A Multicenter, Adaptive, Randomized Blinded Controlled Trial of the Safety and Efficacy of Investigational Therapeutics for the Treatment of COVID-19 in Hospitalized Adults (ACTT-4)
Phase: PHASE3
Conditions: COVID-19
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

DMID/NIAID/NIH 
CONFIDENTIAL 
Page 1 of 172 
 
 
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: 10.0 
 
18 January 2021 
 
 
 
 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 2 of 172 
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 
 
 
 
 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 3 of 172 
TABLE OF CONTENTS 
 
STATEMENT OF COMPLIANCE ................................................................................................ 2 
TABLE OF CONTENTS ................................................................................................................ 3 
LIST OF TABLES ........................................................................................................................ 11 
LIST OF FIGURES ...................................................................................................................... 11 
1. 
OVERALL PROTOCOL SUMMARY ................................................................................ 12 
1.1 
Synopsis ........................................................................................................................ 12 
1.2 
Stages in the adaptive trial ............................................................................................ 17 
1.3 
Study Schema................................................................................................................ 17 
2. 
INTRODUCTION ................................................................................................................ 17 
2.1 
Study Rationale ............................................................................................................. 18 
2.2 
Background ................................................................................................................... 18 
 
Purpose of Study ................................................................................................... 18 
2.3 
Risk/Benefit Assessment .............................................................................................. 18 
3. 
OBJECTIVES AND ENDPOINTS ...................................................................................... 18 
4. 
STUDY DESIGN.................................................................................................................. 21 
4.1 
Overall Design .............................................................................................................. 22 
4.2 
Scientific Rationale for Study Design ........................................................................... 22 
5. 
STUDY POPULATION ....................................................................................................... 22 
5.1 
Specific Populations ...................................................................................................... 22 
5.2 
Strategies for Recruitment and Retention ..................................................................... 23 
 
Recruitment ........................................................................................................... 23 
 
Retention ............................................................................................................... 23 
 
Compensation Plan for Subjects ........................................................................... 23 
 
Costs ...................................................................................................................... 23 
6. 
STUDY PRODUCT.............................................................................................................. 23 
7. 
STUDY INTERVENTION DISCONTINUATION AND SUBJECT 
DISCONTINUATION/WITHDRAWAL ..................................................................................... 24 
7.1 
Halting Criteria and Discontinuation of Study Intervention ......................................... 24 
 
Individual Study Product Halting ......................................................................... 24 
 
Study Halting ........................................................................................................ 24 
7.2 
Withdrawal from the Study ........................................................................................... 24 
7.3 
Lost to Follow-Up ......................................................................................................... 24 
8. 
STUDY ASSESSMENTS AND PROCEDURES ................................................................ 24 
8.1 
Screening and Efficacy Assessments ............................................................................ 24 
 
Severity and Efficacy Scales ................................................................................. 24 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 4 of 172 
 
Ordinal Scale ..................................................................................................... 24 
 
National Early Warning Score (NEWS) ........................................................... 25 
 
Exploratory assessments ....................................................................................... 26 
 
Viral Load and/or Shedding .............................................................................. 26 
8.2 
Adverse Events and Serious Adverse Events ............................................................... 26 
 
Definition of Adverse Event (AE) ........................................................................ 26 
 
Definition of Serious Adverse Event (SAE) ......................................................... 26 
 
Suspected Unexpected Serious Adverse Reactions (SUSAR) .............................. 27 
 
Classification of an Adverse Event ....................................................................... 27 
 
Severity of Adverse Events ............................................................................... 27 
 
Relationship to Study Intervention ................................................................... 28 
 
Time Period and Frequency for Event Assessment and Follow-Up ..................... 28 
 
Investigators Reporting of AEs ......................................................................... 28 
 
Serious Adverse Event Reporting ......................................................................... 28 
 
Investigators Reporting of SAEs ...................................................................... 29 
 
Regulatory Reporting of SAEs ......................................................................... 29 
 
Reporting of Pregnancy ........................................................................................ 29 
8.3 
Unanticipated Problems ................................................................................................ 29 
 
Definition of Unanticipated Problems .................................................................. 30 
 
Unanticipated Problem Reporting ......................................................................... 30 
9. 
STATISTICAL CONSIDERATIONS.................................................................................. 30 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ....... 30 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ............................................ 30 
 
Informed Consent Process .................................................................................... 31 
 
Requirements for Permission by Parents/Guardians and Assent by Children 
(in case of a minor) ........................................................................................................... 32 
 
Other Informed Consent Procedures ............................................................. 32 
 
Study Termination and Closure ............................................................................ 32 
 
Confidentiality and Privacy .................................................................................. 33 
 
Secondary Use of Stored Specimens and Data ..................................................... 33 
 
Data Sharing for Secondary Research .......................................................... 34 
 
Key Roles and Study Governance ........................................................................ 34 
 
Safety Oversight.................................................................................................... 34 
 
Protocol team oversight ................................................................................ 34 
 
Data Safety Monitoring Board ...................................................................... 34 
 
Clinical Monitoring ............................................................................................... 35 
 
Data Handling and Record Keeping ..................................................................... 35 
 
Data Collection and Management Responsibilities ...................................... 35 
 
Study Record Retention ................................................................................ 36 
 
Source Records ............................................................................................. 36 
 
Protocol Deviations ............................................................................................... 36 
 Publication and Data Sharing Policy .................................................................... 37 
 Human Data Sharing Plan ..................................................................................... 37 
 Publication ............................................................................................................ 37 
 Conflict of Interest Policy ..................................................................................... 37 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 5 of 172 
10.2 
Additional Considerations ............................................................................................ 38 
 
Research Related Injuries ..................................................................................... 38 
 
Public Readiness and Emergency Preparedness Act ............................................ 38 
10.3 
Abbreviations ................................................................................................................ 39 
10.4 
Protocol Amendment History ....................................................................................... 40 
11. REFERENCES ..................................................................................................................... 49 
Appendix A - ACTT-1: Remdesivir vs Placebo ........................................................................... 52 
Appendix B - ACTT-2: Baricitinib/Remdesivir Vs. Remdesivir ................................................. 53 
Appendix C - ACTT-3: Remdesivir + Interferon beta-1a ............................................................ 54 
1. 
PROTOCOL SUMMARY .................................................................................................... 54 
1.1 
ACTT-3 – Synopsis ...................................................................................................... 54 
1.2 
Schedule of Assessments .............................................................................................. 57 
2. 
INTRODUCTION ................................................................................................................ 58 
2.1 
Background ................................................................................................................... 58 
 
ACTT-3 – Interferon beta-1a /Remdesivir vs. Placebo/Remdesivir Trial ............ 58 
2.2 
Risk/Benefit Assessment .............................................................................................. 60 
 
Known Potential Risks .......................................................................................... 60 
 
Remdesivir ............................................................................................................ 61 
 
Potential Risks of Remdesivir ........................................................................... 62 
 
Potential Benefits of Remdesivir ...................................................................... 63 
 
Assessment of Potential Risks and Benefits of Remdesivir ............................. 63 
 
Subcutaneous Interferon beta-1a ........................................................................... 63 
 
Potential Risks of Subcutaneous Interferon beta-1a ......................................... 63 
 
Potential Benefits of Subcutaneous Interferon beta-1a ..................................... 66 
 
Assessment of Potential Risks and Benefits of Subcutaneous Interferon beta-1a
 
66 
3. 
OBJECTIVES AND ENDPOINTS ...................................................................................... 66 
4. 
STUDY DESIGN.................................................................................................................. 70 
4.1 
Overall Design .............................................................................................................. 70 
4.2 
Scientific Rationale for Study Design ........................................................................... 71 
4.3 
Justification for Dose .................................................................................................... 71 
 
Justification for Dose of Remdesivir .................................................................... 71 
 
Justification for Dose of Subcutaneous Interferon beta-1a ................................... 71 
5. 
STUDY POPULATION ....................................................................................................... 72 
5.1 
Inclusion Criteria .......................................................................................................... 72 
5.2 
Exclusion Criteria ......................................................................................................... 73 
 
Exclusion of Specific Populations ........................................................................ 73 
5.3 
Inclusion of Vulnerable Subjects .................................................................................. 74 
5.4 
Lifestyle Considerations ............................................................................................... 74 
5.5 
Screen Failures .............................................................................................................. 75 
5.6 
Strategies for Recruitment and Retention ..................................................................... 75 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 6 of 172 
 
Recruitment ........................................................................................................... 75 
 
Retention ............................................................................................................... 75 
 
Compensation Plan for Subjects ........................................................................... 76 
 
Costs ...................................................................................................................... 76 
6. 
STUDY PRODUCT.............................................................................................................. 76 
6.1 
Study Product(s) and Administration ........................................................................... 76 
 
Study Product Description .................................................................................... 76 
 
Dosing and Administration ................................................................................... 77 
 
Dose Escalation ..................................................................................................... 77 
 
Dose Modifications ............................................................................................... 77 
 
Overdosage ........................................................................................................... 78 
6.2 
Preparation/Handling/Storage/Accountability .............................................................. 78 
 
Acquisition and Accountability ............................................................................ 79 
 
Formulation, Appearance, Packaging, and Labeling ............................................ 79 
 
Product Storage and Stability................................................................................ 80 
 
Preparation ............................................................................................................ 80 
6.3 
Measures to Minimize Bias: Randomization and Blinding .......................................... 81 
 
Randomization ...................................................................................................... 81 
 
Blinding and Masking Procedures ........................................................................ 82 
6.4 
Study Intervention Compliance .................................................................................... 82 
6.5 
Concomitant Therapy.................................................................................................... 82 
 
Permitted Concomitant Therapy and Procedures ................................................. 82 
 
Prohibited Concomitant Therapy .......................................................................... 83 
 
Rescue Medicine ................................................................................................... 84 
 
Non-Research Standard of Care ............................................................................ 84 
7. 
STUDY INTERVENTION DISCONTINUATION AND SUBJECT 
DISCONTINUATION/WITHDRAWAL ..................................................................................... 84 
7.1 
Halting Criteria and Discontinuation of Study Intervention ......................................... 84 
 
Individual Study Product Halting ......................................................................... 84 
 
Remdesivir Halting ........................................................................................... 85 
 
Subcutaneous Interferon beta-1a and Placebo Injections Halting .................... 85 
 
Study Halting ........................................................................................................ 85 
7.2 
Withdrawal from the Study ........................................................................................... 86 
7.3 
Lost to Follow-Up ......................................................................................................... 86 
7.4 
Readmission .................................................................................................................. 86 
8. 
STUDY ASSESSMENTS AND PROCEDURES ................................................................ 87 
8.1 
Screening and Efficacy Assessments ............................................................................ 87 
 
Screening Procedures ............................................................................................ 87 
 
Efficacy Assessments ............................................................................................ 89 
 
Measures of clinical support, limitations and infection control ........................ 89 
 
Ordinal Scale ..................................................................................................... 90 
 
National Early Warning Score (NEWS) ........................................................... 91 
 
Exploratory Assessments and Secondary Research Samples ............................... 92 
 
SARS-CoV-2 Virology Exploratory Assessment ............................................. 93 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 7 of 172 
 
Immunophenotyping Exploratory Assessment ................................................. 93 
8.2 
Safety and Other Assessments ...................................................................................... 95 
 
Procedures to be Followed in the Event of Abnormal Laboratory Test Values or 
Abnormal Clinical Findings .................................................................................................. 97 
 
Unscheduled Visits ............................................................................................... 97 
8.3 
Adverse Events and Serious Adverse Events ............................................................... 97 
 
Definition of Adverse Event (AE) ........................................................................ 97 
 
Definition of Serious Adverse Event (SAE) ......................................................... 99 
 
Suspected Unexpected Serious Adverse Reactions (SUSAR) ............................ 100 
 
Classification of an Adverse Event ..................................................................... 100 
 
Severity of Adverse Events ............................................................................. 100 
 
Relationship to Study Intervention ................................................................. 101 
 
Time Period and Frequency for Event Assessment and Follow-Up ................... 101 
 
Investigator Reporting of AEs ........................................................................ 101 
 
Serious Adverse Event Reporting ....................................................................... 102 
 
Investigators Reporting of SAEs .................................................................... 102 
 
Regulatory Reporting of SAEs ....................................................................... 102 
 
Reporting of Pregnancy ...................................................................................... 102 
8.4 
Unanticipated Problems .............................................................................................. 103 
 
Definition of Unanticipated Problems ................................................................ 103 
 
Unanticipated Problem Reporting ....................................................................... 103 
9. 
STATISTICAL CONSIDERATIONS................................................................................ 103 
9.1 
Statistical Hypotheses ................................................................................................. 103 
9.2 
Sample Size Determination ......................................................................................... 104 
9.3 
Populations for Analyses ............................................................................................ 108 
9.4 
Statistical Analyses ..................................................................................................... 108 
 
General Approach ............................................................................................... 108 
 
Analysis of the Primary Efficacy Endpoint ........................................................ 108 
 
Analysis of the Secondary Endpoint(s) ............................................................... 108 
 
Analysis of Exploratory Objectives and Endpoints ............................................ 109 
 
Safety Analyses ................................................................................................... 109 
 
Baseline Descriptive Statistics ............................................................................ 109 
 
Planned Interim and Early Analyses ................................................................... 109 
 
Interim Safety Analyses .................................................................................. 110 
 
Interim Efficacy Review ................................................................................. 110 
 
Sub-Group Analyses ........................................................................................... 110 
 
Exploratory Analyses .......................................................................................... 110 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS – ALL 
STAGES ..................................................................................................................................... 111 
Appendix D - ACTT-4: Baricitinib/Remdesivir Vs. Dexamethasone/Remdesivir .................... 112 
1. 
PROTOCOL SUMMARY .................................................................................................. 112 
1.1 
ACTT-4 – Synopsis .................................................................................................... 112 
1.2 
Schedule of Assessments ............................................................................................ 116 
1.3 
Study Schema.............................................................................................................. 117 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 8 of 172 
2. 
INTRODUCTION .............................................................................................................. 118 
2.1 
Background ................................................................................................................. 118 
 
ACTT-4 – Baricitinib/Remdesivir vs. Dexamethasone/Remdesivir Trial .......... 118 
2.2 
Risk/Benefit Assessment ............................................................................................ 120 
 
Known Potential Risks ........................................................................................ 120 
 
Remdesivir (Veklury®) ...................................................................................... 121 
 
Potential Risks of Remdesivir ......................................................................... 121 
 
Potential Benefits of Remdesivir .................................................................... 122 
 
Assessment of Potential Risks and Benefits of Remdesivir ........................... 122 
 
Baricitinib ........................................................................................................... 122 
 
Potential Risks of Baricitinib .......................................................................... 122 
 
Potential Benefits of Baricitinib...................................................................... 125 
 
Assessment of Potential Risks and Benefits of Baricitinib ............................. 125 
 
Dexamethasone ................................................................................................... 125 
 
Potential risks of dexamethasone .................................................................... 125 
 
Potential Benefits of Dexamethasone ............................................................. 126 
 
Assessment of Potential Risks and Benefits of Dexamethasone .................... 126 
3. 
OBJECTIVES AND ENDPOINTS .................................................................................... 126 
4. 
STUDY DESIGN................................................................................................................ 130 
4.1 
Overall Design ............................................................................................................ 130 
4.2 
Scientific Rationale for Study Design ......................................................................... 131 
4.3 
Justification for Dose .................................................................................................. 131 
 
Justification for Dose of Remdesivir .................................................................. 131 
 
Justification for Dose of Baricitinib .................................................................... 131 
 
Justification for Dose of Dexamethasone ........................................................... 131 
5. 
STUDY POPULATION ..................................................................................................... 132 
5.1 
Inclusion Criteria ........................................................................................................ 132 
5.2 
Exclusion Criteria ....................................................................................................... 132 
 
Exclusion of Specific Populations ...................................................................... 133 
5.3 
Inclusion of Vulnerable Subjects ................................................................................ 134 
5.4 
Lifestyle Considerations ............................................................................................. 134 
5.5 
Screen Failures ............................................................................................................ 135 
5.6 
Strategies for Recruitment and Retention ................................................................... 135 
 
Recruitment ......................................................................................................... 135 
 
Retention ............................................................................................................. 136 
 
Compensation Plan for Subjects ......................................................................... 136 
 
Costs .................................................................................................................... 136 
6. 
STUDY PRODUCT............................................................................................................ 136 
6.1 
Study Product(s) and Administration ......................................................................... 136 
 
Study Product Description .................................................................................. 137 
 
Dosing and Administration ................................................................................. 138 
Anti-inflammatory Agents (Dexamethasone/IV placebo + Baricitinib/ po placebo) ................. 138 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 9 of 172 
 
Dose Escalation ................................................................................................... 140 
 
Dose Modifications ............................................................................................. 140 
 
Overdosage ......................................................................................................... 141 
6.2 
Preparation/Handling/Storage/Accountability ............................................................ 141 
 
Acquisition and Accountability .......................................................................... 141 
 
Formulation, Appearance, Packaging, and Labeling .......................................... 142 
 
Product Storage and Stability.............................................................................. 143 
 
Preparation .......................................................................................................... 143 
6.3 
Measures to Minimize Bias: Randomization and Blinding ........................................ 143 
 
Randomization .................................................................................................... 143 
 
Blinding and Masking Procedures ...................................................................... 143 
 
Unblinding at end of study .............................................................................. 143 
 
Unblinding for worsening clinical status ........................................................ 144 
 
Unblinding for adverse event .......................................................................... 144 
6.4 
Study Intervention Compliance .................................................................................. 144 
6.5 
Concomitant Therapy.................................................................................................. 144 
 
Permitted Concomitant Therapy and Procedures ............................................... 144 
 
Prohibited Concomitant Therapy ........................................................................ 145 
 
Assessment of Concomitant Therapies ............................................................... 145 
 
Progression to Intubation/Invasive Mechanical Ventilation. .............................. 146 
 
Non-Research Standard of Care .......................................................................... 147 
7. 
STUDY INTERVENTION DISCONTINUATION AND SUBJECT 
DISCONTINUATION/WITHDRAWAL ................................................................................... 147 
7.1 
Halting Criteria and Discontinuation of Study Intervention ....................................... 147 
 
Individual Study Product Halting ....................................................................... 147 
 
Remdesivir Halting ......................................................................................... 148 
 
Oral and IV Study Product Halting ................................................................. 148 
 
Study Halting ...................................................................................................... 148 
7.2 
Withdrawal from the Study ......................................................................................... 148 
7.3 
Lost to Follow-Up ....................................................................................................... 149 
7.4 
Readmission ................................................................................................................ 149 
8. 
STUDY ASSESSMENTS AND PROCEDURES .............................................................. 149 
8.1 
Screening and Efficacy Assessments .......................................................................... 150 
 
Screening Procedures .......................................................................................... 150 
 
Efficacy Assessments .......................................................................................... 152 
 
Measures of clinical support, limitations and infection control ...................... 152 
 
Ordinal Scale ................................................................................................... 153 
 
National Early Warning Score (NEWS) ......................................................... 154 
 
Exploratory assessments ..................................................................................... 155 
 
Exploratory Assessments and Secondary Research Samples ............................. 155 
 
SARS-CoV-2 Virology Exploratory Assessment ........................................... 157 
 
Immunophenotyping Exploratory Assessment ............................................... 157 
8.2 
Safety and Other Assessments .................................................................................... 158 
 
Procedures to be Followed in the Event of Abnormal Laboratory Test Values or 
Abnormal Clinical Findings ................................................................................................ 160 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 10 of 172 
 
Unscheduled Visits ............................................................................................. 160 
8.3 
Adverse Events and Serious Adverse Events ............................................................. 160 
 
Definition of Adverse Event (AE) ...................................................................... 160 
 
Definition of Serious Adverse Event (SAE) ....................................................... 162 
 
Suspected Unexpected Serious Adverse Reactions (SUSAR) ............................ 163 
 
Classification of an Adverse Event ..................................................................... 163 
 
Severity of Adverse Events ............................................................................. 163 
 
Relationship to Study Intervention ................................................................. 163 
 
Time Period and Frequency for Event Assessment and Follow-Up ................... 164 
 
Investigator Reporting of AEs ........................................................................ 164 
 
Serious Adverse Event Reporting ....................................................................... 164 
 
Investigators Reporting of SAEs .................................................................... 164 
 
Regulatory Reporting of SAEs ....................................................................... 165 
 
Reporting of Pregnancy ...................................................................................... 165 
8.4 
Unanticipated Problems .............................................................................................. 165 
 
Definition of Unanticipated Problems ................................................................ 165 
 
Unanticipated Problem Reporting ....................................................................... 166 
9. 
STATISTICAL CONSIDERATIONS................................................................................ 166 
9.1 
Statistical Hypotheses ................................................................................................. 166 
9.2 
Sample Size Determination ......................................................................................... 166 
9.3 
Populations for Analyses ............................................................................................ 167 
9.4 
Statistical Analyses ..................................................................................................... 168 
 
General Approach ............................................................................................... 168 
 
Analysis of the Primary Efficacy Endpoint ........................................................ 168 
 
Analysis of the Secondary Endpoint(s) ............................................................... 168 
 
Safety Analyses ................................................................................................... 169 
 
Baseline Descriptive Statistics ............................................................................ 170 
 
Planned Interim and Early Analyses ................................................................... 170 
 
Interim Safety Analyses .................................................................................. 170 
 
Interim Efficacy Review ................................................................................. 170 
 
Subgroup Analyses ............................................................................................. 170 
 
Exploratory Analyses .......................................................................................... 171 
 
Multiplicity Adjustment ...................................................................................... 171 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS – ALL 
STAGES ..................................................................................................................................... 172 
 
 
 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 11 of 172 
LIST OF TABLES 
Table 1. National Early Warning Score (NEWS) ......................................................................... 25 
Table 1. Schedule of Assessments (SOA) .................................................................................... 57 
Table 2. National Early Warning Score (NEWS) ......................................................................... 91 
Table 3. Blood Volume for Subjects Consenting for Genetic Testing Involving PAXgene and 
PBMC Collection .......................................................................................................................... 95 
Table 4a. Venipuncture Volumes for Subjects NOT Consenting for Genetic Testing Involving 
Transcriptomics and Complete Immunophenotyping Analysis 1 ................................................. 96 
Table 5b. Venipuncture Volumes for Subjects Consenting for Genetic Testing At Sites that Do 
NOT Collect PBMCs 1 .................................................................................................................. 96 
Table 6c. Venipuncture Volumes for Subjects Consenting for Genetic Testing At Sites that 
Collect PBMCs 1 ........................................................................................................................... 97 
Table 7. Hypothesis tests of interest for ACTT-3 ....................................................................... 103 
Table 8. Number of recoveries needed for 85% power assuming a type I error rate of 5% for 
various recovery ratios. ............................................................................................................... 104 
Table 9: Possible scenarios for the distribution of ordinal outcomes for the control arm at Day 
15................................................................................................................................................. 106 
Table 10: Sample size calculations for scenarios in Table 6 for a two-arm study assuming 85% 
power, a two-sided type I error rate of 5%, and various true odds ratios. .................................. 106 
Table 11. Treatment ordinal outcome proportions under an odds ratio of 1.75 for five scenarios 
in Table 5 at Day 15. ................................................................................................................... 107 
Table 1. Schedule of Assessments (SOA) .................................................................................. 116 
Table 2. Mortality from ACTT-2 and RECOVERY trials. ........................................................ 120 
Table 3. Summary of Adverse Reaction Rates in Subjects with Mild, Moderate, or Severe 
COVID-19 in ACTT-1 ................................................................................................................ 121 
Table 4. Serious Adverse Events Occurring in 5 or More Subjects in Any Preferred Term by 
Treatment Group ......................................................................................................................... 123 
Table 5. National Early Warning Score (NEWS) ....................................................................... 155 
Table 6. Blood Volume for Subjects Consenting for Genetic Testing Involving PAXgene 
Collection .................................................................................................................................... 158 
Table 7. Venipuncture Volumes for Subjects NOT Consenting for Genetic Testing Involving 
Transcriptomics Analysis 1 ......................................................................................................... 159 
Table 8. Venipuncture Volumes for Subjects Consenting for Genetic Testing Involving 
Transcriptomics Analysis 1 ......................................................................................................... 159 
Table 9: Sample size estimates and study power. ....................................................................... 167 
 
 
LIST OF FIGURES 
No table of figures entries found. 
 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 12 of 172 
1. 
OVERALL PROTOCOL SUMMARY 
 
1.1 
Synopsis 
Rationale for Proposed Clinical Study 
In December 2019, the Wuhan Municipal Health Committee identified an outbreak of viral 
pneumonia cases of unknown cause. Coronavirus RNA was quickly identified in some of these 
patients. This novel coronavirus has been designated severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2), and the disease caused by this virus has been designated 
Coronavirus Disease 2019 (COVID-19). There were 59 cases on January 5, 2020, 278 cases on 
January 20, 2020, 318,000 cases on March 22, 2020, and more than 1,800,000 cases and 113,000 
deaths as of April 12, 2020 according to various international health reporting agencies (1). 
Currently there are no approved therapeutic agents available for coronaviruses.  
 
Study Design 
This study is an adaptive randomized double-blind placebo-controlled trial to evaluate the safety 
and efficacy of novel therapeutic agents in hospitalized adults diagnosed with COVID-19. The 
study is a multicenter trial that will be conducted in up to approximately 100 sites globally. The 
study will compare different investigational therapeutic agents to a control arm. New arms can 
be introduced according to scientific and public health needs. There will be interim monitoring to 
allow early stopping for futility, efficacy, or safety. If one therapy proves to be efficacious, then 
this treatment may become the control arm for comparison(s) with new experimental 
treatment(s). Any such change would be accompanied by an updated sample size. This adaptive 
platform is used to rapidly evaluate different therapeutics in a population of those hospitalized 
with moderate to severe COVID-19. The platform will provide a common framework sharing a 
similar population, design, endpoints, and safety oversight. New stages with new therapeutics 
can be introduced and will be described in a stage-specific appendix. One independent Data and 
Safety Monitoring Board (DSMB) will actively monitor interim data in all stages to make 
recommendations about early study closure or changes to study arms.  
 
Subjects will be assessed daily while hospitalized. See Schedule of Assessment in each appendix 
for details. All subjects will undergo a series of efficacy, safety, and laboratory assessments. See 
stage specific schedule of assessment for details.  
 
The primary, key secondary, and other outcomes will be modified for each trial stage.  However, 
common endpiints (allowing comparability across the studies) include: 
 
Study Objectives  
OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
To evaluate the clinical efficacy, as assessed 
by time to recovery, of different 
investigational therapeutics as compared to 
the control arm. 
Day of recovery is defined as the first day on 
which the subject satisfies one of the 
following three categories from the ordinal 
scale: 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 13 of 172 
OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
• Hospitalized, not requiring supplemental 
oxygen - no longer requires ongoing 
medical care; 
• Not hospitalized, but new or increased 
limitation on activities and/or requiring 
new or increased home oxygen; 
• Not hospitalized, no limitations on 
activities. 
Recovery is evaluated up until Day 29. 
To evaluate the clinical efficacy of different 
investigational therapeutics relative to the 
control arm in adults hospitalized with 
COVID-19 according to clinical status (8-
point ordinal scale) at Day 15 
 
 
 
• Death; 
• Hospitalized, on invasive mechanical 
ventilation or ECMO; 
• Hospitalized, on non-invasive ventilation 
or high flow oxygen devices; 
• Hospitalized, requiring supplemental 
oxygen; 
• Hospitalized, not requiring supplemental 
oxygen - requiring ongoing medical care 
(COVID-19 related or otherwise); 
• Hospitalized, not requiring supplemental 
oxygen - no longer requires ongoing 
medical care; 
• Not hospitalized, but new or increased 
limitation on activities and/or requiring 
new or increased home oxygen; 
• Not hospitalized, no limitations on 
activities. 
1. To evaluate the clinical efficacy of 
different investigational therapeutics as 
compared to the control arm as assessed by: 
• Clinical Severity 
o Ordinal scale: 
 Time to an improvement of one 
category and two categories from 
Day 1 (baseline) using an ordinal 
scale. 
 Subject clinical status using ordinal 
scale at Days 3, 5, 8, 11, 15, 22, and 
29.  
 Mean change in the ordinal scale 
from Day 1 to Days 3, 5, 8, 11, 15, 
22, and 29. 
 
 
 
 
• Clinical outcome assessed using ordinal 
scale daily while hospitalized and on Days 
15, 22, and 29. 
 
 
 
 
 
 
 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 14 of 172 
OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
o National Early Warning Score 
(NEWS): 
 Time to discharge or to a NEWS of 
≤ 2 and maintained for 24 hours, 
whichever occurs first.  
 Change from Day 1 to Days 3, 5, 8, 
11, 15, and 29 in NEWS.  
 
 
 
• NEWS assessed daily while hospitalized 
and on Days 15 and 29 (if the subject 
attends an in-person visit or still 
hospitalized) 
o Oxygenation: 
 Oxygenation use up to Day 29. 
 Incidence and duration of new 
oxygen use during the study. 
 
 
• Days of supplemental oxygen (if 
applicable) up to Day 29 
 
o Non-invasive ventilation/high flow 
oxygen: 
 Non-invasive ventilation/high flow 
oxygen use up to Day 29. 
 Incidence and duration of new non-
invasive ventilation or high flow 
oxygen use during the study. 
 
• Days of non-invasive ventilation/high 
flow oxygen (if applicable) up to Day 29 
o Invasive Mechanical Ventilation / 
extracorporeal membrane oxygenation 
(ECMO): 
 Ventilator / ECMO use up to Day 
29. 
 Incidence and duration of new 
mechanical ventilation or ECMO use 
during the study.  
 
 
• Days of invasive mechanical 
ventilation/ECMO (if applicable) up to 
Day 29. 
 
• Hospitalization 
o Duration of hospitalization (days).  
 
 
• Days of hospitalization up to Day 29 
• Mortality 
o 14-day mortality 
o 28-day mortality 
 
 
• Date and cause of death (if applicable) 
 
2. To evaluate the safety of different 
investigational therapeutics as compared to 
the control arm as assessed by: 
• Cumulative incidence of SAEs through 
Day 29. 
 
 
 
• SAEs 
• Grade 3 and 4 AEs  
• WBC with differential, hemoglobin, 
platelets, creatinine, glucose, total 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 15 of 172 
OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
• Cumulative incidence of Grade 3 and 4 
clinical and/or laboratory AEs through 
Day 29. 
• Discontinuation or temporary 
suspension of study product 
administrations (for any reason) 
• Changes in white blood cell (WBC) 
count with differential, hemoglobin, 
platelets, creatinine, glucose, total 
bilirubin, alanine aminotransferase 
(ALT), aspartate aminotransferase 
(AST), and prothrombin time (PT 
reported as INR) over time (analysis of 
lab values in addition to AEs noted 
above). 
bilirubin, ALT, AST, and PT/INR on 
Day 1; Days 3, 5, 8, and 11 (while 
hospitalized); and Days 15 and 29 (if 
attends in-person visit or still 
hospitalized). 
 
Exploratory  
 
To evaluate the virologic efficacy of different 
investigational therapeutics as compared to 
the control arm as assessed by: 
• Percent of subjects with SARS-CoV-2 
detectable in OP sample at Days 3, 5, 
8, 11, 15, and 29.  
• Quantitative SARS-CoV-2 virus in OP 
sample at Days 3, 5, 8, 11, 15, and 29. 
• Development of resistance of SARS-
CoV-2 in OP sample at Days 3, 5, 8, 
11, 15, and 29.  
• Quantitative SARS-CoV-2 virus in 
blood at Days 3, 5, 8, and 11. 
 
 
 
 
• Qualitative and quantitative polymerase 
chain reaction (PCR) for SARS-CoV-2 in 
OP swab on Day 1; Days 3, 5, 8, and 11 
(while hospitalized); and Days 15 and 29 
(if attends in-person visit or still 
hospitalized). 
• Qualitative and quantitative PCR for 
SARS-CoV-2 in blood on Day 1; Days 3, 
5, 8, and 11 (while hospitalized). 
 
Study Population 
This trial will study putative therapeutics in a hospitalized population with moderate to severe 
COVID-19. The platform trial will have common inclusion criteria but will be modified for each 
stage for the unique risk of the study product in that stage. Exclusion criteria are described in 
each stage specific appendix.  
 
Inclusion Criteria 
1. Admitted to a hospital with symptoms suggestive of COVID-19. 
2. Subject (or legally authorized representative) provides informed consent prior to 
initiation of any study procedures. 
3. Subject (or legally authorized representative) understands and agrees to comply with 
planned study procedures. 
4. Male or non-pregnant female adult ≥18 years of age at time of enrollment. 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 16 of 172 
5. Has laboratory-confirmed SARS-CoV-2 infection as determined by PCR or other 
commercial or public health assay in any specimen, as documented by either of the 
following:  
• PCR positive in sample collected < 72 hours prior to randomization; OR 
• PCR positive in sample collected ≥ 72 hours prior to randomization, documented 
inability to obtain a repeat sample (e.g. due to lack of testing supplies, limited 
testing capacity, results taking > 24 hours, etc.) AND progressive disease 
suggestive of ongoing SARS-CoV-2 infection. 
6. Illness of any duration, and at least one of the following: 
• Radiographic infiltrates by imaging (chest x-ray, CT scan, etc.), OR 
• SpO2 ≤ 94% on room air, OR 
• Requiring supplemental oxygen, OR 
• Requiring mechanical ventilation. 
7. Women of childbearing potential must agree to either abstinence or use at least one 
primary form of contraception not including hormonal contraception from the time of 
screening through Day 29.  
8. Agrees to not participate in another clinical trial for the treatment of COVID-19 through 
Day 29. 
 
Exclusion Criteria 
Exclusion criteria are described in each stage specific appendix. 
 
 
Study Phase 
• Phase 3 
 
Study Population 
Hospitalized adults (≥18 years old) with COVID-19. 
 
Study Sites 
There will be up to approximately 100 sites globally. Site selection will be determined as 
information becomes available about the epidemiology of COVID-19. Multiple sites will be 
IRB-approved, but site activation will be dependent on the incidence of COVID-19 at the site.  
 
Study Intervention 
Each stage specific appendix will detail the stage specific study intervention 
 
Study Duration 
The full adaptive study will last for up to 3 years.  
 
Participant Duration 
An individual subject will complete the study in about 29 days, from screening at Day -1 or 1 to 
follow-up on Day 29 ± 3 days.  
 
Safety 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 17 of 172 
• Given the potential severity of COVID-19 and limited information about the expected 
clinical course, there are no pre-specified study stopping rules (except as noted under 
DSMB). A subset of the protocol team will review blinded/pooled data of Grade 3 and 4 
AE / SAE every 2 weeks. If there is a pattern of unexpected AEs that is out of proportion 
to the current understanding of the natural history of the disease, the DSMB will be asked 
to review unblinded safety data in an ad hoc meeting. 
• The DSMB will have access to safety data electronically in real time, will have formal 
safety/efficacy reviews after approximately every 200 subjects have met recovered status 
for each pairwise comparison. Additionally, the DSMB will be available for ad hoc 
reviews for safety concerns as described above. The study will not stop enrollment 
awaiting these DSMB reviews, though the DSMB may recommend temporary or 
permanent cessation of enrollment based on their safety reviews. 
  
1.2 
Stages in the adaptive trial 
Each new intervention represents a new stage in the adaptive design clinical trial. In order to 
clearly convey the protocol elements, interventions, objectives and endpoints for each stage, 
common elements are described in the main protocol document while each stage is noted in a 
stage specific appendix.  
 
The stages in the clinical trial include: 
ACTT-1: Remdesivir vs Placebo  
ACTT-2: Baricitinib/Remdesivir vs. Remdesivir  
ACTT-3: Interferon beta-1a/Remdesivir vs. Remdesivir  
ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
 
1.3 
Study Schema 
 
 
 
 
2. 
INTRODUCTION 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 18 of 172 
2.1 
Study Rationale 
COVID-19 is a respiratory disease caused by a novel coronavirus (SARS-CoV-2) and causes 
substantial morbidity and mortality. There are currently few vaccines approved worldwide and a 
number of them in the pipeline to prevent infection with SARS-CoV-2 or therapeutic agent to 
treat COVID-19. This clinical trial is designed to evaluate investigational therapeutics for the 
treatment of adults hospitalized with COVID-19. 
2.2 
Background 
 
Purpose of Study 
Coronavirus (CoVs) are positive-sense, single stranded, enveloped RNA viruses, many of which 
are commonly found in humans and cause mild symptoms. Over the past two decades, emerging 
pathogenic CoVs capable of causing life-threatening disease in humans and animals have been 
identified, namely, severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002-2003 
and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012.  
 
In December 2019, the Wuhan Municipal Health Committee (Wuhan, China) detected an outbreak 
of viral pneumonia cases of unknown cause. Coronavirus RNA was quickly identified in some 
patients. This novel coronavirus has been designated as SARS-COV-2 and has 89% nucleotide 
identity with bat SARS-like-CoVZXC21 and 82% with that of human SARS-CoV-1. The human 
disease caused by SARS-CoV-2 has been designated COVID-19. In most (~80%) cases, COVID-
19 presents as a mild-to-moderately severe, self-limited acute respiratory illness with fever, cough, 
and shortness of breath. Symptoms are thought to appear 2 to 14 days after exposure. COVID-19 
can be severe, resulting in pneumonia, severe acute respiratory syndrome (ARDS), kidney failure, 
and death. The first US COVID-19 death occurred on February 29, 2020. 
 
During this COVID-19 outbreak, the incidence of cases has rapidly increased such that on January 
5, 2020 there were 59 confirmed cases, 278 cases on January 20, 2020, and more than 318,000 
cases and 13,000 deaths as of March 22, 2020 according to various international health reporting 
agencies. As a result, on January 30, 2020, the International Health Regulations Emergency 
Committee of the World Health Organization (WHO) declared the COVID-19 outbreak a Public 
Health Emergency of International Concern. On January 31, 2020, the US Department of Health 
and Human Services declared a public health emergency in the United States. On March 11, 2020, 
the WHO declared the COVID-19 outbreak a pandemic. Outbreak forecasting and modeling 
suggest that these numbers will continue to rise (2).  
 
Global efforts to evaluate novel antivirals and therapeutic interventions to treat COVID-19 have 
intensified. There is currently no vaccine to prevent SARS-CoV-2 infection or therapeutic agent 
to treat COVID-19. Therefore, there is an urgent public health need for rapid development of 
novel interventions.  
 
2.3 
Risk/Benefit Assessment 
Each stage will detail the stage and study specific risk/benefit assessment.  
3. 
OBJECTIVES AND ENDPOINTS 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 19 of 172 
The overall objective of the study is to evaluate the clinical efficacy and safety of different 
investigational therapeutics relative to the control arm among hospitalized adults who have 
COVID-19.  
 
The primary, key secondary, and other outcomes will be modified for each trial stage.  However, 
common endpoints (allowing comparability across the studies) include: 
 
Study Objectives  
OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
To evaluate the clinical efficacy, as assessed 
by time to recovery, of different 
investigational therapeutics as compared to 
the control arm. 
Day of recovery is defined as the first day on 
which the subject satisfies one of the 
following three categories from the ordinal 
scale: 
• Hospitalized, not requiring supplemental 
oxygen - no longer requires ongoing 
medical care; 
• Not hospitalized, but new or increased 
limitation on activities and/or requiring 
new or increased home oxygen; 
• Not hospitalized, no limitations on 
activities. 
Recovery is evaluated up until Day 29. 
To evaluate the clinical efficacy of different 
investigational therapeutics relative to the 
control arm in adults hospitalized with 
COVID-19 according to clinical status (8-
point ordinal scale) at Day 15 
 
 
 
• Death; 
• Hospitalized, on invasive mechanical 
ventilation or ECMO; 
• Hospitalized, on non-invasive ventilation 
or high flow oxygen devices; 
• Hospitalized, requiring supplemental 
oxygen; 
• Hospitalized, not requiring supplemental 
oxygen - requiring ongoing medical care 
(COVID-19 related or otherwise); 
• Hospitalized, not requiring supplemental 
oxygen - no longer requires ongoing 
medical care; 
• Not hospitalized, but new or increased 
limitation on activities and/or requiring 
new or increased home oxygen; 
• Not hospitalized, no limitations on 
activities. 
1. To evaluate the clinical efficacy of 
different investigational therapeutics as 
compared to the control arm as assessed by: 
• Clinical Severity 
 
 
 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 20 of 172 
OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
o Ordinal scale: 
 Time to an improvement of one 
category and two categories from 
Day 1 (baseline) using an ordinal 
scale. 
 Subject clinical status using ordinal 
scale at Days 3, 5, 8, 11, 15, 22, and 
29.  
 Mean change in the ordinal scale 
from Day 1 to Days 3, 5, 8, 11, 15, 
22, and 29. 
 
• Clinical outcome assessed using ordinal 
scale daily while hospitalized and on Days 
15, 22, and 29. 
 
 
 
 
 
 
 
o National Early Warning Score 
(NEWS): 
 Time to discharge or to a NEWS of 
≤ 2 and maintained for 24 hours, 
whichever occurs first.  
 Change from Day 1 to Days 3, 5, 8, 
11, 15, and 29 in NEWS.  
 
 
 
• NEWS assessed daily while hospitalized 
and on Days 15 and 29 (if the subject 
attends an in-person visit or still 
hospitalized) 
o Oxygenation: 
 Oxygenation use up to Day 29. 
 Incidence and duration of new 
oxygen use during the study. 
 
 
• Days of supplemental oxygen (if 
applicable) up to Day 29 
 
o Non-invasive ventilation/high flow 
oxygen: 
 Non-invasive ventilation/high flow 
oxygen use up to Day 29. 
 Incidence and duration of new non-
invasive ventilation or high flow 
oxygen use during the study. 
 
• Days of non-invasive ventilation/high 
flow oxygen (if applicable) up to Day 29 
o Invasive Mechanical Ventilation / 
extracorporeal membrane oxygenation 
(ECMO): 
 Ventilator / ECMO use up to Day 
29. 
 Incidence and duration of new 
mechanical ventilation or ECMO use 
during the study.  
 
 
• Days of invasive mechanical 
ventilation/ECMO (if applicable) up to 
Day 29. 
 
• Hospitalization 
o Duration of hospitalization (days).  
 
• Days of hospitalization up to Day 29 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 21 of 172 
OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
 
• Mortality 
o 14-day mortality 
o 28-day mortality 
 
 
• Date and cause of death (if applicable) 
 
2. To evaluate the safety of different 
investigational therapeutics as compared to 
the control arm as assessed by: 
• Cumulative incidence of SAEs through 
Day 29. 
• Cumulative incidence of Grade 3 and 4 
clinical and/or laboratory AEs through 
Day 29. 
• Discontinuation or temporary 
suspension of study product 
administrations (for any reason) 
• Changes in white blood cell (WBC) 
count with differential, hemoglobin, 
platelets, creatinine, glucose, total 
bilirubin, alanine aminotransferase 
(ALT), aspartate aminotransferase 
(AST), and prothrombin time (PT 
reported as INR) over time (analysis of 
lab values in addition to AEs noted 
above). 
 
 
 
• SAEs 
• Grade 3 and 4 AEs  
• WBC with differential, hemoglobin, 
platelets, creatinine, glucose, total 
bilirubin, ALT, AST, and PT/INR on 
Day 1; Days 3, 5, 8, and 11 (while 
hospitalized); and Days 15 and 29 (if 
attends in-person visit or still 
hospitalized). 
 
Exploratory  
 
To evaluate the virologic efficacy of different 
investigational therapeutics as compared to 
the control arm as assessed by: 
• Percent of subjects with SARS-CoV-2 
detectable in OP sample at Days 3, 5, 
8, 11, 15, and 29.  
• Quantitative SARS-CoV-2 virus in OP 
sample at Days 3, 5, 8, 11, 15, and 29. 
• Development of resistance of SARS-
CoV-2 in OP sample at Days 3, 5, 8, 
11, 15, and 29.  
• Quantitative SARS-CoV-2 virus in 
blood at Days 3, 5, 8, and 11. 
 
 
 
 
• Qualitative and quantitative polymerase 
chain reaction (PCR) for SARS-CoV-2 in 
OP swab on Day 1; Days 3, 5, 8, and 11 
(while hospitalized); and Days 15 and 29 
(if attends in-person visit or still 
hospitalized). 
• Qualitative and quantitative PCR for 
SARS-CoV-2 in blood on Day 1; Days 3, 
5, 8, and 11 (while hospitalized). 
  
4. 
STUDY DESIGN 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 22 of 172 
4.1 
Overall Design 
This study is an adaptive randomized double-blind placebo-controlled trial to evaluate the safety 
and efficacy of novel therapeutic agents in hospitalized adults diagnosed with COVID-19. The 
study is a multicenter trial that will be conducted in up to approximately 100 sites globally. The 
study will compare different investigational therapeutic agents to a control arm. New arms can 
be introduced according to scientific and public health needs. There will be interim monitoring to 
allow early stopping for futility, efficacy, or safety. If one therapy proves to be efficacious, then 
this treatment may become the control arm for comparison(s) with new experimental 
treatment(s). Any such change would be accompanied by an updated sample size. This adaptive 
platform is used to rapidly evaluate different therapeutics in a population of those hospitalized 
with moderate to severe COVID-19. The platform will provide a common framework sharing a 
similar population, design, endpoints, and safety oversight. New stages with new therapeutics 
can be introduced and will be described in a stage-specific appendix. One independent Data and 
Safety Monitoring Board (DSMB) will actively monitor interim data in all stages to make 
recommendations about early study closure or changes to study arms.  
 
Subjects will be assessed daily while hospitalized. See section study specific Schedule of 
Assessment for details. All subjects will undergo a series of efficacy, safety, and laboratory 
assessments. See stage specific schedule of assessment for details.  
 
The sample size will be described in each stage specific appendix.  
 
4.2 
Scientific Rationale for Study Design 
This study utilizes an adaptive platform design that increases efficiency to identify safe and 
efficacious therapeutic agents for patients with COVID-19 during the current outbreak. Some 
investigational products may be in limited supply and this study design enables continuation of 
the study even if a product becomes unavailable. In addition, the adaptive design allows for the 
evaluation of new therapeutic agents as they are identified and ready for testing in clinical trials. 
As the study is a multicenter, multinational randomized controlled study, we will be able to 
acquire rigorous data about the safety and efficacy of investigational therapeutic agents for 
COVID-19 that will lead to generalizable evidence. Randomization is essential for establishing 
efficacy of these new therapeutic agents. Last, collecting clinical and virologic data on enrolled 
subjects using a standardized timeline and collection instruments should provide valuable 
information about the clinical course of and morbidities associated with COVID-19 in a diverse 
group of hospitalized adults. 
 
5. 
STUDY POPULATION 
This trial will study putative therapeutics in a hospitalized population with moderate to severe 
COVID-19. The platform trial will have common inclusion criteria but may be modified in each 
stage-specific appendix for the unique risk associated with the study product used in that stage. 
Exclusion criteria are described in each stage specific appendix.  
5.1 
Specific Populations 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 23 of 172 
The inclusion of vulnerable subjects and exclusion of specific populations need to be customized 
according to each intervention, with the current understanding of epidemiology and clinical 
disease. Inclusion and exclusion of specific populations will be described for each stage in the 
stage-specific appendices. 
5.2 
Strategies for Recruitment and Retention 
 
Recruitment 
It is anticipated that patients with COVID-19 will present to participating hospitals, and that no 
external recruitment efforts towards potential subjects are needed. Recruitment efforts may also 
include dissemination of information about this trial to other medical professionals / hospitals.  
 
The IRB will approve the recruitment process and all materials provided prior to any recruitment 
to prospective subjects directly. 
 
Screening will begin with a brief discussion with study staff. Some will be excluded based on 
demographic data and medical history (i.e., pregnant, < 18 years of age, renal failure, etc.). 
Information about the study will be presented to potential subjects (or legally authorized 
representative) and questions will be asked to determine potential eligibility. Screening 
procedures can begin only after informed consent is obtained. 
 
 
Retention 
Retention of subjects in this trial is very important for determining the primary endpoint. As 
such, after hospital discharge, participating subjects will be reminded of subsequent study visits 
and every effort will be made to accommodate the subject’s schedule to facilitate follow-up 
within the specified visit window. Additionally, there are many circumstances that influence the 
ability to obtain outcome information after discharge. Follow-up visits may be conducted by 
phone if in-person visits are not feasible.  
 
 
Compensation Plan for Subjects  
Compensation, if any, will be determined locally and in accordance with local IRB requirements, 
and subject to local IRB approval.  
 
 
Costs 
There is no cost to subjects for the research tests, procedures/evaluations and study product while 
taking part in this trial. Procedures and treatment for clinical care including costs associated with 
hospital stay may be billed to the subject, subject’s insurance or third party. 
 
6. 
STUDY PRODUCT 
Each stage in this platform trial may have different study products. Information about the study 
product(s) for a given stage can be found in the stage specific appendix.  

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 24 of 172 
7. 
STUDY INTERVENTION DISCONTINUATION AND 
SUBJECT DISCONTINUATION/WITHDRAWAL 
7.1 
Halting Criteria and Discontinuation of Study Intervention 
 
Individual Study Product Halting 
See the stage specific appendix for specific study product stopping rules.  
 
 
Study Halting 
Given the potential severity of COVID-19, there are no pre-specified study stopping rules. 
Instead there will be close oversight by the protocol team and frequent DSMB reviews of the 
safety data.  
 
7.2 
Withdrawal from the Study 
Subjects are free to withdraw from participation in the study at any time upon request, without 
any consequence. Subjects should be listed as having withdrawn consent only when they no 
longer wish to participate in the study and no longer authorize the Investigators to make efforts 
to continue to obtain their outcome data.  
 
Subjects who withdraw from this study or are lost to follow-up after signing the informed 
consent form (ICF) and administration of the study product, will not be replaced. The reason for 
subject withdrawal from the study will be recorded on the appropriate CRF. 
7.3 
Lost to Follow-Up 
A subject will be considered lost to follow-up if he or she fails to appear for all follow-up 
assessments. In lost to follow-up cases, attempts to contact the subject should be made and these 
efforts should be documented in the subject’s records.  
8. 
STUDY ASSESSMENTS AND PROCEDURES 
8.1 
Screening and Efficacy Assessments 
Each stage will detail the exact assessments to be completed.  Common elements will be used 
across stages to ensure comparability of the data across the stages and interventions.  These 
common elements include: 
 
Severity and Efficacy Scales  
 
The following scales are used throughout the different stages/appendices for both baseline 
assessment of severity and as efficacy endpoints: 
 
 
Ordinal Scale 
The ordinal scale used in this study is as follows (from worst to best): 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 25 of 172 
• Death; 
• Hospitalized, on invasive mechanical ventilation or ECMO; 
• Hospitalized, on non-invasive ventilation or high flow oxygen devices; 
• Hospitalized, requiring supplemental oxygen; 
• Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care 
(COVID-19 related or otherwise); 
• Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical 
care; 
o This would include those kept in hospital for quarantine/infection control, awaiting 
bed in rehabilitation facility or homecare, etc. 
• Not hospitalized, but new or increased limitation on activities and/or requiring new or 
increased home oxygen; 
• Not hospitalized, no limitations on activities 
 
 
National Early Warning Score (NEWS) 
NEWS has demonstrated an ability to discriminate subjects at risk of poor outcomes. (Smith, 
2016). This score is based on 7 clinical parameters (see Table 1). The NEWS is being used as an 
efficacy measure. The NEW Score should be evaluated daily while hospitalized and on Days 15 
and 29. It can be performed concurrently with the Ordinal Scale. This should be evaluated at a 
consistent time for each study day and prior to administration of study product. The 7 parameters 
can be obtained from the hospital chart or electronic medical record (EMR) using the last 
measurement prior to the time of assessment and a numeric score is given for each parameter 
(e.g., a RR of 9 is one point, oxygen saturation of 92 is two points). This is recorded for the day 
obtained (i.e., on Day 3, the vital signs and other parameters from Day 3 are used to obtain NEW 
Score for Day 3). ECMO and mechanically ventilated subjects should be assigned a score of 3 
for RR (RR <8) regardless of the ventilator setting. Subjects on ECMO should get a score of 3 
for heart rate since they are on cardiopulmonary bypass. 
 
