Trial Outcomes & Findings for Facilitation of Zolpidem (≥10 mg) Discontinuation Through Use of Ramelteon in Subjects With Chronic Insomnia (NCT NCT00492232)

Last Updated: 2010-07-20

Results Overview

Participants reduced zolpidem incrementally from Week 3 to Week 10 of the double-blind treatment period (DBTP). A participant who did not take any zolpidem during the last 7 days of the DBTP was defined as having completely discontinued zolpidem by that time point. The number of subjects who discontinued zolpidem at the end of the DBTP was summarized.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

135 participants

Primary outcome timeframe

Week 10

Results posted on

2010-07-20

Participant Flow

Subjects were enrolled at 38 investigative sites in the United States from 26 April 2007 to 28 May 2008.

Subjects completed a 4-week single-blind placebo run-in period prior to randomization in the double-blind treatment period (DBTP). During this time they took placebo-matching tablets once-daily (QD) with concomitant current zolpidem therapy. Subjects used a daily subject diary to record zolpidem dose reduction, daily activities, and sleep quality.

Participant milestones

Participant milestones
Measure	Ramelteon 8 mg QD Ramelteon 8 mg, tablets, orally, once daily for up to 10 weeks in the DBTP.	Placebo QD Ramelteon placebo-matching tablets, orally, once daily for up to 10 weeks in the DBTP.
Placebo Run-in STARTED	0	205
Placebo Run-in COMPLETED	0	135
Placebo Run-in NOT COMPLETED	0	70
Double-Blind Treatment STARTED	65	70
Double-Blind Treatment COMPLETED	47	45
Double-Blind Treatment NOT COMPLETED	18	25
Open-Label Treatment STARTED	89	0
Open-Label Treatment COMPLETED	88	0
Open-Label Treatment NOT COMPLETED	1	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Ramelteon 8 mg QD Ramelteon 8 mg, tablets, orally, once daily for up to 10 weeks in the DBTP.	Placebo QD Ramelteon placebo-matching tablets, orally, once daily for up to 10 weeks in the DBTP.
Placebo Run-in Adverse Event	0	2
Placebo Run-in Protocol Violation	0	3
Placebo Run-in Lost to Follow-up	0	3
Placebo Run-in Withdrawal by Subject	0	8
Placebo Run-in Pregnancy	0	1
Placebo Run-in Entrance criteria not met	0	45
Placebo Run-in Other	0	6
Placebo Run-in Missing	0	2
Double-Blind Treatment Adverse Event	1	2
Double-Blind Treatment Protocol Violation	3	7
Double-Blind Treatment Lost to Follow-up	2	3
Double-Blind Treatment Withdrawal by Subject	4	8
Double-Blind Treatment Lack of Efficacy	1	0
Double-Blind Treatment Other	6	5
Double-Blind Treatment Randomized not treated	1	0
Open-Label Treatment Withdrawal by Subject	1	0

Baseline Characteristics

Facilitation of Zolpidem (≥10 mg) Discontinuation Through Use of Ramelteon in Subjects With Chronic Insomnia

