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| Name | Class |
|---|---|
| H. Lundbeck A/S | INDUSTRY |
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The purpose of this study is to assess the tolerability, safety, and efficacy of brexpiprazole (2.0 mg/day) as adjunctive therapy in adult subjects with a diagnosis of MDD with and without anxious distress
The introduction of atypical antipsychotics has created a renewed interest in adjunctive therapy for MDD, particularly for treatment-resistant MDD. Several atypical antipsychotics have been shown to enhance the response to ADT. This is a phase 3, multicenter, randomized, double-blind, placebo-controlled, fixed-dose trial designed to assess the safety and efficacy of brexpiprazole (2.0 mg/day) as adjunctive therapy to an assigned open-label ADT in depressed subjects with and without anxious distress.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Brexpiprazole + ADT | Experimental | Brexpiprazole + ADT |
|
| Placebo + ADT | Placebo Comparator | Placebo + ADT |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Placebo + ADT | Drug | Placebo + ADT Placebo + FDA Approved Antidepressant (ADT) |
| |
| Measure | Description | Time Frame |
|---|---|---|
| Change in the Montgomery-Asberg Depression | To assess the change in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score from Baseline (End of Phase A [Week 8]) to Week 14. The MADRS was utilized as the primary efficacy assessment of the participant's level of depression and was administered utilizing the Structured Interview Guide for the MADRS (SIGMA). The MADRS consisted of 10 items each with 7 defined grades of severity. The rater decided whether the rating lied on predefined scale steps (0, 2, 4, 6) or between them (1, 3, 5). The 10 items were apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, suicidal thoughts. Each item was scored using a scale of 0 to 6 (a higher score indicates increased severity). The maximum total score was 60; 0, no symptom; 60, severely affected. | From baseline (end of Phase A [Week 8]) to week 14 |
| Measure | Description | Time Frame |
|---|---|---|
| Change in the Sheehan Disability Scale (SDS) From Baseline to End of Treatment | To assess the change in the Sheehan Disability Scale (SDS) Score (the mean of 3 individual item scores) from Baseline (End of Phase A [Week 8]) to Week 14 (End of Phase B). SDS was a 3-item clinician-rated questionnaire used to evaluate impairments in the domains of work, social life, and family life/home responsibility. Each item was scored using a scale of 0 to 10 (a higher score indicates symptoms have disrupted work, social life, and family life/home responsibility extremely). The maximum total score was 30; 0 = not at all, to 30 = extremely. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Claudette Brewer | Otsuka Pharmaceutical Development & Commercialization, Inc. | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Birmingham | Alabama | United States | ||||
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 41055581 | Derived | Kapadia S, Zhang Z, Ardic F, Patel M, Thase ME, Papakostas GI. Adjunctive brexpiprazole in patients with major depressive disorder who show minimal or partial response to antidepressant treatment: post hoc analysis of randomized controlled trials. Int J Neuropsychopharmacol. 2025 Oct 1;28(10):pyaf074. doi: 10.1093/ijnp/pyaf074. | |
| 40852147 |
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Trial consisted of a screening phase and 3 phases. In phase A (8-week single-blind prospective treatment phase) and in phase A+ (Single-blind phase A Responder), there was single treatment group. In phase B (6-week double-blind randomization phase), there were 2 treatment groups. All Outcome Measures were assessed in phase B.
