Insomnia
Conditions
Brief summary
The purpose of this study is to determine if esmirtazapine (Org 50081) is a safe and effective treatment for insomnia. It was anticipated that esmirtazapine would increase mean Total Sleep Time (TST) as recorded in sleep diaries relative to placebo.
Interventions
DRUGEsmirtazapine
Esmirtazapine maleate was provided as tablets for oral use containing either 1.5, 3.0, 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. Tablets were administered orally once daily about 30 minutes prior to bedtime.
DRUGPlacebo
Placebo tablets containing the following excipients: hydroxypropyl cellulose, maize starch (USP name: corn starch), magnesium stearate, and lactose monohydrate. Tablets were administered orally once daily about 30 minutes prior to bedtime.
Sponsors
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
* Has signed written informed consent after the scope and nature of the investigation was explained to them * Has difficulty falling asleep, maintaining sleep or has early morning awakenings
Exclusion criteria
* Significant medical or psychiatric illness causing sleep disturbances * Has a history of bipolar disorder or family (immediate family) of suicide * Has sleep disorder such as sleep related breathing disorder, restless leg syndrome, narcolepsy * Has significant other medical illness such as acute or chronic pain, heart, kidney or liver disease within the last year * Currently diagnosed or meets the criteria for Major Depressive Disorder (MDD) or has been treated for MDD with the last 2 years * Substance abuse, excessive use of alcohol (as determined by the physician) or drug addiction within the last year.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Average Total Sleep Time (TST) as Recorded Daily in the Sleep Diary During the 14-day In-treatment Period | Day 1 to Day 15 | TST was defined as the total amount of time (measured in minutes) that was actually spent sleeping the previous night as recorded daily in the participant's sleep diary. TST values over the 14-day active 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 present was used in the analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Average Sleep Latency (SL) as Recorded Daily in the Sleep Diary During the 14-day In-treatment Period | Day 1 to Day 15 | SL was defined as the duration of time measured in minutes that it took a participant to fall asleep as recorded daily in the participant's sleep diary. SL values over the 14-day active treatment period were averaged for each participant, and average SL was then reported by treatment arm. For participants with missing data, the average of the nights for which TST data were present were used in the analysis. |
| Number of Participants Experiencing an Adverse Event (AE) During the 14-day In-treatment Period | Day 1 to Day 15 | The total number of participants with an AE during the 14-day In-treatment Period was tallied for each treatment arm. An AE was defined as any untoward medical occurrence in a participant or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An AE could therefore have been any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. |
| Number of Participants Who Discontinued From Study Treatment Due to an AE During the 14-day In-Treatment Period | Day 1 to Day 15 | The total number of participants discontinuing from study treatment due to experiencing an AE was tallied for each treatment arm. An AE was defined as any untoward medical occurrence in a participant or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An AE could therefore have been any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Esmirtazapine 1.5 mg Participants took esmirtazapine 1.5 mg tablets once daily by mouth during the 14-day In-treatment Period. No study medication was administered during the Follow-up Period. | 137 |
| Esmirtazapine 3.0 mg Participants took esmirtazapine 3.0 mg tablets once daily by mouth during the 14-day In-treatment Period. No study medication was administered during the Follow-up Period. | 125 |
| Esmirtazapine 4.5 mg Participants took esmirtazapine 4.5 mg tablets once daily by mouth during the 14-day In-treatment Period. No study medication was administered during the Follow-up Period. | 128 |
| Placebo Participants took placebo tablets once daily by mouth during the 14-day In-treatment Period. No study medication was administered during the Follow-up Period. | 135 |
| Total | 525 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Follow-up Period | Adverse Event | 4 | 7 | 9 | 0 |
| Follow-up Period | Lack of compliance | 0 | 0 | 1 | 0 |
| Follow-up Period | Lack of Efficacy | 2 | 0 | 1 | 0 |
| Follow-up Period | Lost to Follow-up | 0 | 4 | 2 | 1 |
| Follow-up Period | Other | 4 | 2 | 1 | 2 |
| Follow-up Period | Reasons not related to trial | 1 | 0 | 1 | 3 |
| Follow-up Period | Withdrawal by Subject | 3 | 5 | 7 | 2 |
| In-treatment Period | No study medication administered | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Esmirtazapine 1.5 mg | Esmirtazapine 3.0 mg | Esmirtazapine 4.5 mg | Placebo | Total |
|---|---|---|---|---|---|
| Age, Continuous | 44.8 Years STANDARD_DEVIATION 12.4 | 45.6 Years STANDARD_DEVIATION 12 | 44.5 Years STANDARD_DEVIATION 12.2 | 46.2 Years STANDARD_DEVIATION 11.3 | 45.3 Years STANDARD_DEVIATION 12 |
| Sex: Female, Male Female | 92 Participants | 85 Participants | 72 Participants | 90 Participants | 339 Participants |
| Sex: Female, Male Male | 45 Participants | 40 Participants | 56 Participants | 45 Participants | 186 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 | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 10 / 137 | 11 / 125 | 9 / 128 | 2 / 135 | 0 / 137 | 0 / 125 | 0 / 128 | 0 / 135 |
| serious Total, serious adverse events | 2 / 137 | 1 / 125 | 1 / 128 | 0 / 135 | 0 / 137 | 0 / 125 | 0 / 128 | 0 / 135 |
Outcome results
Primary
Average Total Sleep Time (TST) as Recorded Daily in the Sleep Diary During the 14-day In-treatment Period
TST was defined as the total amount of time (measured in minutes) that was actually spent sleeping the previous night as recorded daily in the participant's sleep diary. TST values over the 14-day active 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 present was used in the analysis.
