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Such treatments are typically administered sequentially in an integrated fashion. For example, in alcohol\u2010associated hepatitis (AH), an acute liver disease caused by excessive alcohol drinking, successful treatment requires therapies that reduce liver inflammation during the acute phase, followed by interventions that address the underlying alcohol use disorder (AUD) to achieve optimal outcomes. Selecting an optimal treatment combination, however, presents great challenges in study design due to the involvement of multiple drug combinations and treatment phases. In this paper, we describe a new trial design based on a Bayesian model that connects the outcomes from the acute and subsequent treatment phases. We refer to this design as the Bayesian Optimal Adaptive Design for Sequentially Integrated Therapies (BIT) design. BIT incorporates multiple interim analyses with adaptive stopping rules for both futility and superiority, enhancing efficiency while controlling the family\u2010wise type I error rate and maximizing statistical power. We illustrate the use of BIT design in a clinical trial comparing the efficacy of integrated therapy for severe AH, with sample size determination and design parameter optimization. Simulation studies show that the design possesses excellent operating characteristics, including experiment\u2010wise type I error rate control. Although the design's development is motivated by studies of AH treatment, the design framework is broadly applicable to other complex diseases requiring sequentially delivered therapies. R codes are provided for BIT implementation.<\/jats:p>","DOI":"10.1002\/sim.70684","type":"journal-article","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:05:38Z","timestamp":1785420338000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Bayesian Optimal Adaptive Clinical Trial Design for Sequentially Integrated Therapies"],"prefix":"10.1002","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-1345-1670","authenticated-orcid":false,"given":"Yining","family":"Li","sequence":"first","affiliation":[{"name":"Department of Biostatistics and Health Data Science Indiana University School of Medicine  Indianapolis IN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-5744-3867","authenticated-orcid":false,"given":"Jiaying","family":"Guo","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company  Indianapolis IN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2056-4909","authenticated-orcid":false,"given":"Samer","family":"Gawrieh","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Hepatology and Gastroenterology Indiana University School of Medicine  Indianapolis IN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-7023-1722","authenticated-orcid":false,"given":"Wei","family":"Shen","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company  Indianapolis IN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0572-4756","authenticated-orcid":false,"given":"Yong","family":"Zang","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Health Data Science Indiana University School of Medicine  Indianapolis IN USA"},{"name":"Center for Computational Biology and Bioinformatics Indiana University School of Medicine  Indianapolis IN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4236-9135","authenticated-orcid":false,"given":"Wanzhu","family":"Tu","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Health Data Science Indiana University School of Medicine  Indianapolis IN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,30]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2013.276300"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1412278"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.32478"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1097\/HEP.0000000000001513"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-018-0014-7"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-024-00936-x"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1809697"},{"issue":"18","key":"e_1_2_13_9_1","first-page":"e876","article-title":"2022 AHA\/ACC\/HFSA Guideline for the Management of Heart Failure: Executive Summary: A Report of the American College of Cardiology\/American Heart Association Joint Committee on Clinical Practice Guidelines","volume":"145","author":"Heidenreich P. 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