Facilitation of Zolpidem Discontinuation Through Use of Ramelteon in Subjects With Chronic Insomnia - Full Text View

Sponsored by:	Takeda Global Research & Development Center, Inc.
Information provided by:	Takeda Global Research & Development Center, Inc.
ClinicalTrials.gov Identifier:	NCT00492232

Purpose

The purpose of this study is to assess whether ramelteon can facilitate the discontinuation of zolpidem in Subjects with Chronic Insomnia

Condition	Intervention	Phase
Chronic Insomnia	Drug: Ramelteon and zolpidem Drug: Zolpidem	Phase IV

Drug Information available for: Zolpidem Ramelteon

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Parallel Assignment, Safety/Efficacy Study
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

Further study details as provided by Takeda Global Research & Development Center, Inc.:

Primary Outcome Measures:

Percentage of Subjects who Discontinue Zolpidem Therapy. [ Time Frame: Week 11 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Change from Baseline in Zolpidem Dosage. [ Time Frame: Weeks 1, 3, 5, 7, 8, 9, and 11 or Final Visit ] [ Designated as 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 ] [ Designated as safety issue: No ]
Percentage of subjects who achieved a 50% Reduction in Zolpidem Dosage. [ Time Frame: Week 11 ] [ Designated as 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 ] [ Designated as safety issue: No ]
Adverse Events. [ Time Frame: Weeks 1, 3, 5, 7, 9, 11, and 12 or Final Visit ] [ Designated as safety issue: Yes ]
Physical Examinations. [ Time Frame: Weeks 5, 11, and 12 or Final Visit ] [ Designated as safety issue: Yes ]
Clinical Laboratory Hematology Test Results. [ Time Frame: Weeks 5, 11, and 12 or Final Visit ] [ Designated as safety issue: Yes ]
Clinical Laboratory Chemistry Test Results. [ Time Frame: Weeks 5, 11, and 12 or Final Visit ] [ Designated as safety issue: Yes ]
Clinical Laboratory Urinalysis Test Results. [ Time Frame: Week 12 or Final Visit ] [ Designated as safety issue: Yes ]
Vital Signs. [ Time Frame: Weeks 5 and 12 or Final Visit ] [ Designated as safety issue: Yes ]
Electrocardiograms. [ Time Frame: Week 12 or Final Visit ] [ Designated as safety issue: Yes ]

Enrollment:	135
Study Start Date:	April 2007
Study Completion Date:	May 2008
Primary Completion Date:	March 2008 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
1: Experimental	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
2: Placebo Comparator	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

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.

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.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00492232

Show 41 Study Locations

Sponsors and Collaborators

Takeda Global Research & Development Center, Inc.

Investigators

Study Director:

Medical Director Clinical Science

Takeda Global Research & Development Center

More Information

Additional Information:

Rozerem Package Insert This link exits the ClinicalTrials.gov site

FDA Safety Alerts and Recalls This link exits the ClinicalTrials.gov site

No publications provided

Responsible Party:	Takeda Global Research & Development Center, Inc. ( Sr. VP, Clinical Science )
Study ID Numbers:	01-06-TL-375-071
Study First Received:	June 25, 2007
Last Updated:	January 23, 2009
ClinicalTrials.gov Identifier:	NCT00492232 History of Changes
Health Authority:	United States: Food and Drug Administration

Keywords provided by Takeda Global Research & Development Center, Inc.:

Chronic Insomnia
Sleep Initiation and Maintenance Disorder
Drug Therapy

Study placed in the following topic categories:

Zolpidem
Sleep Initiation and Maintenance Disorders
Neurotransmitter Agents
Mental Disorders
GABA Agonists

Hypnotics and Sedatives
Central Nervous System Depressants
Dyssomnias
Sleep Disorders
Sleep Disorders, Intrinsic

Additional relevant MeSH terms:

Sleep Initiation and Maintenance Disorders
Zolpidem
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Nervous System Diseases
Physiological Effects of Drugs
Central Nervous System Depressants
Dyssomnias
Sleep Disorders

Pharmacologic Actions
Sleep Disorders, Intrinsic
Mental Disorders
Therapeutic Uses
GABA Agonists
Hypnotics and Sedatives
GABA Agents
Central Nervous System Agents

ClinicalTrials.gov processed this record on May 06, 2009