An Open Label, Phase 2 Study Evaluating the Efficacy and Safety of High-Titer Anti-SARS-CoV-2 Plasma in Hospitalized Patients With COVID-19 Infection
Phase: PHASE2
Conditions: COVID-19
Sponsor: Medical College of Wisconsin

Protocol: Convalescent plasma for sars-cov-2 infection 
Protocol Version 4 dated: 3/10/2021      Page 1 of  38 
 
 
 
Efficacy and Safety of Convalescent Plasma in 
Treating COVID-19 Hospitalized Patients 
 
 
 
 
 
 
NCT04354831 
 
 Version 4 
3/10/2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol: Convalescent plasma for sars-cov-2 infection 
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An Open label, Phase 2 Study Evaluating the Efficacy and Safety of High-Titer 
Anti-SARS-CoV-2 plasma in hospitalized patients with COVID-19 infection 

Protocol: Convalescent plasma for sars-cov-2 infection 
Protocol Version 4 dated: 3/10/2021      Page 3 of  38 
 
 
LIST OF ABBREVIATIONS: 
 
ADR: Adverse Drug Reaction 
ADE: Antibody-mediated enhancement of infection 
AE: Adverse Event/Adverse Experience 
CDC: United States Centers for Disease Control and Prevention 
CFR: Code of Federal Regulations 
CLIA: Clinical Laboratory Improvement Amendment of 1988 
COI: Conflict of Interest 
COVID-19: Coronavirus Disease 
CP: Convalescent Plasma 
CRF: Case Report Form 
DMC: Data Management Center 
DSMB: Data and Safety Monitoring Board 
EUA: Emergency Use Authorization 
FCBP: Females of Childbearing Potential 
FDA: Food and Drug Administration 
GCP: Good Clinical Practice 
HBV: Hepatitis B virus 
HCPOA: Health care power of attorney 
HCV: Hepatitis C virus 
HIV: Human immunodeficiency virus 
HTLV: Human T-cell lymphotropic virus 
IB: Investigator’s Brochure 
ICF: Informed Consent (Informed Consent Form) 
ICH: International Conference on Harmonization 
ICU: Intensive Care Unit 
IEC: Independent ethics committee 
IND: Investigational New Drug Application 
IRB: Institutional review board 
ISBT: International Society of Blood Transfusion 
ISM: Independent Safety Monitor 
IVIG: Intravenous Immune Globulin 
IWRS: Interactive web response system 
LOS: Length of stay 
MERS: Middle East Respiratory Syndrome 
NA: Nuclear antibody 
NP: Nasopharyngeal 
OP: Oropharyngeal 
RBD: Receptor Binding Domain of SARS-Co-V2 virus 
RT-PCR: Reverse Transcriptase Real-Time Polymerase chain reaction 
PK: Pharmacokinetic 
SAE: Serious adverse event 
SARS: Severe Acute Respiratory Syndrome 
SARS-CoV-2: Severe Acute Respiratory Syndrome Coronavirus 2 

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TACO: Transfusion-associated circulatory overload 
T. cruzi: Trypanosoma cruzi 
TRALI: Transfusion-related acute lung injury 
UP: Unanticipated Problem 
UPnonAE: Unanticipated Problem that is not an Adverse Event 
ZIKV: Zika virus 
 

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PROTOCOL SUMMARY: 
 
An Open label, Phase 2 Study Evaluating the Efficacy and Safety of High-Titer Anti- 
SARS-CoV-2 plasma in hospitalized patients with COVID-19 infection 
 
Clinical Phase: 2 
 
IND Sponsor: Medical College of Wisconsin; Dr. Mary Beth Graham 
 
Conducted by: Medical College of Wisconsin in collaboration with Versiti as plasma 
source. 
 
Sample Size: 131 patients in 2 cohorts (ICU cohort called cohort 1 and a hospitalized 
non-ICU cohort or cohort 2) 
 
Study Population: Hospitalized COVID-19 patients >18 years of age with severe 
symptoms as defined in inclusion criteria and within 21 days of symptom onset. 
 
Study Duration: April 15, 2020 to December 31, 2020 
 
Study Design: This is an open label phase 2 trial assessing the efficacy and safety of 
anti-SARS-CoV-2 convalescent plasma in hospitalized patients with acute severe 
respiratory symptoms from COVID-19. Symptomatic patients with clinical or radiological 
interstitial COVID-19 pneumonia and within 21 days of onset of symptoms will be 
enrolled in 2 cohorts – an ICU cohort and a hospitalized non-ICU cohort. 
 
Study Assessments: Refer to Table 1 and Section 8 
 
Summary of Outcome measures: 
 
• Transfer to ICU for hospitalized non-ICU patients 
• Increased O2 requirement (PaO2/FiO2 ratio or SpO2/FIo2), supplemental 
oxygen strategy (nasal cannula, high flow nasal cannula, noninvasive ventilation, 
intubation and invasive mechanical ventilation, rescue ventilation i.e. 
neuromuscular blocking agents, prone positioning, corticosteroids, ECMO) 
• Use if vasopressors, ventilated days, renal support 
• ICU LOS, ICU mortality 
• Hospital LOS, Hospital mortality 
• 28-day mortality 
 
Study Drug: 
 
• SARS-CoV-2 convalescent plasma 2 units 
• Study drug will be administered as a single intravenous infusion 

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Primary Efficacy Objective: 
 
1. Evaluate improvement of sequential organ failure (for ICU cohort) 
2. Evaluate improvement in the risk of transfer to ICU and/or death (for non-ICU 
cohort) 
 
Primary Endpoints: 
 
1. Improvement (Delta) SOFA Score: measured as a change in SOFA score from 
baseline at the time of plasma infusion to 96 hours post infusion (ICU cohort) 
2. Combined primary endpoint of death / intubation (non-ICU cohort)/ ICU transfer 
(non-ICU cohort) 
 
Secondary endpoints: 
 
1. Type and duration of respiratory support 
2. Overall Mortality within first 60 days 
3. Hospital LOS and in hospital mortality 
4. ICU LOS and ICU mortality 
5. Ventilator-free days (non-ICU cohort) 
6. Incidence of secondary infections / co infections 
 
Primary Safety Objective: 
 
Evaluate the safety of treatment with high-titer anti-SARS-CoV-2 plasma in hospitalized 
patients with COVID-19 respiratory symptoms. 
 
Primary Safety Endpoints: 
 
1. Rapid deterioration of respiratory or clinical status on transfusion of SARS-CoV-2 
convalescent plasma due to presumed antibody dependent enhancement or 
other mechanisms 
2. Cumulative incidence of all serious adverse events attributed to plasma therapy 
during the study period: transfusion reaction (fever, rash), transfusion related 
acute lung injury (TRALI), transfusion associated circulatory overload (TACO), 
transfusion related infection 
 
Laboratory Objectives: 
 
1. Anti-SARS-CoV-2 antibody titers at days 0, 4, 7 and 14 (additional days 21 and 28 
may be included, as available). 
2. SARS-CoV-2 RNA by RT-PCR at days 7 and 14. 
3. Research blood draws on days 0, 4, 7 ,14, and 28 to investigate immunology 
and hematologic pathways in severe COVID-19. 
 
