Passive Immunity Trial for Our Nation (PassItOn)
Phase: PHASE3
Conditions: COVID-19, Coronavirus, SARS-CoV-2
Sponsor: Vanderbilt University Medical Center

 
Title: Passive Immunity Trial for Our Nation 
 
National Clinical Trial (NCT) Identified Number: NCT04362176 
 
Protocol: Version 6.0 Date: January 28, 2021 

 
 
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PassItOn Protocol Version 6.0 
September January 28, 2021 
Passive Immunity Trial for Our Nation 
 
 
Title: Passive Immunity Trial for Our Nation  
Acronym: PassItOn  
Protocol Number: 200738 
National Clinical Trial (NCT) Identified Number: NCT04362176 
Principal Investigators: Todd W. Rice, M.D., MSc and Wesley H. Self, M.D., M.P.H. 
Coordinating Center: The Vanderbilt Coordinating Center 
Funders:  Dolly Parton COVID-19 Research Fund and the National Center for Advancing Translational Sciences 
 (NCATS) of the National Institutes of Health (NIH) 
Protocol: Version 6.0 
Date: January 28, 2021 
 
Summary of Changes  
Protocol version 5.0 dated September 15, 2020 to Protocol version 6.0 dated January 28, 2021 
 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
General  
Revise Protocol version to 6.0 dated January 28, 2021 
 
Administrative Change 
 
Page 1 Title Page 
Changed Protocol Version 5.0 dated September 15, 2020 to 
January 28, 2021.  
Administrative Change 
Pages 1-21 Summary of Changes  
Page 22 Protocol 
Signature Page 
Changed Protocol Version 5.0 dated September 15, 2020 to 
January 28, 2021 
Administrative Change 
Pages 23-25 Table of 
Contents 
Revised Table of Contents  
Revised Table of Contents to reflect 
protocol additions and changes 
Page 26 Section 1. 
Abbreviations 
New Abbreviations “ SOFA Sequential organ failure assessment” 
“sIRB single Institutional Review Board” 
“TRALI Transfusion associated acute lung injury” 
“TACO Transfusion associated circulatory overload” 
“VCC Vanderbilt Coordinating Center” 
“VUMC Vanderbilt University Medical Center” 
 
To add missing abbreviations 

 
 
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PassItOn Protocol Version 6.0 
September January 28, 2021 
Pages 27-28 Study Summary 
Study Design 
Add “comparing outcomes of patients randomized to COVID-19 
convalescent plasma versus placebo.” 
 
To further define the study design 
Intervention  
group treatment 
Remove “pathogen reduced” 
To ensure accuracy of the plasma 
description 
Inclusion Criteria 
Remove “of age” 
Grammar correction 
Exclusion Criteria 
Previous Number 5 Text “Receipt of COVID-19 convalescent
plasma or pooled immunoglobulin in the past 30 days 
Current Number 5. Text “Receipt of any SARS-CoV-2 passive 
immunity therapy, such as convalescent plasma, monoclonal
antibodies, or pooled immunoglobulin, in the past 30 days.” 
New Number 9. “Previous laboratory-confirmed SARS-CoV-2 
infection before the current illness” 
New Number 11 “Prior receipt of SARS-CoV-2 vaccine” 
To ensure patient has not previously 
received any SARS-CoV-2 passive 
immunity therapy within 30 days of 
enrollment. 
 
 
To ensure patient has not previously 
had SARS-CoV-2 infection before the 
current illness. 
 
To ensure patient has not previously 
received the SARS-CoV-2 vaccine 
Page 29 Section 3.1 
Background 
Sentence 5 add the word “suggested” 
Change “effectiveness” to “efficacy” 
Grammar corrections 
Page 30 Section 3.1.4 
Rationale for a 
randomized trial among 
hospitalized patients 
Change “effectiveness” to “efficacy” 
Grammar correction 
Page 30 Section 3.3 
Study Design 
Previous Text “Plasma will be collected and distributed to sites
through Vanderbilt University Medical Center’s blood donation
center partner. Anti-SARS-CoV-2 antibody quantification assays
will be completed on donor plasma at Vanderbilt University Medical
Center (VUMC) prior to plasma distribution.” 
Current Text “Plasma will be collected and distributed to sites
through blood donation groups partnering with VUMC’s blood
donation center partner. Anti-SARS-CoV-2 antibody quantification 
assays will be completed on donor plasma at Vanderbilt University 
Medical Center (VUMC) prior to plasma distribution.” 
To allow for multiple blood donation 
centers 
Page 31 Section 4.1 
Inclusion Criteria 
Remove “of age” 
Grammar correction 
Page 31 Section 4.2 
Exclusion Criteria 
Previous Number 5 Text “Receipt of COVID-19 convalescent
plasma or pooled immunoglobulin in the past 30 days 
Current Number 5. Text “Receipt of any SARS-CoV-2 passive 
immunity therapy, such as convalescent plasma, monoclonal
antibodies, or pooled immunoglobulin, in the past 30 days.” 
To ensure patient has not previously 
received any SARS-CoV-2 passive 
immunity therapy within 30 days of 
enrollment. 
 
 
To ensure patient has not previously 

 
 
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PassItOn Protocol Version 6.0 
September January 28, 2021 
New Number 9. “Previous laboratory-confirmed SARS-CoV-2 
infection before the current illness” 
New Number 11 “Prior receipt of SARS-CoV-2 vaccine” 
 
had SARS-CoV-2 infection before the 
current illness. 
 
To ensure patient has not previously 
received the SARS-CoV-2 vaccine 
Page 31 Section 4.5 
Assessment of Eligibility 
and Exclusion Tracking 
Remove “For all excluded patients, including refusal by the treating
clinician or patient/surrogate, a small number of de-identified 
variables will be collected including month and year the patient met
screening criteria, age, sex, ethnicity, patient location, and 
reason(s) patient was excluded.  For the safety of research
personnel and conservation of personal protective equipment,
these encounters may occur via telephone or videophone.” 
 Administrative change 
Page 32 Section 4.6 
Process of Obtaining 
Informed Consent 
Previous Text “Suggestions for the three approaches are outlined
here.” 
Current Text “Suggestions for the two approaches are outlined 
here.”  
Typographical correction 
Page 34 Section 4.7 
Randomization and 
Blinding  
Remove “For the duration of the study, the only individuals that are
knowledgeable about the treatment assignment are the VCC Data 
Specialist and designated Clinical Research Associate, the study
statistician (unblinded), and the study personnel administering the 
plasma or placebo product.” 
Previous Text “Clinical personnel who administer the study product
(convalescent plasma vs placebo) will not be blinded. 
Current Text “Clinical personnel who administer the study product
(convalescent plasma vs placebo) such as the bedside nurse, will
not be blinded.” 
To align with the blinding SOP 
 
 
 
Page 34 Section 4.8 
Minorities and Women 
Previous Text “The demographics of the patients recruited will 
mirror those of patients admitted to the hospital with COVID-19. 
Current Text “The demographics of the patients approached for
enrollment will mirror those of patients admitted to the hospital with
COVID-19. 
To clarify recruitment 
Pages 34-35 Section 5.1 
Treatment of Study 
Participants 
Previous Text “Timing of study procedures is based on the time of 
randomization, which is defined as “Time 0”.  Study Day 1 is
defined as the day of randomization. 
Current Text “Timing of study procedures is based on the time of
initiation of the study product infusion, which is defined as “Time 
0”.  Study Day 1 is defined as the calendar day of study product
infusion.” 
New Text “For patients who are randomized but do not receive
study product, time of randomization will be considered “Time 0” 
and Study 1 will be the calendar day of randomization. For most 
patients, randomization and study product infusion will occur on the
same day; in the event the study product is infused on a different
calendar day than randomization, Study Day 1 is defined as the 
day on which study product is infused. “Baseline status” represents
the patient’s status immediately prior to study infusion, and
To clarify Time 0 and Study 1 in relation 
to randomization. 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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PassItOn Protocol Version 6.0 
September January 28, 2021 
baseline variables should represent information available before
and as close as possible to initiation of the study infusion.” 
Previous Text “Participants randomized to active treatment will
receive 1 unit of convalescent plasma, which has a volume of 200-
399 ml. 
Current Text “Participants randomized to active treatment will 
receive 1 unit of convalescent plasma, which has a volume of 200-
399 ml infused intravenously.” 
Previous Text “The study product (convalescent plasma vs
placebo) will be infused intravenously over 1-3 hours, with the 
specific rate of infusion determined by the site investigator based
on an assessment of how quickly the participant can safely receive
the intravascular volume load.” 
      
Current Text “The duration of infusion is recommended to be
between approximately 1 hour and 3 hours (at the discretion of the 
provider), with the specific rate of infusion determined by the site
investigator based on an assessment of how quickly the participant
can safely receive the intravascular volume load.”         
Previous Text “Study personnel will monitor patients for adverse
reactions to the transfusion while the patient is in the hospital for
72 hours following the infusion; that is transfusion adverse reaction
monitoring will be continued until Study Day 3. For patients who 
are discharged prior to Day 3, study personnel will obtain safety 
outcomes from the patient or surrogate via telephone follow-up 
scheduled at Day 8.” 
Current Text “Study personnel will monitor patients for adverse
reactions to the transfusion while the patient is in the hospital for
72 hours following the infusion; that is transfusion adverse reaction
monitoring will be continued until Study Day 4. For patients who 
are discharged prior to Day 4, study personnel will obtain safety 
outcomes from the patient or surrogate via telephone follow-up 
scheduled at Day 8.” 
 
 
 
To clarify that convalescent plasma will 
be infused intravenously 
 
 
 
 
To clarify that the rate of infusion is 
based on the investigator’s assessment 
 
 
 
 
 
 
 
 
 
Typographical correction 
Page 35 Section 5.1 
Treatment of Study 
Participants under 
Screening 
Previous Text “Screening (pre-randomization)  
1. Screening (must be completed before randomization) 
2. Subject informed consent (obtained before performing study
related activities) 
3. Baseline Evaluation (at screening) (much of the information will 
be obtained from the medical record) 
4. Demographics (Age, sex, ethnicity, race) 
5. Medical history (acute and chronic medical condition,
medications, and allergies). Any medical condition arising after 
enrollment should be recorded as AE 
6. COVID-19 symptom screen (fevers, cough, shortness of breath),
onset of symptoms, source of exposure 
7. Vital signs (blood pressure, pulse, respirations, and
temperature)  
To clarify Screening, consent, and 
baseline  

 
 
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September January 28, 2021 
8. Determination of eligibility as per inclusion/exclusion criteria. 
9. SARS-CoV-2 RT-PCR for eligibility (can be done up to 14 days
prior to randomization) 
10. ABO type and screen (to be done at a timepoint during current 
hospital admission) 
Current Text “Screening, consent, and baseline (pre-
randomization)  
1. Confirm inclusion and exclusion criteria, including identifying a
positive SARS-CoV-2 test 
2. Subject informed consent (obtained before performing study
related activities) 
3. Randomization of eligible subject 
4. Demographics 
5. Medical history 
6. COVID-19 symptoms 
7. Record vital signs 
8. Assessment of clinical status (COVID-19 7-point Ordinal Clinical
Progression Outcomes Scale) 
9. Record new medical conditions  
10. Record concomitant medication  
11. Adverse Event (AE) evaluation 
12. Collection of data for later SOFA score calculation 
13. Prior to study infusion, collect, process and store blood for 
SARS-CoV-2 antibody testing, which will be done at the central
study laboratory. 
14. C-reactive protein (CRP) measurement (record the results of a 
clinically obtained CRP performed within 24 hours prior to study
product infusion; if a CRP was not obtained clinically, perform a 
CRP measurement by study protocol in the local clinical laboratory)
15. Complete Blood Count (CBC) and Complete Metabolic Panel
(CMP) measurement (record the results of a clinically obtained
CBC and CMP performed within 24 hours prior to study product 
infusion; if a CBC and/or CMP was not obtained clinically, perform 
them on study protocol in the local clinical laboratory) 
Page 35 Section 5.1 
Treatment of Study 
Participants under Day 1 
Previous Text “Day 1  
1. Randomization of eligible subjects 
2. Study Product Administration:1unit of convalescent plasma or
Lactated Ringer’s solution with multivitamins will be transfused. 
Study infusion will be monitored per site institutional transfusion
policy.  
3. Assessment of clinical status (COVID-19 7-point Ordinal Clinical
Progression Outcomes Scale) 
4. New medical conditions, concomitant medication, Adverse 
Event (AE) evaluation 
5. Blood for COVID-19 Titer testing, must be collect prior to study 
infusion  
6. CBC, CMP, if not performed as part of standard of care 
7. SOFA Score 
8. C-reactive protein (CRP) measurement” 
To clarify study Day 1 

 
 
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Current Text “Day 1 (Day of Transfusion) 
1. Study Product Administration: 1 unit of convalescent plasma or
Lactated Ringer’s solution with multivitamins will be transfused. 
Study infusion will be monitored per site institutional transfusion
policy.  
2. Adverse Event (AE) evaluation” 
Page 35 Section 5.1 
Treatment of Study 
Participants under Day 2 
New Text “Day 2 (first calendar day after transfusion)  
1. Record vital signs.  
2. Assessment of clinical status (COVID-19 7-point Ordinal Clinical
Progression Outcomes Scale) 
3. Record new medical conditions 
4. AE evaluation  
5. Collection of data for later SOFA score calculation 
6. CBC and CMP measurement (record the results of a clinically 
obtained CBC and CMP; if a CBC and/or CMP was not obtained
clinically, perform them on study protocol in the local clinical 
laboratory if patient remains hospitalized)  
7. If patient remains hospitalized, collect, process and store blood
for SARS-CoV-2 antibody testing, which will be done at the central 
study laboratory.” 
To clarify study assessments and 
procedures for Day 2 
Page 35 Section 5.1 
Treatment of Study 
Participants under Days 
3-8 
Previous Text “Daily on Day 2 thru 8 (or until hospital discharge if
discharged before Day 8) 
1. Vital signs  
2. COVID-19 symptom screen (fevers, cough, shortness of breath)
3. Assessment of clinical status (COVID-19 7-point Ordinal Clinical
Progression Outcomes Scale) 
4. New medical conditions, AE evaluation (Days 2 and 3 only) 
5. CBC, CMP, if not performed as part of standard of care (Days 2,
8 only) 
6. SOFA score (Day 2 and 8 only) 
7. Blood for COVID-19 Titer testing (Day 2 only, if still hospitalized)”
Current Text “Day 3-8 (Daily assessments only while patient
hospitalized) 
1. Record vital signs  
2. Record new medical conditions 
3. Assessment of clinical status (COVID-19 7-point Ordinal Clinical
Progression Outcomes Scale 
4. AE evaluation (through Day 4 only) 
5. Record the results of a clinically obtained CBC and CMP (Day 8 
only and only if clinically available)” 
To clarify study assessments and 
procedures for Days 3-8 
Page 36 Section 5.1 
Treatment of Study 
Participants under Days 
15 and 29 
Previous Text “Day 15 and 29:  
1. COVID-19 symptom screen (fevers, cough, shortness of breath)
2. Assessment of clinical status (COVID-19 7-point Ordinal Clinical
Progression Outcomes Scale 
3. New medical conditions 
Current Text “Day 8, 15, and 29 (by phone if patient discharged 
before assessment day):  
1. Assessment of clinical status (COVID-19 7-point Ordinal Clinical
Progression Outcomes Scale) 
To clarify study assessments and 
procedures for Days 15 and 29 

 
 
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PassItOn Protocol Version 6.0 
September January 28, 2021 
2. New medical conditions 
3. Vital status check” 
Page 36 Section 5.2 
Convalescent Plasma 
Group 
Previous Text “Patients randomized to the active treatment arm will
receive a single dose of 1 unit (200-399 ml) of convalescent plasma
infused intravenously over 1-3 hours.” 
Current Text “Patients randomized to the active treatment arm will
receive a single dose of 1 unit (200-399 ml) of convalescent plasma
infused intravenously per site institutional policy governing blood
product transfusions.” 
New Text “Plasma that is believed to be neutralizing will be used in
this trial and will be prioritized based on neutralizing capabilities.” 
To clarify that convalescent plasma is 
infused per institutional policy and that it 
is infused intravenously 
To clarify prioritization of plasma 
Page 36 Section 5.3 
Control Group 
Remove of 1-3 hours 
Administrative change 
Page 36 Section 5.4 Co-
interventions 
Move Text from Last to 1st paragraph “Use of open label 
convalescent plasma in the first 15 days of the study is strongly
discouraged and will be tracked as protocol non-compliance. 
Remove “(“rescue therapy”) 
Administrative changes 
Page 36 Section 5.5 On-
Study Monitoring 
Previous Text “At any point, if the clinical team has concern about 
a transfusion reaction, they will report that concern to the blood
bank or as per institutional policy.” 
Current Text “At any point, if a clinical team member has a 
concern about a potential transfusion reaction, he/she will report 
that concern to the blood bank or as per institutional policy.” 
Administrative changes 
Page 36 Section 5.6 
Criteria for Stopping 
Study Infusion 
Previous Text “Infusion of study treatment will be halted if any of
the following manifestations of transfusion reaction develop fever,
rash, diffuse itching, tachycardia (increase in heart rate by greater 
than 20 beats per minute).” 
Current Text “Infusion of study treatment will be halted if any of the
following manifestations of transfusion reaction develop fever,
rash, diffuse itching, acute increase in heart rate by greater than 20
beats per minute.” 
Previous Text “If there is significant concern that the symptoms, 
beyond rash or itching, are secondary to transfusion alone, then
transfusion will not be re-started, and the patient will be evaluated
for transfusion reaction.”  
Current Text “If there is significant concern that the symptoms, 
beyond rash or itching, are secondary to the infusion, then infusion
will not be re-started, and the patient will be evaluated for 
transfusion reaction.” 
Previous Text “In addition, the infusion will be stopped and not
restarted if the patient develops any of the following signs or
Administrative changes 

