Safety and Efficacy of Cariprazine in Schizophrenia

• Sponsor: Forest Laboratories (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01104779
• Collaborator: Gedeon Richter Ltd. (Industry)
• Enrollment: 446
• Locations: 41
• Arms: 3
• Actual Duration (Months): 19.6
• Patients Per Site: 10.9
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

The objective of this study is to evaluate the efficacy, safety, and tolerability of cariprazine relative to placebo for the treatment of acute exacerbation of schizophrenia.

Condition or Disease	Intervention/Treatment	Phase
Schizophrenia	Drug: Cariprazine; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 446 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 the Acute Exacerbation of Schizophrenia
• Actual Study Start Date: Apr 27, 2010
• Actual Primary Completion Date: Dec 15, 2011
• Actual Study Completion Date: Dec 15, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cariprazine (3-6 mg/day) Cariprazine once daily fixed-flexible low dose	Drug: Cariprazine; Patients who meet eligibility criteria will be administered a once daily oral dose of cariprazine for six weeks. Upon completion of the study or early termination, patients will undergo a two week safety follow-up period.; Other Names: RGH-188
Experimental: Cariprazine (6-9 mg/day) Cariprazine once daily fixed-flexible high dose	Drug: Cariprazine; Patients who meet eligibility criteria will be administered a once daily oral dose of cariprazine for six weeks. Upon completion of the study or early termination, patients will undergo a two week safety follow-up period.; Other Names: RGH-188
Placebo Comparator: Placebo Placebo	Drug: Placebo; Patients who meet eligibility criteria will be administered a once daily oral dose of placebo for six weeks. Upon completion of the study or early termination, patients will undergo a two week safety follow-up period.

Outcome Measures

Primary Outcome Measures

1. Measurement of Schizophrenia Symptoms: Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score [Baseline to Week 6]

   The Positive and Negative Syndrome Scale is a 30-item rating scale specifically developed to asses both the positive and negative symptom syndromes of patients with schizophrenia. The PANSS total score is rated based on a structured clinical interview with the patient and supporting clinical information obtained from family, hospital staff, or other reliable informants. This assessment provides scores in 9 clinical domains, including a positive syndrome, a negative syndrome, depression, a composite index, and general psychopathology. Each item is scored on a 7-point (1 to 7) scale, with 1 being minimal impact, and 7 being highest impact. The cumulative score ranges from 30 to 210. A negative change score indicates improvement.

Secondary Outcome Measures

1. Measurement of Schizophrenia Symptoms: Change From Baseline in Clinical Global Impression-Severity (CGI-S) [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 60 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 schizophrenia (paranoid type, disorganized type, catatonic type or undifferentiated type), as confirmed by the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (SCID)

• Structured Clinical Interview for the Positive and Negative Syndrome Scale (SCIPANSS) total score ≥ 80 and ≤ 120

• Diagnosis of schizophrenia for a minimum of 1 year before Visit 1

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

Exclusion Criteria:

• Patients with a DSM-IV-TR diagnosis of Schizoaffective disorder, schizophreniform disorder, other psychotic disorders other than schizophrenia, or bipolar I or II disorder

• Patients in their first episode of psychosis

• Pregnant, breast-feeding, and/or planning to become pregnant and/or breastfeed during the study

• Pervasive developmental disorder, mental retardation, delirium, dementia, amnestic and other cognitive disorders

• Known or suspected borderline or antisocial personality disorder or other DSM-IV-TR axis II disorder of sufficient severity to interfere with participation in this study

