Conditions: SARS CoV 2 Infection
Keywords: Prophylaxis Immunocompromised host Transplant Monoclonal antibodies
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 93
Healthy volunteers: no

Brief summary:
This is an open-label study examining the safety and tolerability of sotrovimab, administered in two sequential doses as prophylaxis in immunocompromised patients with impaired humoral immunity against SARS-CoV-2.

Detailed description:
This open-label study evaluated the safety and tolerability of sotrovimab, administered in two sequential doses, as COVID-19 prophylaxis in immunocompromised patients with impaired humoral immunity against SARS-CoV-2. 93 patients were enrolled in this study, 10 patients in an initial lead-in PK cohort initially planned to determine the optimal dosing interval between the first and second dose of sotrovimab and assess the safety and tolerability of the drug (prior to the spread of the BA.2 variant, which made it necessary to administer the repeat sotrovimab dose earlier than originally anticipated, using theoretical modeling and logistical considerations), 50 patients (including the 10 patients in the lead-in PK cohort) in a safety and tolerability lead-in cohort to examine rates of infusion-related reactions (IRR) with a 30-minute sotrovimab IV infusion, and the remainder in an expansion cohort for further assessment of the safety and tolerability of sotrovimab in this patient population, with the sotrovimab infusion duration determined by the rate of IRRs in the 50-patient safety and tolerability lead-in cohort. The first treatment consisted of sotrovimab 500mg as an intravenous (IV) infusion over 30 minutes, followed by a one-hour monitoring period. The second treatment, administered in a time when BA.2 became the dominant SARS-CoV-2 variant, consisted of sotrovimab 2000mg as an intravenous (IV) infusion over 60 minutes, followed by a two-hour monitoring period in the first 10 patients administered this dose, who comprised a second lead-in safety cohort for this 2000mg dose, and a one-hour monitoring period in all patients subsequently receiving their second sotrovimab dose, maintaining this one-hour monitoring period as long as there were no grade \>2 infusion-related reactions or other SAEs potentially related to the sotrovimab dose in this 2000mg dose lead-in safety cohort.

Arms:
arm 1: Two intravenous (IV) doses of sotrovimab were be administered in total - the first on Treatment Day 1 (500mg) and the second on Treatment Day 2, approximately 8-14 weeks after the first dose, at a higher 2000mg dose, in light of the reduced antiviral susceptibility of the BA.2 subvariant to sotrovimab, with the dosing interval determined by theoretical modeling of the duration of efficacy of sotrovimab as antiviral prophylaxis based on the rising prevalence of the Omicron BA.2 subvariant.

Interventions: intervention 1: Sotrovimab
Intervention descriptions: intervention 1: Two intravenous (IV) doses of sotrovimab were administered over the study period, the first 500mg, and the second 2000mg, in light of the reduced antiviral neutralization of sotrovimab against the BA.2 subvariant.

Protocol document:
Prot_SAP_000.pdf: 
1 
DF/HCC Protocol #: 21-755 
 
TITLE:  A Safety and Tolerability Study of Sotrovimab (VIR-7831) Prophylaxis Against 
COVID-19 Infection in Immunocompromised Individuals with Impaired SARS-CoV-2 Humoral 
Immunity 
 
Sponsor-Investigator: 
Sophia Koo, MD, SM 
Division of Infectious Diseases 
Brigham and Women’s Hospital/Dana-Farber Cancer Institute 
skoo@bwh.harvard.edu 
 
*Principal Investigators (PI):  
Sophia Koo, MD, SM 
Division of Infectious Diseases 
Brigham and Women’s Hospital/Dana-Farber Cancer Institute 
skoo@bwh.harvard.edu 
 
Sarah P. Hammond, MD 
Division of Infectious Diseases 
Massachusetts General Hospital 
shammond@mgh.harvard.edu 
 
*Key Co-Investigator: 
Jennifer Manne-Goehler, ScD, MD 
Division of Infectious Diseases 
Brigham and Women’s Hospital 
jmanne@partners.org 
 
Statistician: 
 
 
Study Coordinator:  
Wei Wang, PhD 
 
Katherine Beluch & Alyssa Cho 
Brigham and Women’s Hospital 
Brigham and Women’s Hospital 
wwang4@bwh.harvard.edu 
Dana-Farber Cancer Institute 
 
 
 
 
 
 
 
450 Brookline Avenue 
Responsible Data Manager:  
 
 
Boston, MA 02215 
Isabel Gonzalez-Bocco, MD 
 
 
 
 
 
Katherine_Beluch@dfci.harvard.edu 
Brigham and Women’s Hospital  
 
 
 
 
acho5@bwh.harvard.edu 
Dana-Farber Cancer Institute 
450 Brookline Avenue 
Boston, MA 02215 
Isabel_Gonzalez-Bocco@dfci.harvard.edu  
 
Other Agent(s): Sotrovimab (VIR-7831, GSK4182136, Xevudy), Vir Biotechnology, Inc. 
 
IND #: 159550 
 
IND Sponsor: Sophia Koo, MD, SM 


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SCHEMA 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
 
SCHEMA 
2 
1. 
OBJECTIVES 5 
1.1 
Study Design ............................................................................................................5 
1.2 
Primary Objectives...................................................................................................5 
1.3 
Secondary Objectives...............................................................................................6 
BACKGROUND 
6 
2.1 Study Disease(s).............................................................................................................6 
2.2       IND Agent ..............................................................................................................10 
2.3          Rationale .............................................................................................................13 
2.4 
Correlative Studies Background ............................................................................14 
3. 
PARTICIPANT SELECTION ...........................................................................................14 
3.1    Eligibility Criteria .....................................................................................................14 
3.2 
Exclusion Criteria ..................................................................................................16 
3.3 
Inclusion of Women and Minorities ......................................................................16 
4 
REGISTRATION PROCEDURES ...................................................................................17 
4.1 
General Guidelines for DF/HCC Institutions ........................................................17 
4.2 
Registration Process for DF/HCC Institutions .......................................................17 
4.3 
General Guidelines for Other Investigative Sites ..................................................17 
4.4 
Registration Process for Other Investigative Sites.................................................17 
5. 
TREATMENT PLAN ........................................................................................................17 
5.1. 
Treatment Regimen ................................................................................................17 
5.2. 
Pre-Treatment Criteria ...........................................................................................18 
5.3. 
Agent Administration.............................................................................................19 
5.4. 
General Concomitant Medication and Supportive Care Guidelines ......................22 
5.5. 
Criteria for Taking a Participant Off Protocol Therapy .........................................23 
5.6. 
Duration of Follow Up ...........................................................................................24 
5.7. 
Criteria for Taking a Participant Off Study ...........................................................24 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................25 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................26 
7.1. 
Expected Toxicities ................................................................................................29 
7.2. 
Adverse Event Characteristics ...............................................................................31 
7.3. 
Adverse Event Reporting .......................................................................................32 
7.4. 
Reporting to the Food and Drug Administration (FDA) .......................................34 
7.5. 
Reporting to Hospital Risk Management ...............................................................34 
7.6. 
Routine Adverse Event Reporting .........................................................................34 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................34 


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8.1. 
Sotrovimab .............................................................................................................35 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................45 
9.1. 
Biomarker Studies ..................................................................................................45 
9.2. 
Laboratory Correlative Studies ..............................................................................45 
9.3. 
Special Studies .......................................................................................................45 
10. 
STUDY CALENDAR .......................................................................................................45 
11. 
MEASUREMENT OF EFFECT........................................................................................49 
11.1. Safety and Tolerability Assessments .....................................................................49 
11.2. Drug Concentration Measurements for Pharmacokinetic Assessment ..................54 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................56 
12.1. Data Reporting .......................................................................................................56 
12.2. Data Safety Monitoring..........................................................................................57 
12.3. Collaborative Agreements Language .....................................................................58 
13. 
STATISTICAL CONSIDERATIONS...............................................................................58 
13.1. Study Design/Endpoints.........................................................................................58 
13.2. Sample Size, Accrual Rate and Study Duration ....................................................60 
13.3. Stratification Factors ..............................................................................................61 
13.4. Interim Monitoring Plan ........................................................................................62 
13.5. Analysis of Primary Endpoints ..............................................................................62 
13.6. Analysis of Secondary Endpoints ..........................................................................62 
13.7. Reporting and Exclusions ......................................................................................63 
14. 
PUBLICATION PLAN .....................................................................................................63 
REFERENCES 
64 
APPENDIX A 
KARNOFSKY PERFORMANCE STATUS SCALE ...............................69 
APPENDIX B 
MULTI-CENTER GUIDELINES .............................................................70 
APPENDIX C 
INFORMATION ON POSSIBLE DRUG 
INTERACTIONS ..............................................................................................................71 
APPENDIX D 
COVID-19 CLINICAL SIGNS AND SYMPTOMS 
ASSESSMENT ..................................................................................................................72 
APPENDIX E 
8-Point National Institute of Allergy and Infectious 
Diseases Ordinal Scale (NIAID-OS) for the Assessment of Clinical Status 
in Patients with SARS-CoV-2 Infection ............................................................................73 
 
 
 


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1. 
OBJECTIVES  
 
1.1 
Study Design 
 
This is an open-label study examining the safety and tolerability of sotrovimab, administered in 
two sequential doses as prophylaxis in immunocompromised patients with impaired humoral 
immunity against SARS-CoV-2. Approximately 93 patients will be enrolled in this study, 10 
patients in an initial lead-in PK cohort initially planned to determine the optimal dosing interval 
between the first and second dose of sotrovimab and assess the safety and tolerability of the drug 
(prior to the spread of the BA.2 variant, which made it necessary to administer the repeat 
sotrovimab dose earlier than originally anticipated, using theoretical modeling and logistical 
considerations), 50 patients (including the 10 patients in the lead-in PK cohort) in a safety and 
tolerability lead-in cohort to examine rates of infusion-related reactions (IRR) with a 30-minute 
sotrovimab IV infusion, and the remainder in an expansion cohort for further assessment of the 
safety and tolerability of sotrovimab in this patient population, with the sotrovimab infusion 
duration determined by the rate of IRRs in the 50-patient safety and tolerability lead-in cohort. 
The first treatment consists of sotrovimab 500mg as an intravenous (IV) infusion over 30 
minutes, followed by a one-hour monitoring period. The second treatment, to be administered in 
a time when BA.2 has become the dominant SARS-CoV-2 variant, will consist of sotrovimab 
2000mg as an intravenous (IV) infusion over 60 minutes, followed by a two-hour monitoring 
period in the first 10 patients administered this dose, who will comprise a second lead-in safety 
cohort for this 2000mg dose, and a one-hour monitoring period in all patients subsequently 
receiving their second sotrovimab dose, as long as there are no grade >2 infusion-related 
reactions or other SAEs potentially related to the sotrovimab dose in this 2000mg dose lead-in 
safety cohort. 
 
 
1.2 
Primary Objectives 
 
● Assessment of the safety and tolerability of sotrovimab in immunocompromised patients 
with impaired humoral immunity against SARS-CoV-2, including:  
○ The proportion of patients with treatment-emergent grade 3-4 adverse events 
(TEAEs). 
○ The proportion of patients with treatment-emergent serious adverse events 
(SAEs). 
○ The proportion of patients with adverse events of special interest (AESI), 
including infusion-related and hypersensitivity reactions, the development of 
anti-drug antibody (ADA) levels, and antibody-dependent enhancement (ADE) 
of COVID-19 disease. 
● An assessment of the pharmacokinetics of sotrovimab in immunocompromised patients 
with impaired humoral immunity against SARS-CoV-2. 
 
 
 


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1.3 
Secondary Objectives 
 
• An assessment of rates of symptomatic COVID-19 infection (of any severity) in this 
cohort of immunocompromised patients with impaired humoral immunity against SARS-
CoV-2 after receiving sotrovimab. 
● An assessment of rates of asymptomatic COVID-19 infection in this cohort of 
immunocompromised patients with impaired humoral immunity against SARS-CoV-2 
after receiving sotrovimab. 
● An assessment of rates of severe COVID-19 infection (with hospitalization, intensive 
care unit admission and/or mechanical ventilation, or death), in this cohort of 
immunocompromised patients with impaired humoral immunity against SARS-CoV-2 
after receiving sotrovimab. 
● In patients who develop COVID-19, a determination of the greatest extent of COVID-19 
symptoms using the 8-point National Institute of Allergy and Infectious Diseases ordinal 
scale (NIAID-OS), assessed at the end of hospitalization or 14 days after the diagnosis of 
COVID-19. 
● An assessment of health-related quality of life measures longitudinally in participants 
over the course of the study using the SF-36 instrument. 
 
1.4. Exploratory Objectives 
   
● Assessment of rates of new cellular or antibody-mediated rejection events in SOT 
recipients exposed to sotrovimab. 
● Assessment of rates of new-onset or worsening graft-versus-host disease in HCT 
recipients exposed to sotrovimab. 
● Assessment of rates of new-onset allograft or stem cell failure requiring re-
transplantation in HCT recipients exposed to sotrovimab. 
 
 
BACKGROUND 
 
2.1 Study Disease(s) 
 
Summary of SARS-CoV-2 and an overview of the COVID-19 pandemic 
 
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel single stranded RNA 
betacoronavirus that can cause severe infections in humans, first identified in December 2019, 
and spreading widely across the globe since that time [1-3]. The World Health Organization 
declared COVID-19 a global pandemic on March 11, 2020 [4]. As of September 2021, there 
have been over 4.7 million COVID-19-associated deaths worldwide [5].  
 
Patients infected with SARS-CoV-2 have a wide range of clinical symptoms, from individuals 
who are fully asymptomatic to those with fulminant respiratory and multiorgan failure [6-7]. 
Many patients with COVID-19 experience a range of symptoms including fatigue, body aches, 


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fever or chills, sore throat, cough, shortness of breath, loss of taste or smell, headache, nausea, 
vomiting, or diarrhea [6-8]. Even when mild at onset, there is growing evidence these symptoms 
can persist for prolonged periods of time after the acute infection has resolved. Patients with 
severe SARS-CoV-2 infection often have dyspnea, hypoxemia requiring supplemental oxygen, 
pulmonary edema, lung infiltrates, and systemic inflammation, with elevated interleukin-6 and 
C-reactive protein levels [9-10]. Patients who become critically ill from COVID-19 infection and 
require intensive care and mechanical ventilation have high mortality rates [9]. 
 
Not all patients are similarly affected by COVID-19 infection - there is growing evidence that 
certain factors are associated with particularly severe clinical outcomes. Age is believed to be a 
strong risk factor for poor COVID-19 outcomes, and over 80% of COVID-19-related deaths 
have occurred in people who are 65 years or older [11]. Moreover, an array of pre-existing 
medical conditions have been linked to a high risk of severe disease and death due to COVID-19, 
including obesity and diabetes, chronic lung disease, hypertension, coronary artery disease, and 
underlying immunocompromising states, including both solid organ and stem cell transplants 
[12-13]. Finally, patients with many of these preexisting comorbidities have a significantly 
higher risk of in-hospital mortality [14,15]. 
 
For most patients, a full recovery from SARS-CoV-2 infection occurs 10-20 days after symptom 
onset [16]. However, infections can be severe and prolonged in immunocompromised patients, 
with a recovery period that can last for several months after infection, high associated mortality 
rates, and the selection of new SARS-CoV-2 variants in some of these patients [17-18]. 
 
SARS-CoV-2 Vaccine Responses in Immunocompromised Individuals 
 
Many immunocompromised individuals have an impaired humoral immune response to SARS-
CoV-2 vaccination compared to responses in the general population, especially patients receiving 
anti-CD20 antibodies, solid organ transplant recipients, patients with certain B-cell hematologic 
malignancies, and stem-cell transplant recipients, including CD-19+ chimeric-antigen receptor T 
(CAR-T) cell recipients [19-29]. Only 44-70% of patients exposed to anti-CD20 therapies, 73% 
of hematopoietic cell transplant recipients, and 14% of CD19-CAR-T cell recipients develop 
anti-SARS-CoV-2 spike protein antibodies after two doses of SARS-CoV-2 mRNA vaccination 
[19-23]. Patients with B-cell hematologic malignancies, such as mantle cell lymphoma (44%), 
marginal zone lymphoma (62%), chronic lymphocytic leukemia (37-64%), Waldenstrom’s 
macroglobulinemia (74%), follicular lymphoma (78%), and diffuse large B-cell lymphoma 
(79%), also have significantly impaired humoral responses to SARS-CoV-2 mRNA vaccination, 
especially patients treated with anti-CD20 antibodies, steroids, venetoclax, or Bruton’s tyrosine 
kinase inhibitors, but also patients who have not recently received chemotherapeutic agents [24-
29]. 
 
Patients with solid organ transplantation also have impaired humoral immune responses to 
SARS-CoV-2 vaccination, with only 36-62% developing a measurable antibody response to 2-
vaccine SARS-CoV-2 mRNA regimens, with particularly low humoral responses in older solid 
organ transplant recipients and patients exposed to antimetabolite drugs [30-34]. While a third 
‘booster’ dose of mRNA vaccine increases immunogenicity of the SARS-CoV-2 mRNA 
vaccines, with a detectable serologic response rising from 40% after dose 2 to 68% following 
dose 3, a substantial subset of solid organ transplant patients still do not develop evidence of 
humoral immunity to SARS-CoV-2 [34-36]. 


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Patients with rheumatologic diseases, particularly those receiving rituximab and other anti-CD20 
therapies, and patients with congenital immunodeficiency syndromes also have impaired 
humoral immune responses to SARS-CoV-2 vaccination [37-39]. 
 
These patients are also at higher risk of developing severe COVID-19 disease [9-10]. Therefore, 
alternative approaches are needed to prevent SARS-CoV-2 infection and mitigate disease 
severity in these particularly vulnerable patients. 
  
COVID-19 Variants 
 
With over 240 million confirmed cases and nearly 5 million deaths worldwide due to COVID-19 
to date [40], there has been an accelerated search for both preventive interventions such as 
vaccines and effective therapeutic agents, such as antivirals and monoclonal antibody therapies. 
Over the course of the COVID-19 pandemic, several SARS-CoV-2 variants, including Alpha 
(B.1.1.7), Beta (B.1.351, B.1.351.2, B.1.351.3), Delta (B.1.617.2, AY.1, AY.2, AY.3), and 
Gamma (P.1, P.1.1, P.1.2), have spread widely [17-18].  
 
The Delta and Omicron (BA.1, BA.1.1, BA.2, and BA.3) variants are more infectious and spread 
more efficiently than earlier lineages of SARS-CoV-2 [17, 41-43]. Since December 2021, the 
Omicron lineage has become the dominant variant of SARS-CoV-2 globally, with its distinct 
sublineages, BA.1, BA.1+R346K, BA.2, BA.2 + H78Y, and BA.3, which share 21 mutations in 
the spike protein. BA.2 contains 8 additional unique mutations while BA.1 and BA.1+R346K 
contain 13 and 14 unique mutations, respectively [41]. Importantly, at least 15 of these mutations 
are located in the receptor-binding domain of the S-protein [42]. 
 
Mutations in the spike protein of new variants such as those described above continue to drive 
resistance to existing monoclonal antibody treatment and vaccines [43-44]. Because the S-
protein is the binding site for many monoclonal antibodies and the target of existing SARS-CoV-
2 vaccine products, there has been growing concern about the antiviral efficacy of these agents. 
Several recent studies have demonstrated reduced susceptibility of the BA.2 subvariant to 
Sotrovimab, although the extent to which its antiviral efficacy is affected has varied widely 
across studies [41-42]. Mutations in the spike protein of new variants could potentially continue 
to drive resistance to existing monoclonal antibody treatment and vaccines [42-43]. Prevention 
and treatment strategies need to evolve with sufficient rapidity to address the ongoing 
development of resistance in emerging SARS-CoV-2 variants. 
 
Existing COVID-19 Treatments and Preventive Therapies 
  
COVID-19 Treatments 
  
Antiviral agents: There are three antiviral agents currently authorized for treatment of COVID-
19 in the US. Veklury (remdesivir) is an intravenous (IV) antiviral drug that has been approved 
for the treatment of adults and pediatric patients (12 years of age and older and weighing at least 
40 kg) with COVID-19 requiring hospitalization [13]. In December 2021, ritonavir-boosted 
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aged ≥12 years and weighing ≥40 kg who are within 5 days of symptom onset and considered at 
high-risk The EPIC-HR trial found that this drug reduced the risk of hospitalization or death by 
89% compared to placebo in non-hospitalized high-risk adults with COVID-19 [45]. This agent 
has become first-line therapy for many patients with mild to moderate COVID-19 in the United 
States. Finally, the MOVe-OUT trial of the novel oral antiviral drug molnupiravir found that it 
reduces the risk of hospitalization or death in non-hospitalized patients with mild to moderate 
COVID-19 disease by approximately 30% compared to placebo [46]. This therapy received FDA 
EUA on in December 2021 for the treatment of high-risk adults with mild to moderate COVID-
19, within 5 days of symptom onset and for whom alternative antiviral therapies are not 
accessible or clinically appropriate. 
 
Monoclonal antibodies: Multiple monoclonal antibody therapies have received U.S. Food and 
Drug Administration Emergency Use Authorization. The Regeneron REGEN-COV antibody 
cocktail of casirivimab and imdevimab was approved under EUA for the treatment of mild to 
moderate COVID-19 disease in adults and in pediatric patients (12 years of age or older 
weighing at least 40 kg), who have positive results of direct SARS-CoV-2 viral testing and are at 
high risk for progression to severe COVID-19 and for post-exposure prophylaxis (PEP), but this 
cocktail was later de-authorized due to its severely reduced antiviral efficacy against the 
Omicron variant [47].  
 
In February 2021, the Eli Lilly monoclonal antibodies bamlanivimab and etesevimab received 
EUA for the treatment of adults and children with COVID-19 who are at risk for worsening 
disease progression and for PEP in patients who are not fully vaccinated or not expected to 
mount an adequate immune response to SARS-CoV-2 vaccination, but its distribution was also 
halted in light of severely reduced antiviral efficacy against emerging SARS-CoV-2 variants 
[48]. In May 2021, sotrovimab received EUA for the treatment of mild-to-moderate COVID-19 
in adults and children (12 years of age and older weighing at least 40 kg) with positive results of 
direct SARS-CoV-2 viral testing, and who are at high risk of progression to severe COVID-19, 
including hospitalization or death [49-50]. In March 2022, the distribution of sotrovimab was 
paused due to the spread of the Omicron BA.2 variant, given the reduced antiviral susceptibility 
of this variant to sotrovimab. In February 2022, the antibody bebtelovimab received EUA for the 
treatment of non-hospitalized high-risk patients with mild to moderate COVID-19 [51]. 
Bebtelovimab appears to retain its activity against the Omicron variant of concern (VOC) and 
both its BA.1 and BA.2 subvariants [52]. 
 
Immune modulators: There are two immune modulators, baricitinib (Olumiant) and 
tocilizumab (Actemra), with FDA EUA for the treatment of COVID-19. Baricitinib is authorized 
for the treatment of COVID-19 in combination with Veklury in hospitalized adults and children 
(2 years or older) who are receiving corticosteroids and need supplemental oxygen, mechanical 
ventilation (non-invasive or invasive), or extracorporeal membrane oxygenation (ECMO) [48]. 
Actemra is authorized for use in the same patient population as baricitinib but it does not need to 
be administered in combination with Veklury [53].  
  
Prevention 
 


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Vaccines: In August 2021, the Pfizer-BioNTech COVID-19 messenger RNA vaccine, also 
known as Comirnaty, was approved by the U.S. Food and Drug Administration [54]. 
The Moderna and Janssen COVID-19 vaccines also received FDA EUA, with the Moderna 
vaccine receiving FDA approval [55-56].  
 
Monoclonal antibodies: In addition to these modes of prevention, AZD7442 is an antibody 
combination that was recently shown to be an effective form of COVID-19 pre-exposure 
prophylaxis in the PROVENT Phase III clinical trial [57]. AZD7442 leverages a proprietary half-
life extension technology and may provide 12 months of protection from COVID-19. This 
monoclonal antibody is delivered by intramuscular (IM) injection. 
 
2.2       IND Agent 
 
Sotrovimab Background 
  
S proteins on the surface of SARS-CoV-2 bind to ACE2 receptors in host tissues, allowing viral 
entry into host cells and viral RNA replication [56]. The ACE2 receptor is prone to mutations, 
leading to resistance to currently available monoclonal therapies. Sotrovimab is an 
investigational engineered monoclonal antibody that targets a highly conserved epitope on the 
spike glycoprotein of SARS-CoV-2. Using Xmab Fc technology, this antibody has a 
modification in its Fc region that increases its binding affinity to receptor FcRn in lysosomes in 
endothelial cells, rescuing these antibodies from degradation, prolonging its serum half-life, and 
potentially increasing its bioavailability in tissues such as the respiratory mucosa.  
Sotrovimab targets a highly conserved spike epitope, with amino acid conservation > 99.99% for 
all amino acids based on >2,100,000 available sequences. Variants at two positions, E340 and 
P337, resulted in significant EC50 shifts indicating reduced susceptibility to sotrovimab. E340 
and P337 are 99.99% conserved among sequences in the GISAID database (16 July 2021). 
Sotrovimab neutralizes SARS-CoV-2 live virus and retains activity against alpha (B.1.1.7), beta 
(B.1.351), gamma (P.1), delta (B.1.617.2) and kappa (B.1.617.1) variant live virus. In vitro 
sotrovimab neutralizes and retains activity against the alpha (B.1.1.7), beta (B.1.351), gamma 
(P.1), delta (B.1.617.2). delta plus (AY.1/AY.2) epsilon (B.1.427/B.1.429), iota (B.1.526), kappa 
(B.1.617.1), lambda (C.37) and mu (B.1.621) variant viruses in the VSV/VeroE6 pseudotyped 
virus system; against omicron BA.2 and BA.3, there are fold changes of 15.7 and 7.3, 
respectively, in a pseudotyped virus system, and 35.1 against BA.2 live virus [44, 58-60]. 
 
Sotrovimab has been authorized for the treatment of mild-to-moderate COVID-19 in adults and 
children (12 years of age and older weighing at least 40 kg) with positive results of direct SARS-
CoV-2 viral testing, who are at high risk of progression to severe COVID-19, including 
hospitalization or death, under a U.S. Food and Drug Administration Emergency Use 
Authorization (EUA) [49-50], although starting March 25, 2022, it was no longer authorized in 
states and territories where the proportion of COVID-19 cases caused by the Omicron BA.2 
variant is above 50% [61]. 
  
Drug Interactions 
 


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No formal interaction studies have been conducted with sotrovimab. Sotrovimab is neither 
renally excreted nor metabolized by cytochrome P450 (CYP) enzymes; therefore, interactions 
with concomitant medications that are renally excreted or that are substrates, inducers, or 
inhibitors of CYP enzymes are unlikely.  
 
In in vitro pharmacodynamic studies with remdesivir or bamlanivimab, sotrovimab showed 
additive virologic effect and no antagonism with either agent.  
 
COVID-19 Monoclonal Antibody Efficacy Trial-Intent to Care Early (COMET-ICE) 
Interim Clinical Trial Results 
  
COMET-ICE, a phase 3, randomized, placebo-controlled pivotal trial of sotrovimab for the 
treatment of non-hospitalized patients with symptomatic COVID-19 and at least one risk factor 
for disease progression, was stopped in March 2021 by an independent data monitoring 
committee because of profound efficacy. An interim analysis of this study showed an 85% risk 
reduction in disease progression leading to hospitalization or death in patients treated with a 500 
mg single intravenous dose of sotrovimab, compared to placebo [49]. In this study, 3 patients in 
the sotrovimab treatment group (1% of the 291 patients randomized to this arm) developed 
disease progression leading to hospitalization or death, compared to 21 patients in the placebo 
group (7% of the 292 patients randomized to this arm). Adverse events were reported by 17% of 
patients in the sotrovimab group and 18% of those who received placebo, and serious adverse 
events (SAEs) were less common in patients receiving sotrovimab (2%) than in those receiving 
placebo (6%) [50]. Based on this interim analysis of the COMET-ICE trial, sotrovimab was 
granted a U.S. Food and Drug Administration Emergency Use Authorization (EUA) for the 
treatment of mild-to-moderate COVID-19 in adults and children (12 years of age and older 
weighing at least 40 kg) with positive results of direct SARS-CoV-2 viral testing, and who are at 
high risk of progression to severe COVID-19, including hospitalization or death [49]. 
 
Safety Profile of Sotrovimab in Clinical Studies 
As of August 18, 2021, 1843 participants have received sotrovimab administered intravenously 
(IV) or intramuscularly (IM) in Vir/GSK-sponsored clinical studies. As summarized in the 
sotrovimab Investigator Brochure v3, no safety concerns for sotrovimab have been identified in 
these clinical studies, and sotrovimab has been safe and well-tolerated. 
Rationale for Dose Selection 
 
A dose of 500 mg was selected for the study based on in vitro neutralization data, in vitro 
resistance data, and intravenous (IV) pharmacokinetic (PK) data from the COMET-ICE trial 
[49]. The 500 mg dose is being evaluated in ongoing and halted clinical studies; COMET-ICE 
[NCT04545060], ACTIV-3-TICO [NCT04501978], COMET-PEAK (NCT04779879), COMET-
TAIL (NCT04913675), and Study 217653 (NCT04988152). Sotrovimab (500 mg, IV) was 
assessed in participants with COVID-19 in an early treatment study, VIR-7831-5001 (214367, 
also known as COMET-ICE [NCT04545060]), with the aim of preventing disease progression in 
non-hospitalized participants. For the first planned interim analysis, the Independent Data 
Monitoring Committee (IDMC) met on 10 March 2021 and reviewed data from 583 participants. 


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The IDMC recommended halting enrollment in the trial due to overwhelming efficacy, with an 
85% reduction in the risk of hospitalization or death in the sotrovimab arm versus the placebo 
arm (primary endpoint) [49]. 
 
Sotrovimab neutralized SARS-CoV-2 live virus with an average EC90 value of 186.3 ng/mL 
(range: 125.8 – 329.5 ng/mL) (PC-7831-0105). In resistance analyses, no viral breakthrough was 
observed through 10 passages at fixed concentrations of antibody, indicating the potential for 
sotrovimab to have a high barrier to resistance (PC-7831-0109). Using an increasing 
concentration selection method to force resistance emergence, E340A was identified as a 
monoclonal antibody-resistant mutant (MARM) conferring a >100-fold reduction in 
susceptibility to sotrovimab. Notably, E340 is 99.9% conserved among available SARS-CoV-2 
sequences. Due to the binary nature of the resistance selection results, a specific inhibitory 
quotient (IQ) was not informed by the resistance profiling.  
 
Based on IV PK data from the lead-in and expansion phases of the COMET-ICE study, the mean 
serum concentration of sotrovimab following a single 500 mg IV dose is 40.3 g/mL (N = 469) 
at Day 29. Based on the non-compartmental analysis of intensive PK data from the lead-in phase, 
the sotrovimab median (range) half-life is estimated to be 56.5 (42.4, 77.3) days. 
 
A 500 mg IV dose was initially selected to ensure that sotrovimab concentrations in the lung are 
maintained at or above levels anticipated to be neutralizing for the duration of the treatment 
window [62-66]. In vitro live virus assays indicated that, compared to wild type EC90 (0.288 
μg/mL), Omicron BA.1 and BA.2 confer a 3.5-fold and 35-fold shift in EC90, respectively (PC-
7831-0155). Based on the EC90 of BA.2 and accounting for the lung:serum ratio as 25%, an IV 
dose of 500 mg is expected to maintain serum levels above tissue-adjusted EC90 at day 15 for 
90% of patients and day 34 for 50% of patients. 
 
This study will assess two intravenous (IV) doses of sotrovimab, administered on Treatment Day 
1 and on a second dosing day approximately 8-14 weeks after the first dose. The dosing interval 
to be determined based on PK modeling of the duration of efficacy of sotrovimab as antiviral 
prophylaxis against the Omicron BA.2 subvariant, and the availability of the higher 2000mg 
dose for administration in the study. 
 
The exposure after 2000 mg IV was predicted using a preliminary population PK model that was 
developed using data across several studies including COMET-ICE, COMET-PEAK, BLAZE-4 
and a PK study in individuals of Japanese and Caucasian descent. The predicted median (10th, 
90th percentile) sotrovimab serum concentrations at 16 weeks following a second sotrovimab 
dose of 2000 mg IV given 8 week or 12 weeks after the first 500 mg IV dose are 69.2 (38.7, 
109.4) µg/mL and 64.5 (38.0,105.2) µg/mL, respectively. Tissue-adjusted EC90 values were 
calculated using different assumptions for lung:serum ratio of 25%, 15% or 10% (based on 
literature reports for monoclonal antibodies in general, and were used to estimate coverage above 
tissue-adjusted EC90 following the second dose of sotrovimab 2000 mg IV [67-72]. 
 
When assuming a lung:serum ratio of 25%, a 2000 mg IV dose is expected to provide coverage 
against the Omicron BA.2 variant in 90% of patients for approximately 4 months when given 8-
12 weeks after the first dose. With more conservative assumptions of a lung:serum ratio of 15% 


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and 10%, a 2000 mg IV dose given 8-12 weeks after the initial 500 mg IV dose is expected to 
provide adequate protection against BA.2 in 90% of patients for approximately 2 months. 
 
2.3          Rationale 
 
The primary medical approach to preventing COVID-19 currently is centered on several widely 
available vaccine products. In the United States, there are currently three COVID-19 vaccines 
available, the Pfizer-BioNTech, Moderna, and Johnson and Johnson/Janssen vaccines. Both 
Pfizer-BioNTech and Moderna are messenger RNA vaccines while the Johnson and 
Johnson/Janssen vaccine uses an adenovirus DNA vector. The Pfizer-BioNTech vaccine was 
95% effective at preventing laboratory-confirmed SARS-CoV-2 viral infection, while the 
Moderna vaccine was about 94.1% effective. In comparison, a single dose of the Johnson and 
Johnson vaccine was 66.3% effective in preventing laboratory confirmed SARs-CoV-2 infection. 
Both the Pfizer-BioNTech COVID-19 and Moderna vaccine received full FDA approval in 
August 2021 and January 2022, respectively [6]. 
 
Only 44-70% of patients exposed to anti-CD20 therapies, 73% of hematopoietic cell transplant recipients, 
and 14% of CD19-CAR-T cell recipients, for example, develop SARS-CoV-2 spike protein antibodies 
after two doses of SARS-CoV-2 mRNA vaccination [7-11] Patients with B-cell hematologic 
malignancies, such as chronic lymphocytic leukemia (37-64%), follicular lymphoma (78%), and diffuse 
large B-cell lymphoma (79%), also have significantly impaired humoral responses to SARS-CoV-2 
mRNA vaccination, especially patients treated with anti-CD20 antibodies, steroids, venetoclax, or 
Bruton’s tyrosine kinase inhibitors, but also patients who have not recently received chemotherapeutic 
agents [12-15, 41]. Among two preliminary studies on solid organ transplant patients receiving 
immunosuppressive drugs the prevalence of SARS-CoV-2 spike antibodies was found to be between 20-
40% after two doses of the vaccine [16-17], with similarly low prevalence of spike antibodies in patients 
with rheumatologic diseases receiving anti-CD20 therapies and other immunodeficiency syndromes with 
impaired humoral immune responses [18-20]. Finally, all these patient populations are also at higher risk 
of severe COVID-19 disease, highlighting the need for alternative approaches to prevent SARS-CoV-2 
infection in these particularly vulnerable patients. 
 
There are also several treatments for COVID-19 that are currently approved or under investigation, 
including remdesivir, dexamethasone, tocilizumab, and antivirals (e.g., remdesivir, molnupiravir); 
however, none of these therapies are currently being used for the prevention of COVID-19 disease. 
A monoclonal antibody product called AZD7442 showed evidence of efficacy for COVID-19 pre-
exposure prophylaxis in the PROVENT Phase III clinical trial [57]. 
  
Monoclonal antibodies represent a highly specific and versatile alternative for COVID-19 
prevention and treatment. Given that passive immunity is an instantly effective inducer of 
neutralization, opsonization, complement activation and antibody dependent cellular cytotoxicity 
and does not depend on recipients’ immune response, it appears to be ideal for 
immunocompromised patients who fail to develop SARS-CoV-2 spike antibodies with current 
available vaccines and vaccination guidelines [64]. In May 2021, sotrovimab received U.S. Food 
and Administration Emergency Use Authorization for the treatment of mild-to-moderate COVID-
19 in adults and children (12 years of age and older weighing at least 40 kg) with positive results 
of direct SARS-CoV-2 viral testing, and who are at high risk of progression to severe COVID-19, 
including hospitalization and death [49-50], although as of March 25, 2022, it is no longer 


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authorized for the treatment of mild-moderate COVID-19 in states and territories where the 
proportion of COVID-19 cases caused by the Omicron BA.2 variant exceeds 50% [61]. 
 
The primary objective of this study is to assess the safety and tolerability of sotrovimab, 
administered for the prevention of SARS-CoV-2 infection and COVID-19 disease, and to 
determine the pharmacokinetics of sotrovimab in these patients when administered at baseline 
and with a repeat dose. Immunocompromised individuals with a negative SARS-CoV-2 spike 
antibody remain at an exceptionally high risk of this infection and severe clinical outcomes if 
they become infected, and measures to prevent COVID-19 infection in these vulnerable patients 
are needed. 
 
2.4 
Correlative Studies Background 
 
N/A 
 
 
3. PARTICIPANT SELECTION 
 
3.1    Eligibility Criteria  
 
The study population will consist of immunocompromised adults who have evidence of impaired 
humoral immunity to SARS-CoV-2 based on SARS-CoV-2 spike antibody testing performed 
within 28 days of enrollment. This population is ideal for the study of sotrovimab as pre-
exposure prevention, as these individuals are believed to have impaired immunological 
protection from prior infection or SARS-CoV-2 vaccination, and therefore at particularly high 
risk of acquiring this infection and developing severe disease manifestations. 
 
3.1.1 Participant must be 18 years of age or older at the time of consent and weigh at least 40 
kg. Children will be excluded from this study because dosing and adverse event data are 
limited for the use of sotrovimab in participants <18 years of age. 
 
3.1.2 Participant must have one of the following immunocompromising conditions that 
increases their likelihood of having an impaired humoral immune response to SARS-
CoV2, while also increasing their risk of being infected with SARS-CoV-2 and risk of 
progression to severe COVID-19: 
 
• Exposure to an anti-CD20 monoclonal antibody (e.g. all formulations of rituximab, 
obinutuzumab, ofatumumab, ocrelizumab, ibritumomab, tositumomab) for a hematologic 
malignancy or an autoimmune/inflammatory disease in the 12-month period prior to 
consent. 
• Allogeneic hematopoietic cell transplant ≥ 3 months and ≤ 1 year prior to consent; or 
allogeneic hematopoietic cell transplant >1 year prior to consent plus active graft-versus-
host disease on systemic immunosuppressive therapy. 
• Chimeric antigen receptor (CAR)-T cell therapy ≥ 4 weeks and ≤ 2 years prior to consent. 


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• Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), multiple 
myeloma, or Waldenström macroglobulinemia. 
• Solid organ transplant recipient receiving immunosuppressive therapy. 
• Congenital immunodeficiency syndrome (e.g. Wiskott-Aldrich syndrome, DiGeorge 
syndrome, common variable immunodeficiency). 
• Patients with hematologic malignancy or autoimmune/inflammatory disease exposed to 
immunosuppressive medications specifically associated with a blunted humoral immune 
response to SARS-CoV-2 vaccination (e.g. mycophenolate mofetil, azathioprine, 
methotrexate, Bruton tyrosine kinase inhibitors, ruxolitinib, venetoclax, or corticosteroids 
(prednisone >20mg or equivalent daily for at least 14 days) in the 3-month period prior to 
consent. 
 
3.1.3 Female participants must be: 
 
a. Postmenopausal for at least 1 year; 
b. Post-hysterectomy and/or post-bilateral oophorectomy;  
c. Of childbearing potential, with a negative urine or serum human chorionic 
gonadotropin pregnancy test prior to each sotrovimab dose, and agree to use a 
highly effective method of birth control throughout the study period.  
 
Highly effective methods of birth control for purposes of this study include: 
  
i. 
Use of an established oral, injected, transdermal, intravaginal or implanted 
hormonal form of contraception associated with inhibition of ovulation. 
ii. 
Placement of an intrauterine device or intrauterine hormone-releasing 
system. 
iii. 
Male partner sterilization. 
iv. 
Bilateral tubal occlusion. 
v. 
Sexual abstinence (excluding periodic abstinence [e.g. calendar, ovulation, 
symptom-thermal, or post ovulation methods] and withdrawal). 
 
The effects of sotrovimab on the developing human fetus are unknown. 
Pharmacological studies of sotrovimab have not been conducted in pregnant women 
and there is limited clinical experience using sotrovimab in women who are pregnant 
or breastfeeding. However, there is the potential for sotrovimab to cross the placental 
barrier and be present in breast milk; therefore, this therapy could theoretically be 
passed from mother to child during pregnancy or breastfeeding. For this reason, even 
though monoclonal antibodies are not known to be teratogenic, women of 
childbearing potential must agree to use a highly effective method of birth control 
from enrollment through the study follow-up period.  Should a woman become 
pregnant or suspect she is pregnant while she is participating in this study, she should 


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inform her treating physician immediately. The pregnancy will be followed and any 
safety issue observed will be reported. 
 
3.1.4 Participants must have a negative or low-positive (<50 U/mL) SARS-CoV-2 spike 
antibody assay result within 28 days of consent. 
 
3.2 
Exclusion Criteria 
 
3.2.1 Participants with an active SARS-CoV-2 infection, with a positive SARS-CoV-2 RT-
PCR or antigen test result within 21 days prior to consent. 
 
3.2.2 Participants with symptoms suggestive of SARS-CoV-2 infection. 
 
3.2.3 Close contact (less than 6 feet away for a cumulative total of ≥ 15 minutes over a 24-hour 
period) with an individual with COVID-19 in the 14 days prior to consent. 
 
3.2.4 Individuals who are pregnant or breastfeeding. 
 
3.2.5 Participants who are receiving any other investigational agents. 
 
3.2.6 Participants who, in the judgment of the investigator, are likely to have a life expectancy 
of less than one year. 
 
3.2.7 Known hypersensitivity to any constituent present in sotrovimab or any other anti-SARS-
CoV-2 monoclonal antibody product. 
 
3.2.8 Active enrollment on another interventional research study of any agent for the treatment 
or prophylaxis of SARS-CoV-2 infection. 
 
3.2.9 Exposure to any other anti-SARS-CoV-2 monoclonal antibody product for the treatment 
of COVID-19 in the prior 6 months. 
 
3.2.10 Exposure to any other anti-SARS-CoV-2 monoclonal antibody product for prophylaxis 
against COVID-19 infection in the prior 12 months. 
 
3.2.11 Receipt of a SARS-CoV-2 vaccine dose within the prior 28 days. 
 
3.3 
Inclusion of Women and Minorities 
 
Individuals of all genders, races, and ethnic groups are eligible for this trial. Individuals with 
disabilities, at the extremes of weight, and those whose preferred language is not English will be 
included as study participants if they meet the inclusion and exclusion criteria outlined in 
Sections 3.1 and 3.2.  
 


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4 
REGISTRATION PROCEDURES  
 
4.1 
General Guidelines for DF/HCC Institutions 
 
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore. Registrations must occur prior to the initiation of any protocol-specific therapy or 
intervention. Any participant not registered to the protocol before protocol-specific therapy or 
intervention begins will be considered ineligible and registration will be denied. 
 
An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist. 
 
Following registration, participants may begin protocol-specific therapy and/or intervention. 
Issues that would cause treatment delays should be discussed with the Principal Investigator (PI) 
of the registering site. If the subject does not receive protocol therapy following registration, the 
subject must be taken off study in the CTMS (OnCore) with an appropriate date and reason 
entered.   
 
4.2 
Registration Process for DF/HCC Institutions 
 
Applicable DF/HCC policy (REGIST-101) must be followed.   
 
4.3 
General Guidelines for Other Investigative Sites 
 
N/A 
 
4.4 
Registration Process for Other Investigative Sites 
 
N/A 
 
 
5. TREATMENT PLAN 
 
5.1.Treatment Regimen 
 
This open-label study of sotrovimab, administered as a 500mg intravenous (IV) dose at the start 
of the study (Treatment Day 1) and as a 2000mg intravenous (IV) dose at a second time point 8-
14 weeks after the first dose (Treatment Day 2), determined by PK modeling of the duration of 
efficacy of sotrovimab as antiviral prophylaxis against Omicron BA.2 subvariant, and the 
availability of the higher 2000 mg dose for administration in the study, will provide an 
assessment of the safety and tolerability of this monoclonal antibody as a preventive approach to 
COVID-19 in immunocompromised individuals with impaired humoral immunity to SARS-
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The first treatment consists of sotrovimab 500mg as an intravenous (IV) infusion over 30 
minutes followed by a one-hour monitoring period. The second treatment, to be administered in a 
time when BA.2 has become the dominant SARS-CoV-2 variant, will consist of sotrovimab 
2000mg as an intravenous (IV) infusion over 60 minutes, followed by a two-hour monitoring 
period in the first 10 patients administered this dose, who will comprise a lead-in safety cohort 
for this 2000mg dose, and a one-hour monitoring period in all patients subsequently receiving 
their second sotrovimab dose, as long as there are no grade >2 infusion-related reactions or other 
SAEs potentially related to the sotrovimab dose in this 2000mg dose lead-in safety cohort. The 
infusion time will be 60 minutes for all patients receiving the repeat 2000mg dose. 
 
Treatment will be administered on an outpatient basis. Reported adverse events and potential 
risks are described in Section 7.  Dose modifications are not allowed in this study.  
 
Background Treatments 
 
Patients may have received standard of care therapies for the prevention of SARS-CoV-2 
infection prior to enrollment in this study, including any SARS-CoV-2 vaccines that are 
approved or available under Emergency Use Authorization (EUA) by the U.S. Food and Drug 
Administration. 
 
Rescue Treatments 
 
If study subjects develop COVID-19, they may receive rescue treatment for COVID-19 per the 
local standard of care. If study subjects are exposed to a contact with active COVID-19, they 
may receive post-exposure prophylaxis (PEP) as per the local standard of care. If study subjects 
develop COVID-19 or receive post-exposure prophylaxis after the first sotrovimab dose but prior 
to receiving their second sotrovimab dose, they will not receive the second dose of sotrovimab. 
Completion of the study and other study assessments will be performed according to the study 
schedule. These rescue treatments will not be provided as part of the study. 
 
5.2. Pre-Treatment Criteria 
The screening period is the window between day -7 (7 days prior to Treatment Day 1) and 
Treatment Day 1. The purpose of the screening period is to assess the eligibility of study subjects 
to participate in this study. 
Screening procedures include:  
● Confirmation that the potential study subject meets the inclusion and exclusion criteria 
outlined in Sections 3.1 and 3.2. 
● Participants must have a negative or low-positive (<50 U/mL) SARS-CoV-2 spike 
antibody test result within 28 days of consent, using an assay available under U.S. Food 
and Drug Administration (FDA) Emergency Use Authorization (EUA). Potential study 
subjects who have not yet had SARS-CoV-2 spike antibody testing in this window should 
have a SARS-CoV-2 spike antibody test available under FDA EUA checked, such as the 


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Roche Elecsys Anti-SARS-CoV-2 S assay, both for routine clinical care and to help 
evaluate their eligibility for this study. 
If the study subject meets inclusion and exclusion criteria, screening and Treatment Day 1 
procedures may be performed on the same day. Informed consent should be completed during the 
screening visit. 
Potential study participants need to meet all eligibility criteria outlined in Section 3.1 and 3.2 prior 
to receiving their first dose of sotrovimab. 
5.3.Agent Administration 
 
Study subjects will receive sotrovimab 500mg as an intravenous (IV) infusion over 30 minutes 
on Treatment Day 1 and 2000mg as an intravenous (IV) infusion over 60 minutes on Treatment 
Day 2. Study subjects will be monitored for one hour after the end of each 500mg infusion. After 
receiving the 2000mg dose on Treatment Day 2, which will occur 8-14 weeks after the first dose, 
the first 10 patients administered this dose, who will comprise a lead-in safety cohort for this 
2000mg dose, will be observed for a 2-hour monitoring period. Subsequent patients receiving 
this 2000mg dose will have a one-hour monitoring period following their dose, as long as there 
are no grade 3 or 4 infusion-related reactions or other SAEs potentially related to the sotrovimab 
dose in the 2000mg dose lead-in safety cohort. If there are any grade 3 or 4 infusion-related 
reactions or other SAEs potentially related to the sotrovimab dose in this cohort, infusion time 
may be extended beyond 60 minutes, and the monitoring time may be maintained at 2 hours 
following this dose for subsequent patients. 
 
Sotrovimab is not a vesicant or irritant. 
 
Vital signs (including body temperature, heart rate, blood pressure, oxygen saturation (SpO2), 
and respiratory rate) will be collected according to the schedule outlined in Section 10 (Study 
Calendar), including prior to and following sotrovimab dosing on Treatment Day 1 and the 
Treatment Day 2. Vital signs should be obtained after 5 minutes of rest (supine or sitting). Vitals 
signs that are obtained following each sotrovimab dose should be obtained within 30 minutes 
after drug administration has been completed.  
 
An electrocardiogram (ECG) will be obtained according to the schedule outlined in Section 10 
(Study Calendar), including prior to each dose of sotrovimab. 
 
Serum sotrovimab levels will be measured for PK assessment according to the schedule outlined 
in Section 10 (Study Calendar), including prior to the second dose of sotrovimab on Treatment 
Day 2 and within 1 hour after each sotrovimab dose. 
 
Infusion Reactions 
 
Emergency equipment and medication for the treatment of infusion reactions must be available 
for immediate use if needed during the infusion of study drug. Infusion-related reactions are 


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defined as any relevant adverse events occurring during the infusion and up to 24 hours after 
the infusion. 
 
All infusion-related reactions and hypersensitivity reactions must be reported as adverse 
events of special interest (AESIs). 
 
Pre-medications should not be given routinely prior to the first dose of sotrovimab. If an 
infusion-related reaction occurs during the first dose of sotrovimab that is not severe enough to 
warrant discontinuation of the study treatment for a participant, the study team may decide to 
administer pre-medications prior to the second sotrovimab dose for that participant, 
administering an oral antihistamine agent (e.g. diphenhydramine, loratadine, famotidine) at least 
30 minutes prior to starting the second sotrovimab dose or an intravenous antihistamine agent at 
least 5 minutes prior to starting the second sotrovimab dose. 
 
Management of Local Infusion Site Reactions 
 
Patients may develop local infusion site reactions, including erythema, soreness, pruritus, or 
bleeding, which should be managed according to the table below: 
 
Table 1: Management of Local Injection/Infusion Site Reactions 
Signs and Symptoms 
Management 
Redness, soreness or 
swelling at the 
injection site 
Apply a cold compress to the injection site(s) 
Consider giving an analgesic (e.g., ibuprofen, acetaminophen, 
paracetamol) 
Itching and redness 
Consider giving an anti-pruritic (e.g., diphenhydramine) 
Observe patient closely for the development of generalized 
symptoms 
Slight bleeding 
Apply pressure and an adhesive compress 
Continuous bleeding 
Place gauze pads over the site and maintain direct and firm pressure 
 
Recognizing Systemic Reactions or Anaphylaxis 
 
As with any monoclonal antibody therapy, hypersensitivity reactions to sotrovimab are possible. 
In the COMET-ICE pivotal trial, all hypersensitivity reactions were non-serious, of Grade 1 
(mild) or Grade 2 (moderate) severity and reported in 2% of participants who received 
sotrovimab and in <1% who received placebo (9 participants treated with sotrovimab and 5 
participants treated with placebo) [48]. None of the reactions in either arm led to pausing or 


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discontinuation of the infusions. No anaphylaxis events were reported in the COMET-ICE study 
in participants with mild to moderate COVID-19 not requiring hospitalization at study entry. 
 
A potentially life-threatening allergic reaction (anaphylaxis) was observed in one adult 
participant who received sotrovimab in a study of individuals hospitalized with COVID-19 (the 
ACTIV-3 TICO study). The anaphylaxis was considered by the investigator to be related to 
study treatment. The participant was treated for the allergic reaction and recovered. Another 
patient who received sotrovimab under an emergency expanded access basis developed 
anaphylaxis shortly after the start of infusion and required hospitalization. No further details 
were provided. 
 
Therefore, appropriate drugs and medical equipment to treat acute anaphylactic reactions must 
be immediately available, and study personnel must be trained to recognize and treat 
anaphylaxis. 
 
Interruption of the Intravenous Infusion 
  
The infusion should be paused if any of the following adverse events occur at grade ≤ 2 (mild or 
moderate) severity, as defined in the Division of AIDS (DAIDS) Table for Grading the Severity 
of Adult and Pediatric Adverse Events, Version 2.1 [73]: 
 
● Sustained coughing 
● Rash or pruritus 
● Chills/Rigors 
● Urticaria 
● Diaphoresis/Flushing 
● Hypotension 
● Dyspnea 
● Vomiting 
These reactions should be treated symptomatically (e.g. antihistamines, IV fluids), and the 
infusion may subsequently resume at 50% of the original rate at the investigator’s discretion 
when symptoms of these adverse events improve to  ≤ grade 1. 
If investigators feel there is a medical need to interrupt or discontinue the infusion for any 
reasons other than those listed above, they should use their clinical judgment in responding to 
these potential infusion-related reactions. 
Termination of the Intravenous Infusion 
  
The infusion should be terminated and not restarted if any of the following grade 3 or 4 
adverse events occur, as per DAIDS grading criteria [73]. In addition, if any of these grade 3 or 
4 AEs occurred with the first dose, the subject should not receive the second dose, but should 
continue all other follow-up through end of study visit. 
 
● Anaphylaxis: The most common signs and symptoms of anaphylaxis are cutaneous (e.g., 
sudden onset of generalized urticaria, angioedema, flushing, pruritus). However, 10-20% 


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of patients have no skin findings. Anaphylaxis should be considered if the study subject 
develops the acute onset of an illness with skin and/or mucosal tissue involvement (e.g. 
urticaria, lip swelling, tongue/uvula swelling, or pruritus) with at least one of the 
following: 
 
○ Respiratory compromise (dyspnea, stridor, wheezing, bronchospasm, hypoxemia) 
○ Hypotension or associated symptoms suggestive of end-organ dysfunction (e.g. 
syncope, incontinence) [74]. 
 
● Laryngeal or pharyngeal edema 
● Chest pain 
● Seizure 
● Persistent, symptomatic hypotension (defined as a systolic blood pressure (SBP) < 
90mmHg with symptoms consistent with hypotension (e.g. lightheadedness, syncope) that 
persists despite reducing the infusion rate) 
● Other neurologic symptoms (confusion, loss of consciousness, paresthesia, paralysis) 
● Any other symptom or sign that warrants termination of the IV infusion, according to 
the judgment of the investigator. 
 
Management of Suspected Anaphylaxis 
 
The following procedures should be followed in the event of a suspected anaphylactic reaction 
[75]: 
 
1. Call for additional medical assistance; activate emergency medical services. 
2. Ensure appropriate monitoring is in place, such as continuous ECG and pulse oximetry 
3. First-line treatment: 
a. Administer epinephrine (1.0 mg/ml) aqueous solution (1:1000 dilution) – 0.5 mg 
(0.5ml) IM in the anterolateral thigh OR if using an epinephrine auto-injector – 
use 0.3 mg IM into the anterolateral thigh. 
b. May be repeated every 5-15 minutes up to 3 times. 
4. Optional treatment (antihistamine): 
Diphenhydramine 50 mg oral/IV/intramuscular (IM) OR Hydroxyzine 25 mg 
oral/IM. 
5. Administer supplemental oxygen (8-10 L/minute) via facemask, as needed. 
6. Normal saline rapid bolus – treat hypotension with rapid infusion of 1-2 liters IV. 
7. Monitor the study subject until emergency medical services arrive. 
 
