Apomorphine in Parkinson's Disease Patients With Visual Hallucinations

Study Overview
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Brief Summary
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This randomised, double-blind, placebo-controlled trial will evaluate the efficacy of continuous apomorphine infusion compared to placebo in PD patients with visual hallucinations, inadequately controlled with clozapine and cholinesterase inhibitors.

Detailed Description
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Introduction Visual hallucinations occur frequently in Parkinson's disease (PD). The prevalence of visual hallucinations ranges from 22 to 38%, increasing after long-term follow-up to more than 60%. Risk factors for visual hallucinations are age, disease duration, and cognitive impairment. The treatment of visual hallucinations is cumbersome and options are limited. Only clozapine has been proven to be efficacious without deteriorating the motor symptoms of PD. Instead of oral dopamine agonists and rotigotine, continuous infusion of apomorphine is well-tolerated in PD patients with cognitive impairments and/or visual hallucinations. Even beneficial effect of apomorphine on visual hallucinations are suggested, however there is lack of a randomized controlled trial. The purpose of this randomised, double-blind, placebo-controlled trial is to evaluate the efficacy of continuous apomorphine infusion compared to placebo in PD patients with visual hallucinations, inadequately controlled with clozapine and cholinesterase inhibitors.

Official Title
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Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy of Continuous Subcutaneous Infusion in Parkinson's Disease Patients With Refractory Visual Hallucinations

Conditions
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Parkinson's Disease, Hallucinations, Visual

Intervention / Treatment
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* Drug: Apomorphine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female and male subjects aged ≥30; Diagnosis of established PD, defined by the Movement Disorders Society PD criteria (Postuma et al., 2015); Presence of visual severe hallucinations defined as more than 3 times a week (van Laar et al., 2010); Visual hallucinations must have developed after PD diagnosis; Visual hallucinations must have been optimally treated with reduction of dopamine agonists if possible, and prescription of clozapine and/or cholinesterase inhibitors if needed; Female subjects must complaint with a highly effective contraceptive method (oral hormonal contraception alone is not considered highly effective and must be used in combination with a barrier method) during the study, if sexually active; Subjects should be able and capable of adhering to the protocol, visit schedules, and medication intake according to the judgement of the investigator. Exclusion Criteria: Symptomatic, clinically relevant and medically uncontrolled orthostatic hypotension; Patients with a prolonged QT interval corrected for heart rate according to Bazett's formula (QTc) of >450 ms for male and >470 ms for female at screening, or history of a long QT syndrome; PD medication change (i.e., dopamine-agonists, amantadine, monoamine oxidase (MAO)-B inhibitors, anticholinergics and cholinesterase inhibitors) in last month prior to initiation (van Laar et al., 2010); Active psychosis or a history of significant psychosis; Any medical condition that is likely to interfere with an adequate participation in the study including e.g. current diagnosis of unstable epilepsy, clinically relevant cardiac dysfunction and/or myocardial infarction or stroke within the last 12 months.

Ages Eligible for Study
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Minimum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Apomorphine<br>This arm will be treated with continuous subcutaneous infusion of apomorphine. The infusion will start with 1 mg/hr during the waking day (approximately 16 hours). The flow rate will be adjusted on a weekly basis, and may be increased with 0.5 to 1.0 mg/hr per discretion of the investigator, aiming at the disappearance of visual hallucinations. The duration of treatment is 4 weeks. | Drug: Apomorphine<br>* Continuous subcutaneous infusion of apomorphine during waking day<br>* Other names: N04BC07;|
| Placebo Comparator: Placebo<br>This arm will be treated with continuous subcutaneous infusion of placebo. The infusion will start with 1 mg/hr during the waking day (approximately 16 hours). The flow rate will be adjusted on a weekly basis, and may be increased with 0.5 to 1.0 mg/hr per discretion of the investigator aiming at the disappearance of visual hallucinations. The duration of treatment is 4 weeks. | Drug: Placebo<br>* Continuous subcutaneous infusion of placebo during waking day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Global Impression of Severity | Clinical Global Impression of Severity questionnaire | Four weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Global Impression of Improvement | Clinical Global Impression of Improvement questionnaire | Four weeks | 
| Cognition | Montreal Cognitive Assessment | Four weeks | 
| Depression | Hamilton Anxiety and Depression Scale | Four weeks | 
| Anxiety | Hamilton Anxiety and Depression Scale | Four weeks | 
| Motor symptoms | Part III of Movement Disorders Society - Unified Parkinson's Disease Rating Scale | Four weeks | 
| Motor complications | Part IV of Movement Disorders Society - Unified Parkinson's Disease Rating Scale | Four weeks | 
| Sleeping problems | Parkinson's Disease Sleep Scale | Four weeks | 
| Neuropsychiatric symptoms | Neuropsychiatric Inventory - Questionnaire | Four weeks | 
| Visual Hallucinations | Dutch Visual Hallucinations Questionnaire | Four weeks | 
| Attention | Reaction Time Task | Four weeks | 
| Visual perception | Visual Object and Space Perception battery | Four weeks | 
| Apathy | Apathy Scale | Four weeks | 
| Quality of Life | Parkinson's Disease Questionnaire (shortened version) | Four weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Apomorphine