Safety, Tolerability, and Efficacy of Cariprazine in Participants With Bipolar Depression

• Sponsor: Forest Laboratories (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01396447
• Collaborator: Gedeon Richter Ltd. (Industry)
• Enrollment: 584
• Locations: 88
• Arms: 4
• Actual Duration (Months): 29.5
• Patients Per Site: 6.6
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The objective of this study was to evaluate the efficacy, safety, and tolerability of cariprazine relative to placebo for the treatment of participants with bipolar depression.

Condition or Disease	Intervention/Treatment	Phase
Depression, Bipolar	Drug: Placebo; Drug: Cariprazine	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 584 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 Evaluation of the Safety and Efficacy of Cariprazine in Patients With Bipolar Depression
• Actual Study Start Date: Jul 26, 2011
• Actual Primary Completion Date: Jan 10, 2014
• Actual Study Completion Date: Jan 10, 2014

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Participants received placebo orally once a day for 8 weeks.	Drug: Placebo; Placebo was supplied in capsules.
Experimental: Cariprazine 0.75 mg Participants received cariprazine 0.5 mg orally once on Days 1-2 and cariprazine 0.75 mg orally once a day starting on Day 3 for the remainder of the 8 week treatment period.	Drug: Cariprazine; Cariprazine was supplied in capsules.
Experimental: Cariprazine 1.5 mg Participants received cariprazine 0.5 mg orally once on Days 1-2, cariprazine 0.75 mg orally once on Days 3-4, cariprazine 1.0 mg orally once on Days 5-7, and cariprazine 1.5 mg orally once a day starting on Day 8 for the remainder of the 8 week treatment period.	Drug: Cariprazine; Cariprazine was supplied in capsules.
Experimental: Cariprazine 3.0 mg Participants received cariprazine 0.5 mg orally once on Days 1-2, cariprazine 0.75 mg orally once on Days 3-4, cariprazine 1.0 mg orally once on Days 5-7, cariprazine 1.5 mg orally on Days 8-14, and cariprazine 3.0 mg orally once a day starting on Day 15 for the remainder of the 8 week treatment period.	Drug: Cariprazine; Cariprazine was supplied in capsules.

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in the Montgomery-Åsberg Depression Rating Scale Total Score at Week 6 [Baseline to Week 6]

   The Montgomery-Åsberg Depression Rating Scale is a 10-item, clinician-rated scale that evaluates the participant's depressive symptomatology during the past week. Participants are rated on items assessing feelings of sadness, lassitude, pessimism, inner tension, suicidality, reduced sleep or appetite, difficulty in concentration, and lack of interest. Each item is scored on a 7-point scale with a score of 0 reflecting no symptoms and a score of 6 reflecting symptoms of maximum severity. The scores on the 10 items are summed for a total score that can range from 0 to 60. A higher score indicates greater depression. A negative change score indicates improvement.

Secondary Outcome Measures

1. Change From Baseline in the Clinical Global Impressions-Severity Total Score at Week 6 [Baseline to Week 6]

   The Clinical Global Impressions-Severity scale is a clinician-rated scale that measures the overall severity of a participant's illness in comparison with the severity of illness in other participants the physician has observed. The participant is rated on a scale from 1 to 7 with 1 indicating a "normal state" and 7 indicating "among the most extremely ill participants." A higher score indicates greater illness. 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:

• Participants who have provided informed consent prior to any study specific procedures.

• Participants currently meeting the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria for bipolar I disorder as confirmed by the Structured Clinical Interview (SCID) with a current with a current major depressive episode of at least 4 weeks and not exceeding 12 months in duration.

• Participants with normal physical examination, laboratory, vital signs, and/or echocardiogram (ECG).

• Verified previous manic or mixed episode.

• Participants with a total Hamilton Rating Scale for Depression (HAMD)-17 score ≥ 20.

• Participants with a HAMD-17 item 1 score ≥ 2.

• Participants with a Clinical Global Impression of Severity (CGI-S) score ≥ 4.

Exclusion Criteria:

• Participants with a DSM-IV-TR diagnosis of an axis I disorder other than bipolar I disorder that was the primary focus of treatment within the previous 6 months.

• Women who are pregnant or breast feeding

• Participants with Young Mania Rating Scale (YMRS) total score > 10

• Participants who have dementia, mental retardation, schizophrenia/schizoaffective disorder.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Forest Investigative Site 021	Birmingham	Alabama	United States	35216
2	Forest Investigative Site 017	Springdale	Arkansas	United States	72764
3	Forest Investigative Site 030	Beverly Hills	California	United States	90210
4	Forest Investigative Site 018	Cerritos	California	United States	90703
5	Forest Investigative Site 028	Costa Mesa	California	United States	92626
6	Forest Investigative Site 015	Oceanside	California	United States	92056
7	Forest Investigative Site 011	Temecula	California	United States	92591
8	Forest Investigative Site 012	Jacksonville	Florida	United States	32256
9	Forest Investigative Site 035	Orlando	Florida	United States	32806
10	Forest Investigative Site 013	Winter Park	Florida	United States	32789
11	Forest Investigative Site 038	Atlanta	Georgia	United States	30308
12	Forest Investigative Site 005	Atlanta	Georgia	United States	30328
13	Forest Investigative Site 029	Chicago	Illinois	United States	60640
14	Forest Investigative Site 024	Indianapolis	Indiana	United States	46260
15	Forest Investigative Site 031	Prairie Village	Kansas	United States	66206
16	Forest Investigative Site 041	Lake Charles	Louisiana	United States	70629
17	Forest Investigative Site 040	Shreveport	Louisiana	United States	71104
18	Forest Investigative Site 039	Flowood	Mississippi	United States	39232
19	Forest Investigative Site 026	Creve Coeur	Missouri	United States	63141
20	Forest Investigative Site 037	Las Vegas	Nevada	United States	89102
21	Forest Investigative Site 023	Cherry Hill	New Jersey	United States	08002
22	Forest Investigative Site 014	Marlton	New Jersey	United States	08053
23	Forest Investigative Site 006	Albuquerque	New Mexico	United States	87109
24	Forest Investigative Site 003	Brooklyn	New York	United States	11214
25	Forest Investigative Site 025	New York	New York	United States	10021
26	Forest Investigative Site 036	Canton	Ohio	United States	44718
27	Forest Investigative Site 008	Dayton	Ohio	United States	45417
28	Forest Investigative Site 042	Salem	Oregon	United States	97301
29	Forest Investigative Site 009	Allentown	Pennsylvania	United States	18104
30	Forest Investigative Site 010	Media	Pennsylvania	United States	19063
31	Forest Investigative Site 033	Lincoln	Rhode Island	United States	02865
32	Forest Investigative Site 019	Memphis	Tennessee	United States	38119
33	Forest Investigative Site 007	Dallas	Texas	United States	75231
34	Forest Investigative Site 016	Houston	Texas	United States	77008
35	Forest Investigative Site 027	Houston	Texas	United States	77054
36	Forest Investigative Site 020	San Antonio	Texas	United States	78229
37	Forest Investigative Site 043	Bellevue	Washington	United States	98007
38	Forest Investigative Site 032	Seattle	Washington	United States	98104
39	Forest Investigative Site 311	Kardzhali		Bulgaria	6600
40	Forest Investigative Site 307	Kazanlak		Bulgaria	6100
41	Forest Investigative Site 310	Lovech		Bulgaria	5500
42	Forest Investigative Site 313	Novi Iskar		Bulgaria	1282
43	Forest Investigative Site 309	Pazardzhik		Bulgaria	4400
44	Forest Investigative Site 302	Pleven		Bulgaria	5800
45	Forest Investigative Site 301	Plovdiv		Bulgaria	4002
46	Forest Investigative Site 305	Sofia		Bulgaria	1431
47	Forest Investigative Site 306	Sofia		Bulgaria	1431
48	Forest Investigative Site 308	Tsarev Brod		Bulgaria	9747
49	Forest Investigative Site 312	Tserova Koria		Bulgaria	5047
50	Forest Investigative Site 102	Kelowna	British Columbia	Canada	V1Y 1Z9
51	Forest Investigative Site 103	Penticton	British Columbia	Canada	V2A 4M4
52	Forest Investigative Site 101	Chatham	Ontario	Canada	N7L 5L9
53	Forest Investigative Site 804	Barranquilla		Colombia
54	Forest Investigative Site 806	Barranquilla		Colombia
55	Forest Investigative Site 803	Bogota		Colombia
56	Forest Investigative Site 805	Bogotá		Colombia
57	Forest Investigative Site 808	Bogotá		Colombia
58	Forest Investigative Site 807	Pereira		Colombia
59	Forest Investigative Site 601	Arkhangelsk		Russian Federation	163530
60	Forest Investigative Site 605	Moscow		Russian Federation	107076
61	Forest Investigative Site 607	Moscow		Russian Federation	115522
62	Forest Investigative Site 611	Moscow		Russian Federation	117152
63	Forest Investigative Site 619	Moscow		Russian Federation	127083
64	Forest Investigative Site 603	Nizhniy Novgorod		Russian Federation	603152
65	Forest Investigative Site 612	Saint-Petersburg		Russian Federation	199034
66	Forest Investigative Site 617	Samara		Russian Federation	443016
67	Forest Investigative Site 616	Saratov		Russian Federation	410028
68	Forest Investigative Site 604	St. Petersburg		Russian Federation	190005
69	Forest Investigative Site 606	St. Petersburg		Russian Federation	190121
70	Forest Investigative Site 602	St. Petersburg		Russian Federation	191119
71	Forest Investigative Site 613	St. Petersburg		Russian Federation	191119
72	Forest Investigative Site 608	St. Petersburg		Russian Federation	192019
73	Forest Investigative Site 615	St. Petersburg		Russian Federation	192019
74	Forest Investigative Site 609	Tomsk		Russian Federation	634014
75	Forest Investigative Site 618	Tver		Russian Federation	170005
76	Forest Investigative Site 610	Voronezh		Russian Federation	394052
77	Forest Investigative Site 707	Kerch	AR Crimea	Ukraine	98310
78	Forest Investigative Site 709	Kherson	Vil. Stepanivka	Ukraine	73488
79	Forest Investigative Site 714	Donetsk		Ukraine	83008
80	Forest Investigative Site 712	Ivano-Frankivsk		Ukraine	76014
81	Forest Investigative Site 703	Kharkiv		Ukraine	61068
82	Forest Investigative Site 704	Kharkiv		Ukraine	61068
83	Forest Investigative Site 702	Kharkiv		Ukraine	61103
84	Forest Investigative Site 708	Kyiv		Ukraine	02660
85	Forest Investigative Site 701	Kyiv		Ukraine	04080
86	Forest Investigative Site 710	Odesa		Ukraine	65014
87	Forest Investigative Site 706	Simferopol		Ukraine	95006
88	Forest Investigative Site 705	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: NCT01396447
• Other Study ID Numbers: RGH-MD-56; 2011-002334-39
• First Posted: Jul 18, 2011
• Last Update Posted: May 1, 2018
• Last Verified: Mar 1, 2018

