Stop for futility after the onset of the omicron wave

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.

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.

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