Intramuscular Versus Intravenous SARS-CoV-2 Neutralizing Antibody Sotrovimab for Treatment of COVID-19 (COMET-TAIL): A Randomized Non-inferiority Clinical Trial

Background Convenient administration of coronavirus disease 2019 (COVID-19) treatment in community settings is desirable. Sotrovimab is a pan-sarbecovirus dual-action monoclonal antibody formulated for intravenous (IV) or intramuscular (IM) administration for early treatment of mild/moderate COVID-19. Methods This phase 3, randomized, multicenter, open-label study tested non-inferiority of IM to IV administration using a 3.5% absolute non-inferiority margin. From June to August 2021, patients aged ≥12 years with COVID-19, not hospitalized or receiving supplemental oxygen, and at high risk for progression were randomized 1:1:1 to a single 500-mg IV sotrovimab infusion or 500-mg or 250-mg IM sotrovimab injection. The primary composite endpoint was progression to all-cause hospitalization for >24 hours for acute management of illness or all-cause death through day 29. Results Sotrovimab 500 mg IM was non-inferior to 500 mg IV: 10/376 (2.7%) participants in the sotrovimab 500-mg IM group versus 5/378 (1.3%) in the sotrovimab 500-mg IV group met the primary endpoint (absolute adjusted risk difference: 1.06% [95% confidence interval [CI]: −1.15%, 3.26%]). The CI upper limit was lower than the prespecified non-inferiority margin of 3.5%. 250-mg IM group enrollment was discontinued early because a greater proportion of hospitalizations was seen in that group versus the 500-mg groups. Serious adverse events occurred in <1% to 2% of participants across groups. Four participants experienced serious disease related events and died (500 mg IM: 2/393 [<1%]; 250 mg IM: 2/195 [1%]). Conclusions Sotrovimab 500-mg IM injection was well tolerated and non-inferior to IV administration. IM administration could expand outpatient treatment access for COVID-19. Registration [ClinicalTrials.gov][1] Identifier: [NCT04913675][2] Key Points Sotrovimab 500-mg IM was non-inferior to sotrovimab 500-mg IV for treatment of mild/moderate COVID-19 in high-risk patients, measured by all-cause hospitalization >24h or death through day 29, and was well-tolerated. Sotrovimab IM should provide easier outpatient access to COVID-19 treatment. ### Competing Interest Statement Adrienne E. Shapiro, Jude Acloque, Almena Free, Yaneicy Gonzalez-Rojas, Rubaba Hussain, Erick Juarez, Jaynier Moya, and Naval Parikh report acting as trial investigators for Vir Biotechnology and receiving non-financial support from Vir Biotechnology during the conduct of the study. Anita Kohli reports acting as a trial investigator for Vir Biotechnology and receiving nonfinancial support from Vir Biotechnology during the conduct of the study; grants and consulting fees from Gilead Biosciences; clinical trial payments from Regeneron, Vir Biotechnology, GSK, and Gilead Biosciences; and serving on data safety monitoring or advisory boards for Gilead Biosciences. Elias Sarkis reports acting as a trial investigator for Vir Biotechnology and receiving nonfinancial support from Vir Biotechnology during the conduct of the study; research support from AbbVie, Eli Lilly, Otsuka, Eisai, and Ironshore; and serving on speaker bureaus for Janssen, Teva, and AbbVie. Deborah Cebrik, Maria L. Agostini, Sergio Parra, Sophia Chow, Erik Mogalian, Jennifer E. Sager, Wendy W. Yeh, Elizabeth L. Alexander, and Leah A. Gaffney are employees of Vir Biotechnology and report stock ownership in Vir Biotechnology and third-party funding from GSK to Vir Biotechnology for the submitted work. Phillip S. Pang is an employee of Vir Biotechnology and reports stock ownership in Vir Biotechnology and third-party funding from GSK to Vir Biotechnology for the submitted work and reports patents pending for sotrovimab for the treatment of COVID-19. David K. Hong was an employee of Vir Biotechnology and held stock in Vir Biotechnology at the time of the study; he is currently an employee of Janssen Pharmaceutical Companies of Johnson & Johnson and reports stock ownership in Johnson & Johnson. David Inman, Andrew Skingsley, Daren Austin, Amanda Peppercorn, Ahmed Nader, Nadia Noormohamed, and Qianwen Wang are employees of GSK and report stock ownership in GSK. ### Clinical Trial NCT04913675 ### Funding Statement The study was supported by Vir Biotechnology, Inc. in collaboration with GSK. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee/IRB of Advarra Institutional Review Board, Columbia, Maryland, USA; CEQ at Medical Center of Limited Liability Company Harmoniya krasy, Kyiv, Ukraine; and CPP Sud-Est II - Groupement Hospitalier Est, Bron, France gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data collected for this study will not be made available to others. The study protocol and statistical analysis plan are included in the supplementary data. [1]: http://ClinicalTrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04913675&atom=%2Fmedrxiv%2Fearly%2F2023%2F03%2F24%2F2023.03.21.23287410.atom