Enrichment factors for clinical trials in mild-to-moderate Alzheimer's disease

Abstract

Introduction: Heterogeneity of outcomes in Alzheimer's disease (AD) clinical trials necessitates large sample sizes and contributes to study failures. This analysis determined whether mild-to-moderate AD populations could be enriched for cognitive decline based on apolipoprotein (APOE) ε4 genotype, family history of AD, and amyloid abnormalities.

Methods: Modeling estimated the number of randomized patients needed to detect a 2-point treatment difference on the AD Assessment Scale-Cognitive subscale using placebo data from three randomized, double-blind trials (ClinicalTrials.gov Identifiers: NCT01955161, NCT02006641, and NCT02006654).

Results: An 80% power to detect a 2-point treatment effect required the randomization of 148 amyloid-positive patients; 178 ε4 homozygous or amyloid-positive patients; and 231 ε4 homozygous, family history-positive, or amyloid-positive patients, compared with 1619 unenriched patients (per arm).

Discussion: Enrichment in mild-to-moderate AD clinical trials can be achieved using combinations of biomarkers/risk factors to increase the likelihood of observing potential treatment effects.

Keywords: Alzheimer's disease; Biomarkers; Clinical trial; Enrichment; Power.

Fig. 1

Distribution of biomarkers/risk factors, (A) individually and (B) in combination, among patients receiving placebo. Abbreviations: A+, Amyloid positive (n = 98 tested); APOE, apolipoprotein E; ε4+, APOE ε4 carrier; ε4++, APOE ε4 homozygous; FH+, first-degree relative with Alzheimer's disease.

Fig. 2

Mean score change from baseline among patients receiving placebo, split by individual biomarker/risk factor status. *P < .05, **P < .01, ***P < .001 versus corresponding group without the biomarker/risk factor. Error bars are 95% confidence intervals. Abbreviations: A+, Amyloid positive; AD, Alzheimer's disease; ADAS-Cog, AD Assessment Scale–Cognitive subscale; ADCS-ADL₂₃, AD Cooperative Study–Activities of Daily Living, 23-item version; ADCS-CGIC, AD Cooperative Study–Clinical Global Impression of Change; APOE, apolipoprotein E; ε4++, APOE ε4 homozygous; ε4+−, APOE ε4 heterozygous; ε4−, APOE ε4 noncarrier; FH+, first-degree relative with AD; MMSE, Mini–Mental State Examination; NPI, Neuropsychiatric Inventory.

Fig. 3

Mean score change from baseline among patients receiving placebo, split by combined enrichment group status. *P < .05, **P < .01, ***P < .001 versus corresponding nonenriched group. Error bars are 95% confidence intervals. Abbreviations: A+, Amyloid positive; AD, Alzheimer's disease; ADAS-Cog, AD Assessment Scale–Cognitive subscale; ADCS-ADL₂₃, AD Cooperative Study–Activities of Daily Living, 23-item version; ADCS-CGIC, AD Cooperative Study–Clinical Global Impression of Change; APOE, apolipoprotein E; ε4+, APOE ε4 carrier; ε4++, APOE ε4 homozygous; FH+, first-degree relative with AD; MMSE, Mini–Mental State Examination; NPI, Neuropsychiatric Inventory.

Fig. 4

Estimated study powers to detect a treatment effect based on (A) randomized and (B) screened patients. Abbreviations: A+, amyloid positive; AD, Alzheimer's disease; ADAS-Cog, AD Assessment Scale–Cognitive subscale; APOE, apolipoprotein E; ε4+, APOE ε4 carrier; ε4++, APOE ε4 homozygous; ε4+−, APOE ε4 heterozygous; FH+, first-degree relative with AD; Optimal, optimal power curve (full 2-point treatment effect on the ADAS-Cog. no withdrawal); Phase 3, total phase 3 population.