Abstract Details

Title The Evolution of Randomized Clinical Trial Designs to Assess Therapeutics in Alzheimer Disease

Topic Aging, Dementia, and Behavioral Neurology

Presentation(s) P4 - Poster Session 4 (8:00 AM-9:00 AM)

Poster/Presentation
Number 13-012

Objective To describe temporal changes in the features of randomized clinical trials (RCTs) design for interventions in Alzheimer disease (AD).

Background The success of recent RCTs for 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.

Design/Methods

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.

Results

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%]).

Conclusions <div widget-instance-ama_fulltext_abstract"="" data-widget-name="ArticleFulltext" data-widget-instance="AMA_Fulltext_Abstract">

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.

Authors/Disclosures
Saman Arfaie, MD (McGill Department of Neurology) PRESENTER	Dr. Arfaie has received publishing royalties from a publication relating to health care.
Etienne Aumont	Mr. Aumont has nothing to disclose.
William J. Therriault (McGill Center for Studies in Aging)	Mr. Therriault has nothing to disclose.
Angela T. Kwan, MSc	Miss Kwan has nothing to disclose.
Giovanna Carello Collar, MSc	Miss Carello Collar has nothing to disclose.
Brandon Hall (University of Southern California)	Mr. Hall has nothing to disclose.
João Pedro Ferrari Souza	Mr. Ferrari Souza has nothing to disclose.
Marcel S. Woo, MD	Dr. Woo has nothing to disclose.
ARTHUR CASSA MACEDO, MD	Dr. CASSA MACEDO has received research support from Alzheimer Society of Canada. Dr. CASSA MACEDO has received research support from McGill University.
Cecile Tissot, PhD	Dr. Tissot has nothing to disclose.
Lydia Trudel	Ms. Trudel has nothing to disclose.
Nesrine Rahmouni	Miss Rahmouni has nothing to disclose.
Stijn Servaes	Dr. Servaes has nothing to disclose.
Paolo Vitali, MD (McGill University Research Centre for Studies on Aging)	Dr. Vitali has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Lilly. Dr. Vitali has received personal compensation in the range of $500-$4,999 for serving as a Consultant for novonordisk. Dr. Vitali has received personal compensation in the range of $500-$4,999 for serving as a Consultant for eisai. Dr. Vitali has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for BTX.
Jean-Paul N. Soucy, MD	Dr. Soucy has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eisai Canada. Dr. Soucy has received research support from CIHR. Dr. Soucy has a non-compensated relationship as a Associate with Weston Foundation that is relevant to AAN interests or activities.
Tharick A. Pascoal, Sr., MD, PhD (University of Pittsburgh)	Dr. Pascoal has nothing to disclose.
Eduardo R. ZIMMER, PhD, BPHARM	Dr. ZIMMER has received personal compensation in the range of $500-$4,999 for serving as a Consultant for NOVO NORDISK. Dr. ZIMMER has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for NEXT INNOVATIVE THERAPEUTICS. Dr. ZIMMER has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for MASIMA. Dr. ZIMMER has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for NOVO NORDISK. Dr. ZIMMER has stock in MASIMA. The institution of Dr. ZIMMER has received research support from ALZHEIMERS ASSOCIATION. The institution of Dr. ZIMMER has received research support from CNPQ. The institution of Dr. ZIMMER has received research support from FAPERGS. The institution of Dr. ZIMMER has received research support from BRAZILIAN MINISTRY OF HEALTH. The institution of Dr. ZIMMER has received research support from SERRAPILHEIRA INSTITUTE . The institution of Dr. ZIMMER has received research support from NATIONAL ACADEMY OF NEUROPSYCHOLOGY.
Serge G. Gauthier, MD (Douglas Hospital)	Dr. Gauthier has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for TauRx . Dr. Gauthier has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Lilly Canada . Dr. Gauthier has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Eisai . Dr. Gauthier has received personal compensation in the range of $50,000-$99,999 for serving on a Scientific Advisory or Data Safety Monitoring board for ENIGMA USA. Dr. Gauthier has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for AmyriAD. Dr. Gauthier has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Medesis. Dr. Gauthier has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Alzheon. Dr. Gauthier has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Karuna. Dr. Gauthier has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Otsuka . Dr. Gauthier has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for NovoNordisk. Dr. Gauthier has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Biogen Canada. Dr. Gauthier has received personal compensation in the range of $5,000-$9,999 for serving as an officer or member of the Board of Directors for Sharon Francis Foundation . Dr. Gauthier has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for JPAD. Dr. Gauthier has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Lundbeck Foundation . Dr. Gauthier has received publishing royalties from a publication relating to health care.
Pedro Rosa Neto, MD, PhD (McGIll University)	Dr. Rosa Neto has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novo Nordisk.

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