Autistic Disorder, Behavioral Symptoms
Conditions
Keywords
Serious behavioral problems in children and adolescents with AD
Brief summary
This study will compare the effectiveness (how well the drug works) of aripiprazole with placebo (fixed dose) in reducing serious behavioral problems in children and adolescents with a diagnosis of autistic disorder (AD).
Interventions
DRUGAripiprazole
Tablets, Oral, once daily, 8 weeks
DRUGPlacebo
Tablets, Oral, once daily, 8 weeks
Sponsors
Otsuka Pharmaceutical Development & Commercialization, Inc.
Otsuka America Pharmaceutical
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
6 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Meets current Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) diagnostic criteria for AD and demonstrates serious behavioral problems; diagnosis confirmed by Autism, Diagnostic Interview-Revised (ADI-R). * CGI score \> = 4 AND an ABC Irritability/Agitation subscale score \> = 18 at screening and baseline (randomization) * Mental age of at least 18 months * Male or female 6 to 17 years of age inclusive, at the time of randomization
Exclusion criteria
* Patients considered treatment resistant to neuroleptic medication based on lack of therapeutic response to 2 different neuroleptics after treatment of at least 3 weeks each * Patients previously treated and not responding to aripiprazole treatment * The patient is currently diagnosed with another disorder on the autism spectrum, including PDD-NOS, Asperger's Disorder, Rett's Disorder, Fragile-X Syndrome or Childhood Disintegrative Disorder * Current diagnosis of bipolar disorder, psychosis, schizophrenia, or major depression * A seizure in the past year * History of severe head trauma or stroke * Non-pharmacologic therapy (e.g., psychotherapy, behavior modification) should be stable prior to screening and consistent throughout the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change (Week 8 - Baseline) in the Autistic Behavior Checklist (ABC) Irritability Subscale Score | Week 8 | The ABC is a 58-item informant-based assessment of problem behaviors in children/adolescents with mental retardation. Items are rated on a 4-point scale (0=no problem, 3=severe problem), and resolve into 5 domain subscales. A decrease in score indicates improvement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Clinical Global Impressions Improvement Scale (CGI-I) Score | Week 8 | The CGI scale is a clinician-rated global assessment of a patient's improvement over time. Baseline assessment rated a patient's condition on a 7-point scale (1=no symptoms, 7=very severe symptoms). Subsequent assessed improvement relative to baseline symptoms on a 7-point CGI-I item scale (1=very much improved, 7=very much worse). |
| Number of Participants With Response at Week 8 | Week 8 | Response defined as a ≥ 25% reduction from baseline to endpoint in the ABC Irritability Subscale score and a CGI-I score of 1 or 2 at endpoint. |
| Mean Change (Week 8 - Baseline) in the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS; Compulsion Scale Only) | Week 8 | CY-BOCS=10-item assessment of obsessive-compulsive symptoms in patients \<18 years. 5 items pertaining to compulsions rate symptoms (time spent, interference with functioning, distress, resistance, control) on a 5-point scale (0=no symptoms/minimum severity, 4=extreme symptoms/maximum severity). A decreased in value indicates improvement. |
| Mean Change (Week 8 - Baseline) in the Other ABC Subscale Scores | Week 8 | Mean change (Week 8 - baseline) in the other ABC subscale scores (lethargy/social withdrawal; stereotypic behavior; hyperactivity/ noncompliance; inappropriate speech). A decrease in value indicates improvement. |
