Visual hallucinations (VH) are the most common non-motor symptoms in Parkinson’s disease (PD). As an independent predictor for cognitive decline and nursing home placement they form an important disability milestone in the course of PD. According to current clinical guidelines minor VH do not require treatment per se. But as minor VH precede the stage of major VH without insight and PD associated psychosis (PDP) they offer an opportunity for early intervention. Neuroleptic drugs delay the transition into PDP but are unsuitable for early treatment of VH due to their side effects. We hypothesize that cholinesterase inhibitors (ChEI) are a well-tolerated alternative for the early treatment of minor VH to delay the progression to PDP.
Objective: investigate whether early treatment with ChEI delays the progression of minor VH to major VH without insight or PDP. In addition, we will measure motor control, psychotic symptoms, cognitive impairment, adverse events, quality of life, caregiver burden and care use. We assess the cost-effectiveness of early chronic treatment of VH with ChEI.
Study design: a randomized, double blind, placebo-controlled, multi-center trial with an economic evaluation.
Intervention: rivastigmine capsule 6 mg BID for 24 months or placebo BID for 24 months.
Outcome measures: the primary outcome is the proportion of patients that lose insight or convert to PDP. This endpoint is defined as (1) a score of 3 or 4 respectively on the UPDRS1-MDS thought disorder item or (2) the need to start treatment with atypical neuroleptic drugs.
Secondary outcome measures are motor control (UPDRS III), psychotic symptoms (BPRS), cognitive impairment (MMSE), the number of adverse events, quality of life (PDQOL), caregiver burden (ZCBI), and care use. All relevant costs will be measured and valued.
Sample size/Data analysis: assuming that 65% of the patients treated with placebo and 40% treated with ChEI will reach the primary study endpoint in 24 months, we aim to include 166 patients (83 per arm) to detect this difference with 80% power and a 25% estimated withdrawal rate. The proportional difference will be analyzed with a Chi square test. The median time-to-event will be analyzed with Kaplan-Meier Survival Analysis and the Logrank test. The economic evaluation will be performed from a societal perspective; cost-effectiveness ratios, planes and acceptability curves will be estimated with bootstrapping techniques.
Time schedule: preparations will take 2 months, inclusion will take 24 months, follow-up of 24 months and analysis 3 months. Results are expected after 53 months.