A Multicenter, Adaptive, Randomized, Blinded Controlled Trial of the Safety and Efficacy of Investigational Therapeutics for Hospitalized Patients With COVID-19 (Trial H3: BRII-196/BRII-198)
Phase: PHASE3
Conditions: COVID-19
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

 A Multicenter, Adaptive, 
Randomized, Blinded Controlled 
Trial of the Safety and Efficacy of 
Investigational Therapeutics for 
Hospitalized Patients With 
COVID-19 (Trial H3: BRII-196/
BRII-198)
   Version 1.0
20 November 2020
  NCT05780424

Appendix H3: BRII-196+BRII-198 – version 1.0 (20 November 2020) 
 
The content of this appendix is confidential and should only be viewed 
by persons covered by the CDA entered between BRII and NIAID in 
relation to the TICO / ACTIV-3 study.   
 
This appendix provides detailed information pertaining to the study of this investigational 
agent. If not stated otherwise, the text in the master protocol gives the approach that will be 
taken to study this agent.    
H.3.1. Introduction and rationale for studying the agent 
 
BRII-196 and BRII-198 are two fully human immunoglobulin G (IgG)-1 monoclonal 
antibodies (mAb) derived from antibodies P2C-1F11 and P2B-1G5, respectively, that 
were isolated directly from human B cells of a convalescent COVID-19 patient [1-3]. 
These mAbs target distinct epitopes in the SARS-CoV-2 receptor binding domain (RBD) 
in the coronavirus spike (S) glycoprotein. SARS-CoV-2 S uses the angiotensin-
converting enzyme 2 (ACE2) to enter cells via interaction with the RBD [4]. Therefore, 
mAbs against the RBD will prevent virus binding to ACE2, blocking virus entry and virus 
infection. BRII-196 and BRII-198 are potent in neutralizing SARS-CoV-2 viruses in 
pseudo-virus as well as live virus neutralization assays. The targeting of different 
epitopes in the viral antigen by the BRII-196 and BRII-198 cocktail is a strategy to reduce 
the generation and selection of resistant virus as compared to single antibody. Further, 
the fragment crystallizable (Fc) region of BRII-196 and BRII-198 is engineered with a 
triple-amino-acid (M252Y/S254T/T256E [YTE]) substitution to allow an extended half-life 
[5, 6]. The introduction of YTE also reduces the binding activity against Fcγ receptors by 
approximately 3 folds, thereby minimizing the potential risk of Fc-mediated antibody-
dependent enhancement (ADE). 
 
Brii Biosciences (BriiBio) is a multinational biopharmaceutical company that discovers 
and develops innovative medicines to address unmet public health needs with a focus 
on infectious diseases.  BriiBio operates in the US headquartered in Durham, NC and 
operates in China headquartered in Beijing, with facilities and staff also in San Francisco, 
CA and Shanghai.  
 
Neutralizing mAbs that can inhibit viral replication and potentially mitigate the severity of 
disease caused by viral infection represent an important therapeutic option in the 
treatment of known and emerging infectious diseases. Whereas one antiviral agent 
(remdesivir) has been demonstrated to have clinical benefit in the target population for 
this trial and is now part of standard-of-care (see Appendix I), it is plausible that additional 
antiviral effects from the combination of the neutralizing mAbs BRII-196 and BRII-198 
together with the remdesivir may provide additive, if not synergistic, antiviral effect and 
hence, contribute to improvement in time to sustained recovery.  
 
