Study of Brexpiprazole as Adjunctive Treatment of Sleep Disturbances in Patients With Major Depressive Disorder

Study Overview
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Brief Summary
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To assess effects of brexpiprazole on sleep patterns of depressed patients with sleep disturbances.

Official Title
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Interventional, Open-label, Flexible-dose, Exploratory Study of Brexpiprazole as Adjunctive Treatment of Sleep Disturbances in Patients With Major Depressive Disorder

Conditions
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Sleep Disturbances

Intervention / Treatment
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* Drug: Brexpiprazole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria - at Screening: The patient has a Major Depressive Episode (MDE) associated to Major Depressive Disorder (MDD), diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Text Revision (DSM-IV-TR™). The current MDE should be confirmed using the Mini International Neuropsychiatric Interview (MINI). The patient has an inadequate response to at least one antidepressant treatment (including the treatment the patient is taking at screening) in the current MDE, as documented by self-report as less than a pre-defined response on the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (ATRQ). The patient has a pre-defined Montgomery Aasberg Depression Rating Scale (MADRS) total score, and a pre-defined Clinical Global Impression - Severity of Illness (CGI-S) score at screening, and has had the current MDE for ≥10 weeks. The patient is currently treated for the current MDE with an adequate selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressant treatment for ≥6 weeks, at the same dosage for ≥2 weeks. The patient has sleep disturbances (difficulty falling asleep and/or difficulty staying asleep and/or problem waking up too early) confirmed by a pre-defined Insomnia Severity Index (ISI) score. The patient agrees to protocol-defined use of effective contraception. Entry Criteria to Treatment Period (Baseline Visit): The patient still fulfils DSM-IV-TR™ criteria for MDE. The patient received the same SSRI or SNRI antidepressant treatment at adequate dose during the entire lead-in period. The patient has a pre-defined MADRS total score. The patient's improvement in the MADRS total score is a pre-defined percentage compared to screening. The patient has a pre-defined Clinical Global Impression - Global Improvement (CGI-I) score. The patient has sleep disturbances (difficulty falling asleep and/or difficulty staying asleep and/or problem waking up too early) confirmed by a pre-defined ISI score. The patient has sleep disturbances confirmed by pre-defined Latency to Persistent Sleep (LPS) and pre-defined Sleep Efficiency (SE). Exclusion Criteria: - The patient is, in the investigator's opinion, unlikely to comply with the protocol or is unsuitable for any reason. Other inclusion and exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Brexpiprazole<br>Brexpiprazole adjunct to open-label treatment with a commercially available antidepressant treatment (ADT) | Drug: Brexpiprazole<br>* 2-3 mg/day, once daily, tablets, for oral use. The patients received 1mg/day brexpiprazole during Week 1 and 2mg/day during Week 2 (up-titration) and from Weeks 3 to 6 they received 3mg/day; depending on tolerability the dose could be reduced to 2mg/day based on the investigator's judgment.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes From Baseline to Week 8 on Sleep Quality as Assessed by Polysomnographic Recorded (PSG) Parameters | The key PSG parameters assessed were the latency to persistent sleep (PSG LPS), sleep onset latency (PSG SOL), wake-time after sleep onset (PSG WASO), total sleep time (PSG TST), number of awakenings (PSG NAW), and sleep efficiency (PSG SE). The results for PSG LPS, PSG SOL, PSG WASO, and PSG TST are presented separately from the PSG NAW, and from the PSG SE due to the different units of measurement involved. As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes. | Baseline and Week 8 | 
| Changes From Baseline to Week 8 on Sleep Quality as Assessed by Polysomnographic Recorded (PSG) Number of Awakenings (PSG NAW) | The key PSG parameters assessed were the latency to persistent sleep (PSG LPS), sleep onset latency (PSG SOL), wake-time after sleep onset (PSG WASO), total sleep time (PSG TST), number of awakenings (PSG NAW), and sleep efficiency (PSG SE). The results for PSG LPS, PSG SOL, PSG WASO, and PSG TST are presented separately from the PSG NAW, and from the PSG SE due to the different units of measurement involved. As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes. | Baseline and Week 8 | 
