Study to Evaluate the Efficacy, Safety and Tolerability of an Oral Aripiprazole/Escitalopram Combination Therapy in Participants With Major Depressive Disorder (MDD)

• Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc. (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT01111565
• Collaborator: (none)
• Enrollment: 137
• Locations: 53
• Arms: 5
• Actual Duration (Months): 10.9
• Patients Per Site: 2.6
• Patients Per Site Per Month: 0.2

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Major Depressive Disorder (MDD)	Drug: Escitalopram; Drug: Aripiprazole	Phase 3

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 137 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Randomized, Double-blind Study to Evaluate the Efficacy, Safety and Tolerability of an Oral Aripiprazole/Escitalopram Combination Therapy in Patients With Major Depressive Disorder
• Actual Study Start Date: Oct 4, 2010
• Actual Primary Completion Date: Sep 1, 2011
• Actual Study Completion Date: Sep 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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+.	Drug: Escitalopram; Escitalopram capsule administered orally, once daily without regard to meals.
Experimental: Phase B+: Single-blind Phase B Responders Participants with response (≥50% reduction in depressive symptom severity in HAM-D17 Total Score; or a HAM-D17 Total Score of <14 at Week 8 or a Clinical Global Impression of Improvement (CGI-I) Score of <3 at the Week 6 or 8) at the end of the Phase B (Week 8) continued treatment with the single-blind escitalopram monotherapy at the dose (10 or 20 mg/day) taken during the final week of Phase B, for an additional 6 weeks (Up to Week 14), in Phase B+.	Drug: Escitalopram; Escitalopram capsule administered orally, once daily without regard to meals.
Experimental: Phase C: Aripiprazole/Escitalopram Combination Participants with incomplete response at Week 8 who were randomized to this arm group received aripiprazole 3, 6, or 12 mg capsule, orally, once daily in combination with the escitalopram 10 or 20 mg orally for 6 weeks (Up to Week 14), in Phase C. No dose adjustments were allowed for escitalopram during Phase C. Participants were titrated to the aripiprazole target dose of 12 mg/day at Week 9 if the initial 6 mg/day dose was tolerated.	Drug: Escitalopram; Escitalopram capsule administered orally, once daily without regard to meals.; Drug: Aripiprazole; Aripiprazole capsule administered orally, once daily without regard to meals.
Experimental: Phase C: Escitalopram Monotherapy Participants with incomplete response at Week 8 who were randomized to this arm group received escitalopram monotherapy 10 or 20 mg capsule, orally, once daily, whichever dose was taken during the final week of Phase B for 6 weeks (Up to Week 14), in Phase C. No dose adjustments were allowed for escitalopram monotherapy during Phase C.	Drug: Escitalopram; Escitalopram capsule administered orally, once daily without regard to meals.
Experimental: Phase C: Aripiprazole Monotherapy Participants with incomplete response at Week 8 who were randomized to this arm group received aripiprazole 3, 6, or 12 mg capsule, orally, once daily for 6 weeks (Up to Week 14), in Phase C. Participants were titrated to the aripiprazole target dose of 12 mg/day at Week 9 if the initial 6 mg/day dose was tolerated. No dose increments were allowed after Week 12; however, doses may have been decreased at any visit, based upon tolerability.	Drug: Aripiprazole; Aripiprazole capsule administered orally, once daily without regard to meals.

