Clinical trial NCT04590586
Conditions: COVID-19
Keywords: SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2
Sponsor: Amgen
Start date: 2020-11-24; Completion date: 2021-08-03
Enrollment: 515 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study is to evaluate the time to confirmed clinical recovery in participants hospitalized with COVID-19. Candidate agents will be evaluated frequently for efficacy and safety, with candidate agents being added to and/or removed from the study on an ongoing basis, depending on the results of their evaluation.

Detailed description:
This adaptive, randomized, placebo-controlled platform study is designed to rapidly assess multiple candidate agents as treatments for COVID-19 in hospitalized patients. Candidate agents will be evaluated frequently (through ongoing monitoring) for futility and safety, with candidate agents being added to and/or removed from the study on an ongoing basis, depending on the results of their evaluation.

For inclusion, participants will need to be hospitalized with a clinical status of Grade 2 to Grade 5, as defined by the following Clinical Severity Status 8-Point Ordinal Scale:

1. Death
2. Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO)
3. Hospitalized, on noninvasive ventilation or high-flow oxygen devices
4. Hospitalized, requiring supplemental oxygen
5. Hospitalized, not requiring supplemental oxygen, requiring ongoing medical care (COVID-19 related or otherwise)
6. Hospitalized, not requiring supplemental oxygen, no longer requires ongoing medical care
7. Not hospitalized, limitation on activities and/or requiring home oxygen
8. Not hospitalized, no limitations on activities

Participants will be randomized equally to either the candidate agent plus standard of care (SoC) or placebo plus SoC in a double-blind fashion. Participants who are randomized to placebo plus SoC will subsequently be randomized equally to a matching placebo corresponding to an available agent whose sub-protocol the patient qualified for (ie, a 2-stage randomization). Each participant in the placebo plus SoC group will only receive one type of placebo. Randomization will be stratified by baseline clinical severity of 2 on the 8-point ordinal scale (yes/no) and remdesivir use at baseline (yes/no).

The study will evaluate each candidate agent separately as an add-on to the SoC to assess safety and efficacy. The comparator group for a candidate agent will include participants randomized to the placebo arm of any sub-protocol according to the following conditions:

* Apremilast sub-protocol: participants who were enrolled concurrently to apremilast and who would have been eligible for the apremilast sub-protocol.
* Lanadelumab sub-protocol: at a site where at least one participant was randomized to either lanadelumab active or placebo arms.
* Zilucoplan sub-protocol: at a site where at least one participant was randomized to either the zilucoplan active or placebo arms.

Arms: arm 1: Participants will be randomized to receive 30 mg apremilast orally twice a day (BID) in addition to standard of care treatment for 14 days or until hospital discharge, death, or discontinuation of investigational product, whichever occurred first. arm 2: Participants will be randomized to receive matching placebo to apremilast orally twice a day in addition to standard of care treatment for 14 days or until hospital discharge, death, or discontinuation of investigational product, whichever occurred first. arm 3: Participants will be randomized to receive lanadelumab 300 mg by intravenous infusion on Day 1, and a second dose administered on Day 4 in addition to standard of care. arm 4: Participants will be randomized to receive placebo to lanadelumab by intravenous infusion on Day 1, and a second dose administered on Day 4 in addition to standard of care. arm 5: Participants will be randomized to receive 32.4 mg zilucoplan by subcutaneous injection every day for 14 days, or until discharge if discharge was before 14 days of treatment in addition to standard of care. arm 6: Participants will be randomized to receive placebo to zilucoplan by subcutaneous injection every day for 14 days, or until discharge if discharge was before 14 days of treatment in addition to standard of care.
Interventions: intervention 1: Standard of care intervention 2: Apremilast intervention 3: Apremilast placebo intervention 4: Lanadelumab intervention 5: Lanadelumab placebo intervention 6: Zilucoplan intervention 7: Zilucoplan placebo
Intervention descriptions: intervention 1: Standard of care (SoC) treatment for COVID-19 infection in line with institutional practice. The SoC may change as new information becomes available about treating COVID-19. intervention 2: Apremilast administered orally as a tablet. intervention 3: Matching apremilast placebo administered orally as a tablet. intervention 4: Lanadelumab administered as an intravenous (IV) infusion. intervention 5: Matching lanadelumab placebo (normal saline) administered as an intravenous (IV) infusion. intervention 6: Zilucoplan administered as a subcutaneous (sc) injection in the abdomen, thigh, or upper arm. intervention 7: Matching zilucoplan placebo administered as a subcutaneous (sc) injection in the abdomen, thigh, or upper arm.

Protocol documents:
Prot_000.pdf: 
CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
1 
TITLE PAGE 
Protocol Title: Industry Alliance Platform Trial to Assess the Efficacy and Safety of Multiple 
Candidate Agents for the Treatment of COVID-19 in Hospitalized Patients 
Master Protocol Number: COV-01 
Product: Multiple candidate agents 
Short Title: COVID-19 Multiple Agents and Modulators Unified Industry Members Trial 
(COMMUNITY) 
Study Phase: 3 
Sponsor Name: Amgen, Inc. 
Legal Registered Address: 
1 Amgen Center Drive 
Thousand Oaks, CA 91320, US 
 
Regulatory Agency Identifying Number(s): IND 150485 
 
 
 
 
 
 
EudraCT 2020-002594-10 
 
Date of Protocol: 16 April 2021 
Version: Protocol Amendment 4 
 
Responsible Medical Expert: 
 Amgen, Inc. 
 
PPD
 


CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
2 
Sponsor Signatory: 
 
 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
 
 
 
 
April 16, 2021 
 
 Amgen, Inc. 
 Date 
 
 
PPD
 
PPD


CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
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TABLE OF CONTENTS 
TABLE OF TABLES 
...............................................................................................................6 
TABLE OF FIGURES 
.............................................................................................................6 
PROTOCOL AMENDMENT SUMMARY 
..........................................................................7 
1.0 
PROTOCOL SUMMARY ........................................................................................11 
1.1 
Synopsis 
...........................................................................................................11 
1.2 
Schema 
............................................................................................................17 
1.3 
Example Schedule of Activities 
.....................................................................18 
2.0 
INTRODUCTION......................................................................................................21 
2.1 
Study Rationale 
..............................................................................................21 
2.2 
Background ....................................................................................................21 
2.3 
Benefit/Risk Assessment 
................................................................................22 
3.0 
OBJECTIVES AND ENDPOINTS 
..........................................................................23 
4.0 
STUDY DESIGN 
........................................................................................................25 
4.1 
Overall Design 
................................................................................................25 
4.2 
Scientific Rationale for Study Design 
...........................................................26 
4.3 
Justification for Dose 
.....................................................................................27 
4.4 
End of Study Definition 
.................................................................................27 
5.0 
STUDY POPULATION 
............................................................................................28 
5.1 
Inclusion Criteria 
...........................................................................................28 
5.2 
Exclusion Criteria 
..........................................................................................29 
5.3 
Lifestyle Considerations 
................................................................................29 
5.4 
Screen Failures 
...............................................................................................29 
6.0 
STUDY INTERVENTIONS .....................................................................................30 
6.1 
Study Intervention(s) Administered 
.............................................................30 
6.2 
Preparation/Handling/Storage/Accountability 
...........................................30 
6.3 
Measures to Minimize Bias: Randomization and Blinding........................31 
6.4 
Study Treatment Compliance 
.......................................................................31 
6.5 
Concomitant Therapy 
....................................................................................32 
6.6 
Dose Modification 
..........................................................................................32 
7.0 
DISCONTINUATION OF STUDY TREATMENT AND PATIENT 
DISCONTINUATION/WITHDRAWAL 
................................................................33 
7.1 
Discontinuation of Study Treatment 
............................................................33 


CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
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7.2 
Patient Discontinuation/Withdrawal from the Study 
.................................33 
7.3 
Lost to Follow-up 
...........................................................................................34 
8.0 
STUDY ASSESSMENTS AND PROCEDURES 
....................................................35 
8.1 
Efficacy Assessments .....................................................................................35 
8.1.1 Clinical Severity Status 8-Point Ordinal Scale 
..................................35 
8.1.2 Other Efficacy Assessments 
..............................................................37 
8.2 
Safety Assessments 
.........................................................................................38 
8.2.1 Physical Examinations 
.......................................................................38 
8.2.2 Vital Signs 
.........................................................................................38 
8.2.3 Clinical Safety Laboratory Assessments 
...........................................38 
8.3 
Viral Diagnosis 
...............................................................................................39 
8.4 
Adverse Events 
...............................................................................................39 
8.4.1 Time Period and Frequency for Collecting AE and SAE 
Information 
........................................................................................39 
8.4.2 Method of Detecting AEs and SAEs 
.................................................40 
8.4.3 Follow-up of AEs and SAEs .............................................................40 
8.4.4 Regulatory Reporting Requirements for SAEs .................................40 
8.4.5 Pregnancy 
..........................................................................................42 
8.4.6 Adverse Events of Special Interest 
....................................................42 
8.4.7 Disease-Related Events and/or Disease-Related Outcomes 
..............42 
8.5 
Treatment of Overdose 
..................................................................................42 
8.6 
Pharmacokinetics 
...........................................................................................43 
8.7 
Pharmacodynamics 
........................................................................................43 
8.8 
Blood for Potential Future Research............................................................43 
9.0 
STATISTICAL CONSIDERATIONS 
.....................................................................44 
9.1 
Sample Size Determination 
...........................................................................44 
9.2 
Populations for Analyses 
...............................................................................46 
9.3 
Statistical Analyses.........................................................................................46 
9.3.1 Primary Efficacy Endpoint Analyses ................................................46 
9.3.2 Key Secondary Endpoint Analyses 
...................................................46 
9.3.3 Other Endpoint Analyses 
...................................................................47 
9.3.4 Missing Data 
......................................................................................47 
9.4 
Review Committees 
........................................................................................48 
9.4.1 Joint Steering Committee 
..................................................................48 
9.4.2 Independent Data Monitoring Committee 
.........................................48 
10.0 REFERENCES 
...........................................................................................................49 
11.0 APPENDICES 
............................................................................................................50 
Appendix 1 Abbreviations 
...................................................................................51 
Appendix 2 Regulatory, Ethical, and Study Oversight Considerations 
..........53 
Protocol Compliance 
........................................................................................53 
Regulatory and Ethical Considerations 
............................................................53 


CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
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Financial Disclosure.........................................................................................54 
Insurance 
..........................................................................................................54 
Informed Consent Process 
...............................................................................54 
Data Protection.................................................................................................55 
Administrative Structure 
..................................................................................55 
Medical Monitor ..............................................................................................55 
Dissemination of Clinical Study Data..............................................................55 
Data Quality Assurance 
...................................................................................56 
Source Documents 
...........................................................................................56 
Study and Study Center Closure 
......................................................................57 
Publication Policy 
............................................................................................57 
Appendix 3 Clinical Laboratory Tests 
...............................................................59 
Appendix 4 Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
.....................................61 
Appendix 5 Contraceptive Guidance and Collection of Pregnancy 
Information 
.....................................................................................................65 
Appendix 7 Summary of Futility Probabilities and Boundaries .....................69 
Appendix 8 Signature of Investigator ................................................................70 
 
CCI
 


CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
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TABLE OF TABLES 
Table 1 
Study Objectives and Endpoints 
......................................................................23 
Table 2 
Clarification of the 8-point Ordinal Scale for Scores 2 Through 5..................36 
Table 3 
Clarification of the 8-point Ordinal Scale for Scores 6 Through 8..................36 
Table 4 
Analysis Sets for the Master Protocol 
..............................................................46 
Table 5 
Protocol-required Safety Laboratory Assessments 
..........................................60 
Table 6 
Summary of Futility Probabilities and Boundaries with 88.3% Power 
Using Pocock Futility Boundaries 
...................................................................69 
Table 7 
Summary of Futility Probabilities and Boundaries with 88.3% Power 
Using Pocock Futility Boundaries for the Negative Treatment Effect 
Scenario (HR=0.9) 
...........................................................................................69 
 
TABLE OF FIGURES 
Figure 1 
Study Schema (with Hypothetical Example) 
...................................................17 
 


CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
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PROTOCOL AMENDMENT SUMMARY 
Protocol Amendment 4 
Protocol Amendment 4 (dated 16 April 2021) replaces Protocol Amendment 3 (dated 
22 October 2020). The amendment incorporates the following main changes:  
• Provides updated statistics regarding coronavirus disease 2019 (COVID-19) cases and deaths 
as well as racial and ethnic disparities related to the disease. 
• Adds clarification that in regions where more than one sub-protocol has received local 
regulatory and Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
approval, it is required that participating sites are activated for enrollment for all approved 
sub-protocols. 
• Adds the inclusion criterion “randomized within 5 days of hospitalization.” 
• Modifies exclusion criterion from “patient has any condition for which, in the opinion of the 
Investigator, participation would not be in the best interest of the patient (eg, compromise 
their well-being) or that could prevent, limit, or confound the protocol-specified assessments 
(eg, patients unable to swallow study medication tablets)” to “patient with past 
medical/surgical history and/or any current condition for which, in the opinion of the 
Investigator, participation would be a safety risk or could affect the integrity of data.” 
• Adds the exclusion criterion “where, in the opinion of the Investigator, progression to death 
is imminent and inevitable within the next 48 hours, irrespective of the provision of 
treatments.” 
• Modifies description of emergency unblinding procedures to indicate that “if the Investigator 
decides that unblinding is warranted, the Investigator may, at his/her discretion, contact the 
Sponsor to discuss the situation prior to unblinding a patient’s treatment assignment unless 
this could delay emergency treatment of the patient.” 
• Regarding concomitant therapy, adds collection of data regarding receipt of any COVID-19 
vaccine regardless of when the vaccine was received. 
• Updates clarifications regarding the 8-point ordinal scale scores. 
Protocol Amendment 3 
Protocol Amendment 3 (dated 22 October 2020) replaced Protocol Amendment 2 (dated 
05 October 2020). The amendment incorporated the following main changes: 
• Expanded background information to include data regarding the epidemiology of COVID-19 
as well as racial and ethnic disparities related to the disease. 
• In the Schedule of Activities: 
− Clarified procedures for obtaining/recording patient height and weight. 
− Removed the optional clinical safety laboratory assessments (hematology, clinical 
chemistry, and liver function tests) on Days 5, 11, and 18. 


CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
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• Removed language regarding operational adjustment of the number of enrolled patients. 
• Removed language regarding adjustment of alpha spending as part of the interim analyses. 
• Updated methods for primary efficacy endpoint analyses. 
• Removed language regarding analysis methods for continuous other endpoints. 
• In Appendix 7: 
− Provided p-values for the boundary of futility, non-binding. 
− Removed the summary of futility probabilities and boundaries for the primary 
analysis. 
− Removed language regarding enrollment rate assumption and negative treatment 
effect scenario. 
Protocol Amendment 2 
Protocol Amendment 2 (dated 05 October 2020) replaced Protocol Amendment 1 (dated 
24 August 2020). The amendment incorporated the following main changes: 
• Clarified that this Master Protocol will continue enrolling patients as long as there is at least 
one active sub-protocol. 
• Clarified that other secondary endpoint (distribution of 8-point ordinal scale at Days 8, 15, 
and 29, as well as the worst postbaseline score on 8-point ordinal scale from baseline to 
Day 29) and 
 
 
 
 
• Clarified that interim analyses will evaluate futility and safety, but not efficacy, of candidate 
agents; the two-sided alpha level was updated to reflect this change. Also, provided updated 
summary of futility probabilities and boundaries in Appendix 7. 
• Clarified how patients who are discharged from the hospital to hospice care will be handled 
in the analyses. 
• In the Schedule of Activities: 
− Clarified that medical history includes the date of diagnosis of acute respiratory 
distress syndrome, if present. 
− Clarified that for patients requiring high-flow oxygen, mechanical ventilation 
(invasive/noninvasive), or extracorporeal membrane oxygenation only, provide FiO
2 
requirement. 
− Clarified that on Day 1, the National Early Warning Score 2 is to be assessed prior to 
study drug administration. 
− Added that clinical safety laboratory assessments are to be completed ‘all other days 
while in hospital’ and these data are to be collected on the electronic case report form.
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CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
9 
• Clarified that patients will be stratified at randomization by baseline clinical severity of 2 on 
the 8-point ordinal scale (yes/no) and remdesivir use at baseline (yes/no). 
• Added the following exclusion criteria: 
− Active tuberculosis or a history of incompletely treated tuberculosis. 
− Active, uncontrolled systemic bacterial or fungal infection(s). 
• Clarified the definition of ‘sustained’ clinical recovery as clinical recovery without 
readmission to a hospital by Day 60. 
• Removed the definition of clinically significant abnormal laboratory findings. Also, clarified 
which abnormal laboratory test results meet the adverse event definition. 
• Clarified serious adverse event reporting procedures and removed language regarding 
reporting of events not reported per the standard process for expedited reporting of serious 
adverse events. 
• Clarified that contact information for the candidate agent owner will be listed in the 
corresponding sub-protocol. 
• Clarified how missing data for the primary endpoint will be handled. 
Protocol Amendment 1 
Protocol Amendment 1 (dated 24 August 2020) replaced the final Version 4 protocol (dated 
20 July 2020). The amendment incorporated the following main changes: 
• The study design was modified to be a double-blind, placebo-controlled platform study: 
− Study design section was updated. 
− Randomization and blinding details were added. 
− Where appropriate, references to ‘candidate agent’ were amended to ‘study treatment’ 
(ie, candidate agent or placebo). 
− Sample size details were modified. 
− Safety data collection procedures were modified to collect all adverse events. 
− Summary of early success and futility probabilities and boundaries tables was 
modified in Appendix 7. 
• Key secondary endpoint (and corresponding objective) was added: incidence of patients 
achieving ≥2-point improvement from baseline or fit-for-discharge on the ordinal scale at 
Day 29, with fit-for-discharge defined as categories 6, 7, and 8 on the 8-point ordinal scale. 
• Clarified that key secondary endpoint is incidence of oxygen-free recovery. 
• The endpoint to evaluate distribution of 8-point ordinal scale at Days 8, 15, and 29, as well as 
the worst postbaseline score on 8-point ordinal scale from randomization to Day 29 was 
moved from key secondary endpoints to other secondary endpoints. 
• 
 
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CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
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• Specified the categories of adverse events to be analyzed as secondary endpoints. 
• 
 
• Some endpoints included Day 22 as a time point; as some patients will have been discharged 
by this point, this time point was removed from those endpoints. 
• Specified that the Sequential Organ Failure Assessment score will no longer be assessed. 
• Clarified that arterial blood gases will no longer be assessed. 
• Clarified that severe acute respiratory syndrome coronavirus 2 antigen testing can be the 
diagnostic test performed at screening; this included a modification to inclusion criterion #1. 
• Exclusion criterion #6 was modified to clarify patients participating in another clinical study 
of an investigational medicinal product or other unapproved (or investigational) treatment 
for COVID-19 would be excluded. 
• A concomitant medication review at Day 60 was added. Clarified that concomitant 
medication review would also occur at screening (Day -1 or Day 1) so that medication(s) the 
patient is receiving at the time of, or during the two weeks prior to, enrollment (including 
screening) would be captured. 
• Clarified that the sub-protocols could define additional endpoints. 
• Clarified that patients randomized to study treatments in a specific sub-protocol would follow 
the Schedule of Activities in that sub-protocol. 
• Expanded details of clinical safety laboratory testing added, and time points refined.
CCI
 


CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
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1.0 PROTOCOL SUMMARY 
1.1 Synopsis 
Protocol Title: Industry Alliance Platform Trial to Assess the Efficacy and Safety of Multiple Candidate 
Agents for the Treatment of COVID-19 in Hospitalized Patients 
Rationale: 
There is a high unmet medical need for therapeutic agents available to treat coronavirus disease 2019 
(COVID-19), an inflammatory disease caused by severe acute respiratory syndrome coronavirus 2 
(SARS-CoV-2), and there is an urgent public health need for rapid development of such interventions. 
This adaptive, randomized, placebo-controlled platform study is designed to rapidly assess multiple 
candidate agents as treatments for COVID-19 in hospitalized patients. Candidate agents will be evaluated 
frequently (through ongoing monitoring) for futility and safety, with candidate agents being added to 
and/or removed from the study on an ongoing basis, depending on the results of their evaluation. Patients 
to be included in the study are required to be hospitalized with confirmed active SARS-CoV-2 infection 
and may require either ongoing medical care, supplemental oxygen, noninvasive ventilation or high-flow 
oxygen devices, or invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO). 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
• To evaluate time to confirmed clinical recovery 
• Time to confirmed clinical recovery through 
Day 29, ie, fit-for-discharge, as defined by 
achieving a score of 6, 7, or 8 on the 8-point 
ordinal scale of clinical severity status, without 
being rehospitalized through Day 29: 
1. Death 
2. Hospitalized, on invasive mechanical 
ventilation or ECMO 
3. Hospitalized, on noninvasive ventilation or 
high-flow oxygen devices 
4. Hospitalized, requiring supplemental oxygen 
5. Hospitalized, not requiring supplemental 
oxygen, requiring ongoing medical care 
(COVID-19 related or otherwise) 
6. Hospitalized, not requiring supplemental 
oxygen, no longer requires ongoing medical 
care 
7. Not hospitalized, limitation on activities 
and/or requiring home oxygen 
8. Not hospitalized, no limitations on activities 
Key Secondary 
 
• To evaluate oxygen-free recovery 
• Incidence of oxygen-free recovery at Day 29, 
defined as patients who are alive, discharged, and 
not receiving supplemental oxygen. 


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Protocol Amendment 4, 16 April 2021 
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• To evaluate improvement or being 
fit-for-discharge 
• Incidence of ≥2-point improvement from baseline 
or fit-for-discharge on the ordinal scale at Day 29, 
with fit-for-discharge defined as categories 6, 7, 
and 8 on the 8-point ordinal scale. 
• To evaluate all-cause mortality 
• Incidence of all-cause mortality through Day 29. 
Other Secondary 
 
• To evaluate the distribution across categories on 
the 8-point ordinal scale, and the worst outcome 
• Distribution of 8-point ordinal scale at Days 8, 15, 
and 29, as well as the worst postbaseline score on 
8-point ordinal scale from baseline to Day 29. 
• To evaluate intensive care unit (ICU) days 
• Number of ICU days from Day 1 through Day 29. 
• To evaluate invasive mechanical ventilator days 
• Number of invasive mechanical ventilator days 
from Day 1 through Day 29. 
• To evaluate clinical recovery 
• Incidence of clinical recovery, as defined by 
achieving a score of 6, 7, or 8 on the 8-point 
ordinal scale of clinical severity status by Days 8, 
15, and 29. 
• To evaluate sustained clinical recovery 
• Incidence of sustained clinical recovery as 
confirmed by Day 60 follow-up. 
• To evaluate the safety of candidate agents as 
add-on therapy to standard of care (SoC) in 
patients with COVID-19 
• Incidence of adverse events (AEs) in the following 
categories: 
− All treatment-emergent AEs 
− Serious AEs 
− AEs with Common Terminology Criteria 
for Adverse Events Grade 3 or higher 
− AEs leading to dose modifications 
− AEs leading to study treatment 
discontinuation 
Exploratory 
 
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CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
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Overall Design: 
COVID-19 Multiple Agents and Modulators Unified Industry Members Trial (COMMUNITY) is an 
adaptive, randomized, placebo-controlled platform study, designed to rapidly evaluate candidate agents 
for the treatment of COVID-19. The study will include hospitalized adult patients (≥18 years of age) who 
have infection with SARS-CoV-2, the virus that causes COVID-19, as confirmed by laboratory tests 
and/or point-of-care tests. For inclusion, patients will need to be hospitalized with a clinical status of 
Grade 2 (hospitalized, on invasive mechanical ventilation or ECMO) to Grade 5 (hospitalized, not 
requiring supplemental oxygen, requiring ongoing medical care [COVID-19 related or otherwise]), as 
defined by an 8-point ordinal scale of clinical severity (see above). 
This study aims to identify efficacious candidate agents for treatment of COVID-19. The candidate agents 
may include, but will not be limited to, antivirals, vascular agents, or immunomodulatory agents. Each 
sub-protocol will specify a single candidate agent or a combination of candidate agents to be 
administered. 
This Master Protocol outlines the overall design of the study, including the population, inclusion and 
exclusion criteria, randomization scheme, primary, secondary, and exploratory outcomes, study design, 
statistical methodology, and planned analyses that are common for all candidate agents to be evaluated. 
The Master Protocol is structured such that multiple candidate agents from different pharmaceutical 
companies can be evaluated simultaneously. The plan is to add candidate agents as they are identified, 
and/or to remove therapies based on results of interim analyses (eg, due to futility or if they are 
considered unsafe). The shared placebo control group for a candidate agent will include only patients 
randomized during the same period in which the candidate agent group is randomized, which will be 
defined in the Statistical Analysis Plan. Patients will be randomized equally to either the candidate agent 
plus SoC or placebo plus SoC in a double-blind fashion. Patients who are randomized to placebo plus 
SoC will subsequently be randomized equally to a matching placebo corresponding to an available agent 
whose sub-protocol the patient qualified for (ie, a 2-stage randomization). Each patient in the placebo plus 
SoC group will only receive one type of placebo. Therefore, patients may be aware of which sub-protocol 
they were randomized to but not to whether they will receive active agent or placebo investigational 
product. The comparator group for a candidate agent will include patients randomized to any matching 
placebo for a candidate agent available at the time of randomization for that agent. 
Sub-protocols will outline the scientific rationale, additional eligibility criteria (if necessary), treatment 
dose and regimen, statistical analysis populations, and other specifics unique to each candidate agent. The 
sub-protocols may define adverse events of special interest and can include pharmacokinetic (PK) and/or 
pharmacodynamic assessments that are appropriate for the specific candidate agent. The endpoints 
specified in this Master Protocol will not be altered in the sub-protocols, but the sub-protocol may define 
additional endpoints. In order to enroll, a patient must meet all entry criteria for both the Master Protocol 
and at least one active sub-protocol.
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CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
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The study will evaluate each candidate agent separately as an add-on to the SoC to assess safety and 
efficacy. Interim analyses may be performed for each candidate agent during the course of the study to 
evaluate futility for candidate agents. 
Randomization will be stratified by baseline clinical severity of 2 on the 8-point ordinal scale (yes/no) and 
remdesivir use at baseline (yes/no). 
Enrollment of patients will be continuous throughout the study for each candidate agent until the total 
number of planned patients for that agent is enrolled, until futility criteria is met at an interim analysis, or 
if the agent is considered unsafe. The Master Protocol will continue enrolling patients as long as there is 
at least one active sub-protocol. 
In addition, centers may elect to participate in separate Investigator-initiated studies collecting additional 
data on patients (eg, PK analyses), as their resources permit. 
Number of Patients: 
The expected number of patients is presented as part of the sample size determination below. 
Treatment Groups and Duration: 
Patients will be screened on Day -1 (the day before the first dose of study treatment [candidate agent or 
placebo/SoC] is scheduled) or Day 1 and will remain in the hospital from Day 1 until discharge. All 
patients will receive SoC treatment, either with a blinded candidate agent or its matching blinded placebo. 
The SoC will be based on appropriate local written guidelines in place at a site at the time of treatment in 
the study; the SoC may change during the course of the study as new information becomes available 
about treating COVID-19. Dosing with the study treatment (as an add-on to SoC) will commence on 
Day 1. Patients will be assessed daily while hospitalized. If they are discharged from the hospital prior to 
Day 15, they will have study visits at Days 15 and 29 as an outpatient by telemedicine. The last day of 
primary assessments will be Day 29. An end-of-study visit will be conducted on Day 60 (±4 days) via 
telemedicine (unless the patient is still hospitalized in which case it would be conducted in person). 
Statistical methods: 
Sample size determination: 
Assuming a median time to clinical recovery of 11 days for patients randomized to an active treatment 
group plus SoC compared with 15 days for those randomized to placebo plus SoC, 350 patients are 
needed per arm in order to observe 490 clinical recovery events between the 2 treatment groups being 
compared at the primary analysis. This sample size will provide approximately 88% power to detect a 
hazard ratio (HR) of 1.364 for the occurrence of a clinical recovery event, when comparing each 
candidate agent plus SoC with placebo plus SoC, at a 1-sided significance level of 0.025. 
This sample size will provide the following information about the key secondary endpoints: assuming the 
oxygen-free recovery rate at Day 29 is 65% for the placebo group, a sample size of 350 patients per arm 
will provide approximately 80% power to detect at least a 9.7% absolute increase in the proportion of 
patients who achieve oxygen-free recovery at Day 29. Assuming 70% of patients randomized to placebo 
plus SoC achieve at least 2-point improvement from baseline or fit-for-discharge on the 8-pt ordinal scale, 
350 patients per arm will provide approximately 80% power to detect a 9.2% absolute increase in this 
proportion with a candidate agent plus SoC at Day 29. Assuming the all-cause mortality rate through 
Day 29 is 15% for the placebo plus SoC group, a sample size of 350 patients per arm will provide 80% 
power to detect an absolute reduction of 6.75% (8.25% rate for any candidate agent plus SoC) in the 
mortality rate by Day 29. Assuming a mortality rate of 15% for the placebo plus SoC group and 19% for a 
candidate agent plus SoC (ie, an adverse treatment effect of 4%), with a sample size of 350 per arm, the 
chance to observe a decrease in the mortality rate of at least 1% with a candidate agent plus SoC 
compared to placebo plus SoC is approximately 4%. 


CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
15 
For a sub-protocol where the primary analysis population is a subset of the randomized population, the 
sample size may be adjusted in a sub-protocol as applicable to power the designated primary analysis 
population. 
Analysis sets: 
• Full Analysis Set: All patients who are randomized. 
• Safety Set: All patients who are randomized and take at least one dose of study treatment or 
placebo. 
Analysis methods: 
Patients who achieve a 7 on the 8-pt ordinal scale but are discharged to hospice care will not be 
considered as having met clinical recovery or oxygen-free recovery. 
Primary Efficacy Endpoint Analyses 
The time to confirmed clinical recovery through Day 29, as defined by achieving a score of 6, 7, or 8 on 
the 8-point ordinal scale of clinical severity status, ie, fit-for-discharge, without being rehospitalized 
through Day 29, will be compared between the selected candidate agent plus SoC and contemporaneous 
placebo plus SoC, using a stratified log-rank test, stratifying for baseline clinical severity of 2 on the 
8-point ordinal scale (yes/no) and remdesivir use at baseline (yes/no), with patients who have died prior to 
or on Day 29 censored at Day 29. The p-value associated with the stratified log-rank test statistic at the 
time of the primary analysis will be compared at the 2-sided 0.05 alpha level. The p-value will also be 
compared with the specified boundaries at the interim analyses for futility in order to serve as guidance 
for the Independent Data Monitoring Committee (IDMC) to make recommendations based on the totality 
of available information at the time of the interim analyses. The HR for the treatment arm plus SoC 
versus placebo plus SoC will be estimated using a Cox regression, adjusting for randomization 
stratification factors, with deaths censored at Day 29. 
Key Secondary Endpoint Analyses 
The key secondary endpoint of incidence of oxygen-free recovery at Day 29, defined as patients who are 
alive, discharged, and not receiving supplemental oxygen at Day 29, will be analyzed using a logistic 
regression with baseline clinical severity of 2 on the 8-point ordinal scale (yes/no) and remdesivir use at 
baseline (yes/no) included as covariates. 
The key secondary endpoint of incidence of patients achieving ≥2 point improvement from baseline or 
being fit-for-discharge on the ordinal scale at Day 29, with fit-for-discharge defined as categories 6, 7, 
and 8 on the 8-point ordinal scale at Day 29, will be analyzed using logistic regression with baseline 
clinical severity of 2 on the 8-point ordinal scale (yes/no) and remdesivir use at baseline (yes/no) included 
as covariates.  
The key secondary endpoint of the incidence of all-cause mortality through Day 29 will be analyzed using 
a logistic regression with baseline clinical severity of 2 on the 8-point ordinal scale (yes/no) and 
remdesivir use at baseline (yes/no) included as covariates. 
If a candidate agent plus SoC achieves statistical significance on the primary endpoint compared to 
placebo plus SoC, the three key secondary endpoints will be tested in a hierarchical testing sequence in 
the following order: oxygen-free recovery at Day 29, at least a 2 point improvement from baseline on the 
8-point ordinal scale or being fit for discharge at Day 29, and all-cause mortality through Day 29. 
Other Endpoint Analyses 
For the other secondary endpoints, a binary endpoint will be analyzed by logistic regression including 
baseline clinical severity of 2 on the 8-point ordinal scale (yes/no) and remdesivir use at baseline (yes/no) 
as covariates. For ordinal other secondary endpoints, the number and percentage of patients in each 
category will be provided for each treatment arm and will be analyzed using a proportional odds model, 
including the baseline clinical severity of 2 on the 8-point ordinal scale for clinical severity (yes or no) 
and remdesivir use at baseline (yes or no) as stratification variables. 


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Data Monitoring Committee: 
An IDMC will monitor ongoing data to ensure patient well-being and safety as well as study integrity. 
The IDMC will be asked to make recommendations to the Joint Steering Committee regarding early 
termination or modification of the evaluation of a candidate agent. More details will be provided in the 
IDMC charter.
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1.2 Schema 
Figure 1 
Study Schema (with Hypothetical Example) 
 
FA=final analysis; IA=interim analysis; PA=primary analysis; SoC=standard of care. ‘×’ indicates that futility 
boundary has been met. 
IA1 and IA2 will be planned at information fractions of approximately 25% and 55% of expected number of 
recoveries, ie, after approximately 123 and 270 patients have met the primary endpoint of clinical recovery on a 
particular candidate agent plus SoC and placebo plus SoC, respectively. 
PA will occur after approximately 350 patients have been randomized to an active agent plus SoC and have had the 
opportunity to complete the Day 29 visit. 
FA will occur after all patients randomized to that agent plus SoC and the concurrent placebo plus SoC controls 
have had the opportunity to complete the Day 60 visit. 
Note: In the above example, Agents #1, #2, and #5 met the futility boundary at IA1 while Agent #3 met the futility 
boundary at IA2, and so those agents could be discontinued in the study due to futility. 
Note: Patients who are randomized to placebo plus SoC will be subsequently randomized equally to a matching 
placebo corresponding to an available agent whose sub-protocol the patient qualified for (ie, a 2-stage 
randomization). 


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1.3 Example Schedule of Activities 
 
Screening 
Baseline 
 
 
 
 
Day (± Window) 
Day -1 or 
Day 1 
Day 1 
Daily Until Hospital 
Discharge (or Daily Until 
Day 29 While in Hospital) 
Day 15a 
(±2 days) 
Day 29a 
(±3 days) 
Day 60a 
(±4 days) 
(End of 
Study) 
ELIGIBILITY 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Relevant medical historyb 
X 
 
 
 
 
 
Review of SARS-CoV-2 diagnostic tests 
(obtained during the previous 72 hours, if 
available) 
X 
 
 
 
 
 
SARS-CoV-2 diagnostic testc 
X 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
X 
 
 
 
 
12-lead electrocardiogram 
X 
 
 
 
 
 
STUDY INTERVENTION 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
Administration of study treatment 
 
Defined in sub-protocol 
 
Treatment with SoC 
 
SoC will be based on the practices of the study center 
STUDY PROCEDURES 
 
 
 
 
 
 
Physical examination (including height and 
weight)d 
X 
 
 
 
 
 
Vital signs, including body temperature, 
pulse rate, blood pressure, respiratory rate, 
SpO2, FiO2e 
 
Xf 
X 
Xg 
Xg 
 
Ordinal scale 
 
Xf 
X 
X 
X 
X 
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Screening 
Baseline 
 
 
 
 
Day (± Window) 
Day -1 or 
Day 1 
Day 1 
Daily Until Hospital 
Discharge (or Daily Until 
Day 29 While in Hospital) 
Day 15a 
(±2 days) 
Day 29a 
(±3 days) 
Day 60a 
(±4 days) 
(End of 
Study) 
Clinical assessmentsh 
 
Xf 
X 
X 
X 
Xi 
Assessment of floor status (ICU yes/no) 
 
X 
Xg 
Xg 
Xg 
 
Assessment of rehospitalization for 
discharged patientsj 
 
 
 
X 
X 
X 
Concomitant medication review (including 
use of vasopressors) 
X 
Xf 
X 
X 
X 
X 
Adverse event evaluation 
X 
X 
X 
X 
X 
X 
SAFETY LABORATORY 
 
 
 
 
 
 
Clinical safety laboratory assessments 
Xk,l 
Xf,m,n 
Days 3o, 8
m, 22
m, and at 
dischargem,p 
All other days while in 
hospitalq 
Xm,r 
Xm 
 
Pregnancy test for females of childbearing 
potential 
Xk 
 
 
 
 
 
RESEARCH LABORATORY 
 
 
 
 
 
 
Abbreviations: ARDS=acute respiratory distress syndrome; eCRF=electronic case report form; FiO2=fraction of inspired oxygen; ICF=informed consent form; 
ICU=intensive care unit; 
; SARS-CoV-2= severe acute respiratory syndrome coronavirus 2; SoC=standard of care; 
SpO2=oxygen saturation. 
Note: Additional assessments, if required, will be defined in the sub-protocol. 
a These visits will be performed even if a patient has already been discharged. If discharged prior to scheduled visit, these visits will be conducted via 
telemedicine. For visits conducted by telephone, it may not be possible to perform some scheduled assessments (eg, vital signs). The Day 29 assessments will 
also be performed, where possible, for patients who discontinue the study prematurely. 
b Medical history includes estimated date and time of first COVID-19 related symptoms and co-morbidities (eg, respiratory [including date of diagnosis of 
ARDS, if present], cardiovascular, metabolic, malignancy, endocrine, gastrointestinal, immunologic, renal).
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c Oropharyngeal/nasal swab for polymerase chain reaction determination of SARS-CoV-2 or for SARS-CoV-2 antigen testing. Only to be performed if no 
diagnostic test results are available that have been obtained during the previous 72 hours. 
d If height and/or weight cannot be obtained at the Screening Visit (Day -1 or Day 1), these parameters can be recorded as a combination of patient-reported data 
and data obtained from recent medical records (ie, at hospital admission). 
e For patients requiring high-flow oxygen, mechanical ventilation (invasive/noninvasive), or extracorporeal membrane oxygenation only, provide FiO
2 
requirement. 
f Baseline assessments should be performed prior to study drug administration. 
g To be assessed only while hospitalized. 
h Includes oxygen requirement (ie, mode of delivery/liters of oxygen flow, FiO
2 requirement), stop date of oxygen for patients who were discharged on home 
oxygen, extracorporeal membrane oxygenation support, noninvasive or invasive ventilator requirement, including start and stop of low- or high-flow oxygen 
supply or of any form of ventilation, and need for renal replacement therapy. Noninvasive ventilation refers to the delivery of mechanical ventilation to the 
lungs using techniques that do not require an endotracheal airway. 
i Only stop date of oxygen for patients who were discharged on home oxygen. 
j Information recorded is yes/no, hospitalization date, discharge date. 
k Laboratory tests performed within the 48 hours prior to enrollment will be accepted for determination of eligibility. 
l Hematology and clinical chemistry. 
m Hematology, clinical chemistry, liver function tests, cardiac panel, and coagulation. 
n Any laboratory tests performed as part of routine clinical care can be used for safety laboratory testing. 
o Hematology, clinical chemistry, and liver function tests. 
p If not done or entered into the eCRF within previous day. 
q Hematology, clinical chemistry, and liver function tests will be collected on the eCRF, if available, while the patient is in hospital. 
r This assessment will be performed on Day 15 or date of discharge, if earlier. 
 


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2.0 INTRODUCTION 
2.1 Study Rationale 
There is a high unmet medical need for therapeutic agents available to treat coronavirus 
disease 2019 (COVID-19), an inflammatory disease caused by severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2), and there is an urgent public health need for rapid development of 
such interventions. This adaptive platform study is designed to rapidly assess multiple candidate 
agents as treatments for COVID-19 in hospitalized patients. Candidate agents will be evaluated 
frequently (through ongoing monitoring) for futility and safety, with candidate agents being 
added to and/or removed from the study on an ongoing basis, depending on the results of their 
evaluation. Patients to be included in the study are required to be hospitalized with confirmed 
active SARS-CoV-2 infection and may require either ongoing medical care, supplemental 
oxygen, noninvasive ventilation or high-flow oxygen devices, or invasive mechanical ventilation 
or extracorporeal membrane oxygenation (ECMO). 
2.2 Background 
Coronaviruses are single-stranded RNA viruses capable of causing life-threatening disease in 
humans and animals. The novel coronavirus SARS-CoV-2, first identified during an outbreak of 
viral pneumonia cases of unknown cause in China, binds via the angiotensin-converting 
enzyme 2 receptor located on alveolar cells and intestinal epithelia.
1 The virus is mutating, 
indicating that virulence and transmission will shift over time, and showing diversity in critical 
surface protein. Evidence suggests there are 2 groups of SARS-CoV-2; L-type and S-type.
2 
S-type is the less aggressive (30%); the L-type is now the most prevalent version (70%) and is 
more aggressive. 
Most of the initial SARS-CoV-2 infections outside of China were travel associated (ie, from 
people who had traveled from the infected regions of China to other countries), although 
person-to-person transmission of SARS-CoV-2 in other countries was quickly established. On 
11 March 2020, reports of 118,000 cases and 4,291 deaths in 114 countries prompted the World 
Health Organization to declare COVID-19 a pandemic. Less than a month later, worldwide cases 
had reached over 3.5 million, with over 240,000 deaths attributed to COVID-19. By the end of 
March 2021, over 126 million cases of COVID-19 and over 2.7 million deaths had been reported 
globally.3 
Central to elucidating the epidemiology of SARS-CoV-2 is surveillance of the clinical 
characteristics and outcomes of individuals diagnosed with COVID-19.4 Traditional 
epidemiologic risk factors such as geographic variation, advanced age, and comorbid conditions 
have emerged as clear risk factors for COVID-19.5 Sex-related differences in COVID-19 health 
outcomes have also been reported; despite equal numbers of COVID-19 cases between sexes, 
fatality rates are higher in men than in women.
6 


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In addition to factors of geography, age, comorbidity, and sex, concern is growing that racial and 
ethnic minority communities experience a disproportionate burden of COVID-19 morbidity and 
mortality. Indeed, in the United States, compared to White, non-Hispanic persons, the 
COVID-19 case rate, hospitalization rate, and death rate are higher among Black or African 
American non-Hispanic persons (1.1, 2.9, and 1.9 times higher, respectively), Hispanic or Latino 
persons (1.3, 3.1, and 2.3 times higher, respectively), and American Indian or Alaska native, 
non-Hispanic persons (1.7, 3.7, and 2.4 times higher, respectively).
7 
These data highlight the urgent need for immediate comprehensive studies and robust analyses 
that combine genomic data, chart records, clinical symptoms, and demographic data to help 
better understand COVID-19 and enable risk assessment, triage, and public health resource 
planning. Current clinical studies involve the use of already approved medications for other 
indications (repurposing) where it is thought that they might also be effective in the treatment of 
COVID-19, as well as development of antiviral agents and antibody-based therapies against the 
virus. 
Inclusion of a population that encompasses the epidemiologic and demographic risk factors 
relevant to COVID-19 in clinical studies is critical to development of efficacious treatments that 
will stem the impact of this disease. Given that the racial and ethnic minorities most impacted by 
COVID-19 are historically under-represented in clinical studies generally, proactive efforts and 
ongoing attention should be given to ensuring these populations are included at a rate 
commensurate with the overall population at a minimum, if not closer to COVID-19 case rates. 
This platform study will test multiple candidate agents, with the aim of identifying potentially 
efficacious treatments in the shortest timeframe possible. In addition, it will support secondary 
research objectives that are critical for understanding the disease, spread of infection, and robust 
tests to track it. 
2.3 Benefit/Risk Assessment 
There exists a high unmet medical need for therapeutic agents to treat COVID-19; it can range 
from mild to severe disease, the latter including pneumonia, severe acute respiratory syndrome, 
multi-organ failure, and death. 
While there may not be direct benefits for an individual patient participating in this study, there 
may be benefits to society if a safe and efficacious therapeutic agent can be identified during the 
global COVID-19 outbreak. 
Detailed information about the known and expected risks and reasonably expected adverse 
events (AEs) of each candidate agent may be found in the corresponding sub-protocol for that 
agent. 


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3.0 OBJECTIVES AND ENDPOINTS 
Table 1 
Study Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
• To evaluate time to confirmed clinical recovery 
• Time to confirmed clinical recovery through 
Day 29, ie, fit-for-discharge, as defined by 
achieving a score of 6, 7, or 8 on the 8-point 
ordinal scale of clinical severity status, without 
being rehospitalized through Day 29: 
1. Death 
2. Hospitalized, on invasive mechanical 
ventilation or extracorporeal membrane 
oxygenation (ECMO) 
3. Hospitalized, on noninvasive ventilation or 
high-flow oxygen devices 
4. Hospitalized, requiring supplemental oxygen 
5. Hospitalized, not requiring supplemental 
oxygen, requiring ongoing medical care 
(COVID-19 related or otherwise) 
6. Hospitalized, not requiring supplemental 
oxygen, no longer requires ongoing medical 
care 
7. Not hospitalized, limitation on activities 
and/or requiring home oxygen 
8. Not hospitalized, no limitations on activities 
Key Secondary 
 
• To evaluate oxygen-free recovery 
• Incidence of oxygen-free recovery at Day 29, 
defined as patients who are alive, discharged, and 
not receiving supplemental oxygen. 
• To evaluate improvement or being 
fit-for-discharge 
• Incidence of ≥2-point improvement from baseline 
or fit-for-discharge on the ordinal scale at Day 29, 
with fit-for-discharge defined as categories 6, 7, 
and 8 on the 8-point ordinal scale. 
• To evaluate all-cause mortality 
• Incidence of all-cause mortality through Day 29. 
Other Secondary 
 
• To evaluate the distribution across categories on 
the 8-point ordinal scale, and the worst outcome 
• Distribution of 8-point ordinal scale at Days 8, 15, 
and 29, as well as the worst postbaseline score on 
8-point ordinal scale from baseline to Day 29. 
• To evaluate intensive care unit (ICU) days 
• Number of ICU days from Day 1 through Day 29. 
• To evaluate invasive mechanical ventilator days 
• Number of invasive mechanical ventilator days 
from Day 1 through Day 29. 


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• To evaluate clinical recovery 
• Incidence of clinical recovery, as defined by 
achieving a score of 6, 7, or 8 on the 8-point 
ordinal scale of clinical severity status by Days 8, 
15, and 29. 
• To evaluate sustained clinical recovery 
• Incidence of sustained clinical recovery as 
confirmed by Day 60 follow-up. 
• To evaluate the safety of candidate agents as 
add-on therapy to standard of care in patients with 
COVID-19 
• Incidence of AEs in the following categories: 
− All treatment-emergent AEs 
− Serious AEs 
− AEs with Common Terminology Criteria 
for Adverse Events Grade 3 or higher 
− AEs leading to dose modifications 
− AEs leading to study treatment 
discontinuation 
Exploratory 
 
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4.0 STUDY DESIGN 
4.1 Overall Design 
COVID-19 Multiple Agents and Modulators Unified Industry Members Trial (COMMUNITY) 
is an adaptive, randomized, placebo-controlled platform study designed to rapidly evaluate 
candidate agents in the treatment of COVID-19. The study will include hospitalized adult 
patients (≥18 years of age) who have infection with SARS-CoV-2, the virus that causes 
COVID-19, as confirmed by laboratory tests and/or point-of-care tests. For inclusion, patients 
will need to be hospitalized with a clinical status of Grade 2 (hospitalized, on invasive 
mechanical ventilation or ECMO) to Grade 5 (hospitalized, not requiring supplemental oxygen, 
requiring ongoing medical care [COVID-19 related or otherwise]), as defined by an 8-point 
ordinal scale of clinical severity (see Section 8.1.1). 
This study aims to identify efficacious candidate agents for treatment of COVID-19. The 
candidate agents may include, but will not be limited to, antivirals, vascular agents, or 
immunomodulatory agents. Each sub-protocol will specify a single candidate agent or a 
combination of candidate agents to be administered. In regions where more than one 
sub-protocol has received local regulatory and Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC) approval, it is required that participating sites are activated for 
enrollment for all approved sub-protocols. 
This Master Protocol outlines the overall design of the study, including the population, inclusion 
and exclusion criteria, randomization scheme, primary, secondary, and exploratory endpoints, 
study design, statistical methodology, and planned analyses that are common for all candidate 
agents to be tested. The Master Protocol is structured such that multiple candidate agents from 
different pharmaceutical companies can be evaluated simultaneously. The plan is to add 
candidate agents as they are identified, and/or to remove therapies based on results of interim 
analyses (eg, due to futility or if they are considered unsafe). The shared placebo control group 
for a candidate agent will include only patients randomized during the same period in which the 
candidate agent group is randomized, which will be defined in the sub-protocol Statistical 
Analysis Plan (SAP). Patients will be randomized equally to either the candidate agent plus 
standard of care (SoC) or placebo plus SoC in a double-blind fashion. Patients who are 
randomized to placebo plus SoC will be subsequently randomized equally to a matching placebo 
corresponding to an available agent whose sub-protocol the patient qualified for (ie, a 2-stage 
randomization). Each patient in the placebo plus SoC group will only receive one type of 
placebo. Therefore, patients may be aware of which sub-protocol they were randomized to but 
not to whether they will receive active agent or placebo investigational product. The comparator 
group for a candidate agent will include patients randomized to any matching placebo for a 
candidate agent available at the time of randomization for that agent. 


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Patients will be screened on Day -1 (the day before the first dose of study treatment [candidate 
agent or placebo/SoC] is scheduled) or Day 1 and will remain in the hospital from Day 1 until 
discharge. All patients will receive SoC treatment, either with blinded candidate agent or 
matching blinded placebo. The SoC will be based on appropriate local written guidelines in place 
at a site at the time of treatment in the study; the SoC may change during the course of the study 
as new information becomes available about treating COVID-19. Dosing with the study 
treatment (as an add-on to SoC) will commence on Day 1. Patients will be assessed daily while 
hospitalized. If they are discharged from the hospital prior to Day 15, they will have study visits 
at Days 15 and 29 as an outpatient by telemedicine. The last day of primary assessments will be 
Day 29. An end-of-study visit will be conducted on Day 60 (±4 days) via telemedicine (unless 
the patient is still hospitalized in which case it would be conducted in person). 
Sub-protocols will outline the scientific rationale, additional eligibility criteria (if necessary), 
treatment dose and regimen, statistical analysis populations, and other specifics unique to each 
candidate agent. The sub-protocols may define AEs of special interest and can include 
pharmacokinetic (PK) and/or pharmacodynamic assessments that are appropriate for the specific 
candidate agent. The endpoints specified in this Master Protocol will not be altered in the 
sub-protocols, but the sub-protocol may define additional endpoints. In order to enroll, a patient 
must meet all entry criteria for both the Master Protocol and at least one active sub-protocol. 
The study will evaluate the candidate agents as an add-on to the SoC to assess safety and 
efficacy. Interim analyses may be performed for each candidate agent to evaluate futility for 
candidate agents. 
Patients will be stratified at randomization by baseline clinical severity of 2 on the 8-point 
ordinal scale (yes/no) and remdesivir use at baseline (yes/no). 
Enrollment of patients will be continuous throughout the study for each candidate agent until the 
total number of planned patients for that agent is enrolled or until futility criteria is met at the 
interim analyses, or if the agent is considered unsafe.  
In addition, centers may elect to participate in separate Investigator-initiated studies collecting 
additional data on patients (eg, PK analyses), as their resources permit. 
4.2 Scientific Rationale for Study Design 
There is a high unmet medical need for therapeutic agents available to treat COVID-19, an 
inflammatory disease caused by SARS-CoV-2, and there is an urgent public health need for 
rapid development of such interventions. This platform study is designed to rapidly assess 
multiple candidate agents as treatments for COVID-19 in hospitalized patients. Candidate agents 
may be added to and/or removed from the study on an ongoing basis, depending on the results of 
their evaluation. Patients to be included in the study are required to be hospitalized with 
confirmed active SARS-CoV-2 infection and require either ongoing medical care (Grade 5 on 


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the 8-point ordinal scale), supplemental oxygen (Grade 4), noninvasive ventilation or high-flow 
oxygen devices (Grade 3), or invasive mechanical ventilation or ECMO (Grade 2). 
4.3 Justification for Dose 
Justification for the dose of each candidate agent will be included in the corresponding 
sub-protocol. 
4.4 End of Study Definition 
For each sub-protocol, the end of the study for that candidate agent will be defined as the date on 
which the last patient randomized to that sub-protocol completes their last scheduled procedure 
as shown in the Schedule of Activities (SoA). 
For the overall study, the end of the study will be defined as the date on which the last patient 
completes the last scheduled procedure for the final sub-protocol to be concluded. 


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5.0 STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
Inclusion and exclusion criteria will be checked at screening and rechecked at baseline. The 
inclusion and exclusion criteria listed below may be supplemented by additional criteria 
stipulated in the sub-protocols that are specific to the target candidate being tested (eg, criteria 
related to safety concerns of the candidate agent or to prohibited medications). In order to enroll, 
a patient or legally authorized representative must sign an informed consent form (ICF) and meet 
all entry criteria for both the Master Protocol and at least one active sub-protocol. 
5.1 Inclusion Criteria 
Patients are eligible to be included in the study only if all of the following criteria apply (as well 
as all criteria from the appropriate sub-protocol): 
1. Adults (≥18 years of age) with active SARS-CoV-2 infection confirmed by laboratory tests 
and/or point-of-care tests (eg, commercial or public health assay, which is approved for 
emergency use). If no diagnostic test results are available that have been obtained during the 
previous 72 hours, then a test should be performed as part of the screening assessment (see 
Section 8.3). 
2. A score of Grade 2 (hospitalized, on invasive mechanical ventilation or ECMO), Grade 3 
(hospitalized, on noninvasive ventilation or high-flow oxygen devices), Grade 4 
(hospitalized, requiring supplemental oxygen), or Grade 5 (hospitalized, not requiring 
supplemental oxygen, requiring ongoing medical care [COVID-19 related or otherwise]), as 
defined by an 8-point ordinal scale. 
3. a) Male patients: 
• A male patient must agree to use contraception as detailed in Appendix 5 of this protocol 
during the treatment period and for at least 6 weeks (or longer if defined in the sub-protocol) 
after the last dose of study treatment and refrain from donating sperm during this period. 
b) Female patients:  
• A female patient is eligible to participate if she is not pregnant (see Appendix 5), not 
breastfeeding, and at least one of the following conditions applies: 
i) Not a woman of childbearing potential (WOCBP) as defined in Appendix 5. 
OR 
ii) A WOCBP who agrees to follow the contraceptive guidance in Appendix 5 during the 
treatment period and for at least 6 weeks (or longer if defined in the sub-protocol) 
after the last dose of study treatment. 


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4. Ability to provide informed consent signed by the study patient or legally authorized 
representative. 
5. Ability and willingness to participate in telephone/telemedicine follow-up visits if needed. 
6. Randomized within 5 days of hospitalization. 
5.2 Exclusion Criteria  
Patients are excluded from the study if any of the following criteria apply (or any of the criteria 
from the appropriate sub-protocol): 
1. Patient with past medical/surgical history and/or any current condition for which, in the 
opinion of the Investigator, participation would be a safety risk or could affect the integrity of 
data. 
2. Stage 4 severe chronic kidney disease or requiring dialysis. 
3. Screening 12-lead electrocardiogram (ECG) with a measurable QTc interval according to 
Fridericia correction ≥500 ms. 
4. Anticipated transfer to another hospital that is not a study center within 72 hours. 
5. Patients who are currently pregnant or who are not willing to discontinue breastfeeding. 
6. Patients participating in another clinical study of an investigational medicinal product or 
other unapproved (or investigational) treatment for COVID-19. 
7. Active tuberculosis or a history of incompletely treated tuberculosis. 
8. Active, uncontrolled systemic bacterial or fungal infection(s). 
9. Where, in the opinion of the Investigator, progression to death is imminent and inevitable 
within the next 48 hours, irrespective of the provision of treatments. 
5.3 Lifestyle Considerations 
Any lifestyle considerations that are specific to the candidate agent will be defined in the 
corresponding sub-protocol. 
Female patients are advised to avoid becoming pregnant during the study; treatment with 
candidate agent will be discontinued for patients who become pregnant. Similarly, male patients 
will be advised to avoid their partners becoming pregnant during the study. 
5.4 Screen Failures 
Screen failures are defined as patients who consent to participate in the clinical study but are not 
subsequently randomly assigned to study treatment. A minimal set of screen failure information 
may be collected to ensure transparent reporting of screen failure patients to meet the 
Consolidated Standards of Reporting Trials publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes demography, screen failure details, 
and any serious adverse event (SAE). 


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6.0 STUDY INTERVENTIONS 
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo, or 
medical device(s) intended to be administered to a patient according to the study protocol. In this 
protocol, the term ‘study treatment’ is typically used to refer to either the candidate agent or 
placebo (and not SoC). 
6.1 Study Intervention(s) Administered 
This platform study will include multiple treatments (candidate agents) and matching placebos 
(each candidate agent will have its own matching placebo) from different pharmaceutical 
companies. Each candidate agent included within the study will have a sub-protocol that will 
provide details of that treatment (including placebo), including route and mode of administration, 
dose, dosage regimen, and duration of treatment. In lieu of matching placebos, candidate agent 
sub-protocols may utilize an unblinded pharmacist to prepare the study treatment. 
These candidate agents may include, but will not be limited to, antivirals, vascular agents, or 
immunomodulatory agents; first-in-human agents will not be considered as candidate agents. 
The SoC will be based on appropriate guidelines in place at a site at the time of treatment on the 
study. The SoC may change during the course of the study as new information becomes available 
about treating COVID-19. 
6.2 Preparation/Handling/Storage/Accountability 
Study treatment (candidate agent or placebo) will be shipped to the study center either directly 
from participating companies, from the Sponsor or candidate agent owner, or from other regional 
or local drug repositories. All other supplies will be provided by the study center. 
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatments received and any discrepancies are reported and 
resolved before use of the study treatment. 
Only patients enrolled in the study may receive a study treatment and only authorized study 
center staff may supply or administer study treatments. All study treatments must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in accordance 
with the labeled storage conditions with access limited to the Investigator and authorized study 
center staff. 
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records). 
Further guidance and information for the final disposition of unused study treatments are 
provided in the Pharmacy Manual for the study treatment. 


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The Investigator, a member of the study center staff, or a hospital pharmacist must maintain an 
adequate record of the receipt and distribution of all study treatments using the Drug 
Accountability Form. These forms must be available for inspection at any time. 
6.3 Measures to Minimize Bias: Randomization and Blinding 
The study will randomize patients on an ongoing basis, in a double-blind manner, to receive 
either one of the active candidate agents plus SoC or to receive placebo plus SoC. 
Randomization will be performed using an Interactive Voice/Web Response System 
(IVRS/IWRS). The system will initially randomize to either an active candidate agent or 
generically to placebo plus SoC. If a patient is randomized to placebo plus SoC, the system will 
then further randomize the patient to a specific candidate agent’s placebo from within the list of 
candidate agents available at the site and for which the patient was determined to be eligible. In 
either of these cases, the blinded team will be aware of the sub-protocol to which the patient has 
been randomized, but not whether it is the active agent or the agent’s matching placebo. The 
system will limit randomization to those agents (or matching placebo) that are active for 
randomization, have not reached their total number of planned patients, have been approved by 
the site, and for which the patient matches the inclusion/exclusion criteria. 
If candidate agents are added to and/or dropped from the study, randomization will proceed with 
an equal probability of assignment to each of the remaining candidate agents, except for 
situations where a patient does not meet the eligibility criteria for, and hence would be excluded 
from, one or more of the sub-protocols.  
Study treatment will be dispensed at randomization or according to the sub-protocol SoA. 
Returned study treatment should not be re-dispensed to patients. 
The IVRS/IWRS will be programmed with blind-breaking instructions. In case of an emergency, 
the Investigator has the sole responsibility for determining if unblinding of a patient’s treatment 
assignment is warranted. Patient safety must always be the first consideration in making such a 
determination. If the Investigator decides that unblinding is warranted, the Investigator may, at 
his/her discretion, contact the Sponsor to discuss the situation prior to unblinding a patient’s 
treatment assignment unless this could delay emergency treatment of the patient. If a patient’s 
treatment assignment is unblinded, the Sponsor must be notified within 24 hours after breaking 
the blind. The date and reason that the blind was broken must be recorded in the source 
documentation and electronic case report form (eCRF), as applicable. The IVRS/IWRS will also 
be programmed with the ability for the safety team to perform a similar blind-breaking activity. 
6.4 Study Treatment Compliance 
For each study treatment, the prescribed dosage, timing, and mode of administration may not be 
changed, except as defined in Section 6.6. Any departures from the intended regimen must be 
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Each dose of study treatment (candidate agent or placebo) will be administered by a member of 
the clinical research team who is qualified and licensed to administer the study product. 
Administration and date, time, and route will be entered into the eCRF. 
6.5 Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the patient is receiving at the time of, or during the two weeks 
prior to, enrollment (including screening) or receives during the study must be recorded in the 
eCRF. In addition, receipt of any COVID-19 vaccine, regardless of when the vaccine was 
received, must be recorded in the eCRF. The following data must be collected in the eCRF for all 
concomitant therapies, including any COVID-19 vaccine: 
• Reason for use. 
• Dates of administration including start and end dates. 
• Dosage information including dose and frequency. 
The Medical Monitor should be contacted if there are any questions regarding concomitant 
therapy. 
If the local SoC per written policies or guidelines (ie, not just an individual clinician decision) 
includes use of off-label medications, then use of these medications during the study is 
permitted. Therapies taken for comorbid conditions, other than COVID-19, are allowed. 
A list of excluded medications/therapy will be provided for each candidate agent in the 
corresponding sub-protocol. 
6.6 Dose Modification 
An Independent Data Monitoring Committee (IDMC) will actively monitor interim safety and 
efficacy data throughout the duration of the study to make recommendations about dose 
modifications, as well as early study closure or changes to the study treatment arms. 
Details of permitted dose modifications for specific candidate agents will be detailed in the 
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7.0 DISCONTINUATION OF STUDY TREATMENT AND 
PATIENT DISCONTINUATION/WITHDRAWAL  
7.1 Discontinuation of Study Treatment 
A patient may withdraw from study treatment at any time at his/her own request or may be 
withdrawn from study treatment at any time at the discretion of the Sponsor or Investigator for 
safety, behavioral, compliance, or administrative reasons. Specifically, a patient in this study 
may discontinue their assigned candidate agent (or placebo) for any of the following reasons: 
• Patient (or their legally authorized representative) requests to discontinue study drug. 
• Occurrence of any medical condition or circumstance that does not allow the patient to 
adhere to the requirements of the protocol or patient fails to comply with protocol 
requirements or study-related procedures. 
• Any SAE, clinically significant AE, severe laboratory abnormality (including abnormal liver 
function test results, see below), intercurrent illness, or other medical condition that indicates 
to the Investigator that continued participation is not in the best interest of the patient. 
• Pregnancy recognized post start and prior to end of study treatment. 
Unless the patient withdraws consent, those who discontinue study treatment early should remain 
in the study for further acquisition of endpoint measurements. The reason for patient 
discontinuation of study treatment should be documented in the eCRF. 
Discontinuation of the study treatment for abnormal liver tests should be considered by the 
Investigator when a patient meets one of the following conditions, after consultation with the 
Medical Monitor: 
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >8 × upper limit of 
normal (ULN) 
• ALT or AST >3 × ULN and either 
− total bilirubin level >2 × ULN, or  
− prothrombin time >1.5 × ULN 
7.2 Patient Discontinuation/Withdrawal from the Study 
A patient may withdraw from the study at any time at his/her own request. 
If the patient withdraws consent for disclosure of future information, the Sponsor or designee 
may retain and continue to use any data collected before such a withdrawal of consent. 
If a patient withdraws from the study, he/she may request destruction of any residual remaining 
samples taken and not tested, and the Investigator must document this in the study center study 


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records. However, any laboratory or test data generated from samples that have already been 
processed and included in secondary translational research may not be recalled. 
See SoA (Section 1.3) for data to be collected at the time of study discontinuation and follow-up 
and for any further evaluations that need to be completed. The specific SoA for a treatment arm, 
either active candidate agent or placebo, will be detailed in the corresponding sub-protocol. 
7.3 Lost to Follow-up 
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits (or does not participate in telephone/telemedicine follow-up visits) and is unable to be 
contacted by the study center. 
The following actions must be taken if a patient fails to return to the study center for a required 
study visit: 
• All efforts should be made to ascertain the vital status of the patient. 
• The study center must attempt to contact the patient and reschedule the missed visit as soon 
as possible and counsel the patient on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the patient wishes to and/or should continue in the 
study. 
• Before a patient is deemed lost to follow-up, the Investigator or designee must make every 
effort to regain contact with the patient (where possible, three telephone calls and, if 
necessary, a certified letter to the patient’s last known mailing address or local equivalent 
methods). These contact attempts should be documented in the patient’s medical record. 
• Should the patient continue to be unreachable, he/she will be considered to have withdrawn 
from the study. Efforts will be made to collect data from public sources to establish vital 
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8.0 STUDY ASSESSMENTS AND PROCEDURES 
Note: Given the nature of the disease and the condition of the patients, it may not always be 
possible to perform all planned assessments at all time points; however, all efforts should be 
made to perform assessments as long as it considered clinically safe to do so. 
An example SoA is presented in Section 1.3. The specific SoA for a treatment arm, either active 
candidate agent or placebo will be detailed in the corresponding sub-protocol. 
Protocol waivers or exemptions are not allowed. 
Immediate safety concerns should be discussed with the 
 Medical Monitor immediately 
upon occurrence or awareness to determine if the patient should continue or discontinue study 
treatment. 
Adherence to the study design requirements, including those specified in the corresponding 
sub-protocol for the candidate agent, is essential and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential patients 
meet all eligibility criteria. The Investigator will maintain a screening log to record details of all 
patients screened and to confirm eligibility or record reasons for screening failure, as applicable.  
Procedures conducted as part of the patient’s routine clinical management (eg, blood work) and 
obtained before signing of the ICF may be utilized for screening or baseline purposes provided 
the procedures met the protocol-specified criteria and were performed within the timeframe 
defined in the SoA. 
8.1 Efficacy Assessments 
8.1.1 
Clinical Severity Status 8-Point Ordinal Scale 
For the purposes of this study, the condition of each potential patient in the study will be 
assessed using an 8-point category ordinal scale8: 
1. Death 
2. Hospitalized, on invasive mechanical ventilation or ECMO 
3. Hospitalized, on noninvasive ventilation or high-flow oxygen devices 
4. Hospitalized, requiring supplemental oxygen 
5. Hospitalized, not requiring supplemental oxygen, requiring ongoing medical care 
(COVID-19 related or otherwise) 
6. Hospitalized, not requiring supplemental oxygen, no longer requires ongoing medical care 
7. Not hospitalized, limitation on activities and/or requiring home oxygen 
8. Not hospitalized, no limitations on activities
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Clarifications regarding the ordinal scale scores are provided in Table 2 and Table 3. To be 
considered for inclusion in the study, patients must be Grade 2 to 5 on this scale at screening and 
at baseline. 
Table 2 
Clarification of the 8-point Ordinal Scale for Scores 2 Through 5 
Ordinal 
Scale 
Score 
General Description 
Expanded Description 
2 
IMV or ECMO 
ECMO or IMV, which includes closed systems, utilizing 
endotracheal intubation or tracheostomy, with ventilator 
assistance. 
3 
NIV, high-flow oxygen 
delivery (>10 L/min) 
NIV includes APAP, BiPAP, and CPAP. High-flow delivery 
systems include HFNC, non-rebreather face mask, and venturi 
mask where the oxygen flow rate is >10 L/min. 
4 
Low-flow oxygen delivery 
(<10 L/min) 
Low-flow oxygen delivery systems include simple face mask and 
simple nasal cannula where the oxygen flow rate is <10 L/min. 
5 
No oxygen requirement 
Not requiring supplemental oxygen but requiring in-hospital 
medical care for any active medical issues. 
Abbreviations: APAP = automatic positive airway pressure; BiPAP = bilevel positive airway pressure; 
CPAP = continuous positive airway pressure; ECMO = extracorporeal membrane oxygenation; 
HFNC = high-flow nasal cannula; IMV = invasive mechanical ventilation; min = minute; NIV = noninvasive 
ventilation. 
A patient will be considered as fit-for-discharge if he/she achieves a score of 6, 7, or 8 on the 
ordinal scale (ie, as a minimum, the patient does not require ongoing hospitalized medical care) 
at least once on the study. Patients who achieve a 7 on the ordinal scale but are discharged to 
hospice care will not be considered as being fit-for-discharge. 
Table 3 
Clarification of the 8-point Ordinal Scale for Scores 6 Through 8 
Ordinal 
Scale 
Score 
General Description 
Expanded Description 
6 
Fit-for-discharge but 
hospitalized 
No longer requiring acute in-hospital medical care; clinically stable 
for discharge, may have ADL limitations, but is awaiting 
post-hospital/outpatient placement, or may have a delay in sourcing 
new or additional home care that makes discharge unadvisable. 
7 
Fit-for-discharge, not 
hospitalized with limitations 
in ADLs and/or oxygen 
needs 
Not hospitalized. This category is reserved for patients with 
limitations in ADL and/or who require home oxygen. 
8 
Fit-for-discharge, not 
hospitalized and no 
limitations in ADL 
Not hospitalized. This category describes patients with no limitations 
in ADL and/or those who have returned to baseline pre-COVID-19 
performance. 
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The primary endpoint will be time to confirmed clinical recovery through Day 29, ie, 
fit-for-discharge, as defined by achieving a score of 6, 7, or 8 on the 8-point ordinal scale of 
clinical severity status, without being rehospitalized through Day 29. 
Incidence of patients achieving ≥2-point improvement from baseline on the ordinal scale or 
fit-for-discharge at Day 29, with fit-for-discharge defined as categories 6, 7, and 8 on the 8-point 
ordinal scale will be a key secondary endpoint. 
Distribution across categories on the 8-point ordinal scale at Days 8, 15, and 29, as well as the 
worst postbaseline score on 8-point ordinal scale from randomization to Day 29, the clinical 
recovery (based on patients who achieve a score of 6, 7, or 8) on Days 8, 15, and 29, and the 
sustained clinical recovery as confirmed by Day 60 will be secondary endpoints. ‘Sustained’ is 
defined as clinical recovery without readmission to a hospital by Day 60. 
8.1.2 
Other Efficacy Assessments 
The following will be evaluated as key secondary endpoints in addition to the key secondary 
endpoints described in Section 8.1.1: 
• Incidence of oxygen-free recovery at Day 29, defined as patients who are alive, discharged, 
and not receiving supplemental oxygen.  
• Incidence of all-cause mortality through Day 29. 
The following will be evaluated as other secondary endpoints: 
• The number of intensive care unit (ICU) days and invasive mechanical ventilator days from 
Day 1 through Day 29. This should include patients who are receiving ICU-level care, even 
though they might not physically be in an established ICU floor.
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8.2 Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (Section 1.3). The specific 
SoA for a treatment arm, either active candidate agent or placebo will be detailed in the 
corresponding sub-protocol. 
8.2.1 
Physical Examinations 
A general physical examination will be performed at screening, including measurement of height 
and weight. 
8.2.2 
Vital Signs 
Temperature, pulse rate, blood pressure, and respiratory rate will be assessed. Blood pressure and 
pulse measurements will be assessed with a completely automated device. SpO2 will also be 
assessed. Manual techniques will be used only if an automated device is not available. 
FiO2, the fractional inspired oxygen, will also be recorded. 
Measurements will be taken in line with standard practices for the study center. 
Vital signs measurements will contribute to the NEWS2 score (see Section 8.1.2). 
8.2.3 
Clinical Safety Laboratory Assessments 
Fasting is not required before collection of laboratory samples. See Appendix 3 for the list of 
clinical laboratory tests to be performed and the SoA (Section 1.3) for the timing and frequency. 
Additional assessments, if required, will be defined in the sub-protocol, as will the sub-protocol 
SoA. 
Additional tests may be performed at any time during the study as deemed necessary by the 
Investigator and/or appropriate designee, or as required by local regulations.  
All protocol-required laboratory assessments must be conducted in accordance with the 
laboratory manual and the SoA. 
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If laboratory values from non-protocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in patient management or are considered clinically 
significant by the Investigator and/or appropriate designee (for example, SAE or AE or dose 
modification), then the results must be recorded in the eCRF. 
Reviewing and Recording Test Results 
The Investigator and/or appropriate designee must review the laboratory report, document this 
review, and record any clinically relevant changes occurring during the study in the AE section 
of the eCRF. The laboratory reports must be filed with the source documents.  
Repeating Testing After Clinically Significant Abnormal Findings 
All laboratory tests with values considered clinically significantly abnormal during participation 
in the study or within 28 days after the last dose of study intervention should be repeated until 
the values return to normal or baseline or are no longer considered clinically significant by the 
Investigator or the Medical Monitor during study participation. If such values do not return to 
normal/baseline within a period of time judged reasonable by the Investigator, the etiology 
should be identified and the candidate agent owner notified. 
8.3 Viral Diagnosis 
Either qualitative and/or quantitative polymerase chain reaction determination of SARS-CoV-2 
or SARS-CoV-2 antigen testing in oropharyngeal/nasal swab will be performed at screening if 
no diagnostic test results are available that have been obtained during the previous 72 hours. 
8.4 Adverse Events 
The definitions of an AE or SAE can be found in Appendix 4. 
AEs may be reported by the patient (or, when appropriate, by a caregiver, surrogate, or the 
patient’s legally authorized representative). 
The Investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE and remain responsible for following up AEs 
that are serious, considered related to the study treatment or study procedures, or that caused the 
patient to discontinue the study treatment (see Section 7.0).  
8.4.1 
Time Period and Frequency for Collecting AE and SAE Information  
AEs will be collected from provision of informed consent until the final follow-up visit, at the 
time points specified in the SoA (Section 1.3 and applicable sub-protocol). 
All SAEs will be recorded and reported to 
 within 24 hours, as indicated in Appendix 4. 
The Investigator will submit any updated SAE data to 
 within 24 hours of it being 
available.
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Investigators are not obligated to actively seek AEs or SAEs after conclusion of the study 
participation. However, if the Investigator learns of any SAE, including a death, at any time after 
a patient has been discharged from the study, and he/she considers the event to be reasonably 
related to the study treatment or study participation, the Investigator must promptly notify 
. 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 4. 
8.4.2 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the patient is the preferred method to inquire about 
AE occurrences.  
8.4.3 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each patient at 
subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, the event is 
otherwise explained, or the patient is lost to follow-up (as defined in Section 7.3). Further 
information on follow-up procedures is given in Appendix 4. 
8.4.4 
Regulatory Reporting Requirements for SAEs 
Clinical sites must notify  
 Safety of any SAE, without regard to causality, within 24 hours 
after becoming aware of its occurrence. Any nonserious AE which worsens and eventually meets 
the criteria for an SAE must also be reported as a new SAE. 
Information regarding SAEs will be transmitted to  
 Safety using the Serious Adverse 
Event Form within Electronic Data Capture (EDC), which must be completed by the clinical site 
within 24 hours of becoming aware of its occurrence. The SAE form in EDC should include a 
clearly written narrative describing signs, symptoms and treatment of the event, diagnostic 
procedures, as well as any relevant laboratory data and an assessment of the causal relationship 
between the event and the investigational product(s). Information not available at the time of the 
initial report (eg, an end date for the AE, laboratory values received after the report, or hospital 
discharge summary) must be documented. All follow-up information must be reported as soon as 
the relevant information is available.  
The initial and follow-up reports of an SAE should be made using the electronic data collection 
tool. If necessary, as a backup, reports can be made by e-mail or facsimile (fax). The contact 
details are: 
 
 
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The  
 Medical Safety Advisor (or designee) must also be notified within 24 hours should 
any patient experience an SAE. Contact information for the SAE Coordinator will be provided 
on the SAE form/completion instructions. 
Contact information for the candidate agent owner will be listed in the corresponding 
sub-protocol, should the sites need to contact the candidate agent owner to discuss any medical, 
safety related questions or SAEs. 
An unlisted (unexpected) AE is one in which the nature or severity is not consistent with the 
applicable product reference safety information. For investigational product(s), the expectedness 
of an AE will be determined by whether or not it is listed in the reference safety information (eg, 
Investigator’s Brochure). Investigators will be notified, and the reference safety information will 
be updated, if any pattern of AEs or laboratory abnormalities is found to be related to compound 
dosing during studies going forward. 
The start date of an SAE reported on the Serious Adverse Event Form must be the same as the 
start date of the corresponding AE documented on the eCRF. If a change in severity is noted for 
the existing AE, it must be recorded. If a worsened AE meets the criteria for an SAE, the start 
date of the SAE must be the same as the start date of the worsened AE. 
All SAEs that have not resolved by the end of the study, or that have not resolved upon 
discontinuation of the patient’s participation in the study, must be followed until any of the 
following occurs: 
• The event resolves; 
• The event stabilizes; 
• The event returns to baseline, if a baseline value is available; 
• The event can be attributed to agents other than the study drugs or to factors unrelated to 
study conduct; 
• It becomes unlikely that any additional information can be obtained (patient or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration of 
due diligence with follow-up efforts). 
Investigator safety reports must be prepared for suspected unexpected serious adverse reactions 
according to local regulatory requirements and Sponsor policy and forwarded to Investigators as 
necessary. Any SAE reports will be reported by the Investigators (or designee) to their local 
IRB/IEC in accordance with local reporting requirements and reporting timelines. 
Similarly, 
 will determine whether an SAE must be reported in an expedited manner to 
regulatory authorities, in accordance with regulatory requirements. If so, 
 will report the 
event to the regulatory authorities in accord with applicable reporting timelines. 
Investigational New Drug (IND) safety reports should also be submitted as a cross-report to the 
relevant commercial INDs of the individual candidate agent owners.
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 will submit a platform Development Safety Update Report (DSUR) for the Master 
Protocol. The platform DSUR will contain data for all compounds and will be presented in a 
tabular format throughout the document.  
 has the ability to redact the tabs in order to 
provide each candidate agent owner with their own required data while still protecting all other 
candidate agent owners’ data. 
 will inform the candidate agent owner of any important safety findings related to the 
candidate agent that arise during the conduct of this study. Similarly, the candidate agent owner 
will inform 
 of any important safety findings related to the candidate agent that they 
become aware of from other studies. 
A joint safety team, with representatives from each candidate agent owner, will meet on a regular 
basis throughout the study to discuss important safety findings that may impact the study. 
8.4.5 
Pregnancy 
All initial reports of pregnancy must be reported to  
 Safety (see Section 8.4.4) by the 
investigational staff within 24 hours of their knowledge of the event using the pregnancy 
reporting form. After the expected pregnancy end date, site will provide  
 Safety with the 
pregnancy outcome, delivery, and infant details for completion and reporting. Abnormal 
pregnancy outcomes are considered SAEs and must be reported using the Serious Adverse Event 
Form. Any patient who becomes pregnant during treatment must immediately discontinue 
treatment with the study treatment.  
In addition, pregnancies in partners of male patients included in the study will be reported by the 
investigation staff within 24 hours of their knowledge of the event using the pregnancy reporting 
form. 
8.4.6 
Adverse Events of Special Interest 
AEs of special interest will be specific to the target candidate agent and, as such, may be defined 
in the corresponding sub-protocol. 
8.4.7 
Disease-Related Events and/or Disease-Related Outcomes 
Progression, signs, or symptoms of the disease being studied and clinically significant abnormal 
laboratory findings or other abnormal safety assessments which are associated with the 
underlying disease should be reported, as appropriate, as an AE or SAE. 
8.5 Treatment of Overdose 
In the event of an overdose of a candidate agent, the Investigator/treating physician should: 
1. Contact the 
 Medical Monitor immediately.
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2. Closely monitor the patient for any AEs/SAEs and laboratory abnormalities until the 
candidate agent can no longer be detected systemically. 
3. Obtain a plasma sample for PK analysis if requested by the Medical Monitor (determined on 
a case-by-case basis). 
4. Document the quantity of the excess dose as well as the duration of the overdose in the 
eCRF. 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the patient. 
8.6 Pharmacokinetics 
Any PK assessments performed will be specific to the candidate agent and will be discussed in 
the corresponding sub-protocol, including a schedule for collection of samples of blood or other 
biological samples for analysis. 
If a patient refuses blood collection for PK analysis, or it is not possible to collect samples for 
logistical reasons, this will not be considered a protocol violation as the PK analysis is not a 
primary or secondary objective of the protocol. 
8.7 Pharmacodynamics 
8.8 Blood for Potential Future Research
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9.0 STATISTICAL CONSIDERATIONS 
9.1 Sample Size Determination  
A total of 350 patients are planned to be randomized to each candidate agent plus SoC. 
Simultaneously, patients will be randomized to placebo plus SoC throughout the course of the 
study. The subset of the placebo plus SoC group, regardless of which sub-protocol the placebo 
belongs, enrolled concurrently to any active agent with matching inclusion/exclusion criteria will 
serve as its comparator group. The primary efficacy endpoint to compare selected treatments plus 
SoC to placebo plus SoC will be the time to clinical recovery up to Day 29, ie, fit-for-discharge, 
as defined by achieving a score of 6, 7, or 8 on the 8-point ordinal scale of clinical severity 
status, without rehospitalization. 
Assuming a median time to clinical recovery of 11 days for patients randomized to an active 
treatment group plus SoC compared with 15 days for those randomized to placebo plus SoC,10 
350 patients are needed per arm in order to observe 490 clinical recovery events between the 
2 treatment groups being compared at the primary analysis. This sample size will provide 
approximately 88% power to detect a hazard ratio (HR) of 1.364 for the occurrence of the 
clinical recovery events, when comparing each candidate agent plus SoC with placebo plus SoC, 
at a 1-sided significance level of 0.025. 
This sample size will provide the following information about the key secondary endpoints: 
assuming the oxygen-free recovery rate at Day 29 is 65% for the placebo plus SoC group, a 
sample size of 350 patients per arm will provide approximately 80% power to detect a 9.7% 
absolute increase in the proportion of patients who have oxygen-free recovery at Day 29 among 
the active treatment group plus SoC group. Assuming 70% of patients randomized to placebo 
plus SoC achieve at least 2-point improvement from baseline on the 8-pt ordinal scale or being 
fit-for-discharge at Day 29, 350 patients per arm will provide approximately 80% 
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detect a 9.2% absolute increase in this proportion with a candidate agent plus SoC at Day 29. 
Assuming the all-cause mortality rate through Day 29 is 15% for the placebo plus SoC group, a 
sample size of 350 patients per arm will provide 80% power to detect an absolute reduction of 
6.75% (8.25% rate for a candidate agent) in the mortality rate by Day 29 in the active treatment 
plus SoC group. Assuming a mortality rate of 15% for the placebo plus SoC group and 19% for a 
candidate agent plus SoC (ie, an adverse treatment effect of 4%), with a sample size of 350 per 
arm, the chance to observe a decrease in the mortality rate of at least 1% with a candidate agent 
plus SoC compared to placebo plus SoC is approximately 4%. The sample size calculation was 
performed using EAST 6.5. 
For a sub-protocol where the primary analysis population is a subset of the randomized 
population, the sample size may be adjusted as applicable to power the designated primary 
analysis population as appropriate. More details will be presented in the sub-protocol SAP. 
Each candidate agent will be evaluated for futility at up to 2 interim analyses. These interim 
analyses will be planned at information fractions of approximately 25% and 55% of expected 
number of recoveries, ie, after approximately 123 and 270 patients have met the primary 
endpoint of clinical recovery on a particular candidate agent plus SoC and placebo plus SoC, 
respectively. However, the timing of the interim analyses may be adjusted due to operational 
considerations, eg, actual enrollment rate. 
For the interim analyses, a Pocock beta spending function will be used for non-binding futility 
boundary specification. This strategy will allow for ineffective agents to be identified early for 
discontinuation of further evaluation. Assuming no treatment effect for a candidate agent plus 
SoC compared with placebo plus SoC, there is a 49.7% chance that enrollment to this agent is 
stopped at the first interim analysis and 34.6% chance at the second interim analysis. Under the 
scenario that treatment has a negative effect on outcomes (Table 7 in Appendix 7) these 
probabilities become 72.3% and 24.7%, respectively. 
The primary analysis for a candidate agent will occur after 350 patients have been randomized to 
an active agent plus SoC and have had the opportunity to complete the Day 29 visit, when 
approximately 490 clinical recovery events are expected to have been observed, unless an agent 
is stopped early for futility. The final analysis for a candidate agent will occur after all patients 
randomized to that agent plus SoC and the concurrent placebo plus SoC controls have had the 
opportunity to complete the Day 60 visit. 
Appendix 7 presents a summary of futility incremental probabilities at the first interim, second 
interim, and the primary analyses together with Pocock futility boundaries in the scenario of 
88.3% estimated power when the analyses occur at information fractions of 25% and 55% of 
expected number of recoveries, respectively. 
Details will be provided in the IDMC charter and SAP. 


