Trial Outcomes & Findings for Safety and Tolerability of Aripiprazole in Adolescents With Schizophrenia or Children and Adolescents With Bipolar I Disorder, Manic or Mixed Episode With or Without Psychotic Features. (NCT NCT01122927)

Results Overview

An AE was defined as any untoward medical occurrence in a participant or participant enrolled in a clinical trial and which did not necessarily have a causal relationship with the study medication. A treatment emergent adverse event (TEAE) was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study medication, whether or not considered to have a causal relationship with the study medication. A serious-AE or reaction was any untoward occurrence that, at any dose, was fatal, life-threatening, required inpatient hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, or was any other medically significant event that, based on appropriate medical judgment, may have jeopardized the participant and may have required medical or surgical intervention to prevent one of the outcomes listed above.

Recruitment status

TERMINATED

Study phase

PHASE3

Target enrollment

524 participants

Primary outcome timeframe

Adverse events were recorded from the time of the informed consent was signed throughout the 24 month treatment period until the follow-up visit 30 (± 3) days after the end of trial.

Results posted on

2016-02-08

Participant Flow

This trial was conducted in 524 participants at 118 trial sites in the following 13 countries: Bulgaria, Croatia, Hungary, India, Malaysia, Philippines, Poland, Romania, Russia, Serbia, Taiwan, Ukraine, and the United States.

524 participants entered this trial (297 participants in the conversion phase and 510 participants in the open-label treatment phase). In the latter, 362 were de novo participants (283 participants entered into the conversion phase) and 148 rolled over from Trial NCT01149655.

Participant milestones

Participant milestones
Measure	Conversion Phase Participants who entered this phase were converted from his or her antipsychotic to the minimum target dose of 10 mg/day aripiprazole monotherapy and continued to increase the dose up to a maximum of 30 mg/day, or for tolerability reasons, to reduce the aripiprazole dose to no less than 5 mg/day.	Open-label Treatment Phase Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.
Period 1 - Conversion Phase STARTED	297	0
Period 1 - Conversion Phase COMPLETED	283	0
Period 1 - Conversion Phase NOT COMPLETED	14	0
Period 2- Open-label Treatment Phase STARTED	0	510
Period 2- Open-label Treatment Phase COMPLETED	0	198
Period 2- Open-label Treatment Phase NOT COMPLETED	0	312

Reasons for withdrawal

Reasons for withdrawal
Measure	Conversion Phase Participants who entered this phase were converted from his or her antipsychotic to the minimum target dose of 10 mg/day aripiprazole monotherapy and continued to increase the dose up to a maximum of 30 mg/day, or for tolerability reasons, to reduce the aripiprazole dose to no less than 5 mg/day.	Open-label Treatment Phase Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.
Period 1 - Conversion Phase Adverse Event	3	0
Period 1 - Conversion Phase Met Withdrawal Criteria	1	0
Period 1 - Conversion Phase Physician Decision	2	0
Period 1 - Conversion Phase Withdrawal by Subject	7	0
Period 1 - Conversion Phase Protocol Deviation	1	0
Period 2- Open-label Treatment Phase Lost to Follow-up	0	21
Period 2- Open-label Treatment Phase Adverse Event	0	33
Period 2- Open-label Treatment Phase Sponsor Discontinued Trial	0	165
Period 2- Open-label Treatment Phase Met Withdrawal Criteria	0	9
Period 2- Open-label Treatment Phase Physician Decision	0	12
Period 2- Open-label Treatment Phase Withdrawal by Subject	0	65
Period 2- Open-label Treatment Phase Lack of Efficacy	0	7

Baseline Characteristics

Safety and Tolerability of Aripiprazole in Adolescents With Schizophrenia or Children and Adolescents With Bipolar I Disorder, Manic or Mixed Episode With or Without Psychotic Features.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	All Study Participants n=524 Participants Participants who entered open-label treatment phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.
Age, Continuous	15.2 Years STANDARD_DEVIATION 1.6 • n=93 Participants
Sex: Female, Male Female	316 Participants n=93 Participants
Sex: Female, Male Male	208 Participants n=93 Participants

PRIMARY outcome

Timeframe: Adverse events were recorded from the time of the informed consent was signed throughout the 24 month treatment period until the follow-up visit 30 (± 3) days after the end of trial.

Population: All participants who had received at least one dose of oral aripiprazole.

An AE was defined as any untoward medical occurrence in a participant or participant enrolled in a clinical trial and which did not necessarily have a causal relationship with the study medication. A treatment emergent adverse event (TEAE) was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study medication, whether or not considered to have a causal relationship with the study medication. A serious-AE or reaction was any untoward occurrence that, at any dose, was fatal, life-threatening, required inpatient hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, or was any other medically significant event that, based on appropriate medical judgment, may have jeopardized the participant and may have required medical or surgical intervention to prevent one of the outcomes listed above.

Outcome measures

Outcome measures
Measure	Open-label Treatment Phase n=510 Participants Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 2 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 3 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 4 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 5 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.
Number of Participants With Adverse Events (AEs) Participants with TEAEs	349 Participants	—	—	—	—
Number of Participants With Adverse Events (AEs) Participants with serious TEAEs	49 Participants	—	—	—	—
Number of Participants With Adverse Events (AEs) Participants with severe TEAEs	33 Participants	—	—	—	—
Number of Participants With Adverse Events (AEs) Discontinued due to AEs	32 Participants	—	—	—	—

SECONDARY outcome

Timeframe: Baseline to Month 24

Population: All participants who had received at least one dose of oral aripiprazole.

The laboratory values were one of the 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. Abnormal laboratory values in participants were reported as SAE/AEs and are reported in the SAE/other AE section of this report.

