Effectiveness of Atomoxetine in Treating ADHD Symptoms in Children and Adolescents With Autism

Targeted Pharmacologic Interventions for Autism: A Double-Blind, Placebo-Controlled Trial of Atomoxetine in Children and Adolescents With Autism

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00498173

Enrollment

Registered

2007-07-09

Start date

2007-07-31

Completion date

2015-10-31

Last updated

2025-11-14

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Autism

Keywords

Autistic Disorder, Autism Spectrum Disorder

Brief summary

This study will evaluate the effectiveness of atomoxetine in treating children with attention deficit hyperactivity disorder symptoms associated with autistic disorder, Asperger's syndrome, and pervasive developmental disorder, not otherwise specified.

Detailed description

Autism is a developmental disorder that can cause severe and pervasive impairment in thinking, feeling, language, and the ability to relate to others. It is usually first diagnosed in early childhood. Children with autism demonstrate repetitive behaviors or interests and deficits in social interaction, verbal communication, and nonverbal communication. In addition, they often have unusual responses to sensory experiences, such as certain sounds or the way objects look. Some symptoms of attention deficit hyperactivity disorder (ADHD), such as inattention, hyperactivity, and impulsivity, are also associated with autism. Atomoxetine is a selective norepinephrine reuptake inhibitor that is used to treat ADHD. It works differently, however, than stimulant drugs and may help to reduce ADHD symptoms in children with autism. This study will evaluate the effectiveness of atomoxetine in treating children with ADHD symptoms associated with autism. Potential participants will first attend a screening visit, which will include a psychiatric diagnostic interview, a practice session for swallowing pill capsules, a physical exam, an electrocardiogram (ECG), a blood test, and an assessment of pubertal stage. Females of childbearing age will also undergo a urine pregnancy test. In an initial double-blind study phase, eligible participants will be randomly assigned to receive either atomoxetine or placebo for 8 weeks. A baseline visit will include several rating scales, observations, and an interview to assess adaptive functioning. These measures and procedures will be used to keep track of symptoms, side effects, and behavior that could change during the study. Children who are assigned to placebo and do not notice an improvement in their ADHD symptoms will be given the opportunity to receive atomoxetine at the end of 8 weeks. Study visits will occur once a week for 4 weeks, and then every other week for the remainder of the 8 weeks. During these visits, many of the baseline questionnaires and interviews will be repeated. At the Week 8 visit, the physical exam, ECG, blood tests, and some baseline questionnaires will also be repeated. All children who respond well to atomoxetine may continue taking the drug for an additional 10 months. During this time, participants will report to the clinic once a month for the first 4 months, then once at the end of 7 months, and finally once at the end of 10 months. The same measures and procedures that were done during the 8-week phase will be done during the 10-month phase of this study.

Interventions

DRUGAtomoxetine

Available tablet strengths of atomoxetine: 5 mg, 10 mg, 25 mg, 40 mg. Week 1 participant takes 0.5 mg/kg/day, Week 2: 0.8 mg/kg/day, Week 3: 1.2 mg/kg/day. Potential exists for dose increase at Week 4 to 1.8 mg/kg/day based on clinical global impression-improvement rating at Week 4.

DRUGPlacebo

Placebo tablets dosages: 5 mg, 10 mg, 25 mg, 40 mg.

Study design

Allocation

RANDOMIZED

Intervention model

SEQUENTIAL

Primary purpose

TREATMENT

Masking

TRIPLE (Subject, Caregiver, Investigator)

Intervention model description

At the end of the 8-week double-blind, placebo-controlled study, participants randomized to placebo who are not responders at the end of 8 weeks will be treated with atomoxetine for 8 weeks during an open-label trial. All participants who are rated much improved or very much improved on the CGI-I following treatment with atomoxetine (i.e., atomoxetine responders) during either the 8-week placebo-controlled trial or the 8-week open-label phase for placebo nonresponders will be eligible to enter the 10-month open-label extension phase of the study.

