| 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 | 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 |
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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 |
| Evaluate the efficacy of paliperidone PR relative to aripiprazole in the treatment of symptoms of schizophrenia in adolescent subjects (aged 12 to 17 years of age, inclusive) at the Week 8 endpoint as measured by the change from baseline in the Positive and Negative Syndrome Scale in Schizophrenia (PANSS) total score. |
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| E.2.2 | Secondary objectives of the trial |
Evaluate the maintenance of clinical stability with paliperidone PR compared with aripiprazole at the Week 26 (as measured from Week 8) endpoint based on PANSS total score and Clinical Global Impression Severity (CGI-S) criteria, emergence of clinically significant suicidal or homicidal ideation, and the need for hospitalization due to psychiatric illness.
Compare the efficacy of paliperidone PR relative to aripiprazole in change from baseline in negative symptoms as measured by the PANSS negative symptom factor score (based on Marder factor) to the
Week 8 and Week 26 endpoints.
Assess the change in the PANSS total score of paliperidone PR compared with aripiprazole from baseline to Week 26 endpoint.
Assess the change in the global impression of severity of illness associated with the use of paliperidone PR compared with aripiprazole as measured by the CGI-S scale at the Week 8 and Week 26 endpoints.
For further objectives please see protocol |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Male or female between 12 and 17 years of age, inclusive. Subject may become 18 years of age during the study but should be 17 years of age at the time of signing the informed consent.
Subjects must currently meet the DSM-IV criteria for schizophrenia (295.10, 295.20, 295.30, 295.60, 295.90) and have experienced symptoms of the illness for at least one year. The K-SADS-PL questionnaire will be used to establish the diagnosis (including
all supplements). Subjects should have had at least one treatment (>6 weeks of treatment at a therapeutic dose) with an antipsychotic before participation in this study.
Subject must give assent to participate before screening procedures begin. In countries where subjects aged 12-17 years inclusive can give consent, the subject must sign the informed consent document (per local laws).
Parent(s) or the legal guardian(s) of the subject must sign an informed consent document indicating that they understand the purpose of and the procedures required for the study and give permission for their child’s participation in the study before
screening procedures begin
Subjects must have a PANSS score between 60 and 120 inclusive at screening (and whose physician believes that the subject is not receiving optimal clinical benefit or is experiencing a problem with safety or tolerability of their current anti-psychotic medication)
Subjects must be otherwise physically healthy on the basis of a physical examination, medical history, ECG, and the results of clinical laboratory tests carried out within 21 days before baseline.
Female subjects must either:
– be incapable of pregnancy because of hysterectomy or tubal ligation.
– if heterosexually active and capable of pregnancy, have been using an acceptable method of contraception (hormonal contraceptives, intrauterine device, spermicide and barrier or double barrier methods) for at least 1 month before study entry and agree to continue the use of one of these contraception methods for the duration of the study.
– if sexually abstinent and capable of pregnancy, agree to continue abstinence or to use an acceptable method of birth control (either hormonal contraceptives, intrauterine device, spermicide and barrier or double barrier method) should sexual activity commence.
To participate in the optional pharmacogenomic component of this study, subjects (or their legally-acceptable representative) must have signed the informed consent form for pharmacogenomic research indicating willingness to participate in the pharmacogenomic component of the study (where local regulations permit). Refusal to give consent for this component does not exclude a subject from participation in
the clinical study.
Subjects must not be a danger to themselves or others, and must have family support available to be maintained as outpatients. The Columbia Suicide Severity Rating Paliperidone PR: Clinical Protocol Scale, Baseline and Since Last Visit Forms will be used to assess suicidal ideation, intensity, and behavior at screening and baseline visits respectively. Subjects must answer no to items 1 and 2 in the C-SSRS Since Last Visit Version administered at baseline in order to be enrolled in the study.
Weight >=29 Kg
A responsible adult must be available to accompany the subject to the investigational site at each visit, to provide reliable information for all study related evaluations, and to accurately and reliably dispense the study drug as directed
Subjects must agree to be hospitalized at any time during the study, if it is deemed clinically necessary by the investigator.
Subjects must be able to meet study requirements. If a subject is unable to read study information, study personnel may read the questions to the subject and mark his or her choices |
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| E.4 | Principal exclusion criteria |
•Subjects who, at screening, meet the DSM-IV criteria for dissociative disorder, bipolar disorder, major depressive disorder, schizoaffective disorder, schizophreniform disorder, autistic disorder, or primary substance-induced psychotic disorder. Other comorbid disorders e.g., attention-deficit hyperactivity disorder (ADHD) are allowed, as long as the diagnosis of schizophrenia is the primary diagnosis and the comorbid disorders in the investigator’s judgment do not require medications (See Section 8, Concomitant Therapy)
•Subjects with mild, moderate, or severe mental retardation (i.e., documented intelligence quotient [IQ] <70), established by previous IQ testing or history
•Subjects with a known or suspected history of substance dependence (including alcohol, but excluding nicotine and caffeine) according to the DSM-IV criteria in the 3 months preceding screening.
