A Six Week, Double-Blind Randomized, Efficacy and Safety, Sleep Lab Trial With Esmirtazapine (Org 50081) (P05707)

• Sponsor: Merck Sharp & Dohme LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00506389
• Collaborator: Parexel (Industry)
• Enrollment: 419
• Arms: 3
• Actual Duration (Months): 8.3

Study Details

Study Description

Brief Summary

The purpose of this trial is to investigate the efficacy, safety and tolerability of esmirtazapine (Org 50081) compared to placebo in patients with chronic primary insomnia.

Condition or Disease	Intervention/Treatment	Phase
Insomnia	Drug: Esmirtazapine; Drug: Placebo	Phase 3

Detailed Description

Insomnia is a common complaint or disorder throughout the world. About one third of the population in the industrial countries reports difficulty initiating or maintaining sleep, resulting in a non-refreshing or non-restorative sleep. The majority of the insomniacs suffer chronically from their complaints. It has been reported that in patients with chronic insomnia lasting longer than six months, 50% had a past or current mental disorder. This raises the possibility that treatment of insomnia may reduce the risk for psychological conditions. This double-blind, placebo-controlled, parallel, randomized clinical trial is designed to assess the efficacy and safety of esmirtazapine in patients suffering from chronic primary insomnia.

Study Design

• Study Type: Interventional
• Actual Enrollment: 419 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Six-Week Double-Blind Randomized, Placebo-Controlled, Parallel Group, Efficacy and Safety, Sleep Lab Trial With Org 50081 in Patients With Chronic Primary Insomnia
• Actual Study Start Date: Jun 6, 2007
• Actual Primary Completion Date: Feb 13, 2008
• Actual Study Completion Date: Feb 13, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Esmirtazapine 3.0 mg Participants took placebo tablets on Days -7 and -6, esmirtazapine 3.0 mg tablets on Days 1-42, and placebo tablets on Days 43-50. Tablets were taken by mouth once daily in the evening.	Drug: Esmirtazapine; Esmirtazapine maleate was provided as tablets for oral use containing 3.0 mg, or 4.5 mg of active compound. In addition, tablets contain the following excipients: hydroxypropyl cellulose, maize starch (United States Pharmacopeia [USP] name corn starch), magnesium stearate, and lactose monohydrate.; Other Names: ORG 50081
Experimental: Esmirtazapine 4.5 mg Participants took placebo tablets on Days -7 and -6, esmirtazapine 4.5 mg tablets on Days 1-42, and placebo tablets on Days 43-50. Tablets were taken by mouth once daily in the evening.	Drug: Esmirtazapine; Esmirtazapine maleate was provided as tablets for oral use containing 3.0 mg, or 4.5 mg of active compound. In addition, tablets contain the following excipients: hydroxypropyl cellulose, maize starch (United States Pharmacopeia [USP] name corn starch), magnesium stearate, and lactose monohydrate.; Other Names: ORG 50081
Placebo Comparator: Placebo Participants took placebo tablets on Days -7 and -6, placebo tablets on Days 1-42, and placebo tablets on Days 43-50. Tablets were taken by mouth once daily in the evening.	Drug: Placebo; The placebo tablets contained the following excipients: hydroxypropyl cellulose, maize starch (USP name corn starch), magnesium stearate, and lactose monohydrate.

Outcome Measures

Primary Outcome Measures

1. Average Wake Time After Sleep Onset (WASO) During the In-Treatment Period [From Day 1 to Day 36]

   WASO was defined as the total objective time awake after the onset of persistent sleep until the end of the 8-hour sleep cycle period as measured by polysomnography (PSG). WASO was calculated as the mean of Nights 1, 15, and 36.

Secondary Outcome Measures

1. Average Latency to Persistent Sleep (LPS) During the In-Treatment Period [From Day 1 to Day 36]

   LPS was defined as the time in minutes from lights out to the first 20 consecutive epochs scored as sleep as measured by PSG. LPS was calculated as the mean of Nights 1, 15, and 36.