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Tucson	Arizona	United States	85710
2		Chino	California	United States	91710
3		Riverside	California	United States	92506
4		Torrance	California	United States	90502
5		Hamden	Connecticut	United States	06518
6		Marietta	Georgia	United States	30060
7		Belmont	Massachusetts	United States	02478
8		Weymouth	Massachusetts	United States	02190
9		Saint Charles	Missouri	United States	63301
10		Saint Louis	Missouri	United States	63141
11		Brooklyn	New York	United States	11235
12		Garfield Heights	Ohio	United States	44125
13		Philadelphia	Pennsylvania	United States	19107
14		East Providence	Rhode Island	United States	02914
15		Kirkland	Washington	United States	98033
16		Penticton	British Columbia	Canada	V2A 4M4
17		Vancouver	British Columbia	Canada	V6Z 2L4
18		Burlington	Ontario	Canada	L7R 4E2
19		Osijek		Croatia	31000
20		Rijeka		Croatia	51000
21		Zagreb		Croatia	10000
22		Zagreb		Croatia	10090
23		Douai		France	59500
24		Elancourt		France	78990
25		Baja		Hungary	6500
26		Balassagyarmat		Hungary	2660
27		Budapest		Hungary	1053
28		Budapest		Hungary	1137
29		Gyula		Hungary	5700
30		Hyderabad	Andhra Pradesh	India	500034
31		Visakhapatnam	Andhra Pradesh	India	530002
32		Mumbai	Maharashtra	India	400605
33		Tampoi	Johor Bahru	Malaysia	80100
34		Tampoi	Johor Bahru	Malaysia	81200
35		Kajang	Selangor	Malaysia	43000
36		Kuala Lumpur		Malaysia	50603
37		Belchatow		Poland	97-400
38		Bialystok		Poland	15-464
39		Bialystok		Poland	15-879
40	Study Site 1	Choroszcz		Poland	16-070
41	Study Site 2	Choroszcz		Poland	16-070
42		Sosnowiec		Poland	41-200
43		Tuszyn		Poland	95-080
44	Study Site 1	Cape Town		South Africa	7530
45	Study Site 2	Cape Town		South Africa	7530
46		Durban		South Africa	3630
47		Pretoria		South Africa	0001
48		Pretoria		South Africa	0145
49		Pretoria		South Africa	0181
50		Barcelona		Spain	08003
51		Salamanca		Spain	37002
52		Göteborg		Sweden	41685
53		Malmö		Sweden	21135

Sponsors and Collaborators

• Otsuka Pharmaceutical Development & Commercialization, Inc.

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Otsuka Pharmaceutical Development & Commercialization, Inc.
• ClinicalTrials.gov Identifier: NCT01111565
• Other Study ID Numbers: 31-08-263; 2010-018859-97
• First Posted: Apr 27, 2010
• Last Update Posted: Dec 21, 2021
• Last Verified: Dec 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Otsuka Pharmaceutical Development & Commercialization, Inc.: Major Depressive Disorder; MDD; Depression
• Additional relevant MeSH terms: Disease; Depressive Disorder; Depression; Depressive Disorder, Major; Aripiprazole; Citalopram

Study Results

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 Detail

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.

Arm/Group Title	Phase B: Single-blind Prospective Treatment Phase	Phase B+: Single-blind Phase B Responders	Phase C: Aripiprazole/Escitalopram Combination	Phase C: Escitalopram Monotherapy	Phase C: Aripiprazole Monotherapy
Arm/Group Description	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+.	Participants with response (≥50% reduction in depressive symptom severity in HAM-D17 Total Score; or a HAM-D17 Total Score of <14 at Week 8 or a Clinical Global Impression of Improvement (CGI-I) Score of <3 at the Week 6 or 8) at the end of the Phase B (Week 8) continued treatment with the single-blind escitalopram monotherapy at the dose (10 or 20 mg/day) taken during the final week of Phase B, for an additional 6 weeks (Up to Week 14), in Phase B+.	Participants with incomplete response at Week 8 who were randomized to this arm group received aripiprazole 3, 6, or 12 mg capsule, orally, once daily in combination with the escitalopram 10 or 20 mg orally for 6 weeks (Up to Week 14), in Phase C. No dose adjustments were allowed for escitalopram during Phase C. Participants were titrated to the aripiprazole target dose of 12 mg/day at Week 9 if the initial 6 mg/day dose was tolerated.	Participants with incomplete response at Week 8 who were randomized to this arm group received escitalopram monotherapy 10 or 20 mg capsule, orally, once daily, whichever dose was taken during the final week of Phase B for 6 weeks (Up to Week 14), in Phase C. No dose adjustments were allowed for escitalopram monotherapy during Phase C.	Participants with incomplete response at Week 8 who were randomized to this arm group received aripiprazole 3, 6, or 12 mg capsule, orally, once daily for 6 weeks (Up to Week 14), in Phase C. Participants were titrated to the aripiprazole target dose of 12 mg/day at Week 9 if the initial 6 mg/day dose was tolerated. No dose increments were allowed after Week 12; however, doses may have been decreased at any visit, based upon tolerability.
Period Title: Phase B (Weeks 0 to 8)
STARTED	137	0	0	0	0
COMPLETED	71	0	0	0	0
NOT COMPLETED	66	0	0	0	0
Period Title: Phase B (Weeks 0 to 8)
STARTED	0	26	16	14	15
COMPLETED	0	19	11	10	11
NOT COMPLETED	0	7	5	4	4

