Asperger's Disorder, Autistic Disorder, Pervasive Developmental Disorder NOS
Conditions
Keywords
Autism Spectrum Disorder, D-cycloserine, Social Skills Training
Brief summary
The purpose of this study is to determine the effectiveness of D-cycloserine for improving social impairment in child with pervasive developmental disorders (PDD).
Detailed description
This study will evaluate the efficacy of D-Cycloserine given 30 minutes prior to each of 10 weekly Social Skills Training Sessions for the treatment of social impairment in children (ages 5-11 years) with PDD during a randomized placebo-controlled trial. This will examine our central hypothesis that D-cycloserine will enhance learning of social skills in children with PDD's.
Interventions
DRUGD-cycloserine
50 mg dose administered 30 minutes prior to each of the ten Social Skill Training Sessions
DRUGPlacebo
Placebo pill administered 30 minutes prior to each of the ten Social Skill Training Sessions
Sponsors
United States Department of Defense
Indiana University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
5 Years to 11 Years
Healthy volunteers
Yes
Inclusion criteria
* DSM-IV-TR diagnosis of autism, Asperger's disorder, or PDD not otherwise specified (NOS) base on a semi-structured review of DSM-IV-R criteria and mental status examination as wll as a complete parental history obtained from the Autism Diagnostic Interview-Revised (ADI-R) and a complete systematic patient interview utilizing the Autism Diagnostic Observation Schedule (ADOS). * Males and females ages 5-11 years. * Significant social impairment as evidenced by a parent-rated Social Responsiveness Scale (SRS) T-score of 60 or greater. * TSSA score of 70% or less on both parent questionnaire and child assessment. Children not showing significant impairment in the four specific social skill areas (greetings/goodbyes, conversations, game play, and understanding emotions) targeted by the SST are less likely to benefit from treatment. * Communication Standard Score of 70 or greater on the Vineland-II. * Full Scale IQ greater than 70. * Subjects must not be taking any psychotropic drugs affecting glutamate neurotransmission (riluzole, memantine, acamprosate, topiramate, amantadine, among others). Subjects may not be taking more than two psychotropic drugs. Dosing of all concomitant psychotropic drugs targeting core social and/or communication impairment must be stable for eight weeks prior to randomization. Dosing of all concomitant psychotropic drugs treating other features associated with pervasive developmental disorders (insomnia, inattention, hyperactivity, anxiety, irritability among others0 must be stable for two weeks (with the exception of four weeks for fluoxetine) prior to randomization. * Able to participate in group SST based on semi-structured parent and child interview. * Legal guardian has provided written informed consent and the subject has provided written informed assent. Expectation that a majority of subjects will be able to assent but the potential for the younger children and/or those that are cognitively impaired will not be able to assent.
Exclusion criteria
* Subjects with diagnoses of Rett's disorder or childhood integrative disorder will not be enrolled since these disorders have a different etiology, course, and treatment response. Furthermore, children with these disorders may not function at a high enough level in terms of cognition or language in order to benefit from the SST. * Initiation of a new psychosocial intervention within 90 days prior to randomization. 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), with the exception of concurrent social skills training, 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) are not considered significant. * Subjects exhibiting significant disruptive, aggressive, self-injurious, or sexually inappropriate behavior will not be eligible for enrollment. * Presence of current DSM-IV-TR psychiatric disorders that require alternative pharmacotherapy or different treatment including psychotic disorders, or major affective disorders, obsessive-compulsive disorder, panic disorder, or substance related disorders. * Presence of any medical condition that would make treatment with DCS less safe. Subjects with significant cardiac, hepatic, or renal disease will be excluded due to concerns about pharmacokinetic alterations or adverse effects. Subjects with a history of a seizure disorder are permitted if the subject has been seizure free for 6 months and is currently treated with an anticonvulsant that has been stable for 4 weeks. D-Cycloserine is an U.S. FDA Pregnancy Category C drug. Because of the unknown effects of DCS on the developing human fetus, females of childbearing potential will be given a urine pregnancy test and required to use a suitable form of birth control during the study. A positive pregnancy test result excludes the subject. * Presence of any other condition that would make the participants unable to comply with the requirements of the study for any reason.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Social Responsiveness Scale (SRS) Change | Completed at Baseline and Week 11 | 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 scores 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 |
| Social Responsiveness Scale (SRS) at Follow-Up | Completed at Week 22 | 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 scores 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Global Impressions Improvement Scale Responder Analysis | Week 11 | The CGI Global Improvement (CGI-I) is a clinician-rate scale designed to take into account all factors to arrive at an assessment of severity and response to treatment, including parent report, parent-rated measures, teacher-rated measures, and clinician-rated measures. The CGI-I is rated 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) at a single time-point. The CGI-I was completed at each visit, but only at week 11 were those subjects classified as much or very much improved defined as responders and all other classifications will be regarded as non-responders. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited from academic autism treatment centers, local schools, and community organizations.
