A Phase 1, Double-blind, Randomized, Placebo-controlled Study to Evaluate Safety and Pharmacokinetics of Anti-SARS-CoV-2 Immunoglobulin Intravenous (Human) Investigational Product (COVID-HIGIV) Administered as a Single Dose Regimen to Healthy Adults
Phase: PHASE1
Conditions: COVID-19
Sponsor: Emergent BioSolutions

Clinical Study Protocol EBS-CVH-003 
Version 4.0, 21 Apr 2021 
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Confidential and Proprietary 
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EBS-CVH-003 Clinical Study Protocol 
A Phase 1, Double-blind, Randomized, Placebo-controlled Study to Evaluate 
Safety and Pharmacokinetics of Anti-SARS-CoV-2 Immunoglobulin 
Intravenous (Human) Investigational Product (COVID-HIGIV) 
Administered as a Single Dose Regimen to Healthy Adults  
Version 4.0 
21 Apr 2021 
Funding Source:  
The United States Department of Defense 
Study Sponsor: 
Emergent BioSolutions Canada Inc. 
Document History 
Protocol Version 
Date 
1.0 
14.Sep.2020
2.0 
22.Oct.2020
3.0 
03.Feb.2021
4.0 
21.Apr.2021
CONFIDENTIAL 
This document is a confidential communication of the Sponsor.  Acceptance of this 
document constitutes an agreement by the recipient that no unpublished information 
contained within will be published or disclosed without prior written approval, except that 
this document may be disclosed to the appropriate Ethics Committee and Regulatory 
Authority under the condition that they keep it confidential. 
  Version: 4.0
Effective Date: 21 Apr 2021
NCT04661839

Clinical Study Protocol EBS-CVH-003 
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Page 2 of 76 
 
 
 
 
A Phase 1, Double-blind, Randomized, Placebo-controlled Study to 
Evaluate Safety and Pharmacokinetics of Anti-SARS-CoV-2 
Immunoglobulin Intravenous (Human) Investigational Product (COVID-
HIGIV) Administered as a Single Dose Regimen to Healthy Adults  
EBS-CVH-003 
Version 4.0 
21 Apr 2021 
Study Sponsor: 
Emergent BioSolutions Canada Inc. 
(Emergent BioSolutions) 
 
R3T 5Y3, Canada 
 
Sponsor’s Clinical Study Scientist: 
 
 
  
 
 
Sponsor’s Study Medical Monitor: 
 
 
  
 
Immediately Reportable Adverse Events: 
 
 
 
            
  
 
 
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Signatory Page 
 
EBS-CVH-003, Version 4.0: 
A Phase 1, Double-blind, Randomized, 
Placebo-controlled Study to Evaluate Safety 
and Pharmacokinetics of Anti-SARS-CoV-2 
Immunoglobulin Intravenous (Human) 
Investigational Product (COVID-HIGIV) 
Administered as a Single Dose Regimen to 
Healthy Adults  
 
Clinical Site: 
Icahn School of Medicine at Mount Sinai 
 New York, NY 10029, 
United States 
 
My signature below verifies that I have read and agree to this protocol.  I am aware of my 
responsibilities as an Investigator under the GCP guidelines of ICH, the Declaration of 
Helsinki, local regulations (as applicable) and the study protocol, and I agree to conduct the 
study according to these regulations. 
 
Site Principal 
Investigator: 
 
 
 
 
Principal Investigator Name (print) 
Title (print) 
 
 
 
 
 
 
 
Principal Investigator Signature 
 Date (DD/MMM/YYYY) 
 
 
Sponsor Signatory: 
 
 
 
Emergent 
BioSolutions 
 
 
 
Date (DD/MMM/YYYY) 
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EBS-CVH-003 Protocol Synopsis 
 
Title 
A Phase 1, Double-blind, Randomized, Placebo-controlled Study to 
Evaluate Safety and Pharmacokinetics of Anti-SARS-CoV-2 
Immunoglobulin Intravenous (Human) Investigational Product (COVID-
HIGIV) Administered as a Single Dose Regimen to Healthy Adults  
Sponsor 
Emergent BioSolutions Canada Inc. (Emergent BioSolutions) 
 
R3T 5Y3, Canada 
Funding Source The United States Department of Defense 
Study Start 
Q4 2020 
Objectives 
The objectives of the study are to assess safety and pharmacokinetics (PK) 
of several dose levels of COVID-HIGIV in healthy adults. 
Primary Objectives:  
• To evaluate safety of three dose levels of COVID-HIGIV 
administered IV as a single dose to healthy adults. 
• To evaluate PK of three dose levels of COVID-HIGIV 
administered IV as a single dose to healthy adults. 
Endpoints 
Primary Endpoints 
The following primary safety endpoints will be evaluated:  
• Adverse events (AEs) within 72 hours post-dosing. 
• AEs leading to discontinuation or temporary suspension of infusion. 
• AEs and serious adverse events (SAEs) in healthy adults up to 84 days 
post-administration of a single dose. 
The following primary COVID-HIGIV PK endpoints (based on PK sample 
test results by an immunobinding IgG assay and a pseudovirus 
neutralization assay) will be evaluated in healthy adults: 
• AUC0-last: area under the concentration-time curve from time 0 to the 
last quantifiable concentration after dosing. 
• AUC0-inf: AUC0-last plus the additional area extrapolated to infinity after 
dosing 
• AUC0-14d after dosing. 
• AUC0-28d after dosing. 
• Cmax: maximum observed concentration after dosing. 
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• Tmax: time at which Cmax occurs after dosing. 
• Cmin28d: observed or estimated concentration at 28 days after dosing 
• λz: terminal elimination rate constant after dosing. 
• T1/2: apparent terminal elimination half-life after dosing. 
• CL: systemic clearance after dosing. 
• VZ: volume of distribution after dosing. 
Secondary PK Endpoints: following body weight normalized PK 
parameters will be estimated as PK parameter divided by subject body 
weight (kg) at baseline. 
• CmaxBWN: Body weight normalized Cmax  
• Cmin28dBWN: Body weight normalized Cmin28d 
• AUC0-14dBWN: Body weight normalized AUC0-14d 
• AUC0-28dBWN: Body weight normalized AUC0-28d 
• AUC0-lastBWN: Body weight normalized AUC0-last 
• AUC0-infBWN: Body weight normalized AUC0-inf 
 
Subject 
Population 
Healthy adult (18-60 years of age) non-pregnant females and males, with 
no evidence of prior exposure to SARS-CoV-2 (negative RT-PCR result 
for SARS-CoV-2 RNA and negative SARS-CoV-2 antibody test result) at 
Screening. 
Sample Size 
28 subjects  
Number of 
Study Sites 
One site in US:  
Icahn School of Medicine at Mount Sinai 
 New York, NY 10029, United States 
Test Product 
COVID-HIGIV is a purified liquid immunoglobulin G (IgG) preparation 
containing antibodies (including neutralizing antibodies) to SARS-CoV-2. 
COVID-HIGIV is intended for IV administration only. COVID-HIGIV 
product contains a target of 100 mg/mL protein and is formulated with 250 
mM proline and polysorbate 80 (0.03% w/w).  
Reference 
Product 
The reference product will be a placebo control consisting of normal saline 
(0.9% w/v sodium chloride) liquid solution suitable for IV administration. 
Placebo dose will be prepared to match the volume of COVID-HIGIV 
dose. 
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Dosage 
Three dose levels of COVID-HIGIV are planned for the study:  
• Dosage 1: 100 mg/kg (≈1 mL/kg), with a maximum of 100 mL for 
≥100 kg body weight  
• Dosage 2: 200 mg/kg (≈2 mL/kg), with a maximum of 200 mL for 
≥100 kg body weight  
• Dosage 3: 400 mg/kg (≈4 mL/kg), with a maximum of 400 mL for 
≥100 kg body weight  
Protocol Design 
This study will be a Phase 1, single-center, double-blind, randomized, 
placebo-controlled design to evaluate three dose levels of COVID-HIGIV 
for safety and PK in healthy adults. Healthy adult subjects will be enrolled 
into the study to receive a single dose.   
Study Arm 
No. of Subjects 
Dosing Schedule – Day 1 
1 
8 
COVID-HIGIV dosage 1* 
2 
8 
COVID-HIGIV dosage 2** 
3 
8 
COVID-HIGIV dosage 3*** 
4 
4 
Placebo (saline) 
* 100 mg/kg (≈1 mL/kg), with a maximum of 100 mL COVID-HIGIV for ≥100 kg body weight. 
** 200 mg/kg (≈2 mL/kg), with a maximum of 200 mL COVID-HIGIV for ≥100 kg body weight. 
*** 400 mg/kg (≈4 mL/kg), with a maximum of 400 mL COVID-HIGIV for ≥100 kg body weight. 
 
Twenty-eight subjects will be enrolled and randomized 2:2:2:1 into four 
study arms to receive a single intravenous (IV) dose of one of three 
COVID-HIGIV dose levels (1-3) or saline placebo (4), respectively (see 
the table above). 
The enrollment/dosing of the first seven subjects (randomized 2:2:2:1) in 
the study) will be staggered wherein no more than three subjects will be 
dosed on the same day (to be dosed at least one hour apart). Principal 
Investigator (PI) and the Sponsor’s Medical Monitor (MM) will review 
blinded data (up to 24 hours after end of IV infusion) before proceeding 
with dosing subsequent set of remaining subjects for the stagger. Available 
safety (blinded) data will be reviewed by Study Monitoring Committee 
(SMC) (consisting of at least three independent external members) after 
seven subjects have completed at least 72 hours of safety follow-up. If 
unblinding of the safety data is required, closed session by the SMC will 
be held. An overall decision by the SMC will be made whether or not to 
proceed with full randomization (2:2:2:1) and dosing of the remaining 
study subjects (n=21). 
Following dosing, each subject will stay overnight in the inpatient unit for 
close observation; each dosed subject will be discharged from the inpatient 
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unit once all assessments at 24 hours post-dosing timepoint (i.e., Day 2) 
are completed.  
The SMC will perform overall ongoing review of safety data during the 
study. Study enrollment and administration of study treatments may be 
temporarily paused by the SMC for safety review if any of the following 
occur after study product administration and during the study’s follow-up 
period: 
• One or more serious adverse event(s) [SAE(s)].  
• Three or more of the same adverse events (AEs) classified as 
grade 3 severity. 
• Five or more of the same AEs classified as grade 2 severity. 
Note: refer to Section 8.2 for AE severity grading. 
Placebo recipients may be unblinded upon request after all subjects have 
completed Day 29 to allow them to follow current COVID-19 vaccination 
guidelines.   
Subjects will be followed up for safety and PK up to 84 days post-
administration of a single dose.  
If any subjects become positive for SARS-CoV-2 during the study follow-
up period, they will be assessed using modified WHO ordinal score (see 
Appendix I – Modified WHO Ordinal Scale) until they compete their last 
follow-up visit (via telemedicine).  
Inclusion 
Criteria 
The following criteria will be used for inclusion into the study: 
1. 
Able and willing to provide written informed consent 
(voluntarily signed by the subject) prior to performing study 
procedures. 
2. 
Females and males 18-60 years of age, inclusive.  
3. 
Have a body mass index (BMI) less than or equal to 35.0 
kg/m2. 
4. 
Women who are either: 
A) Not of childbearing potential: either surgically sterile (at 
least six weeks post bilateral tubal ligation, bilateral 
oophorectomy or hysterectomy); or post-menopausal 
(defined as ≥50 years of age with a history of ≥12 months 
without menses prior to randomization in the absence of 
other pathologic or physiologic causes, following cessation 
of exogenous sex-hormonal treatment); OR   
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B) Women of childbearing potential (WOCBP) who are not 
planning to be pregnant during the study period and meet all 
of the following criteria: 
Negative PT prior to randomization/dosing at Day 1; and 
Use of a highly effective contraception during the study 
period: 
• Hormonal contraceptives (e.g., implants, pills, patches) 
initiated ≥30 days prior to Day 1; or 
• Intrauterine device (IUD) inserted ≥30 days prior to Day 
1; or 
• Double barrier type of birth control (e.g., male condom 
with female diaphragm, male condom with cervical 
cap). 
5. 
Subject understands and agrees to comply with planned study 
procedures. 
6. 
Healthy as determined by the Principal Investigator based on 
medical history, physical exam, vital signs, urinalysis, blood 
chemistry and hematology test results at Screening and 
evidence of no prior exposure to SARS-CoV-2 (i.e., RT-PCR 
negative for SARS-CoV-2 and negative for SARS-CoV-2 
antibodies) at Screening. 
Exclusion 
Criteria 
The following criteria will be used for study exclusion: 
1. 
Use of any investigational product, within 30 days prior to 
Screening, or use of any SARS-CoV-2 vaccines or monoclonal 
antibodies, or COVID-19 convalescent plasma at any time prior 
to Screening or during the study follow-up period, or subject 
plans to participate in another clinical study during the study 
period.   
2. 
Screening clinical laboratory test result greater than the 
laboratory's upper limit of normal (ULN) for alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), 
random glucose, total and/or bilirubin, blood urea nitrogen 
(BUN), or creatinine. Other serum chemistry parameters that 
are not within the reference range will not be considered 
exclusionary unless deemed clinically significant by the 
Principal Investigator. 
3. 
History of allergy or hypersensitivity to blood or plasma 
products or to COVID-HIGIV excipients (proline, PS80). 
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4. 
History of allergy to latex or rubber. 
5. 
History of hemolytic anemia. 
6. 
History of IgA deficiency. 
7. 
Receipt of any blood product within the past 12 months. 
8. 
Plasma donation within 7 days or significant blood loss or 
blood donation within 56 days of randomization/dosing. 
9. 
History of known congenital or acquired immunodeficiency or 
receipt of immunosuppressive therapy (e.g., prednisone or 
equivalent for more than two consecutive weeks within the past 
three months). 
10. History of thrombosis or hypercoagulable state with increased 
risk of thrombosis. 
11. History of clinically significant chronic illness (e.g., requiring 
hospitalization in the past three months) such as cardiac, 
pulmonary, renal, hepatic or other chronic conditions. 
12. Receipt of a live vaccine within 28 days prior to screening or 
anticipated receipt of a live vaccine during the study period. 
13. Currently pregnant, breastfeeding, or planning to become 
pregnant during the study. 
14. History of, or suspected substance abuse problem (including 
alcohol). 
15. Other medical condition which may place subject at increased 
risk due to participation in the study as determined by the 
investigator. 
16. Any planned elective surgery or procedure during the follow-up 
period that impacts study compliance. 
17. An opinion of the investigator that it would be unwise to allow 
the individual to be randomized into the study. 
Visits and 
Assessments 
For a tabular summary of visits/assessments refer to Table 1 at the end of 
the synopsis. 
Screening: in-clinic visit; within seven days prior to randomization. 
• Informed consent. 
• Eligibility assessment. 
• Demography (age, gender, race/ethnicity, height, body weight, BMI).  
• NP swab sample for SARS-CoV-2 point-of-care RT-PCR test. 
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• Medical history and ongoing medications. 
• Complete physical exam (to include assessment of general appearance, 
and the following body systems: head/eyes/ears/nose/throat, 
respiratory, cardiovascular, gastrointestinal, dermatological, 
lymphatic/hematological, musculoskeletal, neurological, 
metabolic/endocrine). 
• For WOCBP: instruct on use of contraception from the time of 
Screening through end of study (up to Day 85. 
• Vital signs including body temperature, blood pressure (seated), pulse, 
SpO2 (pulse oximetry) and respiratory rate.  
• Safety laboratory assessments: 
• Chem 7 panel [sodium (Na+), potassium (K+), chloride (Cl−), 
bicarbonate (HCO3−), blood urea nitrogen (BUN), creatinine, 
glucose], total and direct bilirubin, alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), lactate dehydrogenase (LDH),  
• Complete blood count (CBC); i.e., red blood cells, white blood 
cells, platelets, hemoglobin, and hematocrit, with differential 
(neutrophils, eosinophils, basophils, monocytes and lymphocytes).  
• Urinalysis. 
• Viral marker testing [Human immunodeficiency virus 1/2 (HIV 1/2) 
antibody, Hepatitis B virus (HBV) surface antigen, Hepatitis C virus 
(HCV) antibody]. 
• Serum PT, if WOCBP. 
• Serum sample for SARS-CoV-2 antibody (IgM, IgG) point-of-care 
rapid test. 
• Provide counselling to subjects on precautions/measures to prevent 
contracting SARS-CoV-2 infection. 
Randomization/Dosing – Day 1: in-clinic visit. 
• If WOCBP, perform urine pregnancy test (UPT). 
• If required, update medical history and ongoing medications. 
• Inquire if the subject has had a suspected or confirmed exposure to 
SARS-CoV-2 in the period of Screening visit to Day 1. 
• Confirm eligibility. 
• Collect NP swab sample for SARS-CoV-2 point-of-care RT-PCR test. 
• Collect pre-dose serum sample (within 4 hours prior to dosing) for 
SARS-CoV-2 antibody level assessment. 
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• Vital signs [body temperature, blood pressure (seated), pulse, SpO2 
(pulse oximetry) and respiratory rate]; within 2 hours prior to dosing. 
• Randomize. 
• Administer randomized study treatment via a single IV infusion. 
• Monitor/assess AEs during the infusion and after the end of infusion 
for the time period the subject is in the clinic (i.e., for at least 24 hours 
after end of the infusion). 
• Concomitant medications. 
• Vital signs [body temperature, blood pressure (seated), pulse, SpO2 
(pulse oximetry) and respiratory rate] at 30 minutes (±5 mins) and 1 
hour (±10 mins) after end of IV infusion. 
• Serum samples for post-dosing assessment of SARS-CoV-2 antibodies 
at 1 hour (±15 mins), 2 hours (±15 mins), 4 hours (±30 mins), 8 hours 
(±1 hour) and 12 hours (±1 hour) after end of IV infusion. 
• Keep the subject in the inpatient unit overnight (i.e., for 24 hours after 
end of IV infusion). 
 
