Asperger's Disorder, Attention Deficit Hyperactivity Disorder, Autism, Pervasive Development Disorder
Conditions
Keywords
Autism, PDD NOS, Attention Deficit Hyperactivity Disorder, Parent Management Training
Brief summary
The study will evaluate the effectiveness of atomoxetine (Strattera) with and without Parent Management Training (PMT) in children with Autism, Asperger's Disorder, or Pervasive Developmental Disorder Not Otherwise Specified (PDDNOS) who have symptoms of Attention Deficit Hyperactivity Disorder (ADHD). This is a double-blind placebo, parallel study where the atomoxetine will have a dose titration over a 6 week period. All children will be seen weekly during this titration period, with additional visits at Week 8 and Week 10. Families assigned to the PMT arm will have an additional weekly meeting with a clinician for a total of 9 PMT visits. PMT involves teaching parents to implement behavioral interventions with their children. Subjects who are clinical responders (ADHD Responders and Compliance Responders) from the 10 week study period will be followed every 4 weeks in a 24-week extension study. Subjects who are clinical nonresponders will continue in PMT if they received PMT during the double-blind phase, and they will receive an open trial of atomoxetine if they were on placebo during the double-blind phase. All subjects (responders and nonresponders) will be invited to participate in follow-up assessments every 4 weeks for 24 weeks after the completion of the double-blind phase.
Interventions
DRUGPlacebo
Placebo + parent management treatment
BEHAVIORALParent Management Training
DRUGatomoxetine
atomoxetine
Sponsors
University of Pittsburgh
Ohio State University
University of Rochester
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
5 Years to 14 Years
Healthy volunteers
No
Inclusion criteria
* Children 5 yrs to 14 years 11 mos with clinical diagnosis of Autism, Asperger's Disorder, or PDDNOS based upon the ADI-R and clinical evaluation by DSM-IV criteria, * Mental age equal to or greater than 24 months, * ADHD symptoms based upon the CASI and clinical confirmed diagnosis, * CGIS-S rating of 4 or grater for ADHD symptoms, * A mean item score of \>1.5 on both the Parent and Teacher (non-parent caregiver) SNAP-IV 18 ADHD symptoms or the 9-symptom hyperactive-impulsive subscale (symptoms must be cross-situational), * Reliable care provider available to bring subject to clinic visits and weekly sessions.
Exclusion criteria
* DSM-IV diagnosis of schizophrenia, schizoaffective disorder psychotic disorder NOS,bipolar disorder, or major depression (if accompanied by a family history of bipolar disorder) based upon evidence of suicidality, CASI, and clinical interview/history, * Prior failed adequate trial of atomoxetine, * Use of other psychotropic medications that produce CNS effects, * Diagnosis of bipolar disorder, major depression, hypertension, cardiovascular disease, narrow angle glaucoma, other significant physical illness, * Pregnancy or sexually active females (intercourse in the past 6 months, reported by either the subject or caregiver), * Currently on effective medication treatment for ADHD, * Prior involvement in Parent Management Training or other similar program, * Currently on albuterol or taking beta blockers, * Taking supplements or other complementary medical treatments where dose cannot be held at current level for duration of study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Were Attention Deficit Hyperactivity Disorder (ADHD) Respondents | week 10 | Respondents were defined as having ≥30% decrease on the SNAP and CGI-I\<=2). The Swanson, Nolan, and Pelham (SNAP)-IV Parent and Teacher Rating Scales were used to measure ADHD and oppositional symptoms at home and school. The SNAP-IV ADHD section contains items for each of the 18 Diagnostic and Statistical Manual of Mental Disorders-IV symptoms of ADHD rated from 0 (not at all) to 3 (very much). The Clinical Global Impressions Scale (CGI) includes subscales for severity of illness and global improvement. The Severity scale is scored from 1 (normal) to 7 (extremely ill), with a rating of ≥4 required for inclusion. The Improvement score ranged from 1 (very much improved) through 4 (no change) to 7 (very much worse). The CGI was completed by a blinded rater based on parent/child interview and review of completed parent and school behavior problem questionnaires at each study visit. |
