| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Schizophrenia in Adolescent Patients |
|
| E.1.1.1 | Medical condition in easily understood language |
| Schizophrenia in 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.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary objective of this study is to evaluate the efficacy of aripiprazole compared
with placebo, as measured by time to exacerbation of psychotic symptoms/impending
relapse, in adolescent schizophrenic subjects who have maintained stability for 2 consecutive weekly time points on oral aripiprazole with at least 7 weeks of treatment. |
|
| E.2.2 | Secondary objectives of the trial |
| To evaluate the safety and tolerability of oral aripiprazole as maintenance treatment in adolescent subjects with schizophrenia. |
|
| 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 the parent/guardian or legal 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.
2. Male and female subjects aged 13 to 17 years, inclusive, at the time of informed consent/assent until randomization in Phase 3.
3. Subjects with a current diagnosis of schizophrenia, and a history of the illness for at least 6 months prior to screening.
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. 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. Subjects with a history of relapse and/or exacerbation of symptoms when they are not receiving antipsychotic treatment.
8. Inpatient or outpatient status.
9. Ability of the subject, the subject’s parent/guardian or the legal 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.
10. 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.
11. Subjects who are receiving antipsychotic(s) other than aripiprazole must be cross-titrated to 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 in order to enter Phase 2, but higher doses may be achieved based on the subject’s clinical need and investigator judgment. Subjects who have received or are receiving clozapine are excluded from the study.
12. Subjects who are treated with non-branded generic aripiprazole must also be cross-titrated to achieve a 10 mg target dose of study aripiprazole. Also, the total dose of the generic aripiprazole and study aripiprazole (at any given time in Phase 1) cannot exceed a total of 30 mg/day.
13. By the end of screening, eligible subjects who are receiving oral branded aripiprazole (ie, Abilify™) monotherapy at a dose between 10 and 30 mg/day for treatment of schizophrenia at screening can enter Phase 2 directly.
14. Adequate washout of prohibited concomitant medications prior to entry into Phase 2, including ≥ 14 days for prohibited mood stabilizers, ≥ 14 days for prohibited antidepressants [≥ 28 days for fluoxetine or Symbyax (olanzapine/fluoxetine)], ≥ 6 months for marketed or investigational depot antipsychotics.
15. For subjects who enter Phase 2 directly from screening: Subjects who are receiving no more than one benzodiazepine after screening. NOTE: If a subject is receiving two benzodiazepines at screening, attempts should be made to discontinue one of them, if clinically warranted, to allow potential subjects to enter the study. The second benzodiazepine should be tapered off over an appropriate amount of time within the established duration of the screening period to prevent any withdrawal effects, and the subject should be maintained on the remaining benzodiazepine for at least 14 days prior to the first dose of study medication in Phase 2.
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 |
Sex and Reproductive Status
1. Sexually active males who are not practicing double-barrier 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 double-barrier 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, birth control 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. Subjects with a current DSM-IV-TR diagnosis other than schizophrenia, including an Axis I (DSM-IV-TR) diagnosis of schizoaffective disorder, major depressive disorder, autism, pervasive developmental disorder (PDD), OCD, or PTSD. Subjects with a diagnosis of ADD/ADHD and treated with stimulants or other ADD/ADHD medications within 1 year are prohibited.
4. 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. Subjects with attention deficit disorder or attention deficit hyperactivity disorder and/or the patient was on stimulant treatment for any period of time over the last one year prior to screening.
6. Subjects with a clinical presentation and/or history of any neurodevelopmental disorder except Tourette’s syndrome.
7. 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.
8. Subjects with schizophrenia that is considered treatment resistant to antipsychotic medication, including relapse while on adequate doses of aripiprazole, by history.
9. 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.
Medical History and Concurrent Disease
10. 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.
11. Subjects who have met DSM-IV-TR criteria for substance dependence (including alcohol and
benzodiazepines, but excluding caffeine and nicotine) within the past 180 days prior to screening.
