Safety and Efficacy of Cariprazine as an Adjunctive to Antidepressant Therapy in Major Depressive Disorder

• Sponsor: Forest Laboratories (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01469377
• Collaborator: Gedeon Richter Ltd. (Industry)
• Enrollment: 819
• Locations: 72
• Arms: 3
• Actual Duration (Months): 23.9
• Patients Per Site: 11.4
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

An outpatient study to evaluate the safety and efficacy of cariprazine as adjunct to antidepressant therapy (ADT) in participants with major depressive disorder (MDD) who have an inadequate response to ADT alone. This clinical study compared cariprazine + ADT with placebo

• ADT in outpatients with a diagnosis of MDD and an inadequate response to ADT. The study consisted of approximately 2 weeks of screening and washout followed by 8 weeks of double-blind treatment followed by a 1 week safety follow-up.

Condition or Disease	Intervention/Treatment	Phase
Major Depressive Disorder	Drug: Placebo; Drug: Cariprazine	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 819 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Double-Blind, Placebo-Controlled Study of Cariprazine (RGH-188) as Adjunctive Therapy in Major Depressive Disorder
• Actual Study Start Date: Dec 15, 2011
• Actual Primary Completion Date: Dec 12, 2013
• Actual Study Completion Date: Dec 12, 2013

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Participants received placebo orally once a day for 8 weeks. Each participant continued to take the same dose of antidepressant therapy (bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, sertraline, venlafaxine, or vilazodone) the participant was receiving prior to entering this study throughout treatment.	Drug: Placebo; Placebo was supplied in capsules
Experimental: Cariprazine 1-2 mg Participants received cariprazine orally once a day for 8 weeks. Participants received cariprazine 0.5 mg on Days 1 and 2 and 1.0 mg on Days 3-7. At the investigator's discretion dose levels could be increased during Week 2. Dose levels allowed during Week 2 were 1.0 or 1.5 mg. A second dose increase was allowed starting at Week 3. Dose levels allowed during Week 3 and the remainder of the treatment period were 1.0, 1.5, or 2.0 mg. Each participant continued to take the same dose of antidepressant therapy (bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, sertraline, venlafaxine, or vilazodone) the participant was receiving prior to entering this study throughout treatment.	Drug: Cariprazine; Cariprazine was supplied in capsules.
Experimental: Cariprazine 2-4.5 mg Participants received cariprazine orally once a day for 8 weeks. Participants received cariprazine 0.5 mg on Days 1 and 2, 1.0 mg on Day 3, 1.5 mg on Day 4, and 2.0 mg on Days 5-7. At the investigator's discretion dose levels could be increased during Week 2. Dose levels allowed during Week 2 were 2.0 or 3.0 mg. A second dose increase was allowed starting at Week 3. Dose levels allowed during Week 3 and the remainder of the treatment period were 2.0, 3.0, or 4.5 mg. Each participant continued to take the same dose of antidepressant therapy (bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, sertraline, venlafaxine, or vilazodone) the participant was receiving prior to entering this study throughout treatment.	Drug: Cariprazine; Cariprazine was supplied in capsules.

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score at Week 8 [Baseline to Week 8]

   The MADRS is a clinician-rated scale to assess depressive symptomatology during the preceding week. Participants are rated on 10 items (feelings of sadness, lassitude, pessimism, inner tension, suicidality, reduced sleep or appetite, difficulty concentrating, and lack of interest) each on a 7-point scale from 0 (no symptoms) to 6 (symptoms of maximum severity). The total score ranges from 0 to 60 with a higher score indicating more depression. A negative change score indicates improvement.

Secondary Outcome Measures

1. Change From Baseline in the Sheehan Disability Scale (SDS) Total Score at Week 8 [Baseline to Week 8]

   The SDS measures an individual's perception of the extent to which his or her emotional symptoms are disrupting his or her functioning in 3 domains, work/school, social life/leisure activities, and family life/home responsibilities. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male or female outpatients 18 to 65 years of age, inclusive.