Post-Dosing Assessments (Days 2-85): 
Day 2 – Discharge Day [i.e., 24 hours (±2 hours) after end of IV 
infusion]; in-clinic visit.  
• Assessment of AEs and concomitant medications.   
• Serum sample for SARS-CoV-2 antibody PK assessment. 
• Safety laboratory assessments (chem 7 panel, total and direct bilirubin, 
ALT, AST, LDH, CBC with differential). 
• Urinalysis.  
• Vital signs [body temperature, blood pressure (seated), pulse, SpO2 
(pulse oximetry) and respiratory rate]. 
• Targeted physical exam (if clinically indicated). 
• Assessment of clinical status based on modified WHO ordinal scale. 
Note: perform this assessment ONLY if the subject’s prior RT-PCR 
test (i.e., Day 1) returned as positive. 
• Remind the subjects of precautions/measures to prevent contracting 
SARS-CoV-2 infection. 
• Discharge the subject. 
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Day 4 (3±0.5 days)*, Day 8 (7±1 day)*, Day 15 (14±2 days)*, Day 22 
(21±2 days)*, Day 29 (28±2 days)*, Day 43 (42±3 days)* and Day 57 
(56±3 days)*: visits conducted as in-clinic or telemedicine/home 
healthcare follow-ups. 
* Visits are indicated as calendar days, while the time post-dosing (after 
end of IV infusion) and the visit windows are indicated in the brackets. 
Perform the following in-clinic or via telemedicine follow-up: 
• Assessment of AEs and concomitant medications.   
• Targeted physical exam, if clinically indicated. Based on the 
investigator’s assessment of adverse events/concomitant medication 
during telemedicine follow-up, an unscheduled visit (in-clinic) can be 
arranged to conduct a targeted physical exam. The investigator can also 
refer the subject to their healthcare provider or urgent care if more 
immediate medical attention is required.  
• Assessment of clinical status based on modified WHO ordinal scale 
and COVID-19 symptoms (if reported). Note: perform the assessment 
(via telemedicine) ONLY if the subject became positive at any time 
during the study period (i.e., Day 2 - Day 85). 
• Remind the subjects of precautions/measures to prevent contracting 
SARS-CoV-2 infection. 
In-clinic staff or home healthcare attendant to perform the following: 
• NP swab sample for SARS-CoV-2 point-of-care RT-PCR test. 
• Serum sample for SARS-CoV-2 antibody PK assessment. 
• Blood sample for safety laboratory assessments (chem 7 panel, total 
and direct bilirubin, ALT, AST, LDH, CBC with differential) at Day 4 
only; at other follow-ups, collect sample only if clinically indicated (as 
per investigator’s discretion during in-clinic or telemedicine follow-
up). 
• Sample for urinalysis at Day 4 only; at other follow-ups, collect sample 
only if clinically indicated (as per investigator’s discretion during in-
clinic or telemedicine follow-up).  
• Vital signs [body temperature, blood pressure (seated), pulse, SpO2 
(pulse oximetry) and respiratory rate] at Day 4 only; perform only if 
clinically indicated (as per investigator/sub-investigator’s assessment 
of the subject in-clinic or during the telemedicine follow-up). 
Day 85 (±3 days)*: visit conduced in-clinic or as telemedicine/home 
healthcare follow-up. 
* Visit window is based in relation to Day 1 visit. 
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Perform the following in-clinic or via telemedicine follow-up:  
• Assessment of AEs and concomitant medications.   
• Targeted physical exam, if clinically indicated. Based on the 
investigator’s assessment of adverse events/concomitant medications 
during the telemedicine follow-up, an unscheduled visit (in-clinic) can 
be arranged to conduct a targeted physical exam. The investigator can 
also refer the subject to their healthcare provider or urgent care if more 
immediate medical attention is required. 
• Assessment of clinical status based on modified WHO ordinal scale 
and COVID-19 symptoms (if reported). Note: perform the assessment 
ONLY if the subject became positive at any time post-dosing during 
the study period. 
• Remind the subjects of precautions/measures to prevent contracting 
SARS-CoV-2 infection. 
In-clinic staff or home healthcare attendant to perform the following: 
• NP swab samples for SARS-CoV-2 point-of-care RT-PCR test. 
• Serum sample for SARS-CoV-2 antibody PK assessment. 
• Safety laboratory assessments: 
o Blood sample for Chem 7 panel, total and direct bilirubin, ALT, 
AST, LDH, CBC with differential). Note: collect sample only if 
clinically indicated (as per the investigator’s discretion during in-
clinic or telemedicine follow-up).  
o Sample for urinalysis. Note: collect sample only if clinically 
indicated (as per the investigator’s discretion during in-clinic or 
telemedicine follow-up).  
• Blood sample for viral marker testing (HIV 1/2 antibody, HBV surface 
antigen, HCV antibody). 
• Vital signs [body temperature, blood pressure (seated), pulse, SpO2 
(pulse oximetry) and respiratory rate]. Note: perform only if clinically 
indicated (as per investigator’s discretion during in-clinic or 
telemedicine follow-up). 
• If WOCBP, perform UPT. 
Withdrawal Visit (WV): in-clinic or telemedicine/home healthcare 
follow-up. 
Perform if withdrawal occurs at any time during the follow-up period, but 
outside of scheduled visits / visit windows. 
Perform the following in-clinic or via telemedicine follow-up: 
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• Assessment of AEs and concomitant medications.  
• Targeted physical exam, if clinically indicated. Based on the 
investigator’s assessment of adverse events/concomitant medications 
during telemedicine follow-up, an unscheduled visit (in-clinic) can be 
arranged to conduct a targeted physical exam. The investigator can also 
refer the subject to their healthcare provider or urgent care if immediate 
medical attention is required. 
• Assessment of clinical status based on modified WHO ordinal scale 
and COVID-19 symptoms (if reported). Note: perform the assessments 
(via telemedicine) ONLY if the subject became positive at any time 
post-dosing during the study period. 
• Remind the subjects of precautions/measures to prevent contracting 
SARS-CoV-2 infection. 
In-clinic staff or home healthcare attendant to perform the following: 
• NP swab samples for SARS-CoV-2 point-of-care RT-PCR test. 
• Serum sample for SARS-CoV-2 antibody PK assessment. 
• Safety laboratory assessments: 
o Chem 7 panel, total and direct bilirubin, ALT, AST, LDH, CBC 
with differential) if clinically indicated (as per investigator’s 
discretion during in-clinic or telemedicine follow-up).  
o Urinalysis if clinically indicated (as per investigator’s discretion 
during in-clinic or telemedicine follow-up). 
• Blood sample for viral marker testing (HIV 1/2 antibody, HBV surface 
antigen, HCV antibody). 
• Vital signs [body temperature, blood pressure (seated), pulse, SpO2 
(pulse oximetry) and respiratory rate]. Note: perform vital signs 
assessment only if clinically indicated (as per investigator’s discretion 
during in-clinic or telemedicine follow-up). 
• If WOCBP, perform UPT. 
Unscheduled Visit(s): in-clinic or telemedicine/home healthcare follow-
up. 
Subjects can be evaluated during an unscheduled visit if the investigator 
deems it necessary to further follow-up on subject’s safety. The following 
may be performed at an unscheduled visit at investigator’s discretion: 
Perform the following in-clinic or via telemedicine follow-up: 
• Assessment of AEs and concomitant medications. 
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• Targeted physical exam, if clinically indicated. Based on the 
investigator’s assessment of adverse events/concomitant medications 
during telemedicine follow-up, an unscheduled visit (in-clinic) can be 
arranged to conduct a targeted physical exam. The investigator can also 
refer the subject to their healthcare provider or urgent care if immediate 
medical attention is required. 
•  Assessment of clinical status based on modified WHO ordinal scale 
and COVID-19 symptoms (if reported). Note: perform this assessment 
(via a telemedicine) ONLY if the subject became positive at any time 
post-dosing during the study period. 
• Remind the subjects of precautions/measures to prevent contracting 
SARS-CoV-2 infection. 
In-clinic staff or home healthcare attendant to perform the following: 
• NP swab samples for SARS-CoV-2 point-of-care RT-PCR test.  
• Safety laboratory assessments  
o Blood sample for Chem 7 panel, total and direct bilirubin, ALT, 
AST, LDH, CBC with differential).  
o Sample for urinalysis.  
• Vital signs [body temperature, blood pressure (seated), pulse, SpO2 
(pulse oximetry) and respiratory rate]. 
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Table 1 Schedule of Events  
Assessments 
In-Clinic Visits 
 
In-clinic Visits or Telemedicine/Home Healthcare Follow-ups 
Screening  
(≤7 days prior 
to Day 1) 
Day 
1 
Day 
2 
Day 
4 
Day 
8 
Day 
15 
Day 
22 
Day 
29 
Day 
43 
Day 
57 
Day  
85  
Withdrawal 
Visit (WV) 
Unscheduled 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
X 
X1 
 
 
 
 
 
 
 
 
 
 
 
Demography (age, gender, race/ethnicity, height, body weight, BMI) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history & ongoing medications 
X 
X2 
 
 
 
 
 
 
 
 
 
 
 
Complete physical exam   
X 
 
 
 
 
 
 
 
 
 
 
 
 
Targeted physical exam3 
 
 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
Counselling on measures to prevent SARS-CoV-2 infection 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization and dosing (IV infusion) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Discharge (24±2 hrs after end of IV infusion)  
 
 
X 
 
 
 
 
 
 
 
 
 
 
Vital signs [body temperature, blood pressure (seated), pulse, SpO2 
(pulse oximetry), respiratory rate] 
X 
X4 
X 
X 
X5 
X5 
X5 
X5 
X5 
X5 
X5 
X5 
X 
Safety laboratory tests 
X 
 
X 
X 
X6 
X6 
X6 
X6 
X6 
X6 
X6 
X6 
X 
Urinalysis 
X 
 
X 
X 
X7 
X7 
X7 
X7 
X7 
X7 
X7  
X7  
X 
Urine pregnancy test, if WOCBP 
 
X8 
 
 
 
 
 
 
 
 
X 
X 
 
Viral markers (HBV surface antigen, HCV antibody, HIV 1/2 
antibody) 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
NP sample for SARS-CoV-2 point-of-care RT-PCR 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum sample for SARS-CoV-2 antibody (IgM, IgG) point-of-
care rapid test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serum sample for SARS-CoV-2 antibody PK 
 
X9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse events & concomitant medications 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
COVID-19 symptoms/modified WHO ordinal scale9 
 
 
X10 
X10 
X10 
X10 
X10 
X10 
X10 
X10 
X10 
X10 
X10 
1 Review and confirm eligibility. 
2 If required, update medical history and ongoing medications. 
3 Perform only if clinically indicated. Based on the investigator’s assessments of adverse events/concomitant medications at telemedicine follow-ups, an unscheduled in-clinic visit can be arranged to perform 
targeted PE.  
4 Collect vital signs within 2 hours prior to dosing and at 30±5 mins and 1 hour±10 mins after end of IV infusion. 
5 Perform vital signs assessment at Day 4 only; at other follow-ups perform if clinically indicated. 
6 Perform safety laboratory tests (chem 7 panel, total and direct bilirubin, ALT, AST, LDH, CBC with differential) only if clinically indicated (as per the investigator’s discretion during in-clinic or telemedicine 
follow-up).  
7 Perform urinalysis only if clinically indicated (as per the investigator’s discretion during in-clinic or telemedicine follow-up).  
8 Perform UPT prior to randomization on Day 1.  
9 Collect serum PK samples at pre-dose (within 2 hrs prior to dosing) and post-dose (after end of IV infusion) at 1 hr±15 min, 2 hrs±15 min, 4 hrs±30 min, 8 hrs±1 hr and 12 hrs±1 hour. 
10 Perform (via telemedicine) only if the subject became SARS-CoV-2 positive at any time post-dosing during the study period. 
 
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Table of Contents   
A PHASE 1, DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED 
STUDY TO EVALUATE SAFETY AND PHARMACOKINETICS OF ANTI-
SARS-COV-2 IMMUNOGLOBULIN INTRAVENOUS (HUMAN) 
INVESTIGATIONAL PRODUCT (COVID-HIGIV) ADMINISTERED AS A 
SINGLE DOSE REGIMEN TO HEALTHY ADULTS ..............................................1 
VERSION 4.0 
1 
21 APR 2021 
1 
A PHASE 1, DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED 
STUDY TO EVALUATE SAFETY AND PHARMACOKINETICS OF ANTI-
SARS-COV-2 IMMUNOGLOBULIN INTRAVENOUS (HUMAN) 
INVESTIGATIONAL PRODUCT (COVID-HIGIV) ADMINISTERED AS A 
SINGLE DOSE REGIMEN TO HEALTHY ADULTS ..............................................2 
EBS-CVH-003 
2 
VERSION 4.0 
2 
21 APR 2021 
2 
SIGNATORY PAGE ...............................................................................................................3 
EBS-CVH-003 PROTOCOL SYNOPSIS ..............................................................................4 
TABLE OF CONTENTS ......................................................................................................17 
LIST OF TABLES 20 
LIST OF ABBREVIATIONS ...............................................................................................21 
1 
INTRODUCTION.........................................................................................................24 
1.1 
Background Information ....................................................................................24 
1.1.1 
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and 
Coronavirus Disease 2019 (COVID-19) .............................................................24 
1.2 
Study Drug ............................................................................................................26 
1.2.1 
Anti-SARS-CoV-2 Immunoglobulin Intravenous (Human) – COVID-HIGIV .26 
1.2.2 
COVID-HIGIV as a Therapeutic Intervention for SARS-CoV-2/COVID-19 ...27 
1.3 
Clinical Study Rationale ......................................................................................28 
2 
STUDY HYPOTHESIS, OBJECTIVES AND ENDPOINTS ...................................29 
2.1 
Study Hypothesis ..................................................................................................29 
2.2 
Study Objectives...................................................................................................29 
2.2.1 
Primary Objectives..............................................................................................29 
2.3 
Study Endpoints ...................................................................................................29 
2.3.1 
Primary Endpoints ..............................................................................................29 
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3 
INVESTIGATIONAL PLAN ......................................................................................31 
3.1 
Study Design .........................................................................................................31 
3.2 
Study Center(s).....................................................................................................32 
3.3 
Sample Size ...........................................................................................................32 
3.4 
Randomization .....................................................................................................32 
3.5 
Blinding .................................................................................................................32 
4 
SELECTION OF STUDY SUBJECTS .......................................................................34 
4.1 
Subject Inclusion Criteria ...................................................................................34 
4.2 
Subject Exclusion Criteria ..................................................................................34 
4.3 
Subject Withdrawal .............................................................................................35 
4.3.1 
Subject Withdrawal Criteria ...............................................................................36 
4.3.2 
Subject Replacement ...........................................................................................36 
4.3.3 
Follow-up for Withdrawn Subjects .....................................................................36 
5 
INVESTIGATIONAL PRODUCT INFORMATION ...............................................37 
5.1 
COVID-HIGIV .....................................................................................................37 
5.1.1 
Packaging and Formulation ................................................................................37 
5.1.2 
Labeling ..............................................................................................................37 
5.1.3 
Shipment .............................................................................................................37 
5.1.4 
Storage Conditions ..............................................................................................38 
5.1.5 
Preparation ..........................................................................................................38 
5.1.6 
Administration ....................................................................................................39 
5.1.7 
Drug Accountability............................................................................................39 
5.2 
Description of Reference Treatment, Comparator and/or Placebo ................40 
6 
STUDY PROCEDURES ..............................................................................................41 
6.1 
Screening ...............................................................................................................41 
6.2 
Day 1 – Randomization and Dosing ...................................................................41 
6.3 
Post-Dosing Assessments .....................................................................................42 
6.3.1 
Day 2 – Discharge ...............................................................................................42 
6.3.2 
Days 4, 8, 15, 22, 29, 43 and 57..........................................................................43 
6.3.3 
Day 85 .................................................................................................................44 
6.3.4 
Withdrawal Visit (WV).......................................................................................44 
6.3.5 
Unscheduled Visit(s) ...........................................................................................45 
6.4 
Handling of Samples for PK and SARS-CoV-2 Viral Samples .......................46 
6.5 
Shipment of Samples for PK Testing .................................................................46 
6.6 
Pharmacokinetic Sample Analysis .....................................................................46 
6.7 
Concomitant Medications ...................................................................................46 
7 
ASSESSMENT OF PK .................................................................................................48 
7.1 
PK Parameters .....................................................................................................48 
7.1.1 
Assessment of PK Parameters ............................................................................48 
8 
ASSESSMENT OF SAFETY .......................................................................................49 
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8.1 
Definitions .............................................................................................................49 
8.1.1 
Adverse Event .....................................................................................................49 
8.1.2 
Serious Adverse Event ........................................................................................49 
8.1.3 
Adverse Drug Reaction .......................................................................................50 
8.2 
Assessment of Severity .........................................................................................50 
8.3 
Assessment of Causality ......................................................................................51 
8.4 
Description of Known Adverse Event Profile for COVID-HIGIV .................51 
8.5 
Eliciting Adverse Events......................................................................................51 
8.6 
Requirements for Immediately Reportable Events ..........................................52 
8.6.1 
Principal Investigator's Reporting Requirements ...............................................52 
8.6.2 
Emergent’s Reporting Requirements ..................................................................53 
8.7 
Reporting of Other Information - Unanticipated Problems ............................53 
8.8 
Follow-up of Adverse Events ..............................................................................54 
8.8.1 
Follow-up of Nonserious Adverse Events ..........................................................54 
8.8.2 
Follow-up of Serious Adverse Events ................................................................54 
8.9 
Study Monitoring Committee .............................................................................55 
8.10 
Breaking the Blind for Individual Subjects .......................................................55 
8.11 
Study Safety-Pause Rule......................................................................................55 
9 
STATISTICAL CONSIDERATIONS ........................................................................56 
9.1 
Sample Size Calculation ......................................................................................56 
9.2 
Analysis Sets .........................................................................................................56 
9.3 
Study Endpoints ...................................................................................................56 
9.3.1 
Primary Safety Endpoints ...................................................................................56 
9.3.2 
Primary PK Endpoints ........................................................................................57 
9.4 
Handling of Missing Data ....................................................................................58 
9.5 
Interim Analyses ..................................................................................................58 
9.6 
Planned Method of Analyses ...............................................................................58 
9.6.1 
Subject Disposition, Demographics, Medical History and Study Treatment 
Exposure .............................................................................................................58 
9.6.2 
Safety Analyses ...................................................................................................58 
9.6.3 
PK Analyses ........................................................................................................60 
10 
DATA HANDLING PROCEDURES ..........................................................................61 
10.1 
Recording of Data ................................................................................................61 
10.2 
Data Quality Assurance .......................................................................................61 
10.3 
Record Retention .................................................................................................61 
10.4 
Data Management ................................................................................................62 
10.4.1 Data Collection and Discrepancy Management ..................................................62 
10.4.2 Laboratory Data ..................................................................................................62 
10.5 
File Management at the Investigational Site .....................................................62 
10.6 
Protocol Deviations ..............................................................................................63 
11 
REGULATORY AND ETHICAL ISSUES ................................................................64 
11.1 
Ethical Considerations.........................................................................................64 
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11.2 
Informed Consent ................................................................................................64 
11.3 
Independent Ethics Committee/Institutions Review Board .............................64 
11.4 
Study Files and Materials ....................................................................................65 
12 
ADMINISTRATIVE ASPECTS..................................................................................66 
12.1 
Clinical Study Agreement ...................................................................................66 
12.2 
Documentation Required Prior to Clinical Study Initiation ...........................66 
12.3 
Clinical Study Registration .................................................................................66 
12.4 
Liability and Insurance .......................................................................................66 
12.5 
Subject Identification and Confidentiality ........................................................67 
12.6 
Monitoring ............................................................................................................67 
12.7 
Protocol Amendments .........................................................................................67 
12.8 
Use of Study Data and Publications ...................................................................67 
12.9 
Future Use of Stored Samples .............................................................................67 
13 
REFERENCES ..............................................................................................................68 
APPENDIX I – MODIFIED WHO ORDINAL SCALE ....................................................73 
APPENDIX II – GRADING OF COVID-19 SYMPTOMS ...............................................74 
APPENDIX III – GRADING OF ADVERSE EVENTS ....................................................75 
APPENDIX IV – GRADING OF VITAL SIGNS ...............................................................76 
List of Tables    
Table 1 Schedule of Events......................................................................................................16 
Table 2 Overview of Study Design ..........................................................................................31 
Table 3 Generic AE Grading Scale ..........................................................................................50 
 
