Industry Alliance Platform Trial to Assess the Efficacy and Safety of Multiple Candidate Agents for the Treatment of COVID-19 in Hospitalized Patients
Phase: PHASE3
Conditions: COVID-19
Sponsor: Amgen

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 
3 
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 
4 
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 
5 
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 
6 
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 
7 
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 
8 
• 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.
CCI
 

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. 
• 
 
CCI
 

CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
10 
• 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 
11 
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. 

CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
12 
• 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 
 
CCI

CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
13 
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.
CCI
 

CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
14 
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. 

CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
16 
 
 
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.
CCI
 

CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
17 
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). 

CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
18 
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 
CCI

CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
19 
 
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).
CCI
 
CCI

CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
20 
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. 
 

CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
21 
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 

CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
22 
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. 

CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
23 
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. 

CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
24 
• 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 
 
CCI
 

CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
25 
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. 

CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
26 
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 

CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
27 
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. 

CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
28 
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. 

CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
29 
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). 

CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
30 
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. 

CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
31 
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 
recorded in the eCRFs. 

CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
32 
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 
corresponding sub-protocol. 

CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
33 
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 

CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
34 
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 
status. 

CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
35 
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
CCI
 

CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
36 
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. 
Abbreviations: ADL = activities of daily living; COVID-19 = coronavirus disease 2019. 

CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
37 
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.
CCI
 
CCI

CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
38 
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. 
CCI
 

CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
39 
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.
CCI
 
CCI

CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
40 
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: 
 
 
CCI
 
CCI
CCI
CCI

CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
41 
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.
CCI
 
CCI
CCI

CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
42 
 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.
CCI
 
CCI
CCI
CCI
CCI
CCI
CCI

CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
43 
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
CCI
 
CCI

CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
44 
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% 
CCI
power to 

CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
45 
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. 

CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
46 
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 

CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
47 
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.
CCI
 

CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
48 
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. 

CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
49 
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]. 

CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
50 
11.0 APPENDICES 

CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
51 
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
CCI
 

CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
52 
Abbreviation 
Definition 
SoC 
Standard of care 
SpO2 
Oxygen saturation 
ULN 
Upper limit of normal 
WOCBP 
Woman of childbearing potential 
 

CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
53 
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.
CCI
 

CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
54 
− 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. 
CCI
 
CCI
CCI

CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
55 
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.
CCI
 
CCI
CCI
CCI

CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
56 
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.
CCI
 
CCI

CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
57 
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 
participated sufficiently in the work to take public responsibility for appropriate portions of the 

CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
58 
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. 

CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
59 
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. 

CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
60 
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 
 

CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
61 
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 
start of the study that do not worsen. 
 

CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
62 
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. 
 

CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
63 
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. 
CCI
CCI
CCI

CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
64 
• 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. 
CCI
 
CCI
CCI
CCI
CCI
CCI

CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
65 
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. 

CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
66 
• 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.  
 

CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
67 
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. 
CCI
 
CCI
CCI

CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
68
CCI
 

CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
69 
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. 

CONFIDENTIAL 
COV-01 – Master Protocol 
Protocol Amendment 4, 16 April 2021 
70 
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:               ___________________________ 
 
 
 
 
 
___________________________ 
 
 
 
 
 
___________________________ 
 

CONFIDENTIAL 
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 
 
 
PPD
PPD

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
 

CONFIDENTIAL 
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 
 

CONFIDENTIAL 
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
 

CONFIDENTIAL 
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. 

CONFIDENTIAL 
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. 

CONFIDENTIAL 
COV-01-001 – Sub-protocol for Lanadelumab-IV 
Version 1.2, 26 October 2020 
9 
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 
CCI

CONFIDENTIAL 
COV-01-001 – Sub-protocol for Lanadelumab-IV 
Version 1.2, 26 October 2020 
10 
 
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.
CCI
 
CCI

CONFIDENTIAL 
COV-01-001 – Sub-protocol for Lanadelumab-IV 
Version 1.2, 26 October 2020 
11 
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. 

CONFIDENTIAL 
COV-01-001 – Sub-protocol for Lanadelumab-IV 
Version 1.2, 26 October 2020 
12 
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). 
CCI
 

CONFIDENTIAL 
COV-01-001 – Sub-protocol for Lanadelumab-IV 
Version 1.2, 26 October 2020 
13 
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). 

CONFIDENTIAL 
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. 

