Dyssomnias, Mental Disorders, Sleep Disorder, Intrinsic, Sleep Disorders, Sleep Initiation and Maintenance Disorders
Conditions
Keywords
placebo controlled, randomized, double blind
Brief summary
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).
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.
Interventions
DRUGEsmirtazapine
One esmirtazapine 4.5 mg tablet once a day
DRUGPlacebo
One placebo tablet once a day
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Total Sleep Time (TST) - 6-Month Treatment Period | Baseline and the Mean of Weeks 14-26 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Experienced Adverse Events (AEs) | Up to 31 weeks | 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. |
| Number of Participants Who Discontinued Study Drug Due to an AE | Up to 27 weeks | 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. |
| Change From Baseline in Sleep Latency (SL) - 6-Month Treatment Period | Baseline and the Mean of Weeks 14-26 | 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. |
| Change From Baseline in Wake Time After Sleep Onset (WASO) - 6-Month Treatment Period | Baseline and the Mean of Weeks 14-26 | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Number of Awakenings (NAW) - 6-Month Treatment Period | Baseline and the Mean of Weeks 14-26 | 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. |
| Change From Baseline in Investigator Global Rating (IGR) - 7-Day Discontinuation Period | Baseline and End of 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. |
| Change From Baseline in Sleep Quality - 6-Month Treatment Period | Baseline and the Mean of Weeks 14-26 | 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. |
| Change From Baseline in Satisfaction With Sleep Duration - 6-Month Treatment Period | Baseline and the Mean of Weeks 14-26 | 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 | Baseline and Week 26 | 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. |
| Change From Baseline in Investigator Global Rating (IGR) - 6-Month Treatment Period | Baseline and Week 26 | 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. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Esmirtazapine 4.5 mg Participants receive esmirtazapine 4.5 mg tablets, administered QD for 6 months | 342 |
| Placebo Participants receive placebo tablets, administered QD for 6 months | 115 |
| Total | 457 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| 6-Month Treatment Period | Adverse Event | 47 | 0 | 7 |
| 6-Month Treatment Period | Lack of Efficacy | 34 | 0 | 25 |
| 6-Month Treatment Period | Lost to Follow-up | 7 | 0 | 2 |
| 6-Month Treatment Period | Not Treated | 2 | 0 | 1 |
| 6-Month Treatment Period | Other | 16 | 0 | 4 |
| 6-Month Treatment Period | Uncooperative Reasons Unrelated to Trial | 21 | 0 | 6 |
| 6-Month Treatment Period | Withdrawal by Subject | 14 | 0 | 5 |
| 7-Day Discontinuation Period | Not Treated | 1 | 1 | 1 |
| 7-Day Discontinuation Period | Other | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Esmirtazapine 4.5 mg | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 47.4 years STANDARD_DEVIATION 11.4 | 49.0 years STANDARD_DEVIATION 11.1 | 47.8 years STANDARD_DEVIATION 11.3 |
| Sex: Female, Male Female | 210 Participants | 71 Participants | 281 Participants |
| Sex: Female, Male Male | 132 Participants | 44 Participants | 176 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 183 / 342 | 40 / 115 |
| serious Total, serious adverse events | 8 / 342 | 2 / 115 |
Outcome results
Primary
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.
Time frame: Baseline and the Mean of Weeks 14-26
Population: The Intent-To-Treat (ITT) population consisted of all participants who received at least one dose of study drug and had a baseline and at least one postbaseline TST efficacy assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Esmirtazapine 4.5 mg | Change From Baseline in Total Sleep Time (TST) - 6-Month Treatment Period | 65.9 minutes | Standard Deviation 71.9 |
| Placebo | Change From Baseline in Total Sleep Time (TST) - 6-Month Treatment Period | 19.3 minutes | Standard Deviation 62.1 |
p-value: <0.000195% CI: [35, 62.5]ANCOVA
Secondary
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.
Time frame: Baseline and the Mean of Weeks 14-26
Population: The ITT population consisted of all participants who received at least one dose of study drug and had a baseline and at least one postbaseline SL efficacy assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Esmirtazapine 4.5 mg | Change From Baseline in Sleep Latency (SL) - 6-Month Treatment Period | -29.7 minutes | Standard Deviation 47.3 |
| Placebo | Change From Baseline in Sleep Latency (SL) - 6-Month Treatment Period | -26.9 minutes | Standard Deviation 46.8 |
p-value: 0.214595% CI: [-12.6, 2.8]ANCOVA
Secondary
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.
Time frame: Baseline and the Mean of Weeks 14-26
Population: The ITT population consisted of all participants who received at least one dose of study drug and had a baseline and at least one postbaseline WASO efficacy assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Esmirtazapine 4.5 mg | Change From Baseline in Wake Time After Sleep Onset (WASO) - 6-Month Treatment Period | -46.4 minutes | Standard Deviation 57.7 |
| Placebo | Change From Baseline in Wake Time After Sleep Onset (WASO) - 6-Month Treatment Period | -20.8 minutes | Standard Deviation 51.4 |
p-value: <0.000195% CI: [-34.5, -15.4]ANCOVA
Secondary
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.
Time frame: Up to 27 weeks
Population: The AST population consisted of all participants who received at least one dose of any study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Esmirtazapine 4.5 mg | Number of Participants Who Discontinued Study Drug Due to an AE | 47 participants |
| Placebo | Number of Participants Who Discontinued Study Drug Due to an AE | 7 participants |
Secondary
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.
Time frame: Up to 31 weeks
Population: The All-Subjects-Treated (AST) population consisted of all participants who received at least one dose of any study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Esmirtazapine 4.5 mg | Number of Participants Who Experienced Adverse Events (AEs) | 253 participants |
| Placebo | Number of Participants Who Experienced Adverse Events (AEs) | 75 participants |
Other Pre-specified
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.
Time frame: Baseline and Week 26
Population: The ITT population consisted of all participants who received at least one dose of study drug and had a baseline and a Week 26 IGR efficacy assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Esmirtazapine 4.5 mg | Change From Baseline in Investigator Global Rating (IGR) - 6-Month Treatment Period | -2.1 score on a scale | Standard Deviation 1.4 |
| Placebo | Change From Baseline in Investigator Global Rating (IGR) - 6-Month Treatment Period | -1.4 score on a scale | Standard Deviation 1.4 |
Other Pre-specified
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.
Time frame: Baseline and End of 7-day Discontinuation Period
Population: The ITT population consisted of all participants who received at least one dose of study drug and had a baseline and a 7-Day Discontinuation Period IGR efficacy assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Esmirtazapine 4.5 mg | Change From Baseline in Investigator Global Rating (IGR) - 7-Day Discontinuation Period | 0.3 score on a scale | Standard Deviation 0.7 |
| Placebo | Change From Baseline in Investigator Global Rating (IGR) - 7-Day Discontinuation Period | 0.5 score on a scale | Standard Deviation 1 |
| Placebo/Placebo | Change From Baseline in Investigator Global Rating (IGR) - 7-Day Discontinuation Period | 0.0 score on a scale | Standard Deviation 0.7 |
Other Pre-specified
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.
Time frame: Baseline and the Mean of Weeks 14-26
Population: The ITT population consisted of all participants who received at least one dose of study drug and had a baseline and at least one postbaseline NAW efficacy assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Esmirtazapine 4.5 mg | Change From Baseline in Number of Awakenings (NAW) - 6-Month Treatment Period | -0.8 number of awakenings | Standard Deviation 1.2 |
| Placebo | Change From Baseline in Number of Awakenings (NAW) - 6-Month Treatment Period | -0.5 number of awakenings | Standard Deviation 0.9 |
Other Pre-specified
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.
Time frame: Baseline and the Mean of Weeks 14-26
Population: The ITT population consisted of all participants who received at least one dose of study drug and had a baseline and at least one postbaseline Satisfaction with Sleep Duration efficacy assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Esmirtazapine 4.5 mg | Change From Baseline in Satisfaction With Sleep Duration - 6-Month Treatment Period | 18.3 score on a scale | Standard Deviation 20.1 |
| Placebo | Change From Baseline in Satisfaction With Sleep Duration - 6-Month Treatment Period | 7.2 score on a scale | Standard Deviation 15.9 |
Other Pre-specified
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.
Time frame: Baseline and the Mean of Weeks 14-26
Population: The ITT population consisted of all participants who received at least one dose of study drug and had a baseline and at least one postbaseline Sleep Quality efficacy assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Esmirtazapine 4.5 mg | Change From Baseline in Sleep Quality - 6-Month Treatment Period | 16.1 score on a scale | Standard Deviation 19.5 |
| Placebo | Change From Baseline in Sleep Quality - 6-Month Treatment Period | 5.8 score on a scale | Standard Deviation 14 |
Other Pre-specified
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.
Time frame: Baseline and Week 26
Population: The ITT population consisted of all participants who received at least one dose of study drug and had a baseline and a Week 26 SF-36 efficacy assessment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Esmirtazapine 4.5 mg | Change From Baseline in Two Aggregate Measures of Short Form 36 (SF-36) Health Survey Score - 6-Month Treatment Period | Change from BL at Week 26 - PCS | 1.6 score on a scale | Standard Deviation 6.8 |
| Esmirtazapine 4.5 mg | Change From Baseline in Two Aggregate Measures of Short Form 36 (SF-36) Health Survey Score - 6-Month Treatment Period | Change from BL at Week 26 - MCS | 4.6 score on a scale | Standard Deviation 10.8 |
| Placebo | Change From Baseline in Two Aggregate Measures of Short Form 36 (SF-36) Health Survey Score - 6-Month Treatment Period | Change from BL at Week 26 - PCS | -0.2 score on a scale | Standard Deviation 6 |
| Placebo | Change From Baseline in Two Aggregate Measures of Short Form 36 (SF-36) Health Survey Score - 6-Month Treatment Period | Change from BL at Week 26 - MCS | 4.5 score on a scale | Standard Deviation 9.1 |