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| ID | Type | Description | Link |
|---|---|---|---|
| 21106 | Other Identifier | Organon Protocol Number | |
| 2007-005236-92 | EudraCT Number |
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Esmirtazapine 4.5 mg | Experimental | Participants receive esmirtazapine 4.5 mg tablets, administered once a day for 6 months |
|
| Placebo | Placebo Comparator | Participants receive placebo tablets, administered once a day for 6 months |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Esmirtazapine | Drug | One esmirtazapine 4.5 mg tablet once a day |
| |
| 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 |
| 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 |
| 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. |
Inclusion Criteria:
Exclusion Criteria:
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| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 32351205 | Derived | 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. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Esmirtazapine 4.5 mg/Esmirtazapine 4.5 mg | Participants receive esmirtazapine 4.5 mg tablets, administered once a day (QD) for 6 months, then participants receive esmirtazapine 4.5 mg tablets, administered QD for 7 days |
| FG001 | Esmirtazapine 4.5 mg/Placebo |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| 6-Month Treatment Period |
|
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| Placebo |
| Drug |
One placebo tablet once a day |
|
| 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 |
| 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 |
Participants receive esmirtazapine 4.5 mg tablets, administered QD for 6 months, then participants receive placebo tablets, administered QD for 7 days |
| FG002 | Placebo/Placebo | Participants receive placebo tablets, administered QD for 6 months, then participants receive placebo tablets, administered QD for 7 days |
| Treated |
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| COMPLETED |
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| NOT COMPLETED |
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| 7-Day Discontinuation Period |
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The Baseline Analysis Population consists of all participants who received study drug. Two participants in the esmertazapine 4.5 mg group and one participant in the placebo group did not receive study drug.
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| ID | Title | Description |
|---|---|---|
| BG000 | Esmirtazapine 4.5 mg | Participants receive esmirtazapine 4.5 mg tablets, administered QD for 6 months |
| BG001 | Placebo | Participants receive placebo tablets, administered QD for 6 months |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | years |
| |||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | 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. | Posted | Mean | Standard Deviation | minutes | Baseline and the Mean of Weeks 14-26 |
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| 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. | The All-Subjects-Treated (AST) population consisted of all participants who received at least one dose of any study drug. | Posted | Number | participants | Up to 31 weeks |
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| 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. | The AST population consisted of all participants who received at least one dose of any study drug. | Posted | Number | participants | Up to 27 weeks |
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| 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. | 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. | Posted | Mean | Standard Deviation | minutes | Baseline and the Mean of Weeks 14-26 |
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| 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. | 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. | Posted | Mean | Standard Deviation | minutes | Baseline and the Mean of Weeks 14-26 |
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| 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. | 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. | Posted | Mean | Standard Deviation | number of awakenings | Baseline and the Mean of Weeks 14-26 |
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| 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. | 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. | Posted | Mean | Standard Deviation | score on a scale | Baseline and the Mean of Weeks 14-26 |
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| 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. | 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. | Posted | Mean | Standard Deviation | score on a scale | Baseline and the Mean of Weeks 14-26 |
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| 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. | 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. | Posted | Mean | Standard Deviation | score on a scale | Baseline and Week 26 |
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| 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. | 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. | Posted | Mean | Standard Deviation | score on a scale | Baseline and Week 26 |
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| 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. | 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. | Posted | Mean | Standard Deviation | score on a scale | Baseline and End of 7-day Discontinuation Period |
|
Up to 30 days after last dose of study drug (up to 31 weeks)
AE data include AEs that occurred during the 6-month Treatment Period and the 7-day Discontinuation Period. AEs are reported for the study drug participants were receiving at the time the AE occurred.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Esmirtazapine 4.5 mg | Participants receive esmirtazapine 4.5 mg tablets, administered QD | 8 | 342 | 183 | 342 | ||
| EG001 | Placebo | Participants receive placebo tablets, administered QD | 2 | 115 | 40 | 115 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Coronary artery disease | Cardiac disorders | MedDRA 12.1 | Systematic Assessment |
| |
| Retinal vein occlusion | Eye disorders | MedDRA 12.1 | Systematic Assessment |
| |
| Sudden visual loss | Eye disorders | MedDRA 12.1 | Systematic Assessment |
| |
| Pancreatitis | Gastrointestinal disorders | MedDRA 12.1 | Systematic Assessment |
| |
| Infectious mononucleosis | Infections and infestations | MedDRA 12.1 | Systematic Assessment |
| |
| Cartilage injury | Injury, poisoning and procedural complications | MedDRA 12.1 | Systematic Assessment |
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| Concussion | Injury, poisoning and procedural complications | MedDRA 12.1 | Systematic Assessment |
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| Facial bones fracture | Injury, poisoning and procedural complications | MedDRA 12.1 | Systematic Assessment |
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| Fall | Injury, poisoning and procedural complications | MedDRA 12.1 | Systematic Assessment |
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| Limb injury | Injury, poisoning and procedural complications | MedDRA 12.1 | Systematic Assessment |
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| Road traffic accident | Injury, poisoning and procedural complications | MedDRA 12.1 | Systematic Assessment |
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| Synovial rupture | Injury, poisoning and procedural complications | MedDRA 12.1 | Systematic Assessment |
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| Intervertebral disc protrusion | Musculoskeletal and connective tissue disorders | MedDRA 12.1 | Systematic Assessment |
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| Osteoarthritis | Musculoskeletal and connective tissue disorders | MedDRA 12.1 | Systematic Assessment |
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| Nerve compression | Nervous system disorders | MedDRA 12.1 | Systematic Assessment |
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| Bunion operation | Surgical and medical procedures | MedDRA 12.1 | Systematic Assessment |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Dry mouth | Gastrointestinal disorders | MedDRA 12.1 | Systematic Assessment |
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| Fatigue | General disorders | MedDRA 12.1 | Systematic Assessment |
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| Nasopharyngitis | Infections and infestations | MedDRA 12.1 | Systematic Assessment |
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| Weight increased | Investigations | MedDRA 12.1 | Systematic Assessment |
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| Increased appetite | Metabolism and nutrition disorders | MedDRA 12.1 | Systematic Assessment |
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| Dizziness | Nervous system disorders | MedDRA 12.1 | Systematic Assessment |
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| Headache | Nervous system disorders | MedDRA 12.1 | Systematic Assessment |
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| Somnolence | Nervous system disorders | MedDRA 12.1 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Senior Vice President, Global Clinical Development | Merck Sharp & Dohme Corp | 1-800-672-6372 | ClinicalTrialsDisclosure@merck.com |
| ID | Term |
|---|---|
| D007319 | Sleep Initiation and Maintenance Disorders |
| D001523 | Mental Disorders |
| D020920 | Dyssomnias |
| D012893 | Sleep Wake Disorders |
| D020919 | Sleep Disorders, Intrinsic |
| ID | Term |
|---|---|
| D009422 | Nervous System Diseases |
| D009461 | Neurologic Manifestations |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| D000078785 | Mirtazapine |
| ID | Term |
|---|---|
| D003984 | Dibenzazepines |
| D006575 | Heterocyclic Compounds, 3-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
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| Male |
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| Counts |
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| Participants |
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| Units | Counts |
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| Participants |
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| Placebo/Placebo |
Participants receive placebo tablets, administered QD for 6 months during the Treatment Period, followed by placebo tablets, administered QD for 7 days during the Discontinuation Period |
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