Efficacy and Safety of Melatonin PR and Clonazepam in Patients With REM Sleep Behavior Disorder in Parkinson Disease

Study Overview
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Brief Summary
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The purpose of this study is to determine whether melatonin prolonged-release (PR) and clonazepam are effective and safe in the treatment of rapid eye movement behavior disorder (RBD) of patients with Parkinson's disease (PD).

Detailed Description
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RBD is one of the representative non-motor symptoms of PD. Patients with RBD show dream-enacting behaviors such as punching, kicking, singing, screaming, or somnambulism. These can interfere in sleep quality and increase the risk of falling down from the bed and physical injuries of both the patient and sleep partner. Therefore, qualities of life of the patient and sleep partner are negatively influenced by presence of RBD. Clonazepam has been used for treatment of choice of RBD. However, the efficacy of clonazepam is not proven in the clinical trial. Clonazepam has several side effects that could be problematic in PD patients such as increasing fall-down risk, daytime somnolence, and cognitive decline. Melatonin is a second-line treatment option for RBD, but there has been only one randomized crossover trial that evaluated the efficacy of melatonin on RBD. Finally, there has been no study that evaluate and compare the efficacy and safety of melatonin and clonazepam for treatment of RBD.

Official Title
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A Randomized Double-Blind, Double-Dummy, Crossover Study to Evaluate the Efficacy and Safety of Prolonged-Release Melatonin and Clonazepam in Patients With Rapid Eye Movement (REM) Sleep Behavior Disorder in Parkinson Disease

Conditions
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REM Sleep Behavior Disorder, Parkinson Disease

Intervention / Treatment
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* Drug: Melatonin PR
* Drug: Clonazepam
* Drug: Melatonin PR placebo
* Drug: Clonazepam placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject was enrolled voluntarily and understood the contents of this clinical trial Subject was diagnosed as Parkinson disease (PD) Hoehn and Yahr (H&Y) stage 1, 2, or 3 Existence of caregivers who can provide a information about symptoms of rapid eye movement sleep disorder (RBD) of the participant RBD frequency is one or more per week Existence of RBD by answering yes to the question (RBD-1Q): Have you ever been told, or suspected yourself, that you seem to 'act out your dreams' while asleep (for example, punching, flailing your arms in the air, making running movements, etc.)? Good compliance for reporting PGI scores and sleep diary Exclusion Criteria: Existence of cognitive decline hard to participate in the clinical trial Hypersensitivity to melatonin or clonazepam Previous melatonin or clonazepam treatment within 1 month Changing anti-parkinsonian medications within 1 month Current treatment with sedatives or hypnotics at bedtime Diagnosed as epilepsy or current treatment with anti-epileptic drugs Severe trauma history due to RBD Lactating, pregnant, or possible pregnant Subject has confusion or visual hallucination in daytime Diagnosed as obstructive sleep apnea or severe snoring Diagnosed as other parasomnia Presence of severe psychiatric illness Alcoholics or drug abuser Myasthenia gravis Acute narrow-angle glaucoma Prior participation to other clinical trials within 3 months Presence of severe comorbidities or a cancer Existence of illness or problems which makes difficult to be enrolled to this trial judged by clinicians

