A Phase 4 interventional study of atomoxetine and Behavior Modification Therapy in Attention Deficit Hyperactivity Disorder, sponsored by State University of New York at Buffalo. Completed at 1 site in United States. Open to participants aged 6 Years to 12 Years. Per ClinicalTrials.gov, last updated 2020-10-20.
Sponsored by State University of New York at Buffalo · Phase 4, Interventional, and Treatment
Background: Multiple studies have found Atomoxetine (Strattera) to be efficacious but there is only one published study specifically designed to evaluate its efficacy in school settings. In this 7 week placebo-controlled study, Atomoxetine (ATX) at mean dose of 1.3 mg/kg, significantly reduced teacher rated ADHD symptoms (Weiss et al., 2005). However, children are typically referred for treatment because of "real life" problems in functioning, not symptoms (Pelham, Fabiano, \& Massetti, 2005). While ATX has been found to produce functional improvements at home, the Weiss study found limited results in this area at school.
Furthermore, almost no research has examined the effects of combining ATX and behavior therapy (BT). In the MTA, adding BT to stimulants improved teacher ratings of hyperactivity/impulsivity and increased the number of subjects reaching optimal response (Swanson et al., 2001). Therefore, it is possible that the addition of BT to ATX may improve functional performance in the classroom. The effects of combined therapy may be even larger for ATX as monotherapy with nonstimulants produces smaller effect sizes than with stimulants.
Objective: The primary objective was to evaluate the effects of ATX alone and in combination with BT on the school functioning of 56 children ages 6-12 with ADHD. Outcomes were assessed using traditional symptoms measures as well as functional measures of academic and behavioral improvements in the classroom.
The objectives were evaluated in an 8 week open label trial of where half of the participants were randomly assigned to receive (ATX+BT) while the rest received only ATX. An open label design was employed as the efficacy of ATX for ADHD symptoms has been established and to ensure that all patients received at least one active treatment. Parents in the ATX+BT group attended an eight week parenting course using the Community Oriented Parent Education (COPE) program (Cunningham, Bremner, \& Secord, 1998) while the child participated in an eight week social skills course. Teachers implemented a Daily Report Card (DRC) to track classroom behaviors. In the BT group, the child's DRC performance was communicated daily to parents and tied to consequences at home and school. In the ATX group, parents were not provided with the DRCs. The ATX dosing protocol was as follows: .5mg/kg per day on days 1-3, .8mg/kg/day days 4-7, 1.2mg/kg days 8+. After 3 weeks, subjects were eligible to increase to 1.8mg/kg/day. ATX was dosed once in the morning but could be dosed BID to address tolerability. The mean final dose was 1.4mg/kg/day.
To be enrolled, children must have had an IQ > 75, not failed a trial of ATX, met DSM criteria for ADHD but not other psychiatric comorbidities except ODD/CD and be in good physical health. Children already taking ADHD medication were enrolled only if the average symptom score on the ADHD subscale of the Disruptive Behaviors Disorders (DBD) scale was >2 (moderate impairment). ADHD was confirmed by parent report on the DISC and the DBD, which rates all DSM 3R and IV symptoms of ODD, CD and ODD on a 0-3 likert scale. Subjects were also required to evidence ADHD symptoms in the classroom as rated on the IOWA Conners. Psychiatric comorbidities were assessed using the DISC.
Measures of treatment response included:
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Exclusion Criteria:
The presence of Oppositional Defiant Disorder (ODD), Conduct Disorder (CD) or learning disabilities will not result in exclusion from the study as they are commonly occurring comorbidities that have not been found to moderate response to ADHD treatments (Jensen et al., 2001). Enrollment in special education services will also not be an exclusionary criteria as work by this research group has found that such services do not affect response to ADHD treatments (Niemic, Fabiano, Pelham, \& Fuller, 2002).
atomoxetine plus behavior therapy
Drug: atomoxetine · Behavioral: Behavior Modification Therapy
atomoxetine alone
Drug: atomoxetine
open label treatment dosed up to 1.8mg/kg/day
Also known as: Drug Therapy
8 week behavioral modification course with school consultation, parenting groups using COPE and child social skills group
Also known as: Behavior Therapy
Rule Violations During Direct Classroom Observation at Endpoint (Week 8)
Observations were conducted using the Student Behavior Teacher Response Observation Code. After learning the classroom rules, observers watched children in their classrooms for 30 minutes during an academic activity and recorded each time the subject violated a classroom rule. Total classroom rule violations were used as the primary outcome measures for the study.
Time frame: Endpoint (Week 8)
Impairment Rating Scale (Parent Completed) at Endpoint
The IRS is a 8 item measure that uses visual-analogue scales to evaluate the child's problem level and need for treatment in developmentally important areas, such as peer relationships, adult-child relationships, academic performance, and classroom behavior 51. The scale is scored from 0 (no problem) to 6 (extreme problem). The scale has excellent test-retest and inter-rater reliability and well supported validity 51, 52.
Time frame: Endpoint (Week 8)
Impairment Rating Scale (Teachers) at Endpoint
The IRS is a 6 item measure that uses visual-analogue scales to evaluate the child's problem level and need for treatment in developmentally important areas, such as peer relationships, adult-child relationships, academic performance, and classroom behavior. The scale is scored from 0 (no problem) to 6 (extreme problem). The scale has excellent test-retest and inter-rater reliability and well supported validity.
Time frame: Endpoint (Week 8)
Pittsburgh Side Effects Rating Scale (PSERS)(Parent Completed) at Endpoint:
The PSERS measures adverse events commonly associated with stimulant medication and has been used in multiple studies of ADHD. For this study, the PSERS was modified to also assess adverse emotional events potentially associated with ATX, including suicidal statements. The resulting scale consisted of 14 items (an additional sleep item for parents) rated from 0 ("none") to 3 ("severe"). An overall side effects score was computed by averaging across all ratings and used in analyses.
Time frame: Endpoint (Week 8)
Pittsburgh Side Effects Rating Scale (PSERS)(Teacher Rated):
The PSERS measures adverse events commonly associated with stimulant medication and has been used in multiple studies of ADHD. For this study, the PSERS was modified to also assess adverse emotional events potentially associated with ATX, including suicidal statements. The resulting scale consisted of 13 items (for teachers) rated from 0 ("none") to 3 ("severe"). An overall side effects score was computed by averaging across all ratings and used in analyses.
Time frame: at weeks 8 (Endpoint)
Disruptive Behavior Disorders Rating Scale ODD Subscale (DBD- Parent Completed) at Endpoint
The DBD consists of 8 items that are the DSM-IV symptoms of Oppositional Defiant Disorder (ODD). Items on the DBD were rated by parents and teachers using Likert scales that ranged from 0 ("not at all") to 3 ("very much"). The factor structure, reliability and validity of the DBD have been supported in multiple studies.
Time frame: Endpoint (Week 8)
Disruptive Behavior Disorder Rating Scale ODD Subscale(DBD- Teacher Completed) at Endpoint
The DBD consists of 8 items that are the DSM-IV symptoms of Oppositional Defiant Disorder (ODD). Items on the DBD were rated by parents and teachers using Likert scales that ranged from 0 ("not at all") to 3 ("very much"). The factor structure, reliability and validity of the DBD have been supported in multiple studies.
Time frame: Endpoint (Week 8)
Social Skills Rating Scale Problem Behavior Subscale(SSRS Parent) at Endpoint
completed by parents to measure children's problem behaviors (PB). Items are rated from 0 ("not at all") to 2 ("very often"). The scale has 55 items. The score reported below is the sum total of the items on the scale and then averaged for the whole group. Therefore, the range can be between 0 and 110. A higher score indicates a better outcome.
Time frame: Endpoint (Week 8)
Social Skills Rating Scale Problem Behavior Subscale(SSRS Teachers) at Endpoint
The SSRS was completed by teachers to measure children's problem behaviors (PB). Items are rated from 0 ("not at all") to 2 ("very often"). The scale has 55 items. The score reported below is the sum total of the items on the scale and then averaged for the whole group. Therefore, the range can be between 0 and 110. A higher score indicates a better outcome.
Time frame: Endpoint (Week 8)
ADHD Subscale of the DBD (Parent Completed) at Endpoint
The DBD consists of 18 items that are the DSM-IV symptoms of ADHD. Items on the DBD were rated by parents and teachers using Likert scales that ranged from 0 ("not at all") to 3 ("very much"). The factor structure, reliability and validity of the DBD have been supported in multiple studies.
Time frame: Endpoint (Week 8)
ADHD Subscale of the DBD (Teacher Completed) at Endpoint
The ADHD subscale of the DBD consists of 18 items that are the DSM-IV symptoms of ADHD. Items on the DBD were rated by parents and teachers using Likert scales that ranged from 0 ("not at all") to 3 ("very much"). The factor structure, reliability and validity of the DBD have been supported in multiple studies.
Time frame: Endpoint (Week 8)
Subjects were recruited from schools, pediatric offices and the local community through radio and print advertisement. Subjects were recruited between Jan of 2007 and the spring of 2008.
| Milestone | Combined Therapy | Drug Therapy |
|---|---|---|
| Started | 29 | 27 |
| Completed | 24 | 25 |
| Not completed | 5 | 2 |
| Withdrew: Lack of efficacy | 3 | 1 |
| Withdrew: Withdrawal by subject | 1 | 1 |
| Withdrew: Adverse event | 1 | 0 |
Observations were conducted using the Student Behavior Teacher Response Observation Code. After learning the classroom rules, observers watched children in their classrooms for 30 minutes during an academic activity and recorded each time the subject violated a classroom rule. Total classroom rule violations were used as the primary outcome measures for the study.
| number occurences per 30 mins | Combined Therapy | Drug Therapy |
|---|---|---|
| Rule Violations During Direct Classroom Observation at Endpoint (Week 8) | 6.15 ± 1.37 | 4.93 ± 1.36 |
The IRS is a 8 item measure that uses visual-analogue scales to evaluate the child's problem level and need for treatment in developmentally important areas, such as peer relationships, adult-child relationships, academic performance, and classroom behavior 51. The scale is scored from 0 (no problem) to 6 (extreme problem). The scale has excellent test-retest and inter-rater reliability and well supported validity 51, 52.
| units on a scale | Combined Therapy | Drug Therapy |
|---|---|---|
| Impairment Rating Scale (Parent Completed) at Endpoint | 2.66 ± .37 | 2.84 ± .36 |
The IRS is a 6 item measure that uses visual-analogue scales to evaluate the child's problem level and need for treatment in developmentally important areas, such as peer relationships, adult-child relationships, academic performance, and classroom behavior. The scale is scored from 0 (no problem) to 6 (extreme problem). The scale has excellent test-retest and inter-rater reliability and well supported validity.
| units on a scale | Combined Therapy | Drug Therapy |
|---|---|---|
| Impairment Rating Scale (Teachers) at Endpoint | 2.02 ± 0.42 | 2.29 ± 0.43 |
The PSERS measures adverse events commonly associated with stimulant medication and has been used in multiple studies of ADHD. For this study, the PSERS was modified to also assess adverse emotional events potentially associated with ATX, including suicidal statements. The resulting scale consisted of 14 items (an additional sleep item for parents) rated from 0 ("none") to 3 ("severe"). An overall side effects score was computed by averaging across all ratings and used in analyses.
| units on a scale | Combined Therapy | Drug Therapy |
|---|---|---|
| Pittsburgh Side Effects Rating Scale (PSERS)(Parent Completed) at Endpoint: | .38 ± .06 | .34 ± .06 |
The PSERS measures adverse events commonly associated with stimulant medication and has been used in multiple studies of ADHD. For this study, the PSERS was modified to also assess adverse emotional events potentially associated with ATX, including suicidal statements. The resulting scale consisted of 13 items (for teachers) rated from 0 ("none") to 3 ("severe"). An overall side effects score was computed by averaging across all ratings and used in analyses.
| units on a scale | Combined Therapy | Drug Therapy |
|---|---|---|
| Pittsburgh Side Effects Rating Scale (PSERS)(Teacher Rated): | .23 ± .05 | .21 ± .05 |
The DBD consists of 8 items that are the DSM-IV symptoms of Oppositional Defiant Disorder (ODD). Items on the DBD were rated by parents and teachers using Likert scales that ranged from 0 ("not at all") to 3 ("very much"). The factor structure, reliability and validity of the DBD have been supported in multiple studies.
| units on a scale | Combined Therapy | Drug Therapy |
|---|---|---|
| Disruptive Behavior Disorders Rating Scale ODD Subscale (DBD- Parent Completed) at Endpoint | .90 ± .13 | 1.12 ± .13 |
The DBD consists of 8 items that are the DSM-IV symptoms of Oppositional Defiant Disorder (ODD). Items on the DBD were rated by parents and teachers using Likert scales that ranged from 0 ("not at all") to 3 ("very much"). The factor structure, reliability and validity of the DBD have been supported in multiple studies.
