Major Depressive Disorder (MDD)
Conditions
Keywords
Major Depressive Disorder, MDD, Depression
Brief summary
This will be a multicenter, randomized, double-blind study designed to assess the efficacy, safety and tolerability of an oral Aripiprazole/Escitalopram combination therapy in participants with MDD who have demonstrated an incomplete response to a prospective trial of Escitalopram, and report a treatment history for the current MDD episode of an inadequate response to at least one and no more than three adequate trials of an approved antidepressant other than Escitalopram. An inadequate response is defined as less than a 50% reduction in depressive symptom severity as assessed by the participant's self-report on the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (ATRQ) and evaluated by the investigator as part of the participant's medical and psychiatric history. An adequate trial is defined as an antidepressant treatment for at least 6 weeks duration (or at least 3 weeks for combination treatments) at an approved dose as specified in the ATRQ.
Detailed description
The study will be organized as follows: * Screening Phase * Single-blind Prospective Treatment Phase * Single-blind Continuation Phase (Responder) or Double-blind Randomization Phase (non-Responder) * 30 day Post Treatment Follow-up Assigned Interventions: * Escitalopram monotherapy * Aripiprazole/Escitalopram combination therapy * Aripiprazole monotherapy
Interventions
DRUGEscitalopram
Escitalopram capsule administered orally, once daily without regard to meals.
DRUGAripiprazole
Aripiprazole capsule administered orally, once daily without regard to meals.
DRUGBlinded capsule
Blinded capsule administered orally, once daily.
Sponsors
Otsuka Pharmaceutical Development & Commercialization, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Participants with a current diagnosis of a major depressive episode. The current depressive episode must be ≥8 weeks in duration * Participants willing to discontinue all prohibited psychotropic medication starting from the time of signing the informed consent and during the study period * Participants with a Hamilton Depression Rating Scale (HAM-D17) Total Score ≥18 at the Baseline Visit for the Prospective Treatment Phase
Exclusion criteria
* Lack of prior treatment with an antidepressant during the current depressive episode * Participants who report treatment with adjunctive or monotherapy antipsychotic treatment during the current depressive episode * Participants experiencing hallucinations, delusions or any psychotic symptomatology in the current depressive episode * Participants with epilepsy or significant history of seizure disorders * Participants with a clinically significant current diagnosis of borderline, antisocial, paranoid, schizoid, schizotypal or histrionic personality disorder * Participants who have received electroconvulsive therapy (ECT) in the last 10 years
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase C: Mean Change From End of Phase B (Week 8) in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score to End of Phase C (Week 14) | Week 8 to Week 14 | The MADRS assessed severity of depressive symptoms. It ranges from a minimum of 0 to a maximum of 60 (higher scores indicating a greater severity of depressive symptoms). Participants are rated on 10 items (feelings of sadness, lassitude, pessimism, inner tension, suicidality, reduced sleep or appetite, difficulty concentrating, and a lack of interest) each on a 7-point scale from 0 (no symptoms) to 6 (symptoms of maximum severity). A negative change from Week 8 indicates improvement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase C: Mean Clinical Global Impression - Improvement (CGI-I) Scale Score at the End of Phase C (Week 14) | Week 14 | CGI-I is a 7-point clinician-rated scale ranging from 1 to 7, rated as 1, very much improved; 2, much improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; or 7, very much worse. A higher score indicates greater impairment. |
| Phase C: Mean Change From End of Phase B (Week 8) in the Sheehan Disability Scale (SDS) Mean Score to End of Phase C (Week 14) | Week 8 to Week 14 | SDS is a 3-item clinician-rated questionnaire used to evaluate impairments in the domains of work, social life/leisure, and family life/home responsibility. The participant is asked to rate the degree to which their functioning is impaired on an 11-point scale, ranging from 0 (not at all) to 10 (extremely). The scores for the 3 domains are summed into a total score that ranges from 0 (unimpaired) to 30 (highly impaired). A higher score indicates greater impairment. A negative change from Week 8 indicates improvement. |
Countries
Estonia, Finland, Germany, India, Italy, Mexico, South Korea, Taiwan, United States
Participant flow
Recruitment details
Participants took part in the study at 69 investigative sites in Estonia, Finland, Germany, India, Italy, Mexico, South Korea, Taiwan, Ukraine, and the United States from 13 July 2010 to 20 September 2011.