5.4. 
General Concomitant Medication and Supportive Care Guidelines 
 
Patients are not permitted to receive any medication specified in the exclusion criteria for study 
enrollment (Section 3.2), including active enrollment on another interventional research study of 


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any agent for the treatment or prophylaxis of SARS-CoV-2 infection, receipt of any other anti-
SARS-CoV-2 monoclonal antibody product for the treatment of COVID-19 in the prior 6 months 
or for prophylaxis against COVID-19 in the prior 12 months, or receipt of a SARS-CoV-2 vaccine 
dose within the 28 days prior to consent or during the study period.  
 
Patients who develop COVID-19 during the study follow-up period or have close contact with an 
individual who has COVID-19 and qualify for post-exposure prophylaxis may receive treatment 
per the local standard of care. 
 
If patients are due for another dose of SARS-CoV-2 vaccination during the study period, patients 
may receive this dose any time after receiving sotrovimab, outside of the 2-week period before 
their second sotrovimab dose [76]. Patients may receive other available anti-SARS-CoV-2 
monoclonal antibodies authorized for pre-exposure prophylaxis, such as tixagevimab/cilgavimab, 
≥ 10 weeks after their 2000mg sotrovimab dose, as a 2000mg IV dose of sotrovimab will protect 
50% of participants with a serum concentration above EC90 of BA.2 at 14.76 µg/mL for 10 weeks, 
assuming a lung:serum ratio at 15% and assuming 100% of SARS-CoV-2 infections are caused by 
the BA.2 variant at this time. 
 
Patients may otherwise continue their normal regimen of medications and procedures. 
 
Sotrovimab is neither renally excreted nor metabolized by cytochrome P450 (CYP) enzymes, and 
interactions with concomitant medications that are renally excreted or that are substrates, inducers, 
or inhibitors of CYP enzymes are unlikely. 
 
5.5. 
Criteria for Taking a Participant Off Protocol Therapy 
 
The study will last approximately 44-50 weeks (see Section 10 for the schedule of study visits, 
assessments, and sample collection): 
  
● Screening window: patients will have a screening period that lasts up to 7 days (Day -7 to 
Treatment Day 1). 
● Study period: From Treatment Day 1 to the end of treatment visit, patients will be 
followed according to the schedule of in-person and remote study visits, assessments, and 
sample collection points as outlined in Section 10. 168 days after Treatment Day 2, patients 
will have an in-person end of treatment (EOT) visit for sample collection and assessments. 
● Final remote visit: Patients will have a remote/telephone end of study (EOS) visit 36 
weeks/252 days after their final dose of sotrovimab, which corresponds to approximately 
5 half-lives of sotrovimab since the final dose. 
 
Subjects may be discontinued from the study drug (but continue to follow study procedures) for 
any of the following reasons:  
 
• Occurrence of an AE that, in the investigator’s opinion, warrants discontinuation of the 
subject from receiving further study drug. 
• Pregnancy or initiation of breastfeeding. 


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• Treatment with other monoclonal antibodies active against SARS-CoV-2 for post-
exposure prophylaxis after having a household contact with COVID-19 or for treatment of 
COVID-19 prior to Treatment Day 2. 
 
Participants will be removed from the protocol therapy when any of these criteria apply.  The 
reason for removal from protocol therapy, and the date the participant was removed, must be 
documented in source documents and in the eCRF. 
 
Participants removed from protocol therapy prior to dose 2 of study drug for any of the reasons 
listed above will not receive a second dose of sotrovimab, but they will be asked to complete all 
other study assessments according to the study calendar (Section 10).  
 
When a participant is removed from protocol therapy and/or is off of the study, the participant’s 
status must be updated in OnCore in accordance with REGIST-OP-1. 
 
5.6. 
Duration of Follow Up 
 
Participants will be followed for 36 weeks after their second dose of sotrovimab (corresponding 
to approximately 5 half-lives of sotrovimab since the final dose) or death, whichever occurs first.  
 
Participants removed from protocol therapy due to unacceptable adverse event(s) will be 
followed until resolution or stabilization of the adverse event. 
 
5.7. 
Criteria for Taking a Participant Off Study 
 
Subjects may be discontinued from the study for any of the following reasons:  
 
● Withdrawal of consent by the subject and/or the subject’s legally authorized 
representative. Any patient has the right to withdraw from the study at any time, for any 
reason, and without repercussions. As excessive withdrawals might threaten the 
interpretability and generalizability of the results, withdrawal of patients should be 
avoided whenever possible.  
● Loss to follow-up (every attempt should be made to contact the subject). 
● Intercurrent illness that prevents further administration of treatment. 
● Death. 
 
Participants who are discontinued from the study will be asked to complete an early termination 
visit (with study procedures as per the Treatment Day 2 + 168 day/end of treatment visit) at the 
time of study discontinuation. 
 
The reason for a subject’s discontinuation of treatment or withdrawal from the study will be 
documented clearly in the source documents and in the eCRF. In addition, the study team will 
ensure the participant’s status is updated in OnCore in accordance with REGIST-OP-1. 
 
 


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6. DOSING DELAYS/DOSE MODIFICATIONS 
 
Study subjects will receive two doses of sotrovimab, on Treatment Day 1 and Treatment Day 2. 
Dose modifications for individual patients are not allowed. 
 
Interruption of the Intravenous Infusion 
  
The infusion should be paused if any of the following adverse events occur at grade ≤ 2 (mild or 
moderate) severity, as defined in the Division of AIDS (DAIDS) Table for Grading the Severity 
of Adult and Pediatric Adverse Events, Version 2.1 [73]: 
 
● Sustained coughing 
● Rash or pruritus 
● Chills/Rigors 
● Urticaria 
● Diaphoresis/Flushing 
● Hypotension 
● Dyspnea 
● Vomiting 
These reactions should be treated symptomatically (e.g. antihistamines, IV fluids), and the 
infusion may subsequently resume at 50% of the original rate at the investigator’s discretion 
when symptoms of these adverse events improve to  ≤ grade 1. 
If investigators feel there is a medical need to interrupt or discontinue the infusion for any 
reasons other than those listed above, they should use their clinical judgment in responding to 
these potential infusion-related reactions. 
Termination of the Intravenous Infusion 
  
The infusion should be terminated and not restarted if any of the following grade 3 or 4 
adverse events occur, as per DAIDS grading criteria [73]. In addition, if any of these grade 3 or 
4 AEs occurred with the first dose, the subject should not receive the second dose, but should 
continue all other follow-up through end of study visit. 
 
● Anaphylaxis: The most common signs and symptoms of anaphylaxis are cutaneous (e.g., 
sudden onset of generalized urticaria, angioedema, flushing, pruritus). However, 10-20% 
of patients have no skin findings. Anaphylaxis should be considered if the study subject 
develops the acute onset of an illness with skin and/or mucosal tissue involvement (e.g. 
urticaria, lip swelling, tongue/uvula swelling, or pruritus) with at least one of the 
following: 
 
○ Respiratory compromise (dyspnea, stridor, wheezing, bronchospasm, hypoxemia) 
○ Hypotension or associated symptoms suggestive of end-organ dysfunction (e.g. 
syncope, incontinence) [74]. 
 


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● Laryngeal or pharyngeal edema 
● Chest pain 
● Seizure 
● Persistent, symptomatic hypotension (defined as a systolic blood pressure (SBP) < 
90mmHg with symptoms consistent with hypotension (e.g. lightheadedness, syncope) that 
persists despite reducing the infusion rate) 
● Other neurologic symptoms (confusion, loss of consciousness, paresthesia, paralysis) 
● Any other symptom or sign that warrants termination of the IV infusion, according to 
the judgment of the investigator. 
 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of reported and/or potential AEs (Section 7.1) and the characteristics of an 
observed AE (Section 7.2) will determine whether the event requires expedited reporting in 
addition to routine reporting. 
 
Following the first dose of sotrovimab on Treatment Day 1 and up to the end of study visit (36 
weeks after Treatment Day 2), study investigators must promptly record and report all 
treatment-emergent serious adverse events (SAEs), grade 2 unexpected and related 
treatment-emergent AEs, grade 3 or 4 treatment-emergent AEs (TEAEs). All adverse 
events of special interest (AESIs), regardless of grade, must be reported. 
 
These events may be directly observed, unsolicited (reported spontaneously by the patient), or 
solicited by questioning the study subject at each in-person and remote study visit. Patients 
should be questioned in a general way, without asking about the occurrence of any specific 
symptoms. The assessment of SAEs, TEAEs, and AESIs will be conducted by the investigator or 
qualified sub-investigators to determine causality and severity.  
 
Events should be: 
 
● Clearly documented in the site’s source documentation with the investigator’s signature. 
● Followed up proactively at subsequent visits or contacts until the SAE, grade 3-4 TEAE, 
or AESI has resolved, stabilized, are otherwise explained, or the participant is lost to 
follow-up. 
● Preferably reported as a diagnosis term. When a diagnosis term is unavailable, a primary 
report with a sign or symptom as the AE term should be entered until the diagnosis becomes 
available. 
 
Isolated abnormal laboratory results, vital signs, and other diagnostic results or findings should be 
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For events that are serious due to hospitalization, the reason for hospitalization must be reported 
as the serious adverse event (diagnosis or symptom requiring hospitalization). 
 
Adverse Event Definition 
 
An adverse event (AE) is defined as an untoward medical occurrence in a clinical study 
participant, temporally associated with the use of a study intervention, whether it is or is not 
considered related to the study intervention. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease (new or 
exacerbated) temporally associated with the use of a study intervention [77]. 
 
Events that meet the definition of an AE include:  
 
● Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition. 
● New conditions detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study. 
● Signs, symptoms, or the clinical sequelae of a suspected intervention or intervention 
interaction. 
● Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdoses should be reported regardless of sequelae. 
● Clinically significant changes in laboratory assessments. 
 
Events that do not meet the definition of an AE include: 
 
● "Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will 
be reported as an AE or SAE if they fulfill the definition of an AE or SAE. 
● Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant's condition. 
● The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant's 
condition. 
● Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
● Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 


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● Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
 
An unsolicited AE is one that was not solicited using a diary or form with pre-specified criteria. 
Unsolicited AEs are obtained either by asking a general question or unprompted by a participant 
who has signed the informed consent. Unsolicited AEs include serious and non-serious AEs. 
Potential unsolicited AEs may be medically attended (i.e., symptoms or illnesses requiring a 
hospitalization, or emergency room visit, or visit to/by a health care provider). The participants 
will be instructed to contact the site as soon as possible to report medically attended event(s), 
as well as any events that, though not medically attended, are of participant concern. Detailed 
information about reported unsolicited AEs will be collected by qualified site personnel and 
documented in the participant's records. 
  
Serious Adverse Event Definition 
  
A SAE is any untoward medical occurrence that at any dose: 
 
● Results in death – includes all deaths, even those that appear to be completely unrelated 
to the study drug (e.g., a car accident in which a patient is a passenger). 
● Is life-threatening – in the view of the investigator, the patient is at immediate risk of 
death at the time of the event. This does not include an adverse event that hypothetically 
might have caused death, had it been more severe. 
● Requires inpatient hospitalization or prolongation of existing hospitalization. In 
general, hospitalization signifies that the participant has been admitted (usually involving 
at least an overnight stay) at the hospital or emergency ward for observation and/or 
treatment that would not have been appropriate in the physician’s office or outpatient 
setting. Complications that occur during hospitalization are AE. If a complication 
prolongs hospitalization or fulfills any other serious criteria, the event is serious. When in 
doubt as to whether “hospitalization” occurred or was necessary, the AE should be 
considered serious. Of note, hospitalization for elective treatment of a pre-existing 
condition that did not worsen from baseline is not considered an AE. 
● Results in persistent or significant disability/incapacity (substantial disruption of one’s 
ability to conduct normal life functions). This definition is not intended to include 
experiences of relatively minor medical significance such as uncomplicated headache, 
nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g. sprained ankle) which 
may interfere with or prevent everyday life functions but do not constitute a substantial 
disruption. 
● Is a congenital anomaly/birth defect. 
● Is an important medical event – Important medical events may not be immediately life-
threatening or result in death or hospitalization, but may jeopardize the patient or may 
require intervention to prevent one of the other serious outcomes listed above (e.g. 
invasive or malignant cancers, intensive treatment in an emergency room or at home for 


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allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization; or development of intervention dependency or intervention abuse). 
● Additional sponsor SAE:  Hy’s Law case: ALT ≥ 3x upper limit of normal (ULN) AND 
total bilirubin ≥ 2xULN (>35% direct bilirubin) OR INR >1.5 must be reported as a 
SAE. 
● Medical or scientific judgment should be exercised by the investigator in deciding whether 
SAE reporting is appropriate in other situations such as significant medical events that may 
jeopardize the participant or may require medical or surgical intervention to prevent one of 
the other outcomes listed in the above definition. These events should usually be 
considered serious. 
Criteria for reporting SAEs (Section 7.3) must be followed for these events. 
7.1. 
Expected Toxicities 
 
7.1.1. Adverse Event List for Sotrovimab 
 
Adverse Events of Special Interest in Study Subjects Receiving Sotrovimab 
Adverse events of special interest (AESI) will be assessed from patient consent until the end of 
study visit (36 weeks after Treatment Day 2). 
Adverse events of special interest are defined as relevant known toxicities of therapeutic 
monoclonal antibodies and will be monitored by the study team during the study, including: 
● Hypersensitivity reactions or anaphylaxis. See Section 5.3 for guidance on the 
management of suspected hypersensitivity reactions or anaphylaxis. Hypersensitivity 
reactions any time following sotrovimab dosing developed in 2% of patients who 
received sotrovimab and <1% who received placebo, with a rash developing in some of 
these patients and bronchospasm 12 days after the sotrovimab dose in a patient with pre-
existing asthma; all events were considered non-serious and most were grade 1 in 
severity. There were no anaphylaxis events in COMET-ICE. 
 
A potentially life-threatening allergic reaction (anaphylaxis) was observed in one adult 
participant who received sotrovimab in the study of individuals hospitalized with 
COVID-19 (the ACTIV-3 TICO study), however. The anaphylaxis was considered by the 
investigator to be related to study treatment. The participant was treated for the allergic 
reaction and recovered. Another patient who received sotrovimab under an emergency 
expanded access basis developed anaphylaxis shortly after the start of infusion and 
required hospitalization. No further details were provided. 
● Infusion related reactions. See Section 5.3 for guidance on the management of 
suspected infusion-related reactions. Infusion-related reactions developed in 1% of 
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of dosing in COMET-ICE. Events reported within 24 hours of study treatment were 
pyrexia, chills, dizziness, dyspnea, pruritus, rash, and infusion-related reactions; all 
events were Grade 1 (mild) or Grade 2 (moderate) and none led to treatment interruption 
or discontinuation. 
● Immunogenicity-related adverse events (development of anti-drug antibodies (ADA)). 
Unwanted immunogenicity may lead to the production of ADA by the host, which may 
inactivate the therapeutic effects of the treatment and, in rare cases, induce adverse 
events. 
 
Immunogenicity will be characterized by an assessment of ADA titers according to the 
Study Calendar (Section 10) over the study period, at the baseline/Treatment Day 1 visit 
prior to the administration of the first sotrovimab dose, day 29, at the sotrovimab second 
dose visit prior to the administration of the second sotrovimab dose, day 29 after the 
second sotrovimab dose, and day 168 after the second sotrovimab dose (the EOT visit). 
The ADA response categories and titer categories are defined as follows: 
 
○ Negative: Sample with a confirmed negative result. 
○ Positive: Sample with a confirmed positive result. 
○ Treatment-induced: Subject that develops ADA de novo following drug 
administration (baseline negative or missing). 
○ Treatment-boosted: Subject with pre-existing ADA that are increased relative to 
baseline following drug administration (e.g titer ≥ 9x baseline titer). 
○ Transient ADA: Subject with treatment-induced ADA detected at only one time 
point (excluding baseline and final visit) or subject with two or more time points 
that are separated by no more than 16 weeks between the first and last ADA 
positive samples (irrespective of any negative samples in between) and the last 
sample is ADA negative. 
○ Persistent ADA: Subject with treatment-induced ADA detected at two or more 
time points where the first and last ADA positive samples (irrespective of any 
negative samples in between) are separated by 16 weeks or longer or Subject with 
treatment-induced ADA detected at the final time point. 
 
● Adverse events potentially related to antibody-dependent enhancement (ADE) of 
COVID-19 infection. 
 
Antibody-dependent enhancement (ADE) of disease theoretically can occur by 
facilitating viral entry into host cells and enhancing viral replication in these cells, by 
increasing viral fusion with target host cells, enhancing viral replication in these cells, or 
by enhancing disease pathology from viral antigen-antibody related immune complex 
deposition or complement activation and immune cell recruitment in target organs. This 
study will include participant follow-up for a period of 5 sotrovimab half-lives to assess 
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may manifest as an increased incidence of severe or prolonged disease in those who 
develop SARS-CoV-2 infection. 
 
There will not be a placebo arm in this study, but patients who develop incident COVID-
19 infection over the study follow-up period will be assessed for potential ADE, which 
may manifest as increased severity or duration of illness in patients temporally related to 
sotrovimab exposure. 
 
All infusion-related reactions and hypersensitivity reactions, per DAIDS grading criteria, and 
suspected ADE in patients who develop COVID-19, must be reported as AESIs. These AESIs 
must be followed up proactively at subsequent visits or contacts until they have resolved, 
stabilized, are otherwise explained, or the participant is lost to follow-up. ADA will be assessed 
at the end of the study in serum samples collected over the study period. 
 
 
7.2. 
Adverse Event Characteristics 
 
 
Determining the Severity of Adverse Events 
 
The severity of adverse events (including test findings classified as adverse events) will be graded 
for each AE using the current version of the DAIDS grading criteria [73]. All appropriate treatment 
areas should have access to a copy of the DAIDS grading scale; a copy can be downloaded from 
the 
National 
Institute 
of 
Allergy 
and 
Infectious 
Diseases 
at: 
https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf.  
 