 
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List of Abbreviations 
Abbreviation  
Definition 
ACE2 
Angiotensin-converting enzyme 2 
ADE 
Antibody-dependent enhancement  
ADR 
Adverse drug reaction 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AMS 
Aseptic meningitis syndrome 
ANTHRASIL® 
Anthrax immune globulin intravenous (human) 
ARDS 
Acute respiratory distress syndrome  
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration-time curve 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CCP 
COVID-19 convalescent plasma  
CFR 
Code of Federal Regulations 
Cmax 
Maximum serum concentration 
CNJ-016® 
Vaccinia immune globulin intravenous (human) 
COVID-19 
Coronavirus disease 2019 
COVID-HIGIV 
Anti-SARS-CoV-2 Immunoglobulin Intravenous (Human) 
CRF 
Case report form 
CV 
Coefficient of variation 
DMP 
Data management plan 
EC 
Ethics committee 
ECMO 
Extracorporeal membrane oxygenation 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
FDA 
Food and Drug Administration in US 
GCP 
Good clinical practices  
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Abbreviation  
Definition 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HepaGam B® 
Hepatitis B immune globulin (human)  
HIV 
Human immunodeficiency virus 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
ICU 
Intensive care unit 
IEC 
Independent ethics committee 
IgA 
Immunoglobulin A 
IgG 
Immunoglobulin G (gamma globulin) 
IgM 
Immunoglobulin M 
IGIV 
Immunoglobulin intravenous 
IL-1 
Interleukin-1  
IL-6 
Interleukin-6 
IP 
Investigational product 
IPD 
Important protocol deviation 
IRB 
Institutional review board 
IV 
Intravenous route of administration  
LDH 
Lactate dehydrogenase 
LLOQ 
Lower limit of quantitation  
LOD 
Limit of detection 
LOQ 
Limit of quantitation  
mAb 
Monoclonal antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 
MM 
Medical monitor 
NP-028 
Anti-SARS-CoV-2 Immunoglobulin Intravenous (Human) 
OHRP 
Office for Human Research Protection 
PE 
Physical exam 
PEP 
Post-exposure prophylaxis 
PI 
Principal investigator 
PK 
Pharmacokinetics 
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Abbreviation  
Definition 
ppm 
Parts per million 
PS80 
Polysorbate 80 
PSO 
Post symptom onset 
PT 
Pregnancy test 
PT/PTT 
Prothrombin time/partial thromboplastin time 
REB 
Research ethics board 
RNA 
Ribonucleic acid 
RTSM 
Randomization and trial supply management 
RT-qPCR 
Reverse transcriptase quantitative polymerase chain reaction 
RT-PCR 
Reverse transcriptase polymerase chain reaction 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAR 
Serious adverse drug reaction 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SD 
Standard deviation 
SMC 
Study monitoring committee 
SOC 
System organ class 
SUSAR 
Suspected unexpected serious adverse drug reactions 
T½ 
Apparent first order terminal elimination half-life 
Tmax 
Time at which Cmax occurs 
TnBP 
Tri-n-butyl phosphate 
TNF-α 
Tumor necrosis factor alpha 
TRALI 
Transfusion-related acute lung injury  
TX-100 
Triton X-100 (octyl phenylpolyethylene glycol ether) 
UPT 
Urine pregnancy test  
US 
United States of America 
VARIZIG® 
Varicella zoster immune globulin intravenous (human) 
VIGIV 
Vaccinia immune globulin intravenous (human) 
WinRho® SDF 
Rho (D) immune globulin intravenous (human)  
WHO 
World Health Organization 
 
 
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1 
INTRODUCTION  
1.1 
Background Information 
1.1.1 Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and 
Coronavirus Disease 2019 (COVID-19) 
The COVID-19 pandemic caused by SARS-CoV-2 has resulted in significant worldwide 
increase in hospitalizations for pneumonia with multiorgan failure (1). In December 2019, a 
cluster of patients with pneumonia of unknown cause in Wuhan, China was reported and by 
January 2020 the causative agent of the illness was identified; initially termed novel coronavirus 
2019 (2019-nCoV) and later renamed to SARS-CoV-2 (2). Due to the spread of SARS-CoV-2 
resulting in sudden increase in COVID-19 cases throughout the world, a pandemic was declared 
by World Health Organization (WHO) in March 2020. By early September 2020, >26 million 
COVID-19 cases and >864,000 COVID-19 attributed deaths have been reported to the WHO. 
SARS-CoV-2 transmission typically occurs via respiratory droplets from close face-to-face 
contact (within six feet/two meters) and, to a lesser degree, via contaminated surfaces (3). 
Aerosol spread (airborne transmission) may occur (4), but the role of airborne transmission in 
humans remains unclear (5). It is estimated that up to 62% of SARS-CoV-2 transmission may 
occur via pre-symptomatic carriers (3).  
SARS-CoV-2 utilizes its envelope homotrimeric Spike (S) glycoprotein to interact with a cellular 
receptor on human cells termed angiotensin-converting enzyme 2 (ACE2). Binding with ACE2 
triggers a cell membrane fusion cascade leading to viral cellular entry (6), (7). Cell types within 
tissues of nasopharynx, lung, heart, esophagus, kidney, bladder and ileum (i.e., type II alveolar 
cells, myocardial cells, proximal tubule cells of the kidney, ileum and esophagus epithelial cells, 
and bladder urothelial cells) express ACE2, which suggests tissue targets for SARS-CoV-2 
infection (8), (9).  
SARS-CoV-2 viremia starts in the upper respiratory tract, and typically peaks around time of 
symptom onset (4-5 days post-infection); however, viral shedding starts 2-3 days prior to 
symptom onset (10). Pharyngeal viral shedding is high within the first week post-infection at a 
time when symptoms are typically mild (11). Although SARS-CoV-2 RNA can be detected in 
throat swabs for up to six weeks after the onset of symptoms, viral cultures are generally SARS-
CoV-2 negative 8 days after symptom onset (10), (11), (12).  
Humoral immune response is induced during SARS-CoV-2 infection; IgM and IgA antibodies 
are typically detectable 5 days (range: 3-6 days) post symptom onset (PSO), while IgG 
antibodies are detectable 14 days (range: 5-18 days) PSO (13), (14). The IgM response starts to 
decline 25-30 days PSO, while IgA and IgG responses remain stable 40 days (15) and 3 months 
PSO (16), respectively. Neutralizing SARS-CoV-2 antibodies are detectable 10-15 days post 
symptom onset (13) and can persist up to 3 months (16). T-cell responses against SARS-CoV-2 
Spike protein have been characterised and correlated well with IgG and IgA antibody titres in 
COVID-19 patients (17). 
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As previously mentioned, the incubation period for SARS-CoV-2 is approximately 4-5 days 
(range: 2-7 days) (18), (19), and most individuals who develop symptoms (~98%) will do so 
within 11.5 days post-infection (18). COVID-19 has various clinical manifestations, including 
the most commonly reported symptoms of fever, dry cough and dyspnea (shortness of breath); 
other reported symptoms include fatigue, myalgia, nausea/vomiting or diarrhea, headache, 
weakness, rhinorrhea, anosmia, ageusia, hypoxia, pneumonia (20), (21), (22). However, current 
clinical experience with COVID-19 patients indicates hematologic, cardiovascular, renal, 
gastrointestinal and hepatobiliary, endocrinologic, neurologic, ophthalmologic, and dermatologic 
symptoms, which may reflect extrapulmonary dissemination and replication of SARS-CoV-2 
(23). 
Most COVID-19 patients present with mild disease (81%); however, 14% of patients develop 
severe COVID-19 [characterized by hospitalization (median time from symptom onset to 
hospitalization is 7 days; range: 3-9 days), (24), worsening of dyspnea and hypoxia, severe 
pneumonia with >50% lung involvement on imaging], while 5% of patients progress to critical 
COVID-19 [manifested as respiratory failure/acute respiratory distress syndrome (ARDS), septic 
shock and/or multiorgan system dysfunction, which can result in death] (19), (22), (25), (26).  
Mild COVID-19 resolves 5–7 days (and up to 14 days) after symptom onset without requirement 
for special medical interventions. Some infected individuals are asymptomatic after SARS-CoV-
2 infection but are capable of transmitting the virus (27), (28). Approximately 25% of infected 
patients have underlying health conditions; however, 60-90% of hospitalized COVID-19 patients 
have significant comorbidities, including hypertension, obesity, diabetes, cardiovascular disease, 
chronic pulmonary disease, chronic kidney disease, malignancy and chronic liver disease (24), 
(29), (30). Abnormal laboratory values observed in hospitalized patients include lymphopenia 
(83%), elevated inflammatory markers (e.g., C-reactive protein, ferritin, tumor necrosis factor-α 
(TNF-α), interleukins (IL-1, IL-6)] indicative of cytokine storm, and abnormal coagulation 
parameters (e.g., prolonged prothrombin time, thrombocytopenia, elevated D-dimer (46% of 
patients), low fibrinogen) (31), (32), (33). Complications due to COVID-19 other than 
lung/pulmonary abnormalities include impaired function of the heart, brain, liver, kidney and 
coagulation system (23).  
Mortality in hospitalized COVID-19 patients ranges from 15% to 20%; however, up to 40% 
mortality has been observed among patients requiring intensive care unit (ICU) admission (29). 
In addition, hospital mortality ranges from <5% among patients <40 years to 35% for patients 
aged 70-79 years and >60% for patients aged 80-89 years (24). 
Supportive care, including supplemental oxygen and mechanical ventilation, is the main 
treatment for severe/critical COVID-19 patients. However, recent clinical studies indicate that 
dexamethasone decreases mortality (subgroup analysis suggests benefit is limited to patients who 
require supplemental oxygen and who have symptoms for >7 days) and remdesivir improves 
time to recovery (subgroup analysis suggests benefit is limited to patients not receiving 
mechanical ventilation); both are currently recommended for treatment of COVID-19 patients 
(34), (35). Other classes of drugs are being assessed in clinical studies for treatment of COVID-
19 (to either resolve ongoing viremia and/or to manage various COVID-19 manifestations), 
including antivirals (e.g., umifenovir), antibody-based therapies (e.g., COVID-19 convalescent 
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plasma), anti-inflammatory agents (e.g., statins), immunomodulatory therapies (e.g., tocilizumab, 
sarilumab, anakinra, ruxolitinib), anticoagulants [e.g., heparin; albeit, thromboprophylaxis with 
heparin is currently recommended for hospitalized COVID-19 patients (35)] and anti-fibrotics 
(e.g., tyrosine kinase inhibitors). Despite the enormous current efforts into clinical investigations 
of either repurposed drug therapies or development of new products, there are no approved 
therapeutic interventions to prevent SARS-CoV-2 infection or to treat COVID-19. Therefore, 
there still exists an unmet medical need for interventions that would resolve SARS-CoV-2 
infection and improve clinical outcomes in COVID-19 patients. 
1.2 
Study Drug  
1.2.1 Anti-SARS-CoV-2 Immunoglobulin Intravenous (Human) – COVID-HIGIV  
COVID-HIGIV is a hyperimmune product that consists of purified immunoglobulin (IgG) 
fraction of human plasma containing antibodies (including neutralizing antibodies) to SARS-
CoV-2. COVID-HIGIV is prepared from pooled plasma collected at US Food and Drug 
Administration (FDA)-licensed and/or registered plasma and/or blood collection centers from 
healthy, adult donors who have elevated levels of SARS-CoV-2 antibodies.  
The final product is a liquid that contains 85–115 mg/mL protein (target 100 mg/mL) of which at 
least 90% is purified human IgG, stabilized with 250 mM proline and 0.03% polysorbate 80 
(PS80), at target pH 5.8. During the viral inactivation step of the manufacturing process, tri-n-
butyl phosphate (TnBP) and Triton-X-100 (TX-100) are used and may be presented in trace 
amounts in the final product [≤1 parts per million (ppm) for TnBP and ≤5 ppm for TX-100]. 
The potency of the final product is determined by a validated immunoassay that measures 
concentration of binding SARS-CoV-2 antibodies (
 
) in relation to a standard; the final drug product is also characterized by a wild-type 
SARS-CoV-2 neutralization assay (refer to the most current version of the Investigator’s 
Brochure). 
COVID-HIGIV is provided as a sterile liquid for IV administration only. The product is a clear 
to slightly opalescent and colorless or pale-yellow liquid essentially free of foreign particles. 
The active ingredient of COVID-HIGIV is human immunoglobulin (IgG), which is a normal 
constituent of the human body and therefore it is not expected to be toxic to humans. At the 
proposed COVID-HIGIV doses (≤100-400 mg/kg) for this study, exposure levels of excipients 
(proline, PS80) and residuals (TnBP, TX-100) are well below maximum tolerated doses in 
animals; hence, these substances are not expected to pose any clinically significant health risks to 
study subjects (refer to the most current version of the Investigator’s Brochure for more details).  
Emergent BioSolutions is developing COVID-HIGIV for post-exposure prophylaxis following 
SARS-CoV-2 exposure and for treatment of COVID-19. 
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1.2.2 COVID-HIGIV as a Therapeutic Intervention for SARS-CoV-2/COVID-19 
COVID-HIGIV (code name: NP-028) is intended as a passive immunization therapy (i.e., 
passive transfer of antibodies) that would provide suitable levels of SARS-CoV-2 antibodies for 
binding and neutralization of SARS-CoV-2 preventing viral cellular entry and potentially 
augmenting the immune response.  
Although no animal studies have been done to date with COVID-HIGIV, passive transfer of anti-
SARS-CoV-2 antibodies with neutralizing activity [e.g., monoclonal antibodies (mAbs) isolated 
from recovered COVID-19 patients] has been shown to be effective at modulating SARS-CoV-2 
infection and reducing viral load (including in the lung tissue) and disease burden in animals 
after exposure to SARS-CoV-2 (36), (37), (38). In addition, clinical data on passive transfer of 
SARS-CoV-2 antibodies via transfusion of convalescent plasma collected from individuals who 
recovered from COVID-19 (i.e., CCP; which contains binding and neutralizing IgA, IgM and 
IgG antibodies against SARS-CoV-2) to COVID-19 patients suggest that there are no elevated 
safety risks due to CCP transfusion and that there may be a potential clinical benefit in patients 
with severe COVID-19 (39), (40), (41), (42), (43). 
The overall safety profile of COVID-HIGIV is anticipated to be comparable to other 
commercially available human hyperimmune IGIV products, including those hyperimmune IGIV 
products manufactured by Emergent (VARIZIG®, HepaGam B®, ANTHRASIL®, WinRho® 
SDF, CNJ-016®-VIGIV) (44), (45), (46), (47), (48). The most common types of adverse 
reactions to hyperimmune IGIV products are non-anaphylactic infusion reactions, such as back 
or abdominal pain, nausea and vomiting within the first 30 minutes of infusion. Usually there is 
no dyspnea or other clinically significant changes in vital signs. Fever, headache, chills, rash, 
fatigue may begin at the end of the IV infusion and continue for several hours. More severe 
reactions of this type may require treatment with corticosteroids or acetaminophen and persist for 
several hours after the infusion. These may be treated symptomatically. The incidence of adverse 
reactions associated with IV administration of immunoglobulin products is reported by the 
manufacturers to be typically in the range of 1 to 15% (44), (45), (46), (47), (48), (49), (50), (51), 
(52). Infrequent events associated with IV immunoglobulin treatment have also been reported 
(mostly in individuals with risk factors for developing these events), such as hypersensitivity 
reactions, renal failure, aseptic meningitis syndrome (AMS), hemolysis, transfusion-related acute 
lung injury (TRALI) and thrombotic events (53). Potential risk of antibody-dependent 
enhancement (ADE) in COVID-19 patients following treatment with antibody-based therapies 
has not been clinically observed (e.g., in COVID-19 patients after transfusion of convalescent 
COVID-19 plasma); however, COVID-HIGIV recipients will be closely monitored for disease 
worsening throughout the study period. 
Overall, there is currently proof-of-concept efficacy animal data with SARS-CoV-2 passive 
antibody transfer (with SARS-CoV-2 mAbs isolated from recovered COVID-19 patients) and 
some clinical experience with CCP in COVID-19 patients to suggest that an antibody therapeutic 
such as COVID-HIGIV would elevate SARS-CoV-2 neutralizing antibody levels sufficiently to 
impact SARS-CoV-2 viral load and to potentially improve clinical outcomes.  
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1.3 
Clinical Study Rationale 
This study is designed to evaluate safety and PK of three COVID-HIGIV dose levels 
administered IV as a single dose to healthy adults. 
Like other human IGIV products, the hyperimmune products manufactured by Emergent (see 
Section 1.2.2) have been studied in several healthy adult volunteers and clinical studies with 
patients; the safety profile of these hyperimmune products is consistent with other commercial 
IGIV/hyperimmune products and the PK profile is typically similar to PK of licensed 
IGIV/hyperimmune products, with a half-life of approximately 24 to 30 days after IV 
administration. The proposed doses for this clinical study (≤100-400 mg/kg) are within the dose 
levels tested in clinical studies of other licensed IGIV/hyperimmune products and are expected to 
display similar safety and PK profile to those products.  
Results from this clinical study will provide safety information on the intravenously administered 
COVID-HIGIV, as well as PK parameters such as peak COVID-HIGIV plasma levels, trough 
titers of SARS-CoV-2 antibodies and COVID-HIGIV half-life in healthy adults; the safety data 
and PK parameters from this study (along with data available from other ongoing or planned 
clinical studies with COVID-HIGIV) will be used for dose optimization/dose selection for the 
proposed COVID-HIGIV indications (treatment of COVID-19; post-exposure prophylaxis of 
COVID-19). 
 