• Currently meet the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria for moderate to severe major depressive disorder (MDD).

• Current major depressive episode of at least 8 weeks and not exceeding 24 months in duration.

• Ongoing inadequate response to protocol allowed antidepressant therapy (ADT).

Exclusion Criteria:

• Principal DSM-IV-TR-based diagnosis of an axis I disorder, other than MDD,

• Women who are pregnant, or planning to become pregnant or breastfeed during the study or not practicing reliable contraception that will continue through out the study.

• History of meeting DSM-IV-TR criteria for:

1. Depressive episode with psychotic or catatonic features.

2. Manic, hypomanic or mixed episode, including bipolar disorder and substance induced manic, hypomanic or mixed episode.

3. Schizophrenia, schizoaffective, or other psychotic disorder.

4. Obsessive-compulsive disorder.

5. Bulimia or anorexia nervosa.

6. Dementia, amnesic, or other cognitive disorder.

7. Mental retardation.

• Participants considered a suicide risk.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Forest Investigative Site 077	Garden Grove	California	United States	92845
2	Forest Investigative Site 019	National City	California	United States	91950
3	Forest Investigative Site 039	Oceanside	California	United States	92056
4	Forest Investigative Site 015	Orange	California	United States	92868
5	Forest Investigative Site 050	Orange	California	United States	92868
6	Forest Investigative Site 008	Redlands	California	United States	92374
7	Forest Investigative Site 066	Sherman Oaks	California	United States	91403
8	Forest Investigative Site 063	Gainesville	Florida	United States	32607
9	Forest Investigative Site 029	Jacksonville	Florida	United States	32256
10	Forest Investigative Site 012	Kissimmee	Florida	United States	34741
11	Forest Investigative Site 023	Miami	Florida	United States	33183
12	Forest Investigative Site 026	Orlando	Florida	United States	32806
13	Forest Investigative Site 062	Atlanta	Georgia	United States	30328
14	Forest Investigative Site 065	Smyrna	Georgia	United States	30080
15	Forest Investigative Site 074	Prairie Village	Kansas	United States	66206
16	Forest Investigative Site 040	Flowood	Mississippi	United States	39232
17	Forest Investigative Site 068	Creve Coeur	Missouri	United States	63141
18	Forest Investigative Site 061	Cherry Hill	New Jersey	United States	08002
19	Forest Investigative Site 038	Marlton	New Jersey	United States	08053
20	Forest Investigative Site 030	Albuquerque	New Mexico	United States	87106
21	Forest Investigative Site 076	Brooklyn	New York	United States	11235
22	Forest Investigative Site 037	Mount Kisco	New York	United States	10549
23	Forest Investigative Site 067	New York	New York	United States	10021
24	Forest Investigative Site 049	New York	New York	United States	10168
25	Forest Investigative Site 047	Canton	Ohio	United States	44718