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9.2 Populations for Analyses 
For purposes of analysis, the analysis sets in Table 4 are defined. Specific analysis sets may be 
defined in sub-protocols or their corresponding SAPs. 
Table 4 
Analysis Sets for the Master Protocol 
Analysis Set 
Description 
Full Analysis Set 
All patients who are randomized. 
Safety Set 
All patients who are randomized and take at least one dose of study treatment 
or placebo. 
9.3 Statistical Analyses 
The SAPs (for the Master Protocol and for the sub-protocols) will describe the patient analysis 
sets to be included in the analyses and procedures for accounting for missing, unused, and 
spurious data. General principles will be specified in Master Protocol SAP, while specific 
populations and method of handling multiplicity (eg, testing sequences) might be given in 
sub-protocols and further detailed in sub-protocol SAPs. 
Efficacy and safety results will be summarized by scheduled times for the respective analysis 
sets, where appropriate. 
9.3.1 
Primary Efficacy Endpoint Analyses 
The time to confirmed clinical recovery through Day 29, as defined by achieving a score of 6, 7, 
or 8 on the 8-point ordinal scale of clinical severity status, ie, fit-for-discharge, without being 
rehospitalized through Day 29, will be compared between the selected candidate agent plus SoC 
and contemporaneous placebo plus SoC, using a stratified log-rank test, stratifying for baseline 
clinical severity of 2 on the 8-point ordinal scale (yes/no) and remdesivir use at baseline (yes/no), 
with patients who have died prior to or on Day 29 censored at Day 29. Patients who score a 7 on 
the 8-point ordinal scale but are discharged to hospice care will not be considered as 
‘fit-for-discharge.’ The p-value associated with the stratified log-rank test statistic at the time of 
the primary analysis will be compared at the 2-sided 0.05 alpha level. The p-value will also be 
compared with the specified boundaries at the interim analyses for futility in order to serve as 
guidance for the IDMC to make recommendations based on the totality of available information 
at the time of the interim analyses. The HR for the treatment arm plus SoC versus placebo plus 
SoC will be estimated using a Cox regression, adjusting for randomization stratification factors, 
with deaths censored at Day 29. 
9.3.2 
Key Secondary Endpoint Analyses 
The key secondary endpoint of incidence of oxygen-free recovery at Day 29, defined as patients 
who are alive, discharged, and not receiving supplemental oxygen at Day 29, will be analyzed 


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using a logistic regression model with baseline clinical severity of 2 on the 8-point ordinal scale 
(yes/no) and remdesivir use at baseline (yes/no) included as covariates. 
The key secondary endpoint of incidence of patients achieving ≥2-point improvement from 
baseline or being fit-for-discharge on the ordinal scale at Day 29, with fit-for-discharge defined 
as categories 6, 7, and 8 on the 8-point ordinal scale at Day 29, will be analyzed using logistic 
regression with baseline clinical severity of 2 on the 8-point ordinal scale (yes/no) and 
remdesivir use at baseline (yes/no) included as covariates. 
The key secondary endpoint of the incidence of all-cause mortality through Day 29 will be 
analyzed using a logistic regression with baseline clinical severity of 2 on the 8-point ordinal 
scale (yes/no) and remdesivir use at baseline (yes/no) included as covariates. 
A hierarchical testing procedure will be used to control the family-wise type I error over the 
primary hypothesis and three key secondary hypotheses. With this approach, when a particular 
null hypothesis is rejected, the alpha allocated to that hypothesis can be reallocated to other 
hypothesis tests. The hierarchical testing procedure will be implemented in the order of the 
primary endpoint followed by the three key secondary endpoints in the following order: 
oxygen-free recovery at Day 29, at least a 2-point improvement from baseline on the 8-point 
ordinal scale or being fit-for-discharge at Day 29, and all-cause mortality through Day 29. 
9.3.3 
Other Endpoint Analyses 
For the other secondary endpoints, a binary endpoint will be analyzed by logistic regression 
including baseline clinical severity of 2 on the 8-point ordinal scale (yes/no) and remdesivir use 
at baseline (yes/no) as covariates. For ordinal other secondary endpoints, the number and 
percentage of patients in each category will be provided for each treatment arm and will be 
analyzed using a proportional odds model, including the baseline clinical severity of 2 on the 
8-point ordinal scale for clinical severity (yes or no) and remdesivir use at baseline (yes or no) as 
stratification variables. 
 
 
9.3.4 
Missing Data 
All patients recruited into the study will be accounted for, including those who did not complete 
the study along with the reasons for withdrawal. Patients who withdraw from the study will have 
the reason(s) for withdrawal collected in the eCRF. For the key secondary endpoint of 
oxygen-free recovery at Day 29, patients with missing data preventing definition of status 
regarding oxygen-free recovery at Day 29 will not be considered as having met criteria defining 
the endpoint. Details will be presented in the SAP.
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9.4 Review Committees 
9.4.1 
Joint Steering Committee 
A Joint Steering Committee (JSC) will evaluate the recommendations to make decisions on the 
candidate agents within the study, and it will provide guidance, advice, and recommendations to 
the program on relevant clinical issues related to the strategy, implementation, and conduct of the 
study. 
9.4.2 
Independent Data Monitoring Committee 
An IDMC will monitor ongoing data to ensure patient well-being and safety as well as study 
integrity. The IDMC will be asked to make recommendations to the JSC regarding early 
termination or modification of the evaluation of a candidate agent. More details will be provided 
in the IDMC charter. 
A data safety review by the IDMC may be conducted regularly, whereas whether the interim 
analyses would be conducted or not for a certain agent will be determined by the number of 
observed occurrences of clinical recovery in that particular experimental arm and 
contemporaneous placebo + SoC. 


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10.0 REFERENCES 
1. Hamming I, Timens W, Bulthuis ML, Lely AT, Navis G, van Goor H. Tissue distribution 
of ACE2 protein, the functional receptor for SARS coronavirus. A first step in 
understanding SARS pathogenesis. J Pathol. 2004 Jun;203(2):631-7. 
2. Tang X, Wu C, Li X, et al. On the origin and continuing evolution of SARS-CoV-2. Natl 
Sci Rev. 2020;nwaa036. 
3. World Health Organization. COVID-19 situation reports. 
https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports 
[accessed 02 April 2021]. 
4. Price-Haywood EG, Burton J, Fort D, Seoane L. Hospitalization and mortality among 
Black patients and White patients with COVID-19. N Engl J Med. 2020 
Jun;382(26):2534-43. 
5. Muñoz-Price LS, Nattinger AB, Rivera F, et al. Racial disparities in incidence and 
outcomes among patients with COVID-19. JAMA Netw Open. 2020 Sep;3(9):e2021892. 
6. Spagnolo PA, Manson JE, Joffe H. Sex and gender differences in health: what the 
COVID-19 pandemic can teach ss. Ann Intern Med. 2020 Sep;173(5):385-6. 
7. Centers for Disease Control and Prevention. COVID-19 hospitalization and death by 
race/ethnicity. https://www.cdc.gov/coronavirus/2019-ncov/covid-data/investigations-
discovery/hospitalization-death-by-race-ethnicity.html [accessed 02 April 2021] 
8. ClinicalTrials.gov. Adaptive COVID-19 Treatment Trial (ACTT). 
https://clinicaltrials.gov/ct2/show/study/NCT04280705 [accessed 08 May 2020]. 
9. Royal College of Physicians. National Early Warning Score (NEWS) 2: Standardising the 
Assessment of Acute‐illness Severity in the NHS – Updated Report of a Working Party. 
Royal College of Physicians: London, 2017. 
https://www.rcplondon.ac.uk/file/8504/download [accessed 08 May 2020]. 
10. National Institutes of Health. COVID-19 is an emerging, rapidly evolving situation. 
29 April 2020. https://www.nih.gov/news-events/news-releases/nih-clinical-trial-shows-
remdesivir-accelerates-recovery-advanced-covid-19 [accessed 08 May 2020]. 


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11.0 APPENDICES 


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Appendix 1 
Abbreviations 
Abbreviation 
Definition 
21 CFR 
Code of Federal Regulations Title 21 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
COVID-19 
Coronavirus disease 2019 
DSUR 
Development Safety Update Report 
ECG 
Electrocardiogram 
ECMO 
Extracorporeal membrane oxygenation 
eCRF 
Electronic case report form 
EDC 
Electronic Data Capture 
FiO2 
Fraction of inspired oxygen 
FSH 
Follicle stimulating hormone 
GCP 
Good Clinical Practice 
HR 
Hazard ratio 
HRT 
Hormone replacement therapy 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
ICU 
Intensive care unit 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Response System 
JSC 
Joint Steering Committee 
PK 
Pharmacokinetic 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SoA 
Schedule of Activities
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Abbreviation 
Definition 
SoC 
Standard of care 
SpO2 
Oxygen saturation 
ULN 
Upper limit of normal 
WOCBP 
Woman of childbearing potential 
 


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Appendix 2 
Regulatory, Ethical, and Study Oversight Considerations 
Protocol Compliance 
The Investigator agrees to comply with the requirements of the Protocol and Good Clinical 
Practice (GCP). Prospective, planned deviations or waivers to the protocol are not permitted; 
eg, it is not acceptable to enroll a patient if they do not meet the eligibility criteria or restrictions 
specified in the protocol. 
Accidental protocol deviations can happen at any time. They must be adequately documented on 
the relevant forms and reported to the Chief Investigator and 
 immediately.  
Deviations from the protocol, which are found to frequently recur, are not acceptable and will 
require immediate action by the Sponsor. Frequent non-compliances could potentially be 
classified as a serious breach. 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the Master Protocol and sub-protocols and 
with the following: 
− Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines. 
− Applicable International Council for Harmonisation (ICH) GCP Guidelines. 
− Applicable laws and regulations. 
• The Master Protocol, sub-protocol, protocol amendments, ICF, Investigator Brochures, and 
other relevant documents (eg, advertisements) must be submitted to an IRB/IEC by the 
Investigator and reviewed and approved by the IRB/IEC before the study is initiated. 
• In regions where more than one sub-protocol has received local regulatory and IRB/IEC 
approval, it is required that participating sites are activated for enrollment for all approved 
sub-protocols. 
• Any substantial amendments to the protocol will require IRB/IEC and regulatory authority 
approval, when applicable, before implementation of changes made to the study design, 
except for changes necessary to eliminate an immediate hazard to patients.  
• The Investigator will be responsible for the following: 
− Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC. 
− Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures.
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− Providing oversight of the conduct of the study at the study center and adherence to 
requirements of the Code of Federal Regulations Title 21 (21 CFR), ICH guidelines, 
the IRB/IEC, European regulation 536/2014 for clinical studies (if applicable), and all 
other applicable local regulations. 
• After reading the protocol, each Investigator will sign the protocol signature page and send a 
copy of the signed page to the Sponsor or designee 
(Appendix 8). The study will 
not start at any study center at which the Investigator has not signed the protocol. 
Financial Disclosure 
Investigators and sub-Investigators will provide the Sponsor or designee  
 with sufficient, 
accurate financial information as requested to allow the Sponsor or designee  
 to submit 
complete and accurate financial certification or disclosure statements to the appropriate 
regulatory authorities. Investigators are responsible for providing information on financial 
interests during the course of the study and for one year after completion of the study. 
Insurance 
Sponsor will provide insurance in accordance with local guidelines and requirements as a 
minimum for the patients in this study. The terms of the insurance will be kept in the study files. 
Due to the coronavirus public health crisis, in the US the federal government has a program that 
may provide compensation to the patient or their family if the patient experiences serious 
physical injuries or death as a result of participating in this clinical trial covered by the Public 
Readiness and Emergency Preparedness Act. More information regarding this Countermeasures 
Injury Compensation Program is available at https://www.hrsa.gov/cicp/index.html or by calling 
1-855-266-2427. 
Informed Consent Process 
The Investigator or his/her representative will explain the nature of the study to the patient or 
his/her legally authorized representative and answer all questions regarding the study.  
Patients must be informed that their participation is voluntary. Patients or their legally authorized 
representative will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act requirements, where applicable, and the IRB/IEC or study center.  
The medical record must include a statement that informed consent was obtained before the 
patient was entered in the study and the date the consent was obtained. The authorized person 
obtaining the informed consent must also sign the ICF. 
Patients must be re-consented to the most current version of the ICF(s) during their participation 
in the study. 
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A copy of the ICF(s) must be provided to the patient or the patient’s legally authorized 
representative.  
Data Protection 
Patients will be assigned a unique identifier by 
. Any patient records or datasets that are 
transferred to the Sponsor, designee  
, or any candidate agent owner will contain the 
identifier only; patient names or any information which would make the patient identifiable will 
not be transferred. 
The patient must be informed that his/her personal study-related data will be used by the Sponsor 
in accordance with local data protection law. The level of disclosure must also be explained to 
the patient. 
The patient must be informed that his/her medical records may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by the Sponsor, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities. 
Administrative Structure 
The trial will be overseen by a JSC that has decision-making rights on critical decisions that 
impact the platform trial. The JSC, at a minimum, will be composed of a senior representative of 
each company participating in the trial. 
The administrative structure will be documented in more detail in the Trial Master File. 
Medical Monitor 
The 
 (Medical Monitor) is available for 24 hours a 
day/7 days a week urgent contact.  
The following additional numbers are available for urgent contact: 
 
 
 
 
 
 
 
Dissemination of Clinical Study Data 
The results of the study should be reported within one year from the end of the overall clinical 
study. Irrespective of the outcome, the Sponsor will submit to US National Institutes of Health’s 
website www.ClinicalTrials.gov and other publicly-accessible sites within one year from the end 
of the overall clinical study. It shall be accompanied by a summary written in a manner that is 
understandable to laypersons.
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Data Quality Assurance 
All patient data relating to the study will be recorded on eCRFs unless transmitted to the Sponsor 
or designee 
 electronically (eg, laboratory data). The Investigator is responsible for 
verifying that data entries are accurate and correct by physically or electronically signing the 
eCRF.  
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.  
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents.  
The Sponsor or designee 
 is responsible for the data management of this study including 
quality checking of the data.  
Study monitors will perform ongoing source data review to confirm that data entered into the 
eCRF by authorized study center personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of patients are being protected; and that the study is being 
conducted in accordance with the currently approved protocol and any other study agreements, 
ICH GCP, and all applicable regulatory requirements.  
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the Investigator in accordance with local regulations. No records may be destroyed 
during the retention period without the written approval of the Sponsor. No records may be 
transferred to another location or party without written notification to the Sponsor.  
Source Documents 
The Investigator/institution should maintain adequate and accurate source documents and study 
records that include all pertinent observations on each of the study center’s patients. Source data 
should be attributable, legible, contemporaneous, original, accurate, and complete. Changes to 
source data should be traceable, should not obscure the original entry, and should be explained if 
necessary (eg, via an audit trail). 
Source documents provide evidence for the existence of the patient and substantiate the integrity 
of the data collected. Source documents are filed at the Investigator’s study center. 
Data reported on the eCRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
Investigator may need to request previous medical records or transfer records, depending on the 
study. Also, current medical records must be available. 
Definition of what constitutes source data can be found in the eCRF completion guidelines.
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Study and Study Center Closure 
The Sponsor reserves the right to close the study center or terminate the study at any time for any 
reason at the sole discretion of the Sponsor. Study centers will be closed upon study completion. 
A study center is considered closed when all required documents and study supplies have been 
collected and a study center closure visit has been performed. 
The Investigator may initiate study center closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study center by the Sponsor or Investigator may include but 
are not limited to: 
• Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the Sponsor’s procedures, or GCP guidelines. 
• Inadequate recruitment of patients by the Investigator. 
• Discontinuation of further study treatment development. 
Publication Policy 
To coordinate dissemination of data from this study, the Sponsor may facilitate the formation of 
a Publication Committee, the governance and responsibilities of which are set forth in a 
Publication Charter. The committee is expected to solicit input and assistance from other 
Investigators and to collaborate with authors and Amgen staff, as appropriate, as defined in the 
Publication Charter. Membership on the committee does not guarantee authorship. The criteria 
described below are to be met for every publication. 
Authorship of any publications resulting from this study will be determined on the basis of the 
Uniform Requirement for Manuscripts Submitted to Biomedical Journals International 
Committee of Medical Journal Editors Recommendations for the Conduct of Reporting, Editing, 
and Publications of Scholarly Work in Medical Journals, which states: Authorship credit is to be 
based on: (1) substantial contributions to conception and design, acquisition of data, or analysis 
and interpretation of data; (2) drafting the article or revising it critically for important intellectual 
content; (3) final approval of the version to be published; and (4) agreement to be accountable 
for all aspects of the work in ensuring that questions related to the accuracy or integrity of any 
part of the work are appropriately investigated and resolved. Authors need to meet conditions 1, 
2, 3, and 4. 
When a large, multicenter group has conducted the work, the group is to identify the individuals 
who accept direct responsibility for the manuscript. These individuals must fully meet the criteria 
for authorship defined above. Acquisition of funding, collection of data, or general supervision 
of the research group, alone, does not justify authorship. All persons designated as authors must 
qualify for authorship, and all those who qualify are to be listed. Each author must have 
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content. All publications (eg, manuscripts, abstracts, oral/slide presentations, book chapters) 
based on this study must be submitted to the Publication Committee for review. The Clinical 
Trial Agreement among the institution, Investigator, and the Consortium will detail the 
procedures for, and timing of, the Publication Committee’s review of publications. 


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Appendix 3 
Clinical Laboratory Tests  
The minimum tests to be performed are detailed in Table 5. Any additional tests that are specific 
for the candidate agent will be detailed in the corresponding sub-protocol. Clinical laboratory 
tests will be performed at a local laboratory. 
Protocol-specific requirements for inclusion or exclusion of patients are detailed in Section 5.0 of 
the protocol. 
Additional tests may be performed at any time during the study as determined necessary by the 
Investigator or required by local regulations. 
Changes to some laboratory parameters are anticipated for any patients moving on to ECMO 
therapy. 
Investigators must document their review of each laboratory safety report. 


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Table 5 
Protocol-required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet Count 
Hemoglobin 
White blood cell count with differential: 
  Neutrophils 
  Lymphocytes 
  Monocytes 
  Eosinophils 
  Basophils 
Coagulation 
D-dimer test 
Fibrinogen 
Activated partial thromboplastin time (aPTT) 
Prothrombin time (PT) 
International Normalized Ratio (INR) 
C-reactive protein 
Ferritin 
Lactate dehydrogenase (LDH) 
Procalcitonin 
Clinical 
Chemistry 
Potassium 
Sodium 
Calcium 
Magnesium 
Phosphate 
Bicarbonate 
Creatinine 
Glucose 
Liver Function 
Tests 
Alkaline phosphatase 
Total bilirubin 
Aspartate aminotransferase (AST) 
Alanine aminotransferase (ALT) 
Gamma-glutamyl transferase (GGT) 
Cardiac Panel 
Creatine kinase (MB fraction) 
Triglycerides 
Troponin 
 


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Appendix 4 
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
For completeness, the full guidance for AE reporting is presented in this appendix. 
Definition of AE 
AE Definition 
• An AE is any untoward medical occurrence in a patient or subject, temporally associated with the use 
of study treatment, whether or not considered related to the study treatment. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of 
study treatment. 
 
Events Meeting the AE Definition  
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety 
assessments (eg, ECG, radiological scans, vital signs measurements), including those that worsen from 
baseline, considered clinically significant in the medical and scientific judgment of the Investigator. 
• Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study treatment administration even though it may have 
been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study treatment or a 
concomitant medication. Overdose per se will not be reported as an AE/SAE unless it is an intentional 
overdose taken with possible suicidal/self-harming intent. Such overdoses should be reported 
regardless of sequelae. 
• “Lack of efficacy” or “failure of expected pharmacological action” per se will not be reported as an AE 
or SAE. Such instances will be captured in the efficacy assessments. However, the signs, symptoms, 
and/or clinical sequelae resulting from lack of efficacy will be reported as AE or SAE if they fulfill the 
definition of an AE or SAE. 
 
Events NOT Meeting the AE Definition  
• Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to the 
procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the 
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Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
An SAE is defined as any untoward medical occurrence that, at any dose: 
a) Results in death 
b) Is life-threatening 
The term ‘life-threatening’ in the definition of “serious” refers to an event in which the patient was at risk 
of death at the time of the event. It does not refer to an event, which hypothetically might have caused 
death, if it were more severe. 
c) Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the patient has been detained (usually involving at least an 
overnight stay) at the hospital or emergency ward for observation and/or treatment that would not have 
been appropriate in the physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other serious criteria, the 
event is serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE should 
be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is not 
considered an AE. 
d) Results in persistent disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. 
• This definition is not intended to include experiences of relatively minor medical significance such as 
uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (eg, sprained 
ankle) which may interfere with or prevent everyday life functions but do not constitute a substantial 
disruption. 
e) Is a congenital anomaly/birth defect 
f) Other situations: 
• Medical or scientific judgment should be exercised in deciding whether SAE reporting is appropriate 
in other situations such as important medical events that may not be immediately life-threatening or 
result in death or hospitalization but may jeopardize the patient or may require medical or surgical 
intervention to prevent one of the other outcomes listed in the above definition. These events should 
usually be considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that do not result in 
hospitalization, or development of drug dependency or drug abuse. 
 


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Recording and Follow-up of AE and/or SAE 
AE and SAE Recording 
• When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (eg, 
hospital progress notes, laboratory reports, and diagnostics reports) related to the event. 
• The Investigator will then record all relevant AE/SAE information in the eCRF. Each event must be 
recorded separately. 
• It is not acceptable for the Investigator to send photocopies of the patient’s medical records to 
 
in lieu of completion of the AE/SAE eCRF page. 
• There may be instances when copies of medical records for certain cases are requested by 
. In 
this case, all patient identifiers, with the exception of the patient number, will be redacted on the copies 
of the medical records before submission to 
. 
• The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or 
other clinical information. Whenever possible, the diagnosis (not the individual signs/symptoms) will 
be documented as the AE/SAE. 
Assessment of Intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during the study and 
assign it to one of the following Common Terminology Criteria for Adverse Events grades:  
• Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention 
not indicated. 
• Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age appropriate 
instrumental activities of daily living (preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc). 
• Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living 
(bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden). 
• Grade 4 Life-threatening consequences; urgent intervention indicated. 
• Grade 5 Death related to AE. 
An event is defined as ‘serious’ when it meets at least one of the predefined outcomes as described in 
the definition of an SAE, NOT when it is rated as severe (Grade 3 and higher). 
 
Assessment of Causality 
• The Investigator is obligated to assess the relationship between study treatment and each occurrence of 
each AE/SAE. The AE must be characterized as related or unrelated. 
o “Related” conveys that there are facts, evidence, and/or arguments to suggest a causal 
relationship for the individual case. 
o “Unrelated” is used if there is not a reasonable possibility that the study treatment caused the 
AE.  
• The Investigator will use clinical judgment to determine the relationship. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as well 
as the temporal relationship of the event to study treatment administration will be considered and 
investigated. 
• The Investigator will also consult the Investigator’s Brochure and/or Product Information, for 
marketed products, in his/her assessment. 
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• For each AE/SAE, the Investigator must document in the medical notes that he/she has reviewed the 
AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred, and the Investigator has minimal information 
to include in the initial report to 
. However, it is very important that the Investigator always 
make an assessment of causality for every event before the initial transmission of the SAE data to 
. 
• The Investigator may change his/her opinion of causality in light of follow-up information and send an 
SAE follow-up report with the updated causality assessment. 
• The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
 
Follow-up of AEs and SAEs 
• The Investigator is obligated to perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested by 
 to elucidate the nature and/or 
causality of the AE or SAE as fully as possible. This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health care professionals. 
• If a patient dies during participation in the study or during a recognized follow-up period, the 
Investigator will provide 
 with a copy of any postmortem findings including histopathology. 
• New or updated information will be recorded in the originally completed eCRF. 
• The Investigator will submit any updated SAE data to 
 within 24 hours of receipt of the 
information. 
 
Reporting of SAEs 
SAE Reporting via an Electronic Data Collection Tool 
• The primary mechanism for reporting an SAE to 
 will be the electronic data collection tool. 
• If the electronic system is unavailable for more than 24 hours, then the study center will use the paper 
SAE data collection tool (see next section). 
• The study center will enter the SAE data into the electronic system as soon as it becomes available. 
• After the study is completed at a given study center, the electronic data collection tool will be taken 
off-line to prevent the entry of new data or changes to existing data. 
• If a study center receives a report of a new SAE from a patient or receives updated data on a previously 
reported SAE after the electronic data collection tool has been taken off-line, then the study center can 
report this information on a paper SAE form (see next section) or to the Medical Safety Advisor/SAE 
Coordinator by telephone. 
SAE Reporting via Paper Case Report Form 
• Facsimile transmission of the SAE paper case report form is the preferred method to transmit this 
information to the Medical Safety Advisor or the SAE Coordinator. 
• In rare circumstances and in the absence of facsimile equipment, notification by telephone is 
acceptable with a copy of the SAE data collection tool sent by overnight mail or courier service. 
• Initial notification via telephone does not replace the need for the Investigator to complete and sign the 
SAE eCRF pages within the designated reporting time frames. 
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COV-01 – Master Protocol 
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Appendix 5 
Contraceptive Guidance and Collection of Pregnancy 
Information 
Definitions: 
Woman of Childbearing Potential 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with one of the following: 
a) Documented hysterectomy. 
b) Documented bilateral salpingectomy. 
c) Documented bilateral oophorectomy. 
Note: Documentation can come from the study center personnel’s: review of the patient’s 
medical records, medical examination, or medical history interview. 
3. Postmenopausal female: 
a) A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormone replacement therapy (HRT). However, in the absence of 
12 months of amenorrhea, a single FSH measurement is insufficient.  
b) Females on HRT and whose menopausal status is in doubt will be required to use one of 
the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
Contraception Guidance 
Male patients 
• Male patients with female partners of childbearing potential are eligible to participate if they 
agree to ONE of the following:  
− Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent. 
− Agree to use a male condom plus partner use of a contraceptive method with a failure 
rate of <1% per year as described in the table below when having penile-vaginal 
intercourse with a WOCBP who is not currently pregnant. 
• In addition, male patients must refrain from donating sperm for the duration of the study and 
for 6 weeks (or longer if defined in the sub-protocol) after the last dose of study treatment. 


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• Male patients with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile-vaginal intercourse or use a male condom during each episode of penile penetration 
for the duration of the study and for 6 weeks (or longer if defined in the sub-protocol) after 
the last dose of study treatment. 
Female patients 
Female patients of childbearing potential are eligible to participate if they agree to use a highly 
effective method of contraception consistently and correctly as described in the table below. 
Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User Dependent
 a  
Failure rate of <1% per year when used consistently and correctly.  
Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulationb  
• Oral.  
• Intravaginal.  
• Transdermal. 
Progestogen only hormonal contraception associated with inhibition of ovulation 
• Oral. 
• Injectable.  
Highly Effective Methods That Are User Independent a  
Implantable progestogen only hormonal contraception associated with inhibition of ovulation
b 
• Intrauterine device. 
• Intrauterine hormone-releasing system. 
Bilateral tubal occlusion. 
Vasectomized Partner  
A vasectomized partner is a highly effective birth control method provided that the partner is the sole male sexual 
partner of the WOCBP, and the absence of sperm has been confirmed. If not, an additional highly effective method 
of contraception should be used.  
Sexual Abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study treatment. The reliability of sexual abstinence 
needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the patient.  
NOTES:  
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with 
local regulations regarding the use of contraceptive methods for patients participating in clinical studies.  
b Hormonal contraception may be susceptible to interaction with the study treatment, which may reduce the efficacy 
of the contraceptive method. In this case, 2 highly effective methods of contraception should be utilized during 
the treatment period and for at least 6 weeks (or longer if defined in the sub-protocol) after the last dose of study 
treatment.  
 


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Pregnancy Testing: 
WOCBP should only be included after a confirmed menstrual period and a negative highly 
sensitive pregnancy test. 
Pregnancy testing will also be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected.  
Collection of Pregnancy Information 
Study treatment will be discontinued for patients who become pregnant. 
The Investigator will collect pregnancy information on any female patient who becomes 
pregnant while participating in this study. Information will be recorded on the appropriate form 
and submitted to 
within 24 hours of learning of a patient’s pregnancy. The patient will be 
followed to determine the outcome of the pregnancy. The Investigator will collect follow-up 
information on the patient and the neonate and the information will be forwarded to 
. 
Generally, follow-up will not be required for longer than 6 to 8 weeks beyond the estimated 
delivery date. Any termination of pregnancy will be reported, regardless of fetal status (presence 
or absence of anomalies) or indication for the procedure. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy will be reported as an AE or SAE. A spontaneous abortion is 
always considered to be an SAE and will be reported as such. 
Any poststudy pregnancy-related SAE considered reasonably related to the study treatment by 
the Investigator will be reported to 
 as described in Section 8.4.4. While the Investigator is 
not obligated to actively seek this information in former patients, he or she may learn of an SAE 
through spontaneous reporting. 
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COV-01 – Master Protocol 
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Appendix 7 
Summary of Futility Probabilities and Boundaries 
Table 6 
Summary of Futility Probabilities and Boundaries with 88.3% Power Using 
Pocock Futility Boundaries 
Analysis 
Total Number of 
Events 
(Information 
Fraction) 
Boundary of 
Futility, Non-
binding (HR) 
Boundary of 
Futility, 
Non-binding 
(p-value) 
Incremental 
Probability to 
Declare Futility 
Under the Null 
(HR=1) 
First Interim 
123 (25%) 
≤0.998 
0.503 
0.497 
Second Interim 
270 (55%) 
≤1.121 
0.175 
0.346 
Abbreviation: HR=hazard ratio. 
Assume 1-sided α of 0.025. 
Interim analysis using Pocock futility boundaries at 25% and 55% information fraction. 
HR boundaries are translated from p-values. Dependent of relative timing and will be re-calculated for Independent 
Data Monitoring Committee. 
Table 7 
Summary of Futility Probabilities and Boundaries with 88.3% Power Using 
Pocock Futility Boundaries for the Negative Treatment Effect Scenario 
(HR=0.9) 
Analysis 
Total Number of 
Events 
(Information 
Fraction) 
Boundary of 
Futility, 
Non-binding (HR) 
Boundary of 
Futility, 
Non-binding 
(p-value) 
Incremental 
Probability to 
Declare Futility 
Under the Negative 
Treatment Effect 
Scenario (HR=0.9) 
First Interim 
123 (25%) 
≤0.998 
0.503 
0.723 
Second Interim 
270 (55%) 
≤1.121 
0.175 
0.247 
Abbreviation: HR=hazard ratio. 
Assume 1-sided α of 0.025. 
Interim analysis using Pocock futility boundaries at 25% and 55% information fraction. 
HR boundaries are translated from p-values. Dependent of relative timing and will be re-calculated for Independent 
Data Monitoring Committee. 


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COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
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Appendix 8 
Signature of Investigator 
PROTOCOL TITLE: Industry Alliance Platform Trial to Assess the Efficacy and Safety of 
Multiple Candidate Agents for the Treatment of COVID-19 in Hospitalized Patients 
PROTOCOL NO: COV-01 
VERSION:   
Protocol Amendment 4 
This protocol is a confidential communication of the Sponsor. I confirm that I have read this 
protocol, I understand it, and I will work according to this protocol. I will also work consistently 
with the ethical principles that have their origin in the Declaration of Helsinki and that are 
consistent with Good Clinical Practices and the applicable laws and regulations. Acceptance of 
this document constitutes my agreement that no unpublished information contained herein will 
be published or disclosed without prior written approval from the Sponsor. 
Instructions to the Investigator:  Please SIGN and DATE this signature page. PRINT your name, title, and the name of the study 
center in which the study will be conducted. Return the signed copy to the CRO/Sponsor. 
 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
 
Signature of Investigator:       
__________________________            Date:  ________ 
Printed Name:                                 ___________________________ 
Investigator Title:                            ___________________________ 
 
Name/Address of Center:               ___________________________ 
 
 
 
 
 
___________________________ 
 
 
 
 
 
___________________________ 
 


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COV-01-001 – Sub-protocol for Lanadelumab-IV 
Version 1.2, 26 October 2020 
1 
TITLE PAGE 
Master Protocol Title: Industry Alliance Platform Trial to Assess the Efficacy and Safety of 
Multiple Candidate Agents for the Treatment of COVID-19 in Hospitalized Patients 
Sub-protocol Number: COV-01-001 
Sub-protocol for Candidate Agent: Lanadelumab-IV 
Short Title: COVID-19 Multiple Agents and Modulators Unified Industry Members Trial 
(COMMUNITY) 
Study Phase: 3 
Candidate Agent Owner: Takeda Development Center Americas 
Legal Registered Address: 95 Hayden Avenue, Lexington, MA 02421, USA 
 
Regulatory Agency Identifying Number(s):  IND 150485 
  
  
  
  
  
 
EudraCT 2020-002594-10 
 
Date of Sub-protocol: 26 October 2020 
Version: 1.2 
 
Candidate Agent Owner Contact: 
 
 
 
PPD
 
 


CONFIDENTIAL 
COV-01-001 – Sub-protocol for Lanadelumab-IV 
Version 1.2, 26 October 2020 
2 
Candidate Agent Owner (Takeda) Signatory: 
 
 
I have read this sub-protocol in its entirety and agree to conduct this part of the study accordingly: 
 
Takeda Development Center Americas 
 Date 
 
 
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CONFIDENTIAL 
COV-01-001 – Sub-protocol for Lanadelumab-IV 
Version 1.2, 26 October 2020 
3 
TABLE OF CONTENTS 
TITLE PAGE 
...........................................................................................................................1
 
TABLE OF CONTENTS ........................................................................................................3
 
TABLE OF TABLES 
...............................................................................................................5
 
TABLE OF FIGURES 
.............................................................................................................5
 
PROTOCOL VERSION SUMMARY 
...................................................................................6
 
1.0 
SUB-PROTOCOL SUMMARY 
.................................................................................7
 
1.1 
Overview of Sub-protocol ................................................................................7
 
1.2 
Schedule of Activities 
.......................................................................................9
 
1.3 
End of Study Definition for Sub-protocol 
....................................................13 
2.0 
BACKGROUND/RATIONALE IN SUPPORT OF LANADELUMAB-IV 
IN COVID-19 .............................................................................................................14 
2.1 
Benefit/Risk Assessment 
................................................................................14
 
2.2 
Dose Justification for Lanadelumab-IV.......................................................15
 
3.0 
STUDY POPULATION 
............................................................................................18
 
3.1 
Enrolment and Screening 
..............................................................................18
 
3.2 
Eligibility Criteria 
..........................................................................................18
 
3.2.1 Inclusion Criteria 
...............................................................................18
 
3.2.2 Exclusion Criteria 
..............................................................................18
 
3.3 
Primary Analysis Population 
........................................................................18 
3.4 
Discontinuation of Study Treatment and Patient 
Discontinuation/Withdrawal 
.........................................................................19
 
3.4.1 Discontinuation of Study Treatment .................................................19 
3.4.2 Patient Discontinuation/Withdrawal from the Study ........................19
 
4.0 
STUDY ASSESSMENTS AND PROCEDURES 
....................................................20
 
4.1 
Safety Assessments 
.........................................................................................20
 
4.1.1 Adverse Events 
..................................................................................20 
4.1.2 Clinical Safety Laboratory Assessments 
...........................................22
 
4.2 
Pharmacokinetic Assessments 
......................................................................22
 
4.3 
Pharmacodynamic Assessments 
...................................................................23
 
4.4 
Plasma Anti-Drug Antibody Testing 
............................................................23
 
4.5 
Future Biomedical Research 
.........................................................................23
 


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COV-01-001 – Sub-protocol for Lanadelumab-IV 
Version 1.2, 26 October 2020 
4 
5.0 
STUDY TREATMENT 
.............................................................................................24
 
5.1 
Treatment Plan...............................................................................................24
 
5.2 
Study Drug Administration ..........................................................................24
 
5.3 
Preparation/Handling/Storage/Accountability 
...........................................24
 
5.4 
Dose Modifications and Toxicity Management 
...........................................25 
5.5 
Treatment of Overdose 
..................................................................................26
 
5.6 
Concomitant Medications .............................................................................26
 
5.6.1 Rescue Medication ............................................................................26
 
5.7 
Study Drug Information 
................................................................................26
 
6.0 
REFERENCES 
...........................................................................................................27
 
7.0 
APPENDICES 
............................................................................................................30
 
Appendix 1
 Abbreviations 
...................................................................................31
 
Appendix 2
 Clinical Laboratory Tests 
...............................................................32
 
Appendix 3 Signature of Investigator ................................................................34 
 


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COV-01-001 – Sub-protocol for Lanadelumab-IV 
Version 1.2, 26 October 2020 
5 
TABLE OF TABLES 
Table 1 
Predicted Clinical Exposure Margins Compared to Observed 
Exposure (NOAEL) in Cynomolgus Monkeys 
................................................17 
Table 2
 
Protocol-required Safety Laboratory Assessments 
..........................................33
 
 
TABLE OF FIGURES 
Figure 1 
Potential Role of the Kallikrein-kinin System in Lung Inflammation 
and Hypercoagulability in Coronavirus Disease 2019 .......................................8
 


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COV-01-001 – Sub-protocol for Lanadelumab-IV 
Version 1.2, 26 October 2020 
6 
PROTOCOL VERSION SUMMARY 
Protocol Version 1.2 
Protocol Version 1.2 (dated 26 October 2020) replaces the final Version 1.1 protocol (dated 
20 October 2020). The version incorporates the following main changes: 
• In the Schedule of Activities: 
− Clarifies procedures for obtaining/recording patient height and weight. 
− Removes the optional clinical safety laboratory assessments (hematology, clinical 
chemistry, and liver function tests) on Days 5, 11, and 18. 
Protocol Version 1.1 
Protocol Version 1.1 (dated 20 October 2020) replaces the final Version 1.0 protocol (dated 
06 October 2020). The version incorporates the following main changes: 
• Adds C-reactive protein, lactate dehydrogenase, ferritin, fibrinogen, and D-dimer to the list 
of pharmacodynamic assessments. 
• Clarifies timing of sample collection for pharmacokinetic and pharmacodynamic 
assessments. 


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COV-01-001 – Sub-protocol for Lanadelumab-IV 
Version 1.2, 26 October 2020 
7 
1.0 SUB-PROTOCOL SUMMARY 
1.1 Overview of Sub-protocol 
Lanadelumab (TAKHZYRO™, TAK-743, formerly SHP643 or DX-2930) is currently approved 
for prophylaxis to prevent attacks of hereditary angioedema (HAE) in patients aged 12 years and 
older. It is a recombinant, fully human, immunoglobulin G1, kappa light chain, monoclonal 
antibody and is a highly potent and a specific inhibitor of plasma kallikrein (pKal). pKal is a 
protease that cleaves high molecular weight kininogen (HMWK) to generate cleaved HMWK 
(cHMWK) and bradykinin. Bradykinin is a potent proinflammatory and vasodilative nonameric 
peptide responsible for the characteristic symptoms of localized swelling, pain, and inflammation 
that contributes to several of the deleterious consequences also seen in acute respiratory distress 
syndrome (ARDS). Blocking bradykinin production with a pKal inhibitor could allow for control 
over bradykinin production during serious and prolonged coronavirus disease 2019 (COVID-19) 
illness. One of the most severe complications of COVID-19 is ARDS, a life-threatening 
condition characterized by an acute onset of lung edema, severe hypoxemia, and loss of 
pulmonary compliance (Wu et al., 2020). Patients with COVID-19 who develop ARDS have an 
increased risk of death with a mortality rate exceeding 50% (Wu et al., 2020). While the 
molecular mechanisms inciting ARDS are not well-elucidated, there is evidence of activation of 
the kallikrein-kinin system (KKS), also known as the contact activation system, in lung injury 
(Hess et al., 2017). As a highly potent and specific inhibitor of pKal, lanadelumab could provide 
persistent control over bradykinin production during serious COVID-19 illness and 
reduce/prevent ARDS. 
ARDS is characterized as a systemic inflammatory process whereby damage to the endothelium 
in the pulmonary vasculature results in the influx of immune cells, accumulation of protein-rich 
edema fluid within the interstitium and alveolus, and secretion of inflammatory cytokines 
contributing to further disruption of endothelial-alveolar barrier (Thompson, 2017). Activation of 
the KKS (ie, contact system) in ARDS may occur as a result of endothelial injury and barrier 
disruption (eg, subendothelial collagen, apoptotic cells, or other negatively charged substances), 
including virally infected endothelial cells (Taylor et al., 2013). 
Once activated, the KKS can contribute to the pathogenesis of ARDS via 2 synergizing 
mechanisms (Johnson and Matthay, 2010; Wachtfogel et al., 1983; Abdallah et al., 2010; 
Toossi et al., 1992; Hess et al., 2017; Wachtfogel et al., 1986; Khan et al., 2006; 
Qadri and Bader, 2018): 
• The cleavage of HMWK to produce bradykinin, a potent vasodilator and cause of edema; and 
• The activation of coagulation factor XII (FXII) through a positive feedback loop which in 
turn leads to the activation of inflammatory cells, the production of proinflammatory 
cytokines, and initiation of the intrinsic coagulation pathway. 




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COV-01-001 – Sub-protocol for Lanadelumab-IV 
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1.2 Schedule of Activities 
 
Screening Baseline 
 
 
 
 
Day (± Window) 
Day -1 or 
Day 1 
Day 1 
Daily Until Hospital Discharge (or Daily 
Until Day 29 While in Hospital) 
Day 15a 
(±2 days) 
Day 29a 
(±3 days) 
Day 60a 
(±4 days) 
(End of 
Study) 
ELIGIBILITY 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Relevant medical historyb 
X 
 
 
 
 
 
Review of SARS-CoV-2 diagnostic 
tests (obtained during the previous 
72 hours, if available) 
X 
 
 
 
 
 
SARS-CoV-2 diagnostic testc 
X 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
X 
 
 
 
 
12-lead electrocardiogram 
X 
 
Date of discharge only 
 
 
 
STUDY INTERVENTION 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
Administration of Study Drugd 
 
X 
Day 4 
 
 
 
Treatment with SoC 
 
SoC will be based on the practices of the study center 
STUDY PROCEDURES 
 
 
 
 
 
 
Physical examination (including height, 
weight)e 
X 
 
 
 
 
 
Vital signs, including body temperature, 
pulse rate, blood pressure, respiratory 
rate, SpO
2, FiO2f 
 
Xg 
X 
Xh 
Xh 
 
Ordinal scale 
 
Xg 
X 
X 
X 
X 
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COV-01-001 – Sub-protocol for Lanadelumab-IV 
Version 1.2, 26 October 2020 
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Screening Baseline 
 
 
 
 
Day (± Window) 
Day -1 or 
Day 1 
Day 1 
Daily Until Hospital Discharge (or Daily 
Until Day 29 While in Hospital) 
Day 15a 
(±2 days) 
Day 29a 
(±3 days) 
Day 60a 
(±4 days) 
(End of 
Study) 
Clinical assessmentsi 
 
Xg 
X 
X 
X 
Xj 
Assessment of floor status (ICU yes/no) 
 
X 
Xh 
Xh 
Xh 
 
Assessment of rehospitalization for 
discharged patientsk 
 
 
 
X 
X 
X 
Concomitant medication review 
(including use of vasopressors) 
X 
Xg 
X 
X 
X 
X 
Adverse event evaluation 
X 
X 
X 
X 
X 
X 
SAFETY LABORATORY 
 
 
 
 
 
 
Clinical safety laboratory assessments 
Xl,m 
Xg,n,o 
Days 3p, 8
n, 22n, and at dischargen,q 
All other days while in hospitalr 
Xn,s 
Xn 
 
Pregnancy test for females of 
childbearing potential 
Xl 
 
 
 
 
 
RESEARCH LABORATORY 
 
 
 
 
 
 
PKt 
 
X 
Days 4, 7 
X 
X 
 
PDt 
 
X 
Days 4, 7 
X 
X 
 
Plasma antidrug antibody sampleu 
 
X 
 
X 
X 
 
Abbreviations: Ang2=angiopoietin 2; ARDS=acute respiratory distress syndrome; cHMWK=cleaved high molecular weight 
kininogen; COVID-19=coronavirus disease 2019; CRP=C-reactive protein; eCRF=electronic case report form; FDP=fibrin 
degradation products; FiO2=fraction of inspired oxygen; ICU=intensive care unit; IFN= interferon; IL=interleukin; IV=intravenous; 
LDH=lactate dehydrogenase; 
; PAI-1=plasminogen-activator inhibitor-1; 
PD=pharmacodynamic; PK=pharmacokinetic; pKal= plasma kallikrein; SARS-CoV-2=severe acute respiratory syndrome 
coronavirus 2; SoC=standard of care; SpO
2=oxygen saturation; TNF=tumor necrosis factor. 
Note: Additional assessments for this sub-protocol are highlighted in bold and italics.
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COV-01-001 – Sub-protocol for Lanadelumab-IV 
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a These visits will be performed even if a patient has already been discharged. If discharged prior to scheduled visit, these visits will be 
conducted via telemedicine. For visits conducted by telephone, it may not be possible to perform some scheduled assessments (eg, 
vital signs). The Day 29 assessments will also be performed, where possible, for patients who discontinue the study prematurely. 
b Medical history includes estimated date and time of first COVID-19 related symptoms and co-morbidities (eg, respiratory [including 
date of diagnosis of ARDS, if present], cardiovascular, metabolic, malignancy, endocrine, gastrointestinal, immunologic, renal). 
c Oropharyngeal/nasal swab for polymerase chain reaction determination of SARS-CoV-2 or for SARS-CoV-2 antigen testing. Only to 
be performed if no diagnostic test results are available that have been obtained during the previous 72 hours. 
d Study drug must be infused over a period of 60 minutes ± 15 minutes. Study drug administration start and stop times must be 
recorded in source documents and the eCRF. The clock time of the second infusion should be approximately the same as the 
first infusion. 
e If height and/or weight cannot be obtained at the Screening Visit (Day -1 or Day 1), these parameters can be recorded as a 
combination of patient-reported data and data obtained from recent medical records (ie, at hospital admission). 
f For patients requiring high-flow oxygen, mechanical ventilation (invasive/noninvasive), or extracorporeal membrane oxygenation 
only, provide FiO
2 requirement. 
g Baseline assessments should be performed prior to study drug administration. 
h To be assessed only while hospitalized. 
i Includes oxygen requirement (ie, mode of delivery/liters of oxygen flow, FiO
2 requirement), stop date of oxygen for patients who 
were discharged on home oxygen, extracorporeal membrane oxygenation support, noninvasive or invasive ventilator requirement, 
including start and stop of low- or high-flow oxygen supply or of any form of ventilation, and need for renal replacement therapy. 
Noninvasive ventilation refers to the delivery of mechanical ventilation to the lungs using techniques that do not require an 
endotracheal airway. 
j Only stop date of oxygen for patients who were discharged on home oxygen. 
k Information recorded is yes/no, hospitalization date, discharge date. 
l Laboratory tests performed within the 48 hours prior to enrolment will be accepted for determination of eligibility. 
m Hematology and clinical chemistry. 
n Hematology, clinical chemistry, liver function tests, cardiac panel, and coagulation. 
o Any laboratory tests performed as part of routine clinical care can be used for safety laboratory testing. 
p Hematology, clinical chemistry, and liver function tests. 
q If not done or entered into the eCRF within previous day. 
r Hematology, clinical chemistry, and liver function tests will be collected on the eCRF, if available, while the patient is in hospital. 
s This assessment will be performed on Day 15 or date of discharge, if earlier. 


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COV-01-001 – Sub-protocol for Lanadelumab-IV 
Version 1.2, 26 October 2020 
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t Samples for PK/PD assessments will be collected temporally as close as possible to Hour 0 (start of study drug infusion/dosing) 
within 60 minutes before the infusion as well as at the end of the infusion on Day 1 (within 30 minutes post infusion). If 
feasible, samples for PK and PD will be collected at Days 4, 7, 15, and 29 (or hospital discharge, if earlier) at any time during 
the day. Start and end of study drug infusion times (day, hour, minute) for each dose should be accurately recorded per 24-hour 
clock. All PK/PD sampling times (day, hour, minute) should be accurately recorded per 24-hour clock. No sample collection is 
required after discharge. 
 
 
u Antidrug antibody samples will be collected at Day 1 (pre-infusion within 30 minutes before the infusion) and at Days 15 and 29 
(or hospital discharge, if earlier). 
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COV-01-001 – Sub-protocol for Lanadelumab-IV 
Version 1.2, 26 October 2020 
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1.3 End of Study Definition for Sub-protocol 
The Master Protocol defines the end of study for the overall platform study. 
For this specific sub-protocol, the end of the study will be defined as the date on which the last 
patient randomized to this sub-protocol completes the last scheduled procedure as shown in the 
Schedule of Activities (SoA; Section 1.2). 


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COV-01-001 – Sub-protocol for Lanadelumab-IV 
Version 1.2, 26 October 2020 
14 
2.0 BACKGROUND/RATIONALE IN SUPPORT OF 
LANADELUMAB-IV IN COVID-19 
Since the start of the COVID-19 pandemic, the Candidate Agent Owner (Takeda) has received 
anecdotal reports from physicians in Brazil, Italy, and the Netherlands who have produced 
positive clinical outcomes in patients with COVID-19 by treating with repeat doses of icatibant. 
A case-control study reporting these findings from the Netherlands has been recently published 
(van de Veerdonk et al., 2020). Icatibant is a competitive antagonist selective for the bradykinin 
receptor B2, with an affinity similar to bradykinin, that is currently approved for the treatment of 
acute attacks of HAE in adults 18 years of age and older. Icatibant inhibits bradykinin from 
binding to the B2 receptor and thereby treats the clinical symptoms of an acute, episodic attack 
of HAE (Firazyr, 2015). 
The clinical observation that COVID-19 can lead to fluid extravasation and accumulation within 
the lungs has led some treating physicians in Europe to utilize icatibant in critically ill patients. 
Preliminary observations (along with a separate ongoing investigator-sponsored study) indicate 
positive outcomes with icatibant, suggesting that sustained inhibition of bradykinin signaling 
may provide clinical benefit throughout the course of COVID-19 by preventing proinflammatory 
effects and fluid extravasation and accumulation within the lungs. As icatibant has a short 
halflife (t½)
 of approximately 1.4 hours after a single subcutaneous 30 mg dose (Firazyr, 2015), a 
medication with a significantly longer t½ which modulates the KKS and reduces the production 
of bradykinin may impart additional therapeutic benefit. In contrast to icatibant, lanadelumab has 
a longer t
½ of approximately 14 days (Takhyzro, 2018), which Takeda hypothesizes should allow 
for superior control over bradykinin production during serious and prolonged COVID-19 illness. 
In addition, given that lanadelumab is a pKal inhibitor, it is reasonable to hypothesize that pKal 
inhibition may help to reduce inflammation and coagulation driven by FXII, which is activated 
by pKal through a positive feedback loop (Kenniston et al., 2014). Additionally, it has the 
advantage of reducing activation of the B1 receptor by des-Arg9 BK, a bradykinin metabolite. 
Bradykinin B1 receptor has been found to be upregulated in response to tissue injury or 
inflammation (Passos et al., 2004). 
It is believed that the validated lanadelumab mechanism of action, coupled with the available 
literature and anecdotal reports of icatibant use in COVID-19, provide a reasonable rationale for 
evaluating the efficacy and safety of lanadelumab in patients hospitalized with COVID-19. 
2.1 Benefit/Risk Assessment 
Based on the mechanism of action of lanadelumab, there is strong scientific rationale and high 
unmet medical need to evaluate the use of lanadelumab as a therapy for KKS-mediated 
inflammation associated with COVID-19. 


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ARDS is a life-threatening condition characterized by an acute onset, lung edema formation, 
severe hypoxemia, and loss of pulmonary compliance (Johnson and Matthay, 2010). Lung 
trauma, including viral infection with SARS-CoV-2 infection, can lead to ARDS, which is 
associated with severe inflammatory (influx of inflammatory cells and cytokine production) and 
procoagulant activity in the airways that can result in tissue and organ damage 
(Johnson and Matthay, 2010; Wu et al., 2020). 
There exists a serious unmet medical need in patients hospitalized with COVID-19 pneumonia. 
Therefore, the main goal in managing patients hospitalized with COVID-19 pneumonia is to 
provide supportive care and monitor for complications including ARDS. Treatment of 
progressive ARDS is primarily supportive and includes invasive mechanical ventilation. The best 
strategy to improve patient outcomes is to reduce or prevent ARDS. This could not only improve 
patient outcomes, but also reduce intensive care management which may strain already limited 
healthcare resources. 
Clinical evidence supports the need for early intervention in patients hospitalized with 
COVID-19 pneumonia. Studies of Chinese patients hospitalized for COVID-19 show that 
development of ARDS can occur within a median time of 2 days from the date of admission 
(Huang et al., 2020; Wu et al., 2020). Therefore, lanadelumab administered intravenously (IV) 
soon after hospital admission could benefit patients with respiratory symptoms and 
reduce/prevent ARDS; thereby avoiding the need for invasive mechanical ventilation.  
The overall risk in this patient population is outweighed by the potential benefits of lanadelumab. 
Therefore, the benefit-risk appears to be favorable and supports treatment with IV lanadelumab 
(Lanadelumab-IV) in this patient population. Details on the use of the IV route of administration 
is discussed in Section 2.2. 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events (AEs) of lanadelumab may be found in the Investigator’s Brochure and 
Package Insert. 
2.2 Dose Justification for Lanadelumab-IV 
The 300 mg dose via IV administration is chosen for this trial based on the following rationale: 
Previously reported measurements of prekallikrein consumption in plasma indicate that the 
extent of ongoing KKS activation in ARDS (estimated on the basis of prekallikrein consumption 
to generate between 170 and 300 nM pKal in the plasma) may be greater than in patients with 
HAE (estimated pKal: 20 to 186 nM) (Velasco et al., 1986; Carvalho et al., 1988; 
Schapira et al., 1983; Cugno, 1988; Sexton et al., 2017). As lanadelumab is a tight binding 
inhibitor, excess levels of pKal activity are expected to be controlled by approximately 
stoichiometric drug concentrations in plasma. The pharmacokinetic (PK) and pharmacodynamic 
(PD) properties of lanadelumab have been well characterized in patients with HAE following 


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subcutaneous (SC) administration with a population PK/PD modeling and simulation approach 
(using cHMWK as an indirect inhibition marker). Following SC administration of 300 mg of 
lanadelumab every 2 weeks (approved dosage for HAE indication), the time to maximum 
concentration (T
max) was 4 days or later with maximum concentration (Cmax) of approximately 
34 μg/mL, which may not meet the treatment needs in patients with progressing COVID-19 
illness; therefore, IV administration is proposed.  
IV administration will provide much earlier T
max (approximately 1 hour for 60 minutes of 
infusion) as compared to SC administration. Since high variability in the time course and 
severity of COVID-19 pneumonia has been reported, a 300 mg dose on Day 1 with an additional 
dose administered after 3 days (ie, on Day 4) are considered to meet such exposure requirements 
based on the clinical pharmacology properties of lanadelumab. To support the safety evaluation, 
exposure to Lanadelumab-IV was predicted by simulation using a 2-compartment IV model with 
PK parameters estimated by fitting the model to mean values of lanadelumab concentrations in 
HAE clinical studies, for a single 300 mg IV infusion, and 300 mg IV infusion on Day 1 and 
Day 4 (Table 1). Although Takeda has not tested the IV route of administration in the HAE 
clinical trials, the exposure (predicted C
max and area under the concentration-time curve) to 
lanadelumab is comparable to the exposure observed in the clinical package; the sufficient safety 
margins for the proposed IV dosing regimen by the nonclinical HAE package are provided 
(Table 1) using No Observed Adverse Effect Level exposure observed in both Good Laboratory 
Practice (GLP) and non-GLP monkey toxicity studies.  
Thus, the IV route of administration is proposed for the study in patients hospitalized with 
COVID-19 pneumonia. One dose will be administered on Day 1, and a second dose will be 
administered on Day 4. Two Phase 1 studies utilizing lanadelumab via IV administration are 
currently ongoing. TAK-743-1002, a Phase1b study in patients with COVID-19, has not yet 
enrolled. However, TAK-743-1003, a Phase 1a healthy volunteer study, has completed 
enrollment and dosing. Preliminary, blinded interim safety data available at the time of this 
subprotocol finalization have shown no safety signals. 
 


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Table 1 Predicted Clinical Exposure Margins Compared to Observed Exposure 
(NOAEL) in Cynomolgus Monkeys 
Cynomolgus Monkey Exposure (NOAEL) 
GLP Toxicity  
Repeat-Dose IV Study 
(Day 21 to 28) 
Non-GLP Tolerability 
Single-Dose IV Study 
(Day 0 to 28) 
AUClast (µg*hr/mL) 
123000 
137500 
Cmax (µg*mL) 
1640 
1155 
Human 300 mga  
Safety Margin 
AUC0-672 (µg*hr/mL) 
17281 
7.1 
8.0 
Cmax (µg*mL) 
94.1 
17 
12 
Human 2×300 mgb 
Safety Margin 
AUC0-672 (µg*hr/mL) 
33532 
3.7 
4.1 
Cmax (µg*mL) 
130 
13 
8.9 
AUC0-672=area under the plasma concentration-time curve 
from time 0 to 672; AUC
last=area under the plasma 
concentration-time curve 
from time 0 to the time of last concentration measured; C
max=maximum plasma concentration; 
GLP=Good Laboratory Practice; IV=intravenous(ly); NOAEL=No Observed Adverse Effect Level. 
a Infused over 60 minutes on Day 1. 
b Infused over 60 minutes on Days 1 and 4 (individual doses separated by 3 days). 
 


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3.0 STUDY POPULATION 
3.1 Enrolment and Screening 
Refer to the Master Protocol for enrolment and screening procedures. 
3.2 Eligibility Criteria 
Overall inclusion and exclusion criteria are presented in Sections 5.1 and 5.2 of the Master 
Protocol, respectively. Patients must meet all inclusion criteria and no exclusion criteria for the 
Master Protocol to be considered for inclusion in this COV-01-001 sub-protocol. 
The following sections detail variations to those criteria that are specific to this sub-protocol. 
3.2.1 
Inclusion Criteria 
No additional criteria. 
3.2.2 
Exclusion Criteria 
Additional exclusion criteria that are specific to the sub-protocol are as follows: 
X1. Known or suspected hypersensitivity to lanadelumab or any of its excipients. 
X2. Previous (within 3 months prior to baseline) or current use of immunomodulators 
(eg, methotrexate, azathioprine, 6-mercaptopurine, tumor necrosis factor [TNF] α inhibitor, 
Janus kinase [JAK] inhibitor, alpha-integrin inhibitor). 
X3. Known or suspected venous thromboembolism. 
X4. Previous (within 3 months [or 5 half-lives, whichever is greater] of screening) or current use 
of pKal inhibitor or bradykinin receptor blocker. 
3.3 Primary Analysis Population 
The analyses on the primary and key secondary efficacy endpoints, as defined in the Master 
Protocol, will be performed in the Primary Analysis Population for this sub-protocol.  
The Primary Analysis Population for this sub-protocol will consist of randomized patients with a 
baseline clinical severity status of Grade 3 to 5 on the 8-point ordinal scale of clinical severity. 
Consistent with Section 9.1 of the Master Protocol, the planned sample size for this sub-protocol, 
a total of 490 events between the lanadelumab plus standard of care group and placebo plus 
standard of care group, as well as the target randomized population of 350 patients per group to 
achieve these events, are both applicable to the Primary Analysis Population made of patients of 
Grade 3 to 5 at baseline. Patients of baseline Grade 2 are enrolled in addition to these totals. 


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3.4 Discontinuation of Study Treatment and Patient 
Discontinuation/Withdrawal 
The reason for and date of discontinuation from study treatment and/or from study participation 
will be collected for all randomized patients who prematurely discontinue study treatment or 
participation. 
3.4.1 
Discontinuation of Study Treatment  
A patient in this study may discontinue the study treatment per the criteria listed in Section 7 of 
the Master Protocol. 
3.4.2 
Patient Discontinuation/Withdrawal from the Study  
In addition to the criteria listed in the Master Protocol, a patient in this study may withdraw from 
the study for any of the reasons detailed below: 
• Candidate Agent Owner or its designee stops the patient’s participation in this 
sub-protocol or Candidate Agent Owner stops the sub-protocol for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and good 
clinical practice. 


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4.0 STUDY ASSESSMENTS AND PROCEDURES 
In addition to the study assessments and procedures described in Section 8.0 of the Master 
Protocol, assessments specific to this COV-01-001 sub-protocol will be performed as described 
in the following sections. The SoA for this sub-protocol is presented in Section 1.2. 
4.1 Safety Assessments 
• Treatment-emergent AEs, including serious AEs (SAEs) and AEs of special interest (AESI; 
Section 4.1.1.2)  
4.1.1 
Adverse Events 
4.1.1.1 Adverse Events from Approved Indications 
The safety and tolerability of lanadelumab have been well characterized in HAE patients 
following SC administration. 
Lanadelumab was approved by the US Food and Drug Administration on 23 August 2018 for 
prophylaxis to prevent attacks of HAE in patients aged 12 years and older. The safety, 
tolerability, efficacy and PK and PD results from these studies to date demonstrate that 
lanadelumab is safe and efficacious in HAE patients and have served as the basis of submissions 
for global expansion. 
Per the reference labeling US Prescribing Information, the most common adverse reactions are 
injection site reactions, upper respiratory infections, headache, rash, myalgia, dizziness, and 
diarrhea. Other adverse reactions that occurred at a higher incidence in lanadelumab-treated 
patients compared to placebo include hypersensitivity, increased aspartate transaminase, and 
increased alanine transaminase. 
Hypersensitivity is an important identified risk and is discussed in the warnings and precautions 
of the reference labelling. Immunogenicity and liver toxicity (European Union-specific) are 
important potential risks for lanadelumab and are monitored closely. Based on the review of the 
safety data from the completed and ongoing clinical trials, the known cumulative exposure and 
continuous pharmacovigilance monitoring for the risks, the benefit-risk continues to be 
favorable. Always refer to the latest version of the lanadelumab Investigator’s Brochure for the 
overall benefit/risk assessment and the most accurate and current information regarding drug 
metabolism, PK, efficacy, and safety of lanadelumab. 
4.1.1.2 Adverse Events of Special Interest 
CCI
AESI will be captured and monitored during this study. Investigators will report all AESI to 
, regardless of causality, using the same timelines as described for SAE reporting 
(ie, within 24 hours of awareness). This information will be further distributed to the Sponsor 
(Amgen) and Candidate Agent Owner (Takeda).  


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The following are defined as AESI for Lanadelumab-IV in this protocol: 
• Hypersensitivity reactions; and 
• Events of disordered coagulation. 
Predefined AESI in registrational clinical studies of lanadelumab in HAE patients were 
hypersensitivity reactions and disordered coagulation (bleeding events or hypercoagulable 
events). The incidence of hypersensitivity in the lanadelumab-treated population was low with 
no events of anaphylaxis reported and no antidrug antibodies (ADA) detected in these patients. 
The incidence of disordered coagulation was similarly low with no cases of related bleeding or 
hypercoagulable events. 
Hypersensitivity Reactions 
As hypersensitivity reactions have been observed for monoclonal antibodies as a class, these 
events are considered AESI for this study. Investigators will report all diagnoses, or signs and 
symptoms when diagnoses cannot be determined, that are consistent with hypersensitivity 
reactions, regardless of causality, within 24 hours from the time of study drug administration. 
Investigators will report hypersensitivity reactions that occur after 24 hours, only if the reactions 
are suspected to be related to study drug. 
Events of Disordered Coagulation 
Bleeding AESI 
Although activated partial thromboplastin time prolongation due to pKal inhibition is an 
artifactual in vitro phenomenon attributed to an interaction with the laboratory test, as a 
precautionary measure in evaluating the safety of Lanadelumab-IV, bleeding events will be 
reported as AESI for this study. Investigators will report all diagnoses, or signs and symptoms 
when diagnoses cannot be determined, that are consistent with a clinical event of bleeding. 
Coagulation testing (Appendix 2) should be performed when possible, and when temporally 
reasonable, with any reports of bleeding or for clinical conditions possibly indicative of bleeding. 
Hypercoagulable AESI 
Investigators will report all diagnoses, or signs and symptoms when diagnoses cannot be 
determined, that are consistent with a thrombotic or embolic etiology. 
4.1.1.3 Safety Reporting 
CCI
All SAEs, AESI, and overdoses will be recorded and reported to  
 Safety within 24 hours 
after becoming aware of its occurrence. The initial and follow-up reports should be made using 
the Electronic Data Capture tool. If necessary, as a backup, reports can be made by e-mail or 
facsimile (fax). The contact details are:  


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The  
 Medical Safety Advisor (or designee) must also be notified within 24 hours should 
any patient experience an SAE. Contact information for the SAE Coordinator will be provided 
on the SAE form/completion instructions. 
Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of patients and the safety of a study 
treatment under clinical investigation are met. 
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study treatment under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, Institutional Review Boards (IRB)/Independent Ethics Committees 
(IEC), and Investigators. 
Investigator safety reports must be prepared for suspected unexpected serious adverse reactions 
according to local regulatory requirements and Sponsor policy and forwarded to Investigators as 
necessary. 
An Investigator who receives an Investigator safety report describing an SAE or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will review and then file it 
along with the Investigator’s Brochure and will notify the IRB/IEC, if appropriate according to 
local requirements. 
4.1.2 
Clinical Safety Laboratory Assessments 
Blood samples will be collected for safety assessments during hospitalization, in accordance with 
the SoA (Section 1.2) and Appendix 2. Safety parameters will be the same as those included in 
the Master Protocol, with the addition of fibrin degradation products. 
4.2 Pharmacokinetic Assessments 
Plasma samples for PK analysis will be collected temporally as close as possible to Hour 0 (start 
of study drug infusion/dosing) within 60 minutes before the infusion as well as at the end of the 
infusion on Day 1 (within 30 minutes post infusion). If feasible, plasma samples for PK analysis 
will also be collected on Days 4, 7, 15, and 29 (or hospital discharge, if earlier) at any time 
during the day (Section 1.2)
CCI
. All PK sampling times (day, hour, minute) should be accurately 
recorded per 24-hour clock. No sample collection is required after discharge. PK samples are to 
be shipped to the study central laboratory and routed to a specialty laboratory for analysis. 
 
CCI
CCI


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4.3 Pharmacodynamic Assessments 
Blood and plasma samples for PD analyses will be collected temporally as close as possible to 
Hour 0 (start of study drug infusion/dosing) within 60 minutes before the infusion as well as at 
the end of the infusion on Day 1 (within 30 minutes post infusion). If feasible, samples for PD 
analyses will also be collected on Days 4, 7, 15, and 29 (or hospital discharge, if earlier) at any 
time during the day (Section 1.2). All PD sampling times (day, hour, minute) should be 
accurately recorded per 24-hour clock. No sample collection is required after discharge.
 
 
Samples will be shipped to 
the study central laboratory and routed to a specialty laboratory for analysis.
 
4.4 Plasma Anti-Drug Antibody Testing 
Plasma samples for determination of the presence or absence of neutralizing or non-neutralizing 
ADA will be collected at Day 1 (pre-infusion) and at Days 15 and 29 (or hospital discharge, if 
earlier) (Section 1.2). Additional testing may be required in patients who have positive ADA. All 
sampling times (day, hour, minute) should be accurately recorded per 24-hour clock. Samples 
will be shipped to the study central laboratory and routed to a specialty laboratory for analysis. 
 