Eligibility

Sex/Gender

ALL

Age

5 Years to 15 Years

Healthy volunteers

Inclusion criteria

* Diagnosis of an autism spectrum disorder (autistic disorder, Asperger's syndrome, and pervasive developmental disorder, not otherwise specified). * Significant hyperactivity, inattention, or impulsivity as determined by a score on an investigator-administered ADHD Rating Scale (ADHDRS)-Home Version that is at least 1.5 standard deviations above the mean for age and sex * Parent/caregiver's primary complaint about the child is inattention, hyperactivity, and/or impulsivity (ADHD symptoms) * Symptoms present for 6 months prior to study entry * Psychotropic drug-free for at least 2 weeks prior to starting study medication. This drug-free period will be 5 weeks for fluoxetine (Prozac).

Exclusion criteria

* Weighs less than 15 kg (about 33 pounds) * Any another psychiatric disorder that may require a different treatment, including psychotic disorders, major affective disorders, obsessive-compulsive disorder, panic disorder, or substance-related disorders * Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) diagnosis of Rett's disorder or childhood disintegrative disorder * Presence of extreme aggression or self-injury * Currently taking an effective psychotropic drug * Currently using other medications that may be unsafe to take with atomoxetine (e.g., potent CYP 2D6 inhibitors, intravenous albuterol, monoamine oxidase inhibitors\[MAO\]) * Inability to swallow study medication * Presence of a medical condition that would make treatment with atomoxetine unsafe (e.g., unstable hypertension or cardiac disease, asthma requiring frequent treatment with albuterol, narrow angle glaucoma, pregnancy, etc.) * Mental age of less than 18 months * Previous adequate trial of atomoxetine * Previous evidence of hypersensitivity or an allergic reaction to atomoxetine * Clinically significant abnormalities in laboratory measures indicating an undiagnosed medical condition as determined by the study physician in discussion with the participant's primary care physician * Clinically significant abnormalities on ECG as determined by a pediatric cardiologist * Pregnant * Initiation of a new psychosocial intervention within 90 days prior to starting study medication. Participants who have recently had a significant change in their psychosocial interventions will not be eligible until this intervention has been stable for 90 days in order to avoid confounding results of the study. Stable interventions (e.g., speech and occupational therapy) will be allowed to continue during the course of the study. Minor changes in ongoing treatment (e.g., missed therapy sessions due to holiday/vacation planned break in therapy due to school holidays) will not be considered significant.

Design outcomes

Primary

Measure	Time frame	Description
ADHD Rating Scale (ADHDRS)-Home Version Total Score (Randomized Phase)	8 weeks	The ADHD Rating Scale (ADHD-RS) is an 18-item scale directly derived from DSM-IV criteria for Attention Deficit Hyperactivity Disorder with established reliability, validity and sensitivity to change. The ADHD-RS-IV is investigator-administered biweekly during the 8-week double-blind, placebo-controlled phase of the study. The scale consists of 2 subscales: inattention (9 items) and hyperactivity-impulsivity (9 items). If 3 or more items are skipped, the clinician should use extreme caution in interpreting the scale. Results from this rating scale alone should not be used to make a diagnosis. The total score can range form 0 to 54, with a higher score indicating greater severity. Estimates are adjusted for baseline score, study stratum, and site, which were set at their sample means.

