Abstract Details

Title Using Predictive Models to Reduce Heterogeneity in Alzheimer’s Disease Clinical Trials

Topic Aging, Dementia, and Behavioral Neurology

Presentation(s) S26 - Experimental Therapeutics in Dementia (1:48 PM-2:00 PM)

Poster/Presentation
Number 005

Background Enrolling individuals unlikely to show MCD with placebo treatment may make it more difficult to demonstrate the benefits of active treatment on cognition.

Objective 1. To investigate the proportion of individuals showing meaningful cognitive decline (MCD) in the placebo arm of Alzheimer’s disease (AD) trials during trials. 2. To evaluate data-driven predictive models for identifying participants who will show MCD if given placebo.

Design/Methods

We used data from the placebo arm of five Phase III trials: two trials of semagacestat (LFAN and LZAN) and three trials of solanezumab (EXPEDITON1, EXPEDTION2, EXPEDITION3). We identified a group with MCD based on a score change on the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog11; change of ≥4 from baseline to last trial visit), and a group with stable cognition (SC), defined as no MCD (change of <4 from baseline to last trial visit). Machine learning (ML) models were trained to classify participants into individuals with MCD vs. SC using baseline predictors (demographics, neuropsychological tests, genotype, and imaging when available). Predictive values of these models were evaluated against longitudinal rates of disease progression.

Results Total pooled placebo sample included 1982 individuals. MCD was not observed in 42-58% of placebo-treated participants at the end of trials. Positive predictive values of the predictive ML models were approximately 12-25% higher than the sample rate of MCD, while negative predictive values of models were approximately 15-24% higher than the base rate of participants who had SC at the end of trial.

Conclusions Despite enrollment in a clinical trial, 42-58% of participants in the placebo arm of five AD trials did not show MCD. Using predictive models can potentially increase sensitivity to treatment effects and reduce sample size requirements by increasing the proportion of participants with MCD enrolled in both arms of clinical trials.

Authors/Disclosures
Ali Ezzati, MD (University of California, Irvine) PRESENTER	Dr. Ezzati has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Mist Research. Dr. Ezzati has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for BioDelivery Sciences International (BDSI) . The institution of Dr. Ezzati has received research support from NIA. The institution of Dr. Ezzati has received research support from Alzheimer's Association. The institution of Dr. Ezzati has received research support from Cure Alzheimer's Fund.
Kellen Petersen (Albert Einstein College of Medicine)	No disclosure on file
Bhargav Nallapu	No disclosure on file
Richard B. Lipton, MD, FAAN (Albert Einstein College of Medicine)	Dr. Lipton has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Allergan/Abbvie. Dr. Lipton has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Amgen. Dr. Lipton has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Biohaven. Dr. Lipton has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Eli Lilly. Dr. Lipton has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Lundbeck. Dr. Lipton has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for GlaxoSmithKline. Dr. Lipton has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Teva. Dr. Lipton has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Vedanta. Dr. Lipton has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Merck. Dr. Lipton has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Grifols. Dr. Lipton has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Pfizer. Dr. Lipton has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Axon. Dr. Lipton has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Satsuma. Dr. Lipton has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Genentech. Dr. Lipton has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Cool Tech. Dr. Lipton has received personal compensation in the range of $500-$4,999 for serving as a Consultant for BDSI. Dr. Lipton has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Linpharma. Dr. Lipton has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Allergan/Abbvie. Dr. Lipton has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biohaven. Dr. Lipton has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Eli Lilly. Dr. Lipton has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Lundbeck. Dr. Lipton has stock in Biohaven. Dr. Lipton has stock in Manistee. Dr. Lipton has stock in Axon. Dr. Lipton has stock in CoolTech. The institution of Dr. Lipton has received research support from Teva. The institution of Dr. Lipton has received research support from Amgen. The institution of Dr. Lipton has received research support from Allergan/Abbvie. The institution of Dr. Lipton has received research support from Gammacore. The institution of Dr. Lipton has received research support from Axsome. The institution of Dr. Lipton has received research support from Charleston Labs. The institution of Dr. Lipton has received research support from Eli Lilly. The institution of Dr. Lipton has received research support from Satsuma. The institution of Dr. Lipton has received research support from NIH . The institution of Dr. Lipton has received research support from Veterans Administration. Dr. Lipton has received publishing royalties from a publication relating to health care.