Trial Outcomes & Findings for Safety and Tolerability of Open-Label Flexible-dose Brexpiprazole as Maintenance Treatment in Adolescents With Schizophrenia (NCT NCT03238326)

Participants took part in the study at multiple sites globally from 23 August 2017 to 22 April 2025. 14 participants underwent a cross-titration and received brexpiprazole for up to 4 weeks in conversion period followed by subsequent enrollment in De-Novo open label treatment (OLT) period.

Of the 295 participants who were enrolled for the study, 294 participants received the study treatment, and 1 participant did not receive the study drug. All eligible participants who rolled over from the previous study 331-10-234 (NCT03198078), and de novo participants received brexpiprazole tablets during this study.

Safety and Tolerability of Open-Label Flexible-dose Brexpiprazole as Maintenance Treatment in Adolescents With Schizophrenia

An AE is defined as any untoward medical occurrence in a clinical trial participant administered a medicinal product and which does not necessarily have a causal relationship with the study treatment.

An AE is defined as any untoward medical occurrence in a clinical trial participant administered a medicinal product and which does not necessarily have a causal relationship with the study treatment. A serious adverse event (SAE) is any AE occurring at any dose that results in death, life-threatening experience, persistent or significant disability/incapacity, in-patient hospitalization or prolongs hospitalization or congenital anomaly/birth defect. A serious TEAE is defined as an AE that occurred or worsened after the first dose of study treatment up until 30 days after the last dose.

An AE is defined as any untoward medical occurrence in a clinical trial participant administered a medicinal product and which does not necessarily have a causal relationship with the study treatment. Participants who discontinued the trial due to AEs were recorded.

Clinical laboratory assessments included clinical chemistry (alanine aminotransferase \[ALT\], alkaline phosphatase, aspartate aminotransferase \[AST\], creatinine phosphokinase (CPK), gamma glutamyl transferase, lactate dehydrogenase.

Clinical laboratory assessments included clinical chemistry (bilirubin, urea nitrogen, calcium, glucose, cholesterol including low-density lipoprotein (LDL-C), creatinine, Triglycerides \[TG\]).

Clinical laboratory assessments of HbA1c are reported in this outcome measure.

Clinical laboratory assessments included hematology including the red blood cell count (RBC Count).

Clinical laboratory assessments included hematology (basophils, eosinophils, neutrophils, leukocytes, lymphocytes, white blood cell (WBC) count, platelets).

Clinical laboratory assessments of pH are reported in this outcome measure.

Clinical laboratory assessments included prolactin for both males and females.

Clinical laboratory assessments including chloride and potassium are reported in this outcome measure.

Laboratory assessments included hematology, chemistry, and urinalysis. Abnormality criteria included: In mg/dL \[high bilirubin≥2.0, low calcium≤8.2, high cholesterol fasting≥240, HDL-C, Fasting\<40 male(M)/ \< 50 female(F); LDL-C, fasting≥160, high glucose, fasting≥100, non-fasting≥200 high TG, fasting≥150, high urate≥8.5 F/≥10.5 M, high protein urine≥2 units increase\]; high creatine kinase(units per liter \[U/L\])\>3xupper limit of normal (ULN)\]; high eosinophils/leukocytes ≥10%;ALT\>3×ULN; in mEq/L \[Cl≤ 90; potassium≤ 2.5; sodium low≤ 126, high ≥156\]; platelets≤75000/mm3; hemoglobin≤11g/dL M/≤ 9.5 F; glucose, urine≥2 units inc.; casts≥2 units inc.; hematocrit≤37% and decrease of≥3% points, M/≤ 32% and ≥3% points dec.,F. Number of participants with clinically significant laboratory test abnormalities were reported as per criteria defined in protocol. The categories with at least 1 participant with clinically significant abnormalities are reported.

Vital sign measurements included pulse rate assessed in beats per minute in standing and supine position.

Vital sign measurements included systolic blood pressure (SBP) and diastolic blood pressure (DBP). Blood pressure measurements were made in the supine and standing positions after the participant has been in each position at least 3 minutes.

Vital sign measurements included height assessed in centimeters.

Vital sign measurements included weight assessed in kilograms.

Vital sign measurements included temperature assessed in celsius.

Vital sign measurements- Z-score for body weight (BW), height, and BMI. To adjust for normal growth, z-scores were derived, which normalize for the natural growth of pediatric patients and adolescents. Z-score was calculated as the deviation of the participant's each parameter from the mean for the respective parameter of the reference population divided by the standard deviation (SD) for the reference population. Z-score-0 represents the population mean for the respective parameter. Positive Z-scores-values above the mean, negative Z-scores indicate values below the mean. BW and BMI: Higher Z-scores-Potential overweight/obesity (worse outcome if excessive). Lower Z-scores -Underweight (worse outcome if extreme). Height: Higher Z-scores-Taller than average (neutral unless clinically relevant). Lower Z-scores → Short stature (may indicate growth issues). Z ≥ +2-Above normal range (e.g., overweight or obesity for BMI). Z ≤ -2-Below normal range (e.g., underweight or short stature).

Vital sign measurements included body mass index (BMI).

