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

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, once daily (QD), can facilitate the discontinuation of zolpidem in subjects with chronic insomnia.

Study Overview

• Status: Completed
• Conditions: Chronic Insomnia
• Intervention / Treatment: Drug: Ramelteon and zolpidem; Drug: Placebo and zolpidem

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 135
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Arkansas
    • Hot Springs, Arkansas, United States
  • California
    • Anaheim, California, United States
    • Fountain Valley, California, United States
    • La Mesa, California, United States
    • Los Angeles, California, United States
    • Redlands, California, United States
    • San Diego, California, United States
    • San Francisco, California, United States
    • Santa Monica, California, United States
  • Colorado
    • Denver, Colorado, United States
  • Florida
    • Clearwater, Florida, United States
    • Hollywood, Florida, United States
    • Kissimmee, Florida, United States
    • Naples, Florida, United States
    • Pembroke Pines, Florida, United States
    • Winter Park, Florida, United States
  • Georgia
    • Atlanta, Georgia, United States
    • Austell, Georgia, United States
  • Idaho
    • Boise, Idaho, United States
  • Kentucky
    • Louisville, Kentucky, United States
  • Louisiana
    • Metairie, Louisiana, United States
  • Maryland
    • Chevy Chase, Maryland, United States
  • Missouri
    • St. Louis, Missouri, United States
  • Nebraska
    • Lincoln, Nebraska, United States
  • New York
    • New York, New York, United States
    • West Seneca, New York, United States
  • North Carolina
    • Raleigh, North Carolina, United States
    • Wilmington, North Carolina, United States
  • Ohio
    • Cincinnati, Ohio, United States
    • Toledo, Ohio, United States
  • Oregon
    • Portland, Oregon, United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States
  • South Carolina
    • Greer, South Carolina, United States
  • Tennessee
    • Fayetteville, Tennessee, United States
  • Texas
    • Austin, Texas, United States
    • Dallas, Texas, United States
    • Fort Worth, Texas, United States
    • Houston, Texas, United States
    • San Angelo, Texas, United States
    • San Antonio, Texas, United States
  • Utah
    • Salt Lake City, Utah, United States

Participation Criteria

Eligibility Criteria

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

Description

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

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
EXPERIMENTAL: Ramelteon 8 mg QD and current Zolpidem therapy; Zolpidem therapy will be reduced by dose, frequency, or both for up to 10 weeks.	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.; Other Names: TAK-375; Ambien®; Rozerem™
PLACEBO_COMPARATOR: Placebo QD and current Zolpidem therapy; Zolpidem therapy will be 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.; Other Names: Ambien®

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Takeda

Study record dates

Study Major Dates

• Study Start: April 1, 2007
• Primary Completion (ACTUAL): March 1, 2008
• Study Completion (ACTUAL): May 1, 2008

Study Registration Dates

• First Submitted: June 25, 2007
• First Submitted That Met QC Criteria: June 25, 2007
• First Posted (ESTIMATE): June 27, 2007

Study Record Updates

• Last Update Posted (ESTIMATE): July 20, 2010
• Last Update Submitted That Met QC Criteria: July 13, 2010
• Last Verified: July 1, 2010

More Information

Terms related to this study

• Keywords: Drug Therapy; Chronic Insomnia; Sleep Initiation and Maintenance Disorder
• Additional Relevant MeSH Terms: Mental Disorders; Nervous System Diseases; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Sleep Initiation and Maintenance Disorders; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Hypnotics and Sedatives; GABA Agents; Sleep Aids, Pharmaceutical; GABA-A Receptor Agonists; GABA Agonists; Zolpidem
• Other Study ID Numbers: 01-06-TL-375-071; U1111-1114-3262 (REGISTRY: WHO)