• Substance abuse or dependence within the prior 3 months

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Forest Investigative Site 48	Costa Mesa	California	United States	92626
2	Forest Investigative Site 50	Long Beach	California	United States	90813
3	Forest Investigative Site 42	Paramount	California	United States	90723
4	Forest Investigative Site 054	San Diego	California	United States	92102
5	Forest Investigative Site 41	Kissimmee	Florida	United States	34741
6	Forest Investigative Site 055	Atlanta	Georgia	United States	30308
7	Forest Investigative Site 44	Rockville	Maryland	United States	20850
8	Forest Investigative Site 45	Saint Louis	Missouri	United States	63118
9	Forest Investigative Site 52	Las Vegas	Nevada	United States	89102
10	Forest Investigative Site 40	Cedarhurst	New York	United States	11516
11	Forest Investigative Site 46	Cincinnati	Ohio	United States	45219
12	Forest Investigative Site 47	Philadelphia	Pennsylvania	United States	19139
13	Forest Investigative 49	Memphis	Tennessee	United States	38119
14	Forest Investigative Site 51	Houston	Texas	United States	77021
15	Forest Investigative Site 43	Irving	Texas	United States	75062
16	Forest Investigative Site 601	Bello	Antioquia	Colombia	051053
17	Forest Investigative Site 604	Pereira	Risaralda	Colombia	660003
18	Forest Investigative Site 602	Bogota		Colombia	110121
19	Forest Investigative Site 605	Bogota		Colombia	111166
20	Forest Investigative Site 505	Vijayawada	Andhra Pradesh	India	520002
21	Forest Investigative Site 514	Visakhapatnam	Andhra Pradesh	India	530017
22	Forest Investigative Site 503	Ahmedabad	Gujarat	India	380006
23	Forest Investigative Site 519	Ahmedabad	Gujarat	India	380006
24	Forest Investigative Site 501	Ahmedabad	Gujarat	India	380013
25	Forest Investigative Site 508	Ahmedabad	Gujarat	India	380015
26	Forest Investigative Site 504	Bangalore	Karna	India	560010
27	Forest Investigative Site 517	Mangalore	Karna	India	575001
28	Forest Investigative Site 515	Mangalore	Karna	India	575018
29	Forest Investigative Site 516	Mysore	Karna	India	570015
30	Forest Investigative Site 500	Aurangabad	Mahara	India	431005
31	Forest Investigative Site 510	Mumbai	Mahara	India	400026
32	Forest Investigative Site 513	Nashik	Mahara	India	422101
33	Forest Investigative Site 511	Pune	Mahara	India	411001
34	Forest Investigative Site 502	Pune	Mahara	India	411030
35	Forest Investigative Site 509	Rajkot	Rajastan	India	360002
36	Forest Investigative Site 507	Kanpur	Uttar Pradesh	India	208005
37	Forest Investigative Site 518	Lucknow	Uttar Pradesh	India	226006
38	Forest Investigative Site 506	Varanasi	Uttar Pradesh	India	201010
39	Forest Investigative Site 704	Johannesburg	Gauteng	South Africa	2198
40	Forest Investigative Site 703	Cape Town	W Cape	South Africa	7530
41	Forest Investigative Site 706	Cape Town	W Cape	South Africa	7535

Sponsors and Collaborators

• Forest Laboratories
• Gedeon Richter Ltd.

Investigators

• Study Director: Raffaele Migliore, MA, Forest Laboratories

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Forest Laboratories
• ClinicalTrials.gov Identifier: NCT01104779
• Other Study ID Numbers: RGH-MD-05
• First Posted: Apr 15, 2010
• Last Update Posted: Nov 14, 2018
• Last Verified: Oct 1, 2018

• Keywords provided by Forest Laboratories: Schizophrenia; Acute Schizophrenia; Psychotropic Drugs; Antipsychotic Agents; Mental Disorders; Dopamine Agents; Central Nervous System Agents
• Additional relevant MeSH terms: Schizophrenia; Cariprazine

Study Results

Participant Flow

Pre-assignment Detail	Randomization and treatment assignment were based on a randomization scheme prepared by Allergan Biostatistics prior to the start of the study. No-drug washout period of up to 7 days.

Arm/Group Title	Placebo	Cariprazine (3-6 mg/Day)	Cariprazine (6-9 mg/Day)
Arm/Group Description	Oral administration. Once per day.	Oral administration. Once per day.	Oral administration. Once per day.
Period Title: Overall Study
STARTED	147	151	148
COMPLETED	88	96	86
NOT COMPLETED	59	55	62

Baseline Characteristics

Arm/Group Title	Placebo	Cariprazine (3-6 mg/Day)	Cariprazine (6-9 mg/Day)	Total
Arm/Group Description	Oral administration. Once per day.	Oral administration. Once per day.	Oral administration. Once per day.	Total of all reporting groups
Overall Participants	147	151	148	446
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	36.7 (11.3)	36.6 (10.5)	35.5 (9.3)	36.3 (10.4)
Sex/Gender, Customized (Count of Participants)
Male	110 74.8%	118 78.1%	113 76.4%	341 76.5%
Female	37 25.2%	33 21.9%	35 23.6%	105 23.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	23 15.6%	24 15.9%	27 18.2%	74 16.6%
Not Hispanic or Latino	124 84.4%	127 84.1%	121 81.8%	372 83.4%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Count of Participants)
White	26 17.7%	28 18.5%	30 20.3%	84 18.8%
Black or African-American	51 34.7%	56 37.1%	53 35.8%	160 35.9%
Asian	56 38.1%	56 37.1%	56 37.8%	168 37.7%
American Indian or Alaska Native	1 0.7%	1 0.7%	1 0.7%	3 0.7%
Native Hawaiian or Other Pacific Islander	1 0.7%	0 0%	2 1.4%	3 0.7%
Other	12 8.2%	10 6.6%	6 4.1%	28 6.3%

Outcome Measures

1. Primary Outcome

Title	Measurement of Schizophrenia Symptoms: Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score
Description	The Positive and Negative Syndrome Scale is a 30-item rating scale specifically developed to asses both the positive and negative symptom syndromes of patients with schizophrenia. The PANSS total score is rated based on a structured clinical interview with the patient and supporting clinical information obtained from family, hospital staff, or other reliable informants. This assessment provides scores in 9 clinical domains, including a positive syndrome, a negative syndrome, depression, a composite index, and general psychopathology. Each item is scored on a 7-point (1 to 7) scale, with 1 being minimal impact, and 7 being highest impact. The cumulative score ranges from 30 to 210. A negative change score indicates improvement.
Time Frame	Baseline to Week 6

Outcome Measure Data

Analysis Population Description

Intent-to-Treat Population, consisting of all patients in the Safety Population who had at least one postbaseline assessment of the PANSS total score.

Arm/Group Title	Placebo	Cariprazine (3-6 mg/Day)	Cariprazine (6-9 mg/Day)
Arm/Group Description	Oral administration. Once per day.	Oral administration. Once per day.	Oral administration. Once per day.
Measure Participants	145	147	147
Least Squares Mean (Standard Error) [Units on a Scale]	-16.0 (1.6)	-22.8 (1.6)	-25.9 (1.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Cariprazine (3-6 mg/Day)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0029
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-6.8
	Confidence Interval	(2-Sided) 95%; -11.3 to -2.4
	Parameter Dispersion	Type: Value:
	Estimation Comments	Cariprazine 3-6 mg/day vs Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Cariprazine (6-9 mg/Day)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-9.9
	Confidence Interval	(2-Sided) 95%; -14.5 to -5.3
	Parameter Dispersion	Type: Value:
	Estimation Comments	Cariprazine 6-9 mg/day vs Placebo

2. Secondary Outcome

Title	Measurement of Schizophrenia Symptoms: Change From Baseline in Clinical Global Impression-Severity (CGI-S)
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, consisting of all patients in the Safety Population who had at least one postbaseline assessment of the PANSS total score.

