Pre-Randomization Predictors of Study Discontinuation in a Preclinical Alzheimer's Disease Randomized Controlled Trial.

BACKGROUND

Participant discontinuation from study treatment in a clinical trial can leave a trial underpowered, produce bias in statistical analysis, and limit interpretability of study results. Retaining participants in clinical trials for the full study duration is therefore as important as participant recruitment.

OBJECTIVE

This analysis aims to identify associations of pre-randomization characteristics of participants with premature discontinuation during the blinded phase of the Anti-Amyloid treatment in Asymptomatic AD (A4) Study.

DESIGN

All A4 trial randomized participants were classified as having prematurely discontinued study during the blinded period of the study for any reason (dropouts) or completed the blinded phase of the study on treatment (completers).

SETTING

The trial was conducted across 67 study sites in the United States, Canada, Japan and Australia through the global COVID-19 pandemic.

PARTICIPANTS

The sample consisted of all 1169 A4 trial randomized participants.

MEASUREMENTS

Pre-randomization demographic, clinical, amyloid PET and genetic predictors of study discontinuation were evaluated using a univariate generalized linear mixed model (GLMM), with discontinuation status as the binary outcome, each predictor as a fixed effect, and site as a random effect to account for differences among study sites in the trial. Characteristics significant at p<0.10 were then included in a multivariable GLMM.

RESULTS

Among randomized participants, 339 (29%) discontinued the study during the blinded period (median follow-up time in trial: 759 days). From the multivariable analysis, the two main predictors of study discontinuation were screening State-Trait Anxiety Inventory (STAI) scores (OR = 1.07 [95%CI = 1.02; 1.12]; p=0.002) and age (OR = 1.06 [95%CI = 1.03; 1.09]; p<0.001). Participants with a family history of dementia (OR = 0.75 [95%CI = 0.55; 1.01]; p=0.063) and APOE ε4 carriers (OR = 0.79 [95%CI = 0.6; 1.04]; p=0.094) were less likely to discontinue from the study, with the association being marginally significant. In these analyses, sex, race and ethnicity, cognitive scores and amyloid/tau PET scores were not associated with study dropout.

CONCLUSIONS

In the A4 trial, older participants and those with higher levels of anxiety at baseline as measured by the STAI were more likely to discontinue while those who had a family history of dementia or were APOE ε4 carriers were less likely to drop out. These findings have direct implications for future preclinical trial design and selection processes to identify those individuals at greatest risk of dropout and provide information to the study team to develop effective selection and retention strategies in AD prevention studies.

Déclaration de conflit d'intérêts

RR has received research support from the National Institutes of Health (NIH), the Alzheimer’s Association, American Heart Association, Eli Lilly and Eisai. KCH, RY, and JRS are employees and minor shareholders of Eli Lilly and Company. KH, OL and KE have received research support from the National Institutes of Health (NIH), the Alzheimer’s Association, American Heart Association, and Eisai. MD has received research funding from the National Institutes of Health, Janssen, Eli Lilly, and Eisai, reports consulting fees from Roche and his spouse is a full-time employee of Janssen. DMH is part of the AHEAD 3-45 Study team. AHEAD A3-45 Study is a public-private partnership with funding from the National Institutes of Aging/NIH, Eisai, and Co., GHR Foundation, Alzheimer’s Association, and philanthropic donors. Additionally, she receives direct funding from the Alzheimer’s Association and American Heart Association. ALP has received research support from the National Institutes of Health (NIH), Alzheimer’s Association, Hart Family Foundation, Alector, Cognition Therapeutics, Eisai, Eli Lilly, and Vivoryon. She has served as a consultant for Medscape. AGS has received research support from the National Institutes of Health (NIH), the Alzheimer’s Association, Eli Lilly, Biogen, Eisai, Janssen, Vivoryon, Cassava, Bristol Myers Squibb, and the American College of Radiology. PSA has received grants or contracts from the National Institutes of Health (NIH), Alzheimer’s Association, Foundation for NIH (FNIH), Lilly, Janssen and Eisai and consulting fees from Merck, Biogen, AbbVie, Roche, and Immunobrain Checkpoint. RAS reports grant support from Eisai, and Eli Lilly and reported serving as a consultant for AbbVie, AC Immune, Alector, Bristol-Myers-Squibb, Ionis, Janssen, Genentech, Merck, Prothena, Roche, and Vaxxinity. JG has received research support from the National Institutes of Health (NIH), the Alzheimer’s Association, BrightFocus Foundation, Eli Lilly, Biogen, Genentech, and Eisai. He has received personal fees for providing consulting to SiteRx and editorial service to Alzheimer’s and Dementia.