A Dose-finding Trial of OPC-34712 in Patients With Schizophrenia

• Sponsor: Otsuka Pharmaceutical Co., Ltd. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01451164
• Collaborator: (none)
• Enrollment: 459
• Location: 1
• Arms: 4

Study Details

Study Description

Brief Summary

To investigate the efficacy and safety of OPC-34712 in comparison with placebo in patients with schizophrenia.

Condition or Disease	Intervention/Treatment	Phase
Schizophrenia	Drug: OPC-34712; Drug: OPC-34712; Drug: OPC-34712; Drug: Placebo	Phase 2/Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 459 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Dose-finding Trial of OPC-34712 in Patients With Schizophrenia
• Study Start Date: Oct 1, 2011
• Actual Primary Completion Date: Jun 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: High dose	Drug: OPC-34712; orally administered once daily
Experimental: Mid dose	Drug: OPC-34712; orally administered once daily
Experimental: Low dose	Drug: OPC-34712; orally administered once daily
Placebo Comparator: Placebo	Drug: Placebo; orally administered once daily

Outcome Measures

Primary Outcome Measures

1. Mean Change From Baseline to Week 6 in Positive and Negative Syndrome Scale (PANSS) Total Score [Baseline, Weeks 1, 2, 3, 4, 5, and 6]

   The PANSS consisted of three subscales: a total of 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 (absence of symptoms) and a score of 7 (extremely severe symptoms). The PANSS total score was the sum of the rating scores for 7 positive scale items, 7 negative scale items, and 16 general psychopathology scale items from the PANSS panel. The PANSS total score ranged from 30 (best possible outcome) to 210 (worst possible outcome).

Secondary Outcome Measures

1. Mean Change From Baseline to Week 6 in PANSS Positive Subscale Score. [Baseline, Weeks 1, 2, 3, 4, 5, and 6]

   PANSS consisted of three subscales: a total of 30 symptom constructs. For each construct, severity was rated on a 7-point scale, with a score of 1 (absence of symptoms) and a score of 7 (extremely severe symptoms). The PANSS positive subscale score was the sum of the rating scores for the 7 positive scale items from the PANSS panel. The 7 positive symptom constructs are delusions, conceptual disorganization, hallucinatory behavior, excitement, grandiosity, suspiciousness, and hostility. The PANSS positive subscale score ranged from 7 (best possible outcome) to 49 (worst possible outcome).

2. Mean Change From Baseline to Week 6 in PANSS Negative Subscale Score. [Baseline, Weeks 1, 2, 3, 4, 5, and 6]

   The PANSS consisted of three subscales: a total of 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 (absence of symptoms) and a score of 7 (extremely severe symptoms). The PANSS negative subscale score was the sum of the rating scores for the 7 negative scale items from the PANSS panel. The 7 negative symptom constructs: blunted affect, emotional withdrawal, poor rapport, passive/apathetic social withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, stereotyped thinking. The PANSS negative subscale score ranged from 7 (best possible outcome) to 49 (worst possible outcome).

3. Mean Change From Baseline to Week 6 in Clinical Global Impression-Severity of Illness (CGI-S) [Baseline, Weeks 1, 2, 3, 4, 5, and 6]

   Severity of illness for each participant was rated using the CGI-S, which was the secondary efficacy endpoint. To perform this assessment, the study physician answered the following question: "Considering your total clinical experience with this particular population, how mentally ill is the participant at this time?" Response choices included: 0 = not assessed; 1 = normal, not at all ill; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill participants.

4. Mean Clinical Global Impression-Improvement (CGI-I) Scale Score at Week 6. [Baseline, Weeks 1, 2, 3, 4, 5, and 6]

   The efficacy of trial medication was rated for each participant using the CGI-I. The study physician would rate the participant's total improvement whether or not it is due entirely to drug treatment. All responses were compared to the participant's condition at Baseline prior to the first dose of double-blind study medication. Response choices included: 0 = not assessed, 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Patients age 18 years or older to less than 65 years (at time of informed consent) diagnosed with schizophrenia based on DSM-IV-TR diagnostic criteria

• Patients who are hospitalized, or judged to required hospitalization, for acute relapse of schizophrenia at time of informed consent

