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Principal Investigator: Guogen Shan
Organization: UNIVERSITY OF FLORIDA
Fiscal Year: 2024
Award: $289,505
Funding agency: National Institute on Aging
Project Summary/Abstract
Alzheimer’s disease (AD) is characterized by heterogeneity in sex, race, APOE ε4 status, and tau. APOE ε4
status has been used to stratify AD patients in clinical trials (e.g., the aducanumab trial). Women with AD
have faster cognitive decline compared to men with AD from longitudinal studies. African Americans decline
faster than Whites on memory tests and visuospatial functioning. Furthermore, we know that the changes
in cognitive functions are negatively associated with tau levels. In addition to the heterogeneity, another
challenge facing AD trials is the follow-up time in study designs. In the recent aducanumab trial, the dose of
aducanumab was increased during the course of the study for APOE ε4 positive patients, but their follow-up
times remained unchanged. The proposed project will respond to PAR-19-070: Research on Current Topics in
Alzheimer’s Disease and Its Related Dementias. We will develop adaptive designs to allow the modification
of follow-up time for patients with dose change in Aim 1. The published results from the aducanumab trial
will be used in simulation studies to compare the statistical performance of the proposed adaptive designs
with the existing designs without follow-up time change. Our simulation results indicated that our proposed
adaptive designs guarantee the type I error rate and power, while the existing designs do not. In Aim 2,
we will develop new optimal composite scores for each subpopulation by using the baseline data and the
rate of change over time to better understand the differences in cognition and trajectories of decline. We
will develop one optimal composite score for each subpopulation stratified by sex, race, APOE ε4 status, and
tau, based on data from the ADNI study. We will demonstrate how best to manage statistically the effects
of demographic, genetic, and biomarker factors on cognitive ability of AD patients. The optimal composite
scores are expected to be more sensitive to detect cognition change compared to the measures we traditionally
use. In 2019, the Food and Drug Administration released a final guidance on developing enrichment strategies
in clinical investigations to promote innovation in drug development. Treatment effect heterogeneity exists
among patients with different characteristics. Identifying subpopulations who are more likely to respond to
a new treatment at a given dose would significantly increase the success rate of AD trials and avoid the types
of issues that occurred in the aducanumab trial. Adaptive enrichment designs for AD trials will measure
the treatment effectiveness of each subpopulation at the interim analysis for futility based stopping, and can
save sample sizes compared to the existing designs. We will add a constraint on the probability of ‘wrong’
stopping for futility to avoid stopping the enrollment for a possible effective treatment on a subpopulation.
This project will provide new statistical tools for AD research to efficiently identify individuals at risk of AD
and quickly detect disease progression for AD patients with different characteristics.
Terms: <AD dementia><Active Follow-up><Aducanumab><Affect><African American><African American group><African American individual><African American people><African American population><African Americans><Afro American><Afroamerican><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer risk factor><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimer's disease patient><Alzheimer's disease risk><Alzheimer's patient><Alzheimers Dementia><Amentia><Amyloid><Amyloid Substance><Apolipoproteins><BIIB037><Biological Markers><Biology><Characteristics><Clinical Trials><Cognition><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Communities><Data><Dementia><Disease Progression><Disturbance in cognition><Dose><Drugs><Enrollment><Exposure to><Family><Food and Drug Administration><Futility><Genes><Genetic><Heterogeneity><Impaired cognition><Individual><Individuals from minority><Individuals of minority><Length><Longitudinal Studies><MT-bound tau><Measures><Medication><Memory><Methods><Minority Groups><Minority People><Minority Population><Minority individual><Modification><Outcome><Outcome Measure><Participant><Patients><Performance><Pharmaceutical Preparations><Phase 1b Trial><Phase III study><Phase Ib Trial><Primary Senile Degenerative Dementia><Probability><Publishing><Race><Races><Research><Research Design><Rest><Risk Factors><Sample Size><Study Type><Testing><Time><Treatment Effectiveness><USFDA><United States Food and Drug Administration><Visit><Visuospatial><Woman><active followup><aduhelm><alzheimer risk><bio-markers><biologic marker><biomarker><clinical investigation><cognitive ability><cognitive dysfunction><cognitive function><cognitive loss><design><designing><drug development><drug/agent><effective therapy><effective treatment><enroll><flexibility><flexible><follow up><follow-up><followed up><followup><improved><innovate><innovation><innovative><insight><long-term study><longitudinal outcome studies><longterm study><measurable outcome><men><microtubule bound tau><microtubule-bound tau><neural imaging><neuro-imaging><neuroimaging><neurological imaging><novel><open source><outcome measurement><patient living with Alzheimer's disease><patient suffering from Alzheimer's disease><patient with Alzheimer's><patient with Alzheimer's disease><phase 3 study><prevent><preventing><primary degenerative dementia><primary outcome><racial><racial background><racial origin><rate of change><response to therapy><response to treatment><senile dementia of the Alzheimer type><sex><simulation><study design><success><tau><tau Proteins><tau factor><therapeutic response><therapy response><tool><treatment effect><treatment response><treatment responsiveness><trial design><verbal><visual spatial><τ Proteins>