Vital sign measurements included SBP, and DBP, pulse rate, body temperature, body weight, BMI, and height. Vital sign measurements included pulse rate in supine and standing positions (low: \<50 beats per minute \[bpm\] and decrease ≥15 bpm; High: \>120 bpm and increase ≥15 bpm), SBP in supine and standing positions (low: \<110 mmHg and decrease ≥20 mmHg; High: \>120 mmHg and increase ≥20 mmHg), DBP in supine and standing positions (low: \<60 mmHg and decrease ≥15 mmHg; High: \>80 mmHg and increase ≥15 mmHg), weight in kg (low: ≥7% decrease; High: ≥7% increase), orthostatic hypotension, (≥20mmHg decrease in SBP or ≥10 mmHg in DBP in heart rate from supine to standing). Number of participants with clinically significant abnormalities in vital signs were reported as per criteria defined in protocol. The categories with at least one participant with clinically significant abnormalities in vital signs are reported.

12-lead ECG recordings were obtained for parameters including PR interval, QRS duration, QT interval, QTcB \[QT interval as corrected for heart rate by Bazett's formula\] interval, QTcF \[QT interval as corrected for heart rate by Fridericia's formula\] interval, QTcN \[QT interval corrected for heart rate by the FDA Neuropharm\] interval, and RR interval.

Twelve-lead ECG recordings were obtained for parameters including mean heart rate.

12-lead ECG recordings were obtained for certain parameters and the 12-lead ECG abnormality criteria included bradycardia ≤ 50 bpm and decrease ≥15 bpm; sinus bradycardia ≤ 50 bpm and decrease of ≥ 15 bpm, supraventricular premature beat (SVPB)-not present at baseline and present post baseline, ventricular premature beat (VPB)- not present at baseline and present post baseline; and primary (1°) atrioventricular (AV) block (PR ≥200 milliseconds \[msec\] and increase of ≥50 msec, right bundle-branch block (RBBB) and symmetrical T-wave inversion (Sym T Wave Inv) - both not present at baseline and present post baseline; Increase in QTc-QTcF ≥ 450 msec for males, ≥ 470 msec for females. Number of participants with clinically significant ECG abnormalities was reported as per the criteria defined in the protocol. The categories with at least 1 participant with clinically significant ECG abnormalities are reported.

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. A negative change reflects an improvement or reduction in the severity of abnormal movements.

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). Each item is rated on a 5-point scale, with a score of zero representing absence of symptoms, and a score of 4 representing a severe condition. The SAS Total Score is the sum of the scores for all 10 items, ranging from 0-40. A negative change reflects an improvement or reduction in Parkinsonism severity.

The BARS score is based only on the item of "Global Clinical Assessment of Akathisia". The BARS consists of 4 items related to akathisia as follows. Item 1: objective observation of akathisia by the investigator; Item 2: subjective feelings of restlessness by the participant; Item 3: subjective distress due to akathisia; and Item 4: global clinical assessment of akathisia. The first 3 items will be rated on a 4-point Likert scale from 0 to 3, with 0 representing absence of symptoms and 3 representing a severe condition. The BARS global clinical assessment score refers to the ratings from the 4th item Global Clinical Assessment of Akathisia, which is a 6-point Likert scale from 0 to 5, with 0 representing absence of symptoms and 5 representing severe akathisia. Total score is the sum of the scores of all 4 items, ranging from 0 to 14. Higher score indicates severe akathisia. A negative change from baseline reflects improvement or reduction in the severity of akathisia symptoms.

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.

The UKU rating scale is a semi-structured interview used to assess the side effects of participants being treated with antipsychotic drugs. Each item (i.e., each symptom) of the UKU side effects is defined by the means of a 4-point-scale (0-1-2-3) if it is assessed in psychic, autonomic (auto), neurologic, other categories. In general, Degree 0 means "doubtfully or not present (NP)", and Degrees 1, 2, and 3 indicate that the symptom is present to a mild, moderate or severe degree, respectively.

The NY-AACENT is used to detect changes in cognitive function for neurological or psychiatric problems, specifically created to be used in pediatric population (ages 12 -17), but could be used with other age groups, as appropriate. Each of the 7 items is derived from the 7 domains as follows: Working Memory, Attention/Vigilance, Verbal Learning/Memory, Visual Learning/Memory, Reasoning and Problem Solving, Speed of Processing, and Social Cognition. Each score is derived as follows: 0=not present in the past week; 1=present (during past week) and mild; 2=present (during past week) and moderate; 3=present (during past week) and severe; and 4=present (during past week) and extreme; and the item score is set to missing/unknown. The NY-AACENT total score is calculated by summing up 7 individual item scores at participant-visit level. The Total range is 0-28. Higher scores reflects greater severity and frequency of cognitive problems and lower scores shows absence or mild cognitive issues.

The Tanner scale is a classification system used to assess physical development during puberty, detailing five distinct stages of growth. The Tanner Staging Scale assessment consists of 2 domains for girls and 3 domains for boys. Participants with change in Tanner Staging Scale (Stage 1-5) Score are reported.

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. A negative change from baseline reflects improvement or reduction in symptom severity.

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 (+ve) scale items, 7 negative (-ve) 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. A negative change from baseline reflects improvement or reduction in symptom severity.

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. A negative (-ve) change from baseline reflects improvement or reduction in symptom severity.

The CGAS is a 100-point rating scale measuring psychological, social and school functioning for children aged 6-17. The scale is separated into 10-point sections with the score ranging from 0-100, 1 to 10 indicates the need for constant supervision and 91 to 100 indicates superior functioning in all areas. A positive change from baseline reflects improvement in functioning.

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 following question: "Considering your total clinical experience with this particular population, how mentally ill is the patient at this time?" Response choices include: 0 = not assessed; 1 = normal, not at all ill; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill patients. Higher scores indicate worse condition.

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.