This trial was conducted in 837 participants at 51 trial sites in the following 5 countries:Germany,Hungary,Poland,Slovakia,andUnited States (US).A total of 1144 participants with major depressive disorder were screened for the trial, 837 enrolled into Phase A,394 were randomized into Phase B and 322 continued treatment with placebo+ADT in Phase A+
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| ID | Title | Description |
|---|---|---|
| FG000 | Phase A: All ADT (Antidepressant Therapy) | Participants meeting entrance criteria who were experiencing a major depressive episode with a HAM-D17 Total Score of greater than or equal 18 at baseline were enrolled into an 8-week Single-blind Prospective Treatment Phase (Phase A). All participants received single-blind placebo plus an investigator determined, open-label, ADT. Once assigned to an ADT by the investigator, participants remained on the same ADT for the duration of the trial. At the Week 8 visit, the IWRS (Interactive web response system) determined based on scores entered by the investigator, whether a participant was a "Phase A Responder" or a "Phase A Inadequate Responder." |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Phase A |
|
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| Brexpiprazole +ADT |
| Drug |
Brexpiprazole + ADT Tablet, Oral, 2mg brexpiprazole and FDA Approved Antidepressant (ADT) |
|
| From baseline (end of Phase A [Week 8]) to week 14 |
| Change From End of Phase A to End of Phase B in MADRS Total Score for the Subpopulation With <25% Improvement From Baseline of Phase A to End of Phase A in MADRS Total Score | To assess the change from end of Phase A (Week 8 visit) to end of Phase B (Week 14 visit) in MADRS Total Score for the subpopulation with < 25% improvement from baseline of Phase A (Week 0) to end of Phase A (Week 8) in MADRS Total Score. The MADRS was utilized as the primary efficacy assessment of the participant's level of depression and was administered utilizing the Structured Interview Guide for the MADRS (SIGMA). The MADRS consisted of 10 items each with 7 defined grades of severity. The 10 items were apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, suicidal thoughts. Each item was scored using a scale of 0 to 6 (a higher score indicates increased severity). The maximum total score was 60; 0, no symptom; 60, severely affected. | From baseline (end of Phase A [Week 8]) to week 14 |
| Change From End of Phase A to End of Phase B in MADRS Total Score for the Subpopulations With Anxious Distress as Specified in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V). | To assess the change from end of Phase A (Week 8) to end of Phase B (Week 14) in MADRS Total Score for the subpopulations with anxious distress as specified in DSM-V. The MADRS was utilized as the primary efficacy assessment of the participant's level of depression and was administered utilizing the Structured Interview Guide for the MADRS (SIGMA). The MADRS consisted of 10 items each with 7 defined grades of severity. The 10 items were apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, suicidal thoughts. Each item was scored using a scale of 0 to 6 (a higher score indicates increased severity). The maximum total score was 60; 0, no symptom; 60, severely affected. | From baseline (end of Phase A [Week 8]) to week 14 |
| Beverly Hills |
| California |
| United States |
| Denver | Colorado | United States |
| Hialeah | Florida | United States |
| Orlando | Florida | United States |
| Alpharetta | Georgia | United States |
| Smyrna | Georgia | United States |
| Baltimore | Maryland | United States |
| Boston | Massachusetts | United States |
| Rochester Hills | Michigan | United States |
| Cherry Hill | New Jersey | United States |
| Jamaica | New York | United States |
| New York | New York | United States |
| Staten Island | New York | United States |
| Raleigh | North Carolina | United States |
| Cincinnati | Ohio | United States |
| Edmond | Oklahoma | United States |
| Portland | Oregon | United States |
| Salem | Oregon | United States |
| Philadelphia | Pennsylvania | United States |
| Lincoln | Rhode Island | United States |
| Columbia | South Carolina | United States |
| Memphis | Tennessee | United States |
| Wichita Falls | Texas | United States |
| Murray | Utah | United States |
| Woodstock | Vermont | United States |
| Charlottesville | Virginia | United States |
| Richmond | Virginia | United States |
| Seattle | Washington | United States |
| Spokane | Washington | United States |
| Achim | Germany |
| Berlin | Germany |
| Düsseldorf | Germany |
| Frankfurt | Germany |
| Freiburg im Breisgau | Germany |
| Oranienburg | Germany |
| Stralsund | Germany |
| Würzburg | Germany |
| Budapest | Hungary |
| Győr | Hungary |
| Gdansk | Poland |
| Lubin | Poland |
| Sosnowiec | Poland |
| Warsaw | Poland |
| Bratislava | Slovakia |
| Kosice-Barca | Slovakia |
