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

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ClinicalTrials.gov Identifier: NCT00498173
Recruitment Status : Completed
First Posted : July 9, 2007
Results First Posted : August 14, 2017
Last Update Posted : August 14, 2017
Sponsor:
Collaborator:
National Institute of Mental Health (NIMH)
Information provided by (Responsible Party):
Christopher John McDougle, M.D., Massachusetts General Hospital

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Sequential Assignment;   Masking: Triple (Participant, Care Provider, Investigator);   Primary Purpose: Treatment
Condition Autism
Interventions Drug: Atomoxetine
Drug: Placebo
Enrollment 60
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Atomoxetine Placebo Atomoxetine (Open Label Trial)
Hide Arm/Group Description

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.

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.

Placebo-treated subjects from the randomized trial that don't respond to placebo will be offered an 8-week open-label trial of atomoxetine.
Period Title: Phase 1-Blinded Randomization (8 Weeks)
Started 29 31 0
Completed 27 30 0
Not Completed 2 1 0
Reason Not Completed
no post-baseline ratings             2             1             0
Period Title: Phase 2-Atomoxetine Open Label (8 Weeks)
Started 0 0 26
Completed 0 0 26
Not Completed 0 0 0
Arm/Group Title Atomoxetine Placebo Total
Hide Arm/Group Description

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.