CONFIDENTIAL 
COV-01-001 – Sub-protocol for Lanadelumab-IV 
Version 1.2, 26 October 2020 
15 
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 

CONFIDENTIAL 
COV-01-001 – Sub-protocol for Lanadelumab-IV 
Version 1.2, 26 October 2020 
16 
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. 
 

CONFIDENTIAL 
COV-01-001 – Sub-protocol for Lanadelumab-IV 
Version 1.2, 26 October 2020 
17 
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). 
 

CONFIDENTIAL 
COV-01-001 – Sub-protocol for Lanadelumab-IV 
Version 1.2, 26 October 2020 
18 
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. 

CONFIDENTIAL 
COV-01-001 – Sub-protocol for Lanadelumab-IV 
Version 1.2, 26 October 2020 
19 
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. 

CONFIDENTIAL 
COV-01-001 – Sub-protocol for Lanadelumab-IV 
Version 1.2, 26 October 2020 
20 
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).  

CONFIDENTIAL 
COV-01-001 – Sub-protocol for Lanadelumab-IV 
Version 1.2, 26 October 2020 
21 
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:  

CONFIDENTIAL 
COV-01-001 – Sub-protocol for Lanadelumab-IV 
Version 1.2, 26 October 2020 
22 
 
  
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

CONFIDENTIAL 
COV-01-001 – Sub-protocol for Lanadelumab-IV 
Version 1.2, 26 October 2020 
23 
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

CONFIDENTIAL 
COV-01-001 – Sub-protocol for Lanadelumab-IV 
Version 1.2, 26 October 2020 
24 
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. 

CONFIDENTIAL 
COV-01-001 – Sub-protocol for Lanadelumab-IV 
Version 1.2, 26 October 2020 
25 
• 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

CONFIDENTIAL 
COV-01-001 – Sub-protocol for Lanadelumab-IV 
Version 1.2, 26 October 2020 
26 
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

CONFIDENTIAL 
COV-01-001 – Sub-protocol for Lanadelumab-IV 
Version 1.2, 26 October 2020 
27 
6.0 REFERENCES 
Abdallah, R. T., Keum, J.-S., Lee, M.-H., Wang, B., Gooz, M., Luttrell, D. K., Luttrell, L. M. 
and Jaffa, A. A. 2010. Plasma Kallikrein Promotes Epidermal Growth Factor Receptor 
Transactivation and Signaling in Vascular Smooth Muscle through Direct Activation of 
Protease-activated Receptors. J Biol Chem, 285, 35206-15. 
 
Carvalho, A. C., DeMarinis, S., Scott, C. F., Silver, L. D., Schmaier, A. H. and Colman, R. 
W. 1988. Activation of the contact system of plasma proteolysis in the adult respiratory 
distress syndrome. J Lab Clin Med, 112, 270-7. 
 
Cugno, M., Bergamaschini, L., Cicardi, M. and Agostoni, A. 1988. Haemostasis contact 
system and fibrinolysis in hereditary angioedema (Cl-inhibitor deficiency). J Clin Chem Clin 
Biochem, 26, 423-7. 
 
Firazyr (icatibant injection). Full Prescribing Information. Lexington, MA: Shire. Revised 
12/2015. 
 
Hess, R., Wujak, L., Hesse, C., Sewald, K., Jonigk, D., Warnecke, G., Fieguth, H. G., de 
Maat, S., Maas, C., Bonella, F., Preissner, K. T., Weiss, B., Schaefer, L., Kuebler, W. M., 
Markart, P. and Wygrecka, M. 2017. Coagulation factor XII regulates inflammatory 
responses in human lungs. Thromb Haemost, 117, 1896-907. 
 
Huang, C., Wang, Y., Li, X., Ren, L., Zhao, J., Hu, Y., Zhang, L., Fan, G., Xu, J., Gu, X., 
Cheng, Z., Yu, T., Xia, J., Wei, Y., Wu, W., Xie, X., Yin, W., Li, H., Liu, M., Xiao, Y., Gao, 
H., Guo, L., Xie, J., Wang, G., Jiang, R., Gao, Z., Jin, Q., Wang, J. and Cao, B. 2020. 
Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet, 
395, 497-506. 
 
Johnson, E. R. and Matthay, M. A. 2010. Acute lung injury: epidemiology, pathogenesis, and 
treatment. J Aerosol Med Pulm Drug Deliv, 23, 243-52. 
 
