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

Jens D. Lundgren, CHIP Centre of Excellence for Health, Immunity and Infections, Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark.
Birgit Grund, Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, Minnesota.
Christina E. Barkauskas, Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University, Durham, North Carolina.
Thomas L. Holland, Division of Infectious Diseases, Department of Medicine, Duke University, Durham, North Carolina.
Robert L. Gottlieb, Baylor University Medical Center, Dallas, Texas.
Uriel Sandkovsky, Baylor University Medical Center, Dallas, Texas.
Samuel M. Brown, Intermountain Medical Center, Murray, and University of Utah, Salt Lake City, Utah.
Kirk U. Knowlton, Intermountain Healthcare, Salt Lake City, Utah.
Wesley H. Self, Department of Emergency Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
D Clark Files, Section on Pulmonary, Critical Care, Allergy, and Immunology, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina.
Mamta K. Jain, University of Texas Southwestern Medical Center, Dallas, Texas.
Thomas Benfield, Department of Infectious Diseases, Hvidovre and Amager Hospital, University of Copenhagen, Hvidovre, Denmark.
Michael E. Bowdish, Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California.
Bradley G. Leshnower, Division of Cardiothoracic Surgery, Emory University School of Medicine, Atlanta, Georgia.
Jason V. Baker, Hennepin Healthcare Research Institute and University of Minnesota, Minneapolis, Minnesota.
Jens-Ulrik Jensen, CHIP Centre of Excellence for Health, Immunity and Infections, Rigshospitalet, Copenhagen, and Respiratory Medicine Section, Department of Internal Medicine, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup, Denmark.
Edward M. Gardner, Denver Public Health, Denver Health and Hospital Authority, Denver, Colorado.
Adit A. Ginde, Department of Emergency Medicine, School of Medicine, University of Colorado, Aurora, Colorado.
Estelle S. Harris, University of Utah, Salt Lake City, Utah.
Isik S. Johansen, Department of Infectious Diseases, Odense University Hospital, Odense, Denmark.
Norman Markowitz, Department of Infectious Diseases, Henry Ford Hospital, Detroit, Michigan.
Michael A. Matthay, Department of Medicine and Department of Anesthesia and Cardiovascular Research Institute, The University of California, San Francisco, San Francisco, California.
Lars Østergaard, Aarhus University Hospital Skejby, Aarhus, Denmark.
Christina C. Chang, The Kirby Institute, University of New South Wales, Sydney, New South Wales, Australia.
Anna L. Goodman, Medical Research Council Clinical Trials Unit at University College London and Guy's & St Thomas' NHS Foundation Trust, London, United Kingdom.
Weizhong Chang, Laboratory of Human Retrovirology and Immunoinformatics, Frederick National Laboratory for Cancer Research, Frederick, Maryland.
Robin L. Dewar, Leidos Biomedical Research, Frederick, Maryland.
Norman P. Gerry, Advanced Biomedical Laboratories, Cinnaminson, New Jersey.
Elizabeth S. Higgs, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland.
Helene Highbarger, Leidos Biomedical Research and AIDS Monitoring Laboratory, Frederick National Laboratory for Cancer Research, Frederick, Maryland.
Daniel D. Murray, CHIP Centre of Excellence for Health, Immunity and Infections, Rigshospitalet, Copenhagen, Denmark.

Document Type

Journal Article

Publication Date

2-1-2022

Journal

Annals of internal medicine

Volume

175

Issue

2

DOI

10.7326/M21-3507

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 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.

Department

Medicine

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