| Percentage of Participants Who Were Autism Spectrum Disorder Respondents | week 10 | Respondents were defined as having ≥30% decrease on the HSQ and CGI-I≤2). The 25-item HSQ was adapted by the Research Units on Pediatric Psychopharmacology Autism Network to evaluate behavioral noncompliance in children with autism spectrum disorder (ASD). The Home Situations Questionnaire - Pervasive Developmental Disorder (HSQ) is a 25-item parent rating scale assessing noncompliance. Parents are asked to indicate whether each item is a problem and, if so, its severity from 1 (mild) to 9 (severe). The School Situations Questionnaire (SSQ) is a 9-item teacher rating scale that assesses noncompliance. The SSQ is a companion instrument to the HSQ and uses the same rating scale. The Clinical Global Impressions Scale (CGI) includes subscales for severity of illness and global improvement. The Severity scale is scored from 1 (normal) to 7 (extremely ill), |
Countries
United States
Participant flow
Recruitment details
200 participants were screened. 131 passed screening. Participants failed screening for the following reasons: 16 Attention Deficit Hyperactivity Disorder (ADHD) not confirmed, 23 Autism Spectrum Disorder not confirmed, 7 previous parent therapy or mental age too low, 23 for other reasons.
Pre-assignment details
Two participants who passed screening withdrew and one child became ineligible because of ADHD severity declining at baseline.
Participants by arm
| Arm | Count |
|---|---|
| Atomoxetine + Parent Management Training ATX doses were split twice daily to prevent side effects. However, once-daily dosing was allowed if strongly preferred by a given family. ATX doses were individually adjusted according to a weight-based dosage schedule, with medical clinicians allowed to delay increases or to reduce doses due to AEs. The initial dose was 0.3 mg/kg/day (rounded to the nearest 5 mg) with weekly escalations by 0.3 mg/kg/day, unless there were limiting side effects or no further room for improvement, to a target dose of 1.2 mg/kg/day, and could be increased to a maximum of 1.8 mg/kg/day based on clinical status and response.
Parent Management Training-Families assigned to PT met weekly for individual sessions with a PT clinician. Sessions were adapted from the RUPP Parent Training Manual and covered topics such as preventing behavior problems, reinforcement, time out, and planned ignoring. Each session lasted 60 to 90 minutes and included didactic materials, videos, and role playing. | 32 |
| Atomoxetine Without Parent Management Training ATX doses were split twice daily to prevent side effects. However, once-daily dosing was allowed if strongly preferred by a given family. ATX doses were individually adjusted according to a weight-based dosage schedule, with medical clinicians allowed to delay increases or to reduce doses due to AEs. The initial dose was 0.3 mg/kg/day (rounded to the nearest 5 mg) with weekly escalations by 0.3 mg/kg/day, unless there were limiting side effects or no further room for improvement, to a target dose of 1.2 mg/kg/day, and could be increased to a maximum of 1.8 mg/kg/day based on clinical status and response. | 32 |
| Placebo + Parent Management Training Sugar pill administered twice daily
Parent Management Training-Families assigned to PT met weekly for individual sessions with a PT clinician. Sessions were adapted from the RUPP Parent Training Manual and covered topics such as preventing behavior problems, reinforcement, time out, and planned ignoring. Each session lasted 60 to 90 minutes and included didactic materials, videos, and role playing. | 32 |
| Placebo Without Parent Management Training Sugar pill administered twice daily. | 32 |
| Total | 128 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 3 | 2 | 5 | 5 |
| Overall Study | could not swallow medication | 2 | 0 | 0 | 0 |
| Overall Study | Lack of Efficacy | 1 | 0 | 2 | 2 |
| Overall Study | Lost to Follow-up | 1 | 1 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 | 3 |
Baseline characteristics
