Atomoxetine Versus Placebo for Symptoms of Attention-Deficit/Hyperactivity Disorder (ADHD) in Children and Adolescents With Autism Spectrum Disorder

Study Overview
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Brief Summary
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The purpose of this study is to determine whether atomoxetine is effective in reducing ADHD (Attention Deficit/Hyperactivity Disorder) symptoms in children and adolescents with ASD (Autism Spectrum Disorder).

Official Title
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A Randomized, Double-blind Comparison of Atomoxetine Hydrochloride and Placebo for Symptoms of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents With Autism Spectrum Disorder

Conditions
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Autistic Disorder, Attention Deficit Disorder With Hyperactivity

Intervention / Treatment
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* Drug: Atomoxetine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria (most important): ASD (autistic disorder or Asperger's disorder or Pervasive Developmental Disorder - Not Otherwise Specified [PDD NOS]) Criteria A through D for Attention-Deficit/Hyperactivity Disorder (ADHD) At least 1.5 standard deviations above the age norm for their diagnostic subtype using published norms for the ADHD Rating Scale-IV-Parent Version Intelligence quotient (IQ) score > 60 Exclusion Criteria (most important): weight under 20 kg Patients who meet Diagnostic and Statistical Manual of Mental Disorders Fourth Edition, Text Revision (DSM-IV-TR) criteria for ASD other than Autistic Disorder, PDD-NOS or Asperger's Disorder;history of Bipolar I or II disorder, schizophrenia, another psychotic disorder, substance abuse;Have a significant medical condition such as heart disease, hypertension, liver or renal failure, pulmonary disease, or seizure disorder identified by history, physical examination, or laboratory tests; Patients who have taken (or are currently taking) anticonvulsants for seizure control. patients at serious suicidal risk. Contraindication to the use of atomoxetine Patients who in the investigator's judgment are likely to need psychotropic medications apart from the drug. Patients who at any time during Study Period II are likely to begin a structured psychotherapy, likely to require hospitalization (i.e. in-patient treatment) or likely to be dismissed from in-patient treatment. Psychotherapy (including hospitalization) initiated at least 2 months prior to study participation is acceptable; however, after study participation has begun, only during Study Period III supportive or educational therapy is permitted.

