Oxytocin and Social Cognitive Skills Groups

Autism Spectrum Disorder Clinical Trial

— ION-ASD  

Official title:

Integrated Oxytocin and Nonverbal, Emotion Recognition, and Theory of Mind Training for Children With Autism Spectrum Disorder

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02918864
• Other study ID #: 14062403
• Status: Completed
• Phase: Phase 2
• Start date: June 15, 2016
• Est. completion date: September 2021

Study information

• Verified date: April 2024
• Source: Rush University Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to evaluate the feasibility, safety, and preliminary efficacy of integrating targeted dosing of intranasal oxytocin with a social cognitive skills group therapy for school-aged children with autism spectrum disorder (ASD).

Description:

The study is a proof-of-concept, combination intervention designed to address individual treatment targets presumed to influence social learning in school-aged children with autism spectrum disorder (ASD). This proposal builds upon prior research on an empirically supported social cognitive skills training curriculum, NETT (Nonverbal communication, Emotion recognition, and Theory of mind Training). NETT is a cognitive-behavioral intervention (CBI) for nonverbal communication, emotion recognition, and theory of mind deficits in youth with ASD. In this two-phase, 3 year, single-blind, contact controlled study, school-aged children with ASD (n=60) will be randomized into a 12-session, parallel group design of Integrated Oxytocin and NETT (ION) or a control social group condition (facilitated play). The study aims to evaluate the safety, tolerability, and efficacy of integrating the neuropeptide, oxytocin (OXT), with the social cognitive curriculum, as well as to identify targets of change and pre-treatment factors predictive of response to ION-ASD. Maintenance of treatment effects will also be assessed 1 month and 3 months post-treatment.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 40
• Est. completion date: September 2021
• Est. primary completion date: September 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 8 Years to 11 Years

Eligibility

Inclusion Criteria

1. Male or female outpatients, 8-11 years of age inclusive

2. Meet Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) for Autism Spectrum Disorder. DSM-V criteria will be established by a clinician with expertise with individuals with ASD. Best estimate Diagnosis will be reached using DSM-5 criteria, the Autism Diagnostic Observation Schedule (ADOS-2) and the Autism Diagnostic Interview (ADI-R), or Autism Screening Interview.

3. Mean score of 9 or less on mentalizing items of Strange Stories Test (Highest possible score = 12, items 21-25, 27).

4. Have a Clinician's Global Impression-Severity (CGI-S) score = 4 (moderately ill) at Baseline.

5. Verbal and performance scale intelligence quotient (IQ) = 80 (both subtests of the Wechsler Intelligence Scale for Children-V (WISC-V) = 70).

6. If already receiving stable concomitant medications, have continuous participation during the preceding 30 days prior to Screening, and not electively initiate new or modify ongoing medications for the duration of the study. For serotonergic agents, 6 months on a stable dose is required.

7. If already receiving stable non-pharmacologic educational, behavioral, and/or dietary interventions, have continuous participation during the preceding 3 months prior to Screening, and not electively initiate new or modify ongoing interventions for the duration of the study.

8. Have normal physical examination and laboratory test results at Screening. If abnormal, the finding(s) must be deemed not clinically significant by the Treating Clinician.

9. Ability to speak and understand English sufficiently to allow for the completion of all study assessments.

10. Ability to obtain written assent from the participant as well as written informed consent from their parent(s)/legal guardian.

Exclusion Criteria

1. Patients born prior to 35 weeks gestational age.

2. Patients with a primary psychiatric diagnosis other than ASD.

3. Patients with a medical history of neurological disease, including, but not limited to, epilepsy/seizure disorder (except simple febrile seizures), movement disorder, tuberous sclerosis, fragile X, and any other known genetic syndromes, or known abnormal brain MRI/structural lesion.

4. Pregnant female patients, sexually active female patients on hormonal birth control and sexually active females who do not use at least two types of non-hormonal birth control.

5. Patients with evidence or history of malignancy or any significant hematological, endocrine, cardiovascular (including any rhythm disorder), respiratory, renal, hepatic, or gastrointestinal disease.

6. Patients with one or more of the following: hemophilia (bleeding problems, recent nose and brain injuries), abnormal blood pressure (hypotension or hypertension), drug abuse, immunity disorder or severe depression.