Table 1. National Early Warning Score (NEWS) 
 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 26 of 172 
  Level of consciousness = alert (A), and non-alert and arousable only to voice (V) or pain (P), and 
unresponsive (U).  
 
 
Exploratory assessments 
 
Viral Load and/or Shedding 
OP swabs are preferred, but if these are not obtainable, nasopharyngeal (NP) or nasal swabs may 
be substituted. Due to limited lack of swabs and other supplies at some sites and limitations on 
personal protective equipment (PPE), the inability to obtain these samples are not considered 
protocol deviations and should be documented in the subject’s record.  
 
8.2 
Adverse Events and Serious Adverse Events 
 
Definition of Adverse Event (AE) 
AE means any untoward medical occurrence associated with the use of an intervention in 
humans, whether or not considered intervention-related. An AE can therefore be any unfavorable 
and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of medicinal (investigational) product. If multiple abnormalities are part 
of the same clinical syndrome, they can be reported together as one AE under a unifying clinical 
diagnosis. For example, the diagnosis of bacterial sepsis may include hypotension, positive blood 
culture, and increased white blood cell count. 
 
Any medical condition that is present at the time that the subject is screened will be considered 
as baseline and not reported as an AE. However, if the severity of any pre-existing (baseline) 
medical condition increases above baseline to severity grade 3 or 4, it should be recorded as an 
AE. 
 
Given the nature of severity of the underlying illness, subjects will have many symptoms and 
abnormalities in vital signs and laboratory values. Only Grade 3 and 4 AEs will be captured in 
this trial. In addition, the following AEs will be reported: 
• Any Grade 2 or higher suspected drug-related hypersensitivity reactions associated with 
study product administration will be reported as an AE. 
 
Intermittent abnormal laboratory values or vital sign measurements common in the severely ill 
populations (such as electrolyte abnormalities, low blood pressure, hyperglycemia, etc.) that are 
part of the same clinical diagnosis (e.g., uncontrolled diabetic) can be recorded once with the 
worst grade for each adverse event (grade 3 and 4 only for this trial), with the start and stops 
dates of the intermittent syndrome. If there is clear resolution of the event, and then recurrence, it 
should be treated as a separate adverse event. Resolution is defined as return to baseline (either 
normal if was normal at Day 1, or baseline (Day 1) grade if already an abnormality on the 
toxicity table at Day 1) for > 48 hours.  
 
 
 
Definition of Serious Adverse Event (SAE) 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 27 of 172 
An AE or suspected adverse reaction is considered serious (i.e., is an SAE) if, in the view of 
either the investigator or the Sponsor, it results in any of the following outcomes: 
• Death; 
• A life-threatening AE; 
• Inpatient hospitalization or prolongation of existing hospitalization; 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions; or 
• A congenital anomaly/birth defect. 
 
Important medical events that may not meet the above criteria may be considered serious when, 
based upon appropriate medical judgment, they may jeopardize the subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias, convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse. 
 
“Life-threatening” refers to an AE that at occurrence represents an immediate risk of death to a 
subject. An event that may cause death if it occurs in a more severe form is not considered life-
threatening. Similarly, a hospital admission for an elective procedure is not considered a SAE. 
 
All SAEs, as with any AE, will be assessed for severity and relationship to study intervention. 
 
All SAEs will be recorded on the SAE CRF. 
 
All SAEs will be followed through resolution or stabilization by a licensed study physician (for 
IND studies, a physician listed on the Form FDA 1572 as the site PI or Sub-Investigator). 
 
All SAEs will be reviewed and evaluated by DMID and will be sent to the DSMB (for periodic 
review), and the IRB/IEC. 
 
Suspected Unexpected Serious Adverse Reactions (SUSAR) 
A SUSAR is any SAE where a causal relationship with the study product is at least reasonably 
possible but is not listed in the Package Insert, and/or Summary of Product Characteristics. 
 
Classification of an Adverse Event 
The determination of seriousness, severity, and causality will be made by an on-site investigator 
who is qualified (licensed) to diagnose AE information, provide a medical evaluation of AEs, 
and classify AEs based upon medical judgment. This includes but is not limited to physicians, 
physician assistants, and nurse practitioners. 
 
Severity of Adverse Events 
All AEs and SAEs will be assessed for severity using the DAIDS Table for Grading the Severity 
of Adult and Pediatric Adverse Events, version 2.1 (July 2017).  
 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 28 of 172 
For AEs not included in the Table, the following guidelines will be used to describe severity. In 
addition, all deaths related to an AE are to be classified as grade 5 according to the DAIDS Table.  
 
 
• Moderate (Grade 2): Events that are usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual activities of daily living and 
causes discomfort but poses no significant or permanent risk of harm to the research 
subject. 
 
• Severe (Grade 3): Events that interrupt usual activities of daily living, or significantly 
affect clinical status, or may require intensive therapeutic intervention. Severe events are 
usually incapacitating. 
 
• Severe (Grade 4): Events that are potentially life threatening. 
 
• Deaths (Grade 5): All deaths related to an AE are to be classified as grade 5. (per DAIDS 
Table). 
 
 Relationship to Study Intervention 
For each reported adverse reaction, the PI or designee must assess the relationship of the event to 
the study product using the following guideline: 
 
• Related – There is a temporal relationship between the study intervention and event, and 
the AE is known to occur with the study intervention or there is a reasonable possibility 
that the study intervention caused the AE. Reasonable possibility means that there is 
evidence to suggest a causal relationship between the study intervention and the AE. 
 
• Not Related – There is not a reasonable possibility that the administration of the study 
intervention caused the event, there is no temporal relationship between the study 
intervention and event onset, or an alternate etiology has been established. 
 
Time Period and Frequency for Event Assessment and Follow-Up 
For this study, all Grade 3 and 4 AEs, all SAEs occurring from the time the informed consent is 
signed through the Day 29 visit will be documented, recorded, and reported. In addition, any 
Grade 2 or higher suspected drug-related hypersensitivity reactions associated with study product 
administration will be reported as an AE.  
 
 
Investigators Reporting of AEs 
Information on all AEs will be recorded on the appropriate CRF. All clearly related signs, 
symptoms, and results of diagnostic procedures performed because of an AE should be grouped 
together and recorded as a single diagnosis. If the AE is a laboratory abnormality that is part of a 
clinical condition or syndrome, it should be recorded as the syndrome or diagnosis rather than 
the individual laboratory abnormality. Each AE will also be described in terms of duration (start 
and stop date), severity, association with the study product, action(s) taken, and outcome. 
 
Serious Adverse Event Reporting 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 29 of 172 
 
Investigators Reporting of SAEs 
Any AE that meets a protocol-defined criterion as a SAE must be submitted within 24 hours of 
site awareness on an SAE form to the DMID Pharmacovigilance Group, at the following 
address:  
 
DMID Pharmacovigilance Group 
Clinical Research Operations and Management Support (CROMS) 
6500 Rock Spring Dr. Suite 650 
Bethesda, MD 20817, USA 
SAE Hot Line: 1-800-537-9979 (US) or 1-301-897-1709 (outside US) 
SAE FAX Number: 1-800-275-7619 (US) or 1-301-897-1710 (outside US) 
SAE Email Address: PVG@dmidcroms.com 
 
Other supporting documentation of the event may be requested by the DMID Pharmacovigilance 
Group and should be provided as soon as possible. The DMID Medical Monitor will review and 
assess the SAE for regulatory reporting and potential impact on study subject safety and protocol 
conduct. 
 
At any time after completion of the study, if the site PI or appropriate sub-investigator becomes 
aware of an SAE that occurred during the subject’s participation in the study, the site PI or 
appropriate sub-investigator will report the event to the DMID Pharmacovigilance Group. 
 
Regulatory Reporting of SAEs 
Following notification from the site PI or appropriate sub-investigator, DMID, as the IND 
Sponsor, will report any SUSAR in an IND safety report to the FDA and will notify all 
participating site PIs as soon as possible. DMID will report to the FDA any unexpected fatal or 
life-threatening suspected adverse reaction as soon as possible, but in no case later than 7 
calendar days after the Sponsor’s initial receipt of the information. If the event is not fatal or life-
threatening, the IND safety report will be submitted within 15 calendar days after the Sponsor 
determines that the information qualifies for reporting as specified in 21 CFR Part 312.32. 
Relevant follow up information to an IND safety report will be submitted as soon as the 
information is available. Upon request from the FDA, DMID will submit to the FDA any 
additional data or information that the agency deems necessary, as soon as possible, but in no 
case later than 15 calendar days after receiving the request. 
 
SAEs that are not SUSARs will be reported to the FDA at least annually in a summary format 
which includes all SAEs. 
 
Sites may have additional local reporting requirements (to the IRB and/or national regulatory 
authority).  
 
Reporting of Pregnancy 
Pregnancy is not an AE. However, any pregnancy that occurs during study participation should 
be reported to the Sponsor on the appropriate CRF. Pregnancy should be followed to outcome.  
8.3 
Unanticipated Problems 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 30 of 172 
 
Definition of Unanticipated Problems 
An Unanticipated Problem (UP) is any event, incident, experience, or outcome that meets the 
following criteria: 
• Unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the IRB-approved research 
protocol and informed consent document; and (b) the characteristics of the subject 
population being studied; 
 Related to participation in the research (meaning there is a reasonable possibility that the 
incident, experience, or outcome may have been caused by the procedures involved in the 
research); and 
 Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
 
Unanticipated Problem Reporting 
To satisfy the requirement for prompt reporting, all UPs will be reported using the following 
timeline: 
 UPs that are SAEs will be reported to the IRB and to the Statistical and Data 
Coordinating Center (SDCC)/study Sponsor within 24 hours of the investigator becoming 
aware of the event per the above describe SAE reporting process. 
 Any other UP will be reported to the IRB and to the SDCC/study Sponsor within 3 days 
of the investigator becoming aware of the problem. 
9. 
STATISTICAL CONSIDERATIONS 
This is an adaptive platform study is intended to allow for several adaptations: 1) sample size re-
estimation and 2) addition of new experimental arm(s) into one stage, or 3) addition of separate 
study stages. A brief summary is provided the study specific appendix for each stage. Details 
will be described in the statistical analysis plan (SAP) for each stage.  
 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1 
Regulatory, Ethical, and Study Oversight Considerations 
This study will be conducted in conformity with the principles set forth in The Belmont Report: 
Ethical Principles and Guidelines for the Protection of Human Subjects of Research (US 
National Commission for the Protection of Human Subjects of Biomedical and Behavioral 
Research; April 18, 1979), and the federal policy for the Protection of Human Subjects codified 
in 45 CFR Part 46, 21 CFR Part 50 (Protection of Human Subjects), and the ICH E6 (R2). 
 
Each institution engaged in this research will hold an OHRP-approved FWA. OHRP-registered 
IRBs will review and approve this protocol, associated informed consent documents, recruitment 
material, and handouts or surveys intended for the subjects, prior to the recruitment, screening, 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 31 of 172 
and enrollment of subjects. The IRB review shall be in accordance with 45 CFR 46 and 21 CFR 
50, 21 CFR 56 (IRBs), and other federal, state, and local regulations and policies, as applicable. 
 
Site IRBs may have additional national and local regulations. 
 
Any amendments to the protocol or consent materials will be approved by the IRB before they 
are implemented. IRB review and approval will occur at least annually throughout the duration 
of the study. The investigator will notify the IRB of deviations from the protocol and SAEs, as 
applicable to the IRB policy. 
 
DMID must receive the documentation that verifies IRB-approval for this protocol, informed 
consent documents, and associated documents prior to the recruitment, screening, and enrollment 
of subjects, and any IRB-approvals for continuing review or amendments as required by the 
DMID. 
 
Informed Consent Process 
Informed consent is a process that is initiated prior to an individual agreeing to participate in a 
trial and continuing throughout the individual’s trial participation. Investigators or designated 
research staff will obtain a subject’s informed consent in accordance with the requirements of 45 
CFR 46, 21 CFR 50 and 21 CFR 56 for FDA-regulated studies, state and local regulations and 
policy, and ICH E6 GCP before any study procedures or data collection are performed. 
Typically, subjects or their legally authorized representatives (LAR) receive a concise and 
focused presentation of key information about the clinical trial, verbally and with a written 
consent form. Subjects will be asked to read and review the consent form. Subjects (or LAR) 
must sign the ICF prior to starting any study procedures being done specifically for this trial. 
Once signed, a copy of the ICF will be given to the subject or the LAR for their records. 
 
However, due to strict respiratory isolation policies, limited access to COVID-19 patient rooms 
and SARS-CoV-2 transmissibility via droplet-contaminated paper, verbal consent and alternative 
methods of obtaining consent (e.g., by phone) will be allowed if approved by the IRB. In 
addition, if a signed paper copy of the ICF is allowed by hospital policy, how it will be obtained 
and stored will need to be determined. Any variation from the standard consent process due to 
isolation and infection control should be sent to the IRB for approval prior to enrollment. The 
site should document the process in their regulatory files and demonstrate that the process has 
IRB concurrence or approval. 
 
Regardless of the method for obtaining consent, the key information about the study will be 
organized and presented in lay terminology and language that facilitates understanding why one 
might or might not want to participate. The site should translate the consent into non-English 
languages consistent with the local population. Translations should be sent to the sponsor for any 
necessary back translations. New information will be communicated by the site PI to subjects 
who consent to participate in this trial in accordance with IRB requirements. The informed 
consent document will be updated, and subjects will be re-consented per IRB requirements, if 
necessary. 
 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 32 of 172 
 
Requirements for Permission by Parents/Guardians and Assent by Children (in 
case of a minor) 
Not Applicable 
 
 
Other Informed Consent Procedures 
Subjects will be asked for consent to collect additional blood, the use of residual specimens, and 
samples for secondary research. Extra blood will be drawn for secondary research during each 
visit when a study blood samples are obtained.  
 
The stored samples will be labeled with barcodes to maintain confidentiality. Research with 
identifiable samples and data may occur as needed; however, subject confidentiality will be 
maintained as described for this protocol and with IRB approval. 
 
Samples designated for secondary research use may be used for understanding the SARS-CoV-2 
infection, the immune response to this infection, and the effect of therapeutics on these factors.  
Samples will not be used to create immortal cell lines, neither sold for commercial profit. 
Although the results of any future research may be patentable or have commercial profit, 
subjects will have no legal or financial interest in any commercial development resulting from 
any future research. 
There are no direct benefits to the subject for extra specimens collected or from the secondary 
research. No results from secondary research will be entered into the subject’s medical record. 
Incidental findings will not be shared with the subject, including medically actionable incidental 
findings, unless required by law. 
Subjects may withdraw permission to use samples for secondary use at any time. They will need 
to contact the study site and the samples will be removed from the study repository after this 
study is completed and documentation will be completed that outlines the reason for withdrawal 
of permission for secondary use of samples.  
 
 
Study Termination and Closure 
Section 7, Study Intervention Discontinuation and Subject Discontinuation/Withdrawal, 
describes the temporary halting of the study. 
 
This study may be prematurely terminated if there is sufficient reasonable cause, including but 
not limited to: 
• Determination of unexpected, significant, or unacceptable risk to subjects 
• Results of interim analysis 
• Insufficient compliance with protocol requirements 
• Data that are not sufficiently complete and/or not evaluable 
• Regulatory authorities decide that study should be terminated 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 33 of 172 
If the study is prematurely terminated, then the site PI will promptly inform study subjects and 
the IRB as applicable. The site PI will assure appropriate follow-up for the subjects, as 
necessary. 
 
The Sponsor will notify regulatory authorities as applicable. 
 
Confidentiality and Privacy 
Subject confidentiality is strictly held in trust by the participating investigators, their staff, and 
the Sponsor(s) and their agents. This confidentiality is extended to cover clinical information 
relating to subjects, test results of biological samples, and all other information generated by 
participation in the study. No identifiable information concerning subjects in the study will be 
released to any unauthorized third party. Subject confidentiality will be maintained when study 
results are published or discussed in conferences. 
 
The study monitor, other authorized representatives of the Sponsor, representatives of the IRB, 
and/or regulatory agencies may inspect all documents and records required to be maintained by 
the investigator, including but not limited to medical records (office, clinic, or hospital) and 
pharmacy records for the subjects in this study. The clinical study site will permit access to such 
records. 
 
All source records including electronic data will be stored in secured systems in accordance with 
institutional policies and federal regulations. 
 
All study data and research specimens that leave the site (including any electronic transmission 
of data) will be identified only by a coded number that is linked to a subject through a code key 
maintained at the clinical site. Names or readily identifying information will not be released 
unless DMID approves and it aligns with the consent form, or according to laws for required 
reporting. 
 
Secondary Use of Stored Specimens and Data 
This section applies to those subjects who consented to storage of samples for secondary 
research. Secondary Human Subject Research is the re-use of identifiable data or identifiable 
biospecimens that were collected from some other ‘‘primary’’ or ‘‘initial’’ activity, such as the 
data and samples collected in this protocol. Any use of the sample or data for secondary research 
purposes, however, will be presented in a separate protocol and require separate IRB approval. 
 
Each sample will be labeled only with a barcode and a unique tracking number to protect subject 
confidentiality. Secondary research with coded samples and data may occur; however, subject 
confidentiality will be maintained as described for this protocol. An IRB review of the secondary 
research using coded specimens is required. 
 
The subject’s decision can be changed at any time by notifying the study doctors or nurses in 
writing. If the subject subsequently changes his/her decision, the samples will be destroyed if the 
samples have not been used for research or released for a specific research project. 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 34 of 172 
 
Data Sharing for Secondary Research 
Data from this study may be used for secondary research. All of the individual subject data 
collected during the trial will be made available after de-identification. The SAP and Analytic 
Code will also be made available. This data will be available immediately following publication, 
with no end date.  
 
The investigator may request removal of data on individual study subjects from NIH data 
repositories in the event that a research subject withdraws or changes his or her consent. 
However, some data that have been distributed for approved research use cannot be retrieved. 
 
Key Roles and Study Governance 
The study is sponsored by DMID. Decisions related to the study will be made by a protocol team 
that includes representatives from all countries, and separate networks within a country. 
 
Safety Oversight 
 
Protocol team oversight 
A subset of the protocol team will review blinded pools of AE data every 2 weeks to ensure no 
significant number of unexpected AEs (AEs that do not fit with the known course of COVID-
19). If there are a significant number of unexpected AEs, the DSMB will be asked to review 
unblinded safety data in an ad hoc meeting.  
 
Data Safety Monitoring Board 
Safety oversight will be conducted by a DSMB that is an independent group of experts that 
monitors subject safety and advises DMID. The DSMB members will be separate and 
independent of study personnel participating in this trial and should not have scientific, financial 
or other conflicts of interest related to this trial. The DSMB will consist of members with 
appropriate expertise to contribute to the interpretation of the data from this trial. The DSMB 
should be as broadly informed as possible regarding emerging evidence from related studies. The 
DSMB will operate under the guidelines of a DMID-approved charter that will be written at the 
organizational meeting of the DSMB. The DSMB will review SAEs on a regular basis and ad 
hoc during this trial. The DMID Medical Monitor will be responsible for reviewing SAEs in real 
time. The DSMB will review SAEs on a regular basis and ad hoc during this trial. 
 
The DSMB will conduct the following reviews: 
• Intermittent safety reviews at a frequency as determined by the DSMB. The DSMB will 
have access to safety data electronically in real time.  
• Formal safety/efficacy reviews after approximately every 200 subjects have met 
recovered status for each pairwise comparison 
• Ad hoc meeting if the protocol team raises any concerns 
• A final review meeting after final clinical database lock, to review the cumulative 
unblinded safety data for this trial.  
 
The study will not stop enrollment awaiting these DSMB reviews, although the DSMB may 
recommend temporary or permanent cessation of enrollment based on their safety reviews. 
  
Additional data may be requested by the DSMB, and interim statistical reports may be generated 
as deemed necessary and appropriate by DMID. The DSMB may receive data in aggregate and 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 35 of 172 
presented by treatment arm. The DSMB may also be provided with expected and observed rates 
of the expected AEs in an unblinded fashion and may request the treatment assignment be 
unblinded for an individual subject if required for safety assessment. The DSMB will review 
grouped and unblinded data in the closed session only. At each meeting, the DSMB will make a 
recommendation as to the advisability of proceeding with study interventions (as applicable), and 
to continue, modify, or terminate this trial. 
 
 
Clinical Monitoring 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial subjects are 
protected and that the reported trial data are accurate, complete, and verifiable. Clinical 
monitoring also ensures that conduct of the trial is in compliance with the currently approved 
protocol/ amendment(s), ICH, GCP, and with applicable regulatory requirement(s) and Sponsor 
requirements. Clinical monitoring will also verify that any critical study procedures are 
completed following specific instructions in the protocol-specific MOP. 
 
Monitoring for this study will be performed by DMID or their designee. Details of clinical site 
monitoring are documented in a clinical monitoring plan (CMP). The CMP describes in detail 
who will conduct the monitoring, at what frequency monitoring will be done, at what level of 
detail monitoring will be performed, and the distribution of monitoring reports. Monitoring visits 
will include, but are not limited to, review of regulatory files, accountability records, CRFs, 
ICFs, medical and laboratory reports, site study intervention storage records, training records, 
and protocol and GCP compliance. Site monitors will have access to each participating site, 
study personnel, and all study documentation according to the DMID-approved site monitoring 
plan. Study monitors will meet with site PIs to discuss any problems and outstanding issues and 
will document site visit findings and discussions. 
 
Data Handling and Record Keeping 
 
Data Collection and Management Responsibilities 
Data collection is the responsibility of the study personnel at the participating clinical study site 
under the supervision of the site PI. The site PI must maintain complete and accurate source 
documentation. 
 
Clinical research data from source documentation (including, but not limited to, AE/SAEs, 
concomitant medications, medical history, physical assessments, clinical laboratory data) will be 
entered by the clinical study site into CRFs via a 21 CFR Part 11-compliant internet data entry 
system provided by the SDCC. The data system includes password protection and internal 
quality checks, such as automatic range checks, to identify data that appear inconsistent, 
incomplete, or inaccurate. AEs and concomitant medications will be coded according to the most 
current versions of MedDRA and WHODrug, respectively. 
 
The SDCC for this study will be responsible for data management, quality review, analysis, and 
reporting of the study data. 
 
The IND Sponsor is responsible for review of data collection tools and processes, and review of 
data and reports. 
 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 36 of 172 
A separate study specific Study Data Standardization Plan (SDSP) appendix will be developed 
which describes the technical recommendations for the submission of human study data and 
related information in a standardized electronic format throughout product development. 
 
At the end of the study, a copy of all datasets including annotated CRFs and data dictionary will 
be provided to DMID. 
 
Study Record Retention 
Study related records, including the regulatory file, study product accountability records, consent 
forms, subject source documents and electronic records should be maintained for a period of 2 
years following the date a marketing application is approved for the investigational product for 
the indication for which it is being investigated; or, if no application is to be filed or if the 
application is not approved for such indication, until 2 years after the investigation is 
discontinued and FDA is notified. These documents should be retained for a longer period, 
however, if required by local policies or regulations. No records will be destroyed without the 
written consent of DMID. Consent forms with specimen retention linked to identifiable 
specimens will be maintained for as long as the specimens remain in identifiable format, and a 
minimum of three years after use of the identifiable specimens in nonexempt human subject 
research. 
 
Source Records 
Source data are all information in original records (and certified copies of original records) of 
clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial. Source data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Each participating site will maintain 
appropriate medical and research records for this trial, in compliance with ICH GCP, regulatory, 
and institutional requirements. Data recorded in the CRF derived from source documents should 
be consistent with the data recorded on the source documents.  
 
It is understood that biocontainment may necessitate alternative processes for storing consents 
and other source documents. Each site will determine and document this process. 
 
Interview of subjects is sufficient for obtaining medical history. Solicitation of medical records 
from the subject’s primary care provider is not required. 
 
Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, any process that is 
noted in the protocol and refers to details in the protocol-specific MOP, or GCP requirements or 
any critical study procedures with specific instructions in ancillary documents referenced in the 
protocol such as a protocol-specific MOP. 
 
The noncompliance may be either on the part of the subject, the investigator, or the study site 
staff. Following a deviation(s), corrective actions should be developed by the site and 
implemented promptly. All individual protocol deviations will be addressed in subject study 
records. 
 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 37 of 172 
It is the responsibility of the site PI and personnel to use continuous vigilance to identify and 
report deviations within five working days of identification of the protocol deviation, or within 
five working days of the scheduled protocol-required activity. All deviations must be promptly 
reported to DMID per the protocol deviation reporting procedures. Protocol deviations must be 
sent to the local IRB/IEC per their guidelines. The site PI and personnel are responsible for 
knowing and adhering to their IRB requirements. A completed copy of the DMID Protocol 
Deviation Form must be maintained in the Regulatory File, as well as in the subject’s chart if the 
deviation is subject specific. 
 
Publication and Data Sharing Policy 
Following completion of the study, results of this research will be published in a scientific 
journal. As this is an adaptive study and given the public health urgency to disseminate results, 
data from individual comparisons (i.e. the initial 2 study arms) can be published when those arms 
are fully enrolled and all subjects in those arms are followed through to completion of the study.  
 
Data will be available immediately following publication, with no end date, with data sharing at 
the discretion of the Sponsor. Sites may also obtain individual or country level data from the 
database for separate publications is desired. Publication may occur prior to completion of a final 
clinical study report for the entire trial. 
 
Human Data Sharing Plan 
This study will be conducted in accordance with the following publication and data sharing 
policies and regulations: 
• NIH Public Access Policy, which ensures that the public has access to the published 
results of NIH funded research. It requires scientists to submit final peer-reviewed journal 
manuscripts that arise from NIH funds to the digital archive PubMed Central upon 
acceptance for publication. 
 
Publication 
Following completion of the study, the protocol team is expected to publish the results of this 
research in a scientific journal. This study will adhere to the following publication and data 
sharing policies and regulations: 
• This study will comply with the NIH Public Access Policy, which ensures that the public 
has access to the published results of NIH funded research. As such, the final peer-
reviewed journal manuscripts will accessible to the public on PubMed Central no later 
than 12 months after publication. 
 
Conflict of Interest Policy 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who have 
a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed 
and managed. Furthermore, persons who have a perceived conflict of interest will be required to 
have such conflicts managed in a way that is appropriate to their participation in the design and 
conduct of this trial. DMID has established policies and procedures for all study group members 
to disclose all conflicts of interest and will establish a mechanism for the management of all 
reported dualities of interest. 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 38 of 172 
10.2 
Additional Considerations 
 
Research Related Injuries 
For any potential research related injury, the site PI or designee will assess the subject. Study 
personnel will try to reduce, control, and treat any complications from this study. Immediate 
medical treatment may be provided by the participating study site. As needed, referrals to 
appropriate specialist or other health care facilities will be provided to the subject. The site PI 
should then determine if an injury occurred as a direct result of the tests or treatments that are 
done for this trial. 
 
Immediate medical treatment may be provided by the participating site, such as giving 
emergency medications to stop immediate allergic reactions. No financial compensation will be 
provided to the subject by NIAID, NIH or the participating site for any injury suffered due to 
participation in this trial. 
 
 
Public Readiness and Emergency Preparedness Act 
The drugs remdesivir, baricitinib, interferon beta-1a, and all other study products to be evaluated 
using the ACTT clinical trial platform during this pandemic and the efforts for this clinical trial 
are covered under the Public Readiness and Emergency Preparedness Act (PREP Act) and the 
Declaration issued by the Secretary of the U.S. Department of Health and Human Services under 
that Act. Under the PREP Act and the Declaration, covered persons (such as manufacturers, 
distributers, program planners, and other qualified persons who prescribe, administer or dispense 
study product) are immune from liability from the administration, or use of a covered 
countermeasure, such as remdesivir and baricitinib. The PREP Act provides immunity for 
covered persons from liability, unless the injury was caused by willful misconduct. The 
Declaration invoking the PREP Act for COVID-19 covered countermeasures was made on 
March 17, 2020 and is retroactively effective from February 4, 2020. 
The PREP Act also established the Countermeasures Injury Compensation Program (CICP) to 
provide compensation for serious injuries or death that occur as the direct result of the 
administration or use of certain countermeasures. Any requests for compensation must be filed 
within one year of the administration or use of the covered countermeasure. Requests for 
Benefits must be made to the Health Resources and Services Administration’s (HRSA) 
Countermeasures Injury Compensation Program (http://www.hrsa.gov/cicp/) by filing a Request 
for Benefits Form and all required medical records and supporting documentation. Additional 
information on filing a Request for Benefits is available on the CICP’s website at 
http://www.hrsa.gov/cicp/. Compensation may then be available for reasonable and necessary 
medical benefits, lost wages and/or death benefits to eligible individuals for certain injuries in 
accordance with regulations published by the Secretary of HHS (found at 42 CFR part 110).  
If an individual suffers a serious physical injury or death from the administration or use of a 
covered countermeasure in this study, the individual, the individual’s legal or personal 
representative, the administrator/executor of a deceased individual’s estate, or certain survivors 
may request benefits from the CICP. A serious physical injury means an injury that warranted 
hospitalization (whether or not the person was actually hospitalized) or that led to a significant 
loss of function or disability. The CICP is the payer of last resort. This means that it only covers 
expenses or provides benefits that other third-party payers (such as health insurance, the 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 39 of 172 
Department of Veterans Affairs, or Workers’ Compensation programs) do not have an obligation 
to pay. 
If the Secretary of HHS does not make a final determination on the individual’s request within 
240 days, or if the individual decides not to accept the compensation, the injured individual or 
his representative may pursue a tort claim in the US District Court for the District of Columbia, 
but only if the claim involves willful misconduct and meets the other requirements for suit under 
the PREP Act. Any award is reduced by any public or private insurance or worker’s 
compensation available to the injured individual. Awards for non-economic damages, such as 
pain, suffering, physical impairment, mental anguish, and loss of consortium are also limited. If 
the individual accepts compensation, or if there is no willful misconduct, then the individual does 
not have a tort claim that can be filed in a US Federal or a State court. 
10.3 
Abbreviations 
Abbreviation 
Definition 
AE 
Adverse Event 
ALT 
Alanine Transaminase 
ARDS 
Acute Respiratory Distress Syndrome 
AST 
Aspartate Transaminase 
BP 
Blood Pressure 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Clinical Monitoring Plan 
CMS 
Clinical Material Services 
Cr 
Creatinine 
CRF 
Case Report Form 
CROMS 
Clinical Research Operations and Management Support 
CSR 
Clinical Study Report 
CMP 
Clinical Monitoring Plan 
CQMP 
Clinical Quality Management Plan 
DHHS 
Department of Health and Human Services 
DMID 
Division of Microbiology and Infectious Diseases 
EC 
Ethics Committee 
eGFR 
Estimated Glomerular Filtration Rate 
EMR 
Electronic Medical Record 
FDA 
Food and Drug Administration 
FWA 
Federal Wide Assurance 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
Hgb 
Hemoglobin 
HR 
Heart Rate 
IB 
Investigator’s Brochure 
ICD 
International Classification of Diseases 
ICF 
Informed Consent Form 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 40 of 172 
Abbreviation 
Definition 
ICH 
International Council for Harmonisation 
IND 
Investigational New Drug Application 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IV 
Intravenous 
JAK 
Janus kinase 
LAR 
Legally Authorized Representative 
MCG 
Microgram 
MedDRA 
Medical Dictionary for Regulatory Activities 
MERS 
Middle East Respiratory Syndrome 
MOP 
Manual of Procedures 
N 
Number (typically refers to subjects) 
NDA 
New Drug Application 
NEWS 
National Early Warning Score 
NIAID 
National Institute of Allergy and Infectious Diseases 
NIH 
National Institutes of Health 
NP 
Nasopharyngeal 
OHRP 
Office for Human Research Protections 
OP 
Oropharyngeal  
PHI 
Protected Health Information 
PI 
Principal Investigator 
PLT 
Platelet 
PP 
Per Protocol 
PT 
Prothrombin Time 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SARS 
Severe Acute Respiratory Syndrome 
SBECD 
Sulfobutylether-beta-cyclodextrin 
SDCC 
Statistical and Data Coordinating Center 
SDSP 
Study Data Standardization Plan 
SNP 
Single Nucleotide Polymorphisms 
SOA 
Schedule of Assessments 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T. Bili 
Total Bilirubin 
TNF 
Tumor Necrosis Factor 
UP 
Unanticipated Problem 
US 
United States 
WBC 
White Blood Cell 
10.4 
Protocol Amendment History 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 41 of 172 
Version/Date 
 
 
Section 
Description of 
Change 
Brief Rationale 
2.0 
2MAR2020 
 
 
 
Overall 
This version addresses the comments received from the US 
FDA, Japanese PDMA, DSMB, IRBs, and NIAID scientific 
review. 
 
Improved 
clarity and 
brevity 
Multiple areas throughout the document were reworded to 
improve clarity (recognized after implementation) and 
edited to minimize redundant statements. 
1.1 
Number of sites 
increased from 
50 to 
approximately 
75 
Given the currently unpredictable epidemiology, additional 
sites will improve the ability to enroll the study in a timely 
manner. 
 
Sample size 
increased 
Version 1 sample size table and statements in the text did 
not align. The new assumptions use a slightly smaller 
treatment effect (OR 1.75) and the 8-category scale and 
give the sample size of 440. 
 
Addition of 
phone call on 
Day 22 
Recent information from the outbreak in China suggest 
some COVID-19 patients worsen between 2 and 4 weeks of 
illness. We added Day 22 because of concerns that the peak 
illness may be missed. There are also concerns if the more 
severe population will be discharged by Day 29. 
 
Ordinal scale 
was increased 
to 8 categories. 
This addresses the concern raised by several reviews that 
“Hospitalized not on oxygen” is two separate populations – 
those still needing medical care and those kept in hospital 
just for infection control. 
 
Objectives and 
endpoints were 
put into table 
format 
Multiple comments that the tabular form of objectives and 
endpoints (that was previously in Section 4) was much 
easier to read and understand. 
 
Added 
inclusion 
criteria for 
admission to 
hospital 
This was implied throughout the document, but never stated 
in the inclusion criteria. 
 
Inclusion 
criteria #8 
Contraceptive requirement aligned to new IB from February 
21, 2020 
 
Phase of study 
Changed to phase 3. After discussion with company, and 
new IB that outlines safety data of > 500 subjects, the 
company thought this was more accurately called a phase 3 
trial. 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 42 of 172 
1.2 
Schedule of 
Assessments 
updated 
To include Day 22. Footnotes also revised for clarity. 
2.2 
Background 
updated 
To reflect current understanding of SARS-CoV, COVID-
19, and new data from IB. 
3. 
Separating 
objectives 
about non-
invasive from 
invasive 
mechanical 
ventilation 
Elsewhere in the protocol, it was mentioned that this data 
would be captured separately, but it mistakenly never made 
into an endpoint. 
 
Added Day 14 
mortality 
To allow better assessment of short and long term mortality. 
4 
Rewritten for 
clarity 
These paragraphs were substantially rewritten, but aside 
from the changes note above the content is not different. 
8 
Screening is 
more detailed 
These edits reflect so ambiguity discovered with the first 
enrollment. 
8.1.2 
Efficacy 
assessments 
more detailed 
More detail is provided to facilitate these assessments. Also, 
each component that contribute to the categories will not be 
captured separately. This will allow the ordinal scale as 
structured, but also will allow analysis of alternative ordinal 
scales. 
8.1.3.1 
Viral load in 
plasma and 
resistance 
The assessment of viral load in plasma and detection of 
resistance was previously noted on the SOA, but never 
discussed in the text. This has now been added in this 
section. 
9.2 
Sample size 
calculations 
With the addition of one category to the ordinal scale, the 
estimates per category must change leading to new tables. 
3.0 
27MAR2020 
 
 
 
Improved 
clarity  
Multiple areas throughout the document were reworded to 
improve clarity (issues that arose with implementation)  
 
Flexibility 
The pandemic has limited ability for people to be seen in 
follow-up due to infection control and restrictions on travel. 
Additionally, staff at some sites have limited ability to go 
into rooms due to limited personal protective equipment. So 
flexibility has been added where possible while still 
ensuring safety and good scientific data.  
1.1 
Sample Size 
Increase 
The sample size was changed to reflect ensuring sufficient 
samples for the endpoint of interest which 400 subjects with 
a “recovered” status (per the primary objective). 
Additionally, enrollment is permitted after the 400 
recoveries up to April 20 to provide additional data about 
important subgroups. 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 43 of 172 
 
Primary 
Endpoint 
Given evolving data, the precise day of assessment of the 
primary endpoint is not clear. Modeling of the prior 
endpoint suggested if the day is chosen incorrectly, the 
power is significantly decreased. So the primary endpoint 
has been changed from a ordinal scale on a given day to 
days to recovery (the best three categories of the ordinal 
scale).  
 
Key secondary 
endpoint 
The prior primary endpoint has been labeled as the key 
secondary endpoint. 
 
Inclusion 
Criteria #5 
Given delays of PCR results in some sites (given number of 
tests and throughput within the lab), the PCR positive 
requirement has been written to allow flexibility if the PCR 
results are delayed.  
 
Inclusion 
Criteria #6 
Removed auscultation requirement given challenges of 
accurate auscultation while in full PPE.  
 
Exclusion 
Criteria #2 
Cutoff of eGFR to 30 was decreased after discussion with 
the manufacturer and FDA.  
 
Sites 
Increased to 100 given unpredictable epidemiology of 
COVID-19 
 
DSMB 
Given the rapid pace of enrollment, the prior plans for 
DSMB oversight are not practical, so this has been modified 
with input from the DSMB on when they would like to have 
interim reviews.  
2.3.2 
Drug 
interaction 
Corrected erroneous statements about CYP inhibition.  
5.3 
Vulnerable 
Subjects 
Allow inclusion of those that are incapable of consent such 
as cognitively impaired. Prior version noted consent by a 
LAR, but it was not described in this section.  
6 
Study Product 
Updated throughout for 2 issues. First, the newly 
manufactured lot of remdesivir is in 100mg vials. Second, 
there is limited supply of placebo and the options for using 
saline with an opaque bag for the control infusion was 
added.  
6.5 
Concomitant 
Therapy 
There has been significant increase in use of off label 
therapies for COVID-19, including many repurposed agents 
and therapies targeting immune response. So additional 
wording was added to cover these scenarios to minimize 
additional confounding medications.  
8.1.3 
Sample 
Processing  
Some sites are reporting needing to process samples in 
BSL-3 and/or have limitations on processing, shipping, 
storage, etc. of samples. So wording was added to allow 
exclusion of these samples (which may be cost prohibitive)  
8.2 
Venipuncture 
volume 
This table was corrected for total volumes, but not new 
samples were added.  
9 
Statistical 
Considerations 
This section was rewritten to given the change in sample 
size. 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 44 of 172 
10.1.1 
Informed 
consent 
Given isolation and infection control issues with COVID-
19, traditional consenting documentation is not always 
possible. This section was rewritten to allow alternative 
consent processes and documentation as long as these are 
acceptable to the site’s IRB.  
4.0 
13APR2020 
Note – version 4 was submitted to the US FDA and some IRBs, but given the 
interim DSMB findings this version was never implemented.  
 
General, 
Appendix A, 
Appendix B 
As this is an adaptive study, an additional treatment stage 
“ACTT-2” was added. To allow better organization, the 
general protocol was separated from the study specific 
Appendix A (remdesivir vs placebo) and Appendix B (2x2 
study factorial design of +/- remdesivir and +/- baricitinib). 
 
Appendix B 
Appendix B is a new stage in the platform study that 
describes all study specifics of the 2x2 study factorial 
design of +/- remdesivir and +/- baricitinib 
Appendix B- 
1 
Synopsis 
A new synopsis for ACTT-2 was added. 
App B - 1.2 
SOA 
A revised SOA was added. This is similar to the ACTT-1 
SOA, but footnotes have been edited for clarity.  
App B - 2.2 
Risk 
Risk of baricitinib was added, along with prior language 
about the risk of remdesivir.  
App B - 3 
Objectives 
ACTT-2 will use the same objectives from ACTT-1. 
App B - 4 
Study Design 
The study design and justification for studying baricitinib in 
a factorial study was added.  
App B - 5 
Study 
Population 
ACTT-2 will use similar inclusion and exclusion criteria, 
with some additions unique to the risk or mechanism of 
action of baricitinib. 
App B - 6 
Study Product 
Information about baricitinib was added. 
App B - 9 
Statistical 
Consideration 
While similar to ACTT -1, additional information was 
added for how the factorial design would be analyzed, and 
how arms may be dropped based on ACTT-1 findings.  
5.0 
4MAY2020 
 
 
Appendix B - 
1 
Synopsis 
Information about the preliminary findings from ACTT-1 
was added. 
App B - 1 
Synopsis and 
throughout 
Descriptions of the study design was revised to reflect a 2 
arms study - Baricitinib/Remdesivir Vs. Remdesivir 
App B – 1 
Synopsis and 
9.2 
A new sample size was calculated to reflect the 2 arm 
design, and the likely lower anticipated treatment effect of a 
second agent (i.e. the incremental value of no treatment to 1 
treatment is likely larger than from 1 treatment to a 
combination. 
App B – 1 
Synopsis and 
throughout 
Wording has been added to reflect that all subjects (both 
arms) will receive remdesivir.  

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 45 of 172 
App B – 
2.2.2.2 
Potential 
benefits 
Updated with the preliminary findings from ACTT-1. 
App B – 
2.2.3.1 
Potential Risks 
of Baricitinib 
Updated with additional language about drug-drug 
interactions as requested by the FDA.  
App B – 
6.1.1 
Study Product 
Description 
Additional wording was added to better describe the 
baricitinib placebo. 
App B – 
6.3.1 
Randomization 
Stratification was revised to match the ordinal scale 
categories rather than separate criteria.  
App B – 
6.3.2 
Blinding and 
masking 
This section was added to clearly describe the blinding of 
study product (baricitinib only), and the unblinding process 
(both routine and unplanned for given subjects).  
App B – 
8.1.3.2 
Exploratory 
endpoints 
Exploratory endpoints were added for cytokine assessments 
to support the mechanism of action of the baricitinib arm.  
App B – 
8.3.5.1 
Reporting of 
AEs 
Added wording for better reporting of new infections, and 
requested by the FDA.  
App B – 
8.3.6.1 
Investigator 
reporting of 
SAEs 
Revised wording for SAE reporting. All SAEs are saptured 
in the regular database. Only those SAEs that are judged to 
be related to either study product are submitted on a larger 
SAE form.  
6.0 
21MAY2020 
 
 
Appendix B – 
1.1 
Exclusion 
Criteria 
Added exclusion for remdesivir use prior to study entry 
(exclusing 3 or more doses). 
Appendix B – 
1.1 
Exclusion 
Criteria 
Separated prior exclusion based on immunosuppressants 
into different categories with different time periods (based 
on FDA’s comments). Small molecule exclusion shortened 
to 1 week and some biologics increased to 3 months.  
Appendix B – 
1.1 
Exclusion 
Criteria 
Revised exclusion for corticosteroid use to permit larger 
amounts prior to enrollment (this is often used for 
syndromes related to COVID such as asthma exacerbation, 
and the prior wording was too restrictive).  
Appendix B – 
4.2 
Scientific 
Rationale for 
Study Design 
This section was blank before, so scientific rationale for 
ACTT-2 was added (scientific rational was previously 
conveyed in the background, but not this section). 
Appendix B – 
5.4 
Lifestyle 
Considerations 
Revised to be more precise regarding what types of studies 
subjects can be co-enrolled in (reflecting questions that 
have arisen during the study). 
Appendix B – 
6.5 
Concomitant 
Medications  
Rewritten extensively for clarity. The one substantive 
change was to permit corticosteroids as needed for standard 
care for non-COVID-19 syndromes.  
7.0 
15Jul2020 
 
 
 
General 
The Public Readiness and Emergency Preparedness Act 
(PREP Act) was moved from Appendix C (for US sites 
only) to the main protocol document as this is available for 
all sites including international sites.  

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 46 of 172 
 
Appendix A 
As ACTT-1 as detailed in Appendix A is completed and the 
database is locked, Appendix A was removed from the 
protocol document (to keep the protocol document a 
manageable size).  
 
Appendix C 
As this is an adaptive study, an additional treatment stage 
“ACTT-3” was added. This stage will evaluate remdesivir + 
interferon beta-1a compared to remdesivir alone (+ placebo 
control). All sections within Appendix C are new with this 
version.  
 
8.0 
17Sep2020 
 
 
Appendix C – 
1.1 
General 
Updated to reflect the DSMB recommendation to close 
enrollment in ordinal category 6, and potential reasons for 
this.  
Appendix C – 
1.1 
Inclusion 
Allows Saliva PCR  for SARS-CoV-2 testing. 
Appendix C – 
1.1 
Exclusion 
Excludes those in ordinal category 6 and 7. 
Appendix C – 
1.2 
Schedule of 
Assessment 
Updated to reflect option additional samples for those that 
agree to genetic testing.  
2.2.1 
Known 
potential risks 
Updated to include risks of genetic testing.  
3 
Objectives and 
Endpoints 
Key secondary endpoint revised to include those in ordinal 
4 and 5 only (from ordinal category 4-6). 
3 
Objectives and 
Endpoints 
Added exploratory endpoint for immunophenotyping. 
6.3.1 
Randomization 
Revised to note closing of ordinal category 6, and specific 
DSMB recommendations.  
6.5.1 and 
6.5.2 
Concomitant 
therapy 
Rewritten for clarity.  
8.1.3.2 
 
Added details for the exploratory endpoint of 
immunophenotyping. 
8.2 
Venipuncture 
volume tables 
Revised tables and added tables to describe the anticipated 
venipuncture volumes for those getting genetic testing and 
PBMC collection.  
8.3.1 
Adverse events 
Reworded to give examples of when new and worsening 
COVID-19 related AEs  should be reported.  
9.3 
Sample Size 
Revised, still with same treatment effect size (and thus same 
recoveries), but with revised calculations for total sample 
size. 
9.0 
10Nov2020 
 
 
Main 
protocol 
document, 
General 
As this is a platform trial, the main protocol document 
serves as a general overview.  These edits remove specific 
details that may be confused or contradict the currently 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 47 of 172 
sections 1, 
1.3, 3, 5, 8  
active study stage.  All of the details that are removed can 
still be found in the study specific appendix.   
Appendix B 
General 
As ACTT-2 as detailed in Appendix B is completed and the 
database is locked, Appendix B was removed from the 
protocol document (to keep the protocol document a 
manageable size). 
Appendix D 
General 
As this is an adaptive study, an additional treatment stage 
ACTT-4 was added to Appendix D. This stage will evaluate  
Baricitinib/Remdesivir vs Dexamethasone/Remdesivir.  
All sections within Appendix D are new with this version.  
10.0 15 Jan 
2021 
 
 
Appendix D– 
2  
Introduction 
Added information about EUA Baricitinib.  
 
Appendix D – 
3 
Objectives 
Added secondary objective: to evaluate the clinical efficacy 
of treatment arms among subjects with a baseline ordinal 
scale of 5 as assessed by the proportion that do not progress 
to ordinal scale 6, 7 or 8 at any time by Day 29. 
Added Exploratory Objective of a Alternative Desirability of 
Outcome Ranking (DOOR) at Day 15 and 29  
 
Appendix D– 
5.2 
 
Exclusion 
Criteria 
 
Revised criterion  #1 to add clarification about those who 
have been early terminated.  
Revised #5, to change the eGFR lower limit from 20 to 15 
per FDA comment, and a clarified that  HD and HF patients 
are also excluded.  
Revised #12: clarified prior Baricitinib use, and pre-study 
use of monoclonal antibody for SARS-CoV-2 
Revised #14: clarified language about dexamethasone 
dosage 
Revised #15: clarified steroid should be po or IV 
Revised#18: clarified COVID 19 vaccine is allowed: 
ADDED #19: to exclude those who have had VTE during 
the current COVID-19 illness. 
Appendix D – 
5.6. 
Strategies 
for 
Recruitment 
and Retention 
 
5.6.1. 
Revised: clarified language on pre-screening and screening 
activities 
 
Appendix D – 
6.1. 
Study 
Product(s) and 
Administration  
 
6.1.2. 
Added language clarifying dosing and administration of 
Remdsivir, and also the anti-inflammatory IP, particularly 
the options to consider if dexamethasone received as per 
SOC prior to enrollment but on day of enrollment.  
 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 48 of 172 
Appendix D – 
6.1 
Study 
Product(s) and 
Administration  
 
6.1.4. Dosing Modifications 
-Remdesivir: changed the cutoff to stop Remdesivir infusion, 
from 20 mL/min  to 15  mL/min as per FDA recommendation 
-Clarified language for holding oral IP and potential need for 
anti-inflammatory coverage and  allowance of off-study anti-
inflammatory after oral IP held for more than 2 days : 
 
Appendix D – 
6.3. 
Measures 
to 
minimize bias 
6.3.2.1.: Unblinding at end of study 
Clarified timepoints when the data will be locked: 
 
6.3.2.3. Unblinding for adverse event.  Clarified language on 
unblinding for SAE as per FDA recommendation.  
Appendix D– 
6.5 
Concomitant 
Medications  
6.5.2.  
Added language on potential clinical need for anti-
inflammatory coverage if oral is held for more than 2 days.  
 
