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Evaluating the Effectiveness of Aripiprazole and D-Cycloserine to Treat Symptoms Associated With Autism

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ClinicalTrials.gov Identifier: NCT00198107
Recruitment Status : Completed
First Posted : September 20, 2005
Results First Posted : March 29, 2019
Last Update Posted : April 9, 2019
Sponsor:
Collaborator:
National Institute of Mental Health (NIMH)
Information provided by (Responsible Party):
Indiana University

Tracking Information
First Submitted Date  ICMJE September 12, 2005
First Posted Date  ICMJE September 20, 2005
Results First Submitted Date  ICMJE April 30, 2018
Results First Posted Date  ICMJE March 29, 2019
Last Update Posted Date April 9, 2019
Study Start Date  ICMJE September 2005
Actual Primary Completion Date September 2011   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 27, 2019)
  • Mean Post-baseline Aberrant Behavior Checklist Irritability Score, Parent Report, Double-blind Phase [ Time Frame: Weeks 1, 2, 3, 4, 6, and 8 ]
    The Aberrant Behavior Checklist (ABC) is a symptom checklist for assessing problem behaviors in individuals ages 6 to 54 with mental retardation. The full ABC is a 58-item parent rating with five factors: Irritability, Social Withdrawal, Stereotypy, Hyperactivity and Inappropriate Speech. It has been used as a primary outcome measure in several trials of children with developmental disabilities. The interpretation of the tool and its subscales is that higher scores, indicate greater severity. Fifteen item scores with values ranging from 0 (not a problem) to 3 (problem is severe) are summed to arrive at the total irritability scale store ranging from 0 to 45. Means were estimated using a repeated measures linear regression model with treatment group, baseline score, study week (in categories), and sex x Tanner stage stratum as covariates. A linear contrast estimated the average across study timepoints. Confidence intervals reflect a Bonferroni multiple testing correction accounting
  • Odds of Improvement as Measured by the Clinical Global Impression-Global Improvement Scale (Improvement Defined as CGI-I=1 or CGI-I=2) [ Time Frame: Weeks 1, 2, 3, 4, 6 and 8 ]
    Clinical Global Impressions (Guy, 1976) 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, with lower scores indicating greater improvement (1=very much improved and 2=much improved). Participants with a CGI-I score of 1 or 2 were classified as improved. Odds were estimated using a repeated measures logistic regression model with treatment group, study week (in categories), and sex x Tanner stage stratum as covariates. A linear contrast estimated the average log odds across study timepoints. Confidence intervals reflect a Bonferroni multiple testing correction accounting for the selection of two primary outcomes.
Original Primary Outcome Measures  ICMJE
 (submitted: September 12, 2005)
  • - Irritability subscale of the Aberrant Behavior Checklist (ABC) after 8 weeks of Double-Blind Treatment and after Open-Label Treatment
  • - Clinical Global Impression (CGI)-global improvement item (CGI-I) after 8 weeks of Double-Blind Treatment and after Open-Label Treatment
Change History Complete list of historical versions of study NCT00198107 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: March 27, 2019)
  • Mean Post-baseline Aberrant Behavior Checklist Hyperactivity Score, Parent Report, Double-blind Phase [ Time Frame: Weeks 1, 2, 3, 4, 6 and 8 ]
