RUBY: Study of the Safety and Effectiveness of Esmirtazapine in Participants With Chronic Primary Insomnia (P05706)

• Sponsor: Merck Sharp & Dohme LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00482612
• Collaborator: (none)
• Enrollment: 526
• Arms: 4
• Actual Duration (Months): 20.1

Study Details

Study Description

Brief Summary

The purpose of this study is to determine if esmirtazapine (Org 50081) is a safe and effective treatment for insomnia. It was anticipated that esmirtazapine would increase mean Total Sleep Time (TST) as recorded in sleep diaries relative to placebo.

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 526 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Two-Week, Double Blind, Placebo-Controlled, Randomized, Parallel Group, Efficacy and Safety Out-Patient Trial With Org 50081 in Patients With Chronic Primary Insomnia
• Actual Study Start Date: Dec 7, 2006
• Actual Primary Completion Date: Aug 11, 2008
• Actual Study Completion Date: Aug 11, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Esmirtazapine 1.5 mg Esmirtazapine 1.5 mg tablet, oral administration in the evening, once daily, for 2 weeks	Drug: Esmirtazapine; Esmirtazapine maleate was provided as tablets for oral use containing either 1.5, 3.0, 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. Tablets were administered orally once daily about 30 minutes prior to bedtime.; Other Names: Org 50081 MK-8265
Experimental: Esmirtazapine 3.0 mg Esmirtazapine 3.0 mg tablet, oral administration in the evening, once daily, for 2 weeks	Drug: Esmirtazapine; Esmirtazapine maleate was provided as tablets for oral use containing either 1.5, 3.0, 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. Tablets were administered orally once daily about 30 minutes prior to bedtime.; Other Names: Org 50081 MK-8265
Experimental: Esmirtazapine 4.5 mg Esmirtazapine 4.5 mg tablet, oral administration in the evening, once daily, for 2 weeks	Drug: Esmirtazapine; Esmirtazapine maleate was provided as tablets for oral use containing either 1.5, 3.0, 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. Tablets were administered orally once daily about 30 minutes prior to bedtime.; Other Names: Org 50081 MK-8265
Placebo Comparator: Placebo Placebo to esmirtazapine	Drug: Placebo; Placebo tablets containing the following excipients: hydroxypropyl cellulose, maize starch (USP name: corn starch), magnesium stearate, and lactose monohydrate. Tablets were administered orally once daily about 30 minutes prior to bedtime.

Outcome Measures

Primary Outcome Measures

1. Average Total Sleep Time (TST) as Recorded Daily in the Sleep Diary During the 14-day In-treatment Period [Day 1 to Day 15]

   TST was defined as the total amount of time (measured in minutes) that was actually spent sleeping the previous night as recorded daily in the participant's sleep diary. TST values over the 14-day active 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 present was used in the analysis.

Secondary Outcome Measures

1. Average Sleep Latency (SL) as Recorded Daily in the Sleep Diary During the 14-day In-treatment Period [Day 1 to Day 15]

   SL was defined as the duration of time measured in minutes that it took a participant to fall asleep as recorded daily in the participant's sleep diary. SL values over the 14-day active treatment period were averaged for each participant, and average SL was then reported by treatment arm. For participants with missing data, the average of the nights for which TST data were present were used in the analysis.

2. Number of Participants Experiencing an Adverse Event (AE) During the 14-day In-treatment Period [Day 1 to Day 15]

   The total number of participants with an AE during the 14-day In-treatment Period was tallied for each treatment arm. An AE was defined as any untoward medical occurrence in a participant or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An AE could therefore have been any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.

3. Number of Participants Who Discontinued From Study Treatment Due to an AE During the 14-day In-Treatment Period [Day 1 to Day 15]

   The total number of participants discontinuing from study treatment due to experiencing an AE was tallied for each treatment arm. An AE was defined as any untoward medical occurrence in a participant or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An AE could therefore have been any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Has signed written informed consent after the scope and nature of the investigation was explained to them

• Has difficulty falling asleep, maintaining sleep or has early morning awakenings

Exclusion Criteria:

• Significant medical or psychiatric illness causing sleep disturbances

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

• Has sleep disorder such as sleep related breathing disorder, restless leg syndrome, narcolepsy

• Has significant other medical illness such as acute or chronic pain, heart, kidney or liver disease within the last year

• Currently diagnosed or meets the criteria for Major Depressive Disorder (MDD) or has been treated for MDD with the last 2 years

• Substance abuse, excessive use of alcohol (as determined by the physician) or drug addiction within the last year.

