Brexpiprazole as Adjunctive Treatment in Patients With Major Depressive Disorder With an Inadequate Response to Antidepressant Treatment

Study Overview
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Brief Summary
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To evaluate the long-term efficacy and safety of brexpiprazole as an adjunctive treatment to an antidepressant treatment (ADT) for adult patients with Major Depressive Disorder (MDD).

Detailed Description
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The total duration of the study was 32 weeks and the study consisted of Periods A, B, and A+. Patients entered the study in Period A and were treated open-label with one of six commercially available antidepressant treatments (ADTs) for 8 weeks. Patients who met the blinded response criteria at the Week 6 Visit, were deemed early responders and were withdrawn from the study. At Week 8, patients with inadequate response to placebo + ADT, as per the randomisation criteria, entered Period B and were randomised to received double-blind brexpiprazole + ADT or placebo + ADT for 24 weeks. Non-randomised patients continued in Period A+ and received placebo + ADT until the end of the study. The primary objective was to compare the efficacy and safety of brexpiprazole with placebo. This comparison occurred Period B; therefore, the focus is Period B.

Official Title
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Interventional, Randomised, Double-blind, Parallel-group, Placebo-controlled, Flexible-dose Long-term Study to Evaluate the Maintenance of Efficacy and Safety of 1 to 3 mg/Day of Brexpiprazole as Adjunctive Treatment in Patients With Major Depressive Disorder With an Inadequate Response to Antidepressant Treatment

Conditions
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Major Depressive Disorder

Intervention / Treatment
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* Drug: Placebo
* Drug: Brexpiprazole
* Drug: ADT


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The patient is an outpatient consulting a psychiatrist. The patient has an MDD diagnosed according to DSM-IV-TR™. The current Major Depressive Episode (MDE) should be confirmed using the Mini International Neuropsychiatric Interview (MINI). The patient has a moderate to severe depression and an insufficient response to at least one and no more than three adequate antidepressant treatments. The patient agrees to protocol-defined use of effective contraception. Exclusion Criteria: The patient has any current psychiatric disorder or Axis I disorder (DSM-IV-TR™ criteria), established as the primary diagnosis, other than MDD. The patient has a current Axis II (DSM-IV-TR™) diagnosis of borderline, antisocial, paranoid, schizoid, schizotypical or histrionic personality disorder. The patient has experienced/experiences hallucinations, delusions or any psychotic symptomatology in the current MDE. The patient suffers from mental retardation, organic mental disorders, or mental disorders due to a general medical condition (DSM-IV-TR™ criteria). The patient, in the opinion of the investigator or according to Columbia-Suicide Severity Rating Scale (C-SSRS), is at significant risk of suicide. The patient has had neuroleptic malignant syndrome. The patient has any relevant medical history or current presence of systemic disease. The patient has, at the Screening Visit an abnormal ECG that is, in the investigator's opinion, clinically significant. The patient has a history of cancer, other than basal cell or Stage 1 squamous cell carcinoma of the skin, that has not been in remission for >5 years prior to the first dose of IMP. 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: 75 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo adjunct to open-label treatment with a commercially available antidepressant (ADT) | Drug: Placebo<br>* Once daily, tablets, orally<br>Drug: ADT<br>* Duloxetine, escitalopram, fluoxetine, paroxetine IR, sertraline, venlafaxine XR; dosing according to label<br>|
| Experimental: Brexpiprazole<br>Brexpiprazole adjunct to open-label treatment with a commercially available ADT | Drug: Brexpiprazole<br>* 1, 2, or 3 mg/day, once daily dose, tablets, orally. Uptitration in weekly steps from 1 mg/day<br>Drug: ADT<br>* Duloxetine, escitalopram, fluoxetine, paroxetine IR, sertraline, venlafaxine XR; dosing according to label<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Full Remission During the Randomised Treatment Period | Full remission is defined as a Montomery and Åsberg Depression Rating Scale (MADRS) total score ≤10 and a ≥50% decrease from randomisation in MADRS total score for at least 8 consecutive weeks during randomized treatment. The MADRS is a depression rating scale consisting of 10 items, each rated 0 to 6. The 10 items represent the core symptoms of depressive illness. The overall score ranges from 0 (symptoms absent) to 60 (severe depression). The MADRS total score is the sum of the 10 items. | From randomisation to end of Period B (24 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Full Functional Remission During the Randomised Treatment Period | Full functional remission is defined as a Sheehan Disability Scale (SDS) total score <=6 and all SDS domain scores <=2 observed for at least 8 consecutive weeks during the randomised treatment period. The SDS assesses functional impairment in 3 domains: work/school, social life or leisure activities, and home life or family responsibilities. The participant rates the extent to which each aspect is impaired on a 10-point visual analog scale, from 0 (not at all) to 10 (extremely). The 3 scores are added together to calculate the total score, which ranges from 0 to 30, with higher scores indicating more impairment. | From randomisation to end of Period B (24 weeks) | 
| Full Global Score Remission During the Randomised Treatment Period | Full global score remission is defined as a Clinical Global Impression - Severity of Illness (CGI-S) score <=2 observed for at least 8 consecutive weeks during the randomised treatment period. The CGI-S is a 7-point scale where the clinician rates the severity of the patient's illness at the time of assessment, relative to the clinician's past experience with patients who have the same diagnosis, on the following scale: 1, normal, not at all ill; 2, borderline mentally ill; 3, mildly ill; 4, moderately ill; 5, markedly ill; 6, severely ill; or 7, extremely ill. | From randomisation to end of Period B (24 weeks) | 
| Total Time in Remission During the Randomised Treatment Period | The total time the patient spends in remission during randomised treatment. Remission is defined as a MADRS total score <=10 and a >=50% decrease from randomisation in MADRS total score. Time in remission is defined as the sum of days over all periods between Period B visits where remission was obtained. The period between two visits is counted as in remission if the patient was in remission when the period started. | From randomisation to end of Period B (24 weeks) | 
| Time to Full Remission During the Randomised Treatment Period | The time from randomisation until full remission has been obtained. Full remission is defined as a MADRS total score ≤10 and a ≥50% decrease from randomisation in MADRS total score for at least 8 consecutive weeks during randomised treatment. The time to full remission was calculated using Kaplan-Meier Methods. | From randomisation to end of Period B (24 weeks) | 
| Full Remission Sustained During the Randomised Treatment Period | Full remission sustained is defined as having obtained full remission and remain in remission until completion of the study. Full remission is defined as a MADRS total score ≤10 and a ≥50% decrease from randomisation in MADRS total score for at least 8 consecutive weeks during randomised treatment. | From randomisation to end of Period B (24 weeks) | 
| Change From Randomisation to Week 6 in MADRS Total Score During the Randomised Treatment Period | The MADRS is a depression rating scale consisting of 10 items, each rated 0 to 6. The 10 items represent the core symptoms of depressive illness. The overall score ranges from 0 (symptoms absent) to 60 (severe depression). The MADRS total score is the sum of the 10 items. | From randomisation to week 6 | 
| Change From Randomisation to Week 24 in MADRS Total Score During the Randomised Treatment Period | The MADRS is a depression rating scale consisting of 10 items, each rated 0 to 6. The 10 items represent the core symptoms of depressive illness. The overall score ranges from 0 (symptoms absent) to 60 (severe depression). The MADRS total score is the sum of the 10 items. | From randomisation to end of Period B (24 weeks) | 
| Response at Week 6 During the Randomised Treatment Period | Response is defined as a >=50% decrease from randomisation in MADRS total score. | From randomisation to week 6 | 
| Response at Week 24 During the Randomised Treatment Period | Response is defined as a >=50% decrease from randomisation in MADRS total score. | From randomisation to end of Period B (24 weeks) | 
| Remission at Week 6 During the Randomised Treatment Period | Remission is defined as a MADRS total score <=10 and a >=50% decrease from randomisation in MADRS total score. | From randomisation to week 6 | 
| Remission at Week 24 in the Randomised Treatment Period | Remission is defined as a MADRS total score <=10 and a >=50% decrease from randomisation in MADRS total score. | From randomisation to end of Period B (24 weeks) | 
| Change From Randomisation to Week 6 in SDS Total Score During the Randomised Treatment Period | The SDS assesses functional impairment in 3 domains: work/school, social life or leisure activities, and home life or family responsibilities. The participant rates the extent to which each aspect is impaired on a 10-point visual analog scale, from 0 (not at all) to 10 (extremely). The 3 scores are added together to calculate the total score, which ranges from 0 to 30, with higher scores indicating more impairment. | From randomisation to week 6 | 
| Change From Randomisation to Week 24 in SDS Total Score During the Randomised Treatment Period | The SDS assesses functional impairment in 3 domains: work/school, social life or leisure activities, and home life or family responsibilities. The participant rates the extent to which each aspect is impaired on a 10-point visual analog scale, from 0 (not at all) to 10 (extremely). The 3 scores are added together to calculate the total score, which ranges from 0 to 30, with higher scores indicating more impairment. | From randomisation to end of Period B (24 weeks) | 
| Change From Randomisation to Week 6 in CGI-S Score During the Randomised Treatment Period | The CGI-S is a 7-point scale where the clinician rates the severity of the patient's illness at the time of assessment, relative to the clinician's past experience with patients who have the same diagnosis on the following scale: 1, normal, not at all ill; 2, borderline mentally ill; 3, mildly ill; 4, moderately ill; 5, markedly ill; 6, severely ill; or 7, extremely ill. | From randomisation to week 6 | 
| Change From Randomisation to Week 24 in CGI-S Score During the Randomised Treatment Period | The CGI-S is a 7-point scale where the clinician rates the severity of the patient's illness at the time of assessment, relative to the clinician's past experience with patients who have the same diagnosis on the following scale: 1, normal, not at all ill; 2, borderline mentally ill; 3, mildly ill; 4, moderately ill; 5, markedly ill; 6, severely ill; or 7, extremely ill. | From randomisation to end of Period B (24 weeks) | 
| Change From Randomisation to Week 6 in Q-LES-Q (SF) Total Score During the Randomised Treatment Period | The original Q-LES-Q is a patient self-rated scale designed to measure the degree of enjoyment and satisfaction experienced by patients in various areas of daily life. It consists of 93 items to measure: physical health, feelings, work, household duties, school, leisure time activities, social relations, and general activities. The Q-LES-Q short form (SF) contains 16 items from the general activities section. Each item is rated on a 5-point scale ranging from 1 (very poor) to 5 (very good). The total score is the sum of the first 14 items. The last two scores are stand-alone items. The total score ranges from 14 to 70. | From randomisation to week 6 | 
| Change From Randomisation to Week 24 in Quality of Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q (SF)) Total Score During the Randomised Treatment Period | The original Q-LES-Q is a patient self-rated scale designed to measure the degree of enjoyment and satisfaction experienced by patients in various areas of daily life. It consists of 93 items to measure: physical health, feelings, work, household duties, school, leisure time activities, social relations, and general activities. The Q-LES-Q short form (SF) contains 16 items from the general activities section. Each item is rated on a 5-point scale ranging from 1 (very poor) to 5 (very good). The total score is the sum of the first 14 items. The last two scores are stand-alone items. The total score ranges from 14 to 70. | From randomisation to end of Period B (24 weeks) |