Phase IV Long-term Maintenance Study of Aripiprazole in the Treatment of Irritability Associated With Autistic Disorder

Study Overview
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Brief Summary
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The purpose of this study is to determine whether pediatric participants with irritability associated with autistic disorder who have responded to aripiprazole treatment will experience a relapse significantly later when continuing therapy with aripiprazole than will participants who receive placebo

Detailed Description
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Phase 1: Single blind/ Phase 2: Double blind

Official Title
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Safety and Efficacy of Aripiprazole in the Long-term Maintenance Treatment of Pediatric Patients With Irritability Associated With Autistic Disorder

Conditions
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Irritability Associated With Autistic Disorder

Intervention / Treatment
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* Drug: Aripiprazole
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Male or female children or adolescents, 6 to 17 years of age, inclusive, at the time of the baseline visit Meets current diagnostic criteria of the Diagnostic and Statistical Manual-of Mental Disorders IV-Text Revised for autistic disorder and displays behaviors such as tantrums, aggression, self-injurious behavior, or a combination of these problems. Diagnosis of autistic disorder will be confirmed by the Autism Diagnostic Interview-Revised. Participant or designated guardian or caregiver is able to comprehend and satisfactorily comply with the protocol requirements, in the opinion of the investigator. Demonstrates behaviors such as tantrums, aggression, or self-injury or a combination of these problems An Aberrant Behavior Checklist Irritability subscale score ≥18 AND a Clinical Global Impressions Severity score ≥4 at the Screening and Baseline Visits. Mental age of at least 24 months Key Exclusion Criteria: Treatment resistant to neuroleptic medication, based on lack of therapeutic response to 2 different neuroleptics after treatment for at least 3 weeks each. Previous treatment with aripiprazole for at least 3 weeks duration at an adequate daily dose, without demonstrating a clinically meaningful response. Lifetime diagnosis of bipolar disorder, psychosis, or schizophrenia, or a current diagnosis of major depressive disorder Diagnosis of Pervasive Developmental Disorder-Not Otherwise Specified, Asperger's Syndrome, Rett's Syndrome, childhood disintegrative disorder, or Fragile X Syndrome History of neuroleptic malignant syndrome At significant risk for suicide based on history or routine psychiatric status examination A seizure within the past year History of severe head trauma or stroke History or current evidence of any unstable medical conditions that would expose the patient to undue risk of a significant adverse event or interfere with assessments of safety or efficacy during the course of the trial Weight lower than 15 kg Known allergy or hypersensitivity to aripiprazole or other dihidrocarbostyrils History of a clinically significant low white blood cell count or a drug-induced leukopenia/neutropenia Any other medically significant abnormal laboratory test or vital sign result or electrocardiogram finding

Ages Eligible for Study
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Minimum Age: 6 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: Aripiprazole<br> | Drug: Aripiprazole<br>* Tablets, Oral, 2-15 mg, once daily, 13-42 weeks<br>* Other names: Abilify;|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Tablets, Oral, 0 mg, once daily, 16 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients Relapsing by Week 16 | Time of relapse=date when patient meets relapse criteria. There are 4 definitions for relapse: 1. Patient meets the following criteria for 2 consecutive visits: (a) Aberrant Behavior Checklist Irritability score ≥25% than score at end of Phase 1 AND (b) Clinical Global Impression Improvement scale rating of 'Much Worse' or 'Very Much Worse' relative to rating at end of Phase 1. If relapse criteria met at 1 visit, 2nd visit should occur in about 1 week to reevaluate whether relapse criteria are still met. 2. Patient discontinues for Lost to Follow-up after a visit in which he or she met Definition 1 criteria (a&b). 3. Patient begins a prohibited drug (whether a study investigator or outside source prescribed) to treat worsening symptoms of irritability of autistic disorder after a visit where patient met Definition 1 criteria (a&b). 4. Patient discontinues due to hospitalization for worsening symptoms of irritability or due to lack of efficacy based on investigator's assessment. | From end of Phase 1 (Date of randomization) to Week 16 of Phase 2 and end of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adjusted Mean Change From Baseline to Week 16 on the Aberrant Behavior Checklist Irritability (ABC-I) Subscale Score (Last Observation Carried Forward [LOCF]) | ABC is an informant-based checklist used to assess and classify problem behaviors of children and adolescents with mental retardation. The 58 items are rated on a 4-point scale (0=not at all a problem to 3=the problem is severe in degree), and resolve into 5 subscales: 1) irritability, agitation; 2) lethargy, social withdrawal; 3) stereotypic behavior; 4) hyperactivity, noncompliance; and 5) inappropriate speech. The ABC can be completed by parents, special educators, psychologists, direct caregivers, nurses, and others knowing the participant. Psychometric assessment of the ABC indicates that its subscales have high internal consistency, adequate reliability, and established validity. The ABC-I Subscale Score ranges from 0 to 45, with a negative change in score signifying improvement. LOCF data set includes data recorded at a given visit or, if no observation was recorded at that visit, data carried forward from the prior visit. chg=change; BL=baseline; APR=aripiprazole; vs=versus. | From Baseline (end of Phase 1) to Week 16 of Phase 2 | 
| Change From Baseline in Mean Clinical Global Impression Improvement (CGI-I) Scale Score at Week 16 (Last Observation Carried Forward [LOCF]) | CG-I rating scale permits global evaluation of patient's improvement over time. At baseline (BL), CGI Severity of Illness assessment is performed, in which the clinician rates severity of patient's condition on a 7-point scale ranging from 1=no symptoms to 7=very severe symptoms. Higher total score=worse symptoms. At subsequent visits, clinician assesses patient's improvement relative to symptoms at baseline on CGI-I 7-point scale ranging from 1=very much improved to 7=very much worse. Since the drug targets irritability symptoms, the CGI focuses on severity of irritability secondary to autistic disorder. Lower score=more improved symptoms. LOCF data set includes data recorded at a given visit or, if nothing recorded, data areccarried forward from the prior visit. For secondary endpoints (endpt), hierarchical testing was used to keep overall experiment-wise type I error rate to <=0.05. diff=difference; IS=irritability scale; PA=primary analysis; signif=significance/significantly. | From Baseline (end of Phase 1) to Week 16 of Phase 2 | 
| Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), and Adverse Events (AEs) Leading to Discontinuation During Phase 1 | AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. | Weekly from Week 1 to Week 26 and continuously to end of treatment |