A 6-Month Efficacy and Safety Study of Org 50081 in Adult Patients With Chronic Primary Insomnia (21106/P05701/MK-8265-002)

A 6-Month, Double-Blind, Randomized, Placebo-Controlled, Parallel Group Outpatient Trial, Investigating the Efficacy and Safety of Org 50081 in Adult Patients With Chronic Primary Insomnia

To investigate the long-term efficacy and safety of treatment with esmirtazapine (Org 50081, SCH 900265, MK-8265) compared to placebo, in participants with chronic primary insomnia. Primary efficacy variable is Total Sleep Time (TST).

Study Overview

• Status: Completed
• Conditions: Mental Disorders; Dyssomnias; Sleep Initiation and Maintenance Disorders; Sleep Disorders; Sleep Disorder, Intrinsic
• Intervention / Treatment: Drug: Esmirtazapine; Drug: Placebo

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 (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 Wake Time After Sleep Onset (WASO), as compared to placebo.

The current study is designed to assess the long-term efficacy and safety of esmirtazapine in a double-blind, randomized, placebo-controlled, parallel group outpatient trial in participants suffering from chronic primary insomnia. During the 6-month treatment period, participants are randomly assigned to receive either esmirtazapine or placebo. Then, during the 7-day discontinuation period, participants who received esmirtazapine in the 6-month treatment period are randomly assigned to receive either esmirtazapine or placebo, while participants who received placebo in the 6-month treatment period continue to receive placebo.

• Study Type: Interventional
• Enrollment (Actual): 460
• Phase: Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• are at least 18 and less than 65 years;
• sign written informed consent after the scope and nature of the investigation have been explained;
• have shown capability to complete the LogPad questionnaires;
• have difficulty falling asleep, maintaining sleep or have early morning awakening;

Exclusion Criteria:

• Significant medical or psychiatric illness causing sleep disturbances.
• Have a history of bipolar disorder or attempted suicide or have a family (immediate family) history of suicide.
• Have a sleep disorder such as sleep-related breathing disorder, restless leg syndrome, narcolepsy.
• Significant other medical illness such as acute or chronic pain, heart-, kidney-, or liver disease within the last year.
• Currently diagnosed or meet the criteria for Major Depressive Disorder (MDD) or have been treated for MDD in the last 2 years.
• Substance abuse, excessive use of alcohol (determined by the physician) or drug addiction within the last year.
• Are night workers or rotating shift workers or plan to travel through more than 3 time-zones.
• Routinely nap during the day.
• Have a Body Mass Index (BMI) of 36 or more.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Esmirtazapine 4.5 mg; Participants receive esmirtazapine 4.5 mg tablets, administered once a day for 6 months	Drug: Esmirtazapine; One esmirtazapine 4.5 mg tablet once a day
Placebo Comparator: Placebo; Participants receive placebo tablets, administered once a day for 6 months	Drug: Placebo; One placebo tablet once a day

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Total Sleep Time (TST) - 6-Month Treatment Period	TST was defined as the time recorded for sleep diary question 6 "How much time did you actually spend sleeping?" as reported by participants using a LogPad (hand-held electronic data capture device). Baseline was defined as the mean TST from the Placebo Run-in Period. Change from Baseline was calculated as the mean of combined data from Weeks 14 through 26, using a last observation carried forward (LOCF) approach.	Baseline and the Mean of Weeks 14-26

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Who Experienced Adverse Events (AEs)	An AE is defined as any unfavorable and unintended change in the structure, function or chemistry of the body whether or not considered related to study drug. The number of participants who experienced AEs is combined for the 6-Month Treatment Period and the 7-Day Discontinuation Period.	Up to 31 weeks
Number of Participants Who Discontinued Study Drug Due to an AE	An AE is defined as any unfavorable and unintended change in the structure, function or chemistry of the body whether or not considered related to study drug. The number of participants who discontinued study drug due to an AE is combined for the 6-Month Treatment Period and the 7-Day Discontinuation Period.	Up to 27 weeks
Change From Baseline in Sleep Latency (SL) - 6-Month Treatment Period	SL was defined as the time recorded for sleep diary question 3 "How long did it take you to fall asllep?", as reported by participants using a LogPad. Baseline was defined as the mean SL from the Placebo Run-in Period. Change from Baseline was calculated as the mean of combined data from Weeks 14 through 26, using an LOCF approach.	Baseline and the Mean of Weeks 14-26
Change From Baseline in Wake Time After Sleep Onset (WASO) - 6-Month Treatment Period	WASO was defined as the time recorded for sleep diary question 5 "How much time were you awake, after falling asleep initially?", as reported by participants using a LogPad. Baseline was defined as the mean WASO from the Placebo Run-in Period. Change from Baseline was calculated as the mean of combined data from Weeks 14 through 26, using an LOCF approach.	Baseline and the Mean of Weeks 14-26

