| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Schizophrenia in Adolescent Patients or Child and Adolescent Patients with Bipolar I Disorder, Manic or Mixed Episode with or without Psychotic Features |
|
| E.1.1.1 | Medical condition in easily understood language |
| Schizophrenia in Adolescents and Bipolar I disorder in Children and Adolescents. |
|
| E.1.1.2 | Therapeutic area | Psychiatry and Psychology [F] - Behavioral Disciplines and Activities [F04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10039626 |
| E.1.2 | Term | Schizophrenia |
| E.1.2 | System Organ Class | 10037175 - Psychiatric disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10004939 |
| E.1.2 | Term | Bipolar I disorder |
| E.1.2 | System Organ Class | 10037175 - Psychiatric disorders |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The objective of this study is to further characterize the long-term safety and tolerability of aripiprazole in adolescent subjects with schizophrenia and child and adolescent subjects with Bipolar I Disorder, manic or mixed episode, with or without psychotic features. |
|
| E.2.2 | Secondary objectives of the trial |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion Criteria Assessed at Screening
1. Study specific written informed consent/assent obtained from a parent/guardian or legally acceptable representative,
as applicable for local laws, 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 study at any time. All informed consent/assent procedures must be in accordance with the study center’s institutional review
board/ethics committee (IRB/IEC) and local regulatory requirements. If the rollover subject should turn 18 years of age (or the age of adulthood as specified by local laws or regulations) within 4 weeks prior to entry into Study 267 or during Study 267 participation, an informed consent must be obtained from the subject.
2) Adolescent male and female subjects including:
Schizophrenia:
• De novo subjects aged 13 to 17 years at the time of signing the informed consent/assent
• Rollover subjects from Study 266
Bipolar Manic or Mixed Episode:
• De novo subjects aged 10 to 17 years at the time of signing the informed consent/assent.
3. All Subjects: Co-morbid diagnoses are permitted including Attention Deficit Disorder (ADD), Attention Deficit Hyperactivity Disorder (ADHD), Conduct Disorder (CD), and Oppositional Defiant Disorder (ODD) and anxiety disorders (except Post Traumatic Stress Disorder [PTSD] and Obsessive Compulsive Disorder [OCD]).
Subjects with Schizophrenia: Subjects with a current diagnosis of schizophrenia, as defined by DSM-IV-TR criteria (and confirmed by the K-SADS-PL for de novo subjects only), and a history of the illness (diagnosis or
symptoms) for at least 6 months prior to screening (as per subject, family, or healthcare provider, or by previous medical records). Schizophrenia must be the primary DSM-IV-TR axis I diagnosis. The diagnosis of schizophrenia must be made and documented initially by an adequately trained clinician (eg, adolescent psychiatrist or local medical equivalent). For de novo subjects, the diagnosis should be confirmed by utilizing the K-SADSPL performed by an adequately trained clinician once at the time of the entry into Study 267. If a rollover subject does not have a completed K-SADS-PL assessment from Study 266, then this assessment must be completed at Screening for Study 267.
Subjects with Bipolar Manic or Mixed Episode:
Subjects with a current diagnosis of Bipolar I disorder, manic or mixed episode with or without psychotic features experiencing symptoms at least for a week, as defined by
Axis I (DSM-IV-TR) criteria, confirmed by K-SADS-PL, and have a Young Mania Rating Scale (YMRS) score ≥ 20 at Baseline.
4. Subjects who, in the investigator’s judgment, require treatment with antipsychotic medication(s).
5. Subjects who have shown previous response to antipsychotic treatment (other than clozapine) and are not resistant to treatment with other antipsychotics, according
to the investigator’s clinical judgment.
6. Subjects who are currently being treated with oral antipsychotics other than clozapine, and subjects who are not resistant to treatment with other antipsychotics. De novo subjects who have been without antipsychotic treatment for no more than 3 weeks prior to screening will be considered as being treated currently for the purpose of determining eligibility for this trial.