Study population (for both cohorts): Refer to section 5.1 of main protocol 

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Contents 
1. 
Background and scientific rationale ................................................................................ 9 
2. 
Known potential risks from clinical trial ......................................................................... 12 
3. 
Known potential benefits of clinical trial ........................................................................ 13 
4. 
Investigational plan .......................................................................................................... 13 
4.1 Study Objectives .............................................................................................................. 13 
4.2 Study Definitions.............................................................................................................. 14 
5. Study population ................................................................................................................. 14 
5.1 Eligibility Criteria (for both cohorts) .................................................................................. 15 
5.2 Table 1: Schedule of Events ............................................................................................17 
5.3 Subject Withdrawal .......................................................................................................... 18 
6. Treatment ............................................................................................................................ 18 
6.1 Rationale for doses .......................................................................................................... 18 
6.2 Study drug administration ................................................................................................ 18 
6.3 Concomitant medications ................................................................................................ 19 
7. Statistical considerations ................................................................................................... 19 
7.1 Analysis of AE data ......................................................................................................... 19 
7.2 Analysis of anti-SARS-CoV-2 titers .................................................................................. 19 
7.3 Endpoints ........................................................................................................................19 
7.4 Analysis of primary endpoints ..........................................................................................20 
7.5 Analysis of secondary endpoints ..................................................................................... 20 
7.5.1 Type and duration of respiratory support ...................................................................20 
7.5.2 Overall mortality within first 60 days .......................................................................... 20 
7.5.3 Hospital LOS and in-hospital mortality ....................................................................... 20 
7.5.4 ICU LOS and ICU mortality ....................................................................................... 20 
7.5.5 Ventilator-free days ................................................................................................... 21 
7.6 Sample size considerations ............................................................................................. 21 
8. Study procedures ................................................................................................................ 21 
9. Efficacy, virology measures: .............................................................................................. 22 
10. Risks and benefits ............................................................................................................ 23 
11. Safety measures ................................................................................................................ 23 
11.1 Adverse Event ............................................................................................................... 23 
11.2 Serious Adverse Event (SAE) ........................................................................................ 24 
11.2.1 SAEs are reported in the following manner ............................................................. 24 

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11.2.2 Unanticipated Problem Involving Risk to Subject or Other (UPIRSO) .......................25 
11.2.3 Adverse Events Not Meeting SAE Definition .......................................................... 25 
11.2.4 Protocol Deviation.................................................................................................. 25 
11.3 Reporting Interval .......................................................................................................... 25 
12. Safety Oversight ................................................................................................................ 26 
12.1 Monitoring Plan .............................................................................................................. 27 
12.2 Halting Criteria for the Study .......................................................................................... 27 
13. Ethics/Protection of human subjects .............................................................................. 28 
13.1 Ethical Standard ............................................................................................................ 28 
13.2 Institutional Review Board ............................................................................................. 28 
13.3 Informed Consent Process ........................................................................................... 28 
13.4 Subject Confidentiality ................................................................................................... 30 
14. Research Sample Disposition .......................................................................................... 30 
15. Data management and monitoring ................................................................................... 31 
15.1 Source Documents ........................................................................................................ 31 
15.2 Data Management Plan ................................................................................................ 31 
16. References: ....................................................................................................................... 32 
APPENDIX 1: SOFA SCORE ................................................................................................... 34 
APPENDIX 2: Research Blood Sample Collection and Shipping Instructions ....................36 

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1. Background and scientific rationale 
 
Since there are no known curative therapeutic options for SARS-CoV-2 infection (and 
the related clinical disease COVID-19) patients with potentially life-threatening disease, 
there is considerable interest in passive transfer of immunity using plasma from patients 
who cleared virus and mounted a successful humoral immune response. Human 
convalescent plasma or hyperimmune globulin has been used as treatment of many 
viral illnesses and could be rapidly available when there are sufficient numbers of 
people who have recovered1. These individuals with adequate levels of IgG or IgM titers 
and confirmed clearance of virus are ideal donors of convalescent plasma. The natural 
history of this disease with a substantial majority clearing the disease spontaneously 
lends itself to the development of a strategy around convalescent donor plasma for 
seriously affected patients2. 
 
Passive antibody therapy involves the administration of antibodies to a given agent to a 
susceptible individual for the purpose of preventing or treating an infectious disease due 
to that agent. Use of convalescent plasma has been studied in outbreaks of other 
respiratory infections, including the 2009-2010 H1N1 influenza virus pandemic, 2003 
SARS-CoV-1 epidemic, and the 2012 MERS-CoV epidemic3-6. Convalescent plasma or 
immunoglobulins have been used as a last resort to improve the survival rate of patients 
with SARS whose condition continued to deteriorate despite treatment with pulsed 
methylprednisolone6. In the 2013 African Ebola epidemic too, a non-randomized study 
in Sierra Leone revealed a significant increase in survival for those treated with 
convalescent whole blood relative to those who received standard treatment5. A meta- 
analysis of 32 studies pooling SARS coronavirus infection and severe influenza showed 
a consistent and overall statistically significant reduction in the odds of mortality 
following CP therapy, compared with placebo or no therapy7. 
 
In the ongoing COVID-19 preliminary data have emerged suggesting clinical benefit8. 
Shen et al showed treated 5 patients with COVID-19 pneumonia with convalescent 
donor derived plasma between day 10 - 20 of hospitalization. All were severely ill with 
respiratory failure requiring mechanical ventilation (4 patients) or ECMO at the time of 
therapy. The administered donor plasma had demonstrable anti–SARS-CoV-19 
antibodies and in vitro studies demonstrated neutralizing activity. Notably all patients 
had clinical and virologic improvement in about a week after plasma with resolution of 
fever, improved SOFA scores and SARS-CoV-2 viral clearance between 1 and 12 days 
after receipt of plasma. The results are confounded by the co-administration of antiviral 
treatment primarily with lopinavir/ritonavir (although this therapy was not shown to be 
effective in a randomized study)9. All patients also had an increase in neutralizing 
antibody titers. Very similar promising results have been reported by a group from China 
who reported clinical improvement in 10 patients treated with a single 200 mL of 
convalescent plasma. 
 
The major caveats to these data are the lack of a control group and the subsequent 
inability to determine the true clinical effect of this intervention or whether patients might 
have recovered without this therapy. Additionally, the timing of plasma administration 

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has been pointed out as a matter of debate since it is not clear if earlier administration 
might have been associated with different clinical outcomes2. We believe that the data 
from Shen et al provide strong evidence to support the possibility of evaluating this in 
larger cohort involving patients with COVID-19 and moderate to severe illness. Passive 
antibody administration is currently the only means of providing immediate immunity to 
susceptible persons and immunity of any measurable kind for COVID-19 patients10. 
 
In contrast, active vaccination requires the induction of an immune response that takes 
time to develop and varies depending on the vaccine recipient. Some 
immunocompromised patients fail to achieve an adequate immune response. 
 
Thus, passive antibody therapy has a storied history going back to the 1890s and is 
summarized by Casadevall et al10. Prior to the development of specific antimicrobial 
therapy this was in fact a mainstay of therapy. In the case of SARS-CoV-2, there is 
clear evidence of the development of neutralizing antibodies, both IgM and IgG fairly 
quickly after infection in patients who demonstrate viral clearance. In a series of 23 
patients, To et al showed that viral load peaked during the first week of illness then 
gradually declined over the second week. IgG and IgM antibodies started to increase on 
around day 10 after symptom onset, and most patients had seroconversion within the 
first 3 weeks11. Most importantly, IgG and IgM antibody levels against the SARS-CoV-2 
internal nucleoprotein (NP) and the surface spike receptor binding domain (RBD) 
correlated with neutralizing activity. As more individuals contract COVID-19 and 
recover, the number of potential donors will continue to increase and make this more 
feasible for the growing number of severely ill individuals too12. 
 
A general principle of passive antibody therapy is that it is more effective when used for 
prophylaxis or earlier in the disease course than for treatment of advanced disease. 
When used for therapy, antibody is most effective when administered shortly after the 
onset of symptoms. The reason for temporal variation in efficacy is not well understood 
but could reflect that passive antibody works by neutralizing the initial inoculum, which is 
likely to be much smaller than that of established disease. Another explanation is that 
antibody works by modifying the inflammatory response, which is also easier during the 
initial immune response, at which time the patient may not be too symptomatic13. Our 
plan is to treat a majority of patients who are sick enough to warrant 
hospitalization prior to the onset of overwhelming disease. Additionally, a smaller 
cohort of patients who need ICU level care will be enrolled provided expected life 
expectancy is >72 hrs. Given the data from Shen et al we feel it is reasonable to 
treat patients who are on mechanical ventilation but not those with overwhelming 
disease. 
 
The plasma product we administer will be collected by Versiti per AABB and GMP 
approved protocols from recovered asymptomatic individuals who have complete 
resolution from SARS-CoV-2 infection, virologic clearance and presence of 
antiviral antibody titers. 

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There are news reports that convalescent plasma was used for therapy of patients with 
COVID-19 in China during the current outbreak 
(http://www.xinhuanet.com/english/2020-02/28/c_138828177.htm). Although few details 
are available from the Chinese experience and published studies involved small 
numbers of patients, the available information suggests that convalescent plasma 
administration reduces viral load and was safe. 
 
Ancillary Research Laboratory Studies: 
 
Exploring the inflammatory and hemostatic milieu in severe COVID-19: 
Evidence is accumulating that the inflammatory and hemostatic response is uniquely 
engaged in COVID-infected patients. Coagulopathy, microvascular, arterial, and venous 
thrombosis are being reported with increasing frequency14,15. The response of the 
immune and hemostatic system to COVID infection is largely unknown. We plan to 
investigate hemostatic pathways during the hospitalization phase of patients receiving 
plasma therapies. 
 
Investigating the specificity and affinity of SARS-Co-V2 antibodies: 
Although convalescent COVID-19 sera likely have neutralizing antibodies against 
SARS2-CoV-2, the quantity and quality of neutralizing antibodies in convalescent sera 
from each individual will vary dramatically. It is not clear which characteristics of SARS- 
CoV-2-specific antibodies in the infused plasma determine the antiviral potency. 
Moreover, as noted above administration of convalescent sera possesses risks of 
causing inadvertent side effects such as immunological reactions, transfusion-related 
acute lung injury, or antibody-dependent enhancement. In contrast, 
a human recombinant monoclonal neutralizing antibody against SARS2-CoV-2 can be 
selected to have the characteristics associated with high antiviral potency and 
overcome the potential risks, can be produced on a large scale and safely used 
as prophylactic and therapeutic treatment for SARS-CoV-2 infection. Based on our 
experience in cloning antigen-specific B cells from human patients and our studies of 
PF4/heparin-specific B cells, we propose two specific research analyses. First, we will 
investigate the role of isotype, specificity and affinity in determining neutralization 
potency of SARS-CoV-2-specific antibodies in COVID-19 convalescent sera and study 
the antibody responses in COVID-19 patients through single-cell sequencing. Secondly, 
we will clone RBD-specific antibodies from single B cells of convalescent COVID-19 
patients. 
 
The proposed studies will help to identify the most potent sera and monoclonal antibodies 
from convalescent COVID-19 patients for prophylaxis and/or treatment of COVID-19. 
These approaches will help prevent SARS-CoV-2 spread among high-risk individuals i.e. 
frontline health care providers and people that are coming into close contact with patients 
and will likely be used to treat patients with COVID-19. 

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2. Known potential risks from clinical trial 
 
a. An important theoretical risk involves the phenomenon of antibody-mediated 
enhancement of infection (ADE). ADE can occur for several viral diseases and 
involves an enhancement of disease in the presence of certain antibodies. For 
coronaviruses, several mechanisms for ADE have been described and there is 
the theoretical concern that antibodies to one type of coronavirus could enhance 
infection to another viral strain (12). It may be possible to predict the risk of ADE 
of SARS-CoV-2 experimentally, as proposed for MERS. Since the proposed use 
of convalescent plasma in the COVID-19 epidemic would rely on preparations 
with high titers of neutralizing antibody against the same virus, SARS2-CoV-2, 
ADE may be unlikely. The available evidence from the use of convalescent 
plasma in patients with SARS1 and MERS (13) and evidence of its use in 
patients with COVID-19 (Shen et al), suggest it is safe. Nevertheless, caution 
and vigilance will be required as proposed in the safety end points. 
 
b.  Another theoretical risk is that antibody administration to those exposed to 
SARS-CoV-2 may avoid disease but modify the immune response such that 
those individuals mount attenuated immune responses, which would leave them 
vulnerable to subsequent re-infection. In this regard, passive antibody 
administration before vaccination with respiratory syncytial virus was reported to 
attenuate humoral but not cellular immunity (14). This concern could be 
investigated as part of a clinical trial by measuring immune responses in those 
exposed and treated with convalescent plasma to prevent disease. If the concern 
proved real these individuals could be vaccinated against COVID-19 when a 
vaccine becomes available. These concerns seem modest compared to the 
possibility of limiting the duration and severity of disease, and avoiding 
interventions like mechanical ventilation, ARDS and sepsis. 
 
c.  Transfusion associated risk common to any blood products could also be 
associated with donor plasma including transmission of transfusion transmitted 
viruses (e.g. HIV, HBV, HCV, etc.), allergic transfusion reactions, anaphylaxis to 
transfusion, febrile transfusion reaction, transfusion related acute lung injury 
(TRALI), transfusion associated cardiac overload (TACO), and ABO mediated 
hemolysis. In order to minimize the risks of disease transmission, standard 
pathogen reduction techniques will be utilized as per Versiti protocol. Using 
donors who fulfill donor eligibility requirements, blood donation, and frequent 
apheresis plasma donation with the exception of recent illness, in this case 
COVID-19 infection. 

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3. Known potential benefits of clinical trial 
 
A key potential benefit is treatment for established infection. Convalescent plasma 
would be administered to those with clinical disease in an effort to reduce their 
symptoms and mortality. Based on the historical experience with antibody 
administration, it can be anticipated that antibody administration relatively early in the 
course of disease would more effective in preventing disease progression than in the 
treatment of established severe disease. 
 
Given that historical and current anecdotal data on use of convalescent plasma suggest 
it is safe in coronavirus infection, the high mortality of COVID-19, particularly in elderly 
and vulnerable persons, suggests that the benefits of its use in those at high risk for 
death or with early disease outweigh the risks. However, for all cases where 
convalescent plasma administration is considered, a risk-benefit assessment must be 
conducted to assess individual variables. 
 
 
4. Investigational plan 
 
4.1 Study Objectives 
Primary Efficacy Objective: 
1. Evaluate improvement of sequential organ failure (for ICU cohort) 
2. Evaluate improvement in the risk of transfer to ICU and/or death (for non-ICU 
cohort) 
 
Primary Endpoints: 
 
1. Improvement (Delta) SOFA Score measured as a change in SOFA score from 
baseline at the time of plasma infusion to 96 hours post infusion (ICU cohort) 
2. Combined primary endpoint of death / intubation (non-ICU cohort)/ ICU transfer 
(non-ICU cohort) 
 
Secondary endpoints: 
 
1. Type and duration of respiratory support (see definitions in Section 7.5.1) 
2. Overall Mortality within first 60 days 
3. Hospital LOS and in hospital mortality 
4. ICU LOS and ICU mortality 
5. Ventilator-free days (non-ICU cohort) 
6. Incidence of secondary infections / co infections 

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Primary Safety Objective: 
 
Evaluate the safety of treatment with high-titer anti-SARS-CoV-2 plasma in hospitalized 
patients with COVID-19 respiratory symptoms. 
 
Primary Safety Endpoints: 
 
1. Rapid deterioration of respiratory or clinical status on transfusion of SARS-CoV-2 
convalescent plasma due to presumed antibody dependent enhancement or 
other mechanisms. Since patients in this study are already in respiratory distress, 
further worsening of respiratory status will be defined as below and causes 
attributed by treating physician. Any escalation of oxygenation or ventilatory 
needs within the 12 hours after plasma infusion will be considered as a 
deterioration. This includes new requirement for supplemental oxygen in a 
person not on oxygen, an increase of >25% in FiO2; need for non invasive or 
invasive mechanical ventilation in subjects not requiring these at the time of 
infusion. In patients already on mechanical ventilation, an increase in PEEP and 
or FiO2 of >25% will also be considered a respiratory deterioration. 
2. Cumulative incidence of all serious adverse events attributed to plasma therapy 
during the study period: transfusion reaction (fever, rash), transfusion related 
acute lung injury (TRALI), transfusion associated circulatory overload (TACO), 
transfusion related infection 
 
Laboratory Objectives: 
 
1. Anti-SARS-CoV-2 antibody titers at days 0, 4, 7 and 14 (additional days 21 and 28 
may be included, as available). 
2. SARS-CoV-2 RNA by RT-PCR at days 7 and 14. 
3. Research blood draws on days 0, 4, 7,14, and 28 to investigate immunology 
and hematologic pathways in severe COVID-19. 
 
4.2 Study Definitions: 
 
1. Enrolled: From time consented to participate until designated as a screen failure 
or have either been discontinued from the study or completed it. 
2. Screen Failures: signed informed consent, but then determined to be ineligible or 
withdraws before being treated. 
3. Discontinued: enrolled, but then withdrawn by investigator or subject withdraws 
consent 
4. Completed: Subjects are considered to have completed when they are followed 
through day 60 or day of death if death occurred prior to day 60 
 
5. Study population 
 
Patients will be enrolled in 2 cohorts independent of each other. Cohort 1 will consist of 
patients who are admitted to the ICU. Cohort 2 will consist of patients who are admitted 
to a non-ICU floor. Patients transferring from non-ICU to ICU floors or vice versa will be 

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analyzed in the cohort corresponding to the location of signing consent.  Each cohort will 
be analyzed independently. 