| Changes From Baseline to Week 8 on Sleep Quality as Assessed by Polysomnographic Recorded (PSG) Sleep Efficiency (PSG SE) | The key PSG parameters assessed were the latency to persistent sleep (PSG LPS), sleep onset latency (PSG SOL), wake-time after sleep onset (PSG WASO), total sleep time (PSG TST), number of awakenings (PSG NAW), and sleep efficiency (PSG SE). The results for PSG LPS, PSG SOL, PSG WASO, and PSG TST are presented separately from the PSG NAW, and from the PSG SE due to the different units of measurement involved. As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes. | Baseline and Week 8 | 
| Changes From Baseline to Week 8 on Sleep Quality as Assessed by the Consensus Sleep Diary for Morning (CSD-M) Sleep Efficiency (SE) | The key CSD-M parameters assessed were the sleep efficiency (CSD-M SE), total sleep time (CSD-M TST), sleep onset latency (CSD-M SOL), wake-time after sleep onset (CSD-M WASO), and number of awakenings (CSD-M NAW). The results for CSD-M SE are presented separately from CSD-M TST, CSD-M SOL, and CSD-M WASO, and from CSD-M NAW due to the different units of measurement involved. As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes. | Baseline and Week 8 | 
| Changes From Baseline to Week 8 on Sleep Quality as Assessed by the Consensus Sleep Diary for Morning (CSD-M) | The key CSD-M parameters assessed were the sleep efficiency (CSD-M SE), total sleep time (CSD-M TST), sleep onset latency (CSD-M SOL), wake-time after sleep onset (CSD-M WASO), and number of awakenings (CSD-M NAW). The results for CSD-M SE are presented separately from CSD-M TST, CSD-M SOL, and CSD-M WASO, and from CSD-M NAW due to the different units of measurement involved. As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes. | Baseline and Week 8 | 
| Changes From Baseline to Week 8 on Sleep Quality as Assessed by the Consensus Sleep Diary for Morning (CSD-M) Number of Awakenings (NAW) | The key CSD-M parameters assessed were the sleep efficiency (CSD-M SE), total sleep time (CSD-M TST), sleep onset latency (CSD-M SOL), wake-time after sleep onset (CSD-M WASO), and number of awakenings (CSD-M NAW). As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes. | Baseline and Week 8 | 
| Changes From Baseline to Week 8 in Sleep Architecture as Assessed With Polysomnography | The key sleep architecture parameters assessed with polysomnography were the percentage of time and duration spent in Stages N1 (non-rapid eye movement [non-REM]), N2 (non-REM), N3 (non-REM), and REM, respectively, as well as the duration of latency to REM sleep. The results for the percentage of time spent at each stage is presented separately from the duration due to the different units of measurement involved. As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes. | Baseline and Week 8 | 
| Changes From Baseline to Week 8 in Sleep Architecture as Assessed With Polysomnography (Continued) | The key sleep architecture parameters assessed with polysomnography were the percentage of time and duration spent in Stages N1 (non-rapid eye movement [non-REM]), N2 (non-REM), N3 (non-REM), and REM, respectively, as well as the duration of latency to REM sleep. The results for the percentage of time spent at each stage is presented separately from the duration due to the different units of measurement involved. As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes. | Baseline and Week 8 | 
| Change From Baseline to Week 8 in ISI Total Score | The Insomnia Severity Index (ISI) is a patient-rated scale desgined to measure the patient's perception of his/her insomnia. The ISI comprises 7 items: difficulty falling asleep, difficulty staying asleep, problems waking up early in the morning, satisfaction with current sleep pattern, interference with daily functioning, how much others notice the sleep problem impairs quality of life, and distress caused by the sleep problem. Each of the 7 items is rated on a 5-point scale from 0 (best situation) to 4 (worst situation). The total score of the 7 items ranges from 0 to 28, with higher values indicating worse outcome. As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes. | Baseline and Week 8 | 
| Change From Baseline to Week 8 on ESS Total Score | The Epworth Sleepiness Scale (ESS) is a is a patient-rated scale designed to measure daytime sleepiness. The ESS consists of 8 items describing different situations/activities and the patients rate the chance of them dozing off or falling asleep when they are in these situations. Each item is rated on a 4-point scale from 0 (would never dose) to 3 (high change of dozing). The total score of the 8 items ranges from 0 to 24, with higher values indicating worse outcome. As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes. | Baseline and Week 8 | 
