Phase 1 Study to Assess the Safety/Tolerability of Brexpi... | NCT01670279

Name	Class
H. Lundbeck A/S	INDUSTRY

Label	Type	Description	Intervention Names
Cohort 1	Experimental	14 day titration phase and two fixed dose phases. The first fixed dose phase is 14 days with a daily dose of 2mg brexpiprazole/placebo. The second fixed dose phase is 14 days with a daily dose of 3 mg brexpiprazole/placebo.	Drug: Brexpiprazole
Cohort 2	Experimental	14 day titration phase and a 14 day fixed dose phase a daily dose of 3mg brexpiprazole/placebo.	Drug: Brexpiprazole
Cohort 3	Experimental	21 day titration phase and a 14 day fixed dose phase a daily dose of 3mg brexpiprazole/placebo.	Drug: Brexpiprazole
Placebo	Placebo Comparator	Placebo	Drug: Placebo

Name	Type	Description	Arm Group Labels	Other Names
Brexpiprazole	Drug	up to 3mg oral dose once daily	Cohort 1 Cohort 2 Cohort 3

Measure	Description	Time Frame
Number of Participants Who Tolerated Brexpiprazole	Safety and tolerability of brexpiprazole was noted to be primary outcome measure. Brexpiprazole was judged to be tolerated if at least 6 out of 8 (75%) of the participants in a test cohort tolerated the dose after 14 days of QD dosing at the end of the fixed dose phase based on the blinded data. Dose toleration was defined as follows: during the course of the trial, the participants did not experience any moderate or severe adverse events (AEs) or potentially clinically relevant changes from Baseline in laboratory values, vital signs, electrocardiogram (ECG) tracings, Columbia-Suicide Severity Rating Scale (C-SSRS), or extrapyramidal symptom (EPS) ratings, which were assessed as possibly related to the study drug, and would have warranted a dose decrease or discontinuation of the study drug. The safety and tolerability of brexpiprazole was defined by parameters: AEs, laboratory values, vital signs, ECG, C-SSRS, or EPS ratings, the results of each of the parameters reported separately.	45 Days
Number of AEs Reported.	The AEs were one of the primary parameters to measure the safety and tolerability of individual participants. The AEs were captured for all participants from the time the ICF was signed until the end of the trial. AEs were measured throughout the 14-day titration and 28-day fixed dose phase until follow-up (30 [±2] days after last dose of study medication).	Throughout the study, up to 119 days
Incidence of Laboratory Values of Potential Clinical Significance	The laboratory values were one of the primary parameters to measure the safety and tolerability of individual participants. Incidence of TEAEs of potential clinical relevance include abnormal values in serum chemistry, hematology, urinalyses and prolactin tests that were identified based on pre-defined criteria.	Titration Day 7, Fixed dose Day 14 and 28 and Last Visit
Incidence of Vital Signs of Potential Clinical Significance	The vital signs were one of the primary parameters to measure the safety and tolerability of individual participants. Incidence of TEAEs of potential clinical relevance included abnormal values in heart rate, systolic and diastolic blood pressure, respiratory rate and weight that were identified based on pre-defined criteria.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Subjects who are able to provide written informed consent
Ability to understand the nature of the trial and follow protocol requirements
Male and female patients 70 to 85 years of age
Subjects with normal or clinically stable findings on physical examination, medical history, clinical laboratory determinations, ECGs in relation to age
BMI of 18 to 35 kg/m2.
Stable subjects with a principal psychiatric diagnosis of MDD
Subjects willing to discontinue all prohibited psychotropic and other prohibited medication

Exclusion Criteria:

Sexually active males who are not practicing 2 different methods of birth control during the trial and for 30 days after the last dose of trial medication or who will not remain abstinent during the trial and for 30 days after the last dose
Subjects who have had a vagus nerve stimulation device implanted or who have received ECT within 6 months of Screening
Subjects with a current Axis I (DSM-IV-TR) diagnosis of:
- Delirium, dementia, amnestic, or other cognitive disorder
- Eating disorder (including anorexia nervosa or bulimia)
- Obsessive-compulsive disorder
- Panic disorder
- Posttraumatic stress disorder or current or prior Axis I (DSM-IV-TR) diagnosis of Schizophrenia, schizoaffective disorder, or other psychotic disorder, Bipolar I or II disorder or bipolar disorder not otherwise specified
Subjects with a clinically significant current Axis II (DSM-IV-TR) diagnosis of borderline, antisocial, paranoid, schizoid, schizotypal, or histrionic personality disorder
Subjects experiencing hallucinations, delusions, or any psychotic symptomatology
Subjects who have Active Suicidal Ideation with Some Intent to Act and whose most recent episode occurred within the last 6 months
Subjects who have met DSM-IV-TR criteria for substance abuse or dependence within the past 180 days
Subjects with hypothyroidism or hyperthyroidism and/or an abnormal result for free T4 at Screening
Subjects who currently have clinically significant neurological, hepatic, renal, metabolic, hematological, immunological, cardiovascular, pulmonary, or gastrointestinal disorders
Subjects with IDDM
Subjects with uncontrolled hypertension (DBP > 95 mmHg) or symptomatic hypotension
Subjects with epilepsy, a history of epilepsy, or a history of seizure
Subjects with a positive drug screen for cocaine or other drugs of abuse
The following laboratory test and ECG results are exclusionary:
1. Platelets ≤ 75,000/mm3
2. Hemoglobin ≤ 9 g/dL
3. Neutrophils, absolute ≤ 1000/mm3
4. AST > 3 × upper limit of normal
5. ALT > 3 × upper limit of normal
6. Creatinine ≥ 2 mg/dL
7. HbA1c ≥ 7%
8. QTcF ≥ 450 msec
Treatment with a MAOI within the 2 weeks prior to the first dose of trial medication
Use of benzodiazepines and/or hypnotics within 1 week prior the first dose of trial medication
Use of oral neuroleptics within 30 days prior to or long-acting approved neuroleptics ≤ 1 full cycle plus 14 days prior to the first dose of trial medication on Day 1
Prohibited concomitant medications used prior to randomization or anticipated need for such medications during the trial
Subjects who would be likely to require prohibited concomitant therapy during the trial
Subjects who received brexpiprazole in any prior clinical trial
Subjects with a history of neuroleptic malignant syndrome
Subjects with a history of true allergic response to more than 1 class of medications
Prisoners or subjects who are compulsorily detained for treatment of either a psychiatric or physical illness
Subjects who participated in a clinical trial within the last 180 days or who participated in more than 2 clinical trials within the past year.

Name	Affiliation	Role
James M. Youakim, MD	Otsuka Pharmaceutical Development & Commercialization, Inc.	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Accurate Clinical Trials		Kissimmee	Florida		United States
Miami Jewish Health System

ID	Title	Description
FG000	Brexpiprazole-Cohort 1	In the titration phase, participants received 0.5 mg brexpiprazole QD for 7 days, followed by 1 mg brexpiprazole QD for 7 days. In the fixed dose phase, participants received 2 mg brexpiprazole QD for 14 days, followed by 3 mg brexpiprazole QD for 14 days.
FG001

ID	Title	Description
BG000	Brexpiprazole-Cohort 1	In the titration phase, participants received 0.5 mg brexpiprazole QD for 7 days, followed by 1 mg brexpiprazole QD for 7 days. In the fixed dose phase, participants received 2 mg brexpiprazole QD for 14 days, followed by 3 mg brexpiprazole QD for 14 days.
BG001	Brexpiprazole-Cohort 2	In the titration phase, participants received 0.5 mg brexpiprazole QD for 7 days, followed by 1 mg brexpiprazole QD for 7 days. In the fixed dose phase, participants received 3 mg brexpiprazole QD for 14 days.
BG002	Placebo	In the titration phase, participants received 0.5 mg placebo QD for 7 days, followed by 1 mg placebo QD for 7 days. In the fixed dose phase, Cohort 1: participants received 2 mg placebo QD for 14 days, followed by 3 mg placebo QD for 14 days. Cohort 2: participants received 3 mg placebo QD for 14 days.
BG003	Total	Total of all reporting groups

