Study of the Safety and Efficacy of Two Fixed Doses of OPC-34712 as Adjunctive Therapy in the Treatment of Adults With Major Depressive Disorder (the Polaris Trial)

Study Overview
=================
Brief Summary
-----------------
To compare the effect of OPC-34712 (brexpiprazole) to the effect of placebo (an inactive substance) as add on treatment to an assigned FDA approved antidepressant treatment (ADT) in patients with Major Depressive Disorder who demonstrate an incomplete response to a prospective trial of the same assigned FDA approved ADT

Official Title
-----------------
A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Trial of the Safety and Efficacy of Two Fixed Doses of OPDC-34712 as Adjunctive Therapy in the Treatment of Adults With Major Depressive Disorder, the Polaris Trial

Conditions
-----------------
Mood Disorders, Depression, Depressive Disorder, Depressive Disorder, Major, Mental Disorders

Intervention / Treatment
-----------------
* Drug: OPC-34712 + ADT
* Drug: Placebo + ADT
* Drug: Placebo + ADT


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female subjects between 18 and 65 years of age, with diagnosis of major depressive disorder, as defined by DSM-IV-TR criteria The current depressive episode must be equal to or greater than 8 weeks in duration Subjects must report a history for the current depressive episode of an inadequate response to no more than three adequate antidepressant treatments Exclusion Criteria: Females who are breast-feeding and/or who have a positive pregnancy test result prior to receiving study drug Subjects who report an inadequate response to more than three adequate trials of antidepressant treatments during current depressive episode at a therapeutic dose for an adequate duration Subjects with a current Axis I (DSM-IV-TR) diagnosis of: Delirium, dementia, amnestic or other cognitive disorder, Schizophrenia, schizoaffective disorder, or other psychotic disorder, Bipolar I or II disorder Subjects with a clinically significant current Axis II (DSM-IV-TR) diagnosis of borderline, antisocial, paranoid, schizoid, schizotypal or histrionic personality disorder

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

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase B<br>Drug: OPC-34712 + ADT Drug: Placebo + ADT | Drug: OPC-34712 + ADT<br>* Tablets, Oral, 1 or 3 mg OPC-34712 and FDA Approved Antidepressant Therapy (ADT)<br>Drug: Placebo + ADT<br>* Placebo + FDA Approved Antidepressant (ADT)<br>|
| Placebo Comparator: Phase A<br>Drug: Placebo + ADT | Drug: Placebo + ADT<br>* Placebo + FDA Approved Antidepressant (ADT)<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From the End of Phase A (Week 8 Visit) to Phase B (Week 14 Visit) in the Montgomery-Asberg Depression Rating Scale for the Efficacy Sample Set | The MADRS was utilized as the primary efficacy assessment of a participant's level of depression. The MADRS consisted of 10 items, all rated on a 0 to 6 scale with 0 being the best rating and 6 being the worst rating. The MADRS total score were to be unevaluable if less than 8 of the 10 items were recorded. If 8 or 9 of the 10 items were recorded, the MADRS total score was the mean of the recorded items multiplied by 10 and then rounded of to the first decimal place. The MADRS Total Score is the sum of ratings for all 10 items. The possible total scores are from 0 to 60, with higher values indicating worse outcome. | Baseline and Week 14 | 
| Mean Change in MADRS Total Score From Baseline End of Week 8 to Week 14 for the Efficacy Sample Per Final Protocol | The MADRS was utilized as the primary efficacy assessment of a participant's level of depression. The MADRS consisted of 10 items, all rated on a 0 to 6 scale with 0 being the best rating and 6 being the worst rating. The MADRS total score were to be unevaluable if less than 8 of the 10 items were recorded. If 8 or 9 of the 10 items were recorded, the MADRS total score was the mean of the recorded items multiplied by 10 and then rounded of to the first decimal place. The MADRS Total Score is the sum of ratings for all 10 items. The possible total scores are