2. Average Subjective Total Sleep Time (TST) During the In-Treatment Period [From Day 1 to Day 36]

   TST was defined as the total amount of time in minutes that was actually spent sleeping the previous night as recorded daily in the participant's sleep diary. TST values over the 6 week In-Treatment Period were averaged for each participant, and average TST was then reported by treatment arm. For participants with missing data, the average of the nights for which TST data were available was used in the analysis.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Documented diagnosis of chronic primary insomnia

Exclusion Criteria:

• Other sleep disorder such as sleep apnea, restless leg syndrome, narcolepsy, sleep/wake rhythm disorders

• Has significant medical or psychiatric illness as causing the sleep disorder

• Diagnosed with major depressive disorder

• Substance abuse within the past year

• Night worker or work on rotating shifts

• Has had serious head injury, stroke, epilepsy

• Has a history of bipolar disorder or family (immediate family) history of suicide

• Smokes more than 15 cigarettes per day and cannot abstain from smoking during the night or in the sleep laboratory

• Drinks beverages containing more than 500 mg caffeine per day

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Merck Sharp & Dohme LLC
• Parexel

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Merck Sharp & Dohme LLC
• ClinicalTrials.gov Identifier: NCT00506389
• Other Study ID Numbers: P05707; 176002
• First Posted: Jul 25, 2007
• Last Update Posted: Oct 2, 2018
• Last Verified: Sep 1, 2018

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Merck Sharp & Dohme LLC: Sleep Initiation and Maintenance Disorders, Sleep Disorders, Intrinsic Dyssomnias, Sleep Disorders, Nervous System Diseases, Mental Disorders
• Additional relevant MeSH terms: Sleep Initiation and Maintenance Disorders; Mirtazapine

Study Results

Participant Flow

Arm/Group Title	Esmirtazapine 3.0 mg	Esmirtazapine 4.5 mg	Placebo
Arm/Group Description	Participants took placebo tablets during the 10- to 14-day Placebo Washout Period, esmirtazapine 3.0 mg tablets during the 6-week In-treatment Period, and placebo tablets during the 1-week Placebo Withdrawal Period. After this, participants were followed for safety up to Day 50 during the Follow-Up Period.	Participants took placebo tablets during the 10- to 14-day Placebo Washout Period, esmirtazapine 4.5 mg tablets during the 6-week In-treatment Period, and placebo tablets during the 1-week Placebo Withdrawal Period. After this, participants were followed for safety up to Day 50 during the Follow-Up Period.	Participants took placebo tablets during the 10- to 14-day Placebo Washout Period, placebo tablets during the 6-week In-treatment Period, and placebo tablets during the 1-week Placebo Withdrawal Period. After this, participants were followed for safety up to Day 50 during the Follow-Up Period.
Period Title: In-treatment Period
STARTED	143	139	137
All Participants Treated	139	138	136
COMPLETED	117	124	125
NOT COMPLETED	26	15	12
Period Title: In-treatment Period
STARTED	139	138	136
COMPLETED	139	138	136
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	Esmirtazapine 3.0 mg	Esmirtazapine 4.5 mg	Placebo	Total
Arm/Group Description	Participants took placebo tablets during the 10- to 14-day Placebo Washout Period, esmirtazapine 3.0 mg tablets during the 6-week In-treatment Period, and placebo tablets during the 1-week Placebo Withdrawal Period. After this, participants were followed for safety up to Day 50 during the Follow-Up Period.	Participants took placebo tablets during the 10- to 14-day Placebo Washout Period, esmirtazapine 4.5 mg tablets during the 6-week In-treatment Period, and placebo tablets during the 1-week Placebo Withdrawal Period. After this, participants were followed for safety up to Day 50 during the Follow-Up Period.	Participants took placebo tablets during the 10- to 14-day Placebo Washout Period, placebo tablets during the 6-week In-treatment Period, and placebo tablets during the 1-week Placebo Withdrawal Period. After this, participants were followed for safety up to Day 50 during the Follow-Up Period.	Total of all reporting groups
Overall Participants	143	139	137	419
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	43.5 (11.3)	44.5 (11.5)	46.6 (10.5)	44.9 (11.2)
Sex: Female, Male (Count of Participants)
Female	98 68.5%	89 64%	90 65.7%	277 66.1%
Male	45 31.5%	50 36%	47 34.3%	142 33.9%

Outcome Measures

1. Primary Outcome

Title	Average Wake Time After Sleep Onset (WASO) During the In-Treatment Period
Description	WASO was defined as the total objective time awake after the onset of persistent sleep until the end of the 8-hour sleep cycle period as measured by polysomnography (PSG). WASO was calculated as the mean of Nights 1, 15, and 36.
Time Frame	From Day 1 to Day 36

Outcome Measure Data

Analysis Population Description

The Intent-to-Treat (ITT) group consisted of all participants who were randomized, received at least one dose of double-blind trial medication, and had at least one post-randomization efficacy assessment. Fifteen participants from 1 site were excluded from all efficacy analyses.

