Title (Use Title Case)

Title (use title case)

Sponsored by:

Pharmaceutical Support Provided by: (if applicable)

IND # or non-IND Protocol

Protocol Chair:

Protocol Co-Chair(s):

Protocol Vice Chair(s):

Clinical Trials Specialist:

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CONTENTS

SITES PARTICIPATING IN THE STUDY...... 4 PROTOCOL TEAM ROSTER...... 5 STUDY MANAGEMENT...... 6 ACRONYMS/ABBREVIATIONS...... 6 SCHEMA...... 7

1.0 HYPOTHESIS AND STUDY OBJECTIVES...... 8 1.1 Hypothesis...... 8 1.2 Primary Objective(s)...... 8 1.3 Secondary Objectives...... 8 1.4 Substudy Objectives...... 8

2.0 INTRODUCTION...... 8 2.1 Background...... 8 2.2 Rationale...... 8

3.0 STUDY DESIGN...... 8

4.0 SELECTION AND ENROLLMENT OF SUBJECTS...... 8 4.1 Inclusion Criteria...... 8 4.2 Exclusion Criteria...... 8 4.3 Study Enrollment ProceduresG...... 9 4.4 Substudy Enrollment Procedures (as required)...... 9 4.5 Coenrollment Guidelines (as required)...... 9

5.0 STUDY TREATMENT (OR INTERVENTION)...... 10 5.1 Regimens (or Intervention), Administration, and Duration...... 10 5.2 Study Product Formulation and Preparation...... 10 5.3 Product Supply, Distribution, and Accountability...... 10 5.4 Concomitant Medications...... 10 5.5 Adherence Assessment (as required)...... 10

6.0 CLINICAL AND LABORATORY EVALUATIONS...... 11 6.1 Schedule of Events...... 11 6.2 Timing of Evaluations...... 12 6.3 Instructions for Evaluations...... 13

7.0 CLINICAL MANAGEMENT ISSUES...... 15 7.1 Toxicity...... 15 7.2 Other Diseases...... 15 7.3 Pregnancy...... 15 7.4 Breast-feeding (if applicable)...... 15 A____ DRAFT Version 0.X MM/DD/YY

CONTENTS (Cont’d) Page

8.0 CRITERIA FOR DISCONTINUATION...... 15 8.1 Permanent Treatment Discontinuation...... 15 8.2 Premature Study Discontinuation...... 16

9.0 STATISTICAL CONSIDERATIONS...... 16 9.1 General Design Issues...... 16 9.2 Endpoints...... 16 9.3 Randomization and Stratification...... 16 9.4 Sample Size and Accrual...... 16 9.5 Monitoring...... 16 9.6 Analyses...... 16

10.0 PHARMACOLOGY PLAN...... 16 10.1 Pharmacology Objectives...... 17 10.2 Pharmacology Study Design...... 17 10.3 Primary and Secondary Data, Modeling, and Data Analysis...... 17 10.4 Anticipated Outcomes...... 17

11.0 DATA COLLECTION AND MONITORING AND ADVERSE EVENT REPORTING ...... 17 11.1 Records to Be Kept...... 17 11.2 Role of Data Management...... 17 11.3 Clinical Site Monitoring and Record Availability...... 17 11.4 Expedited Adverse Event Reporting to ...... 18

12.0 HUMAN SUBJECTS...... 18 12.1 Institutional Review Board (IRB) Review and Informed Consent...... 18 12.2 Subject Confidentiality...... 19 12.3 Study Discontinuation...... 19

13.0 PUBLICATION OF RESEARCH FINDINGS...... 19

14.0 BIOHAZARD CONTAINMENT...... 19

15.0 REFERENCES...... 20

APPENDIX I...... 21

APPENDIX X: SAMPLE INFORMED CONSENT (always last) 4 A____ DRAFT Version 0.X MM/DD/YY

SITES PARTICIPATING IN THE STUDY

Sites Participating in the Main Study (remove Main if no substudy) 5 DRAFT Version 0.X MM/DD/YY

PROTOCOL TEAM ROSTER

Chair Consultant(s) to the Protocol Team (optional) Co-Chairs Laboratory Data Coordinator Vice Chair(s)

Clinical Representative (if appointed)

(Appropriate) Branch Phone: FAX: E-Mail:

Clinical Trials Specialist

Statistician(s)

Scientific Committee Representative (if assigned)

Data Manager

Pharmacist

Immunologist (optional)

Virologist (optional)

Neurologist (optional)

