Study of Brexpiprazole as Adjunctive Treatment of Irritability in Patients With Major Depressive Disorder and an Inadequate Response to Antidepressant Therapy

Major Depressive Disorder Clinical Trial

Official title:

Interventional, Open-label, Flexible-dose, Exploratory Study of Brexpiprazole as Adjunctive Treatment of Irritability in Patients With Major Depressive Disorder and an Inadequate Response to Antidepressant Therapy

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01942785
• Other study ID #: 15353A
• Status: Completed
• Phase: Phase 3
• First received: September 11, 2013
• Last updated: February 16, 2016
• Start date: October 2013

Study information

• Verified date: February 2016
• Source: H. Lundbeck A/S
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

To explore the anti-impulsive and anti-aggressive properties of brexpiprazole in a naturalistic setting of depressed patients with irritability.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 55
• Est. primary completion date: July 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

Main selection criteria at screening visit:

• 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 percentage response on the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (ATRQ).

• Pre-defined MADRS total score

• Pre-defined CGI-S total score

• The patient has had the current MDE for =10 weeks

• The patient is receiving a SSRI or SNRI antidepressant treatment for =6 weeks, at same dosage for =2 weeks

• Pre-defined Inventory of Depressive Symptomatology - Clinician-Rated - 30 items (IDS-C 30) Item 6 Mood (irritable) score

Main inclusion criteria at baseline visit:

• The patient still fulfils DSM-IV-TR™ criteria for MDE

• Pre-defined MADRS total score

• Pre-defined CGI-I (Lead-in period) score

• The patient received the same SSRI or SNRI antidepressant treatment at adequate doses during the entire lead-in period

• The patient has less than a pre-defined percentage decrease in MADRS score at the end of the lead-in period as compared to the screening visit

• The patient still has the pre-defined IDS-C 30 Item 6 Mood (Irritable) score

Exclusion Criteria:

• The patient has any current psychiatric disorder or Axis I disorder (DSM-IV-TR™ criteria), established as the principal diagnosis, other than MDD. All anxiety disorders, impulse-control disorders such as intermittent explosive disorder, as well as non-suicidal self-injury are not excluded diagnoses as far as they are not considered as principal diagnosis.

• The patient has a current Axis II (DSM-IV-TR™) diagnosis of antisocial, borderline, paranoid, schizoid, schizotypical, or histrionic personality disorder.

• The patient has experienced/experiences hallucinations, delusions, or any psychotic symptomatology in the current MDE.

• The patient, in the opinion of the investigator or based on C-SSRS rating, is at significant risk of suicide.

• The patient has started formal cognitive or behavioural therapy or systematic psychotherapy within 6 weeks prior to screening, or plans to start such therapy during the study. Any ongoing formal psychotherapy initiated more than 6 weeks prior to screening should be continued with the same methodology and at the same frequency and intensity during the entire study.

• The patient has a current diagnosis or history of substance abuse or dependence (excluding nicotine or caffeine) or alcohol abuse or dependence (DSM-IV-TR™ criteria) <6 months prior to the Screening Visit.

• The patient reports adjunctive treatment with an antipsychotic medication together with an antidepressant for 3 weeks or more during the current MDE.

• The patient has received electroconvulsive therapy (ECT) <6 months prior to the Screening Visit or at any time during the current MDE (if its duration is longer than 6 months).

• The patient has had vagus nerve stimulation or a deep brain stimulation device implanted for the management of depression.

Other inclusion and exclusion criteria may apply.

Study Design

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Depression
• Depressive Disorder
• Depressive Disorder, Major
• Irritability
• Major Depressive Disorder

Intervention

Drug:
• Brexpiprazole
2-3 mg/day, once daily dose, 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 judgement.

