
<p>2018 Ebola MCM RCT Protocol IND#: 125530 <br>Page 1 of 92 <br>4 October 2019, version 7.0 </p><p><strong>CONFIDENTIAL </strong></p><p><strong>A Multicenter, Multi-Outbreak, Randomized, Controlled </strong><br><strong>Safety and Efficacy Study of Investigational Therapeutics for the Treatment of Patients with Ebola Virus Disease </strong></p><p><strong>Short Title: </strong></p><p>2018 Ebola MCM RCT Protocol </p><p><strong>Sponsored by: </strong></p><p>Office of Clinical Research Policy and Regulatory Operations (OCRPRO) National Institute of Allergy and Infectious Diseases 5601 Fishers Lane Bethesda, MD 20892 </p><p><strong>NIH Protocol Number: Protocol IND #: </strong></p><p>19-I-0003 125530 </p><p><strong>ClinicalTrials.gov Number: </strong>NCT03719586 <strong>Date: Version: </strong></p><p>4 October 2019 7.0 </p><p><strong>CONFIDENTIAL </strong></p><p><strong>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. </strong></p><p>2018 Ebola MCM RCT Protocol IND#: 125530 <br>Page 2 of 92 <br>4 October 2019, version 7.0 </p><p><strong>CONFIDENTIAL </strong></p><p><strong>KEY ROLES </strong><br><strong>DRC Principal Investigator: </strong></p><p>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 </p><p>Email: <a href="mailto:[email protected]" target="_blank">[email protected] </a></p><p><strong>Other International Investigators: Statistical Lead: </strong></p><p>see Appendix E Lori Dodd, PhD Biostatistics Research Branch, DCR, NIAID 5601 Fishers Lane, Room 4C31 Rockville, MD 20852 Phone: 240-669-5247 </p><p>Email: <a href="mailto:[email protected]" target="_blank">[email protected] </a></p><p><strong>U.S. Principal Investigator: Data Coordinating Center: </strong></p><p>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] </p><p>Clinical Trials Research Section Biostatistics Research Branch Division of Clinical Research, NIAID 5601 Fishers Lane, Room 4C31 Rockville, MD 20852 </p><p><strong>Federalwide assurance (FWA) numbers: </strong>00005897 (NIH) </p><p>00025422 (Kinshasa School of Public Health) </p><p><strong>Protocol Development Team Steering Committee DSMB </strong></p><p>see Appendix E see Appendix E see Appendix E see Appendix E </p><p><strong>Medical Monitors</strong>: </p><p>2018 Ebola MCM RCT Protocol IND#: 125530 <br>Page 3 of 92 <br>4 October 2019, version 7.0 </p><p><strong>CONFIDENTIAL </strong></p><p><strong>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 </strong></p><p><strong>TABLE OF CONTENTS </strong></p><p>KEY ROLES................................................................................................................................... 2 TABLE OF CONTENTS................................................................................................................ 3 PROTOCOL SUMMARY.............................................................................................................. 8 PRÉCIS......................................................................................................................................... 13 </p><ul style="display: flex;"><li style="flex:1">1</li><li style="flex:1">BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ............................. 14 </li></ul><p>Background....................................................................................................................... 14 <br>Filoviruses..................................................................................................................... 14 Transmission and Disease............................................................................................. 14 Latest Outbreaks ........................................................................................................... 15 Therapy ......................................................................................................................... 16 RCT of ZMapp (PREVAIL II) ..................................................................................... 18 <br>Rationale for Study ........................................................................................................... 18 <br>STUDY OBJECTIVES......................................................................................................... 20 <br>Primary Objective............................................................................................................. 20 Secondary Objectives........................................................................................................ 20 Exploratory Objectives ..................................................................................................... 20 <br>STUDY DESIGN.................................................................................................................. 20 <br>General.............................................................................................................................. 20 <br>Extension Phase ............................................................................................................ 23 <br>Study Endpoints................................................................................................................ 23 <br>Primary Endpoint.......................................................................................................... 23 Secondary Endpoints .................................................................................................... 23 Exploratory Endpoints .................................................................................................. 24 <br>Overview of Study Drugs ................................................................................................. 24 Considerations in Choice of Study Drugs......................................................................... 24 Definitions for the Purpose of this Study.......................................................................... 26 <br>STUDY POPULATION....................................................................................................... 26 <br>Research Subject Recruitment.......................................................................................... 26 <br>Participation of Site Employees.................................................................................... 27 <br>Inclusion Criteria .............................................................................................................. 27 Exclusion Criteria ............................................................................................................. 