7. Patients who are currently taking oxytocin (OXT) or have taken intranasal oxytocin (IN-OXT) in the past with no response.

8. Patients who have an Aberrant Behavior Checklist (ABC) Irritability subscale score > 19 at screening

9. Patients with sensitivity to OXT or any components of its formulation.

10. Patients unable to tolerate venipuncture procedures for blood sampling.

11. Patients in foster care for whom the state is defined as a legal guardian.

12. If they have an arrhythmia present on ECG, that upon consultation with a cardiologist, is deemed to be clinically significant.

13. Patients with any of the following clinical lab results

1. Alanine transaminase (ALT) or aspartate transaminase (AST) levels of = 5 times the upper limit of normal, or if clinical jaundice occurs

2. Sodium levels of > 152 mmol/L or < 128 mmol/L

3. Potassium levels of > 6 mmol/L in a non-hemolyzed sample

4. Glucose levels of > 11 mmol/L or < 2.8 mmol/L

5. Hemoglobin levels of < 100 g/L

6. Blood urea nitrogen (BUN) levels of > 100 mmol/L

7. Creatinine levels of > 100 µmol/L

8. Osmolality levels of > 330 mmol/kg

Related Conditions & MeSH terms

• Autism Spectrum Disorder
• Autistic Disorder
• Child Development Disorders, Pervasive

Intervention

Drug:
• Oxytocin
This is an integrated pharmacological-behavioral intervention targeting social cognitive skills for school-aged children with ASD. Four doses of intranasal oxytocin (24 IUs/dose) will be delivered each week before weekly homework and group therapy sessions.

Behavioral:
• Social Cognitive Skills Training
Social cognitive skills training utilize cognitive behavioral strategies such as problem identification, affective education, performance feedback, and weekly homework activities to target impairments in nonverbal synchrony, emotional expression, and interpretation of intent. The NETT curriculum is manualized and anchored in CBI strategies, such as problem identification, affective education, performance feedback, and weekly homework activities. Parent education sessions run concurrently with child groups to help facilitate generalization.
• Facilitated Play Therapy
The facilitated play therapy group is a manualized treatment designed to tailor play to the interests and abilities of group members. Therapists use general therapeutics strategies such as reflective functioning statements to foster communication with therapists as well as between peers. Standard educational practices for children with ASD such as visual supports, schedules, and short-directed statements are also used. The concurrent parent group is supportive in nature.

Locations

Country	Name	City	State
United States	Rush University Medical Center	Chicago	Illinois

Sponsors (5)

Lead Sponsor	Collaborator
Rush University Medical Center	Eotvos Lorand University, Northwestern University, University of Chicago, University of Illinois at Chicago

Country where clinical trial is conducted

United States, 

References & Publications (1)

