VA CoronavirUs Research and Efficacy Studies-1 (VA CURES-1)
Phase: PHASE3
Conditions: COVID-19
Sponsor: VA Office of Research and Development

VA CoronavirUs Research and Efficacy Studies-1 (VA CURES-1)
Principal Investigators: 
Edward N. Janoff, MD, and Sheldon Brown, MD
Sponsor: 
Office of Research and Development
U.S. Department of Veterans Affairs
Version 1.9
10 September 2021 
PRIVILEGED AND CONFIDENTIAL
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1
TABLE OF CONTENTS
STATEMENT OF COMPLIANCE........................................................................................................................................5
Executive Summary.........................................................................................................................................................5
1
PROTOCOL SUMMARY.......................................................................................................................................6
1.1
Synopsis...................................................................................................................................................6
1.2
Study Schema..........................................................................................................................................8
1.3
Schedule of Activities (SOA)..................................................................................................................10
2
INTRODUCTION................................................................................................................................................12
2.1
Study Rationale......................................................................................................................................12
2.2
Background............................................................................................................................................12
2.3
Risk/Benefit Assessment.......................................................................................................................14
2.3.1
Known Potential Risks.......................................................................................................14
2.3.2
Known Potential Benefits..................................................................................................14
2.3.3
Assessment of Potential Risks and Benefits......................................................................15
3
OBJECTIVES AND ENDPOINTS..........................................................................................................................16
4
STUDY DESIGN..................................................................................................................................................21
4.1
Overall Design........................................................................................................................................21
4.2
Scientific Rationale for Study Design.....................................................................................................21
4.3
Justification for Dose.............................................................................................................................21
4.4
End of Study Definition..........................................................................................................................21
5
STUDY POPULATION.........................................................................................................................................22
5.1
Inclusion Criteria....................................................................................................................................22
5.2
Exclusion Criteria...................................................................................................................................22
5.3
Lifestyle Considerations........................................................................................................................23
5.4
Screen Failures.......................................................................................................................................23
5.5
Strategies for Recruitment and Retention............................................................................................23
6
STUDY INTERVENTION......................................................................................................................................24
6.1
Study Intervention(s) Administration....................................................................................................24
6.1.1
Study Intervention Description..........................................................................................24
6.1.2
Dosing and Administration................................................................................................24
6.2
Preparation/Handling/Storage/Accountability.....................................................................................24
6.2.1
Acquisition and accountability..........................................................................................24
6.2.2
Formulation, Appearance, Packaging, and Labeling.........................................................24
6.2.3
Product Storage and Stability............................................................................................25
6.2.4
Preparation........................................................................................................................25
6.3
Measures to Minimize Bias: Randomization and Blinding....................................................................25
6.3.1
Randomization...................................................................................................................25
6.3.2
Blinding 26
6.4
Study Intervention Compliance.............................................................................................................26
6.5
Concomitant Therapy............................................................................................................................26
6.5.1
Concomitant Medications.................................................................................................27
6.5.2
Rescue Medicine................................................................................................................27
7
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT DISCONTINUATION/WITHDRAWAL.............28
7.1
Discontinuation of Study Intervention..................................................................................................28
7.2
Participant Discontinuation/Withdrawal from the Study.....................................................................28
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7.3
Lost to Follow-Up..................................................................................................................................28
8
STUDY ASSESSMENTS AND PROCEDURES........................................................................................................29
8.1
Consent and Screening Procedures.......................................................................................................29
8.1.1
Consent Process.................................................................................................................29
8.1.2
Screening Procedures........................................................................................................29
8.2
Baseline, Randomization and Product Administration.........................................................................29
8.3
Efficacy and Exploratory assessments...................................................................................................30
8.3.1
Measures of clinical support and limitations....................................................................30
8.3.2
WHO Ordinal scale of patient clinical status.....................................................................31
8.3.3
National Early Warning Score 2 (NEWS2)..........................................................................31
8.3.4
Death and Duration of Hospitalization..............................................................................31
8.3.5
Exploratory assessments...................................................................................................31
8.4
Safety and Other Assessments..............................................................................................................31
8.4.1
Clinical laboratory evaluations..........................................................................................31
8.4.2
Respiratory specimen........................................................................................................32
8.4.3
Procedures to be followed in the event of abnormal clinical findings..............................32
8.4.4
Unscheduled visit...............................................................................................................33
8.4.5
Concomitant Medications.................................................................................................33
8.5
Adverse Events and Serious Adverse Events.........................................................................................33
8.5.1
Definition of Adverse Events (AE)......................................................................................33
8.5.2
Definition of Serious Adverse Events (SAE).......................................................................34
8.5.3
Classification of an Adverse Event.....................................................................................34
8.5.4
Time Period and Frequency for Event Assessment and Follow-Up..................................36
8.5.5
Adverse Event Reporting...................................................................................................36
8.5.6
Serious Adverse Event Reporting......................................................................................37
8.5.7
Reporting Events to Participants.......................................................................................38
8.5.8
Events of Special Interest..................................................................................................38
8.5.9
Reporting of Pregnancy.....................................................................................................38
8.6
Unanticipated Problems........................................................................................................................38
8.6.1
Definition of Unanticipated Problems (UP).......................................................................38
8.6.2
Unanticipated Problem Reporting.....................................................................................38
8.6.3
Reporting Unanticipated Problems to Participants...........................................................39
9
STATISTICAL CONSIDERATIONS........................................................................................................................40
9.1
Statistical Hypotheses...........................................................................................................................40
9.2
Sample Size Determination...................................................................................................................40
9.3
Populations for Analyses.......................................................................................................................42
9.4
Statistical Analyses................................................................................................................................42
9.4.1
General Approach..............................................................................................................42
9.4.2
Analysis of the Primary Efficacy Endpoint(s).....................................................................42
9.4.3
Analysis of the Secondary Endpoint(s)..............................................................................43
9.4.4
Safety Analyses..................................................................................................................44
9.4.5
Baseline Descriptive Statistics...........................................................................................44
9.4.6
Planned Interim Analyses..................................................................................................44
9.4.7
Sub-Group Analyses...........................................................................................................46
9.4.8
Exploratory Analyses.........................................................................................................46
10
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS.......................................................47
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10.1
Regulatory, Ethical, and Study Oversight Considerations.....................................................................47
10.1.1
Informed Consent Process.................................................................................................47
10.1.2
Study Discontinuation and Closure...................................................................................49
10.1.3
Confidentiality and Privacy................................................................................................49
10.1.4
Future Use of Stored Specimens and Data........................................................................50
10.1.5
Key Roles and Study Governance......................................................................................50
10.1.6
Safety Oversight.................................................................................................................53
10.1.7
Clinical Monitoring.............................................................................................................53
10.1.8
Study Monitoring...............................................................................................................54
10.1.9
Training and Supervision...................................................................................................56
10.1.10
Quality Assurance and Quality Control.............................................................................56
10.1.11
Data Handling and Record Keeping...................................................................................57
10.1.12
Protocol Deviations............................................................................................................59
10.1.13
Publication and Data Sharing Policy..................................................................................60
10.1.14
Conflict of Interest Policy...................................................................................................61
10.2
ABBREVIATIONS.....................................................................................................................................61
10.3
Protocol Amendment History................................................................................................................63
REFERENCES..................................................................................................................................................................73
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STATEMENT OF COMPLIANCE
The trial will be conducted in accordance with International Conference on Harmonization Good 
Clinical Practice (ICH GCP), applicable United States (US) Code of Federal Regulations (CFR), 
and applicable VA policies, regulations and procedures. The Study Chairs will assure that no 
deviations from, or changes to the protocol will take place without prior agreement from the 
funding agency and documented approval from the VA Central Institutional Review Board 
(CIRB), except where necessary to eliminate an immediate hazard(s) to the trial participants. All 
personnel involved in the conduct of this study will have completed Human Subjects Protection 
and ICH GCP Training prior to participation in study activities.
The protocol, informed consent form, recruitment materials, and all participant materials will be 
submitted to the VA CIRB for review and approval.  Approval of both the protocol and the 
consent form must be obtained before any participant is enrolled.  Any amendment to the 
protocol will require review and approval by the VA CIRB before the changes are implemented 
to the study.  All changes to the consent form will be VA CIRB approved; a determination will be 
made regarding whether a new consent needs to be obtained from participants who provided 
consent using a previously approved consent form.
EXECUTIVE SUMMARY
The very acute onset and rapid dissemination of SARS-Coronavirus-2 (SARS-COV-2) across 
the world  over several months precluded  the early availability  of effective preventive  and 
therapeutic interventions. The impact of SARS-CoV-2 is substantial with hospitalization of about 
20% of those infected, half of whom require intensive care due to respiratory failure from which 
death may ensue. Prominent among those who preferentially experience this high incidence of 
morbidity and mortality are men over age 65 years with underlying comorbidities such as 
hypertension, diabetes, lung, heart, kidney or liver disease, obesity and immunocompromise1; 2, 
clinical features commonly shared by the Veteran population.  Effective therapies are currently 
quite limited.  We propose to bolster immune defense against the virus with convalescent 
plasma  that  contributes  antiviral  antibodies  and,  potentially,  non-antibody  factors  to  its 
therapeutic activity. 
Hospitalized Veterans with documented SARS-CoV-2 infection and evidence of early respiratory 
compromise  (hypoxemia  and  requirement  for  oxygen)  will  be  randomized  to  receive 
convalescent plasma or a masked saline placebo.  The primary outcome is the rapidity and 
frequency of progression to respiratory failure or death in the two groups.  The randomized, 
double-blind  placebo-controlled  design  is  essential  to  confirm  the  utility  or  the  futility  of 
convalescent plasma, building on mostly promising safety and outcomes with convalescent 
plasma in 6 anecdotal and case series of 56 patients with SARS-CoV-23-8 and a small non-
randomized  trial with  retrospective controls  9. However,  observational and non-randomized 
studies may miss systematic bias and are not always confirmed with controlled randomized 
trials for other viral infections10,11-15, thus the rigorous controlled trial of convalescent plasma 
proposed in VA CoronavirUs Research and Efficacy Studies-1 (VA CURES-1).
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1
PROTOCOL SUMMARY
1.1
SYNOPSIS 
Title
VA CoronavirUs Research and Efficacy Studies-1 (VA CURES-1).
Study Description
The full VA CURES program is a newly initiated series of adaptive, double-blind placebo-
controlled,  randomized  clinical  trials  (RCTs)  to  evaluate  the  safety  and  efficacy  of  novel 
therapeutic agents in hospitalized adults diagnosed with COVID-19. This framework will permit 
multicenter trials to be conducted in VA Medical Centers to compare different investigational 
therapeutic agents to a single contemporaneous control arm consisting of best supportive care 
(BSC). Interim monitoring will allow early stopping for futility, efficacy, or safety. After VA 
CURES-1 testing convalescent plasma vs saline is launched, new arms or new trials can be 
introduced  according  to  scientific  and  public  health  needs.  If  one  therapy  proves  to  be 
efficacious, this treatment may become the control arm for comparison(s) with new experimental 
treatment(s). Any such change would be accompanied by an updated sample size and an 
amended protocol. 
This adaptive platform is used to rapidly evaluate different therapeutics in a population of those 
hospitalized with moderate to severe COVID-19. The platform will provide a common framework 
sharing a similar population, design, endpoints, and safety oversight. New stages with new 
therapeutics  can  be  introduced  and  will  be  described  in  a  stage-specific  appendix.  One 
independent Data and Monitoring Committee (DMC) will actively monitor interim data in all 
stages to make recommendations about early study closure or changes to study arms.
This VA CURES adaptive design RCTs may involve multiple stages, each investigating different 
interventions. To convey clearly the protocol elements, interventions, objectives and endpoints 
for each stage, common elements are described in the main protocol document while each 
stage is noted in a stage-specific appendix.
The first stage in the clinical trial (VA CURES-1) is: 
Stage 1: Convalescent Plasma vs Saline 
If convalescent plasma is shown to be beneficial in Stage 1, we may proceed to the next stage 
(VA CURES-1a) under amended design and subsequent approval:
Stage 1a: Convalescent Plasma vs Fresh Frozen Plasma 
If convalescent plasma is shown not to be beneficial in Stage 1, we will design a RCT testing an 
alternative agent.
Study Objectives
The primary objective of the VA CURES program is to evaluate the clinical efficacy of different 
investigational therapeutics compared with the control arm by binary analysis of the composite 
primary outcome of acute hypoxemic respiratory failure or all-cause death by Day 28.  Acute 
hypoxemic respiratory failure is defined as the initiation of mechanical ventilation [either via 
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endotracheal  intubation  or  as  non-invasive  positive  pressure  ventilation  (NIPPV)  for  an 
indication other than for pre-diagnosed sleep apnea at outpatient settings] OR extracorporeal 
membrane oxygenation (ECMO).
The  secondary  objectives  are  to  evaluate  the  clinical  efficacy  and  safety  of  different 
investigational therapeutics compared to the control arm as assessed by the secondary efficacy 
outcomes and the safety outcomes defined in the stage-specific Objectives and Endpoints. 
Each stage may prioritize different secondary endpoints for the purpose of multiple comparison 
analyses.
Study Outcomes
Primary efficacy outcome: Proportion of participants developing acute hypoxemic respiratory 
failure or all-cause death up to day 28.
Key secondary efficacy outcome: Time to recovery (as determined by attaining a score of 1,2 or 
3 on the World Health Organization (WHO) 8-point ordinal scale). 
Study Population
This trial will study putative therapeutics in a hospitalized adult population (≥18 years old) with 
moderate to severe COVID-19. The trial will have common inclusion and exclusion criteria but 
may be modified for each stage for the unique risk of the study product in that stage. 
Inclusion Criteria 
1) Age 18 or older.
2) Confirmed acute SARS-CoV-2 infection.
3) Requirement for supplemental oxygen therapy that is either new or at least 2 Lpm greater 
than previous outpatient chronic therapy.
4) Ability to provide written informed consent from patient or legally authorized representative 
(LAR).
Exclusion Criteria
1) anticipated hospitalization <48 hours.
2) anticipated respiratory failure (as defined above) or death within 48 hours.
3) Septic shock or multiple organ dysfunction or failure.
4) Current or anticipated participation in another randomized trial for SARS-CoV-2.
Study Phase
Phase 3
Study Sites
VA CURES-1 will initially engage 25 VA Medical Centers nationally.  Site selection will be 
determined by presence of: 1) sufficient numbers of cases of COVID-19; 2) a committed local 
site  investigator  (LSI);  3)  established  infrastructure  for  clinical  trials  (study  coordinator(s), 
research pharmacist, blood bank); 4) onsite clinical laboratory; and 5) laboratory facilities for 
study sample processing, labeling and storage.  Multiple sites will be IRB-approved via VA 
CIRB, but site activation will be dependent on the incidence of SARS-CoV-2 at that site.
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Study Intervention
Study interventions will vary depending on the stages or trials under VA CURES. VA CURES-1 
compares convalescent plasma versus saline.
Study Duration
The series of studies comprising the full VA CURES adaptive study will last for up to 60 months. 
This specific protocol (VA CURES-1) will have a specific timeline (20 months) within the full VA 
CURES  adaptive  protocol.   The  study  can  be  terminated  early  if  the  target  number  of 
participants is met or if the interim analysis demonstrates efficacy, harm or futility accordingly to 
protocol-specified stopping boundaries.
Participant Duration
An individual subject will complete the study in up to 35 days, from screening and randomization 
at Day -3 to 0, to follow-up on Day 29 + 3 days.
1.2
STUDY SCHEMA 
This  adaptive  design  clinical  trial  may  involve  multiple  stages  each  investigating  different 
interventions. In order to clearly convey the protocol elements, interventions, objectives and 
endpoints for each stage, common elements are described in the main protocol document while 
each stage is noted in a stage-specific appendix. Below is the study schema for Stage 1.
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Figure 1. Study Schema
Prior to 
Randomization
Day 1
Baseline
Days 1-29
Follow-up 
Visit 1
Day 15 
Follow-up
Visit 2
Day 22
Follow-up
Visit 3
Day 29
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Total N:  Obtain informed consent. Screen potential participants by 
inclusion and exclusion criteria; obtain history, document.
Randomize
Arm 2 
Control Arm
Arm 1
Convalescent Plasma
Perform baseline assessments.
<refer to Section 1.3, Schedule of Activities>
Start study intervention. 
Study Intervention and Hospitalization Period:
Daily Study Assessments Until Hospital Discharge;
Research and Safety Lab Assessments Day 2, 4, 7 if hospitalized
<refer to Section 1.3, Schedule of Activities>
Follow-up assessments of study endpoints, research and safety labs
<refer to Section 1.3, Schedule of Activities>
Follow-up assessments of study endpoints
<refer to Section 1.3, Schedule of Activities>
Follow-up assessments of study endpoints, research and safety labs
<refer to Section 1.3, Schedule of Activities>
 
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1.3
SCHEDULE OF ACTIVITIES (SOA) 
Table 1. Schedule of Assessments
Day ± Window
Up to 72 hrs.
prior to 
Randomization 
Time
Day 1
Up to 36 hrs. 
after 
Randomization 
Time
Day 2 -
 Hospital 
Discharge
Day 
15 ±2
Day 
22 ±3
Day 29 
+315
Procedures
Eligibility
Randomization/
Baseline
Product 
Administration
Hospitalization14 
Period
Initial Discharge
Follow-up Visit 1 
(15d)
Follow-up Visit 2 
(22d)
Follow-up Visit 3 
(29d)
Obtain signed Informed 
Consent1
X
Obtain Demographics & 
Medical History data
X
Perform physical exam
X
Review 
-SARS-CoV-2 results
X
Administer pregnancy 
test for females
X
Review Eligibility
X
Randomize participant
X3
Assess Admission Signs 
and Symptoms
X4
Collect Vital Signs2 
(NEWS2)
X4
X9
X13
X13
Collect Clinical status 
data2
X4
X9
X
X
X
Evaluate Adverse Events
X4
X
X9
X
X
X
X
Review Concomitant 
Medications
X4
X7
X
X
X
X
Obtain Safety Labs5
-Hematology, chemistry, 
liver tests
X4
X10,12
X13
X13
Obtain Exploratory 
Research Labs6
-Blood 
-Respiratory sample
X4
X11,12
X13
X13
Administer Study 
Product
X8
Obtain Discharge info
X
Collect Readmission 
data, if applicable
X
X
X
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Notes:
1 This form is completed by the participant or legal representative.  
2 Refer to Section 8.1 of the protocol for details of clinical data to be collected including 
WHO ordinal score, National Early Warning Score (NEWS2), oxygen requirement, 
mechanical ventilator requirement, etc.
 3 Randomization must occur within 72 hours of initial hospital admission.
 4 Baseline assessments should be performed before the first study product administration: 

Day 1 safety labs and Day 1 exploratory research specimens can be collected up to 
24 hours prior to randomization and before the first study product administration. 

Laboratory tests performed as part of routine clinical care up to 24 hours before 
randomization will be accepted for the baseline safety laboratory tests. 

