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.
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 17-item Hamilton Depression Rating Scale (HAM-D17) Total Score ≥18 at the Baseline 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 (or decrease) from baseline indicates a reduction (or improvement) in symptoms. Last observation carried forward (LOCF) method was used for analyses. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase C: Clinical Global Impression - Improvement Scale (CGI-I) 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. LOCF method was used for analyses. |
| 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). Scores of 0 to 3 indicate mild functional impairment, 4 to 6 indicate moderate functional impairment, and 7 to 9 indicate marked functional impairment. 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 score indicates improvement. LOCF method was used for analyses. |
Countries
Canada, Croatia, France, Hungary, India, Malaysia, Poland, South Africa, Spain, Sweden, United States
Participant flow
Recruitment details
Participants took part in the study at 70 investigative sites in the United States, Canada, France, India, Malaysia, Poland, and South Africa from 4 October 2010 to 1 September 2011.
Pre-assignment details
A total of 137 participants were enrolled in Phase B (Single-blind Prospective Treatment Phase) to receive escitalopram monotherapy(10 or 20mg/day),of which 26 responders continued to Phase B+(Single-blind Phase B Responders),received escitalopram monotherapy(10 or 20mg/day).45 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 Escitalopram 10 mg capsule, orally, once daily increased to 20 mg/day at the Week 1 (end of Week 1) based upon tolerability profile, for 8 weeks. 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+. | 137 |
| Total | 137 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Phase B + and Phase C (Weeks 9 to 14) | Adverse Event | 0 | 0 | 2 | 0 | 0 |
| Phase B + and Phase C (Weeks 9 to 14) | Investigator Withdrew Subjects | 0 | 0 | 0 | 1 | 0 |
| Phase B + and Phase C (Weeks 9 to 14) | Lost to Follow-up | 0 | 0 | 0 | 1 | 0 |
| Phase B + and Phase C (Weeks 9 to 14) | Sponsor Discontinued Study | 0 | 7 | 3 | 2 | 3 |
| Phase B + and Phase C (Weeks 9 to 14) | Subjects Withdrew Consent | 0 | 0 | 0 | 0 | 1 |
| Phase B (Weeks 0 to 8) | Adverse Event | 1 | 0 | 0 | 0 | 0 |
| Phase B (Weeks 0 to 8) | Investigator Withdrew Subject | 1 | 0 | 0 | 0 | 0 |
| Phase B (Weeks 0 to 8) | Lack of Efficacy as Determined by the Investigator | 1 | 0 | 0 | 0 | 0 |
| Phase B (Weeks 0 to 8) | Lost to Follow-up | 3 | 0 | 0 | 0 | 0 |
| Phase B (Weeks 0 to 8) | Protocol Deviation | 1 | 0 | 0 | 0 | 0 |
| Phase B (Weeks 0 to 8) | Sponsor Discontinued Study | 58 | 0 | 0 | 0 | 0 |
| Phase B (Weeks 0 to 8) | Subject Withdrew Consent | 1 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Phase B: Single-blind Prospective Treatment Phase |
|---|---|
| Age, Continuous | 43.3 Years STANDARD_DEVIATION 12.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 129 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 10 Participants |
| Race (NIH/OMB) Black or African American | 26 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 | 11 Participants |
| Race (NIH/OMB) White | 90 Participants |
| Sex: Female, Male Female | 90 Participants |
| Sex: Female, Male Male | 47 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 / 137 | 0 / 26 | 0 / 16 | 0 / 14 | 0 / 15 |
| other Total, other adverse events | 65 / 137 | 4 / 26 | 12 / 16 | 11 / 14 | 13 / 15 |
| serious Total, serious adverse events | 0 / 137 | 0 / 26 | 0 / 16 | 0 / 14 | 0 / 15 |
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 (or decrease) from baseline indicates a reduction (or improvement) in symptoms. Last observation carried forward (LOCF) method was used for analyses.
Time frame: Week 8 to Week 14
Population: Intent-to-treat (ITT) Sample included all participants in the Randomized Sample who received at least one dose of double blind trial medication and had at least one post-randomization efficacy evaluation in Phase C.
| 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) | -9.0 score on a scale | Standard Error 2.1 |
| 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) | -3.6 score on a scale | Standard Error 2.2 |
| 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) | -3.8 score on a scale | Standard Error 2.1 |
p-value: =0.07995% CI: [-11.5, 0.7]ANCOVA
p-value: =0.08595% CI: [-11.2, 0.7]ANCOVA
Secondary
Phase C: Clinical Global Impression - Improvement Scale (CGI-I) Score at the End of Phase C
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. LOCF method was used for analyses.
Time frame: Week 14
Population: ITT Sample included all participants in the Randomized Sample who received at least one dose of double blind trial medication and had at least one post-randomization efficacy evaluation in Phase C.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase C: Aripiprazole/Escitalopram Combination | Phase C: Clinical Global Impression - Improvement Scale (CGI-I) Score at the End of Phase C | 2.5 score on a scale | Standard Error 0.2 |
| Phase C: Escitalopram Monotherapy | Phase C: Clinical Global Impression - Improvement Scale (CGI-I) Score at the End of Phase C | 3.0 score on a scale | Standard Error 0.2 |
| Phase C: Aripiprazole Monotherapy | Phase C: Clinical Global Impression - Improvement Scale (CGI-I) Score at the End of Phase C | 2.9 score on a scale | Standard Error 0.2 |
p-value: =0.14895% CI: [-1.1, 0.1]Cochran-Mantel-Haenszel
p-value: =0.24295% CI: [-1, 0.3]Cochran-Mantel-Haenszel
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). Scores of 0 to 3 indicate mild functional impairment, 4 to 6 indicate moderate functional impairment, and 7 to 9 indicate marked functional impairment. 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 score indicates improvement. LOCF method was used for analyses.
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 trial medication and had at least one post-randomization efficacy evaluation in Phase C. Overall number of participants analyzed are participants with data available 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) | -1.6 score on a scale | Standard Error 0.7 |
| 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) | -1.8 score on a scale | Standard Error 0.7 |
| 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) | -0.6 score on a scale | Standard Error 0.7 |
p-value: =0.9195% CI: [-1.8, 2.1]ANCOVA
p-value: =0.29195% CI: [-3, 0.9]ANCOVA