Efficacy and Safety Study of Org 50081 (Esmirtazapine) in Elderly Participants (P05709)

Phase 3

Completed

• Conditions: Insomnia; Sleep Initiation and Maintenance Disorders; Mental Disorders; Dyssomnias; Sleep Disorders
• Interventions: Drug: Esmirtazapine; Drug: Placebo

• Registration Number: NCT00561821
• Lead Sponsor: Merck Sharp & Dohme LLC

Brief Summary

This study was conducted to investigate the efficacy of treatment with Org 50081 (Esmirtazapine)

compared to placebo in elderly participants with chronic primary

insomnia. Primary efficacy variable is Wake time After Sleep

Onset (WASO), averaged over all in-treatment time points

and measured by polysomnography (PSG).

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.

The maleic acid salt of Org 4420, code name Org 50081, known as Esmirtazapine, was

selected for development in the treatment of insomnia. The

first clinical trial with Esmirtazapine was a proof-of-concept trial

with a four-way cross-over design. All 3 Esmirtazapine dose

groups showed a statistically significant positive effect on

TST (objective and subjective) and WASO, as compared to

placebo.

The current study is designed to assess the efficacy and safety

of Esmirtazapine in a double-blind, placebo-controlled, parallel,

randomized trial in elderly participants suffering from chronic

primary insomnia.

Study Timeline

• Study First Submitted: 2007-11-19
• Study First Submitted QC: 2007-11-19
• Study Start: 2007-11-20
• Study First Posted: 2007-11-21
• Primary Completion: 2009-12-21
• Study Completion: 2009-12-21
• Disposition First Submitted: 2010-02-03
• Disposition First Submitted QC: 2010-02-03
• Disposition First Posted: 2010-02-05
• Results First Submitted: 2014-06-30
• Results First Submitted QC: 2014-08-04
• Results First Posted: 2014-08-05
• Status Verified: 2018-09
• Last Update Submitted: 2018-09-04
• Last Update Posted: 2018-10-03

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 538

Inclusion Criteria

• are at least 65 years of age at screening;
• sign written informed consent after the scope and

nature of the investigation have been explained to

them, before screening evaluations;

• are able to speak, read and understand the language of

the investigator, study staff (including raters) and the

informed consent form, and possess the ability to

respond to questions, follow instructions and complete

questionnaires;

• have demonstrated capability to independently

complete the LogPad questionnaires and have

completed the questionnaires at least 6 out of 7 days of

the week preceding randomization;

• have a regular sleep pattern, meaning bedtime regularly

occurs between 2100 hours and 2400 hours, with no more variation

from these boundaries than 2 times/ week, with 5-8.5

hours in bed;

• have a documented diagnosis of chronic primary

insomnia, defined as fulfillment of the Diagnostic and Statistical Manual of Mental Disorders IV - Text Revision (DSM-IV-TR) criteria

for primary insomnia (DSM-IV-TR 307.42) with a duration

of >= 1 month; fulfill the following PSG criteria on the

two screening/baseline PSG nights:

• average Total Sleep Time (TST) < 6.5 h (and each night greater than or

equal to 3 h and < 7 h),

• average WASO greater than or equal to 45 minutes

(and each night greater than or equal to 30 min),

• average Latency to Persistent Sleep (LPS) 15 min (and each night greater than or

equal to 10 min).

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Exclusion Criteria

• have other sleep disorders (DSM-IV-TR), such as sleep

related breathing disorders Apnea-Hypopnea Index (AHI) greater than or equal

to 15), Periodic Leg Movements with Arousals Index (PLMAI)

greater than or equal to 10), restless leg syndrome,

narcolepsy, circadian sleep wake rhythm disorders,

Rapid Eye Movement (REM) behavioral disorder or any parasomnia;

• have any significant medical or DSM-IV-TR

psychiatric illness causing the sleep disturbances;

• currently meet diagnostic criteria for DSM-IV-TR

depression Major Depressive Disorder (MDD) or have been diagnosed and treated

for MDD within the last 2 years;

• have a history of bipolar disorder, a history of suicide attempt or a family history of suicide. A family history of suicide is defined as any history of suicide in the first and second degree family (parents, siblings, grandparents, or offspring), or a pattern of completed suicides (more than one) in the third degree family (aunts, uncles, nieces and nephews);
• have a history or signs of dementia or other serious

cognitive impairment, as defined by a score of less than

26 on the Mini-Mental State Examination;

• have a significant, unstable medical illness e.g. acute or

chronic pain, hepatic, renal, metabolic or cardiac

disease;

• had serious head injury or stroke within the past year,

or a history of (non-febrile) seizures;

• have clinically relevant electrocardiogram (ECG) abnormalities at

screening, as judged by the investigator;

• have clinically relevant abnormal hematology or

biochemistry values at screening, as judged by the

investigator;

• have DSM-IV-TR substance abuse or DSM-IV-TR

addiction within the last year;