Units	Counts
Participants	BG0006 BG0017 BG0025 BG00318

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Number of Participants Who Tolerated Brexpiprazole

Safety and tolerability of brexpiprazole was noted to be primary outcome measure. Brexpiprazole was judged to be tolerated if at least 6 out of 8 (75%) of the participants in a test cohort tolerated the dose after 14 days of QD dosing at the end of the fixed dose phase based on the blinded data. Dose toleration was defined as follows: during the course of the trial, the participants did not experience any moderate or severe adverse events (AEs) or potentially clinically relevant changes from Baseline in laboratory values, vital signs, electrocardiogram (ECG) tracings, Columbia-Suicide Severity Rating Scale (C-SSRS), or extrapyramidal symptom (EPS) ratings, which were assessed as possibly related to the study drug, and would have warranted a dose decrease or discontinuation of the study drug. The safety and tolerability of brexpiprazole was defined by parameters: AEs, laboratory values, vital signs, ECG, C-SSRS, or EPS ratings, the results of each of the parameters reported separately.

Tolerability assessed in phase 1 trial in healthy participants (18-45 years) with MDD as adjunct therapy to ADTs; the efficacy assessed in phase 3 trials in participants (18-65 years) with MDD as adjunct therapy to ADTs. Thus, safety/tolerability of brexpiprazole in participants (>65 years) with MDD as adjunct therapy to ADTs was not characterized.

Posted

Number

participants

45 Days

ID	Title	Description
OG000	Brexpiprazole-Cohort 1	In the titration phase, participants received 0.5 mg brexpiprazole QD for 7 days, followed by 1 mg brexpiprazole QD for 7 days. In the fixed dose phase, participants received 2 mg brexpiprazole QD for 14 days, followed by 3 mg brexpiprazole QD for 14 days.
OG001	Brexpiprazole-Cohort 2	In the titration phase, participants received 0.5 mg brexpiprazole QD for 7 days, followed by 1 mg brexpiprazole QD for 7 days. In the fixed dose phase, participants received 3 mg brexpiprazole QD for 14 days.
OG002	Placebo	In the titration phase, participants received 0.5 mg placebo QD for 7 days, followed by 1 mg placebo QD for 7 days. In the fixed dose phase, Cohort 1: participants received 2 mg placebo QD for 14 days, followed by 3 mg placebo QD for 14 days. Cohort 2: participants received 3 mg placebo QD for 14 days.

Units	Counts
Participants	OG0006 OG0017 OG0025

Title

Denominators

Categories

Title	Measurements
	OG0006 OG0017 OG0025

Primary

Number of AEs Reported.

The AEs were one of the primary parameters to measure the safety and tolerability of individual participants. The AEs were captured for all participants from the time the ICF was signed until the end of the trial. AEs were measured throughout the 14-day titration and 28-day fixed dose phase until follow-up (30 [±2] days after last dose of study medication).

The safety dataset included all randomized participants who received at least one dose of study medication.

Posted

Number

Events

Throughout the study, up to 119 days

ID	Title	Description
OG000	Brexpiprazole-Cohort 1	In the titration phase, participants received 0.5 mg brexpiprazole QD for 7 days, followed by 1 mg brexpiprazole QD for 7 days. In the fixed dose phase, participants received 2 mg brexpiprazole QD for 14 days, followed by 3 mg brexpiprazole QD for 14 days.
OG001	Brexpiprazole-Cohort 2	In the titration phase, participants received 0.5 mg brexpiprazole QD for 7 days, followed by 1 mg brexpiprazole QD for 7 days. In the fixed dose phase, participants received 3 mg brexpiprazole QD for 14 days.
OG002	Placebo	In the titration phase, participants received 0.5 mg placebo QD for 7 days, followed by 1 mg placebo QD for 7 days. In the fixed dose phase, Cohort 1: participants received 2 mg placebo QD for 14 days, followed by 3 mg placebo QD for 14 days. Cohort 2: participants received 3 mg placebo QD for 14 days.

Primary

Incidence of Laboratory Values of Potential Clinical Significance

The laboratory values were one of the primary parameters to measure the safety and tolerability of individual participants. Incidence of TEAEs of potential clinical relevance include abnormal values in serum chemistry, hematology, urinalyses and prolactin tests that were identified based on pre-defined criteria.

