Irritability Associated With Autistic Disorder
Conditions
Brief summary
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
Phase 1: Single blind/ Phase 2: Double blind
Interventions
DRUGAripiprazole
Tablets, Oral, 2-15 mg, once daily, 13-42 weeks
DRUGPlacebo
Tablets, Oral, 0 mg, once daily, 16 weeks
Sponsors
Bristol-Myers Squibb
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
6 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients Relapsing by Week 16 | From end of Phase 1 (Date of randomization) to Week 16 of Phase 2 and end of treatment | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Adjusted Mean Change From Baseline to Week 16 on the Aberrant Behavior Checklist Irritability (ABC-I) Subscale Score (Last Observation Carried Forward [LOCF]) | From Baseline (end of Phase 1) to Week 16 of Phase 2 | 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. |
| Change From Baseline in Mean Clinical Global Impression Improvement (CGI-I) Scale Score at Week 16 (Last Observation Carried Forward [LOCF]) | From Baseline (end of Phase 1) to Week 16 of Phase 2 | 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. |
| Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), and Adverse Events (AEs) Leading to Discontinuation During Phase 1 | Weekly from Week 1 to Week 26 and continuously to end of treatment | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation, and Treatment-related AEs During Phase 2 | Weekly from Weeks 1 through 16 (end of treatment) of Phase 2 | 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. Treatment-related=having certain, probable, possible, or missing relationship to study drug. |
Countries
United States
Participant flow
Pre-assignment details
Of 215 participants enrolled, 58 discontinued during screening and before entry into Phase 1. Of the 58 who discontinued, 1 withdrew for an adverse event, 12 withdrew consent, 8 were lost to follow-up, 36 no longer met study criteria, and 1 withdrew for other reason.
Participants by arm
| Arm | Count |
|---|---|
| Aripiprazole, 2-15 mg Once Daily (Titered to Optimum Dose) Phase 2: Aripiprazole was continued at the dose prescribed at the end of Phase 1, once daily for 16 weeks. The dose (within the range of 2-15 mg/day) could have been adjusted based on efficacy and tolerability. | 41 |
| Placebo Phase 2: Participants received placebo for 16 weeks. | 44 |
| Total | 85 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Phase 1 (Stabilization Phase) | Adverse Event | 12 | 0 |
| Phase 1 (Stabilization Phase) | Lack of Efficacy | 25 | 0 |
| Phase 1 (Stabilization Phase) | Lost to Follow-up | 8 | 0 |
| Phase 1 (Stabilization Phase) | No longer meets study criteria | 7 | 0 |
| Phase 1 (Stabilization Phase) | Poor compliance/noncompliance | 2 | 0 |
| Phase 1 (Stabilization Phase) | Sponsor's administrative reason | 11 | 0 |
| Phase 1 (Stabilization Phase) | Withdrawal by Subject | 7 | 0 |
| Phase 2 (Randomization Phase) | Adverse Event | 0 | 1 |
| Phase 2 (Randomization Phase) | Lack of Efficacy | 13 | 23 |
| Phase 2 (Randomization Phase) | Lost to Follow-up | 1 | 0 |
| Phase 2 (Randomization Phase) | Poor compliance/noncompliance | 0 | 1 |
| Phase 2 (Randomization Phase) | Withdrawal by Subject | 5 | 0 |
Baseline characteristics
| Characteristic | Aripiprazole, 2-15 mg Once Daily (Titered to Optimum Dose) | Placebo | Total |
|---|---|---|---|
| Age, Customized | 10.0 Years | 11.0 Years | 10.0 Years |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 3 Participants | 3 Participants |
| Race/Ethnicity, Customized Black or African American | 8 Participants | 11 Participants | 19 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized White | 31 Participants | 28 Participants | 59 Participants |
| Sex: Female, Male Female | 11 Participants | 6 Participants | 17 Participants |
| Sex: Female, Male Male | 30 Participants | 38 Participants | 68 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 112 / 155 | 11 / 39 | 5 / 43 |
| serious Total, serious adverse events | 1 / 155 | 0 / 39 | 0 / 43 |
Outcome results
Primary
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.