    The Aberrant Behavior Checklist (ABC) is a symptom checklist for assessing problem behaviors in individuals ages 6 to 54 with mental retardation. The full ABC is a 58-item Parent rating with five factors: Irritability, Social Withdrawal, Stereotypy, Hyperactivity and Inappropriate Speech. The 16-item Hyperactivity subscale covers overactivity, impulsiveness, inattention and noncompliance. It has been used as a primary outcome measure in several trials of children with developmental disabilities. The interpretation of the tool and its subscale is that higher scores, indicate greater severity. Sixteen item scores with values ranging from 0 (not a problem) to 3 (problem is severe) are summed to arrive at the total score ranging from 0 to 48. Means were estimated using a repeated measures linear regression model with treatment group, baseline score, study week (in categories), and sex x Tanner stage stratum as covariates. A linear contrast estimated the average across study timepoints.
  • Mean Post-baseline Aberrant Behavior Checklist Inappropriate Speech Score, Parent Report, Double-blind Phase [ Time Frame: Weeks 1, 2, 3, 4, 6, and 8 ]
    The Aberrant Behavior Checklist (ABC) is a symptom checklist for assessing problem behaviors in individuals ages 6 to 54 with mental retardation. The full ABC is a 58-item Parent rating with five factors: Irritability, Social Withdrawal, Stereotypy, Hyperactivity and Inappropriate Speech. It has been used as a primary outcome measure in several trials of children with developmental disabilities. The interpretation of the tool and its subscales is that higher scores, indicate greater severity. Four item scores with values ranging from 0 (not a problem) to 3 (problem is severe) are summed to arrive at the total inappropriate speech scale score ranging from 0 to 12. Means were estimated using a repeated measures linear regression model with treatment group, baseline score, study week (in categories), and sex x Tanner stage stratum as covariates. A linear contrast estimated the average across study timepoints.
  • Mean Post-baseline Aberrant Behavior Checklist Social Withdrawal Score, Parent Report, Double-blind Phase [ Time Frame: Weeks 1, 2, 3, 4, 6, and 8 ]
    The Aberrant Behavior Checklist (ABC) is a symptom checklist for assessing problem behaviors in individuals ages 6 to 54 with mental retardation. The full ABC is a 58-item Parent rating with five factors: Irritability, Social Withdrawal, Stereotypy, Hyperactivity and Inappropriate Speech. It has been used as a primary outcome measure in several trials of children with developmental disabilities. The interpretation of the tool and its subscales is that higher scores, indicates greater severity. Sixteen item scores with values ranging from 0 (not a problem) to 3 (problem is severe) are summed to arrive at the total social withdrawal scale score ranging from 0 to 48. Means were estimated using a repeated measures linear regression model with treatment group, baseline score, study week (in categories), and sex x Tanner stage stratum as covariates. A linear contrast estimated the average across study timepoints.
  • Mean Post-baseline Aberrant Behavior Checklist Stereotypy Score, Parent Report, Double-blind Phase [ Time Frame: Weeks 1, 2, 3, 4, 6, and 8 ]
    The Aberrant Behavior Checklist (ABC) is a symptom checklist for assessing problem behaviors in individuals ages 6 to 54 with mental retardation. The full ABC is a 58-item Parent rating with five factors: Irritability, Social Withdrawal, Stereotypy, Hyperactivity and Inappropriate Speech. It has been used as a primary outcome measure in several trials of children with developmental disabilities. The interpretation of the tool and its subscales is that higher scores, indicates greater severity. Seven item scores with values ranging from 0 (not a problem) to 3 (problem is severe) are summed to arrive at the total stereotypy scale score ranging from 0 to 21. Means were estimated using a repeated measures linear regression model with treatment group, baseline score, study week (in categories), and sex x Tanner stage stratum as covariates. A linear contrast estimated the average across study timepoints.
  • Mean Post-baseline Score on a Modified Version of the Compulsion Subscale of the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS) [ Time Frame: Weeks 2, 4, 6 and 8 ]
