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    Summary
    EudraCT Number:2007-000403-15
    Sponsor's Protocol Code Number:01-06-TL-375-081
    National Competent Authority:Austria - BASG
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2007-09-06
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedAustria - BASG
    A.2EudraCT number2007-000403-15
    A.3Full title of the trial
    A Randomized, Double-Blind, Placebo-Controlled, Polysomnography plus Outpatient Study to Determine the Safety and Efficacy of 4 mg Ramelteon in Adults with Chronic Insomnia
    A.4.1Sponsor's protocol code number01-06-TL-375-081
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorTakeda Global Research & Development Centre (Europe) Ltd.
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameRamelteon
    D.3.2Product code TAK-375
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRamelteon
    D.3.9.2Current sponsor codeTAK-375
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number4
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Information not present in EudraCT
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Information not present in EudraCT
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product Yes
    D.3.11.13.1Other medicinal product typesmall molecule melatonin agonist
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    insomnia characterised by difficulty with sleep onset
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10053851
    E.1.2Term Chronic insomnia
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the efficacy of ramelteon 4 mg compared to placebo in subjects with chronic insomnia.
    E.2.2Secondary objectives of the trial
    The secondary objective of this study is to evaluate the safety (including next-morning residual effects, rebound and withdrawal) and other sleep parameters of ramelteon 4 mg compared to placebo in subjects with chronic insomnia.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. The subject is male or female aged 18 to 64 years, inclusive.
    2. A female subject of childbearing potential who is sexually active agrees to use adequate contraception from Screening throughout the duration of the study. Women NOT of childbearing potential are defined as those who have been surgically sterilized (hysterectomy, oophorectomy, tubal ligation) or who are postmenopausal (defined as at least 2 years since last regular menses). Acceptable methods of contraception are defined in Section 9.1.15 Contraception and Pregnancy Avoidance Procedure.
    3. Female subjects must have negative serum pregnancy test result at the screening visit (Visit1) and a negative urine pregnancy test result on the evening of the PSG screening visit (Visit 3).
    4. The subject is capable of understanding and complying with protocol requirements and only those subjects that have fully understood and signed the informed consent document at screening, prior to any study related procedures being performed, will be enrolled into the study.
    5. The subject or the subject’s legally acceptable representative signs a written informed consent form prior to the initiation of any study procedures.
    6. The subject has a body mass index between 18 and 34, inclusive.
    7. Based on sleep history, the subject has had chronic insomnia for at least 3 months, as defined by the following:
    (a) The predominant complaint is difficulty initiating or maintaining sleep, or nonrestorative sleep, for at least 3 months.
    (b) The sleep disturbance (or associated daytime fatigue) causes clinically significant distress or impairment in social, occupational, or other important areas of functioning.
    (c) The sleep disturbance does not occur exclusively during the course of narcolepsy, breathing-related sleep disorder, circadian rhythm sleep disorder, or parasomnia.
    (d) The disturbance does not occur exclusively during the course of another mental disorder (eg, major depressive disorder, generalized anxiety disorder, delirium).
    (e) 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.
    8. Based on sleep history, the subject reports a history of subjective sleep latency (sSL) ≥45 minutes and a subjective total sleep time (sTST) ≤6.5 hours, for at least 3 months.
    9. Based on sleep history, the subject’s habitual bedtime is between 10:00 PM and 1:00 AM.
    10. On at least 3 of the first 5 nights of single-blind run-in placebo treatment, the subject must have an sSL of ≥45 minutes and an sTST of <6.5 hours. Note: The sSL and sTST inclusion criteria are not required to be met on the same nights.
    11. The difference of the average sSL from first 3 nights of data in the first week of single-blind run-in (eg, Nights -21 to -19) to the average of the last 3 nights of data in the first week of single-blind run-in (eg, nights -17 to -15) must be ≤ 30 minutes.
    12. The difference of the average sSL from first 3 nights of data in the first week of single-blind run-in (eg, Nights -21 to -19) to the average of the last 3 nights of data in the second week of single-blind run-in (eg, nights -10 to -8) must be ≤ 30 minutes.
    13. The difference of the average sSL from first 3 nights of data in the first week of single-blind run-in (eg, Nights -21 to -19) to the average of the last 3 nights of data in the third week of single-blind run-in (eg, nights -3 to -1) must be ≤ 30 minutes.
    14. The subject is willing to have a fixed bedtime and agrees to go to bed within ± 30 minutes of the habitual bedtime during the entire study, exceptions will be allowed at weekends that are not within 2 days of a PSG visit. (This fixed bedtime also must be followed during the PSG assessment visits).
    15. The subject has consistent access to a touch-tone phone and is willing to complete all telephone questionnaires within 60 minutes of wake time each morning throughout the entire duration of the study.
    16. The subject is willing to remain in bed for at least 6.5 hours each night during the entire study.
    17. Based on sleep history, the subject normally uses pharmacologic assistance to sleep 0 to 4 (maximum allowable) times per week in the last 3 months. Subjects must agree to discontinue the use of all sleep aids beginning 1 week prior to the first dose of single-blind study medication and throughout the entire duration of the study.
    18. The subject must complete the postsleep questionnaire (PSQ) morning questionnaire on at least 5 of 7 mornings for all 3 weeks of single-blind run-in.
    19. The subject has mean latency to persistent sleep of ≥20 minutes on 2 consecutive screening nights, with neither night less than 15 minutes, via PSG screening assessment during the single-blind placebo run-in period.