See Visit Schedule Grid for more details.
 5 Safety laboratory tests include WBC with differential, hemoglobin, platelets, creatinine, 
glucose, total bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
and prothrombin time (PT). 
6 Research Specimens include respiratory samples and 30mL of blood for research studies 
(2 tablespoons) as feasible. Nasopharyngeal (NP) swabs are preferred, but if these are not 
obtainable, oropharyngeal (OP), saliva (S) or anterior nares swabs (AN) may be substituted.   
 7If  product  administration  starts  on  day  of  randomization  (Day  1),  then  concomitant 
medications only need to be reviewed one time, at day of randomization
8 Ideally, product administration should start on the same day as randomization (Day 1) but 
may be started up to 36 hours after randomization.
9 Obtain clinical status data, vital sign data (for NEWS2), and assess adverse events daily 
during hospitalization, both during initial hospitalization and for readmissions.
10 Obtain safety labs only on Days 2, 4, and 7 if hospitalized, including readmissions. Any 
laboratory tests performed as part of routine clinical care within the visit windows specified in 
Table 5 can be used for safety laboratory testing.
11Blood for research studies only on Days 2, 4, and 7 and swabs for RT-PCR only on Days 4, 
and 7, if hospitalized (includes readmissions). 
12 If not hospitalized at study site on Day 2, 4 or 7, no need to collect any labs or specimen on 
that day.
13 For Day 15, 22, and 29 follow-up visits: 

If not hospitalized and have an in-person visit on Day 15 and 29: collect NEWS2, 
safety laboratory tests, and research laboratory samples. 

If discharged, collect hospital readmission data at each subsequent visit.

Day 22 visit (after discharge) is generally done by phone or telehealth. 

In-person
 
  visits (after discharge) are preferred and strongly encouraged for Days 
15 and 29. However, when quarantine and other factors limit the participant’s 
ability to return to the site for the visit, they may be performed by telehealth or by 
phone.
14 Hospitalization period includes initial hospitalization and readmissions. 
15 The final visit cannot occur before Day 29.
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2
INTRODUCTION
2.1
STUDY RATIONALE 
Since December 2019, SARS-Coronavirus 2 (SARS-CoV-2; COVID-19) infections are over 6 
million persons and approaching 200,000 deaths in the US with a continually rising rate of 
infection. Of the ≈20% of patients admitted to hospital, up to half progress to ICU admission, 
respiratory failure or death. Prominent among these progressors are older men, particularly 
those with underlying comorbidities (e.g., hypertension, diabetes, lung, heart, kidney or liver 
disease,  obesity  and  immunocompromised)1,  all  common  among  Veterans.   Effective 
interventions are few, other than recently-approved remdesivir, which shortened hospital stay 
but did not decreased overall mortality16.  Convalescent plasma from persons recovered from 
SARS-CoV-2 infection is readily available for treatment.  
Convalescent plasma therapy is being used empirically, although only five of six small uncon­
trolled case series (total n=56) in SARS-CoV-23-8 and a recent study with non-randomized 
controls9 suggest improved selected clinical, virologic and laboratory outcomes and outcomes in 
another small randomized trial were equivocal17.  For other infections, such as influenza and 
Ebola virus, promising observational studies were not reliably confirmed by controlled trials 10,11-
15.  In multiple infections, use of convalescent plasma has been distinguished by its safety profile 
but not by the consistency of its benefit.  The current double-blind, placebo-controlled RCT is 
designed to determine definitively whether this intervention is effective in a population at high 
risk  of  complications  and  death  from  SARS-CoV-2  infection.   We  compare  the  effect  of 
convalescent plasma vs. saline placebo with a robust study design, adequate sample size and 
statistical and logistical rigor to assure that the interventions we make to treat serious disease 
are well-validated to support its use or to move on to test other potentially safe and effective 
treatments.  
2.2
BACKGROUND 
Purpose of the Study
The newly emergent coronavirus SARS-CoV-2 has exceeded two earlier highly fatal species—
severe  acute  respiratory  syndrome  coronavirus  (SARS-CoV)  in  2003  and  Middle  East 
respiratory syndrome coronavirus (MERS) in 2012 in the speed and breadth of its transmission 
worldwide  and  four  common  upper  respiratory  coronavirus  species  in  its  virulence  and 
associated mortality.  Described initially in Wuhan, China, the infection has already spread to 
infect over 25 million persons worldwide with 860,000 deaths as of September 1, 2020, and 
over 6 million infected in the U.S. and approaching 200,000 deaths. Although the majority of 
persons infected recover naturally based on their own innate and adaptive immune responses, 
up to 20% are ultimately hospitalized with an increased risk of respiratory failure and death. 
Persons age 65 years or older represent a minority of infections but comprise the majority of 
those with complications, hospitalization and death1,18.  These outcomes are most prominent 
among older persons with comorbidities, e.g., chronic lung, cardiac and renal disease, as well 
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as  hypertension,  diabetes,  obesity  and  immunosuppression1;  2, conditions  common  among 
veterans.
In the absence of an effective vaccine or other biologic preventive measures, treatment options 
for  those  with  serious  disease  are  also  limited.  To  date,  only  one  antiviral  medication 
(remdesivir)  has  shown  efficacy  to  shorten  time  to  recovery  but  not  decrease  mortality16. 
Multiple  medications  to  limit  viral  replication,  minimize  inflammation,  modulate  immune 
responses are in broad empiric use and testing19, but none other has been proven to be 
effective20-23 and a number have untoward side effects22.
Convalescent  plasma  from  persons  recovered  from  SARS-CoV-2  is  being  used  to  treat 
hospitalized  individuals  with  complicated  COVID-19  infection.  Although  relatively  safe  and 
widely used, only sparse data support the efficacy of this intervention to limit respiratory failure 
and death.  With other infections (SARS, influenza, Ebola), initiation of plasma therapy early in 
hospitalization was variably associated with improved outcomes14,24,25, outcomes that may not 
be  consistently  confirmed  in  randomized  controlled  trials26,27.  Validating  the  efficacy  of 
convalescent  plasma  therapy  for  COVID-19  is  an  important  goal,  given  the  contradiction 
between results of ad hoc versus controlled evaluations of convalescent plasma for other acute 
viral infections. We will determine the ability of convalescent plasma initiated early in the course 
of hospitalized disease to decrease respiratory failure and death from SARS-CoV-2 with a 
robust prospective, randomized, placebo-controlled study protocol.  In the context of an acute 
threatening pandemic, we are compelled to intervene; we propose to determine whether we are 
using an effective intervention and doing no harm.
Study Design
The parent VA CURES study is an adaptive set of randomized double-blind placebo-controlled 
trials to evaluate the safety and efficacy of novel therapeutic agents in hospitalized adults 
diagnosed with COVID-19; VA CURES-1 determines the impact of convalescent plasma vs. 
saline on critical clinical outcomes. The study is a multicenter trial that will be conducted at VA 
Medical Centers to compare different investigational therapeutic agents to a control arm. New 
arms can be introduced according to scientific and public health needs. There will be interim 
monitoring to allow early stopping for futility, efficacy, or safety. If one therapy proves to be 
efficacious,  then  this  treatment  may  become  the  control arm  for  comparison(s)  with  new 
experimental treatment(s). Any such change would be accompanied by an updated sample 
size. This adaptive platform is used to rapidly evaluate different therapeutics in a population of 
those hospitalized with moderate to severe COVID-19. The platform will provide a common 
framework sharing a similar population, design, endpoints, and safety oversight. New stages 
with new therapeutics can be introduced and will be described in a stage-specific appendix. One 
independent Data and Monitoring Committee (DMC) will actively monitor interim data in all 
stages to make recommendations about early study closure or changes to study arms.
This  adaptive  design  clinical  trial  may  involve  multiple  stages  each  investigating  different 
interventions. In order to clearly convey the protocol elements, interventions, objectives and 
endpoints for each stage, common elements are described in the main protocol document while 
each stage is noted in a stage-specific appendix.
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The first stage in the clinical trial is: 
Stage 1: Convalescent Plasma vs Saline (VA CURES-1)
If convalescent plasma is shown to be beneficial in Stage 1, we may proceed to the next stage 
(Stage 1a) under separate review and protocol:
Stage 1a: Convalescent Plasma vs Fresh Frozen Plasma (VA CURES-1a)
Participants will be assessed daily while hospitalized with a series of efficacy, safety, and 
laboratory assessments. See stage-specific schedule of assessments for details.
2.3
RISK/BENEFIT ASSESSMENT  
2.3.1 KNOWN POTENTIAL RISKS 
Reported risks with convalescent plasma have been very few, despite its broad use in patients 
with influenza, SARS-CoV, MERS and Ebola virus. Among 5,000 patients with SARS-CoV-2, 
serious adverse events in the first 4 hours after transfusion were <1%, but included death in 
0.3% in these very ill patients28.  Based on an extensive clinical experience with fresh frozen 
plasma, infrequent reactions include pulmonary edema from transfusion-associated circulatory 
overload (TACO).  There may be a possibility of mild transfusion reactions with urticaria or more 
severe reactions such as transfusion-related acute lung injury (TRALI) occurring shortly after 
transfusion in the following circumstances: ABO blood group incompatibility, highly or less 
reactive  transfused  anti-human  leukocyte  antigen  (HLA)  Class  II  antibody,  anti-human 
neutrophil antigen (HNA) antibody and antibodies to IgA among IgA-deficient recipients.  Fresh 
frozen plasma overall is associated with 1:9,500 risk of incompatible plasma-related hemolysis. 
Most  hospitals  have  a  daily  maximum  amount  of  allowable  transfusion  of  incompatible 
plasma29,30.  The hemolysis risk with transfusion of incompatible plasma is ~1:12,000 for TRALI 
in HLA Ab-tested platelet/plasma units (only previously pregnant females tested).  
Passive administration may inhibit subsequent antibody production and subsequent protection 
from disease, as reported for Respiratory Syncytial Virus (RSV).  Although the U.S. blood 
supply is screened for all known transmissible pathogens, there is also a potential risk for the 
transmission of currently unrecognized pathogens.  
2.3.2 KNOWN POTENTIAL BENEFITS 
The possibility that use of convalescent immune plasma may be associated with benefits is 
supported by a limited number of small case series 3,5-7 and a non-randomized controlled study 
with SARS-CoV-29, and  few prospective randomized trials with SARS-CoV 24, MERS25,31.  These 
benefits  have  included  decreased  oxygen  requirement,  improved  pulmonary  infiltrates, 
decreased duration of hospitalization, more rapid resolution of viral detection, improvement in 
inflammatory laboratory parameters and, in some cases, mortality3,24,32.  More substantial results 
support the use of convalescent plasma with influenza with decreased mortality and length of 
hospital stay10,25,33, particularly in very early studies and when administered earlier in the course 
of disease and hospitalization (≤4 days for influenza). 
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Mechanistically,  the  potency  of  convalescent  plasma  is  thought  to  be  due  to  neutralizing 
antibodies, particularly to the surface S spike and receptor binding domain of the virus34 that 
prevent binding to epithelial and other target cells as well as cell-to-cell spread. However, 
antibodies may also enhance virulence mechanisms as well as neutralize 35-37.   Antibodies in 
convalescent plasma may facilitate clearance of bacterial and viral coinfections and modify 
inflammation and modulate  T cell function38, limit neutrophil adhesion  to and activation  of 
endothelial cells and support antigen-presentation to facilitate immune responses.
It is also possible that non-convalescent plasma would have some benefit. Polyclonal antibodies 
in plasma likely avoid selection of viral escape mutants that can accompany therapy with 
monoclonal  antibodies.   Non-neutralizing  antibodies  may  serve  a  range  of  Fc-mediated 
protective effects39,40 by supporting antibody-dependent cellular cytotoxicity (ADCC) by natural 
killer (NK) and cytotoxic lymphocytes to kill infected cells and supporting phagocytosis of virus 
and infected cells (ADCP).  Non-antibody protective functions of plasma may mediate inhibition 
of inflammation and cytokine production and regulate complement-dependent lung epithelial 
and vascular endothelial damage41 with regulatory proteins such as CD5542.  The volume of 
plasma infused is unlikely to modify clotting parameters.
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS 
The safety of fresh frozen plasma, including convalescent immune plasma from persons with 
SARS-CoV-2, given to persons with active disease is high.  The potential benefits, as above, 
include decreased mortality, decreased hospital length of stay and improvement in hypoxemia, 
pulmonary  infiltrates  and  overall  clinical  status  by  a  range  of  mechanisms.   All  of  these 
outcomes are based on very sparse case series and almost all studies are of low or very low 
quality, lacked controls groups, and were at moderate to high risk of bias25.  Hence, we believe 
that equipoise about the risks and benefits exist. A prospective randomized placebo-controlled 
study provides credible and actionable results to support or negate the use of this intervention. 
The results also provide a solid rationale for more selective and effective interventions with 
antibody  alone  (purified  polyclonal  or  monoclonal),  non-immune  plasma  alone,  or  specific 
plasma components that may be more readily accessible and affordable to persons within the 
VA
 
and
 
worldwide.
 
 
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3
OBJECTIVES AND ENDPOINTS
Table 2.  Objectives and Endpoints.
OBJECTIVES
ENDPOINTS (OUTCOME 
MEASURES)
Primary
To evaluate the clinical efficacy of 
different investigational therapeutics as 
compared to the control arm as assessed 
by:

Proportion of patients who died from 
any cause or had respiratory failure 
by Day 28

Died from any cause;

Respiratory failure is defined by requiring 
mechanical ventilation, with or without 
endotracheal intubations, or extra-corporeal 
membrane oxygenation.
This is evaluated up to and including Day 28.
Key Secondary
To evaluate the clinical efficacy of different 
investigational therapeutics as compared to 
the control arm, as assessed by:

Time (in days) to recovery (as 
defined by attaining stages 1, 2 or 3 
on the WHO 8-point ordinal scale)
Day of recovery is defined as the first day on
which the subject satisfies one of the 
following three categories from the WHO 
ordinal scale:

Hospitalized, not requiring supplemental 
oxygen;

Not hospitalized, limitation on activities 
and/or requiring home oxygen;

Not hospitalized, no limitations on 
activities.
This is evaluated up to and including Day 28.
Additional Secondary 
1. To evaluate the clinical efficacy of 
different investigational therapeutics as 
compared to the control arm as assessed 
by:

Time (in days) to death or respiratory 
failure by Day 28
Time to death or respiratory failure is defined as 
the first day on which the subject died from any 
cause or had respiratory failure (defined above).
This is evaluated up to and including Day 28.
2. To evaluate the clinical efficacy of 
different investigational therapeutics as 
compared to the control arm as assessed 
by:

Proportion of patients who died from 
any cause, had respiratory failure or 
required humidified heated high-flow 
nasal cannula (HHHFNC) at ≥ 15 
Lpm by Day 28

Time (in days) to death or respiratory 
failure or HHHFNC at ≥ 15 Lpm by 
Day 28
This is evaluated up to and including Day 28.
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3. To evaluate the clinical efficacy of 
different investigational therapeutics as 
compared to the control arm as assessed 
by:

Mortality
o
28-day all-cause mortality

Date and cause of death (if 
applicable)

Clinical Severity
1) 8-point ordinal scale: (WHO)

Time to an improvement of 
one category from Day 1 
(baseline) using the WHO 
ordinal scale.

Time to an improvement of two 
categories from Day 1 
(baseline) using the WHO 
ordinal scale.

Subject  clinical  status  using 
ordinal scale at Days 2, 4, 7, 11, 
14, 21, and 28.

Mean change in the WHO ordinal 
scale  from  Day  1  (baseline)  to 
Days 2, 4, 7, 11, 14, 21, and 28.
WHO ordinal scale (See Table 3)
Clinical outcome assessed using ordinal scale 
daily while hospitalized and on Days 14, 21, and 
28.
2) National Early Warning 
Score (NEWS2)43,44:

Time to discharge from initial 
hospitalization or to a NEWS2 
of ≤ 2 and maintained for 24 
hours, whichever occurs first. 

Change from Day 1 (baseline) 
to Days 2, 4, 7, 11, 15, and 29 
in NEWS2. 
NEWS2 assessed daily while hospitalized and 
on Days 15 and 29 (if the participant attends an 
in-person visit or still hospitalized)

Hospitalization

Duration of initial hospitalization 
(days).

Number of hospitalizations related 
to COVID-19
Number and days of hospitalizations up to and 
including Day 28
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4. To evaluate the safety of different 
investigational therapeutics as 
compared to the control arm as 
assessed by:

Cumulative incidence of SAEs 
through Day 29.

Cumulative incidence of Grade 3 
and 4 clinical and/or laboratory AEs 
through Day 29.

Discontinuation or temporary 
suspension of study product 
administrations (for any reason)