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Number of Awakenings (NAW) - 6-Month Treatment Period	NAW was defined as the number of times recorded for sleep diary question 4a "How many times did you wake up during the night?", as reported by participants using a LogPad. Baseline was defined as the mean NAW from the Placebo Run-in Period. Change from Baseline was calculated as the mean of combined data from Weeks 14 through 26, using an LOCF approach.	Baseline and the Mean of Weeks 14-26
Change From Baseline in Sleep Quality - 6-Month Treatment Period	Sleep Quality was assessed using a Visual Analog Scale (VAS) in response to the sleep diary question 7 "Rate the quality of your sleep last night", as reported by participants using a LogPad. Responses could range from 0=Very poor to 100=Excellent, with a higher score indicating greater sleep quality. Baseline was defined as the mean Sleep Quality score from the Placebo Run-in Period. Change from Baseline was calculated as the mean of combined data from Weeks 14 through 26, using an LOCF approach.	Baseline and the Mean of Weeks 14-26
Change From Baseline in Satisfaction With Sleep Duration - 6-Month Treatment Period	Satifaction with Sleep Duration was assessed using a Visual Analog Scale (VAS) in response to the sleep diary question 8 "How satisfied are you about your sleep duration of last night?", as reported by participants using a LogPad. Responses could range from 0=Very unsatisfied to 100=Fully satisfied, with a higher score indicating great satisfaction with sleep duration. Baseline was defined as the mean Satisfaction with Sleep Duration score from the Placebo Run-in Period. Change from Baseline was calculated as the mean of combined data from Weeks 14 through 26, using an LOCF approach.	Baseline and the Mean of Weeks 14-26
Change From Baseline in Two Aggregate Measures of Short Form 36 (SF-36) Health Survey Score - 6-Month Treatment Period	SF-36 is a participant-rated questionnaire that consists of 8 scaled scores: vitality, physical functioning, bodily pain, general health perceptions, physical role functioning, emotional role functioning, social role functioning, and mental health, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each of the 8 questions carries equal weight. The SF-36 can be divided into 2 aggregate summary measures: the Physical Component Summary (PCS) and the Mental Component Summary (MCS). The scores can range from 0 to 100, with a lower score indicating more disability. Baseline was defined as the SF-36 score assessed at randomization.	Baseline and Week 26
Change From Baseline in Investigator Global Rating (IGR) - 6-Month Treatment Period	The IGR is a clinician-rated 7-point scale used to assess the severity of illness. Severity is rated on a scale from 1=Normal to 7=Extremely severe. Baseline was defined as the last non-missing value obtained during the Placebo Run-in Period. IGR assessments were done at Baseline of the 6-Month Treatment Period and and at the end of the 6-Month Treatment Period to assess the effects of treatment.	Baseline and Week 26
Change From Baseline in Investigator Global Rating (IGR) - 7-Day Discontinuation Period	The IGR is a clinician-rated 7-point scale used to assess the severity of illness. Severity is rated on a scale from 1=Normal to 7=Extremely severe. Baseline was defined as the last non-missing value obtained during the Placebo Run-in Period. IGR assessments were done at Baseline of the 6-Month Treatment Period and and at the end of the 7-day Discontinuation Period to assess the effects of discontinuing treatment.	Baseline and End of 7-day Discontinuation Period

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• Ivgy-May N, Hajak G, van Osta G, Braat S, Chang Q, Roth T. Efficacy and safety of esmirtazapine in adult outpatients with chronic primary insomnia: a randomized, double-blind placebo-controlled study and open-label extension. J Clin Sleep Med. 2020 Sep 15;16(9):1455-1467. doi: 10.5664/jcsm.8526.

Study record dates

Study Major Dates

• Study Start (Actual): March 4, 2008
• Primary Completion (Actual): November 19, 2009
• Study Completion (Actual): November 19, 2009

Study Registration Dates

• First Submitted: February 29, 2008
• First Submitted That Met QC Criteria: February 29, 2008
• First Posted (Estimate): March 10, 2008

Study Record Updates

• Last Update Posted (Actual): October 2, 2018
• Last Update Submitted That Met QC Criteria: September 4, 2018
• Last Verified: September 1, 2018

More Information

Terms related to this study

• Keywords: randomized; placebo controlled; double blind
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Neurologic Manifestations; Disease; Sleep Wake Disorders; Sleep Initiation and Maintenance Disorders; Mental Disorders; Dyssomnias; Parasomnias; Sleep Disorders, Intrinsic; Physiological Effects of Drugs; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Tranquilizing Agents; Psychotropic Drugs; Serotonin Agents; Antidepressive Agents; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Anti-Anxiety Agents; Serotonin 5-HT3 Receptor Antagonists; Histamine H1 Antagonists; Histamine Antagonists; Histamine Agents; Adrenergic alpha-Antagonists; Adrenergic alpha-2 Receptor Antagonists; Mirtazapine
• Other Study ID Numbers: P05701; 21106 (Other Identifier: Organon Protocol Number); 2007-005236-92 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: https://www.merck.com/clinical-trials/pdf/ProcedureAccessClinicalTrialData.pdf