Rosiglitazone monotherapy in mild-to-moderate Alzheimer's disease: results from a randomized, double-blind, placebo-controlled phase III study

Abstract

Background/aims: A phase II study of the peroxisome proliferator-activated receptor-γ agonist rosiglitazone extended release (RSG XR) in mild-to-moderate Alzheimer's disease (AD) detected a treatment benefit to cognition in apolipoprotein E(APOE)-ε4-negative subjects. The current phase III study with prospective stratification by APOE genotype was conducted to confirm the efficacy and safety of RSG XR in mild-to-moderate AD. An open-label extension study assessed the long-term safety and tolerability of 8 mg RSG XR.

Methods: This double-blind, randomized, placebo-controlled study enrolled 693 subjects. Within 2 APOE allelic strata (ε4-positive, ε4-negative), subjects were randomized (2:2:2:1) to once-daily placebo, 2 mg RSG XR, 8 mg RSG XR or 10 mg donepezil (control). Coprimary endpoints were change from baseline to week 24 in the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog) score, and week 24 Clinician's Interview-Based Impression of Change plus caregiver input (CIBIC+).

Results: At week 24, no significant differences from placebo in change from baseline in coprimary endpoints were detected with either the RSG XR dose in APOE-ε4-negative subjects or overall. For donepezil, no significant treatment difference was detected in ADAS-Cog; however, a significant difference was detected (p = 0.009) on the CIBIC+. Peripheral edema was the most common adverse event for 8 mg RSG XR (15%) and placebo (5%), and nasopharyngitis for 2 mg RSG XR (7%).

Conclusion: No evidence of efficacy of 2 mg or 8 mg RSG XR monotherapy in cognition or global function was detected in the APOE-ε4-negative or other analysis populations. The safety and tolerability of RSG XR was consistent with its known pharmacology.

Trial registration: ClinicalTrials.gov NCT00428090 NCT00550420.

Fig. 1

Study design.

Fig. 2

Primary endpoint testing hierarchy.

Fig. 3

Subject disposition. PV = Protocol violation. ^a58 subjects failed run-in. ^bTwo randomized subjects (1 in the placebo and 1 in the donepezil group) did not take the study drug. ^c6 subjects in the placebo group, 4 in the 2-mg group, 9 in the 8-mg group, and 7 in the donepezil group had no postbaseline efficacy data.

Fig. 4

Adjusted means (95% CI) for the coprimary endpoints. a ADAS-Cog score change from baseline at week 24. b CIBIC+ score at week 24. ^aUnadjusted p.