 
4.5 Future Biomedical Research 
CCI
 
 
 
 
 
 
CCI
CCI
CCI


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5.0 STUDY TREATMENT 
5.1 Treatment Plan 
Patients eligible for treatment will receive either IV administration of lanadelumab diluted in 
100 mL sterile 0.9% sodium chloride solution or placebo in a double-blind manner. Study 
treatment will be administered along with standard of care in line with institutional practice. 
Lanadelumab will be supplied by Takeda prepackaged in a study kit. Each study kit will contain 
one (1) vial of lanadelumab 300 mg/vial liquid form. The comparator product is matching 
placebo (normal saline [NS], 0.9% sodium chloride) for infusion (provided by the site). Further 
details are provided in the Pharmacy Manual. 
Unblinded pharmacy personnel will be responsible for providing the study drug(s) to the blinded 
study personnel for dosing as per the randomization scheme. 
5.2 Study Drug Administration 
Based on the mechanism of action, PK/PD extrapolations, prior experience with lanadelumab in 
clinical trials, and supportive safety profile based on the existing clinical package, the 
recommended double-blind dose is an infusion of lanadelumab 300 mg or placebo IV, 1 dose on 
Day 1 and a second dose on Day 4. 
The infusion of lanadelumab or placebo must be administered over a period of 
60 minutes ± 15 minutes and must use an infusion set with an in line, sterile, non-pyrogenic, low 
protein-binding filter (pore size of 0.2 μm or less). Infusion should begin within 3 hours of 
preparation. Refer to the Pharmacy Manual for a list of infusion sets and infusion pumps 
acceptable for use with lanadelumab. 
The times of the beginning and the end of infusion will be recorded. Dosing interruptions will be 
recorded. 
5.3 Preparation/Handling/Storage/Accountability 
Storage and handling 
• Store vials refrigerated at 36°F to 46°F (2°C to 8°C). 
• Do not freeze.  
• Do not shake. 
• Keep the vial in the original carton in order to protect the vial from light. 
Preparation 
• Lanadelumab-IV will be supplied as a clear to slightly opalescent, colorless to slightly yellow 
solution. Do not use any vial that appears discolored or contains visible particles. Avoid 
vigorous agitation of the vial. 


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• Take the Lanadelumab-IV vial out of the refrigerator 15 minutes before injecting to allow it 
to equilibrate to room temperature. 
• Using aseptic technique, withdraw 2 mL of Lanadelumab-IV from the vial using an 18-gauge 
needle. 
• Following local process, add the Lanadelumab-IV to 100 mL sterile 0.9% sodium chloride 
infusion bag and infuse over a period of 60 minutes ± 15 minutes on Day 1, followed by a 
second dose on Day 4. 
• For patients assigned to placebo, administer NS via IV infusion over a period of 
60 minutes ± 15 minutes on Day 1, followed by a second administration on Day 4. 
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported and 
resolved before use of the study treatment. 
Only patients enrolled in the study may receive study treatment, and only authorized study center 
staff may supply or administer study treatment. All study treatments must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to the Investigator and authorized study center 
staff. 
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records). 
Further guidance and information for the final disposition of unused study treatment can be 
found in the Pharmacy Manual. 
The Investigator, a member of the study center staff, or a hospital pharmacist must maintain an 
adequate record of the receipt and distribution of all study medication using the Drug 
Accountability Form. These forms must be available for inspection at any time. 
5.4 Dose Modifications and Toxicity Management 
No dedicated clinical study of lanadelumab has been conducted in patients with renal or hepatic 
impairment. 
 
 
 
 
 
CCI
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the  
 Medical Monitor based on the clinical evaluation of the patient. 
CCI


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5.5 Treatment of Overdose 
There have been no reports of overdose with lanadelumab. 
For this study, any dose of study drug greater than 300 mg in less than a 72-hour time period will 
be considered an overdose. Investigators should report all overdose events to  
 using the 
same timelines as described for SAE reporting (ie, within 24 hours of awareness). This 
information will be further distributed to Takeda. 
Takeda does not recommend specific treatment for an overdose. 
In the event of an overdose, the Investigator/treating physician should: 
1. Contact the  
 Medical Monitor immediately. 
2. Closely monitor the patient for any AE/SAE and laboratory abnormalities. 
3. Document the quantity of the excess dose as well as the duration of the overdose in the 
electronic case report form. 
4. Hold administration of the next dose (if applicable) until further instructions are received 
from the  
 Medical Monitor. 
5.6 Concomitant Medications 
No dedicated drug interaction studies have been conducted with lanadelumab.  
The use of immunomodulators (eg, methotrexate, azathioprine, 6-mercaptopurine, TNFα 
inhibitor, JAK inhibitor, alpha-integrin inhibitor) are prohibited during participation in the study. 
5.6.1 
Rescue Medication 
Not applicable to this sub-protocol. 
5.7 Study Drug Information 
Lanadelumab is currently marketed under the TAKHZYRO tradename as a sterile, 
preservative-free, clear to slightly opalescent, colorless to slightly yellow solution currently 
approved in a single-dose glass vial for SC injection only; injection: 300 mg/2 mL (150 mg/mL) 
solution. 
Takeda intends to use currently approved TAKHZYRO vials to be diluted in 100-mL sterile 
0.9% sodium chloride solution bags for IV administration (Luo et al, 2020). 
The Lanadelumab-IV and placebo solutions will be administered in the same manner 
(Section 5.3)
CCI
. The placebo solution will match the active solution in appearance. 
CCI
CCI


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Hess, R., Wujak, L., Hesse, C., Sewald, K., Jonigk, D., Warnecke, G., Fieguth, H. G., de 
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Huang, C., Wang, Y., Li, X., Ren, L., Zhao, J., Hu, Y., Zhang, L., Fan, G., Xu, J., Gu, X., 
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Johnson, E. R. and Matthay, M. A. 2010. Acute lung injury: epidemiology, pathogenesis, and 
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Conley, G. P., Chen, J., Viswanathan, M., Kastrapeli, N., Cosic, J., Mason, S., DiLeo, M., 
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Khan, M. M., Bradford, H. N., Isordia-Salas, I., Liu, Y., Wu, Y., Espinola, R. G., 
Ghebrehiwet, B. and Colman, R. W. 2006. High-molecular-weight kininogen fragments 
stimulate the secretion of cytokines and chemokines through uPAR, Mac-1, and gC1qR in 
monocytes. Arterioscler Thromb Vasc Biol, 26, 2260-6. 
 
Luo, S., McSweeney, K. M., Wang, T., Bacot, S. M., Feldman, G. M. and Zhang, B. 2020. 
Defining the right diluent for intravenous infusion of therapeutic antibodies. MAbs, 12, 
1685814. 
 


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Passos, G. F., Fernandes, E. S., Campos, M. M., Araujo, J. G. V. C., Pesquero, J. J., Souza, 
G. E. P., Avellar, N. C. W, Teixeira, M. M. and Calixto, J. B. 2004. Kinin B1 receptor up-
regulation after lipopolysaccharide administration: role of proinflammatory cytokines and 
neutrophil influx. J Immunol, 172, 1839-47. 
 
Qadri, F. and Bader, M. 2018. Kinin B1 receptors as a therapeutic target for inflammation. 
Expert Opin Ther Targets, 22, 31-44. 
 
Schapira, M., Silver, L. D., Scott, C. F., Schmaier, A. H., Prograis, L. J. Jr, Curd, J. G. and 
Colman, R. W. 1983 Prekallikrein activation and high-molecular-weight kininogen 
consumption in hereditary angioedema. N Engl J Med, 308, 1050-3. 
 
Sexton, D. J., Faucette, R., Kenniston, J. Wang, Y., Rong, H. 2017 Approaches to Estimate 
Plasma Kallikrein Inhibition Levels Required for Attack Prophylaxis in hereditary 
angioedema. European Academy of Allergy and Clinical Immunology Congress 2017, 17–21 
June 2017, Helsinki, Finland. 
 
Takhyzro (lanadelumab-flyo). Full Prescribing Information. Lexington MA: Dyax Corp. 
Revised 11/2018. 
Taylor, S. L., Wahl-Jensen, V., Copeland, A. M., Jahrling, P. B. and Schmaljohn, C. S. 2013. 
Endothelial cell permeability during hantavirus infection involves factor XII-dependent 
increased activation of the kallikrein-kinin system. PLoS Pathog, 9, e1003470. 
 
Thompson, B. Chambers, R. C. and Liu, K. D. 2017. Acute Respiratory Distress Syndrome.  
N Engl J Med, 377, 562-72. 
 
Toossi, Z., Sedor, J. R., Mettler, M. A., Everson, B., Young, T. and Ratnoff, O. D. 1992. 
Induction of expression of monocyte interleukin 1 by Hageman factor (factor XII). Proc Natl 
Acad Sci U S A, 89, 11969-72. 
 
van de Veerdonk, F. L., Netea, M. G., van Deuren, M., van der Meer, J. W., de Mast, Q., 
Bruggemann, R. J., and van der Hoeven, H. 2020. Kallikrein-kinin blockade in patients with 
COVID-19 to prevent acute respiratory distress syndrome. Elife, 9, e57555. 
 
Velasco, F., Torres, A., Guerrero, A., Andres, P., Guerrero, R., Aljama, P. and Alvarez, F. 
1986. Behaviour of the contact phase of blood coagulation in the adult respiratory distress 
syndrome (ARDS). Thromb Haemost, 55, 357-60. 
 
Wachtfogel, Y. T., Kucich, U., James, H. L., Scott, C. F., Schapira, M., Zimmerman, M., 
Cohen, A. B. and Colman, R. W. 1983. Human plasma kallikrein releases neutrophil elastase 
during blood coagulation. J Clin Invest, 72, 1672-7. 
 
Wachtfogel, Y. T., Pixley, R. A., Kucich, U., Abrams, W., Weinbaum, G., Schapira, M. and 
Colman, R. W. 1986. Purified plasma factor XIIa aggregates human neutrophils and causes 
degranulation. Blood, 67, 1731-7. 
 


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Wu, C., Chen, X., Cai, Y., Xia, J., Zhou, X., Xu, S., Huang, H., Zhang, L., Zhou, X., Du, C., 
Zhang, Y., Song, J., Wang, S., Chao, Y., Yang, Z., Xu, J., Zhou, X., Chen, D., Xiong, W., 
Xu, L., Zhou, F., Jiang, J., Bai, C., Zheng, J. and Song, Y. 2020. Risk Factors Associated 
With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 
2019 Pneumonia in Wuhan, China. JAMA Intern Med, 2020;180(7):934-943. 
 
Zhou, F., Yu, T., Du, R., Fan, G., Liu, Y., Liu, Z., Xiang, J., Wang, Y., Song, B., Gu, X., 
Guan, L., Wei, Y., Li, H., Wu, X., Xu, J., Tu, S., Zhang, Y., Chen, H. and Cao, B. 2020. 
Clinical Course and Risk Factors for Mortality of Adult Inpatients With COVID-19 in 
Wuhan, China: A Retrospective Cohort Study. Lancet, 395, 1054-62. 
 


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30 
7.0 APPENDICES 


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COV-01-001 – Sub-protocol for Lanadelumab-IV 
Version 1.2, 26 October 2020 
31 
Appendix 1 
Abbreviations 
Abbreviation 
Definition 
ADA 
antidrug antibodies 
AE 
adverse event 
AESI 
adverse event of special interest 
ARDS 
acute respiratory distress syndrome 
cHMWK 
cleaved high molecular weight kininogen 
Cmax 
maximum observed concentration 
COVID-19 
coronavirus disease 2019 
des-Arg9 BK 
bradykinin metabolite 
FXII 
coagulation factor XII 
GLP 
Good Laboratory Practice 
HAE 
hereditary angioedema 
HMWK 
high molecular weight kininogen 
IEC 
Independent Ethics Committee 
IL 
interleukin 
IRB 
Institutional Review Board 
IV 
intravenous(ly) 
JAK 
Janus kinase 
KKS 
kallikrein-kinin system 
NS 
normal saline 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
pKal 
plasma kallikrein 
SAE 
serious adverse event  
SARS-CoV-2 
severe acute respiratory syndrome coronavirus-2 
SC 
subcutaneous(ly) 
t
½ 
half-life 
Tmax 
time to maximum concentration 
TNF 
tumor necrosis factor 
 


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COV-01-001 – Sub-protocol for Lanadelumab-IV 
Version 1.2, 26 October 2020 
32 
Appendix 2 
Clinical Laboratory Tests  
The minimum tests to be performed are detailed in Table 2, with any additional tests specific for 
the candidate agent highlighted in bold italics. Clinical laboratory tests will be performed at a 
local laboratory. 
Protocol-specific requirements for inclusion or exclusion of patients are detailed in the Master 
Protocol. 
Additional tests may be performed at any time during the study as determined necessary by the 
Investigator or required by local regulations. 
Changes to some laboratory parameters are anticipated for any patients moving on to 
extracorporeal membrane oxygenation therapy. 
Investigators must document their review of each laboratory safety report. 


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COV-01-001 – Sub-protocol for Lanadelumab-IV 
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33 
Table 2  
Protocol-required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet Count 
Hemoglobin 
White blood cell count with differential: 
  Neutrophils 
  Lymphocytes 
  Monocytes 
  Eosinophils 
  Basophils 
Coagulation 
D-dimer test 
Fibrinogen 
Activated partial thromboplastin time (aPTT) 
Prothrombin time (PT) 
International Normalized Ratio (INR) 
C-reactive protein 
Ferritin 
Lactate dehydrogenase (LDH) 
Procalcitonin 
Fibrin degradation products 
Clinical 
Chemistry 
Potassium 
Sodium 
Calcium 
Magnesium 
Phosphate 
Bicarbonate 
Creatinine 
Glucose 
Liver Function 
Tests 
Alkaline phosphatase 
Total bilirubin 
Aspartate aminotransferase (AST) 
Alanine aminotransferase (ALT) 
Gamma-glutamyl transferase (GGT) 
Cardiac Panel 
Creatine kinase (myocardial band [MB] fraction) 
Triglycerides 
Troponin 
Note: Additional assessments for this sub-protocol are highlighted in bold and italics. 
 


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COV-01-001 – Sub-protocol for Lanadelumab-IV 
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34 
Appendix 3 
Signature of Investigator 
PROTOCOL TITLE: Industry Alliance Platform Trial to Assess the Efficacy and Safety of 
Multiple Candidate Agents for the Treatment of COVID-19 in Hospitalized Patients 
SUB-PROTOCOL NO: 
COV-01-001 
SUB-PROTOCOL FOR CANDIDATE AGENT: Lanadelumab-IV 
VERSION:     
1.2 
This sub-protocol is a confidential communication of the Sponsor (Amgen) and Candidate Agent 
Owner (Takeda). I confirm that I have read this sub-protocol, I understand it, and I will work 
according to this sub-protocol, in conjunction with the Master Protocol for the overall platform 
study. I will also work consistently with the ethical principles that have their origin in the 
Declaration of Helsinki and that are consistent with Good Clinical Practices and the applicable 
laws and regulations. Acceptance of this document constitutes my agreement that no unpublished 
information contained herein will be published or disclosed without prior written approval from 
the Sponsor. 
Instructions to the Investigator: Please SIGN and DATE this signature page. PRINT your name, title, and the name of the study 
center in which the study will be conducted. Return the signed copy to the CRO/Candidate Agent Owner (Takeda). 
 
I have read this sub-protocol in its entirety and agree to conduct this part of the study 
accordingly: 
 
Signature of Investigator:         
___________________________            Date:  ________ 
Printed Name:                                  ___________________________ 
Investigator Title:                             ___________________________ 
 
Name/Address of Center:                ___________________________ 
  
  
  
  
  
___________________________ 
  
  
  
  
  
___________________________ 


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COV-01-004 – Sub-protocol for apremilast 
Version 4.0, 14 April  2021 
1 
TITLE PAGE 
Master Protocol Title: Industry Alliance Platform Trial to Assess the Efficacy and Safety of 
Multiple Candidate Agents for the Treatment of COVID-19 in Hospitalized Patients 
Sub-protocol Number: COV-01-004 
Sub-protocol for Candidate Agent APREMILAST 
Short Title: COVID-19 Multiple Agents and Modulators Unified Industry Members Trial 
(COMMUNITY) 
Study Phase: 3 
Sponsor Name: Amgen, Inc. 
Legal Registered Address:  1 Amgen Center Drive 
 
Thousand Oaks, CA 91320, US 
 
Regulatory Agency Identifying Number(s): IND 150485 
  
  
  
  
  
 
EudraCT 2020-002594-10 
 
The Sponsor is conducting this study to determine whether apremilast can safely and effectively be used 
to treat COVID-19 in accordance with the United States Secretary of the Department of Health and 
Human Services’ (HHS’s) Declaration under the Public Readiness and Emergency Preparedness (PREP) 
Act for medical countermeasures against COVID-19 (COVID-19 Declaration) effective 
04 February 2020. The purpose of this study is to test whether apremilast results in clinical benefit in 
patients hospitalized with COVID-19. This study is authorized to proceed under an approved 
Investigational New Drug (IND) application in accordance with the public health and medical response of 
Food and Drug Administration (FDA), an Authority Having Jurisdiction as described under the PREP 
Act, to prescribe, administer, deliver, distribute or dispense this Covered Countermeasure as defined by 
and following the United States HHS’s COVID-19 Declaration. 
 
Date of Sub-protocol: 14 April 2021 
Version: 4.0 
 
Candidate Agent Owner Contact: 
 
PPD
 
 


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COV-01-004 – Sub-protocol for apremilast 
Version 4.0, 14 April  2021 
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Candidate Agent Owner: 
 
 
I have read this sub-protocol in its entirety and agree to conduct this part of the study accordingly: 
  
  
  
  
 
April 16, 2021 
 
Amgen, Inc 
 Date 
 
 
 
 
 
 
PPD
 
 
PPD


CONFIDENTIAL 
COV-01-004 – Sub-protocol for apremilast 
Version 4.0, 14 April  2021 
3 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT SUMMARY 
..........................................................................4
 
1.0 
SUB-PROTOCOL SUMMARY 
.................................................................................6
 
1.1 
Overview of Sub-protocol ................................................................................6
 
1.2 
Schedule of Activities 
.......................................................................................7
 
1.3 
End of Study Definition for Sub-protocol 
....................................................10 
2.0 
BACKGROUND/RATIONALE IN SUPPORT OF APREMILAST IN 
COVID-19 
...................................................................................................................11 
2.1 
Benefit/Risk Assessment 
................................................................................12
 
2.2 
Dose Justification for Apremilast 
.................................................................13
 
3.0 
STUDY POPULATION 
............................................................................................15
 
3.1 
Enrollment and Screening 
.............................................................................15
 
3.2 
Eligibility Criteria 
..........................................................................................15
 
3.2.1 Inclusion Criteria 
...............................................................................15
 
3.2.2 Exclusion Criteria 
..............................................................................15
 
3.3 
Discontinuation of Study Treatment and Patient 
Discontinuation/Withdrawal 
.........................................................................15
 
4.0 
ADDITIONAL SUB-PROTOCOL STUDY ASSESSMENTS AND 
PROCEDURES 
..........................................................................................................16
 
4.1 
Pharmacokinetic Assessments 
......................................................................16
 
4.2 
Pharmacodynamic Assessments 
...................................................................16
 
5.0 
SUB-PROTOCOL STUDY TREATMENT 
............................................................17
 
5.1 
Treatment Plan...............................................................................................17
 
5.2 
Study Drug Administration ..........................................................................17
 
5.3 
Preparation/Handling/Storage/Accountability 
...........................................17
 
5.4 
Dose Modifications and Toxicity Management 
...........................................18 
5.5 
Treatment of Overdose 
..................................................................................18
 
5.6 
Concomitant Medications .............................................................................18
 
5.6.1 Rescue Medicine ...............................................................................20
 
5.7 
Study Drug Information 
................................................................................20
 
6.0 
REFERENCES 
...........................................................................................................21
 
7.0 
APPENDICES 
............................................................................................................22
 
Appendix 1
 Abbreviations 
...................................................................................23
 
Appendix 2 CYP3A Inducers 
..............................................................................24
 
Appendix 3 Signature of Investigator ................................................................25 
 


CONFIDENTIAL 
COV-01-004 – Sub-protocol for apremilast 
Version 4.0, 14 April  2021 
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PROTOCOL AMENDMENT SUMMARY 
Protocol Amendment 3 (Version 4.0) 
Protocol Amendment 3 (Version 4.0; dated 14 April 2021) replaces the final Protocol 
Version 3.1 (dated 26 October 2020). The amendment incorporates the following main changes: 
• Provides updated apremilast clinical trial data. 
• Includes text relative to discontinuation of study treatment and patient 
discontinuation/withdrawal. 
• 
 
 
• To align with the Master Protocol, removes statement that “concomitant treatments will be 
recorded throughout the study from time of enrollment (including screening) until the End of 
Study Visit.” 
Protocol Version 3.1 
Protocol Version 3.1 (dated 26 October 2020) replaced the final Protocol Amendment 2 
(Version 3.0; dated 08 October 2020). The version incorporated the following main changes: 
• In the Schedule of Activities: 
− Clarified procedures for obtaining/recording patient height and weight. 
− Removed the optional clinical safety laboratory assessments (hematology, clinical 
chemistry, and liver function tests) on Days 5, 11, and 18. 
Protocol Amendment 2 (Version 3.0) 
Protocol Amendment 2 (dated 08 October 2020) replaced Protocol Amendment 1 (dated 
27 August 2020). 
The amendment incorporated the following changes: 
• Provided Candidate Agent Owner contact information. 
• In the Schedule of Activities: 
o Clarified that medical history includes the date of diagnosis of acute respiratory 
distress syndrome, if present. 
o Clarified that for patients requiring high-flow oxygen, mechanical ventilation 
(invasive/noninvasive), or extracorporeal membrane oxygenation only, provide 
FiO2 requirement.  
o 
CCI
Clarified that on Day 1, the National Early Warning Score 2 is to be assessed 
prior to study drug administration. 


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COV-01-004 – Sub-protocol for apremilast 
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o Added that clinical safety laboratory assessments are to be completed ‘all other 
days while in hospital’ and these data are to be collected on the electronic case 
report form. 
• Clarified procedures for the treatment of overdose. 
Protocol Amendment 1 (Version 2.0) 
Protocol Amendment 1 (dated 27 August 2020) replaced the final Version 1.0 protocol (dated 
24 June 2020). 
The amendment incorporated the following changes: 
• The study design was modified to be a double-blind, placebo-controlled platform study. 
o Schedule of Activities table was updated. 
o Where appropriate, reference to placebo was added (ie, apremilast or placebo). 
• Schedule of Activities table was updated to specify that study treatment will be 
administered as twice daily dosing from Day 1 to Day 14 or until hospital discharge, 
whichever occurs first. 


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COV-01-004 – Sub-protocol for apremilast 
Version 4.0, 14 April  2021 
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1.0 SUB-PROTOCOL SUMMARY 
1.1 Overview of Sub-protocol 
This sub-protocol is designed to assess the efficacy and safety of apremilast plus standard of care 
(SoC) in patients hospitalized for coronavirus disease 2019 (COVID-19). 
This study will evaluate whether apremilast plus SoC could be a useful therapeutic in the current 
management landscape where patients are hospitalized for progressive respiratory signs and 
symptoms due to COVID-19.  
Twice daily (BID) apremilast 30 mg is the same dose approved for treatment of psoriatic arthritis 
(PsA), plaque psoriasis (PsO), and oral ulcers associated with Behçet’s disease (BD). 
 


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COV-01-004 – Sub-protocol for apremilast 
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1.2 Schedule of Activities 
 
Screening 
Baseline 
 
 
 
 
Day (± Window) 
Day -1 or 
Day 1 
Day 1 
Daily Until Hospital 
Discharge (or Daily Until 
Day 29 While in Hospital) 
Day 15a 
(±2 days) 
Day 29a 
(±3 days) 
Day 60a 
(±4 days) 
(End of 
Study) 
ELIGIBILITY 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Relevant medical historyb 
X 
 
 
 
 
 
Review of SARS-CoV-2 diagnostic tests 
(obtained during the previous 72 hours, if 
available) 
X 
 
 
 
 
 
SARS-CoV-2 diagnostic testc 
X 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
X 
 
 
 
 
12-lead electrocardiogram 
X 
 
 
 
 
 
STUDY INTERVENTION 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
Administration of study treatment BID 
 
Daily from Day 1 to Day 14 or until 
hospital discharge, whichever occurs first 
 
 
 
Treatment with SoC 
 
SoC will be based on the practices of the study center 
STUDY PROCEDURES 
 
 
 
 
 
 
Physical examination (including height and 
weight)d 
X 
 
 
 
 
 
Vital signs, including body temperature, 
pulse rate, blood pressure, respiratory rate, 
SpO2, FiO2e 
 
Xf 
X 
Xg 
Xg 
 
CCI


CONFIDENTIAL 
COV-01-004 – Sub-protocol for apremilast 
Version 4.0, 14 April  2021 
8 
 
Screening 
Baseline 
 
 
 
 
Day (± Window) 
Day -1 or 
Day 1 
Day 1 
Daily Until Hospital 
Discharge (or Daily Until 
Day 29 While in Hospital) 
Day 15a 
(±2 days) 
Day 29a 
(±3 days) 
Day 60a 
(±4 days) 
(End of 
Study) 
Ordinal scale 
 
Xf 
X 
X 
X 
X 
Clinical assessmentsh 
 
Xf 
X 
X 
X 
Xi 
Assessment of floor status (ICU yes/no) 
 
X 
Xg 
Xg 
Xg 
 
Assessment of rehospitalization for 
discharged patientsj 
 
 
 
X 
X 
X 
Concomitant medication review (including 
use of vasopressors) 
X 
Xf 
X 
X 
X 
X 
Adverse event evaluation 
X 
X 
X 
X 
X 
X 
SAFETY LABORATORY 
 
 
 
 
 
 
Clinical safety laboratory assessments 
Xk,l 
Xf,m,n 
Days 3
o, 8
m, 22
m, and at 
dischargem,p 
All other days while in 
hospitalq 
Xm,r 
Xm 
 
Pregnancy test for females of childbearing 
potential 
Xk 
 
 
 
 
 
RESEARCH LABORATORY 
 
 
 
 
 
 
Blood for pharmacokinetic assessment 
 
 
Day 8 
X 
 
 
Abbreviations: ARDS=acute respiratory distress syndrome; COVID-19=coronavirus disease 2019; eCRF=electronic case report form; FiO2=fraction of inspired 
oxygen; ICU=intensive care unit; 
; SARS-CoV-2= severe acute respiratory syndrome coronavirus 2; SoC=standard 
of care; SpO2=oxygen saturation. 
Note: Additional assessments, if required, will be defined in the sub-protocol. 
a
CCI
 These visits will be performed even if a patient has already been discharged. If discharged prior to scheduled visit, these visits will be conducted via 
telemedicine. For visits conducted by telephone, it may not be possible to perform some scheduled assessments (eg, vital signs). The Day 29 assessments will 
also be performed, where possible, for patients who discontinue the study prematurely. 
CCI


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COV-01-004 – Sub-protocol for apremilast 
Version 4.0, 14 April  2021 
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b Medical history includes estimated date and time of first COVID-19 related symptoms and co-morbidities (eg, respiratory [including date of diagnosis of 
ARDS, if present], cardiovascular, metabolic, malignancy, endocrine, gastrointestinal, immunologic, renal). 
c Oropharyngeal/nasal swab for polymerase chain reaction determination of SARS-CoV-2 or for SARS-CoV-2 antigen testing. Only to be performed if no 
diagnostic test results are available that have been obtained during the previous 72 hours. 
d If height and/or weight cannot be obtained at the Screening Visit (Day -1 or Day 1), these parameters can be recorded as a combination of patient-reported data 
and data obtained from recent medical records (ie, at hospital admission). 
e For patients requiring high-flow oxygen, mechanical ventilation (invasive/noninvasive), or extracorporeal membrane oxygenation only, provide FiO2 
requirement. 
f Baseline assessments should be performed prior to study drug administration. 
g To be assessed only while hospitalized. 
h Includes oxygen requirement (ie, mode of delivery/liters of oxygen flow, FiO2 requirement), stop date of oxygen for patients who were discharged on home 
oxygen, extracorporeal membrane oxygenation support, noninvasive or invasive ventilator requirement, including start and stop of low- or high-flow oxygen 
supply or of any form of ventilation, and need for renal replacement therapy. Noninvasive ventilation refers to the delivery of mechanical ventilation to the 
lungs using techniques that do not require an endotracheal airway. 
i Only stop date of oxygen for patients who were discharged on home oxygen. 
j Information recorded is yes/no, hospitalization date, discharge date. 
k Laboratory tests performed within the 48 hours prior to enrollment will be accepted for determination of eligibility. 
l Hematology and clinical chemistry. 
m Hematology, clinical chemistry, liver function tests, cardiac panel, and coagulation. 
n Any laboratory tests performed as part of routine clinical care can be used for safety laboratory testing. 
o Hematology, clinical chemistry, and liver function tests. 
p If not done or entered into the eCRF within previous day. 
q Hematology, clinical chemistry, and liver function tests will be collected on the eCRF, if available, while the patient is in hospital. 
r This assessment will be performed on Day 15 or date of discharge, if earlier. 


CONFIDENTIAL 
COV-01-004 – Sub-protocol for apremilast 
Version 4.0, 14 April  2021 
10 
1.3 End of Study Definition for Sub-protocol 
The Master Protocol defines the end of study for the overall platform study. 
For this specific sub-protocol, the end of the study will be defined as the date on which the last 
patient included within this sub-protocol is assessed or receives an intervention for evaluation in 
the sub-protocol (ie, last patient last visit), including any additional parts in the sub-protocol 
(eg, safety follow-up), as applicable. 
An individual patient is considered to have completed the study if he/she has had the opportunity 
to complete the End of Study Visit (Day 60) as shown in the Schedule of Activities (Section 1.2).  


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COV-01-004 – Sub-protocol for apremilast 
Version 4.0, 14 April  2021 
11 
2.0 BACKGROUND/RATIONALE IN SUPPORT OF 
APREMILAST IN COVID-19 
Since the outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 
infection (causing COVID-19) in December 2019, this rapidly evolving pandemic has infected 
23,964,800 people and has claimed 820,989 lives globally (John Hopkins COVID-19 data 
source, as of 26 August 2020). Compared to the typical, annual influenza epidemic, COVID-19 
is associated with a mortality rate that is 10-fold higher, with a disproportionately higher rate of 
death among the elderly and individuals with underlying comorbidities 
(Wu and McGoogan, 2020). Although the vast majority of patients appear asymptomatic, or 
present with mild symptoms, experience from China has revealed that 14% of patients present 
with severe disease and 5% have a critical presentation associated with respiratory failure, shock, 
or multi-organ system dysfunction (Wu and McGoogan, 2020). The morbidity and mortality 
associated with this illness has been significant; in the United States, 19% of COVID-19 patients 
with known disposition have required hospitalization, with 6% of all patients requiring intensive 
care unit (ICU) admission (United States Centers for Disease Control [US CDC], 2020b). The 
clinical course in severe cases of COVID-19 infection is characterized by a hyperinflammatory 
immune response and often a rapid progression to acute respiratory distress syndrome (ARDS), 
resulting in a high ICU mortality rate, ranging from 39% to 72% (United States Centers for 
Disease Control [US CDC], 2020a). These high ICU mortality rates from China were also 
observed in Italy, where the ICU mortality was 26% with worse outcomes observed for older 
patients (≥ 64 years of age, 36%) compared to younger patients (≤ 63 years of age, 15%) 
(Grasselli et al, 2020). 
There is an unmet medical need for effective therapies for COVID-19. Clinical management of 
the disease has been limited solely to supportive measures, with frequent off-label use of 
unproven or experimental therapies. Therefore, there is a significant high unmet need for an 
effective therapy for management of COVID-19. Additionally, recent data from COVID-19 
infections have demonstrated an increase in proinflammatory cytokines, such as interleukin 
(IL)-6 and tumor necrosis factor alpha (TNFα), with higher levels being observed in patients 
with more severe disease (Wu and Chen et al, 2020; Huang et al, 2020). Characterization of the 
disease to date has identified this inappropriate hyperinflammatory immune response as a key 
driver leading to the clinical decompensation observed in COVID-19 patients; thus, a therapeutic 
that mitigates this immune response might be able to alter the clinical disease course. 
Apremilast is an oral phosphodiesterase 4 (PDE4) inhibitor that has been approved in adult 
patients for treatment of PsA, PsO, and BD. Phosphodiesterase 4 is expressed in both the innate 
and adaptive cellular components of the immune system. Inhibition of PDE4 results in elevation 
of intracellular cyclic adenosine monophosphate (cAMP) levels, down regulating inflammatory 
responses through reduced expression of TNFα, IL-23, and other proinflammatory cytokines 
(Schafer et al, 2014). In addition, inhibition of PDE4 also increases anti-inflammatory cytokines 


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such as IL-10 (Eigler, 1998). In clinical studies of PsA and PsO, compared to placebo, treatment 
with apremilast had a significant impact on changes in plasma cytokines, including reduction of 
inflammatory cytokines TNFα, IL-8, IL-6, IL-17, monocyte chemoattractant protein-1 (MCP-1), 
macrophage inflammatory protein-1 beta (MIP-1β), and increase of anti-inflammatory mediators 
IL-10 and IL-1RA (Schafer et al, 2015; Apremilast Investigator’s Brochure). 
Since apremilast reduces proinflammatory cytokines, such as IL-6 and TNFα expression, in other 
inflammatory states, it is hypothesized that apremilast can suppress the hyperinflammatory 
response associated with COVID-19 and prevent progression of the morbid clinical course. 
Finally, ibudilast, another PDE4 inhibitor, inhibited TNFα and IL-2 in a 
lipopolysaccharide-stimulation mouse model of neonatal ARDS, and reduced pulmonary injury 
in this context (Yang et al, 2020), providing further preclinical rationale in support of evaluating 
apremilast in treatment of COVID-19 in hospitalized patients.  
A detailed description of the chemistry, pharmacology, and safety of apremilast is provided in 
the Investigator’s Brochure. 
2.1 Benefit/Risk Assessment 
Apremilast has not been evaluated in patients with COVID-19. However, there is some evidence 
from nonclinical studies that apremilast and another PDE4 inhibitor, ibudilast, may improve 
pulmonary manifestations in patients with COVID-19. Apremilast is generally well-tolerated and 
does not have an increased risk of serious infections or other identified risks that could preclude 
its use in this patient population.   
As of 20 March 2021, apremilast had been administered at daily doses ranging from 10 to 
105 mg/day to more than 9,000 patients in completed and ongoing clinical studies, 
approximately 7,235 of whom received apremilast in 30 Phase 2, Phase 3, and Phase 4 studies in 
multiple indications including PsA, PsO, and BD. 
In pivotal Phase 3 studies, BID apremilast 30 mg resulted in statistically significant and 
clinically meaningful improvements in the signs and symptoms of PsA, PsO, and BD. The most 
commonly observed treatment-emergent adverse events (ie, those reported in > 5% of patients) 
have been diarrhea, nausea, headache (including tension headache), upper respiratory tract 
infections, and nasopharyngitis. The majority of treatment-emergent adverse events of diarrhea, 
nausea, and headache, occurred within the first 2 weeks of treatment and most resolved within 
4 weeks. The majority of reported treatment-emergent adverse events were mild or moderate in 
severity and resolved while patients continued apremilast treatment. The incidence of serious 
adverse events was low and comparable between apremilast and placebo treatment groups in the 
placebo-controlled periods and was not driven by any single preferred term or any specific 
individual organ toxicity. There was no evidence of an increased risk of serious or opportunistic 
infections in the Phase 3 studies. The safety profile of apremilast is comparable across its 
approved indications in PsA, PsO, and BD. 


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COV-01-004 – Sub-protocol for apremilast 
Version 4.0, 14 April  2021 
13 
As of 20 March 2021, a total of approximately 10,000 patients have been enrolled in clinical 
studies in which 9,312 patients have received apremilast; worldwide exposure to commercial 
apremilast is approximately 736,035 unique patients with a cumulative exposure of 
376,044 patient years. In the US, a total of 457,379 patients have been exposed to apremilast 
since it was approved in March 2014. The safety profile of apremilast in the postmarketing 
setting remains similar to that observed in the registrational clinical program. The most 
frequently reported adverse events have been gastrointestinal (diarrhea, nausea, vomiting, 
abdominal discomfort) and nervous system disorders (headache). The benefit-risk balance of 
apremilast remains favorable for the approved indications. 
In the approved indications, apremilast is initially titrated from 10 mg once daily (QD) to 30 mg 
BID over the first 5 days of therapy, which is intended to reduce the gastrointestinal symptoms 
associated with initial therapy. During the initial Phase 1 studies, more patients reported 
gastrointestinal adverse events at the initiation of apremilast. In general, these events were mild 
to moderate in severity and did not lead to discontinuation. As a result, a titration regimen was 
implemented. For this study, as the potential effect of apremilast in the inflammatory cascade is 
expected to be during the first days of therapy, no titration regimen will be used. It is not 
expected that the initiation of apremilast without titration will change the risk benefit. Patients 
will be closely monitored during the 14-day treatment period. 
Although risks of treatment with apremilast are known, the benefits for patients with COVID-19 
are potential and the absence of effective treatments of COVID-19 complications during this 
pandemic, warrant investigations such as this study. 
The above benefit-risk assessment supports the conduct of this clinical trial. Reference should be 
made to the Investigator’s Brochure or product labeling for further data on apremilast.  
2.2 Dose Justification for Apremilast 
The apremilast dose to be evaluated in this study is 30 mg BID, the same dose approved for 
treatment of PsA, PsO, and BD. Inhibition of PDE4 results in the down-regulation of 
proinflammatory cytokines. In clinical studies of PsA and PsO, compared to placebo, treatment 
with BID apremilast 30 mg resulted in significant suppression on a range of serum cytokines, 
including IL-8, MCP-1, MIP-1β, TNFα, IL-6, ferritin, and IL-2 (Schafer et al, 2015). Apremilast 
pharmacokinetics are not expected to differ between COVID-19 patients and other patient 
populations and it is expected that apremilast systemic exposures attained with 30 mg BID in the 
approved indications will also be effective in modulating the increases in proinflammatory 
cytokines observed in COVID-19 infections and thus help prevent progression of the morbid 
clinical course (Chen et al, 2020; Huang et al, 2020).  
In vitro studies have shown that the half-maximal concentration (IC50) needed to inhibit PDE4 is 
0.074 μM and for cytokines including TNFα, interferon gamma (IFN-γ), and IL-12p70 is 0.11, 
0.013, and 0.12 μM, respectively (Schett et al, 2010). At the approved dose of 30 mg BID, the 


CONFIDENTIAL 
COV-01-004 – Sub-protocol for apremilast 
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14 
exposures in patients with PsA is approximately 550 ng/mL (1 µM) at steady-state 
(Study CC-10004-PK-010). These exposures are well above the IC
50 values required for 
inhibition of cytokines as well as chemokines. 
In a Phase 1 study in healthy subjects (Study CC-10004-PK-007), multiple doses of apremilast 
were evaluated as QD or BID dosing for 14 days (doses ranging from 40 mg QD to 80 mg QD 
and 40 mg BID). During the 14 days of dose administration, nausea occurred more frequently 
during the first week of dosing, and less frequently thereafter. In addition, this study evaluated 
the frequency of gastrointestinal related adverse events with and without dose titration for 40 mg 
QD for 14 days. The proportion of subjects who reported nausea was lower in the dose group 
with titration (44%) compared to the dose group without (78%). Overall, the dose titration group 
had fewer total number of adverse events reported (34 adverse events with dose titration versus 
72 adverse events reported by the group without titration). 
Twice daily apremilast 30 mg without titration has been evaluated in 3 Phase 1 studies in healthy 
subjects and subjects with PsA (N = 106 subjects) for a duration of 4 to 10 days 
(Studies CC-10004-PK-008, CC-10004-PK-010, and CC-10004-CP-020). This regimen without 
titration was well-tolerated and there were no discontinuations reported due to 
gastrointestinal-related adverse events following start of therapy. The most common adverse 
event observed was headache, followed by nausea, and vomiting, which were mostly mild in 
severity.  
In the setting of COVID-19, in which progression of the clinical course occurs rapidly, 
apremilast will not be initially titrated since rapid attainment of steady-state exposures to 
maximize the chance of clinical efficacy is more important than mitigating the incidence of 
generally mild gastrointestinal symptoms that were largely well-tolerated in studies without 
titration. 


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15 
3.0 STUDY POPULATION 
3.1 Enrollment and Screening 
Investigators will be expected to maintain a screening log of all potential study candidates that 
includes limited information about the potential candidate (eg, date of screening). 
Eligibility criteria will be evaluated during screening. 
Before any study-specific activities/procedures, the appropriate written informed consent must 
be obtained. 
3.2 Eligibility Criteria 
Overall inclusion and exclusion criteria are presented in Sections 5.1 and 5.2 of the Master 
Protocol, respectively. Patients must meet all inclusion criteria and no exclusion criteria for the 
Master Protocol to be considered for inclusion in the COV-01-004 sub-protocol. The following 
sections detail variations to those criteria that are specific to this sub-protocol. 
3.2.1 
Inclusion Criteria 
No additional inclusion criteria are specific for the sub-protocol. 
3.2.2 
Exclusion Criteria 
Additional exclusion criteria that are specific to the sub-protocol are as follows: 
Prior/Concomitant Therapy 
X1. Current treatment with apremilast, or another agent of similar mechanism of action, for any 
indication within 1 week prior to first dose of investigational product. 
X2. Concurrent use at screening or randomization of cytochrome P450 (CYP)3A inducers 
(eg, rifampin, phenobarbital, carbamazepine) within 1 week prior to first dose of investigational 
product. 
Other Exclusions 
X3. Known hypersensitivity to apremilast or any excipients in formulation. 
3.3 Discontinuation of Study Treatment and Patient 
Discontinuation/Withdrawal 
The reason for and date of discontinuation from study treatment and/or from study participation 
will be collected for all randomized patients who prematurely discontinue study treatment or 
participation. A patient may discontinue study treatment or withdraw from the study per the 
criteria listed in Section 7 of the Master Protocol. 


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4.0 ADDITIONAL SUB-PROTOCOL STUDY ASSESSMENTS 
AND PROCEDURES 
In addition to the study assessments and procedures described in Section 8.0 of the Master 
Protocol, assessments specific to the COV-01-004 sub-protocol will be performed as described 
in the following sections. The Schedule of Activities for this sub-protocol is presented in 
Section 1.2. 
4.1 Pharmacokinetic Assessments 
Blood will be collected on Days 8 and 15 for assessment of apremilast concentrations. The date 
and time of the pharmacokinetic sample collection will be documented on the electronic case 
report form (eCRF). 
4.2 Pharmacodynamic Assessments 
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5.0 SUB-PROTOCOL STUDY TREATMENT 
5.1 Treatment Plan 
Patients will receive BID either apremilast 30 mg or placebo in a double-blind manner plus SoC 
for 14 days or until hospital discharge, death, or discontinuation of investigational product, 
whichever occurs first. 
5.2 Study Drug Administration 
The tablet formulation of apremilast or placebo will be provided in a double-blind manner in 
bottles throughout the entire study. 
Double-blind treatment (apremilast or placebo) will be taken orally BID, with doses 
approximately 12 hours apart, without restriction of food or drink. 
 
 
The quantity of tablets, type of administration (intact or disintegrated tablets), date/time of each 
dose, and box number of study treatment are to be recorded on the patient’s eCRF. 
5.3 Preparation/Handling/Storage/Accountability 
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported and 
resolved before use of the study treatment. 
Only patients enrolled in the study may receive study treatment and only authorized study center 
staff may supply or administer study treatment. All study treatments must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to the Investigator and authorized study center 
staff. 
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records). 
CCI
The Investigator, a member of the study center staff, or a hospital pharmacist must maintain an 
adequate record of the receipt and distribution of all study medication using the Drug 
Accountability Form. These forms must be available for inspection at any time. 


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5.4 Dose Modifications and Toxicity Management 
The reason for dose change of study treatment is to be recorded on the patient’s eCRF. 
The dose of apremilast or placebo is to be reduced as follows: 
• Study treatment administration should be reduced to QD in patients with creatinine 
clearance of < 30 mL/min (estimated by the Cockcroft-Gault equation). 
• If gastrointestinal adverse events associated with the start of therapy are not mitigated 
with antiemetics and/or antidiarrheals, study treatment dosing may be reduced to QD for 
1 to 3 days. Thereafter, the dose should be increased to 30 mg BID. 
• Study treatment is to be withheld if a patient requires renal replacement therapy, such as 
hemodialysis. Treatment may be resumed the next day if renal replacement therapy is no 
longer needed, if prior to Day 14. If dosing is resumed, daily dose will be based on the 
patient’s creatinine clearance. 
5.5 Treatment of Overdose 
Overdose for this protocol, on a per dose basis, is defined as any amount over the 
protocol-specified dose of apremilast or placebo (30 mg BID) given to a patient, regardless of 
any associated adverse events or sequelae. On a schedule or frequency basis, an overdose is 
defined as anything more frequent than the protocol required schedule or frequency.  
The Sponsor does not recommend specific treatment for an overdose. 
In the event of an overdose, the Investigator/treating physician should: 
1. Contact the 
 Medical Monitor immediately. 
2. Closely monitor the patient for any adverse event/serious adverse event and laboratory 
abnormalities. 
3. Document the quantity of the excess dose as well as the duration of the overdose in the 
eCRF. 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the 
 Medical Monitor based on the clinical evaluation of the patient. 
5.6 Concomitant Medications 
Throughout the study, Investigators may prescribe any concomitant medications or treatments 
deemed necessary to provide adequate supportive care except for excluded medications. 
CCI
 
CCI


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The following medications are prohibited: 
• CYP3A inducers (ie, rifampicin, phenobarbital, carbamazepine), see Appendix 2 
• Concurrent use of a PDE4 antagonist 
Concomitant medications in a hospitalized population change daily and are difficult to collect 
and attribute to success and failure of therapy and impact on safety. Therefore, emphasis is 
placed on collection of the following concomitant medications:  
• vasopressors (eg, dopamine, epinephrine) 
• antidiarrheals 
• antiemetics 
• anticoagulants (eg, heparin, lovenox) 
• corticosteroids 
• non-steroidal anti-inflammatory drugs (NSAIDs) 
• antipyretics other than NSAIDs 
• antivirals (eg, hydroxychloroquine, lopinavir, ritonavir) 
• antifungals 
• antibacterial 
• antimycobacterials 
• antiprotozoans 
• immune mediating therapies (eg, INF-β, convalescent serum, immunomodulators taken 
for underlying comorbid medical conditions) 
• angiotensin converting enzymes  
• angiotensin receptor inhibitors/blockers 
• CYP3A inducers (eg, rifampicin) 
• PDE4 antagonists 
For concomitant medications, collect name of medication, reason for use, dates of administration 
(including start and end dates), and dosage information (including dose, unit, and frequency). 


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5.6.1 
Rescue Medicine 
Not applicable. 
5.7 Study Drug Information 
The chemical name of apremilast is acetamide, N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-
(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl].  
The 30 mg tablet formulation of apremilast will be provided in bottles throughout the study. 
Apremilast will be shipped to the site from regional or local drug repositories. All other supplies 
will be provided by the site. 
The placebo will be administered as tablets ready for oral administration matching the active 
tablets in color, size, and shape. 
Apremilast or matching placebo will be taken orally BID, with doses approximately 12 hours 
apart, without restriction of food or drink. 
 
 
 
CCI
The quantity of tablets, type of administration (intact or disintegrated tablet), date/time of each 
dose, and box number of study treatment are to be recorded on the patient’s eCRF. 


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6.0 REFERENCES 
Apremilast Investigator’s Brochure. Thousand Oaks, CA. Amgen Inc. 
Chen G, Wu D, Guo W, et al. Clinical and immunological features of severe and moderate 
coronavirus disease 2019. J Clin Invest. 2020;130(5):2620‐2629. 
Eigler A, Siegmund B, Emmerich U et al. Anti‐inflammatory activities of cAMP‐elevating 
agents: enhancement of IL‐10 synthesis and concurrent suppression of TNF production. J Leukoc 
Biol. 1998;63(1):101-107. 
Grasselli G, Zangrillo A, Zanella A, et al. Baseline characteristics and outcomes of 1591 patients 
infected with SARS-CoV-2 admitted to the ICUs of the Lombardy Region, Italy. JAMA. 
2020;323(16):1574-1581. 
Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus 
in Wuhan, China. Lancet. 2020;395(10223):497-506. 
Schafer P, Chen P, Fang L, Wang A, Chopra R. The pharmacodynamic impact of apremilast, an 
oral phosphodiesterase 4 inhibitor, on circulating levels of inflammatory biomarkers in patients 
with psoriatic arthritis: substudy results from a phase III, randomized, placebo-controlled trial 
(PALACE 1). J Immunol Res. 2015;2015:906349. 
Schafer PH, Parton A, Capone L et al. Apremilast is a selective PDE4 inhibitor with regulatory 
effects on innate immunity. Cell Signal. 2014;26(9):2016-2029. 
Schett G, Sloan VS, Stevens RM, Schafer P. Apremilast: a novel PDE4 inhibitor in the treatment 
of autoimmune and inflammatory diseases. Ther Adv Musculoskelet Dis. 2010;2(5):271-278. 
United States Centers for Disease Control. Interim Clinical Guidance for Management of 
Patients with Confirmed Coronavirus Disease (COVID-19). Revised 03 April 2020a. 
https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidance-management-patients.html. 
Accessed 27 April 2020. 
United States Centers for Disease Control. CDC COVID-19 Response Team. Severe Outcomes 
Among Patients with Coronavirus Disease 2019 (COVID-19) - United States, February 12-
March 16, 2020b. MMWR Morb Mortal Wkly Rep. 2020;69(12):343‐346. 
Wu C, Chen X, Cai Y, et al. Risk factors associated with acute respiratory distress syndrome and 
death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med. 
2020;180(7):934-943. 
Wu Z, McGoogan J. Characteristics of and important lessons from the coronavirus disease 2019 
(COVID-19) outbreak in China. summary of a report of 72
 314 cases from the Chinese center for 
disease control and prevention. JAMA. 2020;323(13):1239-1242. 
Yang X, Yu Y, Xu J, et al. Clinical course and outcomes of critically ill patients with SARS-
CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet 
Respir Med. 2020;8(5):475‐481. 


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7.0 APPENDICES 


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COV-01-004 – Sub-protocol for apremilast 
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Appendix 1 
Abbreviations  
Abbreviation  
Explanation 
ARDS 
acute respiratory distress syndrome 
BD 
Behçet’s disease  
BID 
twice daily 
cAMP 
cyclic adenosine monophosphate 
eCRF 
electronic case report form 
FIO2 
fraction of inspired oxygen 
IC
50 
half-maximal concentration 
ICU 
intensive care unit 
IFN-γ 
interferon gamma 
IL 
Interleukin 
IPPA 
Investigational Product Preparation and Administration 
MCP-1 
monocyte chemoattractant protein-1 
MIP-1β 
macrophage inflammatory protein-1 beta 
NSAID 
nonsteroidal anti-inflammatory drug 
O2 
oxygen 
PCR 
polymerase chain reaction 
PDE4 
phosphodiesterase 4 
PsA 
psoriatic arthritis 
PsO 
plaque psoriasis 
QD 
once daily 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SoC 
standard of care 
TNFα 
tumor necrosis factor alpha 
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Appendix 2 
CYP3A Inducers 
 
 
Strong inducers 
Moderate inducers 
Weak inducers 
CYP3A 
apalutamide, carbamazepine, 
enzalutamide, mitotane, phenytoin, 
rifampin, St. John’s wort 
bosentan, efavirenz, etravirine, 
phenobarbital, primidone 
armodafinil, modafinil, 
rufinamid 
Abbreviations: CYP3A=cytochrome P450 A 
Note: Strong, moderate, and weak inducers are drugs that decreases the area under the concentration time curve of 
sensitive index substrates of a given metabolic pathway by ≥ 80%, ≥ 50% to < 80%, and ≥ 20% to < 50%, 
respectively. 
This table is presented to provide examples of clinical index inducers and not intended to be an exhaustive list. 
Source: https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-
substrates-inhibitors-and-inducers#table3-3. Accessed 09 April 2021. 
 


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Appendix 3 
Signature of Investigator 
PROTOCOL TITLE: Industry Alliance Platform Trial to Assess the Efficacy and Safety of 
Multiple Candidate Agents for the Treatment of COVID-19 in Hospitalized Patients 
SUB-PROTOCOL NO: 
COV-01-004 
SUB-PROTOCOL FOR CANDIDATE AGENT APREMILAST 
VERSION:     
4.0 
This sub-protocol is a confidential communication of the Sponsor. I confirm that I have read this 
sub-protocol, I understand it, and I will work according to this sub-protocol, in conjunction with 
the Master Protocol for the overall platform study. I will also work consistently with the ethical 
principles that have their origin in the Declaration of Helsinki and that are consistent with Good 
Clinical Practices and the applicable laws and regulations. Acceptance of this document 
constitutes my agreement that no unpublished information contained herein will be published or 
disclosed without prior written approval from the Sponsor. 
Instructions to the Investigator: Please SIGN and DATE this signature page. PRINT your name, title, and the name of the study 
center in which the study will be conducted. Return the signed copy to the CRO/Sponsor. 
 
I have read this sub-protocol in its entirety and agree to conduct this part of the study 
accordingly: 
 
Signature of Investigator:         
__________________________            Date:  ________ 
Printed Name:                                  ___________________________ 
Investigator Title:                             ___________________________ 
 
Name/Address of Center:                ___________________________ 
  
  
  
  
  
___________________________ 
  
  
  
  
  
___________________________ 
 


CONFIDENTIAL 
COV-01-005 – Sub-protocol for zilucoplan 
Version 1.2, 03 November 2020 
1 
TITLE PAGE 
Master Protocol Title: Industry Alliance Platform Trial to Assess the Efficacy and Safety of 
Multiple Candidate Agents for the Treatment of COVID-19 in Hospitalized Patients 
Sub-protocol Number: COV-01-005 
Sub-protocol for Candidate Agent: Zilucoplan 
Short Title: COVID-19 Multiple Agents and Modulators Unified Industry Members Trial 
(COMMUNITY) 
Study Phase: 3 
Candidate Agent Owner:   
UCB Biopharma SRL 
Legal Registered Address:  
Allée de la Recherche 60 
1070 Brussels, Belgium 
Regulatory Agency Identifying Number(s):  IND 150485 
EudraCT 2020-002594-10 
Date of Sub-protocol: 03 November 2020 
Version: 1.2 
Candidate Agent Owner Contact: 
PPD
 
Translational Medicine, UK Satellite Hub 
UCB Biopharma SRL 
 
PPD


CONFIDENTIAL 
COV-01-005 – Sub-protocol for zilucoplan 
Version 1.2, 03 November 2020 
2 
Candidate Agent Owner (UCB Biopharma SRL) Signatory: 
 
 
 
I have read this sub-protocol in its entirety and agree to conduct this part of the study accordingly: 
          03 NOV 2020                                                           
Translational Medicine, UK Satellite Hub 
UCB Biopharma SRL 
 
Date 
PPD
 
 


CONFIDENTIAL 
COV-01-005 – Sub-protocol for zilucoplan 
Version 1.2, 03 November 2020 
3 
TABLE OF CONTENTS 
TABLE OF TABLES 
...............................................................................................................5 
TABLE OF FIGURES 
.............................................................................................................6 
PROTOCOL VERSION SUMMARY 
...............................................................
....................7 
1.0 
SUB-PROTOCOL SUMMARY 
...............................................................
..................8 
1.1 
Overview of Sub-protocol................................................................................8 
1.2 
Schedule of Activities 
.......................................................................................9 
1.3 
End of Study Definition for Sub-protocol 
....................................................13 
2.0 
BACKGROUND/RATIONALE IN SUPPORT OF ZILUCOPLAN IN 
COVID-19 
...................................................................................................................14 
2.1 
Background - Inflammation in COVID-19 Infection 
.................................14 
2.2 
Evidence for C5 Inhibition in COVID-19 
....................................................16 
2.3 
Benefit/Risk Assessment 
................................................................................18 
2.4 
Dose Justification for Zilucoplan 
.................................................................19 
3.0 
STUDY POPULATION 
............................................................................................22 
3.1 
Enrollment and Screening 
.............................................................................22 
3.2 
Eligibility Criteria 
..........................................................................................22 
3.2.1 Inclusion Criteria 
...............................................................................22 
3.2.2 Exclusion Criteria 
..............................................................................22 
3.3 
Discontinuation of Study Treatment and Patient 
Discontinuation/Withdrawal 
.........................................................................22 
3.3.1 Discontinuation of Study Treatment .................................................22 
3.3.2 Patient Discontinuation/Withdrawal from the Study ........................23 
4.0 
STUDY ASSESSMENTS AND PROCEDURES 
....................................................24 
4.1 
Safety Assessments 
.........................................................................................24 
4.1.1 Adverse Events 
...............................................................
...................24 
4.1.2 Clinical Safety Laboratory Assessments 
...........................................26 
4.2 
Pharmacokinetic Assessments 
......................................................................26 
4.3 
Pharmacodynamic and Biomarker Assessments 
........................................26 
4.4 
Anti-drug Antibody Testing 
..........................................................................27 
4.5 
27 
5.0 
STUDY TREATMENT 
.............................................................................................28 
5.1 
Treatment Plan...............................................................................................28 
5.2 
Study Drug Administration ..........................................................................28 
5.3 
Preparation/Handling/Storage/Accountability 
...........................................28 
5.4 
Dose Modifications and Toxicity Management 
...........................................29
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COV-01-005 – Sub-protocol for zilucoplan 
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5.5 
Treatment of Overdose 
.................................................................................29 
5.6 
Concomitant Medications .............................................................................29 
5.6.1 Dosing with Remdesivir or Dexamethasone 
.....................................30 
5.6.2 Rescue Medicine ...............................................................................30 
5.7 
Study Drug Information 
...............................................................................30 
6.0 
REFERENCES 
..........................................................................................................31 
7.0 
APPENDICES 
............................................................................................................33 
Appendix 1 Abbreviations 
...................................................................................34 
Appendix 2 Clinical Laboratory Tests 
...............................................................36 
Appendix 3 Signature of Investigator ................................................................38 
  


CONFIDENTIAL 
COV-01-005 – Sub-protocol for zilucoplan 
Version 1.2, 03 November 2020 
5 
TABLE OF TABLES 
Table 1 
Exposure to Zilucoplan in Completed Clinical Studies 
...................................18 
Table 2 
Protocol-required Safety Laboratory Assessments 
..........................................37 
 


CONFIDENTIAL 
COV-01-005 – Sub-protocol for zilucoplan 
Version 1.2, 03 November 2020 
6 
TABLE OF FIGURES 
Figure 1 
Escalating Phases of Disease Progression with COVID-19, with 
Associated Signs, Symptoms, and Potential Phase-specific Therapies 
...........14 
Figure 2  
Mean Complement Activity as Measured by Sheep Red Blood Cell 
Assay (% Hemolysis) 
......................................................................................21 
 


CONFIDENTIAL 
COV-01-005 – Sub-protocol for zilucoplan 
Version 1.2, 03 November 2020 
7 
PROTOCOL VERSION SUMMARY 
Protocol Version 1.2 
Protocol Version 1.2 (dated 03 November 2020) replaces the final Version 1.1 protocol (dated 
26 October 2020). The version incorporates the following main changes: 
 Updates background information relative to treatments approved and recommended for 
treatment of coronavirus disease 2019 (COVID-19). 
 Clarifies that all patients, regardless of study treatment assignment (zilucoplan or placebo) 
will receive antibiotic prophylaxis. This clarification affects the following sections: 
 Section 1.2, Schedule of Activities (footnote d). 
 Section 2.3, Benefit/Risk Assessment. 
 Section 3.2, Eligibility Criteria. 
 Section 4.1.1.1, Adverse Events from Zilucoplan. 
 Section 5.6, Concomitant Medications. 
 Clarifies criteria for discontinuation of study treatment and discontinuation/withdrawal from 
the study. 
Protocol Version 1.1 
Protocol Version 1.1 (dated 26 October 2020) replaced the final Version 1.0 protocol (dated 
12 October 2020). The version incorporated the following main changes: 
 In the Schedule of Activities: 
 Clarified procedures for obtaining/recording patient height and weight. 
 Removed the optional clinical safety laboratory assessments (hematology, clinical 
chemistry, and liver function tests) on Days 5, 11, and 18. 
 
 


CONFIDENTIAL 
COV-01-005 – Sub-protocol for zilucoplan 
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1.0 SUB-PROTOCOL SUMMARY 
1.1 Overview of Sub-protocol 
COVID-19 Multiple Agents and Modulators Unified Industry Members Trial (COMMUNITY) 
is an adaptive, randomized, placebo-controlled platform study, designed to rapidly evaluate 
candidate agents for the treatment of coronavirus disease 2019 (COVID-19). This sub-protocol 
will treat hospitalized adult patients (≥ 18 years) who have an active infection with severe acute 
respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19, as 
confirmed by laboratory tests and/or point of care tests. 
Zilucoplan is a 15-amino acid macrocyclic peptide complement inhibitor designed for the 
treatment of conditions in which inappropriate activation of complement component 5 (C5) has 
been demonstrated to play a role. 
Zilucoplan will be administered subcutaneously to patients infected with SARS-CoV-2 every 
day for 14 days (if the patient is discharged before 14 days of treatment, zilucoplan should be 
stopped at time of discharge or 24 hours before discharge). This sub-protocol outlines the 
scientific rationale, additional eligibility criteria, treatment schema, and other specifics where 
different from the Master Protocol. 
 


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COV-01-005 – Sub-protocol for zilucoplan 
Version 1.2, 03 November 2020 
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1.2 Schedule of Activities 
 
Screening  Baseline 
 
 
 
 
Day (± Window) 
Day -1 or 
Day 1  
Day 1 
Daily Until Hospital 
Discharge (or Daily 
Until Day 29 While in 
Hospital)  
Day 15a (± 2 days) 
Day 29a 
(± 3 days) 
Day 60a 
(± 4 days) 
(End of Study) 
ELIGIBILITY 
 
 
 
 
 
 
Informed consent 
X  
 
 
 
 
 
Demographics 
X  
 
 
 
 
 
Relevant medical historyb 
X  
 
 
 
 
 
Review of SARS-CoV-2 diagnostic tests 
(obtained during the previous 72 hours, 
if available)  
X  
 
 
 
 
 
SARS-CoV-2 diagnostic testc  
X  
 
 
 
 
 
Inclusion and exclusion criteria 
X  
X 
 
 
 
 
12-lead ECG 
X  
 
 
 
 
 
STUDY INTERVENTION 
 
 
 
 
 
 
Randomization 
  
X 
 
 
 
 
Administration of study treatment 
 
Daily from Day 1 to Day 14 or until 
hospital discharge, whichever occurs 
first 
 
 
 
Treatment with SoC 
 
SoC will be based on the practices of the study center  
Antibiotic prophylaxis 
 
X 
Xd 
Xd 
Xd 
 
STUDY PROCEDURES 
 
 
 
 
 
 
Physical examination (including height 
and weight)
e 
X  
 
 
 
 
 


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Screening  Baseline 
 
 
 
 
Day (± Window) 
Day -1 or 
Day 1  
Day 1 
Daily Until Hospital 
Discharge (or Daily 
Until Day 29 While in 
Hospital)  
Day 15a (± 2 days) 
Day 29a 
(± 3 days) 
Day 60a 
(± 4 days) 
(End of Study) 
Vital signs, including body temperature, 
pulse rate, blood pressure, respiratory 
rate, SpO
2, FiO
2f 
  
X
g 
X 
Xh 
Xh 
 
Ordinal scale 
  
X
g 
X 
X 
X 
X 
Clinical assessmentsi 
  
X
g 
X 
X 
X 
Xj 
Assessment of floor status (ICU yes/no)  
  
X 
Xh 
Xh 
Xh 
 
Assessment of rehospitalization for 
discharged patientsk 
 
 
 
X 
X 
X 
Concomitant medication review 
(including use of vasopressors) 
X  
Xg 
X 
X 
X 
X 
Adverse event evaluation 
X  
X 
X 
X 
X 
X 
SAFETY LABORATORY 
 
 
 
 
 
 
Clinical safety laboratory assessments 
Xl,m  
X
g,n,o 
Days 3p, 8
n, 22
n, and at 
dischargen,q 
All other days while 
hospitalizedr 
Xn,s 
Xn 
 
Pregnancy test for females of 
childbearing potential 
Xl  
 
 
 
 
 
RESEARCH LABORATORY 
 
 
 
 
 
 
Blood (EDTA and SST) for zilucoplan 
concentration analysis (PK), 
pharmacodynamic, and exploratory 
biomarkerst 
 
X 
Days 3 and 8 (± 1 day) 
while hospitalized, and 
day of discharge 
Xu 
Xu 
 
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Screening  Baseline 
 
 
 
 
Day (± Window) 
Day -1 or 
Day 1  
Day 1 
Daily Until Hospital 
Discharge (or Daily 
Until Day 29 While in 
Hospital)  
Day 15a (± 2 days) 
Day 29a 
(± 3 days) 
Day 60a 
(± 4 days) 
(End of Study) 
Blood (SST) ADA 
 
X  
Day of discharge 
Xu 
Xu 
 
ADA = anti-drug antibody; ARDS = acute respiratory distress syndrome; C = component; COVID-19 = coronavirus disease 2019; ECG = electrocardiogram; 
eCRF = electronic case report form; EDTA = ethylenediaminetetra-acetic acid; FiO
2 = fraction of inspired oxygen; G-CSF = granulocyte colony-stimulating 
factor; GM-CSF = granulocyte-macrophage colony-stimulating factor; ICU = intensive care unit; IFNγ = interferon gamma; IL = interleukin; 
IL-1RA = interleukin-1 receptor antagonist; IP-10 = interferon gamma-induced protein 10; MASP = mannose-associated serine protease; MCP-1 = monocyte 
chemoattractant protein 1; MIP-1a = macrophage inflammatory protein 1a; 
; PK = pharmacokinetic; 
SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; SoC = standard of care; SpO2 = oxygen saturation; SST = serum-separating tubes; 
TNFα = tumor necrosis factor alpha. 
Note: Additional assessments for this sub-protocol are highlighted in bold and italics. 
a These visits will be performed even if a patient has already been discharged. If discharged prior to scheduled visit, these visits will be conducted via 
telemedicine. For visits conducted by telephone, it may not be possible to perform some scheduled assessments (eg, vital signs). The Day 29 assessments will 
also be performed, where possible, for patients who discontinue the study prematurely. 
b Medical history includes estimated date and time of first COVID-19 related symptoms and co-morbidities (eg, respiratory [including date of diagnosis of 
ARDS, if present], cardiovascular, metabolic, malignancy, endocrine, gastrointestinal, immunologic, renal). 
c Oropharyngeal/nasal swab for polymerase chain reaction determination of SARS-CoV-2 or for SARS-CoV-2 antigen testing. Only to be performed if no 
diagnostic test results are available that have been obtained during the previous 72 hours. 
d Antibiotic prophylaxis decided by the Investigator for a maximum of 28 days starting with the first dose of zilucoplan or placebo (ie, during zilucoplan or 
placebo treatment and an additional 14 days after cessation of zilucoplan or placebo). Consultation with a local microbiologist and/or infectious disease 
specialist is recommended to select the antibiotic prophylaxis. Guidelines about treatment and prevention of Neisseria meningitidis-caused meningitis 
should also be considered. If the patient is discharged prior to finishing antibiotic prophylaxis, it can be confirmed by telephone at Day 29 if prophylaxis 
was completed at home. 
e If height and/or weight cannot be obtained at the Screening Visit (Day -1 or Day 1), these parameters can be recorded as a combination of patient-reported data 
and data obtained from recent medical records (ie, at hospital admission). 
f For patients requiring high-flow oxygen, mechanical ventilation (invasive/noninvasive), or extracorporeal membrane oxygenation only, provide FiO
2 
requirement. 
g Baseline assessments should be performed prior to study drug administration. 
h To be assessed only while hospitalized. 
i Includes oxygen requirement (ie, mode of delivery/liters of oxygen flow, FiO
2
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 requirement), stop date of oxygen for patients who were discharged on home 
oxygen, extracorporeal membrane oxygenation support, noninvasive or invasive ventilator requirement, including start and stop of low- or high-flow oxygen 
supply or of any form of ventilation, and need for renal replacement therapy. Noninvasive ventilation refers to the delivery of mechanical ventilation to the 
lungs using techniques that do not require an endotracheal airway. 
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j Only stop date of oxygen for patients who were discharged on home oxygen. 
k Information recorded is yes/no, hospitalization date, discharge date. 
l Laboratory tests performed within the 48 hours prior to enrollment will be accepted for determination of eligibility. 
m Hematology and clinical chemistry. 
n Hematology, clinical chemistry, liver function tests, cardiac panel, and coagulation. 
o Any laboratory tests performed as part of routine clinical care can be used for safety laboratory testing. 
p Hematology, clinical chemistry, and liver function tests. 
q If not done or entered into the eCRF form within previous day. 
r Hematology, clinical chemistry, and liver function tests will be collected on the eCRF, if available, while the patient is in hospital. 
s This assessment will be performed on Day 15 or date of discharge, if earlier. 
t 
 
 
 
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1.3 End of Study Definition for Sub-protocol 
The Master Protocol defines the end of study for the overall platform study. 
For this specific sub-protocol, the end of the study will be defined as the date on which the last 
patient randomized to this sub-protocol completes the last scheduled procedure as shown in the 
Schedule of Activities (SoA; Section 1.2). 


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2.0 BACKGROUND/RATIONALE IN SUPPORT OF 
ZILUCOPLAN IN COVID-19 
2.1 Background - Inflammation in COVID-19 Infection 
Pharmacotherapy targeted against SARS-CoV-2 holds the greatest promise when applied early in 
the course of COVID-19, but its usefulness in advanced stages may be doubtful. Similarly, use of 
anti-inflammatory therapy applied too early may not be necessary and could even provoke viral 
replication such as in the case of corticosteroids. It appears that there are 2 distinct but 
overlapping pathological subsets, the first triggered by the virus itself and the second by the host 
response (Figure 1). 
Figure 1 
Escalating Phases of Disease Progression with COVID-19, with Associated 
Signs, Symptoms, and Potential Phase-specific Therapies 
 
ARDS = acute respiratory distress syndrome; CRP = C-reactive protein; IL = interleukin; FiO2 = fraction of inspired 
oxygen; JAK = janus kinase; LDH = lactate dehydrogenase; NT-proBNP = N-terminal pro b-type natriuretic 
peptide; PaO2 = partial pressure of oxygen; SIRS = systemic inflammatory response syndrome. 
Source: Siddiqi and Mehra, 2020 [12] 
 
Acute respiratory distress syndrome (ARDS) is characterized by severe, acute inflammatory 
responses in the lung, resulting in diffuse damage to the alveolar-capillary barrier, flooding the 
airspaces with protein-rich edema fluid, with severe gas-exchange abnormalities as a result. 
Among well-known causes of ARDS are viral pneumonia caused by influenza and corona 
viruses such as SARS-CoV (including SARS-CoV2, the strain of coronavirus that causes 


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COVID-19) and Middle East respiratory syndrome coronavirus (MERS-CoV). Acute respiratory 
distress syndrome is a cause of death and the main reason for the current need of intensive care 
unit beds and ventilators to treat patients with COVID-19. 
Remdesivir is the only approved treatment in the United States (US) for COVID-19. It is 
approved for use in adult and pediatric patients 12 years of age and older, who weigh at least 
40 kg, for the treatment of COVID-19 requiring hospitalization. In addition, the COVID-19 
Treatment Guidelines Panel recommends using dexamethasone for the treatment of COVID-19 
in patients who are mechanically ventilated, and in patients who require supplemental oxygen 
but who are not mechanically ventilated, on the basis of the preliminary report from the 
Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial. Alternative glucocorticoids 
such as prednisone, methylprednisolone, or hydrocortisone may also be used. The Food and 
Drug Administration has also issued an Emergency Use Authorization (EUA) to permit the 
emergency use of the unapproved product COVID-19 convalescent plasma to treat hospitalized 
patients with COVID-19. 
Currently, limited information is available on the host innate immune status of 
SARS-CoV-2-infected patients. The descriptions of increased total neutrophils, reduced total 
lymphocytes, increased serum levels of interleukin (IL)-6, and increased serum levels of 
C-reactive protein suggest a strong inflammatory response [2]. This is supported further by 
reports detecting abnormally high plasma levels of innate cytokines such as interferon 
gamma-induced protein 10 (IP-10), monocyte chemoattractant protein 1 (MCP-1), and 
macrophage inflammatory protein-1a (MIP-1a); or of high levels of pro-inflammatory cytokines 
(including IL-2, IL-7, IL-10, granulocyte colony-stimulating factor [G-CSF], IP-10, MCP-1, 
MIP-1a, and tumor necrosis factor alpha [TNFα]). The overall picture is like other high 
consequence coronavirus epidemics (SARS-CoV and MERS-CoV) and underlines the fact that 
leukocyte alterations, dysregulated interferon signaling, and cytokine release syndrome (CRS) 
could be important in the pathogenesis of COVID-19. 
The symptoms of COVID-19 vary from mild to ARDS, the latter of which is generally 
associated with dysregulated immune cytokine production. Currently, little is known about the 
interplay between the compositions of the immune responses and the extent of clinical 
symptoms. Some patient populations (eg, ages > 70 years, patients with co-morbidities) are 
prone to develop more severe symptoms and require medical interventions. In some severe cases, 
infection can cause pneumonia, ARDS, kidney failure, and even death [7]. Death results from 
respiratory failure and is associated in a substantial percentage of patients with an inflammatory 
syndrome and a cytokine storm with ARDS and features of macrophage activation 
syndrome/hemophagocytic lymphohistiocytosis that should be better defined [10]. 


