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: NCT01111539
• Collaborator: (none)
• Enrollment: 211
• Locations: 62
• Arms: 5
• Actual Duration (Months): 14.3
• Patients Per Site: 3.4
• 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; Drug: Blinded capsule	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: 211 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: Jul 13, 2010
• Actual Primary Completion Date: Sep 20, 2011
• Actual Study Completion Date: Sep 20, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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+.	Drug: Escitalopram; Escitalopram capsule administered orally, once daily without regard to meals.; Drug: Blinded capsule; Blinded capsule administered orally, once daily.
Experimental: Phase B+: Single-blind Phase B Responders Participants with response (≥50% reduction in depressive symptom severity in Hamilton Depression Rating Scale {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 blinded capsules) taken during the final week of Phase B, for up to maximum of Week 14, in Phase B+.	Drug: Escitalopram; Escitalopram capsule administered orally, once daily without regard to meals.; Drug: Blinded capsule; Blinded capsule administered orally, once daily.
Experimental: Phase C: Aripiprazole/Escitalopram Combination Participants with incomplete response (less than 50% reduction in depressive symptom severity between Baseline and Week 8 measured by the HAM-D17 Total Score and HAM-D17 Total Score of ≥14 at Week 8 and CGI-I Score of ≥3 at Week 6 and 8) at Week 8 received initial dose of aripiprazole 6 mg blinded capsule, orally, once daily at Week 9. Participants were up titrated to aripiprazole target dose of 12 mg/day at Week 10 (if initial 6 mg/day dose was tolerated) or down titrated to 3 mg/day (if significant tolerability issues arise on initial 6 mg/day dose), and thereafter received same dose up to maximum of Week 14. No dose increases were allowed for aripiprazole after end of Week 12, however, doses might be decreased at any visit based upon tolerability. In combination with aripiprazole, participants received escitalopram (10 or 20 mg/day blinded capsules) taken during final week of Phase B for up to maximum Week 14, in Phase C. No dose adjustments allowed for escitalopram during Phase C.	Drug: Escitalopram; Escitalopram capsule administered orally, once daily without regard to meals.; Drug: Aripiprazole; Aripiprazole capsule administered orally, once daily without regard to meals.; Drug: Blinded capsule; Blinded capsule administered orally, once daily.
Experimental: Phase C: Escitalopram Monotherapy Participants with incomplete response (less than a 50% reduction in depressive symptom severity between the Baseline and Week 8 as measured by the HAM-D17 Total Score and a HAM-D17 Total Score of ≥14 at Week 8 and a CGI-I Score of ≥3 at Week 6 and 8) at Week 8, received escitalopram dose (10 or 20 mg/day blinded capsules) taken during the final week of Phase B for up to maximum 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.; Drug: Blinded capsule; Blinded capsule administered orally, once daily.
Experimental: Phase C: Aripiprazole Monotherapy Participants with incomplete response (less than a 50% reduction in depressive symptom severity between the Baseline and Week 8 as measured by the HAM-D17 Total Score and a HAM-D17 Total Score of ≥14 at Week 8 and a CGI-I Score of ≥3 at Week 6 and 8) at Week 8, received initial dose of aripiprazole 6 mg blinded capsule, orally, once daily for Week 9. Participants were up titrated to the aripiprazole target dose of 12 mg/day at Week 10 (if the initial 6 mg/day dose was tolerated) or down titrated to 3 mg/day (if significant tolerability issues arise on the initial 6 mg/day dose), and thereafter received the same dose for up to maximum of Week 14. No dose increases were allowed for aripiprazole after the end of Week 12, however, doses might be decreased at any visit based upon tolerability.	Drug: Aripiprazole; Aripiprazole capsule administered orally, once daily without regard to meals.; Drug: Blinded capsule; Blinded capsule administered orally, once daily.

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 from Week 8 indicates improvement.

Secondary Outcome Measures

1. 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.

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). 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.

