = Severe

AM PM

Q 1 - Mild □ 2 = Moderate

AM

: Day

PM

(Circle A M or P M )

____ Month

1 - Mild 2 « Moderate 3 - Severe

AM

PM

___ Month

□ 1 - Mild O 2 = Moderate 0 3 = Severe

AM J p***

___ Day

□ 1 = Mild 0 2 * Moderate 0 3 = Severe

AM

PM

____

Month

□ 1 = Mild □ 2 - Moderate □ 3 = Severe

(Circle A M or PM)

Day

Day

□ 1 - Mild 0 2 = Moderate 3 ) 3 = Severe

AM pM

(Circle A M or PM) :

Month

n i = Miid □ 2 = Moderate □ 3 = Severe

AM PM

L__L_J

___ Month

AM

PM

(Circle A M or PM)

____ Month

□ 1 - Mild 2 ] 2 = Moderate □ 3 -Severe

(Circle A M or PM)

Day

____ Month

AM pM

(Circle A M or PM) J _ _ _|

Month

Q 1 = Mild □ 2 - Moderate 0 3 = Severe

AM

:

I

I

(Circle A M or P M )

O 3 « Severe

Comments:

F3.4

604

1 « Mild

O 2 = Moderate 0 3 = Severe

PM

____ Month

□

(Circle A M or P M ) ___

1 = Mild 2 = Moderate

□ 3 » Severe

AM PM

L__

Severity (check one) □ □

AM

L _ _ J _ ] PM (Circle A M or PM)

____ Month

Duration (min)

NTG Taken

Activity When Pain Started

DIARY CARD PROTOCOL NO.

PATIENT NO. .

INVESTIGATOR NO.

1 4 0 3 _________

PATIENT NAME _ _ _ _._____. ______________________

DATE 1)

PEAK FLOW READING

AM PM

2) ASTHMA LAST NIGHT 0 1 2 3

3)

Good night Slept well, but some coughing/wheezing Awakened briefly because o f coughing/sheezing Bad night, awakened multiple times or for prolonged period (greater than 30 minutes)

ACTIVITY TODAY 0 1 2 3

4)

Can tolerate all activity Cannot tolerate vigorous physical activity Symptoms w i t h routine activities Could not participate in school/work/routine activities

WHEEZE TODAY 0 1 2 3

None Transient, lasting less than 30 minutes no more than twice More than twice and/or longer than 30 minutes Continuous

5) SHORTNESS OF BREATH TODAY 0 1 2 3

6)

None Mild: occasional with no restriction of activity Moderate: frequent with normal activity restricted at times Severe: almost continuous with normal activity severely restricted

COUGH TODAY 0 1 2 3

None Present but not interfering with normal activities Moderate, interrupting normal activities once Spasms interrupting normal activities more than once

0 1 2 3

0 1 2 3

0 1 2 3

0 1 2 3

0 1 2 3

0 1 2 3

0 1 2 3

0 1 2 3

0 1 2 3

0 1 2 3

0 1 2 3

0 1 2 3

0 1 2 3

0 1 2 3

0 1 2 3

0 1 2 3

0 1 2 3

0 1 2 3

0 1 2 3

0 1 2 3

0 1 2 3

0 1 2 3

0 1 2 3

0 1 2 3

0 1 2 3

0 1 2 3

0 1 2 3

0 1 2 3

0 1 2 3

0 1 2 3

0 1 2 3

0 1 2 3

0 1 2 3

0 1 2 3

0 1 2 3

0 1 2 3

0 1 2 3

0 1 2 3

0 1 2 3

0 1 2 3

7) OTHER MEDICATION Write the name of the drug, and the strength below. Under each day write how many tablets/sprays etc. that you took that day.

1.

Inhaler (puffs/day)

2. 3. 4. 8) SIDE EFFECTS

605

G. PATIENT TERMINATION AND MISCELLANEOUS FORMS A JL-J J L V 1 T JLJLJL 1 1 *

Title 1. Termination and Premature Patient Discontinuation 2. Global Clinical Impressions 3. Additional and Unscheduled Patient Visits 4. Comment Log and Investigator Verification Forms

A Lwil

Form Numbers

Page Numbers

G.l.l-G.1.32

611-645

G.2.1a-G.2.6 G.3.1-G.3.4

647-652 653-656

G.4.1a—G.4.5

657-661

GENERAL POINTERS AND COMMENTS •

When reasons for premature termination are listed, the form must state whether the respondent should indicate all reasons or only the major reason(s).

•

Do not ask the question “Did the patient complete the trial per protocol?” Some investigators or clinical trial staff will answer no if the patient missed a scheduled clinic visit, missed some doses, or had a minor protocol deviation. A more relevant question is “Was the patient prematurely discontinued from the trial?” Consider having a form to evaluate the patient’s quality of participation in the trial (e.g., as planned, minor irregularities, or major irregularities). Global clinical impressions are less useful in Phase I than in Phases II and III trials. Protocols requiring two or more clinic visits should have data collection forms for additional or unscheduled visits. A form for comments provides a n important means of collecting any information that does not fit elsewhere and should also help prevent data or comments being written in the margins or on inappropriate forms (G.4).

• • • •

607

PATIENT TERMINATION AND MISCELLANEOUS FORMS

• Forms for premature patient discontinuation should indicate whether the investigator made the decision to discontinue the patient or the patient chose to drop out. Almost no patient discontinuation forms allow for this distinction.