| Characteristic | Atomoxetine + Parent Management Training | Atomoxetine Without Parent Management Training | Placebo + Parent Management Training | Placebo Without Parent Management Training | Total |
|---|---|---|---|---|---|
| Age, Continuous | 8.0 years STANDARD_DEVIATION 1.9 | 8.6 years STANDARD_DEVIATION 2.3 | 7.7 years STANDARD_DEVIATION 1.5 | 8.2 years STANDARD_DEVIATION 2.4 | 8.1 years STANDARD_DEVIATION 2.1 |
| Region of Enrollment United States | 32 participants | 32 participants | 32 participants | 32 participants | 128 participants |
| Sex: Female, Male Female | 1 Participants | 6 Participants | 5 Participants | 8 Participants | 20 Participants |
| Sex: Female, Male Male | 31 Participants | 26 Participants | 27 Participants | 24 Participants | 108 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 59 / 63 | 61 / 62 |
| serious Total, serious adverse events | 0 / 63 | 0 / 62 |
Outcome results
Primary
Percentage of Participants Who Were Attention Deficit Hyperactivity Disorder (ADHD) Respondents
Respondents were defined as having ≥30% decrease on the SNAP and CGI-I\<=2). The Swanson, Nolan, and Pelham (SNAP)-IV Parent and Teacher Rating Scales were used to measure ADHD and oppositional symptoms at home and school. The SNAP-IV ADHD section contains items for each of the 18 Diagnostic and Statistical Manual of Mental Disorders-IV symptoms of ADHD rated from 0 (not at all) to 3 (very much). The Clinical Global Impressions Scale (CGI) includes subscales for severity of illness and global improvement. The Severity scale is scored from 1 (normal) to 7 (extremely ill), with a rating of ≥4 required for inclusion. The Improvement score ranged from 1 (very much improved) through 4 (no change) to 7 (very much worse). The CGI was completed by a blinded rater based on parent/child interview and review of completed parent and school behavior problem questionnaires at each study visit.
Time frame: week 10
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Atomoxetine + Parent Management Training | Percentage of Participants Who Were Attention Deficit Hyperactivity Disorder (ADHD) Respondents | 45.2 percentage of participants |
| Atomoxetine Without Parent Management Training | Percentage of Participants Who Were Attention Deficit Hyperactivity Disorder (ADHD) Respondents | 46.9 percentage of participants |
| Placebo + Parent Management Training | Percentage of Participants Who Were Attention Deficit Hyperactivity Disorder (ADHD) Respondents | 29.0 percentage of participants |
| Placebo Without Parent Management Training | Percentage of Participants Who Were Attention Deficit Hyperactivity Disorder (ADHD) Respondents | 19.4 percentage of participants |
p-value: 0.47Chi-squared
Primary
Percentage of Participants Who Were Autism Spectrum Disorder Respondents
Respondents were defined as having ≥30% decrease on the HSQ and CGI-I≤2). The 25-item HSQ was adapted by the Research Units on Pediatric Psychopharmacology Autism Network to evaluate behavioral noncompliance in children with autism spectrum disorder (ASD). The Home Situations Questionnaire - Pervasive Developmental Disorder (HSQ) is a 25-item parent rating scale assessing noncompliance. Parents are asked to indicate whether each item is a problem and, if so, its severity from 1 (mild) to 9 (severe). The School Situations Questionnaire (SSQ) is a 9-item teacher rating scale that assesses noncompliance. The SSQ is a companion instrument to the HSQ and uses the same rating scale. The Clinical Global Impressions Scale (CGI) includes subscales for severity of illness and global improvement. The Severity scale is scored from 1 (normal) to 7 (extremely ill),
Time frame: week 10
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Atomoxetine + Parent Management Training | Percentage of Participants Who Were Autism Spectrum Disorder Respondents | 22.6 percentage of participants |
| Atomoxetine Without Parent Management Training | Percentage of Participants Who Were Autism Spectrum Disorder Respondents | 43.8 percentage of participants |
| Placebo + Parent Management Training | Percentage of Participants Who Were Autism Spectrum Disorder Respondents | 38.7 percentage of participants |
| Placebo Without Parent Management Training | Percentage of Participants Who Were Autism Spectrum Disorder Respondents | 16.4 percentage of participants |
p-value: 0.95Chi-squared