Trial Outcomes & Findings for Effectiveness of Atomoxetine in Treating ADHD Symptoms in Children and Adolescents With Autism (NCT NCT00498173)

NCT ID: NCT00498173

Last Updated: 2025-11-14

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

60 participants

Primary outcome timeframe

8 weeks

Results posted on

2025-11-14

Participant Flow

Participant milestones

Participant milestones
Measure
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.
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.
Atomoxetine (Open Label Trial)
Placebo-treated subjects from the randomized trial that don't respond to placebo will be offered an 8-week open-label trial of atomoxetine.
Phase 1-Blinded Randomization (8 weeks)
STARTED
29
31
0
Phase 1-Blinded Randomization (8 weeks)
COMPLETED
27
30
0
Phase 1-Blinded Randomization (8 weeks)
NOT COMPLETED
2
1
0
Phase 2-Atomoxetine Open Label (8 weeks)
STARTED
0
0
26
Phase 2-Atomoxetine Open Label (8 weeks)
COMPLETED
0
0
26
Phase 2-Atomoxetine Open Label (8 weeks)
NOT COMPLETED
0
0
0

Reasons for withdrawal

Reasons for withdrawal
Measure
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.
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.
Atomoxetine (Open Label Trial)
Placebo-treated subjects from the randomized trial that don't respond to placebo will be offered an 8-week open-label trial of atomoxetine.
Phase 1-Blinded Randomization (8 weeks)
no post-baseline ratings
2
1
0