Locations

Country	Name	City	State
United States	US001	Dayton	Ohio
United States	US011	Denver	Colorado
United States	US006	Gaithersburg	Maryland
United States	US019	Glendale	California
United States	US018	Hallandale Beach	Florida
United States	US009	Jacksonville	Florida
United States	US003	Jamaica	New York
United States	US004	Memphis	Tennessee
United States	US016	Oakland	California
United States	US005	Orlando	Florida
United States	US007	Portland	Oregon
United States	US014	San Diego	California
United States	US002	Seattle	Washington
United States	US015	Tucson	Arizona
United States	US012	Weymouth	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
H. Lundbeck A/S

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change From Baseline to Week 6 in SIS Total Score	The Sheehan Irritability Scale (SIS) is a patient-rated scale designed to measure irritability. The SIS consists of 7 subscales assessing irritability, frustration, edginess/impatience/overreaction, moodiness, anger with self, anger with others, and temper. The subscales are summarised to give the total score which ranges from 0 to 70, 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 6	No
Primary	Change From Baseline to Week 6 in SIS Item 1 Score	The Sheehan Irritability Scale (SIS) is a patient-rated scale designed to measure irritability. The SIS item 1 assess how much the patient has suffered from irritability in the past week. The SIS item 1 ranged from 0 to 10 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 6	No
Primary	Change From Baseline to Week 6 in IDS-C30 Item 6 Score	The 30-item Inventory of Depressive Symptomatology - Clinician-Rated (IDS-C30) is a clinician-rated scale designed to assess the severity of depressive symptoms. The IDS-C30 item 6 measures mood (irritable) and is rated on a 4-point anchored scale from 0 (least severe) to 3 (most severe) 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 6	No
Primary	Change From Baseline to Week 6 in Delay Discounting - Log-transformed MCQ Scores	The Monetary Choice Questionnaire (MCQ) is a patient-completed questionnaire designed to measure delay discounting, an index of impulsive behaviour. The MCQ consists of 27 choices between immediate and delayed rewards. The patients choose repeatedly between two hypothetical sums of money: a smaller amount now or a larger amount in the future (for example, ''Would you prefer $27 today or $50 in 21 days?"). The answers provide an estimate of the patient's discounting rate. The discounting rate parameter takes values between 0 and 1 and higher discounting rates indicate impulsivity. As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes.	Baseline and Week 6	No
Primary	Change From Baseline to Week 6 in BIS-11 Total Score	The Barratt Impulsiveness Scale, Version 11 (BIS-11) is a patient-rated scale designed to assess impulsive personality traits. The BIS-11 consists of 30 items scored on a 4-point scale ranging from 1 (rarely/never) to 4 (almost always/always). The total score ranges from 30 to 120 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 6	No
Primary	Change From Baseline to Week 6 in KSQ Anger-hostility Subscore	The Kellner Symptom Questionnaire (KSQ) is a patient-rated scale designed to assess distress using symptoms of depression, anxiety, anger-hostility, and somatization. The KSQ anger-hostility subscale score ranges from 0 to 23 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 6	No
Primary	Shift From Baseline to Week 6 in Anger Attacks (AAQ)	The Anger Attacks Questionnaire (AAQ) is a patient-rated scale designed to assess the presence of anger attacks over a period of time. The AAQ consists of 7 items. Patients are classified as having anger attacks when exhibiting the following 4 criteria: 1) irritability, 2) overreaction to minor annoyances, 3) occurrence of anger attacks (at least one of which occurred within the period), and 4) experienced 4 or more specific symptoms during at least one of the attacks. As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes.	Baseline and Week 6	No
Primary	Change From Baseline to Week 6 in IDS-C30 Total Score	The 30-item Inventory of Depressive Symptomatology - Clinician-Rated (IDS-C30) is a clinician-rated scale designed to assess the severity of depressive symptoms. The IDS-C30 consists of 30 items assessing the symptoms of depression, as well as commonly associated symptoms (for example, anxiety, irritability), and topics relevant to melancholic or atypical features; the patient rates only one of the 2 items assessing appetite (decreased or increased), and only one of the 2 items assessing weight (loss or gain). Each of the items is rated on a 4-point anchored scale from 0 (least severe) to 3 (most severe). The total score is the sum of the 28 scored items, and ranges from 0 to 84, 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 6	No
Primary	Change From Baseline to Week 6 in KSQ Depression Subscore	The Kellner Symptom Questionnaire (KSQ) is a patient-rated scale designed to assess distress using symptoms of depression, anxiety, anger-hostility, and somatization. The KSQ depression subscale score ranges from 0 to 23, 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 6	No
Primary	Change From Baseline to Week 6 in MADRS Total Score	The Montgomery and Åsberg 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. Symptoms are rated on a 7-point scale from 0 (no symptom) to 6 (severe symptom). 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 6	No
Primary	Change From Baseline to Week 6 in CPFQ Total Score	The Massachusetts General Hospital 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 6	No
Primary	Change From Baseline to Week 6 in CGI-S Score	The Clinical Global Impression severity of illness (CGI-S) provides 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). As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes.	Baseline and Week 6	No
Primary	CGI-I Score at Week 6	The Clinical Global Impression - global improvement CGI-I provides 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). In all cases, the assessment should be made independent of whether the rater believes the improvement is drug-related or not. As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes.	Week 6	No
Primary	Change From Baseline to Week 6 in KSQ Total Score	The Kellner Symptom Questionnaire (KSQ) is a patient-rated scale designed to assess distress using symptoms of depression, anxiety, anger-hostility, and somatization. The KSQ consists of 92 items which form the basis for the four subscales: depression, anxiety, anger-hostility, and somatic; of which 68 items indicate symptoms (symptom subscales) and 24 items are antonyms of some of the symptoms and indicate well-being (well-being subscales). A "yes" or "true" response on the symptom subscales scores 1, and a "no" or "false" on the well-being subscales scores 1. The maximum score for each symptom subscale is 17, and the maximum score for each well-being subscale is 6. The score of each subscale ranges from 0 to 23 (the sum of the symptom subscale and the well-being subscale). A higher score indicates more distress. The total score ranges from 0 to 92. As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes.	Baseline and Week 6	No
Primary	Change From Baseline to Week 6 in Delay Discounting - Log-transformed EDT DPDT Scores	DPDT consists of approximately 110 choices between an immediate reward or a higher delayed reward, and between an immediate reward or a higher reward that only comes with a certain probability. The tasks are scored independently of each other and do not yield a total score. There will be two derived variables from this task; a delayed discounting rate and a probability discounting rate. The delay discounting value takes values from 0 and up, a higher delay discounting value indicates greater impulsivity. As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes.	Baseline and Week 6	No
Primary	Change From Baseline to Week 6 in Delay Discounting - EDT DRT Score	DRT consists of 60 choices between an immediate reward or a higher delayed reward. The number of impulsive choices will be a continuous variable estimated from how many immediate choices based on 60 possible. The number ranges between 0 and 60, with a higher value indicating more impulsivity. As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes.	Baseline and Week 6	No
Primary	Change From Week 6 to Week 10 in SIS Total Score	The Sheehan Irritability Scale (SIS) is a patient-rated scale designed to measure irritability. The SIS consists of 7 subscales assessing irritability, frustration, edginess/impatience/overreaction, moodiness, anger with self, anger with others, and temper. The patient rates the extent to which they have suffered from these symptoms. Each subscale has verbal descriptors (not at all, mildly, moderately, markedly, and extremely) as well as numerical scores from 0 (not at all) to 10 (extremely) that provide more precise levels of the verbal descriptors. One additional question assesses number of days impaired by irritability over the period. The subscales are summarised to give the total score which ranges from 0 to 70, with higher values indicating worse outcome. As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes.	Week 6 and Week 10	No
Primary	Change From Week 6 to Week 10 in SIS Item 1 Score	The Sheehan Irritability Scale (SIS) is a patient-rated scale designed to measure irritability. The SIS item 1 assess how much the patient has suffered from irritability in the past week, using verbal descriptors (not at all, mildly, moderately, markedly, and extremely) as well as numerical scores from 0 (not at all) to 10 (extremely) that provide more precise levels of the verbal descriptors. The SIS item 1 ranged from 0 to 10 with higher values indicating worse outcome. As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes.	Week 6 and Week 10	No
Primary	Change From Week 6 to Week 10 in Delay Discounting - MCQ Scores	The Monetary Choice Questionnaire (MCQ) is a patient-completed questionnaire designed to measure delay discounting, an index of impulsive behaviour. The MCQ consists of 27 choices between immediate and delayed rewards. The patients choose repeatedly between two hypothetical sums of money: a smaller amount now or a larger amount in the future (for example, ''Would you prefer $27 today or $50 in 21 days?"). The answers provide an estimate of the patient's discounting rate. The discounting rate parameter takes values between 0 and 1 and higher discounting rates indicate impulsivity. As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes.	Week 6 and Week 10	No
Primary	Change From Week 6 to Week 10 in BIS-11 Total Score	The Barratt Impulsiveness Scale, Version 11 (BIS-11) is a patient-rated scale designed to assess impulsive personality traits. The BIS-11 consists of 30 items scored on a 4-point scale ranging from 1 (rarely/never) to 4 (almost always/always). The scores provide information to assess 6 first-order factors (attention, motor, self-control, cognitive complexity, perseverance, and cognitive instability impulsiveness) and 3 second-order factors (motor impulsiveness, non-planning impulsiveness, and attentional impulsiveness). The total score ranges from 30 to 120 with higher values indicating worse outcome. As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes.	Week 6 and Week 10	No
Primary	Change From Week 6 to Week 10 in KSQ Anger-hostility Subscore	The Kellner Symptom Questionnaire (KSQ) is a patient-rated scale designed to assess distress using symptoms of depression, anxiety, anger-hostility, and somatization. The KSQ anger-hostility subscale score ranges from 0 to 23 with higher values indicating worse outcome. As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes.	Week 6 and Week 10	No
Primary	Change From Week 6 to Week 10 in KSQ Depression Subscore	The Kellner Symptom Questionnaire (KSQ) is a patient-rated scale designed to assess distress using symptoms of depression, anxiety, anger-hostility, and somatization. The KSQ depression subscale score ranges from 0 to 23, with higher values indicating worse outcome . As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes.	Week 6 and Week 10	No
Primary	Change From Week 6 to Week 10 in CGI-S Score	The Clinical Global Impression severity of illness (CGI-S) provides 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). As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes.	Week 6 and Week 10	No
Primary	Change From Baseline to Week 6 in MADRS Total Score in Patients With a Pre-defined Baseline BIS-11 Total Score	The Montgomery and Åsberg 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. Symptoms are rated on a 7-point scale from 0 (no symptom) to 6 (severe symptom). The total score of the 10 items ranges from 0 to 60, with higher values indicating worse outcome. Subgroup analyses were performed for the change from Baseline to Week 6 in MADRS total score based on the patients' BIS-11 total score at Baseline. The subgroups denoted BIS-11_HIGH had a BIS-11 total score at Baseline =median at baseline and the subgroups denoted BIS-11_LOW had a BIS-11 total score	Baseline and Week 6	No
Primary	Change From Baseline to Week 6 in CGI-S Score in Patients With a Pre-defined Baseline BIS-11 Total Score	The subgroups denoted BIS-11_HIGH had a BIS-11 total score at Baseline =median at baseline and the subgroups denoted BIS-11_LOW had a BIS-11 total score	Baseline and Week 6	No
Primary	CGI-I Score at Week 6 Patients With a Pre-defined Baseline BIS-11 Total Score	The subgroups denoted BIS-11_HIGH had a BIS-11 total score at Baseline =median at baseline and the subgroups denoted BIS-11_LOW had a BIS-11 total score	Week 6	No