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 ramelteon can facilitate the discontinuation of zolpidem in Subjects with Chronic Insomnia

Study Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), 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.

Although normal control of the sleep-wake cycle is exerted by the suprachiasmatic nucleus via melatonin-1 and melatonin-2 receptors, current pharmacologic treatments for insomnia mainly involve GABAergic (gamma-aminobutyric acid) mechanisms: most currently prescribed sleep agents are benzodiazepine receptor agonists, which induce sleep by binding to the benzodiazepine receptor site of the GABA-A receptor complex. Gamma-aminobutyric acid is the major inhibitory transmitter in the central nervous system, and its receptors are distributed widely throughout the brain. In addition to sleep, benzodiazepine receptor agonists can cause a wide range of ancillary effects not directly related to sleep, depending on the precise subset of GABA-A receptors activated. These include sedative, anxiolytic, muscle-relaxant, and amnesic effects. The risk of tolerance, dependence, and abuse associated with the benzodiazepine receptor agonists may also reflect effects of these drugs on the GABA-A receptor complex.

Ramelteon is under global development as a sleep-promoting agent. Ramelteon demonstrates affinity and selectivity for human melatonin-1 or melatonin-2 receptors. Ramelteon also demonstrates full agonist activity relative to melatonin in cells expressing human melatonin-1 or melatonin-2 receptors.

Ramelteon and its major metabolite, M-II, have negligible affinity for the GABA-A receptor complex, as well as for receptors that bind dopamine, serotonin, acetylcholine, glutamate, noradrenaline, and various neuropeptides, cytokines, and opiates.

Zolpidem is the most commonly prescribed hypnotic in the USA 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.

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: 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 Discontinue Zolpidem Therapy.
  • Time Frame: Week 11
    Safety Issue?: No

Secondary Measures

• Change from Baseline in Zolpidem Dosage.
  • Time Frame: Weeks 1, 3, 5, 7, 8, 9, and 11 or Final Visit
    Safety Issue?: No
• Change from Baseline in Frequency of Zolpidem Consumption.
  • Time Frame: Weeks 1, 3, 5, 7, 8, 9, and 11 or Final Visit
    Safety Issue?: No
• Percentage of subjects who achieved a 50% Reduction in Zolpidem Dosage.
  • Time Frame: Week 11
    Safety Issue?: No
• Percentage of Subjects who Achieve a 50% Reduction in the Frequency of Zolpidem Dosage.
  • Time Frame: Weeks 3, 5, 7, and 9 or Final Visit
    Safety Issue?: No
• Adverse Events.
  • Time Frame: Weeks 1, 3, 5, 7, 9, 11, and 12 or Final Visit
    Safety Issue?: Yes
• Physical Examinations.
  • Time Frame: Weeks 5, 11, and 12 or Final Visit
    Safety Issue?: Yes
• Clinical Laboratory Hematology Test Results.
  • Time Frame: Weeks 5, 11, and 12 or Final Visit
    Safety Issue?: Yes
• Clinical Laboratory Chemistry Test Results.
  • Time Frame: Weeks 5, 11, and 12 or Final Visit
    Safety Issue?: Yes
• Clinical Laboratory Urinalysis Test Results.
  • Time Frame: Week 12 or Final Visit
    Safety Issue?: Yes
• Vital Signs.
  • Time Frame: Weeks 5 and 12 or Final Visit
    Safety Issue?: Yes
• Electrocardiograms.
  • Time Frame: Week 12 or Final Visit
    Safety Issue?: Yes

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 or 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 un-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 July 02, 2009

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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