Trial to Evaluate the Short-term Safety & Efficacy of Brexpiprazole Monotherapy in the Treatment of Adolescents With Schizophrenia

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) to 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 ranges from 30 (best possible outcome) to 210 (worst possible outcome). Higher scores indicate worsening of symptoms. Least squares (LS) mean was determined by Mixed-effect model repeated measures (MMRM) method with fixed effect of treatment, (pooled) clinical center visit, treatment visit interaction, baseline value and baseline visit interaction as a covariate, and with an unstructured covariance.

Time frame: Baseline to Week 6

Population: Efficacy sample included all randomized participants who received at least 1 dose of IMP, had a baseline assessment, and at least one post-baseline assessment of the PANSS Total Score.

The AIMS assessment consists of 12 items rating the involuntary movements: Facial and oral movements (4 items), extremity movements (2 items), and trunk movements (1 item) were observed unobtrusively while the participant is at rest and the investigator also made global judgments on the participant's dyskinesias (2 items), and dental status (2 items). Severity of each item was rated on a 5-point scale, with a score of 0 (absence of symptoms) to 4 (severe condition). Total Score is the sum of the scores of all 12 items, ranging from 0 to 48, higher scores indicate severe condition. LS mean was determined by ANCOVA model with treatment and study center as main effects and baseline value as covariate.

Time frame: Baseline up to last visit (approximately 6 weeks)

Population: Safety sample included all randomized participants who received at least 1 dose of IMP. 'Overall number of participants analyzed' indicates the number of participants with data available for the outcome measure analysis.

The BARS consists of 4 items related to akathisia: objective observation of akathisia by the investigator, subjective feelings of restlessness by the participant, subjective distress due to akathisia, and global clinical assessment of akathisia. The first 3 items were rated on a 4-point scale, with a score of 0 (absence of symptoms) to 3 (severe condition) and the global clinical assessment was rated on a 6-point scale, with a score of 0 (absence of symptoms) to 5 (severe akathisia). Total score is the sum of the scores of all 4 items, ranging from 0 to 14, higher scores indicate severe condition. LS mean was determined by ANCOVA model with treatment and study center as main effects and baseline value as covariate.

Time frame: Baseline up to last visit (approximately 6 weeks)

Population: Safety sample included all randomized participants who received at least 1 dose of IMP. 'Overall number of participants analyzed' indicates the number of participants with data available for the outcome measure analysis.

The SAS 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). Severity of each item was rated on a 5-point scale, with a score of 0 (absence of symptoms) to 4 (severe condition). The SAS total score is the sum of the scores of all 10 items, ranging from 0 to 40 where lower scores indicate less severe condition. LS mean was determined by Analysis of Covariance (ANCOVA) model with treatment and study center as main effects and baseline value as covariate.

Time frame: Baseline up to last visit (approximately 6 weeks)

Population: Safety sample included all randomized participants who received at least 1 dose of IMP. 'Overall number of participants analyzed' indicates the number of participants with data available for the outcome measure analysis.

The CGAS is a 100-point rating scale measuring psychological, social, and school functioning for children aged 6-17 years and provides a global measure of the severity of disturbance. The scale is separated into 10-point sections that are headed with a description of the level of functioning and followed by examples matching the interval. The score ranges from 0-100, 1 to 10 indicates the need for constant supervision and 91 to 100 indicates superior functioning in all areas. Higher scores indicate better functioning. LS mean was determined by MMRM method with fixed effect of treatment, (pooled) clinical center visit, treatment visit interaction, baseline value, and baseline visit interaction as a covariate, and with an unstructured covariance.

Time frame: Baseline to Week 6

Population: Efficacy sample included all randomized participants who received at least 1 dose of IMP, had a baseline assessment, and at least one post-baseline assessment of the PANSS Total Score.

The CGI-S scale is an investigator-rated evaluation that assesses the severity of a participant's illness on a 7-point scale, ranging from 1 to 7. The investigator answered the question: Considering your total clinical experience with this particular population, how mentally ill is the participant at this time?. Response choices were: 0 = not assessed; 1 = normal, not at all ill; 2 = borderline ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill participants. Higher scores indicate worse condition. LS mean was determined by the MMRM method with fixed effect of treatment, (pooled) clinical center visit, treatment visit interaction, baseline value, and baseline visit interaction as a covariate, and with an unstructured covariance.