Soorya LV, Siper PM, Beck T, Soffes S, Halpern D, Gorenstein M, Kolevzon A, Buxbaum J, Wang AT. Randomized comparative trial of a social cognitive skills group for children with autism spectrum disorder. J Am Acad Child Adolesc Psychiatry. 2015 Mar;54(3):208-216.e1. doi: 10.1016/j.jaac.2014.12.005. Epub 2014 Dec 20. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change From Baseline in Social Behavior Impairment (SBI) Composite	The change from baseline in SBI is represented by the slope of each group. The primary outcome is the difference between groups in this rate of change or the group*time interaction. SBI is a composite score based on Soorya et al. (2015) which identified measures that comprise this metric. Scores from the Children's Communication Checklist-2 (CCC-2) Social Relations and Nonverbal Communication subscales and the Griffith Empathy Measure (GEM) were standardized as z-scores using the sample means and standard deviations at baseline. CCC-2 subscale scores and reversed GEM total scores were used so higher z-scores reflect more impairment across measures. The SBI outcome was subsequently derived by averaging the z-scores. At baseline, the sample average SBI z-score equals 0; higher individual scores indicate relatively more impairment in social behavior skills. Larger, negative slopes represent improvement.	Baseline and Week 12 (Endpoint)
Primary	Rate of Change From Baseline in Social Behavior Impairment (SBI) Composite	The change from baseline in SBI is represented by the slope of each group. The primary outcome is the difference between groups in this rate of change or the group*time interaction. SBI is a composite score based on Soorya et al. (2015) which identified measures that comprise this metric. Scores from the Children's Communication Checklist-2 (CCC-2) Social Relations and Nonverbal Communication subscales and the Griffith Empathy Measure (GEM) were standardized as z-scores using the sample means and standard deviations at baseline. CCC-2 subscale scores and reversed GEM total scores were used so higher z-scores reflect more impairment across measures. The SBI outcome was subsequently derived by averaging the z-scores. At baseline, the sample average SBI z-score equals 0; higher individual scores indicate relatively more impairment in social behavior skills. Larger, negative slopes represent improvement.	Baseline and Week 12 (Endpoint)
Primary	Change From Baseline in Social Behavior Impairment (SBI) Composite	The change from baseline in SBI is represented by the slope of each group. The primary outcome is the difference between groups in this rate of change or the group*time interaction. SBI is a composite score based on Soorya et al. (2015) which identified measures that comprise this metric. Scores from the Children's Communication Checklist-2 (CCC-2) Social Relations and Nonverbal Communication subscales and the Griffith Empathy Measure (GEM) were standardized as z-scores using the sample means and standard deviations at baseline. CCC-2 subscale scores and reversed GEM total scores were used so higher z-scores reflect more impairment across measures. The SBI outcome was subsequently derived by averaging the z-scores. At baseline, the sample average SBI z-score equals 0; higher individual scores indicate relatively more impairment in social behavior skills. Larger, negative slopes represent improvement.	Baseline and Week 16 (1-month follow-up)
Primary	Rate of Change From Baseline in Social Behavior Impairment (SBI) Composite	The change from baseline in SBI is represented by the slope of each group. The primary outcome is the difference between groups in this rate of change or the group*time interaction. SBI is a composite score based on Soorya et al. (2015) which identified measures that comprise this metric. Scores from the Children's Communication Checklist-2 (CCC-2) Social Relations and Nonverbal Communication subscales and the Griffith Empathy Measure (GEM) were standardized as z-scores using the sample means and standard deviations at baseline. CCC-2 subscale scores and reversed GEM total scores were used so higher z-scores reflect more impairment across measures. The SBI outcome was subsequently derived by averaging the z-scores. At baseline, the sample average SBI z-score equals 0; higher individual scores indicate relatively more impairment in social behavior skills. Larger, negative slopes represent improvement.	Baseline and Week 16 (1-month follow-up)
Primary	Change From Baseline in Social Behavior Impairment (SBI) Composite	The change from baseline in SBI is represented by the slope of each group. The primary outcome is the difference between groups in this rate of change or the group*time interaction. SBI is a composite score based on Soorya et al. (2015) which identified measures that comprise this metric. Scores from the Children's Communication Checklist-2 (CCC-2) Social Relations and Nonverbal Communication subscales and the Griffith Empathy Measure (GEM) were standardized as z-scores using the sample means and standard deviations at baseline. CCC-2 subscale scores and reversed GEM total scores were used so higher z-scores reflect more impairment across measures. The SBI outcome was subsequently derived by averaging the z-scores. At baseline, the sample average SBI z-score equals 0; higher individual scores indicate relatively more impairment in social behavior skills. Larger, negative slopes represent improvement.	Baseline and Week 24 (3-month follow-up)
