To Assess the Safety and Tolerability of an Oral Aripiprazole/Escitalopram Combination Therapy in Participants With Major Depressive Disorder (MDD)

Study Overview
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Brief Summary
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This is a multicenter, 52-week, open-label study designed to assess the safety and tolerability of an oral aripiprazole/escitalopram combination therapy in outpatients with major depressive disorder (MDD). Enrollment into the study will be from eligible participants who have completed participation in Protocol 31-08-255 [NCT01111539], 31-08-256 [NCT01111552], or 31-08-263 [NCT01111565] (rollover participants).

Official Title
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A Multicenter, 52-week, Open-label Study to Assess the Safety and Tolerability of an Oral Aripiprazole/Escitalopram Combination Therapy in Patients With Major Depressive Disorder

Conditions
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Major Depressive Disorder (MDD)

Intervention / Treatment
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* Drug: Aripiprazole
* Drug: Escitalopram


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants who participated in Protocol 31-08-255, 31-08-256, or 31-08-263. Exclusion Criteria: Participants with a current need for involuntary commitment or who have been hospitalized ≤ 28 days of the Baseline Visit for the current major depressive episode. Participants with a diagnosis of delirium, dementia, amnestic or other cognitive disorder, schizophrenia, schizoaffective disorder, or other psychotic disorder, Bipolar I or II disorder, eating disorder (including anorexia nervosa or bulimia), obsessive compulsive disorder, panic disorder, or posttraumatic stress disorder. Participants with a diagnosis of borderline, antisocial, paranoid, schizoid, schizotypal or histrionic personality disorder. Participants experiencing hallucinations, delusions, or any psychotic symptomatology in the current depressive episode. Participants who have met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria for substance abuse in the past 6 months (prior to the Baseline Visit) and/or dependence up to and including the past 12 months (prior to the Baseline Visit), including alcohol and benzodiazepines, but excluding caffeine and nicotine. Participants with two positive drug results for cocaine should be excluded from the study. Participants with hypothyroidism or hyperthyroidism. Participants with a significant risk of committing suicide based on history, investigator's judgment, and/or evaluation based on the Columbia-Suicide Severity Rating Scale (C-SSRS). Participants who currently have clinically significant neurological, hepatic, renal, metabolic, hematological, immunological, cardiovascular, pulmonary, or gastrointestinal disorders. Participants with insulin-dependent diabetes mellitus (IDDM). Participants with epilepsy or significant history of seizure disorders, except for a single childhood febrile seizure, post-traumatic, etc.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 66 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Group composed of eligible rollover participants who completed one of the previous studies: 31-08-255 [NCT01111539], 31-08-256 [NCT01111552], or 31-08-263 [NCT01111565]
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Prior Aripiprazole/Escitalopram Combination Therapy<br>Aripiprazole capsules, orally at the daily dose of 3, 6, or 12 mg, in combination with escitalopram 10 or 20 mg orally, once daily in combination with escitalopram 10 or 20 mg (i.e., the final dose taken during the previous study), orally, once daily, for 36 weeks. Participants were titrated to the aripiprazole target dose of 12 mg/day at Week 1 if the initial 6 mg/day dose was tolerated. The dose adjustments were allowed for aripiprazole to establish the maximum tolerated dose (MTD) by Week 4. Participants who received aripiprazole/escitalopram combination therapy in the double-blind treatment period in previous studies were included in this group. | Drug: Aripiprazole<br>* Aripiprazole oral capsules<br>* Other names: OPC-14597;Drug: Escitalopram<br>* Escitalopram oral capsules<br>|
| Experimental: Prior Escitalopram<br>Aripiprazole capsules, orally at the daily dose of 3, 6, or 12 mg, in combination with escitalopram 10 or 20 mg orally, once daily in combination with escitalopram 10 or 20 mg (i.e., the final dose taken during the previous study), orally, once daily, for 36 weeks. Participants were titrated to the aripiprazole target dose of 12 mg/day at Week 1 if the initial 6 mg/day dose was tolerated. The dose adjustments were allowed for aripiprazole to establish the MTD by Week 4. Participants who received escitalopram in the double-blind treatment period in previous studies were included in this group. | Drug: Aripiprazole<br>* Aripiprazole oral capsules<br>* Other names: OPC-14597;Drug: Escitalopram<br>* Escitalopram oral capsules<br>|