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2 
STUDY HYPOTHESIS, OBJECTIVES AND ENDPOINTS 
2.1 
Study Hypothesis 
No statistically-powered hypothesis is tested in this Phase 1 study. 
2.2 
Study Objectives 
2.2.1 Primary Objectives 
The following primary objectives will be evaluated:  
• To evaluate PK of three dose levels of COVID-HIGIV administered IV as a single dose 
to healthy adults.  
• To evaluate safety of three dose levels of COVID-HIGIV administered as a single dose to 
healthy adults. 
2.3 
Study Endpoints 
2.3.1 Primary Endpoints 
The following primary safety endpoints will be evaluated:  
• AEs within 72 hours post-dosing. 
• AEs leading to discontinuation or temporary suspension of infusion. 
• AEs and SAEs in healthy adults up to 84 days post- administration of a single COVID-
HIGIV dose. 
The following primary PK endpoints (based on PK sample test results of an immunobinding IgG 
assay and a pseudovirus neutralization assay) will be evaluated in healthy adults: 
• Primary PK Endpoints (at each of the three COVID-HIGIV dose levels): 
o AUC0-last: area under the concentration-time curve from time 0 to the last quantifiable 
concentration after dosing. 
o AUC0-inf: AUC0-last plus the additional area extrapolated to infinity after dosing. 
o AUC0-14d after dosing. 
o AUC0-28d after dosing. 
o Cmax: maximum observed concentration after dosing. 
o Tmax: time at which Cmax occurs after dosing. 
o Cmin28d: observed or estimated concentration at 28 days after dosing. 
o λz: terminal elimination rate constant after dosing. 
o T1/2: apparent terminal elimination half-life after dosing. 
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o CL: systemic clearance after dosing. 
o VZ: volume of distribution after dosing. 
Secondary PK Endpoints: following body weight normalized PK parameters will be estimated 
as PK parameter divided by subject body weight (kg) at baseline. 
o CmaxBWN: Body weight normalized Cmax  
o Cmin28dBWN: Body weight normalized Cmin28d 
o AUC0-14dBWN: Body weight normalized AUC0-14d 
o AUC0-28dBWN: Body weight normalized AUC0-28d 
o AUC0-lastBWN: Body weight normalized AUC0-last 
o AUC0-infBWN: Body weight normalized AUC0-inf 
 
 
 
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3 
INVESTIGATIONAL PLAN 
3.1 
Study Design 
This study will be a Phase 1, single-center, randomized, double-blind, placebo-controlled design 
to assess safety and PK of COVID-HIGIV in healthy adults.  
Healthy adult subjects are planned to be enrolled and randomized to receive a single dose; see 
Table 2 below.  
Eligible subjects will be randomized 2:2:2:1 to four study treatment arms to receive a single IV 
infusion of one of three COVID-HIGIV dose levels (1-3) or saline placebo (4), respectively. 
Table 2 Overview of Study Design 
Study Arm 
No. of Subjects 
Dosing Schedule – Day 1 Visit 
1 
8 
COVID-HIGIV dosage 1* 
2 
8 
COVID-HIGIV dosage 2** 
3 
8 
COVID-HIGIV dosage 3*** 
4 
4 
Placebo (saline) 
* 100 mg/kg (≈1 mL/kg), with a maximum of 100 mL COVID-HIGIV for ≥100 kg body weight. 
** 200 mg/kg (≈2 mL/kg), with a maximum of 200 mL COVID-HIGIV for ≥100 kg body weight. 
*** 400 mg/kg (≈4 mL/kg), with a maximum of 400 mL COVID-HIGIV for ≥100 kg body weight. 
 
Following randomization and dosing on Day 1, subjects will be kept in the inpatient unit and will 
be discharged the following day (Day 2 visit). Subjects will be followed for safety and PK up to 
84 days (up to Day 85 visit) post-dosing. 
Overall study duration for subjects will be up to 91 days (seven days of screening period and 84 
days of follow-up post-randomization).  
The enrollment/dosing of the first seven subjects (2:2:2:1 randomization) in the study will be 
staggered, wherein no more than three subjects will be dosed on the same day (dosing at least 1 
hour apart). Principal Investigator (PI) and the Sponsor’s Medical Monitor (MM) will review 
blinded data (up to 24 hours after end of IV infusion) before proceeding with dosing subsequent 
set of staggered subjects. Available safety (blinded) data will be reviewed by Study Monitoring 
Committee (SMC) (consisting of at least three independent external medical monitors) after 
seven subjects have completed at least 72 hours of safety follow-up. If unblinding of the safety 
data is required, closed session by the SMC will be held. An overall decision by the SMC will be 
made to proceed with full randomization (2:2:2:1) and dosing of the remaining study subjects 
(n=21). The SMC will perform overall ongoing review of safety data during the study. Study 
enrollment and administration of study treatments may be temporarily paused by the SMC for 
safety review, if required (see Section 8.11 for study safety-pausing rules).  
Subjects who become positive for SARS-CoV-2 at any time post-dosing follow-up period will be 
withdrawn from the study (no further specimen collections), but will be followed up for safety 
only via telemedicine until their originally scheduled last follow-up visit. Subjects who report 
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clinical signs/symptoms of COVID-19 during telephone contact follow-ups will be classified in 
severity by site staff as grade 1-4 (see Appendix II – Grading of COVID-19 Symptoms), while 
overall clinical status of the subjects with COVID-19 will be assessed by the site staff using 
modified WHO ordinal scale as outlined (see Appendix I – Modified WHO Ordinal Scale).  
3.2 
Study Center(s) 
This study will be conducted at a single center in the US. 
3.3 
Sample Size  
There was no formal sample size calculation for this Phase 1 study. However, based on previous 
experience with hyperimmune globulin products manufactured by Emergent (see Section 1.2.2) 
in Phase 1 clinical studies with healthy adults, Emergent deems that the number of subjects 
planned to receive COVID-HIGIV is sufficient to descriptively assess safety and PK of three 
COVID-HIGIV dose levels administered by IV to healthy adults. 
In total, 28 subjects are planned for the study(8 subjects/dose level, and 4 placebo subjects). 
3.4 
Randomization 
Randomization/dosing of the first seven subjects in the study will be staggered; seven subjects 
will be randomized 2:2:2:1 (two subjects at COVID-HIGIV dosage level 1, two subjects at 
COVID-HIGIV dosage level 2, two subjects at COVID-HIGIV dosage 3 and one placebo 
subject). After the SMC review of the safety data from the first seven subjects, and if the 
enrollment is recommended to proceed, the remaining subjects (n=21) will be randomized 
2:2:2:1.  
Randomization list will be generated by a Randomization and Trial Supply Management 
(RTSM) system vendor. The designated individual at the site receiving the randomization codes 
will be unblinded (pharmacist). Details on the randomization procedures will be provided in the 
Pharmacy Manual. 
3.5 
Blinding 
The pharmacy staff assigned to this Phase 1 clinical study will be unblinded to access the 
randomization assignment and prepare the study treatments. All doses of study treatments will be 
prepared in the same total volume in the IV infusion bags; in addition, bag covers will be used to 
mask the bags to maintain the blind.  
There will be designated (subcontracted) unblinded clinical study monitors and an independent 
unblinded Quality Assurance (QA) representative (if needed). In addition, designated personnel 
at the bioanalytical laboratory who will be assigned to perform PK sample testing may indirectly 
become unblinded due to nature of test results; however, measures will be implemented not to 
disseminate bioanalytical laboratory results until required. Other personnel involved in the 
conduct of the clinical study will remain blinded until database lock and final unblinding. 
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Access to information in electronic data capture (EDC) system will be blinded using role-based 
permissions. Randomization group and study treatment dispensing data will be provided to 
Emergent after database lock and unblinding. Dosing data will be reconciled with the 
randomized treatment group for each subject by the unblinded monitor, and any deviations will 
be reported in the Clinical Study Report (CSR).  
Upon request, subjects who received placebo will be informed of their treatment assignment after 
all subjects have completed the Day 29 to follow current COVID-19 vaccine recommendations. 
Placebo recipients will be kept in the study for safety follow-up, but no PK samples will be 
drawn.   
While this is a double-blind study, an unscheduled unblinding may occur at any point after the 
infusion. Details on the reasons for unblinding and the associated unblinding procedures will be 
described in the Pharmacy Manual. In an event of unblinding, Emergent must be notified. 
 
 
 
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4 
SELECTION OF STUDY SUBJECTS 
4.1 
Subject Inclusion Criteria 
Subjects must meet the following inclusion criteria to participate in the study: 
1. 
Able and willing to provide written informed consent (voluntarily signed by the 
subject) prior to performing any study procedures. 
2. 
Females or males, 18-60 years of age, inclusive. 
3. 
Body mass index (BMI) less than or equal to 35.0 kg/m2. 
4. 
Women who are either: 
A) Not of childbearing potential: surgically sterile (at least six weeks post bilateral 
tubal ligation, bilateral oophorectomy or hysterectomy), or post-menopausal 
(defined as ≥50 years of age with a history of ≥12 months without menses prior 
to randomization in the absence of other pathologic or physiologic causes, 
following cessation of exogenous sex-hormonal treatment); OR 
B) Women of childbearing potential (WOCBP) who are not planning to be pregnant 
during the study period and meet all of the following criteria: 
 
Negative pregnancy test prior to randomization/dosing at Day 1; and 
Use of a highly effective contraception during the study period: 
• Hormonal contraceptives (e.g., implants, pills, patches) initiated ≥30 days 
prior to Day 1; or 
• Intrauterine device (IUD) inserted ≥30 days prior to Day 1; or 
• Double barrier type of birth control (e.g., male condom with female 
diaphragm, male condom with cervical cap). 
5. 
Subject understands and agrees to comply with planned study procedures. 
6. 
Healthy as determined by principal investigator based on medical history, physical 
exam, vital signs, urinalysis, blood chemistry and hematology test results at Screening 
and no evidence of prior exposure to SARS-CoV-2 (i.e., RT-PCR negative for SARS-
CoV-2 and negative for SARS-CoV-2 antibodies) at Screening. 
4.2 
Subject Exclusion Criteria 
Subjects who have any of the following exclusion criteria will be excluded from the study: 
1. 
Use of any investigational product within 30 days prior to Screening or use of any 
SARS-CoV-2 vaccines or monoclonal antibodies, or COVID-19 convalescent plasma 
at any time prior to Screening or during study follow-up period, or subject plans to 
participate in another clinical study during the study period.   
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2. 
Screening clinical laboratory test result greater than the laboratory's upper limit of 
normal (ULN) for alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
random glucose, total and/or bilirubin, blood urea nitrogen (BUN), or creatinine. 
Other serum chemistry parameters that are not within the reference range will not be 
considered exclusionary unless deemed clinically significant by the principal 
investigator. 
3. 
History of hypersensitivity to blood or plasma products or to COVID-HIGIV 
excipients (proline, PS80). 
4. 
History of allergy to latex or rubber. 
5. 
History of hemolytic anemia. 
6. 
History of IgA deficiency. 
7. 
Receipt of any blood product within the past 12 months. 
8. 
Plasma donation within 7 days or significant blood loss or blood donation within 56 
days of randomization/dosing. 
9. 
History of known congenital or acquired immunodeficiency or receipt of 
immunosuppressive therapy (e.g., prednisone or equivalent for more than two 
consecutive weeks within the past three months). 
10. History of thrombosis or hypercoagulable state with increased risk of thrombosis. 
11. History of clinically significant chronic illness (e.g., requiring hospitalization in the 
past three months) such as cardiac, pulmonary, renal, hepatic or other chronic 
conditions. 
12. Receipt of a live vaccine within 28 days prior to screening or anticipated receipt of a 
live vaccine during the study period. 
13. Currently pregnant, breastfeeding, or planning to become pregnant during the study. 
14. History of, or suspected substance abuse problem (including alcohol). 
15. Other medical condition which may place subject at increased risk due to 
participation in the study as determined by the investigator. 
16. Any planned elective surgery or procedure during the follow-up period that impacts 
study compliance. 
17. An opinion of the investigator that it would be unwise to allow the individual to be 
randomized into the study. 
4.3 
Subject Withdrawal 
The subjects must be available, without coercion, for all parts of the study. If continued 
participation jeopardizes the subject’s health, the subject should be withdrawn from the study. 
The investigator is encouraged to consult Emergent prior to the withdrawal of any subject, 
except in the event of a medical emergency. The reason for withdrawal of any subject must be 
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clearly documented on the study source documents and the appropriate Electronic Case Report 
Form (eCRF). 
4.3.1 Subject Withdrawal Criteria 
All subjects are free to withdraw from participation in this study at any time, for any reason, 
specified or unspecified, and without penalty or loss of benefits to which the subject is otherwise 
entitled. In addition, subjects may be withdrawn from the study for any of, but not limited to, the 
following reasons: 
• The subject develops an intercurrent illness that prevents completion of the study. 
• The subject becomes positive for SARS-CoV-2 at any time post-dosing. 
• It is the opinion of the principal investigator that it is unwise for the subject to continue in 
the study. 
• The subject is not compliant with the requirements of the study to the satisfaction of the 
investigator and/or sponsor (e.g., non-cooperative, misses appointments, unreported use 
of concomitant medications). 
• The subject is lost to follow-up. 
If a subject is withdrawn from the study, they will not be re-entered into the study for any reason. 
4.3.2 Subject Replacement 
Subjects withdrawn from the study or who withdraw consent after randomization will not be 
replaced. 
4.3.3 Follow-up for Withdrawn Subjects 
Every attempt will be made to ensure that subjects who are withdrawn, or who withdraw from 
the study during the active treatment or follow-up period, will complete all safety and available 
assessments for the Withdrawal Visit (WV) visit as outlined in this protocol; see Table 1 or 
Section 6.3.3  for a list of recommended WV assessments. The investigator should inform the 
subjects that these assessments are for their own safety. 
 
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5 
INVESTIGATIONAL PRODUCT INFORMATION 
5.1 
COVID-HIGIV  
5.1.1 Packaging and Formulation 
COVID-HIGIV is a sterile liquid preparation of purified human immunoglobulin (IgG) fraction 
containing SARS-CoV-2 antibodies. The final product contains 85-115 mg/mL of human plasma 
proteins (target 100 mg/mL), of which at least 90% is human IgG. COVID-HIGIV is formulated 
with 250 mM proline and 0.03% (w/w) PS80 and has a pH between 5.5 and 6.0 (target pH 5.8). 
The final product contains no preservatives. 
The final COVID-HIGIV product will be supplied in 50 mL Type 1 glass vials sealed with 20 
mm siliconized bromobutyl rubber stoppers, aluminum seals, and plastic flip-off caps. The 
extractable volume per vial is 25.0 mL. Each vial is intended for single use. The vials will be 
provided in shelf cartons (4 vials per shelf carton). 
For more information, please refer to the most current version of the Investigator’s Brochure for 
COVID-HIGIV. 
5.1.2 Labeling 
COVID-HIGIV vial and shelf carton labels will include information that will comply with US 
regulations, in the appropriate language(s).  
For dispensing labels for secondary receptacles, refer to Section 5.1.5.  
5.1.3 Shipment  
COVID-HIGIV will be shipped to the site at a temperature of 2-8°C (35-46°F). During shipment, 
the temperature will be monitored to ensure the required temperature conditions are maintained. 
The site pharmacist or designate will be responsible for checking the number of vials and the 
condition of the vials received and entering this information into the drug accountability records, 
reporting the condition to Emergent or designate. The site pharmacist or designate will be 
responsible for assessment of the shipping temperature including upload of temperature data 
from the electronic temperature monitoring device, as well as returning of the shipping container 
and all required documentation to Emergent or designate. Study treatment will be released for 
use by the site only after the data logger results are reviewed and written authorization has been 
issued to the investigator/designate by Emergent. Temperature excursions during shipment must 
be reported to Emergent as per instructions provided in the Pharmacy Manual. 
At the end of the study, or upon request of Emergent, all unused, partially used or empty vials 
will be returned to Emergent or destroyed at the site as directed by Emergent. 
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5.1.4 Storage Conditions 
Once at the site, COVID-HIGIV vials must be stored at 2-8C (35-46F) in a secured area until 
used for dose preparation by the assigned pharmacy staff. The temperature in the storage area 
should be monitored with properly calibrated instruments and recorded on a temperature log. 
Temperature excursions must be reported to Emergent or designate as per instructions provided 
in the Pharmacy Manual. 
For further information, refer to the COVID-HIGIV Investigator’s Brochure and the Pharmacy 
Manual. 
5.1.5 Preparation 
The site must maintain documentation of a clear written formalized procedure for study drug 
preparation activities (including any sample labels and documentation to be completed), and 
documented training and delegation of the activity to appropriate study staff. 
Subject identifier (subject ID number) must be recorded on the labels of the vial(s) used to 
prepare the dose. The unblinded pharmacy staff assigned to this study will prepare COVID-
HIGIV as follows: 
Visually inspect the vials to ensure the product is free from particulate matter and discoloration 
prior to dose preparation and administration. The solution should be clear or slightly opalescent 
and colorless or pale yellow.  Do not use solutions that are cloudy or have particulates.  DO 
NOT SHAKE VIALS; AVOID FOAMING. 
Prepare COVID-HIGIV at the required dosage into an IV infusion bag (note: all doses are to be 
prepared to maximum volume of 400 mL; refer to Pharmacy Manual for details around dose 
preparation). In general, perform the following:  
• Remove the protective caps from the product vials. 
• Wipe the exposed central portion of the rubber stopper with an isopropyl alcohol swab. 
• Withdraw the vial content (note: extractable volume is up to 25.0 mL per vial) into a 
sterile syringe (that can accommodate up to 25.0 mL) using standard aseptic techniques 
and transfer the content into an appropriately sized and labeled IV infusion bag.  
• If multiple transfers of content from COVID-HIGIV vials are needed to prepare the total 
dose in the IV infusion bag, use aseptic techniques to prevent contamination.  
Once punctured, use the vial contents to prepare the infusion bag promptly. COVID-HIGIV 
contains no preservative. Vials are for single use only. Do not reuse or save vial(s) for future 
use.  
Retain used and empty vials for drug accountability as per instructions in the Pharmacy Manual. 
The IV infusion bag for COVID-HIGIV (and placebo) requires that the dispensing label is 
affixed to the bag. The label on the IV infusion bag will capture at a minimum: subject ID, 
expiry date of the prepared dose (i.e., <24 hours after dose preparation), the investigator’s name, 
protocol code (EBS-CVH-003) and caution statement “For investigational use only”. The IV 
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infusion bag will require a cover to maintain the blind. Protective coverings for the IV infusion 
bags will be provided by Emergent as part of the study materials.   
Record date of the infusion, start/stop times and the total volume infused. For further details, 
refer to the Pharmacy Manual. 
5.1.6 Administration 
Ensure the recipient is adequately hydrated prior to initiation of IV infusion. 
Administer COVID-HIGIV by IV infusion through a dedicated IV line using a constant infusion 
pump (e.g., IVAC® pump or equivalent). 
Administer COVID-HIGIV within 24 hours of preparation into an IV infusion bag.  
Set the starting infusion rate at 1.0 mL/min for the first 30 minutes. If the infusion is well 
tolerated, double the infusion rate to 2.0 mL/min for the next 30 minutes, and if tolerated, double 
the rate to 4.0 mL/min (maximum rate) which should be used for the remainder of the infusion.  
For example, at the recommended infusion rates above (with no interruptions or reduction in the 
infusion rates), dose volume of 400 mL should be infused within 2.5 hours. 
Monitor subjects closely during infusion and within 24 hours after completion of COVID-HIGIV 
infusion. 
If AEs occur during the IV infusion, such as grade 1 (mild) events of flushing, headache, chills, 
fatigue, nausea, slight changes in pulse rate or blood pressure, slow the rate of infusion or 
temporarily stop the infusion until symptoms subside (at discretion of the investigator). Once the 
AEs resolve, resume the infusion at a rate that is comfortable to the subject (e.g., start the 
infusion at half of the last tolerated infusion rate and increase gradually). If the recipient 
experiences grade 2 (moderate) or higher AEs such as chest pain, difficulty breathing, vomiting, 
arthralgia, or severe headache, unresponsive to slowing the infusion rate or stopping of the 
infusion, do not resume the infusion.  
Stop the infusion if serious AEs develop (e.g., anaphylaxis, severe hypersensitivity reactions) 
and administer appropriate medical management. Do not restart the infusion. 
5.1.7 Drug Accountability 
The investigator is responsible for maintaining accurate inventory records of COVID-HIGIV.  
The pharmacist or pharmacy staff designate will inventory all COVID-HIGIV shipments upon 
receipt, acknowledge possession by signing all required documentation, and returning these to 
the sponsor. The investigator must ensure that all drug supplies are kept in a secure location in 
the site pharmacy in accordance with recommended storage conditions. A site pharmacist 
(unblinded) or a designated individual (unblinded) not involved in study treatment 
administration/study assessments will maintain a current inventory and ongoing record of test 
material supplies using the Drug Accountability Form provided by the sponsor.  This inventory 
record for the COVID-HIGIV will include: 
• Protocol name, number and sponsor 
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• Product name and description 
• Study site and investigator name 
• Product lot number and date of manufacture and/or Use-by/Expiry/Re-test date 
• Number of vials dispensed, date and time of dispensing and study subject for whom 
product was dispensed 
• Product balance 
• Name and title of qualified individual dispensing product. 
These records will be reviewed by unblinded representatives contracted out by the sponsor and 
may be reviewed by regulatory agencies. 
5.2 
Description of Reference Treatment, Comparator and/or Placebo  
This study is not using a reference treatment or a comparator; rather a placebo control will be 
used. The intended placebo is a normal saline (0.9% w/v sodium chloride) liquid solution 
suitable for IV administration. In general, placebo will be prepared at the same volume as 
COVID-HIGIV doses, and administration of placebo will be the same as for COVID-HIGIV 
(e.g., IV infusion, starting infusion rates/incremental increases in infusion rates). Refer to the 
Pharmacy Manual for details on the placebo. 
 