Changes in complete blood count with 
differential, hemoglobin, platelets, 
creatinine, glucose, total bilirubin, 
alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), and 
prothrombin time (PT) reported as 
international normalized ratio (INR) 
over time (analysis of lab values in 
addition to AEs noted above).
SAEs
Grade 3 and 4 AEs
Change in total WBC number, neutrophil 
number, lymphocyte number, hemoglobin, 
platelets, creatinine, glucose, total bilirubin, 
ALT, AST, and PT/INR from Day 1 to Days 2, 
4, and 7 (while hospitalized); and Days 15 and 
29 (if attends in-person visit or still 
hospitalized).
Exploratory 
1.
To examine if the effect of 
convalescent plasma is associated 
with the days of symptoms at time of 
plasma administration
Plasma administered on day ≤7 vs. >7 days of 
symptoms on primary outcome
2.
To examine if effect of convalescent 
plasma differs by comorbidities
Primary outcome in persons with ≤2 or ≥3 
comorbidities (age ≥65 years, chronic lung, 
cardiac and renal disease, hypertension, 
diabetes, obesity and immunosuppression)
3.
Research sample collection and 
management for future 
investigations:
Respiratory samples on days 1, 4, 7, 
15, 29 and 30 mL of blood on days 1, 2, 
4, 7 in hospital and days 15 and 29 in- 
or outpatient.
Sample Collection (Research lab draw with 
routine labs), preparation, labeling, shipping, 
storage and monitoring will be addressed in a 
future amendment.
4.
Impact of donor convalescent 
plasma parameters on the activity 
of administered plasma
• Donor plasma samples retained by Vitalant 
Blood services and provided to CURES-1 
investigators will be tested for antibody levels, 
neutralization against SARS-CoV2, inflammatory 
and other mediators in relation to clinical and 
laboratory outcomes in study subjects.
World Health Organization (WHO) Ordinal Scale
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WHO 8-point ordinal scale for clinical improvement, modified for use in this study, is described 
in Table 3. Note that this scale is being calculated to permit comparability of VA CURES-1 to 
other studies of experimental therapies for COVID-19, although a clinical score of “5” by the 
WHO scale differs from the operational definition of acute hypoxemic respiratory failure for use 
in determining this study’s primary outcome. 
Table 3.  Modified WHO 8-point Ordinal Scale for Clinical Improvement
Patient State
Descriptor
Clinical Score
Uninfected
No clinical or Virologic evidence of infection
0
Ambulatory
No limitation of activity
1
Limitation of activity and/or home oxygen
2
Hospitalized 
         Mild disease
Hospitalized, no oxygen therapy
3
Oxygen by mask or nasal prong
4
Hospitalized
         Severe disease
Humidified high-flow oxygen
5a
Non-invasive ventilation
5b
Intubation and mechanical Ventilation
6
Ventilation + additional organ support—
pressors, RRT, ECMO
7
Dead
Death
8
National Early Warning Score-2
NEWS2 has demonstrated an ability to discriminate subjects at risk of poor outcomes43.  This 
score is based on seven clinical parameters (see Table 4). The NEWS2 is being used as an 
efficacy measure. The NEWS2 Score should be evaluated daily while hospitalized and on Days 
15  and  29.  It can  be  performed  concurrently  with  the  Ordinal  Scale.  NEWS2  should  be 
evaluated at a consistent time for each applicable study day, if possible. The seven parameters 
can be obtained from the hospital chart or electronic medical record (EMR) using the last 
measurement prior to the time of assessment.  A numeric score is given for each parameter 
(e.g., a RR of 9 is one point, oxygen saturation of 92 is two points). This value is recorded for 
the day obtained (i.e., on Day 3, the vital signs and other parameters from Day 3 are used to 
obtain  NEWS2  Score  for  Day  3).  ECMO  and  mechanically  ventilated  subjects  should  be 
assigned a score of 3 for RR (RR <8) regardless of the ventilator setting. Subjects on ECMO 
should get a score of 3 for heart rate since they are on cardiopulmonary bypass. 
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Table 4. The NEWS Scoring System 43
Physiological 
parameter
Score
3
2
1
0
1
2
3
Respiration rate (per 
minute)
≤ 8
9-11
12-20
21-24
≥ 25
SpO2 Scale 1 (%)
≤ 91
92-93
94-95
≥ 96
SpO2 Scale 21 (%)
≤ 83
84-85
86-87
88-92
≥ 93 on 
air
93-94 
on 
oxygen
95-96 
on 
oxygen
≥ 97
on 
oxygen
Air or oxygen?
Oxygen
Air
Systolic blood 
pressure (mmHg)
≤ 90
91-100
101-110
111-219
≥ 220
Pulse (per minute)
≤ 40
41-50
51-90
91-110
111-130
≥ 131
Consciousness2
Alert
CVPU
Temperature (C)
≤ 35.0
35.1-
36.0
36.1-
38.0
38.1-
39.0
≥ 39.1
1SpO2 Scale 2 is used only for participants with history of pre-existing suspected or confirmed hypercapnia. 
2Level of consciousness = alert (A), conscious but non-alert (C) and arousable only to voice (V) or pain (P), or 
unresponsive (U).
4
STUDY DESIGN 
4.1
OVERALL DESIGN
The VA CoronavirUs Research and Efficacy Study-1 (VA CURES-1) is designed to determine 
the safety and efficacy of convalescent plasma to prevent progression to respiratory failure and 
death among persons hospitalized with SARS-CoV-2 and who require supplemental oxygen.
This  adaptive  design  clinical  trial  may  involve  multiple  stages  each  investigating  different 
interventions. 
The first stage in the clinical trial is: 
Stage 1: Convalescent Plasma vs Saline 
If convalescent plasma is shown to be beneficial in Stage 1, we will proceed to Stage 2:
Stage 2: Convalescent Plasma vs Fresh Frozen Plasma 
4.2
SCIENTIFIC RATIONALE FOR STUDY DESIGN
Convalescent plasma contains SARS-CoV-2-specific antibodies that support neutralization and 
other antiviral activities that will inhibit viral replication and lyse infected cells to limit underlying 
tissue damage and inflammation. Administration of convalescent plasma early in the course of 
infection in the hospital will increase the days to and prevent respiratory failure and death before 
irreversible lung and vascular damage ensues.
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4.3
JUSTIFICATION FOR DOSE
The planned plasma volume for this study is 400-600 mL. Plasma is collected in ~200-250 mL 
units.  All studies to date using convalescent plasma have used 200-600 mL (1-2 units) of 
plasma. This dose typically provides sufficient antibodies to maintain or increase virus-specific 
levels in plasma of recipients and is generally well-tolerated for volume. If 400-600 mL volume is 
deemed excessive due to e.g., congestive heart failure or oliguria, then 200-250 mL will be 
given if deemed safe by the primary clinicians and study staff.
4.4
END OF STUDY DEFINITION
The  study  is  completed  for  each  subject  on  day  29  (+3  days)  after  administration  of 
convalescent plasma or on the day of death.
5
STUDY POPULATION
5.1
INCLUSION CRITERIA 
Veterans must meet ALL of the following criteria to be eligible to participate:
1.
Admitted to a participating VA clinical site with symptoms suggestive of SARS-CoV-2 
infection.
2.
Participant (or legally authorized representative) provides informed consent prior to initiation 
of any study procedures.
3.
Participant (or legally authorized representative) understands and agrees to comply with 
planned study procedures.
4.
Veteran ≥ 18 years of age at time of screening.
5.
Has laboratory-confirmed SARS-CoV-2 infection as determined by polymerase chain 
reaction (PCR) or antigen test, as documented by either of the following:
(1) RT-PCR or antigen positive (nasopharyngeal, oropharyngeal, saliva, lower 
respiratory) in sample collected ≤ 72 hours prior to screening;
(2) RT-PCR or antigen positive in sample collected > 72 hours but ≤ 168 hours (i.e. 7 
days) prior to screening, documented inability to obtain a repeat sample (e.g. due to 
lack of testing supplies, limited testing capacity, results taking > 24 hours, etc.), AND 
progressive disease suggestive of ongoing SARS-CoV-2 infection.
6.
Requiring oxygen by nasal cannula or by face-mask as a new treatment (or if previously 
on home oxygen, at a liter flow at least 2 Lpm greater than home prescription), but not 
on humidified heated high-flow nasal cannula (HHHFNC) at ≥ 15 Lpm.
7.
Can be randomized within 72 hours of initial hospital admission.
8.
Agrees not to participate in another therapeutic clinical trial for the treatment of COVID-19 or 
SARS-CoV-2 through Day 29 without approval from the investigator(s).  Taking part in other 
research studies, including those unrelated to SARS-CoV-2, without first discussing it with 
the investigators of this study may invalidate the results of this study, as well as that of the 
other study. 
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5.2
EXCLUSION CRITERIA 
An individual who meets any of the following criteria will be excluded from participation in this 
study:
1.
Respiratory failure requiring mechanical ventilation, non-invasive ventilation including CPAP 
(for an indication other than previously diagnosed sleep apnea and maintained on outpatient 
settings), or extra-corporeal membrane oxygenation or anticipated to require any of those 
treatments or to die within 24 hours. 
2.
Anticipated discharge from the hospital or transfer to another hospital that is not a study site 
within 72 hours.
3.
History of previous transfusion reaction.
4.
Previously documented serum IgA deficiency (<7 mg/dL)
5.
Documented to have received convalescent plasma in the last 60 days.
5.3
LIFESTYLE CONSIDERATIONS 
During this study, participants are asked to:

Avoid participating in another interventional clinical trial for the treatment of SARS-CoV-2 
or SARS-CoV-2. Co-enrollment for natural history studies of SARS-CoV-2 is permitted or 
studies unrelated to of SARS-CoV-2 can be considered if PI of both studies agree.
5.4
SCREEN FAILURES. 
Following Consent and after screening evaluations have been completed, the LSI or designee 
will review the inclusion/exclusion criteria and determine the subject’s eligibility for the study. If 
there is any uncertainty, the Local Site Investigator (LSI) should make the decision on whether a 
potential subject is eligible for study enrollment.
5.5
STRATEGIES FOR RECRUITMENT AND RETENTION
Patients recruited to the study will be from those admitted to acute inpatient medical services. 
Research staff will employ several strategies to identify potentially eligible subjects. No external 
recruitment methods are anticipated.
Materials summarizing the purpose and design of the study, key interventions, and key inclusion 
and exclusion criteria will be made available to clinical providers caring for patients hospitalized 
with SARS-CoV-2.
Potential participants will be identified by IRB-approved review of CPRS charts and hospital 
admission logs under a HIPAA waiver. Pre-screening for preliminary eligibility will be performed 
by a member of the site research team, usually the Site Coordinator, who will complete a 
checklist of key inclusion and exclusion criteria. If a priori requirements for enrollment are met, 
permission will be obtained, if not previously granted, from the patient’s clinical provider to seek 
informed consent for participation in the study from the patient or his/her authorized healthcare 
proxy.
Over 30 VA Medical Centers have expressed interest in participating in this study. In the last 
three months of the epidemic, 1,890 patients with SARS-CoV-2 were admitted to the top 25 VA 
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medical  center  targeted  for  inclusion  in  this  study.  The  study  is  proposed  to  require 
approximately 702 participants admitted with SARS-CoV-2, assuming a 30% primary event 
frequency in the study sample, to have 85% power for detecting a 10% absolute reduction in the 
primary event with convalescent plasma (i.e., hazard ratio 0.7). Among 568 patients admitted 
with SARS-CoV-2 to the Detroit VA, 69% achieved the primary endpoint of respiratory failure or 
death, although these frequencies may decrease with less ill patients admitted and more skilled 
management over time.  Proactive and consistent team management and communication will 
be required for effective ongoing recruitment.
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6
STUDY INTERVENTION 
6.1
STUDY INTERVENTION(S) ADMINISTRATION 
6.1.1 STUDY INTERVENTION DESCRIPTION
Patients will be randomized within 72 hours of admission to receive 1) 400-600 mL of ABO 
compatible convalescent plasma from the hospital blood bank or 2) sterile saline, each wrapped 
in non-disclosing paper with translucent tubing over approximately 4 hours. If volume overload 
is a concern, 200-300 mL will be infused by pump over 2 hours.
6.1.2 DOSING AND ADMINISTRATION
The dose of convalescent plasma, or placebo, that will be utilized in this study is consistent with 
the
 
April
 
8,
 
2020
 
published
 
by
 
the
 
FDA 
(https://www.fda.gov/vaccines-blood-biologics/investigational-new-drug-ind-or-device-
exemption-ide-process-cber/recommendations-investigational-covid-19-convalescent-plasma).  
We will utilize a target dose of two units of plasma with antibodies to SARS-CoV-2, based on 
previously studied dosing established in SARS1, in which a weight-based dose of 5 mL/kg has 
been utilized.
Study intervention will be started within 36 hours of randomization, at a rate of 150 mL per hour 
or less. The administration of each unit should last approximately up to 2 hours, and the elapsed 
time between each transfusion should not exceed 12 hours. Time at start and end of transfusion 
should be recorded. Vital signs will be measured prior to transfusion, 10-20 minutes after start of 
transfusion, at completion of transfusion or if discontinued and 30-60 minutes after the end of 
the transfusion.
6.2
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
6.2.1 ACQUISITION AND ACCOUNTABILITY 
Convalescent plasma is obtained from contracted blood service providers, either locally or 
shipped overnight to requesting centers.  Plasma is obtained from veterans and others who 
have no symptoms for 28 days after recovery from SARS-CoV-2 infection or who have no 
symptoms for 14-27 days and have a negative nasopharyngeal swab for SARS-CoV-2 RNA. 
Plasma units are stored in designated areas in the local VA Blood Bank.
Detailed information about drug handling procedures can be found in the Drug Treatment & 
Handling Procedures (DTHP).
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING
Blinded study intervention will be supplied to the research staff in a manner that does not 
identify the active versus placebo. The research staff will remain blinded to the treatment group 
assignment. Detailed information about drug handling procedures can be found in the Drug 
Treatment & Handling Procedures (DTHP).
6.2.3 PRODUCT STORAGE AND STABILITY
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Clinical  supplies  must  be  stored  in  a  secure,  limited-access  location  under  the  storage 
conditions specified on the label. Sites are responsible for providing secure storage for study 
drugs in the Pharmacy or elsewhere as directed by federal and local laws, regulations, policies, 
and procedures. Investigational drugs must be stored separately from non-study drug inventory 
to avoid co-mingling  of investigational and clinical drug products. Site pharmacists should 
consult VHA Handbook 1108.04 “Investigational Drugs and Supplies” Clinical supplies may not 
be used for any purpose other than that stated in the protocol. The investigational drug will be 
dispensed and administered only for the purposes specified in this protocol. The local site 
investigator (LSI) is responsible for assuring that the investigational product is administered only 
to study patients by qualified and approved personnel. The LSI is ultimately responsible for all 
study drug at their clinical site. Receipt and dispensing of trial medication must be recorded by 
an authorized person at the trial site. 
The study product is a commercially available product with expiration dating assigned by the 
provider. The site will monitor the dating of all study drug to ensure that the drug will not expire 
through the anticipated administration and use by the patient.
Detailed information about proper storage procedures can be found in the Drug Treatment & 
Handling Procedures (DTHP).
6.2.4 PREPARATION
Study intervention will be prepared on site consistent with local policies and procedures and 
started within 36 hours of randomization. The administration of each unit will be performed by 
qualified individuals, in a blinded fashion.
Detailed information about proper preparation and blinding procedures can be found in the Drug 
Treatment & Handling Procedures (DTHP).
6.3
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
6.3.1 RANDOMIZATION
The study will randomize participants in equal probabilities to study treatment arms. Currently 
there are two study treatment arms: convalescent plasma versus saline. Participants will be 
randomized in 1:1 ratio to these two arms. If additional arms are added to or dropped from the 
trial, randomization  will proceed with an equal probability  to each of the remaining  arms. 
Randomization will be stratified by participating site and by age (≥65 vs. <65 years old). 
The IWRS (Interactive Web Response System) will be used by authorized study site personnel 
to randomize eligible participants. It is an intranet-based application that is hosted behind the 
VA firewall on a VA server at the CSPCRPCC. It is only accessible on the VA network to 
authenticated VA personnel. Access to study data is restricted to personnel that have registered 
in the IWRS and have been authorized by the study team. All communication to or from the 
IWRS is encrypted using Hypertext Transfer Protocol Secure (HTTPS) and is secured using a 
VA furnished Secure Sockets Layer (SSL) certificate.
6.3.2 BLINDING
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The study interventions will be provided and administered to all participants in a similar fashion 
to achieve blinding. The participants, site investigators, clinical prescribers, site coordinators, 
and most other individuals involved in this study will be blinded to the treatment assignment. 
Furthermore, the blind will not routinely be broken in order to select post-study, pharmacologic 
treatment for SARS-CoV-2 infection administered by clinical healthcare providers. 
Blinding will be maintained except for when knowledge of the study treatment assignment will 
influence the medical treatment of the participant. There may be cases of breaking the blind for 
emergency medical necessity (emergency unmasking), where the clinical research pharmacist 
may access treatment assignment information, as necessary. If emergency unblinding becomes 
necessary during local business hours, the treating provider should contact the Local Site 
Investigator. The LSI should then contact the Study Chair to discuss the situation  before 
requesting that a participant be unblinded by the CSPCRPCC. Outside of local business hours, 
the treating provider should contact CSPCRPCC directly at a number that is available 24 hours 
per day, 7 days per week to discuss the need for unblinding and to have the unblinding 
performed if indicated. Efforts should be made to avoid unblinding unless medically necessary 
for emergency treatment decisions.
Participants who require emergency unblinding for clinical safety will be discontinued from study 
intervention. Study staff will be provided with training on emergency unblinding procedures.
Participants  or  their  legally  authorized  representative  will  be  provided  with  a  Participant 
Identification Card that lists site staff telephone numbers and a 24-hour CSPCRPCC contact 
number. The research facility’s name and the two possible study treatments are also listed on 
the  card.  The  Participant  Identification  Card  will  include  the  participant’s  Randomization 
Number,  which  can  be  used  to  determine  the  participant’s  treatment  assignment  should 
emergency unblinding be required for patient safety.
  
6.4
STUDY INTERVENTION COMPLIANCE 
The study intervention consists of intravenous administration of 200-600mL of convalescent 
plasma or an equivalent volume of 0.9% saline administered in two equally divided doses, less 
than 12 hours apart. The order will be entered by the site LSI or authorized designee and study 
product will be administered by clinical staff according to standard procedures for transfusion of 
component blood products. 
Compliance with study intervention will be assessed using case report forms entered by local 
site staff following completed transfusion of study intervention.
The reason for failure or partial administration of study product will be recorded by study staff.
6.5
CONCOMITANT THERAPY 
Therapy prior to enrollment with any other experimental treatment or off-label use of marketed 
medications  that  are  intended  as  specific  treatment  for  SARS-CoV-2  infection  (i.e.,  post-
exposure prophylaxis) are permitted.
Participants who are taking remdesivir for COVID-19 or another antiviral for a concurrent 
infection  (e.g.  oseltamivir  for  an  influenza  virus,  lopinavir/ritonavir  for  HIV,  etc.),  or 
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immunosuppressive  drugs  for  other  medical  conditions  (corticosteroids  for  an  unrelated 
condition, tocilizumab for rheumatoid arthritis, hydroxychloroquine for lupus, etc.) may continue 
with the treatment.
Participants entering the trial may be prescribed therapy for SARS-CoV-2 that has received 
preliminary FDA approval whether available by prescription or under an expanded access 
program (EAP), e.g. remdesivir or dexamethasone. These medications may be initiated or 
continued. However, participants may not have previously received or be given SARS-CoV-2 
convalescent plasma under the Mayo or any other EAP.
A participant cannot participate in another clinical trial for the treatment of SARS-CoV-2 until 
after Day 29. However, if the participant has progressed to respiratory failure in the hospital (see 
definition in  Section 3), another experimental treatment protocol may be initiated, but only if 
there is a sponsor-approved agreement between the leadership of both trials. The agreement 
will consider potential impact of dual enrollment on study outcomes and participant safety and 
establish procedures to coordinate adverse event monitoring and reporting of dual-enrolled 
participants.
6.5.1 CONCOMITANT MEDICATIONS
Use of concurrent medications is allowed if they are part of local best supportive care for SARS-
CoV-2 infection.
Pretreatment  with  appropriate  medication  to  minimize  transfusion  reactions  (e.g. 
acetaminophen, diphenhydramine) may be given at the discretion of the local site investigator 
and consistent with local site’s transfusion protocols.
Pre-admission  level  A  medications  will  be  collected  by  class  at  baseline.  Concomitant 
medications taken for the prevention and treatment of COVID-19 in the 7 days prior to Study 
Day 1 (day of randomization) and concomitant medications prescribed from hospital admission 
through Day 28 will be collected by study site staff using the designated case report form. This 
information will be collected via chart review, or in person or telehealth/telephone interviews, 
when appropriate. 
6.5.2 RESCUE MEDICINE
Not applicable.
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7
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1
DISCONTINUATION OF STUDY INTERVENTION
Not applicable
7.2
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY
Participants are free to withdraw from full participation in the study at any time upon request, 
without any consequences.  
If a participant requests to be withdrawn from the study, the LSI or delegee may offer the 
participant an option of limited participation. The two limited participation options that 
may be offered are:
1.
A participant can choose to withdraw from receiving study product, but agree to all other 
follow-up, including study staff contact and laboratory testing.
OR
2.
A participant may choose to withdraw from direct participation in all study activities but allow 
ongoing medical records review by study staff (no contact). 
A participant may also choose to withdraw completely from all study activities.  If a 
participant fully withdraws consent, no study procedures may be performed, and no 
more data may be collected as of the time point at which the patient withdrew consent.  
In any of the situations above, study personnel will ascertain and clearly document in the EHR 
any limits to ongoing participation. A participant’s usual medical care is not affected by whether 
study participation continues (fully or to a lesser degree) or ends.
If a participant withdraws consent or is withdrawn from the study by the Local Site Investigator 
(LSI), an Early Termination Form will be completed. Data collected up to the point of withdrawal 
will be used in the analyses.  If a participant agrees to limited participation the site must 
complete a Reduced Participation form.
7.3
LOST TO FOLLOW-UP
Every  attempt  must  be  made  to  ensure  that  the  participant  attends  all  study  visits  and 
assessment calls. Prior to a visit, the site staff will place reminder telephone calls and/or text 
messages. If a participant does not show for a visit or misses an assessment call, the site staff 
will  try to re-schedule  the contact within the target visit window.  Attempts to contact the 
participant should be documented in the subject’s records.
A  participant  is  considered  lost  to  follow-up  if he  or  she  fails  to appear  for all  follow-up 
assessments. If a participant is lost to follow-up, a Study Completion Form will be completed.
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8
STUDY ASSESSMENTS AND PROCEDURES
8.1
CONSENT AND SCREENING PROCEDURES
8.1.1 CONSENT PROCESS
The consent process can start as soon as the prospective participant is admitted to the hospital. 
After a prospective participant is admitted to the hospital or transferred from another hospital, 
the  Site  Coordinator  (SC)  reviews  Informed  Consent  Form  (ICF)  and  HIPAA  with  the 
prospective participant or his/her legally authorized representative (LAR). Once the prospective 
participant or LAR signs the ICF/HIPAA (by signing a hard copy or via e-consent, if available), 
screening can start.  Participants who are enrolled based on approval on their behalf by their 
LAR must be consented for continued participation in the study should they later become 
competent prior to Day 29. See Section 10.1.1.2.
8.1.2 SCREENING PROCEDURES
Participants must be randomized within 72 hours of initial hospital admission. However, in many 
cases consent and all the screening assessments can be done in less than 24 hours. If that is 
the case, randomization, baseline assessments, specimen collection, and the study product 
administration can occur on the same calendar day as the consent and screening procedures.
After the informed consent, the following assessments are performed to determine eligibility and 
obtain baseline data: 

Confirm the positive SARS-CoV-2 test result via RT-PCR or antigen test (per inclusion 
criteria). 

