Responses to a Neutralizing Monoclonal Antibody for Hospitalized Patients With COVID-19 According to Baseline Antibody and Antigen Levels : A Randomized Controlled Trial

Abstract

Background: In a randomized, placebo-controlled, clinical trial, bamlanivimab, a SARS-CoV-2-neutralizing monoclonal antibody, given in combination with remdesivir, did not improve outcomes among hospitalized patients with COVID-19 based on an early futility assessment.

Objective: To evaluate the a priori hypothesis that bamlanivimab has greater benefit in patients without detectable levels of endogenous neutralizing antibody (nAb) at study entry than in those with antibodies, especially if viral levels are high.

Design: Randomized, placebo-controlled trial. (ClinicalTrials.gov: NCT04501978).

Setting: Multicenter trial.

Patients: Hospitalized patients with COVID-19 without end-organ failure.

Intervention: Bamlanivimab (7000 mg) or placebo.

Measurements: Antibody, antigen, and viral RNA levels were centrally measured on stored specimens collected at baseline. Patients were followed for 90 days for sustained recovery (defined as discharge to home and remaining home for 14 consecutive days) and a composite safety outcome (death, serious adverse events, organ failure, or serious infections).

Results: Among 314 participants (163 receiving bamlanivimab and 151 placebo), the median time to sustained recovery was 19 days and did not differ between the bamlanivimab and placebo groups (subhazard ratio [sHR], 0.99 [95% CI, 0.79 to 1.22]; sHR > 1 favors bamlanivimab). At entry, 50% evidenced production of anti-spike nAbs; 50% had SARS-CoV-2 nucleocapsid plasma antigen levels of at least 1000 ng/L. Among those without and with nAbs at study entry, the sHRs were 1.24 (CI, 0.90 to 1.70) and 0.74 (CI, 0.54 to 1.00), respectively (nominal P for interaction = 0.018). The sHR (bamlanivimab vs. placebo) was also more than 1 for those with plasma antigen or nasal viral RNA levels above median level at entry and was greatest for those without antibodies and with elevated levels of antigen (sHR, 1.48 [CI, 0.99 to 2.23]) or viral RNA (sHR, 1.89 [CI, 1.23 to 2.91]). Hazard ratios for the composite safety outcome (<1 favors bamlanivimab) also differed by serostatus at entry: 0.67 (CI, 0.37 to 1.20) for those without and 1.79 (CI, 0.92 to 3.48) for those with nAbs.

Limitation: Subgroup analysis of a trial prematurely stopped because of futility; small sample size; multiple subgroups analyzed.

Conclusion: Efficacy and safety of bamlanivimab may differ depending on whether an endogenous nAb response has been mounted. The limited sample size of the study does not allow firm conclusions based on these findings, and further independent trials are required that assess other types of passive immune therapies in the same patient setting.

Primary funding source: U.S. government Operation Warp Speed and National Institute of Allergy and Infectious Diseases.

Figures

Figure 1:

Sustained recovery for bamlanivimab versus placebo: overall (A), and according to neutralizing antibody (nAb) status at entry: (C) nAb negative and (D) nAb positive.* (B) summarizes the recovery status at day 90 for cohorts displayed in (A), (C) and (D). * The sub-hazard ratios in (C) were nominally different from those in (D) (p=0.018 for difference). Abbreviations: nAB= neutralising antibody status from a surrogate viral neutralization test; sHR= sub-hazard ratio for time to sustained recovery (also called “recovery rate ratio”).

Figure 2.

Sustained recovery according to subgroups at study entry: nAb status and levels of viral measures (plasma antigen and nasal viral RNA)+. * Nominal P-values for differences in the treatment effect across subgroups (interactions between the subgroup indicator and treatment group indicator) are as follows: subgroups by nAb status, P=0.018; antigen level by nAb status, P=0.038; viral RNA level by nAb status, P† low viral RNA = viral RNA level < 10,000 cp/mL, negative, or indeterminate + See Appendix Figures S9–S11 for other subgroupings. Abbreviations: Ag = plasma nucleocapside antigen levels at study entry; nAb = neutralising antibody status from a surrogate viral neutralization test at study entry; sHR=sub-hazard ratio for time to sustained recovery (also called “recovery rate ratio”); viral RNA = quantification of viral copies in fluid from nasal swab at study entry.

Figure 3.

A composite safety outcome (death, serious adverse event, organ failure or serious infection) (top row, A-C) and death (bottom row, D-F) for bamlanivimab versus placebo: overall (left column, A, D), and according to neutralizing antibody (nAb) status at entry: (middle column, B, E) negative and (right column C, F) positive. The hazard ratios in (B) were different from those in (C) (nomial p=0.03 for difference), as were the those in (E) versus (F) (nominal p=0.04). See table S7 for overview of all predefined safety outcomes. Abbreviations: nAb=neutralising antibody status from a surrogate viral neutralization test at study entry; SAE=serious adverse event.