| units on a scale | Combined Therapy | Drug Therapy |
|---|---|---|
| Disruptive Behavior Disorder Rating Scale ODD Subscale(DBD- Teacher Completed) at Endpoint | .54 ± .15 | .71 ± .14 |
completed by parents to measure children's problem behaviors (PB). Items are rated from 0 ("not at all") to 2 ("very often"). The scale has 55 items. The score reported below is the sum total of the items on the scale and then averaged for the whole group. Therefore, the range can be between 0 and 110. A higher score indicates a better outcome.
| units on a scale | Combined Therapy | Drug Therapy |
|---|---|---|
| Social Skills Rating Scale Problem Behavior Subscale(SSRS Parent) at Endpoint | 16.48 ± 1.21 | 19.53 ± 1.19 |
The SSRS was completed by teachers to measure children's problem behaviors (PB). Items are rated from 0 ("not at all") to 2 ("very often"). The scale has 55 items. The score reported below is the sum total of the items on the scale and then averaged for the whole group. Therefore, the range can be between 0 and 110. A higher score indicates a better outcome.
| units on a scale | Combined Therapy | Drug Therapy |
|---|---|---|
| Social Skills Rating Scale Problem Behavior Subscale(SSRS Teachers) at Endpoint | 13.88 ± 1.25 | 13.96 ± 1.29 |
The DBD consists of 18 items that are the DSM-IV symptoms of ADHD. Items on the DBD were rated by parents and teachers using Likert scales that ranged from 0 ("not at all") to 3 ("very much"). The factor structure, reliability and validity of the DBD have been supported in multiple studies.
| units on a scale | Combined Therapy | Drug Therapy |
|---|---|---|
| ADHD Subscale of the DBD (Parent Completed) at Endpoint | 1.07 ± 0.11 | 1.47 ± 0.11 |
The ADHD subscale of the DBD consists of 18 items that are the DSM-IV symptoms of ADHD. Items on the DBD were rated by parents and teachers using Likert scales that ranged from 0 ("not at all") to 3 ("very much"). The factor structure, reliability and validity of the DBD have been supported in multiple studies.
| units on a scale | Combined Therapy | Drug Therapy |
|---|---|---|
| ADHD Subscale of the DBD (Teacher Completed) at Endpoint | 1.01 ± 0.13 | 1.13 ± 0.13 |
Collected over The Pittsburgh Side Effect Rating Scale (PSERS) measures adverse events commonly associated with ADHD medication rated from 0 ("none") to 3 ("severe"). Both teachers and parents completed it at weeks 1, 3 and 8.. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Combined Therapy | — | 0/29 (0%) | 25/29 (86.2%) |
| Drug Therapy | — | 0/27 (0%) | 24/27 (88.9%) |
| Event | Combined Therapy | Drug Therapy |
|---|---|---|
| motor ticsNervous system disorders | 4/29 | 4/7 |
| crabby/irritablePsychiatric disorders | 14/29 | 11/27 |
| dulled/tired lookingPsychiatric disorders | 13/29 | 10/27 |
| anxietyPsychiatric disorders | 10/29 | 12/27 |
| picking at skinPsychiatric disorders | 9/29 | 10/27 |
| stomachachesGastrointestinal disorders | 8/29 | 4/27 |
| depressed mood/crying episodesPsychiatric disorders | 8/29 | 5/27 |
| appetite lossMetabolism and nutrition disorders | 7/29 | 2/27 |
| headachesNervous system disorders | 5/29 | 3/27 |
| withdrawn from othersPsychiatric disorders | 5/29 | 3/27 |
| Age, Categorical(Participants) | Combined Therapy | Drug Therapy | Total |
|---|---|---|---|
| <=18 years | 29 | 27 | 56 |
| Between 18 and 65 years | 0 | 0 | 0 |
| >=65 years | 0 | 0 | 0 |
| Age, Continuous(years) | Combined Therapy | Drug Therapy | Total |
|---|---|---|---|
| Mean | 8.3 ± 1.6 | 8.9 ± 1.5 | 8.59 ± 1.581 |
| Sex: Female, Male(Participants) | Combined Therapy | Drug Therapy | Total |
|---|---|---|---|
| Female | 24 | 21 | 45 |
| Male | 5 | 6 | 11 |
| Region of Enrollment(participants) | Combined Therapy | Drug Therapy | Total |
|---|---|---|---|
| United States | 29 | 27 | 56 |
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State University of New York at Buffalo