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2.2 Evidence for C5 Inhibition in COVID-19 
Early defense against coronavirus infections includes a role for the “early” components of the 
complement pathway, in particular mannose-binding lectin (MBL). In SARS-CoV, the surface 
S protein contains highly glycosylated, high-mannose structures. Case control studies of 
569 patients with SARS and 1188 control subjects identified that MBL of the lectin pathway 
played a key role in the initiation of the innate immune response and that the distribution of 
MBL gene polymorphisms was significantly different between patients with SARS and control 
subjects, with a higher frequency of haplotypes associated with low or deficient serum levels of 
MBL in patients with SARS than in control subjects [8]. 
In vitro studies demonstrated that MBL could bind SARS-CoV in a dose- and calcium-dependent 
fashion, suggesting that binding is through the carbohydrate recognition domains of MBL. These 
results suggest that MBL contributes to the first-line host defense against SARS-CoV and that 
MBL deficiency is a susceptibility factor for the acquisition of SARS. It is therefore likely that 
MBL might play a role in the first-line host defense against SARS-CoV-2. 
Currently, there is no evidence that “late” components (ie, component 3 [C3] and C5) of the 
complement pathway are involved in the defense against SARS-CoV-2; however, aberrant 
activation of these components by virus-induced cellular damage is thought to promote broad 
tissue injury in coronavirus infections. Complement activation has long been known to be 
associated with ARDS and sepsis. Component 5a (C5a), a potent anaphylatoxin, recruits 
neutrophils to the site of initial damage or infection and drives tissue damage by the release of 
reactive oxygen species and tissue-degrading enzymes. Component 5a also induces 
inflammatory cytokines such as IL-8, IL-6, IL-17, and TNFα from a variety of cell types and 
contributes to the cytokine storm associated with ARDS and sepsis [1, 11, 15]. 
A report assessing C5a levels, polymorphonuclear granulocyte aggregation, and development of 
ARDS demonstrated a highly significant relationship between C5a positivity and ARDS; and this 
was significant even when excluding patients with sepsis from the analysis [5]. Historical studies 
document the formation of soluble C5b-9 complex in plasma preceding the development of 
ARDS [9]. 
A broad role for complement in mediating ARDS-like tissue injury in mouse models has been 
demonstrated. In a mouse model of SARS-CoV infection, inhibition by knock-out of the late 
complement pathway (C3-/-) results in protection from disease [4]. Component 3 deficiency 
eliminates the key component required for C5 activation and, as a result, animals are unable to 
generate C5a or C5b. In C3-deficient mice, weight loss and respiratory function were 
significantly improved relative to that of control mice (wild-type C3 background). Neither 
depletion of component 4 (C4) nor factor B (upstream in the complement cascade to C3) resulted 
in similar protection. Lung pathology scores were reduced in the C3-/- mice relative to controls. 
Analysis of the cellular inflammatory response to mouse-adapted SARS-CoV (SARS-CoV 


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MA15) infection reveals significant reductions in pathogenic inflammatory monocyte and 
neutrophil populations, both of which are implicated in human SARS-CoV pathology [16], 
indicating that complement signaling contributes to pulmonary disease and inflammatory cell 
recruitment. Finally, several pro-inflammatory cytokines, including IL-6, TNFα, IL-1a, and 
G-CSF were reduced in lungs of C3-/- mice relative to controls. Importantly, no change in viral 
loads were observed in C3-/- mice, underscoring that inhibiting the late/distal part of the 
complement cascade does not affect virus neutralization [4]. 
In another mouse model, MERS-CoV infection-induced inflammation and pyroptosis was found 
to be mediated by C5a release and nucleotide-binding oligomerization domain (NOD)-like 
receptor family pyrin domain containing 3 (NLRP3) inflammasome activation. Blocking the 
C5a-Complement C5a Receptor 1 (C5aR1) axis with an anti-C5aR1 antibody, when 
administered immediately prior to virus inoculation, ameliorated lung inflammation (pyroptosis 
and macrophage infiltration) together with markers of systemic inflammation [4]. 
Further support for a role of complement in COVID-19 infection can be found in animal studies 
of avian influenza viruses. In humans, avian influenza H5N1 virus is associated with ARDS and 
is histopathologically similar to patients infected with SARS-CoV. In mice, acute lung injury in 
avian influenza H5N1-infected mice appears to be complement-mediated. C3, C5b-9, and MBL 
were deposited in lung tissue; and complement receptors C3aR and C5aR were up-regulated. 
Treatment of H5N1 infected mice with a C3aR antagonist, an anti-C5a monoclonal antibody, or 
cobra venom factor to deplete complement C3 and C5 significantly alleviated lung inflammation 
and disease [14]. Likewise, avian influenza H7N9 virus causes lung injury and ARDS 
resembling the disease in H5N1 and SARS-CoV infected patients. 
Infection of African green monkeys with H7N9 virus resulted in intense acute lung injury and 
systemic inflammatory response syndrome (SIRS) associated with complement activation. 
Treatment of H7N9-infected monkeys with an intravenously administered monoclonal antibody 
against C5a substantially attenuated disease, reducing lung histopathological injury and lung 
inﬁltration of macrophages and neutrophils. The treatment decreased the intensity of SIRS with 
minimal changes in body temperature and markedly reduced plasma levels of inﬂammatory 
cytokines [14]. These data indicate that excessive complement activation plays an important role 
in viral-induced lung damage, and that complement inhibition at the level of C3 or C5 may be 
effective in the treatment of ARDS. 
Recent preliminary data assessing an anti-C5a monoclonal antibody in COVID-19 further 
support the use of C5 inhibition in this illness. A strong deposition of complement components 
MBL, mannose-associated serine protease (MASP)-2, C4, C3, and C5-9 in the lung tissue of 
deceased COVID-19 patients was reported, as well as a significant increase in serum C5a levels 
in patients with severe disease [3]. As expected, activation was via the lectin pathway of 
complement [8]. Two hospitalized patients were treated with repeated injections of an anti-C5a 
monoclonal antibody over approximately 13 days. Fever was reduced almost immediately; and 


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rapid improvements in oxygen saturation, C-reactive protein, lymphocyte numbers, and clinical 
condition were observed. 
Zilucoplan binds complement C5 and blocks generation of the 2 active fragments: C5a, a potent 
anaphylatoxin and neutrophil chemoattractant; and C5b, a component of the membrane attack 
complex (MAC), and the subsequent binding of C5b to C6 to assemble MAC. This will block the 
activation of C5b-9; and the formation of MAC causes endothelial cell and platelet activation, 
and loss of membrane integrity and lysis/damage in other cell types. 
Overall, these data support the conclusion that the use of zilucoplan to inhibit C5, and to prevent 
the production of C5a and C5b, may be effective in reducing inflammatory cytokine production, 
neutrophil activation, and ultimately progression to ARDS in patients who have been infected 
with the SARS-CoV-2 virus. 
2.3 Benefit/Risk Assessment 
The current world-wide pandemic of COVID-19 is putting unforeseen stress on the entire 
primary, secondary, and tertiary medical systems, leading to unseen triage of patients that 
potentially benefit or not from admission to intensive care units when they develop respiratory 
failure. 
Across the program, 196 participants have been exposed to zilucoplan with > 100 patient-years 
(> 40,000 injections) in healthy study participants, patients with generalized myasthenia 
gravis (gMG), paroxysmal nocturnal hemoglobinuria (PNH), immune mediated necrotizing 
myopathy, and renal impairment.  
To date, zilucoplan has shown a favorable safety and good tolerability profile across all studies. 
Completed clinical studies are summarized in Table 1. 
Table 1  
Exposure to Zilucoplan in Completed Clinical Studies 
Dosing 
Study Population 
Total N 
Exposed 
Single and multiple sc doses up to  
 
 
Healthy study participants 
83 
Multiple sc doses up to 
 
 
Adult study participants with gMG  
78 
Multiple sc doses up to 
 
 
Adult study participants with PNH  
29 
Multiple sc doses up to 
 
 
Adult study participants with IMNM  
6 
IMNM = immune mediated necrotizing myopathy; gMG = generalized myasthenia gravis; PNH = paroxysmal 
nocturnal hemoglobinuria; sc = subcutaneous. 
 
 
 
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No major safety risks have been identified. A difference in the overall adverse event (AE) 
profiles was seen among the clinical trials in different populations: few AEs occurred in healthy 
controls and stable renally impaired patients; the AE profile in PNH reflected the hemolytic 
anemia characteristic of the underlying disease; in the gMG population, many AEs were 
reflective of multiple comorbidities, longstanding use of corticosteroid and immunosuppressive 
therapies, and the more advanced age of this population. 
Treatment with the approved C5 inhibitors eculizumab and ravulizumab, as well as rare genetic 
deficiencies in C5, are associated with an increased risk for infection with encapsulated bacteria, 
most notably Neisseria meningitidis (N. meningitidis), but not for viral infections generally, or 
for coronavirus infections in particular. Immune protection against coronavirus infection is 
understood to rely primarily upon neutralizing humoral immunity and cluster of differentiation 8 
cytotoxic adaptive T cell cellular immunity, rather than innate immunity and the complement 
system. Therefore, C5 inhibition is not expected mechanistically to impair the immune response 
to coronavirus (or to a vaccine once one is available). 
Given the increased risk for N. meningitidis infection with complement C5 inhibition or deficit, 
patients who had received zilucoplan in ambulatory clinical trials were required to have 
documentation of N. meningitidis vaccination (and booster if appropriate) prior to treatment 
initiation. In addition, while on zilucoplan, patients were monitored closely for signs and 
symptoms of N. meningitidis infection, including self-monitoring based on detailed instructions 
about the signs and symptoms of possible meningococcal infections. 
To prevent the risk of meningococcal disease and prevent other infections with encapsulated 
bacteria, patients need to receive prophylactic antibiotics (eg, intravenous third generation 
cephalosporin while in the hospital, followed by oral ciprofloxacin upon discharge until 14 days 
after the last zilucoplan or placebo administration). 
The potential benefits of C5 inhibition by the administration of zilucoplan treatment in 
COVID-19 patients are considered to outweigh the potential risks associated with this treatment. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of zilucoplan may be found in the Investigator’s Brochure. 
2.4 Dose Justification for Zilucoplan 
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Figure 2   
Mean Complement Activity as Measured by Sheep Red Blood Cell Assay 
(% Hemolysis) 
 
LLOQ = lower limit of quantification. 
Source: Howard et al., 2020 [6] 
 


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3.0 STUDY POPULATION 
3.1 Enrollment and Screening 
Refer to the Master Protocol for enrollment and screening procedures. 
3.2 Eligibility Criteria 
Overall inclusion and exclusion criteria are presented in Sections 5.1 and 5.2 of the Master 
Protocol, respectively. Patients must meet all inclusion criteria and no exclusion criteria for the 
Master Protocol to be considered for inclusion in this COV-01-005 sub-protocol. 
The following sections detail the variations to those criteria that are specific to this sub-protocol. 
3.2.1 
Inclusion Criteria 
An additional inclusion criterion that is specific to the sub-protocol is as follows: 
X1. 
Antibiotic prophylaxis: PLEASE NOTE that all patients must be willing to take antibiotic 
prophylaxis concomitantly, starting with the first dose of zilucoplan or placebo. 
3.2.2 
Exclusion Criteria 
An additional exclusion criterion that is specific to the sub-protocol is as follows: 
X1. 
Participants with unresolved or suspected infection with N. meningitidis or a past history 
of N. meningitidis (eg, in a complement-deficient patient) should not receive treatment 
with zilucoplan or placebo. 
3.3 Discontinuation of Study Treatment and Patient 
Discontinuation/Withdrawal 
The reason for and the date of discontinuation from study treatment and/or from study 
participation will be collected for all randomized patients who prematurely discontinue study 
treatment or participation. 
3.3.1 
Discontinuation of Study Treatment  
A patient in this study may discontinue the study treatment per the criteria listed in Section 7 of 
the Master Protocol. In addition, a patient may discontinue study treatment if UCB or its 
designee stops the patient’s participation in this sub-protocol for medical, safety, regulatory, or 
other reasons consistent with applicable laws, regulations, and Good Clinical Practice (GCP). 
Regardless of study treatment discontinuation, all patients who maintain consent to be followed 
for additional outcome information will remain in the study for all important safety and efficacy 
assessments, as specified in the Master Protocol. 


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3.3.2 
Patient Discontinuation/Withdrawal from the Study  
In line with the Master Protocol, a patient in this study may: 
 Withdraw himself or herself from the study via withdrawal of consent. 
 Be withdrawn from the study due to loss to follow-up. 


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4.0 STUDY ASSESSMENTS AND PROCEDURES 
In addition to the study assessments and procedures described in Section 8.0 of the Master 
Protocol, assessments specific to this COV-01-005 sub-protocol will be performed as described 
in the following sections. The SoA for this sub-protocol is presented in Section 1.2. 
4.1 Safety Assessments 
Safety assessments include treatment-emergent AEs, including serious AEs (SAEs). 
4.1.1 
Adverse Events 
4.1.1.1 Adverse Events from Zilucoplan 
To date, zilucoplan has shown a favorable safety and good tolerability profile across all studies 
in healthy participants and patients with gMG, PNH, immune mediated necrotizing 
myopathy (IMNM), and renal impairment. No major safety risks have been identified to date, 
with > 100 patient years of exposure and > 40,000 injections administered in clinical trials. A 
difference in the overall AE profiles was seen among the clinical trials in different populations: 
few AEs occurred in healthy controls and stable renally impaired patients; the AE profile in PNH 
reflected the hemolytic anemia characteristic of the underlying disease; and in the gMG 
population, many AEs were reflective of multiple comorbidities, longstanding use of 
corticosteroid and immunosuppressive therapies, and the more advanced age of this population. 
Although no meningococcal infections have been identified with zilucoplan treatment to date, it 
is well established that inhibition of complement C5 and the terminal complement pathway 
increases the susceptibility to infection with encapsulated bacteria, in particular N. meningitidis. 
This risk is also described in the prescribing information for the approved complement C5 
inhibitor eculizumab (Soliris® US Package Insert 2017) [13]. 
Given the increased risk for N. meningitidis infection with complement C5 inhibition or deficit, 
patients who have received zilucoplan in ambulatory clinical trials were required to have 
documentation of N. meningitidis vaccination (and booster if appropriate) prior to treatment 
initiation. In addition, while on zilucoplan, patients were monitored closely for signs and 
symptoms of N. meningitidis infection, including self-monitoring based on detailed instruction 
about the signs and symptoms of possible meningococcal infections. 
Considering the acuity of the indication and short duration of treatment (maximum of 14 days), 
vaccination and induction of humoral immunity prior to initiation of zilucoplan therapy is not 
feasible in the context of COVID-19. Therefore, the risk of Neisseria infection must be mitigated 
by the concomitant administration of antibiotic prophylaxis as decided by the Investigator for a 
maximum of 28 days starting with the first dose of zilucoplan or placebo (ie, during study drug 
treatment and an additional 14-day period after the cessation of zilucoplan or placebo). 
Antibiotics can be, eg, intravenous third generation cephalosporin while in the hospital followed 


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by oral ciprofloxacin upon discharge until 14 days after the last zilucoplan or placebo 
administration. Consultation with a local microbiologist and/or infectious disease specialist is 
recommended to select the antibiotic prophylaxis. Guidelines about the treatment and prevention 
of N. meningitidis-caused meningitis should also be considered. 
4.1.1.2 Adverse Events of Special Interest 
No adverse events of special interest have been defined for zilucoplan in this sub-protocol. 
4.1.1.3 Safety Reporting 
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All SAEs and overdoses will be recorded and reported to  
 Safety within 24 hours after 
becoming aware of its occurrence. The initial and follow-up reports should be made using the 
Electronic Data Capture tool. If necessary, as a backup, reports can be made by e-mail or 
facsimile (fax). The contact details are:  
  
  
 
The  
 Medical Safety Advisor (or designee) must also be notified within 24 hours if any 
patient experiences an SAE. Contact information for the  
 SAE Coordinator will be 
provided on the SAE form/completion instructions. 
Notification by the Investigator to the Sponsor of an SAE as per the timelines detailed in the 
safety management plan is essential so that legal obligations and ethical responsibilities towards 
the safety of patients and the safety of a study treatment under clinical investigation are met. 
The Candidate Agent Owner has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study treatment under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements relating to 
safety reporting to the regulatory authority, Institutional Review Boards (IRBs)/Independent 
Ethics Committees (IECs), and Investigators. 
Investigator safety reports must be prepared for suspected unexpected serious adverse reactions 
according to local regulatory requirements and Sponsor policy and forwarded to Investigators as 
necessary. 
An Investigator who receives an Investigator safety report describing an SAE or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will review and then file it 
along with the Investigator’s Brochure and will notify the IRB/IEC, if appropriate according to 
local requirements. 
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4.1.2 
Clinical Safety Laboratory Assessments 
Blood samples will be collected for safety assessments during hospitalization, in accordance with 
the SoA (Section 1.2) and Appendix 2. The safety parameters will be the same as those included 
in the Master Protocol. 
4.1.2.1 Reviewing and Recording Test Results 
The Investigator and/or appropriate designee must review the laboratory report, document this 
review, and record any clinically relevant changes occurring during the study in the AE section 
of the electronic case report form (eCRF). The laboratory reports must be filed with the source 
documents. Clinically significant abnormal laboratory findings are those that are not associated 
with the underlying disease, unless judged by the Investigator to be more severe than expected 
for the patient’s condition. 
4.1.2.2 Repeating Testing After Clinically Significant Abnormal Findings 
All laboratory tests with values considered clinically significantly abnormal during participation 
in the study or within 28 days after the last dose of study intervention should be repeated until 
the values return to normal or baseline or are no longer considered clinically significant by the 
Investigator or the Medical Monitor during study participation. If such values do not return to 
normal/baseline within a period of time judged reasonable by the Investigator, the etiology 
should be identified, and the Candidate Agent Owner notified. 
4.2 Pharmacokinetic Assessments 
Plasma samples (from whole blood collection) will be collected from all patients (placebo and 
active treatment arms) for the measurement of plasma concentrations of zilucoplan, as specified 
in the SoA (Section 1.2). Sample analysis may be limited to a select set of samples collected 
throughout the study. Plasma concentrations of zilucoplan will be summarized descriptively at 
each scheduled assessment. Plasma concentrations of zilucoplan may be used for population PK 
modeling and may be combined with data from other studies where plasma concentrations of 
zilucoplan were collected. The actual date and time (24-hour clock time) of each sample will be 
recorded in the electronic case report form (eCRF). Instructions for the collection and handling 
of biological samples will be provided in the Laboratory Manual. 
 
 
4.3 Pharmacodynamic and Biomarker Assessments 
Blood samples (plasma and serum) for pharmacodynamic and biomarker analysis will be 
collected as specified in the SoA (Section 1.2
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arms). Sample analysis may be limited to a select set of samples collected throughout the study. 
 
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Instructions pertaining to sample collection, processing, storage, labeling, and shipping are 
provided in the Laboratory Manual for this study. 
 
 
 
 
 
 
4.4 Anti-drug Antibody Testing 
Serum samples (from whole blood collection) will be collected for the evaluation of the presence 
or absence of ADA response as specified in the SoA (Section 1.2) from all patients (placebo and 
active treatment arms). Sample analysis may be limited to a select set of samples collected 
throughout the study. 
Instructions for the collection and handling of biological samples will be provided in the 
Laboratory Manual. 
 
 
4.5 
 
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5.0 STUDY TREATMENT 
5.1 Treatment Plan 
Patients eligible for treatment will receive treatment once daily as a sc injection for the planned 
treatment duration. 
5.2 Study Drug Administration 
The investigational drug product will be provided in prefilled syringes containing 32.4 mg of 
zilucoplan (0.81 mL) or placebo for sc injection in the abdomen (preferred site), thigh, or upper 
arm. 
The investigational drug product is placed into a Becton Dickinson UltraSafe Plus device 
assembled with a finger flange and plunger rod. The prefilled syringes are designed for 
self-administration. 
The prefilled syringes containing 32.4 mg of zilucoplan or placebo will be provided in kits 
containing 7 prefilled syringes each. 
This dose is equivalent to that administered to the highest weight bracket in prior weight-based 
dosing regimens and is expected to achieve rapid, profound, and sustained complement 
inhibition with acceptable safety and tolerability. 
5.3 Preparation/Handling/Storage/Accountability 
Zilucoplan should be stored at 2°C to 8°C (36°F to 46°F) at the study site. Once dispensed, 
zilucoplan may be stored at room temperature (20°C to 25°C [68°F to 77°F]) for up to 45 days 
protected from sources of heat, light, and damage. Storage of zilucoplan outside of room 
temperatures should be avoided. The Investigator or designee must confirm appropriate 
temperature conditions have been maintained during transit for all study treatment received and 
any discrepancies are reported and resolved before use of the study treatment. 
Only patients enrolled in the study may receive study treatment, and only authorized study center 
staff may supply or administer study treatment. All study treatments must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to the Investigator and authorized study center 
staff. 
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records). 
Further guidance and information for the final disposition of unused study treatment are provided 
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The Investigator, a member of the study center staff, or a hospital pharmacist must maintain an 
adequate record of the receipt and distribution of all study medication using the Drug 
Accountability Form. These forms must be available for inspection at any time. 
5.4 Dose Modifications and Toxicity Management 
To date, zilucoplan has shown good tolerability and a favorable safety profile across studies in 
healthy participants and patients with renal impairment, PNH, and gMG. No major safety risks 
have been identified to date.  
No dose modifications are anticipated; stopping zilucoplan will be left to the decision of the 
Investigator in consultation with the  
 Medical Monitor based on the clinical evaluation of 
the patient. 
5.5 Treatment of Overdose 
For this study, any dose of zilucoplan or placebo greater than 32.4 mg within a 24-hour time 
period will be considered an overdose. 
It is not anticipated that overdose of zilucoplan or placebo will lead to acute or specific systemic 
AEs. In the case of overdose, clinically appropriate supportive measures should be instituted as 
determined by the clinical scenario and in consultation with the  
 Medical Monitor. 
In the event of an overdose, the Investigator should: 
1. Contact the  
 Medical Monitor immediately. 
2. Closely monitor the patient for any AE/SAE and laboratory abnormalities. 
3. Obtain a plasma sample for PK analysis within 2 days from the date of the last dose of study 
treatment if requested by the  
 Medical Monitor (determined on a case-by-case basis). 
4. Document the quantity of the excess dose as well as the duration of the overdose in the 
eCRF. 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the  
 Medical Monitor based on the clinical evaluation of the patient. 
5.6 Concomitant Medications 
To mitigate the risk of Neisseria infection, concomitant administration of antibiotic prophylaxis 
decided by the Investigator is required for a maximum of 28 days starting with the first dose of 
zilucoplan or placebo (ie, during study drug treatment and an additional 14 days after cessation 
of zilucoplan or placebo). Consultation with a local microbiologist and/or infectious disease 
specialist is recommended to select the appropriate antibiotic prophylaxis. Guidelines about 
treatment and prevention of N. meningitidis
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If the patient is discharged prior to finishing antibiotic prophylaxis, it can be confirmed by 
telephone at Day 29 if prophylaxis is completed at home. 
Additional antibiotics can be administered as per the Investigator’s judgment. 
5.6.1 
Dosing with Remdesivir or Dexamethasone 
No change in dose is recommended for patients taking both zilucoplan and remdesivir or 
dexamethasone. Safety monitoring under Early Access to Medicines scheme guidance must be 
followed as outlined in the Master Protocol. 
5.6.2 
Rescue Medicine 
Rescue medicines are not applicable to this sub-protocol. 
5.7 Study Drug Information 
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Zilucoplan (RA101495) is a 15-amino acid macrocyclic peptide complement inhibitor designed 
for the treatment of conditions in which inappropriate activation of complement C5 has been 
demonstrated to play a role. Zilucoplan binds to C5 with high affinity and prevents its cleavage 
by C5 convertases into the cleavage products C5a and C5b. Inhibition of C5 cleavage prevents 
the downstream assembly and cytolytic activity of the Mac. 
Zilucoplan binds to the domain of C5 that corresponds to C5b. If any C5b is generated, it will be 
blocked from binding to C6 by zilucoplan, thereby preventing the subsequent assembly of the 
Mac (C5b-9). 
 
 
 


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6.0 REFERENCES 
1. Bosmann M, Ward PA. Role of C3, C5 and anaphylatoxin receptors in acute lung injury 
and in sepsis. In: Lambris J, Hajishengallis G (eds) Current Topics in Innate Immunity II. 
Adv Exp Med Biol 2012;946:147-159. Springer, New York. doi: 
10.1007/978-1-4614-0106-3_9., vol 946:147-159. 
2. Cossarizza A, De Biasi S, Guaraldi G, Girardis M, Mussini C. Modena Covid-19 
Working Group (MoCo19)#. SARS-CoV-2, the virus that causes COVID-19: Cytometry 
and the new challenge for global health. Cytometry A 2020;97(4):340-343. 
doi:10.1002/cyto.a.24002 
3. Gao, T, Hu M, Zhang X, et al. Highly pathogenic coronavirus N protein aggravates lung 
injury by MASP-2-mediated complement over-activation. medRxiv 2020. 
https://doi.org/10.1101/2020.03.29.20041962. 
4. Gralinski LE, Sheahan TP, Morrison TE, et al. Complement activation contributes to 
severe acute respiratory syndrome coronavirus pathogenesis. mBio 2018;9(5):e01753-18. 
5. Hammerschmidt DE, Weaver LJ, Hudson LD, Craddock PR, Jacob HS. Association of 
complement activation and elevated plasma-C5a with adult respiratory distress syndrome. 
Pathophysiological relevance and possible prognostic value. Lancet 
1980;1(8175):947-949. 
6. Howard JF Jr, Nowak RJ, Wolfe GI, et al. Clinical effects of the self-administered 
subcutaneous complement inhibitor zilucoplan in patients with moderate to severe 
generalized myasthenia gravis: Results of a phase 2 randomized, double-blind, 
placebo-controlled, multicenter clinical trial. JAMA Neurol 2020;77(5):582-592. 
7. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel 
coronavirus in Wuhan, China. Lancet 2020;395(10223):497-506. 
8. Ip WKE, Chan KH, Law HKW, et al. Mannose-binding lectin in severe acute respiratory 
syndrome coronavirus infection. J Infect Dis 2005;191(10):1697-1704. 
9. Langlois PF, Gawryl MS. Accentuated formation of the terminal C5b-9 complement 
complex in patient plasma precedes development of the adult respiratory distress 
syndrome. Am Rev Resp Dis 1988;138(2):368-375. 
10. Mehta P, McAuley DF, Brown M, et al. COVID-19: consider cytokine storm syndromes 
and immunosuppression. Lancet 2020;395(10229):1033-1034. 
11. Potey PMD, Rossi AG, Lucas CD, Dorward DA. Neutrophils in the initiation and 
resolution of acute pulmonary inflammation: understanding biological function and 
therapeutic potential. J Pathol 2019;247(5):672-685. 


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12. Siddiqi HK, Mehra MR. COVID-19 illness in native and immunosuppressed states: A 
clinical-therapeutic staging proposal. J Heart Lung Transplant 2020;39(5):405-407. 
13. Soliris® US Package Insert 2017. 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125166s417lbl.pdf  
14. Sun S, Zhao G, Liu C, et al. Inhibition of complement activation alleviates acute lung 
injury induced by highly pathogenic avian influenza H5N1 virus infection. Am J Respir 
Cell Mol Biol 2013;49(2):221-230. 
15. Swank DW, Moore SB. Roles of the neutrophil and other mediators in adult respiratory 
distress syndrome. Mayo Clin Proc 1989;64(9):1118-1132. 
16. Van den Brand JMA, Haagmans BL, van Riel D, Osterhaus ADME, Kuiken T. The 
pathology and pathogenesis of experimental severe acute respiratory syndrome and 
influenza in animal models. J Comp Pathol 2014;151(1):83-112. 
 


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7.0 APPENDICES 


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COV-01-005 – Sub-protocol for zilucoplan 
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Appendix 1  
Abbreviations 
Abbreviation 
Definition 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ARDS  
Acute respiratory distress syndrome 
C3 
Component 3 
C4 
Component 4 
C5 
Component 5 
C5aR1  
Complement C5a Receptor 1 
COMMUNITY 
COVID-19 Multiple Agents and Modulators Unified Industry Members Trial 
COVID-19  
Coronavirus disease 2019 
CRO 
Contract research organization 
CRP 
C-reactive protein 
CRS 
Cytokine release syndrome 
DNA 
Deoxyribonucleic acid 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EUA 
Emergency use authorization 
Fax 
Facsimile 
FiO2 
Fraction of inspired oxygen 
GCP 
Good Clinical Practice 
G-CSF  
Granulocyte colony-stimulating factor 
GM-CSF  
Granulocyte-macrophage colony stimulating factor 
gMG 
Generalized myasthenia gravis 
ICU 
Intensive care unit 
IEC 
Independent Ethics Committee 
IL 
Interleukin 
IMNM  
Immune mediated necrotizing myopathy 
IP-10 
Interferon gamma-induced protein 10 
IRB 
Institutional Review Board 
JAK 
Janus kinase 
LDH 
Lactate dehydrogenase 


CONFIDENTIAL 
COV-01-005 – Sub-protocol for zilucoplan 
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35 
Abbreviation 
Definition 
MAC 
Membrane attack complex 
MASP  
Mannose-associated serine protease 
MBL 
Mannose-binding lectin 
MCP-1  
Monocyte chemoattractant protein 1 
MERS-CoV  
Middle East respiratory syndrome coronavirus  
MIP-1a  
Macrophage inflammatory protein 1a 
NLRP3  
NOD-like receptor family pyrin domain containing 3 
N. meningitidis 
Neisseria meningitidis 
NOD 
Nucleotide-binding oligomerization domain 
NT-proBNP  
N-terminal pro b type natriuretic peptide 
PaO2 
Partial pressure of oxygen 
PNH 
Paroxysmal nocturnal hemoglobinuria 
SAE 
Serious adverse event 
SARS 
Severe acute respiratory syndrome 
SARS-CoV  
Severe acute respiratory syndrome coronavirus  
SARS-CoV-2  
Severe acute respiratory syndrome coronavirus 2  
SIRS 
Systemic inflammatory response syndrome 
SoA 
Schedule of Activities 
TNFα 
Tumor necrosis factor alpha 
US 
United States 


CONFIDENTIAL 
COV-01-005 – Sub-protocol for zilucoplan 
Version 1.2, 03 November 2020 
36 
Appendix 2  
Clinical Laboratory Tests  
The minimum tests to be performed are detailed in Table 2. Clinical laboratory tests will be 
performed at a local laboratory. 
Protocol-specific requirements for the inclusion or exclusion of patients are detailed in the 
Master Protocol. 
Additional tests may be performed at any time during the study as determined necessary by the 
Investigator or required by local regulations. 
Changes to some laboratory parameters are anticipated for any patients moving on to 
extracorporeal membrane oxygenation therapy. 
Investigators must document their review of each laboratory safety report. 


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COV-01-005 – Sub-protocol for zilucoplan 
Version 1.2, 03 November 2020 
37 
Table 2  
Protocol-required Safety Laboratory Assessments 
Laboratory Assessments 
Parameters 
Hematology 
Platelet count 
Hemoglobin 
White blood cell count with differential: 
  Neutrophils 
  Lymphocytes 
  Monocytes 
  Eosinophils 
  Basophils 
Coagulation 
D-dimer test 
Fibrinogen 
Activated partial thromboplastin time 
Prothrombin time 
International Normalized Ratio 
C-reactive protein 
Ferritin 
Lactate dehydrogenase 
Procalcitonin 
Clinical Chemistry 
Potassium 
Sodium 
Calcium 
Magnesium 
Phosphate 
Bicarbonate 
Creatinine 
Glucose 
Liver Function Tests 
Alkaline phosphatase 
Total bilirubin 
Aspartate aminotransferase 
Alanine aminotransferase 
Gamma-glutamyl transferase 
Cardiac Panel 
Creatine kinase (myocardial band fraction) 
Triglycerides 
Troponin 
 


CONFIDENTIAL 
COV-01-005 – Sub-protocol for zilucoplan 
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38 
Appendix 3  
Signature of Investigator 
PROTOCOL TITLE:  Industry Alliance Platform Trial to Assess the Efficacy and Safety of 
Multiple Candidate Agents for the Treatment of COVID-19 in Hospitalized Patients 
SUB-PROTOCOL NO:  
COV-01-005 
SUB-PROTOCOL FOR CANDIDATE AGENT: Zilucoplan 
VERSION:    
1.2 
This sub-protocol is a confidential communication of the Sponsor (Amgen) and Candidate Agent 
Owner (UCB Biopharma SPRL). I confirm that I have read this sub-protocol; I understand it; and 
I will work according to this sub-protocol, in conjunction with the Master Protocol for the overall 
platform study. I will also work consistently with the ethical principles that have their origin in 
the Declaration of Helsinki and that are consistent with Good Clinical Practice (GCP) and the 
applicable laws and regulations. Acceptance of this document constitutes my agreement that no 
unpublished information contained herein will be published or disclosed without prior written 
approval from the Sponsor. 
Instructions to the Investigator: Please SIGN and DATE this signature page. PRINT your name, title, and the name of the study 
center in which the study will be conducted. Return the signed copy to the contract research organization (CRO)/Candidate Agent 
Owner (UCB Biopharma SRL). 
 
I have read this sub-protocol in its entirety and agree to conduct this part of the study 
accordingly: 
 
Signature of Investigator:      ___________________________       Date:  __________________ 
Printed Name:                         ___________________________ 
Investigator Title:                    ___________________________ 
 
Name/Address of Center:       ___________________________ 
  
  
  
  
___________________________ 
  
  
  
  
___________________________ 
 

SAP_001.pdf: 
Amgen Inc 
Master Protocol COV-01 
Master Statistical Analysis Plan 
Page 1 of 118 
 
 
 
 
 
Version Number: 
Amendment 1, v1.0 
 
Version Date:  
23Apr2021 
 
 
 
 
 
 
 
 
 
 
 
MASTER STATISTICAL ANALYSIS PLAN  
 
MASTER PROTOCOL: COV-01 (COMMUNITY) 
 
INDUSTRY ALLIANCE PLATFORM TRIAL TO ASSESS THE EFFICACY 
AND SAFETY 
OF MULTIPLE CANDIDATE AGENTS 
FOR 
THE 
TREATMENT OF COVID-19 IN HOSPITALIZED PATIENTS 
 
AUTHOR: 
 
VERSION NUMBER AND DATE: AMENDMENT 1 V1.0, 23APR2021 
 
 
 
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Amgen Inc 
Master Protocol COV-01 
Master Statistical Analysis Plan 
Page 3 of 118 
 
 
 
 
 
Version Number: 
Amendment 1, v1.0 
 
Version Date:  
23Apr2021 
 
 
 
 
 
 
 
MODIFICATION HISTORY 
Unique Identifier 
for this Version 
Date of the 
Document 
Version 
Author 
Significant Changes from  
Previous Version 
Final, v1.0 
18Nov2020 
 
Not Applicable – First Version 
Amendment 1 v1.0 
23Apr2021 
 
Updated Master Protocol version on which the Master 
SAP is based from version 3, dated 22-Oct-2020, to 
version 4, dated 16-Apr-2021. 
Updated definition of the data cut-off date for the 
Interim, Primary and Final Analyses of a sub-protocol in 
order to prevent potential inadvertent unblinding of 
patients randomized to the placebo plus SoC treatment 
group of another subprotocol included in the shared 
placebo plus SoC control arm of the sub-protocol of 
interest; 
Clarified that the ‘concurrent’ definition for selection of 
the concurrent placebo plus SoC patients for the control 
arm of a sub-protocol will be assessed on a site-by-site 
basis rather than across all sites; 
Updated definition of the safety analysis set so that 
patients randomized to the placebo arm of sub-protocol 
X selected for the shared placebo plus SoC control arm 
of sub-protocol Y who started taking subprotocol Y 
candidate agent for another indication after baseline will 
be presented under the shared placebo plus SoC control 
arm for sub-protocol Y safety analysis; 
Clarified that data collected during a discharge visit will 
also be mapped using time window for the by-visit 
summaries; 
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Amgen Inc 
Master Protocol COV-01 
Master Statistical Analysis Plan 
Page 4 of 118 
 
 
 
 
 
Version Number: 
Amendment 1, v1.0 
 
Version Date:  
23Apr2021 
 
 
 
 
 
 
 
Added summaries further broken down by sub-protocol 
for the shared placebo plus SoC control arm to Sections 
9 to 12; 
Added a tipping point sensitivity analysis for the 
primary efficacy endpoint; 
For each key secondary efficacy endpoint, removed the 
last observation carried forward (LOCF) sensitivity 
analysis as well as sensitivity analysis based on observed 
data (when applicable), and added a multiple imputation 
sensitivity analysis; 
Clarified that the 95% two-sided confidence interval 
(CI) obtained from a logistic regression model will be 
the 95% two-sided Wald CI; 
Added subgroup analyses by time since hospital 
admission at Study Day 1 (≤ 5 days or > 5 days) for the 
primary and key secondary efficacy endpoints. 
For each subprotocol, added separate summaries for 
patients randomized to the placebo plus SoC treatment 
group of the concerned sub-protocol for the prior and 
concomitant medications summaries as well as all safety 
summaries; 
Added risk difference and associated 95% two-sided 
Wald CI for the treatment comparison of the overall 
incidence of serious treatment-emergent adverse events 
(TEAEs) and overall incidence of adverse events of 
special interest (when applicable for a sub-protocol); 
Added summary of most common (5%) non-serious 
adverse events (AEs) 
 
 
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Master Protocol COV-01 
Master Statistical Analysis Plan 
Page 5 of 118 
 
 
 
 
 
Version Number: 
Amendment 1, v1.0 
 
Version Date:  
23Apr2021 
 
 
 
 
 
 
 
TABLE OF CONTENTS 
1. 
INTRODUCTION............................................................................................................. 11 
2. 
STUDY OBJECTIVES ..................................................................................................... 11 
2.1. 
Primary Objective ..................................................................................................................... 11 
2.2. 
Key Secondary Objectives ........................................................................................................ 11 
2.3. 
Other Secondary Objectives ..................................................................................................... 11 
2.4. 
Exploratory Objectives ............................................................................................................. 12 
3. 
STUDY DESIGN ............................................................................................................... 13 
3.1. 
General Description................................................................................................................... 13 
3.2. 
Schedule of Activities ................................................................................................................ 16 
3.3. 
Changes to Planned Analyses from Master Protocol ............................................................. 16 
4. 
PLANNED ANALYSES ................................................................................................... 16 
4.1. 
IDMC Safety Analyses .............................................................................................................. 16 
4.2. 
Interim Analyses ........................................................................................................................ 17 
4.3. 
Primary Analysis ....................................................................................................................... 19 
4.4. 
Final Analysis ............................................................................................................................. 20 
4.5. 
Selection of the Control Arm for an Analysis ......................................................................... 21 
5. 
ANALYSIS SETS.............................................................................................................. 22 
5.1. 
Full Analysis Set ........................................................................................................................ 22 
5.2. 
Safety Analysis Set ..................................................................................................................... 22 
5.3. 
Process for Analysis Set Assignment ....................................................................................... 23 
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Master Protocol COV-01 
Master Statistical Analysis Plan 
Page 6 of 118 
 
 
 
 
 
Version Number: 
Amendment 1, v1.0 
 
Version Date:  
23Apr2021 
 
 
 
 
 
 
 
6. 
GENERAL CONSIDERATIONS ................................................................................... 23 
6.1. 
Study Day ................................................................................................................................... 23 
6.2. 
Baseline ....................................................................................................................................... 24 
6.3. 
Unscheduled Visits, Retests, Discharge, and Early Termination Data ................................. 24 
6.4. 
Windowing Conventions ........................................................................................................... 25 
6.5. 
Common Calculations ............................................................................................................... 25 
7. 
STATISTICAL CONSIDERATIONS ............................................................................ 25 
7.1. 
Sample Size Calculation ............................................................................................................ 25 
7.2. 
Missing data ............................................................................................................................... 27 
7.3. 
Statistical Tests .......................................................................................................................... 27 
7.4. 
Multiple Comparisons/ Multiplicity ......................................................................................... 27 
7.5. 
Multicenter Studies ................................................................................................................... 28 
7.6. 
Adjustments for Covariates and Factors to be Included in Analyses ................................... 28 
7.7. 
Examination of Subgroups ....................................................................................................... 29 
7.8. 
Software Version ....................................................................................................................... 31 
8. 
OUTPUT PRESENTATIONS ......................................................................................... 31 
9. 
DISPOSITION AND WITHDRAWALS ........................................................................ 32 
9.1. 
Disposition .................................................................................................................................. 32 
9.1.1. 
Derivations .................................................................................................................................. 33 
9.2. 
Protocol Deviations .................................................................................................................... 33 
10. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ....................... 33 
10.1. 
Derivations ................................................................................................................................. 34 
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Master Statistical Analysis Plan 
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Version Date:  
23Apr2021 
 
 
 
 
 
 
 
11. 
DISEASE HISTORY ........................................................................................................ 34 
11.1. 
Derivations ................................................................................................................................. 36 
12. 
MEDICAL HISTORY ...................................................................................................... 37 
13. 
PRIOR AND CONCOMITANT MEDICATIONS........................................................ 38 
14. 
EXPOSURE TO STUDY DRUG ..................................................................................... 39 
15. 
COMPLIANCE WITH STUDY DRUG ......................................................................... 40 
16. 
EFFICACY ENDPOINTS................................................................................................ 40 
16.1. 
Primary Efficacy ........................................................................................................................ 40 
16.1.1. 
Time to Confirmed Clinical Recovery through Day 29, without Re-Hospitalization Through 
Day 29 ......................................................................................................................................... 40 
16.1.2. 
Missing Data Imputation Method for Primary Efficacy Endpoint .............................................. 44 
16.1.3. 
Main Analysis of Primary Efficacy Endpoint.............................................................................. 44 
16.1.4. 
Sensitivity Analyses for Primary Efficacy Endpoint ................................................................... 45 
16.1.5. 
Supplementary Analyses for Primary Efficacy Endpoint ............................................................ 46 
16.2. 
Secondary Efficacy .................................................................................................................... 47 
16.2.1. 
Secondary Efficacy Endpoints..................................................................................................... 47 
16.2.1.1. 
Incidence of Patients with Oxygen-Free Recovery at Day 29 ..................................................... 47 
16.2.1.2. 
Incidence of Patients with ≥ 2-point Improvement from Baseline or Fit for Discharge on the 
Ordinal Scale at Day 29 ............................................................................................................... 48 
16.2.1.3. 
Incidence of All-Cause Mortality through Day 29 ...................................................................... 49 
16.2.1.4. 
Distribution of Patients across the Categories of the 8-point Ordinal Scale for Clinical Severity 
at Days 8, 15, and 29 ................................................................................................................... 49 
16.2.1.5. 
Worst Post-Baseline Score on 8-point Ordinal Scale from Baseline to Day 29 .......................... 49 
16.2.1.6. 
Number of ICU Days from Day 1 through Day 29 ..................................................................... 50 
16.2.1.7. 
Number of Invasive Mechanical Ventilator Days from Day 1 through Day 29 .......................... 51 
16.2.1.8. 
Incidence of Patients with Clinical Recovery by Days 8, 15, and 29 .......................................... 51 
16.2.1.9. 
Incidence of Patients with Sustained Clinical Recovery as Confirmed by Day 60 Follow-up .... 51 
16.2.2. 
Missing Data Imputation Method for Secondary Efficacy Endpoints ......................................... 52 
16.2.2.1. 
Binary Endpoints ......................................................................................................................... 52 
16.2.2.2. 
Ordinal Endpoints ........................................................................................................................ 52 
16.2.3. 
Main Analysis of Secondary Efficacy Endpoints ........................................................................ 53 
16.2.3.1. 
Binary Endpoints ......................................................................................................................... 53 
16.2.3.2. 
Ordinal Endpoints ........................................................................................................................ 54 
16.2.4. 
Sensitivity Analyses for Secondary Efficacy Endpoints ............................................................. 54 
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16.2.5. 
Supplementary Analyses for Secondary Efficacy Endpoints ...................................................... 56 
16.3. 
Exploratory Efficacy ................................................................................................................. 57 
16.4. 
Additional Efficacy .................................................................................................................... 67 
16.4.1. 
Additional Efficacy Endpoint ...................................................................................................... 67 
16.4.1.1. 
Incidence of All-Cause Mortality through Day 60 ...................................................................... 67 
16.4.2. 
Missing Data Imputation Method for Additional Efficacy Endpoint .......................................... 67 
16.4.3. 
Analysis of Additional Efficacy Endpoint ................................................................................... 67 
16.4.4. 
Sensitivity Analyses for Additional Efficacy Endpoint ............................................................... 67 
16.4.5. 
Supplementary Analyses for Additional Efficacy Endpoint ........................................................ 68 
16.5. 
Interim Analysis ........................................................................................................................ 69 
16.5.1. 
Interim Analysis for Futility ........................................................................................................ 69 
17. 
SAFETY ENDPOINTS .................................................................................................... 71 
17.1. 
Adverse Events .......................................................................................................................... 71 
17.1.1. 
All TEAEs ................................................................................................................................... 72 
17.1.1.1. 
CTC Grading for AEs .................................................................................................................. 72 
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17.1.1.2. 
Relationship to Study Drug, Non-Study Drug, and Study Procedure .......................................... 72 
17.1.2. 
Fatal Adverse Events ................................................................................................................... 72 
17.1.3. 
Serious Adverse Events ............................................................................................................... 73 
17.1.4. 
Most Common Non-Serious Adverse Events .............................................................................. 73 
17.1.5. 
TEAEs Leading to Dose Modifications ....................................................................................... 73 
17.1.6. 
TEAEs Leading to Discontinuation of Study Treatment ............................................................. 73 
17.1.7. 
AESIs .......................................................................................................................................... 73 
17.2. 
Laboratory Evaluations ............................................................................................................ 74 
17.2.1. 
Laboratory Normalization ........................................................................................................... 75 
17.2.2. 
CTCAE Toxicity Grades ............................................................................................................. 75 
17.2.3. 
Laboratory Reference Ranges ..................................................................................................... 76 
17.3. 
Vital Signs .................................................................................................................................. 76 
17.3.1. 
Vital Signs Markedly Abnormal Criteria .................................................................................... 77 
17.4. 
ECG Evaluations ....................................................................................................................... 78 
17.5. 
Physical Examination ................................................................................................................ 78 
18. 
DATA NOT SUMMARIZED OR PRESENTED .......................................................... 78 
19. 
REFERENCES .................................................................................................................. 79 
APPENDIX 1 PARTIAL DATE CONVENTIONS ............................................................... 80 
Algorithm for Treatment Emergence of Adverse Events ....................................................................................... 80 
Algorithm for Prior / Concomitant Medications .................................................................................................... 81 
APPENDIX 2 PROGRAMMING CONVENTIONS FOR OUTPUTS ............................... 82 
Dates & Times ............................................................................................................................................................ 82 
Spelling Format.......................................................................................................................................................... 82 
Paper Size, Orientation, and Margins ..................................................................................................................... 82 
Fonts ........................................................................................................................................................................... 82 
Presentation of Treatment arms ............................................................................................................................... 82 
Presentation of Nominal Visits ................................................................................................................................. 83 
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Descriptive Statistics .................................................................................................................................................. 83 
Percentages ................................................................................................................................................................. 83 
p-values ....................................................................................................................................................................... 83 
Listings ....................................................................................................................................................................... 84 
APPENDIX 4 VASOPRESSOR DRUG CODES AS PER THE WHO DRUG GLOBAL 
DICTIONARY, SEPTEMBER 2020, VERSION B3 .................................... 86 
APPENDIX 5 LABORATORY ASSESSMENTS ............................................................... 109 
APPENDIX 6 CTCAE TOXICITY GRADE, VERSION 5.0 ............................................. 111 
 
 
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1. INTRODUCTION 
This master statistical analysis plan (SAP) describes the rules and conventions to be used in the presentation and 
analysis of efficacy and safety data for protocol COV-01 (COMMUNITY). It describes the data to be summarized 
and analyzed, including specifics of the statistical analyses to be performed.  
This master SAP is based on amendment 4 of the master protocol, dated 16-Apr-2021. 
Presentation and analysis of efficacy and safety data specific to the sub-protocols as well as to the pharmacokinetic 
(PK) and pharmacodynamic (PD) endpoints will be described in separate sub-protocol SAPs. 
2. STUDY OBJECTIVES 
2.1. PRIMARY OBJECTIVE 
The primary objective is to evaluate time to confirmed clinical recovery. 
2.2. KEY SECONDARY OBJECTIVES 
The key secondary objectives are: 
• 
To evaluate oxygen-free recovery; 
• 
To evaluate improvement or being fit-for-discharge; 
• 
To evaluate all-cause mortality. 
2.3. OTHER SECONDARY OBJECTIVES 
The other secondary objectives are: 
• 
To evaluate the distribution across categories on the 8-point ordinal scale, and the worst outcome; 
• 
To evaluate intensive care unit (ICU) days; 
• 
To evaluate invasive mechanical ventilator days; 
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• 
To evaluate clinical recovery; 
• 
To evaluate sustained clinical recovery; 
• 
To evaluate the safety of candidate agents as add-on therapy to standard of care (SoC) in patients with 
COVID-19. 
2.4. EXPLORATORY OBJECTIVES 
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3. STUDY DESIGN 
3.1. GENERAL DESCRIPTION 
Coronavirus disease 2019 (COVID-19) Multiple Agents and Modulators Unified Industry Members Trial 
(COMMUNITY) is an adaptive, randomized, placebo-controlled platform study designed to rapidly evaluate 
candidate agents in the treatment of COVID-19. The study will include hospitalized adult patients (≥18 years of age) 
who have infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes 
COVID-19, as confirmed by laboratory tests and/or point of care tests. For inclusion, patients will need to be 
hospitalized with a clinical status of Grade 2 (hospitalized, on invasive mechanical ventilation or ECMO) to Grade 5 
(hospitalized, not requiring supplemental oxygen, requiring ongoing medical care [COVID-19 related or 
otherwise]), as defined by an 8-point ordinal scale for clinical severity (refer to Section 16.1.1).  
This study aims to identify efficacious candidate agents for treatment of COVID-19. The candidate agents may 
include, but will not be limited to, antivirals, vascular agents or immunomodulatory agents. Each sub-protocol will 
specify a single candidate agent or a combination of candidate agents to be administered.  
The Master Protocol outlines the overall design of the study, including the population, inclusion and exclusion 
criteria, randomization scheme, primary, secondary, and exploratory endpoints, study design, statistical 
methodology, and planned analyses that are common for all candidate agents to be tested. The Master Protocol is 
structured such that multiple candidate agents from different pharmaceutical companies can be evaluated 
simultaneously. The plan is to add candidate agents as they are identified and/or to remove therapies based on results 
of interim analyses (IAs; e.g., due to futility or if they are considered unsafe). The shared placebo control group for a 
candidate agent will include only patients randomized during the same period in which the candidate agent is opened 
for enrollment (refer to Section 4.5).  Patients will be randomized equally to either the candidate agent plus SoC or 
placebo plus SoC in a double-blind fashion. Patients who are randomized to placebo plus SoC will be subsequently 
randomized equally to a matching placebo corresponding to an available candidate agent whose sub-protocol the 
patient qualified for (i.e., a 2-stage randomization). Each patient in the placebo plus SoC group will receive one type 
of placebo.  Therefore, patients may be aware of which sub-protocol they were randomized to but not whether they 
will receive active agent or placebo investigational product.  The comparator group of a candidate agent will include 
patients randomized to any matching placebo for a candidate agent available at the time of randomization for that 
agent (refer to Section 4.5). 
Patients will be screened on Day -1 (the day before the first dose of study treatment [candidate agent plus SoC or 
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placebo plus SoC] is scheduled) or Day 1 and will remain in the hospital from Day 1 until discharge.  All patients 
will receive SoC treatment, either with blinded candidate agent or matching blinded placebo.  The SoC will be based 
on appropriate local written guidelines in place at the site at the time of treatment in the study; the SoC may change 
during the course of the study as new information about treating COVID-19 becomes available.  Dosing with the 
study treatment (as an add-on to SoC) will commence on Day 1. Patients will be assessed daily while hospitalized.  
If they are discharged from the hospital prior to Day 15, they will have study visits at Days 15 and 29 as an 
outpatient by telemedicine.  The last day of primary assessments will be Day 29.  An end-of-study visit will be 
conducted on Day 60 (± 4 days) via telemedicine (unless the patient is still hospitalized in which case it would be 
conducted in person). 
Sub-protocols will outline the scientific rationale, additional eligibility criteria (if necessary), treatment dose and 
regimen, statistical analysis populations, and other specifics unique to each candidate agent. The sub-protocols may 
define adverse events of special interest (AESIs) and can include PK and/or PD assessments that are appropriate for 
the specific candidate agent. In order to enroll, a patient must meet all entry criteria for both the Master Protocol and 
at least one active sub-protocol. 
The study will evaluate the candidate agents as an add-on to the SoC to assess safety and efficacy. IAs may be 
performed for each candidate agent to evaluate futility for candidate agents.  
Patients will be stratified at randomization by baseline clinical severity of 2 on the 8-point ordinal scale (yes/no) and 
remdesivir use at baseline (yes/no).  
Enrollment of patients will be continuous throughout the study for each candidate agent until the total number of 
planned patients for that agent is enrolled or until futility criteria is met at an IA, or if the agent is considered unsafe.  
In addition, centers may elect to participate in separate Investigator-initiated studies collecting additional data on 
patients, as their resources permit.  
 
 
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Figure 1 
Study Schema (with hypothetical example)  
 
 
FA=final analysis; IA=interim analysis; PA = primary analysis; SoC=standard of care. ‘×’ indicates that futility boundary has 
been met.  
Note: IA1 and IA2 will be planned at information fractions of approximately 25% and 55% of expected number of recoveries i.e., 
after approximately 123 and 270 patients have met the primary endpoint of confirmed clinical recovery on a particular 
candidate agent plus SoC and placebo plus SoC, respectively. 
Note: PA will occur after approximately 350 patients have been randomized to an active agent plus SoC and have had the 
opportunity to complete the Day 29 visit. 
Note: FA will occur after all patients randomized to that agent plus SoC and the concurrent placebo plus SoC controls have had 
the opportunity to complete the Day 60 visit. 
Note: In the above example, Agents #1, #2, and #5 met the futility boundary at IA1, while Agent #3 met the futility boundary at 
IA2, and so those agents could be discontinued in the study due to futility. 
Note: Patients who are randomized to placebo plus SoC will be subsequently randomized equally to a matching placebo 
corresponding to an available agent whose sub-protocol the patient qualified for (i.e., a 2-stage randomization). 
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3.2. SCHEDULE OF ACTIVITIES 
An example of a schedule of activities can be found in Section 1.3 of the Master Protocol. Each sub-protocol may 
have its own schedule of activities. 
3.3. CHANGES TO PLANNED ANALYSES FROM MASTER PROTOCOL 
• 
The ‘average ordinal scale for clinical severity score over Day 1 to Day 29’ other secondary efficacy endpoint is 
updated to ‘average ordinal scale for clinical severity score over Day 2 to Day 29’ since Day 1 is the baseline 
value. 
4. PLANNED ANALYSES 
The following analyses will be performed for each sub-protocol: 
• 
Independent data monitoring committee (IDMC) safety analyses; 
• 
IAs for futility reviewed by the IDMC; 
• 
Primary analysis; 
• 
Final analysis. 
4.1. IDMC SAFETY ANALYSES 
An IDMC will monitor ongoing data to ensure patient well-being and safety as well as study integrity. The IDMC 
will be asked to make recommendations to the joint steering committee (JSC) regarding early termination or 
modification of the evaluation of a candidate agent.  
The JSC will evaluate the IDMC recommendation(s) to make decisions on the candidate agent(s) within the study, 
and it will provide guidance, advice, and recommendations to the program on relevant clinical issues related to the 
strategy, implementation, and conduct of the study. 
Unless otherwise indicated, definitions and derivations for the IDMC safety analyses will be based on those required 
for the primary analysis contained in this SAP (refers to Section 4.3). The data cut-off for the first IDMC safety 
meeting will be 4 weeks after the first patient is randomized into any sub-protocol. Thereafter, the data-cut will be 
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approximately every 4 weeks.  Each sub-protocol other than the one to which the very first patient was randomized 
to will start to be included in the monthly IDMC safety meetings 4 weeks after the first patient is randomized into 
the sub-protocol.  Safety outputs will be based on the safety analysis set (refer to Section 5.2). 
The 
 Biostatistics study team will remain blinded to the IDMC safety analysis results. Once the programs 
have been produced and validated by the 
 Biostatistics study team in a blinded fashion, these programs will 
be sent to 
 Unblinded statistician, independent from the study team, who will apply the randomization 
schedule and provide the IDMC members with a set of unblinded outputs.  The list of the unblinded personnel (i.e., 
 Unblinded Biostatistics team members as well as recipients of the unblinded results sent by 
 
Unblinded Biostatistician) will be documented in the Unblinding Plan, which will be finalized before the data cut-
off for the first IDMC safety analysis. 
Refer to the IDMC Charter for more details about the IDMC composition, responsibilities, meeting frequency, list of 
outputs to be provided, etc. 
4.2. INTERIM ANALYSES 
Each candidate agent will be evaluated for futility at up to two IAs.  For sub-studies under the master protocol, an IA 
will take place after: 
• 
The appropriate number of primary efficacy endpoint events has occurred (refer to Section 16.5); 
• 
Sponsor authorization of this SAP; 
• 
Sponsor authorization of the analysis sets (refer to Section 5.3); 
• 
Interim or final database lock of each sub-protocol contributing to the shared control group of the candidate 
agent, as appropriate; 
• 
Interim database lock of the concerned candidate agent (refer to Data Management [DM] Interim Database 
Lock Plan). 
The data cut-off date will be the date when approximately the required number of events is reached for an IA (refer 
to Section 16.5.1) and the last patient having the event is from the sub-protocol of interest for the IA, because if the 
last patient with an event is from a sub-protocol other than the one of interest, the patient’s treatment arm will 
automatically be unblinded since those patients can only be included in the shared placebo plus SoC control arm of 
the sub-protocol of interest.  Efficacy outputs will be based on the full analysis set (FAS; refer to Section 5.1) and 
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include data from patients who have had the opportunity to complete the Day 29 study visit or discontinued from 
study before or on the IA data cut-off date, whichever occur first, while safety outputs will be based on the safety 
analysis set (refer to Section 5.2) and include all data included in the database at the time of the interim database 
lock.   
Unless otherwise specified, definitions and derivations for the IAs will be based on those required for the primary 
analysis contained in this SAP (refers to Section 4.3).   
As for the IDMC safety analyses, results of each IA will be reviewed by the IDMC. The IDMC will be asked to 
make recommendations to the JSC regarding early termination of the evaluation of a candidate agent due to futility 
based on pre-defined stopping rules (refer to Section 16.5.1). 
The JSC will evaluate the IDMC recommendation(s) to make decisions on the candidate agent(s) within the study, 
and it will provide guidance, advice, and recommendations to the program on relevant clinical issues related to the 
strategy, implementation, and conduct of the study. 
Due to the shared placebo plus SoC treatment arm, both the 
 Biostatistics study team and 
 Unblinded 
statistician, independent from the study team, will be involved in the monitoring of the overall number of patients 
having met the primary endpoint of confirmed clinical recovery through Day 29, without re-hospitalization through 
Day 29 (refer to Section 16.1.1), across a particular candidate agent plus SoC and its contemporaneous shared 
placebo plus SoC treatment arms to confirm the timing of each IA.  Once the programs have been produced and 
validated by the 
 Biostatistics study team in a blinded fashion, these programs will be sent to 
 
Unblinded statistician who will apply the randomization schedule and inform 
 Blinded statistician of the 
overall number of patients having the event (n) and overall number of patients included in the analysis (N).  No 
results by treatment arm will be generated by the programs and no information by treatment arm will be shared with 
 Blinded statistician (refer to the Unblinding Plan for the list of the unblinded personnel i.e.,
 
Unblinded statistician, etc.). 
The 
 Biostatistics study team will remain blinded to the IA results. Once the programs have been produced 
and validated by the 
 Biostatistics study team in a blinded fashion, these programs will be sent to 
 