Baseline Characteristics

IQ scores were not obtained for 2 children assigned to atomoxetine and 1 child assigned to placebo.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure
Atomoxetine
n=29 Participants
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.
Placebo
n=31 Participants
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.
Total
n=60 Participants
Total of all reporting groups
Age, Continuous
9.3 years
STANDARD_DEVIATION 2.6 • n=29 Participants
8.4 years
STANDARD_DEVIATION 2.1 • n=31 Participants
8.8 years
STANDARD_DEVIATION 2.4 • n=60 Participants
Sex: Female, Male
Female
3 Participants
n=29 Participants
3 Participants
n=31 Participants
6 Participants
n=60 Participants
Sex: Female, Male
Male
26 Participants
n=29 Participants
28 Participants
n=31 Participants
54 Participants
n=60 Participants
Ethnicity (NIH/OMB)
Hispanic or Latino
2 Participants
n=29 Participants
2 Participants
n=31 Participants
4 Participants
n=60 Participants
Ethnicity (NIH/OMB)
Not Hispanic or Latino
26 Participants
n=29 Participants
28 Participants
n=31 Participants
54 Participants
n=60 Participants
Ethnicity (NIH/OMB)
Unknown or Not Reported
1 Participants
n=29 Participants
1 Participants
n=31 Participants
2 Participants
n=60 Participants
Race (NIH/OMB)
American Indian or Alaska Native
0 Participants
n=29 Participants
0 Participants
n=31 Participants
0 Participants
n=60 Participants
Race (NIH/OMB)
Asian
0 Participants
n=29 Participants
0 Participants
n=31 Participants
0 Participants
n=60 Participants
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
0 Participants
n=29 Participants
0 Participants
n=31 Participants
0 Participants
n=60 Participants
Race (NIH/OMB)
Black or African American
5 Participants
n=29 Participants
0 Participants
n=31 Participants
5 Participants
n=60 Participants
Race (NIH/OMB)
White
22 Participants
n=29 Participants
30 Participants
n=31 Participants
52 Participants
n=60 Participants
Race (NIH/OMB)
More than one race
0 Participants
n=29 Participants
1 Participants
n=31 Participants
1 Participants
n=60 Participants
Race (NIH/OMB)
Unknown or Not Reported
2 Participants
n=29 Participants
0 Participants
n=31 Participants
2 Participants
n=60 Participants
Region of Enrollment
United States
29 participants
n=29 Participants
31 participants
n=31 Participants
60 participants
n=60 Participants
Attending Public School
24 Participants
n=29 Participants
27 Participants
n=31 Participants
51 Participants
n=60 Participants
Indiana University School of Medicine Site
25 Participants
n=29 Participants
27 Participants
n=31 Participants
52 Participants
n=60 Participants
Tanner Stage 3 or Greater
3 Participants
n=29 Participants
1 Participants
n=31 Participants
4 Participants
n=60 Participants
DSM-IV Diagnosis
Autistic Disorder
14 Participants
n=29 Participants
9 Participants
n=31 Participants
23 Participants
n=60 Participants
DSM-IV Diagnosis
Asperger's Disorder
5 Participants
n=29 Participants
9 Participants
n=31 Participants
14 Participants
n=60 Participants
DSM-IV Diagnosis
Pervasive Developmental Disorder (PDD-NOS)
10 Participants
n=29 Participants
13 Participants
n=31 Participants
23 Participants
n=60 Participants
Concomitant Medication Use
22 Participants
n=29 Participants
20 Participants
n=31 Participants
42 Participants
n=60 Participants
IQ
74.7 units on a scale
STANDARD_DEVIATION 18.5 • n=27 Participants • IQ scores were not obtained for 2 children assigned to atomoxetine and 1 child assigned to placebo.
84.4 units on a scale
STANDARD_DEVIATION 15.2 • n=30 Participants • IQ scores were not obtained for 2 children assigned to atomoxetine and 1 child assigned to placebo.
79.8 units on a scale
STANDARD_DEVIATION 17.4 • n=57 Participants • IQ scores were not obtained for 2 children assigned to atomoxetine and 1 child assigned to placebo.
Clinical Global Impression-Severity
Moderate
16 Participants
n=29 Participants
17 Participants
n=31 Participants
33 Participants
n=60 Participants
Clinical Global Impression-Severity
Marked
13 Participants
n=29 Participants
12 Participants
n=31 Participants
25 Participants
n=60 Participants
Clinical Global Impression-Severity
Severe
0 Participants
n=29 Participants
2 Participants
n=31 Participants
2 Participants
n=60 Participants
Attention Deficit Hyperactivity Disorder (ADHD) Rating Scale Total
37.2 units on a scale
STANDARD_DEVIATION 7.6 • n=29 Participants
41.5 units on a scale
STANDARD_DEVIATION 5.8 • n=31 Participants
39.4 units on a scale
STANDARD_DEVIATION 7.0 • n=60 Participants
Aberrant Behavior Checklist, Hyperactivity
29.1 units on a scale
STANDARD_DEVIATION 11.8 • n=29 Participants
31.7 units on a scale
STANDARD_DEVIATION 10.0 • n=31 Participants
30.5 units on a scale
STANDARD_DEVIATION 10.9 • n=60 Participants
Social Responsiveness Scale
84.5 units on a scale
STANDARD_DEVIATION 9.9 • n=29 Participants
84.4 units on a scale
STANDARD_DEVIATION 10.3 • n=31 Participants
84.5 units on a scale
STANDARD_DEVIATION 10.0 • n=60 Participants
Vineland Adaptive Behavior Composite Score
73.1 units on a scale
STANDARD_DEVIATION 12.5 • n=29 Participants
72.5 units on a scale
STANDARD_DEVIATION 8.7 • n=31 Participants
72.8 units on a scale
STANDARD_DEVIATION 10.6 • n=60 Participants
Pediatric Quality of Life Inventory Health Related Functioning
56.3 units on a scale
STANDARD_DEVIATION 18.8 • n=29 Participants
60.5 units on a scale
STANDARD_DEVIATION 19.6 • n=31 Participants
58.5 units on a scale
STANDARD_DEVIATION 19.2 • n=60 Participants
Pediatric Quality of Life Inventory Family Functioning
52.4 units on a scale
STANDARD_DEVIATION 24.2 • n=29 Participants
53.1 units on a scale
STANDARD_DEVIATION 23.4 • n=31 Participants
52.7 units on a scale
STANDARD_DEVIATION 23.6 • n=60 Participants
Pediatric Anxiety Rating Scale, 5-Item Total
8.5 units on a scale
STANDARD_DEVIATION 6.5 • n=29 Participants
8.9 units on a scale
STANDARD_DEVIATION 6.0 • n=31 Participants
8.7 units on a scale
STANDARD_DEVIATION 6.2 • n=60 Participants

PRIMARY outcome

Timeframe: 8 weeks

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

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.

Outcome measures

Outcome measures
Measure
Atomoxetine
n=27 Participants
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.
Placebo
n=30 Participants
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.
ADHD Rating Scale (ADHDRS)-Home Version Total Score (Randomized Phase)
28.7 units on a scale
Interval 24.3 to 33.0
34.0 units on a scale
Interval 30.0 to 38.0

SECONDARY outcome

Timeframe: 8 weeks

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

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.

