A phase II study in patients with Alzheimer's disease to assess the preliminary efficacy and maximum tolerated dose of rivastigmine (Exelon).

Rivastigmine is a carbamate acetylcholinesterase (AChE) inhibitor with central selectivity. Early studies showed that daily doses up to 6 mg/day have some efficacy in patients with dementia of the Alzheimer type (DAT). The present study was designed to assess the safety, tolerability and efficacy of rivastigmine at doses up to 12 mg/day. A total of 114 patients with mild-moderate DAT were randomly assigned to either rivastigmine (b.i.d. (twice daily) or t.i.d. (three times daily)) or placebo in a double-blind fashion titrated to their maximum tolerated dose over 10 weeks followed by an eight-week maintenance phase. The mean maximum tolerated dose was approximately 10 mg/day (b.i.d. or t.i.d.). Gastrointestinal complaints, the majority of which were mild to moderate, were the most frequently reported adverse events. No clinically relevant changes in vital signs, haematology or organ function were detected. Significantly more patients taking rivastigmine b.i.d. were considered improved according to the Clinicians' Interview-Based Impression of Change-Plus (CIBIC-Plus) vs. placebo (57% vs. 16%, respectively; P = 0.027). The Nurses' Observation Scale for Geriatric Patients (NOSGER) (memory component) and the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) also improved in the rivastigmine b.i.d. group vs. placebo (mean change from baseline on NOSGER = -0.7 vs. +1.3, respectively; P = 0.037: mean change from baseline on ADAS-cog = -2.7 vs. +0.2, respectively; P = 0.054). Despite the relatively small size and limited duration of the study, the finding that rivastigmine induced changes in the same (positive) direction in all three dimensions measured suggests that rivastigmine at doses of up to 12 mg/day has useful efficacy in patients with mild-moderate DAT. Reports from larger phase III studies confirm this finding. The results of this study also suggest that b.i.d. is the more efficacious regimen and has comparable tolerability to the t.i.d. regimen.