12. Subjects who have epilepsy, a history of seizures (except
for a single childhood febrile seizure or post-traumatic seizure), 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 adverse event 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 (eg, history of myocardial infarction or ischemic heart disease, arrhythmia, congestive heart failure, or cancer); subjects with a co-morbid serious systemic illness that requires pharmacotherapy.
13. Subjects with a history of subclinical hypothyroidism (TSH ≥ 4 mIU/L), known hypothyroidism or hyperthyroidism (unless condition has been stabilized with medications for at least the past 90 days prior to entry into Phase 1 or Phase 2).
14. 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%, 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.
A full list of Other Exclusion Criteria is contained in the protocol
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint of this study is the time from randomization to exacerbation of psychotic symptoms/impending relapse in Phase 3, where impending relapse is defined as meeting any of the following 5 criteria:
1) CGI-Improvement of ≥ 5 (minimally worse)
AND
• an increase on any of the following individual PANSS items (conceptual disorganization, hallucinatory behavior, suspiciousness, unusual thought content) to a score > 4 with an absolute increase of ≥ 2 on that specific item since randomization OR
an increase on any of the following individual PANSS items (conceptual disorganization, hallucinatory behavior, suspiciousness, unusual thought content) to a score > 4 and an absolute increase of ≥ 4 on the combined 4 PANSS items (conceptual disorganization, hallucinatory behavior, suspiciousness, unusual thought content) since randomization OR
2) a CGI-I score of 6 or 7 (much or very much worse)
OR
3) Hospitalization due to worsening of illness (including partial hospitalization programs), but excluding hospitalization for psychosocial reasons
OR
4) Any suicidal behavior or answers of “yes” to Questions 4 or 5 on the suicidal ideation section of the C-SSRS
OR
5) Violent or aggressive behavior resulting in clinically significant self-injury, injury to
another person, or property damage or inability to attend school due to this behavior. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
The following secondary efficacy endpoints will be compared in Phase 3 between the aripiprazole treatment group and the placebo group at endpoint:
• Percentage of subjects meeting exacerbation of psychotic symptoms/impending relapse criteria
• Percentage of responders in each treatment group (ie, response defined as meeting stability criteria)
• Percentage of subjects achieving remission, where remission is defined as a score of ≤ 3 on each of the following specific PANSS items, maintained for a period of 6 months: delusions (P1), unusual thought content (G9), hallucinatory behavior (P3), conceptual disorganization (P2), mannerisms/posturing (G5), blunted affect (N1), social withdrawal (N4), and lack of spontaneity (N6)
• Time to discontinuation for all causes
Other Endpoints:
Efficacy:
• Mean change from baseline to endpoint in PANSS Total Score
• Mean change from baseline to endpoint in CGI-S score
• Mean CGI-I score at endpoint
• Mean change from baseline to endpoint in PANSS positive and negative subscales
• Mean change from baseline to endpoint in CGAS
Safety:
• The frequency and severity of AEs, seriousness of AEs (clinical and laboratory), and discontinuation from study due to AEs
• The frequency of symptom items for the the New York Assessment for Adverse Cognitive Effects of Neuropsychiatric Treatment: (NY-AACENT)
• The frequency of side effects for the UKU Side
Effects Rating Scale
• Analysis of potential suicide events recorded on the C-SSRS
• Mean change from baseline and incidence of clinically significant changes from baseline for clinical laboratory tests and urinalysis results (including fasting blood lipids and glucose, serum prolactin, insulin, and creatinine phosphokinase [CPK]), vital signs 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
• Baseline and postbaseline Tanner Staging
• Mean change from baseline of z-scores for height and body weight, mean changes of BMI and waist circumference
• Mean change from baseline to endpoint on the AIMS, SAS, and BARS
Other Outcomes:
• Change from baseline to endpoint for P-QLES-Q |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| 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 | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
Will this trial be conducted at a single site globally?
| No |
| E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
| India |
| Malaysia |
| Philippines |
| Romania |
| Russian Federation |
| Taiwan |
| United States |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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