Pharmacologist (optional)

Neuropsychologist (optional)

Investigators (optional)

Field Representative

Laboratory Technologist

Industry Representative(s) (if appropriate) DRAFT Version 0.X MM/DD/YY

STUDY MANAGEMENT

ACRONYMS/ABBREVIATIONS 7 DRAFT Version 0.X MM/DD/YY

SCHEMA

XXXX Title

DESIGN

DURATION

SAMPLE SIZE

POPULATION

STRATIFICATION (as required)

REGIMEN OR INTERVENTION (as required)

SUBSTUDIES (as required) 8 DRAFT Version 0.X MM/DD/YY

1.0 HYPOTHESIS AND STUDY OBJECTIVES

1.1 Hypothesis

1.2 Primary Objective(s)

1.3 Secondary Objectives

1.4 Substudy Objectives (as required)

2.0 INTRODUCTION

2.1 Background

2.2 Rationale

3.0 STUDY DESIGN

4.0 SELECTION AND ENROLLMENT OF SUBJECTS

4.1 Inclusion Criteria

4.2 Exclusion Criteria

4.2.1 Clinical contraindications

4.2.2 Breast-feeding

4.2.3 Excluded medications

4.2.4 Known allergy/sensitivity or any hypersensitivity to components of study drug(s) or their formulation

4.2.5 Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements

4.2.6 Serious illness requiring systemic treatment and/or hospitalization within XX days prior to entry 9 DRAFT Version 0.X MM/DD/YY

4.3 Study Enrollment Procedures

4.3.1 Prior to implementation of this protocol, sites must have the protocol and protocol consent form(s) approved by their local institutional review board (IRB).

Once a candidate for study entry has been identified, details will be carefully discussed with the subject. The subject (or, when necessary, the parent or legal guardian if the subject is younger than 18 years of age or under guardianship) will be asked to read and sign the approved protocol consent form.

4.3.2 Prisoner Participation

The Division of has concluded that this protocol does NOT meet Federal requirements governing prisoner participation in clinical trials and should NOT be considered by local IRBs for the recruitment of prisoners. OR The Division of has concluded that this protocol meets Federal requirements governing prisoner participation in clinical trials (45.CFR 46.306). Local IRBs have the final decision as to whether prisoners may participate in the study. Sites should refer to the Division of Policy and Procedures Manual before submitting the protocol to the IRB.

4.3.3 Randomization/Registration

For subjects from whom informed consent has been obtained, but who are deemed ineligible or who do not enroll into the initial protocol step, an Screening Failure Results form must be completed and keyed into the database. [Not required for amending protocols.]

4.4 Substudy Enrollment Procedures (as required)

4.5 Coenrollment Guidelines (as required)

Sites are strongly encouraged to coenroll subjects in A5128. Coenrollment in A5128, “Plan for Obtaining Informed Consent to Use Stored Human Biological Materials (HBM) for Currently Unspecified Analyses,” does not require permission from the AXXXX protocol chairs. For specific questions and approval for coenrollment in other studies, sites must contact the protocol chairs via e-mail as described in the Study Management section. 10 DRAFT Version 0.X MM/DD/YY

5.0 STUDY TREATMENT (OR INTERVENTION)

5.1 Regimens ( or Intervention ), Administration, and Duration

5.2 Study Product Formulation and Preparation

5.3 Pharmacy: Product Supply, Distribution, and Accountability

5.3.1 Study Product Acquisition

(Insert name of study product and provider) will be available through the Clinical Research Products Management Center. The pharmacist can obtain the study product(s) for this protocol by following the instructions in the manual Pharmacy Guidelines and Instructions for Clinical Trials Networks in the section Study Product Control.

5.3.2 Study Product Accountability

The pharmacist is required to maintain complete records of all study products received from the Clinical Research Products Management Center and subsequently dispensed. All unused study products must be returned to the Clinical Research Products Management Center (or as otherwise directed by the sponsor) after the study is completed or terminated. The procedures to be followed are provided in the manual Pharmacy Guidelines and Instructions for Clinical Trials Networks in the section Study Product Control.

5.4 Concomitant Medications

Below (is a list/are lists) of selected concomitant medications. (This/These) list(s) is/are) only current as of the date of this protocol. Therefore, whenever a concomitant medication or study agent is initiated or a dose changed, investigators must review the concomitant medications’ and study agents' most recent package inserts, Investigator’s Brochures, or updated information from to obtain the most current information on drug interactions, contraindications, and precautions.

