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Ram-TIME: Ramelteon for the Treatment of Insomnia and Mood Stability in Patients With Euthymic Bipolar Disorder

Sponsor
Lehigh Valley Hospital (Other)
Overall Status
Completed
CT.gov ID
NCT00552760
Collaborator
Takeda (Industry)
90
Enrollment
1
Location
2
Arms
30
Duration (Months)
3
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to determine whether treating sleep difficulties in patients with bipolar disorder also improves their mood stability.

Condition or Disease Intervention/Treatment Phase
Phase 4

Detailed Description

Patients with euthymic bipolar disorder, although free of significant mood symptoms, often have continued sleep disturbances. Improving patients' sleep by also normalizing the circadian rhythm will lead to fewer mood exacerbations. Ramelteon offers a new and more pharmacologically exact mechanism to re-synchronize the SCN. The administration of ramelteon for bipolar patients will improve sleep and will cause fewer mood exacerbations.

Patients with bipolar disorder often experience frequent mood alterations that are attempted to be controlled by mood stabilizing agents and anti-psychotic agents. Both classes of medications have numerous significant side effects. Establishing that ramelteon is helpful in the sleep of patients with bipolar disorder and helpful in mood stability will increase the number of treatment options for bipolar patients.

Study Design

Study Type:
Interventional
Actual Enrollment :
90 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Double (Participant, Investigator)
Primary Purpose:
Treatment
Official Title:
A Double-Blind, Randomized, Placebo-Controlled Trial of Ramelteon for the Treatment of Insomnia and Mood Stability in Patients With Euthymic Bipolar Disorder.
Study Start Date :
Nov 1, 2007
Actual Primary Completion Date :
Mar 1, 2010
Actual Study Completion Date :
May 1, 2010

Arms and Interventions

Arm Intervention/Treatment
Experimental: Ramelteon

8 mg

Drug: Ramelteon
one 8 mg tablet at bedtime for up to 6 months
Other Names:
  • Rozerem

    		•
    Placebo Comparator: Placebo

    Drug: Placebo
    one tablet at bedtime for up to 6 months

    Outcome Measures

    Primary Outcome Measures

    1. Pittsburgh Sleep Quality Index (PSQI) Global Score [Monthly for 6 months]

      Self-rated scale to measure quality of sleep via questions regarding sleep latency, duration, efficiency, disturbances, use of sleep medication, and daytime dysfunction. Scores range from 0-21, higher scores represent more significant sleep disturbance.

    Secondary Outcome Measures

    1. Montgomery-Asberg Depression Rating Scale (MADRS) Total Score [Monthly for 6 months]

      10-item, standardized, well-validated scale used to measure severity of depressive symptoms; sensitive to treatment effects in depressed outpatients. Scores range from 0-60, higher scores represent more severe depressive symptoms.

    2. Young Mania Rating Scale (YMRS) Total Score [Monthly for 6 months]

      11-item standardized, well-validated scale used to measure manic symptoms; sensitive to treatment effects in manic patients. Scores range from 0-60, higher scores represent more severe manic symptoms.

    3. Clinical Global Impressions Bipolar Version(CGI-BP) Severity of Illness Overall Score [Monthly for 6 months]

      3-part (mania, depression, overall bipolar illness), physician-administered scale used to assess global illness severity; used to measure change. Each part is rated from 1-7, higher scores represent more severe mental illness. Only overall bipolar rating was used.

    4. Cumulative Proportion of Participants in Each Arm Surviving Without Relapse [Monthly for 6 months]

      Survival analysis techniques, including Kaplan Meier curves, were used to evaluate group differences in time to relapse. Relapse was defined as a medication initiation or change for manic/depressed/mixed symptoms, a hospitalization for manic/depressed/mixed symptoms, MADRS score >= 16, YMRS score > 14, and suicide risk or imminent risk of suicide. Time to relapse was measured discretely in terms of the number of assessment visits until discontinued from the study.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 65 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    1. Provision of written informed consent before initiation of any study-related procedures

    2. Men and women aged 18 to 65 years.

    3. A documented clinical diagnosis according to the DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision) meeting criteria 296.4x Bipolar I disorder, most recent episode manic, 296.6x Bipolar I disorder, most recent episode mixed, or 296.5x Bipolar I disorder, most recent episode depressed.