Outcome measures

Outcome measures
Measure
Atomoxetine
n=27 Participants
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.
Placebo
n=30 Participants
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.
ADHD Rating Scale (ADHDRS)-Home Version Inattention and Hyperactivity Scores (Randomized Phase)
Hyperactivity
13.7 units on a scale
Interval 11.4 to 16.0
16.8 units on a scale
Interval 14.7 to 19.0
ADHD Rating Scale (ADHDRS)-Home Version Inattention and Hyperactivity Scores (Randomized Phase)
Inattention
14.7 units on a scale
Interval 12.4 to 17.0
17.3 units on a scale
Interval 15.2 to 19.4

SECONDARY outcome

Timeframe: 8 weeks

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

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.

Outcome measures

Outcome measures
Measure
Atomoxetine
n=27 Participants
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.
Placebo
n=30 Participants
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.
Aberrant Behavior Checklist (ABC) (Randomized Phase)
Lethargy
7.2 units on a scale
Interval 5.1 to 9.3
8.3 units on a scale
Interval 6.3 to 10.2
Aberrant Behavior Checklist (ABC) (Randomized Phase)
Hyperactivity
24.2 units on a scale
Interval 20.5 to 27.9
28.2 units on a scale
Interval 24.7 to 31.7
Aberrant Behavior Checklist (ABC) (Randomized Phase)
Inappropriate Speech
4.4 units on a scale
Interval 3.5 to 5.4
5.6 units on a scale
Interval 4.7 to 6.5
Aberrant Behavior Checklist (ABC) (Randomized Phase)
Irritability
15.6 units on a scale
Interval 12.9 to 18.3
13.8 units on a scale
Interval 11.3 to 16.3
Aberrant Behavior Checklist (ABC) (Randomized Phase)
Stereotypy
4.7 units on a scale
Interval 3.1 to 6.3
5.2 units on a scale
Interval 3.7 to 6.6

SECONDARY outcome

Timeframe: 8 weeks

Population: Four participants from the Atomoxetine arm, and two participants from the Placebo arm did not have post-baseline measures.

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.

Outcome measures

Outcome measures
Measure
Atomoxetine
n=25 Participants
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.
Placebo
n=29 Participants
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.
Social Responsiveness Scale (SRS) (Randomized Phase)
83.0 units on a scale
Interval 79.9 to 86.0
82.0 units on a scale
Interval 79.2 to 84.8

SECONDARY outcome

Timeframe: 8 weeks

Population: Four participants from the Atomoxetine arm, and two participants from the Placebo arm did not have post-baseline measures.

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.

Outcome measures

Outcome measures
Measure
Atomoxetine
n=25 Participants
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.
Placebo
n=29 Participants
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.
Vineland Adaptive Behavior Scales (VABS) Composite Score (Randomized Phase)
73.4 units on a scale
Interval 70.8 to 76.0
74.9 units on a scale
Interval 72.5 to 77.2

SECONDARY outcome

Timeframe: 8 weeks

Population: Four participants from the Atomoxetine arm, and two participants from the Placebo arm did not have post-baseline measures.

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.

Outcome measures

Outcome measures
Measure
Atomoxetine
n=25 Participants
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.
Placebo
n=29 Participants
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.
Pediatric Quality of Life Inventory (Randomized Phase)
Health
64.2 units on a scale
Interval 57.5 to 70.9
62.2 units on a scale
Interval 56.0 to 68.4
Pediatric Quality of Life Inventory (Randomized Phase)
Family
55.2 units on a scale
Interval 47.3 to 63.0
53.0 units on a scale
Interval 45.7 to 60.2

SECONDARY outcome

Timeframe: 8 weeks

Population: Four participants from the Atomoxetine arm, and two participants from the Placebo arm did not have post-baseline measures.

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.

Outcome measures

Outcome measures
Measure
Atomoxetine
n=25 Participants
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.
Placebo
n=29 Participants
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.
Pediatric Anxiety Rating Scale, 5-Item Total (Randomized Phase)
7.3 units on a scale
Interval 5.6 to 9.1
8.5 units on a scale
Interval 6.8 to 10.1

SECONDARY outcome

Timeframe: 8 weeks

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

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.

