STEP 210: Multicenter, Open-label, Safety and Tolerability Study

• Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01649557
• Collaborator: (none)
• Enrollment: 244
• Locations: 71
• Arm: 1
• Duration (Months): 25
• Patients Per Site: 3.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This will be a multicenter, 52 week, open label study to assess the safety and tolerability of oral OPC-34712 (1 to 6 mg) as monotherapy in adult patients with schizophrenia. The study will be conducted on an outpatient basis. Enrollment into the study will be drawn from eligible subjects who have completed participation in Study 331-07- 203 and who, in the investigator's judgment, would benefit from continued treatment with oral OPC-34712.

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 244 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Multicenter, Open-label Study to Assess the Safety and Tolerability of Oral OPC-34712 as Monotherapy in Adult Patients With Schizophrenia
• Study Start Date: Aug 1, 2009
• Actual Primary Completion Date: Aug 1, 2011
• Actual Study Completion Date: Sep 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Open-label OPDC-34712	Drug: OPC-34712; oral administered once daily

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Adverse Events (AEs) During First 6 Weeks. [From Baseline up to 6 weeks]

   AE was defined as any new medical problem, or exacerbation of an existing problem, experienced by a participant while enrolled in the trial, whether or not it was considered drug related by the investigator. A serious adverse event (SAE) was any untoward medical occurrence that resulted in death or was life-threatening or required inpatient hospitalization or prolonged hospitalization. A treatment-emergent AE (TEAE) was defined as an AE that started after start of study medication or an AE that continued from baseline and that worsened, was serious, was study medication related, or resulted in death, discontinuation, interruption, or reduction of study medication.

2. Number of Participants With AEs in 52-Week Enrollers. [From Baseline up to 52 weeks]

   AE was defined as any new medical problem, or exacerbation of an existing problem, experienced by a participant while enrolled in the trial, whether or not it was considered drug related by the investigator. A SAE was any untoward medical occurrence that resulted in death or was life-threatening or required inpatient hospitalization or prolonged hospitalization. A TEAE was defined as an AE that started after start of study medication or an AE that continued from baseline and that worsened, was serious, was study medication related, or resulted in death, discontinuation, interruption, or reduction of study medication.

Secondary Outcome Measures

1. Change From Baseline in Total Score of Positive and Negative Syndrome Scale (PANSS) by Study Week and at the Last Visit. [Baseline, Day 4, Week 1, 2, 4, 6, 8, 14, 20, 26, 32, 38, 44, 52 and Last Visit]

   The PANSS consisted of three subscales that contained a total of 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 that indicated the absence of symptoms and a score of 7 indicated extremely severe symptoms. The PANSS total score was the sum of the rating scores for 7 positive subscale items, 7 negative subscale items, and 16 general psychopathology subscale items from the PANSS panel. The PANSS total score ranges from 30-210, with higher scores indicating more severe symptoms.

2. Change From Baseline in Clinical Global Impression- Severity of Illness Scale (CGI-S) Score. [Baseline, Day 4, Week 1, 2, 4, 6, 8, 14, 20, 26, 32, 38, 44, 52 and Last Visit]

   The severity of illness for each participant were rated using the CGI-S. To perform this assessment, the investigator were to answer the following question: "Considering your total clinical experience with this particular population, how mentally ill was the participant at that time?" Response choices include: 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.

3. Change From Baseline in Personal and Social Performance Scale (PSP) Total Score. [Baseline, Week 1, 2, 6, 26, 52 and Last Visit]

   The PSP was a validated clinician-rated scale that measured personal and social functioning in four domains: socially useful activities (e.g, work and study), personal and social relationships, self-care, and disturbing and aggressive behaviors. Impairment in each of these domains was rated as absent, mild, manifest, marked, severe, or very severe. These ratings were then converted to a total score based on a 100-point scale using algorithms to identify the appropriate 10-point interval, and the rater's judgment that determined the total score within the 10-point interval. Participants with a PSP total score of 71 to 100 were considered to have mild functional difficulty. Scores of 31 to 70 represented manifest disabilities of various degrees and ratings of 1 to 30 indicated minimal functioning that required intense support and/or supervision.

4. Mean Clinical Global Impression- Improvement Scale (CGI-I) Total Score. [Day 4, Week 1, 2, 4, 6, 8, 14, 20, 26, 32, 38, 44, 52 and Last Visit]

   The efficacy of study medication was rated for each participant using the CGI-I. The investigator rated the participants total improvement whether or not it was due to the drug treatment. All responses were compared to the participants condition at Screening/Baseline (i.e, Week 6 visit of Protocol NCT00905307). 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.

5. Change From Baseline in PANSS Positive Subscale Score. [Baseline, Day 4, Week 1, 2, 4, 6, 8, 14, 20, 26, 32, 38, 44, 52 and Last Visit]

   The PANSS consisted of three subscales that contained a total of 30 symptom constructs. For each symptom construct, severity is rated on a 7-point scale, with a score of 1 indicated the absence of symptoms and a score of 7 indicated extremely severe symptoms. In positive subscale, the 7 positive symptom constructs were: delusions, conceptual disorganization, hallucinatory behavior, excitement, grandiosity, suspiciousness/persecution, and hostility. The PANSS positive symptom score ranges from 7-49, with higher scores indicating more severe symptoms.

6. Change From Baseline in PANSS Negative Subscale Score. [Baseline, Day 4, Week 1, 2, 4, 6, 8, 14, 20, 26, 32, 38, 44, 52 and Last Visit]

   The PANSS consisted of three subscales that contained a total of 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 indicated the absence of symptoms and a score of 7 indicated extremely severe symptoms. In negative subscale the severity was rated for the following 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 symptom score ranges from 7-49, with higher scores indicating more severe symptoms.