Kenniston, J. A., Faucette, R. R., Martik, D., Comeau, S. R., Lindberg, A. P., Kopacz, K. J., 
Conley, G. P., Chen, J., Viswanathan, M., Kastrapeli, N., Cosic, J., Mason, S., DiLeo, M., 
Abendroth, J., Kuzmic, P., Ladner, R. C., Edwards, T. E., TenHoor, C., Adelman, B. A., 
Nixon, A. E. and Sexton, D. J. 2014. Inhibition of plasma kallikrein by a highly specific 
active site blocking antibody. J Biol Chem, 289, 23596-608. 
 
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. 
 

CONFIDENTIAL 
COV-01-001 – Sub-protocol for Lanadelumab-IV 
Version 1.2, 26 October 2020 
28 
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. 
 

CONFIDENTIAL 
COV-01-001 – Sub-protocol for Lanadelumab-IV 
Version 1.2, 26 October 2020 
29 
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. 
 

CONFIDENTIAL 
COV-01-001 – Sub-protocol for Lanadelumab-IV 
Version 1.2, 26 October 2020 
30 
7.0 APPENDICES 

CONFIDENTIAL 
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 
 

CONFIDENTIAL 
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. 

CONFIDENTIAL 
COV-01-001 – Sub-protocol for Lanadelumab-IV 
Version 1.2, 26 October 2020 
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. 
 

CONFIDENTIAL 
COV-01-001 – Sub-protocol for Lanadelumab-IV 
Version 1.2, 26 October 2020 
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:                ___________________________ 
  
  
  
  
  
___________________________ 
  
  
  
  
  
___________________________ 

CONFIDENTIAL 
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
 
 

CONFIDENTIAL 
COV-01-004 – Sub-protocol for apremilast 
Version 4.0, 14 April  2021 
2 
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 
4 
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. 

CONFIDENTIAL 
COV-01-004 – Sub-protocol for apremilast 
Version 4.0, 14 April  2021 
5 
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. 

CONFIDENTIAL 
COV-01-004 – Sub-protocol for apremilast 
Version 4.0, 14 April  2021 
6 
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). 
 

CONFIDENTIAL 
COV-01-004 – Sub-protocol for apremilast 
Version 4.0, 14 April  2021 
7 
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

CONFIDENTIAL 
COV-01-004 – Sub-protocol for apremilast 
Version 4.0, 14 April  2021 
9 
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).  

CONFIDENTIAL 
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 

CONFIDENTIAL 
COV-01-004 – Sub-protocol for apremilast 
Version 4.0, 14 April  2021 
12 
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. 

CONFIDENTIAL 
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 
Version 4.0, 14 April  2021 
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. 

CONFIDENTIAL 
COV-01-004 – Sub-protocol for apremilast 
Version 4.0, 14 April  2021 
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. 

CONFIDENTIAL 
COV-01-004 – Sub-protocol for apremilast 
Version 4.0, 14 April  2021 
16 
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 
CCI
 
 
 

CONFIDENTIAL 
COV-01-004 – Sub-protocol for apremilast 
Version 4.0, 14 April  2021 
17 
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. 

CONFIDENTIAL 
COV-01-004 – Sub-protocol for apremilast 
Version 4.0, 14 April  2021 
18 
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

CONFIDENTIAL 
COV-01-004 – Sub-protocol for apremilast 
Version 4.0, 14 April  2021 
19 
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). 

CONFIDENTIAL 
COV-01-004 – Sub-protocol for apremilast 
Version 4.0, 14 April  2021 
20 
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. 

CONFIDENTIAL 
COV-01-004 – Sub-protocol for apremilast 
Version 4.0, 14 April  2021 
21 
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. 

CONFIDENTIAL 
COV-01-004 – Sub-protocol for apremilast 
Version 4.0, 14 April  2021 
22 
7.0 APPENDICES 

CONFIDENTIAL 
COV-01-004 – Sub-protocol for apremilast 
Version 4.0, 14 April  2021 
23 
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 
CCI

CONFIDENTIAL 
COV-01-004 – Sub-protocol for apremilast 
Version 4.0, 14 April  2021 
24 
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. 
 

CONFIDENTIAL 
COV-01-004 – Sub-protocol for apremilast 
Version 4.0, 14 April  2021 
25 
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
CCI
 

CONFIDENTIAL 
COV-01-005 – Sub-protocol for zilucoplan 
Version 1.2, 03 November 2020 
4 
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 
Version 1.2, 03 November 2020 
8 
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. 
 