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5.1 Eligibility Criteria (for both cohorts) 
Inclusion Criteria: 
1. Age > 18 years or older 
2. Hospitalized as an in-patient with positive COVID-19 test by PCR 
3. Presence of symptomatic disease with any one of severe features as below: 
 
• 
Respiratory Rate >= 24/min 
• 
Hypoxia defined as a person requiring >3L/min of supplemental 
oxygen OR oxygen saturation of <94% on room air 
• 
New onset or worsening of respiratory symptoms with radiologic 
confirmation of bilateral ground glass opacities that cannot be 
attributed to another cause 
• 
Chief complaint of dyspnea / shortness of breath without 
meeting above RR or oxygen requirements 
 
4. Patient or patient and witness or LAR / HCPOA is willing and able to provide 
verbal / telephonic/ physical or electronic informed consent and comply with all 
protocol and IRB requirements. If patient is unable to consent due to incapacity, 
health care POA should be defined and able to consent for the patient. 
5. Patients are allowed to receive all standard of care treatments and or join other 
clinical trials. 
 
Exclusion Criteria 
 
1. FCBP with positive pregnancy test (mandatory) 
2. Breastfeeding females 
3. Receipt of pooled immunoglobulin (e.g. IVIG or other hyperimmune globulin 
products) in past 14 days. This does not apply to monoclonal antibodies. 
4. Mechanical ventilation for > 14 days 
5. Days from symptom onset >21 days 
6. Expected survival < 72 hours 
7. Contraindication to transfusion or history of prior reactions to transfusion blood 
products including any proven history of TRALI 

 
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5.2 Table 1: Schedule of Events 
Study period 
Screen 
Baseline 
Prior to plasma 
Transfusion 
Follow-up6 
Monthly 
follow-up6 
Day 
-3 to 0 
0 
0 
1 
4 
7 
14 
28 
60 
Eligibility 
Informed consent 
x 
Demographic and medical history 
x 
COVID-19 symptom screen 
x 
Chest x-ray or chest CT 
x 
SARS-CoV-2 RT-PCR for eligibility 
x 
Serum/urine pregnancy test in FCBP w/in 7 days of 
study transfusion 
x 
ABO type and antibody screen 
x 
Treatment 
Donor Plasma Administration 
x 
Drug infusion 
x 
Study Procedures 
Vital signs 
x 
x 
x3 
Daily clinical assessments 
during hospital stay. SOFA 
score in ICU patients 
Physical examination 
x 
x 
Symptom screen 
x 
x 
x 
Concomitant medications 
x 
x 
x 
x 
x 
x 
x 
x 
SOFA score2 
x 
x 
x 
x 
x 
Adverse event monitoring 
x 
x 
x 
Throughout study period 
Laboratory testing 
CBC diff / CMP/ DIC panel 
x 
x 
x 
x 
x 
x1 
Ferritin/CRP/LDH 
x 
x 
x 
x 
x 
x1 
Immunoglobulin Panel 
x 
SARS-CoV-2 RT-PCR 
x5 
 
 
SARS-CoV-2 antibody research blood sample4 
x 
x 
x 
x 
x1 
Research Blood Samples to Versiti4 
x 
x 
x 
x 
x1 
1. All labs after the day of discharge from hospital are optional. 
2. Refer to appendix 1. 
3. Vital signs will be measured immediately prior to infusion, 10-20 minutes after start of infusion, at completion of infusion and 30-60 minutes after the end of the 
Infusion. 
4. Refer to section 14 and appendix 2. 
5. Baseline RT PCR for study entry is adequate. 
6. +/- 2-day window 

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5.3 Subject Withdrawal 
 
1. Subjects or HCPOA can terminate study participation and/or withdraw consent at any time 
without prejudice. 
2. Subjects who withdraw from the study who have received study treatment will not be 
replaced. Subjects who have never received study treatment can be replaced. 
3. The investigator may withdraw subjects if they are lost to follow up, non-compliant with 
study procedures or if the investigator determines that continued participation in the study 
would be harmful to the subject or the integrity of the study data. 
4. Discontinuation of the study: the study sponsor, FDA and IRB all have the right to 
terminate this study at any time. 
 
6. Treatment 
 
1. Study drug: The investigational product is anti-SARS-CoV-2 convalescent plasma 
obtained from patients identified as having recovered from COVID-19 as per Versiti 
plasma collection protocols. 
2. Donors and samples will have been screened for transfusion-transmitted infections (as per 
current AABB and FDA standards) both through the use of the uniform donor 
questionnaire and FDA mandated blood donor screening tests by Versiti. 
3. ABO compatible plasma will be used to reduce risk of hemolysis. 
 
6.1 Rationale for doses 
 
Recommended dose will be 2 units of plasma for all patients.   
 
6.2 Study drug administration 
 
• Drug will be administered once consent, eligibility confirmation, enrollment, and 
screening/baseline procedures have been completed. 
• Infusion rate  500 mL/hour. 
• Pretreatment to minimize transfusion reactions (e.g. acetaminophen, diphenhydramine) may 
be given per investigator and clinical care team discretion. 
• If an AE develops during infusion, the infusion may be slowed or stopped as per 
investigator’s decision. 
o Most reactions to plasma are relatively minor and the infusion can generally be 
continued. Infusion site burning and non-allergic systemic effects can generally be 
managed with slowing of the infusion. Infusion can generally be continued in cases of 
itching or hives after pausing the transfusion, administering antihistamines, and 
observing the patient for worsening symptoms. 
o Severe allergic reactions such as, bronchospasm and hypotension, and may require 
discontinuation of the infusion. 

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6.3 Concomitant medications 
 
Concomitant medications will be documented on the CRF and these include: 
 
• Prescription medications 
• Any other clinical trials 
• Over the counter medications 
• Herbal treatments/nutritional supplements 
• Blood products administered 
 
7. Statistical considerations 
 
Patients will be enrolled in 2 cohorts independent of each other. Cohort 1 will consist of 41 
patients who are admitted to the ICU. Cohort 2 will consist of 90 patients who are admitted to a 
non-ICU floor. The two cohorts will be analyzed independently. For sample size considerations 
please see section 7.6. 
 
For each cohort, descriptive summaries of continuous and other numeric variables will consist of 
the summary statistics: median, minimum and maximum values. Categorical variables will be 
summarized by the frequency and proportion of subjects falling into each category. Unless 
otherwise indicated, percentages in tables will be column percentages, using the total number of 
observations in the population as the denominator. Exact confidence intervals for binomial 
proportions will be derived using the Clopper-Pearson method. 
 
7.1 Analysis of AE data 
 
Analysis of AE data will primarily be descriptive based on MedDRA coding of events. The 
proportion of subjects experiencing an SAE and the proportion experiencing a Grade 3 or higher 
event will be presented. 
 
7.2 Analysis of anti-SARS-CoV-2 titers 
 
Analysis of titers will also primarily be descriptive, at days 0,4, 7 and 14 post study treatment 
administration. 
 
7.3 Endpoints 
 
Primary Endpoint: 
 
Cohort 1: Delta SOFA Score (change in SOFA score) from baseline at the time of plasma 
infusion to 96 hours post infusion (ICU cohort). 
 
The Sequential Organ Failure Assessment (SOFA) Score is a mortality prediction score that is 
based on the degree of dysfunction of six organ systems. The score is calculated on admission 
and every 24 hours until discharge using the worst parameters measured during the prior 24 
hours16. Calculation of SOFA score is described in Appendix 117. 
 
Cohort 2: Combined primary end point of death, intubation or ICU transfer (non-ICU cohort). 

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Primary Hypotheses: 
 
Cohort 1: the probability of decrease in SOFA score of at least 2 after 96 hours from the 
intervention is higher than 20%. An increase to 40% would be clinically meaningful. 
 
Cohort 2: the probability of death, intubation or ICU transfer is lower than 60%. A decrease to 
45% would be clinically meaningful. 
 
7.4 Analysis of primary endpoints 
 
The proportion of patients achieving the primary endpoint will be reported with a two-sided 95% 
exact Clopper-Pearson confidence interval. The primary hypothesis will be evaluated using an exact 
binomial test at a one-sided 2.5% significance level. 
 
