Conditions: COVID-19
Keywords: COVID-19 COVID 19 Coronaviridae Infections Coronavirus Infections RNA Virus Infections Virus Diseases Nidovirales Infections SARS-CoV-2 SARS Coronavirus ACTIV-3 ACTIV3 TICO
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 58
Healthy volunteers: no

Brief summary:
This study looks at the safety and effectiveness of PF-07304814 in treating COVID-19 in people who have been hospitalized with the infection. Participants in the study will be treated with either PF-07304814 plus current standard of care (SOC), or with placebo plus current SOC. This is ACTIV-3/TICO Treatment Trial H6.

Detailed description:
This is a treatment trial of the ACTIV-3/TICO master protocol (NCT04501978) to evaluate the safety and efficacy of PF-07304814 in hospitalized patients infected with COVID-19.

This is a randomized, blinded, controlled sub-study of PF-07304814 plus current SOC against placebo plus current SOC. The placebo arm may be shared across other sub-studies of the ACTIV-3/TICO master protocol. When more than one drug is being tested at the same time, participants will be randomly allocated to treatments or placebo.

Randomization will be stratified by study site pharmacy and disease severity. There are 2 disease severity strata: participants without organ failure (severity stratum 1) and participants with organ failure (severity stratum 2).

An independent Data and Safety Monitoring Board (DSMB) will regularly review interim analyses and summarize safety and efficacy outcomes. The pace of enrollment with be initially restricted, and there will be an early review of safety data by the DSMB. At the outset of the trial, only participants in disease severity stratum 1 will be enrolled. This will continue until approximately 300 participants are enrolled and followed for 5 days. The exact number will vary according to the speed of enrollment and the timing of DSMB meetings. Prior to expanding enrollment to also include patients in disease severity stratum 2, safety will be evaluated and a pre-specified futility assessment by the DSMB will be carried out using 2 ordinal outcomes assessed at Day 5.

If PF-07304814 passes the futility assessment, enrollment of participants will be expanded, seamlessly and without any data unblinding, to include participants in disease severity stratum 2 as well as those in disease severity stratum 1. Future interim analyses will be based on the primary endpoint of sustained recovery and will use pre-specified guidelines to determine early evidence of benefit, harm, or futility for the investigational agent. Participants will be followed for 18 months following randomization.

This trial will be conducted in several hundred clinical sites. Participating sites are affiliated with networks funded by the United States National Institutes of Health (NIH) and the US Department of Veterans Affairs.

Arms:
arm 1: * PF-07304814 250 mg per day for 5 days; administered as a constant rate IV infusion
* Remdesivir is provided to all study participants as SOC unless contraindicated for an individual patient; administered by IV infusion arm 2: * Placebo administered by IV infusion
* Remdesivir is provided to all study participants as SOC unless contraindicated for an individual patient; administered by IV infusion

Interventions: intervention 1: PF-07304814 intervention 2: Placebo intervention 3: Remdesivir
Intervention descriptions: intervention 1: PF-07304814 is a phosphate ester prodrug of PF-00835231 (active moiety), a potent and selective inhibitor of the SARS-CoV-2 3CLpro. intervention 2: Commercially available 0.9% sodium chloride solution intervention 3: Antiviral agent

Protocol document:
SAP_002.pdf: 
 Statistical Analysis Plan
A Multicenter, Adaptive, Randomized, 
Blinded Controlled Trial of the Safety 
and Efficacy of Investigational 
Therapeutics for Hospitalized Patients 
With COVID-19 (Trial H6: 
PF-07304814)
   Version 3.1
  23 February 2022
    NCT05780541


ACTIV-3/TICO SAP 
February 23, 2022 
1 
Statistical Analysis Plan 
Version 3.1 
Therapeutics for Inpatients with COVID-19 (TICO) 
A Multicenter, Adaptive, Randomized, Blinded Controlled Trial of the 
Safety and Efficacy of Investigational Therapeutics 
for Hospitalized Patients with COVID-19 
Clinicaltrials.gov identifier: NCT04501978 
EudraCT number: 2020-003278-37 
Version Date 
Who 
Comments 
1.0 
06 October 2020 
BG 
TICO ACTIV-3 INSIGHT 014 Protocol v1.0, 27 July 2020 
Investigational agent: LY-Cov555 
2.0 
28 January 2021 
BG 
TICO ACTIV-3 INSIGHT 014 Protocol v2.0, 3 November 2020 and 
v3.0, 7 January 2021 
Investigational agents: Vir-7831; BRII-196 and BRII-198; AZD7442 
2.1 
22 February 2021 
BG 
Added detail to win ratio analyses and risk score specifications 
3.0 
26 January 2022 
BG 
TICO ACTIV-3 INSIGHT 014 Protocol v4.0 (12 Mar 2021), v5.0 (9 
Apr 2021), and v5.1 (17 Aug 2021) with letter of amendment #1 of 
19 Aug 2021.  Plans for biomarker analyses are included, based on 
the supplemental analysis plan dated April 14, 2021. 
3.1 
23 February 2022 
BG 
Added appendix for MP0420 


ACTIV-3/TICO SAP 
 
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2 
Contents 
1 
Introduction ...............................................................................................................................4 
1.1 Objective of the Statistical Analysis Plan ........................................................................... 4 
1.2 Description of the Study Design......................................................................................... 5 
1.3 Randomization ................................................................................................................... 7 
1.4 Sample Size Estimates ...................................................................................................... 8 
2 
Interim DSMB Reviews: Goals and Format ............................................................................9 
3 
Analysis Principles .................................................................................................................11 
4 
Enrolment and Eligibility ........................................................................................................16 
5 
Baseline Characteristics ........................................................................................................16 
6 
Administration of Study Treatment .......................................................................................17 
7 
Safety Analyses ......................................................................................................................18 
8 
Efficacy Analyses ...................................................................................................................23 
8.1 Primary Efficacy Endpoint and Primary Analysis ............................................................. 23 
8.2 Key Secondary Outcomes ............................................................................................... 26 
8.3 Other Secondary Outcomes ............................................................................................ 27 
9 
Subgroup Analyses ................................................................................................................29 
9.1 Outcomes, Subgroups, and Methods .............................................................................. 29 
9.2 Subgroups by Antibody Serostatus, Plasma Antigen, and Viral RNA Levels .................. 31 
10 Interim Monitoring Guidelines for the DSMB .......................................................................34 
10.1 Early Assessment of Safety ............................................................................................. 34 
10.2 Early Assessment of Futility ............................................................................................. 35 
10.2.1 
Interim Monitoring Guidelines for Early Assessment of Futility ................................35 
10.2.2 
Analyses of the Pulmonary and Pulmonary+ outcomes on Day 5 ...........................36 
10.3 Interim Monitoring Guidelines for the Primary Endpoint .................................................. 38 
10.4 Interim Monitoring for Futility............................................................................................ 39 
11 Data Completeness and Study Conduct ...............................................................................40 
12 SARS-CoV-2 Antibody, Antigen, and Viral RNA Levels ......................................................41 
12.1 Associations of Baseline Levels with Clinical Outcomes ................................................. 41 
12.2 Plasma Antigen Levels Through Day 5............................................................................ 41 
12.3 Antibody Levels Through Day 5 ....................................................................................... 43 
13 Exploratory Analyses .............................................................................................................44 
13.1 Associations Between the Pulmonary and Pulmonary+ Outcomes and Time to 
Sustained Recovery.................................................................................................... 44 
13.2 Disease Progression Risk Score ..................................................................................... 44 
14 Unblinding of Treatment Comparisons ................................................................................44 


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15 Distribution of Reports ...........................................................................................................45 
16 References ..............................................................................................................................46 
Appendix A. Definition of the Pulmonary and Pulmonary+ ordered categorical outcomes .47 
Appendix B. Definition of Clinical Organ Failure and Serious Infection .................................48 
Appendix C. Safety Data Collection ...........................................................................................49 
Appendix D. Schedule of Assessments .....................................................................................51 
Appendix E. Modifications to the Statistical Analysis Plan for AZD7442 ...............................53 
E-1 Analysis population .......................................................................................................... 53 
E-2 Increase in Target Number of Primary Events and Sample Size Beyond That Specified 
in the Master Protocol ................................................................................................. 53 
E-3 Power Estimation Prior to Unblinding .............................................................................. 54 
E-4 Primary Analysis: Simultaneous Tests in the Overall Cohort and in the nAb-Negative 
Subgroup, Method and Power Considerations ........................................................... 55 
E-5 Data Analysis Considerations for the Two Co-Primary Hypotheses ................................ 57 
E-6 Interim Monitoring Guidelines .......................................................................................... 58 
E-7 Subgroup Analyses by Vaccine and Immunosuppression Status .................................... 58 
E-8 Subgroup Analyses by Viral Strain .................................................................................. 60 
E-9 Missing Outcomes and Missing Baseline nAb Status ...................................................... 62 
Appendix F. Antibody, Antigen, and viral RNA Assays and Outcomes .................................63 
Appendix G. Modifications to the Statistical Analysis Plan for MP0420 .................................65 
Appendix H. List of Acronyms ....................................................................................................67 
 
 
 


ACTIV-3/TICO SAP 
 
February 23, 2022 
 
4 
1 Introduction 
1.1 
Objective of the Statistical Analysis Plan 
The objective of this statistical analysis plan (SAP) is to provide a description of the general 
analytic strategy and the statistical methods that will be used to analyze the data for the TICO 
(Therapeutics for Inpatients with COVID-19) Phase III randomized, blinded, controlled, platform 
trial. This SAP applies to versions 3-5.1 of the TICO protocol.  In version 2, two investigational 
agents are being studied, a SARS-CoV-2 neutralizing monoclonal antibody (nMAb) (Vir-7831) 
which is being developed by Vir Biotechnology (Vir) (San Francisco, CA) and GlaxoSmithKline 
(GSK) (Brentford, U.K.), and two nMAbs given sequentially (BRII-196 and BRII-198) which are 
being developed by Brii Biosciences (Durham, NC and Beijing). In protocol version 3, a third 
investigational agent is added, AZD7442, which is a combination of two nMAbs by AstraZeneca 
(Cambridge, U.K.); in version 4.0, MP0420, a DARPin® molecules was added; in version 5.0 
(5.1), PF07304814, an antiviral protease inhibitor was added.  
 
Participants are followed for death or re-hospitalization up to month 12 in version 2, and up to 
month 18 in versions 3, 4, and 5.   The nMAbs and MP0420 are given by single infusion, or two 
sequential infusions for BRII-196 and BRII-198.  PF07304814 requires a continuous infusion 
for 5 days. 
 
The primary objective of the platform trial is to determine whether investigational agents, that 
are aimed at enhancing the host immune response to SARS-CoV-2 infection, or directly 
enhancing viral control in order to limit disease progression,  are safe and superior to control 
(e.g., placebo) when given with standard of care (SOC) for the primary endpoint of time to 
sustained recovery evaluated up to 90 days of follow-up. 
 
In the platform trial, several agents may be investigated in parallel, or staggered with 
overlapping times; investigational agents may be added or dropped.  When more than one 
agent is being tested concurrently, where possible, participants will be randomly allocated 
across agents (as well as between the agent and its matched placebo), and the control group 
is pooled across the concurrently randomized, agent-specific matched placebo groups. Thus, 
each investigational agent and the corresponding pooled control group form their own 
randomized trial, and several agents may (at least partially) share their pooled control groups.   
 
 
This SAP: 
• Provides a short description of the study design (sections 1.2-1.4) 
• Describes goals of the interim reviews by the independent DSMB and the planned format 
of the review meetings (section 2) 
• Describes the planned data analyses presented in the reports to the DSMB (sections 3-
13). General analysis principles are summarized in section 3, safety analyses are 
described in section 7, efficacy analyses in section 8, and interim monitoring guidelines 
in section 10. 
• Describes data summaries to be provided regularly to study leadership to aid in 
monitoring trial conduct and data quality; these data summaries will be pooled across 
treatment groups, and will be restricted to enrolment, baseline data, and summaries of 
data completeness and study conduct.    
 


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5 
The SAP for TICO will be updated by blinded study statisticians and clinical investigators 
following protocol amendments and prior to the unblinding the results for each investigational 
agent.  For the latter, the blinded statisticians and clinical investigators will review data (pooled 
across treatment groups) on baseline characteristics, the number of participants who received 
a complete or partial infusion, and missing data due to withdrawal or loss to follow-up.  A small 
group of the team will be unblinded to the pooled primary event rate to re-estimate sample size. 
 
1.2 
Description of the Study Design 
This section is adapted from Section 1 of the TICO protocol versions 2.0 and 3.0. 
 
Design 
TICO is a master protocol to evaluate the safety and efficacy of multiple investigational 
agents aimed at modifying the host immune response to severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2) infection, or directly enhancing viral control in order to limit 
disease progression.  
Trials within this protocol will be adaptive, randomized, blinded and initially placebo-
controlled. Participants will receive standard of care (SOC) treatment as part of this protocol. 
If an investigational agent shows superiority over placebo, SOC for the study of future 
investigational agents may be modified accordingly.  
The protocol is for a phase III randomized, blinded, controlled platform trial that allows 
investigational agents to be added and dropped during the course of the study for efficient 
testing of new agents against control (i.e., placebo + SOC) within the same trial infrastructure. 
When more than one agent is being tested concurrently, participants will be randomly 
allocated across agents (as well as between the agent and its placebo). For analysis, placebo 
groups of concurrently randomized agents will be pooled; therefore, control groups may 
overlap for different agents. 
Randomization will be stratified by study site pharmacy and disease severity.  There are 2 
disease severity strata, defined as below: 
• Disease severity stratum 1: Absence of all of the following: stroke, meningitis 
encephalitis, myelitis, myocardial infarction, myocarditis, pericarditis, symptomatic 
congestive heart failure (NYHA class III or IV), arterial or deep venous thrombosis or 
pulmonary embolism, requirement for invasive mechanical ventilation, ECMO, 
mechanical circulatory support, vasopressor therapy, or new renal replacement 
therapy.   
 
• Disease severity stratum 2: Presence of at least one of the excluded conditions or 
treatments in disease severity stratum 1.  
The primary endpoint is the time from randomization to sustained recovery, defined as 
being discharged from the index hospitalization, followed by being alive and home for 14 
consecutive days prior to Day 90. The definition of home will be operationalized as the level 
of residence or facility where the participant was residing prior to hospital admission leading 
to enrollment in this protocol. 
An independent Data and Safety Monitoring Board (DSMB) will regularly review interim 
analyses that summarize safety and efficacy outcomes. For any agent, at the outset of the 


ACTIV-3/TICO SAP 
 
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6 
trial, only participants in disease severity stratum 1 will be enrolled. This more restricted 
enrollment will continue until approximately 150 participants per study arm are enrolled and 
followed for 5 days.  At this point, the DSMB will carry out a pre-specified assessment of 
futility, based on two 7-category ordinal outcomes (pulmonary and pulmonary+), assessed at 
Day 5. The pulmonary and pulmonary+ outcomes are described in Appendix A.  Safety of the 
investigational agents will also be assessed. 
For investigational agents passing this initial futility assessment, enrolment of patients in 
disease severity stratum 1 will continue, and it is planned to also expand enrollment, 
seamlessly and without any data unblinding, to include participants in disease severity 
stratum 2.  The expansion to include more severely ill participants will be subject to 
recommendations by the FDA and the DSMB based on safety considerations.   
After the initial futility assessment is passed, future interim analyses will be based on the 
primary endpoint of sustained recovery and will use pre-specified guidelines to determine 
early evidence of benefit, harm or futility for the investigational agent. 
Primary Objective 
The primary objective of this protocol is to determine whether investigational agents,  aimed at 
enhancing the host immune response to SARS-CoV-2 infection, or directly enhancing viral 
control in order to limit disease progression,  are safe and superior to control (e.g., placebo) 
when given with SOC for the primary endpoint of time to sustained recovery evaluated up to 90 
days after randomization. 
 
For all agents studied in TICO, the investigational agents/placebo have been given with study-
supplied remdesivir unless contraindicated.  
 
Duration 
Participants will be followed for 18 months following randomization in versions 3-5 of the 
protocol. Primary and most secondary outcomes will be collected during the first 90 days of 
follow-up only.  Follow-up beyond 90 days is planned because the half-lives of some agents 
indicate that potentially meaningful amounts may remain in the body after 90 days of follow-
up.  After 90 days through the end of follow-up, hospitalizations and deaths will be 
ascertained. 
Sample size 
This phase III trial is planned to provide 90% power to detect a 25% increase in the rate of 
sustained recovery for an investigational agent compared to placebo at the 0.025, 1-sided level 
of significance.  This requires 843 primary events (i.e., participants who achieve sustained 
recovery).  Randomization of 1,000 participants, equally allocated to each investigational agent 
and placebo, followed for 90 days is estimated to result in the required number of primary 
events.  The event target may be achieved earlier if more than 1,000 participants are enrolled.  
Sample size will be evaluated periodically by study team members who are blinded to interim 
results on treatment difference and may be increased to maintain power for the hypothesized 
difference in sustained recovery between the investigational agent and placebo.  
 
Population 
The study population consists of inpatient adults (≥18 years) who have had COVID-19 
symptoms ≤ 12 days.  Initially, enrollment is restricted to disease severity stratum 1.  After a 
pre-specified review by the DSMB for safety and futility, when approximately 150 participants 


ACTIV-3/TICO SAP 
 
February 23, 2022 
 
7 
are enrolled per study arm, eligibility for randomization will be expanded to also include patients 
in disease severity stratum 2, subject to recommendations by the FDA and DSMB. 
 
Stratification 
Randomization is stratified by study site pharmacy; once enrolment is expanded to also 
include disease severity stratum 2, randomization will also be stratified by disease severity 
stratum. 
Monitoring 
An independent DSMB will review interim data on a regular basis for safety and efficacy. An 
initial futility assessment will be performed after the first 300 participants (150 in the active and 
150 in the placebo arms) are enrolled and have Day 5 data; this initial assessment is based on 
two ordinal outcomes (pulmonary and pulmonary+ outcomes at Day 5).  Afterwards, the DSMB 
will use pre-specified guidelines to identify agents with clear evidence of efficacy for the primary 
outcome and, if so, recommend unblinding of the trial results for that agent. Conversely, the 
DSMB may recommend discontinuation of an investigational agent if the risks are judged to 
outweigh the benefits or if futility assessments indicate that there is low probability that an 
investigational agent will achieve statistical significance for the primary endpoint of sustained 
recovery.  
For an investigational agent, if the trial is stopped early or if the trial continues until the pre-
specified number of primary endpoints is reached, further enrollment of the investigational 
agent will be terminated if applicable, and the trial data for the investigational agent will be 
unblinded and reported with data through 90 days of follow-up. Follow-up of all participants will 
continue through 18 months (12 months in version 2.0 of the protocol) using the data collection 
plan described in the master protocol. 
Agent-specific Considerations 
For individual investigational agents, the trial design may be modified, for example, the planned 
sample size for AZD7442 was increased from 1000 to 1500. Sample size was increased 
because data from the RECOVERY trial and the TICO trial of bamlanivimab indicated that the 
beneficial effect of antibody treatment could be based on the presence of neutralizing 
antibodies (nAbs) at entry, with nAb negative participants benefiting from antibody treatment 
and nAb positive participants showing no benefit or possible harm. In addition to increasing the 
sample size, the primary analysis for AZD7442 was modified, to test two hypotheses 
simultaneously while controlling the familywise type 1 error rate: treatment groups will be 
compared for time to sustained recovery in the full analysis population as well as in the 
subgroup of participants who were SARS-CoV-2 nAb seronegative at baseline using Holm’s 
method for simultaneous tests.  Such modifications are described in agent-specific appendices. 
 
1.3 
Randomization 
The randomization is described in section 6.1 of the protocol.  
 
Patients will be equally allocated to each investigational agent + SOC or to placebo + SOC. For 
example, for a study of a single investigational agent, participants will be randomized in a 1:1 
ratio to the investigational agent or placebo. If a patient is eligible for two investigational agents 
and the placebo can be shared, the allocation will be 1:1:1 to investigational agent A, agent B, 
or placebo.  Because the two investigational agents (A and B) may require different placebos 


ACTIV-3/TICO SAP 
 
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8 
(for example, when infusion volumes differ), the 1:1:1 allocation ratio will be achieved through 
a two-step randomization procedure: in step 1, the participant is randomized 2:1 to “active” 
versus “placebo”; in step 2, the participant is randomized 1:1 to A versus B.  With k agents, this 
can be viewed as an initial k:1 allocation to “active” versus “placebo”, followed by a second, 
even allocation to one of the available agents (for example, if a participant was allocated to 
“placebo” in step 1, then the step 2 allocation will be 1:1 to “matched placebo for A” versus 
“matched placebo for B”).  For the analysis, the concurrent agent-specific placebo groups will 
be pooled, resulting in a 1:1 allocation ratio for comparing each investigational agent versus 
the (pooled placebo) control group.  If investigational agents are added or dropped, the 
allocation ratio to active versus placebo will be appropriately modified, and sample size will be 
recalculated as appropriate.  
 
Randomization will be stratified by study site pharmacy (several clinical sites may share one 
pharmacy) and severity of disease at entry; the two disease severity strata are defined in 
section 1.2 of this SAP. 
 
If more than one investigational agent is being compared with placebo and they have different 
contraindications, it is possible that a participant is eligible only for a subset of agents.   
 
Comparisons will be of each investigational treatment against its control arm. The control arm 
consists of all participants who were “at risk” of being randomized to the investigational agent 
but were randomized to a control group instead. This concept is relevant when the 
randomization includes investigational agents with different eligibility criteria, when agents are 
introduced into the platform trial at different time points, or randomization to one of the agents 
is halted temporarily. Formal randomization includes agent-specific matched placebo groups, 
and the placebo groups will be pooled across agents, but only participants who 1) were eligible 
for the investigational agent under consideration, and 2) were randomized contemporaneously 
and at participating sites will be included in the control group for a given agent.  At the time of 
randomization, for each participant, indicator variables will be set that record whether an agent 
was included in the randomization for that participant (e.g., indicator A=1, indicator B=1, 
indicator C=0 if the participant was eligible to be randomized to agents A and B, but not C).  
The pooled control group for agent A then consists of all participants who were randomized to 
(any) placebo, and for whom indicator A=1. 
 
1.4 
Sample Size Estimates 
The planned sample size for each pairwise comparison is 1,000 participants (500 participants 
in each group). The sample size is sufficient to detect a recovery rate ratio (RRR) of 1.25 for 
time to sustained recovery with 90% power, using a one-sided test with a significance level of 
0.025.  The treatment groups are compared using Gray’s test with ρ=0, the competing risks 
analogue of the log-rank test. 
 
Sample size calculations are described in detail in Section 6.3 of the protocol.  
 
Blinded sample size re-estimation will be carried out before enrollment is complete to determine 
whether the planned sample size of 1,000 participants followed for 90 days will yield the 
planned number of 843 primary events.  The blinded sample size re-estimation does not involve 
unblinding of the treatment difference.  It will be based on the pooled outcome data. Sample 
size may be increased to achieve the event target in the planned follow-up of 90 days.  A 


ACTIV-3/TICO SAP 
 
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9 
sample size increase may also be considered in order to achieve the event target before all 
participants are followed for 90 days. 
 
When 300 participants (150 per study arm) are enrolled and have Day 5 outcome data, an early 
futility assessment is planned.  This assessment will be based on two ordinal outcomes, 
denoted as “pulmonary” and the “pulmonary+”; both are ordered categorical outcomes with 7 
categories, assessed on Day 5 (the two outcomes are described in Appendix A). Treatment 
groups will be compared using proportional odds models. With 300 participants, the early futility 
assessment is powered to detect a summary OR=1.60 with power of 95%, using a one-sided 
test with significance level of 0.30.1  Given the two-outcome decision rules, an investigational 
agent with a summary OR=1.60 at Day 5 for both outcomes, would pass the futility assessment 
with a power between 93% and 98%, and a type I error between 0.21 and 0.39.  
 
 
2 Interim DSMB Reviews: Goals and Format 
Each investigational agent versus control will be reviewed as a separate clinical trial; 
separate data reports will be prepared for each investigational agent and the corresponding 
randomized (pooled) placebo group.   
 
Goals of the interim reviews: 
- 
Protect the safety of study participants.   
- 
Advise on stopping or modifying the trial for efficacy, for patient safety in case of 
emerging data on harm, or for futility.   
- 
After the first 300 participants are enrolled (150 participants per arm; all in disease 
severity stratum 1), advise on continuing the trial, and on expanding the study population 
to include more severely ill patients (disease severity stratum 2). 
- 
Review the conduct of the trial 
- 
If an investigational agent is stopped (due to efficacy, safety, or futility), the DSMB may 
be asked to advise on the timing of unblinding the data, in case the unblinding of the 
shared pooled placebo group may impact the integrity of the ongoing trial for another 
agent (section 14). 
 
The DSMB will conduct frequent safety reviews.  For an investigational agent with minimal pre-
existing data, the first safety review will be conducted after 20-30 participants have been 
enrolled (10-15 per study arm) and Day 5 data are available, before increasing the pace of 
enrollment.  Subsequent reviews will be timed according to the recommendations of the DSMB 
and study leadership.  After the early futility review when 300 participants are enrolled (150 per 
study arm), further futility reviews would be expected to occur at approximately 50% and 75% 
information time (the number of observed sustained recoveries as a proportion of the targeted 
number of 843 events).   
 
The DSMB may request interim reports that are focused on safety at any time. 
 
Review meetings for each agent will typically consist of an Executive session (optional; 
closed), open session, closed session, and a second open session to give feedback to study 
leadership (optional).  If several agents are reviewed at the same meeting, agents will be 


ACTIV-3/TICO SAP 
 
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10 
reviewed consecutively, either with a sequence of open and closed sessions, or with one open 
session and one closed session (provided there are no unblinding conflicts). 
 
Masking of treatment group labels in interim reports: In the open reports, any data reports 
will be pooled across the two treatment groups (the specific investigational agent and its pooled 
control group as described above). In the closed reports, treatment group labels will masked; 
for example as “Group A” versus “Group B”.  The treatment group labels will be consistent 
across all analyses and over subsequent reports.  The DSMB will be unmasked to the treatment 
group labels.   
 
Open report to the DSMB  
The open reports for each investigational agent versus placebo comparison will contain: 
• A synopsis of the trial design and current status of the platform trial  
• Responses of the study team to DSMB requests  
• A summary prepared by the study leadership 
• Data summaries for enrolment, eligibility violations and protocol deviations, baseline 
characteristics 
• Summary reports for data completeness and study conduct, pooled across treatment 
groups.  
• Emerging external data, e.g., results of phase I or II trials on the investigational agent, 
will also be provided to the DSMB by the study leadership. This is usually included with 
the open report, but may be shared confidentially if needed. 
 
All data summaries in the open report will be pooled across the investigational agent and 
placebo control.  The open reports will be prepared by the blinded statisticians in cooperation 
with the unblinded statisticians.  In addition to the DSMB, open reports will be provided to the 
study team, and posted on the website for access by study investigators.   
 
While the study is ongoing, summaries by treatment group, and comparisons of the 
investigational agent versus placebo are restricted to the confidential closed report to the 
DSMB. Additionally, all summaries of follow-up data other than the data completeness and 
study conduct reports (pooled across the two treatment groups) will be restricted to the 
confidential closed report.  For the planned sample size re-estimations prior to completion, 
the pooled number of primary events and the pooled event rate will be provided to the blinded 
study statisticians and study leadership.  On a case-by-case basis, other pooled follow-up data 
may be provided if explicitly approved by the DSMB. 
 
Closed report to the DSMB  
All data summaries in the closed report will be by (masked) treatment group. The closed reports 
for a full review will contain: 
• Specific data summaries requested by the DSMB or study leadership 
• Data summaries in the open report, by treatment group (enrollment, baseline 
characteristics, eligibility violations) 
• Data summaries to assess safety of the investigational treatment, described in sections 
6 and 7. Data summaries for the primary “efficacy outcomes” and selected secondary 
outcomes will also be included in each report, because these data contain information 
about the risk/benefit profile of the investigational agent. Efficacy analyses are described 
in section 8.   


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11 
• Subgroup analyses for sustained recovery and important safety outcomes will be 
conducted when the sample size is sufficiently large.  Analyses are described in section 
9. 
• Data summaries on data completeness and study conduct, described in section 11 
• Interim monitoring boundaries for efficacy or harm (section 10) 
• Futility analyses (sections 10.2 and 10.4) 
• Listings of grade 3 and 4 adverse events, serious adverse events (SAE), clinical organ 
failure and serious infections (PSEE), unanticipated problems (UP), suspected 
unexpected serious adverse reactions (SUSAR), and deaths. 
 
Data reports will follow a similar format for all investigational agents.  Each agent will 
have a small assigned team of unblinded statisticians, with 2-3 alternating teams when 2 or 
more agents are investigated in parallel.  The unblinded statistician teams will cooperate in 
designing the master layout for the data reports and will serve as each other’s backup when 
needed.  The unblinded statisticians will be unblinded to several investigational agents in the 
platform trial; those for which they serve as primary statisticians, and those for which they serve 
as backup or advisory statisticians. 
 
 
3 Analysis Principles  
Each investigational agent versus control will be treated as a separate clinical trial; data 
reports will be for one “target” investigational agent and its corresponding randomized (pooled) 
control group.  Investigational agents will not be directly compared against each other, unless 
explicitly stated in the agent-specific data analysis plan and agreed upon by all stakeholders.  
Therefore, in the event that several investigational agents are included in the platform trial in 
parallel, the pairwise comparisons of each agent versus control will not be adjusted for potential 
inflation of Type I error “due to multiple comparisons”.  
 
Comparisons will be of each investigational treatment against its (pooled) control arm.   
 
Analysis populations:  
• Comparisons for safety outcomes will be by modified intention-to-treat (mITT). The mITT 
analysis is restricted to participants who received a complete or partial infusion of the 
investigational agent/placebo; participants who did not receive any of the investigational 
agent/placebo are excluded. 
• Comparisons for efficacy endpoints will be by intention-to-treat (ITT), unless otherwise 
stated.  If analyses are by ITT, sensitivity analyses by mITT will be carried out for primary 
outcomes and key secondary outcomes. 
• The analysis populations will be reconsidered prior to unblinding with consideration of 
the number of participants who were not infused, whether reasons for not infusing are 
independent of the treatment assignment, and the number of participants who have no 
follow-up data due to withdrawal of consent prior to infusion.    
 
Pooled control group: As stated in section 1.3 above, the control arm for any investigational 
agent will be pooled across the agent-specific control groups for all agents that concurrently 
participated in the randomization. Specifically, the pooled control group for investigational agent 
A consists of all participants who might have been randomized to agent A but were randomized 


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12 
to a placebo group instead. This concept is relevant when a participant is eligible to be 
randomized to more than one investigational agent, and agents were introduced into the 
platform trial at different time points or have different eligibility criteria.  
 
In order to identify the pooled control group for each investigational agent correctly, the 
randomization application is setting indicator variables at the time of randomization for each 
participant that record whether an agent was included in the randomization (e.g., indicator A=1, 
indicator B=1, indicator C=0 if the participant was eligible to be randomized to agents A and B, 
but not C).  The pooled control group for agent A then consists of all participants who were 
randomized to (any) placebo, and for whom indicator A=1. 
 
Therefore, only participants who 1) were eligible for the investigational agent under 
consideration, 2) were randomized contemporaneously and at participating sites, and 3) were 
randomized to placebo will be included in the control group for a given agent. 
 
Descriptive statistics will be reported overall and by randomized group. For categorical 
outcomes, the number and percent in each category will be reported; percentages will be of 
non-missing values, if data are not complete.  Continuous variables will be summarized by 
median (interquartile range [IQR]) and/or mean (SD). Continuous variables may be categorized 
(e.g., age may be broken into categories to investigate the distribution across age groups). 
 
Stratification: Tests comparing the investigational agent versus control for primary outcomes 
and key secondary outcomes will be stratified according to the planned randomization strata 
(disease severity and site pharmacy), provided participant numbers are sufficiently large.  In 
this analysis plan, “stratification by disease severity” refers to the two disease severity 
randomization strata described in section 1.2.  Initially, participants are enrolled only in disease 
severity stratum 1, until the investigational agent has passed the initial futility assessment (when 
300 participants are enrolled for the pairwise comparison; 150 per study arm) and has been 
approved to expand enrolment to include participants from both strata 1 and 2.  In this SAP, we 
use the notation “stratification by disease severity and site pharmacy” to denote the following: 
• For analyses that include only participants in disease severity stratum 1, analyses will 
be stratified by site pharmacy. 
• For analyses that include participants in both disease severity strata, analyses will be 
stratified by site pharmacy within each disease severity stratum; this means, the maximal 
possible number of strata is twice the number of site pharmacies.  For analyses where 
stratification is implemented through addition of indicator variables for strata to the 
model, the strata would be defined through main effects for disease severity, for site 
pharmacy, and the interaction between disease severity and site pharmacy. 
 
Because there are many site pharmacies, some strata may be small, particularly early in the 
trial. In order to avoid loss of power, any stratum that contains too few participants (less than 
10-20 participants or events) should be pooled with other strata (of the same disease severity, 
and preferably within the same country or geographical region). Thus, several small strata may 
be pooled together, or pooled with a larger stratum.  
 
For time-to-event analyses, if strata are too small for fitting separate baseline hazard functions, 
strata may be added as a categorical covariate to models instead.  Whenever possible, 
however, analyses should be stratified by disease severity (with separate baseline hazard 
functions). 


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13 
 
For binary outcomes, probabilities will be compared between the investigational agent and its 
control group using Cochran-Mantel-Haenszel tests (CMH) or logistic regression.  If the 
numbers are sufficiently large, CMH tests will be stratified according to the planned 
randomization strata (disease severity and site pharmacy), as described above under 
“stratification”.  Odds ratios (OR) with 2-sided 95% confidence intervals (CI) will be estimated 
using logistic regression models. 
 
For longitudinally measured binary outcomes, the treatment effect through follow-up will be 
estimated with 95% confidence intervals using generalized estimating equations (GEE) with a 
logit link function; the treatment effect is estimated via the interaction between the indicator for 
treatment group and the indicator for follow-up (versus baseline) visits.  When there is more 
than one follow-up visit, “visit number” (day) may be included as categorical variable in the 
model, for variance reduction; alternatively, “time” may be included as a continuous variable. 
 
Ordered categorical outcomes (pulmonary and pulmonary+) will be compared between 
treatment groups using proportional odds models, and the summary OR will be estimated with 
a 2-sided 95% CI.2  Additionally, to aid the interpretation, the ordinal outcome will be 
dichotomized according to cumulative probabilities of the ordered categories, comparing 
treatment groups for proportions of participants in category 1, in the “best 2 categories”, “best 
3 categories”, etc.; these comparisons will be performed using logistic regression (or stratified 
CMH tests).   
 
For interim analyses of the ordinal outcomes, if one or more recently enrolled participants have 
died (i.e., their outcome status is known) but their current administrative follow-up has not yet 
reached the time point at which the treatment groups are to be compared (e.g., day 5), analyses 
will be restricted to participants with administrative follow-up greater or equal to the target time 
point.  
 
Models will be adjusted for the baseline categories of the pulmonary+ outcome and for study 
pharmacy, by including the corresponding indicator variables in the model.  
• If the number of observations is too small to adjust for both categorical covariates, 
preference will be given to the adjustment for the pulmonary+ category at baseline. Site 
pharmacy categories may be collapsed as described above under “stratification”. 
• For the initial futility analysis (after 150 participants per arm have Day 5 data), the 
adjustment for the pulmonary+ categories and pharmacy will be additive. 
• For key analyses, unadjusted OR estimates will also be provided as sensitivity analyses.  
 
The validity of the proportional odds assumption will be assessed by testing for heterogeneity 
in the log ORs (for the treatment effect) across the dichotomized cumulative ordered categories 
in the corresponding logistic regression model (partial proportional odds model, test for 
“unequal slopes”).   
• The primary sensitivity analysis testing the proportional odds assumption will compare 
the unadjusted proportional odds model for the treatment comparison (null model) 
versus a partial proportional odds model that allows for “unequal slopes” across the 
dichotomized cumulative categories (i.e., when testing the proportional odds assumption 
for the treatment comparison with respect to the pulmonary outcome on Day 5, the model 
will allow for heterogeneous ORs across the Day 5 pulmonary categories) as well as 


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14 
across the stratification covariates (i.e., the baseline pulmonary+ categories and site 
pharmacy strata) (full partial proportional odds model). 
 
 
Continuous outcomes will be compared between treatment groups using ANCOVA models 
for comparing means, if the ANCOVA model assumptions hold. If the distributions of the 
continuous outcomes are skewed, outcomes may be transformed, or compared between 
treatment groups using rank-based methods, such as the Wilcoxon test, or quantile (median) 
regression.   
 
Comparisons between treatment groups for a continuous outcome will be adjusted for baseline 
values of the outcome, for the purpose of variance reduction, unless there are concerns over 
model stability with such an adjustment.  For this purpose, the baseline value will be included 
as covariate in the model (e.g., ANCOVA, linear mixed models). 
 
To estimate the treatment effect for longitudinally measured continuous outcomes, the outcome 
will usually be defined as “change from baseline” (difference at follow-up visit minus baseline 
value).  The treatment effect through follow-up will then be estimated with 95% confidence 
intervals using generalized estimating equations (GEE) with an indicator for treatment group, 
or, in the case of Gaussian responses, the corresponding mixed effects models with random 
effects for participants.  When there is more than one follow-up visit, “visit number” (day) may 
be included as categorical variable in the model, for variance reduction; alternatively, “time” 
may be included as continuous variable. Models will also be adjusted for the baseline values 
of the outcome variable. 
 
Time-to-event outcomes will be summarized with Kaplan-Meier estimates for cumulative 
probabilities over time, and compared between treatment groups using log-rank tests or Cox 
proportional hazards models, or the corresponding competing risk analogues when death is a 
competing risk for the outcome.  In particular, the primary endpoint of “time to sustained 
recovery” will be analyzed taking into account the competing risk of death. The following 
competing risk methods will be used: 
• Aalen-Johansen estimator for the cumulative incidence function (analogue to the 
Kaplan-Meier estimate)3 
• Gray’s test with ρ=0 (analogue to the log-rank test)4 
• Fine-Gray estimates and tests for the sub-distribution hazard ratio (analogue to the Cox 
proportional hazards model).5,6 
 
The proportional hazards assumption will be tested by adding an interaction term for time by 
treatment group to the model. The cumulative proportions of participants who experienced the 
event will also be compared at given time points (specified in secondary objectives, e.g., at 28 
days); in this case, the cumulative proportions will be estimated using Kaplan-Meier estimates 
or the competing risks analogue, and/or as proportion of participants who reached the time 
point (e.g., time since randomization > 28 days).   
 
The administrative follow-up time is defined as the minimum of (cut date minus 
randomization date) or the analysis time period.  For example, the analysis time period for the 
primary endpoint of sustained recovery is 90 days, and the analysis time period for the 
important safety endpoint, the composite of grade 3 and 4 events, SAEs, organ failure, serious 


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15 
infection or death, is 5 days or 28 days. The administrative censoring date is the earlier of 
the cut-date of the dataset, or randomization date plus analysis time period. 
Comment: The notion of “administrative censoring” is important in time-to-event analyses in the 
presence of competing risks. For example, the Fine-Gray method for estimating the sub-hazard 
ratio for sustained recovery can be approximated by using a Cox proportional hazards model 
where follow-up time for participants who died prior to achieving sustained recovery is not 
censored at death, but at the administrative censoring date. 
 
Censoring for time-to-event analyses 
For interim analyses, the type of censoring used will depend on the data collection schedule. 
• If the reporting of the endpoint is data-driven (e.g., SAEs and deaths are reported as 
they occur), then follow-up is censored at the administrative censoring date, at the date 
of withdrawal, or loss to follow-up, whichever occurs earliest.     
• If the date of the event is elicited retrospectively at fixed study visits spaced more than 
one week apart (e.g., “sustained recovery”), follow-up will be censored at the last day 
the endpoint status was ascertained. 
• Sensitivity analyses will be provided for key analyses when the outcome status is 
uncertain. 
 
For final analyses, follow-up will be censored on the last day the outcome status was 
ascertained.   
 
Adverse events (AEs) will be classified by system organ class according to MedDRA®1 
(currently version 24.1 [September 2021] is used; when new versions are implemented, items 
are recoded). AEs will be graded according to the DAIDS Table for Grading the Severity of 
Adult and Pediatric Adverse Events, Corrected Version 2.1 (July 2017) (also referred to as the 
DAIDS AE Grading Table).7  Cause of death will also be coded according to MedDRA®.   
 
The number and percent of participants with grade 1-4 AEs will be summarized by day and 
grade, and by MedDRA® System Organ Class and grade. The percentage of participants with 
AEs will be compared between treatment groups according to grade cut-offs, e.g., “percent of 
participants with any AE”, “percent of participants with grade 2 or higher AEs”, etc., using CMH 
tests. The total number of events and median (IQR) of events per participant will also be 
summarized.   
 
Additionally, the incidence of grade 3 and higher AEs will be summarized (number and percent 
of participants), and compared between treatment groups using time-to-event methods. 
 
Significance level, two-sided tests: Unless noted otherwise, statistical tests and confidence 
intervals will be 2-sided, confidence intervals will have approximate 95% coverage probability, 
and test results with P-values < 0.05 will be considered “significant”.  Percentages will be 
reported to at least one decimal place. P-values will be given to 2 significant figures. 
 
Cut-date for interim reviews: Analysis data sets will be frozen (locked) several days (or 
weeks) prior to the review date, to allow the unblinded statisticians time to prepare a consistent 
 
1 The Medical Dictionary for Regulatory Activities terminology is the international medical terminology developed 
under the auspices of the International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use (ICH). MedDRA® is a registered trademark of the International Federation of 
Pharmaceutical Manufacturers and Associations (IFPMA) 


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16 
report.  The cut-date may be earlier than the date of the data freeze, to allow for lag time in the 
reporting of events.  Early in the trial, the cut date and freeze date will be very close to the 
review date, to ensure timely safety reviews.   
 
 
4 Enrolment and Eligibility 
For the open report, the following enrolment and eligibility summaries will be provided: 
 
• Enrolment over calendar time: plot by day or week, cumulative and increments.  
• Enrolment by site pharmacy and by country: number (%) 
• Eligibility: number (%) and reasons for eligibility violations 
 
These summaries will be provided overall, and by disease severity randomization stratum. 
 
For the closed report, enrolment and eligibility violations will be summarized by treatment group. 
 
 
5 Baseline Characteristics 
Baseline characteristics will be based on information collected on baseline and screening 
forms.  For the open report, baseline characteristics will be summarized pooled across the two 
treatment groups (investigational agent and the “pooled” control group as described in section 
2 above).   
 
For the closed report, baseline characteristics will be summarized by treatment group.     
 
The following baseline characteristics will be reported; unless noted otherwise, categorical 
variables will be summarized with numbers (%) in each category, and continuous variables will 
be summarized with median (IQR); in the open report, in addition, the mean (SD) and range 
may be provided.  When enrolment has been completed, frequency distributions of these 
characteristics, including cut points for discretizing continuous measures, will be considered for 
defining subgroups in the final report.  
 
• Demographics 
o 
Age: distribution in categories 18-29, 30-39, 40-49, 50-59, 60-69, 70-79, ≥80 years; 
and summary as continuous variable  
o 
Sex at birth: number (%) male, female 
o 
Ethnic group: number (%) Asian, Black, Latino/Hispanic, White, other 
o 
Type of residence (“home”) 
o 
Country of enrolment 
• COVID-19 related characteristics 
o 
Duration of symptoms prior to enrolment 
o 
Use of remdesivir prior to enrolment  
o 
Pulmonary and pulmonary+ ordinal outcomes, number (%) in each category 
o 
NEWS: summary as continuous variable 
o 
Respiratory function scale (modified Borg dyspnea scale; continuous outcome) 


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17 
o 
Disease severity randomization stratum (for investigational agents that enrol in both 
strata), number (%) in each category 
o 
Receipt of SARS-CoV-2 vaccination, and type of vaccine (and if received as part of a 
blinded clinical trial, in which case the vaccine may be active or control) 
• Other clinical characteristics 
o 
Concomitant treatments  
o 
Corticosteroid use will be summarized overall, and separately by oxygen requirement 
at baseline (no supplemental oxygen, < 4 L/min, conventional supplemental oxygen > 
4 L/min, high-flow oxygen or mechanical ventilation/ECMO) 
o 
History of chronic conditions (cardiovascular disease, diabetes, asthma, chronic 
obstructive pulmonary disease, hypertension, chronic kidney disease, hepatic 
impairment, cancer, or immunosuppressive disorder [HIV, and other than HIV]) 
o 
Prior cerebrovascular event 
o 
Prior myocardial infarction (MI) 
o 
Requirement of continuous chronic supplemental oxygen 
o 
BMI (<30, 30-39.9, 40+) 
o 
Pregnancy (not applicable to protocol versions 2 and 3) 
• Laboratory values: as continuous outcomes, and number (%) of grade 3 or 4 abnormalities 
according to the DAIDS AE Grading Table. 
 
Some biomarkers will be measured centrally from stored samples, for example, hsCRP, IL-6, 
D-dimer, SARS-CoV-2 antibody, antigen, and viral RNA levels, and SARS-CoV-2 genome 
sequencing and variant identification.  If these measures are available, they will be included in 
interim reports. 
 
6 Administration of Study Treatment 
These data are an important part of the safety review, with particular emphasis on infusion-
related reactions and symptoms occurring during or within up to 2 hours after the infusion.  
These reactions and symptoms will be graded according to the DAIDS AE Grading Table. 
The administration of study treatment is also an essential element of study conduct.  Several 
summaries, pooled across treatment groups, will be included in the open report or provided to 
study leadership.  Any summaries of adverse events or infusion-related reactions are 
restricted to the closed report.   
For investigational agents administered as a one-time infusion, the following statistics 
will be used to summarize the infusion in each treatment group (active and control): 
• Number and percentage of participants receiving complete infusion, partial infusion, infusion 
paused but resumed for complete infusion, or not infused (comparison by intention-to-treat). 
• Number and percentage of participants with infusion-related reactions and symptoms 
(reported during the infusion or within 2 hours after the infusion), by grade. (Closed report 
only) 
• Number and percentage of participants with an incident AE, SAE, UP or SUSAR on Day 0 
during or after the infusion, overall and by oxygen requirement category at time of infusion 
(oxygen requirement at baseline, unless updated information is available; categories: no 
supplemental oxygen, < 4 L/min, conventional supplemental oxygen > 4 L/min, high-flow 
oxygen or mechanical ventilation/ECMO).  Types of AEs will be summarized by system 
organ class and by grade. (Closed report only) 


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18 
• Number and percentage of participants who received: 
o Prior to infusion, medication to prevent infusion reactions, and type of medication 
o During or within 2 hours after infusion, medication to treat infusion reactions, and 
type of medication (Closed report only) 
• Among participants infused, the day of infusion (same day as randomization, next day, > 1 
day after randomization), and time between randomization and beginning of infusion 
(median hours, IQR). 
• Among participants receiving full infusion, duration of infusion (median minutes, IQR). 
• Time from vial puncture (beginning of preparation of the study agent by the pharmacist) to 
the end of the infusion, and number and percent of participants for whom the agent-specific 
time window was exceeded. 
• Remdesivir:   
o Number and percent of participants who received (any) remdesivir, and number of days 
remdesivir was administered: median, IQR, distribution. (Closed report only) 
o Number and percent of participants who received remdesivir prior to the day of 
randomization, overall and by number of days prior 
o On the day of randomization:  Number and percent of participants who received 
remdesivir prior to the investigational agent; after the investigational agent; no 
remdesivir.   
 
Treatment groups will be compared by mITT (excluding participants who did not receive any 
investigational agent/placebo), unless specified otherwise.  The treatment comparisons will be 
performed using the methods described in section 3 for binary and continuous outcomes 
(stratified CMH test for comparing percentages, and Wilcoxon rank-sum test [or quantile 
regression for comparing medians], respectively).  
 
Selected summaries will also be provided separately for the two disease severity strata. 
 
 
7 Safety Analyses 
The planned timing of safety reviews is described in section 2.  An overview of the safety data 
collection is provided in Appendix C.   
 
Analysis cohort:  Safety analyses will be carried out on participants who received a complete 
or partial infusion of the investigational agent (modified intention-to-treat [mITT]), unless 
otherwise stated. 
 
A comprehensive safety review includes: 
• Comparison of the treatment groups for the primary safety endpoint, its components, and 
analyses of secondary safety outcomes (described in this section) 
• Analyses of infusion-related reactions and symptoms, described in section 6 
• Evaluation of the “efficacy outcomes” (the pulmonary and pulmonary+ ordinal outcomes 
early in follow-up, and time to sustained recovery), which contain important safety 
information.  
 