Time frame: From end of Phase 1 (Date of randomization) to Week 16 of Phase 2 and end of treatment
Population: All participants who were randomized in Phase 2
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aripiprazole, 2-15 mg Once Daily (Titered to Optimum Dose) | Percentage of Patients Relapsing by Week 16 | 32 Percentage of participants |
| Placebo | Percentage of Patients Relapsing by Week 16 | 50 Percentage of participants |
p-value: 0.09795% CI: [0.28, 1.12]Stratified log rank
Secondary
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.
Time frame: From Baseline (end of Phase 1) to Week 16 of Phase 2
Population: All participants who were randomized and took at least 1 dose of double-blind medication in Phase 2 and who had at least 1 efficacy evaluation after the start of Phase 2 study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aripiprazole, 2-15 mg Once Daily (Titered to Optimum Dose) | Adjusted Mean Change From Baseline to Week 16 on the Aberrant Behavior Checklist Irritability (ABC-I) Subscale Score (Last Observation Carried Forward [LOCF]) | 5.2 Units on a scale | Standard Error 1.61 |
| Placebo | Adjusted Mean Change From Baseline to Week 16 on the Aberrant Behavior Checklist Irritability (ABC-I) Subscale Score (Last Observation Carried Forward [LOCF]) | 9.6 Units on a scale | Standard Error 1.56 |
p-value: 0.05195% CI: [-8.82, 0.02]ANCOVA
Secondary
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.
Time frame: From Baseline (end of Phase 1) to Week 16 of Phase 2
Population: All participants who were randomized and took at least 1 dose of double-blind medication in Phase 2 and who had at least 1 efficacy evaluation after the start of Phase 2 study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aripiprazole, 2-15 mg Once Daily (Titered to Optimum Dose) | Change From Baseline in Mean Clinical Global Impression Improvement (CGI-I) Scale Score at Week 16 (Last Observation Carried Forward [LOCF]) | 4.2 Units on a scale | Standard Error 0.26 |
| Placebo | Change From Baseline in Mean Clinical Global Impression Improvement (CGI-I) Scale Score at Week 16 (Last Observation Carried Forward [LOCF]) | 4.8 Units on a scale | Standard Error 0.26 |
p-value: 0.0995% CI: [-1.3, 0.1]ANCOVA
Secondary
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.
Time frame: Weekly from Week 1 to Week 26 and continuously to end of treatment
Population: All participants who took at least 1 dose of single-blind aripiprazole in Phase 1
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Aripiprazole, 2-15 mg Once Daily (Titered to Optimum Dose) | Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), and Adverse Events (AEs) Leading to Discontinuation During Phase 1 | AEs leading to discontinuation | 13 Participants |
| Aripiprazole, 2-15 mg Once Daily (Titered to Optimum Dose) | Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), and Adverse Events (AEs) Leading to Discontinuation During Phase 1 | Death | 0 Participants |
| Aripiprazole, 2-15 mg Once Daily (Titered to Optimum Dose) | Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), and Adverse Events (AEs) Leading to Discontinuation During Phase 1 | SAEs | 1 Participants |
Other Pre-specified
Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation, and Treatment-related AEs During Phase 2
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. Treatment-related=having certain, probable, possible, or missing relationship to study drug.
Time frame: Weekly from Weeks 1 through 16 (end of treatment) of Phase 2
Population: All participants who were randomized and took at least 1 dose of double-blind medication in Phase 2
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Aripiprazole, 2-15 mg Once Daily (Titered to Optimum Dose) | Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation, and Treatment-related AEs During Phase 2 | Death | 0 Participants |
| Aripiprazole, 2-15 mg Once Daily (Titered to Optimum Dose) | Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation, and Treatment-related AEs During Phase 2 | SAEs | 0 Participants |
| Aripiprazole, 2-15 mg Once Daily (Titered to Optimum Dose) | Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation, and Treatment-related AEs During Phase 2 | AEs leading to discontinuation | 0 Participants |
| Aripiprazole, 2-15 mg Once Daily (Titered to Optimum Dose) | Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation, and Treatment-related AEs During Phase 2 | Treatment-related AEs | 9 Participants |
| Placebo | Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation, and Treatment-related AEs During Phase 2 | Treatment-related AEs | 6 Participants |
| Placebo | Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation, and Treatment-related AEs During Phase 2 | Death | 0 Participants |
| Placebo | Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation, and Treatment-related AEs During Phase 2 | AEs leading to discontinuation | 0 Participants |
| Placebo | Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation, and Treatment-related AEs During Phase 2 | SAEs | 0 Participants |