• drink more than 2 alcoholic drinks in a day. One drink is approximately equal to: 12 oz or 360 ml of beer (regular or light), or 4 oz or 120 ml of red or white wine, or 2 oz or 60 ml of desert wine (e.g. port, sherry), or 12 oz or 360 ml of wine cooler (regular or light), or 1 oz or 30 ml or spirits (80 to 100 proof, e.g. whiskey, vodka);
• are routinely sleeping during daytime (napping) for more than 20 minutes per day, 3 days or more per week;
• are night workers or rotating shift workers currently, or in the past 6 months
• use of psychotropic drugs affecting sleep within two weeks prior to randomization (fluoxetine: five weeks);
• use of concomitant medication affecting sleep (e.g. anxiolytics, sedatives, antidepressants, antipsychotics, centrally active sedating antihistamines, central nervous system (CNS)

stimulants, alpha-2-antagonists, respiratory stimulants and decongestants);

• smoke > 15 cigarettes per day and/or can not abstain from smoking during the night;
• drink excessive amounts of caffeinated beverages/day (more than 500 mg caffeine per day);
• have a body mass index (BMI) >= 36;
• have a positive urine drug screen at screening or at baseline;
• have a known hypersensitivity to mirtazapine or to any of the excipients;

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Esmirtazapine 0.5 mg	Esmirtazapine	one placebo tablet daily for 14 days, followed by one 0.5 mg tablet Esmirtazapine daily for 16 days, and then one placebo tablet daily for 7 days
Esmirtazapine 0.5 mg	Placebo	one placebo tablet daily for 14 days, followed by one 0.5 mg tablet Esmirtazapine daily for 16 days, and then one placebo tablet daily for 7 days
Esmirtazapine 1.5 mg	Esmirtazapine	one placebo tablet daily for 14 days, followed by one 1.5 mg tablet Esmirtazapine daily for 16 days, and then one placebo tablet daily for 7 days
Esmirtazapine 1.5 mg	Placebo	one placebo tablet daily for 14 days, followed by one 1.5 mg tablet Esmirtazapine daily for 16 days, and then one placebo tablet daily for 7 days
Placebo	Placebo	one placebo tablet daily for 14 days, followed by one placebo tablet daily for 16 days, and then one placebo tablet daily for 7 days
Esmirtazapine 3.0 mg	Esmirtazapine	one placebo tablet daily for 14 days, followed by one 3.0 mg tablet Esmirtazapine daily for 16 days, and then one placebo tablet daily for 7 days
Esmirtazapine 3.0 mg	Placebo	one placebo tablet daily for 14 days, followed by one 3.0 mg tablet Esmirtazapine daily for 16 days, and then one placebo tablet daily for 7 days

Primary Outcome Measures

Name	Time	Method
Average Wake Time After Sleep Onset Measured by Polysomnography	Up to Day 16	Wake time after sleep onset (WASO) is the total time awake between sleep onset and "lights on"; i.e. from the onset of persistent sleep until the end of the 8-hour polysomnography (PSG) recording. PSG assesses the quality of sleep by monitoring brain waves, breathing, heart function, muscle activity and eye movement. PSG measurements of WASO (observed data only) taken during the 16-day double-blind treatment period, over days 1 and 2 and days 15 and 16, were averaged.