7.5 Analysis of secondary endpoints 
 
7.5.1 Type and duration of respiratory support 
The number of patients requiring each type of respiratory support will be tabulated. The duration of 
support will be summarized with median and inter-quartile range. For the purposes of this protocol 
respiratory support will be captured and classified in the following categories18: 
1. Supplemental Oxygen by nasal cannula, simple mask, non-rebreather mask and defined by 
flow rate in liters/min 
2. High Flow Nasal Oxygen with flow rates and FiO2 setting 
3. Non-invasive positive pressure ventilation with flow, FiO2 and pressure settings defined 
4. Mechanical Ventilation with FiO2, Pressure and ventilator settings defined 
5. Extra corporeal Membrane Oxygenation (ECMO). 
 
7.5.2 Overall mortality within first 60 days 
The overall survival of the subjects will be estimated using the Kaplan-Meier method and presented 
with 95% confidence bands. Subjects may be censored if they had a routine discharge (not hospice, 
or another hospital), and could not be contacted for further follow-up. Overall mortality at 60 days 
post-intervention will be estimated using the Kaplan-Meier estimate. 
 
7.5.3 Hospital LOS and in-hospital mortality 
In-hospital mortality will be estimated as the observed proportion of subjects who died during the 
hospital stay and presented with a 95% exact Pearson confidence interval. Hospital length of stay 
will be considered only among subjects discharged alive and will be summarized with median and 
inter-quartile range. 
 
7.5.4 ICU LOS and ICU mortality 
ICU length of stay and mortality will be considered in Cohort 1 and among subjects in Cohort 2 who 
are admitted to an ICU. ICU mortality will be estimated as the observed proportion of subjects who 
died during the hospital stay and presented with a 95% exact Clopper-Pearson confidence interval. 
ICU length of stay will be considered only among subjects discharged alive and will be summarized 
with median and inter-quartile range. 

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7.5.5 Ventilator-free days 
Ventilator-free days will be considered only in Cohort 1. It will be defined as the number of days 
during 28 days after the intervention that the subject is alive and does not require ventilator support. 
Ventilator-free days will be summarized with median and inter-quartile range. 
 
 
7.6 Sample size considerations 
 
The cohort sizes were selected to achieve at least 80% power of rejecting the null hypotheses at a 
one-sided 2.5% significance level if the true probability of the primary outcome is at its clinically 
meaningful value. A single stage exact binomial study design was used. 
 
Cohort 1: With 41 subjects the study will have 80% power to reject the null hypothesis of ≤20% 
probability of a 2-point decrease in SOFA at a one-sided 2.5% significance level, if the underlying 
probability is 40%. The treatment will be considered successful if 14 or more subjects achieve the 
primary endpoint. 
 
Cohort 2: With 90 subjects the study will have 80% power to reject the null hypothesis of ≥60% 
probability of death, intubation or ICU transfer, if the underlying probability is 45%. The treatment 
will be considered successful if 44 or fewer subjects achieve the primary endpoint. 
 
 
8. Study procedures 
 
Consenting Process: 
 
Consent is difficult in patients with acute respiratory symptoms who are in isolation. Therefore, an 
electronic or phone call or video conference consenting process will be used to document informed 
consent from patients or HCPOA (refer to section 13.3 for further details). Research staff will make 
contact info available to patients who have further inquiries about the project. Once a patient 
consents to participate in the trial, a member of the study team will assign them a unique patient 
number (UPN). These UPNs will be assigned to subjects sequentially (MCW-COV-001, MCW-COV- 
002, MCW-COV-003, etc.). Patients are enrolled on the trial once they have consented and are 
deemed eligible. 
 
Day -3 to -0: 
1. Subject informed consent (obtained before performing study related activities) 
2. Screening (must be completed before enrollment) 
3. Baseline Evaluation (at screening) (much of the information will be obtained from the medical 
record) 
a. Demographics (age, sex ethnicity, race) 
b. Medical history (timing of exposure to COVID-19 source patient if known, acute and 
chronic medical conditions, concomitant medications, allergies. Any medical condition 
arising after consent should be recorded as AE 
c. COVID-19 symptom screen (fevers, cough, shortness of breath), onset of symptoms, 
source of contagion 
d. Vital signs 
e. Physical exam 

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f. Chest x-ray or chest CT 
g. ABO type and antibody screen documentation or test if not done 
h. COVID-19 testing (RT-PCR or rapid test) from any source 
i. Pregnancy test (serum or urine) for females of childbearing potential within 7 days 
prior to infusion 
j. Determination of eligibility as per inclusion/exclusion criteria age. 
k. HCPOA or witness information 
 
 
Day 0: 
1. Assessment of clinical status by standard symptom and physical examination including 
calculation of SOFA score in ICU patients. SOFA score will be calculated as per Appendix 1. 
2. Study Plasma Administration: 1-2 units of plasma will be transfused. Time at start and end 
time of infusion will be recorded and vital signs will be measured immediately prior to 
infusion, 10-20 minutes after start of infusion, at completion of infusion and 30-60 minutes 
after the end of the infusion. 
3. New medical conditions, concomitant medication, and AE evaluation 
4. Physical examination 
5. CBC with Diff, comprehensive metabolic panel, DIC panel, ferritin, LDH, immunoglobulin 
panel, and C-reactive protein 
6. Research Samples as detailed in Table 1 (Schedule of events) 
 
Days 1-14 (or for duration of hospitalization) – Refer to table 1 for specific day: 
1. Vital signs daily 
2. COVID-19 symptom screen (fevers, cough, shortness of breath) 
3. Assessment of clinical status 
4. New medical conditions, concomitant medication, and AE evaluation 
5. Physical examination 
6. SOFA score 
7. CBC with Diff, comprehensive metabolic panel, CRP, Ferritin, DIC panel, LDH 
8. Research Samples as detailed in Table 1 (Schedule of events) 
 
Day 28  (Refer to Table 1): 
Follow-up by phone is acceptable if alive and at home. 
Current admission; at home vs. in hospital (ICU or not), on supplemental O2 or not, back to work 
(fully, partially, SNF, nursing home, LTAC) 
 
1. COVID-19 symptom screen (fevers, cough, shortness of breath) 
2. SOFA score if in ICU 
3. Assessment of clinical status with physical exam if in hospital / clinic 
4. New medical conditions, concomitant medication, and AE evaluation 
5. If still hospitalized, follow procedures listed in table 1. 
6. Optional labs (CBC with Diff, comprehensive metabolic panel, CRP, Ferritin, DIC panel, LDH; 
Research Labs) – all labs beyond day 14 are optional. 
 
9. Efficacy, virology measures: 
Clinical Efficacy 

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Clinical assessment will be standard of care subjective symptom assessment and physical 
examination as documented in daily progress notes. SOFA score will be documented for ICU 
resident patients. 
 
Virologic measures 
 
1. Serologic positivity and neutralization antibody titers for anti-SARS-CoV-2 at days 0, 4, 7 and 
14, whenever possible given sample availability, patient mortality, reluctance to come to 
MCW for testing. 
 
10. Risks and benefits 
 
Potential Benefits of treatment: 
The potential benefits of antiviral treatment with anti-SARS CoV-2 plasma in patients with 
respiratory symptoms consistent with interstitial pneumonia at high risk for requiring ICU 
admission are not known. However, it is anticipated that treatment will decrease the risk of 
disease progression requiring ICU admission and aggressive respiratory support including 
possible mechanical ventilation (and other ICU support). 
 
Potential benefits of clinical monitoring and virologic testing: 
Subjects enrolled in the study may reduce their chances of disease progression. 
 
Potential risks: 
1. Risks of plasma: Fever, chills, rash, headache, serious allergic reactions, TRALI, TACO, 
transmission of infectious agents 
2. Risks of phlebotomy: local discomfort, bruising, hematoma, bleeding, fainting 
3. Total blood draws will not exceed 100 mL during the entire study 
4. Risks of oropharyngeal and throat swab: local discomfort, vomiting 
 
Alternatives: 
The alternative to participation in this study is routine care and or other clinical trials. 
Participation in this trial does not preclude enrollment in any other clinical trial. 
 
11. Safety measures 
 
1. Laboratory evaluations consistent with ongoing standard medical care may include radiographic 
imaging modalities such as chest x-rays and chest CT. 
2. Clinical assessment and monitoring for infusion reaction on day of infusion as per standard of 
care blood transfusion guidelines. 
3. Safety laboratory tests (ABO typing, pregnancy testing, CBC, CRP, and comprehensive 
metabolic panel) will be performed at the local CLIA-certified clinical laboratory as per schedule 
of assessments in Table 1. 
 