6.5.3: 
Added language about recording steroids use after discharge 
through Day 29 (+6 day window) visit 
 
6.5.4: Clarified procedures for subjects progressing to OS 7  
Added language specifying exceptions to steroid prohibition 
(low dose immunosuppression in solid organ transplant 
patients or mineralocotricoids in shock). 
Appendix D– 
7.1 
Halting Criteria 
and 
Discontinuation 
of 
Study 
Intervention 
 
7.1.1. Revised and restructured language on halting any IP 
due to hypersensitivity, which is clinically significant.  
 
7.1.1.2 Combined the halting rules for oral and IV study 
products as per FDA recommendations 
 
Appendix D – 
8.1 
Screening and 
Efficacy 
Assessments 
8.1.1. Screening procedures  
-Clarified COVID 19 vaccine documentation, also removed 
height and weight from screening procedures, and removed 
hight and weight as screening procedure.  
-Added language clarifying what to do for early 
terminations, before and after receiveing the study drugs. 
-Clarified acceptable timing of pregnancy test during 
current hospitalization (i.e., confinement to hospital)  
 
8.1.2.1 Added language on different oxygen devices, to 
clarify the classification for low versus high flow delivery.  
  
8.1.3. Added details on day 60 visit 
 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 49 of 172 
 
 
11. 
REFERENCES 
1. 
JHU Coronavirus Resource Center. COVID-19 Dashboard by the Center for Systems 
Science and Engineering (CSSE) at Johns Hopkins University (JHU) 2020 [Available from: 
https://coronavirus.jhu.edu/map.html. 
2. 
Hadjadj J, Yatim N, Barnabei L, Corneau A, Boussier J, Smith N, et al. Impaired type I 
interferon activity and inflammatory responses in severe COVID-19 patients. Science. 
2020;369(6504):718-24. 
3. 
Blanco-Melo D, Nilsson-Payant BE, Liu WC, Uhl S, Hoagland D, Moller R, et al. 
Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19. Cell. 
2020;181(5):1036-45 e9. 
4. 
Trouillet-Assant S, Viel S, Gaymard A, Pons S, Richard JC, Perret M, et al. Type I IFN 
immunoprofiling in COVID-19 patients. J Allergy Clin Immunol. 2020;146(1):206-8 e2. 
5. 
Arunachalam PS, Wimmers F, Mok CKP, Perera R, Scott M, Hagan T, et al. Systems 
biological assessment of immunity to mild versus severe COVID-19 infection in humans. 
Science. 2020;369(6508):1210-20. 
6. 
Mantlo E, Bukreyeva N, Maruyama J, Paessler S, Huang C. Antiviral activities of type I 
interferons to SARS-CoV-2 infection. Antiviral Res. 2020;179:104811. 
7. 
Sallard E, Lescure FX, Yazdanpanah Y, Mentre F, Peiffer-Smadja N. Type 1 interferons 
as a potential treatment against COVID-19. Antiviral Res. 2020;178:104791. 
8. 
Stockman LJ, Bellamy R, Garner P. SARS: systematic review of treatment effects. PLoS 
Med. 2006;3(9):e343. 
9. 
Hensley LE, Fritz LE, Jahrling PB, Karp CL, Huggins JW, Geisbert TW. Interferon-beta 
1a and SARS coronavirus replication. Emerg Infect Dis. 2004;10(2):317-9. 
10. 
Lokugamage KG, Hage A, Schindewolf C, Rajsbaum R, Menachery VD. SARS-CoV-2 
is sensitive to type I interferon pretreatment. bioRxiv. 2020. 
11. 
Davoudi-Monfared E, Rahmani H, Khalili H, Hajiabdolbaghi M, Salehi M, Abbasian L, 
et al. Efficacy and safety of interferon beta-1a in treatment of severe COVID-19: A randomized 
clinical trial. medRxiv. 2020:2020.05.28.20116467. 
12. 
Hung IF, Lung KC, Tso EY, Liu R, Chung TW, Chu MY, et al. Triple combination of 
interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to 
hospital with COVID-19: an open-label, randomised, phase 2 trial. Lancet. 
2020;395(10238):1695-704. 
13. 
Zhou Q, Chen V, Shannon CP, Wei XS, Xiang X, Wang X, et al. Interferon-alpha2b 
Treatment for COVID-19. Front Immunol. 2020;11:1061. 
14. 
Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, et al. 
Remdesivir for the Treatment of Covid-19 - Preliminary Report. N Engl J Med. 2020. 
15. 
Group RC, Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, et al. Dexamethasone 
in Hospitalized Patients with Covid-19 - Preliminary Report. N Engl J Med. 2020. 
16. 
Markowitz CE. Interferon-beta: mechanism of action and dosing issues. Neurology. 
2007;68(24 Suppl 4):S8-11. 
Appendix D– 
9.4. 
Statistical 
Analysis 
 
9.4.6.2. Added clarification on analysis in terms of 
multiplicity adjustments.  

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 50 of 172 
17. 
Kasper LH, Reder AT. Immunomodulatory activity of interferon-beta. Ann Clin Transl 
Neurol. 2014;1(8):622-31. 
18. 
Cakebread JA, Xu Y, Grainge C, Kehagia V, Howarth PH, Holgate ST, et al. Exogenous 
IFN-beta has antiviral and anti-inflammatory properties in primary bronchial epithelial cells from 
asthmatic subjects exposed to rhinovirus. J Allergy Clin Immunol. 2011;127(5):1148-54 e9. 
19. 
Ward SE, Loutfy MR, Blatt LM, Siminovitch KA, Chen J, Hinek A, et al. Dynamic 
changes in clinical features and cytokine/chemokine responses in SARS patients treated with 
interferon alfacon-1 plus corticosteroids. Antivir Ther. 2005;10(2):263-75. 
20. 
Wang BX, Fish EN. Global virus outbreaks: Interferons as 1st responders. Semin 
Immunol. 2019;43:101300. 
21. 
Prokunina-Olsson L, Alphonse N, Dickenson RE, Durbin JE, Glenn JS, Hartmann R, et 
al. COVID-19 and emerging viral infections: The case for interferon lambda. J Exp Med. 
2020;217(5). 
22. 
O'Brien TR, Thomas DL, Jackson SS, Prokunina-Olsson L, Donnelly RP, Hartmann R. 
Weak Induction of Interferon Expression by SARS-CoV-2 Supports Clinical Trials of Interferon 
Lambda to Treat Early COVID-19. Clin Infect Dis. 2020. 
23. 
Chu H, Chan JF, Wang Y, Yuen TT, Chai Y, Hou Y, et al. Comparative replication and 
immune activation profiles of SARS-CoV-2 and SARS-CoV in human lungs: an ex vivo study 
with implications for the pathogenesis of COVID-19. Clin Infect Dis. 2020. 
24. 
Hadjadj J, Yatim N, Barnabei L, Corneau A, Boussier J, Pere H, et al. Impaired type I 
interferon activity and exacerbated inflammatory responses in severe Covid-19 patients. 
medRxiv. 2020:2020.04.19.20068015. 
25. 
Alhazzani W, Moller MH, Arabi YM, Loeb M, Gong MN, Fan E, et al. Surviving Sepsis 
Campaign: Guidelines on the Management of Critically Ill Adults with Coronavirus Disease 
2019 (COVID-19). Crit Care Med. 2020;48(6):e440-e69. 
26. 
Zhao Z, Zhang F, Xu M, Huang K, Zhong W, Cai W, et al. Description and clinical 
treatment of an early outbreak of severe acute respiratory syndrome (SARS) in Guangzhou, PR 
China. J Med Microbiol. 2003;52(Pt 8):715-20. 
27. 
Arabi YM, Shalhoub S, Mandourah Y, Al-Hameed F, Al-Omari A, Al Qasim E, et al. 
Ribavirin and Interferon Therapy for Critically Ill Patients With Middle East Respiratory 
Syndrome: A Multicenter Observational Study. Clin Infect Dis. 2020;70(9):1837-44. 
28. 
Omrani AS, Saad MM, Baig K, Bahloul A, Abdul-Matin M, Alaidaroos AY, et al. 
Ribavirin and interferon alfa-2a for severe Middle East respiratory syndrome coronavirus 
infection: a retrospective cohort study. Lancet Infect Dis. 2014;14(11):1090-5. 
29. 
Loutfy MR, Blatt LM, Siminovitch KA, Ward S, Wolff B, Lho H, et al. Interferon 
alfacon-1 plus corticosteroids in severe acute respiratory syndrome: a preliminary study. Jama. 
2003;290(24):3222-8. 
30. 
Hu X, Miller L, Richman S, Hitchman S, Glick G, Liu S, et al. A novel PEGylated 
interferon beta-1a for multiple sclerosis: safety, pharmacology, and biology. J Clin Pharmacol. 
2012;52(6):798-808. 
31. 
Hu X, Shang S, Nestorov I, Hasan J, Seddighzadeh A, Dawson K, et al. COMPARE: 
Pharmacokinetic profiles of subcutaneous peginterferon beta-1a and subcutaneous interferon 
beta-1a over 2 weeks in healthy subjects. Br J Clin Pharmacol. 2016;82(2):380-8. 
32. 
Patten SB, Francis G, Metz LM, Lopez-Bresnahan M, Chang P, Curtin F. The 
relationship between depression and interferon beta-1a therapy in patients with multiple 
sclerosis. Mult Scler. 2005;11(2):175-81. 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Main protocol document 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 51 of 172 
33. 
Ehret M, Sobieraj DM. Prevention of interferon-alpha-associated depression with 
antidepressant medications in patients with hepatitis C virus: a systematic review and meta-
analysis. Int J Clin Pract. 2014;68(2):255-61. 
34. 
Udina M, Hidalgo D, Navines R, Forns X, Sola R, Farre M, et al. Prophylactic 
antidepressant treatment of interferon-induced depression in chronic hepatitis C: a systematic 
review and meta-analysis. J Clin Psychiatry. 2014;75(10):e1113-21. 
35. 
Kavanagh D, McGlasson S, Jury A, Williams J, Scolding N, Bellamy C, et al. Type I 
interferon causes thrombotic microangiopathy by a dose-dependent toxic effect on the 
microvasculature. Blood. 2016;128(24):2824-33. 
36. 
Hegen H, Auer M, Deisenhammer F. Pharmacokinetic considerations in the treatment of 
multiple sclerosis with interferon-beta. Expert Opin Drug Metab Toxicol. 2015;11(12):1803-19. 
37. 
Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected 
with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506. 
38. 
Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to 
COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 
2020. 
39. 
Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for 
mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. 
Lancet. 2020;395(10229):1054-62. 
40. 
Genovese MC, Smolen JS, Takeuchi T. THU0078 Safety Profile Of Baricitinib For The 
Treatment Of Rheumatoid Arthritis Up To 7 Years: An Updated Integrated Safety Analysis. 
Annals of the Rheumatic Diseases. 2019;78:308-309. 
41. 
Favalli EG, Biggioggero M, Maioli G, Caporali R. Baricitinib for COVID-19: a suitable 
treatment? Lancet Infect Dis. 2020. 
42. 
Winthrop KL, Bingham CO, 3rd, Komocsar WJ, Bradley J, Issa M, Klar R, et al. 
Evaluation of pneumococcal and tetanus vaccine responses in patients with rheumatoid arthritis 
receiving baricitinib: results from a long-term extension trial substudy. Arthritis Res Ther. 
2019;21(1):102. 
43. 
Liggins GC, Howie RN. A controlled trial of antepartum glucocorticoid treatment for 
prevention of the respiratory distress syndrome in premature infants. Pediatrics. 1972;50(4):515-
25. 
44. 
Klein JP, Logan B, Harhoff M, Andersen PK. Analyzing survival curves at a fixed point 
in time. Stat Med. 2007;26(24):4505-19. 
45. 
Hochberg Y, Tamhane AC. Multiple comparison procedures. New York: Wiley; 1987. 
xxii, 450 p. p. 
46. 
Proschan MA, Brittain EH. A primer on strong vs weak control of familywise error rate. 
Stat Med. 2020;39(9):1407-13. 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix A - ACTT-1: Remdesivir vs Placebo 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 52 of 172 
 
APPENDIX A - ACTT-1: REMDESIVIR VS PLACEBO 
ACTT- 1 was closed to enrollment on April 29, 2020. 
All follow up visits have been completed. 
ACTT-1 database was locked on June 25, 2020.  
 
 
The details of the ACTT-1 stage of the protocol have been removed from the protocol document. 
Please see protocol version 6.0 dated 25 May 2020 for the final version of the ACTT-1 stage of 
this protocol. 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix B - ACTT-2: Baricitinib/Remdesivir vs Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 53 of 172 
 
APPENDIX B - ACTT-2: BARICITINIB/REMDESIVIR VS. REMDESIVIR  
ACTT-2 was closed to enrollment on June 30, 2020. 
All follow up visits have been completed. 
ACTT-2 database was locked on September 9, 2020.  
 
 
The details of the ACTT-2 stage of the protocol have been removed from the protocol document. 
Please see protocol version 8.0 dated 28 Sep 2020 for the final version of the ACTT-2 stage of 
this protocol.  

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix C - ACTT-3: Remdesivir + Interferon Beta-1a 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 54 of 172 
 
APPENDIX C - ACTT-3: REMDESIVIR + INTERFERON BETA-1A  
1. 
PROTOCOL SUMMARY 
1.1 
ACTT-3 – Synopsis 
Study overview  
ACTT-3 will evaluate the combination of subcutaneous interferon beta-1a and remdesivir 
compared to placebo and remdesivir. In vitro studies suggest significant suppression of the 
intrinsic interferon response following SARS-CoV-2 infection. (1-6) Recent data from several 
studies indicate that there may be a subset of hospitalized patients with COVID-19 who lack a 
prominent interferon signature despite high viral titers and this phenotype may be associated with 
worse clinical outcomes (2-5). Type 1 interferon can inhibit SARS-CoV, MERS-CoV, and SARS-
CoV-2 in vitro (6-9) and recent data suggests that SARS-CoV-2 may be more sensitive than SARS-
CoV to inhibition by interferon (6, 10). Lastly, two small RCTs and an exploratory, non-
randomized clinical trial in hospitalized adult COVID-19 patients suggest a possible clinical 
benefit from treatment with interferon beta (11-13). In summary, there is emerging data that 
suggests interferon may be a good candidate to improve outcomes of patients with COVID-19. 
 
Enrollment Period 
It is anticipated that enrollment may be completed in 3 to 4 months. 
 
General 
The design of ACTT-3 will follow the design of ACTT-1 and ACTT-2. Subjects will be assessed 
daily while hospitalized. If the subjects are discharged from the hospital, they will have a study 
visit at Days 15, 22, and 29. For discharged subjects, it is preferred that the Day 15 and 29 visits 
are in person to obtain safety laboratory tests and OP swab and blood (serum only) samples for 
secondary research as well as clinical outcome data. However, infection control or other 
restrictions may limit the ability of the subject to return to the clinic. In this case, these visits may 
be conducted by phone, home visit or remote telehealth procedure as per institutional standards. If 
Day 15 and 29 visits are conducted by phone or remotely by telehealth procedure, only clinical 
data will be obtained (i.e., no specimens). The Day 22 visit does not have laboratory tests or 
collection of samples and is conducted by phone or remote telehealth procedure.  
 
The trial will enroll only those subjects with mild moderate disease (defined as being in ordinal 
category 4 and 5). The trial initially enrolled ordinal category 6 (those on high flow oxygen or non-
invasive mechanical ventilation), but enrollment in this category was closed September 4, 2020 
after the DSMB reviewed interim safety data and noted concern for risk in this category. Emerging 
data from ACTT-1 (remdesivir vs placebo) (14) and the RECOVERY trial (dexamethasone vs 
standard of care) (15) suggests that the hospitalized population may be a continuum where control 
of the virus is most important in mild disease and control of the host inflammatory response is 
most important late in the disease. Interferon, having antiviral as well - and anti-inflammatory 
properties, may have increased the inflammation seen in those enrolled as ordinal category 6. 
Therefore neither ordinal category 6 or 7 (those on mechanical ventilation or ECMO) will be 
enrolled in this trial. The DSMB confirmed that there was no signal or concern for harm in ordinal 
4 or 5 categories, and they recommended the study continue to enroll patients in those groups. 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix C - ACTT-3: Remdesivir + Interferon Beta-1a 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 55 of 172 
 
The trial will accrue until approximately 831 recoveries. Assuming that 90% of subjects achieve 
recovery in 28 days, the total sample size is approximately 923.  
 
Study Population 
Hospitalized adults (≥18 years old) with COVID-19. 
 
Inclusion Criteria 
1. Admitted to a hospital with symptoms suggestive of COVID-19. 
2. Subject (or legally authorized representative) provides informed consent prior to 
initiation of any study procedures. 
3. Subject (or legally authorized representative) understands and agrees to comply with 
planned study procedures. 
4. Male or non-pregnant female adults ≥ 18 years of age at time of enrollment. 
5. Has laboratory-confirmed SARS-CoV-2 infection as determined by PCR or other 
commercial or public health assay (e.g., NAAT and antigen tests) in any respiratory 
specimen or saliva, as documented by either of the following:  
• PCR or other assay positive in sample collected < 72 hours prior to 
randomization; OR 
• 
PCR or other assay positive in sample collected ≥ 72 hours but < 7 days prior to 
randomization AND progressive disease suggestive of ongoing SARS-CoV-2 
infection. 
Note: if written documentation of the positive test result is not available at the time of 
enrollment (e.g., report came from other institution), the subject may be enrolled but the PCR 
should be repeated at the time of enrollment.  
6. Illness of any duration, and at least one of the following: 
• Radiographic infiltrates by imaging (chest x-ray, CT scan, etc.), OR 
• SpO2 ≤ 94% on room air, OR 
• Requiring supplemental oxygen 
7. Women of childbearing potential must agree to either abstinence or use at least one 
primary form of contraception not including hormonal contraception from the time of 
screening through Day 29.  
8. Agrees to not participate in another clinical trial (both pharmacologic and other types of 
interventions) for the treatment of COVID-19 through Day 29. 
 
Exclusion Criteria 
1. Anticipated discharge from the hospital or transfer to another hospital which is not a 
study site within 72 hours. 
2. Subject meets criteria for ordinal scale category 6 or 7 at the time of screening.  
3. Subject has a positive test for influenza virus during this current hospital admission 
4. Subjects with an estimated glomerular filtration rate (eGFR) < 30 mL/min are excluded 
unless in the opinion of the PI, the potential benefit of receiving remdesivir outweighs the 
potential risk of study participation. 
5. ALT or AST > 5 times the upper limits of normal. 
6. Total white cell blood cell count (WBC) <1500 cells/µL. 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix C - ACTT-3: Remdesivir + Interferon Beta-1a 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 56 of 172 
7. Platelet count <50,000/µL. 
8. History of chronic liver disease (e.g., jaundice, ascites, hepatic encephalopathy, history of 
bleeding esophageal or gastric varices). No laboratory testing is needed.  
9. Pregnancy or breast feeding (lactating women who agree to discard breast milk from Day 
1 to three weeks after the last study product is given are not excluded). 
10. Allergy to any study medication including history of hypersensitivity to natural or 
recombinant interferon beta or human albumin. 
11. Patient has a chronic or acute medical condition or is taking a medication that cannot be 
discontinued at enrollment, that in the judgement of the PI, places them at unacceptable 
risk for a poor clinical outcome if they were to participate in the study.  
12. Received three or more doses of remdesivir, including the loading dose, outside of the 
study for COVID-19.  
13. Received convalescent plasma or intravenous immunoglobulin [IVIg] for the treatment of 
COVID-19. 
14. Received any interferon product within two weeks of screening, either for the treatment 
of COVID-19 or for a chronic medical condition (e.g., multiple sclerosis, HCV 
infection). 
15. Received any of the following in the two weeks prior to screening as treatment of 
COVID-19: 
• small molecule tyrosine kinase inhibitors (e.g., baricitinib, imatinib, gefitinib, 
acalabrutinib, etc.); 
• monoclonal antibodies targeting cytokines (e.g., TNF inhibitors, anti-interleukin-1 
[IL-1], anti-IL-6 [tocilizumab or sarilumab], etc.);  
• monoclonal antibodies targeting T-cells or B-cells as treatment for COVID-19. 
16. Prior enrollment in ACTT-3 
 
Study Intervention 
Subjects will be randomized into two arms (1:1).  
 
Arm 1 
Arm 2 
Interferon beta-1a SQ injection + 
remdesivir IV 
Placebo SQ injection + remdesivir IV 
 
 
All subjects will receive remdesivir as a 200 mg intravenous (IV) loading dose on Day 1, followed 
by a 100 mg once-daily IV maintenance dose during hospitalization up to a maximum of 10 total 
doses (i.e., loading + maintenance doses received during study and pre-study if applicable). The 
duration of dosing may be adjusted by the site similar to what is described in the emergency use 
authorization and based on a subject’s clinical course and ultimate disease severity.  
 
For the subcutaneous interferon beta-1a or placebo component, subjects will receive either active 
product or placebo as follows: 
• Interferon beta-1a will be administered every other day as a 44-microgram subcutaneous 
dose for a total of 4 doses while hospitalized.  

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix C - ACTT-3: Remdesivir + Interferon Beta-1a 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 57 of 172 
• A matching placebo will be administered every other day as a subcutaneous injection for 
a total of 4 doses while hospitalized.  
 
Duration of therapy: 
• IV remdesivir – 5 - 10 consecutive days while hospitalized. A full 10-day course in 
patients still in the hospital is not required per protocol. 
• Subcutaneous (interferon beta-1a or placebo) component – Days 1, 3, 5, and 7 while 
hospitalized. 
• Both stop on discharge from hospital. If readmitted after discharge, see Section 7.4. 
 
1.2 
Schedule of Assessments 
Table 1. Schedule of Assessments (SOA) 
  
Screen 
Baseline  
Study Intervention Period 
Follow-up Visits  
Day +/- Window 
−1 or 
1 
1 
Daily until hospital 
discharge 
157  
± 2 
227 
± 3 
297 
+ 6 
ELIGIBILITY 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
Demographics & Medical Hx 
X 
 
 
 
 
 
Review SARS-CoV-2 results 
X 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY INTERVENTION 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
Administration of 
investigational agent 
 
• Remdesivir daily infusion for 5-10 
days or until discharge.  
• Interferon beta-1a or placebo SQ 
injection on Days 1, 3, 5, and 7, or 
until discharge. 
 
 
 
 
 
 
 
 
 
STUDY PROCEDURES 
 
 
 
 
 
 
Targeted physical exam 
 
X 
 
 
 
 
Vital signs including SpO2 1 
 
X4 
Daily until discharge8 
X9 
 
X9 
Clinical data collection 2  
 
X4 
Daily until discharge8 
X9 
X9 
X9 
Adverse event evaluation 
 
X4 
Daily until discharge8 
X9 
X9 
X9 
Concomitant medication review 
X 
X 
From Day -7 to Day 29 
 
 
 
 
 
 
 
 
 
 
SAFETY LABORATORY 
 
 
 
 
 
 
Safety hematology, chemistry 
and liver tests 
X3 
X4,5,6,7 
Day 3, 5, 8, 11 (all ± 1 
day) if hospitalized6,7 
X9 
 
X9 
Pregnancy test for females of 
childbearing potential 
X3 
 
 
 
 
 
 
 
 
 
 
 
 
RESEARCH LABORATORY FOR ALL SUBJECTS 
 
 
 
Blood for plasma to test by PCR 
for SARS-CoV-2 and cytokines/ 
inflammatory markers 
 
X4 
Day 3, 5, 8, 11 (all ± 1 
day) if hospitalized 
 
 
X9 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix C - ACTT-3: Remdesivir + Interferon Beta-1a 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 58 of 172 
Oropharyngeal swab 10 
 
X4 
Day 3, 5, 8, 11 (all ± 1 
day) if hospitalized 
X9 
 
X9 
Blood for serum (secondary 
research) 
 
X4 
Day 3, 5, 8, 11 (all ± 1 
day) if hospitalized 
X9 
 
X9 
ONLY FOR SUBJECTS CONSENTING FOR GENETIC RESEARCH 
 
 
 
Blood for RNA for transcriptomic 
analysis (in PAXgene tube)  
 
X4 
Day 3, 8 (all ± 1 day) if 
hospitalized 
X9, 11 
 
X9 
Blood for PBMC to T cells/innate 
cells and epigenetics (in CPT) 12 
 
X4,12 
Day 8 (all ± 1 day) if 
hospitalized12 
X9, 11, 12 
 
X9, 12 
Notes: 
1Vital signs include temperature, systolic blood pressure, heart rate, respiratory rate, O2 saturation and level of 
consciousness. Vital signs collected as part of standard care may be used.  
2 Refer to Section 8.1.2 of the protocol for details of clinical data to be collected including ordinal score, NEWS, oxygen 
requirement, mechanical ventilator requirement, etc. 
3 Screening laboratory tests include: white blood cell (WBC) count, platelet count, ALT, AST, and creatinine (and calculate 
an estimated glomerular filtration rate (eGFR) the formula used is determined by the sites, but should be consistent 
throughout the study), and pregnancy test. Laboratory tests performed in the 48 hours prior to enrollment will be accepted 
for determination of eligibility. See Section 8.1.1. for more information about pregnancy tests in post-partum women. 
4 Baseline assessments should be performed prior to first study product administration. Results of Day 1 (baseline) laboratory 
assessment do not need to be reviewed to determine if initial study product should be given. 
5 Laboratory tests performed as part of routine clinical care in the 36 hours prior to first dose will be accepted for the 
baseline safety laboratory tests. Baseline may be the same as the screening laboratory tests.  
6 Safety laboratory tests include WBC count, differential, hemoglobin, platelet count, creatinine, total bilirubin, ALT, AST, 
INR, d-dimer, and C-reactive protein (CRP). Note: D-dimer and CRP values may predict severity and support assessment of 
outcomes and unlike other safety laboratory values, D-dimer and CRP should not be graded.  
7 Any laboratory tests performed as part of routine clinical care within the specified visit window can be used for safety 
laboratory testing.  
8 Daily until hospital discharge or end of study, whichever comes first. See Section 8.1.2.1 for more information about doing 
an ordinal scale assessment on the day after hospital discharge and on the day after a subject dies. 
9 In-person visits are preferred but recognizing quarantine and other factors may limit the subject’s ability to return to the 
site for the visit. In this case, the visit may be performed by phone call, home visit or remote telehealth procedure as per 
institutional standards. If subject is still hospitalized during the follow-up period, they should get Day 15, 22 and 29 
assessments along with the daily clinical data collection. 
• 
If still hospitalized at Day 15 and 29 or returns to the site for an in-person visit or home visit: collect clinical data, 
vital signs, safety laboratory tests, and research laboratory samples (OP swab and serum only) as able.  
• 
If phone call or remote telehealth visit only on Days 15 and 29 and all Day 22 visits: assess adverse events, clinical 
status (ordinal scale), readmission to a hospital, and mortality only. 
10 Oropharyngeal swabs are preferred, but if these are not obtainable, nasopharyngeal or nasal swabs may be substituted.  
11.Subjects who consented for genetic testing and are discharged prior to Day 8 (or Day 11 for proteomics) should get blood 
drawn at Day 15. That is, if subject is missing either a Day 8 Paxgene or CPT sample, or Day 11 proteomic sample, get 
missing sample (proteomics, PAXgene or PBMC) at the Day 15 visit if site is able to do an in-person visit. 
12. Only collected at selected clinical trial sites that are capable of collecting and processing PBMCs. 
  
 
2. 
INTRODUCTION 
2.1 
Background 
 
ACTT-3 – Interferon beta-1a /Remdesivir vs. Placebo/Remdesivir Trial 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix C - ACTT-3: Remdesivir + Interferon Beta-1a 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 59 of 172 
Data from ACTT-1 showed that hospitalized adults with COVID-19 who were randomized to 
receive remdesivir had a shorter time to clinical recovery than those who received placebo (10 vs. 
15 days, recovery rate ratio 1.29 (95% CI 1.12 to 1.49, p<0.001) (14). The odds of improvement 
were higher in the group that received remdesivir than in the placebo group (odds ratio 1.50; 95% 
CI 1.2 to 1.9, p < 0.001). After the release of these preliminary findings, the U.S. Food and Drug 
Administration (FDA) issued an Emergency Use Authorization (EUA) to permit the use of 
remdesivir for treatment of suspected or laboratory-confirmed COVID-19 in adults and children 
hospitalized with severe disease. Remdesivir has also received, full or conditional approval in 
several other countries. On August 28, 2020, the FDA expanded the scope of the EUA to include 
hospitalized patients with suspected or laboratory-confirmed mild or moderate COVID-19 based 
on final data from ACTT-1 and two other clinical studies. 
 
While remdesivir is emerging as the standard of care for COVID-19, significant morbidity and 
mortality still occur despite its use. In ACTT-3, we will evaluate if we can improve clinical 
outcomes among hospitalized COVID-19 adult patients by administering combination therapy 
with subcutaneous interferon beta-1a. Subcutaneous interferon beta-1a was selected because of its 
in vitro potency against SARS-CoV-2, known safety profile, and worldwide availability as a 
licensed drug.  
 
Interferons are naturally occurring proteins and glycoproteins that are produced in response to 
pathogens, cancers and other biologic inducers and effect both innate and adaptive immune 
responses. There are three major classes of interferons with distinct biologic actions: type I 
interferons (-α,-β,-δ,-ε,-ζ,-κ,-τ, and -ω), type II interferons (-γ) and type III interferons (-λ1, -λ2, -
λ3). Interferon beta is produced by several cell types including fibroblasts and macrophages (16, 
17). Natural interferon beta and interferon beta-1a are glycosylated with a single N-linked complex 
carbohydrate. Glycosylation of proteins can affect their stability, activity, aggregation, 
biodistribution, and serum half-life. Interferon beta-1a is a 166 amino acid glycoprotein with a 
molecular weight of approximately 22,500 Daltons. It is produced by recombinant DNA 
technology using genetically engineered Chinese Hamster Ovary cells into which the human 
interferon beta gene has been introduced. The amino acid sequence of interferon beta-1a is 
identical to that of natural human interferon beta. 
Interferon-β has antiviral and anti-inflammatory properties. In response to infection with a single-
stranded RNA virus, type I interferons including interferon beta are initially expressed after 
recognition of double-stranded RNA, the replicative intermediate of the virus, by cellular pattern-
recognition receptors, such as melanoma differentiation-associated gene 5 (MDA-5; also known 
as Ifih1) and toll-like receptors (TLR), leading to activation of interferon regulatory factor (IRF) 
3 and induction of interferon-β expression. Secreted interferon-β then functions in either an 
autocrine or paracrine manner to activate the Janus kinase–signal transducer and activator of 
transcription (STAT) pathway, inducing a wave of de novo transcription of antiviral genes, as well 
as expression of more type I interferon (18). For these reasons, interferon has been suggested as a 
putative therapeutic for SARS-CoV-2 (19, 20).  
Interferon may be a good candidate for the treatment of COVID-19 because in vitro studies suggest 
weak induction of interferon following SARS-CoV-2 infection (6, 8, 10, 21-23). Preliminary data 
from a cohort of hospitalized patients with COVID-19 indicate that there may be a subset of 
patients who lack a prominent interferon signature despite high viral titers and this phenotype may 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix C - ACTT-3: Remdesivir + Interferon Beta-1a 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 60 of 172 
be associated with worse clinical outcomes [(3, 4, 24) and unpublished data, from NIAID’s 
Immune Phenotyping in a COVID-19 Cohort study (IMPACC)]. Type 1 interferon can inhibit 
SARS-CoV, MERS-CoV, and SARS-CoV-2 in vitro (6-8, 25) and recent data suggests that SARS-
CoV-2 may be more sensitive than SARS-CoV to inhibition by interferon (6, 10).  
Cohort studies evaluating the efficacy of type I interferons for the treatment of SARS-CoV and 
MERS-CoV did not demonstrate clinical benefit (26-28). An uncontrolled cohort study of 
subcutaneous interferon alpha in the SARS-CoV-1 outbreak in Canada in 2003 demonstrated 
interferon plus corticosteroids was associated with reduced disease-associated impaired oxygen 
saturation, more rapid resolution of radiographic lung abnormalities, and lower levels of creatine 
kinase. (29) 
In a cohort study of interferon alpha 2b in Wuhan, Hubei Province, China, nebulized interferon 
therapy decreased time to clearance of virus in upper airway secretions by a mean of seven days 
compared to arbidol (a drug with no known anti-SARS-CoV-2 activity) (13).  
In an open-label, randomized study (NCT04276688) in hospitalized adults with mild COVID-19 
disease evaluated lopinavir/ritonavir (LPV/r) and ribavirin plus subcutaneous interferon beta-1b 
(in those initiating treatment <7 days after onset) compared with a LPV/r control group (12). They 
found that combination treatment was associated with shorter median time from treatment 
initiation to negative RT-PCR result in nasopharyngeal swab (7 vs. 12 days), earlier resolution of 
symptoms (4 vs. 8 days), and shorter hospital stay (9 vs. 14.5 days) compared with control (LPV/r). 
There was no significant difference in time to negative RT-PCR result, time to resolution of 
symptoms, or duration of hospital stay between arms among the subgroup of patients who did not 
receive interferon beta-1b. In this study, interferon beta-1b (8 million units on alternate days) was 
administered for 1, 2, or 3 doses when initiated on day 5-6, 3-4, or 1-2, respectively, following 
symptom onset. Fifty-two of 86 patients randomized to the combination treatment arm received 
all 3 drugs, and 41 patients in control arm received LPV/r.  
An open-label, randomized study in hospitalized adults with severe suspected or RT-PCR-
confirmed COVID-19 in Iran evaluated subcutaneous interferon beta-1a (44 mcg SQ, 3 times per 
week for 2 weeks) plus standard care (7 to 10 days of hydroxychloroquine plus LPV/r or 
atazanavir/ritonavir) compared with standard care alone (42 in combined, 39 in control arm) (11). 
Time to clinical response defined as hospital discharge or 2-score improvement in a 6-category 
ordinal scale did not differ significantly between the arms (9.7 vs. 8.3 days); duration of hospital 
stays, ICU stay, and mechanical ventilation also did not differ between the arms. However, a higher 
proportion (67% vs. 44%) of patients in the treatment arm compared with the control arm were 
discharged by day 14 (OR=2.5; 95%CI: 1.05- 6.37). The 28-day overall mortality was significantly 
lower in the interferon group (19% vs. 44%, p=0.015). There were no significant drug reactions 
within 14 days of treatment. 
In summary, the data suggest that SARS-CoV-2 infection may decrease interferon response, and 
two small RCTs in COVID-19 are suggestive of possible benefit from treatment with interferon 
beta. 
2.2 
Risk/Benefit Assessment 
 
Known Potential Risks 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix C - ACTT-3: Remdesivir + Interferon Beta-1a 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 61 of 172 
 
Risks of Phlebotomy 
Potential risks of participating in this trial are those associated with having blood drawn, the IV 
catheterization, possible reactions to the study interventions (as noted in Section 2.2.2 and 2.2.3), 
and breach of confidentiality. 
 
Drawing blood may cause transient discomfort and fainting. Fainting is usually transient and 
managed by having the subject lie down and elevate his/her legs. Bruising at the blood collection 
sites may occur but can be prevented or lessened by applying pressure to the blood draw site for a 
few minutes after the blood is taken. IV catheterization may cause insertion site pain, phlebitis, 
hematoma formation, and infusate extravasation; less frequent but significant complications 
include bloodstream and local infections. Subcutaneous injections may cause pain and discomfort 
and result in erythema and bruising of the skin at the infection site. The use of aseptic (sterile) 
technique will make infection at the site where blood will be drawn or at catheter site less likely. 
 
Risks to Privacy 
Subjects will be asked to provide personal health information (PHI). All attempts will be made to 
keep this PHI confidential within the limits of the law. However, there is a chance that 
unauthorized persons will see the subject’s PHI. All study records will be kept in a locked file 
cabinet or maintained in a locked room at the participating clinical site. Electronic files will be 
password protected. Only people who are involved in the conduct, oversight, monitoring, or 
auditing of this trial will be allowed access to the PHI that is collected. Any publication from this 
trial will not use information that will identify subjects. Organizations that may inspect and/or 
copy research records maintained at the participating site for quality assurance and data analysis 
include groups such as the IRB, NIAID and applicable regulatory agencies (e.g., FDA). For more 
information about confidentiality and privacy see Section 10.1.3. 
 
Risks of Targeted Genetic Testing (applicable only to subjects consenting for genetic 
research) 
Study analyses will not result in discoveries about identity or paternity. This study will not involve 
genetic tests intended to discover disease-determining genes. However, study analyses could 
potentially result in medically relevant incidental findings. In the future, novel disease-associated 
phenotypes may be discovered that might be identified in samples stored under this study. During 
the informed consent process, potential subjects will be informed about the transcriptomics and 
interferon-stimulating-gene (ISG) analysis that will be conducted as part of an exploratory 
analysis. They will be given the opportunity to ask questions and decide if they would like to 
participate in that part of the study. Genetic findings can have emotional and psychological 
consequences as well as implications for health, employability, and insurability for the subject and 
family members. Samples and the resulting data will be coded and kept private. Additionally, to 
protect confidentiality, results will be entered into a password-protected database restricted to the 
PI or appointed designees.  
 
 
Remdesivir  

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix C - ACTT-3: Remdesivir + Interferon Beta-1a 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 62 of 172 
 
Potential Risks of Remdesivir  
Remdesivir is not currently licensed in all countries where this study is conducted. In some 
countries where this study is conducted it is licensed, in some countries it is available under 
Emergency Use Authorization or conditional approvals, and in some countries, it is still considered 
an investigational therapeutic agent. As such, there are limited clinical data available for 
remdesivir.  
 
Hypersensitivity reactions including infusion-related and anaphylactic reactions have been 
observed during and following administration of remdesivir. Signs and symptoms may include 
hypotension, tachycardia, bradycardia, dyspnea, wheezing, angioedema, rash, nausea, vomiting, 
diaphoresis, and shivering.  
 
Asymptomatic transaminase elevations have been observed in healthy volunteers who received 
200 mg of remdesivir followed by 100 mg doses for up to 10 days. Transaminase elevations have 
also been reported in patients with COVID-19 who received remdesivir in clinical trials. As 
transaminase elevations have been reported as a component of COVID-19, including in patients 
receiving placebo in clinical trials of remdesivir, discerning the contribution of remdesivir to 
transaminase elevations in this patient population is challenging. Preliminary data from a large 
randomized trial (ACTT-1) showed no differences in hepatotoxicity between the remdesivir and 
placebo arm. 
 
In nonclinical animal studies, toxicity studies found dose-dependent and reversible kidney injury 
and dysfunction. In clinical studies, no evidence of nephrotoxicity has been observed with single 
doses of remdesivir up to 225 mg or multiple once daily doses of remdesivir 150 mg for up to 14 
days. A 150-mg dose of the solution and lyophilized formulations of remdesivir contains 9 g and 
4.5 g, respectively, of sulfobutylether-beta-cyclodextrin (SBECD), for which the maximum daily 
recommended daily dose (based on a European Medicines Agency (EMA) safety review) is 
approximately 250 mg/kg. Because SBECD is renally cleared, subjects with moderate or severe 
renal impairment may have SBECD exposures greater than those with less severe renal impairment 
or normal renal function. Based on this information, patients with an estimated glomerular 
filtration rate (eGFR) of less than 30 mL/min will be assessed by the PI and they will be eligible 
only if the benefit of participation outweighs the risk. 
 
See Package Insert for full discussion of clinical experience and risks.  
 
Coadministration of remdesivir and chloroquine phosphate or hydroxychloroquine sulfate is not 
recommended based on in vitro data demonstrating an antagonistic effect of chloroquine on the 
intracellular metabolic activation and antiviral activity of remdesivir. In a study using human 
epithelium derived from HeLa-T (Hep2) cells, there was a 2-fold increase in ED50 with an increase 
of chloroquine from 0 to160 nM. Another study that evaluated the co-incubation of 1 uM 
remdesivir with either 1 uM chloroquine or 10 uM chloroquine found that there is a dose dependent 
inhibition of the formation of the active nucleoside triphosphate metabolite of remdesivir.  
 
Currently, SARS-CoV-2 is susceptible to remdesivir. There is potential for SARS-CoV-2 
developing resistance to remdesivir during treatment, which could result in decreased efficacy. 
The clinical impact of the development of resistance is not clear at this time.  

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix C - ACTT-3: Remdesivir + Interferon Beta-1a 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 63 of 172 
 
In vitro induction studies have demonstrated that a clinically relevant interaction with 
contraceptive steroids is considered to be of limited clinical significance. However, for this study, 
the use of hormonal contraception with remdesivir is not recommended as the sole method for 
preventing pregnancy. 
 
 
Potential Benefits of Remdesivir 
ACTT-1 demonstrated that subjects that received remdesivir had a 29% faster time to recovery 
(medians of 10 vs 15 days, recovery rate ratio 1.29 (1.12, 1.49), p<0.001), and a decrease in 
mortality (11.4% vs 15.2% by 28 days, p = 0.07). As a result, all subjects in ACTT-3 will be given 
remdesivir.  
 
This drug may be available outside of clinical trials, though given varying states of licensure (as 
described above) and limited availability, one potential benefit of participating may be receiving 
remdesivir as part of the study.  
 
 
Assessment of Potential Risks and Benefits of Remdesivir 
Remdesivir is generally a well-tolerated medication. There are liver toxicities that have been 
observed in prior studies. These have been self-limited and resolved after cessation of the 
medication. There is the potential for renal toxicities as observed in pre-clinical data. By excluding 
those with elevated liver transaminases and decreased kidney function, and appropriate monitoring 
during the study, we can minimize the risk to subjects. While remdesivir is currently the only 
therapeutic antiviral agent known to be effective for COVID-19, there may not be benefits for an 
individual subject depending on timing of initial infusion relative to disease onset and presence of 
viral replication. However, we will try to mitigate this risk by assessing PCR positivity for 
eligibility and enrolling eligible subjects in a timely manner. The potential risks therefore are 
thought to be acceptable given the potential benefits.  
 
 
Subcutaneous Interferon beta-1a 
 
Potential Risks of Subcutaneous Interferon beta-1a  
Interferon beta-1a was first approved for licensure by the FDA in 1996 for intramuscular injection 
(AVONEX®); a subcutaneous injection was approved in 2002 (Rebif®). Interferon beta-1a is 
indicated for the treatment of patients with relapsing forms of multiple sclerosis and has been 
extensively studied in clinical trials (30, 31).  
In a randomized, double-blind placebo-controlled trial, the most common adverse reactions among 
patients with relapsing multiple sclerosis who received 44 micrograms of subcutaneous interferon 
beta-1a three times per week for two years were depression, headache, influenza-like symptoms 
(e.g., fatigue, fever, rigors, chest pain, back pain, myalgia, arthralgia), abdominal pain, 
lymphadenopathy, leukopenia, transaminitis, and injection site reactogenicity. The most 
frequently reported adverse reactions resulting in clinical intervention (e.g., discontinuation of 
Rebif®, adjustment in dosage, or the need for concomitant medication to treat an adverse reaction) 
were injection site reactions, influenza-like symptoms, depression, and elevation of liver enzymes. 
The influenza-like symptoms typically last for about one day after injection, and the occurrence of 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix C - ACTT-3: Remdesivir + Interferon Beta-1a 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 64 of 172 
these symptoms lessen or go away with time. Additional risks have been described with chronic 
treatment with interferon beta. It is unknown to what degree these risks apply to short term 
treatments, though it should be assumed similar risks exist.  
Interferon beta-1a has been associated with worsening depression and exacerbating psychotic 
disorders. A study by Patten et al., that reviewed data from 23 clinical trials of subcutaneous 
interferon beta-1a involving 3995 multiple sclerosis patients found an association between 
depression and interferon use during the first 6 months of therapy (10% of IFN-treated subjects 
versus 8% of placebo recipients) (32). No association was found between interferon treatment and 
suicide attempts. The most consistent risk factor was a prior history of depression. Depressive 
symptoms are common in the early stages of treatment, but typically peak between 4 and 16 weeks 
(33). Prophylactic treatment with antidepressants reduces the risk of IFN-related depression; 
antidepressants also effectively treat the condition (34). In this inpatient study, it is not feasible to 
assess worsening depression and determine relatedness to study product as critical COVID-19 
illness and long-term confinement in quarantine are likely to worsen symptoms of major 
depression. We will inform potential subjects of the risk at the time of informed consent so they 
can determine whether the benefit of participation outweighs the risk of developing depression or 
having pre-existing symptoms of depression worsen. During the study, subjects with pre-existing 
depression or other psychiatric conditions will continue to receive treatment for these conditions 
as clinically indicated.  
Asymptomatic elevation of liver transaminases can occur among those taking interferon beta-1a. 
These effects are generally transient and transaminase levels normalize upon temporary 
discontinuation of Rebif. Severe hepatic injury including hepatic failure has been reported rarely 
in patients taking interferon beta-1a. In ACTT-3, we will mitigate risk of liver injury by excluding 
patients with elevated AST and/or ALT from participating in the study. For those enrolled, we will 
monitor liver transaminase levels and hold subcutaneous injections when ALT and/or AST >5 
times upper limits of normal. Lastly, we will discontinue subcutaneous injections if subject 
develops symptomatic drug-induced liver injury and/or ALT and/or AST >8 times the upper limits 
of normal.  
Decreased peripheral blood counts have been described among those treated with interferon beta-
1a including leukopenia, thrombocytopenia, neutropenia, lymphocytopenia, and anemia. We will 
mitigate the risk to the subject by limiting participation based on platelet count and WBC count at 
time of screening and actively monitoring the WBC count, differential, and hemoglobin. 
Subcutaneous injections will be held if the subject develops severe leukopenia and/or 
thrombocytopenia. 
Cases of thrombotic microangiopathy (TMA) including thrombotic thrombocytopenic purpura 
(TTP) and hemolytic uremic syndrome have been reported with interferon beta products, including 
Rebif® (35). Some of these cases have been fatal. Cases have been reported several weeks to years 
after starting interferon beta. These adverse reactions have been identified during post-approval 
use of Rebif®. Because these events are passively reported from a population of uncertain size, it 
is not possible to reliably estimate their frequency or relationship to the drug. While the diagnosis 
of TMA may be difficult in hospitalized COVID-19 patients, safety laboratory monitoring will 
enable detection of the characteristic clinical features of TMA including thrombocytopenia, 
microangiopathic hemolytic anemia, and acute kidney injury. The principal treatment of drug-
induced TMA is withdrawal of the suspected drug so subcutaneous injections will be discontinued 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix C - ACTT-3: Remdesivir + Interferon Beta-1a 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 65 of 172 
if clinical signs and symptoms and laboratory findings consistent with TMA are detected. Cases 
will be managed as clinically indicated.  
New or worsening autoimmune disorders have been described including systemic lupus 
erythematosus and autoimmune hepatitis. These adverse reactions have been identified during 
post-approval use of Rebif®. Because these events are passively reported from a population of 
uncertain size, it is not possible to reliably estimate their frequency or relationship to the drug. As 
the risk of COVID-19 is likely larger than these risks, subjects with autoimmune disorders are 
permitted to participate in the study. All potential subjects will be informed of the risk for 
autoimmune diseases worsening or the development of a new autoimmune disorder at the time of 
informed consent. 
Seizures have been temporally associated with interferon beta in clinical trials and post-marketing 
surveillance. It is not known if the events were related to multiple sclerosis, the active drug, or a 
combination of both. According to the package insert, a relationship between occurrence of 
seizures and the use of Rebif® has not been established. The subcutaneous injections (interferon 
beta-1a/placebo) will be discontinued if subject has a seizure that is not attributable to COVID-19, 
a medical complication associated with COVID-19, or other medical condition. 
In clinical trials, the majority of subjects who received Rebif® had inflammation at the injection 
site. Other less common adverse reactions associated with subcutaneous interferon beta-1a 
included necrosis, atrophy, edema and hemorrhage at the injection site. During the study, we will 
alternate the injections site and monitor for signs of local reaction.  
Rebif® contains albumin derived from human blood. Because of this, patients who have a history 
of hypersensitivity to human albumin will not be allowed to participate in the study. In addition, 
patients with a history of hypersensitivity to natural or recombinant interferon or any other 
component of the formulation will not be allowed to participate. Anaphylaxis is a rare complication 
and allergic reactions including skin rash and urticaria can also occur. If a subject develops 
anaphylaxis that is temporally related to subcutaneous injection, the injections will be 
discontinued. 
Data from a large population-based cohort study, as well as other published studies over several 
decades, have not identified a drug-associated risk of major birth defects with the use of interferon 
beta during early pregnancy. Findings regarding a potential risk for low birth weight or miscarriage 
with the use of interferon beta in pregnancy have been inconsistent. However, interferon beta may 
cause harm to the fetus based on animal reproduction studies. While no teratogenic effect on fetal 
development were observed in pregnant non-human primates (NHP) given interferon beta-1a at 
100 times the recommended weekly human dose based on a body surface area comparison, 
abortifacient effects were observed in NHPs after three to five doses were administered at this 
level. There are no adequate and well-controlled studies with interferons in pregnant women to 
determine if interferon can cause miscarriage in humans. Because of this, pregnant women will 
not be allowed to participate in the study. 
 
It is not known whether interferon beta-1a is excreted in human milk. Because of the potential of 
serious adverse reactions in nursing infants, lactating women will need to agree to discard breast 
milk from Day 1 to three weeks after the last study product is given.  

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix C - ACTT-3: Remdesivir + Interferon Beta-1a 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 66 of 172 
 
See package insert for Rebif® for full discussion of clinical experience and risks.  
 
 
Potential Benefits of Subcutaneous Interferon beta-1a 
Subcutaneous interferon beta-1a may or may not improve the clinical outcome of an individual 
subject with COVID-19 who participates in this trial. However, there is potential benefit to society 
from their participation in this study resulting from insights gained about the therapeutic agents 
under study as well as the natural history of the disease. While there may not be benefits for an 
individual subject, there may be benefits to society if another safe, efficacious therapeutic agent 
can be identified during this global COVID-19 pandemic.  
 
 
Assessment of Potential Risks and Benefits of Subcutaneous Interferon beta-1a  
In the context of the cumulative knowledge for subcutaneous interferon beta-1a regarding the 
safety profile, the potential to inhibit SARS-CoV-2 replication and favorable distribution in tissues 
including the lungs, the benefit/risk balance for this study is assessed to be favorable. Given what 
we learned from our staged enrollment approach including frequent DSMB safety reviews, as of 
September 4, 2020, patients with an ordinal scale score of 6 at enrollment are not eligible for 
enrollment, and those with an ordinal scale score of 4 or 5 at enrollment who progress to a 6 or 7, 
will have injectable study product discontinued. In this way, we maximize the potential benefit for 
subjects enrolled in ACTT-3 while preventing harm.  
 
3. 
OBJECTIVES AND ENDPOINTS 
The overall objective of the study is to evaluate the clinical efficacy and safety of different 
investigational therapeutics relative to the control arm among hospitalized adults who have 
COVID-19. 
 
OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
Primary 
 
To evaluate the clinical efficacy of RDV+ 
interferon beta-1a compared to RDV + 
placebo, as assessed by time to recovery for 
patients with baseline ordinal score 4, 5 and 6. 
Day of recovery is defined as the first day on 
which the subject satisfies one of the 
following three categories from the ordinal 
scale: 
• Hospitalized, not requiring supplemental 
oxygen – no longer requires ongoing 
medical care; 
• Not hospitalized, but new or increased 
limitation on activities and/or new or 
increased requirement for home oxygen; 
• Not hospitalized, no limitations on 
activities. 
Recovery is evaluated up until Day 29 (+ 6 
days). 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix C - ACTT-3: Remdesivir + Interferon Beta-1a 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 67 of 172 
OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
Key Secondary  
 
To evaluate the clinical efficacy of RDV+ 
interferon beta-1a compared to RDV + 
placebo, as assessed by clinical status (8-point 
ordinal scale) at Day 15 for patients with 
baseline ordinal score 4 and 5. 
 
 
 
• Death; 
• Hospitalized, on invasive mechanical 
ventilation or ECMO; 
• Hospitalized, on non-invasive ventilation 
or high flow oxygen devices; 
• Hospitalized, requiring supplemental 
oxygen; 
• Hospitalized, not requiring supplemental 
oxygen – requiring ongoing medical care 
(COVID-19 related or otherwise); 
• Hospitalized, not requiring supplemental 
oxygen – no longer requires ongoing 
medical care; 
• Not hospitalized, but new or increased 
limitation on activities and/or new or 
increased requirement for home oxygen; 
• Not hospitalized, no limitations on 
activities. 
To evaluate the clinical efficacy of RDV+ 
interferon beta-1a compared to RDV + 
placebo, as assessed by time to recovery for 
patients  with a baseline ordinal score of 4 and 
5. 
 
Day of recovery is defined as the first day on 
which the subject satisfies one of the 
following three categories from the ordinal 
scale: 
• Hospitalized, but not requiring 
supplemental oxygen and– no longer 
requires ongoing medical care; 
• Not hospitalized, but new or increased 
limitations on activities and/or new or 
increased requirement for home oxygen; 
• Not hospitalized, no limitations on 
activities. 
 
Recovery is evaluated up until Day 29 (+ 6 
days). 
Additional Secondary- by baseline severity 
moderate (4 or 5) and severe (6) 
 
To evaluate the clinical efficacy of RDV+ 
interferon beta-1a compared to RDV + 
placebo as assessed by: 
• Clinical Severity 
o Ordinal scale: 
 Time to an improvement of one 
category and two categories from 
 
 
 
• Clinical outcome assessed using ordinal 
scale daily while hospitalized and on Days 
15, 22, and 29. 
 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix C - ACTT-3: Remdesivir + Interferon Beta-1a 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 68 of 172 
OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
Day 1 (baseline) using an ordinal 
scale. 
 Subject clinical status using ordinal 
scale at Days 3, 5, 8, 11, 15, 22, and 
29.  
 Mean change in the ordinal scale 
from Day 1 to Days 3, 5, 8, 11, 15, 
22, and 29. 
 
 
 
 
 
 
 
o National Early Warning Score 
(NEWS): 
 Time to discharge or to a NEWS of 
≤ 2 and maintained for 24 hours, 
whichever occurs first.  
 Change from Day 1 to Days 3, 5, 8, 
11, 15, and 29 in NEWS.  
 
 
 
• NEWS assessed daily while hospitalized 
and on Days 15 and 29. 
o Oxygenation: 
 Oxygenation use up to Day 29. 
 Incidence and duration of new 
oxygen use during the study. 
 
 
• Days of supplemental oxygen (if 
applicable) up to Day 29 
 
o Non-invasive ventilation/high flow 
oxygen: 
 Non-invasive ventilation/high flow 
oxygen use up to Day 29. 
 Incidence and duration of new non-
invasive ventilation or high flow 
oxygen use during the study. 
 
