Pervasive Developmental Disorder
Conditions
Keywords
PDD NOS
Brief summary
The purpose of this study is to develop a better tolerated and more effective pharmacologic treatment with individuals with Pervasive Developmental Disorder. This is a double-blind, placebo-controlled study of aripiprazole in the management of the maladaptive behaviors of Pervasive Developmental Disorder. The investigators hypothesize that aripiprazole will be more effective than placebo for reducing aggression, tantrum and self-injurious behavior in children with Pervasive Developmental Disorder.
Detailed description
Pervasive developmental disorders (PDDs) are characterized by severe impairments in social interaction and communication in addition to restricted patterns of interests and activities. Research suggests that a dysregulation of the dopamine and serotonin systems contributes to these interfering behaviors in individuals with PDD. After benefits of typical neuroleptics were reported in subjects with PDD, research shifted to the atypical antipsychotics which have been shown to be better tolerated and effective in this population. However, the atypical antipsychotics have also been associated with adverse effects. Thus there remains a need for a novel pharmacotherapy that would be safe and effective for children and adolescents with PDDs. The primary objectives of this study are to determine whether aripiprazole is effective and well tolerated for irritability in children and adolescents with PDD not otherwise specified (NOS) during an 8-week acute phase and whether the effectiveness and tolerability of aripiprazole is maintained during a 16-week continuation phase.
Interventions
Minimum dose of 2 mg per day to a maximum dose of 20 mg per day over 8-weeks of treatment.
DRUGPlacebo oral capsule
Placebo will be identical in size and appearance to study drug.
Sponsors
National Institute of Mental Health (NIMH)
Bristol-Myers Squibb
Indiana University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
5 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Male and female outpatients between the ages of 5 and 17 years and greater than or equal to 15 kg body weight. * Diagnostic and Statistical Manual of Mental Disorders Fourth Edition, Text Revised (DSM-IV-TR) diagnosis of Pervasive Developmental Disorder Not Otherwise Specified (PDD NOS). * Psychotropic medication-free for at least 2 days prior to screening laboratory tests and electrocardiogram (ECG). * Significant irritability as determined by a Clinical Global Impression Severity score of greater or equal to 4 (Moderately ill) and a score of equal to or greater than 18 on the Aberrant Behavior Checklist Irritability Subscale. * Intelligence quotient (IQ) of equal to or greater than 50 based on the Wechsler Intelligence Scale for Children (WISC), 4th edition; the Leiter International Test of Intelligence-Revised will be used if a child is nonverbal but thought to have an IQ greater than or equal to 50.
Exclusion criteria
* DSM-IV-TR diagnosis other than PDD NOS (autistic disorder, Asperger's disorder, Rett's disorder, or childhood disintegrative disorder), schizophrenia, bipolar disorder or substance abuse within the last 6 months. * Comorbid disorder with possible association to autism (e.g., Fragile X Syndrome, Tuberous Sclerosis). * A significant medical condition such as heart, liver, renal, or pulmonary disease, or a seizure disorder, as determined by history, physical examination, or laboratory testing. * Subjects with an active seizure disorder (history of febrile seizures in early childhood will be considered. * Females with a positive urine pregnancy test. * Evidence of a prior adequate trial of aripiprazole (defined as equal to or greater than 2 weeks at equal to or greater than 5 mg per day. When there is not evidence of a prior adequate trial, subjects must be medication-free for a least 2 weeks prior to baseline. * History of neuroleptic malignant syndrome. * Subjects who, in the opinion of the investigator, are unsuitable in any other way to participate in this study, including being unable to comply with the requirements of the study for any reason. * Hypersensitivity to aripiprazole \[e.g., allergic response or serious adverse effect\] (significant tachycardia).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Improved as Measured by the Clinical Global Impression-Global Improvement Scale (Improvement Defined as CGI-I=1 or CGI-I=2) | Double-blind phase study exit - up to 8 weeks | Clinical Global Impressions (Guy, 1976) global improvement (CGI-I) is designed to take into account all factors to arrive at an assessment of response to treatment. The CGI-I scale ranges from 1 to 7, with lower scores indicating greater improvement (1=very much improved and 2=much improved). Participants with a CGI-I score of 1 or 2 were classified as improved. Four participants assigned to placebo completed an exit interview prior to week 8. One participant assigned to placebo and one participant assigned to aripiprazole withdrew from the study without completing an exit interview. |