| Changes From Baseline to Week 8 in Response Speed as Assessed Using a PVT Device | The psychomotor vigilance task (PVT) measures sustained or vigilant attention by recording response time (milliseconds) to a visual/or auditory stimulus that appears at random inter-stimulus intervals (range: from 2 to 10 seconds). The patient was instructed to monitor a red rectangular box on the computer screen and to press a response button as soon as a yellow stimulus counter appeared on the screen. The parameters assessed using a PVT device were response speed and number of lapses. The results for response speed is presented separately from the number of lapses due to the different units of measurement involved. As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes. | Baseline and Week 8 | 
| Changes From Baseline to Week 8 in Number of Lapses as Assessed Using a PVT Device | The psychomotor vigilance task (PVT) measures sustained or vigilant attention by recording response time (milliseconds) to a visual/or auditory stimulus that appears at random inter-stimulus intervals (range: from 2 to 10 seconds). The patient was instructed to monitor a red rectangular box on the computer screen and to press a response button as soon as a yellow stimulus counter appeared on the screen. The parameters assessed using a PVT device were response speed and number of lapses. The results for response speed is presented separately from the number of lapses due to the different units of measurement involved. As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes. | Baseline and Week 8 | 
| Change From Baseline to Week 8 on BL-VAS-s (Evening) Score | The Bond-Lader Visual Analogue Scale - Sedation (BL-VAS-s) is a patient-rated scale designed to assess the current level of sedation. The BL-VAS-s was assessed for the evening (19:00 to 23:59 hours), morning (00:00 to 08:59 hours) and at noon (11:00 to 13:59 hours). The BL-VAS-s is a single item scale rated on a 100mm visual analogue scale. The score is measured from the left to a mark made on the line by the patient and ranges from 0 (alert) to 100 (drowsy). As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes. | Baseline and Week 8 | 
| Change From Baseline to Week 8 on BL-VAS-s (Morning) Score | The Bond-Lader Visual Analogue Scale - Sedation (BL-VAS-s) is a patient-rated scale designed to assess the current level of sedation. The BL-VAS-s was assessed for the evening (19:00 to 23:59 hours), morning (00:00 to 08:59 hours) and at noon (11:00 to 13:59 hours). The BL-VAS-s is a single item scale rated on a 100mm visual analogue scale. The score is measured from the left to a mark made on the line by the patient and ranges from 0 (alert) to 100 (drowsy). As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes. | Baseline and Week 8 | 
| Change From Baseline to Week 8 on BL-VAS-s Scores (Noon) | The Bond-Lader Visual Analogue Scale - Sedation (BL-VAS-s) is a patient-rated scale designed to assess the current level of sedation. The BL-VAS-s was assessed for the evening (19:00 to 23:59 hours), morning (00:00 to 08:59 hours) and at noon (11:00 to 13:59 hours). The BL-VAS-s is a single item scale rated on a 100mm visual analogue scale. The score is measured from the left to a mark made on the line by the patient and ranges from 0 (alert) to 100 (drowsy). As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes. | Baseline and Week 8 | 
| Change From Baseline to Week 8 in CPFQ Total Score | The Cognitive and Physical Functioning Questionnaire (CPFQ) is a patient-rated scale designed to assess cognitive and executive dysfunction including symptoms of fatigue in mood and anxiety disorders. The CPFQ consists of 7 items, each rated on a scale from 1 (greater than normal functioning) to 6 (poorer than normal functioning). The total score of the 7 items ranges from 7 to 42, with higher values indicating worse outcome. As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes. | Baseline and Week 8 | 
| Changes From Baseline to Week 8 in Circadian and Biological Rhythm | The parameters used to assess circadian and biological rhythm were the time to peak cortisol concentration, time to dim-light melatonin onset (DLMO) and phase angle. As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes. | Baseline and Week 8 | 
| Change From Baseline to Week 8 in MADRS Total Score | The Montgomery Aasberg Depression Rating Scale (MADRS) is a 10-item rating scale designed to assess the severity of the symptoms in depressive illness and to be sensitive to treatment effects. Items in the scale assess apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts. Symptoms are rated on a 7-point scale from 0 (no symptoms) to 6 (severe symptoms). Definitions of severity are provided at two-point intervals. The total score of the 10 items ranges from 0 to 60, with higher values indicating worse outcome. As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes. | Baseline and Week 8 | 