Time frame: Baseline to Week 6

Population: Efficacy sample included all randomized participants who received at least 1 dose of IMP, had a baseline assessment, and at least one post-baseline assessment of the PANSS Total Score.

PANSS has 7 positive symptom constructs: delusions, conceptual disorganization, hallucinatory behavior, excitement, grandiosity, suspiciousness/persecution, hostility; and 7 negative symptom constructs: blunted affect, emotional withdrawal, poor rapport, passive/apathetic social withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, stereotyped thinking. Each item's severity was rated on 7-point scale, with score of 1 (absence of symptoms) to 7 (extremely severe symptoms). PANSS positive & negative subscale scores were the sum of rating scores for 7 positive & 7 negative items respectively. Both scores range from 7 (best possible outcome) to 49 (worst possible outcome). Higher scores denote worsening of symptoms. LS mean was determined by MMRM method with fixed effect of treatment, (pooled) clinical center visit, treatment visit interaction, baseline value, and baseline visit interaction as a covariate, and with an unstructured covariance.

Time frame: Baseline to Week 6

Population: Efficacy sample included all randomized participants who received at least 1 dose of IMP, had a baseline assessment, and at least one post-baseline assessment of the PANSS Total Score.

Change in BMI was reported in kilograms per square meter (kg/m\^2).

Time frame: Baseline up to last visit (approximately 6 weeks)

Population: Safety sample included all randomized participants who received at least 1 dose of IMP. 'Overall number of participants analyzed indicates the number of participants with data available for outcome measure analysis.

Change in height was reported in centimeters (cm).

Time frame: Baseline up to last visit (approximately 6 weeks)

Population: Safety sample included all randomized participants who received at least 1 dose of IMP. 'Overall number of participants analyzed' indicates the number of participants with data available for the outcome measure analysis.

Change in waist circumference was reported in 'cm'.

Time frame: Baseline up to last visit (approximately 6 weeks)

Population: Safety sample included all randomized participants who received at least 1 dose of IMP. 'Overall number of participants analyzed' indicates the number of participants with data available for outcome measure analysis at the specified time point.

Change in weight was reported, in kilograms (kg).

Time frame: Baseline up to last visit (approximately 6 weeks)

Population: Safety sample included all randomized participants who received at least 1 dose of IMP. 'Overall number of participants analyzed' indicates the number of participants with data available for outcome measure analysis.

The efficacy of brexpiprazole in the treatment was rated for each participant using the CGI-I. The investigator rated the participant's total improvement whether or not it was entirely due to drug treatment on a 7-point scale, ranging from 0 to 7. Response choices were: 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. Higher scores indicate worse condition. Mean CGI-I scale score was determined by LOCF method.

Time frame: Week 6

Population: Efficacy sample included all randomized participants who received at least 1 dose of IMP, had a baseline assessment, and at least one post-baseline assessment of the PANSS Total Score.

An AE was defined as any untoward medical occurrence in a participant administered with a medicinal product that does not necessarily have a causal relationship with the treatment.

Time frame: From the first dose of study drug up to 21 days after the last dose of study drug (up to approximately 9 weeks)

Population: Safety sample included all randomized participants who received at least 1 dose of IMP.

C-SSRS is a scale used to report at least one occurrence of any suicidal behavior or suicidal ideation. Suicidal behavior was defined as reporting any of the following items: actual attempt, interrupted attempt, aborted attempt, and preparatory acts or behavior. The suicidal ideation 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) and the total score ranges from 0 to 25. Lower scores indicate improvement.

Time frame: From the first dose of study drug up to last dose of study drug (up to approximately 6 weeks)

Population: Safety sample included all randomized participants who received at least 1 dose of IMP.

The NY-AACENT is used to detect changes in cognitive function subsequent to pharmacological or similar treatments for neurological or psychiatric problems, specifically designed to be used in pediatric population (ages 12 to 17), but could have been utilized with other age groups, as appropriate. Number of participants with at least one occurrence of the corresponding signs/symptoms are reported in this outcome measure.

Time frame: From the first dose of study drug up to last dose of study drug (up to approximately 6 weeks)

Population: Safety sample included all randomized participants who received at least 1 dose of IMP.

Vital sign measurements included body weight, systolic blood pressure (SBP), and diastolic blood pressure (DBP). Blood pressure measurements were made in the supine, sitting, and standing positions after the participant had been in each position for at least 3 minutes as defined in SAP.