Outcome measures

Outcome measures
Measure	Open-label Treatment Phase n=510 Participants Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 2 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 3 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 4 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 5 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.
Incidence of Laboratory Values of Potential Clinical Relevance Chemistry-Alanine transaminase	11 participants	—	—	—	—
Incidence of Laboratory Values of Potential Clinical Relevance Chemistry-Aspartate transaminase	8 participants	—	—	—	—
Incidence of Laboratory Values of Potential Clinical Relevance Chemistry-Bilirubin, total	20 participants	—	—	—	—
Incidence of Laboratory Values of Potential Clinical Relevance Chemistry-Calcium	30 participants	—	—	—	—
Incidence of Laboratory Values of Potential Clinical Relevance Chemistry-Chloride	158 participants	—	—	—	—
Incidence of Laboratory Values of Potential Clinical Relevance Chemistry-Cholesterol, total, fasting	68 participants	—	—	—	—
Incidence of Laboratory Values of Potential Clinical Relevance Chemistry-Creatine phosphokinase, total	40 participants	—	—	—	—
Incidence of Laboratory Values of Potential Clinical Relevance Chemistry-Glutamyl transferase	78 participants	—	—	—	—
Incidence of Laboratory Values of Potential Clinical Relevance Chemistry-HDL cholesterol, fasting	128 participants	—	—	—	—
Incidence of Laboratory Values of Potential Clinical Relevance Chemistry-LDL cholesterol, calculation,	2 participants	—	—	—	—
Incidence of Laboratory Values of Potential Clinical Relevance Chemistry-Phosphorus inorganic	135 participants	—	—	—	—
Incidence of Laboratory Values of Potential Clinical Relevance Chemistry-Protein, total serum	81 participants	—	—	—	—
Incidence of Laboratory Values of Potential Clinical Relevance Chemistry-Triglycerides, fasting	46 participants	—	—	—	—
Incidence of Laboratory Values of Potential Clinical Relevance Hematology-Eosinophils	19 participants	—	—	—	—
Incidence of Laboratory Values of Potential Clinical Relevance Hematology-Hemoglobin	14 participants	—	—	—	—
Incidence of Laboratory Values of Potential Clinical Relevance Hematology-White blood cell count	9 participants	—	—	—	—
Incidence of Laboratory Values of Potential Clinical Relevance Urinalysis-Protein, urine	348 participants	—	—	—	—
Incidence of Laboratory Values of Potential Clinical Relevance Urinalysis-Specific gravity	188 participants	—	—	—	—
Incidence of Laboratory Values of Potential Clinical Relevance Others-Insulin	49 participants	—	—	—	—
Incidence of Laboratory Values of Potential Clinical Relevance Others-Insulin, fasting	78 participants	—	—	—	—
Incidence of Laboratory Values of Potential Clinical Relevance Others-Prolactin	324 participants	—	—	—	—

SECONDARY outcome

Timeframe: Baseline to Month 24

Population: All participants who had received at least one dose of oral aripiprazole. Any clinically relevant abnormal changes were recorded as TEAEs.

The physical examination evaluation was one of the 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.

Outcome measures

Outcome measures
Measure	Open-label Treatment Phase n=510 Participants Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 2 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 3 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 4 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 5 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.
Incidence of Physical Examination Findings of Potential Clinical Relevance	0 participants	—	—	—	—

SECONDARY outcome

Timeframe: Baseline to Month 24

Population: All participants who had received at least one dose of oral aripiprazole.

Vital signs are taken at Baseline, Weeks 1, 2, 3, 4, 6, 8, and Months 3, 4, 6, 9, 12, 15, 18, 21, 24 of Phase 2 (Visits beyond Month 12 only for de novo subjects). Assessments included orthostatic (supine and standing) blood pressure (BP), heart rate and body temperature. 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. Abnormal vital signs in participants were reported as SAE/AEs and are reported in the SAE/other AE section of this report.

Outcome measures

Outcome measures
Measure	Open-label Treatment Phase n=510 Participants Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 2 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 3 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 4 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 5 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.
Incidence of Vital Signs of Potential Clinical Relevance Heart rate supine-Increase ≥15 bpm	1 participants	—	—	—	—
Incidence of Vital Signs of Potential Clinical Relevance Heart rate supine-Decrease ≥15 bpm	1 participants	—	—	—	—
Incidence of Vital Signs of Potential Clinical Relevance Heart rate standing-Increase ≥15 bpm	4 participants	—	—	—	—
Incidence of Vital Signs of Potential Clinical Relevance Heart rate standing-Decrease ≥15 bpm	0 participants	—	—	—	—
Incidence of Vital Signs of Potential Clinical Relevance Systolic supine bp-Increase ≥20 mmHg	36 participants	—	—	—	—
Incidence of Vital Signs of Potential Clinical Relevance Systolic supine bp-Decrease ≥20 mmHg	31 participants	—	—	—	—
Incidence of Vital Signs of Potential Clinical Relevance Systolic standing bp-Increase ≥20 mmHg	38 participants	—	—	—	—
Incidence of Vital Signs of Potential Clinical Relevance Systolic standing bp-Decrease ≥20 mmHg	40 participants	—	—	—	—
Incidence of Vital Signs of Potential Clinical Relevance Diastolic supine bp-Increase ≥15 mmHg	41 participants	—	—	—	—
Incidence of Vital Signs of Potential Clinical Relevance Diastolic supine bp-Decrease ≥15 mmHg	19 participants	—	—	—	—
Incidence of Vital Signs of Potential Clinical Relevance Diastolic standing bp-Increase ≥15 mmHg	53 participants	—	—	—	—
Incidence of Vital Signs of Potential Clinical Relevance Diastolic standing bp-Decrease ≥15 mmHg	13 participants	—	—	—	—
Incidence of Vital Signs of Potential Clinical Relevance Weight gain ≥7%	195 participants	—	—	—	—
Incidence of Vital Signs of Potential Clinical Relevance Weight loss ≥7%	45 participants	—	—	—	—

SECONDARY outcome

Timeframe: Baseline to Month 24

Population: All participants who had received at least one dose of oral aripiprazole.

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.

Outcome measures

Outcome measures
Measure	Open-label Treatment Phase n=510 Participants Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 2 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 3 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 4 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 5 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.
Mean Change From Baseline by Week in Abnormal Involuntary Movement Scale (AIMS) Week 1 (N=486)	-0.02 Units on a scale Standard Deviation 0.24	—	—	—	—
Mean Change From Baseline by Week in Abnormal Involuntary Movement Scale (AIMS) Week 2 (N=507)	-0.01 Units on a scale Standard Deviation 0.25	—	—	—	—
Mean Change From Baseline by Week in Abnormal Involuntary Movement Scale (AIMS) Week 3 (N=507)	0.01 Units on a scale Standard Deviation 0.36	—	—	—	—
Mean Change From Baseline by Week in Abnormal Involuntary Movement Scale (AIMS) Week 4 (N=507)	-0.01 Units on a scale Standard Deviation 0.27	—	—	—	—
Mean Change From Baseline by Week in Abnormal Involuntary Movement Scale (AIMS) Week 6 (N=507)	0.02 Units on a scale Standard Deviation 0.56	—	—	—	—
Mean Change From Baseline by Week in Abnormal Involuntary Movement Scale (AIMS) Week 8 (N=507)	-0.02 Units on a scale Standard Deviation 0.28	—	—	—	—
Mean Change From Baseline by Week in Abnormal Involuntary Movement Scale (AIMS) Month 3 (N=507)	-0.00 Units on a scale Standard Deviation 0.31	—	—	—	—
Mean Change From Baseline by Week in Abnormal Involuntary Movement Scale (AIMS) Month 6 (N=507)	-0.02 Units on a scale Standard Deviation 0.40	—	—	—	—
Mean Change From Baseline by Week in Abnormal Involuntary Movement Scale (AIMS) Month 9 (N=506)	0.01 Units on a scale Standard Deviation 0.55	—	—	—	—
Mean Change From Baseline by Week in Abnormal Involuntary Movement Scale (AIMS) Month 12 (N=507)	-0.02 Units on a scale Standard Deviation 0.41	—	—	—	—
Mean Change From Baseline by Week in Abnormal Involuntary Movement Scale (AIMS) Month 15 (N=360)	-0.01 Units on a scale Standard Deviation 0.43	—	—	—	—
Mean Change From Baseline by Week in Abnormal Involuntary Movement Scale (AIMS) Month 18 (N=360)	-0.04 Units on a scale Standard Deviation 0.35	—	—	—	—
Mean Change From Baseline by Week in Abnormal Involuntary Movement Scale (AIMS) Month 21 (N=360)	-0.01 Units on a scale Standard Deviation 0.52	—	—	—	—
Mean Change From Baseline by Week in Abnormal Involuntary Movement Scale (AIMS) Month 24 (N=360)	-0.04 Units on a scale Standard Deviation 0.34	—	—	—	—

SECONDARY outcome

Timeframe: Baseline to Month 24

Population: All participants who had received at least one dose of oral aripiprazole.

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.

Outcome measures

Outcome measures
Measure	Open-label Treatment Phase n=510 Participants Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 2 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 3 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 4 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 5 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.
Mean Change From Baseline by Week in Simpson-Angus Scale (SAS) Total Score Week 8 (N=507)	-0.21 Units on a scale Standard Deviation 1.34	—	—	—	—
Mean Change From Baseline by Week in Simpson-Angus Scale (SAS) Total Score Week 1 (N=486)	-0.08 Units on a scale Standard Deviation 0.89	—	—	—	—
Mean Change From Baseline by Week in Simpson-Angus Scale (SAS) Total Score Week 2 (N=507)	-0.11 Units on a scale Standard Deviation 1.22	—	—	—	—
Mean Change From Baseline by Week in Simpson-Angus Scale (SAS) Total Score Week 3 (N=507)	-0.08 Units on a scale Standard Deviation 1.23	—	—	—	—
Mean Change From Baseline by Week in Simpson-Angus Scale (SAS) Total Score Week 4 (N=507)	-0.18 Units on a scale Standard Deviation 1.37	—	—	—	—
Mean Change From Baseline by Week in Simpson-Angus Scale (SAS) Total Score Week 6 (N=507)	-0.12 Units on a scale Standard Deviation 1.49	—	—	—	—
Mean Change From Baseline by Week in Simpson-Angus Scale (SAS) Total Score Month 3 (N=507)	-0.23 Units on a scale Standard Deviation 1.56	—	—	—	—
Mean Change From Baseline by Week in Simpson-Angus Scale (SAS) Total Score Month 6 (N=507)	-0.31 Units on a scale Standard Deviation 1.48	—	—	—	—
Mean Change From Baseline by Week in Simpson-Angus Scale (SAS) Total Score Month 9 (N=506)	-0.35 Units on a scale Standard Deviation 1.50	—	—	—	—
Mean Change From Baseline by Week in Simpson-Angus Scale (SAS) Total Score Month 12 (N=507)	-0.36 Units on a scale Standard Deviation 1.51	—	—	—	—
Mean Change From Baseline by Week in Simpson-Angus Scale (SAS) Total Score Month 15 (N=360)	-0.43 Units on a scale Standard Deviation 1.78	—	—	—	—
Mean Change From Baseline by Week in Simpson-Angus Scale (SAS) Total Score Month 18 (N=360)	-0.48 Units on a scale Standard Deviation 1.74	—	—	—	—
Mean Change From Baseline by Week in Simpson-Angus Scale (SAS) Total Score Month 21 (N=360)	-0.49 Units on a scale Standard Deviation 1.82	—	—	—	—
Mean Change From Baseline by Week in Simpson-Angus Scale (SAS) Total Score Month 24 (N=360)	-0.53 Units on a scale Standard Deviation 1.81	—	—	—	—

SECONDARY outcome

Timeframe: Baseline to Month 24

Population: All participants who had received at least one dose of oral aripiprazole.

The BARS was an EPS rating scale. The BARS 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).

Outcome measures

Outcome measures
Measure	Open-label Treatment Phase n=510 Participants Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 2 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 3 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 4 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 5 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.
Mean Change From Baseline by Week in Barnes Akathisia Rating Scale (BARS) Score Month 21 (N=360)	-0.04 Units on a scale Standard Deviation 0.50	—	—	—	—
Mean Change From Baseline by Week in Barnes Akathisia Rating Scale (BARS) Score Week 1 (N=487)	-0.02 Units on a scale Standard Deviation 0.26	—	—	—	—
Mean Change From Baseline by Week in Barnes Akathisia Rating Scale (BARS) Score Week 2 (N=507)	-0.02 Units on a scale Standard Deviation 0.35	—	—	—	—
Mean Change From Baseline by Week in Barnes Akathisia Rating Scale (BARS) Score Week 3 (N=507)	-0.02 Units on a scale Standard Deviation 0.35	—	—	—	—
Mean Change From Baseline by Week in Barnes Akathisia Rating Scale (BARS) Score Week 4 (N=507)	-0.03 Units on a scale Standard Deviation 0.33	—	—	—	—
Mean Change From Baseline by Week in Barnes Akathisia Rating Scale (BARS) Score Week 6 (N=507)	-0.03 Units on a scale Standard Deviation 0.36	—	—	—	—
Mean Change From Baseline by Week in Barnes Akathisia Rating Scale (BARS) Score Week 8 (N=507)	-0.02 Units on a scale Standard Deviation 0.41	—	—	—	—
Mean Change From Baseline by Week in Barnes Akathisia Rating Scale (BARS) Score Month 3 (N=507)	-0.00 Units on a scale Standard Deviation 0.45	—	—	—	—
Mean Change From Baseline by Week in Barnes Akathisia Rating Scale (BARS) Score Month 6 (N=507)	-0.03 Units on a scale Standard Deviation 0.44	—	—	—	—
Mean Change From Baseline by Week in Barnes Akathisia Rating Scale (BARS) Score Month 9 (N=506)	-0.04 Units on a scale Standard Deviation 0.43	—	—	—	—
Mean Change From Baseline by Week in Barnes Akathisia Rating Scale (BARS) Score Month 12 (N=507)	-0.04 Units on a scale Standard Deviation 0.42	—	—	—	—
Mean Change From Baseline by Week in Barnes Akathisia Rating Scale (BARS) Score Month 15 (N=360)	-0.02 Units on a scale Standard Deviation 0.47	—	—	—	—
Mean Change From Baseline by Week in Barnes Akathisia Rating Scale (BARS) Score Month 18 (N=360)	-0.05 Units on a scale Standard Deviation 0.48	—	—	—	—
Mean Change From Baseline by Week in Barnes Akathisia Rating Scale (BARS) Score Month 24 (N=360)	-0.05 Units on a scale Standard Deviation 0.47	—	—	—	—

SECONDARY outcome

Timeframe: Baseline to Month 24

Population: All participants who had received at least one dose of oral aripiprazole.

The NY-AACENT is not a validated scale. It was included in this trial because of concerns that regulatory authorities (the European Committee for Medicinal Products for Human Use \[CHMP\] and the Paediatric Sub-Committee of the European Medicinal Agency \[PDCO\]) had regarding drug induced cognitive impairment. No validated scale addressing these issues was available at the time of the trial. The NY-AACENT was used to detect changes in cognitive function subsequent to pharmacological or similar treatments for neurological or psychiatric problems. It was specifically designed to be used in pediatric populations (ages 12 to 17), but could have been utilized with other age groups, as appropriate.

Outcome measures

Outcome measures
Measure	Open-label Treatment Phase n=510 Participants Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 2 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 3 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 4 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 5 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.
Number of Participants With Cognitive Impairment for Each New York Assessment for Adverse Cognitive Effects of Neuropsychiatric Treatment (NY-AACENT) Visual learning/memory	138 participants	—	—	—	—
Number of Participants With Cognitive Impairment for Each New York Assessment for Adverse Cognitive Effects of Neuropsychiatric Treatment (NY-AACENT) Working memory	237 participants	—	—	—	—
Number of Participants With Cognitive Impairment for Each New York Assessment for Adverse Cognitive Effects of Neuropsychiatric Treatment (NY-AACENT) Attention/vigilance	306 participants	—	—	—	—
Number of Participants With Cognitive Impairment for Each New York Assessment for Adverse Cognitive Effects of Neuropsychiatric Treatment (NY-AACENT) Verbal learning/memory	233 participants	—	—	—	—
Number of Participants With Cognitive Impairment for Each New York Assessment for Adverse Cognitive Effects of Neuropsychiatric Treatment (NY-AACENT) Reasoning and problem solving	308 participants	—	—	—	—
Number of Participants With Cognitive Impairment for Each New York Assessment for Adverse Cognitive Effects of Neuropsychiatric Treatment (NY-AACENT) Speed of processing	276 participants	—	—	—	—
Number of Participants With Cognitive Impairment for Each New York Assessment for Adverse Cognitive Effects of Neuropsychiatric Treatment (NY-AACENT) Social congnition	307 participants	—	—	—	—

SECONDARY outcome

Timeframe: Baseline to Last Visit

Population: All those participants who had received at least one dose of oral aripiprazole during the open-label treatment phase.

Tanner staging was completed together with the physical examination by the same trial-affiliated clinician in the most inconspicuous manner for the participant as possible. Tanner staging assessment consisted of 2 domains (pubic hair and breast development) for girls and 3 domains (pubic hair, penis development, and testes development) for boys. A participant who reached Stage 5 (both in pubic hair and genitalia) did not need to continue with Tanner Staging assessment and the Tanner Staging scales of this participant were imputed as 5 for all of the following scheduled time points up to and including the completion visit/ET visit. The clinician arrived at a single score summarizing the domains (not individual domain scores) when evaluating the participant. The total shift data for last visit is presented below.

Outcome measures

Outcome measures
Measure	Open-label Treatment Phase n=7 Participants Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 2 n=24 Participants Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 3 n=79 Participants Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 4 n=196 Participants Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 5 n=204 Participants Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.
Baseline and Post-Baseline Tanner Staging Last Visit (Post-Baseline score of 1) (N= 1)	1 participants	0 participants	0 participants	0 participants	0 participants
Baseline and Post-Baseline Tanner Staging Last Visit (Post-Baseline score of 2) (N= 9)	4 participants	5 participants	0 participants	0 participants	0 participants
Baseline and Post-Baseline Tanner Staging Last Visit (Post-Baseline score of 3) (N= 39)	2 participants	9 participants	28 participants	0 participants	0 participants
Baseline and Post-Baseline Tanner Staging Last Visit (Post-Baseline score of 4) (N= 134)	0 participants	7 participants	33 participants	94 participants	0 participants
Baseline and Post-Baseline Tanner Staging Last Visit (Post-Baseline score of 5) (N= 327)	0 participants	3 participants	18 participants	102 participants	204 participants

SECONDARY outcome

Timeframe: Baseline to Month 24

Population: All participants who had received at least one dose of oral aripiprazole.

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). Suicidal ideation was defined as reporting any type of suicidal ideation. 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. 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.

Outcome measures

Outcome measures
Measure	Open-label Treatment Phase n=510 Participants Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 2 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 3 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 4 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 5 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.
Mean Change From Baseline for Columbia-Suicide Severity Rating Scale (C-SSRS) in Suicidal Ideation Intensity Total Score Week 8 (N= 484)	-0.4 Units on a scale Standard Deviation 2.0	—	—	—	—
Mean Change From Baseline for Columbia-Suicide Severity Rating Scale (C-SSRS) in Suicidal Ideation Intensity Total Score Week 1 (N= 487)	-0.4 Units on a scale Standard Deviation 2.1	—	—	—	—
Mean Change From Baseline for Columbia-Suicide Severity Rating Scale (C-SSRS) in Suicidal Ideation Intensity Total Score Week 2 (N= 483)	-0.4 Units on a scale Standard Deviation 2.2	—	—	—	—
Mean Change From Baseline for Columbia-Suicide Severity Rating Scale (C-SSRS) in Suicidal Ideation Intensity Total Score Week 3 (N= 477)	-0.4 Units on a scale Standard Deviation 2.2	—	—	—	—
Mean Change From Baseline for Columbia-Suicide Severity Rating Scale (C-SSRS) in Suicidal Ideation Intensity Total Score Week 4 (N= 491)	-0.4 Units on a scale Standard Deviation 2.2	—	—	—	—
Mean Change From Baseline for Columbia-Suicide Severity Rating Scale (C-SSRS) in Suicidal Ideation Intensity Total Score Week 6 (N= 488)	-0.3 Units on a scale Standard Deviation 2.1	—	—	—	—
Mean Change From Baseline for Columbia-Suicide Severity Rating Scale (C-SSRS) in Suicidal Ideation Intensity Total Score Month 3 (N= 478)	-0.3 Units on a scale Standard Deviation 2.2	—	—	—	—
Mean Change From Baseline for Columbia-Suicide Severity Rating Scale (C-SSRS) in Suicidal Ideation Intensity Total Score Month 4 (N= 472)	-0.3 Units on a scale Standard Deviation 2.1	—	—	—	—
Mean Change From Baseline for Columbia-Suicide Severity Rating Scale (C-SSRS) in Suicidal Ideation Intensity Total Score Month 6 (N= 458)	-0.2 Units on a scale Standard Deviation 2.5	—	—	—	—
Mean Change From Baseline for Columbia-Suicide Severity Rating Scale (C-SSRS) in Suicidal Ideation Intensity Total Score Month 9 (N= 407)	-0.2 Units on a scale Standard Deviation 1.8	—	—	—	—
Mean Change From Baseline for Columbia-Suicide Severity Rating Scale (C-SSRS) in Suicidal Ideation Intensity Total Score Month 12 (N= 302)	-0.3 Units on a scale Standard Deviation 2.0	—	—	—	—
Mean Change From Baseline for Columbia-Suicide Severity Rating Scale (C-SSRS) in Suicidal Ideation Intensity Total Score Month 15 (N= 261)	-0.2 Units on a scale Standard Deviation 1.9	—	—	—	—
Mean Change From Baseline for Columbia-Suicide Severity Rating Scale (C-SSRS) in Suicidal Ideation Intensity Total Score Month 18 (N= 247)	-0.1 Units on a scale Standard Deviation 2.0	—	—	—	—
Mean Change From Baseline for Columbia-Suicide Severity Rating Scale (C-SSRS) in Suicidal Ideation Intensity Total Score Month 21 (N= 212)	-0.1 Units on a scale Standard Deviation 1.8	—	—	—	—
Mean Change From Baseline for Columbia-Suicide Severity Rating Scale (C-SSRS) in Suicidal Ideation Intensity Total Score Month 24 (N= 180)	-0.0 Units on a scale Standard Deviation 1.9	—	—	—	—
Mean Change From Baseline for Columbia-Suicide Severity Rating Scale (C-SSRS) in Suicidal Ideation Intensity Total Score Last Visit (N= 507)	-0.1 Units on a scale Standard Deviation 2.5	—	—	—	—

SECONDARY outcome

Timeframe: Baseline to Month 24

Population: All participants who had received at least one dose of oral aripiprazole.

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). Suicidal ideation was defined as reporting any type of suicidal ideation. The below reported N value is the number of participants with specified suicidal ideation/behavior at the given time point.