| Mean Change (Week 8 - Baseline) in CGI-Severity (CGI-S) | Week 8 | A CGI-S assessment (a 7-point scale to evaluate the severity of symptoms) was performed at baseline (1=no symptoms; 7=very severe symptoms). The patient's improvement relative to the symptoms at baseline on were assessed on a 7-point CGI-I (1=very much improved; 7=very much worse). A decrease in value indicates improvement. |
| Summary of Safety | continuously throughout the study | Deaths, Adverse Events (AEs), Serious AEs (SAEs), Treatment-Emergent AEs and AEs leading to discontinuation |
| Change From Baseline in Body Weight | Week 8 | Adjusted mean change (Week 8 - baseline) in body weight |
Countries
United States
Contacts
STUDY_DIRECTORBristol-Myers Squibb
Bristol-Myers Squibb
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo | 52 |
| Aripiprazole 5 mg | 53 |
| Aripiprazole 10 mg | 59 |
| Aripiprazole 15 mg | 54 |
| Total | 218 |
Baseline characteristics
| Characteristic | Total | Placebo | Aripiprazole 5 mg | Aripiprazole 10 mg | Aripiprazole 15 mg |
|---|---|---|---|---|---|
| Age, Customized 13 to 17 years | 52 participants | 17 participants | 9 participants | 14 participants | 12 participants |
| Age, Customized 6 to 12 years | 166 participants | 35 participants | 44 participants | 45 participants | 42 participants |
| Body Mass Index | 20.41 kg/m2 STANDARD_DEVIATION 5.933 | 20.49 kg/m2 STANDARD_DEVIATION 4.777 | 19.91 kg/m2 STANDARD_DEVIATION 6.124 | 21.06 kg/m2 STANDARD_DEVIATION 6.649 | 20.14 kg/m2 STANDARD_DEVIATION 6.033 |
| Ethnicity, Customized Hispanic/Latino | 25 Participants | 8 Participants | 5 Participants | 7 Participants | 5 Participants |
| Ethnicity, Customized Not Hispanic/Latino | 193 Participants | 44 Participants | 48 Participants | 52 Participants | 49 Participants |
| Height | 140.8 centimeters STANDARD_DEVIATION 17.38 | 144.9 centimeters STANDARD_DEVIATION 18.82 | 136.5 centimeters STANDARD_DEVIATION 14.66 | 142.3 centimeters STANDARD_DEVIATION 17.87 | 139.3 centimeters STANDARD_DEVIATION 17.24 |
| Race, Customized Asian | 6 participants | 3 participants | 1 participants | 2 participants | 0 participants |
| Race, Customized Black or African American | 50 participants | 13 participants | 13 participants | 15 participants | 9 participants |
| Race, Customized Native Hawaiian or Other Pacific Islander | 1 participants | 0 participants | 0 participants | 0 participants | 1 participants |
| Race, Customized Other | 6 participants | 1 participants | 2 participants | 1 participants | 2 participants |
| Race, Customized White | 155 participants | 35 participants | 37 participants | 41 participants | 42 participants |
| Sex/Gender, Customized Female | 23 Participants | 4 Participants | 6 Participants | 9 Participants | 4 Participants |
| Sex/Gender, Customized Male | 195 Participants | 48 Participants | 47 Participants | 50 Participants | 50 Participants |
| Weight | 42.9 kilograms STANDARD_DEVIATION 21.07 | 45.6 kilograms STANDARD_DEVIATION 20.01 | 38.9 kilograms STANDARD_DEVIATION 18.26 | 44.8 kilograms STANDARD_DEVIATION 22.38 | 42.2 kilograms STANDARD_DEVIATION 22.99 |
| Weight Group <40 kilograms | 126 Participants | 24 Participants | 35 Participants | 33 Participants | 34 Participants |
| Weight Group ≥40 kilograms | 92 Participants | 28 Participants | 18 Participants | 26 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| other Total, other adverse events | 51 / 59 | 42 / 54 | 37 / 52 | 31 / 51 |
| serious Total, serious adverse events | 1 / 59 | 0 / 54 | 1 / 52 | 0 / 51 |
Outcome results
Primary
Mean Change (Week 8 - Baseline) in the Autistic Behavior Checklist (ABC) Irritability Subscale Score
The ABC is a 58-item informant-based assessment of problem behaviors in children/adolescents with mental retardation. Items are rated on a 4-point scale (0=no problem, 3=severe problem), and resolve into 5 domain subscales. A decrease in score indicates improvement.
