Objective: To evaluate the long-term efficacy of donepezil on global function, cognition, and Activities of Daily Living (ADL) in patients with mild to moderate Alzheimers disease (AD), and assess the influence of a 1-year delay in treatment initiation.
Design: 286 patients were enrolled into a 1-year, randomized, double-blind study. At end of Year 1, 81 donepezil- and 76 placebo-treated patients entered into a 2-year open-label extension study.
Methods: All patients in the extension study received donepezil, 5 mg/day for 4 weeks followed by 10 mg/day, where possible, for 2 years. Efficacy outcome measures included the Gottfries-Brćne Scale (GBS), the Mini-Mental State Examination (MMSE), the Global Deterioration Scale (GDS) and the Progressive Deterioration Scale (PDS). Patients were assessed at Weeks 12, 24, 36, 52, 78, 104, 130 and 156. Mixed regression analysis compared changes on these measures between continuously treated donepezil patients and those with a 1-year delayed treatment start, over 3 years. A reference projected placebo group was calculated using data from placebo patients during the double-blind period.
Results: 56 (69.1%) patients receiving continuous donepezil treatment and 58 (76.3%) in the delayed-start group completed the 2-year extension. Patients receiving donepezil for 3 years had significantly less cognitive decline than those with a delayed start (Overall: P=0.004). A significant treatment difference in favor of continuous donepezil treatment was observed at Week 156 on the MMSE (P<0.05). Patients receiving continuous therapy had less global deterioration, measured on GBS, than those with delayed treatment (P=0.056). This was supported by the more favorable response of 3 years continuous donepezil treatment compared with delayed treatment, as measured by the GDS (P = 0.02). As expected, following initiation of donepezil treatment at Year 1, patients originally randomized to placebo showed a slower functional decline on the PDS, between treatment Weeks 52 and 78, than those who received continuous donepezil. By the end of the study (Week 156) patients in both groups had reached the same level of change, although overall, there was a trend in favor of continuous treatment (PDS: P=0.09). Delayed-start patients showed benefits in global and cognitive functioning and ADL compared with the projected placebo group.
Conclusions: Patients who received continuous donepezil treatment maintained greater levels of global function, cognition and ADL than those who had a 1-year treatment delay. However, receiving donepezil after a 1-year treatment delay also resulted in benefits when compared with no treatment.
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