Assessing the Causality of Adverse Events 
  
The investigator must provide an assessment of causality, determining whether there is a 
reasonable possibility that the investigational drug caused the adverse event, based on evidence or 
facts, clinical judgement, and the following definitions: 
 
● Related: the adverse event follows a reasonable temporal sequence from study drug 
administration and cannot be reasonably explained by the nature of the reaction, patient’s 
clinical, or other external factors OR the adverse event follows a reasonable temporal 
sequence from study drug administration and is a known reaction to the drug under study 
or its class of drugs or is predicted by known pharmacology. 
○ Definite – the AE is clearly related to the study treatment. 
○ Probable – the AE is likely related to the study treatment. 
○ Possible – the AE may be related to the study treatment. 
● Not likely to be related: the adverse event does not follow a reasonable sequence from 
study drug administration or can be reasonably explained by the nature of the reaction, 
patient’s clinical state, or other external factors. 
○ Unlikely – the AE is unlikely to be related to the study treatment. 
○ Unrelated – the AE is clearly not related to the study treatment. 


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The causality assessment must be made based on the available information and can be updated if 
new information becomes available. The investigator should consider the temporal relationship 
(time to AE onset vs. time drug was administered), nature of the reaction (immediate vs. long 
term), clinical and pathological features, concomitant medications, underlying disease, and past 
medical history of the patient, while assessing causality. 
 
All treatment-emergent SAEs, grade 2 AEs that are both unexpected and thought to be related to 
the study treatment, treatment-emergent grade 3 or 4 AEs (TEAEs), and all adverse events of 
special interest (AESIs), regardless of grade, must be reported with: 
 
● The investigator’s assessment of the event’s seriousness, severity, and causality in relation 
to the study drug. 
● A detailed narrative summarizing the course of the event, including its evaluation, 
treatment, and outcome should be provided on the AE eCRF. 
● Specific or estimated dates of event onset, treatment, and resolution. 
 
Source documents (including hospital or medical records, diagnostic reports, etc.) will be 
summarized in the narrative on the AE eCRF and retained at each study site, and available upon 
request for review. 
 
 
7.3. 
Adverse Event Reporting  
 
 
7.3.1. In the event of an unanticipated problem or life-threatening complications, treating 
investigators must immediately notify the sponsor-investigator. 
 
 
7.3.2. Investigators must report to the sponsor-investigator any adverse event (AE) that occurs 
after the initial dose of study treatment, during treatment, within 30 days of the last dose 
of treatment on the local institutional SAE form, and for this study, through the end of 
study visit 36 weeks after the second dose of sotrovimab.  
 
 
7.3.3. Adverse Event Reporting Guidelines 
 
All participating sites will report AEs to the Sponsor-Investigator per DF/HCC requirements, and 
the Institutional Review Board (IRB) of record for each site as applicable per IRB policies. The 
table below indicates which events must be reported to the DF/HCC Sponsor-Investigator. 
 
 
 
 
 


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Table 2. DF/HCC Reportable Adverse Events (AEs) 
 
 
 
 
Attribution 
DF/HCC Reportable Adverse Events(AEs) 
Gr. 2 & 3 AE 
Expected 
Gr. 2 & 3 AE 
Unexpected 
Gr. 4 AE Expected 
Gr. 4 AE 
Unexpected 
Gr. 5 AE 
Expected or 
Unexpected 
Unrelated 
Unlikely 
Not required 
Not required 
5 calendar days# 
5 calendar days 
24 hours* 
Possible 
Probable 
Definite 
 
Not required 
 
5 calendar days 
 
5 calendar days# 
 
5 calendar days 
 
24 hours* 
# If listed in protocol as expected and not requiring expedited reporting, event does not need to be reported. 
 
* For participants enrolled and actively participating in the study or for AEs occurring within 30 days of the last 
intervention, events must be reported within 1 business day of learning of the event. 
 
 
Furthermore, all adverse events of special interest (AESIs) of any severity, as outlined in Section 
7.1.1, should be reported to the sponsor-investigator within 24 hours of the investigator’s 
knowledge of the event (except for ADA, which will be assessed at the end of the study in serum 
samples collected over the study period). 
 
Expedited reporting requirements for AEs occurring on studies under an IND are as outlined in 
the table below: 
 
Table 3. Expedited Reporting Requirements for Adverse Events that Occur on Studies 
under an IND within 30 Days of the Last Administration of the Investigational 
Agent/Intervention 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor  ANY Serious Adverse Events, whether or not they 
are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon 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. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the sponsor-
investigator, IRB, and FDA within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 
Calendar Days 


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Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be reported to the sponsor investigator within 24 hours 
of learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour 
report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar days 
of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows: 
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events 
 
 
7.3.4. Protocol-Specific Adverse Event Reporting Exclusions 
 
N/A 
 
7.4. 
Reporting to the Food and Drug Administration (FDA) 
 
The Sponsor-Investigator will be responsible for all communications with the FDA. The 
Sponsor-Investigator will report to the FDA, regardless of the site of occurrence, any serious 
adverse event that meets the FDA’s criteria for expedited reporting following the reporting 
requirements and timelines set by the FDA. 
 
7.5. 
Reporting to Hospital Risk Management 
 
Each site PI will report to their local Risk Management Office any participant safety reports, 
sentinel events, or unanticipated problems that require reporting per institutional policy. The 
sponsor-investigator will also report any events that merit communication with the IRB via email 
concurrently to GSK (within 24 hours of the sponsor-investigator’s knowledge of the event). 
 
7.6. 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions to the sponsor-
investigator on the case report forms.  AEs reported through expedited processes (e.g., 
reported to the IRB, FDA, etc.) must also be reported in routine study data submissions. 
 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational agent 
administered in this study can be found in Section 7.1 and in the Investigator Brochure v3.  
 


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8.1. 
Sotrovimab 
 
8.1.1. Description 
Sotrovimab (VIR-7831, GSK4182136, Xevudy) is a dual action engineered human IgG1κ 
monoclonal anitibody derived from the parental monoclonal antibody S309, a potent neutralizing 
antibody that binds to a highly conserved epitope of the SARS-CoV and SARS-CoV-2 spike 
protein receptor binding domain. The amino acid sequence of the complementarity-determining 
regions of sotrovimab is identical to the parent molecule S309, with the exception of one amino 
acid modification (N55Q) introduced to aid antibody developability. The Fc domain of 
sotrovimab has been engineered to provide extended half-life through the introduction of the 
well-characterized LS modification (M438L and N444S), which extends antibody half-life and is 
also expected to enhance distribution to the respiratory mucosa. Sotrovimab has a molecular 
weight of 150 kDa.  
Intensive lead-in PK data from the COMET-ICE trial indicates that sotrovimab has a median 
terminal half-life of 48.8 days. 
Sotrovimab, as a monoclonal antibody, is degraded into small peptides and individual amino 
acids. The high molecular weight of sotrovimab (approximately 150 kDa) suggests that renal 
elimination of intact sotrovimab is unlikely to be of importance and the clearance of sotrovimab 
is predicted to be largely mediated by proteolysis.  
No formal interaction studies have been conducted with sotrovimab. Sotrovimab is neither 
renally excreted nor metabolized by cytochrome P450 (CYP) enzymes; therefore, interactions 
with concomitant medications that are renally excreted or that are substrates, inducers, or 
inhibitors of CYP enzymes are unlikely.  In in vitro pharmacodynamic studies with remdesivir or 
bamlanivimab, sotrovimab showed additive virologic effect and no antagonism with either agent.  
 
8.1.2. Form 
 
Sotrovimab is supplied in single-dose vials containing 500mg of sotrovimab in a volume of 8mL 
(62.5 mg/mL). Sotrovimab is a clear, colorless or yellow to brown solution. Sotrovimab is 
manufactured in compliance with cGMP regulations by Vir Biotechnology, Inc. 
 
8.1.3. Storage and Stability 
 
Study drug will be stored at each site at 2°C to 8°C [36°F to 46°F].  Vials should be stored 
upright and protected from light. Vials should never be frozen. 
 
Sotrovimab is preservative-free; therefore, once diluted, the infusion solution should be 
administered immediately. If immediate administration is not possible, the diluted solution of 
sotrovimab may be stored for up to 4 hours at room temperature (20°C to 25°C [68°F to 77°F]), 
with the infusion starting within 2 hours of removal from refrigeration and completing (including 


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flushing the line) within 4 hours of removal of the bag from refrigeration, or refrigerated up to 
24 hours (2°C to 8°C [36°F to 46°F]). 
 
8.1.4. Compatibility 
 
Sotrovimab must be diluted prior to intravenous (IV) administration in 0.9% sodium chloride, as 
outlined in Section 8.1.7 below and in the Pharmacy Manual. 
 
8.1.5. Handling 
Sotrovimab injection should be prepared by a qualified healthcare professional using aseptic 
technique. Under normal conditions of handling and administration, study drug is not expected to 
pose significant safety risks to site staff, but adequate precautions should be taken to avoid direct 
eye or skin contact and the generation of aerosols or mists. 
8.1.6. Availability 
 
Open label vials of Sotrovimab/VIR-7831 will be shipped from the study sponsor to the 
Investigational Drug Services (IDS) pharmacy at Brigham and Women’s Hospital or the 
investigational pharmacy at Massachusetts General Hospital. For study patients enrolled and 
treated at Dana-Farber Cancer Institute, vials shipped to the IDS Pharmacy at Brigham and 
Women’s Hospital will be transferred to the Dana-Farber Cancer Institute Pharmacy as needed via 
the inter-institutional drug transfer process. Each vial will contain 500mg of investigational drug 
in a volume of 8mL (62.5mg/mL). Vials will be labeled with a single panel label, with two types 
of clinical labeled stock available from supply (samples shown below). 
 
 
 
 
8.1.7. Preparation 
 
Sotrovimab must be diluted prior to intravenous (IV) administration, as outlined in Section 3.4 
of the Pharmacy Manual. 


NCI Protocol #: N/A 
Version Date: March 31, 2022 
 
37 
Sotrovimab (VIR-7831) has been tested for compatibility with the materials listed below. Care 
should be taken to use equipment made from the materials listed when preparing and 
administering the doses. 
Equipment required for IV administration of a 500mg dose:  
• 
Pre-filled 50mL 0.9% saline infusion bags or empty 50mL infusion bags and bulk normal 
saline OR pre-filled 100mL 0.9% saline infusion bags or empty 100mL infusion bags and 
bulk normal saline 
• 
Bag spike 
• 
Venting dispensing pin 
• 
10mL, 30mL, and 50mL sterile syringes 
• 
0.2μm in-line filter (not required but recommended) 
• 
21-gauge stainless steel sterile needles  
• 
Sterile infusion set  
• 
Individual protective equipment  
• 
Polypropylene Syringe  
• 
Infusion pump for dosing (flow rate of 50 - 200mL/hr)  
• 
Amber UV light-inhibiting (UVLI) sleeve to protect the study drug infusion bag from 
light during infusion. 
Compatible materials:  
A list of materials that have been shown to be compatible with Sotrovimab (VIR-7831) at a 
500mg dose are:  
• 
Polyvinylchloride (PVC) with and without DEHP  
• 
Polyolefin (PO)  
• 
Polycarbonate containers/syringes  
• 
Ultra low density polyethylene  
• 
Ethyl vinyl alcohol copolymer (EVOH, EVA)  
• 
Silicone tubing  
• 
Polyvinylidene fluoride (PVDF) filter materials  
• 
Polyethersulfone (PES) filter materials  
• 
Type I Glass 
If available, it is recommended to use a laminar flow hood for dose solution preparations. 
Infusions must be prepared aseptically by the pharmacist/designated site staff. Aseptic technique 
must be strictly observed throughout the preparation process.  
Preparation of Each Sotrovimab (VIR-7831) Dose (500mg):  
 
1. Complete the infusion bag label for VIR-7831 with the following information using a 
permanent black marker:  
 
a. Participant study ID number 


NCI Protocol #: N/A 
Version Date: March 31, 2022 
 
38 
b. Site number where the infusion will be administered. 
 
2. Remove one (1) vial of study drug from refrigeration. Allow the vial to equilibrate to 
ambient room temperature, protected from light, for at least 15 minutes. 
 
3. Visually inspect the vial for 5 seconds to ensure it is free from particulate matter and that 
there is no visible damage to the vial.  
 
4. Gently swirl the vial several times before use without creating air bubbles. 
 
a. Do not shake or vigorously agitate the vial.  
b. If a vial is identified to be unusable: 
  
a. Take a photo of the damaged vial, if possible.  
b. Record details of the vial for accountability purposes. 
c. Retrieve a new vial and restart the preparation.  
d. Destroy the damaged vial per institutional policies and procedures. 
e. Follow the pharmacy procedure for updating study drug inventory.  
 
5. The intravenous (IV) solution can be prepared using either empty sterile infusion bags or 
pre-filled infusion bags. There is an option to use either 50mL or 100mL infusion bags. 
(using aseptic precautions to prevent contamination). 
 
Use of pre-filled, 50mL infusion bag: 
 
• Using an appropriately sized fresh syringe and 21-ga needle, draw 8mL of normal saline 
from the infusion bag. 
• Use a 10mL syringe fitted with a 21-ga needle to draw 8mL from the vial of study drug.  
• Inject the 8mL of study drug into the infusion bag via the septum to bring the total 
volume to approximately 50mL. 
• Record the time the vial was punctured on the infusion bag label using a permanent black 
marker (this information MUST be visible through the amber UV light-inhibiting (UVLI) 
sleeve). 
• Discard any unused portion left inside the vial, as the product contains no preservative. 
The study drug inside the vial is single use only and should only be used for one study 
participant. 
• Prior to the infusion, gently rock the infusion bag back and forth by holding the prepared 
bag in two hands and gently move one hand down to get the fluid to move down and 
move the other hand up to get the fluid to move up. Repeat this action 3 to 5 times. DO 
NOT invert the infusion bag. Avoid forming air bubbles. Make sure to efficiently 
homogenize in areas of low solvent flow access around injection ports.  
• An amber UV light-inhibiting (UVLI) sleeve should be used to protect the infusion bag 
containing diluted study drug from light during infusion. 
 
Use of an empty sterile 50mL infusion bag: 
 


NCI Protocol #: N/A 
Version Date: March 31, 2022 
 
39 
• Use a 10mL syringe fitted with a 21-ga needle to draw 8mL from the vial of study drug.  
• Inject the 8mL of study drug into the empty infusion bag via the septum.  
• Using an appropriately sized fresh syringe and 21-ga needle, add 42mL of normal saline 
to the infusion bag via the septum to bring total volume to approximately 50mL. 
• Record the time the vial was punctured on the infusion bag label using a permanent black 
marker (this information MUST be visible through the amber UVLI sleeve). 
• Discard any unused portion left inside the vial, as the product contains no preservative. 
The study drug inside the vial is single use only and should only be used for one study 
participant.  
• Prior to the infusion, gently rock the infusion bag back and forth by holding the prepared 
bag in two hands and gently move one hand down to get the fluid to move down and 
move the other hand up to get the fluid to move up. Repeat this action 3 to 5 times. DO 
NOT invert the infusion bag. Avoid forming air bubbles. Make sure to efficiently 
homogenize in areas of low solvent flow access around injection ports.  
• An amber UV light-inhibiting (UVLI) sleeve should be used to protect the infusion bag 
containing diluted study drug from light during infusion. 
 
Use of pre-filled, 100mL infusion bag: 
 
• Using an appropriately sized fresh syringe and 21-ga needle, draw 58mL of normal saline 
from the infusion bag.  
• Use a 10mL syringe fitted with a 21-ga needle to draw 8mL from the vial of study drug.  
• Inject the 8mL of study drug into the infusion bag via the septum to bring the total 
volume to approximately 50mL.  
• Record the time the vial was punctured on the infusion bag label using a permanent black 
marker (this information MUST be visible through the amber UVLI sleeve).  
• Discard any unused portion left inside the vial as the product contains no preservative. 
The study drug inside the vial is single use only and should only be used for one study 
participant. 
• Prior to the infusion, gently rock the infusion bag back and forth by holding the prepared 
bag in two hands and gently move one hand down to get the fluid to move down and 
move the other hand up to get the fluid to move up. Repeat this action 3 to 5 times. DO 
NOT invert the infusion bag. Avoid forming air bubbles. Make sure to efficiently 
homogenize in areas of low solvent flow access around injection ports.  
• An amber UV light-inhibiting (UVLI) sleeve should be used to protect the infusion bag 
containing diluted study drug from light during infusion. 
 
Use of an empty sterile 100mL infusion bag:  
 
• Use a 10mL syringe fitted with a 21-ga needle to draw 8mL from the vial of study drug. 
• Inject the 8mL of study drug into the empty infusion bag via the septum.  
• Using an appropriately sized fresh syringe and 21-ga needle, add 42mL of normal saline 
to the infusion bag via the septum to bring total volume to approximately 50mL. 
• Record the time the vial was punctured on the infusion bag label using a permanent black 
marker (this information MUST be visible through the amber UVLI sleeve). 


NCI Protocol #: N/A 
Version Date: March 31, 2022 
 
40 
• Discard any unused portion left inside the vial as the product contains no preservative. 
The study drug inside the vial is single use only and should only be used for one study 
participant.  
• Prior to the infusion, gently rock the infusion bag back and forth by holding the prepared 
bag in two hands and gently move one hand down to get the fluid to move down and 
move the other hand up to get the fluid to move up. Repeat this action 3 to 5 times. DO 
NOT invert the infusion bag. Avoid forming air bubbles. Make sure to efficiently 
homogenize in areas of low solvent flow access around injection ports.  
• An amber UV light-inhibiting (UVLI) sleeve should be used to protect the infusion bag 
containing diluted study drug from light during infusion. 
 
6. Complete the infusion bag label for Sotrovimab (VIR-7831) with the following 
information using a permanent black marker. At a minimum the labels should contain the 
following information: 
STUDY 14210 OPEN-LABEL MEDICATION 
Sotrovimab (VIR-7831) 
Subject ID #:  .....................  
Study Site #: .....................  
Visit #: .............................. 
Date: ................................. 
Lot #: …………................ 
 
Time when vial was punctured for intravenous infusion: .....................  
Time IV bag preparation complete: .....................  
Expiration time: .....................  
Prepared by: .....................  
 
7. Apply the infusion bag label to the infusion bag. 
 
8. Details of dose preparation should be recorded on the Dose Preparation Form in the 
Pharmacy Manual or site equivalent. For each dose preparation, a new copy of this form 
is used to record the date, the participant number, the dosing day/week, the the number of 
vials used, the time of dose preparation, the expiration time and the name and signature 
of the person preparing the dose. 
 
9. Attach an infusion set to the infusion bag. Follow institutional policy for the use of an in-
line filter for administration. 
 
10. Follow institutional procedures for priming the infusion set and programing the infusion 
pump. 
 
Sotrovimab must be diluted prior to administration and must not be administered as an 
intravenous push or bolus. 
 


NCI Protocol #: N/A 
Version Date: March 31, 2022 
 
41 
Follow local SOPs/site processes to maintain the sotrovimab dose at 18-25°C during transport 
to the clinic for administration. 
 
