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A traditional MAMS trial often decreases the expected sample size of the trial compared with just running a multi\u2010arm approach, but with the drawback of an increase in maximum sample size. For academic led trials, this poses a particular challenge, as funding is typically based on the maximum required sample size. To address this, drop\u2010the\u2010loser designs were introduced, where a fixed number of treatments are dropped at each interim stage, thereby reducing the maximum sample size. In this work, we propose an enhanced multi\u2010stage drop\u2010the\u2010loser design that also allows for early stopping of the entire trial for superiority. This approach aims to retain the benefits of a reduced maximum sample size while also lowering the expected sample size. The proposed design is motivated by a trial in atrial fibrillation. We derive analytical expressions for the type I error rate, power, and expected sample size, and compare the proposed design's performance to alternative methods. We outline the key requirements for implementing the proposed design and discuss the contexts in which it should be considered. For the motivating example, the results show that the proposed design substantially reduces the expected sample size compared to a standard drop\u2010the\u2010loser design, while lowering the maximum sample size relative to running a traditional MAMS trial or multiple separate trials.<\/jats:p>","DOI":"10.1002\/sim.70642","type":"journal-article","created":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T07:40:26Z","timestamp":1782286826000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Multi\u2010Stage Drop\u2010the\u2010Loser Design With Superiority Boundaries"],"prefix":"10.1002","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4997-8742","authenticated-orcid":false,"given":"Peter","family":"Greenstreet","sequence":"first","affiliation":[{"name":"Ottawa Methods Centre Ottawa Hospital Research Institute  Ontario Canada"},{"name":"School of Epidemiology and Public Health University of Ottawa  Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manel","family":"Khan","sequence":"additional","affiliation":[{"name":"Ottawa Methods Centre Ottawa Hospital Research Institute  Ontario Canada"},{"name":"School of Epidemiology and Public Health University of Ottawa  Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salmaan","family":"Kanji","sequence":"additional","affiliation":[{"name":"Department of Pharmacy The Ottawa Hospital  Ontario Canada"},{"name":"Clinical Epidemiology Ottawa Hospital Research Institute  Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pouya","family":"Motazedian","sequence":"additional","affiliation":[{"name":"School of Epidemiology and Public Health University of Ottawa  Ontario Canada"},{"name":"Division of Cardiology University of Ottawa Heart Institute  Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6459-8801","authenticated-orcid":false,"given":"Andrew","family":"Seely","sequence":"additional","affiliation":[{"name":"Department of Surgery Ottawa Hospital Research Institute  Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Sibley","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine Queen's University  Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim","family":"Ramsay","sequence":"additional","affiliation":[{"name":"Ottawa Methods Centre Ottawa Hospital Research Institute  Ontario Canada"},{"name":"School of Epidemiology and Public Health University of Ottawa  Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,24]]},"reference":[{"issue":"11","key":"e_1_2_10_2_1","doi-asserted-by":"crossref","DOI":"10.1038\/nrd.2018.198","article-title":"How Much Do Phase III Trials Cost?","volume":"17","author":"Mullard A.","year":"2018","journal-title":"Nature Reviews. 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