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Merck Sharp & Dohme LLC

Investigators

• Study Director: Medical Director, Merck Sharp & Dohme LLC

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Merck Sharp & Dohme LLC
• ClinicalTrials.gov Identifier: NCT00482612
• Other Study ID Numbers: P05706; 176001; MK-8265-003
• First Posted: Jun 5, 2007
• Last Update Posted: Oct 3, 2018
• Last Verified: Sep 1, 2018

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Additional relevant MeSH terms: Sleep Initiation and Maintenance Disorders; Mirtazapine

Study Results

Participant Flow

Arm/Group Title	Esmirtazapine 1.5 mg	Esmirtazapine 3.0 mg	Esmirtazapine 4.5 mg	Placebo
Arm/Group Description	Participants took esmirtazapine 1.5 mg tablets once daily by mouth during the 14-day In-treatment Period. Participants were followed for safety during a Follow-up Period, in which no study medication was administered.	Participants took esmirtazapine 3.0 mg tablets once daily by mouth during the 14-day In-treatment Period. Participants were followed for safety during a Follow-up Period, in which no study medication was administered.	Participants took esmirtazapine 4.5 mg tablets once daily by mouth during the 14-day In-treatment Period. Participants were followed for safety during a Follow-up Period, in which no study medication was administered.	Participants took placebo tablets once daily by mouth during the 14-day In-treatment Period. Participants were followed for safety during a Follow-up Period, in which no study medication was administered.
Period Title: In-treatment Period
STARTED	137	125	129	135
Treated	137	125	128	135
COMPLETED	137	125	128	135
NOT COMPLETED	0	0	1	0
Period Title: In-treatment Period
STARTED	137	125	128	135
COMPLETED	123	107	106	127
NOT COMPLETED	14	18	22	8

Baseline Characteristics

Arm/Group Title	Esmirtazapine 1.5 mg	Esmirtazapine 3.0 mg	Esmirtazapine 4.5 mg	Placebo	Total
Arm/Group Description	Participants took esmirtazapine 1.5 mg tablets once daily by mouth during the 14-day In-treatment Period. No study medication was administered during the Follow-up Period.	Participants took esmirtazapine 3.0 mg tablets once daily by mouth during the 14-day In-treatment Period. No study medication was administered during the Follow-up Period.	Participants took esmirtazapine 4.5 mg tablets once daily by mouth during the 14-day In-treatment Period. No study medication was administered during the Follow-up Period.	Participants took placebo tablets once daily by mouth during the 14-day In-treatment Period. No study medication was administered during the Follow-up Period.	Total of all reporting groups
Overall Participants	137	125	128	135	525
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	44.8 (12.4)	45.6 (12.0)	44.5 (12.2)	46.2 (11.3)	45.3 (12.0)
Sex: Female, Male (Count of Participants)
Female	92 67.2%	85 68%	72 56.3%	90 66.7%	339 64.6%
Male	45 32.8%	40 32%	56 43.8%	45 33.3%	186 35.4%

Outcome Measures

1. Primary Outcome

Title	Average Total Sleep Time (TST) as Recorded Daily in the Sleep Diary During the 14-day In-treatment Period
Description	TST was defined as the total amount of time (measured in minutes) that was actually spent sleeping the previous night as recorded daily in the participant's sleep diary. TST values over the 14-day active 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 present was used in the analysis.
Time Frame	Day 1 to Day 15

Outcome Measure Data

Analysis Population Description

The Intent-To-Treat Group consisted of all randomized participants who received at least one dose of double-blind trial medication, and had baseline and at least one post-baseline measurement for at least one efficacy assessment.

Arm/Group Title	Esmirtazapine 1.5 mg	Esmirtazapine 3.0 mg	Esmirtazapine 4.5 mg	Placebo
Arm/Group Description	Participants took esmirtazapine 1.5 mg tablets once daily by mouth during the 14-day In-treatment Period.	Participants took esmirtazapine 3.0 mg tablets once daily by mouth during the 14-day In-treatment Period.	Participants took esmirtazapine 4.5 mg tablets once daily by mouth during the 14-day In-treatment Period.	Participants took placebo tablets once daily by mouth during the 14-day In-treatment Period.
Measure Participants	135	121	126	133
Mean (Standard Deviation) [Minutes]	382.14 (68.155)	382.77 (81.172)	394.83 (85.575)	351.40 (78.551)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Esmirtazapine 1.5 mg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments	Baseline TST was used as a covariate.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Esmirtazapine 3.0 mg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments	Baseline TST was used as a covariate.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Esmirtazapine 4.5 mg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments	Baseline TST was used as a covariate.