BriiBio is evaluating the safety, tolerability, and pharmacokinetics (PK) of each antibody 
in two randomized, placebo-controlled, single-ascending-dose, Phase 1, first in human 
studies at three dose levels of BRII-196 (750 mg, 1500 mg, 3000 mg) in study BRII-196-
001 (NCT04479631)[7] and three dose levels of BRII-198 (750 mg, 1500 mg, 3000 mg) 

in study BRII-198-001 (NCT04479644)[8]. In each study of 16 healthy volunteers, the 
active formulation is injected into an IV bag of normal saline before being administered 
intravenously. Subjects of each dose cohort, for each respective study, are randomized 
in a ratio of 3:1 to receive either the active formulation or placebo (normal saline). 
Subjects remain as inpatients at the clinical investigational site for sample collection and 
assessments for 7 days post-dose and thereafter return to the clinic at designated visit 
times for additional sample collection and assessments, with the last visit scheduled on 
Day 181. A Safety Review Committee (SRC) performs ongoing reviews of safety and 
tolerability based on data collected in pre-planned cohorts to guide the progress of the 
study and ensure the safety of the subjects. Both studies completed enrollment of 
planned subjects and preliminary safety, tolerability, and PK data from these studies are 
supportive of the dose selected for use in this study. 
  
H3.1.1 Potential risk and benefits from BRII-196+BRII-198  
Anticipated risk is considered low, based on the known mechanism of action for human- 
derived neutralizing antibodies in acute viral disease states.  BRII-196 and BRII-198 are 
highly specific mAb directed at foreign (non-human) epitope(s).  The parent antibodies 
were isolated from B lymphocytes of a naturally convalescent SARS-CoV-2-infected 
patient. Hence, BRII-196 and BRII-198 have undergone natural positive and negative 
selection pressures in vivo, unlike humanized antibodies generated in mice.  Therefore, 
off-target binding, tissue cross-reactivity and immunogenicity are considered unlikely, 
which is further supported by the absence of binding to membranes of monkey and 
human tissues in tissue cross-reactivity studies. The complementarity determining 
regions (CDRs) of BRII-196 are identical to the parent mAb P2C-1F11.  BRII-198 is only 
different in one amino acid in the CDR3 of precursor mAb, P2B-1G5 (to reduce 
manufacturing development risk). In the Fc domain of BRII-196 and BRII-198, three 
clinically validated amino acid modifications (M252Y/S254T/T256E [YTE]) were 
introduced to extend half-life [5, 6]. 
BRII-196 targets a discontinuous binding site that contains 23 amino acid residues in the 
RBD of the spike protein that are located in the interface of the ACE2 receptor binding 
site (11 of 23 amino acids are known to bind to this receptor). BRII-198, however, has 
minimal competition with ACE2 and BRII-196 but strong competition with S309 (VIR-
7831), a mAb specifically recognizing the core domain of RBD. These results indicate 
that BRII-198 exerts its neutralizing ability through the binding to the core domain in the 
RBD of the spike protein. Therefore BRII-196 and BRII-198 target the RBD through 
distinct, non-competitive, complementary neutralizing mechanisms. In vitro studies 
suggest that the two antibodies act additively, if not synergistically [2, 3]. Additionally, the 
combination of two antibodies, like BRII-196 and BRII-198, reduced the chance of 
resistant escape mutants of SARS-CoV-2, in vitro, compared to antibodies being studied 
alone [9].  
Potential risks for infusion of an IgG1 mAb directed toward a microbial pathogen are 
mostly associated with either infusion-related immediate and non-immediate 
hypersensitivity reactions, or infusion-related cytokine release syndrome. Signs and 
symptoms of infusion-related immediate hypersensitivity reactions may include, but are 