| Mean Post-baseline Aberrant Behavior Checklist Irritability Subscale Score, Parent Report, Double-blind Phase | Weeks 1, 2, 3, 4, 6 and 8 | The Aberrant Behavior Checklist (ABC) is a symptom checklist for assessing problem behaviors in individuals ages 6 to 54 years-old with mental retardation. The full ABC is a 58-item parent rating with five factors: Irritability, Social Withdrawal, Stereotypy, Hyperactivity and Inappropriate Speech. It has been used as a primary outcome measure in several trials in children with developmental disabilities. The interpretation of the tool and its subscales is that a greater number of items indicates greater severity. The range of scores for the Irritability subscale is 0 to 45. Means were estimated using a repeated measures linear regression model with treatment group, baseline score, study week (in categories), and Tanner stage as covariates. A linear contrast estimated the average across study timepoints. Confidence intervals reflect a Bonferroni multiple testing correction accounting for the selection of two primary outcomes. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Post-baseline Aberrant Behavior Checklist Hyperactivity Subscale Score, Parent Report, Double-blind Phase | Weeks 1, 2, 3, 4, 6 and 8 | The Aberrant Behavior Checklist (ABC) is a symptom checklist for assessing problem behaviors in individuals ages 6 to 54 years-old with mental retardation. The full ABC is a 58-item parent rating with five factors: Irritability, Social Withdrawal, Stereotypy, Hyperactivity and Inappropriate Speech. The 16-item Hyperactivity subscale covers overactivity (7 items), impulsiveness (2 items), inattention (3 items) and noncompliance (4 items). It has been used as a primary outcome measure in several trials in children with developmental disabilities. The interpretation of the tool and its subscales is that a greater number of items indicates greater severity. The range of scores is 0 to 48 on the Hyperactivity subscale. Means were estimated using a repeated measures linear regression model with treatment group, baseline score, study week (in categories), and Tanner stage as covariates. A linear contrast estimated the average across study timepoints. |
| Mean Post-baseline Aberrant Behavior Checklist Inappropriate Speech Subscale Score, Parent Report, Double-blind Phase | Weeks 1, 2, 3, 4, 6 and 8 | The Aberrant Behavior Checklist (ABC) is a symptom checklist for assessing problem behaviors in individuals ages 6 to 54 years-old with mental retardation. The full ABC is a 58-item parent rating with five factors: Irritability, Social Withdrawal, Stereotypy, Hyperactivity and Inappropriate Speech. It has been used as a primary outcome measure in several trials in children with developmental disabilities. The interpretation of the tool and its subscales is that a greater number of items indicates greater severity. The range of scores for the Inappropriate Speech subscale is 0 to 12. Means were estimated using a repeated measures linear regression model with treatment group, baseline score, study week (in categories), and Tanner stage as covariates. A linear contrast estimated the average across study timepoints. |
| Mean Post-baseline Aberrant Behavior Checklist Social Withdrawal Subscale Score, Parent Report, Double-blind Phase | Weeks 1, 2, 3, 4, 6 and 8 | The Aberrant Behavior Checklist (ABC) is a symptom checklist for assessing problem behaviors in individuals ages 6 to 54 years-old with mental retardation. The full ABC is a 58-item Parent rating with five factors: Irritability, Social Withdrawal, Stereotypy, Hyperactivity and Inappropriate Speech. It has been used as a primary outcome measure in several trials in children with developmental disabilities. The interpretation of the tool and its subscales is that a greater number of items indicates greater severity. The range of scores for the Social Withdrawal subscale is 0 to 48. Means were estimated using a repeated measures linear regression model with treatment group, baseline score, study week (in categories), and Tanner stage as covariates. A linear contrast estimated the average across study timepoints. |
| Mean Post-baseline Aberrant Behavior Checklist Stereotypy Subscale Score, Parent Report, Double-blind Phase | Weeks 1, 2, 3, 4, 6 and 8 | The Aberrant Behavior Checklist (ABC) is a symptom checklist for assessing problem behaviors in individuals ages 6 to 54 years-old with mental retardation. The full ABC is a 58-item parent rating with five factors: Irritability, Social Withdrawal, Stereotypy, Hyperactivity and Inappropriate Speech. It has been used as a primary outcome measure in several trials in children with developmental disabilities. The interpretation of the tool and its subscales is that a greater number of items indicates greater severity. The range of scores for the Stereotypy subscale is 0 to 21. Means were estimated using a repeated measures linear regression model with treatment group, baseline score, study week (in categories), and Tanner stage as covariates. A linear contrast estimated the average across study timepoints. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm 1. Aripiprazole Oral Product Participants will receive Aripiprazole oral product with a minimum dose of 2 mg per day to a maximum dose of 20 mg per day over 8-weeks of treatment.