Unblinded statistician, independent from the study team, who will apply the randomization schedule and provide the 
IDMC members with a set of unblinded outputs.  The list of the unblinded personnel (i.e.,
 Unblinded 
Biostatistics team members as well as recipients of the unblinded results sent by 
 Unblinded Biostatistician) 
will be documented in the Unblinding Plan, which will be finalized before the data cut-off for the first IDMC safety 
analysis. 
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Refer to the IDMC Charter for more details about the IDMC composition, responsibilities, meeting frequency, list of 
outputs to be provided, etc. 
4.3. PRIMARY ANALYSIS 
The primary analysis for a candidate agent will take place after: 
• 
Approximately 350 patients have been randomized to the candidate agent plus SoC active arm of the sub-
protocol of interest and approximately 350 patients have been randomized to the shared placebo plus SoC 
control arm of the sub-protocol of interest (refer to Section 4.5), and last patient randomized into one of these 
two arms is from the sub-protocol of interest, because if the last randomized patient is from a sub-protocol other 
than the one of interest, the patient’s treatment arm will automatically be unblinded since those patients can 
only be included in the shared placebo plus SoC control arm of the sub-protocol of interest; 
• 
The last patient randomized to that candidate agent plus SoC treatment arm or its concurrent shared placebo 
plus SoC control arm have had the opportunity to complete the Day 29 study visit or discontinued from study 
before or on the Day 29 study visit; 
• 
Sponsor authorization of this SAP; 
• 
Sponsor authorization of the analysis sets (refer to Section 5.3); 
• 
Interim or final database lock of each sub-protocol contributing to the shared control group of the candidate 
agent, as applicable; 
• 
Interim database lock of the concerned candidate agent database (refer to DM Interim Database Lock Plan).   
The data cut-off date will be the date the last patient completed the Day 29 study visit or discontinued from the study 
before or on the Day 29 study visit, whichever occurs first. 
With the following exception, all planned analyses identified in this SAP will be performed by 
 Biostatistics 
at the time of the primary analysis of a sub-protocol.  The exception is the summary and analysis of the secondary 
efficacy endpoint incidence of sustained clinical recovery as confirmed by Day 60 (refer to Section 16.2.1.9) which 
will be performed at the time of the final analysis of a sub-protocol (refer to Section 4.4). 
For each sub-protocol, additional outputs to be produced at the time of the primary analysis may be specified in sub-
protocol SAPs. 
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The 
 Biostatistics study team will remain blinded to the results of the primary analysis. Once the programs 
have been produced and validated by the 
 Biostatistics study team in a blinded fashion, these programs will 
be sent to 
 Unblinded statistician, independent from the study team, who will apply the randomization 
schedule and provide to a pre-identified and limited number of people within the Sponsor of the concerned sub-
protocol with a set of unblinded outputs.  The list of the unblinded personnel (i.e., 
 Unblinded Biostatistics 
team members as well as recipients of the unblinded results sent by 
 Unblinded Biostatistician) will be 
documented in the Unblinding Plan, which will be finalized before the data cut-off for the first IDMC safety 
analysis. 
4.4. FINAL ANALYSIS 
The final analysis for a candidate agent will take place after: 
• 
Approximately 350 patients have been randomized to the active arm of the sub-protocol of interest and 
approximately 350 patients have been randomized to the shared placebo plus SoC control arm of the sub-
protocol of interest (refer to Section 4.5), and last patient randomized into one of these two treatment arms is 
from the sub-protocol of interest, because if the last randomized patient is from a sub-protocol other than the 
one of interest, the patient’s treatment arm will automatically be unblinded since those patients can only be 
included in the shared placebo plus SoC control arm of the sub-protocol of interest; 
• 
The last patient randomized to that candidate agent plus SoC treatment arm and its concurrent shared placebo 
plus SoC control arm (refer to Section 4.5) have had the opportunity to complete the Day 60 visit or 
discontinued from the study,  
• 
Sponsor authorization of this SAP,  
• 
Interim or final database lock of each sub-protocol contributing to the shared control group of the candidate 
agent, as applicable;  
• 
Final database lock of the concerned candidate agent. 
Unless otherwise specified, definitions and derivations for the final analysis will be based on those required for the 
primary analysis contained in this SAP (refer to Section 4.3).  The outputs to be produced at the time of the final 
analysis of a sub-protocol are: 
• 
Summary of patient disposition (refer to Section 9.1); 
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• 
Summary of protocol deviations (refer to Section 9.2) 
• 
Summary of concomitant medications (refer to Section 13); 
• 
Summary and analysis of the incidence of sustained clinical recovery as confirmed by Day 60 (other secondary 
efficacy endpoint; refer to Section 16.2.3.1); 
• 
Summary of all-cause mortality through Day 60 (additional efficacy endpoint; refer to Section 16.4.3); 
• 
All summaries planned for the AEs (refer to Section 17.1). 
For each sub-protocol, additional outputs to be produced at the time of the final analysis may be specified in sub-
protocol SAPs. 
The
 Biostatistics study team will remain blinded to the results of the final analysis of each subprotocol with 
the exception of the final analysis of the last sub-protocol reaching this milestone. Once the programs have been 
produced and validated by the 
 Biostatistics study team in a blinded fashion, these programs will be sent to 
 Unblinded statistician, independent from the study team, who will apply the randomization schedule and 
provide to a pre-identified and limited number of people within the Sponsor of the concerned sub-protocol with a set 
of unblinded outputs.  The list of the unblinded personnel (i.e., 
 Unblinded Biostatistics team members as 
well as recipients of the unblinded results sent by 
 Unblinded Biostatistician) will be documented in the 
Unblinding Plan, which will be finalized before the data cut-off for the first IDMC safety analysis. 
4.5. SELECTION OF THE CONTROL ARM FOR AN ANALYSIS 
The subset of the placebo plus SoC group, regardless of which sub-protocol the placebo patient belongs, enrolled 
concurrently to an active agent with matching inclusion/exclusion criteria will serve as the control arm for the 
analysis of a candidate agent.  An exception to this definition is that if a sub-protocol X is not open at a site for 
screening, the concurrent placebo from other active sub-protocol(s) at that site will not be eligible for inclusion in 
the control arm for sub-protocol X.  This is because patient’s eligibility for sub-protocol X cannot be determined 
without sub-protocol consent and obtaining consent for a sub-protocol is not possible until that sub-protocol is 
opened at a site for screening.  It is to be noted that a patient randomized to the placebo arm of sub-protocol X 
taking the candidate agent of sub-protocol Y for another approved indication (based on data collected on the 
Concomitant Medications page of the eCRF) at the time of randomization will not be eligible for the control arm of 
the sub-protocol Y. 
For each sub-protocol and each site, ‘concurrently’ is defined as the period starting on the date the site was opened 
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for screening for the sub-protocol and ending on the date of the last patient randomized into that sub-protocol for an 
interim, primary, and final analyses.  For IDMC safety analyses, the date of the data cut-off will be used in lieu of 
the date of the last patient randomized into the sub-protocol. 
5. ANALYSIS SETS 
For purposes of analysis, the analysis sets in this section are defined for all sub-protocols. Specific additional 
analysis sets may be defined in sub-protocols or their corresponding sub-protocol SAPs. 
5.1. FULL ANALYSIS SET 
For each sub-protocol, the full analysis set (FAS) will contain all patients who were randomized to the sub-protocol 
candidate agent plus SoC arm as well as all patients who were randomized to any placebo plus SoC arm included in 
the control arm of the candidate agent (refer to Section 4.5). 
For displays and analyses based on FAS, patients will be classified according to randomized treatment. 
5.2. SAFETY ANALYSIS SET 
For each sub-protocol, the safety analysis set will contain all patients included in the FAS (refer to Section 5.1) who 
took at least one dose study drug. If there is any doubt whether a patient was treated or not, he/she will be assumed 
treated with the study drug for the purposes of analysis.  
For analyses and displays based on the safety analysis set, patients will be classified according to the actual 
treatment received (based on data captured on the interactive web response system [IWRS]). That is, a patient 
randomized to a placebo plus SoC arm who received at least one dose of the candidate agent during the course of the 
study will be classified under the candidate agent plus SoC arm and a patient randomized to the candidate agent plus 
SoC arm who never received the candidate agent will be classified under the control arm.  
If a patient randomized to the placebo arm of sub-protocol X is selected for the control arm of sub-protocol Y (refer 
to Section 4.5) and begins taking the candidate agent of sub-protocol Y for another approved indication after 
randomization as a concomitant medication (based on data captured on the Concomitant Medications page of the 
eCRF), this patient will still be presented under the control arm of sub-protocol Y for summaries based on the safety 
analysis set and a listing of all AEs will be provided for such patients, if they exist. 
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5.3. PROCESS FOR ANALYSIS SET ASSIGNMENT 
The analysis sets that will be used to summarize, analyze, and list the data collected during the course of this study 
are all defined based on objective criteria only.  That is, none of the analysis set definitions included in this SAP 
contains subjective criteria (e.g., major protocol deviation potentially having an impact on the efficacy data).  Hence, 
the authorization of this SAP will also stand for the agreement and authorization of the inclusion/exclusion of each 
patient in each of these analysis sets.  
If analysis sets defined in a sub-protocol SAP involve subjective criteria, the process for analysis set assignment 
prior to interim, primary or final database locks will be detailed in the sub-protocol SAPs.  
6. GENERAL CONSIDERATIONS 
6.1. STUDY DAY 
Study day will be calculated from the day of the first dose of the study drug for patients who received at least one 
dose of study drug and from the day of randomization for randomized patients who were never dosed, and will be 
used to show start/stop day of assessments and events. 
Study day will be computed as follows: 
• 
Study Day = (Date of interest –Date of first dose of study drug/randomization, as appropriate) + 1 if the date of 
interest is on or after the date of first dose of study drug/randomization, as appropriate; 
• 
Study Day = (Date of interest – Date of first dose of study drug/randomization, as appropriate) if the date of 
interest is prior to the date of first dose of study drug/randomization, as appropriate. 
Based on these formula, Study Day 1 will be the day of the first dose of the study drug for patients who received at 
least one dose of study drug and the day of randomization for randomized patients who were never dosed. 
In the situation where the date of interest is partial or missing, Study Day and any corresponding durations will be 
considered as missing in the analyses and the date of interest will be presented as partial or missing in the listings. 
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6.2. BASELINE 
Unless otherwise specified, baseline is defined as the last non-missing measurement (including unscheduled 
measurements) taken prior to the first dose of study drug for patients who received at least one dose of study drug 
and as the last non-missing measurement (including unscheduled measurements) taken prior to randomization for 
randomized patients who were never dosed. In the case where the last non-missing measurement and first dose of 
study drug/randomization dates coincide, time will be considered. If time is not collected, missing or unknown, 
measurements taken on the same day of the first dose, or same day as randomization for subjects not dosed, will be 
considered as the baseline measurement unless the assessment was scheduled to be collected post-first dose/post-
randomization in the master/sub-protocol (refer to Section 3.2).  
For adverse events (AEs) commencing on the date of the first dose of study drug/randomization, time of onset of the 
AE will be considered when determining if the event was pre-baseline (not treatment-emergent) or post-baseline 
(treatment-emergent).  Medications that are ongoing or commencing on the date of the first dose of study 
drug/randomization will be considered as concomitant medications (refer to Section 13) . Partial or completely 
missing AE and medication dates will be handled as described in Appendix 1. 
6.3. UNSCHEDULED VISITS, RETESTS, DISCHARGE, AND EARLY 
TERMINATION DATA 
For by-visit summaries, data recorded at the nominal visit will be presented. That is, unscheduled visits will not be 
included in by-visit summaries but might contribute to the baseline timepoint (refer to Section 6.2) and/or 
worst/maximum/minimum post-baseline value, where required (e.g., shift table).  
In case of a retest when retest is defined as having a blood sample tested twice, the latest available measurement for 
that blood sample will be used for the by-visit summaries.  In case of a retest when retest is defined as having two 
blood samples collected on the same day, results from the last blood sample will be used for the by-visit summaries. 
Refer to Section 6.4 for the conventions to map discharge and early termination data to protocol-defined visit 
windows.  Discharge and early termination data might also contribute to the worst/maximum/minimum post-
baseline value, where required (e.g. shift table). 
Listings will include all scheduled, unscheduled, retest, discharge, and early discontinuation data. 
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6.4. WINDOWING CONVENTIONS  
Discharge and early termination data will be mapped based on the scheduled Study Day of each scheduled visit with 
adjusted protocol-defined visit window, as specified in the appropriate sub-protocol schedule of activities (refer to 
Section 3.2). 
If discharge or early termination data are mapped to a scheduled visit for which data from the scheduled visit are 
also available (i.e., non-missing), the data collected at the scheduled visit will be used in the by-visit summaries. If 
discharge or early termination data are mapped to a scheduled visit for which data from the scheduled visit are not 
available (i.e., missing), data from the discharge or early termination visit will be used in the by-visit summaries, as 
applicable. 
6.5. COMMON CALCULATIONS 
Change from baseline will be calculated as: 
• 
Change from baseline = Observed value at post-baseline visit – Baseline value 
Percent change from baseline will be calculated as: 
• 
Percent change from baseline = (Change from baseline / Baseline value) * 100 
7. STATISTICAL CONSIDERATIONS 
For continuous data, descriptive statistics (i.e., n [number of patients with available data], mean, standard deviation 
[SD], minimum, 25th percentile (Q1), median, 75th percentile (Q3), and maximum values) will be presented by 
treatment arm and visit, when applicable. 
For categorical data, the number and percentage of patients in each category will be presented by treatment arm and 
visit, when applicable. 
7.1. SAMPLE SIZE CALCULATION 
A total of up to 350 patients are planned to be randomized to each candidate agent plus SoC.  Simultaneously, 
patients will be randomized to placebo plus SoC throughout the course of the study.  The subset of shared placebo 
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plus SoC treatment arm, regardless of which sub-protocol the placebo belongs, enrolled concurrently to an active 
agent with matching inclusion/exclusion criteria will serve as comparator (refer to Section 4.5).  The primary 
efficacy endpoint to compare selected treatment plus SoC to placebo plus SoC included in the control arm will be 
the time to confirmed clinical recovery through Day 29 i.e., fit for discharged (defined by achieving a score of 6, 7 
or 8 on the 8-point ordinal scale for clinical severity status), without re-hospitalization through Day 29 (refer to 
Section 16.1.1).  
Assuming a median time to confirmed clinical recovery of 11 days for patients randomized to a candidate agent plus 
SoC arm compared with 15 days for those randomized to its concurrent placebo plus SoC arm, 350 patients are 
needed per arm in order to observe 490 confirmed clinical recovery events between the 2 treatment arms being 
compared at the primary analysis of a sub-protocol. This sample size will provide approximately 88% power to 
detect a hazard ratio (HR) of 1.364 for the occurrence of the confirmed clinical recovery events, when comparing 
each candidate agent plus SoC with their concurrent placebo plus SoC arm, at a one-sided significance level of 
0.025.  
This sample size will provide the following information about the key secondary efficacy endpoints:  
• 
Assuming the oxygen-free recovery rate at Day 29 is 65% for the concurrent placebo plus SoC arm of a 
candidate agent, a sample size of 350 patients per arm will provide approximately 80% power to detect a 9.7% 
absolute increase in the proportion of patients who have oxygen-free recovery at Day 29 in the candidate agent 
plus SoC arm; 
• 
Assuming 70% of patients randomized to the concurrent placebo plus SoC arm of a candidate agent achieve at 
least 2-point improvement from baseline on the 8-point ordinal scale or are fit for discharge at Day 29, 350 
patients per arm will provide approximately 80% power to detect a 9.2% absolute increase in this proportion 
with a candidate agent plus SoC arm at Day 29; 
• 
Assuming the all-cause mortality rate through Day 29 is 15% for the concurrent placebo plus SoC arm of a 
candidate agent, a sample size of 350 patients per arm will provide 80% power to detect an absolute reduction 
of 6.75% (8.25% rate for the candidate agent plus SoC arm) in the mortality rate by Day 29.  Assuming a 
mortality rate of 15% for the concurrent placebo plus SoC arm of a candidate agent and 19% for the candidate 
agent plus SoC arm (i.e., an adverse treatment effect of 4%) with a sample size of 350 per arm, the chance to 
observe a decrease in the mortality rate of at least 1% with a candidate agent plus SoC arm compared to its 
concurrent placebo plus SoC arm is approximately 4%. 
The sample size calculation was performed using EAST 6.5.  
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For a sub-protocol where the primary analysis population is a subset of the randomized population, the sample size 
may be adjusted as applicable to power the designated primary analysis population as appropriate.  
Each candidate agent may be evaluated for futility at up to two IAs (refer to Section 16.5). 
7.2. MISSING DATA 
Missing efficacy data will be handled as described in Sections 16.1.2, 16.2.2, and 16.3.2 of this SAP.  
Missing safety data will not be imputed. Partially or completely missing AE and medication dates will be handled as 
described in Appendix 1. 
7.3. STATISTICAL TESTS 
Unless otherwise specified, all statistical tests will be conducted at the two-sided 0.05 significance level at the 
primary analysis.  Confidence Intervals (CIs) will be two-sided with 95% coverage, unless otherwise specified. 
7.4. MULTIPLE COMPARISONS/ MULTIPLICITY 
No adjustment to control the family-wise type I error over the two IAs and the primary analysis of a candidate agent 
is needed as both IAs will be for futility only (refer to Section 16.5). 
At the time of the primary analysis of each candidate agent, the primary efficacy endpoint will be tested at the 0.05 
alpha level.  Then, a hierarchical testing procedure will be used to test the three key secondary hypotheses (refer to 
Section 16.2.3.1). With this approach when a particular null hypothesis is rejected, the alpha allocated to that 
hypothesis can be reallocated to other hypothesis tests.  The hierarchical testing procedure will be implemented in 
the following order: 
1. Primary endpoint: Time to confirmed clinical recovery through Day 29, without re-hospitalization through 
Day 29 (refer to Sections 16.1.1 and 16.1.3);  
2. Key Secondary endpoint: Incidence of oxygen-free recovery at Day 29 (refer to Sections 16.2.1.1 and 
16.2.3.1); 
3. Key secondary endpoint: Incidence of ≥ 2-point improvement from baseline or fit for discharge on the 
ordinal scale at Day 29 (refer to Sections 16.2.1.2 and 16.2.3.1); 
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4. Key secondary endpoint: Incidence of all-cause mortality through Day 29 (refer to Sections 16.2.1.3 and 
16.2.3.1). 
In the hierarchical testing procedure, the formal testing can be performed for a step only when the statistical 
significance is declared for all the endpoints tested in the previous steps. If the testing sequence is stopped at a 
particular step, only nominal p-value will be provided for the remaining endpoints in the testing sequence.  
Only nominal p-values will be provided for the non-key secondary endpoints and no statistical inference will be 
performed for the 
and safety endpoints.   
7.5. MULTICENTER STUDIES 
This study will be conducted by multiple investigators at multiple centers.  For each sub-protocol, data from all 
patients included in the candidate agent plus SoC arm will be pooled together in the analyses of the sub-protocol, 
regardless of the patient’s centers.  Similarly, data from all patients included in the control arm of the candidate 
agent will be pooled together in the analyses of the sub-protocol, regardless of the patient’s centers. 
Statistical analyses will be adjusted for the countries.  Subgroup analyses by country might be performed for the 
primary and key secondary efficacy endpoints (refer to Sections 7.7, 16.1.5, and 16.2.5).   
If data are too sparse for at least one country (i.e., less than 10% of FAS patients, regardless of the treatment arm), 
countries will be pooled into regions based on geographical area (e.g., North America, Latin America, Western 
Europe, Eastern Europe, and Rest of the World).  In that case, statistical analyses will be adjusted for regions instead 
of countries.  
For each sub-protocol, determination of the countries or regions to be included in the statistical models will be 
finalized in a blinded fashion before a sub-protocol database lock for an IA or Primary Analysis (refer to Sections 
4.2 and 4.3) based on emerging data. 
7.6. ADJUSTMENTS FOR COVARIATES AND FACTORS TO BE 
INCLUDED IN ANALYSES 
The analyses will be adjusted for the following covariates and factors. For details of their inclusion in the models, 
refer to Sections 16.1.3, 16.2.3, and 16.3.3. 
• 
Baseline value of the concerned endpoint, when applicable; 
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• 
Baseline clinical severity score of 2 randomization strata (yes or no), as captured on the IWRS; 
• 
Remdesivir at baseline randomization strata (yes or no), as captured on the IWRS; 
• 
Country (or region; refer to Section 7.5). 
Sensitivity analyses replacing the randomization strata as captured in IWRS by the randomization strata as derived 
based on the data captured on the electronic case report form (eCRF) might be performed if at least 10% of the 
patients are mis-stratified at the time of randomization for a stratification variable (refer to Section 16.1.4) i.e.,  
• 
Baseline clinical severity score of 2 (yes or no) as captured on the Ordinal Scale for Clinical Severity page of 
the eCRF; 
• 
Remdesivir use at baseline (yes or no) based on data collected on the Concomitant Medications page of the 
eCRF (i.e., medications that were taken by a patient on the day the patient was randomized to a sub-protocol). 
7.7. EXAMINATION OF SUBGROUPS 
Subgroup analyses will be conducted as supplementary analyses for the primary and key secondary efficacy 
endpoints as stated in Sections 16.1.5 and 16.2.5, respectively.  
The subgroups are: 
• 
Age (years) at informed consent (≥ 18 - ≤ 49, ≥ 50 - ≤ 64; ≥ 65 - ≤ 84 or ≥ 85); 
• 
Sex (male or female); 
• 
Race (White, Black or African American or Other); 
• 
Ethnicity (Hispanic or Latino or not Hispanic or Latino); 
• 
Country (or region; refer to Section 7.5); 
• 
Obesity co-morbidity at screening (BMI < 30 kg/m2 or BMI ≥ 30 kg/m2); 
• 
Diabetes co-morbidity at screening (yes or no); 
• 
Cardiovascular disease co-morbidity at screening (yes or no); 
• 
Hypertension co-morbidity at screening (yes or no); 
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• 
Chronic lung disease co-morbidity at screening (yes or no); 
• 
Chronic liver disease co-morbidity at screening (yes or no); 
• 
Kidney disease co-morbidity at screening (yes or no); 
• 
Immunosuppressive/Immunocompromise disorder co-morbidity at screening (yes or no); 
• 
Time since hospital admission (≤ 5 days or > 5 days; refer to Section 11.1); 
• 
Baseline clinical severity score of 2 randomization strata (yes or no) as captured on the IWRS; 
• 
Disease severity at baseline (2, 3, 4, or 5) based on the ordinal scale for clinical severity as captured on the 
Ordinal Scale for Clinical Severity page on the eCRF; 
• 
Disease severity score of 2, 3 or 4 (yes or no) at baseline based on the ordinal scale for clinical severity as 
captured on the Ordinal Scale for Clinical Severity page on the eCRF  
• 
Remdesivir use at baseline randomization strata (yes or no) as captured on the IWRS; 
• 
Concomitant use of remdesivir at any time during the period of the endpoint of interest (yes or no) based on 
collected on the Concomitant Medications page of the eCRF (for concomitant use definition, refer to Section 
13).  The concomitant use of remdesivir at any time during the period of the endpoint of interest in the ‘yes’ 
subgroup will be further broken down by duration of concomitant use of remdesivir, where the duration of 
concomitant use categories (e.g., < x days or ≥ x days) will be determined in a blinded fashion based on 
emerging data before the interim database lock of a candidate agent primary analysis; 
• 
Dexamethasone use at baseline (yes or no) based on data collected on the Concomitant Medications page of the 
eCRF (i.e., medications that were being taken by a patient on the day the patient was randomized to a sub-
protocol); 
• 
Concomitant use of dexamethasone at any time during the period of the endpoint of interest (yes or no) based 
on data collected on the Concomitant Medications page of the eCRF (for concomitant use definition, refer to 
Section 13). The concomitantly use dexamethasone at any time during the period of the endpoint of interest 
‘yes’ subgroup will be further broken down by duration of concomitant use of dexamethasone, where the 
duration of concomitant use categories (e.g., < x days or ≥ x days) will be determined in a blinded fashion based 
on emerging data before the interim database lock of a candidate agent primary analysis. 
For age subgroups, if data are too sparse for the ‘≥ 18 - ≤ 49’ or ‘≥ 50 - ≤ 64’ subgroups (i.e., less than 10% of FAS 
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patients, regardless of the treatment arm), these two subgroups will be pooled together into a ‘≥ 18 - ≤ 64’ subgroup.  
Similarly, if data are too sparse for the ‘≥ 65 - ≤ 84 or ‘≥ 85’ subgroups, these two subgroups will be pooled together 
in a ‘≥ 65’ subgroup.  If even after pooled two subgroups, the resulting ‘≥ 18 - ≤ 64’ or ‘≥ 65’ subgroup is still less 
than 10% of FAS patients, regardless of the treatment arm, only descriptive statistics will be provided for the 
concerned subgroup. 
For race subgroups, if data are too sparse for the ‘Black or African American’ or ‘Other’ subgroups (i.e., less than 
10% of FAS patients, regardless of the treatment arm), the ‘Black or African American’ and ‘Other’ subgroups will 
be pooled together into a ‘Non-White’ subgroup.  If even after having pooled these two subgroups the number of 
patients in the resulting ‘Non-White’ subgroup is still less than 10% of FAS patients, regardless of the treatment 
arm, only descriptive statistics will be provided for the ‘Non-White’ subgroup. 
For the disease severity at baseline subgroups, if data are too sparse for the subgroups of patients with a disease 
severity at baseline of 3 or 4 (i.e., less than 10% of FAS patients, regardless of the treatment arm), these two 
subgroups will be pooled together.  If data are too sparse for the subgroup of patients with a disease severity at 
baseline of 2, pooled 3/4 (if applicable) or 5, only descriptive statistics will be provided for the concerned 
subgroups.  That is, the subgroup of patients with a disease severity at baseline of 2 or 5 will not be pooled with any 
other subgroup. 
For any other subgroups, if data are too sparse (i.e., less than 10% of FAS patients for a subgroup, regardless of the 
treatment arm), only descriptive statistics will be provided for the concerned subgroups. 
Additional subgroups might be defined based on emerging data to explore the impact of medical therapy in COVID-
19 with proven efficacy (e.g., vaccine use, other evolving SoC, etc.). The decision to add such subgroups and their 
definition will be taken in a blinded fashion before the interim database lock of a candidate agent primary analysis 
based on data captured on the Concomitant Medications page of the eCRF.  
7.8. SOFTWARE VERSION 
All analyses will be conducted using SAS version 9.4.  
8. OUTPUT PRESENTATIONS 
Appendix 2 shows conventions for presentation of data in outputs.  
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The table, figure, and listing (TFL) shells provided with this SAP describe the presentations for each sub-protocol in 
accordance with this master SAP and therefore, the format and content of the summary tables, figures, and listings to 
be provided by 
 Biostatistics.  If a sub-protocol has additional endpoints or analyses, additional TFL shells 
will be provided with the sub-protocol SAP.  
9. DISPOSITION AND WITHDRAWALS 
All patients who provide informed consent will be accounted for in this study.  
9.1. DISPOSITION 
Number and percentages of patients treated, ongoing on study drug, who completed/ discontinued early from 
treatment (including reason for withdrawal), ongoing in study, and who completed/discontinued early from the study 
(including reason for withdrawal) will be provided overall and by treatment arm based on the FAS.  The control arm 
of a candidate agent (refer to Section 4.5) will be further broken down by sub-protocol.  It is to be noted that the 
number and percentage of patients ongoing on study drug and ongoing in study will be excluded from the summary 
at the time of the final analysis. 
In addition, a Kaplan-Meier curve (product-limit estimate) of time to discontinuation from study, in days, for each 
treatment arm will be provided along with a summary of the associated statistics including, the 25th, 50th (median), 
and 75th percentiles, and their corresponding two-sided 95% CIs.  The control arm of a candidate agent (refer to 
Section 4.5) will be further broken down by sub-protocol.  Patients who are ongoing in the study at the time of an 
analysis will be censored at the date of the last contact before or on the date of the data cut-off for the analysis and 
patients who completed the study will be censored at study completion.  The standard errors (SEs) will be computed 
using the Greenwood’s formula, the CI for the median will be calculated according to Brookmeyer and Crowley 
(1982), and the CIs for the survival function estimates at above mentioned time points will be derived from the 
Kaplan-Meier estimates using the log-log transformation 
Number of patients included and excluded from each analysis set (including reason for exclusion) will be 
summarized overall and by treatment arm based on the FAS.  The control arm of a candidate agent (refer to Section 
4.5) will be further broken down by sub-protocol. 
Listings for randomization schemes/codes and disposition data will be provided separately. 
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9.1.1. 
DERIVATIONS 
• 
Time to discontinuation from study (days) = (Date of study discontinuation – Date of Study Day 1 [refer to 
Section 6.1]) + 1 
Date of study discontinuation will be captured on the Disposition page of the eCRF. 
Patients who are ongoing in the study at the time of an analysis will be censored at the date of the last contact before 
or on the date of the data cut-off for the analysis and patients who completed the study will be censored at study 
completion. 
9.2. PROTOCOL DEVIATIONS 
All protocol deviations (critical, major, and minor) will be recorded in the clinical trial management system (CTMS) 
protocol deviations log for the duration of the study (refer to the Protocol Deviations Management Plan for the 
definition of critical, major, and minor protocol deviations).  Site-level identified protocol deviations will be 
replicated for all patients ongoing in the study at the site at the time of the protocol deviation and presented in the 
summary outputs as patient-level protocol deviation. 
Number and percentage of patients with critical and major protocol deviations will be provided overall and by 
treatment arm based on the FAS for each category of protocol deviations specified in the Protocol Deviations 
Management Plan. The control arm of a candidate agent (refer to Section 4.5) will be further broken down by sub-
protocol. 
A listing of all protocol deviations (critical, major, and minor) will be provided. 
10. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
The following demographic and other baseline characteristics will be reported for this study: 
• 
Age (years) – in integers, calculated relative to date of consent: 
o 
As a continuous variable; 
o 
As a categorical variable (≥ 18 - ≤ 49, ≥ 50 - ≤ 64, ≥ 65 - ≤ 84, or ≥ 85); 
• 
Sex (male or female); 
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• 
Childbearing potential for female patients only (yes or no) and reasons if not of childbearing potential; 
• 
Race: 
o 
American Indian or Alaska Native, Asian, Black or African American, Native Hawaiian or Other 
Pacific Islanders, White, multiple, not reported, or unknown;  
o 
White, Black or African American, others, not reported, or unknown; 
• 
Ethnicity (Hispanic or Latino, not Hispanic or Latino, not reported, or unknown); 
• 
Country; 
• 
Region (if applicable, refer to Section 7.5); 
• 
Height (cm); 
• 
Weight (kg); 
• 
Body Mass Index (BMI) (kg/m2); 
Demographic and other baseline characteristics will be summarized overall and by treatment arm based on the FAS.  
The control arm of a candidate agent (refer to Section 4.5) will be further broken down by sub-protocol.  No 
statistical testing will be carried out for any demographic or other baseline characteristic. 
Demographic and other baseline characteristics data will be listed. 
10.1. DERIVATIONS 
BMI, in kg/m2, will be calculated as follows:  
• 
BMI (kg/ m2) = Weight (kg)/ [Height (m)2] 
11. DISEASE HISTORY 
The following disease history endpoints will be summarized overall and by treatment arm based on the FAS.  The 
control arm of a candidate agent (refer to Section 4.5) will be further broken down by sub-protocol.  
• 
Time since onset of first COVID-19 symptom(s) (days) – calculated relative to Study Day 1 (refer to Section 
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6.1) 
• 
Time since COVID-19 diagnosis (days) – calculated relative to Study Day 1; 
• 
Time since hospital admission (days) – calculated relative to Study Day 1; 
• 
Patients on supplemental oxygen at Study Day 1 (yes or no); 
• 
Type of supplemental oxygen only for patients receiving supplemental oxygen at Study Day 1; 
• 
Time since start of supplemental oxygen (days) - calculated relative to Study Day 1 only for patients on 
supplemental oxygen at Study Day 1; 
• 
Patients receiving ICU/high dependency unit (HDU)-level care at Study Day 1 (yes or no); 
• 
Time since start of ICU/HDU-level care (days) – calculated relative to Study Day 1 only for patients receiving 
ICU/HDU-level care at Study Day 1; 
• 
Patients on invasive mechanical ventilation at Study Day 1 (yes or no); 
• 
Type of invasive mechanical ventilation at Study Day 1 only for patients on invasive mechanical ventilation at 
Study Day 1; 
• 
Time since start of invasive mechanical ventilation (days) – calculated relative to Study Day 1 only for patients 
on invasive mechanical ventilation at Study Day 1; 
• 
Patients diagnosed with acute respiratory distress syndrome (ARDS; yes or no); 
• 
Time since ARDS diagnosis (days) – calculated related to Study Day 1 only for patients diagnosed with ARDS; 
• 
Patients with or without each of the following COVID-19 symptoms at screening.  For each symptom, patients 
with the symptom will be further broken down by severity (mild, moderate, severe, or unknown): 
o 
Cough; 
o 
Fever; 
o 
Myalgia; 
o 
Diarrhea; 
o 
Dyspnea; 
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o 
Fatigue/malaise; 
o 
Loss of appetite; 
o 
Loss of smell; 
o 
Loss of taste. 
• 
Baseline clinical severity score (2, 3, 4, or 5, as well as 2 or 3/4/5) as captured on the Ordinal Scale for Clinical 
Severity page of the eCRF; 
• 
NEWS2 total score at baseline; 
• 
Oxygen saturation (SpO2; %) at baseline; 
• 
Fraction of Inspired Oxygen (FiO2; %) at baseline.  
All disease history characteristics will be listed. 
11.1. DERIVATIONS 
Time since events, in days, will be calculated as follows: 
• 
Time since onset of first COVID-19 symptom(s) (days) = (Date of Study Day 1 [refer to Section 6.1] – Date of 
onset of first COVID-19 symptom[s]); date of onset of COVID-19 symptoms as captured on the Medical 
History page of the eCRF; 
• 
Time since COVID-19 diagnosis (days) = (Date of Study Day 1 - Date of COVID-19 diagnosis); date of 
COVID-19 diagnosis as captured on the Medical History page of the eCRF; 
• 
Time since hospital admission (days) = (Date of Study Day 1 – Date of hospital admission); where date of 
hospital admission will be the earliest date of hospital admission captured on the Hospitalization page of the 
eCRF; 
• 
Time since start of supplemental oxygen (days) = (Date of Study Day 1 – Date of start of supplemental oxygen) 
if patient is already on supplemental oxygen at Study Day 1; where the date of start of supplemental oxygen 
will be earliest date of start of supplemental oxygen as captured on the Supplemental Oxygen and Mechanical 
Ventilation page of the eCRF. That is, time since start of supplemental oxygen will not be computed for patients 
not on supplemental oxygen at Study Day 1; 
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• 
Time since start of ICU/HDU-level care (days) = (Date of Study Day 1 – Date of start of ICU/HDU-level care) 
if patient is already receiving ICU/HDU-level care at Study Day 1; where the date of start of ICU/HDU-level 
care will be the earliest date of start of ICU/HDU-level care captured on the Hospitalization page of the eCRF; 
That is, time since start of ICU/HDU-level care will not be computed for patients not receiving ICU/HDU-level 
care at Study Day 1; 
• 
Time since start of invasive mechanical ventilation (days) = (Date of Study Day 1 – Date of start of invasive 
mechanical ventilation) if patient is already on invasive mechanical ventilation at Study Day 1; where the date 
of start of invasive mechanical ventilation will be the earliest date of start of invasive mechanical ventilation 
captured on the Supplemental Oxygen and Mechanical Ventilation page of the eCRF. That is, time since start of 
invasive mechanical ventilation will not be computed for patients not on invasive mechanical ventilation at 
Study Day 1. 
• 
Time since ARDS diagnosis (days) = (Date of Study Day 1 – Date of ARDS diagnosis) if patient was diagnosed 
with ARDS at screening; where the date of start of ARDS diagnosis as captured on the Medical History of the 
eCRF. That is, time since ARDS will not be computed for patients not already diagnosed with ARDS at 
screening. 
12. MEDICAL HISTORY 
Medical history is defined as any medical conditions/diseases that started and stopped before screening as well as 
any medical conditions/diseases that started before screening AND were ongoing at the time of screening. 
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 23.1 or 
later and will be summarized by System Organ Class and PT overall and by treatment arm based on the FAS.  The 
control arm of a candidate agent (refer to Section 4.5) will be further broken down by sub-protocol.  A patient 
having more than one medical condition/disease within the same System Organ Class or PT will be counted only 
once for that System Organ Class or PT.  In the summary, System Organ Classes will be sorted in alphabetical order 
and within each System Organ Class, PTs will be sorted in decreasing order of total frequency. 
Additionally, for each of the following COVID-19 comorbidities, the number and percentage of patients, as captured 
on the Medical History page of the eCRF, will be reported overall and by treatment arm based on the FAS. The 
control arm of a candidate agent (refer to Section 4.5) will be further broken down by sub-protocol. 
• 
Any comorbidity, defined as having any of the comorbidities listed below; 
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• 
Obesity (refer to Sections 7.7 and 10.1); 
• 
Diabetes; 
• 
Cardiovascular disease; 
• 
Hypertension; 
• 
Chronic lung disease; 
• 
Chronic liver disease; 
• 
Kidney disease; 
• 
Immunosuppressive/immunodeficiency disorder. 
13. PRIOR AND CONCOMITANT MEDICATIONS 
All medications collected on the Concomitant Medications page of the eCRF will be classified as either: 
• 
Prior medications, defined as any medication that started and stopped prior to the date of Study Day 1 (refer to 
Section 6.1); 
or 
• 
Concomitant medications, defined as: 
o 
Any medication that started before the date of Study Day 1 AND ended on or after the date of Study 
Day 1, or were ongoing at that time; 
o 
Any medication that started on or after the date of Study Day 1. 
Partially or completely missing medication start and stop dates will be handled as described in Appendix 1. 
All medications will be coded using the World Health Organization (WHO) Drug Global dictionary, version 
September 2020 B3 or later. 
Concomitant medications will be summarized by Anatomical Therapeutic Class (ATC) level 2 and preferred drug 
name overall and by treatment arm based on the FAS. A patient having more than one medication within the same 
ATC level 2 or preferred drug name will be counted only once for that ATC level 2 or preferred drug name. Further, 
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for each sub-protocol, separate summaries will also be presented for patients randomized to the sub-protocol placebo 
plus SoC treatment group. 
Additionally, the number and percentages of patients receiving following medications of interest will be summarized 
overall and by treatment arm based on the FAS.  For each sub-protocol, summaries will also be presented for the 
subset of patients randomized to the Placebo to the candidate agent plus SoC treatment group of the sub-protocol. 
• 
Remdesivir use at baseline (yes or no) based on data collected on the Concomitant Medications page of the 
eCRF (i.e., medications that were being taken by a patient on the day the patient was randomized to a sub-
protocol); 
• 
Concomitant use of remdesivir at any time during the period of the analysis being performed  (yes or no; refer 
to Section 7.7); 
• 
Dexamethasone use at baseline (yes or no) based on data collected on the Concomitant Medications page of the 
eCRF (i.e., medications that were being taken by a patient on the day the patient was randomized to a sub-
protocol); 
• 
Concomitant use of dexamethasone at any time during the period of the analysis being performed (yes or no; 
refer to Section 7.7); 
• 
Steroid use at baseline (yes or no) based on data collected on the Concomitant Medications page of the eCRF 
(i.e., medications that were being taken by a patient on the day the patient was randomized to a sub-protocol); 
• 
Concomitant steroid use at any time during the period of the analysis being performed (yes or no; refer to 
Section 7.7). 
All medications (prior and concomitant) will be listed. 
14. EXPOSURE TO STUDY DRUG 
Each candidate agent included within the study will have a sub-protocol that will provide details of that treatment, 
including route and mode of administration, dose, dosage regimen, and duration of treatment. The derivations for 
study drug exposure as well as summaries and analyses of exposure are therefore not covered in this master protocol 
SAP but will be covered in the SAP for each sub-protocol. 
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15. COMPLIANCE WITH STUDY DRUG 
Similar to study drug exposure, derivations of compliance to study drug as well as summaries and analyses of study 
drug compliance, are not covered in this master protocol SAP, but will be covered in the SAP for each sub-protocol. 
16. EFFICACY ENDPOINTS 
Unless otherwise indicated, all efficacy summaries and figures will be presented by treatment arm and visit, when 
appropriate, based on the FAS.  Listings will be provided for all efficacy data. 
16.1. PRIMARY EFFICACY 
Unless otherwise indicated, all efficacy summaries and analyses will be presented based on the FAS. 
16.1.1. 
TIME TO CONFIRMED CLINICAL RECOVERY THROUGH DAY 29, WITHOUT RE-
HOSPITALIZATION THROUGH DAY 29 
The primary efficacy endpoint is the time to confirmed clinical recovery through Day 29, i.e., fit for discharge 
(defined by achieving a score of 6, 7, or 8 on the 8-point ordinal scale for clinical severity), without being re-
hospitalized through Day 29.   
It is to be noted that: 
• 
The re-hospitalization-free requirement does not apply to patients who achieved an ordinal scale score of 6 that 
were never discharged from the hospital before Day 29.  For such patients, the re-hospitalization-free 
requirement is superseded by not having a subsequent worsening on the ordinal scale score (i.e., a score < 6 on 
the ordinal scale for clinical severity) that would remain until Day 29; 
• 
Patients achieving a score of 7 on the ordinal scale for clinical severity discharged to hospice care will be 
considered as not fit for discharge in the analysis. 
The ordinal scale for clinical severity is as follows: 
1. Death; 
2. Hospitalized, on invasive mechanical ventilation or ECMO; 
3. Hospitalized, on non-invasive ventilation or high-flow oxygen devices; 
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4. Hospitalized, requiring supplemental oxygen; 
5. Hospitalized, not requiring supplemental oxygen, requiring ongoing medical care (COVID-19 related or 
otherwise); 
6. Hospitalized, not requiring supplemental oxygen, no longer requires ongoing medical care; 
7. Not hospitalized, limitation on activities and/or requiring home oxygen; 
8. Not hospitalized, no limitations on activities. 
Time to confirmed clinical recovery through Day 29, without re-hospitalization through Day 29, will be measured in 
days from the date of Study Day 1 (refer to Section 6.1):  
• 
Time to confirmed clinical recovery through Day 29, without re-hospitalization through Day 29 (days) = 
(Date of event – Date of Study Day) + 1 
Refer to Section 6.1 for the definition of Study Day 1. 
The following algorithm will be followed to determine if a patient met the event (i.e., confirmed clinical recovery 
through Day 29, without rehospitalization through Day 29) or should be censored: 
1. First, the patient’s alive status by Day 29 will be verified as per data collected on the Death Details page of 
the eCRF.  If the patient died before or on Day 29, he/she will be censored at Day 29.  If the patient has not 
died by Day 29, then go to step 2; 
2. Second, the patient’s study discontinuation status by Day 29 will be verified as per data collected on the 
Disposition page of the eCRF.  If the patient discontinued from the study before or on Day 29, he/she will 
be censored at date of discontinuation from study.  If the patient was still ongoing in the study at Day 29, 
then go to step 3; 
3. Last, it will be verified if a patient had a score of 6, 7 or 8 on the 8-point ordinal scale (as captured on the 
Ordinal Scale for Clinical Severity page of the eCRF) before or on Day 29: 
a. 
For patients who had a score of 6 on the 8-point ordinal scale and were never discharged from the 
hospital before Day 29, it will be checked if patient worsened on the 8-point ordinal scale (i.e., had 
a score < 6) before or on Day 29: 
i. If so (i.e., patient worsened) and patient never subsequently re-reached a score of 6 
before or on Day 29, the patient will be censored at Day 29; 
ii. If so (i.e., patient worsened) but patient subsequently re-reached a score of 6 before or on 
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Day 29, the patient will be considered as having the event and the date of the event will 
be the earliest date on which the patient re-reached a score of 6; 
iii. If not (i.e., patient did not worsen), the patient will be considered as having the event and 
the date of the event will be the earliest date on which the patient had a score of 6 before 
or on Day 29; 
b. For patients who had a score of 7 on the 8-point ordinal scale, it will first be verified if patient was 
discharged to hospice care as per data captured on the Hospitalization page of the eCRF. 
i. If so (i.e., patient was discharged to hospice care), the patient will be considered as not fit 
for discharge and will be censored at Day 29; 
ii. If not (i.e., patient was discharged, but not to hospice care), then go to step c. 
c. 
For patients who had a score of 7 (discharged, but not to hospice care) or 8 on the 8-point ordinal 
scale, it will be verified if patient was re-hospitalized before or on Day 29 as per data captured on 
the Hospitalization page of the eCRF.  To do so, it will be checked if a patient had at least one 
record where the hospitalization start date is after the earliest date on which the patient had a score 
of 7 or 8 but before or on Day 29. 
i. If so (i.e., patient was re-hospitalized), the patient will be censored at Day 29; 
ii. If not (i.e., patient was not re-hospitalized), the patient will be considered as having the 
event and the date of the event will be the earliest date on which patient had a score ≥ 6 
before or on Day 29; 
d. Patients who never had a score of 6, 7 or 8 on the 8-point ordinal scale, did not discontinue from 
the study or died before or on Day 29 will be censored at Day 29 
 
Refer to Figure 2 for a schematic of the primary endpoint determination of date of event and censoring. 
 
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Figure 2 
Schematic of Determination of Primary Efficacy Endpoint Date of 
Event or Censoring 
 
* For patients who had a score of 6, worsened, re-reached a score of 6, and were never discharged from the hospital before or on Day 29, earliest 
date on which the patient re-reached a score of 6. 
 
Yes 
Yes 
No 
No 
Yes 
No 
Yes 
No 
 
 
 
 
Reached a score of 6 and did not worsen, 
reached a score of 6, worsened, but re-reached a score of 6 
or reached a score of 7 (discharged, but not to hospice 
care) or 8 and was not re-hospitalized before or on Day 29? 
Event on the 
Earliest 
Score ≥ 6* 
Reached a score of 6, worsened, and never re-reached a score of 6, 
reached a score of 7 and was discharged to hospice care or 
reached a score of 7 (discharged but not to hospice care) or 8 and was 
re-hospitalized before or on Day 29? 
Died before 
or on Day 
29? 
Discontinued from 
study before or on 
Day 29? 
Censored at 
Discontinuation 
Censored at 
Day 29 
Censored at 
Day 29 
Censored at 
Day 29 
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16.1.2. 
MISSING DATA IMPUTATION METHOD FOR PRIMARY EFFICACY ENDPOINT 
For the time to confirmed clinical recovery (days) through Day 29, without re-hospitalization through Day 29, 
missing ordinal scale for clinical severity scores and missing hospitalization data will not be imputed before 
applying the censoring rules for the main analysis of the primary efficacy endpoint (refer to Section 16.1.1). 
16.1.3. 
MAIN ANALYSIS OF PRIMARY EFFICACY ENDPOINT 
For the time to confirmed clinical recovery through Day 29, without re-hospitalization through Day 29, as defined in 
Section 16.1.1, the number and percentage of patients with and without the event will be presented by randomized 
treatment arm.  For patients who did not meet the event, the main reason for censoring (refer to Section 16.1.1) will 
be summarized similarly. 
Kaplan-Meier curves (product-limit estimate) will be provided by treatment arm for the time to confirmed clinical 
recovery though Day 29, without re-hospitalization through Day 29. Kaplan-Meier estimate of the time to confirmed 
clinical recovery through Day 29, without re-hospitalization through Day 29, in days, will be provided at the 25th, 
50th (median), and 75th percentiles time along with their corresponding two-sided 95% CIs.  The estimates of the SEs 
will be computed using the Greenwood’s formula, the CI for the median will be calculated according to Brookmeyer 
and Crowley (1982), and the CIs for the survival function estimates at above mentioned time points will be derived 
from the Kaplan-Meier estimates using the log-log transformation.  Kaplan-Meier estimates of the probability of 
having the event will also be provided at Day 29 along with the number of patients with the event and the number of 
patients at risk at that time.   
The difference between a candidate agent plus SoC arm and its control arm will be compared using a stratified log-
rank test. The stratification factor will be the baseline clinical severity of 2 on the 8-point ordinal scale (yes or no) 
stratification variable, remdesivir use at baseline (yes or no) stratification variable, both as captured on the IWRS, 
and country (region; refer to Section 7.5).  The p-value associated with the stratified log-rank test statistic will be 
provided and compared at the two-sided 0.05 alpha level at the time of the primary analysis of a candidate agent.  
The p-value will also be compared to the specified boundaries at the IAs for futility in order to serve as guidance for 
the IDMC to make recommendations based on the totality of available information at the time of the IAs (refer to 
Section 16.5). 
Additionally, a Cox proportional hazards model will be performed including the baseline clinical severity of 2 on the 
8-point ordinal scale (yes or no) stratification variable, remdesivir use at baseline (yes or no) stratification variable, 
both as captured on the IWRS, country (region), and treatment arm as factors.  Ties will be handled using the exact 
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method.  The HR (candidate agent plus SoC vs. placebo plus SoC) and corresponding two-sided 95% CI will be 
provided. 
For the methods to control the overall alpha level of a sub-protocol at the two-sided 0.05 level, refer to Section 7.4. 
16.1.4. 
SENSITIVITY ANALYSES FOR PRIMARY EFFICACY ENDPOINT 
The following sensitivity analyses to the main analysis of the primary efficacy endpoint will be performed: 
• 
Sensitivity to stratification variables: The main analysis to the primary efficacy endpoint (refer to Section 
16.1.3) may be repeated but stratification variables as derived based on the eCRF data (refer to Section 7.6) will 
be included in the model instead of the stratification variables as captured on the IWRS.  This analysis will be 
performed only if at least 10% of patients are mis-stratified at the time of randomization for a stratification 
variable; 
• 
Sensitivity to censoring assumptions #1: The main analysis of the primary efficacy endpoint will be repeated 
but patients who discontinued early from the study before or on Day 29 will be censored at Day 29; 
• 
Sensitivity to censoring assumptions #2: The main analysis of the primary efficacy endpoint will be repeated 
but, for patients who discontinued early from the study before or on Day 29, the last patients’ known event 
status will be carried forward to Day 29 before applying the censoring rules for the main analysis of the primary 
efficacy endpoint (refer to Section 16.1.1). 
• 
Sensitivity to censoring assumptions #3: The primary analysis assumes that censoring is at random (CAR) for 
patients who discontinued early from the study before or on Day 29 (refer to Section 16.1.3).  For this 
sensitivity analysis, the time to event (refer to Section 16.1.1) will be imputed only for these patients using a 
model that assumes censoring not at random (CNAR). The model will assume that these patients would have 
hazard following discontinuation from study that is reduced by some factor delta () compared with hazard of 
remaining patients in their group who have similar key baseline characteristics (Lipkovich et al, 2016), where 
reduced hazard rate indicates a longer time to event (confirmed clinical recovery through Day 29, without re-
hospitalization through Day 29).  In order to stress-test the assumption of CAR with an assumption that is less 
favorable to a candidate agent plus SoC treatment arm, a  < 1 will be used for the candidate agent plus SoC 
treatment arm while a  = 1 will be used for the concurrent shared placebo plus SoC control arm as  = 1, which 
corresponds to the CAR assumption.   
Multiple imputation method using covariates-adjusted and delta-adjusted piecewise exponential survival model 
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as suggested in Lipkovich et al, 2016, will be used as the imputation method separately for each treatment arm. 
For each sub-protocol, the prior distribution and pieces used in this covariates-adjusted and delta-adjusted 
piecewise exponential survival model will be determined in a blinded fashion prior to the DBL for a sub-
protocol Primary Analysis. The model will include the baseline clinical severity of 2 on the 8-point ordinal scale 
stratification variable (yes or no), remdesivir use at baseline stratification variable (yes or no), both as captured 
on the IWRS, and country (region; refer to Section 7.5) as covariates.  
If the imputed event time exceeds Day 29, the patient will be censored at Day 29.  Multiple imputation (MI) 
method will be used where 100 imputed datasets will be generated using above model and a seed of 2102. 
Each of the multiply-imputed datasets will then be analyzed using the same stratified log-rank test and Cox 
regression model as for the main analysis to the primary efficacy endpoint (refer to Section 16.1.3).  The 
survival distribution quartiles (25th, 50th [median], and 75th percentiles), log-rank statistics, and hazard ratios 
will be combined as suggested in Moscovici and Ratitch, 2017.  The combined statistics and p-value associated 
with the combined log-rank statistic will be presented.   
A tipping point analysis will be implemented where the above described MI will first be performed using a  = 
0.95 for the candidate agent plus SoC treatment arm and then repeated but decreasing the -adjustment applied 
to the candidate agent plus SoC treatment arm gradually by reduction of 0.05 (i.e., 0.95, 0.90, 0.85, etc.) until 
the study conclusion is not significant anymore.  For each of these analyses, the  used for the concurrent shared 
placebo plus SoC control arm will always remain 1. The  when the study conclusion becomes non-significant 
will be referred to as the tipping point. 
Additional sensitivity analyses might be specified in the sub-protocol SAPs. 
16.1.5. 
SUPPLEMENTARY ANALYSES FOR PRIMARY EFFICACY ENDPOINT 
The following supplementary analyses to the main analysis of the primary efficacy endpoint will be performed: 
• 
The main analysis to the primary efficacy endpoint will be repeated (refer to Section 16.1.3) but without 
country (region; refer to Section 7.5) included as stratification variable; 
• 
The main analysis of the primary efficacy endpoint will be repeated but without the requirement for follow-up 
confirmation.  That is, for this analysis, patients will be considered as having met the event as soon as they 
reach a score of 6, 7 or 8 on the 8-point ordinal scale, regardless of if they subsequently worsened or were re-
hospitalized before or on Day 29, exception of patients with a score of 7 discharged to hospice care who will 
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still be considered as not having the event;  
• 
The main analysis of the primary efficacy endpoint will be repeated for each subgroup defined in Section 7.7. 
For subgroups corresponding to one of the factors included in the main model, the corresponding factor will be 
excluded from the model.  For example, the remdesivir use at baseline (yes/no) stratification variable as 
captured on the IWRS will not be included in the model for the analysis of the patients who received remdesivir 
at randomization as captured on the IWRS subgroup, and analysis of the patients who did not receive remdesivir 
at randomization as captured on the IWRS subgroup. 
16.2. SECONDARY EFFICACY 
16.2.1. 
SECONDARY EFFICACY ENDPOINTS 
16.2.1.1. 
Incidence of Patients with Oxygen-Free Recovery at Day 29 
The first key secondary efficacy endpoint is the incidence of patients with oxygen-free recovery at Day 29, defined 
as the proportion of patients who were alive, discharged, and not receiving supplemental oxygen at Day 29. 
1. The alive status of a patient at Day 29 (yes or no) will be determined as follows based on data captured on 
the Death Details page of the eCRF: patients who died before or on Day 29 will be considered as not being 
alive at Day 29 while patients without any data captured on this page of the eCRF before or on Day 29 but 
with some data captured on any other page of the eCRF on or after Day 29 will be considered to be alive at 
Day 29; 
2. The patient’s discharge status (yes or no) at Day 29 will be established as follows based on data collected 
on the Ordinal Scale for Clinical Severity page of the eCRF: a patient will be considered as being 
discharged at Day 29 if 1) their ordinal scale score is 7 at Day 29 and patient was not discharged to hospice 
care or 2) their ordinal scale score is 8 at Day 29.  Discharge to hospice care status will be verified based on 
data collected on the Hospitalization page of the eCRF.  To do so, the outcome of the hospitalization record 
with the latest stop date before or on Day 29 will be examined.  The hospitalization outcome of that record 
should not be ‘Home: Hospice Care’ or ‘Hospice Medical Facility’ for a patient with an ordinal scale score 
of 7 at Day 29 to be considered as discharged at that time.  Patients who discontinued early from study 
before Day 29 will be considered as having a missing discharged status at Day 29; 
3. The patient’s oxygen-free status (yes or no) at Day 29 will be determined as follows: data collected on the 
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Supplemental Oxygen and Mechanical Ventilation page of the eCRF will be examined to verify if the 
patient has a record where the start date of supplemental oxygen/mechanical ventilation is before or on Day 
29 and stop date of supplemental oxygen/mechanical ventilation is after Day 29* or is ongoing at Day 29.  
Patients without such record will be considered as being oxygen-free at Day 29 while patient with such 
record will be considered as being not oxygen-free at Day 29.  Patients who discontinued early from study 
before Day 29 will be considered as having a missing oxygen-free status at Day 29. 
* That is, patients who stopped receiving supplemental oxygen/mechanical ventilation on Day 29 will be 
considered as being oxygen-free at Day 29. 
All three criteria (alive, discharged, and not receiving supplemental oxygen at Day 29) must be fulfilled for a patient 
to be considered as having an oxygen-free recovery at Day 29.  That is, as soon as a patient does not fulfill at least 
one of the three criteria, he/she will be considered as not having an oxygen-free recovery at Day 29, regardless of 
the status of the other criteria.  Should the status of one of the three criteria be missing while the two other criteria 
are fulfilled or missing, patients’ oxygen-free recovery at Day 29 will be considered as missing. 
Scenario 
Alive at Day 29 
(as per step 1) 
Discharge at Day 29 
(as per step 2) 
Oxygen-free at Day 29 
(as per step 3) 
Oxygen-free Recovery 
at Day 29 
1 
Alive 
Yes 
Yes 
Yes 
2 
Dead 
Yes, No, Missing 
Yes, No, Missing 
No 
3 
Alive, Dead, Missing 
No 
Yes, No, Missing 
No 
4 
Alive, Dead, Missing 
Yes, No, Missing 
No 
No 
5 
Missing 
Yes, Missing 
Yes, Missing 
Missing 
6 
Alive, Missing 
Missing 
Yes, Missing 
Missing 
7 
Alive, Missing 
Yes, Missing 
Missing 
Missing 
Refer to Section 16.2.2.1 for handling of missing oxygen-free recovery at Day 29 status. 
16.2.1.2. 
Incidence of Patients with ≥ 2-point Improvement from Baseline or Fit for 
Discharge on the Ordinal Scale at Day 29 
The second key secondary efficacy endpoint is the incidence of patients with ≥ 2-point improvement from baseline 
or fit for discharge on the 8-point ordinal scale for clinical severity (refer to Section 16.1.1) at Day 29, where fit for 
discharge is defined as having a score of 6, 7 or 8 on the ordinal scale for clinical severity.  Patients with an ordinal 
scale score of 7 must not have been discharged to hospice care to be considered as fit for discharge. 
By endpoint definition, patients with an ordinal scale score of 6, 7 (but not discharged to hospice care) or 8 at Day 
29 will be considered as having met the event (yes) at Day 29, regardless of their change from baseline in ordinal 
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scale score, while patients with a score of 7 discharged to hospice care will be considered as not having met the 
event, also regardless of their change from baseline in ordinal scale score.  For patients hospitalized and not 
considered as fit for discharge at Day 29 i.e., patients with an ordinal scale score < 6, the ‘≥ 2-point improvement 
from baseline’ requirement (yes or no) will be established based on the patient’s change from baseline in the ordinal 
scale at Day 29, where change from baseline will be computed as defined in Section 6.5. 
Refer to Section 16.2.2.1 for handling of missing ≥ 2-point improvement from baseline or fit for discharge on the 8-
point ordinal scale for clinical severity status. 
16.2.1.3. 
Incidence of All-Cause Mortality through Day 29 
The third key secondary efficacy endpoint is the incidence of all-cause mortality through Day 29, defined as the 
proportion of patients having died due to any cause before or on Day 29. Patients’ alive/death status by Day 29 will 
be determined based on data captured on the Death Details page of the eCRF.  If a patient does not have any data 
captured on the Death Details page of the eCRF by Day 29 but his/her ‘subject status’ captured on the Contact page 
of the eCRF at Day 29 is alive or he/she had some data captured on any other page of the eCRF on or after Day 29, 
he/she will be considered alive on Day 29. 
Refer to Section 16.2.2.1 for handling of missing alive/death through Day 29 status. 
16.2.1.4. 
Distribution of Patients across the Categories of the 8-point Ordinal Scale for 
Clinical Severity at Days 8, 15, and 29 
An ‘other secondary efficacy endpoint’ is the distribution of patients across the categories of the 8-point ordinal 
scale for clinical severity at Days 8, 15, and 29 i.e., the proportion of patients in each category of the 8-point ordinal 
scale for clinical severity at Days 8, 15, and 29.  It is to be noted that patients with a score of 7 discharged to hospice 
care will be pooled with patients with a score of 1 (death) for this ‘other secondary efficacy endpoint’. 
Refer to Section 16.1.1 for the description of the 8-point ordinal scale and to Section 16.2.2.1 for handling of 
missing ordinal scale scores. 
16.2.1.5. 
Worst Post-Baseline Score on 8-point Ordinal Scale from Baseline to Day 29 
An ‘other secondary efficacy endpoint’ is the worst post-baseline score (lower scores are worse) through Day 29 in 
the 8-point ordinal scale (refer to Section 16.1.1), derived from all scores recorded after baseline up to and including 
Day 29.  It is to be noted that patients with a score of 7 discharged to hospice care will be considered as having a 
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score of 1 (death) instead of a score of 7 for this ‘other secondary efficacy endpoint. 
Refer to Section 16.2.2.2 for handling of missing ordinal scale scores. 
16.2.1.6. 
Number of ICU Days from Day 1 through Day 29 
An ‘other secondary efficacy endpoint’ is the number of ICU days from Day 1 through Day 29.  This endpoint will 
be considered as an ordinal endpoint. 
For each patient, the number of ICU days from Day 1 through Day 29 will be derived based on the sum of the 
duration of any episodes of ICU admission between Day 1 and Day 29, inclusively, for patients who were alive on 
Day 29. Episodes of ICU admission will be identified based on data recorded on the Hospitalization page of the 
eCRF, where Hospitalization Status is recorded as ICU/HDU.  For patients who were discharged to hospice care or 
died before or on Day 29, the number of ICU days from Day 1 through Day 29 will be set to 30 (worst possible 
scenario). 
The duration, in days, of an episode of ICU admission will be derived as follows: 
• 
Duration of an episode of ICU admission (days) = (Date of ICU discharge – Date of ICU admission) + 1 
If the start date of an episode of ICU admission is prior to Day 1, it will be set to the date of Study Day 1 (refer to 
Section 6.1) when deriving ICU duration for that episode. 
If an episode of ICU admission is ongoing at Day 29 or at the time of analysis, the stop date of the admission will be 
set to the minimum of: 
• 
The start date of any subsequent ICU admission; 
• 
Day 29; 
• 
The data cut-off date for the analysis. 
If there are any overlapping dates of ICU admission, a Day will only be counted once when deriving the overall 
number of ICU days for a patient.  For example, if a patient has a record where the start and stop Study Days of the 
ICU/HDU admission are Day 3 and Day 10, respectively, and another record where the start and stop Study Days of 
ICU/HDU admission are Day 9 and Day 12, respectively, Days 9 and 10 will be counted only once in the overall 
number of ICU days for that patient. 
Refer to Section 16.2.2.2 for handling of missing number of ICU days from Day 1 through Day 29. 
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16.2.1.7. 
Number of Invasive Mechanical Ventilator Days from Day 1 through Day 29 
For each patient, the ‘other secondary efficacy endpoint’ of the number of invasive mechanical ventilator days from 
Day 1 through Day 29, inclusively, will be considered as an ordinal endpoint and derived similarly to the number of 
ICU days from Day 1 through Day 29 (refer to Section 16.2.1.6) but using the data collected on the Supplemental 
Oxygen and Mechanical Ventilation page of the eCRF where Type of supplemental oxygen is recorded as Invasive 
Mechanical Ventilation. 
Refer to Section 16.2.2.2 for handling of missing number of invasive mechanical ventilation days from Day 1 
through Day 29. 
16.2.1.8. 
Incidence of Patients with Clinical Recovery by Days 8, 15, and 29 
An ‘other secondary efficacy endpoint’ is the incidence of patients with clinical recovery at Days 8, 15, and 29, 
defined as the proportion of patients being fit for discharge (i.e., patients achieving a score of 6, 7, or 8 on the 8-
point ordinal scale for clinical severity; refer to Section 16.1.1) at Days 8, 15, and 29, respectively, as per data 
recorded on the Ordinal Scale for Clinical Severity page of the eCRF.  It is to be noted that patients with a score of 7 
discharged to hospice care will not be considered as being fit for discharge for this ‘other secondary efficacy 
endpoint’. 
Refer to Section 16.2.2.1 for handling of missing clinical recovery status by Days 8, 15, and 29. 
16.2.1.9. 
Incidence of Patients with Sustained Clinical Recovery as Confirmed by Day 60 
Follow-up 
An ‘other secondary efficacy endpoint’ is the incidence of patients with sustained clinical recovery as confirmed by 
Day 60 follow-up, defined as the proportion of patients considered as being fit for discharge (i.e., achieving a score 
of 6, 7, or 8 on the 8-point ordinal scale for clinical severity) through Day 29, without re-hospitalization by Day 60 
(refer to Section 16.1.1), as per the Ordinal Scale for Clinical Severity and Hospitalization pages of the eCRF.  It is 
to be noted that patients with a score of 7 discharged to hospice care before or on Day 29 will not be considered as 
being fit for discharge for this ‘other secondary efficacy endpoint’. 
Similarly to the primary efficacy endpoint, patients achieving a score of 6 on the ordinal scale for clinical severity 
before or on Day 29 will be considered as having sustained clinical recovery if they have no worsening of their 
ordinal scale score by Day 60 (i.e., a score < 6 on the ordinal scale for clinical severity) or were discharged from the 
hospital after Day 29 and were not re-hospitalized by Day 60. 
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Refer to Section 16.2.2.1 for handling of missing sustained clinical recovery as confirmed by Day 60 status. 
16.2.2. 
MISSING DATA IMPUTATION METHOD FOR SECONDARY EFFICACY ENDPOINTS 
16.2.2.1. 
Binary Endpoints 
For the incidence of oxygen-free recovery at Day 29 endpoint, the algorithm defined in Section 16.2.1.1 will first be 
applied.  Then, patients with a missing oxygen-free recovery status at Day 29 will considered as not having met the 
event for this key secondary efficacy endpoint. 
For the incidence of patients with ≥ 2-point improvement from baseline or fit for discharge on the ordinal scale at 
Day 29 endpoint (refer to Section 16.2.1.2), patients with a missing ordinal scale score at Day 29 due to patient’s 
death, discontinuation from study before or on Day 29 or for any other reason (with the following exception) will be 
considered as not having met the event at Day 29 for that key secondary endpoint.  The only exception is for patients 
with a missing ordinal scale score at Day 29 for which the latest non-missing ordinal scale score before Day 29 was 
7 (but not discharge to hospice care) or 8.  These patients will be assumed to be fit for discharge at Day 29 and so, as 
having met the event. 
For the incidence of all-cause mortality through Day 29 endpoint (refer to Section 16.2.1.3), patients with an 
unknown alive/death status at Day 29 due to discontinuation from study for a reason other than death or missing data 
will be considered as alive in the analysis, exception of patients for who the last-missing ordinal scale score was 7 
and that have been discharged to hospice care before discontinuing from study before Day 29.  These patients will 
be considered as dead at Day 29 for the main analysis of this key secondary efficacy endpoint. 
For the clinical recovery by Day 8 endpoint (refer to Section 16.2.1.8), any patient who died before or on Day 8, 
discontinued from study before or on Day 8 or with missing clinical recovery status at Day 8 will be considered as 
not having clinical recovery by Day 8.  Missing clinical recovery by Days 15 and 29 will be handled similarly. 
For the sustained clinical recovery as confirmed by Day 60 follow-up endpoint (refer to Section 16.2.1.9), any 
patient who died before or on Day 60, discontinued study before Day 60 or with a missing 8-point ordinal scale 
score at Day 60 will be counted as not having sustained clinical recovery. 
16.2.2.2. 
Ordinal Endpoints 
Missing ordinal scale scores will be imputed as follows for the distribution of patients across the categories of the 8-
point ordinal scale for clinical severity at Day 8 endpoints (refer to Section 16.2.1.4):  
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• 
Patients who died prior to Day 8 will have a score of 1 used for Day 8; 
• 
For all other occurrences of patient with missing ordinal score at Day 8 (e.g., patients who discontinued from 
the study before Day 8, etc.), the last non-missing post-baseline ordinal scale score before Day 8 (included data 
collected at unscheduled post-baseline visits) will be used to impute the missing ordinal scale score at Day 8 
exception of patients for who the last non-missing post-baseline ordinal scale score before Day 8 is 7 that were 
discharged to hospice care. For these patients, the missing ordinal scale score at Day 8 will be imputed to 1. 
Missing ordinal scale score at Days 15 and 29 will be imputed similarly. 
For the worst post-baseline score on the 8-point ordinal scale from baseline to Day 29 endpoint(refer to Section 
16.2.1.5), patients who have died prior to Day 29 will have their worst post-baseline ordinal scale score from Day 1 
to Day 29 set to a score of 1.  For patients who are alive at Day 29, no imputation of missing post-baseline ordinal 
scale scores will be performed.  The worst post-baseline ordinal scale score will be identifying among the non-
missing post-baseline ordinal scale scores (including data collected at unscheduled post-baseline visits). 
For the number of ICU days and number of invasive mechanical ventilation days endpoints (refer to Sections 
16.2.1.6 and 16.2.1.7, respectively), missing data will not be imputed. 
16.2.3. 
MAIN ANALYSIS OF SECONDARY EFFICACY ENDPOINTS 
Refer to Section 7.4 for more information about the hierarchical testing procedure that will be used to test the three 
key secondary hypotheses.  Only nominal p-values will be provided for the non-key secondary endpoints. 
16.2.3.1. 
Binary Endpoints 
For the incidence of patients with oxygen-free recovery at Day 29 (refer to Section 16.2.1.1), incidence of patients 
with ≥ 2-point improvement from baseline or fit for discharge on the ordinal scale at Day 29 (refer to Section 
16.2.1.2), incidence of all-cause mortality through Day 29 (refer to Section 16.2.1.3), incidence of patients with 
clinical recovery at Days 8, 15 and 29 (refer to Section 16.2.1.8), and incidence of patients with sustained clinical 
recovery as confirmed by Day 60 follow-up (refer to Section 16.2.1.9), the number and percentage of patients with 
and without the event will be provided by treatment arm.  For the incidence of all-cause mortality, primary reason of 
death will also be summarized by treatment arm. 
For each of these endpoints, a logistic regression will be performed to test the difference between a candidate agent 
plus SoC and placebo plus SoC treatment arms, including the baseline clinical severity of 2 on the 8-point ordinal 
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scale for clinical severity (yes or no) stratification variable, remdesivir use at baseline (yes or no) stratification 
variable, both as captured on the IWRS, country (region; refer to Section 7.5), and treatment arm as factors. The 
estimate of the relative risk (risk difference) between the two treatment arms, the corresponding two-sided 95% 
Wald CI, and the p-value obtained from the logistic regression model will be provided. 
The odds ratio (of candidate agent plus SoC vs. placebo plus SoC) for having the event at the specified Day and its 
two-sided 95% CI will also be presented. 
16.2.3.2. 
Ordinal Endpoints 
For the incidence of patients in each category of the 8-point ordinal scale for clinical severity at Days 8, 15, and 29 
endpoints (refer to Section 16.2.1.4), the number and percentage of patients in each ordinal scale category will be 
provided at each specified Day for each treatment arm and will be analyzed using a proportional odds model, 
including the baseline clinical severity of 2 on the 8-point ordinal scale for clinical severity (yes or no) stratification 
variable, remdesivir use at baseline (yes or no) stratification variable, both as captured on the IWRS, country 
(region; refer to Section 7.5), and treatment arm as factors. 
The odds ratio (candidate agent plus SoC vs. placebo plus SoC) of having a higher score than any given category k 
of the ordinal scale at Days 8, 15, and 29, their two-sided 95% CI, and associated p-value will be presented for each 
specified Day, where it is assumed that the odds ratio does not differ depending upon k. 
The worst post-baseline score on the 8-point ordinal scale for clinical severity from randomization to Day 29 (refer 
to Section 16.2.1.5) and each “number of days” endpoint (refer to Sections 16.2.1.6 and 16.2.1.7) will be 
summarized and analyzed similarly. 
Shift tables from baseline to each post-baseline day up to Day 29 as well as to the worst post-baseline score will also 
be provided for the 8-point ordinal scale for clinical severity. 
16.2.4. 
SENSITIVITY ANALYSES FOR SECONDARY EFFICACY ENDPOINTS 
The following sensitivity analyses to the main analysis of each key secondary efficacy endpoint will be performed.  
No sensitivity analyses will be performed for the non-key secondary efficacy endpoints. 
• 
Sensitivity to stratification variables: The main analysis of each key secondary efficacy endpoint will be 
repeated but the stratification variables as derived based on the eCRF data (refer to Section 7.6) will be included 
in the model instead of the stratification variables as captured on the IWRS if at least 10% of patients are mis-
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stratified at the time of randomization for a stratification variable. 
• 
Sensitivity analysis to missing data assumption #1: 
o 
For the incidence of patients with oxygen-free recovery at Day 29 (refer to Section 16.2.1.1), a 
multiple imputation approach will be applied to impute the missing oxygen-free recovery status (yes or 
no) at Day 29 for subjects who discontinued from study before or on Day 29 using a logistic regression 
including effects for the treatment arm, baseline clinical severity of 2 on the 8-point ordinal scale for 
clinical severity stratification variable (yes or no), remdesivir use at baseline stratification variable (yes 
or no), both as captured on the IWRS, and country (or region; refer to Section 7.5).  One hundred (100) 
imputed datasets will be generated using a seed of 2504. 
Each imputed dataset will then be analyzed using the same model as for the main analysis of this key 
secondary efficacy endpoint (refer to Section 16.2.3.1). 
The relative risks and parameter estimates for the effects of the logistic regression model and their SEs 
will then be combined using the Rubin’s rule to obtain a combined estimate of the treatment arm effect 
and its SE, and the associated p-value will be provided.  The relative risks and odds ratios will first be 
log transformed and then combined to obtain a combined relative risk and combined odds ratio, and 
their associated 95% CI.  The combined relative risk and combined odds ratio, and associated 95% CI, 
will be back-transformed before being displayed; 
o 
For the incidence of patients with ≥ 2-point improvement from baseline or fit for discharge on the 
ordinal scale at Day 29 (refer to Section 16.2.1.2), the same sensitivity analysis using multiple 
imputation as described above as for the key secondary efficacy endpoint of incidence of patients with 
oxygen-free recovery at Day 29 will be performed for this key secondary efficacy endpoint, but using a 
seed of 1228 ; 
o 
For the incidence of all-cause mortality through Day 29 (refer to Section 16.2.1.3), the same sensitivity 
analysis using multiple imputation as described above  as for the key secondary efficacy endpoint  of 
incidence of patients with oxygen-free recovery at Day 29 will be performed for this key secondary 
efficacy endpoint, but using a seed of 2007.  
• 
Sensitivity analysis to missing data assumption #2:  
o 
For the incidence of all-cause mortality through Day 29, a tipping point analysis will be performed. For 
patients who discontinued early from the study, all possible combinations of the number of patients 
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dead or alive at Day 29 will be considered and the main analysis of this key secondary efficacy 
endpoint will be repeated for each combination. 
A dot plot will be produced with number of patients with unknown death status at Day 29 imputed to 
death for the shared placebo plus SoC treatment arm reported on the x-axis and number of patients 
with unknown death status at Day 29 imputed to death for the candidate agent plus SoC treatment arm 
reported on the y-axis, and distinguishing between combination that results in statistically significant 
treatment effect (a dot is displayed for the combination) vs. not statistically significant treatment effect 
(no dot is displayed for the combination).  The clinical plausibility of the combinations on the 
boundary will be discussed in the clinical study report (CSR) to evaluate robustness of study 
conclusions to missing data.  
16.2.5. 
SUPPLEMENTARY ANALYSES FOR SECONDARY EFFICACY ENDPOINTS 
The main analysis of each key secondary efficacy endpoint will be repeated for each subgroup defined in Section 
7.7.  For subgroups corresponding to one of the factors included in the main model, the corresponding factor will be 
excluded from the model.  For example, the remdesivir use at baseline (yes/no) stratification variable, as captured on 
the IWRS, will not be included in the analysis of the patients who received remdesivir at randomization subgroup, as 
captured on the IWRS, and analysis of the patients who did not receive remdesivir at randomization subgroup, as 
captured on the IWRS. 
The following supplementary analyses will also be performed for the incidence to all-cause mortality key secondary 
efficacy endpoint:  
• 
For the incidence of all-cause mortality through Day 29, the time to all-cause death, in days, will be derived as 
follows: 
o 
Time to all-cause mortality (days) = 
(Date of all-cause death/Date of censoring - Date of Study Day 1 [refer to Section 6.1]) + 1. 
The date of death will be taken from data captured on the Death Details page of the eCRF. 
For patients who were alive on Day 29, time to all cause-mortality will be censored at Day 29. For 
patients with an unknown alive status at the time of the analysis due to missing data, time to all-cause 
mortality will be censored at the latest date on which the patient was known to be alive before or on the 
data cut-off date of the analysis.  The last date the patient was known to be alive will be the latest date 
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collected on any page of the eCRF. For patients who discontinued from the study before the time of the 
analysis, time to all-cause mortality will be censored at the date of study discontinuation, as captured 
on the Disposition page of the eCRF. 
Number and percentage of patients with and without the event will be presented by randomized 
treatment arm.  For patients who did not meet the event, the main reason for censoring will be 
summarized similarly. 
The incidence of all-cause mortality through Day 29 along with its two-sided 95% CI by treatment arm 
will then be estimated using Kaplan-Meier survival curves of the time to all-cause mortality.  Kaplan-
Meier survival curves by treatment arm will also be provided. 
The 25th percentile, 50th percentile (median), and 75th percentile of time to all-cause mortality (days) 
with the corresponding two-sided 95% CIs based on the Kaplan-Meier survival curves (refer to Section 
16.2.4) for each treatment arm will also be presented.  The estimate of the SEs will be computed using 
Greenwood’s formula, the CI for the median will be calculated according to Brookmeyer and Crowley 
(1982) and the other CIs will be derived from the Kaplan-Meier estimates using the log-log 
transformation. 
A Cox proportional hazard model will be performed, including the baseline clinical severity of 2 on the 
8-point ordinal scale for clinical severity (yes or no), remdesivir use at baseline (yes or no) 
stratification variables, both as captured on the IWRS, country (region), and treatment arm as factors.  
Ties will be handled using the exact method.  The hazard ratio of the candidate agent plus SoC vs. 
placebo plus SoC, its associated two-sided 95% CI, and p-value will be provided. 
No supplementary analyses will be performed for the non-key secondary efficacy endpoints. 
16.3. EXPLORATORY EFFICACY 
16.3.1. 
EXPLORATORY EFFICACY ENDPOINTS 
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16.3.4. 
SENSITIVITY ANALYSES FOR EXPLORATORY EFFICACY ENDPOINTS 
 
16.3.5. 
SUPPLEMENTARY ANALYSES FOR EXPLORATORY EFFICACY ENDPOINTS 
 
16.4. ADDITIONAL EFFICACY 
16.4.1. 
ADDITIONAL EFFICACY ENDPOINT 
16.4.1.1. 
Incidence of All-Cause Mortality through Day 60 
An additional efficacy endpoint is the incidence of all-cause mortality through Day 60, defined as the proportion of 
patients having died due to any cause before or on Day 60. Patients death before or at Day 60 will be based on data 
captured on the Death Details page of the eCRF. 
16.4.2. 
MISSING DATA IMPUTATION METHOD FOR ADDITIONAL EFFICACY ENDPOINT 
Patients with an unknown alive/death status at Day 60 will be considered as alive at Day 60. 
16.4.3. 
ANALYSIS OF ADDITIONAL EFFICACY ENDPOINT 
The number and percentage of patients alive and dead through Day 60 (refer to Section 16.4.1.1) along with the two-
sided 95% CI for the percentage of patients dead through Day 60 will be provided by treatment arm.  Primary reason 
of death will also be summarized by treatment arm.  No statistical inference will be performed for this endpoint but 
treatment effect estimate (i.e., relative risk, odds ratio) and two-sided 95% CI will be provided. 
16.4.4. 
SENSITIVITY ANALYSES FOR ADDITIONAL EFFICACY ENDPOINT 
No sensitivity analyses will be performed for the additional efficacy endpoint. 
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16.4.5. 
SUPPLEMENTARY ANALYSES FOR ADDITIONAL EFFICACY ENDPOINT 
The time to all-cause death through Day 60, in days, will be derived as follows: 
• 
Time to all-cause mortality through Day 60 (days) = 
(Date of death / Date of censoring - Date of Study Day 1 [refer to Section 6.1]) + 1. 
The date of death will be taken from data captured on the Death Details page of the eCRF. 
For patients who were alive or patients with an unknown alive status at the time of the analysis due to missing data, 
time to all-cause mortality will be censored at the latest date on which the patient was known to be alive before or on 
Day 60.  The last date the patient was known to be alive will be the latest date collected on any page of the eCRF. 
For patients who discontinued from the study before Day 60, time to all-cause mortality will be censored at the date 
of study discontinuation, as captured on the Disposition page of the eCRF. 
Number and percentage of patients with and without the event will be presented by randomized treatment arm.  For 
patients who did not meet the event, the main reason for censoring (refer to Section 16.1.1) will be summarized 
similarly. 
The incidence of all-cause mortality through Day 60 along with its two-sided 95% CI by treatment arm will then be 
estimated using Kaplan-Meier survival curves of the time to all-cause mortality through Day 60.  Kaplan-Meier 
survival curves by treatment arm will also be provided. 
The 25th percentile, 50th percentile (median), and 75th percentile of time to all-cause mortality (days) with the 
corresponding two-sided 95% CIs based on the Kaplan-Meier survival curves for each treatment arm will be 
presented.  The estimate of the SEs will be computed using Greenwood’s formula, the CI for the median will be 
calculated according to Brookmeyer and Crowley (1982) and the CIs for the survival function estimates at above 
mentioned time points will be derived from the Kaplan-Meier estimates using the log-log transformation. 
Finally, a Cox proportional hazard model will be performed, including the baseline clinical severity of 2 on the 8-
point ordinal scale for clinical severity (yes or no), remdesivir use at baseline (yes or no) stratification variables, 
both as captured on the IWRS, country (region), and treatment arm as factors.  Ties will be handled using the exact 
method.  The hazard ratio of the candidate agent plus SoC vs. placebo plus SoC and its associated two-sided 95% CI 
will be provided. 
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16.5. INTERIM ANALYSIS 
16.5.1. 
INTERIM ANALYSIS FOR FUTILITY 
Each candidate agent may be evaluated for futility at up to two IAs.   
The IAs will be based on analyses of the primary efficacy endpoint (refer to Section 16.1.1), using the analysis 
methods described in Section 16.1.3. 
The IAs are planned at information fractions of approximately 25% and 55% of expected number of confirmed 
clinical recoveries (refer to Table 1), i.e., after approximately 123 and 270 patients have met the primary endpoint of 
confirmed clinical recovery on a particular candidate agent plus SoC and its contemporaneous placebo plus SoC, 
respectively. However, the timing of these IAs may be adjusted due to operational considerations, e.g., actual 
enrollment rate.  
For the IAs, a Pocock beta spending function will be used for non-binding futility boundary specification. This 
strategy will allow for ineffective agents to be identified early for discontinuation of further evaluation. Assuming 
no treatment effect for a candidate agent plus SoC arm compared with placebo plus SoC patients included in the 
control arm of the candidate agent, there is a 49.7% chance that enrolment to this agent is stopped at the first IA and 
34.6% chance at the second IA. Under the scenario that treatment has a negative effect on outcome (refer to 
Table 2), these probabilities become 72.3% and 24.7%, respectively.  
The primary analysis for a candidate agent will occur after 350 patients have been randomized to a particular 
candidate agent plus SoC and have had the opportunity to complete the Day 29 visit, when approximately 490 
confirmed clinical recovery events are expected to have been observed in total across the candidate plus SoC arm 
and placebo plus SoC patients included in the control arm of the candidate agent, unless a candidate agent is stopped 
early for futility.  The final analysis of a candidate agent will occur after all patients randomized to that candidate 
agent plus Soc and the concurrent placebo plus SoC controls have had the opportunity to complete the Day 60 visit. 
Table 1 and Table 2 present a summary of futility incremental probabilities at the first interim and second interim 
analyses together with Pocock futility boundaries in the scenario of 88.3% estimated power when the IAs occur at 
information fraction of 25% and 55% of expected number of recoveries, respectively.  
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Table 1 
Summary of Futility Probabilities and Boundaries with 88.3% Power using 
Pocock Futility Boundaries  
Analysis 
Total Number of 
Events 
(Information 
Fraction) 
Boundary of 
Futility,  
Non-binding  
(HR) 
Boundary of 
Futility,  
Non-binding  
(p-value) 
Incremental 
Probability to 
Declare Futility 
under the Null 
(HR=1) 
First Interim 
123 (25%) 
≤ 0.998 
0.503 
0.497 
Second Interim 
270 (55%) 
≤ 1.121 
0.175 
0.346 
HR=hazard ratio. 
Assume 1-sided α of 0.025. 
Interim analyses using Pocock futility boundaries at 25% and 55% information fraction. 
HR boundaries are translated from p-values, dependent of relative timing, and will be re-calculated for IDMC. 
 
Table 2 
Summary of Futility Probabilities and Boundaries with 88.3% Power using 
Pocock Futility Boundaries for the Negative Treatment Scenario (HR=0.9) 
Analysis 
Total Number of 
Events 
(Information 
Fraction) 
Boundary of 
Futility, 
Non-binding  
(HR) 
Boundary of 
Futility, Non-
binding 
(p-value) 
Incremental 
Probability to 
Declare Futility 
under the Negative 
Treatment Effect 
Scenario (HR=0.9) 
First Interim 
123 (25%) 
≤ 0.998 
0.503 
0.723 
Second Interim 
270 (55%) 
≤ 1.121 
0.175 
0.247 
HR=hazard ratio. 
Assume 1-sided α of 0.025. 
Interim analyses using Pocock futility boundaries at 25% and 55% information fraction. 
HR boundaries are translated from p-values, dependent of relative timing, and will be re-calculated for IDMC. 
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17. SAFETY ENDPOINTS 
All safety summaries will be presented by treatment arm based on the safety analysis set.  Further, for each sub-
protocol, separate summaries will also be presented for patients randomized to the placebo plus SoC treatment group 
of the sub-protocol.   
There will be no statistical comparisons between the treatment arms for safety data. 
17.1. ADVERSE EVENTS 
Each AE will be classified as either: 
• 
Prior, defined as any AE that started or worsened in severity on or after the date of signed informed consent but 
before the first dose of study drug; 
• 
Treatment-emergent, defined as any AE that started or worsened in severity on or after the first dose of study 
drug. 
If time of the first dose of study drug and time of start of AEs are available, then the times will be taken into account 
for determining TEAEs. Refer to Appendix 1 for handling of partial and completely missing dates for AEs.  In the 
case where it is not possible to define an AE as treatment emergent or not, the AE will be classified by the worst 
case; i.e. treatment emergent.  
AEs will be coded using the MedDRA dictionary, version 23.1 or later.  Summaries by System Organ Class and PT 
will be sorted as follows: System Organ Classes will be sorted in alphabetical order and within each System Organ 
Class, PTs will be sorted by decreasing order to total frequency. 
An overall summary of number and percentage of patients within each of the categories described in the sub-
sections below will be provided by treatment arm.  Should a patient experience multiple events within a category, 
the patient will be counted only once for that category. Additionally, the risk difference of the overall incidence rates 
of serious TEAEs and overall incidence rates of AESIs (when applicable for a sub-protocol) between treatment and 
control arms will be presented along with its 95% two-sided Wald CI. 
All AEs (prior and TEAE) will be listed. 
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17.1.1. 
ALL TEAES 
Number and percentage of patients with at least one TEAE will be presented by System Organ Class and PT.  
Should a patient experience multiple events within a System Organ Class or PT, the patient will be counted only 
once for that System Organ Class or PT. 
Number and percentage of patients with at least one TEAE will be broken down further separately by maximum 
severity (CTCAE Grades 1-5), CTCAE Grade ≥3, relationship to study drug (not related and related), and 
relationship to non-study drug (not related and related). 
17.1.1.1. 
CTC Grading for AEs 
Toxicity will be classified as mild (Grade 1), moderate (Grade 2), severe (Grade 3), life-threatening (Grade 4) or 
fatal (Grade 5) according to the CTCAE, version 5: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_5x7.pdf 
Should a patient experience multiple events within a System Organ Class or PT, only the patient’s worst CTCAE 
grade will be counted for that System Organ Class or PT. 
17.1.1.2. 
Relationship to Study Drug, Non-Study Drug, and Study Procedure 
Relationship to study drug, relationship to non-study drug, and relationship to study procedure, as indicated by the 
Investigator, will be classified as unrelated or related. 
Should a patient experience multiple events within a System Organ Class or PT, only the patient’s worst relationship 
(i.e., related) will be counted for that System Organ Class or PT.  
TEAEs will not be summarized by the relationship to study procedure, but relationship to study procedure will be 
listed. 
17.1.2. 
FATAL ADVERSE EVENTS 
Fatal TEAEs are those events which are recorded as Fatal or with a CTCAE grade of 5 on the Adverse Events page 
of the eCRF. A summary of fatal TEAEs by System Organ Class and PT will be prepared. 
A listing of all fatal AEs will be provided. 
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17.1.3. 
SERIOUS ADVERSE EVENTS 
SAEs are those events recorded as Serious on the Adverse Events page of the eCRF.  A summary of serious TEAEs 
by System Organ Class and PT will be prepared.  Should a patient experience multiple events within a System 
Organ Class or PT, the patient will be counted only once for that System Organ Class or PT. 
A listing of all SAEs will be provided 
17.1.4. 
MOST COMMON NON-SERIOUS ADVERSE EVENTS 
Number and percentage of patients with at least one most common non-serious TEAE will be presented by PT, 
where most common is defined as a PT with at least 5% of patients in at least one treatment arm.  Should a patient 
experience multiple events within a PT, the patient will be counted only once for that PT. 
17.1.5. 
TEAES LEADING TO DOSE MODIFICATIONS 
TEAEs leading to dose modification are those events recorded with “Action Taken with study treatment” on the 
Adverse Events pages of the eCRF of any of the following: Dose increased, Dose reduced, Dose rate reduced, or 
Drug interrupted. A summary of TEAEs leading to dose modification by System Organ Class and PT will be 
prepared.  Should a patient experience multiple events within a System Organ Class or PT, the patient will be 
counted only once for that System Organ Class or PT. 
17.1.6. 
TEAES LEADING TO DISCONTINUATION OF STUDY TREATMENT 
TEAEs leading to permanent discontinuation of study treatment are those events recorded with Action Taken with 
study treatment of Drug withdrawal on the Adverse Events page of the eCRF. A summary of TEAEs leading to 
permanent discontinuation of study drug by System Organ Class and PT will be prepared.  Should a patient 
experience multiple events within a System Organ Class or PT, the patient will be counted only once for that System 
Organ Class or PT. 
A listing of all AEs leading to permanent discontinuation of study drug will be provided. 
17.1.7. 
AESIS 
For applicable sub-protocols, refer to sub-protocol SAP for more details. 
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17.2. LABORATORY EVALUATIONS 
A serum or urine pregnancy test will be performed at screening.  Hematology, coagulation, and chemistry (including 
cardiac enzymes and liver function tests) laboratory tests will be performed as per the schedule of events (refer to 
the example schedule of events in Section 1.3 of the master protocol but note that each sub-protocol will have its 
own schedule of events). 
A list of laboratory tests to be included in the outputs is included in Appendix 5.  It is to be noted that additional 
laboratory tests might be collected in a sub-protocol. 
Results of quantitative laboratory tests reported as “< X”, i.e. below the lower limit of quantification (BLQ) or 
“> X”, i.e. above the upper limit of quantification (ULQ), will be converted to X for the purpose of quantitative 
summaries, but will be presented as recorded, i.e. as “< X” or “> X” in the listings.  Observed values will then be 
normalized (refer to Section 17.2.1) before being summarized and changes from baseline will be computed based on 
the normalized observed values. 
The following summaries will be provided by treatment arm for each hematology, coagulation, and chemistry test: 
• 
Observed, change, and percent change from baseline values in Standard International (SI) units by visit (for 
quantitative tests) 
• 
Box and whisker plots over time in SI units (for selected quantitative tests at IDMC safety data review meetings 
and IAs only) 
• 
Shift from baseline to the worst post-baseline observed value according to the CTCAE toxicity grades (for 
quantitative tests with available CTCAE toxicity grades; refer to Section 17.2.2) 
• 
Listing of patients with at least one laboratory observed value meeting a CTCAE toxicity grade ≥ 3 (for 
quantitative tests with available CTCAE toxicity grades; refer to Section 17.2.2) 
• 
Shifts from baseline to the maximum/minimum post-baseline observed value according to reference range 
criteria (for quantitative tests without CTCAE toxicity grades; refer to Section 17.2.3) 
• 
Listing of patients with at least one abnormal laboratory observed value outside the reference range criteria (for 
quantitative tests without CTCAE toxicity grades; refer to Section 17.2.3) 
• 
Maximum post-baseline ALT/AST observed value categorized as < 3 x upper limit of normal (ULN), ≥ 3 to < 5 
x ULN, ≥ 5 to < 10 x ULN or ≥ 10 ULN by maximum post-baseline total bilirubin observed value categorized 
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as < 2 x ULN or ≥ 2 x ULN 
• 
Scatter plots of the maximum post-baseline observed value in ALT value by the maximum post-baseline 
observed value in TBL value, both expressed as multiple of ULN 
• 
Scatter plots of the maximum post-baseline observed value in AST value by the maximum post-baseline 
observed value in TBL value, both expressed as multiple of ULN 
• 
A listing of patients with at least one observed value in ALT value > 3 x ULN, AST value > 3 x ULN or TBL 
value ≥ 2 x ULN will be provided 
17.2.1. 
LABORATORY NORMALIZATION 
If a laboratory test has different reference ranges in the database, observed values of all patients will first be 
standardized to a common standard unit and then, normalized to a common set of standardized reference range using 
the location-scale normalization formula (Chuang-Stein, 1992):  
• 
𝑦= 𝐿𝑦+ (𝑥− 𝐿𝑋) (𝑈𝑌− 𝐿𝑌)
(𝑈𝑋− 𝐿𝑋) 
where: 
o 
y = normalized and standardized observed value; 
o 
x = standardized observed value; 
o 
LY = Lower limit of the reference range chosen to be the common standardized reference range; 
o 
UY = Upper limit of the reference range chosen to be the common standardized reference range; 
o 
LX = Lower limit of the reference range associated with the standardized observed value; 
o 
UX = Upper limit of the reference range associated with the standardized observed value. 
It is to be noted that the choice of the common standardized reference range is arbitrary. 
17.2.2. 
CTCAE TOXICITY GRADES 
Quantitative laboratory tests with available CTCAE toxicity grades will be categorized as follows where higher 
grades representing a more severe toxicity (refer to Appendix 6 for each test toxicity grade criteria):  
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• 
Grade 1 (i.e., mild); 
• 
Grade 2 (i.e., moderate); 
• 
Grade 3 (i.e., severe); 
• 
Grade 4 (i.e., life-threatening); 
• 
Grade 5 (i.e., death). 
 
Although not defined in the CTCAE toxicity grading system, version 5, non-missing laboratory test results not 
meeting any of the 5 grades defined in the CTCAE toxicity grading system will be categorized as ‘No Event’ for the 
purpose of the shift from baseline summaries. 
17.2.3. 
LABORATORY REFERENCE RANGES 
Quantitative laboratory tests will be compared with the relevant laboratory reference ranges in SI units and 
categorized as: 
• 
Low: Below the lower limit of the laboratory reference range 
• 
Normal: Within the laboratory reference range (upper and lower limit included) 
• 
High: Above the upper limit of the laboratory reference range 
17.3. VITAL SIGNS 
The following vital sign parameters will be collected as per the schedule of events (refer to the example schedule of 
events in Section 1.3 of the master protocol, but note that each sub-protocol will have its own schedule of events): 
• 
Systolic blood pressure (SBP) (mmHg); 
• 
Diastolic blood pressure (DBP) (mmHg); 
• 
Pulse rate (beats per minute [bpm]); 
• 
Oxygen saturation (%); 
• 
FiO2 (%); 
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• 
Respiratory rate (breaths/min); 
• 
Body temperature (⁰C). 
 