SPECIFIC POINTERS AND COMMENTS ON INDIVIDUAL FORMS G.l Termination and Premature Patient Discontinuation • Most forms specifically ask whether the patient completed the entire trial (G.1.1). ® Most forms request the reasons patients who did not complete the entire trial dropped out or were discontinued (G.l.3). ® Useful information includes the date and cause of death and the date that medicine was discontinued (G.1.1). • Reasons for discontinuation may be categorized as being due to adverse events, lack of efficacy, or administrative decisions (G.l.5); they may also be grouped into primary and secondary reasons (G.1.6). • Posttrial follow-up forms are often essential to have, although they are seldom used (G.l.8 and G.l.9). • Information on patient completion may be requested for each period of the trial (G.1.11). • The patient’s status and address may be important to obtain (G.l.13). • A clinical summary may be used in lieu of a formal discontinuation form (G.l. 16). • Other terminology applied to final visit forms includes clinical summary (G.l. 19); discharge evaluation (G.l. 20), and treatment outcome (G.l.22). • Categories of reasons for premature termination may be stated (G.l.24) or defined (G.l.25). • Detailed questions on patient participation may be posed (G.l.31.1 and G.l.31. 2). G.2 Global Clinical Impressions • Multiple forms are presented on G.2.1 and G.2. 2. ® Global impressions may focus on disease status (G.2. lb, G.2.3) or improvement (G.2.2b and G.2.4). • Global assessment of disease severity may ask the investigator to compare the patient with others with the disease (G.2.3) or only to compare the patient with his or her own baseline (G.2.4). • Patients may be asked to complete the same global assessment as the investigator on disease severity in terms of changes from baseline (G.2.4). • Clinical assessment of treatment cure, failure, recurrence of disease, or other outcomes may be used as the global evaluation (G.2.5). ® Patient questionnaires may be very simple and may be read to the patient (G.2.6), or the patient may complete them. G.3 Additional and Unscheduled Patient Visits ® Forms for additional visits may be highly specific and identical to standard visits, except for the title (G.3.1).

608

PATIENT TERMINATION AND M I S C E L L A N E O U S F O R M S

•

Forms may include those for additional tests (G.3.1) and/or for unscheduled contacts (G.3.2). ® Forms to indicate a missed visit may be created (G.3.4). G.4 Comment Log and Investigator Verification Forms

• Multiple forms are given on page G.4.1. • Most comment logs merely provide space for text or data that should be captured and is inappropriate elsewhere (G.4.1). • Including a date column by all comment lines is an excellent idea rather than solely requesting the respondent to add dates (G.4.1). • Investigator verification may be requested on every page of data collection forms (G.4.1), once at each visit (G.4.5), or once per entire treatment of a patient (G.4.4).

609

G1 TERMINATION AND PREMATURE PATIENT DISCONTINUATION Form 16 Termination Record Patient Initials

Patient Study #

I I I F

M

Protocol Study Center #

L

Location

As of the end of study drug treatment: 1. Did the patient complete the entire course of the study as specified i n the protocol? YES NO If NO, why not? (Check all that apply) (1) (2) (3) (4) (5) (6)

Patient did not return for drug administration or refused testing Patient experienced clinically significant adverse experience(s) (Include on Adverse Experiences page) Medication was ineffective Patient terminated for administrative reasons Patient experienced intercurrent illness Patient expired (This information is required by the FDA.) Date of death M

D

Y

Cause of death (7)

Other, specify

2. Date medication discontinued M

D

Y

COMMENTS.

G.1.1

611

Final

EvaIua tion Yes

No

Did the patient complete the entire study? If yes, complete the following: Date last procedure completed and patient released:

■

■

MM ' ED ' YY

If no, complete the following: Date study medication discontinued:

. MM ' ED ' YY

Date last procedure completed and patient withdrawn:

|

[

Reason for Discontinuation: Adverse Experience (categorize below) Disease progression / Worsening CHF Death

________________ specify using exact wording from AE page

Protocol Violation (categorize below) Non-compliance with study medication Loss to follow-up

specify

Does the patient have an adverse event that was ongoing at the final visit? If yes, complete the Post Study Follow-up pages after resolution of the event or after safety has been adequately evaluated. Will the patient enter the long-term extension study? If yes, patients completing at least week 4 may enter LTX within 1-7 days. Patients withdrawing from double-blind prior to week 4 may not enter LTX until after the projected date for the week 4 visit. Comments may be recorded in the General Comment Section on the next page.

612

G.1.2

PATIENT NUMBER:

STUDY TERMINATION SHEET Page 1 of 1 DATE:

month

day

FIRST 3 LETTERS OF LAST NAME:

,— .— . I I I

year

II IIIIIII month

LAST KNOWN DATE PATIENT TOOK STUDY MEDICATION:

day

year

I I I I I I I l_]

WAS THE PATIENT TERMINATED FROM THE STUDY BEFORE THE FINAL VISIT?:

1. No

2. Yes (If " Y e s , " Please Complete Remainder Of This Page)

INDICATE WHO INITIATED THE DISCONTINUATION:

1. Investigator

3. 2. Patient

4. Other: (specify)

CIRCLE ONE PRINCIPAL REASON:

1. Adverse Experience (Specify Below And On Medical Problem(s) Form) 2. Unsatisfactory Therapeutic Response 3. Concomitant Illness (Specify Below And On Medical Problem(s) Form) 4. Found Not To Meet Study Criteria 5. Use Of Unacceptable Concomitant Medication 6 . Failure To Follow Appointment Schedule 7. Therapy Refusal 8. Abnormal Laboratory Values 9. Lost To Follow-Up 10. Administrative Problems 1 1. Death

PROVIDE ALL RELEVANT INFORMATION RELATED TO REASON FOR TERMINATION INCLUDING CONTRIBUTORY FACTORS:

G.1.3

613

PATIENT NUMBER:

FINAL VISIT REPORT

FIRST 3 LETTERS OF LAST N A M E :

Page 1 of 1 month

day

year

I I I I I I [ L_

DATE:

H A S PATIENT DROPPED O U T OR DISCONTINUED THERAPY?: 1. N o

2. Yes Uf "Yes," Complete This Visit And Study Termination Sheet) PHYSICAL EXAMINATION

WEIGHT:

BLOOD PRESSURE

II

I

I pounds

POSITION

TIME (24 Hour Clock)