Pre-assignment details
A total of 211 participants were enrolled in Phase B (Single-blind Prospective Treatment Phase) to receive escitalopram monotherapy(10 or 20mg/day),of which 45 responders continued to Phase B+(Single-blind Phase B Responders),received escitalopram monotherapy(10 or 20mg/day),84 non-responders were randomized in 1:1:1 ratio to Phase C(Double-blind Randomization Phase),received aripiprazole/escitalopram combination therapy or escitalopram or aripiprazole monotherapy.
Participants by arm
| Arm | Count |
|---|---|
| Phase B: Single-blind Prospective Treatment Phase Participants received initial dose of escitalopram 10 milligram (mg) blinded capsule (over-encapsulated tablet), orally, once daily, increased to 20 mg/day at the end of Week 1 based upon tolerability profile, for up to maximum of Week 8. No dose reductions were allowed after Week 4 and no dose increments were allowed after Week 3. Participants with incomplete response at the end of the Phase B (Week 8) entered Phase C and the rest of the participants continued to Phase B+. | 211 |
| Total | 211 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Phase B+ and Phase C (Weeks 9 to 14) | Adverse Event | 0 | 0 | 1 | 0 | 2 |
| Phase B+ and Phase C (Weeks 9 to 14) | Investigator Withdrew Subject | 0 | 0 | 0 | 1 | 0 |
| Phase B+ and Phase C (Weeks 9 to 14) | Lost to Follow-up | 0 | 0 | 1 | 0 | 1 |
| Phase B+ and Phase C (Weeks 9 to 14) | Protocol Deviation | 0 | 0 | 0 | 0 | 1 |
| Phase B+ and Phase C (Weeks 9 to 14) | Sponsor Discontinued Study | 0 | 7 | 4 | 5 | 5 |
| Phase B+ and Phase C (Weeks 9 to 14) | Subject Met Withdrawal Criteria | 0 | 0 | 0 | 0 | 1 |
| Phase B+ and Phase C (Weeks 9 to 14) | Subject Withdrew Consent | 0 | 0 | 0 | 2 | 0 |
| Phase B (Day 1 to Week 8) | Adverse Event | 5 | 0 | 0 | 0 | 0 |
| Phase B (Day 1 to Week 8) | Investigator Withdrew Subject | 1 | 0 | 0 | 0 | 0 |
| Phase B (Day 1 to Week 8) | Lack of Efficacy as Determined by the Investigator | 1 | 0 | 0 | 0 | 0 |
| Phase B (Day 1 to Week 8) | Lost to Follow-up | 6 | 0 | 0 | 0 | 0 |
| Phase B (Day 1 to Week 8) | Protocol Deviation | 2 | 0 | 0 | 0 | 0 |
| Phase B (Day 1 to Week 8) | Sponsor Discontinued Study | 60 | 0 | 0 | 0 | 0 |
| Phase B (Day 1 to Week 8) | Subject Withdrew Consent | 7 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Phase B: Single-blind Prospective Treatment Phase |
|---|---|
| Age, Continuous | 44.4 years STANDARD_DEVIATION 11.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 42 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 168 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 16 Participants |
| Race (NIH/OMB) Asian | 36 Participants |
| Race (NIH/OMB) Black or African American | 23 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 6 Participants |
| Race (NIH/OMB) White | 130 Participants |
| Sex: Female, Male Female | 140 Participants |
| Sex: Female, Male Male | 71 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 211 | 0 / 45 | 0 / 28 | 0 / 27 | 0 / 28 |
| other Total, other adverse events | 82 / 211 | 3 / 45 | 18 / 28 | 11 / 27 | 17 / 28 |
| serious Total, serious adverse events | 2 / 211 | 0 / 45 | 0 / 28 | 1 / 27 | 1 / 28 |
Outcome results
Primary
Phase C: Mean Change From End of Phase B (Week 8) in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score to End of Phase C (Week 14)
The MADRS assessed severity of depressive symptoms. It ranges from a minimum of 0 to a maximum of 60 (higher scores indicating a greater severity of depressive symptoms). Participants are rated on 10 items (feelings of sadness, lassitude, pessimism, inner tension, suicidality, reduced sleep or appetite, difficulty concentrating, and a lack of interest) each on a 7-point scale from 0 (no symptoms) to 6 (symptoms of maximum severity). A negative change from Week 8 indicates improvement.
