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

Primary Purpose

REM Sleep Behavior Disorder, Parkinson Disease

Status
Unknown status
Phase
Phase 2
Locations
Korea, Republic of
Study Type
Interventional
Intervention
Melatonin PR
Clonazepam
Melatonin PR placebo
Clonazepam placebo
Sponsored by
Seoul National University Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for REM Sleep Behavior Disorder focused on measuring REM Sleep Behavior Disorder, Parkinson Disease, Randomized Controlled Trial, Clinical Trial, Melatonin, Clonazepam

Eligibility Criteria

30 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Seoul National University Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Arm Label

Group 1

Group 2

Group 3

Group 4

Group 5

Group 6

Arm Description

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

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

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

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

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

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

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Mean change of the Clinical Global Impression-Severity scale (CGI-S)
Patient Global Impression-Improvement scale (PGI-I)
Mean change of the Patient Global Impression-Severity scale (PGI-S)
modified RBD Questionnaire-HongKong (mRBDQ-HK)
Mean change of the Epworth Sleepiness Scale (ESS)
Mean change of the Parkinson Disease Sleep Scale (PDSS)
Mean change of the Montreal Cognitive Assessment (MoCA)
Mean change of the Unified Parkinson's Disease Rating Scale (UPDRS)
Sleep diary

Full Information

First Posted
May 31, 2016
Last Updated
June 2, 2016
Sponsor
Seoul National University Hospital
Collaborators
Kuhnil Pharmaceutical Co., Ltd.
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1. Study Identification

Unique Protocol Identification Number
NCT02789592
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
Study Type
Interventional

2. Study Status

Record Verification Date
June 2016
Overall Recruitment Status
Unknown status
Study Start Date
July 2016 (undefined)
Primary Completion Date
December 2019 (Anticipated)
Study Completion Date
December 2019 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Seoul National University Hospital
Collaborators
Kuhnil Pharmaceutical Co., Ltd.

4. Oversight

Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
REM Sleep Behavior Disorder, Parkinson Disease
Keywords
REM Sleep Behavior Disorder, Parkinson Disease, Randomized Controlled Trial, Clinical Trial, Melatonin, Clonazepam

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
30 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Group 1
Arm Type
Experimental
Arm Description
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
Arm Title
Group 2
Arm Type
Experimental
Arm Description
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
Arm Title
Group 3
Arm Type
Experimental
Arm Description
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
Arm Title
Group 4
Arm Type
Experimental
Arm Description
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
Arm Title
Group 5
Arm Type
Experimental
Arm Description
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
Arm Title
Group 6
Arm Type
Experimental
Arm Description
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
Intervention Type
Drug
Intervention Name(s)
Melatonin PR
Other Intervention Name(s)
Circadin
Intervention Description
For experimental treatment of RBD
Intervention Type
Drug
Intervention Name(s)
Clonazepam
Other Intervention Name(s)
Rivotril
Intervention Description
For experimental treatment of RBD
Intervention Type
Drug
Intervention Name(s)
Melatonin PR placebo
Other Intervention Name(s)
Placebo tablet of Melatonin PR
Intervention Description
Placebo pill manufactured to mask melatonin PR 2mg tablet
Intervention Type
Drug
Intervention Name(s)
Clonazepam placebo
Other Intervention Name(s)
Placebo tablet of clonazepam
Intervention Description
Placebo pill manufactured to mask clonazepam 0.5mg tablet
Primary Outcome Measure Information:
Title
Clinical Global Impression-Improvement scale (CGI-I)
Description
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.
Time Frame
Four weeks (plus or minus 3 days)
Secondary Outcome Measure Information:
Title
Mean change of the Clinical Global Impression-Severity scale (CGI-S)
Time Frame
Four weeks (plus or minus 3 days)
Title
Patient Global Impression-Improvement scale (PGI-I)
Time Frame
Four weeks (plus or minus 3 days)
Title
Mean change of the Patient Global Impression-Severity scale (PGI-S)
Time Frame
Four weeks (plus or minus 3 days)
Title
modified RBD Questionnaire-HongKong (mRBDQ-HK)
Time Frame
Four weeks (plus or minus 3 days)
Title
Mean change of the Epworth Sleepiness Scale (ESS)
Time Frame
Four weeks (plus or minus 3 days)
Title
Mean change of the Parkinson Disease Sleep Scale (PDSS)
Time Frame
Four weeks (plus or minus 3 days)
Title
Mean change of the Montreal Cognitive Assessment (MoCA)
Time Frame
Four weeks (plus or minus 3 days)
Title
Mean change of the Unified Parkinson's Disease Rating Scale (UPDRS)
Time Frame
Four weeks (plus or minus 3 days)
Title
Sleep diary
Time Frame
Four weeks (plus or minus 3 days)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
30 Years
Accepts Healthy Volunteers
No
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Beomseok Jeon, MD, PhD
Email
brain@snu.ac.kr
First Name & Middle Initial & Last Name or Official Title & Degree
Chae Won Shin, MD, MSc
Email
chroma0202@gmail.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Beomseok Jeon, MD, PhD
Organizational Affiliation
Seoul National University Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Seoul National University Hospital
City
Seoul
Country
Korea, Republic of

12. IPD Sharing Statement

Plan to Share IPD
Undecided
Citations:
PubMed Identifier
22447623
Citation
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.
Results Reference
background
PubMed Identifier
21832215
Citation
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.
Results Reference
background
PubMed Identifier
20561180
Citation
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.
Results Reference
background
PubMed Identifier
23886593
Citation
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.
Results Reference
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Efficacy and Safety of Melatonin PR and Clonazepam in Patients With REM Sleep Behavior Disorder in Parkinson Disease

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