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Ramelteon 8 mg QD n=65 Participants Ramelteon 8 mg, tablets, orally, once daily for up to 10 weeks in the DBTP.	Placebo QD n=70 Participants Ramelteon placebo-matching tablets, orally, once daily for up to 10 weeks in the DBTP.	Total n=135 Participants Total of all reporting groups
Age Continuous	51.5 years STANDARD_DEVIATION 13.45 • n=5 Participants	47.0 years STANDARD_DEVIATION 12.98 • n=7 Participants	49.2 years STANDARD_DEVIATION 13.35 • n=5 Participants
Sex: Female, Male Female	42 Participants n=5 Participants	49 Participants n=7 Participants	91.0 Participants n=5 Participants
Sex: Female, Male Male	23 Participants n=5 Participants	21 Participants n=7 Participants	44.0 Participants n=5 Participants
Race/Ethnicity, Customized Asian	1 Subjects n=5 Participants	1 Subjects n=7 Participants	2.0 Subjects n=5 Participants
Race/Ethnicity, Customized Black or African American	5 Subjects n=5 Participants	9 Subjects n=7 Participants	14.0 Subjects n=5 Participants
Race/Ethnicity, Customized White	59 Subjects n=5 Participants	59 Subjects n=7 Participants	118.0 Subjects n=5 Participants
Race/Ethnicity, Customized Multiracial	0 Subjects n=5 Participants	1 Subjects n=7 Participants	1.0 Subjects n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	10 Participants n=5 Participants	9 Participants n=7 Participants	19.0 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	55 Participants n=5 Participants	61 Participants n=7 Participants	116.0 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0.0 Participants n=5 Participants
Baseline average total daily zolpidem dosage ≤10 mg	56 subjects n=5 Participants	60 subjects n=7 Participants	116 subjects n=5 Participants
Baseline average total daily zolpidem dosage >10 mg	8 subjects n=5 Participants	10 subjects n=7 Participants	18 subjects n=5 Participants
Baseline average total daily zolpidem dosage Information not available	1 subjects n=5 Participants	0 subjects n=7 Participants	1 subjects n=5 Participants
Use of pharmacological assistance to sleep 4 nights per week	8 subjects n=5 Participants	9 subjects n=7 Participants	17 subjects n=5 Participants
Use of pharmacological assistance to sleep >4 nights per week	57 subjects n=5 Participants	61 subjects n=7 Participants	118 subjects n=5 Participants
Weekly frequency zolpidem consumption 0-3 nights per week	0 subjects n=5 Participants	0 subjects n=7 Participants	0 subjects n=5 Participants
Weekly frequency zolpidem consumption 4 nights per week	2 subjects n=5 Participants	1 subjects n=7 Participants	3 subjects n=5 Participants
Weekly frequency zolpidem consumption 5 nights per week	8 subjects n=5 Participants	9 subjects n=7 Participants	17 subjects n=5 Participants
Weekly frequency zolpidem consumption 6 nights per week	8 subjects n=5 Participants	7 subjects n=7 Participants	15 subjects n=5 Participants
Weekly frequency zolpidem consumption 7 nights per week	46 subjects n=5 Participants	53 subjects n=7 Participants	99 subjects n=5 Participants
Weekly frequency zolpidem consumption Information not available	1 subjects n=5 Participants	0 subjects n=7 Participants	1 subjects n=5 Participants
Baseline weekly zolpidem dosage	68.7 Dosage (mg) STANDARD_DEVIATION 17.71 • n=5 Participants	70.3 Dosage (mg) STANDARD_DEVIATION 20.37 • n=7 Participants	69.5 Dosage (mg) STANDARD_DEVIATION 19.09 • n=5 Participants
Weekly frequency zolpidem consumption	6.53 nights per week STANDARD_DEVIATION 0.835 • n=5 Participants	6.60 nights per week STANDARD_DEVIATION 0.769 • n=7 Participants	6.57 nights per week STANDARD_DEVIATION 0.799 • n=5 Participants

PRIMARY outcome

Timeframe: Week 10

Population: Analysis was performed on all randomized subjects who took at least 1 dose of study drug, who had completed the DBTP, and who had sufficient zolpidem dosage data in the last 7 days of the DBTP.

Outcome measures

Outcome measures
Measure	Ramelteon 8 mg QD n=52 Participants Ramelteon 8 mg, tablets, orally, once daily for up to 10 weeks in the DBTP.	Placebo QD n=49 Participants Ramelteon placebo-matching tablets, orally, once daily for up to 10 weeks in the DBTP.
Percentage of Participants Who Discontinued Zolpidem Therapy	28.8 Percentage of participants	32.7 Percentage of participants

SECONDARY outcome

Timeframe: Baseline and Weeks 1-2

Dosages of zolpidem taken were recorded during Weeks 1-2 of the DBTP. Differences in dosages from baseline were summarized. Weekly dosage was calculated as total amount of zolpidem taken divided by the number of days within the phase, multiplied by 7.

Outcome measures

Outcome measures
Measure	Ramelteon 8 mg QD n=52 Participants Ramelteon 8 mg, tablets, orally, once daily for up to 10 weeks in the DBTP.	Placebo QD n=49 Participants Ramelteon placebo-matching tablets, orally, once daily for up to 10 weeks in the DBTP.
Change From Baseline in Weekly Zolpidem Dosage During Weeks 1-2	-11.8 Dose (mg) Standard Error 3.06	-11.6 Dose (mg) Standard Error 3.11

SECONDARY outcome

Timeframe: Baseline and Weeks 3-4

Dosages of zolpidem taken were recorded during Weeks 3-4 of the DBTP. Differences in dosages from baseline were summarized. Weekly dosage was calculated as total amount of zolpidem taken divided by the number of days within the phase, multiplied by 7.