• Patients who are experiencing acute exacerbation of psychotic symptoms

Exclusion Criteria:

• Female patients who are breastfeeding or who have a positive pregnancy test (urine) result prior to receiving investigational medicinal product

• Patients presenting a first episode of schizophrenia based on the clinical judgment of the investigator

• Patients who are diagnosed with a disease other than schizophrenia (schizoaffective disorder, major depressive disorder, bipolar disorder, posttraumatic stress disorder, anxiety disorder, delirium, dementia, amnesia, or other cognitive disorder) based on current DSM-IV-TR Axis Ι criteria, or who are diagnosed with a personality disorder (borderline, paranoid, histrionic, schizotypal, schizoid, or antisocial)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Kanto Region		Japan

Sponsors and Collaborators

• Otsuka Pharmaceutical Co., Ltd.

Investigators

• Study Director: kyoji Imaoka, Operating Officer, Otsuka Pharmaceutical Co., Ltd.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Otsuka Pharmaceutical Co., Ltd.
• ClinicalTrials.gov Identifier: NCT01451164
• Other Study ID Numbers: 331-10-002; JapicCTI-111631
• First Posted: Oct 13, 2011
• Last Update Posted: Oct 3, 2019
• Last Verified: Oct 1, 2016

• Additional relevant MeSH terms: Schizophrenia

Study Results

Participant Flow

Arm/Group Title	Brexpiprazole 1mg	Brexpiprazole 2mg	Brexpiprazole 4mg	Placebo
Arm/Group Description	Brexpiprazole 1 mg tablet once daily for 6 weeks.	Brexpiprazole 2 mg tablet once daily for 6 weeks.	Brexpiprazole 4 mg tablet once daily for 6 weeks.	Placebo tablet once daily for 6 weeks.
Period Title: Overall Study
STARTED	115	115	113	116
COMPLETED	72	81	68	70
NOT COMPLETED	43	34	45	46

Baseline Characteristics

Arm/Group Title	Brexpiprazole 1mg	Brexpiprazole 2mg	Brexpiprazole 4mg	Placebo	Total
Arm/Group Description	Brexpiprazole 1 mg tablet once daily for 6 weeks.	Brexpiprazole 2 mg tablet once daily for 6 weeks.	Brexpiprazole 4 mg tablet once daily for 6 weeks.	Placebo tablet once daily for 6 weeks.	Total of all reporting groups
Overall Participants	115	115	113	116	459
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	115 100%	115 100%	113 100%	116 100%	459 100%
>=65 years	0 0%	0 0%	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	44.7 (11.5)	43.3 (12.0)	44.1 (11.9)	45.0 (11.9)	44.3 (11.8)
Sex: Female, Male (Count of Participants)
Female	64 55.7%	54 47%	58 51.3%	65 56%	241 52.5%
Male	51 44.3%	61 53%	55 48.7%	51 44%	218 47.5%
Region of Enrollment (participants) [Number]
Japan	115 100%	115 100%	113 100%	116 100%	459 100%

Outcome Measures

1. Primary Outcome

Title	Mean Change From Baseline to Week 6 in Positive and Negative Syndrome Scale (PANSS) Total Score
Description	The PANSS consisted of three subscales: a total of 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 (absence of symptoms) and a score of 7 (extremely severe symptoms). The PANSS total score was the sum of the rating scores for 7 positive scale items, 7 negative scale items, and 16 general psychopathology scale items from the PANSS panel. The PANSS total score ranged from 30 (best possible outcome) to 210 (worst possible outcome).
Time Frame	Baseline, Weeks 1, 2, 3, 4, 5, and 6

Outcome Measure Data

Analysis Population Description

Efficacy sample（FAS : Full Analysis Set） consisted of all participants who received at least one dose of study medication and have Baseline and at least one Post-Baseline PANSS total score evaluation.

Arm/Group Title	Brexpiprazole 1mg	Brexpiprazole 2mg	Brexpiprazole 4mg	Placebo
Arm/Group Description	Brexpiprazole 1 mg tablet once daily for 6 weeks.	Brexpiprazole 2 mg tablet once daily for 6 weeks.	Brexpiprazole 4 mg tablet once daily for 6 weeks.	Placebo tablet once daily for 6 weeks.
Measure Participants	112	113	109	113
Week1	-2.68 (1.04)	-4.59 (1.03)	-3.42 (1.05)	-3.09 (1.03)
Week2	-5.07 (1.36)	-7.93 (1.33)	-6.80 (1.36)	-4.54 (1.34)
Week3	-6.92 (1.60)	-11.00 (1.55)	-9.42 (1.59)	-6.00 (1.58)
Week4	-8.40 (1.81)	-12.35 (1.74)	-11.21 (1.80)	-5.67 (1.80)
Week5	-8.13 (2.02)	-13.97 (1.93)	-11.09 (2.01)	-6.62 (2.03)
Week6	-8.26 (2.10)	-14.95 (2.00)	-11.49 (2.10)	-7.63 (2.11)

2. Secondary Outcome

Title	Mean Change From Baseline to Week 6 in PANSS Positive Subscale Score.
Description	PANSS consisted of three subscales: a total of 30 symptom constructs. For each construct, severity was rated on a 7-point scale, with a score of 1 (absence of symptoms) and a score of 7 (extremely severe symptoms). The PANSS positive subscale score was the sum of the rating scores for the 7 positive scale items from the PANSS panel. The 7 positive symptom constructs are delusions, conceptual disorganization, hallucinatory behavior, excitement, grandiosity, suspiciousness, and hostility. The PANSS positive subscale score ranged from 7 (best possible outcome) to 49 (worst possible outcome).
Time Frame	Baseline, Weeks 1, 2, 3, 4, 5, and 6

Outcome Measure Data

Analysis Population Description

Efficacy sample（FAS : Full Analysis Set） consisted of all participants who received at least one dose of study medication and have Baseline and at least one Post-Baseline PANSS total score evaluation.

Arm/Group Title	Brexpiprazole 1mg	Brexpiprazole 2mg	Brexpiprazole 4mg	Placebo
Arm/Group Description	Brexpiprazole 1 mg tablet once daily for 6 weeks.	Brexpiprazole 2 mg tablet once daily for 6 weeks.	Brexpiprazole 4 mg tablet once daily for 6 weeks.	Placebo tablet once daily for 6 weeks.
Measure Participants	112	113	109	113
Week1	-0.96 (0.36)	-1.31 (0.36)	-0.70 (0.36)	-1.09 (0.35)
Week2	-1.72 (0.45)	-2.31 (0.44)	-1.61 (0.45)	-2.25 (0.44)
Week3	-2.07 (0.52)	-3.21 (0.51)	-2.71 (0.52)	-2.57 (0.52)
Week4	-2.39 (0.57)	-3.69 (0.54)	-3.09 (0.56)	-2.90 (0.56)
Week5	-2.19 (0.62)	-4.05 (0.60)	-2.89 (0.62)	-3.26 (0.63)
Week6	-2.22 (0.64)	-4.32 (0.61)	-3.15 (0.64)	-3.69 (0.64)

3. Secondary Outcome

Title	Mean Change From Baseline to Week 6 in PANSS Negative Subscale Score.
Description	The PANSS consisted of three subscales: a total of 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 (absence of symptoms) and a score of 7 (extremely severe symptoms). The PANSS negative subscale score was the sum of the rating scores for the 7 negative scale items from the PANSS panel. The 7 negative symptom constructs: blunted affect, emotional withdrawal, poor rapport, passive/apathetic social withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, stereotyped thinking. The PANSS negative subscale score ranged from 7 (best possible outcome) to 49 (worst possible outcome).
Time Frame	Baseline, Weeks 1, 2, 3, 4, 5, and 6

Outcome Measure Data

Analysis Population Description

EEfficacy sample（FAS : Full Analysis Set） consisted of all participants who received at least one dose of study medication and have Baseline and at least one Post-Baseline PANSS total score evaluation.

Arm/Group Title	Brexpiprazole 1mg	Brexpiprazole 2mg	Brexpiprazole 4mg	Placebo
Arm/Group Description	Brexpiprazole 1 mg tablet once daily for 6 weeks.	Brexpiprazole 2 mg tablet once daily for 6 weeks.	Brexpiprazole 4 mg tablet once daily for 6 weeks.	Placebo tablet once daily for 6 weeks.
Measure Participants	112	113	109	113
Week1	-0.54 (0.27)	-0.83 (0.27)	-0.71 (0.27)	-0.59 (0.27)
Week2	-1.08 (0.37)	-1.46 (0.36)	-1.76 (0.36)	-0.72 (0.36)
Week3	-1.64 (0.41)	-2.41 (0.39)	-2.27 (0.40)	-1.14 (0.40)
Week4	-2.36 (0.46)	-2.90 (0.44)	-2.94 (0.46)	-0.81 (0.46)
Week5	-2.31 (0.52)	-3.24 (0.50)	-3.19 (0.52)	-0.85 (0.52)
Week6	-2.34 (0.55)	-3.48 (0.52)	-3.24 (0.55)	-1.20 (0.55)

4. Secondary Outcome

Title	Mean Change From Baseline to Week 6 in Clinical Global Impression-Severity of Illness (CGI-S)
Description	Severity of illness for each participant was rated using the CGI-S, which was the secondary efficacy endpoint. To perform this assessment, the study physician answered the following question: "Considering your total clinical experience with this particular population, how mentally ill is the participant at this time?" Response choices included: 0 = not assessed; 1 = normal, not at all ill; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill participants.
Time Frame	Baseline, Weeks 1, 2, 3, 4, 5, and 6

Outcome Measure Data

Analysis Population Description

Efficacy sample（FAS : Full Analysis Set） consisted of all participants who received at least one dose of study medication and have Baseline and at least one Post-Baseline PANSS total score evaluation.

Arm/Group Title	Brexpiprazole 1mg	Brexpiprazole 2mg	Brexpiprazole 4mg	Placebo
Arm/Group Description	Brexpiprazole 1 mg tablet once daily for 6 weeks.	Brexpiprazole 2 mg tablet once daily for 6 weeks.	Brexpiprazole 4 mg tablet once daily for 6 weeks.	Placebo tablet once daily for 6 weeks.
Measure Participants	112	113	109	113
Week1	-0.13 (0.06)	-0.18 (0.06)	-0.09 (0.06)	-0.15 (0.06)
Week2	-0.26 (0.08)	-0.36 (0.08)	-0.34 (0.08)	-0.25 (0.08)
Week3	-0.38 (0.09)	-0.52 (0.09)	-0.50 (0.09)	-0.36 (0.09)
Week4	-0.48 (0.09)	-0.62 (0.09)	-0.50 (0.09)	-0.40 (0.09)
Week5	-0.45 (0.11)	-0.81 (0.10)	-0.56 (0.10)	-0.52 (0.11)
Week6	-0.52 (0.11)	-0.85 (0.11)	-0.62 (0.11)	-0.57 (0.11)

5. Secondary Outcome

Title	Mean Clinical Global Impression-Improvement (CGI-I) Scale Score at Week 6.
Description	The efficacy of trial medication was rated for each participant using the CGI-I. The study physician would rate the participant's total improvement whether or not it is due entirely to drug treatment. All responses were compared to the participant's condition at Baseline prior to the first dose of double-blind study medication. Response choices included: 0 = not assessed, 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse.
Time Frame	Baseline, Weeks 1, 2, 3, 4, 5, and 6

Outcome Measure Data

Analysis Population Description

Efficacy sample（FAS : Full Analysis Set） consisted of all participants who received at least one dose of study medication and have Baseline and at least one Post-Baseline PANSS total score evaluation.