In addition to the full DSMB reviews, more frequent, shorter safety reports may be provided to 
the DSMB, for example, weekly safety reports early in the trial. 


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19 
 
This section describes the primary safety outcome, and the analyses of AEs, SAEs, UPs, 
SUSARs, and deaths.  Comparisons between treatment groups will be stratified by study 
pharmacy and by disease severity at study entry (as described in section 3 under 
“stratification”). 
 
In order to streamline the reporting of events, it was decided that certain protocol-specified 
exempt events (PSEE) are not reported as SAEs, unless they are considered related to the 
study treatment by the investigator.  The events are listed in Appendix B; their composite is 
referred to as clinical organ failure or serious infections.  While the clinical organ failure or 
serious infection events are serious events like SAEs, these events are reported not on the 
SAE eCRF unless they are considered related to the study treatment, but are reported as study 
endpoints on various other eCRFs.  
 
The following safety and tolerability outcomes will be analyzed. If sample size permits, models 
will be stratified by disease severity and study site pharmacy, as described in section 3 under 
“stratification”, unless noted otherwise. 
 
 
• The primary safety endpoint is a composite of incident grade 3 or 4 clinical adverse 
events, SAEs, clinical organ failure or serious infections, or death through Day 5.  The 
number and proportion of participants experiencing one of these events up through Day 5 
will be tabulated, and treatment groups will be compared using a CMH test stratified by 
study site pharmacy and by disease severity at study entry.  
o Mortality will be analyzed as a key secondary outcome, see below. 
o The individual components of the composite outcome will be summarized. 
o Sensitivity analyses:  For interim analyses, while the trial is still enrolling, treatment 
groups will also be compared for time to event through Day 5 using a log-rank test, 
stratified by site pharmacy and disease severity at study entry; the HR will be 
estimated with a 95% CI using a Cox proportional hazards model, and the cumulative 
proportion of participants with events over the first 5 days in each treatment group 
will be estimated using Kaplan-Meier curves.  
 
Comment: For investigational agents that are administered as a one-time infusion, such as nMAbs, 
the composite outcome at Day 5 is the primary measure to assess safety while the trial is still 
enrolling, as described in the protocol.  This safety outcome and other safety outcomes through Day 
28 will be considered along with the ordinal outcomes at Day 5 at interim data reviews by the DSMB 
to assess futility. When a trial is unblinded after the Day 90 follow-up is completed, however, 
treatment comparisons through Day 90 provide a more comprehensive evaluation of the 
investigational agent. For the publication of the main results for a specific agent, “time to death” and 
the composite of “death, SAE, clinical organ failure, or serious infections” through Day 90 would 
usually be presented as the main safety analyses, along with other safety outcomes.  This decision 
will be agent-specific, and will be specified prior to the unblinding of the data for the agent. 
 
• All-cause mortality through follow-up will be analyzed using time-to-event methods. 
Cumulative proportions of participants who died in each treatment group will be estimated 
using Kaplan-Meier estimates, and summarized in tables (proportion of participants who 
died by Days 5, 7, 14, 28, 60, 90, month 6, 12, and 18) and figures (Kaplan-Meier curves 
with pointwise 95% CIs). Treatment groups will be compared for time to death using log-
rank tests, stratified by study site pharmacy and disease severity, and an overall HR will be 


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20 
estimated with 95% CIs using stratified Cox proportional hazards models.  Two other 
analyses will also be carried out to investigate the pattern of mortality differences, if any, 
between the treatment groups: 1) the proportional hazards assumption will be investigated; 
and 2) hazard ratios during the first 28 days of follow-up versus after 28 days will be 
estimated and compared. 
 
• Cause of death will be MedDRA coded and summarized by treatment group. 
 
• The following composite endpoints will be analyzed using time-to-event methods 
(cumulative proportions of participants with events will be estimated using Kaplan-Meier 
curves with pointwise 95% CIs; treatment groups will be compared using log-rank tests; 
numbers and percent of participants with events will be summarized by treatment group, 
and overall HRs with 95% CI will be estimated using Cox proportional hazards models): 
o Composite of incident grade 3 or 4 clinical adverse events, SAEs, clinical organ 
failure or serious infection, or death through Day 28 
 Components of the composite endpoint will be also be summarized, overall 
and by system organ class.  Proportions of participants who experienced any 
of these events by Day 28 will be compared using stratified CMH tests or 
logistic regression. 
o Composite of SAEs, clinical organ failure, serious infection, or death through Day 
28 and Day 90 
o Composite of hospital re-admission or death through 18 months 
 
• Treatment groups will be compared for the incidence of non-pulmonary events in the 
pulmonary+ ordinal outcome that are not part of the pulmonary outcome, through Day 5 and 
Day 7 (using time-to-event methods, with death as competing risk). These events are shown 
in red in Appendix A. 
 
• AEs, SAEs, and UPs will be classified by MedDRA system organ class.  AEs will be 
graded for severity according to the DAIDS AE Grading Table.  Grade 1-4 clinical AEs will 
be reported at baseline (Day 0 prior to infusion of the investigational agent), Day 0 after the 
infusion, Days 1-7, and on Days 14 and 28.   
 
The number and percent of participants with AEs will be summarized by day (Day 0 
separately prior and after the infusion) and grade, and by system organ class and grade.  
Comparisons between treatment groups will be for the proportion of participants with AEs 
of a given grade or higher (i.e., any grade, grade 2+, grade 3+, grade 4).  The treatment 
comparisons will be performed using stratified CMH tests or logistic regression.   
o For comparisons by day, the proportion of participants with any grade AEs will be 
compared for Days 0 (after infusion) through 7, and on Days 14 and 28. 
o For comparisons by grade, the proportion of participants who experienced any grade 
AEs (grade 2+ AEs, etc.) between Day 0 (after the infusion) through Day 7 will be 
compared. 
o For the comparison by system organ class, CMH tests will be performed if the 
number of participants with AEs is sufficiently large.  System organ classes may be 
split up into MedDRA preferred terms (PT) for system organ classes where the 
treatment difference is significant.  
 


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21 
Other clinically meaningful AE groupings (beyond system organ class) may be developed 
by the study team, who are blinded to the treatment effect. 
 
• In addition to any grade AEs through Day 7, grade 3 and 4 clinical AEs are being reported 
through Day 28.  The number and percent of participants with incident grade 3 or 4 AEs 
through Day 28 will be summarized, overall and by system organ class, and compared 
between treatment groups using stratified CMH tests. (A grade 3 or 4 AE is considered 
“incident” if the event was not present at baseline or increased to grade 3 or 4 from grades 
1 or 2.)  
 
To illustrate the time course, the incidence of grade 3 or 4 AEs or death through Day 28 will 
be summarized by treatment group using Kaplan-Meier estimates of the cumulative 
incidence functions (CIF).  
 
• Infusion-related reactions and symptoms during infusion or within 2 hours after infusion of 
the investigational agent or placebo, and infusion cessation prior to completion will be 
tabulated and compared between treatment groups; analyses are described in section 6. 
 
• Treatment groups will be compared for the proportion of participants who developed organ 
failure or serious infections through Day 28 and through Day 90, overall and by individual 
components, using stratified CMH tests.  Individual components of this composite 
outcome will be tabulated.  
 
• Treatment groups will be compared for incidence of organ failure, serious infections, or 
death through Day 28 and through Day 90, using Cox proportional hazards models; 
cumulative incidence functions will be estimated using Kaplan-Meier estimates. 
 
• Treatment groups will be compared for incidence of a composite of fatal and non-fatal 
cardiovascular and thromboembolic events, a subset of the organ failure outcome (items 
6b1, 6e2, 6e3, and 6f2 in Appendix B).  Treatment groups will be compared using Cox 
proportional hazards models; cumulative proportions of participants with such events will 
be estimated using Kaplan-Meier estimates. 
Comment: Death for causes other than cardiovascular or thromboembolic events is a 
competing risk.  As sensitivity analysis, the treatment groups will be compared using Aalen-
Johansen estimates for the cumulative incidence functions and Fine-Gray models to estimate 
the sub-hazard ratio (investigational agent versus placebo) for the composite outcome. If 
results differ substantially from the Cox regression and Kaplan-Meier estimates, mortality for 
reasons other than CVD and thromboembolic events will be investigated in detail. 
 
• Treatment groups will be compared for new requirements of dialysis, overall and in 
subgroups by eGFR level (<30 mL/min versus >30 mL/min at study entry), and subgroups 
by nAb status at study entry (nAb negative or positive). 
 
Motivation: In a joint analysis of data from the first three agents studied in TICO 
(bamlanivimab, sotrovimab, and BRII 196/198), the incidence of dialysis was elevated in 
the active treatment group compared with placebo (18 versus 2 events, HR=5.7 [95% CI: 
1.2-24.6]).  This safety signal was seen only among those who were nAb seronegative at 
study entry (16 events in the active arms versus 2 placebo, HR=5.0 [95% CI: 1.1 to 22.0]), 


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22 
while only 2 events occurred among those who were nAb seropositive at study entry, both 
in the active arms.  The mean time from enrollment to needing dialysis was 21 days. 
Comment: Of the 20 participants with “incident dialysis”, 2 had required dialysis prior to their 
COVID-19, and thus may be mis-classified for treatment-emergent dialysis. Both had eGFR < 
10 mL/min at study entry and thus were at high risk for dialysis, and both had been allocated to 
active treatment. 
 
Hypothesis:  The incidence of dialysis is elevated with nMAb treatment compared with 
placebo, in particular among those with eGFR < 30 mL/min, and among those who are 
nAb seronegative at study entry. 
 
• Treatment groups will be compared for mean changes in laboratory test values from 
baseline to Day 5, and for incidence of grade 3 and 4 laboratory abnormalities at Day 5 (new 
abnormality or increase in grade). Laboratory tests are conducted locally, and include serum 
creatinine, AST/SGOT or ALT/SGPT, WBC, hemoglobin, platelet counts, lymphocyte 
counts, and C-reactive protein.  Statistical methods are described in section 3. 
 
• Participants who are pregnant are not eligible for enrolment. For participants who become 
pregnant, pregnancy outcomes will be summarized. 
 
• In addition to the safety outcomes specified in the platform protocol, other targeted safety 
outcomes for specific investigational agents may be specified in appendices to the protocol.  
Analyses will be specified in the corresponding agent-specific appendix to this SAP. 
 
Listings of SAEs, clinical organ failure and serious infections, incident grade 3 and 4 AEs, UPs, 
SUSARs, and deaths (with cause of death) by treatment group will be provided at each DSMB 
meeting, with new events highlighted.  The listings will include important baseline 
characteristics, such as age, sex, and disease severity (pulmonary outcome category) at study 
entry.  
 
Further safety assessments may be considered. 
 
Corticosteroid use will be monitored; concomitant medication use is collected at baseline and 
at Day 5. 
• Corticosteroid use (any use at baseline or Day 5) will be summarized by treatment group 
and by oxygen requirement (worst category through Day 5: no supplemental oxygen,  
< 4 L/min, conventional supplemental oxygen > 4 L/min, high-flow oxygen or mechanical 
ventilation/ECMO).   
• Corticosteroid use on Day 5 will be summarized by treatment group and by oxygen 
requirement (worst category on Day 5, as above).   
 
The impact of study arm on composite safety outcomes and their components at day 5, 28 and 
90 will be assessed for subgroups defined by baseline characteristics, including SARS-CoV-2 
antibody serostatus, antigen levels, demographics, duration of symptoms at enrollment, 
baseline classification of “home”, clinical history and presentation (including disease severity 
stratum and pulmonary+ ordinal outcome at baseline).  Tests for homogeneity of the treatment 
effect across subgroups will be carried out.   
 
Outcomes and methods for subgroup analyses are described in detail in section 9.  


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8 Efficacy Analyses 
Analysis cohort: Comparisons between each investigational agent and its concurrently 
randomized (pooled) controls will be by intention-to-treat (ITT) unless otherwise stated.   
 
8.1 
Primary Efficacy Endpoint and Primary Analysis 
The primary efficacy outcome of the trial is “time from randomization to sustained recovery 
through Day 90”. Sustained recovery is defined as being discharged from the index 
hospitalization, followed by being alive and home for 14 consecutive days.   
Comment: The shortest possible time to sustained recovery is 14 days (this would require the 
patient to be discharged from the hospital on the day of randomization), and a patient would 
have to be discharged from the index hospitalization no later than Day 76 to achieve sustained 
recovery by Day 90. 
 
Definition of Home for the primary endpoint: 
According to the protocol, section 4.2, Home is defined as the level of residence or facility 
where the participant was residing prior to hospital admission leading to enrollment in this 
protocol.  
Residence or facility groupings to define home are:  
1) Independent/community dwelling with or without help, including house, apartment, 
undomiciled/homeless, shelter, or hotel  
2) Residential care facility (e.g., assisted living facility, group home, other non-medical 
institutional setting)  
3) Other healthcare facility (e.g., skilled nursing facility, acute rehab facility) 
4) Long-term acute care hospital (hospital aimed at providing intensive, longer term acute 
care services, often for more than 28 days).  
Lower (less intensive) level of residence or facility will also be considered as home. By 
definition, “home” cannot be a “short-term acute care” facility. Participants previously affiliated 
with a “long-term acute care” hospital recover when they return to the same or lower level of 
care.  
Readmission from “home” (to a higher level of care) may occur and if this occurs within 14 
days of the first discharge to “home”, then the primary endpoint will not be reached until such 
time as the participant has been at home for 14 consecutive days.  
Participants residing in a facility solely for public health or quarantine purposes will be 
considered as residing in the lowest level of required residence had these public health 
measures not been instated.   
 
Primary analysis 
The investigational agent will be compared to the (pooled) control group for time to sustained 
recovery through Day 90 by intention-to-treat, using Gray’s test with ρ=0.4  The test will be 


ACTIV-3/TICO SAP 
 
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24 
stratified by disease severity at entry and by site pharmacy (as described in section 3 under 
“stratification”). Gray’s test compares the cumulative incidence functions for sustained recovery 
between the treatment groups, taking into account the “competing risk” of death in analyzing 
sustained recovery. Gray’s test with ρ=0 is the competing-risks analogue of the log-rank test.   
 
Comments:  
1. Comparisons will be presented such that recovery rate ratios (RRR) >1 denote superiority of the 
investigational agent. 
2. For AZD7442, the primary analysis is hierarchical: the overall comparison between treatment groups 
is followed by a comparison within the subgroup of participants who are nAb seronegative at study 
entry (described in Appendix E). 
 
Analyses for the sustained recovery endpoint require methods that take into account the 
competing risk of death, as participants may die before ever achieving sustained recovery.  The 
sustained recovery outcome requires knowledge of a participant’s residence status for at least 
14 days after arriving “home” (as defined above). 
 
• The cumulative incidence functions for sustained recovery will be estimated by treatment 
group, using Aalen-Johansen estimators.3 The estimates will be plotted over time, and 
tabulated at selected time points (days 15, 21, 28, 42, 60, 75, 90). The Aalen-Johansen 
estimator for a cumulative incidence function is the analogue of the Kaplan-Meier estimator 
in the presence of competing risks.   
• The recovery rate ratio (RRR) for time to sustained recovery of the investigational agent 
versus control will be estimated, as a point estimate with a 95% CI, using the Fine-Gray 
model, stratified by disease severity at study entry and study site pharmacy.5,6  The 
corresponding p-value for RRR=1 versus the two-sided alternative will be calculated.  The 
Fine-Gray method is the competing risks equivalent of Cox proportional hazards models; 
the RRR compares the cumulative incidence rates of sustained recovery between the study 
arms and is a sub-distribution hazards ratio (sHR).   
• To aid in the interpretation of the estimated treatment difference, the median days to 
sustained recovery (through Day 90) will be estimated for the investigational agent and the 
control group.  Medians will be compared using the Wilcoxon rank sum test or quantile 
(median) regression.  Participants who die at any time up to Day 90 will be assigned 91 
days. 
 
 
Censoring:  
• Participants who are alive but have not experienced sustained recovery will be censored at 
the last date the endpoint status was ascertained (for interim analyses as well as the final 
analysis). 
• For interim monitoring, two sensitivity analyses will be performed:  
1. Follow-up for time to sustained recovery will be censored administratively at the cut-date 
for the current report or Day 90, whichever comes first, with last known endpoint status 
carried forward.  For participants who died, this type of censoring is integrated into Gray’s 
test; using a log-rank test would require carrying forward the “not recovered” status for 
participants who died, up to the administrative censoring date.   


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25 
2. Administrative censoring as described above will be applied, with the modification that 
participants who have been discharged from the hospital, were “home” at the latest date 
when residence was ascertained (but for < 14 days), and, if they have remained there, 
would have been at home for 14+ days by the cut-date, will be imputed as having 
experienced sustained recovery (achieved on day 14 at home). 
Participants who withdrew consent or were lost to follow-up will be censored at the date of 
withdrawal or the last date the endpoint status was known, respectively. 
In the first sensitivity analysis, the “not recovered” status is carried forward to the 
administrative censoring date; in the second analysis, “sustained recovery” is assumed at 
the earliest possible date.  The first analysis potentially underestimates the rate of recovery, 
whereas the second analysis overestimates the recovery rate. In all analyses for time to 
sustained recovery, death is treated as competing risk. 
 
 
Ascertainment of sustained recovery  
The date of discharge from the index hospital will be recorded.  Irrespective of the timing of the 
hospital discharge, there will be patient contact approximately every two weeks, on Days 14, 
28, 42, 60, 75, and 90, either at a scheduled clinic visit or through phone contact.  At these time 
points, a) vital status, and b) the location of the participant over time will be recorded, to assess 
whether the participant had been “at home” for 14 days. Therefore, the outcome status of 
sustained recovery will usually be ascertained within 3 weeks or less of the date the outcome 
was achieved. 
 
• To illustrate the status of the primary endpoint, the recovery status of participants will be 
described over time with the following categories (at interim reviews):  
1. At home for 14+ days (reached the primary endpoint of sustained recovery)  
Did not reach sustained recovery, and:  
2. At home, < 14 days  
3. Discharged from the hospital, but not at home  
4. Hospitalized  
5. Dead  
6. Primary endpoint status unknown.   
The proportions of participants in each of the 6 categories will be summarized over time, by 
treatment group (stacked bar graphs and tables).  In this analysis, both “sustained recovery” 
and “death” are absorbing states. 
 
 
Assessment of model assumptions 
• The trial was powered to detect an RRR of 1.25 with 90% power; this requires 843 sustained 
recoveries among the 1000 participants by Day 90.  The rate of recoveries will be monitored, 
overall and within the two disease severity strata.  Deviations of the observed distribution 
from the hypothesized distribution in the control arm will be monitored, and the impact on 
the power of the trial will be assessed.  Prior to the completion of the trial for the 
investigational agent, sample size will be re-estimated by the blinded statisticians on the 
study team, based on the pooled rate of sustained recovery. 
 


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26 
• The Fine-Gray model assumes that the sub-distribution rate ratio for sustained recovery is 
constant over time, similar to Cox proportional hazards models.  The assumption of constant 
RRR will be tested by including an interaction effect between time and treatment indicator.   
 
 
Sensitivity Analyses 
• As sensitivity analyses, the primary comparison will be repeated after excluding 
participants who did not receive any of the investigational agent/placebo (modified 
intention-to-treat).  
• Sensitivity analyses for the primary endpoint comparisons will include consideration of 
home oxygen above pre-morbid oxygen use (described in section 4.2.2 item 12 of the 
protocol).  For these sensitivity analyses, sustained recovery will be re-defined as: 
a. “Discharged to home, alive at home without use of continuous supplemental 
oxygen for an uninterrupted 14 day period” 
b. “Discharged to home, alive at home for an uninterrupted 14 day period, and no 
supplemental oxygen use a the end of the 14 day period” 
• If the RRR is not constant (test described under “assessment of model assumptions” 
above), as a sensitivity analysis, the RRR will be estimated within time periods, for 
example, Day 14-28, Day 29-60, Day 61-90. 
• Additional sensitivity analyses are described under “censoring” above. 
 
8.2 
Key Secondary Outcomes 
• Mortality is a key secondary outcome; analyses are described in section 7.  
 
• To supplement the separate analyses of time to sustained recovery and time to death, the 
two endpoints will be analyzed jointly using the “win ratio” method for the composite 
outcome of time to recovery or death.8  The win ratio will be calculated using the matched 
pairs method described in Pocock (2012).8  Pairs will be formed by ranking the participants 
in each treatment group according to a risk score, described in section 13.2, and pairing the 
participants in groups A (here referring to the investigational drug) and B (referring to 
control) with equal ranks. Details are given below.  
 
o If both treatment groups have the same number of observations, the win ratio is 
calculated as follows: 
Step 1: Calculate the risk score for all participants, and order participants by the risk 
score in each treatment group. If needed, break ties at random. Each participant forms 
a “matched pair” with the participant of equal rank order in the other treatment group. 
Step 2: For each pair, determine whether the participant in group A wins, loses, or 
neither: 
a. Compare pairs for time to death, for all pairs where one or both participants died.  If 
the participant in group A died, wins and losses are computed as follows: 
- 
If the matched participant in group B has longer follow-up, then A loses and 
B wins. 
- 
If the matched participant in group B has shorter follow-up and is alive at the 
censoring date, then neither group wins. 
Repeat for pairs where the participant in group B died. 


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27 
b. Compare remaining pairs for time to sustained recovery.   
- 
If A achieved sustained recovery, and time to sustained recovery is longer for 
B, then A wins and B loses; vice versa for B.   
- 
If A achieved sustained recovery, and B was censored without reaching 
sustained recovery before A reached sustained recovery, then neither group 
wins; vice versa for B. 
- 
Otherwise, neither group wins. 
Step 3: Calculate the win ratio as the number of wins in group A divided by the total 
number of pairs with a win or a loss in group A. Calculate the 95% CI for the win ratio 
and p-value as described in Pocock (2012).8  
o If one treatment group has more participants than the other, select |
|
A
B
n
n
−
 participants 
at random from the larger group and delete. Calculate the win ratio, 95% CI and p-value 
for the resulting matched pairs.  Repeat the random selection of observations to delete 
501 times; identify the matched pairs data set that corresponds to the median win ratio; 
the final values of the win ratio, 95% CI and p-value are those calculated from this data 
set. 
o If both treatment groups have the same number of observations, but some ranked risk 
scores are tied within a treatment group, a similar process may be used to repeat the 
random breaking of ties, with the final win ratio chosen as the median over repeated 
random tie breaks. 
 
With this approach, time to death is first used to determine the winning group (i.e., longer 
time to death), then time to sustained recovery is used to determine the winning group (i.e., 
shorter time to recovery): in this manner, the win ratio combines these conflicting outcomes 
into a composite while recognizing the importance of mortality.  
 
8.3 
Other Secondary Outcomes 
The protocol defines a number of secondary endpoints in addition to the two key endpoints 
described in section 8.2 above.  These analyses will be carried out for the final report.  Selected 
secondary endpoints may also be analyzed for interim monitoring reports, to help evaluate the 
safety and efficacy of the investigational agent.  
 
Below, the secondary outcomes from section 4.2.2 of the protocol are cited, with a short 
description of the analysis methods.  For each outcome, the treatment group comparisons will 
be stratified by disease severity at study entry and by site pharmacy, as described in section 3 
under “stratification”.   
 
• Time to discharge for the initial hospitalization.  Treatment groups will be compared using 
time-to-event methods that take into account the competing risk of death, similar to the 
analyses for time to sustained recovery described in section 8.1.  
o Hospital readmissions will be summarized using methods for recurrent events (i.e. 
those who are readmitted will re-enter the risk set).9   
• Days alive outside of a short-term acute care hospital up to day 90. For this analysis, the 
“last-off” method will be used, i.e., days from the latest hospital discharge to day 90 will 
be counted. A person who dies within 90 days will be assigned a value of 0, consistent 
with the approach taken in trials of intensive care-based interventions.  We will present 


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28 
the median days by group and test the hypothesis of no difference between arms with a 
Wilcoxon rank sum test.   
o For interim analyses, only participants who have reached Day 90 (administrative 
follow-up for those who died) will be included, to avoid bias.  Alternatively, a 
shorter time period may be used. 
• Pulmonary+ and pulmonary ordinal outcomes on Days 1-7, and the pulmonary ordinal 
outcome on Days 14 and 28.  The proportion of participants in each category of the 
pulmonary and pulmonary+ outcomes will be summarized over time (both outcomes at 
days 1-7, the pulmonary outcome also at Days 14 and 28); at each of those days, 
treatment groups will be compared using proportional odds models as described in 
section 3; the proportional odds models will be adjusted for the categories of the 
pulmonary+ outcome at baseline and for study site pharmacy.  If participants in both 
disease severity strata are enrolled, the models will also be adjusted for the interaction 
between disease severity stratum and pharmacy. 
Additionally, the ordinal outcomes will be dichotomized (“category 1”, “best 2 categories” 
through “best 5 categories”), and proportions will be compared between treatment 
groups at selected time points using logistic regression. For these analyses, the key 
dichotomized outcome considers the “best 2 categories”, which is similar to the 
“recovery” outcome in the ACTT-1 trial. 
• Clinical organ failure or serious infections, defined by development of any one or more 
of the clinical events listed in Appendix B, through Days 28 and 90. The development of 
organ failure or serious infections will be analyzed as a binary outcome, and the 
proportions of participants who developed organ failure, serious infections or death will 
be compared across arms using stratified CMH tests, overall and for individual 
components.  
• A composite of death, clinical organ failure, or serious infection through Days 28 and 90 
(see Appendix B).  Treatment groups will be compared using standard time-to-event 
methods, since death is part of the outcome and not a competing risk. (Also described 
in section 7 as safety analysis). 
• Outcomes assessed in other treatment trials of COVID-19 for hospitalized participants 
in order to facilitate cross-trial comparisons and overviews (e.g. 6- , 7-, and 8-category 
ordinal scales assessed at Days 1-7, 14 and 28; time to improvement in 1 or 2 categories 
of ordinal scale; time to best 3 categories of ordinal scale, and binary outcomes defined 
by improvement or worsening based on other ordinal outcomes).  We will try to match 
the analyses in the other trials, to get results that can be compared. These analyses will 
not be performed for interim reports to the DSMB, unless requested. 
• A composite of cardiovascular events (outcomes listed in items b1, e2 and e3 in 
Appendix B) and thromboembolic events (item f2). Time to event methods will be used 
that take into account the competing risk of death, e.g., Gray’s test to compare treatment 
groups. 
 
 


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29 
 
9 Subgroup Analyses 
As stated in the protocol (section 11.2 in version 5.1), subgroup analyses for the primary 
efficacy outcome (time to sustained recovery) and for important safety outcomes will be 
performed. The goal is to determine whether and how the treatment effect (active versus 
control) differs qualitatively across various subgroups defined at baseline, and whether there 
are safety concerns in specific subgroups.  Tests for heterogeneity of the treatment effect 
across subgroups will be carried out. 
9.1 
Outcomes, Subgroups, and Methods 
The following outcomes will be considered for subgroup analyses: 
• Time to sustained recovery (primary efficacy outcome) 
• Time to the composite of death, SAE, organ failure, or serious infections through Day 90 
• Time to death through Day 28, Day 90, and 18 months 
• The composite of grade 3 and 4 events, SAEs, clinical organ failure, serious infections, 
or death through Day 5 and Day 28 
• The Pulmonary and Pulmonary+ ordinal outcomes on Day 5 
• Time to discharge from the index hospitalization, an outcome used in other COVID-19 
trials. 
 
To support the interpretation of the subgroup analyses for composite outcomes, components 
of the composites will also be analyzed. 
 
Subgroup analyses will be performed by the following baseline factors: 
• Disease severity (categories of the pulmonary+ outcome at study entry, randomization 
stratum).  This subgroup analysis will be used at interim analyses after expansion of 
enrollment to assess if the treatment effect varies across the severity strata. 
• Duration of symptoms prior to enrollment  
• Age (18-49, 50-59, 60-69, 70-79, 80+) 
• Biological sex 
• Race/ethnicity 
• Geographic location 
• Level of residence (home) at the time COVID-19 symptoms developed 
• Baseline pulmonary status (mutually exclusive subgroups: not on supplemental oxygen, 
supplemental oxygen < 4 L/min, supplemental oxygen > 4 L/min, HFNC or NIV; invasive 
mechanical ventilation or ECMO) 
• Body mass index (BMI) 
• History of chronic conditions (cardiovascular disease, diabetes, asthma, chronic 
obstructive pulmonary disease, hypertension, chronic kidney disease, hepatic impairment, 
or cancer), and number of chronic conditions (none, 1, 2, 3 or more). 
• Plasma antibody status.  See section 9.2 below.  
• Plasma antigen level.  See section 9.2 below. 
• SARS-CoV-2 viral RNA level based on midturbinate swab. See section 9.2 below. 
• Biomarkers of inflammation and coagulation (including IL-6, hsCRP, and D-dimer) 
• Concomitant medications, including subgroups formed by: 


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30 
o Use of remdesivir prior to study entry (unless contraindicated, participants in both 
treatment groups were to receive remdesivir up to 10 days as background therapy) 
o Use of corticosteroids (4 subgroup categories, formed by the combinations of 
supplemental oxygen use [yes/no] and corticosteroid use at study entry) 
 
For the AZD7442 investigational agent, additional subgroup analyses will be carried out for 
the following subgroups defined at baseline; subgroups, hypotheses and analyses are 
described in Appendix E: 
• SARS-CoV-2 vaccination status.  Subgroups will be formed by vaccination status and by 
type of vaccine.   
• Immunosuppressive state  
• SARS-CoV-2 viral genome sequence and variant lineage.  
 
 
As a general rule, subgroup analyses will be carried out using statistical models that are 
stratified by disease severity; for time-to-event analyses, stratified Fine-Gray or Cox 
proportional hazards models will be used, while for other outcomes, models will include the 
disease severity indicator as covariate.  Global tests for heterogeneity of the treatment effect 
across subgroups will be carried out, by adding the interaction between the subgroup 
indicator and the treatment group indicator to a model that contains the treatment group 
indicator and subgroup variable as “main effects”.  In case the subgroup was formed by 
categorizing a continuous variable, the models used for the subgroup analyses will contain 
the (continuous) subgroup variable as covariate, and the interaction term in the expanded 
model will be formed between the subgroup indicator and the continuous variable. 
 
Subgroup analyses for the primary endpoint of time to sustained recovery will use the Fine-
Gray model (with death as competing risk), stratified by disease severity at study entry. Within 
each subgroup, the number and percent of recovered participants and median time to recovery 
will be calculated by treatment group, and sHRs with 95% CIs comparing the investigational 
agent versus control will be estimated. Global tests for heterogeneity of the treatment effect 
across subgroups will be carried out, by adding the interaction between the subgroup indicator 
and the treatment group indicator to the model that contains data across all subgroups.  Median 
time to recovery will be estimated using Aalen-Johansen estimators. 
 
Subgroup analyses for the composite safety endpoint at Day 5 will use logistic regression, 
stratified by disease severity at study entry.  Within each subgroup, the number and percent of 
participants with events will be calculated by treatment group, and ORs with 95% CIs comparing 
the investigational agent versus control will be estimated.  Global tests for heterogeneity of the 
treatment effect across subgroups will be carried out, by testing for interactions between the 
treatment group and the subgroup variable in an expanded model, as described above.  
Additionally, subgroup analyses for the composite safety endpoint through Day 5 will be 
conducted using Cox proportional hazards models, stratified by disease severity. 
 
Subgroup analyses for all-cause mortality and safety endpoints that are analyzed using 
time-to-event methods (through Day 5, Day 28 and through Day 90) will use stratified Cox 
proportional hazards models, since death is part of the composite endpoints and not a 
competing risk.  HRs will be estimated with 95% CIs for each subgroup, and global tests of 
heterogeneity of the treatment effect will be carried out, as described above.  The proportional 
hazards models will be stratified by disease severity. 


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31 
 
Subgroup analyses for the pulmonary and pulmonary+ ordinal outcomes on Day 5 will use 
proportional odds models, adjusted for the pulmonary or pulmonary+ category at study entry.  
In order to summarize the distributions across the categories of the ordinal outcome, the mean 
score (using 1-7 for best to worst) will be calculated by treatment group within each subgroup.  
For each subgroup, summary ORs with 95% CIs will be calculated. Global tests for 
heterogeneity of the treatment effect across subgroups will be carried out, as described above. 
 
Subgroup analyses for time to discharge from the index hospitalization will use the Fine-
Gray model (with death as competing risk), stratified by disease severity at study entry.  Similar 
analyses as described above for time to sustained recovery will be carried out. 
 
 
Additionally, subgroup analyses will be conducted for subgroups formed by a disease 
progression risk score at baseline. The construction of this risk score has been published and 
will be revisited as data on the sustained recovery endpoint accumulate for new investigational 
agents.10  
 
Unless specified otherwise (e.g., the subgroups by nAb status at study entry for AZD7442 
described in Appendix E), subgroup analyses will not be adjusted for multiple comparisons.  
Subgroup analyses will be interpreted with caution due to limited power and uncontrolled type 
I error.  
 
9.2 
Subgroups by Antibody Serostatus, Plasma Antigen, and Viral RNA 
Levels 
An addendum to the SAP for version 1 of TICO, dated 14 April 2021, described analysis 
plans for antibody, antigen, viral RNA levels and biomarkers of inflammation and coagulation 
for monoclonal antibodies studied in TICO.  This analysis plan was developed before the 
corresponding biomarker data were available.  Results for the first three investigational 
agents, bamlanivimab, sotrovimab, and BRII-196/198, were published.11  These analyses 
informed the current analysis plan for antibody, antigen, and viral RNA data.  
 
This section motivates and describes subgroup analyses by baseline antibody serostatus, 
plasma antigen levels, and viral RNA levels.  Assays are described in Appendix F.  Briefly, 
plasma samples collected at study entry and at days 1, 3 and 5 were used to measure anti-
spike receptor binding domain (RBD) neutralizing antibodies (nAbs) in a surrogate viral 
neutralization test, anti-nucleocapsid (anti-N) binding antibody levels, and semi-quantitative 
anti-Spike IgG levels. Qualitative and quantitative plasma SARS-CoV-2 N antigen was 
measured using a microbead-based immunoassay by Quanterix (Billerica, MA, USA). SARS-
CoV-2 viral RNA levels were measured from a mid-turbinate nasal swab. SARS-CoV-2 
genome sequencing and variant identification were also determined using Illumina whole 
genome sequencing of the mid-turbinate nasal swab at baseline. 
 
Statistical models for the subgroup analyses depend on the investigated endpoint, and were 
described in section 9.1. 
 
The two key subgroup hypotheses concern a differential treatment effect (active versus 
placebo) across subgroups by nAb serostatus for nMAb and antiviral treatments: 


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32 
 
Hypothesis 1:  Patients who are nAb seronegative (GenScript ELISA) at study entry will 
benefit more from the investigational agent (compared to placebo) than patients with 
higher endogenous antibody levels.  Furthermore, those who are nAb seronegative AND 
have high antigen levels will benefit more from the investigational agent compared to 
placebo than other subgroups categorized by both antibody and antigen levels. 
 
Hypothesis 2:  Patients who are nAb seronegative (Genscript) AND have high levels of RNA 
from nasal turbinate swab will benefit more from the investigational agent compared to 
placebo than other subgroups categorized by both antibody and RNA levels. 
 
To address these hypotheses, the following subgroups will be considered: 
• Participants who are nAb negative at study entry, versus nAb positive.  SARS-CoV-2 
anti-spike neutralizing antibody levels by GenScript are expressed as percent binding 
inhibition.  Specimens with levels < 30% are considered nAb negative (30% is the 
manufacturer’s cutoff for positivity), specimens with levels >30% are considered nAb 
positive.  In the TICO bamlanivimab trial, 50% of participants had endogenous nAbs 
(i.e., were nAb positive). 
• Subgroups by plasma antigen level will be formed by using the median antigen level 
at study entry as a cut-point (< median versus > median).  In the TICO bamlanivimab 
trial, the median antigen level was approximately 1000 ng/L.   
• Four subgroups formed by the bivariate combinations of nAb status (negative versus 
positive) and plasma antigen levels (< median versus ≥ median).   
• Subgroups by Viral RNA levels by qualitative RT-PCR analysis on mid-turbinate nasal 
swabs will be formed using the median RNA levels (< median vs > median).  In the 
TICO bamlanivimab trial, the median was approximately 10,000 cp/mL. 
• Four subgroups formed by the bivariate combinations of nAb status (negative versus 
positive) and viral RNA levels (< median versus >median).   
 
Subgroup analyses will be performed for the efficacy and safety outcomes listed in section 
9.1.  The key efficacy outcome for the subgroup analyses will be time to sustained recovery 
through day 90, and key safety outcomes will be the composite of death, SAEs, organ failure 
and serious infections through day 90, mortality through day 90, and the composite of death, 
SAEs, organ failure, serious infections, and grade 3 or 4 AEs through day 28.  Methods are 
described in section 9.1 above. 
Comment:  In TICO, the neutralizing antibody status is determined at a central lab; while the 
baseline antibody status is being determined on an ongoing basis while the trial is enrolling, 
there is some delay due to batch shipping and processing time.  Subgroup analyses by baseline 
nAb status will be included in interim reports to the DSMB when sufficient data are available for 
meaningful analyses. 
 
Similar hypotheses as for the nAb subgroups will be assessed for subgroups formed by the 
additional two antibody assays; these analyses will be considered exploratory:   
• Subgroups formed by anti-N antibody status (positive versus negative at study entry), 
and bivariate subgroups formed by the combinations of anti-N Ab status and plasma 
antigen or viral RNA levels.  Anti-N antibody levels are measured using a SARS-CoV-2 


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33 
antibody assay by BioRad (Hercules, CA, USA) measuring total (IgA, IgG, and IgM) 
anti-nucleoprotein. For the subgroup analyses, participants with anti-N levels <1 will be 
considered “anti-N Ab negative”, those with levels >1 will be considered “anti-N Ab 
positive”. 
Comment: Results of the BioRad anti-N antibody measurement are defined in terms of 
“specimen ratios”.  According to the manufacturer, specimen ratios less than 0.8 are 
considered negative, those with a specimen ratio between 0.8 and 1.0 are considered 
equivocal, and those > 1.0 are considered positive for the presence of anti-SARS-CoV-2 
antibodies.  For the subgroup analyses, participants with negative and equivocal anti-N Ab 
results will be combined and referred to as “anti-N negative”. 
 
• Subgroups formed by quantitative anti-Spike IgG (Quanterix) antibody status 
(positive versus negative), and bivariate subgroups formed by the combinations of anti-
Spike IgG status and plasma antigen or viral RNA levels.  Specimens with antibody 
levels < 770 ng/mL will be considered “anti-Spike IgG antibody negative”, those with 
levels > 770 ng/mL will be considered “anti-Spike IgG positive”.  
 
 
Motivation for the hypotheses: 
In the TICO bamlanivimab trial, there was no difference in time to sustained recovery by day 
90, RRR=0.99 (95% CI: 0.79 to 1.22), p=0.89.  However, the treatment effect varied by nAb 
status at baseline; among patients who were nAbs negative and positive at entry, the RRRs 
were 1.24 (95% CI: 0.90-1.70) and 0.74 (95% CI: 0.54-1.00), respectively (p=0.02 for 
differential treatment effect).  This means, there was a trend towards benefit with 
bamlanivimab among those who did not have endogenous nAbs at study entry, while time to 
sustained recovery was longer with bamlanivimab compared to placebo among those who 
already had endogenous nAbs.  Moreover, among those who were nAb negative, the 
difference between bamlanivimab and placebo was more evident if plasma antigen or nasal-
swab viral RNA were above the median levels at study entry.  Results for subgroups by anti-N 
Ab status had a similar pattern, but less pronounced. 
 
Motivation for safety analyses by nAb status:  
In an analysis of the combined data for first three nMAbs investigated in TICO (bamlanivimab, 
sotrovimab, and BRII-196/198), the risk of the composite safety outcome of death, SAE, organ 
failure, or serious infections through Day 90 was similar in the “active” versus placebo arms, 
but a safety signal was identified among participants with pre-existing endogenous neutralizing 
antibodies (nAbs).  Specifically, the risk of the composite outcome at day 90 was 25.3% in the 
(pooled) active arms compared with 27.2% in the (pooled) placebo groups, HR=0.95 (95% CI: 
0.72 to 1.25).  The treatment effect on the composite safety outcome at day 90 differed by nAb 
serostatus at baseline, however; in participants who were nAb negative at baseline, HR=0.72 
(95% CI: 0.50 to 1.02) (HR<1 favors the “active” group), and HR=1.42 (95% CI: 0.91 to 2.22) 
(favoring the placebo group) among those who were nAb positive at baseline, nominal p-value 
for interaction p=0.02. In the placebo group, the rate for the composite safety endpoint was 
higher among those who were nAb negative at baseline compared with those who were nAb 
positive (33% versus 20%, respectively); those who were nAb negative at baseline were sicker 
from COVID-19 at study entry and also had a lower chance of sustained recovery.  Mortality 
followed a similar pattern as the composite outcome; there was no evidence for a difference 
between the active versus placebo groups in the overall analyses (pooled across the three 
nMAbs), HR=1.13 (95% CI:0.67 to 1.88), while the treatment effect on mortality differed 


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34 
according to baseline nAb status, with HR=0.72 (95% CI: 0.39-1.33) (HR<1 favoring the active 
arm) among those who were nAb negative, compared to HR=3.64 (95% CI: 1.05 to 12.65) 
among those who were nAb positive. 
 
 
10 Interim Monitoring Guidelines for the DSMB 
Each investigational agent versus placebo comparison will be treated as a separate clinical 
trial; stopping boundaries will be derived to allow for multiple interim looks, but will not be 
additionally inflated to adjust for simultaneous analysis of multiple investigational agents, 
except when explicitly stated in the agent-specific protocol appendix and statistical analysis 
plan. 
The DSMB will be asked to recommend early termination or modification only when there is 
clear and substantial evidence of a treatment difference (unless a trial is stopped for futility). 
10.1 Early Assessment of Safety 
For investigational agents with minimal pre-existing data, the pace of enrollment will be initially 
restricted and the DSMB will be asked to review safety data for the first 20 to 30 participants 
before increasing the pace of enrollment. 
Subsequently, the DSMB will carry out regular reviews of safety data reports.  These reports 
will include summaries of infusion–related events, grade 1-4 AEs, SAEs, organ failure, serious 
infections, and deaths, including the primary safety outcome at Day 5, and Day 28. Event 
listings for incident grade 3 and 4 AEs, SAEs, organ failure and serious infections, SUSARs, 
UPs and deaths will be provided (events that were reported since the previous review will be 
marked).  Narratives will be provided for selected SAEs, SUSARs or UPs, particularly those 
judged related to study treatment.  Analyses are described in section 7.   
Monitoring boundary for harm: 
• Until the first 300 participants are enrolled (150 per study arm) and the early futility 
analysis is conducted, the treatment groups will also be compared for the “pulmonary” 
and “pulmonary+” ordinal outcomes at Day 5, using a proportional odds model stratified 
by study pharmacy and pulmonary+ outcome category at baseline. A Haybittle-Peto 
boundary with 2.5 standard deviation (SD) for the first 50 participants enrolled and 2.0 
SD afterwards will be used as a guideline for harm.    
• After the study population is expanded to include disease severity stratum 2, these 
analyses are performed by disease severity stratum. 
At the discretion of the DSMB, these safety reports will be prepared at a frequency they specify, 
for example, weekly.  The DSMB may also request additional data summaries. 
 


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10.2 Early Assessment of Futility 
10.2.1 Interim Monitoring Guidelines for Early Assessment of Futility 
Early in the trial, enrolment is restricted to participants in disease severity stratum 1.  When 
Day 5 data for the first (approximately) 300 participants (150 per study arm) are available, the 
DSMB will review interim data and use pre-specified guidelines for early evidence of sufficient 
activity of the investigational agent that justifies continuing enrolment for the agent and 
expanding eligibility criteria to include participants in disease severity stratum 2 as well as 
stratum 1.  Because the risk-benefit trade-off may be more complex than can be captured in 
pre-specified guidelines, decisions to terminate an agent for futility will include a broad 
assessment of the available data, and may be postponed until more data is available. 
The early futility monitoring uses two co-primary outcomes, denoted by “pulmonary” and 
“pulmonary+”, assessed on Day 5.  Both are ordered categorical outcomes with 7 categories, 
described in section 4.1 of the protocol and in Appendix A to this SAP.  The pulmonary outcome 
considers largely respiratory-related disease, similar to the ordinal outcome in the ACTT-1 
trial.12  The pulmonary+ outcome has the same categories for pulmonary complications (e.g., 
requirements for oxygen), and additionally includes extra-pulmonary outcomes such as 
thrombotic, myocardial, and cerebral complications of COVID-19.   
 
Guidelines for the early futility assessment are as follows: 
a. If the investigational agent is superior to placebo (i.e., p < 0.3 for a one-sided test) in 
both the pulmonary+ and pulmonary intermediate ordinal outcomes, then enrolment for 
the agent will expand to complete the trial. 
b. If there is insufficient evidence for superiority versus control (i.e., one-sided p>0.3) in 
each of the two outcomes, then stop randomization. 
c. If there is evidence (1-sided p < 0.3) for an association for one endpoint and not the 
other, then the agent may or may not advance depending on the risk/benefit profile 
emerging from the data at this early stage.  If the effect estimate for both outcomes is on 
the side of benefit, the preference would be towards advancing the agent and expanding 
enrollment to include disease severity stratum 2. 
The DSMB will be asked to review whether the discordance is attributable to a positive 
or negative effect on extra-pulmonary organ dysfunction (the difference in the two ordinal 
scale categories, the conditions included in pulmonary+ but not in the pulmonary 
endpoint), and whether the same ordinal outcomes assessed on other days yield similar 
results, and weigh the risk/benefit profile. For example, if there is a significant positive 
effect on the pulmonary score and the lack of significant effect on the pulmonary+ score 
is driven by a lack of difference in the milder thrombotic symptoms in category 4 of the 
pulmonary+ scale (e.g. deep venous thrombosis) and there is no evidence of any raised 
risk of thrombosis overall, the agent will advance. Conversely, if the agent is superior to 
the control group with respect to the pulmonary outcome, but clearly inferior to the control 
group with respect to the pulmonary+ outcome or has a concerning safety profile, it will 
not advance.   
Analyses of the primary efficacy endpoint, time to sustained recovery, will also be provided to 
the DSMB, as supporting information. These analyses are described in section 8.1. 
 


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36 
If available, subgroup analyses by nAb status at study entry (nAb negative or positive) will also 
be provided. 
 
10.2.2 Analyses of the Pulmonary and Pulmonary+ outcomes on Day 5 
• Treatment groups will be compared by intention to treat.  
 
• For each of the two ordinal outcomes, the number and percentage of participants in each 
of the categories on Day 5 will be tabulated, and the OR of the active versus control 
group will be estimated using a proportional odds model with indicators for the 
investigational agent group (active versus control) and for the categories of the ordinal 
pulmonary+ outcome at baseline (to adjust for baseline severity of illness).2  The model 
will be stratified by site pharmacy.   
 
The summary tables will show the adjusted summary OR with 95% CI, estimated as 
described above, as primary analysis.  In addition, the unadjusted summary OR with 
95% CI will be shown as sensitivity analysis (estimated using a proportional odds model 
without adjustment for the pulmonary+ baseline category or site pharmacy).  In the case 
that the adjusted OR differs substantially from the unadjusted OR, the reason for the 
deviation will be explored. 
 
Comments:  
o Results will be presented such that OR>1 favors the investigational agent, denoting 
higher odds of more favorable disease categories in the group randomized to 
investigational agent compared with control. 
 
o In order to avoid overestimating the proportion of participants who died, participants who 
died prior to Day 5 will only be included in the Day 5 summaries of the pulmonary and 
pulmonary+ outcomes if their time from randomization to cut-date is at least 5 days, and 
similarly for analyses on other days.  Mortality is a key secondary endpoint and will be 
summarized cumulatively as an additional analysis. 
 
 
• For the initial futility analysis, the tests comparing the investigational agent versus 
placebo will be performed using a (1-sided) type 1 error rate of 30%. This means, the 
investigational agent will be considered “superior” to the control with respect to the 
pulmonary (or pulmonary+) outcome, if the estimated summary OR is greater than 1, 
and the p-value < 0.30.   
 
The summary reports will show the estimated summary OR with 95% CI, the signed Z-
value for the test statistic comparing the treatment groups, and the one-sided p-value for 
superiority, calculated in the primary analysis (i.e., using the proportional odds model 
that is adjusted for the pulmonary+ category at baseline and stratified by site pharmacy, 
as described above).  As sensitivity analysis, these values will also be calculated using 
the unadjusted proportional odds model and included in the summary report. 
 
