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A Multicenter, Adaptive, Randomized Blinded Controlled Trial of The A Multicenter, Adaptive, Randomized Blinded Controlled Trial of the Safety and Efficacy of Investigational Therapeutics for the Treatment of COVID-19 in Hospitalized Adults Short Title: Adaptive COVID-19 Treatment Trial (ACTT) DMID Protocol Number: 20-0006 Sponsor: Division of Microbiology and Infectious Diseases (DMID), National Institute of Allergy and Infectious Diseases, National Institutes of Health Version Number: 6.0 25 May 2020 DMID/NIAID/NIH CONFIDENTIAL Page 1 of 146 Protocol 20-0006 Version 6.0 Adaptive COVID-19 Treatment Trial (ACTT) 25 May 2020 Main protocol document STATEMENT OF COMPLIANCE Each institution engaged in this research will hold a current Federalwide Assurance (FWA) issued by the Office of Human Research Protection (OHRP) for federally funded research. The Institutional Review Board (IRB)/Independent or Institutional Ethics Committee (IEC) must be registered with OHRP as applicable to the research. The study will be carried out in accordance with the following as applicable: • All National and Local Regulations and Guidance applicable at each site • The International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) E6(R2) Good Clinical Practice, and the Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research, Report of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research • United States (US) Code of Federal Regulations (CFR) 45 CFR Part 46: Protection of Human Subjects • US Food and Drug Administration (FDA) Regulations: 21 CFR Part 50 (Protection of Human Subjects), 21 CFR Part 54 (Financial Disclosure by Clinical Investigators), 21 CFR Part 56 (IRBs), 21 CFR Part 11, and 21 CFR Part 312 (Investigational New Drug Application), and/or 21 CFR 812 (Investigational Device Exemptions) • The policies and procedures of National Institutes of Health (NIH) Office of Extramural Research and Division of Microbiology and Infectious Diseases (DMID) The signature below provides the necessary assurance that this study will be conducted according to all stipulations of the protocol including statements regarding confidentiality, and according to local legal and regulatory requirements, US federal regulations, and ICH E6(R2) GCP guidelines. Site Investigator Signature: Signed: Date: Name and Title DMID/NIAID/NIH CONFIDENTIAL Page 2 of 146 Protocol 20-0006 Version 6.0 Adaptive COVID-19 Treatment Trial (ACTT) 25 May 2020 Main protocol document TABLE OF CONTENTS STATEMENT OF COMPLIANCE ................................................................................................ 2 TABLE OF CONTENTS ................................................................................................................ 3 LIST OF TABLES .......................................................................................................................... 9 LIST OF FIGURES ...................................................................................................................... 10 1. OVERALL PROTOCOL SUMMARY ................................................................................ 11 1.1 Synopsis ........................................................................................................................ 11 1.2 Stages in the adaptive trial ............................................................................................ 16 1.3 Schedule of Assessments .............................................................................................. 16 1.4 Study Schema................................................................................................................ 17 2. INTRODUCTION ................................................................................................................ 18 2.1 Study Rationale ............................................................................................................. 18 2.2 Background ................................................................................................................... 18 Purpose of Study ................................................................................................... 18 2.3 Risk/Benefit Assessment .............................................................................................. 19 3. OBJECTIVES AND ENDPOINTS ...................................................................................... 19 4. STUDY DESIGN.................................................................................................................. 22 4.1 Overall Design .............................................................................................................. 22 4.2 Scientific Rationale for Study Design........................................................................... 23 5. STUDY POPULATION ....................................................................................................... 23 5.1 Inclusion Criteria .......................................................................................................... 23 5.2 Exclusion Criteria ......................................................................................................... 24 5.3 Specific Populations...................................................................................................... 24 5.4 Strategies for Recruitment and Retention ..................................................................... 24 Recruitment ........................................................................................................... 24 Retention ............................................................................................................... 24 Compensation Plan for Subjects ........................................................................... 24 Costs ...................................................................................................................... 24 6. STUDY PRODUCT.............................................................................................................. 25 7. STUDY INTERVENTION DISCONTINUATION AND SUBJECT DISCONTINUATION/WITHDRAWAL..................................................................................... 25 7.1 Halting Criteria and Discontinuation of Study Intervention ......................................... 25 Individual Study Product Halting ......................................................................... 25 Study Halting ........................................................................................................ 25 7.2 Withdrawal from the Study ........................................................................................... 25 7.3 Lost to Follow-Up ......................................................................................................... 25 DMID/NIAID/NIH CONFIDENTIAL Page 3 of 146 Protocol 20-0006 Version 6.0 Adaptive COVID-19 Treatment Trial (ACTT) 25 May 2020 Main protocol document 8. STUDY ASSESSMENTS AND PROCEDURES ................................................................ 25 8.1 Screening and Efficacy Assessments ............................................................................ 25 Screening Procedures ............................................................................................ 25 Efficacy Assessments............................................................................................ 27 Exploratory assessments ....................................................................................... 29 8.2 Safety and Other Assessments ...................................................................................... 30 Procedures to be Followed in the Event of Abnormal Laboratory Test Values or Abnormal Clinical Findings .................................................................................................. 31 Unscheduled Visits ............................................................................................... 31 8.3 Adverse Events and Serious Adverse Events ............................................................... 32 Definition of Adverse Event (AE) ........................................................................ 32 Definition of Serious Adverse Event (SAE) ......................................................... 32 Suspected Unexpected Serious Adverse Reactions (SUSAR).............................. 33 Classification of an Adverse Event ....................................................................... 33 Time Period and Frequency for Event Assessment and Follow-Up ..................... 34 Serious Adverse Event Reporting ......................................................................... 34 Reporting of Pregnancy ........................................................................................ 35 8.4 Unanticipated Problems ................................................................................................ 35 Definition of Unanticipated Problems .................................................................. 35 Unanticipated Problem Reporting......................................................................... 36 9. STATISTICAL CONSIDERATIONS.................................................................................. 36 10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ....... 36 10.1 Regulatory, Ethical, and Study Oversight Considerations............................................ 36 Informed Consent Process ...................................................................................
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