| Liptovský Mikuláš | Slovakia |
| Ardic F, Zhang Z, Hogan M. Effects of adjunctive brexpiprazole in patients with major depressive disorder and sleep disturbance: a post hoc analysis of three randomized trials. Front Psychiatry. 2025 Aug 7;16:1618176. doi: 10.3389/fpsyt.2025.1618176. eCollection 2025. |
| 40607746 | Derived | Kapadia S, Zhang Z, Csoboth C, Patel M, Thase ME, Papakostas GI. Adjunctive brexpiprazole in patients with unresolved symptoms of depression on antidepressant treatment who are early in the disease course: post hoc analysis of randomized controlled trials. Int J Neuropsychopharmacol. 2025 Aug 1;28(8):pyaf050. doi: 10.1093/ijnp/pyaf050. |
| 38421922 | Derived | McIntyre RS, Bubolic S, Zhang Z, MacKenzie EM, Therrien F, Miguelez M, Boucher M. Effects of Adjunctive Brexpiprazole on Individual Depressive Symptoms and Functioning in Patients With Major Depressive Disorder and Anxious Distress: Post Hoc Analysis of Three Placebo-Controlled Studies. J Clin Psychopharmacol. 2024 Mar-Apr 01;44(2):133-140. doi: 10.1097/JCP.0000000000001825. |
| 37656180 | Derived | Newcomer JW, Meehan SR, Chen D, Brubaker M, Weiss C. Changes in Metabolic Parameters and Body Weight in Patients With Prediabetes Treated With Adjunctive Brexpiprazole for Major Depressive Disorder: Pooled Analysis of Short- and Long-Term Clinical Studies. J Clin Psychiatry. 2023 Aug 28;84(5):23m14786. doi: 10.4088/JCP.23m14786. |
| 37099968 | Derived | McIntyre RS, Therrien F, Ismail Z, Meehan SR, Miguelez M, Larsen KG, Chen D, MacKenzie EM, Thase ME. Effects of adjunctive brexpiprazole on patient life engagement in major depressive disorder: Post hoc analysis of Inventory of Depressive Symptomatology Self-Report data. J Psychiatr Res. 2023 Jun;162:71-78. doi: 10.1016/j.jpsychires.2023.04.012. Epub 2023 Apr 12. |
| 31577867 | Derived | Newcomer JW, Eriksson H, Zhang P, Meehan SR, Weiss C. Changes in Metabolic Parameters and Body Weight in Patients With Major Depressive Disorder Treated With Adjunctive Brexpiprazole: Pooled Analysis of Phase 3 Clinical Studies. J Clin Psychiatry. 2019 Oct 1;80(6):18m12680. doi: 10.4088/JCP.18m12680. |
| 30508090 | Derived | Hobart M, Zhang P, Weiss C, Meehan SR, Eriksson H. Adjunctive Brexpiprazole and Functioning in Major Depressive Disorder: A Pooled Analysis of Six Randomized Studies Using the Sheehan Disability Scale. Int J Neuropsychopharmacol. 2019 Mar 1;22(3):173-179. doi: 10.1093/ijnp/pyy095. |
| 29873953 | Derived | Hobart M, Skuban A, Zhang P, Augustine C, Brewer C, Hefting N, Sanchez R, McQuade RD. A Randomized, Placebo-Controlled Study of the Efficacy and Safety of Fixed-Dose Brexpiprazole 2 mg/d as Adjunctive Treatment of Adults With Major Depressive Disorder. J Clin Psychiatry. 2018 May 22;79(4):17m12058. doi: 10.4088/JCP.17m12058. |
| FG001 | Phase B: Brexpiprazole + ADT | Participants received brexpiprazole 2 mg and ADT orally once daily for 6 weeks. |
| FG002 | Phase B: Placebo + ADT | Participants received matching placebo and ADT orally once daily for 6 weeks. |
| FG003 | Phase A +: ALL ADT | Phase A+ included participants who met criteria for a response at the end of the prospective treatment phase (Week 8 visit of Phase A) and participants who were not suitable for randomization in Phase B per the judgment of the investigator or medical monitor. Treatment response in Phase A was determined at the Week 8 visit based on improvement or lack of improvement of the participant's depressive symptoms, which was confirmed by clinical criteria that prospectively defined response. Participant response was determined from clinical data that were entered into the IWRS at each visit. Participants in Phase A+ received single-blind placebo+ADT for an additional 6 weeks, for a total of 14 weeks, and attended visits at Weeks 11 and 14. |
| COMPLETED |
|
| NOT COMPLETED |
|
|
| Phase B |
|
|
| Phase A+ |
|
|
Baseline measures are based on the participants from the Double-blind Randomization Phase
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| ID | Title | Description |
|---|---|---|
| BG000 | Brexpiprazole + ADT | Phase B: Brexpiprazole +Antidepressant therapy (ADT): Participants received brexpiprazole 2mg and ADT orally once daily for 6 weeks. |
| BG001 | Placebo + ADT | Phase B: Placebo + Antidepressant therapy (ADT): Participants received matching placebo and ADT orally once daily for 6 weeks |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| 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 |
| ||||||||||||||||
| Race/Ethnicity, Customized | Count of Participants | Participants | No |
| |||||||||||||||
| Region of Enrollment | Number | participants |
|