    E.4Principal exclusion criteria
    1. The subject has a known hypersensitivity to ramelteon or related compounds, including melatonin.
    2. The subject has participated in a study involving ramelteon within 6 months of initial Screening Visit.
    3. The subject has participated in any other investigational study and/or taken any investigational drug within 30 days or 5 half-lives (whichever is longer) prior to the first night of single-blind study medication.
    4. The subject has sleep schedule changes required by employment (eg, shift worker) within 3 months prior to the first night of single-blind study medication, or has flown across greater than 3 time zones within 7 days prior to screening.
    5. The subject has participated in a weight loss program or has substantially altered his or her exercise routine within 30 days prior to the first night of single-blind study medication.
    6. The subject has ever had a history of seizures; sleep apnea, restless leg syndrome, periodic leg movements during sleep (PLMS), chronic obstructive pulmonary disease, fibromyalgia, schizophrenia, bipolar disorder, mental retardation, cognitive disorder or a positive test result for the aforementioned ailments on the screening PSG.
    7. The subject has a history of psychiatric disorder within the past 12 months.
    8. The subject has a history of drug addiction or drug abuse within the past 12 months.
    9. The subject has a history of alcohol abuse within the past 12 months.
    10. The subject has a current significant neurological (including cognitive and psychiatric disorders), hepatic, renal, endocrine, cardiovascular, gastrointestinal, pulmonary, hematological, or metabolic disease, unless currently controlled and stable with protocol-allowed medication 30 days prior to the first night of single blind study medication.
    11. The subject uses tobacco products (including nicotine gum and patch) during nightly awakenings.
    12. The subject has used any central nervous system medication, 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. These medications must not have been used to treat psychiatric disorders.
    13. The subject intends to continue taking any disallowed medication or any prescription medication or over-the counter (OTC) 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 and OTC medications taken in the 3 weeks prior to Screening.
    14. The subject has any clinically important abnormal finding as determined by a medical history, physical examination, electrocardiogram, or clinical laboratory tests, as determined by the investigator.
    NOTE: Subjects with clinically significant abnormal laboratory values being considered for the study must be approved by both the sponsor and the principal investigator.
    15. The subject has a history of hepatitis B or C.
    16. The subject has a positive urine drug screen for an illegal substance at the initial Screening Visit.
    NOTE: Subjects with positive urine drug screen for legal substances, including alcohol, at initial screening, where a washout is possible must be approved by both the sponsor and the principal investigator.
    17. The subject has a positive urine drug screen at PSG screening or a positive alcohol breathalyzer test at PSG screening or randomization.
    NOTE: Subjects with positive alcohol breathalyzer test at PSG screening will be allowed to wash-out and reschedule the visit within the protocol allowed visit window.
    18. The subject exhibits a placebo response during the single-blind placebo run-in period. A placebo response is defined as having
    (a) a difference in average sSL >30 minutes from first 3 nights of data in the first week of single-blind run-in to the average of the last 3 nights of data in the first week of single-blind run-in.
    (b) a difference in average sSL >30 minutes from first 3 nights of data in the first week of single-blind run-in to the average of the last 3 nights of data in the second week of single-blind run-in.
    (c) a difference in average sSL >30 minutes from first 3 nights of data in the first week of single-blind run-in to the average of the last 3 nights of data in the third week of single-blind run-in.
    (sSL as calculated from the reported PSQ-interactive voice-activated response system [IVRS] information (Appendix F).
    19. The subject has an apnea hypopnea index (per hour of sleep) >10 as seen on PSG, on the first night of the PSG screening.
    20. The subject has PLMS with arousal index (per hour of sleep) >10 as seen on PSG on the first night of PSG screening.
    21. If subject is female and pregnant or breastfeeding she will be excluded from this study
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy variable will be the mean latency to persistent sleep (LPS) via PSG, over Nights 1 and 2 of double-blind treatment.

    The secondary efficacy variables will be mean LPS via PSG over Nights 15 and 16, and over Nights 29 and 30.
    Additional secondary efficacy variables will be total sleep time (TST), sleep efficiency, wake time after persistent sleep, number of awakenings after persistent sleep as determined by PSG. Subjective assessment of treatment outcomes will be captured using PSQ-IVRS, sSL, sTST, subjective sleep quality, subjective awake time, subjective number of awakenings, and subjective ease of falling back to sleep as determined by PSQ/sleep diary.
    Additional parameters will be recorded using the digit symbol substitution test, memory recall test, and visual analog scale.
    Measures of LPS will be used to assess rebound insomnia upon single-blind placebo run-out period. The subjective morning alertness and ability to concentrate will be captured via PSQ. The Tyrer Benzodiazepine Withdrawal Symptom Questionnaire will be used to assess subjective effects of withdrawal from study medication.
    Sleep architecture variables include percentage of TST in rapid eye moment (REM) sleep, stage 1, 2 and 3/4 nonrapid eye movement sleep, and latency to REM as determined by PSG.
    Safety variables will include adverse events, laboratory tests, vital signs, electrocardiogram results, and physical exam findings.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind Yes
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Single blind run in to double blind phase
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    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.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA25
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    E.8.7Trial 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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months10
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state50
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 240
    F.4.2.2In the whole clinical trial 1200
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2007-09-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2007-08-07
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2008-03-28
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