Take a focused medical history, including the following information: 
o
History of chronic medical conditions including chronic oxygen requirement prior 
to onset of COVID-19. 
o
History of any previous transfusion reactions. 

Whether they are participating in another clinical trial or plan to enroll in another clinical 
trial in the next 30 days. 

Height and weight (height can be self-reported). 

Results of recent radiographic imaging (x-ray or CT scan). 

SpO2.

Urine or serum pregnancy test (in women of childbearing potential). 
Clinical screening laboratory evaluations will be performed locally by the site laboratory.
8.2
BASELINE, RANDOMIZATION AND PRODUCT ADMINISTRATION
Baseline assessments should be performed before the first study product administration. 
The  following  eligibility/baseline  assessments  can  be  done  up  to  72  hours  prior  to 
randomization  time:  demographic  information  (age,  ethnicity,  gender,  body  mass  index), 
medical history/baseline comorbidities (e.g. obesity, smoking, diabetes, hypertension, cardiac, 
renal, liver, and lung disease), and physical exam. 
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Baseline clinical status data are collected right before randomization. Baseline vital signs 
(NEWS2) should be collected closest to randomization time and must be collected within 24 
hours prior to randomization time. 
The  following  additional  baseline  assessments  are  collected  prior  to  study  product 
administration: 

COVID-19 signs and symptoms, including day of onset,

Medications for this current illness taken in the 7 days prior to Day 1 (See Section 6.5),

Designated pre-admission medications by class (See Section 6.5), 

Adverse events (See Section 8.5), 

Safety and research labs (See Section 8.4). 
Day 1 safety and research labs should be collected up to 24 hours prior to randomization and 
before first study product administration. Laboratory tests performed as part of routine clinical 
care within the same time period will be accepted for Day 1 safety laboratory tests.
Ideally, product administration should start on the same day as randomization (Day 1), but 
may be started up to 36 hours after randomization.
8.3
EFFICACY AND EXPLORATORY ASSESSMENTS
For all eligibility, baseline, and study intervention assessments and follow-up visits, refer to 
Table 1:  Schedule of Assessments  for procedure to be done, and details below for each 
assessment. 
8.3.1 MEASURES OF CLINICAL SUPPORT AND LIMITATIONS
On each study day through Day 29, the following measures for the previous day will be 
recorded. That is, on Day 3, Day 2 measures are assessed as occurring anytime in that 24 
hours period (12 midnight to 12 midnight): 

Disposition (hospitalized -ICU, hospitalized – non-ICU, not hospitalized, died)

Additional organ support (e.g., kidneys, blood pressure support)

ECMO requirement

Invasive mechanical ventilation (via endotracheal tube or tracheostomy tube) 
requirement

Non-invasive mechanical ventilation requirement including CPAP (for an indication other 
than previously diagnosed sleep apnea)

Heated high flow nasal cannula ≥ 15 L/min 

Supplemental oxygen requirement

Limitations of physical activity (self-assessed)
Site staff will record the above measures daily during initial hospitalization. After discharge from 
initial  hospitalization,  site  staff  will  collect  the  above  measures  via  in-person  (preferred), 
telehealth or telephone follow-up on Study Days 15 and 29, and via telehealth/telephone follow-
up on Study Day 22. At the time of initial hospital discharge, participants will be provided with a 
log to help them record the above measures daily and report the data to site staff at follow-up. 
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8.3.2 WHO ORDINAL SCALE OF PATIENT CLINICAL STATUS
The ordinal scale is an assessment of the clinical status at the first assessment of a given study 
day. From the measures collected in  Section 8.3.1, this ordinal scale can be derived. The 
modified WHO 8-point Ordinal Scale for Clinical Improvement used in this study is provided in 
Table 3 (See Section 3, Objectives and Endpoints). 
8.3.3 NATIONAL EARLY WARNING SCORE 2 (NEWS2) 
The NEWS2 point score (https://www.mdcalc.com/national-early-warning-score-news-2)43 will 
be used (see Table 4, Section 3, Objectives and Endpoints):
1) to assess the severity of illness and comparability of subjects in the convalescent plasma and 
control groups at enrollment, and 
2) to compare changes in score over time between the two groups. Patients who die will be 
coded on their values on the day of death if the values are available.
8.3.4 DEATH AND DURATION OF HOSPITALIZATION
The study will also collect the following information up to Day 29:

Death: Date of death and cause of death 

Duration of initial hospitalization: Date of discharge from current hospitalization and 
discharge location
8.3.5 EXPLORATORY ASSESSMENTS
To evaluate the impact of onset of symptoms 
relative to the time of plasma on the effect of 
convalescent plasma on primary outcome
Plasma administered on day ≤7 vs. >7 days 
of symptoms on primary outcome
To evaluate the impact of comorbidity on the 
effect of convalescent plasma on primary 
outcome
Primary outcome in persons with ≤2 or ≥3 
comorbidities (age ≥65 years, chronic lung, 
cardiac and renal disease, hypertension, 
diabetes, obesity and immunosuppression)
To evaluate the relationship of clinical, 
immunologic, inflammatory, metabolic, 
coagulation, endocrinologic and microbiologic 
outcomes.
Using stored nasal swab fluid, plasma and 
blood cells, we will test for antibodies, 
antibody activity, cytokines, RNA transcripts 
and soluble and cellular markers of COVID-
19 perturbations.
Characterize the impact of specific 
parameters of convalescent plasma 
administered to subject on immunologic, 
inflammatory, metabolic, coagulation, and 
endocrinologic outcomes in study subjects.
Using samples of administered convalescent 
plasma, determine specific antibody levels, 
neutralization, cytokines and other soluble 
markers in relation to these outcomes in the 
plasma of study subjects and their 
outcomes.
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8.4
SAFETY AND OTHER ASSESSMENTS
AEs/SAEs will be identified spontaneously through patient reports, actively elicited during study 
visits  through  open-ended  questioning  and  examination  and  gathered  at  the  time  of  any 
telehealth or telephone contact and review of the medical record. See Section 8.5.
8.4.1 CLINICAL LABORATORY EVALUATIONS 

Blood will be drawn at the time points indicated in the Schedule of Assessments (Table 
1) and in Table 5.

Blood volumes are indicated in Table 5. 

Blood type will be determined on Day 1 before product administration.

Fasting is not required before collection of laboratory samples. 

Minimal clinical safety laboratory tests include WBC, differential, Hgb, PLT, creatinine, 
glucose, total bilirubin, AST, ALT, and PT. Sites that do not have access to a test for PT/
INR will be allowed to report an INR. 

Day 1 clinical laboratory evaluations are drawn prior to initial study product 
administration as a baseline and results do not need to be reviewed to determine if initial 
study product administration should be given. 

Clinical laboratory testing will be performed at each clinical trial site in real time. 
Table 5: Blood volume and collection windows.
Randomizatio
n/ Baseline
Day +/- Window 
1 
2 + 1
4 + 1
7 ± 1
15 ± 2
29 ± 3
Safety 
hematology, 
chemistry and 
liver tests 
X
14mL1
X2 
14mL1
X2 
14mL1
X2
14mL1
X3
14mL1
X3
14mL1
Blood for 
research
X4,5
30mL
X2,5
30mL
X2,5
30mL
X2,5
30mL
X3,5
30mL
X3,5
30mL
Total blood 
volume
44mL
44mL
44mL
44mL
44mL
44mL
Total all study 
days
Up to 264 mL
1. For Randomization/Baseline visit, total volume calculated assumes there are no laboratory tests done 
as part of routine clinical care up to 24 hours prior to randomization. For all other visits, total volume 
calculated assumes there were no laboratory tests performed as part of routine clinical care in the 
specified visit window for that assessment: Day 2 + 1, Day 4 + 1, Day 7 ± 1, Day 15 ± 2 and Day 29 ± 3, if  
still hospitalized (this includes initial hospitalization or re-hospitalization to the same VA hospital). 
2. Safety laboratory tests and blood for research will be collected on Days 2, 4, and 7 if the participant is 
hospitalized at these time points (initial hospitalization or re-hospitalization at the study site).
3. Safety laboratory tests and blood for research will be collected on Day 15 and 29 if the participant is 
still hospitalized at these time points or if they return for an in-person outpatient visit and the site has the 
capacity to collect blood in the outpatient setting.
4. Collected before participant receives study product. 
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5. 30 mL (approximately 2 tablespoons) of blood will be collected.
8.4.2 RESPIRATORY SPECIMEN
To measure viral clearance rates following treatment, respiratory samples will be collected at 
baseline (up to 24 hours prior to randomization and before product administration), on Days 4 
and 7 while hospitalized and during in-person visits on Days 15 and 29.  This includes initial 
hospitalization  as  well  as  re-hospitalization  to  the  same  VA  hospital.  Because  there  is 
controversy over the best sample type and potential difficulty obtaining specific sample types at 
certain clinical sites, a decision on allowable types (nasopharyngeal vs. oral vs. saliva) will be 
described in the Operations Manual. 
8.4.3 PROCEDURES TO BE FOLLOWED IN THE EVENT OF ABNORMAL 
CLINICAL FINDINGS
If a physiologic parameter (e.g., vital signs, or laboratory value) is outside of clinically expected 
range, then the measurement may be repeated once if, in the judgment of the investigator, the 
abnormality is the result of an acute, short-term, rapidly reversible condition or was an error. A 
physiologic  parameter  may  also  be  repeated  if  there  is  a  technical  problem  with  the 
measurement  caused  by  malfunctioning  or  an  inappropriate  measuring  device  (i.e., 
inappropriate-sized BP cuff).
8.4.4 UNSCHEDULED VISIT
If clinical considerations require the subject to be contacted or seen prior to the next scheduled 
assessment to assure the participant’s well-being, it is permissible in this protocol. 
8.4.5 CONCOMITANT MEDICATIONS 
Concomitant medications will be collected on the day of randomization, the day of study drug 
administration, the day of discharge or development of a primary outcome event, at days 15, 22 
and 29 after enrollment, and during unscheduled visits if applicable. 
8.5
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
Timely and complete reporting of safety information assists study management in identifying 
any untoward medical occurrence, thereby allowing: a) protection of safety of study participants; 
b) a greater understanding of the overall safety profile of the study treatments and therapeutic 
modalities; c) improvements in study design or procedures; and d) consistency with Good 
Clinical Practice.
All serious adverse events and the following non-serious adverse events will be collected and 
reported to the sponsor on study CRFs:

Treatment-related adverse events of any severity: transfusion reaction (fever, rash), 
transfusion related acute lung injury (TRALI), transfusion associated circulatory overload 
(TACO), transfusion related infections. 

Adverse events that have a grade 3 severity, regardless of attribution; 
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
SARS-CoV-2 related adverse events and have a grade 3 severity, regardless of 
attribution: cardiac arrythmias, cardiac arrest, need for ECMO or ventricular assistance, 
thromboembolic or thrombotic complications, need for intensive medical care, need for 
increased oxygen support or mechanical ventilation, sustained low blood pressure 
requiring IV pressure support.
These events will be collected and reported on study CRFs from the time of randomization and 
until becoming lost to follow-up, discontinuing study participation early, or completing the final 
study visit, whichever occurs first. Details are described below.
8.5.1 DEFINITION OF ADVERSE EVENTS (AE)
An  AE  is  any untoward  physical or  psychological  occurrence  in  a human  participating  in 
research or associated with the use of a drug in a human. An AE can be any unfavorable and 
unintended event, including an abnormal laboratory finding, symptom, or disease associated 
with the research or the use of a medical investigational test article. An AE does not necessarily 
have to have a causal relationship with the research or medical investigational test article. (See 
21 CFR 312.32(a) and VHA Handbooks 1058.01 and 1200.05).
8.5.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) 
An AE is considered an SAE if, in the view of either the investigator or sponsor, it results in any 
of the following outcomes: 
•
Death;
•
A life-threatening experience;
•
Inpatient hospitalization or prolongation of existing hospitalization;
•
A persistent, significant, or permanent incapacity or substantial disruption in the 
participant’s body function/structure, physical activities and/or quality of life;
•
Congenital anomaly/birth defect; or
•
Important medical events that may not be immediately life-threatening, result in 
death, or require hospitalization may be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the participant and may require 
medical or surgical intervention to prevent one of the outcomes listed in this 
definition. Such events include intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result 
in hospitalization; or development of drug dependency or drug abuse. (See 21 CFR 
312.32(a) and VHA Handbooks 1058.01 and 1200.05)
8.5.3 CLASSIFICATION OF AN ADVERSE EVENT 
1.1.1.1 SEVERITY OF EVENT
The Common Terminology Criteria for Adverse Events (CTCAE) v5 
[https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/
CTCAE_v5_Quick_Reference_8.5x11.pdf] will be used to establish the severity of AEs. To 
determine an AE’s severity, the CTCAE v5 will be consulted, and the threshold levels for AEs 
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listed in the CTCAE v5 will be used. If an AE is not listed in the CTCAE v5, then the following 
severity definitions adopted from the CTCAE v5 will be applied to determine the severity:

Grade 1 (Mild): asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 

Grade 2 (Moderate): minimal, local or noninvasive intervention indicated; limiting age 
appropriate instrumental Activities of Daily Living (ADL)*. 

Grade 3 (Severe): medically significant but not immediately life-threatening; disabling; 
limiting self-care ADL**.
Note: A Semi-colon indicates ‘or’ within the description of the grade. 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden.
1.1.1.2 RELATIONSHIP TO STUDY INTERVENTION
Relatedness involves an assessment of the degree of causality (attributability) between the 
study intervention and the event. Site investigators will be asked to provide an assessment of 
relatedness  of  the  event  to  the  study  intervention.  The  assessment  provided  by  the  site 
investigator is part of the information used by the sponsor to determine if the event represents 
an alteration in the safety profile of the study intervention. All events with a reasonable causal 
relationship to the study intervention should be considered “related”. A definite relationship does 
not need to be established. This study will use the following relatedness scale to categorize an 
event:

Definitely Related: The event is clearly related to the study intervention – i.e. an event 
that follows a reasonable temporal sequence from administration of the study 
intervention follows a known or expected response pattern to the suspected intervention 
that is confirmed by improvement on stopping and reappearance of the event on 
repeated exposure and that could not be reasonably explained by the known 
characteristics of the participant’s clinical state.

Possibly Related: An event that follows a reasonable temporal sequence from 
administration of the study intervention follows a known or expected response pattern to 
the suspected intervention, but that could readily have been produced by a number of 
other factors.
Not Related: The event is clearly not related to the investigational agent/procedure, i.e. another 
cause  of  the  event  is  most  plausible;  and/or  a  clinically  plausible  temporal  sequence  is 
inconsistent with the onset of the event and the study intervention and/or a causal relationship is 
considered biologically implausible.
8.5.3.1 EXPECTEDNESS 
An AE that is new or greater than previously known, in terms of nature, severity, or frequency of 
occurrence, or any other unanticipated serious problem associated with the investigation that 
relates to the rights, safety, or welfare of subjects, as documented in the protocol or other 
materials approved by the IRB of record or the characteristics of the study population. Such 
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materials may include but are not limited to: the informed consent form, safety plan, clinical 
investigator’s brochure (or CSPCPRCC’s Drug Information Report), and product labeling (see 
VHA Handbook 1058.01). The Sponsor will concur or disagree with the site investigator’s 
assessment as to whether an adverse event is anticipated or unanticipated (sometimes referred 
to as expected/unexpected, respectively).
The following AEs are considered uncommon, but anticipated in this study population:

Related to the study intervention
 
 : transfusion reaction (fever, rash), transfusion related 
acute lung injury (TRALI), transfusion associated circulatory overload (TACO), 
transfusion related infections.

Related to COVID-19 disease progression
 
 : cardiac arrythmias, cardiac arrest, need for 
ECMO or ventricular assistance, thromboembolic or thrombotic complications, need for 
intensive medical care, need for increased oxygen support or mechanical ventilation, 
sustained low blood pressure requiring IV pressure support.
As these AEs will be considered anticipated, they will not generally require expedited reporting 
to the CIRB. The frequency of these events will be monitored regularly during aggregate data 
review. In the event the frequency of any of these events is identified to be greater than 
anticipated during aggregate analysis, the event will then be reported as a serious unanticipated 
problem.
8.5.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND 
FOLLOW-UP
Timely and complete reporting of safety information assists study management in identifying 
any untoward medical occurrence, thereby allowing:

Protection of study participants’ safety;

A greater understanding of the overall safety profile of the study interventions and 
therapeutic modalities;

Appropriate modification of the study protocol, if needed;

Improvements in study design or procedures;

Compliance with regulatory requirements.
The  Site  Study  Personnel  is  responsible  for  the  AE  and  SAE  reporting  requirements  as 
described in this protocol, including closely monitoring all participants for new AEs and/or SAEs. 
Data on AEs and/or SAEs will be collected by:

Spontaneous reports from the participant or participant’s family;

Elicited during the follow-up visits through open-ended questioning and examination;

Gathered through medical record reviews during the follow-up period.

Reviewing accuracy and completeness of all AEs and/or SAEs reports.

Complying with CSP policies for reporting AEs and/or SAEs.

Complying with local Research & Development Committee (R&DC) policies for reporting 
AEs and/or SAEs.

Complying with:
o
VA Central IRB (http://www.research.va.gov/vacentralirb/) requirements.
o
VHA Handbook 1058.01, Research Reporting Compliance Requirements
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o
VHA Handbook 1108.04, Investigational Drug and Supplies

Notifying VA Central and local R&DC of safety issues reported to the investigator by the 
CSP.

