{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T17:03:58Z","timestamp":1786122238697,"version":"build-2736575974"},"reference-count":11,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T00:00:00Z","timestamp":1783036800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T00:00:00Z","timestamp":1783036800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100004339","name":"Sanofi","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004339","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["dom-pubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Diabetes Obesity Metabolism"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>The importance of randomised trials for discerning an intervention's effect rests on randomisation's ability to create groups with (on average) equal hazards of future outcomes. The frequency with which this does not occur in well\u2010designed large trials with a high event rate was studied.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Research Design and Methods<\/jats:title>\n                    <jats:p>Data from 8215 participants in the Outcomes Reduction with an Initial Glargine Intervention (ORIGIN) trial's biomarker study were used to simulate multiple trials. Participants were repeatedly randomised to two groups. After each randomisation, the hazard of death in people assigned to one versus the other was calculated. A set of 1000 randomisations was repeated 1000 times, and the number of pairs for which the hazard ratio was &lt;\u20090.85 or &gt;\u20091.18 was tabulated within each set of 1000. Whether such imbalances in hazard could be detected or mitigated by adjusting for baseline covariates was explored using adjusted Cox models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In a median of 3 (IQR 2, 4) of 1000 randomisations (0.3%) the hazard ratio for death of assignment to one group versus the other was &lt;\u20090.85 or &gt;\u20091.18 by chance alone. This imbalance was not apparent from baseline data and could not be fully mitigated by adjustment for baseline independent predictors of death using data from four randomisations that yielded imbalanced hazards.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>One out of every 300\u2013400 large, two\u2010arm outcomes trials have imbalances in the baseline hazard of the primary outcome that are large enough to misrepresent the true effect of the intervention.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/dom.71070","type":"journal-article","created":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T07:13:50Z","timestamp":1783062830000},"page":"8595-8601","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Highly Powered Large Outcomes Randomised Controlled Trial Will Usually, but Not Always, Have Balanced Groups at Baseline"],"prefix":"10.1111","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8072-2836","authenticated-orcid":false,"given":"Hertzel C.","family":"Gerstein","sequence":"first","affiliation":[{"name":"Population Health Research Institute, McMaster University and Hamilton Health Sciences  Hamilton Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zayeeda","family":"Labiba","sequence":"additional","affiliation":[{"name":"Population Health Research Institute, McMaster University and Hamilton Health Sciences  Hamilton Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sibylle","family":"Hess","sequence":"additional","affiliation":[{"name":"Sanofi  Frankfurt Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6139-1197","authenticated-orcid":false,"given":"Kamel","family":"Mohammedi","sequence":"additional","affiliation":[{"name":"Population Health Research Institute, McMaster University and Hamilton Health Sciences  Hamilton Ontario Canada"},{"name":"Universit\u00e9 de Bordeaux  Pessac France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yueci","family":"Zhou","sequence":"additional","affiliation":[{"name":"Population Health Research Institute, McMaster University and Hamilton Health Sciences  Hamilton Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shun Fu","family":"Lee","sequence":"additional","affiliation":[{"name":"Population Health Research Institute, McMaster University and Hamilton Health Sciences  Hamilton Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,3]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2018.6360"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2022.21506"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chest.2020.03.013"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/sim.7901"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.105.594945"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1203858"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2017-00273"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.115.015744"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-022-25296-x"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(05)61034-3"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchf.2022.02.007"}],"container-title":["Diabetes, Obesity and Metabolism"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dom-pubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/dom.71070","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/dom-pubs.onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/dom.71070","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/dom-pubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/dom.71070","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T08:52:34Z","timestamp":1786092754000},"score":1,"resource":{"primary":{"URL":"https:\/\/dom-pubs.onlinelibrary.wiley.com\/doi\/10.1111\/dom.71070"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,3]]},"references-count":11,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2026,9]]}},"alternative-id":["10.1111\/dom.71070"],"URL":"https:\/\/doi.org\/10.1111\/dom.71070","archive":["Portico"],"relation":{},"ISSN":["1462-8902","1463-1326"],"issn-type":[{"value":"1462-8902","type":"print"},{"value":"1463-1326","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,3]]},"assertion":[{"value":"2026-04-28","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication 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