The following summaries will be provided by treatment arm for each vital sign parameter: 
• 
Observed and change from baseline values by visit; 
• 
Number and percentages of patients with at least one markedly abnormal post-baseline observed value/change 
from baseline (refer to Section 17.3.1); 
• 
Listing of patients with at least one markedly abnormal observed value/change from baseline (refer to Section 
17.3.1). 
17.3.1. 
VITAL SIGNS MARKEDLY ABNORMAL CRITERIA 
Markedly abnormal vital sign observed values and/or change from baseline will be identified in accordance with the 
following predefined markedly abnormal criteria: 
Variable 
Unit 
Low 
High 
SBP 
mmHg 
≤ 90 mmHg AND  
change from Baseline ≤ -20 mmHg 
≥ 180 mmHg AND 
change from Baseline ≥ 20 mmHg 
DBP 
mmHg 
≤ 50 mmHg AND 
change from Baseline ≤ -15 mmHg 
≥ 105 mmHg AND 
change from Baseline ≥ 15 mmHg 
Pulse rate 
bpm 
≤ 50 bpm AND 
change from Baseline ≤ -15 bpm 
≥ 120 bpm AND 
change from Baseline ≥ 15 bpm 
Oxygen 
saturation 
% 
< 94 % 
Not applicable 
Body 
temperature 
C 
Not applicable 
≥ 38.3 C AND 
change from Baseline ≥ 1.1 C 
 
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17.4. ECG EVALUATIONS 
12-lead electrocardiograms (ECGs) will be performed at screening only to assess exclusion criteria 3 of the master 
protocol.  As such ECG data will not be assessed as a safety parameter.  
17.5. PHYSICAL EXAMINATION 
A general physical examination will be performed at screening only.  As such, physical examination will not be 
assessed as a safety parameter. 
18. DATA NOT SUMMARIZED OR PRESENTED 
Data that will not be summarized or listed are: 
• 
Reason for screen failure; 
• 
Inclusion/exclusion criteria; 
• 
SARS-CoV-2 test results; 
• 
Pharmacogenetics sampling; 
• 
Pregnancy test results; 
• 
Screening ECG parameters; 
• 
Screening physical examination; 
• 
Contact information; 
• 
Comments. 
These data will be available in the Study Data Tabulation Model (SDTM) datasets. 
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19. REFERENCES  
Brookmeyer R, Crowley J. A (1982) Confidence Interval for the Median Survival Time. Biometrics 38:29-41. 
Chuang-Stein C (1992). Summarizing laboratory data with different reference ranges in multi-center clinical trials. 
Drug Information Journal 26(1);77-84. 
Lipkovich I, Ratitch B, and O’Kelly M (2016). Sensitivity to censored-at-random assumption in the analysis of time-
to-event endpoints. Pharmaceutical Statistics 15;216-229. DOI:10.1002/pst.1738 
Moscovici J and Ratitch B (2017).  Combining Survival Analysis Results after Multiple Imputation of Censored 
Event Times. PharmaSUG-Paper SP05. 
Royal College of Physicians (2017). National Early Warning Score (NEWS) 2: Standardizing the Assessment of 
Acute-illness Severity in the NHS – Updated Report of a Working Party. London. 
https://www.rcplondon.ac.uk/file/8504/download [accessed 08 May 2020]. 
Rubin DB (1987).  Multiple Imputations for Nonresponse in Surveys.  New York, NY: John Wiley & Sons, Inc. 
 
 
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APPENDIX 1 PARTIAL DATE CONVENTIONS 
ALGORITHM FOR TREATMENT EMERGENCE OF ADVERSE EVENTS 
START DATE 
END DATE 
ACTION 
Known 
Known/Partial/ 
Missing 
If AE start date/time < date/time of first dose of study drug, 
then not a TEAE; 
Otherwise, TEAE. 
 
 
 
Partial, but known components 
show that AE started before date 
of first dose of study drug 
Known/Partial/ 
Missing 
Not TEAE. 
 
 
 
Partial and known components 
show that AE started on or after 
date of first dose of study drug 
Known/Partial/ 
Missing 
Assume TEAE. 
 
 
 
Missing 
Known 
If AE end date/time < date/time of first dose of study drug, 
then not TEAE; 
Otherwise, TEAE. 
Partial 
If known components of AE end date/time show that AE 
stopped before date/time of first dose of study drug, then not 
TEAE; 
Otherwise, TEAE. 
Missing 
Assume TEAE. 
Note: If an AE started prior to first dose of study drug but worsened after the first dose of study drug, it will be 
reported as a separate adverse event with new AE start date/time. 
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ALGORITHM FOR PRIOR / CONCOMITANT MEDICATIONS 
START DATE 
STOP DATE 
ACTION 
Known, Partial or 
Missing 
Known 
If medication stop date < date of first dose of study drug, assign as prior; 
Otherwise, assign as concomitant  
Partial 
If known components of medication stop date show that medication stopped 
before date of first dose of study drug, assign as prior; 
Otherwise, assign as concomitant 
Missing, or 
ongoing 
Can never be assigned as prior, therefore assign as concomitant. 
 
 
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APPENDIX 2 PROGRAMMING CONVENTIONS FOR OUTPUTS 
DATES & TIMES 
Depending on data available, dates and times will take the form yyyy-mm-dd hh:mm. 
SPELLING FORMAT 
English US.  
PAPER SIZE, ORIENTATION, AND MARGINS 
The size of paper will be letter and the page orientation will be landscape. Margins will provide at least 1 inch (2.54 
centimeters) of white space all around the page. 
FONTS 
The font type ‘Courier New’ will be used, with a font size of 8.  The font color will be black with no bolding, 
underlining, italics or subscripting. 
PRESENTATION OF TREATMENT ARMS 
For outputs, treatment arms will be represented as follows and in the given order: 
Treatment arm 
Tables and Graphs 
Listings 
<<Agent>> plus SoC 
1 
1 
Placebo plus SoC 
2 
2 
Total [1] 
3 
n/a 
Screen Failure 
n/a 
3 
[1] Not applicable for efficacy tables, safety tables and graphs. 
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PRESENTATION OF NOMINAL VISITS 
For outputs, nominal visits will be represented as follows and in that order: 
Long Name (default) 
Short Name  
Screening 
Scrn 
Baseline 
Base 
Day x, where x = 1 to 29 
Day x, where x= 1 to 29 
Day 60 
Day 60 
DESCRIPTIVE STATISTICS 
If the original data has N decimal places, then the summary statistics will have the following number of decimal 
places: 
• 
Minimum and maximum: N; 
• 
Mean, Q1, median, Q3, lower and upper bounds of two-sided 95% CI: N + 1; 
• 
SD and SE: N + 2 
PERCENTAGES 
Percentages will be reported to one decimal place.  Rounding will be applied, except for percentages < 0.1 but > 0.0 
which will be presented as ‘< 0.1’ and percentages < 100.0 but >99.9 which will be presented as ‘>99.9’. 
Where counts are zero, no percentages will appear in the output. 
P-VALUES 
p-values will be reported to three decimal places.  Rounding will be applied, except for the p-values < 0.001 which 
will be presented as ‘< 0.001’ and p-values < 1.000 but > 0.999 which will be presented as ‘> 0.999’. 
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LISTINGS 
All listings will be ordered by the following (unless otherwise indicated in the output template): 
• 
Randomized treatment arm (or treatment received if it’s a safety output) 
• 
Patient ID 
• 
Parameter, when applicable 
• 
Date/Time, when applicable 
• 
Timepoint, when applicable 
 
 
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APPENDIX 4 VASOPRESSOR DRUG CODES AS PER THE WHO DRUG 
GLOBAL DICTIONARY, SEPTEMBER 2020, VERSION B3 
 
Drug code 
Product Name 
Active Ingredients 
00360702173 
3-hydroxytyramine HCL 
Dopamine hydrochloride 
00360702174 
3-hydroxytyramine hydrochloride 
Dopamine hydrochloride 
00493402134 
46236 
Dobutamine hydrochloride 
00360702138 
A si ke ding 
Dopamine hydrochloride 
00360702012 
Abbodop 
Dopamine hydrochloride 
00493402057 
Abbott dobutamine hydrochloride 
Dobutamine hydrochloride 
00360702103 
Abbott dopamine hcl 
Dopamine hydrochloride 
00360702024 
Actopamin 
Dopamine hydrochloride 
00493402099 
Adregotec 
Dobutamine hydrochloride 
00003902019 
Adreject 
Epinephrine hydrochloride 
00003902041 
Adren 
Epinephrine hydrochloride 
00003901075 
Adrenaclick 
Epinephrine 
00003901055 
Adrenal 
Epinephrine 
00003901002 
Adrenalin 
Epinephrine 
00003902015 
Adrenalin 
Epinephrine hydrochloride 
00003903015 
Adrenalin 
Epinephrine bitartrate 
00003903051 
Adrenalin aguettant 
Epinephrine bitartrate 
00003901069 
Adrenalin apotek ab 
Epinephrine 
00003903057 
Adrenalin bradex 
Epinephrine bitartrate 
00003901063 
ADRENALIN Carino 
Epinephrine 
00003901027 
Adrenalin chl sankyo 
Epinephrine 
00003902052 
Adrenalin chloride 
Epinephrine hydrochloride 
00003902031 
Adrenalin cl 
Epinephrine hydrochloride 
00003901103 
Adrenalin galen 
Epinephrine 
00003902026 
Adrenalin hcl 
Epinephrine hydrochloride 
00003902063 
Adrenalin hydrochloride 
Epinephrine hydrochloride 
00003903031 
Adrenalin hydrotar 
Epinephrine bitartrate 
00003902018 
Adrenalin IMS 
Epinephrine hydrochloride 
CCI
CCI
PPD
CCI


Amgen Inc 
Master Protocol COV-01 
Master Statistical Analysis Plan 
Page 87 of 118 
 
 
 
 
 
Version Number: 
Amendment 1, v1.0 
 
Version Date:  
23Apr2021 
 
 
 
 
 
 
 
Drug code 
Product Name 
Active Ingredients 
00003903040 
Adrenalin Infectopharm 
Epinephrine bitartrate 
00003901062 
Adrenalin Injeel 
Epinephrine 
00003903038 
Adrenalin Jenapharm 
Epinephrine bitartrate 
00003901101 
Adrenalin labatec 
Epinephrine 
00003903010 
Adrenalin Leiras 
Epinephrine bitartrate 
00003903048 
Adrenalin Martindale Pharma 
Epinephrine bitartrate 
00003901026 
Adrenalin medica 
Epinephrine 
00003903008 
Adrenalin medihal 
Epinephrine bitartrate 
00003903014 
Adrenalin Merck NM 
Epinephrine bitartrate 
00003903042 
Adrenalin mylan 
Epinephrine bitartrate 
00003901106 
Adrenalin osel 
Epinephrine 
00003901107 
Adrenalin solofarm 
Epinephrine 
00003903052 
Adrenalin stragen 
Epinephrine bitartrate 
00003901022 
Adrenalin streuli 
Epinephrine 
00003903033 
Adrenalin Tartrate 
Epinephrine bitartrate 
00003903024 
Adrenalina 
Epinephrine bitartrate 
00003902037 
Adrenalina 
Epinephrine hydrochloride 
00003901019 
Adrenalina 
Epinephrine 
00003903054 
Adrenalina Aguettant 
Epinephrine bitartrate 
00003902042 
Adrenalina apolo 
Epinephrine hydrochloride 
00003901047 
Adrenalina biol 
Epinephrine 
00003902057 
Adrenalina braun 
Epinephrine hydrochloride 
00003902048 
Adrenalina clorhidrato 
Epinephrine hydrochloride 
00003901048 
Adrenalina fada 
Epinephrine 
00003901066 
Adrenalina galenica senese 
Epinephrine 
00003902013 
Adrenalina level 
Epinephrine hydrochloride 
00003902007 
Adrenalina llorente 
Epinephrine hydrochloride 
00003902014 
Adrenalina miro 
Epinephrine hydrochloride 
00003902065 
Adrenalina ogna 
Epinephrine hydrochloride 
00003902028 
Adrenalina pisa 
Epinephrine hydrochloride 
00003901021 
Adrenalina sintetica 
Epinephrine 
00003903045 
Adrenalina wzf 
Epinephrine bitartrate 
00003903005 
Adrenaline 
Epinephrine bitartrate 
CCI
CCI
PPD
CCI


Amgen Inc 
Master Protocol COV-01 
Master Statistical Analysis Plan 
Page 88 of 118 
 
 
 
 
 
Version Number: 
Amendment 1, v1.0 
 
Version Date:  
23Apr2021 
 
 
 
 
 
 
 
Drug code 
Product Name 
Active Ingredients 
00003902047 
Adrenaline 
Epinephrine hydrochloride 
00003901003 
Adrenaline 
Epinephrine 
00003903055 
Adrenaline (Epinephrine) Injection BP 1:1000 
Epinephrine bitartrate 
00003902060 
Adrenaline (HCl) Sterop 
Epinephrine hydrochloride 
00003901089 
Adrenaline (tartrate) Aguettant 
Epinephrine 
00003903037 
Adrenaline (Tartrate) Sterop 
Epinephrine bitartrate 
00003903026 
Adrenaline acid tartrate 
Epinephrine bitartrate 
00003901040 
Adrenaline aguettant 
Epinephrine 
00003901094 
Adrenaline aurum 
Epinephrine 
00003901041 
Adrenaline b.braun 
Epinephrine 
00003901042 
Adrenaline cooper 
Epinephrine 
00003903036 
Adrenaline Demo 
Epinephrine bitartrate 
00003903056 
Adrenaline fresenius 
Epinephrine bitartrate 
00003902025 
Adrenaline hcl 
Epinephrine hydrochloride 
00003902053 
Adrenaline hydrochloride 
Epinephrine hydrochloride 
00003901098 
Adrenaline jr mylan 
Epinephrine 
00003901072 
Adrenaline Lavois 
Epinephrine 
00003902072 
Adrenaline life 
Epinephrine hydrochloride 
00003903046 
Adrenaline link 
Epinephrine bitartrate 
00003901091 
Adrenaline martindale 
Epinephrine 
00003901099 
Adrenaline mylan 
Epinephrine 
00003902062 
Adrenaline Parke-Davis 
Epinephrine hydrochloride 
00003901058 
Adrenaline pch 
Epinephrine 
00003903049 
Adrenaline renaudin 
Epinephrine bitartrate 
00003901100 
Adrenaline solopharm 
Epinephrine 
00003901093 
Adrenaline sophar 
Epinephrine 
00003903043 
Adrenaline tartrate 
Epinephrine bitartrate 
00003901102 
Adrenaline/ariti 
Epinephrine 
00003902059 
Adrenalini 
Epinephrine hydrochloride 
00003903029 
Adrenalini bitartras 
Epinephrine bitartrate 
00003902068 
Adrenalini hcl 
Epinephrine hydrochloride 
00003902069 
Adrenalini hydrochloridum 
Epinephrine hydrochloride 
00003902056 
Adrenalini hydrotartras 
Epinephrine hydrochloride 
CCI
CCI
PPD
CCI


Amgen Inc 
Master Protocol COV-01 
Master Statistical Analysis Plan 
Page 89 of 118 
 
 
 
 
 
Version Number: 
Amendment 1, v1.0 
 
Version Date:  
23Apr2021 
 
 
 
 
 
 
 
Drug code 
Product Name 
Active Ingredients 
00003903030 
Adrenalini hydrotartras 
Epinephrine bitartrate 
00003903032 
Adrenalini tartras 
Epinephrine bitartrate 
00003904003 
Adrenalin-neutrale 
Epinephryl borate 
00003903016 
Adrenalinum 
Epinephrine bitartrate 
00003901081 
Adrenalinum 
Epinephrine 
00003901087 
Adrenol 
Epinephrine 
00127502065 
Adrenor 
Norepinephrine bitartrate 
00003903027 
Adrenotone 
Epinephrine bitartrate 
00003901051 
Adrine 
Epinephrine 
00003901076 
Adrinor 
Epinephrine 
00127501007 
ADS-Noltron 
Norepinephrine 
00003901097 
Adyphren amp kit 
Epinephrine 
00003901085 
Allerject 
Epinephrine 
00003901061 
Altellus 
Epinephrine 
00493402104 
An chang 
Dobutamine hydrochloride 
00003902051 
Anaguard 
Epinephrine hydrochloride 
00003902012 
Ana-guard 
Epinephrine hydrochloride 
00003901045 
Anahelp 
Epinephrine 
00003901044 
Anakit 
Epinephrine 
00003901031 
Anapen 
Epinephrine 
00003902045 
Anapen 
Epinephrine hydrochloride 
01872201012 
Antidiuretic hormone 
Vasopressin 
00493402085 
Ao wan yuan 
Dobutamine hydrochloride 
00493402067 
Ao wang yan 
Dobutamine hydrochloride 
00360702128 
Aprical dopamida 
Dopamine hydrochloride 
01872201024 
Argipresina 
Vasopressin 
01872201016 
Argipressin 
Vasopressin 
00127503002 
Arterenol 
Norepinephrine hydrochloride 
01872201018 
Arterina 
Vasopressin 
00360702175 
Asl-279 
Dopamine hydrochloride 
00003903035 
Aspen Adrenaline 
Epinephrine bitartrate 
00003903004 
Asthmahaler 
Epinephrine bitartrate 
00003901028 
Asthsedan 
Epinephrine 
CCI
CCI
PPD
CCI


Amgen Inc 
Master Protocol COV-01 
Master Statistical Analysis Plan 
Page 90 of 118 
 
 
 
 
 
Version Number: 
Amendment 1, v1.0 
 
Version Date:  
23Apr2021 
 
 
 
 
 
 
 
Drug code 
Product Name 
Active Ingredients 
00003901073 
Auvi q 
Epinephrine 
00360702159 
Bagotropin 
Dopamine hydrochloride 
00127502064 
Biemefrin 
Norepinephrine bitartrate 
00003902005 
Bosmin 
Epinephrine hydrochloride 
00003901029 
Bosmin 
Epinephrine 
00003901009 
Bronkaid 
Epinephrine 
00003902032 
Bronkaid 
Epinephrine hydrochloride 
00493402010 
Bubucin 
Dobutamine hydrochloride 
00493402112 
Butamine 
Dobutamine hydrochloride 
00493402143 
Cardease 
Dobutamine hydrochloride 
00127502063 
Cardenor 
Norepinephrine bitartrate 
00127502040 
Cardiamed 
Norepinephrine bitartrate 
00493402118 
Cardiforce 
Dobutamine hydrochloride 
00493402050 
Cardiject 
Dobutamine hydrochloride 
00493402056 
Cardiomin 
Dobutamine hydrochloride 
00360702105 
Cardiopal 
Dopamine hydrochloride 
00493402149 
Cardiotrex 
Dobutamine hydrochloride 
00493402160 
Cardob 
Dobutamine hydrochloride 
00493402120 
Cardomin 
Dobutamine hydrochloride 
00360702144 
Cardopa 
Dopamine hydrochloride 
00360702016 
Catabon 
Dopamine hydrochloride 
00360702152 
Catherine 
Dopamine hydrochloride 
00360702038 
Catherine amel 
Dopamine hydrochloride 
00003903058 
CCM Adrenaline Injection 
Epinephrine bitartrate 
00360702109 
Cetadop 
Dopamine hydrochloride 
00003901088 
Chenpen 
Epinephrine 
00360702187 
Clorhidrat de dopamina 
Dopamine hydrochloride 
00360702131 
Clorhidrato dopamina 
Dopamine hydrochloride 
00493402037 
Cloridrato de dobutamina 
Dobutamine hydrochloride 
00360702081 
Cloridrato de dopamina 
Dopamine hydrochloride 
00360702066 
Clorpamina 
Dopamine hydrochloride 
00360702151 
Constriction 
Dopamine hydrochloride 
00493402152 
Corbusin 
Dobutamine hydrochloride 
CCI
CCI
PPD
CCI


Amgen Inc 
Master Protocol COV-01 
Master Statistical Analysis Plan 
Page 91 of 118 
 
 
 
 
 
Version Number: 
Amendment 1, v1.0 
 
Version Date:  
23Apr2021 
 
 
 
 
 
 
 
Drug code 
Product Name 
Active Ingredients 
00360702167 
Cordodopa 
Dopamine hydrochloride 
00360702170 
Cordodopa Forte 
Dopamine hydrochloride 
00360702052 
Corskool 
Dopamine hydrochloride 
01872201020 
Cpressin p 
Vasopressin 
00360702013 
Critpan 
Dopamine hydrochloride 
00493402025 
Cryobutol 
Dobutamine hydrochloride 
00493402126 
Dasomin 
Dobutamine hydrochloride 
00360702045 
Dasomin 
Dopamine hydrochloride 
00003901049 
Davinefrina 
Epinephrine 
00003901064 
Denolin Adrenaline 
Epinephrine 
00493401002 
Dobaden 
Dobutamine 
00493402093 
Dobamin 
Dobutamine hydrochloride 
00493402044 
Dobamine 
Dobutamine hydrochloride 
00493402088 
Dobcard 
Dobutamine hydrochloride 
00493402052 
Dobicard 
Dobutamine hydrochloride 
00493402147 
Dobier s 
Dobutamine hydrochloride 
00493402109 
Dobine 
Dobutamine hydrochloride 
00493402036 
Dobtan 
Dobutamine hydrochloride 
00493402140 
Dobuca 
Dobutamine hydrochloride 
00493402133 
Dobucard 
Dobutamine hydrochloride 
00493402053 
Dobucef 
Dobutamine hydrochloride 
00493402054 
Dobucin 
Dobutamine hydrochloride 
00493402034 
Dobucor 
Dobutamine hydrochloride 
00493402077 
Dobuha 
Dobutamine hydrochloride 
00493402005 
Dobuject 
Dobutamine hydrochloride 
00493402125 
Dobulex 
Dobutamine hydrochloride 
00493402157 
Dobulon 
Dobutamine hydrochloride 
00493402161 
Dobumarc 
Dobutamine hydrochloride 
00493402151 
Dobumean 
Dobutamine hydrochloride 
00493402045 
Dobumin 
Dobutamine hydrochloride 
00493402137 
Dobumine 
Dobutamine hydrochloride 
00493402116 
Dobunex pf 
Dobutamine hydrochloride 
00493402021 
Dobupum 
Dobutamine hydrochloride 
CCI
CCI
PPD
CCI


Amgen Inc 
Master Protocol COV-01 
Master Statistical Analysis Plan 
Page 92 of 118 
 
 
 
 
 
Version Number: 
Amendment 1, v1.0 
 
Version Date:  
23Apr2021 
 
 
 
 
 
 
 
Drug code 
Product Name 
Active Ingredients 
00493402017 
Doburack 
Dobutamine hydrochloride 
00493402079 
Doburak 
Dobutamine hydrochloride 
00493402043 
Doburan 
Dobutamine hydrochloride 
00493402087 
Dobusol 
Dobutamine hydrochloride 
00493402094 
Dobustat 
Dobutamine hydrochloride 
00493402078 
Dobutal 
Dobutamine hydrochloride 
00493402048 
Dobutam 
Dobutamine hydrochloride 
00493402004 
Dobutamin 
Dobutamine hydrochloride 
00493402012 
Dobutamin abbott 
Dobutamine hydrochloride 
00493402089 
Dobutamin Admeda 
Dobutamine hydrochloride 
00493402159 
Dobutamin carinopharm 
Dobutamine hydrochloride 
00493402102 
Dobutamin ebewe 
Dobutamine hydrochloride 
00493402013 
Dobutamin Fresenius 
Dobutamine hydrochloride 
00493402059 
Dobutamin giulini 
Dobutamine hydrochloride 
00493402130 
Dobutamin hameln 
Dobutamine hydrochloride 
00493402022 
Dobutamin hexal 
Dobutamine hydrochloride 
00493402106 
Dobutamin ratiopharm 
Dobutamine hydrochloride 
00493401004 
Dobutamina 
Dobutamine 
00493402040 
Dobutamina 
Dobutamine hydrochloride 
00493402032 
Dobutamina abbott 
Dobutamine hydrochloride 
00493402086 
Dobutamina Aps 
Dobutamine hydrochloride 
00493402098 
Dobutamina bioindustria 
Dobutamine hydrochloride 
00493402146 
Dobutamina Claris 
Dobutamine hydrochloride 
00493402041 
Dobutamina fabra 
Dobutamine hydrochloride 
00493402115 
Dobutamina fu 
Dobutamine hydrochloride 
00493402138 
Dobutamina Generis 
Dobutamine hydrochloride 
00493402141 
Dobutamina genthon 
Dobutamine hydrochloride 
00493402024 
Dobutamina gi pisa 
Dobutamine hydrochloride 
00493402026 
Dobutamina gi tecn 
Dobutamine hydrochloride 
00493402139 
Dobutamina gray 
Dobutamine hydrochloride 
00493402035 
Dobutamina inibsa 
Dobutamine hydrochloride 
00493402023 
Dobutamina kendric 
Dobutamine hydrochloride 
00493402132 
Dobutamina Norgreen 
Dobutamine hydrochloride 
CCI
CCI
PPD
CCI


Amgen Inc 
Master Protocol COV-01 
Master Statistical Analysis Plan 
Page 93 of 118 
 
 
 
 
 
Version Number: 
Amendment 1, v1.0 
 
Version Date:  
23Apr2021 
 
 
 
 
 
 
 
Drug code 
Product Name 
Active Ingredients 
00493402156 
Dobutamina panpharma 
Dobutamine hydrochloride 
00493402033 
Dobutamina rovi 
Dobutamine hydrochloride 
00493402103 
Dobutamina sanderson 
Dobutamine hydrochloride 
00493401001 
Dobutamine 
Dobutamine 
00493402007 
Dobutamine 
Dobutamine hydrochloride 
00493402062 
Dobutamine abbott 
Dobutamine hydrochloride 
00493402075 
Dobutamine Aguettant 
Dobutamine hydrochloride 
00493402063 
Dobutamine antigen 
Dobutamine hydrochloride 
00493402047 
Dobutamine baxter 
Dobutamine hydrochloride 
00493402068 
Dobutamine CF 
Dobutamine hydrochloride 
00493402122 
Dobutamine Claris 
Dobutamine hydrochloride 
00493402030 
Dobutamine dakota 
Dobutamine hydrochloride 
00493402097 
Dobutamine EG 
Dobutamine hydrochloride 
00493402155 
Dobutamine fresenius 
Dobutamine hydrochloride 
00493402111 
Dobutamine hameln 
Dobutamine hydrochloride 
00493402028 
Dobutamine hcl 
Dobutamine hydrochloride 
00493402073 
Dobutamine hcl DBL 
Dobutamine hydrochloride 
00493402072 
Dobutamine hexal 
Dobutamine hydrochloride 
00493402001 
Dobutamine Hydrochloride 
Dobutamine hydrochloride 
00493403001 
Dobutamine lactobionate 
Dobutamine lactobionate 
00493402046 
Dobutamine mayne pharma (ben) 
Dobutamine hydrochloride 
00493402029 
Dobutamine merck 
Dobutamine hydrochloride 
00493402108 
Dobutamine mylan 
Dobutamine hydrochloride 
00493402076 
Dobutamine Panpharma 
Dobutamine hydrochloride 
00493402113 
Dobutamine Qualimed 
Dobutamine hydrochloride 
00493402136 
Dobutamine sdz 
Dobutamine hydrochloride 
00493402092 
Dobutamine winthrop 
Dobutamine hydrochloride 
00493402049 
Dobutamine-abbott 
Dobutamine hydrochloride 
00493402066 
Dobutamine-bc 
Dobutamine hydrochloride 
00493402091 
Dobutamin-hameln 
Dobutamine hydrochloride 
00493402135 
Dobutamini hydrochloridum 
Dobutamine hydrochloride 
00493401003 
Dobutaminum 
Dobutamine 
00493402039 
Dobutamol 
Dobutamine hydrochloride 
CCI
CCI
PPD
CCI


Amgen Inc 
Master Protocol COV-01 
Master Statistical Analysis Plan 
Page 94 of 118 
 
 
 
 
 
Version Number: 
Amendment 1, v1.0 
 
Version Date:  
23Apr2021 
 
 
 
 
 
 
 
Drug code 
Product Name 
Active Ingredients 
00493402090 
Dobutan 
Dobutamine hydrochloride 
00493402107 
Dobutanil 
Dobutamine hydrochloride 
00493402144 
Dobutasel 
Dobutamine hydrochloride 
00493402061 
Dobutel 
Dobutamine hydrochloride 
00493402150 
Dobuthaver 
Dobutamine hydrochloride 
00493402038 
Dobutil 
Dobutamine hydrochloride 
00493402121 
Dobutin 
Dobutamine hydrochloride 
00493402127 
Dobutina 
Dobutamine hydrochloride 
00493402002 
Dobutrex 
Dobutamine hydrochloride 
00493402080 
Dobutrex k 
Dobutamine hydrochloride 
00493402096 
Dobutrim 
Dobutamine hydrochloride 
00493402158 
Dobutrust 
Dobutamine hydrochloride 
00493402071 
Dobux 
Dobutamine hydrochloride 
00493402019 
Dobux nichiiko 
Dobutamine hydrochloride 
00493402058 
Dobuxin 
Dobutamine hydrochloride 
00493402124 
Dobuzef 
Dobutamine hydrochloride 
00360702101 
Docard 
Dopamine hydrochloride 
00360702064 
Dofamin 
Dopamine hydrochloride 
00360702186 
Dofamine 
Dopamine hydrochloride 
00360702172 
Dofamine Ferein 
Dopamine hydrochloride 
00493402119 
Dofuse 
Dobutamine hydrochloride 
00360702040 
Dolpamil 
Dopamine hydrochloride 
00360702116 
Domin 
Dopamine hydrochloride 
00360702093 
Domine 
Dopamine hydrochloride 
00493402128 
Dominic 
Dobutamine hydrochloride 
00360702014 
Dominin 
Dopamine hydrochloride 
00360702162 
Domins 
Dopamine hydrochloride 
00360702050 
Donapan 
Dopamine hydrochloride 
00360702044 
Doncal 
Dopamine hydrochloride 
00360702058 
Dopa kit 
Dopamine hydrochloride 
00360702082 
Dopabane 
Dopamine hydrochloride 
00360702185 
Dopabas 
Dopamine hydrochloride 
00360702113 
Dopac 
Dopamine hydrochloride 
CCI
CCI
PPD
CCI


Amgen Inc 
Master Protocol COV-01 
Master Statistical Analysis Plan 
Page 95 of 118 
 
 
 
 
 
Version Number: 
Amendment 1, v1.0 
 
Version Date:  
23Apr2021 
 
 
 
 
 
 
 
Drug code 
Product Name 
Active Ingredients 
00360702161 
Dopacef 
Dopamine hydrochloride 
00360702147 
Dopacin 
Dopamine hydrochloride 
00360702083 
Dopacris 
Dopamine hydrochloride 
00360702140 
Dopadren 
Dopamine hydrochloride 
00360702178 
Dopaglan 
Dopamine hydrochloride 
00360702143 
Dopamax 
Dopamine hydrochloride 
00360702117 
Dopamex 
Dopamine hydrochloride 
00360702003 
Dopamin 
Dopamine hydrochloride 
00360702136 
Dopamin Admeda 
Dopamine hydrochloride 
00360702030 
Dopamin braun 
Dopamine hydrochloride 
00360702065 
Dopamin ebewe 
Dopamine hydrochloride 
00360702029 
Dopamin fresenius 
Dopamine hydrochloride 
00360702025 
Dopamin giulini 
Dopamine hydrochloride 
00360702114 
Dopamin hausmann 
Dopamine hydrochloride 
00360702070 
Dopamin natter 
Dopamine hydrochloride 
00360702150 
Dopamin Sintetica 
Dopamine hydrochloride 
00360702126 
Dopamin solvay 
Dopamine hydrochloride 
00360701004 
Dopamina 
Dopamine 
00360702080 
Dopamina 
Dopamine hydrochloride 
00360702165 
Dopamina 3m 
Dopamine hydrochloride 
00360702076 
Dopamina abbott 
Dopamine hydrochloride 
00360702182 
Dopamina basi 
Dopamine hydrochloride 
00360702168 
Dopamina clorhidrato 
Dopamine hydrochloride 
00360702194 
Dopamina cloridrato 
Dopamine hydrochloride 
00360702087 
Dopamina duncan 
Dopamine hydrochloride 
00360702164 
Dopamina exakta 
Dopamine hydrochloride 
00360702130 
Dopamina fides 
Dopamine hydrochloride 
00360702160 
Dopamina fu 
Dopamine hydrochloride 
00360702069 
Dopamina gi zafiro 
Dopamine hydrochloride 
00360702181 
Dopamina grifols 
Dopamine hydrochloride 
00360702068 
Dopamina kendrick 
Dopamine hydrochloride 
00360702163 
Dopamina northia 
Dopamine hydrochloride 
00360702078 
Dopamina pht 
Dopamine hydrochloride 
CCI
CCI
PPD
CCI


Amgen Inc 
Master Protocol COV-01 
Master Statistical Analysis Plan 
Page 96 of 118 
 
 
 
 
 
Version Number: 
Amendment 1, v1.0 
 
Version Date:  
23Apr2021 
 
 
 
 
 
 
 
Drug code 
Product Name 
Active Ingredients 
00360702077 
Dopamina salf 
Dopamine hydrochloride 
00360702183 
Dopamina surar pharma 
Dopamine hydrochloride 
00360701001 
Dopamine 
Dopamine 
00360702007 
Dopamine 
Dopamine hydrochloride 
00360702119 
Dopamine abbott 
Dopamine hydrochloride 
00360702074 
Dopamine aguettant 
Dopamine hydrochloride 
00360702095 
Dopamine fresenius 
Dopamine hydrochloride 
00360702071 
Dopamine hcl 
Dopamine hydrochloride 
00360702111 
Dopamine hcl abbott 
Dopamine hydrochloride 
00360702102 
Dopamine hcl-fresenius 
Dopamine hydrochloride 
00360702096 
Dopamine hycrochloride 
Dopamine hydrochloride 
00360702001 
Dopamine hydrochloride 
Dopamine hydrochloride 
00360702115 
Dopamine hydrochloride dbl 
Dopamine hydrochloride 
00360702124 
Dopamine hydrochloride kobayashi 
Dopamine hydrochloride 
00360702134 
Dopamine Hydrochloride Mochida 
Dopamine hydrochloride 
00360702133 
Dopamine Hydrochloride Shionogi 
Dopamine hydrochloride 
00360702073 
Dopamine lucien 
Dopamine hydrochloride 
00360702075 
Dopamine merck 
Dopamine hydrochloride 
00360702193 
Dopamine mylan 
Dopamine hydrochloride 
00360702127 
Dopamine nativelle 
Dopamine hydrochloride 
00360702146 
Dopamine PCH 
Dopamine hydrochloride 
00360702072 
Dopamine pierre fabre 
Dopamine hydrochloride 
00360702062 
Dopamine premix 
Dopamine hydrochloride 
00360702135 
Dopamine Renaudin 
Dopamine hydrochloride 
00360702057 
Dopamine towa 
Dopamine hydrochloride 
00360702190 
Dopamine/anfarm 
Dopamine hydrochloride 
00360702099 
Dopamine-p 
Dopamine hydrochloride 
00360702100 
Dopaminex 
Dopamine hydrochloride 
00360702176 
Dopamini hydrochloridum 
Dopamine hydrochloride 
00360701003 
Dopaminum 
Dopamine 
00360702129 
Dopaminum hydrochloricum 
Dopamine hydrochloride 
00360702085 
Dopamol 
Dopamine hydrochloride 
00360702094 
Dopan 
Dopamine hydrochloride 
CCI
CCI
PPD
CCI


Amgen Inc 
Master Protocol COV-01 
Master Statistical Analysis Plan 
Page 97 of 118 
 
 
 
 
 
Version Number: 
Amendment 1, v1.0 
 
Version Date:  
23Apr2021 
 
 
 
 
 
 
 
Drug code 
Product Name 
Active Ingredients 
00360702098 
Dopaplus 
Dopamine hydrochloride 
00360702166 
Dopaqard 
Dopamine hydrochloride 
00360702041 
Doparalmin 
Dopamine hydrochloride 
00360702192 
Dopasel 
Dopamine hydrochloride 
00360702092 
Dopasin 
Dopamine hydrochloride 
00360702191 
Dopasunny 
Dopamine hydrochloride 
00360702180 
Dopatropin 
Dopamine hydrochloride 
00360702123 
Dopavate 
Dopamine hydrochloride 
00360702195 
Dopazef 
Dopamine hydrochloride 
00360702110 
Doperba 
Dopamine hydrochloride 
00360702063 
Dophamin 
Dopamine hydrochloride 
00360702120 
Dopin 
Dopamine hydrochloride 
00360702106 
Dopina 
Dopamine hydrochloride 
00360702097 
Dopinga 
Dopamine hydrochloride 
00360702033 
Dopmin 
Dopamine hydrochloride 
00360701002 
Dopmin 
Dopamine 
00493402016 
Dopmin 
Dobutamine hydrochloride 
00493402081 
Dopmin-k 
Dobutamine hydrochloride 
00360702179 
Dopnax 
Dopamine hydrochloride 
00360702088 
Dopramine 
Dopamine hydrochloride 
00360702139 
Dopress 
Dopamine hydrochloride 
00360702196 
Doprina 
Dopamine hydrochloride 
00493402082 
Doputamin 
Dobutamine hydrochloride 
00493402100 
Doputamin Fuji 
Dobutamine hydrochloride 
00493402020 
Doputamin h hexal 
Dobutamine hydrochloride 
00493402083 
Doputamin k 
Dobutamine hydrochloride 
00493402101 
Dotamin 
Dobutamine hydrochloride 
00493402055 
Dotrex 
Dobutamine hydrochloride 
00493402145 
Dotropina 
Dobutamine hydrochloride 
00003901079 
Drenalin 
Epinephrine 
00127502068 
Drenorep 
Norepinephrine bitartrate 
00493402148 
Dubuject 
Dobutamine hydrochloride 
00493402114 
Duvig 
Dobutamine hydrochloride 
CCI
CCI
PPD
CCI


Amgen Inc 
Master Protocol COV-01 
Master Statistical Analysis Plan 
Page 98 of 118 
 
 
 
 
 
Version Number: 
Amendment 1, v1.0 
 
Version Date:  
23Apr2021 
 
 
 
 
 
 
 
Drug code 
Product Name 
Active Ingredients 
00360702079 
Dynatra 
Dopamine hydrochloride 
00360702021 
Dynatra dopamine 
Dopamine hydrochloride 
00360702020 
Dynos 
Dopamine hydrochloride 
00003902039 
Dyspne inhalante 
Epinephrine hydrochloride 
00003901039 
Dyspne-inhal 
Epinephrine 
00493402142 
E.m.c. dobutamina 
Dobutamine hydrochloride 
00493402123 
Easydobu 
Dobutamine hydrochloride 
00360702149 
Easydopa 
Dopamine hydrochloride 
00003901065 
Efrinalin 
Epinephrine 
00360702047 
Elebumin 
Dopamine hydrochloride 
00003903047 
Emerade 
Epinephrine bitartrate 
00003903044 
Enatrate 
Epinephrine bitartrate 
01872201008 
Encrise 
Vasopressin 
00003901096 
Ephedrix 
Epinephrine 
00003902033 
Epi e-z 
Epinephrine hydrochloride 
00003902034 
Epi e-z pen jr. 
Epinephrine hydrochloride 
00003902071 
Epibbas 
Epinephrine hydrochloride 
00003903034 
Epifrin 
Epinephrine bitartrate 
00003902022 
Epifrin 
Epinephrine hydrochloride 
00003904004 
Epinal 
Epinephryl borate 
00003902049 
Epinefrina 
Epinephrine hydrochloride 
00003901050 
Epinefrina 
Epinephrine 
00003901001 
Epinephrine 
Epinephrine 
00003902030 
Epinephrine 
Epinephrine hydrochloride 
00003903006 
Epinephrine 
Epinephrine bitartrate 
00003903001 
Epinephrine bitartrate 
Epinephrine bitartrate 
00003902070 
Epinephrine HCL 
Epinephrine hydrochloride 
00003902001 
Epinephrine hydrochloride 
Epinephrine hydrochloride 
00003901070 
Epinephrine minijet 
Epinephrine 
00003901108 
Epinephrine professional 
Epinephrine 
00003901105 
Epinephrinesnap v 
Epinephrine 
00003901077 
Epinephrinum 
Epinephrine 
00003904001 
Epinephryl borate 
Epinephryl borate 
CCI
CCI
PPD
CCI


Amgen Inc 
Master Protocol COV-01 
Master Statistical Analysis Plan 
Page 99 of 118 
 
 
 
 
 
Version Number: 
Amendment 1, v1.0 
 
Version Date:  
23Apr2021 
 
 
 
 
 
 
 
Drug code 
Product Name 
Active Ingredients 
00127504004 
Epinor 
Norepinephrine bitartrate monohydrate 
00003901014 
Epipen 
Epinephrine 
00003901082 
Epipen 2-pak 
Epinephrine 
00003901084 
Epipen jr 
Epinephrine 
00003901037 
Epipen jr 2-pak 
Epinephrine 
00003901104 
Epipen junior 
Epinephrine 
00003901020 
Epiquick 
Epinephrine 
00003902043 
Epiren 
Epinephrine hydrochloride 
00003902054 
Epirenamin 
Epinephrine hydrochloride 
00003902064 
Epirenin 
Epinephrine hydrochloride 
00003901086 
Episnap 
Epinephrine 
00003901071 
Epista 
Epinephrine 
00003903003 
Epitrate 
Epinephrine bitartrate 
00003902073 
Epix 
Epinephrine hydrochloride 
00003901024 
Eppy 
Epinephrine 
00003904002 
Eppy n 
Epinephryl borate 
00003901013 
Eppy plus 
Epinephrine 
00360702022 
Evetant 
Dopamine hydrochloride 
00360702059 
Evetant hexal 
Dopamine hydrochloride 
00360702056 
Evetant towa 
Dopamine hydrochloride 
00003902011 
Fastjekt 
Epinephrine hydrochloride 
00003902038 
Fastjekt junior 
Epinephrine hydrochloride 
00127502036 
Fioritina 
Norepinephrine bitartrate 
00127502073 
Forefrin 
Norepinephrine bitartrate 
00360702042 
Gabans 
Dopamine hydrochloride 
00493402065 
Gendobu 
Dobutamine hydrochloride 
00360702004 
Giludop 
Dopamine hydrochloride 
00003902066 
Gingi pak z twist 
Epinephrine hydrochloride 
00003901012 
Gingipak 
Epinephrine 
00360702156 
Gipamine 
Dopamine hydrochloride 
00003902027 
Glaucon 
Epinephrine hydrochloride 
00003903011 
Glaucon 
Epinephrine bitartrate 
00003902010 
Glaufrin 
Epinephrine hydrochloride 
CCI
CCI
PPD
CCI


Amgen Inc 
Master Protocol COV-01 
Master Statistical Analysis Plan 
Page 100 of 118 
 
 
 
 
 
Version Number: 
Amendment 1, v1.0 
 
Version Date:  
23Apr2021 
 
 
 
 
 
 
 
Drug code 
Product Name 
Active Ingredients 
00003901015 
Glauposine 
Epinephrine 
00127502028 
Hemitartarato de Norepinefrina 
Norepinephrine bitartrate 
00493402015 
Hercarenone d 
Dobutamine hydrochloride 
00360702086 
Hettytropin 
Dopamine hydrochloride 
00003901046 
Hydren 
Epinephrine 
00127502014 
Hyponor 
Norepinephrine bitartrate 
00493402153 
Imatim 
Dobutamine hydrochloride 
00003902023 
Ims adrenaline 
Epinephrine hydrochloride 
00360702061 
Ims dopamine 
Dopamine hydrochloride 
00360702112 
Indop 
Dopamine hydrochloride 
00003902055 
Infectokrupp 
Epinephrine hydrochloride 
00003903053 
Infectokrupp 
Epinephrine bitartrate 
00127502034 
Infunor 
Norepinephrine bitartrate 
00493402095 
Inocard 
Dobutamine hydrochloride 
00493402131 
Inodex 
Dobutamine hydrochloride 
00493402117 
Inoject 
Dobutamine hydrochloride 
00360702090 
Inophan 
Dopamine hydrochloride 
00360702118 
Inopin 
Dopamine hydrochloride 
00493402027 
Inotop 
Dobutamine hydrochloride 
00493402003 
Inotrex 
Dobutamine hydrochloride 
00493402060 
Inotrop 
Dobutamine hydrochloride 
00360702067 
Inotropin 
Dopamine hydrochloride 
00360702084 
Inotropisa 
Dopamine hydrochloride 
00360702005 
Inovan 
Dopamine hydrochloride 
00360702002 
Intropin 
Dopamine hydrochloride 
00360702060 
Intropin ahs 
Dopamine hydrochloride 
00003901032 
Isopto ephinal 
Epinephrine 
00003901025 
Isopto epinal 
Epinephrine 
00003901007 
Isoptoepinal 
Epinephrine 
00003903039 
Jext 
Epinephrine bitartrate 
00360702031 
Kakodin 
Dopamine hydrochloride 
00360702137 
Kakodin D 
Dopamine hydrochloride 
00493402051 
Kardia 
Dobutamine hydrochloride 
CCI
CCI
PPD
CCI


Amgen Inc 
Master Protocol COV-01 
Master Statistical Analysis Plan 
Page 101 of 118 
 
 
 
 
 
Version Number: 
Amendment 1, v1.0 
 
Version Date:  
23Apr2021 
 
 
 
 
 
 
 
Drug code 
Product Name 
Active Ingredients 
00127502049 
L noradrenalina braun 
Norepinephrine bitartrate 
00003901035 
L-adrenalin 
Epinephrine 
00003901078 
L-epinephrine 
Epinephrine 
00127501003 
Levarterenol 
Norepinephrine 
00127502038 
Levarterenol bitartrate 
Norepinephrine bitartrate 
00127503007 
Levarterenol HCL 
Norepinephrine hydrochloride 
00127503008 
Levarterenol hydrochloride 
Norepinephrine hydrochloride 
00003902008 
Levocon 
Epinephrine hydrochloride 
00127502005 
Levonor 
Norepinephrine bitartrate 
00127502002 
Levophed 
Norepinephrine bitartrate 
00127502023 
Levophed bitartrat 
Norepinephrine bitartrate 
00127502003 
Levophed bitartrate 
Norepinephrine bitartrate 
00127501009 
Levophrine 
Norepinephrine 
00003903019 
Liadren 
Epinephrine bitartrate 
00360702177 
Loxin 
Dopamine hydrochloride 
00003903009 
Lyophrin 
Epinephrine bitartrate 
00360702043 
Martburn 
Dopamine hydrochloride 
00003902024 
Mediastman 
Epinephrine hydrochloride 
00003903020 
Medihaler 
Epinephrine bitartrate 
00003903002 
Medihaler-epi 
Epinephrine bitartrate 
00360702169 
Medopa 
Dopamine hydrochloride 
00360702158 
Megadose 
Dopamine hydrochloride 
00493402162 
Mekard 
Dobutamine hydrochloride 
00127502081 
Mephrin 
Norepinephrine bitartrate 
00003901030 
Mf adrenalin 
Epinephrine 
00360702148 
Micro Dopamine 
Dopamine hydrochloride 
00003903028 
Micro-adrenaline 
Epinephrine bitartrate 
00003902004 
Micronefrin 
Epinephrine hydrochloride 
00003901059 
Min-I-Jet Adrenalin 
Epinephrine 
00360702141 
Miocina 
Dopamine hydrochloride 
00493402031 
Miozac 
Dobutamine hydrochloride 
00360702051 
Mitasmin 
Dopamine hydrochloride 
00493402129 
Mobitil 
Dobutamine hydrochloride 
CCI
CCI
PPD
CCI


Amgen Inc 
Master Protocol COV-01 
Master Statistical Analysis Plan 
Page 102 of 118 
 
 
 
 
 
Version Number: 
Amendment 1, v1.0 
 
Version Date:  
23Apr2021 
 
 
 
 
 
 
 
Drug code 
Product Name 
Active Ingredients 
00360702104 
Myocard 
Dopamine hydrochloride 
00360702184 
Myofast 
Dopamine hydrochloride 
00360702171 
Myomine 
Dopamine hydrochloride 
00360702189 
Myotil 
Dopamine hydrochloride 
00127502058 
N Epi 
Norepinephrine bitartrate 
00003901004 
Nebulogenum hectalini 
Epinephrine 
00127502086 
Nefrinor 
Norepinephrine bitartrate 
00003902058 
Neosynephrine Badrial 
Epinephrine hydrochloride 
00127502090 
Nevoleen 
Norepinephrine bitartrate 
00127502083 
Nobify 
Norepinephrine bitartrate 
00127502008 
Nor adrenalin 
Norepinephrine bitartrate 
00127501010 
Nor adrenalin 
Norepinephrine 
00127502020 
Norad 
Norepinephrine bitartrate 
00127502087 
Norad 4 
Norepinephrine bitartrate 
00127502041 
Noradrec 
Norepinephrine bitartrate 
00127502013 
Noradren 
Norepinephrine bitartrate 
00127501005 
Noradrenalin 
Norepinephrine 
00127502006 
Noradrenalin 
Norepinephrine bitartrate 
00127503005 
Noradrenalin 
Norepinephrine hydrochloride 
00127503006 
Nor-Adrenalin 
Norepinephrine hydrochloride 
00127502017 
Nor-adrenalin 
Norepinephrine bitartrate 
00127502051 
Noradrenalin Abcur 
Norepinephrine bitartrate 
00127502084 
Noradrenalin aguettant 
Norepinephrine bitartrate 
00127502010 
Noradrenalin Bichsel 
Norepinephrine bitartrate 
00127502045 
Noradrenalin Hospira 
Norepinephrine bitartrate 
00127502094 
Noradrenalin ligula pharma 
Norepinephrine bitartrate 
00127502011 
Noradrenalin mayrhofer 
Norepinephrine bitartrate 
00127502042 
Noradrenalin naf sykehusapoteket 
Norepinephrine bitartrate 
00127502061 
Noradrenalin orpha 
Norepinephrine bitartrate 
00127502007 
Noradrenalin sad 
Norepinephrine bitartrate 
00127502098 
Noradrenalin sintetica 
Norepinephrine bitartrate 
00127503004 
Noradrenalina 
Norepinephrine hydrochloride 
00127502043 
Noradrenalina 
Norepinephrine bitartrate 
CCI
CCI
PPD
CCI


Amgen Inc 
Master Protocol COV-01 
Master Statistical Analysis Plan 
Page 103 of 118 
 
 
 
 
 
Version Number: 
Amendment 1, v1.0 
 
Version Date:  
23Apr2021 
 
 
 
 
 
 
 
Drug code 
Product Name 
Active Ingredients 
00127501006 
Noradrenalina 
Norepinephrine 
00127502071 
Noradrenalina basi 
Norepinephrine bitartrate 
00127502015 
Noradrenalina biol 
Norepinephrine bitartrate 
00127502025 
Noradrenalina braun 
Norepinephrine bitartrate 
00127502050 
Noradrenalina Combino pharm 
Norepinephrine bitartrate 
00127502067 
Noradrenalina Generis 
Norepinephrine bitartrate 
00127501008 
Noradrenalina Max vision 
Norepinephrine 
00127502029 
Noradrenalina Normon 
Norepinephrine bitartrate 
00127502089 
Noradrenalina novophar 
Norepinephrine bitartrate 
00127502016 
Noradrenalina richet 
Norepinephrine bitartrate 
00127502033 
Noradrenalina tartrato 
Norepinephrine bitartrate 
00127502092 
Noradrenalina tartrato aguettant 
Norepinephrine bitartrate 
00127501002 
Noradrenaline 
Norepinephrine 
00127502021 
Noradrenaline 
Norepinephrine bitartrate 
00127504003 
Noradrenaline 
Norepinephrine bitartrate monohydrate 
00127502097 
Noradrenaline (Norpinephrine) 
Norepinephrine bitartrate 
00127502055 
Noradrenaline acid tartrate anhydrous 
Norepinephrine bitartrate 
00127502012 
Noradrenaline aguettant 
Norepinephrine bitartrate 
00127502079 
Noradrenaline bnm 
Norepinephrine bitartrate 
00127503009 
Noradrenaline dl-form hydrochloride 
Norepinephrine hydrochloride 
00127502046 
Noradrenaline Hospira 
Norepinephrine bitartrate 
00127503010 
Noradrenaline hydrochloride 
Norepinephrine hydrochloride 
00127503011 
Noradrenaline hydrochloride, dl-form 
Norepinephrine hydrochloride 
00127502088 
Noradrenaline kabi 
Norepinephrine bitartrate 
00127502078 
Noradrenaline medis 
Norepinephrine bitartrate 
00127502026 
Noradrenaline Merck 
Norepinephrine bitartrate 
00127502085 
Noradrenaline mylan 
Norepinephrine bitartrate 
00127502072 
Noradrenaline myx 
Norepinephrine bitartrate 
00127502037 
Noradrenaline PCH 
Norepinephrine bitartrate 
00127502027 
Noradrenaline Renaudin 
Norepinephrine bitartrate 
00127502059 
Noradrenaline saiph 
Norepinephrine bitartrate 
00127502091 
Noradrenaline Sintetica 
Norepinephrine bitartrate 
00127502074 
Noradrenaline tartrate renaudin 
Norepinephrine bitartrate 
CCI
CCI
PPD
CCI


Amgen Inc 
Master Protocol COV-01 
Master Statistical Analysis Plan 
Page 104 of 118 
 
 
 
 
 
Version Number: 
Amendment 1, v1.0 
 
Version Date:  
23Apr2021 
 
 
 
 
 
 
 
Drug code 
Product Name 
Active Ingredients 
00127502056 
Noradrenalini tartras 
Norepinephrine bitartrate 
00127501012 
Noradrenalinum 
Norepinephrine 
00127502053 
Noradria 
Norepinephrine bitartrate 
00127502047 
Norages 
Norepinephrine bitartrate 
00127502060 
Noraline 
Norepinephrine bitartrate 
00127502069 
Norbit 
Norepinephrine bitartrate 
00127502077 
Norene 
Norepinephrine bitartrate 
00127502044 
Norepin 
Norepinephrine bitartrate 
00127502039 
Norepine 
Norepinephrine bitartrate 
00127502035 
Norepinefrina 
Norepinephrine bitartrate 
00127501014 
Norepinefrina 
Norepinephrine 
00127502048 
Norepinefrina northia 
Norepinephrine bitartrate 
00127502075 
Norepinefrina vitalis 
Norepinephrine bitartrate 
00127502024 
Norepinefrine 
Norepinephrine bitartrate 
00127503003 
Norepinephrine 
Norepinephrine hydrochloride 
00127502004 
Norepinephrine 
Norepinephrine bitartrate 
00127501001 
Norepinephrine 
Norepinephrine 
00127502001 
Norepinephrine Bitartrate 
Norepinephrine bitartrate 
00127504001 
Norepinephrine bitartrate monohydrate 
Norepinephrine bitartrate monohydrate 
00127503012 
Norepinephrine HCL 
Norepinephrine hydrochloride 
00127503001 
Norepinephrine hydrochloride 
Norepinephrine hydrochloride 
00127502093 
Norepinephrine sopharma 
Norepinephrine bitartrate 
00127502057 
Norepinephrine tartrate 
Norepinephrine bitartrate 
00127501013 
Norepinephrinum 
Norepinephrine 
00127502019 
Norepirin 
Norepinephrine bitartrate 
00127502082 
Noreprin 
Norepinephrine bitartrate 
00127502052 
Norphed 
Norepinephrine bitartrate 
00127501011 
Norpin 
Norepinephrine 
00127502018 
Norpine 
Norepinephrine bitartrate 
00127502096 
Northix 
Norepinephrine bitartrate 
01872201009 
Novopressina-V 
Vasopressin 
00003902061 
Oboi Epinephrine 
Epinephrine hydrochloride 
00003901034 
Oftan adrenalin 
Epinephrine 
CCI
CCI
PPD
CCI


Amgen Inc 
Master Protocol COV-01 
Master Statistical Analysis Plan 
Page 105 of 118 
 
 
 
 
 
Version Number: 
Amendment 1, v1.0 
 
Version Date:  
23Apr2021 
 
 
 
 
 
 
 
Drug code 
Product Name 
Active Ingredients 
00003901011 
Oftan-adrenalin 
Epinephrine 
00360702107 
Oridop 
Dopamine hydrochloride 
00003902009 
Orostat 
Epinephrine hydrochloride 
00003901095 
Penepin 
Epinephrine 
00003903041 
Pharma Q Adrenaline 
Epinephrine bitartrate 
00360702188 
Pharma q dopamine 
Dopamine hydrochloride 
00003903050 
Pharma-q adrenaline 
Epinephrine bitartrate 
00003902050 
Phenylephrin 
Epinephrine hydrochloride 
00003901080 
Phinev 
Epinephrine 
00127502032 
Pidram 
Norepinephrine bitartrate 
00003901036 
Pinadrina 
Epinephrine 
01872202006 
Pitressin 
Vasopressin tannate 
01872201002 
Pitressin 
Vasopressin 
01872201006 
Pitressin aqueous 
Vasopressin 
01872201013 
Pitressin tanato 
Vasopressin 
01872202004 
Pitressin Tannat in Oil 
Vasopressin tannate 
01872202002 
Pitressin tannate 
Vasopressin tannate 
01872201011 
Pitressin tannate 
Vasopressin 
01872202007 
Pitressin tannate in oil 
Vasopressin tannate 
01872201015 
Pitressin tannate in oil 
Vasopressin 
01872202003 
Pitressin tannate oil 
Vasopressin tannate 
00493402008 
Posiject 
Dobutamine hydrochloride 
00003901056 
Posumin 
Epinephrine 
00360702032 
Predopa 
Dopamine hydrochloride 
00360702132 
Predopa Kyowa 
Dopamine hydrochloride 
00360702125 
Predopa merck hoei 
Dopamine hydrochloride 
01872201003 
Pressyn 
Vasopressin 
01872201007 
Pressyn ar 
Vasopressin 
00127502009 
Pridam 
Norepinephrine bitartrate 
00003901067 
Primatene 
Epinephrine 
00003901060 
Primatene mist 
Epinephrine 
00360702108 
Proinfark 
Dopamine hydrochloride 
00493402154 
Pusogard 
Dobutamine hydrochloride 
CCI
CCI
PPD
CCI


Amgen Inc 
Master Protocol COV-01 
Master Statistical Analysis Plan 
Page 106 of 118 
 
 
 
 
 
Version Number: 
Amendment 1, v1.0 
 
Version Date:  
23Apr2021 
 
 
 
 
 
 
 
Drug code 
Product Name 
Active Ingredients 
00127502066 
Q phrine 
Norepinephrine bitartrate 
00003903021 
Racepinephrine 
Epinephrine bitartrate 
00003902006 
Racord 
Epinephrine hydrochloride 
00127502062 
Radline 
Norepinephrine bitartrate 
00127504002 
Raivas 
Norepinephrine bitartrate monohydrate 
00493402110 
Retamex 
Dobutamine hydrochloride 
00360702006 
Revimine 
Dopamine hydrochloride 
00360702015 
Revivan 
Dopamine hydrochloride 
00003903017 
S2 
Epinephrine bitartrate 
00003902036 
S-2 
Epinephrine hydrochloride 
00360702018 
Sabax dopamine 
Dopamine hydrochloride 
00127502080 
Sandine 
Norepinephrine bitartrate 
00003903012 
Sanepi 
Epinephrine bitartrate 
00127502070 
Seladrenalin 
Norepinephrine bitartrate 
00360702153 
Seminiet 
Dopamine hydrochloride 
00003901008 
Simplene 
Epinephrine 
00127502076 
Sinora 
Norepinephrine bitartrate 
00127502095 
Softamicid 
Norepinephrine bitartrate 
00003902067 
Spinefe 
Epinephrine hydrochloride 
00493402084 
Starzen 
Dobutamine hydrochloride 
00127502054 
Stenor 
Norepinephrine bitartrate 
00127502031 
Steradin 
Norepinephrine bitartrate 
00360702157 
Sterile dopamine concentrate 
Dopamine hydrochloride 
01872201014 
Stimate 
Vasopressin 
00003901090 
Supradin 
Epinephrine 
00003901005 
Suprarenin 
Epinephrine 
00003902029 
Suprarenin 
Epinephrine hydrochloride 
00003901074 
Surgident 
Epinephrine 
00003902002 
Sus-phrine 
Epinephrine hydrochloride 
00003901038 
Sus-phrine 
Epinephrine 
00003901092 
Symjepi 
Epinephrine 
00360702055 
Taiadopa 
Dopamine hydrochloride 
00360702017 
Tensamin 
Dopamine hydrochloride 
CCI
CCI
PPD
CCI


Amgen Inc 
Master Protocol COV-01 
Master Statistical Analysis Plan 
Page 107 of 118 
 
 
 
 
 
Version Number: 
Amendment 1, v1.0 
 
Version Date:  
23Apr2021 
 
 
 
 
 
 
 
Drug code 
Product Name 
Active Ingredients 
00493402042 
Toburex 
Dobutamine hydrochloride 
00003901023 
Tonogen 
Epinephrine 
00360702154 
Tronjin 
Dopamine hydrochloride 
00360702089 
Tropin 
Dopamine hydrochloride 
00360702046 
Tsurudopami 
Dopamine hydrochloride 
00127502099 
Turktipsan noradrenalin 
Norepinephrine bitartrate 
00003901057 
Twinject 
Epinephrine 
00360702091 
Udopa 
Dopamine hydrochloride 
00360702145 
Upamine 
Dopamine hydrochloride 
00360702121 
Uramin 
Dopamine hydrochloride 
00493402064 
Utamine 
Dobutamine hydrochloride 
00003902003 
Vaponefrin 
Epinephrine hydrochloride 
00003902020 
Vaponefrin hisamitsu 
Epinephrine hydrochloride 
00003902021 
Vaponefrin tokyo mi shokai 
Epinephrine hydrochloride 
01872201023 
Vascel 
Vasopressin 
00127502022 
Vascon 
Norepinephrine bitartrate 
00003903025 
Vasocon 
Epinephrine bitartrate 
01872201025 
Vasopar 
Vasopressin 
01872201017 
Vasopin 
Vasopressin 
01872201001 
Vasopressin 
Vasopressin 
01872201010 
Vasopressin injection 
Vasopressin 
01872201022 
Vasopressin sandoz 
Vasopressin 
01872201005 
Vasopressin tannat 
Vasopressin 
01872202005 
Vasopressin tannat 
Vasopressin tannate 
01872202001 
Vasopressin tannate 
Vasopressin tannate 
01872201019 
Vasopressina 
Vasopressin 
01872201004 
Vasopressine 
Vasopressin 
01872202008 
Vasopressini tannas 
Vasopressin tannate 
01872201021 
Vasostrict 
Vasopressin 
00360702122 
Vidopa 
Dopamine hydrochloride 
00003901053 
Weradren 
Epinephrine 
00360702155 
Yaelista 
Dopamine hydrochloride 
00360702049 
Yaelista mita 
Dopamine hydrochloride 
CCI
CCI
PPD
CCI


Amgen Inc 
Master Protocol COV-01 
Master Statistical Analysis Plan 
Page 108 of 118 
 
 
 
 
 
Version Number: 
Amendment 1, v1.0 
 
Version Date:  
23Apr2021 
 
 
 
 
 
 
 
Drug code 
Product Name 
Active Ingredients 
00360702142 
Zetarina 
Dopamine hydrochloride 
 
 
CCI
CCI
PPD
CCI


Amgen Inc 
Master Protocol COV-01 
Master Statistical Analysis Plan 
Page 109 of 118 
 
 
 
 
 
Version Number: 
Amendment 1, v1.0 
 
Version Date:  
23Apr2021 
 
 
 
 
 
 
 
APPENDIX 5 LABORATORY ASSESSMENTS 
Hematology (SI unit) 
 
• 
Platelets count (x10E9/L) 
 
• 
Hemoglobin (g/L) 
 
• 
White blood cell (WBC) count total (x10E9/L) 
 
• 
Absolute neutrophils count (x10E9/L) 
• 
Relative neutrophils count (%) 
• 
Absolute lymphocyte count (x10E9/L) 
• 
Relative lymphocyte count (%) 
• 
Absolute monocyte count (x10E9/L) 
• 
Relative monocyte count (%) 
• 
Absolute eosinophils count (x10E9/L) 
• 
Relative eosinophils count (%) 
• 
Absolute basophils count (x10E9/L) 
• 
Relative basophils count (%) 
 
Coagulation (SI unit) 
 
• 
D-dimer (mg/Lmg/L) 
• 
C-reactive protein (CRP) (mg/L) 
• 
Fibrinogen (g/L) 
• 
Ferritin (µg/L) 
• 
Activated partial thromboplastin time (s) 
• 
Lactate dehydrogenase (LDH) (IU/L) 
• 
Prothrombin time (PT) (s) 
• 
Procalcitonin (µg/L) 
• 
International normalized ratio (INR) 
 
 
 
 
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Amgen Inc 
Master Protocol COV-01 
Master Statistical Analysis Plan 
Page 110 of 118 
 
 
 
 
 
Version Number: 
Amendment 1, v1.0 
 
Version Date:  
23Apr2021 
 
 
 
 
 
 
 
 
Chemistry (SI unit) 
 
• 
General 
 
o 
Potassium (mmol/L) 
o 
Phosphate (mmol/L)  
o 
Sodium (mmol/L) 
o 
Bicarbonate (mmol/L)  
o 
Calcium (mmol/L) 
o 
Creatinine (µmol/L)  
o 
Magnesium (mmol/L) 
o 
Glucose (mmol/L) 
• 
Liver Function Tests 
 
o 
Alkaline phosphatase (ALP) (IU/L) 
o 
Alanine transaminase (ALT) (IU/L) 
o 
Total bilirubin (µmol/L) 
o 
Gamma glutamyl transferase (GGT) (IU/L)  
o 
Aspartate transaminase (AST) (IU/L) 
 
• 
Cardiac Panel 
 
o 
Creatine kinase (CK) (IU/L) 
o 
Troponin I (µg/L)  
o 
CK MB isoenzyme fraction of CK (IU/L) 
o 
Troponin T (µg/L) 
o 
Triglycerides (mmol/L) 
  
 
 
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Amgen, Inc.  
Master Protocol COV-01 
Master Statistical Analysis Plan 
Page 111 of 118 
 
 
 
 
 
Version Number: 
Amendment 1, v1.0 
 
Version Date:  
23Apr2021 
 
 
 
 
 
 
 
APPENDIX 6 CTCAE TOXICITY GRADE, VERSION 5.0 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm (accessed on 22-Apr-2020) 
CTCAE Term 
Laboratory Test 
No Event 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Platelet count decreased 
Platelet count 
(x10E9/L) 
≥ LLN 
≥ 75 x 10E9/L 
– < LLN 
≥ 50 - 
< 75 x 10E9/L 
≥ 25 - 
< 50 x 10E9/L 
< 25 x 10E9/L 
n/a 
Anemia 
Hemoglobin (g/L) 
≥ LLN 
≥ 100 g/L - 
< LLN 
≥ 80 - 
< 100 g/L 
< 80 g/L 
n/a 
n/a 
Hemoglobin increased 
Hemoglobin (g/L) 
No increase 
from baseline 
Increase from 
baseline > 0 - ≤ 
20 g/L 
Increase from 
baseline > 20 - 
≤ 40 g/L 
Increase from 
baseline 
> 40 g/L 
n/a 
n/a 
White blood cell (WBC) 
decreased 
WBC (x 10E9/L) 
≥ LLN 
≥ 3.0 x 10E9/L 
– < LLN 
≥ 2.0 - 
< 3.0 x 10E9/L 
≥ 1.0 - < 2.0 x 
10E9/L 
< 1.0 x 10E9/L 
n/a 
Leukocytosis 
WBC (x 10E9/L) 
≤ 100 x 
10E9/L 
n/a 
n/a 
> 100 x 10E9/L 
n/a 
n/a 
Absolute neutrophils 
count decreased 
Absolute neutrophils 
count (x 10E9/L) 
≥ LLN 
≥ 1.5 x 10E9/L 
– < LLN 
≥ 1.0 - 
< 1.5 x 10E9/L 
≥ 0.5 - < 1.0 x 
10E9/L 
< 0.5 x 10E9/L 
n/a 
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Amgen, Inc.  
Master Protocol COV-01 
Master Statistical Analysis Plan 
Page 112 of 118 
 
 
 
 
 
Version Number: 
Amendment 1, v1.0 
 
Version Date:  
23Apr2021 
 
 
 
 
 
 
 
CTCAE Term 
Laboratory Test 
No Event 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Absolute lymphocytes 
count decreased 
Absolute lymphocytes 
count (x 10E9/L) 
≥ LLN 
≥ 0.8 x 10E9/L 
– < LLN 
≥ 0.5 - 
< 0.8 x 10E9/L 
≥ 0.2 - 
< 0.5 x 10E9/L 
< 0.2 x 10E9/L 
n/a 
Absolute lymphocytes 
count increased 
Absolute lymphocytes 
count (x 10E9/L) 
≤ 4 x 10E9/L 
n/a 
> 4 – 
≤ 20 x 10E9/L 
> 20 x 10E9/L 
n/a 
n/a 
Eosinophilia 
Absolute eosinophils 
count (x 10E9/L) 
≤ ULN or 
≤ Baseline 
> ULN and 
> Baseline 
n/a 
n/a 
n/a 
n/a 
Fibrinogen decreased 
Fibrinogen (g/L) 
≥ LLN if 
baseline 
normal; 
no decrease 
from baseline 
if baseline 
abnormal 
≥ 0.75 - 
< 1 x LLN if 
baseline 
normal; 
> 0 - < 25% 
decrease from 
baseline if 
baseline 
abnormal 
≥ 0.5 - 
< 0.75 x LLN 
if baseline 
normal; 
≥ 25 - < 50% 
decrease from 
baseline if 
baseline 
abnormal 
≥ 0.25 - 
< 0.5 x LLN if 
baseline 
normal; 
≥ 50 - < 75% 
decrease from 
baseline if 
baseline 
abnormal 
< 0.25 x LLN if 
baseline 
normal; 
≥ 75% decrease 
from baseline if 
baseline 
abnormal 
 
Activated partial 
thromboplastin time 
(aPTT) prolonged 
aPTT (s) 
≤ ULN 
> ULN – 
≤ 1.5 x ULN 
> 1.5 – 
≤ 2.5 x ULN 
> 2.5 ULN 
n/a 
n/a 
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Amgen, Inc.  
Master Protocol COV-01 
Master Statistical Analysis Plan 
Page 113 of 118 
 
 
 
 
 
Version Number: 
Amendment 1, v1.0 
 
Version Date:  
23Apr2021 
 
 
 
 
 
 
 
CTCAE Term 
Laboratory Test 
No Event 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
International normalized 
ratio (INR) increased 
INR 
≤ 1.2 if not on 
anticoagulant; 
≤ baseline if 
on 
anticoagulant 
> 1.2 – ≤1.5 if 
not on 
anticoagulant; 
> baseline - 
≤ 1.5 x baseline 
if on 
anticoagulant 
> 1.5 – ≤2.5 if 
not on 
anticoagulant; 
> 1.5 - ≤ 2.5 x 
baseline if on 
anticoagulant 
> 2.5 if not on 
anticoagulant; 
> 2.5 x baseline 
if on 
anticoagulant 
n/a 
n/a 
Blood lactate 
dehydrogenase (LDH) 
increased 
LDH (IU/L) 
≤ ULN 
> ULN 
n/a 
n/a 
n/a 
n/a 
Hyperkalemia 
Potassium (mmol/L) 
≤ ULN 
> ULN – 
≤ 5.5 mmol/L 
> 5.5 – 
≤ 6.0 mmol/L 
> 6.0 – 
≤ 7.0 mmol/L 
> 7.0 mmol/L 
n/a 
Hypokalemia 
Potassium (mmol/L) 
≥ LLN 
≥ 3.0 mmol/L – 
< LLN; 
asymptomatic; 
no intervention 
indicated 
≥ 3.0 mmol/L – 
< LLN; 
symptomatic; 
intervention 
indicated 
≥ 2.5 - 
< 3.0 mmol/L 
< 2.5 mmol/L 
n/a 
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Amgen, Inc.  
Master Protocol COV-01 
Master Statistical Analysis Plan 
Page 114 of 118 
 
 
 
 
 
Version Number: 
Amendment 1, v1.0 
 
Version Date:  
23Apr2021 
 
 
 
 
 
 
 
CTCAE Term 
Laboratory Test 
No Event 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Hypernatremia 
Sodium (mmol/L) 
≤ ULN 
> ULN – ≤ 150 
mmol/L 
> 150 – 
≤ 155 mmol/L 
> 155 – 
≤ 160 mmol/L 
> 160 mmol/L 
n/a 
Hyponatremia 
Sodium (mmol/L) 
≥ LLN 
≥ 130 mmol/L 
– < LLN 
≥ 125 - 
< 130 mmol/L 
and 
asymptomatic 
≥ 120 - 
< 125 mmol/L 
or 
≥ 125 - 
< 130 mmol/L 
and 
symptomatic 
< 120 mmol/L 
n/a 
Hypermagnesemia 
Magnesium (mmol/L) 
≤ ULN 
> ULN – 
≤ 1.23 mmol/L 
n/a 
> 1.23 – 
≤ 3.30 mmol/L 
> 3.30 mmol/L 
n/a 
Hypomagnesemia 
Magnesium (mmol/L) 
≥ LLN 
≥ 0.5 mmol/L – 
< LLN 
≥ 0.4 - 
< 0.5 mmol/L 
≥ 0.3 - 
< 0.4 mmol/L 
< 0.3 mmol/L 
n/a 
Blood bicarbonate 
decreased 
Bicarbonate (mmol/L) 
≥ LLN 
< LLN 
n/a 
n/a 
n/a 
n/a 
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Amgen, Inc.  
Master Protocol COV-01 
Master Statistical Analysis Plan 
Page 115 of 118 
 
 
 
 
 
Version Number: 
Amendment 1, v1.0 
 
Version Date:  
23Apr2021 
 
 
 
 
 
 
 
CTCAE Term 
Laboratory Test 
No Event 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Creatinine increased 
Creatinine (µmol/L) 
≤ ULN 
> ULN – 
≤ 1.5 x ULN 
> 1.5 – 
≤ 3.0 x ULN  
or 
> 1.5 – ≤3.0 x 
baseline 
> 3.0 – 
≤ 6.0 x ULN  
or 
> 3.0 x baseline 
> 6.0 x ULN 
n/a 
Hypoglycemia 
Glucose (mmol/L) 
≥ LLN 
≥ 3.0 mmol/L – 
< LLN 
≥ 2.2 - 
< 3.0 mmol/L 
≥ 1.7 - 
< 2.2 mmol/L 
< 1.7 mmol/L 
n/a 
Alkaline phosphatase 
(ALP) increased 
ALP (U/L) 
≤ ULN if 
baseline 
normal;  
≤ 2.0 x 
baseline if 
baseline 
abnormal 
> ULN – 
≤ 2.5 x ULN if 
baseline 
normal;  
> 2.0 - 
≤ 2.5 x baseline 
if baseline 
abnormal 
> 2.5 – 
≤ 5.0 x ULN if 
baseline 
normal; 
> 2.5 – 
≤ 5.0 x baseline 
if baseline 
abnormal 
> 5.0 – 
≤ 20.0 x ULN if 
baseline 
normal; 
> 5.0 – ≤ 20.0 x 
baseline if 
baseline 
abnormal 
> 20.0 x ULN if 
baseline 
normal; 
> 20.0 x 
baseline if 
baseline 
abnormal 
n/a 
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Amgen, Inc.  
Master Protocol COV-01 
Master Statistical Analysis Plan 
Page 116 of 118 
 
 
 
 
 
Version Number: 
Amendment 1, v1.0 
 
Version Date:  
23Apr2021 
 
 
 
 
 
 
 
CTCAE Term 
Laboratory Test 
No Event 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Blood bilirubin 
increased 
Total bilirubin 
(µmol/L) 
≤ ULN if 
baseline 
normal;  
≤ baseline if 
baseline 
abnormal 
> ULN – 
≤ 1.5 x ULN if 
baseline 
normal;  
> baseline - ≤ 
1.5 x baseline 
if baseline 
abnormal 
> 1.5 – 
≤ 3.0 x ULN if 
baseline 
normal;  
> 1.5 - ≤ 3.0 x 
baseline if 
baseline 
abnormal 
> 3.0 – ≤ 10.0 x 
ULN if baseline 
normal;  
> 3.0 - ≤ 10.0 x 
baseline if 
baseline 
abnormal 
> 10.0 x ULN if 
baseline 
normal;  
> 10.0 x 
baseline if 
baseline 
abnormal 
 
n/a 
Aspartate transaminase 
(AST) increased 
AST (U/L) 
≤ ULN if 
baseline 
normal;  
≤ 1.5 x 
baseline if 
baseline 
abnormal 
> ULN – 
≤ 3.0 x ULN if 
baseline 
normal;  
> 1.5 - ≤ 3.0 x 
baseline if 
baseline 
abnormal 
> 3.0 – 
≤ 5.0 x ULN if 
baseline 
normal; 
> 3.0 – ≤ 5.0 x 
baseline if 
baseline 
abnormal 
> 5.0 – ≤ 20.0 x 
ULN if baseline 
normal; 
> 5.0 – ≤ 20.0 x 
baseline if 
baseline 
abnormal 
> 20.0 x ULN if 
baseline 
normal; 
> 20.0 x 
baseline if 
baseline 
abnormal 
n/a 
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Amgen, Inc.  
Master Protocol COV-01 
Master Statistical Analysis Plan 
Page 117 of 118 
 
