Intramuscular Versus Intravenous SARS-CoV-2 Neutralizing Antibody Sotrovimab for Treatment of COVID-19 (COMET-TAIL): A Randomized Non-inferiority Clinical Trial
Adrienne E Shapiro, Elias Sarkis, Jude Acloque, Almena Free, Yaneicy Gonzalez-Rojas, Rubaba Hussain, Erick Juarez, Jaynier Moya, Naval Parikh, David Inman, Deborah Cebrik, Ahmed Nader, Nadia Noormohamed, Qianwen Wang, Andrew Skingsley, Daren Austin, Amanda Peppercorn, Maria L Agostini, Sergio Parra, Sophia Chow, Erik Mogalian, Phillip S Pang, David K Hong, Jennifer E Sager, Wendy W Yeh, Vir Biotechnology, Inc Elizabeth L Alexander, Dr Leah A Gaffney, Dr Anita Kohli
doi:10.1101/2023.03.21.23287410
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.
Funding The study was supported by Vir Biotechnology, Inc. in collaboration with GSK.
Author Contributions PSP, DKH, EA, WWY, EM, JES, DA, SC, and AP conceptualized and designed the study. All authors acquired, analyzed and/or interpreted the data. DI and DC conducted the statistical analyses. AK, LAG, and DI accessed and verified the data. All authors drafted the manuscript and critically reviewed and revised the manuscript for important intellectual content. All authors had full access to all the data in the study, take responsibility for the accuracy of the analysis, and had authority over manuscript preparation and the decision to submit the manuscript for publication.
Conflict of Interest Disclosures
References
Agostini, Schnell, Di Iulio, Resistance analysis in the COMET-TAIL study: participants with mild-to-moderate COVID-19 treated with intramuscular or intravenous sotrovimab, Open Forum Infect Dis
Atique, Ghafoor, Javed, Fatima, Yousaf et al., Correlation of viral load with the clinical and biochemical profiles of COVID-19 patients, Cureus
Cameroni, Bowen, Rosen, Broadly neutralizing antibodies overcome SARS-CoV-2 Omicron antigenic shift, Nature
Cathcart, Havenar-Daughton, Lempp, The dual function monoclonal antibodies VIR-7831 and VIR-7832 demonstrate potent in vitro and in vivo activity against SARS-CoV-2. bioRxiv,
doi:10.1101/2021.03.09.434607Chen, Nirula, Heller, SARS-CoV-2 neutralizing antibody LY-CoV555 in outpatients with covid-19, N Engl J Med
Cheng, Reyes, Satram, Real-world effectiveness of sotrovimab for the early treatment of COVID-19 during SARS-CoV-2 Delta and Omicron waves in the USA, Infect Dis Ther
Dougan, Azizad, Chen, Bebtelovimab, alone or together with bamlanivimab and etesevimab, as a broadly neutralizing monoclonal antibody treatment for mild to moderate, ambulatory COVID-19. medRxiv,
doi:10.1101/2022.03.10.22272100Dougan, Nirula, Azizad, Bamlanivimab plus etesevimab in mild or moderate Covid-19, N Engl J Med
Goldstein, Walensky, The challenges ahead with monoclonal antibodies: from authorization to access, JAMA
Gottlieb, Nirula, Chen, Effect of bamlanivimab as monotherapy or in combination with etesevimab on viral load in patients with mild to moderate COVID-19: a randomized clinical trial, JAMA
Gupta, Gonzalez-Rojas, Juarez, Early COVID-19 treatment with SARS-CoV-2 neutralizing antibody sotrovimab, N Engl J Med
Gupta, Gonzalez-Rojas, Juarez, Effect of sotrovimab on hospitalization or death among high-risk patients with mild to moderate COVID-19: a randomized clinical trial, JAMA
Harman, Nash, Webster, Comparison of the risk of hospitalization among BA.1 and BA.2 COVID-19 cases treated with sotrovimab in the community in England. medRxiv,
doi:10.1101/2022.10.21.22281171Martin-Blondel, Marcelin, Soulie, Sotrovimab to prevent severe COVID-19 in high-risk patients infected with Omicron BA.2, J Infect
Park, Pinto, Walls, Imprinted antibody responses against SARS-CoV-2 Omicron sublineages, Science
Sager, El-Zailik, Passarell, Population pharmacokinetics and exposureresponse analysis of sotrovimab in the early treatment of COVID-19, CPT Pharmacometrics Syst Pharmacol,
doi:10.1002/psp4.12958Vanblargan, Errico, Halfmann, An infectious SARS-CoV-2 B
Weinreich, Sivapalasingam, Norton, REGEN-COV antibody combination and outcomes in outpatients with COVID-19, N Engl J Med
Wu, Carr, Harvey, WHO's therapeutics and COVID-19 living guideline on mAbs needs to be reassessed, Lancet
Zheng, Green, Tazare, Comparative effectiveness of sotrovimab and molnupiravir for prevention of severe covid-19 outcomes in patients in the community: observational cohort study with the OpenSAFELY platform, BMJ
Zheng, Tazare, Nab, Comparative effectiveness of Paxlovid versus sotrovimab and molnupiravir for preventing severe COVID-19 outcomes in nonhospitalised patients: observational cohort study using the OpenSAFELY platform, medRxiv,
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'group-title': 'Infectious Diseases (except HIV/AIDS)',
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'publisher': 'Cold Spring Harbor Laboratory',
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'abstract': '<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>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%]).</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Sotrovimab '
'500-mg IM injection was well tolerated and non-inferior to IV administration. IM '
'administration could expand outpatient treatment access for '
'COVID-19.</jats:p></jats:sec><jats:sec><jats:title>Registration</jats:title><jats:p><jats:ext-link '
'xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" '
'xlink:href="http://ClinicalTrials.gov">ClinicalTrials.gov</jats:ext-link>Identifier:<jats:ext-link '
'xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="clintrialgov" '
'xlink:href="NCT04913675">NCT04913675</jats:ext-link></jats:p></jats:sec><jats:sec><jats:title>Key '
'Points</jats:title><jats:p>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.</jats:p></jats:sec>',
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