□ ZmOrnr

systolic

diastolic

1. Sitting

PULSE:

2. Standing

PULSE:

3 . Supine PULSE: PULSE:

LIST ANY SIGNIFICANT FINDINGS SINCE THE LAST EXAMINATION U f "None," Circle):

/minute /minute /minute /minute

NONE

HAS PATIENT USED ALCOHOL IN THE PAST 7 2 HOURS?:

1. N o

2. Yes

WAS URINE DRUG SCREEN CONDUCTED?:

1. N o

2. Yes

COMMENTS:

_________________________________ _ _

G.1.4 614

Illi IIII Illi I I I ~l

CONCLUSION O F PATIENT PARTICIPATION PATIENT INITIALS (3) ___

___

DATE PARTICIPATION CONCLUDED DATE DRUG DISCONTINUED (month/day/year) (month/day/year) _______

Drug ID PATIENT NUMBER

_______ _______

Please check the primary reason why this patient concluded participation in this trial.

A. Completed trial

oD

B. Premature discontinuation from trial. 1.. Adverse event* (check one): The adverse event(s) must be recorded on the ‘Adverse Event Report’ form. a. worsening of disease under study

iD

b. worsening of pre-existing disease

20

c. other adverse event

3D

2. Lack of efficacy (no change in disease under study)

40

3. Administrative (check one and explain below): a. protocol violation

................................... s D

b. lost to follow-up

60

c. withdrawal of consent (not related to 1 or 2 above)

?□

d. other

sD

Explain

*Adverse events which are still present at the patient’s last trial visit must be followed until the events have been resolved or follow-up is agreed adequate by the principal monitor and the investigator. Appropriate information should be recorded on an ‘Adverse Event Report’ form.

FOR OFFICE USE ONLY

PRINCIPAL INVESTIGATOR’S DECLARATION By signing and dating this page, I declare that I have reviewed for accuracy all case report form pages for this patient; the information contained on these pages accurately reflects the medical record including the results of tests and evaluations performed on the dates specified. Principal Investigator’s Signature:

Date:

G.1.5 615

STUDY TERMINATION RECORD

PLEASE PRINT LEGIBLY PATIENT NUMBER >UBJECz 1 NUMBER

_

DO NOT WRITE I N SHADED AREAS

USE BLACK BALL-POINT PEN

PATIENT INITIALS SUBJEU T INITIALS _

DATE OF COMPLETION OF* * (OPTIONAL.)

—

(M / D / Y )

DID THE PATIENT COMPLETE THE STUDY?

YES

Note:The text of this question may vary per protocol focus.

* 'Post event to be specified

* NO

If NO, indicate primary and secondary reasons for discontinuation. REASON (S) FOR DISCONTINUATION

PRIMARY REASON (check one only) (1)

SECONDARY REASON (S) (check as many as applicable) (2)

ADVERSE REACTION -specify on the STUDY EVENT RECORD (Form

01

OTHER MEDICAL EVENT -specify on the STUDY EVENT RECORD (Form )

18

FAILED T O RETURN -specify reason if known

02

UNSATISFACTORY RESPONSE - EFFICACY

05

PROTOCOL VIOLATION -specify

06

PATIENT DIED

13

OTHER NONMEDICAL EVENT -specify

19

PATIENT REQUEST - other than recorded above -specify

04

, certify that I have examined all of the pages of this case (Investigator’s name) report set for this patient (subject) and found them to be complete and accurate. INVESTIGATOR'S SIGNATURE

DATE

616

G.1.6

STU DY TITLE

FINAL REPORT D O NOT WRITE I N SHADED AREAS

4/90

94-1603-15

PRINCIPAL MONITOR

INVESTIGATOR'SNO.

PRINCIPAL INVESTIGATOR

SUBJECT'S INITIALS

SUBJECT NO.

MONITOR N A M E PROTOCOL NO.

STUDY PERIOD

DATE OF EVALUATION

M/0000/0000 Date that last dose of investigational medication was taken:

M0

1 0AY / Y” / /

T i m e (0001-2400): _

REASON FOR DISCONTINUATION OF STUDY MEDICATION .

i—i

l

DAY

MO,

—

(Check t h e p r i m a r y reason)

,

,

YR.

—

-----

CHECK ONLY ONE

--------------

[Ji End of planned study course □ 2 Lack of efficacy □ 3 Improvement MEDICAL EVENKS)

□ « Death during study 0 5 Medical Event(s) - - serious* □ □

Also complete a MEDICAL EVENT FORM (MEF)

Medical Event(s)-- non-serious 7 Intercurrent illness (see protocol for definition) s

ADMINISTRATIVE

Q 8 Subject found t o be ineligible f o r protocol after investigational medication started □ 9 Protocol violation □ ,o Subject's request (must n o t be related t o a Medical Event or any problem w i t h investigational medication) Subject lost t o follow-up □

Also EXPLAI N BELOW

I2 Other

* serious = fatalorlifethreatening, permanently disabling, requires or prolongs in-patient hospitalization, or a congenital anomaly, cancer, or medication overdose. Also include any other event the investigator judges to be serious.

NOTE:

If any medical event is still ongoing at this time, its resolution should be recorded on a Post-Study Follow-up Report.

I v e r i f y that a l l case report forms accurately display t h e results o f examinations, tests, a n d evaluations p e r f o r m e d o n t h i s subject, a n d that, t o t h e best o f m y k n o w l e d g e , a l l protocol requirements, including dose a d m i n i s t r a t i o n , followed. were — 75; . — _ _____ — 0AY

M0

_

__

/

_/

INVESTIGATOR'S SIGNATURE: -

—

—

—

M0

.

/

MONITOR REVIEW BY:

G.1.7

DAY

", YR. /

617

STUDY TITLE

POST-STUDY FOLLOW-UP REPORT 94-1603-16

Please use this form o n l y t o report t h e course o f a n unresolved Medical Event [ME] (includes clinically relevant a b n o r m a l safety laboratory values) f r o m t h e t i m e o f t h e SHADED AREAS FINAL REPORT u n t i l resolution o f t h e event. DQ NQT WRITE

4/90

PRINCIPAL MONITOR

PRINCIPAL INVESTIGATOR

INVESTIGATOR'S NO.

SUBJECT'S INITIALS

SUBJECT NO.

MONITOR N A M E PROTOCOL NO.

DATE OF EVALUATION

DAY

MO.

YR.

M/0000/0000 PLEASE ANSWER ALL QUESTIONS

USE ONE FORM FOR EACH EVENT

1 . Identify ME being followed:

START DATE:

(Use same terminology as used o n the last Medical Event Form (MEF) if possible)

M0

- I /

2 . D i d this M E resolve since t h e last report?

DAV

I /

. Do No* ,Yes

If Yes: DATE RESOLVED: Were t h e r e a n y residual effects?

YR.

DAY

MO.

/

/

L No . . m w L I , Yes - e x p l a i n :

This form s h o u l d b e s u b m i t t e d every t i m e a change i n t h i s subject's status occurs u n t i l M E has resolved 3 . D i d this M E require medical intervention?

0

No

, Yes I f Yes, describe:

4 . D i d this M E require o r p r o l o n g hospitalization?

0

I f Yes, describe:

5 . D i d t h i s subject die? I

MO.

I f Yes, specify:

Date o f d e a t h AUTOPSY

DAY

□

/

YR.

/

/ 0

Notdone I

Probable Cause 11 Report Available

I

1 Report Attached

COMMENTS:

MO.

i

DAY

I

YR.

DAY

/

YR.

INVESTIGATOR'S SIGNATURE: MONITOR REVIEW BY:

618

G.1.8

No

Post

Evaluation

Follow-Up

PATIENT #

PATIENT'S INITIALS: F

Cmpd

Project

IND

NDA

Protocol

Study

Dept.

Section

M L

INSTRUCTIONS: This form i s t o be used for following any c l i n i c a l l y s i g n i f i c a n t f i n d i n g s o c c u r r i n g s i n c e the i n i t i a t i o n o f the treatment period that have n o t returned t o b a s e l i n e o r acceptable values a t the time o f the final posttreatment v i s i t , Give d a t e and d e s c r i p t i o n o f a l l p e r t i n e n t e v e n t s and note a c t i o n taken, i f a n y . Abnormal Event ( s )

Date o f Onset

Date o f Resolution

Check one Has P a t i e n t Completed Treatment P e r i o d ?

1.

YES NO

2.

3. TESTS PERFORMED

Test

Date

Value

Normal Value Range (Units)

Test

Date

Value

Normal Value Range (Units)

INVESTIGATOR'S COMMENT LOG (Date each e n t r y and i n d i c a t e a c t i o n s t a k e n . )

FINAL OUTCOME OF EACH ABNORMAL EVENT:

M.D. E d i t e d by

Date

Date G.1.9

Investigator's Signature

619

SUMMARY FORM

Inv. No.

Protocol

Date

Pt. No.

Pt. nitials First, Middle, Last)

Month

Did the patient complete the study? If not, explain:

O'

Day

Visit Mn jXIU, Year

< □ Yes 1

Were there any significant factors not recorded elsewhere i n the case report form which may have y es affected study results? If yes, explain:

Have pages 9, 14, 18, 22, 24, 30, and 32 been signed by the Principal Investigator? o = No (please sign forms)

1 = Yes

I confirm that the information given i n this case report form is accurate and complete.

Date: L_l_ J

Signed: (Principal Investigator's Name)

G.1.10

620

Month

_ _I Day

Year

..............

SUMMARY FORM

Inv. No.

Protocol

Pt. nitials

I

Pt. No.

First. Middle, last)

Did the patient complete the titration period?

_____ Pate Month

Day

Year

0 = No

1 = Yes

(check one)

0 = No

1 = Yes

(check one)

If not, explain:

Did the patient enter the maintenance period? If not, explain:

Did the patient complete the maintenance period?

0 = No

1 = Yes

(check one)

If not, explain:

Were there any significant factors not recorded elsewhere in the case report which may have

If Yes, explain:

Yes

3 = No

affected study results?

(check one)

______________________________________________________

" I have reviewed the data contained i n this case report and attest to the accuracy and completeness thereof"

Date: ---- ---- -------- ------

Signed: (Principal Investigator's Name)

Month

bay

Yeat

G.1.11

621

PATIENT NUMBER:

STUDY TERMINATION SHEET Page 1 of 1 DATE:

month I

I

FIRST 3 LETTERS OF LAST NAME:

year

day I T

]

I

I

]

LAST KNOWN DATE PATIENT TOOK STUDY MEDICATION:

I

I

year

day

month I

I

I

I

I

I

I

INDICATE WHO INITIATED THE DISCONTINUATION:

3. Sponsor

1. Investigator

4. Other:

2. Patient

(specify) CIRCLE ONE PRINCIPAL REASON:

1. Adverse Experience (Specify Below And On Medical Problem(s) Form) 2. Unsatisfactory Therapeutic Response 3. Concomitant Illness (Specify Below And On Medical Problemls) Form) 4. Found Not To Meet Study Criteria 5. Use Of Unacceptable Concomitant Medication 6. Failure To Follow Appointment Schedule 7. Therapy Refusal 8. Abnormal Laboratory Values 9. Lost To Follow-Up 10. Administrative Problems 1 1. Death

PROVIDE ALL RELEVANT INFORMATION RELATED TO REASON FOR TERMINATION INCLUDING CONTRIBUTORY FACTORS:

G.1.12

622

,— ,— . I I I

PATIENT NUMBER:

POST-TREATMENT FOLLOW UP

FIRST 3 LETTERS OF LAST NAME:

Page 1 of 1 month DATE:

day

year

I I I I I I I I

DISEASE STATE (Circle One And Attach Appropriate Report!: 1. Disease Free 2. Recurrent Disease