Managing and reporting AEs or SAEs, and responding when questions arise, in 
consultation with the Site Physician, Clinical Research Pharmacist, or Study Chair.
The study investigator will assess and record all AEs according to seriousness, expectedness, 
relatedness to study drug and action taken.
1.1.2 ADVERSE EVENT REPORTING 
The following non-serious adverse events will be collected and reported to the sponsor on study 
CRFs:

Treatment-related adverse events that are listed in Section 8.5.3.3 at any severity; and,

Adverse events that have a grade 3 severity, regardless of attribution; and,

SARS-CoV-2 related adverse events that are listed in Section 8.5.3.3 and have a grade 
3 severity, regardless of attribution.
These  adverse  events  will  be  collected  and  reported  on  study  CRFs  from  the  time  of 
randomization and until, becoming lost to follow-up, discontinuing study participation early, or 
completing the final study visit, whichever occurs first.
All unresolved AEs must be followed up, at least every 30 calendar days, until one of the 
following  outcome  categories  is  met:  resolved,  no  further  change  expected,  study 
discontinuation, or end of study participation with appropriate transfer of care. New information 
for unresolved AEs will be collected on the AE Follow-up CRF. If a patient receives care at a 
non-VA  facility  for  an  adverse  event  they  experience,  research  personnel  will  obtain  the 
requisite release of information form(s) from the patient and once received, acquire the pertinent 
medical records from the facility. 
1.1.3 SERIOUS ADVERSE EVENT REPORTING 
All SAEs will be collected and reported to the sponsor on study CRFs. SAEs will be collected 
and reported on study CRFs from the time of randomization, and until becoming lost to follow-
up, discontinuing study participation early, or completing the final study visit, whichever occurs 
first. All SAEs will also be recorded on the AE Tracking & Evaluation Record and documented in 
the electronic VA medical record. If a patient receives care at a non-VA facility for a SAE, 
research personnel will obtain the requisite release of information form(s) from the patient and 
acquire the pertinent medical records from the facility.
All unresolved SAEs must be followed up, at least every 30 calendar days, until either resolved, 
no further change is expected, or the participant has reached the end of the study participation 
with appropriate transfer of care. New information for unresolved SAEs will be collected on the 
SAE Follow-up CRF. 
A.       Site Expedited Reporting of Serious Adverse Events to the Sponsor
All SAEs will be reported by submission of the event on a CRF into the reporting system within 3 
calendar days of the Study Site Personnel becoming aware of the event. 
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B.       Site Reporting Requirements to the VA Central IRB 
Sites are additionally responsible for following the VA Central IRB policy in submitting safety 
data, unanticipated serious problems, and protocol deviations. The VA Central IRB’s most 
recent policy including a table of reporting requirements, instructions, and forms can be found at 
http://www.research.va.gov/vacentralirb/policies.cfm.
C.       Sponsor Reporting of Related and Unexpected Serious Adverse Events
All SAEs will be assessed by the study Sponsor to determine if an event is anticipated or 
unanticipated. SAEs found by the Sponsor to be both related to the investigational treatment 
and unexpected will be reported in accordance with requirements outlined in CSP SOP 3.6 and 
applicable FDA regulations. Any FDA reporting requirements will be handled by the sponsor, not 
by individual sites
D.       Sponsor Reporting of Adverse and Serious Adverse Events to the DMC
The Study Biostatisticians, with coordination from CSPCRPCC, will tabulate and summarize all 
AEs and all SAEs for the DMC on a schedule set by the DMC, but no less than every 6 months. 
The DMC will also determine when the committee should be unblinded to treatment assignment 
in reviewing AE/SAE data. The DMC will advise the CSR&D Director whether the study should 
continue or be stopped for safety reasons.
1.1.4 REPORTING EVENTS TO PARTICIPANTS 
If a safety event experienced by a participant during the trial’s conduct provides new safety 
information involving potential significant risk to current and future participants, participants will 
be notified of the safety event in compliance with CSP standard operating procedures.    
1.1.5 EVENTS OF SPECIAL INTEREST 
The following Events of Special Concern will be reported by the Safety Management Team in 
accordance  with  CSP  standard  operating  procedures:   suicide,  a  death  due  to  unusual 
circumstances, a  medical  error,  an  overdose  of  the  study  drug, or when  a  participant  is 
responsible for another person’s death, great bodily harm, or significant property damage.
1.1.6 REPORTING OF PREGNANCY 
As a strategy to mitigate risk to any pregnant or breastfeeding woman, participants who are 
pregnant or breastfeeding at time of randomization will be followed for any safety outcomes until 
the end of study participation. Appropriate transition of care will take place at the end of the 
study in the event any serious adverse events occurred. Sites will notify the Chair’s Office and 
the CSPCC and CSPCRPCC as soon as they become aware of any participant who becomes 
pregnant during the study, collection of safety data will continue until the end of participation.
1.2
UNANTICIPATED PROBLEMS
1.2.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP)
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The  Office  for  Human  Research  Protections  (OHRP)  considers  unanticipated  problems 
involving risks to participants or others to include, in general, any incident, experience, or 
outcome that meets all of the following criteria: 
•
Unexpected in terms of nature, severity, or frequency given (a) the research 
procedures that are described in the protocol-related documents, such as the IRB-
approved research protocol and informed consent document; and (b) the 
characteristics of the participant population being studied; 
•
Related or possibly related to participation in the research (“possibly related” means 
there is a reasonable possibility that the incident, experience, or outcome may have 
been caused by the procedures involved in the research); and 
•
Suggests that the research places participants or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized.
1.2.2  UNANTICIPATED PROBLEM REPORTING 
Serious Unanticipated Problems require prompt reporting. The Sponsor must be notified within 
72 hours of the site investigator becoming aware of the event. Sites will report Ups to the VA 
Central IRB in accordance with VA CIRB requirements and timeframes, as detailed on the VA 
CIRB website.
1.2.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS 
Participants will be informed of any important new information that may affect their safety or 
their willingness to participate.
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2
STATISTICAL CONSIDERATIONS 
2.1
STATISTICAL HYPOTHESES
The primary null hypothesis tests whether the proportion of death or respiratory failure by Day 
28 differs between the experimental arm (convalescent plasma) and the control arm (saline). 
The  key  secondary  null  hypothesis  tests  whether  time  to  recovery  differs  between  the 
experimental and control arms.
2.2
SAMPLE SIZE DETERMINATION
Primary endpoint
The Chi-square test will be used to compare treatment arms on the proportion of death from any 
cause or respiratory failure up to and including Day 28, with two-sided significance level = 0.05.
A meta-analysis of studies of SARS coronavirus infection and severe influenza reported that 
convalescent plasma led to an absolute reduction in the risk of mortality from 7% to 23% and a 
54% greater likelihood of discharge by day 2225. These data suggest that the treatment benefit 
of convalescent plasma in reducing the risk of death and respiratory failure may be substantial, 
particularly early in hospitalization. For this trial we conservatively assume a 10% absolute 
reduction (30% in the control group and 20% in the convalescent plasma group) given that this 
trial allows local standard of care in both arms, which may include effective medications for 
COVID-19.
Table 6. Required number of participants to have 80%, 85% or 90% power for the primary 
outcome, assuming no missing data. 
Proportion in 
the control 
group
Absolute 
reduction
Corresponding 
proportion in the 
plasma group
Number of participants needed
80% power
85% power
90% power
35%
11%
24%
532
610
712
10%
25%
652
746
874
9%
26%
858
976
1134
8%
27%
1042
1192
1396
30%
11%
19%
474
542
634
10%
20%
582
666
778
9%
21%
730
834
976
8%
22%
936
1072
1254
25%
11%
14%
400
458
536
10%
15%
496
566
662
9%
16%
624
714
836
8%
17%
806
922
1080
Table 6 provides the total number of participants needed for 80%, 85% or 90% power to detect 
a range of differences in the primary outcome, using the z-test with a two-sided significance 
level = 0.05 and assuming no missing data. A total of 666 participants are needed to have 85% 
power for a 10% absolute reduction when the proportion of death or respiratory failure is 30% in 
the control group (Table 6). This sample size has 76% power to detect a 9% absolute reduction 
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when the control rate is 30% and has 90% (81%) power to detect a 10% absolute reduction 
when the control rate is 25% (35%) (Table 7).  
Table 7. Power of a study of 666 participants to detect differences in the primary 
outcome, assuming no missing data. 
Proportion in 
the control 
group
Absolute 
reduction
Corresponding proportion 
in the convalescent 
plasma group
Power
35%
11%
24%
88%
10%
25%
81%
9%
26%
72%
8%
27%
61%
30%
11%
19%
91%
10%
20%
85%
9%
21%
76%
8%
22%
66%
25%
11%
14%
95%
10%
15%
90%
9%
16%
83%
8%
17%
72%
We do not plan to inflate the target number of events for the planned interim analysis described 
in Section 9.4.6 below. The planned early stopping boundaries are conservative and the impact 
on power is negligible: the power with 666 participants (with no missing data) is 84.0%. 
Assuming 5% of participants have missing data on primary outcome (such as due to lost of 
follow-up or early withdrawal from the study), we plan to randomize 702 (=702/0.95) 
participants.
Key secondary endpoint
The key secondary endpoint is time to recovery up to and including Day 28. Currently there is 
limited information about the anticipated effect size or the proportion of participants who will 
recover by Day 28. A preliminary review of data from ACCT-1 demonstrated a recovery rate 
ratio of 1.312.
Table 8 gives the power of the study for time to recovery in a study of sample size 702, for a 
range of treatment to control recovery rate ratio and proportion of recovery by day 28. If 
approximately 70% of study participants recover by Day 28, a study of 702 participants will have 
83% power to detect a recovery rate ratio of 1.3. 
Table 8. Power for time to recovery for a study of 702 participants
Recovery 
rate ratio
Overall proportion of recovery by day 28
80%
75%
70%
65%
1.20
58%
55%
52%
49%
1.25
75%
73%
70%
66%
1.30
87%
85%
83%
80%
1.35
94%
93%
91%
89%
1.40
98%
97%
96%
95%
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Number of sites and recruitment period
Based on CDW data, there were over 3000 Veterans admitted to VA Medical Centers for SARS-
CoV-2 infections in January-April 2020, and 40-50% of them had respiratory failure or death 
within 28 days of hospital admission. In March-May 2020, the top 25 VA Medical Centers had 
on average 29 (median = 24) hospital admissions per month. Conservatively, assuming each 
participating site can randomize on average 2 participants per month, the target sample size 
702 can be achieved by 15 months of recruitment at 25 sites. We estimate up to 2000 patients 
may be screened before enrollment and up to 1500 patients enrolled/consented in order to have 
702 randomizations. 
2.3
POPULATIONS FOR ANALYSES
The primary analysis will be based on an intention-to-treat population, including all participants 
randomized. The safety analysis will be based on a modified intent-to-treat population consisting 
of all participants who received at least one dose of any study intervention.
2.4
STATISTICAL ANALYSES
2.4.1 GENERAL APPROACH
This  is  a  double-blind  controlled  randomized  trial  testing  a  superiority  hypothesis  of 
convalescent  plasma  versus  saline  with  a  two-sided  type  I  error  rate  of  5%.  Secondary 
hypotheses  have  been  ordered according  to relative  importance,  with  one  key  secondary 
hypothesis highlighted. These will be described according to the appropriate summary statistics 
(e.g., proportions for categorical data, means with 95% confidence intervals for continuous data, 
median for time-to-event data).
A statistical analysis plan will be developed prior to unblinding of study and database lock. 
2.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S)
The primary efficacy analysis to compare the proportion of death or respiratory failure by Day 28 
will be done by the Chi-square test. Difference in the proportions and the 95% confidence 
interval will be presented. To account for randomization stratification factors, site and age (≥65 
vs <65 years old), we will use a logistic regression model with site and age as covariates, or as 
random effects in a generalized linear mixed effects model. We will also perform regression 
analyses  to  adjust  for  baseline  patient  characteristics  (including  age,  sex,  race,  Hispanic 
ethnicity, ABO blood type, BMI, hypertension, chronic lung, heart or kidney diseases, diabetes, 
immunosuppression). Odds ratios and 95% confidence intervals will be provided. 
Every attempt will be made to obtain outcome data for all participants. While we anticipate 
minimum loss of follow-up in this short follow-up study, small amounts of missing primary 
outcome data may occur. In such cases, subjects without the primary outcome data will be 
excluded from the primary analysis. Sensitivity analyses will evaluate the impact of making 
different assumptions about missing observations and use analysis methods such as multiple 
imputations. These analyses will be defined in the Statistical Analysis Plan.
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2.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S)
Key secondary endpoint, time to recovery:
The primary analysis for time to recovery by Day 28 is an unadjusted log-rank test. Deaths will 
be considered as never recovering and censored at Day 28.  Kaplan-Meier curves and 95% 
confidence bounds will be provided. If data permit, we may perform a stratified log-rank test 
where stratification is according to participating site and age (≥65 vs <65 years old), i.e. site and 
age are randomization stratification factors. We will also perform Cox regression to adjust for 
baseline patient characteristics (including age, sex, race, Hispanic ethnicity, BMI, hypertension, 
chronic lung, heart or kidney diseases, immunosuppression). Recovery rate ratio and 95% 
confidence interval will be provided.
Other secondary endpoints:
1) Binary data (e.g., 28-day mortality) will be summarized as a percent with 95% 
confidence intervals. Comparisons between arms will be presented as differences 
in proportions with 95% confidence intervals.
2) The ordinal scale of patient clinical status will be used to estimate a proportional 
odds  model.  The  hypothesis  test will  perform a  test to  evaluate  whether  the 
common odds ratio for treatment is equal to one. If data permit, a test stratified by 
site will also be performed. The distribution of severity results will be summarized 
by treatment arm as percentages. Efforts to minimize loss-to-follow-up will be 
considerable. However, small amounts of missing data may occur. In such cases, 
subjects without final outcome data will be excluded from the analysis. Sensitivity 
analyses will evaluate the impact of making different assumptions about missing 
observations. These analyses will be defined in the Statistical Analysis Plan.
3) Differences in time-to-event endpoints (e.g., time to respiratory failure or death 
and time to at least a one category improvement in the ordinal scale) by treatment 
will be summarized with log-rank tests, Kaplan-Meier curves and 95% confidence 
bounds. The same procedure will be used to compare time to at least a two-
category improvement. Hazard ratios (for time to respiratory failure or death) or 
improvement rate ratios (for time to improvement) and 95% confidence intervals 
will be provided.
4) Change in ordinal scale at specific time points will be summarized by proportions 
(e.g., proportion who have a 1-, 2-, 3-, or 4-point improvement or 1-, 2-, 3-, 4-
point worsening).
5) Duration  of  event  (e.g.,  duration  of  initial  hospitalization)  will  be  summarized 
according to median days with quartiles.
6) Categorical data (e.g., ordinal scale by day) may be summarized according to 
proportions by category and/or odds ratios with confidence intervals.
We recognize that allowing study participants to participate in another SARS-CoV-2 treatment 
trial after progressing to respiratory failure (Section 6.5) may affect the interpretation of the 
primary intent-to-treat analyses for secondary outcomes (e.g., time to recovery and all-cause 
mortality), especially if one arm has a higher proportion of respiratory failures, leading to a 
higher proportion in that arm receiving other SARS-CoV-2 treatments. We will take caution in 
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the interpretation of results. We will also conduct sensitivity analyses to assess robustness of 
results, such as incorporating other trial participation as a (time-varying) covariate in the model, 
imputation, or inverse probability weighting. 
2.4.4 SAFETY ANALYSES
AEs and SAEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), 
counted both at the patient level and event level.  Severity, frequency, and relationship of AEs 
and SAEs to study intervention will be presented by System Organ Class (SOC) and preferred 
term groupings. We will compare the proportions of participants experiencing an SAE, treatment 
related non-serious AEs,  SARS-CoV-2  related adverse events of grade 3 severity, or non-
serious adverse events of grade 3, by Chi-square test or Fisher’s exact test, as appropriate.
2.4.5 BASELINE DESCRIPTIVE STATISTICS
Baseline characteristics will be summarized by treatment arm. Continuous variables will be 
summarized by the mean and standard deviation. Categorical variables will be described by the 
proportion in each category (with the corresponding sample size numbers).
2.4.6 PLANNED INTERIM ANALYSES 
9.4.6.1 INTERIM SAFETY ANALYSIS
Summary of safety data (AEs and SAEs) by treatment group will be presented to DMC at the 
planned interim analyses and at least every 6 months, or at other frequencies if requested by 
the DMC.  AEs and SAEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA),  counted  both  at  the  patient  level  and  event  level.  Severity,  frequency,  and 
relationship of AEs and SAEs to study intervention will be presented by System Organ Class 
(SOC) and preferred term groupings. Safety monitoring will be ongoing (see Section 8.3).  The 
unblinded statistical team will prepare these reports for review by the DMC.
9.4.6.2 INTERIM EFFICACY AND FUTILITY ANALYSIS
We plan to conduct two interim efficacy analyses of the primary efficacy endpoint at 33% and 
67% of total information to allow early stopping of the study when there is sufficient evidence 
that the convalescent plasma group is superior. The ρ-family alpha spending function of ρ=2.5 
with a one-sided significance level 0.025 will be used as a guide for the DMC (non-binding). The 
type I error spent at the interim efficacy analysis will depend on the actual information time of 
the interim analysis according to the alpha spending function. If the study is not stopped at 
interim, the remaining type I error will be spent at the final analysis of the primary outcome. For 
example, if the two interim analyses occur at exactly 33% and 67% information time, the 
efficacy boundaries in the z-scale are -2.947 and -2.401, respectively, and the cumulative type I 
error spent at the two looks are 0.002 and 0.009, respectively; the remaining type I error 0.041 
will be allocated to the final analysis. 
Conditional power will be presented as an additional guide to the DMC for futility stopping (non-
binding). Conditional power is the probability of obtaining a statistically significant treatment 
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benefit of convalescent plasma at the end of the study given the data accumulated thus far and 
assuming a hypothesized treatment effect thereafter. If the conditional power is less than 10% 
under the original treatment effect assumption (30% vs. 20%), consideration should be given to 
stopping the trial. 
Table 9 gives the operating characteristics of the early stopping boundaries for a study of 666 
participants, assuming no missing data, the interim analyses are performed at 33% and 67% 
information  time (222  and  444  participants,  respectively),  and  true  proportion  of death  or 
respiratory failure is 30% in the control group. When the plasma group also has 30% death or 
respiratory failure (that is, no difference between the two groups), the study has 5.2% probability 
of crossing the futility boundary at the first interim analysis and 59% probability of crossing the 
futility boundary at the second interim analysis. When the plasma group has a 10% absolute 
reduction  as  compared  to  the  control  group  (that  is,  30%  vs.  20%),  the  study  has  11% 
probability of crossing the efficacy boundary at the first interim analysis and 41% probability of 
crossing the efficacy boundary at the second interim analysis. 
The  unblinded  statistical  team  will  prepare  these  closed  reports  for  DMC  review  and 
recommendations. Analyses will be presented with blinded codes for treatment arms to protect 
the possibility that the interim report may fall into the wrong hands. A DMC charter will further 
describe procedures and membership.   
Table 9. Operating characteristics of the early stopping boundaries for a study with 666 
participants, assuming the proportion of respiratory failure or death on or before day 28 
is 30% in the control group and there are no missing data on the primary outcome. Each 
result is based on 100,000 simulations.
True 
absolute 
reduction
Probability of crossing boundaries at 
the first interim analysis at 33% 
information time (222 patients)
Probability of crossing boundaries at 
the second interim analysis at 67% 
information time (444 patients)
Crossing efficacy 
boundary
Crossing futility 
boundary
Crossing efficacy 
boundary
Crossing futility 
boundary
-10%
<0.001
0.477
<0.001
0.518
-5%
<0.001
0.202
<0.001
0.730
0%
0.002
0.052
0.007
0.591
5%
0.017
0.007
0.098
0.203
8%
0.056
0.001
0.266
0.060
9%
0.081
0.001
0.339
0.036
10%
0.112
<0.001
0.411
0.019
11%
0.149
<0.001
0.477
0.010
12%
0.201
<0.001
0.521
0.004
9.4.6.3 ADMINISTRATIVE MONITORING
The DMC will also monitor study progress and conduct. This administrative monitoring will focus 
on participant intake (overall and within site), adequacy of randomization, adherence to study 
protocol (e.g., completeness of follow-up, study intervention adherence and withdrawals, study 
withdrawals, timely submission of data, timely resolution of data queries, randomization of non-
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eligible patients), baseline comparability of treatment groups, and other operational aspects of 
the study. 
2.4.7 SUB-GROUP ANALYSES
Subgroup  analyses  for the  primary outcome  will  evaluate  the  treatment effect  across  the 
following subgroups:
1) Received study product (plasma/saline) ≤7 days vs. >7 days after onset of symptoms
2) Have ≤2 vs. ≥3 comorbidities at baseline (age ≥65 years, underlying chronic lung, heart, 
kidney disease, hypertension, diabetes, obesity or immunosuppression)
3) Age <65 vs. ≥65
4) BMI <35 vs. ≥35
A forest plot will display point estimates and confidence intervals across subgroups. Interaction 
tests will be conducted to determine whether the treatment effect varies by subgroup. We may 
adjust for selected baseline covariates in the assessment of interactions. We anticipate that 
convalescent  plasma  has  a  larger  benefit  in  those  treated  early  (≤7  days  after  onset  of 
symptoms), having more comorbidities at baseline, or older (≥65 years old), and a smaller 
benefit
 
in
 
obese
 
individuals.
 
