Non-inferiority Trial on Monoclonal Antibodies in COVID-19

Study Overview
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Brief Summary
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Currently, 3 anti-SARS-CoV-2 monoclonal antibody products have received Emergency Use Authorizations from the Italian Medicines Agency (AIFA) for the treatment of mild to moderate COVID-19 in non hospitalized patients with laboratory-confirmed SARS-CoV-2 infection who are at high risk for progressing to severe disease and/or hospitalization (bamlanivimab plus etesevimab, sotrovimab, and casirivimab plus imdevimab). Differently from casirivimab/imdevimab and sotrovimab, the European Medicines Agency (EMA) has never recommended authorising the combination bamlanivimab/etesevimab for treating COVID-19. Moreover, the evidence on sotrovimab relies on the interim analysis results of an ongoing randomised placebo-controlled clinical trial [1], unlike the combinations bamlanivimab/etesevimab and casirivimab/imdevimab, whose results of the randomised placebo-controlled trials were published after having completed the enrolment [2,3]. The study aims at assessing the non-inferiority of bamlanivimab plus etesevimab and sotrovimab vs. casirivimab plus imdevimab on COVID-19 progression in patients aged at least 50 years at an early stage of the disease. The progression of COVID-19 disease (hospitalization, need for supplementary oxygen therapy at home, death) within 14 days of randomisation is the composite outcome variable on which the calculation of the sample size is based. Based on available data regarding the reduction in the number of hospitalisations and medical visits with the use of casirivimab plus imdevimab at an early-stage of COVID-19, a disease progression of 5% has been estimated in the reference arm. 5% delta margin was considered clinically relevant, taking into account both the estimates of disease progression in the study population in absence of early treatment with monoclonal antibodies (20%, based on national data) and the efficacy of the reference standard. Therefore, 1260 participants will be randomly assigned in an equal ratio between the reference standard and each of the other two experimental arms (1:1:1). Randomization will be computer-generated in permuted blocks with a stratification based on site.

Detailed Description
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Sample size. The parameters for the sample size estimation were derived from the only double-blind, randomised, placebo-controlled trial assessing the clinical efficacy of casirivimab/imdevimab (reference standard) [3]. Hospitalisation related to COVID-19 or all-cause mortality in this study occurred in 7 of 736 patients in the casirivimab/imdevimab 1200-mg group (1.0%) and in 24 of 748 patients in the placebo group who underwent randomisation concurrently (3.2%) (relative risk reduction, 70.4%; P=0.002). Assuming a non-inferiority margin of 5%, 420 patients per group were needed to achieve 90% power with a 1-sided α level of .025, allowing for 5% dropout. A 5% non-inferiority margin was chosen as the maximal difference between treatments in COVID-19 progression that would be clinically acceptable by consultation with Infectious Diseases and clinical trial specialists involved in the protocol development.

Official Title
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Adaptive, Randomized, Non-inferiority Trial to Evaluate the Efficacy of Monoclonal Antibodies in Outpatients With Mild or Moderate COVID-19

Conditions
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COVID-19

Intervention / Treatment
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* Drug: Bamlanivimab Etesevimab
* Drug: Sotrovimab
* Drug: Casirivimab-Imdevimab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 50 years Informed consent by the subject or legally authorized representative Laboratory-confirmed SARS-CoV-2 infection, as determined by antigen or nucleic acid identification in any specimen, within 4 days of eligibility assessment Peripheral oxygen saturation ≥ 94% on room air and not requiring supplemental oxygen Onset of symptoms within 4 days of eligibility assessment. Onset time of symptoms is defined as the time when the patient experienced the presence of at least one of the following SARS-CoV-2 infection-associated symptoms for the first time [4]: cough, nasal congestion, sore throat, feeling hot or feverish, myalgia, fatigue, headache, anosmia/ageusia, nausea, vomiting, and/or diarrhoea Exclusion Criteria: Previously or currently hospitalized or requiring hospitalization Respiratory distress with respiratory rate ≥ 25 breaths/min Heart rate ≥ 125 beats per minute Peripheral oxygen saturation ≤ 93% on room air at sea level Known allergies to any of the components used in the formulation of the trial drugs Hemodynamic instability requiring use of pressors within 24 hours of randomization Suspected or proven serious, active bacterial, fungal, viral, or other infection (besides COVID-19) that could potentially lead to hospitalization within 30 days Any co-morbidity requiring surgery within 7 days or that is considered life-threatening within 90 days History of positive SARS-CoV-2 test prior to 4 days of the eligibility assessment Previous treatment with a SARS-CoV-2 specific monoclonal antibody History of convalescent COVID-19 plasma treatment Participation in a clinical study involving an investigational intervention within the last 30 days Pregnancy or breast feeding Investigator site personnel directly affiliated with this study Sexually active women of childbearing potential or sexually active men who are unwilling to practice effective contraception prior to the initial dose/start of the first treatment, during the study, and for at least 6 months after the last dose Inability to participate to the study follow-up

Ages Eligible for Study
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Minimum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bamlanivimab Etesevimab<br>Bamlanivimab 700 mg + Etesevimab 1400 mg administered in 250 mL prefilled 0.9% sodium chloride injection infusion solution over one hour | Drug: Bamlanivimab Etesevimab<br>* Single intravenous infusion of bamlanivimab 700 mg and etesevimab 1400 mg, administered together [1 bamlanivimab vial (700 mg/20 mL) and 2 etesevimab vials (700 mg/20 mL)] in a 250-mL prefilled 0.9% Sodium Chloride infusion bag over one hour.<br>|
| Experimental: Sotrovimab<br>Sotrovimab 500 mg administered in 100 mL prefilled 0.9% sodium chloride injection infusion solution over 1/2 hour | Drug: Sotrovimab<br>* Single intravenous infusion of sotrovimab 500 mg (500 mg/8 mL), administered in 100 mL prefilled 0.9% sodium chloride injection infusion solution over 1/2 hour.<br>|
| Active Comparator: Casirivimab Imdevimab<br>Casirivimab 600 mg + Imdevimab 600 mg administered in 250 mL prefilled 0.9% sodium chloride injection infusion solution over one hour | Drug: Casirivimab-Imdevimab<br>* Single intravenous infusion of casirivimab 600 mg + imdevimab 600 mg, administered together in 250 mL prefilled 0.9% sodium chloride injection infusion solution over one hour. Casirivimab and imdevimab are each supplied in individual single use vials. Casirivimab is available as 300 mg/2.5 mL (120 mg/mL) or 1332 mg/11.1 mL (120 mg/mL). Imdevimab is available as 300 mg/2.5 mL (120 mg/mL) or 1332 mg/11.1 mL (120 mg/mL).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| COVID-19 progression | (1) hospitalization or (2) need of supplemental oxygen therapy at home or (3) death within 14 days of randomisation | 14 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Visits to the Emergency Room | Number of visits to the Emergency Room without subsequent hospitalization within 28 days of randomization | 28 days | 
| Duration of supplemental oxygen therapy | Days of supplemental oxygen therapy within 90 days of randomization | 90 days | 
| Duration of hospitalization | Days of any hospitalization within 90 days of randomization | 90 days | 
| Non-invasive ventilation | Rate of patients undergoing non-invasive ventilation within 28 days of randomization | 28 days | 
| Duration of non-invasive ventilation | Days of non-invasive ventilation within 90 days of randomization | 90 days | 
| Mechanical ventilation | Rate of patients undergoing mechanical ventilation within 28 of randomization | 28 days | 
| Duration of mechanical ventilation | Days of mechanical ventilation within 90 days of randomization | 90 days | 
| 28-day mortality | Death rate at 28 days of randomization | 28 days | 
| Duration of symptoms | Days of symptoms within 90 days of randomization | 90 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Coronavirus Infections, Monoclonal antibodies, Bamlanivimab Etesevimab, Casirivimab Imdevimab, Sotrovimab