Time frame: Week 8
Population: Efficacy population=all randomized participants minus 3 patients in the placebo group (1 lost to follow-up, 1 withdrew consent, 1 no longer met study criteria), 1 participant in the 5-mg group who withdrew consent, and 1 participant in the 15-mg group who had elevated potassium levels. Data set is LOCF.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Change (Week 8 - Baseline) in the Autistic Behavior Checklist (ABC) Irritability Subscale Score | -8.4 units on a scale | Standard Error 1.39 |
| Aripiprazole 5 mg | Mean Change (Week 8 - Baseline) in the Autistic Behavior Checklist (ABC) Irritability Subscale Score | -12.4 units on a scale | Standard Error 1.36 |
| Aripiprazole 10 mg | Mean Change (Week 8 - Baseline) in the Autistic Behavior Checklist (ABC) Irritability Subscale Score | -13.2 units on a scale | Standard Error 1.25 |
| Aripiprazole 15 mg | Mean Change (Week 8 - Baseline) in the Autistic Behavior Checklist (ABC) Irritability Subscale Score | -14.4 units on a scale | Standard Error 1.31 |
Secondary
Change From Baseline in Body Weight
Adjusted mean change (Week 8 - baseline) in body weight
Time frame: Week 8
Population: Safety population=all randomized participants minus 3 patients in the placebo group (1 no longer met study criteria, 2 did not have measurement at baseline and Week 8), and 1 participant in the 5-mg group who withdrew consent. Data set is LOCF.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Body Weight | 0.3 kilograms | Standard Error 0.32 |
| Aripiprazole 5 mg | Change From Baseline in Body Weight | 1.3 kilograms | Standard Error 0.31 |
| Aripiprazole 10 mg | Change From Baseline in Body Weight | 1.3 kilograms | Standard Error 0.29 |
| Aripiprazole 15 mg | Change From Baseline in Body Weight | 1.5 kilograms | Standard Error 0.3 |
Secondary
Mean Change (Week 8 - Baseline) in CGI-Severity (CGI-S)
A CGI-S assessment (a 7-point scale to evaluate the severity of symptoms) was performed at baseline (1=no symptoms; 7=very severe symptoms). The patient's improvement relative to the symptoms at baseline on were assessed on a 7-point CGI-I (1=very much improved; 7=very much worse). A decrease in value indicates improvement.
Time frame: Week 8
Population: Efficacy population=all randomized participants minus 3 patients in the placebo group (1 lost to follow-up, 1 withdrew consent, 1 no longer met study criteria), 1 participant in the 5-mg group who withdrew consent, and 1 participant in the 15-mg group who had elevated potassium levels. Data set is LOCF.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Change (Week 8 - Baseline) in CGI-Severity (CGI-S) | -0.6 units on a scale | Standard Error 0.16 |
| Aripiprazole 5 mg | Mean Change (Week 8 - Baseline) in CGI-Severity (CGI-S) | -0.9 units on a scale | Standard Error 0.15 |
| Aripiprazole 10 mg | Mean Change (Week 8 - Baseline) in CGI-Severity (CGI-S) | -1.0 units on a scale | Standard Error 0.13 |
| Aripiprazole 15 mg | Mean Change (Week 8 - Baseline) in CGI-Severity (CGI-S) | -1.1 units on a scale | Standard Error 0.15 |
Secondary
Mean Change (Week 8 - Baseline) in the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS; Compulsion Scale Only)
CY-BOCS=10-item assessment of obsessive-compulsive symptoms in patients \<18 years. 5 items pertaining to compulsions rate symptoms (time spent, interference with functioning, distress, resistance, control) on a 5-point scale (0=no symptoms/minimum severity, 4=extreme symptoms/maximum severity). A decreased in value indicates improvement.
Time frame: Week 8
Population: Efficacy population=all randomized participants minus 3 patients in the placebo group (1 lost to follow-up, 1 withdrew consent, 1 no longer met study criteria), 1 participant in the 5-mg group who withdrew consent, and 1 participant in the 15-mg group who had elevated potassium levels. Data set is LOCF.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Change (Week 8 - Baseline) in the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS; Compulsion Scale Only) | -1.7 units on a scale | Standard Error 0.5 |
| Aripiprazole 5 mg | Mean Change (Week 8 - Baseline) in the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS; Compulsion Scale Only) | -2.6 units on a scale | Standard Error 0.5 |
| Aripiprazole 10 mg | Mean Change (Week 8 - Baseline) in the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS; Compulsion Scale Only) | -2.4 units on a scale | Standard Error 0.44 |
| Aripiprazole 15 mg | Mean Change (Week 8 - Baseline) in the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS; Compulsion Scale Only) | -3.2 units on a scale | Standard Error 0.47 |
Secondary
Mean Change (Week 8 - Baseline) in the Other ABC Subscale Scores
Mean change (Week 8 - baseline) in the other ABC subscale scores (lethargy/social withdrawal; stereotypic behavior; hyperactivity/ noncompliance; inappropriate speech). A decrease in value indicates improvement.
Time frame: Week 8
Population: Efficacy population=all randomized participants minus 3 patients in the placebo group (1 lost to follow-up, 1 withdrew consent, 1 no longer met study criteria), 1 participant in the 5-mg group who withdrew consent, and 1 participant in the 15-mg group who had elevated potassium levels. Data set is LOCF.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Mean Change (Week 8 - Baseline) in the Other ABC Subscale Scores | ABC Social Withdrawal Subscale Score | -5.2 units on a scale | Standard Error 1.16 |
| Placebo | Mean Change (Week 8 - Baseline) in the Other ABC Subscale Scores | ABC Stereotypy Subscale Score | -1.8 units on a scale | Standard Error 0.69 |
| Placebo | Mean Change (Week 8 - Baseline) in the Other ABC Subscale Scores | ABC Hyperactivity Subscale Score | -7.7 units on a scale | Standard Error 1.67 |
| Placebo | Mean Change (Week 8 - Baseline) in the Other ABC Subscale Scores | ABC Inappropriate Speech Subscale Score | -1.1 units on a scale | Standard Error 0.46 |
| Aripiprazole 5 mg | Mean Change (Week 8 - Baseline) in the Other ABC Subscale Scores | ABC Stereotypy Subscale Score | -4.5 units on a scale | Standard Error 0.68 |
| Aripiprazole 5 mg | Mean Change (Week 8 - Baseline) in the Other ABC Subscale Scores | ABC Social Withdrawal Subscale Score | -5.8 units on a scale | Standard Error 1.15 |
| Aripiprazole 5 mg | Mean Change (Week 8 - Baseline) in the Other ABC Subscale Scores | ABC Hyperactivity Subscale Score | -14.0 units on a scale | Standard Error 1.64 |
| Aripiprazole 5 mg | Mean Change (Week 8 - Baseline) in the Other ABC Subscale Scores | ABC Inappropriate Speech Subscale Score | -2.0 units on a scale | Standard Error 0.45 |
| Aripiprazole 10 mg | Mean Change (Week 8 - Baseline) in the Other ABC Subscale Scores | ABC Hyperactivity Subscale Score | -13.3 units on a scale | Standard Error 1.5 |
| Aripiprazole 10 mg | Mean Change (Week 8 - Baseline) in the Other ABC Subscale Scores | ABC Stereotypy Subscale Score | -4.2 units on a scale | Standard Error 0.63 |
| Aripiprazole 10 mg | Mean Change (Week 8 - Baseline) in the Other ABC Subscale Scores | ABC Inappropriate Speech Subscale Score | -1.8 units on a scale | Standard Error 0.41 |
| Aripiprazole 10 mg | Mean Change (Week 8 - Baseline) in the Other ABC Subscale Scores | ABC Social Withdrawal Subscale Score | -4.9 units on a scale | Standard Error 1.06 |
| Aripiprazole 15 mg | Mean Change (Week 8 - Baseline) in the Other ABC Subscale Scores | ABC Stereotypy Subscale Score | -4.5 units on a scale | Standard Error 0.66 |
| Aripiprazole 15 mg | Mean Change (Week 8 - Baseline) in the Other ABC Subscale Scores | ABC Hyperactivity Subscale Score | -16.3 units on a scale | Standard Error 1.59 |
| Aripiprazole 15 mg | Mean Change (Week 8 - Baseline) in the Other ABC Subscale Scores | ABC Social Withdrawal Subscale Score | -7.9 units on a scale | Standard Error 1.11 |
| Aripiprazole 15 mg | Mean Change (Week 8 - Baseline) in the Other ABC Subscale Scores | ABC Inappropriate Speech Subscale Score | -2.3 units on a scale | Standard Error 0.43 |
Secondary
Mean Clinical Global Impressions Improvement Scale (CGI-I) Score
The CGI scale is a clinician-rated global assessment of a patient's improvement over time. Baseline assessment rated a patient's condition on a 7-point scale (1=no symptoms, 7=very severe symptoms). Subsequent assessed improvement relative to baseline symptoms on a 7-point CGI-I item scale (1=very much improved, 7=very much worse).