Primary	Rate of Change From Baseline in Social Behavior Impairment (SBI) Composite	The change from baseline in SBI is represented by the slope of each group. The primary outcome is the difference between groups in this rate of change or the group*time interaction. SBI is a composite score based on Soorya et al. (2015) which identified measures that comprise this metric. Scores from the Children's Communication Checklist-2 (CCC-2) Social Relations and Nonverbal Communication subscales and the Griffith Empathy Measure (GEM) were standardized as z-scores using the sample means and standard deviations at baseline. CCC-2 subscale scores and reversed GEM total scores were used so higher z-scores reflect more impairment across measures. The SBI outcome was subsequently derived by averaging the z-scores. At baseline, the sample average SBI z-score equals 0; higher individual scores indicate relatively more impairment in social behavior skills. Larger, negative slopes represent improvement.	Baseline and Week 24 (3-month follow-up)
Primary	Change From Baseline in Social Cognition (SC) Composite	The change from baseline in SC is represented by the slope of each group. The primary outcome is the difference between groups in this rate of change or the group*time interaction. SC is a composite score, including the Reading the Mind in the Eyes Test (RMET) and the Diagnostic Analysis of Nonverbal Accuracy-2 (DANVA2), based on Soorya et al. (2015). RMET has 28 items rated correct/incorrect (total 0-28). DANVA2 contains 4 sets of 24 items rated correct/incorrect (total 0-96). Percent correct was calculated for each measure given the difference in denominators and to allow for administrative omissions. Percentages were standardized as z-scores using the sample means and standard deviations at baseline. The SC outcome was subsequently derived by averaging the z-scores. At baseline, the sample average SC z-score equals 0; higher individual scores reflect stronger skills on social cognitive tasks compared to lower scores. Larger, positive slopes indicate skill improvement.	Baseline and Week 12 (Endpoint)
Primary	Rate of Change From Baseline in Social Cognition (SC) Composite	The change from baseline in SC is represented by the slope of each group. The primary outcome is the difference between groups in this rate of change or the group*time interaction. SC is a composite score, including the Reading the Mind in the Eyes Test (RMET) and the Diagnostic Analysis of Nonverbal Accuracy-2 (DANVA2), based on Soorya et al. (2015). RMET has 28 items rated correct/incorrect (total 0-28). DANVA2 contains 4 sets of 24 items rated correct/incorrect (total 0-96). Percent correct was calculated for each measure given the difference in denominators and to allow for administrative omissions. Percentages were standardized as z-scores using the sample means and standard deviations at baseline. The SC outcome was subsequently derived by averaging the z-scores. At baseline, the sample average SC z-score equals 0; higher individual scores reflect stronger skills on social cognitive tasks compared to lower scores. Larger, positive slopes indicate skill improvement.	Baseline and Week 12 (Endpoint)
Primary	Change From Baseline in Social Cognition (SC) Composite	The change from baseline in SC is represented by the slope of each group. The primary outcome is the difference between groups in this rate of change or the group*time interaction. SC is a composite score, including the Reading the Mind in the Eyes Test (RMET) and the Diagnostic Analysis of Nonverbal Accuracy-2 (DANVA2), based on Soorya et al. (2015). RMET has 28 items rated correct/incorrect (total 0-28). DANVA2 contains 4 sets of 24 items rated correct/incorrect (total 0-96). Percent correct was calculated for each measure given the difference in denominators and to allow for administrative omissions. Percentages were standardized as z-scores using the sample means and standard deviations at baseline. The SC outcome was subsequently derived by averaging the z-scores. At baseline, the sample average SC z-score equals 0; higher individual scores reflect stronger skills on social cognitive tasks compared to lower scores. Larger, positive slopes indicate skill improvement.	Baseline and Week 16 (1-month follow-up)