Time frame: Week 8 to Week 14
Population: ITT Sample included all participants in the Randomized Sample who received at least one dose of double-blind study medication and had at least one post-randomization efficacy evaluation.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Phase C: Aripiprazole/Escitalopram Combination | Phase C: Mean Change From End of Phase B (Week 8) in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score to End of Phase C (Week 14) | -8.0 score on a scale | Standard Error 1.5 |
| Phase C: Escitalopram Monotherapy | Phase C: Mean Change From End of Phase B (Week 8) in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score to End of Phase C (Week 14) | -7.0 score on a scale | Standard Error 1.5 |
| Phase C: Aripiprazole Monotherapy | Phase C: Mean Change From End of Phase B (Week 8) in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score to End of Phase C (Week 14) | -4.3 score on a scale | Standard Error 1.5 |
Comparison: The statistical analyses was performed by fitting an analysis of covariance (ANCOVA) model to the change from baseline data (Week 8 Visit) for the MADRS Total Score at the Week 14 visit (LOCF). The model included baseline MADRS Total Score as a covariate and treatment as the main effect.p-value: =0.64495% CI: [-5.2, 3.3]ANCOVA
Comparison: The statistical analyses will be performed by fitting an ANCOVA model to the change from baseline data (Week 8 Visit) for the MADRS Total Score at the Week 14 visit (LOCF). The model will include baseline MADRS Total Score as a covariate and treatment as the main effect.p-value: =0.0895% CI: [-7.8, 0.4]ANCOVA
Secondary
Phase C: Mean Change From End of Phase B (Week 8) in the Sheehan Disability Scale (SDS) Mean Score to End of Phase C (Week 14)
SDS is a 3-item clinician-rated questionnaire used to evaluate impairments in the domains of work, social life/leisure, and family life/home responsibility. The participant is asked to rate the degree to which their functioning is impaired on an 11-point scale, ranging from 0 (not at all) to 10 (extremely). The scores for the 3 domains are summed into a total score that ranges from 0 (unimpaired) to 30 (highly impaired). A higher score indicates greater impairment. A negative change from Week 8 indicates improvement.
Time frame: Week 8 to Week 14
Population: ITT Sample included all participants in the Randomized Sample who received at least one dose of double-blind study medication and had at least one post-randomization efficacy evaluation. Overall number of participants analyzed are the participants with evaluable data for analyses.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Phase C: Aripiprazole/Escitalopram Combination | Phase C: Mean Change From End of Phase B (Week 8) in the Sheehan Disability Scale (SDS) Mean Score to End of Phase C (Week 14) | -1.2 score on a scale | Standard Error 0.4 |
| Phase C: Escitalopram Monotherapy | Phase C: Mean Change From End of Phase B (Week 8) in the Sheehan Disability Scale (SDS) Mean Score to End of Phase C (Week 14) | -1.2 score on a scale | Standard Error 0.4 |
| Phase C: Aripiprazole Monotherapy | Phase C: Mean Change From End of Phase B (Week 8) in the Sheehan Disability Scale (SDS) Mean Score to End of Phase C (Week 14) | -0.2 score on a scale | Standard Error 0.4 |
p-value: =0.99595% CI: [-1.2, 1.2]ANCOVA
p-value: =0.11895% CI: [-2.1, 0.2]ANCOVA
Secondary
Phase C: Mean Clinical Global Impression - Improvement (CGI-I) Scale Score at the End of Phase C (Week 14)
CGI-I is a 7-point clinician-rated scale ranging from 1 to 7, rated as 1, very much improved; 2, much improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; or 7, very much worse. A higher score indicates greater impairment.
Time frame: Week 14
Population: ITT Sample included all participants in the Randomized Sample who received at least one dose of double-blind study medication and had at least one post-randomization efficacy evaluation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase C: Aripiprazole/Escitalopram Combination | Phase C: Mean Clinical Global Impression - Improvement (CGI-I) Scale Score at the End of Phase C (Week 14) | 2.6 score on a scale | Standard Error 0.2 |
| Phase C: Escitalopram Monotherapy | Phase C: Mean Clinical Global Impression - Improvement (CGI-I) Scale Score at the End of Phase C (Week 14) | 2.9 score on a scale | Standard Error 0.2 |
| Phase C: Aripiprazole Monotherapy | Phase C: Mean Clinical Global Impression - Improvement (CGI-I) Scale Score at the End of Phase C (Week 14) | 3.0 score on a scale | Standard Error 0.1 |
p-value: =0.36695% CI: [-0.8, 0.3]Cochran-Mantel-Haenszel
p-value: =0.13895% CI: [-0.9, 0.1]Cochran-Mantel-Haenszel