O1‐04‐06: Effects of rosiglitazone as monotherapy in APOE4‐stratified subjects with mild‐to‐moderate Alzheimer's disease

A phase 2 study of the PPARγ agonist, rosiglitazone extended release (RSG XR), in mild-to-moderate Alzheimer's disease (AD) detected a treatment effect on cognition that appeared to depend on APOE4 allele status (AVA100193, Risner ME, et al. Pharmacogenom J. 2006;6:246-254). The APOE4-negative group improved compared with placebo, whereas the APOE4-positive group did not. The current study was designed to enable rigorous evaluation of effects in APOE subgroups. In this double-blind, placebo-controlled study (AVA105640), 553 subjects (ITT population) with mild-to-moderate AD (MMSE score 10-23 at screening) were genotyped and stratified into APOE4-positive (1 or 2 copies of APOE4) and APOE4-negative (no APOE4 alleles) groups. Within each stratum, following a 4-week placebo run-in period, subjects were randomised in a 2:2:2:1 ratio to placebo, RSG XR 2 mg/day, RSG XR 8 mg/day, or donepezil 10 mg/day (positive control) for 24 weeks. Co-primary efficacy endpoints were change from baseline in the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) score and the Clinician's Interview-Based Impression of Change with caregiver input (CIBIC+) score at week 24. Repeated measures analysis was conducted for 3 populations: APOE4-negative subjects, all subjects except those carrying 2 APOE4 alleles (all-except-E4/E4 population), and the full population. Safety and tolerability were also assessed. Baseline characteristics were comparable across treatment groups (Table 1) and analysis populations. At week 24, no statistically significant differences between RSG XR 2 mg or 8 mg and placebo were detected in the co-primary endpoints in any of the populations assessed (Table 2). For donepezil, no significant differences from placebo were detected for change in ADAS-Cog score; however, differences from placebo on the CIBIC+ score were significant in the all-except-E4/E4 and full populations (Table 2). The safety and tolerability of rosiglitazone and donepezil were consistent with their known pharmacology. The study did not detect any statistically significant effects of RSG XR monotherapy on cognition or global function. Changes in cognition for donepezil were not significant compared to placebo, but changes in global function did achieve statistical significance, suggesting that this study had adequate assay sensitivity.