Efficacy and Safety of Ramelteon Combined With Gabapentin in Treating Patients With Insomnia

Overview[ - collapse ][ - ]

Purpose The purpose of this study is to determine the efficacy and safety of ramelteon, once daily (QD), taken in combination with Gabapentin for treating insomnia.
ConditionSleep Initiation and Maintenance Disorders
InterventionDrug: Ramelteon and gabapentin
Drug: Ramelteon and gabapentin
Drug: Ramelteon
Drug: Gabapentin
Drug: Placebo
PhasePhase 2
SponsorTakeda
Responsible PartyTakeda
ClinicalTrials.gov IdentifierNCT00755508
First ReceivedSeptember 17, 2008
Last UpdatedFebruary 27, 2012
Last verifiedFebruary 2012

Tracking Information[ + expand ][ + ]

First Received DateSeptember 17, 2008
Last Updated DateFebruary 27, 2012
Start DateNovember 2005
Estimated Primary Completion DateSeptember 2006
Current Primary Outcome MeasuresMean objective wake time after persistent sleep onset in sleep lab. [Time Frame: Nights: 1 and 2.] [Designated as safety issue: No]
Current Secondary Outcome Measures
  • Subjective wake time after persistent sleep onset determined by the post-sleep questionnaire. [Time Frame: Nights: 1, 2, 3, 4, 5, 6 and 7.] [Designated as safety issue: No]
  • Number of awakenings after persistent sleep polysomnography. [Time Frame: Nights: 1 and 2] [Designated as safety issue: No]
  • Subjective number of awakenings as determined by post-sleep questionnaire. [Time Frame: Nights: 1, 2, 3, 4, 5, 6 and 7.] [Designated as safety issue: No]
  • Latency to persistent sleep and total sleep time as determined by polysomnography. [Time Frame: Nights: 1 and 2] [Designated as safety issue: No]
  • Subjective sleep latency, subjective total sleep time and subjective sleep quality determined by post-sleep questionnaire. [Time Frame: Nights: 1, 2, 3, 4, 5, 6 and 7.] [Designated as safety issue: No]
  • Daytime functioning determined by pre-sleep questionnaire. [Time Frame: Nights: 1, 2, 3, 4, 5, 6 and 7.] [Designated as safety issue: No]

Descriptive Information[ + expand ][ + ]

Brief TitleEfficacy and Safety of Ramelteon Combined With Gabapentin in Treating Patients With Insomnia
Official TitleA Phase 2, Double-Blind, Randomized, Placebo-Controlled, Parallel-Group, Multicenter, Proof-of-Concept Study to Evaluate the Safety and Efficacy of ROZEREM™ Taken in Combination With Gabapentin for the Treatment of Subjects With Chronic Insomnia
Brief Summary
The purpose of this study is to determine the efficacy and safety of ramelteon, once daily
(QD), taken in combination with Gabapentin for treating insomnia.
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 quality of life has identified
significant insomnia-related morbidities that relate to work productivity, health care
utilization, and risk of depression. Insomnia is also associated with diminished work
output, absenteeism, and greater rates of accidents. gamma-aminobutyric acid is the major
inhibitory transmitter in the central nervous system and most currently prescribed sleep
agents are benzodiazepine receptor agonists, which induce sleep by binding to the
benzodiazepine receptor site of the gamma-aminobutyric acid -A receptor complex. In addition
to sleep, benzodiazepine receptor agonists can cause a wide range of ancillary effects not
directly related to sleep, including sedative, anxiolytic, muscle-relaxant, and amnesic
effects, and have risks of tolerance, dependence, and abuse potential.

Gabapentin is a novel anti-epileptic drug, which is currently used in subjects with partial
seizures. Some studies have shown that gabapentin also has an effect on sleep architecture.
In several studies, which included healthy subjects, epileptic subjects, and subjects with
restless leg syndrome, the use of gabapentin been shown to prolong slow-wave sleep, increase
total sleep time and sleep efficiency, and decrease number of awakenings.

Ramelteon is a melatonin receptor agonist with affinity for the human melatonin receptor
subtype 1, melatonin receptor subtype 2 and selectivity over the melatonin receptor subtype
3 receptor. It also demonstrates agonist activity in vitro relative to melatonin in cells
expressing human melatonin receptor subtype 1 or melatonin receptor subtype 2 receptors. The
binding of melatonin at these receptors is thought to contribute to maintenance of the
circadian rhythm underlying the normal sleep-wake cycle.

The purpose of this trial is to determine if the co-administration of Ramelteon and
gabapentin may produce increased sleep efficiency through reduction of wake time after
persistent sleep onset, in addition to the reduction in sleep latency and increase in sleep
duration. Study participation is anticipated to be about one month.
Study TypeInterventional
Study PhasePhase 2
Study DesignAllocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
ConditionSleep Initiation and Maintenance Disorders
InterventionDrug: Ramelteon and gabapentin
Ramelteon 4 mg, tablets, orally, once daily and gabapentin 400 mg, capsules, orally, once daily for up to one week.
Other Names:
  • TAK-375
  • Ramelteon
  • Neurontin®
  • Rozerem
Drug: Ramelteon and gabapentin
Ramelteon 8 mg, tablets, orally, once daily and gabapentin 800 mg, capsules, orally, once daily for up to one week.
Other Names:
  • TAK-375
  • Ramelteon
  • Neurontin®
  • Rozerem
Drug: Ramelteon
Ramelteon 8 mg, tablets, orally, once daily and gabapentin placebo-matching capsules, orally, once daily for up to one week.
Other Names:
  • TAK-375
  • Ramelteon
  • Rozerem
Drug: Gabapentin
Ramelteon placebo-matching tablets, orally, once daily and gabapentin 800 mg, capsules, orally, once daily for up to one week.
Other Names:
  • Neurontin®
  • Rozerem
Drug: Placebo
Ramelteon placebo-matching tablets, orally, once daily and gabapentin placebo-matching capsules, orally, once daily for up to one week.
Other Names:
Rozerem
Study Arm (s)
  • Experimental: Ramelteon 4 mg QD and Gabapentin 400 mg QD
  • Experimental: Ramelteon 8 mg QD and Gabapentin 800 mg QD
  • Experimental: Ramelteon 8 mg QD and Gabapentin Placebo QD
  • Active Comparator: Gabapentin 800 mg QD
  • Placebo Comparator: Placebo

Recruitment Information[ + expand ][ + ]

Recruitment StatusCompleted
Estimated Enrollment378
Estimated Completion DateSeptember 2006
Estimated Primary Completion DateSeptember 2006
Eligibility Criteria
Inclusion Criteria:

- Female patients of childbearing potential must be nonpregnant and nonlactating, and
utilizing an acceptable method of contraception.

- Based on sleep history, the subject has had primary insomnia as defined by the
Diagnostic and Statistical Manual of Mental Disorders, 4th Edition Revised
(DSM-IV-TR™) for at least 3 months.

- Based on sleep history, reports a subjective sleep latency greater than or equal to
45 minutes and reports wake time after persistent sleep onset of greater than or
equal to 45 minutes.

- Has an average wake time after persistent sleep onset of at least 60 minutes as
determined by polysomnography during Screening (Day minus 7 PM through Day minus 5
AM). Wake time after persistent sleep onset must be greater than or equal to 30
minutes each night of polysomnography Screening.

- Reports wake time after persistent sleep onset values of at least 60 minutes on at
least 3 of the 7 nights during the single-blind screening period (Day minus 6 AM
through Day 1 AM) as determined by post-sleep questionnaire.

- Has an average latency to persistent sleep of at least 20 minutes as determined by
polysomnography during Screening (Day minus 7 PM through Day minus 5 AM).

- Based on sleep history, has an habitual bedtime between 9:00 PM and 1:00 AM.

- The subject is willing to have a fixed bedtime and agrees to go to bed within plus or
minus 30 minutes of the habitual bedtime during the entire study and agrees to remain
in bed for at least 8 hours each night.