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 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Cerritos	California	United States	90703
2		Costa Mesa	California	United States	92626
3		Irvine	California	United States	92618
4		San Diego	California	United States	92102
5		Santa Ana	California	United States	92705
6		Denver	Colorado	United States	80204
7		Cromwell	Connecticut	United States	06416
8		Hartford	Connecticut	United States	06106
9		Fort Walton Beach	Florida	United States	32547
10		Gainesville	Florida	United States	32607
11		Chicago	Illinois	United States	60612
12		Libertyville	Illinois	United States	60048
13		Boston	Massachusetts	United States	02114
14		Fall River	Massachusetts	United States	02721
15		Albuquerque	New Mexico	United States	87109
16		Bronx	New York	United States	10467
17		Fresh Meadows	New York	United States	11366
18		Staten Island	New York	United States	10305
19		Cary	North Carolina	United States	27518
20		Oklahoma City	Oklahoma	United States	73112
21		Memphis	Tennessee	United States	38119
22		DeSoto	Texas	United States	75115
23		Richmond	Virginia	United States	23230
24		Brown Deer	Wisconsin	United States	53223
25		Jamejala		Estonia	71024
26		Tallinn		Estonia	10617
27		Tartu		Estonia	50406
28		Tartu		Estonia	50407
29		Helsinki		Finland	00250
30		Helsinki		Finland	00260
31		Kuopio		Finland	70100
32		Oulu		Finland	90100
33		Berlin		Germany	10117
34		Berlin		Germany	10969
35		Hamburg		Germany	20246
36		Munich		Germany	80336
37		Ostfildern		Germany	73760
38	Study Site 1	Ahmedabad	Gujarat	India	380006
39	Study Site 2	Ahmedabad	Gujarat	India	380006
40		Mangalore	Karnataka	India	575001
41		Mumbai	Maharashtra	India	400026
42		Pune	Maharashtra	India	411030
43		Varanasi	Uttar Pradesh	India	221005
44		Catania		Italy	95123
45		Siena		Italy	53100
46		Gwangju		Korea, Republic of	501-75
47		Seoul		Korea, Republic of	138-736
48		Seoul		Korea, Republic of	139-872
49		Seoul		Korea, Republic of	150-713
50		Seoul		Korea, Republic of	156-755
51		Mexico	DF	Mexico	06700
52		Tlalnepantla de Baz	Estado Do Mexico	Mexico	54050
53		Zapopan	Jalisco	Mexico	45200
54		Monterrey	Nuevo Leon	Mexico	64040
55		Culiacan	Sinaloa	Mexico	80020
56		Villahermosa	Tabasco	Mexico	86035
57		Durango		Mexico	34000
58		San Luis Potosi		Mexico	78218
59		Changhua		Taiwan	500
60		Kaohsiung		Taiwan	802
61		Keelung		Taiwan	204
62		Taoyuan		Taiwan	333

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: NCT01111539
• Other Study ID Numbers: 31-08-255; 2010-018796-21
• First Posted: Apr 27, 2010
• Last Update Posted: Oct 20, 2021
• Last Verified: Sep 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 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 Detail

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.

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	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+.	Participants with response (≥50% reduction in depressive symptom severity in Hamilton Depression Rating Scale {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 blinded capsules) taken during the final week of Phase B, for up to maximum of Week 14, in Phase B+.	Participants with incomplete response (less than 50% reduction in depressive symptom severity between Baseline and Week 8 measured by the HAM-D17 Total Score and HAM-D17 Total Score of ≥14 at Week 8 and CGI-I Score of ≥3 at Week 6 and 8) at Week 8 received initial dose of aripiprazole 6 mg blinded capsule, orally, once daily at Week 9. Participants were up titrated to aripiprazole target dose of 12 mg/day at Week 10 (if initial 6 mg/day dose was tolerated) or down titrated to 3 mg/day (if significant tolerability issues arise on initial 6 mg/day dose), and thereafter received same dose up to maximum of Week 14. No dose increases were allowed for aripiprazole after end of Week 12, however, doses might be decreased at any visit based upon tolerability. In combination with aripiprazole, participants received escitalopram (10 or 20 mg/day blinded capsules) taken during final week of Phase B for up to maximum Week 14, in Phase C. No dose adjustments allowed for escitalopram during Phase C.	Participants with incomplete response (less than a 50% reduction in depressive symptom severity between the Baseline and Week 8 as measured by the HAM-D17 Total Score and a HAM-D17 Total Score of ≥14 at Week 8 and a CGI-I Score of ≥3 at Week 6 and 8) at Week 8, received escitalopram dose (10 or 20 mg/day blinded capsules) taken during the final week of Phase B for up to maximum Week 14, in Phase C. No dose adjustments were allowed for escitalopram monotherapy during Phase C.	Participants with incomplete response (less than a 50% reduction in depressive symptom severity between the Baseline and Week 8 as measured by the HAM-D17 Total Score and a HAM-D17 Total Score of ≥14 at Week 8 and a CGI-I Score of ≥3 at Week 6 and 8) at Week 8, received initial dose of aripiprazole 6 mg blinded capsule, orally, once daily for Week 9. Participants were up titrated to the aripiprazole target dose of 12 mg/day at Week 10 (if the initial 6 mg/day dose was tolerated) or down titrated to 3 mg/day (if significant tolerability issues arise on the initial 6 mg/day dose), and thereafter received the same dose for up to maximum of Week 14. No dose increases were allowed for aripiprazole after the end of Week 12, however, doses might be decreased at any visit based upon tolerability.
Period Title: Phase B (Day 1 to Week 8)
STARTED	211	0	0	0	0
COMPLETED	129	0	0	0	0
NOT COMPLETED	82	0	0	0	0
Period Title: Phase B (Day 1 to Week 8)
STARTED	0	45	28	28	28
Intent-to-treat (ITT) Sample	0	45	28	27	28
Safety Sample	0	45	28	27	28
COMPLETED	0	38	22	20	18
NOT COMPLETED	0	7	6	8	10

