| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 8 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10053851 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of this study is to evaluate the near maximum effect of ramelteon 8mg once daily based on balance platform versus placebo with zopiclone 7.5mg as a reference arm in subjects with chronic insomnia with subject’s eyes open. |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the treatment effect of ramelteon 8mg once daily in reduction of objective and subjective latency to persistent sleep (LPS) and changes in balance postural sway with eyes closed compared to placebo with Zopiclone 7.5mg as a reference arm in subjects with chronic insomnia.
To evaluate the residual pharmacological effect, sleep architecture and withdrawal effect of ramelteon 8mg once daily compare to placebo with Zopiclone 7.5mg as a reference arm in subjects with chronic insomnia.
To evaluate the safety of ramelteon in insomniac population.
Third objective(s):
The third objective of this study is to evaluate daytime function activities. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
General
• The subject is a male or female 18 to 64 years of age, inclusive.
• The subject is capable of understanding and willing to comply with the protocol and has signed the informed consent document at screening prior to any study related procedures being performed.
Study-specific
• The subject, if female, is non-pregnant and non-lactating. Females of childbearing potential must use appropriate birth control (barrier methods, hormonal contraceptives, and/or intrauterine devices) for the entire duration of the study. Females who are not of childbearing potential must be postmenopausal for 1 year or have a history of hysterectomy and/or bilateral oophorectomy.
• Based on sleep history, the subject has had chronic insomnia as defined by the following:
• A complaint is difficulty initiating or maintaining sleep or of nonrestorative sleeps that lasts for at least 3 months.
• The sleep disturbance (or associated daytime fatigue) causes clinically significant distress or impairment in social, occupational, or other important areas of functioning.
• The disturbance does not occur exclusively during the course of Narcolepsy, Breathing-Related Sleep Disorder, Circadian Rhythm Sleep Disorder or a Parasomnia.
• The subject’s sleep disturbance does not occur exclusively during the course of another mental disorder (eg, Major Depressive Disorder, Generalised Anxiety Disorder, a delirium).
• The disturbance is not due to the direct physiological effects of a substance (eg, a drug of abuse, a medication) or a general medical condition.
• Based on sleep history, the subjects reports history sSL greater than or equal to 45 minutes, and sTST less than or equal to 6.5 hours.
• The subject has mean LPS of ≥20 minutes on two consecutive screening nights with neither night less than 15 minutes.
• The subject’s habitual bedtime is between 10:00 p.m. and 1:00 a.m.
• Subjects should be able to stand with eyes closed, arms at side and feet apart at hips width for at least one minute with out taking a step.
• The subject has a body mass index (BMI) between 18 and 34, inclusive.
* Based on sleep history, the subject uses pharmacological assistance to sleep 0 to 4 times per week in the last 3 months. Subject must agree to discontinue use of all pharmacological sleep aids beginning one week prior to the dose of single-blind study medication and throughout the entire duration of the study. |
|
| E.4 | Principal exclusion criteria |
General
• Subjects with a history of psychiatric disorder, or alcohol / drug abuse within the last 12 months.
• The subject uses tobacco products during nightly awakenings.
• The subject has a known hypersensitivity to ramelteon, zopiclone or related compounds, including melatonin.
• The subject has any additional condition(s) that in the Investigator’s opinion would: a) affect sleep/wake function, b) prohibit the subject from completing the study, or c) not be in the best interest of the subject.
Study-specific
• The subject has participated in any other investigational study and/or taken any investigational drug within 30 days or five half-lives prior to the first night of single-blind study medication, whichever is longer.
• The subject has sleep schedule changes required by employment (e.g. shift worker) within three months prior to the first night of single-blind study medication, or has flown across greater than three time zones within seven days prior to screening.
• Subject has a history of or currently has conditions that would affect balance such as orthostatic hypotension, dizziness, vertigo, or benign paraoxysmal positional vertigo (BPPV).
• The subject has ever had a history of seizures; sleep apnoea, COPD, restless leg syndrome (RLS), periodic leg movement syndrome (PLMS), or fibromyalgia.
• The subject has a history of psychiatric disorder (including anxiety, depression, mental retardation, cognitive disorder, bipolar illness and schizophrenia) within the past 6 months.
• The subject has a history of drug addiction or drug abuse within the past 12 months.
• The subject has a history of alcohol abuse within the past 12 months, as defined in DSM-IV-TR TM, or regularly consumes more than 14 alcoholic drinks per week, or consumed any alcoholic drinks within 24 hours of all PSG visits.
• The subject has a current significant neurological (including cognitive and psychiatric disorders), hepatic, renal, endocrine, cardiovascular, gastrointestinal, pulmonary, haematological, or metabolic disease, unless currently controlled and stable with protocol-allowed medication 30 days prior to the first night of single blind study medication.
• The subject has used melatonin, or other drugs or supplements known to affect sleep/wake function within 1 week (or 5 half lives of the drug, whichever is longer) prior to the first day of single-blind study medication.
• The subject has used any central nervous system medication within 1 week (or 5 half lives of the drug, whichever is longer) prior to the first day of single-blind study medication.
• The subject has a positive urine drug screen including alcohol at screening or a positive breathalyser test at each check-in.
• The subject has an apnoea hypopnoea index (per hour of sleep) >10 as seen on PSG, on the first night of the PSG screening.
• The subject has periodic leg movement (PLM) with arousal index (per hour of sleep) >10 as seen on PSG, on the first night of PSG screening.
• Subjects who have lower limb prosthetics.
* The subject has participated in a weight loss program or has substantially altered their exercise routine witihin 30 days prior to the first night of single-blind study medication.
* The subject intends to continue taking any disallowed medication or any prescription medication, over-the-counter (OTC) or herbal medication that is known to affect the sleep/wake function or otherwise interfere with evaluation of the study medication. The subject must report all prescription, OTC or herbal medications taken in the 3 weeks prior to screening.
* The subject has any clinically important abnormal finding as determined by a medical history, physical examination, ECG, or clinical laboratory tests, as determined by the investigator. European responsible medical officer must approve subjects with clinically significant abnormal laboratory values being considered for the study with Takeda Europe R&D Centre Ltd and the Principal Investigator. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary variable for this study is the calculated area of centre of pressure (COP) recorded on the balance platform.
The secondary variables for this study will include the efficacy varaiables mean LPS, subjective sleep latency (sSL), sbjective total sleep time (sTST), number of awakenings, sWASO, subjective quality sleep, restorative nature of sleep, morning alertness and ability to concentrate; the residual pharmacological effect variables digit symbol substitution test (DSST) and memory recall tests; the sleep architecture variables percentage of total sleep time in REM sleep, Stage 1, 2 and 3, 4 NREM sleep and latency of REM as determined by PSG screening, as well as subject's ability to stand on balance platform Night 14.
The safety variables for this study will include adverse events, laboratory tests, vital signs and physical examination findings. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
|
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| 14 nights of single blind placebo medication with 28 nights of double blind treatment |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
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