| Experimental: Prior Aripiprazole<br>Aripiprazole capsules, orally at the daily dose of 3, 6, or 12 mg, in combination with escitalopram 10 or 20 mg orally, once daily in combination with escitalopram 10 or 20 mg (i.e., the final dose taken during the previous study), orally, once daily, for 36 weeks. Participants were titrated to the aripiprazole target dose of 12 mg/day at Week 1 if the initial 6 mg/day dose was tolerated. The dose adjustments were allowed for aripiprazole to establish the MTD by Week 4. Participants who received aripiprazole in the double-blind treatment period in previous studies were included in this group. | Drug: Aripiprazole<br>* Aripiprazole oral capsules<br>* Other names: OPC-14597;Drug: Escitalopram<br>* Escitalopram oral capsules<br>|
| Experimental: Prior Single-blind Escitalopram<br>Aripiprazole capsules, orally at the daily dose of 3, 6, or 12 mg, in combination with escitalopram 10 or 20 mg orally, once daily in combination with escitalopram 10 or 20 mg (i.e., the final dose taken during the previous study), orally, once daily, for 36 weeks. Participants were titrated to the aripiprazole target dose of 12 mg/day at Week 1 if the initial 6 mg/day dose was tolerated. The dose adjustments were allowed for aripiprazole to establish the MTD by Week 4. Participants who received escitalopram in the single-blind treatment period in previous studies were included in this group. | Drug: Aripiprazole<br>* Aripiprazole oral capsules<br>* Other names: OPC-14597;Drug: Escitalopram<br>* Escitalopram oral capsules<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs (STEAEs), Severe (Grade 3 or Higher) TEAEs, and Discontinuations From the Trial Due to TEAEs | An AE was defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it did not necessarily have to have a causal relationship with this treatment. An AE was considered serious if it was fatal; life-threatening; persistently or significantly disabling or incapacitating; required in-patient hospitalization or prolonged hospitalization; a congenital anomaly/birth defect; or other medically significant event that, based upon appropriate medical judgment, may have jeopardized the participant and may have required medical or surgical intervention. TEAE is defined as an adverse event that started after start of study drug treatment. The Common Terminology Criteria for Adverse Events v3.0 (CTCAE) was used to determine the severity wherein Grade 1=mild AE, Grade 2=moderate AE, Grade 3=severe AE, Grade 4=life-threatening or disabling AE, Grade 5=death related to AE. | From first dose up to 30 days post last dose (Up to approximately 40 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in Clinical Global Impression - Severity of Illness Scale (CGI-S) Score | The severity of illness was rated using a 7-point CGI-S. CGI-S scores range from 1 to 7, where 1=normal, not at all ill, 2=borderline mentally ill, 3=mildly ill, 4=moderately ill, 5=markedly ill, 6=severely ill, 7=among the most extremely ill participants. A negative mean change from Baseline indicates improvement. | Baseline; Weeks 1, 2, 4, 6, 8, 14, 20, 26, 32 and End of the study visit (Week 43 or before) | 
| Mean Change From Baseline in Patient Global Impression - Severity of Depression Scale (PGI-S) Score | The severity of illness was rated using a 7-point PGI-S. PGI-S scores range from 1 to 7, where 1=not depressed at all, 2=only occasionally depressed to a mild degree, 3=mildly depressed half the time, 4=moderately depressed most of the time, 5=moderately depressed almost all of the time, 6=severely depressed all the time, 7=extremely depressed all the time. A negative mean change from Baseline indicates improvement. | Baseline; Weeks 1, 2, 4, 6, 8, 14, 20, 26, 32 and End of the study visit (Week 43 or before) | 
| Number of Participants With Potentially Clinically Significant Vital Sign Abnormalities | Criteria for potentially clinically significant vital sign abnormalities: Heart rate [beats per minute (BPM)]: >120, increase >=15, <50, decrease >=15; systolic blood pressure [millimeter of mercury (mmHg)]: >180, increase >=20, <90, decrease >=20; diastolic blood pressure (mmHg): >105, increase >=15, <50, decrease >=15; orthostatic hypotension: >=20 mmHg decrease in systolic blood pressure and >=25 bpm increase in heart rate from supine to sitting; weight (kg) gain: increase >=7%; or weight loss: decrease >=7%. Only categories with at least 1 participant with event are reported. | Up to 40 weeks | 