5.4.1 Required Medications

5.4.2 Prohibited Medications

5.4.3 Precautionary Medications

5.5 Adherence Assessment ( as required ) 11 DRAFT Version 0.X MM/DD/YY

6.0 CLINICAL AND LABORATORY EVALUATIONS

6.1 Schedule of Events Post-Entry Evaluations (Weeks) Evaluation Screening Pre-Entry Entry 4 8 12 16 20 24 32 40 48 Discontinuation Evals. Documentation of HIV Medical History/Medication History Clinical Assessment Hematology Liver Function Tests Chemistry Urinalysis Pregnancy Testing

Stored Plasma/PBMC/Serum Metabolic Studies Pharmacokinetic Studies Questionnaires Substudy Evaluations 12 DRAFT Version 0.X MM/DD/YY

6.2 Timing of Evaluations

6.2.1 Screening and Pre-Entry Evaluations

Screening and pre-entry evaluations must occur prior to the subject’s starting any study medications, treatments, or interventions.

Screening

Screening evaluations to determine eligibility must be completed within XX days [30-45 for example] prior to study entry unless otherwise specified.

In addition to data being collected on subjects who enroll into the study, demographic, clinical, and laboratory data on screening failures will be captured in a screening log and entered into the database. [Not required for amending protocols.]

Pre-Entry (as required)

Pre-entry evaluations must be completed at least XX days [or XX hours] after screening evaluations have been completed and at least XX days [or XX hours] prior to entry evaluations unless otherwise specified.

6.2.2 Entry Evaluations

Entry evaluations must occur XX hours [e.g., at least 24 hours] after pre- entry/screening evaluations unless otherwise specified. Subject must begin treatment within XX days [or XX hours] after registration/randomization.

6.2.3 Post-Entry Evaluations

On-Treatment Evaluations (as required)

Post-Treatment Evaluations (as required)

Study Completion Evaluations (as required)

Event-Driven Evaluations (as required)

6.2.4 Discontinuation Evaluations

Evaluations for Randomized or Registered Subjects Who Do Not Start Study Treatment

All CRFs must be completed and keyed for the period up to and including week 0.

Premature Treatment Discontinuation Evaluations (as required) 13 DRAFT Version 0.X MM/DD/YY

Premature Study Discontinuation Evaluations (as required)

6.3 Instructions for Evaluations

All clinical and laboratory information required by this protocol is to be present in the source documents. Sites must refer to the Source Document Guidelines on the

All stated evaluations are to be recorded on the CRF and keyed into the database unless otherwise specified.

6.3.1 Documentation of medical condition

6.3.2 Medical History

The medical history must include all diagnoses identified by the criteria for clinical events and other diagnoses. [Team may wish to specify additional events not included in the criteria.] For current criteria, refer to the appendix identified in the study CRF. Any allergies to any medications and their formulations must be documented.

6.3.3 Medication History

A medication history must be present, including start and stop dates. The table below lists the medications that must be included in the history. [See the table in section 6.3.3 of the Guidelines.]

6.3.4 Clinical Assessments

Complete Physical Exam A complete physical examination (indicate timeframe, e.g. prior to entry and at time points indicated on schedule) is to include at a minimum an examination of the skin, head, mouth, and neck; auscultation of the chest; cardiac exam; abdominal exam; examination of the lower extremities for edema; and Karnofsky performance test. The complete physical exam will also include signs and symptoms, diagnoses, and vital signs (temperature, pulse, respiration rate, and blood pressure).

Targeted Physical Exam A targeted physical examination is to include vital signs (temperature, pulse, respiration rate, and blood pressure) and is to be driven by any previously identified or new signs or symptoms including diagnoses that the subject has experienced within [XX days prior to entry/since the last visit].

Height

Weight 14 DRAFT Version 0.X MM/DD/YY

Signs and Symptoms At entry, all grades that occurred XX days before entry must be recorded; post- entry, only signs and symptoms Grade [X] must be recorded. Record all signs and symptoms that led to a change in treatment, regardless of grade.

Diagnoses Record all diagnoses identified by the criteria for clinical events and other diseases. (The team may wish to include additional events not specified by the criteria.)

Concomitant Medications Record (insert concomitant medications for the CRF).

The following [insert targeted concomitant medications] must be present only in the source documents.

Study Treatment ( Intervention ) Modifications Record all study drug modifications, including initial doses, subject-initiated and/or protocol-mandated modifications, inadvertent and deliberate interruptions at each visit [or specify visits]. Record any permanent discontinuation of treatment.