    The CYBOCS- PDD is a semi-structured clinician-rated scale designed to rate the current severity of repetitive behavior in children with idiopathic autism spectrum disorders. Once the current repetitive behaviors are identified, they are rated on: Time Spent, Interference, Distress, Resistance, and Control. Each of these items is scored from 0 (least symptomatic) to 4 (most symptomatic), yielding a Total score from 0 to 20. Higher scores indicate higher severity. Means were estimated using a repeated measures linear regression model with treatment group, baseline score, study week (in categories), and sex x Tanner stage stratum as covariates. A linear contrast estimated the average across study timepoints.
  • Mean Vineland Maladaptive Behavior Subscales Total Score, Week 8 [ Time Frame: Week 8 ]
    The Vineland Adaptive Behavior Scales, (Survey Interview Form) is a measure of adaptive behavior in children, adolescents and adults. It yields an overall standard score (Adaptive Behavior Composite, ABC) and age standard scores in four domains. ABC scores have a mean of 100 and a standard deviation of 15 (range = 20 to 160). Higher scores suggest a higher level of adaptive functioning. An increase in standard scores from Baseline to the Final Visit indicates improvement. Means were estimated using a repeated measures linear regression model with treatment group, study week (in categories, baseline or 8 weeks), and sex x Tanner stage stratum as covariates.
  • Mean Autism Diagnostic Observation Schedule (ADOS) Social Affect and Restricted and Repetitive Behaviors Total Score, Week 8 [ Time Frame: Week 8 ]
    Autism Diagnostic Observation Scale (ADOS) (Lord), Modules 1-3 yields scores in 2 scales: Social Affect and Restricted and Repetitive Behavior. The ADOS has been repeatedly evaluated as a diagnostic measure, it has also been used as an outcome measure of autism severity (Aldred et al., 2004; Gutstein, 2007; Owly et al, 2001, Green et al, 2010). For modules 1-3, scores ranging from 0-2 on 14 items are summed to arrive at the Social Affect and Restricted and Repetitive Behavior Total Score, which ranges from 0 to 28. Higher scores indicate greater autism severity. Means were estimated using a repeated measures linear regression model with treatment group, study week (in categories, baseline or 8 weeks), and sex x Tanner stage stratum as covariates
  • Mean Social Reciprocity Scale (SRS) Total Score, Week 8 [ Time Frame: Week 8 ]
    The 65-item 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 individual item is summed to create a total raw score. A total score results are 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. Means were estimated using a repeated measures linear regression model with treatment group, study week (in categories, baseline or 8 weeks), and sex x Tanner stage stratum as covariates.
Original Secondary Outcome Measures  ICMJE
 (submitted: September 12, 2005)
  • - The ABC subscales other than the Irritability subscale after 8 weeks of Double-Blind Treatment and after Open-Label Treatment
  • - Vineland Maladaptive Behavior Subscales which are part of the Vineland Adaptive Behavior Scales after 8 weeks of Double-Blind Treatment and after Open-Label Treatment
  • - A Modified version of the “compulsion” subscale of the Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS) after 8 weeks of Double-Blind Treatment and after Open-Label Treatment
  • - Autism Diagnostic Observation Schedule (ADOS) after 8 weeks of Double-Blind Treatment and after Open-Label Treatment
  • - Social Reciprocity Scale (SRS) after 8 weeks of Double-Blind Treatment and after Open-Label Treatment
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Evaluating the Effectiveness of Aripiprazole and D-Cycloserine to Treat Symptoms Associated With Autism
Official Title  ICMJE Novel Pharmacological Strategies in Autism
Brief Summary This study will determine the effectiveness of aripiprazole and D-Cycloserine in treating symptoms associated with autism in children.
Detailed Description