2. Secondary Outcome

Title	Average Sleep Latency (SL) as Recorded Daily in the Sleep Diary During the 14-day In-treatment Period
Description	SL was defined as the duration of time measured in minutes that it took a participant to fall asleep as recorded daily in the participant's sleep diary. SL values over the 14-day active treatment period were averaged for each participant, and average SL was then reported by treatment arm. For participants with missing data, the average of the nights for which TST data were present were used in the analysis.
Time Frame	Day 1 to Day 15

Outcome Measure Data

Analysis Population Description

The Intent-To-Treat Group consisted of all randomized participants who received at least one dose of double-blind trial medication and had baseline and at least one post-baseline measurement for at least one efficacy assessment.

Arm/Group Title	Esmirtazapine 1.5 mg	Esmirtazapine 3.0 mg	Esmirtazapine 4.5 mg	Placebo
Arm/Group Description	Participants took esmirtazapine 1.5 mg tablets once daily by mouth during the 14-day In-treatment Period.	Participants took esmirtazapine 3.0 mg tablets once daily by mouth during the 14-day In-treatment Period.	Participants took esmirtazapine 4.5 mg tablets once daily by mouth during the 14-day In-treatment Period.	Participants took placebo tablets once daily by mouth during the 14-day In-treatment Period.
Measure Participants	135	121	126	133
Mean (Standard Deviation) [Minutes]	48.93 (34.59)	52.02 (38.95)	50.80 (45.76)	60.13 (42.98)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Esmirtazapine 1.5 mg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0014
	Comments
	Method	ANCOVA
	Comments	Baseline SL was used as a covariate.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Esmirtazapine 3.0 mg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0135
	Comments
	Method	ANCOVA
	Comments	Baseline SL was used as a covariate.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Esmirtazapine 4.5 mg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments	Baseline SL was used as a covariate.

3. Secondary Outcome

Title	Number of Participants Experiencing an Adverse Event (AE) During the 14-day In-treatment Period
Description	The total number of participants with an AE during the 14-day In-treatment Period was tallied for each treatment arm. An AE was defined as any untoward medical occurrence in a participant or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An AE could therefore have been any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.
Time Frame	Day 1 to Day 15

Outcome Measure Data

Analysis Population Description

The All-Subjects-Treated Group consisted of all participants who received at least 1 dose of trial medication.

Arm/Group Title	Esmirtazapine 1.5 mg	Esmirtazapine 3.0 mg	Esmirtazapine 4.5 mg	Placebo
Arm/Group Description	Participants took esmirtazapine 1.5 mg tablets once daily by mouth during the 14-day In-treatment Period.	Participants took esmirtazapine 3.0 mg tablets once daily by mouth during the 14-day In-treatment Period.	Participants took esmirtazapine 4.5 mg tablets once daily by mouth during the 14-day In-treatment Period.	Participants took placebo tablets once daily by mouth during the 14-day In-treatment Period.
Measure Participants	137	125	128	135
Number [Number of participants]	35 25.5%	41 32.8%	41 32%	28 20.7%

4. Secondary Outcome

Title	Number of Participants Who Discontinued From Study Treatment Due to an AE During the 14-day In-Treatment Period
Description	The total number of participants discontinuing from study treatment due to experiencing an AE was tallied for each treatment arm. An AE was defined as any untoward medical occurrence in a participant or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An AE could therefore have been any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.
Time Frame	Day 1 to Day 15

Outcome Measure Data

Analysis Population Description

The All-Subjects-Treated Group consisted of all participants who received at least 1 dose of trial medication.

Arm/Group Title	Esmirtazapine 1.5 mg	Esmirtazapine 3.0 mg	Esmirtazapine 4.5 mg	Placebo
Arm/Group Description	Participants took esmirtazapine 1.5 mg tablets once daily by mouth during the 14-day In-treatment Period.	Participants took esmirtazapine 3.0 mg tablets once daily by mouth during the 14-day In-treatment Period.	Participants took esmirtazapine 4.5 mg tablets once daily by mouth during the 14-day In-treatment Period.	Participants took placebo tablets once daily by mouth during the 14-day In-treatment Period.
Measure Participants	137	125	128	135
Number [Number of participants]	4 2.9%	7 5.6%	9 7%	0 0%