Secondary

Measure	Time frame	Description
Aberrant Behavior Checklist (ABC) (Randomized Phase)	8 weeks	The Aberrant Behavior Checklist (ABC) is a 58-item questionnaire with 5 subscales derived by factor analysis: Irritability, Social Withdrawal, Stereotypy, Hyperactivity, and Inappropriate. It has been extensively used in psychopharmacological studies of autism and assesses many symptoms that are either central to autism (Social Withdrawal, Stereotypy, and Inappropriate Speech) or frequently a target of treatment (Irritability). Each item of the 58-item scale is scored on a 4-point scale (0=never a problem to 3=severe problem). The interpretation of the tool and its sub-scales is that a greater number of items, indicates greater severity. The range of scores per subscale are: Social Withdrawal/Lethargy 0-48; Stereotypy 0-21; Irritability 0-45; Hyperactivity 0-48; Inappropriate Speech 0-12. Parent ratings occur every 2 weeks during the study. Estimates are adjusted for baseline score, study stratum, and site, which were set at their sample means.
Social Responsiveness Scale (SRS) (Randomized Phase)	8 weeks	The Social Responsiveness Scale (SRS) is completed by the parent in order to assess whether additional improvements in social functioning occur with atomoxetine, as observed in our pilot study. This 65-item questionnaire will be completed at baseline and at the end of 8 weeks. The SRS is a standardized measure of the core symptoms of autism. Each item is scored on a 4-point Likert scale. The score of each item is summed to create a total score. Total score results as follows: 0-62: within normal limits; 63-79 mild range of impairment; 80-108: moderate range of impairment; 109-149: severe range of impairment. Estimates are adjusted for baseline score, study stratum, and site, which were set at their sample means.
Vineland Adaptive Behavior Scales (VABS) Composite Score (Randomized Phase)	8 weeks	The Vineland Adaptive Behavior Scales, Second Edition (VABS) is used to assess adaptive functioning in four domains: Communication, Daily Living Skills, Socialization, and Motor Skills. This is a well-standardized open-ended interview used to assess the overall functioning of children and adults. This measure is especially important for subjects with PDDs given that their intellectual level is not always comparable to their adaptive functioning. The Vineland Maladaptive Behavior subscales will be included with these measures as these have been shown to be responsive to drug effects in other clinical trials in this population. The VABS will be done at baseline and at the end of 8 weeks. The composite score represents a standard score (mean = 100 and standard deviation of 15; range = 20-160) on which higher scores indicate a higher level of adaptive functioning. Estimates are adjusted for baseline score, study stratum, and site, which were set at their sample means.
Pediatric Quality of Life Inventory (Randomized Phase)	8 weeks	Quality of life is assessed with the Pediatric Quality of Life Inventory (PedsQL 4.0). This instrument is well-validated and widely used for measuring health-related quality of life in children and adolescents. It also appears to be a valid instrument for use with children with psychiatric disorders. The Generic Core scales include 23 items. The health related and family functioning scores range from 0 to 100, with higher scores indicating better quality of life. The Family Impact module will be included to assess any change in family functioning. This will be completed at baseline and at the end of 8 weeks. Estimates are adjusted for baseline score, study stratum, and site, which were set at their sample means.