26	Forest Investigative Site 021	Dayton	Ohio	United States	45417
27	Forest Investigative Site 022	Portland	Oregon	United States	97210
28	Forest Investigative Site 027	Salem	Oregon	United States	97301
29	Forest Investigative Site 069	Bridgeville	Pennsylvania	United States	15017
30	Forest Investigative Site 025	Philadelphia	Pennsylvania	United States	19139
31	Forest Investigative Site 031	Reading	Pennsylvania	United States	19604
32	Forest Investigative Site 048	Memphis	Tennessee	United States	38119
33	Forest Investigative Site 024	Austin	Texas	United States	78731
34	Forest Investigative Site 020	Dallas	Texas	United States	75231
35	Forest Investigative Site 070	Houston	Texas	United States	77054
36	Forest Investigative Site 080	San Antonio	Texas	United States	78229
37	Forest Investigative Site 028	Salt Lake City	Utah	United States	84106
38	Forest Investigative Site 032	Bellevue	Washington	United States	98007
39	Forest Investigative Site 034	Kirkland	Washington	United States	98033
40	Forest Investigative Site 203	Tallinn		Estonia	10614
41	Forest Investigative Site 201	Tallinn		Estonia	10617
42	Forest Investigative Site 206	Tallinn		Estonia	11615
43	Forest Investigative Site 205	Tallinn		Estonia	13517
44	Forest Investigative Site 204	Tartu		Estonia	50406
45	Forest Investigative Site 208	Tartu		Estonia	50417
46	Forest Investigative Site 207	Tartu		Estonia	51014
47	Forest Investigative Site 202	Võru		Estonia	65608
48	Forest Investigative Site 301	Helsinki		Finland	100
49	Forest Investigative Site 302	Helsinki		Finland	100
50	Forest Investigative Site 304	Helsinki		Finland	100
51	Forest Investigative Site 303	Helsinki		Finland	40100
52	Forest Investigative Site 305	Kuopio		Finland	70110
53	Forest Investigative Site 308	Oulu		Finland	90100
54	Forest Investigative Site 307	Pori		Finland	28100
55	Forest Investigative Site 602	Banska Stiavnica		Slovakia	96901
56	Forest Investigative Site 603	Bardejov		Slovakia	08501
57	Forest Investigative Site 604	Bratislava		Slovakia	82007
58	Forest Investigative Site 606	Bratislava		Slovakia	85101
59	Forest Investigative Site 601	Michalovce		Slovakia	7101
60	Forest Investigative Site 605	Rimavska Sobota		Slovakia	97901
61	Forest Investigative Site 607	Rimavska Sobota		Slovakia	97912
62	Forest Investigative Site 803	Lund		Sweden	22222
63	Forest Investigative Site 802	Malmö		Sweden	21152
64	Forest Investigative Site 801	Stockholm		Sweden	17145
65	Forest Investigative Site 705	Stepanivka	Kherson	Ukraine	73488
66	Forest Investigative Site 703	Kharkiv		Ukraine	61068
67	Forest Investigative Site 704	Kharkiv		Ukraine	61068
68	Forest Investigative Site 702	Kyiv		Ukraine	02660
69	Forest Investigative Site 701	Kyiv		Ukraine	04080
70	Forest Investigative Site 710	Lugansk		Ukraine	91045
71	Forest Investigative Site 709	Odesa		Ukraine	65014
72	Forest Investigative Site 706	Vinnytsia		Ukraine	21005

