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; p = 0.2969).

At week 208, the patients in the donepezil group had better scores on the ACE-R (p < 0.005) and the CDR (p < 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.