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6 
STUDY PROCEDURES 
6.1 
Screening  
Screening period is within seven days prior to Day 1. 
Eligible subjects will first undergo informed consent counselling. Once informed consent has 
been obtained, subjects will undergo a screening visit in the clinic to ascertain their eligibility for 
the study.  
Perform the following screening visit assessments: 
• Informed consent.  
• Eligibility. 
• Collection of demography information (age, gender, race/ethnicity, height, body weight, 
BMI).  
• NP swab sample for SARS-CoV-2 point-of-care RT-PCR test. 
• Medical history and ongoing medications. 
• Complete physical exam (to include assessment of general appearance, and the following 
body systems: head/eyes/ears/nose/throat, respiratory, cardiovascular, gastrointestinal, 
dermatological, lymphatic/hematological, musculoskeletal, neurological, 
metabolic/endocrine). 
• For WOCBP: instruct on use of contraception from the time of Screening through end of 
study period (up to Day 85 visit). 
• Vital signs including body temperature, blood pressure (seated), pulse, SpO2 (pulse 
oximetry) and respiratory rate.  
• Safety laboratory assessments: 
o Chem 7 panel [sodium (Na+), potassium (K+), chloride (Cl−), bicarbonate (HCO3−), 
BUN, creatinine, glucose], total and direct bilirubin, ALT, AST, LDH,  
o CBC (red blood cells, white blood cells, hemoglobin, hematocrit) with differential 
(neutrophils, eosinophils, basophils, monocytes, lymphocytes).  
o Urinalysis. 
• Viral marker testing (HIV 1/2 antibody, HBV surface antigen, HCV antibody). 
• SARS-CoV-2 antibody (IgM, IgG) point-of-care rapid test. 
• Provide counselling to subjects on precautions/measures to prevent contracting SARS-
CoV-2 infection. 
6.2 
Day 1 – Randomization and Dosing  
Perform the following assessments on Day 1: 
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• If WOCBP, perform UPT.  
• If required, update medical history and ongoing medications. 
• Inquire if the subject has had a suspected or confirmed exposure to SARS-CoV-2 in the 
period of Screening visit to Day 1. 
• Confirm eligibility. 
• Vital signs [body temperature, blood pressure (seated), pulse, SpO2 (pulse oximetry) and 
respiratory rate]; within 2 hours prior to dosing. 
• Collect NP swab sample for SARS-CoV-2 point-of-care PCR test. 
• Collect pre-dose serum sample (within 4 hours prior to dosing) for SARS-CoV-2 
antibody PK assessment. 
• Randomize. 
• Administer randomized study treatment via IV infusion. 
• Monitor/assess AEs during the infusion and after the end of infusion for the time period 
the subject is in the clinic (i.e., for at least 24 hours after end of the infusion). 
• Vital signs [body temperature, blood pressure (seated), pulse, SpO2 (pulse oximetry) and 
respiratory rate] at 30 minutes (±5 mins) and 1 hour (±10 mins) after end of IV infusion. 
• Serum samples for PK assessment of SARS-CoV-2 antibodies at 1 hour (±15 mins), 2 
hours (±15 mins), 4 hours (±30 mins), 8 hours (±1 hour) and 12 hours (±1 hour) after end 
of IV infusion. 
• Keep the subject in the inpatient unit overnight (i.e., for 24 hours after end of IV 
infusion). 
• Record any concomitant medications (if applicable).  
6.3 
Post-Dosing Assessments 
6.3.1 Day 2 – Discharge 
Day 2 (in-clinic visit) will occur 24 hours (±2 hours) after end of IV infusion on Day 1. Perform 
the following: 
• Assessment of AEs and concomitant medications.   
• Serum sample for SARS-CoV-2 antibody PK assessment. 
• Safety laboratory assessments (chem 7 panel, total and direct bilirubin, ALT, AST, LDH, 
CBC with differential). 
• Urinalysis.  
• Vital signs [body temperature, blood pressure (seated), pulse, SpO2 (pulse oximetry) and 
respiratory rate]. 
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• Targeted physical exam (if clinically indicated). 
• Assessment of clinical status based on modified WHO ordinal scale. Note: perform this 
assessment ONLY if the subject’s prior RT-PCR test (i.e., Day 1) returned as positive. 
• Remind the subjects of the precautions/measures to prevent SARS-CoV-2 infection.  
• Discharge the subject. 
6.3.2 Days 4, 8, 15, 22, 29, 43 and 57 
Visits are conducted as in-clinic or telemedicine/home healthcare follow-ups. 
Visit windows are as follows (in relation to end of IV infusion):  
Day 4: 3 days±12 hours; Day 8: 7±1 days; Day 15: 14±2 days; Day 22: 21±2 days; Day 29: 28±2 
days; Day 43: 42±3 days; Day 57: 56±3 days. 
Perform the following in-clinic or via telemedicine follow-up: 
• Assessment of AEs and concomitant medications.   
• Targeted physical exam, if clinically indicated. Based on the investigator’s assessment of 
adverse events/concomitant medications during telemedicine follow-up, an unscheduled 
visit (in-clinic) can be arranged to conduct a targeted physical exam. The investigator can 
also refer the subject to their healthcare provider or urgent care if immediate medical 
attention is required. 
• Assessment of clinical status based on modified WHO ordinal scale and COVID-19 
symptoms (if reported). Note: perform the assessments (via a telephone contact) ONLY if 
the subject became positive at any time post-dosing during the study period.  
• Remind the subjects of precautions/measures to prevent contracting SARS-CoV-2 
infection. 
In-clinic staff or home healthcare attendant to perform the following: 
• NP swab sample for SARS-CoV-2 point-of-care RT-PCR test. 
• Serum sample for SARS-CoV-2 antibody PK assessment. 
• Blood sample for safety laboratory assessments (chem 7 panel, total and direct bilirubin, 
ALT, AST, LDH, CBC with differential) at Day 4 only; at other follow-ups, collect 
sample only if clinically indicated (as per investigator’s discretion during in-clinic or 
telemedicine follow-up). 
• Urinalysis at Day 4 only; at other follow-ups, collect sample only if clinically indicated 
(as per investigator’s discretion during in-clinic or telemedicine follow-up).  
• Vital signs [body temperature, blood pressure (seated), pulse, SpO2 (pulse oximetry) and 
respiratory rate]. Note: perform vital signs assessment at Day 4 only; at other visits 
perform if clinically indicated (as per investigator’s discretion during in-clinic or 
telemedicine follow-up). 
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6.3.3 Day 85   
Visit conducted as telemedicine/home healthcare follow-up. 
Visit window for Day 85: 84±3 days (in relation to Day 1 visit). 
Perform the following in-clinic or via telemedicine follow-up: 
• Assessment of AEs and concomitant medications.   
• Targeted physical exam if clinically indicated. Based on the investigator’s assessment of 
adverse events/concomitant medications during telemedicine follow-up, an unscheduled 
visit (in-clinic) can be arranged to conduct a targeted physical exam. The investigator can 
also refer the subject to their healthcare provider or urgent care if immediate medical 
attention is required. 
• Assessment of clinical status based on modified WHO ordinal scale and COVID-19 
symptoms (if reported). Note: perform the assessments (via telemedicine) ONLY if the 
subject became positive at any time post-dosing during the study period. 
• Remind the subjects of precautions/measures to prevent contracting SARS-CoV-2 
infection. 
In-clinic staff or home healthcare attendant to perform the following: 
• NP swab sample for SARS-CoV-2 point-of-care RT-PCR test. 
• Serum sample for SARS-CoV-2 antibody PK assessment. 
• Blood sample for safety laboratory assessments (Chem 7 panel, total and direct bilirubin, 
ALT, AST, LDH, CBC with differential), if clinically indicated (as per investigator’s 
discretion during in-clinic or telemedicine follow-up).  
• Sample for urinalysis, if clinically indicated (as per investigator’s discretion during in-
clinic or telemedicine follow-up). 
• viral marker testing (HIV 1/2 antibody, HBV surface antigen, HCV antibody). 
• Vital signs [body temperature, blood pressure (seated), pulse, SpO2 (pulse oximetry) and 
respiratory rate]. Note: perform vital signs assessment only if clinically indicated (as per 
investigator’s discretion during in-clinic or telemedicine follow-up). 
• If WOCBP, perform UPT. 
6.3.4 Withdrawal Visit (WV)  
Visit can be conducted as in-clinic or telephone/home healthcare follow-up. 
Perform if withdrawal occurs at any time during the follow-up period, but outside of scheduled 
visits / visit windows. 
Perform in-clinic or via telemedicine follow-up: 
• Assessment of AEs and concomitant medications. 
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• Targeted physical exam if clinically indicated. Based on the investigator’s assessment of 
adverse events/concomitant medications during telemedicine follow-up, an unscheduled visit 
(in-clinic) can be arranged to conduct a targeted physical exam. The investigator can also 
refer the subject to their healthcare provider or urgent care if immediate medical attention is 
required. 
• Assessment of clinical status based on modified WHO ordinal scale and COVID-19 
symptoms (if reported). Note: perform the assessments (via telemedicine) ONLY if the 
subject became positive at any time post-dosing during the study period. 
• Remind the subjects of precautions/measures to prevent contracting SARS-CoV-2 infection.  
In-clinic staff or home healthcare attendant to perform the following;  
• NP swab samples for SARS-CoV-2 point-of-care RT-PCR test. 
• Serum sample for SARS-CoV-2 antibody PK assessment. 
• Safety laboratory assessments: 
o Blood sample for Chem 7 panel, total and direct bilirubin, ALT, AST, LDH, CBC with 
differential) if clinically indicated (as per investigator’s discretion during in-clinic or 
telemedicine follow-up).  
o Sample for urinalysis if clinically indicated (as per investigator’s discretion during in-
clinic or telemedicine follow-up). 
• Vital signs [body temperature, blood pressure (seated), pulse, SpO2 (pulse oximetry) and 
respiratory rate]. Note: perform vital signs assessment only if clinically indicated (as per 
investigator’s discretion during in-clinic or telemedicine follow-up). 
• If WOCBP, perform UPT. 
6.3.5 Unscheduled Visit(s)  
Visit is conducted in-clinic or as telephone/home healthcare follow-up. 
Subjects can be evaluated during an unscheduled visit if the investigator deems it necessary to 
further follow-up on subject’s safety. 
Any unscheduled visit(s) must be recorded on the Unscheduled Visit eCRF.  
The following may be performed at an unscheduled visit at investigator’s discretion in-clinic or 
via telemedicine follow-up: 
• Assessment of AEs and concomitant medications.  
• Targeted physical exam. 
• Assessment of clinical status based on modified WHO ordinal scale and COVID-19 
symptoms (if reported). Note: perform the assessments (via telemedicine) ONLY if the 
subject became positive at any time post-dosing during the study period. 
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• Remind the subjects of precautions/measures to prevent contracting SARS-CoV-2 
infection. 
In-clinic staff or home healthcare attendant to perform the following:  
• NP swab samples for SARS-CoV-2 point-of-care RT-PCR test.  
• Blood sample for safety laboratory assessments (chem 7 panel, total and direct bilirubin, 
ALT, AST, LDH, CBC with differential). 
• Sample for urinalysis.  
• Vital signs [body temperature, blood pressure (seated), pulse, SpO2 (pulse oximetry) and 
respiratory rate]. 
Subjects may be referred for emergency medical care (i.e., to emergency room, for 
hospitalization), if clinically indicated. Subjects will inform the site of any emergency medical 
care (either by phone call or at the next in-clinic visit). Any healthcare emergency encounter will 
be documented in the eCRF. 
6.4 
Handling of Samples for PK and SARS-CoV-2 Viral Samples 
For details around sample handling/processing for PK (serum samples) and SARS-CoV-2 testing 
(NP swabs) refer to the Laboratory Manual.  
In general, each sample will be labelled with the following information: 
• Study Protocol Number (EBS-CVH-003) 
• Subject ID 
• Study Visit and nominal time point (e.g., D1, 2h: Day 1 visit, 2 hour sampling time point) 
• Sample Code (e.g., bar code) 
6.5 
Shipment of Samples for PK Testing 
For details on sample shipment of samples for PK testing refer to the Laboratory Manual.  
6.6 
Pharmacokinetic Sample Analysis  
The PK sample testing will be performed using validated immunobinding IgG PK assay and a 
pseudovirus neutralization assay. The primary PK analysis will be based on a validated PK 
immunobinding IgG assay and a pseudovirus neutralization assay test results generated by 
Emergent BioSolutions facility.  
6.7 
Concomitant Medications 
The use of concomitant medication that the investigator considers unnecessary will be 
discouraged. No pre-infusion pre-medication will be permitted. Medications to treat minor 
ailments (headache, nausea, etc.) will be allowed at the discretion of the investigator. Study 
subjects will be questioned about all concomitant medications during in-clinic follow-up visits 
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including all herbal preparations and non-prescription medications that they are receiving. This 
information will be recorded on the appropriate eCRF.  
Concomitant medications taken in relation to adverse events and/or COVID-19 will be noted.  
Elective blood- or plasma-derived products/plasma exchange procedures during the study are not 
allowed. If these are required for medical emergency reasons; the use of these types of 
products/procedures and the reason for such use will be recorded by the investigator (or 
designate) in the eCRF. 
 
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7 
ASSESSMENT OF PK  
7.1 
PK Parameters 
PK parameters of three dose levels of COVID-HIGIV administered IV as a single dose will be 
determined in healthy adults (see Section 9.3.1). The assessments described below will be used 
to derive serum concentrations of SARS-CoV-2 antibodies (by testing PK samples with validated 
immunobinding IgG and pseudovirus neutralization assays) to calculate the PK parameters.   
7.1.1 Assessment of PK Parameters 
For subjects that receive a single IV infusion of one of three COVID-HIGIV dose levels, analysis 
of PK will include PK sample test results (from samples collected by assigned site staff) from 
pre-dose on Day 1 and post-dose timepoints at Day 1, including 1 hour (±15 mins), 2 hours (±15 
mins), 4 hours (±30 mins), 8 hours (±1 hour) and 12 hours (±1 hour) after end of IV infusion. In 
addition, the following post-dose timepoints will be included (brackets indicate time after end of 
IV infusion): Day 2 (24±2 hours), Day 4 (3±0.5 days), Day 8 (7±1 days), Day 15 (14±2 days), 
Day 22 (21±2 days), Day 29 (28±2 days), Day 43 (42±3 days), Day 57 (56±3 days) and Day 85 
(84±3 days).  
 