Outcome measures

Outcome measures
Measure
Atomoxetine
n=27 Participants
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.
Placebo
n=30 Participants
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.
Odds of Clinical Global Impression-Improvement Scale, Very Much or Much Improved (1 or 2) (Randomized Phase)
0.53 odds of improvement
Interval 0.22 to 1.26
0.11 odds of improvement
Interval 0.04 to 0.35

SECONDARY outcome

Timeframe: 8 weeks

Population: 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

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.

Outcome measures

Outcome measures
Measure
Atomoxetine
n=26 Participants
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.
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.
Change in ADHD Rating Scale (ADHDRS)-Home Version Total Score (Open-label Trial)
-15.4 units on a scale
Interval -19.9 to -11.0

SECONDARY outcome

Timeframe: 8 weeks

Population: 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

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.

Outcome measures

Outcome measures
Measure
Atomoxetine
n=26 Participants
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.
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.
Change in ADHD Rating Scale (ADHDRS)-Home Version Inattention and Hyperactivity Scores (Open-label Trial)
Inattention
-8.1 units on a scale
Interval -10.4 to -5.7
Change in ADHD Rating Scale (ADHDRS)-Home Version Inattention and Hyperactivity Scores (Open-label Trial)
Hyperactivity
-7.3 units on a scale
Interval -9.7 to -5.0

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure
Atomoxetine
n=26 Participants
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.
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.
Change in Aberrant Behavior Checklist (ABC) (Open-label Trial)
Irritability
-4.5 units on a scale
Interval -7.1 to -1.8
Change in Aberrant Behavior Checklist (ABC) (Open-label Trial)
Lethargy
-4.0 units on a scale
Interval -6.1 to -1.9
Change in Aberrant Behavior Checklist (ABC) (Open-label Trial)
Stereotypy
-2.3 units on a scale
Interval -3.4 to -1.2
Change in Aberrant Behavior Checklist (ABC) (Open-label Trial)
Hyperactivity
-11.5 units on a scale
Interval -15.6 to -7.5
Change in Aberrant Behavior Checklist (ABC) (Open-label Trial)
Inappropriate Speech
-1.7 units on a scale
Interval -2.6 to -0.9

SECONDARY outcome

Timeframe: 8 weeks

Population: 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

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.

Outcome measures

Outcome measures
Measure
Atomoxetine
n=26 Participants
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.
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.
Change in Social Responsiveness Scale (SRS) (Open-label Trial)
-5.8 units on a scale
Interval -9.5 to -2.1

SECONDARY outcome

Timeframe: 8 weeks

Population: 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

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

Outcome measures

Outcome measures
Measure
Atomoxetine
n=26 Participants
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.
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.
Change in Vineland Adaptive Behavior Scales (VABS) Composite Score (Open-label Trial)
5.8 units on a scale
Interval 3.3 to 8.2

SECONDARY outcome

Timeframe: 8 weeks

Population: 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

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.

Outcome measures

Outcome measures
Measure
Atomoxetine
n=26 Participants
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.
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.
Change in Pediatric Quality of Life Inventory (Open-label Trial)
Health
4.1 units on a scale
Interval -1.9 to 10.0
Change in Pediatric Quality of Life Inventory (Open-label Trial)
Family
13.6 units on a scale
Interval 6.8 to 20.3

SECONDARY outcome

Timeframe: 8 weeks

Population: 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

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.

Outcome measures

Outcome measures
Measure
Atomoxetine
n=26 Participants
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.
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.
Change in Pediatric Anxiety Rating Scale, 5-item Total (Open-label Trial)
-1.8 units on a scale
Interval -4.5 to 0.9

Adverse Events

Atomoxetine (Randomized)

Serious events: 0 serious events
Other events: 27 other events
Deaths: 0 deaths

Placebo (Randomized)

Serious events: 0 serious events
Other events: 28 other events
Deaths: 0 deaths

Atomoxetine (Open Label Trial)

