Safety of Ramelteon in Subjects With Mild to Moderate Obstructive Sleep Apnea

Study Overview
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Brief Summary
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The purpose of this study is to assess the safety of ramelteon, once daily (QD), in individuals with obstructive sleep apnea.

Detailed Description
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Insomnia is characterized by difficulties initiating and maintaining sleep, or complaints of non-restorative and non-refreshing sleep. Transient insomnia affects approximately one-third to one-half of the US population, based on the results of 2 surveys of representative samples of the adult US population conducted by the Gallup Organization in which respondents were asked if they had ever had difficulty sleeping. Based on reports of regular or frequent sleep difficulty, results from the same studies suggest that approximately one-tenth of the US population experiences chronic insomnia. The ideal treatment for insomnia would reduce the latency to onset of sleep and increase total sleep time, without a negative impact on sleep architecture and without safety concerns or next-day effects. Ramelteon is under global development by Takeda Chemical Industries, Ltd., for the treatment of transient and chronic insomnia and for the treatment of Circadian Rhythm Sleep Disorders. This study is being conducted to assess the safety of Ramelteon in subjects with obstructive sleep apnea. Participation this this study is anticipated to be about 1.5 months.

Official Title
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A Phase II Safety Study of TAK-375 in Subjects With Mild to Moderate Obstructive Sleep Apnea

Conditions
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Sleep Apnea, Obstructive

Intervention / Treatment
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* Drug: Ramelteon or Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria 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. Clinical history of chronic obstructive pulmonary disease and a confirmatory diagnosis based on pulmonary function tests at screening. Moderate: forced expiratory volume in one second/ forced vital capacity less than 70% and forced expiratory volume 135-75% of predicted. Post-bronchodilator forced expiratory volume in one second change from baseline of less than 12%. Negative chest x-ray at screening, other than findings consistent with mild to moderate chronic obstructive pulmonary disease, within the last 6 months. Arterial oxygen saturation during sleep greater than 85% for at least 99% of the recording period, with no arterial oxygen saturation readings less than 80% as assessed by pulse oximetry at polysomnography screening. Arterial oxygen saturation during wakefulness greater than 91% (both supine and sitting) as assessed by pulse oximetry at screening. Habitual bedtime is between 8:30 p.m. and 12:00 a.m. Body mass index between 18 and 34, inclusive. Agrees to remain in the study center for three overnight stays. Exclusion Criteria: Known hypersensitivity to ramelteon or related compounds, including melatonin. Known hypersensitivity to Ventolin® or related compounds. Previously participated in a study involving ramelteon. Participated in any other investigational study and/or taken any investigational drug within 30 days or five half-lives prior to Day 1 of study medication, whichever is longer. Clinical history of acute or chronic respiratory failure, severe chronic obstructive pulmonary disease, or hypercapnia (Partial Pressure of Oxygen in Arterial Blood greater than or equal to45 mmHg). History of or currently has right ventricular hypertrophy on electrocardiogram or right heart failure. Periodic leg movement with arousal index (per hour of sleep) greater than 20 as seen at polysomnography screening. Apnea hypopnea index greater than 15 as seen at polysomnography screening. Acute clinically significant illness within 2 weeks or has been hospitalized within 4 weeks of study participation. Sleep schedule changes required by employment within three months prior to Day 1 of study medication, or has flown across greater than three time zones within seven days prior to screening. Participated in a weight loss program or has substantially altered their exercise routine within 30 days prior to Day 1 of study medications. History of seizures, sleep apnea, restless leg syndrome, period limb movement disorder, other known sleep disorders, schizophrenia, bipolar disease, mental retardation, or cognitive disorder. History of psychiatric disorder within the past 12 months. History of drug addiction or drug abuse within the past 12 months. History of alcohol abuse within the past 12 months and/or regularly consumes 4 or more alcoholic drinks per day. Unable to discontinue the use of hypnotics for the duration of the study. Any clinically important abnormal finding, other than chronic obstructive pulmonary disease, as determined by medical history, physical examination, electrocardiogram, or clinical laboratory tests, as determined by the investigator. Current significant neurological, hepatic, renal, endocrine, cardiovascular, gastrointestinal, pulmonary, hematologic, or metabolic disease, unless currently controlled and stable with protocol-allowed medication 30 days prior to Day 1 of study medication. Hematocrit value greater than 55% at screening. Positive hepatitis panel. 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 Is required to take or continues taking any disallowed medication, prescription medication, herbal treatment or over-the counter medication, including: Anxiolytics Hypnotics Antidepressants Anticonvulsants Sedating H1 antihistamines Systemic steroids Decongestants Over-the-counter and prescription stimulants Over-the-counter and prescription diet aids Central nervous system active drugs and narcotic analgesics Lipophilic beta blockers Melatonin St. John's Wort Kava-kava Gingko biloba

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 64 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: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ramelteon 16 mg QD or Placebo QD<br> | Drug: Ramelteon or Placebo<br>* Ramelteon 16 mg, tablet, orally, once daily for Periods 1 or 2 and ramelteon placebo-matching tablets, orally, once daily for Periods 1 or 2.<br>* Other names: TAK-375;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Apnea Hypopnea Index measured by Respiratory Inductance Plethysmography (RIP) |  | Periods 1 and 2. | 
| Central Apnea Index. |  | Periods 1 and 2. | 
| Mean Oxygen Saturation for the entire night. |  | Periods 1 and 2. | 
| Obstructive Apnea Index. |  | Periods 1 and 2. | 
| Hypopnea Index. |  | Periods 1 and 2. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Oxygen Saturation for the entire night. |  | Periods 1 and 2. | 
| Oxygen Saturation Means for Awake Sleep Stage. |  | Periods 1 and 2. | 
| Oxygen Saturation Means for Non-Rapid Eye Movement Sleep Stage. |  | Periods 1 and 2. | 
| Oxygen Saturation Means for Rapid Eye Movement Sleep Stage. |  | Periods 1 and 2. | 
| Percentage of oxygen saturation is less than 80%. |  | Periods 1 and 2. | 
| Latency to Persistent Sleep. |  | Periods 1 and 2. | 
| Total Sleep Time. |  | Periods 1 and 2. | 
| Sleep Efficiency. |  | Periods 1 and 2. | 
| Awake Time after Persistent Sleep. |  | Periods 1 and 2. | 
| Number of Awakenings after Persistent Sleep. |  | Periods 1 and 2. | 
| Subjective Sleep Latency. |  | Crossover Period 1 AM; Crossover Period 2 AM | 
| Subjective Total Sleep Time. |  | Periods 1 and 2. | 
| Subjective Sleep Quality. |  | Periods 1 and 2. | 
| Subjective Number of Awakenings. |  | Periods 1 and 2. | 
| Subjective Ease of Falling Back to Sleep after Awakening. |  | Periods 1 and 2. | 
| Subjective Level of Alertness. |  | Periods 1 and 2. | 
| Subjective Ability to Concentrate. |  | Periods 1 and 2. | 
| Percentage of Total Sleep Time in REM sleep |  | Periods 1 and 2. | 
| Percentage of Total Sleep Time in Stage 1 NREM sleep |  | Periods 1 and 2. | 
| Percentage of Total Sleep Time in Stage 2 NREM sleep |  | Periods 1 and 2. | 
| Percentage of Total Sleep Time in Stage 3/4 NREM sleep |  | Periods 1 and 2. | 
| Percentage of Total Sleep Time in latency to REM as determined by polysomnography |  | Periods 1 and 2. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Insomnia, Sleep Apnea, Obstructive, Drug Therapy