6.3.5 Laboratory Evaluations

At screening, pre-entry, and entry all laboratory values must be recorded. For post-entry assessments, record all Grade [X] laboratory values. All laboratory toxicities that led to a change in treatment, regardless of grade, must be recorded. [Team to specify required tests.]

Hematology

PT, PTT (as required)

Liver Function Tests

Blood Chemistries

Urinalysis [Specify whether a microscopic exam is required.]

Pregnancy Test For women with reproductive potential: Serum or urine -HCG (urine test must have a sensitivity of 25-50 mIU/mL). 15 DRAFT Version 0.X MM/DD/YY

6.3.6 Specialty Assays (e.g. Immunology Studies)

6.3.7 Additional Specialty Assays

6.3.8 Metabolic Studies

6.3.9 Pharmacokinetic Studies [See section 10.0, Pharmacology Plan.]

6.3.10 Other Laboratory Studies

6.3.11 Procedures

[See Protocol Development Guidelines for a list of possible procedures.]

6.3.12 Questionnaires

6.3.13 Substudies

7.0 CLINICAL MANAGEMENT ISSUES

7.1 Toxicity

7.2 Other Diseases

7.3 Pregnancy

7.4 Breast-feeding (if applicable)

8.0 CRITERIA FOR DISCONTINUATION

8.1 Permanent Treatment Discontinuation

 Drug-related toxicity  Requirement for prohibited concomitant medications (see section 5.4).  Pregnancy or breast-feeding (if applicable).  Reaching a defined clinical endpoint (as applicable).  Completion of treatment as defined in the protocol.  Request by subject to terminate treatment.  Clinical reasons believed life threatening by the physician, even if not addressed in the toxicity section of the protocol. 16 DRAFT Version 0.X MM/DD/YY

8.2 Premature Study Discontinuation

 Failure by the subject to attend [XX] consecutive clinic visits.  Subject repeatedly noncompliant [team should define, e.g., % on average] with study medications as prescribed.  Pregnancy or breast-feeding (if applicable).  Request by the subject to withdraw.  Request of the primary care provider if s/he thinks the study is no longer in the best interest of the subject.  Subject judged by the investigator to be at significant risk of failing to comply with the provisions of the protocol as to cause harm to self or seriously interfere with the validity of the study results.  A defined study endpoint reached (if applicable).  At the discretion of the , IRB, Food and Drug Administration (FDA), Office for Human Research Protections (OHRP), , investigator, or pharmaceutical supporter. (If a non-IND study, remove “Food and Drug Administration (FDA)”; if no pharmaceutical support, remove “pharmaceutical supporter” from this bullet.)

9.0 STATISTICAL CONSIDERATIONS (Provided by the SDAC statistician.)

9.1 General Design Issues

9.2 Endpoints

9.2.1 Primary Endpoints (including definitions)

9.2.2 Secondary Endpoints (including definitions)

9.2.3 Substudy Endpoints (as required)

9.3 Randomization and Stratification

9.4 Sample Size and Accrual

(For main study and substudies.)

9.5 Monitoring

9.6 Analyses

10.0 PHARMACOLOGY PLAN

If no Pharmacology Plan, leave heading and add “Not applicable” and delete sections 10.1 - 10.4. 17 DRAFT Version 0.X MM/DD/YY

10.1 Pharmacology Objectives

10.2 Pharmacology Study Design

10.3 Primary and Secondary Data, Modeling, and Data Analysis

10.4 Anticipated Outcomes

11.0 DATA COLLECTION AND MONITORING AND ADVERSE EVENT REPORTING

11.1 Records to Be Kept

Case report forms (CRF) will be provided for each subject. Subjects must not be identified by name on any CRFs. Subjects will be identified by the patient identification number (PID) and study identification number (SID) provided by the Data Management Center upon (randomization/registration).

11.2 Role of Data Management

11.2.1 Instructions concerning the recording of study data on CRFs will be provided by the Data Management Center. Each is responsible for keying the data in a timely fashion.

11.2.2 It is the responsibility of the XXXX to assure the quality of computerized data for each study. This role extends from protocol development to generation of the final study databases.

11.3 Clinical Site Monitoring and Record Availability

11.3.1 Site monitors under contract to the National Institute of Allergy and Infectious Diseases () will visit participating clinical research sites to review the individual subject records, including consent forms, CRFs, supporting data, laboratory specimen records, and medical records (physicians’ progress notes, nurses’ notes, individuals’ hospital charts), to ensure protection of study subjects, compliance with the protocol, and accuracy and completeness of records. The monitors also will inspect sites’ regulatory files to ensure that regulatory requirements are being followed and sites’ pharmacies to review product storage and management.