 
2.4.8 EXPLORATORY ANALYSES
We will explore if the treatment benefit of convalescent plasma differs by race (White vs. other 
races) and ethnicity (Hispanic vs. non-Hispanic), after adjusting for demographics (such as age, 
sex) and social economic status (such as highest attained educational level and income level) 
and if feasible, air-pollution data from geo-coding. We will also explore if the treatment benefit 
differs by ABO blood type.
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3
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
3.1
Regulatory, Ethical, and Study Oversight Considerations
3.1.1
INFORMED CONSENT PROCESS
3.1.1.1
CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS 
PROVIDED TO PARTICIPANTS
Consent forms describing in detail the study intervention, study procedures, and risks will be 
given to the participant. Written documentation of informed consent is required prior to starting 
intervention/administering study interventions.  
3.1.1.2
CONSENT PROCEDURES AND DOCUMENTATION
Informed consent is a process that is initiated prior to the prospective participant’s agreeing to 
participate in the study and continues throughout the potential participant’s study participation. 
The most current, CIRB-approved version of the consent form must be used.
The prospective participant will be informed of the rationale for the study, follow-up procedures 
that are required, and potential risks and benefits of participation. Prospective participants have 
the option of having family and/or anyone else they deem appropriate present during the 
informed consent process. The site personnel will verbally discuss the study and all elements of 
the informed consent document. The prospective participant and/or LAR will be informed that 
he/she may refuse to participate or withdraw from the study at any time without, in any way, 
jeopardizing his/her medical care or benefits in the VA system. 
The prospective participant or LAR will be given the informed consent form and encouraged to 
carefully read and review the document and ask any and all questions.  The site staff will 
address questions raised. The prospective participant is then given the opportunity to provide 
informed consent to participate in the study and to sign the Informed Consent Form.  If the 
patient is unable to provide informed consent and there is a LAR, investigators should obtain 
consent from the patient’s LAR. The Informed Consent Form can be signed on a hard copy or 
signed electronically via approved mechanisms.
If the prospective participant or LAR provides informed consent and signs the form, the original 
form is filed in the Subject Consent Forms Master File, a copy is sent to the Palo Alto CSPCC, a 
copy is filed per local site VA policy, and another copy is given to the patient or LAR. No 
research procedures may be performed prior to obtaining consent. In addition, each consented 
patient or LAR must sign a VA research HIPAA authorization (on a hard copy or electronically, if 
available).  
Although the consenting process can be done in the patient’s room, due to the nature of the 
risks of exposure to a COVID-19 patient, direct communication with the patient may not be 
feasible or safe. Accordingly, the informed consent may be provided by video or phone: 

Site personnel will obtain the patient’s phone number (e.g. bedside phone or cell phone), 
and arrange a three-way call or video conference with the patient or LAR, an impartial 
witness, and if desired and feasible, additional persons requested by the patient or LAR 
(e.g., next of kin). 
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
To ensure that patients are approached in a consistent fashion, a standard process 
should be used when contacting the patient remotely that will accomplish the following: 
o
Identification of who is on the call. 
o
Review of the ICF with the patient by the site personnel and response to any 
questions the patient may have,
o
Confirmation by the witness that the patient’s questions have been answered,
o
Confirmation by the site personnel that the patient is willing to participate in the 
trial and sign the informed consent document while the witness is listening on the 
phone, 
o
Verbal confirmation by the patient that they would like to participate in the trial 
and that they have signed and dated the informed consent document that is in 
their possession. 
If the patient/LAR signs a hard copy of the informed consent form, the signed informed  
consent document can be obtained by the following procedure and included in the study 
records:

Full copy of the Informed Consent is provided to patient and/or LAR during consent for 
review that they keep.

Signature page given to patient or LAR at the time of consent; the patient or LAR signs 
the consent using gloves and a pen that stay in the room.

Signature page placed in a plastic zip-lock bag that is wiped with purple top wipe before 
leaving room and then again outside of room after provided with fresh gloves.

Signature page can be scanned while in bag.

Signature page removed and added to full consent after 1 week.

Sites can also use UV if that is local procedure.
If a hard copy of signed informed consent document will not be able to be collected from  
the  patient’s  location and  included  in  the  study  records,  the  following  two  options  are 
acceptable to provide documentation that the patient signed the informed consent document: 
• Option #1: Attestations by the witness who participated in the call and by the site personnel 
that the participant or LAR confirmed that they agreed to participate in the study and signed the 
informed consent, 
Please note: It is recommended that the documented verbal confirmation include information 
on the version of the IRB-approved informed consent document that was used, such as IRB-
approval date and version. 
• Option #2: A photograph of the informed consent document with attestation by the person 
entering the photograph into the study record that states how that photograph was obtained and 
that it is a photograph of the informed consent signed by the patient or LAR.
A copy of the informed consent document signed by the site personnel and witness should 
include a notation by the site personnel of how the consent was obtained, e.g. telephone, 
photograph, e-consent. The note should document how it was confirmed that the patient signed 
the ICF (i.e., either using attestation by the witness and investigator, the photograph of the 
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signed consent, or e-consent). If applicable, the note should include a statement of why the ICF 
signed by the patient was not retained, e.g., due to contamination of the document by infectious 
material. 
Site personnel will send CSPCC the informed consent document signed by the participant or 
LAR or obtained via one of the two options described above via netapp share folder within 30 
days of consent.
Re-consent
Participants enrolled by their LAR must be consented for continued participation in study should 
they later become competent prior to day 29.  The data and samples collected prior to the point 
when the participant declines to continue participation can be used in the analysis.  
8.5.5   STUDY DISCONTINUATION AND CLOSURE
When a study is prematurely terminated, refer to Section 7, Study Intervention Discontinuation 
and Participant Discontinuation/Withdrawal, for handling of enrolled study participants.
This study may be suspended or prematurely terminated if there is sufficient reasonable cause. 
Written  notification,  documenting  the  reason  for  study  suspension  or  termination,  will  be 
provided by the suspending or terminating party to study participants, investigator, funding 
agency, and regulatory authorities.  If the study is prematurely terminated or suspended, the 
Study Chairs will promptly inform study participants, the VA CIRB, and sponsor and will provide 
the reason(s) for the termination or suspension.  Study participants will be contacted, as 
applicable, and be informed of changes to study visit schedule.
Circumstances that may warrant termination or suspension include, but are not limited to:

Determination of unexpected, significant, or unacceptable risk to participants;

Demonstration of efficacy that would warrant stopping;

Insufficient compliance to protocol requirements;

Data that are not sufficiently complete and/or evaluable.
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor and CIRB.
3.1.2  CONFIDENTIALITY AND PRIVACY 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their  staff,  and  the  sponsor  and  their  interventions.  Therefore,  the  study  protocol, 
documentation, data, and all other information generated will be held in strict confidence. No 
information concerning the study, or the data will be released to any unauthorized third party 
without prior written approval of the sponsor. 
All research activities will be conducted in as private a setting as possible.
The study monitor, other authorized representatives of the sponsor, representatives of the 
CIRB,  regulatory  agencies  or  the  Cooperative  Studies  Program  Research  Pharmacy 
Coordinating  Center  (CSPRPCC)  may  inspect  all  documents  and  records  required  to  be 
maintained by the investigator, including but not limited to, medical records (office, clinic, or 
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hospital) and pharmacy records for the participants in this study. The clinical study site will 
permit access to such records.
The study participant’s contact information will be securely stored at each clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure 
location for as long a period as dictated by the reviewing IRB, Institutional policies, or sponsor 
requirements.
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be transmitted to and stored at the Palo Alto Cooperative Studies Program 
Coordinating  Center (CSPCC).  This will  not include  the participant’s  contact or identifying 
information. Rather, individual participants and their research data will be identified by a unique 
study identification number. The study data entry and study management systems used by 
clinical sites and by CSPCC research staff will be secured and password protected. At the end 
of the study, all study databases will be de-identified and archived at the Palo Alto CSPCC.
3.1.3
FUTURE USE OF STORED SPECIMENS AND DATA 
See also Section 10.1.3, Confidentiality and Privacy and Section 10.1.11, Data Handling and 
Record Keeping, for further information on future use of study records.
Data collected for this study will be analyzed and stored at the Palo Alto Cooperative Studies 
Program Coordinating Center (CSPCC). After the study is completed, the de-identified, archived 
data will continue to be stored at the Palo Alto CSPCC, accessible for use by researchers 
including those outside of the study with an approved Data Use Agreement. The biospecimens 
collected in the study for current and future research will be kept at the Cooperative Studies 
Program Albuquerque Central Biorepository in Albuquerque, NM unless otherwise specified. All 
stored specimens and data used for current and future experimental analysis, both clinical and 
laboratory, by laboratories and investigators within and outside the VA system will be linked to 
study identification number with no direct subject identifiers or PII/PHI. Thus, all subject data will 
be deidentified and anonymized with demographic but no specific HIPAA-designated variables. 
The  biospecimens  will  be  accessible  for  future  research  with  an  approved  Sample  Use 
Agreement. The VA CIRB will oversee the biorepository for this study. All samples will be 
destroyed by standard practice within 20 years of study completion. Sample destruction will be 
validated according to the Standard Operating Procedures of the VA Biorepository.
3.1.4
KEY ROLES AND STUDY GOVERNANCE
Position
Name and E-Mail 
Address
Mailing Address
Phone Number
Study Chairs
Edward N. Janoff, MD
Edward.Janoff@va.gov 
RMR VA Medical Center
1700 N. Wheeling St; 111L
Aurora, CO 80045-7211
Cell: 303-437-
6400
VA: 720-723-
6255
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Position
Name and E-Mail 
Address
Mailing Address
Phone Number
Sheldon T. Brown, MD
Sheldon.brown@va.gov
James J Peters VA Medical 
Center
130 W. Kingsbridge Rd (SUB-
J)
Bronx, NY 10468
Off: 718-584-
9000, Ext. 6666
Cell: 917-842-
6989
National Study 
Coordinator
Ashlea Mayberry, BN
Ashlea.Mayberry@va.gov
Rocky Mountain Regional 
VAMC
1700 N Wheeling, A3-317A
Aurora, CO 80045
Office: 720 857 
5141
Cell: 720 545 
8968
Study 
Biostatisticians
Mei-Chiung Shih, PhD
Mei-Chiung.Shih@va.gov
VA Cooperative Studies 
Program Coordinating Center
701-B N. Shoreline Blvd
Mountain View, CA 94043
(650) 493-5000
Ext. 22367 (Dial 
1, then 2 for 
Menlo Park)
Ilana Belitskaya-Levy, 
PhD
Ilana.Belitskaya-
Levy@va.gov    
VA Cooperative Studies 
Program Coordinating Center
701-B N. Shoreline Blvd
Mountain View, CA 94043
(650) 493-5000
Ext. 21009 (Dial 
1, then 2 for 
Menlo Park)
Study Project 
Manager
Lisa Zehm, MS
Lisa.Zehm@va.gov
VA Cooperative Studies 
Program Coordinating Center
701-B N. Shoreline Blvd
Mountain View, CA 94043
(650) 493-5000
Ext. 28805 (Dial 
1, then 2 for 
Menlo Park)
Study 
Pharmacists
Alexa Goldberg, 
PharmD
Alexa.Argyres@va.gov 
Department of Veterans 
Affairs
Cooperative Studies Program
Clinical Research Pharmacy 
Coordinating Center
2401 Centre Ave SE
Albuquerque, NM 87106
(505) 248-3203
Ext. 6318
Elliott Miller, PharmD, MS
Elliott.Miller@va.gov 
Department of Veterans 
Affairs
Cooperative Studies Program
Clinical Research Pharmacy 
Coordinating Center
2401 Centre Ave SE
Albuquerque, NM 87106
(505) 248-3203
Ext. 6327
The organizational and administrative/monitoring structure of this study will include the following 
components: 
      Administrative/Study Management 

Clinical Science Research and Development (CSR&D)  

Cooperative Studies Program Coordinating Center (CSPCC)  

Study Chairs’ Office  

CSP Clinical Research Pharmacy Coordinating Center (CSPCRPCC) 
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
Participating VA Medical Centers 

Executive Committee
Monitoring

Data Monitoring Committee (DMC)  

VA Central IRB (CIRB)

