Efficacy and Tolerability of Ramelteon in Patients With Rapid Eye Movement (REM) Behavior Disorder and Parkinsonism

• Sponsor: Northwestern University (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00745030
• Collaborator: Takeda (Industry)
• Enrollment: 3
• Location: 1
• Arms: 2
• Duration (Months): 18
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

Parkinson's disease (PD) is the second most common neurodegenerative disorder of the elderly that affects a million patients in US. Sleep dysfunction impacts up to 90% of PD patients. PD patients experience a variety of sleep disorders including parasomnias, specifically REM behavior disorder (RBD) that can precede the onset of motor manifestations of PD. RBD has negative consequences on patients' and their bed partners' quality of life mainly due to its impact on the sleep quality and day time alertness. RBD also predisposes affected individuals and their bed partners to physical injuries.

There are no FDA approved treatments for RBD. Clonazepam is the most commonly used treatment but carries risks of daytime sedation, tolerance, and withdrawal symptoms. More recently, melatonin has been demonstrated to be effective in several small studies. Ramelteon, a selective melatonin receptor agonist with favorable safety profile, could potentially be effective for the treatment of RBD.

This pilot protocol will investigate safety and efficacy of ramelteon for the treatment of RBD in subjects with parkinsonism. We plan to recruit 20 subjects with RBD diagnosed based on the clinical interview and confirmed by the polysomnographic (PSG) data. The study is designed as a prospective randomized placebo controlled 12-week study. Primary outcome measure will be change in frequency of RBD events based on the daily sleep diaries. Secondary outcome measure will be change in the amount of tonic muscle activity based on the results of the baseline and final PSG. A number of other secondary and exploratory outcome measures will be collected

Condition or Disease	Intervention/Treatment	Phase
REM Behavior Disorder; Parkinsonism	Drug: Rozerem; Drug: Placebo	N/A

Detailed Description

See above.

Study Design

• Study Type: Interventional
• Actual Enrollment: 3 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Efficacy and Tolerability of Ramelteon in Patients With REM Behavior Disorder and Parkinsonism: A Placebo Controlled, Double Blind, Randomized, Prospective Pilot Study
• Study Start Date: Jun 1, 2008
• Actual Primary Completion Date: Dec 1, 2009
• Actual Study Completion Date: Dec 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 Ramelteon (TAK-375) 8mg tablets	Drug: Rozerem; Subjects take 1 8mg tablet 30 minutes before bedtime everyday for 8 weeks.; Other Names: Ramelteon TAK-375
Placebo Comparator: 2 Placebo 8 mg tablets	Drug: Placebo; Placebo 8 mg tablets

Outcome Measures

Primary Outcome Measures

1. Change in the Frequency of RBD Based on the Daily Sleep Diaries, Completed Daily for the Duration of the Study by the Study Subjects' Bed Partners/Caregivers [12 weeks]

   Change in the frequency of RBD based on the daily sleep diaries, completed daily for the duration of the study by the study subjects' bed partners/caregivers. Data will not be analyzed. The protocol is being terminated due to low subject enrollment and recruitment.

Secondary Outcome Measures

1. Change in the Amount of Tonic Muscle Activity Based on the Results of the Baseline and Final Polysomnographic (PSG) Study [8 weeks]

2. Changes in Mean TST, LPS, WASO (Based on PSG) [8 weeks]

3. Changes in Clinician Global Impression Scale of Improvement (CGI-I) [10 weeks]

4. Changes in RBD Structured Questionnaire (Completed by Patient and Bed Partner) [12 weeks]

5. Changes in Patient Completed Parkinson's Disease Sleep Scale (PDSS)- the Only Validated PD Specific, Questionnaire-based, Sleep Evaluation Scale [12 weeks]

6. Changes in Patient Completed Epworth Sleepiness Scale (ESS) [12 weeks]

7. Changes in Beck Depression Inventory (BDI) [12 weeks]

8. Changes in Pittsburgh Sleep Quality Index (PSQI) (Patient Completed) [12 weeks]

9. Changes in Patient Completed The Fatigue Severity Scale (FSS) [12 weeks]

10. Changes in Patient Completed PDQ-39 Scale(PD-specific Quality of Life Scale) [12 weeks]

11. Changes in Physician Completed United Parkinson's Disease Rating Scale (UPDRS) [12 weeks]

12. Changes in Mini-Mental State Exam (MMSE) [12 weeks]

13. Changes in The Montreal Cognitive Assessment Scale (MoCA) [12 weeks]

14. Study Terminated Due to Low Subject Recruitment and Enrollment. []

    Low subject recruitment and enrollment

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Diagnosis of parkinsonism (idiopathic PD, multiple systems atrophy, Lewy body dementia)

• RBD frequency of at least once per week based on the RBD screening clinical questionnaire

• PSG evidence of RBD

• Presence of bed partner/caregiver who sleeps in the same room as PD patient

Exclusion Criteria:

• Known hypersensitivity to ramelteon or related compounds, including melatonin and melatonin-related compounds.