DATE OF RECURRENCE:

I

I

I

year

day

month

I. I

I

I

I

I

PATIENT STATUS (Circle One): 1. Will Continue To Be Seen At This Office 2. Lost To Follow Up 3. Moved (Complete Below) Name

___________________________________________________. ________

Address

Physician's Name Address

4. Died (Specify Below) month

day

year

DATE OF DEATH: AUTOPSY:

1. No

2. Yes (Attach Report)

CAUSE OF DEATH:

1. Not Tumor Related

2. Tumor Related

5. Recurrent Disease (No Further Follow Up Required)

G.1.13

623

PATIENT DISCONTINUATION RECORD Patient's Initials:

F

/ ------/-----M

L

Patient #

Date: ------/ M

D

/

Compd*

Proj. it

IND*

NDA #

Protocol No.:

Study No.

Dept:

Section:

Y

2

What was the last study month that patient completed? YEAR

MONTH

3. How would you judge the compliance of this patient throughout the study? a. Took medication as prescribed. b. Some irregularities, but primarily took medication as prescribed. c. Significant irregularities. 4. In your opinion, did this patient benefit from the study medication. Yes

□□□□□□□□

1. Patient discontinued from study because: NDA approved for indication Development of indication discontinued by Other (specify) a. Patient did not return for treatment or refused treatment. b. Patient experienced clinically significant symptoms. c. Patient presented clinically significant laboratory or physical abnormality. d. Patient deviated from protocol. e. Patient experienced deterioration in disease status (i.e., increase in seizures) f. Pregnancy. g. Death. h. Other. _____________________ ______________________________

NoO

a. b. c. Unk.

5. Comments

M.D. Edited by

624

Date

Date

Investigator s Signature

G.1.14

Clinical Report Form Drug Identification Indication Visit Page 1 of

PATIENT SUMMARY

/ First

Discontinued Study

Final Dose

Patient Initials Mo

Middle Last

/

/ Day

Yr

Mo

/ Day

Yr

CIRCLE ONE REASON (1-18) FOR DISCONTINUATION FROM STUDY Protocol Complete

1 = Patient Completed Protocol (No Other Reason Applies)

Event necessitated discontinuation

2 = Adverse Event

Death*

3 = Study Disease 4 = Other

Date of Death

/ Mo

/ Day

Autopsy Performed 1 = Yes Yr 2 = No 3 = Unknown

If reason for discontinuation is 2 or 4, complete the following information from the RECORD OF EVENTS section. (ONLY ONE TERM, THE PRIMARY EVENT, SHOULD BE LISTED). Classification Term

_____ _____—

Event Number

Visit Number

’Contact immediately in event of death. Obtain a copy of the autopsy report and the death certificate and/or hospital discharge summary. Forward to as soon as possible. Explain the circumstances of the death in the Study Summary Comments.

G.l.15.1

625

Clinical Report Form Drug Identification Indication

Visit Page 2 of

PATIENT SUMMARY CONTINUED

5 = Patient Perception

Satisfactory Response

6 = Physician Perception 7 = Both

8 = Patient Perception

Lack of Efficacy

9 = Physician Perception 10 = Both

Lost to Follow-up

11 = Unable to Contact Patient

Patient Decision

12 = Moved 13 = Personal Conflict 14 = Other (Please Specify)

15 = Entry Criteria Not Met

Protocol Requirements

16 = Interim Criteria Not Met 17 = Variance

18 = Clinical Relapse

Relapse

626

G.l.15.2

PROT. NO.

PATIENT INITIALS

ALLOC. NO.

please print or write clearly

OUTCOME CLINICAL EVALUATION

BACTERIOLOGIC EVALUATION

Bacteriologic cure

Positive clinical response

Bacteriologic cure with superinfection

Mixed clinical response

Bacteriologic cure with colonization

Failure

Bacteriologic cure with relapse

Not evaluable

Bacteriologic cure with resistance

Reason

_________________________

Bacteriologic failure Bacteriologic failure with superinfection Bacteriologic failure with resistance Not evaluable Did the patient expire during the study period? YES

NO

If yes, cause of death: ----------------------------------------------------Date of death: Was an autopsy performed?

YES

NO

If possible, please a t t a c h autopsy report

G.1.16

627

Protocol No. Subject No.:

Subject Initials:

DISCONTINUATION/COMPLETION INFORMATION

DID THE SUBJECT WITHDRAW FROM THE THERAPY PREMATURELY? 1 No

D

2

Yes

D

3

Unknown (Lost to Follow-up)

IF YES, SPECIFY REASON

_____________

10 Adverse experience, specify 20 Resistant pathogen 30 Clinical (symptomatic) failure

□

40

Presumptive diagnosis unconfirmed (no initial pathogen)

50

Personal reason

60

Other; specify

INVESTIGATOR’S STATEMENT I certify that: I have carefully examined and verified all entries o n this case record form. All information entered onto these forms by myself and/or my associates is correct.

Investigator’s Signature

628

Date

G.1.I7

Protocol No. Investigator’s No.:

Subject No.:

Subject Initials:

DISCONTINUATION REPORT DISCONTINUATION/COMPLETION INFORMATION DATE LAST MEDICATION TAKEN:

/

/

Month

Day

DID SUBJECT COMPLETE THE STUDY?

□,

LAST CYCLE: Year

No

Q

2

Yes

IN NO, SPECIFY REASON FOR DISCONTINUATION: 1

Personal Reason

2 Adverse Experience, specify 3

Protocol Violation, specify

□

4

Lost to Follow-up

□

5

Pregnancy: LMP:

/ Month

6

___________________________________________________________________

Other, specify

/ Day

Estimated Date of Conception: Year

/ Month

Year

__ _________________________________________________________________

Comments:

_ ______ _

DATE O F NEXT BLEEDING AFTER DISCONTINUATION O F STUDY DRUG:

/ Month

DURATION O F BLEEDING:

/ Day

/ Day

Year

DAYS SCHEDULE THREE MONTH POSTTREATMENT CONTACT DATE

INVESTIGATOR SIGNATURE

G.1.18

629

CLINICAL SUMMARY Inv. No.

Protocol

Pt. No.

Pt. Initials

Month

{First. Middle. Last)

Did patient complete the study?

Date

I I No

Day

I I Yes

If not how long did the patient participate? If no, please specify the reason patient failed to complete the study: O

non compliance

Q

lost to follow-up adverse event (please explain) exacerbation of signs/symptoms (please explain) intercurrent illness (please explain) blood pressure did not qualify other

(Date patient began placebo run-in)

*Date study treatment started: Month

Day

Year

Month

Day

Year

Date study treatment stopped:

G.1.19

630

Year

DISCHARGE EVALUATION Inv. No.

Protocol

Pt. Initials

Pt. No.

Date Month

(First. Middle, Last)

Day

Year

Clinical Response 1 = Success - No clinical evidence o f systemic or wound infection occurring as a result o f the surgical procedure during the hospitalized post-operative course. 2 = Failure - Clinical evidence (wound inflammation, edema, erythema, formation of abscesses, local purulence) of wound infection believed t o be related t o the surgical procedure during the hospitalized post-operative course. If failure, was infection: or or or

Superficial (located above fascia)

( 1)

Deep (located below fascia)

(2)

Both

(3)

Indeterminate (degree o f involvement unclear)

(4)

Clinical Evaluability 1 = Evaluable 2 = Nonevaluable (specify below) cement and irrigation) timing

number of doses

Bacterioloqic Response 1 = Success - No pathogens identified during the hospitalized post-operative course. 2 = Failure - Identification o f a significant pathogen(s) from wound drainage or body fluid i n patients w i t h n o other source of infection. Bacterioloqic Evaluability 1 = Evaluable 2 = Nonevaluable (specify below) L U Concurrent administration of NON-STUDY antibiotic (including additions to bone cement and irrigation) I I Improper administration of study drug timing number of doses □

Patient withdrew from study for reasons not related t o an adverse event

G.1.20

631

Page Vlisit

Date (M/D/Y)

Study Site

Investigator Name

Subject’s Study Number

LI

Ml

Subject’s First Name

COMPLIANCE WITHDRAWAL No | |

Yes | | 1)

□

Was the subject in compliance with protocol stipulations and the medication schedule? If no, please comment:

2) Was the subject withdrawn from the study? If yes, Date: -----Z — Z — Time:

M

D

Y

MT

Reason: -----------------------------------------------------------------------------------------------------------------------

DISCHARGE INFORMATION

Time

Date of Discharge:

Discharge:

FOLLOW-UP INFORMATION (Approximately 1 Week After Discharge) No I |

Yes | |

Was subject contacted to determine health status? If yes, Date Contacted:

—— Z - —■

M

D

Y

Comments:

G.1.21

632

MT

D O NOT WRITE IN SCREENED AREAS PATIENT IDENTIFICATION I.D. NO. INITIALS !

INVESTIGATOR

PROJECT N O

STUDY EDP NO.

PT. EDP NO.

TREATMENT OUTCOME (To be completed for all patients) □ L

STUDY COMPLETED YR. DAY MO.

THERAPY COMPLETED

(Patient completed full course of therapy) PREMATURE TERMINATION OF TREATMENT (For only those patients who did not complete full course of study) REASON FOR PREMATURE TERMINATION OF TREATMENT

□ A

DATE TERMINATED DAY YR.

MO.

(Check appropriate category) ADVERSE EXPERIENCES If Laboratory, specify test If Clinical, specify

□ B

INSUFFICIENT THERAPEUTIC RESPONSE

□ C

EARLY IMPROVEMENT

□ D

REFUSED TREATMENT

□ E

DIED DURING STUDY

□ F

FAILURE TO RETURN FOR FOLLOW-UP

□ G

DID NOT COOPERATE

□ H

PROTOCOL VIOLATION

□I

ENTRY VIOLATION

□ J

INTERCURRENT ILLNESS

□ K

ADMINISTRATIVE/OTHER

If therapy terminated early, explain briefly:

G.1.22

633

D O N O T WRITE I N SCREENED AREAS INVESTIGATOR

PATIENT IDENTIFICATION I.D. NO. INITIALS I I I I

STUDY EDP NO

PROJECT NO.

(Check one)

TREATMENT OUTCOME

DATE MO. i DAY I I I I I I I

TERMINATED EARLY (Give reason below)

COMPLETED STUDY

CONTINUING

EJL

YR.

(Check appropriate category)

REASON FOR EARLY TERMINATION OF TREATMENT A

P t EDP NO.

ADVERSE EXPERIENCES

F

FAILURE T O RETURN FOR FOLLOW-UP

H

PROTOCOL VIOLATION

_ _ _ _________________ (Specify)

(If Laboratory, specify test)

(If Clinical, specify) B

TREATMENT FAILURE

J

INTERCURRENT ILLNESS

_____________________ (Specify)

E

PATIENT DEATH (Specify below)

K

ADMINISTRATIVE/OTHER

_____________________ (Specify)

TERMINATION

MAINTENANCE

E N D O F INDUCTION

(Check one')

["RESPONSE

(CheciTonej

DISEASE RESPONSE AT TIME OF

1

[

PD 04

S Q3

MR D6

PR D2

CR □!

PATIENT DEATH REPORT

111■ II ill

DRUG

PROTOCOL NO.

Sis

i

j

DRUG C O D E NO.

AGE

SEX (Check one)

CHECK IF N O N E

MALE

DATE O F DEATH MO. I DAY I YR.