    4. PSQI total score of >=5.

    5. MADRS total score of <=12.

    6. YMRS total score of <= 12

    7. Female patients of childbearing potential must have a negative urine pregnancy test at enrollment and be willing to use a reliable method of birth control, i.e., double-barrier method, oral contraceptive, implant, dermal contraception, long-term injectable contraceptive, intrauterine device or tubal ligation, during the study.

    8. Be able to understand and comply with the requirements of the study, as judged by the investigator.

    9. Outpatient status at enrollment.

    Exclusion Criteria:

    1. Patients with a diagnosis of DSM-IV Axis II disorder which has a major impact on the patient's current psychiatric status.

    2. Presence of prohibited medications of antidepressants (including MAOI's) and systemic corticosteroids.

    3. Patients with a diagnosis of primary insomnia disorders

    4. Patients with a diagnosis of severe chronic obstructive pulmonary disease

    5. A clinical finding that is untreated (eg, hypertension, poorly controlled diabetes, angina) or that, in the opinion of the investigator, would be negatively affected by the study medication or that would affect the study medication.

    6. Patients with active substance abuse diagnoses (except tobacco abuse).

    7. Known history of intolerance or hypersensitivity to ramelteon or to any other component in the tablet.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Lehigh Valley Hospital, Department of Psychiatry Allentown Pennsylvania United States 18103

    Sponsors and Collaborators

    • Lehigh Valley Hospital
    • Takeda

    Investigators

    • Principal Investigator: Edward R. Norris, MD, Lehigh Valley Hospital

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    Responsible Party:
    Edward R. Norris, MD, Physician-Investigator, Lehigh Valley Hospital
    ClinicalTrials.gov Identifier:
    NCT00552760
    Other Study ID Numbers:
    • 07-006R
    First Posted:
    Nov 2, 2007
    Last Update Posted:
    Apr 14, 2014
    Last Verified:
    Mar 1, 2014
    Additional relevant MeSH terms:
    Bipolar Disorder

    Study Results

    Participant Flow

    Recruitment Details Recruitment began in October 2007 and was completed by August 2009. Participants, who at the time were receiving outpatient psychiatric services through Lehigh Valley Hospital, were recruited via referral through the department of psychiatry, and also through print advertisement. Participants received a $20 travel stipend for each appointment.
    Pre-assignment Detail 90 participants signed the informed consent document, 7 were screen failures, and 83 were randomized to receive either Ramelteon or placebo. During the study, both groups were maintained on their usual medications for bipolar disorder and were not allowed to have any meds changed, as this would signify a manic or depressed event.
    Arm/Group Title Ramelteon Placebo
    Arm/Group Description one 8 mg tablet at bedtime for up to 6 months one tablet at bedtime for up to 6 months
    Period Title: Overall Study
    STARTED 42 41
    COMPLETED 16 8
    NOT COMPLETED 26 33

    Baseline Characteristics

    Arm/Group Title Ramelteon Placebo Total
    Arm/Group Description one 8 mg tablet at bedtime for up to 6 months one tablet at bedtime for up to 6 months Total of all reporting groups
    Overall Participants 42 41 83
    Age (Count of Participants)
    <=18 years
    0
    0%
    0
    0%
    0
    0%
    Between 18 and 65 years
    42
    100%
    41
    100%
    83
    100%
    >=65 years
    0
    0%
    0
    0%
    0
    0%
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    46.6
    (11.0)
    45.2
    (10.8)
    45.9
    (10.9)
    Sex: Female, Male (Count of Participants)
    Female
    26
    61.9%
    26
    63.4%
    52
    62.7%
    Male
    16
    38.1%
    15
    36.6%
    31
    37.3%
    Region of Enrollment (participants) [Number]
    United States
    42
    100%
    41
    100%
    83
    100%

