Cholinesterase Inhibitors to Slow Progression of Visual Hallucinations in Parkinson&Apos;s Disease (CHEVAL)
Rationale: 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, and that brain network analysis is suitable to predict treatment response.
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, mood disorders, daytime sleepiness, adverse events and compliance, disability, caregiver burden and care use. We assess the cost-effectiveness of early chronic treatment of VH with ChEI. Finally, we analyse changes of functional brain networks before and during treatment.
Study design: A randomized, double blind, placebo-controlled, multi-center trial with an economic evaluation.
Study population: 168 patients with PD and VH after fulfilling the in-and exclusion criteria.
Intervention: Rivastigmine capsule 6 mg BID or placebo BID for 24 months.
Main study parameters/endpoints: The primary outcome measure is the median time until PD patients with minor VH progress to major VH without insight. The clinical endpoint is defined as the start with antipsychotic treatment. Secondary outcome measures are changes in motor control, psychotic symptoms, cognitive impairment, mood disorders, daytime sleepiness, cholinergic deficiency, the number of adverse events, compliance, disability and caregiver burden. The median time until PD patients with minor VH progress to PD dementia is measured by means of changes in cognitive function. The secondary neurophysiological outcome measures are peak frequency, functional connectivity, topological network organisation and the direction of information flow. All relevant costs will be measured and valued.
Nature and extent of the burden and risks associated with participation, benefit and group relatedness: The burden of participation consists of a total of 5 clinical visits (every 6 months), 5 telephone interviews on adverse events during the escalation phase and 9 questionnaires on health related costs (every 3 months). In a subgroup 3 additional visits for EEG recording are needed. There is a risk for adverse reactions with rivastigmine treatment; the most common are nausea and vomiting.
Drug: Placebo (for rivastigmine)
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
|Official Title:||Cholinesterase Inhibitors to Slow Progression of Visual Hallucinations in Parkinson's Disease:a Multi-center Placebo-controlled Trial.|
- time to start with antipsychotic treatment for visual hallucinations [ Time Frame: 24 months ] [ Designated as safety issue: Yes ]the time until Parkinson's disease patients with minor visual hallucinations progress to major visual hallucinations without insight (according to UPDRS 1 - MDS). The clinical endpoint is defined as the start with antipsychotic treatment.
- motor control [ Time Frame: 24 months ] [ Designated as safety issue: No ]change in motor control measured by UPDRS 3 - MDS
- psychotic symptoms [ Time Frame: 24 months ] [ Designated as safety issue: No ]change in occurence or severity of psychotic symptoms according to Scale of Assessment of Positive Symptoms (SAPS) and UPDRS 1 MDS.
- cognitive function [ Time Frame: 24 months ] [ Designated as safety issue: No ]change in cognitive function as measured by Mini Mental State Examination, Montreal Cognitive Assessment, Parkinson's Disease - Cognitive Rating Scale
- mood disturbance [ Time Frame: 24 months ] [ Designated as safety issue: No ]Mood disturbance according to the Hospital Anxiety and Depression Scale
- daytime sleepiness [ Time Frame: 24 months ] [ Designated as safety issue: No ]Daytime sleepiness on the Epworth Sleepiness Scale
- cholinergic deficiency [ Time Frame: 24 months ] [ Designated as safety issue: No ]Cholinergic deficiency, as a possible predictor for response to treatment, measured with the Cholinersterase Inhibitor Prognosticator
- adverse events [ Time Frame: 24 months ] [ Designated as safety issue: Yes ]Number and type of adverse events
- compliance [ Time Frame: 24 monhts ] [ Designated as safety issue: No ]Compliance to treatment measured by the number of remaining capsules after every 6 months of follow-up
- disability [ Time Frame: 24 months ] [ Designated as safety issue: No ]Disability based on the AMC Linear Disability Score
- caregiver burden [ Time Frame: 24 months ] [ Designated as safety issue: No ]Caregiver burden according to the Zarit Caregiver Burden Inventory
- care use [ Time Frame: 24 months ] [ Designated as safety issue: No ]Care use measured with the EuroQol-5D
- EEG power analysis [ Time Frame: 12 months ] [ Designated as safety issue: No ]peak frequency / relative power analysis
- EEG functional connectivity [ Time Frame: 12 months ] [ Designated as safety issue: No ]functional connectivity (phase lag index)
- EEG topological network organisation [ Time Frame: 12 months ] [ Designated as safety issue: No ]topological network organisation (minimum spanning tree)
- EEG flow direction [ Time Frame: 12 months ] [ Designated as safety issue: No ]direction of information flow (directed phase lag index)
- EEG frequency band analysis [ Time Frame: 12 months ] [ Designated as safety issue: No ]EEG analysis per frequency band
|Study Start Date:||November 2013|
|Estimated Study Completion Date:||December 2018|
|Estimated Primary Completion Date:||December 2018 (Final data collection date for primary outcome measure)|
Placebo Comparator: Placebo
placebo capsule for oral use 6,0 mg BID during 24 months of follow-up
Drug: Placebo (for rivastigmine)
Capsule. Dose 3,0 - 6,0 mg BID
Other Name: Placebo
rivastigmine capsule for oral use 6,0 mg BID during 24 months of follow-up
Capsule. Dose 3,0 - 6,0 mg BID
Other Name: Exelon
Show Detailed Description
Please refer to this study by its ClinicalTrials.gov identifier: NCT01856738
|Contact: Tom van Mierlo, firstname.lastname@example.org|
|Contact: Elisabeth Foncke, email@example.com|
|Academic Medical Center||Recruiting|
|Amsterdam, Netherlands, 1100 DD|
|Contact: Rob de Bie, dr 003120-5663415 firstname.lastname@example.org|
|Principal Investigator: Rob de Bie, Dr|
|University Medical Center Groningen||Recruiting|
|Groningen, Netherlands, 9700 RB|
|Contact: Teus van Laar, Dr 003150-3612449 email@example.com|
|Principal Investigator: Teus van Laar, Dr|
|Atrium Medical Center||Recruiting|
|Heerlen, Netherlands, 6401 CX|
|Contact: Gerrit Tissingh 003145-5766666 firstname.lastname@example.org|
|Principal Investigator: Gerrit Tissingh, Dr|
|University Medical Center St Radboud||Recruiting|
|Nijmegen, Netherlands, 6500 HB|
|Contact: Bart Post, dr 003124-3615202 email@example.com|
|Principal Investigator: Bart Post, Dr|
|Principal Investigator:||Elisabeth Foncke, Dr.||VU University Medical Center|