Outcome measures

Outcome measures
Measure	Ramelteon 8 mg QD n=52 Participants Ramelteon 8 mg, tablets, orally, once daily for up to 10 weeks in the DBTP.	Placebo QD n=49 Participants Ramelteon placebo-matching tablets, orally, once daily for up to 10 weeks in the DBTP.
Change From Baseline in Weekly Zolpidem Dosage During Weeks 3-4	-35.3 Dose (mg) Standard Error 2.89	-35.6 Dose (mg) Standard Error 2.93

SECONDARY outcome

Timeframe: Baseline and Weeks 5-6

Dosages of zolpidem taken were recorded during Weeks 5-6 of the DBTP. Differences in dosages from baseline were summarized. Weekly dosage was calculated as total amount of zolpidem taken divided by the number of days within the phase, multiplied by 7.

Outcome measures

Outcome measures
Measure	Ramelteon 8 mg QD n=52 Participants Ramelteon 8 mg, tablets, orally, once daily for up to 10 weeks in the DBTP.	Placebo QD n=48 Participants Ramelteon placebo-matching tablets, orally, once daily for up to 10 weeks in the DBTP.
Change From Baseline in Weekly Zolpidem Dosage During Weeks 5-6	-40.2 Dose (mg) Standard Error 3.18	-42.1 Dose (mg) Standard Error 3.22

SECONDARY outcome

Timeframe: Baseline and Weeks 7-8

Dosages of zolpidem taken were recorded during Weeks 7-8 of the double blind period. Differences in dosages from baseline were summarized.

Outcome measures

Outcome measures
Measure	Ramelteon 8 mg QD n=51 Participants Ramelteon 8 mg, tablets, orally, once daily for up to 10 weeks in the DBTP.	Placebo QD n=48 Participants Ramelteon placebo-matching tablets, orally, once daily for up to 10 weeks in the DBTP.
Change From Baseline in Weekly Zolpidem Dosage During Weeks 7-8	-52.1 Dose (mg) Standard Error 3.49	-49.9 Dose (mg) Standard Error 3.49

SECONDARY outcome

Timeframe: Baseline and Weeks 9-10

Dosages of zolpidem taken were recorded during Weeks 9-10 of the DBTP. Differences in dosages from baseline were summarized. Weekly dosage was calculated as total amount of zolpidem taken divided by the number of days within the phase, multiplied by 7.

Outcome measures

Outcome measures
Measure	Ramelteon 8 mg QD n=52 Participants Ramelteon 8 mg, tablets, orally, once daily for up to 10 weeks in the DBTP.	Placebo QD n=49 Participants Ramelteon placebo-matching tablets, orally, once daily for up to 10 weeks in the DBTP.
Change From Baseline in Weekly Zolpidem Dosage During Weeks 9-10	-60.6 Dose (mg) Standard Error 3.27	-60.7 Dose (mg) Standard Error 3.31

SECONDARY outcome

Timeframe: Baseline and Weeks 1-2

The number of nights zolpidem was taken was recorded during Weeks 1-2 of the DBTP. Weekly frequency was calculated as the number of nights zolpidem was taken divided by the number of days within the period, multiplied by 7. Differences in frequency from BL were summarized.

Outcome measures

Outcome measures
Measure	Ramelteon 8 mg QD n=52 Participants Ramelteon 8 mg, tablets, orally, once daily for up to 10 weeks in the DBTP.	Placebo QD n=49 Participants Ramelteon placebo-matching tablets, orally, once daily for up to 10 weeks in the DBTP.
Change From Baseline in Weekly Zolpidem Frequency During Weeks 1-2	0.13 nights per week Standard Error 0.183	0.04 nights per week Standard Error 0.186

SECONDARY outcome

Timeframe: Weeks 3-4

The number of nights zolpidem was taken was recorded during Weeks 3-4 of the DBTP. Weekly frequency was calculated as the number of nights zolpidem was taken divided by the number of days within the period, multiplied by 7. Differences in frequency from baseline were summarized.

Outcome measures

Outcome measures
Measure	Ramelteon 8 mg QD n=52 Participants Ramelteon 8 mg, tablets, orally, once daily for up to 10 weeks in the DBTP.	Placebo QD n=49 Participants Ramelteon placebo-matching tablets, orally, once daily for up to 10 weeks in the DBTP.
Change From Baseline in Weekly Zolpidem Frequency During Weeks 3-4	-0.08 nights per week Standard Error 0.288	-0.26 nights per week Standard Error 0.292

SECONDARY outcome

Timeframe: Weeks 5-6

The number of nights zolpidem was taken was recorded during Weeks 5-6 of the DBTP. Weekly frequency was calculated as the number of nights zolpidem was taken divided by the number of days within the period, multiplied by 7. Differences in frequency from baseline were summarized.