not limited to: anaphylaxis, angioedema, bronchospasm, chills, diarrhea, hypotension, 
itching, skin rash, shortness of breath, urticarial, tachycardia, and throat irritation or chest 
tightness. Additional signs and symptoms associated with cytokine release syndrome 
may also include fever, headache, myalgia, nausea, and vomiting.  
A theoretical risk is that BRII-196 or BRII-198 may cause antibody-dependent 
enhancement (ADE) of viral replication (section 3.2 of the master protocol).  This is based 
on responses observed to some monoclonal antibody therapies used in other unrelated 
viral diseases, namely Dengue and Zika virus infections.  Unlike ADE associated with 
Dengue and Zika virus infections, this phenomenon has not been clearly established for 
coronavirus infections, such as severe acute respiratory syndrome (SARS) and Middle 
East respiratory syndrome (MERS), and has not been reported to date with SARS-CoV-
2.  Additionally, limited experience with the use of convalescent serum as a treatment for 
patients with severe COVID-19 has not indicated safety concerns [10]. BRII-196 and 
BRII-198 will be administered to patients at sufficiently high dose levels to neutralize 
SARS-CoV-2 and avoid sub-neutralizing concentrations in the presence of virus that are 
typically associated with ADE. In addition, there was no ADE observed in over 20,000  
COVID-19 patients who were treated with convalescence plasma [11] and in the recently 
published study in infants who received YTE-containing RSV mAb over 1 year in vivo 
entering second RSV season [12].  With a total of 37 representative tissues from human 
and cynomolgus monkeys, BRII-196 and BRII-198 had no cross reactivity at 
concentration up to 10 ug/mL and this is consistent with highly specific affinity to the RBD 
region of the spike protein of SARS-CoV-2 virus.  Both BRII-196 and BRII 198 with YTE 
modification in Fc regions exhibited reduced binding activity by approximately three-fold 
to human Fcγ receptors (FcγRIIIa-F158/V158 and FcγRIIa-H131/R131), and no ADCC 
activity in the assay using primary NK cells in the presence of BRII-196 [2, 3]. These 
results suggest BRII-196 and BRII-198 may have a reduced risk of potential Fc-mediated 
ADE. 
As of 24 August 2020, all healthy volunteers who were administered study drug in the 
BRII-196-001 (NCT04479631)[7] and BRII-198-001 (NCT04479644)[8] studies are 
under follow-up. A total of 16 subjects were randomized in the ongoing BRII-196-001 
study and completed dosing: 750 mg (3 subjects), 1500 mg (6 subjects), 3000 mg 
(3 subjects), and placebo (4 subjects). A total of 17 subjects were randomized in the 
ongoing BRII-198-001 study of which 16 subjects completed dosing: 750 mg 
(3 subjects), 1500 mg (6 subjects), 3000 mg (3 subjects), and placebo (4 subjects). The 
demographic profile of subjects across dose levels in the BRII-196-001 and BRII-198-
001 studies was comparable with respect to mean age (mean age of subjects by study: 
32 and 33 years, respectively), gender (81% and 88% male, respectively), racial 
distribution (88% and 94% Han Chinese, respectively), and mean body mass index 
(22 kg/m2, in both studies). At the dose level of up to 3000 mg, both BRII-196 and BRII-
198 were well tolerated. No infusion-related reaction, hypersensitivity reaction, or 
adjustment of infusion rate due to AEs during the administration have been reported. No 
SAEs or AEs of Grade 3 or above (Common Terminology Criteria for Adverse Events 
(CTCAE); a grading system) have been reported. No medical interventions were needed. 

