Effect of donepezil for dementia prevention in Parkinson's disease with severe hyposmia (The DASH-PD study): A randomized long-term placebo-controlled trial.

BACKGROUND

Dementia greatly contributes to poor prognosis in patients with Parkinson's disease (PD). We previously reported that severe olfactory dysfunction may be a good predictor of Parkinson's disease dementia (PDD). In this trial, we investigated whether early administration of donepezil to patients with severe hyposmia can reduce the development of PDD.

METHODS

This was a multi-centre, randomized, double-blind, parallel group, placebo-controlled trial in patients with non-demented PD with severe hyposmia (The Donepezil Application for Severe Hyposmic Parkinson's Disease [DASH-PD] study). A total of 201 patients were randomly allocated to receive donepezil or placebo in addition to standard therapy for PD. Patients were followed up every 6 months until the onset of PDD or for a maximum of 4 years. The primary endpoint was the onset of dementia. The secondary endpoint was cognitive impairment measured by Addenbrooke's Cognitive Examination-Revised (ACE-R) and the Clinical Dementia Rating (CDR).(UMIN000009958: February 2013 to May 2019).

FINDINGS

A total of 201 hyposmic patients with PD were randomly assigned to a treatment: 103 to donepezil and 98 to placebo. Overall, 141 (70%) patients completed the 4-year intervention. During follow-up, 7 of 103 (6.8%) patients in the donepezil group and 12 of 98 (12.2%) patients in the placebo group developed PDD; however, the hazard ratio of PDD incidence was not statistically significant (hazard ratio (HR), 0.609; 95% confidence interval, 0.240 to 1.547;  = 0.2969). At week 208, the patients in the donepezil group had better scores on the ACE-R ( < 0.005) and the CDR ( < 0.005) than those taking placebo.

INTERPRETATION

Administration of donepezil to PD patients with severe olfactory dysfunction for 4 years did not change the incidence of dementia but had a beneficial effect on neuropsychological function, with good tolerability.

FUNDING

The Ministry of Health Labour and Welfare and the Japan Agency for Medical Research and Development provided funding for this study.