The Study of Combination Use of Melatonin Receptor Agonist for Dose Reduction or Interruptions of Benzodiazepine (BZD) and Non-BZD Hypnotics on Chronic Insomnia

Study Overview
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Brief Summary
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To investigate effects on combination use of Ramelteon in the dose reduction or interruption process of (non-)BZD hypnotics during the dose reduction or interruption algorithm.

Detailed Description
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The hypnotic 'Ramelteon' does not have effect on Gamma Aminobutyric Acid (GABA-A) receptor that relates to the formation of addiction to the BZD or non-BZD hypnotics. Some results of clinical trials has been reported that the dose reduction or interruption of (non-)BZD hypnotics was achieved on combination use of Ramelteon by using its characteristic of the action mechanism with safely and effectively. However, these results have not been confirmed with randomized controlled trials.

Official Title
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The Placebo Controlled Randomized Double Blind Multicenter Study to Investigate Effectiveness and Safety of Combination Use of Melatonin Receptor Agonist for Dose Reduction or Interruptions of BZD and Non-BZD Hypnotics on Chronic Insomnia

Conditions
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Chronic Insomnia

Intervention / Treatment
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* Drug: Ramelteon 8mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects meeting Criteria 1 or 2 and Criteria 3 and all subsequent criteria will be included in the study: Patients diagnosed as chronic insomnia having sleep onset disturbance, and with a duration of the disease of at least 6 months Patients diagnosed with chronic insomnia comorbid with mood disorders (depression or bipolar disorder) can be included to this study if they have remission of mood symptoms. Patients taking (non-)BZD hypnotics (including etizolam at bedtime) at a fixed dose in the following patterns since at least 1 month prior to consent (over 90% of drug compliance should be confirmed at the time of medical interview): Patients taking 2 drugs at the usual dose (1 unit) Patients taking 3 drugs at the usual dose (1 unit) Patients taking 4 drugs at the usual dose (1 unit) Patients taking a drug at 2-fold of the usual dose (2 units) Patients taking a drug at 2-fold of the usual dose (2 units) and a drug at the usual dose (1 unit) Patients taking a drug at 2-fold of the usual dose (2 units) and 2 drugs at the usual dose (1 unit) Patients taking 2 drugs at 2-fold of the usual dose (2 units) Patients whose total dosage are 2～4 units of 1～4 drugs can be also included. But attention needed not to conflict with exclusion criteria 2. ※Dosage cannot exceeded 2 units per 1 drug. Patients whose symptoms of insomnia were stabilized, and the investigators determined that the (non-) BZD hypnotics could be reduced or discontinued Patients aged 20 years or older at the time of consent Patients who are willing to comply with algorithm for dose reduction and discontinuation Patients who can understand the content of the study and provide consent to participate in the study in writing on their own will. Exclusion Criteria: Subjects meeting any of the following criteria will not be included in the study: Patients with secondary insomnia Patients taking (non-)BZD hypnotics at a dose exceeding 2-fold of the usual dose Patients taking barbiturate and non-barbiturate hypnotics and Suvorexant. Patients taking hypnotics other than medicinal pharmaceuticals (including Over The Counter (OTC), supplements believed to be effective for insomnia and melatonin ) Patients taking mianserin hydrochloride, mirtazapine, and trazodone hydrochloride Patients taking antipsychotics Patients taking anxiolytic or clonazepam at bedtime *Patient taking anxiolytic and/or clonazepam at times except for bed-time will be included in the study. However, dosage and timing of administration can not be changed during the study period. Patients who took ramelteon within 1 month prior to the informed consent Patients in whom the dose of psychotropics except for the items 2～7 were changed within 1 month prior to the informed consent Patients who are comorbid with depression or bipolar disordered and in whom depressive symptoms have not remitted Patients in whom frequency in Q9 of PHQ thoughts that you would be better off dead or thoughts of hurting yourself in some way is more than half the days (in the past 2 weeks) or the total score is 10 or higher Patients with dementia, schizophrenia, drug dependence and alcoholic Patients with liver/kidney disorder, female subjects who are pregnant or in breast-feeding, and malignant neoplasm Night workers Patients meeting contraindications for ramelteon Other patients judged ineligible for participation in the study by the investigator

