A Double-blind, Placebo-controlled Study of the Safety and Efficacy of Paliperidone Extended Release (ER) in the Treatment of Schizophrenia in Adolescent Patients

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy, safety, and tolerability of 3 weight-based, fixed-dose groups of paliperidone extended release (ER) compared with placebo in adolescent patients between 12 to 17 years of age, who are diagnosed with schizophrenia. Paliperidone ER is an atypical antipsychotic agent approved by the U.S. Food and Drug Administration for the treatment of schizophrenia in adults. Patients may be voluntary inpatients or outpatients at the time of the screening visit, but should have returned to their usual living situation by Day 21 of the double-blind treatment phase. The study duration is approximately 10 weeks. Patients who have completed this study or who were discontinued from this study due to lack of efficacy but have completed at least 21 days of double-blind treatment and are expected to benefit from paliperidone treatment, may enter an optional open-label safety study.

Detailed Description
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The study is a multicenter, randomized (treatment group is assigned by chance), double-blind (neither the physician nor the patient knows which treatment group the patient is in), parallel-group, placebo controlled study. This study will enroll adolescent men and women who have schizophrenia as specified by the Diagnostic and Statistical Manual of Mental Disorders; 4th Edition (DSM-IV) diagnosis of schizophrenia (295.10, 295.20, 295.30, 295.60, and 295.90) as confirmed by the Kiddie-Sads-Present and Lifetime Version (KSADS-PL), and who should have a Positive and Negative Syndrome Scale (PANSS) score that is between 60 and 120, inclusive, at screening and baseline. Before any study related procedure is performed, the patient and his parent or legal guardian must have provided assent and signed an informed consent form, respectively. The study consists of 3 phases: a screening phase, a 6-week double-blind treatment phase with an end-of-study or early withdrawal visit, and a 1 week follow-up visit for patients who do not enter the optional open-label safety study. In the screening phase, a trained clinician will complete the K SADS-PL interview, including all 5 supplements, to confirm the DSM-IV diagnostic criteria for schizophrenia. In addition, the K-SADS-PL screening diagnostic interview items for suicide must each have a score of <=2, as follows: item a), recurrent thoughts of death; item b), suicidal thoughts; item c), suicide attempts and their seriousness; item d), suicide attempts and their lethality; and item e) self harming behavior. Women of childbearing potential will undergo a urine pregnancy test at screening, baseline, Week 4, and at end of study or upon early withdrawal from the study. Patients who are receiving prohibited medications, such as antidepressants, lithium, drugs of abuse, and alcohol, will enter a washout period during which medications will be tapered down and eventually stopped. The screening and washout phase may not exceed 21 days. In the double-blind treatment phase, at the baseline visit, the inclusion and exclusion criteria will be reviewed. Patients who continue to meet the criteria will be randomly assigned (as in the toss of a coin) to 1 of 4 dose groups. Patients weighing between 29 to <51 kilograms (kg) will receive paliperidone ER 1.5, 3.0, or 6.0 milligrams (mg) or matching placebo. Patients weighing >=51 kg will receive paliperidone ER 1.5, 6.0, or 12.0 mg or matching placebo. Patients will come to the study site for weekly visits during this phase. A follow-up visit will occur 1 week after the end of treatment for those patients who will not enter the open-label study. Efficacy and safety procedures will be performed at specified times during the study. Efficacy procedures include the administration of the PANSS, Children's Global Assessment (CGAS), Clinical Global Impression-Severity (CGI-S) and a sleep visual analog scale. Safety assessments include a physical examination (ECG measurements, vital signs, weight, height, and waist measurements), clinical laboratory testing, drug screen, Simpson and Angus Scale (SAS), Barnes Akathisia Rating Scale (BARS), Abnormal Involuntary Movement Scale (AIMS), Tanner Staging, concomitant medications and the recording of adverse events. A Data Safety Monitoring Board will oversee the conduct of the study and review adverse event reports and laboratory test results. The total volume of blood drawn for laboratory evaluation throughout the study, including 10 milliliters (mL) for the optional pharmacogenomics testing, is approximately 66 mL for each patient. Blood samples will be collected to explore the pharmacokinetics of paliperidone in adolescent patients. The study hypothesis is that at least 1 paliperidone ER dose group will be superior to placebo in improving the symptoms of schizophrenia as measured by the change in total PANSS score from the baseline to endpoint (Week 6). Paliperidone ER 1.5, 3.0, 6.0, or 12.0 mg or matching placebo will be administered daily in the morning before 10 a.m., and at approximately the same time each day. Study drug administration should occur in a consistent manner relative to the intake of food (i.e., either before or after breakfast, or without any breakfast) throughout the study. Study drug should be swallowed whole and with water. Study drug will be administered for 6 weeks.