    Outcome Measures

    1. Primary Outcome
    Title Pittsburgh Sleep Quality Index (PSQI) Global Score
    Description Self-rated scale to measure quality of sleep via questions regarding sleep latency, duration, efficiency, disturbances, use of sleep medication, and daytime dysfunction. Scores range from 0-21, higher scores represent more significant sleep disturbance.
    Time Frame Monthly for 6 months

    Outcome Measure Data

    Analysis Population Description
    Intent to Treat Analysis; excludes 7 screen failures.
    Arm/Group Title Ramelteon Placebo
    Arm/Group Description one 8 mg tablet at bedtime for up to 6 months one tablet at bedtime for up to 6 months
    Measure Participants 42 41
    Baseline
    10.17
    (0.53)
    10.88
    (0.53)
    Month 1
    8.16
    (0.56)
    9.28
    (0.57)
    Month 2
    7.93
    (0.63)
    9.71
    (0.64)
    Month 3
    7.89
    (0.68)
    10.38
    (0.78)
    Month 4
    7.21
    (0.62)
    9.03
    (0.75)
    Month 5
    6.62
    (0.59)
    8.66
    (0.77)
    Month 6
    6.90
    (0.72)
    8.76
    (0.98)
    2. Secondary Outcome
    Title Montgomery-Asberg Depression Rating Scale (MADRS) Total Score
    Description 10-item, standardized, well-validated scale used to measure severity of depressive symptoms; sensitive to treatment effects in depressed outpatients. Scores range from 0-60, higher scores represent more severe depressive symptoms.
    Time Frame Monthly for 6 months

    Outcome Measure Data

    Analysis Population Description
    Intent to Treat Analysis; excludes 7 screen failures
    Arm/Group Title Ramelteon Placebo
    Arm/Group Description one 8 mg tablet at bedtime for up to 6 months one tablet at bedtime for up to 6 months
    Measure Participants 42 41
    Baseline
    7.79
    (0.42)
    8.27
    (0.43)
    Month 1
    8.34
    (0.67)
    8.90
    (0.68)
    Month 2
    7.23
    (0.84)
    11.13
    (0.85)
    Month 3
    9.17
    (1.00)
    11.85
    (1.24)
    Month 4
    8.45
    (1.05)
    13.03
    (1.39)
    Month 5
    8.56
    (1.24)
    11.59
    (1.73)
    Month 6
    10.40
    (1.48)
    10.46
    (2.18)
    3. Secondary Outcome
    Title Young Mania Rating Scale (YMRS) Total Score
    Description 11-item standardized, well-validated scale used to measure manic symptoms; sensitive to treatment effects in manic patients. Scores range from 0-60, higher scores represent more severe manic symptoms.
    Time Frame Monthly for 6 months

    Outcome Measure Data

    Analysis Population Description
    Intent to Treat Analysis; excludes 7 screen failures
    Arm/Group Title Ramelteon Placebo
    Arm/Group Description one 8 mg tablet at bedtime for up to 6 months one tablet at bedtime for up to 6 months
    Measure Participants 42 41
    Baseline
    7.02
    (0.43)
    6.59
    (0.44)
    Month 1
    5.89
    (0.51)
    6.46
    (0.52)
    Month 2
    5.91
    (0.80)
    7.75
    (0.82)
    Month 3
    6.60
    (0.84)
    8.09
    (1.00)
    Month 4
    5.93
    (0.70)
    4.95
    (0.93)
    Month 5
    5.18
    (0.65)
    5.71
    (0.88)
    Month 6
    6.51
    (1.00)
    6.72
    (1.35)
    4. Secondary Outcome
    Title Clinical Global Impressions Bipolar Version(CGI-BP) Severity of Illness Overall Score
    Description 3-part (mania, depression, overall bipolar illness), physician-administered scale used to assess global illness severity; used to measure change. Each part is rated from 1-7, higher scores represent more severe mental illness. Only overall bipolar rating was used.
    Time Frame Monthly for 6 months