Arm/Group Title	Brexpiprazole 1mg	Brexpiprazole 2mg	Brexpiprazole 4mg	Placebo
Arm/Group Description	Brexpiprazole 1 mg tablet once daily for 6 weeks.	Brexpiprazole 2 mg tablet once daily for 6 weeks.	Brexpiprazole 4 mg tablet once daily for 6 weeks.	Placebo tablet once daily for 6 weeks.
Measure Participants	112	113	109	113
Week1	3.87 (0.92)	3.84 (0.96)	4.01 (0.93)	3.92 (1.04)
Week2	3.87 (1.10)	3.68 (1.02)	3.79 (1.13)	3.88 (1.26)
Week3	3.89 (1.20)	3.53 (1.04)	3.77 (1.20)	3.92 (1.36)
Week4	3.83 (1.23)	3.51 (1.16)	3.81 (1.23)	3.90 (1.36)
Week5	3.92 (1.27)	3.42 (1.23)	3.76 (1.30)	3.86 (1.48)
Week6	3.90 (1.32)	3.49 (1.30)	3.78 (1.33)	3.83 (1.49)

Adverse Events

Time Frame	Adverse events were monitored from signing of the informed consent form until follow-up for up to 30 days after the last dose of study medication.
Arm/Group Title	Brexpiprazole 1mg		Brexpiprazole 2mg		Brexpiprazole 4mg		Placebo
Arm/Group Description	Brexpiprazole 1 mg tablet once daily for 6 weeks.		Brexpiprazole 2 mg tablet once daily for 6 weeks.		Brexpiprazole 4 mg tablet once daily for 6 weeks.		Placebo tablet once daily for 6 weeks.
All Cause Mortality
	Brexpiprazole 1mg		Brexpiprazole 2mg		Brexpiprazole 4mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/115 (0%)		0/114 (0%)		0/113 (0%)		0/116 (0%)
Serious Adverse Events
	Brexpiprazole 1mg		Brexpiprazole 2mg		Brexpiprazole 4mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/115 (7%)		5/114 (4.4%)		5/113 (4.4%)		5/116 (4.3%)
Blood and lymphatic system disorders
Eosinophilia	1/115 (0.9%)		0/114 (0%)		0/113 (0%)		0/116 (0%)
Gastrointestinal disorders
Gastric ulcer haemorrhage	0/115 (0%)		1/114 (0.9%)		0/113 (0%)		0/116 (0%)
Investigations
Blood creatine phosphokinase increased	1/115 (0.9%)		0/114 (0%)		0/113 (0%)		0/116 (0%)
Electroencephalogram abnormal	1/115 (0.9%)		0/114 (0%)		0/113 (0%)		0/116 (0%)
Psychiatric disorders
Schizophrenia	7/115 (6.1%)		5/114 (4.4%)		4/113 (3.5%)		5/116 (4.3%)
Psychiatric symptom	1/115 (0.9%)		0/114 (0%)		0/113 (0%)		0/116 (0%)
Respiratory, thoracic and mediastinal disorders
Asphyxia	0/115 (0%)		0/114 (0%)		1/113 (0.9%)		0/116 (0%)
Other (Not Including Serious) Adverse Events
	Brexpiprazole 1mg		Brexpiprazole 2mg		Brexpiprazole 4mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	49/115 (42.6%)		46/114 (40.4%)		49/113 (43.4%)		56/116 (48.3%)
Gastrointestinal disorders
Constipation	8/115 (7%)		8/114 (7%)		7/113 (6.2%)		9/116 (7.8%)
Vomiting	7/115 (6.1%)		5/114 (4.4%)		8/113 (7.1%)		4/116 (3.4%)
Diarrhoea	4/115 (3.5%)		3/114 (2.6%)		6/113 (5.3%)		2/116 (1.7%)
Nausea	4/115 (3.5%)		6/114 (5.3%)		3/113 (2.7%)		2/116 (1.7%)
Dental caries	6/115 (5.2%)		0/114 (0%)		4/113 (3.5%)		1/116 (0.9%)
Infections and infestations
Nasopharyngitis	12/115 (10.4%)		8/114 (7%)		10/113 (8.8%)		11/116 (9.5%)
Investigations
Blood prolactin increased	1/115 (0.9%)		3/114 (2.6%)		7/113 (6.2%)		3/116 (2.6%)
Nervous system disorders
Headache	8/115 (7%)		9/114 (7.9%)		3/113 (2.7%)		5/116 (4.3%)
Akathisia	2/115 (1.7%)		4/114 (3.5%)		6/113 (5.3%)		8/116 (6.9%)
Psychiatric disorders
Schizophrenia	20/115 (17.4%)		13/114 (11.4%)		23/113 (20.4%)		28/116 (24.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.