Is monoclonal antibody (mAb) treatment effective in nonhospitalized patients with COVID-19 caused by the Delta variant?
In this propensity score–matched cohort study (n = 3069) and randomized comparative effectiveness trial (n = 3558), mAb treatment (casirivimab-imdevimab or sotrovimab) compared with no mAb treatment was associated with reduced hospitalization or death by 28 days, and sotrovimab compared with casirivimab-imdevimab resulted in 86% probability of inferiority and 79% probability of equivalence in the odds of improvement in hospital-free days within 28 days after mAb treatment.
Findings of this study suggest that casirivimab-imdevimab and sotrovimab were both associated with reduced risk of hospitalization or death and had similar effectiveness, although they did not meet the prespecified criteria for statistical inferiority or equivalence.
The effectiveness of monoclonal antibodies (mAbs), casirivimab-imdevimab and sotrovimab, is unknown in patients with mild to moderate COVID-19 caused by the SARS-CoV-2 Delta variant.
To evaluate the effectiveness of mAb against the Delta variant compared with no mAb treatment and to ascertain the comparative effectiveness of casirivimab-imdevimab and sotrovimab.
Design, Setting, and Participants
This study comprised 2 parallel studies: (1) a propensity score–matched cohort study of mAb treatment vs no mAb treatment and (2) a randomized comparative effectiveness trial of casirivimab-imdevimab and sotrovimab. The cohort consisted of patients who received mAb treatment at the University of Pittsburgh Medical Center outpatient infusion centers and emergency departments from July 14 to September 29, 2021. Participants were patients with a positive SARS-CoV-2 test result who were eligible to receive mAbs according to emergency use authorization criteria.
For the trial, patients were randomized to either intravenous casirivimab-imdevimab or sotrovimab according to a system therapeutic interchange policy.
Main Outcomes and Measures
For the cohort study, risk ratio (RR) estimates for the primary outcome of hospitalization or death by 28 days were compared between mAb treatment and no mAb treatment using propensity score–matched models. For the comparative effectiveness trial, the primary outcome was hospital-free days (days alive and free of hospitalization) within 28 days after mAb treatment, where patients who died were assigned −1 day in a bayesian cumulative logistic model adjusted for treatment location, age, sex, and time. Inferiority was defined as a 99% posterior probability of an odds ratio (OR) less than 1. Equivalence was defined as a 95% posterior probability that the OR was within a given bound.
A total of 3069 patients (1023 received mAb treatment: mean [SD] age, 53.2 [16.4] years; 569 women [56%]; 2046 had no mAb treatment: mean [SD] age, 52.8 [19.5] years; 1157 women [57%]) were included in the prospective cohort study, and 3558 patients (mean [SD] age, 54  years; 1919 women [54%]) were included in the randomized comparative effectiveness trial. In propensity score–matched models, mAb treatment was associated with reduced risk of hospitalization or death (RR, 0.40; 95% CI, 0.28-0.57) compared with no treatment. Both casirivimab-imdevimab (RR, 0.31; 95% CI, 0.20-0.50) and sotrovimab (RR, 0.60; 95% CI, 0.37-1.00) were associated with reduced hospitalization or death compared with no mAb treatment. In the clinical trial, 2454 patients were randomized to receive casirivimab-imdevimab and 1104 patients were randomized to receive sotrovimab. The median (IQR) hospital-free days were 28 (28-28) for both mAb treatments, the 28-day mortality rate was less than 1% (n = 12) for casirivimab-imdevimab and less than 1% (n = 7) for sotrovimab, and the hospitalization rate by day 28 was 12% (n = 291) for casirivimab-imdevimab and 13% (n = 140) for sotrovimab. Compared with patients who received casirivimab-imdevimab, those who received sotrovimab had a median adjusted OR for hospital-free days of 0.88 (95% credible interval, 0.70-1.11). This OR yielded 86% probability of inferiority for sotrovimab vs casirivimab-imdevimab and 79% probability of equivalence.
Conclusions and Relevance
In this propensity score–matched cohort study and randomized comparative effectiveness trial, the effectiveness of casirivimab-imdevimab and sotrovimab against the Delta variant was similar, although the prespecified criteria for statistical inferiority or equivalence were not met. Both mAb treatments were associated with a reduced risk of hospitalization or death in nonhospitalized patients with mild to moderate COVID-19 caused by the Delta variant.
ClinicalTrials.gov Identifier: NCT04790786
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Accepted for Publication: May 17, 2022.
Published: July 14, 2022. doi:10.1001/jamanetworkopen.2022.20957
Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2022 Huang DT et al. JAMA Network Open.
Corresponding Author: David T. Huang, MD, MPH, Critical Care Medicine, Emergency Medicine, Clinical and Translational Science, University of Pittsburgh, 606B Scaife Hall, Pittsburgh, PA 15213 (email@example.com).
Author Contributions: Drs Huang and Seymour had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Huang, McCreary, Bariola, Minnier, Shovel, Wisniewski, Nace, Sullivan, Axe, Weissman, Wells, Bart, S. Berry, Linstrum, Montgomery, McVerry, Yealy, Angus, Seymour.
