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

NCT01856738 | Terminated Phase 4 DMC

• 2 other identifiers: NL44622.029.132013-001722-25
• Study Type: interventional
• Target: 91
• Locations: 1 country
• Sites: 4

Brief Summary

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.

Conditions

Parkinson's Disease

Keywords

Parkinson's disease; Visual hallucinations; Rivastigmine; Cholinesterase inhibitor; Randomized controlled trial; Cost-effectiveness analysis

Outcome Measures

Primary Outcomes (1)

• time to start with antipsychotic treatment for visual hallucinations

  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.

  24 months

Secondary Outcomes (16)

• motor control

  24 months

• psychotic symptoms

  24 months

• cognitive function

  24 months

• mood disturbance

  24 months

• daytime sleepiness

  24 months

Study Arms (2)

Placebo

PLACEBO COMPARATOR

placebo capsule for oral use 6,0 mg BID during 24 months of follow-up

Drug: Placebo (for rivastigmine)

Rivastigmine

EXPERIMENTAL

rivastigmine capsule for oral use 6,0 mg BID during 24 months of follow-up

Drug: Rivastigmine

Interventions

Rivastigmine DRUG

Capsule. Dose 3,0 - 6,0 mg BID

Also known as: Exelon

Rivastigmine

Placebo (for rivastigmine) DRUG

Capsule. Dose 3,0 - 6,0 mg BID

Also known as: Placebo

Placebo

Eligibility Criteria

• Age: 40 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Amsterdam UMC, location VUmc: lead
• Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA): collaborator
• Atrium Medical Center: collaborator
• University Medical Center Groningen: collaborator
• Leiden University Medical Center: collaborator
• University Medical Center Nijmegen: collaborator
• International Parkinson Fonds Germany GmbH: collaborator
• ZonMw: The Netherlands Organisation for Health Research and Development: collaborator

Study Sites (4)

Academic Medical Center

Amsterdam, 1100 DD, Netherlands

Location

University Medical Center Groningen

Groningen, 9700 RB, Netherlands

Location

Atrium Medical Center

Heerlen, 6401 CX, Netherlands

Location

University Medical Center St Radboud

Nijmegen, 6500 HB, Netherlands

Location

MeSH Terms

Conditions

Parkinson Disease; Hallucinations

Interventions

Rivastigmine

Condition Hierarchy (Ancestors)

Parkinsonian Disorders; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Perceptual Disorders; Neurobehavioral Manifestations; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Phenylcarbamates; Carbamates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals

Study Officials

• Elisabeth Foncke, Dr.

  Amsterdam UMC, location VUmc

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: drs T.J.M. van Mierlo

Study Record Dates

• First Submitted: May 14, 2013
• First Posted: May 17, 2013
• Study Start: November 1, 2013
• Primary Completion: September 1, 2018
• Study Completion: September 1, 2018
• Last Updated: October 9, 2018

Record last verified: 2018-10

Locations

NL (4)