• Days of non-invasive ventilation/high 
flow oxygen (if applicable) up to Day 29 
o Invasive Mechanical Ventilation / 
extracorporeal membrane oxygenation 
(ECMO): 
 Ventilator / ECMO use up to Day 
29. 
 Incidence and duration of new 
mechanical ventilation or ECMO use 
during the study.  
 
 
• Days of invasive mechanical 
ventilation/ECMO (if applicable) up to 
Day 29. 
 
• Hospitalization 
o Duration of hospitalization (days).  
 
 
• Days of hospitalization up to Day 29 
• Mortality 
o 14-day mortality 
 
• Date and cause of death (if applicable) 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix C - ACTT-3: Remdesivir + Interferon Beta-1a 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 69 of 172 
OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
o 28-day mortality 
 
 
• Laboratory efficacy: 
o d-dimer, and C-reactive protein (CRP) 
over time 
 
 
• d-dimer, CRP on Day 1; Days 3, 5, 8, and 
11 (while hospitalized); and Days 15 and 
29 (if attends in-person visit or still 
hospitalized). 
 
2. To evaluate the safety of RDV+ interferon 
beta-1a compared to RDV + placebo as 
assessed overall, and by baseline ordinal scale 
category (categories 4 and 5 versus category 
6) by: 
• Cumulative incidence of SAEs through 
Day 29. 
• Cumulative incidence of Grade 3 and 4 
clinical and/or laboratory AEs through 
Day 29. 
• Discontinuation or temporary 
suspension of study product 
administrations (for any reason) 
• Changes in white blood cell (WBC) 
count with differential, hemoglobin, 
platelets, creatinine, total bilirubin, 
alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), and 
INR over time (analysis of lab values in 
addition to AEs noted above). 
 
 
 
 
• SAEs 
• Grade 3 and 4 AEs  
• WBC count with differential, 
hemoglobin, platelets, creatinine, total 
bilirubin, ALT, AST, and INR on Day 1; 
Days 3, 5, 8, and 11 (while hospitalized); 
and Days 15 and 29 (if attends in-person 
visit or still hospitalized). 
 
Exploratory  
 
To evaluate the virologic efficacy of RDV+ 
interferon beta-1a compared to RDV + 
placebo as compared to the control arm as 
assessed by: 
• Percent of subjects with SARS-CoV-2 
detectable in OP sample at Days 3, 5, 
8, 11, 15, and 29.  
• Quantitative SARS-CoV-2 virus in OP 
sample at Days 3, 5, 8, 11, 15, and 29. 
 
 
 
 
 
 
• Qualitative and quantitative polymerase 
chain reaction (RT-PCR) for SARS-CoV-
2 in OP swab on Day 1; Days 3, 5, 8, and 
11 (while hospitalized); and Days 15 and 
29 (if attends in-person visit or still 
hospitalized). 
 
• Deep sequencing of the SARS-CoV-2 
virus for those subjects with sustained 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix C - ACTT-3: Remdesivir + Interferon Beta-1a 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 70 of 172 
OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
• Development of resistance of SARS-
CoV-2 in OP sample at Days 3, 5, 8, 
11, 15, and 29.  
 
 
• Quantitative SARS-CoV-2 virus in 
blood at Days 3, 5, 8, and 11. 
 
viral shedding (to be defined after 
qualitative PCR results are available)_ 
 
• Qualitative and quantitative PCR for 
SARS-CoV-2 in blood on Day 1; Days 3, 
5, 8, and 11 (while hospitalized). 
 
To define immunophenotype of subjects most 
likely to benefit from interferon beta-1a by 
analyzing markers of inflammation, 
transcriptomics, epigenetics and cell 
populations. 
• Proteomic analysis of cytokines, markers 
of inflammation, and other circulating 
proteins Day 1; Days 3, 5, 8, and 11 
(while hospitalized) and Day 29 
• Additionally, in a subset of subjects: 
o Transcriptomic analysis of RNA in 
whole blood and individual immune 
cells on Days 1, 3, 8 and 29 
o Analysis of interferon-stimulated-
gene (ISG) expression levels on 
Days 1, 3, 8 and 29 
o Assessment of T-cell and innate 
immune cells subpopulations in 
PBMCs on Days 1, 3, 8 and 29 
o Epigenetic modifications based on 
analysis of DNA extracted from 
PBMCs on Days 1 and 29 
 
 
 
4. 
STUDY DESIGN 
4.1 
Overall Design 
ACTT-3 will evaluate the combination of subcutaneous interferon beta-1a and remdesivir 
compared to remdesivir plus placebo. Subjects will be assessed daily while hospitalized. If the 
subjects are discharged from the hospital, they will have a study visit at Days 15, 22, and 29. For 
discharged subjects, it is preferred that the Day 15 and 29 visits are in person to obtain safety 
laboratory tests and OP swab and blood (serum only) samples for secondary research as well as 
clinical outcome data. However, infection control or other restrictions may limit the ability of the 
subject to return to the clinic. In this case, these visits may be conducted by phone call, home visit 
or remote telehealth procedure as per institutional standards. If the Day 15 and 29 visits are 
conducted by phone or remotely, only clinical data will be obtained (i.e., no specimens collected). 
The Day 22 visit does not have laboratory tests or collection of samples and is conducted by phone 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix C - ACTT-3: Remdesivir + Interferon Beta-1a 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 71 of 172 
or remote telehealth procedure unless the subject is still hospitalized at Day 22 and then the visit 
is conducted in person.  
 
The primary outcome is time to recovery by Day 29. Recovery is defined by discharge from the 
hospital (i.e., ordinal scale categories 1 or 2) or subject is still hospitalized, but not requiring 
supplemental oxygen and no longer requires ongoing medical care (category 3). See table above 
in Section 3 for more details.  
4.2 
Scientific Rationale for Study Design 
As the study is a multicenter, multinational randomized controlled study, we will be able to acquire 
rigorous data about the safety and efficacy of investigational therapeutic agents for COVID-19 
that will lead to generalizable evidence. Randomization is essential for establishing efficacy of 
these new therapeutic agents. Last, collecting clinical and virologic data on enrolled subjects using 
a standardized timeline and collection instruments should provide valuable information about the 
clinical course of and morbidities associated with COVID-19 in a diverse group of hospitalized 
adults. 
 
The ACTT-3 design will specifically evaluate the contribution of interferon beta-1a antiviral and 
immunomodulatory effect in combination with remdesivir while the control arm will receive the 
monotherapy with remdesivir plus placebo.  
 
4.3 
Justification for Dose 
 
Justification for Dose of Remdesivir 
The dose of remdesivir used in this study will be the same dose used in ACTT-1 and ACTT-2 and 
that is available under the EUA, with updates on duration of therapy and dosing for patients with 
low eGFR to reflect the wording in the EUA. The duration of dosing may be adjusted by the site 
similar to what is described in the EUA. The maximum number of doses to be given during 
hospitalization is ten doses. This includes the loading dose and all maintenance doses given during 
the study and pre-study if applicable. 
 
 
Justification for Dose of Subcutaneous Interferon beta-1a  
We will be administering a subcutaneous 44 mcg dose of Rebif® (interferon beta-1a) every other 
day for 4 doses while a subject is hospitalized. This is the dose that has been used in other COVID-
19 clinical trials including the World Health Organization’s Solidarity Trial.  
 
Interferon beta has a bioavailability of about 30% after subcutaneous or intramuscular 
administration, demonstrating peak serum concentrations within several hours of a dose (36). 
Serum levels of interferon beta-1a typically peak 3 to 15 hours after intramuscular administration. 
After injection, it is absorbed mainly in the lymphatics. Interferon beta is distributed throughout 
the body, and likely does not cross the blood-brain barrier. It is unclear whether interferon beta 
crosses the placenta. Interferon beta is excreted by hepatic and renal pathways. In healthy 
volunteers, a single subcutaneous injection of 60 mcg of Rebif® resulted in a peak serum 
concentration (Cmax) of 5.1 ± 1.7 IU/mL (mean ± SD), with a median time of peak serum 
concentration (Tmax) of 16 hours. The serum elimination half-life (t1/2) was 69 ± 37 hours. 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix C - ACTT-3: Remdesivir + Interferon Beta-1a 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 72 of 172 
Following every other day subcutaneous injections, an increase in AUC of approximately 240% 
was observed, suggesting that accumulation of interferon beta-1a occurs after repeat 
administration. Total clearance is approximately 33-55 L/hours.  
5. 
STUDY POPULATION 
Male and non-pregnant female adults ≥18 years of age or older with COVID-19 and who meet all 
eligibility criteria will be enrolled at up to approximately 100 clinical trial sites globally. The target 
population should reflect the community at large. The estimated time from screening (Day -1 or 
Day 1) to end of study for an individual subject is approximately 29 days.  
 
Subject Inclusion and Exclusion Criteria must be confirmed by any clinician named on the 
delegation log. If there is any uncertainty, the PI should make the decision on whether a potential 
subject is eligible for study enrollment. There is no exclusion for receipt of SARS-CoV-2 vaccine 
(experimental or licensed). 
 
5.1 
Inclusion Criteria 
1. Admitted to a hospital with symptoms suggestive of COVID-19. 
2. Subject (or legally authorized representative) provides informed consent prior to 
initiation of any study procedures. 
3. Subject (or legally authorized representative) understands and agrees to comply with 
planned study procedures. 
4. Male or non-pregnant female adults ≥ 18 years of age at time of enrollment. 
5. Has laboratory-confirmed SARS-CoV-2 infection as determined by PCR or other 
commercial or public health assay (e.g., NAAT and antigen tests) in any respiratory 
specimen or saliva, as documented by either of the following:  
• PCR or other assay positive in sample collected < 72 hours prior to 
randomization; OR 
• 
PCR or other assay positive in sample collected ≥ 72 hours but < 7 days prior to 
randomization AND progressive disease suggestive of ongoing SARS-CoV-2 
infection. 
Note: if written documentation of the positive test result is not available at enrollment (e.g. 
report from other institution), the subject may be enrolled but the PCR should be repeated at 
the time of enrollment.  
6. Illness of any duration, and at least one of the following: 
• Radiographic infiltrates by imaging (chest x-ray, CT scan, etc.), OR 
• SpO2 ≤ 94% on room air, OR 
• Requiring supplemental oxygen 
 
7. Women of childbearing potential must agree to either abstinence or use at least one 
primary form of contraception not including hormonal contraception from the time of 
screening through Day 29.  
8. Agrees to not participate in another clinical trial (both pharmacologic and other types of 
interventions) for the treatment of COVID-19 through Day 29. 
 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix C - ACTT-3: Remdesivir + Interferon Beta-1a 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 73 of 172 
5.2 
Exclusion Criteria 
1. Anticipated discharge from the hospital or transfer to another hospital which is not a 
study site within 72 hours. 
2. Subject meets criteria for ordinal scale category 6 or 7 at the time of screening.  
3. Subject has a positive test for influenza virus during this current hospital admission. 
4. Subjects with an estimated glomerular filtration rate (eGFR) < 30 mL/min are excluded 
unless in the opinion of the PI, the potential benefit of receiving remdesivir outweighs the 
potential risk of study participation. 
5. ALT or AST > 5 times the upper limits of normal. 
6. Total white cell blood cell count (WBC) <1500 cells/µL. 
7. Platelet count <50,000/µL. 
8. History of chronic liver disease (e.g., jaundice, ascites, hepatic encephalopathy, history of 
bleeding esophageal or gastric varices). No laboratory testing is needed.  
9. Pregnancy or breast feeding (lactating women who agree to discard breast milk from Day 
1 until three weeks after the last study product is given are not excluded). 
10. Allergy to any study medication including history of hypersensitivity to natural or 
recombinant interferon beta or human albumin. 
11. Patient has a chronic or acute medical condition or is taking a medication that cannot be 
discontinued at enrollment, that in the judgement of the PI, places them at unacceptable 
risk for a poor clinical outcome if they were to participate in the study.  
12. Received three or more doses of remdesivir, including the loading dose, outside of the 
study for COVID-19.  
13. Received convalescent plasma or intravenous immunoglobulin [IVIg]) for the treatment 
of COVID-19. 
14. Received any interferon product within two weeks of screening, either for the treatment 
of COVID-19 or for a chronic medical condition (e.g., multiple sclerosis, HCV infection) 
15. Received any of the following in the two weeks prior to screening as treatment of 
COVID-19: 
• small molecule tyrosine kinase inhibitors (e.g. baricitinib, imatinib, gefitinib, 
acalabrutinib, etc.); 
• monoclonal antibodies targeting cytokines (e.g., TNF inhibitors, anti-interleukin-1 
[IL-1], anti-IL-6 [tocilizumab or sarilumab], etc.);  
• monoclonal antibodies targeting T-cells or B-cells as treatment for COVID-19 
16. Prior enrollment in ACTT-3 
 
 
Exclusion of Specific Populations 
Children and adolescents will not be included in this trial. Remdesivir has only been used in a 
small number of pediatric patients. Interferon beta-1a has not been studied in pediatric patients, 
and no formal trials of Rebif® have been conducted in children or adolescents. Initial information 
about the epidemiology of COVID-19 indicates that the overwhelming burden of severe disease 
occurs among older adults, especially those with comorbidities. Given significant gaps in 
knowledge in this population, and a low incidence of severe morbidity/ mortality in children, this 
research is not known to have the prospect of direct benefit to individual child subjects, and the 
risk/benefits do not warrant inclusion of this population into this trial at this time.  
 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix C - ACTT-3: Remdesivir + Interferon Beta-1a 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 74 of 172 
In nonclinical reproductive toxicity studies, remdesivir demonstrated no adverse effect on embryo-
fetal development when administered to pregnant animals. Embryonic toxicity was seen when 
remdesivir was initiated in female animals prior to mating and conception, but only at a 
systemically toxic dose. Remdesivir has not been studied in pregnant women. Toxicology studies 
in all tested animal species (rats, mice and monkeys) showed that subcutaneous interferon beta-1a 
was well tolerated both in single-dose and repeat-dose studies. Interferon beta-1a showed no 
evidence of mutagenicity or teratogenicity, however it may have abortifacient potential. Because 
the effects of the study products on the fetus and the pregnant woman are not fully known, pregnant 
women will not be eligible for the trial.  
 
In animal studies, remdesivir metabolites have been detected in the nursing pups of mothers given 
remdesivir. It is not known whether remdesivir is secreted in human milk. Similar animal studies 
have not been conducted for Rebif® and it is not known whether subcutaneous interferon beta-1a 
is excreted in human milk. Because the effects of remdesivir and subcutaneous interferon beta-1a 
on the breastfeeding infant is not known, women who are breast feeding will not be eligible for 
the trial unless they agree to discard breast milk produced from Day 1 to three weeks after the last 
study product is given.  
 
5.3 
Inclusion of Vulnerable Subjects 
Certain subjects are categorized as vulnerable populations and require special treatment with 
respect to safeguards of their well-being. For this clinical trial, examples include cognitively 
impaired or mentally disabled persons and intubated individuals who are sedated. When it is 
determined that a potential research subject is cognitively impaired, federal and institutional 
regulations permit researchers to obtain consent from a legally authorized representative (LAR). 
The study team will obtain consent from these vulnerable subjects using an IRB-approved 
protocol- specific process for consent using a LAR. For this clinical trial, we will not enroll 
prisoners or detainees as subjects.  
 
For subjects for whom a LAR gave consent, during the course of the study, if the subject regains 
the capacity to consent, informed consent must be obtained from the subject and the subject offered 
the ability to leave the study if desired. 
5.4 
Lifestyle Considerations 
During this study, subjects are asked to: 
• Refrain from drinking alcohol through Day 15.  
• Avoid getting pregnant during the study from Day 1 through Day 29. 
• Agreed not to participate in another clinical trial for the treatment of COVID-19 or SARS-
CoV-2. This includes interventional trials that evaluate treatment of SARS-CoV-2 
infection as well as the disease pathogenesis (e.g., experimental treatment trials for the 
COVID-19-related thrombo-occlusive disease respiratory complications and dysregulated 
immune response to the virus). Co-enrollment for natural history studies of COVID-19 or 
studies of SARS-CoV-2 diagnostics are permitted; however, participation in both ACTT 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix C - ACTT-3: Remdesivir + Interferon Beta-1a 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 75 of 172 
and these studies can only occur if the recommended blood collection volumes are not 
exceeded.  
5.5 
Screen Failures 
Following consent, after the screening evaluations have been completed, the investigator or 
designee is to review the inclusion/exclusion criteria and determine the subject’s eligibility for the 
study. If there is any uncertainty, the PI should make the decision on whether a potential subject 
is eligible for study enrollment.  
 
Only basic demographic information and the reason(s) for ineligibility will be collected on screen 
failures. Subjects who are found to be ineligible will be told the reason(s) for ineligibility. 
 
Individuals who do not meet the criteria for participation in this study (screen failure) because of 
an abnormal laboratory finding may be rescreened once.  
5.6 
Strategies for Recruitment and Retention 
 
Recruitment 
It is anticipated that patients with COVID-19 will present for hospitalization to participating 
clinical trial sites, and that no external recruitment efforts towards potential subjects are needed. 
Recruitment efforts may also include dissemination of information about this trial to other medical 
professionals / hospitals. The IRB will approve the recruitment process and all materials provided 
prior to any recruitment to prospective subjects directly. 
 
Screening will begin with a brief discussion with study staff. Some will be excluded based on 
demographic data and medical history (e.g., pregnant, < 18 years of age, chronic liver disease, 
etc.). Information about the study will be presented to potential subjects or LAR and questions will 
be asked to determine potential eligibility. Screening procedures can begin only after informed 
consent is obtained. 
 
 
Retention 
Retention of subjects is critical to the success of the trial since the primary endpoint is measured 
through Day 29 (+ 6-day window) and every effort should be made to retain subjects in the study. 
As such, after hospital discharge, subjects will be reminded of subsequent study visits and every 
effort will be made accommodate the subject’s schedule to facilitate follow-up within the specified 
visit window. However, there are many circumstances impact a site’s ability to obtain outcome 
information after discharge. For example, given the clinical course of COVID-19, a subject may 
be readmitted to another hospital after discharge and therefore be unavailable at Day 15 or Day 
22. Even if a study visit is missed or study product is discontinued, every effort should be made to 
keep subjects in the study to monitor for safety, mortality and ordinal scale at Day 29. Subjects 
should not be withdrawn from the study because a site is unable to contact them for a follow-up 
visit.  
 
Another common lost-to-follow-up scenario during ACTT-1, involved subjects (or their LARs) 
asking that the study products and blood draws be discontinued due to terminal illness. These 
subjects should also be encouraged to remain in study for the final Day 29 ordinal scale 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix C - ACTT-3: Remdesivir + Interferon Beta-1a 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 76 of 172 
determination by chart review or phone call. To facilitate retention, follow-up visits may be 
conducted by phone, home visit or remote telehealth procedure as per institutional standards if in-
person visits at the clinical site on Days 15 and 29 are not feasible. Day 22 visit is by phone call 
or remote telehealth procedure. 
 
 
Compensation Plan for Subjects  
Compensation, if any, will be determined locally and in accordance with local IRB requirements 
and approval.  
 
 
Costs 
There is no cost to subjects for the research tests, procedures/evaluations and study product while 
taking part in this trial. Procedures and treatment for clinical care including costs associated with 
hospital stay may be billed to the subject, subject’s insurance or third party. 
 
6. 
STUDY PRODUCT 
6.1 
Study Product(s) and Administration  
 
Subjects will be randomized into one of two arms (1:1). 
 
 
Arm 1 
Arm 2 
Interferon beta-1a SQ injection + remdesivir IV 
Placebo SQ injection + remdesivir IV 
 
 
Study Product Description  
Remdesivir component: 
Remdesivir is a single diastereomer monophosphoramidate prodrug designed for the intracellular 
delivery of a modified adenine nucleoside analog GS-441524. In addition to the active ingredient, 
the lyophilized and solution formulations of remdesivir contain the following inactive ingredients: 
water for injection, SBECD, and hydrochloric acid and/or sodium hydroxide. 
 
Interferon beta-1a /Subcutaneous Placebo component: 
Rebif®, an interferon beta-1a, is a purified 166 amino acid glycoprotein produced by recombinant 
DNA technology using genetically engineered Chinese Hamster Ovary cells into which the human 
interferon beta gene has been introduced. The amino acid sequence of Rebif® is identical to natural 
fibroblast derived human interferon beta.  
 
Rebif® (interferon beta-1a) is formulated as a sterile solution in a prefilled syringe intended for 
subcutaneous injection. Each prefilled syringe contains 0.5 mL of Rebif®. Each 0.5 mL of Rebif® 
will contain 44 mcg of interferon beta-1a, 4 mg human albumin, USP; 27.3 mg mannitol, USP; 
0.4 mg sodium acetate; and water for injection, USP.  

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix C - ACTT-3: Remdesivir + Interferon Beta-1a 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 77 of 172 
Placebo subcutaneous injection will be either: 
 Matching empty syringes that will be filled with 0.5 mL 0.9% normal saline at each site 
pharmacy; OR 
 Matching syringes prefilled with 0.5 mL 0.9% normal saline or 0.5 mL sterile water for 
injection.  
 
 
Dosing and Administration 
All subjects will receive remdesivir as a 200 mg intravenous (IV) loading dose on Day 1, followed 
by a 100 mg once-daily IV maintenance dose up to a 10-day total course while hospitalized. 
Enrollment may proceed for subjects who received one or two doses of remdesivir under EUA or 
similar mechanism prior to randomization. If subjects already received the loading dose, then start 
at 100 mg/day on Day 1. Any doses of remdesivir under an EUA (or similar mechanism) within 1 
week of enrollment will be counted, so the maximum number of remdesivir doses given to a 
subject is 10 (i.e. EUA doses + doses on this trial). If one or two doses of remdesivir were 
administered (under EUA or similar mechanism) prior to study enrollment, this should be 
documented in eClinical as a concomitant medication given prior to Day 1. 
 
For the subcutaneous interferon beta-1a / placebo component, subjects will receive either active 
product or placebo as follows: 
• Interferon beta-1a will be administered every other day as a 44-microgram subcutaneous 
dose for a total of 4 doses while hospitalized  
• A saline placebo will be administered every other day as a subcutaneous injection for a 
total of 4 doses while hospitalized 
 
Study teams will instruct the administering nurse to use a different site for each subcutaneous 
injection. If there is an injection site reaction including skin that is irritated, edematous, reddened, 
bruised, or necrotic, the study product should not be administered into the affected area. If possible, 
select a unique site for each subsequent injection. 
 
Dosing of the two medications does not need to occur at the same time. 
 
Duration of therapy: 
• IV remdesivir – up to 10 consecutive days while hospitalized (i.e., maximum of 10 total 
infusions pre-enrollment and during study). 
• Subcutaneous (Interferon beta-1a or placebo) component – Days 1, 3, 5, and 7, while 
hospitalized.  
• Both stop on discharge from hospital. If readmitted after discharge, see Section 7.4. 
 
 
Dose Escalation 
Not Applicable 
 
 
Dose Modifications 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix C - ACTT-3: Remdesivir + Interferon Beta-1a 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 78 of 172 
The protocol-required safety laboratories (per the SOA) are anticipated to be sufficient for 
evaluating for dose modifications, but if other laboratory data obtained as part of standard care are 
available, these should also be used in the evaluation.  
 
Remdesivir component: 
The infusion should be held and not given if the subject is found to have any of the following 
laboratory values: 
 
• eGFR decreases to < 20 mL/min 
o Remdesivir infusion will be held until the eGFR increases to a point that the potential 
benefit of giving remdesivir outweighs the potential risk. Note: this is consistent with 
the FDA Fact Sheet instructions for Health Care Providers, US EUA of Veklury® 
(remdesivir): “Veklury is not recommended in adult patients with eGFR less than 30 
mL/min…unless the potential benefit outweighs the potential risk”. 
• ALT and/or AST increases to > 5 times upper limits of normal (ULN) 
o Remdesivir infusion will be held and not be restarted until the ALT and AST ≤ 5 
times ULN. 
 
Interferon beta-1a /Subcutaneous Placebo component: 
The subcutaneous injection should be held and not given if the subject is found to have any of 
the following laboratory values: 
 
• ALT and/or AST increases to > 5 times ULN 
o Subcutaneous injection will be held and resume when ALT and AST ≤ 5 times ULN.  
• Total white cell blood cell count (WBC) <1000 cells/µL 
o Subcutaneous injection will be held and resume when WBC ≥1000 cells/ µL 
• Platelet count <25,000/µL 
o Subcutaneous injection will be held and resume when platelet count ≥ 25,000/µL. 
 
Any dose that is held as described above, may be given later that day if the laboratory parameters 
improve. Any dose that is missed during the study due to any reason is not made up. The treatment 
course continues as described above even if the subject becomes PCR negative while hospitalized.  
 
For laboratory values that meet permanent discontinuation thresholds (see Section 7.1), study 
product should be discontinued. However, if in the opinion of the investigator, the laboratory 
abnormality is due to intercurrent illness or another identified factor, laboratory tests may be 
repeated.  
 
 
Overdosage 
Overdose is not anticipated in the context of a clinical trial. Subjects will be given the 
subcutaneous injection every other day and daily infusions of remdesivir. No study product will 
be given after hospital discharge. 
 
6.2 
Preparation/Handling/Storage/Accountability 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix C - ACTT-3: Remdesivir + Interferon Beta-1a 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 79 of 172 
 
 
Acquisition and Accountability 
Investigational products (IP) will be shipped to the site either directly from participating 
companies, from the Sponsor, or from other regional or local drug repositories. All other supplies 
should be provided by the site. Multiple lots of each IP may be supplied. 
 
Study products received at the sites will be open label and not kit specific, unless specified in the 
protocol-specific Manual of Procedures (MOP) or pharmacy manual. See the MOP Appendices 
for detailed information on the preparation, labeling, storage, and administration of investigational 
products.  
 
Accountability: 
The site PI is responsible for study product distribution and disposition and has ultimate 
responsibility for study product accountability. The site PI may delegate to the participating site’s 
research pharmacist responsibility for study product accountability. The participating site’s 
research pharmacist will be responsible for maintaining complete records and documentation of 
study product receipt, accountability, dispensation, storage conditions, and final disposition of the 
study product(s). Time of study drug administration to the subject will be recorded on the 
appropriate data collection form (CRF). All study product(s), whether administered or not, must 
be documented on the appropriate study product accountability record or dispensing log. The 
Sponsor’s monitoring staff will verify the participating site’s study product accountability records 
and dispensing logs per the site monitoring plan. Refer to the protocol-specific MOP for details on 
storing study medications.  
Destruction: 
After the study treatment period has ended or as appropriate over the course of the study after 
study product accountability has been performed, used active and placebo product can be 
destroyed on-site following applicable site procedures with a second staff member observing and 
verifying the destruction.  
Unused product at the end of the study should be saved until instructed by the Sponsor. 
 
 
Formulation, Appearance, Packaging, and Labeling 
Remdesivir component 
Remdesivir may be supplied in two formulations: 
• The lyophilized formulation of remdesivir is a preservative-free, white to off-white or 
yellow, lyophilized solid containing 150 mg or 100 mg of remdesivir to be reconstituted 
with 29 mL or 19 mL (respectively) of sterile water for injection respectively and diluted 
into IV infusion fluids prior to IV infusion. Following reconstitution, each vial contains a 
5 mg/mL remdesivir concentrated solution with sufficient volume to allow withdrawal of 
30 mL (150 mg of remdesivir) or 20 mL (100 mg of remdesivir). It is supplied as a sterile 
product in a single-use, Type 1 clear glass vial. In addition to the active ingredient, the 
lyophilized formulation of remdesivir contains the following inactive ingredients: water 
for injection, SBECD, hydrochloric acid, and/or sodium hydroxide. For more information, 
refer to the MOP. 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix C - ACTT-3: Remdesivir + Interferon Beta-1a 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 80 of 172 
• The concentrated solution is supplied as a single dose vial containing 100 mg/20 mL (5 
mg/mL) of remdesivir per vial for dilution into 0.9% sodium chloride infusion bag. It is a 
sterile, preservative-free, clear, colorless to yellow, aqueous-based concentrated solution 
that is to be diluted into 0.9% sodium chloride infusion bag prior to administration by 
intravenous infusion. Remdesivir injection, 100 mg/20 mL (5 mg/mL), is supplied in a 
single-dose clear glass vial. For more information, refer to the MOP and EUA Fact Sheet. 
 
Remdesivir will be labeled according to manufacturer specifications. 
 
Subcutaneous Interferon beta-1a component 
 
Rebif® (interferon beta-1a) is formulated as a sterile solution. It is supplied as a prefilled syringe 
intended for subcutaneous injection. Each prefilled syringe contains 0.5 mL of Rebif®. Each 0.5 
mL of Rebif® will contain 44 mcg of interferon beta-1a, 4 mg human albumin, USP; 27.3 mg 
mannitol, USP; 0.4 mg sodium acetate; and water for injection, USP.  
Subcutaneous placebo component 
Placebo will match the active product in appearance. Placebo subcutaneous injection is 0.9% 
normal saline. The placebo will be supplied as either: 
 Matching empty syringes that will be filled with approximately 0.5 mL 0.9% normal 
saline at each site pharmacy; OR 
 Matching syringes prefilled with 0.5 mL 0.9% normal saline or 0.5 mL sterile water for 
injection.  
 
Study products will be supplied by the sponsor or its designee in accordance with current Good 
Manufacturing Practice (cGMP). 
 
 
Product Storage and Stability 
The MOP provides instructions for the preparation, handling, and storage of remdesivir. The 
MOP describes site responsibility and accountability for the administered products. Interferon 
beta-1a drug product will be described in the package insert. See most recent version of package 
insert posted on the Emmes website. 
 
 
Preparation 
Refer to the protocol-specific MOP for details about preparation.  
 
Remdesivir is not considered a hazardous drug as defined by NIOSH and ASHP hazard 
classification systems. The study products may be prepared in a clean room but do not need to be 
prepared or handled in a fume hood. Measures that minimize drug contact with the body should 
always be considered during handling, preparation, and disposal procedures as indicated in the 
Package Insert.  
 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix C - ACTT-3: Remdesivir + Interferon Beta-1a 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 81 of 172 
For Rebif® (interferon beta-1a) it is supplied as a close system and therefore no specific handling 
is required. See MOP for preparing Placebo for Rebif. 
 
6.3 
Measures to Minimize Bias: Randomization and Blinding 
 
 
Randomization  
Randomization will be stratified by: 
• Site 
• Severity of illness at enrollment (by ordinal scale) 
o Hospitalized, requiring supplemental oxygen, or 
o Hospitalized, not requiring supplemental oxygen. 
 
Note: Category 7 (hospitalized, on invasive mechanical ventilation/ECMO) and Category 6 
(hospitalized, on non-invasive ventilation or high flow oxygen devices) are not eligible for 
enrollment. See description of recommendations made by the DSMB on September 4, 2020 
below. 
 
The randomization procedure will be described in the MOP.  
 
There was the hypothetical concern that interferon may worsen the pro-inflammatory state seen in 
COVID-19 late in the clinical course of the disease. For this reason, enrollment was staged based 
on severity of disease.  
 
• For the first 2 weeks of the study, enrollment was limited to non-intubated, hospitalized 
COVID-19 patients who meet all eligibility criteria (i.e., patients with baseline ordinal 
scale score of 4, 5 or 6).  
• On September 4, 2020, the DSMB met for an interim safety review of the ACTT-3 data. 
After their review, they notified NIAID that their recommendation was to close further 
enrollment to patients with a baseline ordinal score of 6. The DSMB noted there was no 
increase in mortality in this group, but that the risk/benefit in this group did not warrant 
further enrollment. Specifically, it was recommended by the DSMB:  
o No further enrollment of subjects with ordinal score of 6 at time of randomization. 
o Do not enroll subjects with ordinal score of 7 at time of randomization 
o Continue to enroll patients with a baseline ordinal score of 4 and 5.  
• Furthermore, the DSMB recommended: 
o Subjects currently enrolled who have an ordinal score of 6, should not be given any 
more study injections (interferon/placebo) for the remainder of the study.  
o Subjects enrolled as a baseline ordinal 4 or 5 and remain as ordinal 4 or 5, should 
continue to receive study injections (interferon/placebo) and remdesivir per 
protocol.  
o If a subject is enrolled as a baseline ordinal 4 or 5 and progresses to ordinal 6 or 7, 
the study injections (interferon/placebo) should be discontinued for the remainder 
of the study. In this case, the remdesivir infusions would continue per protocol. 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix C - ACTT-3: Remdesivir + Interferon Beta-1a 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 82 of 172 
Importantly, all subjects should remain in the study and followed through day 29 
in accordance with the protocol. 
 
 
Blinding and Masking Procedures 
As both arms are receiving remdesivir, the remdesivir product is not blinded and study infusions 
can be labeled accordingly.  
 
The subcutaneous interferon beta-1a/matching placebo component is blinded. Interferon beta-1a 
and placebo will be identical in appearance. 
 
Unblinding of the study will occur after all subjects enrolled have reached the end of study, and 
these visits are monitored and data is cleaned, or if the DSMB recommends unblinding.  
Treatment group-level unblinded analyses of subjects randomized in ordinal score category 6 
may be conducted and published prior to the end of the trial to communicate the safety signal 
observed in this group by the DSMB during a safety review. If this analysis is conducted, only 
members of the unblinded analysis team will have access to subject-level treatment data while 
the study is ongoing; all other members of the study group will remain blinded to individual 
subject treatments as originally planned.  
 
If AEs occur and investigators are concerned about the treatment allocation, the treatment can be 
discontinued. If a Serious Adverse Event occurs, that is thought to be related to the study drug, 
and the treating clinician believes that knowledge of the treatment arm may change the therapy 
provided to the patient, the individual subject can be unblinded. The procedure for unblinding 
will be further detailed in the Manual of Operations. 
 
6.4 
Study Intervention Compliance 
Each dose of study product will be administered by a member of the clinical research team who 
is qualified and licensed to administer the study product. Administration and date, and time, will 
be entered into the case report form (CRF). 
 
6.5 
Concomitant Therapy 
 
Permitted Concomitant Therapy and Procedures 
Receipt of any exclusionary treatments or medications prior to screening will be assessed at 
screening to determine eligibility as described in the exclusion criteria. Exclusionary medications 
include the receipt of convalescent plasma or intravenous immunoglobulin [IVIg]) for the 
treatment of COVID-19. It also includes small molecule tyrosine kinase inhibitors (e.g., baricitinib, 
imatinib, gefitinib, acalabrutinib) or monoclonal antibodies targeting cytokines (e.g., TNF 
inhibitors, anti-interleukin-1 [IL-1], anti-IL-6 [tocilizumab or sarilumab]), or T-cells or B-cells, 
taken in the two weeks prior to screening for the treatment of COVID-19. Lastly, those who 
received interferon within 2 weeks of screening either for the treatment of COVID-19 or for a 
chronic medical condition (e.g., multiple sclerosis, HCV infection) will not be eligible for the 
study. 
 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix C - ACTT-3: Remdesivir + Interferon Beta-1a 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 83 of 172 
For patients that are eligible for the study, other therapy received prior to enrollment with any other 
experimental treatment or off-label use of marketed medications that are intended as specific 
treatment for COVID-19 or the SARS-CoV-2 infection (i.e., post-exposure prophylaxis [PEP]) are 
permitted but must be discontinued on enrollment. There is no waiting period between 
discontinuation of these treatments and administration of study products. However, these prior 
treatments and their end date should be documented on the Concomitant Medication (CCM) form 
in the Advantage eClinical system.  
 
Medications used for other non-COVID-19 diseases that also are claimed to be treatments for 
COVID-19, do not need to be discontinued at the time of enrollment. Examples would include 
lopinavir/ritonavir for HIV, hydroxychloroquine for lupus, etc. The disease being treated is 
important: if used as an off-label medication for COVID-19 treatment, they are prohibited; if used 
for non-COVID-19 diseases, they are allowable.  
 
 
Prohibited Concomitant Therapy 
A subject cannot participate in another clinical trial for the treatment of COVID-19 until after Day 
29 (see exclusion criteria).  
 
Once enrolled, concomitant medications for the treatment of COVID-19 as described in written 
policy or guideline (i.e., not just an individual clinician decision) are permitted. In the absence of 
a local written standard of care, the National Institutes of Health (NIH) COVID-19 Treatment 
Guidelines may be used (https://www.covid19treatmentguidelines.nih.gov/). This includes anti-
inflammatory medications such as dexamethasone and convalescent plasma. Concomitant use of 
any other experimental treatment or off-label use of marketed medications intended as specific 
treatment for COVID-19 or SARS-CoV-2 infection, and not specified in the local or NIH COVID-
19 Treatment Guidelines are prohibited. Specifically, use of any biologic therapy not specified on 
the written policy or guideline are prohibited including: monoclonal antibodies targeting cytokines 
(e.g., TNF inhibitors; interleukin-1[IL-1], IL-6 [tocilizumab or sarilumab]), or T-cells (e.g., 
abatacept); monoclonal antibodies targeting B-cells (e.g., rituximab, and including any targeting 
multiple cell lines including B-cells); JAK inhibitor(s) (e.g., baricitinib, imatinib, gefitinib, 
acalabrutinib); and any type of interferon, convalescent plasma, or immunoglobulin (IgG) 
therapies for COVID-19. Similarly, the concomitant use of hydroxychloroquine to treat COVID-
19 is prohibited unless it is included in the local institutional treatment guidelines.  
 
On August 23, 2020, the FDA issued an EUA for COVID-19 convalescent plasma for the treatment 
of hospitalized patients with COVID-19.  The NIH COVID-19 Treatment Guidelines were updated 
on September 1, 2020 and concludes that “there are insufficient data to recommend either for or 
against the use of convalescent plasma for the treatment of COVID-19”.  According to the NIH 
Guidelines and the EUA Fact Sheet for Health Care Providers, convalescent plasma should not be 
considered the standard of care for the treatment of patients with COVID-19.  However, if a site 
has adopted convalescent plasma as part of their institutional standard of care for the treatment of 
COVID-19 patients, it is allowed as described above. 
 
Concomitant medications will be assessed from 7 days prior to enrollment to Day 29 or upon 
discharge, whichever comes first. All prescription medications should be recorded during this 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix C - ACTT-3: Remdesivir + Interferon Beta-1a 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 84 of 172 
time period with the exceptions listed in the bullets below. All medications, except biologics and 
corticosteroids, can be recorded once regardless of the number of times it was given during the 
time period. For example, vasopressors should be recorded when first dose given (as the start 
date) and the last dose given (as the end date) during the period of assessment.  
 
Sites do not need to record any of the following categories of medications in the eClinical system 
during the period from Day -7 through Day 29: 
o All topical medications: ointments, creams, and lotions; 
o All intranasal medications: nasal decongestants, nasal allergy medications, nasal steroids, 
and nasal saline drops/sprays;  
o All ophthalmic medications: ophthalmic allergy medication, ophthalmic medications for 
infection, and ophthalmic medications for eye dryness (e.g., saline eye drops); 
o Antiseptic mouth wash, lozenges; 
o Cough medication: mucolytics, cough suppressants, and expectorates; 
o GI medications: H2 blockers, proton pump inhibitors, GI stimulants, prokinetics, laxatives, 
stool softeners, antacids, anti-diarrheal and anti-nausea medications; 
o Insulin and medications for diabetic control; 
o Symptomatic care medications: antipyretics, antihistamines, decongestants, and NSAIDs;  
o Vitamins, minerals or herbal supplements, dietary supplements, iron/ferrous sulfate, 
magnesium, calcium, electrolyte replacement; 
o Albumin infusions; 
o Melatonin; 
o Nicotine patch, lozenge, gum, or nasal spray, or other product to treat tobacco dependence; 
o Dyes: iodine – based dye, barium sulfate, and diatrizoate sodium. 
 
See the MOP for more information about recording concomitant medications. 
 
 
Rescue Medicine 
Not Applicable 
 
 
Non-Research Standard of Care 
Not Applicable 
 
7. 
STUDY INTERVENTION DISCONTINUATION AND 
SUBJECT DISCONTINUATION/WITHDRAWAL 
7.1 
Halting Criteria and Discontinuation of Study Intervention 
 
Individual Study Product Halting  
Study product administration for any given subject may be stopped for SAEs, clinically significant 
adverse events, severe laboratory abnormalities, or any other medical conditions that indicate to 
the Investigator that continued dosing is not in the best interest of the patient. 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix C - ACTT-3: Remdesivir + Interferon Beta-1a 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 85 of 172 
In addition, a subject in this clinical study may discontinue study drug at their request for any 
reason. Every effort should be made to encourage subjects to remain in the study for the duration 
of their planned outcome assessments through Day 29. Subjects should be educated on the 
continued scientific importance of their data, even if they discontinue study drug.  
Unless the subject withdraws consent, those who discontinue study drug early will remain in the 
study and followed through Day 29. The reason for subject discontinuation of study drug(s) should 
be documented in the case report form. 
 
 
Remdesivir Halting 
See Section 6.1.4. for information about dosing modifications due to laboratory abnormalities. 
For an individual subject, remdesivir infusions must be stopped if they have a suspected drug-
related event of hypersensitivity (Grade 2 or higher) during or shortly after receiving the infusion. 
While there are no criteria for grading “hypersensitivity” in the Division of AIDS (DAIDS) Table 
for Grading the Severity of Adverse Events, sites should use acute allergic reaction from that 
toxicity table. Subjects who have the infusion stopped for a Grade 2 or higher allergic reaction that 
is temporally associated with the infusion and the PI believes it to be related to study product will 
not receive any more remdesivir. 
 
 
Subcutaneous Interferon beta-1a and Placebo Injections Halting 
See Section 6.1.4. for information about dosing modifications due to laboratory abnormalities. 
The subject should not receive any additional subcutaneous injections for the remainder of the 
study if a subject develops any of the following conditions during the study:  
 
• Disease progresses to the point that the subject requires high-flow oxygen or other non-
invasive ventilatory support (i.e., a category 6 on ordinal scale) or mechanical ventilation 
or ECMO (category 7). Note: even if they improve to a category 4 or 5 before study Day 
7, no additional subcutaneous injections will be given. 
• Anaphylaxis temporally associated with subcutaneous injection 
• Seizures not attributable to COVID-19, a medical complication of COVID-19 or another 
medical condition 
• Thrombotic microangiopathy including thrombotic thrombocytopenic purpura and 
hemolytic uremic syndrome thought to be due to interferon beta-1a  
• ALT or AST >8 times ULN 
• Suspected drug-induced liver injury with symptomatic disease (i.e., jaundice, right upper 
quadrant pain or tenderness, fatigue, nausea, vomiting, etc.) 
 
 
Study Halting 
Given the potential severity of COVID-19, there are no pre-specified study stopping rules. 
Instead there will be close oversight by the protocol team and frequent DSMB reviews of the 
safety data.  

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix C - ACTT-3: Remdesivir + Interferon Beta-1a 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 86 of 172 
 
7.2 
Withdrawal from the Study 
Subjects are free to withdraw from participation in the study at any time upon request, without 
any consequence. Subjects should be listed as having withdrawn consent only when they no 
longer wish to participate in the study and no longer authorize the Investigators to make efforts 
to continue to obtain their outcome data or safety assessment. 
  
The investigator may also withdraw a subject from the study. However, the investigator will be 
encouraged to allow subjects to remain in the study to be followed for safety and final outcome 
assessment at Day 29 (i.e., the ordinal scale and mortality) even if they decide to discontinue 
study products and research laboratory draws. Withdrawing a subject from the study due to an 
inability to contact them for the Day 15 and/or Day 22 follow-up visit is discouraged given the 
possibility of readmission and chaotic social circumstances resulting from the pandemic. 
 
Subjects who withdraw from this study or are lost to follow-up after signing the informed 
consent form (ICF) and administration of the study product, will not be replaced. The reason for 
subject withdrawal from the study will be recorded on the appropriate CRF.  
 
7.3 
Lost to Follow-Up 
A subject will be considered lost to follow-up if the site is unable to contact him or her by phone 
or other means such as text, email, fax or letter (as approved by the IRB) for all follow-up 
assessments at Day 15, 22 and 29. In lost to follow-up cases, attempts to contact the subject 
should be made and these efforts should be documented in the subject’s records.  
7.4 
Readmission  
If a subject is discharged from the hospital and then readmitted prior to Day 11, they may be given 
the remainder of the remdesivir infusions and if prior to Day 8, they may be given the remainder 
of the subcutaneous injections. If the subject did not withdraw his/her consent to participate in the 
study, there is no need to reconsent upon readmission to the study hospital. However, the site will 
need to inform them that since he/she was readmitted, study product administration will resume 
and confirm that they still agree to receive study product.  
 
The natural history of COVID-19 and its impact on pre-existing medical conditions is not 
completely understood. Because of this, all readmissions, regardless of reason, should be 
documented and the subject should get daily clinical status assessments (i.e., ordinal scale and 
NEWS) and other procedures done as per the SOA upon readmission. If the subject is re-admitted 
with diminished mental capacity, the site should discuss continued study participation with a LAR.  
 
The study team will need to notify the study pharmacist of the readmission. The subject will not 
get the doses that they missed after being discharged. Upon readmission, the subject will get 
maintenance doses of infusion only since they already received the loading dose of the study 
product infusion on Day 1. No study product infusions should be given past Day 10. No 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix C - ACTT-3: Remdesivir + Interferon Beta-1a 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 87 of 172 
subcutaneous injection should be given past Day 7. For all data collection procedures required for 
those readmitted, please see the MOP.  
 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
8.1 
Screening and Efficacy Assessments 
 
Screening Procedures 
Screening procedures may be done over one to two calendar days (from Day -1 to Day 1). 
However, in many cases all the screening assessments can be done in less than 24 hours. If that is 
the case, Day 1 pre-study product administration baseline assessments, specimen collection and 
the initial study product administration can occur on the same calendar day as the screening 
procedures.  
 
After the informed consent, the following assessments are performed to determine eligibility: 
• 
Confirm the positive SARS-CoV-2 test result (per inclusion criteria).  
• 
Take a focused medical history, including the following information:  
• Day of onset of COVID-19 signs and symptoms. 
• History of chronic medical conditions, including chronic liver disease and chronic 
oxygen requirement. This includes use of continuous positive airway pressure 
(CPAP) ventilatory support at night and oxygen by nasal cannula at home or nursing 
home prior to onset of COVID-19. See conditions included on the Medical History 
(CMX) data collection form. 
• History of medication allergies including history of hypersensitivity to natural or 
recombinant interferon, human albumin, or any other component of the interferon 
beta-1a formulation. 
• Medications and therapies for this current illness taken in the 7 days prior to Day 1, 
and history of any medication listed in the exclusion criteria. 
• Ask if they are participating in another clinical trial or plan to enroll in another 
clinical trial in the next 28 days. 
• 
Women of childbearing potential should be counseled to either practice abstinence or use at 
least one primary form of contraception not including hormonal contraception from the time 
of screening through Day 29. Women should be confirmed to not be breastfeeding. 
• 
Note: If a woman is either postmenopausal (i.e., has had ≥12 months of spontaneous 
amenorrhea) or surgically sterile (i.e., has had a hysterectomy, bilateral ovariectomy 
(oophorectomy), or bilateral tubal ligation), she is not considered to be of 
childbearing potential.  
• 
Height and weight (height can be self-reported). 
• 
Results of recent radiographic imaging (x-ray or CT scan). 
• SpO2.  

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix C - ACTT-3: Remdesivir + Interferon Beta-1a 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 88 of 172 
• 
Blood for screening laboratory evaluations if not done as part of routine clinical care in the 
preceding 48 hours: 
 ALT and AST 
• Assess if ALT or AST > 5 times ULN 
 WBC  
• Assess if WBC <1500 cells/µL 
 Platelet count 
• Assess if platelet count <50,000/µL  
 Creatinine (and calculate eGFR).  
• Any automated calculation by the clinical laboratory or published formula for the 
calculation of eGFR is acceptable. The site should select a formula to be used for 
all subjects enrolled at the site for the duration of the study. 
• 
Urine or serum pregnancy test (in women of childbearing potential). See instructions below 
for women who are less than 6 weeks postpartum: 
 Do not do a pregnancy test if the patient is post-partum and has not left the hospital 
since delivery. The pregnancy test will likely give a false-positive result as serum 
human chorionic gonadotropin (hCG) is usually detected for up to 4 to 6 weeks after 
delivery. 
 For women who are less than 6 weeks postpartum and have left the hospital, any 
positive pregnancy test should be repeated to determine if the HCG is declining as 
predicted after delivery and therefore the result is a false-positive. Of note, women who 
are less than 6 weeks postpartum and have had heterosexual intercourse since delivery 
and hospital discharge are unlikely to be pregnant because the average time to first 
ovulation varies from 45 to 94 days postpartum, with the earliest reported ovulations at 
25 and 27 days postpartum.  
 
Clinical screening laboratory evaluations will be performed locally by the site laboratory. The 
volume of venous blood to be collected is presented in Table 3. A screening lab (i.e., from the 
hematology and chemistry laboratory panels) may be repeated once if, in the opinion of the 
investigator, the laboratory abnormality is due to an intercurrent transient condition or it is an 
aberrant laboratory value.  
 
The overall eligibility of the subject to participate in the study will be assessed once all screening 
values are available. The screening process can be suspended prior to complete assessment at any 
time if exclusions are identified by the study team. 
 
Study subjects who qualify will be randomized in the Advantage eClinical system, and all others 
will be registered as screen failures. The ordinal scale and the NEWS should be done at the time 
of randomization; the site will need this data to randomize the subject in eClinical. The study team 
has 24 hours to complete other Day 1 baseline assessments prior to the first study product 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix C - ACTT-3: Remdesivir + Interferon Beta-1a 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 89 of 172 
administration including the collection of OP swab and blood and completing or recording a 
baseline physical examination that was done. Clinical laboratory tests collected as part of routine 
care of the patients in the 36 hours prior to first dose qualify for baseline safety tests on Day1. 
 
 
Efficacy Assessments 
For all baseline assessments and follow-up visits, refer to the Schedule of Assessments (SOA) 
for procedure to be done, and details below for each assessment. 
 
 
Measures of clinical support, limitations and infection control 
The subject’s clinical status, which is largely measured by the ordinal scale and NEWS, will be 
captured on each study day while hospitalized through Day 29 (+ 6-day window) or day after death 
whichever comes first. The ordinal scale will also be captured on the day after discharge from the 
hospital. This will be done so that discharge and death are accurately recorded and captured in the 
eClinical system. For subjects who received oxygen by nasal cannula or CPAP ventilatory support 
at night at home prior to having COVID-19, sites should assign a recovery ordinal scale score of 
1 or 2 when discharged to home after recovery. The assignment of category 1 versus category 2 
will depend on whether they have new or increased physical limitations post-COVID-19 and/or if 
they have new or increased home oxygen requirement compared with the pre-COVID-19 time 
period.  
 
It is important to capture all deaths that occur during the study as this is one of the outcomes of the 
study. Death is a category on the ordinal scale. If a subject dies during the study, an ordinal scale 
assessment should be completed for the day after death because the ordinal scale captures the worst 
clinical assessment for the previous day. If a subject dies within the window of the final study visit 
(i.e., Day 29 + 6-day window), complete an ordinal scale assessment on the day after death.  
 
If a subject is discharged prior to Day 15, clinical status is collected on Day 15 and 29 if the subject 
returns for an in-person clinic visit or by phone, home visit or remote telehealth procedure as per 
institutional standards if an in-person visit at the clinical trial site is not possible. Clinical status 
will also be captured on Day 22 during a phone call or remote telehealth visit. Unlike the NEWS, 
the ordinal scale can also be evaluated over the phone or by a remote telehealth procedure if the 
discharged subject is unable to return to the clinical trial site for visits on Day 15 and 29 as well 
as on Day 22.  
 
Except for Day 1, when the ordinal scale and the NEWS is captured at the time of randomization, 
a site should try to complete the ordinal scale and the NEWS at approximately the same time each 
day. Ideally, complete the ordinal scale concurrently with NEWS just prior to study product 
administration, as time permits. The following measures are recorded for the ordinal scale: 
 
• Hospitalization. 
• Oxygen requirement. 
• Non-invasive mechanical ventilation (via mask) requirement. 
• High flow oxygen requirement. 
• Invasive mechanical ventilation (via endotracheal tube or tracheostomy tube) 
requirement. 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix C - ACTT-3: Remdesivir + Interferon Beta-1a 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 90 of 172 
• ECMO requirement. 
• Ongoing medical care preventing hospital discharge (COVID-19 related or other medical 
conditions). 
• Limitations of physical activity (self-assessed and reported as new or increased 
limitations as compared to status prior to the onset of COVID-19). 
• Isolated for infection control purposes. 
 
 
Ordinal Scale 
The ordinal scale is the primary measure of clinical outcome. The scale used in this study is as 
follows (from worst to best), and categories 1, 2 and 3 represent recovery for a subject: 
 
Category 8: Death; 
Category 7: Hospitalized, on invasive mechanical ventilation or ECMO; 
Category 6: Hospitalized, on non-invasive ventilation or high flow oxygen devices; 
Category 5: Hospitalized, requiring supplemental oxygen; 
Category 4: Hospitalized, not requiring supplemental oxygen – requiring ongoing 
medical care (COVID-19 related or otherwise); 
 
Category 3: Hospitalized, not requiring supplemental oxygen – no longer requires 
ongoing medical care; This would include those kept in hospital for quarantine/infection 
control, awaiting bed in rehabilitation facility or homecare, etc. 
 
Category 2: Not hospitalized, but new or increased limitation on activities and/or 
requiring new or increased home oxygen; 
 
Category 1: Not hospitalized, no limitations on activities 
 
To determine a subject’s clinical status using the ordinal scale: On Day 1, report their clinical 
status at randomization. As there should be <24 hours between randomization and infusion, the 
ordinal scale at done at randomization suffices as the Day 1 ordinal scale. After Day 1, collect the 
ordinal scale daily while hospitalized from Day 2 through Day 29 by providing the worst clinical 
assessment for the previous day (i.e., midnight to midnight; 00:00 – 23:59 (24-hr clock)).  
 
For those who are discharged prior to Day 15, collect ordinal scale on follow-up Days 15, 22 and 
29 by providing the worst clinical assessment for the previous day (i.e., midnight to midnight; 
00:00 – 23:59 (24-hr clock)). For example, on study Day 3 when completing the form, the worse 
clinical outcome measure of Day 2 is captured with the worst being death followed by ECMO, 
mechanical ventilation, etc. The Day 2 measurement is assessed as occurring anytime in that 24-
hour period (00:00 to 23:59).  
 
It is important to capture all deaths that occur during the study as this is one of the outcomes of the 
study. Death is a category on the ordinal scale. If a subject dies during the study, the site will need 
to complete an ordinal scale assessment for the day after death. If a subject dies within the window 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix C - ACTT-3: Remdesivir + Interferon Beta-1a 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 91 of 172 
of the final study visit (i.e., Day 29 + 6-day window), complete an ordinal scale assessment on the 
day after death. For more information about the data collected for the ordinal scale, see the MOP. 
 
 
National Early Warning Score (NEWS) 
The NEWS has demonstrated an ability to discriminate subjects at risk of poor outcomes. (Smith, 
2016). The NEWS is being used as an efficacy measure in this study (Table 2). The score is based 
on seven clinical parameters including temperature, systolic blood pressure, heart rate, respiratory 
rate, oxygen saturation, and level of consciousness. The NEWS should be evaluated daily while 
hospitalized and on Days 15 and 29, and can be performed concurrently with the ordinal scale.  
The NEWS and ordinal scale should be evaluated at approximately the same time each study day 
for an individual subject and just prior to the expected infusion time. The seven parameters can be 
obtained from vital signs collected as part of the standard of care and documented in the hospital 
chart or electronic medical record. The last measurement prior to the time of assessment (including 
parameters collected prior to the time of consent) should be recorded. A numeric score is given for 
each parameter (e.g., a RR of 9 is one point, oxygen saturation of 92 is two points). This is recorded 
for the day obtained (i.e., on Day 3, the vital signs and other parameters from Day 3 are used to 
obtain NEW Score for Day 3). ECMO and mechanically ventilated subjects should be assigned a 
score of 3 for RR (RR <8) regardless of the ventilator setting. Subjects on ECMO should get a 
score of 3 for heart rate since they are on cardiopulmonary bypass. 
 
For details about collection of NEWS, refer to the MOP. 
 
 Table 2. National Early Warning Score (NEWS) 
 
Level of consciousness = alert (A), and non-alert and arousable only to voice (V) or pain (P), and unresponsive 
(U).  
If the subject is on ECMO or invasive mechanical ventilation, they will be given score of 3 (≤8 RR) for 
respiratory rate regardless of ventilator setting. For subjects on ECMO, they will also receive a score of 3 
(≤40 HR) for heart rate. 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix C - ACTT-3: Remdesivir + Interferon Beta-1a 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 92 of 172 
 
 
Exploratory Assessments and Secondary Research Samples 
The schedule of assessments (SOA, Section 1.2) lists the collection timepoints for specimens for 
both exploratory endpoints and for secondary research.  Sites may opt out of specimen collection 
for secondary research; only serum is collected for secondary research.  Subjects will be consented 
for genetic testing for the second exploratory endpoint. Sites will draw blood (via PAXgene tube) 
for subjects who consent to genetic testing, and at selected sites, blood will be drawn for peripheral 
blood mononuclear cells (PBMC) collection for these consenting subjects.  Proteomic (cytokines 
and other protein) analysis will be done for all subjects using plasma drawn per the schedule 
outlined in the SOA. In some cases, serum may be substituted for plasma for cytokine analyses 
(upon approval by the Sponsor). Data from exploratory assessments may not be submitted as part 
of the primary Clinical Study Report (CSR) for this trial. The data may be submitted separately as 
one or more addenda to the primary CSR. 
 
It is preferred that these samples are collected and sent to the NIAID repository to be tested in one 
central laboratory. Current US Centers for Disease Control and Prevention (CDC) guidance is 
these samples can be processed in a Biosafety Laboratory (BSL) 2 environment. However, 
institutions may impose restrictions on processing the samples (i.e., they may require BSL-3) or 
there may be restrictions on sending samples. In these circumstances, the following apply: 
 
Blood for plasma   
• If the samples can be processed but cannot be sent to the repository, the samples may be 
stored locally.  
• The sponsor may elect to have some of these  samples run locally, pending confirmation 
of the assays to be used and the qualifications of the local laboratory. The sponsor will 
work with the site to determine when this could occur and how these data can be 
imported into the study database.  
• If a BSL-3 environment is needed for processing these samples, these samples may be 
omitted.  
 
Oropharyngeal or Nasopharyngeal/nasal specimen 
• If the samples can be processed but cannot be sent to the repository, the samples may be 
stored locally.  
• The sponsor may elect to have some or all of these samples run locally, pending 
confirmation of the assays to be used and the qualifications of the local laboratory. The 
sponsor will work with the site to determine when this could occur and how these data 
can be imported into the study database.  
• If a BSL-3 environment is needed for processing these samples, these samples may be 
omitted.  
 
Whole blood for transcriptomics analysis and interferon-stimulating-gene (ISG) analysis 
• Subjects who consent to genetic testing will have a whole blood sample (~2.5 mL in 
PAXgene tube) 
• These samples will be tested in a central laboratory, not locally. 
 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix C - ACTT-3: Remdesivir + Interferon Beta-1a 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 93 of 172 
Blood for PBMCs 
• Some subjects who consent to genetic testing will have blood for PBMCs collected. This 
will occur only at select clinical trial sites. 
• PBMCs  will be tested in a central laboratory, not locally 
 
Blood for serum (for secondary research) 
• If the samples can be processed but not sent to the repository, the samples may be stored 
locally.  
• If a BSL-3 environment is needed for processing these samples, these samples may be 
omitted.  
 
 
SARS-CoV-2 Virology Exploratory Assessment 
As outlined on the SOA, OP samples (collected by swab) and plasma and serum will be collected 
on Day 1; and Days 3, 5, 8, and 11 (while hospitalized) and Day 29; and only OP swabs and serum 
on Day 15 (if attends an in-person visit or still hospitalized). Samples are stored as outlined in the 
MOP. Virologic assessments may include PCR or other nucleic acid tests for duration of viral 
RNA, viral load determination and/or the emergence of antiviral resistance.  
 
OP samples are preferred, but if these are not obtainable, nasopharyngeal (NP) samples (collected 
by NP swab) or nasal swab may be substituted. Due to limited lack of swabs and other supplies at 
some sites and limitations on personal protective equipment (PPE), the inability to obtain these 
samples are not considered protocol deviations and should be documented in the subject’s record.  
 
 
Immunophenotyping Exploratory Assessment  
As outlined in the SOA, blood will be collected for a plasma proteomic analysis of cytokines, 
chemokines, markers of inflammation, and other circulating proteins; whole blood (PAXgene 
tubes) for a transcriptomic analysis of RNA and interferon stimulated gene (ISG) analysis; and 
whole blood PBMCs for an epigenetic analysis and a T cell and innate immune cell phenotyping 
assessment. Samples will be collected, processed and stored as described in the MOP. Only select 
sites will collect and process PBMCs. All sites should collect PAXgene tube for subjects 
consenting to have their samples used for the targeted genetic analysis. If a BSL-3 environment is 
needed for processing of these samples, or if samples cannot be shipped to a central laboratory, 
these samples may be omitted and the omission documented each time omitted.  
 
Blood for plasma for proteomic analysis 
• An aliquot of the collected plasma will be analyzed for cytokines, chemokines, markers of 
inflammation and other circulating proteins on Days 1, 3, 5, 8 and 11 and Day 29 (see SOA 
for details). This blood volume is not an additional 0.5 mL but considered as part of the 8 
mL plasma taken on these days.  
• A subset will have the sample processed using a high-throughput proteomic assay. The 
remainder of subjects will have their samples processed using an antibody-based assay for 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix C - ACTT-3: Remdesivir + Interferon Beta-1a 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 94 of 172 
cytokines.  
 
Whole blood for transcriptomics analysis and ISG analysis 
• Subjects who consent to genetic testing will have a whole blood sample (~2.5 mL in 
PAXgene tube) analyzed using an RNA sequencing assay (RNA-Seq, Illumina). 
Transcriptomics and ISG analysis will be done on Days 1, 3 and 8, and Day 29 (if attends 
in-person visit or still hospitalized) (See SOA for details). 
• Subjects who consent to genetic testing and are discharged prior to Day 8 and therefore 
miss the PAXgene tube collection at Day 8, this sample will be drawn at Day 15. If the 
subject is discharged prior to Day 11 and they miss the Day 11 blood collection, they will 
have blood for plasma proteomic assessment drawn at Day 15.  
• Analysis may include, but not limited to the following assessments depending on the 
sample quality and quantity: 
• Cellular transcriptional activity in immune cell subsets as analyzed by RNA-seq 
or microarrays;  
• Whole blood transcriptome as analyzed by RNA-seq; 
• Single-cell transcriptome as analyzed by RNA-seq or CITE-seq. 
• Description of blood collection in PAXgene tubes for RNA are provided in the MOP. 
 
Blood of PBMCs 
• Some subjects who consent to genetic testing will have blood for PBMCs collected. This 
will occur only at select clinical trial sites. PBMCs will be used to do T-cell and innate 
immune cell phenotyping using samples from Days 1, 3 and 8, and Day 29 and epigenetics 
using Day 1 and Day 29 samples.  
• If a subject is discharged prior to Day 8, this sample will be drawn at Day 15.  
• Description of blood collection in CPTs and processing of blood for PBMCs are provided 
in the MOP. 
• Analysis of PBMCs may include, but not limited to the following assessments depending 
on the sample quality and quantity: 
• PBMC transcriptome as analyzed by RNA-seq; 
• Frequency of leukocytes (to include lymphocyte subsets) in peripheral blood as 
analyzed by complete blood count (CBC) with differential and clinical and 
research flow cytometry; 
• Cellular chromatin accessibility in immune cell subsets as analyzed by the assay 
for transposase-accessible chromatin using sequencing (ATAC-seq); 
• Serum antibody titers; and  
• Additional “omics” assays for assessing immune receptor repertoires, profiling 
molecular states in cells or for quantifying the relative abundance of circulating 
molecules to assess the state of the immune system, or characterizing the 
microbiome in healthy volunteers. 
 
Proposed Timing of Samples for Immunophenotyping Exploratory Objective  
The estimated peak of pathological inflammation is 21 days post-symptom onset. In ACTT-3, 
patients are not enrolled until 7 to 10 days post-symptom onset. For this reason, we propose 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix C - ACTT-3: Remdesivir + Interferon Beta-1a 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 95 of 172 
samples be taken Days 1, 3 and 8 (or if discharged prior to Day 8 then blood is drawn at Day 
15) and then at Day 29.See Table 2 for projected blood volumes for PAXgene and PBMC 
sample collection.  
 
 
Table 3. Blood Volume for Subjects Consenting for Genetic Testing Involving PAXgene 
and PBMC Collection 
Study 
Day 
Transcriptomics and ISG analysis 
Cell Phenotyping and Epigenomics* 
1 
2.5 mL blood, PAXgene blood RNA 
tube 
 
25.5 mL blood in 3 Cell Preparation Tube 
(CPT) 
3 
2.5 mL blood, PAXgene tube 
None 
5 
None 
None 
8 
2.5 mL blood, PAXgene tube 
25.5 mL blood in 3 CPT 
11 
None 
None 
15 
None (unless missed Day 8) 
None (unless missed Day 8) 
29 
2.5 mL blood, PAXgene tube 
25.5 mL to 42.5 mL blood in 5 CPTs 
*Epigenetic analysis done using PBMC sample and only done using the Day 1 and Day 29 samples. 
 
8.2 
Safety and Other Assessments 
Study procedures are specified in the SOA. A study physician licensed to make medical diagnoses 
and listed on the 1572 will be responsible for all trial-related medical decisions. 
 
Physical examination:  
A targeted physical examination will be performed at baseline prior to initial study product 
administration on Day 1. The baseline physical examination can be one that is conducted from 
screening to Day 1. No routine physical exam is needed for study visits after Day 1.  
 
Study staff at some sites are not allowed into the subject’s rooms due to a limited supply of PPE 
and the need for strict respiratory isolation measures for COVID-19 patients. Because of limited 
access to subjects, physical exams can be performed by any licensed provider at the study hospital 
even if they are not study staff listed on the 1572. The study team can extract information from the 
hospital chart or EMR.  
 
Clinical laboratory evaluations: 
• Fasting is not required before collection of laboratory samples. 
• Blood will be collected at the time points indicated in the SOA.  
• Clinical safety laboratory tests include WBC count, differential, hemoglobin, 
platelet count, creatinine, total bilirubin, AST, ALT, and INR. C-reactive protein 
and d-dimer are not safety laboratory tests but will be collected at the same time 
as the safety labs.  
• Day 1 clinical laboratory evaluations are drawn prior to initial study product 
administration as a baseline and results do not need to be reviewed to determine if 
initial study product administration should be given. See SOA for details. 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix C - ACTT-3: Remdesivir + Interferon Beta-1a 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 96 of 172 
• Clinical laboratory testing will be performed at each clinical trial site in real time.  
 
Table 4a. Venipuncture Volumes for Subjects NOT Consenting for Genetic Testing 
Involving Transcriptomics and Complete Immunophenotyping Analysis 1 
 
Screen 
Baseline 
 
 
 
 
 
 
Day +/- Window 
−1 to 1 
1 ± 1 
3 ± 1 
5 ±1 
8 ± 1 
11 ± 1 
15 ± 2 
29 + 6 
Safety hematology, 
chemistry and liver 
tests 
 
X 
10mL2 
X 
10mL2 
X 
10mL2 
X 
10mL2 
X 
10mL2 
X 
10mL2 
 X3 
10mL2 
X3 
10mL2 
Blood for Serum 
 
 
X 
24mL 
X 
24mL 
X 
24mL 
X 
24mL 
X 
24mL 
X 
24mL 
X 
24mL 
Plasma  
(includes PCR and 
proteomics) 
 
X 
8mL 
X 
8mL 
X 
8mL 
X 
8mL 
X 
8mL 
 
X 
8 mL 
Total volume 
10mL 
42mL 
42mL 
42mL 
42mL 
42mL 
34mL 
42mL 
Total all study days 
 
 
 
 
 
 
 
~296 mL 
1. See SOA in Section 1.2 for specific tests to be performed. 
2. Total volume calculated assumes there are no routine clinical laboratory were done within 48 hours of screening 
that can be used for determining eligibility and no routine clinical laboratory tests were done within the window for 
that visitor 24 hours of Day 1, 3, 5, 8 and 11 and 48 hours for Day 15 and 72 hours for Day 29 if still hospitalized.  
3. Safety laboratory tests will be collected on Day 15 and 29 if the subject is still hospitalized at these time points or 
if they return for an in-person outpatient visit and the site has the capacity to collect blood in the outpatient setting. 
 
Table 5b. Venipuncture Volumes for Subjects Consenting for Genetic Testing At Sites that 
Do NOT Collect PBMCs 1  
 
Screen 
Baseline 
 
 
 
 
 
 
Day +/- Window 
−1 to 1 
1 ± 1 
3 ± 1 
5 ±1 
8 ± 1 
11 ± 1 
15 ± 2 
29 + 6 
Safety hematology, 
chemistry, liver tests 
X 
10mL2 
X 
10mL2 
X 
10mL2 
X 
10mL2 
X 
10mL2 
X 
10mL2 
 X3 
10mL2 
X3 
10mL2 
Blood for Serum 
 
X 
16 mL 
X 
16mL 
X 
16mL 
X 
16mL 
X 
16mL 
X 
16mL 
X 
16mL 
Plasma (PCR and 
proteomics) 
 
X 
8 mL 
X 
8 mL 
X 
8 mL 
X 
8 mL 
X 
8 mL 
(X)4--- 
X  
8 mL 
Blood in PAXgene 
tube 
 
X 
2.5 mL 
X 
2.5 mL 
--- 
X 
2.5 mL 
--- 
(X)4--- 
X 
2.5 mL 
Total volume if 
involved in 
exploratory analysis 
10mL 
36.5 mL 
36.5m
L 
34 mL 
36.5 mL 
34 mL 
26mL 
36.5 mL 
Total all study days 
 
 
 
 
 
 
 
250 mL 
1. See SOA in Section 1.2 for specific tests to be performed. 
2. Total volume calculated assumes there are no routine clinical laboratory were done within 48 hours of screening 
that can be used for determining eligibility and no routine clinical laboratory tests were done within the window for 
that visitor 24 hours of Day 1, 3, 5, 8 and 11 and 48 hours for Day 15 and 72 hours for Day 29 if still hospitalized.  
3. Safety laboratory tests will be collected on Day 15 and 29 if the subject is still hospitalized at these time points or 
if they return for an in-person outpatient visit and the site has the capacity to collect blood in the outpatient setting. 
4. If subject discharged prior to Day 8 (i.e., PAXGene tube not collected) or Day 11 (i.e., proteomics not collect), 
site will collect Day 8 and/or Day 11 samples at Day 15 follow-up visit 
 
 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix C - ACTT-3: Remdesivir + Interferon Beta-1a 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 97 of 172 
Table 6c. Venipuncture Volumes for Subjects Consenting for Genetic Testing At Sites that 
Collect PBMCs 1  
  
Screen 
Baseline 
 
 
 
 
 
 
Day +/- Window 
−1 to 1 
1 ± 1 
3 ± 1 
5 ±1 
8 ± 1 
11 ± 1 
15 ± 2 
29 + 6 
Safety hematology, 
chemistry, liver tests 
X 
10mL2 
X 
10mL2 
X 
10mL2 
X 
10mL2 
X 
10mL2 
X 
10mL2 
 X3 
10mL2 
X3 
10mL2 
Blood for Serum 
 
X 
8 mL 
X 
8 mL 
X 
8 mL 
X 
8 mL 
X 
8 mL 
X 
8 mL 
X 
8 mL 
Plasma (PCR and 
proteomics) 
 
GET THIS FROM 
CPT TUBE 
 
X4 
8 mL 
X4 
8 mL 
X4 
8 mL 
X4 
8 mL 
X4 
8 mL 
(X) 4,5--- 
X  
8 mL 
Blood in PAXgene 
tube 
 
X 
2.5 mL 
X 
2.5 mL 
--- 
X 
2.5 mL 
--- 
(X)5--- 
X 
2.5 mL 
Blood for PBMCs in 
Cell Preparation 
Tube (CPT) 
 
X 
25.5 mL 
--- 
--- 
X 
25.5 mL 
--- 
(X) 4,5--- 
X 
25.5 to 
42.5 mL 
Total volume if 
involved in 
exploratory analysis 
10mL 
46 mL 
20.5 mL 
18 mL 
46 mL 
18 mL 
18 mL 
54 -71 
mL 
Total all study days 
 
 
 
 
 
 
 
230.5 to 
247.5 mL 
1. See SOA in Section 1.2 for specific tests to be performed. 
2. Total volume calculated assumes there are no routine clinical laboratory were done within 48 hours of screening 
that can be used for determining eligibility and no routine clinical laboratory tests were done within the window for 
that visitor 24 hours of Day 1, 3, 5, 8 and 11 and 48 hours for Day 15 and 72 hours for Day 29 if still hospitalized.  
3. Safety laboratory tests will be collected on Day 15 and 29 if the subject is still hospitalized at these time points or 
if they return for an in-person outpatient visit and the site has the capacity to collect blood in the outpatient setting. 
4. Plasma will be collected from CPT tube for the proteomics analysis (0.5 mL plasma needed) 
5. If subject discharged prior to Day 8 (i.e., PAXGene tube not collected) or Day 11 (i.e., proteomics not collect), 
site will collect Day 8 and/or Day 11 samples at Day 15 follow-up visit 
 
 
Procedures to be Followed in the Event of Abnormal Laboratory Test Values or 
Abnormal Clinical Findings 
If a physiologic parameter (e.g., vital signs, or laboratory value) is outside of the protocol-specified 
range, then the measurement may be repeated once if, in the judgment of the investigator, the 
abnormality is the result of an acute, short-term, rapidly reversible condition or was an error. A 
physiologic parameter may also be repeated if there is a technical problem with the measurement 
caused by malfunctioning or an inappropriate measuring device (i.e., inappropriate-sized BP cuff). 
 
 
Unscheduled Visits 
If clinical considerations require the subject to be contacted or seen prior to the next schedule 
assessment to assure the subject’s well-being, it is permissible in this protocol. However, no 
research data is collected at this visit.  
8.3 
Adverse Events and Serious Adverse Events 
 
Definition of Adverse Event (AE) 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix C - ACTT-3: Remdesivir + Interferon Beta-1a 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 98 of 172 
AE means any untoward medical occurrence associated with the use of an intervention in humans, 
whether or not considered intervention related. If multiple abnormalities are part of the same 
clinical syndrome, they can be reported together as one AE under a unifying clinical diagnosis. 
 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of medicinal (investigational) 
product. Only Grade 3 and 4 AEs will be captured in this trial and Grade 2 or higher suspected 
drug-related hypersensitivity reactions associated with study product administration. For example, 
worsening respiratory status from Grade 2 (respiratory distress) at Day 1 to Grade 4 (respiratory 
failure) at Day 5 is a condition temporarily associated with use of an intervention and by definition 
is an AE and should be reported even if the investigator believes that this is part of the natural 
history of the disease.  
 
All study required solicited safety laboratory test results will be recorded into the eCRF including 
all Grade 1 and 2 abnormalities.  As the Grade 1 and 2 abnormalities are tracked and available 
within the data system, the Grade 1 and 2 laboratory abnormalities are not expected to be reported 
as adverse events and will not be reviewed by the clinical Monitor. 
 
Given the severity of the underlying illness, subjects will have many symptoms and abnormalities 
in vital signs and laboratory values. As COVID-19 is an emerging, systemic disease involving not 
only the upper and lower respiratory tract, but also the gastrointestinal tract, cardiovascular system, 
endothelial cells, and central nervous system (olfactory neurons), it is important to document 
respiratory AE as well as AEs involving other systems. New symptoms not part of the subject’s 
COVID-19 syndrome at Day 1, should be captured as adverse events. For example, if a subject 
develops new grade 3 gastrointestinal symptoms after Day 1, the gastrointestinal symptoms should 
be reported.  
 
For ACTT-3, the AE reporting window begins with the initial administration of the first study 
product and ends on the last visit (i.e., not from the time the ICF is signed as in ACTT-2). Any 
medical condition that is present at the time that the subject signs the ICF will be considered as 
baseline and not reported as an AE. However, if the severity of any pre-existing (at baseline) 
medical condition increases above baseline to severity grade 3 or 4, it should be recorded as an 
AE. The start date for reporting of an AE/SAE is the date the AE became a Grade 3 AE.  
 
In addition, the following AEs will be reported: 
 
• Any Grade 2 or higher suspected drug-related hypersensitivity reactions associated with 
study product administration will be reported as an AE. 
 
Unsolicited laboratory values collected as part of standard of care, will need to be reported only if 
Grade 3 or above and only if clinically significant and/or part of a diagnosis or a clinical syndrome. 
In this case, if laboratory and vital sign abnormalities are part of the clinical syndrome, they should 
be reported as one AE under one clinical diagnosis or syndrome. Example: Low oxygen 
level/arterial blood gases could be part of respiratory failure diagnosis. 
 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix C - ACTT-3: Remdesivir + Interferon Beta-1a 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 99 of 172 
Intermittent abnormal laboratory values or vital sign measurements common in the severely ill 
populations (such as electrolyte abnormalities, low blood pressure, hyperglycemia, etc.) that are 
part of the same clinical diagnosis (e.g., uncontrolled diabetic) can be recorded once with the 
highest grade for each adverse event (grade 3 and 4 only for this trial), with the start and stops 
dates of the intermittent syndrome. If there is clear resolution of the event, and then recurrence, it 
should be treated as a separate adverse event. Resolution is defined as return to baseline (either 
normal if was normal at Day 1, or baseline (Day 1) grade if already an abnormality on the toxicity 
table at Day 1) for > 48 hours.  
 
D-dimer and CRP should not be graded. These are collected on the same schedule as the safety 
laboratory tests (see SOA). However, they will be used in the assessment of study outcomes.  
 
Standardized reporting of AE is essential to interpretation of data between clinical trial sites in 
multi-site clinical trials. The following recommendations are the result of an internal evaluation of 
safety data collected during ACTT-1 and ACTT-2. 
• Medical conditions that rise to the level of an AE  should be reported as an AE and not the 
procedure used to treat that condition. For example, “respiratory failure with ventilator 
support indicated” should be reported as a Grade 4 respiratory failure AE per the DAIDS 
toxicity table versus reporting an intubation (a surgical procedure) as an AE. 
• Clinical syndromes should be reported rather than each symptom, vital sign, or laboratory 
abnormality separately. For example, respiratory failure should be reported as an AE rather 
than separately reporting respiratory acidosis, hypotension, hypoxia; or AKI should be 
reported instead of low eGFR, high creatinine level and CRRT dialysis procedure. 
• Adverse events that worsen from baseline at Day 1 to a Grade 3 or Grade 4 AE or SAE 
during the study should be reported. This includes worsening of respiratory signs and 
symptoms. An AE is any untoward medical occurrence associated with the use of an 
intervention (including investigational products), whether or not considered intervention 
related. This means that the condition may be associated with the underlying disease 
process (COVID-19), but we would still report as an AE.  
• Readmissions that are due to worsening of medical conditions and requiring inpatient 
hospitalization are SAEs by a definition and should be reported. Readmissions for social 
reasons and not for worsening of medical condition (e.g., readmissions of nursing home 
residents or homeless readmitted for monitoring purposes only) is not an SAE. 
 
 
Definition of Serious Adverse Event (SAE) 
An AE or suspected adverse reaction is considered serious (i.e., is an SAE) if, in the view of 
either the investigator or the Sponsor, it results in any of the following outcomes: 
• Death;.  
• A life-threatening AE; 
• Inpatient hospitalization or prolongation of existing hospitalization; 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix C - ACTT-3: Remdesivir + Interferon Beta-1a 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 100 of 172 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions; or 
• A congenital anomaly/birth defect. 
 
Grade 4 AEs (potentially life-threatening events) are not always SAEs unless they are imminently 
life threatening.  
 
Important medical events that may not meet the above criteria may be considered serious when, 
based upon appropriate medical judgment, they may jeopardize the subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples 
of such medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias, convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse. 
 
“Life-threatening” refers to an AE that at occurrence represents an immediate risk of death to a 
subject. An event that may cause death if it occurs in a more severe form is not considered life-
threatening. Similarly, a hospital admission for an elective procedure is not considered a SAE. 
 
All SAEs, as with any AE, will be assessed for severity and relationship to study intervention. 
 
All SAEs will be recorded on the AE CRF and reported to DMID (see Section 8.3.6). 
 
All SAEs will be followed through resolution or stabilization by a licensed study physician (for 
IND studies, a physician listed on the Form FDA 1572 as the site PI or Sub-Investigator). 
 
All SAEs will be reviewed and evaluated by DMID and will be sent to the DSMB (for periodic 
review), and the IRB/IEC. 
 
 
Suspected Unexpected Serious Adverse Reactions (SUSAR) 
A SUSAR is any SAE where a causal relationship with the study product is at least reasonably 
possible but is not listed in the Investigator Brochure (IB), Package Insert, and/or Summary of 
Product Characteristics. 
 
 
Classification of an Adverse Event 
The determination of seriousness, severity, and causality will be made by an on-site investigator 
who is qualified (licensed) to diagnose AE information, provide a medical evaluation of AEs, 
and classify AEs based upon medical judgment. This includes but is not limited to physicians, 
physician assistants, and nurse practitioners. 
 
 
Severity of Adverse Events 
All AEs and SAEs will be assessed for severity using the DAIDS Table for Grading the Severity 
of Adult and Pediatric Adverse Events, version 2.1 (July 2017).  
 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix C - ACTT-3: Remdesivir + Interferon Beta-1a 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 101 of 172 
For AEs not included in the Table, the following guidelines will be used to describe severity. In 
addition, all deaths related to an AE are to be classified as grade 5 according to the DAIDS Table.  
 
• Moderate (Grade 2): Events that are usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual activities of daily living and 
causes discomfort but poses no significant or permanent risk of harm to the research 
subject. 
 
• Severe (Grade 3): Events that interrupt usual activities of daily living, or significantly 
affect clinical status, or may require intensive therapeutic intervention. Severe events are 
usually incapacitating. 
 
• Potentially life-threatening event (Grade 4): Events that are potentially life threatening. 
 
 
• Deaths (Grade 5): All deaths related to an AE are classified as grade 5 (per DAIDS 
Table). 
 
 
Relationship to Study Intervention 
For each reported adverse reaction, the PI or designee must assess the relationship of the event to 
the study product using the following guideline: 
 
• Related – There is a temporal relationship between the study intervention and event, and 
the AE is known to occur with the study intervention or there is a reasonable possibility 
that the study intervention caused the AE. Reasonable possibility means that there is 
evidence to suggest a causal relationship between the study intervention and the AE. 
 
• Not Related – There is not a reasonable possibility that the administration of the study 
intervention caused the event, there is no temporal relationship between the study 
intervention and event onset, or an alternate etiology has been established. 
 
 
Time Period and Frequency for Event Assessment and Follow-Up 
For this study, all Grade 3 and 4 AEs, and all SAEs occurring from the time the first study 
product is initially given on Day 1 through the Day 29 visit will be documented, recorded, and 
reported. 
 
 
Investigator Reporting of AEs 
Information on AEs will be recorded on the appropriate CRF. All clearly related signs, symptoms, 
and results of diagnostic procedures performed because of an AE should be grouped together and 
recorded as a single diagnosis. If the AE is a laboratory abnormality that is part of a clinical 
condition or syndrome, it should be recorded as the syndrome or diagnosis rather than the 
individual laboratory abnormality. Each AE will also be described in terms of duration (start and 
stop date), severity, association with the study product, action(s) taken, and outcome. 
 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix C - ACTT-3: Remdesivir + Interferon Beta-1a 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 102 of 172 
 
Serious Adverse Event Reporting 
 
Investigators Reporting of SAEs 
Any AE that meets a protocol-defined criterion as an SAE that is judged to be related to either 
study product must be submitted within 24 hours of site awareness on an SAE form to the DMID 
Pharmacovigilance Group, at the following address:  
 
DMID Pharmacovigilance Group 
Clinical Research Operations and Management Support (CROMS) 
6500 Rock Spring Dr. Suite 650 
Bethesda, MD 20817, USA 
SAE Hot Line: 1-800-537-9979 (US) or 1-301-897-1709 (outside US) 
SAE FAX Number: 1-800-275-7619 (US) or 1-301-897-1710 (outside US) 
SAE Email Address: PVG@dmidcroms.com 
 
Other supporting documentation of the event may be requested by the DMID Pharmacovigilance 
Group and should be provided as soon as possible. The DMID Medical Monitor will review and 
assess the SAE for regulatory reporting and potential impact on study subject safety and protocol 
conduct. At any time after completion of the study, if the site PI or appropriate sub-investigator 
becomes aware of an SAE that occurred during the subject’s participation in the study, the site PI 
or appropriate sub-investigator will report the event to the DMID Pharmacovigilance Group. 
 
SAEs that that are judged to be not related to study product are still captured on the AE case report 
form, but do not require separate reporting to the DMID Pharmacovigilance Group. 
 
 
Regulatory Reporting of SAEs 
Following notification from the site PI or appropriate sub-investigator, DMID, as the IND Sponsor, 
will report any SUSAR in an IND safety report to the FDA and will notify all participating site PIs 
as soon as possible. DMID will report to the FDA any unexpected fatal or life-threatening 
suspected adverse reaction as soon as possible, but in no case later than 7 calendar days after the 
Sponsor’s initial receipt of the information. If the event is not fatal or life-threatening, the IND 
safety report will be submitted within 15 calendar days after the Sponsor determines that the 
information qualifies for reporting as specified in 21 CFR Part 312.32. Relevant follow up 
information to an IND safety report will be submitted as soon as the information is available. Upon 
request from the FDA, DMID will submit to the FDA any additional data or information that the 
agency deems necessary, as soon as possible, but no case later than 15 calendar days after receiving 
the request. 
 
SAEs that are not SUSARs will be reported to the FDA at least annually in a summary format 
which includes all SAEs. 
 
Sites may have additional local reporting requirements (to the IRB and/or national regulatory 
authority). 
  
 
Reporting of Pregnancy 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix C - ACTT-3: Remdesivir + Interferon Beta-1a 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 103 of 172 
Pregnancy is not an AE. However, any pregnancy that occurs during study participation should 
be reported to the Sponsor on the appropriate CRF. Pregnancy should be followed to outcome.  
8.4 
Unanticipated Problems 
 
Definition of Unanticipated Problems 
An Unanticipated Problem (UP) is any event, incident, experience, or outcome that meets the 
following criteria: 
• Unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the IRB-approved research 
protocol and informed consent document; and (b) the characteristics of the subject 
population being studied; 
 Related to participation in the research (meaning there is a reasonable possibility that the 
incident, experience, or outcome may have been caused by the procedures involved in the 
research); and 
 Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
 
 
Unanticipated Problem Reporting 
To satisfy the requirement for prompt reporting, all Ups will be reported using the following 
timeline: 
 UPs that are SAEs will be reported to the IRB and to the Statistical and Data 
Coordinating Center (SDCC)/study Sponsor within 24 hours of the investigator becoming 
aware of the event per the above describe SAE reporting process. 
 Any other UP will be reported to the IRB and to the SDCC/study Sponsor within 3 days 
of the investigator becoming aware of the problem. 
 
9. 
STATISTICAL CONSIDERATIONS 
9.1 
Statistical Hypotheses 
 
The primary hypothesis tests whether the time-to-recovery by Day 29 differs between the 
experimental and control arms. 
 
Table 7. Hypothesis tests of interest for ACTT-3 
 
ACTT-3  
 
Primary hypothesis 
RDV + interferon-beta-1a versus RDV + placebo 
  

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix C - ACTT-3: Remdesivir + Interferon Beta-1a 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 104 of 172 
A key secondary hypothesis tests the null distribution of a similar distribution of 8-point ordinal 
scale at Day 15. For this, the parameter of interest is the “common odds ratio,” which quantifies 
the shift in the severity distribution resulting from treatment. For an efficacious treatment, an odds 
ratio greater than 1 quantifies an improvement in disease severity; a value of 2 indicates a bigger 
improvement than a value of 1.25. The null hypothesis to be tested is that the odds of improvement 
on the ordinal scale is the same for the control and experimental treatment arms (i.e., the common 
odds ratio is 1). It is worth noting that, for large sample sizes, the test based on the proportional 
odds model is nearly the same as the Wilcoxon rank sum test. 
 
9.2 
Sample Size Determination 
 
Primary endpoint: The log-rank test will be used to compare treatment arms with respect to time 
to recovery. For the log-rank test, the two key determinants of power are the total number of 
events (i.e., recoveries) E and the treatment-to-control ratio of the rate of recovery, R. The 
number of events required for power 1 −𝛽𝛽 to detect a recovery rate ratio of θ using a two-tailed 
test at alpha=0.05 is approximately 
𝐸𝐸= 4൫1.96 + 𝑧𝑧𝛽𝛽൯
2
{ln(𝜃𝜃)}2
, 
 
 
where 𝑧𝑧𝛽𝛽 is the 100(1 −𝛽𝛽)th percentile of the standard normal distribution. 
The force of recovery (sometimes loosely referred to as the “recovery ratio”) is the analogue of 
the hazard ratio and the term “recovery rate ratio” is the analogue of the hazard ratio in this setting. 
A recovery rate ratio of 1.31 was reported in Cao, Wang, Wen et al. (2020) for a lopinavir/ritonavir 
trial that used time to improvement by 2 categories as primary endpoint. A preliminary review of 
data from ACTT-1 demonstrated a recovery rate ratio 1.312. It is unlikely the second component 
of treatment will have a similar effect size. Therefore a recovery ratio of 1.25 is assumed for this 
trial. A total of 723 recoveries are needed for a recovery ratio of 1.25 with 85% power. Table 5 
provides power for various recovery rate ratios.  
 
 
 
Table 8. Number of recoveries needed for 85% power assuming a type I error rate of 5% 
for various recovery ratios. 
 
Recovery 
rate ratio 
(θ) 
Number of recoveries 
needed for 85% 
power 
1.20 
1080 
1.25 
723 
1.30 
523 
1.35 
400 
1.40 
318 
 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix C - ACTT-3: Remdesivir + Interferon Beta-1a 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 105 of 172 
The study will enroll participants until 831 recoveries. Initially the study was powered for 723 
recoveries in those in ordinal score 4-6 at baseline, with an increase to 831 recoveries due to 
anticipated lower efficacy in ordinal score 7. The same assumption will now be made that ordinal 
score 6 will have a lower efficacy, and therefore the number of  recoveries will remain 
unchanged. However, we anticipate that approximately 90% of subjects recover within 28 days, 
and therefore the total sample size will be approximately 923. The date of study closure will be 
estimated based on enrollment rate and recovery/enrollment percentages. 
 
Key secondary: A sample size can be computed using an (assumed) ordinal scale distribution 
for the control arm and the odds ratio representing clinical improvement. The odds ratio 
represents the odds of improvement in the ordinal scale for combination treatment relative to the 
control arm [Whitehead, 1993]. The sample size to detect a given odds ratio for 1:1 
randomization using a 2-tailed test at level α is given by 
 
12൫𝑧𝑧α/2 + 𝑧𝑧β൯
2
λ2(1 −∑
𝑝𝑝𝑖𝑖
3
𝐾𝐾
𝑖𝑖=1
), 
 
where λ is the log odds ratio, 𝑝𝑝𝑖𝑖 is the overall probability (combined over both arms) of being in 
the ith category of the K ordinal outcomes, and 𝑧𝑧α/2 and 𝑧𝑧𝛽𝛽 are the 1 −α/2 and 1 −β quantiles 
of the standard normal distribution.  
 
Table 6 displays five scenarios considered for outcome probabilities in the control arm for 
sample size determination. There is significant uncertainty with these assumptions given the 
limited data available. Table 6 shows a range of sample sizes for odds ratios ranging from 1.25 to 
2.5 for 85% power. For 90% power, increase the sample size by 17%. Table 8 displays the 
probabilities of being in different categories of the ordinal scale under an odds ratio of 1.75. A 
total sample size of 396 gives approximately 85% power to detect an odds ratio of 1.75 using a 
2-tailed test at level α = 0.05. The categories of the 8-point ordinal scale are: 
 
• Death; 
• Hospitalized, on invasive mechanical ventilation or ECMO; 
• Hospitalized, on non-invasive ventilation or high flow oxygen devices; 
• Hospitalized, requiring supplemental oxygen; 
• Hospitalized, not requiring supplemental oxygen – requiring ongoing medical care 
(COVID-19 related or otherwise); 
• Hospitalized, not requiring supplemental oxygen – no longer requires ongoing medical 
care; 
• Not hospitalized, but new or increased limitation on activities and/or requiring new or 
increased home oxygen; 
• Not hospitalized, no limitations on activities. 
 
Note that the data elements contributing to this scale will be captured separately, in order to 
facilitate different orderings or groupings, as might arise if external data provide information 
about the clinical course of disease.  
 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix C - ACTT-3: Remdesivir + Interferon Beta-1a 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 106 of 172 
 
Table 9: Possible scenarios for the distribution of ordinal outcomes for the control arm at 
Day 15. 
 
Anticipated 
Different scenarios for control arm 
  
Scenario 1 
Scenario 2 
Scenario 3 
Scenario 4 
Scenario 5 
 
 
more mild disease                       more severe disease 
Severity Outcome 
outcome (%) outcome (%) 
outcome (%) outcome (%) outcome (%) 
Death 
2 
1 
1 
2 
3 
Hospitalized, on 
mechanical ventilation or 
ECMO 
1 
1 
1 
1 
3 
Hospitalized, on non-
invasive ventilation or 
high flow oxygen devices 
2 
1 
1 
2 
4 
Hospitalized, requiring 
supplemental oxygen 
7 
2 
5 
5 
9 
Hospitalized, not requiring 
supplemental oxygen – 
requiring ongoing medical 
care (COVID-19 related 
or otherwise) 
8 
5 
7 
17 
23 
Hospitalized, not requiring 
supplemental oxygen – no 
longer requires ongoing 
medical care 
10 
9 
10 
20 
25 
Not hospitalized, 
limitation on activities 
and/or requiring home 
oxygen 
30 
36 
35 
25 
18 
Not hospitalized, no 
limitations on activities 
40 
45 
40 
28 
15 
 
 
Table 10: Sample size calculations for scenarios in Table 6 for a two-arm study assuming 
85% power, a two-sided type I error rate of 5%, and various true odds ratios.  
True odds 
ratio 
Total sample size 
 
Scenario 1 
Scenario 2 
Scenario 3 
Scenario 4 
Scenario 5 
1.25 
2420 
2554 
2459 
2293 
2252 
1.5  
744 
786 
755 
700 
684 
1.75 
396 
419 
401 
370 
360 
2.0 
262 
277 
265 
243 
236 
2.25 
194 
206 
196 
179 
173 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix C - ACTT-3: Remdesivir + Interferon Beta-1a 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 107 of 172 
True odds 
ratio 
Total sample size 
 
Scenario 1 
Scenario 2 
Scenario 3 
Scenario 4 
Scenario 5 
2.5 
154 
163 
155 
141 
136 
 
 
Table 11. Treatment ordinal outcome proportions under an odds ratio of 1.75 for five 
scenarios in Table 5 at Day 15. 
  
Scenario 
1 
Scenario 
2 
Scenario 
3 
Scenario 
4 
Scenario 
5 
 
Anticipated more mild disease                more severe disease 
Severity Outcome 
Control % 
Treatment % 
Control % 
Treatment % 
Control % 
Treatment % 
Control % 
Treatment % 
Control % 
Treatment % 
Death 
2 
1.2 
1 
0.6 
1 
0.6 
2 
1.2 
3 
1.7 
Hospitalized, on mechanical 
ventilation or ECMO 
1 
0.6 
1 
0.6 
1 
0.6 
1 
0.6 
3 
1.8 
Hospitalized, on non-invasive 
ventilation or high flow 
oxygen devices 
2 
1.2 
1 
0.6 
1 
0.6 
2 
1.2 
4 
2.5 
Hospitalized, requiring 
supplemental oxygen 
7 
4.3 
2 
1.2 
5 
3.0 
5 
3.1 
9 
5.8 
Hospitalized, not requiring 
supplemental oxygen – 
requiring ongoing medical 
care (COVID-19 related or 
otherwise) 
8 
5.3 
5 
3.1 
7 
4.4 
17 
11.5 
23 
17.4 
Hospitalized, not requiring 
supplemental oxygen – no 
longer requires ongoing 
medical care; 
10 
7.2 
9 
5.9 
10 
6.8 
20 
16.2 
25 
24.4 
Not hospitalized, limitation 
on activities and/or requiring 
home oxygen 
30 
26.5 
36 
29.3 
35 
30.2 
25 
25.9 
18 
22.7 
Not hospitalized, no 
limitations on activities 
40 
53.8 
45 
58.9 
40 
53.8 
28 
40.5 
15 
23.6 
Note that columns may not sum to exactly 100 due to rounding errors. 
 
Other key secondaries for testing combination therapy compared to control will be detailed in an 
addendum SAP 
 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix C - ACTT-3: Remdesivir + Interferon Beta-1a 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 108 of 172 
9.3 
Populations for Analyses 
 
An adjudication or review committee consisting of the DMID MO, her designees and the blinded 
statistical team may review endpoints, medications, deviations, and other special cases where 
expert opinion is requested for handling complicated cases.  
The primary analysis will be based on an intention-to-treat population, including all subjects 
randomized. Similarly, safety analyses will be based a modified intent-to-treat population 
consisting of all subjects who received at least one dose of any investigational product.  
 
9.4 
Statistical Analyses 
 
General Approach 
This is a double-blind placebo controlled randomized trial testing a superiority hypothesis with a 
two-sided type I error rate of 5%. Secondary hypotheses have been ordered according to relative 
importance, with one key secondary hypothesis highlighted. These will be described according to 
the appropriate summary statistics (e.g., proportions for categorical data, means with 95% 
confidence intervals for continuous data, median for time-to-event data).  
 
A statistical analysis plan will be developed and filed with the study sponsor prior to unblinding 
of study and database lock.  
 
 
Analysis of the Primary Efficacy Endpoint 
The primary efficacy analysis is a stratified log-rank test, where stratification is according to 
baseline disease severity as defined by ordinal scale. Deaths will be considered as never recovering 
and censored at Day 29. In ACTT-3, the analyses conducted will depend on the results from 
ACTT-1 according to Table 4. 
 
 
Analysis of the Secondary Endpoint(s) 
The ordinal scale will be used to estimate a proportional odds model by disease strata. The 
hypothesis test will perform a stratified test to evaluate whether the common odds ratio for 
treatment is equal to one. The distribution of severity results will be summarized by treatment 
arm as percentages. Efforts to minimize loss-to-follow-up will be considerable. However, small 
amounts of missing data may occur. In such cases, subjects without final outcome data will be 
excluded from the analysis. Sensitivity analyses will evaluate the impact of making different 
assumptions about missing observations. These analyses will be defined in the SAP.  
Differences in time-to-event endpoints (e.g., time to at least a one category improvement in 
ordinal scale) by treatment will be summarized with Kaplan-Meier curves and 95% confidence 
bounds. The same procedure will be used to compare time to at least a two-category 
improvement. 
Change in ordinal scale at specific time points will be summarized by proportions (e.g., 
proportion who have a 1-, 2-, 3-, or 4-point improvement or 1-, 2-, 3-, 4-point worsening). 
 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix C - ACTT-3: Remdesivir + Interferon Beta-1a 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 109 of 172 
Duration of event (e.g., duration of mechanical ventilation) will be summarized according to 
median days with quartiles. 
 
Binary data (e.g., incidence of new oxygen use) will be summarized as a percent with 95% 
confidence intervals. Comparisons between arms will be presented as differences in proportions 
with 95% confidence intervals. 
 
Categorical data (e.g., 28-day mortality or ordinal scale by day) may be summarized according to 
proportions by category and/or odds ratios with confidence intervals.  
 
Procedures for handling missing data, including informative censoring (e.g., a missing duration 
of oxygen use endpoint due to a death), will be described in the SAP. 
 
 
 
Analysis of Exploratory Objectives and Endpoints 
Exploratory objectives and endpoints for immunophenotyping including transcriptomics, 
interferon-simulating gene analysis, proteomics, epigenetics, and T cell and innate immune cell 
phenotyping will be handled in a separate analysis plan. Samples for the exploratory objectives 
are outlined in this protocol and details of sample collection, processing, storage and shipping is 
described in detail the MOP, however, the analysis will not take place in real-time, during study 
enrollment. Depending on the timing of the completion of these assays, exploratory results will 
be submitted as one or more addenda to the primary CSR. 
 
 
Safety Analyses 
Safety endpoints include death through Day 29 (+ 6 days), SAEs and Grade 3 and 4 AEs. These 
events will be analyzed univariately and as a composite endpoint. Time-to-event methods will be 
used for death and the composite endpoint. Each AE will be counted once for a given subject and 
graded by severity and relationship to COVID-19 or study intervention. AEs will be coded using 
the current version of the Medical Dictionary for Regulatory Activities (MedDRA). AEs will be 
presented by system organ class, duration (in days), start- and stop-date. Adverse events leading 
to premature discontinuation from the study intervention and serious AEs will be presented either 
in a table or a listing.  
 
 
Baseline Descriptive Statistics 
Baseline characteristics will be summarized by treatment arm. For continuous measures the mean, 
median, minimum, maximum and standard deviation will be summarized. Categorical variables 
will be described by the proportion in each category (with the corresponding sample size numbers).  
 
 
Planned Interim and Early Analyses  
A DSMB will monitor ongoing results to ensure subject well-being and safety as well as study 
integrity. The DSMB will be asked to recommend early termination or modification only when 
there is clear and substantial evidence of a treatment difference. More details about the interim 
analyses are described in section 9.4.6.1 and 9.4.6.2 below as well as a separate guidance document 
for the DSMB.  

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix C - ACTT-3: Remdesivir + Interferon Beta-1a 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 110 of 172 
 
On September 4, 2020, the DSMB met for an interim safety review of ACTT-3 data, and they 
recommended that DMID close further enrollment to patients with a baseline ordinal score of 6. 
Given that there are multiple clinical trials evaluating interferon beta for the treatment of COVID-
19 worldwide, a public announcement describing the change in enrollment was made to inform 
the scientific community. If necessary, there may be an early evaluation of safety outcomes for the 
category 6 subjects enrolled in ACTT-3. Specifically, after study Day 29, for all subjects enrolled 
at an ordinal score of 6, those subjects only may be unblinded and an interim analysis may occur. 
This could be done if needed in order to determine the risk in this group of patients and convey 
this risk to other sponsors who can then use this information to make modifications if needed to 
their ongoing studies. This would be followed by a full analysis after the final data cleaning. The 
SAP has been modified to describe this interim analysis as well as a revised analysis for the ordinal 
6 category.  
 
 
Interim Safety Analyses 
Safety analyses will evaluate Grade 3 and 4 AE and SAEs by treatment arm. Safety monitoring 
will be ongoing with the DSMB reviewing safety data approximately every two weeks during the 
study. The unblinded statistical team will prepare these reports for review by the DSMB.  
 
 
Interim Efficacy Review 
The Lan-DeMets spending function analog of the O’Brien-Fleming boundaries will be used to 
monitor the primary endpoint as a guide for the DSMB for an overall two-sided type-I error rate 
of 0.05. Interim efficacy analyses will be conducted at approximately 50% and 100% of total 
information.  
 
Conditional power will be presented as an additional guide to the DSMB. Conditional power 
allows computation of the probability of obtaining a statistically significant result by the end of 
the trial given the data accumulated thus far, incorporating and assuming a hypothesized treatment 
effect (e.g., the treatment effect assumed for sample size determination) thereafter. If conditional 
power is less than 20% under the original trial assumptions, consideration should be given to 
stopping the trial.  
 
The unblinded statistical team will prepare these closed reports for DSMB review and 
recommendations. Analyses will be presented with blinded codes for treatment arms to protect 
against the possibility that the DSMB report may fall into the wrong hands. A DSMB charter will 
further describe procedures and membership.  
 
 
Sub-Group Analyses 
Subgroup analyses for the primary outcomes will evaluate the treatment effect across the following 
subgroups: geographic region, duration of symptoms prior to enrollment, baseline disease severity 
(ordinal scale), age, race, ethnicity, sex, and comorbidities. A forest plot will display confidence 
intervals across subgroups. Interaction tests will be conducted to determine whether the effect of 
treatment varies by subgroup. 
 
Exploratory Analyses 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix C - ACTT-3: Remdesivir + Interferon Beta-1a 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 111 of 172 
An exploratory analysis will compare treatment efficacy estimates according to the various scales 
outlined in section 8.1.3. Specifically, the probability of falling into category “i” or better will be 
compared between arms for each i.  
 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS – ALL STAGES 
All supporting documentation and operational considerations are applicable to the entire platform 
trial and are not unique to the individual stages. These are therefore covered in the main protocol 
document. 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix D - ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 112 of 172 
 
APPENDIX D - ACTT-4: BARICITINIB/REMDESIVIR VS. 
DEXAMETHASONE/REMDESIVIR  
 
1. 
PROTOCOL SUMMARY 
1.1 
ACTT-4 – Synopsis 
Study overview 
Severe COVID-19 is marked by a hyperinflammatory state characterized by upregulation of 
multiple cytokines. Multiple therapeutic strategies have been proposed to counter this 
inflammatory phase. To date, only two anti-inflammatory medications have demonstrated 
efficacy in large randomized trials – dexamethasone and baricitinib.  
 
In the Randomized Evaluation of Covid-19 Therapy (RECOVERY) trial, treatment with 
dexamethasone demonstrated a lower mortality rate, 22.9% in the dexamethasone group versus 
25.7% in the usual care group (absolute difference 2.8%; p<0.001).(15) In ACTT-2, treatment 
with baricitinib in addition to remdesivir demonstrated a shorter median time-to-recovery of 7 
days versus 8 days with remdesivir alone [rate ratio for recovery 1.16, P=0.03] and a lower 28-
day mortality of 5.1% and 7.8% in the combination and control arms, respectively (absolute 
difference 2.7%; P>0.05). (Kalil et al, 2020)  
 
These two studies, however, are very different – different study populations, different baseline 
mortality rates, and different data collected. Only ACTT-2 was blinded, and only in ACTT-2 was 
the anti-inflammatory intervention given in addition to an antiviral. Therefore direct comparison 
of these studies to determine which interventions are of value in which populations is difficult. 
ACTT-4 will evaluate adult patients hospitalized with COVID-19 and requiring supplemental 
oxygen by low flow, high flow or non-invasive mechanical ventilation modalities to determine if 
baricitinib or dexamethasone in combination with remdesivir are more effective at preventing 
progression to mechanical ventilation or death (among other outcomes) or if they are similar.  
 
Enrollment Period:  
It is anticipated the enrollment will be completed in 3-4 months. 
 
General 
ACTT-4 will evaluate the combination of baricitinib and remdesivir compared to dexamethasone 
and remdesivir in adult patients hospitalized with COVID-19 and requiring supplemental 
oxygen. Subjects will be assessed daily while hospitalized. If the subjects are discharged from 
the hospital, they will have a study visit at Days 15, 22, and 29. For discharged subjects, it is 
preferred that the Day 15 and 29 visits are in person to obtain safety laboratory tests, OP swabs, 
plasma (Day 29), and serum for secondary research as well as clinical outcome data. However, if 
infection control or other restrictions limit the ability of the subject to return to the clinic, these 
visits may be conducted by phone and only clinical data will be obtained. The Day 22 visit does 
not have laboratory tests or collection of samples and is conducted by phone. Additionally, in 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix D - ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 113 of 172 
ACTT-4, subjects will be contacted by phone, via a telehealth remote visit or in-person visit at 
approximately 2 months after randomization to assess long term efficacy and safety outcomes. 
 
We anticipate that this trial will require 1348 subjects. Assuming that 8% of subjects are lost to 
follow-up by Day 29, the total sample size is approximately 1500.  
 
Study Population 
Hospitalized adults (≥18 years old) with COVID-19 requiring supplemental oxygen administered 
by low flow, high flow or non-invasive mechanical ventilation modalities. 
 
Inclusion Criteria 
1. Hospitalized with symptoms suggestive of COVID-19. 
2. Subject (or legally authorized representative) provides informed consent prior to 
initiation of any study procedures and understands and agrees to comply with planned 
study procedures. 
3. Male or non-pregnant female adults ≥ 18 years of age at time of enrollment. 
4. Illness of any duration and has laboratory-confirmed SARS-CoV-2 infection as 
determined by PCR or other commercial or public health assay (e.g. NAAT, antigen test) 
in any respiratory specimen or saliva ≤14 days prior to randomization. 
5. Within the 7 days prior to randomization requiring new use of supplemental oxygen (or 
increased oxygen requirement if on chronic oxygen) and requires at the time of 
randomization low or high flow oxygen devices or use of non-invasive mechanical 
ventilation (ordinal scale category 5 or 6). 
6. Women of childbearing potential must agree to either abstinence or use at least one 
primary form of contraception not including hormonal contraception from the time of 
screening through Day 29.  
7. Agrees not to participate in another blinded clinical trial (both pharmacologic and other 
types of interventions) for the treatment of COVID-19 through Day 29 (see Section 5.4 
for more information about concurrent trial participation). 
 
Exclusion Criteria 
1. Prior enrollment in ACTT-3 or ACTT-4. Note: this includes subjects whose participation 
in ACTT was terminated early.  
2. On invasive mechanical ventilation at the time of randomization (ordinal scale category 
7).  
3. Anticipated discharge from the hospital or transfer to another hospital which is not a 
study site within 72 hours of randomization. 
4. Positive test for influenza virus during the current illness (influenza testing is not 
required by protocol). 
5. Subjects with a low glomerular filtration rate (eGFR), specifically: 
a. Subjects with an eGFR 15-30 mL/min are excluded unless in the opinion of the 
PI, the potential benefit of participation outweighs the potential risk of study 
participation. 
b. All subjects with an eGFR <15 mL/min are excluded. 
c. All subjects on hemodialysis and/or hemofiltration at the time of screening, 
irrespective of eGFR, are excluded. 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix D - ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 114 of 172 
6. Neutropenia (absolute neutrophil count <700 cells/μL, 0.7 x 103/μL). 
7. Lymphopenia (absolute lymphocyte count <200 cells/μL, 0.20 x 103/μL). 
8. Received five or more doses of remdesivir including the loading dose, outside of the 
study as treatment for COVID-19.  
9. Pregnancy or breast feeding (lactating women who agree to discard breast milk from Day 
1 until two weeks after the last study product is given are not excluded). 
10. Allergy to any study medication. 
11. Received convalescent plasma or intravenous immunoglobulin [IVIg] for COVID-19, the 
current illness for which they are being enrolled. 
12. Received any of the following in the two weeks prior to screening as treatment of 
COVID-19: 
• More than one dose of baricitinib for the treatment of COVID-19; 
• Other small molecule tyrosine kinase inhibitors (e.g. imatinib, gefitinib, acalabrutinib, 
etc.); 
• monoclonal antibodies targeting cytokines (e.g., TNF inhibitors, anti-interleukin-1 
[IL-1], anti-IL-6 [tocilizumab or sarilumab], etc.);  
• monoclonal antibodies targeting T-cells or B-cells as treatment for COVID-19. 
Note: receipt of anti-SARS-CoV-2 mAb prior to enrollment (e.g. bamlanivimab) for their 
current COVID-19 illness is not exclusionary 
13. Use of probenecid that cannot be discontinued at study enrollment. 
14. Received 6 mg or more of dexamethasone po or IV (or equivalent for other 
glucocorticoids) in one day, on more than one day in the 7 days prior to time of 
randomization. Note: 6 mg dexamethasonedose equivalents include 40 mg prednisone, 32 
mg methylprednisolone and 160 mg hydrocortisone. 
15. Received ≥20 mg/day of prednisone po or IV (or equivalent for other glucocorticoids) for 
≥14 consecutive days in the 4 weeks prior to screening. 
16. Have diagnosis of current active or latent tuberculosis (TB), if known, treated for less 
than 4 weeks with appropriate therapy (by history only, no screening required). 
17. Serious infection (besides COVID-19), immunosuppressive state, or immunosuppressive 
medications that in the opinion of the investigator could constitute a risk when taking 
baricitinib or dexamethasone. 
18. Have received any live vaccine (that is, live attenuated) within 4 weeks before screening, 
or intend to receive a live vaccine (or live attenuated) during the study. Note: Use of non-
live (inactivated) vaccinations including SARS-CoV-2 vaccine is allowed for all subjects. 
19. Had a known VTE (deep vein thrombosis [DVT] or pulmonary embolism [PE]) during 
the current COVID-19 illness. 
 
Study Intervention 
Subjects will be randomized into two arms (1:1). 
 
Arm 1 
Arm 2 
Baricitinib tablets +  
Placebo IV + 
Remdesivir IV 
Placebo tablets +  
Dexamethasone IV +  
Remdesivir IV 
 
 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix D - ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 115 of 172 
All subjects will receive standard antiviral treatment with remdesivir as a 200 mg intravenous (IV) 
loading dose on Day 1, followed by a 100 mg once-daily IV maintenance dose during 
hospitalization up to a maximum of 10 total doses (i.e., loading + maintenance doses received 
during study and pre-study if applicable). See Section 6.1.4 for details of dosing and dose 
modification.  
 
For the baricitinib component, subjects will receive either: 
• Baricitinib 4 mg** orally (po) (two 2 mg tablets) or dissolved* per NG tube, daily for the 
duration of the hospitalization up to a 14-day total course.  
• Placebo given as two tablets** orally (po) or dissolved per NG tube, daily for the 
duration of the hospitalization up to a 14-day total course. 
* See MOP for instructions on how to prepare and administer baricitinib to patients 
having difficulty swallowing 
** Dose of oral study product will be decreased or held based on eGFR. Specifically: 
eGFR Value  
Dose of Baricitinib/Oral Placebo 
≥60 mL/min 
Two tablets (4 mg total) once daily  
No dose adjustment 
30 - <60 mL/min 
One tablet (2 mg) once daily 
15 - <30 mL/min 
One tablet (2 mg) QOD – every 
other day 
<15 mL/min or require hemodialysis or 
hemofiltration 
Hold oral study product  
 
For the dexamethasone component, subjects will receive either active product or placebo as 
follows: 
• Dexamethasone will be administered as a 6 mg slow IV push over 3 to 5 minutes (1.5 
mL) daily for the duration of the hospitalization up to a 10-day total course. 
• A normal saline placebo will be given as a slow IV push over 3 to 5 minutes daily for the 
duration of the hospitalization up to a 10-day total course 
• If local standards use other means of administration (such as IV infusion), these may be 
used for both active and placebo. 
• Any pre-study dexamethasone (max 1 dose per inclusion criteria) is not counted towards 
the 10 day course.  
 
Duration of therapy: 
• IV remdesivir – 5 - 10 days while hospitalized. 
o The recommended treatment duration for most subjects is 5 days.  
o If a patient does not demonstrate clinical improvement, or deteriorates to require 
invasive mechanical ventilation and/or extracorporeal membrane oxygenation 
(ECMO), treatment may be extended for up to 5 additional days for a total 
treatment duration of up to 10 days. 
• Oral baricitinib (or oral placebo) – 14 days while hospitalized. 
• IV dexamethasone (or IV placebo) – 10 days while hospitalized. 
• All medications stop on discharge from hospital.  

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix D - ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 116 of 172 
o Of note, if a subject is retained in the hospital for non-COVID-19 related issues 
and no longer requires supplemental oxygen and ongoing medical care (i.e., 
ordinal scale category 3), the PI may decide to discontinue all medications.  
 
1.2 
Schedule of Assessments 
 
Table 1. Schedule of Assessments (SOA) 
 
  
Screen 
Baseline  
Study Intervention Period 
Follow-up Visits  
 
Day +/- Window 
−1 or 1 
1 
Daily until hospital 
discharge 
157  
± 2 
227 
± 3 
297 
+ 6 
60 
-7 -  
+14 
ELIGIBILITY 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
Demographics & Medical Hx 
X 
 
 
 
 
 
 
Review SARS-CoV-2 results 
X 
 
 
 
 
 
 
 Review influenza results if 
available 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY INTERVENTION 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
Administration of 
investigational agents 
 
• Remdesivir: IV daily for 5-10 days 
or until discharge.  
• Baricitinib or placebo: po daily until 
day 14 or discharge 
• Dexamethasone or placebo: IV daily 
until day 10 or discharge 
 
 
 
 
 
 
 
 
 
 
 
STUDY PROCEDURES 
 
 
 
 
 
 
 
Targeted physical exam 1 
 
X 
 
 
 
 
 
Vital sign and NEWS score 1 
 
X 
 
 
 
 
 
Clinical data collection 2  
 
X4 
Daily until discharge8 
X9 
X9 
X9 
X 
Adverse event evaluation 
 
 
Daily until discharge8 
X9 
X9 
X9 
 
Concomitant medication review 
X 
X 
From Day -7 to Day 29. 
Stop collection after 
discharge 
 
 
 
 
 
 
 
 
 
 
 
 
CLINICAL LABORATORY 
 
 
 
 
 
 
 
Screening clinical lab tests 
X3 
 
 
 
 
 
 
Pregnancy test for females of 
childbearing potential 
X3 
 
 
 
 
 
 
Safety hematology, chemistry 
and liver tests 
 
X4,5,6,7 
Day 3, 5, 8, 11 (all ± 1 
day) if hospitalized 6,7 
X9 
 
X9 
 
 
 
 
 
 
 
 
 
RESEARCH LABORATORY FOR ALL SUBJECTS 
 
 
 
 
Blood for plasma to test by PCR 
for SARS-CoV-2 and cytokines/ 
inflammatory markers 
 
X4 
Day 3, 5, 8, 11 (all ± 1 
day) if hospitalized 
 
 
X9 
 
Oropharyngeal swab 10 
 
X4 
Day 3, 5, 8, 11 (all ± 1 
day) if hospitalized 
X9 
 
X9 
 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix D - ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 117 of 172 
Blood for serum (exploratory 
and secondary research) 
 
X4 
Day 3, 5, 8, 11 (all ± 1 
day) if hospitalized 
X9 
 
X9 
 
ONLY FOR SUBJECTS CONSENTING FOR GENETIC RESEARCH 
 
 
 
 
Blood for RNA for 
transcriptomic analysis (in 
PAXgene tube)  
 
X4 
Day 3, 8 (all ± 1 day) if 
hospitalized 
X9, 11 
 
X9 
 
Notes: 
 
1Targeted physical exam and NEWS (with vital signs) done at baseline. Exam done by the treating licensed 
healthcare provider may be used. The baseline exam can be one that is conducted from screening to Day 1. 
2 Refer to Section 8.1.2 of the protocol for details of clinical data to be collected for ordinal score, oxygen 
requirement, mechanical ventilator requirement, etc. 
3 Screening clinical laboratory tests include: white blood cell (WBC) count with differential, absolute neutrophil 
count (ANC), absolute lymphocyte count (ALC), and creatinine. Sites calculate an estimated glomerular filtration 
rate (eGFR) using the formula selected by the site that is used consistently throughout the study. Laboratory tests 
performed in the 48 hours prior to enrollment will be accepted for determination of eligibility. A pregnancy test 
should be done at screening for females of childbearing potential. See Section 8.1.1. for more information about 
pregnancy tests in post-partum women. 
4 Baseline (Day 1) assessments should be performed prior to first study product administration. Results of Day 1 
laboratory assessment do not need to be reviewed to determine if initial study product should be given. In ACTT-4, 
vitamin D will be assessed on Day 1 only. It will be used to evaluate outcomes and should not be graded as it is not 
a safety laboratory. 
5 Laboratory tests performed as part of routine clinical care in the 36 hours prior to first dose will be accepted for 
the baseline (Day 1) safety laboratory tests. Baseline may be the same as the screening laboratory tests.  
6 Safety laboratory tests include: WBC count with differential, hemoglobin, platelet count, creatinine, glucose, 
total bilirubin, ALT, AST, and INR. D-dimer and C-reactive protein (CRP) are collected at the same time points as 
the safety labs but should not be graded like the safety labs. D-dimer and CRP may predict severity and support 
assessment of outcomes.  
7 Any laboratory tests performed as part of routine clinical care within the specified visit window can be used for 
safety laboratory testing.  
8 Daily until hospital discharge or Day 29, whichever comes first. See Section 8.1.2.1 for more information about 
doing an ordinal scale assessment on the day after hospital discharge and on the day after a subject dies. 
9 In-person visits are preferred but recognizing quarantine and other factors may limit the subject’s ability to 
return to the site for the visit. In this case, the visit may be performed by phone call, home visit or remote 
telehealth procedure as per institutional standards. If subject is still hospitalized during the follow-up period, they 
should get Day 15, 22 and 29 assessments along with the daily clinical data collection. 
• 
If still hospitalized at Day 15 and 29 or returns to the site for an in-person visit or home visit: collect 
clinical data, safety laboratory tests, and research laboratory samples as able.  
• 
If phone call or remote telehealth visit only on Days 15 and 29 and all Day 22 visits: assess adverse events, 
ordinal scale, readmission to a hospital, and mortality only. At the Day 60 visit, assess oxygen use, physical 
limitations, readmissions, and clinical outcomes including mortality. See Section 8.1.2.1 for more information. 
10 Oropharyngeal swabs are preferred, but if these are not obtainable, nasopharyngeal or nasal swabs may be 
substituted.  
11.Subjects who consented for genetic testing and are discharged prior to Day 8 and therefore missing the Day 8 
Paxgene tube collection should get blood drawn at Day 15, if feasible. 
 
 
1.3 
Study Schema 
 
 
 
 
 
Stage 4 
ACTT-4 
Baricitinib po + IV Placebo + Remdesivir 
Dexamethasone IV + po Placebo + Remdesivir 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix D - ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 118 of 172 
 
 
2. 
INTRODUCTION 
2.1 
Background 
 
ACTT-4 – Baricitinib/Remdesivir vs. Dexamethasone/Remdesivir Trial 
ACTT is a multi-site, global clinical trial platform designed to evaluate the clinical efficacy and 
safety of putative investigational therapeutic agents among hospitalized adults with laboratory-
confirmed Covid-19. There have been three, phase 3, randomized, double-blind, placebo-
controlled trials conducted using the ACTT platform, ACTT-1, ACTT-2 and ACTT-3. Each new 
ACTT study is considered another stage of the trial.  
 
Data from ACTT-1 showed that hospitalized adults with COVID-19 who were randomized to 
receive remdesivir had a shorter time to clinical recovery than those who received placebo (10 
vs. 15 days, recovery rate ratio 1.29 (95% CI 1.12 to 1.49, p<0.001) (14). The odds of 
improvement on an ordinal scale by Day 15 were higher in the group that received remdesivir 
than in the placebo group (odds ratio 1.5; 95% CI 1.2 to 1.9, p < 0.001). After the release of these 
preliminary findings, the U.S. Food and Drug Administration (FDA) issued an Emergency Use 
Authorization (EUA) for remdesivir. On October 22, 2020, the FDA approved remdesivir (trade 
name, Veklury®) for use in adults and children 12 years of age and older for the treatment of 
COVID-19 requiring hospitalization. Veklury is the first treatment for COVID-19 to receive 
FDA approval. Remdesivir has also received, full or conditional approval in approximately 50 
other countries.  
 
While remdesivir is considered the standard antiviral for COVID-19, significant morbidity and 
mortality still occur despite its use. Early in the outbreak, it was observed that COVID-19 
patients who developed severe respiratory disease including acute respiratory distress syndrome 
(ARDS) had increased levels of cytokines consistent with that seen in patients infected with 
other pathogenic coronaviruses (e.g., SARS) (37-39). It is postulated that this dysregulated 
inflammatory immune response contributes to the excessive mortality and targeting this response 
would further improve outcomes. While multiple strategies have been proposed to counter the 
hyper-inflammation, to date only two anti-inflammatory strategies have demonstrated efficacy in 
large randomized trials – dexamethasone and baricitinib.  
 
In ACTT-2, subjects receiving the combination treatment of baricitinib and remdesivir had a 
shorter median time-to-recovery of 7 days (95% confidence interval (CI), 6 to 8 days) when 
compared with patients who received remdesivir and placebo (8 days; 95% CI, 7 to 9 days) with 
control [rate ratio for recovery [RRR] 1.16, 95% CI 1.01 to 1.32; P=0.03)]. Patients who 
received combination treatment were 30% more likely to have clinical improvement by day 15 
than those in the control arm (odds ratio [OR] 1.3; 95%CI 1.0 to 1.6). The patients who benefited 
the most from combination treatment were those requiring high-flow oxygen or non-invasive 
ventilation at enrollment with a median of 10 days to recovery compared with 18 days in control 
group (RRR 1.5, 95% CI 1.1 to 2.1) and the best clinical improvement by day 15 (OR 2.2; 95% 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix D - ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 119 of 172 
CI 1.4 to 3.6). Baricitinib also showed benefit to those on low flow oxygen with a median of 5 
days to recovery compared with 6 days in control group (RRR 1.17, 95% CI 0.98 to 1.39) and 
the clinical improvement by day 15 (OR 1.2; 95% CI 0.9 to 1.6). Patients who received 
combination treatment with baricitinib and remdesivir and those in the control arm had a similar 
incidence of adverse and serious adverse events including infections and venous thromboembolic 
events (VTE). On November 19, 2020, the FDA issued an Emergency Use Authorization (EUA) 
for the use of baricitinib in combination with remdesivir in hospitalized adults and children aged 
≥2 years with COVID-19 who require supplemental oxygen, invasive mechanical ventilation, or 
extracorporeal membrane oxygenation (ECMO).  
 
The Randomized Evaluation of Covid-19 Therapy (RECOVERY) trial is a controlled, open- 
label randomized trial, involving all major hospitals in the UK. The trial compared a range of 
possible treatments in patients who were hospitalized with Covid-19. Included, was a treatment 
arm assigned to receive oral or intravenous dexamethasone (at a dose of 6 mg once daily for up 
to 10 days) or to received usual care alone. Overall, 22.9% in the dexamethasone group and 
25.7% in the usual care group died within 28 days after randomization (age-adjusted rate ratio, 
0.83; 95% confidence interval [CI], 0.75 to 0.93; P<0.001). In the dexamethasone group, the 
incidence of death was lower than that in the usual care group among patients receiving invasive 
mechanical ventilation (29.3% vs. 41.4%; rate ratio, 0.64; 95% CI, 0.51 to 0.81) and among 
those receiving supplemental oxygen without invasive mechanical ventilation (23.3% vs. 26.2%; 
rate ratio, 0.82; 95% CI, 0.72 to 0.94) but not among those who were receiving no supplemental 
oxygen respiratory support at randomization (17.8% vs. 14.0%; rate ratio, 1.19; 95% CI, 0.91 to 
1.55). Remdesivir was not used routinely in the RECOVERY trial. 
 
The ACTT-2 and RECOVERY trials are very different: 
• ACTT 2 randomized patients to baricitinib, a JAK inhibitor and RDV or RDV alone. 
RECOVERY randomized patients to dexamethasone or standard care. 
• Different study populations – ACTT-2 had more restrictive study criteria due to the use 
of remdesivir and baricitinib. Exclusions for liver or renal dysfunctions or cytopenias 
may have selected for a less ill population compared to RECOVERY. 
• Different baseline mortalities – the ACTT-2 study had a mortality of 5.1-7.8% compared 
to 22.9-25.7% in RECOVERY. Even when directly comparing the study population that 
were not on supplemental oxygen at study entry - the ACTT-2 study had no deaths 
compared to 14.0-17.8% in RECOVERY.  
• Study periods - The trials were conducted at slightly different periods early in the 
pandemic. RECOVERY was conducted March 19 to June 8 and ACTT-2 was conducted 
May 8-June 30. 
• Antivirals - All subjects in ACTT-2 were given remdesivir whereas only 3 (< 1%) in 
RECOVERY were given remdesivir. 
• Blinded - ACTT-2 was a double-blind randomized control trial and RECOVERY was 
open label (i.e., not blinded).  
 
Given the above, direct comparison of these studies is difficult. However, the relative risk ratios 
also suggest these two anti-inflammatory strategies may be optimal in different inpatient 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix D - ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 120 of 172 
populations, with baricitinib having the larger effect in the high flow or low flow oxygen group 
and dexamethasone having the largest effect in those on mechanical ventilation (see Table 2). 
 
Table 2. Mortality from ACTT-2 and RECOVERY trials. 
  
  
Ordinal Score at Baseline 
  
Overall 
4 
Not on oxygen 
5 
Low flow oxygen 
6 
High flow oxygen / 
NIMV 
7 
Mechanical 
ventilation/ECMO 
Mortality– ACTT-2 
  
Bari 
+ RDV 
(n=515) 
Placebo 
+ RDV 
(n=518) 
Bari 
+ RDV 
(n=70) 
Placebo 
+ RDV 
(n=72) 
Bari 
+ RDV 
(n=287) 
Placebo 
+ RDV 
(n=276) 
Bari 
+ RDV 
(n=104) 
Placebo 
+ RDV 
(n=113) 
Bari 
+ RDV 
(n=54) 
Placebo 
+ RDV 
(n=57) 
Hazard ratio (95% 
CI)  
0.65  
(0.39, 1.08) ;p=0.09 
NE 
 
0.4  
(0.14, 1.14) 
0.55  
(0.22, 1.37) 
1.00  
(0.45, 2.22) 
28 Day mortality %  
(95% CI) 
5.1 
(3.5, 7.6) 
7.8  
(5.7, 10.6) 
0  
(NE, NE) 
0 
(NE, NE) 
1.9  
(0.8, 4.4) 
4.7  
(2.7, 8.1) 
7.4  
(3.6, 15.0) 
12.9  
(7.7, 21.3) 
23.1  
(13.8, 37.1) 
22.6 
 (13.5, 36.4) 
Mortality – RECOVERY Trial 
  
Overall 
No oxygen 
Oxygen only 
Mechanical ventilation 
  
Dex 
(n=2104) 
Usual 
Care 
(n=4321) 
Dex 
(n=501) 
Usual 
Care 
(n=1034) 
Dex  
(n=1279) 
Usual Care 
(n=2604) 
Dex  
(n=324) 
Usual Care 
(n=683) 
Hazard ratio for 
mortality 
0.83 
p<0.001 
1.19 
 
0.82 
 
0.64 
 
 28 Day mortality % 
22.9 
25.7 
17.8 
14.0 
23.3 
26.2 
29.3 
41.4 
 
For this reason, direct comparison of these two anti-inflammatory interventions is important. 
ACTT-4 will evaluate patients hospitalized with COVID-19 and requiring oxygen and determine 
if baricitinib or dexamethasone (both in addition to remdesivir) is superior or if they are 
comparable. 
 
2.2 
Risk/Benefit Assessment 
 
Known Potential Risks 
Potential risks of participating in this trial are those associated with the study interventions, 
having blood drawn, the IV catheterization, and breach of confidentiality. 
 
Drawing blood may cause transient discomfort and fainting. Fainting is usually transient and 
managed by having the subject lie down and elevate his/her legs. Bruising at the blood collection 
sites may occur but can be prevented or lessened by applying pressure for a few minutes after the 
blood is taken. IV catheterization may cause insertion site pain, phlebitis, hematoma formation, 
and infusate extravasation; less frequent but significant complications include bloodstream and 
local infections. The use of aseptic (sterile) technique will make infection at the site where blood 
will be drawn or at catheter site less likely. 
 
Risks to Privacy 
Subjects will be asked to provide personal health information (PHI). All attempts will be made to 
keep this PHI confidential within the limits of the law. However, there is a chance that 
unauthorized persons will see the subject’s PHI. All study records will be kept in a locked file 
cabinet or maintained in a locked room at the participating clinical site. Electronic files will be 
password protected. Only people who are involved in the conduct, oversight, monitoring, or 
auditing of this trial will be allowed access to the PHI that is collected. Any publication from this 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix D - ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 121 of 172 
trial will not use information that will identify subjects. Organizations that may inspect and/or 
copy research records maintained at the participating site for quality assurance and data analysis 
include groups such as the IRB, NIAID and applicable regulatory agencies (e.g., FDA). For more 
information about confidentiality and privacy see Section 10.1.3. 
 
 
Remdesivir (Veklury®) 
 Potential Risks of Remdesivir  
Remdesivir is an approved antiviral and may be obtained as part of standard care outside the 
clinical trial. For the purpose of the ACTT trials, remdesivir is still considered a study product 
being used as part of an investigational trial and it will be tracked and monitored accordingly.  
 
Transaminase elevations have been observed in healthy volunteers who received remdesivir; the 
transaminase elevations were mild (Grade 1) to moderate (Grade 2) in severity and resolved 
upon discontinuation of remdesivir. Transaminase elevations have also been reported in patients 
with COVID-19 who received remdesivir.  
 
Coadministration of remdesivir and chloroquine phosphate or hydroxychloroquine sulfate is not 
recommended based on cell culture data demonstrating an antagonistic effect of chloroquine on 
the intracellular metabolic activation and antiviral activity of remdesivir. 
 
In ACTT-1, the collection of adverse event data in this trial was limited to severe (Grade 3) or 
potentially life-threatening (Grade 4) adverse events, serious adverse events, adverse events 
leading to study drug discontinuation, and moderate (Grade 2) severity or higher hypersensitivity 
reactions. Rates of adverse reactions (≥ Grade 3), serious adverse reactions, and adverse 
reactions leading to treatment discontinuation are presented in Table 3. 
 
Table 3. Summary of Adverse Reaction Rates in Subjects with Mild, Moderate, or Severe 
COVID-19 in ACTT-1 
Types of Adverse Reactions 
Remdesivir N=532 n (%) 
Placebo N=516 n (%) 
Adverse reactions, Grades ≥3 
41 (8%) 
46 (9%) 
Serious adverse reactions 
2 (0.4%)a 
3 (0.6%) 
Adverse reactions leading to 
treatment discontinuation 
11 (2%)b 
15 (3%)  
a Seizure (n=1), infusion-related reaction (n=1).  
b. Seizure (n=1), infusion-related reaction (n=1), transaminases increased (n=3), ALT increased and AST 
increased (n=1), GFR decreased (n=2), acute kidney injury (n=3). 
 
Remdesivir is a substrate for CYP2C8, CYP2D6, and CYP3A4. However, coadministration with 
inhibitors of these CYP isoforms is unlikely to markedly increase remdesivir levels, as its 
metabolism is likely to be predominantly mediated by hydrolase activity. See package insert, and 
additional product related information for full discussion of clinical experience and risks.  
 
There is the potential of the SARS-CoV-2 developing resistance to remdesivir, which could result 
in decreased efficacy. The clinical impact of the development of resistance is not clear at this time.  

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix D - ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 122 of 172 
 Potential Benefits of Remdesivir 
In ACTT-1, remdesivir was found to be efficacious and safe. Specifically, patients who received 
remdesivir had a shorter time to recovery (the primary end point) than those who received placebo 
(median, 10 days vs. 15 days; rate ratio for recovery, 1.29 [95% CI,1.12 to 1.49]) and were more 
likely to have improvement in the ordinal scale score at day 15 (key secondary end point; odds 
ratio, 1.5; 95% CI, 1.2 to 1.9). Other secondary end points supported these findings including 
remdesivir treatment resulting in a shorter time to improvement of one and of two ordinal scale 
categories, a shorter time to discharge or to a sustained National Early Warning Score of 2 or 
lower, and a shorter length of initial hospital stay (median, 12 days vs. 17 days). All-cause 
mortality was 11.4% with remdesivir and 15.2% with placebo (hazard ratio, 0.73; 95% CI, 0.52 
to 1.03). Serious adverse events were reported in 131 of the 532 patients who received remdesivir 
(24.6%) and in 163 of the 516 patients who received placebo (31.6%). 
 
 Assessment of Potential Risks and Benefits of Remdesivir 
As a result of ACTT-1 findings, remdesivir is given to most subjects hospitalized with COVID-
19, though this may vary based on availability and approval in a given country. Society at large 
may benefit from their participation in this study resulting from insights gained about the efficacy 
of remdesivir combined with either baricitinib or dexamethasone. Determining the optimal anti-
inflammatory strategy to combined with an antiviral for the treatment of severe COVID-19 may 
benefit society during this global COVID-19 pandemic.  
 
In ACTT-1, Remdesivir was found to have a good safety profile compared to placebo. SAEs 
were reported in 131 of the 532 patients who received remdesivir (24.6%) and in 163 of the 516 
patients who received placebo (31.6%). There were 47 serious respiratory failure adverse events 
in the remdesivir group (8.8% of patients), including acute respiratory failure and the need for 
endotracheal intubation, and 80 in the placebo group (15.5% of patients). No deaths were 
considered by the investigators to be related to treatment assignment. Grade 3 or 4 adverse 
events occurred on or before day 29 in 273 patients (51.3%) in the remdesivir group and in 295 
(57.2%) in the placebo group; 41 events were judged by the investigators to be related to 
remdesivir and 47 events to placebo. The most common nonserious adverse events occurring in 
at least 5% of all patients included decreased glomerular filtration rate, decreased hemoglobin 
level, decreased lymphocyte count, respiratory failure, anemia, pyrexia, hyperglycemia, 
increased blood creatinine level, and increased blood glucose level. The incidence of these 
adverse events was generally similar in the remdesivir and placebo groups. The potential risks 
are therefore thought to be acceptable given the potential benefits. 
 
 
Baricitinib 
 Potential Risks of Baricitinib 
Baricitinib is licensed drug with a known safety profile. It is indicated for the treatment of 
moderately to severely active rheumatoid arthritis (RA) in adults who have had an inadequate 
response to one or more TNF antagonist therapies. The US product labeling indicates a boxed 
warning for the risk of serious infections, malignancies and thrombosis, while warnings and 
precautions include serious infections, thrombosis, gastrointestinal perforations, abnormal 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix D - ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 123 of 172 
laboratory assessments (potential changes in lymphocytes, neutrophils, hemoglobin, liver 
enzymes, and lipids), and avoidance with the use of live vaccines.  
 
A recent study of patients with active RA exposed to baricitinib including 3770 patients and 
10,127 patient years for a maximum exposure of 7 years found no significant differences in 
adverse events among patients who received baricitinib 4-mg vs placebo (40). This included 
adverse events leading to permanent drug discontinuation, death, malignancy, serious infection, 
or major adverse cardiovascular events. Incidence rates for deep vein thrombosis/pulmonary 
embolism were numerically higher in baricitinib 4-mg vs placebo; Incidence rates were similar 
by dose in 2-mg/4-mg-extended dataset. Malignancy (excluding non-melanoma skin cancer) 
Incidence rates were 0.8 (2-mg) and 1.0 (4-mg; as-randomized analysis). Fewer than 1% of 
patients discontinued due to abnormal laboratory results. The frequency of herpes zoster was 
higher for baricitinib 4-mg vs placebo (1.4 vs 0.4) baricitinib 4-mg vs 2-mg (1.4 vs 1.0).  
 
While it is difficult to extrapolate the potential risks of baricitinib in RA to a hospitalized 
COVID-19 population, the duration of baricitinib treatment will be limited to up to 14 days and 
no major safety signals where seen in ACTT-2. In ACTT-2, Grade 3 or 4 adverse events (AE) 
occurred in 207 patients (41%) in the combination arm and 238 (47%) in the control arm. 
Twenty-five AEs were judged to be related to combination treatment and 28 to control. The most 
common Grade 3 or 4 AEs occurring in at least 5% of all patients were hyperglycemia, anemia, 
decreased lymphocyte count, and acute kidney injury. The incidence of these adverse events was 
similar between treatment arms. Of note, a similar proportion of patients in the combination 
treatment arm and control arm were reported to have a serious or non-serious venous 
thromboembolism (VTE) AE (21 patients (4%) versus 16 patients (3%), respectively (RD 1; 
95% CI -1 to 3). 
 
Serious adverse events (SAE) occurred in 77 patients (15%) in the combination treatment arm 
and six of these events were thought to be related to study product (Table 4). SAE occurred in 
103 patients (20%) in the control arm and five of these events were thought to be related to study 
product. All SAE, all AE, SAE with fatal outcome, and AE leading to discontinuation of study 
drug, were each significantly lower in the combination compared to the control group. Overall, 
serious and non-serious infection AE were lower in the combination (30 patients (6%) versus 
controls (56 patients (11%), respectively (RD -5; (95%CI -5 to -2). Patients who received 
corticosteroids post-randomization (N=223) compared to those who did not (N=793) had a 
higher rate of new infection AE and SAE: 51 patients (23%), 39 patients (4.9%). 
 
Table 4. Serious Adverse Events Occurring in 5 or More Subjects in Any Preferred Term 
by Treatment Group 
MedDRA System Organ Class 
Preferred Term 
Baricitinib + RDV 
(N = 507) 
No.(%) 
Placebo + RDV 
(N = 509) 
No.(%) 
Any System Organ Class 
Any Preferred Term 
77 (15.2) 
103 (20.2) 
Cardiac disorders 
Cardiac arrest 
2 (0.4) 
3 (0.6) 
General disorders and administration site conditions 
Multiple organ dysfunction syndrome 
1 (0.2) 
6 (1.2) 
Infections and infestations 
Septic shock 
4 (0.8) 
8 (1.6) 
 
Pneumonia 
2 (0.4) 
8 (1.6) 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix D - ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 124 of 172 
MedDRA System Organ Class 
Preferred Term 
Baricitinib + RDV 
(N = 507) 
No.(%) 
Placebo + RDV 
(N = 509) 
No.(%) 
 
Sepsis 
1 (0.2) 
4 (0.8) 
Renal and urinary disorders 
Acute kidney injurya 
5 (1.0) 
11 (2.2) 
 
Renal failurea 
0 (-) 
5 (1.0) 
Respiratory, thoracic and mediastinal disorders 
Respiratory failureb 
24 (4.7) 
37 (7.3) 
 
Acute respiratory failureb 
16 (3.2) 
9 (1.8) 
 
Acute respiratory distress syndrome 
4 (0.8) 
9 (1.8) 
 
Respiratory distressc 
4 (0.8) 
6 (1.2) 
 
Pulmonary embolism 
5 (1.0) 
1 (0.2) 
 
Hypoxiac 
3 (0.6) 
3 (0.6) 
 
Dyspnoeac 
1 (0.2) 
4 (0.8) 
 
Pneumothorax 
1 (0.2) 
4 (0.8) 
Vascular disorders 
Hypotension 
5 (1.0) 
5 (1.0) 
 
Shock 
2 (0.4) 
4 (0.8) 
No. = number of subjects reporting at least one event. 
a The combined number of subjects with acute kidney injury or renal failure are 5 for Baricitinib + RDV and 16 for Placebo + RDV. 
b The combined number of subjects with respiratory failure or acute respiratory failure is 40 for Baricitinib + RDV and 46 for Placebo + RDV. 
c The combined number of subjects with dyspnoea, hypoxia or respiratory distress are 8 for Baricitinib + RDV and 13 for Placebo + RDV. 
 
 
In addition, the half-life of Baricitinib is approximately 12 hours which will lead to a very short 
washout period once discontinued. JAK–STAT signal blocking by baricitinib produces an 
impairment of interferon responses. Interferons are important for the innate control of viral 
replication. Thus baricitinib could potentially increase viral replication (41) though this has not 
been described in the cases series of baricitinib in COVID-19.  
 
Adverse drug reactions of baricitinib include the potential for VTE (deep vein thrombosis 
/pulmonary embolism). There is evidence to suggest that COVID-19 patients are at increased 
risk of thromboembolic events from infection with SARS-CoV-2. The etiology this may be 
tissue injury from the SARS-CoV-2 or may be due to inflammation via pro-inflammatory 
cytokine upregulation of tissue factor. In ACTT-2, a similar proportion of patients in the 
baricitinib + remdesivir arm and remdesivir only (control) arm were reported to have a serious or 
non-serious VTE related AE (21 patients (4%) versus 16 patients (3%), respectively; RD 1; 95% 
CI 1 to 3). Investigators are recommended to add VTE prophylaxis in all hospitalized patients 
given the risk of VTE. As thrombocytopenia can be seen in COVID-19, the risk/benefit of VTE 
prophylaxis should be made by the treating clinician. 
 
Baricitinib is not recommended in patients taking strong Organic Anion Transporter 3 (OAT3) 
inhibitors (probenecid in the main clinically relevant medication). Patients who take probenecid 
and are unable to discontinue it at study entry will not be eligible for the study.  
Drug-drug interactions with concomitantly administered baricitinib and remdesivir are unlikely. 
In vitro, baricitinib is a substrate of cytochrome P450 (CYP) 3A and the following transporters: 
organic anion transporter (OAT) 3, P-glycoprotein (Pgp), breast cancer resistance protein 
(BCRP), and multidrug and toxic extrusion protein (MATE) 2-K. However, in vivo, baricitinib is 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix D - ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 125 of 172 
primarily eliminated by the kidneys, with minimal hepatic clearance. The only clinically relevant 
drug-drug interaction observed with baricitinib is with concomitant administration of strong 
inhibitors of OAT3, such as probenecid. Available data for remdesivir does not suggest that 
remdesivir is an OAT3 inhibitor. Therefore, the potential for remdesivir to affect the 
pharmacokinetics (PK) of baricitinib is unlikely.  
  
Baricitinib is also unlikely to affect the PK of other drugs, including remdesivir. Available data 
for remdesivir suggests that it is a substrate for CYP2C8, CYP2D6, CYP3A4, OATP1B1, and 
Pgp (EMA 2020). In vitro, baricitinib did not significantly inhibit or induce the activity of CYPs 
3A, 1A2, 2B6, 2C9, 2C19, and 2D6. Additionally, no clinically meaningful changes in the PK of 
several CYP3A substrates were observed when co-administered with baricitinib. Since 
baricitinib does not inhibit these particular CYPs, and transporters, a drug-drug interaction 
between baricitinib and remdesivir is unlikely.  
 
More detailed information about the known risks and reasonably expected adverse events of 
baricitinib may be found in the Investigator’s Brochure (IB).  
 
 Potential Benefits of Baricitinib 
Given the ACTT-2 results, baricitinib likely improves the clinical outcome of hospitalized adult 
patients with COVID-19 requiring supplemental oxygen or non-invasive ventilation compared to 
remdesivir alone. However, this drug is available outside of the clinical trial. It is not known if 
treatment with baricitinib is better than treatment with dexamethasone. While there may not be a 
benefit for an individual subject, there may be benefits to society during this global COVID-19 
pandemic to understand which of these anti-inflammatory strategies are best in which 
populations.  
 
 Assessment of Potential Risks and Benefits of Baricitinib 
While baricitinib have been shown to be effective in COVID-19 hospitalized patients, there may 
not be a significant advantage for an individual subject to participate in this trial. However, there 
is also not a significant risk of participation.  
 
 
Dexamethasone  
 Potential risks of dexamethasone 
Dexamethasone is a licensed drug with a known safety profile. It is indicated in hormone diseases, 
rheumatic collagen disorders, GI and respiratory disorders (sarcoidosis, beryllioses, etc.). 
Common side effects include hyperglycemia, secondary infections, psychiatric effects, and 
avascular necrosis. Dexamethasone can also cause side effects involving the musculoskeletal 
system (muscle weakness, steroid myopathy, osteoporosis); gastrointestinal system (peptic ulcer 
with possible subsequent perforation and hemorrhage, perforation of the small and large bowel, 
pancreatitis, abdominal distention, and ulcerative esophagitis); skin (impaired wound healing, thin 
fragile skin, petechiae and ecchymoses, erythema); nervous system (convulsions); and 
cardiovascular system. Fluid and electrolyte disturbances can occur with dexamethasone use 
including sodium and fluid retention, congestive heart failure in susceptible patients, potassium 
loss, hypokalemic alkalosis, and hypertension. These fluid and electrolyte disturbances are less 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix D - ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 126 of 172 
common with dexamethasone than other corticosteroids since dexamethasone does not have any 
mineralocorticoid activity. Prolonged use of systemic corticosteroids may increase the risk of 
reactivation of latent infections (e.g., hepatitis B virus, herpesvirus infections, strongyloidiasis, 
tuberculosis). The risk of reactivation of latent infections for a 10-day course of dexamethasone (6 
mg once daily) is not well-defined. The RECOVERY trial did not collect routine AEs or SAEs, so 
it is unknown how this side effect profile is altered when dexamethasone is used to treat adult 
hospitalized patients with COVID-19. 
 
 Potential Benefits of Dexamethasone 
Given the RECOVERY results, dexamethasone likely improves the clinical outcome of adult 
patients hospitalized with COVID-19. However, this drug is available outside of the clinical trial. 
It is not known if treatment with dexamethasone is better than treatment with baricitinib. While 
there may not be benefits for an individual subject, there may be benefits to society during this 
global COVID-19 pandemic to understand which of these anti-inflammatory strategies are best 
in which populations.  
 
 Assessment of Potential Risks and Benefits of Dexamethasone 
While dexamethasone has been shown to be effective in COVID-19 hospitalized patients, there 
may not be a significant advantage for an individual subject to participate in this trial. However, 
there is also not a significant risk of participation.  
 
3. 
OBJECTIVES AND ENDPOINTS 
The overall objective of ACTT-4 is to evaluate the clinical efficacy and safety of baricitinib and 
remdesivir (Arm 1) versus dexamethasone and remdesivir (Arm 2) among hospitalized adults 
who have COVID-19. 
 
OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
Primary Objective and Endpoint 
To evaluate the clinical efficacy of 
baricitinib + remdesivir versus 
dexamethasone + remdesivir as 
assessed by the mechanical 
ventilation free survival by Day 29. 
Proportion of subjects not meeting criteria for one of 
the following two ordinal scale categories at any time 
by Day 29 
• Category 8: Death 
• Category 7: Hospitalized, on invasive mechanical 
ventilation or ECMO 
 
Key Secondary Objective and Endpoint 
To evaluate the clinical efficacy of 
baricitinib + remdesivir versus 
dexamethasone + remdesivir 
according to clinical status (8-point 
ordinal scale) at Day 15. 
 
Proportion of subjects meeting criteria for each of the 
8 ordinal scale categories on Day 15  
• Category 8: Death; 
• Category 7: Hospitalized, on invasive mechanical 
ventilation or ECMO; 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix D - ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 127 of 172 
OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
 
 
• Category 6: Hospitalized, on non-invasive 
ventilation or high flow oxygen devices; 
• Category 5: Hospitalized, requiring supplemental 
oxygen; 
• Category 4: Hospitalized, not requiring 
supplemental oxygen – requiring ongoing medical 
care (COVID-19 related or otherwise); 
• Category 3: Hospitalized, not requiring 
supplemental oxygen – no longer requires ongoing 
medical care; 
• Category 2: Not hospitalized, but has new or 
increased limitation on activities and/or new or 
increased requirement for home oxygen over 
baseline, pre-COVID-19 status; 
• Category 1: Not hospitalized, patient is back to 
their baseline, pre-COVID-19 status, that is, no 
new or increased limitations on activities and no 
new or increased oxygen use. 
 
Additional Secondary Objectives and Endpoints 
To evaluate the clinical efficacy of 
baricitinib + remdesivir versus 
dexamethasone + remdesivir among 
subjects with a baseline ordinal scale 
of 5 as assessed by the proportion 
that do not progress to ordinal scale 
6, 7 or 8 at any time by Day 29. 
Proportion of subjects not meeting criteria for one of 
the following ordinal scale categories at any time by 
Day 29 
• Category 8: Death 
• Category 7: Hospitalized, on invasive mechanical 
ventilation or ECMO 
• Category 6: Hospitalized, on non-invasive 
ventilation or high flow oxygen devices 
 
Mortality 
 14-day mortality 
 28-day mortality 
 
 
• Date of death (if applicable) 
 
Time to recovery by Day 29 
 
Day of recovery is defined as the first day on which 
the subject satisfies one of the following three ordinal 
scale categories: 
• Category 3: Hospitalized, not requiring 
supplemental oxygen – no longer requires ongoing 
medical care; 
• Category 2: Not hospitalized, but has new or 
increased limitation on activities and/or new or 
increased requirement for home oxygen over 
baseline, pre-COVID-19 status; 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix D - ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 128 of 172 
OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
• Category 1: Not hospitalized, patient is back to their 
baseline, pre-COVID-19 status, that is, no new or 
increased limitations on activities and no new or 
increased oxygen use. 
 
Time to an improvement of one 
category and two categories from 
Day 1 (baseline) using ordinal 
scale. 
 
Day of one and two category improvement from 
baseline ordinal score  
 
Subject clinical status using ordinal 
scale at Days 3, 5, 8, 11, 15, 22, and 
29.  
 
• Clinical outcome assessed using ordinal scale daily 
while hospitalized and on Days 15, 22, and 29. 
 
Desirability of Outcome Ranking 
(DOOR) at Day 15 and Day 29 
 
• DOOR at Day 15 and 29 based on ordinal scale:  
1- Recovered (category 1, 2 or 3 on ordinal scale) 
2- Improved (≥ 1 category improvement of ordinal 
scale compared with baseline) & no SAE 
3- Improved (≥ 1 category improvement of the 
ordinal scale compared with baseline) & SAE 
(related or unrelated) 
4- No change in ordinal scale from baseline & no 
SAE 
5- No change in ordinal scale from baseline & SAE 
(related or unrelated) 
6- Worsening (≥ 1 category worse in ordinal scale 
from baseline)  
7- Death 
o Oxygenation 
 Oxygenation use up to Day 29. 
 Incidence and duration of new 
oxygen use during the study. 
 
 
• Days of supplemental oxygen (if applicable) up to 
Day 29 
 
o Non-invasive ventilation/high 
flow oxygen 
 Non-invasive ventilation/high 
flow oxygen use up to Day 29. 
 Incidence and duration of new 
non-invasive ventilation or high 
flow oxygen use during the study. 
 
• Days of non-invasive ventilation/high flow oxygen 
(if applicable) up to Day 29 
o Invasive Mechanical Ventilation 
/ extracorporeal membrane 
oxygenation (ECMO) 
 
• Days of invasive mechanical ventilation/ECMO (if 
applicable) up to Day 29. 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix D - ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 129 of 172 
OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
 Ventilator / ECMO use up to Day 
29. 
 Incidence and duration of new 
mechanical ventilation or ECMO 
use during the study.  
 
 
o Hospitalization 
 Duration of hospitalization (days).  
 
 
• Days of hospitalization up to Day 29 
o Laboratory efficacy 
 d-dimer, and C-reactive protein 
(CRP) over time 
 
• d-dimer, CRP on Day 1; Days 3, 5, 8, and 11 
(while hospitalized); and Days 15 and 29 (if 
attends in-person visit or still hospitalized). 
 
Safety Objectives and Endpoints 
To evaluate the safety of baricitinib + 
remdesivir versus dexamethasone + 
remdesivir as assessed by: 
• Cumulative incidence of SAEs 
through Day 29. 
• Cumulative incidence of Grade 
3 and 4 clinical and/or 
laboratory AEs through Day 29. 
• Discontinuation or temporary 
suspension of study product 
administrations (for any 
reason)). 
• Changes in white blood cell 
(WBC) count with differential, 
hemoglobin, platelets, 
creatinine, glucose, total 
bilirubin, alanine 
aminotransferase (ALT), 
aspartate aminotransferase 
(AST), prothrombin time (PT 
reported as INR)). 
 
 
 
 
 
• SAEs 
• Grade 3 and 4 AEs  
• Incidence and number of discontinuation or 
temporary suspension of study product.  
• WBC with differential, hemoglobin, platelets, 
creatinine, glucose, total bilirubin, ALT, AST, 
and INR on Day 1; Days 3, 5, 8, and 11 (while 
hospitalized); and Days 15 and 29 (if attends in-
person visit or still hospitalized). 
 