Acquisition, analysis, or interpretation of data: Huang, McCreary, Bariola, Wadas, Albin, Marroquin, K. Kip, Collins, Schmidhofer, Nace, Meyers, Garrard, Peck Palmer, Wells, Yang, L. Berry, S. Berry, Crawford, McGlothlin, Khadem, Ricketts, Kennedy, Pidro, Nakayama, Zapf, P. Kip, Haidar, Snyder, McVerry, Yealy, Angus.
Drafting of the manuscript: Huang, McCreary, Collins, Axe, Meyers, Bart, Yang, Kennedy, Zapf, Seymour.
Critical revision of the manuscript for important intellectual content: Huang, McCreary, Bariola, Minnier, Wadas, Shovel, Albin, Marroquin, K. Kip, Schmidhofer, Wisniewski, Nace, Sullivan, Weissman, Garrard, Peck Palmer, Wells, L. Berry, S. Berry, Crawford, McGlothlin, Khadem, Linstrum, Montgomery, Ricketts, Pidro, Nakayama, Zapf, P. Kip, Haidar, Snyder, McVerry, Yealy, Angus.
Statistical analysis: K. Kip, Yang, L. Berry, S. Berry, Crawford, McGlothlin, Kennedy.
Administrative, technical, or material support: Bariola, Minnier, Wadas, Shovel, Albin, Marroquin, Collins, Schmidhofer, Nace, Sullivan, Axe, Meyers, Garrard, Peck Palmer, Wells, Bart, Khadem, Linstrum, Montgomery, Ricketts, Pidro, Nakayama, Zapf, Haidar, Yealy, Angus, Seymour.
Supervision: Huang, Bariola, Minnier, Marroquin, Schmidhofer, Wells, Yealy, Angus, Seymour.
Conflict of Interest Disclosures: Dr Bariola reported receiving grants from Merck and salary support from Infectious Disease Connect outside the submitted work. Dr L.R. Berry reported receiving funding for design and analysis work from Berry Consultants during the conduct of the study. Dr S. Berry reported being part owner of and receiving funding for design and analysis work from Berry Consultants during the conduct of the study. Dr Crawford reported receiving funding for design and analysis work from Berry Consultants during the conduct of the study and outside the submitted work. Dr McGlothlin reported receiving personal fees from UPMC during the conduct of the study. Dr Khadem reported receiving grants from Merck outside the submitted work. Mr Kennedy reported receiving grants from National Institute of General Medical Sciences (NIGMS) of the National Institutes of Health (NIH) during the conduct of the study. Dr Haidar reported receiving grants from AstraZeneca during the conduct of the study and grants from Karius outside the submitted work. Dr McVerry reported receiving grants from NIH National Heart, Lung, and Blood Institute, grants from Bayer Pharmaceuticals Inc, personal fees from Boehringer Ingelheim, and grants from Translational Breast Cancer Research Consortium outside the submitted work. Dr Seymour reported receiving grants from NIH NIGMS outside the submitted work. No other disclosures were reported.
Data Sharing Statement: See Supplement 3.
Additional Contributions: We thank the clinical staff as well as the support and administrative staff at the UPMC monoclonal antibody infusion centers: Michelle Adam, RN; Jodi Ayers, MS; Ashley Beyerl, BS; Trudy Bloomquist, MSN; Tina Borneman, BPharm; Mikaela Bortot, BS; Jonya Brooks, RN; James Cable, MS; Sherry Casali, RPh; Jeana Colella, MS; Jennifer Dueweke, MS; Jesse Duff, RN; Janice Dunsavage, MAS; Jessica Fesz, MSN; Kathleen Flinn, MPA; Daniel Gessel, MHSA; Amy Helmuth, MS; Erik Hernandez, PharmD; Larry Hruska, BFA; Allison Hydzik, BS; Le Ann Kaltenbaugh, RN; LuAnn King, RN; Jim Krosse, RPh; Sheila Kruman, MBA; Amy Lukanski, DNP; Hilary Maskiewicz, MHA; Debra Masser, RN; Katelyn Mayak, MS; Rebecca Medva, MHMS; Theresa Murillo, RN; Melanie Pierce, RN; Teressa Polcha, RN; Kevin Pruznak, MSN; Debra Rogers, RN; Rozalyn Russell, MHA; Sarah Sakaluk, MSN; Heather Schaeffer, BSN; Robert Shulik, MBA; Libby Shumaker, RN; Susan Spencer, RN; Ashley Steiner, MA; Betsy Tedesco, DNP; Ken Trimmer, BS; Jennifer Zabala, BSN, RN; and their entire teams. We also thank the staff at the following organizations for curating and managing the data: UPMC Clinical Analytics, the UPMC Wolff Center, and Biostatistics and Data Management Core at the CRISMA Center in the Department of Critical Care Medicine at the University of Pittsburgh. These individuals received no additional compensation, outside of their usual salary, for their contributions.
Additional Information: The US government provided casirivimab-imdevimab, and GlaxoSmithKline and Vir Biotechnology provided sotrovimab. Preliminary results were shared with GlaxoSmithKline and Vir Biotechnology before preprint submission, but the organization had no role in manuscript preparation or interpretation of results.
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