Most lab abnormalities were transient and returned to normal range or baseline level 
within 2 weeks without any clear pattern nor correlation to dose. 
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events of BRII-196 and BRII-198 may be found in the 
Investigator’s Brochure(s) (IB) [2, 3] and Participant Information Leaflet. 
Given the data on BRII-196 and BRII-198 from the on-going Phase 1 studies, the well-
described safety profile of other therapeutic monoclonal antibodies, the pre-clinical safe 
toxicology profile, and the limited disease directed therapeutic options for patients with 
COVID-19 illness, the overall benefit-risk assessment of this study is considered 
favorable. 
H3.1.2 Motivation for agent selection by the ACTIV Trial Oversight Committee (TOC) 
The ACTIV-2/3 Agent Selection Committee (ASC) reviewed the Brii Biosciences SARS-
CoV-2 neutralizing antibody cocktail (BRII-196 and BRII-198) voted in favor of the agent 
proceeding into ACTIV-2 and ACTIV-3, and the TOC endorsed that recommendation.  
Brii Bioscience’s BRII-196 and BRII-198 antibodies were supported because Brii 
Biosciences presented strong preclinical data for viral neutralization, Live virus 
neutralization BRII-196 IC50 0.024 μg/ml, BRII-198 IC50 0.030 μg/ml and Live virus 
neutralization BRII-196 IC90 ≤ 0.296μg/ml. BRII-198 IC90 ≤ 0.490μg/ml.  BRII-196 
and BRII-198 are human neutralizing immunoglobulin G1 that bind distinct epitopes in 
receptor binding domain (RBD) in spike protein of SARS-CoV-2 virus. They are 
M257Y/S259T/T261E (YTE) modified isoforms of monoclonal antibodies derived from B 
cells of a recovered COVID-19 patient. BRII-196 neutralizes SARS-CoV-2 by directly 
blocking the binding of receptor ACE2 to RBD for viral entry. The structural analysis of 
BRII-196 Fab complexed with the RBD protein provided insights into the neutralization 
mechanism. It revealed a highly conserved conformational antigenic site comprised of 
23 contact residues in RBD and 11 of them are used by ACE2 to bind SARS-CoV-2. 
Unlike BRII-196, BRII-198 demonstrated no or little competing capacity with ACE2 and 
BRII-196, indicating two antibodies have distinct and non-overlapping epitopes, and 
neutralize virus through different mechanisms. As expected, when evaluated in the live 
virus microneutralization assay in combination, they displayed moderate additive effect.  
While the YTE modification improves the half-life of antibodies to provide prolonged 
duration of protection and extended therapeutic treatment window, it reduces binding 
activity to human Fcγ receptors, thereby minimizing the potential risk of Fc-mediated 
antibody-dependent enhancement. 
In addition, the ASC appreciated that Brii Bioscience was targeting date for 
Investigational New Drug (IND) submission was early September, and that its Phase 1 
study should be complete by mid-September, with the candidate agent ready to enter 
ACTIV clinical trials by late September pending Phase 1 results. In addition, BRII-196 
and BRII-198 will be the first cocktail to be tested in ACTIV, exciting the ASC to assess 
a few combination agents.  Finally, the ASC found the manufacturing and scalability 
strategy for Brii Biosciences sufficient for the full trial and beyond. 

Brii statement regarding plans for licensure: BriiBio is a biopharmaceutical company 
whose goal is to bring important medical breakthroughs to as many patients in as many 
countries as possible. It would therefore be BriiBio’s general intent to pursue licensure in 
countries where the trial occurs. In the case of the COVID-19 pandemic, the actual 
decision to pursue licensure will be impacted by other factors which may include: status 
of the COVID pandemic in the country and medical need, availability of other therapies 
including vaccines, available drug supply and other supply feasibility issues, and other 
regulatory considerations.  
H3.1.3 Justification for dose chosen for BRII-196 and BRII-198   
The 1000 mg / 1000 mg clinical doses of the BRII-196 and BRII-198 combination therapy 
in the Phase 2/3 study is selected by considering the in vitro and in vivo pharmacology 
results, hypothesized in vivo target coverage requirements, predicted human serum drug 
concentration profiles, available safety data, including nonclinical toxicology data and 
preliminary clinical safety, and tolerability results from the ongoing Phase 1 studies in 
healthy adult participants. 
 