| Change From Baseline to Week 8 in CGI-S Score | The Clinical Global Impression - Severity of Illness (CGI-S) scale assesses the clinician's impression of the patient's current state of mental illness. The clinician uses his or her clinical experience of this patient population to rate the severity of the patient's current mental illness on a 7-point scale ranging from 1 (normal - not at all ill) to 7 (among the most extremely ill patients), with higher values indicating worse outcome. As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes. | Baseline and Week 8 | 
| Percentage of MADRS Responders at Week 8 | The Montgomery Aasberg Depression Rating Scale (MADRS) is a 10-item rating scale designed to assess the severity of the symptoms in depressive illness and to be sensitive to treatment effects. Items in the scale assess apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts. Symptoms are rated on a 7-point scale from 0 (no symptoms) to 6 (severe symptoms). Definitions of severity are provided at two-point intervals. The total score of the 10 items ranges from 0 to 60, with higher values indicating worse outcome. Response was defined as a ≥50% decrease in MADRS total score from baseline. As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes. | Week 8 | 
| Percentage of MADRS Remitters at Week 8 | The Montgomery Aasberg Depression Rating Scale (MADRS) is a 10-item rating scale designed to assess the severity of the symptoms in depressive illness and to be sensitive to treatment effects. Items in the scale assess apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts. Symptoms are rated on a 7-point scale from 0 (no symptoms) to 6 (severe symptoms). Definitions of severity are provided at two-point intervals. The total score of the 10 items ranges from 0 to 60, with higher values indicating worse outcome. Remission was defined as a MADRS total score ≤10 and a ≥50% decrease in MADRS total score from baseline. As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes. | Week 8 | 
| Changes From Baseline to Week 8 on Sleep Quality as Assessed by Actigraphy (ACT) Parameters | The key ACT parameters assessed were the total sleep time (ACT TST), wake-time after sleep onset (ACT WASO), sleep onset latency (ACT SOL), sleep efficiency (ACT SE), and the number of awakenings (ACT NAW). The results for ACT TST, ACT WASO, and ACT SOL are presented separately from ACT SE, and from ACT NAW, due to the different units of measurement involved. As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes. | Baseline and Week 8 | 
| Changes From Baseline to Week 8 on Sleep Efficiency (SE) as Assessed by Actigraphy (ACT) | The key ACT parameters assessed were the total sleep time (ACT TST), sleep efficiency (ACT SE), sleep onset latency (ACT SOL), wake-time after sleep onset (ACT WASO), and the number of awakenings (ACT NAW). The results for ACT TST, ACT SE, ACT WASO, and ACT NAW are presented separately from ACT SOL as the number of patients available for analysis was different. As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes. | Baseline and Week 8 | 
| Changes From Baseline to Week 8 on Number of Awakenings (NAW) as Assessed by Actigraphy (ACT) | The key ACT parameters assessed were the total sleep time (ACT TST), sleep efficiency (ACT SE), sleep onset latency (ACT SOL), wake-time after sleep onset (ACT WASO), and the number of awakenings (ACT NAW). The results for ACT TST, ACT SE, ACT WASO, and ACT NAW are presented separately from ACT SOL as the number of patients available for analysis was different. As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes. | Baseline and Week 8 | 
| Change From Baseline to Week 8 in BRIAN Total Score | The Biological Rhythms Interview of Assessment in Neuropsychiatry (BRIAN) is a clinician-rated scale designed to assess biological rhythms. The BRIAN consists of 18 items divided in 4 subscales: sleep (5 items), activity (5 items), social (4 items), and eating pattern (4 items). Each item is rated on a scale from 1 (no difficulties) to 4 (serious difficulties). The total score of the 18 items ranges from 18 to 72, with higher values indicating worse outcome. As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes. | Baseline and Week 8 | 
| CGI-I Score at Week 8 | The Clinical Global Impression - Global Improvement (CGI-I) assesses the clinician's impression of the patient's improvement (or worsening). The clinician assesses the patient's condition relative to a baseline on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse), with higher values indicating worse outcome. As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes. | Baseline and Week 8 |