from 0 to 60, with higher values indicating worse outcome. | Baseline and Week 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From End of Phase A (Week 8 Visit) in MADRS Total Score for Every Study Week Visit in Phase B Other Than Week 14 Visit for the Efficacy Sample Set | The MADRS was utilized as the primary efficacy assessment of a participant's level of depression. The MADRS consisted of 10 items, all rated on a 0 to 6 scale with 0 being the best rating and 6 being the worst rating. The MADRS total score were to be unevaluable if less than 8 of the 10 items were recorded. If 8 or 9 of the 10 items were recorded, the MADRS total score was the mean of the recorded items multiplied by 10 and then rounded of to the first decimal place. The MADRS Total Score is the sum of ratings for all 10 items. The possible total scores are from 0 to 60, with higher values indicating worse outcome. | Week 8, 9, 10, 11, 12, and 13 | 
| Mean Change From End of Phase A (Week 8 Visit) in MADRS Total Score for Every Study Week Visit in Phase B Other Than Week 14 Visit for the Efficacy Sample Per Final Protocol | The MADRS was utilized as the primary efficacy assessment of a participant's level of depression. The MADRS consisted of 10 items, all rated on a 0 to 6 scale with 0 being the best rating and 6 being the worst rating. The MADRS total score were to be unevaluable if less than 8 of the 10 items were recorded. If 8 or 9 of the 10 items were recorded, the MADRS total score was the mean of the recorded items multiplied by 10 and then rounded of to the first decimal place. The MADRS Total Score is the sum of ratings for all 10 items. The possible total scores are from 0 to 60, with higher values indicating worse outcome. | Week 8, 9, 10, 11, 12, and 13 | 
| Mean Change From End of Phase A (Week 8 Visit) to End of Phase B (Week 14 Visit) in Sheehan Disability Scale (SDS) Mean Scores for the Efficacy Sample Set | The SDS was a self-rated instrument used to measure the effect of the participants symptoms on work/school, social life, and family/home responsibilities. For each of the three items, scores ranged from 0 through 10. The number most representative of how much each area was disrupted by symptoms was marked along the line from 0= not at all to 10= extremely. For the work/school item, no response was to be entered if the participant did not work or go to school for reasons unrelated to the disorder and a response therefore not being applicable. The Mean SDS score were calculated over the three item scores. All three item scores were needed to be available with the exception of the work/school item score when this item was not applicable. | Week 11 and Week 14 | 
| Mean Change From End of Phase A (Week 8 Visit) to End of Phase B (Week 14 Visit) in SDS Mean Scores for the Efficacy Sample Per Final Protocol | The SDS was a self-rated instrument used to measure the effect of the participants symptoms on work/school, social life, and family/home responsibilities. For each of the three items, scores ranged from 0 through 10. The number most representative of how much each area was disrupted by symptoms was marked along the line from 0= not at all, to 10= extremely. For the work/school item, no response was to be entered if the participant did not work or go to school for reasons unrelated to the disorder and a response therefore not being applicable. The Mean SDS score were calculated over the three item scores. All three item scores were needed to be available with the exception of the work/school item score when this item was not applicable. | Week 11 and Week 14 | 
| Change From Baseline (End of Phase A [Week 8]) in SDS Item Scores for the Efficacy Sample Set | The SDS is a self-rated instrument used to measure the effect of the patient's symptoms on work/school, social life, and family/home responsibilities. For each of the three items, scores range from 0 through 10. The number most representative of how much each area was disrupted by symptoms is marked along the line from 0 = not at all, to 10 = extremely. For the work/school item, no response was to be entered if the patient did not work or go to school for reasons unrelated to the disorder and a response therefore not being applicable. The Mean SDS Score will be calculated over the three item scores. All three item scores need to be available with the exception of the work/school item score when this item is not applicable. | Week 11 and Week 14 | 