| Mean Change From Baseline in Body Weight |  | Baseline; Weeks 1, 2, 4, 6, 8, 14, 20, 26, 32 and End of the study visit (Week 43 or before) | 
| Mean Change From Baseline in Body Mass Index (BMI) | BMI= weight(kg)/[height(m)^2]. | Baseline, Week 26 and End of the study visit (Week 43 or before) | 
| Number of Participants With Potentially Clinically Significant Laboratory Test Abnormalities | The laboratory values were one of the parameters to measure the safety and tolerability of individual participants. Participants with potentially clinically significant lab values in serum chemistry, hematology, urinalyses and prolactin tests that were identified based on pre-defined criteria were reported. Any value outside the normal range was flagged for the attention of the investigator who assessed whether or not a flagged value is of clinical significance. The categories with at least one participants with abnormal lab value as assessed by the Investigator are reported. | Up to 40 weeks | 
| Mean Change From Baseline in Laboratory Test Results: Prolactin | Prolactin is a hormone released by the pituitary gland. The prolactin test measures the amount of prolactin in the blood. Prolactin is responsible for the breast growth and milk production during pregnancy and after birth. The normal prolactin levels range from 20 to 25 ng/mL in males and females and 80 to 400 ng/mL in pregnant women. A negative mean change from Baseline indicates reduction in the prolactin levels. | Baseline, Weeks 8, 26, and End of the study visit (Week 43 or before) | 
| Mean Change From Baseline in Laboratory Test Results: Hemoglobin A1c (HbA1c) | The HbA1c is also known as glycosylated hemoglobin. It is the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound. The mean change in the value of HbA1c was analyzed relative to Baseline. The HbA1c of <6.0% signifies the normal blood glucose level. A negative mean change from Baseline indicates improvement. | Baseline, Week 8, and End of the study visit (Week 43 or before) | 
| Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Abnormalities | Incidence of clinically relevant abnormal ECG values were reported as change from Baseline in heart rate (Tachycardia - ≥15 beats per minute (bpm), Bradycardia ≤15 bpm; Rhythm (Sinus tachycardia ≥15 bpm increase, Sinus bradycardia decrease of ≥15 bpm from Baseline); Presence of - supraventricular premature beat; ventricular premature beat; supraventricular tachycardia; ventricular tachycardia; atrial fibrillation and flutter. Conduction - Presence of primary, secondary or tertiary atrioventricular block, left bundle-branch block, right bundle-branch block, pre-excitation syndrome, other intraventricular conduction blocked QRS ≥0.12 second increase of ≥0.02 second. Acute, subacute or old Infarction, Presence of myocardial ischemia, symmetrical T-wave inversion. Increase in QTc - QTc ≥450 msec ≥10% increase. Any clinically significant change from Baseline assessed by the Investigator are reported. Only categories with at least 1 participant with event are reported. | Up to 40 weeks | 
| Number of Participants With Potentially Clinically Significant Physical Examination Findings |  | Up to 40 weeks | 
| Mean Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) Total Score | The AIMS is a 12-item scale. The first 10 -items are rated from 0 to 4 (0=best, 4=worst). An item score of 0, depending on the item, either means: no abnormal involuntary movement (AIM), or no incapacitation due to AIM, or no awareness of AIM. An item score of 4 either means: severe AIM, or severe incapacitation due to AIM, or being aware of, and severe distress caused by AIM. Items 11 and 12, related to dental status, have dichotomous responses, 0=no and 1=yes. The AIMS Total Score is the sum of the ratings for the first seven items. The possible total scores are from 0 to 28, where a higher score indicates worst outcome. A negative mean change from Baseline indicates improvement. | Baseline; Weeks 1, 2, 4, 6, 8, 14, 20, 26, 32 and End of the study visit (Week 43 or before) | 
| Mean Change From Baseline in Simpson-Angus Scale (SAS) Total Score | The SAS is a rating scale used to measure extrapyramidal symptoms (EPS). The SAS is a 10-item scale, with each item rated from 1 to 5, with 1 being normal and 5 being the worst. The SAS total score is the sum of ratings for all 10 items, with possible total scores from 10 to 50. A negative mean change from Baseline indicates improvement. | Baseline; Weeks 1, 2, 4, 6, 8, 14, 20, 26, 32 and End of the study visit (Week 43 or before) | 