FEMALE D2

1

I I

I I

I

I

lliill

■ WAS AUTOPSY PERFORMED? (Check one) NO

YES

1

2

PRIMARY DIAGNOSIS (Immediate cause of death)

UNDERLYING CAUSE(S) OF DEATH

(Check one)

RELATIONSHIP O F TEST DRUG T O PATIENT DEATH N O T RELATED □1 PRELIMINARY REPORT

POSSIBLE

REMOTE

05

04

PROBABLE D6

FINAL REPORT (Supersedes preliminary report)

634

G.1.23

D O NOT WRITE IN SCREENED AREAS INVESTIGATOR

PATIENT IDENTIFICATION I.D. NO. INITIALS I

PROJECT NO,

I I

TREATMENT OUTCOME (To b e completed for all patients)

L

STUDY COMPLETED MO. I DAY I YR. I I l I

THERAPY COMPLETED (Patient completed full course of therapy) PREMATURE TERMINATION OF TREATMENT (For only those patients w h o did not complete full course o f study)

REASON FOR PREMATURE TERMINATION OF TREATMENT

DATE TERMINATED MO. I DAY I YR. I I I I

(Check appropriate category)

F

ADVERSE EXPERIENCES

A

FAILURE TO RETURN FOR FOLLOW-UP

(If Laboratory specify test) G DID NOT COOPERATE (If Clinical, specify) QH

INSUFFICIENT THERAPEUTIC RESPONSE

B

PROTOCOL VIOLATIC~)N

____ (Specify)

C EARLY IMPROVEMENT

1

ENTRY VIOLATION

D REFUSED TREATMENT

J

INTERCURRENT ILLN ESS ___________________ (Specify)

K

ADMINISTRATIVE/OTIHER ___________________ (Specify)

DIED DURING STUDY

E

(Specify)

I N CASE O F PATIENT DEATH DID PATIENT DIE DURING TREATMENT OR UP TO 2 WEEKS POST THERAPY

DATE OF DEATH MO. I DAY I YR. I I I I

YES NO 0 2 1 WAS AUTOPSY PERFORMED YES NO

1

2

If yes, give findings

CAUSE OF DEATH (Presumption, if no autopsy)

RELATIONSHIP O F TEST DRUG TO PATIENT DEATH REMOTE UNRELATED 4 1

POSSIBLE 5

COMMENTS (Date a n d sign all comments)

PROBABLE 0 6 CHECK IF NONE

G.1.24

635

D O NOT WRITE IN SCREENED AREAS INVESTIGATOR

PATIENT IDENTIFICATION INITIALS 1 I.D. NO.

PROJECT NO.

STUDY £DP N O

PT. EDP NO.

1 1

TREATMENT OUTCOME

(Check one)

DID PATIENT COMPLETE FULL STUDY? YES NO IF NO, PLEASE COMPLETE FOLLOWING SECTION O N PREMATURE TERMINATION OF TREATMENT

REASONS AND DEFINITIONS FOR PREMATURE TERMINATION O F TREATMENT

(DROPOUTS) Check the box which explains why patient did not complete full study. A

STUDY COMPLETED MO. I DAY I YR. 1 1 1 1 DATE TERMINATED MO. I DAY I YR. 1 1 1 1 i i

ADVERSE EXPERIENCES

Drug-related (remote, possible, or probable) side effects (clinical or laboratory) prompted premature termination of test drug. If Laboratory, specify test

________________________________________

If Clinical, specify _______________________________________________ B

INSUFFICIENT THERAPEUTIC RESPONSE

The test drug did not satisfactorily effect a therapeutic benefit (efficacy failure, as distinguished from toxicity failure) and the patient and/or investigator therefore chose to terminate test drug prematurely. c

EARLY IMPROVEMENT

Disease under study remitted prior to completion of the prescribed course of test drug treatment, no longer justifying continued test drug intake. This does not imply that the remission was related to the test drug; it may have been spontaneous or related to other factors. D

REFUSED TREATMENT

Patient refuses medication for non-medical reasons, or for reasons the physician deems insufficient to warrant termination. E F

DIED DURING STUDY FAILURE TO RETURN FOR FOLLOW-UP

The patient did not return for the follow-up visit(s) following dispensing of test drug. G H

DID NOT COOPERATE PROTOCOL VIOLATION

The patient’s findings or conduct failed to meet the protocol entry criteria or failed to adhere to the protocol requirements. The violation necessitated premature dropout from the study. (Specify)

I

ENTRY VIOLATION (Specify) ------------------------------------------------------------------

J

INTERCURRENT ILLNESS

A disease (other than the primary diagnosis) became apparent (may have pre-existed baseline) during test drug treatment and necessitated premature test drug termination. (Specify)

K

ADMINISTRATIVE/OTHER

Causes of premature termination from test drug other than the above, such as illness of investigator, theft or loss of study drugs, termination of study b y sponsor, etc. (Specify)

636

G.1.25

WITHDRAWALS AND DROPOUTS/CLINICAL SUMMARY Inv. No.

Protocol

Pt. Initials

Pt. No.

Enrollment

WITHDRAWALS AND DROPOUTS

Did the patient complete the first part of the study (through the one month follow-up visit)? Yes

No

□□□□□□

I f no, please indicate the reason: Treatment Failure

Adverse Event Did not return Non-compliance (urine) ____________________________

Protocol violation, specify Other

Date o f withdrawal : Month

Day

Year

Did the patient complete the entire study (through the one year follow-up visit)? O No

Q

Yes

If no, please indicate the reason: ZZJ Lost t o follow-up ZZJ Developed signs and symptoms of early Lyme disease due t o CU recurrence or

C

reinfection

Z ] Protocol violation, specify _________________________ Z J Other Date o f withdrawal : Month

Day

Year

CLINICAL SUMMARY

Please provide any observations or information that would assist the reviewer i n evaluating

G.1.26

637

WITHDRAWALS AND DROPOUTS/CLINICAL SUMMARY Inv. No.

Protocol

Pt. No.

