| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Psychiatry and Psychology [F] - Mental Disorders [F03] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10039636 |
| E.1.2 | Term | Schizophrenia simple |
| E.1.2 | System Organ Class | 100000004873 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The objective of the trial is to characterize the long-term safety and tolerability of brexpiprazole in adolescents with schizophrenia. |
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| E.2.2 | Secondary objectives of the trial |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion Criteria for Rollover Subjects from Trial 331 10 234
1. Written informed consent/assent obtained from a legally acceptable representative (eg, guardian) or subject prior to the initiation of any protocol-required procedures. In addition, the subject must provide informed assent at screening and must be able to understand that he or she can withdraw from the trial at any time. All informed consent/assent procedures must be in accordance with the trial site’s IRB/IEC and local regulatory requirements.
2. Ability, in the opinion of the principal investigator, of the subject and the subject’s legally acceptable representative (eg, guardian) or caregiver(s) to understand the nature of the trial and follow protocol requirements, including the prescribed dosage regimens, tablet ingestion, and discontinuation of prohibited concomitant medications, to read and understand the written word in order to complete subject-reported outcomes measures, and to be reliably rated on assessment scales.
3. Male and female subjects 13 to 18 years of age, inclusive, at the time of informed consent/assent and at baseline. Subjects who turned 18 years old during Trial 331-10-234 are permitted in this trial.
4. Subjects who complete Trial 331-10-234 and who, in the opinion of the investigator, could potentially benefit from monotherapy treatment with oral brexpiprazole for schizophrenia.
5. Outpatient status at the last visit of Trial 331-10-234.
Inclusion Criteria for De Novo Subjects
1. Written informed consent obtained from a legally acceptable representative (eg, guardian) prior to the initiation of any protocol-required procedures. In addition, the subject must provide informed assent at screening and must be able to understand that he or she can withdraw from the trial at any time. All informed consent/assent procedures must be in accordance with the trial site’s IRB/IEC and local regulatory requirements.
2. Ability, in the opinion of the principal investigator, of the subject and the subject’s legally acceptable representative (eg, guardian) or caregiver(s) to understand the nature of the trial and follow protocol requirements, including the prescribed dosage regimens, tablet ingestion, and discontinuation of prohibited concomitant medications, to read and understand the written word in order to complete subject-reported outcomes measures, and to be reliably rated on assessment scales.
3. Male and female subjects 13 to 17 years of age, inclusive, at the time of informed consent/assent and at baseline (Day 1).
4. Subjects with a current primary diagnosis of schizophrenia, as defined by DSM-5 criteria and a history of the illness (diagnosis or symptoms) for at least 6 months prior to screening. The confirmation of the diagnosis of schizophrenia for this trial should be made by an adequately trained clinician (psychiatrist, or local medical equivalent who is experienced in treating adolescents with schizophrenia), and the diagnosis should then be confirmed utilizing the K SADS-PL performed by an adequately trained rater at the time of entry into Trial 331-10-236. (Subjects with a diagnosis of ADHD and treated with stimulants or other ADHD medications within 1 month are prohibited.)
5. Subjects who, in the investigator’s judgment, require treatment with antipsychotic medication(s).
6. Outpatient status.
7. Subjects willing to discontinue all prohibited psychotropic medications to meet protocol-required washouts prior to and during the trial period.
Inclusion Criteria Assessed Prior to Entry into the Conversion Period
8. Adequate washout of prohibited concomitant medications (see Table 4.1-1).
9. Subject is receiving antipsychotic(s) other than clozapine. These subjects must be cross-titrated to brexpiprazole monotherapy over 1 to 4 weeks in the conversion period to a minimum dose of 1 mg/day as a starting dose in the open-label treatment period (see Section 3.2.2.1).
Inclusion Criteria Assessed Prior to Entry into the Open-label Treatment Period
10. Adequate washout of prohibited concomitant medications (see Table 4.1-1).
11. Subject is ready to receive oral brexpiprazole as monotherapy for treatment of schizophrenia.
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| E.4 | Principal exclusion criteria |
Key exclusion criteria include the following:
• 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 with psychotic symptoms that are better accounted for by another general medical condition(s) or direct effect of a substance (eg, medication, illicit drug use).
• Any neurological disorder, with the exception of Tourette’s syndrome.
• Subjects experiencing acute depressive symptoms within the past 30 days prior to screening that, according to the investigator’s judgment, require treatment with an antidepressant.
• Subjects with schizophrenia who are considered treatment resistant to antipsychotic medication, including aripiprazole or brexpiprazole, at an adequate dose and duration as confirmed by medical history, investigator judgment, or subject report. Subjects with a history of relapse due to lack of medication compliance or drug abuse can be considered based on investigator judgment.
• Subjects with a history of failure of clozapine treatment or response to clozapine treatment only.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoints of this trial are the frequency and severity of AEs, serious treatment-emergent adverse events (TEAEs) (clinical and laboratory), and discontinuation from trial due to AEs. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Throughout the course of the trial. |
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| E.5.2 | Secondary end point(s) |
The secondary safety endpoints are as follows:
• Mean change from baseline and incidence of clinically significant abnormalities in clinical laboratory tests and urinalysis results (including fasting blood lipids, glucose and insulin, serum prolactin, glycosylated hemoglobin [HbA1c] and creatine phosphokinase [CPK]), vital signs (supine and standing positions), weight, height, body mass index (BMI), waist circumference, and ECG parameters
• Mean change from baseline on the Abnormal Involuntary Movement Scale (AIMS), Simpson-Angus Scale (SAS), and Barnes Akathisia Rating Scale (BARS)
• Analysis of potential suicide events recorded on the C SSRS
• Comprehensive psychotropic side effects as assessed by UKU side effect rating scale
• The frequency of symptom items for the clinician-administered NY-AACENT
• Baseline and postbaseline Tanner Staging Scale data
• Time to discontinuation due to AE
The secondary efficacy endpoints are as follows:
• Change in the PANSS Total Score and the Positive and Negative Subscale Scores
• Change in the CGAS Score
• Clinical Global Impression Severity (CGI-S) scale
• Clinical Global Impression Improvement (CGI-I) scale
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| baseline and post baseline |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 52 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Croatia |
| Hungary |
| Mexico |
| Netherlands |
| Poland |
| Romania |
| Serbia |
| Spain |
| Ukraine |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| Last visit of last subject |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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