    Outcome Measure Data

    Analysis Population Description
    Intent to Treat Analysis; excludes 7 screen failures
    Arm/Group Title Ramelteon Placebo
    Arm/Group Description one 8 mg tablet at bedtime for up to 6 months one tablet at bedtime for up to 6 months
    Measure Participants 42 41
    Baseline
    2.14
    (0.13)
    2.15
    (0.13)
    Month 1
    2.29
    (0.15)
    2.25
    (0.15)
    Month 2
    2.24
    (0.18)
    2.90
    (0.19)
    Month 3
    2.53
    (0.22)
    2.93
    (0.27)
    Month 4
    2.36
    (0.21)
    2.98
    (0.29)
    Month 5
    2.46
    (0.23)
    2.99
    (0.34)
    Month 6
    2.54
    (0.23)
    2.41
    (0.34)
    5. Secondary Outcome
    Title Cumulative Proportion of Participants in Each Arm Surviving Without Relapse
    Description Survival analysis techniques, including Kaplan Meier curves, were used to evaluate group differences in time to relapse. Relapse was defined as a medication initiation or change for manic/depressed/mixed symptoms, a hospitalization for manic/depressed/mixed symptoms, MADRS score >= 16, YMRS score > 14, and suicide risk or imminent risk of suicide. Time to relapse was measured discretely in terms of the number of assessment visits until discontinued from the study.
    Time Frame Monthly for 6 months

    Outcome Measure Data

    Analysis Population Description
    Intent to Treat Analysis; excludes 7 screen failures.
    Arm/Group Title Ramelteon Placebo
    Arm/Group Description one 8 mg tablet at bedtime for up to 6 months one tablet at bedtime for up to 6 months
    Measure Participants 42 41
    Baseline
    1.00
    2.4%
    1.00
    2.4%
    Month 1
    0.929
    2.2%
    0.951
    2.3%
    Month 2
    0.849
    2%
    0.588
    1.4%
    Month 3
    0.716
    1.7%
    0.448
    1.1%
    Month 4
    0.661
    1.6%
    0.384
    0.9%
    Month 5
    0.632
    1.5%
    0.320
    0.8%
    Month 6
    0.566
    1.3%
    0.320
    0.8%

    Adverse Events

    Time Frame
    Adverse Event Reporting Description
    Arm/Group Title Ramelteon Placebo
    Arm/Group Description one 8 mg tablet at bedtime for up to 6 months one tablet at bedtime for up to 6 months
    All Cause Mortality
    Ramelteon Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN)
    Serious Adverse Events
    Ramelteon Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/42 (0%) 0/41 (0%)
    Other (Not Including Serious) Adverse Events
    Ramelteon Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 12/42 (28.6%) 12/41 (29.3%)
    Gastrointestinal disorders
    Diarrhea NOS 1/42 (2.4%) 1 0/41 (0%) 0
    General disorders
    Dizziness 1/42 (2.4%) 1 0/41 (0%) 0
    Dry mouth 0/42 (0%) 0 1/41 (2.4%) 1
    Fatigue 1/42 (2.4%) 1 4/41 (9.8%) 4
    Forgetfulness 0/42 (0%) 0 1/41 (2.4%) 1
    Headache NOS 1/42 (2.4%) 1 1/41 (2.4%) 1
    Insomnia exacerbated 1/42 (2.4%) 1 0/41 (0%) 0
    Restless legs 0/42 (0%) 0 1/41 (2.4%) 1
    Somnolence 3/42 (7.1%) 3 1/41 (2.4%) 1
    Vivid dreams 3/42 (7.1%) 3 1/41 (2.4%) 1
    Psychiatric disorders
    Anxiety 1/42 (2.4%) 1 2/41 (4.9%) 2

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    All Principal Investigators ARE 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.

    Results Point of Contact

    Name/Title Edward R. Norris, MD
    Organization Lehigh Valley Hospital
    Phone (610) 402-5766
    Email Edward.Norris@lvh.com
    Responsible Party:
    Edward R. Norris, MD, Physician-Investigator, Lehigh Valley Hospital
    ClinicalTrials.gov Identifier:
    NCT00552760
    Other Study ID Numbers:
    • 07-006R
    First Posted:
    Nov 2, 2007
    Last Update Posted:
    Apr 14, 2014
    Last Verified:
    Mar 1, 2014