• Use of hypnotics or other sedatives within a month prior to the study initiation

• Presence of active psychosis

• Use of neuroleptics, except for the atypical neuroleptics - specifically quetiapine (the dose should not exceed 50mg/day)

• Use of antidepressants unless the patient has been on a stable dose for at least three months

• Use of Venlafaxine (Effexor®)

• Presence of cognitive impairment, defined as the Mini Mental Status Examination (MMSE) score <24

• Presence of depression defined as the Beck Depression Inventory (BDI) score >14

• Significant sleep disordered breathing (defined as an apnea-hypopnea index>15 events/hr of sleep on screening PSG), significant periodic limb movement disorder (defined as a PLM index>10 events/hr of sleep with awakening on screening PSG)

• Travel through two time zones within a month prior to the study initiation

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Northwestern University	Chicago	Illinois	United States	60611

Sponsors and Collaborators

• Northwestern University
• Takeda

Investigators

• Principal Investigator: Tanya Simuni, M.D., Northwestern University, Department of Neurology
• Study Director: Aleksandar Videnovic, M.D., Northwestern University, Department of Neurology

Study Documents (Full-Text)

None provided.

More Information

Publications

• Boeve BF, Silber MH, Ferman TJ, Lucas JA, Parisi JE. Association of REM sleep behavior disorder and neurodegenerative disease may reflect an underlying synucleinopathy. Mov Disord. 2001 Jul;16(4):622-30.
• Boeve BF, Silber MH, Ferman TJ. Melatonin for treatment of REM sleep behavior disorder in neurologic disorders: results in 14 patients. Sleep Med. 2003 Jul;4(4):281-4.
• Boeve BF, Silber MH, Parisi JE, Dickson DW, Ferman TJ, Benarroch EE, Schmeichel AM, Smith GE, Petersen RC, Ahlskog JE, Matsumoto JY, Knopman DS, Schenck CH, Mahowald MW. Synucleinopathy pathology and REM sleep behavior disorder plus dementia or parkinsonism. Neurology. 2003 Jul 8;61(1):40-5.
• Borja NL, Daniel KL. Ramelteon for the treatment of insomnia. Clin Ther. 2006 Oct;28(10):1540-55. Review.
• Chaudhuri KR, Pal S, DiMarco A, Whately-Smith C, Bridgman K, Mathew R, Pezzela FR, Forbes A, Högl B, Trenkwalder C. The Parkinson's disease sleep scale: a new instrument for assessing sleep and nocturnal disability in Parkinson's disease. J Neurol Neurosurg Psychiatry. 2002 Dec;73(6):629-35.
• Gagnon JF, Bédard MA, Fantini ML, Petit D, Panisset M, Rompré S, Carrier J, Montplaisir J. REM sleep behavior disorder and REM sleep without atonia in Parkinson's disease. Neurology. 2002 Aug 27;59(4):585-9.
• Kunz D, Bes F. Melatonin as a therapy in REM sleep behavior disorder patients: an open-labeled pilot study on the possible influence of melatonin on REM-sleep regulation. Mov Disord. 1999 May;14(3):507-11.
• Roth T, Seiden D, Sainati S, Wang-Weigand S, Zhang J, Zee P. Effects of ramelteon on patient-reported sleep latency in older adults with chronic insomnia. Sleep Med. 2006 Jun;7(4):312-8. Epub 2006 May 18.
• Schenck CH, Bundlie SR, Mahowald MW. Delayed emergence of a parkinsonian disorder in 38% of 29 older men initially diagnosed with idiopathic rapid eye movement sleep behaviour disorder. Neurology. 1996 Feb;46(2):388-93. Erratum in: Neurology 1996 Jun;46(6):1787.
• Schenck CH, Bundlie SR, Patterson AL, Mahowald MW. Rapid eye movement sleep behavior disorder. A treatable parasomnia affecting older adults. JAMA. 1987 Apr 3;257(13):1786-9.
• Simuni T. Somnolence and other sleep disorders in Parkinson's disease: the challenge for the practicing neurologist. Neurol Clin. 2004 Oct;22(3 Suppl):S107-26. Review.
• Takeuchi N, Uchimura N, Hashizume Y, Mukai M, Etoh Y, Yamamoto K, Kotorii T, Ohshima H, Ohshima M, Maeda H. Melatonin therapy for REM sleep behavior disorder. Psychiatry Clin Neurosci. 2001 Jun;55(3):267-9.
• Thorpy MJ. Sleep disorders in Parkinson's disease. Clin Cornerstone. 2004;6 Suppl 1A:S7-15. Review.

