Subcutaneous sarilumab for the treatment of hospitalized patients with moderate to severe COVID19 disease: A pragmatic, embedded randomized clinical trial

{ 'indexed': {'date-parts': [[2024, 8, 13]], 'date-time': '2024-08-13T16:52:42Z', 'timestamp': 1723567962425}, 'reference-count': 28, 'publisher': 'Public Library of Science (PLoS)', 'issue': '2', 'license': [ { 'start': { 'date-parts': [[2022, 2, 25]], 'date-time': '2022-02-25T00:00:00Z', 'timestamp': 1645747200000}, 'content-version': 'vor', 'delay-in-days': 0, 'URL': 'https://creativecommons.org/publicdomain/zero/1.0/'}], 'funder': [ { 'DOI': '10.13039/100000050', 'name': 'National Heart, Lung, and Blood Institute', 'doi-asserted-by': 'publisher', 'award': ['1K12HL138049-01'], 'id': [{'id': '10.13039/100000050', 'id-type': 'DOI', 'asserted-by': 'publisher'}]}], 'content-domain': {'domain': ['www.plosone.org'], 'crossmark-restriction': False}, 'abstract': '<jats:sec id="sec001">\n' '<jats:title>Importance and objective</jats:title>\n' '<jats:p>The aim of this pragmatic, embedded, adaptive trial was to measure the effectiveness ' 'of the subcutaneous anti-IL-6R antibody sarilumab, when added to an evolving standard of care ' '(SOC), for clinical management of inpatients with moderate to severe COVID-19 ' 'disease.</jats:p>\n' '</jats:sec>\n' '<jats:sec id="sec002">\n' '<jats:title>Design</jats:title>\n' '<jats:p>Two-arm, randomized, open-label controlled trial comparing SOC alone to SOC plus ' 'sarilumab. The trial used a randomized play-the-winner design and was fully embedded within ' 'the electronic health record (EHR) system.</jats:p>\n' '</jats:sec>\n' '<jats:sec id="sec003">\n' '<jats:title>Setting</jats:title>\n' '<jats:p>5 VA Medical Centers.</jats:p>\n' '</jats:sec>\n' '<jats:sec id="sec004">\n' '<jats:title>Participants</jats:title>\n' '<jats:p>Hospitalized patients with clinical criteria for moderate to severe COVID-19 but not ' 'requiring mechanical ventilation, and a diagnostic test positive for SARS-CoV-2.</jats:p>\n' '</jats:sec>\n' '<jats:sec id="sec005">\n' '<jats:title>Interventions</jats:title>\n' '<jats:p>Sarilumab, 200 or 400 mg subcutaneous injection. SOC was not pre-specified and could ' 'vary over time, e.g., to include antiviral or other anti-inflammatory drugs.</jats:p>\n' '</jats:sec>\n' '<jats:sec id="sec006">\n' '<jats:title>Main outcomes and measures</jats:title>\n' '<jats:p>The primary outcome was intubation or death within 14 days of randomization. All data ' 'were extracted remotely from the EHR.</jats:p>\n' '</jats:sec>\n' '<jats:sec id="sec007">\n' '<jats:title>Results</jats:title>\n' '<jats:p>Among 162 eligible patients, 53 consented, and 50 were evaluated for the primary ' 'endpoint of intubation or death. This occurred in 5/20 and 1/30 of participants in the ' 'sarilumab and SOC arms respectively, with the majority occurring in the initial 9 ' 'participants (3/4 in the sarilumab and 1/5 in the SOC) before the sarilumab dose was ' 'increased to 400 mg and before remdesivir and dexamethasone were widely adopted. After ' 'interim review, the unblinded Data Monitoring Committee recommended that the study be stopped ' 'due to concern for safety: a high probability that rates of intubation or death were higher ' 'with addition of sarilumab to SOC (92.6%), and a very low probability (3.4%) that sarilumab ' 'would be found to be superior.</jats:p>\n' '</jats:sec>\n' '<jats:sec id="sec008">\n' '<jats:title>Conclusions and relevance</jats:title>\n' '<jats:p>This randomized trial of patients hospitalized due to respiratory compromise from ' 'COVID-19 but not mechanical ventilation found no benefit from subcutaneous sarilumab when ' 'added to an evolving SOC. The numbers of patients and events were too low to allow definitive ' 'conclusions to be drawn, but this study contributes valuable information about the role of ' 'subcutaneous IL-6R inhibition in the treatment of hospitalized COVID-19 patients. Methods ' 'developed and piloted during this trial will be useful in conducting future studies more ' 'efficiently.