A Safety and Tolerability Study of Sotrovimab (VIR-7831) Prophylaxis Against COVID-19 in Immunocompromised Individuals

A Safety and Tolerability Study of Sotrovimab (VIR-7831) Prophylaxis Against COVID-19 Infection in Immunocompromised Individuals With Impaired SARS-CoV-2 Humoral Immunity

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.

Study Overview

• Status: Active, not recruiting
• Conditions: SARS CoV 2 Infection
• Intervention / Treatment: Drug: Sotrovimab

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.

• Study Type: Interventional
• Enrollment (Actual): 93
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Katherine Beluch; Phone Number: 58733 (617)732-5500; Email: Katherine_Beluch@dfci.harvard.edu
• Study Contact Backup: Name: Alyssa Cho; Phone Number: 58733 (617)732-5500; Email: acho5@bwh.harvard.edu

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 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.

• Participant must have one of the following immunocompromising conditions that increases their likelihood of having an impaired humoral immune response to SARS-CoV-2, while also increasing their risk of being infected with SARS-CoV-2 and risk of progression to severe COVID-19:

  1. 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.
  2. 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.
  3. Chimeric antigen receptor (CAR)-T cell therapy ≥ 4 weeks and ≤ 2 years prior to consent.
  4. Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), multiple myeloma, or Waldenström macroglobulinemia.
  5. Solid organ transplant recipient receiving immunosuppressive therapy.
  6. Congenital immunodeficiency syndrome (e.g. Wiskott-Aldrich syndrome, DiGeorge syndrome, common variable immunodeficiency).
  7. 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.

• Female participants must be:

  1. Postmenopausal for at least 1 year;
  2. Post-hysterectomy and/or post-bilateral oophorectomy;
  3. 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.
• Participants must have a negative or low-positive (<50 U/mL) SARS-CoV-2 spike antibody assay result within 28 days of consent.

Exclusion Criteria:

• 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.
• Participants with symptoms suggestive of SARS-CoV-2 infection.
• 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.
• Individuals who are pregnant or breastfeeding.
• Participants who are receiving any other investigational agents.
• Participants who, in the judgment of the investigator, are likely to have a life expectancy of less than one year.
• Known hypersensitivity to any constituent present in sotrovimab or any other anti-SARSCoV-2 monoclonal antibody product.
• Active enrollment on another interventional research study of any agent for the treatment or prophylaxis of SARS-CoV-2 infection.
• Exposure to any other anti-SARS-CoV-2 monoclonal antibody product for the treatment of COVID-19 in the prior 6 months.
• Exposure to any other anti-SARS-CoV-2 monoclonal antibody product for prophylaxis against COVID-19 infection in the prior 12 months.
• Receipt of a SARS-CoV-2 vaccine dose within the prior 28 days.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

OTHER: Sotrovimab; 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.

Drug: Sotrovimab; 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.; Other Names: VIR-7831

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients with treatment-emergent adverse events, serious adverse events, and adverse events of specific interest	Assessment of the safety and tolerability of sotrovimab in immunocompromised patients with impaired humoral immunity against SARS-CoV-2. This measure will include: 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.	36 weeks after the second dose of sotrovimab
Serum sotrovimab levels to assess pharmacokinetics over time, with determination of maximum serum sotrovimab concentration (Cmax)	Cmax determination	36 weeks after the second dose of sotrovimab
Serum sotrovimab levels to assess pharmacokinetics over time, with determination of time to maximal sotrovimab serum concentration (Tmax)	Tmax determination	36 weeks after the second dose of sotrovimab
Serum sotrovimab levels to assess pharmacokinetics over time, with determination of minimal sotrovimab serum concentration (Cmin)	Cmin determination	36 weeks after the second dose of sotrovimab
Serum sotrovimab levels to assess pharmacokinetics over time, with determination of last sotrovimab concentration (Clast)	Clast determination	36 weeks after the second dose of sotrovimab
Serum sotrovimab levels to assess pharmacokinetics over time, with determination of time of last measurable sotrovimab concentration (Tlast)	Tlast determination	36 weeks after the second dose of sotrovimab
Serum sotrovimab levels to assess pharmacokinetics over time, with determination of area under the curve extrapolated to infinity (AUC(0-∞)	AUC(0-∞)	36 weeks after the second dose of sotrovimab
Serum sotrovimab levels to assess pharmacokinetics over time, with determination of AUC(0-∞) vs. dose	AUC(0-∞) vs. dose	36 weeks after the second dose of sotrovimab
Serum sotrovimab levels to assess pharmacokinetics over time, with determination of half life (t 1/2)	Sotrovimab half-life (t 1/2)	36 weeks after the second dose of sotrovimab
Serum sotrovimab levels to assess pharmacokinetics over time, with determination of sotrovimab concentration in serum 28 days after dosing (C28)	Concentration in serum 28 days after dosing (C28)	28 weeks after the first dose of sotrovimab

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Symptomatic COVID-19 infection of any severity	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.	36 weeks after the second dose of sotrovimab
Asymptomatic COVID-19 infection	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.	36 weeks after the second dose of sotrovimab
Severe COVID-19 infection	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.	36 weeks after the second dose of sotrovimab
Greatest extent of COVID-19 symptoms	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), ranging from 1-8 with higher scores corresponding to worse clinical outcomes, assessed at the end of hospitalization or 14 days after the diagnosis of COVID-19.	36 weeks after the second dose of sotrovimab (study subjects are at risk of developing COVID-19 infection over the entire study period).
Health-related quality of life	Health-related quality of life will be measured longitudinally during the study using the Short Form Health Survey (SF-36) instrument.	36 weeks after the second dose of sotrovimab

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
New cellular or antibody-mediated rejection events in solid organ transplant recipients	Assessment of rates of new cellular or antibody-mediated rejection events in solid organ transplant (SOT) recipients exposed to sotrovimab.	36 weeks after the second dose of sotrovimab
New-onset or worsening graft-versus-host disease in hematopoietic cell transplant recipients	Assessment of rates of new-onset or worsening graft-versus-host disease in hematopoietic cell transplant (HCT) recipients exposed to sotrovimab.	36 weeks after the second dose of sotrovimab
New-onset allograft or stem cell failure requiring retransplantation in HCT recipients	Assessment of rates of new-onset allograft or stem cell failure requiring retransplantation in HCT recipients exposed to sotrovimab.	36 weeks after the second dose of sotrovimab

Collaborators and Investigators

• Sponsor: Sophia Koo, M.D.
• Collaborators: Massachusetts General Hospital; GlaxoSmithKline; Dana-Farber Cancer Institute

Study record dates

Study Major Dates

• Study Start (ACTUAL): February 7, 2022
• Primary Completion (ANTICIPATED): April 1, 2023
• Study Completion (ANTICIPATED): April 1, 2023

Study Registration Dates

• First Submitted: January 25, 2022
• First Submitted That Met QC Criteria: January 26, 2022
• First Posted (ACTUAL): January 27, 2022

Study Record Updates

• Last Update Posted (ESTIMATE): February 9, 2023
• Last Update Submitted That Met QC Criteria: February 7, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: Transplant; Prophylaxis; Monoclonal antibodies; Immunocompromised host
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Infections
• Other Study ID Numbers: 21-755

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No