- Based on sleep history, has not been using pharmacological assistance to sleep or
uses pharmacological assistance no more than 4 times per week during the 3 months
prior to Initial Screening.

- Has consistent access to a touch-tone phone and are willing to complete telephone
questionnaires twice daily during participation in the study.

Exclusion Criteria:

- Has a known hypersensitivity to gabapentin or its ingredients, ramelteon or related
compounds, including melatonin, and 5-hydroxytryptophan.

- Has participated in any other investigational study and/or taken any investigational
drug within 30 days prior to the first dose of single-blind study medication.

- Has sleep schedule changes required by employment (eg, shift worker) within 3 months
prior to the first dose of single-blind study medication.

- Has flown across greater than 3 time zones within 7 days prior to Initial Screening,
or will travel across 2 or more time zones during the course of the study.

- Has participated in a weight loss program or has substantially altered their exercise
routine within 30 days prior to the first dose of single-blind study medication.

- Has ever had a history of seizures, sleep apnea, and/or chronic obstructive pulmonary
disease.

- Has a history of psychiatric disorder (including anxiety, depression, mental
retardation, cognitive disorder, bipolar illness and schizophrenia) within the past 6
months of Initial Screening.

- Has a history of fibromyalgia.

- Has a history of drug addiction or drug abuse within the past 12 months of Initial
Screening.

- Has a history of alcohol abuse within the past 12 months, as defined in DSM-IV-TR™
and/or regularly consumes more than 2 alcoholic drinks per day.

- Has a current significant hepatic, endocrine, cardiovascular, gastrointestinal,
pulmonary, hematological, metabolic or neurological disorders, unless currently
controlled and stable with protocol-allowed medication, within 30 days prior to the
first dose of single-blind study medication.

- Has any diagnosed renal impairment within 30 days prior to the first dose of
single-blind study medication.

- Has a previous history of cancer, other than basal cell carcinoma, that has not been
in remission for at least 5 years prior to the first dose of single-blind study drug.

- Uses tobacco products or any other products that may interfere with the sleep wake
cycle during nightly awakenings.

- Is required to take or intends to continue taking any disallowed medication or any
prescription medication or over-the counter medication that is known to affect the
sleep/wake function or otherwise interfere with evaluation of the study medication,
including:

- Anxiolytics central nervous system active drugs (including herbal)

- Hypnotics Narcotic analgesics

- Antidepressants Beta blockers

- Anticonvulsants St. John's Wort

- Sedating H1 antihistamines Kava-kava

- Systemic steroids Ginkgo-biloba

- Respiratory stimulants over-the counter and prescription stimulants

- Sedating decongestants over-the counter and prescription diet aids

- Antipsychotics over-the counter sleep aids

- Muscle relaxants Antacids

- Melatonin and all other drugs or supplements known to affect sleep/wake
function.

- Has a positive hepatitis panel including anti- hepatitis A virus, hepatitis B surface
antigen or anti-hepatitis C virus.

- Has a positive urine drug screen including alcohol at Initial Screening or a positive
breathalyzer test at each polysomnography Screening check-in.

- Has an apnea hypopnea index (per hour of sleep) >15 as seen on polysomnography, on
the first night of the polysomnography screening.

- Has a history of restless leg syndrome.

- The subject has a body mass index of less than 18 or greater than 34 (weight
/height2).

- Has any additional condition(s) that in the Investigator's opinion would:

- Affect sleep/wake function

- Prohibit the subject from completing the study

- Not be in the best interest of the subject.
GenderBoth
Ages18 Years
Accepts Healthy VolunteersNo
ContactsNot Provided
Location CountriesNot Provided

Administrative Information[ + expand ][ + ]

NCT Number NCT00755508
Other Study ID Numbers01-05-TL-375-055
Has Data Monitoring CommitteeNo
Information Provided ByTakeda
Study SponsorTakeda
CollaboratorsNot Provided
Investigators Study Director: Sr. VP Clinical Science Takeda
Verification DateFebruary 2012