Responses to a Neutralizing Monoclonal Antibody for Hospitalized Patients With COVID-19 According to Baseline Antibody and Antigen Levels : A Randomized Controlled Trial.
Por:
Lundgren JD, Grund B, Barkauskas CE, Holland TL, Gottlieb RL, Sandkovsky U, Brown SM, Knowlton KU, Self WH, Files DC, Jain MK, Benfield T, Bowdish ME, Leshnower BG, Baker JV, Jensen JU, Gardner EM, Ginde AA, Harris ES, Johansen IS, Markowitz N, Matthay MA, Østergaard L, Chang CC, Goodman AL, Chang W, Dewar RL, Gerry NP, Higgs ES, Highbarger H, Murray DD, Murray TA, Natarajan V, Paredes R, Parmar MKB, Phillips AN, Reilly C, Rupert AW, Sharma S, Shaw-Saliba K, Sherman BT, Teitelbaum M, Wentworth D, Cao H, Klekotka P, Babiker AG, Davey VJ, Gelijns AC, Kan VL, Polizzotto MN, Thompson BT, Lane HC and Neaton JD
Publicada:
1 feb 2022
Ahead of Print:
21 dic 2021
Resumen:
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.
Filiaciones:
Lundgren JD:
CHIP Centre of Excellence for Health, Immunity and Infections, Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark
Grund B:
Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, Minnesota
Barkauskas CE:
Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University, Durham, North Carolina
Holland TL:
Division of Infectious Diseases, Department of Medicine, Duke University, Durham, North Carolina
Gottlieb RL:
Baylor University Medical Center, Dallas, Texas
Sandkovsky U:
Baylor University Medical Center, Dallas, Texas
Brown SM:
Intermountain Medical Center, Murray, and University of Utah, Salt Lake City, Utah
Knowlton KU:
Intermountain Healthcare, Salt Lake City, Utah
Self WH:
Department of Emergency Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
Files DC:
Section on Pulmonary, Critical Care, Allergy, and Immunology, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina
Jain MK:
University of Texas Southwestern Medical Center, Dallas, Texas
Benfield T:
Department of Infectious Diseases, Hvidovre and Amager Hospital, University of Copenhagen, Hvidovre, Denmark
Bowdish ME:
Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California
Leshnower BG:
Division of Cardiothoracic Surgery, Emory University School of Medicine, Atlanta, Georgia
Baker JV:
Hennepin Healthcare Research Institute and University of Minnesota, Minneapolis, Minnesota
Jensen JU:
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
Gardner EM:
Denver Public Health, Denver Health and Hospital Authority, Denver, Colorado
Ginde AA:
Department of Emergency Medicine, School of Medicine, University of Colorado, Aurora, Colorado
Harris ES:
University of Utah, Salt Lake City, Utah
Johansen IS:
Department of Infectious Diseases, Odense University Hospital, Odense, Denmark
Markowitz N:
Department of Infectious Diseases, Henry Ford Hospital, Detroit, Michigan
Matthay MA:
Department of Medicine and Department of Anesthesia and Cardiovascular Research Institute, The University of California, San Francisco, San Francisco, California
Østergaard L:
Aarhus University Hospital Skejby, Aarhus, Denmark
Chang CC:
The Kirby Institute, University of New South Wales, Sydney, New South Wales, Australia
Goodman AL:
Medical Research Council Clinical Trials Unit at University College London and Guy's & St Thomas' NHS Foundation Trust, London, United Kingdom
Chang W:
Laboratory of Human Retrovirology and Immunoinformatics, Frederick National Laboratory for Cancer Research, Frederick, Maryland
Dewar RL:
Leidos Biomedical Research, Frederick, Maryland
Gerry NP:
Advanced Biomedical Laboratories, Cinnaminson, New Jersey
Higgs ES:
National Institute of Allergy and Infectious Diseases, Bethesda, Maryland
Highbarger H:
Leidos Biomedical Research and AIDS Monitoring Laboratory, Frederick National Laboratory for Cancer Research, Frederick, Maryland
Murray DD:
CHIP Centre of Excellence for Health, Immunity and Infections, Rigshospitalet, Copenhagen, Denmark
Murray TA:
Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, Minnesota
Natarajan V:
Laboratory of Molecular Cell Biology, Frederick National Laboratory for Cancer Research, Frederick, Maryland
:
Infectious Diseases Department and IrsiCaixa AIDS Research Institute, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
Parmar MKB:
Medical Research Council Clinical Trials Unit and Institute of Clinical Trials and Methodology at University College London, London, United Kingdom
Phillips AN:
Institute for Global Health, University College London, London, United Kingdom
Reilly C:
Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, Minnesota
Rupert AW:
AIDS Monitoring Laboratory, Frederick National Laboratory for Cancer Research, Frederick, Maryland
Sharma S:
Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, Minnesota
Shaw-Saliba K:
National Institute of Allergy and Infectious Diseases, Bethesda, Maryland
Sherman BT:
Laboratory of Human Retrovirology and Immunoinformatics, Frederick National Laboratory for Cancer Research, Frederick, Maryland
Teitelbaum M:
Leidos Biomedical Research, Frederick, Maryland
Wentworth D:
Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, Minnesota
Cao H:
Gilead Sciences, Foster City, California
Klekotka P:
Eli Lilly and Company, Indianapolis, Indiana
Babiker AG:
Medical Research Council Clinical Trials Unit at University College London, London, United Kingdom
Davey VJ:
U.S. Department of Veterans Affairs, Washington, DC
Gelijns AC:
Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, New York
Kan VL:
Veterans Affairs Medical Center and School of Medicine and Health Sciences, George Washington University, Washington, DC
Polizzotto MN:
The Kirby Institute, University of New South Wales, and St Vincent's Hospital, Sydney, New South Wales, Australia
Thompson BT:
Division of Pulmonary and Critical Care, Department of Medicine, Massachusetts General Hospital, and Harvard Medical School, Boston, Massachusetts
Lane HC:
National Institute of Allergy and Infectious Diseases, Bethesda, Maryland
Neaton JD:
Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, Minnesota
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