11.3.2 The site investigator will make study documents (e.g., consent forms, drug distribution forms, CRFs) and pertinent hospital or clinic records readily available for inspection by the local IRB, the site monitors, the FDA, the , the Office for Human Research Protections (OHRP), and the pharmaceutical supporter(s) or designee for confirmation of the study data. [If non-IND, remove “the FDA”; if no pharmaceutical support, remove “pharmaceutical supporter(s) or designee.”] 18 DRAFT Version 0.X MM/DD/YY

11.4 Expedited Adverse Event Reporting to

EAE Reporting Requirements for this Study [The underlined headings below may be removed at protocol development.]

EAE Reporting Level This study uses the [standard, intensive, or targeted] level of expedited AE reporting as defined in the EAE Manual.

Study Agents for Expedited Reporting to The study agents that must be considered in determining relationships of AEs requiring expedited reporting to are [Insert a list of study agent(s) or drug categories.]

Grading Severity of Events

EAE Reporting Periods Adverse events must be reported on an expedited basis at the [standard, intensive, or targeted] level during the protocol-defined EAE Reporting Period, which is [Choose one of the following.]

 The entire study duration for an individual subject (from study enrollment until study completion or discontinuation of the subject from study participation for any reason).

 The entire study duration for an individual subject (from study enrollment until study completion or discontinuation of the subject from study participation for any reason) and for a period of [XX weeks] after the subject’s last study visit has been completed. [NOTE: See Guidelines.]

After the end of the protocol-defined EAE Reporting Period stated above, sites must report serious, unexpected, clinical suspected adverse drug reactions if the study site staff becomes aware of the event on a passive basis, i.e., from publicly available information.

12.0 HUMAN SUBJECTS

12.1 Institutional Review Board (IRB) Review and Informed Consent

This protocol and the informed consent document (Appendix XX) and any subsequent modifications will be reviewed and approved by the IRB or ethics committee responsible for oversight of the study. A signed consent form will be obtained from the subject (or parent, legal guardian, or person with power of attorney for subjects who cannot consent 19 DRAFT Version 0.X MM/DD/YY

for themselves, such as those below the legal age of consent). The consent form will describe the purpose of the study, the procedures to be followed, and the risks and benefits of participation. A copy of the consent form will be given to the subject, parent, or legal guardian, and this fact will be documented in the subject’s record.

12.2 Subject Confidentiality

All laboratory specimens, evaluation forms, reports, and other records that leave the site will be identified by coded number only to maintain subject confidentiality. All records will be kept locked. All computer entry and networking programs will be done with coded numbers only. Clinical information will not be released without written permission of the subject, except as necessary for monitoring by IRB, the FDA, the , the OHRP, or the pharmaceutical supporter(s) or designee. [If a non-IND study, remove “FDA”; if no pharmaceutical support, remove “pharmaceutical supporter or designee.”]

12.3 Study Discontinuation

The study may be discontinued at any time by the IRB, the , the pharmaceutical supporter(s), the FDA, the OHRP, or other government agencies as part of their duties to ensure that research subjects are protected. [If a non-IND study, remove “FDA”; if no pharmaceutical support, remove “pharmaceutical supporter or designee.”]

13.0 PUBLICATION OF RESEARCH FINDINGS

Publication of the results of this trial will be governed by policies. Any presentation, abstract, or manuscript will be made available for review by the pharmaceutical supporter(s) prior to submission. [If no pharmaceutical support, remove the second sentence.]

14.0 BIOHAZARD CONTAINMENT

As the transmission of HIV and other blood-borne pathogens can occur through contact with contaminated needles, blood, and blood products, appropriate blood and secretion precautions will be employed by all personnel in the drawing of blood and shipping and handling of all specimens for this study, as currently recommended by the Centers for Disease Control and Prevention and the National Institutes of Health.

All dangerous goods materials, including diagnostic specimens and infectious substances, must be transported according to the instructions detailed in the International Air Transport Association (IATA) Dangerous Goods Regulations.

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15.0 REFERENCES

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APPENDIX I

This format will allow the title and first page number of each appendix to appear in the Table of Contents.

The Sample Informed Consent will continue to be numbered as it has been (i.e., Page 1 of X).