Ages Eligible for Study
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Minimum Age: 20 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: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm R<br>Co-administer following medication for 12 weeks since informed consent; R group: taking capsule of Ramelteon 8mg once daily before sleeping. | Drug: Ramelteon 8mg<br>* Ramelteon 8mg once daily before bedtime for 12 weeks since informed consent<br>|
| Placebo Comparator: Arm PL<br>Co-administer following medication for 12 weeks since informed consent; Placebo group: taking capsule of Placebo once daily before bedtime. | Drug: Placebo<br>* Placebo capsule once daily before bedtime for 12 weeks since informed consent<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The achievement ratio of the 50% dose reduction of (non-)BZD hypnotics (Diazepam conversion value) at 12weeks or withdrawal without any deterioration of insomnia symptoms. | Evaluate the achievement ratio of the 50% or more of dose reduction by Participant's diary | 12 weeks | 
| The rate of subjects who achieved more than 50% dose reduction of (non-)BZD hypnotics (Diazepam conversion value) at 12 weeks or withdrawal since informed consent. | The rate of subjects who achieved more than 50% of dose reduction (Diazepam conversion value) will be assessed by Participant's diary | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The achievement ratio of the 50% dose reduction (Diazepam conversion value) at 4weeks and 8weeks | The rate of subjects who achieved more than 50% dose reduction (Diazepam conversion value) will be assessed by Participant's diary | at 4 weeks and 8weeks | 
| The average of the dose reduction rate at 4weeks, 8weeks and 12weeks | The average of the dose reduction rate will be assessed by Participant's diary | at 4 weeks, 8weeks and 12 weeks | 
| The achievement ratio of the 100% dose reduction at 12weeks or withdrawal | The achievement ratio of the 100% dose reduction will be assessed by Participant's diary | 12 weeks | 
| The variation in total score of Pittsburg Sleep Quality Index (PSQI) at 4weeks, 8weeks and 12weeks | The variation in total score of PSQI will be assessed by the PSQI value sets sets at week 0, 4, 8 and 12. (The range of total score is 0-21. Higher scores represent worse tendency of the symptoms.) | at 0, 4, 8 and 12 weeks | 
| The variation in total score of Athens Insomnia Scale (AIS) at 4weeks, 8weeks and 12weeks | The variation in total score of AIS will be assessed by the AIS value sets at week 0, 4, 8 and 12. (The range of total score is 0-24. Higher scores represent worse tendency of the symptoms.) | at 0, 4, 8 and 12 weeks | 
| The variation in Patient health questionnaire (PHQ-9) score at 4weeks, 8weeks and 12weeks | The variation in PHQ-9 score will be assessed by the PHQ-9 value sets at week 0, 4, 8 and 12. (The range of total score is 0-27. Higher scores represent worse tendency of the symptoms.) | at 0, 4, 8 and 12 weeks | 
| Guide to the use of the clinical withdrawal assessment scale for benzodiazepines (CIWA-B) score at 4weeks, 8weeks and 12weeks | The variation in CIWA-B (Guide to the use of the clinical withdrawal assessment scale for benzodiazepines) score will be assessed by the CIWA-B value sets at week 4, 8 and 12. (The range of total score is 0-80. Higher scores represent worse tendency of the symptoms.) | at 4, 8 and 12 weeks | 
| Patient global impression of therapy (PGI) score at 12weeks or withdrawal | PGI(Patient global impression of therapy) score will be assessed by the PGI value sets at 12weeks or withdrawal. (The range of total score is 0-21. Higher scores represent worse tendency of the symptoms.) | 12 weeks | 
| The variation in Ben-dep(Benzodiazepine Dependence Self-Report Questionnaire) score at 12weeks or withdrawal | The variation in Ben-dep score will be assessed by the Ben-dep value sets at 0 and 12weeks or withdrawal. (The range of total score is 0-100. Higher scores represent worse tendency of the symptoms.) | at 0 and 12 weeks | 
| Adverse Events | Adverse Events will be determined by the latest version of MedDRA/J （Medical Dictionary for Regulatory Activities/J). | 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic insomnia, Ramelteon, Rozerem, dose reduction