| Change From Baseline (End of Phase A [Week 8]) in SDS Item Scores for the Efficacy Sample Set Per Final Protocol | The SDS is a self-rated instrument used to measure the effect of the patient's symptoms on work/school, social life, and family/home responsibilities. For each of the three items, scores range from 0 through 10. The number most representative of how much each area was disrupted by symptoms is marked along the line from 0 = not at all, to 10 = extremely. For the work/school item, no response was to be entered if the patient did not work or go to school for reasons unrelated to the disorder and a response therefore not being applicable. The Mean SDS Score will be calculated over the three item scores. All three item scores need to be available with the exception of the work/school item score when this item is not applicable. | Week 11 and Week 14 | 
| Mean Change From End of Phase A (Week 8 Visit) to Phase B by Study Week in Clinical Global Impression Severity of Illness (CGI-S) for the Efficacy Sample Set | The severity of illness for each participant was rated using the CGI-S. To perform this assessment, the study physician had to answer the following question: Considering your total clinical experience with this particular population, how mentally ill is the participant at this time? Response choices included: 0 = not assessed; 1 = normal, not at all ill; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill participants. | Weeks 8, 9, 10, 11, 12,13 and 14 | 
| Mean Change From End of Phase A (Week 8 Visit) to Phase B by Study Week in Clinical CGI-S for the Efficacy Sample Per Final Protocol | The severity of illness for each participant was rated using the CGI-S. To perform this assessment, the study physician had to answer the following question: Considering your total clinical experience with this particular population, how mentally ill is the participant at this time? Response choices included: 0 = not assessed; 1 = normal, not at all ill; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill participants. | Weeks 8, 9, 10, 11, 12, 13, and 14 | 
| Mean Change From End of Phase A (Week 8 Visit) for Every Study Week Visit in Phase B in Inventory of Depressive Symptomatology (Self-Report) IDS-SR Total Score for the Efficacy Sample Set | IDS-SR was a 30-item self-report measured to assess core diagnostic depressive symptoms and atypical and melancholic symptom features of major depressive disorders. The IDS-SR consists of 30 items, all rated on a 0 to 3 scale with 0 being the best rating and 3 being the worst rating. Besides item 9, two sub-items 9A and 9B exist, with possible scores of 1, 2 or 3 for item 9A, and 0 or 1 for item 9B. The scores for these two sub-items were not included in the calculation of the total score. The IDS-SR Total Score was the sum of ratings of 28 item scores. The possible IDSSR Total Score ranged from 0 to 84. The IDS-SR Total Score was un-evaluable if less than 23 of the 28 items were recorded. If the number of items recorded was at least 23 and at most 27, the IDS-SR Total Score was the mean of the recorded items multiplied by 28, and was then rounded off to the first decimal place. | Weeks 8, 9, 10, 11, 12, 13, and 14 | 
| Mean Change From End of Phase A (Week 8 Visit) for Every Study Week Visit in Phase B in IDS-SR Total Score for the Efficacy Sample Per Final Protocol | The IDS-SR was a 30-item self-report measured to assess core diagnostic depressive symptoms as well as atypical and melancholic symptom features of major depressive disorders. The IDS-SR consists of 30 items, all rated on a 0 to 3 scale with 0 being the best rating and 3 being the worst rating. Besides item 9, two sub-items 9A and 9B exist, with possible scores of 1, 2 or 3 for item 9A, and 0 or 1 for item 9B. The scores for these two sub-items were not included in the calculation of the total score. The IDSSR Total Score was the sum of ratings of 28 item scores. The possible IDSSR Total Score ranged from 0 to 84. The IDS-SR Total Score was un-evaluable if less than 23 of the 28 items were recorded. If the number of items recorded was at least 23 and at most 27, the IDS-SR Total Score was the mean of the recorded items multiplied by 28, and was then rounded off to the first decimal place. | Weeks 8, 9, 10, 11, 12, 13, and 14 | 