Comment: At the recommendation of the FDA, for monoclonal antibodies studied, patients 
requiring high-flow oxygen or mechanical ventilation (invasive or non-invasive) are not eligible 
for enrolment unless the investigational agent passes the initial futility assessment.  At that time, 
the FDA will be consulted.  This was done for AZD7442 after it passed the initial futility 


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37 
assessment and the FDA allowed expansion of enrollment.  This initial enrollment restriction 
does not apply to investigational agents other than monoclonal antibodies.   
 
If eligibility is restricted to disease severity stratum 1, adjusting the treatment comparison for the 
pulmonary+ outcome at baseline is identical to adjusting for the following categories defined by 
oxygen requirement: 
o No supplemental oxygen (pulmonary+ category 2) 
o Supplemental oxygen < 4 L/min (or < 4 L/min above premorbid requirements) 
(pulmonary+ category 3)  
o Supplemental oxygen > 4 L/min (or > 4 L/min above premorbid requirements, but not 
high-flow oxygen) (pulmonary+ category 4)  
 
• To supplement the overall summary odds ratios for the 7-category outcomes, each 
dichotomized definition of improvement that can be formulated from the components of 
the ordinal outcomes will be considered separately; for example, treatment groups will 
be compared for the proportions of participants in category 1 on Day 5, proportions in 
categories 1 or 2 (“best two categories”), in categories 1-3, etc.  Proportions will be 
tabulated, and odds ratios for active versus control groups will be estimated with 2-sided 
95% CIs using logistic regression models. These analyses need to be interpreted with 
caution, because they are not adjusted for inflation of type I error due to multiple 
comparisons. 
 
• Subgroup analyses will be carried out for the Pulmonary and Pulmonary+ outcomes on 
Day 5, to supplement the early futility analyses.  The goal is to determine whether the 
treatment effect differs across subgroups, and to aid the DSMB in considerations on 
whether there are safety concerns in specific subgroups. Principles for subgroup 
analyses are described in section 9.1; here, subgroup analyses are based on the 
proportional odds models.  In particular, heterogeneity of the treatment effect across the 
baseline pulmonary+ categories will be assessed. 
 
• After an investigational agent has passed initial futility assessment and enrollment has 
been expanded to include participants in disease severity stratum 2, treatment 
comparisons for the pulmonary and pulmonary+ outcomes on Day 5 continue, and will 
be performed separately for each of the two disease severity strata, to assess safety for 
the more severely ill participants in stratum 2. 
 
 
Missing data: Unknown outcome status for the pulmonary or pulmonary+ outcomes on 
Day 5: 
The following items describe how missing data will be treated for the primary analyses of the 
pulmonary or pulmonary+ outcomes on Day 5. As needed, these methods may be also applied 
to analyses at other time points (e.g., Day 7).   
• Interim analyses:  
o Only participants with Day 5 data for the pulmonary outcome will be included for the 
Day 5 comparisons. The number and proportion of participants with unknown 
outcome status will be summarized.   
Comment: If the cut date is less than 10 days before the data freeze date, Day 5 data for 
the ordinal outcomes are considered “missing” only for participants with at least 10 days of 
administrative follow-up. 
 


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• Final analyses after completion of the trial:  
o If Day 5 data are missing for a substantial proportion of participants (e.g., more 
than 5% of the mITT cohort), multiple imputation will be used to impute missing Day 
5 data for the pulmonary and pulmonary+ outcomes.  For the imputation, the 
following baseline covariates will be considered in addition to the indicator for 
treatment group: age, sex, country, duration of symptoms prior to enrollment, status 
of the ordinal pulmonary (or pulmonary+) outcome, and presence of comorbidities. 
Ten rounds of imputation will be used to estimate the summary odds ratio.  
o The number and proportion of participants with missing data will be reported. 
 
 
Sensitivity analyses 
• As sensitivity analyses, the treatment groups will be compared by modified intention-
to-treat (mITT) after excluding participants who did not receive any of the assigned 
investigational agent (active or control). This mITT analysis will be provided at important 
decision points, e.g., when the test statistic approaches the monitoring boundary, and 
for the final analyses after completion of the trial.  
• Treatment groups will be compared for the pulmonary and pulmonary+ outcomes on 
Days 1-7, to monitor the consistency of the treatment effect over time. 
 
Assessment of model assumptions 
• For the pulmonary and pulmonary+ outcomes at Day 5, the proportionality assumption 
of the odds ratio will be assessed (by including the interaction between the treatment 
group indicator and indicators for the Day 5 cumulative ordinal categories in the model, 
as well as the interactions between the treatment group indicator and the indicators for 
the strata by baseline pulmonary+ categories and site pharmacy; this corresponds to 
testing for separate slopes using a partial proportional odds model, see section 3 under 
“ordered categories”). If there is evidence for non-proportionality, the summary odds 
ratio in the proportional odds model will still be used to quantify the treatment effect, and 
the analyses of the dichotomized ordinal outcome categories will be used to help 
interpret the treatment effect.   
 
• The sample size of 300 (150 per study arm) is sufficient to detect a summary OR of 1.60 
for the comparison of the investigational agent versus control for each of the two ordinal 
outcomes with 95% power. The power of the tests depends on the hypothesized OR and 
the hypothesized distribution in the control group used for the sample size calculations.  
At the time of the early futility review, the deviation of the observed distribution from the 
hypothesized distribution in the control arm will be assessed, and the impact on the 
power of the trial will be estimated.  
 
10.3 Interim Monitoring Guidelines for the Primary Endpoint 
This section describes the interim monitoring guidelines that apply after the investigational 
agent has passed the initial futility assessment (after approximately 150 participants per study 
arm are enrolled). 
 
As a guideline, asymmetric boundaries will be provided to monitor the primary endpoint (time 
to sustained recovery) for overwhelming benefit or for harm.  The trial of an investigational 
agent should be stopped for efficacy only if there is clear and convincing evidence of superiority 


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39 
of the agent versus the pooled control group with respect to the primary outcome, time to 
sustained recovery. For monitoring superiority, the Lan-DeMets spending function analogue of 
the O’Brien-Fleming boundaries will be used, with a 1-sided 0.025 level of significance over 
multiple looks.  For computing the Lan-DeMets boundary, the information fraction at each 
interim analysis will be the observed total number of sustained recoveries divided by the 
planned number of sustained recoveries (N=843).   
 
The monitoring boundary for harm is asymmetric, requiring less evidence to stop for harm than 
for superiority; a Haybittle-Peto boundary with 2.5 SD for the first 50 participants enrolled and 
2.0 SD afterwards will used as a guideline for harm. With this approach, less evidence will be 
required for crossing a boundary for harm than for benefit. 
 
At each full interim review after the first 169 participants have achieved sustained recovery 
(20% information time), the following will be provided:  
• Signed square root of the value of the test statistic for Gray’s test with ρ=0, (“Z-value”) 
comparing the investigational agent versus the control group for the primary endpoint 
through Day 90, plotted over information time, and the asymmetric monitoring 
boundaries: the O’Brien-Fleming boundary with Lan-DeMets α-spending function for 
superiority (one-sided test with α=0.025), and the asymmetric, Haybittle-Peto boundary 
for harm described above. 
 
o Comment: Test statistics for the primary treatment comparison will be coded such that 
the value of the test statistic > 0 favors the investigational agent.  Thus, in case of harm, 
the Haybittle-Peto boundary with 2 SD of the normalized test statistic, is crossed if the Z-
value for the test statistic is below -2, irrespective of information time.   
 
In addition to the current value of the test statistic, the corresponding values of the test 
statistic at the previous reviews will be plotted over information time, (1) as presented at 
the previous DSMB meetings, and (2) re-calculated with current data (using the cut-
dates of the previous reports).  
 
• History of the estimated rate ratios for time to sustained recovery with 95% CIs and p-
values (by Fine-Gray’s method), and normalized test statistic values and p-values for 
Gray’s test at previous DSMB reviews, as presented, and recalculated with the current 
data (using the cut-date of the previous reports).  The latter provides information on the 
influence of a possible time lag in the ascertainment of sustained recovery. 
 
 
 
10.4 Interim Monitoring for Futility 
After investigational agents have passed the initial futility assessment (based on the pulmonary 
and pulmonary+ outcomes at Day 5, assessed for the first 300 participants), further futility 
analyses will be based on the primary outcome of time to sustained recovery.. The aim of these 
analyses will be to consider whether an investigational agent should be discontinued due to a 
low probability of achieving statistical significance for the primary endpoint of sustained 
recovery at the completion of the 90 day follow-up. 
 
Conditional power calculations for time to sustained recovery will be presented under a range 
of scenarios. In the primary futility analysis, it will be assumed that the treatment effect for the 


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40 
future, as yet unobserved follow-up will be as hypothesized in the study design (RRR=1.25). 
As secondary analysis, the treatment effect for future follow-up will be assumed to be similar to 
the observed effect. Additional scenarios may be provided. Typical futility guidelines 
recommend stopping a trial when conditional power (assuming the originally hypothesized 
treatment effect for the future follow-up) is below 10%-15%.13 
 
As a guideline, futility will first be assessed when 50% of the planned number of sustained 
recoveries have occurred, and a value of 15% will be suggested as a threshold for the 
conditional power. An additional assessment will take place at 75% of the events.  Conditional 
power will be computed using Gray’s test with ρ=0, the competing risk analogue of the log-rank 
test.14 
 
Decisions to terminate an agent for futility will include a broad assessment of the risk/benefit 
trade-off in addition to these guidelines. 
 
 
11 Data Completeness and Study Conduct 
According to the protocol, the pulmonary and pulmonary+ outcomes will be assessed on days 
0-7; the decision rules for at the initial futility assessment are based on these outcomes on 
Day 5.  The pulmonary outcome will also be assessed on Days 14 and 28.  The primary 
outcome, “time to sustained recovery”, will be assessed through Day 90.  Clinical data will be 
collected on Days 0-7, 14, 28, 60 and 90; mortality and re-hospitalizations will be assessed 
through 18 months. After hospital discharge, in-person visits are scheduled on Days 1, 3, 5, 
28, and 90, when blood is collected (plasma and serum); other visits may be conducted by 
phone (Days 7, 14, 42, 60, and 75).  The data collection schedule is included in Appendix D 
of this SAP. 
 
Data completeness and study conduct reports will be provided by treatment group (for the 
closed report) and pooled across treatment groups (for the open report).  Data summaries for 
the infusion of the investigational agent on Day 0 are described in Section 6; several of those 
reports are also relevant for monitoring study conduct and will be included in the open report 
or provided to study leadership, pooled across treatment groups. 
 
The following data summaries will be provided to assess data completeness and study 
conduct: 
• Number and percent of participants with protocol deviations, and type of protocol deviation 
• Expected and observed number (% of expected) of participants who completed visits on 
Days 1-7, 14, 28, 42, 60, 75, and 90.  
• Expected and observed number (% of expected) of participants with known outcome status 
for the pulmonary and the pulmonary+ outcomes on Day 5. 
• Ascertainment of the primary outcome: Expected and observed number (% of expected) of 
participants with known status of “time to sustained recovery” at days 28, 60, and 90.  To 
ascertain “sustained recovery”, several elements are required: vital status; the status of 
hospitalization; if discharged, the status of the residence (“home” versus other). 
• Expected and observed number (% of expected) of participants with known vital status at 
days 5, 14, 28, 60 and 90, and at months 6, 12, and 18.  


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41 
• Number and percent of participants who withdrew consent or were lost to follow-up (no 
contact and unknown vital status for 45+ days).   
• If substantial numbers of participants are lost to follow-up (e.g., more than 10% of 
participants), Kaplan-Meier estimates for the cumulative proportion of participants who are 
lost to follow-up over time, by treatment group, will be provided (closed report only). 
• Listing of participants who withdrew consent, including dates of randomization, pulmonary+ 
category at baseline, receipt of study treatment, date of withdrawal, and reason of 
withdrawal.  
• Length of follow-up: Median, IQR, range  
• Collection of specimens: Expected and observed number (% of expected) of participants 
with specimens collected as specified by the protocol, by visit.   
• Expected and observed numbers of participants with local laboratory data at baseline and 
on Day 5. 
 
A visit counts as “expected” if the visit window has closed or the data have been received.   
 
12 SARS-CoV-2 Antibody, Antigen, and Viral RNA Levels 
SARS-CoV-2 neutralizing antibody (nAb) levels, anti-N antibody levels, and plasma antigen 
levels are measured in stored plasma specimens collected at baseline (Day 0), Day 1, Day 3, 
and Day 5. SARS-CoV-2 RNA levels are determined from mid-turbinate nasal swabs, collected 
at baseline.  Assays are described in Appendix F.   
 
The statistical analyses described in this section are based on the analysis plan for antibody 
and antigen data for bamlanivimab (LY-CoV555), the Addendum to Statistical Analysis Plan 
(Version 1.0) Therapeutics for Inpatients with COVID-19 (TICO) ACTIV-3 INSIGHT 014, dated 
14 April 2021.  The current update to the SAP is further informed by the completed analyses of 
antibody, antigen, and viral RNA data for bamlanivimab, sotrovimab, and BRII 196/198, the first 
three investigational agents in TICO.11 
 
Antibody, antigen, and viral RNA levels are determined centrally, and may not be available at 
interim analyses. If data are available, key analyses will be included in interim reports. 
 
12.1 Associations of Baseline Levels with Clinical Outcomes 
For each treatment group, associations of baseline antibody status (negative versus positive), 
levels of plasma antigen, and levels of viral RNA at study entry, with time to sustained recovery 
through day 90 (primary efficacy outcome) and with important safety outcomes will be 
assessed.   
 
12.2 Plasma Antigen Levels Through Day 5 
Plasma antigen levels over time (Baseline, Days 1, 3, and 5) will be described using the 
following summary statistics, by treatment group, for all participants with follow-up data, and 
separately for participants who were nAb negative versus nAb positive at study entry: 
• Number and percent of participants with antigen levels < 3 ng/L (“antigen negative”), 
and number and percent of participants with antigen levels < median antigen levels at 


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42 
study entry (the cut-point used for subgroup analyses). 
• Side-by-side box plots of antigen levels.  Antigen levels < 3 ng/L (the lower limit of 
quantification) will be imputed as 2.9, and antigen levels will plotted on the log10-scale.  
• Geometric mean concentrations (GMC) of the antigen levels 
 
Hypothesis 1: Over the first 5 days, antigen levels will decline faster in those receiving the 
investigational agent compared to those receiving placebo.  
 
Hypothesis 2: The treatment effect (investigational agent versus placebo) on the antigen 
levels is stronger among participants who are nAb negative at study entry compared with 
those who are nAb positive at study entry.   
 
To address these hypotheses, treatment groups will be compared for the percentage of 
participants who are antigen negative (i.e., antigen levels < 3 ng/L) at Days 1, 3, and 5, overall 
(Hypothesis 1) and within subgroups (Hypothesis 2).  
• At each time point, the treatment difference will be estimated using a logistic regression 
model with the log10-transformed baseline antigen level and disease severity indicator 
as covariates, and ORs with 95% CIs and p-values will be cited.   
• In addition to the treatment comparisons at each time point (Days 1, 3, and 5), 
longitudinal GEE models will be fitted for the proportion of participants who are antigen 
negative over time, and slopes over time will be compared between treatment groups. 
The GEE models will be adjusted for baseline levels and disease severity. 
• In addition to estimating the treatment differences within each subgroup, heterogeneity 
of the treatment effect across subgroups by baseline nAb status (Hypothesis 2) will be 
assessed by testing for an interaction between the treatment group indicator and the 
subgroup indicator for baseline nAb status in an expanded GEE model. 
• Unadjusted analysis will also be performed, as sensitivity analysis. 
Comment:  Within the full study population, treatment comparison will be adjusted for nAb status at 
study entry by including the nAb status and disease severity indicators as covariates.  Within nAb 
subgroups, comparisons will be adjusted for disease severity. 
 
As secondary analyses, treatment groups will also be compared for the percentage of 
participants with antigen levels < median antigen level at study entry, as well as for the 
geometric mean concentration (GMC) of antigen levels. 
 
In order to compare treatment groups for geometric mean concentration (GMC) of antigen 
levels,  antigen levels < 3 ng/L will be imputed as 2.9 ng/L, and the treatment difference will be 
estimated as the GMC ratio for the investigational agent versus placebo.  For this analysis, 
plasma antigen levels will be log10-transformed, mean differences will be estimated with 95% 
CIs in ANCOVA models that include the treatment indicator as fixed effect and the baseline 
log10 antigen level and disease severity indicator as covariates, and the treatment difference 
will be back-transformed to the original scale to estimate the GMC ratio.  These analyses will 
be performed in the full study population, as well as within subgroups by nAb status.  
Heterogeneity of the treatment effect across subgroups will be assessed by testing for an 
interaction between treatment group and subgroup indicator in expanded ANCOVA models for 
the log10-transformed antigen levels. 
 


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12.3 Antibody Levels Through Day 5 
Levels of nAb and anti-N antibodies at baseline, Days 1, 3, and 5 will be described using the 
following summary statistics, by treatment group, for all participants with follow-up data, and 
separately within subgroups by antibody status (positive versus negative) at study entry.  To 
investigate nAb levels over time, subgroups will be formed by nAb status.  To investigate anti-
N antibody levels over time, subgroups will be formed by anti-N antibody status.  Similar 
analyses will be performed for anti-Spike IgG antibody levels.  
• Number and percent of participants with nAb percent binding ratio > 30% (“nAb 
positive”) 
• Number and percent of participants with anti-N Ab specimen ratio > 1 (“anti-N antibody 
positive”)   
• Number and percent of participants with anti-Spike IgG antibody level > 770 ng/mL 
(“anti-Spike IgG positive”) 
• Side-by-side box plots of nAb, anti-N, and anti-Spike IgG antibody levels over time   
• Median concentrations of the nAb, anti-N, and anti-Spike IgG antibody levels 
 
Comment: The manufacturer of the anti-N antibody assay (BioRad) considers samples with 
specimen ratios < 0.8 as “antibody negative”, and samples with values between 0.8 and 1 as 
“equivocal”.  For our analyses, we refer to all samples with specimen ratio < 1 as “anti-N negative”. 
 
Treatment groups will be compared for the following outcomes, overall and within subgroups 
by antibody status at study entry: 
• The percentage of participants who are nAb positive (i.e., percent binding ratio > 30%) 
at Days 1, 3, and 5, overall and within subgroups by nAb status at study entry.   
• The percentage of participants who are anti-N antibody positive (i.e., specimen ratio > 
1) at Days 1, 3, and 5, overall and within subgroups by anti-N antibody status at study 
entry.   
• The percentage of participants who are anti-Spike IgG antibody positive (i.e., antibody 
level > 770 ng/mL) at study entry at Days 1, 3, and 5, overall and within subgroups by 
anti-spike IgG antibody levels at study entry.   
Statistical methods are similar to those described for comparing antigen levels over time.   
 
In addition, at Days 1, 3, and 5, treatment groups will be compared for mean antibody levels 
(nAb, anti-N, and anti-Spike IgG levels), and the mean difference (investigational agent minus 
placebo) will be estimated with 95% CIs, overall and in subgroups by antibody status, using  
ANCOVA models that include the treatment indicator as fixed effect, and the baseline antibody 
level (continuous covariate) and disease severity indicator as covariates.  Treatment groups 
will also be compared for mean change over time using longitudinal mixed effects models, 
comparing slopes of mean antibody levels over time between treatment groups.  Heterogeneity 
of the treatment effect across subgroups will be assessed by testing for an interaction between 
treatment group and subgroup indicator in expanded longitudinal mixed effects models.   
Comment:  The analyses of mean levels of nAb and anti-N antibody levels are exploratory, as the 
assays are qualitative.  In contrast, the anti-Spike IgG antibody assay is semi-quantitative, and for 
that assay percentiles will be considered in subgroup analyses as well as classification of results 
as antibody negative/positive. 
 
 


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13 Exploratory Analyses 
13.1 Associations Between the Pulmonary and Pulmonary+ Outcomes and 
Time to Sustained Recovery 
At the early futility assessment when 300 participants (150 per study arm) are enrolled and 
have Day 5 data, estimated treatment differences in the pulmonary and pulmonary+ ordinal 
outcomes on Day 5 are used to identify promising investigational agents to continue to be 
studied with the clinical outcome of “time to sustained recovery”. In exploratory analyses, we 
will investigate whether the early pulmonary and pulmonary+ outcomes on Day 5 are an 
adequate predictor for time to sustained recovery, to re-evaluate our initial futility decision rule. 
 
• Associations between the pulmonary and pulmonary+ ordinal outcomes at Day 5 with 
time to sustained recovery will be estimated using Cox proportional hazards models, 
pooled across treatment groups.  To illustrate these associations, median time to 
sustained recovery will be estimated by category of the ordinal outcomes on Day 5, using 
Aalen-Johansen estimates of the cumulative incidence function. 
 
Ideally, the goal would be to evaluate the extent to which treatment differences in the pulmonary 
outcomes on Day 5 predict treatment differences in time to sustained recovery through Day 90.  
A detailed analysis plan will be developed at a later time. 
 
13.2 Disease Progression Risk Score 
A disease progression risk score, calculated at baseline, will be used to form subgroups of 
participants with low or high predicted risk for subgroup analyses for safety and efficacy 
outcomes, and to pair participants for the win ratio analyses described in section 8.2.   
 
The risk score for a participant is defined as the estimated probability that the Pulmonary 
outcome on Day 5 is in one of the categories 5, 6 or 7 (5=non-invasive ventilation or high-flow 
oxygen, 6=invasive ventilation, 7=death). The probability is estimated using a logistic 
regression model for the corresponding binary outcome (Pulmonary categories >5 vs <5 on 
Day 5) with the following baseline predictors: age, sex, Pulmonary category at baseline, days 
since symptom onset, NEW score, and indicator variables for the following risk factors:  
asthma/COPD, diabetes, CVD, heart failure, hypertension, HIV or other immune deficiency, 
and renal impairment. The risk score will be derived from the pooled data for the investigational 
agent/placebo groups.  Thus, the risk score will be specific to each investigational agent. 
 
 
14 Unblinding of Treatment Comparisons 
For any investigational agent, trial results will be unblinded when the pre-specified number of 
primary endpoints is reached; results may be unblinded earlier upon the recommendation of 
the DSMB if the sponsor and study leadership concur.  In this case, trial results for the 
investigational agent will be unblinded and reported with available data through 90 days of 
follow-up.  After that, data collection will continue as outlined in the data collection plan; under 
protocol version 3.0, death and re-hospitalizations will be recorded through 18 months. 
 


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While the trial is ongoing, access to any data summaries by treatment group (investigational 
agent or control groups) will be restricted to the members of the DSMB, the DSMB’s Executive 
Secretary, and the unblinded statisticians.  
 
When the trial for an investigational agent is concluded, data for the investigational agent and 
the corresponding pooled control group will be unblinded and provided to the study team.   
 
The timing of the unblinding of data for one agent may require consideration, if: 
• the control group is substantially shared with another agent for which the trial is still 
ongoing, and  
• pooled data on treatment outcomes for the ongoing trial are available to investigators. 
 
In this case, the need for a speedy unblinding has to be balanced with maintaining trial integrity 
for other agents in the platform trial, and the DSMB will be consulted as to the timing of the 
unblinding. 
 
15 Distribution of Reports 
• Open report: ACTIV-3 leadership team; DAIDS Medical Officer; selected NIAID staff; 
representatives of the companies; and all recipients of the unblinded closed report.  After 
the DSMB meeting, the open report and the DSMB summary statement will be posted 
to the trial’s web site, open to all investigators. 
• Closed report: DSMB members, Executive Secretary of the DSMB, unblinded 
statisticians.  
• Web reports (accessible by all investigators and study staff):  
o Enrollment summaries by site and over time (updated daily) 
o Baseline characteristics 
o Selected summary measures on data quality and study conduct (pooled across 
treatment groups). 
• Additionally, selected summary measures on study conduct will be provided to study 
leadership upon request (pooled across treatment groups). 


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16 References 
 
1. 
Whitehead J. Sample size calculations for ordered categorical data. Stat Med 
1993;12:2257-71. 
2. 
McCullagh P. Regression Models for Ordinal Data. Journal of the Royal Statistical 
Society Series B (Methodological) 1980;42:109-42. 
3. 
Aalen OO, Johansen S. An Empirical Transition Matrix for Non-Homogeneous 
Markov Chains Based on Censored Observations. Scandinavian Journal of Statistics 
1978;5:141-50. 
4. 
Gray RJ. A Class of K-Sample Tests for Comparing the Cumulative Incidence of a 
Competing Risk. Annals of Statistics 1988;16:1141-54. 
5. 
Fine JP, Gray RJ. A Proportional Hazards Model for the Subdistribution of a 
Competing Risk. J Am Stat Assoc 1999;94:496-509. 
6. 
Zhou B, Latouche A, Rocha V, Fine J. Competing risks regression for stratified data. 
Biometrics 2011;67:661-70. 
7. 
Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric 
Adverse Events, Corrected Version 2.1. 2017. (Accessed August 14, 2020, at 
https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf.) 
8. 
Pocock SJ, Ariti CA, Collier TJ, Wang D. The win ratio: a new approach to the analysis 
of composite endpoints in clinical trials based on clinical priorities. Eur Heart J 2012;33:176-
82. 
9. 
Wei LJ, Lin DY, Weissfeld L. Regression-Analysis of Multivariate Incomplete Failure 
Time Data by Modeling Marginal Distributions. J Am Stat Assoc 1989;84:1065-73. 
10. 
ACTIV-3 TICO LY-CoV555 Study Group, Lundgren JD, Grund B, et al. A Neutralizing 
Monoclonal Antibody for Hospitalized Patients with Covid-19. N Engl J Med 2021;384:905-
14. 
11. 
Lundgren JD, Grund B, Barkauskas CE, et al. Responses to a Neutralizing 
Monoclonal Antibody for Hospitalized Patients with COVID-19 According to Baseline 
Antibody and Antigen Levels  Annals of Internal Medicine 2021. 
12. 
Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the Treatment of Covid-19 
- Preliminary Report. N Engl J Med 2020. 
13. 
Proschan MA, Lan KKG, Wittes JT. Statistical monitoring of clinical trials : a unified 
approach. New York, NY: Springer; 2006. 
14. 
Logan BR, Zhang MJ. The use of group sequential designs with common competing 
risks tests. Stat Med 2013;32:899-913. 
15. 
Holm S. A simple sequentially rejective multiple test procedure. Scandinavian Journal 
of Statistics 1979;6:65-70. 
 


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Appendix A. Definition of the Pulmonary and Pulmonary+ 
ordered categorical outcomes 
 
The Pulmonary categorical outcome is primarily defined based on oxygen requirements. The 
categories of the Pulmonary+ outcome are similar, except that categories 4 and 5 also capture 
selected extra-pulmonary complications, highlighted in red below. 
 
Pulmonary outcome 
Pulmonary+ outcome 
1. Can independently undertake usual 
activities with minimal or no symptoms 
 
1. Can independently undertake usual 
activities with minimal or no symptoms 
 
2. Symptomatic and currently unable to 
independently undertake usual activities 
but no need of supplemental oxygen (or 
not above premorbid requirements) 
2. Symptomatic and currently unable to 
independently undertake usual activities 
but no need of supplemental oxygen (or 
not above premorbid requirements) 
3. Supplemental oxygen (<4 liters/min, or 
<4 liters/min above premorbid 
requirements) 
3. Supplemental oxygen (<4 liters/min, or 
<4 liters/min above premorbid 
requirements) 
4. Supplemental oxygen (≥4 liters/min, or 
≥4 liters/min above premorbid 
requirements, but not high-flow oxygen) 
4. Supplemental oxygen (≥4 liters/min, or 
≥4 liters/min above premorbid 
requirements, but not high-flow oxygen) 
or any of the following:  stroke (NIH 
Stroke Scale [NIHSS] ≤14), meningitis, 
encephalitis, myelitis, myocardial 
infarction, myocarditis, pericarditis, new 
onset CHF NYHA class III or IV or 
worsening to class III or IV, arterial or 
deep venous thromboembolic events   
5. Non-invasive ventilation or high-flow 
oxygen 
5. Non-invasive ventilation or high-flow 
oxygen, or signs and symptoms of an 
acute stroke (NIHSS >14) 
6. Invasive ventilation, extracorporeal 
membrane oxygenation (ECMO), 
mechanical circulatory support, or new 
receipt of renal replacement therapy 
6. Invasive ventilation, ECMO, mechanical 
circulatory support, new receipt of renal 
replacement therapy, or vasopressor 
therapy 
7. Death 
7. Death 
 
The term “usual activities”, in categories 1 and 2 for both outcomes, refers to activities of daily 
living that the participant was able to undertake prior to the current illness. 
 
 
 


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Appendix B. Definition of Clinical Organ Failure and Serious 
Infection 
 
According to the protocol, section 4.2.2., clinical organ failure is defined by development of any 
one or more of the following clinical events (see PIM for criteria for what constitutes each of 
these conditions):  
 
a. Respiratory dysfunction: 
1. Respiratory failure defined as receipt of high flow nasal oxygen, non-invasive 
ventilation, invasive mechanical ventilation, or ECMO 
 
b. Cardiac and vascular dysfunction: 
1. Myocardial infarction (MI) 
2. Myocarditis or pericarditis  
3. Congestive heart failure (CHF): new onset NYHA class III or IV, or worsening to 
class III or IV 
4. Hypotension requiring institution of vasopressor therapy 
 
c. Renal dysfunction: 
1. New requirement for renal replacement therapy  
 
d. Hepatic dysfunction: 
1. Hepatic decompensation 
 
e. Neurological dysfunction 
1. Acute delirium 
2. Cerebrovascular event (stroke, cerebrovascular accident [CVA]) 
3. Transient ischemic events (i.e., CVA symptomatology resolving <24 hrs) 
4. Encephalitis, meningitis or myelitis 
 
f. Haematological dysfunction: 
1. Disseminated intravascular coagulation 
2. New arterial or venous thromboembolic events, including pulmonary embolism 
and deep vein thrombosis 
3. Major bleeding events (>2 units of blood within 24 hours, bleeding at a critical site 
[intracranial, intraspinal, intraocular, pericardial, intraarticular, intramuscular with 
compartment syndrome, or retroperitoneal], or fatal bleeding). 
 
Serious infection is defined as: 
g. Serious infection: 
1. Intercurrent, at least probable, documented serious disease caused by an infection 
other than SARS-CoV-2, requiring antimicrobial administration and care within an 
acute-care hospital.  
 
 


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Appendix C. Safety Data Collection 
 
Table C-1. Overview of Safety Data Collection (protocol version 3, section 10).* 
 
Infusion 
+2 hrs 
 Days 0-7 
Day 14 
Day 28 
Day 90 
Months 
6, 12, 
and 18 
Infusion-related reactions 
and symptoms 
X 
 
 
 
 
 
Clinical AEs of any grade 
severity 
 
X 
X 
X 
 
 
Grade 3 and 4 clinical AEs 
from Day 7 through Day 281 
 
 
X 
X 
 
 
Targeted laboratory 
abnormalities of any grade 
 
X 
(Day 5) 
 
 
 
 
Hospital admissions and 
deaths 
 
Collected through Month 18 
Targeted clinical events 
collected as study 
endpoints2 
Collected through Day 90 
 
SAEs not exempt from 
reporting (i.e., not 
considered a protocol 
specified exempt event)2 
Collected through Day 90 
 
Any SAE related to study 
intervention 
Collected through Day 90 
 
Unanticipated problems 
Collected through Day 90 
 
 
1 Grade 3 and 4 clinical AEs on Days 1-7 are reported each day; those occurring between Days 8 and 
14 are reported at the Day 14 visit, and those occurring between Days 15 and 28 are reported at the 
Day 28 visit.  
2 Protocol-specified exempt serious events (PSEE); these events are listed below.  See section 10.2.5 
of the TICO study protocol and the PIM for information on PSEE. 
 
* In protocol version 2.0, the data collection is identical, except that hospital re-admissions 
and deaths are collected through Month 12 only. 
 


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Protocol-specified exempt events (protocol section 10.2.5) 
The following events are protocol-specified exempt events.  They are not reported as AEs or 
SAEs, unless the investigator considered that there was a reasonable possibility that the 
study intervention (blinded investigational agent/ placebo or study-supplied SOC treatment) 
caused the event. 
• Death 
• Stroke 
• Meningitis 
• Encephalitis 
• Myelitis 
• Myocardial infarction 
• Myocarditis 
• Pericarditis 
• New onset of worsening of CHF (NYHA class 3 or 4) 
• Arterial or deep vein thromboembolic events 
• Respiratory failure defined as receipt of high flow nasal oxygen, non-invasive 
ventilation, invasive mechanical ventilation or ECMO 
• Hypotension requiring vasopressor therapy 
• Renal dysfunction requiring renal replacement therapy 
• Hepatic decompensation 
• Neurologic dysfunction, including acute delirium and transient ischemic events 
• Disseminated intravascular coagulation 
• Major bleeding events 
• Serious infections 
 
 
 


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Appendix D. Schedule of Assessments 
 
Table D-1. Schedule of Assessments (protocol version 5.1, Appendix B).* 
 
Screen 
or Day 0 
Day 
0 
Follow-up Study Day; shaded columns denote in-person visits 
Day 
−1/01 
0 
1 
2 
3 
4 
5 
6 
7 
14 
28 
42 
60 
75 
90 
6M 
12M 
18M 
Acceptable deviation 
from day 
0 
0 
0 
0 
0 
0 
0 
0 
+1 
+2 
+3 
+3 
+5 
+5 +10 ±14 
±14 
±14 
ELIGIBILITY & BASELINE 
DATA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline medical (incl. 
duration of COVID-19) and 
social history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline medications 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Symptom-directed  
physical exam by the 
clinical team 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review SARS-CoV-2 test 
results 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Local laboratory testing 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test or 
other documentation of 
pregnancy status 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY INTERVENTION 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug/Placebo 
Administration 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assess infusion completion 
and adverse reactions 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY PROCEDURES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical assessment for 
pulmonary ordinal outcome 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Clinical assessment for 
pulmonary+ ordinal 
outcome 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Vital signs for NEW score 
assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Respiratory function scale 
assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hospitalization status 
 
 
 
 
X 
 
X 
 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
Changes in 
residence/facility 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
Interim medical history 
 
 
 
 
 
 
 
 
X 
X 
X 
 
X 
 
X 
 
 
 
Interim medications 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
Clinical AEs of any grade 
on days indicated 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Clinical AEs reaching grade 
3 or 4 severity through Day 
28 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
Research sample storage 
(plasma and serum)2  
X 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 Midturbinate swab for 
central SARS-CoV-2 viral 
load testing2 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAEs and unanticipated 
problems 
 
 
Report as they occur 
 
 
 
Deaths 
 
 
Report as they occur 
Hospitalization Summary 
 
 
Report upon hospital discharge 
 
 
 
Hospital Readmissions 
 
 
Report upon hospital discharge 


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1 Screening must be performed within 24 hours of randomization. 
  
2 Blood draw and swab collection in some cases can be obtained after randomization but before the infusion.  If it 
is not possible to do an in-person on Day 3 or Day 5, the blood draws may be done one day earlier or one day 
later (but the participant should be telephoned to record the clinical data on the indicated study day).   
 
* In addition, in protocol versions 3.0 and higher, pregnancy outcomes will be collected for 
female participants who become pregnant during the study.  
 
 
 


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Appendix E. Modifications to the Statistical Analysis Plan for 
AZD7442 
 
 
Investigational Agent 
Appendix H4 (version 2 dated 09 April 2021) of the TICO protocol describes agent-specific 
protocol elements for AZD7442 by AstraZeneca. AZD7442 is comprised of two immunoglobulin 
G (IgG)-1 kappa monoclonal antibodies (AZD8895 and AZD1061) which neutralize SARS-CoV-
2 by binding to unique, non-overlapping epitopes on the RBD of the viral spike protein.   
 
E-1 Analysis population  
Treatment comparisons for efficacy and safety outcomes will be by modified intention-to-treat 
(mITT). The mITT analysis is restricted to participants who received a complete or partial 
infusion of the investigational agent/placebo; participants who did not receive any of the 
investigational agent/placebo are excluded.  The TICO platform protocol specifies ITT for the 
efficacy analyses “unless otherwise stated”, and mITT for safety analyses. 
 
Justification for changing the study population to mITT for efficacy analyses:  In the TICO trial 
of AZD7442, 1455 patients were randomized (ITT population).  In preliminary, near final data, 
of the 1455 randomized participants, 1417 were infused the blinded AZD7442 or placebo.  Of 
the remaining 38 participants, 35 had withdrawn consent prior to infusion (no follow-up data 
after Day 0 were collected for 34 of the 35), and information was pending on 3 participants as 
of December 28, 2021.  Because the treatment assignment was blinded, the reasons for not 
receiving an infusion are independent from the treatment assignment.  Therefore, the risk of 
bias due to restricting analyses to the mITT cohort is low.  Moreover, follow-up data are not 
available for most of the participants who did not receive an infusion.  With this approach, the 
risk and benefits of AZD7442 will be evaluated in the same population. 
Comment: Investigators were unblinded to summaries of the infusion status of participants, 
pooled across treatment groups. These analyses were included in the open DSMB reports. 
 
E-2 Increase in Target Number of Primary Events and Sample Size Beyond 
That Specified in the Master Protocol  
The event target and sample size for AZD7442 was increased on August 19, 2021 with a letter 
of amendment.  This increase was based on the results of other trials (the RECOVERY trial 
and the ACTIV-3/TICO trials of bamlanivimab, VIR-7831 and BRII-196/198) and utilized pooled 
outcome data for AZD7442 to estimate the revised sample size.  The new event target for the 
AZD7442 trial was 1,228.  It was estimated that extending enrolment to September 30, 2021 
would achieve a sample size of 1,500 participants, which was estimated to be required to 
achieve the event target of 1,228.  With this event target a RRR of 1.20 could be detected with 
90% power at the 0.05 (2-sided) level of significance.  It also provided 90% power to detect a 
RRR of 1.28 for the subgroup of participants who are seronegative for neutralizing SARS-CoV-
2 antibodies (nAb) at study entry (see Letter of Amendment of 19 August 2021). 
 


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E-3 Power Estimation Prior to Unblinding 
On December 28, 2021, prior to unblinding any treatment comparisons for the trial of AZD7442, 
power was re-assessed based on updated pooled (AZD7442 and placebo groups combined) 
primary endpoint results.  Pooled primary outcome data on December 28, 2021 are given in 
the table below. 
 
Table E-1. Recovery status of participants in the AZD7442 trial as of December 28, 2021 
 
1455 Participants Randomized 
 
1417 Infused and 38 not infused (35 withdrew consent) 
 
nAb 
negative 
nAb 
positive 
Specimen 
not yet 
analyzed 
Specimen 
not available 
TOTAL 
Recovery status through Day 
90 
N=616 
N=657 
N=107 
N=37 
N=1417 
Withdrew prior to recovery 
2 
4 
0 
0 
6 
Day 90 window closed and 
recovery status unknown 
17 
5 
0 
1 
23 
Day 90 window not yet closed* 
and recovery status unknown 
0 
1 
3 
0 
4 
 
 
 
 
 
 
Achieved sustained recovery 
508 
586 
76 
25 
1195 
Home < 14 days 
7 
5 
0 
0 
12 
Discharged from hospital, but 
not home 
9 
3 
0 
2 
14 
Hospitalized 
12 
10 
2 
1 
25 
Died before recovery 
61 
43 
26 
8 
138 
* The Day 90 window extends to Day 100. 
 
The mITT study population included 1417 participants. At this time, most of the 90-day follow-
up was completed.  The last patient was randomized on September 30, 2021 and the visit 
window for the Day 90 visit extends to 100 days (January 8, 2022).   
 
Overall, the number of primary events was 1,195, 33 events less than the target of 1,228.  As 
the table below indicates, this does not have a material effect on power. 
   
Table E-2. Power estimates in the full study population: Recovery rate ratios (RRR) that can be detected 
with 80-90% power and 0.05 (2-sided) significance level, assuming 1195 sustained recovery events 
pooled across treatment groups 
Power 
RRR 
0.90 
1.206 
0.85 
1.189 
0.80 
1.176 
 
Table E-3 below summarizes power estimates for the subgroup of participants who were nAb-
negative at study entry.  This subgroup is currently 48% of those for whom the baseline nAb 
status was determined.  We anticipate results for 107 additional patients in January 2022.  The 
effect sizes (recovery rate ratio [RRR]) that can be detected with 90%, 85%, and 80% power 
for different estimates of the final number of primary events for the nAb-negative subgroup are 
summarized below; as of December 28, 2021, 508 participants in this subgroup had achieved 
sustained recovery, and 76 participants among those for whom the nAb status is not yet known. 


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Table E-3. Power estimates in the nAb negative subgroup: RRRs that can be detected with 80-90% 
power and 0.05 (2-sided) significance level, assuming 542-562 sustained recovery events  
Power 
RRR (542 events) 
RRR (552 events) 
RRR (562 events) 
0.90 
1.321 
1.318 
1.315 
0.85 
1.294 
1.291 
1.288 
0.80 
1.272 
1.269 
1.267 
 
In preliminary data in August 2021, 56% of participants were nAb-negative.  With the more 
complete baseline data on December 28, 2021, this percentage is estimated as 48%. 
 
The power estimates given in Tables E-2 and E-3, the decline in the estimated percentage of 
participants who were nAb-negative, and further consideration of  the relative importance of the 
treatment comparisons in the full study cohort as well as the in the nAb-negative subgroup led 
to the plan to test both hypotheses (benefit of AZD7442 in the full study population, and benefit 
of AZD7442 in the subgroup of nAb-negative participants) simultaneously while controlling the 
family-wise type 1 error rate.  This is described in section E-4 below. 
 
E-4 Primary Analysis: Simultaneous Tests in the Overall Cohort and in the 
nAb-Negative Subgroup, Method and Power Considerations 
 
Primary analysis: Two hypotheses will be tested using mITT analyses.  The family-wise type 1 
error rate will be controlled at the 0.05 (2-sided) level of significance.  The two primary 
comparisons are: 
 
• AZD7442 versus placebo for time to sustained recovery in the overall mITT cohort; and 
• AZD7442 versus placebo for time to sustained recovery in the subgroup of participants 
in the mITT cohort who were nAb-negative at study entry. 
 
The Holm method will be used to control the family-wise error rate.15  With this approach, the 
two primary comparisons are considered on an equal footing (i.e., co-primary hypotheses).  
With the Holm method, p-values for the 2 hypotheses will be ordered from lowest to highest.  
The lower of the two p-values will be compared with a 0.025 (0.05/2) 2-sided level of 
significance.  If that test result is significant (i.e., p<0.025), the second p-value will be 
compared with a 0.05 (2-sided) level of significance.  This method controls the family-wise 
type 1 error rate for both comparisons at 0.05 (2-sided). 
 
Power was estimated considering the estimated number of participants with a primary 
endpoint of sustained recovery for the nAb negative and positive subgroups.  Based on the 
results of recently reported trials mentioned in section E-2, we expect the recovery rate ratio 
(RRR) for AZD7442 versus placebo to be greater (more favorable for AZD7442 than placebo) 
for the nAb-negative subgroup than for the nAb-positive subgroup. 
 
The following assumptions were made for the power estimates given in the figure and table 
below; projections for event numbers are based on Table E-1: 
• Sustained recovery by Day 90 will be experienced by an estimated 545 participants in 
the nAb-negative subgroup. This projection includes the 508 participants who have had 
experienced the endpoint by December 28, 2021, and 37 additional participants who 


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56 
experienced a sustained recovery endpoint (either nAb negative participants with 
unknown recovery status or participants for whom nAb status at baseline had not yet 
been determined on December 28, 2021). 
• In the overall cohort, 1202 participants will achieve sustained recovery; this projection 
includes the 1195 participants who had achieved sustained recovery as of December 
28, 2021, plus a small proportion of participants with as yet unknown outcome status.  
• 48% of the study participants would be nAb-negative at study entry 
 
With 545 primary events in the nAb-negative subgroup, power is 0.90 to detect a RRR=1.32 
at the 0.05 (2-sided) level of significance.  With the above assumptions, and assuming 
RRR=1.32 for the nAb-negative subgroup, power for the comparison of AZD7442 and 
placebo in the overall cohort and within the nAb-negative subgroup was estimated for a range 
of values of the RRR for the nAb-positive subgroup.  In Table E-4 below, the first column 
shows the assumed RRR among the nAb-positive subgroup, the second column shows the 
corresponding overall RRR (assuming RRR=1.32 among the nAb-negative subgroup), and 
columns 3 and 4 show the estimated power to detect RRR=1.32 among the nAb-negative 
subgroup and the computed RRR (column 2) in the overall study cohort, respectively, using 
Holm’s method to control the simultaneous Type 1 error to 0.05. For example, assuming 
RRR=1.0 among the nAb-positive subgroup and RRR=1.32 among the nAb-negative 
subgroup, the overall RRR would be 1.14, and the treatment difference between AZD7442 
and placebo would be detected with power of 0.858 in the nAb-negative subgroup, and with 
power of 0.63 in the overall study population.   
Comment: In a single test with 5% significance level, power was estimated at 90% to detect 
RRR=1.32 in the nAb-negative subgroup; assuming RRR=1.14 in the full study cohort, the power 
in the nAb-negative subgroup is decreased to 86% with Holm’s procedure because the p-value for 
the nAb-negative subgroup would more likely be the smaller of the two p-values, and thus would 
be compared to 0.025 instead of 0.05. 
 
Table E-4. Power to detect a treatment difference in sustained recovery between AZD7442 and 
placebo within the nAb-negative subgroup and overall, assuming an RRR of 1.32 among the nAb-
negative subgroup and a range of RRRs between 1.30 and 0.95 for the nAb-positive subgroup, and 
using Holm’s method to control the familywise Type 1 error. 
Assumed RRR 
Power using Holm’s method 
Among the nAb-
positive subgroup 
Overall* 
To detect RRR=1.32 
among the nAb-negative 
subgroup 
To detect the 
overall RRR 
(column 2) 
1.30 
1.31 
0.900 
0.994 
1.25 
1.28 
0.899 
0.985 
1.20 
1.26 
0.897 
0.967 
1.15 
1.23 
0.892 
0.933 
1.10 
1.20 
0.884 
0.873 
1.05 
1.17 
0.871 
0.774 
1.00 
1.14 
0.858 
0.630 
0.95 
1.11 
0.848 
0.453 
* RRR for sustained recovery in the overall study population, assuming RRR=1.32 among the nAb-negative 
subgroup and the RRR in column 1 among the nAb-positive subgroup 
 
Figure E-1 below shows the data from Table E-4 in a graph. The power of Holm’s testing 
procedure to detect a treatment effect is plotted versus a range of assumed RRRs among the 
nAb-positive participants (horizontal axis, column 1 of Table E-4); the dashed line shows the 


ACTIV-3/TICO SAP 
 
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57 
power to detect RRR=1.32 for the nAb-negative subgroup (column 3 in Table E-4), and the 
solid line shows the power to detect the corresponding treatment effect in the overall cohort 
(column 4 in Table E-4).   
 
Figure E-1. Estimated power to detect a treatment difference in sustained recovery between AZD7442 
and placebo in the overall study population (solid line) and within the subgroup of nAb-negative 
participants (dashed line), for a range of RRRs among nAb-positive participants and assuming 
RRR=1.32 for nAb-negative participants. 
 
 
 
E-5 Data Analysis Considerations for the Two Co-Primary Hypotheses 
The analysis of the primary endpoint will follow the methods described in sections 3 
(stratification) and 8.1 (Gray’s test for the primary comparisons and Fine-Gray models to 
estimate RRRs and 95% CIs, stratified by study site pharmacy).  The following additional 
considerations apply to the AZD7442 study: 
 
• The same stratification will be used for testing both co-primary hypotheses.  Using 
blinded baseline data available on January 21, 2022, the strata were determined as 
follows. To avoid sparse strata, study pharmacies were pooled following the principles 
described in section 3.  Seven strata, each including at least 20 participants in the nAb-
negative subgroup, were formed using large sites where possible and combining small 
sites with each other or with a larger site where that was not.  In addition, some very 
small sites that only enrolled participants who were nAb-positive were combined with 
one of the 7 strata.  For the 99 sites that enrolled at least one participant, the 7 strata 
will be defined as follows: 1) 3 strata for the 3 U.S. sites that enrolled at least 20 nAb 
negative participants; 2) 1 stratum for all other U.S. sites; 3) 1 stratum for sites in 
Denmark, Greece, the United Kingdom, and Singapore; 4) 1 stratum for sites in Spain; 
and 5) 1 stratum for sites in Uganda. 
0.400
0.600
0.800
1.000
0.400 0.500 0.600 0.700 0.800 0.900 1.000
Power
0.90
1.00
1.10
1.20
1.30
0.90
1.00
1.10
1.20
1.30
RRR (nAb-positives)
nAb-negatives
Overall


ACTIV-3/TICO SAP 
 
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58 
• No participants were randomized in disease severity stratum 2 (defined in section 1.2; 
in particular, stratum 2 included participants requiring invasive mechanical ventilation 
or ECMO).  Therefore, the originally planned stratification of analyses by disease 
severity stratum can’t be carried out.  Early in the trial, participants requiring non-
invasive ventilation (NIV) or oxygen from a high-flow nasal cannula (HFNC) also were 
excluded. Beginning July 19, 2021, eligibility was expanded to include participants 
requiring NIV or HFNC. Considering this expansion of eligibility criteria, a sensitivity 
analysis will be carried out using a Fine-Gray model that only stratifies by oxygen 
requirements at baseline.  A sensitivity analysis without any stratification will also be 
carried out.  
• A subgroup analysis by calendar date of enrollment will also be carried out (2 
subgroups: participants enrolled before July 19, 2021 and at or after July 19, 2021). 
The cut-point was chosen because on July 19, 2021, the first patient who required 
HFNC or NIV was enrolled after eligibility was expanded to include such patients. 
 