Based on the potent and unique RBD binding properties and in vitro antiviral 
neutralization activity, BRII-196 can be used as the main clinical efficacy component of 
the combination therapy. BRII-198 also demonstrated potent antiviral neutralizing activity 
in vitro, has a non-competitive RBD target binding epitope that is different from BRII-196 
and does not block the binding of ACE2 to the RBD region. These unique properties of 
BRII-198 make it a potentially important additional clinical efficacy component in the 
combination therapy in order to achieve a more effective treatment of COVID-19 patients 
infected with WT and different mutations of SARS-CoV-2 viruses and to minimize 
potential viral escape risk. Similar to reported data from other anti-SARS-CoV-2 
antibodies [13, 14], preliminary results indicated BRII-196 and BRII-198 combination 
therapy (1:1 ratio) treatment led to effective viral clearance and less body weight loss in 
the in vivo hACE-2 mouse model. Based on the above considerations, it is believed that 
the equivalent dose strategy of the BRII-196 and BRII-198 combination therapy will 
efficiently utilize unique characteristics of both antibodies that will lead to anticipated 
clinical efficacy. 
 
Based on previous experience with other antiviral neutralizing mAbs [15-17], as well as 
preliminary in vivo efficacy data in the hACE2 hamster model, it is hypothesized that drug 
coverage of 10-30 folds of in vitro IC90 at the sites of infection, e.g. nasal cavity and lung, 
is needed for effective treatment of COVID-19 patients. Literature reported biodistribution 
coefficients of monoclonal antibodies in the nasal cavity and lung are about 3-4% [15] 
and 10-15% [18] of the corresponding serum drug concentrations, respectively. Based 
on this assessment, the target minimal serum BRII-196 and BRII-198 concentrations are 
100-300 folds of in vitro IC90 for at least 3-weeks, the target duration considered suitable 
for neutralizing antibody therapy [19, 20].  
 
A population PK model was built and applied to predict human PK profiles of BRII-196 
and BRII-198. To support fixed dose strategy, body weight has been incorporated as a 
covariate in the population PK model, and the covariate analysis suggested minimal 
impact of body weight to the pharmacokinetics of BRII-196 and BRII-198. The model 
predicted terminal half-life is 89.2 days (10th-90th percentile:  65.2 - 124 days) that is in 

the reported range of other YTE mAbs in human [5, 6]. Interim data from the ongoing 
BRII-196 and BRII-198 Phase 1 studies in the healthy adult participants is consistent 
with the predicted concentration – time profiles at dose levels of 750 and 1500 mg. The 
proposed dose of 1000 mg of each antibody is predicted to have sufficient target 
coverage individually over minimally 3-week period.  
 
In addition, the nonclinical and preliminary clinical safety data also support the proposed 
dose of 1000 mg / 1000 mg for BRII-196 and BRII-198. BRII-196 and BRII-198 were well 
tolerated after two weekly doses of 100 or 300 mg/kg in the GLP 14-day toxicity studies 
with 56-day recovery. The “No-Observed Adverse Effect Level” (NOAEL) was 300 mg/kg 
for BRII-196 and BRII-198, the highest dose level tested in the studies. At the proposed 
dose of 1000 mg, the safety margins for BRII-196 were approximately 6.8-fold (human 
equivalent dose (HED)), 34-fold (Cmax) and 23-fold (AUC). The corresponding safety 
margins for BRII-198 were approximately 6.8-fold (HED), 29-fold (Cmax) and 23-fold 
(AUC). In addition, the combined dose of BRII-196 and BRII-198 was well tolerated in a 
single dose acute toxicity study in rats with the NOAEL at 300 mg/kg for each antibody. 
In the in vitro tissue cross reaction (TCR) study using representative human and 
cynomolgus monkey tissues, BRII-196 and BRII-198 had no cross reactivity with both 
human and cynomolgus tissues at concentrations up to 4-10 folds of the optimal positive 
staining concentrations. At the dose level of up to 3000 mg, both BRII-196 and BRII-198 
were well tolerated in the ongoing Phase 1 studies in the healthy adult participants.  
 
Based on the PK and PK/PD assessment and the available nonclinical and clinical safety 
profile, the following doses of BRII-196 and BRII-198 was chosen for study in ACTIV-3: 
1000 mg and 1000 mg, respectively.  
 
