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This study aimed to evaluate the effect of an alternative indicator of treatment response on sample size requirements and the use of a minimization strategy for randomization.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Sample size estimates were compared when based on the commonly used endpoint of the proportion of patients achieving stable culture conversion (SCC) at 12 weeks versus a novel but corresponding indicator of treatment response based on a model of changes in mycobacterial load (MBL) over time. The non-linear mixed effects model, calibrated using data from a RR-TB cohort in the same setting, included a longitudinal MBL decline, a probabilistic component for mycobacteria presence in sputum, and a time-to-event model for culture positivity. Data were simulated for a prespecified treatment effect to compare the power of detecting the treatment effect for various sample sizes when using the commonly used endpoint and alternative indicator of treatment response. Additionally, the impact of random patient allocation versus a minimization strategy for randomization on covariate imbalance was assessed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>To achieve 80% power, 410 individuals were needed using the commonly used endpoint versus 110 participants when using the non-linear mixed effects model, corresponding to a 73% reduction in sample size. A small sample size results in high baseline covariate imbalance with random treatment group allocation, with a median relative imbalance of 0.104 for 110 participants versus 0.053 for 410 participants. This imbalance was reduced to 0.036 for 110 participants when an adaptive minimization procedure was implemented.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Using a model of mycobacterial burden changes over time as an alternative indicator of treatment response, combined with a minimization procedure during the randomization process, significantly reduced the sample size which could, if validated, enhance the efficiency of RR-TB clinical trial design.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12874-025-02697-w","type":"journal-article","created":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T12:46:43Z","timestamp":1764074803000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Improving the efficiency of drug resistant tuberculosis treatment trials: a time-to-event alternative marker for bacteriological response and adaptive minimization for randomization"],"prefix":"10.1186","volume":"25","author":[{"given":"Elise","family":"De Vos","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annelies","family":"Van Rie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven","family":"Abrams","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,11,25]]},"reference":[{"key":"2697_CR1","unstructured":"World Health Organisation. 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Advances in clinical trial design for development of new TB treatments\u2014Translating international tuberculosis treatment guidelines into National strategic plans: experiences from Belarus, South Africa, and Vietnam. PLoS Med. 2019;16(10):e1002896.","journal-title":"PLoS Med"}],"container-title":["BMC Medical Research Methodology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12874-025-02697-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12874-025-02697-w\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12874-025-02697-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T14:04:59Z","timestamp":1764079499000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcmedresmethodol.biomedcentral.com\/articles\/10.1186\/s12874-025-02697-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,25]]},"references-count":59,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["2697"],"URL":"https:\/\/doi.org\/10.1186\/s12874-025-02697-w","relation":{},"ISSN":["1471-2288"],"issn-type":[{"value":"1471-2288","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,25]]},"assertion":[{"value":"26 December 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 September 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 November 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The SMARTT trial received ethical approval from the ethics committees of the University of the Free State Health Sciences Research Ethics Committee (UFS-HSD2019\/0364\/2004), Stellenbosch University Health Research Ethics Committee (N19\/07\/100), and the University of Antwerp (21\/18\/239). Written, informed consent to participate was obtained from all piloting participants. The EXIT-RIF study was approved by the Human Research Ethics Committee of the University of the Witwatersrand in South Africa (M111139) and the Institutional Review Board of the University of North Carolina at Chapel Hill in the United States (11-2273) and was conducted in accordance with the ethical principles of the Declaration of Helsinki. Approval of study activities was obtained from relevant health authorities. Participants gave verbal consent by phone (recorded). Waiver of consent was obtained for patients who had died or were LTFU from TB care prior to study enrolment and could not be contacted despite multiple attempts.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"265"}}