The safety dataset included all randomized participants who received at least one dose of study medication.

Posted

Number

Participants

Titration Day 7, Fixed dose Day 14 and 28 and Last Visit

ID	Title	Description
OG000	Brexpiprazole-Cohort 1	In the titration phase, participants received 0.5 mg brexpiprazole QD for 7 days, followed by 1 mg brexpiprazole QD for 7 days. In the fixed dose phase, participants received 2 mg brexpiprazole QD for 14 days, followed by 3 mg brexpiprazole QD for 14 days.
OG001	Brexpiprazole-Cohort 2	In the titration phase, participants received 0.5 mg brexpiprazole QD for 7 days, followed by 1 mg brexpiprazole QD for 7 days. In the fixed dose phase, participants received 3 mg brexpiprazole QD for 14 days.
OG002	Placebo	In the titration phase, participants received 0.5 mg placebo QD for 7 days, followed by 1 mg placebo QD for 7 days. In the fixed dose phase, Cohort 1: participants received 2 mg placebo QD for 14 days, followed by 3 mg placebo QD for 14 days. Cohort 2: participants received 3 mg placebo QD for 14 days.

Primary

Incidence of Vital Signs of Potential Clinical Significance

The vital signs were one of the primary parameters to measure the safety and tolerability of individual participants. Incidence of TEAEs of potential clinical relevance included abnormal values in heart rate, systolic and diastolic blood pressure, respiratory rate and weight that were identified based on pre-defined criteria.

The safety dataset included all randomized participants who received at least one dose of study medication.

Posted

Number

Participants

Baseline, Titration Day 1, 2, 7, 8, Fixed Days 1, 2, 14, 15, 28, 29, Early Termination and Last Visit.

ID	Title	Description
OG000	Brexpiprazole-Cohort 1	In the titration phase, participants received 0.5 mg brexpiprazole QD for 7 days, followed by 1 mg brexpiprazole QD for 7 days. In the fixed dose phase, participants received 2 mg brexpiprazole QD for 14 days, followed by 3 mg brexpiprazole QD for 14 days.
OG001	Brexpiprazole-Cohort 2	In the titration phase, participants received 0.5 mg brexpiprazole QD for 7 days, followed by 1 mg brexpiprazole QD for 7 days. In the fixed dose phase, participants received 3 mg brexpiprazole QD for 14 days.
OG002	Placebo	In the titration phase, participants received 0.5 mg placebo QD for 7 days, followed by 1 mg placebo QD for 7 days. In the fixed dose phase, Cohort 1: participants received 2 mg placebo QD for 14 days, followed by 3 mg placebo QD for 14 days. Cohort 2: participants received 3 mg placebo QD for 14 days.

Primary

Incidence of ECG Evaluations of Potential Clinical Significance

The measurement of ECG was one of the primary parameters to measure the safety and tolerability of individual participants. Incidence of TEAEs of potential clinical relevance include abnormal changes in heart rate and ECG intervals of PR, QRS, QT, QTcB, and QTcF that were identified based on pre-defined criteria.

The safety dataset included all randomized participants who received at least one dose of study medication.

Posted

Number

Participants

Titratrion Day 1 and 7, Fixed dose Day 1, 14, 28, Early Termination

ID	Title	Description
OG000	Brexpiprazole-Cohort 1	In the titration phase, participants received 0.5 mg brexpiprazole QD for 7 days, followed by 1 mg brexpiprazole QD for 7 days. In the fixed dose phase, participants received 2 mg brexpiprazole QD for 14 days, followed by 3 mg brexpiprazole QD for 14 days.
OG001	Brexpiprazole-Cohort 2	In the titration phase, participants received 0.5 mg brexpiprazole QD for 7 days, followed by 1 mg brexpiprazole QD for 7 days. In the fixed dose phase, participants received 3 mg brexpiprazole QD for 14 days.
OG002	Placebo	In the titration phase, participants received 0.5 mg placebo QD for 7 days, followed by 1 mg placebo QD for 7 days. In the fixed dose phase, Cohort 1: participants received 2 mg placebo QD for 14 days, followed by 3 mg placebo QD for 14 days. Cohort 2: participants received 3 mg placebo QD for 14 days.