Official Title
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A Randomized, Multicenter, Double-Blind, Weight-Based, Fixed-Dose, Parallel-Group, Placebo-Controlled Study of the Efficacy and Safety of Extended Release Paliperidone for the Treatment of Schizophrenia in Adolescent Subjects, 12 to 17 Years of Age

Conditions
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Schizophrenia

Intervention / Treatment
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* Drug: Paliperidone ER
* Drug: Placebo
* Drug: Paliperidone ER
* Drug: Paliperidone ER


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must meet the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM IV) criteria for schizophrenia (295.10, 295.20, 295.30, 295.60, 295.90) for 1 year (the diagnosis will be established using the K-SADS-PL, including all supplements) Must not be a danger to themselves or others, and must have family support available to be maintained as an outpatient Should have had at least 1 adequate treatment with an antipsychotic before participation in this study Must have a PANSS score between 60 and 120, inclusive, at screening and baseline Weight >=29 kg Exclusion Criteria: Meet the DSM-IV criteria at screening 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 medication Mild, moderate, or severe mental retardation (i.e., documented intelligence quotient [IQ] <70) established by previous IQ testing or history Women who are pregnant (as confirmed by urine pregnancy test performed at screening or baseline), planning to become pregnant or are nursing Have a known or suspected history of seizure disorder, or neuroleptic malignant syndrome, encephalopathic syndrome, tardive dyskinesia, or insulin dependent diabetes mellitus Presence of any significant or unstable cardiovascular, respiratory, renal, hepatic, hematologic, endocrine, immunologic, or other systemic disease

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 001<br>Paliperidone ER 1.5 mg tablet once daily for 6 weeks | Drug: Paliperidone ER<br>* 1.5 mg tablet once daily for 6 weeks<br>|
| Experimental: 002<br>Paliperidone ER 3 mg or 6 mg tablet once daily for 6 weeks | Drug: Paliperidone ER<br>* 3 mg or 6 mg tablet once daily for 6 weeks<br>|
| Experimental: 003<br>Paliperidone ER 6 mg or 12 mg tablet once daily for 6 weeks | Drug: Paliperidone ER<br>* 6 mg or 12 mg tablet once daily for 6 weeks<br>|
| Placebo Comparator: 004<br>Placebo Once daily for 6 weeks | Drug: Placebo<br>* Once daily for 6 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the PANSS Total Score From Baseline to the Last Postrandomization Assessment in the Double-blind Period of the Study. | The Positive and Negative Syndrome Scale (PANSS) measures the severity of psychotic symptoms of schizophrenia. Scores range from 30 to 210, where 30=best and 210=worst. The change in PANSS total score for all eligible subjects was measured from the beginning of the study to the end. | 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to End Point in Clinical Global Impression-Severity (CGI-S) Scale | The CGI-S rating scale was used to assess the severity of a subject's overall clinical condition. Scores range from 1 to 7, where 1=best and 7=worst. | 6 weeks | 
| Change From Baseline to End Point in Children's Global Assessment (CGAS) Score | The CGAS score assesses psychological, social, and school functioning for children 6 to 17 years of age. Scores range from 1 to 100, where 100=best and 1=worst. | 6 weeks | 
| Change From Baseline to End Point in Sleep Visual Analog Scale (VAS) for Quality of Sleep. | The sleep VAS for sleep quality is a scale for measuring the quality of sleep experienced by a patient. Scores range from 0 to 100, where 100=best and 0=worst. | 6 weeks | 
| Change From Baseline to End Point in Sleep VAS for Daytime Drowsiness | The sleep VAS for daytime drowsiness is a scale for measuring the drowsiness experienced by a patient. Scores range from 0 to 100, where 100=best and 0=worst. | 6 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Schizophrenia, Antipsychotic