Safety and tolerability of rosiglitazone XR in a randomised, placebo-controlled study in APOE4-stratified subjects with mild-to-moderate Alzheimer's disease

Background: Cerebral insulin resistance may contribute to Alzheimer's disease (AD). Initial studies with insulin and insulin-sensitizing compounds suggest a beneficial effect on AD. The efficacy and safety of an extended-release formulation of rosiglitazone (RSG XR) in AD were evaluated in a previous 24-week, placebo-controlled study (AVA100193) followed by a 48-week open-label extension study (AVA100468, Zvartau-Hind M, et al. Eur J Neurol. 2007;14[Suppl1]:57). RSG XR generally was safe and well tolerated for up to 72 weeks of treatment, with an overall tolerability profile consistent with that in studies in type 2 diabetes. Methods: In this double-blind, placebo-controlled study (AVA105640), 579 subjects (safety 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 for 24 weeks. Safety assessments included: adverse events (AEs), vital signs, clinical chemistry, and haematology. Results were summarized for 3 populations: APOE4-negative subjects, all subjects except those carrying 2 APOE4 alleles (all-except-E4/E4), and the full population. Results: Rates of study discontinuation due to AEs were 4-5% in the RSG XR and placebo groups and 10% in the donepezil group. The most frequent AEs were oedema, nasopharyngitis, hyperlipidaemia, diarrhoea, headache, and nausea (Table 1). The frequency of ischaemic AEs was low and similar across groups (Table 2). Serious AEs were reported for 31 subjects (4-7% across groups) and included 2 deaths (1 RSG XR 8 mg, 1 placebo). Mean values for total and LDL cholesterol increased in the RSG XR groups; the changes were small in magnitude. Changes in other laboratory parameters were consistent with the known safety profile of RSG. The safety and tolerability profiles among APOE subgroups and the full population were comparable. Conclusions: RSG XR 2 mg and 8 mg once daily for 24 weeks appeared to be well-tolerated in subjects with mild-to-moderate AD. The safety profiles in the populations assessed were comparable to that established for type 2 diabetes.

View Large Image Download to PowerPoint

View Large Image Download to PowerPoint