Outcome measures

Outcome measures
Measure	Ramelteon 8 mg QD n=52 Participants Ramelteon 8 mg, tablets, orally, once daily for up to 10 weeks in the DBTP.	Placebo QD n=48 Participants Ramelteon placebo-matching tablets, orally, once daily for up to 10 weeks in the DBTP.
Change From Baseline in Weekly Zolpidem Frequency During Weeks 5-6	-0.05 nights per week Standard Error 0.396	-0.60 nights per week Standard Error 0.400

SECONDARY outcome

Timeframe: Baseline and Weeks 7-8

The number of nights zolpidem was taken was recorded during Weeks 7-8 of the DBTP. Weekly frequency was calculated as the number of nights zolpidem was taken divided by the number of days within the period, multiplied by 7. Differences in frequency from baseline were summarized.

Outcome measures

Outcome measures
Measure	Ramelteon 8 mg QD n=51 Participants Ramelteon 8 mg, tablets, orally, once daily for up to 10 weeks in the DBTP.	Placebo QD n=48 Participants Ramelteon placebo-matching tablets, orally, once daily for up to 10 weeks in the DBTP.
Change From Baseline in Weekly Zolpidem Frequency During Weeks 7-8	-1.10 nights per week Standard Error 0.475	-1.24 nights per week Standard Error 0.475

SECONDARY outcome

Timeframe: Baseline and Weeks 9-10

The number of nights zolpidem was taken was recorded during Weeks 9-10 of the DBTP. Weekly frequency was calculated as the number of nights zolpidem was taken divided by the number of days within the period, multiplied by 7. Differences in frequency from baseline were summarized.

Outcome measures

Outcome measures
Measure	Ramelteon 8 mg QD n=52 Participants Ramelteon 8 mg, tablets, orally, once daily for up to 10 weeks in the DBTP.	Placebo QD n=49 Participants Ramelteon placebo-matching tablets, orally, once daily for up to 10 weeks in the DBTP.
Change From Baseline in Weekly Zolpidem Frequency During Weeks 9-10	-2.22 nights per week Standard Error 0.534	-2.34 nights per week Standard Error 0.542

SECONDARY outcome

Timeframe: Weeks 1-10

Population: Analysis was performed on all randomized subjects who took at least 1 dose of study drug, had completed the DBTP, and had sufficient zolpidem dosage data in the last 7 days of the DBTP. Estimates could not be reported with correct statistical inference due to small sample sizes by method of discontinuation (ie, most subjects reduced zolpidem dose).

Participants who took no zolpidem during the last 7 days of the DBTP were completely discontinued from zolpidem. Participants who completely discontinued zolpidem via reduction in zolpidem use frequency (alone) were not summarized.

Outcome measures

Outcome measures
Measure	Ramelteon 8 mg QD n=52 Participants Ramelteon 8 mg, tablets, orally, once daily for up to 10 weeks in the DBTP.	Placebo QD n=49 Participants Ramelteon placebo-matching tablets, orally, once daily for up to 10 weeks in the DBTP.
Participants Who Completely Discontinued Zolpidem at the End of Double-Blind Treatment Period, by Method of Discontinuation Reduction in Dose	12 participants	8 participants
Participants Who Completely Discontinued Zolpidem at the End of Double-Blind Treatment Period, by Method of Discontinuation Reduction in Dose and Frequency	3 participants	8 participants

SECONDARY outcome

Timeframe: Baseline and Week 10

Participants who achieved a 50% reduction in zolpidem dosage (or frequency) at the end of the DBTP (ie, the end of Reduction Phase 4) were summarized. The reduction in dosage at Reduction Phase 4=\[1-(Reduction Phase 4 weekly dosage/baseline weekly dosage)\]\*100%.

Outcome measures

Outcome measures
Measure	Ramelteon 8 mg QD n=52 Participants Ramelteon 8 mg, tablets, orally, once daily for up to 10 weeks in the DBTP.	Placebo QD n=49 Participants Ramelteon placebo-matching tablets, orally, once daily for up to 10 weeks in the DBTP.
Participants Who Achieved a 50% Reduction in Zolpidem Dosage at the End of the Double-Blind Treatment Period	48 participants	42 participants

SECONDARY outcome

Timeframe: Baseline and Weeks 1-10

Population: Analysis was performed on all subjects who were randomized and received at least 1 dose of double-blind medication during the study. Subjects were analyzed by the treatment they were randomized to receive.

Participants who achieved a 50% reduction in zolpidem dosage at any previously defined 2-week period (ie, reduction phase) during the DBTP were summarized. The reduction in dosage at any time=\[1-(reduction phase weekly dosage/baseline weekly dosage)\]\*100%.