Aripiprazole oral product: Minimum dose of 2mg per day to a maximum of 20 mg per day over 8-weeks of treatment. | 17 |
| Arm 2. Placebo Oral Capsule Participants will receive matching (identical in size and appearance to study drug) placebo oral capsules over 8-weeks of treatment.
Placebo oral capsule: Placebo will identical in size and appearance to study drug. | 16 |
| Total | 33 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Lack of Efficacy | 1 | 3 |
| Overall Study | Lost to Follow-up | 0 | 1 |
Baseline characteristics
| Characteristic | Arm 1. Aripiprazole Oral Product | Total | Arm 2. Placebo Oral Capsule |
|---|---|---|---|
| Age, Continuous | 9.8 years STANDARD_DEVIATION 3 | 9.6 years STANDARD_DEVIATION 2.7 | 9.5 years STANDARD_DEVIATION 2.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 16 Participants | 32 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 4 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 15 Participants | 26 Participants | 11 Participants |
| Region of Enrollment United States | 17 participants | 33 participants | 16 participants |
| Sex: Female, Male Female | 2 Participants | 7 Participants | 5 Participants |
| Sex: Female, Male Male | 15 Participants | 26 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 17 | 0 / 16 |
| other Total, other adverse events | 16 / 17 | 13 / 16 |
| serious Total, serious adverse events | 0 / 17 | 0 / 16 |
Outcome results
Primary
Mean Post-baseline Aberrant Behavior Checklist Irritability Subscale Score, Parent Report, Double-blind Phase
The Aberrant Behavior Checklist (ABC) is a symptom checklist for assessing problem behaviors in individuals ages 6 to 54 years-old with mental retardation. The full ABC is a 58-item parent rating with five factors: Irritability, Social Withdrawal, Stereotypy, Hyperactivity and Inappropriate Speech. It has been used as a primary outcome measure in several trials in children with developmental disabilities. The interpretation of the tool and its subscales is that a greater number of items indicates greater severity. The range of scores for the Irritability subscale is 0 to 45. Means were estimated using a repeated measures linear regression model with treatment group, baseline score, study week (in categories), and Tanner stage as covariates. A linear contrast estimated the average across study timepoints. Confidence intervals reflect a Bonferroni multiple testing correction accounting for the selection of two primary outcomes.
Time frame: Weeks 1, 2, 3, 4, 6 and 8
Population: All randomized study participants
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm 1. Aripiprazole Oral Product | Mean Post-baseline Aberrant Behavior Checklist Irritability Subscale Score, Parent Report, Double-blind Phase | 18.3 units on a scale |
| Arm 2. Placebo Oral Capsule | Mean Post-baseline Aberrant Behavior Checklist Irritability Subscale Score, Parent Report, Double-blind Phase | 26.4 units on a scale |
Primary
Number of Participants Improved as Measured by the Clinical Global Impression-Global Improvement Scale (Improvement Defined as CGI-I=1 or CGI-I=2)
Clinical Global Impressions (Guy, 1976) global improvement (CGI-I) is designed to take into account all factors to arrive at an assessment of response to treatment. The CGI-I scale ranges from 1 to 7, with lower scores indicating greater improvement (1=very much improved and 2=much improved). Participants with a CGI-I score of 1 or 2 were classified as improved. Four participants assigned to placebo completed an exit interview prior to week 8. One participant assigned to placebo and one participant assigned to aripiprazole withdrew from the study without completing an exit interview.
Time frame: Double-blind phase study exit - up to 8 weeks
Population: All randomized study participants who completed an exit interview
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1. Aripiprazole Oral Product | Number of Participants Improved as Measured by the Clinical Global Impression-Global Improvement Scale (Improvement Defined as CGI-I=1 or CGI-I=2) | 11 participants |
| Arm 2. Placebo Oral Capsule | Number of Participants Improved as Measured by the Clinical Global Impression-Global Improvement Scale (Improvement Defined as CGI-I=1 or CGI-I=2) | 3 participants |
Secondary
Mean Post-baseline Aberrant Behavior Checklist Hyperactivity Subscale Score, Parent Report, Double-blind Phase
The Aberrant Behavior Checklist (ABC) is a symptom checklist for assessing problem behaviors in individuals ages 6 to 54 years-old with mental retardation. The full ABC is a 58-item parent rating with five factors: Irritability, Social Withdrawal, Stereotypy, Hyperactivity and Inappropriate Speech. The 16-item Hyperactivity subscale covers overactivity (7 items), impulsiveness (2 items), inattention (3 items) and noncompliance (4 items). It has been used as a primary outcome measure in several trials in children with developmental disabilities. The interpretation of the tool and its subscales is that a greater number of items indicates greater severity. The range of scores is 0 to 48 on the Hyperactivity subscale. Means were estimated using a repeated measures linear regression model with treatment group, baseline score, study week (in categories), and Tanner stage as covariates. A linear contrast estimated the average across study timepoints.