 
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8 
ASSESSMENT OF SAFETY 
The safety of COVID-HIGIV will be assessed by collection of adverse events (AEs), laboratory 
test results (blood chemistry and hematology, urinalysis), concomitant medications, medical 
history updates, vital signs and physical exam results. 
The occurrence of AEs will be monitored throughout all phases of the study and will cover all 
participating subjects. Any medical history changes that occur after baseline (Day 1) but before 
dosing will be updated as medical history. Capture of AEs starts during IV infusion of study 
treatment and until the end of study period (up to Day 85 visit). Unanticipated problems related 
to study procedure may be collected following enrollment. 
Adverse events are to be elicited by the investigator (or designate) by asking the subject non-
leading questions. The association of the AE to COVID-HIGIV is to be judged by the 
investigator as related or unrelated (see Section 8.3 below). 
8.1 
Definitions 
8.1.1 Adverse Event 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product. 
NOTE: A diagnosis should be preferentially captured as an adverse event term and signs and 
symptoms should be captured only in the absence of a unifying diagnosis. In the event that there 
are multiple diagnoses, then all diagnoses should be captured. The worsening of an existing 
sign, symptom or disease is also considered to be an AE. An abnormal laboratory finding 
deemed by the Principal Investigator as not clinically significant will not be captured as an AE, 
but an abnormal laboratory finding that worsens after dosing with the study drug, from not 
clinically significant to clinically significant, is considered an AE. Surgical procedures are not 
AE’s. They are the action taken to treat a medical condition. Interventions that were planned 
prior to study entry for medical conditions that started prior to study entry but did not worsen 
during the clinical study are not reported as AEs. 
8.1.2 Serious Adverse Event 
Any untoward medical occurrence that at any dose: results in death, is life threatening, requires 
inpatient hospitalization or prolongation of existing hospitalization, results in persistent or 
significant disability/incapacity, or is a congenital anomaly/birth defect. 
Important medical events which may not result in death, be life threatening, or require 
hospitalization may be considered a SAE when, based upon appropriate medical judgment, they 
may jeopardize the patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. 
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NOTE: Death is an outcome and not an event. The condition leading to death is the event. Death 
will be considered an event only when no other information regarding the cause of death is 
available. 
Hospitalization that is planned before inclusion into the study or outpatient treatment without 
overnight hospitalization is not considered a SAE. Hospitalization that occurs during a study for 
social reasons (e.g., transportation difficulties, respite care) is not considered to be SAE. 
8.1.3 Adverse Drug Reaction 
Any noxious and unintended response to a medicinal (investigational) product related to any 
dose. 
8.1.3.1 
Expected Adverse Drug Reaction/Event 
An adverse reaction, the nature or severity of which is consistent with the applicable product 
information (e.g., Investigator’s Brochure for an unapproved investigational product or package 
insert/summary of product characteristics for an approved product). 
8.1.3.2 
Unexpected Adverse Drug Reaction/Events 
An adverse reaction, the nature or severity of which is not consistent with the applicable product 
information (e.g. Investigator’s Brochure for an unapproved investigational product or package 
insert/summary of product characteristics for an approved product).  
8.2 
Assessment of Severity 
All AEs (clinical and laboratory abnormalities) irrespective of relationship to study treatment, 
including those that are not of a serious nature and those that are expected, will be documented 
by the investigators (or designate) in the source documents and appropriately recorded on AE 
eCRF. All AEs will be examined by the investigator or sub-investigator(s) for assessment of AE 
severity using the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events 
(see Appendix III – Grading of Adverse Events). For AEs that are not included in the DAIDS AE 
Grading Table, use the following generic scale is: 
Table 3 Generic AE Grading Scale 
Grade 1  
(mild) 
Mild symptoms causing no or minimal interference with usual social & functional activities 
with intervention not indicated 
Grade 2 
(moderate) 
Moderate symptoms causing greater than minimal interference with usual social & functional 
activities with intervention indicated 
Grade 3 
(severe) 
Severe symptoms causing inability to perform usual social & functional activities with 
intervention or hospitalization indicated 
Grade 4 
(potentially life-
threatening)  
Potentially life-threatening symptoms causing inability to perform basic self-care functions 
with intervention indicated to prevent permanent impairment, persistent disability 
Grade 5 (death) 
Death 
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8.3 
Assessment of Causality  
The Investigator is responsible for the assessment of the causality of an AE. Emergent’s Medical 
Monitor will also assess SAE causality, independent of the Investigator. 
The following guidelines are provided for assessment of causality: 
• Unrelated: No relationship between the investigational product and the reported event. 
• Possibly related: The event follows a reasonable temporal sequence from the time of 
administration of investigational product and/or follows a known response pattern to the 
investigational product but could also have been produced by other factors. 
• Probably related: A reasonable temporal sequence of the event with administration of IP 
exists and, based on the known response to the investigational product, known or 
previously reported adverse reactions to the investigational product or similar products, 
or in the Investigator's (or designee) clinical judgment the association of the event with 
the investigational product seems likely. 
• Definitely related: A clinical event, including laboratory test abnormality, occurring in a 
plausible time relationship to investigational product administration, and which cannot be 
explained by concurrent disease or other drugs or chemicals (e.g., injection site pain, 
anaphylaxis, TRALI). The response to withdrawal of the investigational product 
(DECHALLENGE) should be clinically plausible. The event must be definitive 
pharmacologically or phenomenologically, using a satisfactory RECHALLENGE 
procedure if necessary.  
If the relationship between the AE and the investigational product is determined to be 
“definitely”, “possibly” or “probably,” the event will be considered to be “related” to the 
investigational product. 
8.4 
Description of Known Adverse Event Profile for COVID-HIGIV 
For general description of safety profile for COVID-HIGIV, see Section 1.2.2. For more details, 
refer to the most current version of the Investigator’s Brochure. 
8.5 
Eliciting Adverse Events 
AEs reported spontaneously by the subject and/or in response to an open question from the 
Investigator (or designee) or revealed by observation (e.g., during physical exam or from a 
clinical laboratory test result) will be recorded by the Investigator (or designee) on the AE eCRF 
if they occurred during the study period, regardless of causal association with the investigational 
product. 
All AEs reported from the signing of the ICF until immediately before dosing of investigational 
product on Day 1, will be recorded as signs and symptoms on the Medical History eCRF. 
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Reporting of AEs is required for any new observation presenting during and after investigational 
product dosing or for a deterioration of baseline condition (e.g., increased severity/frequency). 
Occurrence of AEs will be monitored throughout the study and will cover all participating 
subjects. Study subjects will be provided with a 24-hour telephone number to contact study 
personnel in case of an untoward reaction. 
8.6 
Requirements for Immediately Reportable Events  
8.6.1 Principal Investigator's Reporting Requirements 
The investigator will report all SAEs and confirmed pregnancies to Emergent within 24 hours of 
the investigator’s knowledge of occurrence. The PV SAE and pregnancy forms are available 
within the EDC system.  Pharmacovigilance is notified of SAEs and pregnancies through a 
‘trigger’ email which is delivered to 
 
However, safety information may also be provided directly from the site via email to 
  
The details of the SAE report should be completed within three days of the investigator’s 
knowledge of occurrence of the SAE. 
For SAEs, the Serious Adverse Event Report Form will be completed (abbreviated hereafter 
SAE Report Form). The SAE Report Form is NOT the same as the AE eCRF. Subject identifiers 
(e.g., name, address, telephone number, social security number, medical record number, or 
hospital/laboratory number) must be redacted from the source documentation attached to the 
SAE Report Form.  
All SAEs that are unexpected must be reported to the IRB/IEC/REB by the Investigator (or 
designee) as required by ICH GCP E6. 
While pregnancy itself is not considered an AE, pregnancy outcomes of spontaneous 
miscarriage, congenital anomaly, or birth defect are considered to be SAEs and must be reported. 
Elective abortions without complications will not be handled as AEs.  
If a subject becomes pregnant during a study, Emergent will be notified. All pregnancies where 
conception occurred after first exposure to the investigational product through the End of Study 
visit are to be followed to outcome (e.g., delivery, spontaneous/elective/therapeutic abortion), 
including after the study is completed and even if the subject is withdrawn from the study. If a 
pregnancy results in an abnormal outcome that the reporting health care professional considers 
might be due to the investigational product, then the guidelines for expedited reporting of 
serious, unexpected adverse drug reactions should be followed. 
Any pregnancy that occurs during study participation must be reported using a clinical study 
pregnancy forms (“Pregnancy Notification Form” and “Pregnancy Follow-up Form”). To ensure 
subject safety, each pregnancy must be reported to Emergent within 24 hours of learning of its 
occurrence. The pregnancy must be followed up to determine outcome (including premature 
termination) and status of mother and child. Pregnancy complications and elective terminations 
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for medical reasons must be reported as an AE or SAE. Spontaneous abortions must be reported 
as an SAE. 
Any SAE occurring in association with a pregnancy brought to the Investigator’s attention 
during or after the subject has completed the study and considered by the Investigator as possibly 
related to the study treatment, must be promptly reported to Emergent. 
The Investigator is responsible to notify their IRB/IEC/REB according to their policy for SAE or 
pregnancy reporting. 
8.6.2 Emergent’s Reporting Requirements  
Emergent will report suspected unexpected serious adverse drug reactions (SUSARs) to the FDA 
and to the principal investigator in an individual case safety report as soon as possible, no later 
than 15 calendar days after Emergent becomes aware of the SUSAR. 
Unexpected fatal or life-threatening suspected adverse reactions will be reported to the FDA as 
soon as possible but in no case later than seven calendar days after Emergent’s initial receipt of 
the information. 
8.7 
Reporting of Other Information - Unanticipated Problems 
For investigational sites in the United States, as outlined by the Office for Human Research 
Protection (OHRP), unanticipated problems must be reported to the IRB/IEC/REB according to 
the requirements of 45 CFR Part 46. Unanticipated problems are considered to include any 
incident, experience, or outcome that meets ALL the following criteria: 
• Unexpected (in terms of nature, severity, or frequency) given: 
o Procedures that are described in the study-related documents, such as the 
IRB/IEC/REB approved research protocol and informed consent document. 
o The characteristics of the subject population being entered into the study. 
• Related or possibly related to participation in the study which means there is a reasonable 
possibility that the incident, experience, or outcome may have been caused by the sample 
collection. 
• Suggests that the study places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
An incidence, experience, or outcome that meets the three criteria above generally will warrant 
consideration of substantive changes in the study or informed consent process/document or other 
corrective actions in order to protect the safety, welfare, or rights of subjects or others. Only a 
small subset of AEs occurring in human subjects participating in a clinical study will meet these 
three criteria for an unanticipated problem. There are other types of incidents, experiences, and 
outcomes that occur during the conduct of clinical study that represent unanticipated problems 
but are not considered AEs. For example, some unanticipated problems involve social or 
economic harm instead of the physical or psychological harm associated with AEs. In other 
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cases, unanticipated problems place subjects or others at increased risk of harm, but no harm 
occurs. 
The Investigator should promptly notify the IRB when an unanticipated problem involving risks 
to subjects or others is identified. Also, the Investigator should notify the Emergent of 
unanticipated problem(s), as well as to the US Army Medical Research and Development 
Command (USAMRDC) Office of Research Protections (ORP) – Human Research Protection 
Office (HRPO). 
8.8 
Follow-up of Adverse Events 
All AEs/SAEs will be followed until resolution, stabilization, or up to 30 days after the last study 
visit. 
8.8.1 Follow-up of Nonserious Adverse Events 
Nonserious AEs that are identified on the last scheduled visit must be recorded on the AE eCRF 
with the current status noted. All nonserious AEs that are ongoing at this time will be recorded as 
“Not Recovered/Not Resolved” on the AE eCRF. The status of ongoing, previously reported 
AEs will be subject to active follow-up. Subjects will be interviewed at the study visits to 
determine if any previously on-going AEs are resolved. 
8.8.2 Follow-up of Serious Adverse Events 
Confirmed SAEs will be recorded on the AE eCRF.  
The Investigator will provide or arrange appropriate care for subjects for whom SAEs are 
experienced.  
All SAEs will be followed by the Investigator until at least one of the following conditions is 
met:  
• The SAE is resolved or stable if expected to remain chronic. 
• The subject is referred to a specialist or other physician for treatment and follow-up. The 
Principal Investigator (or designee) will follow the subject’s condition even if the subject 
is seen by another physician, to obtain information about the diagnosis and outcome and 
any treatments and medications administered for the event. 
The following will be considered acceptable reasons for discontinuation of follow-up of ongoing 
SAEs: 
• Subject withdraws consent.  
• Subject is referred to appropriate long-term medical care. 
• Subject is considered lost to follow-up. 
It is expected that the investigational site will obtain supporting medical records from 
appropriate physicians and record this information on the SAE Report Form and AE eCRF. The 
site must report SAE to Emergent (study MM and Global PV Department) within 24 hours of 
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knowledge of the SAE and the SAE Report Form must be completed and provided to Emergent’s 
study MM and to Global PV Department within 72 hours 
 
. Additional information received related to any SAE must be 
forwarded within 24 hours of awareness to the Emergent Global PV Department 
  
8.9 
Study Monitoring Committee 
An independent Study Monitoring Committee (SMC) will provide on-going review of safety 
data during the study. The SMC (consisting of at least three independent external members) will 
be responsible for assessing safety and monitoring overall conduct and integrity of the study. In 
fulfilling these responsibilities, the SMC may make recommendations concerning continuation 
and/or pausing/stopping of the study (see Section 8.11) as it relates to safety and risk to the study 
subject population as outlined in the SMC Charter. 
8.10 
Breaking the Blind for Individual Subjects 
While this is a double-blind study, the blind may be broken if a subject’s health or safety is at 
risk and knowledge of the study arm may be beneficial to the medical management of the 
subject. In an event of unblinding, Emergent must be notified. 
If the Investigator determines that knowledge of a subject’s treatment assignment is urgently 
needed in order to guide treatment or ensure the subject’s safety, the Investigator may perform 
emergency unblinding via RTSM system. The Investigator may not delegate this responsibility. 
The Investigator must attempt to notify Emergent’s Medical Monitor prior to unblinding and 
must notify Emergent’s study MM within 24 hours after unblinding at the latest. 
If a subject’s study treatment assignment is unblinded for safety reasons, or if a subject becomes 
accidentally unblinded for any reason, the subject will be requested to remain in the study for 
safety follow-up. Documentation of breaking the blind must be entered in the study subjects’ 
source documents with the following information recorded: (1) date and time the blind was 
broken; (2) the rationale behind the unblinding decision/occurrence; (3) the names of the 
personnel involved; and (4) date of contact with Emergent’s study MM. 
8.11 
Study Safety-Pause Rule 
Study enrollment and administration of study treatments may be temporarily paused by the SMC 
for safety review, if any of the following occur after study treatment administration and during 
the study’s follow-up period: 
• One or more SAE(s).  
• Three or more of the same AEs classified as grade 3 severity. 
• Five or more of the same AEs classified as grade 2 severity. 
These events will be reviewed by the SMC and a recommendation will be made. The procedures 
will be outlined in the SMC Charter.  
 
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9 
STATISTICAL CONSIDERATIONS 
This section is a summary of the planned statistical analyses. The details are described in the 
Statistical Analysis Plan (SAP). 
Subject disposition will be provided for all who sign and date the ICF. 
9.1 
Sample Size Calculation 
There was no formal sample size calculation for this Phase 1 study. However, based on previous 
experience with hyperimmune globulin products manufactured by Emergent (see Section 1.2.2) 
in Phase 1 clinical studies with healthy adults, Emergent deems the number of subjects planned 
to receive study treatments (one of three dose levels of COVID-HIGIV or saline placebo) in the 
study [N=28; n=8 COVID-HIGIV dosage 1; n=8 COVID-HIGIV dosage 2; n=8 COVID-HIGIV 
dosage 3, n=4 placebo] is sufficient to descriptively assess COVID-HIGIV safety and PK of a 
single dose in healthy adults. 
9.2 
Analysis Sets 
The following analysis sets will be evaluated in the study: 
• Safety Set (SS): all randomized subjects who receive any amount of COVID-HIGIV or 
placebo, analyzed according to the actual study treatment arm. 
• PK Set (PKS): all subjects who are randomized and received COVID-HIGIV according 
to the protocol and with evaluable PK data (i.e., no major protocol deviations affecting 
PK sampling and results, adequate number of PK sample test results).  
9.3 
Study Endpoints 
9.3.1 Primary Safety Endpoints 
The following primary safety endpoints will be evaluated:  
• Frequency and severity of AEs within 72 hours post-dosing. 
• AEs leading to discontinuation or temporary suspension of infusion. 
•  AEs and SAEs in healthy adults up to 84 days post-administration of a single dose. 
The primary safety endpoints will be evaluated using the following safety assessments over the 
84-day follow-up period after administration of a single COVID-HIGIV dose: 
• Adverse events. 
• Physical exams (complete and/or targeted physical exams). 
• Safety laboratory tests (chem 7 panel, total and direct bilirubin, ALT, AST, LDH, CBC 
with differential, urinalysis). 
• Vital signs (oral temperature, seated blood pressure, resting heart rate, pulse oximetry and 
respiratory rate). 
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• Concomitant medications. 
9.3.2 Primary PK Endpoints 
The following primary PK endpoints will be evaluated in healthy adults: 
• Primary PK Endpoints (at each of the three COVID-HIGIV dose levels): 
o AUC0-last: area under the concentration-time curve from time 0 to the last 
quantifiable concentration after dosing. 
o AUC0-inf: AUC0-last plus the additional area extrapolated to infinity after dosing.  
o AUC0-14d after dosing. 
o AUC0-28d after dosing. 
o Cmax: maximum observed concentration after dosing. 
o Tmax: time at which Cmax occurs after dosing. 
o Cmin28d: observed or estimated concentration at 28 days after dosing. 
o λz: terminal elimination rate constant after dosing. 
o T1/2: apparent terminal elimination half-life after dosing. 
o CL: systemic clearance after dosing. 
o VZ: volume of distribution after dosing. 
Secondary PK Endpoints: following body weight normalized PK parameters will be estimated 
as PK parameter divided by subject body weight (kg) at baseline. 
o CmaxBWN: Body weight normalized Cmax  
o Cmin28dBWN: Body weight normalized Cmin28d 
o AUC0-14dBWN: Body weight normalized AUC0-14d 
o AUC0-28dBWN: Body weight normalized AUC0-28d 
o AUC0-lastBWN: Body weight normalized AUC0-last 
o AUC0-infBWN: Body weight normalized AUC0-inf 
 
The PK endpoints will be based on serum concentrations of SARS-CoV-2 binding and 
neutralizing antibodies after IV administration of a single COVID-HIGIV dose (up to 84 days 
post-dosing). Serum concentrations of SARS-CoV-2 binding and neutralizing antibodies will be 
measured by validated immunobinding (IgG) and pseudovirus neutralization PK assays and the 
results will be used to calculate the primary PK endpoints.  
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9.4 
Handling of Missing Data 
When calculating summary statistics, including geometric mean and 95% confidence intervals 
(CIs) and PK (SARS-CoV-2 binding and/or neutralizing antibody) concentrations below the 
assay’s limit of quantitation (LOQ) and/or detection (LOD) will be imputed as half of LOQ/LOD 
values. If the lower bounds of the CIs are below lower LOQ (LLOQ), it will be replaced by 
“<LLOQ” in the output. Unless otherwise specified, no imputation will be made for missing data 
and complete data analysis will be used. Missing data due to the COVID-19 pandemic will be 
indicated. 
9.5 
Interim Analyses 
The SMC will perform blinded review of the safety days after the first seven subjects have 
completed at least 72 hours of safety follow-up.  
9.6 
Planned Method of Analyses 
In general, continuous endpoints will be summarized by descriptive statistics including number 
of subjects, mean, standard deviation (SD), median, minimum and maximum. Logarithmic 
transformation will be used when appropriate, coefficient of variation (CV), geometric mean, 
and geometric CV will also be summarized. Categorical endpoints will be summarized by the 
total number of subjects, frequencies and percentages. Unless otherwise specified, CIs are two-
sided with 95% confidence. Non-compartment method will be used for estimating PK 
parameters. 
9.6.1 Subject Disposition, Demographics, Medical History and Study Treatment 
Exposure 
Subject disposition, including early termination reasons, will be summarized by study treatment 
for all subjects. Major protocol deviations will be presented for the safety population. Subject 
demographics, medical history, and study treatment dosing data will be tabulated for the ITT 
population and the safety population. Study disruption due to the COVID-19 pandemic will be 
indicated in the listing of subject disposition. 
9.6.2 Safety Analyses 
All safety analyses will be conducted on the safety population by treatment group.. 
Adverse Events (AE)/Serious Adverse Events (SAE): 
AE will be coded to system organ class (SOC) and preferred term using the Medical Dictionary 
for Regulatory Activities (MedDRA), using the most current version at the time of coding. AEs 
will be defined as events beginning after study treatment administration that were not present 
prior to study treatment administration or those that were present prior to study treatment 
administration and subsequently worsened in severity.  
• AE within 72 hours post-dosing will be summarized by SOC and preferred term. 
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• AEs and SAEs within 84 days post-dosing will be summarized in the same manner as 
described above in the first bullet. 
• Discontinuation or temporary suspension of infusion will be summarized by treatment 
group. 
Clinical Laboratory Test Results: 
Laboratory test results and change from baseline will be summarized by time point and study 
treatment.  The clinical significance of abnormality will be assessed by the Investigator. 
Abnormal laboratory results will be graded with severity grade 1 to 4 (grade 1=mild, through 
grade 4=potentially life-threatening) according to the DAIDS Table for Grading the Severity of 
Adult and Pediatric Adverse Events (see Appendix III). For severity not specifically listed in the 
severity grading criteria, the PI or designee will use the grading criteria for “illness or clinical 
AE” to assign the AE severity grading.  
Values not meeting criteria for severity of at least grade 1 will be considered as grade 0. 
Shift table of abnormality (Low, Normal, High) will be provided for selective laboratory 
parameters by treatment groups and timepoints. 
Shift table of severity grade (0, 1-2, ≥3) will be provided for selective laboratory parameters by 
treatment groups and timepoints. 
Vital Signs: 
Vital signs include the following parameters: oral temperature, seated blood pressure, resting 
heart rate, pulse oximetry and respiratory rate. Vital sign results and change from baseline will 
be summarized by time point and study treatment. 
Abnormal vital sign results will be assessed and assigned a severity grade 1 to 4 (see Appendix 
IV – Grading of Vital Signs). Grade 0 includes all values not meeting criteria for severity of at 
least Grade 1.  
Normality/Abnormality shift from baseline, and severity grade shift from baseline will be 
summarized by treatment group and timepoints in the same manner as for laboratory data. 
Concomitant Medications:  
Concomitant medications will be coded using the WHO Drug Dictionary and displayed by 
treatment group for the safety population. Concomitant medications for COVID-19 treatment 
will be summarized separately, if applicable. 
Clinical Status based on Modified WHO Ordinal Scale:  
For subjects that become SARS-CoV-2 positive during the study period (at any time post-dosing 
on Day 1 and up to last follow-up visit/contact) and report COVID-19 symptoms, maximum 
score on the modified WHO ordinal scale (see Appendix I – Modified WHO Ordinal Scale) will 
be provided, as well as the score at the last follow-up visit/contact. 
 
 
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COVID-19 Symptoms: 
For subjects that become SARS-CoV-2 positive during the study period (at any time post-dosing 
on Day 1 and up to last visit/contact) and report COVID-19 symptoms, the frequencies and 
percentages of subjects reporting COVID-19 symptoms will be presented by treatment arm. A 
summary of COVID-19 symptoms by maximum severity (see Appendix II – Grading of COVID-
19 Symptoms) will be performed, for each symptom and for any symptoms. 
9.6.3 PK Analyses 
PK analysis will be conducted using the results of binding IgG and pseudovirus neutralization 
antibody assays (primary PK analysis) for each dose level of COVID-HIGIV. Binding IgG and 
neutralizing SARS-CoV-2 antibody serum concentrations versus time will be plotted and 
summarized by treatment groups. PK parameters will be estimated using standard non-
compartmental method (i.e., trapezoidal method). Actual times and not nominal times will be 
used in the analysis, and concentrations below the assay’s limit of quantitation (LOQ) and/or 
detection (LOD) will be imputed as half of LOQ/LOD values. Calculated PK parameters will 
include those listed in Section 9.3.1. Subjects with elevated baseline levels of SARS-CoV-2 
antibodies or subjects with inadequate number of PK time-points (e.g., no pre-dose sample, or no 
measurable post-dose samples) may be excluded from the PK analysis. Baseline correction may 
be implemented, if necessary.  
 
 
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10 DATA HANDLING PROCEDURES 
10.1 
Recording of Data 
Per ICH guidelines, study documents will be retained for one of the following periods: 
• A period of at least two years after the date of the last approval of a marketing application 
in an ICH region until there are no pending or contemplated marketing applications; 
• A period of at least two years after Emergent has notified the regulatory authority(ies) 
that clinical investigation with this product is discontinued. 
The Investigator must not dispose of any records relevant to this study without either (1) written 
permission from Emergent or (2) provision of an opportunity for Emergent to collect such 
records. The Investigator will be responsible to maintain adequate and accurate electronic or hard 
copy source documents of all observations and data generated during this study, including any 
data queries received from Emergent or designee. Such documentation is subject to inspection by 
Emergent or its designee(s) and relevant regulatory agencies. If the Investigator withdraws from 
the study (e.g., due to relocation or retirement), all study-related records will be transferred to a 
mutually agreed upon designee within Emergent’s specified timeframe. Notice of such transfer 
will be given to Emergent in writing. 
10.2 
Data Quality Assurance 
Emergent’s Quality Assurance Department (or designee) may conduct investigational site audits 
either on-site or remotely, before study initiation, during the study, or after study completion. 
Audits will include, but are not limited to, review of source documents, verification of eCRFs 
against source documents and review of essential documents to ensure compliance with protocol 
and applicable local and federal regulations. The Investigator agrees to participate in site audits 
and assist in the prompt resolution of any issues found during audits. 
In the event the Investigator is contacted by a regulatory agency in relation to this study, the 
Investigator and investigational site staff must be available to respond to reasonable requests and 
inspection queries made during the inspection process. The Investigator must provide Emergent 
with copies of all correspondence that may affect the review of the current study (e.g., Form 
FDA 483, inspectional observations, warning letters). Emergent will provide any needed 
assistance in responding to regulatory inspections. 
10.3 
Record Retention 
A study document binder will be provided by Emergent for the investigator for all requisite study 
documents (constituting the “Investigator Study File”). 
Following completion of the study, the investigator will retain copies of the approved study 
protocol, ICF, relevant source documents, and all other supporting documentation related to the 
study according to applicable regulatory requirements. 
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The investigator must arrange for the retention of the subject identification codes for at least 25 
years after the completion or discontinuation of the study (Revised Canadian CTA Regulations, 
September 2001). Subject files and other source data must be securely stored and kept for the 
maximum time permitted by the hospital, institution or private practice but not less than 25 years 
after completion or termination of the study. Archival data may be held on microfiche or 
electronic record, provided that a backup exists, and that hard copy can be obtained from it if 
required.  If source documents are to be destroyed as per hospital or local regulatory policy, the 
investigator is requested to contact Emergent. 
Records from the study that identify the subject will be confidential except that they may be 
inspected by Emergent representatives for the study, the IRB/EC, the FDA, other government 
agencies as appropriate, and will not otherwise be released except as required by law. All 
information provided to the investigator by Emergent is to be considered confidential unless 
otherwise stated. 
10.4 
Data Management 
A validated, electronic data capture (EDC) system will be used during the study. Data 
management activities to be performed for the study will be described in detail in the Data 
Management Plan (DMP). 
10.4.1 Data Collection and Discrepancy Management 
The study will employ eCRFs provided by Emergent. Certain clinical information requested in 
this protocol will be recorded on these eCRFs. The Investigator is responsible for the adequacy 
and accuracy of all data entered on the eCRFs. The Investigator is also responsible for signing all 
eCRFs, after which they will be locked by Emergent to prevent further data entry or 
modification.  
For further information on eCRFs please refer to the CRF Completion Guidelines. Details on 
data handling will be described in the Data Management Plan (DMP). 
10.4.2 Laboratory Data 
This study will employ electronic transfers of external laboratory data generated from clinical 
specimens collected by the Investigator. The Investigator is responsible for the adequacy and 
accuracy of data associated with collection of these specimens. Emergent is responsible for 
ensuring the adequacy and accuracy of the data generated by external laboratories. 
10.5 
File Management at the Investigational Site 
The Investigator will ensure that the essential study documents are maintained in accordance 
with the ICH GCP Guidelines and as required by applicable local and federal regulations. The 
Investigator/Institution will take measures to prevent accidental or premature destruction of these 
documents. 
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10.6 
Protocol Deviations 
The Principal Investigator agrees to conduct the clinical study in compliance with the protocol 
agreed to by Emergent and approved by the investigational site’s IRB/IEC/REB. 
A protocol deviation is any change, divergence, or departure from the study design or procedures 
defined in the protocol. 
The Investigator or investigational site staff may not deviate from the protocol, except, in rare 
circumstances, as necessary to eliminate immediate hazards to study subjects. In such event, both 
Emergent and IRB/IEC/REB will be immediately notified.  
The occurrence of protocol deviations will be routinely monitored for evaluation of Investigator 
compliance with the protocol, GCP, and regulatory requirements. Emergent will review all 
protocol deviations on an ongoing basis and will be responsible for determining if the deviation 
should be categorized as an Important Protocol Deviation (IPD). IPDs may require additional 
documentation as requested by Emergent. 
Continued protocol deviations despite re-education of investigational site personnel, or persistent 
protocol deviations that are reportable to regulatory agencies may result in discontinued 
shipment of investigational product and termination of further enrollment at the investigational 
site, or termination of the investigational site from the study.  
Protocol deviations due to the COVID-19 pandemic will be recorded, assessed, and indicated. 
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11 REGULATORY AND ETHICAL ISSUES 
11.1 
Ethical Considerations 
This study must be conducted in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki and in compliance with the protocol, current ICH GCP Guidelines, 
and applicable local and federal regulations, and all other applicable local laws. Each 
investigational site will seek approval by an IRB/IEC/REB according to regional requirements. 
The IRB/IEC/REB will evaluate the ethical, scientific and medical appropriateness of the study. 
Further, in collecting and handling subject data and completing eCRFs, the Investigator and 
investigational site staff will take measures to ensure adequate care in protecting subject privacy. 
To this end, a subject identification number will be used to identify each subject. 
11.2 
Informed Consent 
Informed consent is a process that is initiated prior to the subject’s agreeing to participate in the 
study and continues throughout their study participation.  
Emergent or designee will generate and provide a master ICF template to each investigational 
site for development of a site-specific ICF.  
All site-specific ICF must be in compliance with ICH GCP Guidelines, local regulatory 
requirements, and legal requirements and must be approved by Emergent or designee and the 
IRB/IEC/REB. Emergent or designee will advise the investigational site of required changes to 
the master ICF template during the course of the study. 
The subject will be asked to read and review the document. The Investigator will explain the 
research study to the participant 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 will have 
the opportunity to carefully review the written consent form and ask questions prior to signing. 
The participants should have the opportunity to discuss the study with their family or think about 
it prior to agreeing to participate. The participant will sign the informed consent/assent document 
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/assent document will be given to the participants for 
their records. The informed consent/assent process will be conducted and documented in the 
source document (including the date), and the form signed, before the participant undergoes any 
study-specific procedures. 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. 
11.3 
Independent Ethics Committee/Institutions Review Board 
Before the start of the study, the Investigator’s Brochure, the protocol, proposed informed 
consent form(s), subject compensation (if any), Emergent-approved study materials and 
advertisements, and any other written information to be provided to the subject, will be 
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submitted to a properly constituted IRB for review. Emergent must receive a copy of the written 
approval from the IRB for all of the above applicable documents prior to recruitment of subjects 
into the study and shipment of COVID-HIGIV. 
The IRB must provide written approval for all amendments to any of the above documents prior 
to implementation of these amendments at the investigational site. The investigator is obliged to 
report SAEs, as well as any unanticipated problems, to the IRB in addition to other information 
as required by the IRB. 
The names (or title, if IRB procedures prohibit publishing of names) and associated backgrounds 
of the members of IRB (to assist in assuring that the board membership is properly constituted 
and operates according to 21 CFR part 56) will be given to Emergent prior to the start of the 
study along with a signed and dated statement stating that the protocol and Informed Consent 
Form and, where applicable, any other document listed above, have been approved by them. 
All correspondence between the investigator and the IRB will be available for review by 
Emergent (or designate), CRO personnel, and the applicable regulatory authority(ies). 
11.4 
Study Files and Materials 
Source data are all information, original records of clinical findings, and observations in a 
clinical study necessary for the reconstruction and evaluation of the study. The source 
documentation requirements described below apply to all source documentation and study 
records in any form, including those maintained in the Institution’s Electronic Health Record 
system, if applicable. 
The Investigator/Institution will maintain adequate and accurate source documents and study 
records that include all pertinent information related to subjects’ participation in the study, 
including details but not limited to signed and dated notes on consenting, eligibility, medical 
history, study assessments, Investigational Product administration, adverse events, concomitant 
medications, subject follow-up information and other relevant observations. 
Source data should be attributable, legible, contemporaneous, original, accurate, and complete. 
Changes to source data should be traceable, should not obscure the original entry and should be 
explained if necessary (e.g., via an audit trail). 
The Investigator/Institution shall permit study-related monitoring, audits, IRB/IEC/REB review, 
and regulatory inspection(s), providing direct access to source data/documents.  
Records from the study that identify the subject will be confidential except that they may be 
given to and inspected by Emergent (or designee), the IRB/IEC/REB, the applicable regulatory 
authorities, other government agencies as appropriate, and will not otherwise be released except 
as required by law. All information provided to the Investigator by Emergent is to be considered 
confidential unless otherwise stated. 
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12 ADMINISTRATIVE ASPECTS 
12.1 
Clinical Study Agreement 
This study will be conducted under a Clinical Study Agreement between Emergent (or delegate) 
and the respective institutions representing the study sites. Any financial support given to the 
study sites will be detailed in the Clinical Study Agreement. The Clinical Study Agreement, 
which must be signed before the start of any study related procedures, will clearly delineate the 
responsibilities and obligations of the investigator and Emergent, and will form the contractual 
basis upon which the study will be conducted. 
12.2 
Documentation Required Prior to Clinical Study Initiation  
The investigator (or designate) is responsible for forwarding the following documents to 
Emergent for review prior to study initiation: 
• Signed protocol signature page, form FDA 1572 (or equivalent, depending on local 
regulatory requirements), financial disclosure form, debarment certification statement, 
Clinical Study Agreement, and any other required regulatory documents. 
• Copy of IRB-approved informed consent form. 
• Copy of the written IRB approval for the protocol, Investigator’s Brochure, informed 
consent form(s), subject compensation (if any), any study materials and advertising, and 
any other written information to be provided to the subject. 
• Current Curriculum Vitae and a photocopy of medical license (if applicable) of the 
principal investigator, co/sub investigators and other site personnel as required by 
Emergent/CRO. 
• Written statement that the IRB/IEC/REB is properly constituted and operates according 
to ICH GCP Guidelines and applicable local and federal regulations. Investigators 
participating in this study, if IRB/IEC/REB members, should state in writing that they 
have abstained from voting in regard to this protocol.  
• Laboratory normal ranges and documentation of laboratory certification. 
• Signed site contract agreement. 
12.3 
Clinical Study Registration 
Emergent is responsible for registration of EBS-CVH-003 study to Clinicaltrials.gov in 
accordance with applicable regulations. 
12.4 
Liability and Insurance 
Emergent will adhere to local regulations and guidelines regarding clinical study compensation 
to subjects whose health is adversely affected by taking part in the study. Compensation for 
injury will be described in the ICF. 
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12.5 
Subject Identification and Confidentiality 
The investigator must ensure the anonymity of each subject is maintained at all times. Subjects 
should only be identified by their initials and Subject Study ID number on the CRF, or on any 
other study documents provided to Emergent or their designate(s). Any documents that identify 
the subject should be kept in strict confidence by the principal investigator.  
12.6 
Monitoring 
The assigned clinical study monitor will verify eCRF entries against source documentation at 
regular intervals throughout the study to verify adherence to the protocol; completeness, 
accuracy, and consistency of the data; and adherence to ICH GCP Guidelines and local and 
federal regulations applicable to the conduct of the clinical study. The Principal Investigator 
must make source documentation accessible to the study monitor as needed to verify the 
information in eCRFs. The Investigator agrees to meet with the study monitor at regular intervals 
to discuss study progress and ensure that any problems detected in the course of data monitoring 
are resolved appropriately. 
12.7 
Protocol Amendments 
Protocol amendments will only be made by Emergent. In general, any change to the protocol 
must be made in the form of a formal amendment to the protocol and must be approved in 
writing by the Principal Investigator, Emergent, and the IRB/IEC/REB prior to implementation. 
The Investigator must receive written IRB/IEC/REB approval for all protocol amendments prior 
to implementing protocol amendments at the investigational site; copies of IRB/IEC/REB 
correspondence including approval/disapproval letters from the IRB/IEC/REB must be provided 
to Emergent. 
12.8 
Use of Study Data and Publications 
Data arising from this study are the sole property of Emergent. Emergent must provide written, 
prior agreement to any publication based, in whole or in part, on data from this study. All 
proposed abstracts, manuscripts or presentations from the study must be provided to Emergent 
for review at least 60 days prior to submission for publication/presentation. Any information 
identified by Emergent as confidential must be deleted prior to submission. The Publication 
Policy applicable to this protocol is the one agreed upon and described in the Clinical Study 
Agreement between Emergent and the principal investigator. 
12.9 
Future Use of Stored Samples 
Stored specimens (e.g., PK samples) will be identified by subject ID/sample numbers/codes for 
future testing after unblinding. Subjects will be asked to consent to the future use of the samples 
as part of the informed consent process. Samples may be retained until at least 2 years after the 
last approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed since 
the formal discontinuation of clinical development. 
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13 REFERENCES 
1. 
Van Damme W, Dahake R, Delamou A, Ingelbeen B, Wouters E, Vanham G, et al. The 
COVID-19 pandemic: Diverse contexts; different epidemics-how and why? BMJ Glob 
Health. 2020;5(7):e003098. 
2. 
Gorbalenya AE, Baker SC, Baric R, de Groot RJ, Drosten C, Gulyaeva AA, et al. The 
species severe acute respiratory syndrome-related coronavirus: Classifying 2019-nCoV and 
naming it SARS-CoV-2. Nat Microbiol. 2020;5, 536–544. 
3. 
Ganyani T, Kremer C, Chen D, Torneri A, Faes C, Wallinga J, et al. Estimating the 
generation interval for coronavirus disease (COVID-19) based on symptom onset data, 
March 2020. Euro Surveill. 2020;25(17):pii=2000257. 
4. 
Morawska L, Milton DK. It is time to address airborne transmission of COVID-19 
[published online ahead of print, 2020 Jul 6]. Clin Infect Dis. 2020;ciaa939. 
5. 
Klompas M, Baker MA, Rhee C. Airborne transmission of SARS-CoV-2: Theoretical 
considerations and available evidence. JAMA. Published online July 13, 2020.  
6. 
Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsenet S, eal. SARS-
CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven 
protease inhibitor. Cell. 2020;181(2):271-280.e8. 
7. 
Walls AC, Park YJ, Tortorici MA, Wall A, McGuire AT, Veesler D. Structure, function, and 
antigenicity of the SARS-CoV-2 spike glycoprotein. Cell. 2020;181(2):281-292.e6. 
8. 
Zou X, Chen K, Zou J, Han P, Hao J, Han Z. Single-cell RNA-seq data analysis on the 
receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 
2019-nCoV infection. Front Med. 2020;14(2):185-192. 
9. 
Qi F, Qian S, Zhang S, Zhang Z. Single Cell RNA Sequencing of 13 human tissues identify 
cell types and receptors of human coronaviruses. Biochem Biophys Res Commun. 
2020;526(1):135-140. 
10. He, X., Lau, E.H.Y., Wu, P, Deng X, Wang J, Hao X, et al. Temporal dynamics in viral 
shedding and transmissibility of COVID-19. Nat Med 26, 672–675 (2020). 
11. Wölfel R, Corman VM, Guggemos W, Seilmaier M, Zange S, Müller MA, et al. Virological 
assessment of hospitalized patients with COVID-2019. Nature 2020;581, 465–469. 
12. Sun J, Xiao J, Sun R, Tang X, Liang C, Lin H, et al. Prolonged persistence of SARS-CoV-2 
RNA in body fluids. Emerg Infect Dis. 2020;26(8):1834-1838. 
13. Guo L, Ren L, Yang S, Xiao M, Chang D, Yang F, et al. Profiling early humoral response to 
diagnose novel coronavirus disease (COVID-19). Clin Infect Dis. 2020;71(15):778-785. 
  Version: 4.0                    Effective Date: 21 Apr 2021