27 Vulnerable Populations..................................................................................................... 27 <br>Pregnant Women........................................................................................................... 27 Inclusion of Children and Neonates.............................................................................. 28 Adults Who Are Unable to Provide Initial or Ongoing Consent.................................. 28 <br>Subject Withdrawal........................................................................................................... 28 Discontinuation of Subject by Investigator....................................................................... 28 Discontinuation of Study .................................................................................................. 29 <br>STUDY PROCEDURES ...................................................................................................... 29 <br>Personnel for Study Procedures........................................................................................ 29 Site-Specific Considerations............................................................................................. 29 Schedule of Evaluations (see also Table 2 below)............................................................ 30 Screening and Informed Consent...................................................................................... 33 <br>Demographics ............................................................................................................... 33 <br>23</p><p>4</p><p>5</p><p><strong>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 Deleted: </strong></p><p>2018 Ebola MCM RCT Protocol IND#: 125530 <br>Page 4 of 92 <br>4 October 2019, version 7.0 </p><p><strong>CONFIDENTIAL </strong></p><p>Medical History ............................................................................................................ 33 Clinical Data ................................................................................................................. 33 Determination of Eligibility.......................................................................................... 33 <br>Day 1................................................................................................................................. 33 <br>Baseline Evaluation ...................................................................................................... 33 Baseline Laboratory Testing......................................................................................... 34 Randomization.............................................................................................................. 35 <br>Study Drug Administration and Pharmacokinetic Sampling............................................ 35 <br>Pharmacokinetic Sampling ........................................................................................... 35 <br>Follow-Up Study Days ..................................................................................................... 35 <br>Follow-up Daily Assessment and oSOC....................................................................... 35 Clinical Safety Laboratory Testing............................................................................... 36 <br>Special Follow-up Assessments........................................................................................ 36 <br>Day of Discharge .......................................................................................................... 36 Day 28........................................................................................................................... 36 Day 58........................................................................................................................... 37 Pregnancy...................................................................................................................... 37 Extended Follow-Up..................................................................................................... 37 <br>STATISTICAL CONSIDERATIONS.................................................................................. 37 <br>Design overview ............................................................................................................... 37 Less strict error rate control.............................................................................................. 37 Study hypotheses and statistical analysis.......................................................................... 38 Power and sample size...................................................................................................... 39 Interim monitoring............................................................................................................ 41 <br>RISKS AND BENEFITS...................................................................................................... 42 <br>Potential Risks .................................................................................................................. 42 <br>Unknown Risks............................................................................................................. 42 Risks of Phlebotomy..................................................................................................... 43 Risks to the Study Personnel and the Environment...................................................... 43 <br>Potential Benefits.............................................................................................................. 43 Alternatives....................................................................................................................... 43 <br>RESEARCH USE OF STORED HUMAN SAMPLES, SPECIMENS, AND DATA ........ 43 <br>Intended Use of the Samples/Specimens/Data ................................................................. 43 Storage of Samples/Specimens/Data ................................................................................ 44 Reporting Loss or Destruction of Samples/Specimens/Data............................................ 44 <br>REMUNERATION PLAN................................................................................................... 44 <br>67</p><p>8910 ASSESSMENT OF SAFETY............................................................................................... 