Efficacy and Safety of Sarilumab in Hospitalized Patients With Coronavirus Disease 2019: A Randomized Clinical Trial

Sivapalasingam et al., Clinical Infectious Diseases, doi:10.1093/cid/ciac153, REGENERON P2, NCT04315298

Feb 2022

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Phase 2 and phase 3 RCTs with 1,365 hospitalized COVID-19 patients showing no significant improvement with sarilumab vs placebo. Post-hoc analysis suggests a potential mortality benefit with sarilumab in mechanically ventilated patients receiving corticosteroids at baseline. Phase 2 and phase 3 results are listed separately1,2.

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risk of death, 6.8% higher, HR 1.07, p = 0.89, treatment 180, control 90, adjusted per study, all 400mg patients.

risk of death, 1341.2% higher, RR 14.41, p = 0.03, treatment 9 of 51 (17.6%), control 0 of 25 (0.0%), continuity correction due to zero event (with reciprocal of the contrasting arm), 400mg, severe patients, phase 2, day 60.

risk of death, 30.0% lower, HR 0.70, p = 0.28, treatment 23 of 88 (26.1%), control 15 of 44 (34.1%), NNT 13, adjusted per study, 400mg, critical patients, phase 2, day 60.

risk of death, 2.0% higher, HR 1.02, p = 0.97, treatment 17 of 41 (41.5%), control 9 of 21 (42.9%), NNT 72, adjusted per study, 400mg, MSOD patients, phase 2, day 60.

risk of death, 22.4% higher, HR 1.22, p = 0.41, treatment 187, control 90, adjusted per study, all 200mg patients.

risk of death, 300.0% higher, HR 4.00, p = 0.55, treatment 2 of 50 (4.0%), control 0 of 25 (0.0%), continuity correction due to zero event (with reciprocal of the contrasting arm), 200mg, severe patients, phase 2, day 60.

risk of death, 21.0% higher, HR 1.21, p = 0.55, treatment 38 of 94 (40.4%), control 15 of 44 (34.1%), adjusted per study, 200mg, critical patients, phase 2, day 60.

risk of death, 15.0% higher, HR 1.15, p = 0.74, treatment 20 of 43 (46.5%), control 9 of 21 (42.9%), adjusted per study, 200mg, MSOD patients, phase 2, day 60.

risk of no improvement, 4.4% higher, RR 1.04, p = 0.91, treatment 180, control 90, all 400mg patients.

risk of no improvement, 292.2% higher, RR 3.92, p = 0.04, treatment 16 of 51 (31.4%), control 2 of 25 (8.0%), 400mg, severe patients, phase 2, day 22.

risk of no improvement, 39.7% lower, RR 0.60, p = 0.006, treatment 35 of 88 (39.8%), control 29 of 44 (65.9%), NNT 3.8, 400mg, critical patients, phase 2, day 22.

risk of no improvement, 7.1% higher, RR 1.07, p = 0.79, treatment 23 of 41 (56.1%), control 11 of 21 (52.4%), 400mg, MSOD patients, phase 2, day 22.

risk of no improvement, 12.2% lower, RR 0.88, p = 0.30, treatment 187, control 90, all 200mg patients.

risk of no improvement, no change, RR 1.00, p = 1.00, treatment 4 of 50 (8.0%), control 2 of 25 (8.0%), 200mg, severe patients, phase 2, day 22.

risk of no improvement, 20.9% lower, RR 0.79, p = 0.14, treatment 49 of 94 (52.1%), control 29 of 44 (65.9%), NNT 7.3, 200mg, critical patients, phase 2, day 22.

risk of no improvement, 15.4% higher, RR 1.15, p = 0.60, treatment 26 of 43 (60.5%), control 11 of 21 (52.4%), 200mg, MSOD patients, phase 2, day 22.

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1. Sivapalasingam et al., Efficacy and Safety of Sarilumab in Hospitalized Patients With Coronavirus Disease 2019: A Randomized Clinical Trial, Clinical Infectious Diseases, doi:10.1093/cid/ciac153.oup.com, doi.org.

2. Sivapalasingam (B) et al., Efficacy and Safety of Sarilumab in Hospitalized Patients With Coronavirus Disease 2019: A Randomized Clinical Trial, Clinical Infectious Diseases, doi:10.1093/cid/ciac153.oup.com, doi.org.

