Tolerability, safety, and efficacy of the 1-step titration scheme of rivastigmine patch 10 cm2 in japanese patients with mild-to-moderate Alzheimer’s disease: A 24-week randomized controlled study

A one-step titration schedule for rivastigmine patch (initiated at 5 cm2 [9 mg/day] and titrated to 10 cm2 [18 mg/day] after 4 weeks) is used to treat patients with Alzheimer's disease (AD) outside Japan. The currently-approved schedule in Japan is a 3-step titration (initiated at 2.5 cm2 [4.5 mg/day] and titrated by 2.5 cm2 every 4 weeks to 10 cm2), requiring at least 12 weeks to reach the effective dose (10 cm2). We investigated whether a 1-step titration of the rivastigmine patch is well-tolerated and effective in Japanese patients with AD, in comparison with a 3-step titration. This 24-week, multicenter, parallel-group, randomized, double-blind study was conducted in Japan between July 2012 and May 2014. Patients with mild-to-moderate AD (Mini-Mental State Examination [MMSE] 10-20) aged 50 to 85 years were randomized 1:1 to either a 1-step or 3-step titration schedule. The primary endpoint was the proportion of patients with adverse events (AEs) leading to treatment discontinuation. If the between-treatment difference was within the pre-specified acceptance range of ±9.0%, 1-step titration was determined to be as well-tolerated as 3-step titration. Secondary endpoints included efficacy parameters: AD Assessment Scale Japan-Cognitive Subscale, MMSE, and Japanese-Clinical Global Impression of Change. Of 216 patients randomized, 170 patients (78.7%) completed the study. All but one of the randomized patients were included in the safety analysis (1-step, 107; 3-step, 108). The proportion of patients discontinuing treatment due to AEs was 15.0% (16/107) in the 1-step group and 18.5% (20/108) in the 3-step group. The observed difference between treatments of the proportion of discontinuation due to AEs (1-step titration group – 3-step titration group) was −3.6% (95% confidence interval: −17.0, 9.6). Since the point-estimate of the observed difference falls within the pre-specified range, the study met its primary objective. The reported AEs were similar between the groups. The study showed similar efficacy between both groups at Week 24. These data support the use of a 1-step titration schedule for Japanese patients with mild-to-moderate AD.