Facilitation of Zolpidem (≥10 mg) Discontinuation Through Use of Ramelteon in Subjects With Chronic Insomnia

Study Overview
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Brief Summary
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The purpose of this study is to assess whether ramelteon, once daily (QD), can facilitate the discontinuation of zolpidem in subjects with chronic insomnia.

Detailed Description
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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.

Official Title
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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

Conditions
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Chronic Insomnia

Intervention / Treatment
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* Drug: Ramelteon and zolpidem
* Drug: Placebo and zolpidem


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ramelteon 8 mg QD and current Zolpidem therapy<br>Zolpidem therapy will be reduced by dose, frequency, or both for up to 10 weeks. | Drug: Ramelteon and zolpidem<br>* Ramelteon 8 mg, tablets, orally, once daily and current zolpidem therapy incrementally reduced by dose, frequency, or both for up to 10 weeks.<br>* Other names: Ambien®;|
| Placebo Comparator: Placebo QD and current Zolpidem therapy<br>Zolpidem therapy will be reduced by dose, frequency, or both for up to 10 weeks. | Drug: Placebo and zolpidem<br>* Ramelteon placebo-matching tablets, orally, once daily and current zolpidem therapy incrementally reduced by dose, frequency, or both for up to 10 weeks.<br>* Other names: Ambien®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Discontinued Zolpidem Therapy | Participants reduced zolpidem incrementally from Week 3 to Week 10 of the double-blind treatment period (DBTP). A participant who did not take any zolpidem during the last 7 days of the DBTP was defined as having completely discontinued zolpidem by that time point. The number of subjects who discontinued zolpidem at the end of the DBTP was summarized. | Week 10 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Weekly Zolpidem Dosage During Weeks 1-2 | Dosages of zolpidem taken were recorded during Weeks 1-2 of the DBTP. Differences in dosages from baseline were summarized. Weekly dosage was calculated as total amount of zolpidem taken divided by the number of days within the phase, multiplied by 7. | Baseline and Weeks 1-2 | 
| Change From Baseline in Weekly Zolpidem Dosage During Weeks 3-4 | Dosages of zolpidem taken were recorded during Weeks 3-4 of the DBTP. Differences in dosages from baseline were summarized. Weekly dosage was calculated as total amount of zolpidem taken divided by the number of days within the phase, multiplied by 7. | Baseline and Weeks 3-4 | 
| Change From Baseline in Weekly Zolpidem Dosage During Weeks 5-6 | Dosages of zolpidem taken were recorded during Weeks 5-6 of the DBTP. Differences in dosages from baseline were summarized. Weekly dosage was calculated as total amount of zolpidem taken divided by the number of days within the phase, multiplied by 7. | Baseline and Weeks 5-6 | 
| Change From Baseline in Weekly Zolpidem Dosage During Weeks 7-8 | Dosages of zolpidem taken were recorded during Weeks 7-8 of the double blind period. Differences in dosages from baseline were summarized. | Baseline and Weeks 7-8 | 
| Change From Baseline in Weekly Zolpidem Dosage During Weeks 9-10 | Dosages of zolpidem taken were recorded during Weeks 9-10 of the DBTP. Differences in dosages from baseline were summarized. Weekly dosage was calculated as total amount of zolpidem taken divided by the number of days within the phase, multiplied by 7. | Baseline and Weeks 9-10 | 
| Change From Baseline in Weekly Zolpidem Frequency During Weeks 1-2 | The number of nights zolpidem was taken was recorded during Weeks 1-2 of the DBTP. Weekly frequency was calculated as the number of nights zolpidem was taken divided by the number of days within the period, multiplied by 7. Differences in frequency from BL were summarized. | Baseline and Weeks 1-2 | 
| Change From Baseline in Weekly Zolpidem Frequency During Weeks 3-4 | The number of nights zolpidem was taken was recorded during Weeks 3-4 of the DBTP. Weekly frequency was calculated as the number of nights zolpidem was taken divided by the number of days within the period, multiplied by 7. Differences in frequency from baseline were summarized. | Weeks 3-4 | 
| Change From Baseline in Weekly Zolpidem Frequency During Weeks 5-6 | The number of nights zolpidem was taken was recorded during Weeks 5-6 of the DBTP. Weekly frequency was calculated as the number of nights zolpidem was taken divided by the number of days within the period, multiplied by 7. Differences in frequency from baseline were summarized. | Weeks 5-6 | 
| Change From Baseline in Weekly Zolpidem Frequency During Weeks 7-8 | The number of nights zolpidem was taken was recorded during Weeks 7-8 of the DBTP. Weekly frequency was calculated as the number of nights zolpidem was taken divided by the number of days within the period, multiplied by 7. Differences in frequency from baseline were summarized. | Baseline and Weeks 7-8 | 
| Change From Baseline in Weekly Zolpidem Frequency During Weeks 9-10 | The number of nights zolpidem was taken was recorded during Weeks 9-10 of the DBTP. Weekly frequency was calculated as the number of nights zolpidem was taken divided by the number of days within the period, multiplied by 7. Differences in frequency from baseline were summarized. | Baseline and Weeks 9-10 | 
| Participants Who Completely Discontinued Zolpidem at the End of Double-Blind Treatment Period, by Method of Discontinuation | Participants who took no zolpidem during the last 7 days of the DBTP were completely discontinued from zolpidem. Participants who completely discontinued zolpidem via reduction in zolpidem use frequency (alone) were not summarized. | Weeks 1-10 | 
| Participants Who Achieved a 50% Reduction in Zolpidem Dosage at the End of the Double-Blind Treatment Period | Participants who achieved a 50% reduction in zolpidem dosage (or frequency) at the end of the DBTP (ie, the end of Reduction Phase 4) were summarized. The reduction in dosage at Reduction Phase 4=[1-(Reduction Phase 4 weekly dosage/baseline weekly dosage)]*100%. | Baseline and Week 10 | 
| Participants Who Achieved a 50% Reduction in Zolpidem Dosage at Any Time During the Double-Blind Treatment Period | Participants who achieved a 50% reduction in zolpidem dosage at any previously defined 2-week period (ie, reduction phase) during the DBTP were summarized. The reduction in dosage at any time=[1-(reduction phase weekly dosage/baseline weekly dosage)]*100%. | Baseline and Weeks 1-10 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic Insomnia, Sleep Initiation and Maintenance Disorder, Drug Therapy