CONFIDENTIAL 
COV-01-005 – Sub-protocol for zilucoplan 
Version 1.2, 03 November 2020 
9 
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  
 
 
 
 
 

CONFIDENTIAL 
COV-01-005 – Sub-protocol for zilucoplan 
Version 1.2, 03 November 2020 
10 
 
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 
 
CCI
CCI

CONFIDENTIAL 
COV-01-005 – Sub-protocol for zilucoplan 
Version 1.2, 03 November 2020 
11 
 
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
CCI
 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. 
CCI

CONFIDENTIAL 
COV-01-005 – Sub-protocol for zilucoplan 
Version 1.2, 03 November 2020 
12 
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 
 
 
 
u
CCI
 This assessment will be performed if the patient is in the hospital.

CONFIDENTIAL 
COV-01-005 – Sub-protocol for zilucoplan 
Version 1.2, 03 November 2020 
13 
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). 

CONFIDENTIAL 
COV-01-005 – Sub-protocol for zilucoplan 
Version 1.2, 03 November 2020 
14 
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 

CONFIDENTIAL 
COV-01-005 – Sub-protocol for zilucoplan 
Version 1.2, 03 November 2020 
15 
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]. 

CONFIDENTIAL 
COV-01-005 – Sub-protocol for zilucoplan 
Version 1.2, 03 November 2020 
16 
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 

CONFIDENTIAL 
COV-01-005 – Sub-protocol for zilucoplan 
Version 1.2, 03 November 2020 
17 
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 

CONFIDENTIAL 
COV-01-005 – Sub-protocol for zilucoplan 
Version 1.2, 03 November 2020 
18 
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. 
 
 
 
CCI
CCI
CCI
CCI
CCI

CONFIDENTIAL 
COV-01-005 – Sub-protocol for zilucoplan 
Version 1.2, 03 November 2020 
19 
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 
CCI
 
 
 
 
 
 

CONFIDENTIAL 
COV-01-005 – Sub-protocol for zilucoplan 
Version 1.2, 03 November 2020 
20 
CCI
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 

CONFIDENTIAL 
COV-01-005 – Sub-protocol for zilucoplan 
Version 1.2, 03 November 2020 
21 
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] 
 

CONFIDENTIAL 
COV-01-005 – Sub-protocol for zilucoplan 
Version 1.2, 03 November 2020 
22 
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. 

CONFIDENTIAL 
COV-01-005 – Sub-protocol for zilucoplan 
Version 1.2, 03 November 2020 
23 
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. 

CONFIDENTIAL 
COV-01-005 – Sub-protocol for zilucoplan 
Version 1.2, 03 November 2020 
24 
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 

CONFIDENTIAL 
COV-01-005 – Sub-protocol for zilucoplan 
Version 1.2, 03 November 2020 
25 
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 
CCI
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. 
CCI
CCI
CCI

CONFIDENTIAL 
COV-01-005 – Sub-protocol for zilucoplan 
Version 1.2, 03 November 2020 
26 
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
CCI
) from all patients (placebo and active treatment 
arms). Sample analysis may be limited to a select set of samples collected throughout the study. 
 
CCI

CONFIDENTIAL 
COV-01-005 – Sub-protocol for zilucoplan 
Version 1.2, 03 November 2020 
27 
 
 
 
 
 
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 
 
CCI
 
 
 
 
 
 
 
 
 
 
 
 
CCI
CCI
CCI
CCI

CONFIDENTIAL 
COV-01-005 – Sub-protocol for zilucoplan 
Version 1.2, 03 November 2020 
28 
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 
in the Pharmacy Manual. 

CONFIDENTIAL 
COV-01-005 – Sub-protocol for zilucoplan 
Version 1.2, 03 November 2020 
29 
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
CCI
-caused meningitis should also be considered. 
CCI
CCI
CCI
CCI

CONFIDENTIAL 
COV-01-005 – Sub-protocol for zilucoplan 
Version 1.2, 03 November 2020 
30 
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 
CCI
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). 
 
 
 

CONFIDENTIAL 
COV-01-005 – Sub-protocol for zilucoplan 
Version 1.2, 03 November 2020 
31 
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. 

CONFIDENTIAL 
COV-01-005 – Sub-protocol for zilucoplan 
Version 1.2, 03 November 2020 
32 
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. 
 

CONFIDENTIAL 
COV-01-005 – Sub-protocol for zilucoplan 
Version 1.2, 03 November 2020 
33 
7.0 APPENDICES 

CONFIDENTIAL 
COV-01-005 – Sub-protocol for zilucoplan 
Version 1.2, 03 November 2020 
34 
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 
Version 1.2, 03 November 2020 
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. 

CONFIDENTIAL 
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 
Version 1.2, 03 November 2020 
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:       ___________________________ 
  
  
  
  
___________________________ 
  
  
  
  
___________________________