An Open-Label, Controlled, Phase 1, Safety and Exploratory Efficacy Study of Convalescent Plasma for Severely Ill, Hospitalized Participants With COVID-19 Pneumonia Caused by SARS-CoV-2.
Phase: PHASE1
Conditions: COVID-19
Sponsor: University of Pennsylvania

 
Office of Clinical Research 
 
 
 
Confidential and Proprietary Information of the Trustees of the University of Pennsylvania 
8032 Maloney Bldg. | 3400 Spruce St | Philadelphia, PA  19104-6061 | Tel: (215) 662-4484 | Fax: 215-614-0378 
www.med.upenn.edu/ocr 
 
 
 
PROTOCOL #843003 (PENNCCP-02): AN OPEN-LABEL, 
CONTROLLED, PHASE 1, SAFETY AND EXPLORATORY EFFICACY 
STUDY OF CONVALESCENT PLASMA FOR SEVERELY ILL, 
HOSPITALIZED PARTICIPANTS WITH COVID-19 PNEUMONIA 
CAUSED BY SARS-COV-2 
 
 
NCT04397757 
 
 
VERSION DATE: 28-AUG-2020 
 
 
 
 
 
 

 
Protocol PennCCP-02 - COVID-19 Convalescent Plasma for Hospitalized Population 
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CLINICAL RESEARCH PROTOCOL 
INVESTIGATIONAL 
PRODUCT(S): 
Penn COVID-19 Convalescent Plasma 
STUDY 
NUMBER(S): 
IRB 
Number 
843003 
Other 
Protocol 
Identifiers  
PennCCP-02 
PROTOCOL(S) TITLE: 
An Open-Label, Controlled, Phase 1, Safety and Exploratory 
Efficacy Study of Convalescent Plasma for Severely Ill, 
Hospitalized Participants with COVID-19 Pneumonia Caused by 
SARS-CoV-2 
IND NUMBER 
20836 
REGULATORY 
SPONSOR: 
University of Pennsylvania 
3400 Spruce Street; 
8032 Maloney Building 
Philadelphia, PA, 19104 
FUNDING SPONSOR(S): 
University of Pennsylvania 
MEDICAL DIRECTOR 
Katharine J. Bar, MD 
ORIGINAL PROTOCOL 
DATE: 
15-Apr-2020 
VERSION NUMBER: 
Version 4 
VERSION DATE: 
28-Aug-2020 
 
 
 
 

 
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Table of Contents 
Clinical Research Protocol ................................................................................................ 1 
1 
Study Summary .......................................................................................................... 8 
1.1 
Synopsis .................................................................................................................. 8 
1.2 
Key Roles and Study Governance ...................................................................... 14 
1.3 
Schema .................................................................................................................. 14 
2 
Introduction and Rationale ..................................................................................... 15 
2.1 
Study Rationale .................................................................................................... 15 
2.2 
Background .......................................................................................................... 15 
2.2.1 
COVID-19 ....................................................................................................... 15 
2.2.2 
Passive Immunotherapy in Coronavirus Disease ....................................... 15 
2.2.3 
Passive Immunotherapy in Other Viral Infection ...................................... 16 
2.3 
Risk/Benefit Assessment ...................................................................................... 17 
2.3.1 
Known Potential Risks .................................................................................. 17 
2.3.1.1 
Risk of Plasma Transfusions................................................................... 17 
2.3.1.2 
Risk of Antibody-Mediated Enhancement (ADE) of Infection ........... 18 
2.3.1.3 
Risk of Antibody-Mediated Acute Lung Injury ................................... 18 
2.3.1.4 
Risk of Decreased Protective Immunity ................................................ 19 
2.3.1.5 
Risk of Plasma Transfusions Interaction with Immunization ............. 19 
2.3.1.6 
Risk of Phlebotomy .................................................................................. 19 
2.3.1.7 
Risk of Nasopharyngeal Swab ................................................................ 20 
2.3.1.8 
Risk of Oropharyngeal Swab .................................................................. 20 
2.3.1.9 
Risk of Endotracheal Aspirate ............................................................... 20 
2.3.2 
Known Potential Benefits .............................................................................. 20 
2.3.2.1 
Benefits of Treatment .............................................................................. 20 
2.3.2.2 
Alternatives .............................................................................................. 20 
2.3.3 
Assessment of Potential Risks and Benefits ................................................. 20 
2.3.3.1 
Assessment of Potential Risks and Benefits in Pregnant Individuals . 21 
3 
Study Objectives and Endpoints ............................................................................. 22 
3.1 
Primary Objectives .............................................................................................. 22 
3.2 
Secondary Objectives and Endpoints ................................................................ 22 
3.3 
Exploratory Objectives and Endpoints ............................................................. 25 
4 
Study Plan ................................................................................................................. 27 
4.1 
Study Design ......................................................................................................... 27 
4.2 
Scientific Rationale for Study Design ................................................................ 27 
4.3 
Justification for Dose ........................................................................................... 28 
4.4 
End of Study Definition ....................................................................................... 29 
5 
Study Population ...................................................................................................... 30 
5.1 
Inclusion Criteria ................................................................................................. 30 
5.2 
Exclusion Criteria ................................................................................................ 30 
5.3 
Lifestyle Considerations ...................................................................................... 30 
5.4 
Screen Failures ..................................................................................................... 30 
5.5 
Strategies for Recruitment and Retention ......................................................... 31 
5.5.1 
Recruitment .................................................................................................... 31 
5.5.2 
Retention ......................................................................................................... 31 

 
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5.5.3 
Costs ................................................................................................................ 31 
6 
Study Intervention .................................................................................................... 32 
6.1 
Study Intervention(s) Administration ................................................................ 32 
6.1.1 
Study Intervention Description .................................................................... 32 
6.1.2 
Dosing and Administration ........................................................................... 32 
6.2 
Preparation/Handling/Storage/Accountability ................................................. 33 
6.2.1 
Acquisition and Accountability .................................................................... 33 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ................................. 33 
6.2.3 
Preparation ..................................................................................................... 33 
6.3 
Measures to Minimize Bias: Randomization and Blinding ............................. 33 
6.4 
Study Intervention Compliance.......................................................................... 33 
6.5 
Concomitant Therapy ......................................................................................... 33 
6.5.1 
Rescue Medicine ............................................................................................. 33 
7 
Study Intervention Discontinuation and Participant Discontinuation/Withdrawal
 .................................................................................................................................... 34 
7.1 
Discontinuation of Study Intervention ............................................................... 34 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................... 34 
7.3 
Lost To Follow-Up ............................................................................................... 34 
8 
Study Assessment and Procedures .......................................................................... 35 
8.1 
Screening and Efficacy Assessments .................................................................. 35 
8.1.1 
Screening Procedures .................................................................................... 35 
8.1.1.1 
Screening Procedures in Pregnant Women ........................................... 36 
8.1.2 
Measures of clinical support, limitations and infection control ................ 36 
8.1.3 
Ordinal Scale .................................................................................................. 37 
8.1.4 
National Early Warning Score (NEWS) ...................................................... 38 
8.2 
Exploratory Assessments .................................................................................... 39 
8.2.1 
Virologic and Serologic Assays ..................................................................... 39 
8.2.2 
Alternative Ordinal Scales ............................................................................ 39 
8.3 
Safety and Other Assessments ............................................................................ 39 
8.3.1 
Procedures to be Followed in the Event of Abnormal Laboratory Test Values 
or Abnormal Clinical Findings ..................................................................... 40 
8.4 
Adverse Events and Serious Adverse Events .................................................... 40 
8.4.1 
Definition of Adverse Events (AE) ............................................................... 40 
8.4.2 
Definition of Serious Adverse Events (SAE) ............................................... 40 
8.4.3 
Classification of an Adverse Event ............................................................... 41 
8.4.3.1 
Severity of Event ...................................................................................... 41 
8.4.3.2 
Relationship to Study Intervention ........................................................ 42 
8.4.3.3 
Expectedness ............................................................................................ 43 
8.4.4 
Time Period and Frequency for Event Assessment and Follow-Up ......... 43 
8.4.5 
Adverse Event Reporting .............................................................................. 44 
8.4.5.1 
Reporting Period ...................................................................................... 44 
8.4.5.2 
Investigator Reporting: Notifying the Study Sponsor .......................... 44 
8.4.5.3 
Investigator Reporting: Local Reporting Requirements ..................... 44 
8.4.6 
Serious Adverse Event Reporting ................................................................ 44 
8.4.7 
Reporting Events to Participants ................................................................. 45 
8.4.8 
Events of Special Interest .............................................................................. 45 

 
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8.4.9 
Reporting of Pregnancy ................................................................................ 45 
8.5 
Unanticipated Problems ...................................................................................... 45 
8.5.1 
Definition of Unanticipated Problems (UP) ................................................ 45 
8.5.2 
Unanticipated Problem Reporting ............................................................... 46 
8.5.3 
Reporting Unanticipated Problems to Participants ................................... 47 
9 
Statistical Considerations ........................................................................................ 48 
9.1 
Statistical Hypotheses .......................................................................................... 48 
9.2 
Sample Size Determination ................................................................................. 49 
9.3 
Populations for Analyses ..................................................................................... 50 
9.4 
Statistical Analyses .............................................................................................. 50 
9.4.1 
General Approach ......................................................................................... 50 
9.4.2 
Analysis of the Primary Endpoint(s)............................................................ 51 
9.4.3 
Analysis of the Secondary Endpoint(s) ........................................................ 51 
9.4.4 
Safety Analyses ............................................................................................... 52 
9.4.5 
Baseline Descriptive Statistics ...................................................................... 52 
9.4.6 
Planned Interim Analyses ............................................................................. 52 
9.4.7 
Sub-Group Analyses ...................................................................................... 53 
9.4.8 
Tabulation of Individual Participant Data .................................................. 53 
9.4.9 
Exploratory Analyses .................................................................................... 53 
10 Supporting Documentation and Operational Considerations .............................. 54 
10.1 
Regulatory, Ethical, and Study Oversight Considerations .............................. 54 
10.1.1 
Informed Consent Process ............................................................................ 54 
10.1.1.1 
Consent/Assent and Other Informational Documents Provided To 
Participants .............................................................................................. 54 
10.1.1.2 
Consent Procedures and Documentation .............................................. 54 
10.1.2 
Study Discontinuation and Closure ............................................................. 54 
10.1.3 
Confidentiality and Privacy .......................................................................... 55 
10.1.4 
Future Use of Stored Specimens and Data .................................................. 55 
10.1.5 
Safety Oversight ............................................................................................. 56 
10.1.6 
Clinical Monitoring ....................................................................................... 56 
10.1.7 
Quality Assurance and Quality Control ...................................................... 57 
10.1.8 
Data Handling and Record Keeping ............................................................ 58 
10.1.8.1 
Data Collection and Management Responsibilities .............................. 58 
10.1.8.2 
Study Records Retention ......................................................................... 58 
10.1.9 
Protocol Deviations ........................................................................................ 58 
10.1.10 
Publication and Data Sharing Policy ........................................................... 59 
10.1.11 
Conflict of Interest Policy ............................................................................. 59 
10.2 
Additional Considerations .................................................................................. 60 
10.2.1 
Research Related Injuries ............................................................................. 60 
10.3 
Protocol Amendment History ............................................................................. 60 
11 References ................................................................................................................. 61 
12 Appendix ................................................................................................................... 65 
12.1 
Schedule of Activities (SoA) ................................................................................ 65 
12.2 
Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric 
Adverse Events, Corrected version 2.1 (July 2017) .......................................... 66 

 
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Table of Tables 
Table 1: National Early Warning Score (NEWS) ......................................................... 38 
Table 2: Venipuncture Volumes1 ................................................................................... 39 
Table 3. Probability of detecting zero individuals or at least one individual with an 
Adverse Event (AE) for a variety of different underlying AE rates and sample size 
N =40 ..................................................................................................................... 49 
Table 4: Schedule of Activities ........................................................................................ 65 
 
 
 

 
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Abbreviations 
ACIP 
Advisory Committee on Immunization Practices 
ALT 
alanine aminotransferase 
AE 
adverse event  
ARDS 
acute respiratory distress syndrome 
AST 
aspartate aminotransferase 
BMT 
bone marrow transplant 
BP 
blood pressure 
CDC 
The Centers for Disease Control and Prevention 
CMV 
cytomegalovirus 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
DSMB 
Data and Safety Monitoring Board 
ECMO 
extra corporeal membrane oxygenation 
FDA 
Food and Drug Administration  
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice  
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICH 
The International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IND 
Investigational New Drug Application 
IRB 
institutional review board 
ISBT 
International Society of Blood Transfusion 
IVIG 
intravenous immune globulin  
JAMA 
Journal of the American Medical Association 
LIP 
Licensed Individual Practitioner 
MMWR 
Morbidity and Mortality Weekly Report  
MN 
microneutralization 
NAT 
nucleic acid testing  
OTC 
over the counter 
PCCP 
Penn COVID-19 Convalescent Plasma 
PCR 
polymerase chain reaction 
PK 
pharmacokinetic 
RSV 
respiratory syncytial virus 
SAE 
serious adverse event 
SARS 
severe acute respiratory syndrome 
TRALI 
transfusion-related acute lung injury 
VIG 
vaccinia immune globulin 
 
 
 

 
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1 STUDY SUMMARY 
1.1 
Synopsis 
Title:  
An Open-Label, Controlled, Phase 1, Safety and Exploratory Efficacy Study 
of Convalescent Plasma for Severely Ill, Hospitalized Participants with 
COVID-19 Pneumonia Caused by SARS-CoV-2. 
Short Title: 
COVID-19 Convalescent Plasma for Hospitalized Population 
Study 
Description:  
This open-label, controlled, phase 1 trial will assess the safety and efficacy of 
convalescent plasma in severely ill, hospitalized participants with pneumonia 
due to COVID-19. This study will enroll adults 18 years old and older, 
including pregnant women. 
A total of 80 eligible participants will be randomized to receive either 2 units 
of convalescent plasma collected from ABO-compatible donors who have 
recovered from COVID-19 and standard of care (treatment arm) or standard of 
care alone (control arm).  Participants in the treatment arm will receive 2 units 
of convalescent plasma on Study Day 1 in addition to standard of care. 
Participants will be assessed on study Day 1 (pre-dose), 30 minutes after each 
unit of plasma, on all Study Days while hospitalized, and Study Days 15, 22, 
29, and 60. All participants will undergo a series of safety and efficacy, 
assessments.  Blood samples will be collected on Days 1 (prior to plasma 
administration), 3, 8, 15, 29, and 60. Oropharyngeal or endotracheal samples 
will be collected on Days 1 (prior to plasma administration), 3, 5, 8, 11, and 
15. 
Objectives:  
Primary Objectives 
The overall objective of the study is to evaluate the safety and explore the 
efficacy of treatment with convalescent plasma plus standard care vs. standard 
care alone in hospitalized participants with confirmed COVID-19 disease. 
Secondary Objectives 
For the secondary objectives, we will compare treatment and control arms 
with clinical severity scales.  
Primary 
Endpoint:  
The primary safety objective will be assessed by the cumulative incidence of 
serious adverse events (SAEs) at Study Day 29. 
The primary efficacy objective will be assessed by comparison of clinical 
severity between participants in the treatment versus control arms, as 
measured by a modified 8-point ordinal severity score on Study Day 29. The 
modified score treats all participants who have reached levels 1-3 as 
recovered. 

 
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o National Early Warning 
Score (NEWS): 
 
Time to discharge or to a NEWS 
of 
≤ 2 and maintained for 24 
hours, whichever occurs 
first 
 Change from Day 1 to 
Days 3, 5, 8, 11, 15, and 29 
in NEWS 
 
 
• 
NEWS assessed daily while 
hospitalized and on Days 15 and 29. 
o Oxygenation: 
 
Oxygenation free days to Day 29. 
 
Incidence and duration of new 
oxygen use during the study. 
 
 
Days of supplemental oxygen (if 
applicable) 
o Non-invasive 
ventilation/high flow oxygen: 
 
Non-invasive 
ventilation/high flow oxygen 
- free days to Day 29. 
• 
Incidence and 
duration of new non- 
invasive ventilation 
or high flow oxygen 
use during the study. 
 
 
• 
Days of non-invasive 
ventilation (if applicable). 
• 
Days of high flow oxygen (if 
applicable). 
o Invasive Mechanical Ventilation / 
extracorporeal membrane 
oxygenation (ECMO): 
 
Ventilator / ECMO free 
days to Day 29. 
 
Incidence and duration of 
new mechanical 
ventilation or ECMO use 
during the study. 
 
 
• 
Days of invasive mechanical 
ventilation (if applicable). 
• 
Days of ECMO (if applicable). 
• 
Hospitalization 
o Duration of hospitalization. 
 
• 
Days of hospitalization 
• 
Mortality 
o Survival time 
o 14-day mortality 
o 28-day mortality 
 
• 
Date and cause of death (if applicable) 
2. Evaluate the safety of convalescent 
plasma administration comparing 
treatment vs. control arms by: 
• 
Cumulative incidence of Grade 3 
and 4 clinical and/or laboratory 
AEs through Day 29. 
• 
Changes in WBC with differential, 
hemoglobin, platelets, creatinine, 
glucose, total bilirubin, ALT, AST, 
and PT over time (analysis of lab 
values in addition to AEs noted 
above). 
 
 
• 
SAEs 
• 
Grade 3 and 4 AEs 
• 
WBC with differential, hemoglobin, 
platelets, creatinine, glucose, total 
bilirubin, ALT, AST, and PT on Day 
1; Days 3, 5, 8, and 11 (while 
hospitalized); and Days 15 and 29 (if 
lab collection is possible). 

 
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o Invasive Mechanical Ventilation / 
extracorporeal membrane 
oxygenation (ECMO): 
 
Ventilator / ECMO free 
days to Day 29. 
 
Incidence and duration of 
new mechanical 
ventilation or ECMO use 
during the study. 
 
 
• 
Days of invasive mechanical 
ventilation (if applicable). 
• 
Days of ECMO (if applicable). 
 
Evaluate the virologic efficacy of 
convalescent plasma as assessed by: 
• 
Percent of participants with detectable 
SARS-CoV-2 in OP or ET samples at 
Days 3, 5, 8, 11, and 15. 
• 
Quantitative SARS-CoV-2 in OP or 
ET samples at Days 3, 5, 8, 11, and 15. 
• 
Qualitative SARS-CoV-2 in OP or ET 
samples at Days 3, 5, 8, 11, and 15. 
 
• 
Quantitative and Qualitative PCR 
for SARS-CoV-2 in OP or ET swab 
at Day 1; Days 3, 5, 8, 11, and 15. 
 
Evaluate the timing and titer of anti-
SARS-CoV-2 antibody responses after 
convalescent plasma administration 
• 
Plasma antibody binding and 
neutralization on Day 1; Days 3 8, 
15, 29, and 60 
Evaluate the timing and quality of 
SARS-CoV-2 cellular responses after 
convalescent plasma administration 
• 
Cellular responses in whole blood on 
Day 1; Days 3, 8, Days 15 29, and 
60 
Evaluate the change in inflammatory 
responses with convalescent plasma 
administration 
 
 
 
Evaluate the change in clinical status 
(by clinical severity score) to the 
change in inflammatory markers 
 
• 
Plasma and cellular markers of 
inflammation on Day 1; Days 3, 8, 
15, 29, and 60 
 
• 
Ferritin, C Reactive Protein, D-
Dimer, Fibrinogen, Erythrocyte 
Sedimentation Rate, Triglycerides, 
IL-6 on Study Day 1, 3, 5, 8, 11, 15, 
29, and 60 (when available). 
Study Population: 
Severely-ill, hospitalized adults >18 years old with COVID-19 pneumonia 
Phase: 
Phase I 
Enrolling Sites: 
This is a single site study conducted in the Hospitals of the University of 
Pennsylvania. 
Description of 
Study 
Intervention: 
This open label, randomized, controlled, phase I study will assess the 
administration of 2 units of convalescent plasma collected from ABO-
compatible donors who have recovered from COVID-19.  Participants will be 
randomized 1:1 to receive either convalescent plasma on Study Day 1 in 
addition to standard care or standard care alone. 
Study Duration: 
We expect the study to last 6 months from initiation 

 
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2 INTRODUCTION AND RATIONALE 
2.1 
Study Rationale 
Coronavirus disease (COVID-19), the syndrome caused by SARS-CoV-2, causes significant morbidity 
and mortality in a subset of infected individuals. In the most severely affected individuals, COVID-19 
causes pneumonia and acute respiratory distress syndrome (ARDS) requiring mechanical ventilation. 
There are currently no effective biomedical therapies available, beyond supportive therapy, to treat 
COVID-19. Convalescent plasma from individuals who have recovered from COVID-19 may contain 
high titer anti-SARS-CoV-2 neutralizing antibodies that could help treat the disease. 
2.2 
Background 
2.2.1 
COVID-19 
Emerging infectious diseases can be defined as “infections that have newly appeared in a population or 
have existed previously but are rapidly increasing in incidence or geographic range.” [1, 2]  Over the 
last decade there has been an increase in recognized emerging or re-emerging infectious diseases.  This 
includes, but is not limited to Nipah virus, Lassa virus, Hantavirus, Hendra virus, West Nile virus, 
avian influenza, severe acute respiratory syndrome (SARS), Middle Eastern respiratory syndrome 
(MERS), and COVID-19 caused by SARS-CoV-2.  For emerging diseases that have no treatment, the 
use of convalescent plasma is often invoked. 
COVID-19, the clinical disease caused by SARS-CoV-2, was first recognized in a cluster of 
pneumonia cases in Wuhan, China in late 2019 [48]. Since then, COVID-19 has rapidly evolved into a 
pandemic of unprecedented scope.  As of April 1, 2020, COVID-19 had infected over a million 
individuals and resulted in more than 50,000 deaths worldwide (JHU CRS site).  In the United States, 
the COVID-19 epidemic is growing in prevalence, with more than 200,000 diagnosed infections and 
more than 5,000 deaths (JHU CRS site). 
COVID-19 has a range of clinical severity, with a proportion of patients experiencing severe disease, 
causing pneumonia, acute respiratory distress syndrome, and hypoxic respiratory failure requiring 
mechanical ventilation.  For severely ill COVID-19 patients, there are currently no effective 
biomedical interventions beyond supportive care. Due to the morbidity and mortality occurring in 
severe COVID-19 disease, the testing of additional therapeutic options is warranted.  One potential 
therapeutic that is rapidly available is the use of convalescent plasma as passive immunotherapy. 
2.2.2 
Passive Immunotherapy in Coronavirus Disease 
Over the past 20 years, two other coronaviruses have caused epidemics and substantial morbidity and 
mortality. SARS, first detected in 2003, and MERS, first detected in 2012, both caused severe disease 
in a proportion of infected individuals.  The lack of effective therapeutics led to the use of passive 
immunotherapy with convalescent plasmas.  In a large, single-arm, open-label study from Hong Kong, 
80 SARS patients with disease that had progressed on the standard of care therapies received passive 
immunotherapy [29]. The convalescent plasma was obtained from SARS patients who were afebrile 
for at least 7 days and 14 days from initial presentation. Of the 80 SARS-infected study participants 
receiving plasma, 33 experienced a study-defined “good outcome” by meeting discharge criteria within 

 
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22 days from plasma administration. More frequent good outcomes were seen in participants receiving 
plasma early (within 14 days of presentation) and before development of SARS antibodies. 
Importantly, no immediate adverse events were noted.  
For COVID-19, there have been two recently published case series describing a total of 15 individuals 
treated with convalescent plasma.  In the first publication, Shen and colleagues described five critically 
ill COVID-19 patients with laboratory-confirmed disease, acute respiratory distress syndrome (ARDS) 
on mechanical ventilation, and high viral loads, who received plasma between day 10 and 22 of 
hospitalization.  All five participants experienced clinical improvement after plasma administration, 
with improvement in respiratory function in all five and hospital discharge in three of the five [30].  
The second report describes ten severely ill participants who received 1 unit of COVID-19 
convalescent plasma between day 10 and 20 of symptomatic disease [31].  Of the ten plasma 
recipients, three were supported by mechanical ventilation, five were receiving high- or low-flow 
supplemental oxygen, while two were not receiving supplemental oxygen. After plasma 
administration, clinical disease generally improved in terms of required oxygen support, lung imaging, 
and lab abnormalities, including leukopenia and some inflammatory markers.  Importantly, there were 
no serious adverse events in either report.  Although these trials are both small and uncontrolled, they 
describe generally safe and positive clinical responses to COVID-19 convalescent plasma 
administration. They also highlight the need for controlled trial data to determine the clinical utility of 
COVID-19 convalescent plasma administration. 
2.2.3 
Passive Immunotherapy in Other Viral Infection 
A number of viral diseases are treated with antibody preparations with variable results.  These antibody 
preparations can be given as either convalescent plasma or intravenous immunoglobulin (IVIG). 
Curative treatment with IVIG is rare.  Red blood cell aplasia caused by parvovirus B19 infection is the 
only recognized viral infection in which treatment with IVIG may eradicate the infection.  [3, 4] 
However, there is considerable evidence that immune globulin preparations may modify the natural 
history of viral diseases. These are summarized below. 
Influenza: Passive immunotherapy with convalescent plasma has been studied in many contexts 
against various strains of influenza.  A cohort study of patients with severe H1N1 2009 disease in 
Hong Kong compared outcomes in patients who received convalescent plasma with those who 
declined enrollment to the study, demonstrating a lower mortality in the plasma recipients [26].  A 
multicenter, prospective, double-blind, randomized trial of H1N1 2009-immune plasma formulated 
into immunoglobulin, H-IVIG vs. normal IVIG.  H-IVIG treatment was associated with significantly 
lower 5- and 7-day post-treatment viral loads [27]. Recently, a large United States multi-center, 
double-blinded trial of high-titer vs. low-titer anti-influenza plasma in individuals with severe 
influenza A.  The high-titer plasmas conferred no significant clinical benefit over the non-immune 
plasmas [28]. 
Cytomegalovirus (CMV): CMV enriched immune globulin preparations have shown benefit when 
used in combination with ganciclovir in the treatment of CMV pneumonia. [5]  This immune globulin 
preparation is also utilized in the treatment of ganciclovir-resistant CMV infections.  
Respiratory Syncytial Virus (RSV): In adult bone marrow transplant (BMT) patients with RSV 
pneumonia, combination therapy using aerosolized ribavirin and standard IVIG (500 mg/kg every 

 
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other day for 12 days) for the treatment had a 22% mortality rate, compared to a historical mortality 
rate of 70%. [6] In pediatric BMT patients with RSV pneumonia, patients treated with combination 
aerosolized ribavirin and RSV antibody enriched IVIG (RespiGam®) had a 9.1% mortality, compared 
with a historical 50-70% mortality rate of such patients given ribavirin alone. [7] 
Vaccinia Virus: Certain complications of vaccination with the vaccinia virus (smallpox vaccine) are 
treated with vaccinia immune globulin (VIG). These included generalized vaccinia, eczema 
vaccinatum, and progressive vaccinia. There have been no controlled trials of the efficacy of VIG. 
However, anecdotal experience suggests that treatment with VIG for these conditions is beneficial, and 
is now considered the standard of care. [8] 
Hepatitis A: IVIG has also been shown useful in hepatitis A. Persons who have been recently exposed 
to hepatitis A and who have not been previously vaccinated with hepatitis A are recommended to 
receive standard IVIG as post-exposure prophylaxis. This is based on data that showed IVIG, when 
administered within 2 weeks following an exposure to hepatitis A, is greater than 85% effective in 
preventing hepatitis A. [9] IVIG can also attenuate the clinical expression of hepatitis A infection when 
given later in the incubation period. [10] Standard IVIG is used because it does contain sufficient anti-
hepatitis A antibodies.  
Hepatitis B: For patients with hepatitis B and cirrhosis undergoing orthotopic liver transplant, hepatitis 
B hyperimmune IgG is given pre-operatively and post-operatively to prevent reinfection with hepatitis 
B. This has been shown to be 50-85% effective in preventing recurrence of hepatitis B in the 
transplanted liver. [11, 12] This efficacy may be improved with the concurrent use of the antiviral 
lamivudine. [12] 
Rabies: Rabies hyperimmune IgG is the standard recommended therapy after exposure to the rabies 
virus/rabid animal. [13] 
Argentine Hemorrhagic Fever: Convalescent plasma from survivors is the standard of care and has 
been shown to reduce mortality from 50% to 4% if therapy is initiated within 8 days after disease 
onset. [14] 
 
2.3 
Risk/Benefit Assessment 
2.3.1 
Known Potential Risks 
2.3.1.1 
Risk of Plasma Transfusions 
Common risks of plasma transfusions may include one or more of the following: fever, rash, hives, or 
headache. Other more serious risks are rare and may include the following: serious allergic reactions 
including anaphylaxis, bacterial infections, or viral infections like hepatitis B, hepatitis C, and human 
immunodeficiency virus (HIV).  
Transfusion-related acute lung injury (TRALI) may occur, but this risk is minimized by screening 
female donors for anti-HLA class I and class II antibodies in this study. TRALI is characterized by a 
clinical constellation of symptoms including dyspnea, hypotension and fever. Although the precise 

 
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pathogenesis of TRALI remains unknown, it has been shown to be related to the transfusion of anti-
HLA class I and anti-neutrophil antibodies most often from plasma from multiparous women 
(antibodies presumably generated during pregnancy) or donors who have received multiple blood 
transfusions though the introduction of universal leukoreduction of blood products has largely 
mitigated the production of HLA antibodies in response to transfusion. The risk of TRALI was 
reported as 1 out of 5000 transfusions in 2005 before these safety measures were put into place. [15]  
The infused plasma volume of 2 units is roughly 500 mL, so there is the risk of volume overload in the 
recipient, which could cause pulmonary edema. Participants with preexisting conditions who may not 
tolerate this volume of plasma will be excluded from this study, but this condition could still occur in 
recipients. 
There is also a possible increased risk of thrombotic events associated with plasma transfusion in 
severely-ill patients.  This has been reported in cancer, trauma, and surgical patients [32, 33, 34, 35]. It 
is possible that an increased risk of thrombotic events, including deep vein thrombosis or pulmonary 
embolism, could accompany plasma administration in severely-ill patients. There are case reports of 
pulmonary emboli occurring after administration of IVIG and plasma therapy, though definitive 
studies assessing risk are lacking. [16] In one series 5 of 10 participants critically ill with H1N1 were 
shown to have pulmonary emboli. [17] This high percentage has not been shown in other H1N1 series, 
and pulmonary emboli have been shown to develop in approximately 10-15% of critically ill adults. 
[18] However, the potential risk of pulmonary embolism exists.  
2.3.1.2 
Risk of Antibody-Mediated Enhancement (ADE) of Infection 
There is a theoretical risk that the antibodies within convalescent plasma could enhance SARS-CoV-2 
infection.  ADE has been reported in several other virus infections, usually in the setting of antibodies 
that cross-react between two related viral strains (e.g., Dengue infection) or weak or non-neutralizing 
antibodies (HIV-1) [36, 37].  We have seen minimal virus evolution, to date, in the COVID-19 
pandemic, making cross-reactive antibodies less likely.  Convalescent plasma from recently infected 
individuals likely contains high-titer neutralizing antibodies, making a predominantly weak or non-
neutralizing effect less likely.  Further, reports of convalescent plasma use in SARS and COVID-19, 
though few and uncontrolled, have not suggested enhanced infection 26, 30].  Continued study and 
assessment for ADE is warranted. 
2.3.1.3 
Risk of Antibody-Mediated Acute Lung Injury 
There is a theoretical risk of antibody-mediated acute lung injury with convalescent plasma 
administration.  Antibody-mediated acute lung injury has been reported in a nonhuman primate model 
of SARS-CoV-1 [38].  In this study, rhesus macaques with anti-SARS-CoV-1 antibodies via active or 
passive immunization, demonstrated pro-inflammatory lung responses during acute SARS infection.  
This phenomenon has not been reported in the observational reports of convalescent plasma 
administration in either SARS-CoV-1 or COVID-19, but remains a theoretical concern, especially in 
plasma administration during acute or early infection.   

 
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2.3.1.4 
Risk of Decreased Protective Immunity 
Immune responses to past Coronavirus diseases, including SARS and MERS, have been shown to be 
transient and directly related to the severity of illness.  Patients with asymptomatic or mild disease had 
lower titer and less durable markers of immunity, including antibody responses [39].  Mechanistically, 
antibody-based therapy aims to neutralize and/or clear virus, leading to less antigen for immune 
recognition and response maturation. Thus, it is possible that modifying the course of disease and 
decreasing viral antigen burden could hamper the duration or magnitude of protective immune 
responses after COVD-19 recovery.  This theoretical effect should be further investigated, and 
convalescent plasma-treated individuals considered for enhanced vaccination strategies, as they are 
developed.  The risk of decreased protective immunity is outweighed in moderately and severely 
individuals requiring hospitalization and/or ventilation, for whom the immediate risks of disease are 
more substantial. 
2.3.1.5 
Risk of Plasma Transfusions Interaction with Immunization 
The Advisory Committee on Immunization Practices (ACIP) advises that people who receive plasma 
products wait 7 months (assuming they receive 10 mL/kg) from administration of the plasma before 
receiving the measles vaccine (given as MMR - mumps, measles and rubella) or the varicella 
(chickenpox) vaccine. This is because these are live virus vaccines, and antibodies in the plasma may 
limit the immune response to the vaccine. Antibody-containing blood products do not interfere with 
the immune response to yellow fever vaccine and are not believed to interfere with the response to live 
typhoid, live attenuated influenza, rotavirus, or zoster vaccines.  While both varicella and zoster 
vaccines use an attenuated varicella virus, the zoster vaccine is at least 14 times greater amount of 
virus than that found in varicella vaccine explaining the difference in ACIP recommendations.  The 
amount of plasma administered in this study is 20-30% less than in the ACIP guidance (7-8 mL/kg for 
most participants), so the deferral period is likely slightly less (i.e., 5-6 months). [40]. 
In a separate document, ACIP stresses the importance of rubella and varicella immunity among women 
of child-bearing age and recommends “the postpartum vaccination of women without evidence of 
immunity to rubella or varicella with MMR, varicella, or MMRV vaccines should not be delayed 
because of receipt of anti-Rho(D) globulin or any other blood product during the last trimester of 
pregnancy or at delivery. These women should be vaccinated immediately after giving birth…[41].  
While not explicitly stated, we assume this supersedes the deferral considerations above.  Attempts by 
the sponsor to clarify this issue directly with ACIP were unsuccessful. 
2.3.1.6 
Risk of Phlebotomy 
The primary risks of phlebotomy include local discomfort, occasional bleeding or bruising of the skin 
at the site of needle puncture, and rarely hematoma, infection, or fainting. At the time of enrollment 
and during study visits, each participant will be asked about participation in other research studies to 
ensure that blood draws do not exceed the following amounts for all research protocols combined: 10.5 
mL/kg or 550 mL, whichever is smaller, over any 8-week period for adults, and no more than 5 mL/kg 
may in a single day (no more than 9.5 mL/kg may be drawn over any 8-week period) for persons under 
the age of 18. 

 
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2.3.1.7 
Risk of Nasopharyngeal Swab 
The primary risk of a nasal swab is local discomfort. Rarely, there can be local bleeding from the nasal 
mucosa, which is controlled with local measures such as pressure or packing with gauze. 
2.3.1.8 
Risk of Oropharyngeal Swab 
The primary risk of an oropharyngeal swab is local discomfort. This swab can stimulate the gag reflex, 
and very rarely vomiting. 
2.3.1.9 
Risk of Endotracheal Aspirate 
The primary risk of endotracheal aspirate is cough, and rarely can cause a small amount of bleeding. 
2.3.2 
Known Potential Benefits 
2.3.2.1 
Benefits of Treatment 
The benefits of antiviral treatment with convalescent immune plasma in patients with severe COVID-
19 disease are unknown. However, it is possible (and it is the hypothesis), that convalescent plasma in 
addition to standard of care (i.e., supportive care and institutional and/or medical provider 
recommended therapies) will more rapidly decrease viral replication, reduce the duration and severity 
of illness, reduce complications, and improve outcomes after infection with COVID-19 compared to 
not receiving convalescent plasma. 
2.3.2.2 
Alternatives 
The alternative to participation in this study is routine standard of care, which can include 
supplemental oxygen, fluids, and other symptomatic treatments. Additional treatments for this type of 
participants may include experimental antivirals and/or immunomodulators (e.g., hydroxychloroquine) 
determined by clinical practice and the rapidly evolving evidence base. 
2.3.3 
Assessment of Potential Risks and Benefits 
There is a substantial risk of morbidity and mortality in COVID-19 disease, especially in intubated, 
mechanically ventilated patients.  Mortality rates vary across clinical cohorts, but recent reports 
suggest mortality rates up to 28% in hospitalized patients in China (REFS).  At this time, there are no 
effective COVID-19 therapeutics and standard of care involves supportive therapy (e.g., oxygen, 
fluids), with consideration of a variety of unproven, experimental treatments (e.g., antivirals and 
immunomodulators). 
The administration of blood products, including plasma, is a common and well tolerated clinical option 
used in multiple indications. There are limited reports of the effects of convalescent plasma for 
COVID-19, with just two small observational studies describing a total of 15 patients, to date [30, 31].  
The experience from these studies and studies of convalescent plasma in other viral infections suggest 
that plasma administration is safe and well tolerated and may confer clinical benefit.  Thus, for severe 
COVID-19 disease, the possible therapeutic benefit of convalescent plasma outweighs the minimal 
safety risks. 

 
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2.3.3.1 
Assessment of Potential Risks and Benefits in Pregnant Individuals 
2.3.3.1.1 
Rationale for inclusion of Pregnant Women in COVID-19 clinical research 
There is growing consensus on the ethical and practical need to more proactively consider inclusion of 
pregnant women in clinical research, including in COVID-19 studies [42]. Formal studies provide 
evidence-based guidance on treatment options for application in medically compromised pregnancies. 
The supervision of the patient and the quality of the data acquired in formal, preferably controlled, 
studies is superior to that received in the post-marketing environment.  Safety and efficacy information 
will be obtained sooner and with fewer pregnant women and fetuses exposed than if the drug 
information is obtained following its release on the market (recognizing, as with all drugs, that some 
objectives cannot be met until widespread use occurs).  In particular, advocacy groups recommend that 
pregnant women should be included in clinical research when participation in a study provides 
potential therapeutic benefit and the anticipated benefits exceed the anticipated risks and when their 
exclusion cannot be justified by scientific rationale [43] . 
2.3.3.1.2 
Risks and Benefits of plasma and antibody administration in Pregnant Women 
The use of fresh frozen plasma in pregnancy is considered standard of care and is used for several 
conditions, including massive bleeding or coagulation disorders, as described in clinical society 
guidelines, (eg, the British Royal College of Obstetrics and Gynaecologists) [44]. Further, the use of 
antibody preparations, like IVIG, are used commonly to treat autoimmune or coagulation disorders and 
to protect the fetus from maternal antibody disorders [45, 46, 47]. The known risks of plasma infusion, 
including TRALI and volume overload complications discussed above for all populations, remain 
issues for pregnant women, but have not been reported in higher frequency or severity.  Given the 
frequent and generally safe experience with plasma administration and the potential benefit of plasma 
in severe-disease, administration of convalescent plasma is regarded as a reasonable strategy to 
evaluate. 
 
 
 
 

 
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3 STUDY OBJECTIVES AND ENDPOINTS 
3.1 
Primary Objectives 
The overall objective of the study is to evaluate the safety and explore the efficacy of treatment with 
convalescent plasma plus standard care vs. standard care alone in severely ill hospitalized participants 
with confirmed COVID-19 disease.  
The primary safety objective will be assessed by the cumulative incidence of serious adverse events 
(SAEs) at Study Day 29.  
The primary efficacy objective will be assessed a comparison of the clinical severity between 
participants in the treatment versus control arms, where severity is measured by the modified 8-point 
ordinal clinical severity scale at Day 29. The modified score treats all participants who have reached 
levels 1-3 as recovered. 
3.2 
Secondary Objectives and Endpoints 
For the secondary objectives, we will compare treatment and control arms based on the following list 
of clinical endpoints which capture different aspects of disease severity. 

 
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OBJECTIVES 
ENDPOINTS (OUTCOME MEASURES) 
1. Evaluate the clinical efficacy of convalescent plasma 
administration  by comparing treatment vs control arms 
• 
Clinical Severity 
o Ordinal scale: 
 
Time to recovery, defined by time to levels 
1-3 on the ordinal scale 
 
Time to an improvement of one category 
and two categories from Day 1 using an 
ordinal scale. 
 
Participant clinical status using ordinal scale at 
Days 3, 5, 8, 11,15, 22, and 29. 
 
Mean change in the ordinal scale from Day 1 
to Days 3, 5, 8, 11, 15, 22, and 29. 
• Clinical outcome assessed using ordinal 
scale daily while hospitalized and on Day 15, 
22, and 29. 
• Clinical status assessment (8-point ordinal 
scale) includes:  
1. Not hospitalized, no limitations on activities. 
2. Not hospitalized, limitation on activities and/or 
requiring home oxygen; 
3. Hospitalized, not requiring supplemental 
oxygen - no longer requires ongoing medical 
care; 
4. Hospitalized, not requiring supplemental 
oxygen - requiring ongoing medical care 
(COVID-19 related or otherwise); 
5. Hospitalized, requiring supplemental oxygen; 
6. Hospitalized, on non-invasive ventilation or 
high flow oxygen devices; 
7. Hospitalized, on invasive mechanical 
ventilation or ECMO; 
8. Death 
o National Early Warning Score 
(NEWS): 
 
Time to discharge or to a NEWS of 
≤ 2 and maintained for 24 hours, 
whichever occurs first 
 Change from Day 1 to Days 3, 5, 8, 11, 15, 
and 29 in NEWS. 
• 
NEWS assessed daily while hospitalized and on 
Days 15 and 29. 
o Oxygenation: 
 
Oxygenation free days to Day 29. 
 
Incidence and duration of new oxygen use during 
the study. 
 
Days of supplemental oxygen (if applicable) 

 
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OBJECTIVES 
ENDPOINTS (OUTCOME MEASURES) 
o Non-invasive ventilation/high flow oxygen: 
 
Non-invasive ventilation/high flow oxygen - 
free days to Day 29. 
• 
Incidence and duration of new non- 
invasive ventilation or high flow 
oxygen use during the study. 
• 
Days of non-invasive ventilation (if 
applicable). 
• 
Days of high flow oxygen (if applicable). 
o Invasive Mechanical Ventilation / extracorporeal 
membrane oxygenation (ECMO): 
 
Ventilator / ECMO free days to Day 29. 
 
Incidence and duration of new 
mechanical ventilation or ECMO use 
during the study. 
• 
Days of invasive mechanical ventilation (if 
applicable). 
• 
Days of ECMO (if applicable). 
• 
Hospitalization 
o Duration of hospitalization. 
• 
Days of hospitalization 
• 
Mortality 
o Survival Time 
o 14-day mortality 
o 28-day mortality 
• 
Date and cause of death (if applicable) 
2. Evaluate the safety of convalescent plasma plus 
standard care vs. standard of care alone by: 
• 
Cumulative incidence of Grade 3 and 4 clinical 
and/or laboratory AEs through Day 29. 
• 
Changes in WBC with differential, hemoglobin, 
platelets, creatinine, glucose, total bilirubin, ALT, 
AST, and PT over time (analysis of lab values in 
addition to AEs noted above). 
• 
SAEs 
• 
Grade 3 and 4 AEs 
• 
WBC with differential, hemoglobin, platelets, 
creatinine, glucose, total bilirubin, ALT, AST, and PT 
on Day 1; Days 3, 5, 8, and 11 (while hospitalized); 
and Days 15 and 29 (if attends in-person visit or still 
hospitalized). 
 

 
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3.3 
Exploratory Objectives and Endpoints 
 
OBJECTIVES 
ENDPOINTS (OUTCOME MEASURES) 
Exploratory 
 
Evaluate the clinical efficacy of convalescent plasma 
administration as compared to active drug (e.g., 
Remdesivir) recipients in DMID Protocol Number: 
20-0006 or other relevant COVID-19 Protocols 
• 
Clinical Severity 
o Ordinal scale: 
 
Time to recovery, defined by time to 
levels 1-3 on the ordinal scale 
 
Time to an improvement of one category 
and two categories from Day 1 using an 
ordinal scale. 
 
Participant clinical status using ordinal scale 
at Days 3, 5, 8, 11,15, 22, and 29. 
 
Mean change in the ordinal scale from Day 1 
to Days 3, 5, 8, 11, 15, 22, and 29. 
 
 
 
 
• 
Clinical outcome assessed using ordinal scale 
daily while hospitalized and on Day 15, 22, and 
29. 
o National Early Warning Score 
(NEWS): 
 
Time to discharge or to a NEWS of 
≤ 2 and maintained for 24 hours, 
whichever occurs first 
 Change from Day 1 to Days 3, 5, 8, 11, 
15, and 29 in NEWS. 
 
 
NEWS assessed daily while hospitalized and on Days 15 
and 29. 
o Oxygenation: 
 
Oxygenation free days to Day 29. 
 
Incidence and duration of new oxygen use 
during the study. 
 
Days of supplemental oxygen (if applicable) 
o Non-invasive ventilation/high flow 
oxygen: 
 
Non-invasive ventilation/high flow oxygen 
- free days to Day 29. 
 
Incidence and duration of new non- 
invasive ventilation or high flow oxygen 
use during the study. 
 
 
• 
Days of non-invasive ventilation (if 
applicable). 
• 
Days of high flow oxygen (if applicable). 
 
o Invasive Mechanical Ventilation / 
extracorporeal membrane oxygenation 
(ECMO): 
 
Ventilator / ECMO free days to Day 
29. 
 
Incidence and duration of new 
mechanical ventilation or ECMO use 
during the study. 
 
 
• 
Days of invasive mechanical ventilation (if 
applicable). 
• 
Days of ECMO (if applicable). 
 

 
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OBJECTIVES 
ENDPOINTS (OUTCOME MEASURES) 
Evaluate the virologic efficacy of convalescent plasma as 
assessed by: 
• 
Percent of participants with detectable SARS-CoV-2 
in OP or ET samples at Days 3, 5, 8, 11, and 15. 
• 
Quantitative SARS-CoV-2 in OP or ET samples at 
Days 3, 5, 8, 11, and 15. 
• 
Qualitative SARS-CoV-2 in OP or ET samples at 
Days 3, 5, 8, 11, and 15. 
• 
Quantitative and Qualitative PCR for SARS-CoV-2 
in OP or ET swab at Day 1; Days 3, 5, 8, and 11 
(while hospitalized) and Days 15, if available. 
Evaluate the timing and titer of anti-SARS-CoV-2 
antibody responses after convalescent plasma 
administration 
• 
Plasma antibody binding and neutralization on Day 1 
(prior to plasma administration); Days 3, 8, 15, 29, 
and visit Day 60. 
Evaluate the timing and quality of SARS-CoV-2 cellular 
responses after convalescent plasma administration 
• 
Cellular responses in whole blood on Day 1(prior to 
plasma administration); Days 3, 8, 15, 29, and visit 
Day 60. 
Evaluate the change in inflammatory responses with 
convalescent plasma administration 
• 
Plasma and cellular markers of inflammation on Day 
1(prior to plasma administration); Days 3, 8, 15, 29, 
and visit Day 60. 
Evaluate the change in clinical status by 8-point ordinal 
scale and/or NEWS with change in inflammatory markers 
• 
Ferritin, C Reactive Protein, D-Dimer, Fibrinogen, 
Erythrocyte Sedimentation Rate, Triglycerides, IL-6 
on Study Day 1, 3, 5, 8, 11, 15, 29 (when available). 
Evaluate the safety of convalescent plasma 
administration as compared to active drug (e.g., 
Remdesivir) recipients in DMID Protocol Number: 
20-0006 
• 
Cumulative incidence of Grade 3 and 4 clinical 
and/or laboratory AEs through Day 29. 
Changes in WBC with differential, hemoglobin, 
platelets, creatinine, glucose, total bilirubin, ALT, AST, 
and PT over time (analysis of lab values in addition to 
AEs noted above). 
 
 
• 
SAEs 
• 
Grade 3 and 4 AEs 
WBC with differential, hemoglobin, platelets, creatinine, 
glucose, total bilirubin, ALT, AST, and PT on Day 1; 
Days 3, 5, 8, and 11 (while hospitalized); and Days 15 and 
29 (if attends in-person visit or still hospitalized). 
Compare the safety of plasma plus standard care vs. 
standard care alone by cumulative incidence of serious 
adverse events by day 60 
 
 
• 
SAEs 
 

 
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4 STUDY PLAN 
4.1 
Study Design 
80 participants will be enrolled and randomized. All participants will be followed through Study Day 
60. The study population will consist of adults >18 years of age hospitalized, intubated and 
mechanically ventilated with confirmed COVID-19 pneumonia caused by SARS-CoV-2. 
This randomized, controlled, open-label, phase 1 trial will assess the safety and efficacy of 
convalescent plasma in severely ill, hospitalized participants with pneumonia due to COVID-19. This 
study will enroll adults over the age of 18, including pregnant women. 
A total of 80 eligible participants will be randomized 1:1 to either receive standard care and 2 units of 
convalescent plasma collected from ABO-compatible donors who have recovered from COVID-19 or 
standard care alone.  Participants in the treatment arm will receive convalescent plasma on Study Day 
1 in addition to standard care. Participants will be assessed daily while hospitalized through Study Day 
29.  Participants discharged from the hospital will be asked to attend remaining study visits at Study 
Days 15, 22, 29, and 60. The Study Day 22 visit may be conducted by phone. All participants will 
undergo a series of safety, efficacy, and laboratory assessments.  Blood samples will be collected on 
Days 1 (prior to plasma administration), 3, 5, 8, 11, 15, 29, and 60. Oropharyngeal or endotracheal 
samples will be collected as possible on Days 1 (prior to plasma administration), 3, 5, 8, 11, and 15. 
Given the COVID-19 restrictions and the difficulty some of the participants might have to attend an in 
person visit after hospital discharge, the collection of Day 60 data for primary and secondary endpoints 
and the collection of Day 60 research samples for exploratory tests may be performed up to 90 days 
following the Day 60 visit. 
4.2 
Scientific Rationale for Study Design 
This randomized, open-label trial is intended to evaluate the effect of treatment with convalescent 
plasma in hospitalized COVID-19 patients.  There are no data from randomized, controlled trials 
demonstrating clinical benefit for any therapies for COVID-19. Further, there are no randomized, 
controlled studies of passive immunotherapy for coronavirus related disease, including SARS, MERS, 
and COVID-19.  Thus, quality evidence from controlled trials is valuable.  
The current standard of care for COVID-19 patients is unclear and in flux.  Several treatment options 
are recommended for COVID-19 patients as per Departmental or Hospital system guidelines, but none 
are FDA-approved nor supported by strong clinical trials evidence. Given the potential severity of 
disease in COVID-19 patients and the limited validated treatment options available, the study will 
include hospital system- or medical provider-directed standard of care treatments in both treatment and 
control arms, including experimental or non-FDA approved therapeutics. 
There are three possible benefits of a plasma infusion that may be unrelated to any binding of SARS-
CoV-2 viruses by antibodies in the plasma: 
• Volume load 
• Oncotic load  

 
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• Fc binding – The Fc of the antibodies (the non-virus binding end of the antibody) present in 
plasma (both influenza and other antibodies) will bind to receptors in the body. This binding may 
modulate the immune response. It is for this reason that IVIG (concentrated antibody preparations) 
is sometimes used in autoimmune diseases. Volume load would have the largest effect. This 
volume effect could be beneficial, though a volume load in an ill population may also increase the 
risk to the subject. 
 
Nonimmune plasma was considered as a placebo, but there may be cross-reactive antibodies in this 
plasma that would complicate analysis and/or nonspecific immune modulating effects from Fc binding. 
A half-normal saline with albumin was entertained as a better physical representation of study plasma, 
but this approach has several shortcomings. First, the albumin will provide oncotic pressure, i.e., it 
would not be a true inactive placebo. Second, the sequential labeling in the blood bank would be 
difficult to replicate on this compound, and therefore the labeling would be able to distinguish placebo 
from active plasma. Therefore, it would still need to be masked.  Finally, identification of plasma 
donor without recent COVID-19 is challenging, given the limited availability of serologic assays to 
disprove recent infection. Thus, many asymptomatic donors may have recently been infected COVID-
19 and their plasma would not serve as a control. 
Given the potential for increased risk with a saline control, and the inability to effectively blind the 
study (discussed below) immune plasma will be compared with standard care (i.e., there is no 
comparator infusion, saline or other). If a treatment effect is determined to exist, then subsequent 
studies can dissect the components of the treatment effect (volume load, Fab binding of virus, Fc 
binding with immune modulation, and oncotic pressure). 
This study is not blinded. Saline or other controls would be significantly different in appearance 
compared to plasma. Plasma needs to be distributed from blood banks. However, hospital blood banks 
do not have the capabilities of distributing placebo. Conversely, pharmacies could not distribute the 
study plasma. Hospitals have systems for double-checking administration of blood products, as well as 
documentation of the administration of blood products in the hospital record (paper or electronic). 
Mechanisms for documentation of administration of a study drug would not be sufficient for 
documentation of a blood product, and the mechanisms for documentation of plasma products would 
not be amenable to documentation of a blinded study product. Therefore, effectively blinding the 
study, wherein there is high likelihood that the investigative team does not know whether the 
participant received plasma or saline, was not felt to be practical. 
Participants will be randomized in a 1:1 ratio. Higher ratios were considered (i.e., 2:1 or 3:1 
active:control); however this would hamper the assessment of the control rate of the various efficacy 
assessments, making planning future confirmatory studies difficult.  
4.3 
Justification for Dose 
Plasma volume in adults can be estimated by multiplying actual body weight in kilograms by 40 
mL/kg. [19] For 70-kg person, the plasma volume would be estimated to be 2800 mL (40 mL/kg x70 
kg). 

 
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Standard plasma dosing is 2 units, (~200-250 mL per unit).  At the discretion of the principal 
investigator, patients less than 90kg or with concern for volume overload, may receive 1 unit of 
plasma. 
The volume of a unit of plasma is 200-250 mL. Therefore, the study dose of 2 units of plasma could be 
equal to as much as 500 mL. A plasma volume of 500 mL at an anti-SARS-CoV-2 titer of 1:160 would 
increase the titer in the plasma to approximately 1:25; then fall to 1:13 after equilibration with the 
extravascular space.  
The dose of anti-SARS-CoV-2 antibodies needed to modify COVID-19 clinical disease is not known.  
The range of anti-SARS-CoV-2 titers in individuals who have recovered from COVID-19 is not fully 
characterized; in the recently described cohort of 5 patients receiving convalescent plasma, anti-SARS-
CoV-2 titers ranged from 1:1,800 to 16,200 by ELISA for IgM and ELISA for IgG, and 1:80 to 1:480 
to neutralizing antibody (Shen JAMA 2020). A second observational description of convalescent 
plasma in China identified ten donors. In their cohort of 40 plasma donors, 39 had neutralizing 
antibody titers >1:160, while a single donor had titers of 1:32, as determined by plaque reduction assay 
(Duan PNAS 2020). 
In Influenza studies, Rockman et al demonstrated in a H5N1 model in ferrets, that achieving a HI titer 
of 1:8 with a hyperimmune IVIG without any other antivirals was sufficient in preventing death if 
given early in the illness (during fever), and in delaying death if given at the onset of severe disease. 
[20] 
4.4 
End of Study Definition 
A participant is considered to have completed the study if he or she has completed all phases of the 
study including the Day 60 visit shown in the Schedule of Activities (SoA), Appendix 12.1. Given the 
COVID-19 restrictions and the difficulty some of the participants might have to attend an in person 
visit after hospital discharge, the collection of Day 60 data for primary and secondary endpoints and 
the collection of Day 60 research samples for exploratory tests may be performed up to 90 days 
following the Day 60 visit. 

 
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5 STUDY POPULATION 
5.1 
Inclusion Criteria 
1. Adult ≥18 years of age  
2. Laboratory-confirmed SARS-CoV-2 infection as determined by PCR or other authorized or 
approved assay in any specimen collected within 72 hours prior to enrollment. 
Note – An exception must be requested to the Sponsor if ≥72 hours since positive test. 
3. Hospitalized in participating facility. 
4. Documentation of pneumonia with radiographic evidence of infiltrates by imaging (e.g., chest 
x-ray or CT scan). 
5. Abnormal respiratory status that is judged worse than baseline by the investigator and as 
documented at any point within 24 hours prior to randomization, consistent with ordinal scale 
levels 5, 6 or 7, specifically defined as: 
• Room air saturation of oxygen (SaO2) < 93%, OR  
• Requiring supplemental oxygen, OR 
• Tachypnea with respiratory rate ≥30  
6. Patient or proxy is willing and able to provide written informed consent and comply with all 
protocol requirements 
5.2 
Exclusion Criteria 
1. Contraindication to transfusion (e.g., severe volume overload, history of severe allergic 
reaction to blood products), as judged by the investigator. 
2. Clinical suspicion that the etiology of acute illness (acute decompensation) is primarily due to a 
condition other than COVID-19 
3. Receipt of other investigational therapy as a part of another clinical trial. 
a. Note: investigational therapies used as part of clinical care, (eg, remdesivir, 
hydroxychloroquine) are permissible.  
 
5.3 
Lifestyle Considerations 
Not applicable. 
5.4 
Screen Failures 
After the screening evaluations have been completed, the investigator or designee is to review the 
inclusion/exclusion criteria and determine the participant’s eligibility for the study. 

 
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Only the reason(s) for ineligibility will be collected on screen failures. Participants who are found to be 
ineligible will be told the reason(s) for ineligibility. 
Individuals who do not meet the criteria for participation in this study (screen failure) because of an 
abnormal laboratory finding may be rescreened once. 
5.5 
Strategies for Recruitment and Retention 
5.5.1 
Recruitment 
Screening will begin with a brief discussion with study staff.  If patient is mechanically ventilated and 
both studies are open to enrollment, information about both PennCCP-01 and PennCCP-02 will be 
provided to all potential participants and or legally authorized representative.  Information regarding 
the risks and benefits and scientific aims of the single arm study PennCCP-01 and the randomized, 
controlled study PennCCP-02 will be presented.  If patient is ineligible for PennCCP-01, information 
about this randomized study only will be presented to potential participants (or legally authorized 
representative) and questions will be asked to determine potential eligibility. Screening procedures can 
begin only after informed consent is obtained by a Study Investigator. 
5.5.2 
Retention 
Retention of participants in this trial is very important for determining the primary endpoint. As such, 
after hospital discharge, participants will be reminded of subsequent study visits and every effort will 
be made to accommodate the participant’s schedule to facilitate follow-up within the specified visit 
window. Additionally, there are many circumstances that influence the ability to obtain outcome 
information after discharge. Follow-up visits may be conducted by phone if in-person visits are not 
feasible. Data and samples may be collected from subject’s home, office, or hospital visits. 
5.5.3 
Costs 
There is no cost to participants for the research tests, procedures/evaluations and study product while 
taking part in this trial. Procedures and treatment for clinical care including costs associated with 
hospital stay may be billed to the participant, participant’s insurance or third party. 

 
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6 STUDY INTERVENTION 
6.1 
Study Intervention(s) Administration 
6.1.1 
Study Intervention Description 
Participants in the treatment arm will receive standard care plus 2 units of COVID-19 convalescent 
plasma on Study Day 1.  Participants will receive plasma compatible with their blood type (per 
standard blood bank practice). 
6.1.2 
Dosing and Administration 
Participants will be randomized 1:1, stratified on mechanical ventilation and receipt of remdesivir at 
baseline, to receive either PCCP and standard care (treatment arm) or standard care alone (control 
arm). 
For those participants assigned to the treatment group, the study plasma should be administered as 
soon as possible. Before administration of study plasma, the investigator must check for appropriate 
investigational study label on the plasma bag. 
The calendar date and 24-hour clock time for study plasma administration should be recorded for the 
start and end of each infusion. The two infusions should be separated by at least 1 hour after the end of 
the first and the start of the second infusion in order to assess for any immediate AEs from the first 
unit. The interval may be extended if clinically indicated. This should be noted on the infusion record 
and will not be considered a protocol violation. 
If an AE considered related to the administration of the investigational product occurs during infusion, 
the infusion may be slowed temporarily or permanently discontinued, as deemed appropriate by the 
investigator. As a guide, local side effects (e.g., infusion site burning),  nonallergic systemic effects 
(e.g., chills), and mild allergic reactions (itching, hives) can generally be alleviated by slowing the rate 
of infusion, whereas serious allergic side effects (e.g., wheezing, hypotension) should result in the 
cessation of study plasma infusion. The treating investigator is ultimately responsible for making the 
decision to slow or stop study plasma infusion. If the infusion is discontinued, the participant should be 
treated according to best available local practices and procedures, and the Principal Investigator should 
notify the Sponsor Medical Director and HUP Blood Bank. Reason(s) for premature discontinuation of 
any plasma infusion must be documented in the medical record (source document) and on the CRF. 
As with any foreign protein, allergic reactions to dose administration are possible. Therefore, 
appropriate drugs such as Benadryl® and epinephrine and medical equipment to treat acute allergic 
reactions must be immediately available, and study personnel must be trained to recognize and treat 
allergic reactions. If generalized urticaria, hypotension, or anaphylaxis occurs, the infusion of plasma 
should be immediately discontinued. Treatment should be given in an appropriate timeframe as 
medically indicated. 
All participants will be observed for at least 1 hour after administration of study plasma. Appropriate 
medical treatment should be given as needed based on best available local practices and procedures. 

 
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6.2 
Preparation/Handling/Storage/Accountability 
6.2.1 
Acquisition and Accountability 
The Penn Blood Bank will release a thawed product, in a bag containing between 200-250 mL. The 
Principal Investigator will ensure an adequate accountability of the investigational product 
6.2.2 
Formulation, Appearance, Packaging, and Labeling 
The product ready to be administered will be provided in a bag labelled using an ISBT-128 compliant 
label and will include the investigational product language as required by regulation. Product Storage 
and Stability. 
Product will be stored in the HUP Stem Cell Laboratory until it is released to the PI at the time of 
transfusion. 
6.2.3 
Preparation 
Preparation: Frozen product will be transported from the HUP Stem Cell Laboratory back to the HUP 
Blood Bank to be thawed before issuing to the patient’s transfusion team. 
6.3 
Measures to Minimize Bias: Randomization and Blinding 
Individuals will be randomized to the intervention or control arm in a 1:1 ratio. Randomization will 
occur in a blinded fashion using Redcap. Allocation will be determined using a permuted block 
algorithm with varying block sizes. We will stratify randomization based on whether or not a patient is 
on mechanical ventilation and on remdesivir at baseline. Though the intervention will not be blinded, 
we will attempt to minimize bias by blinding study personnel, such as individuals running laboratory 
assays, to the extent that it is possible. 
6.4 
Study Intervention Compliance 
Not applicable. 
6.5 
Concomitant Therapy 
All participants will be monitored throughout the study for use of concomitant medications. Any 
prescription medications including IVIG, blood products, over-the-counter (OTC) preparations, herbal 
remedies, and/or nutritional supplements taken during the study period must be recorded on the CRF. 
It is also anticipated that participants may be treated with antibacterial agents, either for concomitant 
infection, or bacterial superinfection. The final decision for antibiotics (need, drug[s] and dose) and 
other medications will be made by the treating physician (except as noted below under Prohibited 
Medications). 
6.5.1 
Rescue Medicine 
Not applicable. 

 
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7 STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
Participants will be considered to have completed the study if they are followed through Study Day 60 
(+ 90 days) and complete the final study visit (or followed through to death at or before 60 days).  
7.1 
Discontinuation of Study Intervention 
Participants (or their legal surrogates if participants become unable to make informed decisions) can 
terminate study participation at any time without prejudice. If a participant terminates participation 
before completing the study, the reason for this decision will be recorded in the CRF. Participants who 
withdraw from the study will not be replaced. 
Participants who indicate interest in withdrawing from the study should also be asked permission to be 
contacted at Day 29 and Day 60 (+90 days) by telephone for vital status (date of discharge, disposition, 
and any adverse events that occurred during the study). This is not considered full withdrawal of 
consent, but the modified consent for limited follow-up should be noted in the medical record. 
Participants who fully withdraw consent will not be contacted further. 
7.2 
Participant Discontinuation/Withdrawal from the Study 
The investigator also has the right to withdraw participants from the study. Participants may be 
withdrawn from the study for either of the following reasons: 
• The participant is lost to follow-up. 
• The investigator believes that continuation in the study would be detrimental to the participant. 
 
If appropriate, the participant should not be fully withdrawn but rather have limited further study 
interventions. This limited follow-up would entail contacting the participant on Day 29 by telephone 
for vital status (date of discharge, disposition, and any AEs that occurred during the study). The reason 
for withdrawal from the study is to be recorded on the CRF.  
If a non-serious AE is unresolved at the time of discontinuation, efforts should be made to follow up 
until the event resolves or stabilizes, the participant is lost to follow-up, or there is some other 
resolution of the event. The investigator is to make every attempt to follow all SAEs to resolution. 
7.3 
Lost To Follow-Up 
Participants who miss a study visit should be contacted to reschedule. If participants cannot be 
contacted immediately, attempts should continue until study completion. Lost to follow-up is defined 
as unsuccessful contact after at least two documented telephone calls and one written letter.  
Any participant withdrawn from the study will not be replaced.  

 
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8 STUDY ASSESSMENT AND PROCEDURES 
8.1 
Screening and Efficacy Assessments 
For all efficacy assessments and follow-up visits, refer to SoA (Table 4) for procedure to be done, and 
details below for each assessment. 
 
8.1.1 
Screening Procedures 
After the informed consent, some or all of the following assessments are performed to determine 
eligibility requirements as specified in the inclusion and exclusion criteria: 
• Confirm the positive SARS-CoV-2 test result. 
o If the original sample was >72 hours prior to planned randomization, an exception must 
be requested to the Sponsor. 
• Take a focused medical history, including the following information: 
o Day of onset of COVID-19 signs and symptoms 
o History of chronic medical conditions related to inclusion and exclusion criteria 
o Medication allergies 
o Review medications and therapies for this current illness taken in the 7 days prior to 
Day 1 and record on the appropriate CRF. 
• Women of childbearing potential should be counseled to either practice abstinence or use at 
least one primary form of contraception from screening through Day 60. 
o Acceptable forms of contraception include barrier methods, copper or hormonal IUDs, 
implantable hormonal contraception, or oral contraceptives.  
o Note: If a woman is either postmenopausal (i.e., has had ≥12 months of spontaneous 
amenorrhea) or surgically sterile (i.e., has had a hysterectomy, bilateral ovariectomy 
(oophorectomy), or bilateral tubal ligation), she is not considered to be of childbearing 
potential 
• Obtain height and weight (height can be self-reported) 
• Review results of recent radiographic imaging (x-ray or CT scan) 
• Perform a targeted physical exam focused on lung auscultation 
• Check a SpO2 

 
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• Obtain blood for screening laboratory evaluations if not done as part of routine clinical care in 
the preceding 48 hours: 
o type and screen 
• Clinical screening laboratory evaluations will be performed locally by the site laboratory. 
• The overall eligibility of the participant to participate in the study will be assessed once all 
screening values are available. The screening process can be suspended prior to complete 
assessment at any time if exclusions are identified by the study team. 
• Study participants who qualify will be immediately randomized. 
 
8.1.1.1 
Screening Procedures in Pregnant Women 
To best understand risk and benefit of study enrollment for pregnant women, we will follow this SOP 
for consideration of enrollment. 
Standard Operating Procedure for Pregnant Patients: 
1. Maternal Fetal Medicine (Obstetrical service managing pregnant patients) consults Infectious 
Diseases  
2. Obstetrics (OB) and Infectious Diseases (ID) study physicians discuss possible enrollment in 
study, considering factors including fetal gestational age, maternal co-morbidities, severity of 
COVID-19 disease, volume status.  
3. Discussion between OB, ID, patient (if possible) and patient legally authorized representative 
on risks and benefits of study.  
4. With enrollment and plasma administration: close observation in acute setting (eg, in COVID-
19 unit, ICU or Labor & Delivery) 
5. Continue close monitoring after plasma administration. Participants will be followed through 
the 60 days of the study. Data will not be collected after the Day 60 visit nor will data be 
collected on neonates. 
 
The volume of venous blood to be collected is presented in Table 2. 
8.1.2 
Measures of clinical support, limitations and infection control 
On each study day while hospitalized through Study Day 29, the following measures for the previous 
day will be recorded. i.e., on Day 3, Day 2 measures are assessed as occurring anytime in that 24 hour 
period (00:00 to 23:59h): 
• Hospitalization 
• Oxygen requirement 
• Non-invasive mechanical ventilation (via mask) requirement 

 
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• High flow oxygen requirement. 
• Invasive mechanical ventilation (via endotracheal tube or tracheostomy tube) requirement. 
• ECMO requirement. 
• Ongoing medical care preventing hospital discharge (COVID-19 related or other medical 
conditions) 
• Limitations of physical activity (self-assessed). 
• Isolated for infection control purpose 
 
If drawn for clinical care, record inflammatory markers, including: 
• Ferritin, C Reactive Protein, D-Dimer, Fibrinogen, Erythrocyte Sedimentation Rate, 
Triglycerides, IL-6. 
If and when a participant is discharged from the hospital, they will continue with study visits as an 
outpatient, for all Study Days that are applicable, including Days 15, 29, and 60.  Outpatient visits will 
involve the participant returning to clinic, unless other reasonable accommodations for evaluations and 
blood draws can be arranged. Day 22 Study visit can be as a phone call. Given the COVID-19 
restrictions and the difficulty some of the participants might have to attend an in person visit after 
hospital discharge, the collection of Day 60 data for primary and secondary endpoints and the 
collection of Day 60 samples for exploratory tests may be performed up to 90 days following the Day 
60 visit. For these participants, the Day 60 data may be obtained from the information already entered 
in the clinical records by any clinician, or by contacting the participant by phone up to 90 days 
following the Day 60 visit to obtain retrospective data. 
 
8.1.3 
Ordinal Scale 
The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. 
From the measures collected in 8.1.2.1, this ordinal scale can be constructed.  
The scale used in this study is as follows: 
1. Not hospitalized, no limitations on activities. 
2. Not hospitalized, limitation on activities and/or requiring home oxygen; 
3. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 
4. Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care 
(COVID-19 related or otherwise); 
5. Hospitalized, requiring supplemental oxygen; 

 
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6. Hospitalized, on non-invasive ventilation or high flow oxygen devices; 
7. Hospitalized, on invasive mechanical ventilation or ECMO; 
8. Death 
 
By assessing the individual components however, alternative scales can be constructed. 
8.1.4 
National Early Warning Score (NEWS) 
NEWS has demonstrated an ability to discriminate participants at risk of poor outcomes. (Smith, 
2016). This score is based on 7 clinical parameters (see Table 1). The NEWS is being used as an 
efficacy measure. This should be evaluated at the first assessment of a given study day and prior to 
administration of study product. The 7 parameters can be obtained from the hospital chart using the 
last measurement prior to the time of assessment and a numeric score given for each parameter (e.g., a 
RR of 9 is one point, oxygen saturation of 92 is two points). This is recorded for the day obtained. i.e., 
on Day 3, Day 3 score is obtained and recorded as Day 3. 
Table 1: National Early Warning Score (NEWS) 
 
Level of consciousness = alert (A), and arousable only to voice (V) or pain (P), and unresponsive (U). 

 
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8.2 
Exploratory Assessments 
8.2.1 
Virologic and Serologic Assays 
OP swabs or ET samples and blood will be collected on Day 1 3, 5, 8, 11, and 15 and stored as 
outlined in the MOP. Blood samples will be collected on Day 1, 3, 8, 15, 29 and Day 60 visit The 
assays used to detect and characterize virologic and immune responses are in development or 
experimental in nature. Therefore, while viral and immunologic responses to convalescent plasma 
therapy are thought to be an important endpoint, considering the limitations above, they are listed as 
exploratory endpoints. 
8.2.2 
Alternative Ordinal Scales 
Given the limited clinical data available for COVID-19, the best construct of ordinal scale is not 
known. Additional data may be used to construct different ordinal scales to test their utility in a 
treatment study. These are hypothesis generating and will not be submitted as part of a final CSR. 
8.3 
Safety and Other Assessments 
Study procedures are specified in the SOA. A study physician licensed to make medical diagnoses and 
listed on the 1572 will be responsible for all trial-related medical decisions. 
 Physical examination: A symptom-directed (targeted) physical examination will be performed 
at screening and when needed to evaluate possible adverse event(s) (i.e. any new symptoms). 
No physical exam is needed for routine study visits. 
 Clinical laboratory evaluations: 
• Fasting is not required before collection of laboratory samples. 
• Blood will be collected at the time points indicated in the SOA. Clinical laboratory 
parameters include WBC, differential, Hgb, PLT, Creatinine, glucose, total 
bilirubin, AST, ALT, and PT. 
• This testing will be performed at each clinical trial site in real time. 
 
Table 2: Venipuncture Volumes1 
 
Screen 
Baseline 
 
 
 
 
 
 
 
Day +/- Window 
-1 to 1 
-1 to 1 
3±1 
5±1 
8±1 
11±1 
15±2 
29±2 
60±5 
Type and screen 
X 
10 mL 
 
 
 
 
 
 
 
 
Safety hematology, 
chemistry, liver tests 
 
X 
10 mL 
X 
10 mL 
X 
10 mL 
X 
10 mL 
X 
10 mL 
X 
10 mL 
X 
10 mL 
 
Blood for plasma/ 
serum and cells, 
including research 
assays 
 
X 
32 mls 
X 
32 mL 
 
X 
32 mL 
 
X 
32 mL 
X 
24 mL 
X 
32 mL 

 
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Total volume 
10 mL 
42 mL 
42 mL 
10 mL 
34 mL 
10 mL 
42 mL 
34 mL 
32 mL 
Total volume all study 
days 
 
 
 
 
 
 
 
 
264 mL 
1  See SOE for specific tests to be performed. 
2  Total volume calculated assumes no routine clinical laboratory results that can be used for the screening, baseline, and 
safety laboratory values.  
3  Samples may be collected for up to 90 days following the Day 60 visit. 
 
8.3.1 
Procedures to be Followed in the Event of Abnormal Laboratory Test Values 
or Abnormal Clinical Findings 
If a physiologic parameter (e.g., vital signs, or laboratory value) is outside of the protocol- specified 
range, then the measurement may be repeated once if, in the judgment of the investigator, the 
abnormality is the result of an acute, short-term, rapidly reversible condition or was an error. A 
physiologic parameter may also be repeated if there is a technical problem with the measurement 
caused by malfunctioning or an inappropriate measuring device (i.e., inappropriate-sized BP cuff). 
8.4 
Adverse Events and Serious Adverse Events 
8.4.1 
Definition of Adverse Events (AE) 
AE means any untoward medical occurrence associated with the use of an intervention in humans, 
whether or not considered intervention-related. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of medicinal (investigational) product. 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the severity of any pre-existing medical condition 
increases, it should be recorded as an AE. 
Given the nature of severity of the underlying illness, participants will have many symptoms and 
abnormalities in vital signs and laboratory values. All Grade 3 and 4 AEs will be captured as AEs in 
this trial. 
8.4.2 
Definition of Serious Adverse Events (SAE) 
A SAE is defined as “An AE or suspected adverse reaction is considered serious if, in the view of 
either the investigator or the Sponsor, it results in any of the following outcomes: 
 Death; 
 A life-threatening AE; 
 Inpatient hospitalization or prolongation of existing hospitalization; 
 A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions; or 

 
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 A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered serious when, based upon appropriate medical judgment, they may jeopardize the 
participant and may require medical or surgical intervention to prevent one of the outcomes listed in 
this definition. Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias, convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse. 
“Life-threatening” refers to an AE that at occurrence represents an immediate risk of death to a 
participant. An event that may cause death if it occurs in a more severe form is not considered life- 
threatening. Similarly, a hospital admission for an elective procedure is not considered a SAE. 
All SAEs, as with any AE, will be assessed for severity and relationship to study intervention by the 
Principal Investigator or qualified sub-investigator and will be recorded on the appropriate CRF. 
All SAEs will be followed through resolution or stabilization by the Principal Investigator or qualified 
sub-investigator. 
8.4.3 
Classification of an Adverse Event 
The determination of seriousness, severity, and causality will be made by the Principal Investigator or 
qualified sub-Investigator upon medical judgment. Qualified sub-investigator includes but is not 
limited to physicians, physician assistants, and nurse practitioners. 
8.4.3.1 
Severity of Event 
All AEs and SAEs will be assessed for severity, according to the Division of AIDS (DAIDS) Table for 
Grading the Severity of Adult and Pediatric Adverse Events, version 2.1 (July 2017) (see 
Appendix 12.2). 
For AEs not included in the protocol defined grading system, the following guidelines will be used to 
describe severity. 
 Mild (Grade 1): Events that are usually transient and may require only minimal or no 
treatment or therapeutic intervention and generally do not interfere with the participant’s usual 
activities of daily living. 
 Moderate (Grade 2): Events that are usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing discomfort but 
poses no significant or permanent risk of harm to the research participant. 
 Severe (Grade 3): Events interrupt usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention. Severe events are usually 
incapacitating. 
 Severe (Grade 4): Events that are potentially life threatening. 

 
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AEs characterized as intermittent require documentation of onset and duration of each episode. The 
start and stop dates (duration) of each reported AE will be recorded on the appropriate CRF. Changes 
in the severity of an AE will be documented to allow an assessment of the duration of the event at each 
level of intensity. 
8.4.3.2 
Relationship to Study Intervention 
For each reported adverse reaction, the PI and Sponsor must assess the relationship of the event to the 
study product using the following guideline: 
All adverse events (AEs) must have their relationship to the study intervention (product, process, 
and/or procedure) assessed by the clinician who examines and evaluates the participant based on 
temporal relationship and his/her clinical judgment. The degree of certainty about causality will be 
graded using the categories below. In a clinical trial, the study product must always be considered. 
 Definitely Related – There is clear evidence to suggest a causal relationship, and other 
possible contributing factors can be ruled out. The clinical event, including an abnormal 
laboratory test result, occurs in a plausible time relationship to PCCP administration and 
cannot be explained by concurrent disease or other drugs or chemicals. The response to 
withdrawal of the PCCP (dechallenge) should be clinically plausible. The event must be 
pharmacologically or phenomenologically definitive, with use of a satisfactory rechallenge 
procedure if necessary. 
 Probably Related – There is evidence to suggest a causal relationship, and the influence of 
other factors is unlikely. The clinical event, including an abnormal laboratory test result, 
occurs within a reasonable time after administration of the PCCP, is unlikely to be attributed to 
concurrent disease or other drugs or chemicals, and follows a clinically reasonable response on 
withdrawal (dechallenge). Rechallenge information is not required to fulfill this definition. 
 Possibly Related – There is some evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time after administration of the trial medication). However, other 
factors may have contributed to the event (e.g., the participant’s clinical condition, other 
concomitant events). Although an AE may rate only as “possibly related” soon after discovery, 
it can be flagged as requiring more information and later be upgraded to “probably related” or 
“definitely related”, as appropriate. 
 Unlikely to be related – A clinical event, including an abnormal laboratory test result, whose 
temporal relationship to PCCP administration makes a causal relationship improbable (e.g., the 
event did not occur within a reasonable time after administration of the <study intervention>) 
and in which other drugs or chemicals or underlying disease provides plausible explanations 
(e.g., the participant’s clinical condition, other concomitant treatments). 
 Unrelated – The AE is completely independent of PCCP administration, and/or evidence exists 
that the event is definitely related to another etiology. There must be an alternative, definitive 
etiology documented by the clinician. 

 
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8.4.3.3 
Expectedness 
The Principal Investigator will be responsible for determining whether an adverse event (AE) is 
expected or unexpected. An AE will be considered unexpected if the nature, severity, or frequency of 
the event is not consistent with the risk information previously described for the study intervention. 
8.4.4 
Time Period and Frequency for Event Assessment and Follow-Up 
Safety will be assessed by monitoring and recording potential adverse effects using the Division of 
AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, version 2.1 
(July 2017 at each study visit. Participants will be monitored by medical histories, physical 
examinations, and other studies. If the DAIDS Table for Grading the Severity of Adult and Pediatric 
Adverse Events, version 2.1 (July 2017) (See Appendix 12.2) grading does not exist for an adverse 
event, the severity of mild, moderate, severe, life-threatening, and death, corresponding to Grades 1-5, 
will be used whenever possible. 
At each contact with the participant, the investigator will seek information on adverse events by non-
directive questioning and, as appropriate, by examination. Adverse events may also be detected when 
they are volunteered by the participant during the screening process or between visits, or through 
physical examination, laboratory test, or other assessments. Information on all adverse events will be 
recorded in the source documentation. To the extent possible, adverse events will be recorded as a 
diagnosis and symptoms used to make the diagnosis recorded within the diagnosis event. If the AE is a 
laboratory abnormality that is part of a clinical condition or syndrome, it should be recorded as the 
syndrome or diagnosis rather than the individual laboratory abnormality. 
As much as possible, each adverse event or follow-up information will be evaluated to determine: 
1. Severity grade (DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, 
Corrected version 2.1 (July 2017). See Appendix 12.2. 
2. Duration (start and end dates) 
3. Relationship to the study treatment or process – [Reasonable possibility that AE is related: No 
(unrelated/ not suspected) or Yes (a suspected adverse reaction)]. If yes (suspected) - is the 
event possibly, probably or definitely related to the investigational treatment? 
4. Expectedness to study treatment or process – [Unexpected – if the event severity and/or 
frequency is not described in the investigator brochure (if applicable) or protocol]. 
5. Action taken with respect to study or investigational treatment or process (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable) 
6. Whether medication or therapy taken (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy) 
7. Whether the event is serious 

 
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Once an adverse event is detected, it should be followed until its resolution or until it is judged to be 
permanent, and assessment should be made at each visit (or more frequently, if necessary) of any 
changes in severity, the suspected relationship to the study treatment, the interventions required to treat 
it, and the outcome. 
For this study, all Grade 3 and 4 AEs, all SAEs occurring from the time the informed consent is signed 
through the Day 60 visit will be documented, recorded, assessed, and reported. In addition, any grade 1 
or 2 or higher hypersensitivity reaction is also reported as an AE. 
8.4.5 
Adverse Event Reporting 
8.4.5.1 
Reporting Period 
Adverse events will be reported from the time of informed consent until study completion. 
8.4.5.2 
Investigator Reporting: Notifying the Study Sponsor 
Information on all AEs should be recorded on the appropriate CRF. 
Every SAE, regardless of suspected causality (e.g., relationship to study product(s) or study 
procedure(s) or disease progression) must be reported to the sponsor within 24 hours of learning of its 
occurrence. 
Recurrent episodes, complications, or progression of the initial SAE must be reported to the Sponsor as 
a follow-up to the original episode within 24 hours of the investigator receiving the follow-up 
information. A SAE considered completely unrelated to a previously reported one should be reported 
separately as a new event. 
Send the SAE report to the psom-ind-ide@pobox.upenn.edu indicating the protocol number and the 
study product. 
New information regarding the SAE will be reported as it becomes available and in the same manner 
that the initial SAE (i.e. SAE form). The investigator must follow the event to resolution or until the 
event is deemed and documented irreversible, whichever is longer. 
8.4.5.3 
Investigator Reporting: Local Reporting Requirements 
The investigator will report AEs and SAEs to the IRB/EC of record and other local regulatory groups 
per the local requirements. 
8.4.6 
Serious Adverse Event Reporting 
The study clinician will immediately report to the sponsor any serious adverse event, whether or not 
considered related to the Penn COVID-19 Convalescent Plasma, including those listed in the protocol 
or investigator brochure and must include an assessment of whether there is a reasonable possibility 
that the Penn COVID-19 Convalescent Plasma caused the event. Study endpoints that are serious 

 
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adverse events (e.g., all-cause mortality) must be reported in accordance with the protocol unless there 
is evidence suggesting a causal relationship between the Penn COVID-19 Convalescent Plasma and 
the event (e.g., death from anaphylaxis). In that case, the investigator must immediately report the 
event to the sponsor. 
New information regarding the SAE will be reported as it becomes available and in the same manner 
that the initial SAE (i.e. SAE form). All serious adverse events (SAEs) will be followed until 
satisfactory resolution or until the site investigator deems the event to be chronic or the participant is 
stable. Other supporting documentation of the event may be requested by the study sponsor and should 
be provided as soon as possible. 
The SAE reports to the Sponsor should be sent to: psom-ind-ide@pobox.upenn.edu indicating the 
protocol number and the study product 
The study sponsor will be responsible for notifying the Food and Drug Administration (FDA) of any 
unexpected fatal or life-threatening suspected adverse reaction per applicable regulations. In addition, 
the sponsor must notify the FDA, as applicable and all participating investigators of potential serious 
risks, from clinical trials or any other source, as per the applicable regulation. 
A SUSAR is any SAE where a causal relationship with the study product or process or procedure is at 
least reasonably possible but is not listed in the IB, Package Insert, and/or Summary of Product 
Characteristics  
8.4.7 
Reporting Events to Participants 
The Sponsor does not plan to report adverse events to participants unless it is required by regulation, 
the IRB or FDA. 
8.4.8 
Events of Special Interest 
There are no events of special interest in this protocol. 
8.4.9 
Reporting of Pregnancy 
Pregnancy, in and of itself, is not regarded as an AE unless there is suspicion that study drug or process 
may have interfered with the effectiveness of a contraceptive medication or method. Pregnancy is not a 
contraindication to receipt of plasma transfusion and will not be reported or followed if not associated 
to an adverse event. 
8.5 
Unanticipated Problems 
8.5.1 
Definition of Unanticipated Problems (UP) 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks 
to participants or others to include, in general, any incident, experience, or outcome that meets all the 
following criteria: 

 
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 Unexpected in terms of nature, severity, or frequency given (a) the research procedures that 
are described in the protocol-related documents, such as the Institutional Review Board (IRB)-
approved research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied; 
 Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
 Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
 
UP are generally non-medical events, as medical events would be capture under AEs. 
8.5.2 
Unanticipated Problem Reporting 
Unanticipated problems (UPs) such as: 
 Post-marketing withdrawal of a drug, device, or biologic used in a research protocol due to 
safety concerns. 
 FDA ban of a drug, device, or biologic used in a research protocol due to safety concerns. 
 Complaint of a participant when the complaint indicates unexpected risks, or the complaint 
cannot be resolved by the research team 
 Breach of confidentiality 
 Incarceration of a participant when the research was not previously approved under Subpart C 
and the investigator believes it is in the best interest of the participant to remain on the study 
 Premature closure of a study (e.g., due safety, lack of efficacy, feasibility, financial reasons, 
etc.) should be reported by the investigator to the Sponsor and the reviewing Institutional 
Review Board (IRB). The UP report will include the following information: 
 Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number; 
 A detailed description of the event, incident, experience, or outcome;  
 An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP; 
 A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP. 
 

 
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To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline: 
 UPs that are serious adverse events (SAEs) will be reported as any other SAE. 
 Any other UP will be reported to the Sponsor and IRB within 3 days of the investigator 
becoming aware of the problem. 
 
8.5.3 
Reporting Unanticipated Problems to Participants 
The Sponsor does not plan to report adverse events to participants unless it is required by regulation, 
the IRB or FDA. 

 
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9 STATISTICAL CONSIDERATIONS 
9.1 
Statistical Hypotheses 
• Primary Safety Endpoint: Cumulative incidence of serious adverse events (SAEs), i.e. the 
proportion of individuals with at least one SAE, at Day 29. 
• We hypothesize that 2 units of convalescent plasma will be safe and will not result in a 
difference in SAE rates between the experimental and control arms. The analysis will be primarily 
descriptive summaries by arm. We will calculate the proportion of individuals that experience at 
least one SAE by arm, along with 95% Clopper Pearson confidence intervals. We expect any 
related AE to happen relatively shortly after infusion but will assess the AE at all study timepoints. 
Overall SAE rates, those broken down by system organ class and preferred term will be 
summarized.  
• Primary Efficacy Endpoint: Comparison of clinical severity between patients on the 
experimental versus control arms, determined by the modified 8-point ordinal severity score on 
Study Day 29. The modified score treats all subjects who have reached levels 1-3 as recovered. 
• The key parameter of interest will be the comparison of clinical severity between individuals 
receiving the experimental intervention versus control, as measured by a clinical severity score that 
takes into account the modified 8-point ordinal severity score in a prioritized manner. For the 
modification, recovery will be defined by reaching levels 1-3 on the 8-point ordinal severity score. 
The null hypothesis is that experimental individuals will have the same median severity as control 
individuals. The severity score is based on a procedure by Shaw and Fay 2016 [21], which ranks 
participants based on their Day 29 ordinal severity. All survivors better than non-survivors, 
individuals with shorter recovery times as better, and individuals with shorter times to death as 
worse. For individuals who survive but had not yet recovered by Day 29, they will be ranked 
according to their Day 29 ordinal severity, with individuals achieving the same ordinal severity 
being ranked according to time to reaching that level of severity. More details are provided in the 
Statistical Analysis Plan (SAP). This type of severity score, or prioritized outcome, has been 
advocated in many settings such as infectious disease and cardiovascular outcome settings 
[22,24,25]. This analysis will have more power to detect differences than looking only at one 
individual endpoint. Shaw and Fay 2016 showed this test statistic can be interpreted as a weighted 
average of the log-rank type test statistic for survival and the one for time to recovery amongst 
survivors.  The individual endpoints, time to recovery and time to death, will also be examined as 
secondary endpoints. 
• Secondary Efficacy Endpoint(s): Comparison between arms of time to recovery and survival. 
• The null hypothesis is that the two arms will have the same recovery time and the same 
survival time. Kaplan-Meier survival curves will be calculated by arm and compared with a Peto-
Peto generalized Wilcoxon test. In the event that deaths that occur, the cumulative incidence of 
recovery will be estimated and compared between groups using Gray’s test, which will be able to 
capture a lower time to recovery due to either a slower event rate or a higher death rate. For 
interpretive purposes the cause specific hazard ratios for will also be calculated for each event type, 

 
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survival and recovery, along with the Peto-Peto test. In the event of no deaths, time to recovery will 
be summarized with the Kaplan-Meier and compared using the Peto-Peto generalized Wilcoxon 
test.  Analyses of other secondary endpoints listed in Section 3.2 are listed below in Section 9.4. 
 
9.2 
Sample Size Determination 
A total of 80 participants are expected to enroll and be randomized in a 1:1 fashion to one of two study 
arms. Sample sizes are determined by desire to estimate safety and to provide a preliminary idea of 
efficacy. Given patients will be hospitalized at enrollment, we expect very low missing data rates for 
early safety and efficacy endpoints. We also expect to be able to have good follow-up post discharge 
until the end of the study. Patients will be analyzed for safety if they receive at least one dose of the 
experimental treatment. For efficacy endpoints, analyses will be according to the intent-to-treat 
principle and outcomes on all enrolled participants will be included for analysis. All power 
calculations assume Type I error rate of alpha=0.05. Power calculations were done using STATA/SE 
v16.0. 
With a sample size of 40 for a given arm, the expected probability of observing zero or at least one 
adverse event at varying underlying adverse event rates under a binomial distribution is shown below 
in Table 3. At this sample size, it is likely to see at least one person with an adverse event even with 
relatively small rates of adverse reactions.  For example, 40 individuals in one arm, there is an 80% 
chance of observing at least one individual with an event if the underlying AE rate is 4%. The analysis 
of AE rates will primarily be descriptive due to the lack of power to make formal comparisons with the 
control arm.  
Table 3. Probability of detecting zero individuals or at least one individual with an 
Adverse Event (AE) for a variety of different underlying AE rates and 
sample size N =40 
AE rate 
Pr(0 events) 
Pr(1+ event) 
0.001 
0.96 
0.04 
0.005 
0.82 
0.18 
0.01 
0.67 
0.33 
0.02 
0.45 
0.55 
0.03 
0.30 
0.70 
0.04 
0.20 
0.80 
0.05 
0.13 
0.87 
0.10 
0.01 
0.99 
 
While the sample size is driven by safety considerations, we also consider the operating characteristics 
of the proposed sample size for the analysis of the primary and secondary efficacy endpoints. The 
primary efficacy outcome is a comparison of the clinical severity score. The severity score is based on 

 
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a procedure by Shaw and Fay 2016 [21], which ranks all survivors better than non-survivors, 
individuals with shorter recovery times as better, individuals with shorter times to death as worse, and 
non-recovered survivors ranked according to their Day 29 severity score. We considered the power to 
reject the null hypothesis that there is a 50-50 chance that the individuals receiving the experimental 
treatment had lower severity compared to the control arm. The analysis of the Win Ratio [22], which 
simply ranks the experimental participant with a matched control participant as either better or worse 
by considering the time to death, if evaluable, and otherwise considers the patient ranking according to 
the time to recovery, or time to Day 29 severity score if not-recovered, and reduces to a simple 
binomial proportion. For 40 matched experimental-control pairs, we have over 80% power to reject the 
null proportion= 50% if the experimental treatment is associated with a 80% or higher probability of 
having better severity than a control participant.  The proposed analysis for this endpoint, described in 
the previous section, is expected to have even better power by also considering the timing of the event 
and not just the binary outcome of better or worse [21]. 
One can also consider the power to detect a difference in the secondary survival and recovery time 
endpoints. Given the sample size of 40 per arm, only very large differences would be detectable with 
80% power. For example, we will have about 80% power to detect a difference between arms if the 
underlying event rate was 0.50 vs 0.80. Power calculations rely on the Pearson’s chi-squared test 
approximation; log-rank statistics provided similar power to detect a hazard ratio of about 0.30. 
9.3 
Populations for Analyses 
• The safety analysis set includes all participants who received any amount of the study 
intervention and for whom post-infusion safety data are available. 
• The per-protocol (PP) analysis set comprises all participants who completed 1 or 2 unit 
infusions, have no important protocol deviations, and have valid endpoint data available. These 
will be documented and tabulated.  
• The intent-to-treat analysis set includes all participants who were randomized. 
 