This dose is selected to minimize potential concerns about underdosing and thus failing 
to detect an efficacy signal for an efficacious therapy. There are no significant safety 
concerns about using the 1000 mg dose of each of the antibodies, as side effects in 
antibody therapy are not generally dose-dependent. 
H3.2. Agent specific eligibility criteria 
In addition to the inclusion and exclusion criteria outlined in the master protocol, the 
following patients will be excluded: 1) pregnant women; and 2) nursing mothers.  In 
addition, prior to the initial futility assessment which is performed when approximately 
150 participants have been enrolled on BRII-196/BRII-198 and 150 on placebo, patients 
on high-flow oxygen or non-invasive ventilation (category 5 of the pulmonary ordinal 
outcome) will be excluded.  These patients may be eligible for the trial if the initial futility 
assessment is passed by this agent. 
H3.3. Description of investigational agent 
H3.3.1. Administration and duration 
See the PIM and Pharmacy Procedures for details about administration and duration. 
See also section H3.5 below for guidance on the clinical management of the infusion, 
including infusion-related reactions. 
 A dedicated line should be used for infusion of BRII-196 and BRII-198 and they should 
not be mixed or administered with other medications.  

 
The recommended infusion rate is ≤ 4 mL/min. The infusion rate may be reduced as 
deemed necessary if an infusion reaction is observed.  
 
Participants will be closely monitored during the infusion and for at least 2 hours after 
completion of the infusion. Additional monitoring may be necessary based on clinical 
judgement of the study investigator(s) and/or site staff, and in accordance with the 
master protocol. The site must have resuscitation equipment, emergency drugs and 
appropriately trained staff available during the infusion and for at least 2 hours after the 
completion of the infusion. 
 
If a participant has not already received the relevant dose of remdesivir at the day of 
enrolment, and has no contraindications to start remdesivir, it is recommended (but not 
required) that the relevant dose of remdesivir is infused after the infusion of BRII-
196/placebo and BRII-198 /placebo is completed. 
 
H3.3.2. Formulation and preparation 
Both BRII-196 and BRII-198 sterile drug products are packaged in glass vials with a 
concentration of 30 mg/ml and should be stored upright and in the carton at 2-8 °C, 
protected from light.  
The pharmacy will dispense 1000 mg of each agent (see Table H3.1). Placebo is normal 
saline. The study medication is prepared by an unblinded pharmacist at the local 
pharmacy. To ensure blinding of the participant and clinical staff a colored sleeve will be 
placed over the infusion bags.  Preparation of study treatment and blinding procedures 
are described in the PIM and Pharmacy Procedures. 
BRII-196 and BRII-198 should be prepared and dispensed as soon as possible after 
randomization. Both infusions must be completed (including flush of line) within 4 hours 
after preparation if the solution for injection has been stored at room temperature, or 
within 24 hours if the solution has been stored under refrigerated conditions. 
Table H3.1. Study medication overview.  
Intervention Name 
Placebo 
BRII-196 
BRII-198   
Dose Formulation 
0.9% sodium chloride 
solution 
Solution in single-use 
vial (30 mg/mL) 
Solution in single-use 
vial (30 mg/mL)  
Dosage 
Level(s) 
(mg) 
Not applicable 
1000 mg  
1000 mg  
Route of 
administration 
IV infusion 
IV infusion 
IV infusion 
Use 
Placebo 
Experimental 
Experimental 
IMP and NIMP 
IMP 
IMP 
IMP 
Sourcing 
Commercially available 
0.9% sodium chloride 
solution 
manufacture 
and 
testing performed by 
WuXi Biologics Co. Ltd 
manufacture and testing 
performed 
by 
WuXi 
Biologics Co. Ltd 

Packaging and 
Labeling 
Commercially available 
0.9% sodium chloride 
solution 
Study Intervention will 
be provided in glass 
vials 
and 
will 
be 
labeled appropriately 
Study Intervention will be 
provided in glass vials 
and 
will 
be 
labeled 
appropriately 
 
H3.3.3 Supply, distribution, and accountability 
Procedures for ordering and accepting drug, for maintaining inventory of BRII-196+BRII-
198, and for breaking the blind in the event of a medical emergency will be described in 
the Pharmacy Procedures. 
H3.3.4. Contraindicated medications 
No medication is known to be contraindicated in patients receiving the investigational 
agent.  
 