Pediatric Anxiety Rating Scale, 5-Item Total (Randomized Phase)	8 weeks	Since the ABC does not have items which directly assess anxiety, the Pediatric Anxiety Rating Scale (PARS) is administered at week 8 during the study as an exploratory measure. The PARS is a clinician-rated instrument that assesses anxiety symptoms that are commonly associated with social anxiety, separation anxiety, and generalized anxiety disorders. Scaled score ranges form 0-25 with higher scores indicating more severe anxiety symptoms. Estimates are adjusted for baseline score, study stratum, and site, which were set at their sample means.
Odds of Clinical Global Impression-Improvement Scale, Very Much or Much Improved (1 or 2) (Randomized Phase)	8 weeks	The Clinical Global Impressions 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 (1=very much improved; 2= much improved; 3=minimally improved; 4=no change; 5=minimally worse; 6=much worse; 7=very much worse), with lower scores indicating improvement (1=very much improved and 2=much improved). Participants with a CGI-I score of 1 or 2 were classified as improved. Odds of improvement at 8 weeks were estimated using a repeated measures logistic regression model adjusting for baseline severity, study stratum, and site. The CGI-I was administered biweekly during the study. The CGI was focused on the target symptoms of inattention, hyperactivity, and impulsivity.
ADHD Rating Scale (ADHDRS)-Home Version Inattention and Hyperactivity Scores (Randomized Phase)	8 weeks	The ADHD Rating Scale (ADHD-RS) is an 18-item scale directly derived from DSM-IV criteria for Attention Deficit Hyperactivity Disorder with established reliability, validity and sensitivity to change. The ADHD-RS-IV is investigator-administered biweekly during the 8-week double-blind, placebo-controlled phase of the study. The scale consists of 2 subscales: inattention (9 items) and hyperactivity-impulsivity (9 items). If 3 or more items are skipped, the clinician should use extreme caution in interpreting the scale. Results from this rating scale alone should not be used to make a diagnosis. The score for each subscale ranges from 0-27 with a higher score indicating greater severity. Estimates are adjusted for baseline score, study stratum, and site, which were set at their sample means.
Change in ADHD Rating Scale (ADHDRS)-Home Version Inattention and Hyperactivity Scores (Open-label Trial)	8 weeks	The ADHD Rating Scale (ADHD-RS) is an 18-item scale directly derived from DSM-IV criteria for Attention Deficit Hyperactivity Disorder with established reliability, validity and sensitivity to change. The ADHD-RS-IV is investigator-administered biweekly during the 8-week open-label phase of the study. The scale consists of 2 subscales: inattention (9 items) and hyperactivity-impulsivity (9 items). If 3 or more items are skipped, the clinician should use extreme caution in interpreting the scale. Results from this rating scale alone should not be used to make a diagnosis. The score fro each subscale ranges from 0-27, with a higher score indicating greater severity. Change will be determined from the start of the open-label trial to 8 weeks post-start.
Change in Aberrant Behavior Checklist (ABC) (Open-label Trial)	8 weeks	The Aberrant Behavior Checklist (ABC) is a 58-item questionnaire with 5 subscales derived by factor analysis: Irritability, Social Withdrawal, Stereotypy, Hyperactivity, and Inappropriate. It has been extensively used in psychopharmacological studies of autism and assesses many symptoms that are either central to autism (Social Withdrawal, Stereotypy, and Inappropriate Speech) or frequently a target of treatment Irritability). Each item of the 58-item scale is scored on a 4-point scale (0=never a problem to 3=severe problem). The interpretation of the tool and its sub-scales is that a greater number of items, indicates greater severity. The range of scores per subscale are: Social Withdrawal/Lethargy 0-48; Stereotypy 0-21; Irritability 0-45; Hyperactivity 0-48; Inappropriate Speech 0-12. Parent ratings occur every 2 weeks during the study. Change will be determined from the start of the open-label trial to 8 weeks post-start.
