A Multicenter, Multi-Outbreak, Randomized, Controlled Safety And

2018 Ebola MCM RCT Protocol IND#: 125530 Page 1 of 92 4 October 2019, version 7.0 CONFIDENTIAL A Multicenter, Multi-Outbreak, Randomized, Controlled Safety and Efficacy Study of Investigational Therapeutics for the Treatment of Patients with Ebola Virus Disease Short Title: 2018 Ebola MCM RCT Protocol Sponsored by: Office of Clinical Research Policy and Regulatory Operations (OCRPRO) National Institute of Allergy and Infectious Diseases 5601 Fishers Lane Bethesda, MD 20892 NIH Protocol Number: Protocol IND #: 19-I-0003 125530 ClinicalTrials.gov Number: NCT03719586 Date: Version: 4 October 2019 7.0 CONFIDENTIAL This document is confidential. No part of it may be transmitted, reproduced, published, or used by other persons without prior written authorization from the study sponsor and principal investigator. 2018 Ebola MCM RCT Protocol IND#: 125530 Page 2 of 92 4 October 2019, version 7.0 CONFIDENTIAL KEY ROLES DRC Principal Investigator: Jean-Jacques Muyembe-Tamfum, MD, PhD Director-General, DRC National Institute for Biomedical Research Professor of Microbiology, Kinshasa University Medical School Kinshasa Gombe Democratic Republic of the Congo Phone: +243 898949289 Email: <a href="mailto:[email protected]" target="_blank">[email protected] </a>Other International Investigators: Statistical Lead: see Appendix E Lori Dodd, PhD Biostatistics Research Branch, DCR, NIAID 5601 Fishers Lane, Room 4C31 Rockville, MD 20852 Phone: 240-669-5247 Email: <a href="mailto:[email protected]" target="_blank">[email protected] </a>U.S. Principal Investigator: Data Coordinating Center: Richard T. Davey, Jr., MD Clinical Research Section, LIR, NIAID, NIH Building 10, Room 4-1479, Bethesda, MD 20892-1662 Phone: +1-301-496-8029 Email: [email protected] Clinical Trials Research Section Biostatistics Research Branch Division of Clinical Research, NIAID 5601 Fishers Lane, Room 4C31 Rockville, MD 20852 Federalwide assurance (FWA) numbers: 00005897 (NIH) 00025422 (Kinshasa School of Public Health) Protocol Development Team Steering Committee DSMB see Appendix E see Appendix E see Appendix E see Appendix E Medical Monitors: 2018 Ebola MCM RCT Protocol IND#: 125530 Page 3 of 92 4 October 2019, version 7.0 CONFIDENTIAL Deleted: Deleted: Deleted: Deleted: Deleted Deleted Deleted Deleted Deleted Deleted: Deleted: Deleted: Deleted: Deleted: Deleted: Deleted: Deleted Deleted: Deleted Deleted Deleted Deleted: Deleted: Deleted: Deleted: Deleted: Deleted Deleted: Deleted: Deleted: Deleted Deleted Deleted Deleted: Deleted: Deleted: Deleted: Deleted: Deleted: Deleted: Deleted: Deleted TABLE OF CONTENTS KEY ROLES................................................................................................................................... 2 TABLE OF CONTENTS................................................................................................................ 3 PROTOCOL SUMMARY.............................................................................................................. 8 PRÉCIS......................................................................................................................................... 13 <ul style="display: flex;"><li style="flex:1">1</li><li style="flex:1">BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ............................. 14 </li></ul>Background....................................................................................................................... 14 Filoviruses..................................................................................................................... 14 Transmission and Disease............................................................................................. 14 Latest Outbreaks ........................................................................................................... 15 Therapy ......................................................................................................................... 16 RCT of ZMapp (PREVAIL II) ..................................................................................... 18 Rationale for Study ........................................................................................................... 18 STUDY OBJECTIVES......................................................................................................... 20 Primary Objective............................................................................................................. 20 Secondary Objectives........................................................................................................ 20 Exploratory Objectives ..................................................................................................... 20 STUDY DESIGN.................................................................................................................. 20 General.............................................................................................................................. 20 Extension Phase ............................................................................................................ 23 Study Endpoints................................................................................................................ 23 Primary Endpoint.......................................................................................................... 23 Secondary Endpoints .................................................................................................... 23 Exploratory Endpoints .................................................................................................. 24 Overview of Study Drugs ................................................................................................. 24 Considerations in Choice of Study Drugs......................................................................... 24 Definitions for the Purpose of this Study.......................................................................... 26 STUDY POPULATION....................................................................................................... 26 Research Subject Recruitment.......................................................................................... 26 Participation of Site Employees.................................................................................... 27 Inclusion Criteria .............................................................................................................. 27 Exclusion Criteria ............................................................................................................. 27 Vulnerable Populations..................................................................................................... 27 Pregnant Women........................................................................................................... 27 Inclusion of Children and Neonates.............................................................................. 28 Adults Who Are Unable to Provide Initial or Ongoing Consent.................................. 28 Subject Withdrawal........................................................................................................... 28 Discontinuation of Subject by Investigator....................................................................... 28 Discontinuation of Study .................................................................................................. 29 STUDY PROCEDURES ...................................................................................................... 29 Personnel for Study Procedures........................................................................................ 29 Site-Specific Considerations............................................................................................. 29 Schedule of Evaluations (see also Table 2 below)............................................................ 30 Screening and Informed Consent...................................................................................... 33 Demographics ............................................................................................................... 33 2345Deleted Deleted Deleted Deleted: Deleted Deleted Deleted Deleted: Deleted Deleted: Deleted Deleted Deleted: Deleted Deleted Deleted Deleted Deleted Deleted: Deleted: Deleted: Deleted: Deleted: Deleted: Deleted: Deleted: Deleted Deleted Deleted Deleted: Deleted: Deleted: Deleted: Deleted: Deleted: Deleted: Deleted: Deleted: Deleted: Deleted: Deleted Deleted: Deleted Deleted Deleted: 2018 Ebola MCM RCT Protocol IND#: 125530 Page 4 of 92 4 October 2019, version 7.0 CONFIDENTIAL Medical History ............................................................................................................ 33 Clinical Data ................................................................................................................. 33 Determination of Eligibility.......................................................................................... 33 Day 1................................................................................................................................. 33 Baseline Evaluation ...................................................................................................... 33 Baseline Laboratory Testing......................................................................................... 34 Randomization.............................................................................................................. 35 Study Drug Administration and Pharmacokinetic Sampling............................................ 35 Pharmacokinetic Sampling ........................................................................................... 35 Follow-Up Study Days ..................................................................................................... 35 Follow-up Daily Assessment and oSOC....................................................................... 35 Clinical Safety Laboratory Testing............................................................................... 36 Special Follow-up Assessments........................................................................................ 36 Day of Discharge .......................................................................................................... 36 Day 28........................................................................................................................... 36 Day 58........................................................................................................................... 37 Pregnancy...................................................................................................................... 37 Extended Follow-Up..................................................................................................... 37 STATISTICAL CONSIDERATIONS.................................................................................. 37 Design overview ............................................................................................................... 37 Less strict error rate control.............................................................................................. 37 Study hypotheses and statistical analysis.......................................................................... 38 Power and sample size...................................................................................................... 39 Interim monitoring............................................................................................................ 41 RISKS AND BENEFITS...................................................................................................... 42 Potential Risks .................................................................................................................. 42 Unknown Risks............................................................................................................. 42 Risks of Phlebotomy..................................................................................................... 43 Risks to the Study Personnel and the Environment...................................................... 43 Potential Benefits.............................................................................................................. 43 Alternatives....................................................................................................................... 43 RESEARCH USE OF STORED HUMAN SAMPLES, SPECIMENS, AND DATA ........ 43 Intended Use of the Samples/Specimens/Data ................................................................. 43 Storage of Samples/Specimens/Data ................................................................................ 44 Reporting Loss or Destruction of Samples/Specimens/Data............................................ 44 REMUNERATION PLAN................................................................................................... 44 678910 ASSESSMENT OF SAFETY............................................................................................... 45 Definitions......................................................................................................................... 45 Assessment of Safety........................................................................................................ 46 Investigator Assessment of Serious Adverse Events........................................................ 47 Causality ................................................................................................................... 47 Timing and Scope of (S)AE Collection, and of Assessments and of Reporting Responsibilities to the Sponsor..................................................................................................... 48 Unanticipated Problems............................................................................................ 48 Pregnancy.................................................................................................................. 