 
 
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PassItOn Protocol Version 6.0 
September January 28, 2021 
symptoms of anaphylaxis: hives; pruritus; flushing; swollen lips,
tongue or uvula;  worsening of shortness of breath wheezing;
stridor; hypoxemia; a decrease in systolic blood pressure to less 
than 90 mmHg or greater than 30% decrease from baseline or a 
diastolic drop of greater than 30% from baseline; bradycardia less
than 40 beats per minute that is associated with dizziness, nausea 
or feeling faint; any other symptom or sign which in the good clinical
judgment of the study clinician or supervising physician warrants 
halting the infusion.  For example, the rapid onset of 
gastrointestinal symptoms, such as nausea, vomiting, diarrhea,
and cramps, for instance, may be manifestations of anaphylaxis
and may warrant an immediate halt prior to meeting full severe
adverse event (SAE) criteria. 
Current Text “In addition, the infusion will be stopped and not
restarted if the patient develops any of the following signs or
symptoms of anaphylaxis: hives; pruritus; flushing; swollen lips,
tongue or uvula;  worsening of shortness of breath; wheezing; 
stridor; hypoxemia; a decrease in systolic blood pressure to less 
than 90 mmHg or greater than 30% decrease from baseline or a
diastolic drop of greater than 30% from baseline; bradycardia less
than 40 beats per minute that is associated with dizziness, nausea 
or feeling faint; any other symptom or sign which in the good clinical
judgment of the study clinician or supervising provider warrants
halting the infusion.  For example, the rapid onset of 
gastrointestinal symptoms, such as nausea, vomiting, diarrhea, 
and cramps, may be manifestations of anaphylaxis and may 
warrant an immediate halt prior to meeting full severe adverse 
event (SAE) criteria.” 
Previous Text “Any suspected reactions related to study product 
that result in stopping of study infusion must be reported as an
adverse event.“  
Current Text “Any suspected reactions related to study product that
result in stopping of study transfusion must be reported as an
adverse event.“  
Page 37 Section 5.7 Plan 
for Plasma Shortages 
Previous Text “In the event of a shortage of study treatment at a
participating trial site, site personnel should contact the Vanderbilt 
Coordinating Center (VCC) Clinical Trials Operations Manager
regarding this issue. Participants will only be randomized when the
local site has convalescent plasma and placebo available.” 
Current Text “In the event of a shortage of convalescent plasma or 
multivitamin solution for use in the trial at a participating trial site,
site personnel should contact the Vanderbilt Coordinating Center
(VCC) Clinical Trials Operations Manager. Participants will only be 
randomized when convalescent plasma and the placebo solution
are available. 
Administrative changes 
Page 37 Section 6. 
OUTCOMES 
New Text “Definitions for each outcome are detailed in the trial’s
statistical analysis plan (SAP).” 
To clarify location of outcomes 
definitions 

 
 
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Page 38 Section 6.4 
Rationale for Primary 
Outcome 
Previous Text “Since the majority of morbidity from COVID-19 
relates to hypoxemia, the fact that this outcome is tied to degree of
hypoxemic respiratory failure increases its face validity and
relevance. “ 
Current Text “Since the majority of morbidity from COVID-19 
relates to hypoxemia, the fact that COVID-19 Ordinal Scale is tied 
to degree of hypoxemic respiratory failure increases its face validity
and relevance. “  
Administrative change 
Page 38 Section 7. DATA 
AND BIOLOGICAL 
SPECIMEN 
COLLECTION 
Previous Text “7. DATA 
Current Text “7. DATA AND BIOLOGICAL SPECIMEN 
COLLECTION 
Previous Text “We will emphasize data that can be collected from
the electronic health record, radiographs obtained as part of routine
clinical care, and assessments that can be completed over the 
telephone as needed.” 
Current Text “We will emphasize data that can be collected from 
the electronic health record, and assessments that can be 
completed over the telephone.”  
Previous Text “Biological specimens will be collected as part of this
trial in the form of plasma. Specimens will be shipped to VUMC for 
future analysis.”  
Current Text “Plasma samples will be collected as part of this trial 
at baseline (prior to study infusion) and on study Day 2 
(approximately 24 hours after the study infusion. Specimens will 
be shipped to VUMC for future analysis, which will include 
quantitative anti SARS-CoV-2 antibody measurements.”  
  
Administrative changes 
Page 38 Section 7.1 
Baseline Variable 
Collection 
Remove “chest imaging results” 
Previous Text “Highest fraction of inspired oxygen, lowest arterial
oxygen saturation, highest respiratory rate, lowest systolic blood
pressure, highest heart rate in the hour prior to enrollment” 
Current Text “Vital signs” 
Administrative changes 
Pages 38-39 Section 7.2 
Assessments Between 
Hospital Presentation 
and Hospital Discharge 
Remove “and Day 8”, “S/F ratio Day 3”, “chloroquine”, “and time”,
Change “Outcomes” to “assessments” 
Remove “cardiomyopathy” 
Previous Text “Definitions for each outcome will be provided in trial
standard operating procedures.” 
Current Text “Definitions for each variable are detailed in the trials 
statistical analysis plan and are described for enrolling personnel
in the trial manual of operations and/or electronic data capture 
system.” 
Administrative changes 

 
 
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Page 39 Section 7.31 
Acute Care Follow-up 
Previous Text “Non-laboratory safety outcomes after hospital 
discharge” 
Current Text “Selected non-laboratory safety outcomes after
hospital discharge” 
New Text “The follow-up period for vital status (dead versus alive)
is through Study Day 29.  For most patients, we will establish vital 
status during the Study Day 29 visit (either in person for those who
remain in the hospital or by phone for those who have been
discharged).  For patients who are not reached for the Study Day
29 visit, we will seek to establish vital status via phone calls, emails,
and searches through medical records, obituaries, social media,
and other sources.” 
Administrative changes 
To clarify the follow-up period for vital 
status  
Page 40 Section 8. 
STATISTICAL 
CONSIDERATIONS 
Remove “Note: We expect that given the circumstances of this trial
during a rapidly evolving pandemic, the DSMB will need maximum
latitude in modifying the trial if necessary. Alterations may include
adding patients, adding arms to the trial, declining to stop for futility,
or stopping earlier to make the results public. 
Administrative changes 
Page 40 Section 8.1 
Summary 
Previous Text “The key features of the trial are summarized in the
following table.  As the number of sites is still unsettled, some 
values are approximate. This document is a summary of the clinical
trial and analysis plan which is described in greater detail in the trial
simulation report (link), which will be updated to reflect the trial of
1000 subjects.” 
Current Text “The key features of the trial are summarized in the
following table (Table 1).   
Add header to the table “Table 1. Key Statistical features of the
trial” 
Remove “Design goals  
 
1. Frequent evaluation of efficacy and inefficacy in order to
minimize the number of subjects so that results can be
disseminated quickly. 
2. Simple evaluation of efficacy, inefficacy, and futility. 
3. Maintain Type I (false-positive) and Type II (false-negative) error
rates at prespecified levels.” 
Add “ Sample Size| 1000 subjects” 
Add “Inference approach 
The primary point of inference will be the likelihood ratio and
corresponding support interval for the covariate adjusted treatment
effect odds ratio.  Likelihood ratios more extreme than 7 (or 1/7) 
will be interpreted as sufficient evidence to assert efficacy. 
The odds ratio will be estimated with a cumulative probability
ordinal regression model with logit link.” 
Revised statistical plan 

 
 
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Remove “Analysis method  
“The covariate adjusted treatment effect odds ratio will be
estimated with a cumulative probability ordinal regression model
with logit link.” 
Current Planned Interim Analyses Text “There are 3 interim
analyses for safety endpoints, and a final analysis of efficacy
endpoints.  The safety interim analyses will occur after 15 days of
follow-up is completed for the first 150, 450, and 750 patients.  The
final analysis will occur after follow-up is complete for all enrolled
subjects” 
Previous Planned Interim Analyses Text “The first interim analysis
will occur after the follow-up is recorded for 150 subjects.
Subsequent analyses will occur regularly, every 2 weeks or as 
directed by the DSMB.” 
Previous Planned Reporting Triggers” 
1. Efficacy 
2. Inefficacy 
3. Futility 
4. Completion of the study at the maximum sample size 
Current Planned Reporting Triggers “1. There are no planned 
reporting triggers.” 
New Text 
“Planned stopping rules | 
At each interim analysis, the difference in mortality risk will be 
calculated, and the one-sided hypothesis that mortality risk in the 
intervention arm exceeds the mortality risk in placebo will be 
compared to the null hypothesis of equal mortality risk.   The trial 
will be stopped if the likelihood ratio exceeds the threshold listed 
below. “ 
“Type I error rate The combination of a 1/7 likelihood ratio 
threshold and the safety stopping rule result in a simulated type I 
error rate of 0.02” 
“Power The minimal detectable effect at 80% power is 0.73” 
Pages 40-41 Sections  
8.2 Analyses plan 
8.2.1. Model fit 
8.2.2 Missing data 
8.3 Triggers for DSMB 
review 
Sections removed or renumbered 
No longer applicable to the current 
statistical plan 
Page 40 New Section 8.2 New Text 
Revised statistical plan 

 
 
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Planned interim 
analyses for mortality 
“At each interim analysis, the difference in mortality 
risk will be calculated, and the one-sided hypothesis 
that mortality risk in the intervention arm exceeds the 
mortality risk in placebo will be compared to the null 
hypothesis of equal mortality risk.   The trial will be 
stopped if the likelihood ratio exceeds the threshold 
listed below.  Generally, the level of evidence 
required to stop a study for safety concerns is less 
than the level of evidence required to assert efficacy 
of the intervention.  Likewise, there is not the same 
level of concern for type 1 error control for safety 
outcomes as there is for efficacy endpoints; however, 
the threshold values were selected so that the trial-
wise risk of ending early for mortality is 0.1 if the 
treatment is equivalent to placebo.    To provide 
context for the LR thresholds listed in the table below, 
we have also provided  
α𝑁𝑁, the p-value threshold which approximates the LR 
threshold if the p-value were calculated from a 
likelihood ratio test.    
Page 41 Section 8.3.1 
Model fit 
Section 8.2.1 renumbered as Section 8.3.1 
Revised statistical plan 
Page 41 Section 8.3.2 
Missing data 
Section 8.2. renumbered as Section 8.3.2 with the changes listed
below: 
Previous Text “We anticipate rare or no missingness for data points
during the patients in-hospital course.” 
Current Text “We anticipate rare or no missingness for data points 
during a patients in-hospital course.” 
Remove “Missing data for a covariate used in the primary model 
will be imputed using multiple imputation methods.” 
New Text “Missing data for a covariate used in the primary model
will be multiply imputed using predictive mean matching if number 
of observations missing covariate values exceeds 5 percent.  If
fewer than 5% of observations have missing covariate values,
missing values will be imputed with a single conditional mean.” 
Revised statistical plan 
Page 41 Section 8.3.3 
Assertion of efficacy 
New Text “Likelihood ratios more extreme than 7 (or 1/7) will be
interpreted as sufficient evidence to assert efficacy.” 
Revised statistical plan 
Page 41-42 Section 8.4 
Trial characteristics 
Remove all text and tables 
Revised statistical plan 
Page 42 New Section 
8.4.1 Inference 
New Text “Decision making using the likelihood approach in a 
clinical trial centers on three quantities: the point estimate of the
treatment effect (an odds ratio, for example), a corresponding
interval estimate, and a single number summary that measures the
relative evidence for one hypothesis compared to another.  These 
three quantities are not unlike the point estimate, 95% confidence
Revised statistical plan 

 
 
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September January 28, 2021 
interval, and p-value that are generated in frequentist analyses.  In 
fact, the point estimates are often identical, and the interval
estimates are often similar.  The LR and the p-value, however, are 
distinct measures of evidence.  The LR is a ratio: the density of the
trial data if the treatment works (alternative hypothesis) divided by
the density of the trial data if the treatment does not work (null
hypothesis).  A LR of 1 indicates the data are neutral; neither 
hypothesis is supported over the other.  Large LR are evidence in
support of the treatment working while small LR are evidence in 
support of the null.  In short, the LR level of evidence is based on
comparing the likelihood of the data under two competing models
– the alternative hypothesis and the null hypothesis.  This is
different to using a p-value as the level of evidence because the p-
value essentially compares what actually happened in the trial to
what might have happened in the trial if it were repeated infinitely
and the null hypothesis were true. Because it is impossible to 
compute what might have happened if the rules for decision 
making are not fully predefined, using a p-value for decision
making is not well suited for a trial like this one in which DSMB
requests and pandemic circumstances prompt design changes. 
The LR approach on the other hand, is based on a relative 
likelihood of observed outcomes under two competing models at 
the same point in time making it especially appropriate for settings 
where pre-specification of the timing or frequency of sequential
analyses is not possible.   
Even though the LR (instead of the p-value) is the quantity of 
primary interest for decision making, the analysis plan does control
type 1 error.  Sequential likelihood ratio tests of two prespecified
hypotheses have a natural bound on type 1 error of 1/k where k is 
the threshold for asserting efficacy.  In this study, the combination 
of the stopping rule for mortality and the large number of subjects
accrued before the first analysis for efficacy result in a bound-on 
type 1 error well within traditional levels of 0.05.” 
Pages 42-43 New 
Section 8.4.2 Type I error 
rate and power 
New Text “ 
The long-run operating characteristics were estimated by
generating study data to reflect different treatment effect sizes. The
simulated study dataset was evaluated according to the stopping
rule and analysis plan described above. For each effect size, 1000 
simulated datasets were analyzed. A Type I error occurred if the
study asserted efficacy when in fact there was no treatment effect. 
The Type I error rate was calculated as the proportion of null-effect 
studies in which the error occurred. A Type II error occurred if the
study failed to assert efficacy when there was a beneficial 
treatment effect. For each treatment effect, power was calculated
as the proportion of studies that did not result in a Type II error.  
The study endpoint for control subjects was simulated to match the
outcomes in the control arm of a recent clinical trial.3 In each
simulation setting, the distribution for the treatment arm was
calculated by adjusting the control arm outcome distribution
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according to the setting-specific treatment effect size and data
generation model. 
The figure below is the estimated power curve for the trial design
(Figure 1). 
Figure 1. Power of the trial assuming enrollment of 1000
participants. 
 
Page 43 New Section 8.5 
Analysis plan for 
additional analyses of 
the primary endpoint” 
New Section Header 
Revised statistical plan 
Page 43 New Section 
8.5.1 and Section 8.5.2 
New Text “8.5.1 Quantification of effect of donor plasma
characteristics on treatment efficacy 
The impact of the antibody levels and neutralization activity of the
donor plasma on the primary endpoint will be estimated with ordinal
regression models. The models will include the same covariates
listed for the primary endpoint analysis, except the treatment 
assignment variable will be replaced with either (a) a measure of
donor plasma antibody level or (b) a measure of donor plasma
neutralization.  Both variables will be included in models as a
restricted cubic spline in order to capture potential non-linear 
associations with the outcome. 
8.5.2 Effect modification analyses of the primary outcome 
We will examine whether pre-specified baseline variables modified
the effect of treatment group on the primary outcome using tests of
statistical interaction in a proportional odds regression model. 
Independent variables will include study group assignment, the 
potential effect modifier of interest, the interaction between the two,
and the same pre-specified covariates used in the primary model.
Presence of effect modification will be assessed by reference to 
the LR for the interaction term, with values greater than 6 
considered to suggest a potential interaction and values greater
than 7 considered to confirm an interaction.     
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We will examine whether the following pre-specified baseline
variables modify the effect of study group on the primary outcome:
 • Baseline recipient (trial participant) antibody quantification 
 • Baseline COVID scale 
 • Baseline SOFA 
 • ICU/ward enrollment location 
 • Age 
 • Race/ethnicity 
 • Duration of symptoms prior to randomization 
 • Mechanical ventilation status at baseline 
Pages 44-45 New 
Section 8.6 Analysis 
plan for secondary 
endpoints 
8.6.1 Ordinal outcomes 
8.6.2 Binary outcomes 
8.6.3 Time to event 
outcomes 
8.6.4 Outcomes with a 
competing risk of death 
8.6.5 Missing data 
 
New Text  
“The analyses for secondary endpoints will be intent-to-treat, 
meaning that patients will be analyzed according to the 
randomization schedule regardless of the treatment administered. 
The following is a table of secondary endpoints and analyses
(Table 2). 
Table 2. Trial secondary outcomes 
Outcome 
Type 
Analysis 
All-location, all-cause 14-day 
mortality (assessed on Study 
Day 15) 
Binary 
Logistic 
regression 
All-location, all-cause 28-day 
mortality (assessed on Study 
Day 29) 
Binary 
Logistic 
regression 
Survival through 28 days 
Time-to-
event 
Proportional 
hazards 
regression 
Time to hospital discharge 
through 28 days 
Time-to-
event 
Multistate 
model with 
death as a 
competing 
risk 
Time to recovery (defined as 
time from randomization to the 
earlier of final oxygen receipt in 
the hospital or hospital 
discharge) 
Time-to-
event 
CPM with 
logit link 
COVID-19 7-point Ordinal 
Clinical Progression Outcomes 
Scale on Study Day 3, 8 and 29 
Ordinal 
CPM with 
logit link 
Oxygen-free days through Day 
28 
Ordinal 
CPM with 
logit link 
Ventilator-free days through Day 
28  
Ordinal 
CPM with 
logit link 
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Vasopressor-free days through 
Day 28 
Ordinal 
CPM with 
logit link 
ICU-free days through Day 28 
Ordinal 
CPM with 
logit link 
Hospital-free days through Day 
28 
Ordinal 
CPM with 
logit link 
8.6.1 Ordinal outcomes 
Ordinal secondary outcomes will be analyzed using the same
model described for the primary endpoint.  Similar steps to
evaluate model fit and overly influential observations will be
performed. 
8.6.2 Binary outcomes 
Binary secondary outcomes will be analyzed using multivariable
logistic regression models with the same pre-specified covariates
as the primary endpoint.  To assess model calibration and overly
influential observations, graphical displays of calibration and
DFBETAS will be created. 
8.6.3 Time to event outcomes 
Survival will be analyzed with a proportional hazards regression
model.  The key result of the analysis is an estimate of the 
treatment effect hazards ratio.  The same set of covariates used 
for the adjusted analysis of the primary endpoint will also be
included in the analysis of secondary time-to-event endpoints.
Model fit will be assessed with Schoenfeld residuals and with
leave-one-out diagnostics like DFBETAS.  The proportional odds
assumption will be evaluated with graphical displays.  Deviations
from proportionality will trigger sensitivity analyses. 
8.6.4 Outcomes with a competing risk of death 
Some secondary outcomes, like the primary outcome, incorporate 
death as part of the scale.  Others, such as time to discharge, do
not.  Because death censors length of stay, it is a competing
outcome. Outcomes with a competing risk of death will be analyzed
with a multi-state model.  Both the instantaneous risk and 
cumulative risk of the outcome will be reported.    
8.6.5 Missing data 
If missing covariate data occurs, then multiple imputation methods 
similar to those described for the primary endpoint will be used to
estimate the point estimate and confidence interval for the
secondary endpoints.” 
Page 45 New Section 8.7 
Safety Outcomes and 
Adverse Events 
New Text “ 
8.7 Safety Outcomes and Adverse Events 
The frequency and description of safety outcomes and adverse
events will be reported.  The association between intervention
group and safety outcomes will be estimated without covariate
adjustment.  The following table lists the safety outcomes and the
planned analyses (Table 3). 
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Table 3. Trial safety outcomes.  
Outcome 
Type 
Analysis 
Receipt of renal replacement 
therapy 
Binary 
Risk difference 
Documented venous 
thromboembolic disease (DVT 
or PE) 
Binary 
Risk difference 
Documented cardiovascular 
event (myocardial infarction or 
ischemic stroke) 
Binary 
Risk difference 
Transfusion reaction 
(fever/rash) 
Binary 
Risk difference 
Transfusion related acute lung 
injury (TRALI) 
Binary 
Risk difference 
Transfusion associated 
circulatory overload (TACO) 
Binary 
Risk difference 
Transfusion related infection 
Binary 
Risk difference 
Page 46 Section 10.1.1 
Potential risks of 
receiving convalescent 
plasma 
Remove “In order to minimize the risks of disease transmission,
pathogen reduction techniques will be utilized to prepare the 
plasma. “ 
Administrative change 
Page 46 Section 10.2 
Minimalization of Risk 
Previous Text “Convalescent serum has been approved by the 
Food and Drug Administration and has been used in clinical 
practice for decades in a number of patient populations with an
established safety profile. 
Current Text “Convalescent plasma has been approved by the
Food and Drug Administration and has been used in clinical 
practice for decades in a number of patient populations with an
established safety profile.”  
Administrative change 
Page 49 Section 12. 
ADVERSE EVENTS 
Previous Text “This protocol addresses these considerations 
throughout:” 
Current Text “This protocol addresses these considerations 
including the following:” 
Previous Text “3. Proactive education of treating clinicians
regarding relevant reactions to use of convalescent plasma in the
inpatient setting” 
Current Text “3. Proactive education of treating clinicians
regarding relevant adverse reactions to convalescent plasma” 
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Previous Text “4. On-study monitoring of co-interventions (e.g.,
medications) and patient characteristic to intervene before adverse
events occur” 
Current Text “4. On-study monitoring of co-interventions (e.g.,
medications) and patient characteristic to help prevent adverse 
events 
Previous Text “5. Systematic collection of safety outcomes 
relevant to use of convalescent plasma in this setting” 
Current Text “5. Systematic collection of safety outcomes 
relevant to use of convalescent plasma” 
Page 49 Section 12.1 
Adverse Event 
Definitions  
Previous Text “Reportable Serious Adverse Event: Adverse
events that are serious and have a reasonable possibility that the
event was due to a study infusion or procedure. 
Current Text “Serious Adverse Event: Adverse events that are
serious as defined in section 12.2 below.” 
Administrative change 
Page 49-50 Move 
Section 12.3 Serious 
Adverse Events to 
Section 12.2  
Previous Text “As per the FDA and NIH definitions, a serious
adverse event is any adverse event that results in one of the
following outcomes:” 
Current Text “As per the FDA and NIH definitions, and Section 12.1
of this protocol, a serious adverse event is any adverse event that 
results in one of the following outcomes:” 
Move up with previous bullets “•Persistent or significant 
disability/incapacity” 
Previous Text “Report if admission to the hospital or prolongation
of hospitalization was a result of the adverse event.” 
Current Text “Report an adverse event as serious if admission to
the hospital or prolongation of hospitalization was a result of the
adverse event.” 
Previous Text “Report if the adverse event resulted in a substantial
disruption of a person's ability to conduct normal life functions, i.e., 
the adverse event resulted in a significant, persistent or permanent
change, impairment, damage or disruption in the patient's body
function/structure, physical activities and/or quality of life.” 
Current Text “Report an adverse event serious if the adverse event
resulted in a substantial disruption of a person's ability to conduct
normal life functions, i.e., the adverse event resulted in a
significant, persistent or permanent change, impairment, damage
or disruption in the patient's body function/structure, physical
activities and/or quality of life.” 
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Previous Text “Reportable serious adverse events that may not
result in death, be life-threatening, or require hospitalization may 
be considered serious adverse events when, based upon
appropriate medical judgment, they may jeopardize the patient and
may require medical or surgical intervention to prevent one of the
outcomes listed in this definition. 
Current Text “Adverse events that may not result in death, be life-
threatening, or require hospitalization may be considered serious
adverse events when, based upon appropriate medical judgment,
they jeopardize the patient and may require medical or surgical
intervention to prevent one of the outcomes listed in this definition.”
Previous Text “Serious adverse events will be collected during the
first 3 study days, 72 hours after completion of the study plasma
infusion, or until hospital discharge, whichever occurs first, 
regardless of the investigator's opinion of causation.” 
Current Text “Serious adverse events will be collected through 
study day 4, 72 hours after completion of the study infusion, or until
hospital discharge, whichever occurs first, regardless of the
investigator's opinion of causation. 
Page 50 Section 12.3 
Safety Monitoring  
Re-number Section 12.2 to 12.3 Safety Monitoring 
Previous Text “The Investigators will determine daily if any adverse
events occur during the period from enrollment through study day
3, 72 hours after completion of the study plasma infusion, or
hospital discharge, whichever occurs first, and will determine if 
such adverse events are reportable.  Thereafter, adverse events 
are not required to be reported to the IRB unless the investigator
feels the adverse event was related to study infusion or study 
procedures. “ 
Current Text “The investigators will determine daily if any adverse
events occur during the period from enrollment through study day
4,(which is 72 hours after completion of the study product infusion, 
or hospital discharge, whichever occurs first, and will determine if
adverse events are related to study procedures. Adverse events 
are not required to be reported to the IRB unless the investigator
feels the adverse event was related to study infusion or study 
procedures.” 
Previous Text “The following adverse events will be considered
reportable and thus collected in the adverse event case report 
forms:  
• Serious adverse events (as defined in protocol section 12.1 of this
protocol) 
• Non-serious adverse events that are considered by the
investigator to be related to study procedures or of uncertain
relationship  
• Events leading to permanent discontinuation of study infusion” 
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Current Text “The following adverse events will be collected in the 
adverse event case report forms: 
 
• Serious adverse events (as defined in protocol section 12.2 of this
protocol) that are study related (or of uncertain relationship) or 
occur within 72 hours of the study infusion 
• Non-serious adverse events that are study procedures or of
uncertain relationship  
• Events leading to permanent discontinuation of study infusion
(which, by definition, are study related) 
The protocol for reporting adverse events in the trial’s electronic
data capture system are summarized in Table 4. 
 
New Text “ 
Table 4. Protocol for reporting adverse events 
Type of Adverse Event 
Time for Recording 
Serious, study related 
24 hours 
Serious, not study related 72 hours 
Serious, not study related Recording in the EDC 
Not serious, study related 
72 hours 
Not serious, not study Recording in the EDC 
Previous Text “After randomization, adverse events must be
evaluated by the investigator. If the adverse event is judged to be
reportable, as outlined above, then the investigator will report to the 
Lead PIs for assessment of the potential relatedness of each
adverse event to the study treatment or protocol procedure via 
electronic data entry.” 
Current Text “After randomization, adverse events must be
evaluated by the investigator. If the adverse event is judged to be
reportable, as outlined above, then the investigator will report to the
Medical Monitor for assessment of the potential relatedness of 
each adverse event to the study treatment or protocol procedure 
via electronic data entry.” 
New Text “Additional information about adverse event reporting is
included in Appendix B.” 
Page 51 New Section 
12.4 Medical Monitor 
New Text “After randomization, adverse events must be evaluated 
by the investigator. If the adverse event is judged to be reportable, 
as outlined above, then the investigator will report to the Lead PIs
for assessment of the potential relatedness of each adverse event 
to the study treatment or protocol procedure via electronic data
entry. 
Adding Medical Monitor to the study 
Page 51 Section 12.5 
Data and Safety 
Monitoring Board 
(DSMB) 
Previous Text “They will regularly monitor data from this trial,
review and assess the performance of its operations, and make
recommendations to the study team:” 
Current Text “They will regularly monitor data from this trial, review
and assess the performance of its operations, and make
recommendations to the study team. DSMB activities include:” 
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Page 52 Appendix A: 
Schedule of Events 
Updated Schedule of Events  
To align the body of the protocol with 
the Schedule of Events 
Page 53-55 Appendix B:  
Adverse Event 
Reporting and 
Unanticipated Events 
Previous Text “Investigators will report all serious adverse events
that a reasonable possibility that the event was due to a study
infusion or procedure (or of uncertain relatedness), to the VCC
within 24 hours.” 
Current Text “Investigators will report all serious adverse events 
that occur within 72 hours of study infusion to the Vanderbilt
Coordinating Center (VCC) regardless of relatedness.  Serious 
adverse events that are determined to be related to study
procedures (regardless of timing related to study infusion) will be
reported to the VCC within 24 hours.” 
Change “Lead PIs” to “Medical Monitor” 
To align Appendix B with the body of 
the protocol 
Remove Appendices C 
and D 
How the SOFA Score is calculated is being performed by the 
biostatisticians 
SOFA Score is calculated is being 
performed by the biostatisticians 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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PROTOCOL SIGNATURE PAGE 
Passive Immunity Trial for Our Nation (PassItOn) 
Version 6.0  
January 28, 2021 
I agree to conduct the study in accordance with the relevant, current protocol and will not make changes to the protocol 
without prior approval from the IRB of record, except when necessary to protect the safety, rights, or welfare of study 
participants. 
I agree to personally conduct or supervise this study. 
I will ensure that the requirements relating to obtaining informed consent and Ethics Committee (EC) or Institutional 
Review Board (IRB) review and approval are met. 
I agree to maintain adequate and accurate study records and to make those records available for inspection by authorized 
representatives, and/or other applicable regulatory entities. 
I will ensure that an EC or IRB that complies with the requirements of 45 CFR Part 46 will complete initial and continuing 
review and approval of the study. I also agree to promptly report to the EC/IRB all changes to the study and all 
unanticipated problems involving risks to human subjects or others. Additionally, I will not make any changes to the study 
without Sponsor-Investigator and EC/IRB approval, except where necessary to eliminate apparent immediate hazards to 
study participants. 
I agree to ensure that all staff members involved in the conduct of this study are informed about their obligations in 
meeting the above commitments. 
  
Site Investigator: _______________________________  
 (Print/Type)                                                                                                                   
                
Institution Title: ________________________________ 
(Print/Type)                                                                                                                   
                

 
 
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Signed: ____________________________________ Date: _____________ 
Table of Contents 
 
Summary of Changes .................................................................................................................................... 1 
PROTOCOL SIGNATURE PAGE ....................................................................................................................... 22 
1. 
ABBREVIATIONS..................................................................................................................................... 26 
2. 
STUDY SUMMARY .................................................................................................................................. 27 
3. 
TRIAL DESCRIPTION .............................................................................................................................. 29 
3.1 
Background ....................................................................................................................................... 29 
3.1.1 COVID-19 Infection .......................................................................................................................... 29 
3.1.2 Passive antibody therapy ................................................................................................................. 29 
3.1.3 Convalescent donor plasma as a therapeutic for COVID-19 ............................................................ 30 
3.1.4 Rationale for a randomized trial among hospitalized patients .......................................................... 30 
3.2 Study Aims ............................................................................................................................................. 30 
3.2.1 Study aim ........................................................................................................................................ 30 
3.2.2 Study hypothesis ............................................................................................................................. 30 
3.3 Study Design .......................................................................................................................................... 30 
4. 
STUDY POPULATION AND ENROLLMENT ............................................................................................ 31 
4.1 Inclusion Criteria .................................................................................................................................... 31 
4.2 Exclusion Criteria ................................................................................................................................... 31 
4.3 Justification of Exclusion Criteria ............................................................................................................ 31 
4.4 Screening ............................................................................................................................................... 31 
4.5 Assessment of Eligibility and Exclusion Tracking ................................................................................... 31 
4.6 Process of Obtaining Informed Consent ................................................................................................. 32 
4.7 Randomization and Blinding ................................................................................................................... 34 
4.8 Minorities and Women ........................................................................................................................... 34 
5. 
STUDY INTERVENTIONS ....................................................................................................................... 34 
5.1 Treatment of Study Participants ............................................................................................................. 34 
5.2 Convalescent Plasma Group .................................................................................................................. 36 
5.3 Control Group ........................................................................................................................................ 36 
5.4 Co-interventions ..................................................................................................................................... 36 
5.5 On-Study Monitoring .............................................................................................................................. 36 
5.6 
Criteria for Stopping Study Infusion ................................................................................................... 36 
5.7 Plan for Plasma Shortages ..................................................................................................................... 37 
6. 
OUTCOMES ............................................................................................................................................. 37 
6.1 
Primary Outcome .............................................................................................................................. 37 
6.2 Secondary Outcomes ............................................................................................................................. 37 

 
 
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6.3 Safety Outcomes.................................................................................................................................... 37 
6.4 Rationale for Primary Outcome .............................................................................................................. 38 
7. 
DATA AND BIOLOGICAL SPECIMEN COLLECTION .............................................................................. 38 
7.1 Baseline Variable Collection ................................................................................................................... 38 
7.2 Assessments Between Hospital Presentation and Hospital Discharge ................................................... 38 
7.3 Assessments Following Hospital Discharge ........................................................................................... 39 
7.3.1 Acute Care Follow-up ...................................................................................................................... 39 
8. 
STATISTICAL CONSIDERATIONS .......................................................................................................... 40 
8.1 
Summary ........................................................................................................................................... 40 
8.2 Planned interim analyses for mortality .................................................................................................... 40 
8.3 Analysis plan for primary endpoints ........................................................................................................ 41 
8.3.1 Model fit ........................................................................................................................................... 41 
8.3.2 Missing data .................................................................................................................................... 41 
8.3.3 Assertion of efficacy ......................................................................................................................... 41 
8.4 Trial characteristics ................................................................................................................................ 42 
8.4.1 Inference ......................................................................................................................................... 42 
8.4.2 Type I error rate and power ............................................................................................................. 42 
8.5 Analysis plan for additional analyses of the primary endpoint ................................................................. 43 
8.5.1 Quantification of effect of donor plasma characteristics on treatment efficacy .................................. 43 
8.5.2 Effect modification analyses of the primary outcome ....................................................................... 43 
8.6 Analysis plan for secondary endpoints ................................................................................................... 44 
8.6.1 Ordinal outcomes ............................................................................................................................ 44 
8.6.2 Binary outcomes .............................................................................................................................. 44 
8.6.3 Time to event outcomes................................................................................................................... 44 
8.6.4 Outcomes with a competing risk of death ........................................................................................ 45 
8.6.5 Missing data .................................................................................................................................... 45 
8.7 Safety Outcomes and Adverse Events ................................................................................................... 45 
9. 
DATA QUALITY MONITORING AND STORAGE ..................................................................................... 45 
9.1 Data Quality Monitoring .......................................................................................................................... 45 
9.2 Data Storage .......................................................................................................................................... 45 
10. 
RISK ASSESSMENT ............................................................................................................................ 45 
10.1 Potential Risk to Participants ................................................................................................................ 45 
10.1.1 
Potential risks of receiving convalescent plasma ........................................................................ 46 
10.1.2 Potential risks of receiving lactated Ringer’s solution with multivitamins with COVID-19 ................ 46 
10.2 Minimalization of Risk .......................................................................................................................... 46 
10.3 Potential Benefit ................................................................................................................................... 46 
10.4 Risk in Relation to Anticipated Benefit .................................................................................................. 46 
11. 
HUMAN SUBJECTS PROTECTIONS ................................................................................................... 46 