Adverse Events

Time Frame	From Day 1 of the Treatment Period up to 30 days after completion of the Treatment Period (up to 45 days). AE data were not reported for the 1 enrolled participant who did not receive study medication.
Adverse Event Reporting Description	AEs were collected for 525 treated participants separately during the In-Treatment Period (Days 1-15) and during the Follow-up Period (up to Day 45).
Arm/Group Title	Esmirtazapine 1.5 mg In-treatment		Esmirtazapine 3.0 mg In-Treatment		Esmirtazapine 4.5 mg In-treatment		Placebo In-treatment		Esmirtazapine 1.5 mg Follow-up		Esmirtazapine 3.0 mg Folow-up		Esmirtazapine 4.5 mg Follow-up		Placebo Follow-up
Arm/Group Description	Participants took esmirtazapine 1.5 mg tablets once daily by mouth during the 14-day In-treatment Period.		Participants took esmirtazapine 3.0 mg tablets once daily by mouth during the 14-day In-treatment Period.		Participants took esmirtazapine 4.5 mg tablets once daily by mouth during the 14-day In-treatment Period.		Participants took placebo tablets once daily by mouth during the 14-day In-treatment Period.		After receiving 1.5 mg esmirtazipine in the In-Treatment Period, participants were followed for safety during a Follow-up Period in which no study medication was administered.		After receiving 3.0 mg esmirtazipine in the In-Treatment Period, participants were followed for safety during a Follow-up Period in which no study medication was administered.		After receiving 4.5 mg esmirtazipine in the In-Treatment Period, participants were followed for safety during a Follow-up Period in which no study medication was administered.		After receiving placebo in the In-Treatment Period, participants were followed for safety during a Follow-up Period in which no study medication was administered.
All Cause Mortality
	Esmirtazapine 1.5 mg In-treatment		Esmirtazapine 3.0 mg In-Treatment		Esmirtazapine 4.5 mg In-treatment		Placebo In-treatment		Esmirtazapine 1.5 mg Follow-up		Esmirtazapine 3.0 mg Folow-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	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Esmirtazapine 1.5 mg In-treatment		Esmirtazapine 3.0 mg In-Treatment		Esmirtazapine 4.5 mg In-treatment		Placebo In-treatment		Esmirtazapine 1.5 mg Follow-up		Esmirtazapine 3.0 mg Folow-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	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/137 (1.5%)		1/125 (0.8%)		1/128 (0.8%)		0/135 (0%)		0/137 (0%)		0/125 (0%)		0/128 (0%)		0/135 (0%)
Infections and infestations
Appendicitis	0/137 (0%)	0	0/125 (0%)	0	1/128 (0.8%)	1	0/135 (0%)	0	0/137 (0%)	0	0/125 (0%)	0	0/128 (0%)	0	0/135 (0%)	0
Bronchitis	1/137 (0.7%)	1	0/125 (0%)	0	0/128 (0%)	0	0/135 (0%)	0	0/137 (0%)	0	0/125 (0%)	0	0/128 (0%)	0	0/135 (0%)	0
Staphylococcal infection	1/137 (0.7%)	1	0/125 (0%)	0	0/128 (0%)	0	0/135 (0%)	0	0/137 (0%)	0	0/125 (0%)	0	0/128 (0%)	0	0/135 (0%)	0
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	1/137 (0.7%)	1	0/125 (0%)	0	0/128 (0%)	0	0/135 (0%)	0	0/137 (0%)	0	0/125 (0%)	0	0/128 (0%)	0	0/135 (0%)	0
Asthma	1/137 (0.7%)	1	0/125 (0%)	0	0/128 (0%)	0	0/135 (0%)	0	0/137 (0%)	0	0/125 (0%)	0	0/128 (0%)	0	0/135 (0%)	0
Surgical and medical procedures
Abdominoplasty	0/137 (0%)	0	1/125 (0.8%)	1	0/128 (0%)	0	0/135 (0%)	0	0/137 (0%)	0	0/125 (0%)	0	0/128 (0%)	0	0/135 (0%)	0
Other (Not Including Serious) Adverse Events
	Esmirtazapine 1.5 mg In-treatment		Esmirtazapine 3.0 mg In-Treatment		Esmirtazapine 4.5 mg In-treatment		Placebo In-treatment		Esmirtazapine 1.5 mg Follow-up		Esmirtazapine 3.0 mg Folow-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	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/137 (7.3%)		11/125 (8.8%)		9/128 (7%)		2/135 (1.5%)		0/137 (0%)		0/125 (0%)		0/128 (0%)		0/135 (0%)
Nervous system disorders
Somnolence	10/137 (7.3%)	10	11/125 (8.8%)	11	9/128 (7%)	9	2/135 (1.5%)	2	0/137 (0%)	0	0/125 (0%)	0	0/128 (0%)	0	0/135 (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.