If the primary comparison of AZD7442 versus placebo for time to sustained recovery shows a 
significant treatment effect in nAb-negative participants, then major safety, efficacy, and 
subgroup analyses will be conducted for the nAb-negative participants as well as for the full 
study cohort. 
 
E-6 Interim Monitoring Guidelines 
There are 2 changes to the interim monitoring guidelines described in Section 10.3 of this 
SAP: 
• The information fraction for the Lan-DeMets spending function will be based on the 
target of 1,228 sustained recoveries, not 843. 
• As part of the broad assessment of risk/benefit, the DSMB should consider the findings 
in nAb negative and nAb positive subgroups.  For participants who are nAb negative, 
greater benefit with the investigational agent is hypothesized.   
Comment: The antibody status at baseline was unknown for a large proportion of 
participants until late in the trial.  Therefore, separate interim monitoring boundaries were 
not planned for this subgroup. 
 
E-7 Subgroup Analyses by Vaccine and Immunosuppression Status 
The hypotheses in this subsection were developed for the comparison of AZD7442 (a long-
acting antibody combination) versus placebo, but apply more generally to monoclonal 
antibodies and antiviral agents.  The outcomes, and the specific statistical models used for the 
subgroup analyses for each of the outcomes were described in Section 9.1.   
 
The subgroup analyses by vaccination status and immunosuppression status address the 
following hypothesis: 
Hypothesis 1: AZD7442 will have greater efficacy in non-vaccinated, compared to fully or 
partially vaccinated, study participants.  
 


ACTIV-3/TICO SAP 
 
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59 
Hypothesis 2: AZD7442 will have greater efficacy in immunosuppressed, compared to not 
immunosuppressed, study participants. 
 
For vaccination status, three mutually exclusive subgroups will be formed according to the 
current CDC definition of vaccination status: 
a. Fully-vaccinated: Subjects who have onset of acute symptoms of SARS-CoV-2 
infection at least 14 days after receiving: 
i. the second dose of a two-dose SARS-CoV-2 vaccine series, OR  
ii. a single dose of the Janssen (J&J) SARS-CoV-2 vaccine 
 
b. Partially-vaccinated: Subjects who have:  
i. received only one dose of two-dose SARS-CoV-2 vaccine series, OR 
ii. onset of acute symptoms of SARS-CoV-2 infection prior to 14 day following the 
administration of the second dose of a two-dose SARS-CoV-2 vaccine series or 
a single dose of the Janssen (J&J) SARS-CoV-2 vaccine 
 
c. Non-vaccinated: Never received any dose of a SARS-CoV-2 vaccine.  
Comment: Information about booster doses is not available. 
 
Subgroup analyses by immunosuppressive status will consider three mutually exclusive 
subgroups, as defined below:  
• Immunosuppressed, defined as any of the following:  
o Receiving antirejection medication (after solid or stem cell transplant) 
o Receiving biologic medicine to treat autoimmune disease or cancer, excluding IL-1 
inhibitors, IL-6 inhibitors, Janus kinase inhibitors, and TNF inhibitors 
o HIV or other immunosuppressive condition 
• Receiving any of the following immunomodulators: IL-1 inhibitors, IL-6 inhibitors, Janus 
kinase inhibitors, or TNF inhibitors, but not “immunosuppressed” as defined above 
• None of the above 
 
Data from TICO and other studies have shown that baseline vaccination status and 
immunosuppressive status are correlated; in particular, in our study population of patients 
who are hospitalized with COVID-19 pneumonia, the proportion of immunosuppressed 
patients is higher among those who are fully vaccinated compared with those who are 
unvaccinated.  In addition, studies have found that the decline over time in immunity varies 
between vaccines.  In order to address potential confounding between vaccination status, 
immunosuppressive status, and type of vaccine, models for subgroup analyses by vaccination 
status will include immunosuppressive status and type of vaccine (mRNA versus other) as 
covariates.  Similarly, models for subgroup analyses by immunosuppressive status will 
include vaccination status and type of vaccine as covariates.   
 
 
The following exploratory analyses will be conducted if the sample size is large enough for 
meaningful analyses:  
• Subgroups will also be formed by combinations of vaccination status and vaccine type 
(4 categories: not vaccinated; partially vaccinated; fully vaccinated with non-mRNA 
vaccine; fully vaccinated including at least one mRNA vaccine in the sequence).  
Models for this subgroup analysis will be adjusted for immunosuppressive status. 


ACTIV-3/TICO SAP 
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60 
•
Subgroups will be formed by the bivariate combinations of vaccination status and
immunosuppressive status.
In order to facilitate the interpretation of the results of the subgroup analyses, baseline levels 
of antibodies, antigen, and SARS-CoV-2 RNA will be summarized by vaccination status and by 
immunosuppressive status.  These biomarkers include the following:  
•
SARS-CoV-2 antibody levels (nAb by GenScript, anti-N by BioRad, and anti-Spike IgG
antibody levels by Quanterix assays)
•
SARS-CoV-2 antigen levels in plasma
•
Viral RNA by midturbinate swabs
See Appendix F for details on assays and outcome measures. 
E-8 Subgroup Analyses by Viral Strain
Between March 1 and September 30, 2021, 1455 participants were randomized to AZD7442 
or placebo.  The enrollment period included time periods both prior to and after the 
emergence of the Delta variant.  Higher levels of plasma nucleocapsid antigen at baseline 
were observed during enrollments in July-September compared to enrollments in March-
June, which coincided with the emergence and global replacement of the Alpha/other viral 
variants with the Delta variant. Observational studies suggest worse clinical outcome from 
being infected with the Delta than the Alpha viral variant. 
Research Question 1:  Does the treatment effect of AZD7442 versus placebo differ based 
on the viral strain that the participant is infected with? 
Hypothesis:  The benefit of AZD7442 differs between participants who were infected with the 
Delta variant versus those who were infected with other viral variants. 
Justification: The AZD7442 nMAb combination binds to non-overlapping epitopes on the 
SARS-CoV-2 Spike protein, presumably decreasing viral replication and dissemination by 
blocking the ability of the Spike protein to bind to host cells expressing ACE2. As such, 
participants who were infected with the Delta variant versus those who were infected with 
other viral variants may benefit more from treatment with ADZ7442. This may be particularly 
pronounced in the subset of participants who have not yet mounted their own endogenous 
neutralizing antibody response.   
An alternate hypothesis is that the dose of AZD7442 is better able to contain viral replication 
among persons infected with a less virulent viral strain, and hence the relative benefit from 
using AZD7442 could be more pronounced among participants infected with non-Delta than 
Delta viral variants.  
Statistical analyses:  
To address the hypothesis of a differential treatment effect, the investigational agent will be 
compared versus placebo in subgroups by SARS-CoV-2 variant (Delta versus other), and 
tests for differential treatment effects across the subgroups will be performed by testing for 


ACTIV-3/TICO SAP 
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61 
interactions between the treatment and subgroup indicators.  Subgroup analyses will be 
performed for time to sustained recovery (primary efficacy outcome) and key safety 
outcomes, including the composite outcomes of grade 3 or 4 AEs, SAEs, organ failure, 
serious infections, or death through Day 28; SAEs, organ failure, serious infections, or death 
through Day 90; and death through Day 90.  Statistical methods for the subgroup analyses 
are described in Section 9.1.   
Because the composition of the study population may have changed over time, including an 
increase in the proportion of participants infected with the Delta variant, an increase in the 
proportion of vaccinated persons in the general population, and changes in the population 
with respect to supplementary oxygen requirements, models for these subgroup analyses will 
also consider adjustment for vaccination status, and for supplementary oxygen requirements 
at study entry (categories of the ordinal pulmonary outcome). 
Research Question 2:   What is the effect of specific mutations? 
AZD7442 is a combination therapy targeting non-overlapping epitopes in the RBD. While 
mutations found in variants can impact the binding of either one of the nMAbs (including at 
positions R346, K444, V445, G446, N450, L452 G476, E484, Q493K) the combination is 
hypothesized to retain activity. Nevertheless, high quality sequencing of the Spike gene will 
provide information on any relevant RBD mutations that could impact binding of one or both 
nMAbs.  
Hypothesis:  The relative benefit of AZD7442 (vs placebo) is larger for those infected with 
virus without mutations at binding-relevant positions compared with those with such virus 
mutations. 
Statistical Analyses:   
It is expected that the rate of viral variants than contains mutations at the binding-relevant 
positions is low, with correspondingly low power for statistical tests.  For individual mutations 
that occur at sufficiently high rates, and pooled across mutations, subgroup analyses will be 
performed comparing AZD7442 versus placebo within subgroups by the presence versus 
absence of the mutations.  The treatment effect will be compared across subgroups by testing 
for an interaction between the treatment and subgroup indicators.  Subgroup analyses will be 
performed for time to sustained recovery and key safety outcomes, as described above; 
statistical methods are described in section 8.4 of this SAP.  Models will include vaccination 
status and supplementary oxygen requirements (categories of the ordinal pulmonary 
outcome) at baseline as covariates.   
These are exploratory analyses.  In addition, if mutations on other sites occur with sufficient 
frequency, similar analyses will be performed to identify mutations that are associated with 
the outcome of the treatment. 


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E-9 Missing Outcomes and Missing Baseline nAb Status
Missing primary outcome results and 90-day survival status due to withdrawal of consent or 
loss to follow-up will be summarized by treatment group, and tests will be performed whether 
the proportion of missing data is independent of the treatment assignment.  Baseline factors 
related to these missing outcome data, overall and for each treatment group, will be 
determined using logistic regression.  Candidate baseline factors for this investigation include, 
but are not limited to, categories of oxygen requirement (pulmonary outcome), antigen levels, 
and the disease progression risk score (section 13.2). Summaries of missing outcome data 
will also include when patients with missing data were last seen and their last known clinical 
status (e.g., discharged, hospitalized, alive at home).   
As sensitivity analyses, multiple imputation may be used to estimate missing outcomes.  
Other sensitivity analyses may also be considered following unblinding when the final extent 
of missing data is known and the pattern of missing data is investigated.  As of December 28, 
2021, 6 participants had withdrawn consent and 23 additional patients had unknown 
sustained recovery status at 90 days.  Follow-up is ongoing, including attempts to reach 
patients who are lost to follow-up.  Thus, these numbers are likely to change. 
We anticipate that 30-60 participants will not have a baseline specimen that can be used to 
determine nAb status. The primary analysis in the nAb-negative subgroup will be restricted to 
participants with known (nAb-negative) status, while the total cohort will include both, 
participants with known and unknown antibody status.  As a sensitivity analysis, we will 
impute nAb status for these participants using baseline characteristics that include age, 
oxygen requirements, duration of time between symptom onset and randomization, and 
SARS-CoV-2 vaccination status. Using a logistic regression model, baseline predictors of nAb 
status will be determined.  The coefficients from the regression model will be used to classify 
the participants with missing nAb status as negative or positive.  For the imputation of the 
missing nAb status, a range of cut-points will be used: participants will be imputed as nAb-
negative if the predicted probability of having been nAb-negative at baseline is 50% or 
greater, 60% or greater, and 70% or greater.  The primary comparison for the sustained 
recovery endpoint in the nAb-negative subgroup will be repeated including both those with 
known nAb-negative status as well as those who were imputed as nAb-negative, in separate 
analyses for each of the three imputation cut-points.  


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Appendix F. Antibody, Antigen, and viral RNA Assays and 
Outcomes 
SARS-CoV-2 antibody and antigen levels were measured in plasma specimens collected at 
baseline (Day 0), Day 1, Day 3, and Day 5. Antibody and antigen levels were determined 
centrally, by the Frederick National Laboratory, blinded to treatment group.  
Antibody Levels  
SARS-CoV-2 plasma antibody levels were measured using two assays: 
•
Levels of neutralizing antibodies (nAbs) directed against the SARS-CoV-2 receptor
binding domain (RBD) were determined using the GenScript SARS-CoV-2 Surrogate
Virus Neutralization Test (sVNT) assay (GenScript, Piscataway, NJ, USA).
o
Levels of nAbs reported as “percent binding inhibition”.  Specimens with levels
<30% are considered nAb negative, levels > 30% are considered positive for
nAbs (30% is the manufacturer’s cutoff for positivity).
•
BioRad Platelia SARS-CoV-2 Total Ab assay (BioRad, Hercules, CA, USA),
measuring total (IgA, IgG, and IgM) anti-nucleoprotein (Anti-N) antibodies.
o
Results of this antibody measurement are reported as “specimen ratios”.
Specimen ratios are defined as the specimen optical density (OD) divided by the
optical density of the cut-off control R4 (ODMR4).  According to the
manufacturer, specimen ratios less than 0.8 are considered negative, those with
a specimen ratio between 0.8 and 1.0 are considered equivocal, and those >
1.0 are considered positive for the presence of antibodies.
o
Equivocal BioRad antibody levels will be combined with negative levels for all
analyses unless otherwise stated.
•
Quanterix anti-Spike IgG semi-quantitative antibody assay (Simoa® Semi-Quantitative
SARS-CoV-2 IgG Antibody Test, Quanterix, Bellerica, MA, USA).
o
Automated paramagnetic microbead-based immunoassay intended for
qualitative and semi-quantitative detection of IgG antibodies to SARS-CoV-2 in
human dipotassium EDTA plasma using the Quanterix HD-X immunoassay
system.
o
Functional LLoQ of 82 ng/mL
o
Antibody-positive defined as > 770 ng/mL per manufacturer’s recommendation
(“clinical cut-off”)
o
The performance of the assay has not been established in individuals that have
received a COVID-19 vaccine
Comment: For the purpose of comparing natural immunity and whether nMAbs have potential 
benefit in those with such, the GenScript assay will be used. This attempts to quantify neutralizing 
antibody titers, whereas the BioRad assay captures any type of anti-N antibody (against a section 
of virus not causing neutralization).  
Plasma Antigen Levels 
SARS-CoV-2 nucleocapsid antigen levels were determined in 90 µL plasma in duplicate using 


ACTIV-3/TICO SAP 
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64 
a Quanterix assay (Simoa® SARS-CoV-2 N Protein Advantage, Quanterix, Bellerica, MA, 
USA).  The lower limit of quantification for the assay is 3 ng/L.   
o
Antigen levels < 3 ng/L are considered “antigen negative”.
Comments: 
o
When analyzed as continuous variable, Quanterix antigen levels <3 will be set to
2.9 ng/L.
o
When analyzed as continuous variable, antigen levels will be log10-transformed.
SARS-CoV-2 Viral RNA was assessed at baseline from mid-turbinate nasal swabs.  
Qualitative and quantitative assessments of the SARS-CoV-2 RNA in viral transport media 
(proxy for viral load) by RT-PCR were made centrally by ABML. 
•
Qualitative RT-PCR analysis:  Extraction, master mix preparation, and RT-PCR were
performed as described in the CDC 2019-Novel Coronavirus Real-Time RT-PCR
Diagnostic Panel.  RT-PCR was performed on an Applied Biosystems QuantStudio 7
Flex. Ct scores <40 for both nCoV N1 and nCoV N2 probe sets are scored as positive
for the presence of SARS-CoV-2 RNA.
•
Quantitative RT-PCR analysis:  Quantitative RT-PCR analysis of the samples used the
same RNA extracts prepared for the qualitative assay.  Assay conditions were the
same as outlined in the CDC protocol except the RNaseP probe was not used.
Comments: 
o
For subgroup analyses, RNA levels in viral transport media will be categorized as
(<10,000 cp/mL [low] versus >10,000 cp/mL [high]); the cut-point is close to the
median viral RNA level in the TICO bamlanivimab trial.  Indeterminate levels will
usually be combined with negative levels for analyses.
o
When analyzed as continuous variable, RNA levels will be log10-transformed.


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Appendix G. Modifications to the Statistical Analysis Plan for 
MP0420 
Investigational Agent 
Appendix H5, version 2.0 (09 April 2021) of the TICO protocol describes agent-specific 
protocol elements for MP0420 which is being developed by Molecular Partners and Novartis. 
MP0420 is multi-valent DARPin® molecule consisting of 5 DARPin® domains.  MP0420 
simultaneously and specifically binds to 3 epitopes of the receptor-binding domain of the 
SARS-CoV-2 spike protein with three different domains and to human serum albumin with two 
domains. 
Analysis Population 
Treatment comparisons for efficacy and safety outcomes will be by modified intention-to-treat 
(mITT).  The mITT analysis is restricted to participants who received a complete or partial 
infusion of MP0420/placebo; participants who did not receive any MP0420/placebo are 
excluded. The TICO platform protocol specifies ITT for the efficacy analyses “unless 
otherwise stated”, and mITT for safety analyses. 
Justification for changing the study population to mITT for efficacy analyses:  In the TICO trial 
of MP0420, 496 participants were randomized (ITT population).  Of these, 485 were infused 
(complete or partial) with MP0420/placebo and 11 were not. Of the 11 participants not 
infused, 9 withdrew consent prior to infusion.  Follow-up data after Day 0 was collected for the 
2 participants not infused, but remained consented.  Because the treatment assignment was 
blinded, the risk of bias due to restricting analyses to the mITT cohort is low.  With this 
approach, the risk and benefits of MP0420 will be evaluated in the same population. 
Comment: Investigators were unblinded to summaries of the infusion status of participants, 
pooled across treatment groups. These analyses were included in the open DSMB reports. 
Hypersensitivity Events of Special Interest 
In October 2021, we were informed of 3 participants who experienced hypersensitivity 
reactions in a Molecular Partners study of 20 healthy volunteers.  The 3 participants received 
a 400 mg subcutaneous dose of MP0420 and each developed non-serious (mild to moderate) 
rash and joint/body pain 10 to 20 days after the single subcutaneous infusion.  A total of 8 
participants received the 400 mg dose in this study.   
These cases were discussed on October 20, 2021, at a TICO investigator meeting and are 
also described in a memorandum from trial leadership to investigators in ACTIV-3 (TICO) on 
November 2, 2021.  At that time we requested that investigators increase vigilance of 
participants who developed rash and simultaneously joint, muscle, and/or body aches.    
On November 5, 2021, revised informed consents and drug information sheets that described 
these events were sent to sites and to the Advarra central IRB. 
On December 7, 2021, all participants for whom rash adverse events had been reported 
through Day 28 were identified.  Sites were asked to complete an eCRF for each event. 
Eleven participants experienced rash events through Day 28.  The number and percentage of 
participants with a rash event by treatment group will be summarized.  Rash events 
associated with myalgia, arthralgia, or generalized aches and pains will also be summarized 
by treatment group. 


ACTIV-3/TICO SAP 
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66 
Line listing of events will include severity grade, rash characteristics, location, and other 
solicited events that occurred simultaneously. 
No formal statistical testing will be carried out on the rash events alone.  In a supplemental 
analysis for the Day 28 composite safety outcome which includes deaths, SAEs, organ 
failure, serious infection and grade 3 or 4 adverse events, the rash adverse events will be 
included as a separate component. 
Subgroup Analyses 
In addition to the subgroup analyses described in section 9, those described in section E-7 
(vaccine and immunosuppressive status) and E-8 (viral strain) of Appendix E will be carried 
out for MP0420 for the outcomes listed in section 9. 


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Appendix H. List of Acronyms 
ACTIV 
Accelerating COVID-19 Therapeutic Interventions and Vaccines 
ACTT 
Adaptive COVID-19 Treatment Trial 
ADE 
Antibody-dependent enhancement  
AE 
Adverse event 
Anti-N 
Anti-nucleoprotein 
ARDS 
Acute respiratory distress syndrome 
CHF 
Congestive heart failure 
CI 
Confidence interval 
CIF 
Cumulative incidence curve 
CMH 
Cochran-Mantel-Haenszel [test] 
COVID-19 
Coronavirus-Induced Disease 2019  
CVA 
Cerebrovascular accident 
DSMB 
Data and Safety Monitoring Board  
ECMO 
Extracorporeal membrane oxygenation 
EU 
European Union 
FDA 
Food and Drug Administration (US) 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
GEE 
Generalized estimating equations 
GMT 
Geometric mean titer 
HR 
Hazard ratio 
ICC 
International Coordinating Center 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
ICU 
Intensive care unit 
IgG 
Immunoglobulin G 
IL-1 
Interleukin 1 
IL-6 
Interleukin 6 
INSIGHT 
International Network for Strategic Initiatives in Global HIV Trials 
IQR 
Interquartile range 
IRB 
Institutional Review Board 
ITT 
Intention-to-treat 
IV 
Intravenous 
mAb 
Monoclonal antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Myocardial infarction 
mITT 
modified intention-to-treat 
mL 
Milliliter 
nAb 
Neutralizing antibody, here measured by a GenScript assay 
NEW 
National Early Warning [score] 
NIAID 
National Institute of Allergy and Infectious Diseases, NIH (US) 
NIH 
National Institutes of Health (US) 
NIHSS 
National Institutes of Health Stroke Scale/Score 
NYHA 
New York Heart Association 
nMAb 
Neutralizing Monoclonal Antibodies 
OR 
Odds ratio 
PCR 
Polymerase chain reaction 


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68 
PIM 
Protocol Instruction Manual 
PT 
Preferred term 
PSEE 
Protocol-specified exempt (serious) events 
RNA 
Ribonucleic acid 
RR 
Rate ratio 
RRR 
Recovery rate ratio 
SAE 
Serious adverse event 
SARS-CoV-1 
Severe acute respiratory syndrome coronavirus 1 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SAP 
Statistical analysis plan 
sHR 
Sub-distribution hazard ratio; subhazard ratio 
SOC 
Standard of care 
SUSAR 
Suspected unexpected serious adverse reaction 
TOC 
Trial oversight committee  
UMN 
University of Minnesota 
UP 
Unanticipated problem 
U.S. 
United States of America 
WHO 
World Health Organization 
 
 

Prot_001.pdf: 
      Master Protocol
A Multicenter, Adaptive, 
Randomized, Blinded Controlled 
Trial of the Safety and Efficacy of 
Investigational Therapeutics for 
Hospitalized Patients With 
COVID-19 
 Version 5.1
 17 August 2021
  Master Protocol: NCT04501978
Trial H1: NCT05780268 
Trial H2: NCT05780281 
Trial H3: NCT05780424 
Trial H4: NCT05780437 
Trial H5: NCT05780463 
Trial H6: NCT05780541


A Multicenter, Adaptive, Randomized, Blinded Controlled Trial 
of the Safety and Efficacy of Investigational Therapeutics 
for Hospitalized Patients with COVID-19 
Short Title: Therapeutics for Inpatients with COVID-19 (TICO) 
INSIGHT Protocol Number: 014 / ACTIV-3 
NCT 04501978, EudraCT 2020-003278-37 
Version: 5.1, 17 August 2021 
Funded by the National Institute of Allergy and Infectious Diseases (NIAID), 
National Institutes of Health (NIH) 
and carried out by the  
International Network for Strategic Initiatives in Global HIV Trials (INSIGHT) 
University of Minnesota (INSIGHT Statistical and Data Management Center (SDMC) 
In collaboration with four International Coordinating Centers (ICCs) of the INSIGHT Network: 
-Centre of Excellence for Health, Immunity and Infection (CHIP), Rigshospitalet, University of
Copenhagen - Copenhagen, Denmark
-Medical Research Council (MRC) Clinical Trials Unit at University College London (UCL) -
London, United Kingdom
-The Kirby Institute, University of New South Wales - Sydney, Australia
-The Institute for Clinical Research at the Veterans Affairs Medical Center - Washington, D.C.,
United States of America (US)
And other research networks supported by NIAID (AIDS Clinical Trials Group [ACTG], Division 
of Clinical Research [NIH-DCR]), National Heart, Lung, and Blood Institute (NHLBI – 
Cardiothoracic Surgical Trials Network [CTSN] and Prevention and Early Treatment of Acute 
Lung Injury [PETAL]) and the US Department of Veterans Affairs  


Table of Contents 
1 
Protocol Summary .................................................................................................................... 5 
2 
Introduction ............................................................................................................................... 9 
Study rationale .................................................................................................................... 9 
Background ......................................................................................................................... 9 
2.2.1 
SARS-CoV-2 Infection and Coronavirus Disease 19 (COVID-19) ................................ 9 
2.2.2 
Natural history of COVID-19 ......................................................................................... 9 
2.2.3 
Risk factors for clinical progression ............................................................................ 10 
2.2.4 
Hospitalization of people with COVID-19 ................................................................... 11 
2.2.5 
Viral kinetics of SARS-CoV-2 infection ....................................................................... 11 
2.2.6 
Immune responses to SARS-CoV-2 infection ............................................................ 12 
2.2.7 
Current treatment strategies for COVID-19 ................................................................ 12 
2.2.8 
Neutralizing Monoclonal Antibodies (nMAbs) ............................................................. 13 
Investigational Agents ....................................................................................................... 14 
3 
Risk/Benefit Assessment ........................................................................................................ 14 
Known Potential Risks ...................................................................................................... 14 
3.1.1 
Risks of Drawing Blood and IV Catheterization .......................................................... 15 
3.1.2 
Risks of Anaphylaxis, Thrombosis and Fluid Overload due to Study Treatments ...... 15 
3.1.3 
Risks to Privacy .......................................................................................................... 15 
Known Potential Benefits .................................................................................................. 15 
4 
Outcomes ............................................................................................................................... 16 
Ordinal Outcomes for Early Futility Assessments ............................................................. 16 
4.1.1 
Rationale for two ordinal outcomes ............................................................................ 17 
Primary and Secondary Outcomes to Evaluate Efficacy and Safety ................................. 17 
4.2.1 
Rationale for primary outcome ................................................................................... 18 
4.2.2 
Secondary outcomes .................................................................................................. 18 
4.2.3 
Rationale for secondary outcomes ............................................................................. 20 
5 
Objectives ............................................................................................................................... 21 
Primary Objective .............................................................................................................. 21 
Secondary Objectives ....................................................................................................... 21 
6 
Study Design .......................................................................................................................... 22 
Randomization and Stratification ...................................................................................... 23 
Blinding ............................................................................................................................. 25 
Sample size assumptions ................................................................................................. 25 
Schedule of Assessments ................................................................................................. 26 
2.1 
2.2 
2.3 
3.1 
3.2 
4.1 
4.2 
5.1 
5.2 
6.1 
6.2 
6.3 
6.4 


 
Approach to Intercurrent Therapies and Clinical Trial Co-enrollment................................ 26 
7 
Study Population ..................................................................................................................... 27 
 
Inclusion Criteria ............................................................................................................... 27 
 
Exclusion Criteria .............................................................................................................. 28 
 
Costs to Participants ......................................................................................................... 28 
8 
Study Product ......................................................................................................................... 29 
9 
Study Assessments and Procedures ...................................................................................... 29 
 
Screening/Baseline and Follow-up Assessments ............................................................. 29 
9.1.1 
Screening/Baseline Assessments .............................................................................. 29 
9.1.2 
Follow-up Assessments ............................................................................................. 30 
9.1.3 
Stored Samples and Future Research ....................................................................... 31 
10 
Safety Assessment .............................................................................................................. 31 
 
Definitions ...................................................................................................................... 33 
10.1.1 
Adverse Event (AE)................................................................................................. 33 
10.1.2 
Criteria for Seriousness ........................................................................................... 34 
10.1.3 
Unanticipated Problems .......................................................................................... 34 
10.1.4 
Severity ................................................................................................................... 34 
10.1.5 
Causality ................................................................................................................. 35 
10.1.6 
Expectedness ......................................................................................................... 35 
 
Schedule for Reporting of Specific Events ..................................................................... 36 
10.2.1 
Infusion-related reactions ........................................................................................ 36 
10.2.2 
Targeted Laboratory Abnormalities ......................................................................... 36 
10.2.3 
Clinical adverse events of any grade severity on Days 0-7, 14 and 28 ................... 36 
10.2.4 
Grade 3 and 4 clinical adverse events through Day 28 ........................................... 37 
10.2.5 
Protocol specified exempt serious events ............................................................... 37 
10.2.6 
Reportable SAEs .................................................................................................... 37 
10.2.7 
Unanticipated Problems (UPs) ................................................................................ 38 
10.2.8 
Deaths ..................................................................................................................... 38 
10.2.9 
Pregnancy ............................................................................................................... 38 
 
Medical Monitor ............................................................................................................. 39 
 
Halting Enrollment for Safety Reasons .......................................................................... 39 
11 
Statistical Analyses and Monitoring Guidelines .................................................................... 39 
 
Analysis of the Primary Efficacy Endpoint ..................................................................... 39 
 
Analyses of Secondary Efficacy Endpoints, Safety Outcomes, and Subgroups ............ 40 
 
Data Monitoring Guidelines for an Independent DSMB ................................................. 41 
6.5 
7.1 
7.2 
7.3 
9.1 
10.1 
10.2 
10.3 
10.4 
11.1 
11.2 
11.3 


 
Rationale for Early Futility Analysis ............................................................................... 42 
 
Interim Analyses Guidelines .......................................................................................... 43 
11.5.1 
Early Assessment of Safety and Futility .................................................................. 43 
11.5.2 
Monitoring Guidelines for the Primary Endpoint ...................................................... 45 
12 
Protection of Human Subjects and Other Ethical Considerations ........................................ 46 
 
Participating Clinical Sites and Local Review of Protocol and Informed Consent .......... 46 
 
Ethical Conduct of the Study ......................................................................................... 46 
 
Informed Consent of Study Participants ........................................................................ 46 
 
Confidentiality of Study Participants .............................................................................. 47 
 
Regulatory Oversight ..................................................................................................... 47 
 
List of Tables 
Table 1  Overview of Safety Data Collection .................................................................................. 33 
Table 2 Generic AE Grading Scale ................................................................................................ 35 
Table 3. Hypothesized percentage of participants in each category on Day 5 in the Investigational 
agent and placebo groups based on aforementioned assumptions ............................................... 42 
Table 4. Power and type 1 error for the two-outcome decision rule to expand enrollment to strata 1 
and 2 for an investigational agent for correlations of r=0.8 and 0.9 between the marginal test 
statistics for the two outcomes. OR=1.60, total sample size 300. .................................................. 45 
 
List of Figures 
Figure 1.   A Phase 3 Platform Trial for Efficiently Evaluating Multiple Investigational Agents Over 
Time ............................................................................................................................................... 23 
 
 
11.4 
11.5 
12.1 
12.2 
12.3 
12.4 
12.5 


1 
Protocol Summary 
DESIGN 
TICO (Therapeutics for Inpatients with COVID-19) is a master protocol to 
evaluate the safety and efficacy of multiple investigational agents aimed at 
modifying the host immune response to severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2) infection, or directly enhancing viral control in 
order to limit disease progression.  
Trials within this protocol will be adaptive, randomized, blinded and initially 
placebo-controlled. Participants will receive standard of care (SOC) treatment 
as part of this protocol.  
The international trials within this protocol will be conducted in several 
hundred clinical sites. Participating sites are affiliated with networks funded by 
the United States National Institutes of Health (NIH) and the US Department 
of Veterans Affairs. 
The protocol is for a phase III randomized, blinded, controlled platform trial 
that allows investigational agents to be added and dropped during the course 
of the study for efficient testing of new agents against control (i.e., placebo + 
SOC) within the same trial infrastructure. When more than one agent is being 
tested concurrently, participants will be randomly allocated across agents (as 
well as between the agent and its placebo) so the same control group will be 
used, when feasible. Randomization will be stratified by study site pharmacy 
and disease severity.  There are 2 disease severity strata, defined as below: 
Disease severity stratum 1: Absence of all of the following: stroke, meningitis 
encephalitis, myelitis, myocardial infarction, myocarditis, pericarditis, 
symptomatic congestive heart failure (NYHA class III or IV), arterial or deep 
venous thrombosis or pulmonary embolism, requirement for invasive 
mechanical ventilation, ECMO, mechanical circulatory support, vasopressor 
therapy, or new renal replacement therapy. 
Disease severity stratum 2: Presence of at least one of the excluded 
conditions or treatments in disease severity stratum 1.  
The primary endpoint is the time from randomization to sustained recovery, 
defined as being discharged from the index hospitalization, followed by being 
alive and home for 14 consecutive days prior to Day 90. The definition of 
home will be operationalized as the level of residence or facility where the 
participant was residing prior to hospital admission leading to enrollment in 
this protocol. 
An independent Data and Safety Monitoring Board (DSMB) will regularly 
review interim analyses that summarize safety and efficacy outcomes. For 
agents with minimal pre-existing safety knowledge, the pace of enrollment will 
be initially restricted and there will be an early review of safety data by the 
DSMB. For the study of all agents, at the outset of the trial, only participants in 
disease severity stratum 1 will be enrolled. This more restricted enrollment will 
continue until approximately 300 participants are enrolled and followed for 
5 days.  The exact number will vary according to the speed of enrollment and 
the timing of DSMB meetings.   Prior to expanding enrollment to also include 
patients in disease severity stratum 2 safety will be evaluated and a pre-


specified futility assessment by the DSMB will be carried out using 2 ordinal 
outcomes (see below) assessed at Day 5. The first ordinal outcome is a 7-
category outcome largely based on oxygen requirements. The highest (worst) 
category that applies on Day 5 will be assigned. This outcome is referred to 
as the “pulmonary” ordinal outcome, with categories described below:  
1. 
Can independently undertake usual activities with minimal or 
no symptoms 
2. 
Symptomatic and currently unable to independently 
undertake usual activities but no need of supplemental 
oxygen (or not above premorbid requirements)  
3. 
Supplemental oxygen (<4 liters/min, or <4 liters/min above 
premorbid requirements) 
4. 
Supplemental oxygen (≥4 liters/min, or ≥4 liters/min above 
premorbid requirements, but not high-flow oxygen)  
5. 
Non-invasive ventilation or high-flow oxygen  
6. 
Invasive ventilation, extracorporeal membrane oxygenation 
(ECMO), mechanical circulatory support, or new receipt of 
renal replacement therapy  
7. 
Death 
 
The second ordinal outcome, also assessed at Day 5, captures the range of 
organ dysfunction that may be associated with progression of Coronavirus-
Induced Disease 2019 (COVID-19), such as stroke and other coagulation-
related complications. Again, the highest category that applies on day 5 will 
be assigned. Use of this outcome allows further characterization of the extra-
pulmonary manifestations of COVID-19 and the capacity to identify agents 
that improve those extra-pulmonary manifestations. This outcome is referred 
to as the “pulmonary+” ordinal outcome.  
The 7 categories of the pulmonary+ ordinal outcome assessed at Day 5 are: 
1. 
Can independently undertake usual activities with minimal or 
no symptoms 
2. 
Symptomatic and currently unable to independently 
undertake usual activities but no need of supplemental 
oxygen (or not above premorbid requirements)  
3. 
Supplemental oxygen (<4 liters/min, or <4 liters/min above 
premorbid requirements) 
4. 
Supplemental oxygen (≥4 liters/min, or ≥4 liters/min above 
premorbid requirements, but not high-flow oxygen) or any of 
the following:  stroke (NIH Stroke Scale [NIHSS] ≤14), 
meningitis, encephalitis, myelitis, myocardial infarction, 
myocarditis, pericarditis, new onset congestive heart failure 
(CHF) NYHA class III or IV or worsening to class III or IV, 
arterial or deep venous thromboembolic events.  
5. 
Non-invasive ventilation or high-flow oxygen, or signs and 
symptoms of an acute stroke (NIHSS >14)  
6. 
Invasive ventilation, ECMO, mechanical circulatory support, 
vasopressor therapy, or new receipt of renal replacement 
therapy  
7. 
Death 


Both ordinal outcomes are used to assess futility because it is currently 
unclear whether the investigational agents under study will primarily influence 
non-pulmonary outcomes, for which risk is increased with SARS-CoV-2 
infection, in part, through mechanisms that may be different from those that 
influence pulmonary outcomes.  
For investigational agents passing this futility assessment, enrollment of 
participants will be expanded, seamlessly and without any data unblinding, to 
include participants in disease severity stratum 2 as well as those in disease 
severity stratum 1.  Future interim analyses will be based on the primary 
endpoint of sustained recovery and will use pre-specified guidelines to 
determine early evidence of benefit, harm or futility for the investigational 
agent.  
DURATION 
Participants will be followed for 18 months following randomization. Primary 
and most secondary outcomes will be collected during the first 90 days of 
follow-up only.  Follow-up beyond 90 days is planned because the half-lives of 
some agents indicate that potentially meaningful amounts may remain in the 
body after 90 days of follow-up.  During the follow-up between 90 days and 
18 months hospitalizations and deaths will be ascertained. 
SAMPLE SIZE 
This phase III trial is planned to provide 90% power to detect a 25% increase 
in the rate of sustained recovery for an investigational agent compared to 
placebo at the 0.025, 1-sided level of significance.  This requires 843 primary 
events (i.e., participants who achieve sustained recovery).  Randomization of 
1,000 participants, equally allocated to each investigational agent and 
placebo, followed for 90 days is estimated to result in the required number of 
primary events.  The event target may be achieved earlier if more than 
1,000 participants are enrolled.  Sample size will be evaluated periodically by 
study team members who are blinded to interim results and may be increased 
to maintain power for the hypothesized difference in sustained recovery 
between the investigational agent and placebo.  
POPULATION 
The study population consists of inpatient adults (≥18 years) who have had 
COVID-19 symptoms ≤ 12 days.  Initially, approximately 300 participants in 
disease severity stratum 1 will be enrolled.  Afterwards, based on the review 
by the DSMB of safety and futility, eligibility for randomization will be 
expanded to also include patients in disease severity stratum 2.   
STRATIFICATION Randomization will be stratified by study site pharmacy and also by disease 
severity stratum. 
REGIMEN 
Investigational agents suitable for testing in the inpatient setting will be 
prioritized based on in vitro data demonstrating activity against SARS CoV-2 
entry or replication, preclinical data, phase I pharmacokinetic and safety data, 
and clinical data from other ongoing trials. The protocol will initially focus on 
agents for which there is a hypothesized benefit from passive immunization 
including use of neutralizing monoclonal antibodies.  
MONITORING 
An independent DSMB will review interim data on a regular basis and use 
pre-specified guidelines to identify agents with clear evidence of efficacy for 
the primary outcome, and if so recommend unblinding of the trial results for 
that agent. Conversely, the DSMB may recommend discontinuation of an 
investigational agent if the risks are judged to outweigh the benefits or if futility 


assessments indicate that there is low probability that an investigational agent 
will achieve statistical significance for the primary endpoint of sustained 
recovery.  
                                For an investigational agent, if the trial is stopped early or if the trial continues 
until the pre-specified number of primary endpoints is reached, further 
enrollment of the investigational agent will be terminated if applicable, and the 
trial data for the investigational agent will be unblinded and reported with data 
through 90 days of follow-up. Follow-up of all participants will continue 
through 18 months using the data collection plan described in this master 
protocol.   
 
 
A risk-based protocol monitoring plan will be developed to ensure participant 
safety, data integrity, and regulatory compliance during the conduct of the 
trial. 
 
 
 


2 
Introduction 
 
Study rationale 
COVID-19 is a respiratory disease caused by a novel coronavirus (SARS-CoV-2). While 
most cases are mild or asymptomatic, progressive disease can result in hospitalization, 
requirement for mechanical ventilation, and substantial morbidity and mortality.1 While the 
most common mode of disease progression is progressive respiratory failure following the 
development of pneumonia, other severe complications including thrombosis and ischemia 
are increasingly recognized.2,3  
Several clinical trials utilizing novel drugs and repurposing older agents have been 
implemented to investigate the treatment of adults hospitalized with severe COVID-19 (see 
section 2.2.7). Standard-of-care is hence rapidly evolving (see Appendix I for current 
recommendations).  
Our understanding of the humoral immune response is evolving, with some evidence that 
responses are variable between individuals and delayed in some cases.4 It may therefore 
be that viral replication leads to extensive tissue damage and inflammatory responses in 
the lungs and other organs before the development of neutralizing antibodies. 
Augmentation of the humoral immune response to SARS-CoV-2 infection using passive 
immunotherapy to SARS-CoV-2 in hospitalized patients with moderate to severe COVID-19 
may thus improve the disease course and reduce the time to recovery.  
 
Background 
2.2.1 SARS-CoV-2 Infection and Coronavirus Disease 19 (COVID-19) 
In December 2019, the Wuhan Municipal Health Committee identified an outbreak of viral 
pneumonia cases of unknown cause. A novel coronavirus was rapidly identified by 
sequencing and named SARS-CoV-2, and the illness caused by infection with SARS-CoV-2 
has been named COVID-19.5 While SARS-CoV-2 mostly causes a mild respiratory illness, 
some individuals, particularly those who are elderly6,7 and have comorbidities,8 may 
progress to severe disease requiring hospitalization, mechanical ventilation in intensive care 
units, and death. As of 5 October 2020, less than seven months following the declaration of 
a pandemic on 11 March 2020 by the World Health Organization (WHO), there have been 
more than 35 million cases diagnosed and more than 1 million deaths worldwide.1 Over 
300,000 cases continue to be reported daily.5
2.2.2 Natural history of COVID-19 
SARS-CoV-2 has a median incubation period of 4 days (interquartile range [IQR] 2-
7 days)9 and the mean serial interval defined as the time duration between a primary 
case-patient (infector) having symptom onset and a secondary case-patient (infectee) 
having symptom onset for COVID-19 was calculated as 3.96 (95% confidence interval [CI] 
3.53–4.39) days.10 COVID-19 illness is predominantly a respiratory disease typified by upper 
respiratory symptoms in mild cases and pneumonia, respiratory failure and acute respiratory 
distress syndrome (ARDS) in advanced disease. Initial symptoms typically involve the upper 
respiratory tract with cough, sore throat and malaise. Fever is present in approximately 
44-98% of cases. Notably, persons with COVID-19 often experience loss of smell and 
taste.11
Complications of COVID-19 illness include cytopenias (lymphopenia, thrombocytopenia and 
anemia), and acute cardiac events (elevated troponin, changes on electrocardiogram), 
2.1 
2.2 


acute renal injury and renal failure, liver impairment, and neurological events including 
acute cerebrovascular events, impaired consciousness and muscle injury and thrombotic 
events.  
In most patients (approximately 80%) symptoms resolve without the need for intervention 
within five to seven days of symptom onset up to a maximum of 14 days. However, 
approximately 20% of patients show signs of clinical disease progression, most notably 
pneumonia, around day 3 to 8 following symptom onset. Other manifestations of disease 
progression include thrombotic episodes including stroke and myocardial infarction (MI). 
This resembles the documented 6-8 fold excess risk of thrombosis when patients are 
infected with influenza.12  
A proportion of those who progress then further deteriorate, including with the 
development of ARDS around 1-5 days after pneumonic symptom onset.6,13,14,15  Acute 
kidney injury necessitating dialysis and failure of other organs may also occur at this 
severe stage of disease. 
Of the nearly 1,099 persons described in the Wuhan cohort, 16.0% had severe disease 
at presentation; 67 persons (6.1%) reached a composite primary endpoint of intensive 
care admission, mechanical ventilation or death.9,16 As described below, outcomes for 
those requiring mechanical ventilation and with other manifestations of end-organ failure 
are poor, and approaches to prevent this late stage of the disease among those with 
early evidence of progression are critically needed. 
 
Initially in this protocol, we aim to enroll patients hospitalized for medical management of 
COVID-19, close to the onset of clinical symptoms but without end-organ failure having 
developed (disease severity stratum 1).  For agents passing the initial futility assessment 
eligibility for enrollment will be expanded so that patients with or without overt organ 
failure will be enrolled (patients in disease severity stratum 1 or 2). The majority of 
patients will have emerging evidence of pneumonia,but recognizing the expanding range 
of other organs involved in clinical progression of COVID-19, neither the inclusion criteria 
nor the outcomes used in in this trial are limited only to assessment of pneumonia.  
 
2.2.3 Risk factors for clinical progression  
Studies investigating risk factors for progression of COVID-19 and related hospital 
admission are currently few. Reports to date have predominately been based on individuals 
already hospitalized. These include a mix of descriptive information on the patients as well 
as estimates of associations between patient characteristics and disease severity. Older 
age has been found to be strongly related to greater severity16,17,18 and poorer outcome as 
has the presence of conditions such as hypertension, diabetes and coronary heart 
disease.14,16,18,19  Other risk factors identified include ethnicity18 , cigarette smoking16,17,20 
and high body mass index (BMI).21,22,23,24  Gender has not shown a consistent relationship 
with disease severity.16,18,25  However, reports of larger case series and cohorts suggest 
male gender is associated with an increased risk of hospitalization and mortality.26,27,28  
Specific symptoms at presentation that have notably been associated with greater 
likelihood of progression to more severe disease include shortness of breath and elevated 
body temperature.16,29  
Patients with inborn errors of their interferon immunity or who have developed auto-
antibodies that reduces this host-protective immunity appear to be at excess risk of disease 
progression.30,31   


The COVID-19–Associated Hospitalization Surveillance Network (COVID-NET) report on 
1,482 persons who were hospitalized in 14 states in the US in March 2020 show nearly 
75% were aged over 50 years, and nearly 90% had at least one underlying comorbid 
illness.32  
Based on 2.6 million users of the COVID Symptom Tracker App, predominantly in the 
United Kingdom, being older, obese, diabetic or suffering from pre-existing lung, heart or 
renal disease placed participants at increased risk of visiting the hospital with COVID-19.33 
Pre-existing lung disease and diabetes were consistently associated with a higher risk of 
requiring respiratory support.33 A meta-analysis showed that cardiac injury as measured by 
a high sensitivity troponin was associated with higher mortality, higher need for intensive 
care unit (ICU) care, and severe COVID-19 disease.34 
2.2.4 Hospitalization of people with COVID-19 
Countries and jurisdictions differ in the clinical management of COVID-19 patients. Early in 
the epidemic, faced with small numbers of infected persons, some resource-rich countries 
such as Singapore elected to admit all persons with COVID-19 regardless of symptom 
severity to facilitate strict isolation. Admission for reasons of public health or quarantine, 
rather than medical management, continues to be a requirement in some countries, notably 
in Asia.  Elsewhere, it is more common for those with mild illness to be advised to self-
isolate at home, while only those severely unwell are admitted for medical management.  
Thresholds for ICU management also differ globally and are likely to vary significantly even 
within individual countries at different stages of the epidemic. For example, during peaks of 
high incidence, procedures commonly performed only in ICU may be extended to other 
care areas, while patients who might otherwise have been considered for ICU admission 
may be palliated if clinical services are overwhelmed. 
Mortality rates for those who develop end-organ failure requiring intensive support, 
including those admitted to ICU, differ widely. Among 1,591 ICU patients from Lombardy, 
the region in Italy hardest hit by COVID-19, 88% required mechanical ventilation and 11% 
noninvasive ventilation.35 The ICU mortality rate was 26%. Of 1,043 patients with available 
data, 709 (68%) had at least 1 comorbidity, 509 (49%) had hypertension, and 21% had 
cardiovascular disease. Younger patients (≤63 years) compared to older patients, had 
lower ICU mortality and higher rates of discharge from ICU. The median length of stay in 
the ICU was 9 days, though 58% remained in ICU at time of report.35 In the United 
Kingdom, of the 4,078 COVID-19 patients admitted into critical care with reported 
outcomes, 50.7% died in ICU; those requiring advanced respiratory support and renal 
support had worse outcomes.36 These data underline the importance of attenuating the 
disease in its early phase prior to the development of end-organ failure. 
For recovering hospitalized patients who still require supplementary oxygen, an emerging 
clinical practice is to discharge such patients and administer oxygen at their home until it is 
no longer required.   
2.2.5 Viral kinetics of SARS-CoV-2 infection 
Viral kinetic studies have demonstrated extensive SARS-CoV-2 viral replication in the 
pharynx just before and early after symptom onset.37 Viral ribonucleic acid (RNA) shedding 
from the pharynx gradually wanes as symptoms resolve, but viral RNA is still detectable 
weeks after symptom resolution.37,38,39 Median duration of viral shedding was 20 days in 
survivors (longest 37 days), but SARS-CoV-2 was detectable until death in non-survivors.7 
Whether this is viable virus with the potential for continued transmission remains uncertain. 