Outcome measures

Outcome measures
Measure	Open-label Treatment Phase n=510 Participants Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 2 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 3 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 4 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 5 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.
Incidence of Suicidality, Suicidal Behavior and Suicidal Ideation Complete suicidality	0 participants	—	—	—	—
Incidence of Suicidality, Suicidal Behavior and Suicidal Ideation Suicidality	32 participants	—	—	—	—
Incidence of Suicidality, Suicidal Behavior and Suicidal Ideation Suicidal behavior	5 participants	—	—	—	—
Incidence of Suicidality, Suicidal Behavior and Suicidal Ideation Emergence of suicidal behavior	3 participants	—	—	—	—
Incidence of Suicidality, Suicidal Behavior and Suicidal Ideation Suicidal ideation	31 participants	—	—	—	—
Incidence of Suicidality, Suicidal Behavior and Suicidal Ideation Emergence of suicidal ideation	19 participants	—	—	—	—
Incidence of Suicidality, Suicidal Behavior and Suicidal Ideation Emergence of serious suicial ideation	2 participants	—	—	—	—
Incidence of Suicidality, Suicidal Behavior and Suicidal Ideation Worsening of suicidal ideation	26 participants	—	—	—	—

SECONDARY outcome

Timeframe: Baseline to Month 24

Population: All participants who had received at least one dose of oral aripiprazole.

The percentage of participants who discontinued due to all causes other than sponsor terminating the trial was measured from the date of entering the open-label treatment phase to the date of ET for discontinued participants in the open-label treatment phase (ie, time to discontinuation = date of discontinuation \[or date of completion for completed participants\] - date of participant entering the open-label treatment phase + 1). If the participants completed the trial or were discontinued due to the sponsor terminating the trial, they were censored at the time of completion or trial termination, respectively.

Outcome measures

Outcome measures
Measure	Open-label Treatment Phase n=510 Participants Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 2 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 3 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 4 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 5 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.
Percentage of Participants Who Discontinued Due to All Adverse Events From study NCT01149655 (N= 148)	3.4 percentage of participants	—	—	—	—
Percentage of Participants Who Discontinued Due to All Adverse Events De Novo (N= 362)	7.7 percentage of participants	—	—	—	—

SECONDARY outcome

Timeframe: Baseline to Month 24

Population: All participants who had received at least one dose of oral aripiprazole.

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).

Outcome measures

Outcome measures
Measure	Open-label Treatment Phase n=510 Participants Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 2 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 3 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 4 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 5 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.
Mean Change From Baseline in Positive and Negative Symptoms Score (PANSS) Total Score Month 12 (N= 414)	-9.98 Units on a scale Standard Deviation 14.66	—	—	—	—
Mean Change From Baseline in Positive and Negative Symptoms Score (PANSS) Total Score Month 24 (N= 267)	-12.52 Units on a scale Standard Deviation 15.70	—	—	—	—

SECONDARY outcome

Timeframe: Baseline to Month 24

Population: All participants who had received at least one dose of oral aripiprazole.

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).

Outcome measures

Outcome measures
Measure	Open-label Treatment Phase n=510 Participants Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 2 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 3 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 4 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 5 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.
Mean Change From Baseline in PANSS Positive Subscale Score Month 12 (N= 414)	-2.57 Units on a scale Standard Deviation 4.96	—	—	—	—
Mean Change From Baseline in PANSS Positive Subscale Score Month 24 (N= 267)	-2.91 Units on a scale Standard Deviation 5.13	—	—	—	—

SECONDARY outcome

Timeframe: Baseline to Month 24

Population: All participants who had received at least one dose of oral aripiprazole.

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).

Outcome measures

Outcome measures
Measure	Open-label Treatment Phase n=510 Participants Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 2 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 3 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 4 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 5 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.
Mean Change From Baseline in PANSS Negative Subscale Score Month 12 (N= 414)	-2.79 Units on a scale Standard Deviation 4.17	—	—	—	—
Mean Change From Baseline in PANSS Negative Subscale Score Month 24 (N= 267)	-3.48 Units on a scale Standard Deviation 4.63	—	—	—	—

SECONDARY outcome

Timeframe: Baseline to Month 24

Population: All participants who had received at least one dose of oral aripiprazole.

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.

Outcome measures

Outcome measures
Measure	Open-label Treatment Phase n=510 Participants Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 2 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 3 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 4 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 5 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.
Mean Change From Baseline in Clinical Global Impression-Severity (CGI-S) Score Month 24 (N= 267)	-0.77 Units on a scale Standard Deviation 1.04	—	—	—	—
Mean Change From Baseline in Clinical Global Impression-Severity (CGI-S) Score Month 12 (N= 414)	-0.66 Units on a scale Standard Deviation 0.96	—	—	—	—

SECONDARY outcome

Timeframe: Baseline to Month 24

Population: All participants who had received at least one dose of oral aripiprazole.

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.

Outcome measures

Outcome measures
Measure	Open-label Treatment Phase n=510 Participants Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 2 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 3 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 4 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 5 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.
Mean Change in Clinical Global Impression-Improvement (CGI-I) Score Month 12 (N= 408)	2.62 Units on a scale Standard Deviation 1.16	—	—	—	—
Mean Change in Clinical Global Impression-Improvement (CGI-I) Score Month 24 (N= 263)	2.38 Units on a scale Standard Deviation 1.15	—	—	—	—

SECONDARY outcome

Timeframe: Baseline to Month 24

Population: All participants who had received at least one dose of oral aripiprazole.

The YMRS consists of 11 items assessing the core symptoms of mania and was used to assess participants with bipolar I disorder, manic and mixed episodes with or without psychotic features: elevated mood, increased motor activity - energy, sexual interest, sleep, irritability, speech (rate and amount), language - thought disorder, content, disruptive - aggressive behavior, appearance, and insight. Each item had 5 or 9 grades of severity, with lower scores indicating milder symptoms. The number of raters within each trial center was to be kept to a minimum. The YMRS Total Score (range 0 to 44) is the sum of the rating scores for 11 items for assessing the core symptoms of mania. A missing value for any YMRS assessment item(s) could have resulted in a missing YMRS Total Score. A higher YMRS Total Score represents greater severity. In this study, 94 participants had bipolar disorder, this explains the N=94 in the table below and these were de novo participants.

Outcome measures

Outcome measures
Measure	Open-label Treatment Phase n=94 Participants Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 2 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 3 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 4 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 5 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.
Mean Change From Baseline in Young Mania Rating Scale (YMRS) Score Month 12 (N= 93)	-9.71 Units on a scale Standard Deviation 10.23	—	—	—	—
Mean Change From Baseline in Young Mania Rating Scale (YMRS) Score Month 24 (N= 93)	-10.02 Units on a scale Standard Deviation 10.21	—	—	—	—

SECONDARY outcome

Timeframe: Baseline to Month 24

Population: All participants who had received at least one dose of oral aripiprazole.