Clinical Study Protocol EBS-CVH-003 
Version 4.0, 21 Apr 2021 
Emergent BioSolutions 
Confidential and Proprietary 
Page 69 of 76 
 
 
 
 
14. Long Q, Liu B, Deng H,  Wu G, Deng K, Chen Y, et al. Antibody responses to SARS-CoV-2 
in patients with COVID-19. Nat Med 26, 845–848 (2020). 
15. Ma H, Zeng W, He H, Zhao D, Jiang D, Zhou P, et al. Serum IgA, IgM, and IgG responses in 
COVID-19. Cell Mol Immunol. 2020;17(7):773-775. 
16. Wajnberg A, Amanat F, Firpo A, Altman D, Bailey M, Mansour M, et al. SARS-CoV-2 
infection induces robust, neutralizing antibody responses that are stable for at least three 
months. medRxiv 2020.07.14.20151126. Pre-print/not peer reviewed. 
17. Grifoni A, Weiskopf D, Ramirez SI, Mateus J, Dan JM, Moderbacher CR, et al. Targets of T 
cell responses to SARS-CoV-2 coronavirus in humans with COVID-19 disease and 
unexposed individuals. Cell. 2020;181(7):1489-1501.e15. 
18. Lauer SA, Grantz KH, Bi Q, et al. The incubation period of coronavirus disease 2019 
(COVID-19) from publicly reported confirmed cases: Estimation and application. Ann Intern 
Med. 2020;172(9):577- 582. 
19. Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al. Clinical characteristics of 
coronavirus disease 2019 in China. N Engl J Med. 2020;382(18):1708-1720. 
20. Rothan HA, Byrareddy SN. The epidemiology and pathogenesis of coronavirus disease 
(COVID-19) outbreak. J Autoimmun. 2020;109:102433. 
21. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected 
with 2019 novel coronavirus in Wuhan, China [published correction appears in Lancet. 2020 
Jan 30]. Lancet. 2020;395(10223):497-506.  
22. Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 
2019 (COVID-19) outbreak in China: Summary of a report of 72?314 cases from the Chinese 
center for disease control and prevention [published online ahead of print, 2020 Feb 24]. 
JAMA. 
23. Gupta A, Madhavan MV, Sehgal K, Nair N, Mahajan S, Sehrawat TS, et al. Extrapulmonary 
manifestations of COVID-19. Nat Med 26, 1017–1032 (2020). 
24. Garg S, Kim L, Whitaker M, O’Halloran A, Cummings C, Holstein R, et al. Hospitalization 
rates and characteristics of patients hospitalized with laboratory-confirmed coronavirus 
disease 2019 – COVID-NET, 14 States, March 1–30, 2020. MMWR Morb Mortal Wkly Rep 
2020;69:458–464. 
25. Arentz M, Yim E, Klaff L, Lokhandwala S, Riedo F, Chong M, et al. Characteristics and 
outcomes of 21 critically ill patients with COVID-19 in Washington State [published online 
ahead of print, 2020 Mar 19]. JAMA. 2020;323(16):1612-1614. 
  Version: 4.0                    Effective Date: 21 Apr 2021

Clinical Study Protocol EBS-CVH-003 
Version 4.0, 21 Apr 2021 
Emergent BioSolutions 
Confidential and Proprietary 
Page 70 of 76 
 
 
 
 
26. CDC COVID-19 Response Team. Severe outcomes among patients with coronavirus disease 
2019 (COVID-19) - United States, February 12-March 16, 2020. MMWR Morb Mortal Wkly 
Rep. 2020;69(12):343-346. 
27. Hu Z, Song C, Xu C, Jin G, Chen Y, Xu X, et al. Clinical characteristics of 24 asymptomatic 
infections with COVID-19 screened among close contacts in Nanjing, China. Sci China Life 
Sci. 2020;63(5):706-711.  
28. Gandhi M, Yokoe DS, Havlir DV. Asymptomatic transmission, the Achilles' heel of current 
strategies to control Covid-19. N Engl J Med. 2020;382(22):2158-2160. 
29. Richardson S, Hirsch JS, Narasimhan M, Crawford JM, McGinn T, Davidson KW, et al. 
Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized 
with COVID-19 in the New York City area. JAMA. 2020;323(20):2052–2059. 
30. Grasselli G, Zangrillo A, Zanella A, Antonelli M, Cabrini L, Castelli A, et al. Baseline 
characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs 
of the Lombardy region, Italy. JAMA. 2020;323(16):1574–1581. 
31. Qin C, Zhou L, Hu Z, Zhang S, Yang S, Tao Y, et al. Dysregulation of immune response in 
patients with COVID-19 in Wuhan, China [published online ahead of print, 2020 Mar 12]. 
Clin Infect Dis. 2020;ciaa248. 
32. Tan M, Liu Y, Zhou R, Deng X, Li F, Liang K, et al. Immunopathological characteristics of 
coronavirus disease 2019 cases in Guangzhou, China. Immunology. 2020;160(3):261-268. 
33. Levi M, Thachil J, Iba T, Levy JH. Coagulation abnormalities and thrombosis in patients 
with COVID-19. Lancet Haematol. 2020;7(6):e438-e440. 
34. Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, et al. Remdesivir 
for the treatment of Covid-19 - Preliminary report [published online ahead of print, 2020 
May 22]. N Engl J Med. 2020;NEJMoa2007764. 
35. COVID-19 Treatment Guidelines Panel. Coronavirus disease 2019 (COVID-19) treatment 
guidelines. National Institutes of Health. Available at 
https://www.covid19treatmentguidelines.nih.gov/ (accessed on July 09, 2020). 
36. Zost SJ, Gilchuk P, Case JB, Binshtein E, Chen RE, Reidy JX, et al. Potently neutralizing 
and protective human antibodies against SARS-CoV-2 [published online ahead of print, 2020 
Jul 15]. Nature. 2020;10.1038/s41586-020-2548-6. 
37. Rogers TF, Zhao F, Huang D, Beutler N, Burns A, He W, et al. Isolation of potent SARS-
CoV-2 neutralizing antibodies and protection from disease in a small animal model 
[published online ahead of print, 2020 Jun 15]. Science. 2020;eabc7520. 
  Version: 4.0                    Effective Date: 21 Apr 2021

Clinical Study Protocol EBS-CVH-003 
Version 4.0, 21 Apr 2021 
Emergent BioSolutions 
Confidential and Proprietary 
Page 71 of 76 
 
 
 
 
38. Shi R, Shan C, Duan X, Chen Z, Liu P, Song J, et al. A human neutralizing antibody targets 
the receptor binding site of SARS-CoV-2 [published online ahead of print, 2020 May 26]. 
Nature. 2020;10.1038/s41586-020-2381-y. 
39. Duan K, Liu B, Li C, Zhang H, Yu T, Qu J, et al. Effectiveness of convalescent plasma 
therapy in severe COVID-19 patients. Proc Natl Acad Sci U S A. 2020;117(17):9490-9496. 
40. Shen C, Wang Z, Zhao F, Yang Y, Li J, Yuan J, et al. Treatment of 5 critically ill patients 
with COVID-19 with convalescent plasma [published online ahead of print, 2020 Mar 27]. 
JAMA. 
41. Liu, STH, Lin H, Baine I, Wajnberg A, Gumprecht JP, Rahman F, et al. Convalescent plasma 
treatment of severe COVID-19: A matched control study. medRxiv 2020.05.20.20102236. 
Note: this is a pre-peer reviewed pre-print.  
42. Li L, Zhang W, Hu Y, Tong X, Zheng S, Yang J, et al. Effect of convalescent plasma therapy 
on time to clinical improvement in patients with severe and life-threatening COVID-19: A 
randomized clinical trial [published online ahead of print, 2020 Jun 3]. JAMA. 
2020;e2010044. 
43. Joyner MJ, Wright RS, Fairweather D, Senefeld JW, Bruno KA, Klassen SA, et al. Early 
safety indicators of COVID-19 convalescent plasma in 5,000 patients [published online 
ahead of print, 2020 Jun 11]. J Clin Invest. 2020;140200 4. 
44. VariZIG® Product Monograph. Varicella zoster immunoglobulin (human) sterile solution for 
injection. Saol Therapeutics Research Limited. 2018. 
45. HepaGam B® Prescribing Information. Hepatitis B immune globulin intravenous (human). 
Saol Therapeutics Inc. 2018. 
46. WinRho® SDF Prescribing Information. Rho(D) immune globulin intravenous (human). 
Saol Therapeutics Inc. 2018. 
47. ANTHRASIL® Prescribing Information. Anthrax immune globulin intravenous (human). 
Emergent BioSolutions Canada Inc. 2018. 
48. CNJ-016 Prescribing Information. Vaccinia immune globulin intravenous human, VIGIV. 
Emergent BioSolutions Canada Inc. 2018. 
49. BIVIGAM® Prescribing Information. Immune globulin intravenous (human), 10% liquid. 
ADMA Biologics Inc. 2019. 
50. GAMMAPLEX® 10% Prescribing Information. Immune globulin intravenous (human), 10% 
liquid. Bio Products Laboratory Limited. 2019.   
51. Privigen® Prescribing Information. Immune globulin intravenous (human), 10% liquid. CSL 
Behring LLC. 2019. 
  Version: 4.0                    Effective Date: 21 Apr 2021

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Page 72 of 76 
 
 
 
 
52. GAMUNEX®-C Prescribing Information. immune globulin injection (human). Grifols 
Therapeutics LLC. 2020. 
53. Hamrock DJ. Adverse events associated with intravenous immunoglobulin therapy. Int 
Immunopharmacol. 2006;6(4):535-42. 
 
 
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APPENDIX I – MODIFIED WHO ORDINAL SCALE 
Modified WHO Ordinal Scale for COVID-19: 
Ordinal Category  
Categorical Description  
Categorical Definition 
1 
No limiting symptoms due 
to COVID-19. 
Subject can independently undertake usual activities with 
minimal or no symptoms 
2 
Limiting symptoms due to 
COVID-19. 
Subject is symptomatic and currently is unable to 
independently undertake usual activities. 
3 
Moderate end-organ 
dysfunction. 
Subject requires supplemental oxygen <4 liters/min, or <4 
liters/min above pre-morbid requirements*. 
4 
Serious end-organ 
dysfunction. 
Subject currently requires supplemental oxygen (≥4 
liters/min, or ≥4 liters/min above pre-morbid 
requirements*), but not high-flow oxygen OR 
Subject has any symptoms or signs of the following extra-
pulmonary conditions: 
Stroke (NIH Stroke Scale/Score [NIHSS] ≤14), meningitis, 
encephalitis, or myelitis, acute coronary syndromes 
(myocardial infarction, unstable angina), myocarditis, 
pericarditis, or New York Heart Association Class III or IV 
congestive heart failure, arterial or deep venous thrombosis 
including pulmonary embolism. 
5 
Life-threatening end-organ 
dysfunction. 
Subject currently requires non-invasive assisted ventilation 
or high-flow oxygen OR 
Extra-pulmonary condition: 
Symptoms and signs of an acute stroke (NIHSS > 14). 
6 
End-organ failure. 
Subject currently requires invasive assisted ventilation, 
extracorporeal membrane oxygenation, mechanical 
circulatory support, vasopressor therapy or renal 
replacement therapy. 
7 
Death. 
Fatality due to COVID-19. 
 
 
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APPENDIX II – GRADING OF COVID-19 SYMPTOMS 
Use the table below to grade severity of COVID-19 symptoms: 
COVID-19 Related Symptom 
Response Options (Scoring/Grade) 
For items 1-10, what was the severity of your symptom at its worst over the last 24 hours? 
Stuffy or runny nose 
None (0) 
Mild = defined as no interference with daily activity 
(1) 
Moderate = Interference with activity (2) 
Severe= prevents daily activity (3)  
Serious = life threatening or requires hospitalization 
(4) 
Sore throat 
Shortness of breath (difficulty breathing) 
Cough 
Low energy or tiredness 
Muscle or body aches 
Headache 
Chills or shivering 
Nausea (feeling like you wanted to throw up) 
Fever 
None= (0) 
Mild =100.4-102F (1) 
Moderate 102.1-104F (2)  
Severe >104F (3) 
How many times did you vomit (throw up) in the last 
24 hours 
I did not vomit at all (0) 
1-2 times (1) 
3-4 times (2) 
5 or more times (3) 
Life threatening/requires hospitalization (4) 
How many times did you have diarrhea (loose or 
watery stools) in the last 24 hours? 
I did not have diarrhea at all (0) 
1=2 times (1) 
3-4 times (2) 
5 or more times (3) 
Life threatening/requires hospitalization (4) 
Rate your sense of smell in the last 24 hours 
My sense of smell is the SAME as usual (0) 
My sense of smell is LESS than usual (1) 
I have NO sense of smell (2) 
Rate your sense of taste in the last 24 hours 
My sense of taste is the SAME as usual (0) 
My sense of taste is LESS than usual (1) 
I have NO sense of taste (2) 
Responses will be scored on a 1 point scale.  (e.g., My sense of taste is the same as usual (0 points); My 
sense of taste is LESS than usual (1 point); I have NO sense of taste (2 points).  
Note: Score values will not be provided within the response options presented to subjects. 
 
 
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APPENDIX III – GRADING OF ADVERSE EVENTS 
The severity of adverse events will be graded according to the U.S. Department of Health and 
Human Services, National Institutes of Health, National Institute of Allergy and Infectious 
Diseases, Division of AIDS. Division of AIDS (DAIDS) Table for Grading the Severity of Adult 
and Pediatric Adverse Events, Corrected Version 2.1. [July 2017]. Available at: 
https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf 
 
 
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APPENDIX IV – GRADING OF VITAL SIGNS 
Use the following criteria to grade vital signs: 
Grading Scale* 
Grade 1  
(mild) 
Grade 2 
(moderate) 
Grade 3  
(severe) 
Grade 4 
(potentially life-
threatening) 
Temperature  
(C)  
(F) 
 
38.0-38.4 
100.4-101.1 
 
38.5-38.9 
101.2-102.0 
 
39.0-40.0 
102.1-104.0 
 
>40.0 
>104 
Tachycardia 
(beats/min) 
101-115 
116-130 
>130 
ER visit or 
hospitalization for 
arrhythmia 
Bradycardia 
(beats/min) 
50-54 
45-49 
<45 
ER visit or 
hospitalization for 
arrhythmia 
Hypertension 
systolic (mmHg) 
141-150 
151-155 
>155 
ER visit or 
hospitalization for 
malignant 
hypertension 
Hypertension 
diastolic (mmHg) 
91-95 
96-100 
>100 
ER visit or 
hospitalization for 
malignant 
hypertension 
Hypotension 
systolic (mmHg) 
85-89 
80-84 
<80 
ER visit or 
hospitalization for 
hypotensive shock 
Respiratory Rate 
(breaths/min) 
17-20 
21-25 
>25 
Intubation 
SPO2 (%) 
92 - <95 
90 - <92 
85 - <90 
<85 or 
ER visit or 
hospitalization for 
hypoxia 
* Taken from Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive 
Vaccine Clinical Trials {CBER, 2007}, except SPO2. 
 
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