| Mean Change From End of Phase A (Week 8 Visit) to End of Phase B (Week 14 Visit) Hamilton Depression Scale 17 Item Version (HAM)-D17 Total Score for the Efficacy Sample Set | The HAM-D17 was utilized as a secondary assessment of a participants level of depression. The HAM-D (17-Item) consisted of 17 items. Eight items were rated on a 0 to 2 scale (items 4, 5, 6, 12, 13, 14, 16 and 17), while nine items (items 1, 2, 3, 7, 8, 9, 10, 11, and 15) were rated on a 0 to 4 scale (twice the weight of the other items). For all of these items, 0 was the best rating and the highest score (2 or 4) was the worst rating. The possible total scores were from 0 to 52, with higher scores indicating more severe depression. | Baseline and Week 14 | 
| Mean Change From End of Phase A (Week 8 Visit) to End of Phase B (Week 14 Visit) in HAM-D17 Total Score for the Efficacy Sample Set Per Final Protocol | The HAM-D17 was utilized as a secondary assessment of a participants level of depression. The HAM-D (17-Item) consisted of 17 items. Eight items were rated on a 0 to 2 scale (items 4, 5, 6, 12, 13, 14, 16 and 17), while nine items (items 1, 2, 3, 7, 8, 9, 10, 11, and 15) were rated on a 0 to 4 scale (twice the weight of the other items). For all of these items, 0 was the best rating and the highest score (2 or 4) was the worst rating. The possible total scores were from 0 to 52, with higher score indicating more severe depression. | Baseline and Week 14 | 
| Mean Change From End of Phase A (Week 8 Visit) to End of Phase B (Week 14 Visit) in Hamilton Anxiety Rating Scale (HAM-A) Total Score for the Efficacy Sample Set | The HAM-A is utilized for the evaluation of anxiety symptoms. The HAM-A consists of 14 items. Each item is rated on a 0 to 4 scale. For all of these items, 0 is the best rating and 4 is the worst rating. If no item scores are missing, then the HAM-A total score is the sum of all 14 item scores. The possible total scores are from 0 to 56, with higher scores indicating worse anxiety symptoms. | Baseline and Week 14 | 
| Mean Change From End of Phase A (Week 8 Visit) to End of Phase B (Week 14 Visit) in HAM-A Total for the Efficacy Sample Per Final Protocol | The HAM-A is utilized for the evaluation of anxiety symptoms. The HAM-A consists of 14 items. Each item is rated on a 0 to 4 scale. For all of these items, 0 is the best rating and 4 is the worst rating. If no item scores are missing, then the HAM-A total score is the sum of all 14 item scores. The possible total scores are from 0 to 56, with higher score indicating worse anxiety symptoms. | Baseline and Week 14 | 
| Mean CGI-I Score at Each Trial Week Visit in Phase B for the Efficacy Sample Set | The efficacy of study medication was rated for each participant using the CGI-I. The study physician would rate the participant's total improvement whether or not it is due entirely to drug treatment. Response choices included: 0 = not assessed, 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse. | Week 8 to Week 14 | 
| Mean CGI-I Score at Each Trial Week Visit in Phase B for the Efficacy Sample Per Final Protocol | The efficacy of study medication was rated for each participant using the CGI-I. The study physician would rate the participant's total improvement whether or not it is due entirely to drug treatment. Response choices included: 0 = not assessed, 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse. | Weeks 8, 9, 10, 11, 12, 13, and 14 | 
| Percentage of Participants With a MADRS Response During Phase B Relative to the End of Phase A (Week 8 Visit) for the Efficacy Sample Set | MADRS response was defined as >=50 percent reduction in MADRS Total Score from end of Phase A (Week 8). The MADRS was utilized as an efficacy assessment of a participant's level of depression. The MADRS consisted of 10 items, all rated on a 0 to 6 scale with 0 being the best rating and 6 being the worst rating. The MADRS total score were to be unevaluable if less than 8 of the 10 items were recorded. If 8 or 9 of the 10 items were recorded, the MADRS total score was the mean of the recorded items multiplied by 10 and then rounded of to the first decimal place. The MADRS Total Score is the sum of ratings for all 10 items. The possible total scores are from 0 to 60, with higher values indicating worse outcome. | Weeks 8, 9, 10, 11, 12, 13, and 14 | 
| Percentage of Participants With a MADRS Response During Phase B Relative to the End of Phase A (Week 8 Visit) for the Efficacy Sample Per Final Protocol | MADRS response was defined as >=50 percent reduction in MADRS Total Score from end of Phase A (Week 8). The MADRS was utilized as an efficacy assessment of a participant's level of depression. The MADRS consisted of 10 items, all rated on a 0 to 6 scale with 0 being the best rating and 6 being the worst rating. The MADRS total score were to be unevaluable if less than 8 of the 10 items were recorded. If 8 or 9 of the 10 items were recorded, the MADRS total score was the mean of the recorded items multiplied by 10 and then rounded of to the first decimal place. The MADRS Total Score is the sum of ratings for all 10 items. The possible total scores are from 0 to 60, with higher values indicating worse outcome. | Weeks 8, 9, 10, 11, 12, 13, and 14 | 
| Percentage of Participants With a MADRS Remission During Phase B Relative to the End of Phase A (Week 8) for the Efficacy Sample Set | MADRS remission was defined as a < or equal to 10 and > or equal to 50% reduction in MADRS Total Score from end of Phase A (Week 8). The MADRS was utilized as an efficacy assessment of a participant's level of depression. The MADRS consisted of 10 items, all rated on a 0 to 6 scale with 0 being the best rating and 6 being the worst rating. The MADRS total score were to be unevaluable if less than 8 of the 10 items were recorded. If 8 or 9 of the 10 items were recorded, the MADRS total score was the mean of the recorded items multiplied by 10 and then rounded of to the first decimal place. The MADRS Total Score is the sum of ratings for all 10 items. The possible total scores are from 0 to 60, with higher values indicating worse outcome. | Weeks 8, 9, 10, 11, 12, 13 and 14 | 
| Percentage of Participants With a MADRS Remission During Phase B Relative to the End of Phase A (Week 8) for the Efficacy Sample Per Final Protocol | MADRS remission was defined as a < or equal to 10 and > or equal to 50% reduction in MADRS Total Score from end of Phase A (Week 8). The MADRS was utilized as an efficacy assessment of a participant's level of depression. The MADRS consisted of 10 items, all rated on a 0 to 6 scale with 0 being the best rating and 6 being the worst rating. The MADRS total score were to be unevaluable if less than 8 of the 10 items were recorded. If 8 or 9 of the 10 items were recorded, the MADRS total score was the mean of the recorded items multiplied by 10 and then rounded of to the first decimal place. The MADRS Total Score is the sum of ratings for all 10 items. The possible total scores are from 0 to 60, with higher values indicating worse outcome. | Weeks 8, 9, 10, 11, 12, 13 and 14 | 
| Percentage of Participants With a CGI-I Response During Phase B Relative to the End of Phase A (Week 8 Visit) for the Efficacy Sample Set | A CGI-I response was defined as a CGI-I score of 1 (very much improved) or 2 (much improved). | Weeks 8, 9, 10, 11, 12, 13 and 14 | 
| Percentage of Participants With a CGI-I Response During Phase B Relative to the End of Phase A (Week 8 Visit) for the Efficacy Sample Per Final Protocol | A CGI-I response was defined as a CGI-I score of 1 (very much improved) or 2 (much improved). | Weeks, 8, 9, 10, 11, 12, 13, and 14 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
OPC-34712, brexpiprazole, Major Depressive Disorder, Adjunctive Treatment