The CGI-BP scale refers to the global impression of the subject with respect to bipolar disorder. The scale rated the subject's Severity of Illness (CGI-BP-Severity: mania, depression, and overall bipolar illness) and Change From Preceding Phase (CGI-BP-Improvement: mania, depression, and overall bipolar illness) based on a 7- or 8-point scale. Severity of Illness (CGI-BP-Severity) was rated at all visits. At each visit other than Day 0 (Baseline), the Change From Preceding Phase (CGI-BP-Improvement) was judged with respect to participant's condition at Baseline. The CGI-BP Severity Scores (range 1 to 7), as well as CGI-BP Improvement Scores (range 1 to 7) are single-item rating scores, with higher scores representing greater severity or less improvement. Data for 94 de novo participants were available with bipolar disorder.

Outcome measures

Outcome measures
Measure	Open-label Treatment Phase n=94 Participants Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 2 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 3 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 4 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 5 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.
Mean Change From Baseline in Clinical Global Impression Scale - Bipolar (CGI-BP) Version Severity Score Month 12 (N= 93)	-1.26 Units on a scale Standard Deviation 1.33	—	—	—	—
Mean Change From Baseline in Clinical Global Impression Scale - Bipolar (CGI-BP) Version Severity Score Month 24 (N= 93)	-1.30 Units on a scale Standard Deviation 1.37	—	—	—	—

SECONDARY outcome

Timeframe: Baseline to Month 24

Population: All participants who had received at least one dose of oral aripiprazole.

The CGI-BP scale refers to the global impression of the subject with respect to bipolar disorder. The scale rated the subject's Severity of Illness (CGI-BP-Severity: mania, depression, and overall bipolar illness) and Change From Preceding Phase (CGI-BP-Improvement: mania, depression, and overall bipolar illness) based on a 7- or 8-point scale. Severity of Illness (CGI-BP-Severity) was rated at all visits. At each visit other than Day 0 (Baseline), the Change From Preceding Phase (CGI-BP-Improvement) was judged with respect to participant's condition at Baseline. The CGI-BP Severity Scores (range 1 to 7), as well as CGI-BP Improvement Scores (range 1 to 7) are single-item rating scores, with higher scores representing greater severity or less improvement. Only 94 participants had data at Baseline to explain the N=94 in the table below and these were de novo participants.

Outcome measures

Outcome measures
Measure	Open-label Treatment Phase n=94 Participants Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 2 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 3 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 4 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 5 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.
Mean Change From Baseline in Clinical Global Impression Scale - Bipolar Version Improvement Score Month 24 (N= 93)	2.17 Units on a scale Standard Deviation 1.27	—	—	—	—
Mean Change From Baseline in Clinical Global Impression Scale - Bipolar Version Improvement Score Month 12 (N= 93)	2.27 Units on a scale Standard Deviation 1.28	—	—	—	—

SECONDARY outcome

Timeframe: Baseline to Month 24

Population: All participants who had received at least one dose of oral aripiprazole.

The GBI is a self-report inventory with 73 items focusing on mood-related behaviors, including depressive, hypomanic, and biphasic symptoms. For this trial, two 20-item subscales were utilized: one was completed by the parent/guardian or legal representative, as applicable for local laws, and the other was completed by the participant. Responses were given on a 4-point Likert scale, with 0 being never or hardly ever and 3 being very often or almost constantly. The GBI Total Score for mania (range 0 to 30) is the sum of scores for items 1 to 10 and the GBI Total Score for depression (range 0 to 30) is the sum of scores for items 11 to 20 in the GBI Parent/Guardian or Subject Version panel. Scores from the Parent/Guardian and participant Versions were summarized separately. A missing value for any GBI assessment items could have resulted in a missing GBI Total Score. High scores represent greater psychopathology. Data was only available for 80 de novo participants with bipolar disorder.

Outcome measures

Outcome measures
Measure	Open-label Treatment Phase n=80 Participants Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 2 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 3 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 4 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 5 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.
Mean Change From Baseline in General Behavior Inventory (GBI) Scale Total Score for Mania and Depression in Both Parent/Guardian and Subject Version of the Scale Month 12 (N= 78)	-1.62 Units on a scale Standard Deviation 7.20	—	—	—	—
Mean Change From Baseline in General Behavior Inventory (GBI) Scale Total Score for Mania and Depression in Both Parent/Guardian and Subject Version of the Scale Month 24 (N= 78)	-1.82 Units on a scale Standard Deviation 7.37	—	—	—	—

SECONDARY outcome

Timeframe: Baseline to Month 24

Population: All participants who had received at least one dose of oral aripiprazole.

The ADHD-RS-IV is a reliable and easy-to-administer instrument both for diagnosing ADHD in children and adolescents and for assessing treatment response. Containing 18 items, the scale was linked directly to DSM-IV-TR diagnostic criteria for ADHD. There were 3 versions of the scale: a parent questionnaire on home behaviors (English), a parent questionnaire on home behaviors (Spanish), and a teacher questionnaire on classroom behaviors. For this trial, the parent questionnaire on home behaviors (English) was utilized. The ADHD-RS-IV Total Score (range 0 to 54) is the sum of rating scores for 18 items, with higher scores representing greater severity. A missing value for any ADHD-RS-IV assessment items could have resulted in a missing ADHD-RS-IV Total Score. Data were only available for 82 participants with bipolar disorder and these were de novo participants.

Outcome measures

Outcome measures
Measure	Open-label Treatment Phase n=82 Participants Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 2 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 3 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 4 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 5 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.
Mean Change From Baseline in the Attention Deficit Hyperactive Disorders Rating (ADHD-RS-IV) Scale Score Month 12 (N= 81)	-3.25 Units on a scale Standard Deviation 10.43	—	—	—	—
Mean Change From Baseline in the Attention Deficit Hyperactive Disorders Rating (ADHD-RS-IV) Scale Score Month 24 (N= 81)	-2.53 Units on a scale Standard Deviation 10.73	—	—	—	—

SECONDARY outcome

Timeframe: Baseline to Month 24

Population: All participants who had received at least one dose of oral aripiprazole.

The CGAS is a 100-point rating scale measuring psychological, social, and school functioning for children aged 6 to 17. It was adapted from the Adults Global Assessment Scale. The Global Assessment Scale was a rating scale for evaluating the overall functioning of a participant during a specified time period on a continuum from psychological or psychiatric sickness to health. The CGAS is a valid and reliable tool for rating a child's general level of functioning on a health-illness continuum. The CGAS was developed by Schaffer and colleagues to provide a global measure of severity of disturbance in children and adolescents. The CGAS Score (range 1 to 100) is a single-item score for rating a child's general level of functioning on a health-illness continuum, with higher scores representing better functioning.

Outcome measures

Outcome measures
Measure	Open-label Treatment Phase n=94 Participants Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 2 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 3 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 4 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	Tanner Score at Baseline of 5 Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.
Mean Change From Baseline in Children's Global Assessment Scale (CGAS) in Bipolar (de Novo Participants) Month 12 (N= 93)	14.17 Units on a scale Standard Deviation 16.01	—	—	—	—
Mean Change From Baseline in Children's Global Assessment Scale (CGAS) in Bipolar (de Novo Participants) Month 24 (N= 93)	14.00 Units on a scale Standard Deviation 16.23	—	—	—	—

Adverse Events

Conversion Phase

Serious events: 2 serious events

Other events: 40 other events

Deaths: 0 deaths

Open-label Treatment Phase

Serious events: 49 serious events

Other events: 194 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Conversion Phase n=297 participants at risk Participants who entered this phase were converted from his or her antipsychotic to the minimum target dose of 10 mg/day aripiprazole monotherapy and continue to increase the dose up to a maximum of 30 mg/day, or for tolerability reasons, to reduce the aripiprazole dose to no less than 5 mg/day.	Open-label Treatment Phase n=510 participants at risk Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.
Gastrointestinal disorders Vomiting	1.3% 4/297 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.	5.9% 30/510 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.
Infections and infestations Nasopharyngitis	1.7% 5/297 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.	6.7% 34/510 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.
Investigations Weight increased	0.34% 1/297 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.	7.5% 38/510 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.
Nervous system disorders Headache	7.7% 23/297 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.	13.1% 67/510 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.
Nervous system disorders Somnolence	6.7% 20/297 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.	6.5% 33/510 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.
Psychiatric disorders Anxiety	2.0% 6/297 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.	6.3% 32/510 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.
Psychiatric disorders Schizophrenia	0.34% 1/297 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.	5.9% 30/510 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.

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

Measure	Conversion Phase n=297 participants at risk Participants who entered this phase were converted from his or her antipsychotic to the minimum target dose of 10 mg/day aripiprazole monotherapy and continue to increase the dose up to a maximum of 30 mg/day, or for tolerability reasons, to reduce the aripiprazole dose to no less than 5 mg/day.	Open-label Treatment Phase n=510 participants at risk Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.
Congenital, familial and genetic disorders Gilbert's syndrome	0.00% 0/297 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.	0.20% 1/510 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.
Gastrointestinal disorders Gastritis	0.00% 0/297 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.	0.20% 1/510 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.
General disorders Irritability	0.00% 0/297 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.	0.20% 1/510 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.
Infections and infestations Laryngitis	0.00% 0/297 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.	0.20% 1/510 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.
Infections and infestations Tuberculosis	0.00% 0/297 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.	0.20% 1/510 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.
Injury, poisoning and procedural complications Intentional overdose	0.00% 0/297 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.	0.20% 1/510 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.
Injury, poisoning and procedural complications Toxicity to various agents	0.00% 0/297 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.	0.20% 1/510 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.
Investigations Blood creatine phosphokinase	0.00% 0/297 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.	0.20% 1/510 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.
Metabolism and nutrition disorders Decreased appetite	0.00% 0/297 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.	0.20% 1/510 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.
Psychiatric disorders Schizophrenia	0.00% 0/297 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.	3.5% 18/510 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.
Psychiatric disorders Suicidal ideation	0.00% 0/297 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.	1.6% 8/510 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.
Psychiatric disorders Bipolar disorder	0.00% 0/297 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.	1.4% 7/510 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.
Psychiatric disorders Aggression	0.00% 0/297 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.	0.59% 3/510 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.
Psychiatric disorders Agitation	0.00% 0/297 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.	0.59% 3/510 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.
Psychiatric disorders Hallucination, auditory	0.00% 0/297 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.	0.39% 2/510 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.
Psychiatric disorders Suicide attempt	0.00% 0/297 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.	0.39% 2/510 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.
Psychiatric disorders Bipolar I disorder	0.34% 1/297 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.	0.20% 1/510 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.
Psychiatric disorders Depression	0.00% 0/297 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.	0.20% 1/510 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.
Psychiatric disorders Mania	0.00% 0/297 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.	0.20% 1/510 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.
Psychiatric disorders Mental status changes	0.00% 0/297 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.	0.20% 1/510 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.
Psychiatric disorders Mood swings	0.00% 0/297 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.	0.20% 1/510 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.
Psychiatric disorders Psychotic disorder	0.00% 0/297 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.	0.20% 1/510 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.
Psychiatric disorders Self injurious behaviour	0.00% 0/297 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.	0.20% 1/510 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.
Reproductive system and breast disorders Metrorrhagia	0.00% 0/297 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.	0.20% 1/510 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.
Gastrointestinal disorders Tooth disorder	0.34% 1/297 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.	0.00% 0/510 • Adverse events were reported from the signing of the informed consent, during the 24-month treatment period until the follow-up visit 30 (± 3) days after the end of trial.