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


CONCLUSIONS
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.
Gold
Michael
M
Neurosciences Medicines Development Center, GlaxoSmithKline, Stockley Park, Harlow, UK. michael.2.gold@gsk.com
Alderton
Claire
C
Zvartau-Hind
Marina
M
Egginton
Sally
S
Saunders
Ann M
AM
Irizarry
Michael
M
Craft
Suzanne
S
Landreth
Gary
G
Linnamägi
Ulla
U
Sawchak
Sharon
S
D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000544:Alzheimer Disease / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D001057:Apolipoproteins E / Q000235:genetics; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D000077265:Donepezil; D064420:Drug-Related Side Effects and Adverse Reactions; D004487:Edema / Q000139:chemically induced; D005260:Female; D005838:Genotype; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects; D007189:Indans / Q000008:administration & dosage / Q000009:adverse effects; D007361:Intelligence Tests; D007406:Interview, Psychological; D008297:Male; D008875:Middle Aged; D009304:Nasopharyngitis / Q000139:chemically induced; D047495:PPAR gamma / Q000819:agonists; D010880:Piperidines / Q000008:administration & dosage / Q000009:adverse effects; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000009:adverse effects; D016896:Treatment Outcome
D001057:Apolipoproteins E; D002800:Cholinesterase Inhibitors; D007004:Hypoglycemic Agents; D007189:Indans; D047495:PPAR gamma; D010880:Piperidines; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D000077265:Donepezil