Arm/Group Title	Esmirtazapine 3.0 mg	Esmirtazapine 4.5 mg	Placebo
Arm/Group Description	Participants took placebo tablets during the 10- to 14-day Placebo Washout Period, esmirtazapine 3.0 mg tablets during the 6-week In-treatment Period, and placebo tablets during the 1-week Placebo Withdrawal Period. After this, participants were followed for safety up to Day 50 during the Follow-Up Period.	Participants took placebo tablets during the 10- to 14-day Placebo Washout Period, esmirtazapine 4.5 mg tablets during the 6-week In-treatment Period, and placebo tablets during the 1-week Placebo Withdrawal Period. After this, participants were followed for safety up to Day 50 during the Follow-Up Period.	Participants took placebo tablets during the 10- to 14-day Placebo Washout Period, placebo tablets during the 6-week In-treatment Period, and placebo tablets during the 1-week Placebo Withdrawal Period. After this, participants were followed for safety up to Day 50 during the Follow-Up Period.
Measure Participants	133	133	132
Mean (Standard Deviation) [Minutes]	45.6 (25.7)	45.5 (26.5)	76.1 (46.0)

2. Secondary Outcome

Title	Average Latency to Persistent Sleep (LPS) During the In-Treatment Period
Description	LPS was defined as the time in minutes from lights out to the first 20 consecutive epochs scored as sleep as measured by PSG. LPS was calculated as the mean of Nights 1, 15, and 36.
Time Frame	From Day 1 to Day 36

Outcome Measure Data

Analysis Population Description

The ITT group consisted of all participants who were randomized, received at least one dose of double-blind trial medication, and had at least one post-randomization efficacy assessment. Fifteen participants from 1 site were excluded from all efficacy analyses.

Arm/Group Title	Esmirtazapine 3.0 mg	Esmirtazapine 4.5 mg	Placebo
Arm/Group Description	Participants took placebo tablets during the 10- to 14-day Placebo Washout Period, esmirtazapine 3.0 mg tablets during the 6-week In-treatment Period, and placebo tablets during the 1-week Placebo Withdrawal Period. After this, participants were followed for safety up to Day 50 during the Follow-Up Period.	Participants took placebo tablets during the 10- to 14-day Placebo Washout Period, esmirtazapine 4.5 mg tablets during the 6-week In-treatment Period, and placebo tablets during the 1-week Placebo Withdrawal Period. After this, participants were followed for safety up to Day 50 during the Follow-Up Period.	Participants took placebo tablets during the 10- to 14-day Placebo Washout Period, placebo tablets during the 6-week In-treatment Period, and placebo tablets during the 1-week Placebo Withdrawal Period. After this, participants were followed for safety up to Day 50 during the Follow-Up Period.
Measure Participants	133	133	132
Mean (Standard Deviation) [Minutes]	28.7 (28.4)	26.1 (23.0)	40.5 (27.3)

3. Secondary Outcome

Title	Average Subjective Total Sleep Time (TST) During the In-Treatment Period
Description	TST was defined as the total amount of time in minutes that was actually spent sleeping the previous night as recorded daily in the participant's sleep diary. TST values over the 6 week In-Treatment Period were averaged for each participant, and average TST was then reported by treatment arm. For participants with missing data, the average of the nights for which TST data were available was used in the analysis.
Time Frame	From Day 1 to Day 36

Outcome Measure Data

Analysis Population Description

The ITT group consisted of all participants who were randomized, received at least one dose of double-blind trial medication, and had at least one post-randomization efficacy assessment. Fifteen participants from 1 site were excluded from all efficacy analyses.

Arm/Group Title	Esmirtazapine 3.0 mg	Esmirtazapine 4.5 mg	Placebo
Arm/Group Description	Participants took placebo tablets during the 10- to 14-day Placebo Washout Period, esmirtazapine 3.0 mg tablets during the 6-week In-treatment Period, and placebo tablets during the 1-week Placebo Withdrawal Period. After this, participants were followed for safety up to Day 50 during the Follow-Up Period.	Participants took placebo tablets during the 10- to 14-day Placebo Washout Period, esmirtazapine 4.5 mg tablets during the 6-week In-treatment Period, and placebo tablets during the 1-week Placebo Withdrawal Period. After this, participants were followed for safety up to Day 50 during the Follow-Up Period.	Participants took placebo tablets during the 10- to 14-day Placebo Washout Period, placebo tablets during the 6-week In-treatment Period, and placebo tablets during the 1-week Placebo Withdrawal Period. After this, participants were followed for safety up to Day 50 during the Follow-Up Period.
Measure Participants	133	133	132
Mean (Standard Deviation) [Minutes]	384.6 (63.6)	384.6 (66.2)	351.6 (57.2)

