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

Abstract

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.

Keywords: Cholinesterase inhibitor; Dementia; Hyposmia; Parkinson's disease; Prevention.

Figure 1

Trial flow chart. PD=Parkinson's disease, FAS=full analysis set

Figure 2

Proportion of patients with a) a CDR stage of 0 and b) a CDR sum of boxes score of 0 among each treatment group at every 26-week visit. CDR=Clinical Dementia Rating. ^aCDR stage: 0 = no dementia, 0.5 = questionable dementia, 1 = mild dementia, 2 = moderate dementia, and 3 = severe dementia. ^bThe CDR sum of boxes score (range: 0-18) is a total score of six domains of cognitive and functional performance (each rated as 0, 0.5, 1, 2, or 3).

Figure 3

Proportions of patients who reported urinary problems, constipation, lightheadedness on standing, fatigue and tremor in the MDS-UPDRS among each group. MDS-UPDRS=Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale.