Safety and Efficacy of Cariprazine for Mania

• Sponsor: Forest Laboratories (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01058096
• Collaborator: Gedeon Richter Ltd. (Industry)
• Enrollment: 323
• Locations: 28
• Arms: 2
• Duration (Months): 16.9
• Patients Per Site: 11.5
• Patients Per Site Per Month: 0.7

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
Bipolar Disorder; Mania	Drug: Cariprazine; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 323 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: Jul 1, 2011
• Actual Study Completion Date: Jul 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cariprazine Cariprazine 3 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.
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.

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 5-point scale (0-4) and 4-items on a 9-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 was a mixed model for repeated measurements (MMRM) observed cases (OC), 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 was based on a MMRM using the observed cases (OC) 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 004	Long Beach	California	United States	90813
2	Forest Investigative Site 005	Riverside	California	United States	92506
3	Forest Investigative Site 007	San Diego	California	United States	92123
4	Forest Investigative Site 009	Chicago	Illinois	United States	60640
5	Forest Investigative Site 006	Lake Charles	Louisiana	United States	70601
6	Forest Investigative Site 001	Flowood	Mississippi	United States	39232
7	Forest Investigative Site 003	Creve Couer	Missouri	United States	63141
8	Forest Investigative Site 008	Cleveland	Ohio	United States	44109
9	Forest Investigative Site 010	Oklahoma City	Oklahoma	United States	73116
10	Forest Investigative Site 002	Houston	Texas	United States	77008
11	Forest Investigative Site 106	Vijayawada	Andhra Pradesh	India	520002
12	Forest Investigative Site 112	Vizag	Andhra Pradesh	India	530017
13	Forest Investigator Site 108	Varanasi	Durgakund	India	221005
14	Forest Investigative Site 103	Ahmedabad	Gujarat	India	380013
15	Forest Investigative Site 120	Ahmedabad	Gujarat	India	380015
16	Forest Investigative Site 105	Bangalore	Karnataka	India	560010
17	Forest Investigative Site 107	Bangalore	Karnataka	India	560027
18	Forest Investigative Site 118	Mangalore	Karnataka	India	575001
19	Forest Investigative Site 113	Mangalore	Karnataka	India	575018
20	Forest Investigative Site 115	Manipal	Karnataka	India	576104
21	Forest Investigative Site 114	Mysore	Karnataka	India	570004
22	Forest Investigative Site 101	Aurangabad	Maharashtra	India	431005
23	Forest Investigative Site 110	Nasik	Maharashtra	India	422101
24	Forest Investigative Site 111	Pune	Maharashtra	India	411004
25	Forest Investigative Site 104	Pune	Maharashtra	India	411030
26	Forest Investigative Site 121	Chennai	Tamilnadu	India	600003
27	Forest Investigative Site 109	Kanpur	Uttar Pradesh	India	200005
28	Forest Investigative Site 119	Lucknow	Uttar Pradesh	India	226006

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: NCT01058096
• Other Study ID Numbers: RGH-MD-32
• First Posted: Jan 28, 2010
• Last Update Posted: Apr 17, 2017
• Last Verified: Mar 1, 2017

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

Study Results

Participant Flow

Pre-assignment Detail	11 participants from 1 investigational site are not included in the analyses due to Good Clinical Practice (GCP) violations.

Arm/Group Title	Placebo	Cariprazine
Arm/Group Description	Placebo dose-matching cariprazine capsules oral administration, once per day for 3 weeks.	Cariprazine 3 mg - 12 mg capsules oral administration, once per day for 3 weeks.
Period Title: Double-blind Treatment Phase
STARTED	154	158
COMPLETED	106	108
NOT COMPLETED	48	50
Period Title: Double-blind Treatment Phase
STARTED	133	134
COMPLETED	129	130
NOT COMPLETED	4	4

