Effect of Bamlanivimab as Monotherapy or in Combination With Etesevimab on Viral Load in Patients With Mild to Moderate COVID-19: A Randomized Clinical Trial

Abstract

Importance: Coronavirus disease 2019 (COVID-19) continues to spread rapidly worldwide. Neutralizing antibodies are a potential treatment for COVID-19.

Objective: To determine the effect of bamlanivimab monotherapy and combination therapy with bamlanivimab and etesevimab on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load in mild to moderate COVID-19.

Design, setting, and participants: The BLAZE-1 study is a randomized phase 2/3 trial at 49 US centers including ambulatory patients (N = 613) who tested positive for SARS-CoV-2 infection and had 1 or more mild to moderate symptoms. Patients who received bamlanivimab monotherapy or placebo were enrolled first (June 17-August 21, 2020) followed by patients who received bamlanivimab and etesevimab or placebo (August 22-September 3). These are the final analyses and represent findings through October 6, 2020.

Interventions: Patients were randomized to receive a single infusion of bamlanivimab (700 mg [n = 101], 2800 mg [n = 107], or 7000 mg [n = 101]), the combination treatment (2800 mg of bamlanivimab and 2800 mg of etesevimab [n = 112]), or placebo (n = 156).

Main outcomes and measures: The primary end point was change in SARS-CoV-2 log viral load at day 11 (±4 days). Nine prespecified secondary outcome measures were evaluated with comparisons between each treatment group and placebo, and included 3 other measures of viral load, 5 on symptoms, and 1 measure of clinical outcome (the proportion of patients with a COVID-19-related hospitalization, an emergency department [ED] visit, or death at day 29).

Results: Among the 577 patients who were randomized and received an infusion (mean age, 44.7 [SD, 15.7] years; 315 [54.6%] women), 533 (92.4%) completed the efficacy evaluation period (day 29). The change in log viral load from baseline at day 11 was -3.72 for 700 mg, -4.08 for 2800 mg, -3.49 for 7000 mg, -4.37 for combination treatment, and -3.80 for placebo. Compared with placebo, the differences in the change in log viral load at day 11 were 0.09 (95% CI, -0.35 to 0.52; P = .69) for 700 mg, -0.27 (95% CI, -0.71 to 0.16; P = .21) for 2800 mg, 0.31 (95% CI, -0.13 to 0.76; P = .16) for 7000 mg, and -0.57 (95% CI, -1.00 to -0.14; P = .01) for combination treatment. Among the secondary outcome measures, differences between each treatment group vs the placebo group were statistically significant for 10 of 84 end points. The proportion of patients with COVID-19-related hospitalizations or ED visits was 5.8% (9 events) for placebo, 1.0% (1 event) for 700 mg, 1.9% (2 events) for 2800 mg, 2.0% (2 events) for 7000 mg, and 0.9% (1 event) for combination treatment. Immediate hypersensitivity reactions were reported in 9 patients (6 bamlanivimab, 2 combination treatment, and 1 placebo). No deaths occurred during the study treatment.

Conclusions and relevance: Among nonhospitalized patients with mild to moderate COVID-19 illness, treatment with bamlanivimab and etesevimab, compared with placebo, was associated with a statistically significant reduction in SARS-CoV-2 viral load at day 11; no significant difference in viral load reduction was observed for bamlanivimab monotherapy. Further ongoing clinical trials will focus on assessing the clinical benefit of antispike neutralizing antibodies in patients with COVID-19 as a primary end point.

Trial registration: ClinicalTrials.gov Identifier: NCT04427501.

Figure 1.. Patient Enrollment and Treatment Assignment of the BLAZE-1 Trial of Bamlanivimab for Mild to Moderate COVID-19

SARS-CoV-2 indicates severe acute respiratory syndrome coronavirus 2. ^aStratified by duration since symptom onset to randomization (≤8 days vs >8 days). ^bIncluded in the adverse event analysis. ^cHad data on at least 1 postbaseline viral load. ^dThree patients were excluded from the efficacy analysis because they did not have data on at least 1 postbaseline viral load. However, these patients were included in the safety analysis because they did receive the intervention as randomized. ^eFour patients were excluded from the efficacy analysis because they did not have data on at least 1 postbaseline viral load. However, these patients were included in the safety analysis because they did receive the intervention as randomized. ^fHad data on viral load for both baseline and at day 11.

Figure 2.. Change in Log Viral Load and in Viral Load Cycle Threshold Over Time With Bamlanivimab Monotherapy and Bamlanivimab and Etesevimab Combination Therapy

Randomization and infusion occurred on day 1. A, The middle line represents the median change from baseline for log viral load; the boxes represent the interquartile range; the squares inside each box represent the mean; the whiskers extend to the highest and lowest values within 1.5 x the interquartile range of the nearer quartile; and the dots represent observed values outside that range. B, The cycle threshold is defined as the number of cycles required for the fluorescent signal of the polymerase chain reaction assay to cross the threshold (ie, exceeds background level). Cycle threshold levels are inversely proportional to the number of copies of the virus and thus serve to estimate viral load. Virus is presumed to be undetectable beyond approximately 40 cycle thresholds. SARS-CoV-2 indicates severe acute respiratory syndrome coronavirus 2.