7. Percentage of Participants With a Positive Response Rate. [Last Visit]

   Response rate was defined as a reduction of ≥ 30% from Baseline in PANSS total score or CGI-I score of 1 (very much improved) or 2 (much improved) at the Last Visit.

8. Percentage of Participants Who Discontinued Due to Lack of Efficacy. [Last Visit]

   Discontinuation rate for the participants discontinued due to lack of efficacy were examined.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 67 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Subjects who participated in 331-07-203 and who, in the opinion of the investigator, have the potential to benefit from continued administration of OPC-34712 for the treatment of schizophrenia.

2. Outpatient status at last visit of Study 331-07-203.

Exclusion Criteria:

1. Sexually active males who are not practicing two different methods of birth control during the study and for 90 days after the last dose of study medication or who will not remain abstinent during the study and for 90 days after the last dose, or sexually active females of childbearing potential who are not practicing two different methods of birth control during the study and for 30 days after the last dose of study medication or who will not remain abstinent during the study and for 30 days after the last dose. If employing birth control, two of the following precautions must be used: vasectomy, tubal ligation, vaginal diaphragm, intrauterine device, birth control pill, birth control depot injection, birth control implant, condom, or sponge with spermicide.

2. Females who are breast-feeding and/or who have a positive pregnancy test result prior to receiving open-label OPC-34712.

3. Subjects who during the course of their participation in 331-07-203 were treated in violation of the protocol or who developed ANY exclusion criteria during the course of their participation.

4. Subjects who do not continue to meet all applicable inclusion/exclusion criteria for Protocol 331-07-203 at the last visit (ie, Week 6) of Protocol 331-07-203.

5. Subjects who represent a risk of committing suicide based on an answer of "Yes" to either Question 4 (Active Suicidal Ideation with Some Intent to Act, Without Specific Plan) or Question 5 (Active Suicidal Ideation with Specific Plan and Intent) on the "Suicidal Ideation" portion of the C-SSRS, or an answer of "Yes" to any of the suicide-related behaviors (actual attempt, interrupted attempt, aborted attempt, preparatory acts or behavior) on the "Suicidal Behavior" portion of the C-SSRS. A subject who has had any suicidal ideation within the last 6 months, any suicidal behaviors within the last two years, or who in the clinical judgment of the investigator presents a serious risk of suicide should be excluded from the study.

6. Subjects who would be likely to require prohibited concomitant therapy during the study.

7. Any subject who, in the opinion of the investigator, should not participate in the study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Otsuka Investigational Site	Little Rock	Arkansas	United States	72211
2	Otsuka Investigational Site	Escondido	California	United States	92025
3	Otsuka Investigational Site	Garden Grove	California	United States	92845
4	Otsuka Investigational Site	Long Beach	California	United States	90813
5	Otsuka Investigational Site	Oceanside	California	United States	92056
6	Otsuka Investigational Site	Pasadena	California	United States	91106
7	Otsuka Investigational Site	San Diego	California	United States	92102
8	Otsuka Investigational Site	San Diego	California	United States	92123
9	Otsuka Investigational Site	Santa Ana	California	United States	92701
10	Otsuka Investigational Site	Washington	District of Columbia	United States	20016
11	Otsuka Investigational Site	Bradenton	Florida	United States	34208
12	Otsuka Investigational Site	Maitland	Florida	United States	32751
13	Otsuka Investigational Site	St. Louis	Missouri	United States	63118
14	Otsuka Investigational Site	Cedarhurst	New York	United States	11516
15	Otsuka Investigational Site	Philadelphia	Pennsylvania	United States	19139
16	Otsuka Investigational Site	Austin	Texas	United States	78731
17	Otsuka Investigational Site	Burgas		Bulgaria	8000
18	Otsuka Investigational Site	Kazanlak		Bulgaria	6100
19	Otsuka Investigational Site	Pazardzhik		Bulgaria	4400
20	Otsuka Investigational Site	Plovdiv		Bulgaria	4002
21	Otsuka Investigational Site	Radnevo		Bulgaria	6260
22	Otsuka Investigational Site	Ruse		Bulgaria	7003
23	Otsuka Investigational Site	Rijeka		Croatia	51 000
24	Otsuka Investigational Site	Zagreb		Croatia	10 090
25	Otsuka Investigational Site	Vijaywada	Andh Prad	India	520002
26	Otsuka Investigational Site	Visakhapatnam	Andh Prad	India	530017
27	Otsuka Investigational Site	Ahmedabad	Gujarat	India	380015
28	Otsuka Investigational Site	Bangalore	Karna	India	560010
29	Otsuka Investigational Site	Mangalore	Karna	India	575001
30	Otsuka Investigational Site	Mangalore	Karna	India	575018
31	Otsuka Investigational Site	Pune	Mahara	India	411 004
32	Otsuka Investigational Site	Chennai	Tamilnadu	India	600003
33	Otsuka Investigational Site	Varanasi	Uttar Prad	India	221005
34	Otsuka Investigational Site	Chuncheon		Korea, Republic of	200-704
35	Otsuka Investigational Site	Incheon		Korea, Republic of	400-711
36	Otsuka Investigational Site	Incheon		Korea, Republic of	405-760
37	Otsuka Investigational Site	Seoul		Korea, Republic of	143-711
38	Otsuka Investigational Site	Cebu City		Philippines	6000
39	Otsuka Investigational Site	Mandaluyong City		Philippines	1553
40	Otsuka Investigational Site	Arad		Romania	310022
41	Otsuka Investigational Site	Bucuresti 2		Romania	041914
42	Otsuka Investigational Site	Bucuresti 3		Romania	041914
43	Otsuka Investigational Site	Bucuresti		Romania	010825
44	Otsuka Investigational Site	Bucuresti		Romania	041914
45	Otsuka Investigational Site	Cluj - Napoca		Romania	400012
46	Otsuka Investigational Site	Oradea		Romania	410154
47	Otsuka Investigational Site	Moscow Region		Russian Federation	141371
48	Otsuka Investigational Site	Moscow		Russian Federation	115522
49	Otsuka Investigational Site	St. Petersburg		Russian Federation	190121
50	Otsuka Investigational Site	St. Petersburg		Russian Federation	193167
51	Otsuka Investigational Site	St. Petersburg		Russian Federation	197341
52	Otsuka Investigational Site	Zagorodnoye		Russian Federation	117152
53	Otsuka Investigational Site	Belgrade 2		Serbia	11000
54	Otsuka Investigational Site	Belgrade		Serbia	11000
55	Otsuka Investigational Site	Kragujevac		Serbia	34000
56	Otsuka Investigational Site	NoviSad		Serbia	21000
57	Otsuka Investigational Site	Bojnice		Slovakia	92701
58	Otsuka Investigational Site	Bratislava		Slovakia	82606
59	Otsuka Investigational Site	Liptovsky Mikulas		Slovakia	03123
60	Otsuka Investigational Site	Rimavska Sobota		Slovakia	97912
61	Otsuka Investigational Site	Zilina		Slovakia	01207
62	Otsuka Investigational Site	Hualian		Taiwan	981
63	Otsuka Investigational Site	Taipei		Taiwan	249
64	Otsuka Investigational Site	Chernigiv		Ukraine	14005
65	Otsuka Investigational Site	Dnipropetrovsk		Ukraine	49005
66	Otsuka Investigational Site	Kyiv		Ukraine	02660
67	Otsuka Investigational Site	Kyiv		Ukraine	04080
68	Otsuka Investigational Site	Kyiv		Ukraine	04655
69	Otsuka Investigational Site	Simferopol		Ukraine	95006
70	Otsuka Investigational Site	Stepanivka		Ukraine	73488
71	Otsuka Investigational Site	Vinnytsya		Ukraine	21005

