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

Phase 3CompletedNCT03198078

Otsuka Pharmaceutical Development & Commercialization, Inc.316 enrolled

Overview

To determine the safety \& efficacy of brexpiprazole monotherapy in the treatment of adolescents with schizophrenia.

This is a multicenter, randomized, double-blind, placebo- and active-controlled trial to evaluate the safety and efficacy of brexpiprazole monotherapy compared to placebo in adolescent subjects (ages 13-17) with a DSM-5 diagnosis of schizophrenia.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

316

Conditions

Schizophrenia

Interventions

Brexpiprazole (OPC-34712)DRUG

Once-daily, tablets

AripiprazoleDRUG

Once-daily, tablets

PlaceboDRUG

Once-daily, tablets

Eligibility

Sex: ALLMin age: 13 YearsMax age: 17 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Male \& female subjects aged 13-17 years, inclusive at time of consent and at baseline visit, with a primary diagnosis of schizophrenia as defined by DSM-5 criteria and confirmed by K-SADS-PL and a history of the illness for at least 6 months prior to screening. * PANSS score \>= 80, inclusive, at screening and baseline Exclusion Criteria: * Subjects with a DSM-5 diagnosis other than schizophrenia that has been the primary focus of treatment within 3 months of screening. * Subjects with a clinical presentation or history that is consistent with delirium, dementia, amnesia or other cognitive disorders * Subjects who have been hospitalized \> 21 days for a current exacerbation of schizophrenia at the time of baseline. * Any neurological disorder other than Tourette's Syndrome * Subjects at significant risk of committing violent acts, serious self-harm or suicide based on history * Subjects with epilepsy, a history of seizures, severe head trauma or stroke * Subjects who test positive for drugs of abuse at screening

Locations (1)

For additional information regarding sites, contact 844-687-8522

Oklahoma City, Oklahoma, United States

Outcomes

Primary Outcomes

Change From Baseline to Week 6 in Positive and Negative Syndrome Scale (PANSS) Total Score

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

Secondary Outcomes

Change From Baseline to Week 6 in PANSS Positive and Negative Sub-Scales Scores

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

Percentage of Participants Achieving Response

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.

Data from ClinicalTrials.gov

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Time frame: Up to 6 weeks

Percentage of Participants Achieving Remission

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

Change From Baseline to Week 6 in Children's Global Assessment Scale (CGAS) Total Score

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

Change From Baseline to Week 6 in Clinical Global Impression Severity (CGI-S) Scale 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

Mean Clinical Global Impression Improvement (CGI-I) Scale Score at Week 6

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

Number of Participants With Adverse Events (AEs) and Trial Discontinuation Due to AEs

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)

Number of Participants With Treatment-emergent AEs (TEAEs), Serious TEAEs, and TEAEs Graded by Severity

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)

Mean Change From Baseline in Weight

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

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

Mean Change From Baseline in Height

Change in height was reported in centimeters (cm).

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

Mean Change From Baseline in Body Mass Index (BMI)

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

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

Mean Change From Baseline in Waist Circumference

Change in waist circumference was reported in 'cm'.

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

Number of Participants With At Least One Occurrence of Suicidal Behavior or Suicidal Ideation as Recorded on Columbia-Suicide Severity Rating Scale (C-SSRS)

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)

Number of Participants With Potentially Clinically Relevant Laboratory Test Values

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)

Number of Participants With Potentially Clinically Relevant Abnormalities in Vital Signs

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)

Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Parameters

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)

Change From Baseline in Simpson Angus Scale (SAS) Total Score

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)

Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) 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)

Change From Baseline in Barnes Akathisia Rating Scale (BARS) Score

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)

Number of Participants With Severe Psychotropic Side Effects as Assessed by Udvalg for Kliniske Undersogelser (UKU) Rating Scale

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)

Number of Participants With Cognitive Adverse Effects Assessed by New York Assessment for Adverse Cognitive Effects of Neuropsychiatric Treatment (NY-AACENT)

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)