Sponsors and Collaborators

• Forest Laboratories
• Gedeon Richter Ltd.

Investigators

• Study Director: Willie Earley, MD, Allergan

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Forest Laboratories
• ClinicalTrials.gov Identifier: NCT01469377
• Other Study ID Numbers: RGH-MD-75
• First Posted: Nov 10, 2011
• Last Update Posted: May 1, 2018
• Last Verified: Mar 1, 2018

• Keywords provided by Forest Laboratories: Major depressive disorder; Depression
• Additional relevant MeSH terms: Disease; Depressive Disorder; Depression; Depressive Disorder, Major; Cariprazine

Study Results

Participant Flow

Arm/Group Title	Placebo	Cariprazine 1-2 mg	Cariprazine 2-4.5 mg
Arm/Group Description	Participants received placebo orally once a day for 8 weeks. Each participant continued to take the same dose of antidepressant therapy (bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, sertraline, venlafaxine, or vilazodone) the participant was receiving prior to entering this study throughout treatment.	Participants received cariprazine orally once a day for 8 weeks. Participants received cariprazine 0.5 mg on Days 1 and 2 and 1.0 mg on Days 3-7. At the investigator's discretion dose levels could be increased during Week 2. Dose levels allowed during Week 2 were 1.0 or 1.5 mg. A second dose increase was allowed starting at Week 3. Dose levels allowed during Week 3 and the remainder of the treatment period were 1.0, 1.5, or 2.0 mg. Each participant continued to take the same dose of antidepressant therapy (bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, sertraline, venlafaxine, or vilazodone) the participant was receiving prior to entering this study throughout treatment.	Participants received cariprazine orally once a day for 8 weeks. Participants received cariprazine 0.5 mg on Days 1 and 2, 1.0 mg on Day 3, 1.5 mg on Day 4, and 2.0 mg on Days 5-7. At the investigator's discretion dose levels could be increased during Week 2. Dose levels allowed during Week 2 were 2.0 or 3.0 mg. A second dose increase was allowed starting at Week 3. Dose levels allowed during Week 3 and the remainder of the treatment period were 2.0, 3.0, or 4.5 mg. Each participant continued to take the same dose of antidepressant therapy (bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, sertraline, venlafaxine, or vilazodone) the participant was receiving prior to entering this study throughout treatment.
Period Title: Overall Study
STARTED	269	274	276
COMPLETED	234	226	210
NOT COMPLETED	35	48	66

Baseline Characteristics

Arm/Group Title	Placebo	Cariprazine 1-2 mg	Cariprazine 2-4.5 mg	Total
Arm/Group Description	Participants received placebo orally once a day for 8 weeks. Each participant continued to take the same dose of antidepressant therapy (bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, sertraline, venlafaxine, or vilazodone) the participant was receiving prior to entering this study throughout treatment.	Participants received cariprazine orally once a day for 8 weeks. Participants received cariprazine 0.5 mg on Days 1 and 2 and 1.0 mg on Days 3-7. At the investigator's discretion dose levels could be increased during Week 2. Dose levels allowed during Week 2 were 1.0 or 1.5 mg. A second dose increase was allowed starting at Week 3. Dose levels allowed during Week 3 and the remainder of the treatment period were 1.0, 1.5, or 2.0 mg. Each participant continued to take the same dose of antidepressant therapy (bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, sertraline, venlafaxine, or vilazodone) the participant was receiving prior to entering this study throughout treatment.	Participants received cariprazine orally once a day for 8 weeks. Participants received cariprazine 0.5 mg on Days 1 and 2, 1.0 mg on Day 3, 1.5 mg on Day 4, and 2.0 mg on Days 5-7. At the investigator's discretion dose levels could be increased during Week 2. Dose levels allowed during Week 2 were 2.0 or 3.0 mg. A second dose increase was allowed starting at Week 3. Dose levels allowed during Week 3 and the remainder of the treatment period were 2.0, 3.0, or 4.5 mg. Each participant continued to take the same dose of antidepressant therapy (bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, sertraline, venlafaxine, or vilazodone) the participant was receiving prior to entering this study throughout treatment.	Total of all reporting groups
Overall Participants	266	273	273	812
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	46.4 (11.6)	45.5 (11.9)	45.1 (11.4)	45.7 (11.6)
Sex: Female, Male (Count of Participants)
Female	190 71.4%	187 68.5%	201 73.6%	578 71.2%
Male	76 28.6%	86 31.5%	72 26.4%	234 28.8%
Race/Ethnicity, Customized (participants) [Number]
White	230 86.5%	234 85.7%	242 88.6%	706 86.9%
All other races	36 13.5%	39 14.3%	31 11.4%	106 13.1%
Black or African American	32 12%	31 11.4%	24 8.8%	87 10.7%
Asian	1 0.4%	4 1.5%	4 1.5%	9 1.1%
American Indian or Alaska Native	2 0.8%	1 0.4%	1 0.4%	4 0.5%
Other	1 0.4%	3 1.1%	2 0.7%	6 0.7%
Race/Ethnicity, Customized (participants) [Number]
Hispanic or Latino	14 5.3%	17 6.2%	22 8.1%	53 6.5%
Not Hispanic or Latino	252 94.7%	256 93.8%	251 91.9%	759 93.5%
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	81.53 (16.19)	79.69 (16.31)	82.17 (17.37)	81.13 (16.65)
Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	28.93 (5.09)	28.21 (5.51)	29.05 (5.59)	28.73 (5.41)
Waist Circumference (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	94.32 (13.44)	93.36 (14.20)	94.91 (14.66)	94.20 (14.12)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score at Week 8
Description	The MADRS is a clinician-rated scale to assess depressive symptomatology during the preceding week. Participants are rated on 10 items (feelings of sadness, lassitude, pessimism, inner tension, suicidality, reduced sleep or appetite, difficulty concentrating, and lack of interest) each on a 7-point scale from 0 (no symptoms) to 6 (symptoms of maximum severity). The total score ranges from 0 to 60 with a higher score indicating more depression. A negative change score indicates improvement.
Time Frame	Baseline to Week 8

Outcome Measure Data

Analysis Population Description

Intent-to-treat population consisted of all patients in the Safety Population who had at least 1 post-baseline assessment of the MADRS total score.

Arm/Group Title	Placebo	Cariprazine 1-2 mg	Cariprazine 2-4.5 mg
Arm/Group Description	Participants received placebo orally once a day for 8 weeks. Each participant continued to take the same dose of antidepressant therapy (bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, sertraline, venlafaxine, or vilazodone) the participant was receiving prior to entering this study throughout treatment.	Participants received cariprazine orally once a day for 8 weeks. Participants received cariprazine 0.5 mg on Days 1 and 2 and 1.0 mg on Days 3-7. At the investigator's discretion dose levels could be increased during Week 2. Dose levels allowed during Week 2 were 1.0 or 1.5 mg. A second dose increase was allowed starting at Week 3. Dose levels allowed during Week 3 and the remainder of the treatment period were 1.0, 1.5, or 2.0 mg. Each participant continued to take the same dose of antidepressant therapy (bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, sertraline, venlafaxine, or vilazodone) the participant was receiving prior to entering this study throughout treatment.	Participants received cariprazine orally once a day for 8 weeks. Participants received cariprazine 0.5 mg on Days 1 and 2, 1.0 mg on Day 3, 1.5 mg on Day 4, and 2.0 mg on Days 5-7. At the investigator's discretion dose levels could be increased during Week 2. Dose levels allowed during Week 2 were 2.0 or 3.0 mg. A second dose increase was allowed starting at Week 3. Dose levels allowed during Week 3 and the remainder of the treatment period were 2.0, 3.0, or 4.5 mg. Each participant continued to take the same dose of antidepressant therapy (bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, sertraline, venlafaxine, or vilazodone) the participant was receiving prior to entering this study throughout treatment.
Measure Participants	264	273	271
Least Squares Mean (Standard Error) [Units on a scale]	-12.5 (0.5)	-13.4 (0.5)	-14.6 (0.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Cariprazine 1-2 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2404
	Comments	p-values were from an mixed-effects model for repeated measures with treatment group, pooled study center, visit, and treatment-group-by-visit interaction as fixed effects and the baseline value and baseline value-by-visit interaction as covariates.
	Method	Mixed-effect model for repeated measures
	Comments	p-values were adjusted for multiple comparisons using the matched parallel gate-keeping procedure.
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	-0.9
	Confidence Interval	(2-Sided) 95%; -2.4 to 0.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Cariprazine 2-4.5 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0114
	Comments	p-values were from an mixed-effects model for repeated measures with treatment group, pooled study center, visit, and treatment-group-by-visit interaction as fixed effects and the baseline value and baseline value-by-visit interaction as covariates.
	Method	Mixed-effect model for repeated measures
	Comments	p-values were adjusted for multiple comparisons using the matched parallel gate-keeping procedure.
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	-2.2
	Confidence Interval	(2-Sided) 95%; -3.7 to -0.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in the Sheehan Disability Scale (SDS) Total Score at Week 8
Description	The SDS measures an individual's perception of the extent to which his or her emotional symptoms are disrupting his or her functioning in 3 domains, work/school, social life/leisure activities, and family life/home responsibilities. 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.
Time Frame	Baseline to Week 8

Outcome Measure Data

Analysis Population Description

Intent-to-treat population consisted of all patients in the Safety Population who had at least 1 post-baseline assessment of the MADRS total score. Only participants with scores for all 3 domains were included in the analysis.

Arm/Group Title	Placebo	Cariprazine 1-2 mg	Cariprazine 2-4.5 mg
Arm/Group Description	Participants received placebo orally once a day for 8 weeks. Each participant continued to take the same dose of antidepressant therapy (bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, sertraline, venlafaxine, or vilazodone) the participant was receiving prior to entering this study throughout treatment.	Participants received cariprazine orally once a day for 8 weeks. Participants received cariprazine 0.5 mg on Days 1 and 2 and 1.0 mg on Days 3-7. At the investigator's discretion dose levels could be increased during Week 2. Dose levels allowed during Week 2 were 1.0 or 1.5 mg. A second dose increase was allowed starting at Week 3. Dose levels allowed during Week 3 and the remainder of the treatment period were 1.0, 1.5, or 2.0 mg. Each participant continued to take the same dose of antidepressant therapy (bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, sertraline, venlafaxine, or vilazodone) the participant was receiving prior to entering this study throughout treatment.	Participants received cariprazine orally once a day for 8 weeks. Participants received cariprazine 0.5 mg on Days 1 and 2, 1.0 mg on Day 3, 1.5 mg on Day 4, and 2.0 mg on Days 5-7. At the investigator's discretion dose levels could be increased during Week 2. Dose levels allowed during Week 2 were 2.0 or 3.0 mg. A second dose increase was allowed starting at Week 3. Dose levels allowed during Week 3 and the remainder of the treatment period were 2.0, 3.0, or 4.5 mg. Each participant continued to take the same dose of antidepressant therapy (bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, sertraline, venlafaxine, or vilazodone) the participant was receiving prior to entering this study throughout treatment.
Measure Participants	264	273	271
Least Squares Mean (Standard Error) [Units on a scale]	-6.6 (0.5)	-7.7 (0.5)	-8.0 (0.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Cariprazine 1-2 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2404
	Comments	p-values were from an mixed-effects model for repeated measures with treatment group, pooled study center, visit, and treatment-group-by-visit interaction as fixed effects and the baseline value and baseline value-by-visit interaction as covariates.
	Method	Mixed-effect model for repeated measures
	Comments	p-values were adjusted for multiple comparisons using the matched parallel gate-keeping procedure.
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	-1.1
	Confidence Interval	(2-Sided) 95%; -2.5 to 0.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Cariprazine 2-4.5 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1140
	Comments	p-values were from an mixed-effects model for repeated measures with treatment group, pooled study center, visit, and treatment-group-by-visit interaction as fixed effects and the baseline value and baseline value-by-visit interaction as covariates.
	Method	Mixed-effect model for repeated measures
	Comments	p-values were adjusted for multiple comparisons using the matched parallel gate-keeping procedure.
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	-1.4
	Confidence Interval	(2-Sided) 95%; -2.8 to 0.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Adverse Events were collected and recorded from the time the participant signs the informed consent form until 30 days after the last dose of treatment.
Adverse Event Reporting Description	Safety population: All randomized participants who received at least 1 dose of treatment.
Arm/Group Title	Placebo		Cariprazine 1-2 mg		Cariprazine 2-4.5 mg
Arm/Group Description	Participants received placebo orally once a day for 8 weeks. Each participant continued to take the same dose of antidepressant therapy (bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, sertraline, venlafaxine, or vilazodone) the participant was receiving prior to entering this study throughout treatment.		Participants received cariprazine orally once a day for 8 weeks. Participants received cariprazine 0.5 mg on Days 1 and 2 and 1.0 mg on Days 3-7. At the investigator's discretion dose levels could be increased during Week 2. Dose levels allowed during Week 2 were 1.0 or 1.5 mg. A second dose increase was allowed starting at Week 3. Dose levels allowed during Week 3 and the remainder of the treatment period were 1.0, 1.5, or 2.0 mg. Each participant continued to take the same dose of antidepressant therapy (bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, sertraline, venlafaxine, or vilazodone) the participant was receiving prior to entering this study throughout treatment.		Participants received cariprazine orally once a day for 8 weeks. Participants received cariprazine 0.5 mg on Days 1 and 2, 1.0 mg on Day 3, 1.5 mg on Day 4, and 2.0 mg on Days 5-7. At the investigator's discretion dose levels could be increased during Week 2. Dose levels allowed during Week 2 were 2.0 or 3.0 mg. A second dose increase was allowed starting at Week 3. Dose levels allowed during Week 3 and the remainder of the treatment period were 2.0, 3.0, or 4.5 mg. Each participant continued to take the same dose of antidepressant therapy (bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, sertraline, venlafaxine, or vilazodone) the participant was receiving prior to entering this study throughout treatment.
All Cause Mortality
	Placebo		Cariprazine 1-2 mg		Cariprazine 2-4.5 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/266 (0%)		0/273 (0%)		0/273 (0%)
Serious Adverse Events
	Placebo		Cariprazine 1-2 mg		Cariprazine 2-4.5 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/266 (0.4%)		0/273 (0%)		3/273 (1.1%)
Cardiac disorders
Myocardial ischemia	0/266 (0%)		0/273 (0%)		1/273 (0.4%)
General disorders
Non-cardiac chest pain	0/266 (0%)		0/273 (0%)		1/273 (0.4%)
Psychiatric disorders
Agitation	0/266 (0%)		0/273 (0%)		1/273 (0.4%)
Panic attack	0/266 (0%)		0/273 (0%)		1/273 (0.4%)
Depression	1/266 (0.4%)		0/273 (0%)		0/273 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/266 (0%)		0/273 (0%)		1/273 (0.4%)
Other (Not Including Serious) Adverse Events
	Placebo		Cariprazine 1-2 mg		Cariprazine 2-4.5 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	102/266 (38.3%)		121/273 (44.3%)		179/273 (65.6%)
Gastrointestinal disorders
Constipation	5/266 (1.9%)		6/273 (2.2%)		14/273 (5.1%)
Diarrhoea	14/266 (5.3%)		8/273 (2.9%)		8/273 (2.9%)
Dry mouth	7/266 (2.6%)		14/273 (5.1%)		10/273 (3.7%)
Nausea	13/266 (4.9%)		19/273 (7%)		35/273 (12.8%)
General disorders
Fatigue	11/266 (4.1%)		18/273 (6.6%)		27/273 (9.9%)
Metabolism and nutrition disorders
Increased appetite	4/266 (1.5%)		5/273 (1.8%)		14/273 (5.1%)
Nervous system disorders
Akathisia	6/266 (2.3%)		18/273 (6.6%)		61/273 (22.3%)
Dizziness	7/266 (2.6%)		10/273 (3.7%)		14/273 (5.1%)
Headache	36/266 (13.5%)		24/273 (8.8%)		24/273 (8.8%)
Somnolence	14/266 (5.3%)		24/273 (8.8%)		27/273 (9.9%)
Tremor	4/266 (1.5%)		13/273 (4.8%)		21/273 (7.7%)
Psychiatric disorders
Insomnia	17/266 (6.4%)		27/273 (9.9%)		38/273 (13.9%)
Restlessness	7/266 (2.6%)		22/273 (8.1%)		23/273 (8.4%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

All data generated in this study will be the property of Forest Research Institute, Inc. An integrated clinical and statistical report will be prepared at the completion of the study. Publication of the results by the Investigator will be subject to mutual agreement between the Investigator and Forest Research Institute, Inc.