Primary

Incidence of Physical Examination Evaluation of Potential Clinical Significance

The physical examination evaluation was one of the primary parameters to measure the safety and tolerability of individual participants. Incidence of TEAEs of potential clinical relevance include abnormal changes in the following body systems: head, ears, eyes, nose, and throat; thorax; abdomen; urogenital; extremities; neurological; and skin and mucosae.

Safety Sample was analyzed. Any clinically significant condition present at the post-treatment physical examination that was not present at the baseline examination was documented as an adverse event and followed to a satisfactory conclusion. There were no clinically significant physical examination findings reported in this study.

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Number

Participants

Physical examination was performed at Screening, check-in, and discharge

ID	Title	Description
OG000	Brexpiprazole-Cohort 1	In the titration phase, participants received 0.5 mg brexpiprazole QD for 7 days, followed by 1 mg brexpiprazole QD for 7 days. In the fixed dose phase, participants received 2 mg brexpiprazole QD for 14 days, followed by 3 mg brexpiprazole QD for 14 days.
OG001	Brexpiprazole-Cohort 2	In the titration phase, participants received 0.5 mg brexpiprazole QD for 7 days, followed by 1 mg brexpiprazole QD for 7 days. In the fixed dose phase, participants received 3 mg brexpiprazole QD for 14 days.

Primary

Mean Change From Baseline to Study Completion in Simpson-Angus Scale (SAS) Total Score

EPS was one of the primary parameters to measure the safety and tolerability of individual participants. 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.

Safety Sample includes all randomized participants who receive at least one dose of study medication.

Posted

Mean

Standard Deviation

Units on a scale

End of Titration, Day 15, Day 29, Early Termination and Last visit

ID	Title	Description
OG000	Brexpiprazole-Cohort 1	In the titration phase, participants received 0.5 mg brexpiprazole QD for 7 days, followed by 1 mg brexpiprazole QD for 7 days. In the fixed dose phase, participants received 2 mg brexpiprazole QD for 14 days, followed by 3 mg brexpiprazole QD for 14 days.
OG001	Brexpiprazole-Cohort 2	In the titration phase, participants received 0.5 mg brexpiprazole QD for 7 days, followed by 1 mg brexpiprazole QD for 7 days. In the fixed dose phase, participants received 3 mg brexpiprazole QD for 14 days.

Primary

Mean Change From Baseline to Study Completion in Barnes Akathisia Global Score

EPS was one of the primary parameters to measure the safety and tolerability of individual participants. The Barnes Akathisia Rating Scale was an EPS rating scale. The Barnes Akathisia Rating Scale was used to assess the presence and severity of akathisia. This scale consists of 4 items. Only the 4th item, the Global Clinical Assessment of Akathisia, was evaluated in this trial. This item is rated on a 6 point scale, with 0 being best (absent) and 5 being worst (severe akathisia).

Safety Sample includes all randomized participants who receive at least one dose of study medication.

Posted

Mean

Standard Deviation

Units on a scale

End of Titration, Day 15, Day 29, Early Termination and Last visit

ID	Title	Description
OG000	Brexpiprazole-Cohort 1	In the titration phase, participants received 0.5 mg brexpiprazole QD for 7 days, followed by 1 mg brexpiprazole QD for 7 days. In the fixed dose phase, participants received 2 mg brexpiprazole QD for 14 days, followed by 3 mg brexpiprazole QD for 14 days.
OG001	Brexpiprazole-Cohort 2	In the titration phase, participants received 0.5 mg brexpiprazole QD for 7 days, followed by 1 mg brexpiprazole QD for 7 days. In the fixed dose phase, participants received 3 mg brexpiprazole QD for 14 days.
OG002

Primary

Mean Change From Baseline to Study Completion in Abnormal Involuntary Movement Scale (AIMS) Rating Score.

EPS was one of the primary parameters to measure the safety and tolerability of individual participants. The AIMS Scale was an EPS rating scale. The AIMS is a 12 item scale. 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.