Sivapalasingam et al., 26 Feb 2022, Double Blind Randomized Controlled Trial, placebo-controlled, USA, peer-reviewed, median age 61.0, 40 authors, study period 18 March, 2020 - 2 July, 2020, trial NCT04315298 (history) (REGENERON P2). Contact: david.lederer@regeneron.com.

This Paper Sarilumab All

Efficacy and Safety of Sarilumab in Hospitalized Patients With Coronavirus Disease 2019: A Randomized Clinical Trial

Sumathi Sivapalasingam, David J Lederer, Rafia Bhore, Negin Hajizadeh, Gerard Criner, Romana Hosain, Adnan Mahmood, Angeliki Giannelou, Selin Somersan-Karakaya, Meagan P O’brien, Anita Boyapati, Janie Parrino, Bret J Musser, Emily Labriola-Tompkins, Divya Ramesh, Lisa A Purcell, Daya Gulabani, Wendy Kampman, Alpana Waldron, Michelle Ng Gong, Suraj Saggar, Steven J Sperber, Vidya Menon, David K Stein, Magdalena E Sobieszczyk, William Park, Judith A Aberg, Samuel M Brown, Jack A Kosmicki, Julie E Horowitz, Manuel A Ferreira, Aris Baras, Bari Kowal, A Thomas Dicioccio, Bolanle Akinlade, Michael C Nivens, Ned Braunstein, Gary A Herman, George D Yancopoulos, David M Weinreich

Clinical Infectious Diseases, doi:10.1093/cid/ciac153

Background. Open-label platform trials and a prospective meta-analysis suggest efficacy of anti-interleukin (IL)-6R therapies in hospitalized patients with coronavirus disease 2019 (COVID-19) receiving corticosteroids. This study evaluated the efficacy and safety of sarilumab, an anti-IL-6R monoclonal antibody, in the treatment of hospitalized patients with COVID-19. Methods. In this adaptive, phase 2/3, randomized, double-blind, placebo-controlled trial, adults hospitalized with COVID-19 received intravenous sarilumab 400 mg or placebo. The phase 3 primary analysis population included patients with critical COVID-19 receiving mechanical ventilation (MV). The primary outcome was proportion of patients with ≥1-point improvement in clinical status from baseline to day 22. Results. There were 457 and 1365 patients randomized and treated in phases 2 and 3, respectively. In phase 3, patients with critical COVID-19 receiving MV (n = 298; 28.2% on corticosteroids), the proportion with ≥1-point improvement in clinical status (alive, not receiving MV) at day 22 was 43.2% for sarilumab and 35.5% for placebo (risk difference, +7.5%; 95% confidence interval [CI], -7.4 to 21.3; P =.3261), a relative risk improvement of 21.7%. In post hoc analyses pooling phase 2 and 3 critical patients receiving MV, the hazard ratio for death for sarilumab vs placebo was 0.76 (95% CI, .51 to 1.13) overall and 0.49 (95% CI, .25 to .94) in patients receiving corticosteroids at baseline. Conclusions. This study did not establish the efficacy of sarilumab in hospitalized patients with severe/critical COVID-19. Post hoc analyses were consistent with other studies that found a benefit of sarilumab in patients receiving corticosteroids. Clinical Trials Registration. NCT04315298.

Supplementary Data Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author. Agency for Healthcare Research and Quality, and the Centers for Disease Control and Prevention for COVID and non-COVID research that is not related to this article. S. Saggar reports grants from BARDA and fees from Allergan/AbbVie. S. J. S. reports grants from BARDA. V. M., M. E. S., and W. P. report grants from BARDA. D. K. S. has received support to conduct the study from Regeneron Pharmaceuticals and reports grants from BARDA. J. A. A. has received support to conduct the study from Regeneron Pharmaceuticals; reports grants from BARDA, Atea, Emergent Biosolutions, Frontier Technologies, Gilead, Janssen, Pfizer, and ViiV; and reports grants and personal fees from GlaxoSmithKline and Merck. S. M. B. reports grants from BARDA, Sedana, Janssen, NIH, and the Department of Defense; personal fees from Hamilton and New York University and other from Faron; and book fees from Oxford University and Brigham Young University. The remaining author: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been..

