Official Title: “Randomized, Double Blind, Placebo-Controlled Study to Assess Whether the Administration of Ramelteon Could Facilitate the Discontinuation of Zolpidem (Ambien®) ≥10 mg Therapy in Subjects With Chronic Insomnia”

The purpose of this study is to assess whether once-daily ramelteon administration can facilitate the discontinuation of zolpidem in subjects with chronic insomnia.

Study Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Investigator), Placebo Control, Parallel Assignment, Safety/Efficacy Study

Study Primary Completion Date: March 2008

Approximately 60 to 70 million adults in the United States alone are affected by insomnia.

Daytime symptoms of insomnia include tiredness, lack of energy, difficulty concentrating, and irritability. Recent epidemiologic research focusing on the quality of life has identified significant insomnia-related morbidities that relate to work productivity, health care utilization, and risk of depression. Insomnia is associated with diminished work output, absenteeism, and greater rates of accidents.

Zolpidem is the most commonly prescribed hypnotic in the United States for patients suffering from insomnia.

The purpose of this study is to assess whether ramelteon therapy can facilitate the discontinuation of benzodiazepine therapy in long term users. Subject participation in this study is anticipated to be about 17 weeks.

Subjects were screened and enrolled in a 4-week placebo run-in period, may have been randomized to a 10-week double-blind treatment period, and may have completed with a 2-week open-label treatment period. In the double-blind treatment period, subjects were randomized to one of two treatments: either ramelteon 8 mg tablets taken orally once-daily with concomitant current zolpidem therapy or to placebo-matching tablets once daily with concomitant current zolpidem therapy. Subjects incrementally reduced zolpidem therapy by dose, frequency, or both for up to 10 weeks. Only those subjects who completed the double-blind treatment period and had achieved a 50% reduction in zolpidem therapy during the double-blind treatment period participated in the open-label treatment period in which 8 mg ramelteon was administered. Zolpidem consumed during the open-label treatment period was recorded.

Intervention(s) in this Clinical Trial

• Drug: Ramelteon and zolpidem
  • Ramelteon 8 mg, tablets, orally, once daily and current zolpidem therapy incrementally reduced by dose, frequency, or both for up to 10 weeks.
• Drug: Placebo and zolpidem
  • Ramelteon placebo-matching tablets, orally, once daily and current zolpidem therapy incrementally reduced by dose, frequency, or both for up to 10 weeks.

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 1
• Placebo Comparator: 2

Primary Measures

• Percentage of Subjects Who Discontinued Zolpidem Therapy
  • Time Frame: Week 10
    Safety Issue?: No

Secondary Measures

• Change From Baseline in Weekly Zolpidem Dosage During Weeks 1-2
  • Time Frame: Baseline and Weeks 1-2
    Safety Issue?: No
• Change From Baseline in Weekly Zolpidem Dosage During Weeks 3-4
  • Time Frame: Baseline and Weeks 3-4
    Safety Issue?: No
• Change From Baseline in Weekly Zolpidem Dosage During Weeks 5-6
  • Time Frame: Baseline and Weeks 5-6
    Safety Issue?: No
• Change From Baseline in Weekly Zolpidem Dosage During Weeks 7-8
  • Time Frame: Baseline and Weeks 7-8
    Safety Issue?: No
• Change From Baseline in Weekly Zolpidem Dosage During Weeks 9-10
  • Time Frame: Baseline and Weeks 9-10
    Safety Issue?: No
• Change From Baseline in Weekly Zolpidem Frequency During Weeks 1-2
  • Time Frame: Baseline and Weeks 1-2
    Safety Issue?: No
• Change From Baseline in Weekly Zolpidem Frequency During Weeks 3-4
  • Time Frame: Weeks 3-4
    Safety Issue?: No
• Change From Baseline in Weekly Zolpidem Frequency During Weeks 5-6
  • Time Frame: Weeks 5-6
    Safety Issue?: No
• Change From Baseline in Weekly Zolpidem Frequency During Weeks 7-8
  • Time Frame: Baseline and Weeks 7-8
    Safety Issue?: No
• Change From Baseline in Weekly Zolpidem Frequency During Weeks 9-10
  • Time Frame: Baseline and Weeks 9-10
    Safety Issue?: No
• Subjects Who Completely Discontinued Zolpidem at the End of Double-Blind Treatment Period, by Method of Discontinuation
  • Time Frame: Weeks 1-10
    Safety Issue?: No
• Subjects Who Achieved a 50% Reduction in Zolpidem Dosage at the End of the Double-Blind Treatment Period
  • Time Frame: Baseline and Week 10
    Safety Issue?: No
• Subjects Who Achieved a 50% Reduction in Zolpidem Dosage at Any Time During the Double-Blind Treatment Period
  • Time Frame: Baseline and Weeks 1-10
    Safety Issue?: No

Inclusion Criteria

• Chronic insomnia and taking greater than or equal to 10 mg zolpidem at least 4 times per week.
• Has been prescribed zolpidem for difficulty in initiating sleep.
• Must report chronic use of zolpidem greater than or equal to10 mg therapy for a minimum of 3 months prior to entry into Period 1 of the study.
• Must have taken zolpidem greater than or equal to 10 mg therapy for at least 4 of 7 days each week of the 4 weeks immediately prior to entry into the double blind phase, Period 2.
• Expressed a willingness to discontinue zolpidem therapy.
• Habitual bedtime is between 9:00 PM and 1:00 AM based on sleep history.
• Negative test result for hepatitis B surface antigen and hepatitis C virus antibody.
• Females of childbearing potential who are sexually active must agree to use adequate contraception, and can neither be pregnant nor lactating from Screening throughout the duration of the study.

Exclusion Criteria

• Known hypersensitivity to ramelteon, zolpidem, or melatonin.
• Participated in any other investigational study and/or taken any investigational drug within 30 days prior to the first dose of run-in study medication.
• Sleep schedule changes required by employment (eg, shift worker) within 3 months prior to the first night of run-in study medication.
• History of fibromyalgia, history of seizures, sleep apnea, restless leg syndrome, periodic leg syndrome, chronic obstructive pulmonary disease, schizophrenia, bipolar disorder, mental retardation, or cognitive disorder.
• History of drug addiction or drug abuse within the past 12 months.
• History of alcohol abuse within the past 12 months, as defined in Diagnostic and Statistical Manual of Mental Disorders, 4th Edition revised and/or regularly consumes more than 2 alcoholic drinks per day.
• Current significant hepatic, renal, endocrine, cardiovascular, gastrointestinal, pulmonary, hematological, or metabolic disease, unless currently controlled and stable with protocol-allowed medication, within 30 days prior to the first night of run-in study medication.
• Body mass index of less than 18 or greater than 34 (weight /height2).
• Any clinically important abnormal finding as documented by a medical history, physical examination, electrocardiogram, or clinical laboratory tests, as determined by the investigator.
• Positive hepatitis panel.
• Known history of human immunodeficiency virus.
• Any additional conditions(s) that in the investigator's opinion would affect:
• sleep/wake function
• prohibit the subject from completing the study
• indicate that continuation in the study would not be in the best interests of the subject.
• Is required to take or continues taking any disallowed medication, prescription medication, herbal treatment or over-the counter medication, including:
• Melatonin
• Anxiolytics
• Antipsychotics
• Over-the-counter and prescription sedatives
• Hypnotics (excluding zolpidem)
• Narcotic analgesics
• Antidepressants
• Beta-blockers (exception is that Atenolol is permissible)
• Anticonvulsants
• St. John's wort
• Sedating H1 antihistamines
• Kava-kava
• Systemic steroids
• Ginkgo-biloba
• Respiratory stimulants
• Over-the-counter and prescription diet aids
• Sedating Decongestants

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Takeda Global Research & Development Center, Inc.

Overall Clinical Trial Officials and Contacts

Medical Director Clinical Science Study Director Takeda Global Research & Development Center  

Information obtained from ClinicalTrials.gov on February 08, 2010

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00492232

Study ID Number: 01-06-TL-375-071

ClinicalTrials.gov Identifier: NCT00492232

Health Authority: United States: Food and Drug Administration

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