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

A Double-Blind, Randomized, Placebo-Controlled Trial of Ramelteon for the Treatment of Insomnia and Mood Stability in Patients With Euthymic Bipolar Disorder.

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

Study Overview

• Status: Completed
• Conditions: Bipolar Disorder
• Intervention / Treatment: Drug: Ramelteon; Drug: Placebo

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 Type: Interventional
• Enrollment (Actual): 90
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Allentown, Pennsylvania, United States, 18103
      • Lehigh Valley Hospital, Department of Psychiatry

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Placebo	Drug: Placebo; one tablet at bedtime for up to 6 months
EXPERIMENTAL: Ramelteon; 8 mg	Drug: Ramelteon; one 8 mg tablet at bedtime for up to 6 months; Other Names: Rozerem

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pittsburgh Sleep Quality Index (PSQI) Global Score	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.	Monthly for 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Montgomery-Asberg Depression Rating Scale (MADRS) Total Score	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.	Monthly for 6 months
Young Mania Rating Scale (YMRS) Total Score	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.	Monthly for 6 months
Clinical Global Impressions Bipolar Version(CGI-BP) Severity of Illness Overall Score	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.	Monthly for 6 months
Cumulative Proportion of Participants in Each Arm Surviving Without Relapse	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.	Monthly for 6 months

Collaborators and Investigators

• Sponsor: Lehigh Valley Hospital
• Collaborators: Takeda

Publications and helpful links

General Publications

• Buysse DJ, Reynolds CF 3rd, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res. 1989 May;28(2):193-213. doi: 10.1016/0165-1781(89)90047-4.
• Dokucu ME, Yu L, Taghert PH. Lithium- and valproate-induced alterations in circadian locomotor behavior in Drosophila. Neuropsychopharmacology. 2005 Dec;30(12):2216-24. doi: 10.1038/sj.npp.1300764.
• Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979 Apr;134:382-9. doi: 10.1192/bjp.134.4.382.
• Jones SH, Hare DJ, Evershed K. Actigraphic assessment of circadian activity and sleep patterns in bipolar disorder. Bipolar Disord. 2005 Apr;7(2):176-86. doi: 10.1111/j.1399-5618.2005.00187.x.
• American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Washington, CD, American Psychiatric Association, 2000.
• Norris ER, Karen Burke, Correll JR, Zemanek KJ, Lerman J, Primelo RA, Kaufmann MW. A double-blind, randomized, placebo-controlled trial of adjunctive ramelteon for the treatment of insomnia and mood stability in patients with euthymic bipolar disorder. J Affect Disord. 2013 Jan 10;144(1-2):141-7. doi: 10.1016/j.jad.2012.06.023. Epub 2012 Sep 7.

Study record dates

Study Major Dates

• Study Start: November 1, 2007
• Primary Completion (ACTUAL): March 1, 2010
• Study Completion (ACTUAL): May 1, 2010

Study Registration Dates

• First Submitted: October 31, 2007
• First Submitted That Met QC Criteria: October 31, 2007
• First Posted (ESTIMATE): November 2, 2007

Study Record Updates

• Last Update Posted (ESTIMATE): April 14, 2014
• Last Update Submitted That Met QC Criteria: March 17, 2014
• Last Verified: March 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Bipolar and Related Disorders; Bipolar Disorder
• Other Study ID Numbers: 07-006R