Pt. nitials

_____

WITHDRAWALS AND DROPOUTS Did the patient complete 10 days of treatment?

| | No

Did the patient complete the study?

| | Yes

| | No

| | Yes

If n o to either, please indicate the category as defined below: (Check one)

□□□□□□

Treatment Failure

Adverse Event

Unable t o Take Medication Did not return

Recurrence prior t o study completion

Other (specify below):

Date of withdrawal:

FOLLOW-UP MEDICATIONS (Check one) QNo

Yes

If yes, please specify (one per line) Medication

Date Started Indication For Use

Please Print

Mo

Day

Yr

11I I 1 I I 1 I I 11111 CLINICAL SUMMARY Please give a brief summary of the patient's clinical course while participating i n this study. Please attach additional pages i f needed.

638

G.1.27

Page 1 o f 1

FOLLOW-UP FORM 00 - DISPENSATION OF PROTOCOL TREATMENT

D a t e Form Completed:

Pat l e n t Number :

(dd/mm/yy) Study ID:

Subun I t Code :

S t u d y Week:

Key O p e r a t o r Code:

Has t h e p r o t o c o l t r e a t m e n t been d i s p e n s e d

I f Y e s , d a t e P r o t o c o l Treatment f i r s t

Y

d i s p e n s e d (dd/mmm/yy) :

/

N

/

I f No, g i v e r e a s o n s : Patient refused

Y

N

P a t i e n t no-show

Y

N

Patient Inadvertent ly enrol led ( o p e r a t o r e r r o r i n use o f RANDOMIZ program)

Y

N

Treatment c o n t r a i n d i c a t e d

Y

N

Patient died

Y

N

Other

Y

N

I f o t h e r ( spec I f y )

Continue to follow the patient (except those Inadvertently enrolled) I f p o s s i b l e u s i n g FF1700 - D i s c o n t i n u e d f r o m Treatment F o l l o w u p o r the appropriate study specific followup form (If applicable) for the p e r i o d o f t i m e and a t t h e f r e q u e n c y s p e c i f i e d by t h e p r o t o c o l .

G.1.28

639

STUDY

FORM 4 - STUDY DRUG TERMINATION

P a t i e n t Number:

Page 1 o f 1

Date Drug Permanently Stopped (dd/mm/yy):

Study ID:

Subunit Code:

Study Week:

Key Operator Code:

/

/

Reason(s) for permanent study drug t e r m i n a t i o n : ( C i r c l e Y t o a l l t h a t a p p l y ) 1.

P a t i e n t I n i t i a t e d withdrawal? I f Yes, e x p l a i n

Y

N

2.

Advice o f physician?

Y

N

3.

Adverse experience r e q u i r i n g drug t e r m i n a t i o n as r e q u i r e d by t h e p r o t o c o l ? . . . Y

N

4.

P a t i e n t noncomp 1 1ance w i t h study treatment? Y I f Yes, e x p l a i n ______________________________________

N

5.

P a t i e n t l o s t t o follow-up?

Y

N

6.

Development o f AIDS-def I n I n g condition? I f Yes, complete 6a. Opportunistic Infection? 6 b . Neoplasm? 6 c . Other?

Y

N

Y

N

................................... Y

N

Y Y Y

N N N

7.

Development o f severe ARC and e l i g i b l e for p r e s c r i p t i o n ZDV?

8.

Pregnancy d u r i n g study p e r i o d ? . . . . .

9.

Completion o f p r o t o c o l ?

Y

N

10.

Unauthorized use o f o t h e r antl-AIDS drug?

Y

N

11.

a.

Death? Y N b. I f Yes, complete CAUSE OF DEATH FORM (FF1400)

c.

Autopsy performed? I f Yes, complete AUTOPSY/DEATH FORM (FF1300)

12.

Date (dd/mmm/yy): Y

Other?.................................................................... ..................................................................... Y I f Yes , spec I f y ___________________________________

G.1.29

/

N

A l l p a t i e n t s permanently discontinued from study drug a r e t o be f o l l o w e d a t monthly i n t e r v a l s u n t i l f i n a l a n a l y s i s o r death. Use ADVANCED ARC/AIDS DIAGNOSIS (SF1902) t o record f o l l o w - u p data f o r each contact o r v i s i t .

640

/

N

STUDY

3 - FOLLOW-UP MEDICATION HISTORY

Page 1 o f 2

Date o f Pat l e n t V i s i t :

P a t i e n t Number:

(dd/mm/yy ) Subunit Code:

Key Operator Code:

T h i s form must be completed a t each scheduled p r o t o c o l v i s i t w h i l e t h e p a t i e n t remains o n study d r u g .

Instructions:

1 . Has study d r u g been d i s c o n t i n u e d permanently?

Y

N

Y

N

I f Yes: Be sure t o complete STUDY DRUG TERMINATION (SF19O4) and f o l l o w t h e p a t i e n t a t r e g u l a r I n t e r v a l s as s p e c i f i e d by by t h e p r o t o c o l . 2 . I f t h e p a t i e n t remains o n s t u d y d r u g , e n t e r t h e a p p r o p r i a t e numeric code for t h e dose p r e s c r i b e d a t t h i s v i s i t :

STUDY DRUG CODES 0 » F u l I Dose 1 - Step 1 M o d i f i c a t i o n 2 « Step 2 M o d i f i c a t i o n

3 . Has the p a t i e n t taken any concomitant m e d i c a t i o n s s i n c e the p r e v i o u s scheduled p r o t o c o l v i s i t ? I f Yes:

L i s t m e d i c a t i o n s w i t h a p p r o p r i a t e drug codes i n t h e space p r o v i d e d b e l o w . ( E n t e r - 1 i n t h e drug code f i e l d o n t h e l i n e f o l l o w i n g the l a s t e n t r y . ) DRUG CODE (See Appendix I I I )

a)

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DRUG NAME ; ; m«aa«aa»wa«aBaaaamaaaaa«aia«anaan

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