Trial Outcomes & Findings for PET Trial to Assess the Receptor Occupancy of Brexpiprazole in Adult Subjects With Schizophrenia (NCT NCT01854944)

NCT ID: NCT01854944

Last Updated: 2016-02-04

Results Overview

Dopamine receptor occupancy measured using the radiotracer \[11C\]-(+)-PHNO in low and high dose. The binding of brexpiprazole to the D2/D3 receptors were assessed by comparing the binding potential from the Baseline scan (prior to treatment) to that of Day 10 (after treatment). The D2/D3 receptors following administration of a 1- and 4-mg doses of brexpiprazole were assessed and the occupancy estimates were averaged across brain regions 4 hours post-last dose on Day 10.

• Recruitment status: COMPLETED
• Study phase: PHASE1
• Target enrollment: 12 participants
• Primary outcome timeframe: Baseline to 4 hours post-last dose on Day 10
• Results posted on: 2016-02-04

Participant Flow

A Phase 1, single center, open-label trial of up to 12 enrolled participants.

Participants were at the inpatient unit in the New York State Psychiatric Institute between Days -22 and -2. Participants remained inpatient during the drug-free interval at the principal investigator's discretion.

Participant milestones

Measure	Cohort 1 - Brexpiprazole 4 mg Participants in cohort 1 received 1 milligram (mg) tablet of brexpiprazole once daily on Days 1 to 3 and 4-mg tablet of brexpiprazole once daily on Days 4 to 10.	Cohort 2 - Brexpiprazole 1 mg Participants in cohort 2 received 1-mg tablet of brexpiprazole once daily on Days 1 to 10.	Cohort 3 - Brexpiprazole 4 mg Participants in cohort 3 received 1- to 4-mg dose of brexpiprazole (at the study physician's discretion) once daily on Days 1 to 3 and 4-mg tablet of brexpiprazole once daily on Days 4 to 10.
Overall Study STARTED	4	4	4
Overall Study COMPLETED	4	4	3
Overall Study NOT COMPLETED	0	0	1

Reasons for withdrawal

Measure	Cohort 1 - Brexpiprazole 4 mg Participants in cohort 1 received 1 milligram (mg) tablet of brexpiprazole once daily on Days 1 to 3 and 4-mg tablet of brexpiprazole once daily on Days 4 to 10.	Cohort 2 - Brexpiprazole 1 mg Participants in cohort 2 received 1-mg tablet of brexpiprazole once daily on Days 1 to 10.	Cohort 3 - Brexpiprazole 4 mg Participants in cohort 3 received 1- to 4-mg dose of brexpiprazole (at the study physician's discretion) once daily on Days 1 to 3 and 4-mg tablet of brexpiprazole once daily on Days 4 to 10.
Overall Study Withdrawal by Subject	0	0	1

Baseline Characteristics

PET Trial to Assess the Receptor Occupancy of Brexpiprazole in Adult Subjects With Schizophrenia

Baseline characteristics by cohort

Measure	Cohort 1 - Brexpiprazole 4 mg n=4 Participants Participants in cohort 1 received 1-mg tablet of brexpiprazole once daily on Days 1 to 3 and 4-mg tablet of brexpiprazole once daily on Days 4 to 10.	Cohort 2 - Brexpiprazole 1 mg n=4 Participants Participants in cohort 2 received 1-mg tablet of brexpiprazole once daily on Days 1 to 10.	Cohort 3 - Brexpiprazole 4 mg n=4 Participants Participants in cohort 3 received 1- to 4-mg dose of brexpiprazole (at the study physician's discretion) once daily on Days 1 to 3 and 4-mg tablet of brexpiprazole once daily on Days 4 to 10.	Total n=12 Participants Total of all reporting groups
Age, Continuous	38.3 Years STANDARD_DEVIATION 4.4 • n=5 Participants	40.8 Years STANDARD_DEVIATION 11.9 • n=7 Participants	45 Years STANDARD_DEVIATION 6.9 • n=5 Participants	41.3 Years STANDARD_DEVIATION 8.1 • n=4 Participants
Sex: Female, Male Female	3 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants	5 Participants n=4 Participants
Sex: Female, Male Male	1 Participants n=5 Participants	3 Participants n=7 Participants	3 Participants n=5 Participants	7 Participants n=4 Participants

PRIMARY outcome

Timeframe: Baseline to 4 hours post-last dose on Day 10

Population: The positron emission tomography (PET) analysis included all participants who had both the Baseline and Day 10 PET scans performed.

Dopamine receptor occupancy measured using the radiotracer [11C]-(+)-PHNO in low and high dose. The binding of brexpiprazole to the D2/D3 receptors were assessed by comparing the binding potential from the Baseline scan (prior to treatment) to that of Day 10 (after treatment). The D2/D3 receptors following administration of a 1- and 4-mg doses of brexpiprazole were assessed and the occupancy estimates were averaged across brain regions 4 hours post-last dose on Day 10.