Baseline Characteristics

Arm/Group Title	Placebo	Cariprazine	Total
Arm/Group Description	Placebo dose-matching cariprazine capsules oral administration, once per day for 3 weeks.	Cariprazine 3 mg - 12 mg capsules oral administration, once per day for 3 weeks.	Total of all reporting groups
Overall Participants	154	158	312
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	36.7 (11.8)	35.8 (11.4)	36.3 (11.5)
Sex: Female, Male (Count of Participants)
Female	59 38.3%	53 33.5%	112 35.9%
Male	95 61.7%	105 66.5%	200 64.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	5 3.2%	5 3.2%	10 3.2%
Not Hispanic or Latino	149 96.8%	153 96.8%	302 96.8%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Count of Participants)
White	33 21.4%	33 20.9%	66 21.2%
Black/African American	29 18.8%	33 20.9%	62 19.9%
Asian	88 57.1%	91 57.6%	179 57.4%
American Indian or Alaska Native	3 1.9%	0 0%	3 1%
Other	1 0.6%	1 0.6%	2 0.6%
Weight (kilogram (kg)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram (kg)]	71.86 (20.27)	69.55 (20.06)	70.69 (20.17)
Height (centimeter (cm)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [centimeter (cm)]	166.39 (10.64)	165.21 (10.68)	165.79 (10.66)
Body Mass Index (BMI) (kg/meter(m)^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/meter(m)^2]	25.73 (5.98)	25.24 (5.98)	25.48 (5.98)

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 5-point scale (0-4) and 4-items on a 9-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 was a mixed model for repeated measurements (MMRM) observed cases (OC), 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
Arm/Group Description	Placebo dose-matching cariprazine capsules oral administration, once per day for 3 weeks.	Cariprazine 3 mg - 12 mg capsules oral administration, once per day for 3 weeks.
Measure Participants	152	158
Least Squares Mean (Standard Error) [score on a scale]	-15.3 (0.9)	-19.6 (0.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Cariprazine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0004
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-4.3
	Confidence Interval	(2-Sided) 95%; -6.7 to -1.9
	Parameter Dispersion	Type: Value:
	Estimation Comments	cariprazine - 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 was based on a MMRM using the observed cases (OC) 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
Arm/Group Description	Placebo dose-matching cariprazine capsules oral administration, once per day for 3 weeks.	Cariprazine 3 mg - 12 mg capsules oral administration, once per day for 3 weeks.
Measure Participants	152	158
Least Squares Mean (Standard Error) [score on a scale]	-1.3 (0.1)	-1.6 (0.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Cariprazine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0027
	Comments
	Method	MMRM analysis
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.4
	Confidence Interval	(2-Sided) 95%; -0.7 to -0.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	cariprazine - 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 randomized participants who took at least 1 dose of double-blind investigational product.
Arm/Group Title	Placebo		Cariprazine
Arm/Group Description	Placebo dose-matching cariprazine capsules oral administration, once per day for 3 weeks.		Cariprazine 3 mg - 12 mg capsules oral administration, once per day for 3 weeks.
All Cause Mortality
	Placebo		Cariprazine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Cariprazine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/154 (3.2%)		6/158 (3.8%)
General disorders
Non-cardiac chest pain	1/154 (0.6%)		0/158 (0%)
Infections and infestations
Hepatitis E	1/154 (0.6%)		0/158 (0%)
Nervous system disorders
Akathisia	0/154 (0%)		1/158 (0.6%)
Convulsion	0/154 (0%)		1/158 (0.6%)
Psychiatric disorders
Mania	1/154 (0.6%)		3/158 (1.9%)
Suicidal ideation	0/154 (0%)		1/158 (0.6%)
Bipolar disorder	1/154 (0.6%)		0/158 (0%)
Social circumstances
Social stay hospitalisation	1/154 (0.6%)		0/158 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Cariprazine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	69/154 (44.8%)		110/158 (69.6%)
Gastrointestinal disorders
Dyspepsia	7/154 (4.5%)		17/158 (10.8%)
Nausea	10/154 (6.5%)		16/158 (10.1%)
Vomiting	7/154 (4.5%)		16/158 (10.1%)
Constipation	10/154 (6.5%)		14/158 (8.9%)
Diarrhoea	6/154 (3.9%)		11/158 (7%)
Abdominal Discomfort	6/154 (3.9%)		8/158 (5.1%)
General disorders
Pyrexia	5/154 (3.2%)		9/158 (5.7%)
Nervous system disorders
Akathisia	8/154 (5.2%)		35/158 (22.2%)
Extrapyramidal Disorder	3/154 (1.9%)		24/158 (15.2%)
Tremor	9/154 (5.8%)		19/158 (12%)
Headache	16/154 (10.4%)		18/158 (11.4%)
Dizziness	6/154 (3.9%)		14/158 (8.9%)
Somnolence	2/154 (1.3%)		10/158 (6.3%)
Psychiatric disorders
Restlessness	1/154 (0.6%)		10/158 (6.3%)
Insomnia	8/154 (5.2%)		9/158 (5.7%)

Limitations/Caveats

All participants from 1 investigative site are excluded due to 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.