Adverse Events

Time Frame	Day 1 to Day 50
Adverse Event Reporting Description	Adverse events (AEs) were monitored for All Participants Treated (receiving at least one dose of study drug) during the 6-week In-treatment Period and the subsequent 1-week Follow-up Period. Six participants did not receive study drug and were not included.
Arm/Group Title	Esmirtazapine 3.0 mg In-treatment		Esmirtazapine 4.5 mg In-treatment		Placebo In-treatment		Esmirtazapine 3.0 mg Follow-up		Esmirtazapine 4.5 mg Follow-up		Placebo Follow-up
Arm/Group Description	Participants took placebo tablets during the 10- to 14-day Placebo Washout Period, esmirtazapine 3.0 mg tablets during the 6-week In-treatment Period, and placebo tablets during the 1-week Placebo Withdrawal Period. Tablets were taken by mouth once daily in the evening.		Participants took placebo tablets during the 10- to 14-day Placebo Washout Period, esmirtazapine 4.5 mg tablets during the 6-week In-treatment Period, and placebo tablets during the 1-week Placebo Withdrawal Period. Tablets were taken by mouth once daily in the evening.		Participants took placebo tablets during the 10- to 14-day Placebo Washout Period, placebo tablets during the 6-week In-treatment Period, and placebo tablets during the 1-week Placebo Withdrawal Period. Tablets were taken by mouth once daily in the evening.		After participants received placebo tablets during the Placebo Washout Period and 3.0 mg esmirtazapine during the In-treatment Period, participants were followed for safety up to Day 50 during the Follow-up Period.		After participants received placebo tablets during the Placebo Washout Period and 4.5 mg esmirtazapine during the In-treatment Period, participants were followed for safety up to Day 50 during the Follow-up Period.		After participants received placebo tablets during the Placebo Washout Period and placebo during the In-treatment Period, participants were followed for safety up to Day 50 during the Follow-up Period.
All Cause Mortality
	Esmirtazapine 3.0 mg In-treatment		Esmirtazapine 4.5 mg In-treatment		Placebo In-treatment		Esmirtazapine 3.0 mg Follow-up		Esmirtazapine 4.5 mg Follow-up		Placebo Follow-up
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Esmirtazapine 3.0 mg In-treatment		Esmirtazapine 4.5 mg In-treatment		Placebo In-treatment		Esmirtazapine 3.0 mg Follow-up		Esmirtazapine 4.5 mg Follow-up		Placebo Follow-up
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/139 (0%)		1/138 (0.7%)		0/136 (0%)		0/139 (0%)		0/138 (0%)		0/136 (0%)
Blood and lymphatic system disorders
Neutropenia	0/139 (0%)	0	1/138 (0.7%)	1	0/136 (0%)	0	0/139 (0%)	0	0/138 (0%)	0	0/136 (0%)	0
Infections and infestations
Pneumonia streptococcal	0/139 (0%)	0	1/138 (0.7%)	1	0/136 (0%)	0	0/139 (0%)	0	0/138 (0%)	0	0/136 (0%)	0
Sepsis	0/139 (0%)	0	1/138 (0.7%)	1	0/136 (0%)	0	0/139 (0%)	0	0/138 (0%)	0	0/136 (0%)	0
Other (Not Including Serious) Adverse Events
	Esmirtazapine 3.0 mg In-treatment		Esmirtazapine 4.5 mg In-treatment		Placebo In-treatment		Esmirtazapine 3.0 mg Follow-up		Esmirtazapine 4.5 mg Follow-up		Placebo Follow-up
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	20/139 (14.4%)		24/138 (17.4%)		13/136 (9.6%)		2/139 (1.4%)		1/138 (0.7%)		1/136 (0.7%)
Nervous system disorders
Headache	5/139 (3.6%)	7	7/138 (5.1%)	9	9/136 (6.6%)	11	2/139 (1.4%)	2	1/138 (0.7%)	1	1/136 (0.7%)	1
Somnolence	16/139 (11.5%)	18	18/138 (13%)	20	4/136 (2.9%)	4	0/139 (0%)	0	0/138 (0%)	0	0/136 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

All publications must be based on data validated and released by the Sponsor. Any such scientific paper, presentation, or other communication concerning the clinical trial will first be submitted to the Sponsor, at least 6 weeks ahead of estimated publication or presentation, for written consent, which shall not be withheld unreasonably.