Objectives and hypothesis
The primary objective of this study
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 Division of AIDS (DAIDS) grading criteria, b. The proportion of study subjects with treatment-emergent serious adverse events (SAE), 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, and (2) evaluation of the PK of sotrovimab in immunocompromised patients with impaired humoral immunity against SARS-CoV-2 (29). No formal hypothesis tests will be performed and no formal significance tests for comparisons will be made.
s 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 Division of AIDS (DAIDS) grading criteria, b. The proportion of study subjects with treatment-emergent serious adverse events (SAE), 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, and (2) evaluation of the PK of sotrovimab in immunocompromised patients with impaired humoral immunity against SARS-CoV-2 (29). No formal hypothesis tests will be performed and no formal significance tests for comparisons will be made.
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. Sotrovimab will be administered in two sequential doses as prophylaxis in patients with impaired humoral immunity against SARS-CoV-2. A total of 93 patients will be enrolled in this study, 10 patients in a lead-in PK cohort to determine the optimal dosing interval between the first and second dose of sotrovimab and assess the safety and tolerability of the drug, 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 500mg sotrovimab IV infusion, an expansion cohort of patients to further assess 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, and a 10 patient lead-in safety cohort for the second, 2000mg dose of sotrovimab on Treatment Day 2 – this cohort will inform the duration of observation following administration of the drug, with the observation period being reduced from two hours to one hour for the remaining study subjects if none of these patients have a grade 3-4 infusion-related reaction with the 2000mg dose.
Patients meeting the following inclusion criteria are eligible for study enrollment: (1) 18 years or older at the time of consent and weighing at least 40 kg, (2) having an immunocompromising condition that increases the likelihood of having an impaired humoral immune response to SARS-CoV-2 vaccination, such as exposure to an anti-CD20 monoclonal antibody for hematologic malignancy or an autoimmune/inflammatory disease in the 12-month period prior to consent, allogenic 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, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), multiple myeloma, or Waldenström macroglobulinemia, solid organ transplant recipient receiving immunosuppressive therapy, congenital immunodeficiency syndrome, 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) female participants either postmenopausal for at least 1 year, post-hysterectomy and/or post-bilateral oophorectomy, or in women of childbearing potential, having a negative urine or serum human chorionic gonadotropin pregnancy test prior to each sotrovimab dose and agreeing to use a highly effective method of birth control throughout the study period (e.g. oral, injected, transdermal, intravaginal or implanted hormonal form of contraception associated with inhibition of ovulation, placement of an intrauterine device or intrauterine hormone-releasing system, male partner sterilization, bilateral tubal occlusion, sexual abstinence), and (4) a negative or low-positive SARS-CoV2 spike antibody assay result within 28 days of consent (<50 U/mL on a spike antibody assay available under FDA Emergency Use Authorization (EUA) such as the Roche Elecsys SARS-CoV-2 semiquantitative spike antibody assay).
Patients meeting the following exclusion criteria are eligible for study enrollment: (1) active SARS-CoV-2 infection, with a positive SARS-CoV-2 RT-PCR or antigen test result within 21 days prior to consent, (2) symptoms suggestive of SARS-CoV-2 infection at screening, (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, (4) individuals who are pregnant or breastfeeding, (5) receipt of any other investigational agents at the time of study enrollment, (6) individuals likely to have a life expectancy of less than one year, in the judgment of the investigator, (7) known hypersensitivity to any constituent present in sotrovimab or any other anti-SARS-CoV-2 monoclonal antibody products, (8) active enrollment on another interventional research study of any agent for the treatment or prophylaxis of SARS-CoV-2 infection, (9) exposure to any other anti-SARS-CoV-2 monoclonal antibody product for the treatment of COVID-19 in the prior 6 months, (10) exposure to any other anti-SARS-CoV-2 monoclonal antibody product for prophylaxis against COVID-19 infection in the prior 12 months, and (11) receipt of a SARS-CoV-2 vaccine dose within the 28 days prior to enrollment.
Subjects may be discontinued from the study drug for the following reasons: (1) withdrawal of consent by the subject and/or the subject’s legally authorized representative; (2) loss to follow-up; (3) intercurrent illness that prevents further administration of study treatment; or (4) death.