● This product is preservative-free; therefore, the diluted infusion solution should be 
administered immediately. If immediate administration is not possible, store the diluted 
solution of sotrovimab up to 4 hours at room temperature (20°C to 25°C [68°F to 77°F]), 
with the infusion starting within 2 hours of removal from refrigeration and completing 
(including flushing the line) within 4 hours of removal of the bag from refrigeration, or 
refrigerated up to 24 hours (2°C to 8°C [36°F to 46°F]). 
 
Equipment required for IV administration of a 2000mg dose:  
• 
Pre-filled 100mL 0.9% saline infusion bags OR empty 100mL infusion bags and bulk 
normal saline 
• 
Bag spike 
• 
Venting dispensing pin 
• 
10mL, 30mL, and 50mL sterile syringes 
• 
0.2μm in-line filter (not required but recommended) 
• 
21-gauge stainless steel sterile needles  
• 
Sterile infusion set  
• 
Individual protective equipment  
• 
Polypropylene Syringe  
• 
Infusion pump for dosing (flow rate of 50 - 200mL/hr)  
• 
Amber UV light-inhibiting (UVLI) sleeve to protect the study drug infusion bag from 
light during infusion. 
If available, it is recommended to use a laminar flow hood for dose solution preparations. 
Infusions must be prepared aseptically by the pharmacist/designated site staff. Aseptic technique 
must be strictly observed throughout the preparation process.  
Preparation of Each Sotrovimab (VIR-7831) Dose (2000mg):  
 
1. Complete the infusion bag label for VIR-7831 with the following information using a 
permanent black marker:  
a. Participant study ID number 
b. Site number where the infusion will be administered. 
 
2. Remove four (4) vials of study drug from refrigeration. Allow the vials to equilibrate to 
ambient room temperature, protected from light, for at least 15 minutes. 
 
3. Visually inspect the vials for 5 seconds to ensure it is free from particulate matter and that 
there is no visible damage to the vial.  
 
4. Gently swirl the vial several times before use without creating air bubbles. 


NCI Protocol #: N/A 
Version Date: March 31, 2022 
 
42 
 
a. Do not shake or vigorously agitate the vial.  
b. If a vial is identified to be unusable: 
  
a. Take a photo of the damaged vial, if possible.  
b. Record details of the vial for accountability purposes. 
c. Retrieve a new vial and restart the preparation.  
d. Destroy the damaged vial per institutional policies and procedures. 
e. Follow the pharmacy procedure for updating study drug inventory.  
 
5. The intravenous (IV) solution can be prepared using either empty sterile 100mL infusion 
bags or pre-filled 100mL infusion bags (using aseptic precautions to prevent 
contamination). 
 
Use of a pre-filled, 100mL infusion bag: 
 
• Using an appropriately sized fresh syringe and 21-ga needle, draw 32mL of normal saline 
from the infusion bag.  
• Use a 10mL syringe fitted with a 21-ga needle to draw 8mL from the each of the 4 vials 
of study drug.  
• Inject 8mL of study drug from each of the 4 vials into the infusion bag via the septum to 
bring the total volume to approximately 100mL.  
• Record the time the vials were punctured on the infusion bag label using a permanent 
black marker (this information MUST be visible through the amber UVLI sleeve).  
• Discard any unused portion left inside the vials, as the product contains no preservative. 
The study drug inside each vial is single use only and should only be used for one study 
participant. 
• Prior to the infusion, gently rock the infusion bag back and forth by holding the prepared 
bag in two hands and gently move one hand down to get the fluid to move down and 
move the other hand up to get the fluid to move up. Repeat this action 3 to 5 times. DO 
NOT invert the infusion bag. Avoid forming air bubbles. Make sure to efficiently 
homogenize in areas of low solvent flow access around injection ports. 
• An amber UV light-inhibiting (UVLI) sleeve should be used to protect the infusion bag 
containing diluted study drug from light during infusion. 
 
Use of an empty sterile 100mL infusion bag:  
 
• Use a 10mL syringe fitted with a 21-ga needle to draw 8mL from each of the 4 vials of 
study drug. 
• Inject 8mL of study drug from each of the 4 vials into the empty infusion bag via the 
septum, for a total of 32 mL of study drug in the infusion bag. 
• Using an appropriately sized fresh syringe and 21-ga needle, add 68mL of normal saline 
to the infusion bag via the septum to bring total volume to approximately 100mL. 
• Record the time the vials were punctured on the infusion bag label using a permanent 
black marker (this information MUST be visible through the amber UVLI sleeve). 


NCI Protocol #: N/A 
Version Date: March 31, 2022 
 
43 
• Discard any unused portion left inside the vials, as the product contains no preservative. 
The study drug inside each vial is single use only and should only be used for one study 
participant.  
• Prior to the infusion, gently rock the infusion bag back and forth by holding the prepared 
bag in two hands and gently move one hand down to get the fluid to move down and 
move the other hand up to get the fluid to move up. Repeat this action 3 to 5 times. DO 
NOT invert the infusion bag. Avoid forming air bubbles. Make sure to efficiently 
homogenize in areas of low solvent flow access around injection ports.  
• An amber UV light-inhibiting (UVLI) sleeve should be used to protect the infusion bag 
containing diluted study drug from light during infusion. 
 
8. Complete the infusion bag label for Sotrovimab (VIR-7831) with the following 
information using a permanent black marker. At a minimum the labels should contain the 
following information: 
STUDY 14210 OPEN-LABEL MEDICATION 
Sotrovimab (VIR-7831) 
Subject ID #:  .....................  
Study Site #: .....................  
Visit #: .............................. 
Date: ................................. 
Lot #: …………................ 
 
Time when vial was punctured for intravenous infusion: .....................  
Time IV bag preparation complete: .....................  
Expiration time: .....................  
Prepared by: .....................  
 
9. Apply the infusion bag label to the infusion bag. 
 
10. Details of dose preparation should be recorded on the Dose Preparation Form in the 
Pharmacy Manual or site equivalent. For each dose preparation, a new copy of this form 
is used to record the date, the participant number, the dosing day/week, the the number of 
vials used, the time of dose preparation, the expiration time and the name and signature 
of the person preparing the dose. 
 
11. Attach an infusion set to the infusion bag. Follow institutional policy for the use of an in-
line filter for administration. 
 
12. Follow institutional procedures for priming the infusion set and programing the infusion 
pump. 
 
Sotrovimab must be diluted prior to administration and must not be administered as an 
intravenous push or bolus. 
 


NCI Protocol #: N/A 
Version Date: March 31, 2022 
 
44 
Follow local SOPs/site processes to maintain the sotrovimab dose at 18-25°C during transport to 
the clinic for administration. 
 
● This product is preservative-free; therefore, the diluted infusion solution should be 
administered immediately. If immediate administration is not possible, store the diluted 
solution of sotrovimab up to 4 hours at room temperature (20°C to 25°C [68°F to 77°F]), 
with the infusion starting within 2 hours of removal from refrigeration and completing 
(including flushing the line) within 4 hours of removal of the bag from refrigeration, or 
refrigerated up to 24 hours (2°C to 8°C [36°F to 46°F]). 
 
   
8.1.8. Administration 
 
500mg dose: Sotrovimab will be administered as an IV infusion over 30 minutes, followed by a 
one-hour monitoring period, as outlined in the Pharmacy Manual. Special IV tubing is not 
required; filtration with a 0.2 micron in-line filter is recommended but not required. 
 
2000mg dose: The higher 2000mg dose of sotrovimab will be administered as an IV infusion 
over 60 minutes, followed by a 1-2-hour monitoring period, as outlined in the Pharmacy Manual. 
Special IV tubing is not required; filtration with a 0.2 micron in-line filter is recommended but 
not required. 
 
8.1.9. Ordering 
 
A drug supply request form will be sent to GSK/Vir to request vials of study drug (sotrovimab 
500mg in 8mL (62.5 mg/mL)) by each site investigator, as needed. Study drug will be shipped at 
a temperature of 2°C to 8°C [36°F to 46°F] to investigators or designees at each site at regular 
intervals or as needed during the study.  
 
8.1.10. Accountability 
 
All drug accountability records must be kept up to date. Investigators, or a responsible party 
designated by the investigator, at each site must be able to account for all opened and unopened 
study drug, with accountability forms containing dates, quantity of study drug vials, and the name 
of the study medication as they are: 
 
● Dispensed to each study subject 
● Disposed of at the site or returned to the sponsor or designee. 
 
All accountability records must be made available for inspection by the sponsor-investigator, 
sponsor, or designees, including study monitors, and by regulatory agency inspectors as needed. It 
is recommended but not mandatory to save study drug vials for accountability purposes. Copies of 
the accountability records must be provided to the sponsor-investigator at the conclusion of the 
study. Sites may use site-specific accountability logs, as long as it is substantially equivalent to the 
accountability log provided in the pharmacy manual.  


NCI Protocol #: N/A 
Version Date: March 31, 2022 
 
45 
 
8.1.11. Destruction and Return 
 
At specified time points during the study (e.g. at the site close-out visit, following drug 
reconciliation and documentation by the site monitor), all opened and unopened study drug will 
be destroyed at the site with approval of the sponsor or returned to the sponsor or designee. 
 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
9.1. 
Biomarker Studies 
 
N/A 
 
9.2. 
Laboratory Correlative Studies 
 
N/A 
 
9.3. 
Special Studies 
 
N/A 
 
 
10. STUDY CALENDAR 
 
See pages 46-48 below.


46 
 
Day  
Screen 
Treatment Day 1 
(TD1) 
Follow-Up Period 1a 
Treatment Day 2 
(TD2) 
Follow-Up Period 2 
EDC 
Timepoints 
(-)7 to 1 
Pre-
dose 
Dose 
Post-
Dose 
11 
29 
42 
59 
84 
Pre-
dose 
Dose 
Post-
Dose 
TD2 
+3 
TD2 
+11 
TD2 
+ 29 
TD2 
+42 
TD2 
+59 
TD2 
+84 
TD2
+112 
TD2
+140 
TD2+168
/ EOT 
TD2 + 
252/EOS 
  
Week 
  
1 
2 
4 
6 
8 
12 
12 
TD2 + 
0 
TD2 
+2 
TD2 
+4 
TD2 
+6 
TD2 
+8 
TD2 
+12 
TD2
+16 
TD2
+20 
TD+24 
TD2 +36 
 
Visit Numberb 
  
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
Window (Days) 
  
±3 
±
3 
±
3 
±
3 
±3 
±3 
-4 (weeks)/ 
+2 (weeks) 
-1/+2 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
Screening Only 
Inclusion/Exclusion 
Criteriac 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
Screening 
SARS-CoV-2 
Spike Antibody 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
Screening 
Informed Consentd 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
Screening 
Day 1 Onlye 
Demographics  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
Baseline 
Medical Historyf 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
Baseline 
Height and Weight  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
Baseline 
SARS-CoV-2 
Vaccination 
History 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
Baseline 
Verification of 
Inclusion/Exclusion 
Criteriag 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
Baseline 
Treatment  
Study Drug 
Administration 
  
  
X 
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
 
  
  
  
  
TD1, TD2 
Safety and Tolerability Assessments 
Vital Signsh 
  
X 
  
X 
X 
X 
  
  
  
X 
  
X 
Xi 
X 
 X 
  
  
 
  
  
X 
  
TD1 (pre- 
and post-
dose), V2, 
V3, TD2 
(pre- and 
post-dose), 
V8, V9, V10, 
V16 
Physical Exam 
  
X 
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
 
  
  
X 
  
TD1, TD2, 
V16 
Targeted Examj 
  
  
  
  
X 
X 
  
  
  
  
  
  
Xi 
X 
X  
  
  
 
  
  
  
  
 V2, V3, V8, 
V9, V10 
Karnofsky 
Performance Status 
  
X 
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
 
  
  
X 
  
TD1, TD2, 
V16 
12-Lead ECG 
  
X 
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
 
  
  
X 
  
TD1, TD2, 
V16 
Pregnancy Testk 
  
X 
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
 
  
  
  
  
TD1, TD2 


NCI Protocol #: N/A 
Version Date: March 31, 2022 
 
47 
 
Day  
Screen 
Treatment Day 1 
(TD1) 
Follow-Up Period 1a 
Treatment Day 2 
(TD2) 
Follow-Up Period 2 
EDC 
Timepoints 
(-)7 to 1 
Pre-
dose 
Dose 
Post-
Dose 
11 
29 
42 
59 
84 
Pre-
dose 
Dose 
Post-
Dose 
TD2 
+3 
TD2 
+11 
TD2 
+ 29 
TD2 
+42 
TD2 
+59 
TD2 
+84 
TD2
+112 
TD2
+140 
TD2+168
/ EOT 
TD2 + 
252/EOS 
  
Week 
  
1 
2 
4 
6 
8 
12 
12 
TD2 + 
0 
TD2 
+2 
TD2 
+4 
TD2 
+6 
TD2 
+8 
TD2 
+12 
TD2
+16 
TD2
+20 
TD+24 
TD2 +36 
 
Visit Numberb 
  
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
Window (Days) 
  
±3 
±
3 
±
3 
±
3 
±3 
±3 
-4 (weeks)/ 
+2 (weeks) 
-1/+2 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
Local Laboratory 
testing 
  
X 
  
  
  
X 
  
  
  
X 
  
  
 Xi 
 
 X 
  
  
 
  
  
X 
  
TD1, V3, 
TD2, V8, 
V10, V16 
Targeted 
Concomitant 
Medications 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
All visits 
TEAE/AESI 
Monitoring 
 
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
All visits 
SAE Monitoring 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
All visits 
Serum ADA 
  
X 
  
  
  
X  
  
  
  
X  
  
  
  
  
 X 
  
  
 
  
  
X  
  
TD1, V3, 
TD2, V10, 
V16 
Phone Call Follow-
up Visit 
  
 
  
  
  
  
 X 
Xl 
Xm 
  
  
  
  
  
  
 X 
 Xn 
X 
 X 
 X 
  
 X 
V4, V5, V6, 
V11, V12, 
V13, V14, 
V15, V17 
Serum for PK 
Assessment 
  
 
  
X  
 X 
 X 
  
Xo 
  
 X 
  
X  
  
 X 
X  
  
Xp 
 
  
  
X  
  
TD1, V2, V3, 
V5, TD2, V9, 
V10, V12, 
V16 
Biweekly Anterior 
Nasal Swab SARS-
CoV-2 RT-PCRq 
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
All visits 
COVID-19 
Symptom 
Assessmentr 
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
All visits 
SF-36 Quality of 
Life Assessment 
  
 X 
 
  
  
  
  
  
  
 X 
 
  
  
  
  
  
  
 
  
  
 X 
  
TD1, TD2, 
V16 
 


NCI Protocol #: N/A 
Version Date: March 31, 2022 
 
48 
Day  
Screen 
Treatment Day 1 
(TD1) 
Follow-Up Period 1a 
Treatment Day 2 
(TD2) 
Follow-Up Period 2 
EDC 
Timepoints 
(-)7 to 1 
Pre-
dose 
Dose 
Post-
Dose 
11 
29 
42 
59 
84 
Pre-
dose 
Dose 
Post-
Dose 
TD2 
+3 
TD2 
+11 
TD2 
+ 29 
TD2 
+42 
TD2 
+59 
TD2 
+84 
TD2
+112 
TD2
+140 
TD2+168
/ EOT 
TD2 + 
252/EOS 
  
Week 
  
1 
2 
4 
6 
8 
12 
12 
TD2 + 
0 
TD2 
+2 
TD2 
+4 
TD2 
+6 
TD2 
+8 
TD2 
+12 
TD2
+16 
TD2
+20 
TD+24 
TD2 +36 
 
Visit Numberb 
  
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
Window (Days) 
  
±3 
±
3 
±
3 
±
3 
±3 
±3 
-4 (weeks)/ 
+2 (weeks) 
-1/+2 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
NIAID-OS Ordinal 
Scales 
  
 
  
 
 
 
  
  
  
 
  
 
 
 
  
  
  
 
Only if subjects 
develop 
COVID-19 
Transplant-
Associated 
Endpointst 
  
 
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
 
All visits 
 
a: The duration of Follow-Up Period 1 was determined by theoretical modeling of the duration of efficacy of sotrovimab as antiviral prophylaxis in the setting of the rising prevalence of the Omicron BA.2 subvariant. 
b: Visits in green are in-person, visits in red are phone/remote visits, and the day 59 visit in yellow is in-person for the 10 patients in the lead-in PK cohort and phone/remote for all other study subjects. The yellow visits at 
Visits 8 and 12 are in-person for the first 10 participants to receive the second dose of sotrovimab at the 2000mg dose and not required for other study participants. Participants will complete the Day 84 visit if they have not 
received their second dose before 12 weeks. 
c: Inclusion and exclusion criteria are listed in Section 3.1 and 3.2. 
d: The first 10 patients enrolled in the study will provide additional consent for an extra in-person visit on day 59 for a blood draw for serum PK testing to determine the optimal dosing interval between doses 1 and 2 of 
sotrovimab. The first 10 participants to receive their second dose of sotrovimab will consent for the 2-hour post-dose observation period and 2 additional in person-visits (visit 8 and 12).  
e: Screening and baseline procedures may be completed on the same day.  
f: Refer to Section 11.1.2 for details of medical history recording. 
g: Inclusion/exclusion should be confirmed again on Treatment Day 1 if Screening is not performed at the same visit as Treatment Day 1. SARS-CoV-2/COVID-19 symptom assessment should be re-evaluated using the 
Clinical Signs and Symptoms Assessment in Appendix D. 
h: Vital sign collection is described in Section 11.1.6.  
i: Only necessary for the first 10 participants to receive their second sotrovimab dose. 
j: A description of targeted exam parameters can be found in Section 11.1.7. 
k: Pregnancy testing will be performed only in women of childbearing potential. A negative test is needed to administer study drug.  
l: Not needed if patient consented to lead-in PK cohort. 
m: Only necessary for patients who receive their second dose of sotrovimab after day 84. 
n: Not needed if patient is one of the first 10 patients to receive their second sotrovimab dose. 
o: Only necessary for the 10 study subjects enrolled in the lead-in PK cohort. 
p: Only necessary for the first 10 participants to receive their second sotrovimab dose. 
q: Self-administered swabs will always be completed at home even if it is a week the patient is seen at the study site.  
r: COVID-19 symptoms should be assessed using the Clinical Signs and Symptoms Assessment in Appendix D. 
s: To be completed only in study subjects diagnosed with COVID-19 during the follow up period, at the end of hospitalization, or for those who do not require hospitalization, 14 days after diagnosis. NIAID-OS can be found 
in Appendix E. If feasible, patients who develop COVID-19 will be asked to come in for an end of treatment visit, including a PK assessment, as close to the time when they are diagnosed with COVID-19 as possible. 
t: Description of transplant-associated endpoints can be found in Section 11.1.15.


