{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T20:56:05Z","timestamp":1790283365633,"version":"4.1.0"},"reference-count":18,"publisher":"BMJ","issue":"6","license":[{"start":{"date-parts":[[2022,6,6]],"date-time":"2022-06-06T00:00:00Z","timestamp":1654473600000},"content-version":"unspecified","delay-in-days":5,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000005","name":"U.S. Department of Defense","doi-asserted-by":"publisher","award":["W15QKN-16-9-1002"],"award-info":[{"award-number":["W15QKN-16-9-1002"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"accepted":{"date-parts":[[2022,5,16]]},"published-print":{"date-parts":[[2022,6]]},"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>The COVID-19 pandemic brought an urgent need to discover novel effective therapeutics for patients hospitalised with severe COVID-19. The Investigation of Serial studies to Predict Your Therapeutic Response with Imaging And moLecular Analysis (ISPY COVID-19 trial) was designed and implemented in early 2020 to evaluate investigational agents rapidly and simultaneously on a phase 2 adaptive platform. This manuscript outlines the design, rationale, implementation and challenges of the ISPY COVID-19 trial during the first phase of trial activity from April 2020 until December 2021.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and analysis<\/jats:title>\n                    <jats:p>The ISPY COVID-19 Trial is a multicentre open-label phase 2 platform trial in the USA designed to evaluate therapeutics that may have a large effect on improving outcomes from severe COVID-19. The ISPY COVID-19 Trial network includes academic and community hospitals with significant geographical diversity across the country. Enrolled patients are randomised to receive one of up to four investigational agents or a control and are evaluated for a family of two primary outcomes\u2014time to recovery and mortality. The statistical design uses a Bayesian model with \u2018stopping\u2019 and \u2018graduation\u2019 criteria designed to efficiently discard ineffective therapies and graduate promising agents for definitive efficacy trials. Each investigational agent arm enrols to a maximum of 125 patients per arm and is compared with concurrent controls. As of December 2021, 11 investigational agent arms had been activated, and 8 arms were complete. Enrolment and adaptation of the trial design are ongoing.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Ethics and dissemination<\/jats:title>\n                    <jats:p>ISPY COVID-19 operates under a central institutional review board via Wake Forest School of Medicine IRB00066805. Data generated from this trial will be reported in peer-reviewed medical journals.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration number<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT04488081\">NCT04488081<\/jats:ext-link>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjopen-2021-060664","type":"journal-article","created":{"date-parts":[[2022,6,6]],"date-time":"2022-06-06T11:31:11Z","timestamp":1654515071000},"page":"e060664","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":23,"title":["I-SPY COVID adaptive platform trial for COVID-19 acute respiratory failure: rationale, design and operations"],"prefix":"10.1136","volume":"12","clinical-trial-number":[{"clinical-trial-number":"nct04488081","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1595-4080","authenticated-orcid":false,"given":"Daniel Clark","family":"Files","sequence":"first","affiliation":[{"name":"Pulmonary, Critical Care, Allergy and Immunology Division, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A","family":"Matthay","sequence":"additional","affiliation":[{"name":"University of California San Francisco, San Francisco, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolyn S","family":"Calfee","sequence":"additional","affiliation":[{"name":"University of California San Francisco, San Francisco, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil 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