Time frame: From the first dose of study drug up to last dose of study drug (up to approximately 6 weeks)

Population: Safety sample included all randomized participants who received at least 1 dose of IMP. 'Overall number of participants analyzed' indicates the number of participants with at least one post-baseline result for the specified vital signs.

Potentially clinically relevant laboratory values assessed included - serum chemistry \[including blinded prolactin\], hematology, and urinalysis as defined in SAP.

Time frame: From the first dose of study drug up to last dose of study drug (up to approximately 6 weeks)

Population: Safety sample included all randomized participants who received at least 1 dose of IMP. 'Overall number of participants analyzed' indicates the number of participants with data available for the outcome measure analysis. 'Number analyzed' indicates the number of participants with at least one post-baseline numeric result for the specified parameter.

Twelve-lead ECG recordings were obtained after the participant was supine and at rest for at least 5 minutes as defined in SAP.

Time frame: From the first dose of study drug up to last dose of study drug (up to approximately 6 weeks)

Population: Safety sample included all randomized participants who received at least 1 dose of IMP. 'Overall number of participants analyzed' indicates the number of participants with data available for the outcome measure analysis. 'Number analyzed' indicates the number of participants with at least one post-baseline numeric result for the specified parameter.

The UKU rating scale is a semi-structured interview used to assess the side effects of participants being treated with antipsychotic drugs. The scale is divided into 6 sub-scales: Psychic, neurological, autonomic, other, global assessment by subject, and global assessment by doctor. The scale has a total of 48 items, each item is rated on a 4-point scale (0=not present; 1=mild; 2=moderate; 3=severe), and the total score ranges from 0 to 144. Higher ratings indicate greater impairment. The severe side effects are reported in this outcome measure.

Time frame: From the first dose of study drug up to last dose of study drug (up to approximately 6 weeks)

Population: Safety sample included all randomized participants who received at least 1 dose of IMP.

An AE was defined as any untoward medical occurrence in a participant administered with a medicinal product that does not necessarily have a causal relationship with the treatment. An SAE was any AE that results in the appearance of (or worsening of any pre-existing) undesirable signs, symptoms, or medical conditions which is fatal, life-threatening, result in persistent or significant disability/incapacity, constitutes a congenital anomaly/birth defect, and requires inpatient hospitalization or prolongation of existing hospitalization. TEAE is any AE after the start of treatment or if the event was continuous from baseline, medicinal product related, or resulted in death, discontinuation, interruption or reduction of medicinal product. TEAEs were graded on a 3-point scale: 1 (Mild: Discomfort noticed, but no disruption to daily activity), 2 (Moderate: Discomfort sufficient to reduce or affect normal daily activity), and 3 (Severe: Inability to work or perform normal daily activity).

Time frame: From the first dose of study drug up to 21 days after the last dose of study drug (up to approximately 9 weeks)

Population: Safety sample included all randomized participants who received at least 1 dose of IMP.

Remission was defined as a score of ≤ 3 on each of the following specific PANSS items: delusions (positive scale item \[P\] 1), unusual thought content (general scale item \[G\] 9), hallucinatory behavior (P3), conceptual disorganization (P2), mannerisms/posturing (G5), blunted affect (negative scale item \[N\] 1), passive/apathetic social withdrawal (N4), and lack of spontaneity and conversation flow (N6). Each item's severity was rated on 7-point scale, with score of 1 (absence of symptoms) to 7 (extremely severe symptoms). Percentage of participants achieving remission was determined by LOCF method.

Time frame: Up to 6 weeks

Population: Efficacy sample included all randomized participants who received at least 1 dose of IMP, had a baseline assessment, and at least one post-baseline assessment of the PANSS Total Score. Percentages are rounded off to the nearest decimal point.

Response was defined as at least 30% improvement from baseline in PANSS Total Score or CGI score of 1 or 2. 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, and ranges from 30 (best possible outcome) to 210 (worst possible outcome). The CGI scale is an investigator-rated evaluation that assesses the severity of a participant's illness on a 7-point scale, ranging from 1 (normal, not at all ill) to 7 (among the most extremely ill participants). Percentage of participants achieving response was determined by Last Observation Carried Forward (LOCF) method.

Time frame: Up to 6 weeks

Population: Efficacy sample included all randomized participants who received at least 1 dose of IMP, had a baseline assessment, and at least one post-baseline assessment of the PANSS Total Score. Percentages are rounded off to the nearest decimal point.