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Atomoxetine<br>atomoxetine 0.5 mg/kg/day every day (QD), by mouth (PO) for 1 week, atomoxetine 0.8mg/kg/day QD, PO for 1 week, 1.2mg/kg/day QD, PO for 6 weeks then atomoxetine 0.5-1.2 mg/kg/day QD, PO for up to 20 weeks | Drug: Atomoxetine<br> <br> * Other names: Strattera;|
| Placebo Comparator: Placebo<br>placebo every day (QD), by mouth (PO) for 8 weeks Then patients can take atomoxetine 0.5-1.2 mg/kg/day QD, PO up to 20 weeks | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ADHD Rating Scale-IV-Parent Version: Investigator Scored - Total Score | Measures the 18 symptoms contained in the Diagnostic and Statistical Manual of Mental Disorders, Version IV (DSM-IV) diagnosis of Attention-Deficit/Hyperactivity Disorder. Individual item scores range from 0 (none/never or rarely) to 3 (severe/very often). Total scores range from 0 to 54. | Baseline and 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Global Impressions-ADHD-Improvement (CGI-ADHD - I) | Measures total improvement (or worsening) of a patient's ADHD symptoms from the beginning of treatment (1=very much improved, 7=very much worsened). | 8 weeks, 28 weeks | 
| Conners' Teacher Rating Scale - Revised: Short Form (CTRS-R:S) | A 28-item rating scale (0 [not at all/never] to 3 [very much true/very often]) completed by the teacher to assess problem behaviors related to ADHD. Subscale total scores range from 0 to 15 for Oppositional and Cognitive Problems, 0 to 21 for Hyperactivity, and 0 to 36 for ADHD Index. | Baseline, 8 weeks, 28 weeks | 
| ADHD Rating Scale-IV-Parent Version: Investigator Scored Total Score | Measures the 18 symptoms contained in the DSM-IV diagnosis of Attention-Deficit/Hyperactivity Disorder. Individual item scores range from 0 (none/never or rarely) to 3 (severe/very often). Total scores range from 0 to 54. | 28 weeks | 
| Sleep Measure Scale | 10-item parent-based scale assessing sleep problems (6 point Likert scale). Scores: Difficulty falling asleep (1-6); Quality of sleep (3-18); Functional outcome (6-36). Lower scores indicate higher problems with item. Open-ended items: Time to fall asleep (1 [0-15 minutes] to 5 [>1 hour]); Total hours (numbers associated with hours of sleep). | Baseline, 8 weeks, 28 weeks | 
| Aberrant Behavior Checklist (ABC) | The ABC is a 58-item informant-based scale comprised of five subscales (Irritability [15 items], Lethargy [16], Stereotypic Behaviors [7], Hyperactivity [16], Inappropriate Speech [4]). Individual item scores range from 0 (no problem) to 3 (severe problem). Subscale scores are total of individual item scores in subscale: Irritability (0-45); Lethargy (0-48); Stereotypic (0-21); Hyperactivity (0-48); Inappropriate Speech (0-12). | Baseline, 8 weeks, 28 weeks | 
| Children's Social Behavior Questionnaire (CSBQ) Total Score | CSBQ is filled out by parents and consists of 49 items. Items are rated in an ordinal rather than a discrete fashion in order to establish the extent to which problems are present. The CSBQ consists of six subscales. Individual item scores range from 0=does not apply to 2=applies clearly. Total score ranges from 0 to 98. | Baseline, 8 weeks, 28 weeks | 
| General Health Questionnaire (GHQ) Total Score | Parental distress is measured with the GHQ. The raw total score (based on 0-0-1-1 scoring system) can be used as an overall index of psychological distress, ranging from 0 to 12 with higher scores indicating more distress. | Baseline, 8 weeks, 28 weeks | 
| Nijmeegse Ouderlijke Stress Index (NOSI) Total Score | The NOSI contains 123 items to be completed by the primary caregiver. Individual item scores range from 1 (completely agree) to 6 (completely disagree). Total scores range from 123 to 738. | Baseline, 8 weeks, 28 weeks | 
| Amsterdam Neuropsychological Tasks (ANT): Focused Attention Task - Error Rates | Focused attention assessed distractibility. Child needs to identify a specific target (eg, Cherry); non-target is any other fruit. Child presses yes when target occurs in relevant position (eg, one of vertical positions on diamond). Child presses no when target is absent, or when target appears on horizontal position (irrelevant target). Error rates are percentage of missing relevant targets and percentage of false alarms in response to (irr)relevant (non)targets based on number of errors/total number of trials X 100. | Baseline, 8 Weeks | 
| Amsterdam Neuropsychological Tasks (ANT): Focused Attention Task - Reaction Times for Hits and Correct Rejections | Task is the same as described in Outcome Measure #10. Reaction times (RT) for hits are mean RTs of correct responses to relevant targets. RTs for correct rejections are mean RTs for correct rejections are mean RTs for correct no responses to irrelevant targets and relevant nontargets. | Baseline, 8 Weeks | 
| Amsterdam Neuropsychological Tasks (ANT): Focused Attention Task - Standard Deviation of Reaction Times for Hits and Correct Rejections | Task is the same as described in Outcome Measure #10. Standard deviations of reaction times (RT) assess intraindividual variability in RT and refer to the same conditions as those for mean reaction times described in Outcome Measure #11. | Baseline, 8 Weeks | 
| Amsterdam Neuropsychological Tasks (ANT): Memory Search Task - Error Rates | The memory search task aims at measuring serial search processes to be carried out in working memory. There are 2 blocks (loads) with 40 trials each. Load 1 has 1 target to identify (e.g., an animal). A yes is required whenever the target is part of the displayed set of four stimuli (all animals). Load 2 has 2 targets. Whenever 1 of the targets appears in the successively displayed sets of four animals, a yes is required. Targets are present in 50% of trials. Error rates are the percentages of errors made in each task condition, based on the number of errors/total number of trials X 100. | Baseline, 8 Weeks | 
| Amsterdam Neuropsychological Tasks (ANT): Memory Search Task - Reaction Times for Hits and Correct Rejections | Memory search task aims at measuring serial search processes to be carried out in working memory. There are 2 blocks (loads) with 40 trials each. Load 1 has 1 target to remember (one animal). A yes is required whenever the target is part of displayed set of 4 animals. Load 2 has 2 animals. A yes is required whenever one of the animals appears in successively displayed sets of 4 animals. Targets are present in 50% of the trials. Reaction time (RT) for hits is mean RT of correct yes responses to targets. RT correct rejections are mean RTs of correct no responses when target was missing. | Baseline, 8 Weeks | 
| Amsterdam Neuropsychological Tasks (ANT): Memory Search Task - Standard Deviation (SD) of Reaction Times for Hits and Correct Rejections | Task is the same as described in Outcome Measure #14. Standard deviations of reaction times (RT) assess intraindividual variability in RT referring to the two conditions creating hits and correct rejections as mentioned in Outcome Measure #14. | Baseline, 8 weeks | 
| Amsterdam Neuropsychological Tasks (ANT): Pursuit Motor Control Task - Accuracy | A complex visuo-motor flexibility task that aims at measuring eye-hand co-ordination and fine motor control. By moving mouse cursor, the child is required to follow as closely as possible a target that randomly moves across the PC-screen. Accuracy is the mean distance between the mouse cursor and the moving target. | Baseline, 8 weeks | 
| Amsterdam Neuropsychological Tasks (ANT): Pursuit Motor Control Task - Stability of Movement | A complex visuo-motor flexibility task that measures eye-hand co-ordination and fine motor control. By moving mouse cursor, the child is required to follow as closely as possible a target that randomly moves across the PC-screen. Stability is within subject variability of mean distance between cursor and target. | Baseline, 8 weeks | 
| Amsterdam Neuropsychological Tasks (ANT): Go/No-Go Response Inhibition Task - Error Rates | Measures inhibition of pre-potent responses. 24 Go signals (open squares) are presented, randomly mixed with 24 No-Go signals (closed squares). Subjects are required to press a key if a Go signal (target) appears on the screen but to withhold a response if they see a No-Go signal. Error rate is the percentage of key presses to No-Go signals/total number of trials X 100. | Baseline, 8 weeks | 
| Amsterdam Neuropsychological Tasks (ANT): Flanker Interference Task - Error Rates | Measures ability to neglect stimuli interfering with predefined stimulus-response coupling. Child presented with displays of 9 colored squares. Child responds to color of central square by pressing left mouse key when blue, and right mouse key when yellow. Part 1 (40 trials), surrounding squares may be same color (compatible) or different (neutral). Part 2 (80 trials), in 50% of trials, surrounding squares have color corresponding to predefined key press for other hand (incompatible). Error rates are percentages of errors in response to compatible and incompatible signals, respectively. | Baseline, 8 weeks | 
| Amsterdam Neuropsychological Tasks (ANT): Flanker Interference Task - Reaction Times | Task is the same as described in Outcome Measure #19. Mean reaction times (RTs) are computed for correct responses to compatible and incompatible flankers, respectively. | Baseline, 8 weeks | 
| Cytochrome P450 2D6 Genotype | Genotype characterization was used to determine participants' metabolic status. | baseline |