Cohort Effects in Alzheimer's Disease Trials: An Empirical Assessment Utilizing Data from the Alzheimer's Disease Cooperative Study.

ABSTRACT

BACKGROUND: Cohort effects in study populations can impact clinical trial conclusions and generalizability, particularly in trials with planned interim analyses. Long recruitment windows may exacerbate these risks in Alzheimer's disease (AD) trials. OBJECTIVES: To investigate the presence of cohort effects mild-to-moderate AD trials. DESIGN: Retrospective analysis using pooled participant-level data from nine randomized, placebo-controlled trials conducted by the Alzheimer's Disease Cooperative Study (ADCS). SETTING: Trials were multicenter studies conducted by an academic trial network. PARTICIPANTS: The trials enrolled participants with mild, mild-to-moderate, or moderate AD who were over age 50 and had mini mental state exam scores between 12 and 26. Interventions/Exposure We defined a participant's site-standardized enrollment time as the number of days between their screening date and the first screening date among randomized participants at their site within their study. MAIN OUTCOME(S) AND MEASURE(S) Our primary outcome was the 12-month change in the AD assessment scale - cognitive subscale (ADAS-Cog). Secondary outcomes were participant demographics and time to study discontinuation. RESULTS: The pooled sample consisted of N=2,754 at baseline with N=2,191 participants completing a 12-month visit. We found no meaningful differences in the distributions of sex, race and ethnicity, age, years of education or baseline ADAS-Cog score across enrollment time. We found a significant association between enrollment time and 12-month change in ADAS-Cog, with participants enrolling 100 days later tending to experience an increase on the ADAS-Cog of 0.16 points greater (reflecting greater cognitive decline; 95% CI (0.021, 0.294), p = 0.02), after controlling for potential confounding factors. CONCLUSION: We found minimal evidence of clinically relevant cohort effects in ADCS trials. Our results reinforce the original findings of these trials.