 
 
 
 
Version Number: 
Amendment 1, v1.0 
 
Version Date:  
23Apr2021 
 
 
 
 
 
 
 
CTCAE Term 
Laboratory Test 
No Event 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Alanine transaminase 
(ALT) increased 
ALT (U/L) 
≤ ULN if 
baseline 
normal;  
≤ 1.5 x 
baseline if 
baseline 
abnormal 
> ULN – 
≤ 3.0 x ULN if 
baseline 
normal;  
> 1.5 - ≤ 3.0 x 
baseline if 
baseline 
abnormal 
> 3.0 – 
≤ 5.0 x ULN if 
baseline 
normal; 
> 3.0 – ≤ 5.0 x 
baseline if 
baseline 
abnormal 
> 5.0 – ≤ 20.0 x 
ULN if baseline 
normal; 
> 5.0 – ≤ 20.0 x 
baseline if 
baseline 
abnormal 
> 20.0 x ULN if 
baseline 
normal; 
> 20.0 x 
baseline if 
baseline 
abnormal 
n/a 
Gamma glutamyl 
transferase (GGT) 
increased 
GGT (U/L) 
≤ ULN if 
baseline 
normal;  
≤ 2.0 x 
baseline if 
baseline 
abnormal 
> ULN – 
≤ 2.5x ULN if 
baseline 
normal;  
> 2.0 - 
≤ 2.5 x baseline 
if baseline 
abnormal 
> 2.5 – 
≤ 5.0 x ULN if 
baseline 
normal;  
> 2.5 - 
≤ 5.0 x baseline 
if baseline 
abnormal 
> 5.0 – ≤ 20.0 x 
ULN if baseline 
normal;  
> 5.0 - ≤ 20.0 x 
baseline if 
baseline 
abnormal 
> 20.0 x ULN if 
baseline 
normal;  
> 20.0 x 
baseline if 
baseline 
abnormal 
n/a 
CPK increased 
Creatine kinase (U/L) 
≤ ULN 
> ULN – 
≤ 2.5 x ULN 
> 2.5 – 
≤ 5 x ULN 
> 5 – 
≤ 10 x ULN 
> 10 x ULN 
n/a 
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Amgen, Inc.  
Master Protocol COV-01 
Master Statistical Analysis Plan 
Page 118 of 118 
 
 
 
 
 
Version Number: 
Amendment 1, v1.0 
 
Version Date:  
23Apr2021 
 
 
 
 
 
 
. 
CTCAE Term 
Laboratory Test 
No Event 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Hypertriglyceridemia 
Triglycerides 
(mmol/L) 
≤ 1.71 mmol/L 
> 1.71 – 
≤ 3.42 mmol/L 
> 3.42 - 
≤ 5.70 mmol/L 
> 5.70 - 
≤ 11.40 mmol/L 
> 11.40 mmol/L 
n/a 
 
 
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Takeda 
Sub-Protocol COV-01-001 
COV-01-001 Statistical Analysis Plan 
Page 1 of 33 
 
 
 
 
 
Version Number: 
Amendment 3, v1.0 
 
Version Date:  
23-Jul-2021 
 
 
 
 
 
 
 
 
 
 
 
COV-01-001 STATISTICAL ANALYSIS PLAN  
 
INDUSTRY ALLIANCE PLATFORM TRIAL TO ASSESS THE EFFICACY 
AND SAFETY 
OF MULTIPLE CANDIDATE AGENTS 
FOR 
THE 
TREATMENT OF COVID-19 IN HOSPITALIZED PATIENTS 
 
SUB-PROTOCOL NUMBER: COV-01-001 
SUB-PROTOCOL FOR CANDIDATE AGENT: LANADELUMAB-IV 
 
 
AUTHOR: 
 
VERSION NUMBER AND DATE: AMENDMENT 3 V1.0, 23-JUL-2021 
 
 
 
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Takeda 
Sub-Protocol COV-01-001 
COV-01-001 Statistical Analysis Plan 
Page 3 of 33 
 
 
 
 
 
Version Number: 
Amendment 3, v1.0 
 
Version Date:  
23-Jul-2021 
 
 
 
 
 
 
 
MODIFICATION HISTORY 
Unique 
Identifier for 
this Version 
Date of the 
Document 
Version 
Author 
Significant Changes from  
Previous Version 
Final, v1.0 
14-Dec-2020 
 
Not Applicable – First Version 
Amendment 1, 
v1.0 
27-Apr-2021 
 
Updated COV-01-001 sub-protocol version on 
which this subprotocol SAP is based from 
version 1.2, dated 26Oct2020, to version 2.0, 
dated 14Apr2021 
Update title of Sections 11and 13 to be in line 
with Master SAP; 
Added a subgroup that will be used to perform 
supportive analysis for selected safety data and 
related additional supportive analysis; 
Added the risk difference of the overall 
incidence rates of having any treatment-
emergent AESI between the treatment groups 
will be presented along with its 95% two-sided 
Wald CI; 
Added Appendices 1 and 2. 
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Unique 
Identifier for 
this Version 
Date of the 
Document 
Version 
Author 
Significant Changes from  
Previous Version 
Amendment 2, 
v1.0 
24-Jun-2021 
 
Specified that the two Interim Analyses (IAs) 
and Primary Analysis at Day 29 will not be 
performed for this sub-protocol since 
enrollment into COV-01-001 sub-protocol was 
early terminated by the Sponsor on 03-May-
2021 i.e., before the trigger of each of these 
analyses was met. 
Exception of summary statistics for the primary 
efficacy, key secondary, and other secondary 
efficacy endpoints, removed all planned 
efficacy analyses given that 1) enrollment into 
COV-01-001 sub-protocol was early 
terminated by the Sponsor on 03-May-2021, 2) 
number of patients to be included in COV-01-
001 sub-protocol final analysis, and 3) an 
abbreviated Clinical Study Report will be 
created for this sub-protocol. 
Added two-sided 95% exact binomial 
Confidence Interval within each treatment arm, 
when applicable. 
Removed the additional subgroup analyses that 
were to be performed as supportive analysis for 
selected safety data. 
Amendment 3, 
v1.0 
23-Jul-2021 
 
Updated the definition of the Shared Placebo 
Arm 
 
 
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TABLE OF CONTENTS 
1. 
INTRODUCTION............................................................................................................... 9 
2. 
STUDY OBJECTIVES ....................................................................................................... 9 
3. 
STUDY DESIGN ................................................................................................................. 9 
3.1. 
General Description ............................................................................................................................... 9 
3.2. 
Schedule of Activities ............................................................................................................................. 9 
3.3. 
Changes to Planned Analyses from Master Protocol and Sub-Protocol COV-01-001 ..................... 9 
4. 
PLANNED ANALYSES ................................................................................................... 10 
4.1. 
IDMC Safety Analyses ......................................................................................................................... 10 
4.2. 
Interim Analyses................................................................................................................................... 10 
4.3. 
Primary Analysis .................................................................................................................................. 10 
4.4. 
Final Analysis ....................................................................................................................................... 11 
4.5. 
Selection of the Control Arm for an Analysis .................................................................................... 11 
4.5.1. 
IDMC Safety Analyses ................................................................................................................ 11 
4.5.2. 
Final Analysis .............................................................................................................................. 11 
5. 
ANALYSIS SETS.............................................................................................................. 12 
5.1. 
Primary Analysis Set ............................................................................................................................ 12 
5.2. 
Pharmacokinetic Analysis Set ............................................................................................................. 12 
5.3. 
Pharmacodynamic Analysis Set .......................................................................................................... 12 
5.4. 
Plasma Anti-Drug Antibody Analysis Set .......................................................................................... 13 
5.5. 
Process for Analysis Set Assignment .................................................................................................. 13 
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6. 
GENERAL CONSIDERATIONS ................................................................................... 13 
7. 
STATISTICAL CONSIDERATIONS ............................................................................ 13 
7.1. 
Sample Size Calculation....................................................................................................................... 13 
7.2. 
Missing data .......................................................................................................................................... 13 
7.3. 
Statistical Tests ..................................................................................................................................... 14 
7.4. 
Multiple Comparisons/ Multiplicity ................................................................................................... 14 
7.5. 
Multicenter Studies .............................................................................................................................. 14 
7.6. 
Adjustments for Covariates and Factors to be Included in Analyses .............................................. 14 
7.7. 
Examination of Subgroups .................................................................................................................. 14 
7.8. 
Software Version .................................................................................................................................. 14 
8. 
OUTPUT PRESENTATIONS ......................................................................................... 14 
9. 
DISPOSITION AND WITHDRAWALS ........................................................................ 15 
10. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ....................... 15 
11. 
DISEASE HISTORY ........................................................................................................ 15 
12. 
MEDICAL HISTORY ...................................................................................................... 15 
13. 
PRIOR AND CONCOMITANT MEDICATIONS........................................................ 15 
14. 
EXPOSURE TO STUDY DRUG ..................................................................................... 15 
14.1. 
Derivations ............................................................................................................................................ 17 
15. 
COMPLIANCE WITH STUDY DRUG ......................................................................... 17 
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15.1. 
Derivations ............................................................................................................................................ 18 
16. 
EFFICACY ENDPOINTS................................................................................................ 19 
16.1. 
Primary Efficacy .................................................................................................................................. 19 
16.1.1. 
Time to Confirmed Clinical Recovery through Day 29, without Re-Hospitalization Through 
Day 29 ......................................................................................................................................... 19 
16.1.2. 
Missing Data Imputation Method for Primary Efficacy Endpoint .............................................. 19 
16.1.3. 
Main Analysis of Primary Efficacy Endpoint.............................................................................. 19 
16.1.4. 
Sensitivity Analyses for Primary Efficacy Endpoint ................................................................... 20 
16.1.5. 
Supplementary Analyses for Primary Efficacy Endpoint ............................................................ 20 
16.2. 
Secondary Efficacy ............................................................................................................................... 20 
16.2.1. 
Secondary Efficacy Endpoints..................................................................................................... 20 
16.2.1.1. 
Incidence of Patients with Oxygen-Free Recovery at Day 29 ..................................................... 20 
16.2.1.2. 
Incidence of Patients with ≥ 2-point Improvement from Baseline or Fit for Discharge on the 
Ordinal Scale at Day 29 ............................................................................................................... 20 
16.2.1.3. 
Incidence of All-Cause Mortality through Day 29 ...................................................................... 21 
16.2.1.4. 
Distribution of Patients across the Categories of the 8-point Ordinal Scale for Clinical Severity 
at Days 8, 15, and 29 ................................................................................................................... 21 
16.2.1.5. 
Worst Post-Baseline Score on 8-point Ordinal Scale from Baseline to Day 29 .......................... 21 
16.2.1.6. 
Number of ICU Days from Day 1 through Day 29 ..................................................................... 21 
16.2.1.7. 
Number of Invasive Mechanical Ventilator Days from Day 1 through Day 29 .......................... 21 
16.2.1.8. 
Incidence of Patients with Clinical Recovery by Days 8, 15, and 29 .......................................... 21 
16.2.1.9. 
Incidence of Patients with Sustained Clinical Recovery as Confirmed by Day 60 Follow-up .... 21 
16.2.2. 
Missing Data Imputation Method for Secondary Efficacy Endpoints ......................................... 21 
16.2.2.1. 
Binary Endpoints ......................................................................................................................... 21 
16.2.2.2. 
Ordinal Endpoints ........................................................................................................................ 22 
16.2.3. 
Main Analysis of Secondary Efficacy Endpoints ........................................................................ 22 
16.2.3.1. 
Binary Endpoints ......................................................................................................................... 22 
16.2.3.2. 
Ordinal Endpoints ........................................................................................................................ 22 
16.2.4. 
Sensitivity Analyses for Secondary Efficacy Endpoints ............................................................. 22 
16.2.5. 
Supplementary Analyses for Secondary Efficacy Endpoints ...................................................... 23 
16.3. 
Exploratory Efficacy ............................................................................................................................ 23 
16.4. 
Additional Efficacy ............................................................................................................................... 23 
16.5. 
Interim Analysis ................................................................................................................................... 23 
17. 
SAFETY ENDPOINTS .................................................................................................... 23 
17.1. 
Adverse Events ..................................................................................................................................... 24 
17.1.1. 
Adverse Events of Special Interest .............................................................................................. 24 
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17.2. 
Laboratory Evaluations ....................................................................................................................... 24 
17.3. 
Vital Signs ............................................................................................................................................. 24 
17.4. 
ECG Evaluation ................................................................................................................................... 24 
17.5. 
Physical Examination ........................................................................................................................... 25 
18. 
PHARMACOKINETICS ................................................................................................. 25 
19. 
PHARMACODYNAMICS............................................................................................... 26 
20. 
PLASMA ANTI-DRUG ANTIBODY TESTING .......................................................... 26 
21. 
DATA NOT SUMMARIZED OR PRESENTED .......................................................... 26 
APPENDIX 1 HYPERSENSITIVITY REACTIONS ........................................................... 27 
APPENDIX 2 EVENTS OF DISORDERED COAGULATION .......................................... 28 
 
 
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1. INTRODUCTION 
This statistical analysis plan (SAP) describes the rules and conventions to be used in the presentation and analysis of 
data specific to sub-protocol COV-01-001 of master protocol COV-01. It describes the specific data to be 
summarized and analyzed, including specifics of the statistical analyses to be performed. 
This sub-protocol SAP is based on version 2.0 of the sub-protocol COV-01-001, dated 14-Apr 2021. 
For the rules and conventions to be used in the presentation and analysis of data common across all sub-protocols, 
refer to the Master COV-01 SAP. 
2. STUDY OBJECTIVES 
The study objectives are described in the Master COV-01 SAP.  
3. STUDY DESIGN 
3.1. GENERAL DESCRIPTION 
The general description is available in the Master COV-01 SAP.  
3.2. SCHEDULE OF ACTIVITIES 
The schedule of activities can be found in Section 1.2 of the sub-protocol COV-01-001. 
3.3. CHANGES TO PLANNED ANALYSES FROM MASTER PROTOCOL 
AND SUB-PROTOCOL COV-01-001 
Enrollment into sub-protocol COV-01-001 was prematurely terminated by the Sponsor on 03-May-2021 due issues 
with the administration of the study drug.  In conformance with the Food and Drug Administration (FDA) Guidance 
for Submission of Abbreviated Report and Synopsis in Support of Marking Application, an abbreviated Clinical 
Study Report (CSR) will be written for this sub-protocol.  As such, not all analyses planned in the master protocol 
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will be performed for sub-protocol COV-01-001 (refer to Section 4 for more details concerning the analyses to be 
performed for this sub-protocol). 
Definition of the control arm (i.e., the shared placebo + standard of care [SoC] arm) was updated for this sub-
protocol to minimize the randomization imbalance issue noted by the 
 Unblinded Biostatistician and IDMC 
members at the time of 
 (refer to Section 4.5). 
4.  PLANNED ANALYSES 
The analyses initially planned to be performed are listed and described in the Master COV-01 SAP.  However, the 
two Interim Analyses (IAs) for futility and Primary Analysis will not be performed for this sub-protocol since 
enrollment into sub-protocol COV-01-001 was early terminated by the Sponsor on 03-May-2021 (refer to Section 
3.3 for additional details) i.e., before the trigger for each of these analyses was met. That is, the only analysis that 
will be performed, in addition to the monthly IDMC Safety analyses, is the final analysis after all patients who were 
ongoing at the time Sponsor early terminated this sub-protocol completed the study (Day 60 visit) or discontinued 
early from the study, whichever occurs first. 
All outputs described in this sub-protocol SAP will be produced at the time of sub-protocol COV-01-001 final 
analysis.  
4.1. IDMC SAFETY ANALYSES 
Details are provided in the Master COV-01 SAP. 
4.2. INTERIM ANALYSES 
No IAs will be performed for this sub-protocol (refer to Section 4). 
4.3. PRIMARY ANALYSIS 
No primary analysis will be performed for this sub-protocol (refer to Section 4). 
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4.4. FINAL ANALYSIS 
The final analysis for this sub-protocol will take place after: 
• 
Sponsor Authorization of this SAP. 
• 
Final database lock of the database including data from screen failed patients. 
• 
Final database lock of the database of each sub-protocol contributing to the control arm of this sub-protocol 
(refer to Section 4.5). 
• 
Final database lock of the database of this sub-protocol. 
All planned analyses identified in this sub-protocol SAP will be performed by 
 Biostatistics at the time of the 
final analysis of this sub-protocol. 
4.5. SELECTION OF THE CONTROL ARM FOR AN ANALYSIS 
4.5.1. 
IDMC SAFETY ANALYSES 
Details are provided in Master SAP Section 4.5. 
4.5.2. 
FINAL ANALYSIS 
For final analysis of this sub-protocol, the control arm (also referred to as shared placebo + SoC arm) will include all 
patients randomized to the placebo arm of any sub-protocol before this sub-protocol was early terminated (refer to 
section 3.3) at a site at which: 
• 
This sub-protocol was opened for enrollment. 
• 
At least one patient was randomized to either this sub-protocol active (Lanadelumab- intra-venous [IV] + SoC) 
or placebo (placebo to Lanadelumab-IV + SoC) arms. 
That is, patients that satisfy these criteria will be included in the control arm of this sub-protocol regardless of 1) 
whether patients was randomized before this sub-protocol was opened for enrollment at the site (that is, patients 
randomized after enrollment into COV-01-001 sub-protocol was early terminated will be excluded from the control 
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arm of this sub-protocol) and 2) patient’s eligibility to this sub-protocol specific inclusion/ exclusion criteria. 
The purpose of this change from the Master SAP control arm definition (Master SAP Section 4.5) is to minimize the 
randomization imbalance issue noted by the 
 Unblinded Biostatistician and IDMC members at the time of 
.  At the 
time this sub-protocol SAP was finalized, the randomization imbalance was estimated to be approximately 7:1 
between this sub-protocol active and control arms, should the original control arm definition would have been 
retained for the final analysis of this sub-protocol. 
5.  ANALYSIS SETS 
Analysis sets are described in the COV-01 Master SAP.  
Additional analysis sets that are specific to sub-protocol COV-01-001 are described below: 
5.1. PRIMARY ANALYSIS SET 
The primary analysis set will include all randomized patients with a baseline clinical severity status of Grade 3 to 5 
on the 8-point ordinal scale for clinical severity. 
For displays and analyses based on the primary analysis set, patients will be classified according to the randomized 
treatment. 
The main analyses of all efficacy endpoints will be performed on the primary analysis set. 
5.2. PHARMACOKINETIC ANALYSIS SET 
The pharmacokinetic (PK) analysis set will include patients from the safety analysis set (refer to Master COV-01 
SAP Section 5.2) randomized to the Lanadelumab-(IV + SoC arm who have at least one measured concentration 
post dose of Lanadelumab-IV. 
5.3. PHARMACODYNAMIC ANALYSIS SET 
The pharmacodynamic (PD) analysis set will include patients from the safety analysis set (refer to Master COV-01 
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SAP Section 5.2) randomized to COV-01-001 sub-protocol (i.e., Lanadelumab- IV + Standard of Care (SoC) arm or 
Placebo to Lanadelumab-IV + SoC) who have at least one measured biomarker level post dose of Lanadelumab-IV 
(e.g., cHMWk, pKAL, etc.). 
5.4. PLASMA ANTI-DRUG ANTIBODY ANALYSIS SET 
The plasma anti-drug antibody (ADA) analysis set will include patients from the safety analysis set (refer to Master 
COV-01 SAP Section 5.2) randomized to COV-01-001 sub-protocol (i.e., Lanadelumab- IV + Standard of Care 
(SoC) arm or Placebo to Lanadelumab-IV + SoC) who have at least one evaluated ADA response. 
5.5. PROCESS FOR ANALYSIS SET ASSIGNMENT 
As the primary, PK, PD and ADA analysis sets are defined based on objective criteria only, the authorization of this 
sub-protocol SAP will stand for the agreement and authorization of the inclusion/exclusion of each patient in the 
primary, PK, PD and ADA analysis sets.  
6. GENERAL CONSIDERATIONS 
Details are provided in the Master COV-01 SAP. 
7. STATISTICAL CONSIDERATIONS 
7.1. SAMPLE SIZE CALCULATION 
Details are provided in the Master COV-01 SAP. 
7.2. MISSING DATA 
Details are provided in the Master COV-01 SAP. 
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7.3. STATISTICAL TESTS 
Not applicable since no statistical inferences will be performed for the final analysis of this sub-protocol (refer to 
Section 16). 
7.4. MULTIPLE COMPARISONS/ MULTIPLICITY 
Not applicable since no statistical inferences will be performed for the final analysis of this sub-protocol (refer to 
Section 16). 
7.5. MULTICENTER STUDIES 
Details are provided in the Master COV-01 SAP. 
7.6. ADJUSTMENTS FOR COVARIATES AND FACTORS TO BE 
INCLUDED IN ANALYSES 
Not applicable since no statistical inferences will be performed for the final analysis of this sub-protocol (refer to 
Section 16). 
7.7. 
 EXAMINATION OF SUBGROUPS 
No subgroup analyses will be performed for the final analysis of this sub-protocol.       
7.8. SOFTWARE VERSION 
Details are provided in Master COV-01 SAP.  
8. OUTPUT PRESENTATIONS 
Output presentations are described in the Master COV-01 SAP. 
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9. DISPOSITION AND WITHDRAWALS 
Analysis of disposition and withdrawals will be presented as described in the Master COV-01 SAP. 
10. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic characteristics and other baseline characteristics data will be presented as described in the Master 
COV-01 SAP. 
11. DISEASE HISTORY  
Analysis of disease history will be performed as described in the Master COV-01 SAP. 
12. MEDICAL HISTORY 
Analysis of medical history will be performed as described in the Master COV-01 SAP. 
13. PRIOR AND CONCOMITANT MEDICATIONS 
Analysis of prior and concomitant medications will be performed as described in the Master COV-01 SAP. 
14. EXPOSURE TO STUDY DRUG 
Patients randomized to sub-protocol COV-01-001 
Patients randomized to the Lanadelumab-IV + SoC or Placebo + SoC treatment groups of COV-01-001 sub-protocol 
will receive an IV injection of either Lanadelumab-IV 300 mg diluted in normal saline or placebo (normal saline), as 
applicable, in a double-blind manner, one dose on Day 1 and a second dose on Day 4, along with SoC.  
Reason for dose modification of study drug (i.e., dose increased, dose reduced, drug interrupted and drug 
withdrawal) will be captured on the Exposure page of the eCRF.   
 
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Patients included in the control arm of COV-01-001 sub-protocol who were randomized to the Placebo + SoC 
group of a sub-protocol other than COV-01-001 
It is to be noted that the planned duration of exposure to a study drug, planned frequency of administration of the 
study drug, and planned route of administration of the study drug will vary from one sub-protocol to the other, but 
similar information as for COV-01-001 sub-protocol will be captured on the Exposure page of the eCRF of these 
other sub-protocol. 
Exposure to study drug 
The exposure to study drug will be summarized by treatment arm (breaking down the Placebo + SoC arm by sub-
protocol) based on the safety analysis set as follows: 
• 
Duration of exposure: 
o 
Duration of exposure (days) as a continuous variable 
o 
Duration of exposure (days) as a categorical variable: 1 to 3, > 3 to 7, > 7 to 14, > 14 to 29, and > 29 
o 
Total number of doses received as a continuous variable, where the total number of dosed received is 
defined as the total number of doses received by each patient, not the total number of doses received 
across all patients 
o 
For patients randomized to COV-01-001 sub-protocol only, number and percentages of patients who 
received only one dose and number and percentages of patients who received two doses. 
• 
Dose modifications: 
o 
For patients randomized to COV-01-001 sub-protocol only, number and percentage of patients with at 
least one dose partially administered overall and for each dose 
o 
Number and percentage of patients with at least one interrupted dose 
o 
Number and percentage of patients with at least one dose interruption by reason for dose interruption:  
▪ 
Adverse events 
▪ 
Other. 
o 
Total number of dose interruptions as a continuous variable, where the total number of dose 
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interruptions is defined similarly to the total number of doses received 
o 
Among patients with a dose interruption, number and percentage of patients with dose subsequently 
restarted at planned dose level. 
All dosing and exposure data will also be listed.  A listing including patients with at least one dose modification only 
will also be provided. 
14.1. DERIVATIONS 
For patients randomized to a study drug planned to be administered on a daily basis, duration of exposure to study 
drug, in days, will be computed as follows: 
• 
Duration of exposure (days) = (Date of last dose of study drug – Date of first dose of study drug) + 1 
For all other patients (i.e. randomized to a study drug planned to be administered not on a daily basis), duration of 
exposure to study drug, in days, will be computed as follows: 
• 
Duration of exposure (days) = {[Earliest date of (end of planned study treatment period, hospital discharge or 
discontinuation from study drug)] – Date of first dose of study drug} + 1 
15. COMPLIANCE WITH STUDY DRUG 
Compliance with study drug will be summarized by treatment arm (breaking down the Placebo + SoC arm by sub-
protocol) based on the safety analysis set. In addition to the descriptive summary, number and percentage of patients 
in each of the following compliance categories will be presented: 
• 
< 50% 
• 
≥ 50 to < 80% 
• 
≥ 80% to ≤ 100% 
• 
> 100%. 
Compliance data will also be listed. 
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15.1. DERIVATIONS 
For each patient, the compliance will be computed as follows: 
• 
Compliance (%) = (Actual total number of doses / Expected total number of doses) x 100 
where: 
• 
Actual total number of doses is defined as the sum of all doses taken through the course of the study  
• 
Expected total number of doses is defined as the sum of protocol-defined doses to be taken through the course 
of the study and is computed as follows: 
o 
For patients randomized to a study drug administered on a daily basis: 
▪ 
Expected total number of doses  = expected number of doses per day * expected number of days 
under treatment, where the expected number of days under treatment is defined as: {[Earliest date 
of (end of planned study treatment period, hospital discharged or discontinuation from study 
drug)] – Date of first dose of study drug} + 1. 
 
o 
For patients randomized to a study drug planned to be administered not on a daily basis: 
▪ 
Expected total number of doses = Expected number of doses (injections) per day * expected 
number of administration days between randomization and the earliest of (end of planned study 
treatment period, hospital discharged or discontinuation from study drug). 
For example, if a study drug is planned to be administered once on Day 1 and once on Day 4, the 
expected total number of doses is 2; unless patient discontinued from study drug or was 
discharged from the hospital on or after Day 1 but before Day 4, in which case the expected total 
number of doses is 1.  As another example, if the study drug is planned to be administered twice 
daily on every other day from Day 1 to Day 14, the expected total number of doses is 14; unless 
patient discontinued from study drug or was discharged from the hospital let say, on Day 10, in 
which case the expected total number of doses is 10 (i.e., 2 doses [injection] per days * 5 
administration days). 
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16. EFFICACY ENDPOINTS 
Given that only 29 patients were randomized into COV-01-001 sub-protocol and that is expected ~34 patients will 
be included in final analysis of this sub-protocol when taking the shared placebo arm into account instead of ~700 as 
required by the sample size (refer to Master SAP Section 7.1), no statistical inferences will be performed for any 
efficacy endpoint, but two-sided 95% exact binomial Confidence Interval (CI) within each treatment arm will be 
provided, when possible. 
In conformance with the FDA’s Guidance for Submission of Abbreviated Report and Synopsis in Support of 
Marking and publication requirements of ClinicalTrials.gov, summary tables will be presented for the primary and 
key secondary efficacy endpoints (refer to Master SAP Sections 16.1.1, 16.2.1.1, 16.2.1.2, and 16.2.1.3).  Although 
not required by the previously mentioned FDA’s Guidance, summary tables will also be provided for the other 
secondary efficacy endpoints (refer to Master SAP Sections 16.2.1.4 to 16.2.1.9) in order to be compliant with the 
publication requirements of ClinicalTrials.gov. 
Efficacy summaries will be performed as described in the Master COV-01 SAP, except that all endpoints will be 
analyzed on the primary analysis set (refer to Section 5.1) instead of the FAS. 
16.1. PRIMARY EFFICACY 
16.1.1. 
TIME TO CONFIRMED CLINICAL RECOVERY THROUGH DAY 29, WITHOUT RE-
HOSPITALIZATION THROUGH DAY 29 
Details are provided in the Master COV-01 SAP. 
16.1.2. 
MISSING DATA IMPUTATION METHOD FOR PRIMARY EFFICACY ENDPOINT 
Details are provided in the Master COV-01 SAP. 
16.1.3. 
MAIN ANALYSIS OF PRIMARY EFFICACY ENDPOINT 
For the time to confirmed clinical recovery through Day 29, without re-hospitalization through Day 29, as defined in 
the Master SAP Section 16.1.1, the number and percentage of patients with and without the event will be presented 
by randomized treatment arm. Two-sided 95% exact binomial CI for the percentage of patients with the event within 
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each treatment group will be provided.  For patients who did not meet the event, the main reason for censoring will 
be summarized similarly. 
Kaplan-Meier curves (product-limit estimate) will be provided by treatment arm for the time to confirmed clinical 
recovery though Day 29, without re-hospitalization through Day 29. Kaplan-Meier estimate of the time to confirmed 
clinical recovery through Day 29, without re-hospitalization through Day 29, in days, will be provided at the 25th, 
50th (median), and 75th percentiles time along with their corresponding two-sided 95% CIs.  The estimates of the SEs 
will be computed using the Greenwood’s formula, the CI for the median will be calculated according to Brookmeyer 
and Crowley (1982), and the CIs for the survival function estimates at above mentioned time points will be derived 
from the Kaplan-Meier estimates using the log-log transformation.  Kaplan-Meier estimates of the probability of 
having the event will also be provided at Day 29 along with the number of patients with the event and the number of 
patients at risk at that time.   
16.1.4. 
SENSITIVITY ANALYSES FOR PRIMARY EFFICACY ENDPOINT 
 No sensitivity analyses will be performed for this sub-protocol. 
16.1.5. 
SUPPLEMENTARY ANALYSES FOR PRIMARY EFFICACY ENDPOINT 
No supplementary analyses will be performed for this sub-protocol. 
16.2. SECONDARY EFFICACY 
16.2.1. 
SECONDARY EFFICACY ENDPOINTS 
16.2.1.1. 
Incidence of Patients with Oxygen-Free Recovery at Day 29 
Details are provided in the Master COV-01 SAP. 
16.2.1.2. 
Incidence of Patients with ≥ 2-point Improvement from Baseline or Fit for 
Discharge on the Ordinal Scale at Day 29 
Details are provided in the Master COV-01 SAP. 
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16.2.1.3. 
Incidence of All-Cause Mortality through Day 29 
Details are provided in the Master COV-01 SAP. 
16.2.1.4. 
Distribution of Patients across the Categories of the 8-point Ordinal Scale for 
Clinical Severity at Days 8, 15, and 29 
Details are provided in the Master COV-01 SAP. 
16.2.1.5. 
Worst Post-Baseline Score on 8-point Ordinal Scale from Baseline to Day 29 
Details are provided in the Master COV-01 SAP. 
16.2.1.6. 
Number of ICU Days from Day 1 through Day 29 
Details are provided in the Master COV-01 SAP. 
16.2.1.7. 
Number of Invasive Mechanical Ventilator Days from Day 1 through Day 29 
Details are provided in the Master COV-01 SAP. 
16.2.1.8. 
Incidence of Patients with Clinical Recovery by Days 8, 15, and 29 
Details are provided in the Master COV-01 SAP. 
16.2.1.9. 
Incidence of Patients with Sustained Clinical Recovery as Confirmed by Day 60 
Follow-up 
Details are provided in the Master COV-01 SAP. 
16.2.2. 
MISSING DATA IMPUTATION METHOD FOR SECONDARY EFFICACY ENDPOINTS 
16.2.2.1. 
Binary Endpoints 
Details are provided in the Master COV-01 SAP. 
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COV-01-001 Statistical Analysis Plan 
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Version Number: 
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Version Date:  
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16.2.2.2. 
Ordinal Endpoints 
Details are provided in the Master COV-01 SAP. 
16.2.3. 
MAIN ANALYSIS OF SECONDARY EFFICACY ENDPOINTS 
16.2.3.1. 
Binary Endpoints 
For the incidence of patients with oxygen-free recovery at Day 29 (refer to Section 16.2.1.1), incidence of patients 
with ≥ 2-point improvement from baseline or fit for discharge on the ordinal scale at Day 29 (refer to Section 
16.2.1.2), incidence of all-cause mortality through Day 29 (refer to Section 16.2.1.3) , incidence of patients with 
clinical recovery at Days 8, 15 and 29 (refer to Section 16.2.1.8), and incidence of patients with sustained clinical 
recovery as confirmed by Day 60 follow-up (refer to Section 16.2.1.9), the number and percentage of patients with 
and without the event will be provided by treatment arm.  Two-sided 95% exact binomial CI for the percentage of 
patients with the event within each treatment group will be provided.   
For the incidence of all-cause mortality, primary reason of death will also be summarized by treatment arm. 
16.2.3.2. 
Ordinal Endpoints 
For the incidence of patients in each category of the 8-point ordinal scale for clinical severity at Days 8, 15, and 29 
endpoints (refer to Section 16.2.1.4), the number and percentage of patients in each ordinal scale category will be 
provided at each specified Day for each treatment arm. The worst post-baseline score on the 8-point ordinal scale for 
clinical severity from randomization to Day 29 (refer to Section 16.2.1.5) and each “number of days” endpoint (refer 
to Sections 16.2.1.6 and 16.2.1.7) will be summarized similarly. 
Shift tables from baseline to each post-baseline day up to Day 29 as well as to the worst post-baseline score will also 
be provided for the 8-point ordinal scale for clinical severity. 
16.2.4. 
SENSITIVITY ANALYSES FOR SECONDARY EFFICACY ENDPOINTS 
No sensitivity analyses will be performed for this sub-protocol. 
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COV-01-001 Statistical Analysis Plan 
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Version Number: 
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16.2.5. 
SUPPLEMENTARY ANALYSES FOR SECONDARY EFFICACY ENDPOINTS 
The only supplementary analyses that will be performed for this sub-protocol is that Kaplan-Meier product-limit 
estimates of the time to all-cause mortality through Day 29 as described in the Master SAP Section 16.2.5, but the 
hazard ratio of the Lanadelumab-IV + SoC vs. shared placebo + SoC, its associated two-sided 95% CI, and p-value 
based on the Cox proportional hazard model described in the Master SAP will not be provided. 
16.3. EXPLORATORY EFFICACY 
 
 
16.4. ADDITIONAL EFFICACY 
 
 
16.5. INTERIM ANALYSIS 
No IAs will be performed for this sub-protocol since enrollment into this sub-protocol was early terminated by the 
Sponsor before the trigger for the first IA was reached (refer to Master SAP Section 16.5). 
17. SAFETY ENDPOINTS 
The safety analyses will be performed as described in the Master COV-01 SAP based on the safety analysis set. 
In addition, the following analyses will also be performed for the sub-protocol COV-01-001 based on the safety 
analysis set. 
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Sub-Protocol COV-01-001 
COV-01-001 Statistical Analysis Plan 
Page 24 of 33 
 
 
 
 
 
Version Number: 
Amendment 3, v1.0 
 
Version Date:  
23-Jul-2021 
 
 
 
 
 
 
 
17.1. ADVERSE EVENTS    
17.1.1. 
ADVERSE EVENTS OF SPECIAL INTEREST 
The following are defined as adverse events of special interest (AESIs) for Lanadelumab-IV and will be identified 
based on investigator-reported AESIs on the AE page of the CRF: 
• 
Hypersensitivity reactions (refer to Appendix 1); 
• 
Events of disordered coagulation (i.e., bleeding AESIs or hypercoagulable AESIs; refer to Appendix 2) 
A summary of AESIs, overall and by AESI category and PT will be prepared by treatment arm for patients 
randomized to COV-01-001 only.  Should a patient experience multiple events within an AESI category or PT, the 
patient will be counted only once for that AESI category or PT.  Additionally, the risk difference of the overall 
incidence rates of having any treatment-emergent AESI between the treatment arms will be presented along with its 
95% two-sided Wald CI. 
A listing of all AESIs will be provided. 
17.2. LABORATORY EVALUATIONS 
In addition to the laboratory tests listed in Appendix 5 of the Master COV-01 SAP, the fibrin degradation products 
(FDPs) will be included in the outputs. 
The analysis for laboratory parameters is described in the Master COV-01 SAP. 
17.3. VITAL SIGNS 
Analysis of vital signs data will be performed as described in the Master COV-01 SAP. 
17.4. ECG EVALUATION 
Electrocardiogram (ECG) evaluation will be performed at screening and on the day of discharge from the hospital.  
The following ECG parameters will be collected: 
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Takeda 
Sub-Protocol COV-01-001 
COV-01-001 Statistical Analysis Plan 
Page 25 of 33 
 
 
 
 
 
Version Number: 
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23-Jul-2021 
 
 
 
 
 
 
 
• 
Heart rate (beats per minutes [bpm]); 
• 
PR interval (milliseconds [msec]); 
• 
RR interval (msec); 
• 
QRS interval (msec); 
• 
QT interval (msec); 
• 
QTc interval (msec); 
• 
QTcB interval (msec); 
• 
QTcF inerval (msec); 
• 
Overall ECG interpretation as assessed by Investigator (normal; abnormal, not clinically significant; and 
abnormal, clinically significant). 
The observed and change from baseline values of each continuous ECG parameter will be summarized using 
descriptive statistics by treatment arm and visit based on the safety analysis set. 
Number and percentage of patients in each category of the overall ECG interpretation as assessed by the Investigator 
will also be provided by treatment arm and visit based on the safety analysis set. 
17.5. PHYSICAL EXAMINATION 
Analysis of physical examination data will be performed as described in the Master COV-01 SAP. 
18. PHARMACOKINETICS 
PK concentrations of Lanadelumab-IV will be summarized by visit and timepoint (refer to Section 3.2) based on the 
PK analysis set (refer to Section 5.2) overall and broken down further by the ordinal scale for clinical severity score 
at baseline (2 or 3 to 5).  Concentrations that are below the limit of quantification (BLQ) will be treated as a numeric 
value of zero and will be excluded from the geometric statistics.  All PK concentrations will be reported and 
analyzed with 3 significant figures. For the reporting of descriptive statistics, the mean, standard deviation, standard 
error (if reported), and confidence interval (if reported) will be presented to one digit more precision than the source 
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Takeda 
Sub-Protocol COV-01-001 
COV-01-001 Statistical Analysis Plan 
Page 26 of 33 
 
 
 
 
 
Version Number: 
Amendment 3, v1.0 
 
Version Date:  
23-Jul-2021 
 
 
 
 
 
 
 
data.  The minimum, median, and maximum will be presented to the same precision as the source data. Coefficient 
of variation will always be reported to 2 decimal places. 
For Day 1, PK concentrations of Lanadelumab-IV will be summarized for the pre- and post-infusion separately.  
Post-dose timepoints will be presented for Days 4, 7, 15, 29, and day of discharge as PK blood samples can be 
collected at any time during each of these days. 
PK concentrations will be listed according to nominal time points scheduled. 
19. PHARMACODYNAMICS 
 
 
 
 
20. PLASMA ANTI-DRUG ANTIBODY TESTING 
Absence (negative) or presence (positive) of ADA will be summarized and listed by treatment arm across all visits 
(refer to Section 3.2) based on the ADA analysis set.   Positive ADA will be broken down further by neutralizing 
and non-neutralizing ADA. 
21. DATA NOT SUMMARIZED OR PRESENTED 
The list of data not summarized or presented is available in the Master COV-01 SAP. 
 
 
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Takeda 
Sub-Protocol COV-01-001 
COV-01-001 Statistical Analysis Plan 
Page 27 of 33 
 
 
 
 
 
Version Number: 
Amendment 3, v1.0 
 
Version Date:  
23-Jul-2021 
 
 
 
 
 
 
 
APPENDIX 1 HYPERSENSITIVITY REACTIONS 
Preferred Term 
• 
Administration site hypersensitivity 
• 
Documented hypersensitivity to administered product 
• 
Drug hypersensitivity 
• 
Hypersensitivity 
• 
Infusion related hypersensitivity reaction 
• 
Infusion site hypersensitivity 
• 
Injection site hypersensitivity 
• 
Type I hypersensitivity 
• 
Type II hypersensitivity 
• 
Type IV hypersensitivity 
 
 
 
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Sub-Protocol COV-01-001 
COV-01-001 Statistical Analysis Plan 
Page 28 of 33 
 
 
 
 
 
Version Number: 
Amendment 3, v1.0 
 
Version Date:  
23-Jul-2021 
 
 
 
 
 
 
 
APPENDIX 2 EVENTS OF DISORDERED COAGULATION 
Preferred Term 
• 
Abnormal clotting factor 
• 
Acquired antithrombin III deficiency 
• 
Acquired dysfibrinogenaemia 
• 
Acquired factor IX deficiency 
• 
Acquired factor VIII deficiency 
• 
Acquired factor XI deficiency 
• 
Acquired haemophilia 
• 
Acquired protein S deficiency 
• 
Acquired Von Willebrand's disease 
• 
Activated protein C resistance 
• 
Acute haemorrhagic oedema of infancy 
• 
Anaphylactoid syndrome of pregnancy 
• 
Antiphospholipid syndrome 
• 
Antithrombin III deficiency 
• 
Chronic pigmented purpura 
• 
Coagulation disorder neonatal 
• 
Coagulation factor deficiency 
• 
Coagulation factor mutation 
• 
Coagulopathy 
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Takeda 
Sub-Protocol COV-01-001 
COV-01-001 Statistical Analysis Plan 
Page 29 of 33 
 
 
 
 
 
Version Number: 
Amendment 3, v1.0 
 
Version Date:  
23-Jul-2021 
 
 
 
 
 
 
 
Preferred Term 
• 
Congenital coagulopathy 
• 
Congenital dysfibrinogenaemia 
• 
Congenital hypercoagulation 
• 
Dilutional coagulopathy 
• 
Disseminated intravascular coagulation 
• 
Disseminated intravascular coagulation in newborn 
• 
Ecchymosis 
• 
Endothelial protein C receptor polymorphism 
• 
Factor I deficiency 
• 
Factor II deficiency 
• 
Factor II inhibition 
• 
Factor II mutation 
• 
Factor III deficiency 
• 
Factor IX deficiency 
• 
Factor IX inhibition 
• 
Factor V deficiency 
• 
Factor V inhibition 
• 
Factor V Leiden mutation 
• 
Factor VII deficiency 
• 
Factor VII inhibition 
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Takeda 
Sub-Protocol COV-01-001 
COV-01-001 Statistical Analysis Plan 
Page 30 of 33 
 
 
 
 
 
Version Number: 
Amendment 3, v1.0 
 
Version Date:  
23-Jul-2021 
 
 
 
 
 
 
 
Preferred Term 
• 
Factor VIII deficiency 
• 
Factor VIII inhibition 
• 
Factor X deficiency 
• 
Factor X inhibition 
• 
Factor XI deficiency 
• 
Factor XII deficiency 
• 
Factor XIII deficiency 
• 
Factor XIII Inhibition 
• 
Haemophilia 
• 
Haemophilia A with anti factor VIII 
• 
Haemophilia A without inhibitors 
• 
Haemophilia B with anti factor IX 
• 
Haemophilia B without inhibitors 
• 
Haemophilic pseudotumour 
• 
Haemorrhage 
• 
Haemorrhagic diathesis 
• 
Haemorrhagic disease of newborn 
• 
Haemorrhagic disorder 
• 
Haemorrhagic vasculitis 
• 
Henoch-Schonlein purpura 
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Takeda 
Sub-Protocol COV-01-001 
COV-01-001 Statistical Analysis Plan 
Page 31 of 33 
 
 
 
 
 
Version Number: 
Amendment 3, v1.0 
 
Version Date:  
23-Jul-2021 
 
 
 
 
 
 
 
Preferred Term 
• 
Henoch-Schonlein purpura nephritis 
• 
Heparin resistance 
• 
Heparin-induced thrombocytopenia 
• 
Hermansky-Pudlak syndrome 
• 
Hypercoagulation 
• 
Hyperfibrinogenaemia 
• 
Hyperfibrinolysis 
• 
Hyperhomocysteinaemia 
• 
Hyperprothrombinaemia 
• 
Hypersensitivity vasculitis 
• 
Hyperthrombinaemia 
• 
Hypocoagulable state 
• 
Hypofibrinogenaemia 
• 
Hypoprothrombinaemia 
• 
Hypothrombinaemia 
• 
Hypothromboplastinaemia 
• 
Increased tendency to bruise 
• 
Infantile scurvy 
• 
Methylenetetrahydrofolate reductase deficiency 
• 
Methylenetetrahydrofolate reductase polymorphism 
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Takeda 
Sub-Protocol COV-01-001 
COV-01-001 Statistical Analysis Plan 
Page 32 of 33 
 
 
 
 
 
Version Number: 
Amendment 3, v1.0 
 
Version Date:  
23-Jul-2021 
 
 
 
 
 
 
 
Preferred Term 
• 
Mouth haemorrhage 
• 
Oral purpura 
• 
Petechiae 
• 
Plasminogen activator inhibitor polymorphism 
• 
Protein C deficiency 
• 
Protein S deficiency 
• 
Pulmonary embolism 
• 
Purpura 
• 
Purpura fulminans 
• 
Purpura neonatal 
• 
Purpura non-thrombocytopenic 
• 
Purpura senile 
• 
Secondary thrombocytosis 
• 
Septic coagulopathy 
• 
Spontaneous haematoma 
• 
Spontaneous haemorrhage 
• 
Thrombocytosis 
• 
Thrombotic microangiopathy 
• 
Vascular purpura 
• 
Vitamin C deficiency 
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Takeda 
Sub-Protocol COV-01-001 
COV-01-001 Statistical Analysis Plan 
Page 33 of 33 
 
 
 
 
 
Version Number: 
Amendment 3, v1.0 
 
Version Date:  
23-Jul-2021 
 
 
 
 
 
 
 
Preferred Term 
• 
Von Willebrand's disease 
• 
Von Willebrand's factor inhibition 
 
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Amgen Inc 
Sub-Protocol COV-01-004 
COV-01-004 Statistical Analysis Plan 
Page 1 of 18 
 
 
 
 
 
Version Number: 
Amendment 1, v1.0 
 
Version Date:  
23Apr2021 
 
 
 
 
 
 
 
 
 
 
 
COV-01-004 STATISTICAL ANALYSIS PLAN  
 
INDUSTRY ALLIANCE PLATFORM TRIAL TO ASSESS THE EFFICACY 
AND SAFETY 
OF MULTIPLE CANDIDATE AGENTS 
FOR 
THE 
TREATMENT OF COVID-19 IN HOSPITALIZED PATIENTS 
 
SUB-PROTOCOL NUMBER: COV-01-004 
SUB-PROTOCOL FOR CANDIDATE AGENT: APREMILAST 
 
 
AUTHOR: 
 
VERSION NUMBER AND DATE: AMENDMENT 1 V1.0, 23APR2021 
 
 
 
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Amgen Inc 
Sub-Protocol COV-01-004 
COV-01-004 Statistical Analysis Plan 
Page 3 of 18 
 
 
 
 
 
Version Number: 
Amendment 1, v1.0 
 
Version Date:  
23Apr2021 
 
 
 
 
 
 
 
MODIFICATION HISTORY 
Unique 
Identifier for 
this Version 
Date of the 
Document 
Version 
Author 
Significant Changes from  
Previous Version 
Final, v1.0 
24Nov2020 
 
Not Applicable – First Version 
Amendment 1, 
v1.0 
23Apr2021 
 
Updated COV-01-004 sub-protocol version on 
which this subprotocol SAP is based from 
version 3.1, dated 26Oct2020, to version 4.0. 
dated 14Apr2021 
Removed Section 11 (COVID-19 Co-
Morbidities) since this section is now 
combined with Section 12 (Medical History) in 
Master SAP 
Updated title of former Sections 12 (now 
Section 11) and 14 (now 13) to be in line with 
Master SAP. 
Added pharmacodynamic (PD) analysis set 
 
 
 
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TABLE OF CONTENTS 
1. 
INTRODUCTION............................................................................................................... 7 
2. 
STUDY OBJECTIVES ....................................................................................................... 7 
3. 
STUDY DESIGN ................................................................................................................. 7 
3.1. 
General Description ............................................................................................................................... 7 
3.2. 
Schedule of Activities ............................................................................................................................. 7 
3.3. 
Changes to Planned Analyses from Master Protocol COV-01 and Sub-Protocol COV-01-004 ...... 7 
4. 
PLANNED ANALYSES ..................................................................................................... 8 
5. 
ANALYSIS SETS................................................................................................................ 8 
5.1. 
Pharmacokinetic Analysis Set ............................................................................................................... 8 
5.2. 
Pharmacodynamic Analysis Set ............................................................................................................ 8 
5.3. 
Process for Analysis Set Assignment .................................................................................................... 8 
6. 
GENERAL CONSIDERATIONS ..................................................................................... 9 
7. 
STATISTICAL CONSIDERATIONS .............................................................................. 9 
7.1. 
Sample Size Calculation......................................................................................................................... 9 
7.2. 
Missing Data ........................................................................................................................................... 9 
7.3. 
Statistical Tests ....................................................................................................................................... 9 
7.4. 
Multiple Comparisons/Multiplicity ...................................................................................................... 9 
7.5. 
Multicenter Study ................................................................................................................................... 9 
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7.6. 
Adjustments for Covariates and Factors to be Included in Analyses ................................................ 9 
7.7. 
Examination of Subgroups .................................................................................................................. 10 
7.8. 
Software Version .................................................................................................................................. 10 
8. 
OUTPUT PRESENTATIONS ......................................................................................... 10 
9. 
DISPOSITION AND WITHDRAWALS ........................................................................ 10 
10. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ....................... 10 
11. 
DISEASE HISTORY ........................................................................................................ 11 
12. 
MEDICAL HISTORY ...................................................................................................... 11 
13. 
PRIOR AND CONCOMITANT MEDICATIONS........................................................ 11 
14. 
EXPOSURE TO STUDY DRUG ..................................................................................... 11 
14.1. 
Derivations ............................................................................................................................................ 13 
15. 
COMPLIANCE WITH STUDY DRUG ......................................................................... 14 
15.1. 
Derivations ............................................................................................................................................ 14 
16. 
EFFICACY ENDPOINTS................................................................................................ 15 
17. 
SAFETY ENDPOINTS .................................................................................................... 15 
17.1. 
Adverse Events ..................................................................................................................................... 15 
17.2. 
Laboratory Evaluations ....................................................................................................................... 16 
17.3. 
Vital Signs ............................................................................................................................................. 16 
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17.4. 
ECG Evaluations .................................................................................................................................. 16 
17.5. 
Physical Examination ........................................................................................................................... 16 
18. 
PHARMACOKINETICS ................................................................................................. 16 
18.1. 
Derivations ............................................................................................................................................ 17 
19. 
PHARMACODYNAMICS............................................................................................... 18 
20. 
DATA NOT SUMMARIZED OR PRESENTED .......................................................... 18 
 
 
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1. INTRODUCTION 
This statistical analysis plan (SAP) describes the rules and conventions to be used in the presentation and analysis of 
data specific to sub-protocol COV-01-004 of master protocol COV-01. It describes the specific data to be 
summarized and analyzed, including specifics of the statistical analyses to be performed. 
This sub-protocol SAP is based on version 4.0 of the sub-protocol COV-01-004, dated 14Apr2021. 
For the rules and conventions to be used in the presentation and analysis of data common across all sub-protocols, 
refer to the Master COV-01 SAP. 
2. STUDY OBJECTIVES 
The study objectives are described in the Master COV-01 SAP.  
3. STUDY DESIGN 
3.1. GENERAL DESCRIPTION 
The general description is available in the Master COV-01 SAP.  
3.2. SCHEDULE OF ACTIVITIES 
The schedule of activities can be found in Section 1.2 of the sub-protocol COV-01-004. 
3.3. CHANGES TO PLANNED ANALYSES FROM MASTER PROTOCOL 
COV-01 AND SUB-PROTOCOL COV-01-004 
There are no changes to the analyses planned for master protocol COV-01 and sub-protocol COV-01-004. 
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4. PLANNED ANALYSES 
The planned analyses are listed and described in the Master COV-01 SAP. 
All outputs described in this sub-protocol SAP will be produced at the time of sub-protocol COV-01-004 primary 
analysis (refer to COV-01 Master SAP).  
In addition to the outputs planned to be produced at the time of COV-01-004 sub-protocol final analysis (refer to 
COV-01 Master SAP), safety outputs described in this sub-protocol SAP will also be produced at the time of COV-
01-004 sub-protocol final analysis (refer to Section 17.1). 
5. ANALYSIS SETS 
Analysis sets are described in the Master COV-01 SAP.  
An additional analysis set that is specific to sub-protocol COV-01-004 is described below: 
5.1. PHARMACOKINETIC ANALYSIS SET 
The pharmacokinetic (PK) analysis set will include all patients included in the safety analysis set (refer to Master 
COV-01 SAP Section 5.2) who were randomized to the apremilast plus Standard of Care (SoC) treatment group and 
have at least one measured PK concentration. 
5.2. PHARMACODYNAMIC ANALYSIS SET 
The pharmacodynamic (PD) analysis set will include all patients included in the safety analysis set (refer to Master 
COV-01 SAP Section 5.2) who were randomized to the COV-01-004 sub-protocol (i.e., apremilast plus SoC or 
placebo to apremilast + SoC treatment groups) and have at least one measured post-baseline biomarker level. 
5.3. PROCESS FOR ANALYSIS SET ASSIGNMENT 
As the PK analysis set is defined based on objective criteria only, the authorization of this sub-protocol SAP will 
stand for the agreement and authorization of the inclusion/exclusion of each patient in this PK analysis set.  
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6. GENERAL CONSIDERATIONS 
Details are provided in the Master COV-01 SAP. 
7. STATISTICAL CONSIDERATIONS 
7.1. SAMPLE SIZE CALCULATION 
Details are defined in the Master COV-01 SAP. 
7.2. MISSING DATA 
Details are defined in the Master COV-01 SAP. 
7.3. STATISTICAL TESTS 
Details are defined in the Master COV-01 SAP. 
7.4. MULTIPLE COMPARISONS/MULTIPLICITY 
Details are defined in the Master COV-01 SAP. 
7.5. MULTICENTER STUDY 
Details are defined in the Master COV-01 SAP. 
7.6. ADJUSTMENTS FOR COVARIATES AND FACTORS TO BE 
INCLUDED IN ANALYSES 
Details are defined in the Master COV-01 SAP. 
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7.7. EXAMINATION OF SUBGROUPS 
For sub-protocol COV-01-004, additional subgroup analyses will be performed for selected safety data (refer to 
Section 17.1).  The additional subgroup is: 
• 
Patients randomized to sub-protocol COV-01-004 (apremilast plus SoC and placebo plus SoC treatment groups) 
plus patients included in COV-01-004 control arm (refer to Master COV-01 SAP Section 4.5) that have been 
randomized to the placebo plus SoC treatment group of a sub-protocol other than COV-01-004 and who did not 
receive any concomitant dose of apremilast during the course of the study (refer to Master COV-01 SAP 
Section 14 for concomitant use definition).  That is, placebo plus SoC patients included in the control arm of 
COV-01-004 who were randomized to a sub-protocol other than COV-01-004 and who concomitantly took 
apremilast during the course of the study will be excluded from this subgroup. 
It is to be noted that these subgroup analyses will be performed only if more than 10% of patients included in COV-
01-004 control arm, that have been randomized to a sub-protocol other than COV-01-004, concomitantly took 
apremilast during the course of the study. 
7.8. SOFTWARE VERSION 
Details are defined in the Master COV-01 SAP. 
8. OUTPUT PRESENTATIONS 
Output presentations are described in the Master COV-01 SAP. 
9. DISPOSITION AND WITHDRAWALS 
Analysis of disposition and withdrawals is described in the Master COV-01 SAP. 
10. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Analysis of demographic and other baseline characteristics is described in the Master COV-01 SAP. 
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11. DISEASE HISTORY 
Analysis of disease history at screening is described in the Master COV-01 SAP. 
12. MEDICAL HISTORY 
Analysis of medical history is described in the Master COV-01 SAP. 
13. PRIOR AND CONCOMITANT MEDICATIONS 
Analysis of prior and concomitant medications is described in the Master COV-01 SAP. 
14. EXPOSURE TO STUDY DRUG 
Patients randomized to sub-protocol COV-01-004 
Patients randomized to the apremilast plus SoC or placebo plus SoC treatment groups of COV-01-004 sub-protocol 
will receive either an apremilast 30 mg or matching placebo tablet, as applicable, twice daily (BID) in a double-
blind manner for 14 days or until hospital discharge, death, or discontinuation of study drug, whichever occurs first, 
in addition to SoC.  
Reason for dose modification of study drug (i.e., dose increased, dose reduced, drug interrupted, drug withdrawal, 
and unknown) will be captured on the Exposure page of the electronic Case Report Form (eCRF).   
Patients included in the control arm of COV-01-004 sub-protocol who were randomized to the placebo plus 
SoC group of a sub-protocol other than COV-01-004 
It is to be noted that the planned duration of exposure to a study drug, planned frequency of administration of the 
study drug, and planned route of administration of the study drug will vary from one sub-protocol to the other, but 
similar information as for COV-01-004 sub-protocol will be captured on the Exposure page of the eCRF of these 
other sub-protocols. 
 
 
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Exposure to study drug 
The exposure to study drug will be summarized by treatment arm (breaking down the placebo plus SoC arm by sub-
protocol) based on the safety analysis set as follows: 
• 
Duration of exposure: 
o 
Duration of exposure (days) as a continuous variable; 
o 
Duration of exposure (days) as a categorical variable: 1 to 3, > 3 to 7, > 7 to 14, and > 14; 
o 
Total number of doses received as a continuous variable, where the total number of doses received is 
defined as the total number of doses received by each patient, not the total number of doses received 
across all patients. 
• 
Average dose (mg/day) only for patients randomized to sub-protocol COV-01-004; 
• 
Dose modifications: 
o 
Number and percentage of patients with at least one dose reduction; 
o 
Number and percentage of patients with a dose reduction by reason for dose reductions: 
▪ 
Adverse events; 
▪ 
Due to creatinine clearance < 30 mL/min*; 
▪ 
Due to renal replacement therapy*; 
▪ 
Other. 
o 
Total number of dose reductions as a continuous variable, where the total number of dose reductions 
defined similarly to the total number of doses received; 
o 
Among patients with a dose reduction, number and percentage of patients with dose subsequently 
increased back to the planned dose level; 
o 
Number and percentage of patients with at least one interrupted dose; 
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o 
Number and percentage of patients with at least one dose interruption by reason for dose interruption:  
▪ 
Adverse events; 
▪ 
Due to creatinine clearance < 30 mL/min*; 
▪ 
Due to renal replacement therapy*; 
▪ 
Other. 
o 
Total number of dose interruptions as a continuous variable, where the total number of dose 
interruptions is defined similarly to the total number of doses received; 
o 
Among patients with a dose interruption, number and percentage of patients with dose subsequently 
restarted at planned dose level; 
o 
Number and percentage of patients with at least one overdose. 
* Applicable only for patients randomized to sub-protocol COV-01-004. 
All dosing and exposure data will also be listed. 
14.1. DERIVATIONS 
For patients randomized to a study drug planned to be administered on a daily basis, duration of exposure to study 
drug, in days, will be computed as follows: 
• 
Duration of exposure (days) = (Date of last dose of study drug – Date of first dose of study drug) + 1 
For all other patients (i.e. randomized to a study drug planned to be administered not on a daily basis), duration of 
exposure to study drug, in days, will be computed as follows: 
• 
Duration of exposure (days) = {[Earliest date of (end of planned study treatment period, hospital discharge or 
discontinuation from study drug)] – Date of first dose of study drug} + 1 
For patients randomized to sub-protocol COV-01-004 only, the average dose per day will be computed as follows: 
• 
Average dose (mg/day) = Total cumulative dose (mg) / duration of exposure (days) 
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where the total cumulative dose is the computed total cumulative dose (mg) taken by a patient during the course of 
the study. 
15. COMPLIANCE WITH STUDY DRUG 
Compliance with study drug will be summarized by treatment arm (breaking down the placebo plus SoC arm by 
sub-protocol) based on the safety analysis set. In addition to the descriptive summary, the following compliance 
categories will be presented: 
• 
< 80%; 
• 
≥ 80% to < 100% 
• 
100%; 
• 
> 100%. 
Compliance data will also be listed. 
15.1. DERIVATIONS 
For each patient, the compliance will be computed as follows: 
• 
Compliance (%) = (Actual total number of doses / Expected total number of doses) x 100 
where: 
• 
Actual total number of doses is defined as the sum of all doses taken through the course of the study  
• 
Expected total number of doses is defined as the sum of protocol-defined doses to be taken through the course 
of the study and is computed as follows: 
o 
For patients randomized to a study drug administered on a daily basis: 
▪ 
Expected total number of doses  = expected number of doses (injections) per day * expected 
number of days under treatment, where the expected number of days under treatment is defined as: 
{[Earliest date of (end of planned study treatment period, hospital discharged or discontinuation 
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from study drug)] – Date of first dose of study drug} + 1 
 
o 
For patients randomized to a study drug planned to be administered not on a daily basis: 
▪ 
Expected total number of doses = Expected number of doses (injections) per day * number of 
expected administration days between randomization and the earliest of (end of planned study 
treatment period, hospital discharged or discontinuation from study drug).   
 
For example, if a study drug is planned to be administered once on Day 1 and once on Day 4, the 
expected total number of doses is 2; unless patient discontinued from study drug or was 
discharged from the hospital on or after Day 1 but before Day 4, in which case the expected total 
number of doses is 1.  As another example, if the study drug is planned to be administered twice 
daily on every other day from Day 1 to Day 14, the expected total number of doses is 14; unless 
patient discontinued from study drug or was discharged from the hospital let say, on Day 10, in 
which case the expected total number of doses is 10 (i.e., 2 doses [injection] per days * 5 
administration days). 
16. EFFICACY ENDPOINTS 
Efficacy analyses are described in the Master COV-01 SAP. 
17. SAFETY ENDPOINTS 
17.1. ADVERSE EVENTS 
In addition to the safety analyses described in the Master COV-01 SAP, the following analyses will be repeated for 
the subgroup of patients defined in Section 7.7 based on the safety analysis set: 
• 
Overview of treatment-emergent adverse events (TEAEs); 
• 
TEAEs by maximum Common Terminology Criteria for Adverse Events (CTCAE) grade, System Organ Class 
and Preferred Term (PT); 
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• 
TEAEs with a CTCAE grade ≥ 3 by System Organ Class and PT: 
• 
Fatal TEAEs by System Organ Class and PT; 
• 
Serious TEAEs by System Organ Class and PT; 
• 
Most common serious TEAEs by PT, where a most common is defined as at least 1% in at least one treatment 
arm; 
• 
TEAEs leading to dose modification by System Organ Class and PT; 
• 
TEAEs leading to discontinuation of study drug by System Organ Class and PT; 
Patients excluded from the subgroup defined in Section 7.7 will be flagged in the listings of all fatal AEs, all SAEs, 
and all AEs leading to permanent discontinuation of study drug. 
Refer the Master COV-01 SAP Section 18.1 for additional details about these summaries and listings. 
17.2. LABORATORY EVALUATIONS 
Analysis of laboratory evaluations is described in the Master COV-01 SAP. 
17.3. VITAL SIGNS 
Analysis of vital signs is described in the Master COV-01 SAP. 
17.4. ECG EVALUATIONS 
Analysis of electrocardiogram (ECG) evaluations is described in the Master COV-01 SAP. 
17.5. PHYSICAL EXAMINATION 
Analysis of physical examination is described in the Master COV-01 SAP. 
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18. PHARMACOKINETICS 
PK concentrations of apremilast will be summarized and listed by visit and timepoints based on the PK analysis set. 
In addition to the descriptive statistics mentioned in Master COV-01 SAP Appendix 2, the coefficient of variation 
(CV%), geometric mean, geometric standard deviation (SD), and geometric CV% will also be provided for the PK 
concentrations.  Concentrations that are below the limit of quantification (BLQ) will be treated as a numeric value of 
zero. 
PK concentrations of apremilast will be summarized for the following time categories: 
• 
0 - < 3 hours post morning administration of study drug; 
• 
3 - <6 hours post morning administration of study drug; 
• 
6 - < 9 hours post morning administration of study drug; 
• 
9 - <12 hours post morning administration of study drug 
• 
0 - < 3 hours post evening administration of study drug; 
• 
3 - <6 hours post evening administration of study drug; 
• 
6 - < 9 hours post evening administration of study drug; 
• 
9 - <12 hours post evening administration of study drug. 
Scatter plots of plasma concentrations against the time since last dose, in hours, will be provided for each day and 
each dose of study drug (i.e., Day 8 post morning administration of study drug, Day 8 post evening administration of 
study drug, Day 15 post morning administration of study drug, and Day 15 post evening administration of study 
drug). 
18.1. DERIVATIONS 
For each day where a blood sample for PK concentration is planned to collected, the time of the two administrations 
of study drug taken on a day will be compared with the time of the blood sample for PK concentration collected on 
that day as follows in order to derive the timepoint categories specified in Section 18: 
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• 
Time post morning administration of study drug (hours) = {[Time (hours & minutes) of collection of the blood 
sample for PK concentration – Time (hours & minutes) of the morning administration of the study drug] + 1} / 
60 minute if time of collection of the blood sample for PK concentration is before the time of the evening 
administration of the study drug; 
• 
Time post evening administration of study drug (hours) = {[Time (hours & minutes) of collection of the blood 
sample for PK concentration – Time (hours & minutes) of the evening the administration of study drug] + 1} / 
60 minute if time of collection of the blood sample for PK concentration is on or after the time of the evening 
administration of the study drug but before the time of the morning administration of study drug of the next day. 
19. PHARMACODYNAMICS 
 
 
 
20. DATA NOT SUMMARIZED OR PRESENTED 
The list of data not summarized or presented is available in the Master COV-01 SAP. 
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UCB Biopharma SRL 
Sub-Protocol COV-01-005 
COV-01-005 Statistical Analysis Plan 
Page 1 of 55 
 
 
 
 
 
 
Version Number: 
Amendment 2, v1.0 
 
Version Date:  
28-Jul-2021 
 
 
 
 
 
 
 
 
 
 
COV-01-005 STATISTICAL ANALYSIS PLAN 
 
INDUSTRY ALLIANCE PLATFORM TRIAL TO ASSESS THE EFFICACY 
AND SAFETY 
OF MULTIPLE CANDIDATE AGENTS 
FOR 
THE 
TREATMENT OF COVID-19 IN HOSPITALIZED PATIENTS 
 
SUB-PROTOCOL NUMBER: COV-01-005 
SUB-PROTOCOL FOR CANDIDATE AGENT: ZILUCOPLAN 
 
 
AUTHOR: 
 
VERSION NUMBER AND DATE: Amendment 2 v1.0, 28-Jul-2021 
 
 
 
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UCB Biopharma SRL 
Sub-Protocol COV-01-005 
COV-01-005 Statistical Analysis Plan 
Page 3 of 55 
 
 
 
 
 
 
Version Number: 
Amendment 2, v1.0 
 
Version Date:  
28-Jul-2021 
 
 
 
 
 
 
MODIFICATION HISTORY 
 
Unique 
Identifier for 
this Version 
Date of the 
Document 
Version 
Author 
Significant Changes from  
Previous Authorized Version 
Final, v1.0 
11-Jan-2021 
 
Not Applicable – First Version 
Amendment 1, 
v1.0 
27-Apr-2021 
 
Update title of Sections 11and 13 to be in line 
with Master SAP; 
Removed the Ukrainian and Non-Ukrainian 
subgroups and related supplementary analyses; 
Removed supplementary analyses adjusted for 
Ukrainians vs. Non-Ukrainians patients’ status; 
Added subgroup of patients randomized to this 
subprotocol and related supplementary 
analyses; 
Added that the risk difference of the overall 
incidence rates of having any treatment-
emergent AESI between the treatment groups 
will be presented along with its 95% two-sided 
Wald CI. 
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UCB Biopharma SRL 
Sub-Protocol COV-01-005 
COV-01-005 Statistical Analysis Plan 
Page 4 of 55 
 
 
 
 
 
 
Version Number: 
Amendment 2, v1.0 
 
Version Date:  
28-Jul-2021 
 
 
 
 
 
 
Unique 
Identifier for 
this Version 
Date of the 
Document 
Version 
Author 
Significant Changes from  
Previous Authorized Version 
Amendment 2, 
v1.0 
28-Jul-2021 
 
Specified that the two Interim Analyses (IAs) 
and Primary Analysis at Day 29 will not be 
performed for this sub-protocol since 
enrollment into this sub-protocol was 
terminated early by the Sponsor on 07-Jun-
2021 before the trigger of each of these 
analyses was met. 
Exception of summary statistics for the 
primary efficacy endpoint, secondary efficacy 
endpoints (key and other), and the additional 
efficacy endpoint of all-cause mortality 
through Day 60, removed all planned efficacy 
analyses given that 1) enrollment into this sub-
protocol was terminated early by the Sponsor 
on 07-Jun-2021, 2) number of patients to be 
included in COV-01-005 sub-protocol final 
analysis, and 3) an abbreviated Clinical Study 
Report will be created for this sub-protocol. 
Added two-sided 95% exact binomial 
Confidence Interval within each treatment arm, 
when applicable. 
Removed additional subgroup analyses that 
were to be performed for sub-protocol primary 
and key secondary efficacy endpoints. 
 
 
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UCB Biopharma SRL 
Sub-Protocol COV-01-005 
COV-01-005 Statistical Analysis Plan 
Page 5 of 55 
 
 
 
 
 
 
Version Number: 
Amendment 2, v1.0 
 
Version Date:  
28-Jul-2021 
 
 
 
 
 
 
TABLE OF CONTENTS 
1. 
Introduction ................................................................................................................................................. 8 
2. 
Study Objectives ........................................................................................................................................... 8 
3. 
Study Design ................................................................................................................................................. 8 
3.1. 
General Description .................................................................................................................................... 8 
3.2. 
Schedule of Activities .................................................................................................................................. 8 
3.3. 
Changes to Analysis from Master Protocol COV-01 and Sub-Protocol COV-01-005 ................................... 8 
4. 
Planned Analyses .......................................................................................................................................... 9 
4.1. 
IDMC Safety Analyses ................................................................................................................................. 9 
4.2. 
Interim Analyses ......................................................................................................................................... 9 
4.3. 
Primary Analysis ......................................................................................................................................... 9 
4.4. 
Final Analysis .............................................................................................................................................. 9 
4.5. 
Selection of the Control Arm for an Analysis ............................................................................................ 10 
4.5.1. 
IDMC Safety Analyses .......................................................................................................................... 10 
4.5.2. 
Final Analysis ........................................................................................................................................ 10 
5. 
Analysis Sets ............................................................................................................................................... 11 
5.1. 
Pharmacokinetic Analysis Set ................................................................................................................... 11 
5.2. 
Pharmacodynamic Analysis Set ................................................................................................................ 11 
5.3. 
Anti-Drug Antibody Analysis Set ............................................................................................................... 11 
5.4. 
Process for Analysis Set Assignment ......................................................................................................... 11 
6. 
General Considerations .............................................................................................................................. 12 
7. 
Statistical Considerations ........................................................................................................................... 12 
7.1. 
Sample Size Calculation ............................................................................................................................ 12 
7.2. 
Missing Data ............................................................................................................................................. 12 
7.3. 
Statistical Tests ......................................................................................................................................... 12 
7.4. 
Multiple Comparisons/Multiplicity ........................................................................................................... 12 
7.5. 
Multicenter Study ..................................................................................................................................... 12 
7.6. 
Adjustments for Covariates and Factors to be Included in Analyses ........................................................ 13 
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UCB Biopharma SRL 
Sub-Protocol COV-01-005 
COV-01-005 Statistical Analysis Plan 
Page 6 of 55 
 
 
 
 
 
 
Version Number: 
Amendment 2, v1.0 
 
Version Date:  
28-Jul-2021 
 
 
 
 
 
 
7.7. 
Examination of Subgroups ........................................................................................................................ 13 
7.8. 
Software Version ...................................................................................................................................... 13 
8. 
Output Presentations ................................................................................................................................. 13 
9. 
Disposition and Withdrawals ...................................................................................................................... 13 
10. 
Demographic and Other Baseline Characteristics ....................................................................................... 13 
11. 
Disease History ........................................................................................................................................... 13 
12. 
Medical History .......................................................................................................................................... 14 
13. 
Prior and Concomitant Medications ........................................................................................................... 14 
13.1. 
Derivation ................................................................................................................................................. 14 
14. 
Exposure to Study Drug .............................................................................................................................. 15 
14.1. 
Derivations ................................................................................................................................................ 16 
15. 
Compliance with Study Drug ....................................................................................................................... 16 
15.1. 
Derivations ................................................................................................................................................ 17 
16. 
Efficacy Endpoints....................................................................................................................................... 18 
16.1. 
Primary Efficacy ........................................................................................................................................ 19 
16.1.1. 
Time to Confirmed Clinical Recovery through Day 29, without Re-Hospitalization Through Day 29
 
19 
16.1.2. 
Missing Data Imputation Method for Primary Efficacy Endpoint ................................................... 19 
16.1.3. 
Main Analysis of Primary Efficacy Endpoint .................................................................................... 19 
16.1.4. 
Sensitivity Analyses for Primary Efficacy Endpoint ......................................................................... 19 
16.1.5. 
Supplementary Analyses for Primary Efficacy Endpoint ................................................................. 20 
16.2. 
Secondary Efficacy .................................................................................................................................... 20 
16.2.1. 
Secondary Efficacy Endpoints ......................................................................................................... 20 
16.2.2. 
Missing Data Imputation Method for Secondary Efficacy Endpoints ............................................. 20 
16.2.3. 
Main Analysis of Secondary Efficacy Endpoints .............................................................................. 20 
16.2.3.1. 
Binary Endpoints ........................................................................................................................ 20 
16.2.3.2. 
Ordinal Endpoints ....................................................................................................................... 20 
16.2.4. 
Sensitivity Analyses for Secondary Efficacy Endpoints ................................................................... 21 
16.2.5. 
Supplementary Analyses for Secondary Efficacy Endpoints ........................................................... 21 
16.3. 
Exploratory Efficacy .................................................................................................................................. 22 
16.4. 
Additional Efficacy .................................................................................................................................... 22 
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UCB Biopharma SRL 
Sub-Protocol COV-01-005 
COV-01-005 Statistical Analysis Plan 
Page 7 of 55 
 
 
 
 
 
 
Version Number: 
Amendment 2, v1.0 
 
Version Date:  
28-Jul-2021 
 
 
 
 
 
 
16.4.1. 
Additional Efficacy Endpoint ........................................................................................................... 22 
16.4.1.1. 
Incidence of All-Cause Mortality through Day 60 ...................................................................... 22 
16.4.2. 
Missing Data Imputation Method for Additional Efficacy Endpoint ............................................... 22 
16.4.3. 
Analysis of Additional Efficacy Endpoint ......................................................................................... 22 
16.4.4. 
Sensitivity Analyses for Additional Efficacy Endpoint ..................................................................... 22 
16.4.5. 
Supplementary Analyses for Additional Efficacy Endpoint ............................................................. 23 
16.5. 
Interim Analysis ........................................................................................................................................ 23 
17. 
Safety Endpoints ......................................................................................................................................... 23 
17.1. 
Adverse Events .......................................................................................................................................... 24 
17.1.1. 
Adverse Events of Special Interest .................................................................................................. 24 
17.2. 
Laboratory Evaluations ............................................................................................................................. 25 
17.2.1. 
Potential Hy’s Law Events ............................................................................................................... 25 
17.3. 
Vital Signs ................................................................................................................................................. 25 
17.4. 
Electrocardiogram Evaluations ................................................................................................................. 25 
17.5. 
Physical Examination ................................................................................................................................ 25 
18. 
Pharmacokinetic Assessments .................................................................................................................... 25 
18.1. 
Derivation ................................................................................................................................................. 26 
19. 
Pharmacodynamic and Other Biomarker Assessments ............................................................................... 26 
20. 
Anti-Drug Antibody Testing ........................................................................................................................ 27 
21. 
Data Not Summarized or Presented............................................................................................................ 28 
 
 
 
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UCB Biopharma SRL 
Sub-Protocol COV-01-005 
COV-01-005 Statistical Analysis Plan 
Page 8 of 55 
 
 
 
 
 
 
Version Number: 
Amendment 2, v1.0 
 
Version Date:  
28-Jul-2021 
 
 
 
 
 
 
1. INTRODUCTION 
This sub-protocol statistical analysis plan (SAP) describes the rules and conventions to be used in the presentation 
and analysis of data specific to COV-01-005 sub-protocol of Master Protocol COV-01. It describes the specific data 
to be summarized and analyzed, including specifics of the statistical analyses to be performed.  
This sub-protocol SAP is based on sub-protocol version 1.2, dated 03-Nov-2020. 
For the rules and conventions to be used in the presentation and analysis of data common across all sub-protocols, 
refer to the Master COV-01 SAP. 
 