RNAemia has been reported but is relatively rare.38,40  Viral detection in sputum is higher 
and outlasts pharyngeal swabs in those with pneumonia.41  Persons with asymptomatic 
disease clear their virus faster than symptomatic individuals.42 
The contribution of ongoing viral replication to disease progression in the most severe stage 
of COVID-19 (i.e., on ventilator or ECMO) is unclear, but may be minor as we hypothesize 
that any organ damage from the infection may have occurred already and the predominant 
drivers of progression to severe disease/ARDS are those of the uncontrolled local and 
systemic immune response. 
Case reports are emerging to suggest possible reinfection in patients who have recovered 
from SARS-CoV-2 infection.43,44,45,46,47  
2.2.6 Immune responses to SARS-CoV-2 infection 
Notwithstanding the observed high viral loads, and progression of viral shedding from the 
upper to lower respiratory tract in those with progressive disease, the humoral immune 
response to SARS-CoV-2 appears variable and may be slow. While data are still emerging, 
it appears that in a significant proportion of cases antibody responses are not yet evident at 
the time (day 5-7) when disease progression and hospitalization most commonly occur, 
supporting a role for supplementation of the antibody response at that time point.  
For example, two large studies have described antibody responses (immunoglobulin G 
[IgG] and immunoglobulin M [IgM]). In the first, samples from 82 confirmed and 58 probable 
cases of COVID-19 in a cross-sectional analysis demonstrated IgG detection at a median of 
14 (IQR 10-18) days after symptom onset, with IgM detected at a median of 5 days (IQR 3-
6) after symptom onset. Antibodies were absent in around 22% of individuals at 
assessment (IgM), and IgM was most commonly absent in those assessed early (within
7 days of symptom onset).48 In the second study of 262 patients who provided 363 
samples, antibody levels were examined by days from symptom onset. IgM antibodies were 
detectable in just under 40% of patients at day 5-7, rising to 50% at day 8-10, while 
interestingly IgG was detectable in a slightly higher proportion at those time points: just over 
50% at day 5-7, rising to 60% at day 8-10.49 This series was drawn from hospitalized 
patients, but the severity of illness and relationships with disease outcomes were not 
described. Both studies show considerable individual variation in antibody kinetics. Further 
longitudinal studies are underway and will better characterize the kinetics of these 
responses in individuals.50,51
SARS-CoV-2 infection may also induce significant changes in elements of the cellular 
immune response. As the disease process progresses, the peripheral lymphocyte count 
typically declines. The depletion of peripheral lymphocytes likely reflects translocation to the 
pulmonary tissue. The extent that this influx is exclusively helpful to the host, or possibly 
may contribute adversely to disease severity is currently unclear. In severe cases this 
decline in CD4+ and CD8+ lymphocytes is also associated with an increase in activated 
CD4+ and CD8+ subsets, increases in key proinflammatory cytokines including interleukin 6 
(IL-6), and increases in natural killer (NK) cells.52,53 Trials assessing the use of various 
immunomodulatory agents with the aim of dampening this migration and systemic 
inflammation are underway, and may help to clarify this.  
2.2.7 Current treatment strategies for COVID-19 
Hundreds of clinical trials have been completed or are underway to study the safety and 
efficacy of treatments for COVID-19. Treatments being studied include direct anti-viral 
treatments, including repurposed drugs found in vitro to have activity against SARS-CoV-2; 


immune modulators especially in patients with advanced disease; drugs to reduce 
inflammation, including corticosteroids, and modifiers of other pathophysiological pathways 
implicated in disease progression, including potentially anticoagulants and anti-platelet 
agents.  
As results of randomized trials for these and other treatments become available and 
treatment guidelines are updated, standard of care (SOC) for hospitalized patients with 
COVID-19 will change.  This may influence the background treatment recommended (or 
required) by this protocol and/or second line or supportive care treatments recommended 
by the protocol.  To accommodate this fast-moving field Appendix I (which outlines the SOC 
to be recommended in addition to investigational agent or matched placebo) will be 
regularly updated. 
Of note, whereas evidence supports use of the interventions outlined in Appendix I, the 
most optimal approach to applying these interventions remains uncertain, and is the subject 
of ongoing trials.     
2.2.8 Neutralizing Monoclonal Antibodies (nMAbs) 
The ability to rapidly and urgently develop novel therapeutic nMAbs is best illustrated in the 
setting of the 2014-2016 Ebola epidemic. A triple monoclonal antibody (MAb) cocktail, 
ZMapp, which first showed efficacy in guinea pigs,54  was tested in PREVAIL II, a 
randomized controlled trial of 72 patients.55  This trial did not meet pre-specified efficacy 
threshold. Two phase I studies that separately explored a single nMAb against receptor-
binding domain (RBD) Mab11456 and a triple nMAb cocktail of REGN3470-3471-347957 
showed linear pharmacokinetics and a good safety profile, with mild headaches in the latter. 
A large 1:1:1:1 randomised study of 681 patients compared ZMapp as control; remdesivir: 
single nMAb, Mab114 (Ansuvimab) and a triple cocktail of REGN-EB3, with the latter two 
showing superior results for day 28 mortality.58  Four events in three patients were thought 
to be directly related to trial drug – 2 in the ZMapp arm and 1 in the remdesivir arm. 
Mab114 was granted breakthrough therapy designation by the US Food and Drug 
Administration (FDA) and REGN-EB3 was approved for the treatment of Ebola virus 
disease by the FDA.  
SARS-CoV-2 and other pathogenic human coronaviruses encode four major structural 
proteins. The homotrimeric spike (S) protein is essential to viral attachment, fusion, entry 
and transmission and has two functional subunits - S1 subunit for virus-receptor binding 
and S2 subunit for virus-cell membrane fusion. S1 has an N-terminal domain (NTD) and a 
RBD.59,60,61  During infection, SARS-CoV-2 first binds the host cell through interaction 
between its S1-RBD and the cell membrane receptor (angiotensin-converting enzyme 2 or 
ACE2 receptor) triggering conformational changes in the S2 subunit that results in virus 
fusion and entry into the target cell.62  Other structural proteins include the envelope (E) 
protein encompassing the viral envelope, the membrane (M) protein protruding from the cell 
membrane, and nucleocapsid (N) protein covering the viral RNA. There are approximately 
16 non-structural proteins (nsp1–16), and ﬁve to eight accessory proteins.59  As the S 
glycoprotein is surface-exposed and mediates entry into host cells, it is the main target of 
neutralizing antibodies upon infection and the focus of therapeutic and vaccine design62. 
Most currently developed anti-SARS-CoV-2 nMAbs target the viral S protein, most 
commonly the RBD.6364 The structural homology and cross-reactivity across the 
Coronaviridae have enabled knowledge translation from SARS-CoV-1 and MERS to SARS-
CoV-2. Cross-reactivity has been exploited for immune protection. Promising human-
derived nMAbs have been identified from previous SARS-CoV-1 patients and convalescing 


SARS-CoV-2 patients. After the SARS epidemic in 2003, two promising nMAb therapeutics 
were identified - CR3014 and CR3022.65  CR3022 rather than CR3014 showed promise 
against SARS-CoV-266  but recent structure modelling showed that CR3022 binds to a 
cryptic epitope distal to the RBD, only accessible when the RBD is in the up conformation 
and at a specific angle,67 thus limiting its application.  
A new promising S309 antibody targeting the RBD, identified from a previous SARS-CoV-1 
survivor, showed cross-reactivity against SARS-CoV-2 and an Fc variant with a longer half-
life is in accelerated development.61  Similarly, 18F3 and 7B11 against RBD were identified 
from SARS-CoV-1 patients.68  Many papers have detailed identification and development of 
nMAbs from currently convalescing patients with SARS-CoV-2, all targeting the RBD 
including: CB6 which also has shown promise as a prophylaxis and therapeutic model in 
monkey studies69; P2B -2F6,70 311mab-31B5 and 311mab-32D4.71 
Viral escape mutants may render the virus resistant to the neutralising effects of nMAbs.72  
Investigational Agents 
Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) has formed an 
overarching “trial oversight committee (TOC)” for both ACTIV-2 (a parallel study 
assessing COVID-19 therapeutics in outpatients) and ACTIV-3 (this master protocol). 
The TOC will select agents for study in the two protocols. Members of the protocol team 
(non-voting) and NIAID are members of this committee. This committee reviews data for 
investigational agents and considers a number of factors including safety, in vitro 
potency against the virus, resistance, epitope and adequacy of antibody titers if the 
agent is an antibody, scale-up potential in general, and for completing the phase 3 trial in 
particular, and dose and route of administration.  
The same DSMB will review interim data from ACTIV-2 and ACTIV-3 and this should 
facilitate early identification of safety concerns. The protocol team will inform the DSMB 
about emerging data that impacts the study design (e.g., the safety of the investigational 
agent being studied or SOC).  
It is possible that agents from different sources will be combined at some point in the 
conduct of this master protocol. It is also possible that one agent will be identified as 
effective and then incorporated as SOC (providing there is good safety and adequate 
supply). 
Information on dosing, administration, supply and distribution, matching placebo, and any 
special considerations as far as inclusion/exclusion criteria and safety monitoring for each 
investigational agent studied as part of this protocol is outlined in an appendix (see 
Appendix H), including known benefits and risk, justification for dosing, and administration. 
The appendix will also include whether any deviations from aspects of study procedures 
outlined in this master protocol will be needed. The informed consent will describe any risks 
associated with the investigational agents. 
3 
Risk/Benefit Assessment 
 
Known Potential Risks 
Potential risks of participating in this trial are those associated with the product, and these 
are described in an appendix and in the sample informed consent. Other risks include 
2.3 
3.1 


having blood drawn, intravenous (IV) catheterization, thrombosis, the volume of fluid 
infused, and breach of confidentiality.  
3.1.1 Risks of Drawing Blood and IV Catheterization 
Drawing blood may cause transient discomfort and fainting. Fainting is usually transient and 
managed by having the participant lie down and elevate his/her legs. Bruising at the blood 
collection sites may occur but can be prevented or lessened by applying pressure to the 
blood draw site for a few minutes after the blood is taken. IV catheterization may cause 
insertion site pain, phlebitis, hematoma formation, and infusate extravasation; less frequent 
but significant complications include bloodstream and local infections. The use of aseptic 
(sterile) technique will make infection at the site of blood draw or at catheterization less 
likely. 
3.1.2 Risks of Anaphylaxis, Thrombosis and Fluid Overload due to Study 
Treatments 
Infusions of investigational agents likely to be used in this protocol are generally well-
tolerated, except in rare cases of existing allergy to the products infused. However, the 
volume of fluid infused may exacerbate pre-existing CHF. There is slight elevation in the risk 
of thrombosis with standard antibody therapy, and in some cases COVID-19 is associated 
with thrombotic complications. There is a theoretical risk that antibody infusion may worsen 
the disease course via antibody-dependent enhancement (ADE). ADE occurs if specific 
antibodies against a virus increase rather than decrease viral replication and hence worsen 
the disease course. ADE has been observed most clearly in the context of Dengue fever.73 
It is unclear if this phenomenon is present and/or clinically significant in COVID-19, but close 
monitoring of disease outcomes will be maintained during interim safety analyses.  
3.1.3 Risks to Privacy 
Participants will be asked to provide personal health information (PHI). All attempts will be 
made to keep this PHI confidential within the limits of the law. However, there is a chance 
that unauthorized persons will see the participant’s PHI. All source records including 
electronic data will be stored in secured systems in accordance with institutional policies 
and government regulations.  
All study data that leave the site (including any electronic transmission of data) will be 
identified only by a coded number that is linked to a participant through a code key 
maintained at the clinical site. Names or readily identifying information will not be released. 
Electronic files will be password protected. 
Only people who are involved in the conduct, oversight, monitoring, or auditing of this trial 
will be allowed access to the PHI that is collected. Any publication from this trial will not use 
information that will identify study participants. Organizations that may inspect and/or copy 
research records maintained at the participating site for quality assurance and data analysis 
include groups such as the study monitor, other authorized representatives of the 
institutional review board (IRB), NIH, and applicable regulatory agencies (e.g. FDA).  
 
Known Potential Benefits 
While the trial is conducted to test the hypothesis that each investigational agent will reduce 
the risk of further disease progression or reduce the time to sustained recovery, the agents 
studied may or may not prevent these outcomes in any individual who participates in this trial. 
However, there is an anticipated benefit to society from a patient’s participation in this trial, 
due to insights that will be gained about the investigational agent(s) under study as well as 
3.2 


the natural history of the disease. While there may not be benefits for an individual, there will 
be benefits to society if a safe, efficacious therapeutic agent can be identified during this 
global COVID-19 outbreak. 
4 
Outcomes 
This section describes the key outcome measures used in this phase III protocol. At the 
outset of the phase III trial for each investigational agent, only participants in disease 
severity stratum 1 will be enrolled. This more restricted enrollment will continue until 
approximately 300 participants are enrolled.  Prior to expanding enrollment to include 
people in disease severity stratum 2, a pre-specified futility assessment by the DSMB will 
be carried out using two ordinal outcomes (see below) that are assessed at Day 5.  This 
early futility assessment is designed to ensure some minimal level of activity for agents for 
which enrollment continues to the planned sample size of the phase III trial.  
 
Ordinal Outcomes for Early Futility Assessments 
Two ordinal outcomes will be used to assess futility after approximately 300 participants 
have been enrolled. Both outcomes are assessed 5 days after randomization (Day 5); the 
participant’s highest (i.e. most severe) observed score on Day 5 is used. 
The first ordinal outcome, referred to as the “pulmonary” ordinal outcome, is primarily 
defined based on oxygen requirements. The 7 categories of the pulmonary ordinal outcome 
are given below (see Protocol Instructions Manual [PIM] for criteria defining the categories 
and each of the conditions mentioned).  
1. Can independently undertake usual activities with minimal or no symptoms 
2. Symptomatic and currently unable to independently undertake usual activities but 
no need of supplemental oxygen (or not above premorbid requirements)  
3. Supplemental oxygen (<4 liters/min, or <4 liters/min above premorbid 
requirements) 
4. Supplemental oxygen (≥4 liters/min, or ≥4 liters/min above premorbid 
requirements, but not high-flow oxygen)  
5. Non-invasive ventilation or high-flow oxygen  
6. Invasive ventilation, extracorporeal membrane oxygenation (ECMO), mechanical 
circulatory support, or new receipt of renal replacement therapy   
7. Death 
The second ordinal outcome, referred to as “pulmonary+,” also assessed at Day 5, captures 
extrapulmonary complications as well as respiratory dysfunction. The categories of the 
pulmonary+ outcome are defined below (see PIM for criteria defining the categories and 
each of the conditions mentioned). 
1. Can independently undertake usual activities with minimal or no symptoms 
2. Symptomatic and currently unable to independently undertake usual activities but 
no need of supplemental oxygen (or not above premorbid requirements)  
3. Supplemental oxygen (<4 liters/min, or <4 liters/min above premorbid 
requirements) 
4. Supplemental oxygen (≥4 liters/min, or ≥4 liters/min above premorbid 
requirements, but not high-flow oxygen) or any of the following:  stroke (NIH 
Stroke Scale [NIHSS] ≤14), meningitis, encephalitis, myelitis, myocardial 
infarction, myocarditis, pericarditis, new onset CHF NYHA class III or IV or 
worsening to class III or IV, arterial or deep venous thromboembolic events.  
4.1 


5. Non-invasive ventilation or high-flow oxygen, or signs and symptoms of an acute 
stroke (NIHSS >14)  
6. Invasive ventilation, ECMO or mechanical circulatory support; vasopressor 
therapy; or new receipt of renal replacement therapy  
7. Death 
 
The term ”usual activities,” in categories 1 and 2 for both outcomes, refers to activities of 
daily living that the participant was able to undertake prior to the current illness.  
4.1.1 Rationale for two ordinal outcomes 
There is as yet no consensus on the optimal endpoint for determining clinical benefit from 
COVID-19 therapies, including the constituent elements of the endpoint and the timing of its 
assessment after randomization. Both may differ depending on the target population and 
the nature of the treatment studied. 
While the pulmonary ordinal outcome focuses on the pulmonary components of COVID-19, 
the pulmonary+ ordinal outcome captures the range of complications experienced by 
hospitalized patients with COVID-19.  The pulmonary+ outcome recognizes that end-organ 
manifestations in addition to pneumonia and ARDS are increasingly emerging as significant 
contributors to morbidity, including morbidity resulting from the thromboembolic pathology 
of the disease. Emerging extrapulmonary events are also likely to affect the primary 
endpoint of sustained recovery. This ordinal outcome includes 7 well-defined mutually 
exclusive categories, each of which assesses further progression of disease, as well as 
recovery from COVID-19.  
While the two ordinal outcomes are correlated, it is yet to be determined which of these two 
outcomes will best identify the investigational agents that, when given with SOC, have 
activity that merits advancement. 
Day 5 was chosen for the timing of these ordinal outcomes for several reasons based on 
the following assumptions. The impact of the investigational agent on disease progression 
may not be immediate; a few days may be needed to see the effects on clinical outcomes 
as measured by each ordinal outcome. Also, transient treatment effects that are no longer 
present at Day 5 may be clinically less relevant. Assessment of the ordinal outcome at a 
later time point may result in a diminished treatment difference because spontaneous 
recovery from COVID-19 may have begun in many participants. Use of Day 5 to 
characterize the clinical severity of participants in 7 categories as studied here, results in a 
distribution of participants in the placebo group for the ordinal outcome that is sufficiently 
granular and not overly skewed to the most severe or least severe categories and, 
therefore, provides good power for comparing the two treatment groups (see section 6.3). 
Finally, an early time point of ascertaining the outcomes will facilitate more rapid interim 
analyses for these two ordinal outcomes.   
 
Primary and Secondary Outcomes to Evaluate Efficacy and Safety 
The primary endpoint is time from randomization to sustained recovery, defined as 
being discharged from the index hospitalization, followed by being alive and home for 
14 consecutive days prior to Day 90. 
Home is defined as the level of residence or facility where the participant was residing prior 
to hospital admission leading to enrollment in this protocol.  
4.2 


Residence or facility groupings to define home are: 1) Independent/community dwelling 
with or without help, including house, apartment, undomiciled/homeless, shelter, or hotel; 2) 
Residential care facility (e.g., assisted living facility, group home, other non-medical 
institutional setting); 3) Other healthcare facility (e.g., skilled nursing facility, acute rehab 
facility); and 4) Long-term acute care hospital (hospital aimed at providing intensive, 
longer term acute care services, often for more than 28 days).  
Lower (less intensive) level of residence or facility will also be considered as home. By 
definition, “home” cannot be a “short-term acute care” facility. Participants previously 
affiliated with a “long-term acute care” hospital recover when they return to the same or 
lower level of care.  
Readmission from “home” may occur and if this occurs within 14 days of the first discharge 
to “home”, then the primary endpoint will not be reached until such time as the participant 
has been at home for 14 consecutive days.  
Participants residing in a facility solely for public health or quarantine purposes will be 
considered as residing in the lowest level of required residence had these public health 
measures not been instated.  
Some recovering patients are discharged from the hospital while still requiring continuous 
low flow supplementary oxygen to maintain satisfactory blood oxygenation for some period 
of time. Sensitivity analyses will be carried out using outcomes which are variations of the 
definition of sustained recovery.  These outcomes will use definitions of sustained recovery 
that consider continuous use of supplemental oxygen reported during the 14-day period at 
home following discharge.  These outcomes are cited as secondary endpoints. 
4.2.1 Rationale for primary outcome 
The primary outcome is intended to identify efficacy among the investigational agents. 
Whereas mortality may be the most important outcome, the sample size to detect a 
plausible treatment effect for such an outcome would be much larger than outlined in this 
protocol and was judged not to be feasible to be the primary outcome. Nor was mortality 
considered to be the only relevant measure of efficacy in COVID-19. 
The primary outcome is assessed during 90 days of follow-up, which is longer than for other 
trials of investigational agents for COVID-19, which are typically 28 days. The longer follow-
up will allow better ascertainment of recovery from the longer-term consequences of the 
underlying disease, and hence the efficacy of the investigational agent. This is likely to be 
particularly true for patients who experience extra-pulmonary disease in conjunction with 
their COVID-19, and for patients enrolled while receiving care for life-threatening organ 
failure. It is also projected that excess mortality may still be observed beyond Day 28 until 
Day 90. All-cause mortality is an important secondary outcome (see below).  
4.2.2 Secondary outcomes 
In addition to the primary endpoint, several secondary efficacy endpoints will be assessed. 
These endpoints will be assessed for all participants enrolled.  
1. All-cause mortality through 90 days of follow-up 
 
2. Composite of time to sustained recovery and mortality through 90 days of follow-up 
 


3. Time to discharge for the initial hospitalization 
 
4. Days alive outside of a short-term acute care hospital up to day 90 
 
5. Ordinal outcomes, pulmonary+ and pulmonary, on Days 1-7, and pulmonary ordinal 
outcome on Days 14 and 28 
 
6. Clinical organ failure or serious infections defined by development of any one or more of 
the following clinical events through Day 28 (see PIM for criteria for what constitutes 
each of these conditions):  
 
a. Respiratory dysfunction: 
1. Respiratory failure defined as receipt of high flow nasal oxygen, non-
invasive ventilation, invasive mechanical ventilation or ECMO 
 
b. Cardiac and vascular dysfunction: 
1. Myocardial infarction 
2. Myocarditis or pericarditis  
3. CHF: new onset NYHA class III or IV, or worsening to class III or IV 
4. Hypotension requiring institution of vasopressor therapy 
 
c. Renal dysfunction: 
1. New requirement for renal replacement therapy  
 
d. Hepatic dysfunction: 
1. Hepatic decompensation 
 
e. Neurological dysfunction 
1. Acute delirium 
2. Cerebrovascular event (stroke, cerebrovascular accident [CVA]) 
3. Transient ischemic events (i.e., CVA symptomatology resolving <24 hrs) 
4. Encephalitis, meningitis or myelitis 
 
f. Haematological dysfunction: 
1. Disseminated intravascular coagulation 
2. New arterial or venous thromboembolic events, including pulmonary 
embolism and deep vein thrombosis 
3. Major bleeding events (>2 units of blood within 24 hours, bleeding at a 
critical site (intracranial, intraspinal, intraocular, pericardial, intraarticular, 
intramuscular with compartment syndrome, or retroperitoneal), or fatal 
bleeding). 
 
g. Serious infection: 
1. Intercurrent, at least probable, documented serious disease caused by an 
infection other than SARS-CoV2, requiring antimicrobial administration and 
care within an acute-care hospital.  
 
7. A composite of death, clinical organ failure or serious infections (see above)  
 
8. Outcomes assessed in other treatment trials of COVID-19 for hospitalized participants in 
order to facilitate cross-trial comparisons and overviews (e.g. 6- , 7-, and 8-category 


ordinal scales assessed at Days 1-7, 14 and 28; time to improvement in 1 or 2 
categories of ordinal scale; time to best 3 categories of ordinal scale, and binary 
outcomes defined by improvement or worsening based on other ordinal outcomes) 
 
9. A composite of cardiovascular events (outcomes listed above in items 6b1, 6e2 and 
6e3) and thromboembolic events (item 6f2)  
 
10. Safety and tolerability as measured by: 
a. A composite of grade 3 and 4 clinical adverse events, SAEs, clinical organ failure 
or serious infections (see item 6 above) or death through Day 5 (primary safety 
endpoint) and through Day 28 (the components of this composite will also be 
summarized) 
b. Infusion-related reactions of any severity and percentage of participants for whom 
the infusion was interrupted or stopped prior to completion 
c. A composite of SAEs, clinical organ failure or serious infections (see item 6 
above) or death through Day 90 
d. Adverse events of any grade through Day 7 
e. Prevalence of adverse events of any grade at Day 14 and Day 28 
f. A composite of hospitalization readmissions or death through 18 months. 
 
11. Change in antibody profile, overall titers of antibodies and neutralizing antibody levels 
from baseline to Days 1, 3, 5 and 28 and 90 
 
12. Outcomes that consider home use of supplemental oxygen above pre-morbid oxygen 
use for sensitivity analyses for the primary outcome: 
a. Alive at home and no use of continuous supplemental oxygen for an 
uninterrupted 14 day period 
b. Alive at home for an uninterrupted 14 day period and no use of continuous 
supplemental oxygen at the end of the 14 day time period. 
4.2.3 Rationale for secondary outcomes 
Mortality and the composite of time to death or sustained recovery (see section 11.2 for the 
analysis of this outcome using a win ratio statistic)74 are the two key secondary outcomes. 
An effective investigational agent should lead to a favorable trend for those these 
outcomes.  Conclusive evidence for a treatment difference in mortality requires larger 
sample sizes than planned, and we expect that there is better power for detecting a 
treatment effect in the composite outcome than mortality.  
Safety is assessed through a comprehensive review of data collected from baseline through 
follow-up. On day 0, during and immediately after the infusion, infusion-related reactions of 
any grade severity, and premature infusion termination are captured. From study entry 
through Day 28, deaths, grade 3 and 4 clinical adverse events, and the components of the 
two ordinal outcomes assessed at Day 5 contribute to the safety assessment. A composite 
primary safety outcome is defined at Day 5. On Day 0 and Day 5, safety laboratory test 
results are reported, and grading determined (section 9.1). Finally, SAE’s, SUSAR’s, 
(re)admissions for acute care, organ disease, and organ dysfunction including supportive 
treatment hereof, are ascertained during the entire follow-up period.  
The definitions of outcomes in different COVID-19 trials are evolving. It will be important to 
adequately capture data that enables the trial to “reconstruct” outcomes used in other trials. 


Finally, continuous supplemental oxygen is increasingly prescribed for patients discharged 
from the hospital following treatment for COVID-19.  Therefore, it will be important to carry 
out sensitivity analyses that consider home oxygen use in interpreting the results of the trial 
for the primary endpoint of sustained recovery.  
5 
Objectives 
 
Primary Objective 
The primary objective of this protocol is to determine whether investigational agents, initially 
focusing on those that are aimed at enhancing the host immune response to SARS-CoV-2 
infection are safe and superior to control (e.g., placebo) when given with SOC for the 
primary endpoint of time to sustained recovery evaluated up to 90 days after randomization.  
SOC may be modified (updated based on data from this or other trials) during the course of 
evaluating different investigational agents with this master protocol. 
 
Secondary Objectives 
Two key secondary objectives are to compare each investigational agent with control for all-
cause mortality and a composite outcome which considers both time to sustained recovery 
and mortality.  
Other secondary objectives are to compare each investigational agent with control for the 
secondary outcomes stated in section 4. 
In addition, the primary endpoint of time to sustained recovery will be evaluated for 
subgroups defined by the following characteristics measured at enrollment: 
• Disease severity as defined in the design for stratification 
• Age 
• Biological sex 
• Race/ethnicity 
• Type of residence/facility (home)  
• BMI 
• History of chronic conditions (cardiovascular disease, diabetes, asthma, chronic 
obstructive pulmonary disease, hypertension, hepatic impairment, chronic kidney 
disease, cancer) 
• Geographic location 
• Upper respiratory SARS-CoV-2 viral load 
• SARS-CoV-2 neutralizing antibody level 
• Duration of symptoms prior to enrollment 
• Respiratory function scale  
• Organ/respiratory dysfunction category based on each ordinal outcome (pulmonary+ 
and pulmonary)  
• NEW score 
• Disease progression risk score (defined using pooled treatment groups with the 
following baseline predictors of the primary outcome (sustained recovery): age, 
biological sex, duration of symptoms, ordinal category at entry, NEW score, and 
presence of chronic health conditions). 
5.1 
5.2 


6 
Study Design  
TICO (Therapeutics for Inpatients with COVID-19) is a master protocol to evaluate the 
safety and efficacy of multiple investigational agents aimed at modifying the host immune 
response to SARS-CoV-2 infection, or directly enhancing viral control in order to limit 
disease progression. Master protocols can provide a more efficient approach to the 
evaluation of multiple experimental interventions for a single disease such as COVID-19 in 
a continuous manner.  
The trial described in this master protocol is a phase III randomized, blinded, controlled 
platform trial that allows investigational agents to be added and dropped during the study 
for efficient testing of new agents against placebo within the same trial infrastructure. When 
more than one agent is being tested concurrently, participants will be randomized across 
agents, as well as to agent/control. This will allow rapid testing of multiple agents as the 
pooling of controls across agents requires fewer patients to be randomized to the matched 
control arm of each agent.  However, this will only occur when feasible and when multiple 
agents are available to be tested at the same time.  If an investigational agent shows 
superiority over placebo + SOC as initially defined, SOC for future investigational treatment 
evaluations will be modified accordingly.  
 
 
 


Figure 1.   A Phase III Platform Trial for Efficiently Evaluating Multiple 
Investigational Agents Over Time 
Figure 1 illustrates three aspects of the study design.  Investigational agents may enter the 
trial simultaneously or sequentially.  Agents B and C entered the trial simultaneously after 
agent A.  During the time of overlapping randomization for the 3 agents, placebo is shared 
as described in section 6.1.   All 3 agents share a placebo for part of the time in which 
patients in disease severity stratum 1 are enrolled.  For a period of time participants in 
disease severity stratum 2 are only eligible for Agent A/placebo.   
Agents which demonstrate an acceptable risk versus benefit profile in the initial cohort of 
participants in disease severity stratum 1 and pass the futility assessment based on the 
Day 5 ordinal outcomes continue enrollment with expanded eligibility criteria.  This is 
illustrated by both agents A and B.  Both agents advance to enroll participants in disease 
severity stratum 2 as well as 1.  Agent A advances shortly before agent B. 
Agent C illustrates an agent that did not pass the futility assessment in the initial cohort of 
patients in disease severity stratum 1.  Enrollment stopped for agent C.  Follow-up for the 
participants randomized (all in disease severity stratum 1) to agent C/placebo will continue 
through 18 months of follow-up in order to continue to assess safety and other outcomes. 
In some cases, more than one dose of an investigational agent will be studied. For such 
agents, only one of the doses will be advanced to the expanded cohort that includes 
participants in disease severity strata 1 and 2.  
Randomization and Stratification 
Patients will be equally allocated to each investigational agent + SOC or to placebo + SOC. 
For example, for a study of a single investigational agent, participants will be randomized in 
a 1:1 ratio to the investigational agent + SOC or placebo + SOC. If a participant is eligible 
for two investigational agents, the allocation will be 1:1:1 to investigational agent A + SOC, 
agent B + SOC, or placebo + SOC.  Because the two investigational agents (A and B) may 
require different placebos (for example, when infusion volumes differ), the 1:1:1 allocation 
ratio will be achieved through a two-step randomization procedure: in step 1, the participant 
is randomized 2:1 to “active” versus “placebo”; in step 2, the participant is randomized 1:1 
Agent A/placebo 
Agent B/placebo 
Agent C/placebo 
6.1 
Disease severity 
stratum 1 
Continue 
Disease severity 
stratum 1 
Disease severity 
stratum 1 
Continue 
Disease severity 
strata 1 and 2 
Disease severity 
strata 1 and 2 


to A versus B.  With k agents, this can be viewed as an initial k:1 allocation to “active” 
versus “placebo”, followed by a second, even allocation to one of the available agents (for 
example, if a participant was allocated to “placebo” in step 1, then the step 2 allocation will 
be 1:1 to “agent-specific placebo for A” versus “agent-specific placebo for B”).  Sites will be 
informed of the specific investigational agent/placebo (e.g., A or B) to which the participant 
was randomized (see section 6.2). For the analysis, the concurrent agent-specific placebo 
groups will be pooled, resulting in a 1:1 allocation ratio for comparing each investigational 
agent versus the (pooled) placebo group. 
If investigational agents are added or dropped, the allocation ratio to active versus placebo 
will be appropriately modified, and overall sample size will be recalculated as appropriate.  
Randomization will be stratified by study site pharmacy (several clinical sites may share 
one study site pharmacy) and severity of disease at entry.  The two strata that define 
disease severity are: 
Disease severity stratum 1: Absence of all of the following: stroke, meningitis encephalitis, 
myelitis, myocardial infarction, myocarditis, pericarditis, symptomatic congestive heart 
failure (NYHA class III or IV), arterial or deep venous thrombosis or pulmonary embolism, 
requirement for invasive mechanical ventilation, ECMO, mechanical circulatory support, 
vasopressor therapy, or new renal replacement therapy. 
Disease severity stratum 2: Presence of at least one of the excluded conditions or 
treatments in disease severity stratum 1.  
Within each stratum, mass-weighted urn randomization75 will be used to generate the active 
and placebo assignments. This will ensure throughout the trial placebo allocation near the 
intended ratio while also ensuring near equal numbers of active and matched placebo 
assignments to each agent.   
If more than one investigational agent is being compared with placebo and they have 
different contraindications, consideration will be given to allowing participants to enter with 
randomization to each agent versus placebo separately as well as randomization to both 
agents. If the number of participants expected to have a contraindication is small, they will 
be excluded from the trial rather than establishing a separate randomization mechanism. 
Comparisons will be of each investigational treatment against its control arm. The control 
arm consists of all participants who were “at risk” of being randomized to the investigational 
agent but were randomized to a control group instead. This concept is relevant when the 
randomization includes investigational agents with different eligibility criteria or introduction 
into the platform trial at different time points. Formal randomization includes a matched 
placebo group for each agent, and the placebo groups will be pooled across agents, but 
only participants who 1) were eligible for the investigational agent under consideration, and 
2) were randomized contemporaneously in a stratum will be included in the control group 
for a given agent. 
The default randomization allocation to agent (or its placebo) for which a participant is 
eligible is as outlined above. However, in some circumstances this allocation ratio may be 
changed by the (blinded) protocol leadership based on an overall assessment of how the 
master protocol framework is able to produce relevant and novel findings most effectively.  


 
Blinding 
Investigational agents or placebo (as necessary) will be prepared by a pharmacist who is 
not blinded to the treatment assignment.  All other study staff, including those at sites, and 
those in roles spanning multiple sites or spanning the protocol as a whole, will be blinded 
unless otherwise specified herein.  
For investigational agents infused, blinding of the participant and clinical staff will be 
achieved by placing a colored sleeve over the infusion bags used for investigational agents 
and placebos. Placebo will consist of an isotonic crystalloid, referred to as an isotonic saline 
solution.  
When more than one investigational agent is available for randomization, the clinical staff 
will be informed to which investigational agent/placebo the participant was randomly 
assigned for infusion, but they will be blinded to whether the random assignment was to the 
active investigational agent or matching placebo.  
If the blind is broken for safety reasons, this will be recorded, and the protocol chair will be 
notified. In that situation, every attempt will be made to minimize the number of people 
unblinded.  Specific unblinding procedures and instructions are found in the PIM. 
 
Sample size assumptions 
All sample size calculations are aimed at pairwise comparisons between a given 
investigational agent and its control arm.  The following assumptions were made in 
estimating the required sample size for this phase III trial. 
a. The primary analysis will be intention to treat.  Gray’s test with rho=0 will be used,76 
with stratification by disease severity at entry for comparing each investigational 
agent to control for the primary endpoint of time to sustained recovery (see section 
4.2.1).  Gray’s test with rho=0 is the analogue of the log-rank test in the presence of 
competing risks; it is used here to account for the competing risk of death when 
analysing time to sustained recovery. 
 
b. Type 1 error will be set at 0.025 (1-sided). This type 1 error will not be adjusted for 
the number of investigational agents being compared with placebo as each of the 
agents is expected to impact the primary endpoint through different mechanisms. If 
this is not the case, a type 1 error adjustment may be considered.   
 
c. Power is set at 90% to detect a 25% increase in the rate of sustained recovery for 
the investigational treatment compared to placebo. This moderate efficacy is 
assumed considering the findings from ACTT-1 and the percentage of patients in 
each baseline risk category of the pulmonary ordinal outcome.77  For an 
investigational agent that passes the initial futility assessment based on participants 
in disease severity stratum 1 that are initially enrolled, we expect approximately 50% 
of participants enrolled in the cohort expansion that includes both disease severity 
strata 1 and 2 to be in categories 5 or 6 of the ordinal outcome. Since most 
participants enrolled in the initial cohort will be categories 2, 3 or 4 of the ordinal 
outcome, we assume that 35% of patients in the final analysis will be in the more 
severe categories of the ordinal outcome; mortality is expected to be higher for 
participants in the more severe categories at entry. Among surviving patients we 
assume most will have met the criteria for sustained recovery.  
 
6.2 
6.3 


d. With these assumptions for type 1 and type 2 error and a sustained recovery rate 
ratio of 1.25 for the investigational agent versus control, 843 sustained recoveries 
are needed.78,79   
 
e. Given the planned 90 day follow-up for each participant, we estimate that the sample 
size is slightly larger than the number of recoveries (i.e., we expect a low rate of 
loss-to-follow-up or deaths). For 2 groups, we assume that the sample size is 
approximately 20% higher than the number of recoveries, to account for deaths, a 
small number of withdrawals of consent, and a small number of patients remaining in 
the hospital at Day 90. Total sample size for 2 groups is approximately 1,000 
(500 per group).  
 
f. In order to observe 843 sustained recoveries among 1000 participants, and 
assuming 3% withdrawal of consent, at least 87% of participants (pooled across the 
two treatment arms) would have to achieve sustained recovery by Day 90.  
Assuming a recovery rate ratio of 1.25, this corresponds to 89.9% with sustained 
recovery among those randomized to the investigational agent, compared with 
84.1% in the control group.  
 
Sample size will be re-estimated before enrollment is complete to determine whether the 
planned sample size of 1,000 participants followed for 90 days will yield the planned 
number of primary events.  Sample size may be increased to achieve the event target in the 
planned follow-up of 90 days.  A sample size increase may also be considered in order to 
achieve the event target before all participants are followed for 90 days.  
 
 Schedule of Assessments 
Participants will be randomized and given their initial infusion on Day 0. All participants 
randomized will be followed through 18 months following randomization for collection of 
study data (Appendix B and section 9.1 for details).  
 
Approach to Intercurrent Therapies and Clinical Trial Co-enrollment 
In general, the study will take a pragmatic approach to the use of intercurrent, concomitant 
medications. Except for use of convalescent plasma, hyperimmune SARS-CoV-2 
immunoglobulin or nMAb which is not permitted prior to entry or before Day 5, there are few 
restrictions.  
Sponsor and/or protocol leadership may, based upon convincing new evidence, act in the 
interest of participant protection, and in avoidance of confounding, to exclude/dis-allow use 
of any specific concomitant therapy found to be reasonably contraindicated for a well-
defined portion of the study population (see Appendix I). Such a determination may be 
made, communicated, and implemented by a Protocol Clarification Memo until it is 
reasonable to amend the protocol for other reasons.   
Participants will be asked at screening to agree to refrain from participation in other clinical 
trials until at least the assessment at Day 5 except for certain trials approved by trial 
leadership. It is recognised that, in the case of progression during follow-up to life-
threatening disease and end-organ failure (broadly categories 5 and 6 of the intermediate 
outcome measure; section 4.1) there will be considerable clinical concern, and participation 
in an additional clinical trial at that time will not be restricted.  
The protocol leadership will make a determination on the appropriateness of a trial for 
which co-enrolment will be allowed.  
6.4 
6.5 


 
Prior participation in clinical trials (except receipt of hIVIG, convalescent plasma or another 
nMAb) is not restricted, recognising for example that participants may have enrolled in a 
study for mild disease prior to progression and then may wish to participate in this study at 
the onset of progression. 
All participants will be compared throughout follow-up, irrespective of use of concomitant 
treatments. Concomitant treatments will be recorded at baseline, Day 5 and Day 28. The 
study randomization and study site pharmacy stratification will balance the use of 
concomitant medications on average at baseline and these will be summarized with other 
baseline characteristics. Follow-up use of concomitant treatments may differ by treatment 
group reflecting different efficacy/safety of the study treatments and use of concomitant 
treatments will be summarized by treatment group. 
7 Study Population 
For each investigational agent, an estimated 1,000 COVID-19 participants will be enrolled 
at clinical trial sites globally. The time from screening (Day -1 or Day 0) to end of study for 
an individual participant is 18 months. 
Patient eligibility must be confirmed by a study clinician named on the delegation log. 
Initially, approximately 300 participants in the disease severity stratum 1 will be enrolled.  
For investigational agents passing an initial futility assessment for these participants, 
enrollment will be expanded, seamlessly and without any data unblinding, to include 
participants in disease severity stratum 2 as well as those in disease severity stratum 1.   
Protocol inclusion and exclusion criteria are intentionally straightforward and are NOT 
subject to exception for even minor deviations by Study Medical Officers or by the Sponsor 
Medical Monitor. 
 
Inclusion Criteria 
1. Age ≥ 18 years; 
 
2. Informed consent by the patient or the patient’s legally-authorized representative 
(LAR)*; 
 
3. SARS-CoV-2 infection, documented by a nucleic acid test (NAT) or equivalent testing 
within 3 days prior to randomization OR documented by NAT or equivalent testing more 
than 3 days prior to randomization AND progressive disease suggestive of ongoing 
SARS-CoV-2 infection per the responsible investigator (For non-NAT tests, only those 
deemed with equivalent specificity to NAT by the protocol team will be allowed.  A 
central list of allowed non-NAT tests will be maintained.); 
 
4. Duration of symptoms attributable to COVID-19 ≤ 12 days per the responsible 
investigator; 
 
5. Requiring admission for inpatient hospital acute medical care for clinical manifestations 
of COVID-19, per the responsible investigator, and NOT for purely public health or 
quarantine purposes. 
 
*Continuing consent  
7.1 


For participants whose consent was initially obtained from a LAR, but who subsequently 
regain decision-making capacity while in hospital will be approached for consent for 
continuing participation, including continuance of data acquisition. The consent form signed 
by the LAR should reflect that such consent should be obtained. 
 
Exclusion Criteria  
1. Prior receipt of 
• Any SARS-CoV-2 hIVIG, convalescent plasma from a person who recovered from 
COVID-19 or  
•   SARS-CoV-2 nMAb at any time prior to hospitalization;  
 
2. Not willing to abstain from participation in other COVID-19 treatment trials until after Day 
5 (With the approval of study leadership, enrollment before or on Day 5 is permitted for 
individual trials.)  
 
3. In the opinion of the responsible investigator, any condition for which, participation 
would not be in the best interest of the participant or that could limit protocol specified 
assessments; 
 
4. Expected inability to participate in study procedures;  
 
Prior to the initial futility assessment for an investigational agent, the following two 
additional exclusions (5 and 6) which define disease severity stratum 2 apply: 
 
5. Presence at enrollment of any of the following:  
a. stroke  
b. meningitis 
c. encephalitis 
d. myelitis 
e. myocardial infarction 
f. myocarditis 
g. pericarditis 
h. symptomatic CHF (NYHA class III-IV) 
i. arterial or deep venous thrombosis or pulmonary embolism 
 
6. Current requirement for any of the following: 
a. invasive mechanical ventilation 
b. ECMO 
c. mechanical circulatory support 
d. vasopressor therapy 
e. commencement of renal replacement therapy at this admission (i.e. not patients 
on chronic renal replacement therapy).    
 
Exclusions that may be appropriate for an investigational agent studied are referenced in 
the relevant appendix (H) for the investigational agent. The contraindications for use of 
components of SOC are outlined in Appendix I and in the PIM.  
 
Costs to Participants 
There is no cost to participants for the research tests, procedures/evaluations and study 
product while taking part in this trial. Procedures and treatment for clinical care including 
7.2 
7.3 


costs associated with hospital stay may be billed to the participant, participant’s insurance 
or third party. 
8 Study Product 
Investigational agents and SOC treatment to be used are described in Appendices H and I, 
respectively. 
9 Study Assessments and Procedures 
 
Screening/Baseline and Follow-up Assessments 
Data collection at each visit is outlined below and summarized in Appendix B. Day 0 refers 
to the day on which randomization occurs and on which the investigational agent/placebo is 
infused.  Screening and randomization can be done in the same session.  The term 
“baseline” refers to data that are collected prior to randomization. 
9.1.1 Screening/Baseline Assessments 
After obtaining informed consent, the following assessments are performed within 24 hours 
prior to randomization to confirm eligibility and to collect baseline data: 
• Documentation of SARS-CoV-2 infection by NAT or equivalent testing that was 
performed within 3 days prior to randomization, OR documentation by NAT or equivalent 
testing more than 3 days prior to randomization AND progressive disease suggestive of 
ongoing SARS-CoV-2 infection) 
 
• A focused medical history, including the following information:  
 Demographics including age, gender, and type residence or facility prior to 
current illness (i.e. “home”) 
 Day of onset of COVID-19 signs and symptoms 
 Components of ordinal outcomes 
 History of chronic medical conditions, including targeted conditions for 
outcome analysis  
 Targeted concomitant medications and SARS-CoV-2 vaccine trial 
participation 
 
• A focused physical examination including height and weight 
 
• Respiratory function scale 
 
• Blood draw for local laboratory evaluations: 
 White blood cell count 
 Hemoglobin 
 Platelets 
 Lymphocytes 
 CRP  
 Serum creatinine 
 Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) 
 
 Vital signs for NEW score 
 
9.1 


• Plasma and serum specimens for central testing for SARS-CoV-2 antibody determination 
and storage for future related research (four 1.0 mL aliquots of serum and four 1.0 mL 
aliquots of plasma).  Two 9 mL tubes, one SST and one EDTA, of blood (18 mL total) will 
be drawn in order obtain the 8 aliquots. 
 
• Midturbinate nasal swab procedure for central determination of SARS-CoV-2 viral load 
• Contact details (phone, e-mail or other types of contact) for the participant and at least 
two close relatives/friends, to ensure reliable data collection during follow-up in the trial.   
• Urine or serum pregnancy test in women of childbearing potential who do not already 
have evidence of pregnancy 
In some cases, it may not possible to draw blood for local laboratory assessments and 
storage and/or to obtain a midturbinate nasal swab for storage prior to the time of 
randomization.  In these cases, the blood draw and swab collection can be obtained after 
the time of randomization but before the infusion of the blinded investigational 
agent/placebo. 
The overall eligibility of the patient for the study will be assessed once all screening 
information is available. The screening process can be suspended prior to completion of the 
assessment at any time if exclusions are identified by the study team. 
Participants who qualify will be randomized within 24 hours of consent and given the 
infusion of the blinded investigational agent/placebo.  Immediately prior to randomization, 
the disease severity stratum of the participant should be verified. 
On Day 0 following randomization the following are assessed: 
• Adverse events of any grade severity present prior to the infusion 
• Start and stop times of the infusion of the investigational agent/placebo and 
remdesivir 
• Infusion-related reactions to the investigational agent/placebo 
• Medication used prophylactically or therapeutically to manage infusion-related 
reactions 
• New adverse events of any grade severity during and after the infusion 
 
Participants should be monitored for at least 2 hours post infusion and have a final check 
2 hours later. Participants who experience AEs during or after the infusion should be 
followed closely until the resolution of the AE.   
9.1.2 Follow-up Assessments 
Participants will be followed through 18 months following randomization for collection of 
study data (Appendix B). Clinical data will be collected on Days 0-7, 14, 28, 60, 90, 
6 months, 12 months, and 18 months. These data will include discharge status, and interim 
changes in medical history (targeted to components of the intermediate ordinal outcomes 
and secondary endpoints). Local laboratory measurements will also be obtained on Day 5. 
Concomitant medications will be collected on Days 5 and 28, clinical (i.e., not limited to a 
laboratory abnormality) incident AEs of grade 3 and 4 severity through Day 28, and 
hospitalization readmissions and deaths through 18 months. 
Both intermediate ordinal outcomes will be assessed on Days 1-7. Adverse events of any 
grade severity will be collected on Days 0-7.  The pulmonary ordinal outcome will also be 
assessed on Days 14 and 28. On Days 14 and 28 AEs of any grade severity will also be 


collected. Components necessary to determine the pulmonary ordinal outcome will be 
collected to allow the computation of the ordinal outcome for every day through Day 14.  
At the time of discharge, the residence/place of living to which the participant was 
discharged and whether it was the type of residence (i.e. “home”) occupied at the time of 
onset of COVID-19 symptoms will be ascertained.  All changes in this status (e.g., re-
admission to another hospital or an intermediate care facility) will be collected at 
approximately 2 week intervals, starting with the day 14 visit, to assess when the participant 
meets the criterion for the primary endpoint of 14 consecutive days “home”.  With this plan 
we will also address the secondary outcome of total days alive outside of a short-term acute 
care hospital.  
For participants who are no longer hospitalized, in-person visits will be done on study Days 
1, 3, 5, 28 and 90, when blood is collected. At each of these visits, plasma and serum 
specimens for central testing for SARS-CoV-2 antibody determination and storage (four 
1.0 mL aliquots of serum and four 1.0 mL aliquots of plasma) will be obtained for future 
related research.  Two 9 mL tubes, SST and EDTA, of blood (18 mL total) will be drawn in 
order obtain the 8 aliquots.  If it is not possible to do an in-person visit on Day 3 or Day 5, 
the participant should be contacted to record the required clinical data on the study day and 
blood draws may be done one day earlier or one day later.  In person research visits for 
participants at their residents or home health and mobile phlebotomy services may also be 
utilized to complete protocol-required data/specimen collection during follow-up.  
For other visits on Days 7, 14, 42, 60, and 75, 6 months, 12 months, and 18 months, 
contact with the participant for study data collection may be performed by telephone or 
other electronic communication. Other information will be gathered, as outlined in Appendix 
B. This will include information on hospital readmissions (e.g., date of readmission, date of 
discharge, and reason for readmission) and deaths through 18 months.  Safety data 
collection and reporting are described further in section 10.  
9.1.3 Stored Samples and Future Research 
The plasma and serum specimens collected as outlined above and the inoculum from the 
baseline mid-turbinate nasal swab will be stored at a central specimen repository in the US.  
In addition to the specified testing to be done per protocol, the specimens will be available 
for later use in research concerning COVID-19, SARS-CoV-2, and the impact of the study 
treatment.  Proposed research utilizing these specimens will be reviewed and approved by 
the study scientific steering committee.  Results of research tests on individual specimens 
will not be given to participants or their clinicians.  Aggregate research results will be made 
available. 
10 Safety Assessment 
The safety evaluation of the study intervention includes several components, all of which 
will be regularly reviewed by the independent DSMB.  For this protocol, the term “study 
intervention” refers to the investigational agent or placebo, and to study provided SOC 
treatment(s).  
Infusion-related reactions of any grade are only collected for the blinded investigational 
agent/placebo. All other AEs are collected for the study intervention (either the blinded 
investigational agent/placebo or study provided SOC treatment). 
The following information will be collected on eCRFs to evaluate safety: 


• Infusion-related reactions of any grade severity during, or within 2 hours post-
infusion of the investigational agent/placebo. 
• Targeted laboratory results centrally graded for severity at Day 5. 
• Clinical adverse events of any grade severity on Days 0-7, on Day 14 and on Day 28 
(isolated laboratory abnormalities that are not associated with signs, symptoms, or a 
specific clinical diagnosis/syndrome are not collected).  
• Clinical adverse events of grade 3 and 4 through Day 28 (isolated laboratory 
abnormalities that are not associated with signs, symptoms, or a specific clinical 
diagnosis/syndrome are not collected). 
• Clinical events, including death, that are reported on eCRFs as part of the 
pulmonary+ ordinal outcome or as secondary outcomes through Day 90. These are 
considered as protocol specified exempt serious events (see 10.2.5) and are not 
reported on SAE eCRFs unless they are considered related to the study intervention 
(either the blinded investigational agent/placebo or a study-provided SOC treatment).  
Protocol exempt serious events are listed in section 10.2.5 and the PIM. 
• Serious adverse events, including laboratory-only serious events, through Day 90 
that are: 
 Related to the study intervention; or. 
 Not exempt from reporting on the SAE eCRF (events listed in section 10.2.5 
are exempt).  
• Unanticipated problems through Day 90. 
• Deaths through 18 months. 
• Hospital readmissions through 18 months. 
 