H3.3.5. Precautionary medications 
The clinical site should have necessary equipment and medications for the management 
of any infusion reaction (see section H3.5 below).  
 
Premedication for infusions is not planned. However, if an infusion reaction occurs during 
administration or if the participant has a medical history suggesting a potential benefit 
from premedication, the study investigator(s) should determine the appropriate 
premedication. 
 
The investigators and sponsor may decide to recommend premedication, if the frequency 
of infusion reactions among participants warrants it. If minor infusion reactions are 
observed, administration of acetaminophen, 500 mg to 1000 mg, antihistamines and/or 
other appropriately indicated medications may be given prior to the start of infusions for 
subsequent participants. The decision to implement premedication for infusions in 
subsequent participants will be made by the investigator and sponsor and recorded in 
the study documentation. Any premedication(s) given will be documented as a 
concomitant therapy. 
H3.4. Clinical and laboratory evaluations 
 
H3.4.1 Timing of Assessments 
Appendix B outlines the clinical and laboratory monitoring. Assessment and reporting of 
AEs (section 10.1.1), SAEs (section 10.1.2) and unanticipated problems (section 10.1.3) 
and their severity, causality (section 10.1.5) and expectedness (section 10.1.6) is 
performed as outlined in the relevant section of the master protocol.  
 
The half-life of BRII-196 and BRII-198 is 90 days. As outlined in the master protocol, the 
primary endpoint is assessed through day 90, but follow-up will be extended to 18 
months for BRII-196 and BRII-198 to collect hospitalizations and deaths (section 9.1.2). 
 
H3.4.2 Immunogenicity Assessments 
At the visits specified in the master protocol (Days 0, 28, and 90) venous blood samples 
will be collected to determine antibody production against BRII-196+BRII-198. 
Immunogenicity may be assessed by a validated assay designed to detect ADAs in the 
I 

presence of BRII-196+BRII-198. Antibodies may be further characterized for their ability 
to neutralize the activity of BRII-196+BRII-198. Remaining volume from the PK sample 
may also be used for immunogenicity assessments as needed.   
 
H3.4.3. Pharmacokinetic Assessments 
At the visits specified in the master protocol (Days 0, 1, 5, 28, and 90) venous blood 
samples will be collected to determine BRII-196+BRII-198   serum concentration for 
pharmacokinetic assessment. The PK/Immunogenicity assessment will require 2 mL of 
the serum collected, as described in the Master Protocol Appendix B as “Research 
Sample Storage”.  PK samples may be assessed by a validated assay at a bioanalytical 
lab. The PK assessment will use the same 2 ml serum aliquot specified in the 
Immunogenicity assessment section above (H3.4.2). Analysis of samples from placebo-
treated subjects is not planned. Remaining sample used for PK may be pooled and used 
for exploratory metabolism or bioanalytical method experiments as deemed appropriate.  
H3.5. Clinical management issues 
All participants should be monitored closely for 2 hours after the infusion, as there is a 
risk of infusion reaction and hypersensitivity (including anaphylaxis) with any biological 
agent. 
H3.5.1. Symptoms and Signs 
Symptoms and signs that may occur as part of an infusion reaction, include, but are not 
limited to, fever, chills, nausea, headache, bronchospasm, hypotension, angioedema, 
throat irritation, rash including urticaria, pruritus, myalgia, and dizziness.  
Infusion-related reactions’ severity will be assessed and reported using the Division of 
AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, 
Corrected version 2.1 [21] 
H3.5.2. Site Needs 
The clinical site should have necessary equipment, medications, adequately qualified 
and experienced staff with appropriate medical cover for the management of any infusion 
reaction, which may include, but is not limited to, oxygen, IV fluid, epinephrine 
(adrenaline), acetaminophen (paracetamol) and antihistamine. 
The pharmacy must use amber-colored Ultraviolet Light-Inhibiting (UVLI) protective bags 
to place over the infusion bag. The pharmacy will be provided with labels to be placed 
on the IV bag before dispensing (refer to the Pharmacy Procedures). 
The pharmacy is required to provide normal saline and IV bags, similarly shrouded.  
H3.5.3. Management of Infusion Reactions including Discontinuation 
Investigators will use their clinical judgement and standard of care to evaluate and 
manage all infusion reactions. If an infusion reaction occurs, then supportive care should 
be used in accordance with the signs and symptoms. If a severe and potentially life-
threatening infusion reaction occurs with BRII-196+BRII-198/placebo, its use should be 
permanently discontinued. 