Exploratory Objectives and Endpoints 
Alternative Desirability of Outcome 
Ranking (DOOR) 
• DOOR at Day 15 and 29 using alternative ordinal 
scales combining efficacy and safety (to be 
detailed in the statistical analysis plan) 
 
Virology 
 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix D - ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 130 of 172 
OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
To evaluate the virologic efficacy of 
Arm 1 as compared to Arm 2 as 
assessed by: 
• Percent of subjects with SARS-
CoV-2 detectable in OP sample 
at Days 3, 5, 8, 11, 15, and 29.  
• Quantitative SARS-CoV-2 virus 
in OP sample at Days 3, 5, 8, 
11, 15, and 29. 
• Quantitative SARS-CoV-2 virus 
in blood at Days 3, 5, 8, and 11. 
 
 
 
• Qualitative and quantitative polymerase chain 
reaction (PCR) for SARS-CoV-2 in OP swab on 
Day 1; Days 3, 5, 8, and 11 (while hospitalized); 
and Days 15 and 29 (if attends in-person visit or 
still hospitalized). 
• Qualitative and quantitative PCR for SARS-CoV-
2 in blood on Day 1; Days 3, 5, 8, and 11 (while 
hospitalized). 
Serology 
To evaluate the influence of 
baricitinib and dexamethasone on 
SARS-CoV-2 antibody response. 
 
 
• SARS-CoV-2 antibody titers on Day 1, 8, and 29 
Immunophenotype 
To define immunophenotype of 
subjects by analyzing markers of 
inflammation and transcriptomics. 
• Proteomic analysis of cytokines, markers of 
inflammation, and other circulating proteins Day 
1; Days 3, 5, 8, and 11 (while hospitalized) and 
Day 29 
• Additionally, in a subset of all subjects who 
consent to genetic testing: 
o Transcriptomic analysis of RNA in whole 
blood and individual immune cells on Days 
1, 3, 8 and 29 
Chronic Clinical Sequelae 
To describe clinical status of subjects 
2 months after treatment, overall and 
by treatment arm . 
Ordinal scale, incidence of supplemental oxygen use 
and physical disability (more than baseline pre-
COVID-19 status), readmission to hospital; proportion 
of subjects with new diagnoses including deep venous 
thrombosis (DVT), infections, post-traumatic stress 
disorder (PTSD), anxiety and/or depression. 
 
  
4. 
STUDY DESIGN 
4.1 
Overall Design 
ACTT-4 will evaluate the combination of baricitinib and remdesivir compared to dexamethasone 
and remdesivir. Subjects will be assessed daily while hospitalized. After the subjects are 
discharged from the hospital, they will have a study visit at Days 15, 22, and 29  (as applicable). 
For discharged subjects, it is preferred that the Day 15 and 29 visits are in person to obtain safety 
laboratory tests and OP swab, plasma (Day 29) and serum samples for secondary research as 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix D - ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 131 of 172 
well as clinical outcome data. However, infection control or other restrictions may limit the 
ability of the subject to return to the clinic. In this case, these visits may be conducted by phone, 
and only clinical data will be obtained. The Day 22 visit does not have laboratory tests or 
collection of samples and is conducted by phone. Additionally, subjects will be contacted by 
phone at 2 months to assess long term efficacy and safety outcomes as an exploratory outcome. 
4.2 
Scientific Rationale for Study Design 
This study utilizes an adaptive platform design that increases efficiency to identify safe and 
efficacious therapeutic agents for patients with COVID-19 during the current outbreak. In 
addition, the adaptive design allows for the evaluation of new therapeutic agents as they are 
identified and ready for testing in clinical trials. As the study is a multicenter, multinational 
randomized controlled study, we will be able to acquire rigorous data about the safety and 
efficacy of investigational therapeutic agents for COVID-19 that will lead to generalizable 
evidence. Randomization is essential for establishing efficacy of these new therapeutic agents. 
Last, collecting clinical and virologic data on enrolled subjects using a standardized timeline and 
collection instruments should provide valuable information about the clinical course of and 
morbidities associated with COVID-19 in a diverse group of hospitalized adults with confirmed 
SARS-CoV-2 infection. 
 
The ACTT-4 design will specifically evaluate the contributions of blocking inflammatory 
pathways with the JAK inhibitor baricitinib compared with less specific, anti-inflammatory 
effects of dexamethasone while all subjects receive the antiviral remdesivir.  
4.3 
Justification for Dose 
 
Justification for Dose of Remdesivir 
The dose of remdesivir used in this study will be the same dose used in previous ACTT studies, 
and is the US FDA approved doses. The duration of dosing may be adjusted by the site according 
to clinical severity. The maximum number of doses to be given during hospitalization is ten 
doses. This includes the loading dose and all maintenance doses given during the study and pre-
study if applicable. 
 
 
Justification for Dose of Baricitinib 
This study will use the same dose and duration of baricitinib that was evaluated in ACTT-2. This 
4-mg daily dose of baricitinib was originally selected for use in this population of adults 
hospitalized with COVID-19 based on clinical data showing an inhibitory effect on cytokine 
signaling. In patients with RA, the 4-mg dose of baricitinib (but not lower doses) was shown to 
significantly reduce IL-6 levels, assessed after 12 weeks of treatment. In a vaccine response study, 
individuals treated with 4 mg baricitinib can mount an appropriate immune response to a 
pneumococcal vaccine, suggesting that transient exposure to baricitinib will not result in clinically 
meaningful changes to adaptive immunity (42).  
 
Justification for Dose of Dexamethasone 
This study will use the same dose and duration of dexamethasone that was evaluated in the 
RECOVERY trial, the largest and most influential study of dexamethasone in COVID-19.  
 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix D - ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 132 of 172 
5. 
STUDY POPULATION 
Male and non-pregnant female adults ≥18 years of age or older with COVID-19 and who meet 
all eligibility criteria will be enrolled at up to approximately 100 clinical trial sites globally. The 
target population should reflect the community at large.  
 
Subject Inclusion and Exclusion Criteria must be confirmed by an investigator named on the 
delegation log. If there is any uncertainty, the PI should make the decision on whether a potential 
subject is eligible for study enrollment. There is no exclusion for receipt of SARS-CoV-2 
vaccine (experimental or licensed). 
5.1 
Inclusion Criteria 
1. Hospitalized with symptoms suggestive of COVID-19. 
2. Subject (or legally authorized representative) provides informed consent prior to initiation of 
any study procedures and understands and agrees to comply with planned study procedures. 
3. Male or non-pregnant female adults ≥ 18 years of age at time of enrollment. 
4. Illness of any duration and has laboratory-confirmed SARS-CoV-2 infection as determined 
by PCR or other commercial or public health assay (e.g. NAAT, antigen test) in any 
respiratory specimen or saliva ≤14 days prior to randomization. 
5. Within the 7 days prior to randomization requiring new use of supplemental oxygen (or 
increased oxygen requirement if on chronic oxygen) and requires at the time of 
randomization low or high flow oxygen devices or use of non-invasive mechanical 
ventilation (ordinal scale category 5 or 6). 
6. Women of childbearing potential must agree to either abstinence or use at least one primary 
form of contraception not including hormonal contraception from the time of screening 
through Day 29.  
7. Agrees not to participate in another blinded clinical trial (both pharmacologic and other types 
of interventions) for the treatment of COVID-19 through Day 29 (see Section 5.4 for more 
information about concurrent trial participation). 
 
5.2 
Exclusion Criteria 
1. Prior enrollment in ACTT-3 or ACTT-4. Note: this includes subjects whose participation in 
ACTT was terminated early. 
2. On invasive mechanical ventilation at the time of randomization (ordinal scale category 7).  
3. Anticipated discharge from the hospital or transfer to another hospital which is not a study 
site within 72 hours of randomization. 
4. Positive test for influenza virus during the current illness (influenza testing is not required by 
protocol). 
5. Subjects with a low glomerular filtration rate (eGFR), specifically: 
a. Subjects with an eGFR 15-30 mL/min are excluded unless in the opinion of the PI, the 
potential benefit of participation outweighs the potential risk of study participation. 
b. All subjects with an eGFR <15 mL/min  
c.  All subjects on hemodialysis and/or hemofiltration at screening, irrespective of eGFR, 
are excluded. 
6. Neutropenia (absolute neutrophil count <700 cells/μL, 0.7 x 103/μL). 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix D - ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 133 of 172 
7. Lymphopenia (absolute lymphocyte count <200 cells/μL, 0.20 x 103/μL). 
8. Received five or more doses of remdesivir including the loading dose, outside of the study as 
treatment for COVID-19.  
9. Pregnancy or breast feeding (lactating women who agree to discard breast milk from Day 1 
until two weeks after the last study product is given are not excluded). 
10. Allergy to any study medication. 
11. Received convalescent plasma or intravenous immunoglobulin [IVIg] for COVID-19, the 
current illness for which they are being enrolled. 
12. Received any of the following in the two weeks prior to screening as treatment of COVID-
19: 
• More than one dose of baricitinib for the treatment of COVID-19; 
• Other small molecule tyrosine kinase inhibitors (e.g. imatinib, gefitinib, acalabrutinib, 
etc.); 
• monoclonal antibodies targeting cytokines (e.g., TNF inhibitors, anti-interleukin-1 
[IL-1], anti-IL-6 [tocilizumab or sarilumab], etc.);  
• monoclonal antibodies targeting T-cells or B-cells as treatment for COVID-19. 
Note: receipt of anti-SARS-CoV-2 mAb prior to enrollment (e.g. bamlanivimab) for their 
current COVID-19 illness is not exclusionary 
13. Use of probenecid that cannot be discontinued at study enrollment. 
14. Received 6 mg or more of dexamethasone po or IV (or equivalent for other glucocorticoid) in 
one day, on more than one day, in the 7 days prior to time of randomization. Note: 6 mg 
dexamethasone dose equivalents include 40 mg prednisone, 32 mg methylprednisolone and 
160 mg hydrocortisone. 
15. Received ≥20 mg/day of prednisone po or IV (or equivalent for other glucocorticoids) for 
≥14 consecutive days in the 4 weeks prior to screening. 
16. Have diagnosis of current active or latent tuberculosis (TB), if known, treated for less than 4 
weeks with appropriate therapy (by history only, no screening required). 
17. Serious infection (besides COVID-19), immunosuppressive state, or immunosuppressive 
medications that in the opinion of the investigator could constitute a risk when taking 
baricitinib or dexamethasone. 
18. Have received any live vaccine (that is, live attenuated) within 4 weeks before screening, or 
intend to receive a live vaccine (or live attenuated) during the study. Note: Use of non-live 
(inactivated) vaccinations including SARS-CoV-2 vaccine is allowed for all subjects.  
19. Had a known VTE (deep vein thrombosis [DVT] or pulmonary embolism [PE]) during the 
current COVID-19 illness. 
 
 
Exclusion of Specific Populations 
Information about the epidemiology of COVID-19 indicates that the largest burden of severe 
disease requiring hospitalization occurs among older adults, especially those with comorbidities. 
The incidence of severe morbidity and mortality among children and adolescents is low, and the 
clinical spectrum and natural history of COVID-19 among children and adolescents is not well 
understood. There is also limited data about the use of anti-inflammatory medications such as 
dexamethasone or baricitinib in children. Due to these gaps in knowledge of the disease in this 
population, a low incidence of severe disease, and an inability to justify a benefit to this population, 
children and adolescents will not be included in this trial.  

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix D - ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 134 of 172 
 
In nonclinical reproductive toxicity studies, remdesivir demonstrated no adverse effect on embryo-
fetal development when administered to pregnant animals. Embryonic toxicity was seen when 
remdesivir was initiated in female animals prior to mating and conception, but only at a 
systemically toxic dose. Remdesivir has not been studied in pregnant women. While baricitinib is 
a licensed drug with a known safety profile, the limited human data on use of baricitinib in pregnant 
women are not sufficient to inform a drug-associated risk for major birth defects or miscarriage. 
A short course of dexamethasone is routinely used to decrease neonatal complications of 
prematurity in pregnant women with threatened preterm delivery and is generally is well tolerated 
in pregnant women.(43) Infants born of mothers who have received substantial doses of 
corticosteroids during pregnancy should be carefully observed for signs of hypoadrenalism. 
Because the effects of remdesivir and baricitinib on the fetus and the pregnant woman are not fully 
known, pregnant women will not be eligible for the trial.  
 
In animal studies, remdesivir metabolites have been detected in the nursing pups of mothers 
given remdesivir. Baricitinib is present in the milk of lactating rats. There is no information 
available on the presence of baricitinib in human milk or the effects of the drug on the breastfed 
infant. Dexamethasone has been used in lactating women. Corticosteroids appear in breast milk 
and could suppress growth, interfere with endogenous corticosteroid production, or cause other 
unwanted effects. Because the effects of remdesivir and baricitinib on the breastfeeding infant is 
not known, women who are breast feeding will not be eligible for the trial unless they agree to 
discharge breast milk from Day 1 until 2 weeks after the last dose is administered. 
 
5.3 
Inclusion of Vulnerable Subjects 
Certain subjects are categorized as vulnerable populations and require special treatment with 
respect to safeguards of their well-being. For this clinical trial, examples include cognitively 
impaired or mentally disabled persons and intubated individuals who are sedated. When it is 
determined that a potential research subject is cognitively impaired, federal and institutional 
regulations permit researchers to obtain consent from a legally authorized representative (LAR). 
The study team will obtain consent from these vulnerable subjects using an IRB-approved 
protocol- specific process for consent using a LAR. For subjects for whom a LAR gives consent,  
if the subject regains the capacity to consent during the course of the study, informed consent must 
be obtained from the subject and the subject offered the ability to leave the study if desired. 
 
For this clinical trial, we will not enroll prisoners or detainees as subjects.  
 
5.4 
Lifestyle Considerations 
During this study, subjects are asked to: 
• Avoid getting pregnant during the study from Day 1 through Day 29. 
• Not participate in the following types of trials for the treatment of COVID-19 or SARS-
CoV-2 infection:  

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix D - ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 135 of 172 
o Blinded or unblinded interventional trials that evaluate if a non-approved 
medication or intervention is effective are prohibited.  
o Any other blinded interventional trials for treating COVID-19 are prohibited. 
o If a subject is co-enrolled in a prohibited study noted above, this should be 
reported as a protocol deviation, but the subject should not be withdrawn from 
this trial to participate in the other study. Full follow-up should occur per 
protocol.  
• Participation in both ACTT and these studies can only occur if the recommended blood 
collection volumes are not exceeded. 
o Co-enrollment in non-blinded (open-label) interventional studies that evaluate 
how to apply a standard of care intervention or strategy for patients with COVID-
19 (e.g., comparing dose, duration or schedule of VTE prophylaxis regimens; ICU 
strategies such as proning, etc.) is permitted.  
o Co-enrollment in natural history studies of COVID-19 and/or studies of SARS-
CoV-2 diagnostics is permitted.  
5.5 
Screen Failures 
Following consent, after the screening evaluations have been completed, the investigator or 
designee is to review the inclusion/exclusion criteria and determine the subject’s eligibility for the 
study. If there is any uncertainty, the PI should make the decision on whether a potential subject 
is eligible for study enrollment.  
 
Only basic demographic information and the reason(s) for ineligibility will be collected on screen 
failures. Subjects who are found to be ineligible will be told the reason(s) for ineligibility. 
 
Individuals who do not meet the criteria for participation in this study (screen failure) because of 
an abnormal clinical laboratory finding may be rescreened once.  
5.6 
Strategies for Recruitment and Retention 
 
Recruitment 
It is anticipated that patients with COVID-19 will present for hospitalization to participating 
clinical trial sites, and that no external recruitment efforts towards potential subjects are needed. 
Recruitment efforts may also include dissemination of information about this trial to other medical 
professionals / hospitals. The IRB will approve the recruitment process and all materials provided 
prior to any recruitment to prospective subjects directly. 
 
Recruitment activities will include pre-screening activities and will begin with a brief discussion 
between study staff and the subject/LAR before consent. Some subjects will be excluded based on 
demographic data and medical history alone (e.g., pregnant, < 18 years of age, on hemodialysis, 
etc.). In addition, information about the study will be presented to potential subjects or LAR and 
questions will be asked to determine potential eligibility after which time informed consent is 
obtained and further screening is completed (see Section 8.1.1). 
 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix D - ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 136 of 172 
 
Retention 
Retention of subjects is critical to the success of the trial since the primary endpoint is measured 
at Day 29 (+ 6-day window) and every effort should be made to retain subjects in the study. As 
such, after hospital discharge, subjects will be reminded of subsequent study visits and every effort 
will be made accommodate the subject’s schedule to facilitate follow-up within the specified visit 
window. To facilitate retention, follow-up visits may be conducted by phone, home visit or remote 
telehealth procedure as per institutional standards if in-person visits at the clinical site on Days 15 
and 29 are not feasible. The Day 22 visits are by phone call or remote telehealth procedure.  
 
However, there are many circumstances that impact a site’s ability to obtain outcome information 
after discharge. For example, given the clinical course of COVID-19, a subject may be readmitted 
to another hospital after discharge and therefore be unavailable at Day 15 or Day 22. Even if a 
study visit is missed, every effort should be made to keep subjects in the study to monitor for 
safety, readmission and mortality. Subjects should not be withdrawn from the study because a site 
is unable to contact them for a follow-up visit.  
 
Subjects should not be withdrawn from this trial due to terminal illness. If a subject or family is 
pursuing hospice or withdrawal of care, the study visits can be curtailed as needed, but these 
subjects (or their LARs) should be encouraged to remain in study for the Day 29 endpoint 
evaluation by chart review or phone call.  
 
In addition, in ACTT-4 we will have a visit two months after randomization to assess long term 
efficacy and safety outcomes. This visit will be conducted by phone or remote telehealth 
procedure. Because of this visit, sites will need to plan for how they will contact subjects at this 
late time point. 
  
 
Compensation Plan for Subjects  
Compensation, if any, will be determined locally and in accordance with local IRB requirements, 
and subject to local IRB approval.  
 
 
Costs 
There is no cost to subjects for the research tests, procedures/evaluations and study product while 
taking part in this trial. Procedures and treatment for clinical care including costs associated with 
hospital stay may be billed to the subject, subject’s insurance or third party. 
 
6. 
STUDY PRODUCT 
6.1 
Study Product(s) and Administration  
Subjects will be randomized into one of two arms (1:1). 
 
Arm 1 
Arm 2 
Baricitinib tablets +  
Placebo IV + 
Placebo tablets +  
Dexamethasone IV +  

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix D - ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 137 of 172 
Remdesivir IV 
 
Remdesivir IV 
 
 
 
 
Study Product Description  
Remdesivir Component 
Remdesivir is a single diastereomer monophosphoramidate prodrug designed for the intracellular 
delivery of a modified adenine nucleoside analog GS-441524. In addition to the active ingredient, 
the lyophilized and solution formulations of remdesivir contain the following inactive ingredients: 
water for injection, betadex sulfobutyl ether sodium, and hydrochloric acid and/or sodium 
hydroxide. 
 
Baricitinib Component 
Baricitinib is a Janus kinase (JAK) inhibitor with the chemical name [1-(ethylsulfonyl)-3-(4-
(7Hpyrrolo(2,3-d)pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl] acetonitrile and will be 
supplied in 36 count bottles. The treatment will be allocated as one bottle per subject, with some 
overage per bottle. Each tablet contains 2 mg of baricitinib and the following inactive 
ingredients: croscarmellose sodium, magnesium stearate, mannitol, microcrystalline cellulose, 
ferric oxide, lecithin (soya), polyethylene glycol, polyvinyl alcohol, talc and titanium dioxide.  
 
Oral Placebo Component (Baricitinib) 
Placebo for baricitinib tablets also manufactured by Eli Lilly and Company USA, and they contain 
lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. 
The coating for the placebo tablet is identical to that of the corresponding active tablet listed above. 
However, there is no lactose monohydrate in baricitinib, the active oral product. 
 
Dexamethasone Component 
Dexamethasone Sodium Phosphate Injection, USP, is an adrenocortical steroid anti-
inflammatory drug. It is a water-soluble inorganic ester of dexamethasone. Each mL contains 
dexamethasone sodium phosphate equivalent to dexamethasone phosphate 4 mg or 
dexamethasone 3.33 mg; benzyl alcohol 10 mg added as preservative; sodium citrate dihydrate 
11 mg; sodium sulfite 1 mg as an antioxidant; Water for Injection q.s. Citric acid and/or sodium 
hydroxide may have been added for pH adjustment (7.0 to 8.5). Dexamethasone is supplied as a 
5 mL multi-dose vial.  
 
Placebo Component (Dexamethasone) 
The dexamethasone placebo will be 0.9 % sodium chloride injection, USP. The USP grade 0.9% 
Sodium Chloride Injection, or normal saline, is a sterile, nonpyrogenic, isotonic solution; each 
mL contains sodium chloride 9 mg. It contains no bacteriostatic agent, antimicrobial agent, 
preservatives, or added buffer and is supplied only in single-dose containers. The solution may 
contain hydrochloric acid and/or sodium hydroxide for pH adjustment (pH 5.3, range 4.5-7.0). 
This product will be used as the placebo for dexamethasone IV push administration at an equal 
volume at the same schedule.  
 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix D - ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 138 of 172 
 
Dosing and Administration 
Dosing of the medications does not need to occur at the same time. Study Day 1 is the first day 
any of the 3 study products is administered (i.e., study remdesivir, baricitinib/po placebo, or 
dexamethasone/IV placebo given on study) and is used to determine timing of protocol 
assessments and safety analyses as outlined in SOA. Sites have 24 hours between randomization 
(enrollment) and initial study product administration.   
 
Remdesivir 
• 
Up to four doses of remdesivir are allowed prior to randomization. Remdesivir should be given 
as soon as possible after randomization. If a patient receives remdesivir in the emergency 
department late at night or early in the morning on day of enrollment, the dosing may be 
transitioned to daytime hours if desired by allowing a minimum 12-hour window between the 
pre-study dose and Day 1 dose.    
• 
After Day 1, remdesivir should be given approximately every 24 hours +/- 2 hours. Protocol 
deviations do not need to be submitted if remdesivir given outside of this window. Protocol 
deviations should be submitted if a daily dose is missed completely. 
• 
This dosing should occur as described regardless of the options for anti-inflammatory dosing 
discussed below.  
• 
All subjects will receive remdesivir as a 200 mg intravenous (IV) loading dose on Day 1, 
followed by a 100 mg once-daily IV maintenance dose for the duration of the hospitalization 
up to a 10-day total course. If subjects already received the loading dose prior to study 
enrollment, then start at 100 mg/day on Day 1. Any doses of remdesivir given prior to 
enrollment will be counted, so the total duration of remdesivir (i.e. pre-enrollment + on this 
trial) is 10 days (i.e., a maximum of 10 total infusions). Any doses of remdesivir were 
administered prior to study enrollment should be documented in Advantage eClinical as a 
concomitant medication given prior to Day 1. The duration of dosing may be adjusted by the 
site similar to what is described in the package insert and based on a subject’s clinical course 
and ultimate disease severity.  
 
ANTI-INFLAMMATORY AGENTS (DEXAMETHASONE/IV PLACEBO + BARICITINIB/ PO PLACEBO)   
• The anti-inflammatory agents should be given as soon as possible after randomization, but 
they also should be given around the same time so one arm is not receiving treatment sooner 
than the other arm.    
For patients, who have received dexamethasone before enrollment as part of their clinical care:  
• If a patient has received dexamethasone the day prior to enrollment, then the baricitinib/po 
placebo and dexamethasone/IV placebo can be administered right after randomization and 
this becomes Day 1.  
• If a patient has received dexamethasone at any time on the day of enrollment but before 
randomization/enrollment, then there are several options as described below.  
o It is preferred to randomize and give remdesivir + dexamethasone/po placebo + 
baricitinib/IV placebo on the same calendar day as randomization. This could result 
in subjects receiving two doses of dexamethasone on Day 1 (a pre-study dose and 
an on-study dose of dexamethasone/IV placebo).   

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix D - ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 139 of 172 
o If the site is concerned with this high dose of dexamethasone, sites have 24 hours 
between randomization (enrollment) and initial study product administration (i.e. 
both drugs may be delayed until the calendar day after randomization but within 24 
hours of randomization).  
o Alternatively, if necessary (but not preferred), sites may randomize and give 
remdesivir and baricitinib/po placebo on the same calendar day as randomization 
(this becomes Day 1) and on Day 2, give all other study products and submit a 
protocol deviation for missed dose of IV push study product on Day 1 and this 
missed dose of dexamethasone/IV placebo will not be made-up during the study. 
The subject will receive only 9 doses of  dexamethasone/IV placebo from Day 2 
through Day 10. This option allows the PI to decide the risk /benefit ratio of a 
potential double dose of dexamethasone on Day 1 for their patients.   
 
For the baricitinib component, subjects will receive either active product or placebo as follows: 
• Baricitinib will be administered as a 4 mg orally (po) (two, 2mg tablets) or dissolved for 
NG tube, daily for the duration of the hospitalization up to a 14-day total course.  
• A placebo will be given as two tablets po or dissolved for NG tube, daily for the duration 
of the hospitalization up to a 14-day total course.  
• See Section 6.1.4 for dosing modifications for baricitinib for renal failure. 
• See MOP for instructions on how to prepare and administer baricitinib to patients having 
difficulty swallowing 
 
For dexamethasone component, subjects will receive either active product or placebo as follows: 
• Dexamethasone will be administered as a 6 mg slow IV push over 3 to 5 minutes daily 
for the duration of the hospitalization up to a 10-day total course. 
• A placebo will be given as an equal volume normal saline, as a slow IV push daily for the 
duration of the hospitalization up to a 10-day total course. 
• If local standards use other means of administration (such as IV infusion), these may be 
used for both active and placebo after approval of the sponsor. Reports of intense perineal 
pain and/or burning are reported immediately after given IV push too quickly. 
• Any pre-study dexamethasone (see exclusion criteria) is not counted towards the 10 day 
course.  
 
 
Duration of therapy: 
• IV remdesivir – up to 10 days while hospitalized (i.e., maximum of 10 total infusions pre-
enrollment and during study). 
• Oral baricitinib (or oral placebo) – 14 days while hospitalized (i.e., maximum of 14 total 
doses). 
• IV dexamethasone (or IV placebo) – 10 days while hospitalized (i.e., maximum of 10 
total doses). 
• All medications stop on discharge from hospital.  
o Of note, if a subject is retained in the hospital for non-COVID-19 related issues 
and no longer requires supplemental oxygen and ongoing medical care (i.e., 
ordinal scale category 3), the PI may decide to discontinue all medications.  

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix D - ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 140 of 172 
• If readmitted after discharge, see Section 7.4. 
 
 
Dose Escalation 
Not Applicable 
 
 
Dose Modifications 
The protocol-required safety laboratories (per the SOA) are anticipated to be sufficient for 
evaluating for dose modifications, but if other laboratory data obtained as part of standard care are 
available, these should also be used in the evaluation.  
 
Remdesivir component: 
The infusion should be held and not given if the subject is found to have any of the following 
laboratory values: 
 
• eGFR decreases to < 15 mL/min 
o Remdesivir infusion will resume when the eGFR increases to ≥ 15 mL/min and the 
potential benefit of giving remdesivir outweighs the potential risk.  
o If renal function worsens during the study to the point that they require hemodialysis 
or hemofiltration, remdesivir will be discontinued. 
• ALT and/or AST increases to > 10 times upper limits of normal (ULN); resume remdesivir 
infusions when ALT and AST ≤ 5 times ULN. 
 
Baricitinib/Oral Placebo component: 
Dose of oral study product will be decreased or held based on eGFR. Specifically: 
eGFR Value 
Dose of baricitinib or oral placebo 
≥60 mL/min 
Two tablets (4 mg total) once daily  
No dose adjustment 
30 - <60 mL/min 
One tablet (2 mg) once daily 
15 - <30 mL/min 
One tablet (2 mg) QOD – every other day 
<15 mL/min or require hemodialysis or 
hemofiltration 
Hold oral study product  
 
Oral study product should be temporarily interrupted if the subject develops any of the following 
during the study: 
• eGFR decreases to < 15 mL/min; resume oral study product when eGFR ≥ 15 mL/min 
• Absolute neutrophil count (ANC) <500 cells/μL; resume oral study product when ANC ≥ 
700. 
• Absolute lymphocyte count (ALC) <200 cells/μL; resume oral study product when ALC 
≥ 200.  
• ALT and/or AST increases to > 10 times ULN; resume oral study product when the ALT 
and AST ≤ 5 times ULN. 
• New serious infection identified (i.e., SAE infection); may resume oral study product when 
PI believes that the infection is under control  
 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix D - ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 141 of 172 
Any dose that is held as described above, may be given later that day if the laboratory parameters 
improve. Any daily dose that is missed during the study due to any reason is not made up. The 
treatment course continues as described above even if the subject becomes PCR negative while 
hospitalized. If oral study product is held for more than 2 days, consider that the subject may not 
be receiving any anti-inflammatory. If the clinical condition requires, an open-label (off-study) 
dexamethasone or other anti-inflammatory agent may be added while the oral study product is 
held. No protocol deviation for prohibitory medications (i.e., off-study dexamethasone) would be 
required for these days of anti-inflammatory coverage while the subject has oral study product 
held. 
 
For laboratory values that meet permanent discontinuation thresholds (see Section 7.1), study 
product should be discontinued. However, if in the opinion of the investigator, the laboratory 
abnormality is due to intercurrent illness or another identified factor, laboratory tests may be 
repeated once.  
 
 
Overdosage 
Overdose is not anticipated in the context of a clinical trial. Study product will be administered to 
subjects. There is no known antidote for baricitinib. However, if a site inadvertently gives a subject 
excess baricitinib, the site should contact the Sponsor. The subject should receive supportive 
therapy based on the subject´s signs and symptoms. 
 
Reports of acute toxicity and/or death following overdosage of glucocorticoids are rare. In the 
event of overdosage, no specific antidote is available; treatment is supportive and symptomatic.  
6.2 
Preparation/Handling/Storage/Accountability 
 
Acquisition and Accountability 
Investigational products (IP) will be shipped to the site either directly from participating 
companies, from the Sponsor, or from other regional or local drug repositories. All other supplies 
should be provided by the site. Multiple lots of each IP may be supplied. 
 
Study products received at the sites will be open label, unless specified in the protocol-specific 
Manual of Procedures (MOP) or pharmacy manual. See the MOP Appendices for detailed 
information on the preparation, labeling, storage, and administration of investigational products.  
Accountability 
The site PI is responsible for study product distribution and disposition and has ultimate 
responsibility for study product accountability. The site PI may delegate to the participating site’s 
research pharmacist responsibility for study product accountability. The participating site’s 
research pharmacist will be responsible for maintaining complete records and documentation of 
study product receipt, accountability, dispensation, storage conditions, and final disposition of the 
study product(s). Time of study drug administration to the subject will be recorded on the 
appropriate data collection form (CRF). All study product(s), whether administered or not, must 
be documented on the appropriate study product accountability record or dispensing log. The 
Sponsor’s monitoring staff will verify the participating site’s study product accountability records 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix D - ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 142 of 172 
and dispensing logs per the site monitoring plan. Refer to the protocol-specific MOP for details on 
storing study medications.  
Destruction 
After the study treatment period has ended or as appropriate over the course of the study after 
study product accountability has been performed, used active and placebo product can be 
destroyed on-site following applicable site procedures with a second staff member observing and 
verifying the destruction.  
Unused product at the end of the study should be saved until instructed by the Sponsor. 
 
 
Formulation, Appearance, Packaging, and Labeling 
Remdesivir component 
Remdesivir may be supplied in two formulations: 
• The lyophilized formulation of remdesivir is a preservative-free, white to off-white or 
yellow, lyophilized solid containing 100 mg of remdesivir to be reconstituted with 19 mL 
of sterile water for injection respectively and diluted into IV infusion fluids prior to IV 
infusion.  
• The concentrated liquid solution is supplied as a single-dose glass vial containing 100 
mg/20 mL (5 mg/mL) of remdesivir that is a sterile, preservative-free, clear, colorless to 
yellow, aqueous-based concentrated solution to be diluted into 0.9% sodium chloride 
infusion bag prior to administration by intravenous infusion.  
 
Remdesivir will be labeled according to manufacturer specifications. For complete details of the 
preparation, packaging and administration, please see the package insert and the MOP. 
 
Baricitinib component 
Baricitinib tablets are film-coated, immediate-release tablets. The 2 mg tablet is light pink and 
oblong. Each tablet contains 2 mg of baricitinib and the following inactive ingredients: 
croscarmellose sodium, magnesium stearate, mannitol, microcrystalline cellulose, ferric oxide, 
lecithin (soya), polyethylene glycol, polyvinyl alcohol, talc and titanium dioxide. 
 
Oral placebo component 
Placebo tablets match the active product in appearance. The placebo tablets contain lactose 
monohydrate, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. The 
coating for the placebo tablet is identical to that of the corresponding active tablet listed above.  
Study interventions (baricitinib and placebo) will be supplied by the sponsor or its designee in 
accordance with current Good Manufacturing Practice (cGMP). 
 
Dexamethasone component 
According to the package insert, dexamethasone is available as 4 mg per mL in a 5 mL multi-
dose vial. It is a sterile solution of dexamethasone sodium phosphate in water for injection for 
intravenous (IV).  
 
Intravenous placebo for dexamethasone component 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix D - ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 143 of 172 
Intravenous normal saline placebo matches the active dexamethasone product in volume and 
appearance. It is supplied in single-use vial. 
A label with the statement “Caution: New drug -Limited by Federal Law to investigational use” 
will be placed on the immediate package. 
 
 
Product Storage and Stability 
The Pharmacy Manual provides instructions for the preparation, handling, and storage of baricitinib 
drug product and placebo, dexamethasone drug product and placebo and remdesivir, and describes 
site responsibility and accountability for the administered products.  
 
See most recent version of package insert and information as posted on the Emmes website. 
 
 
Preparation 
Refer to the protocol-specific MOP for details about preparation of all study products. 
  
6.3 
Measures to Minimize Bias: Randomization and Blinding 
 
Randomization  
Randomization will be stratified by: 
• Site 
• Severity of illness at enrollment (by ordinal scale) 
o Hospitalized, on non-invasive ventilation or high flow oxygen devices, OR 
o Hospitalized, requiring supplemental oxygen 
 
The randomization procedure will be described in the MOP.  
 
 
Blinding and Masking Procedures 
As both arms are receiving remdesivir, the remdesivir product is not blinded and study infusions 
can be labeled accordingly.  
 
The baricitinib/placebo component is blinded. Baricitinib and placebo tablets are identical in 
appearance. 
 
The dexamethasone/placebo IV component is blinded. Dexamethasone and intravenous placebo 
are identical in appearance. 
 
 Unblinding at end of study 
Unblinding of the study will occur after all subjects enrolled have reached the end of study, these 
visits are monitored, and data is cleaned or if the DSMB recommends unblinding. Data through 
Day 29 will be locked prior to the completion and lock of Day 60 data. DMID and the SDCC 
will be unblinded after the Day 29 database lock.  Clinical sites will not be unblinded to subject-
level treatment assignments until after the Day 60 database lock.  
 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix D - ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 144 of 172 
 Unblinding for worsening clinical status 
If a subject’s clinical status worsens to require mechanical ventilation (ordinal 7), the treating 
clinician may request unblinding in order to use the prior treatment assignment to inform future 
treatment. See section 6.5.4 for preferred alternatives prior to unblinding. Any unblinding for this 
purpose will be tracked by the Sponsor, and sites that frequently unblind subjects in this ordinal 
scale category may have enrollment curtailed by the Sponsor.  
 
 Unblinding for adverse event 
If a Serious Adverse Event occurs, that is thought to be related to the study drug, and the treating 
clinician believes that knowledge of the treatment arm may change the therapy provided to the 
patient, the individual subject can be unblinded. If unblinded for SAE, the investigator may 
decide to have the blinded study product and/or remdesivir infusions discontinued based on the 
adverse event that led to unblinding and the benefit-risk analysis. The subject should remain on 
study through the Day 60 visit. The procedure for emergency unblinding will be further detailed 
in the Manual of Operations. 
 
6.4 
Study Intervention Compliance 
Each dose of study product will be administered by a member of the clinical research team who 
is qualified and licensed to administer the study product. Administration and date, and time, will 
be entered into the case report form (CRF). 
 
6.5 
Concomitant Therapy 
 
Permitted Concomitant Therapy and Procedures 
For patients that are eligible for the study, other therapy received prior to enrollment with any other 
experimental treatment or off-label use of marketed medications that are intended as specific 
treatment for COVID-19 or the SARS-CoV-2 infection (i.e., post-exposure prophylaxis [PEP]) 
must be discontinued on enrollment. There is no waiting period between discontinuation of these 
treatments and administration of study products. However, these prior treatments and their end 
date should be documented on the Concomitant Medication form in the Advantage eClinical 
system.  
 
There are two scenarios in which outpatient experimental treatment or off-label use of marketed 
medications that are intended as specific treatment for COVID-19 do not need to be discontinued. 
First, subjects who are taking another antiviral for a concurrent infection (e.g. lopinavir/ritonavir 
for HIV, etc.) or another existing medical condition (e.g. hydroxychloroquine for lupus, etc.) may 
continue with the treatment. Note that these treatments may be thought of as an off-label 
medication for COVID-19, however, because they were being used prior to study enrollment for 
another indication, they are allowable.  
 
Second, if there is a written policy or guideline for the local standard of care and treatment of 
COVID-19 patients or SARS-CoV-2 infection (i.e., not just an individual clinician decision), 
continuation of these outpatient medications is permitted (except for dexamethasone and 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix D - ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 145 of 172 
baricitinib as noted below). There should be plans on how the concomitant drugs are stopped in 
case of additive toxicities. 
 
On August 23, 2020, the FDA issued an EUA for COVID-19 convalescent plasma for the treatment 
of hospitalized patients with COVID-19. The NIH COVID-19 Treatment Guidelines were updated 
on September 1, 2020 and concludes that “there are insufficient data to recommend either for or 
against the use of convalescent plasma for the treatment of COVID-19”. According to the NIH 
Guidelines and the EUA Fact Sheet for Health Care Providers, convalescent plasma should not be 
considered the standard of care for the treatment of patients with COVID-19. However, if a site 
has adopted convalescent plasma as part of their institutional standard of care for the treatment of 
COVID-19 patients, it is allowed as described above. 
 
VTE prophylaxis is recommended for all patients unless there is a major contraindication such as 
active bleeding events or history of heparin-induced thrombosis. 
 
 
Prohibited Concomitant Therapy 
As the study is comparing baricitinib to dexamethasone, additional baricitinib, dexamethasone and 
other glucocorticoids are prohibited unless the subject worsens and requires invasive mechanical 
ventilation (see Section 6.5.4). In addition, if oral study product is held for more than two days and 
the clinical condition requires, an open-label (off-study) dexamethasone or other anti-
inflammatory agent may be added while the oral study product is held (Section 6.1.4). Exceptions 
to the steroid prohibition include: mineralocorticoids for standard indications are permitted (e.g., 
adrenal insufficiency, shock) and low-dose prednisone as part of immunosuppression regimen for 
solid organ-transplant patients is allowed (e.g., prednisone 5 mg po daily).  
 
Strong inhibitors of organic anion transporter 3 (OAT3) such as probenecid are prohibited during 
the study. 
 
Concomitant use of any other experimental treatment or off-label use of marketed medications 
intended as specific treatment for COVID-19 or SARS-CoV-2 infection, and not specified in the 
local or NIH COVID-19 Treatment Guidelines are prohibited. Specifically, use of any biologic 
therapy not specified on the written policy or guideline are prohibited including: monoclonal 
antibodies targeting cytokines (e.g., TNF inhibitors; interleukin-1[IL-1], IL-6 [tocilizumab or 
sarilumab]), or T-cells (e.g., abatacept); monoclonal antibodies targeting B-cells (e.g., rituximab, 
and including any targeting multiple cell lines including B-cells); JAK inhibitor(s) (e.g., 
baricitinib, imatinib, gefitinib, acalabrutinib, tofasitinib); and any type of interferon, convalescent 
plasma, or immunoglobulin (IgG) therapies for COVID-19. Similarly, the concomitant use of 
hydroxychloroquine to treat COVID-19 is prohibited unless it is included in the local institutional 
treatment guidelines (and even then, it is discouraged given the interaction with remdesivir).  
 
 
Assessment of Concomitant Therapies 
Concomitant medications will be assessed from 7 days prior to enrollment to Day 29 or upon 
discharge, whichever comes first for all medications except corticosteroids. All corticosteroids 
(except nasal, opthalmic, or topical steroids) including dexamethasone, prednisone, prednisolone, 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix D - ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 146 of 172 
and methylprednisolone should be recorded from Day -7 through Day 29 even after discharge 
from the hospital. Recording corticosteroid use after hospital discharge is important because long 
courses of po corticosteroids given after hospital discharge may impact our study endpoints. All 
prescription medications should be recorded during this time period with the exceptions listed in 
the bullets below. All medications, except biologics and corticosteroids, can be recorded once 
regardless of the number of times it was given during the time period. For example, vasopressors 
should be recorded when first dose given (as the start date) and the last dose given (as the end 
date) during the period of assessment.  
 
Sites do not need to record any of the following categories of medications in the eClinical system 
during the period from Day -7 through Day 29: 
o All topical medications: ointments, creams, and lotions; 
o All intranasal medications: nasal decongestants, nasal allergy medications, nasal steroids, 
and nasal saline drops/sprays;  
o All ophthalmic medications: ophthalmic allergy medication, ophthalmic medications for 
infection, and ophthalmic medications for eye dryness (e.g., saline eye drops); 
o Antiseptic mouth wash, lozenges; 
o Cough medication: mucolytics, cough suppressants, and expectorates; 
o GI medications: H2 blockers, proton pump inhibitors, GI stimulants, prokinetics, laxatives, 
stool softeners, antacids, anti-diarrheal and anti-nausea medications; 
o Symptomatic care medications: antipyretics, antihistamines, decongestants, and NSAIDs;  
o Mineral or herbal supplements, dietary supplements, iron/ferrous sulfate, magnesium, 
calcium, electrolyte replacement; 
o Albumin infusions; 
o Melatonin; 
o Nicotine patch, lozenge, gum, or nasal spray, or other product to treat tobacco dependence; 
o Dyes: contrast media, iodine – based dye, barium sulfate, and diatrizoate sodium. 
 
See the MOP for more information about recording concomitant medications. 
 
 
Progression to Intubation/Invasive Mechanical Ventilation.  
In ACTT-4, non-study product (off-study) baricitinib, dexamethasone and other glucocorticoids 
are prohibited unless the subject worsens to require invasive mechanical ventilation (ordinal score 
7). Mineralocorticoids for standard indications are permitted (e.g., adrenal insufficiency, shock). 
Low-dose prednisone as part of immunosuppression regimen for solid organ-transplant patients is 
allowed as part of standard of care (e.g., prednisone 5 mg po daily).  
 
If additional (off-study) baricitinib, dexamethasone or another glucocorticoid is given when a 
subject is not an ordinal scale category 7, the investigator should file a protocol deviation for use 
of the prohibited medication and decide whether the blinded study products should be 
discontinued.  The subject should remain on study and continue with the SOA as described in the 
protocol though the Day 60 visit. An exception to this is when oral study product is held for more 
than 2 days and the clinical condition requires that an open-label (off-study) dexamethasone or 
other anti-inflammatory agent be added while the oral study product is held (see Section 6.1.4).  
 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix D - ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 147 of 172 
If a subject’s clinical status worsens to require invasive mechanical ventilation (ordinal 7), the 
following should occur: 
• The preference is to continue study medication as originally assigned (i.e. continue 
blinded baricitinib or placebo and continue blinded dexamethasone or placebo) as well as 
the remdesivir infusions. The subject should remain on study though the Day 60 visit.  
• Recognizing the treating clinician may request to stop the randomized blinded study 
medication, the next preferred option is that the baricitinib/placebo po component and the 
dexamethasone/placebo IV component are discontinued without unblinding. This will 
allow the treating clinician to pick any regimen needed for the subject. In this scenario, 
remdesivir infusions should continue and the subject should remain on study though the 
Day 60 visit. 
• If the treating clinician needs to know prior treatment, the site investigator can request 
that the subject treatment assignment be unblinded. This is the least preferred option as it 
unblinds treatment assignment. However, it is available to ensure clinicians have 
information available to give their patients optimal care. In this scenario, remdesivir 
infusions should continue and the subject should remain on study through the Day 60 
visit. 
 
The above treatment choices will be tracked for all subjects that worsen to require 
mechanical ventilation (ordinal 7) and will be tracked by the sponsor. Sites that consistently 
unblind subjects in this category may have enrollment curtailed by the sponsor. The MOP 
Part A Clinical, Section 5 and an informational sheet for staff training located on the Emmes 
website titled, Unblinding for Progression to Mechanical Ventilation, describe the 
unblinding procedure and the documentation that is needed.  It is important that sites know 
the procedure so that site staff, the site PI and other ACTT investigators, and the Sponsor 
remain blinded. The unblinded study pharmacist should only unblind the treating clinician to 
the treatment assigmment if unblinding is deemed necessary.  
 
 
Non-Research Standard of Care 
Not Applicable 
 
7. 
STUDY INTERVENTION DISCONTINUATION AND 
SUBJECT DISCONTINUATION/WITHDRAWAL 
7.1 
Halting Criteria and Discontinuation of Study Intervention 
 
Individual Study Product Halting  
Study product administration for any given subject may be stopped for SAEs, clinically significant 
adverse events, severe laboratory abnormalities, or any other medical conditions that indicate to 
the Investigator that continued dosing is not in the best interest of the patient. 
If signs and symptoms of a clinically significant hypersensitivity reaction occurs during or 
shortly after an infusion of Remdsivir or administration of the blinded study products (oral and 
IV push), administration must be stopped and treated as needed. Subjects who have the study 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix D - ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 148 of 172 
product stopped for a safety related issues will not continue with dosing. In addition, subjects 
who have an allergic reaction that is temporally associated with study product administration and 
the PI believes it to be related to study product will not receive any more study product.  See 
Section 7.1.1.2 below for additional  halting criteria for the blinded study products. 
 
In addition, a subject in this clinical study may discontinue study drug at their request for any 
reason. Every effort should be made to encourage subjects to remain in the study for the duration 
of their planned outcome assessments. Subjects should be educated on the continued scientific 
importance of their data, even if they discontinue study drug.  
Unless the subject withdraws consent, those who discontinue study drug early will remain in the 
study. The reason for subject discontinuation of study drug should be documented in the case 
report form. 
 
 Remdesivir Halting 
See Section 6.1.4. for information about dosing modifications due to laboratory abnormalities. 
 
 Oral and IV Study Product Halting 
See Section 6.1.4. for information about dosing modifications for the blinded oral study product 
due to laboratory abnormalities. Otherwise, criteria for discontinuing administration of the 
blinded oral and IV push study products are the same as outlined below. 
 
The subject should not receive any additional blinded oral and IV push study product  if they 
develop any of the following conditions during the study:  
• VTE (DVT/PE). 
• Suspected drug-induced liver injury with the appearance of fatigue, nausea, vomiting, 
right upper-quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%). 
• New malignancy (except for successfully treated basal or squamous cell skin 
carcinoma). 
• A systemic fungal infection is confirmed.  
• Clinically significant hypersensitivity, including anaphylaxis or anaphylactoid reaction 
during administration of either blinded oral or IV study product   
 
 
Study Halting 
Given the potential severity of COVID-19, there are no pre-specified study stopping rules. 
Instead there will be close oversight by the protocol team and frequent DSMB reviews of the 
safety data.  
7.2 
Withdrawal from the Study 
Subjects are free to withdraw from participation in the study at any time upon request, without 
any consequence. Subjects should be listed as having withdrawn consent only when they no 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix D - ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 149 of 172 
longer wish to participate in the study and no longer authorize the Investigators to make efforts 
to continue to obtain their outcome data or safety assessment. 
  
The investigator may also withdraw a subject from the study. However, the investigator will be 
encouraged to allow subjects to remain in the study to be followed for safety and final outcome 
assessment at Days 29 and 60 (i.e., the ordinal scale and mortality) even if they decide to 
discontinue study products and research laboratory draws. Withdrawing a subject from the study 
due to an inability to contact them for the Day 15 and/or Day 22 follow-up visit is discouraged 
given the possibility of readmission and chaotic social circumstances resulting from the 
pandemic. 
 
Subjects who withdraw from this study or are lost to follow-up after signing the informed 
consent form (ICF) and administration of the study product, will not be replaced. The reason for 
subject withdrawal from the study will be recorded on the appropriate CRF.  
7.3 
Lost to Follow-Up 
A subject will be considered lost to follow-up if the site is unable to contact him or her by phone 
or other means such as text, email, fax or letter (as approved by the IRB) for all follow-up 
assessments at Day 15, 22 and 29. In lost to follow-up cases, attempts to contact the subject 
should be made and these efforts should be documented in the subject’s records.  
 
7.4 
Readmission  
If a subject is discharged from the hospital and then readmitted prior to Day 11, they may be given 
the remainder of the remdesivir infusions, baricitinib/po placebo and dexamethasone/IV placebo 
component. If prior to Day 15, they may be given the remainder of the baricitinib/po placebo 
components. If the subject did not withdraw his/her consent to participate in the study, there is no 
need to reconsent upon readmission to the study hospital. However, the site will need to inform 
them that since he/she was readmitted, study product administration will resume and confirm that 
they still agree to receive study product.  
 
The natural history of COVID-19 and its impact on pre-existing medical conditions is not 
completely understood. Because of this, all readmissions, regardless of reason, should be 
documented and the subject should get daily clinical status assessments (i.e., ordinal scale) and 
other procedures done as per the SOA upon readmission. If the subject is re-admitted with 
diminished mental capacity, the site should discuss continued study participation with a LAR.  
 
The study team will need to notify the study pharmacist of the readmission. The subject will not 
get the doses that they missed after being discharged. Upon readmission, the subject will get 
maintenance doses of infusion only since they already received the loading dose of the study 
product infusion on Day 1. No remdesivir or dexamethasone/IV placebo component study product 
infusions should be given past Day 10. No baricitinib/po placebo component should be given past 
Day 14. For all data collection procedures required for those readmitted, please see the MOP.  
 
8. 
STUDY ASSESSMENTS AND PROCEDURES 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix D - ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 150 of 172 
8.1 
Screening and Efficacy Assessments 
 
Screening Procedures 
Post consent screening procedures may be done over one to two calendar days (from Day -1 to 
Day 1). See Section 5.6.1 for allowable pre-screening procedures. However, in many cases all 
the screening assessments can be done in less than 24 hours. If that is the case, Day 1 pre-study 
product administration baseline assessments, specimen collection and the initial study product 
administration can occur on the same calendar day as the screening procedures.  
 
After the informed consent, the following assessments are performed to determine eligibility: 
• 
Confirm the positive SARS-CoV-2 test result (per inclusion criteria).  
• 
Confirm that patient does not have a positive influenza test during the current illness for 
which they are being screened and possibly enrolled. Influenza testing is not required per 
protocol. 
• 
Take a focused medical history, including the following information:  
• Day of onset of COVID-19 signs and symptoms. 
• Prior enrollment in ACTT-3 or ACTT-4. 
• History of vaccinations within 4 weeks before screening and planned vaccinations.  
• Exclusionary vaccine history includes any live vaccine (that is, live attenuated) 
within 4 weeks before screening, or intend to receive a live vaccine (or live 
attenuated) during the study. Note: Use of non-live (inactivated) vaccinations is 
allowed for all subjects including the recently EUA approved COVID-19 vaccines. 
Pre-study receipt of SARS-CoV-2 vaccine should be documented in the Medical 
History eCRF.  
• History of chronic medical conditions, including chronic oxygen requirement and/or 
use of CPAP or BiPAP at home, prior to onset of COVID-19. See conditions included 
in exclusion criteria and on the Medical History (CMX) data collection form. 
• History of medication allergies. 
• Medications and therapies for this current COVID-19 illness and history of any 
medication listed in the exclusion criteria. Site should identify if the patient received 
any dexamethasone in the 7 days prior to randomization.  
• Ask if the patient is participating in another clinical trial or plans to enroll in another 
clinical trial in the next 28 days. 
 