In the following cases, study drug will be withdrawn but patients will continue to follow study procedures, such as: (1) occurrence of an AE that, in the investigator’s opinion, warrants discontinuation of study drug, (2) pregnancy or initiation of breastfeeding, (3) treatment with other monoclonal antibodies active against SARS-CoV-2 for postexposure prophylaxis after having a household contact with COVID-19 or for treatment of COVID-19 prior to Treatment Day 2. Participants removed from protocol therapy prior to dose 2 of the 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.
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 lead-in PK 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. Patients will be enrolled at Brigham and Women’s Hospital, Dana-Farber Cancer Institute, and Massachusetts General Hospital in Boston, MA, USA.
Pre-treatment procedures include confirmation that the potential study subject meets inclusion and exclusion criteria, and that the participant has 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 FDA EUA. Potential study subjects who have not yet had their SARS-CoV-2 spike antibody testing performed in this window should be tested. If the study subject meets inclusion and exclusion criteria, screening and Treatment Day 1 procedures may be performed on the same day. Informed consent will be completed during the screening visit.
Study subjects will receive sotrovimab 500 mg as an intravenous (IV) infusion over 30 minutes on Treatment Day 1 and 2000 mg as an intravenous (IV) infusion over 60 minutes on Treatment Day 2. Study subjects will be monitored for one-hour after the end of the first infusion; for the second infusion, the first 10 study subjects will be monitored for two hours (second lead-in safety cohort for the 2000 mg dose), with a one-hour monitoring period in all subsequent patients as long as there are no grade >2 infusion-related reactions in this second lead-in safety cohort. Prior to the spread of the BA.2 variant, which made it necessary to administer a repeat sotrovimab dose earlier than originally anticipated, using theoretical modeling and logistical considerations, the interval between the two doses was initially going to be determined by modeling the PK data obtained from a 10-person lead-in PK cohort and is anticipated to be between 12 and 24 weeks in length, given the half-life of sotrovimab.
Following the schedule outlined in Table 1, physicians will collect:
- Vital signs, including body temperature, heart rate, blood pressure, oxygen saturation (SpO2), and respiratory rate.
- Karnofsky performance status.
- An electrocardiogram (ECG).
- Pregnancy testing in women of childbearing potential. A negative urine or serum hCG test is required prior to each dose of sotrovimab.
- Local laboratory testing at each study site, including hematology (complete blood count and differential), and blood chemistry (basic metabolic panel and liver function tests) assays at each of the time points outlined in Table 1.
- Serum sotrovimab levels for PK assessment.
Self-collected anterior nasal swabs will be obtained by study subjects biweekly over the study period using the binx health At-Home Nasal Swab COVID-19 Sample Collection Kit, which has FDA EUA for the self-collection of anterior nasal swab specimens at home, for SARS-CoV-2 RT-PCR (30,31).
COVID-19 symptom assessment will be performed at each in-person or remote study visit using the Center for Disease Control and Prevention’s (CDC) list of symptoms commonly associated with COVID-19 (32). Study participants will be asked if they have any of these symptoms de novo or worsening from baseline at each in-person and remote visit, using a questionnaire. 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.
A comprehensive physical exam will be performed according to the schedule outlined in Table 1. 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) and skin exam (e.g. urticaria, ulcerations, erythema multiforme, maculopapular rashes).
Patients who are diagnosed with COVID-19 during the follow-up period will be assessed using the 8-point National Institute of Allergy and Infectious Diseases ordinal scale (NIAID-OS) at the end of hospitalization or, in those who do not require hospitalization, 14 days after the diagnosis of COVID-19.
Health-related quality of life measures will be assessed using the RAND 36-Item Short Form Health Survey (SF-36) instrument (38). Study subjects will complete these surveys at certain study visits, as outlined in Table 1.