Time frame: Week 8
Population: Efficacy population=all randomized participants minus 3 patients in the placebo group (1 lost to follow-up, 1 withdrew consent, 1 no longer met study criteria), 1 participant in the 5-mg group who withdrew consent, and 1 participant in the 15-mg group who had elevated potassium levels. Data set is LOCF.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Clinical Global Impressions Improvement Scale (CGI-I) Score | 3.3 units on a scale | Standard Error 0.18 |
| Aripiprazole 5 mg | Mean Clinical Global Impressions Improvement Scale (CGI-I) Score | 2.6 units on a scale | Standard Error 0.17 |
| Aripiprazole 10 mg | Mean Clinical Global Impressions Improvement Scale (CGI-I) Score | 2.5 units on a scale | Standard Error 0.16 |
| Aripiprazole 15 mg | Mean Clinical Global Impressions Improvement Scale (CGI-I) Score | 2.5 units on a scale | Standard Error 0.17 |
Secondary
Number of Participants With Response at Week 8
Response defined as a ≥ 25% reduction from baseline to endpoint in the ABC Irritability Subscale score and a CGI-I score of 1 or 2 at endpoint.
Time frame: Week 8
Population: Efficacy population=all randomized participants minus 3 patients in the placebo group (1 lost to follow-up, 1 withdrew consent, 1 no longer met study criteria), 1 participant in the 5-mg group who withdrew consent, and 1 participant in the 15-mg group who had elevated potassium levels. Data set is LOCF.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Participants With Response at Week 8 | 17 Participants |
| Aripiprazole 5 mg | Number of Participants With Response at Week 8 | 29 Participants |
| Aripiprazole 10 mg | Number of Participants With Response at Week 8 | 29 Participants |
| Aripiprazole 15 mg | Number of Participants With Response at Week 8 | 28 Participants |
Secondary
Summary of Safety
Deaths, Adverse Events (AEs), Serious AEs (SAEs), Treatment-Emergent AEs and AEs leading to discontinuation
Time frame: continuously throughout the study
Population: Safety population=all randomized participants minus 1 patients in the placebo group (no longer met study criteria), and 1 participant in the 5-mg group who withdrew consent.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Summary of Safety | Deaths | 0 participants |
| Placebo | Summary of Safety | Treatment-emergent SAEs | 0 participants |
| Placebo | Summary of Safety | AEs leading to discontinuation of study medication | 4 participants |
| Placebo | Summary of Safety | Treatment-emergent AEs overall | 37 participants |
| Placebo | Summary of Safety | Treatment-emergent AEs related to study medication | 22 participants |
| Placebo | Summary of Safety | Treatment-emergent extrapyramidal symptom AEs | 6 participants |
| Aripiprazole 5 mg | Summary of Safety | Treatment-emergent extrapyramidal symptom AEs | 12 participants |
| Aripiprazole 5 mg | Summary of Safety | Treatment-emergent AEs overall | 46 participants |
| Aripiprazole 5 mg | Summary of Safety | Deaths | 0 participants |
| Aripiprazole 5 mg | Summary of Safety | AEs leading to discontinuation of study medication | 5 participants |
| Aripiprazole 5 mg | Summary of Safety | Treatment-emergent SAEs | 1 participants |
| Aripiprazole 5 mg | Summary of Safety | Treatment-emergent AEs related to study medication | 37 participants |
| Aripiprazole 10 mg | Summary of Safety | Treatment-emergent SAEs | 1 participants |
| Aripiprazole 10 mg | Summary of Safety | AEs leading to discontinuation of study medication | 8 participants |
| Aripiprazole 10 mg | Summary of Safety | Treatment-emergent AEs overall | 53 participants |
| Aripiprazole 10 mg | Summary of Safety | Treatment-emergent extrapyramidal symptom AEs | 13 participants |
| Aripiprazole 10 mg | Summary of Safety | Treatment-emergent AEs related to study medication | 50 participants |
| Aripiprazole 10 mg | Summary of Safety | Deaths | 0 participants |
| Aripiprazole 15 mg | Summary of Safety | Treatment-emergent AEs related to study medication | 39 participants |
| Aripiprazole 15 mg | Summary of Safety | Treatment-emergent extrapyramidal symptom AEs | 12 participants |
| Aripiprazole 15 mg | Summary of Safety | Treatment-emergent SAEs | 0 participants |
| Aripiprazole 15 mg | Summary of Safety | Treatment-emergent AEs overall | 46 participants |
| Aripiprazole 15 mg | Summary of Safety | Deaths | 0 participants |
| Aripiprazole 15 mg | Summary of Safety | AEs leading to discontinuation of study medication | 4 participants |