Change in Social Responsiveness Scale (SRS) (Open-label Trial)	8 weeks	The Social Responsiveness Scale (SRS) is completed by the parent in order to assess whether additional improvements in social functioning occur with atomoxetine, as observed in our pilot study. This 65-item questionnaire will be completed at baseline and at the end of 8 weeks. The SRS is a standardized measure of the core symptoms of autism. Each item is scored on a 4-point Likert scale. The score of each item is summed to create a total score. Total score results as follows: 0-62: within normal limits; 63-79 mild range of impairment; 80-108: moderate range of impairment; 109-149: severe range of impairment. This 65-item questionnaire will be completed at the start of and at the end of 8 weeks of the open-label trial.
Change in Vineland Adaptive Behavior Scales (VABS) Composite Score (Open-label Trial)	8 weeks	The Vineland Adaptive Behavior Scales, Second Edition (VABS) is used to assess adaptive functioning in four domains: Communication, Daily Living Skills, Socialization, and Motor Skills. This is a well-standardized open-ended interview used to assess the overall functioning of children and adults. This measure is especially important for subjects with PDDs given that their intellectual level is not always comparable to their adaptive functioning. The Vineland Maladaptive Behavior subscales will be included with these measures as these have been shown to be responsive to drug effects in other clinical trials in this population. The composite score represents a standard score (mean = 100 and standard deviation of 15; range = 20-160) on which higher scores indicate a higher level of adaptive functioning. Change will be determined from the start of the open-label phase to 8 weeks
Change in Pediatric Quality of Life Inventory (Open-label Trial)	8 weeks	Quality of life is assessed with the Pediatric Quality of Life Inventory (PedsQL 4.0). This instrument is well-validated and widely used for measuring health-related quality of life in children and adolescents. It also appears to be a valid instrument for use with children with psychiatric disorders. The Generic Core scales include 23 items. The health related and family functioning scores range from 0 to 100, with higher scores indicating better quality of life. The Family Impact module will be included to assess any change in family functioning. This will be completed at the start of the open-label trial and at the end of 8 weeks. Change will be determined from the start of the open-label trial to 8 weeks post-start.
Change in Pediatric Anxiety Rating Scale, 5-item Total (Open-label Trial)	8 weeks	Since the ABC does not have items which directly assess anxiety, the Pediatric Anxiety Rating Scale (PARS) is administered at week 8 during the study as an exploratory measure. The PARS is a clinician-rated instrument that assesses anxiety symptoms that are commonly associated with social anxiety, separation anxiety, and generalized anxiety disorders. Scaled score ranges form 0-25 with higher scores indicating more severe anxiety symptoms.Change will be determined from the start of the open-label trial to 8 weeks post-start.
Change in ADHD Rating Scale (ADHDRS)-Home Version Total Score (Open-label Trial)	8 weeks	The ADHD Rating Scale (ADHD-RS) is an 18-item scale directly derived from DSM-IV criteria for Attention Deficit Hyperactivity Disorder with established reliability, validity and sensitivity to change. The ADHD-RS-IV is investigator-administered biweekly during the 8-week double-blind, placebo-controlled phase of the study. The scale consists of 2 subscales: inattention (9 items) and hyperactivity-impulsivity (9 items). If 3 or more items are skipped, the clinician should use extreme caution in interpreting the scale. Results from this rating scale alone should not be used to make a diagnosis. The total score can range form 0 to 54, with a higher score indicating greater severity. Change will be determined from the start of the open-label trial to 8 weeks post-start.

Countries

United States

Participant flow

Participants by arm

Arm	Count
Atomoxetine Participants will receive flexibly dosed atomoxetine for 8 weeks. Dosage can be increased over the first 4 weeks of study participation and will then be held constant for the remainder of the 8-week trial. Atomoxetine: Available tablet strengths of atomoxetine: 5 mg, 10 mg, 25 mg, 40 mg. Week 1 participant takes 0.5 mg/kg/day, Week 2: 0.8 mg/kg/day, Week 3: 1.2 mg/kg/day. Potential exists for dose increase at Week 4 to 1.8 mg/kg/day based on clinical global impression-improvement rating at Week 4.	29
Placebo Participants will receive blinded, matched placebo for 8 weeks. Dosage can be increased over the first 4 weeks of study participation and will then be held constant for the remainder of the 8-week trial. Placebo: Placebo tablets dosages: 5 mg, 10 mg, 25 mg, 40 mg.	31
Total	60

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002
Phase 1-Blinded Randomization (8 weeks)	no post-baseline ratings	2	1	0

Baseline characteristics

Characteristic	Atomoxetine	Total	Placebo
Aberrant Behavior Checklist, Hyperactivity	29.1 units on a scale STANDARD_DEVIATION 11.8	30.5 units on a scale STANDARD_DEVIATION 10.9	31.7 units on a scale STANDARD_DEVIATION 10
Age, Continuous	9.3 years STANDARD_DEVIATION 2.6	8.8 years STANDARD_DEVIATION 2.4	8.4 years STANDARD_DEVIATION 2.1
Attending Public School	24 Participants	51 Participants	27 Participants
Attention Deficit Hyperactivity Disorder (ADHD) Rating Scale Total	37.2 units on a scale STANDARD_DEVIATION 7.6	39.4 units on a scale STANDARD_DEVIATION 7	41.5 units on a scale STANDARD_DEVIATION 5.8
Clinical Global Impression-Severity Marked	13 Participants	25 Participants	12 Participants
Clinical Global Impression-Severity Moderate	16 Participants	33 Participants	17 Participants
Clinical Global Impression-Severity Severe	0 Participants	2 Participants	2 Participants
Concomitant Medication Use	22 Participants	42 Participants	20 Participants
DSM-IV Diagnosis Asperger's Disorder	5 Participants	14 Participants	9 Participants
DSM-IV Diagnosis Autistic Disorder	14 Participants	23 Participants	9 Participants
DSM-IV Diagnosis Pervasive Developmental Disorder (PDD-NOS)	10 Participants	23 Participants	13 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	2 Participants	4 Participants	2 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	26 Participants	54 Participants	28 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	1 Participants	2 Participants	1 Participants
Indiana University School of Medicine Site	25 Participants	52 Participants	27 Participants
IQ	74.7 units on a scale STANDARD_DEVIATION 18.5	79.8 units on a scale STANDARD_DEVIATION 17.4	84.4 units on a scale STANDARD_DEVIATION 15.2
Pediatric Anxiety Rating Scale, 5-Item Total	8.5 units on a scale STANDARD_DEVIATION 6.5	8.7 units on a scale STANDARD_DEVIATION 6.2	8.9 units on a scale STANDARD_DEVIATION 6
Pediatric Quality of Life Inventory Family Functioning	52.4 units on a scale STANDARD_DEVIATION 24.2	52.7 units on a scale STANDARD_DEVIATION 23.6	53.1 units on a scale STANDARD_DEVIATION 23.4
Pediatric Quality of Life Inventory Health Related Functioning	56.3 units on a scale STANDARD_DEVIATION 18.8	58.5 units on a scale STANDARD_DEVIATION 19.2	60.5 units on a scale STANDARD_DEVIATION 19.6
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	5 Participants	5 Participants	0 Participants
Race (NIH/OMB) More than one race	0 Participants	1 Participants	1 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	2 Participants	2 Participants	0 Participants
Race (NIH/OMB) White	22 Participants	52 Participants	30 Participants
Region of Enrollment United States	29 participants	60 participants	31 participants
Sex: Female, Male Female	3 Participants	6 Participants	3 Participants
Sex: Female, Male Male	26 Participants	54 Participants	28 Participants
Social Responsiveness Scale	84.5 units on a scale STANDARD_DEVIATION 9.9	84.5 units on a scale STANDARD_DEVIATION 10	84.4 units on a scale STANDARD_DEVIATION 10.3
Tanner Stage 3 or Greater	3 Participants	4 Participants	1 Participants
Vineland Adaptive Behavior Composite Score	73.1 units on a scale STANDARD_DEVIATION 12.5	72.8 units on a scale STANDARD_DEVIATION 10.6	72.5 units on a scale STANDARD_DEVIATION 8.7

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —
other Total, other adverse events	27 / 29	28 / 31	26 / 26
serious Total, serious adverse events	0 / 29	0 / 31	0 / 26

Outcome results

Primary

ADHD Rating Scale (ADHDRS)-Home Version Total Score (Randomized Phase)

The ADHD Rating Scale (ADHD-RS) is an 18-item scale directly derived from DSM-IV criteria for Attention Deficit Hyperactivity Disorder with established reliability, validity and sensitivity to change. The ADHD-RS-IV is investigator-administered biweekly during the 8-week double-blind, placebo-controlled phase of the study. The scale consists of 2 subscales: inattention (9 items) and hyperactivity-impulsivity (9 items). If 3 or more items are skipped, the clinician should use extreme caution in interpreting the scale. Results from this rating scale alone should not be used to make a diagnosis. The total score can range form 0 to 54, with a higher score indicating greater severity. Estimates are adjusted for baseline score, study stratum, and site, which were set at their sample means.

Time frame: 8 weeks

Population: Two participants from the Atomoxetine arm, and one participant from the Placebo arm did not have post-baseline measures.

Arm	Measure	Value (MEAN)
Atomoxetine	ADHD Rating Scale (ADHDRS)-Home Version Total Score (Randomized Phase)	28.7 units on a scale
Placebo	ADHD Rating Scale (ADHDRS)-Home Version Total Score (Randomized Phase)	34.0 units on a scale

Secondary

Aberrant Behavior Checklist (ABC) (Randomized Phase)

The Aberrant Behavior Checklist (ABC) is a 58-item questionnaire with 5 subscales derived by factor analysis: Irritability, Social Withdrawal, Stereotypy, Hyperactivity, and Inappropriate. It has been extensively used in psychopharmacological studies of autism and assesses many symptoms that are either central to autism (Social Withdrawal, Stereotypy, and Inappropriate Speech) or frequently a target of treatment (Irritability). Each item of the 58-item scale is scored on a 4-point scale (0=never a problem to 3=severe problem). The interpretation of the tool and its sub-scales is that a greater number of items, indicates greater severity. The range of scores per subscale are: Social Withdrawal/Lethargy 0-48; Stereotypy 0-21; Irritability 0-45; Hyperactivity 0-48; Inappropriate Speech 0-12. Parent ratings occur every 2 weeks during the study. Estimates are adjusted for baseline score, study stratum, and site, which were set at their sample means.

Time frame: 8 weeks

Population: Two participants from the Atomoxetine arm, and one participant from the Placebo arm did not have post-baseline measures.

Arm	Measure	Group	Value (MEAN)
Atomoxetine	Aberrant Behavior Checklist (ABC) (Randomized Phase)	Lethargy	7.2 units on a scale
Atomoxetine	Aberrant Behavior Checklist (ABC) (Randomized Phase)	Hyperactivity	24.2 units on a scale
Atomoxetine	Aberrant Behavior Checklist (ABC) (Randomized Phase)	Stereotypy	4.7 units on a scale
Atomoxetine	Aberrant Behavior Checklist (ABC) (Randomized Phase)	Inappropriate Speech	4.4 units on a scale
Atomoxetine	Aberrant Behavior Checklist (ABC) (Randomized Phase)	Irritability	15.6 units on a scale
Placebo	Aberrant Behavior Checklist (ABC) (Randomized Phase)	Inappropriate Speech	5.6 units on a scale
Placebo	Aberrant Behavior Checklist (ABC) (Randomized Phase)	Irritability	13.8 units on a scale
Placebo	Aberrant Behavior Checklist (ABC) (Randomized Phase)	Lethargy	8.3 units on a scale
Placebo	Aberrant Behavior Checklist (ABC) (Randomized Phase)	Stereotypy	5.2 units on a scale
Placebo	Aberrant Behavior Checklist (ABC) (Randomized Phase)	Hyperactivity	28.2 units on a scale

Secondary

ADHD Rating Scale (ADHDRS)-Home Version Inattention and Hyperactivity Scores (Randomized Phase)

The ADHD Rating Scale (ADHD-RS) is an 18-item scale directly derived from DSM-IV criteria for Attention Deficit Hyperactivity Disorder with established reliability, validity and sensitivity to change. The ADHD-RS-IV is investigator-administered biweekly during the 8-week double-blind, placebo-controlled phase of the study. The scale consists of 2 subscales: inattention (9 items) and hyperactivity-impulsivity (9 items). If 3 or more items are skipped, the clinician should use extreme caution in interpreting the scale. Results from this rating scale alone should not be used to make a diagnosis. The score for each subscale ranges from 0-27 with a higher score indicating greater severity. Estimates are adjusted for baseline score, study stratum, and site, which were set at their sample means.