•History or presence of circumstances that may increase the risk of the occurrence of torsade de pointes or sudden death in association with the use of drugs that prolong
the QTc interval, including:
– At screening and baseline, a supine measured heart rate of <50 bpm for subjects between 13 to 17 years of age, inclusive, and heart rate <55 bpm for subjects 12 years of age.
– demonstration of repeated prolonged QTc Fridericia interval >450 msec, as measured on more than one ECG (either during screening, or from a previous medical record).
– the following cardiac conditions: sick sinus syndrome, complete AV block, congestive heart failure, polymorphic ventricular tachycardia
– clinically relevant hypocalcemia, hypokalemia, or hypomagnesemia
•Concomitant use of drugs that prolong the QTc interval (including Class-I [e.g., quinidine, procainamide] or Class III [e.g., amiodarone, sotalol] antiarrhythmic medications); presence of congenital prolongation of the QT interval (Romano-Ward Syndrome, Jervell, and Lange-Nielsen syndrome)
•Subjects with a known or suspected history of seizure disorder, neuroleptic malignant
syndrome, encephalopathic syndrome, tardive dyskinesia, or insulin dependent diabetes mellitus
•Subjects who have received clozapine in the 2 months before the baseline visit.
•Presence of any significant or unstable cardiovascular, respiratory, renal, hepatic, hematologic, endocrine, immunologic, or other systemic disease
•History of severe preexisting gastrointestinal narrowing (pathologic or iatrogenic) or an inability to swallow oral study drug with the aid of water
•Subjects who, in the opinion of the investigator, should not discontinue or participate in washout of prohibited concomitant psychotropic medications (Section 8, Concomitant Therapy)
•Subjects who have received electroconvulsive therapy in the 3 months preceding
baseline
•Subjects who, despite washout, continue to use any prohibited concomitant medication, substance of abuse, or alcohol within 5 half-lives (up to a maximum of 5 days) before baseline, as evidenced by history or as suggested by a positive urine
drug screen at baseline
•Subjects who have received a depot injectable antipsychotic within 2 treatment cycles before the screening visit
•Clinically significant abnormalities in medical history, physical examination, ECG or biochemistry, hematology, or urinalysis results. Evidence of clinically significant hepatic disease [aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2 times the upper limit of normal] at screening
•Known or suspected hypersensitivity or intolerance to risperidone or paliperidone or
any of the excipients in the formulations
•Subjects who have participated in any investigational drug study in the 30 days
preceding screening or who have participated in 2 or more clinical trials in the past
year, with the exception of R076477-PSZ-3002
– Subjects who discontinue from R076477-PSZ-3002 for lack of efficacy or for
safety/tolerability reasons cannot be enrolled into R076477-PSZ-3003
•Children of employees of the investigator or study center, when the employee has
direct involvement in the proposed study or other studies under the direction of that
investigator or study center
•Subjects within their first psychotic episode
•History of any active malignancy (with the exception of excised basal cell carcinoma)
•Female subjects who are pregnant (as confirmed by urine pregnancy test performed at screening or baseline), planning to become pregnant or are nursing |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint will be the change in the PANSS total score from baseline to the Week 8 end point. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Screening (from 21 days before the study begins [Day -21] to 1 day before the study begins [Day -1]), baseline (Day 1), Day 7, Day 14, Day 28, Day 56 (Week 8), Day 98, Day 140, Day 182 (end of study), or at early withdrawal. |
|
| E.5.2 | Secondary end point(s) |
1. A secondary endpoint will be the proportion of patients maintaining clinical stability at Week 26 (as measured from Week 8) based on PANSS total score and Clinical Global Impression Severity (CGI-S), suicidality or homicidal ideas, or hospitalization.
2. A secondary endpoint will be the change from baseline in the PANSS negative symptom factor score (based on Marder factor) at Week 8 and Week 26.
3. A secondary endpoint will be the change from baseline in the PANSS total score at Week 26.
4. A secondary endpoint will be the change from baseline in CGI-S score at Week 8 and Week 26.
5. A secondary endpoint will be the change from baseline in Personal and Social Performance score at Week 8 and Week 26. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Day 56 (Week 8), Day 98, Day 140, Day 182 (end of study), or at early withdrawal
2. Screening (Day -21 to Day -1), baseline (Day 1), Day 7, Day 14, Day 28, Day 56, Day 98, Day 140, Day 182 (end of study), or at early withdrawal
3. Screening (Day -21 to Day -1), baseline (Day 1), Day 7, Day 14, Day 28, Day 56, Day 98, Day 140, Day 182 (end of study), or at early withdrawal
4. Baseline (Day 1), Day 7, Day 14, Day 28, Day 56, Day 98, Day 140, Day 182 (end of study), or at early withdrawal
5. Baseline (Day 1), Day 7, Day 14, Day 28, Day 56, Day 98, Day 140, Day 182 (end of study), or at early withdrawal |
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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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| 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 | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| 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 |
| Czech Republic |
| India |
| Romania |
| Russian Federation |
| Slovakia |
| Spain |
| Ukraine |
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| 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
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| The study is considered completed with the last visit of the last subject participating in the study. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| 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 | 1 |
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