2. STUDY OBJECTIVES 
The study objectives are described in the Master COV-01 SAP.   
3. STUDY DESIGN 
3.1. GENERAL DESCRIPTION 
The general description is available in the Master COV-01 SAP. 
3.2. SCHEDULE OF ACTIVITIES 
Schedule of activities can be found in Section 1.2 of COV-01-005 sub-protocol. 
3.3. CHANGES TO ANALYSIS FROM MASTER PROTOCOL COV-01 
AND SUB-PROTOCOL COV-01-005 
Enrollment into sub-protocol COV-01-005 was prematurely terminated by the Sponsor on 07-Jun-2021.  In 
conformance with the Food and Drug Administration (FDA) Guidance for Submission of Abbreviated Report and 
Synopsis in Support of Marking Application, an abbreviated Clinical Study Report (CSR) will be written for this 
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UCB Biopharma SRL 
Sub-Protocol COV-01-005 
COV-01-005 Statistical Analysis Plan 
Page 9 of 55 
 
 
 
 
 
 
Version Number: 
Amendment 2, v1.0 
 
Version Date:  
28-Jul-2021 
 
 
 
 
 
 
sub-protocol.  As such, not all analyses initially planned in the Master Protocol COV-01 and Sub-protocol COV-01-
005 will be performed for this sub-protocol (refer to Section 
. for more details 
concerning the analyses to be performed for this sub-protocol). 
4. PLANNED ANALYSES 
The analyses initially planned to be performed are listed and described in the Master COV-01 SAP.  It is to be noted 
that enrollment into sub-protocol COV-01-005 was terminated early by the Sponsor on 07-Jun-2021 before the 
trigger for the two Interim Analyses (IAs) for futility and Primary Analysis have been reached (refer to Master SAP 
Sections 4.2 and 4.3, respectively).  Hence, these analyses will not be performed for this sub-protocol and the only 
analysis that will be performed, in addition to the monthly IDMC Safety analyses, is the final analysis (refer to 
Section 4.4). 
4.1. IDMC SAFETY ANALYSES 
Details are provided in the Master COV-01 SAP. 
4.2. INTERIM ANALYSES 
No IAs will be performed for this sub-protocol (refer to Section 4). 
4.3. PRIMARY ANALYSIS 
No primary analysis will be performed for this sub-protocol (refer to Section 4). 
4.4. FINAL ANALYSIS 
The final analysis for this sub-protocol will take place after: 
• 
All patients to be included in this sub-protocol final analysis who were ongoing at the time Sponsor terminated 
early this sub-protocol completed the study (Day 60 visit) or discontinued early from the study, whichever 
occurs first. 
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UCB Biopharma SRL 
Sub-Protocol COV-01-005 
COV-01-005 Statistical Analysis Plan 
Page 10 of 55 
 
 
 
 
 
 
Version Number: 
Amendment 2, v1.0 
 
Version Date:  
28-Jul-2021 
 
 
 
 
 
 
• 
Sponsor Authorization of this SAP. 
• 
Final database lock of the database including data from screen failed patients. 
• 
Final database lock of the database of each sub-protocol contributing to the control arm of this sub-protocol 
(refer to Section 4.5). 
• 
Final database lock of the database of this sub-protocol. 
All planned analyses identified in this sub-protocol SAP will be performed by 
 Biostatistics at the time of the 
final analysis of this sub-protocol. 
4.5. SELECTION OF THE CONTROL ARM FOR AN ANALYSIS 
4.5.1. 
IDMC SAFETY ANALYSES 
Details are provided in Master SAP Section 4.5. 
4.5.2. 
FINAL ANALYSIS 
For final analysis of this sub-protocol, the control arm (also referred to as shared placebo plus standard of care (SoC) 
arm) will include all patients randomized to the placebo arm of any sub-protocol at a site at which: 
• 
This sub-protocol was opened for enrollment. 
• 
At least one patient was randomized to either this sub-protocol active (zilucoplan plus SoC) or placebo (placebo 
to zilucoplan plus SoC) arms. 
That is, patients that satisfy these criteria will be included in the control arm of this sub-protocol regardless of 1) the 
timing of patient’s randomization into a sub-protocol (i.e., regardless of if patient was randomized before or after 
this sub-protocol was opened for enrollment at the site) and 2) patient’s eligibility to this sub-protocol specific 
inclusion/ exclusion criteria. 
The purpose of this change from the Master SAP control arm definition (Master SAP Section 4.5) is to minimize the 
randomization imbalance issue noted by the 
Unblinded Biostatistician and IDMC members at the time of 
  At the 
time this sub-protocol SAP was finalized, the randomization imbalance was estimated to be approximately 7:1 
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UCB Biopharma SRL 
Sub-Protocol COV-01-005 
COV-01-005 Statistical Analysis Plan 
Page 11 of 55 
 
 
 
 
 
 
Version Number: 
Amendment 2, v1.0 
 
Version Date:  
28-Jul-2021 
 
 
 
 
 
 
between this sub-protocol active and control arms, should the original control arm definition would have been 
retained for the final analysis of this sub-protocol. 
5. ANALYSIS SETS 
Analysis sets are described in the Master COV-01 SAP. 
Additional analysis sets that are specific to sub-protocol COV-01-005 are described below. 
5.1. PHARMACOKINETIC ANALYSIS SET  
The pharmacokinetic (PK) analysis set will include patients from the safety analysis set (refer to Master COV-01 
SAP Section 5.2) who were randomized to the zilucoplan plus SoC treatment arm and had at least one measured 
post-baseline concentration (refer to Master COV-01 SAP Section 6.2 for baseline definition).  
5.2. PHARMACODYNAMIC ANALYSIS SET 
The pharmacodynamic (PD) analysis set will include patients from the safety analysis set (refer to Master COV-01 
SAP Section 5.2) who were randomized to COV-01-005 sub-protocol and had at least one measured biomarker (e.g., 
C5, etc.). 
5.3. ANTI-DRUG ANTIBODY ANALYSIS SET 
The anti-drug antibody (ADA) analysis set will include patients from the safety analysis set (refer to Master COV-
01 SAP Section 5.2) who were randomized to COV-01-005 sub-protocol and had at least one evaluated ADA 
sample (negative or positive). 
5.4. PROCESS FOR ANALYSIS SET ASSIGNMENT 
As the PK, PD, and ADA analysis sets are defined based on objective criteria only, the authorization of this sub-
protocol SAP will stand for the agreement and authorization of the inclusion/exclusion of each patient in these PK, 
PD, and ADA analysis sets. 
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UCB Biopharma SRL 
Sub-Protocol COV-01-005 
COV-01-005 Statistical Analysis Plan 
Page 12 of 55 
 
 
 
 
 
 
Version Number: 
Amendment 2, v1.0 
 
Version Date:  
28-Jul-2021 
 
 
 
 
 
 
6. GENERAL CONSIDERATIONS 
Details are provided in the Master COV-01 SAP. 
7. STATISTICAL CONSIDERATIONS 
7.1. SAMPLE SIZE CALCULATION 
Details are defined in the Master COV-01 SAP. 
7.2. MISSING DATA 
Details are defined in the Master COV-01 SAP. 
7.3. STATISTICAL TESTS 
Not applicable since no statistical inferences will be performed for the final analysis of this sub-protocol (refer to 
Section 16). 
7.4. MULTIPLE COMPARISONS/MULTIPLICITY 
Not applicable since no statistical inferences will be performed for the final analysis of this sub-protocol (refer to 
Section 16). 
7.5. MULTICENTER STUDY 
Details are defined in the Master COV-01 SAP. 
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UCB Biopharma SRL 
Sub-Protocol COV-01-005 
COV-01-005 Statistical Analysis Plan 
Page 13 of 55 
 
 
 
 
 
 
Version Number: 
Amendment 2, v1.0 
 
Version Date:  
28-Jul-2021 
 
 
 
 
 
 
7.6. ADJUSTMENTS FOR COVARIATES AND FACTORS TO BE 
INCLUDED IN ANALYSES 
Not applicable since no statistical inferences will be performed for the final analysis of this sub-protocol (refer to 
Section 16). 
7.7. EXAMINATION OF SUBGROUPS 
No subgroup analyses will be performed for the final analysis of this sub-protocol (refer to Section 16).  
7.8. SOFTWARE VERSION 
Details are defined in the Master COV-01 SAP. 
8. OUTPUT PRESENTATIONS 
Output presentations are described in the Master COV-01 SAP.  
9. DISPOSITION AND WITHDRAWALS 
Analysis of disposition and withdrawals will be presented as described in the Master COV-01 SAP.  
10. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic characteristics and other baseline characteristics data will be presented as described in the Master 
COV-01 SAP. 
11. DISEASE HISTORY 
Analysis of disease history at screening will be performed as described in the Master COV-01 SAP.  
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UCB Biopharma SRL 
Sub-Protocol COV-01-005 
COV-01-005 Statistical Analysis Plan 
Page 14 of 55 
 
 
 
 
 
 
Version Number: 
Amendment 2, v1.0 
 
Version Date:  
28-Jul-2021 
 
 
 
 
 
 
12. MEDICAL HISTORY 
Analysis of medical history will be performed as described in the Master COV-01 SAP. 
13. PRIOR AND CONCOMITANT MEDICATIONS 
In addition to the analysis of prior and concomitant medications described in the Master COV-01 SAP, antibiotic 
prophylaxis, collected on the Antibiotic Prophylaxis page of the electronic Case Report Form (eCRF), will also be 
coded to the World Health Organization (WHO) Drug Global dictionary, version B3 March 2020 (or later). 
Concomitant use (refer to Master COV-01 SAP Section 13 for definition of concomitant use) of antibiotic for any 
indication as well as of antibiotic prophylaxis for Neisseria infection will be summarized separately by Anatomical 
Therapeutic Class (ATC) level 2, preferred drug name, and treatment arm based on the FAS (refer to Master COV-
01 SAP Section 5.1).  Separate summary of patients randomized to COV-01-005 placebo plus SoC treatment group 
will be provided.  A patient having more than one medication within the same ATC level 2 or preferred drug name 
will be counted only once for that ATC level 2 or preferred drug name. 
Furthermore, duration of concomitant use of antibiotic for any indication (days) and number and percentage of 
patients who received antibiotic prophylaxis for Neisseria infections concurrently while receiving the study drug and 
up to 14 days after the last dose of the study drug will be presented by treatment arm based on the FAS.  Separate 
summary of patients randomized to COV-01-005 placebo plus SoC treatment group will be provided. 
All antibiotic prophylaxis will be listed. 
13.1. DERIVATION 
Duration of concomitant use of antibiotic for any indication, in days, will be derived as follows: 
• 
Duration of concomitant use of antibiotic for any indication (days) = {[Date of latest stop date of any antibiotic 
received on or after the first dose of study drug – Latest of (date of earliest start date of antibiotic received on or 
after the first dose of study drug, date of first dose of study drug)] + 1} – [sum of any gap (days) in concomitant 
use of antibiotics for any indication on or after the first dose of study drug] 
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Sub-Protocol COV-01-005 
COV-01-005 Statistical Analysis Plan 
Page 15 of 55 
 
 
 
 
 
 
Version Number: 
Amendment 2, v1.0 
 
Version Date:  
28-Jul-2021 
 
 
 
 
 
 
14. EXPOSURE TO STUDY DRUG 
Patients randomized to sub-protocol COV-01-005 
Patients randomized to zilucoplan plus standard of care (SoC) and placebo plus SoC treatment arms of COV-01-005 
sub-protocol will receive a single daily dose of 32.4 mg of the study drug (prefilled syringes containing 0.81 mL of 
zilucoplan or placebo, as appropriate) administered by subcutaneous (SC) injection in the abdomen (preferred site), 
thigh or upper arm.  
The daily administration of study treatment will start on Day 1 (baseline) and continue to Day 14 or until hospital 
discharge, whichever occurs first. If the patient is discharged before 14 days of treatment, zilucoplan or placebo 
should be stopped at time of discharge or 24 hours before discharge.  
Reason for dose modification of study drug (i.e. dose interrupted or drug withdrawal) will be captured in the 
Exposure page of the eCRF.  
Patients included in the control arm of COV-01-005 sub-protocol who were randomized to the placebo plus 
SoC group of a sub-protocol other than COV-01-005 
It is to be noted that the planned duration of exposure to a study drug, planned frequency of administration of the 
study drug, and planned route of administration of the study drug will vary from one sub-protocol to the other, but 
similar information as for COV-01-005 sub-protocol will be captured on the Exposure page of the eCRF of these 
other sub-protocols. 
Exposure to study drug 
The exposure to study drug will be summarized by treatment arm (breaking down the placebo plus SoC arm by sub-
protocol) based on the safety analysis set as follows: 
• 
Duration of exposure: 
o 
Duration of exposure (days) as a continuous variable; 
o 
Duration of exposure (days) as a categorical variable: 1 to 3, > 3 to 7, > 7 to 14, and > 14; 
o 
Total number of doses received as a continuous variable, where the total number of doses received is 
defined as the total number of doses received by each patient, not the total number of doses received 
across all patients. 
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COV-01-005 Statistical Analysis Plan 
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• 
Dose modifications:  
o 
Number and percentage of patients with at least one interrupted dose; 
o 
Number and percentage of patients with at least one dose interruption by reason for dose interruptions:  
▪ 
Adverse events; 
▪ 
Other. 
o 
Total number of dose interruptions as a continuous variable, where the total number of dose 
interruptions is defined similarly to the total number of doses received; 
• 
Number and percentage of patients with at least one overdose. 
All dosing and exposure data will also be listed. 
14.1. DERIVATIONS 
For patients randomized to a study drug planned to be administered on a daily basis, duration of exposure to study 
drug, in days, will be computed as follows: 
• 
Duration of exposure (days) = (Date of last dose of study drug – Date of first dose of study drug) + 1 
For all other patients (i.e. randomized to a study drug planned to be administered not on a daily basis), duration of 
exposure to study drug, in days, will be computed as follows: 
• 
Duration of exposure (days) = {[Earliest date of (end of planned study treatment period, hospital discharge or 
discontinuation from study drug)] – Date of first dose of study drug} + 1 
15. COMPLIANCE WITH STUDY DRUG 
Compliance with study medication will be summarized by treatment arm (breaking down the placebo plus SoC 
control arm by sub-protocol) based on the safety analysis set.  In addition to the descriptive summary, the following 
compliance categories will be presented: 
 
 
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• 
< 80%; 
• 
≥ 80% to < 100%; 
• 
100%; 
• 
> 100%. 
Compliance data will also be listed.  
15.1. DERIVATIONS 
For each patient, the compliance will be computed as follows: 
• 
Compliance (%) = (Actual total number of doses / Expected total number of doses) x 100 
where: 
• 
Actual total number of doses is defined as the total number of doses (injections) taken (received) through the 
course of the study; 
• 
Expected total number of doses is defined as the total number of protocol-defined doses (injections) to be taken 
(received) through the course of the study and is computed as follows: 
o 
For patients randomized to a study drug administered on a daily basis: 
▪ 
Expected total number of doses  = Expected number of doses (injections) per day * 
expected number of days under treatment, where the expected number of days under 
treatment is defined as: {[Earliest date of (end of planned study treatment period, hospital 
discharged or discontinuation from study drug)] – Date of first dose of study drug} + 1 
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o 
For patients randomized to a study drug planned to be administered not on a daily basis: 
▪ 
Expected total number of doses = Expected number of doses (injections) per day * 
expected number of administration days between randomization and the earliest of (end 
of planned study treatment period, hospital discharged or discontinuation from study 
drug) 
o 
For example, if a study drug is planned to be administered once on Day 1 and once on Day 4, the 
expected total number of doses is 2; unless patient discontinued from study drug or was discharged 
from the hospital on or after Day 1 but before Day 4, in which case the expected total number of doses 
is 1.  As another example, if the study drug is planned to be administered twice daily on every other 
day from Day 1 to Day 14, the expected total number of doses is 14; unless patient discontinued from 
study drug or was discharged from the hospital let say, on Day 10, in which case the expected total 
number of doses is 10 (i.e., 2 doses [injection] per day * 5 administration days). 
16. EFFICACY ENDPOINTS  
Given that only 108 patients were randomized into COV-01-005 sub-protocol by the time enrollment into this sub-
protocol was terminated early by the Sponsor and that is expected that less than the third of the total number of 
patients required by the sample size (i.e., ~700; refer to Master SAP Section 7.1) will be included in the final 
analysis of this sub-protocol, no statistical inferences will be performed for any efficacy endpoint, but two-sided 
95% confidence interval (CI) within each treatment arm will be provided, when possible. 
In conformance with the FDA’s Guidance for Submission of Abbreviated Report and Synopsis in Support of 
Marking, summary tables will be presented for the primary and key secondary efficacy endpoints (refer to Master 
SAP Sections 16.1.1, 16.2.1.1, 16.2.1.2, and 16.2.1.3).  Although not required by the previously mentioned FDA’s 
Guidance, summary tables will also be provided for the other secondary efficacy endpoints (refer to Master SAP 
Sections 16.2.1.4 to 16.2.1.9) in order to be compliant with the publication requirements of ClinicalTrials.gov.  In 
addition, summary tables will also be provided for the additional efficacy endpoint of incidence of all-cause 
mortality through Day 60 (refer to Master SAP Section 16.4.1.1). 
Efficacy summaries will be performed as described in the Master COV-01 SAP. 
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16.1. PRIMARY EFFICACY 
16.1.1. 
TIME TO CONFIRMED CLINICAL RECOVERY THROUGH DAY 29, WITHOUT RE-
HOSPITALIZATION THROUGH DAY 29 
Details are provided in the Master COV-01 SAP. 
16.1.2. 
MISSING DATA IMPUTATION METHOD FOR PRIMARY EFFICACY ENDPOINT 
Details are provided in the Master COV-01 SAP. 
16.1.3. 
MAIN ANALYSIS OF PRIMARY EFFICACY ENDPOINT 
For the time to confirmed clinical recovery through Day 29, without re-hospitalization through Day 29, as defined in 
the Master SAP Section 16.1.1, the number and percentage of patients with and without the event will be presented 
by randomized treatment arm. Two-sided 95% exact binomial Confidence Interval (CI) will also be provided by 
treatment arm for the percentage of patients with the event.  For patients who did not meet the event, the main 
reason for censoring will be summarized similarly. 
Kaplan-Meier curves (product-limit estimate) will be provided by treatment arm for the time to confirmed clinical 
recovery though Day 29, without re-hospitalization through Day 29. Kaplan-Meier estimate of the time to confirmed 
clinical recovery through Day 29, without re-hospitalization through Day 29, in days, will be provided at the 25th, 
50th (median), and 75th percentiles time along with their corresponding two-sided 95% CIs.  The estimates of the SEs 
will be computed using the Greenwood’s formula, the CI for the median will be calculated according to Brookmeyer 
and Crowley (1982), and the CIs for the survival function estimates at above mentioned time points will be derived 
from the Kaplan-Meier estimates using the log-log transformation.  Kaplan-Meier estimates of the probability of 
having the event will also be provided at Day 29 along with the number of patients with the event and the number of 
patients at risk at that time. 
16.1.4. 
SENSITIVITY ANALYSES FOR PRIMARY EFFICACY ENDPOINT 
No sensitivity analyses will be performed for this sub-protocol. 
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16.1.5. 
SUPPLEMENTARY ANALYSES FOR PRIMARY EFFICACY ENDPOINT 
No supplementary analyses will be performed for this sub-protocol. 
16.2. SECONDARY EFFICACY 
16.2.1. 
SECONDARY EFFICACY ENDPOINTS 
Details are provided in the Master COV-01 SAP. 
16.2.2. 
MISSING DATA IMPUTATION METHOD FOR SECONDARY EFFICACY ENDPOINTS 
Details are provided in the Master COV-01 SAP. 
16.2.3. 
MAIN ANALYSIS OF SECONDARY EFFICACY ENDPOINTS 
Details are provided in the Master COV-01 SAP. 
16.2.3.1. 
Binary Endpoints 
For the incidence of patients with oxygen-free recovery at Day 29 (refer to Master SAP Section 16.2.1.1), incidence 
of patients with ≥ 2-point improvement from baseline or fit for discharge on the ordinal scale at Day 29 (refer to 
Master SAP Section 16.2.1.2), incidence of all-cause mortality through Day 29 (refer to Master SAP Section 
16.2.1.3) , incidence of patients with clinical recovery at Days 8, 15 and 29 (refer to Master SAP Section 16.2.1.8), 
and incidence of patients with sustained clinical recovery as confirmed by Day 60 follow-up (refer to Master SAP 
Section 16.2.1.9), the number and percentage of patients with and without the event will be provided by treatment 
arm.  Two-sided 95% exact binomial CI will also be provided by treatment arm for the percentage of patients with 
the event. 
For the incidence of all-cause mortality, primary reason of death will also be summarized by treatment arm. 
16.2.3.2. 
Ordinal Endpoints 
For the incidence of patients in each category of the 8-point ordinal scale for clinical severity at Days 8, 15, and 29 
endpoints (refer to Master SAP Section 16.2.1.4), the number and percentage of patients in each ordinal scale 
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category will be provided at each specified Day for each treatment arm. The worst post-baseline score on the 8-point 
ordinal scale for clinical severity from randomization to Day 29 (refer to Master SAP Section 16.2.1.5) and each 
“number of days” endpoint (refer to Master SAP Sections 16.2.1.6 and 16.2.1.7) will be summarized similarly. 
Shift tables from baseline to each post-baseline day up to Day 29 as well as to the worst post-baseline score will also 
be provided for the 8-point ordinal scale for clinical severity. 
16.2.4. 
SENSITIVITY ANALYSES FOR SECONDARY EFFICACY ENDPOINTS 
No sensitivity analyses will be performed for this sub-protocol. 
16.2.5. 
SUPPLEMENTARY ANALYSES FOR SECONDARY EFFICACY ENDPOINTS 
For the incidence of all-cause mortality through Day 29 key secondary efficacy endpoint, the time to all-cause 
mortality through Day 29, in days, associated will be derived as follows: 
• 
Time to all-cause mortality through Day 29 (days) = 
(Date of death / Date of censoring - Date of Study Day 1 [refer to Maser SAP Section 6.1]) + 1. 
The date of death will be taken from data captured on the Death Details page of the eCRF. 
For patients who were alive on Day 29, time to all cause-mortality will be censored at Day 29. For patients with an 
unknown alive status at the time of the analysis due to missing data, time to all-cause mortality will be censored at 
the latest date on which the patient was known to be alive before or on the data cut-off date of the analysis.  The last 
date the patient was known to be alive will be the latest date collected on any page of the eCRF. For patients who 
discontinued from the study before the time of the analysis, time to all-cause mortality will be censored at the date of 
study discontinuation, as captured on the Disposition page of the eCRF. 
Number and percentage of patients with and without the event will be presented by randomized treatment arm.  For 
patients who did not meet the event, the main reason for censoring will be summarized similarly. 
Kaplan-Meier survival curves by treatment arm will be provided.  The 25th percentile, 50th percentile (median), and 
75th percentile of time to all-cause mortality through Day 29 (days) with the corresponding two-sided 95% CIs based 
on the Kaplan-Meier survival curves (refer to Master SAP Section 16.2.4) for each treatment arm will also be 
presented.  The estimate of the SEs will be computed using Greenwood’s formula, the CI for the median will be 
calculated according to Brookmeyer and Crowley (1982) and the other CIs will be derived from the Kaplan-Meier 
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estimates using the log-log transformation.  Kaplan-Meier estimates of the probability of having the event will also 
be provided at Day 29 along with the number of patients with the event and the number of patients at risk at that 
time. 
No supplementary analyses will be performed for the any other secondary efficacy endpoints. 
16.3. EXPLORATORY EFFICACY 
 
 
16.4. ADDITIONAL EFFICACY 
16.4.1. 
ADDITIONAL EFFICACY ENDPOINT 
16.4.1.1. 
Incidence of All-Cause Mortality through Day 60 
Details are provided in the Master COV-01 SAP. 
16.4.2. 
MISSING DATA IMPUTATION METHOD FOR ADDITIONAL EFFICACY ENDPOINT 
Details are provided in the Master COV-01 SAP. 
16.4.3. 
ANALYSIS OF ADDITIONAL EFFICACY ENDPOINT 
The number and percentage of patients alive and dead through Day 60 (refer to Section 16.4.1.1) will be provided by 
treatment arm along with the two-sided 95% exact binomial CI for the percentage of patients dead through Day 60.  
Primary reason of death will also be summarized by treatment arm. 
16.4.4. 
SENSITIVITY ANALYSES FOR ADDITIONAL EFFICACY ENDPOINT 
No sensitivity analyses will be performed for the additional efficacy endpoint. 
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16.4.5. 
SUPPLEMENTARY ANALYSES FOR ADDITIONAL EFFICACY ENDPOINT 
The time to all-cause death through Day 60, in days, will be derived as follows: 
• 
Time to all-cause mortality through Day 60 (days) = 
(Date of death / Date of censoring - Date of Study Day 1 [refer to Maser SAP Section 6.1]) + 1. 
The date of death will be taken from data captured on the Death Details page of the eCRF. 
For patients who were alive or patients with an unknown alive status at the time of the analysis due to missing data, 
time to all-cause mortality will be censored at the latest date on which the patient was known to be alive before or on 
Day 60.  The last date the patient was known to be alive will be the latest date collected on any page of the eCRF. 
For patients who discontinued from the study before Day 60, time to all-cause mortality will be censored at the date 
of study discontinuation, as captured on the Disposition page of the eCRF. 
Number and percentage of patients with and without the event will be presented by treatment arm.  For patients who 
did not meet the event, the main reason for censoring will be summarized similarly. 
Kaplan-Meier survival curves by treatment arm will be provided.  The 25th percentile, 50th percentile (median), and 
75th percentile of time to all-cause mortality (days) through Day 60 with the corresponding two-sided 95% CIs based 
on the Kaplan-Meier survival curves for each treatment arm will be presented.  The estimate of the SEs will be 
computed using Greenwood’s formula, the CI for the median will be calculated according to Brookmeyer and 
Crowley (1982) and the CIs for the survival function estimates at above mentioned time points will be derived from 
the Kaplan-Meier estimates using the log-log transformation.  Kaplan-Meier estimates of the probability of having 
the event will also be provided at Day 60 along with the number of patients with the event and the number of 
patients at risk at that time. 
16.5. INTERIM ANALYSIS 
No IAs will be performed for this sub-protocol since the trigger for the first IA was not reached by the time 
enrollment into this sub-protocol was terminated early by Sponsor (refer to Master SAP Section 16.5). 
17. SAFETY ENDPOINTS 
In addition to the safety analyses are described in Master COV-01 SAP, the following safety analysis will also be 
provided based on the safety analysis set (refer to Master SAP Section 5.2). 
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17.1. ADVERSE EVENTS 
17.1.1. 
ADVERSE EVENTS OF SPECIAL INTEREST  
The following are defined as adverse events of special interest (AESIs) for this sub-protocol and will be identified 
based on pre-defined coded preferred terms (PTs), high-level terms (HLTs, and/or system organ class: 
• 
Anaphylactic reactions (Medical Dictionary for Regulatory Activities [MedDRA] algorithmic approached; refer 
to Appendix 1); 
• 
Serious anaphylactic reactions (MedDRA algorithmic approached; refer to Appendix 1);  
• 
Hypersensitivity reactions (standardized MedDRA query [SMQ] – narrow scope; refer to Appendix 2); 
• 
Serious hypersensitivity reactions (SMQ – narrow scope: refer to Appendix 2); 
• 
Infections (MedDRA system organ class of ‘Infections and infestations’); 
• 
Serious infections (MedDRA system organ class of ‘Infections and infestations’); 
• 
Neisseria infections (MedDRA high level term [HLT] of ‘Neisseria infections’); 
• 
Serious Neisseria infections (HLT of ‘Neisseria infections’); 
• 
Drug related hepatic disorders (SMQ – comprehensive search; refer to Appendix 3), excluding the ‘Liver 
neoplasms, benign (incl. cysts and polyps)’ and ‘Liver neoplasms, malignant and unspecified’ sub-SMQs. 
A summary of treatment-emergent (refer to Master COV-01 SAP Section 17.1) AESIs overall and by AESI category 
and preferred term (PT) will be prepared by treatment arm for patients randomized to COV-01-005 only.  Should a 
patient experience multiple events within an AESI category or PT, the patient will be counted only once for that 
AESI category or PT.  The risk difference of the overall incidence rates of having any treatment-emergent AESI 
between the treatment arms will be presented along with its two-sided 95% Wald CI. A listing of all AESIs will be 
provided for patients randomized to COV-01-005 only. 
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17.2. LABORATORY EVALUATIONS 
17.2.1. 
POTENTIAL HY’S LAW EVENTS 
In addition to the laboratory analyses described in the Master COV-01 SAP for the identification of the potential 
Hy’ law events, the following summary will also be provided: 
• 
Number and percentages of patients with (ALT > 3 x ULN or AST > 3 x ULN) AND (total bilirubin > 2 x 
ULN) AND (alkaline phosphatase [ALP] < 2 x ULN) at any time after the first dose of study drug and by visit 
for each treatment arm as well as for the subset of patients randomized to the placebo to zilucoplan + SoC 
treatment arm. 
17.3. VITAL SIGNS 
Analysis of vital signs is described in the Master COV-01 SAP. 
17.4. ELECTROCARDIOGRAM EVALUATIONS 
Analysis of electrocardiogram (ECG) evaluations is described in the Master COV-01 SAP. 
17.5. PHYSICAL EXAMINATION 
Analysis of physical examination is described in the Master COV-01 SAP. 
18. PHARMACOKINETIC ASSESSMENTS  
Concentrations of zilucoplan will be summarized descriptively at each scheduled assessment based on the PK 
analysis set (refer to Section 5.1). Geometric mean (geoMean), geometric coefficient of variation (geoCV) and 95% 
CI for the geoMean will also be presented in the summaries of zilucoplan concentration data.  Geometric coefficient 
of variation will be reported as a percentage to 1 decimal place and the 95% CI for the geoMean will use the same 
number of decimal places as the geoMean.  It will be left blank if the geoCV is 0. 
When reporting individual zilucoplan concentration data in listings and presenting summary statistics in tables, the 
following rules will apply: 
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• 
Missing data should be reported as ‘NV’ (no value) in the listings; 
• 
Concentrations below the lower limit of quantification (LLOQ) should be reported as BLQ (below the limit of 
quantification) in the listings; 
• 
To calculate summary statistics, BLQ values should be set to half the LLOQ value and missing values should be 
excluded; 
• 
When the total number of BLQ and missing values exceeds one third of the total then only minimum and 
maximum should be reported for this scheduled assessment. Other summary statistics should be reported as 
missing (“-“). The minimum should be reported as BLQ; 
• 
When the mean value includes one or more replaced BLQ values then a footnote should be included to say 
“contains one or more BLQ values replaced by half the LLOQ value”; 
• 
A minimum of 3 values are required to calculate summary statistics. If only 2 values are available, then these 
should be presented as the minimum and maximum with other summary statistics reported as missing (“- “). 
Zilucoplan concentrations will be listed. 
18.1. DERIVATION 
The geoCV, in percentage, will be calculated using the following formula where SD is the standard deviation from 
the log-transformed data: 
• 
GeoCV (%) = sqrt[exp(SD2) – 1] x 100 
19. PHARMACODYNAMIC AND OTHER BIOMARKER ASSESSMENTS  
 
 
 
 
 
 
 
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20. ANTI-DRUG ANTIBODY TESTING 
Number and percentage of patients with a negative ADA response (i.e., either [negative screen] or [positive screen 
and negative immunodepletion]) and a positive ADA response (i.e., positive screen and positive immunodepletion) 
will be summarized by scheduled visit and treatment arm based on the ADA analysis set (refer to Section 5.3). 
Number and percentage of patients in each of the following categories will also be summarized by treatment arm: 
1. Treatment-induced ADA negative, defined as patients who were ADA negative at baseline as well as at all post-
baseline scheduled visit; 
2. Treatment-induced ADA positive, defined as patients who were ADA negative at baseline and ADA positive at 
at least one post-baseline scheduled visit.  This category also includes patients with a missing ADA response 
status at baseline who had at least one ADA positive response at any post-baseline scheduled visit; 
3. Treatment-reduced ADA, defined as patients who were ADA positive at baseline and ADA negative at all post-
baseline scheduled visit; 
4. Treatment-unaffected ADA, defined as patients who were ADA positive at baseline and ADA positive at at 
least one post-baseline scheduled visit with titer values of the same magnitude as baseline (i.e., equal or less 
than a pre-defined fold difference increase from the baseline value, where the pre-defined fold difference 
increase from the baseline value is defined as the minimum significant ratio [MSR] determined during assay 
validation); 
5. Treatment-boosted ADA positive, defined as patients who were ADA positive at baseline and ADA positive at 
at least one post-baseline scheduled visit with increased in titer values as compare to baseline (i.e., greater than 
the pre-defined fold difference increase from baseline value); 
6. Inconclusive, defined as patients who were ADA negative or positive at baseline for whom some post-baseline 
ADA response assessments are missing, while all other post-baseline ADA response assessments are ADA 
negative; 
7. Total prevalence of pre-Ab i.e., patients in categories 3, 4, and 5 combined; 
8. Total incidence of treatment-emergent ADA positive i.e., patients in categories 2 and 5 combined. 
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The fold difference increase from baseline (i.e., the MSR determined during the assay validation) needed to consider 
a titer value reported post-baseline to be above the assay validation will be noted in the relevant tables and listings. 
All ADA data will be listed.  
21. DATA NOT SUMMARIZED OR PRESENTED 
The list of data not summarized or presented is available in the Master COV-01 SAP.  
 
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APPENDIX 1 MEDDRA ALGORITHMIC APPROACH TO ANAPHYLAXIS 
The SMQ anaphylactic reactions consists of three parts: 
• 
A narrow search containing PTs that represent core anaphylactic reaction terms: 
Category A 
o 
Anaphylactic reaction 
o 
Anaphylactic shock 
o 
Anaphylactic transfusion reaction 
o 
Anaphylactoid reaction 
o 
Anaphylactoid shock 
o 
Circulatory collapse 
o 
Dialysis membrane reaction 
o 
Kronis syndrome 
o 
Shock 
o 
Shock symptom 
o 
Type I hypersensitivity 
 
 
 
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• 
A broad search that contains additional terms that are added to those included in the narrow search. These 
additional terms are signs and symptoms possibly indicative of anaphylactic reaction and categorized in B, C or 
D. 
Category B (Upper Airway/ Respiratory) 
o 
Acute respiratory failure 
o 
Irregular breathing 
o 
Respiratory failure 
o 
Asthma 
o 
Laryngeal dyspnea 
o 
Reversible airways obstruction 
o 
Bronchial oedema 
o 
Laryngeal oedema 
o 
Sensation of foreign body 
o 
Brochospasm 
o 
Laryngospasm 
o 
Sneezing 
o 
Cardio-respiratory distress 
o 
Laryngotracheal oedema 
o 
Stridor 
o 
Chest discomfort 
o 
Mouth swelling 
o 
Swollen tongue 
o 
Chocking 
o 
Nasal obstruction 
o 
Tachypnoea 
o 
Chocking sensation 
o 
Oedema mouth 
o 
Throat tightness 
o 
Circumoral oedema 
o 
Oropharyngeal spasm 
o 
Tongue oedema 
o 
Cough 
o 
Oropharyngeal swelling 
o 
Tracheal obstruction 
o 
Cyanosis 
o 
Respiratory arrest 
o 
Tracheal oedema 
o 
Dyspnoea 
o 
Respiratory distress 
o 
Upper airway obstruction 
o 
Hyperventilation 
o 
Respiratory dyskinesia 
o 
Wheezing 
 
Category C (Angioedema/ Urticaria/ Pruritus/ Flush) 
o 
Allergic oedema 
o 
Injection site urticaria 
o 
Rash 
o 
Angioedema 
o 
Lip oedema 
o 
Rash erythematous 
o 
Erythema 
o 
Lip swelling 
o 
Rash generalized 
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Category C (Angioedema/ Urticaria/ Pruritus/ Flush) 
o 
Eye oedema 
o 
Nodular rash 
o 
Rash pruritic 
o 
Eye pruritus 
o 
Ocular hyperaemia 
o 
Skin swelling 
o 
Eye swelling 
o 
Oedema 
o 
Swelling 
o 
Eyelid oedema 
o 
Periorbital oedema 
o 
Swelling face 
o 
Face oedema 
o 
Pruritus 
o 
Urticaria 
o 
Flushing 
o 
Pruritus allergic 
o 
Urticaria papular 
o 
Generalised erythema 
o 
Pruritus generalised 
 
 
Category D (Cardiovascular / Hypotension) 
o 
Blood pressure decreased 
o 
Cardiac arrest 
o 
Diastolic hypotension 
o 
Blood pressure diastolic 
decreased 
o 
Cardio-respiratory arrest 
o 
Hypotension 
o 
Blood pressure systolic 
decreased 
o 
Cardiovascular insufficiency 
 
 
 
 
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• 
An algorithm approach which combines a number of anaphylactic reaction symptoms in order to increase 
specificity will be used for this sub-protocol.  A potential anaphylactic reaction is defined meeting at least one 
of the following criteria where the different terms occur on either the same day as when an injection was 
administered or one day after: 
o 
A narrow PT from Category A; 
o 
A PT from Category B AND a PT from Category C; 
o 
A PT from Category D AND (a PT from Category B OR a term from Category C). 
 
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APPENDIX 2 SMQ OF HYPERSENSITIVITY REACTIONS (NARROW 
SCOPE) 
Preferred Term 
• 
Administration site hypersensitivity 
• 
Documented hypersensitivity to administered product 
• 
Drug hypersensitivity 
• 
Hypersensitivity 
• 
Infusion related hypersensitivity reaction 
• 
Infusion site hypersensitivity 
• 
Injection site hypersensitivity 
• 
Type I hypersensitivity 
• 
Type II hypersensitivity 
• 
Type IV hypersensitivity 
 
 
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Page 34 of 55 
 
 
 
 
 
 
Version Number: 
Amendment 2, v1.0 
 
Version Date:  
28-Jul-2021 
 
 
 
 
 
 
APPENDIX 3 SMQ OF DRUG RELATED HEPATIC DISORDERS 
(COMPREHENSIVE SEARCH) 
Preferred Term 
• 
5'nucleotidase increased 
• 
Acute graft versus host disease in liver 
• 
Abnormal LFTs 
• 
Acute hepatic congestion 
• 
Abnormal liver function tests 
• 
Acute hepatic failure 
• 
Acholia 
• 
Acute liver damage 
• 
Acquired afibrinogenaemia 
• 
Acute liver failure 
• 
Acquired afibrinogenemia 
• 
Acute liver injury 
• 
Acquired antithrombin III deficiency 
• 
Acute on chronic hepatic failure 
• 
Acquired factor IX deficiency 
• 
Acute on chronic liver failure 
• 
Acquired factor VIII deficiency 
• 
Acute yellow liver atrophy 
• 
Acquired factor XI deficiency 
• 
Advanced chronic liver disease 
• 
Acquired fibrinogen deficiency 
• 
Aggravated bilirubinemia 
• 
Acquired hepatocerebral degeneration 
• 
Alanine aminotransferase abnormal 
• 
Acquired protein S deficiency 
• 
Alanine aminotransferase abnormal NOS 
• 
Acute cholestatic hepatitis 
• 
Alanine aminotransferase increase 
• 
Acute cytolytic hepatitis 
• 
Alanine aminotransferase increased 
• 
Acute derangement of liver function 
• 
Alkaline phosphatase raised 
• 
Acute fatty liver 
• 
Alkaline phosphatase increased 
• 
Acute fulminant hepatitis 
• 
Alkaline phosphatase NOS increased 
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UCB Biopharma SRL 
Sub-Protocol COV-01-005 
COV-01-005 Statistical Analysis Plan 
Page 35 of 55 
 
 
 
 
 
 
Version Number: 
Amendment 2, v1.0 
 
Version Date:  
28-Jul-2021 
 
 
 
 
 
 
Preferred Term 
• 
Alkaline phosphatase serum increased 
• 
Antithrombin III decreased 
• 
Allergic hepatitis 
• 
Artificial extracorporeal liver support 
• 
Alloimmune hepatitis 
• 
Ascites 
• 
ALP increased 
• 
Ascites chylous 
• 
Al-P increased 
• 
Aspartate aminotransferase abnormal 
• 
ALPPS 
• 
Aspartate aminotransferase abnormal NOS 
• 
ALT flare up 
• 
Aspartate aminotransferase increase 
• 
ALT high 
• 
Aspartate aminotransferase increased 
• 
ALT increased 
• 
Associating liver partition and portal vein ligation 
for staged hepatectomy 
• 
Ammonia abnormal 
• 
AST flare up 
• 
Ammonia abnormal NOS 
• 
AST high 
• 
Ammonia increased 
• 
AST increased 
• 
Angioma spider 
• 
AST/ALT ratio abnormal 
• 
Anicteric cholestasis 
• 
Asterixis 
• 
Anorectal varices 
• 
AT-3 decreased 
• 
Anorectal varices bleeding 
• 
Atrophy liver 
• 
Anorectal varices hemorrhage 
• 
Atrophy of hepatocytes 
• 
Anti factor X activity abnormal 
• 
Autoimmune hepatitis 
• 
Anti factor X activity decreased 
• 
Anti factor X activity increased 
 
 
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UCB Biopharma SRL 
Sub-Protocol COV-01-005 
COV-01-005 Statistical Analysis Plan 
Page 36 of 55 
 
 
 
 
 
 
Version Number: 
Amendment 2, v1.0 
 
Version Date:  
28-Jul-2021 
 
 
 
 
 
 
Preferred Term 
• 
Bacterascites 
• 
Bilirubin total abnormal 
• 
Bile output abnormal 
• 
Bilirubin total high 
• 
Bile output decreased 
• 
Bilirubin total increased 
• 
Biliary ascites 
• 
Bilirubin unconjugated increased 
• 
Biliary cirrhosis 
• 
Bilirubin urine present 
• 
Biliary cirrhosis NOS 
• 
Bilirubin value increased 
• 
Biliary cirrhosis primary 
• 
Bilirubinaemia 
• 
Biliary cirrhosis secondary 
• 
Bilirubinaemia aggravated 
• 
Biliary enzyme increased 
• 
Bilirubinemia 
• 
Biliary fibrosis 
• 
Bilirubinemia aggravated 
• 
Biliary stasis 
• 
Biliverdin increased 
• 
Bilirubin abnormal 
• 
Biopsy liver abnormal 
• 
Bilirubin conjugated abnormal 
• 
Bleeding esophageal varices 
• 
Bilirubin conjugated increased 
• 
Bleeding oesophageal varices 
• 
Bilirubin elevated 
• 
Blood alkaline phosphatase abnormal 
• 
Bilirubin excretion disorder 
• 
Blood alkaline phosphatase bone increased 
• 
Bilirubin excretion disorder NOS 
• 
Blood alkaline phosphatase high 
• 
Bilirubin increased 
• 
Blood alkaline phosphatase increased 
• 
Bilirubin indirect increased 
• 
Blood alkaline phosphatase intestine increased 
• 
Bilirubin non-glucuronides high 
• 
Blood alkaline phosphatase liver increased 
 
 
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UCB Biopharma SRL 
Sub-Protocol COV-01-005 
COV-01-005 Statistical Analysis Plan 
Page 37 of 55 
 
 
 
 
 
 
Version Number: 
Amendment 2, v1.0 
 
Version Date:  
28-Jul-2021 
 
 
 
 
 
 
Preferred Term 
• 
Blood alkaline phosphatase NOS increased 
• 
Blood alkaline phosphatase NOS abnormal 
• 
Blood alkaline phosphatase placental increased 
• 
Blood thromboplastin decreased 
• 
Blood alkaline phosphatase renal abnormal 
• 
Bone alkaline phosphatase increased 
• 
Blood alkaline phosphatase renal increased 
• 
Bromosulphthalein retention 
• 
Blood antithrombin III low 
• 
Bromosulphthalein test abnormal 
• 
Blood bilirubin abnormal 
• 
Bromsulphalein retention 
• 
Blood bilirubin increased 
• 
Bromsulphthalein retention 
• 
Blood bilirubin indirect increased 
• 
Bruised liver 
• 
Blood bilirubin unconjugated increased 
• 
BSP abnormal 
• 
Blood cholinesterase abnormal 
• 
BSP excretion delayed 
• 
Blood cholinesterase decreased 
• 
Caput medusae 
• 
Blood fibrinogen abnormal 
• 
Cardia variceal ligation 
• 
Blood fibrinogen abnormal NOS 
• 
Cardiohepatic syndrome 
• 
Blood fibrinogen decreased 
• 
Charcot's cirrhosis 
• 
Blood galactose tolerance abnormal 
• 
Child-Pugh-Turcotte score abnormal 
• 
Blood thrombin abnormal 
• 
Child-Pugh-Turcotte score increased 
• 
Blood thrombin abnormal NOS 
• 
Child-Turcotte-Pugh class A 
• 
Blood thrombin decreased 
• 
Child-Turcotte-Pugh class B 
• 
Blood thromboplastin abnormal 
• 
Child-Turcotte-Pugh class C 
• 
Blood thromboplastin abnormal NOS 
• 
Cholemia 
 
 
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UCB Biopharma SRL 
Sub-Protocol COV-01-005 
COV-01-005 Statistical Analysis Plan 
Page 38 of 55 
 
 
 
 
 
 
Version Number: 
Amendment 2, v1.0 
 
Version Date:  
28-Jul-2021 
 
 
 
 
 
 
Preferred Term 
• 
Cholestasis extrahepatic 
• 
Cholestasis 
• 
Cholestasis intrahepatic 
• 
Chronic non-suppurative destructive cholangitis 
• 
Cholestatic hepatic disorder 
• 
Chronic passive congestion of liver 
• 
Cholestatic hepatitis 
• 
Chronic persistent hepatitis 
• 
Cholestatic icterus 
• 
Chylous ascites 
• 
Cholestatic jaundice 
• 
Cirrhosis biliary 
• 
Cholestatic liver disease 
• 
Cirrhosis liver 
• 
Cholestatic liver injury 
• 
Cirrhosis liver post necrotic 
• 
Cholestatic pruritus 
• 
Cirrhosis liver postnecrotic 
• 
Cholinesterase blood decreased 
• 
Cirrhosis of liver 
• 
Cholinesterase decreased 
• 
Cirrhosis of liver without mention of alcohol 
• 
Cholinesterase low 
• 
Coagulation factor decreased 
• 
Chronic active hepatitis 
• 
Coagulation factor II level abnormal NOS 
• 
Chronic graft versus host disease in liver 
• 
Coagulation factor II level decreased 
• 
Chronic hepatic failure 
• 
Coagulation factor IX level abnormal 
• 
Chronic hepatitis 
• 
Coagulation factor IX level abnormal NOS 
• 
Chronic hepatitis, unspecified 
• 
Coagulation factor IX level decreased 
• 
Chronic hepatopathy due to metabolic defect 
• 
Coagulation factor IX level low 
• 
Chronic liver disease 
• 
Coagulation factor V level abnormal 
• 
Chronic liver injury 
• 
Coagulation factor V level abnormal NOS 
 
 
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UCB Biopharma SRL 
Sub-Protocol COV-01-005 
COV-01-005 Statistical Analysis Plan 
Page 39 of 55 
 
 
 
 
 
 
Version Number: 
Amendment 2, v1.0 
 
Version Date:  
28-Jul-2021 
 
 
 
 
 
 
Preferred Term 
• 
Coagulation factor V level low 
• 
Coagulation factor V level decreased 
• 
Coagulation factor VII level abnormal 
• 
Conjugated bilirubinemia 
• 
Coagulation factor VII level abnormal NOS 
• 
Conjunctiva bulbi coloring yellow 
• 
Coagulation factor VII level decreased 
• 
Conjunctiva bulbi colouring yellow 
• 
Coagulation factor VII level low 
• 
Conjunctiva coloring yellow 
• 
Coagulation factor X level abnormal 
• 
Conjunctiva colouring yellow 
• 
Coagulation factor X level abnormal NOS 
• 
Cruveilhier-Baumgarten syndrome 
• 
Coagulation factor X level decreased 
• 
Cryptogenic cirrhosis 
• 
Coagulation factors decreased 
• 
CT scan liver 
• 
Coloring yellow 
• 
Cytolytic hepatitis 
• 
Colouring yellow 
• 
Damage liver 
• 
Coma hepatic 
• 
De Ritis ratio abnormal 
• 
Compensated cirrhosis 
• 
Decompensated cirrhosis 
• 
Complications of transplanted liver 
• 
Decreased INR 
• 
Computerized tomogram liver 
• 
Decreased plasma fibrinogen 
• 
Computerized tomogram liver abnormal 
• 
Deficiency of bile secretion 
• 
Congestive gastropathy 
• 
Degeneration fatty liver 
• 
Conjugated bilirubin level increased 
• 
Deranged liver function tests 
• 
Conjugated bilirubin level raised 
• 
Derangement of liver function tests 
• 
Conjugated bilirubinaemia 
• 
Diabetic hepatopathy 
 
 
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UCB Biopharma SRL 
Sub-Protocol COV-01-005 
COV-01-005 Statistical Analysis Plan 
Page 40 of 55 
 
 
 
 
 
 
Version Number: 
Amendment 2, v1.0 
 
Version Date:  
28-Jul-2021 
 
 
 
 
 
 
Preferred Term 
• 
DILI 
• 
Encephalopathy hepatic 
• 
Direct bilirubin abnormal 
• 
End stage liver disease 
• 
Direct bilirubin increased 
• 
Esophageal varices 
• 
Direct hyperbilirubinaemia 
• 
Esophageal varices hemorrhage 
• 
Direct hyperbilirubinemia 
• 
Esophageal varices in cirrhosis of liver 
• 
Disease hepatocellular 
• 
Esophageal varices ruptured 
• 
Disorder hepatic 
• 
Esophageal varices with bleeding 
• 
Disorder liver 
• 
Esophageal varices without mention of bleeding 
• 
Disturbance of liver function tests 
• 
Esophagogastric devascularization 
• 
Drug-induced hepatitis 
• 
Exaggerated hypoprothrombinemia 
• 
Drug-induced hepatotoxicity 
• 
Failure hepatorenal 
• 
Drug-induced liver disease 
• 
Failure liver 
• 
Drug-induced liver injury 
• 
Fatty liver 
• 
Duodenal varices 
• 
Fatty liver infiltration 
• 
Dyscholia 
• 
Fatty liver metamorphosis 
• 
Dyscholia 
• 
Fetor hepaticus 
• 
Dysfunction hepatic non-icteric 
• 
Fibrinogen decreased 
• 
Edema due to hepatic disease 
• 
Fibrinogen plasma decreased 
• 
Elevated liver enzyme levels 
• 
Fibrinogenopenia 
• 
Elevated liver enzymes 
• 
Fibrinopenia 
 
 
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UCB Biopharma SRL 
Sub-Protocol COV-01-005 
COV-01-005 Statistical Analysis Plan 
Page 41 of 55 
 
 
 
 
 
 
Version Number: 
Amendment 2, v1.0 
 
Version Date:  
28-Jul-2021 
 
 
 
 
 
 
Preferred Term 
• 
Fibrosis biliary 
• 
Gamma-glutamyltransferase high 
• 
Fibrosis liver 
• 
Gamma-glutamyltransferase increased 
• 
Flapping tremor 
• 
Gammaglutamyltranspeptidase abnormal 
• 
Focal hepatic steatosis 
• 
Gamma-GT increased 
• 
Foetor hepaticus 
• 
Gastric variceal injection 
• 
Fulminant hepatic failure 
• 
Gastric variceal ligation 
• 
Function liver abnormal 
• 
Gastric varices 
• 
Function liver decreased 
• 
Gastric varices bleeding 
• 
Function tests multiple liver abnormal 
• 
Gastric varices hemorrhage 
• 
Galactose elimination capacity test abnormal 
• 
Gastric varices ruptured 
• 
Galactose elimination capacity test decreased 
• 
Gastroesophageal variceal hemorrhage prophylaxis 
• 
Gallbladder ejection fraction decreased 
• 
Gastroesophageal varices 
• 
Gallbladder varices 
• 
Gastroesophageal varices hemorrhage 
• 
Gamma glutamyl transpeptidase increased 
• 
Gastrooesophageal variceal hemorrhage 
prophylaxis 
• 
Gamma GT abnormal 
• 
Gastrooesophageal varices 
• 
Gamma GT increased 
• 
Gastrooesophageal varices haemorrhage 
• 
Gamma GT raised 
• 
GGT increased 
• 
Gamma-glutamyltransferase abnormal 
• 
GGTP abnormal 
• 
Gamma-glutamyltransferase abnormal NOS 
• 
GGTP increase 
 
 
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UCB Biopharma SRL 
Sub-Protocol COV-01-005 
COV-01-005 Statistical Analysis Plan 
Page 42 of 55 
 
 
 
 
 
 
Version Number: 
Amendment 2, v1.0 
 
Version Date:  
28-Jul-2021 
 
 
 
 
 
 
Preferred Term 
• 
Glutamate dehydrogenase increased 
• 
Hepaplastin value decreased 
• 
Glutamic-oxaloacetic transaminase increased 
• 
Hepaplastin low 
• 
Glutamic-pyruvate transaminase increased 
• 
Hepatectomy 
• 
Glutamic-pyruvic transaminase increased 
• 
Hepatectomy NOS 
• 
Glycocholic acid increased 
• 
Hepatic artery flow decreased 
• 
Glycogenic hepatopathy 
• 
Hepatic atrophy 
• 
GOT abnormal 
• 
Hepatic calcification 
• 
GOT increased 
• 
Hepatic cirrhosis 
• 
GOT increased transient 
• 
Hepatic cirrhosis NOS 
• 
GPT abnormal 
• 
Hepatic cirrhosis post necrotic 
• 
GPT increased 
• 
Hepatic coma 
• 
GPT increased transient 
• 
Hepatic congestion 
• 
Graft versus host disease in liver 
• 
Hepatic cyst excision 
• 
Granulomatous liver disease 
• 
Hepatic cytolysis 
• 
Guanase increased 
• 
Hepatic damage 
• 
Hanot's cirrhosis 
• 
Hepatic damage (NOS) 
• 
Hemihepatectomy 
• 
Hepatic decompensation 
• 
Hemorrhagic ascites 
• 
Hepatic disease 
• 
Hepaplastin abnormal 
• 
Hepatic disease NOS 
• 
Hepaplastin decreased 
• 
Hepatic disorder aggravated 
 
 
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UCB Biopharma SRL 
Sub-Protocol COV-01-005 
COV-01-005 Statistical Analysis Plan 
Page 43 of 55 
 
 
 
 
 
 
Version Number: 
Amendment 2, v1.0 
 
Version Date:  
28-Jul-2021 
 
 
 
 
 
 
Preferred Term 
• 
Hepatic disorder NOS 
• 
Hepatic hydrothorax 
• 
Hepatic dysfunction allergic 
• 
Hepatic hypertrophy 
• 
Hepatic dysfunction non-icteric 
• 
Hepatic impairment 
• 
Hepatic dysfunction NOS 
• 
Hepatic induced edema 
• 
Hepatic dysfunction transient 
• 
Hepatic induced oedema 
• 
Hepatic encephalopathy 
• 
Hepatic infiltration eosinophilic 
• 
Hepatic encephalopathy prophylaxis 
• 
Hepatic insufficiency 
• 
Hepatic enzyme abnormal 
• 
Hepatic intracellular deposit of bilirubin 
• 
Hepatic enzyme decreased 
• 
Hepatic intracellular pigmentation 
• 
Hepatic enzyme increased 
• 
Hepatic lesion 
• 
Hepatic enzymes increased 
• 
Hepatic lesion NOS 
• 
Hepatic failure 
• 
Hepatic lipogranuloma 
• 
Hepatic fibrosis 
• 
Hepatic lobule necrosis 
• 
Hepatic fibrosis marker abnormal 
• 
Hepatic lymphocytic infiltration 
• 
Hepatic fibrosis marker increased 
• 
Hepatic macrosteatosis 
• 
Hepatic function abnormal 
• 
Hepatic mass 
• 
Hepatic function abnormal NOS 
• 
Hepatic microsteatosis 
• 
Hepatic function decreased 
• 
Hepatic necrosis 
• 
Hepatic function disorder 
• 
Hepatic necrosis extensive 
• 
Hepatic granuloma 
• 
Hepatic pain 
 
 
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UCB Biopharma SRL 
Sub-Protocol COV-01-005 
COV-01-005 Statistical Analysis Plan 
Page 44 of 55 
 
 
 
 
 
 
Version Number: 
Amendment 2, v1.0 
 
Version Date:  
28-Jul-2021 
 
 
 
 
 
 
Preferred Term 
• 
Hepatic sequestration 
• 
Hepatitis chronic persistent 
• 
Hepatic shock 
• 
Hepatitis drug-induced 
• 
Hepatic size reduced 
• 
Hepatitis flare 
• 
Hepatic steato-fibrosis 
• 
Hepatitis fulminant 
• 
Hepatic steatosis 
• 
Hepatitis granulomatous 
• 
Hepatic trauma 
• 
Hepatitis granulomatous NOS 
• 
Hepatic vascular resistance increased 
• 
Hepatitis necrotising 
• 
Hepatic venous pressure gradient abnormal 
• 
Hepatitis necrotizing 
• 
Hepatic venous pressure gradient increased 
• 
Hepatitis non-icteric 
• 
Hepatitis 
• 
Hepatitis nonspecific 
• 
Hepatitis acute 
• 
Hepatitis NOS 
• 
Hepatitis acute toxic 
• 
Hepatitis reactive non-specific 
• 
Hepatitis aggravated 
• 
Hepatitis symptom 
• 
Hepatitis allergic drug-induced 
• 
Hepatitis toxic 
• 
Hepatitis autoimmune 
• 
Hepatitis toxic drug-induced 
• 
Hepatitis cholestatic 
• 
Hepatitis toxic obstructive 
• 
Hepatitis chronic active 
• 
Hepatitis, unspecified 
• 
Hepatitis chronic active (immune) 
• 
Hepatobiliary disease 
• 
Hepatitis chronic active aggravated 
• 
Hepatobiliary disease NOS 
• 
Hepatitis chronic NOS 
• 
Hepatobiliary insufficiency 
 
 
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UCB Biopharma SRL 
Sub-Protocol COV-01-005 
COV-01-005 Statistical Analysis Plan 
Page 45 of 55 
 
 
 
 
 
 
Version Number: 
Amendment 2, v1.0 
 
Version Date:  
28-Jul-2021 
 
 
 
 
 
 
Preferred Term 
• 
Hepatobiliary pain 
• 
Hepatotoxicity aggravated 
• 
Hepatobiliary scan abnormal 
• 
Hepatotoxicity NOS 
• 
Hepatocellular abnormality 
• 
Hyperammonemia 
• 
Hepatocellular damage 
• 
Hyperbilirubinaemia aggravated 
• 
Hepatocellular damage aggravated 
• 
Hyperbilirubinemia 
• 
Hepatocellular damage NOS 
• 
Hyperbilirubinemia aggravated 
• 
Hepatocellular disturbances 
• 
Hypercholia 
• 
Hepatocellular foamy cell syndrome 
• 
Hyperfibrinolysis 
• 
Hepatocellular injury 
• 
Hypertension portal 
• 
Hepatomegaly 
• 
Hypertransaminasaemia 
• 
Hepatopathy 
• 
Hypertransaminasemia 
• 
Hepatopulmonary syndrome 
• 
Hypertrophic cirrhosis 
• 
Hepatorenal failure 
• 
Hypoalbuminemia 
• 
Hepatorenal syndrome 
• 
Hypocholia 
• 
Hepatosis 
• 
Hypocoagulable state 
• 
Hepatosis aggravated 
• 
Hypofibrinogenemia 
• 
Hepatosplenomegaly 
• 
Hypohepatia 
• 
Hepatosplenomegaly NOS 
• 
Hypoprothrombinemia 
• 
Hepatotoxic effect 
• 
Hypothrombinemia 
• 
Hepatotoxicity 
• 
Hypothromboplastinaemia 
 
 
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UCB Biopharma SRL 
Sub-Protocol COV-01-005 
COV-01-005 Statistical Analysis Plan 
Page 46 of 55 
 
 
 
 
 
 
Version Number: 
Amendment 2, v1.0 
 
Version Date:  
28-Jul-2021 
 
 
 
 
 
 
Preferred Term 
• 
Hypothromboplastinemia 
• 
INR abnormal 
• 
Hy's law case 
• 
INR decreased 
• 
Icteric conjunctivae 
• 
INR increased 
• 
Icteric sclera 
• 
International normalised ratio abnormal NOS 
• 
Icterus 
• 
International normalized ratio abnormal 
• 
Icterus index increased 
• 
International normalized ratio decreased 
• 
Idiopathic portal hypertension 
• 
International normalized ratio increased 
• 
Immune-mediated hepatitis 
• 
Intestinal varices 
• 
Impaired liver function 
• 
Intestinal varices bleeding 
• 
Increased liver stiffness 
• 
Intestinal varices hemorrhage 
• 
Indirect bilirubin increased 
• 
Intra-abdominal venous shunt 
• 
Indirect hyperbilirubinaemia 
• 
Intrahepatic portal hepatic venous fistula 
• 
Indirect hyperbilirubinemia 
• 
Ischemic hepatitis 
• 
Infiltration fatty liver 
• 
Jaundice 
• 
Injury to liver 
• 
Jaundice (excl neonatal) 
• 
Injury to liver with open wound into cavity 
• 
Jaundice cholestatic 
• 
Injury to liver with open wound into cavity, 
unspecified laceration 
• 
Jaundice hepatocellular 
• 
Injury to liver without mention of open wound into 
cavity 
• 
Jaundice NOS 
 
 
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UCB Biopharma SRL 
Sub-Protocol COV-01-005 
COV-01-005 Statistical Analysis Plan 
Page 47 of 55 
 
 
 
 
 
 
Version Number: 
Amendment 2, v1.0 
 
Version Date:  
28-Jul-2021 
 
 
 
 
 
 
Preferred Term 
• 
Jaundice, unspecified, not of newborn 
• 
Liver cirrhosis 
• 
Kayser-Fleischer ring 
• 
Liver cholestasis 
• 
Kupffer cell decrease 
• 
Liver contusion 
• 
Kupffer cell increase 
• 
Liver damage 
• 
Laceration of liver, major, with open wound into 
cavity 
• 
Liver damage aggravated 
• 
Laceration of liver, major, without mention of open 
wound into cavity 
• 
Liver dialysis 
• 
Laceration of liver, minor, with open wound into 
cavity 
• 
Liver disorder 
• 
Laceration of liver, minor, without mention of open 
wound into cavity 
• 
Liver enlargement 
• 
Laceration of liver, moderate, with open wound into 
cavity 
• 
Liver enzyme abnormal 
• 
Laceration of liver, moderate, without mention of 
open wound into cavity 
• 
Liver failure 
• 
Leucine aminopeptidase increased 
• 
Liver fatty 
• 
LFTs raised 
• 
Liver fatty change 
• 
Liver and pancreas transplant rejection 
• 
Liver fatty degeneration 
• 
Liver and small intestine transplant 
• 
Liver fatty deposit 
• 
Liver biopsy abnormal 
• 
Liver fatty deposition 
• 
Liver cell damage 
• 
Liver fatty infiltration 
 
 
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UCB Biopharma SRL 
Sub-Protocol COV-01-005 
COV-01-005 Statistical Analysis Plan 
Page 48 of 55 
 
 
 
 
 
 
Version Number: 
Amendment 2, v1.0 
 
Version Date:  
28-Jul-2021 
 
 
 
 
 
 
Preferred Term 
• 
Liver fatty metamorphosis 
• 
Liver nodule 
• 
Liver fatty phanerosis 
• 
Liver operation 
• 
Liver function test abnormal 
• 
Liver operation NOS 
• 
Liver function test decreased 
• 
Liver pain 
• 
Liver function test increased 
• 
Liver palpable 
• 
Liver function tests abnormal 
• 
Liver palpable subcostal 
• 
Liver function tests abnormal NOS 
• 
Liver repair 
• 
Liver function tests NOS abnormal 
• 
Liver resection 
• 
Liver function tests raised 
• 
Liver retransplantation 
• 
Liver graft dysfunction 
• 
Liver sarcoidosis 
• 
Liver graft function delayed 
• 
Liver scan abnormal 
• 
Liver graft loss 
• 
Liver scan NOS abnormal 
• 
Liver induration 
• 
Liver tender 
• 
Liver inflammation 
• 
Liver tenderness 
• 
Liver injury 
• 
Liver tenderness of 
• 
Liver iron concentration abnormal 
• 
Liver transplant 
• 
Liver iron concentration increased 
• 
Liver transplant failure 
• 
Liver lobectomy 
• 
Liver transplant rejection 
• 
Liver necrosis 
• 
Liver transplantation 
 
 
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UCB Biopharma SRL 
Sub-Protocol COV-01-005 
COV-01-005 Statistical Analysis Plan 
Page 49 of 55 
 
 
 
 
 
 
Version Number: 
Amendment 2, v1.0 
 
Version Date:  
28-Jul-2021 
 
 
 
 
 
 
Preferred Term 
• 
Living donor liver transplant 
• 
Molar ratio of total branched-chain amino acid to 
tyrosine 
• 
Lupoid hepatic cirrhosis 
• 
Monomicrobial non-neutrocytic bacterascites 
• 
Lupus hepatitis 
• 
MRI-PDFF 
• 
Magnetic resonance imaging liver abnormal 
• 
Multivisceral transplantation 
• 
Magnetic resonance proton density fat fraction 
measurement 
• 
Naevus spider acquired 
• 
MELD score abnormal 
• 
Necrosis hepatocellular 
• 
MELD score increased 
• 
Necrosis liver 
• 
Mesenteric varices 
• 
Necrosis liver focal 
• 
Mesocaval shunt 
• 
Nevus spider acquired 
• 
Metabolic liver injury 
• 
Nodular regenerative hyperplasia 
• 
Metamorphosis fatty liver 
• 
Non-alcoholic fatty liver 
• 
Micronodular cirrhosis 
• 
Nonalcoholic fatty liver disease 
• 
Microvesicular fat disease of liver 
• 
Non-alcoholic steatohepatitis 
• 
Minimal hepatic encephalopathy 
• 
Non-cirrhotic portal fibrosis 
• 
Mitochondrial aspartate aminotransferase increased 
• 
Non-cirrhotic portal hypertension 
• 
Mixed hepatocellular-cholestatic injury 
• 
Nonspecific abnormal results of function study of 
liver 
• 
Mixed liver injury 
• 
Nonspecific hepatitis 
• 
Model for end stage liver disease score abnormal 
• 
Nuclear magnetic resonance imaging liver 
abnormal 
• 
Model for end stage liver disease score increased 
• 
Obstructive jaundice 
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UCB Biopharma SRL 
Sub-Protocol COV-01-005 
COV-01-005 Statistical Analysis Plan 
Page 50 of 55 
 
 
 
 
 
 
Version Number: 
Amendment 2, v1.0 
 
Version Date:  
28-Jul-2021 
 
 
 
 
 
 
Preferred Term 
• 
Ocular icterus  
• 
Peritoneal effusion (chronic) 
• 
Oesophageal varices in cirrhosis of liver 
• 
Peritoneal effusion bloody 
• 
Oesophageal varices NOS 
• 
Peritoneal fluid protein abnormal 
• 
Oesophageal varices ruptured 
• 
Peritoneal fluid protein decreased 
• 
Oesophageal varices with bleeding 
• 
Peritoneal fluid protein increased 
• 
Oesophageal varices without mention of bleeding 
• 
Peritoneovenous shunt 
• 
Oesophagogastric devascularisation 
• 
Phanerosis fatty liver 
• 
Oligocholia 
• 
Phosphatase alkaline increased 
• 
Orthotopic liver transplant 
• 
Plasma cholinesterase decreased 
• 
Parenteral nutrition associated cholestasis 
• 
Plasma fibrinogen abnormal 
• 
Parenteral nutrition associated liver disease 
• 
Plasma thrombin abnormal 
• 
Partial hepatectomy 
• 
Plasma thrombin decreased 
• 
Partial splenic embolization 
• 
Plasma thromboplastin abnormal 
• 
Pericardial devascularization 
• 
Plasma thromboplastin decreased 
• 
Perihepatic discomfort 
• 
Pneumobilia 
• 
Perihepatic fluid collection 
• 
Polymicrobial bacterascites 
• 
Perinatal jaundice due to hepatocellular damage 
• 
Portacaval shunt 
• 
Peripancreatic varices 
• 
Portal anastomosis 
• 
Periportal edema 
• 
Portal fibrosis 
• 
Peritoneal effusion 
• 
Portal hypertension 
 
 
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UCB Biopharma SRL 
Sub-Protocol COV-01-005 
COV-01-005 Statistical Analysis Plan 
Page 51 of 55 
 
 
 
 
 
 
Version Number: 
Amendment 2, v1.0 
 
Version Date:  
28-Jul-2021 
 
 
 
 
 
 
Preferred Term 
• 
Portal hypertensive colopathy 
• 
Prophylaxis of gastrooesophageal variceal 
bleeding 
• 
Portal hypertensive enteropathy 
• 
Protein C antigen decreased 
• 
Portal hypertensive gastropathy 
• 
Protein C decreased 
• 
Portal shunt 
• 
Protein S abnormal 
• 
Portal shunt procedure 
• 
Protein S antigen abnormal 
• 
Portal systemic shunt 
• 
Protein S antigen decreased 
• 
Portal systemic shunt procedure 
• 
Protein S decreased 
• 
Portal tract inflammation 
• 
Protein S free decreased 
• 
Portal triaditis 
• 
Protein S total abnormal 
• 
Portal vein cavernous transformation 
• 
Protein S total decreased 
• 
Portal vein dilatation 
• 
Prothrombin abnormal 
• 
Portal vein enlarged 
• 
Prothrombin activity decreased 
• 
Portal vein flow decreased 
• 
Prothrombin consumption increased 
• 
Portal vein pressure increased 
• 
Prothrombin decreased 
• 
Portopulmonary hypertension 
• 
Prothrombin level abnormal 
• 
Prehepatic portal hypertension 
• 
Prothrombin level abnormal NOS 
• 
Primary biliary cholangitis 
• 
Prothrombin level decreased 
• 
Primary biliary cirrhosis 
• 
Prothrombin ratio decreased 
• 
Primary liver transplant nonfunction 
• 
Prothrombin time abnormal 
• 
Prophylaxis of gastroesophageal variceal bleeding 
• 
Prothrombin time abnormal NOS 
 
 
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UCB Biopharma SRL 
Sub-Protocol COV-01-005 
COV-01-005 Statistical Analysis Plan 
Page 52 of 55 
 
 
 
 
 
 
Version Number: 
Amendment 2, v1.0 
 
Version Date:  
28-Jul-2021 
 
 
 
 
 
 
Preferred Term 
• 
Prothrombin time ratio abnormal NOS 
• 
Raised liver function tests 
• 
Prothrombin time ratio decreased 
• 
Regenerative siderotic hepatic nodule 
• 
Prothrombin time increased 
• 
Rejection acute hepatic 
• 
Prothrombin time prolonged 
• 
Rejection chronic hepatic 
• 
Prothrombin time ratio abnormal 
• 
Renal and liver transplant 
• 
Prothrombin time ratio high 
• 
Retention sulfobromophthalein 
• 
Prothrombin time ratio increased 
• 
Retinol binding protein decreased 
• 
Prothrombin time ratio low 
• 
Retrograde portal vein flow 
• 
Prothrombinopenia 
• 
Reye's syndrome 
• 
PT increased 
• 
Reynold's syndrome 
• 
PT prolonged 
• 
Scan liver NOS abnormal 
• 
Pure intrahepatic cholestasis 
• 
Scleral icterus 
• 
Quick's value decreased 
• 
Serum alkaline phosphatase elevated 
• 
Radiation hepatitis 
• 
Serum bilirubin increased 
• 
Radiation-induced liver disease 
• 
Serum cholinesterase decreased 
• 
Raised bilirubin 
• 
Serum glutamic-oxaloacetic ta increased 
• 
Raised INR 
• 
Serum glutamic-oxaloacetic transaminase 
increased 
• 
Raised LFTs 
• 
Serum glutamic-pyruvic ta increased 
• 
Raised liver enzymes 
• 
Serum glutamic-pyruvic transaminase increased 
 
 
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UCB Biopharma SRL 
Sub-Protocol COV-01-005 
COV-01-005 Statistical Analysis Plan 
Page 53 of 55 
 
 
 
 
 
 
Version Number: 
Amendment 2, v1.0 
 
Version Date:  
28-Jul-2021 
 
 
 
 
 
 
Preferred Term 
• 
Serum transaminase increased 
• 
Steatosis hepatic 
• 
SGOT increased 
• 
Stomal varices 
• 
SGPT increased 
• 
Subacute fulminant hepatitis 
• 
Single pass albumin dialysis 
• 
Subacute hepatic failure 
• 
Skin coloring yellow 
• 
Subacute hepatic necrosis 
• 
Skin colouring yellow 
• 
Subacute liver disease 
• 
Small-for-size liver syndrome 
• 
Subicteric 
• 
Spider angioma 
• 
Sugiura procedure 
• 
Spider naevi 
• 
Sulfobromophthalein retention 
• 
Spider nevi 
• 
Sulphobromophthalein retention 
• 
Spider nevus 
• 
Supratherapeutic INR 
• 
Splenic varices 
• 
Syncytial giant cell hepatitis 
• 
Splenic varices bleeding 
• 
Syndrome hepatorenal 
• 
Splenic varices hemorrhage 
• 
Telangiectases acquired 
• 
Splenorenal shunt 
• 
Tenderness liver 
• 
Splenorenal shunt procedure 
• 
Thrombin clotting time abnormal 
• 
Splenorenal varices 
• 
Thrombin clotting time prolonged 
• 
Spontaneous intrahepatic portosystemic venous 
shunt 
• 
Thrombin decreased 
• 
Steatohepatitis 
• 
Thrombin time abnormal 
 
 
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UCB Biopharma SRL 
Sub-Protocol COV-01-005 
COV-01-005 Statistical Analysis Plan 
Page 54 of 55 
 
 
 
 
 
 
Version Number: 
Amendment 2, v1.0 
 
Version Date:  
28-Jul-2021 
 
 
 
 
 
 
Preferred Term 
• 
Thrombin time prolonged 
• 
Unconjugated bilirubinemia 
• 
Thromboplastin decreased 
• 
Unspecified chronic liver disease without mention 
of alcohol 
• 
Todd's cirrhosis 
• 
Unspecified disorder of liver 
• 
Total bile acids increased 
• 
Unspecified injury to liver with open wound into 
cavity 
• 
Total hepatectomy 
• 
Unspecified injury to liver without mention of 
open wound into cavity 
• 
Toxaemia of liver 
• 
Urine ammonia increased 
• 
Toxemia of liver 
• 
Urine bilirubin increased 
• 
Toxic acute liver disease 
• 
Urobilin urine absent 
• 
Transaminase glutamic-oxalacetic increased 
• 
Urobilin urine present 
• 
Transaminase glutamic-pyruvic increased 
• 
Urobilinogen appeared 
• 
Transaminase NOS increased 
• 
Urobilinogen negative 
• 
Transaminase value increased 
• 
Urobilinogen urine decreased 
• 
Transaminases abnormal 
• 
Urobilinogen urine increased 
• 
Transaminases increased 
• 
Urobilinogen urine positive 
• 
Transaminitis 
• 
Varices esophageal 
• 
Transjugular intrahepatic portosystemic shunt 
• 
Varicose veins of abdominal wall 
• 
Ultrasound liver abnormal 
• 
Vascular spider 
• 
Unconjugated bilirubinaemia 
• 
White nipple sign 
 
 
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UCB Biopharma SRL 
Sub-Protocol COV-01-005 
COV-01-005 Statistical Analysis Plan 
Page 55 of 55 
 
 
 
 
 
 
Version Number: 
Amendment 2, v1.0 
 
Version Date:  
28-Jul-2021 
 
 
 
 
 
 
Preferred Term 
• 
X-ray biliary abnormal 
• 
Yellow ocular colouring 
• 
X-ray hepatobiliary abnormal 
• 
Yellow skin 
• 
Yellow ocular coloring 
 
 
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