 
 
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11.1 Selection of Subjects ............................................................................................................................ 47 
11.2 Justification of Including Vulnerable Subjects ....................................................................................... 47 
11.3 Informed Consent ................................................................................................................................. 47 
11.4 Continuing Consent .............................................................................................................................. 47 
11.5 Withdrawal of Consent ......................................................................................................................... 47 
11.6 Identification of Legally Authorized Representatives ............................................................................ 47 
11.7 Justification of Surrogate Consent ........................................................................................................ 48 
11.8 Additional Safeguards for Vulnerable Participants ................................................................................ 48 
11.9 Confidentiality ...................................................................................................................................... 48 
12. 
ADVERSE EVENTS ............................................................................................................................. 49 
12.1 Adverse Event Definitions .................................................................................................................... 49 
12.2 Serious Adverse Events ....................................................................................................................... 49 
12.3 Safety Monitoring ................................................................................................................................. 50 
12.4 Medical Monitor .................................................................................................................................... 51 
12.5 Data and Safety Monitoring Board (DSMB) .......................................................................................... 51 
Appendix A: Schedule of Events .................................................................................................................. 52 
Appendix B:  Adverse Event Reporting and Unanticipated Events ............................................................... 53 
B.1. Unanticipated Problems (UP) ............................................................................................................ 53 
B.2. Determining Relationship of Adverse Events to Study Infusion or Study Procedures ........................ 53 
B.3. Clinical Outcomes that may be Exempt from Adverse Event Reporting ............................................. 54 
B.4. Decision tree for determining if an adverse event is reportable ......................................................... 55 
13. REFERENCES .......................................................................................................................................... 56 
 
 
 
 

 
 
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1. ABBREVIATIONS  
ADE  
Antibody-mediated disease enhancement  
AE  
Adverse event  
ARDS  
Acute respiratory distress syndrome  
CBC  
Complete blood count  
CMP  
Complete metabolic panel  
COVID-19 
Coronavirus Disease 2019  
CRP  
C-reactive protein  
DSMB  
Data safety monitoring board  
DSMBc 
Data safety monitoring board coordination 
DVT  
Deep vein thrombosis  
ECMO 
Extracorporeal membrane oxygenation 
eCRF  
Electronic case report forms  
ELISA  
Enzyme linked immunosorbent assay  
FDA  
Food and Drug Administration  
HBV 
Hepatitis B 
HCV 
Hepatitis C 
HIV 
Human immunodeficiency virus 
ICU  
Intensive care unit  
LAR  
Legally authorized representative  
LR  
Lactated Ringer’s Solution  
MERS  
Middle East Respiratory Syndrome  
PE 
Pulmonary embolism 
PI  
Principal investigator (a clinician responsible for the trial)  
PPE 
Personal protective equipment 
RBD 
Receptor binding domain 
RT-PCR 
Reverse transcription polymerase chain reaction  
SAE  
Serious adverse event  
SARS  
Severe Acute Respiratory Syndrome  
SOFA  
Sequential organ failure assessment  
sIRB 
single Institutional Review Board 
TRALI  
Transfusion associated acute lung injury  
TACO  
Transfusion associated circulatory overload  
VCC 
Vanderbilt Coordinating Center  
VUMC 
Vanderbilt University Medical Center 

 
 
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2. STUDY SUMMARY 
Title 
Passive Immunity Trial for Our Nation 
Acronym 
PassItOn 
Background 
Effective therapies for COVID-19 are urgently needed. Convalescent COVID-19 
donor plasma is the liquid part of blood that is collected from patients who have 
recovered from COVID-19 infection. This plasma contains SARS-CoV-2 specific 
antibodies that may help patients with COVID-19 recover. Preliminary reports 
suggest potential efficacy in small human studies.  Clinical trial data are needed to 
determine whether convalescent donor plasma is efficacious in treating COVID-19.  
Study Design 
Multicenter, blinded, placebo-controlled randomized clinical trial comparing 
outcomes of patients randomized to COVID-19 convalescent plasma versus 
placebo. 
Use of open label convalescent plasma in the first 15 days of the study is strongly 
discouraged.  
Intervention  
group treatment 
1 unit (200–399 ml) of SARS-CoV-2 convalescent plasma infused intravenously  
Control group treatment 
250 ml of Lactated Ringer’s with multivitamins, which visually resembles plasma, 
infused intravenously 
Sample Size 
1000 
Inclusion Criteria 
1. Age greater than or equal to 18 years  
2. 
Currently hospitalized or in an emergency department with anticipated 
hospitalization 
3. 
Symptoms of acute respiratory infection, defined as one or more of the 
following: 
a. Cough 
b. Chills, or a fever (greater than 37.5° C or 99.5° F) 
c. Shortness of breath, operationalized as a patient having any of the 
following: 
i. Subjective shortness of breath reported by a patient or surrogate. 
ii. Tachypnea with respiratory rate of greater than 22 breaths per minute 
iii. Hypoxemia, defined as SpO2 less than 92% on room air, new receipt 
of supplemental oxygen to maintain SpO2 greater than or equal to 
92%, or increased supplemental oxygen to maintain SpO2 greater 
than or equal to 92% for a patient on chronic oxygen therapy 
4. Laboratory-confirmed SARS-CoV-2 infection within the past 14 days 
Exclusion Criteria  
1. Prisoner 
2. Unable to randomize within 14 days after onset of acute respiratory infection 
symptoms 
3. Patient, legal representative, or physician not committed to full support 
(Exception: a patient who will receive all supportive care except for attempts 
at resuscitation from cardiac arrest will not be excluded.) 
4. Inability to be contacted on Day 29-36 for clinical outcome assessment 
5. Receipt of any SARS-CoV-2 passive immunity therapy, such as convalescent 
plasma, monoclonal antibodies, or pooled immunoglobulin, in the past 30 
days.  
6. Contraindications to transfusion or history of prior reactions to transfused 
blood products 
7. Plan for hospital discharge within 24 hours of enrollment  

 
 
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8. Previous enrollment in this trial 
9. Previous laboratory-confirmed SARS-CoV-2 infection before the current 
illness 
10. Enrollment in another clinical trial evaluating monoclonal antibodies, 
convalescent plasma, or another passive immunity therapy. 
11. Prior receipt of SARS-CoV-2 vaccine 
Randomization 
Eligible participants will be randomized 1:1 to convalescent plasma versus 
lactated Ringer’s solution with multivitamins. Randomization will be completed in 
permuted blocks and stratified by site, gender, and age. 
Blinding 
Patients and outcome assessors will be blinded to group assignment. 
Primary Outcome 
COVID-19 7-point Ordinal Clinical Progression Outcomes Scale on Study Day 15: 
1. Not hospitalized with resumption of normal activities. 
2. Not hospitalized, but unable to resume normal activities. 
3. Hospitalized, not on supplemental oxygen. 
4. Hospitalized, and on supplemental oxygen. 
5. Hospitalized, on nasal high-flow oxygen therapy, noninvasive mechanical 
ventilation, or both 
6. Hospitalized, on ECMO, invasive mechanical ventilation, or both. 
7. Death 
Secondary Outcomes 
• 
All-location, all-cause 14-day mortality (assessed on Study Day 15) 
• 
All-location, all-cause 28-day mortality (assessed on Study Day 29) 
• 
Survival through 28 days 
• 
Time to hospital discharge through 28 days 
• 
Time to recovery (defined as time from randomization to the earlier of final 
oxygen receipt in the hospital or hospital discharge).  
• 
COVID-19 7-point Ordinal Clinical Progression Outcomes Scale on Study Day 
3, 8, and 29 
• 
Oxygen-free days through Day 28 
• 
Ventilator-free days through Day 28 
• 
Vasopressor-free days through Day 28 
• 
ICU-free days through Day 28 
• 
Hospital-free days through Day 28 
Safety Outcomes 
• 
Acute kidney injury 
• 
Receipt of renal replacement therapy 
• 
Documented venous thromboembolic disease (DVT or PE) 
• 
Documented cardiovascular event (myocardial infarction or ischemic stroke) 
• 
Transfusion reaction (fever/rash) 
• 
Transfusion related acute lung injury (TRALI) 
• 
Transfusion associated circulatory overload (TACO) 
• 
Transfusion related infection  
Analysis 
The primary analysis will be an intent-to-treat analysis comparing scores on the 
COVID-19 7-point Ordinal Clinical Progression Outcomes Scale on Day 15 
between patients randomized to convalescent plasma versus patients 
randomized to placebo. The key result of the analysis will be an estimate of the 
treatment effect odds ratio, which will be estimated from a cumulative probability 
ordinal regression model (CPM) with logit link. Covariates in the regression model 
will include age, sex, baseline Sequential Organ Failure Assessment (SOFA) 
score, baseline COVID-19 Ordinal Outcomes Scale score, time from symptom 
onset, and site.  

 
 
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3. TRIAL DESCRIPTION 
3.1 Background 
Coronavirus Disease 2019 (COVID-19) is an acute respiratory infectious illness caused by severe acute 
respiratory syndrome coronavirus 2 (SARS-CoV-2).1,2  Although the epidemiology has not been fully 
elucidated, most adults with COVID-19 appear to experience fever, cough, and fatigue and then recover within 
1-3 weeks.  However, a portion of adults with COVID-19 develop severe illness, often manifesting as 
pneumonia and hypoxemic respiratory failure, with continued progression to acute respiratory distress 
syndrome (ARDS) and death in some cases.1–3   Effective therapies that prevent the progression of COVID-19 
are urgently needed.  Passive antibody therapy via convalescent donor serum has generated substantial 
interest due to its established safety and suggested efficacy in other viral diseases including influenza4,5, 
Ebola6, and notably, two other novel coronavirus respiratory diseases, Middle East Respiratory Syndrome 
(MERS)7 and Severe Acute Respiratory Syndrome (SARS)-CoV-1.8 As patients continue to recover from 
COVID-19, convalescent donor plasma becomes a readily available and viable treatment option for COVID-19. 
However, there are potential risks to passive antibody therapy including antibody-mediated enhancement of 
infection (ADE).  Thus, data on the safety and efficacy of convalescent plasma for the treatment of COVID-19 
are needed to inform clinical practice.  In this trial, we will evaluate the safety and efficacy of convalescent 
serum for the treatment of adults hospitalized with COVID-19.  
 
3.1.1 COVID-19 Infection 
COVID-19 was first identified as a cluster of cases of pneumonia among a group of workers from a seafood 
wholesale market in Wuhan, China in December 2019.9  This observation, along with subsequent viral 
genotyping showing significant genetic similarities to the bat coronaviruses10 suggest a zoonotic origin, 
although the specific reservoir and intermediary species remain unclear.11  COVID-19 represents the seventh 
coronavirus known to cause disease in humans.12  Four of the coronaviruses are known to cause symptoms of 
the common cold in immunocompetent individuals while two others (SARS-CoV and MERS-CoV) have caused 
recent outbreaks of severe and sometimes fatal respiratory diseases.13 SARS-CoV-2 appears to exploit the 
same cellular receptor as SARS-CoV and MERS-CoV,14 and its severity may similarly result from a predilection 
for intrapulmonary epithelial cells over cells of the upper airways.15,16  
 
Since the first documented human case, COVID-19 has spread exponentially with over 20 million confirmed 
cases and over 750,000 deaths globally as of August 14, 2020.  While most patients recover after a mild, brief 
illness with fever and cough, the disease has a clinical spectrum ranging from asymptomatic infection17 to 
ARDS and death.18  The most common reasons for ICU care are respiratory failure and ARDS, with a minority 
developing shock and cardiomyopathy.19 The case fatality rate is estimated to be 0.25% to 3.0%.20   
 
3.1.2 Passive antibody therapy 
Passive antibody therapy or passive immunization is the transfer of an active humoral immune response from 
a donor to a recipient. Passive immunity occurs naturally in maternal fetal interactions as the mother’s 
antibodies are given to the fetus across the placenta and are transferred to the newborn in breastmilk.21 More 
relevant to this proposal, artificial passive immunity takes place when antibodies from a disease-immune 
individual are given via plasma as a medication or therapy to a non-immune individual.4 Passive antibody 
therapy has been used to treat infectious diseases since the late 1800’s, and was successfully used in the 
1920’s and 30’s to treat a wide variety of infections including pneumococcal pneumonia, meningococcal 
meningitis, diphtheria, scarlet fever, and measles.22 Convalescent plasma has been used more recently in the 
setting of viral epidemics. One example is the 2009-2010 H1N1 influenza pandemic where convalescent 
plasma was used to treat individuals with severe infection requiring intensive care. Results showed that 
individuals who received convalescent plasma had a reduced viral load, inflammatory cytokine levels, and 
mortality.23 Anecdotal evidence also exists for the success of convalescent plasma treatment in the H5N124,25 
and H7N926 avian flu outbreaks.  In addition, convalescent plasma was used in the 2013 West Africa Ebola 
epidemic where a small nonrandomized study in Sierra Leone showed significantly improved survival rates in 

 
 
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individuals who received plasma compared to controls.6 Two US Ebola patients also received convalescent 
plasma and survived.27 
 
3.1.3 Convalescent donor plasma as a therapeutic for COVID-19 
There have been two other recent coronavirus epidemics associated with high risk of death:  SARS-CoV-1 in 
2003 and MERS in 2012. In the case of both SARS-COV-1 and MERS, high mortality and a lack of therapeutic 
options led to studies of convalescent plasma. The largest of these studies included 80 patients in Hong Kong 
and showed that patients treated before day 14 had improved prognosis, defined by discharge from hospital 
before day 22.28 It is also important to note that individuals who were RT-PCR positive and seronegative for 
coronavirus at the time of therapy had improved prognosis. A second study of three seriously ill SARS patients 
in Taiwan treated with 500 ml of convalescent plasma showed a reduction in plasma virus titer and each 
survived.29 Similar to the SARS studies, three patients with MERS in South Korea were treated with 
convalescent plasma, but only two of the recipients had neutralizing antibody in their plasma.7  Consistent with 
this point, an analysis of 99 samples of convalescent sera from patients with SARS showed that 87 had 
neutralizing antibodies with a geometric mean titer of 1:61 and authors concluded that this was suggestive of 
antibody titer declining over time and/or only few patients make high titer responses.30 Convalescent plasma 
therapy has been used in the current COVID-19 pandemic for critically ill patients. In one case series, 4 
critically ill patients, including one pregnant woman, received convalescent plasma and recovered from the 
infection.31 A second case series of 5 critically ill patients with COVID-19 and ARDS  requiring mechanical 
ventilation who received convalescent plasma with a SARS-CoV-2 specific antibody binding titer greater than 
1:1000 by ELISA also all survived.32 In late February 2020, it was reported that China had treated 245 COVID-
19 patients with convalescent plasma and 91 cases had shown improvement in clinical indicators and 
symptoms.33 
 
3.1.4 Rationale for a randomized trial among hospitalized patients 
The initial symptoms of COVID-19 develop approximately 2-10 days after infection with the SARS-CoV-2 
virus,34 with the progression to respiratory failure and ARDS occurring approximately 7-10 days after the onset 
of symptoms.35 The period between onset of symptoms and development of severe respiratory failure 
represents a potential window for treatment of hospitalized patients to prevent disease progression. 
Convalescent plasma is now commonly being administered to hospitalized patients with COVID-19.  However, 
the effectiveness of convalescent plasma in this setting remains unknown. Therefore, rigorous clinical trial data 
on the efficacy and safety of convalescent plasma as a treatment for COVID-19 are urgently needed to inform 
clinical practice. 
 
 
3.2 Study Aims 
3.2.1 Study aim 
To compare the effect of convalescent plasma versus placebo on clinical outcomes, measured using the 
COVID-19 7-point Ordinal Clinical Progression Outcomes Scale at Day 15, among adults hospitalized with 
COVID-19.  
 
3.2.2 Study hypothesis 
Among adults hospitalized with COVID-19, administration of convalescent plasma will improve clinical 
outcomes at Day 15.  
 
3.3 Study Design 
We will conduct a multi-site, investigator-initiated, blinded, placebo-controlled, randomized clinical trial 
evaluating convalescent donor plasma for the treatment of adults hospitalized with COVID-19. Plasma will be 
collected and distributed to sites through blood donation groups partnering with Vanderbilt University Medical 
Center (VUMC)’s blood donation center partner.  Anti-SARS-CoV-2 antibody quantification assays will be 
completed on donor plasma at VUMC prior to plasma distribution. Only plasma with antibody quantification 
above the neutralizing threshold will be used in the trial.    

 
 
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4. STUDY POPULATION AND ENROLLMENT 
4.1 Inclusion Criteria 
1. Age greater than or equal to 18 years  
2. Currently hospitalized or in an emergency department with anticipated hospitalization. 
3. Symptoms of acute respiratory infection, defined as one or more of the following: 
a. cough 
b. Chills, or a fever (greater than 37.5° C or 99.5° F) 
c. shortness of breath, operationalized as a patient having any of the following:  
i. Subjective shortness of breath reported by a patient or surrogate. 
ii. Tachypnea with respiratory rate greater than 22 breaths per minute. 
iii. Hypoxemia, defined as SpO2 less than 92% on room air, new receipt of supplemental 
oxygen to maintain SpO2 greater than or equal to 92%, or increased supplemental 
oxygen to maintain SpO2 greater than or equal to 92% for a patient on chronic oxygen 
therapy 
4. Laboratory-confirmed SARS-CoV-2 infection within the past 14 days. 
4.2 Exclusion Criteria 
1. Prisoner 
2. Unable to randomize within 14 days after onset of acute respiratory infection symptoms  
3. Patient, legal representative, or physician not committed to full support (Exception: a patient who will 
receive all supportive care except for attempts at resuscitation from cardiac arrest will not be excluded.) 
4. Inability to be contacted on Day 29-36 for clinical outcome assessment 
5. Receipt of any SARS-CoV-2 passive immunity therapy, such as convalescent plasma, monoclonal 
antibodies, or pooled immunoglobulin, in the past 30 days  
6. Contraindications to transfusion or history of prior reactions to transfused blood products 
7. Plan for hospital discharge within 24 hours of enrollment  
8. Previous enrollment in this trial 
9. Previous laboratory-confirmed SARS-CoV-2 infection before the current illness 
10. Enrollment in another clinical trial evaluating monoclonal antibodies, convalescent plasma, or another 
passive immunity therapy. 
11. Prior receipt of a SARS-CoV-2 vaccine 
 
4.3 Justification of Exclusion Criteria 
The exclusion criteria are primarily designed for patient safety. In addition to excluding specific vulnerable 
populations (e.g., prisoners), these criteria are designed to exclude patients for whom receipt of convalescent 
plasma might increase the risk of serious adverse events. Pregnant women are not excluded from the trial. 
 
4.4 Screening 
The site investigator or delegate will screen for hospitalized patients with laboratory confirmed COVID-19 (that 
is, a positive laboratory test for SARS-CoV-2) or a pending SARS-CoV-2 test. Treating clinicians will also be 
instructed to contact the site investigator or delegate for patients with a high clinical suspicion of COVID-19.  
 
4.5 Assessment of Eligibility and Exclusion Tracking 
For patients who appear to meet eligibility criteria after screening, an electronic case report form will be 
completed to determine eligibility and track exclusions. The electronic case report form will be accessed and 
stored in the electronic database.  At the time of entry into the screening database, the patient will be assigned 
a screening number.  
 
If a patient appears to meet all eligibility criteria, the site investigator or delegate will approach the treating 
clinician to ask permission to approach the patient or Legally Authorized Representative (LAR) to confirm 
eligibility, discuss potential study recruitment, and proceed with informed consent.   
 

 
 
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4.6 Process of Obtaining Informed Consent 
Informed consent will be obtained from the patient or from a surrogate decision maker if the patient lacks 
decision-making capacity.  Sites will follow local policies and procedures for obtaining consent.  
Bringing a paper consent form and pen to the bedside of a patient with known COVID-19 and then taking these 
out of the room would violate infection control principles and policies. Given the infectious risk from COVID-19 
and potential shortages of personal protective equipment (PPE), there is a moral and practical imperative to 
minimize face-to-face contact between patients and non-clinical personnel. The current epidemic also presents 
unique challenges to obtaining consent from participant’s legally authorized representative (LAR). To minimize 
infectious risk, many institutions are not allowing visitors to enter the hospital. Furthermore, the LAR is likely to 
have been exposed to the patient and may therefore be under self-quarantine at the time of the informed consent 
discussion. 
Therefore, we will use “no-touch” consent procedures for this trial, employing two main pathways, “paper-based” 
and “electronic.” Suggestions for the two approaches are outlined here.   
Paper-based approach 
1. The informed consent document is delivered to the patient or LAR. 
a. If the patient or LAR is on-site, the informed consent document many be delivered to the patient 
or LAR either by research staff or by clinical staff 
b. If the LAR is off-site, the informed consent document may be emailed, faxed, or otherwise 
electronically transferred to the LAR (method dictated by institutional policy) 
2. Research staff discuss the informed consent document with the patient or LAR either in-person or by 
telephone or videophone.  This step confirms subject/LAR identity. 
3. If the patient or LAR decides to consent to participate, the patient or LAR signs the paper copy of the 
informed consent document. 
4. A photograph is taken of the signature page of the informed consent document and uploaded into the 
electronic database (e.g. REDCap).  
a. If using the patient’s device (such as a patient’s personal cellular phone), a survey link can be 
sent to their device to allow direct upload of the image into the electronic database (e.g. 
REDCap). 
b. If using a staff device, it must be approved to store PHI by the local institution. In that case, 
research personnel can take a photograph of the signature page of the informed consent 
document either directly or through the window or glass door leading into the patient’s room.  
The photograph can then be uploaded into the electronic database.  If a staff device is taken 
into the patient’s room to take a photograph it must be able to be disinfected according to local 
institutional practices.  
5. Research staff and witness provide signatures within the electronic database (e.g. REDCap) confirming 
their participation in the informed consent process. 
6. The patient or LAR retains the paper consent document. The image of the signature page may be 
printed and bundled with a copy of the blank informed consent document for research records. 
 
Electronic approach 
1. The electronic informed consent document is opened on a research device or a link for the electronic 
informed consent document is sent to the patient’s or LAR’s device. 
2. Research staff discuss the informed consent document with the patient or LAR either in person or by 
telephone or videophone. This step confirms subject/LAR identity. 
3. If the patient or LAR decides to consent to participate the patient or LAR signs the electronic informed 
consent document.  This signature may be either: 
a. an actual signature (often tracing a finger on the screen) OR 
b. a username and password specific to the individual signing 
4. Research staff and witness provide signatures within the electronic database (e.g., REDCap) 
confirming their participation in the informed consent process. 

 
 
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5. The image of the signature page may be printed and bundled with a copy of the blank informed consent 
document for research records. 
 
If a hospital device is provided to facilitate electronic or paper-based consent, that device will be disinfected 
according to institutional protocols. 
 
Attestation of informed consent 
If none of the options outlined above (traditional signature and storage of a paper consent form, electronic 
photographs of a signed consent page, or e-consent) are available, study personnel may attest to completion of 
the informed consent process using the procedures outlined below.  Importantly, the process of informed consent 
using this attestation option should not change compared with the traditional method of obtaining informed 
consent for trial participation except for the method of documenting the consent process in the research record.  
Rather than storing a paper document with the participant’s signature, a member of the research team and an 
impartial witness will attest to completion of the informed consent process and that the participant signed the 
informed consent document. This option of attestation of informed consent is not available when obtaining 
consent through an LAR.   
Procedures for attestation of informed consent: 
1. An unsigned paper consent form is provided to the patient by a heath care worker or study member. 
2. The study member obtaining consent arranges an in-person meeting or three-way call or video 
conference with himself/herself, the patient, and an impartial witness. If desired and feasible, additional 
people requested by the patient (e.g., next of kin) may also join this discussion. 
3. Study member reviews consent and answers questions in the presence of the impartial witness. 
4. Patient signs the paper informed consent document while the witness is listening on the phone or 
directly observing. 
5. Patient provides verbal confirmation that he/she would like to participate in the trial, and he/she has 
signed and dated the informed consent document. This signed informed consent document stays with 
the patient due to the risk of spreading the virus.   
6. Study member and witness attest that other techniques for documenting informed consent were not 
available for this participant and that the participant provided written informed consent for trial 
participation by signing a paper informed consent document.  This attestation page with signatures from 
the study member and witness will be save as evidence of the informed consent process.  A signature 
from the participant will not be saved in the research record.   
 
This approach to informed consent detailed above complies with relevant regulations and sub-regulator guidance 
at 
45 
CFR 
46.117, 
45 
CFR 
164.512, 
21 
CFR 
11 
Subpart 
C 
(11.100–11.300), 
https://www.hhs.gov/ohrp/regulations-and-policy/guidance/use-electronic-informed-consent-questions-and-
answers/index.html, 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/informed-
consent. 
 
The information for the informed consent discussion will be provided in a formal document (or electronic 
equivalent) that has been approved by the IRB and in a language comprehensible to the potential participant, 
using an interpreter if necessary. The information presented in the consent form and by the research staff will 
detail the nature of the trial and what is expected of participants, including any potential risks and benefits of 
taking part. It will be clearly stated that the participant is free to withdraw from the trial at any time for any reason 
without prejudice to future care, and with no obligation to give the reason for withdrawal. Where a patient does 
not speak English, a short-form consent and qualified interpreter will be employed, using similar “no-touch” 
principles.  Use of an interpreter and the interpreter’s identity will be documented on the electronic consent. 
After allowing the potential participant or LAR time to read the informed consent document, research staff will 
answer any additional questions.     

 
 
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4.7 Randomization and Blinding 
Participants confirmed to meet all eligibility criteria who have provided informed consent will be randomized 1:1 
to convalescent plasma versus placebo.  A randomized group assignment will be provided from a centralized, 
web-based platform to an unblinded study personnel or delegate, who will order the study product 
(convalescent plasma or matching placebo). Randomization will require provision of the screening number and 
confirmation of patient eligibility. 
Randomization will be completed in permuted blocks and stratified by site, sex, and age. Randomization will be 
accessed through Research Electronic Data Capture (REDCap). The randomization module in REDCap allows 
the statistician to load a randomization table that will allow the study personnel to click a ‘randomize’ button. 
REDCap is a secure, web-based application designed to support data capture for research studies, providing 
1) an intuitive interface for validated data entry; 2) audit trails for tracking data manipulation and export 
procedures; 3) automated export procedures for seamless data downloads to common statistical packages; 
and 4) procedures for importing data from external sources.  
Patients, families, and outcome assessors will be blinded to treatment arm assignment. All other study 
personnel will be encouraged to remain blinded to the participant’s treatment assignment. Additional blinding 
procedure information will be in the PassItOn Blinding Procedure Document.  
Plasma can vary in color, volume, and viscosity depending on donor variables. Therefore, developing a 
universal matching placebo is not possible. In this trial, the placebo solution is lactated Ringer’s with 
multivitamin additives, which looks similar to plasma. The goal of the placebo solution is to maintain blinding of 
the participant, outcome assessors, and study personnel who are not closely involved in administering the 
study product. Clinical personnel who administer the study product (convalescent plasma vs placebo) such as 
the bedside nurse, will not be blinded. As an additional layer of blinding for the participant, plasma and placebo 
will be placed in matching blinding bags prior to administration.  
4.8 Minorities and Women 
No patients will be excluded based on race, ethnicity, or sex. The demographics of the patients approached for 
enrollment will mirror those of patients admitted to the hospital with COVID-19. 
5. STUDY INTERVENTIONS 
5.1 Treatment of Study Participants 
A summary of the trial’s schedule of events is included in Appendix A.  
Timing of study procedures is based on the time of initiation of the study product infusion, which is defined as 
“Time 0”.  Study Day 1 is defined as the calendar day of study product infusion. For patients who are 
randomized but do not receive study product, time of randomization will be considered “Time 0” and Study 1 
will be the calendar day of randomization. For most patients, randomization and study product infusion will 
occur on the same day; in the event the study product is infused on a different calendar day than 
randomization, Study Day 1 is defined as the day on which study product is infused. “Baseline status” 
represents the patient’s status immediately prior to study infusion, and baseline variables should represent 
information available before and as close as possible to initiation of the study infusion. The primary outcome 
will be assessed on Study Day 15 which corresponds to 2 weeks (14 days) after the receipt of the study 
infusion.  
Transfusion of convalescent plasma or placebo will be administered as a single dose by clinical or research 
personnel while the patient is hospitalized and within 24 hours of randomization. Participants randomized to 
active treatment will receive 1 unit of convalescent plasma, which has a volume of 200-399 ml infused 
intravenously. Patients randomized to placebo will receive 250 ml of lactated Ringer’s with multivitamin additives 
infused intravenously. The duration of infusion is recommended to be between approximately 1 hour and 3 hours 
(at the discretion of the provider), with the specific rate of infusion determined by the site investigator based on 
an assessment of how quickly the participant can safely receive the intravascular volume load.     
Study personnel will monitor patients for adverse reactions to the transfusion while the patient is in the hospital 
for 72 hours following the infusion; that is transfusion adverse reaction monitoring will be continued until Study 

 
 
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Day 4. For patients who are discharged prior to Day 4, study personnel will obtain safety outcomes from the 
patient or surrogate via telephone follow-up scheduled at Day 8. Research personnel will also assess patients 
at Day 15 and Day 29; these assessments will be completed by phone if the patient has been discharged from 
the hospital.  
Screening, consent, and baseline  
1. Confirm inclusion and exclusion criteria, including identifying a positive SARS-CoV-2 test 
2. Subject informed consent (obtained before performing study related activities) 
3. Randomization of eligible subject 
4. Demographics 
5. Medical history 
6. COVID-19 symptoms 
7. Record vital signs 
8. Assessment of clinical status (COVID-19 7-point Ordinal Clinical Progression Outcomes Scale) 
9. Record new medical conditions  
10. Record concomitant medication  
11. Adverse Event (AE) evaluation 
12. Collection of data for later SOFA score calculation 
13. Prior to study infusion, collect, process and store blood for SARS-CoV-2 antibody testing, which will be 
done at the central study laboratory. 
14. C-reactive protein (CRP) measurement (record the results of a clinically obtained CRP performed within 
24 hours prior to study product infusion; if a CRP was not obtained clinically, perform a CRP 
measurement by study protocol in the local clinical laboratory) 
15. Complete Blood Count (CBC) and Complete Metabolic Panel (CMP) measurement (record the results of 
a clinically obtained CBC and CMP performed within 24 hours prior to study product infusion; if a CBC 
and/or CMP was not obtained clinically, perform them on study protocol in the local clinical laboratory) 
 
Day 1 (Day of Transfusion) 
1. Study Product Administration: 1 unit of convalescent plasma or Lactated Ringer’s solution with 
multivitamins will be transfused. Study infusion will be monitored per site institutional transfusion policy.  
2. Adverse Event (AE) evaluation 
 
Day 2 (first calendar day after transfusion)  
1. Record vital signs.  
2. Assessment of clinical status (COVID-19 7-point Ordinal Clinical Progression Outcomes Scale) 
3. Record new medical conditions 
4. AE evaluation  
5. Collection of data for later SOFA score calculation 
6. CBC and CMP measurement (record the results of a clinically obtained CBC and CMP; if a CBC and/or 
CMP was not obtained clinically, perform them on study protocol in the local clinical laboratory if patient 
remains hospitalized)  
7. If patient remains hospitalized, collect, process and store blood for SARS-CoV-2 antibody testing, which 
will be done at the central study laboratory.  
 
Day 3-8 (Daily assessments only while patient hospitalized) 
1. Record vital signs  
2. Record new medical conditions 
3. Assessment of clinical status (COVID-19 7-point Ordinal Clinical Progression Outcomes Scale 
4. AE evaluation (through Day 4 only) 
5. Record the results of a clinically obtained CBC and CMP (Day 8 only and only if clinically available)  
 
 

 
 
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Day 8, 15, and 29 (by phone if patient discharged before assessment day):  
1. Assessment of clinical status (COVID-19 7-point Ordinal Clinical Progression Outcomes Scale) 
2. New medical conditions 
3. Vital status check 
 
5.2 Convalescent Plasma Group 
Patients randomized to the active treatment arm will receive a single dose of 1 unit (200-399 ml) of 
convalescent plasma infused intravenously per site institutional policy governing blood product transfusions. 
Convalescent plasma used in this trial will be ABO compatible with the participant’s blood type. The 
convalescent plasma will be supplied to enrolling sites for the trial. Quantitative SARS-CoV-2 antibody testing 
will be completed at Vanderbilt University Medical Center on convalescent plasma used in the trial. Plasma 
that is believed to be neutralizing will be used in this trial and will be prioritized based on neutralizing 
capabilities. Only plasma that contains anti-SARS-CoV-2 antibodies at a level above the threshold for 
neutralization will be used in the trial.  
 
5.3 Control Group 
Participants randomized to the control group will receive a single 250 ml dose of lactated Ringer’s containing 
multivitamins intravenously. This placebo solution will be mixed by local site pharmacies. It is stable under 
refrigeration for up to 24 hours. This solution is similar in appearance to plasma and is used to help blind 
patients, families, and study personnel to treatment assignment.  
5.4 Co-interventions 
Use of open label convalescent plasma in the first 15 days of the study is strongly discouraged and will be 
tracked as protocol deviations. All other treatment decisions will be made by treating clinicians without 
influence from the protocol.  Administration of other antiviral medications will be allowed. The decision to 
administer other antiviral medications will be made by treating clinicians and will be recorded in the case report 
form. The decision to administer immunomodulating medications, including corticosteroids, will be made by 
treating clinicians and will be recorded in the case report from.   
5.5 On-Study Monitoring 
All patients enrolled in the study will be initially hospitalized and will therefore receive monitoring as a part of 
routine clinical care, including monitoring by their physicians, nurses, respiratory therapists, and ancillary staff. 
In addition to routine clinical monitoring, enrolled patients will be monitored per site institutional transfusion 
policy before, during and following the study infusion.  If the patient develops abnormal vital signs during the 
infusion, the infusion will be held, and the patient will undergo evaluation for a transfusion reaction before the 
infusion can be restarted.  At any point, if a clinical team member has a concern about a potential transfusion 
reaction, he/she will report that concern to the blood bank or as per institutional policy. 
5.6 Criteria for Stopping Study Infusion 
Infusion of study treatment will be halted if any of the following manifestations of transfusion reaction develop 
fever, rash, diffuse itching, acute increase in heart rate by greater than 20 beats per minute. If any of these 
symptoms develop, the patient will be evaluated by a clinician or study team member.  Study treatment will be 
held until resolution of the symptoms.  Study treatment will be restarted one time, but if symptoms recur, study 
treatment will be discontinued and not restarted.  If the patient has recurrent symptoms on restarting study 
treatment, the blood bank will be notified to evaluate for potential transfusion reaction.  If there is significant 
concern that the symptoms, beyond rash or itching, are secondary to the infusion, then infusion will not be re-
started, and the patient will be evaluated for transfusion reaction. 
In addition, the infusion will be stopped and not restarted if the patient develops any of the following signs or 
symptoms of anaphylaxis: hives; pruritus; flushing; swollen lips, tongue or uvula;  worsening of shortness of 
breath; wheezing; stridor; hypoxemia; a decrease in systolic blood pressure to less than 90 mmHg or greater 
than 30% decrease from baseline or a diastolic drop of greater than 30% from baseline; bradycardia less than 
40 beats per minute that is associated with dizziness, nausea or feeling faint; any other symptom or sign which 

 
 
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in the good clinical judgment of the study clinician or supervising provider warrants halting the infusion.  For 
example, the rapid onset of gastrointestinal symptoms, such as nausea, vomiting, diarrhea, and cramps, may 
be manifestations of anaphylaxis and may warrant an immediate halt prior to meeting full severe adverse event 
(SAE) criteria. 
Any suspected reactions related to study product that result in stopping of study transfusion must be reported as 
an adverse event.   
5.7 Plan for Plasma Shortages 
In the event of a shortage of convalescent plasma or multivitamin solution for use in the trial at a participating 
trial site, site personnel should contact the Vanderbilt Coordinating Center (VCC) Clinical Trials Operations 
Manager. Participants will only be randomized when convalescent plasma and the placebo solution are available.  
6. OUTCOMES 
Definitions for each outcome are detailed in the trial’s statistical analysis plan (SAP). 
6.1 Primary Outcome 
COVID-19 7-point Ordinal Clinical Progression Outcomes Scale on Study Day 15:  
1.  Not hospitalized with resumption of normal activities.  
2. 
 Not hospitalized, but unable to resume normal activities.  
3. Hospitalized, not on supplemental oxygen.  
4. Hospitalized, on supplemental oxygen.  
5. Hospitalized, on nasal high-flow oxygen therapy, noninvasive mechanical ventilation, or both  
6. Hospitalized, on ECMO, invasive mechanical ventilation, or both.  
7. Death 
 
6.2 Secondary Outcomes 
• 
All-location, all-cause 14-day mortality (assessed on Study Day 15) 
• 
All-location, all-cause 28-day mortality (assessed on Study Day 29) 
• 
Survival through 28 days 
• 
Time to hospital discharge through 28 days 
• 
Time to recovery (defined as time from randomization to the earlier of final oxygen receipt in the hospital or 
hospital discharge) 
• 
COVID-19 7-point Ordinal Clinical Progression Outcomes Scale on Study Day 3, 8 and 29  
• 
Oxygen-free days through Day 28 
• 
Ventilator-free days through Day 28 
• 
Vasopressor-free days through Day 28 
• 
ICU-free days through Day 28 
• 
Hospital-free days through Day 28 
 
6.3 Safety Outcomes 
• 
Acute kidney injury 
• 
Receipt of renal replacement therapy 
• 
Documented venous thromboembolic disease (DVT or PE) 
• 
Documented cardiovascular event (myocardial infarction or ischemic stroke) 
• 
Transfusion reaction (fever/rash) 
• 
Transfusion related acute lung injury (TRALI) 
• 
Transfusion associated circulatory overload (TACO) 
• 
Transfusion related infection  

 
 
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6.4 Rationale for Primary Outcome 
COVID-19 has a broad spectrum of clinical severity. Even among hospitalized patients, most recover without 
experiencing critical illness.36  Designing a trial with statistical power to detect a meaningful difference in ICU-
free days or mortality might require an unfeasibly large sample size and could miss significant morbidity 
experienced by the majority of hospitalized patients.  Since the majority of morbidity from COVID-19 relates to 
hypoxemia, the fact that COVID-19 Ordinal Scale is tied to degree of hypoxemic respiratory failure increases 
its face validity and relevance.  For similar reasons, previous trials of severe influenza have employed a similar 
ordinal outcome.37  This ordinal scale has been selected as an outcome in multiple ongoing COVID-19 trials 
and is a preferred outcome by the World Health Organization Research and Development Blueprint for COVID-
19.38 Use of this standardized outcome will increase the potential to compare the results of this trial with other 
trials and perform meta-analyses. Validated techniques to ask questions about the resumption of normal daily 
activities will be used to distinguish between category 1 and category 2 on the scale.  
7. DATA AND BIOLOGICAL SPECIMEN COLLECTION 
Given the infectious risk from COVID-19 and potential shortages of personal protective equipment (PPE), we 
will minimize face-to-face contact between patients and non-clinical staff.  Additionally, minimizing research 
activities and conducting the trial in a pragmatic manner will increase the ability to complete the trial in the face 
of strained clinical and research resources during the COVID-19 pandemic. We will emphasize data that can 
be collected from the electronic health record, and assessments that can be completed over the telephone.   
Plasma samples will be collected as part of this trial at baseline (prior to study infusion) and on study Day 2 
(approximately 24 hours after the study infusion. Specimens will be shipped to VUMC for future analysis, which 
will include quantitative anti SARS-CoV-2 antibody measurements.  The study principal investigator (PI) and 
collaborators have approval to use all research bio-specimens collected during the conduct of this trial to 
address the research questions described in the consent document.   
7.1 Baseline Variable Collection 
• 
Presence or absence of each inclusion and exclusion criterion 
• 
Date and time of randomization 
• 
Date of symptom onset 
• 
Admission data: date and time of presentation, origin (home, skilled nursing facility, rehabilitation/LTACH, 
nursing home, outside hospital, outside ICU), location at randomization [Emergency Department (ED), 
hospital ward, ICU] 
• 
Demographics (age, sex, race, ethnicity, height, weight) 
• 
Comorbidities 
• 
Acute signs and symptoms: altered mental status, acute hypoxemic respiratory failure, hematology 
laboratory tests, liver function tests, renal function, coagulation studies  
• 
Sequential Organ Failure Assessment (SOFA)33 at enrollment 
• 
Chronic use of medications: corticosteroids, ACE inhibitors, angiotensin receptor blockers, non-steroids anti-
inflammatory drugs, other  
• 
Receipt of open label immunomodulators between hospital presentation and enrollment: corticosteroids, 
tocilizumab, sarilumab, interferon β, other  
• 
Receipt of invasive mechanical ventilation, non-invasive ventilation, high-flow nasal cannula, vasopressors, 
and oxygen therapy between hospital presentation and enrollment 
• 
Vital signs  
• 
COVID-19 7-point Ordinal Clinical Progression Outcomes Scale at enrollment 
• 
CRP, recorded if measured clinically, and collected for research if not measured clinically 
7.2 Assessments Between Hospital Presentation and Hospital Discharge 
• 
Specimen type, date, and result of SARS-CoV-2 testing conducted clinically  
• 
Date and time of study infusion  

 
 
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• 
COVID-19 7-point Ordinal Clinical Progression Outcomes Scale on every day of hospitalization (study Day 
8, 15 and 29 by phone if participant is no longer hospitalized)  
• 
SOFA on Day 2, if hospitalized 
• 
Receipt of open label antivirals between enrollment and hospital discharge: hydroxychloroquine, remdesivir, 
lopinavir/ritonavir, other  
• 
Receipt of open label immunomodulators between enrollment and hospital discharge  
• 
Receipt of open label COVID-19 convalescent plasma  
• 
Date of first receipt of supplemental oxygen (if applicable)  
• 
Date of final receipt of supplemental oxygen (if applicable) 
• 
Date of first receipt of high flow nasal cannula (if applicable)  
• 
Date of final receipt of high flow nasal cannula (if applicable) 
• 
Date of first receipt of non-invasive ventilation (if applicable)  
• 
Date of final receipt of non-invasive ventilation (if applicable) 
• 
Date of first receipt of invasive mechanical ventilation (if applicable)  
• 
Date  of final receipt of invasive mechanical ventilation (if applicable) 
• 
Date of first receipt of extracorporeal membrane oxygenation (if applicable)  
• 
Date of final receipt of extracorporeal membrane oxygenation (if applicable) 
• 
Date of first receipt of vasopressors (if applicable)  
• 
Date of final receipt of vasopressor (if applicable) 
• 
Date of first ICU admission (if applicable)  
• 
Date of final ICU discharge (if applicable) 
• 
Date e of hospital discharge (if applicable) 
• 
Date of death (if applicable) 
• 
Clinically obtained laboratory tests, including blood counts, chemistries, and CRP 
• 
Safety assessments: myocardial infarction, ischemic stroke, deep venous thrombosis or pulmonary 
embolism,  aspartate aminotransferase or alanine aminotransferase levels that are greater than twice the 
local upper limit of normal, stage II or greater acute kidney injury according to KDIGO creatinine criteria39, 
receipt of new renal replacement therapy, transfusion reaction, transfusion related acute lung injury (TRALI), 
Transfusion associated cardiac overload (TACO), transfusion related infection. Definitions for each variable 
are detailed in the trials statistical analysis plan and are described for enrolling personnel in the trial manual 
of operations and/or electronic data capture system. 
7.3 Assessments Following Hospital Discharge  
7.3.1 Acute Care Follow-up 
For participants discharged to home or a post-acute care facility (e.g., long term acute care facilities, skilled 
nursing facilities, or acute rehabilitation facilities) prior to the Day 8, Day 15 or Day 29 assessment, we will 
perform these assessments via telephone follow-up. The Day 8 call window will be Day 8 through 14. The Day 
15 call window will be Day 15 through 22. The Day 29 call window will be Day 29 through 36.  During these 
telephone calls, we will interview the patient, LAR, or facility staff to assess: 
• 
Date of death (if applicable) 
• 
ED visits and hospital readmissions after hospital discharge 
• 
Location at the time of the call (home, long term acute care facility, skilled nursing facility, acute rehabilitation 
facility, hospital) 
• 
Selected non-laboratory safety outcomes after hospital discharge 
• 
COVID-19 7-point Ordinal Clinical Progression Outcomes Scale 
The follow-up period for vital status (dead versus alive) is through Study Day 29.  For most patients, we will 
establish vital status during the Study Day 29 visit (either in person for those who remain in the hospital or by 
phone for those who have been discharged).  For patients who are not reached for the Study Day 29 visit, we 
will seek to establish vital status via phone calls, emails, and searches through medical records, obituaries, social 
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8. STATISTICAL CONSIDERATIONS 
 
8.1 Summary 
The key features of the trial are summarized in the following table (Table 1).   
Table 1. Key Statistical features of the trial 
Feature  
Description  
Primary endpoint  
COVID-19 7-point Ordinal Clinical Progression Outcomes Scale captured on 
study Day 15  
Primary AIM  
Assess if the treatment intervention improves the day 15 endpoint compared 
to the control arm  
Sample size 
1000 subjects 
Inference approach 
The primary point of inference will be the likelihood ratio and corresponding 
support interval for the covariate adjusted treatment effect odds ratio.  
Likelihood ratios more extreme than 7 (or 1/7) will be interpreted as sufficient 
evidence to assert efficacy. 
 
The odds ratio will be estimated with a cumulative probability ordinal 
regression model with logit link. 
Planned Interim Analyses  
There are 3 interim analyses for safety endpoints, and a final analysis of 
efficacy endpoints.  The safety interim analyses will occur after 15 days of 
follow-up is completed for the first 150, 450, and 750 patients. The final 
analysis will occur after follow-up is complete for all enrolled subjects.   
Planned Reporting Triggers  There are no planned reporting triggers. 
Planned stopping rules 
At each interim analysis, the difference in mortality risk will be calculated, and 
the one-sided hypothesis that mortality risk in the intervention arm exceeds 
the mortality risk in placebo will be compared to the null hypothesis of equal 
mortality risk.   The trial will be stopped if the likelihood ratio exceeds the 
threshold listed below.   
Type I error rate 
The combination of a 1/7 likelihood ratio threshold and the safety stopping 
rule result in a simulated type I error rate of 0.02 
Power 
The minimal detectable effect at 80% power is 0.73 
 
8.2 Planned interim analyses for mortality  
At each interim analysis, the difference in mortality risk will be calculated, and the one-sided hypothesis that 
mortality risk in the intervention arm exceeds the mortality risk in placebo will be compared to the null 
hypothesis of equal mortality risk.   The trial will be stopped if the likelihood ratio exceeds the threshold listed 
below.  Generally, the level of evidence required to stop a study for safety concerns is less than the level of 
evidence required to assert efficacy of the intervention.  Likewise, there is not the same level of concern for 
type 1 error control for safety outcomes as there is for efficacy endpoints; however, the threshold values were 
selected so that the trial-wise risk of ending early for mortality is 0.1 if the treatment is equivalent to placebo.    
To provide context for the LR thresholds listed in the table below, we have also provided  
α𝑁𝑁, the p-value threshold which approximates the LR threshold if the p-value were calculated from a likelihood 
ratio test.    
N 
LR 
Threshold 
α𝑁𝑁 
150 
6.3 
0.0275 
450 
4.0 
0.0479 
750 
3.3 
0.0612 

 
 
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8.3 Analysis plan for primary endpoints 
The statistical analysis plan (SAP) contains a more complete description of analysis methods, definitions, and 
sensitivity analyses.  In this section, we reprint relevant portions of the SAP. 
The data from the clinical trial will be analyzed after follow-up is completed for all study subjects. The analysis 
will be intent-to-treat, meaning that patients will be analyzed according to the randomization schedule regardless 
of the treatment administered. The key result of the analysis is an estimate of the treatment effect odds ratio, its 
likelihood ratio when compared to the null, and the corresponding 1/7 likelihood support interval, all of which will 
be estimated from a cumulative probability ordinal regression model (CPM) with logit link. The marginal likelihood 
function for the treatment effect parameter will be the asymptotic regression coefficient distribution; specifically, 
it will be the normal distribution density function with mean and standard deviation equal to the regression 
estimates.  Likelihood ratios more extreme than 7 will be interpreted as sufficient evidence to assert efficacy. In 
order to increase study power, the following variable will also be included into the regression: 
1. Treatment (1 parameter) 
2. Age (2 parameters, restricted cubic spline) 
3. Sex (1 parameter) 
4. SOFA score (1 parameter, linear term) 
5. Baseline COVID-19 7-point Ordinal Clinical Progression Outcomes Scale score (possible range:3-6) (2 
parameters, quadratic) 
6. Time from symptom onset in days (2 parameter, non-linear term) 
7. Site indicator variables (either as a main effect or as a random effect, depending on the number of sites 
enrolling patients) 
 
8.3.1 Model fit 
Model fit will be assessed with probability scale residuals and with leave-one-out diagnostics like DFBETAS. If 
model diagnostics indicate that an alternative link function provides a superior fit, then supplementary information 
will be sent to the DSMB to decide if an alternative link function should be used. 
 
8.3.2 Missing data 
We anticipate rare or no missingness for data points during a patients in-hospital course.  There may be missing 
data for the COVID-19 7-point Ordinal Clinical Progression Outcomes Scale score after hospital discharge, which 
relies on phone follow-up.  After discharge, distinguishing between category 1 and category 2 on the scale 
requires speaking to the participant or surrogate about normal daily activities. If the patient is not reached for 
follow-up phone calls after discharge, the COVID-19 7-point Ordinal Clinical Progression Outcomes Scale score 
will be classified as category 2 (not hospitalized, but unable to resume normal activities).  If the patient is reached 
for a follow-up call post-charge and reports category 1, this classification of category 1 will be carried forward to 
future follow-up calls if the patient cannot be reached. For example, if the patient cannot be reached for the Day 
8, 15, or 29 follow-up calls, a category 2 score will be reported for all three visits.  If the patient is successfully 
contacted on the Day 8 call and reports category 1, and then the patient cannot be reached for a Day 15 call, 
the category 1 score from Day 8 will be carried forward to Day 15.  
 
Missing data for a covariate used in the primary model will be multiply imputed using predictive mean matching 
if number of observations missing covariate values exceeds 5 percent.  If fewer than 5% of observations have 
missing covariate values, missing values will be imputed with a single conditional mean. 
 
8.3.3 Assertion of efficacy 
Likelihood ratios more extreme than 7 (or 1/7) will be interpreted as sufficient evidence to assert efficacy. 
 

 
 
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8.4 Trial characteristics 
8.4.1 Inference 
Decision making using the likelihood approach in a clinical trial centers on three quantities: the point estimate of 
the treatment effect (an odds ratio, for example), a corresponding interval estimate, and a single number 
summary that measures the relative evidence for one hypothesis compared to another.  These three quantities 
are not unlike the point estimate, 95% confidence interval, and p-value that are generated in frequentist analyses.  
In fact, the point estimates are often identical, and the interval estimates are often similar.  The LR and the p-
value, however, are distinct measures of evidence.  The LR is a ratio: the density of the trial data if the treatment 
works (alternative hypothesis) divided by the density of the trial data if the treatment does not work (null 
hypothesis).  A LR of 1 indicates the data are neutral; neither hypothesis is supported over the other.  Large LR 
are evidence in support of the treatment working while small LR are evidence in support of the null.  In short, the 
LR level of evidence is based on comparing the likelihood of the data under two competing models – the 
alternative hypothesis and the null hypothesis.  This is different to using a p-value as the level of evidence 
because the p-value essentially compares what actually happened in the trial to what might have happened in 
the trial if it were repeated infinitely and the null hypothesis were true. Because it is impossible to compute what 
might have happened if the rules for decision making are not fully predefined, using a p-value for decision making 
is not well suited for a trial like this one in which DSMB requests and pandemic circumstances prompt design 
changes. The LR approach on the other hand, is based on a relative likelihood of observed outcomes under two 
competing models at the same point in time making it especially appropriate for settings where pre-specification 
of the timing or frequency of sequential analyses is not possible.   
 
Even though the LR (instead of the p-value) is the quantity of primary interest for decision making, the analysis 
plan does control type 1 error.  Sequential likelihood ratio tests of two prespecified hypotheses have a natural 
bound on type 1 error of 1/k where k is the threshold for asserting efficacy.  In this study, the combination of the 
stopping rule for mortality and the large number of subjects accrued before the first analysis for efficacy result in 
a bound-on type 1 error well within traditional levels of 0.05. 
 
8.4.2 Type I error rate and power 
The long-run operating characteristics were estimated by generating study data to reflect different treatment 
effect sizes. The simulated study dataset was evaluated according to the stopping rule and analysis plan 
described above. For each effect size, 1000 simulated datasets were analyzed. A Type I error occurred if the 
study asserted efficacy when in fact there was no treatment effect. The Type I error rate was calculated as the 
proportion of null-effect studies in which the error occurred. A Type II error occurred if the study failed to assert 
efficacy when there was a beneficial treatment effect. For each treatment effect, power was calculated as the 
proportion of studies that did not result in a Type II error.  
The study endpoint for control subjects was simulated to match the outcomes in the control arm of a recent 
clinical trial.3 In each simulation setting, the distribution for the treatment arm was calculated by adjusting the 
control arm outcome distribution according to the setting-specific treatment effect size and data generation 
model. 
The figure below is the estimated power curve for the trial design (Figure 1). 
Figure 1. Power of the trial assuming enrollment of 1000 participants. 

 
 
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8.5 Analysis plan for additional analyses of the primary endpoint 
8.5.1 Quantification of effect of donor plasma characteristics on treatment efficacy 
The impact of the antibody levels and neutralization activity of the donor plasma on the primary endpoint will be 
estimated with ordinal regression models. The models will include the same covariates listed for the primary 
endpoint analysis, except the treatment assignment variable will be replaced with either (a) a measure of donor 
plasma antibody level or (b) a measure of donor plasma neutralization.  Both variables will be included in models 
as a restricted cubic spline in order to capture potential non-linear associations with the outcome. 
8.5.2 Effect modification analyses of the primary outcome 
We will examine whether pre-specified baseline variables modified the effect of treatment group on the primary 
outcome using tests of statistical interaction in a proportional odds regression model. Independent variables will 
include study group assignment, the potential effect modifier of interest, the interaction between the two, and the 
same pre-specified covariates used in the primary model. Presence of effect modification will be assessed by 
reference to the LR for the interaction term, with values greater than 6 considered to suggest a potential 
interaction and values greater than 7 considered to confirm an interaction.     
We will examine whether the following pre-specified baseline variables modify the effect of study group on the 
primary outcome: 
• 
Baseline recipient (trial participant) antibody quantification 
• 
Baseline COVID scale 
• 
Baseline SOFA 
• 
ICU/ward enrollment location 
• 
Age 
• 
Race/ethnicity 
• 
Duration of symptoms prior to randomization 
• 
Mechanical ventilation status at baseline 
 

 
 
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8.6 Analysis plan for secondary endpoints 
The analyses for secondary endpoints will be intent-to-treat, meaning that patients will be analyzed according to 
the randomization schedule regardless of the treatment administered.  The following is a table of secondary 
endpoints and analyses (Table 2). 
Table 2. Trial secondary outcomes 
Outcome 
Type 
Analysis 
All-location, all-cause 14-day mortality 
(assessed on Study Day 15) 
Binary 
Logistic regression 
All-location, all-cause 28-day mortality 
(assessed on Study Day 29) 
Binary 
Logistic regression 
Survival through 28 days 
Time-to-event 
Proportional 
hazards 
regression 
Time to hospital discharge through 28 
days 
Time-to-event 
Multistate model 
with death as a 
competing risk 
Time to recovery (defined as time from 
randomization to the earlier of final 
oxygen receipt in the hospital or hospital 
discharge) 
Time-to-event 
CPM with logit link 
COVID-19 7-point Ordinal Clinical 
Progression Outcomes Scale on Study 
Day 3, 8 and 29 
Ordinal 
CPM with logit link 
Oxygen-free days through Day 28 
Ordinal 
CPM with logit link 
Ventilator-free days through Day 28  
Ordinal 
CPM with logit link 
Vasopressor-free days through Day 28 
Ordinal 
CPM with logit link 
ICU-free days through Day 28 
Ordinal 
CPM with logit link 
Hospital-free days through Day 28 
Ordinal 
CPM with logit link 
 
8.6.1 Ordinal outcomes 
Ordinal secondary outcomes will be analyzed using the same model described for the primary endpoint.  Similar 
steps to evaluate model fit and overly influential observations will be performed. 
8.6.2 Binary outcomes 
Binary secondary outcomes will be analyzed using multivariable logistic regression models with the same pre-
specified covariates as the primary endpoint.  To assess model calibration and overly influential observations, 
graphical displays of calibration and DFBETAS will be created. 
8.6.3 Time to event outcomes 
Survival will be analyzed with a proportional hazards regression model.  The key result of the analysis is an 
estimate of the treatment effect hazards ratio.  The same set of covariates used for the adjusted analysis of the 
primary endpoint will also be included in the analysis of secondary time-to-event endpoints.   Model fit will be 
assessed with Schoenfeld residuals and with leave-one-out diagnostics like DFBETAS.  The proportional odds 
assumption will be evaluated with graphical displays.  Deviations from proportionality will trigger sensitivity 
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8.6.4 Outcomes with a competing risk of death 
Some secondary outcomes, like the primary outcome, incorporate death as part of the scale.  Others, such as 
time to discharge, do not.  Because death censors length of stay, it is a competing outcome. Outcomes with a 
competing risk of death will be analyzed with a multi-state model.  Both the instantaneous risk and cumulative 
risk of the outcome will be reported.    
8.6.5 Missing data 
If missing covariate data occurs, then multiple imputation methods similar to those described for the primary 
endpoint will be used to estimate the point estimate and confidence interval for the secondary endpoints. 
8.7 Safety Outcomes and Adverse Events 
The frequency and description of safety outcomes and adverse events will be reported.  The association between 
intervention group and safety outcomes will be estimated without covariate adjustment.  The following table lists 
the safety outcomes and the planned analyses (Table 3). 
Table 3. Trial safety outcomes.  
Outcome 
Type 
Analysis 
Receipt of renal replacement therapy 
Binary 
Risk difference 
Documented venous thromboembolic disease 
(DVT or PE) 
Binary 
Risk difference 
Documented cardiovascular event (myocardial 
infarction or ischemic stroke) 
Binary 
Risk difference 
Transfusion reaction (fever/rash) 
Binary 
Risk difference 
Transfusion related acute lung injury (TRALI) 
Binary 
Risk difference 
Transfusion associated circulatory overload 
(TACO) 
Binary 
Risk difference 
Transfusion related infection 
Binary 
Risk difference 
9. DATA QUALITY MONITORING AND STORAGE 
9.1 Data Quality Monitoring 
Data quality will be reviewed remotely using front-end range and logic checks at the time of data entry and back-
end monitoring of data using application programming interface tools connecting the online database to statistical 
software to generate data reports. Patient records and case report forms will also be reviewed by the Vanderbilt 
Coordinating Center (VCC) to evaluate the accuracy and completeness of the data entered into the database 
and monitor for protocol compliance per the study monitoring plan.  The VCC will perform remote monitoring of 
each study site to examine the completeness and accuracy of informed consent documents for study 
participants, documentation of eligibility criteria, and the completeness of study outcome collection. Fully 
identifiable source documents will be requested from participating sites in order to carry out the study monitoring 
plan.  
9.2 Data Storage 
Data will be entered into a secure online database.  All data will be maintained in the secure online database 
until the time of study publication.  At the time of publication, a de-identified version of the database will be 
generated. 
10.  RISK ASSESSMENT 
10.1 Potential Risk to Participants 
Although convalescent plasma is an FDA approved treatment with an established safety profile, potential risks 
exist to participating in this study of convalescent plasma versus placebo for the treatment of COVID-19.   

 
 
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10.1.1 Potential risks of receiving convalescent plasma 
One potential risk to receiving convalescent plasma is the possibility of developing antibody-mediated 
enhancement of infection (ADE). ADE can happen in the setting of viral and bacterial diseases and occurs when 
antibodies increase the severity of disease. ADE has been described in other types of coronaviruses, and it is 
also possible that antibodies to one type of coronavirus could enhance disease with another strain.43 However, 
in the setting of MERS and the closely related SARS-CoV-1, evidence suggests that the use of convalescent 
plasma is safe.7,28,44 Anecdotal evidence of the use of convalescent plasma in COVID-19 also indicates that this 
is a safe treatment option.32,33 Another possible risk to receiving convalescent plasma is that the patient may 
mount a sub-optimal humoral immune response resulting in susceptibility to reinfection as has been seen with 
respiratory syncytial virus.45 However, these concerns seem minor as compared to the possibility of limiting the 
duration and severity of disease, and avoiding interventions like mechanical ventilation, ARDS and sepsis. There 
are also risks associated with any transfusion of plasma including transmission of transfusion transmitted viruses 
(e.g. HIV, HBV, HCV, etc.), allergic transfusion reactions, anaphylaxis to transfusion, febrile transfusion reaction, 
transfusion related acute lung injury (TRALI), transfusion associated cardiac overload (TACO), and hemolysis 
should ABO incompatible plasma be administered.  Another risk of plasma is thrombotic (clotting) complications, 
such as deep venous thrombosis, pulmonary embolism, myocardial infarction, and stroke.  All study participants 
will be closely monitored for adverse events by study personnel. 
10.1.2 Potential risks of receiving lactated Ringer’s solution with multivitamins with COVID-19 
One potential risk to participating in this study is receiving LR with multivitamins rather than convalescent plasma.  
This risk is only relevant if convalescent plasma is ultimately found to be an effective therapy for COVID-19 and 
is not relevant if convalescent plasma is ultimately found to be an ineffective therapy for COVID-19.  This trial 
protocol minimizes this risk through rigorous design to minimize the number of patients who must be enrolled to 
determine whether convalescent plasma is an effective therapy for COVID-19.  The other risks of receiving LR 
are very low and include volume overload and allergic reaction to multivitamins. All study participants will be 
closely monitored for adverse events by study personnel. 
10.2 Minimalization of Risk 
Federal regulations at 45 CFR 46.111(a)(1) require that risks to participants are minimized by using procedures 
which are consistent with sound research design.  This trial protocol incorporates numerous design elements to 
minimize risk to patients that meet this human subject protection requirement.  Convalescent plasma has been 
approved by the Food and Drug Administration and has been used in clinical practice for decades in a number 
of patient populations with an established safety profile. The dose and route of administration of convalescent 
serum in this trial are comparable to the dose and route of administration approved for the treatment of other 
acute viral infections such as SARS and MERS. The trial protocol includes monitoring of adverse events, clinical 
outcomes, and interim analyses by an independent data and safety monitoring board empowered to stop or 
modify the trial at any time.  In addition, all patients will be hospitalized or in an ED with plans to be hospitalized.  
They will be closely monitored by nursing staff during the infusion of the plasma. 
10.3 Potential Benefit 
Study participants may or may not receive any direct benefits from their participation in this study. Administration 
of convalescent plasma may improve clinical outcomes among adults hospitalized for COVID-19 infection. 
10.4 Risk in Relation to Anticipated Benefit 
Federal regulations at 45 CFR 46.111 (a)(2) require that “the risks to subjects are reasonable in relation to 
anticipated benefits, if any, to subjects, and the importance of the knowledge that may reasonably be expected 
to result.” Based on the preceding assessment of risks and potential benefits, the risks to subjects are reasonable 
in relation to anticipated benefits.  Convalescent plasma has been used in clinical practice for decades and 
previously evaluated for the treatment of patients acutely ill from infection with substantial data to support its 
safety and potential efficacy. 
11.  HUMAN SUBJECTS PROTECTIONS 
Each study participant will undergo a consent process as outlined above.  Approval of the central institutional 
review board will be required before any participant is entered into the study.  

 
 
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11.1 Selection of Subjects 
Federal regulations at 45 CFR 46(a)(3) require the equitable selection of subjects. The emergency departments, 
hospital wards, and ICUs of participating sites will be screened to determine if any patient meets inclusion and 
exclusion criteria. Data that have been collected as part of the routine clinical care of the patient will be reviewed 
to determine eligibility. If any patient meets criteria for study enrollment, then the attending physician responsible 
for his or her care will be asked for permission to approach the patient or his or her LAR for informed consent. 
Study exclusion criteria neither unjustly exclude classes of individuals from participation in the research nor 
unjustly include classes of individuals for participation in the research. Hence, the recruitment of participants 
conforms to the principle of distributive justice. 
11.2 Justification of Including Vulnerable Subjects 
The present research aims to investigate the safety and efficacy of convalescent plasma for the treatment of 
patients with COVID-19 who are at high risk for respiratory failure and mortality. Due to the nature of this patient 
population, many of these patients will have impaired decision-making capabilities. Moreover, those with intact 
decision-making capacities probably have milder disease than those with impaired capacity. Therefore, the 
validity of the study and its generalizability to severely ill patients would be compromised by enrolling only those 
participants with retained decision-making capacity. Hence, participants recruited for this trial are not being 
unfairly burdened with involvement in this research. 
11.3 Informed Consent 
Federal regulations 45 CFR 46.111(a)(5) require that informed consent will be sought from each patient or the 
patient’s LAR. Study personnel obtaining informed consent are responsible for ensuring that the patient or LAR 
understands the risks and benefits of participating in the study, answering any questions the patient or LAR may 
have throughout the study and sharing any new information in a timely manner that may be relevant to the 
patient’s or LAR’s willingness to permit the patient’s continued participation in the trial. The study personnel 
obtaining informed consent will make every effort to minimize coercion. All patients or their LARs will be informed 
of the objectives of the study and the potential risks. The informed consent document will be used to explain the 
risks and benefits of study participation to the patient or LAR in simple terms before the patient is entered into 
the study, and to confirm that the patient or LAR is satisfied with his or her understanding of the risks and benefits 
of participating in the study and desires to participate in the study. The investigator is responsible for ensuring 
that informed consent is given by each patient or LAR. This includes obtaining the appropriate signatures and 
dates on the informed consent document prior to the performance of any protocol procedures including 
administration of study agent. 
For additional details, see Section 4. 
11.4 Continuing Consent 
Patients for whom consent was initially obtained from a LAR, but who subsequently regain decision-making 
capacity while in hospital will be approached for consent for continuing participation, including continuance of 
data acquisition. The consent form signed by the LAR should reflect that such consent should be obtained.  The 
process for obtaining consent from these patients will be the same as that outlined in section 4. 
11.5 Withdrawal of Consent 
Participating patients may withdraw or be withdrawn (by the LAR, treating physician, or investigator) from the 
trial at any time without prejudice. Data recorded up to the point of withdrawal will be included in the trial analysis, 
unless consent to use data has also been withdrawn. Withdrawal of consent prior to randomization will constitute 
a screen-failure and will be recorded.  Withdrawal of consent after randomization will lead to discontinuation of 
study interventions but site staff will request access to medical records for data related to the trial.   
11.6 Identification of Legally Authorized Representatives 
Many of the patients approached for participation in this research protocol will have impaired decision-making 
capacity due to critical illness and will not be able to provide informed consent. Accordingly, informed consent 
will be sought from the patient’s LAR.   
Regarding consent from the LAR, the existing federal research regulations (‘the Common Rule’) states at 45 
CFR 46.116 that “no investigator may involve a human being as a subject in research…unless the investigator 

 
 
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has obtained the legally effective informed consent of the subject or the subject’s legally authorized 
representative”; and defines at 45 CFR 46 102 (c) a LAR as “an individual or judicial or other body authorized 
under applicable law to consent on behalf of a prospective subject to the subject’s participation in the 
procedures(s) involved in the research.” The Office of Human Research Protections (OHRP) defined examples 
of “applicable law” as being state statutes, regulations, case law, or formal opinion of a State Attorney General 
that addresses the issue of surrogate consent to medical procedures. Such “applicable law” could then be 
considered as empowering the LAR to provide consent for participant participation in the research. Interpretation 
of “applicable law” may be state specific and will be addressed by the central IRB.  
According to a previous President’s Bioethics Committee (National Bioethics Advisory Committee (NBAC)), an 
investigator should accept a relative or friend of the potential participant who is recognized as an LAR for 
purposes of clinical decision making under the law of the state where the research takes place.46 Finally, OHRP 
has stated in their determination letters that a surrogate could serve as a LAR for research decision making if 
such an individual is authorized under applicable state law to provide consent for the “procedures” involved in 
the research study 
11.7 Justification of Surrogate Consent 
According to the Belmont Report, respect for persons incorporates at least two ethical convictions; first, that 
individuals should be treated as autonomous agents, and second, that persons with diminished autonomy are 
entitled to protection. One method that serves to protect patients is restrictions on the participation of patients in 
research that presents greater than minimal risk. Commentators and research ethics commissions have held the 
view that it is permissible to include incapable participants in greater than minimal risk research as long as there 
is the potential for beneficial effects and that the research presents a balance of risks and expected direct benefits 
similar to that available in the clinical setting.47 Several U.S. task forces have deemed it permissible to include 
incapable participants in research. For example, the American College of Physicians’ document allows 
surrogates to consent to research involving incapable participants only “if the net additional risks of participation 
are not substantially greater than the risks of standard treatment”.48 Finally, NBAC stated that an IRB may 
approve a protocol that presents greater than minimal risk but offers the prospect of direct medical benefits to 
the participant, provided that “the potential subject’s LAR gives permission…”.46 
Consistent with the above ethical sensibilities regarding the participation of decisionally incapable participant in 
research and the previous assessment of risks and benefits in the previous section, the present trial presents a 
balance of risks and potential direct benefits that is similar to that available in the clinical setting. 
11.8 Additional Safeguards for Vulnerable Participants 
The present research will involve participants who might be vulnerable to coercion or undue influence. As 
required in 45CFR46.111(b), we recommend that sites utilize additional safeguards to protect the rights and 
welfare of these participants. Such safeguards might include but are not limited to a) assessment of the potential 
participant’s capacity to provide informed consent, and b) the availability of the LAR to monitor the participant’s 
subsequent participation and withdrawal from the study. The specific nature of the additional safeguards will be 
left to the discretion of the central IRB, in conjunction with the sites. 
11.9 Confidentiality  
Federal regulations at 45 CFR 46 111 (a) (7) requires that when appropriate, there are adequate provisions to 
protect the privacy of participants and to maintain the confidentiality of data. At no time during this study, its 
analysis, or its publication will patient identities be revealed in any manner.  The minimum necessary data 
containing patient or provider identities will be collected.  All patients will be assigned a unique study ID number 
for tracking.  All data collected for this study will be entered directly into a secure online database.  All data will 
be maintained in the secure online database until the time of study publication.  At the time of publication, a de-
identified version of the database will be generated. Further, tools within the secure online database will be used 
so that only the VCC and investigators from the enrolling site will have access to data from participants enrolled 
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12.  ADVERSE EVENTS 
Assuring patient safety is an essential component of this protocol. Convalescent plasma has been approved by 
the Food and Drug Administration and used in clinical practice for decades with an established safety profile.  
Use of convalescent plasma for the treatment of acute respiratory infection due to COVID-19, however, raises 
unique safety considerations.  This protocol addresses these considerations including the following: 
1. Exclusion criteria designed to prevent enrollment of patients likely to experience adverse events with 
receipt of convalescent plasma 
2. Inpatient monitoring of the patient by bedside nurses during and after infusion of the plasma 
3. Proactive education of treating clinicians regarding relevant adverse reactions to convalescent plasma  
4. On-study monitoring of co-interventions (e.g., medications) and patient characteristic to help prevent  
adverse events  
5. Systematic collection of safety outcomes relevant to use of convalescent plasma  
6. Structured reporting of adverse events 
12.1 Adverse Event Definitions 
Adverse Event: Any untoward medical occurrence associated with the use of an infusion or a study procedure, 
whether or not considered infusion related. 
Serious Adverse Event: Adverse events that are serious as defined in section 12.2 below.  
Adverse Reaction: An adverse reaction means any adverse event caused by a study intervention. An adverse 
reaction is a subset of all suspected adverse events where there is a reason to conclude that the study 
intervention caused the event.  
Suspected Adverse Reaction: Any adverse event for which there is a reasonable possibility that the study 
procedures caused the adverse event. Reasonable possibility means there is evidence to suggest a causal 
relationship between the study procedures and the adverse event. A suspected adverse reaction implies a lesser 
degree of certainty about causality than adverse reaction.  
Suspected Unexpected Serious Adverse Reaction (SUSAR): An adverse reaction that is both unexpected 
(not consistent with risks outlined in the study protocol or investigator brochure), serious, and meets the definition 
of a suspected adverse reaction. 
12.2 Serious Adverse Events 
Serious adverse event collection begins after randomization and study procedures have been initiated.  If a 
patient experiences a serious adverse event after consent, but prior to randomization or starting study 
procedures, the event will NOT be collected. Study site personnel must alert the VCC, via data entry in the 
adverse event case report form, of any serious and study procedure related adverse event within 24 hours of 
investigator awareness of the event.  If a serious adverse event is communicated to the VCC is via telephone, it 
should be immediately followed with official notification on the adverse event case report form.  
As per the FDA and NIH definitions, a serious adverse event is any adverse event that results in one of the 
following outcomes: 
• 
Death 
• 
A life-threatening experience (that is, immediate risk of dying) 
• 
Prolonged inpatient hospitalization or re-hospitalization 
• 
Persistent or significant disability/incapacity 
 
As per http://www.fda.gov/Safety/MedWatch/HowToReport/ucm053087.htm: Report an adverse event as 
serious if admission to the hospital or prolongation of hospitalization was a result of the adverse event. 
Emergency department visits that do not result in admission to the hospital should be evaluated for one of the 
other serious outcomes (e.g., life-threatening; required intervention to prevent permanent impairment or damage; 
other serious medically important event). 
 

 
 
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As per http://www.fda.gov/Safety/MedWatch/HowToReport/ucm053087.htm: Report an adverse event serious if 
the adverse event resulted in a substantial disruption of a person's ability to conduct normal life functions, i.e., 
the adverse event resulted in a significant, persistent or permanent change, impairment, damage or disruption 
in the patient's body function/structure, physical activities and/or quality of life. 
Adverse events that may not result in death, be life-threatening, or require hospitalization may be considered 
serious adverse events when, based upon appropriate medical judgment, they jeopardize the patient and may 
require medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Serious adverse events will be collected through study day 4, 72 hours after completion of the study infusion, 
or until hospital discharge, whichever occurs first, regardless of the investigator's opinion of causation.  
12.3 Safety Monitoring  
Assuring patient safety is an essential component of this protocol. Each participating investigator has primary 
responsibility for the safety of the individual participants under his or her care. The investigators will determine 
daily if any adverse events occur during the period from enrollment through study day 4,(which is 72 hours 
after completion of the study product infusion, or hospital discharge, whichever occurs first, and will determine if 
adverse events are related to study procedures. Adverse events are not required to be reported to the IRB unless 
the investigator feels the adverse event was related to study infusion or study procedures.   
The following adverse events will be collected in the adverse event case report forms: 
 
• 
Serious adverse events (as defined in protocol section 12.2 of this protocol) that are study related (or of 
uncertain relationship) or occur within 72 hours of the study infusion 
• 
Non-serious adverse events that are study procedures or of uncertain relationship  
• 
Events leading to permanent discontinuation of study infusion (which, by definition, are study related) 
The protocol for reporting adverse events in the trial’s electronic data capture system are summarized in Table 4.  
Table 4. Protocol for reporting adverse events 
Type of Adverse Event 
Time for Recording in the EDC 
Serious, study related 
24 hours 
Serious, not study related and within 72 hours of infusion 
72 hours 
Serious, not study related and after 72 hours following Recording in the EDC is not required 
Not serious, study related 
72 hours 
Not serious, not study related 
Recording in the EDC is not required  
 
Study-specific clinical outcomes (Primary, Secondary and Safety Outcomes and Assessments During the Study), 
including serious outcomes such as organ failures and death, are systematically recorded in the case report 
forms and are exempt from adverse event reporting unless the investigator deems the event to be related to the 
administration of study plasma or the conduct of study procedures (or of uncertain relationship).  
After randomization, adverse events must be evaluated by the investigator. If the adverse event is judged to be 
reportable, as outlined above, then the investigator will report to the Medical Monitor for assessment of the 
potential relatedness of each adverse event to the study treatment or protocol procedure via electronic data 
entry. Investigators will assess if there is a reasonable possibility that the study procedure caused the event. 
Investigators will also consider if the event is unexpected.  Unexpected adverse events are events not listed in 
the study protocol or investigator’s brochure. Investigators will also determine if adverse events are unanticipated 
given the patient’s clinical course, previous medical conditions, and concomitant medications.   
If a patient's treatment is discontinued as a result of an adverse event, study site personnel must also report the 
circumstances and data leading to discontinuation of treatment in the adverse event case report forms.  
Additional information about adverse event reporting is included in Appendix B.  

 
 
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12.4 Medical Monitor   
The relationship or attribution of an adverse event to the study therapy will be initially determined by the site 
investigator and recorded on the appropriate eCRF. Final determination of attribution for safety reporting will be 
determined by the independent medical monitor. The Medical Monitor may escalate reported events to the DSMB 
chair as appropriate per the DSMB charter.   
The activities of the Medical Monitor will include:  
• 
Being on call for investigators to report and discuss AEs and SAEs 
• 
Reviewing safety data delivered to the DSMB and any safety reports 
• 
Attending DSMB meetings to participate in discussions about safety and AEs 
• 
Participation in discussions about unblinding study team members to study drug allocation to facilitate 
safe treatment of study participants  
 
12.5 Data and Safety Monitoring Board (DSMB) 
The principal role of the DSMB is to assure the safety of participants in the trial. They will regularly monitor data 
from this trial, review and assess the performance of its operations, and make recommendations to the study 
team. DSMB activities include:  
• 
Review of adverse events 
• 
Interim results of the study for evidence of efficacy or adverse events 
• 
Possible early termination of the trial because of new external information, early attainment of study 
objectives, safety concerns, or inadequate performance 
• 
Possible modifications in the clinical trial protocol  
• 
Performance of individual centers  
The DSMB is selected by the study team for their expertise in relevant fields. The DSMB reviews all protocols 
for safety. The DSMB will consist of members with expertise in acute lung injury, transfusion medicine, 
biostatistics, ethics, and clinical trials. Appointment of all members is contingent upon the absence of any 
conflicts of interest. All the members of the DSMB are voting members. An unblinded statistician and coordinating 
center personnel will be responsible for the preparation of all DSMB and adverse event reports and may review 
unblinded data. The DSMB will develop a charter and review the protocol and sample consent form during its 
first meeting. Subsequent DSMB meetings will be scheduled in accordance with the DSMB Charter. When 
appropriate, conference calls may be held in place of face-to-face meetings. Recommendations to end, modify, 
or continue the trial will be prepared by the DSMB. Recommendations for major changes, such as stopping the 
trial, will be communicated to the executive committee/sponsor-investigator.  
 
 

 
 
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APPENDICES 
Appendix A: Schedule of Events  
 
Screening & 
Consent 
Baseline & 
Transfusion 
Follow-up 
Day 
1 or before 
1 
2 
3 
4 
5 
6 
7 
81 
151 
291 
Confirm eligibility, including positive 
SARS-CoV-2 test 
x 
 
 
 
 
 
 
 
 
 
 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
x 
 
 
 
 
 
 
 
 
 
Demographic and Medical history 
 
x 
 
 
 
 
 
 
 
 
 
ABO type (complete on study protocol 
if clinical results not available; follow 
institutional policy) 
 
x4 
 
 
 
 
 
 
 
 
 
Study infusion 
 
X2 
 
 
 
 
 
 
 
 
 
Record vital signs 
 
x 
x3 
x3 
x3 
x3 
x3 
x3 
x3 
 
 
COVID-19 symptom screen 
 
x 
 
 
 
 
 
 
 
 
 
Concomitant medications 
 
x 
 
 
 
 
 
 
 
 
 
Assessment with COVID-19 7-point 
Ordinal Clinical Progression Outcomes 
Scale 
 
x 
x3 
x3 
x3 
x3 
x3 
x3 
x 
x 
x 
Collect data for later calculation of 
SOFA score 
 
x 
x3 
 
 
 
 
 
 
 
 
Record new medical conditions 
 
x 
x3 
x3 
x3 
x3 
x3 
x3 
x 
x 
x 
Adverse event monitoring 
 
x 
x3 
x3 
x3 
 
 
 
 
 
 
CRP (complete on study protocol if 
clinical results not available) 
 
x4 
 
 
 
 
 
 
 
 
 
CBC and CMP (complete on study 
protocol if clinical results not available) 
 
x4 
x3, 4 
 
 
 
 
 
 
 
 
Blood for COVID-19 titer testing 
 
x5 
X3 
 
 
 
 
 
 
 
 
Record the results of a clinically 
obtained CBC and CMP (only if 
clinically available) 
 
 
 
 
 
 
 
 
x 
 
 
1 If patient is discharged before the follow-up visits on Day 8, 15, and 29, follow-up study activities on these days will be performed via phone calls. 
Day 8 call window will be Day 8 through 14. The Day 15 call window will be Day 15 through 22. The Day 29 call window will be Day 29 through 36 
2 Study infusion will be monitored per site institutional transfusion policy. 
3 Only performed if hospitalized. 
4 Only if not performed as part of standard of care. 
5 Must be drawn prior to study infusion. 
 
 

 
 
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Appendix B:  Adverse Event Reporting and Unanticipated Events 
Investigators will report all serious adverse events that occur within 72 hours of study infusion to the Vanderbilt 
Coordinating Center (VCC) regardless of relatedness.  Serious adverse events that are determined to be related 
to study procedures (regardless of timing related to study infusion) will be reported to the VCC within 24 hours. 
Hence, all serious adverse events judged to be related or possibly related to study procedures will be reported 
within 24 hours (Figure 2). The VCC will then notify the single Institutional Review Board (sIRB).  
The Medical Monitor will work collaboratively with the reporting investigator to determine if a serious adverse 
event has a reasonable possibility of having been caused by the study infusion or study procedure, as outlined 
in 21 CFR 312.32(a)(1), and below. The Medical Monitor will be unblinded and will also determine if the event 
is unexpected for convalescent plasma. An adverse event is considered “unexpected” if it is not listed in the 
investigator brochure or the study protocol [21 CFR 312.32(a)]. If a determination is made that a serious 
adverse event has a reasonable possibility of having been caused by a study procedure or the study infusion, it 
will be classified as a suspected adverse reaction. If the suspected adverse reaction is unexpected, it will be 
classified as a serious unexpected suspected adverse reaction (SUSAR).  
The VCC will report all unexpected deaths, serious and treatment related adverse events, and SUSARs to the 
DSMB and sIRB within 7 days after receipt of the report from a clinical site. A written report will be sent to the, 
DSMB, FDA, and the sIRB within 15 calendar days. The DSMB will also review all reported adverse events and 
clinical outcomes during scheduled interim analyses. The VCC will distribute the written summary of the DSMB’s 
periodic review of reported adverse events to the sIRB.  
 
B.1. Unanticipated Problems (UP) 
Investigators must also report Unanticipated Problems, regardless of severity, associated with study procedures 
within 24 hours. An unanticipated problem is defined as follows: any incident, experience, or outcome that meets 
all the following criteria:  
• 
Unexpected, in terms of nature, severity, or frequency, given the research procedures that are described in 
the protocol-related documents, such as the sIRB-approved research protocol and informed consent 
document; and the characteristics of the subject 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.  
• 
Suggests that the research places subjects or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized.  
 
B.2. Determining Relationship of Adverse Events to Study Infusion or Study Procedures 
Investigators will be asked to grade the strength of the relationship of an adverse event to study infusion or 
study procedures as follows:  
• 
Definitely Related: The event follows: a) A reasonable, temporal sequence from a study procedure; and 
b) Cannot be explained by the known characteristics of the patient’s clinical state or other therapies; and 
c) Evaluation of the patient’s clinical state indicates to the investigator that the experience is definitely 
related to study procedures.  
• 
Probably or Possibly Related: The event should be assessed following the same criteria for “Definitely 
Associated”. If in the investigator’s opinion at least one or more of the criteria are not present, then 
“probably” or “possibly” associated should be selected.  
• 
Probably Not Related: The event occurred while the patient was on the study but can reasonably be 
explained by the known characteristics of the patient’s clinical state or other therapies.  
• 
Definitely Not Related: The event is definitely produced by the patient’s clinical state or by other modes 
of therapy administered to the patient.  

 
 
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• 
Uncertain Relationship: The event does not meet any of the criteria previously outlined.  
B.3. Clinical Outcomes that may be Exempt from Adverse Event Reporting 
Study-specific outcomes of acute respiratory infection, COVID-19, and critical illness will be systematically 
collected for all patients in both study groups and are exempt from adverse event reporting unless the 
investigator considers the event to be Definitely Probably, or Possibly Related (or of an Uncertain 
Relationship) to the study infusion or study procedures.  Examples of study-specific clinical outcomes include: 
• 
Death not related to the study procedures  
• 
Neurological events 
o Ischemic stroke 
• 
Cardiovascular events 
o Receipt of vasopressors 
o Cardiomyopathy 
o Myocardial infarction 
o Cardiac arrest 
o Deep vein thrombosis 
o Pulmonary embolism 
• 
Respiratory events 
o Hypoxemia requiring supplemental oxygen 
o Acute respiratory distress syndrome 
o Receipt of mechanical ventilation 
o Receipt of extra-corporeal membrane oxygenation 
• 
Gastrointestinal events 
o Elevation of aspartate aminotransferase or alanine aminotransferase 
• 
Renal events 
o Acute kidney injury 
o Receipt of renal replacement therapy 
• 
Hematologic or coagulation events 
o Neutropenia, lymphopenia, anemia, or thrombocytopenia 
Note: A study-specific clinical outcome may also qualify as a reportable adverse event.  For example, a cardiac 
arrest that the investigator considers Definitely or Possibly Related to the study infusion would be both recorded 
as a study-specific clinical outcome and reported as a Serious and Definitely or Possibly Related Adverse Event. 
 
 
 
 
 
 
 
 
 
 

 
 
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B.4. Decision tree for determining if an adverse event is reportable 
Figure 2. Decision tree for determining if an adverse event is reportable 
 
 
 
Figure adapted from Ranieri VM, Thompson BT, Barie PS et al. Drotrecogin alfa 
(activated) in adults with septic shock. N Engl J Med. 2012 May 31;366 (22):2055-64. 
PMID: 22616830. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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