Protocol for a randomised controlled trial: efficacy of donepezil against psychosis in Parkinson's disease (EDAP)

Introduction: Psychosis, including hallucinations and delusions, is one of the important non-motor problems in patients with Parkinson's disease (PD) and is possibly associated with cholinergic neuronal degeneration. The EDAP (Efficacy of Donepezil against Psychosis in PD) study will evaluate the efficacy of donepezil, a brain acetylcholine esterase inhibitor, for prevention of psychosis in PD. Methods and analysis: Psychosis is assessed every 4 weeks using the Parkinson Psychosis Questionnaire (PPQ) and patients with PD whose PPQ-B score (hallucinations) and PPQ-C score (delusions) have been zero for 8 weeks before enrolment are randomised to two arms: patients receiving donepezil hydrochloride or patients receiving placebo. The patients are then followed for 96 weeks. The primary outcome measure is the time to the event, defined as getting 2 points or more on the PPQ-B score or PPQ-C score, which is assessed using a survival time analysis. The hypothesis being tested is that donepezil prevents psychosis in patients with PD. Efficacy will be tested statistically using the intention-to-treat analysis including a log-rank test or Cox proportional hazard models. Secondary outcomes, such as changes of PPQ scores and Unified Parkinson's Disease Rating Scale scores from baseline will be assessed. Ethics and dissemination: Ethics approval was received from the Central Review Board of the National Hospital Organization, Tokyo, Japan. The trial was declared and registered to the Pharmaceuticals and Medical Devices Agency(PMDA), Japan (No. 22-4018). All participants will receive a written informed consent that was approved by the Central Review. A completed written informed consent is required to enrol in the study. Severe adverse events will be monitored by investigators and in cases where a severe adverse event was previously unreported, it will be reported to the PMDA.