• ClinicalTrials.gov Identifier: NCT00745030
• Other Study ID Numbers: 07-028R
• First Posted: Sep 1, 2008
• Last Update Posted: Apr 21, 2011
• Last Verified: Apr 1, 2011

• Keywords provided by , ,: Parkinson's disease; Multiple Systems Atrophy; Lewy Body Dementia
• Additional relevant MeSH terms: Parkinsonian Disorders; REM Sleep Behavior Disorder; Mental Disorders

Study Results

Participant Flow

Arm/Group Title	Ramelteon (TAK-375) 8mg Tablets	Placebo 8 mg Tablets
Arm/Group Description	Ramelteon (TAK-375) 8mg tablets	Placebo 8 mg tablets
Period Title: Overall Study
STARTED	1	2
COMPLETED	1	2
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Ramelteon (TAK-375) 8mg Tablets	Placebo 8 mg Tablets	Total
Arm/Group Description	Ramelteon (TAK-375) 8mg tablets	Placebo 8 mg tablets	Total of all reporting groups
Overall Participants	1	2	3
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	1 100%	2 100%	3 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57 (0)	57 (7.85)	57 (7.85)
Sex: Female, Male (Count of Participants)
Female	1 100%	0 0%	1 33.3%
Male	0 0%	2 100%	2 66.7%
Region of Enrollment (participants) [Number]
United States	1 100%	2 100%	3 100%

Outcome Measures

1. Primary Outcome

Title	Change in the Frequency of RBD Based on the Daily Sleep Diaries, Completed Daily for the Duration of the Study by the Study Subjects' Bed Partners/Caregivers
Description	Change in the frequency of RBD based on the daily sleep diaries, completed daily for the duration of the study by the study subjects' bed partners/caregivers. Data will not be analyzed. The protocol is being terminated due to low subject enrollment and recruitment.
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ramelteon (TAK-375) 8mg Tablets	Placebo 8 mg Tablets
Arm/Group Description	Ramelteon (TAK-375) 8mg tablets	Placebo 8 mg tablets
Measure Participants	0	0

2. Secondary Outcome

Title	Change in the Amount of Tonic Muscle Activity Based on the Results of the Baseline and Final Polysomnographic (PSG) Study
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Secondary Outcome

Title	Changes in Mean TST, LPS, WASO (Based on PSG)
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Changes in Clinician Global Impression Scale of Improvement (CGI-I)
Time Frame	10 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Secondary Outcome

Title	Changes in RBD Structured Questionnaire (Completed by Patient and Bed Partner)
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Secondary Outcome

Title	Changes in Patient Completed Parkinson's Disease Sleep Scale (PDSS)- the Only Validated PD Specific, Questionnaire-based, Sleep Evaluation Scale
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Secondary Outcome

Title	Changes in Patient Completed Epworth Sleepiness Scale (ESS)
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Secondary Outcome

Title	Changes in Beck Depression Inventory (BDI)
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

9. Secondary Outcome

Title	Changes in Pittsburgh Sleep Quality Index (PSQI) (Patient Completed)
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

10. Secondary Outcome

Title	Changes in Patient Completed The Fatigue Severity Scale (FSS)
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

11. Secondary Outcome

Title	Changes in Patient Completed PDQ-39 Scale(PD-specific Quality of Life Scale)
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

12. Secondary Outcome

Title	Changes in Physician Completed United Parkinson's Disease Rating Scale (UPDRS)
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

13. Secondary Outcome

Title	Changes in Mini-Mental State Exam (MMSE)
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

14. Secondary Outcome

Title	Changes in The Montreal Cognitive Assessment Scale (MoCA)
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

15. Secondary Outcome

Title	Study Terminated Due to Low Subject Recruitment and Enrollment.
Description	Low subject recruitment and enrollment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Arm/Group Title	Ramelteon (TAK-375) 8mg Tablets		Placebo 8 mg Tablets
Arm/Group Description	Ramelteon (TAK-375) 8mg tablets		Placebo 8 mg tablets
All Cause Mortality
	Ramelteon (TAK-375) 8mg Tablets		Placebo 8 mg Tablets
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Ramelteon (TAK-375) 8mg Tablets		Placebo 8 mg Tablets
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/1 (0%)		0/2 (0%)
Other (Not Including Serious) Adverse Events
	Ramelteon (TAK-375) 8mg Tablets		Placebo 8 mg Tablets
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/1 (0%)		0/2 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.