Safety Sample includes all randomized participants who receive at least one dose of study medication.

Posted

Mean

Standard Deviation

Units on a scale

End of Titration, Day 15, Day 29, Early Termination and Last visit

ID	Title	Description
OG000	Brexpiprazole-Cohort 1	In the titration phase, participants received 0.5 mg brexpiprazole QD for 7 days, followed by 1 mg brexpiprazole QD for 7 days. In the fixed dose phase, participants received 2 mg brexpiprazole QD for 14 days, followed by 3 mg brexpiprazole QD for 14 days.
OG001	Brexpiprazole-Cohort 2	In the titration phase, participants received 0.5 mg brexpiprazole QD for 7 days, followed by 1 mg brexpiprazole QD for 7 days. In the fixed dose phase, participants received 3 mg brexpiprazole QD for 14 days.
OG002

Primary

Change From Baseline to Study Completion in C-SSRS Score.

The C-SSRS was one of the primary parameters to measure the safety and tolerability of individual participants. Suicidality was monitored during the trial using the C-SSRS. This scale consists of a baseline evaluation that assesses the lifetime experience of the participant with suicide events and suicidal ideation and a post-baseline evaluation that focuses on suicidality since the last trial visit.

Safety Sample includes all randomized participants who receive at least one dose of study medication.

Posted

Number

Participants

Baseline, End of Titration, Fixed dose Day 14 and 28, Day 15 and 29, Early Termination, Last Visit

ID	Title	Description
OG000	Brexpiprazole-Cohort 1	In the titration phase, participants received 0.5 mg brexpiprazole QD for 7 days, followed by 1 mg brexpiprazole QD for 7 days. In the fixed dose phase, participants received 2 mg brexpiprazole QD for 14 days, followed by 3 mg brexpiprazole QD for 14 days.
OG001	Brexpiprazole-Cohort 2	In the titration phase, participants received 0.5 mg brexpiprazole QD for 7 days, followed by 1 mg brexpiprazole QD for 7 days. In the fixed dose phase, participants received 3 mg brexpiprazole QD for 14 days.
OG002	Placebo

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Atrioventricular block first degree	Cardiac disorders	MedDRA 15.0	Non-systematic Assessment	EG0001 affected6 at risk EG0011 affected6 at risk EG0020 affected5 at risk
Hyperprolactinaemia	Endocrine disorders	MedDRA 15.0	Non-systematic Assessment	EG0001 affected6 at risk EG0010 affected6 at risk EG0020 affected5 at risk
Diarrhoea	Gastrointestinal disorders	MedDRA 15.0	Non-systematic Assessment	EG0000 affected6 at risk EG0011 affected6 at risk EG0020 affected5 at risk
Dyspepsia	Gastrointestinal disorders	MedDRA 15.0	Non-systematic Assessment	EG0000 affected6 at risk EG0012 affected6 at risk EG0020 affected5 at risk
Nausea	Gastrointestinal disorders	MedDRA 15.0	Non-systematic Assessment	EG0000 affected6 at risk EG0012 affected6 at risk EG0020 affected5 at risk
Cardiac murmur	Investigations	MedDRA 15.0	Non-systematic Assessment	EG0000 affected6 at risk EG0011 affected6 at risk EG0020 affected5 at risk
Electrocardiogram QT prolonged	Investigations	MedDRA 15.0	Non-systematic Assessment	EG0000 affected6 at risk EG0011 affected6 at risk EG0020 affected5 at risk
Weight increased	Investigations	MedDRA 15.0	Non-systematic Assessment	EG0002 affected6 at risk EG0010 affected6 at risk EG0020 affected5 at risk
Dizziness	Nervous system disorders	MedDRA 15.0	Non-systematic Assessment	EG0000 affected6 at risk EG0013 affected6 at risk EG0020 affected5 at risk
Headache	Nervous system disorders	MedDRA 15.0	Non-systematic Assessment	EG0001 affected6 at risk EG0010 affected6 at risk EG0021 affected5 at risk
Tremor	Nervous system disorders	MedDRA 15.0	Non-systematic Assessment	EG0001 affected6 at risk EG0010 affected6 at risk EG0020 affected5 at risk
Insomnia	Psychiatric disorders	MedDRA 15.0	Non-systematic Assessment	EG0001 affected6 at risk EG0011 affected6 at risk EG0020 affected5 at risk
Pollakiuria	Renal and urinary disorders	MedDRA 15.0	Non-systematic Assessment	EG0002 affected6 at risk EG0010 affected6 at risk EG0020 affected5 at risk
Oropharyngeal pain	Respiratory, thoracic and mediastinal disorders	MedDRA 15.0	Non-systematic Assessment	EG0001 affected6 at risk EG0010 affected6 at risk EG0021 affected5 at risk
Arthritis	Musculoskeletal and connective tissue disorders	MedDRA 15.0	Non-systematic Assessment	EG0000 affected6 at risk EG0011 affected6 at risk EG0020 affected5 at risk
Back pain	Musculoskeletal and connective tissue disorders	MedDRA 15.0	Non-systematic Assessment	EG0000 affected6 at risk EG0011 affected6 at risk EG0020 affected5 at risk
Pain in extremity	Musculoskeletal and connective tissue disorders	MedDRA 15.0	Non-systematic Assessment	EG0000 affected6 at risk EG0011 affected6 at risk EG0020 affected5 at risk
Upper respiratory tract infection	Infections and infestations	MedDRA 15.0	Non-systematic Assessment	EG0001 affected6 at risk EG0010 affected6 at risk EG0020 affected5 at risk
Oedema peripheral	General disorders	MedDRA 15.0	Non-systematic Assessment	EG0001 affected6 at risk EG0010 affected6 at risk EG0020 affected5 at risk
Constipation	Gastrointestinal disorders	MedDRA 15.0	Non-systematic Assessment	EG0000 affected6 at risk EG0011 affected6 at risk EG0020 affected5 at risk
Dental caries	Gastrointestinal disorders	MedDRA 15.0	Non-systematic Assessment	EG0001 affected6 at risk EG0010 affected6 at risk EG0020 affected5 at risk
Gastrooesophageal reflux disease	Gastrointestinal disorders	MedDRA 15.0	Non-systematic Assessment	EG0000 affected6 at risk EG0011 affected6 at risk EG0020 affected5 at risk
Vomiting	Gastrointestinal disorders	MedDRA 15.0	Non-systematic Assessment	EG0000 affected6 at risk EG0011 affected6 at risk EG0020 affected5 at risk
Eye pruritis	Eye disorders	MedDRA 15.0	Non-systematic Assessment	EG0000 affected6 at risk EG0010 affected6 at risk EG0021 affected5 at risk
Dry eye	Eye disorders	MedDRA 15.0	Non-systematic Assessment	EG0000 affected6 at risk EG0010 affected6 at risk EG0021 affected5 at risk
Blood pressure	Investigations	MedDRA 15.0	Non-systematic Assessment	EG0001 affected6 at risk EG0010 affected6 at risk EG0020 affected5 at risk

ID	Term
D003866	Depressive Disorder
D019964	Mood Disorders
D001523	Mental Disorders

ID	Title	Description	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Brexpiprazole-Cohort 1	In the titration phase, participants received 0.5 mg brexpiprazole QD for 7 days, followed by 1 mg brexpiprazole QD for 7 days. In the fixed dose phase, participants received 2 mg brexpiprazole QD for 14 days, followed by 3 mg brexpiprazole QD for 14 days.	6	6	6
EG001	Brexpiprazole-Cohort 2	In the titration phase, participants received 0.5 mg brexpiprazole QD for 7 days, followed by 1 mg brexpiprazole QD for 7 days. In the fixed dose phase, participants received 3 mg brexpiprazole QD for 14 days.	6	6	6
EG002	Placebo	In the titration phase, participants received 0.5 mg placebo QD for 7 days, followed by 1 mg placebo QD for 7 days. In the fixed dose phase, Cohort 1: participants received 2 mg placebo QD for 14 days, followed by 3 mg placebo QD for 14 days. Cohort 2: participants received 3 mg placebo QD for 14 days.	5	1	5