If a participant is not infused with BRII-196+BRII-198/placebo or the complete infusion is 
not given, all follow-up procedures and reporting’s outlined in the master protocol 
(Appendix B for overview), should be adhered to as indicated. 
H3.5.4. Adverse Events of Special Interest (AESI) 
The following are AESIs for the agent BRII-196+BRII-198 or placebo for BRII-196+BRII-
198:  
• Infusion-related reactions 
• Allergic/hypersensitivity reactions 
H3.6. References 
1. 
Ju, B., et al., Human neutralizing antibodies elicited by SARS-CoV-2 infection. 
Nature, 2020. 584(7819): p. 115-119. 
2. 
Brii Biosciences, BRII-198 Investigator’s Brochure v1.0, 2020. 
3. 
Brii Biosciences, BRII-196 Investigator’s Brochure v1.0, 2020. 
4. 
Walls, A.C., et al., Structure, Function, and Antigenicity of the SARS-CoV-2 Spike 
Glycoprotein. Cell, 2020. 181(2): p. 281-292.e6. 
5. 
Robbie, G.J., et al., A novel investigational Fc-modified humanized monoclonal 
antibody, motavizumab-YTE, has an extended half-life in healthy adults. Antimicrob 
Agents Chemother, 2013. 57(12): p. 6147-53. 
6. 
Saunders, K.O., Conceptual Approaches to Modulating Antibody Effector Functions 
and Circulation Half-Life. Front Immunol, 2019. 10: p. 1296. 
7. 
Brii Biosciences. Safety, Tolerability, and Pharmacokinetics Study of Human 
Monoclonal 
Antibody 
BRII-196. 
Available 
from: 
https://ClinicalTrials.gov/show/NCT04479631. 
8. 
Brii Biosciences. Safety, Tolerability, and Pharmacokinetics Study of Human 
Monoclonal 
Antibody 
BRII-198. 
Available 
from: 
https://ClinicalTrials.gov/show/NCT04479644. 
9. 
Baum, A., et al., Antibody cocktail to SARS-CoV-2 spike protein prevents rapid 
mutational escape seen with individual antibodies. Science, 2020. 369(6506): p. 
1014-1018. 
10. 
Duan, K., et al., Effectiveness of convalescent plasma therapy in severe COVID-19 
patients. Proc Natl Acad Sci U S A, 2020. 117(17): p. 9490-9496. 
11. 
Joyner, M.J., et al., Safety Update: COVID-19 Convalescent Plasma in 20,000 
Hospitalized Patients. Mayo Clin Proc, 2020. 95(9): p. 1888-1897. 
12. 
Griffin, M.P., et al., Single-Dose Nirsevimab for Prevention of RSV in Preterm Infants. 
N Engl J Med, 2020. 383(5): p. 415-425. 
13. 
Baum, A., et al., REGN-COV2 antibody cocktail prevents and treats SARS-CoV-2 
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