Baseline Characteristics

Arm/Group Title	Phase B: Single-blind Prospective Treatment Phase
Arm/Group Description	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+.
Overall Participants	211
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	44.4 (11.1)
Sex: Female, Male (Count of Participants)
Female	140 66.4%
Male	71 33.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	42 19.9%
Not Hispanic or Latino	168 79.6%
Unknown or Not Reported	1 0.5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	16 7.6%
Asian	36 17.1%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	23 10.9%
White	130 61.6%
More than one race	0 0%
Unknown or Not Reported	6 2.8%

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 from Week 8 indicates improvement.
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 study medication and had at least one post-randomization efficacy evaluation.

Arm/Group Title	Phase C: Aripiprazole/Escitalopram Combination	Phase C: Escitalopram Monotherapy	Phase C: Aripiprazole Monotherapy
Arm/Group Description	Participants with incomplete response (less than 50% reduction in depressive symptom severity between Baseline and Week 8 measured by the HAM-D17 Total Score and HAM-D17 Total Score of ≥14 at Week 8 and CGI-I Score of ≥3 at Week 6 and 8) at Week 8 received initial dose of aripiprazole 6 mg blinded capsule, orally, once daily at Week 9. Participants were up titrated to aripiprazole target dose of 12 mg/day at Week 10 (if initial 6 mg/day dose was tolerated) or down titrated to 3 mg/day (if significant tolerability issues arise on initial 6 mg/day dose), and thereafter received same dose up to maximum of Week 14. No dose increases were allowed for aripiprazole after end of Week 12, however, doses might be decreased at any visit based upon tolerability. In combination with aripiprazole, participants received escitalopram (10 or 20 mg/day blinded capsules) taken during final week of Phase B for up to maximum Week 14, in Phase C. No dose adjustments allowed for escitalopram during Phase C.	Participants with incomplete response (less than a 50% reduction in depressive symptom severity between the Baseline and Week 8 as measured by the HAM-D17 Total Score and a HAM-D17 Total Score of ≥14 at Week 8 and a CGI-I Score of ≥3 at Week 6 and 8) at Week 8, received escitalopram dose (10 or 20 mg/day blinded capsules) taken during the final week of Phase B for up to maximum Week 14, in Phase C. No dose adjustments were allowed for escitalopram monotherapy during Phase C.	Participants with incomplete response (less than a 50% reduction in depressive symptom severity between the Baseline and Week 8 as measured by the HAM-D17 Total Score and a HAM-D17 Total Score of ≥14 at Week 8 and a CGI-I Score of ≥3 at Week 6 and 8) at Week 8, received initial dose of aripiprazole 6 mg blinded capsule, orally, once daily for Week 9. Participants were up titrated to the aripiprazole target dose of 12 mg/day at Week 10 (if the initial 6 mg/day dose was tolerated) or down titrated to 3 mg/day (if significant tolerability issues arise on the initial 6 mg/day dose), and thereafter received the same dose for up to maximum of Week 14. No dose increases were allowed for aripiprazole after the end of Week 12, however, doses might be decreased at any visit based upon tolerability.
Measure Participants	28	27	28
Least Squares Mean (Standard Error) [score on a scale]	-8.0 (1.5)	-7.0 (1.5)	-4.3 (1.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase C: Aripiprazole/Escitalopram Combination, Phase C: Escitalopram Monotherapy
	Comments	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.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.644
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	-1.0
	Confidence Interval	(2-Sided) 95%; -5.2 to 3.3
	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	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.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.080
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	-3.7
	Confidence Interval	(2-Sided) 95%; -7.8 to 0.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Phase C: Mean Clinical Global Impression - Improvement (CGI-I) Scale Score at the End of Phase C (Week 14)
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.
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 study medication and had at least one post-randomization efficacy evaluation.

Arm/Group Title	Phase C: Aripiprazole/Escitalopram Combination	Phase C: Escitalopram Monotherapy	Phase C: Aripiprazole Monotherapy
Arm/Group Description	Participants with incomplete response (less than 50% reduction in depressive symptom severity between Baseline and Week 8 measured by the HAM-D17 Total Score and HAM-D17 Total Score of ≥14 at Week 8 and CGI-I Score of ≥3 at Week 6 and 8) at Week 8 received initial dose of aripiprazole 6 mg blinded capsule, orally, once daily at Week 9. Participants were up titrated to aripiprazole target dose of 12 mg/day at Week 10 (if initial 6 mg/day dose was tolerated) or down titrated to 3 mg/day (if significant tolerability issues arise on initial 6 mg/day dose), and thereafter received same dose up to maximum of Week 14. No dose increases were allowed for aripiprazole after end of Week 12, however, doses might be decreased at any visit based upon tolerability. In combination with aripiprazole, participants received escitalopram (10 or 20 mg/day blinded capsules) taken during final week of Phase B for up to maximum Week 14, in Phase C. No dose adjustments allowed for escitalopram during Phase C.	Participants with incomplete response (less than a 50% reduction in depressive symptom severity between the Baseline and Week 8 as measured by the HAM-D17 Total Score and a HAM-D17 Total Score of ≥14 at Week 8 and a CGI-I Score of ≥3 at Week 6 and 8) at Week 8, received escitalopram dose (10 or 20 mg/day blinded capsules) taken during the final week of Phase B for up to maximum Week 14, in Phase C. No dose adjustments were allowed for escitalopram monotherapy during Phase C.	Participants with incomplete response (less than a 50% reduction in depressive symptom severity between the Baseline and Week 8 as measured by the HAM-D17 Total Score and a HAM-D17 Total Score of ≥14 at Week 8 and a CGI-I Score of ≥3 at Week 6 and 8) at Week 8, received initial dose of aripiprazole 6 mg blinded capsule, orally, once daily for Week 9. Participants were up titrated to the aripiprazole target dose of 12 mg/day at Week 10 (if the initial 6 mg/day dose was tolerated) or down titrated to 3 mg/day (if significant tolerability issues arise on the initial 6 mg/day dose), and thereafter received the same dose for up to maximum of Week 14. No dose increases were allowed for aripiprazole after the end of Week 12, however, doses might be decreased at any visit based upon tolerability.
Measure Participants	28	27	28
Mean (Standard Error) [score on a scale]	2.6 (0.2)	2.9 (0.2)	3.0 (0.1)

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	=0.366
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	-0.3
	Confidence Interval	(2-Sided) 95%; -0.8 to 0.3
	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	=0.138
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	-0.4
	Confidence Interval	(2-Sided) 95%; -0.9 to 0.1
	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). 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

Outcome Measure Data

Analysis Population Description

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/Group Title	Phase C: Aripiprazole/Escitalopram Combination	Phase C: Escitalopram Monotherapy	Phase C: Aripiprazole Monotherapy
Arm/Group Description	Participants with incomplete response (less than 50% reduction in depressive symptom severity between Baseline and Week 8 measured by the HAM-D17 Total Score and HAM-D17 Total Score of ≥14 at Week 8 and CGI-I Score of ≥3 at Week 6 and 8) at Week 8 received initial dose of aripiprazole 6 mg blinded capsule, orally, once daily at Week 9. Participants were up titrated to aripiprazole target dose of 12 mg/day at Week 10 (if initial 6 mg/day dose was tolerated) or down titrated to 3 mg/day (if significant tolerability issues arise on initial 6 mg/day dose), and thereafter received same dose up to maximum of Week 14. No dose increases were allowed for aripiprazole after end of Week 12, however, doses might be decreased at any visit based upon tolerability. In combination with aripiprazole, participants received escitalopram (10 or 20 mg/day blinded capsules) taken during final week of Phase B for up to maximum Week 14, in Phase C. No dose adjustments allowed for escitalopram during Phase C.	Participants with incomplete response (less than a 50% reduction in depressive symptom severity between the Baseline and Week 8 as measured by the HAM-D17 Total Score and a HAM-D17 Total Score of ≥14 at Week 8 and a CGI-I Score of ≥3 at Week 6 and 8) at Week 8, received escitalopram dose (10 or 20 mg/day blinded capsules) taken during the final week of Phase B for up to maximum Week 14, in Phase C. No dose adjustments were allowed for escitalopram monotherapy during Phase C.	Participants with incomplete response (less than a 50% reduction in depressive symptom severity between the Baseline and Week 8 as measured by the HAM-D17 Total Score and a HAM-D17 Total Score of ≥14 at Week 8 and a CGI-I Score of ≥3 at Week 6 and 8) at Week 8, received initial dose of aripiprazole 6 mg blinded capsule, orally, once daily for Week 9. Participants were up titrated to the aripiprazole target dose of 12 mg/day at Week 10 (if the initial 6 mg/day dose was tolerated) or down titrated to 3 mg/day (if significant tolerability issues arise on the initial 6 mg/day dose), and thereafter received the same dose for up to maximum of Week 14. No dose increases were allowed for aripiprazole after the end of Week 12, however, doses might be decreased at any visit based upon tolerability.
Measure Participants	27	25	26
Least Squares Mean (Standard Error) [score on a scale]	-1.2 (0.4)	-1.2 (0.4)	-0.2 (0.4)

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	=0.995
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	-0.0
	Confidence Interval	(2-Sided) 95%; -1.2 to 1.2
	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	=0.118
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	-0.9
	Confidence Interval	(2-Sided) 95%; -2.1 to 0.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	From first dose through 30 days after last dose of study drug (up to approximately 18 weeks)
Adverse Event Reporting Description	Phase B Sample- participants who took at least one dose of escitalopram. Phase B+ Sample - participants who responded at end of Phase B (were therefore not randomized) and continued on single-blind escitalopram beyond Week 8. Safety Sample(SS) included those randomized participants in Phase C who received at least one dose of double-blind study medication. 1 participant randomized to escitalopram group, was withdrawn by investigator prior to dosing in Phase C and thus was not included in the SS.
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	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+.		Participants with response (≥50% reduction in depressive symptom severity in Hamilton Depression Rating Scale {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 blinded capsules) taken during the final week of Phase B, for up to maximum of Week 14, in Phase B+.		Participants with incomplete response (less than 50% reduction in depressive symptom severity between Baseline and Week 8 measured by the HAM-D17 Total Score and HAM-D17 Total Score of ≥14 at Week 8 and CGI-I Score of ≥3 at Week 6 and 8) at Week 8 received initial dose of aripiprazole 6 mg blinded capsule, orally, once daily at Week 9. Participants were up titrated to aripiprazole target dose of 12 mg/day at Week 10 (if initial 6 mg/day dose was tolerated) or down titrated to 3 mg/day (if significant tolerability issues arise on initial 6 mg/day dose), and thereafter received same dose up to maximum of Week 14. No dose increases were allowed for aripiprazole after end of Week 12, however, doses might be decreased at any visit based upon tolerability. In combination with aripiprazole, participants received escitalopram (10 or 20 mg/day blinded capsules) taken during final week of Phase B for up to maximum Week 14, in Phase C. No dose adjustments allowed for escitalopram during Phase C.		Participants with incomplete response (less than a 50% reduction in depressive symptom severity between the Baseline and Week 8 as measured by the HAM-D17 Total Score and a HAM-D17 Total Score of ≥14 at Week 8 and a CGI-I Score of ≥3 at Week 6 and 8) at Week 8, received escitalopram dose (10 or 20 mg/day blinded capsules) taken during the final week of Phase B for up to maximum Week 14, in Phase C. No dose adjustments were allowed for escitalopram monotherapy during Phase C.		Participants with incomplete response (less than a 50% reduction in depressive symptom severity between the Baseline and Week 8 as measured by the HAM-D17 Total Score and a HAM-D17 Total Score of ≥14 at Week 8 and a CGI-I Score of ≥3 at Week 6 and 8) at Week 8, received initial dose of aripiprazole 6 mg blinded capsule, orally, once daily for Week 9. Participants were up titrated to the aripiprazole target dose of 12 mg/day at Week 10 (if the initial 6 mg/day dose was tolerated) or down titrated to 3 mg/day (if significant tolerability issues arise on the initial 6 mg/day dose), and thereafter received the same dose for up to maximum of Week 14. No dose increases were allowed for aripiprazole after the end of Week 12, however, doses might be 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	0/211 (0%)		0/45 (0%)		0/28 (0%)		0/27 (0%)		0/28 (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	2/211 (0.9%)		0/45 (0%)		0/28 (0%)		1/27 (3.7%)		1/28 (3.6%)
Hepatobiliary disorders
Cholecystitis acute	0/211 (0%)		0/45 (0%)		0/28 (0%)		1/27 (3.7%)		0/28 (0%)
Injury, poisoning and procedural complications
Fall	1/211 (0.5%)		0/45 (0%)		0/28 (0%)		0/27 (0%)		0/28 (0%)
Head injury	1/211 (0.5%)		0/45 (0%)		0/28 (0%)		0/27 (0%)		0/28 (0%)
Nervous system disorders
Syncope	0/211 (0%)		0/45 (0%)		0/28 (0%)		0/27 (0%)		1/28 (3.6%)
Psychiatric disorders
Suicidal ideation	1/211 (0.5%)		0/45 (0%)		0/28 (0%)		0/27 (0%)		0/28 (0%)
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	0/211 (0%)		0/45 (0%)		0/28 (0%)		0/27 (0%)		1/28 (3.6%)
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	82/211 (38.9%)		3/45 (6.7%)		18/28 (64.3%)		11/27 (40.7%)		17/28 (60.7%)
Eye disorders
Photophobia	0/211 (0%)		0/45 (0%)		0/28 (0%)		0/27 (0%)		2/28 (7.1%)
Vision blurred	2/211 (0.9%)		0/45 (0%)		0/28 (0%)		0/27 (0%)		2/28 (7.1%)
Gastrointestinal disorders
Diarrhoea	12/211 (5.7%)		1/45 (2.2%)		0/28 (0%)		2/27 (7.4%)		0/28 (0%)
Dry mouth	8/211 (3.8%)		1/45 (2.2%)		1/28 (3.6%)		0/27 (0%)		2/28 (7.1%)
Nausea	21/211 (10%)		0/45 (0%)		1/28 (3.6%)		2/27 (7.4%)		4/28 (14.3%)
General disorders
Feeling jittery	0/211 (0%)		0/45 (0%)		1/28 (3.6%)		0/27 (0%)		2/28 (7.1%)
Irritability	2/211 (0.9%)		0/45 (0%)		2/28 (7.1%)		0/27 (0%)		2/28 (7.1%)
Immune system disorders
Seasonal allergy	2/211 (0.9%)		0/45 (0%)		0/28 (0%)		0/27 (0%)		3/28 (10.7%)
Metabolism and nutrition disorders
Increased appetite	1/211 (0.5%)		0/45 (0%)		0/28 (0%)		2/27 (7.4%)		1/28 (3.6%)
Nervous system disorders
Akathisia	0/211 (0%)		0/45 (0%)		2/28 (7.1%)		1/27 (3.7%)		5/28 (17.9%)
Disturbance in attention	1/211 (0.5%)		0/45 (0%)		0/28 (0%)		0/27 (0%)		2/28 (7.1%)
Dizziness	6/211 (2.8%)		0/45 (0%)		1/28 (3.6%)		0/27 (0%)		2/28 (7.1%)
Dyskinesia	0/211 (0%)		0/45 (0%)		0/28 (0%)		0/27 (0%)		2/28 (7.1%)
Headache	36/211 (17.1%)		1/45 (2.2%)		2/28 (7.1%)		2/27 (7.4%)		4/28 (14.3%)
Sedation	3/211 (1.4%)		0/45 (0%)		2/28 (7.1%)		0/27 (0%)		4/28 (14.3%)
Somnolence	12/211 (5.7%)		0/45 (0%)		3/28 (10.7%)		3/27 (11.1%)		1/28 (3.6%)
Psychiatric disorders
Insomnia	4/211 (1.9%)		0/45 (0%)		3/28 (10.7%)		2/27 (7.4%)		1/28 (3.6%)
Restlessness	1/211 (0.5%)		0/45 (0%)		4/28 (14.3%)		1/27 (3.7%)		2/28 (7.1%)
Skin and subcutaneous tissue disorders
Alopecia	0/211 (0%)		0/45 (0%)		0/28 (0%)		0/27 (0%)		2/28 (7.1%)

Limitations/Caveats

The trial was terminated to allow support of additional programs in the central nervous system (CNS) therapeutic area where limited therapies are available and, thus, there exists heightened unmet medical need and is unrelated to any safety issues.

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.