• Keywords provided by Forest Laboratories: Bipolar I disorder; Bipolar depression; Depression; Bipolar disorder
• Additional relevant MeSH terms: Depression; Depressive Disorder; Bipolar Disorder; Cariprazine

Study Results

Participant Flow

Recruitment Details	Adult participants with a diagnosis of bipolar I disorder with a current major depressive episode were considered for participation in the study.

Arm/Group Title	Placebo	Cariprazine 0.75 mg	Cariprazine 1.5 mg	Cariprazine 3.0 mg
Arm/Group Description	Participants received placebo orally once a day for 8 weeks.	Participants received cariprazine 0.5 mg orally once on Days 1-2 and cariprazine 0.75 mg orally once a day starting on Day 3 for the remainder of the 8 week treatment period.	Participants received cariprazine 0.5 mg orally once on Days 1-2, cariprazine 0.75 mg orally once on Days 3-4, cariprazine 1.0 mg orally once on Days 5-7, and cariprazine 1.5 mg orally once a day starting on Day 8 for the remainder of the 8 week treatment period.	Participants received cariprazine 0.5 mg orally once on Days 1-2, cariprazine 0.75 mg orally once on Days 3-4, cariprazine 1.0 mg orally once on Days 5-7, cariprazine 1.5 mg orally on Days 8-14, and cariprazine 3.0 mg orally once a day starting on Day 15 for the remainder of the 8 week treatment period.
Period Title: Overall Study
STARTED	148	143	147	146
Received Treatment	145	141	146	146
COMPLETED	105	103	117	94
NOT COMPLETED	43	40	30	52

Baseline Characteristics

Arm/Group Title	Placebo	Cariprazine 0.75 mg	Cariprazine 1.5 mg	Cariprazine 3.0 mg	Total
Arm/Group Description	Participants received placebo orally once a day for 8 weeks.	Participants received cariprazine 0.5 mg orally once on Days 1-2 and cariprazine 0.75 mg orally once a day starting on Day 3 for the remainder of the 8 week treatment period.	Participants received cariprazine 0.5 mg orally once on Days 1-2, cariprazine 0.75 mg orally once on Days 3-4, cariprazine 1.0 mg orally once on Days 5-7, and cariprazine 1.5 mg orally once a day starting on Day 8 for the remainder of the 8 week treatment period.	Participants received cariprazine 0.5 mg orally once on Days 1-2, cariprazine 0.75 mg orally once on Days 3-4, cariprazine 1.0 mg orally once on Days 5-7, cariprazine 1.5 mg orally on Days 8-14, and cariprazine 3.0 mg orally once a day starting on Day 15 for the remainder of the 8 week treatment period.	Total of all reporting groups
Overall Participants	145	141	146	146	578
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	43.6 (12.0)	40.1 (11.2)	40.9 (11.4)	42.8 (10.8)	41.9 (11.4)
Sex: Female, Male (Count of Participants)
Female	89 61.4%	91 64.5%	92 63%	88 60.3%	360 62.3%
Male	56 38.6%	50 35.5%	54 37%	58 39.7%	218 37.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	12 8.3%	13 9.2%	11 7.5%	12 8.2%	48 8.3%
Not Hispanic or Latino	133 91.7%	128 90.8%	135 92.5%	134 91.8%	530 91.7%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Count of Participants)
White	110 75.9%	111 78.7%	109 74.7%	113 77.4%	443 76.6%
Black or African-American	30 20.7%	26 18.4%	30 20.5%	26 17.8%	112 19.4%
Asian	1 0.7%	1 0.7%	2 1.4%	0 0%	4 0.7%
American Indian or Alaska Native	2 1.4%	1 0.7%	1 0.7%	3 2.1%	7 1.2%
Other	2 1.4%	2 1.4%	4 2.7%	4 2.7%	12 2.1%
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	79.98 (17.08)	80.81 (18.36)	81.43 (16.79)	81.45 (17.86)	80.92 (17.49)
Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	27.81 (5.27)	28.42 (5.71)	28.44 (5.39)	28.28 (5.64)	28.24 (5.50)
Waist circumference (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	91.40 (14.24)	93.32 (15.45)	93.38 (14.55)	93.24 (15.40)	92.83 (14.90)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in the Montgomery-Åsberg Depression Rating Scale Total Score at Week 6
Description	The Montgomery-Åsberg Depression Rating Scale is a 10-item, clinician-rated scale that evaluates the participant's depressive symptomatology during the past week. Participants are rated on items assessing feelings of sadness, lassitude, pessimism, inner tension, suicidality, reduced sleep or appetite, difficulty in concentration, and lack of interest. Each item is scored on a 7-point scale with a score of 0 reflecting no symptoms and a score of 6 reflecting symptoms of maximum severity. The scores on the 10 items are summed for a total score that can range from 0 to 60. A higher score indicates greater depression. A negative change score indicates improvement.
Time Frame	Baseline to Week 6

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All randomized participants who took at least 1 dose of investigational product and had at least 1 post-Baseline assessment of the Montgomery-Åsberg Depression Rating Scale.

Arm/Group Title	Placebo	Cariprazine 0.75 mg	Cariprazine 1.5 mg	Cariprazine 3.0 mg
Arm/Group Description	Participants received placebo orally once a day for 8 weeks.	Participants received cariprazine 0.5 mg orally once on Days 1-2 and cariprazine 0.75 mg orally once a day starting on Day 3 for the remainder of the 8 week treatment period.	Participants received cariprazine 0.5 mg orally once on Days 1-2, cariprazine 0.75 mg orally once on Days 3-4, cariprazine 1.0 mg orally once on Days 5-7, and cariprazine 1.5 mg orally once a day starting on Day 8 for the remainder of the 8 week treatment period.	Participants received cariprazine 0.5 mg orally once on Days 1-2, cariprazine 0.75 mg orally once on Days 3-4, cariprazine 1.0 mg orally once on Days 5-7, cariprazine 1.5 mg orally on Days 8-14, and cariprazine 3.0 mg orally once a day starting on Day 15 for the remainder of the 8 week treatment period.
Measure Participants	141	140	145	145
Least Squares Mean (Standard Error) [units on a scale]	-11.1 (0.9)	-13.0 (0.9)	-15.1 (0.8)	-13.7 (0.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Cariprazine 0.75 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1292
	Comments	The analysis included 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	Repeated measures mixed-effects model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.9
	Confidence Interval	(2-Sided) 95%; -4.3 to 0.5
	Parameter Dispersion	Type: Value:
	Estimation Comments	Cariprazine 0.75 mg vs Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Cariprazine 1.5 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0010
	Comments	The analysis included 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	Repeated measures mixed-effects model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-4.0
	Confidence Interval	(2-Sided) 95%; -6.3 to -1.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	Cariprazine 1.5 mg vs Placebo

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Cariprazine 3.0 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0374
	Comments	The analysis included 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	Repeated measures mixed-effects model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.5
	Confidence Interval	(2-Sided) 95%; -4.9 to -0.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	Cariprazine 3.0 mg vs Placebo

2. Secondary Outcome

Title	Change From Baseline in the Clinical Global Impressions-Severity Total Score at Week 6
Description	The Clinical Global Impressions-Severity scale is a clinician-rated scale that measures the overall severity of a participant's illness in comparison with the severity of illness in other participants the physician has observed. The participant is rated on a scale from 1 to 7 with 1 indicating a "normal state" and 7 indicating "among the most extremely ill participants." A higher score indicates greater illness. A negative change score indicates improvement.
Time Frame	Baseline to Week 6

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All randomized participants who took at least 1 dose of investigational product and had at least 1 post-Baseline assessment of the Montgomery-Åsberg Depression Rating Scale.

Arm/Group Title	Placebo	Cariprazine 0.75 mg	Cariprazine 1.5 mg	Cariprazine 3.0 mg
Arm/Group Description	Participants received placebo orally once a day for 8 weeks.	Participants received cariprazine 0.5 mg orally once on Days 1-2 and cariprazine 0.75 mg orally once a day starting on Day 3 for the remainder of the 8 week treatment period.	Participants received cariprazine 0.5 mg orally once on Days 1-2, cariprazine 0.75 mg orally once on Days 3-4, cariprazine 1.0 mg orally once on Days 5-7, and cariprazine 1.5 mg orally once a day starting on Day 8 for the remainder of the 8 week treatment period.	Participants received cariprazine 0.5 mg orally once on Days 1-2, cariprazine 0.75 mg orally once on Days 3-4, cariprazine 1.0 mg orally once on Days 5-7, cariprazine 1.5 mg orally on Days 8-14, and cariprazine 3.0 mg orally once a day starting on Day 15 for the remainder of the 8 week treatment period.
Measure Participants	141	140	145	145
Least Squares Mean (Standard Error) [units on a scale]	-1.0 (0.1)	-1.1 (0.1)	-1.4 (0.1)	-1.3 (0.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Cariprazine 0.75 mg
	Comments	The analysis included 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.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3025
	Comments
	Method	Repeated measures mixed-effects model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.4 to 0.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	Cariprazine 0.75 mg vs Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Cariprazine 1.5 mg
	Comments	The analysis included 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.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0044
	Comments
	Method	Repeated measures mixed-effects model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.4
	Confidence Interval	(2-Sided) 95%; -0.6 to -0.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Cariprazine 1.5 mg vs Placebo

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Cariprazine 3.0 mg
	Comments	The analysis included 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.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0489
	Comments
	Method	Repeated measures mixed-effects model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.3
	Confidence Interval	(2-Sided) 95%; -0.5 to -0.0
	Parameter Dispersion	Type: Value:
	Estimation Comments	Cariprazine 3.0 mg vs Placebo

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 took at least 1 dose of investigational product.
Arm/Group Title	Placebo		Cariprazine 0.75 mg		Cariprazine 1.5 mg		Cariprazine 3.0 mg
Arm/Group Description	Participants received placebo orally once a day for 8 weeks.		Participants received cariprazine 0.5 mg orally once on Days 1-2 and cariprazine 0.75 mg orally once a day starting on Day 3 for the remainder of the 8 week treatment period.		Participants received cariprazine 0.5 mg orally once on Days 1-2, cariprazine 0.75 mg orally once on Days 3-4, cariprazine 1.0 mg orally once on Days 5-7, and cariprazine 1.5 mg orally once a day starting on Day 8 for the remainder of the 8 week treatment period.		Participants received cariprazine 0.5 mg orally once on Days 1-2, cariprazine 0.75 mg orally once on Days 3-4, cariprazine 1.0 mg orally once on Days 5-7, cariprazine 1.5 mg orally on Days 8-14, and cariprazine 3.0 mg orally once a day starting on Day 15 for the remainder of the 8 week treatment period.
All Cause Mortality
	Placebo		Cariprazine 0.75 mg		Cariprazine 1.5 mg		Cariprazine 3.0 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/145 (0%)		0/141 (0%)		0/146 (0%)		0/146 (0%)
Serious Adverse Events
	Placebo		Cariprazine 0.75 mg		Cariprazine 1.5 mg		Cariprazine 3.0 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/145 (3.4%)		1/141 (0.7%)		2/146 (1.4%)		2/146 (1.4%)
Injury, poisoning and procedural complications
Fall	0/145 (0%)		0/141 (0%)		1/146 (0.7%)		1/146 (0.7%)
Lower limb fracture	0/145 (0%)		0/141 (0%)		0/146 (0%)		1/146 (0.7%)
Injury	0/145 (0%)		0/141 (0%)		1/146 (0.7%)		0/146 (0%)
Nervous system disorders
Vertigo CNS origin	0/145 (0%)		0/141 (0%)		0/146 (0%)		1/146 (0.7%)
Hemiparesis	1/145 (0.7%)		0/141 (0%)		0/146 (0%)		0/146 (0%)
Psychiatric disorders
Depression	1/145 (0.7%)		1/141 (0.7%)		0/146 (0%)		0/146 (0%)
Hypomania	0/145 (0%)		0/141 (0%)		1/146 (0.7%)		0/146 (0%)
Mania	1/145 (0.7%)		0/141 (0%)		0/146 (0%)		0/146 (0%)
Suicidal ideation	1/145 (0.7%)		0/141 (0%)		0/146 (0%)		0/146 (0%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	1/145 (0.7%)		0/141 (0%)		0/146 (0%)		0/146 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Cariprazine 0.75 mg		Cariprazine 1.5 mg		Cariprazine 3.0 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	42/145 (29%)		43/141 (30.5%)		51/146 (34.9%)		56/146 (38.4%)
Gastrointestinal disorders
Nausea	7/145 (4.8%)		12/141 (8.5%)		12/146 (8.2%)		12/146 (8.2%)
Diarrhoea	10/145 (6.9%)		2/141 (1.4%)		9/146 (6.2%)		3/146 (2.1%)
Nervous system disorders
Akathisia	2/145 (1.4%)		4/141 (2.8%)		7/146 (4.8%)		21/146 (14.4%)
Headache	17/145 (11.7%)		11/141 (7.8%)		11/146 (7.5%)		10/146 (6.8%)
Somnolence	7/145 (4.8%)		6/141 (4.3%)		10/146 (6.8%)		10/146 (6.8%)
Psychiatric disorders
Insomnia	12/145 (8.3%)		16/141 (11.3%)		10/146 (6.8%)		17/146 (11.6%)
Restlessness	5/145 (3.4%)		4/141 (2.8%)		4/146 (2.7%)		9/146 (6.2%)

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.