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: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1<br>Phase 1: Melatonin PR 2 mg 1 tablet+Clonazepam placebo 1 tablet, 1/day before sleeping for 4 weeks Phase 2: Clonazepam 0.5 mg 1 tablet+Melatonin PR placebo 1 tablet, 1/day before sleeping for 4 weeks Phase 3: Melatonin PR placebo 1 tablet+Clonazepam placebo 1 tablet, 1/day before sleeping for 4 weeks | Drug: Melatonin PR<br>* For experimental treatment of RBD<br>* Other names: Circadin;Drug: Clonazepam<br>* For experimental treatment of RBD<br>* Other names: Rivotril;Drug: Melatonin PR placebo<br>* Placebo pill manufactured to mask melatonin PR 2mg tablet<br>* Other names: Placebo tablet of Melatonin PR;Drug: Clonazepam placebo<br>* Placebo pill manufactured to mask clonazepam 0.5mg tablet<br>* Other names: Placebo tablet of clonazepam;|
| Experimental: Group 2<br>Phase 1: Clonazepam 0.5 mg 1 tablet+Melatonin PR placebo 1 tablet, 1/day before sleeping for 4 weeks Phase 2: Melatonin PR placebo 1 tablet+Clonazepam placebo 1 tablet, 1/day before sleeping for 4 weeks Phase 3: Melatonin PR 2 mg 1 tablet+Clonazepam placebo 1 tablet, 1/day before sleeping for 4 weeks | Drug: Melatonin PR<br>* For experimental treatment of RBD<br>* Other names: Circadin;Drug: Clonazepam<br>* For experimental treatment of RBD<br>* Other names: Rivotril;Drug: Melatonin PR placebo<br>* Placebo pill manufactured to mask melatonin PR 2mg tablet<br>* Other names: Placebo tablet of Melatonin PR;Drug: Clonazepam placebo<br>* Placebo pill manufactured to mask clonazepam 0.5mg tablet<br>* Other names: Placebo tablet of clonazepam;|
| Experimental: Group 3<br>Phase 1: Melatonin PR placebo 1 tablet+Clonazepam placebo 1 tablet, 1/day before sleeping for 4 weeks Phase 2: Melatonin PR 2 mg 1 tablet+Clonazepam placebo 1 tablet, 1/day before sleeping for 4 weeks Phase 3: Clonazepam 0.5 mg 1 tablet+Melatonin PR placebo 1 tablet, 1/day before sleeping for 4 weeks | Drug: Melatonin PR<br>* For experimental treatment of RBD<br>* Other names: Circadin;Drug: Clonazepam<br>* For experimental treatment of RBD<br>* Other names: Rivotril;Drug: Melatonin PR placebo<br>* Placebo pill manufactured to mask melatonin PR 2mg tablet<br>* Other names: Placebo tablet of Melatonin PR;Drug: Clonazepam placebo<br>* Placebo pill manufactured to mask clonazepam 0.5mg tablet<br>* Other names: Placebo tablet of clonazepam;|
| Experimental: Group 4<br>Phase 1: Melatonin PR 2 mg 1 tablet+Clonazepam placebo 1 tablet, 1/day before sleeping for 4 weeks Phase 2: Melatonin PR placebo 1 tablet+Clonazepam placebo 1 tablet, 1/day before sleeping for 4 weeks Phase 3: Clonazepam 0.5 mg 1 tablet+Melatonin PR placebo 1 tablet, 1/day before sleeping for 4 weeks | Drug: Melatonin PR<br>* For experimental treatment of RBD<br>* Other names: Circadin;Drug: Clonazepam<br>* For experimental treatment of RBD<br>* Other names: Rivotril;Drug: Melatonin PR placebo<br>* Placebo pill manufactured to mask melatonin PR 2mg tablet<br>* Other names: Placebo tablet of Melatonin PR;Drug: Clonazepam placebo<br>* Placebo pill manufactured to mask clonazepam 0.5mg tablet<br>* Other names: Placebo tablet of clonazepam;|
| Experimental: Group 5<br>Phase 1: Clonazepam 0.5 mg 1 tablet+Melatonin PR placebo 1 tablet, 1/day before sleeping for 4 weeks Phase 2: Melatonin PR 2 mg 1 tablet+Clonazepam placebo 1 tablet, 1/day before sleeping for 4 weeks Phase 3: Melatonin PR placebo 1 tablet+Clonazepam placebo 1 tablet, 1/day before sleeping for 4 weeks | Drug: Melatonin PR<br>* For experimental treatment of RBD<br>* Other names: Circadin;Drug: Clonazepam<br>* For experimental treatment of RBD<br>* Other names: Rivotril;Drug: Melatonin PR placebo<br>* Placebo pill manufactured to mask melatonin PR 2mg tablet<br>* Other names: Placebo tablet of Melatonin PR;Drug: Clonazepam placebo<br>* Placebo pill manufactured to mask clonazepam 0.5mg tablet<br>* Other names: Placebo tablet of clonazepam;|
| Experimental: Group 6<br>Phase 1: Melatonin PR placebo 1 tablet+Clonazepam placebo 1 tablet, 1/day before sleeping for 4 weeks Phase 2: Clonazepam 0.5 mg 1 tablet+Melatonin PR placebo 1 tablet, 1/day before sleeping for 4 weeks Phase 3: Melatonin PR 2 mg 1 tablet+Clonazepam placebo 1 tablet, 1/day before sleeping for 4 weeks | Drug: Melatonin PR<br>* For experimental treatment of RBD<br>* Other names: Circadin;Drug: Clonazepam<br>* For experimental treatment of RBD<br>* Other names: Rivotril;Drug: Melatonin PR placebo<br>* Placebo pill manufactured to mask melatonin PR 2mg tablet<br>* Other names: Placebo tablet of Melatonin PR;Drug: Clonazepam placebo<br>* Placebo pill manufactured to mask clonazepam 0.5mg tablet<br>* Other names: Placebo tablet of clonazepam;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Global Impression-Improvement scale (CGI-I) | Clinician assessed rating scale of clinical improvement or worsening relative to a baseline state, scored as 1, very much improved; 2, much improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; or 7, very much worse. | Four weeks (plus or minus 3 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean change of the Clinical Global Impression-Severity scale (CGI-S) |  | Four weeks (plus or minus 3 days) | 
| Patient Global Impression-Improvement scale (PGI-I) |  | Four weeks (plus or minus 3 days) | 
| Mean change of the Patient Global Impression-Severity scale (PGI-S) |  | Four weeks (plus or minus 3 days) | 
| modified RBD Questionnaire-HongKong (mRBDQ-HK) |  | Four weeks (plus or minus 3 days) | 
| Mean change of the Epworth Sleepiness Scale (ESS) |  | Four weeks (plus or minus 3 days) | 
| Mean change of the Parkinson Disease Sleep Scale (PDSS) |  | Four weeks (plus or minus 3 days) | 
| Mean change of the Montreal Cognitive Assessment (MoCA) |  | Four weeks (plus or minus 3 days) | 
| Mean change of the Unified Parkinson's Disease Rating Scale (UPDRS) |  | Four weeks (plus or minus 3 days) | 
| Sleep diary |  | Four weeks (plus or minus 3 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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REM Sleep Behavior Disorder, Parkinson Disease, Randomized Controlled Trial, Clinical Trial, Melatonin, Clonazepam