9.4 
Statistical Analyses 
9.4.1 
General Approach 
Descriptive statistics (mean, standard deviation, minimum, median interquartile range, and maximum 
values for continuous variables; and frequencies and percentages for categorical variables) will be 
computed for all study variables for the above populations. Unless otherwise specified, a complete case 
analysis will be considered such that missing values will not be replaced, and calculations will be done 
on available reported values. If there is a substantial amount of missing data we may consider 
imputation methods and adjust the analyses accordingly. Analyses will primarily be descriptive; 
estimates will be presented with 95% confidence intervals. Any significance testing will be done at the 
0.05 level. Details for the primary and key secondary analyses are provided below. A formal Statistical 
Analysis Plan (SAP) will be developed prior to performing analyses of the study endpoints. 

 
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9.4.2 
Analysis of the Primary Endpoint(s) 
The primary safety endpoint is cumulative incidence of serious adverse events (SAEs) at Day 29, 
calculated separately by arm as the percent of individuals who had at least one SAE by Day 29. The 
SAE rate at all other time points of the study will also be calculated. The overall SAE incidence will be 
presented, as well as separately by system organ class and preferred term groupings. Percentages will 
be based on the number of participants who were treated (the safety analysis set). Additional 
frequencies will be presented with respect to maximum severity and to relationship to COVID19 and 
study product. Multiple occurrences of the same AE will be counted only once according to the highest 
occurring grade and relationship to study product/COVID19.  
The primary efficacy endpoint is the clinical severity score and will be calculated based on all 
randomized individuals (the intent-to-treat set). The key parameter of interest will be the comparison 
of clinical severity between individuals receiving the experimental intervention versus control, as 
measured by a clinical severity score that takes into account the survival time, recovery time, and Day 
29 severity score for survivors who had not recovered by Day 29. Recovery is defined by time to 
reaching levels 1-3 in the 8-point ordinal scale. The severity score for the primary efficacy endpoint is 
calculated based on a procedure proposed by Shaw and Fay 2016 [21], which ranks all survivors better 
than non-survivors, individuals with shorter recovery times as better, and individuals with shorter 
times to death as worse. Shaw and Fay 2016 showed this test statistic can be interpreted as a weighted 
average of the log-rank type test statistic for survival and the one for time to recovery amongst 
survivors. If there are participants who survive to Day 29 but have not yet recovered, their clinical 
severity will be determined by their Day 29 ordinal severity score, using time to reach that level to 
rank those who had the same Day 29 ordinal severity. It is anticipated that this analysis will have more 
power to detect differences than looking only at only an individual endpoint.  Secondary endpoints will 
include a comparison of each of the individual endpoints:  time to recovery and survival. Further 
details for the statistical analysis will be provided in the SAP 
9.4.3 
Analysis of the Secondary Endpoint(s) 
Key secondary efficacy endpoints include survival and time to recovery and will generally be 
calculated using the intent-to-treat set. Kaplan-Meier survival curves will be calculated by arm and 
compared with a Peto-Peto generalized Wilcoxon test. In the event that deaths that occur, the 
cumulative incidence of recovery will be estimated and compared between groups using Gray’s test, 
which will be able to capture a lower time to recovery due to either a slower event rate or a higher 
death rate. For interpretive purposes the cause specific hazard ratios for will also be calculated for each 
event type, survival and recovery, along with the Peto-Peto test. In the event of no deaths, time to 
recovery will be summarized with the Kaplan-Meier and compared using the Peto-Peto generalized 
Wilcoxon test.  
Cumulative incidence curves will be considered for time-to-event endpoints,  treating death as a 
competing risk. Gray’s test, or if the cause-specific hazard ratio was of interest the log-rank test, will 
be used to compare groups. Binary proportions will be estimated along with Clopper-Pearson 95% 
confidence intervals and compared between arms using Fisher’s exact test. Continuous endpoints will 
be summarized with means, SD and normal 95% confidence intervals; Wilcoxon rank-sum will be 
used to compare arms for continuous endpoints. Ordinal endpoints (e.g. 8-point clinical severity score) 
will be summarized by their multinomial proportions across the different categories at Study Day 15, 

 
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22 and 29. An exact Mann-Whitney test will be used to test for whether the ordinal clinical severity 
was higher in one arm versus the other for ordinal endpoints.  Further details for the analysis of 
secondary endpoints will be provided in the Statistical Analysis Plan. 
9.4.4 
Safety Analyses 
The primary outcome is summaries by arm of the cumulative incidence of SAE, as described in 
Section 8.4.2. Safety endpoints include death through Day 29, SAEs, discontinuation of study drug 
infusions, and Grade 3 and 4 AEs. Safety events will be analyzed as individual events and as part of a 
composite endpoint (e.g. any SAE). Proportions at specific study time points and by arm, e.g. Day 15, 
22, 29 and 60, will be tabulated, as well as a Kaplan-Meier curve for death and time to first event for 
the composite endpoint. Each AE will be counted once for a given participant and graded by severity 
and relationship to COVID-19 or study intervention. AEs will be coded using the current version of the 
Medical Dictionary for Regulatory Activities (MedDRA). AEs will be presented by system organ 
class, duration (in days), start- and stop-date. Adverse events leading to premature discontinuation 
from the study intervention and serious treatment-emergent AEs will be summarized. Analyses will be 
primarily descriptive. 
Events that would result in immediate study pause for DSMB review and the potential stopping of the 
study include: transfusion reactions or coagulopathic events. Plasma transfusion is a safe and 
commonly used treatment and so we do not anticipate additional SAE, above what these critically ill 
patients would experience as part of their baseline risk. 
9.4.5 
Baseline Descriptive Statistics 
Baseline characteristics will be summarized for the treatment and control groups. For continuous 
measures, the mean and standard deviation will be summarized. Categorical variables will be described 
by the number and proportion in each category. Of interest will be participant demographics, e.g. age, 
gender, race, as well as clinical and laboratory variables describing co-morbidities and disease severity 
at baseline. P-values for significance testing between groups, e.g., Fisher’s exact test for proportions or 
Wilcoxon Rank Sum for continuous, will be considered but differences between groups interpreted 
primarily qualitatively. 
9.4.6 
Planned Interim Analyses 
A Data Safety Monitoring Board (DSMB) will monitor ongoing results to ensure participant well-
being and safety as well as study integrity. The DSMB will be convened for a detailed review of safety 
data after 10 patients have been enrolled and reached day 15 or at 2 months, whichever comes first, 
and then as needed. No formal statistical interim analyses are planned. Events that would result in 
immediate study pause for DSMB review and the potential stopping of the study include: transfusion 
reactions or coagulopathic events. Plasma transfusion is a safe and commonly used treatment and so 
we do not anticipate additional SAE, above what these critically ill patients would experience as part 
of their baseline risk. 
The study team will provide the DSMB Committee reports of enrollment, baseline characteristics, 
follow-up rates, and safety data.  

 
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9.4.7 
Sub-Group Analyses 
Subgroup analyses for the primary and key secondary efficacy outcomes will be considered to see 
where the differences between the treatment and control groups varied across the following subgroups: 
age, sex, and duration of symptoms prior to enrollment. A forest plot will display confidence intervals 
across subgroups. We do not expect to have enough sample size to conduct formal interaction tests to 
determine whether the effect of treatment varies by subgroup. 
9.4.8 
Tabulation of Individual Participant Data 
The time course of participants clinical and laboratory markers will be considered. Frequency of 
evaluation varies across clinical and laboratory assessments. Adverse event and clinical evaluation will 
occur daily while individual is in hospital and otherwise include Day 15, 22, 29, and 60. Laboratory 
measures will generally occur at days 3, 5, 8 and 11 while participant is in hospital. The full list of 
evaluations are shown in the Schedule of Activities (Appendix 12.1). 
9.4.9 
Exploratory Analyses 
We will analyze a number of biomarkers of immune response and virologic efficacy.  Binary 
proportions will be estimated along with Clopper-Pearson 95% confidence intervals. Continuous 
endpoints will be summarized with means, SD and normal 95% confidence intervals; for skewed data, 
non-parametric statistics, such as the median and interquartile range will be considered. Trends over 
time will be assessed descriptively, as well as with linear mixed effects models if appropriate. We will 
also consider the clinical efficacy of convalescent plasma administration as compared to active drug 
(e.g., Remdesivir) recipients in DMID Protocol Number: 20-0006. Analysis of all comparative 
endpoints will be similar to that for the comparison of the treatment and control groups, as described in 
Section 9.4.3. Further details will be provided in the SAP. 

 
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10 SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1 Regulatory, Ethical, and Study Oversight Considerations 
10.1.1 
Informed Consent Process 
10.1.1.1 
Consent/Assent and Other Informational Documents Provided To Participants 
Consent forms describing in detail the Penn COVID-19 Convalescent Plasma, study procedures, and 
risks are given to the participant and written documentation of informed consent is required prior to 
starting the study intervention. 
10.1.1.2 
Consent Procedures and Documentation 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. Consent forms will be Institutional 
Review Board (IRB)-approved and the participant will be asked to read and review the document. The 
investigator will explain the research study to the participant or legally authorized representative 
(LAR) where appropriate, and answer any questions that may arise. A verbal explanation will be 
provided in terms suited to the participant’s comprehension of the purposes, procedures, and potential 
risks of the study and of their rights as research participants. Participants/LAR will have the 
opportunity to carefully review the written consent form and ask questions prior to signing. The 
participants/LAR should have the opportunity to discuss the study with their family or surrogates or 
think about it prior to agreeing to participate. The participant will sign the informed consent, either 
electronically or wet ink signature prior to any procedures being done specifically for the study. 
Participants must be informed that participation is voluntary and that they may withdraw from the 
study at any time, without prejudice. A copy of the informed consent document will be given to the 
participants for their records. To avoid paper and bio-contaminants, this will be done via electronic 
means. The rights and welfare of the participants will be protected by emphasizing to them that the 
quality of their medical care will not be adversely affected if they decline to participate in this study. 
If the participant is able to consent, the process will be done in person and documentation of the 
participant’s consent will be recorded electronically following the University of Pennsylvania IBB 
guidance. 
10.1.2 
Study Discontinuation and Closure 
This study may be temporarily suspended or prematurely terminated by the Sponsor or the PI at any 
site if there is sufficient reasonable cause. Written notification, documenting the reason for study 
suspension or termination, will be provided by the suspending or terminating party to study 
participants, investigator, funding agency, the Investigational New Drug (IND), the sponsor and the 
FDA. If the study is prematurely terminated or suspended, the Principal Investigator (PI) will promptly 
inform study participants, the Institutional Review Board (IRB), and sponsor and will provide the 
reason(s) for the termination or suspension. Study participants will be contacted, as applicable, and be 
informed of changes to study visit schedule. 

 
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Circumstances that may warrant termination or suspension include, but are not limited to: 
 Determination of unexpected, significant, or unacceptable risk to participants 
 Demonstration of efficacy that would warrant stopping 
 Insufficient compliance to protocol requirements 
 Data that are not sufficiently complete and/or evaluable 
 Determination that the primary endpoint has been met 
 Determination of futility 
 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, 
and satisfy the sponsor, IRB and/or Food and Drug Administration (FDA). 
In terminating the study, the Sponsor and the Principal Investigator will assure that adequate 
consideration is given to the protection of the participants; interests. 
10.1.3 
Confidentiality and Privacy 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their 
staff, and the sponsor(s) and their interventions. This confidentiality is extended to cover testing of 
biological samples and genetic tests in addition to the clinical information relating to participants. 
Therefore, the study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the study or the data will be released to any unauthorized 
third party without prior written approval of the sponsor. 
All research activities will be conducted in as private a setting as possible. 
The study monitor, other authorized representatives of the sponsor, representatives of the Institutional 
Review Board (IRB), regulatory agencies or pharmaceutical company supplying study product may 
inspect all documents and records required to be maintained by the investigator, including but not 
limited to, medical records (office, clinic, or hospital) and pharmacy records for the participants in this 
study. The clinical study site will permit access to such records. 
The study participant’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements. 
10.1.4 
Future Use of Stored Specimens and Data 
Secondary Human Participant Research is the re-use of identifiable data or identifiable biospecimens 
that were collected from some other ‘‘primary’’ or ‘‘initial’’ activity, such as the data and samples 
collected in this protocol. Any use of the sample or data for secondary research purposes, however, 
will be presented in a separate protocol and require separate IRB approval. 

 
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Participants will be asked for consent to collect additional blood, the use of residual specimens, and 
samples for secondary research. Extra blood will be drawn for secondary research during each visit 
when a study blood samples are obtained. 
The stored samples will be labeled with barcodes and a unique tracking number to protect participant’s 
confidentiality. Secondary research with coded samples and data may occur; however, participant 
confidentiality will be maintained as described for this protocol. An IRB review of the secondary 
research using coded specimens is required. 
Samples designated for secondary research use may be used for understanding the SARS-CoV-2 
infection, the immune response to this infection, and the effect of therapeutics on these factors. 
Samples will not be sold for commercial profit. Although the results of any future research may be 
patentable or have commercial profit, participants will have no legal or financial interest in any 
commercial development resulting from any future research. 
There are no direct benefits to the participant for extra specimens collected or from the secondary 
research. No results from secondary research will be entered into the participant’s medical record. 
Incidental findings will not be shared with the participant, including medically actionable incidental 
findings, unless required by law. 
Participants may withdraw permission to use samples for secondary use at any time by notifying the 
study doctors or nurses in writing. If the participant subsequently changes his/her decision, the samples 
will be destroyed if the samples have not been used for research or released for a specific research 
project. 
10.1.5 
Safety Oversight 
Safety oversight will be under the direction of a Data and Safety Monitoring Board (DSMB) composed 
of individuals with the appropriate expertise. Members of the DSMB should be independent from the 
study conduct and free of conflict of interest, or measures should be in place to minimize perceived 
conflict of interest. The DSMB will meet at least semiannually to assess safety and efficacy data on 
each arm of the study. The DSMB operates under the rules of an approved charter that is written and 
reviewed at the organizational meeting of the DSMB. At this time, each data element that the DSMB 
needs to assess will be clearly defined. The DSMB will provide its input to the study sponsor. 
10.1.6 
Clinical Monitoring 
Site monitoring is conducted to ensure that the rights and well-being of trial participants are protected, 
that the reported trial data are accurate, complete, and verifiable, and that the conduct of the trial is in 
compliance with the currently approved protocol/amendment(s), with International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use Good Clinical Practice 
(ICH GCP), and with applicable regulatory requirement(s). 
 Monitoring for this study will be performed by the Office of Clinical Research monitoring 
team. 