An overview of safety data collected during the study is given in Table 1. 


Table 1  Overview of Safety Data Collection 
 
Infusion 
+2 hrs 
 Days 0-7 
Day 14 
Day 28 
Day 90 
Months 
6, 12 
and 18 
Infusion-related reactions 
and symptoms 
X 
 
 
 
 
 
Clinical AEs of any grade 
severity 
 
X 
X 
X  
 
 
Grade 3 and 4 clinical AEs 
from Day 7 through Day 
28* 
 
 
X 
X 
 
 
Targeted laboratory 
abnormalities of any grade 
 
X 
(Day 5) 
 
 
 
 
Hospital admissions and 
deaths 
 
Collected through Month 18 
Targeted clinical events 
collected as study 
endpoints** 
Collected through Day 90 
 
SAEs not exempt from 
reporting (i.e., not 
considered a protocol 
specified exempt event) 
Collected through Day 90 
 
Any SAE related to study 
intervention 
 
Collected through Day 90 
 
Unanticipated problems  
Collected through Day 90 
 
* Grade 3 and 4 clinical AEs on Days 1-7 are reported each day; those occurring 
between Days 8 and 14 are reported at the Day 14 visit, and those occurring between 
Days 15 and 28 are reported at the Day 28 visit. 
** see section 10.2.5 for protocol specified exempt serious events and the PIM 
 
Definitions and methods of reporting each type of event are given below. 
 Definitions 
10.1.1 Adverse Event (AE) 
An AE is any untoward or unfavourable medical occurrence in a study participant, including 
any abnormal sign (e.g., abnormal physical exam or laboratory finding), symptom, or 
disease, temporally associated with their participation in research, whether or not 
considered related to the research. If a diagnosis is clinically evident (or subsequently 
determined), the diagnosis, rather than the individual signs and symptoms or lab 
abnormalities, will be recorded as the AE.  
10.1 


In Appendix H details are outlined for each investigational agent under study of the 
following: specific AEs observed to be possibly associated with the agent in question, and 
how to monitor for, clinically handle and report such AEs, should they arise.  
10.1.2 Criteria for Seriousness 
Events are serious if they lead to one of the following outcomes:  
• 
Death 
• 
Life-threatening (i.e., an immediate threat to life)  
• 
Hospitalization or prolongation of hospitalization 
• 
Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions  
• 
Congenital abnormalities/birth defects  
• 
Other important medical events that may jeopardize the participant and/or may require 
intervention to prevent one of the outcomes listed above 
10.1.3 Unanticipated Problems 
An Unanticipated Problem (UP) is any incident, experience or outcome that is: 
1. Unexpected in terms of nature, severity, or frequency in relation to: 
a. the research risks that are described in the IRB-approved research protocol and 
informed consent document; Investigator’s Brochure or other study documents; and 
b. the characteristics of the population being studied; and 
2. Possibly, probably, or definitely related to participation in the research; and 
3. Places study participants or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized per 
the Investigator’s Brochure(s) (IBs).  
Furthermore, a UP could be an expected event that occurs at a greater frequency than 
would be expected based on current knowledge of the disease and treatment under study. 
The DSMB providing oversight to the study may make such an assessment based on an 
aggregate analysis of events. 
10.1.4 Severity 
The investigator will evaluate all AEs with respect to both seriousness (results in outcomes 
as above) and severity (intensity or grade).  AEs will be graded for severity according to 
the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (also 
known at the DAIDS AE Grading Table; see Appendix D for the URL). 
For specific events that are not included in the DAIDS AE Grading Table, the generic scale 
below is to be used: 


Table 2 GENERIC AE GRADING SCALE 
 
Grade 1 
 
Events causing no or minimal interference with usual social and 
functional activities, and NOT raising a concern, and NOT requiring a 
medical intervention/ therapy. 
Grade 2 
Events causing greater than minimal interference with usual social and 
functional activities; some assistance may be needed; no or minimal 
medical intervention/therapy required. 
Grade 3 
Events causing inability to perform usual social and functional 
activities; some assistance usually required; medical 
intervention/therapy required. 
Grade 4 
Events causing inability to perform basic self-care functions; medical or 
operative intervention indicated to prevent permanent impairment, 
persistent disability, or death 
Grade 5 
Events resulting in death 
10.1.5 Causality 
Causality refers to the likelihood that the event is causally related to the study intervention.  
It will be assessed for SAEs and UPs.  This assessment will be made for both the blinded 
investigational agent/placebo and any study-supplied SOC treatment using the following 
guidelines: 
• 
Reasonable possibility:  There is a clear temporal relationship between the study 
intervention and the event onset; and the event is known to occur with the study 
intervention or there is a reasonable possibility that the study intervention caused the 
event.  Reasonable possibility means that there is evidence to suggest a causal 
relationship between the study intervention and the event. 
 
• 
No reasonable possibility:  There is no evidence suggesting that the study 
intervention caused the event, there is no temporal relationship between the study 
intervention and event onset, or an alternate etiology has been established. 
The causality assessment is based on available information at the time of the assessment 
of the event.  The investigator may revise these assessments as additional information 
becomes available. 
10.1.6 Expectedness 
Expectedness will be assessed for SAEs using the Reference Safety Information section of 
the IBs for the investigational agent and any study-provided background therapy. 
The expectedness assessment is based on available information at the time of the 
assessment of the event.  The investigator may revise these assessments as additional 
information becomes available. 


 Schedule for Reporting of Specific Events 
This section describes the schedule for reporting different types of safety outcomes on 
eCRFs as part of the protocol data collection plan.  It is recognized that in the care of study 
participants, more information may be collected and recorded in the participant’s medical 
record.  The information collected in the medical record serves as source documentation of 
events (e.g., signs, symptoms, diagnoses) considered for reporting on eCRFs as part of 
protocol data collection.  
10.2.1 Infusion-related reactions 
Infusion-related signs/symptoms of any grade that are new or have increased in grade 
compared to their pre-infusion level are reported on the infusion eCRF checklist for the 
investigational agent/or matched placebo if they occur during or within 2 hours post 
infusion.  Any infusion related reaction assessed as meeting SAE criteria will also be 
reported on an SAE eCRF. 
10.2.2 Targeted Laboratory Abnormalities 
Selected laboratory tests are reported from assessments made on Day 0 and Day 5. These 
values will be associated with a severity grade centrally using the laboratory test results 
reported on the eCRFs (using normal ranges when applicable), and with the DAIDS AE 
Grading Table. 
 
Other laboratory abnormalities identified in the course of the participant’s routine clinical 
care (e.g., an isolated elevated glucose level) are not reportable as AEs unless they are 
associated with signs or symptoms, or associated with a specific clinical 
diagnosis/syndrome (e.g., diabetic ketoacidosis), in which case the syndrome/diagnosis is 
reported on the appropriate adverse event eCRF.  In addition, if an isolated laboratory test 
result meets SAE reporting criteria (e.g., the laboratory abnormality meets the criteria for a 
serious event as outlined in section 10.1.2), it should be reported as an SAE on the SAE 
eCRF. 
 
10.2.3 Clinical adverse events of any grade severity on Days 0-7, 14 and 28 
Beginning 2 hours post-infusion of the investigational agent or matched placebo, on Days 
0-7, clinical AEs that are new or that have increased in grade compared to their pre-infusion 
level will be reported on eCRFs.  
 
On Day 14 and on Day 28 AEs of any grade severity that the participant reports that day 
will also be collected on an eCRF. 
 
These reportable AEs should be assessed for SAE/UP (sections 10.2.6 and 10.2.7) 
reporting on the SAE eCRF or for protocol specified exempt serious events (section 10.2.5) 
reporting on the eCRF documenting the hospital course.    
 
This information supplements the data collected on Grade 3 and 4 events since the last 
study visit described in section 10.2.4.  
10.2 


10.2.4 Grade 3 and 4 clinical adverse events through Day 28 
Adverse clinical events reaching Grade 3 or 4 severity level that occur between days 8 and 
28 will be reported on an eCRF at the Day 14 and Day 28 visits.  The date the event 
reached the indicated grade will be collected to permit time-to-event analyses.    
 
These reportable AEs should be assessed for SAE/UP (sections 10.2.6 and 10.2.7) 
reporting on the SAE eCRF or for protocol specified exempt serious events (section 10.2.5) 
reporting on the eCRF documenting the hospital course.    
10.2.5 Protocol specified exempt serious events 
Protocol specified exempt serious events are listed below.  These events are reported 
systematically on eCRFs as study endpoints during follow-up and are further defined in the 
PIM.  They will NOT be reported on the SAE eCRF unless the investigator considered 
that there was a reasonable possibility that the study intervention (blinded 
investigational agent/ placebo or study-supplied SOC treatment) caused the event 
(see section 10.2.6).  These events may occur during the initial hospitalization, lead to a 
re-admission, or occur in a later hospitalization during follow-up.  
The following are protocol specified exempt serious events.  As noted above, these 
events are not reported on the SAE eCRF unless they are considered related to the study 
intervention (blinded investigational agent/placebo or study provided SOC). 
• 
Death 
• 
Stroke 
• 
Meningitis 
• 
Encephalitis 
• 
Myelitis 
• 
Myocardial infarction 
• 
Myocarditis 
• 
Pericarditis 
• 
New onset of worsening of CHF (NYHA class 3 or 4) 
• 
Arterial or deep vein thromboembolic events 
• 
Respiratory failure defined as receipt of high flow nasal oxygen, non-invasive 
ventilation, invasive mechanical ventilation or ECMO 
• 
Hypotension requiring vasopressor therapy 
• 
Renal dysfunction requiring renal replacement therapy 
• 
Hepatic decompensation 
• 
Neurologic dysfunction, including acute delirium and transient ischemic events 
• 
Disseminated intravascular coagulation 
• 
Major bleeding events 
• 
Serious infections 
 
10.2.6 Reportable SAEs 
Reportable SAEs for this study are serious events that are: 
 Related to the study intervention; or. 
 Not exempt from reporting on the SAE eCRF (events listed in section 10.2.5 are 
exempt).  


Deaths, life-threatening events, and other SAEs considered potentially related to the 
blinded investigational agent/placebo or study-supplied SOC treatment, irrespective of 
whether the event is mentioned above as a protocol specified exempt serious event, that 
occur from the time of infusion of the study intervention through the Day 90 visit must be 
recorded by sites on the SAE eCRF within 24 hours of site awareness. 
Suspected unexpected serious adverse reactions (SUSARs) are reportable SAEs that are 
assessed as related to a study intervention and are unexpected per the Reference Safety 
Information of the IB for that intervention.  SUSARs are reported from the INSIGHT Safety 
Office to applicable regulators in an expedited fashion.  SUSARs that result in death or are 
immediately life-threatening are reported to regulators within 7 calendar days of receipt.  All 
other SUSARs are reported to regulators within 15 calendar days.  The INSIGHT Safety 
Office will generate a Safety Report for each SUSAR for distribution to investigators and 
other parties.  Investigators are responsible for submitting Safety Reports to their 
overseeing IRB/EC per requirements. 
SAEs that are not protocol specified exempt serious events and that are not related to the 
study intervention (blinded investigational agent/placebo or study-supplied SOC treatment) 
must be reported on the SAE eCRF within 3 days of site awareness. 
 
SAEs are followed until the outcome of the SAE is known.  If the outcome of an SAE is still 
unknown at the time of the final follow-up visit, the outcome will be entered in the database 
as “unknown.” 
10.2.7 Unanticipated Problems (UPs) 
UPs must be reported via the appropriate eCRF to the INSIGHT Safety Office no later than 
7 calendar days after site awareness of the event. Investigators are responsible for 
submitting UPs that are received from the sponsor to their overseeing IRB/EC.  
Investigators must also comply with all reporting requirements of their overseeing IRB/EC. 
10.2.8 Deaths 
All deaths are reported on the eCRF for deaths.  Deaths considered related to the study 
intervention (blinded investigational agent/placebo or study-supplied SOC) must also be 
reported as an SAE.   
10.2.9 Pregnancy 
Female participants who are or become pregnant 
If required by the agent-specific appendix for the study agent to which the participant has 
been randomized, the investigator will collect pregnancy information on any female 
participant who is or becomes pregnant while participating in this study.   
The participant will then be followed to determine the outcome of the pregnancy and 
reported on the Pregnancy Outcome eCRF.  
Male participants with partners who become pregnant 
The following is only applicable if required by the agent-specific appendix for the study 
agent to which the participant has been randomized.  If an investigator learns that a male 
participant’s partner has become pregnant while the male participant is in this study, the 
investigator is asked to attempt to obtain information on the pregnancy, including its 


outcome, after obtaining consent from the pregnant partner.  The outcome of the pregnancy 
will be reported on the Pregnancy Outcome eCRF. 
 Medical Monitor 
A Medical Monitor appointed by the sponsor will be responsible for reviewing all SAEs, 
making an independent assessment of causality and expectedness, preparing sponsor 
safety reports, and communicating as needed with the DSMB and the Investigational New 
Drug (IND) holder through the study safety office or other mechanism mutually agreed to 
and documented.  
 Halting Enrollment for Safety Reasons 
The sponsor medical monitor or the DSMB may request that enrollment be halted for safety 
reasons (e.g., unacceptably high rate of infusion-related reactions or other unanticipated 
AEs).  If the study is temporarily halted or stopped for safety reasons, IRBs/ethics 
committees will be informed. The IND holder and sponsor, in collaboration with the protocol 
chair and the DSMB, will determine if it is safe to resume the study. The sponsor will notify 
the Site Investigators of this decision. The conditions for resumption of the study will be 
defined in this notification. The Site Investigators will notify their local IRBs/ethics 
committees of the decision to resume the study. 
11 Statistical Analyses and Monitoring Guidelines 
This section describes the analysis for primary and secondary outcomes of the trial. A more 
detailed statistical analysis plan (SAP) has been developed as a separate document.  The 
SAP for each investigational agent may be updated by the blinded statisticians prior to 
unblinding for a specific treatment comparison.   
Comparisons between each investigational agent and concurrent controls will be by 
intention to treat unless otherwise stated.  Safety comparisons will be carried out on 
participants who received a complete or partial infusion of the investigational agent unless 
otherwise specified. It is anticipated that all study site pharmacies serving active sites will 
be randomizing all agents under study at any given time, but if this is not the case, 
comparisons will be restricted to the set of controls enrolled at study site pharmacies where 
the drug was available for randomization. Specifically, the control group for an 
investigational agent will consist of those participants who could have been randomized to 
the agent, but were randomized to a control group instead (i.e., randomized to the matched 
control group of one of the agents included in the randomization). Agents will be compared 
to controls, but not to each other, unless explicitly specified in the analysis plan. 
All analyses will utilize 2-sided tests with a 5% significance level unless otherwise noted. 
 Analysis of the Primary Efficacy Endpoint 
The evaluation for the primary efficacy outcome of the phase III trial, time to sustained 
recovery through Day 90, will be based on Gray’s test with rho=0.80  The test will compare 
the investigational agent versus the control group by intention to treat, and will be stratified 
by disease severity at entry and study site pharmacy. Gray’s test compares the cumulative 
incidence functions for sustained recovery between the treatment groups, taking into 
account the ”competing risk” of death in analysing sustained recovery. Gray’s test with 
rho=0 is the analogue of the log-rank test in the presence of competing risks.  Cumulative 
incidence functions for sustained recovery will be estimated by treatment group using the 
Aalen-Johansen estimator,81 and the recovery rate ratio (RRR) (investigational agent 
10.3 
10.4 
11.1 


versus control) for sustained recovery will be estimated using the Fine-Gray method,82,83 
stratified by disease severity at entry and study site pharmacy; the RRR will be estimated 
as a point estimate with a 95% CI.  The Aalen-Johansen estimator for cumulative incidence 
functions is the analogue of the Kaplan-Meier estimator in the presence of competing risks.  
The Fine-Gray method is the competing risks equivalent of Cox proportional hazards 
models; the RRR compares the cumulative incidence rates of sustained recovery between 
the study arms, and is a sub-distribution hazards ratio.  Analyses for the sustained recovery 
endpoint require methods that take into account the competing risk of death, as participants 
may die before ever achieving sustained recovery.  The “sustained recovery” outcome 
requires knowledge of a participant’s residence status for at least 14 days after arriving 
“home” (as defined in section 4.2); since all participants are hospitalized at study entry, it 
takes at least 15 days to attain this outcome. 
Sensitivity analyses for the primary endpoint comparisons will include consideration of 
home oxygen used as described in section 4.2.2. 
 Analyses of Secondary Efficacy Endpoints, Safety Outcomes, and 
Subgroups 
Mortality is a key secondary outcome; time to death will be compared between the 
investigational agent versus control using a log-rank test, stratified by disease severity and 
study site pharmacy; the hazard ratio will be estimated using a stratified Cox proportional 
hazards model, and the proportion of participants who died by fixed time points (for 
example, Day 28 or Day 90) will be estimated using Kaplan-Meier estimates. To 
supplement the separate analyses of time to sustained recovery and time to death, the two 
endpoints will be analyzed jointly using the “win ratio” method74 for the composite outcome 
of time to recovery or death. At a given time point (Day 90), the win ratio statistic ranks 
participants’ outcomes into three ordered categories, death, alive but not achieved 
sustained recovery, alive and achieved sustained recovery, and ties are broken by time 
since randomization.  So, time to death is first used to determine the winning group (i.e., 
longer time to death), then time to sustained recovery is used to determine the winning 
group (i.e., shorter time to recovery): in this manner these conflicting outcomes can be 
combined into a composite while recognizing the importance of mortality. Matching on 
baseline disease severity will be used to estimate the win ratio statistic.  This combination 
of time to sustained recovery and time to death is also a key secondary analysis. 
The primary safety outcome is a composite of grade 3 or 4 events, SAEs, clinical organ 
failure or serious infections, or death through Day 5, and tests for differences between 
treatment arms will be conducted with a Cochran Mantel Haenszel test stratified by study 
site pharmacy and disease severity at study entry, comparing the proportion of participants 
who had experienced any of these events by Day 5. Treatment differences for each of the 
components of this composite outcome will also be summarized.  This composite safety 
outcome will also be assessed at Day 28 and Day 90. Proportions of participants who 
experienced any of these events will be compared using stratified Cochran Mantel 
Haenszel tests and logistic regression. Time to event analyses will also be used to 
summarize this composite safety outcome.  SAEs and grade 3/4 events will be classified by 
system organ class according to MedDRA.  
Safety analyses also include infusion reactions collected during or within 2 hours after the 
infusion of the investigational agent or placebo.  Proportions of participants who 
experienced infusion reactions or prematurely terminated infusions will be summarized by 
study arm, and Cochran Mantel Haenszel tests will be used to test for differences across 
arms. 
11.2 


Several other secondary efficacy outcomes will also be investigated. The models will 
include an indicator for treatment group, and stratify by study site pharmacy and disease 
severity at study entry as appropriate. Time from study entry to discharge from the hospital 
admission during which randomization took place will be analyzed using the same methods 
as described above for time to sustained recovery. Readmissions will be summarized using 
methods for recurrent events (i.e. those who are readmitted will reenter the risk set).  
Both the pulmonary and pulmonary+ ordinal outcome will be assessed on Days 1 through 
7; the pulmonary ordinal outcome will also be assessed at Days 14 and 28. Proportional 
odds models will be used to compare treatment groups for each ordinal outcome. These 
models will control for study site pharmacy and categories of the pulmonary+ ordinal 
outcome at baseline. A test for the proportional odds assumption across cumulative 
categories and stratification covariates will be performed by testing for separate slopes (a 
partial proportional odds model). In addition, cumulative probabilities of the ordinal outcome 
categories will be compared between treatment groups using logistic regression models. 
Clinical organ failure is a composite of many different organ-specific events, listed in section 
4.2.2, item 7.  This outcome will be summarized as part of both safety and efficacy 
analyses. The incidence of organ failure, serious infection or death through Day 28 will be 
compared between arms using the log-rank test and Cox proportional hazards models.  In 
addition, specific components (e.g., cardiac and vascular dysfunction, or the composite of 
cardiovascular outcomes and thromboembolic events described in section 4.2.2, item 10) 
will be analyzed using time-to-event analyses under competing risks, as described above 
for the primary analysis of sustained recovery.  Proportions of participants who experienced 
organ failure, serious infection or death will be summarized and compared between 
treatment arms using stratified Mantel Haenszel tests, overall and for specific organ 
dysfunctions. 
Longitudinal models for the logarithm of antibody titers will be fit using generalized 
estimating equation-based approaches to titers measured at baseline and Days 1, 3, 5, 28 
and 90 and interactions between time and treatment group will be investigated to assess if 
the treatment effect changes over time. The same approach will be used to examine 
neutralizing titers should such data be available.  
The impact of study arm on the primary efficacy (time to sustained recovery) and safety 
outcomes (composite of grade 3 or 4 events, SAEs, clinical organ failure or serious 
infections, or death through Day 5 and through Day 28, composite of SAE and death 
through Day 90) along with mortality will be assessed for subgroups defined by baseline 
characteristics, including demographics, social determinants, baseline classification of  
“home”, duration of symptoms at enrollment, clinical history and presentation (including 
disease severity stratum and pulmonary+ ordinal outcome at baseline), and tests for 
homogeneity of the treatment effect across subgroups will be carried out. Additionally, 
subgroup analyses will be conducted for subgroups formed by a disease progression risk 
score at baseline. The construction of this risk score will be revisited as new investigational 
agents move through the trial. Subgroup analyses will be interpreted with caution due to 
limited power and uncontrolled type I error. 
 Data Monitoring Guidelines for an Independent DSMB 
An independent DSMB will review interim data and use pre-specified guidelines for early 
evidence of sufficient activity of an investigational agent that justifies continuing enrollment 
for the agent and expanding eligibility criteria to include participants in disease severity 
11.3 


stratum 2 as well as stratum 1.  This assessment will be made by the DSMB when Day 5 
data for approximately 300 participants in disease severity stratum 1 are available. 
For agents which advance to enroll participants in both disease severity strata 1 and 2, the 
DSMB will continue to review interim data on a regular basis and use pre-specified 
guidelines to identify agents with clear evidence of efficacy for the primary outcome, and if 
so recommend unblinding of the trial results for that agent. Conversely, the DSMB may 
recommend discontinuation of an investigational agent if the risks are judged to outweigh 
the benefits or if futility assessments indicate that there is low probability that an 
investigational agent will achieve statistical significance for the primary endpoint of 
sustained recovery.  
 Rationale for Early Futility Analysis 
The early futility analysis based on the intermediate outcome of efficacy using the 
pulmonary and pulmonary+ ordinal outcomes assessed at Day 5 will be carried out for 
approximately 300 participants entering the trial when only enrolling in disease severity 
stratum 1.  The exact number may vary depending on the rate of enrollment and the timing 
of the DSMB meeting.  The potential benefit of the investigational agents studied is 
expected to be greatest in this cohort and the Day 5 data provide an early assessment of 
activity to assess the potential for benefit in the expanded cohort of participants evaluated 
for the primary endpoint. This early futility analysis is based on Day 5 outcomes because 
too few primary endpoints of sustained recovery are expected when 300 participants with 5 
days of follow-up are available.  It allows resources for the platform trial to be more 
efficiently used by identifying agents early that have a low probability of being efficacious 
and stopping enrollment for those agents, while at the same expanding enrollment for 
promising investigational agents that have potential for showing efficacy with a larger 
sample size based on the primary endpoint. 
The sample size of 300 participants in stratum 1 provides 95% power to detect an odds 
ratio (active/placebo) of 1.60 at the 0.30 (1-sided) level of significance.  Data from the 
ACTT-1 trial (remdesivir group) were used to estimate the category percentages for the 
placebo group shown in Table 3 below.  The percentages shown correspond to an odds 
ratio of 1.60 and are the basis for the sample size used for the early futility assessment. 
Table 3. Hypothesized percentage of participants in each category on Day 5 in 
the Investigational agent and placebo groups based on aforementioned 
assumptions  
Pulmonary+ Category 
Investigational 
Agent + SOC 
Placebo 
+ SOC 
1.  No limiting symptoms due to COVID-19 
3.2 
2.0 
2.  Limiting symptoms due to COVID-19 
53.5 
43.0 
3.  Moderate end-organ dysfunction 
20.6 
23.0 
4.  Serious end-organ dysfunction 
12.8 
17.0 
5.  Life-threatening end-organ dysfunction 
5.0 
7.3 
6.  End-organ failure 
4.5 
7.0 
7.  Death 
0.4 
0.7 
11.4 


Total 
100.0 
100.0 
The rationale for a 1-sided alpha level of 0.30 and power 0.95 is based on previous work for 
2-stage cancer trials, where like this platform trial an intermediate outcome was used to 
assess early activity, and a definitive outcome was used to assess efficacy at the end of the 
trial. A re-analysis of 4 trials suggested a 1-sided significance level between 0.2 and 0.3 
was optimal for making a good decision in the early futility assessment. A subsequent 
paper focused on the potential for estimation bias in selected and stopped treatments and 
concluded that its degree was generally small.84,85    
As part of the development of this platform trial, additional work was carried out to support 
the design. That work is briefly summarized below (personal communication).86 
Follmann and Proschan considered a 2-stage trial (where a drug would enter the 2nd stage 
once it had passed the futility assessment) and assumed a sample size of 300 for the initial 
stage, the decision whether the investigational agent would proceed to the 2nd stage taking 
place when all 300 participants had completed Day 5, a total sample size of 1000 for the 
trial, a significance level of 0.30 (1-sided) and power of 0.95 for the initial stage, and a 
significance level of 0.025 (1-sided) and power of 0.90 for the 2nd stage primary endpoint 
comparison. For simplicity, one ordinal outcome was assumed. With these assumptions, 
they showed that power with use of a stage 1 assessment was reduced only slightly from 
the power without the stage 1 review (0.87 versus 0.90). They cite two advantages to the 
approach used here compared to the standard phase III trial without an early evaluation: 1) 
more treatments can be evaluated; and 2) if one-half of the treatments are efficacious and 
one-half are not efficacious, 40% more efficacious treatments are identified.  
 Interim Analyses Guidelines 
Stopping guidelines for use by the DSMB are described below. More specific guidance may 
be specified in the SAP. When several investigational agents are investigated in parallel, 
each agent will be compared to its corresponding, contemporaneously randomized pooled 
placebo group. Each investigational agent versus placebo comparison will be treated as a 
separate clinical trial; stopping boundaries will be derived to allow for multiple interim looks, 
but will not be additionally inflated to adjust for simultaneous analysis of multiple 
investigational agents, except when explicitly stated in the agent-specific protocol appendix 
and statistical analysis plan. 
The DSMB will be asked to recommend early termination or modification only when there is 
clear and substantial evidence of a treatment difference. 
11.5.1 Early Assessment of Safety and Futility 
For investigational agents with minimal pre-existing data, the pace of enrollment will be 
initially restricted and the DSMB will be asked to review safety data for the first 20 to 30 
participants before increasing the pace of enrollment. 
Subsequently the DSMB will carry out regular reviews of safety data reports.  These reports 
will include summaries of lower grade AEs and infusion–related events as well SAEs and 
deaths, including the primary safety outcome.  At the discretion of the DSMB, these reports 
will be prepared at a frequency they specify. 
11.5 


When approximately 300 participants have been enrolled and followed for 5 days, a futility 
assessment will be carried out. The criteria that will be used for the early futility assessment 
of each investigational agent are summarized below: 
a. If the investigational agent is superior (i.e. 1-sided p < 0.3) to placebo for both 
ordinal intermediate outcomes, then enrollment for the agent will expand to 
complete the phase III trial.   
 
b. If there is insufficient evidence for superiority versus control (i.e., 1-sided 
p>0.3) in each of the two outcomes, then stop randomization.   
 
c. If there is evidence (1-sided p < 0.3) for an association for one endpoint and 
not the other, then the agent may or may not advance depending on the 
risk/benefit profile emerging from the data at this early stage.  If the effect 
estimate for both outcomes is on the side of benefit, the preference would be 
towards advancing the agent and expanding enrollment to include disease 
severity stratum 2.    
 
The DSMB will be asked to review whether the discordance is attributable to a positive or 
negative effect on extra-pulmonary organ dysfunction (the difference in the two ordinal 
scale categories, the conditions included in pulmonary+ but not in the pulmonary endpoint), 
and whether the same ordinal outcomes assessed on other days yield similar results, and 
weigh the risk/benefit profile. For example, if there is a significant positive effect on the 
pulmonary score and the lack of significant effect on the pulmonary+ score is driven by a 
lack of difference in the milder thrombotic symptoms in category 4 of the pulmonary+ scale 
(e.g. deep venous thrombosis) and there is no evidence of any raised risk of thrombosis 
overall, the agent will advance. Conversely, if the agent is superior to the control group with 
respect to the pulmonary outcome, but clearly inferior to the control group with respect to 
the pulmonary+ outcome or has a concerning safety profile, it will not advance.  Analyses of 
the primary endpoint, “time to sustained recovery”, will also be provided to the DSMB, as 
supporting information. 
After considering the aforementioned guidelines, the DSMB will be asked to consult with the 
Food Drug Administration before making their recommendation in order to consider any 
relevant external information. 
The power and type 1 error of the complete decision rule considering both outcomes depends 
on the correlation between the two outcomes and on the DSMB’s assessment of discordant 
outcomes. Table 4 shows the power to identify an agent with an hypothesized OR=1.60 using 
the two-outcome decision rule, along with the simultaneous type 1 error, assuming 
correlations of r=0.8 and r=0.9 between the test statistics for the two outcomes. For example, 
if an agent is advanced when one or both of the outcomes show superiority, and assuming a 
correlation of 0.8, then an agent with OR=1.60 will be ”detected” and advanced with 
probability of 98% (power), while an ineffective agent would be advanced with probability of 
39% (type 1 error). This balance between power and type 1 error is selected for the intended 
approach to making the early futility assessment. 
 


 
 
Table 4. Power and type 1 error for the two-outcome decision rule to expand 
enrollment to strata 1 and 2 for an investigational agent for correlations of r=0.8 
and 0.9 between the marginal test statistics for the two outcomes. OR=1.60, 
total sample size 300. 
 
r = 0.8 
r =0.9 
Treatment of discordant 
intermediate outcomes 
Power 
Type 1 
error 
Power 
Type 1 
error 
Expand enrollment if one or both 
outcomes show superiority 
       0.98 
0.39 
0.97 
0.36 
Expand enrollment if both 
outcomes show superiority 
      0.93 
0.21 
0.93 
0.24 
 
During the enrollment of approximately 300 participants in disease severity stratum 1, the 
safety reviews by the DSMB will include treatment comparisons of the safety outcomes 
described in section 4.2.2 that are measured in the first 28 days of follow-up.  In addition, 
for each ordinal outcome at Day 5, a Haybittle-Peto boundary using a 2.5 standard 
deviation (SD) for the first 50 participants enrolled and 2.0 SD afterwards will used as a 
guideline for harm.  
11.5.2 Monitoring Guidelines for the Primary Endpoint 
As a guideline, asymmetric boundaries will be provided to the DSMB to monitor the primary 
endpoint (time to sustained recovery) for each pairwise comparison of investigational agent 
versus control. For monitoring overwhelming benefit of an investigational agent, the Lan-
DeMets spending function analogue of the O’Brien-Fleming boundaries will be used; for 
monitoring harm for the primary endpoint, a Haybittle-Peto boundary using a 2.5 standard 
deviation (SD) for the first 50 participants enrolled and 2.0 SD afterwards will used as a 
guideline. The Lan-DeMets boundary used will be chosen to preserve a 1-sided 0.025 level 
of significance. For computing the Lan-DeMets boundary, the information fraction at each 
interim analysis will be the number of sustained recoveries at the interim analysis (divided 
by the number of sustained recoveries planned) (843). With this approach, less evidence 
will be required for crossing a boundary for harm than for benefit. To account for a possible 
delay in the ascertainment of the primary endpoint status, sensitivity analyses will be 
provided to the DSMB. 
Futility analyses will be carried out. The aim of these analyses will be to consider whether 
an investigational agent should be discontinued due to a low probability of achieving 
statistical significance for the primary endpoint of sustained recovery at the completion of 
the 90 day follow-up. Conditional power calculations for time to sustained recovery will be 
presented under a range of scenarios. In the primary futility analysis, the treatment effect 
for the future, as yet unobserved follow-up will be assumed as hypothesized in the study 
design (RRR=1.25); in alternative scenarios, the treatment effect for future follow-up will be 
assumed to be similar to the observed effect, or more favourable for the investigational 
agent.  Typical futility guidelines recommend stopping a trial when conditional power is 
below 10%-15%, with the higher value later in follow-up as measured by information time.87 
These analyses will be presented to the DSMB by the unblinded statisticians for each 
pairwise comparison. 


12 Protection of Human Subjects and Other Ethical 
Considerations 
  Participating Clinical Sites and Local Review of Protocol and 
Informed Consent 
This study will be conducted by major medical centers participating in INSIGHT and 
partnering networks. It is anticipated that potential participants will be recruited by the site 
investigators (and/or their delegates, as appropriate) and/or that positive SARS-CoV-2 
laboratory testing will be used to enquire about potential enrollment. Information about this 
study will be disseminated to health care providers at enrolling sites. 
Prior to the initiation of the study at each clinical research site, the protocol, informed 
consent form and any participant information materials will be submitted to and approved 
by a central/national IRB/EC and/or the site’s local IRB/EC as required. Likewise, any future 
amendments to the study protocol will be submitted and approved by the same IRB(s) or 
EC(s). After IRB/EC approval, sites must register for this study before screening potential 
participants, and must register for any protocol amendments. Protocol registration 
procedures are described in the PIM. 
 Ethical Conduct of the Study 
The study will be conducted according to the Declaration of Helsinki in its current 
version; the requirements of Good Clinical Practice (GCP) as defined in Guidelines, EU 
Clinical Trials Directive (2001/20/EC), and EU GCP Directive (2005/28/EC); International 
Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human 
Use (ICH) Guidelines; Human Subject Protection and Data Protection Acts; the US 
Office for Human Research Protections (OHRP); or with the local law and regulation, 
whichever affords greater protection of human subjects. 
 Informed Consent of Study Participants 
Informed consent must be obtained (see sample in Appendix A) prior to conducting any 
study-related procedures. For patients who are incapacitated, informed consent may be 
obtained from a legally-authorized representative (LAR).  Capacity will be assessed 
according to local standards and policies.  Local standards and policies will also 
determine who is legally authorized to consent for an individual who is incapacitated.  
Should the individual regain capacity during the study, their direct consent should be 
obtained at the earliest opportunity. 
Electronic consent may be used when a validated and secure electronic system is in 
place to do so, if in compliance with national legislation and approved by the local 
IRB/EC.  Other methods of obtaining documentation of consent may be used when site 
staff are unable to be in direct contact with a potential participant or a legally-authorized 
representative due to infection-control restrictions.  No matter how the participant’s 
consent is obtained and documented, it is expected that consent will be preceded by 
research staff providing an explanation of the research and an opportunity for the 
participant (or their LAR) to have questions answered.  Sites should follow all available 
local or national guidance on suitable methods for obtaining documentation of participant 
(or their LAR) consent. 
12.1 
12.2 
12.3 


 Confidentiality of Study Participants 
The confidentiality of all study participants will be protected in accordance with GCP 
guidelines and national regulations.  
 Regulatory Oversight 
Sites in the US will conduct this trial under the terms of the IND and will adhere to FDA 
regulations found in 21 CFR 312, Subpart D. Sites in countries other than the US will not 
conduct the trial under the IND. As stated in Section 12.2 above, all sites will conduct the 
trial in accordance with the requirements of GCP as codified in their local law and 
regulation, under the oversight of their institution and competent regulatory authority. 
 As part of fulfilling GCP and FDA requirements for adequate trial monitoring, multiple 
modalities will be employed.  The objectives of trial monitoring are to ensure that 
participant rights and safety are protected, to assure the integrity and accuracy of key 
trial data, and to verify that the study has been conducted in accord with GCP standards 
and applicable regulations.   
A specific risk-based protocol monitoring plan will be developed.  The plan will include 
strategies for central monitoring of accumulating data and will take into account site-level 
quality control procedures.  On-site monitoring visits for targeted source document 
verification and review of regulatory and study pharmacy files will be conducted when 
possible, but these tasks will most likely need to be handled remotely during the 
pandemic.  The monitoring plan will outline the frequency of this aspect of monitoring 
based on such factors as study enrollment, data collection status and regulatory 
obligations. 
 
12.4 
12.5 


Appendix A 
Sample Informed Consent form (not agent-specific) 
Sample Informed Consent form 
Short Title: Therapeutics for Inpatients with COVID-19 (TICO) 
Sponsored by: The University of Minnesota (UMN) 
Funded by:  The National Institute of Allergy and Infectious Diseases (NIAID), US National 
Institutes of Health (NIH) 
Full Title of the Study:  A Multicenter, Adaptive, Randomized Blinded Controlled Trial 
of the Safety and Efficacy of Investigational Therapeutics for Hospitalized Patients 
with COVID-19 
CONSENT FOR PARTICIPATING IN AN NIH-FUNDED RESEARCH STUDY  
SITE INVESTIGATOR: ________________________________ PHONE: __________ 
  
 
 
Key information: 
We are asking you to join a research study about COVID-19.  It is your choice whether or 
not you want to join.  This form gives you information about the study that will help you make 
US Office for Human Research Protections (OHRP) Requirements to be read by the 
sites: 
PLEASE NOTE THAT THIS SAMPLE LANGUAGE DOES NOT PREEMPT OR REPLACE LOCAL 
IRB/EC REVIEW AND APPROVAL.  INVESTIGATORS ARE REQUIRED TO PROVIDE THE LOCAL 
IRB/EC WITH A COPY OF THIS SAMPLE LANGUAGE ALONG WITH THE LANGUAGE INTENDED 
FOR LOCAL USE.  LOCAL IRBs/ECs ARE REQUIRED TO WEIGH THE UNIQUE RISKS, 
CONSTRAINTS, AND POPULATION CONSIDERATIONS AS A CONDITION OF ANY APPROVAL.  
ANY DELETION OR SUBSTANTIVE CHANGE OF INFORMATION CONCERNING RISKS OR 
ALTERNATIVE TREATMENT MUST BE JUSTIFIED BY THE INVESTIGATOR, APPROVED BY THE 
LOCAL IRB/EC, AND NOTED IN THE IRB/EC MINUTES.  JUSTIFICATION AND IRB/EC APPROVAL 
OF SUCH CHANGES MUST BE FORWARDED TO THE INTERNATIONAL COORDINATING 
CENTER OR COLLABORATING NETWORK.  SPONSOR-APPROVED CHANGES IN THE 
PROTOCOL MUST BE APPROVED BY THE LOCAL IRB/EC BEFORE USE UNLESS INTENDED 
FOR THE ELIMINATION OF APPARENT IMMEDIATE HAZARD.  NEW INFORMATION SHALL BE 
SHARED WITH EXISTING SUBJECTS AT NEXT ENCOUNTER, WITH ALL NEW SUBJECTS PRIOR 
TO INVOLVEMENT, OR AS THE LOCAL IRB/EC MAY OTHERWISE ADDITIONALLY REQUIRE. 
ALL SITE INSTRUCTION THAT IS INCLUDED IN A TEXT BOX SHOULD BE 
REMOVED FROM THE SITE’S INFORMED CONSENT FOR PARTICIPANTS 


your choice.  You can talk about this with your doctor or family or anyone else you would like 
before you make your choice.  Your choice will not affect the care you are getting for 
COVID-19. 
Why are we doing this study? 
We are studying experimental medicines to treat people with COVID-19.  We are trying to 
find out if giving these medicines can help people in the hospital with COVID-19 get better 
and go home faster.  We are also trying to see if they are safe.  The medicines being tested 
in this study are not yet approved by the US FDA or any other government agency. 
We are asking you to join the study because you are in the hospital with COVID-19.   
What do you have to do if you decide to be in the study? 
The study staff at your hospital will check to see if there is any reason you should not be in 
the study.  They will check your medical history.  They will look at tests commonly done for 
your condition.   
We are testing different types of study medicines.  If you join the study, you will be assigned 
by random chance – like flipping a coin or rolling dice – to get one of these study medicines 
or a salt-water placebo.  You could be in any one of the groups below: 
Investigational agent A 
Investigational agent B 
Placebo (a salt water solution that has no medicine in it) 
Not all of the study medicines listed above may be available to you right now  
If this is the case, then you will be told which ones are available. 
You will have an equal chance of getting any of the available study medicines or the inactive 
placebo.  If all of them are available, then you have a 1 in __chance of being in each of the 
groups listed above.  [Insert number of possibilities from the list above, including placebo, 
e.g. “3”] 
This means your chances of getting a study medicine instead of placebo are ___ out of ___, 
or __%. [nsert the number of active possibilities from the list above, then the total number of 
possibilities, e.g., “2 out of 3.”  Then record the % to which that corresponds, e.g., “67%.”  
Repeat the above for each possibility as an active treatment is eliminated.] 
Your doctor will not decide which group you are in and, just like you, will not know whether 
you are getting an experimental medicine or inactive placebo.  None of the study staff will 
know whether you are getting a study medicine or the placebo.   


We will tell you more about each study medicine you could get in a separate 
information sheet.  You will be given an information sheet for each of the available 
study medicines. 
You will get the study product through a plastic intravenous (IV) tube attached to a needle in 
your arm.  This is called an infusion.  The information sheets will tell you how much liquid 
the infusion will be and how long it should take.   
The infusion is the only thing you will be given that is completely experimental.   
The medicines we are studying can only be used in research.  There are many treatments 
being studied for COVID-19, and some have received US FDA emergency approval or other 
types of approval to be used in some people with COVID-19.  Your doctor and the study 
team will tell you about any treatment options you may have. 
As part of the study, you will also get a drug called remdesivir (also called Veklury) for your 
COVID-19, unless your doctor thinks remdesivir would not be safe for you to take.  
Remdesivir is given once a day by infusion for up to 10 days while you are in the hospital,   
Remdesivir was shown in an earlier study to help people get better faster from COVID-19.  
Remdesivir is approved by the US FDA for treating COVID-19.  It also has approval in other 
countries.  
Any other medicines or treatments you get will be what you would usually get in this hospital 
for your condition.  There may be some additional tests done just for the study.  We will 
describe these below. 
You will be in the study for 18 months.  We will get most of the information for the study in 
the first 3 months. 
We do not know what effects these study medicines may have on a pregnancy or unborn 
baby.  There may be bad effects or no effects.  If you decide to join the study, we strongly 
advise you to not have sex that could make you or a partner pregnant from thetimethat you 
sign this consent formfor some time after you have taken the study medicine.  How long this 
will be depends on which study medicine you have been assigned to get.  This may involve 
not having sex at all (abstinence), or you may use effective birth control (hormonal 
contraceptives like birth control pills or barrier methods with spermicide) to avoid pregnancy.  
Methods like rhythm, sympto-thermal or withdrawal are not considered effective for 
preventing pregnancy.  We will tell you more about this requirement as part of telling you 
about each study medicine you could get.  You should ask the study team about this if you 
have questions or concerns. 
If you get pregnant during the study, please let your study team know as soon as possible.  
We may ask to follow you until your pregnancy is over, to see if there were any problems 
that may have been caused by any of the study treatments. 


If your partner gets pregnant, please let your study team know as soon as possible.  We 
may ask your partner to let us get basic information about her pregnancy.   
You will also need to agree to not be in any other COVID-19 study for the first 5 days you 
are in this study.  There may be exceptions to this requirement.  We will tell you about any 
other studies you can be in during the first 5 days of this study so you can make a choice. 
This is what you will be doing for the study:  
Up to 1 day 
before you get 
study product 
Day 0 (the day you 
get study product) 
Day 1, Day 3, 
Day 5 
Day 2, Day 4 Day 
6, Day 7, Day 14, 
Day 42, Day 60, 
Day 75 
Day 28 and 
Day 90 
Informed consent 
(this document) 
Check to see how 
you are feeling 
Your medical 
history 
Contact 
information like 
telephone 
numbers and 
addresses for you 
and at least two 
close relatives or 
friends 
Infusion of study 
product (the 
experimental 
medicine or else 
placebo) 
Whether you are 
taking certain 
medicines 
Blood tests to check 
your health (9 mL, 
about ½ tablespoon) 
Blood for future 
research (18 mL, 
about 1 tablespoon) 
A swab of your nose 
for virus  
How you are 
feeling 
Blood for future 
research (18 
mL, about a 
tablespoon) 
On Day 5, also 
whether you 
have taken 
certain 
medicines, and 
blood tests to 
check your 
health (9 mL, 
about ½ 
tablespoon) 
How you are 
feeling (Days 2, 4, 
6, 7, 14, 60) 
Update on return 
to home (Days 14, 
42, 60, 75) 
These “visits” may 
take place by 
phone. 
How you are 
feeling 
Blood for future 
research (18 
mL, about a 
tablespoon) 
On Day 28, 
also whether 
you have taken 
certain 
medicines 
Update on 
return to home 
 
If you leave the hospital after just a few days, we will ask you to come back to give a blood 
sample on Day 3 and Day 5 of the study.  You might instead be visited in your home by a 
professional working for the study to get this blood sample. We will also need to take a 
blood sample from you on Day 28 and Day 90.   
After Day 90, we will talk to you three more times by phone, at 6 months, 12 months, 
and 18 months, to see how you are doing and whether you have been in the hospital 
for any reason. 
We may need to get some information from your medical record:  
• By signing this consent, you agree to let us get information for this study from your 
medical record.   
• By signing this consent, you are giving us permission to contact other hospitals or 
medical facilities you are admitted to while you are in the study. We will contact them 
to find out how you are doing.   


• We will ask you to give us information about other people we can contact if we are 
not able to reach you after you leave the hospital.  This is so we can find out how you 
are doing. 


