Rationale for the selection of dual primary endpoints in prevention studies of cognitively unimpaired individuals at genetic risk for developing symptoms of Alzheimer's disease

Abstract

Background: There is a critical need for novel primary endpoints designed to detect early and subtle changes in cognition in clinical trials targeting the asymptomatic (preclinical) phase of Alzheimer's disease (AD). The Alzheimer's Prevention Initiative (API) Generation Program, conducted in cognitively unimpaired individuals at risk of developing AD (e.g., enriched by the apolipoprotein E (APOE) genotype), used a novel dual primary endpoints approach, whereby demonstration of treatment effect in one of the two endpoints is sufficient for trial success. The two primary endpoints were (1) time to event (TTE)-with an event defined as a diagnosis of mild cognitive impairment (MCI) due to AD and/or dementia due to AD-and (2) change from baseline to month 60 in the API Preclinical Composite Cognitive (APCC) test score.

Methods: Historical observational data from three sources were used to fit models to describe the TTE and the longitudinal APCC decline, both in people who do and do not progress to MCI or dementia due to AD. Clinical endpoints were simulated based on the TTE and APCC models to assess the performance of the dual endpoints versus each of the two single endpoints, with the selected treatment effect ranging from a hazard ratio (HR) of 0.60 (40% risk reduction) to 1 (no effect).

Results: A Weibull model was selected for TTE, and power and linear models were selected to describe the APCC score for progressors and non-progressors, respectively. Derived effect sizes in terms of reduction of the APCC change from baseline to year 5 were low (0.186 for HR = 0.67). The power for the APCC alone was consistently lower compared to the power of TTE alone (58% [APCC] vs 84% [TTE] for HR = 0.67). Also, the overall power was higher for the 80%/20% distribution (82%) of the family-wise type 1 error rate (alpha) between TTE and APCC compared to 20%/80% (74%).

Conclusions: Dual endpoints including TTE and a measure of cognitive decline perform better than the cognitive decline measure as a single primary endpoint in a cognitively unimpaired population at risk of AD (based on the APOE genotype). Clinical trials in this population, however, need to be large, include older age, and have a long follow-up period of at least 5 years to be able to detect treatment effects.

Keywords: APCC; APOE genotype; Alzheimer’s disease; Clinical trial simulation; Cognitively unimpaired; Dual endpoints; Model-informed drug development; Preclinical phase; Time to event.

Fig. 1

Cognitive composites over time by progressor status: Individual time profiles and LOESS estimates. APCC, Alzheimer’s Prevention Initiative Preclinical Composite Cognitive; LOESS, locally estimated scatterplot smoothing; MCI, mild cognitive impairment; NACC, National Alzheimer’s Coordinating Center; PACC, Preclinical Alzheimer Cognitive Composite; RBANS, Repeatable Battery for the Assessment of Neuropsychological Status; ROS/MAP/MARS, Religious Orders Study/Memory and Aging Project/Minority Aging Research Study. Trajectories are anchored at the time of diagnosis for progressors to dementia and aligned by the median age of progressors at the time of diagnosis of dementia for progressors to MCI and for non-progressors to MCI/dementia

Fig. 2

Probability of remaining cognitively unimpaired obtained by different survival functions for the TTE model. AD, Alzheimer’s disease; AIC, Akaike’s Information Criterion; CI, confidence interval; MCI, mild cognitive impairment; TTE, time to event. Kaplan-Meier curves: confidence limits are wide for homozygotes due to the small sample size. Non-genotyped subjects were assumed to be non-carriers

Fig. 3

Model diagnostics of the TTE model (VPC). AD, Alzheimer’s disease; CI, confidence interval; KM, Kaplan-Meier; MCI, mild cognitive impairment; TTE, time to event; VPC, visual predictive check. Non-genotyped subjects were assumed to be non-carriers

Fig. 4

Model diagnostics of the APCC model for progressors to MCI/dementia due to AD (VPC). AD, Alzheimer’s disease; APCC, Alzheimer’s Prevention Initiative Preclinical Composite Cognitive; MCI, mild cognitive impairment; VPC, visual predictive check. Diagnosis of MCI/dementia: diagnosis of mild cognitive impairment or dementia due to AD

Fig. 5

Examples of individual profiles of predictions and observed data. APCC, Alzheimer’s Prevention Initiative Preclinical Composite Cognitive; MCI, mild cognitive impairment. Both individual predictions and predictions for a “typical individual” take into account all model covariates; individual predictions are further adjusted by estimates of individual variability not explained by identified covariates