Serious events: 0 serious events
Other events: 26 other events
Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Other adverse events
Measure
Atomoxetine (Randomized)
n=29 participants at risk
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.
Placebo (Randomized)
n=31 participants at risk
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.
Atomoxetine (Open Label Trial)
n=26 participants at risk
Placebo-treated subjects from the randomized trial that don't respond to placebo will be offered an 8-week open-label trial of atomoxetine
Psychiatric disorders
Irritability
34.5%
10/29
22.6%
7/31
26.9%
7/26
Psychiatric disorders
Aggression
17.2%
5/29
32.3%
10/31
19.2%
5/26
General disorders
Sedation/drowsiness
27.6%
8/29
16.1%
5/31
30.8%
8/26
Nervous system disorders
Headache
20.7%
6/29
19.4%
6/31
15.4%
4/26
General disorders
Appetite decrease
31.0%
9/29
6.5%
2/31
53.8%
14/26
Psychiatric disorders
Difficulty falling asleep
20.7%
6/29
16.1%
5/31
11.5%
3/26
Gastrointestinal disorders
Diarrhea
17.2%
5/29
16.1%
5/31
15.4%
4/26
Psychiatric disorders
Self-injurious behavior
20.7%
6/29
9.7%
3/31
15.4%
4/26
Gastrointestinal disorders
Vomiting
17.2%
5/29
12.9%
4/31
26.9%
7/26
Psychiatric disorders
Emotional outburst
17.2%
5/29
9.7%
3/31
19.2%
5/26
Psychiatric disorders
Anxiety
6.9%
2/29
19.4%
6/31
3.8%
1/26
Psychiatric disorders
Increased motor activity
3.4%
1/29
22.6%
7/31
7.7%
2/26
Psychiatric disorders
Change in speech
10.3%
3/29
12.9%
4/31
0.00%
0/26
Infections and infestations
Nasal congestion/cold
13.8%
4/29
6.5%
2/31
19.2%
5/26
Gastrointestinal disorders
Stomach discomfort
13.8%
4/29
6.5%
2/31
19.2%
5/26
Psychiatric disorders
Nightmares or vivid dreams
10.3%
3/29
9.7%
3/31
11.5%
3/26
Gastrointestinal disorders
Nausea
6.9%
2/29
9.7%
3/31
15.4%
4/26
General disorders
Fever
3.4%
1/29
12.9%
4/31
3.8%
1/26
Psychiatric disorders
Social withdrawal
3.4%
1/29
12.9%
4/31
7.7%
2/26
Psychiatric disorders
Restlessness/agitation
13.8%
4/29
0.00%
0/31
0.00%
0/26
Psychiatric disorders
Stereotypy
6.9%
2/29
6.5%
2/31
3.8%
1/26
Gastrointestinal disorders
Constipation
10.3%
3/29
3.2%
1/31
3.8%
1/26
Respiratory, thoracic and mediastinal disorders
Cough
3.4%
1/29
9.7%
3/31
7.7%
2/26
Psychiatric disorders
Sadness
3.4%
1/29
9.7%
3/31
3.8%
1/26
Psychiatric disorders
Disobedience/defiance
6.9%
2/29
3.2%
1/31
3.8%
1/26
Infections and infestations
Flu/upper respiratory
6.9%
2/29
3.2%
1/31
11.5%
3/26
Psychiatric disorders
Interrupted sleep
6.9%
2/29
3.2%
1/31
7.7%
2/26
General disorders
Tiredness/fatigue
6.9%
2/29
3.2%
1/31
3.8%
1/26
Psychiatric disorders
Disinhibition
3.4%
1/29
6.5%
2/31
0.00%
0/26
Renal and urinary disorders
Enuresis
3.4%
1/29
6.5%
2/31
3.8%
1/26
Psychiatric disorders
Euphoria/giddiness
3.4%
1/29
6.5%
2/31
3.8%
1/26
Psychiatric disorders
Body-focused repetitive behavior
0.00%
0/29
9.7%
3/31
0.00%
0/26
Skin and subcutaneous tissue disorders
Not otherwise listed, skin
6.9%
2/29
0.00%
0/31
0.00%
0/26
Vascular disorders
Flushing
6.9%
2/29
0.00%
0/31
0.00%
0/26
General disorders
Appetite increase
0.00%
0/29
6.5%
2/31
0.00%
0/26
General disorders
Accidental injury
0.00%
0/29
6.5%
2/31
0.00%
0/26
Infections and infestations
Eye irritation
0.00%
0/29
0.00%
0/31
7.7%
2/26
Infections and infestations
Sinus condition
0.00%
0/29
0.00%
0/31
7.7%
2/26

Additional Information

Christopher John McDougle, M.D.

Lurie Center for Autism, Massachusetts General Hospital

Phone: 7818601721

Results disclosure agreements

  • Principal investigator is a sponsor employee
  • Publication restrictions are in place