CSP Site Monitoring, Auditing and Resource Team (SMART)
Clinical Science Research and Development establishes overall policies and procedures that 
apply to this master protocol through the study Chairs’ Office and the CSPCC.
The  Palo  Alto CSPCC  and  the Study Chairs’ Office jointly  will perform the day-to-day 
scientific and administrative coordination of the study. These include maintaining the study 
protocol and case report forms; ensuring the appropriate support for the participating centers; 
scheduling meetings and conference calls; answering questions about the protocol; conducting 
site visits; and publishing newsletters. The Palo Alto CSPCC will also prepare interim and final 
progress reports, conduct quality assurance activities, and archive study data at the end of the 
study. 
The CSP Clinical Research Pharmacy Coordinating Center (CSPCRPCC) will manage the 
patient safety monitoring of this study. CSPCRPCC is responsible for monitoring and reporting 
the safety of trial participants through the review, assessment, and communication of serious 
adverse  events  reported  by  study personnel.  Reviewing  responsibilities  will  occur through 
ongoing communication with the Study Chairs, Executive Committee, the Palo Alto CSPCC, and 
CSP Central Office.  In conjunction with the Palo Alto CSPCC, the CSPCRPCC trends and 
analyzes safety data to prepare reports for various committees including the Data Monitoring 
Committee (DMC), VA IRB of record, Study Executive Committee(s), and Safety and Evidence 
Efficiency Meetings (SEEM).
Each participating VA medical center will have a local site investigator (LSI) to be responsible 
administratively  and  scientifically  for  the  conduct  of  the  study  at  the  center. LSIs will  be 
expected to attend all SEEM meetings (via in-person or online meeting/conference call), as well 
as to hire and supervise personnel. Consistent with guidance from CSR&D, the LSI should be 
given adequate protected time to fulfill the responsibilities of that role (typically 1/8 to 2/8 time). 
Prior to participation, each site’s local R&D and the VA CIRB must also review and approve the 
site’s involvement in the study. The Research and Development Committee (R&D) and the VA 
CIRB may require the participating investigator to submit annual reports concerning the status 
of the study at the medical center for local monitoring purposes. 
The Executive Committee is the management and decision-making body for the operational 
aspects  of  the  study,  including  protocol  amendments,  and  will  be  concerned  with  overall 
management of the study. It will be headed by the Study Chairs and will consist of the study 
biostatistician,  clinical  research  pharmacist,  selected  participating  LSIs,  Palo  Alto  CSPCC 
Director and outside consultants as needed. This committee will meet regularly to review 
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blinded data (not broken down by treatment group), decide upon changes in the study, evaluate 
the  performance  of  the  participating  medical  centers,  evaluate  sub-  study  proposals,  and 
discuss publication of the study results. Approval must be obtained from this Committee before 
any study data may be used for presentation or publication.
The Data Monitoring Committee (DMC) will provide independent and unbiased review of the 
study’s ongoing progress and will monitor patient intake, outcomes, adverse events, and other 
issues related to patient safety. The DMC will consist of experts in the study’s subject matter 
field(s), clinical trials, biostatistics, and ethics. These experts will not be participants in the study 
and will not have participated in the planning of the study. The DMC will meet at the planned 
interim analyses and at least every 6 months or at other frequencies specified by the DMC. The 
DMC will consider safety or other circumstances as grounds for early termination, including 
either compelling internal or external evidence of treatment differences or the unfeasibility of 
addressing the study hypothesis (e.g., poor patient intake, poor adherence to the protocol). The 
DMC makes recommendations to the Director of CSR&D about whether the study should 
continue or be stopped. A DMC Charter will be developed to provide more details on DMC 
responsibilities and monitoring methods.
VA Central IRB  will periodically review the study. In addition, any changes to the informed 
consent form or protocol will be reviewed by the VA Central IRB and must be approved prior to 
implementation. 
The CSP Site Monitoring, Auditing and Resource Team (SMART), located at the CSP 
Clinical Research Pharmacy Coordinating Center (CSPCRPCC) in Albuquerque, serves as the 
Quality Assurance arm of CSP and will monitor the trial for compliance with Good Clinical 
Practices. The SMART team will provide study personnel with 1) a GCP overview at the kickoff 
meeting, 2) an in-depth GCP online course through the VA learning management system, 3) 
GCP tools and resources to enhance compliance and to assist study personnel in organizing 
study files and 4) will be available throughout the trial to advise and assist LSIs regarding GCP 
issues.  SMART will monitor the trial in accordance with the Integrated or risk-based Monitoring 
Plan  as  described  in  Section  10.1.7.   SMART  will  also  conduct  periodic  routine  audits 
throughout the course of the study.  In addition, for-cause audits of a participating site may be 
conducted if requested through Palo Alto CSPCC Director or by VA CSR&D Central Office.
3.1.5   SAFETY OVERSIGHT
Safety oversight will be under the direction of a DMC composed of individuals with appropriate 
expertise and the study-specific Safety Management Team lead by the Study CRP. The DMC 
will meet at the planned interim analyses and at least every 6 months to assess safety and 
efficacy data on each arm of the study. The DMC will operate under the rules of an approved 
charter that will be written and reviewed at the organizational meeting of the DMC. At that time, 
each data element that the DMC needs to assess will be clearly defined. The DMC will provide 
its recommendations to the study sponsor (CSR&D). SMART will monitor all clinical sites and 
provide  its  findings  to  the  study  sponsor  (CSR&D)  through  the  CSPCC.  The  Safety 
Management Team will assess all reported protocol-defined serious adverse events in real-time.
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3.1.6
CLINICAL MONITORING
This trial will be conducted in compliance with the currently approved protocol, with International 
Conference on Harmonization Good Clinical Practice (ICH GCP), and with applicable regulatory 
requirement(s). The intent of these regulations is to safeguard participants’ welfare and ensure 
the validity of data resulting from the clinical research. The VA Cooperative Studies Program’s 
Site Monitoring Auditing and Resource Team (SMART) based in Albuquerque, NM will monitor 
and assist LSIs in complying with the above GCP requirements. 
Monitoring 
Study site monitoring will be a collaboration of onsite site visits conducted by SMART Clinical 
Research Monitors; remote (off-site) monitoring performed by SMART and CSPCC Quality 
Assurance  RNs;  and  centralized  statistical  monitoring.   These  visits  and  activities  will  be 
conducted according to the study’s risk-based monitoring plan that will include ongoing periodic 
review of selected site performance indicator(s) as derived from the data submitted by the site, 
findings identified during onsite or remote visits, and interaction with the study site personnel. 
All monitoring feedback will be reviewed periodically by the sponsor. The monitoring plan will be 
assessed for adequacy and effectiveness at least annually and be revised as necessary to 
reflect the protocol specific risks that are identified. 
In addition, the Executive Committee (EC), Data Monitoring Committee (DMC), the Human 
Rights Committee (HRC) at the Palo Alto CSPCC, and the Study Group will help to monitor 
individual and aggregate information for the trial.  To assist sites SMART will provide GCP 
orientation  at the study  organizational  meeting,  or via  computerized  educational  modules. 
SMART will also provide training, manuals and materials to assist study personnel in organizing 
study files and will be available throughout the trial to advise and assist LSIs regarding GCP 
issues. 
Audits 
SMART audit program is separate and distinct from the SMART monitoring program.  Two types 
of audits may occur.  The first type is routine audits.  This audit involves independent site visits 
and are performed at one or more sites after the first year as determined by SMART. The 
second type is for-cause audits.  This audit type is independent of a site as requested by study 
leadership or CSP Central Office. 
Note: Audits may be scheduled or unannounced. 
3.1.7  STUDY MONITORING
By agreeing to participate in the study, the participating medical centers delegate responsibility 
for global monitoring of the ongoing study to the  Clinical Science Research & Development 
(CSR&D) Service, staff at the study site, Palo Alto CSPCC, SMART study monitors, and CSP 
Clinical Research Pharmacy Coordinating Center (CSPCRPCC). However, the local Research 
and Development (R&D) Committee may require the participating local site investigator to 
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submit annual and final progress reports concerning the status of the study at the medical 
center for local monitoring purposes.
Monitoring Performance of Participating Sites
During the study, it may be necessary to drop one or more participating medical centers from 
the study. Such action must have the prior approval of the CSPCC Director and the Director of 
VA Clinical Science Research & Development (CSR&D) Service. Early termination is usually 
based on recommendations from the Executive Committee and the DMC and most often 
reflects inadequate participant intake or serious noncompliance with GCP. This action should 
always  be based on the best interests of the study and study participants and does not 
necessarily imply poor performance on the part of the LSI or the medical center. Termination of 
participating sites will be conducted per CSP guidelines. 
Enrollment Issues
The Study Chairs and the Study Biostatistician will monitor the intake rate and operational 
aspects of the study. Participating medical centers will continue in the study only if adequate 
participant intake is maintained. If recruitment is not proceeding at an appropriate rate, the 
Study Chairs and Study Biostatistician will scrutinize the reasons for participant exclusions and 
other barriers to recruitment.  Based on this information, the Executive Committee may choose 
to  drop  under-performing  sites,  add  additional  sites,  make  modifications  to  the 
inclusion/exclusion criteria, or extend the recruitment period, with the approval/concurrence from 
the DMC, CSPCC Director, and the Director, CSR&D. Participating sites that enroll below target 
may be placed on probation and given an opportunity to improve within a reasonable period 
(e.g. 3 months). If a medical center is placed on probation, the Study Chairs will confer with the 
site personnel and may visit the site, if necessary, to help improve the rate of recruitment. If 
there is no improvement in accrual during the probation period, the site may be subject to 
reduced funding or possible termination as a study site. To prevent the delay in adding new 
sites and to accommodate potential modification of target sample size accordingly to primary 
outcome event rate, we plan to start the study with 25 recruiting sites, which is about 5 more 
than needed from the sample size requirement of 36 participants per year per site.  The 
Executive  Committee  will  take  actions  leading  to  discontinuation  of  a  site  only  with  the 
concurrence of the CSPCC Director. If a site is terminated from the trial, resources will be 
reallocated to other medical centers or used to start up a back-up site.  Central IRB will be 
informed of all site terminations and probations.
Non-adherence to the protocol and/or Good Clinical Practice (GCP) Guidelines
Strict adherence to the protocol and GCP guidelines will be expected of every participating 
medical center and monitored by the DMC, the Executive Committee, and the Study Group. 
Documentation of protocol violations will be required.  Protocol violations must be reported to 
the CSPCC on the appropriate case report form and to the Central IRB to ensure immediate 
hazard to the participant did not occur. Medical centers with repeated protocol violations or 
repeated failures to follow GCP Guidelines will be recommended for termination to the DMC, the 
CSPCC Director, and the Director of CSR&D. If a participating investigator feels that adherence 
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to the protocol may result in an apparent immediate hazard to the participant, the interest of the 
participant must take precedence.
By agreeing to participate in the study, the medical center delegates responsibility for global 
monitoring of the ongoing study to the Cooperative Studies Program and the Study Committees 
listed above. However, the Research and Development (R&D) Committee and the VA Central 
IRB may require the participating investigator to submit annual and final progress reports 
concerning the status of the study at the medical center for local monitoring purposes.
Study/Site Termination and Close-out Plan 
The VA CSR&D, as the sponsor of this study, may stop the trial at any time based on funding 
issues or internal or external evidence that the study is no longer feasible or unethical to 
continue. The Data Monitoring Committee (DMC) may recommend to the sponsor that the trial 
or treatment arms be terminated based on their review of study data for safety, efficacy, futility, 
study integrity or other reasons. Criteria and procedures for placing a site on probation or 
terminating a site from participation will be developed. If a site or the entire trial is terminated, 
participating sites will be notified and given a closeout plan and schedule at that time. 
3.1.8
TRAINING AND SUPERVISION
Training for Local Site investigators, Site Coordinators and Research Assistants 
Training for the LSIs and SCs will occur at the time of a kickoff meeting and at scheduled 
conference calls during the start-up period and throughout the study period. Before recruitment 
starts there will be a kickoff meeting. The attendees will include: Study Chairs, National Study 
Coordinator, CSPCC staff, PCC staff, SMART staff, LSIs, Site Coordinators and other study 
personnel. The main goals of the meeting include:
1.
Review the structure and objectives of the protocol
2.
Review eligibility, recruitment and enrollment strategies
3.
Review the rationale and implementation of the procedures and treatments
4.
Review assessments and reimbursement
5.
Review data management, good clinical practices and adverse event reporting
In case key staff members are not available for this kickoff meeting, a second videoconference 
meeting will be scheduled at which time the key elements of the kickoff will be presented.
Regular conference calls with LSIs and Site Coordinators will be held to review study progress, 
address emergent problems, disseminate changes to study procedures and case report forms, 
and  share  best  practices  and  lessons  learned.  Significant  publications  affecting  the 
understanding of COVID-19 or the study treatments will also be reviewed. 
3.1.9 QUALITY ASSURANCE AND QUALITY CONTROL
Quality control checks and study monitoring will enable the Palo Alto CSPCC to examine the 
database and the clinical sites to ensure data have not been improperly used or accessed. Audit 
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trails and access logs compliant with 21 CFR Part 11 will be checked routinely, and study 
monitors  will  provide  continuing  education  on  GCP  and  check  clinical  site  operations  for 
violations of data security policies and best practices.
Standardization/Validation of Measurements
Details  about  quality  control  for  assessment  procedures  are  provided  in  Section  5.5.3 
(Procedures to Enhance Completion of Assessment Protocols).
Treatment
Details about quality control for treatment are provided in Section 6.
Blinding
This  is  a  double-blinded  placebo-controlled  study.  Details  about  blinding  procedures  are 
provided in Section 6.3.2.
 