Autism is a developmental disorder that affects every child differently. A wide range of symptoms accompany autism, including self-injurious behavior, aggression, and severe tantrums. Despite an improved ability to reduce these symptoms, existing drug treatments continue to be associated with adverse side effects. Also, there is no existing drug treatment that reliably improves social behavior, a core deficit in autism. Studies on drug treatment combinations that are designed to reduce self-injurious behavior, aggression, and severe tantrums and improve social behavior in children with autism have yet to be conducted. This study will address the above-mentioned limitations by evaluating aripiprazole in reducing self-injurious behavior, aggression, and severe tantrums and by evaluating the addition of D-Cycloserine in improving social behavior among children with autism.

This study will include three phases and an add-on component for some children. Participants will be randomly assigned to receive either aripiprazole or a placebo treatment for 8 weeks. Assessments measuring irritability, behavior, and social skills will be conducted at the end of this first phase. Those patients who respond well to aripiprazole will continue to receive aripiprazole treatment for another 16 weeks. This second phase will determine whether aripiprazole is associated with long-term maintenance of symptomatic improvement in patients who respond well to short-term treatment. Assessments will again be conducted at the end of this 16-week period. Those patients whose symptoms have stabilized and continue to improve while on aripiprazole will be asked to participate in the final phase of this study. During the this pilot phase, D-Cycloserine will be added to ongoing treatment with aripiprazole. Patients will take both aripiprazole and D-Cycloserine for an additional 8 weeks to determine if this combination of drug treatments results in improved social behavior once patients' aggression and self-injurious behavior have been stabilized with aripiprazole. At the end of this 8-week period, participants will be assessed for any changes in behavior, irritability, or social skills. Results from this study may aid in developing safer and more effective drug treatments for children and adolescents with autism.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Autistic Disorder
Intervention  ICMJE
  • Drug: Aripiprazole
    Participants will receive 8 weeks of initial treatment with aripiprazole. If responsive to treatment, participants may be assigned to an additional 16 weeks of aripiprazole and then an additional 8 more weeks of aripiprazole with D-cycloserine. Dosing schedule for participants less than 50 kg maximum dose will be 10 mg per day. Dosing schedule for participants greater than 50 kg maximum dose will be 15 mg.
    Other Name: Abilify
  • Drug: Placebo
    Participants assigned to placebo will take a placebo pill for the initial 8 weeks of treatment.
  • Drug: D-cycloserine
    D-cycloserine will be dosed in the range of 25 to 200 mg daily for the final 8 weeks of treatment.
Study Arms  ICMJE
  • Placebo Comparator: 1 Placebo
    Participants will take placebo
    Intervention: Drug: Placebo
  • Active Comparator: 2 Aripiprazole
    Participants will take aripiprazole
    Intervention: Drug: Aripiprazole
  • Active Comparator: 3 Aripiprazole + D-cycloserine
    Participants first will take aripiprazole then will also take D-cycloserine
    Interventions:
    • Drug: Aripiprazole
    • Drug: D-cycloserine
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: April 14, 2017)
81
Original Enrollment  ICMJE
 (submitted: September 12, 2005)
88
Actual Study Completion Date  ICMJE September 2011
Actual Primary Completion Date September 2011   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Weight of at least 15 kg (33.75 lbs)
  • Meets DSM-IV criteria for autistic disorder
  • Outpatient
  • Medication-free for at least 2 weeks prior to baseline for all psychotropic medications. More information about this criterion, including exceptions, can be found in the protocol.
  • Clinical Global Impression Scale Severity score (CGI-S) of at least 4
  • Irritability subscale of the Aberrant Behavior Checklist (ABC) score of at least 18
  • An IQ of at least 35 or a mental age of at least 18 months
  • In good physical health

Exclusion Criteria:

  • Meets DSM-IV criteria for Asperger's disorder, Rett's disorder, childhood disintegrative disorder, any other pervasive developmental disorder (PDD), schizophrenia, psychotic disorder, or bipolar disorder
  • Current or past history of alcohol or other substance abuse within 6 months of study entry
  • Comorbid neurodevelopmental disorder with possible association to autism (e.g., fragile-X syndrome, tuberous sclerosis)
  • A significant medical condition such as heart, liver, kidney, or lung disease, or a seizure disorder
  • Pregnant
  • Prior adequate use of aripiprazole. More information about this criterion can be found in the protocol.
  • Evidence of hypersensitivity to aripiprazole
  • History of neuroleptic malignant syndrome
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 5 Years to 17 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 NCT00198107
Other Study ID Numbers  ICMJE R01MH072961( U.S. NIH Grant/Contract )
R01MH072961 ( U.S. NIH Grant/Contract )
DSIR 82-SEDR
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Indiana University
Study Sponsor  ICMJE Indiana University
Collaborators  ICMJE National Institute of Mental Health (NIMH)
Investigators  ICMJE
Principal Investigator: Christopher J. McDougle, MD Indiana University School of Medicine
PRS Account Indiana University
Verification Date April 2018

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