11.1 Adverse Event 

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Any untoward medical occurrence in a clinical investigation subject who has received a study 
intervention and that does not necessarily have to have a causal relationship with the study product. An 
AE can, therefore, be any unfavorable and unintended sign (including an abnormal laboratory finding, 
for example), symptom, or disease temporally associated with the use of the study product, whether or 
not considered related to the study product. 
 
Unexpected Adverse event: (UAE) An adverse reaction attributed to infused plasma, the nature or 
severity of which is not consistent with the risks outlined in the consent form. 
 
This study will utilize the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, 
located on the CTEP web site: 
 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
 
11.2 Serious Adverse Event (SAE) 
 
An SAE is any adverse event that results in any of the following outcomes: 
1. Death 
2. Life-threatening (immediate risk of death) 
3. Prolongation of existing hospitalization 
4. Persistent or significant disability or incapacity 
5. Important medical events that may not result in death, be life threatening, or require intervention 
or escalation of care may be considered a serious adverse event when, based upon appropriate 
medical judgment, they may jeopardize the subject 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 or convulsions that do not result in inpatient hospitalization. 
 
11.2.1 SAEs are reported in the following manner: 
 
All fatal or life-threatening or unexpected and suspected SAEs will be reported to the IRB and all 
applicable agencies within 24 hours and all other SAEs (non-fatal or non-life-threatening) within 4 
calendar days of study site staff awareness. 
• Every SAE regardless of suspected causality (e.g., relationship to study drugs or study procedure) 
occurring after the subject has signed the consent through the 30 days after the last dose of study 
drugs, AND only SAEs occurring more than 30 days after the last dose of study drugs that the 
investigator suspects a causal relationship to study plasma, must be reported in the study 
database SAE section. These will also be reported to the ISM (Dr. Michael Frank as below) and 
the IRB. All transfusion related AEs and SAEs have to be reported to the hospital blood bank 
additionally in order to start a transfusion AE investigation. 
• All grade 4 and 5 SAEs and any other expedited SAE report to IRB must also be reported to 
FDA (MedWatch 3500A described below) within five calendar days of MCW study staff’s 
awareness. 

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• In addition: if the SAE is unexpected and has a suspected relationship to the study drug, site must 
create a reportable event notice with the MCW IRB, ISM and complete a MedWatch 3500A and 
submit to FDA: 
▪ US FDA MedWatch 3500A found here: 
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm 
 
 
11.2.2 Unanticipated Problem Involving Risk to Subject or Other (UPIRSO) 
 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all of the 
following criteria: 
• Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (sIRB)- 
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). 
• 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. 
 
11.2.3 Adverse Events Not Meeting SAE Definition 
 
• Any medical condition that is present at the time that the participant is screened will be considered 
as baseline condition and captured on the baseline CRF form, not reported as an AE. All new or 
worsening AEs that occur after starting study drug until 30 days post last dose of study plasma 
will be tracked and followed until resolution, stabilization of the event as chronic, subject withdraws 
consent, or is lost to follow-up (including subjects who discontinue early). 
• Changes in the grade of an AE will be documented in the AE CRF to allow an assessment of the 
duration of the event at each level of severity to be performed. Information to be collected includes 
event description, time of onset, clinician’s assessment of severity, expectedness, relationship to 
study product (assessed only by those with the training and authority to make a diagnosis), and 
time of resolution/stabilization of the event. 
 
11.2.4 Protocol Deviation 
 
A deviation from the IRB-approved study procedures designated as serious: 
1. Serious Protocol Deviation: protocol deviation that is also an SAE and/or compromises the 
safety, welfare or rights of subjects or others 
2. Follow safety reporting requirements listed above 
 
11.3 Reporting Interval 
 
All AEs and SAEs will be documented from consenting until study completion at 60 days from study 
infusion or death or discontinuation from the study. All AEs and SAEs will be followed until resolution 
even if this extends beyond the study-reporting period. Resolution of an adverse event is defined as the 

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return to pre-treatment status or stabilization of the condition with the expectation that it will remain 
chronic. 
 
Investigator’s Assessment of Adverse Events 
 
The determination of seriousness, severity, and causality will be made by an on-site investigator who is 
qualified (licensed) to diagnose adverse event information, provide a medical evaluation of adverse 
events, and classify adverse events based upon medical judgment. This includes but is not limited to 
physicians, physician assistants, and nurse practitioners. 
 
Assessment of Seriousness 
1. Event seriousness will be determined according to the protocol definition of an SAE 
2. Assessment of Severity 
 
Event severity will be assigned according to the scale below 
 
1 = Mild: Transient or mild discomfort (<48 hours); no medical intervention/therapy 
required.) 
 
2 = Moderate: Some worsening of symptoms but no or minimal medical 
intervention/therapy required) 
 
3 = Severe: Escalation of medical intervention/therapy required 
 
4 = Life-threatening: Marked escalation of medical intervention/therapy required. 
5= Death 
Assessment of Association 
 
The association assessment categories that will be used for this study are: 
• Associated – The event is temporally related to the administration of the study product and no 
other etiology explains the event. 
• Not Associated – The event is temporally independent of the study product and/or the event 
appears to be explained by another etiology. 
 
The investigator must provide an assessment of association or relationship of AEs to the study product 
based on: 
• Temporal relationship of the event to the administration of study product; 
• Whether an alternative etiology has been identified; 
• Biological plausibility; 
• Existing therapy and/or concomitant medications. 
 
 
12. Safety Oversight 

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12.1 Monitoring Plan 
1. All AEs and SAEs will be reviewed by protocol team. 
2. An Independent Safety Monitor (ISM) will be appointed. The ISM is a physician with expertise in 
infectious diseases and whose primary responsibility is to provide timely independent safety 
monitoring. An ISM has the authority to readily access study participant records. The ISM 
reviews any SAE that occurs at the study site in real time and provides a written assessment. 
Dr. Michael Frank, Chief, Division of Infectious Diseases, Medical College of Wisconsin 
will serve in this role. 
Study monitoring 
a. As per ICH-GCP 5.18 and FDA 21 CFR 312.50, clinical protocols are required to be 
adequately monitored by the study sponsor. 
b. Informed consent process documents for each subject needs to be available. 
c. There is compliance with recording requirements for data points 
d. All SAEs are reported as required 
e. Individual subjects’ study records and source documents align 
f. Investigators are in compliance with the protocol. 
g. Regulatory requirements as per Office for Human Research Protections-OHRP), FDA, 
and applicable guidelines (ICH-GCP) are being followed. 
 
 
12.2 Halting Criteria for the Study 
 
The study enrollment and dosing will be stopped, and an ad hoc review will be performed if any of the 
specific following events occur or, if in the judgment of the study physician or the ISM, subject safety is 
at risk of being compromised: 
 
1. Death within one hour of plasma infusion 
 
2. Occurrence of a life-threatening allergic/hypersensitivity reaction (anaphylaxis), manifested by 
bronchospasm with or without urticaria or angioedema requiring hemodynamic support with 
pressor medications or mechanical ventilation, TRALI, TACO. 
 
3. One subject with an SAE specifically associated with study product. 
 
4. Two subjects with a Grade 3 or higher lab toxicity for the same parameter associated with study 
product. 
 
5. An overall pattern of symptomatic, clinical, or laboratory events that the medical monitor, ISM, or 
IRB consider associated with study product and that may appear minor in terms of individual 
events but that collectively may represent a serious potential concern for safety. 

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6. Any other event(s) which is considered to be a serious adverse event related to the study 
infusion in the good clinical judgment of the responsible physician and or ISM. These will be 
appropriately documented. 
 
 
 
 
Halting Criteria/Rules for Subject Infusion 
 
Infusion of study drug will be halted in a study subject if any of the following manifestations of 
anaphylaxis develop and will not be restarted: 
 
• Skin or mucous membrane manifestations: hives, pruritus, flushing, swollen lips, tongue or uvula 
that do not respond to standard therapy with anti-allergic and steroid medications 
• Respiratory compromise: New onset wheezing, stridor, hypoxemia related to infusion 
• Any other symptom or sign which in the good clinical judgment of the study clinician or supervising 
physician warrants halting the infusion. For example, manifestations of anaphylaxis and may 
warrant an immediate halt prior to meeting full SAE criteria 
 
13. Ethics/Protection of human subjects 
 
13.1 Ethical Standard 
 
We will ensure that the legal and ethical obligations associated with the conduct of clinical research 
involving human subjects are met. 
 
