Cholinesterase Inhibitors to Slow Progression of Visual Hallucinations in Parkinson&Apos;s Disease (CHEVAL)

This study is currently recruiting participants. (see Contacts and Locations)
Verified December 2015 by VU University Medical Center
Sponsor:
Collaborators:
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Atrium Medical Center
University Medical Center Groningen
Leiden University Medical Center
University Medical Center Nijmegen
International Parkinson Fonds Germany GmbH
ZonMw: The Netherlands Organisation for Health Research and Development
Information provided by (Responsible Party):
Tom van Mierlo, VU University Medical Center
ClinicalTrials.gov Identifier:
NCT01856738
First received: May 14, 2013
Last updated: December 28, 2015
Last verified: December 2015
  Purpose

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.


Condition Intervention Phase
Parkinson's Disease
Drug: Rivastigmine
Drug: Placebo (for rivastigmine)
Phase 4

Study Type: Interventional
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.

Resource links provided by NLM:


Further study details as provided by VU University Medical Center:

Primary Outcome Measures:
  • 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.


Secondary Outcome Measures:
  • 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


Estimated Enrollment: 168
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)
Arms Assigned Interventions
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
Experimental: Rivastigmine
rivastigmine capsule for oral use 6,0 mg BID during 24 months of follow-up
Drug: Rivastigmine
Capsule. Dose 3,0 - 6,0 mg BID
Other Name: Exelon

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   40 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • idiopathic PD with bradykinesia and at least two of the following signs; resting tremor, rigidity, and asymmetry (in accordance with clinical diagnostic criteria of the UK PD Society Brain Bank);
  • the presence of minor VH for at least 4 weeks, defined by a score of 1 or 2 on the hallucinations item of the Unified Parkinson's Disease rating Scale (UPDRS)1-MDS;
  • age 40 years and over.

Exclusion Criteria:

  • Parkinson's Disease Psychosis, defined as the need for antipsychotic drug treatment in the opinion of the treating neurologist;
  • Parkinson's Disease Dementia, defined by a score < 24 on the Mini Mental State Examination (MMSE);
  • current delirium (caused by infection or metabolic disturbance);
  • current treatment with amantadine (Symmetrel) or anti-cholinergics, such as trihexyfenidyl (Artane) or biperideen (Akineton);
  • current or recent (<6 months) treatment with Cholinesterase inhibitor, such as rivastigmine (Exelon) or galantamine (Reminyl);
  • recent (<1 month) change in dopaminergic therapy;
  • history of psychosis or severe ophtalmologic disease (e.g. Charles Bonnet syndrome);
  • permanent stay in a nursing home;
  • no informed consent.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01856738

Contacts
Contact: Tom van Mierlo, drs 0031204440708 t.vanmierlo@vumc.nl
Contact: Elisabeth Foncke, dr 0031204442834 e.foncke@vumc.nl

Locations
Netherlands
Academic Medical Center Recruiting
Amsterdam, Netherlands, 1100 DD
Contact: Rob de Bie, dr    003120-5663415    r.m.debie@amc.uva.nl   
Principal Investigator: Rob de Bie, Dr         
University Medical Center Groningen Recruiting
Groningen, Netherlands, 9700 RB
Contact: Teus van Laar, Dr    003150-3612449    t.van.laar@umcg.nl   
Principal Investigator: Teus van Laar, Dr         
Atrium Medical Center Recruiting
Heerlen, Netherlands, 6401 CX
Contact: Gerrit Tissingh    003145-5766666    g.tissingh@atriummc.nl   
Principal Investigator: Gerrit Tissingh, Dr         
University Medical Center St Radboud Recruiting
Nijmegen, Netherlands, 6500 HB
Contact: Bart Post, dr    003124-3615202    b.post@neuro.umcn.nl   
Principal Investigator: Bart Post, Dr         
Sponsors and Collaborators
VU University Medical Center
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Atrium Medical Center
University Medical Center Groningen
Leiden University Medical Center
University Medical Center Nijmegen
International Parkinson Fonds Germany GmbH
ZonMw: The Netherlands Organisation for Health Research and Development
Investigators
Principal Investigator: Elisabeth Foncke, Dr. VU University Medical Center
  More Information

Additional Information:
Responsible Party: Tom van Mierlo, drs T.J.M. van Mierlo, VU University Medical Center
ClinicalTrials.gov Identifier: NCT01856738     History of Changes
Other Study ID Numbers: NL44622.029.13  2013-001722-25 
Study First Received: May 14, 2013
Last Updated: December 28, 2015
Health Authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

Keywords provided by VU University Medical Center:
Parkinson's disease
Visual hallucinations
Rivastigmine
Cholinesterase inhibitor
Randomized controlled trial
Cost-effectiveness analysis

Additional relevant MeSH terms:
Parkinson Disease
Hallucinations
Parkinsonian Disorders
Basal Ganglia Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Movement Disorders
Neurodegenerative Diseases
Perceptual Disorders
Neurobehavioral Manifestations
Neurologic Manifestations
Signs and Symptoms
Cholinesterase Inhibitors
Rivastigmine
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Cholinergic Agents
Neurotransmitter Agents
Physiological Effects of Drugs
Neuroprotective Agents
Protective Agents

ClinicalTrials.gov processed this record on August 24, 2016