 
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 In an effort to ensure the safety of the study personnel and the monitors during the COVID-19 
pandemic, monitoring of the study data will be primarily remote until the restrictions in place 
as a consequence of the COVID-19 pandemic are lifted. 
 The site should ensure that all safety related information is in an electronic record or scanned 
into a secure access application that the monitor can access. Source data verification will be 
conducted between electronic record and the sponsor EDC. 
 The Sponsor will be provided copies of monitoring reports within the time period set by the 
DSMP. 
 Details of clinical site monitoring are documented in a Data Safety Monitoring Plan (DSMP). 
The DSMP describes in detail who will conduct the monitoring, at what frequency monitoring 
will be done, at what level of detail monitoring will be performed, and the distribution of 
monitoring reports. The DSMP is written to allow non safety related items to be deferred to 
later visits if necessary and therefore some items may be deferred to a later visit that can be 
conducted in person. Close out visits will need a follow up in person visit, at a later date. 
 Independent audits or compliance reviews may be conducted by University of Pennsylvania 
Office of Clinical Research to ensure monitoring practices are performed consistently across 
all participating sites and that monitors are following the MP. 
 
10.1.7 
Quality Assurance and Quality Control 
All monitoring and audits are to be performed according to ICH GCP E6(R2). 
Each clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion. An individualized quality management plan will 
be developed to describe a site’s quality management. 
Quality control (QC) procedures will be implemented beginning with the data entry system and data 
QC checks that will be run on the database will be generated. Any missing data or data anomalies will 
be communicated to the site(s) for clarification/resolution. 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical trial 
is conducted and data are generated, and specimens are collected, documented (recorded), and reported 
in compliance with the protocol, International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use Good Clinical Practice (ICH GCP), and applicable regulatory 
requirements (e.g., Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)). 
The investigational site will provide direct access to all trial related sites, source data/documents, and 
reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and 
regulatory authorities. 

 
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10.1.8 
Data Handling and Record Keeping 
10.1.8.1 
Data Collection and Management Responsibilities 
Source data are all information in original records (and certified copies of original records) of clinical 
findings, observations, or other activities in a clinical trial necessary for the reconstruction and 
evaluation of the trial. Source data should be attributable, legible, contemporaneous, original, accurate, 
and complete. 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site 
investigator. The investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. 
Hardcopies of the study visit worksheets will be provided for use as source document worksheets for 
recording data for each participant enrolled in the study. Data recorded in the electronic case report 
form (eCRF) derived from source documents should be consistent with the data recorded on the source 
documents. 
Clinical and laboratory data will be entered into a 21 CFR Part 11-compliant electronic data capture 
system (EDC) that includes individual user account level password protection. The EDC used to 
support this trial is Penn CTMS (Velos version 9) which supports compliant eCRF collection, audit 
trail capabilities and facilitates source data verification. 
10.1.8.2 
Study Records Retention  
Study related records, including the regulatory file, study product accountability records, consent 
forms, participant source documents and electronic records should be maintained until the Sponsor and 
provides notice 
10.1.9 
Protocol Deviations 
The PI and the study team should document all scenarios where the protocol is not followed and 
provide, in particular: 
 Who deviated from the protocol 
 What was the deviation 
 When did the deviation occur 
 How did the deviation happen 
 What is the impact of the deviation 
 A root cause analysis of why the deviation occurred 
 

 
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If the assessment is determined to be of limited impact (minor deviation), the documentation for this 
assessment and the outcome should be reported to the Sponsor at the time of annual report. Reporting 
to the IRB should follow specific local requirements. 
If the assessment results in a determination that any of the following are potentially affected, the 
deviation would be considered of significant impact: 
 having the potential to adversely affect participant safety; OR 
 increases risks to participants; OR 
 adversely affects the integrity of the data; OR 
 violates the rights and welfare of participants, OR 
 affects the participant’s willingness to participate in research. 
 there is a potential for an overall impact on the research that should be shared with the IRB for 
consideration and development of next best steps to address it 
 
These scenarios should be reported to the Sponsor within 10 business days of discovery. Reporting to 
IRB should follow local requirements. 
10.1.10 
Publication and Data Sharing Policy 
Following completion of the study, results of this research will be sent for publication in a scientific 
journal. As this is an adaptive study and given the public health urgency to disseminate results, data 
from individual comparisons (i.e. the initial 2 study arms) can be published when those arms are fully 
enrolled and all participants in those arms are followed through to completion of the study. 
Data will be available immediately following publication, with no end date, with data sharing at the 
discretion of the Sponsor. Publication may occur prior to completion of a final clinical study report for 
the entire trial. 
Any publication, press release, and sharing of data for any reason must be shared with sponsor prior to 
release. 
The investigator is responsible for authoring a final clinical study report and sharing with the sponsor 
team. The Clinical Study Report will be issued within 12 months of data lock and the results summary 
will be posted to clinicaltrials.gov. A manuscript will be progressed for publication in the scientific 
literature if the results provide important scientific or medical knowledge. 
10.1.11 
Conflict of Interest Policy 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical. Therefore, any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 

 
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persons who have a perceived conflict of interest will be required to have such conflicts managed in a 
way that is appropriate to their participation in the design and conduct of this trial. 
10.2 Additional Considerations 
10.2.1 
Research Related Injuries 
The PI will assess participant AEs. 
Immediate medical treatment may be provided by the participating site, such as giving emergency 
medications to stop immediate allergic reactions. No financial compensation will be provided to the 
participant by the Sponsor or the participating site for any injury suffered due to participation in this 
trial. 
10.3 Protocol Amendment History 
 
Version 
Date 
Description of Change  
Brief Rationale 
0.5 
16-May-2020 • 
Original version 
 
2.0 
04-May-2020 • 
Update eligibility criteria and study 
endpoints  
• 
Add rational for inclusion of 
pregnant women 
• 
Updates to the statistical section 
 
 
• 
Administrative changes 
• 
To address IRB and FDA 
stipulations 
 
 
• 
To address FDA non-hold 
comments on IND Advice 
letter 
• 
For clarification purposes 
2.1 
05-May-2020 • 
Addition of stratified randomization 
based on participant’s receipt of 
Remdesivir. 
• 
To allow statistical analysis 
based on the use of Remdesivir 
as standard care. 
2.2 
05-May-2020 • 
Match sample collection dates along 
the protocol 
• 
Consistency along the protocol 
V2.5 
12-May-2020 • 
Clarification of secondary endpoint 
and inclusion criteria 
• 
For clarity purposes 
V3 
21-May-2020 • 
Clarification of primary efficacy 
endpoint  
• 
To address FDA request 
V4 
28-Aug-2020 • 
Clarification of follow up time 
frame. 
• 
For clarification purposes 
 

 
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Zhou F Lancet 2020, Chen N Lancet 2020; Wang D JAMA 2020; Guan W-J NEJM 2020 
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Chuang-Stein C, Cosgrove SE, Fowler Jr VG, Lautenbach E. Desirability of outcome ranking (DOOR) 
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H, Yang Y, Qu J, Qing L, Chen L, Xu Z, Peng L, Li Y, Zheng H, Chen F, Huang K, Jiang Y, Liu D, 
Zhang Z, Liu Y, Liu L: Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent 
Plasma. JAMA 2020. doi: 10.1001/jama.2020.4783. 
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Huang J, Wang Z, Yu J, Gao X, Wang D, Yu X, Li L, Zhang J, Wu X, Li B, Xu Y, Chen W, Peng Y, 
Hu Y, Lin L, Liu X, Huang S, Zhou Z, Zhang L, Wang Y, Zhang Z, Deng K, Xia Z, Gong Q, Zhang 
W, Zheng X, Liu Y, Yang H, Zhou D, Yu D, Hou J, Shi Z, Chen S, Chen Z, Zhang X, Yang X: 
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Sise MJ, King BS: Does resuscitation with plasma increase the risk of venous thromboembolism? J 
Trauma Acute Care Surg 2015 Jan;78(1):39-43. 
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Nilsson KR, Berenholtz SM, Garrett-Mayer E, Dorman T, Klag MJ, Pronovost PJ: Association 
between venous thromboembolism and perioperative allogeneic transfusion. Arch Surg 2007 
Feb;142(2):126-32. 
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Gangireddy C, Rectenwald J, Upchurch G, Wakefield T, Khuri S, Henderson W, Henke P: Risk 
factors and clinical impact of postoperative symptomatic venous thromboembolism. Journal of 
Vascular Surgery 2007 Feb; 45(2): 341-342. 
35. 
Abu-Rustuma N, Richard S, Wilton A, Lev G, Sonoda Y, Hensley M, Gemignani M, Barakat 
R, Chi D: Transfusion utilization during adnexal or peritoneal cancer surgery: Effects on symptomatic 
venous thromboembolism and survival. Gynecologic Oncology 2005; 99(2): 320-326. 
36. 
Halstead SB: Pathogenesis of dengue: challenges to molecular biology. Science 1988, 
239(4839):476-81. 
37. 
Takada A, Kawaoka Y: Antibody-dependent enhancement of viral infection: molecular 
mechanisms and in vivo implications. Rev Med Virol. 2003, 13(6):387-98. 
38. 
Liu L, Wei Q, Lin Q, Fang J, Wang H, Kwok H, Tang H, Nishiura K, Peng J, Tan Z, Wu T, 
Cheung KW, Chan KH, Alvarez X, Qin C, Lackner A, Perlman S, Yuen KY, Chen Z: Anti-spike IgG 
causes severe acute lung injury by skewing macrophage responses during acute SARS-CoV infection. JCI 
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39. 
Alshukairi AN, Khalid I, Ahmed WA, Dada AM, Bayumi DT, Malic LS, Althawadi S, Ignacio 
K, Alsalmi HS, Al-Abdely HM, Wali GY, Qushmaq IA, Alraddadi BM, Perlman S: Antibody 
Response and Disease Severity in Healthcare Worker MERS Survivors. Emerg Infect Dis 2016, 22(6). 
40. 
CDC Yellow Book, Chapter 2, General Recommendations for Vaccination & 
Immunoprophylaxis: https://wwwnc.cdc.gov/travel/page/yellowbook-home-2014. 
41. 
MMWR Morb Mortal Wkly Rep. 2011 Jan 28;60(RR02):1-60. 
42. 
LaCourse S, John-Stewart G, Adams Waldorf K: Importance of inclusion of pregnant and 
breastfeeding women in COVID-19 therapeutic trials. Clinical Infectious Diseases. 2020, 
https://doi.org/10.1093/cid/ciaa444 
43. 
Shields, KE. Pregnancy and the Pharmaceutical Industry, Elsevier Press, 2019. 
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44. 
Royal College of Obstetricians and Gynaecologists (2015), Blood Transfusion in Obstetrics 
(Guide No. 47). Retrieved from https://www.rcog.org.uk/globalassets/documents/guidelines/gtg-47.pdf 
45. 
Winkelhorst D, Murphy MF, Greinacher A, Shehata N, Bakchoul T, Massey E, Baker J, 
Lieberman L, Tanael S, Hume H, Arnold DM, Baidya S, Bertrand G, Bussel J, Kjaer M, Kaplan C, 
Kjeldsen-Kragh J, Oepkes D, Ryan G: Antenatal management in fetal and neonatal alloimmune 
thrombocytopenia: a systematic review. Blood. 2017 Mar 16;129(11):1538-1547. 
46. 
Gamez J, Salvado M, Casellas M, Manrique S, Castillo F. Intravenous immunoglobulin as 
monotherapy for myasthenia gravis during pregnancy. J Neurol Sci. 2017;383:118–122. 
doi:10.1016/j.jns.2017.10.037 
47. 
Winkelmann A, Rommer PS, Hecker M, Zettl UK. Intravenous immunoglobulin treatment in 
multiple sclerosis: A prospective, rater-blinded analysis of relapse rates during pregnancy and the 
postnatal period. CNS Neurosci Ther. 2019;25(1):78–85. doi:10.1111/cns.12985 
48. 
Huang Y, Cheng W, Zhao N, Qu H, Tian J: CT screening for early diagnosis of SARS-CoV-2 
infection. Lancet Infect Dis 2020 Mar 26. pii: S1473-3099(20)30241-3. doi: 10.1016/S1473-
3099(20)30241-3. [Epub ahead of print] 
 
 

 
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12 APPENDIX 
12.1 Schedule of Activities (SoA) 
The following page outlines all of the assessments to be conducted during the study. A detailed 
presentation of assessments immediately follows the table.  
Table 4: Schedule of Activities 
Screen 
Baseline Study Period 
While inpatient 
While inpatient or as outpatient visits 
Day +/- Window 
−1 or 1 
1 
Day 2 to 29 
157 ± 2 
227 ± 3 
297 ± 3 
607 ± 510 
ELIGIBILITY 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
Demographics & Medical History 
X 
 
 
 
 
 
 
Targeted physical exam 
X 
 
 
 
 
 
 
Review SARS-CoV-2 results 
X 
 
 
 
 
 
 
STUDY INTERVENTION 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
Administration of investigational 
plasma 
 
X 
 
 
 
 
 
STUDY PROCEDURES 
 
 
 
 
 
 
 
Vital signs including SpO2 
 
X4 
Daily until discharge 
or Day 29 of 
hospitalization 
X 
 
X 
X 
Clinical data collection1 
 
X4 
Daily until discharge 
or Day 29 of 
hospitalization 
X 
X8 
X 
X 
Targeted medication review 
 
X4 
Daily until discharge 
or Day 29 of 
hospitalization 
X 
 
X 
X 
Adverse event evaluation 
 
X4 
Daily until discharge 
or Day 29 of 
hospitalization 
X 
X 
X 
X 
SAFETY LABORATORY 
 
 
 
 
 
 
 
Type and Screen 
X2,3 
 
 
 
 
 
 
Safety hematology, chemistry and 
liver tests 
X4,5,6 
Day 3, 5, 8, 11 (all ± 
1 day) 
if hospitalized5,6 
X9 
 
X9 
 
Pregnancy test for females of 
childbearing potential 
X2,3 
 
 
 
 
 
 
RESEARCH LABORATORY 
 
 
 
 
 
 
 
Oropharyngeal swab or 
endotracheal sample 
 
X5 
Day 3, 5, 8, 11 (all ± 
1 day) if hospitalized 
X 
 
 
 

 
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Blood for research 
 
X5 
Day 3, 8, (all ± 1 
day) 
X 
 
X 
X 
1 Refer to Section 8.1 of the protocol for details of clinical data to be collected including ordinal score, NEWS, oxygen 
requirement, mechanical ventilator requirement, etc. 
2 Screening laboratory tests include: ALT, AST, creatinine (and calculate an estimated glomerular filtration rate (eGFR)), 
and pregnancy test. 
3 Laboratory tests performed in the 48 hours prior to enrollment will be accepted 
4 Baseline assessments should be performed prior to study drug administration. Laboratory tests performed as part of 
routine clinical care in the 24 hours prior to first dose will be accepted for the baseline safety laboratory tests. Baseline may 
be the same as the screening laboratory tests. 
5 Safety laboratory tests include WBC with differential, hemoglobin, platelets, creatinine, glucose, total bilirubin, ALT, 
AST, and PT. 
6 Any laboratory tests performed as part of routine clinical care within the specified visit window can be used for safety 
laboratory testing. Window during the study period is ±1 day. 
7 In-person visits are preferred but recognizing quarantine and other factors may limit the participant’s ability to return to 
the site for the visit. In this case, these visits may be conducted by phone and blood and OP can be coordinated remotely. 
8 Phone call at Day 22 is to assess clinical status (ordinal scale), adverse events, readmission to a hospital, and mortality 
only. 
9 Safety laboratory tests on Day 15 and 29 if still hospitalized or returns to the site for the visit or at home visit. 
10 The collection of Day 60 data for primary and secondary endpoints and the collection of Day 60 samples for exploratory 
tests may be performed up to 90 days following the Day 60 visit. 
 
12.2 Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric 
Adverse Events, Corrected version 2.1 (July 2017) 
Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events 
(Corrected Version 2.1 - July 2017)pdf