Outcome measures

Outcome measures
Measure	Ramelteon 8 mg QD n=64 Participants Ramelteon 8 mg, tablets, orally, once daily for up to 10 weeks in the DBTP.	Placebo QD n=70 Participants Ramelteon placebo-matching tablets, orally, once daily for up to 10 weeks in the DBTP.
Participants Who Achieved a 50% Reduction in Zolpidem Dosage at Any Time During the Double-Blind Treatment Period	50 participants	50 participants

Adverse Events

Ramelteon 8 mg QD

Serious events: 0 serious events

Other events: 11 other events

Deaths: 0 deaths

Placebo QD

Serious events: 1 serious events

Other events: 7 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Ramelteon 8 mg QD n=64 participants at risk Ramelteon 8 mg, tablets, orally, once daily for up to 10 weeks in the DBTP.	Placebo QD n=70 participants at risk Ramelteon placebo-matching tablets, orally, once daily for up to 10 weeks in the DBTP.
Cardiac disorders Coronary Artery Disease	0.00% 0/64 • Treatment-emergent adverse events with onset dates the same or after the start of double-blind study medication and before the first dose of open-label study medication were summarized for the double-blind medication. Two ramelteon-treated subjects permanently discontinued the study due to adverse events during the double-blind treatment period. One placebo-treated subject had multiple temporary study drug interruptions due to adverse events but did not permanently discontinue the study	1.4% 1/70 • Number of events 1 • Treatment-emergent adverse events with onset dates the same or after the start of double-blind study medication and before the first dose of open-label study medication were summarized for the double-blind medication. Two ramelteon-treated subjects permanently discontinued the study due to adverse events during the double-blind treatment period. One placebo-treated subject had multiple temporary study drug interruptions due to adverse events but did not permanently discontinue the study

Other adverse events

Other adverse events
Measure	Ramelteon 8 mg QD n=64 participants at risk Ramelteon 8 mg, tablets, orally, once daily for up to 10 weeks in the DBTP.	Placebo QD n=70 participants at risk Ramelteon placebo-matching tablets, orally, once daily for up to 10 weeks in the DBTP.
Infections and infestations Upper Respiratory Tract Infections	7.8% 5/64 • Number of events 5 • Treatment-emergent adverse events with onset dates the same or after the start of double-blind study medication and before the first dose of open-label study medication were summarized for the double-blind medication. Two ramelteon-treated subjects permanently discontinued the study due to adverse events during the double-blind treatment period. One placebo-treated subject had multiple temporary study drug interruptions due to adverse events but did not permanently discontinue the study	2.9% 2/70 • Number of events 2 • Treatment-emergent adverse events with onset dates the same or after the start of double-blind study medication and before the first dose of open-label study medication were summarized for the double-blind medication. Two ramelteon-treated subjects permanently discontinued the study due to adverse events during the double-blind treatment period. One placebo-treated subject had multiple temporary study drug interruptions due to adverse events but did not permanently discontinue the study
Nervous system disorders Dizziness	6.2% 4/64 • Number of events 5 • Treatment-emergent adverse events with onset dates the same or after the start of double-blind study medication and before the first dose of open-label study medication were summarized for the double-blind medication. Two ramelteon-treated subjects permanently discontinued the study due to adverse events during the double-blind treatment period. One placebo-treated subject had multiple temporary study drug interruptions due to adverse events but did not permanently discontinue the study	1.4% 1/70 • Number of events 1 • Treatment-emergent adverse events with onset dates the same or after the start of double-blind study medication and before the first dose of open-label study medication were summarized for the double-blind medication. Two ramelteon-treated subjects permanently discontinued the study due to adverse events during the double-blind treatment period. One placebo-treated subject had multiple temporary study drug interruptions due to adverse events but did not permanently discontinue the study
Nervous system disorders Headache	3.1% 2/64 • Number of events 2 • Treatment-emergent adverse events with onset dates the same or after the start of double-blind study medication and before the first dose of open-label study medication were summarized for the double-blind medication. Two ramelteon-treated subjects permanently discontinued the study due to adverse events during the double-blind treatment period. One placebo-treated subject had multiple temporary study drug interruptions due to adverse events but did not permanently discontinue the study	5.7% 4/70 • Number of events 4 • Treatment-emergent adverse events with onset dates the same or after the start of double-blind study medication and before the first dose of open-label study medication were summarized for the double-blind medication. Two ramelteon-treated subjects permanently discontinued the study due to adverse events during the double-blind treatment period. One placebo-treated subject had multiple temporary study drug interruptions due to adverse events but did not permanently discontinue the study

Additional Information

Sr. VP, Clinical Science

Takeda Global Research and Development Center, Inc.

Phone: 800-778-2860

Email: [email protected]

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