Time frame: Weeks 1, 2, 3, 4, 6 and 8
Population: All randomized study participants
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm 1. Aripiprazole Oral Product | Mean Post-baseline Aberrant Behavior Checklist Hyperactivity Subscale Score, Parent Report, Double-blind Phase | 23.8 units on a scale |
| Arm 2. Placebo Oral Capsule | Mean Post-baseline Aberrant Behavior Checklist Hyperactivity Subscale Score, Parent Report, Double-blind Phase | 29.4 units on a scale |
Secondary
Mean Post-baseline Aberrant Behavior Checklist Inappropriate Speech Subscale Score, Parent Report, Double-blind Phase
The Aberrant Behavior Checklist (ABC) is a symptom checklist for assessing problem behaviors in individuals ages 6 to 54 years-old with mental retardation. The full ABC is a 58-item parent rating with five factors: Irritability, Social Withdrawal, Stereotypy, Hyperactivity and Inappropriate Speech. It has been used as a primary outcome measure in several trials in children with developmental disabilities. The interpretation of the tool and its subscales is that a greater number of items indicates greater severity. The range of scores for the Inappropriate Speech subscale is 0 to 12. Means were estimated using a repeated measures linear regression model with treatment group, baseline score, study week (in categories), and Tanner stage as covariates. A linear contrast estimated the average across study timepoints.
Time frame: Weeks 1, 2, 3, 4, 6 and 8
Population: All randomized study participants
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm 1. Aripiprazole Oral Product | Mean Post-baseline Aberrant Behavior Checklist Inappropriate Speech Subscale Score, Parent Report, Double-blind Phase | 4.6 units on a scale |
| Arm 2. Placebo Oral Capsule | Mean Post-baseline Aberrant Behavior Checklist Inappropriate Speech Subscale Score, Parent Report, Double-blind Phase | 6.0 units on a scale |
Secondary
Mean Post-baseline Aberrant Behavior Checklist Social Withdrawal Subscale Score, Parent Report, Double-blind Phase
The Aberrant Behavior Checklist (ABC) is a symptom checklist for assessing problem behaviors in individuals ages 6 to 54 years-old with mental retardation. The full ABC is a 58-item Parent rating with five factors: Irritability, Social Withdrawal, Stereotypy, Hyperactivity and Inappropriate Speech. It has been used as a primary outcome measure in several trials in children with developmental disabilities. The interpretation of the tool and its subscales is that a greater number of items indicates greater severity. The range of scores for the Social Withdrawal subscale is 0 to 48. Means were estimated using a repeated measures linear regression model with treatment group, baseline score, study week (in categories), and Tanner stage as covariates. A linear contrast estimated the average across study timepoints.
Time frame: Weeks 1, 2, 3, 4, 6 and 8
Population: All randomized study participants
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm 1. Aripiprazole Oral Product | Mean Post-baseline Aberrant Behavior Checklist Social Withdrawal Subscale Score, Parent Report, Double-blind Phase | 6.1 units on a scale |
| Arm 2. Placebo Oral Capsule | Mean Post-baseline Aberrant Behavior Checklist Social Withdrawal Subscale Score, Parent Report, Double-blind Phase | 9.6 units on a scale |
Secondary
Mean Post-baseline Aberrant Behavior Checklist Stereotypy Subscale Score, Parent Report, Double-blind Phase
The Aberrant Behavior Checklist (ABC) is a symptom checklist for assessing problem behaviors in individuals ages 6 to 54 years-old with mental retardation. The full ABC is a 58-item parent rating with five factors: Irritability, Social Withdrawal, Stereotypy, Hyperactivity and Inappropriate Speech. It has been used as a primary outcome measure in several trials in children with developmental disabilities. The interpretation of the tool and its subscales is that a greater number of items indicates greater severity. The range of scores for the Stereotypy subscale is 0 to 21. Means were estimated using a repeated measures linear regression model with treatment group, baseline score, study week (in categories), and Tanner stage as covariates. A linear contrast estimated the average across study timepoints.
Time frame: Weeks 1, 2, 3, 4, 6 and 8
Population: All randomized study participants
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm 1. Aripiprazole Oral Product | Mean Post-baseline Aberrant Behavior Checklist Stereotypy Subscale Score, Parent Report, Double-blind Phase | 3.9 units on a scale |
| Arm 2. Placebo Oral Capsule | Mean Post-baseline Aberrant Behavior Checklist Stereotypy Subscale Score, Parent Report, Double-blind Phase | 5.3 units on a scale |