The study of combination use of melatonin receptor agonist for dose reduction or interruptions of BZD and non-BZD hypnotics on chronic insomnia.

JRCT ID: jRCTs031180334

Registered date:18/03/2019

Basic Information

• Recruitment status: Complete
• Health condition(s) or Problem(s) studied: Chronic insomnia
• Date of first enrollment: 06/02/2018
• Target sample size: 130
• Study type: Interventional

Intervention(s)

Subjects determined eligible for inclusion in the study will be randomly assigned to the R or PL group.
Ramelteon combination group (R group): Subjects will take 8mg/dose of ramelteon once daily at bedtime.
Placebol group (PL group): Subjects will take placebo at bedtime.
Subjects in the R group will additionally receive ramelteon and be treated for 12 weeks, and those in the PL group will take placebo for 12 weeks.

Outcome(s)

Primary Outcome

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
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.

Secondary Outcome

1) The rate of achievement of 50% dose reduction (converted to Diazepam) at 4 and 8 weeks
2) Average of dose reduction rate (converted to Diazepam) at 4, 8 and 12 weeks
3) The rate of achievement of 100% dose reduction at 12 weeks (at the time of discontinuation).
4) Change of PSQI and AIS total score from baseline to 4, 8 and 12 weeks
5) Change of PHQ-9 score from baseline to 4, 8 and 12 weeks
6) CIWA-B score at 4, 8 and 12 weeks
7) PGI score at 12 weeks (at the time of discontinuation)
8) Change of Ben-dep score from baseline to 12 weeks (at the time of discontinuation)

Key inclusion & exclusion criteria

• Age minimum: >= 20age old
• Age maximum: Not applicable
• Gender: Both

Include criteria

Subjects meeting Criteria 1 or 2 and Criteria 3 and all subsequent criteria will be included in the study:
1. Patients diagnosed as chronic insomnia having sleep onset disturbance, and with a duration of the disease of at least 6 months
2. 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.
3. 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)
4. Patients whoes symptoms of insomnia were stabilized, and the investigators determined that the (non-) BZD hypnotics could be reduced or discontinued
5. Patients aged 20 years or older at the time of consent
6. Patients who are willing to comply with algorithm for dose reduction and discontinuation
7. Patients who can understand the content of the study and provide consent to participate in the study in writing on their own will.

Exclude criteria

Subjects meeting any of the following criteria will not be included in the study:
1. Patients with secondary insomnia
2. Patients taking (non-)BZD hypnotics at a dose exceeding 2-fold of the usual dose
3. Patients taking barbiturate and non-barbiturate hypnotics and Suvorexant.
4. Patients taking hypnotics other than medicinal pharmaceuticals (including OTC, supplements believed to be effective for insomnia and melatonin)
5. Patients taking mianserin hydrochloride, mirtazapine, and trazodone hydrochloride
6. Patients taking antipsychotics
7. 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.
8. Patients who took ramelteon within 1 month prior to the informed consent
9. Patients in whom the dose of psychotropics except for the items 2-7 were changed within 1 month prior to the informed consent
10. Patients who are comorbid with depression or bipolar disordeand and in whom depressive symptoms have not remitted
11. 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)" , those with the total score of PHQ is 10 or higher, or those answered yes to the items for suicide idea (item 4 or 5).
12. Patients with dementia, schizophrenia, drug dependence and alcoholic
13. Patients with liver/kidney disorder, female subjects who are pregnant or in breast-feeding, and malignant neoplasm
14. Night workers
15. Patients meeting contraindications for ramelteon
16. Other patients judged ineligible for participation in the study by the investigator

Related Information

• Primary Sponsor: Inoue Yuichi
• Source(s) of Monetary Support: Takeda Pharmaceutical Company Limited
• Secondary ID(s): NCT03461042