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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
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

Tracking Information
First Submitted Date  ICMJE July 6, 2007
First Posted Date  ICMJE July 9, 2007
Results First Submitted Date  ICMJE March 17, 2017
Results First Posted Date  ICMJE August 14, 2017
Last Update Posted Date August 14, 2017
Study Start Date  ICMJE July 2007
Actual Primary Completion Date October 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 11, 2017)
ADHD Rating Scale (ADHDRS)-Home Version Total Score (Randomized Phase) [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE
 (submitted: July 6, 2007)
ADHD symptoms [ Time Frame: Weeks 1-4, 6, and 8 ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 11, 2017)
  • ADHD Rating Scale (ADHDRS)-Home Version Inattention and Hyperactivity Scores (Randomized Phase) [ Time Frame: 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.
  • Aberrant Behavior Checklist (ABC) (Randomized Phase) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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.
  • Change in ADHD Rating Scale (ADHDRS)-Home Version Total Score (Open-label Trial) [ Time Frame: 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.
  • Change in ADHD Rating Scale (ADHDRS)-Home Version Inattention and Hyperactivity Scores (Open-label Trial) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: July 6, 2007)
  • Irritability and anxiety [ Time Frame: Weeks 1-4, 6, and 8 ]
  • Core autistic symptoms [ Time Frame: Weeks 1-4, 6, and 8 ]
  • Quality of life [ Time Frame: Weeks 1-4, 6, and 8 ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Effectiveness of Atomoxetine in Treating ADHD Symptoms in Children and Adolescents With Autism
Official Title  ICMJE Targeted Pharmacologic Interventions for Autism: A Double-Blind, Placebo-Controlled Trial of Atomoxetine in Children and Adolescents With Autism
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Sequential Assignment
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.
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Autism
Intervention  ICMJE
  • Drug: 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.
    Other Name: Strattera
  • Drug: Placebo
    Placebo tablets dosages: 5 mg, 10 mg, 25 mg, 40 mg.
Study Arms  ICMJE
  • Experimental: 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.
    Intervention: Drug: Atomoxetine
  • Placebo Comparator: 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.
    Intervention: Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: June 7, 2016)
60
Original Estimated Enrollment  ICMJE
 (submitted: July 6, 2007)
86
Actual Study Completion Date  ICMJE October 2015
Actual Primary Completion Date October 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 5 Years to 15 Years   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00498173
Other Study ID Numbers  ICMJE R01MH077600( U.S. NIH Grant/Contract )
R01MH077600 ( U.S. NIH Grant/Contract )
DDTR B2-NDA ( Other Identifier )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Christopher John McDougle, M.D., Massachusetts General Hospital
Study Sponsor  ICMJE Massachusetts General Hospital
Collaborators  ICMJE National Institute of Mental Health (NIMH)
Investigators  ICMJE
Principal Investigator: Christopher J. McDougle, MD Massachusetts General Hospital
PRS Account Massachusetts General Hospital
Verification Date August 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP