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Trial record 30 of 31 for:    Developmental Disabilities | ( Map: Alabama, United States )

Study of the Safety and Efficacy of Fixed-dose Brexpiprazole (OPC-34712) as Adjunctive Therapy in the Treatment of Adults With Major Depressive Disorder With and Without Anxious Distress

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ClinicalTrials.gov Identifier: NCT02196506
Recruitment Status : Completed
First Posted : July 22, 2014
Results First Posted : August 21, 2018
Last Update Posted : August 21, 2018
Sponsor:
Collaborator:
H. Lundbeck A/S
Information provided by (Responsible Party):
Otsuka Pharmaceutical Development & Commercialization, Inc.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Conditions Depressive Disorder
Depression
Depressive Disorder, Major
Mood Disorders
Mental Disorders
Interventions Drug: Placebo + ADT
Drug: Brexpiprazole +ADT
Enrollment 837
Recruitment Details 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+
Pre-assignment Details 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.
Arm/Group Title Phase A: All ADT (Antidepressant Therapy) Phase B: Brexpiprazole + ADT Phase B: Placebo + ADT Phase A +: ALL ADT
Hide Arm/Group Description 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.” Participants received brexpiprazole 2 mg and ADT orally once daily for 6 weeks. Participants received matching placebo and ADT orally once daily for 6 weeks. 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.
Period Title: Phase A
Started 837 0 0 0
Completed 716 0 0 0
Not Completed 121 0 0 0
Reason Not Completed
Participant Met Withdrawal Criteria             34             0             0             0
Withdrawal by Subject             34             0             0             0
Adverse Event             22             0             0             0
Lost to Follow-up             9             0             0             0
Protocol deviation             12             0             0             0
Participant withdrawn by investigator             10             0             0             0
Period Title: Phase B
Started 0 192 202 0
Completed 0 177 196 0
Not Completed 0 15 6 0
Reason Not Completed
Participant Met Withdrawal Criteria             0             0             1             0
Lack of Efficacy             0             1             2             0
Withdrawal by Participant             0             8             1             0
Adverse Event             0             4             1             0
Lost to Follow-up             0             2             1             0
Period Title: Phase A+
Started 0 0 0 322
Completed 0 0 0 308
Not Completed 0 0 0 14
Reason Not Completed
Participant Met Withdrawal Criteria             0             0             0             1
Withdrawal by Participant             0             0             0             5
Adverse Event             0             0             0             1
Lost to Follow-up             0             0             0             6
Participant withdrawn by investigator             0             0             0             1
Arm/Group Title Brexpiprazole + ADT Placebo + ADT Total
Hide Arm/Group Description

Phase B: Brexpiprazole +Antidepressant therapy (ADT):

Participants received brexpiprazole 2mg 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

Total of all reporting groups
Overall Number of Baseline Participants 192 202 394
Hide Baseline Analysis Population Description
Baseline measures are based on the participants from the Double-blind Randomization Phase
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 192 participants 202 participants 394 participants
43.0  (12.7) 42.7  (12.5) 42.9  (12.6)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 192 participants 202 participants 394 participants
Female
147
  76.6%
144
  71.3%
291
  73.9%
Male
45
  23.4%
58
  28.7%
103
  26.1%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 192 participants 202 participants 394 participants
Hispanic or Latino 11 9 20
Not Hispanic or Latino 181 192 373
Unknown 0 1 1
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 192 participants 202 participants 394 participants
Hungary 16 16 32
United States 100 106 206
Poland 26 26 52
Slovakia 23 25 48
Germany 27 29 56
1.Primary Outcome
Title Change in the Montgomery-Asberg Depression
Hide Description 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.
Time Frame From baseline (end of Phase A [Week 8]) to week 14
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Brexpiprazole + ADT Placebo + ADT
Hide Arm/Group Description:

Phase B: Brexpiprazole +Antidepressant therapy (ADT):

Participants received brexpiprazole 2mg 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

Overall Number of Participants Analyzed 191 202
Least Squares Mean (Standard Error)
Unit of Measure: Units on a scale
-10.4  (0.63) -8.07  (0.61)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Brexpiprazole + ADT, Placebo + ADT
Comments Statistical Analysis at Week 14
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0074
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -2.30
Confidence Interval (2-Sided) 95%
-3.97 to -0.62
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Change in the Sheehan Disability Scale (SDS) From Baseline to End of Treatment
Hide Description 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.
Time Frame From baseline (end of Phase A [Week 8]) to week 14
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Brexpiprazole + ADT Placebo + ADT
Hide Arm/Group Description:

Phase B: Brexpiprazole +Antidepressant therapy (ADT):

Participants received brexpiprazole 2mg 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

Overall Number of Participants Analyzed 187 200
Least Squares Mean (Standard Error)
Unit of Measure: Units on a scale
-1.63  (0.18) -1.41  (0.17)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Brexpiprazole + ADT, Placebo + ADT
Comments Statistical Analysis at Week 14
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3331
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.22
Confidence Interval (2-Sided) 95%
-0.66 to 0.23
Estimation Comments [Not Specified]
3.Secondary Outcome
Title 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
Hide Description 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.
Time Frame From baseline (end of Phase A [Week 8]) to week 14
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Brexpiprazole + ADT Placebo + ADT
Hide Arm/Group Description:

Phase B: Brexpiprazole +Antidepressant therapy (ADT):

Participants received brexpiprazole 2mg 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

Overall Number of Participants Analyzed 161 158
Least Squares Mean (Standard Error)
Unit of Measure: Units on a scale
-11.1  (0.71) -8.87  (0.71)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Brexpiprazole + ADT, Placebo + ADT
Comments Statistical Analysis at Week 14
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0263
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -2.25
Confidence Interval (2-Sided) 95%
-4.23 to -0.27
Estimation Comments [Not Specified]
4.Secondary Outcome
Title 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).
Hide Description 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.
Time Frame From baseline (end of Phase A [Week 8]) to week 14
Hide Outcome Measure Data
Hide Analysis Population Description
Subpopulation of Anxious Distress Sample: Comprised of all participants in the Efficacy Sample who had anxious distress as specified in DSM-V.
Arm/Group Title Brexpiprazole + ADT Placebo + ADT
Hide Arm/Group Description:

Phase B: Brexpiprazole +Antidepressant therapy (ADT):

Participants received brexpiprazole 2mg 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

Overall Number of Participants Analyzed 124 124
Least Squares Mean (Standard Error)
Unit of Measure: Units on a scale
-11.8  (0.81) -8.87  (0.81)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Brexpiprazole + ADT, Placebo + ADT
Comments Statistical Analysis at Week 14
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0099
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -2.98
Confidence Interval (2-Sided) 95%
-5.24 to -0.72
Estimation Comments [Not Specified]
Time Frame 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).
Adverse Event Reporting Description 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.
 
Arm/Group Title Brexpiprazole + ADT Placebo + ADT
Hide Arm/Group Description

Phase B: Brexpiprazole +Antidepressant therapy (ADT):

Participants received brexpiprazole 2mg 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

All-Cause Mortality
Brexpiprazole + ADT Placebo + ADT
Affected / at Risk (%) Affected / at Risk (%)
Total   0/192 (0.00%)      0/202 (0.00%)    
Show Serious Adverse Events Hide Serious Adverse Events
Brexpiprazole + ADT Placebo + ADT
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   1/192 (0.52%)      0/202 (0.00%)    
Ear and labyrinth disorders     
Vertigo * 1  1/192 (0.52%)  1 0/202 (0.00%)  0
1
Term from vocabulary, MedDRA (19.0)
*
Indicates events were collected by non-systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Brexpiprazole + ADT Placebo + ADT
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   49/192 (25.52%)      35/202 (17.33%)    
Infections and infestations     
Upper Respiratory Tract Infection * 1  10/192 (5.21%)  11 10/202 (4.95%)  11
Investigations     
Weight Increased * 1  10/192 (5.21%)  10 1/202 (0.50%)  1
Nervous system disorders     
Akathisia * 1  16/192 (8.33%)  17 10/202 (4.95%)  12
Headache * 1  7/192 (3.65%)  7 15/202 (7.43%)  24
Psychiatric disorders     
Restlessness * 1  16/192 (8.33%)  16 4/202 (1.98%)  4
1
Term from vocabulary, MedDRA (19.0)
*
Indicates events were collected by non-systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
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.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Global Medical Affairs
Organization: Otsuka Pharmaceutical Development and Commercialization, Inc.
Phone: 800 562-3974
Layout table for additonal information
Responsible Party: Otsuka Pharmaceutical Development & Commercialization, Inc.
ClinicalTrials.gov Identifier: NCT02196506     History of Changes
Other Study ID Numbers: 331-13-214
First Submitted: July 18, 2014
First Posted: July 22, 2014
Results First Submitted: May 25, 2017
Results First Posted: August 21, 2018
Last Update Posted: August 21, 2018