Primary	Rate of Change From Baseline in Social Cognition (SC) Composite	The change from baseline in SC is represented by the slope of each group. The primary outcome is the difference between groups in this rate of change or the group*time interaction. SC is a composite score, including the Reading the Mind in the Eyes Test (RMET) and the Diagnostic Analysis of Nonverbal Accuracy-2 (DANVA2), based on Soorya et al. (2015). RMET has 28 items rated correct/incorrect (total 0-28). DANVA2 contains 4 sets of 24 items rated correct/incorrect (total 0-96). Percent correct was calculated for each measure given the difference in denominators and to allow for administrative omissions. Percentages were standardized as z-scores using the sample means and standard deviations at baseline. The SC outcome was subsequently derived by averaging the z-scores. At baseline, the sample average SC z-score equals 0; higher individual scores reflect stronger skills on social cognitive tasks compared to lower scores. Larger, positive slopes indicate skill improvement.	Baseline and Week 16 (1-month follow-up)
Primary	Change From Baseline in Social Cognition (SC) Composite	The change from baseline in SC is represented by the slope of each group. The primary outcome is the difference between groups in this rate of change or the group*time interaction. SC is a composite score, including the Reading the Mind in the Eyes Test (RMET) and the Diagnostic Analysis of Nonverbal Accuracy-2 (DANVA2), based on Soorya et al. (2015). RMET has 28 items rated correct/incorrect (total 0-28). DANVA2 contains 4 sets of 24 items rated correct/incorrect (total 0-96). Percent correct was calculated for each measure given the difference in denominators and to allow for administrative omissions. Percentages were standardized as z-scores using the sample means and standard deviations at baseline. The SC outcome was subsequently derived by averaging the z-scores. At baseline, the sample average SC z-score equals 0; higher individual scores reflect stronger skills on social cognitive tasks compared to lower scores. Larger, positive slopes indicate skill improvement.	Baseline and Week 24 (3-month follow-up)
Primary	Rate of Change From Baseline in Social Cognition (SC) Composite	The change from baseline in SC is represented by the slope of each group. The primary outcome is the difference between groups in this rate of change or the group*time interaction. SC is a composite score, including the Reading the Mind in the Eyes Test (RMET) and the Diagnostic Analysis of Nonverbal Accuracy-2 (DANVA2), based on Soorya et al. (2015). RMET has 28 items rated correct/incorrect (total 0-28). DANVA2 contains 4 sets of 24 items rated correct/incorrect (total 0-96). Percent correct was calculated for each measure given the difference in denominators and to allow for administrative omissions. Percentages were standardized as z-scores using the sample means and standard deviations at baseline. The SC outcome was subsequently derived by averaging the z-scores. At baseline, the sample average SC z-score equals 0; higher individual scores reflect stronger skills on social cognitive tasks compared to lower scores. Larger, positive slopes indicate skill improvement.	Baseline and Week 24 (3-month follow-up)
Secondary	Number of Responder and Non-responder Participants Based on CGI-I Scores at Week 12 (Endpoint)	Global Functioning will be assessed using the Clinical Global Impressions-Improvement (CGI-I) Scale. A study physician followed standard CGI protocols to evaluate global improvement at each time point based on all available sources of information (e.g., caregiver interviews, behavior rating forms). The CGI-I employs a 7-point scale with the lowest score, 1, indicating the best outcome and the highest score, 7, indicating the worst outcome. Participants receiving scores of 1 (very much improved) or 2 (much improved) were considered responders. Participants receiving scores of 5 (minimally worse), 6 (much worse), or 7 (very much worse) were considered non-responders; note, no participant received a score worse than 5 which was used as the cut-off for non-responders. Participants receiving scores of 3 (minimally improved) or 4 (no change) were considered to show no significant change and omitted from the analysis.	Week 12 (Endpoint)
Secondary	Number of Responder and Non-responder Participants Based on CGI-I Scores at Week 16 (1-month Follow-up)	Global Functioning will be assessed using the Clinical Global Impressions-Improvement (CGI-I) Scale. A study physician followed standard CGI protocols to evaluate global improvement at each time point based on all available sources of information (e.g., caregiver interviews, behavior rating forms). The CGI-I employs a 7-point scale with the lowest score, 1, indicating the best outcome and the highest score, 7, indicating the worst outcome. Participants receiving scores of 1 (very much improved) or 2 (much improved) were considered responders. Participants receiving scores of 5 (minimally worse), 6 (much worse), or 7 (very much worse) were considered non-responders; note, no participant received a score worse than 5 which was used as the cut-off for non-responders. Participants receiving scores of 3 (minimally improved) or 4 (no change) were considered to show no significant change and omitted from the analysis.	Week 16 (1-month follow-up)