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 of all reporting groups
Overall Number of Baseline Participants 29 31 60
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 29 participants 31 participants 60 participants
9.3  (2.6) 8.4  (2.1) 8.8  (2.4)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 29 participants 31 participants 60 participants
Female
3
  10.3%
3
   9.7%
6
  10.0%
Male
26
  89.7%
28
  90.3%
54
  90.0%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 29 participants 31 participants 60 participants
Hispanic or Latino
2
   6.9%
2
   6.5%
4
   6.7%
Not Hispanic or Latino
26
  89.7%
28
  90.3%
54
  90.0%
Unknown or Not Reported
1
   3.4%
1
   3.2%
2
   3.3%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 29 participants 31 participants 60 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
Asian
0
   0.0%
0
   0.0%
0
   0.0%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
5
  17.2%
0
   0.0%
5
   8.3%
White
22
  75.9%
30
  96.8%
52
  86.7%
More than one race
0
   0.0%
1
   3.2%
1
   1.7%
Unknown or Not Reported
2
   6.9%
0
   0.0%
2
   3.3%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 29 participants 31 participants 60 participants
29 31 60
Attending Public School   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 29 participants 31 participants 60 participants
24
  82.8%
27
  87.1%
51
  85.0%
[1]
Measure Description: All children attended school. Children not attending public school attended private, specialized, or home school, or a specialized classroom with type of school unspecified.
Indiana University School of Medicine Site  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 29 participants 31 participants 60 participants
25
  86.2%
27
  87.1%
52
  86.7%
Tanner Stage 3 or Greater   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 29 participants 31 participants 60 participants
3
  10.3%
1
   3.2%
4
   6.7%
[1]
Measure Description: Tanner stage (1-5) was used to characterize physical development in children, adolescents, and to stratify randomization.The stage was based on external primary and secondary sex characteristics, such as the size of the breasts, genitalia, and development of pubic hair. Tanner stage increases as the child develops. Randomization lists for each of the four strata defined by pubertal status (prepubertal [Tanner Stage I or 2] vs. postpubertal [Tanner Stage 3-5]) and gender (male vs. female) were utilized.
DSM-IV Diagnosis  
Measure Type: Count of Participants
Unit of measure:  Participants
Autistic Disorder Number Analyzed 29 participants 31 participants 60 participants
14
  48.3%
9
  29.0%
23
  38.3%
Asperger's Disorder Number Analyzed 29 participants 31 participants 60 participants
5
  17.2%
9
  29.0%
14
  23.3%
Pervasive Developmental Disorder (PDD-NOS) Number Analyzed 29 participants 31 participants 60 participants
10
  34.5%
13
  41.9%
23
  38.3%
Concomitant Medication Use  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 29 participants 31 participants 60 participants
22
  75.9%
20
  64.5%
42
  70.0%
IQ   [1] [2] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 27 participants 30 participants 57 participants
74.7  (18.5) 84.4  (15.2) 79.8  (17.4)
[1]
Measure Description: IQ was estimated from the Mullen Scale for 1 child assigned to atomoxetine and the Stanford Binet test for all other children.
[2]
Measure Analysis Population Description: IQ scores were not obtained for 2 children assigned to atomoxetine and 1 child assigned to placebo.
Clinical Global Impression-Severity  
Measure Type: Count of Participants
Unit of measure:  Participants
Moderate Number Analyzed 29 participants 31 participants 60 participants
16
  55.2%
17
  54.8%
33
  55.0%
Marked Number Analyzed 29 participants 31 participants 60 participants
13
  44.8%
12
  38.7%
25
  41.7%
Severe Number Analyzed 29 participants 31 participants 60 participants
0
   0.0%
2
   6.5%
2
   3.3%
Attention Deficit Hyperactivity Disorder (ADHD) Rating Scale Total   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 29 participants 31 participants 60 participants
37.2  (7.6) 41.5  (5.8) 39.4  (7.0)
[1]
Measure Description: 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 scale consists of 2 subscales: inattention (9 items) and hyperactivity-impulsivity (9 items). The total score can range from 0 to 54, with a higher score indicating greater severity.
Aberrant Behavior Checklist, Hyperactivity  
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 29 participants 31 participants 60 participants
29.1  (11.8) 31.7  (10.0) 30.5  (10.9)
Social Responsiveness Scale  
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 29 participants 31 participants 60 participants
84.5  (9.9) 84.4  (10.3) 84.5  (10.0)
Vineland Adaptive Behavior Composite Score   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 29 participants 31 participants 60 participants
73.1  (12.5) 72.5  (8.7) 72.8  (10.6)
[1]
Measure Description: The Vineland Adaptive Behavior Scales, Second Edition is a measure of adaptive behavior in children, adolescents and adults. The composite score has a mean of 100 and a standard deviation of 15 (range = 20 to 160). Higher scores suggest a higher level of adaptive functioning. A rise in standard scores from Baseline to the Final Visit indicates improvement.
Pediatric Quality of Life Inventory Health Related Functioning   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 29 participants 31 participants 60 participants
56.3  (18.8) 60.5  (19.6) 58.5  (19.2)
[1]
Measure Description: Scores range from 0–100, with higher scores indicating better quality of life.
Pediatric Quality of Life Inventory Family Functioning   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 29 participants 31 participants 60 participants
52.4  (24.2) 53.1  (23.4) 52.7  (23.6)
[1]
Measure Description: Scores range from 0–100, with higher scores representing better family functioning.
Pediatric Anxiety Rating Scale, 5-Item Total   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 29 participants 31 participants 60 participants
8.5  (6.5) 8.9  (6.0) 8.7  (6.2)
[1]
Measure Description: Scaled score ranges form 0-25 with higher scores indicating more severe anxiety symptoms.
1.Primary Outcome
Title ADHD Rating Scale (ADHDRS)-Home Version Total Score (Randomized Phase)
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Two participants from the Atomoxetine arm, and one participant from the Placebo arm did not have post-baseline measures.
Arm/Group Title Atomoxetine Placebo
Hide Arm/Group Description:

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.

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.

Overall Number of Participants Analyzed 27 30
Mean (95% Confidence Interval)
Unit of Measure: units on a scale
28.7
(24.3 to 33.0)
34.0
(30.0 to 38.0)
2.Secondary Outcome
Title ADHD Rating Scale (ADHDRS)-Home Version Inattention and Hyperactivity Scores (Randomized Phase)
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Two participants from the Atomoxetine arm, and one participant from the Placebo arm did not have post-baseline measures.
Arm/Group Title Atomoxetine Placebo
Hide Arm/Group Description:

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.

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.

Overall Number of Participants Analyzed 27 30
Mean (95% Confidence Interval)
Unit of Measure: units on a scale
Inattention
14.7
(12.4 to 17.0)
17.3
(15.2 to 19.4)
Hyperactivity
13.7
(11.4 to 16.0)
16.8
(14.7 to 19.0)
3.Secondary Outcome
Title Aberrant Behavior Checklist (ABC) (Randomized Phase)
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Two participants from the Atomoxetine arm, and one participant from the Placebo arm did not have post-baseline measures.
Arm/Group Title Atomoxetine Placebo
Hide Arm/Group Description:

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.