We will send the information you give us to the University of Minnesota (UMN) in the US 
where it will be stored and analyzed.  In this information, only a code number, your year 
of birth, and a 3-letter code that the study staff chooses identifies you.   
The study staff here at this site is responsible for keeping your information safe from 
anyone who should not see it.   
We will send the blood and nose swab samples to a laboratory in the US for storage.  
We will keep them for as long as we have the money and space to do so.  We expect 
this to be many years.  There is more information later in this consent about how we will 
use these samples.   
Why would you want to be in the study? 
If you get the experimental medicine, it is possible it may help you get better, or that you 
may get home faster, but we do not know that.   
Remember that some of the people in this study will get inactive placebo, and will not 
get any experimental medicine. 
By being in this study, you will help doctors learn more about how to treat COVID-19 in 
people in the hospital.  Because many people are getting hospitalized with COVID-19, 
this could help others.  There may be a large health impact if a treatment proves to be 
safe and to work. 
Why would you NOT want to be in the study? 
If you do get one of the experimental medicines, it may not help. It may have harmful 
side effects.   
What are the risks or side effects of the experimental medicines? 
All treatments have risks and may cause side effects.  
Any medicine can cause an allergic reaction.  You may have an allergic reaction to the 
study treatment, including hives, trouble breathing, or other allergic responses. Allergic 
reactions like these are likely to be rare, but may be severe or life-threatening. 
We will watch over you while you are being given the infusion of the study medicine and 
for at least 2 hours after the infusion is finished.  We will give you medical care right 
away if you need it to treat any side effects from the infusion. 
The fluid needed to give the experimental medicine or the placebo may overload your 
body if you have problems managing fluids due to COVID-19 or other conditions. We 
expect this to be rare. 
There are discomforts and risks with blood draws and getting a swab of your nose. You 
will have these things done while you are in the hospital even if you are not in the study.  


You may have some pain, bleeding, or bruising when a needle is put into your vein to 
draw blood or to give the study infusion.  Getting your nose swabbed can be 
uncomfortable and you might gag.  These discomforts and risks are not different from 
what you would have if they were done as part of your regular hospital care for COVID-
19. 
What if you are pregnant or breastfeeding? 
[The following will vary depending on the agents being studied.] 
If you are pregnant or breastfeeding, you can/cannot join this study. 
Additional information: 
Here is some additional information about the study that may help you make your 
choice about whether you want to be in the study. 
The NIH, an agency of the US Federal government, is paying for this study.   
We are required to follow all rules and regulations for human research as well as the 
laws of each country where the study is being done.   
This study is taking place in several countries.  We expect to enroll about 1,000 people 
around the world for each medicine we are studying. 
You do not have to join this research study if you do not want to.  If you choose to join 
the study, you can stop at any time.  If you choose not to join or to stop, the medical 
care you are getting outside of the study will not change. 
If we get any new information that might change whether you want to join or stay in the 
study, we will tell you right away. 
If you do not want to be in this study, you will still get the usual care to treat COVID-19.  
However, you cannot get the study medicine, because it is experimental. 
Vaccines against the virus that causes COVID-19 are starting to be available.  It looks 
like people who have had COVID-19 do not have much chance of catching it again for 
at least 3 to 6 months.  The US Centers for Disease Control and Prevention (CDC) 
recommends that people wait for at least 90 days after they’ve been given certain 
medicines before they get the vaccine. We do not know if the medicines we are 
studying change how you respond to the vaccine during that time.   
What are the risks and benefits of taking remdesivir? 
Remdesivir has been shown to help people who are in the hospital and moderately to 
severely sick with COVID-19 get better about 4 days faster than people who got a 
placebo.  You may be given remdesivir to treat your COVID-19 even if you do not join 
this study.   


The most common side effects of remdesivir included abnormal liver function tests, 
abnormal blood clotting tests, constipation, nausea, vomiting, decreased appetite, and 
headache. The abnormal liver function tests lasted longer than a few days in some 
people, but went back to normal within a few weeks or less. 
Remdesivir might affect the way that other medications are processed by your body.  
They might stay in your body longer, or shorter, or at higher or lower levels.  At the time 
this consent was written, one person in this study had an increase in the level of a 
medication in their blood that was considered by study doctors to be at least possibly 
related to having taken remdesivir.  There did not appear to be any harm from this 
temporary change.  You can ask the study team about this if you are concerned. 
Some people have side effects after the infusion of remdesivir.  Other people have no 
side effects.  People can have allergic reactions to drugs, including hives, trouble 
breathing, or other allergic responses.  Allergic reactions may be severe or life-
threatening.  This is very rare but is also a possible effect of any drug.  We will monitor 
you closely while you are getting remdesivir.  We will give you medical care right away 
to treat any side effects. 
 
What are the costs to you? 
We will give you the study treatment at no cost.  We will pay for all clinic visits, lab work, 
and other tests that are part of this study. 
[The next paragraph is for US sites only.  Sites in other countries should delete the next 
paragraph and replace it with the language appropriate for your location.] 
You, your insurance company, or some other third-party payer must pay for all other 
medicines and hospital costs. 
Will you be paid to be in the study? 
We will compensate you for your time and inconvenience participating in the study.  
[Specific details to be completed by site.] 
What if you are hurt as part of this study? 
If you are hurt because of being in this study, [insert the name of the hospital/clinic] will 
treat your injury right away.  You or your insurance will have to pay for this treatment.  
The study cannot pay you or pay for any care for study-related injuries or for your 
illness. 
[If the above is not true for your site, i.e., if trial insurance covers such cost, please 
replace the above with appropriate language.] 


[The following section, up to “What happens to the blood and swab samples?”, is for US 
sites only.] 
A Declaration under the Public Readiness and Emergency Preparedness (PREP) Act 
was issued by the Secretary of the United States Department of Health and Human 
Services on March 10, 2020.  This Declaration limits the legal rights of a subject 
participating in clinical studies utilizing COVID-19 countermeasures.  Because this study 
is covered by the Prep Act Declaration, covered persons, such as the manufacturers, 
study sponsor, researchers, healthcare providers and others have liability immunity (that 
is, they cannot be sued by you or your family under the laws of the United States). 
If you believe that you may have been harmed as a result of this research study, certain 
claims for serious injury or death caused by the countermeasure may be eligible for 
compensation through the Countermeasures Injury Compensation Program. This is a 
program set up by the United States Government.  
Information about this program can be found at 
https://www.hrsa.gov/cicp/about/index.html or by calling 1-855-266-2427. If you are 
eligible for this program, you must file a claim within one year of the administration or 
use of the covered countermeasure. 
 
What happens to the blood and swab samples? 
We will send the blood and swab samples to a central laboratory in the United States.  
You and your doctor will not get the results of any tests done on these samples.  We 
will not test your DNA (your genes).  We will not sell your samples and they will not be 
used for research aimed at making money (commercial research).  The laboratory 
where the samples are stored will not have any information that could identify you. 
The blood samples will measure how many COVID-19 antibodies are in your blood.  
This will tell us how your immune system responded to your COVID-19.  The swab 
sample will be used to see how much virus is in your body. 
Any blood or swab samples that are left over after these tests will be stored at the 
central laboratory for as long as we are able to keep them.  We hope to use these in the 
future to answer other questions about COVID-19, the virus that causes it, and how 
people respond to treatment.  You and your doctor will not get any results from these 
tests.  Some of the blood will also be given to the companies that made the study 
medicines to help them learn more about its effects. 
You can withdraw your consent for us to keep these samples at any time.  Let your 
study team know if you do not want the study to keep your samples anymore.  We will 
make every effort to destroy all of your samples that are still at the central laboratory. 


How do we protect your privacy? 
We will take every reasonable step to keep your health information private and to keep 
anyone from misusing it. 
Your information (data) and samples will not be identified by name, or in any other way, 
in anything published about this study.   
We will do everything we can to keep your personal information private, but we cannot 
guarantee that nobody will get it.  We may have to release your personal information if 
required by law. 
These people may see your medical and research information: 
• the [insert the name of the hospital/clinic] ethics committee (institutional review 
board [IRB]); 
• the sponsor, the group paying for the research (US NIH), other study research 
staff and study monitors 
• US and other participating countries’ health regulatory agencies, including the US 
FDA. 
They are committed to protecting your privacy. 
As the research staff at [inset the name of the hospital/clinic], we are required to make 
sure that people not involved with this study cannot see your research and medical 
information.  We will keep your research files in a safe place and will handle your 
personal information very carefully.  
Your study data are sent electronically to the UMN in the US through a secure system.  
By signing this consent, you agree to having your data sent to UMN.  No information 
that could directly identify you is sent to UMN.  This is called “pseudonymized data”. 
UMN limits access to the data through security measures. No data breach or 
unauthorized access has ever occurred in this system.  After the study is over, we will 
store the data securely for the period required by law. 
We will share your study data with the US National Institutes of Health (which is paying 
for this study), and with regulators that oversee the study, including the US FDA. We 
are required by law to do this.  We will also share your study data with the drug 
companies that provide the study medicines to help them develop the drugs.   
UMN may share your data and samples with other people who study COVID-19.  UMN 
will take out any information that could possibly identify you before sharing.  This is 
called “anonymizing the data.”  We will not ask you for additional consent for this 
sharing.  UMN will only share data and samples for research projects that are approved 
by the group that is conducting this study. 
This study has a Certificate of Confidentiality from the US Federal Government.  This 
means that UMN cannot share any data it has about you with national, state, or local 


civil, criminal, administrative, legislative, or other authorities unless you specifically allow 
us to share it.   
A description of this clinical trial is available at http://www.ClinicalTrials.gov, as required 
by law, and on the EU Clinical Trials Register (http://www.clinicaltrialsregister.eu/). 
These websites will not include your name or any other direct identifiers such as your 
contact information.  These websites will include a summary of the results of this 
research once the study has been completed.  You can search either website at any 
time. 
[Note for US sites: The following brief HIPAA authorization is provided.  Your site-
specific consent should be modified to reflect the HIPAA authorization language 
requirements at your site.] 
To do this research, we will collect and use your personal data, as described above and 
in any HIPAA Authorization Form we have given you.  It is your choice whether you 
allow us to collect and use your data.  However, you will not be able to be in this study if 
we cannot collect and use your data.  Please tell us whether you agree to have us 
collect and use your personal data by placing your initials in front of your selection. 
 
____Yes, I agree to the collection and processing of my personal data. 
 
____No, I do not agree to the collection and processing of my personal data. 
 
[The following section (up to “What if you have problems or questions?”) is for countries 
subject to the GDPR or similar legislation requiring this information.  It should only be 
included in consents for sites subject to such legislation.  It will vary from place to place 
whether it must be in this consent document, a separate consent document, or an 
information sheet that does not require signature.  The amount of information provided 
may be reduced to meet the requirements of a particular country (e.g., not all 
countries/ECs require an enumeration of all of a data subject’s rights).] 
What are your rights regarding your data? 
The UMN is a public research university, and this study is mostly paid for by the US 
Federal government.  UMN and the study funder require the sponsor (UMN) to follow 
regulations and policies that are meant to protect your privacy.  UMN is also required to 
comply with the General Data Protection Regulation (GDPR), because it processes data 
obtained from people in Europe.   
 


There is no specific authority overseeing the processing of data in the US.  Any 
complaint you might have about the use of your data would be made to your national 
data protection authority. 
The GDPR gives you additional rights which we will tell you about now. 
Right to Information 
You have the right to know what data about you is being processed. You can also get a 
free copy of this data provided. 
Right to Correction 
You have the right to correct any information about you which is incorrect or had 
become incorrect. 
Right to Erasure/Anonymization 
The sponsor is required under both EU and US law to retain data from research studies 
like this one for many years.  However, you have the right to request that your personal 
data be completely anonymized. This is done by destroying the information at your 
study center that links your identity to the pseudonymized data held by the sponsor.  
This means that no one would ever be able to link the data held by the sponsor to you 
personally.  
Right to Restriction of processing 
Under certain conditions, you have the right to demand processing restrictions, i.e. the 
data may then only be stored, not processed. You must apply for this. Please contact 
your study physician or the data protection officer of the study center if you want to do 
so.  This right may be limited if the restriction would affect the reliability of the study 
results. 
Right to Data portability  
You have the right to receive the personal data that you have provided to the study 
center. This will allow you to request that this information be transmitted either to you or, 
where technically possible, to another agency designated by you. 
Right to Contradiction 
You have the right to object at any time to any specific decision or action taken to 
process your personal data.  This right is limited for data that have already been 
processed and may be limited if your objection would affect the reliability of the study 
results. 


Right to Withdrawal of this consent 
You may withdraw your consent at any time with effect for future data collection. This 
withdrawal may be in an informal or verbal communication to your investigator.  If you 
withdraw your consent this will not affect the lawfulness of the data processing that has 
been or will be done with data collected up to the time you withdraw consent.  Data 
already collected will be anonymized. 
If you would like to use one of these rights, please first contact the person responsible 
for the data collection at your study center: 
Person responsible for data collection at the study center: 
Name: 
 
Address:  
Phone: 
 
Email 
 
 
For concerns about data processing and compliance with data protection requirements 
you can also contact the data protection officer responsible for the study center: 
Data protection officer responsible for the study center: 
Name: 
 
Address: 
 
Phone: 
 
Email 
 
 
In addition, you have the right to lodge a complaint with the competent authority if you 
believe that the processing of personal data concerning you is contrary to the GDPR: 
Data protection authority responsible for the study center: 
Name: 
 
Address: 
 
Phone: 
 
Email 
 
 
What if you have problems or questions? 
If you ever have questions about this study, or about the storage or use of your data or 
samples, or if you are hurt by being in the study, contact: 
[name of the investigator or other study staff] 
[telephone number of the above] 
 


If you have questions about your rights as a research participant, you can call: 
[name or title of person on the ethics committee (IRB) or other organization appropriate 
for the site] 
[telephone number of the above]  


SIGNATURE PAGE FOR CONSENT TO PARTICIPATE IN THE TICO STUDY  
I have read this consent or have had it explained to me.  I have had a chance to learn 
about each of the study medicines that I could be assigned to get.  I have been given a 
copy of that information to keep.  I believe that I understand the information.  By signing 
and dating this consent, I am stating that I volunteer to join this study.  I agree to have 
my data sent to and used by the sponsor as described in this consent.  I understand 
that I do not waive any of my legal rights as a study participant by signing this consent.  
I understand that I will receive a copy of this signed and dated consent. 
If you agree to be in this study, please sign and date below. 
 
________________________________________  
Date: _______________ 
Signature of participant 
 
________________________________________ 
Printed name of participant 
 
_____________________________________   Date: _______________ 
Signature of investigator/designee 
 
_____________________________________ 
Printed name of investigator/designee 
 
FOR ADULTS NOT CAPABLE of GIVING CONSENT  
 
________________________________________ 
 Date: _______________ 
Signature of Legally Authorized Representative (LAR)  
 
_____________________________________ 
Printed name of LAR 
 


____________________________________ 
Relationship of LAR to Participant 
(Indicate why the LAR is authorized to act as a surrogate health care decision-maker under state or applicable local law) 
 
Witness to Consent Interview (if applicable) 
On the date given next to my signature, I witnessed the consent interview for the 
research study named above in this document. I attest that the information in this 
consent form was explained to the participant, and the participant indicated that his/her 
questions and concerns were adequately addressed. 
_______________________________________ Date: _______________ 
Signature of witness 
 
________________________________________ 
Printed name of witness 
 
NOTE: This consent form, with the original signatures, MUST be retained on file 
by the Investigator of Record. A copy of the signed and dated consent must be 
given to the participant. A copy should be placed in the participant’s medical 
record, if applicable.  
If no-touch / electronic consent is used, the participant must be provided with a 
copy of the consent in a manner appropriate to the method used to obtain it.  A 
record of the act of consent must also be appropriately retained in the 
participant’s medical record. 


Therapeutics for Inpatients with COVID-19 (TICO) Master Protocol 
B-1
Appendix B 
Schedule of assessments 
Screen 
or Day 
0 
Day 
0 
Follow-up Study Day; shaded columns denote in-person visits 
Day 
−1/01
0 
1 
2 
3 
4 
5 
6 
7 
14 
28 
42 
60 
75 90 
6M 12M 18M 
Acceptable deviation 
from day 
0 
0 
0 
0 
0 
0 
0 
0 
+1
+2
+3
+3
+5
+5 +10 ±14 
±14 
±14 
ELIGIBILITY & 
BASELINE DATA 
Informed consent 
X 
Baseline medical (incl. 
duration of COVID-19) 
and social history 
X 
Baseline medications 
X 
Symptom-directed  
physical exam by the 
clinical team 
X 
Review SARS-CoV-2 test 
results 
X 
Local laboratory testing 
X 
X 
Urine pregnancy test or 
other documentation of 
pregnancy status 
X 
STUDY INTERVENTION 
Randomization 
X 
Study Drug/Placebo 
Administration 
X 
Assess infusion 
completion and adverse 
reactions 
X 
STUDY PROCEDURES 
Clinical assessment for 
pulmonary ordinal 
outcome
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical assessment for 
pulmonary+ ordinal 
outcome 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs for NEW score 
assessment 
X 
Respiratory function scale 
assessment 
X 
Hospitalization status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Changes in 
residence/facility 
X 
X 
X 
X 
X 
X 
Interim medical history 
X 
X 
X 
X 
X 
Interim medications
X 
X 


Therapeutics for Inpatients with COVID-19 (TICO) Master Protocol 
 
B-2 
 
Clinical AEs of any grade 
on days indicated 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Clinical AEs reaching 
grade 3 or 4 severity 
through Day 28 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
Research sample storage 
(plasma and serum)2  
X 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 Midturbinate swab for 
central SARS-CoV-2 viral 
load testing2 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAEs and unanticipated 
problems 
 
 
Report as they occur 
 
 
 
Deaths 
 
 
Report as they occur 
Hospitalization Summary 
 
 
Report upon hospital discharge 
 
 
 
Hospital Readmissions 
 
 
Report upon hospital discharge 
1 Screening must be performed within 24 hours of randomization. 
  
2 Blood draw and swab collection in some cases can be obtained after randomization but before the 
infusion.  If it is not possible to do an in-person on Day 3 or Day 5, the blood draws may be done one day 
earlier or one day later (but the participant should be telephoned to record the clinical data on the 
indicated study day).   
 
  
 


Therapeutics for Inpatients with COVID-19 (TICO) Master Protocol 
 
C-1 
Appendix C  
 INSIGHT 014 / ACTIV-3 protocol team 
 
To oversee the implementation of this master protocol, a protocol team will be formed 
and include: 
• Protocol co-chair(s) 
• NIAID, Division of Clinical Research representatives 
• INSIGHT University of Minnesota representatives 
• INSIGHT International Coordinating Center representatives 
• Representatives from collaborating trials networks 
• Representative from ACTIV-2 protocol team 
• Representatives from collaborating laboratory representatives 
• Representatives from collaborating manufacturers of investigational agents 
• Representatives from site investigators 
• Study biostatisticians  
• Community representative(s) 
A core team consisting of the co-chair(s), ICC leaders, NIAID representatives, study 
statisticians, representatives from collaborating trials networks, and other 
representatives and the INSIGHT PI will also regularly convene to review study 
progress and address study conduct and administrative issues that arise. 


Therapeutics for Inpatients with COVID-19 (TICO) Master Protocol 
 
 
D-1 
Appendix D  
REFERENCES ON THE INSIGHT WEBSITE 
 
The INSIGHT website (www.insight-trials.org) will maintain updated links to the 
following documents referenced in the INSIGHT 014 protocol and to other information 
pertinent to the study: 
• DAIDS toxicity table: (https://rsc.niaid.nih.gov/clinical-research-sites/daids-
adverse-event-grading-tables) 
 
• INSIGHT Publications and Presentations Policy 
(http://insight.ccbr.umn.edu/resources/P&P_policy.pdf) 
 
• Centers for Disease Control and Prevention (CDC) and European Centre for 
Disease Prevention and Control (ECDC) guidance on how to handle infection 
control measures (https://www.cdc.gov/sars/guidance/i-infection/healthcare.html 
and https://www.ecdc.europa.eu/en/publications-data/infection-prevention-and-
control-and-preparedness-covid-19-healthcare-settings). 
 
• Treatment guidelines, incl from NIH and WHO 
(https://www.covid19treatmentguidelines.nih.gov/, 
https://www.who.int/emergencies/diseases/novel-coronavirus-2019/technical-
guidance/patient-management, https://www.idsociety.org/practice-
guideline/covid-19-guideline-treatment-and-management/, 
https://www.hematology.org/covid-19/covid-19-and-vte-anticoagulation and 
https://www.ersnet.org/covid-19-guidelines-and-recommendations-directory)  
 
 


Therapeutics for Inpatients with COVID-19 (TICO) Master Protocol 
 
 
E-1 
Appendix E  
LIST OF ACRONYMS 
 
ACTIV  
Accelerating COVID-19 Therapeutic Interventions and Vaccines  
ACTT 
Adaptive COVID-19 Treatment Trial 
ADE 
antibody-dependent enhancement  
AE 
adverse event 
ARDS 
acute respiratory distress syndrome 
CCP 
convalescent plasma containing COVID-19 antibodies  
CDC 
Centers for Disease Control and Prevention (US) 
CHF 
Congestive heart failure 
CI 
confidence interval 
COVID-19 
Coronavirus-Induced Disease 2019  
CTSN 
Cardiothoracic Surgical Trials Network  
DNA 
deoxyribonucleic acid 
DSMB 
Data and Safety Monitoring Board  
EC 
ethics committee 
ECMO 
extracorporeal membrane oxygenation 
EU 
European Union 
FDA 
Food and Drug Administration (US) 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
hIVIG 
hyperimmune intravenous immunoglobulin from COVID-19 survivors 
HR 
hazard ratio 
ICC 
International Coordinating Center 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
ICU 
intensive care unit 
IEC 
Institutional Ethics Committee 


Therapeutics for Inpatients with COVID-19 (TICO) Master Protocol 
 
 
E-2 
IgG 
immunoglobulin G 
IL-6  
interleukin 6 
INSIGHT 
International Network for Strategic Initiatives in Global HIV Trials 
IQR 
interquartile range 
IRB 
Institutional Review Board 
IV 
intravenous 
IVIG  
intravenous immunoglobulin 
LAR 
Legal Authorized Representative 
mAb 
monoclonal antibody 
MI 
Myocardial infarction 
mL 
milliliter 
NAT 
Nucleic acid test (to identify genomic material; some uses amplification) 
NEW 
National Early Warning 
NIAID 
National Institute of Allergy and Infectious Diseases, NIH (US) 
NIH 
National Institutes of Health (US) 
NIHSS 
National Institutes of Health Stroke Scale/Score 
nMAb 
Neutralizing Monoclonal Antibodies 
OHRP 
Office for Human Research Protections (US) 
OR 
odds ratio 
PCR 
polymerase chain reaction 
PETAL 
Prevention and Early Treatment of Acute Lung Injury 
PHI 
personal health information  
PIM 
Protocol Instruction Manual 
RBD 
receptor-binding domain 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SARS-CoV-1 severe acute respiratory syndrome coronavirus 1 
SARS-CoV-2 severe acute respiratory syndrome coronavirus 2 


Therapeutics for Inpatients with COVID-19 (TICO) Master Protocol 
 
 
E-3 
SOC 
standard of care 
SUSAR 
suspected unexpected serious adverse reaction 
TOC 
trial oversight committee  
UMN 
University of Minnesota 
UP 
Unanticipated problem 
US 
United States of America 
VA 
Veterans Administration 
WHO 
World Health Organization 


Appendix F  
National Early Warning (NEW) Score 
Criteria 
Point Value 
Respiratory Rate (breaths per minute) 
≤8 
+3 
9-11 
+1 
12-20 
0 
21-24 
+2 
≥25 
+3 
Oxygen Saturation (%) 
≤91 
+3 
92-93 
+2 
94-95 
+1 
≥96 
0 
Any Supplemental Oxygen 
Yes 
+2 
No 
0 
Temperature in °C (°F) 
≤35.0 (95) 
+3 
35.1-36.0 (95.1-96.8) 
+1 
36.1-38.0 (96.9-100.4) 
0 
38.1-39.0 (100.5-102.2) 
+1 
≥39.1 (≥102.3) 
+2 
Systolic BP 
≤90 
+3 
91-100 
+2 
101-110 
+1 
111-219 
0 
≥220 
+3 
Heart Rate (beats per minute) 
≤40 
+3 
41-50 
+1 


51-90 
0 
91-110 
+1 
111-130 
+2 
≥131 
+3 
AVPU 
A 
0 
V, P, or U 
+3 
AVPU – Alert, Voice, Pain, Unresponsive. 
 


Appendix G 
Phase I Studies as Part of this Master Protocol 
It is anticipated that novel investigational agents entered into this master protocol will have 
enough safety and dosage data available by studies outside the master protocol, to enable 
them to move directly intoal this protocol. In some instances, sufficient safety and dosage 
data will not be available, and the investigational agent will first require a safety evaluation 
in the form of a phase I dose escalation and dose determination before moving into the 
main master protocol.  
A separate protocol for the Phase I study will be developed for each individual 
investigational agent as a stand-alone document with its own consenting procedure, and 
included here as Appendix G1, G2, etc.   
In this appendix, we describe the overarching framework as to how safety will be evaluated 
in a Phase I dose escalation study, with the understanding that additional details will be 
required as agents identified as being of interest for the master protocol but with insufficient 
prior safety data for entry into the master protocol.  
The dose escalation study described below provides a framework for a Phase I dose 
escalation but a number of design parameters have been left intentionally unspecified 
because they will depend on the specific investigational agent under consideration and the 
current status of the master protocol. Key scientific decisions regarding other design 
parameters including the number of dose levels to be investigated, the definition of dose-
limiting toxicities (DLTs), and the appropriate target population will be determined by the 
protocol leadership together with the overarching ACTIV-2/3 TOC in collaboration with the 
drug developer and study statisticians. Efforts will be made to harmonize these across 
study products, while allowing for learning from prior evaluations and also the incorporation 
of any issues predicted to be critical for a specific agent.  This information will be included 
as new sub-appendices (H1, H2, etc.) in addition to other information regarding the new 
agent when it is entered into the master protocol for stage 1 evaluation. 
a. Dose Escalation
The goal of the Phase I component is to identify the maximum tolerated dose (MTD) of the 
investigational agent, defined as the maximum dose with probability of dose limiting toxicity 
(DLT) less than a specific pre-specified threshold. The basic framework of the Phase I 
component will be a dose escalation study where initial study participants are treated at the 
lowest dose and subsequent participants are treated at progressively higher dose levels 
until the MTD is identified. Dose finding will be guided by the continuous reassessment 
method (CRM). Briefly, the CRM is a Bayesian adaptive Phase I trial design first proposed 
in O’Quigley, et al88 ) and later modified by Piantadosi, et al89 and Goodman, et al.90 The 
CRM is a model-based design that relies on a simple, one-parameter model for estimating 
the probability of DLT at each dose and uses the estimated probabilities of DLT at each 
dose to guide dose escalation. For this trial, we will model the probability of DLT using the 
power model:
P(DLT | dose = j) = djexp(α) 
Where j is the dose level and (d-1, …, dJ) is the “skeleton” for the probability of DLT at each 
dose and the probability of DLT is estimated by estimating the α parameter. 


For the purposes of this appendix, the number of doses or the specific skeleton are 
unspecified.  
Dose finding in the CRM begins by treating the first cohort of three subjects at the initial 
dose level. After the toxicity outcomes for the first cohort are observed, the posterior 
distributions for the probabilities of DLT are updated. The next cohort is treated at the 
current estimate of the MTD, defined as the dose level with estimated probability of DLT 
(posterior mean) closest to the target probability of DLT, under the restriction that untried 
dose levels may not be skipped when escalating. This process continues until the maximum 
sample size is reached or until a pre-specified number of consecutive cohorts are treated at 
the same dose level, whichever comes first. The dose level with estimated probability of 
DLT (posterior mean) closest to the target probability at study completion is declared the 
MTD, and that dose may be carried forward to the master protocol. If at any point in the 
study, the posterior probability suggests that the lowest dose level is excessively toxic, the 
trial will terminate for excess toxicity. The specific threshold for determining excess toxicity 
will be determined when a new treatment is entered into the Phase I portion of the master 
protocol.  
b. Other considerations in dose determination 
 
It is possible that the MTD determined using the above may be higher than the optimal 
dose for evaluation in the next protocol stages. At present, correlative markers of clinical 
activity in COVID-19 are not well understood. As these markers (for example, but not 
limited to, SARS-CoV-2 viral load) are better understood, the above framework could also 
accommodate an approach allowing comparison of identified predictive biomarkers across 
two or more tolerable doses with the goal of identifying recommended doses for 
subsequent clinical evaluation that are below MTD. For example, MTD and one or more 
tolerable dose levels below MTD could be evaluated with respect to performance against 
the biomarkers, with a view to identifying a tolerable dose below MTD that is predicted to be 
effective, to carry forward to the next stage of evaluation in the master protocol (stage 1). 
This biomarker comparison would be secondary to the MTD determination. 
 
c. Definition of DLTs and Sample Size 
The dose escalation study described above provides a framework for a Phase I dose 
escalation but a number of design parameters, including the definition of DLTs and the 
sample size, have not been specified. These depend on the specific investigational agent 
under consideration and the current status of the main master protocol. Efforts will be made 
to harmonize DLT definitions across study products, while allowing for learning from prior 
evaluations and also any toxicities predicted to be critical for a specific agent.  Other design 
parameters, including the sample size, will similarly be determined by the protocol team’s 
study statisticians in collaboration with the drug developer to achieve desired operating 
characteristics.  
d. Population 
Given the early phase of evaluation, this population is likely to differ from the population in 
the master protocol, which includes hospitalized patients with varying stages of 
progression. Accurate determination of toxicity of an agent in early clinical phase is likely to 
be more challenging in patients with significant clinical progression. Consideration may 
therefore be given to restricting enrollment to patients with the lowest risk of clinical 


progression within a hospitalized population, or to populations that are not in need for 
hospitalization except for the purpose of participating in the Phase I study.  
e. Study Sites 
While it is anticipated that the main master protocol will enroll participants at a large number 
of sites in multiple countries, it is anticipated that sites for Phase I studies will be much 
more restricted. Sites will be selected based on Phase I expertise, including ideally the 
availability of dedicated Phase I clinical evaluation units. While multiple sites may 
participate in Phase I studies during the life of the master protocol, for individual agents it is 
anticipated that in most cases evaluation will be performed at a single site. This will 
streamline integration of toxicity assessments into the CRM and the dose escalation 
process. In certain circumstances two or more sites may participate together in evaluation 
of a single Phase I agent, in which governance structures to facilitate rapid communication 
of toxicity data between sites and to the oversight team will be established.  
f. Relationship Between Phase I and the Master Protocol 
Agents evaluated in Phase 1 may or may not proceed to the master protocol, depending on 
results of the Phase 1 evaluation and review by the ACTIV steering committee.  At a 
minimum, evaluation in Phase I will be used to determine the following key elements 
required for evaluation in the main master protocol should the agent proceed. 
 Dose(s) for evaluation for later stages. In master protocol, up to three doses maybe 
evaluated.  
 Any required specific exclusion and inclusion criteria, over and above the general criteria 
outlined in the main master protocol (this will be informed by toxicity and other agent 
characteristics in Phase I).  
While the focus of Phase I evaluation will be safety and dose determination, markers of 
clinical efficacy including the ordinal endpoint at Day 5 may be assessed and information 
will be collected up to 90 days as in the main master protocol will also be collected to inform 
the clinical development of these agents.  
While these data will be used to identify the correct dose or doses to investigate in the 
master protocol, the Phase 1 study will be distinct, and the data will not be incorporated into 
the master protocol. 
 
 
 


Appendix H  
Neutralizing monoclonal antibody. 
 
This appendix will include the following information for each nMAb studied. The rationale for 
studying the agent, justification for entry into the master protocol, and the description and 
administration of the agent. Also, as appropriate, specific AEs observed to be possibly 
associated with the agent in question, and how to monitor for, clinically handle and report such 
AEs, should they arise. Changes in endpoint, SOC, inclusion and/or exclusion criteria, sample 
size estimation and approach to interim analyses and data analyses will also be included if 
appropriate for the investigation of the nMAb in question relative to what is stated in the master 
protocol. Finally, the text will also clarify whether the manufacturer of investigational agent 
plans to pursue licensure in the countries where the trial will occur, should the investigational 
agent be demonstrated in the trial to have overall benefit. 
   Introduction/Rationale for studying the agent 
o Potential risks and benefits of agent 
o Motivation for agent selection with consideration of results from trials of other nMAbs  
• Agent-specific eligibility criteria 
• Description of investigational agent 
o Administration and duration 
o Formulation and preparation 
o Supply, distribution, and accountability 
o Contraindicated medications 
o Precautionary medications 
• Clinical and laboratory evaluations in addition to master protocol 
o Timing 
o Special instructions 
• Clinical management issues 
o Infusion-related reactions 
o Hypersensitivity 
• Pregnancy and breast-feeding considerations 
• Criteria for discontinuation of infusion 
• References 
 
 
 


Appendix I  
Standard of Care 
 
I1. Overview 
Currently, there are no licenced treatments for COVID-19.  One investigational agent, 
remdesivir, is now accepted by several countries’ regulatory bodies for use as part of 
routine care; in the US, FDA has been granted the drug an Emergency Use Authorization. 
Considering the number of randomized trials being conducted to study treatments for 
COVID-19, it is likely that other effective treatments will be identified during performance of 
this master protocol. 
When treatments for COVID-19 are demonstrated to have safety and efficacy, those 
treatments should be considered in designing new studies.  Depending on the scientific 
question, an experimental treatment will be coupled with or compared to a known effective 
treatment.  When such known effective treatments are incorporated into both arms, they are 
called “background therapy” or standard of care (SOC).  In this case, the scientific question 
addressed is whether a new treatment added to an already effective treatment is superior to 
the established effective treatment alone.  
SOC may include general supportive care appropriate to the participant’s clinical status, 
and specific therapeutic agents, and measures to reduce risk of SARS-CoV-2 transmission 
to the participant and health care givers. 
As stated in section 5.1, the objective of this protocol is to evaluate investigational agents -   
aimed at enhancing the host immune response to or impair replication of SARS-CoV-2 
infection - for safety and efficacy compared to placebo control, when all eligible participants 
receive background therapy that is considered effective.  Consistent with precedent, we 
refer to background therapy as standard of care (SOC).  All participants will receive an 
investigational agent (initially a nMAb) + SOC vs. placebo + SOC. 
Below, principles for defining SOC are provided, and recommendations and guidance on 
SOC are given. Whether an individual SOC treatment is provided by the trial or not is based 
on multiple factors, including clinical and scientific considerations. In some cases, the 
decision to administer an SOC treatment is left entirely to the research participant’s primary 
medical team. 
I2. Guiding principles for inclusion of measures as part of SOC  
The SOC will be regularly updated based on review of the scientific literature and updated 
authoritative treatment guidelines on this topic. The standard for including one or more 
measures as SOC, includes a careful review of the existing literature and current guidelines 
(see Appendix D). As for therapeutic agents, those having been shown to be clinically 
effective in properly powered phase III or phase IV trials (i.e., high quality/level 1 evidence) 
and with a reasonable safety profile will be considered by the protocol team for inclusion, if 
recommended by at least one major treatment guideline. This evaluation may also lead to a 
statement that one or more agents are either not recommended or should not be used as 
part of SOC. As knowledge will likely continue to accumulate rapidly, the protocol 
leadership team may occasionally decide to include or exclude an intervention as part of 


SOC before it is recommended in at least one major treatment guideline. In such cases, the 
relevant literature that lead to the determination will be cited.  
The use of a given SOC intervention may apply to all or to a subgroup of the participants in 
the master protocol based on available evidence – the subgroup may be defined based on 
severity of disease, a clinical or laboratory defined feature, or a clinically or laboratory 
defined contraindication for using the SOC treatment. An SOC agent may be mandated for 
participants (required for protocol entry); mandated where not contraindicated (participants 
may enter if that SOC is unsuitable, and not receive that SOC); or recommended subject to 
clinical discretion. SOC may be protocol-supplied where mandated.  
The master protocol acknowledges that there may be local variation in the clinical 
availability of one or more agents chosen to be part of mandated protocol-supplied SOC 
from site to site. While acknowledging risks of inadvertent coercion, the importance of the 
scientific question (how candidate agents perform against the background of the current 
SOC treatments) is a crucial, high-priority question. There is no possible way to answer the 
question of efficacy against the background of an already proven effective agent without 
providing the agent – if not readily available - within the trial.  
I3. Current SOC in the master protocol: 
I3.1 Remdesivir Background Therapy 
Based on the findings of the Adaptive COVID-19 Treatment Trial (ACTT),91 remdesivir will 
be provided to all study participants as SOC unless contraindicated for an individual patient.  
As in the ACTT trial, remdesivir will be administered as a 200 mg IV loading dose, followed 
by a 100 mg once-daily IV maintenance dose while hospitalized up to a 10-day total course.  
Participants taking remdesivir prior to randomization will continue their daily remdesivir 
infusions while hospitalized up to a 10-day course and possibly longer should evidence 
emerge to support this. The primary medical team has discretion to plan for 5 days duration 
in patients that do not require mechanical ventilation or ECMO. If as part of clinical care a 
patient has received a loading dose of remdesivir before randomization, the loading dose 
will not be repeated. Details relating to contraindications, dosing, and monitoring of 
remdesivir are included in the Protocol Instructions Manual [PIM].   
I3.2 Dexamethasone and Other Corticosteroids 
Based on the preliminary findings of the RECOVERY trial 
(https://pubmed.ncbi.nlm.nih.gov/32678530/and in line with NIH treatment guideline (Appendix 
D), it is recommended to consider initiation of corticosteroid therapy in participants with 
COVID-19 who are mechanically ventilated and in patients with COVID-19 who require 
supplemental oxygen but who are not mechanically ventilated.  In patients with minimal 
oxygen need, however, special consideration weighting benefits vs potential risk should be 
given whether to initiate a corticosteroid. Corticosteroids may increase the probability of 
reactivating latent infections including herpes viruses and tuberculosis, hyperglycemia, 
hypernatremia, secondary infections, and may delay clearance of SARS-CoV-2. In 
participants not requiring supplementary oxygen, it is recommended not to initiate a 
corticosteroid. As the RECOVERY trial was performed at or near sea level, for patients 
enrolled at altitude, investigators and clinicians may appropriately avoid corticosteroid 
administration in patients receiving modest flow rates of supplemental oxygen. Treatment 


with a corticosteroid is recommended for a total of 10 days, using doses outlined in this 
table.  
Corticosteroid name 
Daily dose 
Dexamethasone 
6 mg PO or IV 
Prednisone 
~40 mg PO 
Methylprednisolone 
~32 mg IV 
Hydrocortisone 
~160 mg IV 
I3.3 Other Supportive Care 
All participants will be given supportive care for most complications of severe COVID-19 
including: pneumonia, hypoxemic respiratory failure/ARDS, sepsis and septic shock, 
cardiomyopathy and arrhythmia, acute kidney injury, and complications from prolonged 
hospitalization, including secondary bacterial infections, thromboembolism, gastrointestinal 
bleeding, and critical illness polyneuropathy/myopathy. Links to details of such care can be 
found in Appendix D.  Supportive care components of SOC include lung-protective 
ventilation for patients who require invasive mechanical ventilation92 (high quality evidence) 
and prone positioning for mechanically ventilated patients with more than moderate ARDS 
(high quality evidence), treatment with anti-bacterial agents for patients believed to have 
bacterial infection (high quality evidence), guidelines-compliant management of sepsis 
when it is present (moderate quality evidence)93. Use or non-use of extra-corporeal life 
support (ECLS) is not mandated as part of SOC; nor is any specific approach to renal 
replacement therapy.  
Consideration should be given to the use of pharmacological thromboprophylaxis 
(thrombosis prevention) in line with local clinical guidelines for hospitalized patients as 
appropriate for an individual participant, in addition to approaches to maintain mobility and 
minimize other thrombotic risks. Standard approaches to thromboprophylaxis supported by 
high quality evidence include the use of low molecular weight heparin (for example, 
enoxaparin 0.5m/kg daily), which is the preferred agent in some COVID-19 treatment 
guidelines. However other standard approaches in accordance with local and institutional 
guidelines and the medical circumstances of an individual participant may also be 
considered, including the use of low (prophylactic) dose unfractionated heparin (high quality 
evidence). Specialist advice should be sought for participants with pre-existing 
prothrombotic states, or who are pregnant.  
I3.4 Cautions and Contraindications 
Remdesivir is recommended not to be combined with (hydroxy)chloroquine. The 
effectiveness of remdesivir may be reduced if combined with (hydroxy)chloroquine, and 
hence it is not advisable to combine these two medications.94 
It is not recommended to use high dose chloroquine (600 mg twice daily) as SOC due to 
excess harm and not demonstrable benefit. (Hydroxy)chloroquine has no documented 
clinical benefit, and hence not recommended for use as SOC.  


I3.5 SARS-CoV-2 Infection Control 
Minimum standards of protection to reduce the risk of SARS-CoV-2 transmission from trial 
participants to research personnel, participants in other trials, or patients treated in the 
same facility can be found in links displayed in Appendix D. 
 
 


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58 Mulangu S, Dodd LE, Davey RT, Jr., et al. A Randomized, Controlled Trial of Ebola Virus Disease Therapeutics. 
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59 Jiang S, Hillyer C, Du L. Neutralizing Antibodies against SARS-CoV-2 and Other Human Coronaviruses. Trends 
Immunol 2020;41:355-9. 
60 Wang C, Li W, Drabek D, et al. A human monoclonal antibody blocking SARS-CoV-2 infection. Nat Commun 
2020;11:2251. 
61 Pinto D, Park YJ, Beltramello M, et al. Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV 
antibody. Nature 2020. 
62 Walls AC, Park YJ, Tortorici MA, Wall A, McGuire AT, Veesler D. Structure, Function, and Antigenicity of the 
SARS-CoV-2 Spike Glycoprotein. Cell 2020;181:281-92 e6. 
63 Liu L, Wang P, Nair MS, et al.  Potent neutralizing antibodies against multiple epitopes on SARS-CoV-2 spike.  
Nature 2020, doi.org/10.1038/s41586-020-2571-7. 
 
64 Jones BE, Brown-Augsburger PL, Corbett KS, et al.  LY-CoV555, a rapidly isolated potent neutralizing antibody, 
provides protection in a non-human primate model of SARS-CoV-2 infection.  bioRxiv 2020; 
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65 Cheung CY, van der Brink EN, Poon LLM, et al.  Human monoclonal antibody combination against SARS 
coronavirus: synergy and coverage of escape mutants.  PLoS Med 2006; doi.org/10.1371/journal.pmed.0030237. 
 
66 Tian X, Li C, Huang A, Xia S, Lu S, Shi Z, et al. Potent binding of 2019 novel coronavirus spike protein by a 
SARS coronavirus-specific human monoclonal antibody. Emerg Microbes Infect. 2020;9(1):382-5. 
 
67 Yuan M, Wu NC, Zhu X, Lee CD, So RTY, Lv H, et al. A highly conserved cryptic epitope in the receptor binding 
domains of SARS-CoV-2 and SARS-CoV. Science. 2020;368(6491):630-3. 
 
68 Tai W, Zhang X, He Y, Jiang S, Du L. Identification of SARS-CoV RBD-targeting monoclonal antibodies with 
cross-reactive or neutralizing activity against SARS-CoV-2. Antiviral Res. 2020;179:104820. 
 
69 Shi Shi R, Shan C, Duan X, Chen Z, Liu P, Song J, et al. A human neutralizing antibody targets the receptor 
binding site of SARS-CoV-2. Nature. 2020. 
 
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infection. Nature. 2020. 
 
71 Chen X, Li R, Pan Z, Qian C, Yang Y, You R, et al. Human monoclonal antibodies block the binding of SARS-
CoV-2 spike protein to angiotensin converting enzyme 2 receptor. Cell Mol Immunol. 2020. 
 


72 Greaney AJ, Starr TN, Gilchuk P, et al.  Complete mapping of mutations to the SARS-CoV-2 spike receptor-
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73 Wilder-Smith A, Hombach J, Ferguson N, et al. Deliberations of the Strategic Advisory Group 
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74 Pocock Sj, Ariti CA, Collier TJ, et al.  The win ratio: a new approach to the analysis of composite endpoints in 
clinical trials based on clinical prioritites.  Eur Heart J 2012; 33: 176-182. 
  
75 Zhao W. Mass weighted urn design--A new randomization algorithm for unequal allocations. Contemp Clin Trials. 
2015;43:209-216. doi:10.1016/j.cct.2015.06.008 
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Statistics. 1988;16:1141-1154. 
 
77 Beigel JH, Tomashek KM, Dodd, LE, et al.  Remdesivir for the treatment of Covid-19 – final report.  N Engl J Med 
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78 Freedman LS.  Tables of the number of patients reported in clinical trials using the logank test.  Stat Med 1982; 1: 
121-129. 
 
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503. 
 
80 Gray RJ. A Class of K-Sample Tests for Comparing the Cumulative Incidence of a Competing Risk. Annals of 
Statistics. 1988;16:1141-1154. 
 
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Censored Observations. Scand. J. Stat. 1978; 5(3):141–150. 
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1999; 94:496-509. 
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67(2):661-70. 
84 Barthel FM-S, Parmar MKB, Royston P.  How do multi-stage, multi-arm trials compare to the traditional two-arm 
parallel group design – a reanalysis of 4 trials.  Trials 2009; 10:21, doi:.10.1186/1745-6215-10-21. 
 
85 Choodari-Oskooei B, Parmar MKB, Royston P, Bowden J.  Impact of lack-of-benefit stopping rules on treatment 
effect estimates of two-arm multi-stage (TAMS) trials with time to event outcome.  Trials 2013, 14:23, 
http://www.trialsjournal.com/content/14/1/23. 
 
86 Follmann D, Proschan M.  Two stage designs for phase III clinical trials (personal communication). 
  
87 Proschan MA, Lan KKG and Wittes JT. Statistical monitoring of clinical trials : a unified approach. New York, NY: 
Springer; 2006; section 3.2. 
 
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Biometrics 1990; 46: 33-48. 
 
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dose-finding trials.  Cancer Chem and Pharmac 1998; 41: 429-436.  
 


90 Goodman SN, Zahurak ML, Piantadosi S.  Some practical improvements in the continual reassessment method 
for phase 1 studies.  Stat Med 1995; 14: 1149-1151. 
 
91 Beigel JH, Tomashek KM, Dodd LE, et al.  Remdesivir for the treatment of COVID-19 – preliminary report.  N 
Engl J Med 2020 doi: 10.1056/NEJMoa2007764. 
 
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93 https://www.sccm.org/SurvivingSepsisCampaign/Guidelines/Adult-Patients 
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discovered-potential-drug-interaction-may-reduce 
 

ICF_003.pdf: 
 Informed Consent Form
A Multicenter, Adaptive, Randomized, 
Blinded Controlled Trial of the Safety 
and Efficacy of Investigational 
Therapeutics for Hospitalized Patients 
With COVID-19 (Trial H6: 
PF-07304814)
17 August 2021
NCT05780541


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«PiFullName» 
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Revised «PIApprovalDate» 
 
Informed Consent Form  
 
Sponsor / Study Title: 
  
University of Minnesota / INSIGHT / “A Multicenter, 
Adaptive, Randomized, Blinded Controlled Trial of the 
Safety and Efficacy of Investigational Therapeutics for 
Hospitalized Patients with COVID-19” 
 
Protocol Number: 
 
INSIGHT 014/ ACTIV 3 
 
Principal Investigator: 
(Study Doctor) 
 
«PiFullName» 
 
Telephone: 
 
«IcfPhoneNumber» 
 
Address: 
«PiLocations» 
 
 
This form is for use in a research study that may involve participants who may or may 
not have the capacity to consent to take part in the study.  When the participant cannot 
legally consent to take part, pronouns “you” and “your” should be read as referring to 
the participant rather than the person (legally authorized representative) who is signing 
and dating this form for the participant. In cases where the participant’s representative 
gives consent, the participant should be informed about the study to the extent possible 
given his/her understanding. During the course of the study, if the participant regains 
the capacity to consent, informed consent will be obtained from the participant and the 
participant offered the ability to leave the study if desired. 
Key information: 
We are asking you to join a research study about COVID-19.  It is your choice whether 
or not you want to join.  This form gives you information about the study that will help 
you make your choice.  You can talk about this with your doctor or family or anyone else 
you would like before you make your choice.  Your choice will not affect the care you 
are getting for COVID-19. 
 