45 <br>Definitions......................................................................................................................... 45 Assessment of Safety........................................................................................................ 46 Investigator Assessment of Serious Adverse Events........................................................ 47 <br>Causality ................................................................................................................... 47 <br>Timing and Scope of (S)AE Collection, and of Assessments and of Reporting <br>Responsibilities to the Sponsor..................................................................................................... 48 <br>Unanticipated Problems............................................................................................ 48 Pregnancy.................................................................................................................. 49 <br>Reporting Procedures to the IRB...................................................................................... 49 </p><p>2018 Ebola MCM RCT Protocol IND#: 125530 <br>Page 5 of 92 <br>4 October 2019, version 7.0 </p><p><strong>CONFIDENTIAL </strong></p><p><strong>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: </strong></p><p>Annual Reporting to the IRB.................................................................................... 49 <br>Follow-Up of Serious Adverse Events ............................................................................. 50 Sponsor’s Reporting Responsibilities............................................................................... 50 Safety Oversight................................................................................................................ 50 <br>Investigator Safety Monitoring................................................................................. 50 Sponsor Medical Monitor (SMM) ............................................................................ 50 Safety Review and Communications Plan................................................................ 50 Data and Safety Monitoring Board (DSMB)............................................................ 50 <br>11 CLINICAL MONITORING STRUCTURE......................................................................... 51 <br>Site Monitoring Plan......................................................................................................... 51 <br>12 ETHICS/PROTECTION OF HUMAN SUBJECTS ............................................................ 51 <br>Informed Consent Process ................................................................................................ 51 Subject Confidentiality ..................................................................................................... 52 <br>13 DATA MANAGEMENT AND MONITORING................................................................. 52 <br>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 <br>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 </p><p><strong>LIST OF TABLES </strong></p><p>Table 1: Ebola Virus Outbreaks.....................................................<strong>Error! Bookmark not defined. </strong>Table 2. Schedule of Evaluations (subject to individual site capabilities) .. <strong>Error! Bookmark not </strong></p><p><strong>defined. </strong></p><p>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. <strong>Error! </strong></p><p><strong>Bookmark not defined. </strong></p><p><strong>Deleted: </strong></p><p>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. ........................................................................................................<strong>Error! Bookmark not defined. </strong>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...................................................<strong>Error! Bookmark not defined. </strong></p><p><strong>Deleted: Deleted: </strong></p><p><strong>LIST OF FIGURES </strong></p><p>2018 Ebola MCM RCT Protocol IND#: 125530 <br>Page 6 of 92 <br>4 October 2019, version 7.0 </p><p><strong>CONFIDENTIAL </strong></p><p><strong>Deleted: </strong></p><p>Figure 1. Study Schema for Option 1. ...........................................<strong>Error! Bookmark not defined. </strong></p><p>2018 Ebola MCM RCT Protocol IND#: 125530 <br>Page 7 of 92 <br>4 October 2019, version 7.0 </p><p><strong>CONFIDENTIAL </strong></p><p><strong>LIST OF ABBREVIATIONS </strong><br><strong>Abbreviation Term </strong></p><p></p><ul style="display: flex;"><li style="flex:1">AE </li><li style="flex:1">adverse event </li></ul><p>ALT BDBV CBC CFR CNS CRF DAIDS DCR DRC EBOV EHF ETU EVD FDA GCP GP alanine aminotransferase </p><p>species <em>Bundibugyo Ebolavirus </em></p><p>complete blood count Code of Federal Regulations central nervous system case report form Division of AIDS Division of Clinical Research Democratic Republic of Congo </p><p>species <em>Zaire Ebolavirus </em></p><p>Ebola hemorrhagic fever Ebola treatment unit Ebola virus disease Food and Drug Administration Good Clinical Practice Glycoprotein <br>HCW ICH health care worker </p><p><em>International Council for Harmonisation </em></p><p></p><ul style="display: flex;"><li style="flex:1">IgG </li><li style="flex:1">Immunoglobulin G </li></ul><p></p><ul style="display: flex;"><li style="flex:1">IgM </li><li style="flex:1">Immunoglobulin M </li></ul><p></p><ul style="display: flex;"><li style="flex:1">IND </li><li style="flex:1">Investigational New Drug Application </li></ul><p>Institut National de Recherche Biomédicale Institutional Review Board/Ethics Committee Intravenous <br>INRB IRB/EC IV </p><ul style="display: flex;"><li style="flex:1">kg </li><li style="flex:1">Kilogram </li></ul><p>MAb MEURI monoclonal antibody Monitored Emergency Use of Unregistered and Investigational Interventions </p><ul style="display: flex;"><li style="flex:1">MoH </li><li style="flex:1">Ministry of Health </li></ul><p></p><ul style="display: flex;"><li style="flex:1">mg </li><li style="flex:1">Milligram </li></ul><p></p><ul style="display: flex;"><li style="flex:1">mL </li><li style="flex:1">Milliliter </li></ul><p>NIAID NIH NHP <br>National Institute of Allergy and Infectious Diseases National Institutes of Health non-human primate oSOC PK optimized standard of care Pharmacokinetic <br>REGN-EB3 RESTV RCT <br>Regeneron’s triple monoclonal cocktail REGN3470-3471-3479 </p>
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