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

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

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).

Study Overview

• Status: Unknown
• Conditions: Parkinson Disease; REM Sleep Behavior Disorder
• Intervention / Treatment: Drug: Clonazepam; Drug: Melatonin PR; Drug: Melatonin PR placebo; Drug: Clonazepam placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 30
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Beomseok Jeon, MD, PhD; Email: brain@snu.ac.kr
• Study Contact Backup: Name: Chae Won Shin, MD, MSc; Email: chroma0202@gmail.com

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of
    • Seoul National University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 28 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group 1; 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: Clonazepam; For experimental treatment of RBD; Other Names: Rivotril; Drug: Melatonin PR; For experimental treatment of RBD; Other Names: Circadin; Drug: Melatonin PR placebo; Placebo pill manufactured to mask melatonin PR 2mg tablet; Other Names: Placebo tablet of Melatonin PR; Drug: Clonazepam placebo; Placebo pill manufactured to mask clonazepam 0.5mg tablet; Other Names: Placebo tablet of clonazepam
Experimental: Group 2; 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: Clonazepam; For experimental treatment of RBD; Other Names: Rivotril; Drug: Melatonin PR; For experimental treatment of RBD; Other Names: Circadin; Drug: Melatonin PR placebo; Placebo pill manufactured to mask melatonin PR 2mg tablet; Other Names: Placebo tablet of Melatonin PR; Drug: Clonazepam placebo; Placebo pill manufactured to mask clonazepam 0.5mg tablet; Other Names: Placebo tablet of clonazepam
Experimental: Group 3; 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: Clonazepam; For experimental treatment of RBD; Other Names: Rivotril; Drug: Melatonin PR; For experimental treatment of RBD; Other Names: Circadin; Drug: Melatonin PR placebo; Placebo pill manufactured to mask melatonin PR 2mg tablet; Other Names: Placebo tablet of Melatonin PR; Drug: Clonazepam placebo; Placebo pill manufactured to mask clonazepam 0.5mg tablet; Other Names: Placebo tablet of clonazepam
Experimental: Group 4; 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: Clonazepam; For experimental treatment of RBD; Other Names: Rivotril; Drug: Melatonin PR; For experimental treatment of RBD; Other Names: Circadin; Drug: Melatonin PR placebo; Placebo pill manufactured to mask melatonin PR 2mg tablet; Other Names: Placebo tablet of Melatonin PR; Drug: Clonazepam placebo; Placebo pill manufactured to mask clonazepam 0.5mg tablet; Other Names: Placebo tablet of clonazepam
Experimental: Group 5; 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: Clonazepam; For experimental treatment of RBD; Other Names: Rivotril; Drug: Melatonin PR; For experimental treatment of RBD; Other Names: Circadin; Drug: Melatonin PR placebo; Placebo pill manufactured to mask melatonin PR 2mg tablet; Other Names: Placebo tablet of Melatonin PR; Drug: Clonazepam placebo; Placebo pill manufactured to mask clonazepam 0.5mg tablet; Other Names: Placebo tablet of clonazepam
Experimental: Group 6; 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: Clonazepam; For experimental treatment of RBD; Other Names: Rivotril; Drug: Melatonin PR; For experimental treatment of RBD; Other Names: Circadin; Drug: Melatonin PR placebo; Placebo pill manufactured to mask melatonin PR 2mg tablet; Other Names: Placebo tablet of Melatonin PR; Drug: Clonazepam placebo; Placebo pill manufactured to mask clonazepam 0.5mg tablet; Other Names: Placebo tablet of clonazepam

What is the study measuring?

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	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)

Collaborators and Investigators

• Sponsor: Seoul National University Hospital
• Collaborators: Kuhnil Pharmaceutical Co., Ltd.
• Investigators: Principal Investigator: Beomseok Jeon, MD, PhD, Seoul National University Hospital

Publications and helpful links

General Publications

• Arnulf I. REM sleep behavior disorder: motor manifestations and pathophysiology. Mov Disord. 2012 May;27(6):677-89. doi: 10.1002/mds.24957. Epub 2012 Mar 22.
• Sixel-Doring F, Trautmann E, Mollenhauer B, Trenkwalder C. Associated factors for REM sleep behavior disorder in Parkinson disease. Neurology. 2011 Sep 13;77(11):1048-54. doi: 10.1212/WNL.0b013e31822e560e. Epub 2011 Aug 10.
• Kunz D, Mahlberg R. A two-part, double-blind, placebo-controlled trial of exogenous melatonin in REM sleep behaviour disorder. J Sleep Res. 2010 Dec;19(4):591-6. doi: 10.1111/j.1365-2869.2010.00848.x.
• Schenck CH, Montplaisir JY, Frauscher B, Hogl B, Gagnon JF, Postuma R, Sonka K, Jennum P, Partinen M, Arnulf I, Cochen de Cock V, Dauvilliers Y, Luppi PH, Heidbreder A, Mayer G, Sixel-Doring F, Trenkwalder C, Unger M, Young P, Wing YK, Ferini-Strambi L, Ferri R, Plazzi G, Zucconi M, Inoue Y, Iranzo A, Santamaria J, Bassetti C, Moller JC, Boeve BF, Lai YY, Pavlova M, Saper C, Schmidt P, Siegel JM, Singer C, St Louis E, Videnovic A, Oertel W. Rapid eye movement sleep behavior disorder: devising controlled active treatment studies for symptomatic and neuroprotective therapy--a consensus statement from the International Rapid Eye Movement Sleep Behavior Disorder Study Group. Sleep Med. 2013 Aug;14(8):795-806. doi: 10.1016/j.sleep.2013.02.016. Epub 2013 Jul 22. Erratum In: Sleep Med. 2014 Jan;15(1):157.

Study record dates

Study Major Dates

• Study Start: July 1, 2016
• Primary Completion (Anticipated): December 1, 2019
• Study Completion (Anticipated): December 1, 2019

Study Registration Dates

• First Submitted: May 31, 2016
• First Submitted That Met QC Criteria: June 2, 2016
• First Posted (Estimate): June 3, 2016

Study Record Updates

• Last Update Posted (Estimate): June 3, 2016
• Last Update Submitted That Met QC Criteria: June 2, 2016
• Last Verified: June 1, 2016

More Information

Terms related to this study

• Keywords: Melatonin; Randomized Controlled Trial; Parkinson Disease; Clinical Trial; REM Sleep Behavior Disorder; Clonazepam
• Additional Relevant MeSH Terms: Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Sleep Wake Disorders; Parkinsonian Disorders; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Parasomnias; REM Sleep Parasomnias; Disease; Parkinson Disease; Mental Disorders; REM Sleep Behavior Disorder; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Protective Agents; GABA Modulators; GABA Agents; Anticonvulsants; Antioxidants; Melatonin; Clonazepam
• Other Study ID Numbers: H-1604-134-757

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided