Major Depressive Disorder
Conditions
Brief summary
To examine the efficacy and safety of aripiprazole versus placebo as an adjunctive therapy co-administered with either an selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI) in patients with major depressive disorder.
Interventions
DRUGAripiprazole (Fixed dose)
administered orally once daily, 3 mg daily, 6 weeks
DRUGAripiprazole (Titrated dose)
administered orally once daily, 3 to 15 mg daily, 6 weeks
DRUGPlacebo
administered orally once daily, 6 weeks
Sponsors
Otsuka Pharmaceutical Co., Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
20 Years to 74 Years
Healthy volunteers
No
Inclusion criteria
1. Patients who are either inpatients or outpatients 2. Patients who have the ability to understand and to provide informed consent to the examination, observation, and evaluation processes specified in this protocol, and have signed the informed consent form based on a full understanding of the trial 3. Patients diagnosed as having either 296.2x Major Depressive Disorder, Single Episode or 296.3x Major Depressive Disorder, Recurrent according to DSM-IV-TR, and for whom the current episode of major depressive disorder has been ongoing for more than 8 weeks 4. Patients with a HAM-D17 total score of 18 or more
Exclusion criteria
1. Female patients of child bearing potential who wish to become pregnant during the treatment period, or within 4 weeks after study completion/discontinuation 2. Female patients who are pregnant, possibly pregnant, or breast feeding 3. Patients judged to be unable to tolerate any type of antidpressant treatment (including drugs not being used in the current episode of major depressive disorder), based on treatment history to date 4. Patients who have previously received electro-convulsive therapy 5. Patients who have participated in clinical studies on medical devices or other drugs within the past month 6. Patients at risk of having serious adverse events or developing symptoms that could interfere with safety and efficacy evaluations (such as symptoms of fibromyalgia syndrome overlapping with symptoms of depression), based on previous medical history 7. Patients with a history or a complication of diabetes 8. Patients with thyroid disease (excluding patients who are stabilized on drug therapy for at least 3 months) 9. Patients with a history of serotonin syndrome or psychotropic neuroleptic malignant syndrome 10. Patients with a history of seizure disorder (epilepsy etc.)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score | Baseline (the end of the SSRI/SNRI treatment period), at completion of administration | The change in MADRS total score from the end of the SSRI/SNRI treatment period to Week 6 of the placebo-controlled, double-blind treatment period by covariance analysis, and compared the aripiprazole variable dose group with the placebo group as well as the aripiprazole fixed dose group with the placebo group. Higher MADRS score indicates more severe depression, and each item yields a score of 0 to 6. The overall score ranges from 0 to 60. The questionnaire includes questions on the following symptoms 1\. Apparent sadness 2. Reported sadness 3. Inner tension 4. Reduced sleep 5. Reduced appetite 6. Concentration difficulties 7. Lassitude 8. Inability to feel 9. Pessimistic thoughts 10. Suicidal thoughts |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| MADRS Response Rate | Baseline (the end of the SSRI/SNRI treatment period), at completion of administration | The percentage of subjects with a decrease in MADRS total score of 50% or more, from the end of the SSRI/SNRI treatment period to the end of the placebo-controlled, double-blind treatment period (or withdrawal). |
| Mean Change in Sheehan Disability Scale (SDISS) | Baseline (the end of the SSRI/SNRI treatment period), at completion of administration | The endpoint evaluated the change in SDISS from the end of the SSRI/SNRI treatment period to Week 6 of the placebo-controlled, double-blind treatment period. The patient rates the extent to which his or her 1) work, 2) social life or leisure activities, and 3) home life or family responsibilities are impaired by his or her symptoms on a 10-point visual analog scale. The three items may be summed into a single dimensional measure of global functional impairment that ranges from 0 (unimpaired) to 30 (highly impaired). |
Countries
Japan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Variable Dose Group of Aripiprazole Aripiprazole 3\
15 mg were administered orally once daily. During the first week, 3 mg was administered once daily. Thereafter, each week, a dose increase of 3 mg per day was carried out | 194 |
| Fixed Dose Group of Aripiprazole Aripiprazole 3 mg were administered orally once daily | 197 |
| Placebo Group Placebo were administered orally once daily | 195 |
| Total | 586 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 7 | 8 | 2 |
| Overall Study | Change of residence or other commitments | 2 | 2 | 3 |
| Overall Study | Diabetic glucose level or HbA1C>=6.5% | 0 | 1 | 1 |
| Overall Study | Lack of Efficacy | 0 | 0 | 1 |
| Overall Study | Physician Decision | 0 | 1 | 1 |
| Overall Study | Protocol Violation | 4 | 1 | 1 |
| Overall Study | Withdrawal by Subject | 4 | 4 | 3 |
Baseline characteristics
| Characteristic | Variable Dose Group of Aripiprazole | Total | Placebo Group | Fixed Dose Group of Aripiprazole |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 194 Participants | 586 Participants | 195 Participants | 197 Participants |
| Age, Continuous | 38.1 years STANDARD_DEVIATION 9.6 | 38.7 years STANDARD_DEVIATION 9.3 | 38.7 years STANDARD_DEVIATION 9.2 | 39.2 years STANDARD_DEVIATION 9.1 |
| Region of Enrollment Japan | 194 participants | 586 participants | 195 participants | 197 participants |
| Sex: Female, Male Female | 93 Participants | 246 Participants | 80 Participants | 73 Participants |
| Sex: Female, Male Male | 101 Participants | 340 Participants | 115 Participants | 124 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 140 / 194 | 122 / 197 | 92 / 195 |
| serious Total, serious adverse events | 3 / 194 | 2 / 197 | 2 / 195 |
Outcome results
Primary
Mean Change in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score
The change in MADRS total score from the end of the SSRI/SNRI treatment period to Week 6 of the placebo-controlled, double-blind treatment period by covariance analysis, and compared the aripiprazole variable dose group with the placebo group as well as the aripiprazole fixed dose group with the placebo group. Higher MADRS score indicates more severe depression, and each item yields a score of 0 to 6. The overall score ranges from 0 to 60. The questionnaire includes questions on the following symptoms 1\. Apparent sadness 2. Reported sadness 3. Inner tension 4. Reduced sleep 5. Reduced appetite 6. Concentration difficulties 7. Lassitude 8. Inability to feel 9. Pessimistic thoughts 10. Suicidal thoughts
Time frame: Baseline (the end of the SSRI/SNRI treatment period), at completion of administration
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Variable Dose Group of Aripiprazole | Mean Change in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score | -9.6 Rating score | Standard Error 0.6 |
| Fixed Dose Group of Aripiprazole | Mean Change in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score | -10.5 Rating score | Standard Error 0.6 |
| Placebo Group | Mean Change in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score | -7.4 Rating score | Standard Error 0.6 |
p-value: 0.00695% CI: [-3.7, -0.6]ANCOVA
p-value: <0.00195% CI: [-4.6, -1.5]ANCOVA
Secondary
MADRS Response Rate
The percentage of subjects with a decrease in MADRS total score of 50% or more, from the end of the SSRI/SNRI treatment period to the end of the placebo-controlled, double-blind treatment period (or withdrawal).
Time frame: Baseline (the end of the SSRI/SNRI treatment period), at completion of administration
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Variable Dose Group of Aripiprazole | MADRS Response Rate | 39.2 percentage of subjects |
| Fixed Dose Group of Aripiprazole | MADRS Response Rate | 42.1 percentage of subjects |
| Placebo Group | MADRS Response Rate | 28.2 percentage of subjects |
Secondary
Mean Change in Sheehan Disability Scale (SDISS)
The endpoint evaluated the change in SDISS from the end of the SSRI/SNRI treatment period to Week 6 of the placebo-controlled, double-blind treatment period. The patient rates the extent to which his or her 1) work, 2) social life or leisure activities, and 3) home life or family responsibilities are impaired by his or her symptoms on a 10-point visual analog scale. The three items may be summed into a single dimensional measure of global functional impairment that ranges from 0 (unimpaired) to 30 (highly impaired).
Time frame: Baseline (the end of the SSRI/SNRI treatment period), at completion of administration
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Variable Dose Group of Aripiprazole | Mean Change in Sheehan Disability Scale (SDISS) | -1.03 Rating score | Standard Error 0.11 |
| Fixed Dose Group of Aripiprazole | Mean Change in Sheehan Disability Scale (SDISS) | -0.96 Rating score | Standard Error 0.11 |
| Placebo Group | Mean Change in Sheehan Disability Scale (SDISS) | -0.46 Rating score | Standard Error 0.11 |