49 Reporting Procedures to the IRB...................................................................................... 49 2018 Ebola MCM RCT Protocol IND#: 125530 Page 5 of 92 4 October 2019, version 7.0 CONFIDENTIAL Deleted Deleted: Deleted: Deleted: Deleted Deleted Deleted Deleted Deleted: Deleted: Deleted: Deleted: Deleted: Deleted: Deleted: Deleted: Deleted: Deleted: Deleted: Deleted: Deleted: Deleted: Deleted: Deleted: Deleted: Deleted: Deleted: Deleted: Deleted: Deleted: Deleted: Deleted: Annual Reporting to the IRB.................................................................................... 49 Follow-Up of Serious Adverse Events ............................................................................. 50 Sponsor’s Reporting Responsibilities............................................................................... 50 Safety Oversight................................................................................................................ 50 Investigator Safety Monitoring................................................................................. 50 Sponsor Medical Monitor (SMM) ............................................................................ 50 Safety Review and Communications Plan................................................................ 50 Data and Safety Monitoring Board (DSMB)............................................................ 50 11 CLINICAL MONITORING STRUCTURE......................................................................... 51 Site Monitoring Plan......................................................................................................... 51 12 ETHICS/PROTECTION OF HUMAN SUBJECTS ............................................................ 51 Informed Consent Process ................................................................................................ 51 Subject Confidentiality ..................................................................................................... 52 13 DATA MANAGEMENT AND MONITORING................................................................. 52 Data Management Responsibilities................................................................................... 52 Data Capture Methods ...................................................................................................... 52 Types of Data.................................................................................................................... 53 Source Documents and Access to Source Data/Documents............................................. 53 Record Retention .............................................................................................................. 53 Data Sharing Plan ............................................................................................................. 53 Trial Organization............................................................................................................. 53 14 PALM EXTENSION PHASE .............................................................................................. 54 SELECTED REFERENCES ........................................................................................................ 57 APPENDIX A. ZMAPP DRUG INFORMATION ...................................................................... 60 APPENDIX B. REMDESIVIR DRUG INFORMATION ........................................................... 61 APPENDIX C. MAB114 DRUG INFORMATION..................................................................... 62 APPENDIX D. REGN-EB3 DRUG INFORMATION ................................................................ 63 APPENDIX E. OVERSIGHT AND/OR GOVERNANCE COMMITTEES:.............................. 64 APPENDIX F: SAMPLE INFORMED CONSENT AND ASSENT FOR THE RCT ............... 68 APPENDIX G: SAMPLE INFORMED CONSENT AND ASSENT FOR THE EXTENSION PHASE.......................................................................................................................................... 81 LIST OF TABLES Table 1: Ebola Virus Outbreaks.....................................................Error! Bookmark not defined. Table 2. Schedule of Evaluations (subject to individual site capabilities) .. Error! Bookmark not defined. Table 3. Sample sizes for 80%, 85%, and 90% power for two-sided 0.05 level Boschloo exact tests for 20%, 40%, and 50% reductions relative to that of the oSOC plus ZMapp control. Error! Bookmark not defined. Deleted: Table 4. Power for sample sizes of 100, 112, and 132 per arm for two-sided 0.05 level Boschloo exact tests for 20%, 40%, and 50% reductions relative to that of the oSOC plus ZMapp control. ........................................................................................................Error! Bookmark not defined. Table 5. Numbers of deaths by day 28 in each arm to cross the boundary at the first interim analysis with 20 patients per arm...................................................Error! Bookmark not defined. Deleted: Deleted: LIST OF FIGURES 2018 Ebola MCM RCT Protocol IND#: 125530 Page 6 of 92 4 October 2019, version 7.0 CONFIDENTIAL Deleted: Figure 1. Study Schema for Option 1. ...........................................Error! Bookmark not defined. 2018 Ebola MCM RCT Protocol IND#: 125530 Page 7 of 92 4 October 2019, version 7.0 CONFIDENTIAL LIST OF ABBREVIATIONS Abbreviation Term <ul style="display: flex;"><li style="flex:1">AE </li><li style="flex:1">adverse event </li></ul>ALT BDBV CBC CFR CNS CRF DAIDS DCR DRC EBOV EHF ETU EVD FDA GCP GP alanine aminotransferase species Bundibugyo Ebolavirus complete blood count Code of Federal Regulations central nervous system case report form Division of AIDS Division of Clinical Research Democratic Republic of Congo species Zaire Ebolavirus Ebola hemorrhagic fever Ebola treatment unit Ebola virus disease Food and Drug Administration Good Clinical Practice Glycoprotein HCW ICH health care worker International Council for Harmonisation <ul style="display: flex;"><li style="flex:1">IgG </li><li style="flex:1">Immunoglobulin G </li></ul><ul style="display: flex;"><li style="flex:1">IgM </li><li style="flex:1">Immunoglobulin M </li></ul><ul style="display: flex;"><li style="flex:1">IND </li><li style="flex:1">Investigational New Drug Application </li></ul>Institut National de Recherche Biomédicale Institutional Review Board/Ethics Committee Intravenous INRB IRB/EC IV <ul style="display: flex;"><li style="flex:1">kg </li><li style="flex:1">Kilogram </li></ul>MAb MEURI monoclonal antibody Monitored Emergency Use of Unregistered and Investigational Interventions <ul style="display: flex;"><li style="flex:1">MoH </li><li style="flex:1">Ministry of Health </li></ul><ul style="display: flex;"><li style="flex:1">mg </li><li style="flex:1">Milligram </li></ul><ul style="display: flex;"><li style="flex:1">mL </li><li style="flex:1">Milliliter </li></ul>NIAID NIH NHP National Institute of Allergy and Infectious Diseases National Institutes of Health non-human primate oSOC PK optimized standard of care Pharmacokinetic REGN-EB3 RESTV RCT Regeneron’s triple monoclonal cocktail REGN3470-3471-3479

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