Pre-assignment details
One subject with ASD was excluded from analyses due to early dropout prior to taking the study drug.
Participants by arm
| Arm | Count |
|---|---|
| D-cycloserine Subjects randomized to D-cycloserine will be administered 50 mg 30 minutes prior to each of ten Social Skills Training Sessions
D-cycloserine: 50 mg dose administered 30 minutes prior to each of the ten Social Skill Training Sessions | 34 |
| Placebo Subjects randomized to placebo arm will receive placebo pill 30 minutes prior to each of ten Social Skills Training Sessions
Placebo: Placebo pill administered 30 minutes prior to each of the ten Social Skill Training Sessions | 33 |
| Total | 67 |
Baseline characteristics
| Characteristic | Placebo | D-cycloserine | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 33 Participants | 34 Participants | 67 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 8.34 Years STANDARD_DEVIATION 1.7 | 8.49 Years STANDARD_DEVIATION 1.88 | 8.41 Years STANDARD_DEVIATION 1.78 |
| Region of Enrollment United States | 33 participants | 34 participants | 67 participants |
| Sex: Female, Male Female | 6 Participants | 6 Participants | 12 Participants |
| Sex: Female, Male Male | 27 Participants | 28 Participants | 55 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 32 / 34 | 28 / 33 |
| serious Total, serious adverse events | 0 / 34 | 1 / 33 |
Outcome results
Primary
Social Responsiveness Scale (SRS) at Follow-Up
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 scores 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
Time frame: Completed at Week 22
Population: Each group included up to four children with ASD and two typically-developing peer models (TPs) in the same age group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| D-cycloserine | Social Responsiveness Scale (SRS) at Follow-Up | 83.5 units on a scale | Standard Deviation 2.3 |
| Placebo | Social Responsiveness Scale (SRS) at Follow-Up | 89.2 units on a scale | Standard Deviation 2.5 |
p-value: 0.048t-test, 2 sided
Primary
Social Responsiveness Scale (SRS) Change
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 scores 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
Time frame: Completed at Baseline and Week 11
Population: Each group included up to four children with ASD and two typically-developing peer models (TPs) in the same age group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| D-cycloserine | Social Responsiveness Scale (SRS) Change | -13.39 units on a scale | Standard Deviation 16.81 |
| Placebo | Social Responsiveness Scale (SRS) Change | -17.00 units on a scale | Standard Deviation 21.33 |
p-value: 0.45t-test, 2 sided
Secondary
Clinical Global Impressions Improvement Scale Responder Analysis
The CGI Global Improvement (CGI-I) is a clinician-rate scale designed to take into account all factors to arrive at an assessment of severity and response to treatment, including parent report, parent-rated measures, teacher-rated measures, and clinician-rated measures. The CGI-I is rated 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) at a single time-point. The CGI-I was completed at each visit, but only at week 11 were those subjects classified as much or very much improved defined as responders and all other classifications will be regarded as non-responders.
Time frame: Week 11
Population: Each social skills group included up to four children with ASD and two typically-developing peer models (TPs) in the same age group.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| D-cycloserine | Clinical Global Impressions Improvement Scale Responder Analysis | 32.3 percentage of participants |
| Placebo | Clinical Global Impressions Improvement Scale Responder Analysis | 33.3 percentage of participants |
p-value: 0.927Chi-squared