Effectiveness of casirivimab and imdevimab, and sotrovimab during Delta variant surge: a prospective cohort study and comparative effectiveness randomized trial

Abstract

IMPORTANCE The effectiveness of monoclonal antibodies (mAbs), casirivimab and imdevimab, and sotrovimab, for patients with mild to moderate Covid-19 from the Delta variant is unknown. OBJECTIVE To evaluate the effectiveness of mAbs for the Delta variant compared to no treatment, and the comparative effectiveness between mAbs. DESIGN, SETTING, AND PARTICIPANTS Two parallel studies among patients who met Emergency Use Authorization criteria for mAbs from July 14, 2021 to September 29, 2021: i.) prospective observational cohort study comparing mAb treatment to no mAb treatment and, ii.) Bayesian adaptive randomized trial comparing the effectiveness of casirivimab-imdevimab versus sotrovimab. In the observational study, we compared eligible patients who received mAb at an outpatient infusion center at UPMC, to nontreated patients with a positive SARS-CoV-2 test. In the comparative effectiveness trial, we randomly allocated casirivimab-imdevimab or sotrovimab to patients presenting to infusion centers and emergency departments, per system therapeutic interchange policy. EXPOSURE Intravenous mAb per their EUA criteria. MAIN OUTCOMES AND MEASURES For the observational study, risk ratio estimates for hospitalization or death by 28 days were compared between mAb treatment to no mAb treatment using propensity matched models. For the comparative effectiveness trial, the primary outcome was hospital-free days (days alive and free of hospital) within 28 days, where patients who died were assigned -1 day) in a Bayesian cumulative logistic model, adjusted for treatment location, age, sex, and time. Inferiority was defined as a 99% posterior probability of an odds ratio <1. Equivalence was defined as a 95% posterior probability that the odds ratio is within a given bound. RESULTS Among 3,558 patients receiving mAb, the mean age was 54 (SD 18 years), 1,511 (43%) were treated in an infusion center, and 450 (13%) were hospitalized or died by day 28. In propensity matched models, mAb treatment was associated with reduced risk of hospitalization or death compared to no treatment (risk ratio (RR)=0.40, 95% CI: 0.28-0.57). Both casirivimab and imdevimab (RR=0.31, 95% CI: 0.20-0.50), and sotrovimab (RR=0.60, 95% CI: 0.37-1.00) reduced hospitalization or death compared to no mAb treatment. Among patients allocated randomly to casirivimab and imdevimab (n=2,454) or sotrovimab (n=1,104), the median hospital-free days were 28 (IQR 28-28) for both groups, 28-day mortality was 0.5% (n=12) and 0.6% (n=7), and hospitalization by day 28 was 12% (n=291) and 12% (n=140), respectively. Compared to casirivimab and imdevimab, the median adjusted odds ratio for hospital-free days was 0.88 (95% credible interval, 0.70-1.11) for sotrovimab. This odds ratio yielded 86% probability of inferiority of sotrovimab versus casirivimab and imdevimab, and 79% probability of equivalence. CONCLUSIONS AND RELEVANCE In non-hospitalized patients with mild to moderate Covid-19 due to the Delta variant, casirivimab and imdevimab and sotrovimab were both associated with a reduced risk of hospitalization or death. The comparative effectiveness of mAbs appeared similar, though prespecified criteria for statistical inferiority or equivalence were not met. TRIAL REGISTRATION ClinicalTrials.gov: NCT04790786

The impact of neutralizing monoclonal antibodies on the outcomes of COVID‐19 outpatients: A systematic review and meta‐analysis of randomized controlled trials

“… 24 Even more, for patients with mild to moderate COVID‐19 from the Delta variant, a propensity matched models also demonstrated that neutralizing mABs treatment using casirivimab and imdevimab, or sotrovimab was associated with reduced risk of hospitalization or death compared to no treatment (RR: 0.40; 95% CI: 0.28–0.57). 25 In contrast to the recent meta‐analysis of four studies investigating the individual effect of each neutralizing mABs for nonhospitalized patients, no consistent results were found in each comparison. 27 The present meta‐analysis including five RCTs and conducting the overall effect based on the pooled analysis of all included studies demonstrated the benefit of adding neutralizing mABs for nonhospitalized patients.…”

“…In addition, the mortality rate was lower in the neutralizing mAB group than in the control group (0% vs. 3.5%, p = 0.02) 24 . Even more, for patients with mild to moderate COVID‐19 from the Delta variant, a propensity matched models also demonstrated that neutralizing mABs treatment using casirivimab and imdevimab, or sotrovimab was associated with reduced risk of hospitalization or death compared to no treatment (RR: 0.40; 95% CI: 0.28–0.57) 25 . In contrast to the recent meta‐analysis of four studies investigating the individual effect of each neutralizing mABs for nonhospitalized patients, no consistent results were found in each comparison 27 .…”

Sotrovimab: First Approval

“…In a prospective, propensity-matched observational cohort study in non-hospitalized patients with mild to moderate COVID-19 due to Delta variant (n = 3069), casirivimab plus imdevimab or sotrovimab treatment significantly reduced the risk of hospitalization or death by 28 days compared with no treatment (risk ratio 0.4; 95% CI 0.28-0.57), with the comparative effectiveness between the treatments appearing to be similar [39]. In addition, in an ongoing randomized, parallel-assignment, open-label phase III OPTIMISE-C19 trial (NCT04790786) in patients with COVID-19 who received casirivimab plus imdevimab (n = 2454) or sotrovimab (n = 1104), the median hospital-free days were 28 days [39].…”

Emulation of a Target Trial From Observational Data to Compare Effectiveness of Casirivimab/Imdevimab and Bamlanivimab/Etesevimab for Early Treatment of Non-Hospitalized Patients With COVID-19

“…In addition to RCT, data from observational cohorts ( 8 – 11 )have also confirmed the effectiveness of mAbs, but comparative analysis between different options available are lacking ( 12 , 13 ). Considering the rapid epidemiological evolution, with the emergence of new Variants of Concern (VoCs) ( 14 – 16 ) that have been shown to escape ( 17 ) the action of mAbs in vitro ( 18 , 19 ) and in vivo ( 20 ), real-life data about clinical impact and mAb comparison are useful to better clarify the scenario of currently existing drugs.…”