| 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 in the Montgomery-Asberg Depression | To assess the change in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score from Baseline (End of Phase A [Week 8]) to Week 14. The MADRS was utilized as the primary efficacy assessment of the participant's level of depression and was administered utilizing the Structured Interview Guide for the MADRS (SIGMA). The MADRS consisted of 10 items each with 7 defined grades of severity. The rater decided whether the rating lied on predefined scale steps (0, 2, 4, 6) or between them (1, 3, 5). The 10 items were apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, suicidal thoughts. Each item was scored using a scale of 0 to 6 (a higher score indicates increased severity). The maximum total score was 60; 0, no symptom; 60, severely affected. | The primary analysis was performed on Efficacy Sample which included all randomized participants who took at least one dose of trial medication in Phase B and who have both an end of Phase A (Week 8) and at least one post-randomization MADRS Total Score during Phase B. | Posted | Least Squares Mean | Standard Error | Units on a scale | From baseline (end of Phase A [Week 8]) to week 14 |
|
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Secondary | Change in the Sheehan Disability Scale (SDS) From Baseline to End of Treatment | To assess the change in the Sheehan Disability Scale (SDS) Score (the mean of 3 individual item scores) from Baseline (End of Phase A [Week 8]) to Week 14 (End of Phase B). SDS was a 3-item clinician-rated questionnaire used to evaluate impairments in the domains of work, social life, and family life/home responsibility. Each item was scored using a scale of 0 to 10 (a higher score indicates symptoms have disrupted work, social life, and family life/home responsibility extremely). The maximum total score was 30; 0 = not at all, to 30 = extremely. | The primary analysis was performed on Efficacy Sample which included all randomized participants who took at least one dose of trial medication in Phase B and who have both an end of Phase A (Week 8) and at least one post-randomization MADRS Total Score during Phase B. | Posted | Least Squares Mean | Standard Error | Units on a scale | From baseline (end of Phase A [Week 8]) to week 14 |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Secondary | Change From End of Phase A to End of Phase B in MADRS Total Score for the Subpopulation With <25% Improvement From Baseline of Phase A to End of Phase A in MADRS Total Score | To assess the change from end of Phase A (Week 8 visit) to end of Phase B (Week 14 visit) in MADRS Total Score for the subpopulation with < 25% improvement from baseline of Phase A (Week 0) to end of Phase A (Week 8) in MADRS Total Score. The MADRS was utilized as the primary efficacy assessment of the participant's level of depression and was administered utilizing the Structured Interview Guide for the MADRS (SIGMA). The MADRS consisted of 10 items each with 7 defined grades of severity. The 10 items were apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, suicidal thoughts. Each item was scored using a scale of 0 to 6 (a higher score indicates increased severity). The maximum total score was 60; 0, no symptom; 60, severely affected. | Subpopulation of <25% Improvement Sample: Comprised of all participants in the Efficacy Sample who had <25% improvement at the end of Phase A in MADRS Total Score. | Posted | Least Squares Mean | Standard Error | Units on a scale | From baseline (end of Phase A [Week 8]) to week 14 |
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| Secondary | Change From End of Phase A to End of Phase B in MADRS Total Score for the Subpopulations With Anxious Distress as Specified in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V). | To assess the change from end of Phase A (Week 8) to end of Phase B (Week 14) in MADRS Total Score for the subpopulations with anxious distress as specified in DSM-V. The MADRS was utilized as the primary efficacy assessment of the participant's level of depression and was administered utilizing the Structured Interview Guide for the MADRS (SIGMA). The MADRS consisted of 10 items each with 7 defined grades of severity. The 10 items were apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, suicidal thoughts. Each item was scored using a scale of 0 to 6 (a higher score indicates increased severity). The maximum total score was 60; 0, no symptom; 60, severely affected. | Subpopulation of Anxious Distress Sample: Comprised of all participants in the Efficacy Sample who had anxious distress as specified in DSM-V. | Posted | Least Squares Mean | Standard Error | Units on a scale | From baseline (end of Phase A [Week 8]) to week 14 |
|
Participants were assessed for the occurrence of adverse events (AEs) once the participant signed informed consent form through completion of the trial; up to 14-weeks after the participant entered the trial and actively monitored up to 30 (+2) days after their last dose of investigational medicinal product (this could be up to 22 weeks depending on duration of trial participation).
Safety sample comprised of randomized participants in Phase B who received at least one dose of double-blind trial medication. No adverse events were assessed or collected from Phase A or A+ participants as those phases are single-blind, non-randomized, monotherapy treatment periods of the study and are outside of the pre-specified definition of the safety sample per the trial design.
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Brexpiprazole + ADT | Phase B: Brexpiprazole +Antidepressant therapy (ADT): Participants received brexpiprazole 2mg and ADT orally once daily for 6 weeks. | 0 | 192 | 1 | 192 | 49 | 192 |
| EG001 | Placebo + ADT | Phase B: Placebo + Antidepressant therapy (ADT): Participants received matching placebo and ADT orally once daily for 6 weeks | 0 | 202 | 0 | 202 | 35 | 202 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Vertigo | Ear and labyrinth disorders | MedDRA (19.0) | Non-systematic Assessment |
|
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Upper Respiratory Tract Infection | Infections and infestations | MedDRA (19.0) | Non-systematic Assessment |
| |
| Weight Increased | Investigations | MedDRA (19.0) | Non-systematic Assessment |
| |
| Akathisia | Nervous system disorders | MedDRA (19.0) | Non-systematic Assessment |
| |
| Headache | Nervous system disorders | MedDRA (19.0) | Non-systematic Assessment |
| |
| Restlessness | Psychiatric disorders | MedDRA (19.0) | Non-systematic Assessment |
|
The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days from the time submitted to the sponsor for review. The sponsor cannot require changes to the communication and cannot extend the embargo.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Global Medical Affairs | Otsuka Pharmaceutical Development and Commercialization, Inc. | 800 562-3974 |
| ID | Term |
|---|---|
| D003866 | Depressive Disorder |
| D003863 | Depression |
| D003865 | Depressive Disorder, Major |
| D019964 | Mood Disorders |
| D001523 | Mental Disorders |
| ID | Term |
|---|---|
| D001526 | Behavioral Symptoms |
| D001519 | Behavior |
Not provided
Not provided
| ID | Term |
|---|---|
| D000726 | Androgen Antagonists |
| ID | Term |
|---|---|
| D006727 | Hormone Antagonists |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
| D045505 | Physiological Effects of Drugs |
| D020228 | Pharmacologic Actions |
| D020164 | Chemical Actions and Uses |
Not provided
Not provided
| Lack of Efficacy |
|
| Withdrawal by Participant |
|
| Adverse Event |
|
| Lost to Follow-up |
|
| Withdrawal by Participant |
|
| Adverse Event |
|
| Lost to Follow-up |
|
| Participant withdrawn by investigator |
|
| Male |
|
| Not Hispanic or Latino |
|
| Unknown |
|
| United States |
|
| Poland |
|
| Slovakia |
|
| Germany |
|
| Units | Counts |
|---|---|
| Participants |
|
|
|
Phase B: Placebo + Antidepressant therapy (ADT): Participants received matching placebo and ADT orally once daily for 6 weeks |
|
|
|
Phase B: Placebo + Antidepressant therapy (ADT):
Participants received matching placebo and ADT orally once daily for 6 weeks
|
|
|