Randomized Controlled Trial
Study population and setting
This placebo-controlled RCT randomized participants 1:1:1 to placebo or one of two doses of casirivimab and imdevimab (2.4 or 8.0 g dose; REGN-COV2). 275 adult outpatients were enrolled between June 16, 2020, and August 13, 2020 and received a one-time intravenous infusion of treatment. Inclusion required positive SARS-CoV-2 by antigen or RT-PCR assay ≤72 hours prior to randomization. Exclusion criteria included hospitalization, SpO2 ≤93% on room air, and pregnancy. The primary virologic outcome was change in viral load from baseline to day 7; the primary clinical endpoint was the percentage of patients with at least one COVID-19-related medical visit through day 29. Pre-specified secondary outcomes included safety and change in viral load from baseline to various days during the trial. Analyses were stratified by presence or absence of anti-SARS-CoV-2 antibodies at enrollment.
Summary of Main Findings
The median age of participants was 44 years, the mean BMI was 30.25 kg/m^2, most (64%) participants had one or more COVID-19 risk factors, and the median duration of symptoms was 3 days. For the primary virologic endpoint, the combined active treatment group had significantly reduced mean log viral load from baseline to day 7 compared to placebo (-0.41 log10 copies/mL, 95% CI: -1.02 to -0.11), this difference was largest in the serum antibody-negative subgroup, and this remained significant for the serum-negative group alone (-0.56 log10 copies/mL, 95% CI: -0.71 to -0.10). Notably, participants without detectable serum antibodies at baseline had a higher median SARS-CoV-2 RNA. By day 29, fewer patients in the active group experienced at least one COVID-19-related medical visit compared to placebo group (3% and 6% in active and placebo groups; difference -3%, 95% CI: -16 to 9); this result was not significant in the overall group or subgroup without serum antibodies at baseline (6% and 15% in active and placebo groups). Adverse effects were comparable between treatment and placebo group (1% vs. 2%).
The design was double-blind and placebo-controlled, reducing the likelihood of placebo effect or reporting bias. Median time from symptom onset to treatment was relatively short at 3 days, permitting analysis of the effects of early intervention. Patients with the highest viral loads had the highest treatment benefit; for example, in patients with viral load >10^7 copies/mL, the mean reduction in viral load was 2-log greater in the REGN-COV2 group compared to placebo.
Studies of virologic outcomes according to baseline viral load were conducted posthoc, requiring future trials with pre-specified endpoints to confirm. It is unclear whether treatment with REGN-COV2 has a clinically meaningful effect, as primary clinical endpoint and time to alleviation of symptoms were not found to be significant.
This study is the first to assess usage of dual monoclonal neutralizing antibodies for outpatients with mild COVID-19. Consistent with prior work, this study shows that positive antibody status at baseline predicts reduced viral load and reduced COVID-19-related medical visits. This study demonstrated that dual monoclonal anti-spike protein antibodies reduce COVID-19 RNA, especially among those lacking endogenous detectable antibodies at baseline and may reduce clinical visits.
This review was posted on: 12 March 2021