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 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).

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.

Sleep Initiation and Maintenance Disorders, Mental Disorders, Dyssomnias, Sleep Disorders, Sleep Disorder, Intrinsic

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.