Aumont Etienne, Therriault Joseph, Kwan Angela T H, Carello-Collar Giovanna, Arfaie Saman, Hall Brandon J, Ferrari-Souza João-Pedro, Woo Marcel S, Macedo Arthur C, Tissot Cécile, Trudel Lydia, Rahmouni Nesrine, Servaes Stijn, Vitali Paolo, Soucy Jean-Paul, Pascoal Tharick A, Zimmer Eduardo R, Gauthier Serge, Rosa-Neto Pedro
McGill University Research Centre for Studies in Aging, McGill University, Montréal, Quebec, Canada.
Department of Neurology and Neurosurgery, Faculty of Medicine, McGill University, Montréal, Quebec, Canada.
JAMA Netw Open. 2025 Aug 1;8(8):e2529665. doi: 10.1001/jamanetworkopen.2025.29665.
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.
To describe temporal changes in the features of RCT design for interventions in AD.
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.
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 χ2 analyses.
The study included 203 RCTs with 79 589 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.
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.
近期关于阿尔茨海默病（AD）的随机临床试验（RCT）的成功，尤其是那些专注于抗淀粉样蛋白疗法的试验，已经被详细讨论过。然而，在这一成功之前AD的RCT设计特征的演变仍未得到充分探索。
描述AD干预措施的RCT设计特征的时间变化。
2025年1月在PubMed、Scopus和Web of Science数据库中检索了1992年1月至2024年12月发表的2期和3期AD RCT。纳入了对AD干预措施进行研究且设有安慰剂或标准治疗对照组的RCT。四名评估者独立审阅全文以获取研究特征。
从已发表的报告中提取参与者数量、RCT持续时间以及目标人群、结局和资金情况。使用线性回归和χ2分析对这些特征按时间进行分析。
该研究纳入了203项RCT，共79589名参与者测试AD干预措施。从1992年到2024年，2期RCT的平均样本量增加了464%（从42例增加到237例），3期RCT增加了50%（从632例增加到951例），而2期RCT的平均试验持续时间增加了188%（从16周增加到46周），3期RCT增加了256%（从20周增加到71周）。RCT持续时间延长可能部分归因于疾病修饰治疗而非对症治疗的比例增加。同样，最近的试验要求入组时提供AD生物标志物证据（2006年之前36项中有1项[2.7%]，2019年以来76项中有40项[52.6%]）。观察到所研究治疗方法类型存在显著差异，与神经递质或其他RCT相比，抗淀粉样蛋白和抗tau蛋白的RCT更有可能由制药行业资助（抗淀粉样蛋白或抗tau蛋白，71项中有68项[95.8%]；神经递质，69项中有52项[77.6%]；其他，52项中有33项[63.5%]）。RCT透明度有所提高，数据获取声明、注册报告更频繁，且种族和族裔报告更好。
这项AD RCT的方法学研究突出了1992年至2024年AD临床试验关键特征的重大变化。AD RCT规模变得更大、持续时间更长，从而有能力检测出更小的临床差异。样本量和持续时间的增加应能检测出更小、发生更缓慢的结局，这可能会使疗效更缓慢、更细微的疗法的RCT取得成功。
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