• 
Women of childbearing potential should be counseled to either practice abstinence or use at 
least one primary form of contraception not including hormonal contraception from the time 
of screening through Day 29. Women should be confirmed to not be breastfeeding. 
• 
Note: If a woman is either postmenopausal (i.e., has had ≥12 months of spontaneous 
amenorrhea) or surgically sterile (i.e., has had a hysterectomy, bilateral ovariectomy 
(oophorectomy), or bilateral tubal ligation), she is not considered to be of 
childbearing potential.  

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix D - ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 151 of 172 
• 
Blood for screening laboratory evaluations, if not done as part of routine clinical care in the 
preceding 48 hours, should be collected to evaluate the following parameters: 
 White blood cell count (WBC) with differential 
• Assess ANC and ALC as per exclusion criteria 
 
 Serum creatinine (and calculate eGFR)  
• Any automated calculation by the clinical laboratory or published formula for this 
calculation is acceptable. The site should select a formula to be used for all 
subjects enrolled at the site for the duration of the study. 
• 
Do urine or serum pregnancy test during screening for women of childbearing potential or 
site may use test done prior to screening during this current hospital admission as long as 
patient has been confined in hospital since test was done. See instructions below for women 
who are less than 6 weeks postpartum: 
 Do not do a pregnancy test if the patient is post-partum and has not left the hospital 
since delivery. The pregnancy test will likely give a false-positive result as serum 
human chorionic gonadotropin (hCG) is usually detected for up to 4 to 6 weeks after 
delivery. 
 For women who are less than 6 weeks postpartum and have left the hospital, any 
positive pregnancy test should be repeated to determine if the HCG is declining as 
predicted after delivery and therefore the result is a false-positive. Of note, women who 
are less than 6 weeks postpartum and had heterosexual intercourse since delivery and 
hospital discharge are unlikely to be pregnant because the average time to first 
ovulation varies from 45 to 94 days postpartum, with the earliest reported ovulations at 
25 and 27 days postpartum.  
Clinical screening laboratory evaluations will be performed locally by the site laboratory. The 
volume of venous blood to be collected is presented in Table 7. A screening lab (i.e., from the 
hematology and chemistry laboratory panels) may be repeated once if, in the opinion of the 
investigator, the laboratory abnormality is due to an intercurrent transient condition or it is an 
aberrant laboratory value.  
 
The overall eligibility of the subject to participate in the study will be assessed once all screening 
values are available. The screening process can be suspended prior to complete assessment at any 
time if exclusions are identified by the study team. 
 
Study subjects who qualify will be randomized in the Advantage eClinical system, and all others 
will be registered as screen failures. The ordinal scale should be done at the time of randomization; 
the site will need this data to randomize the subject in eClinical. The study team has 24 hours to 
complete other Day 1 baseline assessments prior to the first study product administration including 
the collection of the OP swab and blood and completing or recording a baseline physical 
examination that was done, including weight and height (height can be self reported). Clinical 
laboratory tests collected as part of routine care of the patients in the 36 hours prior to first dose 
qualify for baseline safety tests on Day 1. 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix D - ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 152 of 172 
 
If a subject is found to be ineligible AFTER being randomized and they did not receive any study 
product, the site should file an early study termination and stop all study procedures including 
specimen collection.  
If the subject is found to be ineligible AFTER being randomized and did receive study product, 
they may continue on study if the PI has no safety concerns with their continued participation. The 
site should file a study protocol deviation (i.e., checkbox: met exclusion criteria). However, if the 
PI feels that the risk of participation outweighs the benefit, the site should file an early study 
termination.  
 
Efficacy Assessments 
For all baseline assessments and follow-up visits, refer to the Schedule of Assessments (SOA) 
for procedure to be done, and details below for each assessment. 
 
 Measures of clinical support, limitations and infection control 
The subject’s clinical status, as measured by the ordinal scale, will be captured at randomization 
and Day 2 through Day 29 (+ 6-day window) while hospitalized or day after death whichever 
comes first. The ordinal scale will also be captured on the day after discharge from the hospital. 
This will be done so that discharge and death are accurately recorded and captured in the eClinical 
system. For subjects who received oxygen by nasal cannula or CPAP ventilatory support at night 
at home prior to having COVID-19, sites should assign a recovery ordinal scale score of 1 or 2 
when discharged to home after recovery. The assignment of category 1 versus category 2 will 
depend on whether they have new or increased physical limitations post-COVID-19 and/or if they 
have new or increased home oxygen requirement compared with the baseline, pre-COVID-19 time 
period.  
 
It is important to capture all deaths that occur during the study as this is one of the outcomes of the 
study. Death is a category on the ordinal scale. If a subject dies during the study, an ordinal scale 
assessment should be completed for the day after death because the ordinal scale captures the worst 
clinical assessment for the previous day. If the site is aware of a subject death after the day 29 visit 
but within the window of the Day 29 study visit (i.e., Day 29 + 6-day window), complete an ordinal 
scale assessment on the day after death. 
 
After a subject is discharged, clinical status as measured by ordinal scale will be collected on 
remaining outpatient visits (Day 15, 22, 29, and 60). The ordinal scale can be assessed at an in-
person clinic visit or by phone, home visit or remote telehealth procedure as per institutional 
standards if an in-person visit at the clinical trial site is not possible.  
 
Ordinal scale is an assessment of death or the highest ventilatory support received in the last 24- 
hour period and therefore can be assessed at any time on the subsequent day. The following 
measures are recorded for the ordinal scale. See MOP for more detailed description of ventilatory 
devices in each category: 
 
• Hospitalization. 
• Oxygen requirement. 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix D - ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 153 of 172 
• Non-invasive ventilation requirement (CPAP, BiPAP). 
• High flow oxygen requirement. 
• Invasive mechanical ventilation (via endotracheal tube or tracheostomy tube) 
requirement. 
• ECMO requirement. 
• Ongoing medical care preventing hospital discharge (COVID-19 related or other medical 
conditions). 
• Limitations of physical activity (self-assessed and reported as new or increased 
limitations as compared to status prior to the onset of COVID-19). 
• Isolated for infection control purposes. 
 
 Ordinal Scale 
The ordinal scale is used as the primary clinical assessment of subjects during the study.  
 
The scale used in this study is as follows (from worst to best): 
Category 8: Death; 
Category 7: Hospitalized, on invasive mechanical ventilation or ECMO; 
Category 6: Hospitalized, on non-invasive ventilation or high flow oxygen devices; 
Category 5: Hospitalized, requiring supplemental oxygen; 
Category 4: Hospitalized, not requiring supplemental oxygen – requiring ongoing medical 
care (COVID-19 related or otherwise); 
Category 3: Hospitalized, not requiring supplemental oxygen – no longer requires ongoing 
medical care. This would include those kept in hospital for quarantine/infection control, 
awaiting bed in rehabilitation facility or homecare, etc.; 
Category 2: Not hospitalized, but has new or increased limitation on activities and/or new or 
increased requirement for home oxygen over baseline, pre-COVID-19 status; 
Category 1: Not hospitalized, patient is back to their baseline, pre-COVID-19 status, that is, 
no new or increased limitations on activities and no new or increased oxygen use compared 
with baseline. 
 
As is described in the clinical MOP, specific definitions of ventilatory support for Category 6 and 
5 include:  
Category 6:  
• Non-invasive ventilation includes: CPAP without invasive ventilation (CPAP mask or nasal 
cup devices)  
• BiPAP  
High-flow oxygen device includes:  
• High Flow Nasal Cannula (HFNC): delivers heated and humidified oxygen, with a 
controlled fraction of inspired oxygen (FiO2), at a flow rate of 16 L/min or greater per 
minute via a nasal cannula  
 
Category 5:  
Low-flow oxygen devices provide the delivery of FiO2 at a maximum of 15 liters per minute 
or less and generally less than five liters per minute and include:  
• Non-rebreather mask  

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix D - ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 154 of 172 
• HHFS – high humidified face shield  
• Standard nasal cannula  
• Venturi mask  
• High flow nasal cannula (15 L/min or less) 
• Oxymizer  
 
To determine a subject’s clinical status using the ordinal scale:  
• At randomization, the ordinal scale will be assessed and should reflect a subject’s clinical 
status at the time of randomization. As there should be <24 hours between randomization 
and first study product administration, the ordinal scale done at randomization suffices as 
the Day 1 ordinal scale.  
• After Day 1, collect the ordinal scale daily while hospitalized from Day 2 through Day 29 
by providing the worst clinical assessment for the previous day (i.e., midnight to midnight; 
00:00 – 23:59 (24-hr clock)). For example, on study Day 3 when completing the form, the 
worst clinical outcome measure of Day 2 is captured with the worst being death followed 
by ECMO, mechanical ventilation, etc. The Day 2 measurement is assessed as occurring 
anytime in that 24-hour period (00:00 to 23:59). For those who are discharged prior to Day 
15, collect ordinal scale on follow-up Days 15, 22 and 29 by providing the worst clinical 
assessment for the previous 24-hour period (00:00 to 23:59).  
 
Chronic use of home CPAP and BiPAP pre-COVID-19:  
If a patient’s need for CPAP or BiPAP is a new requirement since enrollment and used to treat 
COVID-19 (illness), a subject should be categorized as a Category 6. If CPAP is used for another 
indication prior to COVID-19 (e.g., non-COVID-19 indication like sleep apnea or BiPAP for 
COPD), this should be considered as their baseline, pre-COVID-19 medical status, and use of these 
devices should not be considered when categorizing patients for ACTT. Patients who require low 
flow supplemental oxygen are an ordinal scale category 5 even if they get CPAP at night in the 
hospital for chronic diagnosis of sleep apnea. Patients who require high flow supplemental oxygen 
or have a new requirement for CPAP or new requirement for BiPAP are an ordinal scale category 
6.  
 
It is important to capture all deaths that occur during the study as this is one of the outcomes of the 
study. Death is a category on the ordinal scale. If a subject dies during the study, the site will need 
to complete an ordinal scale assessment for the day after death. If a subject dies within the window 
of the final study visit (i.e., Day 29 + 6-day window), complete an ordinal scale assessment on the 
day after death. For more information about the data collected for the ordinal scale, see the MOP. 
 
For more information about the data collected for the ordinal scale, see the MOP. 
 
National Early Warning Score (NEWS) 
NEWS has demonstrated an ability to discriminate subjects at risk of poor outcomes. (Smith, 
2016). This score is based on 7 clinical parameters (see Table 5). In ACTT-4, the NEWS is being 
used as a severity of illness scores and should be evaluated at baseline (Day 1) only. The 7 
parameters can be obtained from the hospital chart or electronic medical record (EMR) using 
measurements taken prior to first study product administration. A numeric score is given for each 
parameter (e.g., a RR of 9 is one point, oxygen saturation of 92 is two points). Typically, ECMO 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix D - ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 155 of 172 
and mechanically ventilated subjects should be assigned a score of 3 for RR (RR <8) regardless 
of the ventilator setting. Subjects on ECMO should get a score of 3 for heart rate since they are 
on cardiopulmonary bypass. However, given that in ACTT-4 the NEWS is done at baseline only, 
no patients should be on ECMO or mechanically ventilated on Day 1. 
 
Table 5. National Early Warning Score (NEWS) 
 
  Level of consciousness = alert (A), and non-alert and arousable only to voice (V) or pain (P), and 
unresponsive (U).  
 
 
 Exploratory assessments 
As part of an exploratory endpoint, all subjects will be called at Day 60 (see SOA). During this 
visit conducted by phone call, remote telemedicine visit, or in-person visit, the site will ask the 
subject for information about their health status including current use of supplemental oxygen 
and physical disabilities to determine ordinal score. The site will also ask the subject whether 
they were readmitted to a hospital since Day 29 (or their last visit). They will also be asked about 
any new diagnoses including deep venous thrombosis (DVT), infections, post-traumatic stress 
disorder (PTSD), anxiety and/or depression. The data collection form will be used as a guide for 
this visit. Sites may review the medical record if there is uncertainty about the subject-reported 
diagnoses at the Day 60 visit especially if these occurred as part of a hospital readmission or 
healthcare visit. Sites may review the medical record to collect information at Day 60 if they are 
unable to contact the subject or if the subject has died. If the subject is admitted at Day 60, the 
Day 60 visit may be conducted in person. 
 
 
Exploratory Assessments and Secondary Research Samples 
The schedule of assessments (SOA, Section 1.2) lists the collection timepoints for specimens for 
both exploratory endpoints and for secondary research. Sites may opt out of specimen collection 
for secondary research; only serum is collected for secondary research. Subjects will be consented 
for genetic testing for the second exploratory endpoint. Sites will draw blood (via PAXgene tube) 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix D - ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 156 of 172 
for subjects who consent to genetic testing. Proteomic (cytokines and other protein) analysis will 
be done for all subjects using plasma or serum drawn per the schedule outlined in the SOA. In 
some cases, serum may be substituted for plasma for cytokine analyses (upon approval by the 
Sponsor). Data from exploratory assessments may not be submitted as part of the primary Clinical 
Study Report (CSR) for this trial. The data may be submitted separately as one or more addenda 
to the primary CSR. 
 
It is preferred that these samples are collected and sent to the NIAID repository to be tested in one 
central laboratory. Current US Centers for Disease Control and Prevention (CDC) guidance is 
these samples can be processed in a Biosafety Laboratory (BSL) 2 environment. However, 
institutions may impose restrictions on processing the samples (i.e., they may require BSL-3) or 
there may be restrictions on sending samples. In these circumstances, the following apply: 
 
Blood for plasma  
• If the samples can be processed but cannot be sent to the repository, the samples may be 
stored locally.  
• The sponsor may elect to have some of these samples run locally, pending confirmation 
of the assays to be used and the qualifications of the local laboratory. The sponsor will 
work with the site to determine when this could occur and how these data can be 
imported into the study database.  
• If a BSL-3 environment is needed for processing these samples, these samples may be 
omitted.  
 
Oropharyngeal or Nasopharyngeal/nasal specimen 
• If the samples can be processed but cannot be sent to the repository, the samples may be 
stored locally.  
• The sponsor may elect to have some, or all of these samples run locally, pending 
confirmation of the assays to be used and the qualifications of the local laboratory. The 
sponsor will work with the site to determine when this could occur and how these data 
can be imported into the study database.  
• If a BSL-3 environment is needed for processing these samples, these samples may be 
omitted.  
 
Whole blood for transcriptomics analysis  
• Subjects who consent to genetic testing will have a whole blood sample (~2.5 mL in 
PAXgene tube)). 
• These samples will be tested in a central laboratory, not locally. 
 
Blood for serum 
• If the samples can be processed but not sent to the repository, the samples may be stored 
locally.  
• If a BSL-3 environment is needed for processing these samples, these samples may be 
omitted.  
 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix D - ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 157 of 172 
 
SARS-CoV-2 Virology Exploratory Assessment 
As outlined on the SOA, OP samples (collected by swab) and plasma and serum will be collected 
on Day 1; and Days 3, 5, 8, and 11 (while hospitalized) and Day 29; and only OP swabs and serum 
on Day 15 (if attends an in-person visit or still hospitalized). Samples are stored as outlined in the 
MOP. Virologic assessments may include PCR or other nucleic acid tests for duration of viral 
RNA, viral load determination and/or the emergence of antiviral resistance.  
 
OP samples are preferred, but if these are not obtainable, nasopharyngeal (NP) samples (collected 
by NP swab) or nasal swab may be substituted. Due to limited lack of swabs and other supplies at 
some sites and limitations on personal protective equipment (PPE), the inability to obtain these 
samples are not considered protocol deviations and should be documented in the subject’s record.  
 
 
Immunophenotyping Exploratory Assessment  
As outlined in the SOA, blood will be collected for a plasma proteomic analysis of cytokines, 
chemokines, markers of inflammation, and other circulating proteins in all patients. Whole blood 
(PAXgene tubes) for a transcriptomic analysis of RNA will be collected for those who consent for 
genomic testing. All sites should collect PAXgene tube for subjects consenting to have their 
samples used for the targeted genetic analysis. Samples will be collected, processed and stored as 
described in the MOP. If a BSL-3 environment is needed for processing of these samples, or if 
samples cannot be shipped to a central laboratory, these samples may be omitted, and the omission 
documented each time.  
 
Blood for plasma for proteomic analysis 
An aliquot of the collected plasma will be analyzed for cytokines, chemokines, markers of 
inflammation and other circulating proteins on Days 1, 3, 5, 8 and 11 and Day 29 (see SOA for 
details). This blood volume is not an additional 0.5 mL but considered as part of the mL plasma 
taken on these days. A subset will have the sample processed using a high-throughput proteomic 
assay. The remainder of subjects will have their samples processed using an antibody-based assay 
for cytokines.  
 
Whole blood for transcriptomics analysis 
Subjects who consent to genetic testing will have a whole blood sample (~2.5 mL in PAXgene 
tube) analyzed using an RNA sequencing assay (RNA-Seq, Illumina). Transcriptomics analysis 
will be done on Days 1, 3 and 8, and Day 29 (if attends in-person visit or still hospitalized) (See 
SOA for details). Subjects who consent to genetic testing and are discharged prior to Day 8 and 
therefore miss the PAXgene tube collection at Day 8, this sample will be drawn at Day 15. Analysis 
may include, but not limited to the following assessments depending on the sample quality and 
quantity.  
• Cellular transcriptional activity in immune cell subsets as analyzed by RNA-seq or 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix D - ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 158 of 172 
microarrays;  
• Whole blood transcriptome as analyzed by RNA-seq; 
• Single-cell transcriptome as analyzed by RNA-seq or CITE-seq. 
 
Description of blood collection in PAXgene tubes for RNA are provided in the MOP. 
 
Proposed Timing of Samples for Immunophenotyping Exploratory Objective  
The estimated peak of pathological inflammation is 21 days post-symptom onset. In ACTT-3, 
patients were not enrolled until 7 to 10 days post-symptom onset. For this reason, we propose 
samples be taken Days 1, 3 and 8 (or if discharged prior to Day 8 then blood is drawn at Day 15) 
and then at Day 29. See table below for projected blood volumes for PAXgene sample collection.  
 
 
Table 6. Blood Volume for Subjects Consenting for Genetic Testing Involving PAXgene 
Collection 
Study Day 
Transcriptomics analysis 
1 
2.5 mL blood, PAXgene blood RNA tube 
 
3 
2.5 mL blood, PAXgene tube 
5 
None 
8 
2.5 mL blood, PAXgene tube 
11 
None 
15 
None (unless missed Day 8) 
29 
2.5 mL blood, PAXgene tube 
 
8.2 
Safety and Other Assessments 
 
Study procedures are specified in the SOA. A study physician licensed to make medical diagnoses 
and listed on the 1572 will be responsible for all trial-related medical decisions. 
 
Physical examination:  
A targeted physical examination will be performed at baseline prior to initial study product 
administration on Day 1. The baseline physical examination can be one that is conducted from 
screening to Day 1. No routine physical exam is needed for study visits after Day 1. The physical 
examination DCF will include recording the National Emergency Warning System (NEWS) score 
and whether or not radiographic infiltrates were identified by imaging studies (chest xray, CT 
scan). 
 
Study staff at some sites are not allowed into the subject’s rooms due to a limited supply of PPE 
and the need for strict respiratory isolation measures for COVID-19 patients. Because of limited 
access to subjects, physical exams can be performed by any licensed provider at the study hospital 
even if they are not study staff listed on the 1572. The study team can extract information from the 
hospital chart or EMR.  
 
Clinical laboratory evaluations: 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix D - ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 159 of 172 
• Fasting is not required before collection of laboratory samples. 
• Blood will be collected at the time points indicated in the SOA.  
• Clinical safety laboratory tests include WBC, differential, Hgb, PLT, creatinine, 
glucose, total bilirubin, AST, ALT, and INR.  
• D-dimer, and C-reactive protein are drawn on the same days as the safety 
laboratory tests but are not safety labs and should not be graded. See SOA.  
• Day 1 clinical laboratory evaluations are drawn prior to initial study product 
administration as a baseline and results do not need to be reviewed to determine if 
initial study product administration should be given.  
• On Day 1, Vitamin D levels will be assessed. These will be used to evaluate 
outcomes and should not be graded. 
• Clinical laboratory testing will be performed at each clinical trial site in real time.  
 
 
Table 7. Venipuncture Volumes for Subjects NOT Consenting for Genetic Testing 
Involving Transcriptomics Analysis 1 
 
Screen 
Baseline 
 
 
 
 
 
 
Day +/- Window 
−1 to 1 
1 ± 1 
3 ± 1 
5 ±1 
8 ± 1 
11 ± 1 
15 ± 2 
29 + 6 
Screening and Safety 
hematology, chemistry 
and liver tests 
 
X 
10mL2 
X 
10mL2 
X 
10mL2 
X 
10mL2 
X 
10mL2 
X 
10mL2 
 X3 
10mL2 
X3 
10mL2 
Blood for Serum 
 
 
X 
24mL 
X 
24mL 
X 
24mL 
X 
24mL 
X 
24mL 
X 
24mL 
X 
24mL 
Plasma  
 
 
X 
4mL 
X 
4mL 
X 
4mL 
X 
4mL 
X 
4mL 
 
X 
4 mL 
Total volume 
10mL 
38mL 
38mL 
38mL 
38mL 
38mL 
34mL 
38mL 
Total all study days 
 
 
 
 
 
 
 
~272 
mL 
1. See SOA in Section 1.2 for specific tests to be performed. 
2. Total volume calculated assumes there are no routine clinical laboratory tests were done within 48 hours of 
screening that can be used for determining eligibility (screening tests), or within 36 hours prior to first dose that can 
be used for baseline (Day 1) safety laboratory tests. In addition, it assumes there were no routine clinical laboratory 
tests done within the specified window for visits post baseline on Days 1, 3, 5, 8, and 11, and Days 15 and 29.  
3. Safety laboratory tests will be collected on Day 15 and 29 if the subject is still hospitalized at these time points or 
if they return for an in-person outpatient visit and the site has the capacity to collect blood in the outpatient setting. 
 
Table 8. Venipuncture Volumes for Subjects Consenting for Genetic Testing Involving 
Transcriptomics Analysis 1 
 
Screen 
Baseline 
 
 
 
 
 
 
Day +/- Window 
−1 to 1 
1 ± 1 
3 ± 1 
5 ±1 
8 ± 1 
11 ± 1 15 ± 2 
29 + 6 
Screening and Safety 
hematology, chemistry, 
liver tests 
X 
10mL2 
X 
10mL2 
X 
10mL2 
X 
10mL2 
X 
10mL2 
X 
10mL2 
X3 
10mL2 
X3 
10mL2 
Blood for Serum 
 
X 
24mL 
X 
24mL 
X 
24mL 
X 
24mL 
X 
24mL 
X 
24mL 
X 
24mL 
Plasma  
 
X 
4 mL 
X 
4mL 
X 
4 mL 
X 
4 mL 
X 
4 mL 
 
--- 
X  
4 mL 
Blood in PAXgene tube 
 
X 
2.5 mL 
X 
2.5 mL 
--- 
X 
2.5 mL 
--- 
(X)4 
--- 
X 
2.5 mL 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix D - ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 160 of 172 
Total volume if involved 
in exploratory analysis 
10mL 
40.5mL 
40.5mL 
38mL 
40.5mL 
38mL 
34mL 
40.5mL 
Total all study days 
 
 
 
 
 
 
 
~282mL 
1. See SOA in Section 1.2 for specific tests to be performed. 
2. Total volume calculated assumes there are no routine clinical laboratory tests were done within 48 hours of 
screening that can be used for determining eligibility (screening tests), or within 36 hours prior to first dose that can 
be used for baseline (Day 1) safety laboratory tests. In addition, it assumes there were no routine clinical laboratory 
tests done within the specified window for visits post baseline on Days 1, 3, 5, 8, and 11, and Days 15 and 29.  
3. Safety laboratory tests will be collected on Day 15 and 29 if the subject is still hospitalized at these time points or 
if they return for an in-person outpatient visit and the site has the capacity to collect blood in the outpatient setting. 
4. If subject discharged prior to Day 8 (i.e., PAXGene tube not collected) site will collect Day 8 samples at Day 15 
follow-up visit. 
 
 
 
Procedures to be Followed in the Event of Abnormal Laboratory Test Values or 
Abnormal Clinical Findings 
If a physiologic parameter (e.g., vital signs, or laboratory value) is outside of the protocol-
specified range, then the measurement may be repeated once if, in the judgment of the 
investigator, the abnormality is the result of an acute, short-term, rapidly reversible condition or 
was an error. A physiologic parameter may also be repeated if there is a technical problem with 
the measurement caused by malfunctioning or an inappropriate measuring device (i.e., 
inappropriate-sized BP cuff). 
 
 
Unscheduled Visits 
If clinical considerations require the subject to be contacted or seen prior to the next schedule 
assessment to assure the subject’s well-being, it is permissible in this protocol. However, no 
research data is collected at this visit.  
8.3 
Adverse Events and Serious Adverse Events 
 
Definition of Adverse Event (AE) 
AE means any untoward medical occurrence associated with the use of an intervention in humans, 
whether or not considered intervention related. If multiple abnormalities are part of the same 
clinical syndrome, they can be reported together as one AE under a unifying clinical diagnosis. 
 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of medicinal (investigational) 
product. For example, worsening respiratory status from Grade 2 (respiratory distress) at Day 1 to 
Grade 4 (respiratory failure) at Day 5 is a condition temporarily associated with use of an 
intervention and by definition is an AE and should be reported even if the investigator believes 
that this is part of the natural history of the disease.  
 
All study required solicited safety laboratory test results will be recorded into the eCRF including 
all Grade 1 and 2 abnormalities. As the Grade 1 and 2 abnormalities are tracked and available 
within the data system, the Grade 1 and 2 laboratory abnormalities are not expected to be reported 
as adverse events. 
 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix D - ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 161 of 172 
Given the severity of the underlying illness, subjects will have many symptoms and abnormalities 
in vital signs and laboratory values. As COVID-19 is an emerging, systemic disease involving not 
only the upper and lower respiratory tract, but also the gastrointestinal tract, cardiovascular system, 
endothelial cells, and central nervous system (olfactory neurons), it is important to document 
respiratory AE as well as AEs involving other systems. New symptoms not part of the subject’s 
COVID-19 syndrome at Day 1, should be captured as adverse events. For example, if a subject 
develops new grade 3 gastrointestinal symptoms after Day 1, the gastrointestinal symptoms should 
be reported.  
 
For ACTT-4, the AE reporting window begins with the initial administration of the first study 
product and ends on the Day 29 visit  (i.e., not from the time the ICF is signed as in ACTT-2). Any 
medical condition that is present at the time that the subject signs the ICF will be considered as 
baseline and not reported as an AE. However, if the severity of any pre-existing (at baseline) 
medical condition increases above baseline to severity grade 3 or 4, it should be recorded as an 
AE. The start date for reporting of an AE/SAE is the date the AE became a Grade 3 AE. In addition, 
the following AEs will be reported: 
• Any clinically significant (can be Grade 2 or higher) suspected drug-related 
hypersensitivity reactions associated with study product administration will be reported 
as an AE; 
• Any VTE, defined as PE or DVT, that occur at any time during the study. This does not 
include superficial venous thrombosis. Note: as per the DAIDS toxicity table, thrombosis 
or embolism are Grade 2, 3, 4 and Grade 5 (death) events. 
 
Unsolicited laboratory values collected as part of standard of care, will need to be reported only if 
Grade 3 or above and only if clinically significant and/or part of a diagnosis or a clinical syndrome. 
In this case, if laboratory and vital sign abnormalities are part of the clinical syndrome, they should 
be reported as one AE under one clinical diagnosis or syndrome. Example: Low oxygen 
level/arterial blood gases could be part of respiratory failure diagnosis. 
 
Intermittent abnormal laboratory values or vital sign measurements common in the severely ill 
populations (such as electrolyte abnormalities, low blood pressure, hyperglycemia, etc.) that are 
part of the same clinical diagnosis (e.g., uncontrolled diabetic) can be recorded once with the 
highest grade for each adverse event (grade 3 and 4 only for this trial), with the start and stops 
dates of the intermittent syndrome. If there is clear resolution of the event, and then recurrence, it 
should be treated as a separate adverse event. Resolution is defined as return to baseline (either 
normal if was normal at Day 1, or baseline (Day 1) grade if already an abnormality on the toxicity 
table at Day 1) for > 48 hours.  
 
D-dimer, CRP and Vitamin D levels should not be graded. D-dimer and CRP are collected on the 
same schedule as the safety laboratory tests and Vitamin D is collected on Day 1 only (see the 
SOA). However, these parameters will be used in the assessment of study outcomes.  
 
Standardized reporting of AE is essential to interpretation of data between clinical trial sites in 
multi-site clinical trials. The following recommendations are the result of an internal evaluation of 
safety data collected during ACTT-1 and ACTT-2. 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix D - ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 162 of 172 
• Medical conditions that rise to the level of an AE should be reported as an AE and not the 
procedure used to treat that condition. For example, “respiratory failure with ventilator 
support indicated” should be reported as a Grade 4 respiratory failure AE per the DAIDS 
toxicity table versus reporting an intubation (a surgical procedure) as an AE. 
• Clinical syndromes should be reported rather than each symptom, vital sign, or laboratory 
abnormality separately. For example, respiratory failure should be reported as an AE rather 
than separately reporting respiratory acidosis, hypotension, hypoxia; or AKI should be 
reported instead of low eGFR, high creatinine level and CRRT dialysis procedure. 
• Adverse events that worsen from baseline at Day 1 to a Grade 3 or Grade 4 AE or SAE 
during the study should be reported. This includes worsening of respiratory signs and 
symptoms. An AE is any untoward medical occurrence associated with the use of an 
intervention (including investigational products), whether or not considered intervention 
related. This means that the condition may be associated with the underlying disease 
process (COVID-19), but we would still report as an AE.  
• Readmissions that are due to worsening of medical conditions and requiring inpatient 
hospitalization are SAEs by a definition and should be reported. Readmissions for social 
reasons and not for worsening of medical condition (e.g., readmissions of nursing home 
residents or homeless readmitted for monitoring purposes only) is not an SAE. 
 
 
Definition of Serious Adverse Event (SAE) 
An AE or suspected adverse reaction is considered serious (i.e., is an SAE) if, in the view of 
either the investigator or the Sponsor, it results in any of the following outcomes: 
• Death;  
• A life-threatening AE; 
• Inpatient hospitalization or prolongation of existing hospitalization; 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions; or 
• A congenital anomaly/birth defect. 
 
Grade 4 AEs (potentially life-threatening events) are not always SAEs unless they are imminently 
life threatening.  
 
Important medical events that may not meet the above criteria may be considered serious when, 
based upon appropriate medical judgment, they may jeopardize the subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples 
of such medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias, convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse. 
 
“Life-threatening” refers to an AE that at occurrence represents an immediate risk of death to a 
subject. An event that may cause death if it occurs in a more severe form is not considered life-
threatening. Similarly, a hospital admission for an elective procedure is not considered a SAE. 
 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix D - ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 163 of 172 
All SAEs, as with any AE, will be assessed for severity and relationship to study intervention. 
 
All SAEs will be recorded on the AE CRF and reported to DMID (see Section 8.3.6). 
 
All SAEs will be followed through resolution or stabilization by a licensed study physician (for 
IND studies, a physician listed on the Form FDA 1572 as the site PI or Sub-Investigator). 
 
All SAEs will be reviewed and evaluated by DMID and will be sent to the DSMB (for periodic 
review), and the IRB/IEC. 
 
Suspected Unexpected Serious Adverse Reactions (SUSAR) 
A SUSAR is any SAE where a causal relationship with the study product is at least reasonably 
possible but is not listed in the Investigator Brochure (IB), Package Insert, and/or Summary of 
Product Characteristics. 
 
Classification of an Adverse Event 
The determination of seriousness, severity, and causality will be made by an on-site investigator 
who is qualified (licensed) to diagnose AE information, provide a medical evaluation of AEs, 
and classify AEs based upon medical judgment. This includes but is not limited to physicians, 
physician assistants, and nurse practitioners. 
 Severity of Adverse Events 
All AEs and SAEs will be assessed for severity using the DAIDS Table for Grading the Severity 
of Adult and Pediatric Adverse Events, version 2.1 (July 2017).  
 
For AEs not included in the Table, the following guidelines will be used to describe severity. In 
addition, all deaths related to an AE are to be classified as grade 5 according to the DAIDS Table.  
 
• Moderate (Grade 2): Events that are usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual activities of daily living and 
causes discomfort but poses no significant or permanent risk of harm to the research 
subject. 
 
• Severe (Grade 3): Events that interrupt usual activities of daily living, or significantly 
affect clinical status, or may require intensive therapeutic intervention. Severe events are 
usually incapacitating. 
 
• Potentially life-threatening event (Grade 4): Events that are potentially life threatening. 
 
 
• Deaths (Grade 5): All deaths related to an AE are classified as grade 5 (per DAIDS 
Table). 
 
 Relationship to Study Intervention 
For each reported adverse reaction, the PI or designee must assess the relationship of the event to 
each study product using the following guideline: 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix D - ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 164 of 172 
 
• Related – There is a temporal relationship between the study intervention and event, and 
the AE is known to occur with the study intervention or there is a reasonable possibility 
that the study intervention caused the AE. Reasonable possibility means that there is 
evidence to suggest a causal relationship between the study intervention and the AE. 
 
• Not Related – There is not a reasonable possibility that the administration of the study 
intervention caused the event, there is no temporal relationship between the study 
intervention and event onset, or an alternate etiology has been established. 
 
 
Time Period and Frequency for Event Assessment and Follow-Up 
For this study, all Grade 3 and 4 AEs, and all SAEs occurring from the time the first study product 
is initially given on Day 1 through the Day 29 visit will be documented, recorded, and reported. 
 
 Investigator Reporting of AEs 
Information on AEs will be recorded on the appropriate CRF. All clearly related signs, 
symptoms, and procedures performed because of an AE should be grouped together and recorded 
as a single diagnosis. If the AE is a laboratory abnormality that is part of a clinical condition or 
syndrome, it should be recorded as part of the syndrome or diagnosis rather than the individual 
laboratory abnormality. If a clinical site does not have an upper limit of normal (ULN) or a lower 
limit of normal (LLN) for a graded laboratory parameter (e.g., INR), the site will follow the 
reference range as outlined in the MOP.  
 
Each AE will also be described in terms of duration (start and stop date), severity, association with 
each study product (i.e., baricitinib/po placebo versus dexamethasone/IV placebo versus 
remdesivir infusion), the action(s) taken, and outcome. 
 
Any new infection that occurs on study, regardless of infecting agent (i.e., viral or non-viral) will 
be captured if it is a Grade 3 or 4 AE or SAE. Completion of the Infection Follow-up eCRF page 
is required for each infection reported as an adverse event or SAE with site of infection and source 
of culture provided, if available. The purpose is to document the occurrence of new infections by 
type of infection and not the duration of the new infections. Therefore, capture the first positive 
result(s) for the new infection (e.g., blood or urine culture, molecular diagnostic test result, etc.); 
there is no need to capture repeatedly positive results unless there is a new pathogen identified 
from the same site (e.g., blood) during the infection event. The sponsor will identify infections 
considered to be opportunistic based on Winthrop et al. 2015. 
 
 
Serious Adverse Event Reporting 
 Investigators Reporting of SAEs 
Any AE that meets a protocol-defined criterion as an SAE that is judged to be related to any study 
product must be submitted within 24 hours of site awareness on an SAE form to the DMID 
Pharmacovigilance Group, at the following address:  

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix D - ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 165 of 172 
 
DMID Pharmacovigilance Group 
Clinical Research Operations and Management Support (CROMS) 
6500 Rock Spring Dr. Suite 650 
Bethesda, MD 20817, USA 
SAE Hot Line: 1-800-537-9979 (US) or +1-301-897-1709 (outside US) 
SAE FAX Number: 1-800-275-7619 (US) or +1-301-897-1710 (outside US) 
SAE Email Address: PVG@dmidcroms.com 
 
Other supporting documentation of the event may be requested by the DMID Pharmacovigilance 
Group and should be provided as soon as possible. The DMID Medical Monitor will review and 
assess the SAE for regulatory reporting and potential impact on study subject safety and protocol 
conduct. At any time after completion of the study, if the site PI or appropriate sub-investigator 
becomes aware of an SAE that occurred during the subject’s participation in the study, the site PI 
or appropriate sub-investigator will report the event to the DMID Pharmacovigilance Group. 
 
SAEs that that are judged to be not related to study product are still captured on the AE case report 
form, but do not require separate reporting to the DMID Pharmacovigilance Group. 
 
 Regulatory Reporting of SAEs 
Following notification from the site PI or appropriate sub-investigator, DMID, as the IND Sponsor, 
will report any SUSAR in an IND safety report to the FDA and will notify all participating site PIs 
as soon as possible. DMID will report to the FDA any unexpected fatal or life-threatening 
suspected adverse reaction as soon as possible, but in no case later than 7 calendar days after the 
Sponsor’s initial receipt of the information. If the event is not fatal or life-threatening, the IND 
safety report will be submitted within 15 calendar days after the Sponsor determines that the 
information qualifies for reporting as specified in 21 CFR Part 312.32. Relevant follow up 
information to an IND safety report will be submitted as soon as the information is available. Upon 
request from the FDA, DMID will submit to the FDA any additional data or information that the 
agency deems necessary, as soon as possible, but in no case later than 15 calendar days after 
receiving the request. 
 
SAEs that are not SUSARs will be reported to the FDA at least annually in a summary format 
which includes all SAEs. 
 
Sites may have additional local reporting requirements (to the IRB and/or national regulatory 
authority). 
 
Reporting of Pregnancy 
Pregnancy is not an AE. However, any pregnancy that occurs during study participation should 
be reported to the Sponsor on the appropriate CRF. Pregnancy should be followed to outcome.  
8.4 
Unanticipated Problems 
 
Definition of Unanticipated Problems 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix D - ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 166 of 172 
An Unanticipated Problem (UP) is any event, incident, experience, or outcome that meets the 
following criteria: 
• Unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the IRB-approved research 
protocol and informed consent document; and (b) the characteristics of the subject 
population being studied; 
 Related to participation in the research (meaning there is a reasonable possibility that the 
incident, experience, or outcome may have been caused by the procedures involved in the 
research); and 
 Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
 
Unanticipated Problem Reporting 
To satisfy the requirement for prompt reporting, all UPs will be reported using the following 
timeline: 
 UPs that are SAEs will be reported to the IRB and to the Statistical and Data 
Coordinating Center (SDCC)/study Sponsor within 24 hours of the investigator becoming 
aware of the event per the above describe SAE reporting process. 
 Any other UP will be reported to the IRB and to the SDCC/study Sponsor within 3 days 
of the investigator becoming aware of the problem. 
9. 
STATISTICAL CONSIDERATIONS 
9.1 
Statistical Hypotheses 
The null hypothesis of no difference in the proportion of patients surviving without requiring 
invasive mechanical ventilation between baricitinib/remdesivir and dexamethasone/remdesivir 
will be tested using a superiority test.  
 
A key secondary hypothesis will test whether the distribution of the 8-point ordinal scale at Day 
15 differs between baricitinib/remdesivir and dexamethasone/remdesivir. For this key secondary 
hypothesis, the parameter of interest is the “common odds ratio,” which quantifies the shift in the 
severity distribution resulting from treatment. The null hypothesis to be tested is that the odds of 
improvement on the ordinal scale is the same for the control and experimental treatment arms 
(i.e., the common odds ratio is 1). An odds ratio greater than 1 quantifies an improvement in 
disease severity for the experimental treatment relative to its control. It is worth noting that, for 
large sample sizes, the test based on the proportional odds model is nearly the same as the 
Wilcoxon rank sum test. 
 
9.2 
Sample Size Determination 
The primary hypothesis will be a test of the difference in proportions surviving without requiring 
invasive mechanical ventilation between the two treatment arms by Day 29. Estimating the 
expected treatment effect of baricitinib relative to dexamethasone is difficult given the 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix D - ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 167 of 172 
differences between the ACTT-2 and RECOVERY studies as discussed above. In Table 9 , the 
first row of treatment effects is based on estimates from the ACTT-2 and RECOVERY results 
amongst the cohort that most closely resembles the ACTT-4 target population (those in ordinal 5 
and 6). In the second row, the relative findings were changed to assume a gradual improvement 
in standard of care. This corresponds to a sample size of 1382 subjects. Sample size calculations 
were based on an exact unconditional score test of proportions using StatXact v11.1.0. Assuming 
8% lost to follow-up, the sample size is planned to be approximately 1500 subjects.  
 
The remaining lines demonstrate the power of the proposed sample size. There is good power of 
this trial for multiple scenarios unless the proportions surviving without invasive mechanical 
ventilation is much higher than anticipated (thought to be unlikely) or the difference in the 
proportions is smaller than anticipated (possible, but difficult to anticipate given the data 
available).  
 
The formal analyses will be based on Kaplan-Meier estimates of the proportion of patients 
surviving without mechanical ventilation by Day 29 using a large sample normal approximation 
with Greenwood’s variance formula. Accordingly, power for the final analysis is assumed to be 
equal or slightly higher than the power for the exact score as seen below. 
 
Table 9: Sample size estimates and study power. 
Total Sample 
Size 
Proportion 
Dex Arm 
Surviving 
Through Day 
29 Without 
Mechanical 
Ventilation  
Proportion 
Bari Arm 
Surviving 
Through Day 
29 Without 
Mechanical 
Ventilation 
Power 
(unconditional 
exact score) 
Power (KM + 
Greenwood) 
- Baricitinib from ACTT-2 
(OS 5 and 6)  
- Dexamethasone relative 
efficacy (only those on 
oxygen) from RECOVERY 
applied to ACTT-2 placebo 
arm 
1342 
0.814 
0.87 
80.9% 
80.6% 
Estimate of the above 
proportion applied to current 
outcomes given gradual 
improvement in care 
1382 
0.85 
0.9 
80% 
80.5% 
 
Other scenarios showing 
study power for the sample 
size of 1382 
1382 
0.9 
0.95 
94.5% 
94.9% 
1382 
0.9 
0.925 
37.0% 
37.5% 
1382 
0.85 
0.925 
99.4% 
99.4% 
1382 
0.8 
0.875 
96.6% 
96.6% 
1382 
0.8 
0.85 
68.2% 
68.9% 
Note: two-sided type I error rate 5%; Exact unconditional score test of proportions. 
9.3 
Populations for Analyses 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix D - ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 168 of 172 
The primary analysis will be based on an intention-to-treat population, including all subjects 
randomized. Safety analyses will be based a modified intent-to-treat population consisting of all 
subjects who received at least one dose of any investigational product.  
An Endpoint Review Committee consisting of the DMID MO, her designees and the blinded 
statistical team may review endpoints, medications, deviations, and other special cases where 
expert opinion is requested for handling complicated cases. 
 
9.4 
Statistical Analyses 
 
General Approach 
This is a double-blind, placebo controlled randomized trial testing a superiority hypothesis with a 
two-sided type I error rate of 5%. Secondary hypotheses have been ordered according to relative 
importance, with one key secondary hypothesis highlighted. These will be described according to 
the appropriate summary statistics (e.g., proportions for categorical data, means, medians for 
time-to-event data) and 95% confidence intervals.  
 
A statistical analysis plan will be developed and filed with the study sponsor prior to unblinding 
of study and database lock.  
 
 
Analysis of the Primary Efficacy Endpoint 
The primary efficacy analysis is a test of superiority of the proportion invasive mechanical 
ventilation free survival between the two treatment arms at Day 29. The test statistic will be a 
large sample test of the difference in Kaplan-Meier based estimates of the 28-day probability of 
mechanical ventilation free survival with a two-sided type I error rate of 0.05. The test of 
difference will assume asymptotic normality and use Greenwood’s variance formula. (44)  
If null hypothesis for the overall population is rejected, the analysis will proceed to test the null 
hypothesis within each baseline ordinal scale subgroup following the strategy described below. 
 
 
Analysis of the Secondary Endpoint(s) 
1) The ordinal scale at Day 15 will be used to estimate a proportional odds model within 
different categories of the ordinal scale at baseline. The hypothesis test will perform a 
strata- adjusted test to evaluate whether the common odds ratio for treatment is equal to 
one. The distribution of severity results will be summarized by treatment arm as 
percentages. There will be efforts to minimize loss to follow-up. However, small amounts 
of missing data may occur. In such cases, outcomes may be imputed based on rules 
described in the SAP. Sensitivity analyses will evaluate the impact of making different 
assumptions about missing observations. These analyses will be defined in the SAP.  
 
2) Differences in time-to-event endpoints (e.g., time to recovery or time to at least a one 
category improvement in ordinal scale, time to death) by treatment will be summarized 
with Kaplan-Meier curves and 95% confidence bounds, using the Fine-Gray approach for 
competing events when appropriate.  
 
3) Analysis of mortality data will be evaluated using a Cox proportional hazards model.  

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix D - ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 169 of 172 
 
4) Desirability of outcomes response (DOOR). A revised ordinal scale has been constructed 
to incorporate SAEs. SAE may be related or unrelated to study product. Any SAE 
occurring after study product administration through Day 15 (or through Day 29) will be 
counted: 
 
1- Recovered (OS 1,2,3) 
2- Improved by at least 1 OS from baseline & no SAE 
3- Improved by at least 1 OS from baseline & SAE 
4- No change in OS from baseline & no SAE 
5- No change in OS from baseline & SAE 
6- Worsened by at least 1 OS from baseline 
7- Death (OS 8) 
*OS = ordinal scale score based on the 8-point scale 
 
This DOOR scale will be evaluated at Day 15 and Day 29, and between arm differences 
will be tested using a Mann-Whitney U-statistic.  
 
5) Change from baseline in ordinal scale at specific time points will be summarized by 
proportions (e.g., proportion who have a 1-, 2-, 3-, or 4-point improvement or 1-, 2-, or 3-
point worsening). 
 
6) Duration of event (e.g., duration of mechanical ventilation) will be summarized according 
to median days with quartiles and mean with SD. 
 
7) Binary data (e.g., incidence of new oxygen use) will be summarized as a percent with 
95% confidence intervals. Comparisons between arms will be presented as differences in 
proportions with 95% confidence intervals. 
 
8) Categorical data (e.g., 28-day mortality or ordinal scale by day) may be summarized 
according to proportions by category and/or odds ratios with confidence intervals.  
 
Procedures for handling missing data, including informative censoring (e.g., a missing 
duration of oxygen use endpoint due to a death), will be described in the SAP. 
 
 
Safety Analyses 
Safety endpoints include death through Day 29, SAEs and Grade 3 and 4 AEs. These events will 
be analyzed univariately and as a composite endpoint. Time-to-event methods will be used for 
death and the composite endpoint. Each AE will be counted once for a given subject and graded 
by severity and relationship to COVID-19 or study intervention. AEs will be coded using the 
current version of the Medical Dictionary for Regulatory Activities (MedDRA). AEs will be 
presented by system organ class, duration (in days), start- and stop-date. Adverse events leading 
to premature discontinuation from the study intervention and serious AEs will be presented 
either in a table or a listing.  
 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix D - ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 170 of 172 
 
Baseline Descriptive Statistics 
Baseline characteristics will be summarized by treatment arm. For continuous measures the 
mean and standard deviation will be summarized. Categorical variables will be described by the 
proportion in each category (with the corresponding sample size numbers).  
 
 
Planned Interim and Early Analyses  
A DSMB will monitor ongoing results to ensure subject well-being and safety as well as study 
integrity. The DSMB will be asked to recommend early termination or modification only when 
there is clear and substantial evidence of a treatment difference. More details about the interim 
analyses are described in section 9.4.6.1 and 9.4.6.2 below as well as a separate guidance 
document for the DSMB.  
 
 Interim Safety Analyses 
Safety analyses will evaluate Grade 3 and 4 AEs, SAEs, and all reportable VTE by treatment 
arm. Safety monitoring will be ongoing (see section 8.3). The unblinded statistical team will 
prepare these reports for review by the DSMB.  
 
 Interim Efficacy Review 
The speed of recruitment impacts the utility of an interim analysis to inform reporting of results. 
If enrollment occurs rapidly, an interim efficacy analysis for a primary outcome that requires 
waiting until Day 29 to assess could be of limited use. A considerable portion of the sample 
could be enrolled during the waiting period to assess outcomes and clean data and the DSMB 
review may occur with only a small percentage of the final sample size remaining to be enrolled.  
 
Therefore, the interim analysis for ACTT-4 will depend on the expected duration of enrollment. 
If full enrollment is expected within four months, no interim efficacy analyses are planned. This 
will be estimated by assessed by enrollment 1.5 months after first enrollment.  
• If the study reaches or exceeds 1/3 of total enrollment within 1.5 months (assumes 
slightly slower enrollment at the beginning), no interim efficacy analysis will be 
performed.  
• If the study does not reach 1/3 of total enrollment within1.5 months, an interim analysis 
will occur after the first third of enrolled subjects have reached Day 29.  The 28-day 
estimate will be based on a Kaplan-Meier estimator, which allows all subjects on-study to 
contribute data according to the amount of observation time contributed. The Lan-
DeMets spending function analog of the O’Brien-Fleming boundaries will be used to 
monitor the primary endpoint as a guide for the DSMB with an overall two-sided type-I 
error rate of 0.05. Accordingly, the planned efficacy stopping boundaries are 3.7307 
(33% information) and 1.9605 (100% information). Note that these values are 
approximate; the actual values will follow the prespecified error spending function and 
the information fractions determined by the analysis times. 
 
 
Subgroup Analyses 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix D - ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 171 of 172 
In addition to the planned subgroup analyses within each baseline ordinal scale, the following 
subgroup analyses for the primary outcomes are planned: geographic region, dexamethasone use 
prior to randomization, other steroid use prior to randomization, duration of symptoms prior to 
enrollment, age, race, sex and comorbidities. A forest plot will display confidence intervals 
across subgroups. Interaction tests will be conducted to determine whether the effect of treatment 
varies by subgroup. 
 
Exploratory Analyses 
An exploratory analysis will compare treatment efficacy estimates according to the various 
scales outlined in section 8.1.2. Specifically, the probability of falling into category “i” or better 
will be compared between arms for each i.  
 
Additional exploratory analyses will evaluate different scales for DOOR analyses that were 
described in 9.4.3 item 4. 
 
 
Multiplicity Adjustment 
A fixed sequence testing scheme will control the overall family-wise Type I error rate at a two-
sided  α level of 0.05.  If the primary hypothesis is rejected at two-sided α <0.05, hypothesis 
testing will proceed to four key secondary endpoints. Hypothesis testing will follow the fixed 
ordering below (see figure): 
 
1) Proportion not progressing to ordinal scale 7 or 8; 
2) Day 15 clinical improvement on ordinal scale;  
3) Proportion not progressing to ordinal scale 6, 7 or 8 (amongst baseline ordinal scale 5 
only);  
4) Overall mortality (Day 29); and 
5) Time to recovery (Day 29). 
 
Hypothesis testing will continue at the next endpoint with α = 0.05 only if the previous 
hypothesis is rejected at α=0.05. This method of carrying forward the α -level from the previous 
test is described in the FDA guidance on Multiple Endpoints in Clinical Trials 
[https://www.fda.gov/regulatory-information/search-fda-guidance-documents/multiple-
endpoints-clinical-trials-guidance-industry ].  
 

Protocol 20-0006 
Version 10.0 
Adaptive COVID-19 Treatment Trial (ACTT) 
 
18 Jan 2021 
Appendix D - ACTT-4: Baricitinib/Remdesivir vs Dexamethasone/Remdesivir 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 172 of 172 
 
 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS – ALL STAGES 
All supporting documentation and operational considerations are applicable to the entire 
platform trial and are not unique to the individual stages. These are therefore covered in the main 
protocol document.