 


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Why are we doing this study? 
We are studying experimental drugs to potentially treat people with COVID-19.  
Experimental means that the study drug is not approved by the United States Food and 
Drug Administration (FDA) or any other government agency, and its use is strictly 
limited to research. We are trying to find out if giving these study drugs can help people 
in the hospital with COVID-19 get better and go home faster. We are also trying to see if 
they are safe. 
We are asking you to join the study because you are in the hospital with COVID-19.   
What do you have to do if you decide to be in the study? 
The study staff at your hospital will check to see if there is any reason you should not be 
in the study.  They will check your medical history.  They will look at tests commonly 
done for your condition.   
We are testing different types of study drugs. If you join the study, you will be assigned 
by random chance - like flipping a coin or rolling dice - to get one of these study drugs 
or a salt-water placebo.  You could be in any one of the groups below: 
• 
AZD7442, made by AstraZeneca 
• 
MP0420, made by Molecular Partners and Novartis 
• 
PF-07304814, made by Pfizer 
• 
Placebo (a salt-water solution that has no active drug in it) 
Not all of the study drugs listed above may be available to you right now. If this is the 
case, then you will be told which ones are available.   
You will have at least a 50% chance (1 in 2) of receiving an active drug.  You may have 
as much as a 75% chance (3 in 4).  This chance depends on which study drugs are 
available to you at the study site where you are enrolled. 
Your study doctor will not decide which group you are in, and just like you, will not know 
whether you are getting an experimental drug or inactive placebo. None of the study 
staff will know whether you are getting a drug or the placebo.  
We will tell you more about each study drug you could get in a separate 
information sheet.  You will be given an information sheet for each of the 
available study drugs. 
You will get the study drug through an intravenous (IV) drip through a plastic tube 
attached to a needle in your arm.  This is called an infusion.  The information sheets will 
tell you how much liquid will be in the infusion and how long it should take to get it.  


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The infusion is the only thing you will be given that is completely experimental.  
The drugs we are studying can only be used in research.  There are many treatments 
being studied for COVID-19, and some have received US FDA emergency approval or 
other types of approval to be used in some people with COVID-19.  Your doctor and the 
study team will tell you about any treatment options you may have. 
As part of the study you will also get a study drug called remdesivir (also called Veklury) 
for your COVID-19, unless your study doctor thinks remdesivir would not be safe for you 
to take. Remdesivir is given once a day by infusion for up to 10 days while you are in 
the hospital. Remdesivir was shown in an earlier study to help people get better more 
quickly from COVID-19.  Remdesivir is approved by the US FDA for treating COVID-19. 
It also has approval in many other countries.   
Any other medicines or treatments you get will be what you would usually get in this 
hospital for your condition.  There may be some additional tests done just for the study.  
We will describe these below. 
You will be in the study for 18 months. We will get most of the information for the study 
in the first 3 months. 
We do not know what effects these study drugs may have on a pregnancy or unborn 
baby.  There may be bad effects or no effects.  If you decide to join the study, we 
strongly advise you to not have sex that could make you or a partner pregnant from the 
time you sign and date this consent form for some time after you have taken the study 
drug. How long this will be depends on which study drug you have been assigned to 
get. This may involve not having sex at all (abstinence), or you may use effective birth 
control (hormonal contraceptives like birth control pills or barrier methods with 
spermicide) to avoid pregnancy.  Methods like rhythm, sympto-thermal or withdrawal 
are not considered effective for preventing pregnancy.  We will tell you more about this 
requirement as part of telling you about each study drug you could get. You should ask 
the study team about this if you have questions or concerns. 
If you get pregnant during the study, please let your study team know as soon as 
possible. We may ask to follow you until your pregnancy is over, to see if there were 
any problems that may have been caused by any of the study treatments. 
 
If your partner gets pregnant, please let your study team know as soon as possible. We 
may ask your partner to let us get basic information about her pregnancy. 
You will also need to agree to not be in any other COVID-19 study for the first 5 days 
you are in this study.  There may be exceptions to this requirement.  We will tell you 
about any other studies you can be in during the first 5 days of this study so you can 
make a choice. 


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This is what you will be doing for the study:   
Up to 1 day 
before you 
get study 
drug 
Day 0 (the 
day you get 
study drug) 
Day 1, Day 
3, Day 5 
Day 2, Day 4 
Day 6, Day 7, 
Day 14, Day 
42, Day 60, 
Day 75 
Day 28 and 
Day 90 
• Informed 
consent (this 
document) 
• Check to see 
how you are 
feeling 
• Your medical 
history 
• Contact 
information 
like telephone 
numbers and 
addresses for 
you and at 
least two 
close relatives 
or friends 
• Infusion of 
study drug [the 
experimental 
drug or 
placebo] 
• Whether you 
are taking 
certain 
medicines 
• Blood tests to 
check your 
health (9 mL, 
about ½ 
tablespoon) 
• Blood for future 
research (18 
mL, about 1 
tablespoon) 
• A swab of your 
nose for virus  
• How you are 
feeling 
• Blood for 
future 
research (18 
mL, about a 
tablespoon) 
• On Day 5, 
also check 
whether you 
have taken 
certain 
medicines, 
and blood 
tests to check 
your health (9 
mL, about ½ 
tablespoon) 
• How you are 
feeling (Days 
2, 4, 6, 7, 14, 
60) 
• Update on 
return to 
home (Days 
14, 42, 60, 
75) 
These “visits” 
may take place 
by phone. 
• How you are 
feeling 
• Blood for 
future 
research (18 
mL, about a 
tablespoon) 
• On Day 28, 
also check 
whether you 
have taken 
certain 
medicines 
• Update on 
return to 
home 
 
If you leave the hospital after just a few days, we will ask you to come back to give a 
blood sample on Day 3 and Day 5 of the study. You might instead be visited in your 
home by a professional working for the study to get this blood sample. We will also 
need to take a blood sample from you on Day 28 and Day 90.   
 
 
 


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After Day 90, we will talk to you three more times by phone, at 6 months, 12 
months, and 18 months, to see how you are doing and whether you have been in 
the hospital for any reason. 
We may need to get some information from your medical record: 
• By signing this consent, you agree to let us get information for this study from 
your medical record.   
• By signing this consent, you are giving us permission to contact other hospitals 
or medical facilities you are admitted to while you are in the study. We will 
contact them to find out how you are doing.   
• We will ask you to give us information about other people we can contact if we 
are not able to reach you after you leave the hospital. This is so we can find out 
how you are doing. 
 
We will send the information you give us to the University of Minnesota (UMN) in the US 
where it will be stored and analyzed.  In this information, only a code number, your year 
of birth, and a 3-letter code, that the study staff chooses, identifies you.   
The study staff here at this study site is responsible for keeping your information safe 
from anyone who should not see it.   
We will send the blood and nose swab samples to a laboratory in the US for storage.  
We will keep them for as long as we have the money and space to do so. We expect 
this to be many years.  There is more information later in this consent about how we will 
use these samples.   
Why would you want to be in the study? 
If you get the experimental drug, it is possible it may help you get better, or that you 
may get home faster, but we do not know that.   
Remember that some of the people in this study will get inactive placebo, and will not 
get any experimental drug. 
By being in this study, you will help doctors learn more about how to treat COVID-19 in 
people in the hospital.  Because many people are getting hospitalized with COVID-19, 
this could help others.  There may be a large health impact if a treatment proves to be 
safe and to work. 
Why would you not want to be in the study? 
If you do get one of the experimental drugs, it may not help. It may have harmful side 
effects.   
 
 


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What are the risks or side effects of the experimental drugs? 
All treatments have risks and may cause side effects.   
The risk of the study drugs you may be assigned to are provided in a separate drug 
information sheet for each study group. You should review the applicable drug 
information sheet(s). 
Any drug can cause an allergic reaction.  You may have an allergic reaction to the study 
treatment, including hives, trouble breathing, or other allergic responses. Allergic 
reactions like these are likely to be rare, but may be severe or life-threatening.   
We will watch over you while you are being given the infusion of the study product and 
for at least 2 hours after the infusion is finished.  We will give you medical care right 
away if you need it to treat any side effects from the infusion. 
The fluid needed to give the experimental drug or the placebo may overload your body if 
you have problems managing fluids due to COVID-19 or other conditions. We expect 
this to be rare. 
There are discomforts and risks with blood draws and getting a swab of your nose. You 
will have these things done while you are in the hospital even if you are not in the study.  
You may have some pain, bleeding, or bruising when a needle is put into your vein to 
draw blood or to give the study infusion.  Getting your nose swabbed can be 
uncomfortable and you might gag. These discomforts and risks are not different from 
what you would have if they were done as part of your regular hospital care for COVID-
19. 
What if you are pregnant or breastfeeding? 
[The following will vary depending on the agents being studied.] 
If you are pregnant or breastfeeding, you can/cannot join this study. 
Additional information: 
Here is some additional information about the study that may help you make your 
choice about whether you want to be in the study. 
The NIH, an agency of the US Federal government, is paying for this study.   
We are required to follow all rules and regulations for human research as well as the 
laws of each country where the study is being done.   
This study is taking place in several countries.  We expect to enroll about 1,000 subjects 
around the world for each drug we are studying. 
You do not have to join this research study if you do not want to.  If you choose to join 
the study, you can stop at any time.  If you choose not to join or to stop, the medical 
care you are getting outside of the study now will not change. 


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If we get any new information that might change whether you want to join or stay in the 
study, we will tell you right away. 
If you do not want to be in this study, you will still get the usual care to treat COVID-19.  
However, you cannot get the study drug, because it is experimental. 
Vaccines against the virus that causes COVID-19 are starting to be available. It looks 
like people who have had COVID-19 do not have much chance of catching it again for 
at least 3 to 6 months. The US Centers for Disease Control and Prevention (CDC) 
recommends that people wait for at least 90 days after they’ve been given certain 
medicines before they get the vaccine.   We do not know if the drugs we are studying 
change how you respond to the vaccine during that time.   
What are the risks and benefits of taking remdesivir? 
Remdesivir has been shown to help people who are in the hospital and moderately to 
severely sick with COVID-19 get better about 4 days faster than subjects who got a 
placebo.  You may be given remdesivir to treat your COVID-19 even if you do not join 
this study.   
 
The most common side effects of remdesivir included abnormal liver function tests, 
abnormal blood clotting tests, constipation, nausea, vomiting, decreased appetite, and 
headache. The abnormal liver function tests lasted longer than a few days in some 
people, but went back to normal within a few weeks or less. 
Remdesivir might affect the way that other medications are processed by your body.  
They might stay in your body longer, or shorter, or at higher or lower levels.  At the time 
this consent was written, one person in this study had an increase in the level of a 
medication in their blood that was considered by study doctors to be at least possibly 
related to having taken remdesivir.  There did not appear to be any harm from this 
temporary change.  You can ask the study team about this if you are concerned. 
Some people have some side effects after the infusion of remdesivir.  Other people 
have no side effects.  People can have allergic reactions to drugs, including hives, 
trouble breathing, or other allergic responses. Allergic reactions may be severe or life-
threatening.  This is very rare but is also a possible effect of any drug. We will monitor 
you closely while you are getting remdesivir. We will give you medical care right away to 
treat any side effects. 
What are the costs to you? 
We will give you the study treatment at no cost.  We will pay for all clinic visits, lab work, 
and other tests that are part of this study. 
You, your insurance company, or some other third-party payer must pay for all other 
medicines and hospital costs. 


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Will you be paid to be in the study? 
«Compensation»  
 
We will compensate you for your time and inconvenience participating in the study.   
What if you are hurt as part of this study? 
If you are hurt because of being in this study, the study site will treat your injury right 
away.  You or your insurance will have to pay for this treatment.  The study cannot pay 
you or pay for any care for study-related injuries or for your illness. 
A Declaration under the Public Readiness and Emergency Preparedness (PREP) Act 
was issued by the Secretary of the United States Department of Health and Human 
Services on March 10, 2020.  This Declaration limits the legal rights of a subject 
participating in clinical studies utilizing COVID-19 countermeasures.  Because this study 
is covered by the Prep Act Declaration, covered persons, such as the manufacturers, 
study sponsor, researchers, healthcare providers and others have liability immunity (that 
is, they cannot be sued by you or your family under the laws of the United States). 
If you believe that you may have been harmed as a result of this research study, certain 
claims for serious injury or death caused by the countermeasure may be eligible for 
compensation through the Countermeasures Injury Compensation Program. This is a 
program set up by the United States Government.  
Information about this program can be found at 
https://www.hrsa.gov/cicp/about/index.html or by calling 1-855-266-2427. If you are 
eligible for this program, you must file a claim within one year of the administration or 
use of the covered countermeasure. 
What happens to the blood and swab samples? 
We will send the blood and swab samples to a central laboratory in the United States.  
You and your study doctor will not get the results of any tests done on these samples.  
We will not test your DNA (your genes).  We will not sell your samples and they will not 
be used for research aimed at making money (commercial research).  The laboratory 
where the samples are stored will not have any information that could identify you. 
The blood samples will measure how many COVID-19 antibodies are in your blood.  
This will tell us how your immune system responded to your COVID-19.  The swab 
sample will be used to how much virus is in your body. 
Any blood or swab samples that are left over after these tests will be stored at the 
central laboratory for as long as we are able to keep them.  We hope to use these in the 
future to answer other questions about COVID-19, the virus that causes it, and how 
people respond to treatment.  You and your study doctor will not get any results from 
these tests.  Some of the blood will also be given to the companies that made the study 
drugs to help them learn more about its effects.   


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You can withdraw your consent for us to keep these samples at any time.  Let your 
study team know if you do not want the study to keep your samples anymore. We will 
make every effort to destroy all of your samples that are still at the central laboratory. 
How do we protect your privacy? 
We will take every reasonable step to keep your health information private and to keep 
anyone from misusing it. 
Your information (data) and samples will not be identified by name, or in any other way, 
in anything published about this study.   
We will do everything we can to keep your personal information private, but we cannot 
guarantee that nobody will get it.  We may have to release your personal information if 
required by law. 
These people may see your medical and research information: 
• Advarra Institutional Review Board (Advarra IRB); 
• The sponsor, the group paying for the research (US NIH), other study research 
staff and study monitors 
• US and other participating countries’ health regulatory agencies, including the US 
FDA 
They are committed to protecting your privacy. 
As the research staff at the study site, we are required to make sure that people not 
involved with this study cannot see your research and medical information.  We will 
keep your research files in a safe place and will handle your personal information very 
carefully.  
Your study data are sent electronically to the UMN in the US through a secure system.  
By signing and dating this consent, you agree to having your data sent to UMN.  No 
information that could directly identify you is sent to UMN.  This is called 
“pseudonymized data”. UMN limits access to the data through security measures. No 
data breach or unauthorized access has ever occurred in this system.  After the study is 
over, we will store the data securely for the period required by law. 
We will share your study data with the US National Institutes of Health (which is paying 
for this study), and with regulatory authorities that oversee the study, including the US 
FDA. We are required by law to do this.  We will also share your study data with the 
drug companies that provide the study drugs to help them develop the drugs.   
 
 


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UMN may share your data and samples with other people who study COVID-19.  UMN 
will take out any information that could possibly identify you before sharing.  This is 
called “anonymizing the data.”  We will not ask you for additional consent for this 
sharing.  UMN will only share data and samples for research projects that are approved 
by the group that is conducting this study. 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law. This Web site will not include information that can identify you. At 
most, the Web site will include a summary of the results. You can search this Web site 
at any time. 
A description of this clinical trial is also on the EU Clinical Trials Register 
(http://www.clinicaltrialsregister.eu/). 
This study has a Certificate of Confidentiality from the US Federal Government.  This 
means that UMN cannot share any data it has about you with national, state, or local 
civil, criminal, administrative, legislative, or other authorities unless you specifically allow 
us to share it, or be used as evidence, for example, if there is a court subpoena, unless 
you have consented for this use. Information, documents, or biospecimens protected by 
this Certificate cannot be disclosed to anyone else who is not connected with the 
research except, if there is a federal, state, or local law that requires disclosure (see 
below); if you have consented to the disclosure, including for your medical treatment; or 
if it is used for other scientific research, as allowed by federal regulations protecting 
research subjects.  
The Certificate cannot be used to refuse a request for information from personnel of the 
United States federal or state government agency sponsoring the project that is needed 
for auditing or program evaluation by the agency which is funding this project or for 
information that must be disclosed in order to meet the requirements of the federal Food 
and Drug Administration (FDA).  You should understand that a Certificate of 
Confidentiality does not prevent you from voluntarily releasing information about 
yourself or your involvement in this research. If you want your research information 
released to an insurer, medical care provider, or any other person not connected with 
the research, you must provide consent to allow the researchers to release it. 
 
The Certificate of Confidentiality will not be used to prevent disclosure as required by 
federal, state, or local law of, for instance, child abuse or neglect, harm to self or others, 
and communicable diseases.  
The Certificate of Confidentiality will not be used to prevent disclosure for any purpose 
you have consented to in this informed consent document. 
 
 


University of Minnesota/INSIGHT / INSIGHT 014/ACTIV 3  
Page 11 of 13   
 
 
 
 
«PiFullName» 
Advarra IRB Approved Version 5 May 2021 
Revised «PIApprovalDate» 
 
WHOM TO CONTACT ABOUT THIS STUDY 
During the study, if you experience any medical problems, suffer a research-related 
injury, or have questions, concerns or complaints about the study, please contact the 
study doctor at the telephone number listed on the first page of this consent document. 
If you seek emergency care, or hospitalization is required, alert the treating physician 
that you are participating in this research study.  
An institutional review board (IRB) is an independent committee established to help 
protect the rights of research subjects. If you have any questions about your rights as a 
research subject, and/or concerns or complaints regarding this research study, contact: 
• By mail: 
Study Subject Adviser 
Advarra IRB 
6100 Merriweather Dr., Suite 600 
Columbia, MD 21044 
• or call toll free:    877-992-4724 
• or by email:          adviser@advarra.com 
Please reference the following number when contacting the Study Subject Adviser: 
Pro00045358.


University of Minnesota/INSIGHT / INSIGHT 014/ACTIV 3  
Page 12 of 13   
 
 
 
 
«PiFullName» 
Advarra IRB Approved Version 5 May 2021 
Revised «PIApprovalDate» 
 
SIGNATURE PAGE FOR CONSENT TO PARTICIPATE IN THE RESEARCH STUDY  
I have read this consent or have had it explained to me. I have had a chance to learn 
about each of the study drugs that I could be assigned to get. I have been given a copy 
of that information to keep. I believe that I understand the information.  By signing and 
dating this consent, I am stating that I volunteer to join this study.  I agree to have my 
data sent to and used by the sponsor as described in this consent. I understand that I 
do not waive any of my legal rights as a study participant by signing and dating this 
consent.  I understand that I will receive a copy of this signed and dated consent. 
If you agree to be in this study, please sign and date below. 
 
________________________________________  
Date: _______________ 
Signature of participant 
 
________________________________________ 
Printed name of participant 
 
_____________________________________   
Date: _______________ 
Signature of investigator/designee 
 
_____________________________________ 
Printed name of investigator/designee 
 
FOR ADULTS NOT CAPABLE of GIVING CONSENT  
 
________________________________________ 
 Date: _______________ 
Signature of Legally Authorized Representative (LAR)  
 
 
_____________________________________ 
Printed name of Legally Authorized Representative 
 
 
____________________________________ 
Relationship of Legally Authorized Representative to Participant 
(Indicate why the LAR is authorized to act as a surrogate health care decision-maker under state or applicable local 
law) 
 


University of Minnesota/INSIGHT / INSIGHT 014/ACTIV 3  
Page 13 of 13   
 
 
 
 
«PiFullName» 
Advarra IRB Approved Version 5 May 2021 
Revised «PIApprovalDate» 
 
Witness to Consent Interview (if applicable) 
On the date given next to my signature, I witnessed the consent interview for the 
research study named above in this document. I attest that the information in this 
consent form was explained to the participant, and the participant indicated that his/her 
questions and concerns were adequately addressed. 
 
_______________________________________ 
Date: _______________ 
Signature of witness 
 
 
________________________________________ 
Printed name of witness 
NOTE: This consent form, with the original signatures, MUST be retained on file 
by the Investigator of Record. A copy of the signed and dated consent must be 
given to the participant. A copy should be placed in the participant’s medical 
record, if applicable.  
 


Therapeutics for Inpatients with COVID-19 (TICO) Master Protocol 
17 Aug 2021 
Pfizer-1 
PID: _______________________ 
 
Drug Information Sheet for TICO:  PF-07304814 (Version 2.0) 
 
 
To accompany the informed consent for: 
Therapeutics for Inpatients with COVID-19 (TICO) 
Sponsored by: The University of Minnesota (UMN) 
Funded by:  The National Institute of Allergy and Infectious Diseases (NIAID), US 
National Institutes of Health (NIH) 
Full Title of the Study:  A Multicenter, Adaptive, Randomized Blinded Controlled 
Trial of the Safety and Efficacy of Investigational Therapeutics for Hospitalized 
Patients with COVID-19 
We are going to tell you about one of the experimental medicines you might get in the 
Therapeutics for Inpatients with COVID-19 (TICO) study.   
PF-07304814, which we will call “PF-814” for short, is made by the drug company 
Pfizer.  It is a drug called a protease inhibitor.  It works to keep SARS-CoV-2, the virus 
that causes COVID-19, from being able to make more copies of itself.  This could help 
someone with COVID-19 get better faster.   
PF-814 is given by intravenous (IV) infusion through a plastic tube attached to a needle 
in your arm.  The infusion of either PF-814 or placebo will go on for 5 days or until you 
are able to leave the hospital, whichever comes first.  
Pfizer conducted studies of PF-814 in rats and monkeys.  They saw blood clots and 
changes in laboratory values that have to do with blood clotting and inflammation.  In 
monkeys, the changes were worse in animals that got the drug.  The changes went 
away once the animals were no longer getting the drug or placebo.   
PF-814 has also been studied in humans.  These studies are described below.  The 
laboratory changes seen in animals have not been seen in humans. 
PF-814 was studied in 15 healthy people who did not have COVID-19.  Some of these 
people got PF-814 for a day and some got a salt-water placebo instead.  Twelve (12) 
people had some side effects.  None of these side effects were serious. 
Another study was done in 8 people with COVID-19.  They got PF-814 or a placebo for 
1 day.  Two people had a serious side effect, a blood clot.  One of these people had 
gotten PF-814 at twice the dose we will use in this study, and one had gotten placebo.  
The blood clots were not thought to be due to PF-814.  Blood clots are known to happen 
in people with COVID-19. 
Another study was done in 17 people with COVID-19.  They got PF-814 or a placebo for 
5 days.   


Therapeutics for Inpatients with COVID-19 (TICO) Master Protocol 
17 Aug 2021 
Pfizer-2 
PID: _______________________ 
 
• Three (3) of the 13 people who got PF-814 had serious side effects.   
o One person had severe breathing problems and pneumonia.   
o A second person’s breathing got worse.   
o A third person had a serious blood clot in the lung  The doctor thought the 
person might already have had the clot when they started getting the drug 
 
• One (1) person out of the 4 people who got placebo had serious breathing 
problems and also a serious clot in the lung.  He eventually died from the 
breathing problems.   
 
None of these problems were thought to be due to PF-814.  
Everyone was able to finish the 5 days of treatment.   
These are other side effects seen in these studies in people who took PF-814: 
250 mg/day (this study dose) 
500 mg/day (2 times this study dose) 
• Problem with blood clotting (but not 
a clot) 
• Diarrhea (loose stools) 
• Low platelets 
• Folliculitis (redness/pain in the skin 
around hairs) 
• Slow heartbeat 
• Infusion fluid collecting around where 
the drug goes into your body 
• Ear drum broke 
• Swollen feet (edema) 
• Belly pain 
• Chest pain not due to heart problems 
• Cellulitis (skin infection) 
 
• High blood sugar 
 
• Overly thirsty 
 
• Breathing problems while sleeping 
(sleep apnea) 
 
 
• None of the side effects in the list above were serious.   
• Each was seen in only one person.   
• Some were also seen in people who got placebo. 
 
We will watch you carefully while you are getting PF-814 or placebo.  We will treat you 
right away if you have side effects that bother you. 
People in the hospital with COVID-19 have been known to get blood clots.  If you are 
randomized to get PF-814 or placebo, you will probably get a medicine to prevent blood 
clots (anticoagulant).  You may get this medicine even if you are not randomized to PF-
814 or placebo.   


Therapeutics for Inpatients with COVID-19 (TICO) Master Protocol 
17 Aug 2021 
Pfizer-3 
PID: _______________________ 
 
Your doctor will check laboratory tests related to blood clotting and inflammation while 
you are getting PF-814/placebo.  You may need to have some extra blood drawn before 
you get PF-814/placebo for these tests if you have not already had them done that day.  
This extra blood will be less than 3 mL (about half a teaspoon).  You will also have 
these tests on Day 5.  They may be done on other days as well if your doctor thinks this 
is best. 
You cannot be considered for getting PF-814/placebo if you have ever had a blood clot 
in a large vein (called deep vein thrombosis, DVT) or a blood clot in your lung (called 
pulmonary embolism, PE). 
You cannot be considered for getting PF-814/placebo if you are pregnant or 
breastfeeding a baby.   
If you are assigned to get PF-814/placebo, we strongly advise you NOT to have sex that 
could make you or a partner pregnant for at least 5 weeks after you get PF-
814/placebo.  This may involve not having sex at all (abstinence), or you can use 
effective birth control (hormonal contraceptives like birth control pills or barrier methods 
with spermicide) to avoid pregnancy.  If you or your partner become pregnant within the 
5 weeks after you get the PF-814/placebo please report this to the study team right 
away. 
If your liver is not working well, you may not be able to be considered for getting PF-
814/placebo.  The study doctor can tell you more about this.   
There are some medicines you should not take if you are randomized to PF-
814/placebo.  The study drug could cause these medicines to have more or less of an 
effect than they should.  It is possible that you could stop those medicines while you are 
getting the PF-814/placebo and then start taking them again when you are done.  The 
study doctor will talk to you about this if you are taking any of these medicines.  If you 
are taking one of these medicines and cannot stop taking it, you cannot be randomized 
to PF-814/placebo. 
 

Prot_000.pdf: 
 A Multicenter, Adaptive, 
Randomized, Blinded Controlled 
Trial of the Safety and Efficacy of 
Investigational Therapeutics for 
Hospitalized Patients With 
COVID-19 (Trial H6: 
PF-07304814)
   Version 2.0  
17 August 2021
  NCT05780541


Appendix H6: PF-07304814 – Version 2.0 (17th August 2021) 
 
The content of this appendix is confidential and should only be viewed by 
persons covered by the CDA entered between Pfizer and NIAID in relation 
to the TICO / ACTIV-3 study.   
 
This appendix provides detailed information pertaining to the study of this investigational agent. 
If not stated otherwise, the text in the master protocol gives the approach that will be taken to 
study this agent.    
H.6.1. Introduction and rationale for studying the agent   
 
PF-07304814 is a phosphate ester prodrug of PF-00835231 (active moiety), a potent and 
selective inhibitor of the SARS-CoV-2 3CLpro, to be administered as an IV infusion 
treatment for patients hospitalized with COVID-19. PF-00835231 binds in a covalent, 
reversible manner to the SARS 3CL protease, resulting in broad-spectrum inhibitory 
activity across the alpha, beta and gamma coronavirus types [1]. The SARS 3CL protease 
is a virally encoded enzyme that is critical to the SARS-CoV-2 life cycle, analogous to 
other obligatory virally encoded proteases (e.g., HIV protease, HCV protease)[2]. No close 
human analogs of the coronavirus 3CLpro are known, which makes the 3CLpro an attractive 
antiviral drug target [3]. 
Whereas one antiviral agent (remdesivir) has been demonstrated to have clinical benefit in 
the target population for this trial and is now part of standard-of-care in the USA (see 
Appendix I), treatment options for critically ill Covid-19 patients are still limited. 
Combination of antiviral agents, especially those targeting different steps in the virus life 
cycle, is a frequently employed therapeutic strategy in treating viral diseases. The 
combination of PF-07304814 together with remdesivir has shown in vitro to have additive, 
if not synergistic, antiviral effect [4]. RDV and PF00835231 have different metabolic 
pathways which are not expected to interact. Hence, such combination may contribute to 
improvement in time to sustained recovery.  
Pfizer has evaluated the safety, tolerability, and pharmacokinetics (PK) of intravenously 
administered PF-07304814 in healthy participants in Phase 1 study C4611007. The 
safety, tolerability, and PK of PF-07304814 has also been assessed in hospitalized 
COVID patients in Phase 1b study C4611001.  
H6.1.1 Potential risk and benefits from PF-07304814 
PF-00835231 (the active moiety) has been shown to have SARS-CoV-2 antiviral activity in 
vitro [4], and it is intended to reduce virus titers and thereby reduce disease and risk of 
mortality in SARS-CoV-2 infected patients. On this basis, the potential benefit to individual 
study participants who receive the study intervention may include a shorter time to clinical 
recovery, prevention of ICU admission or invasive mechanical ventilation, and/or a lower 


probability of progressing to more severe illness or death. The potential benefit of the study, 
in general, is that it may provide a new treatment option for hospitalized patients with 
COVID-19 in the context of the global pandemic public health emergency. However, since 
this is the first study to assess the efficacy of PF-07304814, the benefit is unknown. 
 
Potential risks associated with PF-07304814 include inflammatory effects, noted by 
changes in peripheral blood WBCs, coagulation parameters, inflammatory cell infiltrates in 
various tissues, and thrombo-emboli at the infusion site and/or in different tissues. 
Thrombosis and increased inflammation were observed following prolonged exposure of PF 
07304814 in the 14-day non-human primate (NHP) toxicology study [4]. These have no 
known mechanistic basis and are believed to be both monitorable and reversible. As this is 
an investigational agent, there is some risk that is mitigated by close observation of AEs, 
vital signs, ECGs and laboratory assessments. In addition to the standard safety laboratory 
assessments, monitoring of markers of inflammation and coagulation may be performed. 
Clinical attention should be paid to manifestations of inflammation or thrombosis. 
Data from two clinical studies (C4611001 and C4611007) are available [4]. In the dose-
escalation study in healthy volunteers (study C4611007), where PF-07304814 was 
administered as a 24-hour infusion, there was no evidence of a pro-inflammatory effect 
clinically or based on laboratory studies at all dose exposures.  All reported AEs were mild 
in severity and none were reported as treatment related. There were no deaths, SAEs, 
severe AEs or discontinuations due to AEs during this study [4].  
Preliminary data is available from the Phase 1b study (C4611001) [4]. In the Single 
Ascending Dose (Part 1) of the study, 8 participants have completed 24-hour infusion. 
Doses were 250 mg (2 participants), 500 mg (2 participants) or placebo (4 participants). In 
the participants given 250 mg dose, 2 AEs, respiratory failure, considered severe and 
coagulopathy, considered moderate in severity, were reported by 1 participant. Both AEs 
started more than 15 days after the end-of-treatment (EOT). In participants given 500 mg 
dose, 3 AEs were reported by 1 participant. One AE of subclavian vein thrombosis, started 
approximately 24 hours after EOT, was considered severe and serious (SAE). The other 
2 AEs were mild. None of the AEs in the active dose group were considered to be treatment-
related. In participants who received placebo, 14 AEs were reported by 4 participants. Of 
these, 12 AEs were mild and 2 AEs, COVID-19 pneumonia and subclavian vein thrombosis, 
were considered severe and serious (SAEs). One AE of hematuria, mild in severity was 
considered treatment-related by the Investigator, blinded to the study treatment assignment. 
No evidence of sustained proinflammatory effects were noted via laboratory tests which 
included assessment of hsCRP, coagulation parameters (aPTT, PT, D-dimer), ferritin, and 
fibrinogen, among others.  
In the Multiple Ascending Dose (Part 2) of C4611001, in hospitalized patients with COVID-19,  
7 participants received 250 mg and 6 participants received 500 mg of the agent over a 24-
hour period for 5 consecutive days. Four participants received placebo for the same 


duration. In participants who received 250 mg dose for 5 days, 13 AEs were reported by 
4 participants. Of these, 6 AEs were mild, 4 AEs were moderate, and 3 AEs were considered 
severe and serious (SAEs). Of the 3 SAEs, 2 SAEs of acute respiratory distress syndrome 
(ARDS) and pneumonia were reported in 1 participant starting on Day 2 of treatment and 
2 days post-end of treatment, respectively. One SAE of dyspnoea, reported in 1 participant, 
started on Day 1 and lasted for 2 days. In participants who received 500 mg dose, 4 AEs 
were reported in 2 participants. 3 AEs were mild in severity and 1 AE of pulmonary embolism 
(PE), was considered severe and serious (SAE) and identified on Day 4 of infusion of the 
treatment. The SAE was considered un-related to the study drug treatment by the 
Investigator. The participant’s D-dimer levels were elevated at entry and it was suspected 
that the participant had the pulmonary embolism on study entry, but it was undetected at 
that time. None of the other AEs also were considered to be treatment-related. In 
participants who received placebo, 9 AEs were reported in 3 participants. Of these, 4 AEs 
were mild, 3 AEs were moderate and 2 AEs were considered severe and serious (SAEs). 
One AE of liver function test increased, mild in severity, was considered to be treatment-
related by the Investigator, blinded to study drug assignment. The participant was 
discontinued from the study after 4 days of treatment. The 2 SAEs of hypoxia and PE were 
reported in 1 participant on Day 5 of treatment and 2 days post-end of treatment, 
respectively. The participant had a fatal outcome on Day 16 in the study due to AE of 
hypoxia.   
Regarding clinical laboratory assessments, no evidence of sustained proinflammatory 
effects were noted. Laboratory tests included assessment of hsCRP, coagulation 
parameters (aPTT, PT, D-dimer), fibrinogen, among others.  
Overall, based upon available preliminary data from the Phase I studies, PF-07304814 
exhibits an acceptable safety profile. Following the institution of a clinical hold in May 2021 
to review the unblinded data from study C4611001, the US FDA concluded in July 2021 that 
“the current benefit-risk assessment supports continued clinical development of PF-
07304814, but only in the context of a PF-07304814 dose cap in clinical studies until more 
data are available.” The current dose cap for PF-07304814 in patients is 250 mg per 
24 hours for 120 hours. 
More detailed information about the known and expected benefits and risks (including 
adverse events) of PF-07304814 may be found in the Investigator’s Brochure (IB) [4]. 
Given the safety results of nonclinical studies with PF-07304814 and PF-00835231, the 
available clinical data with PF-07304814 from Phase 1 studies and the limited disease-
directed treatment options for patients with COVID-19, the potential risks identified in 
association with PF-07304814 are justified by the anticipated benefits that may be afforded 
to participants hospitalized with COVID-19. 


H6.1.2 Motivation for agent selection by the ACTIV Trial Oversight Committee (TOC) 
The ACTIV Agent Prioritization Committee Antiviral Subteam reviewed the Pfizer PF-
07304814 agent, which is an IV continuous infusion antiviral against the SARS-CoV-2 virus 
and voted in favor of the agent proceeding into ACTIV-3, and the TOC endorsed that 
recommendation.  During the review of Pfizer’s PF-07304814, reviewers felt that they would 
have liked to see more clinical information in the data packet, including information related 
to combination effects with remdesivir, which could have identified a potential drug-drug 
interaction (DDI). Despite these limitations, reviewers felt the application was very strong 
and that the agent’s high potency and sufficient lung exposure merit advancement into 
ACTIV-3 (because continuous infusion is most feasible in an inpatient population).  
Reviewers noted that this one of the first new and unique antiviral agents developed for 
SARS-CoV-2 could help evaluate viral replication in various stages of COVID-19 disease 
which made it important to include in ACTIV-3.  Reviewers noted that escape variants should 
be monitored for changes in this agent’s target, but that PF-07304814 should hold up well.  
Reviewers felt emerging variants were likely given that Gilead is currently investigating 
cases of remdesivir resistance, and this drug would likely need similar studies.  Overall, the 
Antiviral Subteam members recommended advancing the agent into ACTIV-3 with the 
contingency that the Antiviral Subteam review additional Phase I and PK data as they 
become available.  
Pfizer’s statement regarding plans for licensure:  
At the time of study initiation, Pfizer’s intent is to make the investigational product available 
in countries where the trial occurs if the investigational product is proven to be safe/effective.  
The actual decision to pursue licensure may be impacted by other factors which may include 
but are not limited to the status of the COVID-19 pandemic in the country and medical need; 
the impact of COVID-19 on Pfizer’s business; decisions by regulatory authorities impacting 
labeling or marketing, manufacturing processes, safety and/or other matters; supply 
feasibility issues, including availability of raw materials to manufacture and other matters 
related to drug supply; availability of other therapies including vaccines; and other regulatory 
and manufacturing considerations. 
H6.1.3 Justification for dose chosen for PF-07304814  
The dose of PF-07304814 to be studied in this protocol is 250 mg/day for 5 days, given as 
a constant rate intravenous infusion. The selected dose is based on clinical pharmacology 
and safety data, nonclinical pharmacology, in vitro pharmacology, and toxicology findings.  
 
Preliminary data from study C4611001 in hospitalized COVID-19 patients indicate that at 
the dose of 250 mg/day for 5 days, the preliminary clinical safety profile of PF-07304814 is 
acceptable. Draft pharmacokinetic data for the active moiety PF-00835231 (based on the 
first 6 of 8 patients) in the 250-mg / 5 day cohort indicated that the unbound exposures 
relative to the monkey NOAEL in the 14-day GLP-toxicology study are 1.2x and 1.1x for 
AUC24 and Cmax, respectively.  Additionally, the mean unbound concentration at steady 


state was approximately 1.9x the in vitro unbound EC90 and all actively treated participants 
maintained concentrations above the free EC90 concentration from 24 hours after the 
beginning of infusion to the end of infusion. 
  
Based on the above, a dose of 250 mg/day for 5 days, administered as a constant rate 
intravenous infusion is expected to be safe and associated with therapeutic effect. 
H6.2. Agent specific eligibility criteria 
In addition to the inclusion and exclusion criteria outlined in the master protocol, the 
following patients will be excluded: 
1. Participants with moderate to severe hepatic impairment (i.e. Child-Pugh class B or C) 
or acute liver failure.  
2. Participants receiving any medications or substances that are strong inhibitors or 
inducers of cytochrome P450 (CYP) 3A4 (see Section H6.3.4). 
3. Patients will be excluded if taking drugs which have a narrow therapeutic window that 
are substrates of CYP3A4, including but not limited to: astemizole, cisapride, 
cyclosporine, dihydroergotamine, ergotamine, pimozide, quinidine, sirolimus, 
tacrolimus, and terfenadine.   
4. Pregnant women 
5. Nursing mothers 
6. Women of child-bearing potential who are unwilling to acknowledge the strong advice 
to abstain from sexual intercourse with men or practice appropriate contraception 
through 5 weeks of the study. 
7. Men who are unwilling to acknowledge the strong advice to abstain from sexual 
intercourse with women of child-bearing potential or to use barrier contraception 
through 5 weeks of the study. 
8. Patients with a history of deep vein thrombosis or pulmonary thrombotic embolism*.  
 
*Prior to the initial futility assessment which is performed when approximately 150 patients 
have been enrolled on PF-07304814 and 150 on placebo, patients with a history of deep 
vein thrombosis or pulmonary embolism will be excluded.  These patients will be eligible 
for the trial if the initial futility assessment is passed by this agent, and if risk-benefit is 
favorable based on an assessment of available data that is reviewed by the independent 
DSMB. These data will include treatment comparisons of thromboembolic events and 
coagulation markers, and any additional data from studies carried out by Pfizer. 
No other specific inclusion or exclusion criteria need to be altered. 


H6.3. Description of investigational agent 
H6.3.1. Administration and duration 
See the PIM and Pharmacy Procedures for details.  
PF-07304814 250 mg daily dose will be administered as a continuous intravenous infusion 
with a treatment duration of five days or as long as the participant’s clinical presentation 
requires continued hospitalized, should this be shorter than five days. A volume of 
approximately 250 mL will be infused over each 24-hour period and replaced with a newly 
prepared infusion bag every 24 hours. 
 
H6.3.2. Formulation and preparation  
PF-07304814 1000 mg/vial Powder for solution for infusion is a lyophilized sterile drug 
product and is packaged in an open label fashion as one single use vial in a carton. 
Placebo is 0.9% sodium chloride, also commonly referred to as normal saline. 
See Table H6.1 for summary of study medication.  The preparation and administration 
instructions are detailed in the PIM and Pharmacy Procedures.  The study medication is 
prepared by an unblinded pharmacist at the local pharmacy. To ensure blinding of the 
participant and clinical staff a colored sleeve will be placed over the infusion bags used. 
PF-07304814 should be prepared and dispensed as soon as possible after randomization 
and administered as a continuous infusion through a dedicated IV line. Refer to the PIM and 
Pharmacy Procedures for the storage conditions of the reconstituted product as well as the 
timeframe within which the infusion bag is to be fully administered. 
Table H6.1. Study medication overview.  
Intervention Name 
Control 
PF-07304814 
Dose Formulation 
0.9% sodium chloride solution 
PF-07304814 1000 mg/vial Powder for 
Solution for infusion (diluted in 0.9% 
sodium chloride solution) 
DosageLevel(s) 
(mg) 
Not applicable 
250 mg/day  
Route of 
administration 
IV infusion 
IV infusion 
Use 
Control 
Experimental 
IMP and NIMP 
NIMP 
IMP 
Sourcing 
Commercially available 0.9% sodium 
chloride solution in bags 
Pfizer 
Packaging and 
Labeling 
Commercially available 0.9% sodium 
chloride solution in bags 
Study intervention will be provided in 20mL 
single-use 
glass 
vials 
individually 
packaged and labelled appropriately. To 
be diluted in commercially available 0.9% 
sodium chloride solution in bags 


 
H6.3.3 Supply, distribution, and accountability 
Procedures for ordering and accepting drug, for maintaining inventory of PF-07304814, and 
for breaking the blind in the event of a medical emergency will be described in the Pharmacy 
Procedures. 
H6.3.4. Contraindicated medications    
Based on human in vitro and animal in vivo data to date, the major clearance pathway for 
PF-00835231 is predicted to be via CYP3A4 metabolism (with an estimated 76% 
metabolized via CYP3A4). Therefore, concomitant use of any medications or substances 
that are strong inhibitors (Table H6.2) or inducers (Table H6.3) of CYP3A4 are 
contraindicated. Examples of the most common medications likely to be encountered in 
patients hospitalized with COVID-19 that are considered strong inhibitors or inducers of 
CYP3A4 are provided in the tables below. These lists are not necessarily comprehensive. 
Table H6.2. 
Common Medications That are Strong Inhibitors of CYP450 3A4a 
Category 
Examples 
Antiretrovirals 
Indinavir, nelfinavir, ritonavir, saquinavir, delavirdine, amprenavir, 
fosamprenavir, atazanavir, cobicistat, lopinavir, danopravir, boceprivir 
Antifungal: 
Itraconazole, ketoconazole, voriconazole, posaconazole 
Anti-infectives 
Macrolides: telithromycin, clarithromycin 
Antidepressants 
Nefazodone 
Antineoplastic 
Idelalisib 
a. Not a comprehensive list. 
 
Table H6.3. 
Common Medications That are Strong Inducers of CYP450 3A4a 
Category 
Examples 
Anti-infectives 
Rifampin  
Anti-epileptic 
Phenytoin, carbamazepine 
Psychoactive drugs 
St. John's wort 
a. Not a comprehensive list. 
 
The proposed major clearance mechanism for remdesivir is via carboxylesterase (80%) with 
minor contributions by cathepsin A and CYP3A4. Remdesivir is also a weak inhibitor of 
CYP3A4. There is no known significant DDI risk when combining Remdesivir and PF-
07304814 (targeting active moiety PF-00835231 plasma concentrations of 0.5 to 1.5 µM), 
neither as a perpetrator nor as a substrate/victim. 
H6.4. Clinical and laboratory evaluations 
 
H6.4.1 Timing of Assessments   
Appendix B in the master protocol outlines the timing of clinical and laboratory monitoring. 
The following assessments will be added to the safety blood tests, analyzed at the local 
laboratory used by the department for routine diagnosis, and drawn at Day 0 and Day 5: 


Prothrombin time (PT), activated partial thromboplastin time (aPTT), D-dimer, and 
fibrinogen.  
 
PF-07304814/matching placebo is infused continuously for up to 5 days.  Infusion-related 
AEs will be collected each day for the entire duration of the infusion.  Reporting of other 
safety-related events is outlined in Section 10 of the master protocol.  
 
H6.4.2. Pharmacokinetic and Special Safety Assessments 
PK and special safety laboratory assessments will require 1 mL of the plasma and 1 mL of 
the serum from certain venous blood samples collected as described in the Master Protocol 
Appendix B as “Research Sample Storage”.  Aliquots from samples collected on Days 0, 1, 
3, and 5 will be used to determine PF-07304814 and PF-00835231 concentrations (as well 
as potentially other metabolites of PF-07304814) and special safety assessments. Attempts 
should be made to collect the Day 1 and 3 samples at least 2 hours before or 2 hours after 
change of the infusion bag. At selected sites, Day 1 and Day 3 plasma samples will be 
collected using procedure described in the PIM.   
PK will be assessed by a validated assay at a bioanalytical lab. Analysis of samples from 
control subjects is not planned. Results will be forwarded to Pfizer and to the central 
database for TICO at the University of Minnesota.  
Special safety analyses will be conducted in a central laboratory. Samples from control 
subjects will be analysed for comparison with the active treated group. Results will be 
forwarded to Pfizer and to the central database for TICO at the University of Minnesota. 
Remaining samples may be pooled and used for exploratory metabolism or bioanalytical 
method experiments as deemed appropriate. Samples may be shipped to the lab for 
analyses in batches as the trial is unfolding. Results from such analyses will be returned to 
the trial central database. Treatment comparisons using these data and using other data on 
the participants will remain blinded to investigators in the trial until the trial is unblinded.  
H6.5. Clinical management issues  
As part of standard-of-care, it is recommended that participants be placed on medication 
(heparin being the typical choice) in order to reduce risk of thrombotic events.   
Although Fentanyl and Alfentanil have narrow therapeutic windows and are substrates of 
CYP3A4, it can be used in participants while being infused with PF-07304814, but with 
caution as plasma levels may increase while co-administered with PF-07304814.   
Suspicion of DVT and other thromboembolic events: Withdraw participant from study 
infusion and proceed with diagnostic and therapeutic interventions per standard of care.  
Allergic reactions: Withdraw participant from study infusion and proceed with therapeutic 
interventions per standard of care. 


Blockage of infusion line/pump: Replace venous access as soon as possible. Up to 2 hours 
interruption of infusion is allowed per 24-hour period of continuous infusion. 
Treatment with strong inducers or strong inhibitors of CYP 3A4 may be resumed after 
discontinuation of study medication.  
H6.5.4. Adverse Events of Special Interest (AESI)  
Thrombotic events (myocardial infarction, ischemic and hemorrhagic strokes, deep vein 
thrombosis (including those associated with inserted lines), and pulmonary embolism).  
 
These serious events are reported promptly as PSEEs (see master protocol for details) and 
are additionally reported as SAEs if considered to be potentially related to the investigational 
agent.  
 
H6.5.5. Incident Pregnancy in Participants or Their Partners 
The investigator will collect pregnancy information on any female participant who becomes 
pregnant while participating in this study.  
This study agent will be immediately discontinued if pregnancy is discovered in a 
participant during the dosing period; however, the participant will not be withdrawn from 
the study. The participant will continue follow-up in the protocol and should complete all 
protocol defined visit procedures.  The maternal and fetal outcomes, directly relevant to 
the pregnancy, will be requested, and will be reported on the Pregnancy Outcome eCRF.  
If an investigator learns that a male participant’s partner has become pregnant after 
exposure to this study agent, and the male participant is still in this study, the investigator 
is asked to attempt to obtain relevant information on the pregnancy, and in particular, its 
outcome, after obtaining consent from the pregnant partner.  The outcome of the 
pregnancy will be reported on the Pregnancy Outcome eCRF. 
H6.6. References 
1. 
Hoffman, R.L., et al., Discovery of Ketone-Based Covalent Inhibitors of Coronavirus 3CL 
Proteases for the Potential Therapeutic Treatment of COVID-19. Journal of medicinal chemistry, 
2020. 63(21): p. 12725-12747. 
2. 
Kim, J.C., et al., Coronavirus protein processing and RNA synthesis is inhibited by the cysteine 
proteinase inhibitor E64d. Virology, 1995. 208(1): p. 1-8. 
3. 
Cannalire, R., et al., Targeting SARS-CoV-2 Proteases and Polymerase for COVID-19 
Treatment: State of the Art and Future Opportunities. Journal of Medicinal Chemistry, 2020. 
4. 
Pfizer, Investigator's Brochure PF-07304814, Version 2.0, December 2020. 2020. 
5.         Summary of unblinded safety and pharmacokinetic data from section of trial C4611001 
            studying PF-07304814 dosed 500 mg by 24 hours over 120 hours, dated 23rd June 2021.