The screening window prior to study entry will last up to 7 days (Day -7 to Treatment Day 1). The study period will last from Treatment Day 1 to the end of treatment visit, and patients will be followed according to the schedule of in-person and remote study visits, assessments, and sample collection points as outlined in Table 1. 168 days after Treatment Day 2, patients will have an in-person end of treatment (EOT) visit for sample collection and assessments. A final remote end of study (EOS) visit will be conducted over the phone 36 weeks/252 days after each subject’s final dose of sotrovimab. Participants will be followed for 36 weeks in total after their second sotrovimab dose, corresponding approximately with 5 half-lives of sotrovimab since the final dose, or death, whichever occurs first. Participants removed from protocol therapy due to unacceptable adverse events (AEs) will be followed until resolution or stabilization of these AEs.
Primary outcome measures
Sotrovimab safety and tolerability: We will determine the proportion of study subjects with treatment emergent grade 3-4 AEs, as defined by DAIDS grading criteria, the proportion of study subjects with treatment-emergent serious adverse events (SAEs), and the proportion of study subjects with AESI, including infusion-related and hypersensitiveity reactions, the development of antidrug antibody (ADA) levels, and antibody-dependent enhancement (ADE) of COVID-19 disease.
Sotrovimab pharmacokinetics: We will evaluate the pharmacokinetics (PK) of sotrovimab in serum samples collected from study subjects.
Secondary outcome measures
COVID-19 infection: We will measure the proportion of study subjects who develop COVID-19 (of any severity) over the study follow-up period and 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 intensive care unit (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, or d. death due to any cause during the study follow-up period. In patients who develop COVID-19, we will assess the greatest extent of COVID-19 symptoms, according to the 8-point National Institute of Allergy and Infectious Diseases ordinal scale (NIAID-OS), at the end of hospitalization or 14 days after the diagnosis of COVID-19 (32).
Quality of life: We will assess health-related quality of life measures over the study using the Short Form Health Survey (SF-36) instrument, assessed at baseline, 12 weeks, and 24 weeks (33).
Safety and adverse effects
Adverse events of special interest (AESI) will be evaluated from patient consent until the end of study visit 36 weeks after Treatment Day 2. AESI are defined as relevant known toxicities of therapeutic monoclonal antibodies that will be monitored by the study team during the study, including hypersensitivity reactions or anaphylaxis, infusion-related reactions, and immunogenicity-related AEs (development of ADA).
All grade 3-4 TEAEs and all treatment-emergent SAEs, defined using DAIDS grading criteria, will be collected from patient consent until the end of study remote visit, 36 weeks after Treatment Day 2 (29). Patients will be solicited for the development of any AE at each in person or remote visit, and any unsolicited AEs reported will be investigated further.
The planned sample size for this study is 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, including the 10 patients in the 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. Table 2 contains estimates of precision in the estimated grade 3-4 TEAE rate.
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 Table 3.
Data management and monitoring
An analysis of the 10-patient PK lead-in cohort and theoretical PK modeling of the duration of the antiviral efficacy of sotrovimab based on the rising prevalence of the SARS-CoV-2 Omicron 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. The 50-patient safety and tolerability lead-in cohort (inclusive of these 10 study participants) will inform the infusion period for the remaining 43 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, the study subjects in the expansion cohort will continue to receive intravenous sotrovimab over a 30-minute infusion period. Finally, the 10 patients in the 2000 mg dose sotrovimab lead-in cohort will inform the observation period for all patients who receive their 2000 mg dose after these patients, with a two hour observation period following completion of the 2000 mg dose for these 10 patients, reduced to a one hour period for all subsequent patients if there are no grade >2 infusion-related reactions or SAEs potentially related to the study drug in the lead-in safety cohort. These data will be reviewed by the study team.
Syneos Health will provide electronic data capture services and monitor and perform quality checks on data collected from this study. 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.
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 the number of samples. Interpretation of these safety and tolerability data and PK values will be informed by clinical expertise.
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 end of treatment, as assessed by the SF-36 instrument, will be analyzed descriptively, and where appropriate, graphically visualized from baseline to end of treatment. 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.
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 the use of an 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.
In accordance with the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) E6, the sponsor-investigator is responsible for quality control and quality assurance 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. All research personnel participated in the study initiation visit which included training on protocol and quality control assurance.
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, and take all appropriate measures requested by the sponsor-investigator and/or designees of the auditor to resolve any problems found during the audit or inspection.