Time frame: Day 1 to Day 15
Population: The Intent-To-Treat Group consisted of all randomized participants who received at least one dose of double-blind trial medication, and had baseline and at least one post-baseline measurement for at least one efficacy assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Esmirtazapine 1.5 mg | Average Total Sleep Time (TST) as Recorded Daily in the Sleep Diary During the 14-day In-treatment Period | 382.14 Minutes | Standard Deviation 68.155 |
| Esmirtazapine 3.0 mg | Average Total Sleep Time (TST) as Recorded Daily in the Sleep Diary During the 14-day In-treatment Period | 382.77 Minutes | Standard Deviation 81.172 |
| Esmirtazapine 4.5 mg | Average Total Sleep Time (TST) as Recorded Daily in the Sleep Diary During the 14-day In-treatment Period | 394.83 Minutes | Standard Deviation 85.575 |
| Placebo | Average Total Sleep Time (TST) as Recorded Daily in the Sleep Diary During the 14-day In-treatment Period | 351.40 Minutes | Standard Deviation 78.551 |
p-value: <0.0001ANCOVA
p-value: <0.0001ANCOVA
p-value: <0.0001ANCOVA
Secondary
Average Sleep Latency (SL) as Recorded Daily in the Sleep Diary During the 14-day In-treatment Period
SL was defined as the duration of time measured in minutes that it took a participant to fall asleep as recorded daily in the participant's sleep diary. SL values over the 14-day active treatment period were averaged for each participant, and average SL was then reported by treatment arm. For participants with missing data, the average of the nights for which TST data were present were used in the analysis.
Time frame: Day 1 to Day 15
Population: The Intent-To-Treat Group consisted of all randomized participants who received at least one dose of double-blind trial medication and had baseline and at least one post-baseline measurement for at least one efficacy assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Esmirtazapine 1.5 mg | Average Sleep Latency (SL) as Recorded Daily in the Sleep Diary During the 14-day In-treatment Period | 48.93 Minutes | Standard Deviation 34.59 |
| Esmirtazapine 3.0 mg | Average Sleep Latency (SL) as Recorded Daily in the Sleep Diary During the 14-day In-treatment Period | 52.02 Minutes | Standard Deviation 38.95 |
| Esmirtazapine 4.5 mg | Average Sleep Latency (SL) as Recorded Daily in the Sleep Diary During the 14-day In-treatment Period | 50.80 Minutes | Standard Deviation 45.76 |
| Placebo | Average Sleep Latency (SL) as Recorded Daily in the Sleep Diary During the 14-day In-treatment Period | 60.13 Minutes | Standard Deviation 42.98 |
p-value: 0.0014ANCOVA
p-value: 0.0135ANCOVA
p-value: <0.0001ANCOVA
Secondary
Number of Participants Experiencing an Adverse Event (AE) During the 14-day In-treatment Period
The total number of participants with an AE during the 14-day In-treatment Period was tallied for each treatment arm. An AE was defined as any untoward medical occurrence in a participant or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An AE could therefore have been any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.
Time frame: Day 1 to Day 15
Population: The All-Subjects-Treated Group consisted of all participants who received at least 1 dose of trial medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Esmirtazapine 1.5 mg | Number of Participants Experiencing an Adverse Event (AE) During the 14-day In-treatment Period | 35 Number of participants |
| Esmirtazapine 3.0 mg | Number of Participants Experiencing an Adverse Event (AE) During the 14-day In-treatment Period | 41 Number of participants |
| Esmirtazapine 4.5 mg | Number of Participants Experiencing an Adverse Event (AE) During the 14-day In-treatment Period | 41 Number of participants |
| Placebo | Number of Participants Experiencing an Adverse Event (AE) During the 14-day In-treatment Period | 28 Number of participants |
Secondary
Number of Participants Who Discontinued From Study Treatment Due to an AE During the 14-day In-Treatment Period
The total number of participants discontinuing from study treatment due to experiencing an AE was tallied for each treatment arm. An AE was defined as any untoward medical occurrence in a participant or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An AE could therefore have been any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.
Time frame: Day 1 to Day 15
Population: The All-Subjects-Treated Group consisted of all participants who received at least 1 dose of trial medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Esmirtazapine 1.5 mg | Number of Participants Who Discontinued From Study Treatment Due to an AE During the 14-day In-Treatment Period | 4 Number of participants |
| Esmirtazapine 3.0 mg | Number of Participants Who Discontinued From Study Treatment Due to an AE During the 14-day In-Treatment Period | 7 Number of participants |
| Esmirtazapine 4.5 mg | Number of Participants Who Discontinued From Study Treatment Due to an AE During the 14-day In-Treatment Period | 9 Number of participants |
| Placebo | Number of Participants Who Discontinued From Study Treatment Due to an AE During the 14-day In-Treatment Period | 0 Number of participants |