</jats:p>\n' '</jats:sec>\n' '<jats:sec id="sec009">\n' '<jats:title>Trial registration</jats:title>\n' '<jats:p>Clinicaltrials.gov—<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ' 'ext-link-type="uri" xlink:href="https://clinicaltrials.gov/ct2/show/NCT04359901" ' 'xlink:type="simple">NCT04359901</jats:ext-link>; <jats:ext-link ' 'xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" ' 'xlink:href="https://clinicaltrials.gov/ct2/show/NCT04359901?cond=NCT04359901&amp;draw=2&amp;rank=1" ' 'xlink:type="simple">https://clinicaltrials.gov/ct2/show/NCT04359901?cond=NCT04359901&amp;draw=2&amp;rank=1</jats:ext-link>.</jats:p>\n' '</jats:sec>', 'DOI': '10.1371/journal.pone.0263591', 'type': 'journal-article', 'created': {'date-parts': [[2022, 2, 25]], 'date-time': '2022-02-25T18:57:46Z', 'timestamp': 1645815466000}, 'page': 'e0263591', 'update-policy': 'http://dx.doi.org/10.1371/journal.pone.corrections_policy', 'source': 'Crossref', 'is-referenced-by-count': 9, 'title': 'Subcutaneous sarilumab for the treatment of hospitalized patients with moderate to severe ' 'COVID19 disease: A pragmatic, embedded randomized clinical trial', 'prefix': '10.1371', 'volume': '17', 'author': [ { 'ORCID': 'http://orcid.org/0000-0002-9658-5124', 'authenticated-orcid': True, 'given': 'Westyn', 'family': 'Branch-Elliman', 'sequence': 'first', 'affiliation': []}, {'given': 'Ryan', 'family': 'Ferguson', 'sequence': 'additional', 'affiliation': []}, {'given': 'Gheorghe', 'family': 'Doros', 'sequence': 'additional', 'affiliation': []}, { 'ORCID': 'http://orcid.org/0000-0001-5646-4216', 'authenticated-orcid': True, 'given': 'Patricia', 'family': 'Woods', 'sequence': 'additional', 'affiliation': []}, {'given': 'Sarah', 'family': 'Leatherman', 'sequence': 'additional', 'affiliation': []}, {'given': 'Judith', 'family': 'Strymish', 'sequence': 'additional', 'affiliation': []}, {'given': 'Rupak', 'family': 'Datta', 'sequence': 'additional', 'affiliation': []}, {'given': 'Rekha', 'family': 'Goswami', 'sequence': 'additional', 'affiliation': []}, {'given': 'Matthew D.', 'family': 'Jankowich', 'sequence': 'additional', 'affiliation': []}, {'given': 'Nishant R.', 'family': 'Shah', 'sequence': 'additional', 'affiliation': []}, { 'ORCID': 'http://orcid.org/0000-0001-9004-8072', 'authenticated-orcid': True, 'given': 'Thomas H.', 'family': 'Taylor', 'sequence': 'additional', 'affiliation': []}, {'given': 'Sarah T.', 'family': 'Page', 'sequence': 'additional', 'affiliation': []}, {'given': 'Sara J.', 'family': 'Schiller', 'sequence': 'additional', 'affiliation': []}, {'given': 'Colleen', 'family': 'Shannon', 'sequence': 'additional', 'affiliation': []}, {'given': 'Cynthia', 'family': 'Hau', 'sequence': 'additional', 'affiliation': []}, {'given': 'Maura', 'family': 'Flynn', 'sequence': 'additional', 'affiliation': []}, {'given': 'Erika', 'family': 'Holmberg', 'sequence': 'additional', 'affiliation': []}, {'given': 'Karen', 'family': 'Visnaw', 'sequence': 'additional', 'affiliation': []}, {'given': 'Rupali', 'family': 'Dhond', 'sequence': 'additional', 'affiliation': []}, {'given': 'Mary', 'family': 'Brophy', 'sequence': 'additional', 'affiliation': []}, {'given': 'Paul A.', 'family': 'Monach', 'sequence': 'additional', 'affiliation': []}], 'member': '340', 'published-online': {'date-parts': [[2022, 2, 25]]}, 'reference': [ { 'key': 'pone.0263591.ref001', 'article-title': 'The cytokine storms of COVID-19, H1N1 influenza, CRS and MAS compared. 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