49 
11. MEASUREMENT OF EFFECT 
 
11.1. Safety and Tolerability Assessments 
 
Study visits are outlined in Section 10 (the Study Calendar). Study subjects should follow the 
study schedule as outlined as closely as possible. Unscheduled visits may be performed in order 
to review and/or repeat abnormal safety laboratory results, to perform SARS-CoV-2 testing if 
patients report symptoms potentially suggestive of COVID-19 infection, to follow up SAEs or 
AEs, or for other reasons deemed necessary by the principal investigator.  
 
The following parameters will be assessed to establish the baseline health status of study 
participants and examine study participant safety over the study period. 
 
Treatment Day 1-Specific Procedures 
 
11.1.1. Demographics 
 
Standard demographic parameters (e.g., age, sex, race, ethnicity) will be recorded in the eCRF. 
 
11.1.2. Medical History 
Relevant medical conditions that existed or were diagnosed prior to the signing of the informed 
consent form will be recorded as part of the study subject’s medical history in the eCRF. Abnormal 
laboratory values and vital signs observed at the time of informed consent will also be recorded as 
medical history. Any subsequent worsening (clinically significant change in frequency and/or 
intensity) of a pre-existing condition that is temporally associated with the use of the study drug 
will instead be recorded as TEAEs, if they fulfill criteria. 
A targeted past medical history will be recorded in the eCRF, including: 
● Immunocompromising conditions 
● History of prior COVID-19 infection 
● COVID-19 risk factors, based on the Centers for Disease Control and Prevention (CDC) 
list of patients at risk of severe COVID-19 illness [14]: 
○ Malignancy 
○ Solid organ or hematopoietic cell transplant 
○ Chronic kidney disease 
○ Chronic lung disease (including moderate to severe asthma, bronchiectasis, 
bronchopulmonary dysplasia, chronic obstructive pulmonary disease (including 
emphysema and chronic bronchitis), cystic fibrosis, pulmonary embolism, and 
pulmonary hypertension) 
○ Heart conditions (including congestive heart failure, coronary artery disease, 
cardiomyopathies, hypertension) 
○ Diabetes (type 1 or 2) 


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○ Elevated BMI - overweight (25 kg/m2 < BMI < 30 kg/m2) or obesity (BMI ≥ 30 
kg/m2) 
○ Cerebrovascular disease or stroke 
○ Chronic liver disease or cirrhosis (including alcohol-related liver disease, non-
alcoholic fatty liver disease, or autoimmune hepatitis) 
○ HIV infection 
○ Mental health conditions (including depression, schizophrenia spectrum disorders) 
○ Sickle cell disease or thalassemia 
○ Down syndrome 
○ Current or former cigarette smoking 
○ Substance use disorders 
○ Tuberculosis 
● Menopausal history 
11.1.3. Weight and Height 
 
Weight and height will be recorded on Treatment Day 1 prior to the first dose of sotrovimab, 
with BMI calculated from these parameters. 
 
11.1.4. SARS-CoV-2 Vaccination History 
 
SARS-CoV-2 vaccines previously received by each study subject will be recorded, including the 
type of vaccine and dates received. Any SARS-CoV-2 vaccines received during the study period 
will be recorded as concomitant medications. 
 
11.1.5. Verification of Inclusion and Exclusion Criteria 
 
If Screening and Treatment Day 1 procedures are not performed on the same day, inclusion and 
exclusion criteria (outlined in Section 3.1 and 3.2) will need to be verified on Treatment Day 1 
prior to sotrovimab dosing. 
 
Safety and Tolerability Parameters 
 
11.1.6. Vital Signs 
Vital signs will be collected according to the schedule outlined in the Study Calendar (Section 10), 
with collection points prior to and following sotrovimab dosing on Treatment Day 1 and the second 
sotrovimab dosing day, and on day 11 and 29 after the first dose of sotrovimab, day 11 and 29 
after the second dose of sotrovimab, and at the EOT visit. The 10 patients in the 2000mg dose 
lead-in safety cohort will also have vital signs measured on their Treatment Day 2 + 3 day visit.  
Vital signs will include body temperature, heart rate, blood pressure, oxygen saturation (SpO2), 
and respiratory rate. Vital signs should be obtained after 5 minutes of rest (supine or sitting). Vitals 
signs that are obtained following each sotrovimab dose should be obtained within 30 minutes 
after drug administration has been completed. 


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The method used to obtain body temperature should be consistent across all visits for a patient. 
Resting SpO2 (%) will be measured using a fingertip oximeter or similar device. In the event that 
a patient requires supplemental oxygen, oxygen flow rate will be measured (L/min). If a patient 
is mechanically ventilated, FiO2 will be measured. The oxygen device used should be recorded. 
 
11.1.7. Physical Exam 
 
A comprehensive physical exam will be performed prior to the first and second dose of 
sotrovimab and on day 168 after the second sotrovimab dose (the EOT visit), and a targeted 
physical exam will be performed on day 11 and 29 after the first dose of sotrovimab, and day 11 
and 29 after the second dose of sotrovimab. The 10 patients in the 2000mg dose lead-in safety 
cohort will also have a targeted physical exam on their Treatment Day 2 + 3 day visit. 
 
The targeted physical examination will include, but is not limited to assessment of the following: 
 
● Vital signs 
● General appearance of the study subject 
● Lung exam (e.g. crackles, rhonchi, diminished breath sounds) 
● Skin exam (e.g. urticaria, ulcerations, erythema multiforme, maculopapular rashes). 
 
11.1.8. Karnofsky Performance Status 
 
Each study subject’s Karnofsky performance status (Appendix A) will be assessed prior to the 
first and second dose of sotrovimab and on day 168 after the second sotrovimab dose (the EOT 
visit). 
 
11.1.9. Electrocardiogram 
 
A single 12-lead ECG will be obtained and assessed for clinical abnormalities prior to the first 
and second dose of sotrovimab, and on day 168 after the second sotrovimab dose (the EOT visit), 
recording heart rate, PR interval, QRS duration, and QTc in the eCRF. We will use the Fridericia 
formula to determine the QTcF.  
 
11.1.10. 
Pregnancy Testing and Pregnancy Reporting 
Pregnancy testing is required in women of childbearing potential. A negative urine or serum hCG 
test is required in all women of childbearing potential prior to each dose of sotrovimab, on 
Treatment Day 1 and Treatment Day 2. 
Study participants who are women of childbearing potential should use two highly effective 
methods of contraception, as described in Section 3.1.3, throughout the study period up to 36 
weeks after the last dose of sotrovimab (the end of study remote visit). 
Study staff should be informed immediately if a woman of childbearing potential becomes 
pregnant or starts breastfeeding during the study period. 


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11.1.11. 
Local Laboratory Testing 
All laboratory testing will be completed locally at each site. Clinical laboratory parameters will be 
measured at the baseline/Treatment Day visit prior to the administration of the first sotrovimab 
dose, day 29, at the Treatment Day 2 visit prior to the administration of the second sotrovimab 
dose, day 29 after the second sotrovimab dose, and day 168 after the second sotrovimab dose (the 
EOT visit). The 10 patients in the 2000mg dose lead-in safety cohort will also have an additional 
set of local laboratory values measured on their Treatment Day 2 + 3 day visit. 
Laboratory parameters that will be obtained at each of these time points include: 
● Hematology: 
○ Complete blood count (white blood cells, red blood cells, hemoglobin, hematocrit, 
platelet count) 
○ Differential (neutrophils, lymphocytes, monocytes, basophils, eosinophils) 
● Blood Chemistry:  
○ Basic metabolic panel (sodium, potassium, carbon dioxide, chloride, blood urea 
nitrogen (BUN), creatinine, glucose) 
○ Liver function tests (alanine transaminase (ALT), aspartate aminotransferase 
(AST), alkaline phosphatase, bilirubin, total protein, albumin, globulin). 
11.1.12. 
Targeted Concomitant Medications 
 
Any treatment administered from the first dose of sotrovimab on Treatment Day 1 to the end of 
the study period will be considered a concomitant medication. This includes medications that study 
subjects were taking from 30 days prior to consenting to participate in the study and are ongoing 
during the study. 
 
A targeted list of the following concomitant medications will be recorded in the eCRF at each in-
person and remote study visit:  
 
● Putative COVID-19 treatments (e.g. remdesivir, convalescent serum, intravenous 
immunoglobulin (IVIG), IL-6 receptor inhibitors (e.g. sarilumab, tocilizumab), JAK 
inhibitors (e.g. baricitinib), ivermectin), 28 days prior to enrollment and during the study 
period. 
● SARS-CoV-2 vaccination doses. 
● Antipyretics (e.g. aspirin, acetaminophen, ibuprofen). 
● Anticoagulants (e.g. enoxaparin, warfarin, rivaroxaban). 
● Immunosuppressants (e.g. cyclosporine, corticosteroids, methotrexate, mycophenolate 
mofetil, tacrolimus, sirolimus, Bruton tyrosine kinase inhibitors, ruxolitinib, venetoclax). 
● Interferon beta. 
● Theophylline. 
● Antiepileptics (e.g. carbamazepine, divalproex, phenytoin). 


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● Antiarrhythmics (e.g. digoxin, disopyramide, procainamide, amiodarone). 
● Antiviral, antibacterial, and antifungal drugs. 
● Antiparasitics (e.g. chloroquine or hydroxychloroquine). 
● Angiotensin receptor blockers (e.g. losartan, valsartan). 
● Angiotensin converting enzyme inhibitors (e.g. benazepril, lisinopril) 
● Biological therapies (eg. rituximab and other anti-CD20 antibodies, alemtuzumab, 
interferon-gamma inhibitors). 
 
11.1.13. 
Adverse Event Monitoring 
Grade 3-4 treatment-emergent adverse events (TEAEs), as defined using DAIDS grading criteria 
[66], and treatment-emergent serious adverse events (SAEs), as defined using DAIDS grading 
criteria and Section 7, will be collected from patient consent until the end of study remote visit 
(36 weeks after Treatment Day 2). Patients will be solicited for the development of any AEs at 
each in-person or remote visit, and any unsolicited AEs reported will be investigated further. 
11.1.14. 
Adverse Events of Special Interest (AESI) Monitoring 
Adverse events of special interest (AESI) will be collected from patient consent until the end of 
study visit (36 weeks after Treatment Day 2). 
Adverse events of special interest are defined as relevant known toxicities of other therapeutic 
monoclonal antibodies that will be monitored by the study team during the study. 
As outlined in Section 7.1.1, adverse events of special interest for sotrovimab include: 
● Hypersensitivity reactions or anaphylaxis. See Section 5.3 for guidance on the 
management of suspected hypersensitivity reactions or anaphylaxis. 
● Infusion related reactions. See Section 5.3 for guidance on the management of suspected 
infusion-related reactions. 
● Immunogenicity-related adverse events (development of ADA). See Section 7.1.1 for 
more details. 
 
Adverse events potentially related to antibody-dependent enhancement of COVID-19 infection. 
See Section 7.1.1 for more details. 
 
11.1.15. 
Transplant-Associated Endpoints 
 
Study participants who are solid organ transplant (SOT) or hematopoietic cell transplant (HCT) 
recipients will be assessed at each follow-up visit for: 
 
(1) New-onset cellular or antibody-mediated rejection events in solid organ transplant (SOT) 
recipients, with evidence of acute or chronic rejection on allograft biopsy samples or 
evidence of donor-specific antibodies (DSA) in serum samples obtained for workup of 
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(2) New-onset or worsening graft-versus-host disease in hematopoietic cell transplant (HCT) 
recipients. 
(3) New-onset allograft or stem cell failure with the need for re-transplantation in HCT 
recipients. 
 
11.2. Drug Concentration Measurements for Pharmacokinetic Assessment 
 
Serum sotrovimab levels will be measured for pharmacokinetic (PK) assessment within 1 hour 
after the first sotrovimab infusion on Treatment Day 1, 11, 29, 59 (only the 10 patients in the initial 
lead-in cohort will have a serum sotrovimab pharmacokinetic assessment on day 59), prior to the 
second dose of sotrovimab on Treatment Day 2, within 1 hour after the second sotrovimab 
infusion, and 11, 29, 59 (only the 10 patients in the 2000mg dose lead-in cohort will have a serum 
sotrovimab pharmacokinetic assessment on Treatment Day 2 + 59 days), and 168 days after the 
second sotrovimab dose. 
 
The actual date and time of each sample will be recorded in the eCRF. 
 
The PK parameters to be determined for sotrovimab may include, but are not limited to: maximum 
sotrovimab serum concentration (Cmax), time to maximal sotrovimab serum concentration (tmax), 
Cmax vs. dose, minimal sotrovimab serum concentration (Cmin), last serum sotrovimab 
concentration (Clast), time of last measurable sotrovimab concentration (tlast), area under the curve 
extrapolated to infinity (AUC(0-∞)), AUC(0-∞) vs. dose, half-life (t1/2), and concentration in serum 
28 days after dosing (C28). Selected PK parameters will be summarized by descriptive statistics 
for the selected cohort. All parameters will be summarized (mean, standard deviation (SD), % 
coefficient of variation (CV), range, median, and number of samples). 
 
11.3. COVID-19 and Quality of Life Assessments 
 
11.3.1. Self-Collected Anterior Nasal Swabs for SARS-CoV-2 RT-PCR 
 
Patients will collect self-administered anterior nasal swabs bi-weekly over the study period 
through the EOT visit 168 days after Treatment Day 2 using the binx health At-Home Nasal 
Swab COVID-19 Sample Collection Kit, which has Emergency Use Authorization (EUA) for the 
self-collection of anterior nasal swab specimens at home [78-79]. A prepaid shipping envelope 
will be provided with each swab, and patients will submit these swabs to UPS. These dry swab 
specimens can be transported at ambient temperature for testing at an authorized, CLIA-certified 
laboratory, with molecular diagnostic testing performed using an in vitro diagnostic (IVD) assay 
that has received FDA EUA for the diagnosis of SARS-CoV-2. In patients who develop SARS-
CoV-2 infection during the follow-up period, with positive binx health At-Home Nasal Swabs 
assays, the specimen will be retained so spike genes can be sequenced to assess for mutations 
that might confer resistance to sotrovimab or other antibody therapies.  
 
 


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11.3.2. COVID-19 Symptom Assessment 
 
An assessment of COVID-19-related symptoms will be performed at each in-person or remote 
study visit, using the CDC’s list of symptoms commonly associated with COVID-19 [8]: 
 
● Fever or chills 
● Cough 
● Shortness of breath or difficulty breathing 
● Fatigue 
● Muscle or body aches 
● Headache 
● New loss of taste or smell 
● Sore throat 
● Congestion or runny nose 
● Nausea or vomiting 
● Diarrhea. 
 
Study participants will be asked if they have any of these symptoms de novo or worsening from 
their baseline at each in-person and remote visit, using a questionnaire (Appendix D). Due to the 
contagiousness of the BA.2 Omicron variant, the study team will also proactively reach out to 
study participants on a weekly basis by telephone or email to assess for the presence of COVID-
19 symptoms following the second sotrovimab dose. If they report any of these symptoms (new 
or worsening from baseline) at an in-person visit, they will have a nasopharyngeal swab obtained 
for local laboratory RT-PCR testing for SARS-CoV-2. If they report any of these symptoms at a 
remote visit, they will be asked to go to a local laboratory for SARS-CoV-2 RT-PCR testing. 
 
Study participants will also be asked to report any emergency department (ED) visits and inpatient 
hospitalizations, including intensive care hospitalizations, over the study period.  
 
The greatest extent of COVID-19 symptoms, as assessed using the 8-point National Institute of 
Allergy and Infectious Diseases ordinal scale (NIAID-OS), will be assessed in each study subject 
who develops COVID-19, either at the end of hospitalization or, in those who are not hospitalized, 
14 days after the diagnosis of COVID-19 (Appendix E) [80]. 
 
In addition to symptom-triggered testing, study participants will obtain self-collected anterior nasal 
swabs every other week for SARS-CoV-2 RT-PCR testing, using the binx health At-home Nasal 
Swab COVID-19 Sample Collection Kit and user interface, available under a FDA EUA [78]. 
These samples will be shipped at ambient temperature to authorized laboratories designated by 
binx health, Inc., which are certified under the Clinical Laboratory Improvement Amendments of 
1988 (CLIA) and meet requirements to perform high complexity tests and run the specimens 
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test (RT-PCR) for SARS-CoV-2 [79]. Study participants and the study team will receive results of 
this biweekly molecular testing. 
 
Study subjects with any positive RT-PCR SARS-CoV-2 testing result over the study period will 
be considered to have COVID-19, with subjects reporting any new or worsening symptoms 
associated with COVID-19 temporally related to their positive result considered to have 
symptomatic COVID-19 and patients without any new or worsening symptoms temporally related 
to their positive result considered to have asymptomatic COVID-19 infection [8]. 
 
11.3.3. NIAID-OS Ordinal Scale in Study Subjects Who Develop COVID-19 
 
In patients who are diagnosed with COVID-19 during the follow-up period, greatest extent of 
COVID-19 symptoms, as assessed using the 8-point National Institute of Allergy and Infectious 
Diseases ordinal scale (NIAID-OS), will be determined at the end of hospitalization or, in those 
who do not require hospitalization, 14 days after the diagnosis of COVID-19 (Appendix E) [80]. 
 
11.3.4. Quality of Life Questionnaire 
 
Health-related quality of life measures will be assessed prior to the first and second dose of 
sotrovimab and on day 168 after the second sotrovimab dose (the EOT visit) using the RAND 
36-Item Short Form Health Survey (SF-36) instrument [81]. Surveys will be completed at study 
visits by the patient and stored in patient binders, with answers entered into the eCRF. 
 
 
12. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7 
(Adverse Events: List and Reporting Requirements). 
 
12.1. Data Reporting 
 
12.1.1. Method 
 
Syneos Health will provide electronic data capture services. Syneos Health will monitor and 
perform quality checks on data collected for this study.  
 
12.1.2. Responsibility for Data Submission 
 
Investigative sites are responsible for submitting data and/or data forms into the electronic case 
report forms designed to capture specific and relevant study data.  
 
Case Report Form Requirements 
 
Data obtained during the study will be recorded on electronic Case Report Forms (eCRFs) within 
the EDC system by trained site personnel. All required eCRFs must be completed for every patient 
enrolled in the study within 72 hours of each study visit or phone call. The investigator must 


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ensure the accuracy, timeliness, and completeness of the data reported to the sponsor-investigator 
in the eCRFs. After reviewing the clinical data for each patient, the investigator must provide an 
electronic signature. A copy of each patient eCRF casebook is to be retained by the investigator as 
part of the study record. 
 
Any corrections to the eCRF will be entered by the investigator or an authorized designee. Any 
changes, including the date and person performing these corrections, will be visible via the audit 
trail integrated in the EDC system. For corrections made via data queries, the reason for any 
alterations must be provided. 
 