Sponsors and Collaborators

• Otsuka Pharmaceutical Development & Commercialization, Inc.

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Otsuka Pharmaceutical Development & Commercialization, Inc.
• ClinicalTrials.gov Identifier: NCT01649557
• Other Study ID Numbers: 331-08-210
• First Posted: Jul 25, 2012
• Last Update Posted: Oct 29, 2015
• Last Verified: Sep 1, 2015

• Keywords provided by Otsuka Pharmaceutical Development & Commercialization, Inc.: Schizophrenia
• Additional relevant MeSH terms: Schizophrenia

Study Results

Participant Flow

Recruitment Details	The protocol was initially approved as a 6-week trial and later extended to a 52-week trial (Amendment 2). The trial enrolled 244 participants at 73 sites in 12 countries. Of the 244 participants, 28 were included in the 52-week enrollment population.
Pre-assignment Detail	Trial consisted of a screening visit, treatment phase and safety follow-up at 30 (± 2) days after the last dose of medication. Eligible participants for the trial were those who completed protocol NCT00905307 and who in the investigators judgment would benefit from the treatment.

Arm/Group Title	Prior Brexpiprazole	Prior Placebo	Prior Aripiprazole
Arm/Group Description	The participants were grouped based on the medications that they received prior to the trial. The participants in prior brexpiprazole group included the participants who received brexpiprazole prior to the trial. The participants began dosing with brexpiprazole 2 mg daily and the dosage was increased upto 6 mg daily if the dose was well-tolerated.	The participants were grouped based on the medications that they received prior to the trial. The participants in prior placebo group included the participants who received placebo prior to the trial. The participants began dosing with brexpiprazole 2 mg daily and the dosage was increased upto 6 mg daily if the dose was well-tolerated.	The participants were grouped based on the medications that they received prior to the trial. The participants in prior aripiprazole group included the participants who received aripiprazole prior to the trial. The participants began dosing with brexpiprazole 2 mg daily and the dosage was increased upto 6 mg daily if the dose was well-tolerated.
Period Title: Overall Study
STARTED	179	41	24
6-week Enrollers	159	35	22
52-week Enrollers	20	6	2
COMPLETED	135	27	15
NOT COMPLETED	44	14	9

Baseline Characteristics

Arm/Group Title	Prior Brexiprazole	Prior Placebo	Prior Apripiprazole	Total
Arm/Group Description	The participants were grouped based on the medications that they received prior to the trial. The participants in prior brexpiprazole group included the participants who received brexpiprazole prior to the trial. The participants began dosing with brexpiprazole 2 mg daily and the dosage was increased upto 6 mg daily if the dose was well-tolerated.	The participants were grouped based on the medications that they received prior to the trial. The participants in prior placebo group included the participants who received placebo prior to the trial. The participants began dosing with brexpiprazole 2 mg daily and the dosage was increased upto 6 mg daily if the dose was well-tolerated.	The participants were grouped based on the medications that they received prior to the trial. The participants in prior aripiprazole group included the participants who received aripiprazole prior to the trial. The participants began dosing with brexpiprazole 2 mg daily and the dosage was increased upto 6 mg daily if the dose was well-tolerated.	Total of all reporting groups
Overall Participants	179	41	24	244
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	39.1 (10.1)	41.4 (11.2)	41.2 (12)	39.7 (10.5)
Sex: Female, Male (Count of Participants)
Female	69 38.5%	17 41.5%	5 20.8%	91 37.3%
Male	110 61.5%	24 58.5%	19 79.2%	153 62.7%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Adverse Events (AEs) During First 6 Weeks.
Description	AE was defined as any new medical problem, or exacerbation of an existing problem, experienced by a participant while enrolled in the trial, whether or not it was considered drug related by the investigator. A serious adverse event (SAE) was any untoward medical occurrence that resulted in death or was life-threatening or required inpatient hospitalization or prolonged hospitalization. A treatment-emergent AE (TEAE) was defined as an AE that started after start of study medication or an AE that continued from baseline and that worsened, was serious, was study medication related, or resulted in death, discontinuation, interruption, or reduction of study medication.
Time Frame	From Baseline up to 6 weeks

Outcome Measure Data

Analysis Population Description

The safety dataset comprised of those participants who received at least one dose of open-label brexpiprazole and were enrolled in the 6-week study.

Arm/Group Title	Prior Brexpiprazole	Prior Placebo	Prior Aripiprazole
Arm/Group Description	The participants were grouped based on the medications that they received prior to the trial. The participants in prior brexpiprazole group included the participants who received brexpiprazole prior to the trial. The participants began dosing with brexpiprazole 2 mg daily and the dosage was increased upto 6 mg daily if the dose was well-tolerated.	The participants were grouped based on the medications that they received prior to the trial. The participants in prior placebo group included the participants who received placebo prior to the trial. The participants began dosing with brexpiprazole 2 mg daily and the dosage was increased upto 6 mg daily if the dose was well-tolerated.	The participants were grouped based on the medications that they received prior to the trial. The participants in prior aripiprazole group included the participants who received aripiprazole prior to the trial. The participants began dosing with brexpiprazole 2 mg daily and the dosage was increased upto 6 mg daily if the dose was well-tolerated.
Measure Participants	178	41	23
Participants with AEs	79 44.1%	19 46.3%	7 29.2%
Participants with TEAEs	78 43.6%	19 46.3%	7 29.2%
Participants with serious TEAEs	4 2.2%	6 14.6%	1 4.2%
Participants with severe TEAEs	2 1.1%	3 7.3%	2 8.3%

2. Primary Outcome

Title	Number of Participants With AEs in 52-Week Enrollers.
Description	AE was defined as any new medical problem, or exacerbation of an existing problem, experienced by a participant while enrolled in the trial, whether or not it was considered drug related by the investigator. A SAE was any untoward medical occurrence that resulted in death or was life-threatening or required inpatient hospitalization or prolonged hospitalization. A TEAE was defined as an AE that started after start of study medication or an AE that continued from baseline and that worsened, was serious, was study medication related, or resulted in death, discontinuation, interruption, or reduction of study medication.
Time Frame	From Baseline up to 52 weeks

Outcome Measure Data

Analysis Population Description

Those participants who received at least one dose of open-label brexpiprazole and who were enrolled in the 52-week study.

Arm/Group Title	Prior Brexpiprazole	Prior Placebo	Prior Aripiprazole
Arm/Group Description	The participants were grouped based on the medications that they received prior to the trial. The participants in prior brexpiprazole group included the participants who received brexpiprazole prior to the trial. The participants began dosing with brexpiprazole 2 mg daily and the dosage was increased upto 6 mg daily if the dose was well-tolerated.	The participants were grouped based on the medications that they received prior to the trial. The participants in prior placebo group included the participants who received placebo prior to the trial. The participants began dosing with brexpiprazole 2 mg daily and the dosage was increased upto 6 mg daily if the dose was well-tolerated.	The participants were grouped based on the medications that they received prior to the trial. The participants in prior aripiprazole group included the participants who received aripiprazole prior to the trial. The participants began dosing with brexpiprazole 2 mg daily and the dosage was increased upto 6 mg daily if the dose was well-tolerated.
Measure Participants	20	6	2
Participants with AEs	15 8.4%	4 9.8%	2 8.3%
Participants with TEAEs	15 8.4%	4 9.8%	2 8.3%
Participants with serious TEAEs	0 0%	0 0%	0 0%
Participants with severe TEAEs	0 0%	1 2.4%	0 0%

3. Secondary Outcome

Title	Change From Baseline in Total Score of Positive and Negative Syndrome Scale (PANSS) by Study Week and at the Last Visit.
Description	The PANSS consisted of three subscales that contained a total of 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 that indicated the absence of symptoms and a score of 7 indicated extremely severe symptoms. The PANSS total score was the sum of the rating scores for 7 positive subscale items, 7 negative subscale items, and 16 general psychopathology subscale items from the PANSS panel. The PANSS total score ranges from 30-210, with higher scores indicating more severe symptoms.
Time Frame	Baseline, Day 4, Week 1, 2, 4, 6, 8, 14, 20, 26, 32, 38, 44, 52 and Last Visit

Outcome Measure Data

Analysis Population Description

The efficacy analysis dataset comprised those participants who received study medication of brexpiprazole and had at least one Post-Baseline assessment for PANSS total score.

Arm/Group Title	Prior Brexpiprazole	Prior Placebo	Prior Aripiprazole
Arm/Group Description	The participants were grouped based on the medications that they received prior to the trial. The participants in prior brexpiprazole group included the participants who received brexpiprazole prior to the trial. The participants began dosing with brexpiprazole 2 mg daily and the dosage was increased upto 6 mg daily if the dose was well-tolerated.	The participants were grouped based on the medications that they received prior to the trial. The participants in prior placebo group included the participants who received placebo prior to the trial. The participants began dosing with brexpiprazole 2 mg daily and the dosage was increased upto 6 mg daily if the dose was well-tolerated.	The participants were grouped based on the medications that they received prior to the trial. The participants in prior aripiprazole group included the participants who received aripiprazole prior to the trial. The participants began dosing with brexpiprazole 2 mg daily and the dosage was increased upto 6 mg daily if the dose was well-tolerated.
Measure Participants	178	41	23
Day 4 (N= 169, 36, 22)	0.11 (5.86)	-1.25 (3.97)	-1.50 (4.97)
Week 1 (N= 167, 40, 23)	-2.03 (5.49)	-1.53 (7.95)	-1.91 (6.22)
Week 2 (N= 165, 40, 21)	-2.95 (8.80)	-3.43 (10.68)	-1.86 (6.04)
Week 4 (N=148, 34, 18)	-4.65 (8.59)	-4.71 (12.85)	-5.39 (6.30)
Week 6 (N= 138, 31, 15)	-7.51 (8.82)	-7.87 (10.26)	-7.47 (7.22)
Week 8 (N=20, 6, 2)	-8.80 (8.69)	-5.17 (7.55)	-10.00 (1.41)
Week 14 (N=20, 6, 2)	-9.85 (8.09)	6.83 (28.29)	-3.50 (12.02)
Week 20 (N= 20, 5, 2)	-10.20 (9.12)	-4.60 (10.71)	-6.50 (10.61)
Week 26 (N= 19, 5, 2)	-12.89 (9.34)	-5.80 (11.56)	-10.50 (7.78)
Week 32 (N= 18, 5, 2)	-14.67 (10.94)	-3.00 (16.90)	-16.00 (0.00)
Week 38 (N= 17, 3, 2)	-13.24 (10.97)	-4.67 (10.21)	-13.00 (0.00)
Week 44 (N= 17, 2, 2)	-16.00 (10.28)	-4.50 (12.02)	-11.50 (2.12)
Week 52 (N= 16, 2, 2)	-15.00 (10.06)	-5.50 (13.44)	-11.00 (7.07)
Last visit (N= 176, 41, 23)	-5.99 (11.25)	-2.32 (18.97)	-5.96 (8.27)

4. Secondary Outcome

Title	Change From Baseline in Clinical Global Impression- Severity of Illness Scale (CGI-S) Score.
Description	The severity of illness for each participant were rated using the CGI-S. To perform this assessment, the investigator were to answer the following question: "Considering your total clinical experience with this particular population, how mentally ill was the participant at that time?" Response choices include: 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, Day 4, Week 1, 2, 4, 6, 8, 14, 20, 26, 32, 38, 44, 52 and Last Visit

Outcome Measure Data

Analysis Population Description

The efficacy analysis dataset comprised those participants who received study medication of brexpiprazole and had at least one Post-Baseline assessment for PANSS total score.

Arm/Group Title	Prior Brexpiprazole	Prior Placebo	Prior Aripiprazole
Arm/Group Description	The participants were grouped based on the medications that they received prior to the trial. The participants in prior brexpiprazole group included the participants who received brexpiprazole prior to the trial. The participants began dosing with brexpiprazole 2 mg daily and the dosage was increased upto 6 mg daily if the dose was well-tolerated.	The participants were grouped based on the medications that they received prior to the trial. The participants in prior placebo group included the participants who received placebo prior to the trial. The participants began dosing with brexpiprazole 2 mg daily and the dosage was increased upto 6 mg daily if the dose was well-tolerated.	The participants were grouped based on the medications that they received prior to the trial. The participants in prior aripiprazole group included the participants who received aripiprazole prior to the trial. The participants began dosing with brexpiprazole 2 mg daily and the dosage was increased upto 6 mg daily if the dose was well-tolerated.
Measure Participants	178	41	23
Day 4 (N= 169, 36, 22)	0.02 (0.51)	-0.03 (0.29)	0.05 (0.38)
Week 1 (N= 167, 40, 23)	-0.08 (0.47)	-0.05 (0.60)	-0.04 (0.37)
Week 2 (N= 164, 40, 21)	-0.12 (0.63)	-0.18 (0.71)	0.00 (0.32)
Week 4 (N= 148, 34, 18)	-0.25 (0.64)	-0.24 (0.82)	-0.22 (0.43)
Week 6 (N= 139, 31, 15)	-0.40 (0.66)	-0.35 (0.80)	-0.33 (0.49)
Week 8 (N= 20, 6, 2)	-0.20 (0.77)	0.17 (0.41)	0.00 (0.00)
Week 14 (N= 20, 6, 2)	-0.40 (0.68)	0.83 (1.60)	0.50 (0.71)
Week 20 (N= 20, 5, 2)	-0.55 (0.76)	0.20 (0.45)	0.00 (0.00)
Week 26 (N= 19, 5, 2)	-0.63 (0.90)	0.00 (0.71)	0.00 (0.00)
Week 32 (N= 18, 5, 2)	-0.78 (0.81)	0.20 (1.10)	-0.50 (0.71)
Week 38 (N= 17, 3, 2)	-0.71 (0.85)	0.00 (0.00)	-0.50 (0.71)
Week 44 (N= 17, 2, 2)	-0.82 (0.81)	0.00 (0.00)	-0.50 (0.71)
Week 52 (N= 16, 2, 2)	-0.88 (0.81)	0.00 (0.00)	-0.50 (0.71)
Last visit (N= 176, 41, 23)	-0.33 (0.83)	-0.15 (1.20)	-0.30 (0.56)

5. Secondary Outcome

Title	Change From Baseline in Personal and Social Performance Scale (PSP) Total Score.
Description	The PSP was a validated clinician-rated scale that measured personal and social functioning in four domains: socially useful activities (e.g, work and study), personal and social relationships, self-care, and disturbing and aggressive behaviors. Impairment in each of these domains was rated as absent, mild, manifest, marked, severe, or very severe. These ratings were then converted to a total score based on a 100-point scale using algorithms to identify the appropriate 10-point interval, and the rater's judgment that determined the total score within the 10-point interval. Participants with a PSP total score of 71 to 100 were considered to have mild functional difficulty. Scores of 31 to 70 represented manifest disabilities of various degrees and ratings of 1 to 30 indicated minimal functioning that required intense support and/or supervision.
Time Frame	Baseline, Week 1, 2, 6, 26, 52 and Last Visit

Outcome Measure Data

Analysis Population Description

The efficacy analysis dataset comprised those participants who received study medication of brexpiprazole and had at least one Post-Baseline assessment for PANSS total score.

Arm/Group Title	Prior Brexpiprazole	Prior Placebo	Prior Aripiprazole
Arm/Group Description	The participants were grouped based on the medications that they received prior to the trial. The participants in prior brexpiprazole group included the participants who received brexpiprazole prior to the trial. The participants began dosing with brexpiprazole 2 mg daily and the dosage was increased upto 6 mg daily if the dose was well-tolerated.	The participants were grouped based on the medications that they received prior to the trial. The participants in prior placebo group included the participants who received placebo prior to the trial. The participants began dosing with brexpiprazole 2 mg daily and the dosage was increased upto 6 mg daily if the dose was well-tolerated.	The participants were grouped based on the medications that they received prior to the trial. The participants in prior aripiprazole group included the participants who received aripiprazole prior to the trial. The participants began dosing with brexpiprazole 2 mg daily and the dosage was increased upto 6 mg daily if the dose was well-tolerated.
Measure Participants	178	41	23
Week 1 (N= 5, 1, 1)	-2.00 (4.82)	-21.00 (0)	-5.00 (0)
Week 2 (N= 163, 40, 21)	1.00 (7.11)	1.50 (8.16)	0.00 (0.00)
Week 6 (N= 139, 31, 15)	5.00 (9.34)	6.00 (10.86)	1.00 (5.96)
Week 26 (N= 19, 5, 2)	6.00 (5.35)	12.00 (8.07)	2.50 (3.54)
Week 52 (N= 16, 2, 2)	13.00 (7.31)	13.00 (1.41)	0.50 (0.71)
Last visit (N= 171, 41, 22)	4.00 (10.28)	5.00 (15.10)	1.00 (5.32)

6. Secondary Outcome

Title	Mean Clinical Global Impression- Improvement Scale (CGI-I) Total Score.
Description	The efficacy of study medication was rated for each participant using the CGI-I. The investigator rated the participants total improvement whether or not it was due to the drug treatment. All responses were compared to the participants condition at Screening/Baseline (i.e, Week 6 visit of Protocol NCT00905307). 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	Day 4, Week 1, 2, 4, 6, 8, 14, 20, 26, 32, 38, 44, 52 and Last Visit

Outcome Measure Data

Analysis Population Description

The efficacy analysis dataset comprised those participants who received study medication of brexpiprazole and had at least one Post-Baseline assessment for PANSS total score.

Arm/Group Title	Prior Brexpiprazole	Prior Placebo	Prior Aripiprazole
Arm/Group Description	The participants were grouped based on the medications that they received prior to the trial. The participants in prior brexpiprazole group included the participants who received brexpiprazole prior to the trial. The participants began dosing with brexpiprazole 2 mg daily and the dosage was increased upto 6 mg daily if the dose was well-tolerated.	The participants were grouped based on the medications that they received prior to the trial. The participants in prior placebo group included the participants who received placebo prior to the trial. The participants began dosing with brexpiprazole 2 mg daily and the dosage was increased upto 6 mg daily if the dose was well-tolerated.	The participants were grouped based on the medications that they received prior to the trial. The participants in prior aripiprazole group included the participants who received aripiprazole prior to the trial. The participants began dosing with brexpiprazole 2 mg daily and the dosage was increased upto 6 mg daily if the dose was well-tolerated.
Measure Participants	178	41	23
Day 4 (N= 169, 36, 22)	3.70 (0.87)	3.56 (0.88)	3.23 (1.15)
Week 1 (N= 167, 40, 23)	3.51 (0.89)	3.73 (0.93)	3.13 (1.14)
Week 2 (N= 164, 40, 21)	3.41 (1.10)	3.45 (1.28)	3.38 (1.28)
Week 4 (N= 148, 34, 18)	3.14 (1.04)	3.26 (1.21)	2.94 (1.21)
Week 6 (N= 139, 31, 15)	2.86 (0.99)	3.03 (1.28)	2.60 (1.18)
Week 8 (N= 20, 6, 2)	2.80 (0.95)	3.50 (1.22)	3.00 (1.41)
Week 14 (N= 20, 6, 2)	2.75 (0.85)	3.83 (1.60)	4.50 (0.71)
Week 20 (N= 20, 5, 2)	2.70 (1.03)	3.20 (1.30)	4.00 (0.00)
Week 26 (N= 19, 5, 2)	2.74 (0.93)	3.00 (1.41)	4.00 (0.00)
Week 32 (N= 18, 5, 2)	2.56 (0.78)	3.20 (1.79)	3.00 (1.41)
Week 38 (N= 17, 3, 2)	2.53 (0.87)	2.67 (1.15)	3.00 (1.41)
Week 44 (N= 17, 2, 2)	2.35 (0.79)	3.00 (1.41)	3.00 (1.41)
Week 52 (N= 16, 2, 2)	2.31 (0.79)	3.00 (1.41)	3.00 (1.41)
Last visit (N= 176, 41, 23)	3.04 (1.14)	3.32 (1.52)	2.83 (1.19)

7. Secondary Outcome

Title	Change From Baseline in PANSS Positive Subscale Score.
Description	The PANSS consisted of three subscales that contained a total of 30 symptom constructs. For each symptom construct, severity is rated on a 7-point scale, with a score of 1 indicated the absence of symptoms and a score of 7 indicated extremely severe symptoms. In positive subscale, the 7 positive symptom constructs were: delusions, conceptual disorganization, hallucinatory behavior, excitement, grandiosity, suspiciousness/persecution, and hostility. The PANSS positive symptom score ranges from 7-49, with higher scores indicating more severe symptoms.
Time Frame	Baseline, Day 4, Week 1, 2, 4, 6, 8, 14, 20, 26, 32, 38, 44, 52 and Last Visit

Outcome Measure Data

Analysis Population Description

The efficacy analysis dataset comprised those participants who received study medication of brexpiprazole and had at least one Post-Baseline assessment for PANSS total score.

Arm/Group Title	Prior Brexpiprazole	Prior Placebo	Prior Aripiprazole
Arm/Group Description	The participants were grouped based on the medications that they received prior to the trial. The participants in prior brexpiprazole group included the participants who received brexpiprazole prior to the trial. The participants began dosing with brexpiprazole 2 mg daily and the dosage was increased upto 6 mg daily if the dose was well-tolerated.	The participants were grouped based on the medications that they received prior to the trial. The participants in prior placebo group included the participants who received placebo prior to the trial. The participants began dosing with brexpiprazole 2 mg daily and the dosage was increased upto 6 mg daily if the dose was well-tolerated.	The participants were grouped based on the medications that they received prior to the trial. The participants in prior aripiprazole group included the participants who received aripiprazole prior to the trial. The participants began dosing with brexpiprazole 2 mg daily and the dosage was increased upto 6 mg daily if the dose was well-tolerated.
Measure Participants	178	41	23
Day 4 (N= 169, 36, 22)	-0.04 (2.06)	-0.50 (1.36)	0.09 (2.24)
Week 1 (N= 167, 40, 23)	-0.66 (1.91)	-0.25 (2.72)	-0.78 (2.76)
Week 2 (N= 165, 40, 21)	-1.09 (2.92)	-0.70 (3.75)	-0.05 (2.84)
Week 4 (N= 148, 34, 18)	-1.53 (2.96)	-1.06 (3.95)	-1.11 (2.08)
Week 6 (N= 138, 31, 15)	-2.36 (3.21)	-2.03 (3.06)	-1.87 (2.39)
Week 8 (N= 20, 6, 2)	-2.10 (3.02)	-1.67 (2.34)	-2.50 (2.12)
Week 14 (20, 6, 2)	-2.80 (2.65)	2.17 (9.04)	1.00 (4.24)
Week 20 (20, 5, 2)	-2.60 (3.49)	-1.80 (2.39)	0.00 (4.24)
Week 26 (N= 19, 5, 2)	-3.42 (2.99)	-2.60 (2.61)	-3.00 (1.41)
Week 32 (N= 18, 5, 2)	-3.83 (3.54)	-1.00 (4.85)	-5.00 (1.41)
Week 38 (N= 17, 3, 2)	-3.71 (4.10)	-2.67 (2.52)	-3.00 (0.00)
Week 44 (N= 17, 2, 2)	-4.24 (3.53)	-1.50 (2.12)	-4.00 (1.41)
Week 52 (N= 16, 2, 2)	-3.63 (3.74)	-1.50 (2.12)	-4.50 (3.54)
Last visit (N= 176, 41, 23)	-1.74 (3.86)	-0.22 (6.04)	-1.43 (2.87)

8. Secondary Outcome

Title	Change From Baseline in PANSS Negative Subscale Score.
Description	The PANSS consisted of three subscales that contained a total of 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 indicated the absence of symptoms and a score of 7 indicated extremely severe symptoms. In negative subscale the severity was rated for the following 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 symptom score ranges from 7-49, with higher scores indicating more severe symptoms.
Time Frame	Baseline, Day 4, Week 1, 2, 4, 6, 8, 14, 20, 26, 32, 38, 44, 52 and Last Visit

Outcome Measure Data

Analysis Population Description

The efficacy analysis dataset comprised those participants who received study medication of brexpiprazole and had at least one Post-Baseline assessment for PANSS total score.

Arm/Group Title	Prior Brexpiprazole	Prior Placebo	Prior Aripiprazole
Arm/Group Description	The participants were grouped based on the medications that they received prior to the trial. The participants in prior brexpiprazole group included the participants who received brexpiprazole prior to the trial. The participants began dosing with brexpiprazole 2 mg daily and the dosage was increased upto 6 mg daily if the dose was well-tolerated.	The participants were grouped based on the medications that they received prior to the trial. The participants in prior placebo group included the participants who received placebo prior to the trial. The participants began dosing with brexpiprazole 2 mg daily and the dosage was increased upto 6 mg daily if the dose was well-tolerated.	The participants were grouped based on the medications that they received prior to the trial. The participants in prior aripiprazole group included the participants who received aripiprazole prior to the trial. The participants began dosing with brexpiprazole 2 mg daily and the dosage was increased upto 6 mg daily if the dose was well-tolerated.
Measure Participants	178	41	23
Day 4 (N= 169, 36, 22)	-0.01 (1.99)	-0.25 (1.00)	-0.86 (2.12)
Week 1 (N= 167, 40, 23)	-0.47 (2.15)	-0.40 (2.58)	-0.87 (2.44)
Week 2 (N= 165, 40, 21)	-0.68 (2.61)	-0.83 (2.32)	-1.19 (2.52)
Week 4 (N= 148, 34, 18)	-1.03 (2.99)	-1.35 (3.02)	-1.94 (2.48)
Week 6 (N= 138, 31, 15)	-1.70 (3.04)	-1.97 (2.70)	-2.40 (2.61)
Week 8 (N= 20, 6, 2)	-2.55 (2.68)	-1.00 (2.00)	-1.00 (1.41)
Week 14 (N= 20, 6, 2)	-2.85 (3.15)	1.17 (7.05)	-1.50 (2.12)
Week 20 (N= 20, 5, 2)	-3.00 (3.04)	-0.60 (1.14)	-2.00 (2.83)
Week 26 (N= 19, 5, 2)	-3.74 (3.43)	-1.20 (1.48)	-2.50 (2.12)
Week 32 (N= 18, 5, 2)	-4.00 (4.41)	-1.00 (1.87)	-2.50 (3.54)
Week 38 (N= 17, 3, 2)	-3.94 (3.93)	-0.67 (2.08)	-2.50 (3.54)
Week 44 (N= 17, 2, 2)	-4.18 (3.61)	-1.00 (2.83)	-2.50 (3.54)
Week 52 (N= 16, 2, 2)	-4.00 (3.58)	-1.00 (2.83)	-2.00 (1.41)
Last visit (N= 176, 41, 23)	-1.53 (3.28)	-1.10 (3.85)	-2.09 (2.59)

9. Secondary Outcome

Title	Percentage of Participants With a Positive Response Rate.
Description	Response rate was defined as a reduction of ≥ 30% from Baseline in PANSS total score or CGI-I score of 1 (very much improved) or 2 (much improved) at the Last Visit.
Time Frame	Last Visit

Outcome Measure Data

Analysis Population Description

The efficacy analysis dataset comprised those participants who received study medication of brexpiprazole and had at least one Post-Baseline assessment for PANSS total score.

Arm/Group Title	Prior Brexpiprazole	Prior Placebo	Prior Aripiprazole
Arm/Group Description	The participants were grouped based on the medications that they received prior to the trial. The participants in prior brexpiprazole group included the participants who received brexpiprazole prior to the trial. The participants began dosing with brexpiprazole 2 mg daily and the dosage was increased upto 6 mg daily if the dose was well-tolerated.	The participants were grouped based on the medications that they received prior to the trial. The participants in prior placebo group included the participants who received placebo prior to the trial. The participants began dosing with brexpiprazole 2 mg daily and the dosage was increased upto 6 mg daily if the dose was well-tolerated.	The participants were grouped based on the medications that they received prior to the trial. The participants in prior aripiprazole group included the participants who received aripiprazole prior to the trial. The participants began dosing with brexpiprazole 2 mg daily and the dosage was increased upto 6 mg daily if the dose was well-tolerated.
Measure Participants	179	41	24
Number [Percentage of participants]	33.5 18.7%	36.6 89.3%	45.8 190.8%

10. Secondary Outcome

Title	Percentage of Participants Who Discontinued Due to Lack of Efficacy.
Description	Discontinuation rate for the participants discontinued due to lack of efficacy were examined.
Time Frame	Last Visit

Outcome Measure Data

Analysis Population Description

The efficacy analysis dataset comprised those participants who received study medication of brexpiprazole and had at least one Post-Baseline assessment for PANSS total score.

Arm/Group Title	Prior Brexpiprazole	Prior Placebo	Prior Aripiprazole
Arm/Group Description	The participants were grouped based on the medications that they received prior to the trial. The participants in prior brexpiprazole group included the participants who received brexpiprazole prior to the trial. The participants began dosing with brexpiprazole 2 mg daily and the dosage was increased upto 6 mg daily if the dose was well-tolerated.	The participants were grouped based on the medications that they received prior to the trial. The participants in prior placebo group included the participants who received placebo prior to the trial. The participants began dosing with brexpiprazole 2 mg daily and the dosage was increased upto 6 mg daily if the dose was well-tolerated.	The participants were grouped based on the medications that they received prior to the trial. The participants in prior aripiprazole group included the participants who received aripiprazole prior to the trial. The participants began dosing with brexpiprazole 2 mg daily and the dosage was increased upto 6 mg daily if the dose was well-tolerated.
Measure Participants	179	41	24
Number [Percentage of participants.]	2.8 1.6%	0.0 0%	0.0 0%

Adverse Events

Time Frame	AEs were recorded from Screening (ICF was signed) to Follow-up 30 (± 2) days, up to 52 weeks.
Adverse Event Reporting Description	The safety dataset comprised of those participants who received at least one dose of open-label brexpiprazole.
Arm/Group Title	Prior Brexpiprazole		Prior Placebo		Prior Aripiprazole
Arm/Group Description	The participants were grouped based on the medications that they received prior to the trial. The participants in prior brexpiprazole group included the participants who received brexpiprazole prior to the trial. The participants began dosing with brexpiprazole 2 mg daily and the dosage was increased upto 6 mg daily if the dose was well-tolerated.		The participants were grouped based on the medications that they received prior to the trial. The participants in prior placebo group included the participants who received placebo prior to the trial. The participants began dosing with brexpiprazole 2 mg daily and the dosage was increased upto 6 mg daily if the dose was well-tolerated.		The participants were grouped based on the medications that they received prior to the trial. The participants in prior aripiprazole group included the participants who received aripiprazole prior to the trial. The participants began dosing with brexpiprazole 2 mg daily and the dosage was increased upto 6 mg daily if the dose was well-tolerated.
All Cause Mortality
	Prior Brexpiprazole		Prior Placebo		Prior Aripiprazole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Prior Brexpiprazole		Prior Placebo		Prior Aripiprazole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/178 (2.2%)		6/41 (14.6%)		1/23 (4.3%)
Infections and infestations
Bronchitis	0/178 (0%)	0	1/41 (2.4%)	1	0/23 (0%)	0
Influenza	0/178 (0%)	0	1/41 (2.4%)	1	0/23 (0%)	0
Nervous system disorders
Convulsion	0/178 (0%)	0	1/41 (2.4%)	1	0/23 (0%)	0
Psychiatric disorders
Psychotic disorder	2/178 (1.1%)	2	1/41 (2.4%)	1	1/23 (4.3%)	1
Schizophrenia	2/178 (1.1%)	2	3/41 (7.3%)	3	0/23 (0%)	0
Other (Not Including Serious) Adverse Events
	Prior Brexpiprazole		Prior Placebo		Prior Aripiprazole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	31/178 (17.4%)		10/41 (24.4%)		4/23 (17.4%)
Nervous system disorders
Extrapyramidal disorder	2/178 (1.1%)		1/41 (2.4%)		2/23 (8.7%)
Headache	6/178 (3.4%)		5/41 (12.2%)		0/23 (0%)
Tremor	9/178 (5.1%)		1/41 (2.4%)		0/23 (0%)
Psychiatric disorders
Insomnia	10/178 (5.6%)		3/41 (7.3%)		0/23 (0%)
Anxiety	5/178 (2.8%)		0/41 (0%)		2/23 (8.7%)

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.