Baseline Characteristics

Arm/Group Title	Phase B: Single-blind Prospective Treatment Phase
Arm/Group Description	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+.
Overall Participants	137
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	43.3 (12.3)
Sex: Female, Male (Count of Participants)
Female	90 65.7%
Male	47 34.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	6 4.4%
Not Hispanic or Latino	129 94.2%
Unknown or Not Reported	2 1.5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	10 7.3%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	26 19%
White	90 65.7%
More than one race	0 0%
Unknown or Not Reported	11 8%

Outcome Measures

1. Primary Outcome

Title	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)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Phase C: Aripiprazole/Escitalopram Combination	Phase C: Escitalopram Monotherapy	Phase C: Aripiprazole Monotherapy
Arm/Group Description	Participants with incomplete response at Week 8 who were randomized to this arm group received aripiprazole 3, 6, or 12 mg capsule, orally, once daily in combination with the escitalopram 10 or 20 mg orally for 6 weeks (Up to Week 14), in Phase C. No dose adjustments were allowed for escitalopram during Phase C. Participants were titrated to the aripiprazole target dose of 12 mg/day at Week 9 if the initial 6 mg/day dose was tolerated.	Participants with incomplete response at Week 8 who were randomized to this arm group received escitalopram monotherapy 10 or 20 mg capsule, orally, once daily, whichever dose was taken during the final week of Phase B for 6 weeks (Up to Week 14), in Phase C. No dose adjustments were allowed for escitalopram monotherapy during Phase C.	Participants with incomplete response at Week 8 who were randomized to this arm group received aripiprazole 3, 6, or 12 mg capsule, orally, once daily for 6 weeks (Up to Week 14), in Phase C. Participants were titrated to the aripiprazole target dose of 12 mg/day at Week 9 if the initial 6 mg/day dose was tolerated. No dose increments were allowed after Week 12; however, doses may have been decreased at any visit, based upon tolerability.
Measure Participants	16	14	15
Least Squares Mean (Standard Error) [score on a scale]	-9.0 (2.1)	-3.6 (2.2)	-3.8 (2.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase C: Aripiprazole/Escitalopram Combination, Phase C: Escitalopram Monotherapy
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.079
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	-5.4
	Confidence Interval	(2-Sided) 95%; -11.5 to 0.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Phase C: Aripiprazole/Escitalopram Combination, Phase C: Aripiprazole Monotherapy
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.085
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	-5.2
	Confidence Interval	(2-Sided) 95%; -11.2 to 0.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Phase C: Clinical Global Impression - Improvement Scale (CGI-I) Score at the End of Phase C
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Phase C: Aripiprazole/Escitalopram Combination	Phase C: Escitalopram Monotherapy	Phase C: Aripiprazole Monotherapy
Arm/Group Description	Participants with incomplete response at Week 8 who were randomized to this arm group received aripiprazole 3, 6, or 12 mg capsule, orally, once daily in combination with the escitalopram 10 or 20 mg orally for 6 weeks (Up to Week 14), in Phase C. No dose adjustments were allowed for escitalopram during Phase C. Participants were titrated to the aripiprazole target dose of 12 mg/day at Week 9 if the initial 6 mg/day dose was tolerated.	Participants with incomplete response at Week 8 who were randomized to this arm group received escitalopram monotherapy 10 or 20 mg capsule, orally, once daily, whichever dose was taken during the final week of Phase B for 6 weeks (Up to Week 14), in Phase C. No dose adjustments were allowed for escitalopram monotherapy during Phase C.	Participants with incomplete response at Week 8 who were randomized to this arm group received aripiprazole 3, 6, or 12 mg capsule, orally, once daily for 6 weeks (Up to Week 14), in Phase C. Participants were titrated to the aripiprazole target dose of 12 mg/day at Week 9 if the initial 6 mg/day dose was tolerated. No dose increments were allowed after Week 12; however, doses may have been decreased at any visit, based upon tolerability.
Measure Participants	16	14	15
Mean (Standard Error) [score on a scale]	2.5 (0.2)	3.0 (0.2)	2.9 (0.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase C: Aripiprazole/Escitalopram Combination, Phase C: Escitalopram Monotherapy
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.148
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel Row Mean Scores Test was used to determine the p-value.
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	-0.5
	Confidence Interval	(2-Sided) 95%; -1.1 to 0.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Phase C: Aripiprazole/Escitalopram Combination, Phase C: Aripiprazole Monotherapy
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.242
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel Row Mean Scores Test was used to determine the p-value.
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	-0.4
	Confidence Interval	(2-Sided) 95%; -1.0 to 0.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	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)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Phase C: Aripiprazole/Escitalopram Combination	Phase C: Escitalopram Monotherapy	Phase C: Aripiprazole Monotherapy
Arm/Group Description	Participants with incomplete response at Week 8 who were randomized to this arm group received aripiprazole 3, 6, or 12 mg capsule, orally, once daily in combination with the escitalopram 10 or 20 mg orally for 6 weeks (Up to Week 14), in Phase C. No dose adjustments were allowed for escitalopram during Phase C. Participants were titrated to the aripiprazole target dose of 12 mg/day at Week 9 if the initial 6 mg/day dose was tolerated.	Participants with incomplete response at Week 8 who were randomized to this arm group received escitalopram monotherapy 10 or 20 mg capsule, orally, once daily, whichever dose was taken during the final week of Phase B for 6 weeks (Up to Week 14), in Phase C. No dose adjustments were allowed for escitalopram monotherapy during Phase C.	Participants with incomplete response at Week 8 who were randomized to this arm group received aripiprazole 3, 6, or 12 mg capsule, orally, once daily for 6 weeks (Up to Week 14), in Phase C. Participants were titrated to the aripiprazole target dose of 12 mg/day at Week 9 if the initial 6 mg/day dose was tolerated. No dose increments were allowed after Week 12; however, doses may have been decreased at any visit, based upon tolerability.
Measure Participants	14	13	14
Least Squares Mean (Standard Error) [score on a scale]	-1.6 (0.7)	-1.8 (0.7)	-0.6 (0.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase C: Aripiprazole/Escitalopram Combination, Phase C: Escitalopram Monotherapy
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.910
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	0.1
	Confidence Interval	(2-Sided) 95%; -1.8 to 2.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Phase C: Aripiprazole/Escitalopram Combination, Phase C: Aripiprazole Monotherapy
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.291
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	-1.0
	Confidence Interval	(2-Sided) 95%; -3.0 to 0.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	From first dose of study drug through 30 days after the last dose of study drug (up to approximately 22 weeks)
Adverse Event Reporting Description	Phase B Sample included all participants who took at least one dose of escitalopram as indicated on the dosing record. Phase B+ Sample included all participants who responded at the end of Phase B (were therefore not randomized) and who continued on single-blind escitalopram beyond Week 8. Randomized Sample included all participants who were randomized in Phase C.
Arm/Group Title	Phase B: Single-blind Prospective Treatment Phase		Phase B+: Single-blind Phase B Responders		Phase C: Aripiprazole/Escitalopram Combination		Phase C: Escitalopram Monotherapy		Phase C: Aripiprazole Monotherapy
Arm/Group Description	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+.		Participants with response (≥50% reduction in depressive symptom severity in HAM-D17 Total Score; or a HAM-D17 Total Score of <14 at Week 8 or a Clinical Global Impression of Improvement (CGI-I) Score of <3 at the Week 6 or 8) at the end of the Phase B (Week 8) continued treatment with the single-blind escitalopram monotherapy at the dose (10 or 20 mg/day) taken during the final week of Phase B, for an additional 6 weeks (Up to Week 14), in Phase B+.		Participants with incomplete response at Week 8 who were randomized to this arm group received aripiprazole 3, 6, or 12 mg capsule, orally, once daily in combination with the escitalopram 10 or 20 mg orally for 6 weeks (Up to Week 14), in Phase C. No dose adjustments were allowed for escitalopram during Phase C. Participants were titrated to the aripiprazole target dose of 12 mg/day at Week 9 if the initial 6 mg/day dose was tolerated.		Participants with incomplete response at Week 8 who were randomized to this arm group received escitalopram monotherapy 10 or 20 mg capsule, orally, once daily, whichever dose was taken during the final week of Phase B for 6 weeks (Up to Week 14), in Phase C. No dose adjustments were allowed for escitalopram monotherapy during Phase C.		Participants with incomplete response at Week 8 who were randomized to this arm group received aripiprazole 3, 6, or 12 mg capsule, orally, once daily for 6 weeks (Up to Week 14), in Phase C. Participants were titrated to the aripiprazole target dose of 12 mg/day at Week 9 if the initial 6 mg/day dose was tolerated. No dose increments were allowed after Week 12; however, doses may have been decreased at any visit, based upon tolerability.
All Cause Mortality
	Phase B: Single-blind Prospective Treatment Phase		Phase B+: Single-blind Phase B Responders		Phase C: Aripiprazole/Escitalopram Combination		Phase C: Escitalopram Monotherapy		Phase C: Aripiprazole Monotherapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/137 (0%)		0/26 (0%)		0/16 (0%)		0/14 (0%)		0/15 (0%)
Serious Adverse Events
	Phase B: Single-blind Prospective Treatment Phase		Phase B+: Single-blind Phase B Responders		Phase C: Aripiprazole/Escitalopram Combination		Phase C: Escitalopram Monotherapy		Phase C: Aripiprazole Monotherapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/137 (0%)		0/26 (0%)		0/16 (0%)		0/14 (0%)		0/15 (0%)
Other (Not Including Serious) Adverse Events
	Phase B: Single-blind Prospective Treatment Phase		Phase B+: Single-blind Phase B Responders		Phase C: Aripiprazole/Escitalopram Combination		Phase C: Escitalopram Monotherapy		Phase C: Aripiprazole Monotherapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	65/137 (47.4%)		4/26 (15.4%)		12/16 (75%)		11/14 (78.6%)		13/15 (86.7%)
Cardiac disorders
Tachycardia	1/137 (0.7%)		0/26 (0%)		0/16 (0%)		1/14 (7.1%)		0/15 (0%)
Eye disorders
Dry eye	0/137 (0%)		0/26 (0%)		1/16 (6.3%)		0/14 (0%)		0/15 (0%)
Vision blurred	1/137 (0.7%)		0/26 (0%)		1/16 (6.3%)		0/14 (0%)		0/15 (0%)
Gastrointestinal disorders
Dry mouth	7/137 (5.1%)		1/26 (3.8%)		1/16 (6.3%)		1/14 (7.1%)		3/15 (20%)
Nausea	18/137 (13.1%)		2/26 (7.7%)		2/16 (12.5%)		0/14 (0%)		2/15 (13.3%)
Flatulence	1/137 (0.7%)		0/26 (0%)		0/16 (0%)		0/14 (0%)		1/15 (6.7%)
Salivary hypersecretion	0/137 (0%)		0/26 (0%)		1/16 (6.3%)		0/14 (0%)		0/15 (0%)
Vomiting	1/137 (0.7%)		0/26 (0%)		1/16 (6.3%)		0/14 (0%)		0/15 (0%)
General disorders
Asthenia	1/137 (0.7%)		0/26 (0%)		2/16 (12.5%)		0/14 (0%)		1/15 (6.7%)
Fatigue	7/137 (5.1%)		0/26 (0%)		1/16 (6.3%)		2/14 (14.3%)		1/15 (6.7%)
Irritability	2/137 (1.5%)		0/26 (0%)		1/16 (6.3%)		0/14 (0%)		1/15 (6.7%)
Infections and infestations
Upper respiratory tract infection	3/137 (2.2%)		0/26 (0%)		3/16 (18.8%)		0/14 (0%)		0/15 (0%)
Bronchitis	1/137 (0.7%)		0/26 (0%)		0/16 (0%)		0/14 (0%)		1/15 (6.7%)
Gastroenteritis viral	0/137 (0%)		0/26 (0%)		0/16 (0%)		1/14 (7.1%)		0/15 (0%)
Sinusitis	0/137 (0%)		0/26 (0%)		0/16 (0%)		1/14 (7.1%)		0/15 (0%)
Viral infection	0/137 (0%)		0/26 (0%)		0/16 (0%)		0/14 (0%)		1/15 (6.7%)
Injury, poisoning and procedural complications
Procedural pain	0/137 (0%)		0/26 (0%)		1/16 (6.3%)		0/14 (0%)		0/15 (0%)
Investigations
Blood creatine phosphokinase increased	0/137 (0%)		0/26 (0%)		0/16 (0%)		0/14 (0%)		1/15 (6.7%)
Blood creatinine increased	0/137 (0%)		0/26 (0%)		0/16 (0%)		1/14 (7.1%)		0/15 (0%)
Gamma-glutamyltransferase increased	1/137 (0.7%)		0/26 (0%)		0/16 (0%)		1/14 (7.1%)		0/15 (0%)
Weight increased	2/137 (1.5%)		0/26 (0%)		0/16 (0%)		0/14 (0%)		1/15 (6.7%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/137 (0%)		0/26 (0%)		0/16 (0%)		1/14 (7.1%)		0/15 (0%)
Back pain	2/137 (1.5%)		0/26 (0%)		1/16 (6.3%)		0/14 (0%)		0/15 (0%)
Muscle rigidity	0/137 (0%)		0/26 (0%)		1/16 (6.3%)		0/14 (0%)		0/15 (0%)
Muscle tightness	1/137 (0.7%)		0/26 (0%)		0/16 (0%)		0/14 (0%)		1/15 (6.7%)
Myalgia	0/137 (0%)		0/26 (0%)		0/16 (0%)		1/14 (7.1%)		0/15 (0%)
Osteoarthritis	0/137 (0%)		0/26 (0%)		0/16 (0%)		0/14 (0%)		1/15 (6.7%)
Trismus	0/137 (0%)		0/26 (0%)		0/16 (0%)		0/14 (0%)		1/15 (6.7%)
Nervous system disorders
Akathisia	1/137 (0.7%)		0/26 (0%)		2/16 (12.5%)		1/14 (7.1%)		1/15 (6.7%)
Dizziness	9/137 (6.6%)		0/26 (0%)		2/16 (12.5%)		1/14 (7.1%)		1/15 (6.7%)
Headache	15/137 (10.9%)		0/26 (0%)		1/16 (6.3%)		1/14 (7.1%)		2/15 (13.3%)
Lethargy	2/137 (1.5%)		0/26 (0%)		1/16 (6.3%)		1/14 (7.1%)		1/15 (6.7%)
Ataxia	1/137 (0.7%)		0/26 (0%)		1/16 (6.3%)		0/14 (0%)		0/15 (0%)
Drooling	0/137 (0%)		0/26 (0%)		0/16 (0%)		0/14 (0%)		1/15 (6.7%)
Dysgeusia	0/137 (0%)		0/26 (0%)		0/16 (0%)		0/14 (0%)		1/15 (6.7%)
Paraesthesia	1/137 (0.7%)		0/26 (0%)		1/16 (6.3%)		0/14 (0%)		0/15 (0%)
Sedation	2/137 (1.5%)		0/26 (0%)		1/16 (6.3%)		0/14 (0%)		0/15 (0%)
Somnolence	8/137 (5.8%)		1/26 (3.8%)		1/16 (6.3%)		1/14 (7.1%)		3/15 (20%)
Tremor	3/137 (2.2%)		0/26 (0%)		2/16 (12.5%)		1/14 (7.1%)		0/15 (0%)
Visual field defect	0/137 (0%)		0/26 (0%)		0/16 (0%)		0/14 (0%)		1/15 (6.7%)
Psychiatric disorders
Insomnia	2/137 (1.5%)		0/26 (0%)		1/16 (6.3%)		1/14 (7.1%)		2/15 (13.3%)
Restlessness	2/137 (1.5%)		0/26 (0%)		2/16 (12.5%)		0/14 (0%)		4/15 (26.7%)
Anxiety	1/137 (0.7%)		0/26 (0%)		0/16 (0%)		1/14 (7.1%)		0/15 (0%)
Initial insomnia	0/137 (0%)		0/26 (0%)		0/16 (0%)		0/14 (0%)		1/15 (6.7%)
Libido decreased	1/137 (0.7%)		0/26 (0%)		0/16 (0%)		1/14 (7.1%)		0/15 (0%)
Middle insomnia	0/137 (0%)		0/26 (0%)		1/16 (6.3%)		0/14 (0%)		0/15 (0%)
Respiratory, thoracic and mediastinal disorders
Allergic sinusitis	0/137 (0%)		0/26 (0%)		1/16 (6.3%)		0/14 (0%)		0/15 (0%)
Yawning	2/137 (1.5%)		0/26 (0%)		0/16 (0%)		0/14 (0%)		1/15 (6.7%)
Skin and subcutaneous tissue disorders
Night sweats	3/137 (2.2%)		0/26 (0%)		1/16 (6.3%)		0/14 (0%)		0/15 (0%)
Pruritus generalised	0/137 (0%)		0/26 (0%)		0/16 (0%)		1/14 (7.1%)		0/15 (0%)
Vascular disorders
Hot flush	0/137 (0%)		0/26 (0%)		0/16 (0%)		1/14 (7.1%)		0/15 (0%)

Limitations/Caveats

The study was terminated early due to Sponsor decision, closure of this combination therapy program is unrelated to any safety issues, no signals of concern.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Sponsor reserves the right to review results publications prior to public release and can delay such publications for a period greater than 60 days but no more than 120 days from the date that the publication is submitted to the Sponsor for review. Sponsor can require changes to the publication to protect Sponsor's intellectual property rights and/or confidential information and reserves the right to limit publication timing and scope of data published based on the number of study locations.