7. Inpatient or outpatient status, with the exception of acute hospitalization due to psychiatric reasons at the time of screening or before Phase 2. Subjects who rollover from Study 266 who meet the criteria for impending relapse are
exempt from this criteria.
8. Ability of the subject and the subject’s parent/guardian or legally acceptable representative, as applicable for local laws, to comprehend and satisfactorily comply with the 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 reliably rate assessment scales.
9. Females of childbearing potential must have a negative pregnancy test, must be practicing acceptable double barrier methods of contraception (or can confirm abstinence), and must not be pregnant or lactating.
10. Subjects who are receiving antipsychotic(s) other than aripiprazole or clozapine must be cross-titrated to study aripiprazole monotherapy over 4 to 6 weeks using an initial dose of 2 mg/day in Phase 1 to achieve a recommended aripiprazole monotherapy minimum target dose of 10
mg/day after Day 6 in order to enter Phase 2, but higher doses may be achieved based on the subject’s clinical need and investigator.
The full list of inclusion criteria at screening plus Inclusion Criteria Assessed Prior to Entry into Phase 1 and Inclusion Criteria Assessed Prior to Entry into Phase 2 are described in the study protocol.
|
|
| E.4 | Principal exclusion criteria |
ALL SUBJECTS:
1) Sexually active males who are not practicing doublebarrier birth control or who will not remain abstinent during the study and for 90 days following the last dose of
study medication, or sexually active females of childbearing potential who are not practicing doublebarrier birth control or who will not remain abstinent during the study and for 30 days following the last dose of study medication. Abstinence will be permitted if it is confirmed and documented at every study visit. If employing birth control, two of the following precautions must be used: vasectomy, tubal ligation, vaginal diaphragm, intrauterine device (IUD), birth control pill, birth control depot injections, implant, condom or sponge with spermicide.
2) Females who are breast-feeding and/or who have a positive serum pregnancy test result prior to receiving study drug.
Target Disease
3) All Subjects: Axis I (DSM-IV-TR) diagnosis for schizoaffective disorder, autism, pervasive developmental disorder (PDD), OCD, or PTSD.
Subjects with Schizophrenia: Subjects with a current major depressive episode.
Subjects with Bipolar Manic or Mixed Episode: Subjects presenting with a clinical picture and/or history that is consistent with an Axis I (DSM-IV-TR) diagnosis of Bipolar II Disorder or Bipolar Disorder not otherwise specified (NOS).
4. Subjects with a clinical presentation and/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 (ie, medication, illicit drug use, etc.).
5. Any neurological disorder, with the exception of Tourette’s syndrome.
6. Subjects experiencing symptoms consistent with a major depressive episode at the time of screening other than subjects diagnosed with Bipolar I Disorder Mixed Episode.
7. Subjects with schizophrenia or Bipolar Manic or Mixed Episode that is considered treatment resistant to antipsychotic medication, including relapse while on adequate doses of aripiprazole, by history.
8. Subjects who are currently receiving clozapine or have received clozapine, regardless of dose or duration, at any time in the past are ineligible for entry into the study.
9. Subjects who have a significant risk of committing suicide based on history (eg, suicide attempt in the past 1 year) or routine psychiatric status examination, or who
have an answer of “yes” on Questions 4 or 5 (current or over the last 30 days) on the suicidal ideation section of the baseline screening version of the C-SSRS.
10. Subjects who have met DSM-IV-TR criteria for substance dependence within the past 180 days prior to screening.
11. Subjects who have epilepsy, a history of seizures, or a history of severe head trauma or stroke, or have a history or current evidence of other unstable medical conditions that would expose them to undue risk of a significant AE or interfere with assessments of safety or efficacy during the course of the trial, including but not limited to hepatic, renal, respiratory, cardiovascular, endocrine, neurologic, hematologic, or immunologic disease as determined by the clinical judgment of the investigator; subjects with a comorbid serious systemic illness that requires pharmacotherapy.
