{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:09:07Z","timestamp":1786975747682,"version":"build-2736575974"},"reference-count":41,"publisher":"American Medical Association (AMA)","issue":"8","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Netw Open"],"abstract":"\n Importance<\/jats:title>\n The success of recent randomized clinical trials (RCTs) for Alzheimer disease (AD), particularly those focusing on anti-amyloid therapies, has been discussed at length. However, the evolution of RCT design features for AD that preceded this success remain underexplored.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n To describe temporal changes in the features of RCT design for interventions in AD.<\/jats:p>\n <\/jats:sec>\n \n Evidence Review<\/jats:title>\n PubMed, Scopus, and Web of Science databases were searched in January 2025 for phase 2 and 3 AD RCTs published between January 1992 and December 2024. RCTs that investigated an intervention for AD, with a placebo or standard-of-care control group, were included. Four assessors independently reviewed full-text articles to capture study characteristics.<\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n \n The number of participants and the duration of RCTs as well as the target population, outcomes, and funding were extracted from published reports. These features were analyzed with respect to time using linear regression and \u03c7\n 2<\/jats:sup>\n analyses.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n The study included 203 RCTs with 79\u202f589 participants testing interventions in AD. From 1992 to 2024, the mean sample size increased by 464% for phase 2 RCTs (from 42 to 237), and 50% for phase 3 RCTs (from 632 to 951), while the mean trial duration increased by 188% (from 16 to 46 weeks) for phase 2, and 256% (from 20 to 71 weeks) for phase 3 RCTs. This longer duration of RCTs may be partially attributed by a greater share of disease-modifying rather than symptomatic treatments. Similarly, more recent trials required AD biomarker evidence for enrollment (from 1 of 36 [2.7%] before 2006 to 40 of 76 [52.6%] since 2019). A substantial difference in the type of therapeutics researched was observed, with anti-amyloid and anti-tau RCTs being more likely to be funded by the pharmaceutical industry compared with neurotransmitter or other RCTs (anti-amyloid or anti-tau, 68 of 71 [95.8%]; neurotransmitter, 52 of 69 [77.6%]; other, 33 of 52 [63.5%]). RCT transparency improved, with more frequent data accessibility statements, registered reports, and better reporting on race and ethnicity.<\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n This methodology research of AD RCTs highlights substantial changes in key features of AD clinical trials from 1992 to 2024. AD RCTs have become larger and longer, such that they are powered to detect smaller clinical differences. The increased sample sizes and duration should enable the detection of smaller and more slowly occurring outcomes, which may lead to successful RCTs of therapies with slower and more subtle efficacy.<\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jamanetworkopen.2025.29665","type":"journal-article","created":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T15:30:35Z","timestamp":1756481435000},"page":"e2529665","source":"Crossref","is-referenced-by-count":4,"title":["The Evolution of Randomized Clinical Trial Designs to Assess Therapeutics in Alzheimer Disease"],"prefix":"10.1001","volume":"8","author":[{"given":"Etienne","family":"Aumont","sequence":"first","affiliation":[{"name":"McGill University Research Centre for Studies in Aging, McGill University, Montr\u00e9al, Quebec, Canada"},{"name":"Department of Neurology and Neurosurgery, Faculty of Medicine, McGill University, Montr\u00e9al, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Therriault","sequence":"additional","affiliation":[{"name":"McGill University Research Centre for Studies in Aging, McGill University, Montr\u00e9al, Quebec, Canada"},{"name":"Department of Neurology and Neurosurgery, Faculty of Medicine, McGill University, Montr\u00e9al, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela T. 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