Insomnia
Conditions
Keywords
Sleep Initiation and Maintenance Disorders, Sleep Disorders, Intrinsic Dyssomnias, Sleep Disorders, Nervous System Diseases, Mental Disorders
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.
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.
Interventions
DRUGEsmirtazapine
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.
DRUGPlacebo
The placebo tablets contained the following excipients: hydroxypropyl cellulose, maize starch (USP name corn starch), magnesium stearate, and lactose monohydrate.
Sponsors
Parexel
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Esmirtazapine 3.0 mg 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. | 143 |
| Esmirtazapine 4.5 mg 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. | 139 |
| Placebo 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. | 137 |
| Total | 419 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| In-treatment Period | Adverse Event | 11 | 5 | 2 |
| In-treatment Period | Lack of compliance | 1 | 0 | 0 |
| In-treatment Period | Lack of Efficacy | 0 | 2 | 0 |
| In-treatment Period | Lost to Follow-up | 0 | 0 | 1 |
| In-treatment Period | Other | 3 | 3 | 4 |
| In-treatment Period | Randomized but not treated | 4 | 1 | 1 |
| In-treatment Period | Reasons not related to trial | 4 | 1 | 0 |
| In-treatment Period | Withdrawal by Subject | 3 | 3 | 4 |
Baseline characteristics
| Characteristic | Esmirtazapine 3.0 mg | Esmirtazapine 4.5 mg | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 43.5 Years STANDARD_DEVIATION 11.3 | 44.5 Years STANDARD_DEVIATION 11.5 | 46.6 Years STANDARD_DEVIATION 10.5 | 44.9 Years STANDARD_DEVIATION 11.2 |
| Sex: Female, Male Female | 98 Participants | 89 Participants | 90 Participants | 277 Participants |
| Sex: Female, Male Male | 45 Participants | 50 Participants | 47 Participants | 142 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 20 / 139 | 24 / 138 | 13 / 136 | 2 / 139 | 1 / 138 | 1 / 136 |
| serious Total, serious adverse events | 0 / 139 | 1 / 138 | 0 / 136 | 0 / 139 | 0 / 138 | 0 / 136 |
Outcome results
Primary
Average Wake Time After Sleep Onset (WASO) During the In-Treatment Period
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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Esmirtazapine 3.0 mg | Average Wake Time After Sleep Onset (WASO) During the In-Treatment Period | 45.6 Minutes | Standard Deviation 25.7 |
| Esmirtazapine 4.5 mg | Average Wake Time After Sleep Onset (WASO) During the In-Treatment Period | 45.5 Minutes | Standard Deviation 26.5 |
| Placebo | Average Wake Time After Sleep Onset (WASO) During the In-Treatment Period | 76.1 Minutes | Standard Deviation 46 |
Secondary
Average Latency to Persistent Sleep (LPS) During the In-Treatment Period
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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Esmirtazapine 3.0 mg | Average Latency to Persistent Sleep (LPS) During the In-Treatment Period | 28.7 Minutes | Standard Deviation 28.4 |
| Esmirtazapine 4.5 mg | Average Latency to Persistent Sleep (LPS) During the In-Treatment Period | 26.1 Minutes | Standard Deviation 23 |
| Placebo | Average Latency to Persistent Sleep (LPS) During the In-Treatment Period | 40.5 Minutes | Standard Deviation 27.3 |
Secondary
Average Subjective Total Sleep Time (TST) During the In-Treatment Period
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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Esmirtazapine 3.0 mg | Average Subjective Total Sleep Time (TST) During the In-Treatment Period | 384.6 Minutes | Standard Deviation 63.6 |
| Esmirtazapine 4.5 mg | Average Subjective Total Sleep Time (TST) During the In-Treatment Period | 384.6 Minutes | Standard Deviation 66.2 |
| Placebo | Average Subjective Total Sleep Time (TST) During the In-Treatment Period | 351.6 Minutes | Standard Deviation 57.2 |