Secondary Outcome Measures

Name	Time	Method
Average Total Sleep Time Measured by Polysomnography	Up to Day 16	Total sleep time (TST) is the sleep time recorded by PSG. PSG assesses the quality of sleep by monitoring brain waves, breathing, heart function, muscle activity and eye movement. PSG measurements of TST (observed data only) taken during the 16-day double-blind treatment period, over days 1 and 2 and days 15 and 16, were averaged.
Average Latency to Persistent Sleep Measured by Polysomnography	Up to Day 16	Latency to Persistent Sleep (LPS) is the time from lights out to the first 20 consecutive epochs scored as sleep by PSG. PSG assesses the quality of sleep by monitoring brain waves, breathing, heart function, muscle activity and eye movement. PSG measurements of LPS (observed data only) taken during the 16-day double-blind treatment period, over days 1 and 2 and days 15 and 16, were averaged.
Average Number of Awakenings Measured by Polysomnography	Up to Day 16	Number of awakenings (NAW) was measured by PSG. PSG assesses the quality of sleep by monitoring brain waves, breathing, heart function, muscle activity and eye movement. PSG measurements of NAW (observed data only) taken during the 16-day double-blind treatment period, over days 1 and 2 and days 15 and 16, were averaged.
Average Wake Time After Sleep Onset in the First Quarter of the Night Measured by Polysomnography	Up to Day 16	Wake time after sleep onset (WASO) is the total time awake between sleep onset and "lights on"; i.e. from the onset of persistent sleep until the end of the 8-hour PSG recording. WASO was recorded in the first quarter of the night, for at most 2 hours, by PSG. PSG assesses the quality of sleep by monitoring brain waves, breathing, heart function, muscle activity and eye movement. PSG measurements of WASO (observed data only) taken during the 16-day double-blind treatment period, over days 1 and 2 and days 15 and 16, were averaged.
Average Wake Time After Sleep Onset in the Second Quarter of the Night Measured by Polysomnography	Up to Day 16	Wake time after sleep onset (WASO) is the total time awake between sleep onset and "lights on"; i.e. from the onset of persistent sleep until the end of the 8-hour PSG recording. WASO was recorded in the second quarter of the night, for at most 2 hours, by PSG. PSG assesses the quality of sleep by monitoring brain waves, breathing, heart function, muscle activity and eye movement. PSG measurements of WASO (observed data only) taken during the 16-day double-blind treatment period, over days 1 and 2 and days 15 and 16, were averaged.
Average Wake Time After Sleep Onset in the Third Quarter of the Night Measured by Polysomnography	Up to Day 16	Wake time after sleep onset (WASO) is the total time awake between sleep onset and "lights on"; i.e. from the onset of persistent sleep until the end of the 8-hour PSG recording. WASO was recorded in the third quarter of the night, for at most 2 hours, by PSG. PSG assesses the quality of sleep by monitoring brain waves, breathing, heart function, muscle activity and eye movement. PSG measurements of WASO (observed data only) taken during the 16-day double-blind treatment period, over days 1 and 2 and days 15 and 16, were averaged.
Average Wake Time After Sleep Onset in the Fourth Quarter of the Night Measured by Polysomnography	Up to Day 16	Wake time after sleep onset (WASO) is the total time awake between sleep onset and "lights on"; i.e. from the onset of persistent sleep until the end of the 8-hour PSG recording. WASO was recorded in the fourth quarter of the night, for at most 2 hours, by PSG. PSG assesses the quality of sleep by monitoring brain waves, breathing, heart function, muscle activity and eye movement. PSG measurements of WASO (observed data only) taken during the 16-day double-blind treatment period, over days 1 and 2 and days 15 and 16, were averaged.
Average Number of Stage Shifts to Stage 1 or Wake Measured by Polysomnography	Up to Day 16	Number of stage shifts to stage 1 of sleep or to awaken was measured by PSG. A stage shift is the transition measured by PSG between various sleep stages. PSG assesses the quality of sleep by monitoring brain waves, breathing, heart function, muscle activity and eye movement. PSG measurements of the number of stage shifts (observed data only) taken during the 16-day double-blind treatment period, over days 1 and 2 and days 15 and 16, were averaged.
Average Subjective Total Sleep Time Based on Sleep Diary	Up to Day 16	Total Sleep Time (TST) is a subjective time (observed data only) recorded daily by the participant in an electronic diary, that was averaged over the entire 16-day, double-blind treatment period.
Average Subjective Sleep Latency Based on Sleep Diary	Up to Day 16	Sleep latency (SL) is the time taken to fall asleep (observed data only) recorded daily by the participant in an electronic diary, that was averaged over the entire 16-day, double-blind treatment period.
Average Subjective Number of Awakenings Based on Sleep Diary	Up to Day 16	Number of awakenings between sleep onset and final awakening (NAW) is a subjective number (observed data only) recorded daily by the participant in an electronic diary, that was averaged over the entire 16-day, double-blind treatment period.
Average Subjective Wake Time After Sleep Onset Based on Sleep Diary	Up to Day 16	Wake Time after Sleep Onset (WASO) is after falling asleep initially, the subjective time that the participant was awake during the night. Daily recordings by the participant in an electronic diary (observed data only), were averaged over the entire 16-day, double-blind treatment period.
Average Subjective Quality of Sleep Based on Sleep Diary	Up to Day 16	Quality of Sleep (QS) is a subjective number on a Visual Analog Scale ranging from 0 to 100, where very poor is rated at 0, up to excellent, rated at 100. Daily recordings by the participant in an electronic diary (observed data only) were averaged over the entire 16-day, double-blind treatment period.
Average Subjective Satisfaction of Sleep Duration Based on Sleep Diary	Up to Day 16	Satisfaction of Sleep Duration (SSD) is a subjective number on a Visual Analog Scale ranging from 0 to 100, where very unsatisfied is rated at 0, up to fully satisfied, rated at 100. Daily recordings by the participant in an electronic diary (observed data only) were averaged over the entire 16-day, double-blind treatment period.
Number of Participants With an Adverse Event During the 16 Day, Double-blind Treatment Period	Up to Day 16	An Adverse Event (AE) is any untoward occurrence in a participant who is administered any pharmaceutical product, and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding) symptom, or disease temporarily associated with the use of an investigational medicinal product (IMP), whether or not it is related to the IMP.
Number of Participants Who Discontinued Treatment Due to an Adverse Event During the 16 Day, Double-blind Treatment Period	Up to Day 16	An AE is any untoward occurrence in a participant who is administered any pharmaceutical product, and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding) symptom, or disease temporarily associated with the use of an IMP, whether or not it is related to the IMP.