As the Department of Health and Human Services continues to strengthen procedures for human 
subjects’ protections via new regulations, MCW will review these evolving standards in relation to the 
proposed activities and will advise the investigators on those that may apply. 
 
MCW has a Federal wide Assurance (FWA) number on file with the Office for Human Research 
Protections (OHRP). 
 
This assurance commits a research facility to conduct all human subjects’ research in accordance with 
the ethical principles in The Belmont Report and any other ethical standards recognized by OHRP. 
Finally, per OHRP regulations, the research facility will ensure that the mandatory renewal of this 
assurance occurs at the times specified in the regulations. 
 
13.2 Institutional Review Board 
 
MCW IRB will review this protocol and all protocol-related documents and procedures as required by 
OHRP and local requirements before subject enrollment. MCW IRB currently holds and will maintain a 
US FWA issued by OHRP for the entirety of this study. 
 
13.3 Informed Consent Process 

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The informed consent process will be initiated before a potential subject or their HCPOA agrees to 
participate in the study and should continue throughout the individual’s study participation. The subject 
or HCPOA will be consented before any procedures are undertaken for the study. The process for 
consent will be documented in the research records. 
 
Two alternative consent methods will be available for this study: 
1. Electronically: transmitting a consent form via email, obtaining e-consent utilizing an iPad, or 
utilizing a cloud-based system for delivery and communicating in-person with subjects or HCPOA. 
2. Phone Call or Video Conference: Example – this method could include utilizing the phone in the 
subject’s room or utilizing video conferencing services such as WebEx, Skype, etc to connect with 
patient and or HCPOA. 
 
Regardless of the method utilized, a consent form will be provided to the subject either in person by 
health care staff or electronically. 
If consent cannot be obtained electronically or in person, it is required that an impartial witness will be 
present (via phone or teleconference). 
 
When a witness is being utilized, the following must occur: 
1. The witness must be present for the entire consent discussion and confirm that the potential 
subject’s questions have been answered. 
2. The investigator must confirm that the potential subject is willing to participate and sign the consent 
form with the witness present (via phone or teleconference). 
3. The potential subject must confirm that he or she wishes to participate and has signed and dated 
the consent form. 
 
Documenting Informed Consent 
1. Electronically 
Example – The consent form can be signed, scanned, and sent via email or fax from the subject to 
the team. In addition, electronic signatures can be utilized. 
2. Photograph 
Example – The subject or research team can photograph the entire signed consent form by camera, 
cellular phone, etc. and send the picture to the research team. The picture can be taken from 
outside of the isolation area as long as the signed consent form can be seen clearly. 
3. Confirmation 
Example – The impartial witness present for the consenting process can attest that the subject 
confirmed the he/she wished to participate in the project and signed the consent form. 
 
The method of obtaining informed consent should be included in study records along with the signed 
consent form (if available). If a signed consent form is not available for the reasons outlined in this 
document, the study record should include an explanation of which method was used for confirming 
that the subject signed the consent form as well as the explanation of why the originally signed consent 
form could not be filed. 
 
An electronic copy of the signed informed consent document will be available to the subject for their 
records. The consent will explain that subjects may withdraw consent at any time throughout the 
course of the trial. Extensive explanation and discussion of risks and possible benefits of this 
investigation will be provided to the subjects in understandable language. Adequate time will be 
provided to ensure that the subject has time to consider and discuss participation in the protocol. 

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The consent will describe in detail the study interventions/products/procedures and risks/benefits 
associated with participation in the study. The rights and welfare of the subjects will be protected by 
emphasizing that their access to and the quality of medical care will not be adversely affected if they 
decline to participate in this study. 
 
 
 
13.4 Subject Confidentiality 
 
Subject confidentiality is strictly held in trust by the participating investigators, their staff, and the 
sponsors and their agents. No information concerning the study, or the data will be released to any 
unauthorized third party without prior written approval of the sponsor. The results of the research study 
may be published, but subjects’ names or identifiers will not be revealed. Records will remain 
confidential. To maintain confidentiality, the PI will be responsible for keeping records in a locked area 
and results of tests coded to prevent association with subjects’ names. Data entered into computerized 
files will be accessible only by authorized personnel directly involved with the study and will be coded. 
Subjects’ records will be available to the FDA, the NIH, the manufacturer of the study product and their 
representatives, investigators at the site involved with the study, and the IRB. 
 
14. Research Sample Disposition: 
 
Research samples will be drawn from enrolled patients throughout the course of their hospitalization to 
investigate the early immune response and the impact of treatment. In coordination with these studies, 
the development of the adaptive, or immune memory response will be investigated. These samples will 
be drawn in coordination with clinical labs and the blood volume will be limited to 30 ml. These blood 
samples will be processed and studied at the Versiti Blood Research Institute in the labs of Drs. Demin 
Wang, Weiguo Cui, Renren Wen, Lisa Baumann Kreuziger, Zheng Ze, Karin Hoffmeister, and Shawn 
Jobe. Dr. Weiguo Cui as lab investigator will be in overall control of sample security and distribution to 
other investigators named above.  Immunologic and hemostatic assays will be performed on these 
samples in compliance with Medical College of Wisconsin safety guidelines. Research assays will 
include in vitro studies of lymphocyte and antibody development, mediators of the immune response 
particularly circulating cytokines, hemostasis, and platelet function. 
 
Blood samples will be obtained per Table 1 and appendix 2. This will consist of 20ml citrate (blue- 
topped) and 10ml EDTA (purple-topped) tubes. If the collected blood volume is limited by clinical 
condition, sample collection will be limited to 10ml citrate and 10ml EDTA initially, then a 10ml citrate 
tube. Blood samples will be de-identified with only study ID# (refer to section 8), and date/time of 
collection. These samples will be processed at Versiti Blood Research Institute to obtain platelet-poor 
plasma (PPP), platelet-rich plasma (PRP), and enriched platelet and peripheral blood mononuclear 
cell (PBMC) samples. Samples will then be analyzed. Residual de-identified sample will be stored for 
batched analyses at -70C or in liquid nitrogen. 
 
Proposed research activities will take place in the laboratories at the Versiti Blood Research Institute. 
Once collected, samples will be shipped deidentified to the Versiti BRI and received by Dr. 
ui or designee and processed further for research tests as indicated above. Collection, storage, and 
communication of research samples will be conducted in a manner that is compliant with HIPAA 
regulations. 
 

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Refer to appendix 2 for further collection and shipping instructions. 

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15. Data management and monitoring 
 
15.1 Source Documents 
 
The primary source documents for this study will be the subjects’ medical records. If the investigators 
maintain separate research records, both the medical record and the research records will be 
considered the source documents for the purposes of auditing the study. The investigator will retain a 
copy of source documents. The investigator will permit monitoring and auditing of these data, and will 
allow the sponsor, IRB and regulatory authorities access to the original source documents. The 
investigator is responsible for ensuring that the data collected are complete, accurate, and recorded in 
a timely manner. Source documentation (the point of initial recording of information) should support the 
data collected and entered into the study database and must be signed and dated by the person 
recording and/or reviewing the data. All data submitted should be reviewed by the site investigator and 
signed as required with written or electronic signature, as appropriate. Data entered into the study 
database will be collected directly from subjects during study visits or will be abstracted from subjects’ 
medical records. The subjects’ medical records must record their participation in the clinical trial and 
what medications (with doses and frequency) or other medical interventions or treatments were 
administered, as well as any AEs experienced during the trial. 
 
15.2 Data Management Plan 
 
Study data will be collected at the study site(s) and entered into the study database. Data entry is to be 
completed on an ongoing basis during the study. 
 
a. Data Capture Methods 
 
Clinical data will be entered into a RedCAP database which includes password protection and internal 
quality checks to identify data that appear inconsistent, incomplete, or inaccurate. 
 
b. Study Record Retention 
 
The PI is responsible for retaining all essential documents listed in the ICH GCP Guidelines. The FDA 
requires study records to be retained for up to 2 years after marketing approval or disapproval (21 CFR 
312.62), or until at least 2 years have elapsed since the formal discontinuation of clinical development 
of the investigational agent for a specific indication. These records are also to be maintained in 
compliance with IRB/IEC, state, and federal medical records retention requirements, whichever is 
longest. All stored records are to be kept confidential to the extent provided by federal, state, and local 
law. It is the site investigator’s responsibility to retain copies of source documents until receipt of written 
notification to the sponsor. 
 