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This study evaluated the efficacy and ' 'safety of sarilumab, an anti–IL-6R monoclonal antibody, in the treatment of hospitalized ' 'patients with COVID-19.\n' ' \n' ' \n' ' Methods\n' ' In this adaptive, phase 2/3, randomized, double-blind, ' 'placebo-controlled trial, adults hospitalized with COVID-19 received intravenous sarilumab ' '400 mg or placebo. The phase 3 primary analysis population included patients with critical ' 'COVID-19 receiving mechanical ventilation (MV). The primary outcome was proportion of ' 'patients with ≥1-point improvement in clinical status from baseline to day 22.\n' ' \n' ' \n' ' Results\n' ' There were 457 and 1365 patients randomized and treated in phases 2 ' 'and 3, respectively. 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'crossref', 'first-page': '1637', 'DOI': '10.1016/S0140-6736(21)00676-0', 'article-title': 'Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): ' 'a randomised, controlled, open-label, platform trial', 'volume': '397', 'author': 'RECOVERY Collaborative Group.', 'year': '2021', 'journal-title': 'Lancet'}, {'key': '2022082503044331400_CIT0022', 'author': 'World Health Organization.'}, {'key': '2022082503044331400_CIT0023', 'author': 'National Institutes of Health.'}, {'key': '2022082503044331400_CIT0024', 'author': 'World Health Organization.'}, { 'key': '2022082503044331400_CIT0025', 'doi-asserted-by': 'crossref', 'first-page': '499', 'DOI': '10.1001/jama.2021.11330', 'article-title': 'Association between administration of IL-6 antagonists and mortality ' 'among patients hospitalized for COVID-19: a meta-analysis', 'volume': '326', 'author': 'WHO Rapid Evidence Appraisal for COVID-19 Therapies Working Group.', 'year': '2021', 'journal-title': 'JAMA'}], 'container-title': 'Clinical Infectious Diseases', 'original-title': [], 'language': 'en', 'link': [ { 'URL': 'https://academic.oup.com/cid/advance-article-pdf/doi/10.1093/cid/ciac153/43887701/ciac153.pdf', 'content-type': 'application/pdf', 'content-version': 'am', 'intended-application': 'syndication'}, { 'URL': 'https://academic.oup.com/cid/article-pdf/75/1/e380/45514220/ciac153.pdf', 'content-type': 'application/pdf', 'content-version': 'vor', 'intended-application': 'syndication'}, { 'URL': 'https://academic.oup.com/cid/article-pdf/75/1/e380/45514220/ciac153.pdf', 'content-type': 'unspecified', 'content-version': 'vor', 'intended-application': 'similarity-checking'}], 'deposited': { 'date-parts': [[2022, 8, 25]], 'date-time': '2022-08-25T03:07:56Z', 'timestamp': 1661396876000}, 'score': 1, 'resource': {'primary': {'URL': 'https://academic.oup.com/cid/article/75/1/e380/6537638'}}, 'subtitle': [], 'short-title': [], 'issued': {'date-parts': [[2022, 2, 26]]}, 'references-count': 25, 'journal-issue': { 'issue': '1', 'published-online': {'date-parts': [[2022, 2, 26]]}, 'published-print': {'date-parts': [[2022, 8, 24]]}}, 'URL': 'http://dx.doi.org/10.1093/cid/ciac153', 'relation': { 'has-preprint': [ { 'id-type': 'doi', 'id': '10.1101/2021.05.13.21256973', 'asserted-by': 'object'}]}, 'ISSN': ['1058-4838', '1537-6591'], 'subject': [], 'published-other': {'date-parts': [[2022, 7, 1]]}, 'published': {'date-parts': [[2022, 2, 26]]}}

Late treatment
is less effective

Please send us corrections, updates, or comments. c19early involves the extraction of 100,000+ datapoints from thousands of papers. Community updates help ensure high accuracy. Treatments and other interventions are complementary. All practical, effective, and safe means should be used based on risk/benefit analysis. No treatment or intervention is 100% available and effective for all current and future variants. We do not provide medical advice. Before taking any medication, consult a qualified physician who can provide personalized advice and details of risks and benefits based on your medical history and situation. FLCCC and WCH provide treatment protocols.

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