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Rosiglitazone Monotherapy in Mild-to-Moderate Alzheimer’s Disease: Results from a Randomized, Double-Blind, Placebo-Controlled Phase III StudyGold M.c · Alderton C.a · Zvartau-Hind M.a · Egginton S.b · Saunders A.M.d · Irizarry M.c · Craft S.e · Landreth G.f · Linnamägi Ü.g · Sawchak S.c
aNeurosciences Medicines Development Center, GlaxoSmithKline, Stockley Park, and bNeurosciences Medicines Development Center, GlaxoSmithKline, Harlow, UK; cNeurosciences Medicines Development Center, GlaxoSmithKline, Research Triangle Park, N.C., dDeane Drug Discovery Institute, Division of Neurology, Duke University Medical Center, Durham, N.C., eGeriatric Research, Education and Clinical Center, VA Puget Sound Health Care System and Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, Wash., and fDepartment of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA; gDepartment of Neurology and Neurosurgery, University of Tartu, Tartu, Estonia Corresponding Author
Michael Gold, MS, MD
Neurosciences Medicine Development Center
Research Triangle Park, NC (USA)
Tel. +1 919 483 8119, Fax +1 919 315 4687, E-Mail email@example.com
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.
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