| Mean Change From Baseline in Barnes Akathisia Rating Scale (BARS) Global Clinical Assessment of Akathisia (Item 4) Score | The BARS is used to assess the presence and severity of akathisia. This scale consists of 4 items. Only item 4, the 'Global Clinical Assessment of Akathisia', was evaluated for this outcome measure. This item is rated on a 6-point scale, with 0 being best (absent) and 5 being worst (severe akathisia). A negative mean change from Baseline indicates improvement. | Baseline; Weeks 1, 2, 4, 6, 8, 14, 20, 26, 32 and End of the study visit (Week 43 or before) | 
| Percentage of Participants With Suicidal Ideation in Each Item as Measured by the Columbia-Suicide Severity Rating Scale (C-SSRS) | The suicidal ideation compared to Baseline was measured by an increase in suicidal ideation category (1-5 on the C-SSRS) during treatment from the maximum suicidal ideation category at Baseline, or any suicidal ideation during treatment if there is none at Baseline. C-SSRS is used to assess whether participant experienced suicidal ideation (Question 1: wish to be dead; Question 2: non-specific active suicidal thoughts; Question 3: active suicidal ideation with any methods (not plan) without intent to act; Question 4: active suicidal ideation with some intent to act, without specific plan; Question 5: active suicidal ideation with specific plan and intent). A negative change from Baseline indicates improvement. Only those categories and timepoints which have data are reported. | Baseline; Weeks 1, 2, 4, 6, 8, 14 and Last Visit (Week 43 or before) | 
| Mean Change From Baseline in Each Item as Measured by Massachusetts General Hospital Sexual Functioning Inventory (MGH SFI) Subscale Score | The MGH SFI is a measure of a participant's self-reported sexual functioning. The MGH SFI included 5 questions at the baseline assessment, each addressing experiences over the last month: Question a) interest in sex, Question b) ability to get sexually aroused, Question c) ability to achieve orgasm, Question d) ability to get and maintain an erection, and Question e) overall sexual satisfaction. The MGH SFI at post-baseline visits included one additional question: Question f) overall improvement since the last medication change. Each question/item is rated from 1 through 6. For questions a) through e), a score of 1 indicates 'greater than normal', and 6 'totally absent'. For question f), a score of 1 indicates 'very much improved', and 6 'much worse'. All question scores are analyzed separately. No total or mean score is derived. Each subscale score ranges from 0 to 6, higher scores indicates worsening. A negative mean change from Baseline indicates improvement. | Baseline, Weeks 8, 26 and End of the study visit (Week 43 or before) | 
| Mean Change From Baseline in Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF) Overall General Subscore | The Q-LES-Q-SF is a self-report measure designed to enable investigators to easily obtain sensitive measures of the degree of enjoyment and satisfaction experienced by participants in various areas of daily functioning with the help of 14 items of total 16 items of the scale. The overall general subscore is obtained using 14 items of the scale. Each item is scored on a 5-point scale, with 1= Very Poor; 2=Poor; 3=Fair; 4=Good; 5=Very Good. The raw scores are computed to an overall general subscore of 0 to 100 where lower scores indicate less enjoyment or satisfaction with the activity. A positive change from Baseline indicates improvement. | Baseline, Week 8, 26 and End of the study visit (Week 43 or before) | 
| Mean Change From Baseline in Sheehan Disability Scale (SDS) Mean Total Score | The SDS is a self-rated instrument used to measure the effect of the participant'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 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 SDS Mean Score of 0 to 10 was calculated as an average of the three item scores. All three item scores needed to be available with the exception of the work/school item score when this item was not applicable. A negative mean change from Baseline indicates improvement. | Baseline, Weeks 8, 26 and End of the study visit (Week 43 or before) | 
| Mean Change From Baseline in Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ) Total Score | The CPFQ is a brief self-rated scale developed to measure cognitive and executive dysfunction in mood and anxiety disorders. It consists of 7 items. The CPFQ total score ranges from 7 to 42, with higher score representing less satisfaction in cognitive and physical functioning. A negative mean change from Baseline indicates improvement. | Baseline, Weeks 8, 26 and End of the study visit (Week 43 or before) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MDD, Major Depressive Disorder, Depression