Arm/Group Title	Placebo	Cariprazine (3-6 mg/Day)	Cariprazine (6-9 mg/Day)
Arm/Group Description	Oral administration. Once per day.	Oral administration. Once per day.	Oral administration. Once per day.
Measure Participants	145	147	147
Least Squares Mean (Standard Error) [units on a scale]	-1.0 (0.1)	-1.4 (0.1)	-1.6 (0.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Cariprazine (3-6 mg/Day)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0115
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.3
	Confidence Interval	(2-Sided) 95%; -0.6 to -0.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	Cariprazine 3-6 mg/day vs Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Cariprazine (6-9 mg/Day)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.5
	Confidence Interval	(2-Sided) 95%; -0.8 to -0.3
	Parameter Dispersion	Type: Value:
	Estimation Comments	Cariprazine 6-9 mg/day vs Placebo

Adverse Events

Time Frame	Adverse Events were collected for 8 weeks.
Adverse Event Reporting Description	Safety Population: All patients in the randomized population who took at least 1 dose of double-blind investigational product.
Arm/Group Title	Placebo		Cariprazine (3-6 mg/Day)		Cariprazine (6-9 mg/Day)
Arm/Group Description	Oral administration. Once per day.		Oral administration. Once per day.		Oral administration. Once per day.
All Cause Mortality
	Placebo		Cariprazine (3-6 mg/Day)		Cariprazine (6-9 mg/Day)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/147 (0%)		0/151 (0%)		0/148 (0%)
Serious Adverse Events
	Placebo		Cariprazine (3-6 mg/Day)		Cariprazine (6-9 mg/Day)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/161 (8.1%)		9/167 (5.4%)		4/169 (2.4%)
Cardiac disorders
Angina pectoris	0/161 (0%)		0/167 (0%)		1/169 (0.6%)
Hepatobiliary disorders
Hepatitis	0/161 (0%)		0/167 (0%)		1/169 (0.6%)
Investigations
Blood pressure increased	0/161 (0%)		0/167 (0%)		1/169 (0.6%)
Heart rate irregular	0/161 (0%)		0/167 (0%)		1/169 (0.6%)
Metabolism and nutrition disorders
Hyponatraemia	1/161 (0.6%)		1/167 (0.6%)		0/169 (0%)
Nervous system disorders
Psychomotor hyperactivity	3/161 (1.9%)		3/167 (1.8%)		0/169 (0%)
Psychiatric disorders
Psychotic disorder	2/161 (1.2%)		4/167 (2.4%)		1/169 (0.6%)
Schizophrenia	6/161 (3.7%)		2/167 (1.2%)		0/169 (0%)
Anxiety	1/161 (0.6%)		0/167 (0%)		0/169 (0%)
Polydipsia psychogenic	1/161 (0.6%)		0/167 (0%)		0/169 (0%)
Schizophrenia, paranoid type	1/161 (0.6%)		0/167 (0%)		0/169 (0%)
Suicidal ideation	1/161 (0.6%)		0/167 (0%)		0/169 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Cariprazine (3-6 mg/Day)		Cariprazine (6-9 mg/Day)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	54/147 (36.7%)		84/151 (55.6%)		86/148 (58.1%)
Gastrointestinal disorders
Nausea	7/147 (4.8%)		7/151 (4.6%)		14/148 (9.5%)
Constipation	5/147 (3.4%)		14/151 (9.3%)		10/148 (6.8%)
Dyspepsia	6/147 (4.1%)		3/151 (2%)		10/148 (6.8%)
Vomiting	4/147 (2.7%)		8/151 (5.3%)		8/148 (5.4%)
Diarrhoea	2/147 (1.4%)		8/151 (5.3%)		6/148 (4.1%)
Investigations
Weight increased	2/147 (1.4%)		5/151 (3.3%)		8/148 (5.4%)
Nervous system disorders
Akathisia	5/147 (3.4%)		24/151 (15.9%)		25/148 (16.9%)
Headache	19/147 (12.9%)		14/151 (9.3%)		24/148 (16.2%)
Extrapyramidal disorder	4/147 (2.7%)		8/151 (5.3%)		15/148 (10.1%)
Tremor	3/147 (2%)		12/151 (7.9%)		8/148 (5.4%)
Psychiatric disorders
Insomnia	16/147 (10.9%)		10/151 (6.6%)		16/148 (10.8%)
Restlessness	7/147 (4.8%)		10/151 (6.6%)		15/148 (10.1%)

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.