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

• ClinicalTrials.gov Identifier: NCT02789592
• Recruitment Status: Unknown
• First Posted: June 3, 2016
• Last Update Posted: June 3, 2016
• Sponsor: Seoul National University Hospital
• Collaborator: Kuhnil Pharmaceutical Co., Ltd.
• Information provided by (Responsible Party): BS Jeon, Seoul National University Hospital

Tracking Information

• First Submitted Date: May 31, 2016
• First Posted Date: June 3, 2016
• Last Update Posted Date: June 3, 2016
• Study Start Date: July 2016
• Estimated Primary Completion Date: December 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 2, 2016)

Clinical Global Impression-Improvement scale (CGI-I) [ Time Frame: Four weeks (plus or minus 3 days) ]

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.

• Original Primary Outcome Measures: Same as current
• Change History: No Changes Posted

Current Secondary Outcome Measures (submitted: June 2, 2016)

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

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Efficacy and Safety of Melatonin PR and Clonazepam in Patients With REM Sleep Behavior Disorder in Parkinson Disease
• Official Title: 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
• Brief Summary: 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

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
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment

Condition

• REM Sleep Behavior Disorder
• Parkinson Disease

Intervention

• Drug: Melatonin PR
  For experimental treatment of RBD
  Other Name: Circadin
• Drug: Clonazepam
  For experimental treatment of RBD
  Other Name: Rivotril
• Drug: Melatonin PR placebo
  Placebo pill manufactured to mask melatonin PR 2mg tablet
  Other Name: Placebo tablet of Melatonin PR
• Drug: Clonazepam placebo
  Placebo pill manufactured to mask clonazepam 0.5mg tablet
  Other Name: Placebo tablet of clonazepam

Study Arms

• 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
  Interventions:

  • Drug: Melatonin PR
  • Drug: Clonazepam
  • Drug: Melatonin PR placebo
  • Drug: Clonazepam placebo
• 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
  Interventions:

  • Drug: Melatonin PR
  • Drug: Clonazepam
  • Drug: Melatonin PR placebo
  • Drug: Clonazepam placebo
• 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
  Interventions:

  • Drug: Melatonin PR
  • Drug: Clonazepam
  • Drug: Melatonin PR placebo
  • Drug: Clonazepam placebo
• 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
  Interventions:

  • Drug: Melatonin PR
  • Drug: Clonazepam
  • Drug: Melatonin PR placebo
  • Drug: Clonazepam placebo
• 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
  Interventions:

  • Drug: Melatonin PR
  • Drug: Clonazepam
  • Drug: Melatonin PR placebo
  • Drug: Clonazepam placebo
• 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
  Interventions:

  • Drug: Melatonin PR
  • Drug: Clonazepam
  • Drug: Melatonin PR placebo
  • Drug: Clonazepam placebo

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.

Recruitment Information

• Recruitment Status: Unknown status
• Estimated Enrollment (submitted: June 2, 2016): 30
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 2019
• Estimated Primary Completion Date: December 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 30 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Korea, Republic of

Administrative Information

• NCT Number: NCT02789592
• Other Study ID Numbers: H-1604-134-757
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Current Responsible Party: BS Jeon, Seoul National University Hospital
• Original Responsible Party: Same as current
• Current Study Sponsor: Seoul National University Hospital
• Original Study Sponsor: Same as current
• Collaborators: Kuhnil Pharmaceutical Co., Ltd.

Investigators

• Principal Investigator: Beomseok Jeon, MD, PhD; Seoul National University Hospital

• PRS Account: Seoul National University Hospital
• Verification Date: June 2016