Long-term donepezil use for dementia with Lewy bodies: results from an open-label extension of Phase III trial

Etsuro Mori, Manabu Ikeda, Reiko Nagai, Kazutaka Matsuo, Masaki Nakagawa, Kenji Kosaka, Etsuro Mori, Manabu Ikeda, Reiko Nagai, Kazutaka Matsuo, Masaki Nakagawa, Kenji Kosaka

Abstract

Introduction: The long-term efficacy and safety of donepezil 10 mg in patients with dementia with Lewy bodies (DLB) were investigated in a 52-week Phase 3 trial.

Methods: This 52-week study consisted of 16-week randomized placebo-controlled (RCT) and 36-week open-label extension phases. Of 142 DLB patients enrolled in the RCT phase (three arms: placebo, 5 mg, and 10 mg), 110 entered the extension phase. The placebo group of the RCT phase initiated active treatment at week 16, and the active groups maintained allocated treatment and dosages until week 24. After week 24, all patients received 10 mg. Dose reduction to 5 mg for safety concerns was allowed. Efficacy measures included Mini-Mental State Examination (MMSE) for cognitive function and Neuropsychiatric Inventory (NPI) for behavioral symptoms. Safety evaluations included adverse events (AEs) and the unified Parkinson disease rating scale.

Results: In total, 100 subjects completed the study. Cognitive function improvement was sustained for 52 weeks (MMSE at week 52 in 10 mg: 2.8 ± 3.5 (mean ± standard deviation); P <0.001, Student paired t test)). Those who received placebo in the RCT phase showed an improvement after starting active treatment. NPI improved in all the groups throughout the study, including the placebo period. In the subgroup of the 5 mg group without remarkable cognitive or behavioral improvement at week 24, further improvement was observed after a dose increase to 10 mg. After week 24, 21 patients experienced dose reduction. The incidence of any AEs did not increase over time.

Conclusions: The long-term administration of donepezil at 10 mg/day improved cognitive function for up to 52 weeks in patients with DLB without increasing the risk of clinically significant safety events.

Trial registration: NCT01278407. Trial registration date: January 14, 2011.

Figures

Figure 1
Figure 1
Study flow. RCT, randomized placebo-controlled.
Figure 2
Figure 2
Patient disposition.
Figure 3
Figure 3
Mean change in MMSE from baseline (FAS). MMSE, Mini-Mental State Examination; FAS, full-analysis set. (a) PLA-DON10 group started treatment with 3 mg at Week 16, and the dose was increased to 5 mg at Week 18. (b) PLA-DON10 and DON5-DON10 groups started treatment with 10 mg at Week 24 (dose decrease to 5 mg was allowed). *P < 0.05 (paired t test versus Week 0).
Figure 4
Figure 4
Mean MMSE change in subgroups of improved and less-improved by 5 mg (FAS, DON5-DON10 group). MMSE, Mini-Mental State Examination; FAS, full analysis set; LOCF, last observation carried forward. (a)The cognitively improved by 5 mg is defined as a patient with 3 points or more improvement in the MMSE score at Week 24, and the less-improved as a patient with fewer than 3 points improvement. (b)Treatment with 10 mg started at Week 24 (dose decrease to 5 mg was allowed). *P < 0.05 (paired t test versus Week 24).
Figure 5
Figure 5
Mean change in NPI-2 from baseline (FAS). NPI, Neuropsychiatric Inventory; FAS, full analysis set. (a)PLA-DON10 group started treatment with 3 mg at Week 16, and the dose was increased to 5 mg at Week 18. (b)PLA-DON10 and DON5-DON10 groups started treatment with 10 mg at Week 24 (dose decrease to 5 mg was allowed). *P < 0.05 (paired t test).
Figure 6
Figure 6
Mean NPI-2 change in subgroups of improved and less improved by 5 mg (FAS, DON5-DON10 group). NPI, Neuropsychiatric Inventory; FAS, full analysis set; LOCF, last observation carried forward. (a)The behaviorally improved by 5 mg is defined as a patient with 30% or more improvement in NPI-2 score at Week 24, and the less-improved as a patient with less than 30% improvement. (b)Treatment with 10 mg started at Week 24 (dose decrease to 5 mg was allowed). *P < 0.05 (paired t test versus Week 24).
Figure 7
Figure 7
Mean change in ZBI from baseline (FAS). ZBI, Zarit Caregiver Burden Interview; FAS, full analysis set. (a)PLA-DON10 group started treatment with 3 mg at Week 16, and the dose was increased to 5 mg at Week 18. (b)PLA-DON10 and DON5-DON10 groups started treatment at 10 mg from Week 24 (dose decrease to 5 mg was allowed). *P < 0.05 (paired t test).

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