12. Subject with a history of subclinical hypothyroidism (TSH ≥4 mIU/L), known hypothyroidism or hyperthyroidism (unless condition has been stabilized with medications).
13. Subjects who have a medical history of uncontrolled diabetes, labile or unstable diabetes (brittle diabetes), newly diagnosed diabetes, or clinically significant abnormal blood glucose levels (defined as fasting blood glucose ≥ 125 mg/dL). If the result is abnormal, then hemoglobin A1c (HbA1c) testing will automatically be performed. If the HbA1c is ≥ 7%, at screening the subject must be withdrawn and considered a screen failure. At any time during the study, including screening, if a subject’s fasting blood glucose levels are abnormal (≥ 125 mg/dL), then fasting blood glucose testing must be repeated.
14) Subjects who have a positive drug screen for cocaine or cannabis during screening are ineligible. (Subjects who fail the drug screen can be rescreened one additional time within the 42 day screening period. If they pass the second drug screen test they may be enrolled. They may not have a third repeated drug screen during the screening period. Subjects who have two consecutive positive drug screens for cocaine at any time during the study must be withdrawn from the study. Two positive drug screens for other drugs of abuse must be discussed with the medical monitor at anytime during the study and prior to entry into Phase 1 or Phase 2 unless the subject satisfies criteria for dependence, in which case the subject should be withdrawn from the
study.
A full list of Other Exclusion Criteria is contained in the protocol. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Endpoint:
• The frequency and severity of AEs, SAEs (clinical and laboratory), and discontinuation from study due to AEs
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Throughout the duration of the study (max 12 months for rollover subjects)
Throughout the duration of the study (max 24 months for Denovo subjects) |
|
| E.5.2 | Secondary end point(s) |
Safety:
• 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, HbA1c and creatinine phosphokinase [CPK]), vital signs (supine and standing positions) and ECG parameters. A central ECG service will be utilized to review all ECGs in order to standardize interpretations for the safety analysis.
• Review of physical examination findings
• Mean change from baseline of z-scores for height and body weight, mean changes of BMI and waist circumference
• Mean change from baseline on the AIMS, SAS, and BARS
• The frequency of symptom items for the clinician-administered New York Assessment for Adverse Cognitive Effects of Neuropsychiatric Treatment: (NY-AACENT).
• Baseline and postbaseline Tanner Staging
• Analysis of potential suicide events recorded on the C-SSRS
• Time to discontinuation due to AE
Efficacy:
Schizophrenia:
• Mean change from baseline in PANSS Total Score
• Mean change from baseline in PANSS Positive and Negative subscales
• Mean change from baseline in CGI-S score
• Mean CGI-I score at endpoint
• Mean change from baseline in CGAS
Bipolar Manic or Mixed Episode:
• Mean change from baseline in YMRS
• Mean change from baseline in CGI-BP Severity
• Mean CGI-BP Improvement score at endpoint
• Mean change from baseline in GBI
• Mean change from baseline in ADHD-RS-IV
• Mean change from baseline in CGAS
Other Outcomes:
• Change from baseline for P-QLES-Q
• Mean change from baseline on the PANSS Cognitive Subscale Score
• Time to discontinuation for all reasons
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Throughout the duration of the study (max 12 months for rollover subjects)
Throughout the duration of the study (max 24 months for Denovo subjects) |
|
| 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 | Yes |
| 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 |
| long-term safety and tolerability |
|
| 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 | No |
| 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.8.3 |
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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| 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 |
| Bulgaria |
| Hungary |
| India |
| Malaysia |
| Philippines |
| Poland |
| Romania |
| Russian Federation |
| Serbia |
| Taiwan |
| Ukraine |
| United States |
| Croatia |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
| The last visit of the last subject. |
|
| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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