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
Year: 2023
Type: article
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.
Source: Alzheimer s Research & Therapy
Institutions: Novartis (Switzerland), Banner Alzheimer’s Institute
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,690
Funders: Bill and Melinda Gates Foundation, Alzheimer's Association, Amgen, Eli Lilly and Company, Biogen, GHR Foundation, Eisai, Foundation for Biomedical Research and Innovation, National Institutes of Health, Genentech, University of California, San Diego, Novartis Pharma, National Institute on Aging
Awards: G104586243, Epidemiologic Study of Neural Reserve and Neurobiology of Aging, Alzheimer's Disease Research Center, G2830398374, G3159755494, 1Florida Alzheimer's Disease Research Center, Nevada Exploratory Alzheimer's Disease Research Center (NVEADRC), G4505337483, Risk Factors, Pathology, and Clinical Expressions of AD, UAB Alzheimer's Disease Research Center, G4970245363, Rush Alzheimer's Disease Core Center, Alzheimer's Disease Neuroimaging Initiative, Alzheimer's Prevention Initiative APOE4 Trial, New Mexico Alzheimer's Disease Research Center, Arizona Alzheimer's Disease Core Center, Vanderbilt Alzheimer's Disease Research Center, Boston University Alzheimer's Disease Research Center, Yale Alzheimer Disease Research Center, UCSD Shiley-Marcos Alzheimer's Disease Research Center P30, Joint Estimate Diffusion Imaging (JEDI) for improved Tissue Characterization and Neural Connectivity in Aging and Alzheimer's Disease, Michigan Alzheimer's Disease Research Center, University of Kansas Alzheimer's Disease Research Center (KU ADRC), Alzheimer Disease Research Center, Alzheimer's Disease Research Center, Oregon Alzheimer's Disease Research Center, Alzheimer's Disease Research Center, UC Davis Alzheimer's Disease Research Center, Johns Hopkins Alzheimer's Disease Research Center, Indiana Alzheimer's Disease Research Center, Cleveland Alzheimers Disease Research Center, New Approaches to Dementia Heterogeneity, Arizona Alzheimer's Disease Research Center, Stanford Alzheimer's Disease Research Center, Mount Sinai Alzheimer's Disease Research Center, Mayo Alzheimer's Disease Research Center, Racial Differences in Late-Life Cognitive decline and risk of Alzheimer's Disease, University of Washington Alzheimer's Disease Research Center, Duke/UNC Alzheimer's Disease Research Center, Wisconsin Alzheimer's Disease Research Center, Alzheimer's Disease Research Centers, National Alzheimer's Coordinating Center, University of Kentucky Alzheimer's Disease Research Center, NORTHWESTERN Alzheimer's Disease Research Center, Penn Alzheimer's Disease Research Center (ADRC), Alzheimer's Disease Research Center, Massachusetts Alzheimer's Disease Research Center (MADRC), South Texas Alzheimer's Disease Center, Goizueta Alzheimer's Disease Research Center, The Alzheimer's Disease Research Center at the University of California, Irvine, Rush Alzheimer's Disease Research Center
OpenAlex ID: W4323315605