3.1.10 DATA HANDLING AND RECORD KEEPING 
3.1.10.1
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES 
Data Management
The Palo Alto CSPCC will be responsible for the management and quality control of the study 
data. After the study is approved, data forms will be finalized, and field tested. An Operations 
Manual with the instructions for data forms will be provided to the LSIs, Site Coordinators and 
Central RAs to guide the operation and management of the study. A training session at the 
kickoff meeting is planned prior to the initiation of participant enrollment for all study personnel 
to assure uniformity in participant management and data collection procedures, and to train all 
study personnel in study procedures. Training will also be held at subsequent annual Safety and 
Efficiency  Enhancement  Meetings  (SEEMs)  and  on  an  as-needed  basis  for  new  study 
personnel. Site Coordinators and Central RAs will complete data forms promptly and transmit 
them to the Palo Alto CSPCC. Other personnel may also be involved in data submission, such 
as LSIs. For the purposes of this section, anyone completing and submitting study data will be 
considered an end user. If any paper forms are used, the original copies will be kept in the LSI’s 
study files. 
DataFax, by DF/Net Research, is the planned clinical data management system (CDMS). Palo 
Alto CSPCC currently uses DataFax Version 2016 that encrypts data at rest using FIPS 140-2 
compliant encryption.  It allows for both paper data collection and electronic data capture (EDC). 
The authorized study personnel will log into DataFax to enter and submit study data directly on 
electronic case report forms (CRFs), rather than completing and sending a paper CRF. The use 
of paper CRFs may be reserved as a backup process.
Data management staff at the Palo Alto CSPCC will review data completeness and consistency 
and add data queries to items that fail these checks. Most data queries will be triggered in real 
time as study personnel are submitting data. Queries triggered after data submission can be 
accessed through listings available within the system. Data management staff will work with the 
authorized  study  personnel  to  help  resolve  queries.  Queries  will  be  resolved  when  the 
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appropriate corrections to the CRF are made and data resubmitted, or when an explanation is 
provided to allow data management staff to resolve the query. Corrections and changes to the 
data will be reviewed by data management staff. Palo Alto CSPCC may generate and distribute 
targeted data edit reports, as needed.
The  Study  Chairs,  LSIs,  Site  Coordinators,  and  Central RAs  will  receive  periodic  reports 
regarding the quality and quantity of data submitted to the Palo Alto CSPCC. Other quality 
control measures include periodic reports containing participant recruitment information and 
relevant medical data for review by the Study Chairs. The Palo Alto CSPCC will also prepare 
summary  reports  for  the  Study  Chairs,  the  Executive  Committee,  the  Data  Monitoring 
Committee, and other monitoring groups to track study progress, quality of study conduct and 
study data, and adverse events.
Study reports will be generated using the CDMS, Statistical Analysis System (SAS) and other 
tools (e.g., Microsoft Excel and Access). SAS and other statistical software packages will be 
used to conduct the statistical analysis for the study. The Palo Alto CSPCC is using SAS 
Version 9.4 and will upgrade to newer versions once they are purchased and validated. 
Data Security
The CDMS is fully compliant with US Federal regulations regarding electronic data capture 
systems established by the Food and Drug Administration (FDA) under 21 Code of Federal 
Regulations (CFR) 11. Data entered directly into the database provides the official clinical 
record for data collection. Source documentation is handled in the same manner as a paper-
based system. The CDMS is installed on VA servers, which will house the resulting study 
databases, and are located behind the VA network firewall. Authorized study personnel will use 
a two-step login process to access the CDMS. They will first need to log into the VA network 
with their VA credentials and then into the CDMS using a separate login process.  The system 
will be monitored to ensure that all applicable VA regulations and directives are strictly followed. 
Access to the study data is restricted by the Palo Alto CSPCC to properly credentialed research 
staff who have completed required VA security trainings. Only CSP-approved individuals (such 
as staff at the study site, Palo Alto CSPCC, SMART study monitors, and CSP Clinical Research 
Pharmacy  Coordinating  Center  (CSPCRPCC)  will  have  access  to  the  protected  health 
information (PHI) of study participants.
Research data will only be stored on secure VA servers behind the VA firewall. The data will be 
coded with a unique study identifier for each participant and stored using that study identifier. 
Identifiable information, such as the participant’s name, contact information and SSN, will be 
collected for participant tracking and safety purposes. This identifiable information will be either 
encrypted or stored separately from the clinical data. Access to the crosswalk file linking the 
participant’s identifiers and their study data will be restricted to the clinical site, staff at the Palo 
Alto CSPCC, and study monitors, pharmacists, and staff at the CSPCRPCC.  
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In case of improper use or disclosure of study data, the facility’s Information Security Officer 
(ISO), Privacy Officer, and the individual’s direct supervisor must be notified immediately per VA 
Directive and Handbook 6500. Records will be maintained and destroyed per the VHA Records 
Control Schedule (RCS 10-1). 
Quality control checks and study monitoring will enable the Palo Alto CSPCC to examine the 
database and the clinical sites to ensure data have not been improperly used or accessed. Audit 
trails and access logs compliant with 21 CFR Part 11 will be checked routinely, and study 
monitors  will  provide  continuing  education  on  GCP  and  check  clinical  site  operations  for 
violations of data security policies and best practices.
Data Access
Upon final analyses of the stated objectives in this proposal, the study plans to submit results for 
publication  in  scientific  peer-reviewed  journals  and  provide  summary  results  on 
ClinicalTrials.gov. After acceptance of the primary and other stated analyses by a journal, CSP 
will make these publication(s) available via the National Library of Medicine’s PubMed Central 
within a year of the date of publication.
Digital data underlying primary scientific publications from this study will be held as part of a 
data sharing resource maintained by the CSP. Study data held for this purpose may include 
data, data content, format, and organization. The data may be available to the public and other 
VA and non-VA researchers under certain conditions and consistent with the informed consent 
and CSP policy which prioritize protecting participant privacy and confidentiality to the extent 
possible.  A  detailed  plan  for  data  sharing  will  be  developed  in  accordance  with  current 
technology, infrastructure, best practices, and policies and procedures in place at the time of 
oversight committee reviews (e.g., Privacy Board, IRB, Information Security, and IT standards). 
The plan will include how data will be discovered, retrieved, analyzed, and managed and will 
note the materials that are available in machine readable formats.  This plan may be revised to 
ensure  consistency  with  VA,  including  CSP,  policies  and  standards  for  overall  data 
management and sharing.
3.1.10.2
STUDY RECORDS RETENTION 
Research data must be stored for a minimum of 6 years after the end of the study. Records will 
be destroyed in accordance with the VHA Record Control Schedule. Never destroy or discard 
records without prior authorization from Palo Alto CSPCC. The CSPCC will ensure that all study 
related files, including electronic files, are archived and maintained appropriately. Study records 
must also be available for FDA inspection for a minimum of 2 years following study completion.
3.1.11 PROTOCOL DEVIATIONS 
A  protocol  deviation  is  any  noncompliance  with  the  clinical  trial  protocol,  International 
Conference on Harmonization Good Clinical Practice (ICH GCP), federal regulations and/or 
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VHA research requirements. The noncompliance may be either on the part of the participant, 
the investigator, or the study site staff. Because of deviations, corrective actions are to be 
developed by the site and implemented promptly. 
Strict adherence to the protocol and GCP guidelines, regulatory and VA requirements will be 
expected of every participating medical center and monitored by the Study Group, the Executive 
Committee,  and  the  DMC.  Medical  centers  with  repeated  protocol  deviations  might  be 
recommended for termination to the DMC, the CSPCC Director, and the Director of VA CSP. If 
a participating investigator feels that adherence to the protocol may result in an apparent 
immediate hazard to the participant, the interest of the participant must take precedence.
It is the responsibility of the site investigator to use continuous vigilance to identify and report 
deviations within 5 working days of identification of the protocol deviation. Study personnel can 
only knowingly deviate from the protocol in an apparent hazard to the participant. All other 
planned  deviations  require  sponsor  and  CIRB  approval  before  the  deviation  can  be 
implemented. All deviations must be addressed in study source documents and reported to the 
Palo Alto CSPCC.  Protocol deviations must be sent to the VA CIRB per their policies. The site 
investigator is responsible for knowing and adhering to the CIRB requirements.
3.1.12 PUBLICATION AND DATA SHARING POLICY
Publication Policy 
All presentations and publications from this study will be done in accordance with the CSP 
policy as stated in the CSP Guidelines. The presentation or publication of any data collected by 
participating investigators on patients who enter the VA cooperative study is under the control of 
the  study’s  Executive  Committee.  This  is  true  whether  the  publication  or  presentation  is 
concerned with the results of the principal undertaking or is associated with the study in some 
other  way.  No  individual  participating  investigator  is  permitted  to  perform  analyses  or 
interpretations or to make public presentations or seek publication of any of the data other than 
under the auspices and approval of the Executive Committee. It is the policy of the CSP that 
outcome data will not be revealed to the participating investigators and Study Chairs until the 
data collection phase of the study is completed. This policy safeguards against possible biases 
affecting the data collection.
The Executive Committee has the authority to establish one or more publication committees, 
usually made up of subgroups of participating investigators and some members of the Executive 
Committee, to produce presentations and manuscripts for publication. All presentations and 
publications will be circulated to all participating investigators for their review, comments, and 
suggestions, at least four weeks prior to submission of the manuscript to the presenting or 
publication body.
Authorship should include the Study Chairs, the National Study Coordinator, members of the 
Executive  Committee, and Participating  Investigators from top recruiting centers and must 
adhere to the Uniform Requirements for Manuscripts Submitted to Biomedical Journals of the 
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International  Committee  of  Medical  Journal  Editors  (as  defined  by  ICMJE  standard).  The 
number of authors will not exceed individual journal limitations. All publications must give proper 
recognition  to the study’s  funding  source. If an investigator’s  major salary  support and/or 
commitment are from the VA, the investigator must list the VA as his/her primary institutional 
affiliation. Submission of manuscripts or abstracts must follow the applicable VA and VA CSP 
policies. Ideally, a subtitle is used stating, “A VA Cooperative Study.”  A copy of the letter to the 
editor and the manuscript/abstract submitted for publication/presentation should be sent to the 
CSP Director, and for information purposes, to the members of the study’s DMC. The CSP also 
requires that a copy of every manuscript must be reviewed and approved by the CSPCC 
Director prior to submission as a last quality control step.
Planned Publications (partial list):
1.
A paper describing the use of the adaptive design to test multiple treatments. 
2.
A paper describing the study methodology useful for the evaluation of emerging 
COVID-19 treatments.
3.
A paper describing the results for the primary outcome and principal secondary 
outcome measures focused primarily on treatment efficacy and safety.
4.
A paper describing the antibody response and neutralization in plasma over time 
and in relation to outcome.
5.
A paper describing correlates of protection, clinical, laboratory, plasma variables
Public Access to Scientific Publications and Research Data 
All scientific publications reporting the results of this study will be made publicly available. Final 
research data from this study will be made publicly available per VA policy under mechanisms 
that  ensure  that  (i)  the  release  of  such  data  is  compliant  with  all  Federal  statutes  and 
regulations, and (ii) the privacy of individual participants is assured.
3.1.13 CONFLICT OF INTEREST POLICY
The duties and responsibilities of the Study Chairs and local site investigators, including sub-
investigators, require a Research Financial Conflict of Interest Statement to be filed to avoid 
involvement in a real or perceived conflict of interest. Federal employees are prohibited from 
participating personally and substantially in official VA matters affecting their own financial 
interest or those imputed to them. In addition, in research a real or perceived conflict of interest 
occurs when any financial arrangement, situation or action affects or is perceived to exert 
inappropriate influence on the design, review, conduct, results, or reporting of research activities 
or findings. This Statement is to assist employees to avoid a conflict between their official duties 
and private financial interests or affiliations.
3.2
ABBREVIATIONS 
ACOS
Associate Chief of Staff
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ACP
American College of Physicians
ACR
American College of Rheumatology
ADCC
Antibody-Dependent Cellular Cytotoxicity
ADCP
Antibody-Dependent Cellular Phagocytosis
ADL
Activities of Daily Life
AE
Adverse event
AHRQ
Agency for Healthcare Research and Quality
ALT
Alanine aminotransferase
ARDS
Acute respiratory distress syndrome
AST
Aspartate aminotransferase 
BP
Blood pressure
BRDP
Biostatistical Research Data Processing
CDC
Centers for Disease Control
CDMS
Clinical data management system
CDW
Corporate Data Warehouse
CFR
Code of Federal Regulations
CIRB
VA Central IRB
COVID-19
Infectious disease caused by SARS-coronavirus 2
CPAP
Continuous Positive Airway Pressure
CPRS
Computerized Patient Record System
CPT
Current Procedural Terminology
CRF
Case report form
CSP
Cooperative Studies Program
CSPCC
Cooperative Studies Program Coordinating Center
CSR&D
Cooperative Studies Program Central Office
CSPCRPCC Cooperative Studies Program Clinical Research Pharmacy Coordinating Center
CSR&D
Clinical Science Research & Development
CSSEC
Cooperative Studies Scientific Evaluation Committee
DoD
Department of Defense
DMC
Data Monitoring Committee
ECMO
Extracorporeal Membrane Oxygenation
EDC
Electronic data capture
eGFR
Estimated glomerular filtration rate
EHR
VA electronic health record
EMR
VA electronic medical record
ESC
Event of special concern
FDA
United States Food and Drug Administration
FIPS
Federal Information Processing Standards
GCP 
Good clinical practice
HHHFNC
Humidified heated high-flow nasal cannula
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human Immunodeficiency Virus
HLA
Human Leukocyte Antigen
HNA
Anti-human neutrophil antigen
HRC
Human Rights Committee
HSR&D
Health Services Research & Development
HTTPS
Hypertext Transfer Protocol Secure
ICD-10
International Statistical Classification of Diseases, 10th revision
ID
Identification
INR
International normalized ratio
IRB
Institutional Review Board
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ISO
Information Security Officer
ITT
Intent to treat
IWRS
Interactive Web Response System
LAR
Legally authorized representative
LSI
Local Site Investigator
MedDRA 
Medical Dictionary for Regulatory Activities
MERS
Middle East respiratory syndrome coronavirus
MVP
Million Veterans Program
NA
Not applicable
NEWS2
National Early Warning Score-2 
NIH
National Institutes of Health
NK
Natural killer
ORD
VA Office of Research and Development
PHI
Protected health information
PT
Prothrombin time
RA
Research Assistant
R&D
Research & Development Committee
RCS
VHA Records Control Schedule
RSV
Respiratory Syncytial Virus 
SAE
Serious adverse event
SARS
Severe Acute Respiratory Syndrome
SARS-COV
SARS-coronavirus
SARS-COV-2 SARS-coronavirus-2
SAS
Statistical Analysis System
SD
Standard deviation
SE
Standard error
SEEM
Safety and efficiency enhancement meeting
SMART
Site Monitoring, Auditing, and Resource Team
SOP
Standard operating procedures
SpO2
Peripheral Capillary Oxygen Saturation 
SSL
Secure Sockets Layer
SSN
Social Security number
TACO
Transfusion-associated circulatory overload (TACO)
TRALI
Transfusion-related acute lung injury
US
United States
VA
Department of Veterans Affairs
VHA
Veterans Health Administration
VINCI
VA Informatics and Computing Infrastructure 
WBC
White Blood Cells
WH-PBRN
Women’s Health Practice Based Research Network
WHO
World Health Organization
3.3
Protocol Amendment History 
Versio
n
Date
Section(s)
Page 
Numbers in 
Version 
Where 
changes 
were 
Description of Change 
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Implemented
1.2
08/12/2020
Section 1.3
p.10
Updated Table 1: Schedule 
of Assessments:
- The table now describes 
study procedures instead of 
case report forms;
- Clarified timing of 
procedures;
- Added Product 
Administration visit since it 
occurs within 36 hours of 
randomization (thus, it might 
be the next day or even the 
day after;
- Clarified in footnote 3 that 
randomization should occur 
within 72 hours of hospital 
admission;
- Removed unnecessary 
and redundant footnotes;
- Clarified acceptable 
research specimens and 
corrected amounts;
- Clarified that clinical 
status, vital signs and AE 
should be obtained daily 
during hospitalization;
- Clarified that Day 15 and 
29 visits are preferred to be 
conducted in person but 
may be performed by 
telehealth or by phone if 
quarantine or other factors 
limit the participant’s ability 
to return to the site for the 
visit.
1.2
08/12/2020
Section 1.3. 
p.11
Updated notes for Table 1: 
Schedule of Assessments
1.2
08/12/2020
Section 2.1
p. 12
Updated numbers of 
coronavirus infections and 
deaths 
1.2
08/12/2020
multiple
multiple
Replaced “subject” with 
“participant”
1.2
08/12/2020
Section 
2.3.1
p.14
Removed “deficiency” 
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1.2
08/12/2020
Section 3
p.16
Added two secondary 
outcomes:
- proportion of patients who 
died from any cause, had 
respiratory failure or 
required HHHFNC ≥ 15Lpm 
by Day 28; 
-Time (in days) to death, 
respiratory failure or 
HHHFNC at ≥ 15 Lpm by 
Day 28.
1.2
08/12/2020
Section 3
p.17
Corrected study days for 
clinical status assessment: 
Days 14, 21, and 28 as 
assessed on Days 15, 22, 
29.
1.2
08/12/2020
Section 3
p.18
Removed laboratory 
assessments on study day 
11.
1.2
08/12/2020
Section 3
p.18
Changed amount of blood 
drawn for research from two 
7mL vials to 30mL. 
1.2
08/12/2020
Section 5.1.
p.22
IC#4: veterans must be 18 
years or older at the time of 
screening, not enrollment 
(i.e. enrollment is too 
vague)
1.2
08/12/2020
Section 5.1
p.22
IC#5: Clarified the 
acceptable tests for SARS-
CoV-2 confirmation: RT-
PCR or antigen. 
1.2 
08/12/2020
Section 5.1
p.22
IC#5: Clarified the 
acceptable timing of the 
diagnostic confirmation test 
(i.e. not more than 168 
hours prior to screening) 
1.2
08/12/2020
Section 5.1
p.22
IC#6: Corrected the 
humidified heated high-flow 
nasal cannula requirement 
to ≥15 Lpm instead of >15 
Lpm.
1.2
08/12/2020
Section 5.1
p.22
EC#1: Added anticipated 
death within 24 hours to 
EC#1.
1.2
08/12/2020
Section 5.5
p.23
Specified clinical databases 
accessed: CPRS charts and 
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hospital admission logs.
1.2
08/12/2020
Section 
6.3.1
p.25
Added age as a 
stratification factor for 
randomization 
1.2
08/12/2020
Section 6.5
p.26
Made the following changes 
to concomitant therapies 
and medications:
- Clarified that off-label use 
of marketed medications 
that are intended as 
treatment for SARS-COV-2 
infection is permitted and 
does not need to be 
discontinued on enrollment.
- Clarified that participant 
has progressed to 
respiratory failure in the 
hospital, another 
experimental treatment 
protocol may be initiated if 
approved by CIRB and if 
there is an agreement 
between leadership of both 
trials;
- Clarified that pre-
admission level A 
medications need to be 
collected by class at 
baseline;
-Clarified that concomitant 
medications taken for the 
prevention and treatment of 
COVID-19 in the 7 days 
prior to Day 1 and 
medications prescribed from 
hospital admission through 
Day 28 need to be 
collected.
1.2
08/12/2020
Sections 7.2 
and 7.3
p.28
Changed “Study 
Termination Form” to “Study 
Completion Form”.
1.2
08/12/2020
Section 7.2
p.28
Replaced “will” with “must”
1.2 
08/12/2020
Section 
8.1.1
p.29
Added a short description of 
consent process and 
referred to Section 10.1.1.2 
for details.
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1.2 
08/12/2020
Section 
8.1.2
p.29
Made the following changes 
to screening procedures:
- Clarified that participant 
must be randomized within 
72 hours of hospital 
admission;
- Removed history of 
medication allergies from 
screening/baseline 
procedures;
- Moved medications and 
therapies for this current 
illness to Section 8.2;
- Removed FiO2 
assessment.
1.2
08/12/2020
Section 8.2
p.29
Added description and 
timing of baseline, 
randomization and product 
administration procedures.
1.2
08/12/2020
Section 
8.3.2
p.31
Updated section number
1.2
08/12/2020
Section 8.4
p.31
Updated safety and other 
assessments as follows:
- Added reference to Table 
5;
- Changed amount of blood 
collected from two 7mL vials 
to 30mL on Days 1, 2-3, 4-
5, 7±1, 15±2 and 29±3.
- Corrected the blood 
collection window on Day 
29 to 29±3 instead of 29+3;
- Corrected the acceptable 
timing of routine laboratory 
tests to 24 hours prior to 
product administration, not 
48 hours;
- Added Section 8.4.5 to 
specify when Concomitant 
Medications should be 
collected. 
1.2
08/12/2020
Section 8.4
p.32
Modified the amounts of 
blood drawn and collection 
windows in Table 5
1.2
08/12/2020
Section 9.2
p.42
Changed duration of 
recruitment from 12 months 
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to 15 months and number of 
participants randomized per 
month per site from 2.5 to 2.
1.2
08/12/2020
Section 
9.4.2
p.42
Updated statistical analysis 
to account for stratification 
factors
1.2
08/12/2020
Section 
9.4.3
p.43
Added age as a 
stratification factor
1.2
08/12/2020
Section 
9.4.7
p.46
Updated age and BMI limits 
for subgroup analyses:
Age ≥ 65 vs < 65
BMI ≥ 35 vs < 35.
1.2
08/12/2020
Section 
10.1.1.2
p.47
Added details of consent 
procedures and 
documentation for COVID-
19 precautions:
- Informed consent may be 
provided by video or phone;
- Photographs of ICF may 
be accepted;
- Signature page of the ICF 
may be quarantined, then 
added to the ICF. 
1.2
08/12/2020
Section 
10.1.3
p.50
Deleted certificate of 
confidentiality description
1.2
08/12/2020
Section 
10.1.4
p.50
Added that CIRB will 
oversee the biorepository 
for this study
1.2
08/12/2020
Section 
10.1.8
p.54
Removed the wording 
‘during the first 12 months 
of the study’ for site 
performance evaluation.
1.2
08/12/2020
Section 10.2
p.61
Added abbreviation for 
Computerized Patient 
Record System (CPRS); 
removed abbreviation for 
fraction of inspired oxygen 
(FiO2)
1.2
08/12/2020
Section 10.3
p.63
Added protocol amendment 
history
1.3
08/25/2020
Section 1.1
p.7
Clarified that the trial will 
have common 
inclusion/exclusion criteria 
but may be modified for 
each specific stage. 
Removed reference to 
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stage-specific appendix.
1.3 
08/25/2020
Section 1.2
p.8
Added reference to study 
schema for stage 1.
1.3
08/25/2020
Section 1.3
p.11
Clarified that footnote #12 
describes follow-up visits on 
Days 15, 22 and 29 after 
discharge.  
1.3
08/25/2020
Section 5.5
p.23
Corrected that materials 
summarizing purpose and 
design of the study, etc. will 
be made available to clinical 
providers without IRB or 
facility approval.
1.3
08/25/2020
Section 
6.3.1
p.25
Added description of the 
randomization procedure 
(IWRS).
1.3
08/25/2020
Section 8.2
p.30
Corrected that baseline 
clinical status data are 
collected right before 
randomization, not within 24 
hours prior to 
randomization.
1.3
08/25/2020
Section 
8.4.1
p.32
Removed sentences about 
additional laboratory tests 
that might be required in 
other study stages. 
1.3
08/25/2020
Section 9.2
p.40
Added estimates about the 
number needed to be 
screened and consented in 
order to have 702 
randomizations. 
1.3
08/25/2020
Section 
10.1.4
p.50
Corrected section number 
for Data Handling and 
Record Keeping.
1.3
08/25/2020
Section 
10.1.4
p.50
Specified that the 
biospecimens collected in 
the study for current and 
future research will be kept 
at the VA Biorepository in 
Palo Alto.
1.3
08/25/2020
Section 
10.1.4
p.50
Indicated that all samples 
will be destroyed by 
standard practice within 20 
years of study completion 
and that sample destruction 
will be validated according 
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to the SOP of the VA 
Biorepository.
1.3
08/25/2020
Section 
10.1.4
p.51
Removed the name of one 
of the Project Managers 
who is no longer on the 
study (Ashley Scales).
1.4
09/02/2020
Section 1.3
pp.10 and 11
Schedule of Activities 
updated (“Nasopharyngeal 
swab” was changed to 
“Respiratory Sample” in the 
table and footnote).
1.4
09/02/2020
Section 2
p.12
Updated the numbers of 
SARS-Coronavirus 2 (SARS-
CoV-2; COVID-19) infections 
and deaths. 
1.4 
09/02/2020
Section 3
p.19
Removed statement about 
collecting NEWS2 prior to 
product administration. 
1.4
09/02/2020
Section 7.2
p.28
Changed the protocol to 
allow full or limited study 
participation.
1.4
09/02/2020
Section 
8.5.5
pp.36-37
Corrected section number.
1.4 
09/02/2020
Sections 7.2 
and 10.1.1.2
pp.28 and 49 
Moved the paragraph about 
the requirement to re-
consent the participant if he/
she was consented by LAR 
and later became 
competent from Section 7.2 
to Section 10.1.1.2.
1.4
09/02/2020
Section 
10.1.5
p.52
Edited Dr. Janoff’s VA 
phone number. 
1.5
11/09/2020
Section 1.3
p.10
In Table 1, added X for 
evaluation of adverse 
events on day of discharge.
1.5 
11/09/2020
Section 1.3
p.10
In Table 1, changed “blood 
for plasma” to “blood”.
1.5 
11/09/2020
Section 1.3 
p.11
In Table 1, footnote 6, 
changed “blood for plasma” 
to “blood for research 
studies”.
1.5
11/09/2020
Section 1.3 
p.11
In Table 1, footnote 6, 
spelled out 
“nasopharyngeal”.
1.5 
11/09/2020
Section 1.3
p.11
In Table 1, footnote 11, 
changed “Plasma for 
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antibodies” to “Blood for 
research studies”
1.5
11/09/2020
Section 6.5
p.27
Removed the language 
about Central IRB needing 
to approve initiation of 
another experimental 
protocol once a participant 
progresses to respiratory 
failure. 
1.5
11/09/2020
Section 7.3
p.28
Added language to allow 
site staff to send reminder 
text messages prior to a 
visit. 
1.5
11/09/2020
Section 
8.1.1
p.29
Updated to specify that the 
ICF can be a hard copy or e-
consent.
1.5
11/09/2020
Section 
8.3.1
p.30
Added language about a log 
that will be provided to 
participants at the time of 
initial hospital discharge.
1.5
11/09/2020
Section 
10.1.1.2
p.47
Added language that the 
informed consent form can 
be signed on a hard copy or 
signed electronically via 
approved mechanisms.
1.5
11/09/2020
Section 
10.1.1.2
p.47
Added language that the 
HIPAA can be signed on a 
hard copy or electronically, 
if available.
1.5
11/09/2020
Section 
10.1.1.2
p.48
Specified language that was 
specific to if a patient/LAR 
signs a hard copy of the 
informed consent form. 
1.5
11/09/2020
Section 
10.1.5
p.51
Added National Coordinator 
name and contact 
information
1.5
11/09/2020
Section 
10.1.8
p.54
Language that was more 
relevant to the Monitoring 
section was moved from the 
Protocol Deviation section 
to the Monitoring section
1.5
11/09/2020
Section 
10.1.12
pp.59-60
Updated Protocol 
Deviations section. 
1.6 
1/20/2021
Sections 
1.3, 8.2, 
8.4.1 and 
p.11, 30 and 
32
Increased the timing of Day 
1 safety labs and specimen 
collection (i.e. up to 24 
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8.4.2
hours prior to 
randomization).
1.6 
1/20/2021
Section 1.3 
p. 11
Added footnote 12 to clarify 
that if the participant is not 
hospitalized at study site on 
day 2, 4 or 7, there is no 
need to collect labs or 
specimen on that day.
1.6 
1/20/2021
Section 
8.4.1
p. 32
Added footnote 2 to Table 5 
to clarify that safety labs 
and blood for research will 
be collected on Days 2, 4 
and 7 if the participant is 
hospitalized. 
1.6 
1/20/2021
Section 
8.4.2
p. 32
Changed treatment 
administration to product 
administration to make it 
consistent with the rest of 
the protocol.
1.6
1/20/2021
Section 
8.4.3
p. 33
Changed “protocol-
specified” range to “clinically 
expected” range because 
the protocol does not 
specify a range.
1.6
1/20/2021
Section 3
p.18
Added Day 1 blood and 
swab collection to be 
consistent with other parts 
of the protocol.
1.6 
1/20/2021
Section 4.3, 
6.1.1 and 
6.4
p.21, 24 and 
26
Updated treatment volume 
limits for consistency.
1.6
1/20/2021
Section 
10.1.1.2
p.47 
Removed “The consent form 
will be valid for 90 days post 
consent.  If more than 90 days 
passes without the participant 
being randomized, the 
participant or LAR will need to 
be re-consented.” as this is not 
applicable to the current study.
1.6 
1/20/2021
Section 
10.1.1.2
p.49
Added subtitle “Re-consent” 
in order for the language 
about re-consent to be 
searchable in the protocol.
1.6
1/20/2021
Section 
10.1.4
p. 50
Changed the Biorepository 
from VA Biorepository in 
Palo Alto, CA to the 
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Cooperative Studies 
Program Albuquerque 
Central Biorepository in 
Albuquerque, NM. 
1.7
3/3/2021
Sections 1.1 
and 2.2
p. 6 and 14
Changed the next stage of 
VA CURES-1 will be VA 
CURES-1a (rather than VA 
CURES-2). 
1.7
3/3/2021
Sections 
1.3, 5.1, and 
8.1.2
p. 11, 21, and 
29
Changed language to clarify 
that “Randomization must 
occur within 72 hours of 
initial hospital admission”. 
1.7
3/3/2021
Section 3
p. 20
Added footnote 1 to clarify 
that the SpO2 scale 2 
should be used for 
participants with suspected 
or confirmed history of 
hypercapnia. 
1.8
8/6/2021
Section 
8.3.5
p. 31
Added information 
regarding evaluating the 
relationship of clinical, 
immunologic, inflammatory, 
metabolic, coagulation, 
endocrinologic and 
microbiologic outcomes.
1.8
8/6/2021
Section 
10.1.4
p. 50
Added the following 
language, “All stored 
specimens and data used 
for current and future 
experimental analysis, both 
clinical and laboratory, by 
laboratories and 
investigators within and 
outside the VA system will 
be linked to study 
identification number with 
no direct subject identifiers 
or PII/PHI. Thus, all subject 
data will be deidentified and 
anonymized with 
demographic but no specific 
HIPAA-designated 
variables.”
1.9
9/10/2021
Section 3
p. 18
Table 2 was updated to 
include “Impact of donor 
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convalescent plasma 
parameters on the activity of 
administered plasma”
1.9
9/10/2021
Section 
8.3.5
p. 31
Added information 
regarding characterizing the 
impact of specific 
parameters of convalescent 
plasma administered to 
subject on immunologic, 
inflammatory, metabolic, 
coagulation, and 
endocrinologic outcomes in 
study subjects. 
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