Investigators are required to prepare and maintain adequate and accurate patient records, or source 
documents. Each site is responsible for ensuring quality within their records and systems and is 
accountable for ensuring that all source data and eCRF data are entered in an accurate, timely, and 
complete manner. Investigators at each site must keep all source documents on file with the eCRF. 
Case report forms and source documents must be available at all times for inspection by authorized 
representatives of the sponsor-investigator and regulatory authorities. 
 
12.2. Data Safety Monitoring 
 
This is a single-arm, open-label, non-randomized study conducted at three sites within DF/HCC 
(Dana-Farber/Harvard Cancer Center), with the sponsor-investigator and central study team 
having access to all data, so a Data and Safety Monitoring Committee has been deemed to be 
unnecessary. Instead, a qualified independent study monitor (ISM) will evaluate enrollment data 
and all grade 2 or higher unexpected adverse events in the study twice a year. The ISM will issue 
a written monitoring report to the study team after each review, addressing any questions about 
participant safety with the sponsor-investigator and study team and issuing a final 
recommendation as to the study’s continuation. 
 
Monitoring of Study Sites 
 
In accordance with International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) E6, the sponsor-investigator is responsible for quality 
control and quality assurance to ensure that the study is conducted and the data are generated, 
recorded, and reported in compliance with the protocol, good clinical practice (GCP), and any 
applicable regulatory requirements. 
 
Study monitors will conduct remote and in-person monitoring visits to each site periodically during 
the study. This study will use the principles of risk-based monitoring (ICH), with the monitoring 
strategy for any given site varying based on site risk indicators. Investigators at each site must 
allow study-related monitoring and:  
 
● Provide access to all necessary facilities, study data, and documents for internal or 
external inspection or audit as needed. 
● Communicate any information arising from these inspections to the sponsor-investigator 
immediately. 


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● Take all appropriate measures requested by the sponsor-investigator and/or designees or 
auditor to resolve any problems found during the audit or inspection. 
 
Study monitors will perform ongoing source data review to verify that data recorded in the eCRF 
by authorized site personnel are accurate, complete, and verifiable from source documents, that 
the safety and rights of patients are being protected, and that the study is being conducted in 
accordance with the currently approved version of the protocol and any other study agreements, 
ICH GCP, and all applicable regulatory requirements. 
 
Documents subject to audit or inspection include (but are not limited to) all source documents, 
eCRFs, medical records, correspondence, informed consent forms (ICFs), IRB/EC files, 
documentation of certification and quality control of supporting laboratories, and records relevant 
to the study maintained in any supporting pharmacy facilities. Conditions of study material storage 
may also be subject to inspection. In addition, representatives of the sponsor-investigator may 
observe the conduct of any aspect of the clinical study or its supporting activities both within and 
outside of the investigator's institution. In all instances, the confidentiality of the data must be 
respected. 
 
12.3. Collaborative Agreements Language 
 
N/A 
 
 
13. STATISTICAL CONSIDERATIONS 
 
While the current medical approach to preventing COVID-19 consists of several widely 
available vaccine products, individuals with impaired humoral immunity due to a range of 
immunocompromising conditions may fail to develop detectable antibodies even in the setting of 
repeat vaccination. As such, alternative approaches to prevent SARS-CoV-2 infection are needed 
for this population. Sotrovimab is an investigational monoclonal antibody that targets a highly 
conserved epitope on the spike glycoprotein of SARS-CoV-2 and has received FDA EUA for the 
treatment of mild-to-moderate COVID-19 [49]. This is a Phase II open-label safety and 
tolerability study of sotrovimab for the pre-exposure prophylaxis of SARS-CoV-2 infection in 
immunocompromised individuals. 
 
13.1. Study Design/Endpoints 
 
The primary objective of this study is to evaluate the safety and tolerability of sotrovimab as 
pre-exposure prophylaxis for immunocompromised individuals. As such, the primary endpoints 
of this study are: 
 
(1) The safety and tolerability of sotrovimab in immunocompromised patients with impaired 
humoral immunity against SARS-CoV-2 as defined by: 
a. The proportion of study subjects with treatment-emergent grade 3-4 adverse 
events (TEAEs), as defined in the DAIDS grading criteria [66]. 


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b. The proportion of study subjects with treatment-emergent serious adverse events 
(SAE), as defined in Section 7. 
c. The proportion of study subjects with adverse events of special interest (AESI), 
including infusion-related and hypersensitivity reactions, the development of anti-
drug antibody (ADA) levels, and antibody-dependent enhancement (ADE) of 
COVID-19 disease, as outlined in Section 7.1.1. 
(2) Evaluation of the pharmacokinetics of sotrovimab in immunocompromised patients with 
impaired humoral immunity against SARS-CoV-2. 
 
The secondary objectives of this study are to describe COVID-19 infection and quality-of-life 
outcomes in immunocompromised individuals receiving sotrovimab prophylaxis. The secondary 
endpoints of this study relevant to COVID-19 infection include: 
 
(1) The proportion of study subjects that develop COVID-19 (of any severity) over the study 
follow-up period. 
(2) The proportion of study subjects with severe COVID-19, with any of the following 
criteria: 
a. Dyspnea, respiratory rate of 30 or more breaths per minute, blood oxygen 
saturation of 93% or less, a ratio of the partial pressure of arterial oxygen to the 
fraction of inspired oxygen (PaO2:FiO2) < 300 mm Hg, or infiltrates in more than 
50% of the lung field). 
b. Emergency department (ED) visit, inpatient hospitalization, or ICU 
hospitalization within 28 days of a new diagnosis of SARS-CoV-2. 
c. Need for new or increasing supplemental oxygen, OR mechanical ventilation 
within 28 days of a new diagnosis of SARS-CoV-2. 
d. Death due to any cause during the study follow-up period. 
(3) In patients who develop COVID-19, the greatest extent of COVID-19 symptoms, as 
assessed using the 8-point National Institute of Allergy and Infectious Diseases ordinal 
scale (NIAID-OS), assessed at the end of hospitalization or 14 days after the diagnosis of 
COVID-19 [80]. 
(4) Health-related quality of life measures using the Short Form Health Survey (SF-36) 
instrument, assessed at baseline, 12 weeks, and 24 weeks [81]. 
 
Exploratory objectives of this study are to describe transplant-specific outcomes in 
immunocompromised individuals receiving sotrovimab prophylaxis, including: 
 
(4) The proportion of solid organ transplant (SOT) recipient study subjects with new-onset 
cellular or antibody-mediated rejection events. 
(5) The proportion of hematopoietic cell transplant (HCT) recipients with new-onset or 
worsening graft-versus-host disease (GVHD). 
(6) The proportion of HCT recipients with allograft or stem cell failure with the need for re-
transplantation. 
 


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The study has a planned sample size of 93 participants and will accrue all participants within the 
first year of the study. 
 
These participants will be accrued in three stages:  
 
(1) A 10-patient pharmacokinetic lead-in cohort to determine the optimal dosing interval 
between two sequential doses of intravenous sotrovimab, administered as prophylaxis in 
immunocompromised patients with impaired humoral immunity to COVID-19. 
(2) A 50-patient safety and tolerability lead-in cohort (including the 10 patients in the 
pharmacokinetic lead-in cohort) to examine the safety and tolerability of intravenous 
sotrovimab administered over a 30-minute infusion period. 
(3) An expansion cohort for further assessment of the safety and tolerability of intravenous 
sotrovimab. If there are no grade ≥ 2 infusion-related reactions in the 50-patient safety 
and tolerability lead-in cohort, patients in this expansion cohort will receive their 
intravenous sotrovimab doses over a 15-minute infusion period; if there is at least one 
patient with a grade ≥ 2 infusion-related reaction, study subjects in the expansion cohort 
will continue to receive intravenous sotrovimab over a 30-minute infusion period. 
 
The 10 patients in the 2000mg sotrovimab repeat dose lead-in cohort will inform the observation 
period for all patients who receive their 2000mg dose after these patients, with a 2-hour 
observation period following completion of the dose for these 10 patients, reduced to a one-hour 
period for all subsequent patients if there are no grade 3 or 4 infusion-related reactions or other 
SAEs potentially related to the sotrovimab dose in this 2000mg dose lead-in safety cohort. 
 
13.2. Sample Size, Accrual Rate and Study Duration 
 
The planned sample size for this study will be 93 participants, all of whom will be accrued 
within 9-12 months, with follow-up visits for an additional 36 weeks after the last study subject 
receives their last sotrovimab dose, for a total study duration of approximately 2 years. A total 
cohort size of 93 subjects (inclusive of the 10 patients in the initial lead-in PK cohort and in the 
2000mg dose lead-in cohort) will provide a suitably precise assessment of the descriptive safety 
and tolerability profile for a two-dose regimen of IV sotrovimab. This enrollment plan is 
consistent with similar ongoing clinical studies of COVID-19 prophylaxis and justified by the 
relatively broad inclusion criteria for the study, encompassing multiple distinct subgroups of 
immunocompromised patients. The following table contains estimates of the precision in the 
estimated grade 3-4 TEAE rate. 
 
Table 4. Precision in the Estimated Grade 3-4 Treatment-Emergent Adverse Event Rate 
with a Total Cohort Size of 93 Patients 
  
AE Rate 
Exact 95% Confidence Interval 
Probability of Seeing at 
Least One Event 


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61 
1% 
 (0.0%, 5.8%) 
0.607 
2% 
(0.2%, 7.6%) 
0.847 
3% 
(0.7%, 9.1%) 
0.941 
4% 
(1.2%, 10.6%) 
0.978 
5% 
(1.8%, 12.1%) 
0.992 
 
Patients who discontinue their participation in the study prematurely will not be replaced.  
 
The study will end on the date when the last living patient completes the last study visit, 
withdraws from the study, or is lost to follow-up. The accrual targets by study subject race and 
ethnicity are as outlined in the table below: 
 
 
Table 5. Study Accrual Targets by Race/Ethnicity 
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
 
Males 
 
Total 
Hispanic or Latino 
3 
+ 3 
= 6 
Not Hispanic or Latino 
43 
+ 44 
= 87 
Ethnic Category: Total of all 
subjects 
 
46 
+  
47 
=  
93 
Racial Category 
 
American Indian or Alaskan Native 
0 
+ 0 
= 0 
Asian 
2 
+ 2 
= 4 
Black or African American 
4 
+ 4 
= 8 
Native Hawaiian or other Pacific 
Islander 
0 
+ 0 
= 0 
White 
40 
+ 41 
= 81 
Racial Category: Total of all 
subjects 
 
46 
+  
47 
=  
93 
 
(A1 = A2) 
 
(B1 = B2) 
 
(C1 = C2) 
 
13.3. Stratification Factors 
 


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Where possible,  all analyses will be conducted in the full cohort and separately, stratified by 
subtype of underlying immunocompromised status as follows: (1) solid organ transplant 
recipients, (2) participants with a history of hematologic malignancy requiring hematopoietic cell 
transplant and/or history of chimeric antigen receptor (CAR)-T cell therapy, and (3) participants 
with any other hematologic malignancy, autoimmune or inflammatory condition requiring either 
use of anti-CD20 monoclonal antibody or other immunosuppressive medication specifically 
associated with a blunted humoral immune response to SARS-CoV-2, as outlined in the 
inclusion criteria. These analyses, including comparisons of the primary and secondary outcomes 
of interest across these three groups, will permit an exploration of specific differences that may 
be present between subgroups with varying immunological deficits. 
 
13.4. Interim Monitoring Plan 
 
As detailed above, this study will unfold in stages. First, an analysis of the 10-patient 
pharmacokinetic lead-in cohort and theoretical pharmacokinetic modeling of the duration of the 
antiviral efficacy of sotrovimab based on the rising prevalence of the BA.2 variant will define the 
optimal dosing interval between two sequential doses of intravenous sotrovimab. The remaining 
participants will follow the dosing interval defined by this lead-in cohort. Second, the 50-patient 
safety and tolerability lead-in cohort (inclusive of these 10 patients) will inform the infusion 
period for the remaining participants. If there are no grade ≥ 2 infusion-related reactions in this 
initial group, patients in the expansion cohort will receive their intravenous sotrovimab doses 
over a 15-minute infusion period; however, if there is at least one patient with a grade ≥ 2 
infusion-related reaction, study subjects in the expansion cohort will continue to receive 
intravenous sotrovimab over a 30-minute infusion period. These data will be reviewed by the 
study team. Finally, the 10 patients in the 2000mg sotrovimab dose lead-in cohort will inform the 
observation period for all patients who receive their 2000mg dose after these patients, with a 2 
hour observation period following completion of the 2000mg dose for these 10 patients, reduced 
to a one-hour period for all subsequent patients if there are no grade 3 or 4 infusion-related 
reactions or other SAEs potentially related to the sotrovimab dose in this 2000mg dose lead-in 
safety cohort. 
 
13.5. Analysis of Primary Endpoints 
 
No formal hypothesis tests will be performed and no formal significance tests for comparisons will 
be made.  The primary safety and tolerability outcomes of interest will be displayed in the form of 
listings, frequencies, summary statistics, and graphs, where appropriate. Binary data will be 
presented in the form of counts and proportions and continuous data will be presented using 
descriptive statistics (N, mean, SD, median and range). Similarly, descriptive statistics will be 
provided for selected PK parameters of interest for the cohort. All PK parameters will be 
summarized in terms of means, standard deviation (SD), % coefficient of variation (CV), range, 
median, and number of samples. Interpretation of these safety and tolerability data and PK values 
will be informed by clinical expertise. 
 
13.6. Analysis of Secondary Endpoints 
 


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The secondary endpoints of interest in this study will include: (1) COVID-19 infections over the 
study period and (2) self-reported quality of life measures over the course of the study. COVID-
19 infections in this cohort will be summarized using standard descriptive statistics including 
counts and proportions where applicable. Logistic regression models will be used to examine 
sociodemographic and health-related factors associated with incident COVID-19 infection in this 
population over the study period. Covariates such as age, sex, type of immunocompromising 
condition, prior vaccination status and body mass index will be assessed in these models. Changes 
in self-reported quality of life from baseline to the study mid-point and baseline to endline, as 
assessed by the SF-36 instrument, will be analyzed descriptively, and where appropriate, 
graphically visualized from baseline to endline. A linear mixed model with a random slope for 
each participant and an unstructured correlation matrix will be used to examine changes in SF-36 
continuous scores over time and include baseline demographic and relevant clinical parameters as 
fixed effects. 
 
13.7. Reporting and Exclusions 
 
13.7.1. Evaluation of Toxicity 
 
All participants will be evaluable for the primary safety and tolerability endpoints from the time 
of their first treatment. 
 
13.7.2. Evaluation of the Primary Efficacy Endpoint 
 
This study does not include a primary efficacy endpoint. 
 
 
14. PUBLICATION PLAN 
 
The results should be made public within 24 months of reaching the end of the study. The end of 
the study is the time point at which the last living patient completes the last study visit, 
withdraws from the study, or is lost to follow-up. If a report is planned to be published in a peer-
reviewed journal, then that initial release may be an abstract that meets the requirements of the 
International Committee of Medical Journal Editors. A full report of the outcomes should be 
made public no later than three (3) years after the end of the study. 
 


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APPENDIX A 
KARNOFSKY PERFORMANCE STATUS SCALE 
 
Percent 
Description 
100 
Normal, no complaints, no evidence of disease 
90 
Able to carry on normal activity; minor signs or symptoms of 
disease 
80 
Normal activity with effort; some signs or symptoms of disease 
70 
Cares for self, unable to carry on normal activity or to do active 
work 
60 
Requires considerable assistance, but is able to care for most of 
his/her needs 
50 
Requires considerable assistance, and frequent medical care 
40 
Disabled, requires special care and assistance 
30 
Severely disabled, hospitalization indicated. Death not imminent 
20 
Very sick, hospitalization indicated. Death not imminent 
10 
Moribund, fatal processes progressing rapidly 
0 
Dead 
 
 
 
 
 


NCI Protocol #: N/A 
Version Date: March 31, 2022 
 
70 
APPENDIX B 
MULTI-CENTER GUIDELINES 
 
N/A 
 
 
 
 


NCI Protocol #: N/A 
Version Date: March 31, 2022 
 
71 
APPENDIX C 
INFORMATION ON POSSIBLE DRUG INTERACTIONS 
 
Information on Possible Interactions with Other Agents for Patients and Their Caregivers 
and Non-Study Healthcare Team 
 
No formal interaction studies have been conducted with sotrovimab. Sotrovimab is neither 
renally excreted nor metabolized by cytochrome P450 (CYP) enzymes; therefore, interactions 
with concomitant medications that are renally excreted or that are substrates, inducers, or 
inhibitors of CYP enzymes are unlikely.  
 
 
 


NCI Protocol #: N/A 
Version Date: March 31, 2022 
 
72 
APPENDIX D 
COVID-19 CLINICAL SIGNS AND SYMPTOMS ASSESSMENT 
 
Patient Study ID: ________________________________ 
Patient Initials: __________________________________ 
Study Visit Number:______________________________ 
Date: __________________________________________ 
Investigator Signature: ____________________________ 
 
Have you had any of the following symptoms in the past 14 days that are either new 
or worsening? 
◻ Fever or chills 
◻ Cough 
◻ Shortness of breath or difficulty breathing 
◻ Fatigue 
◻ Muscle or body aches 
◻ Headache 
◻ New loss of taste or smell 
◻ Sore throat 
◻ Congestion or runny nose 
◻ Nausea or vomiting 
◻ Diarrhea 
◻ No new or worsening symptoms to report 
 
If you reported any new or worsening symptoms, could they be explained by any of 
your underlying medical conditions, current treatments, or relevant medical history? 
If yes, explain. 
Investigator Judgement 
◻ Screen pass 
◻ Screen fail 
 
 


NCI Protocol #: N/A 
Version Date: March 31, 2022 
 
73 
APPENDIX E 
8-POINT NATIONAL INSTITUTE OF ALLERGY AND 
INFECTIOUS DISEASES ORDINAL SCALE (NIAID-OS) FOR THE ASSESSMENT OF 
CLINICAL STATUS IN PATIENTS WITH SARS-COV-2 INFECTION 
[80] 
 
NIAID-OS Scale 
Value 
Scale Value Description 
1 
Not hospitalized, no limitations on activities 
2 
Not hospitalized, limitation on activities or/or requiring 
home oxygen 
3 
Hospitalized, not requiring supplemental oxygen, no 
longer requires ongoing medical care  
4 
Hospitalized, not requiring supplemental oxygen 
5 
Hospitalized, requiring supplemental oxygen 
6 
Hospitalized, on non-invasive ventilation or high flow 
oxygen devices 
7 
Hospitalized, on invasive mechanical ventilation or 
extracorporeal membrane oxygenation (ECMO) 
8 
Death