Outcome measures

Measure	Brexpiprazole 1mg n=4 Participants Participants received 1-mg tablet of brexpiprazole once daily on Days 1 to 10.	Brexpiprazole 4 mg n=4 Participants Participants received 1-mg brexpiprazole once daily on Days 1 to 3 and 4-mg tablet of brexpiprazole once daily on Days 4 to 10.	Cohort 3 - Brexpiprazole 4 mg Participants in Cohort 3 received one 1- to 4-mg dose of brexpiprazole (at the investigator's discretion) once daily on Days 1 to 3 and one 4-mg tablet of brexpiprazole once daily on Days 4 to 10.
Change in Percentage Dopamine D2/D3 Receptor Occupancy 6-region model (D2 receptor)	36 percentage occupancy Standard Deviation 16	59 percentage occupancy Standard Deviation 5	—
Change in Percentage Dopamine D2/D3 Receptor Occupancy 6-region model (D3 receptor)	2 percentage occupancy Standard Deviation 3	13 percentage occupancy Standard Deviation 10	—
Change in Percentage Dopamine D2/D3 Receptor Occupancy 8-region model (D2 receptor)	27 percentage occupancy Standard Deviation 25	67 percentage occupancy Standard Deviation 15	—
Change in Percentage Dopamine D2/D3 Receptor Occupancy 8-region model (D3 receptor)	1 percentage occupancy Standard Deviation 2	31 percentage occupancy Standard Deviation 8	—

PRIMARY outcome

Timeframe: Baseline to 4 hours post-last dose on Day 10

Population: The PET analysis included all participants who had both the Baseline and Day 10 PET scans performed.

Mean (±SD) Serotonin 5-HT1A Receptor Occupancy Using the Radiotracer [11C]CUMI101 in high dose only. In cohorts 1, 2 and 3, the binding of brexpiprazole to the 5-HT1A receptors was assessed by comparing the binding potential from the Baseline scan (prior to treatment) to that of Day 10 (after treatment). The 5-HT1A receptors following administration of a 4-mg dose of brexpiprazole was assessed and the occupancy estimates were averaged across brain regions 4 hours post-last dose on Day 10.

Outcome measures

Measure	Brexpiprazole 1mg n=4 Participants Participants received 1-mg tablet of brexpiprazole once daily on Days 1 to 10.	Brexpiprazole 4 mg Participants received 1-mg brexpiprazole once daily on Days 1 to 3 and 4-mg tablet of brexpiprazole once daily on Days 4 to 10.	Cohort 3 - Brexpiprazole 4 mg Participants in Cohort 3 received one 1- to 4-mg dose of brexpiprazole (at the investigator's discretion) once daily on Days 1 to 3 and one 4-mg tablet of brexpiprazole once daily on Days 4 to 10.
Change in Percentage 5-HT1A Receptor Occupancy	4 percentage occupancy Standard Deviation 6	—	—

PRIMARY outcome

Timeframe: Baseline and 4 hours post-last dose on Day 10

Population: The PET analysis included all participants who had both the Baseline and Day 10 PET scans performed.

Mean (±SD) Serotonin 5-HT2A Receptor Occupancy Using the Radiotracer [11C]MDL100907 (in low and high dose). The 5-HT2A receptors following administration of 1- and 4-mg doses of brexpiprazole were assessed and the occupancy estimates were averaged across brain regions 4 hours post-last dose on Day 10.

Outcome measures

Measure	Brexpiprazole 1mg n=4 Participants Participants received 1-mg tablet of brexpiprazole once daily on Days 1 to 10.	Brexpiprazole 4 mg n=4 Participants Participants received 1-mg brexpiprazole once daily on Days 1 to 3 and 4-mg tablet of brexpiprazole once daily on Days 4 to 10.	Cohort 3 - Brexpiprazole 4 mg Participants in Cohort 3 received one 1- to 4-mg dose of brexpiprazole (at the investigator's discretion) once daily on Days 1 to 3 and one 4-mg tablet of brexpiprazole once daily on Days 4 to 10.
Change in Percentage 5-HT2A Receptor Occupancy	28 percentage occupancy Standard Deviation 10	45 percentage occupancy Standard Deviation 7	—

PRIMARY outcome

Timeframe: Baseline to 4 hours post-last dose on Day 10

Population: The PET analysis included all participants who had both the Baseline and Day 10 PET scans performed.

Mean (±SD) SERT Occupancy Using the Radiotracer [11C]DASB in high dose only. Occupancy estimates were averaged across brain regions 4 hours post-last dose.

Outcome measures

Measure	Brexpiprazole 1mg n=4 Participants Participants received 1-mg tablet of brexpiprazole once daily on Days 1 to 10.	Brexpiprazole 4 mg Participants received 1-mg brexpiprazole once daily on Days 1 to 3 and 4-mg tablet of brexpiprazole once daily on Days 4 to 10.	Cohort 3 - Brexpiprazole 4 mg Participants in Cohort 3 received one 1- to 4-mg dose of brexpiprazole (at the investigator's discretion) once daily on Days 1 to 3 and one 4-mg tablet of brexpiprazole once daily on Days 4 to 10.
Change in Occupancy at Serotonin Transporter (SERT)	-3 percentage occupancy Standard Deviation 15	—	—

SECONDARY outcome

Timeframe: Baseline to Day 10

Population: The PK analysis included participants who had valid measurements (per clinical pharmacology). Blood samples were collected on Days 1 and 9 at predose and Day 10 at predose and at 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours post-last dose or at early termination (ET).

AUC during a dosing interval at steady-state for brexpiprazole and its metabolite DM-3411. Days 1 and 9: predose (within 15 minutes prior to dosing) Day 10: predose (within 15 minutes prior to dosing) and 1, 2, 3, 4, 5, 6, 8, and 12 hours post-last dose.

Outcome measures

Measure	Brexpiprazole 1mg n=4 Participants Participants received 1-mg tablet of brexpiprazole once daily on Days 1 to 10.	Brexpiprazole 4 mg n=4 Participants Participants received 1-mg brexpiprazole once daily on Days 1 to 3 and 4-mg tablet of brexpiprazole once daily on Days 4 to 10.	Cohort 3 - Brexpiprazole 4 mg n=4 Participants Participants in Cohort 3 received one 1- to 4-mg dose of brexpiprazole (at the investigator's discretion) once daily on Days 1 to 3 and one 4-mg tablet of brexpiprazole once daily on Days 4 to 10.
Area Under the Concentration-time Curve (AUCτ) During a Dosing Interval at Steady-state for Brexpiprazole and Its Metabolite DM-3411 Brexpiprazole	2520 hr*ng/mL Standard Deviation 1290	716 hr*ng/mL Standard Deviation 118	1410 hr*ng/mL Standard Deviation 352
Area Under the Concentration-time Curve (AUCτ) During a Dosing Interval at Steady-state for Brexpiprazole and Its Metabolite DM-3411 DM-3411	807 hr*ng/mL Standard Deviation 205	329 hr*ng/mL Standard Deviation 227	761 hr*ng/mL Standard Deviation 397

SECONDARY outcome

Timeframe: Baseline to Day 10

Population: The PK analysis included participants who had valid measurements (per clinical pharmacology). Blood samples were collected on Days 1 and 9 at predose and Day 10 at predose and at 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours post-last dose or at ET.

(Cmax) Days 1 and 9: predose (within 15 minutes prior to dosing) Day 10: predose (within 15 minutes prior to dosing) and 1, 2, 3, 4, 5, 6, 8, and 12 hours post-last dose.

Outcome measures

Measure	Brexpiprazole 1mg n=4 Participants Participants received 1-mg tablet of brexpiprazole once daily on Days 1 to 10.	Brexpiprazole 4 mg n=4 Participants Participants received 1-mg brexpiprazole once daily on Days 1 to 3 and 4-mg tablet of brexpiprazole once daily on Days 4 to 10.	Cohort 3 - Brexpiprazole 4 mg n=3 Participants Participants in Cohort 3 received one 1- to 4-mg dose of brexpiprazole (at the investigator's discretion) once daily on Days 1 to 3 and one 4-mg tablet of brexpiprazole once daily on Days 4 to 10.
Peak (Maximal) Concentration of Drug in Plasma (Cmax) for Brexpiprazole and Its Metabolite DM-3411 Brexpiprazole	126 ng/mL Standard Deviation 58.3	46.5 ng/mL Standard Deviation 7.47	70.9 ng/mL Standard Deviation 18.8
Peak (Maximal) Concentration of Drug in Plasma (Cmax) for Brexpiprazole and Its Metabolite DM-3411 DM-3411	37.1 ng/mL Standard Deviation 10.8	17.3 ng/mL Standard Deviation 10.4	35.7 ng/mL Standard Deviation 18.6

SECONDARY outcome

Timeframe: Baseline to Day 10

Population: The PK analysis included participants who had valid measurements (per clinical pharmacology). Blood samples were collected on Days 1 and 9 at predose and Day 10 at predose and at 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours post-last dose or at ET.

PK parameter - CL/F was assessed for brexpiprazole only. Days 1 and 9: predose (within 15 minutes prior to dosing) Day 10: predose (within 15 minutes prior to dosing) and 1, 2, 3, 4, 5, 6, 8, and 12 hours post-last dose.

Outcome measures

Measure	Brexpiprazole 1mg n=4 Participants Participants received 1-mg tablet of brexpiprazole once daily on Days 1 to 10.	Brexpiprazole 4 mg n=4 Participants Participants received 1-mg brexpiprazole once daily on Days 1 to 3 and 4-mg tablet of brexpiprazole once daily on Days 4 to 10.	Cohort 3 - Brexpiprazole 4 mg n=4 Participants Participants in Cohort 3 received one 1- to 4-mg dose of brexpiprazole (at the investigator's discretion) once daily on Days 1 to 3 and one 4-mg tablet of brexpiprazole once daily on Days 4 to 10.
Apparent Clearance of Drug From Plasma After Extravascular Administration (CL/F; Only Brexpiprazole)	1960 mL/hr Standard Deviation 960	1420 mL/hr Standard Deviation 242	2970 mL/hr Standard Deviation 831

SECONDARY outcome

Timeframe: Baseline to Day 10

Population: The PK analysis included participants who had valid measurements (per clinical pharmacology). Blood samples were collected on Days 1 and 9 at predose and Day 10 at predose and at 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours post-last dose or at ET.

Tmax for brexpiprazole and its metabolite DM-3411. Days 1 and 9: predose (within 15 minutes prior to dosing) Day 10: predose (within 15 minutes prior to dosing) and 1, 2, 3, 4, 5, 6, 8, and 12 hours post-last dose.

Outcome measures

Measure	Brexpiprazole 1mg n=4 Participants Participants received 1-mg tablet of brexpiprazole once daily on Days 1 to 10.	Brexpiprazole 4 mg n=4 Participants Participants received 1-mg brexpiprazole once daily on Days 1 to 3 and 4-mg tablet of brexpiprazole once daily on Days 4 to 10.	Cohort 3 - Brexpiprazole 4 mg n=4 Participants Participants in Cohort 3 received one 1- to 4-mg dose of brexpiprazole (at the investigator's discretion) once daily on Days 1 to 3 and one 4-mg tablet of brexpiprazole once daily on Days 4 to 10.
Time to Maximum (Peak) Plasma Concentration (Tmax) for Brexpiprazole and Its Metabolite DM-3411 DM-3411	2.42 hour Interval 0.0 to 24.08	1.51 hour Interval 0.0 to 11.92	11.87 hour Interval 3.1 to 24.0
Time to Maximum (Peak) Plasma Concentration (Tmax) for Brexpiprazole and Its Metabolite DM-3411 Brexpiprazole	1.92 hour Interval 0.0 to 2.92	1.50 hour Interval 0.93 to 1.93	4.87 hour Interval 3.1 to 6.0

SECONDARY outcome

Timeframe: Baseline to Day 6, 11 and Last Visit

Population: The safety population included all participants who received at least one dose of study medication.

The AIMS Scale was an extrapyramidal symptoms (EPS) rating scale. The AIMS is a 12 item scale. The first 10 items e.g. facial and oral movements (items 1-4), extremity movements (items 5 and 6), trunk movements (item 7), investigators global assessment of dyskinesia (items 8 to 10). The first 10 items are rated from 0 to 4 (0=best, 4=worst). Items 11 and 12, related to dental status, have dichotomous responses, 0=no and 1=yes. The AIMS Total Score is the sum of the ratings for the first seven items. The possible total scores are from 0 to 28, with a higher score indicating worse outcome. Last Visit is the last scheduled post-baseline evaluation including early termination evaluation.

Outcome measures

Measure	Brexpiprazole 1mg n=4 Participants Participants received 1-mg tablet of brexpiprazole once daily on Days 1 to 10.	Brexpiprazole 4 mg n=4 Participants Participants received 1-mg brexpiprazole once daily on Days 1 to 3 and 4-mg tablet of brexpiprazole once daily on Days 4 to 10.	Cohort 3 - Brexpiprazole 4 mg n=4 Participants Participants in Cohort 3 received one 1- to 4-mg dose of brexpiprazole (at the investigator's discretion) once daily on Days 1 to 3 and one 4-mg tablet of brexpiprazole once daily on Days 4 to 10.
Mean Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) Score Day 6	0 Units on a scale Standard Deviation 0	0 Units on a scale Standard Deviation 0	0.3 Units on a scale Standard Deviation 0.5
Mean Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) Score Day 11	0 Units on a scale Standard Deviation 0	0 Units on a scale Standard Deviation 0	0 Units on a scale Standard Deviation 0
Mean Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) Score Last Visit	0 Units on a scale Standard Deviation 0	0 Units on a scale Standard Deviation 0	0 Units on a scale Standard Deviation 0

SECONDARY outcome

Timeframe: Baseline to Day 6, 11 and Last Visit

Population: The safety population included all participants who received at least one dose of study medication.

The SAS is a rating scale used to measure EPS. The SAS scale consists of a list of 10 symptoms of parkinsonism (gait, arm dropping, shoulder shaking, elbow rigidity, wrist rigidity, head rotation, glabella tap, tremor, salivation, and akathisia), with each item rated from 0 to 4, with 0 being normal and 4 being the worst. The SAS Total score is sum of ratings for all 10 items, with possible Total scores from 0 to 40, with higher scores indicating worse outcome. Last Visit is the last scheduled post-baseline evaluation including early termination evaluation.

Outcome measures

Measure	Brexpiprazole 1mg n=4 Participants Participants received 1-mg tablet of brexpiprazole once daily on Days 1 to 10.	Brexpiprazole 4 mg n=4 Participants Participants received 1-mg brexpiprazole once daily on Days 1 to 3 and 4-mg tablet of brexpiprazole once daily on Days 4 to 10.	Cohort 3 - Brexpiprazole 4 mg n=4 Participants Participants in Cohort 3 received one 1- to 4-mg dose of brexpiprazole (at the investigator's discretion) once daily on Days 1 to 3 and one 4-mg tablet of brexpiprazole once daily on Days 4 to 10.
Mean Change From Baseline in Simpson-Angus Scale (SAS) Total Score Day 6	0.3 Units on scale Standard Deviation 0.5	0 Units on scale Standard Deviation 0	-0.3 Units on scale Standard Deviation 1.3
Mean Change From Baseline in Simpson-Angus Scale (SAS) Total Score Day 11	0 Units on scale Standard Deviation 0	0 Units on scale Standard Deviation 0	-0.7 Units on scale Standard Deviation 1.2
Mean Change From Baseline in Simpson-Angus Scale (SAS) Total Score Last Visit	0 Units on scale Standard Deviation 0	0 Units on scale Standard Deviation 0	-0.5 Units on scale Standard Deviation 1.0

SECONDARY outcome

Timeframe: Baseline to Day 6, 11 and Last Visit

Population: The safety population included all participants who received at least one dose of study medication.

The BARS consisted of 4 items related to akathisia: objective observation of akathisia by the study physician, subjective feelings of restlessness by the participant, participant distress due to akathisia, and global evaluation of akathisia. The first 3 items were rated on a 4-point scale, with a score of 0 = absence of symptoms and a score of 3 = severe condition. The global clinical evaluation were made on a 6-point scale, (0=absent, 1=questionable, 2=mild, 3=moderate, 4=marked, 5=severe). To complete this scale, participants were observed while they were seated and then stood for a minimum of 2 minutes in each position. Symptoms observed in other situations (e.g., while engaged in neutral conversation or engaged in activity on the ward) may also be rated. Subjective phenomena were to be elicited by direct questioning. The BARS total score (when combined) ranged from 0 to 18, with higher values indicating a severe condition.

Outcome measures

Measure	Brexpiprazole 1mg n=4 Participants Participants received 1-mg tablet of brexpiprazole once daily on Days 1 to 10.	Brexpiprazole 4 mg n=4 Participants Participants received 1-mg brexpiprazole once daily on Days 1 to 3 and 4-mg tablet of brexpiprazole once daily on Days 4 to 10.	Cohort 3 - Brexpiprazole 4 mg n=4 Participants Participants in Cohort 3 received one 1- to 4-mg dose of brexpiprazole (at the investigator's discretion) once daily on Days 1 to 3 and one 4-mg tablet of brexpiprazole once daily on Days 4 to 10.
Mean Change From Baseline in Barnes Akathisia Rating Scale (BARS) Score Day 6	0.5 Units on a scale Standard Deviation 1.0	0 Units on a scale Standard Deviation 0	0.5 Units on a scale Standard Deviation 1.0
Mean Change From Baseline in Barnes Akathisia Rating Scale (BARS) Score Day 11	0.5 Units on a scale Standard Deviation 1.0	0 Units on a scale Standard Deviation 0	0.0 Units on a scale Standard Deviation 0.0
Mean Change From Baseline in Barnes Akathisia Rating Scale (BARS) Score Last Visit	0.5 Units on a scale Standard Deviation 1.0	0 Units on a scale Standard Deviation 0	0.0 Units on a scale Standard Deviation 0.0

SECONDARY outcome

Timeframe: Baseline to Last Visit

Population: The safety population included all participants who received at least one dose of study medication.

The C-SSRS captures the occurrence, severity, and frequency of suicide-related thoughts and behaviors during the assessment period. Suicidality was defined as reporting at least one occurrence of any suicidal behavior or suicidal ideation. Suicidal behavior was defined as reporting any type of suicidal behaviors (actual attempt, interrupted attempt, aborted attempt, and preparatory acts or behavior). The suicidal ideation intensity total score is the sum of intensity scores of 5 items (frequency, duration, controllability, deterrents, and reasons for ideation). The score of each intensity item ranges from 0 (none) to 5 (worst) which leads to the range of the total score from 0 to 25, with a higher score indicating a worse outcome. A missing score of any item resulted in a missing total score. If no suicidal ideation was reported, a score of 0 was given to the intensity scale. Last Visit is last scheduled post-baseline evaluation including early termination evaluation.

Outcome measures

Measure	Brexpiprazole 1mg n=4 Participants Participants received 1-mg tablet of brexpiprazole once daily on Days 1 to 10.	Brexpiprazole 4 mg n=4 Participants Participants received 1-mg brexpiprazole once daily on Days 1 to 3 and 4-mg tablet of brexpiprazole once daily on Days 4 to 10.	Cohort 3 - Brexpiprazole 4 mg n=4 Participants Participants in Cohort 3 received one 1- to 4-mg dose of brexpiprazole (at the investigator's discretion) once daily on Days 1 to 3 and one 4-mg tablet of brexpiprazole once daily on Days 4 to 10.
Percentage of Participants Who Reported at Least One Occurrence of Suicidality, Suicidal Behavior and Suicidal Ideation on the Columbia-Suicide Severity Rating Scale (C-SSRS) Suicidality	0 Percentage of participants	0 Percentage of participants	0 Percentage of participants
Percentage of Participants Who Reported at Least One Occurrence of Suicidality, Suicidal Behavior and Suicidal Ideation on the Columbia-Suicide Severity Rating Scale (C-SSRS) Suicidal behaviour	0 Percentage of participants	0 Percentage of participants	0 Percentage of participants
Percentage of Participants Who Reported at Least One Occurrence of Suicidality, Suicidal Behavior and Suicidal Ideation on the Columbia-Suicide Severity Rating Scale (C-SSRS) Suicidal Ideation	0 Percentage of participants	0 Percentage of participants	0 Percentage of participants

SECONDARY outcome

Timeframe: Baseline to Day 6, 11 and Last Visit

Population: The safety sample included participants that are administered at least one dose of study medication.

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). Last Visit is the last scheduled post-baseline evaluation including early termination evaluation.

Outcome measures

Measure	Brexpiprazole 1mg n=4 Participants Participants received 1-mg tablet of brexpiprazole once daily on Days 1 to 10.	Brexpiprazole 4 mg n=4 Participants Participants received 1-mg brexpiprazole once daily on Days 1 to 3 and 4-mg tablet of brexpiprazole once daily on Days 4 to 10.	Cohort 3 - Brexpiprazole 4 mg n=4 Participants Participants in Cohort 3 received one 1- to 4-mg dose of brexpiprazole (at the investigator's discretion) once daily on Days 1 to 3 and one 4-mg tablet of brexpiprazole once daily on Days 4 to 10.
Mean Change From Baseline in Positive and Negative Symptom Scale (PANSS) Total Score Day 6	-4.0 Units on a scale Standard Deviation 7.4	0.3 Units on a scale Standard Deviation 4.0	-2.0 Units on a scale Standard Deviation 3.9
Mean Change From Baseline in Positive and Negative Symptom Scale (PANSS) Total Score Day 11	-1.5 Units on a scale Standard Deviation 5.2	6.0 Units on a scale Standard Deviation 11.1	-4.0 Units on a scale Standard Deviation 10.5
Mean Change From Baseline in Positive and Negative Symptom Scale (PANSS) Total Score Last Visit	-1.5 Units on a scale Standard Deviation 5.2	6.0 Units on a scale Standard Deviation 11.1	-3.0 Units on a scale Standard Deviation 8.7

SECONDARY outcome

Timeframe: Baseline to Day 6, 11 and Last Visit

Population: The safety population included all participants who received at least one dose of study medication.

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 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/persecution, and hostility. The PANSS Positive Subscale ranges from 7 (absence of symptoms) to 49 (extremely severe symptoms). Last Visit is the last scheduled post-baseline evaluation including early termination evaluation.

Outcome measures

Measure	Brexpiprazole 1mg n=4 Participants Participants received 1-mg tablet of brexpiprazole once daily on Days 1 to 10.	Brexpiprazole 4 mg n=4 Participants Participants received 1-mg brexpiprazole once daily on Days 1 to 3 and 4-mg tablet of brexpiprazole once daily on Days 4 to 10.	Cohort 3 - Brexpiprazole 4 mg n=4 Participants Participants in Cohort 3 received one 1- to 4-mg dose of brexpiprazole (at the investigator's discretion) once daily on Days 1 to 3 and one 4-mg tablet of brexpiprazole once daily on Days 4 to 10.
Mean Change From Baseline in PANNS Positive Subscale Score Day 6	-0.8 Units on a scale Standard Deviation 1.0	0.0 Units on a scale Standard Deviation 2.0	-0.8 Units on a scale Standard Deviation 3.9
Mean Change From Baseline in PANNS Positive Subscale Score Day 11	0.5 Units on a scale Standard Deviation 1.0	0.5 Units on a scale Standard Deviation 6.1	-2.7 Units on a scale Standard Deviation 7.5
Mean Change From Baseline in PANNS Positive Subscale Score Last Visit	0.5 Units on a scale Standard Deviation 1.0	0.5 Units on a scale Standard Deviation 6.1	-2.0 Units on a scale Standard Deviation 6.3

SECONDARY outcome

Timeframe: Baseline to Day 6, 11 and Last Visit

Population: The safety population included all participants who received at least one dose of study medication.

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 withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, stereotyped thinking. The PANSS Negative Subscale ranges from 7 (absence of symptoms) to 49 (extremely severe symptoms). Last Visit is the last scheduled post-baseline evaluation including early termination evaluation.

Outcome measures

Measure	Brexpiprazole 1mg n=4 Participants Participants received 1-mg tablet of brexpiprazole once daily on Days 1 to 10.	Brexpiprazole 4 mg n=4 Participants Participants received 1-mg brexpiprazole once daily on Days 1 to 3 and 4-mg tablet of brexpiprazole once daily on Days 4 to 10.	Cohort 3 - Brexpiprazole 4 mg n=4 Participants Participants in Cohort 3 received one 1- to 4-mg dose of brexpiprazole (at the investigator's discretion) once daily on Days 1 to 3 and one 4-mg tablet of brexpiprazole once daily on Days 4 to 10.
Mean Change From Baseline in PANSS Negative Subscale Score Day 6	-2.5 Units on a scale Standard Deviation 4.4	1.0 Units on a scale Standard Deviation 1.0	0.3 Units on a scale Standard Deviation 1.0
Mean Change From Baseline in PANSS Negative Subscale Score Day 11	-1.5 Units on a scale Standard Deviation 2.4	0.5 Units on a scale Standard Deviation 3.0	-0.3 Units on a scale Standard Deviation 3.2
Mean Change From Baseline in PANSS Negative Subscale Score Last Visit	-1.5 Units on a scale Standard Deviation 2.4	0.5 Units on a scale Standard Deviation 3.0	-0.3 Units on a scale Standard Deviation 2.6

SECONDARY outcome

Timeframe: Baseline to Day 6, 11 and Last Visit

Population: The safety population included all participants who received at least one dose of study medication.

The severity of illness for each participant was rated using the CGI-S scale. To assess CGI-S, 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 ill at all; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill participants. Last Visit is the last scheduled post-baseline evaluation including early termination evaluation.

Outcome measures

Measure	Brexpiprazole 1mg n=4 Participants Participants received 1-mg tablet of brexpiprazole once daily on Days 1 to 10.	Brexpiprazole 4 mg n=4 Participants Participants received 1-mg brexpiprazole once daily on Days 1 to 3 and 4-mg tablet of brexpiprazole once daily on Days 4 to 10.	Cohort 3 - Brexpiprazole 4 mg n=4 Participants Participants in Cohort 3 received one 1- to 4-mg dose of brexpiprazole (at the investigator's discretion) once daily on Days 1 to 3 and one 4-mg tablet of brexpiprazole once daily on Days 4 to 10.
Mean Change From Baseline in Clinical Global Impression-Severity (CGI-S) Score Day 6	0.3 Units on a scale Standard Deviation 0.5	0.0 Units on a scale Standard Deviation 0.0	0.8 Units on a scale Standard Deviation 1.0
Mean Change From Baseline in Clinical Global Impression-Severity (CGI-S) Score Day 11	0.5 Units on a scale Standard Deviation 1.0	0.0 Units on a scale Standard Deviation 0.0	1.0 Units on a scale Standard Deviation 1.0
Mean Change From Baseline in Clinical Global Impression-Severity (CGI-S) Score Last Visit	0.5 Units on a scale Standard Deviation 1.0	0.0 Units on a scale Standard Deviation 0.0	0.8 Units on a scale Standard Deviation 1.0

SECONDARY outcome

Timeframe: Baseline to Day 6, 11 and Last Visit

Population: The safety population included all participants who received at least one dose of study medication.

The efficacy of trial medication were rated for each participant using the CGI-I scale. The study physician must 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. Response choices include: 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. Last Visit is the last scheduled post-baseline evaluation including early termination evaluation.

Outcome measures

Measure	Brexpiprazole 1mg n=4 Participants Participants received 1-mg tablet of brexpiprazole once daily on Days 1 to 10.	Brexpiprazole 4 mg n=4 Participants Participants received 1-mg brexpiprazole once daily on Days 1 to 3 and 4-mg tablet of brexpiprazole once daily on Days 4 to 10.	Cohort 3 - Brexpiprazole 4 mg n=4 Participants Participants in Cohort 3 received one 1- to 4-mg dose of brexpiprazole (at the investigator's discretion) once daily on Days 1 to 3 and one 4-mg tablet of brexpiprazole once daily on Days 4 to 10.
Mean Change From Baseline in Clinical Global Impression-Improvement (CGI-I) Score Day 6	4.0 Units on a scale Standard Deviation 0.0	4.0 Units on a scale Standard Deviation 0.0	4.0 Units on a scale Standard Deviation 0.0
Mean Change From Baseline in Clinical Global Impression-Improvement (CGI-I) Score Day 11	3.5 Units on a scale Standard Deviation 1.0	3.8 Units on a scale Standard Deviation 0.5	2.7 Units on a scale Standard Deviation 1.2

Adverse Events

Cohort 1 - Brexpiprazole 4 mg

Serious events: 0 serious events

Other events: 4 other events

Deaths: 0 deaths

Cohort 2 - Brexpiprazole 1 mg

Serious events: 0 serious events

Other events: 2 other events

Deaths: 0 deaths

Cohort 3 - Brexpiprazole 4 mg

Serious events: 0 serious events

Other events: 3 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Cohort 1 - Brexpiprazole 4 mg n=4 participants at risk Participants in cohort 1 received one 1-mg of brexpiprazole once daily on Days 1 to 3 and one 4-mg tablet of brexpiprazole once daily on Days 4 to 10.	Cohort 2 - Brexpiprazole 1 mg n=4 participants at risk Participants in cohort 2 received one 1-mg tablet of brexpiprazole once daily on Days 1 to 10.	Cohort 3 - Brexpiprazole 4 mg n=4 participants at risk Participants in cohort 3 received once 1- to 4-mg dose of brexpiprazole (at the study physician's discretion) once daily on Days 1 to 3 and one 4-mg tablet of brexpiprazole once daily on Days 4 to 10.
Eye disorders Blepharospasm	25.0% 1/4 • Adverse events were reported once the informed consent was signed, throughout the 10-day treatment period until the safety follow-up via telephone 30 (+2) days post-last dose of study medication.	0.00% 0/4 • Adverse events were reported once the informed consent was signed, throughout the 10-day treatment period until the safety follow-up via telephone 30 (+2) days post-last dose of study medication.	0.00% 0/4 • Adverse events were reported once the informed consent was signed, throughout the 10-day treatment period until the safety follow-up via telephone 30 (+2) days post-last dose of study medication.
Gastrointestinal disorders Abdominal discomfort	0.00% 0/4 • Adverse events were reported once the informed consent was signed, throughout the 10-day treatment period until the safety follow-up via telephone 30 (+2) days post-last dose of study medication.	50.0% 2/4 • Adverse events were reported once the informed consent was signed, throughout the 10-day treatment period until the safety follow-up via telephone 30 (+2) days post-last dose of study medication.	0.00% 0/4 • Adverse events were reported once the informed consent was signed, throughout the 10-day treatment period until the safety follow-up via telephone 30 (+2) days post-last dose of study medication.
Gastrointestinal disorders Abdominal pain	25.0% 1/4 • Adverse events were reported once the informed consent was signed, throughout the 10-day treatment period until the safety follow-up via telephone 30 (+2) days post-last dose of study medication.	0.00% 0/4 • Adverse events were reported once the informed consent was signed, throughout the 10-day treatment period until the safety follow-up via telephone 30 (+2) days post-last dose of study medication.	0.00% 0/4 • Adverse events were reported once the informed consent was signed, throughout the 10-day treatment period until the safety follow-up via telephone 30 (+2) days post-last dose of study medication.
Gastrointestinal disorders Dental carries	0.00% 0/4 • Adverse events were reported once the informed consent was signed, throughout the 10-day treatment period until the safety follow-up via telephone 30 (+2) days post-last dose of study medication.	0.00% 0/4 • Adverse events were reported once the informed consent was signed, throughout the 10-day treatment period until the safety follow-up via telephone 30 (+2) days post-last dose of study medication.	25.0% 1/4 • Adverse events were reported once the informed consent was signed, throughout the 10-day treatment period until the safety follow-up via telephone 30 (+2) days post-last dose of study medication.
Gastrointestinal disorders Dyspepsia	25.0% 1/4 • Adverse events were reported once the informed consent was signed, throughout the 10-day treatment period until the safety follow-up via telephone 30 (+2) days post-last dose of study medication.	0.00% 0/4 • Adverse events were reported once the informed consent was signed, throughout the 10-day treatment period until the safety follow-up via telephone 30 (+2) days post-last dose of study medication.	25.0% 1/4 • Adverse events were reported once the informed consent was signed, throughout the 10-day treatment period until the safety follow-up via telephone 30 (+2) days post-last dose of study medication.
General disorders Fatigue	25.0% 1/4 • Adverse events were reported once the informed consent was signed, throughout the 10-day treatment period until the safety follow-up via telephone 30 (+2) days post-last dose of study medication.	0.00% 0/4 • Adverse events were reported once the informed consent was signed, throughout the 10-day treatment period until the safety follow-up via telephone 30 (+2) days post-last dose of study medication.	0.00% 0/4 • Adverse events were reported once the informed consent was signed, throughout the 10-day treatment period until the safety follow-up via telephone 30 (+2) days post-last dose of study medication.
General disorders Malaise	25.0% 1/4 • Adverse events were reported once the informed consent was signed, throughout the 10-day treatment period until the safety follow-up via telephone 30 (+2) days post-last dose of study medication.	0.00% 0/4 • Adverse events were reported once the informed consent was signed, throughout the 10-day treatment period until the safety follow-up via telephone 30 (+2) days post-last dose of study medication.	0.00% 0/4 • Adverse events were reported once the informed consent was signed, throughout the 10-day treatment period until the safety follow-up via telephone 30 (+2) days post-last dose of study medication.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	0.00% 0/4 • Adverse events were reported once the informed consent was signed, throughout the 10-day treatment period until the safety follow-up via telephone 30 (+2) days post-last dose of study medication.	0.00% 0/4 • Adverse events were reported once the informed consent was signed, throughout the 10-day treatment period until the safety follow-up via telephone 30 (+2) days post-last dose of study medication.	25.0% 1/4 • Adverse events were reported once the informed consent was signed, throughout the 10-day treatment period until the safety follow-up via telephone 30 (+2) days post-last dose of study medication.
Nervous system disorders Akathisia	25.0% 1/4 • Adverse events were reported once the informed consent was signed, throughout the 10-day treatment period until the safety follow-up via telephone 30 (+2) days post-last dose of study medication.	0.00% 0/4 • Adverse events were reported once the informed consent was signed, throughout the 10-day treatment period until the safety follow-up via telephone 30 (+2) days post-last dose of study medication.	25.0% 1/4 • Adverse events were reported once the informed consent was signed, throughout the 10-day treatment period until the safety follow-up via telephone 30 (+2) days post-last dose of study medication.
Nervous system disorders Sedation	25.0% 1/4 • Adverse events were reported once the informed consent was signed, throughout the 10-day treatment period until the safety follow-up via telephone 30 (+2) days post-last dose of study medication.	0.00% 0/4 • Adverse events were reported once the informed consent was signed, throughout the 10-day treatment period until the safety follow-up via telephone 30 (+2) days post-last dose of study medication.	0.00% 0/4 • Adverse events were reported once the informed consent was signed, throughout the 10-day treatment period until the safety follow-up via telephone 30 (+2) days post-last dose of study medication.
Psychiatric disorders Agitation	0.00% 0/4 • Adverse events were reported once the informed consent was signed, throughout the 10-day treatment period until the safety follow-up via telephone 30 (+2) days post-last dose of study medication.	25.0% 1/4 • Adverse events were reported once the informed consent was signed, throughout the 10-day treatment period until the safety follow-up via telephone 30 (+2) days post-last dose of study medication.	0.00% 0/4 • Adverse events were reported once the informed consent was signed, throughout the 10-day treatment period until the safety follow-up via telephone 30 (+2) days post-last dose of study medication.
Vascular disorders Peripheral artery thrombosis	0.00% 0/4 • Adverse events were reported once the informed consent was signed, throughout the 10-day treatment period until the safety follow-up via telephone 30 (+2) days post-last dose of study medication.	0.00% 0/4 • Adverse events were reported once the informed consent was signed, throughout the 10-day treatment period until the safety follow-up via telephone 30 (+2) days post-last dose of study medication.	25.0% 1/4 • Adverse events were reported once the informed consent was signed, throughout the 10-day treatment period until the safety follow-up via telephone 30 (+2) days post-last dose of study medication.

Additional Information

Global Medical Affairs

Otsuka Pharmaceutical Development and Commercialization, Inc.

Phone: 800 562-3974

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place

Restriction type: LTE60