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.

Overall Number of Participants Analyzed 27 30
Mean (95% Confidence Interval)
Unit of Measure: units on a scale
Irritability
15.6
(12.9 to 18.3)
13.8
(11.3 to 16.3)
Lethargy
7.2
(5.1 to 9.3)
8.3
(6.3 to 10.2)
Stereotypy
4.7
(3.1 to 6.3)
5.2
(3.7 to 6.6)
Hyperactivity
24.2
(20.5 to 27.9)
28.2
(24.7 to 31.7)
Inappropriate Speech
4.4
(3.5 to 5.4)
5.6
(4.7 to 6.5)
4.Secondary Outcome
Title Social Responsiveness Scale (SRS) (Randomized Phase)
Hide Description 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.
Time Frame 8 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Four participants from the Atomoxetine arm, and two participants from the Placebo arm did not have post-baseline measures.
Arm/Group Title Atomoxetine Placebo
Hide Arm/Group Description:

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.

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.

Overall Number of Participants Analyzed 25 29
Mean (95% Confidence Interval)
Unit of Measure: units on a scale
83.0
(79.9 to 86.0)
82.0
(79.2 to 84.8)
5.Secondary Outcome
Title Vineland Adaptive Behavior Scales (VABS) Composite Score (Randomized Phase)
Hide Description 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.
Time Frame 8 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Four participants from the Atomoxetine arm, and two participants from the Placebo arm did not have post-baseline measures.
Arm/Group Title Atomoxetine Placebo
Hide Arm/Group Description:

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.

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.

Overall Number of Participants Analyzed 25 29
Mean (95% Confidence Interval)
Unit of Measure: units on a scale
73.4
(70.8 to 76.0)
74.9
(72.5 to 77.2)
6.Secondary Outcome
Title Pediatric Quality of Life Inventory (Randomized Phase)
Hide Description 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.
Time Frame 8 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Four participants from the Atomoxetine arm, and two participants from the Placebo arm did not have post-baseline measures.
Arm/Group Title Atomoxetine Placebo
Hide Arm/Group Description:

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.

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.

Overall Number of Participants Analyzed 25 29
Mean (95% Confidence Interval)
Unit of Measure: units on a scale
Health
64.2
(57.5 to 70.9)
62.2
(56.0 to 68.4)
Family
55.2
(47.3 to 63.0)
53.0
(45.7 to 60.2)
7.Secondary Outcome
Title Pediatric Anxiety Rating Scale, 5-Item Total (Randomized Phase)
Hide Description 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.
Time Frame 8 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Four participants from the Atomoxetine arm, and two participants from the Placebo arm did not have post-baseline measures.
Arm/Group Title Atomoxetine Placebo
Hide Arm/Group Description:

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.

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.

Overall Number of Participants Analyzed 25 29
Mean (95% Confidence Interval)
Unit of Measure: units on a scale
7.3
(5.6 to 9.1)
8.5
(6.8 to 10.1)
8.Secondary Outcome
Title Odds of Clinical Global Impression-Improvement Scale, Very Much or Much Improved (1 or 2) (Randomized Phase)
Hide Description 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.
Time Frame 8 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Two participants from the Atomoxetine arm, and one participant from the Placebo arm did not have post-baseline measures.
Arm/Group Title Atomoxetine Placebo
Hide Arm/Group Description:

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.

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.

Overall Number of Participants Analyzed 27 30
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: odds of improvement
0.53
(0.22 to 1.26)
0.11
(0.04 to 0.35)
9.Secondary Outcome
Title Change in ADHD Rating Scale (ADHDRS)-Home Version Total Score (Open-label Trial)
Hide Description 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.
Time Frame 8 weeks
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Hide Analysis Population Description
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
Arm/Group Title Open-label Trial
Hide Arm/Group Description:
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
Overall Number of Participants Analyzed 26
Mean (95% Confidence Interval)
Unit of Measure: units on a scale
-15.4
(-19.9 to -11.0)
10.Secondary Outcome
Title Change in ADHD Rating Scale (ADHDRS)-Home Version Inattention and Hyperactivity Scores (Open-label Trial)
Hide Description 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
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Hide Analysis Population Description
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
Arm/Group Title Open-label Trial
Hide Arm/Group Description:
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
Overall Number of Participants Analyzed 26
Mean (95% Confidence Interval)
Unit of Measure: units on a scale
Inattention
-8.1
(-10.4 to -5.7)
Hyperactivity
-7.3
(-9.7 to -5.0)
11.Secondary Outcome
Title Change in Aberrant Behavior Checklist (ABC) (Open-label Trial)
Hide Description 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
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Hide Analysis Population Description
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/Group Title Open-label Trial
Hide Arm/Group Description:
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
Overall Number of Participants Analyzed 26
Mean (95% Confidence Interval)
Unit of Measure: units on a scale
Irritability
-4.5
(-7.1 to -1.8)
Lethargy
-4.0
(-6.1 to -1.9)
Stereotypy
-2.3
(-3.4 to -1.2)
Hyperactivity
-11.5
(-15.6 to -7.5)
Inappropriate Speech
-1.7
(-2.6 to -0.9)
12.Secondary Outcome
Title Change in Social Responsiveness Scale (SRS) (Open-label Trial)
Hide Description 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.
Time Frame 8 weeks
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Hide Analysis Population Description
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
Arm/Group Title Open-label Trial
Hide Arm/Group Description:
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
Overall Number of Participants Analyzed 26
Mean (95% Confidence Interval)
Unit of Measure: units on a scale
-5.8
(-9.5 to -2.1)
13.Secondary Outcome
Title Change in Vineland Adaptive Behavior Scales (VABS) Composite Score (Open-label Trial)
Hide Description 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
Time Frame 8 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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
Arm/Group Title Open-label Trial
Hide Arm/Group Description:
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
Overall Number of Participants Analyzed 26
Mean (95% Confidence Interval)
Unit of Measure: units on a scale
5.8
(3.3 to 8.2)
14.Secondary Outcome
Title Change in Pediatric Quality of Life Inventory (Open-label Trial)
Hide Description 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.
Time Frame 8 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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
Arm/Group Title Open-label Trial
Hide Arm/Group Description:
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
Overall Number of Participants Analyzed 26
Mean (95% Confidence Interval)
Unit of Measure: units on a scale
Health
4.1
(-1.9 to 10.0)
Family
13.6
(6.8 to 20.3)
15.Secondary Outcome
Title Change in Pediatric Anxiety Rating Scale, 5-item Total (Open-label Trial)
Hide Description 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.
Time Frame 8 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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
Arm/Group Title Open-label Trial
Hide Arm/Group Description:
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
Overall Number of Participants Analyzed 26
Mean (95% Confidence Interval)
Unit of Measure: units on a scale
-1.8
(-4.5 to 0.9)
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Atomoxetine (Randomized) Placebo (Randomized) Atomoxetine (Open Label Trial)
Hide Arm/Group Description

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.

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.

Placebo-treated subjects from the randomized trial that don’t respond to placebo will be offered an 8-week open-label trial of atomoxetine
All-Cause Mortality
Atomoxetine (Randomized) Placebo (Randomized) Atomoxetine (Open Label Trial)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Atomoxetine (Randomized) Placebo (Randomized) Atomoxetine (Open Label Trial)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/29 (0.00%)   0/31 (0.00%)   0/26 (0.00%) 
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Atomoxetine (Randomized) Placebo (Randomized) Atomoxetine (Open Label Trial)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   27/29 (93.10%)   28/31 (90.32%)   26/26 (100.00%) 
Gastrointestinal disorders       
Diarrhea  5/29 (17.24%)  5/31 (16.13%)  4/26 (15.38%) 
Vomiting  5/29 (17.24%)  4/31 (12.90%)  7/26 (26.92%) 
Stomach discomfort  4/29 (13.79%)  2/31 (6.45%)  5/26 (19.23%) 
Nausea  2/29 (6.90%)  3/31 (9.68%)  4/26 (15.38%) 
Constipation  3/29 (10.34%)  1/31 (3.23%)  1/26 (3.85%) 
General disorders       
Sedation/drowsiness  8/29 (27.59%)  5/31 (16.13%)  8/26 (30.77%) 
Appetite decrease  9/29 (31.03%)  2/31 (6.45%)  14/26 (53.85%) 
Fever  1/29 (3.45%)  4/31 (12.90%)  1/26 (3.85%) 
Tiredness/fatigue  2/29 (6.90%)  1/31 (3.23%)  1/26 (3.85%) 
Appetite increase  0/29 (0.00%)  2/31 (6.45%)  0/26 (0.00%) 
Accidental injury  0/29 (0.00%)  2/31 (6.45%)  0/26 (0.00%) 
Infections and infestations       
Nasal congestion/cold  4/29 (13.79%)  2/31 (6.45%)  5/26 (19.23%) 
Flu/upper respiratory  2/29 (6.90%)  1/31 (3.23%)  3/26 (11.54%) 
Eye irritation  0/29 (0.00%)  0/31 (0.00%)  2/26 (7.69%) 
Sinus condition  0/29 (0.00%)  0/31 (0.00%)  2/26 (7.69%) 
Nervous system disorders       
Headache  6/29 (20.69%)  6/31 (19.35%)  4/26 (15.38%) 
Psychiatric disorders       
Irritability  10/29 (34.48%)  7/31 (22.58%)  7/26 (26.92%) 
Aggression  5/29 (17.24%)  10/31 (32.26%)  5/26 (19.23%) 
Difficulty falling asleep  6/29 (20.69%)  5/31 (16.13%)  3/26 (11.54%) 
Self-injurious behavior  6/29 (20.69%)  3/31 (9.68%)  4/26 (15.38%) 
Emotional outburst  5/29 (17.24%)  3/31 (9.68%)  5/26 (19.23%) 
Anxiety  2/29 (6.90%)  6/31 (19.35%)  1/26 (3.85%) 
Increased motor activity  1/29 (3.45%)  7/31 (22.58%)  2/26 (7.69%) 
Change in speech  3/29 (10.34%)  4/31 (12.90%)  0/26 (0.00%) 
Nightmares or vivid dreams  3/29 (10.34%)  3/31 (9.68%)  3/26 (11.54%) 
Social withdrawal  1/29 (3.45%)  4/31 (12.90%)  2/26 (7.69%) 
Restlessness/agitation  4/29 (13.79%)  0/31 (0.00%)  0/26 (0.00%) 
Stereotypy  2/29 (6.90%)  2/31 (6.45%)  1/26 (3.85%) 
Sadness  1/29 (3.45%)  3/31 (9.68%)  1/26 (3.85%) 
Disobedience/defiance  2/29 (6.90%)  1/31 (3.23%)  1/26 (3.85%) 
Interrupted sleep  2/29 (6.90%)  1/31 (3.23%)  2/26 (7.69%) 
Disinhibition  1/29 (3.45%)  2/31 (6.45%)  0/26 (0.00%) 
Euphoria/giddiness  1/29 (3.45%)  2/31 (6.45%)  1/26 (3.85%) 
Body-focused repetitive behavior  0/29 (0.00%)  3/31 (9.68%)  0/26 (0.00%) 
Renal and urinary disorders       
Enuresis  1/29 (3.45%)  2/31 (6.45%)  1/26 (3.85%) 
Respiratory, thoracic and mediastinal disorders       
Cough  1/29 (3.45%)  3/31 (9.68%)  2/26 (7.69%) 
Skin and subcutaneous tissue disorders       
Not otherwise listed, skin  2/29 (6.90%)  0/31 (0.00%)  0/26 (0.00%) 
Vascular disorders       
Flushing  2/29 (6.90%)  0/31 (0.00%)  0/26 (0.00%) 
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Name/Title: Christopher John McDougle, M.D.
Organization: Lurie Center for Autism, Massachusetts General Hospital
Phone: 7818601721
Responsible Party: Christopher John McDougle, M.D., Massachusetts General Hospital
ClinicalTrials.gov Identifier: NCT00498173     History of Changes
Other Study ID Numbers: R01MH077600 ( U.S. NIH Grant/Contract )
R01MH077600 ( U.S. NIH Grant/Contract )
DDTR B2-NDA ( Other Identifier )
First Submitted: July 6, 2007
First Posted: July 9, 2007
Results First Submitted: March 17, 2017
Results First Posted: August 14, 2017
Last Update Posted: August 14, 2017