No study document should be destroyed without prior written agreement between the sponsor and the 
Principal Investigator. Should the investigator wish to assign the study records to another party and/or 
move them to another location, the site investigator must provide written notification of such intent to 
sponsor with the name of the person who will accept responsibility for the transferred records and/or 
their new location. The sponsor must be notified in writing and written permission must be received by 
the site prior to destruction or relocation of research records. 

Protocol: Convalescent plasma for sars-cov-2 infection  
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16. References: 
 
1. 
Casadevall A, Scharff MD: Return to the past: the case for antibody-based therapies in infectious 
diseases. Clin Infect Dis 21:150-61, 1995 
2. 
Roback JD, Guarner J: Convalescent Plasma to Treat COVID-19: Possibilities and Challenges. 
JAMA, 2020 
3. 
Cheng Y, Wong R, Soo YO, et al: Use of convalescent plasma therapy in SARS patients in Hong 
Kong. Eur J Clin Microbiol Infect Dis 24:44-6, 2005 
4. 
Lai ST: Treatment of severe acute respiratory syndrome. Eur J Clin Microbiol Infect Dis 24:583- 
91, 2005 
5. 
Sahr F, Ansumana R, Massaquoi TA, et al: Evaluation of convalescent whole blood for treating 
Ebola Virus Disease in Freetown, Sierra Leone. J Infect 74:302-309, 2017 
6. 
Soo YO, Cheng Y, Wong R, et al: Retrospective comparison of convalescent plasma with 
continuing high-dose methylprednisolone treatment in SARS patients. Clin Microbiol Infect 10:676-8, 2004 
7. 
Mair-Jenkins J, Saavedra-Campos M, Baillie JK, et al: The effectiveness of convalescent plasma 
and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a 
systematic review and exploratory meta-analysis. J Infect Dis 211:80-90, 2015 
8. 
Shen C, Wang Z, Zhao F, et al: Treatment of 5 Critically Ill Patients With COVID-19 With 
Convalescent Plasma. JAMA, 2020 
9. 
Cao B, Wang Y, Wen D, et al: A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe 
Covid-19. N Engl J Med, 2020 
10. 
Casadevall A, Dadachova E, Pirofski LA: Passive antibody therapy for infectious diseases. Nat 
Rev Microbiol 2:695-703, 2004 
11. 
To KK, Tsang OT, Leung WS, et al: Temporal profiles of viral load in posterior oropharyngeal 
saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study. 
Lancet Infect Dis, 2020 
12. 
Zhao J, Yuan Q, Wang H, et al: Antibody responses to SARS-CoV-2 in patients of novel 
coronavirus disease 2019. Clin Infect Dis, 2020 
13. 
Casadevall A, Pirofski LA: Antibody-mediated regulation of cellular immunity and the 
inflammatory response. Trends Immunol 24:474-8, 2003 
14. 
Zhang Y, Xiao M, Zhang S, et al: Coagulopathy and Antiphospholipid Antibodies in Patients with 
Covid-19. N Engl J Med, 2020 
15. 
Zhang T, Sun LX, Feng RE: [Comparison of clinical and pathological features between severe 
acute respiratory syndrome and coronavirus disease 2019]. Zhonghua Jie He He Hu Xi Za Zhi 43:E040, 2020 
16. 
Ferreira FL, Bota DP, Bross A, et al: Serial evaluation of the SOFA score to predict outcome in 
critically ill patients. JAMA 286:1754-8, 2001 
17. 
Vincent JL, Moreno R, Takala J, et al: The SOFA (Sepsis-related Organ Failure Assessment) score 
to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the 
European Society of Intensive Care Medicine. Intensive Care Med 22:707-10, 1996 
18. 
Shelly MP, Nightingale P: ABC of intensive care: respiratory support. BMJ 318:1674-7, 1999

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Protocol: Convalescent plasma for sars-cov-2 infection  
Protocol version 4 dated: 3/10/2021            Page 35 of  38 
 
 
APPENDIX 1: SOFA SCORE 
 
Reference: Vincent JL et al, The SOFA (Sepsis-related Organ Failure Assessment) score to describe 
organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the 
European Society of Intensive Care Medicine. Intensive Care Med. 1996 Jul;22(7):707-10 
 
POINTS ASSIGNED AS BELOW AND ADDED: 
 
 
Variable 
Points 
PaO2/FiO2, mmHg 
≥400 
0 
300-399 
+1 
200-299 
+2 
100-199 and mechanically ventilated 
+3 
<100 and mechanically ventilated 
+4 
Platelets, ×103/µL 
≥150 
0 
100-149 
+1 
50-99 
+2 
20-49 
+3 
<20 
+4 
GLASGOW COMA SCALE 
15 
0 
13–14 
+1 
10–12 
+2 
6–9 
+3 
<6 
+4 
Bilirubin, mg/dL (μmol/L) 
<1.2 (<20) 
0 
1.2–1.9 (20-32) 
+1 
2.0–5.9 (33-101) 
+2 
6.0–11.9 (102-204) 
+3 
≥12.0 (>204) 
+4 

Protocol: Convalescent plasma for sars-cov-2 infection  
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Mean arterial pressure OR administration of vasoactive agents required (listed 
doses are in units of mcg/kg/min) 
No hypotension 
0 
MAP <70 mmHg 
+1 
DOPamine ≤5 or DOBUTamine (any dose) 
+2 
DOPamine >5, EPINEPHrine ≤0.1, or norEPINEPHrine ≤0.1 
+3 
DOPamine >15, EPINEPHrine >0.1, or norEPINEPHrine >0.1 
+4 
Creatinine, mg/dL (μmol/L) (or urine output) 
 
<1.2 (<110) 
0 
1.2–1.9 (110-170) 
+1 
2.0–3.4 (171-299) 
+2 
3.5–4.9 (300-440) or UOP <500 mL/day) 
+3 
≥5.0 (>440) or UOP <200 mL/day 
+4 

Protocol: Convalescent plasma for sars-cov-2 infection  
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APPENDIX 2: Research Blood Sample Collection and Shipping Instructions 
 
Specimen Collection & Handling 
 
 
Peripheral blood collection: 
 
Blood samples will be obtained per Table 1 time points. 
 
Approximately 30ml of whole blood will be collected: 20ml in citrate (blue-topped) and 10ml in EDTA 
(purple-topped) tubes. 
 
If the collected blood volume is limited by clinical condition, sample collection will be limited to 10ml in 
citrate and 10ml in an EDTA tube initially, then 10ml in a citrate tube. 
 
No pre-processing is required. 
 
Specimen Labeling: 
All tubes will be labeled with the study ID# (refer to section 8), and date/time of specimen 
collection. 
 
Transporting and Storage Requirements: 
 
For all transportations, a requisition should accompany all samples. A copy of the requisition will be 
retained at the site. Samples should only be collected Monday thru Friday. Samples should be 
transported to Versiti Blood Research Institute and received by Dr. Cui/designee the same day they 
are collected. Samples should be kept at ambient temperature until transport. The samples will need to 
be transported at ambient temperature. Samples should be packed and transported according to IATA 
regulations. 
Research lab staff are available Monday through Friday between the hours of 7 am and 5 pm. Email 
Dr. Cui’s lab to let them know specimens are being transported. 

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An Open label, Phase 2 Study Evaluating the Efficacy and Safety of High-Titer Anti-SARS-CoV-2 
plasma in hospitalized patients with COVID-19 infection 
 
 
Specimen Requisition Form 
 
 
 
 
Patient Information: 
 
 
Patient Study ID #:   
 
 
 
Peripheral Blood Research Sample Information: 
 
Date of Sample Collection:  
Time of Sample Collection:   
 
 
Time point of collection: 
 
☐ Baseline 
☐ Day 4 
☐ Day 7 
☐ Day 14 
☐ Day 28 
 
 
Person Completing Requisition and Transporting Sample:   
 
 
Phone Number and Email of Person Completing Requisition:   
 
 
Date and Time of Transport of Sample: