Safety and Efficacy of Cariprazine for Bipolar I Disorder

• Sponsor: Forest Laboratories (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01058668
• Collaborator: Gedeon Richter Ltd. (Industry)
• Enrollment: 497
• Locations: 66
• Arms: 3
• Duration (Months): 21.9
• Patients Per Site: 7.5
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The objective of this study is to evaluate the efficacy, safety, and tolerability of cariprazine monotherapy versus placebo for the treatment of acute manic or mixed episodes associated with bipolar I disorder.

Condition or Disease	Intervention/Treatment	Phase
Mania; Bipolar I Disorder	Drug: Cariprazine; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 497 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Double-Blind, Placebo-Controlled, Evaluation of the Safety and Efficacy of Cariprazine in Patients With Acute Mania Associated With Bipolar I Disorder
• Study Start Date: Feb 1, 2010
• Actual Primary Completion Date: Dec 1, 2011
• Actual Study Completion Date: Dec 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cariprazine (3-6 mg/day) Cariprazine 3 milligrams (mg) - 6 mg capsules oral administration, once per day for 3 weeks.	Drug: Cariprazine; Patients who meet eligibility criteria will be administered a once daily oral dose of cariprazine for three weeks. Upon completion of the study or early termination, patients will undergo a two week safety follow-up period.
Experimental: Cariprazine (6-12 mg/day) Cariprazine 6 mg - 12 mg capsules oral administration, once per day for 3 weeks.	Drug: Cariprazine; Patients who meet eligibility criteria will be administered a once daily oral dose of cariprazine for three weeks. Upon completion of the study or early termination, patients will undergo a two week safety follow-up period.
Placebo Comparator: Placebo Placebo dose-matching cariprazine capsules oral administration, once per day for 3 weeks.	Drug: Placebo; Patients who meet eligibility criteria will be administered a once daily oral dose of placebo for three weeks.

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in the Young Mania Rating Scale (YMRS) Total Score at Week 3 [Baseline, Week 3]

   The YMRS is an 11-item scale that assesses manic symptoms based on the participant's perception of his or her condition over the previous 48 hours, as well as the physician's clinical observations during the interview. The 11-items are elevated mood, increased motor activity-energy, sexual interest, sleep, irritability, rate and amount of speech, language-thought disorder, content, disruptive-aggressive behavior, appearance, and insight. The severity of the abnormality for 7-items are rated on a five-point scale (0-4) and 4-items on a nine-point scale (0-8). The individual scores are summed for a total possible score of 0 (best) to 60 (worst). A negative change from Baseline indicates improvement. Analysis is a mixed model for repeated measurements (MMRM) using observed cases, with treatment group, pooled study center, visit, treatment group-by-visit interaction as factors, baseline value and baseline-by-visit interaction as covariates and an unstructured covariance matrix.

Secondary Outcome Measures

1. Change From Baseline in Clinical Global Impression-Severity (CGI-S) Total Score at Week 3 [Baseline, Week 3]

   The CGI-S measures the investigator's assessment of overall severity of the participant's illness compared with the severity of illness in other patients the physician has observed using a 7-point scale (1=Normal, not ill at all to 7= Among the most extremely ill participants). A negative change from Baseline indicates improvement. Analysis is based on a MMRM using the observed cases data, with treatment group, pooled study center, visit, treatment group-by-visit interaction as factors, baseline value and baseline-by-visit interaction as covariates and an unstructured covariance matrix.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

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

• Patients 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 for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (SCID) manic or mixed type with or without psychotic symptoms

• Voluntarily hospitalized for current manic episode

• Patients with normal physical examination, laboratory, vital signs,and/ or electrocardiogram (ECG)

Exclusion Criteria:

• Patients 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 six months

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Forest Investigative Site 018	Little Rock	Arkansas	United States	72211
2	Forest Investigative Site 012	Cerritos	California	United States	90703
3	Forest Investigative Site 010	Costa Mesa	California	United States	92626
4	Forest Investigative Site 005	Oceanside	California	United States	92056
5	Forest Investigative Site 023	San Diego	California	United States	92102
6	Forest Investigative Site 017	San Diego	California	United States	92103
7	Forest Investigative Site 024	Santa Ana	California	United States	92701
8	Forest Investigative Site 016	New Britain	Connecticut	United States	06050
9	Forest Investigative Site 007	Washington	District of Columbia	United States	20016
10	Forest Investigative Site 002	Kissimmee	Florida	United States	34741
11	Forest Investigative Site 003	Orlando	Florida	United States	32821
12	Forest Investigative Site 026	Atlanta	Georgia	United States	30308
13	Forest Investigative Site 013	Honolulu	Hawaii	United States	96813
14	Forest Investigative Site 011	Hoffman Estates	Illinois	United States	60169
15	Forest Investigative Site 021	Greenwood	Indiana	United States	46143
16	Forest Investigative Site 001	Shreveport	Louisiana	United States	71115
17	Forest Investigative Site 006	Rockville	Maryland	United States	20850
18	Forest Investigative Site 025	St. Louis	Missouri	United States	63118
19	Forest Investigative Site 008	Cedarhurst	New York	United States	11516
20	Forest Investigative Site 019	Philadelphia	Pennsylvania	United States	19139
21	Forest Investigative Site 015	Memphis	Tennessee	United States	38119
22	Forest Investigative Site 004	Irving	Texas	United States	75062
23	Forest Investigative Site 014	Bothell	Washington	United States	98011
24	Forest Investigative Site 607	Rijeka		Croatia	51 000
25	Forest Investigative Site 602	Zagreb		Croatia	10 000
26	Forest Investigative Site 605	Zagreb		Croatia	10 000
27	Forest Investigative Site 606	Zagreb		Croatia	10 090
28	Forest Investigative Site 204	Targoviste	Dambovita	Romania	130086
29	Forest Investigative Site 210	Craiova	Dolj	Romania	200745
30	Forest Investigative Site 211	Timisoara	Timis	Romania	300182
31	Forest Investigative Site 212	Focsani	Vrancea	Romania	620165
32	Forest Investigative Site 209	Arad		Romania	310022
33	Forest Investigative Site 203	Bucharest		Romania	041915
34	Forest Investigative Site 205	Bucuresti		Romania	041915
35	Forest Investigative Site 206	Bucuresti		Romania	041915
36	Forest Investigative Site 208	Bucuresti		Romania	041915
37	Forest Investigative Site 202	Constanta		Romania	900002
38	Forest Investigative Site 201	Craiova		Romania	200260
39	Forest Investigative Site 501	Lipetsk		Russian Federation	398007
40	Forest Investigative Site 503	Moscow		Russian Federation	115522
41	Forest Investigative Site 507	Moscow		Russian Federation	115522
42	Forest Investigative Site 510	Moscow		Russian Federation	115522
43	Forest Investigative Site 506	Saint Petersburg		Russian Federation	190005
44	Forest Investigative Site 508	Saint Petersburg		Russian Federation	190121
45	Forest Investigative Site 509	Samara		Russian Federation	443016
46	Forest Investigative Site 504	Saratov		Russian Federation	410028
47	Forest Investigative Site 502	Smolensk		Russian Federation	214019
48	Forest Investigative Site 403	Belgrade		Serbia	11000
49	Forest Investigative Site 404	Belgrade		Serbia	11000
50	Forest Investigative Site 405	Belgrade		Serbia	11000
51	Forest Investigative Site 402	Kragujevac		Serbia	34000
52	Forest Investigative Site 401	Senta		Serbia	24400
53	Forest Investigative Site 308	Dnipropetrovsk		Ukraine	49027
54	Forest Investigative Site 315	Dnipropetrovsk		Ukraine	49115
55	Forest Investigative Site 301	Donetsk		Ukraine	83008
56	Forest Investigative Site 307	Kharkiv		Ukraine	61068
57	Forest Investigative Site 310	Kharkiv		Ukraine	61068
58	Forest Investigative Site 304	Kyiv		Ukraine	01030
59	Forest Investigative Site 305	Kyiv		Ukraine	02660
60	Forest Investigative Site 303	Kyiv		Ukraine	04080
61	Forest Investigative Site 309	Kyiv		Ukraine	04080
62	Forest Investigative Site 312	Kyiv		Ukraine	08631
63	Forest Investigative Site 306	Lugansk		Ukraine	91045
64	Forest Investigative Site 311	Lviv		Ukraine	79021
65	Forest Investigative Site 302	Odessa		Ukraine	65006
66	Forest Investigative Site 314	Poltava		Ukraine	36006

Sponsors and Collaborators

• Forest Laboratories
• Gedeon Richter Ltd.

Investigators

• Study Director: Elizabeth Diaz, MD, Forest Laboratories

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Forest Laboratories
• ClinicalTrials.gov Identifier: NCT01058668
• Other Study ID Numbers: RGH-MD-33
• First Posted: Jan 29, 2010
• Last Update Posted: Apr 12, 2017
• Last Verified: Mar 1, 2017

• Keywords provided by Forest Laboratories: Acute Mania; Bipolar I Disorder
• Additional relevant MeSH terms: Mania; Disease; Cariprazine

Study Results

Participant Flow

Arm/Group Title	Placebo	Cariprazine (3-6 mg/Day)	Cariprazine (6-12 mg/Day)
Arm/Group Description	Placebo dose-matching cariprazine capsules oral administration, once per day for 3 weeks.	Cariprazine 3 milligrams (mg) - 6 mg capsules oral administration, once per day for 3 weeks.	Cariprazine 6 mg - 12 mg capsules oral administration, once per day for 3 weeks.
Period Title: Double-blind Treatment Phase
STARTED	161	167	169
COMPLETED	122	129	119
NOT COMPLETED	39	38	50
Period Title: Double-blind Treatment Phase
STARTED	144	146	148
COMPLETED	139	146	141
NOT COMPLETED	5	0	7

Baseline Characteristics

Arm/Group Title	Placebo	Cariprazine (3-6 mg/Day)	Cariprazine (6-12 mg/Day)	Total
Arm/Group Description	Placebo dose-matching cariprazine capsules oral administration, once per day for 3 weeks.	Cariprazine 3 milligrams (mg) - 6 mg capsules oral administration, once per day for 3 weeks.	Cariprazine 6 mg - 12 mg capsules oral administration, once per day for 3 weeks.	Total of all reporting groups
Overall Participants	161	167	169	497
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	41.5 (11.4)	43.1 (12.2)	41.2 (11.3)	41.9 (11.7)
Sex: Female, Male (Count of Participants)
Female	72 44.7%	77 46.1%	84 49.7%	233 46.9%
Male	89 55.3%	90 53.9%	85 50.3%	264 53.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	10 6.2%	10 6%	4 2.4%	24 4.8%
Not Hispanic or Latino	151 93.8%	157 94%	165 97.6%	473 95.2%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Count of Participants)
White	114 70.8%	117 70.1%	114 67.5%	345 69.4%
Black/African American	44 27.3%	44 26.3%	51 30.2%	139 28%
Asian	1 0.6%	3 1.8%	1 0.6%	5 1%
American Indian or Alaska Native	2 1.2%	1 0.6%	1 0.6%	4 0.8%
Native Hawaiian or Other Pacific Islander	0 0%	1 0.6%	0 0%	1 0.2%
Other	0 0%	1 0.6%	1 0.6%	2 0.4%
Weight (kilogram (kg)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram (kg)]	81.70 (15.96)	82.42 (16.22)	81.49 (16.78)	81.87 (16.30)
Height (centimeter (cm)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [centimeter (cm)]	170.93 (9.88)	170.99 (9.15)	170.25 (9.36)	170.72 (9.45)
Body Mass Index (BMI) (kg/meter(m)^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/meter(m)^2]	27.99 (5.15)	28.22 (5.29)	28.04 (4.92)	28.08 (5.12)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in the Young Mania Rating Scale (YMRS) Total Score at Week 3
Description	The YMRS is an 11-item scale that assesses manic symptoms based on the participant's perception of his or her condition over the previous 48 hours, as well as the physician's clinical observations during the interview. The 11-items are elevated mood, increased motor activity-energy, sexual interest, sleep, irritability, rate and amount of speech, language-thought disorder, content, disruptive-aggressive behavior, appearance, and insight. The severity of the abnormality for 7-items are rated on a five-point scale (0-4) and 4-items on a nine-point scale (0-8). The individual scores are summed for a total possible score of 0 (best) to 60 (worst). A negative change from Baseline indicates improvement. Analysis is a mixed model for repeated measurements (MMRM) using observed cases, with treatment group, pooled study center, visit, treatment group-by-visit interaction as factors, baseline value and baseline-by-visit interaction as covariates and an unstructured covariance matrix.
Time Frame	Baseline, Week 3

Outcome Measure Data

Analysis Population Description

Intent-to-treat Population included all participants who received at least 1 dose of study drug and who had at least 1 post-baseline YMRS assessment.

Arm/Group Title	Placebo	Cariprazine (3-6 mg/Day)	Cariprazine (6-12 mg/Day)
Arm/Group Description	Placebo dose-matching cariprazine capsules oral administration, once per day for 3 weeks.	Cariprazine 3 milligrams (mg) - 6 mg capsules oral administration, once per day for 3 weeks.	Cariprazine 6 mg - 12 mg capsules oral administration, once per day for 3 weeks.
Measure Participants	160	165	167
Least Squares Mean (Standard Error) [score on a scale]	-12.5 (0.8)	-18.6 (0.8)	-18.5 (0.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Cariprazine (3-6 mg/Day)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-6.1
	Confidence Interval	(2-Sided) 95%; -8.4 to -3.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	cariprazine (3-6 mg/day) - placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Cariprazine (6-12 mg/Day)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-5.9
	Confidence Interval	(2-Sided) 95%; -8.2 to -3.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	cariprazine (6-12 mg/day) - placebo

2. Secondary Outcome

Title	Change From Baseline in Clinical Global Impression-Severity (CGI-S) Total Score at Week 3
Description	The CGI-S measures the investigator's assessment of overall severity of the participant's illness compared with the severity of illness in other patients the physician has observed using a 7-point scale (1=Normal, not ill at all to 7= Among the most extremely ill participants). A negative change from Baseline indicates improvement. Analysis is based on a MMRM using the observed cases data, with treatment group, pooled study center, visit, treatment group-by-visit interaction as factors, baseline value and baseline-by-visit interaction as covariates and an unstructured covariance matrix.
Time Frame	Baseline, Week 3

Outcome Measure Data

Analysis Population Description

Intent-to-treat Population included all participants who received at least 1 dose of study drug and who had at least 1 post-baseline YMRS assessment.

Arm/Group Title	Placebo	Cariprazine (3-6 mg/Day)	Cariprazine (6-12 mg/Day)
Arm/Group Description	Placebo dose-matching cariprazine capsules oral administration, once per day for 3 weeks.	Cariprazine 3 milligrams (mg) - 6 mg capsules oral administration, once per day for 3 weeks.	Cariprazine 6 mg - 12 mg capsules oral administration, once per day for 3 weeks.
Measure Participants	160	165	167
Least Squares Mean (Standard Error) [score on a scale]	-1.3 (0.1)	-1.9 (0.1)	-1.9 (0.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Cariprazine (3-6 mg/Day)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.6
	Confidence Interval	(2-Sided) 95%; -0.9 to -0.4
	Parameter Dispersion	Type: Value:
	Estimation Comments	cariprazine (3-6 mg/day) - placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Cariprazine (6-12 mg/Day)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.6
	Confidence Interval	(2-Sided) 95%; -0.9 to -0.3
	Parameter Dispersion	Type: Value:
	Estimation Comments	cariprazine (6-12 mg/day) - placebo

Adverse Events

Time Frame	First dose of study drug to 30 days past last dose (Up to 51 days)
Adverse Event Reporting Description	Safety Population included all participants who received at least 1 dose of study drug.
Arm/Group Title	Placebo		Cariprazine (3-6 mg/Day)		Cariprazine (6-12 mg/Day)
Arm/Group Description	Placebo dose-matching cariprazine capsules oral administration, once per day for 3 weeks.		Cariprazine 3 milligrams (mg) - 6 mg capsules oral administration, once per day for 3 weeks.		Cariprazine 6 mg - 12 mg capsules oral administration, once per day for 3 weeks.
All Cause Mortality
	Placebo		Cariprazine (3-6 mg/Day)		Cariprazine (6-12 mg/Day)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Cariprazine (3-6 mg/Day)		Cariprazine (6-12 mg/Day)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/161 (3.1%)		9/167 (5.4%)		5/169 (3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Endometrial cancer	0/161 (0%)		1/167 (0.6%)		0/169 (0%)
Psychiatric disorders
Mania	3/161 (1.9%)		3/167 (1.8%)		3/169 (1.8%)
Bipolar disorder	1/161 (0.6%)		1/167 (0.6%)		0/169 (0%)
Aggression	0/161 (0%)		1/167 (0.6%)		0/169 (0%)
Bipolar I disorder	1/161 (0.6%)		1/167 (0.6%)		1/169 (0.6%)
Depression	0/161 (0%)		0/167 (0%)		1/169 (0.6%)
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	0/161 (0%)		1/167 (0.6%)		0/169 (0%)
Surgical and medical procedures
Hospitalisation	0/161 (0%)		1/167 (0.6%)		0/169 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Cariprazine (3-6 mg/Day)		Cariprazine (6-12 mg/Day)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	63/161 (39.1%)		89/167 (53.3%)		90/169 (53.3%)
Gastrointestinal disorders
Nausea	9/161 (5.6%)		16/167 (9.6%)		19/169 (11.2%)
Constipation	5/161 (3.1%)		8/167 (4.8%)		18/169 (10.7%)
Vomiting	10/161 (6.2%)		15/167 (9%)		14/169 (8.3%)
Dyspepsia	5/161 (3.1%)		7/167 (4.2%)		10/169 (5.9%)
Diarrhoea	12/161 (7.5%)		4/167 (2.4%)		9/169 (5.3%)
Nervous system disorders
Akathisia	8/161 (5%)		29/167 (17.4%)		38/169 (22.5%)
Headache	15/161 (9.3%)		19/167 (11.4%)		20/169 (11.8%)
Extrapyramidal disorder	8/161 (5%)		16/167 (9.6%)		12/169 (7.1%)
Tremor	3/161 (1.9%)		4/167 (2.4%)		10/169 (5.9%)
Dizziness	4/161 (2.5%)		9/167 (5.4%)		7/169 (4.1%)
Psychiatric disorders
Insomnia	15/161 (9.3%)		16/167 (9.6%)		17/169 (10.1%)
Restlessness	8/161 (5%)		15/167 (9%)		10/169 (5.9%)

Limitations/Caveats

All participants from 1 investigative site were excluded due to Good Clinical Practice (GCP) Violations.

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.