A Multicentre, Randomised, Double-Blind, Double-Dummy, Placebo-Controlled Study to Evaluate the Safety and Efficacy of Ramelteon Compared to Placebo With Zopiclone as a Reference Arm in Adults With Chronic Insomnia

Condition(s) targeted: Chronic Insomnia

Intervention: Ramelteon (Drug)

Phase: Phase 3

Status: Recruiting

Sponsored by: Takeda Europe Research & Development Centre Ltd.

Official(s) and/or principal investigator(s):
Irshaad Ebrahim, MD, Principal Investigator, Affiliation: London Sleep Centre

Overall contact:
Irshaad Ebrahim, MD, Email: irshaad.ebrahim@londonsleepcentre.com.

Randomised, double-blind, double dummy, placebo-controlled, multicentre reference study to examine the effects of ramelteon (TAK-375) on psychomotor and cognitive performance at peak plasma concentration levels and to evaluate the efficacy and safety of ramelteon compared to placebo with zopiclone as a reference arm over 28 consecutive nights in adults diagnosed with chronic insomnia.

Study design: Treatment, Randomized, Double-Blind, Active Control, Parallel Assignment, Safety/Efficacy Study

Detailed description: Randomised, double-blind, double dummy, placebo-controlled, multicentre reference study to examine the effects of ramelteon (TAK-375) on psychomotor and cognitive performance at peak plasma concentration levels and to evaluate the efficacy and safety of ramelteon compared to placebo with zopiclone as a reference arm over 28 consecutive nights in adults diagnosed with chronic insomnia. Ramelteon will be used at a single fixed dose of 8 mg and zopiclone will be used at a single fixed dose of 7. 5mg. There will be initial subject screening, which will include informed consent, inclusion/exclusion criteria assessment, medical history and demographics (including sleep history), prior medication history, physical examination (vital signs) weight, height and body mass index (BMI), laboratory tests (including urine drug test, for female subjects a serum pregnancy test will be performed), and 12 lead electrocardiogram (ECG) recording. Subjects will practice on balance platform. Subjects who fulfil the initial screening criteria will be admitted to the sleep laboratory and will undergo two consecutive nights of Polysomnography (PSG) screening in the sleep laboratory. During the two consecutive nights of single-blind placebo, medication will be taken in a sleep laboratory, PSG recordings will be conducted, practice on the battery of tests that will be performed, inclusion and exclusion criteria and an update of medical history will be reviewed, vital signs will be noted and subjects will undergo a breathalyser test and in female subjects a serum urine pregnancy test will be performed. Subjects will practice the DSST, memory recall tests, and balance platform. (already listed in initial screening above). All subjects will take the single-blind medication over the next 12-day outpatient period. Subjects, who fulfil the eligibility criteria for both nights, including PSG, will be randomly allocated to the double-blind treatment groups prior to Night 1. Once randomised, each subject will receive one of the following medications over the next 28 consecutive nights, ramelteon at a dose of 8mg, zopiclone at a dose of 7. 5mg, or placebo. During this double-blind treatment phase the subjects will report to a sleep laboratory for PSG recordings on Nights 1, 2, 27 and 28; and cognitive and psychomotor assessment will be done the morning (8 hours plus post dose) after Night 1, 2, 27 and 28 nightly doses. On Night 14 the psychomotor and cognitive assessments will be conducted approximately 1. 5 pre dose and 1. 5 to 2 hours post-dose. All other nights, the subjects will take their study medication at home as directed. A regular sleep schedule will be recommended for the outpatient period. Post-sleep questionnaire will be conducted and completed in the sleep laboratory and will include subjective sleep latency (sSL) subjective total sleep time (sTST), number of awakenings, sWASO, subjective sleep quality, restorative nature of sleep, morning alertness and ability to concentrate. Daytime function questionnaire will include daytime ability to function, daytime alertness, daytime ability to concentrate and daytime naps. The following assessments will be conducted on Night 14 in the sleep laboratory:· Balance platform· DSST· Memory recall tests

Minimum age: 18 Years. Maximum age: 64 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Main Criteria for Inclusion:

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 of 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 (e. g. Major Depressive Disorder, Generalised Anxiety Disorder, a delirium). The disturbance is not due to the direct physiological effects of a substance (e. g. 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 ³20 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.

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 paroxysmal positional vertigo (BPPV).· The subject has ever had a history of seizures; sleep apnoea, COPD, RLS, PLMS, schizophrenia, bipolar disorder, mental retardation, cognitive disorder 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-TRTM, 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.

Irshaad Ebrahim, MD, Email: irshaad.ebrahim@londonsleepcentre.com.

Dr I Ebrahim, London, United Kingdom; Recruiting
Irshaad Ebrahim, MBBS
Irshaad Ebrahim, MD, Principal Investigator

Last updated: October 11, 2005