Time frame: 8 weeks

Population: Two participants from the Atomoxetine arm, and one participant from the Placebo arm did not have post-baseline measures.

Arm	Measure	Group	Value (MEAN)
Atomoxetine	ADHD Rating Scale (ADHDRS)-Home Version Inattention and Hyperactivity Scores (Randomized Phase)	Inattention	14.7 units on a scale
Atomoxetine	ADHD Rating Scale (ADHDRS)-Home Version Inattention and Hyperactivity Scores (Randomized Phase)	Hyperactivity	13.7 units on a scale
Placebo	ADHD Rating Scale (ADHDRS)-Home Version Inattention and Hyperactivity Scores (Randomized Phase)	Inattention	17.3 units on a scale
Placebo	ADHD Rating Scale (ADHDRS)-Home Version Inattention and Hyperactivity Scores (Randomized Phase)	Hyperactivity	16.8 units on a scale

Secondary

Change in Aberrant Behavior Checklist (ABC) (Open-label Trial)

The Aberrant Behavior Checklist (ABC) is a 58-item questionnaire with 5 subscales derived by factor analysis: Irritability, Social Withdrawal, Stereotypy, Hyperactivity, and Inappropriate. It has been extensively used in psychopharmacological studies of autism and assesses many symptoms that are either central to autism (Social Withdrawal, Stereotypy, and Inappropriate Speech) or frequently a target of treatment Irritability). Each item of the 58-item scale is scored on a 4-point scale (0=never a problem to 3=severe problem). The interpretation of the tool and its sub-scales is that a greater number of items, indicates greater severity. The range of scores per subscale are: Social Withdrawal/Lethargy 0-48; Stereotypy 0-21; Irritability 0-45; Hyperactivity 0-48; Inappropriate Speech 0-12. Parent ratings occur every 2 weeks during the study. Change will be determined from the start of the open-label trial to 8 weeks post-start.

Time frame: 8 weeks

Population: Placebo-treated subjects that don't respond to placebo will be offered an 8-week open-label trial of atomoxetine, and the open-label extension will be a continuation phase for those subjects that respond to 8 weeks of atomoxetine during the double-blind phase.

Arm	Measure	Group	Value (MEAN)
Atomoxetine	Change in Aberrant Behavior Checklist (ABC) (Open-label Trial)	Irritability	-4.5 units on a scale
Atomoxetine	Change in Aberrant Behavior Checklist (ABC) (Open-label Trial)	Lethargy	-4.0 units on a scale
Atomoxetine	Change in Aberrant Behavior Checklist (ABC) (Open-label Trial)	Stereotypy	-2.3 units on a scale
Atomoxetine	Change in Aberrant Behavior Checklist (ABC) (Open-label Trial)	Hyperactivity	-11.5 units on a scale
Atomoxetine	Change in Aberrant Behavior Checklist (ABC) (Open-label Trial)	Inappropriate Speech	-1.7 units on a scale

Secondary

Change in ADHD Rating Scale (ADHDRS)-Home Version Inattention and Hyperactivity Scores (Open-label Trial)

The ADHD Rating Scale (ADHD-RS) is an 18-item scale directly derived from DSM-IV criteria for Attention Deficit Hyperactivity Disorder with established reliability, validity and sensitivity to change. The ADHD-RS-IV is investigator-administered biweekly during the 8-week open-label phase of the study. The scale consists of 2 subscales: inattention (9 items) and hyperactivity-impulsivity (9 items). If 3 or more items are skipped, the clinician should use extreme caution in interpreting the scale. Results from this rating scale alone should not be used to make a diagnosis. The score fro each subscale ranges from 0-27, with a higher score indicating greater severity. Change will be determined from the start of the open-label trial to 8 weeks post-start.

Time frame: 8 weeks