Secondary	Number of Responder and Non-responder Participants Based on CGI-I Scores at Week 24 (3-month Follow-up)	Global Functioning will be assessed using the Clinical Global Impressions-Improvement (CGI-I) Scale. A study physician followed standard CGI protocols to evaluate global improvement at each time point based on all available sources of information (e.g., caregiver interviews, behavior rating forms). The CGI-I employs a 7-point scale with the lowest score, 1, indicating the best outcome and the highest score, 7, indicating the worst outcome. Participants receiving scores of 1 (very much improved) or 2 (much improved) were considered responders. Participants receiving scores of 5 (minimally worse), 6 (much worse), or 7 (very much worse) were considered non-responders; note, no participant received a score worse than 5 which was used as the cut-off for non-responders . Participants receiving scores of 3 (minimally improved) or 4 (no change) were considered to show no significant change and omitted from the analysis.	Week 24 (3-month follow-up)
Secondary	Change From Baseline in Social Functioning (SRS-2)	The change from baseline in the Social Responsiveness Scale (SRS-2) is represented by the slope of each group. The primary outcome is the difference between groups in this rate of change or the group*time interaction. The SRS-2 is a caregiver reported measure of social behavior in the general population (3-18 yo) used to assess social functioning. The SRS-2 contains 65 items rated on a 4-point scale (1/not true to 4/almost always true). Scores are recoded 0-3 and totaled for a raw score. Raw scores are converted to T-scores based on age and sex. T-scores have a population mean of 50 with a standard deviation of 10. T-scores 60-65 indicate mild social impairment, 66-75 moderate deficits, and above 76 severe deficits strongly associated with autism. Higher SRS-2 T-scores indicate greater severity of social impairment. Larger, negative slopes reflect a greater reduction in severity.	Baseline and Week 12 (Endpoint)
Secondary	Rate of Change From Baseline in Social Functioning (SRS-2)	The change from baseline in the Social Responsiveness Scale (SRS-2) is represented by the slope of each group. The primary outcome is the difference between groups in this rate of change or the group*time interaction. The SRS-2 is a caregiver reported measure of social behavior in the general population (3-18 yo) used to assess social functioning. The SRS-2 contains 65 items rated on a 4-point scale (1/not true to 4/almost always true). Scores are recoded 0-3 and totaled for a raw score. Raw scores are converted to T-scores based on age and sex. T-scores have a population mean of 50 with a standard deviation of 10. T-scores 60-65 indicate mild social impairment, 66-75 moderate deficits, and above 76 severe deficits strongly associated with autism. Higher SRS-2 T-scores indicate greater severity of social impairment. Larger, negative slopes reflect a greater reduction in severity.	Baseline and Week 12 (Endpoint)
Secondary	Change From Baseline in Social Functioning (SRS-2)	The change from baseline in the Social Responsiveness Scale (SRS-2) is represented by the slope of each group. The primary outcome is the difference between groups in this rate of change or the group*time interaction. The SRS-2 is a caregiver reported measure of social behavior in the general population (3-18 yo) used to assess social functioning. The SRS-2 contains 65 items rated on a 4-point scale (1/not true to 4/almost always true). Scores are recoded 0-3 and totaled for a raw score. Raw scores are converted to T-scores based on age and sex. T-scores have a population mean of 50 with a standard deviation of 10. T-scores 60-65 indicate mild social impairment, 66-75 moderate deficits, and above 76 severe deficits strongly associated with autism. Higher SRS-2 T-scores indicate greater severity of social impairment. Larger, negative slopes reflect a greater reduction in severity.	Baseline and Week 16 (1-month follow-up)
Secondary	Rate of Change From Baseline in Social Functioning (SRS-2)	The change from baseline in the Social Responsiveness Scale (SRS-2) is represented by the slope of each group. The primary outcome is the difference between groups in this rate of change or the group*time interaction. The SRS-2 is a caregiver reported measure of social behavior in the general population (3-18 yo) used to assess social functioning. The SRS-2 contains 65 items rated on a 4-point scale (1/not true to 4/almost always true). Scores are recoded 0-3 and totaled for a raw score. Raw scores are converted to T-scores based on age and sex. T-scores have a population mean of 50 with a standard deviation of 10. T-scores 60-65 indicate mild social impairment, 66-75 moderate deficits, and above 76 severe deficits strongly associated with autism. Higher SRS-2 T-scores indicate greater severity of social impairment. Larger, negative slopes reflect a greater reduction in severity.	Baseline and Week 16 (1-month follow-up)
Secondary	Change From Baseline in Social Functioning (SRS-2)	The change from baseline in the Social Responsiveness Scale (SRS-2) is represented by the slope of each group. The primary outcome is the difference between groups in this rate of change or the group*time interaction. The SRS-2 is a caregiver reported measure of social behavior in the general population (3-18 yo) used to assess social functioning. The SRS-2 contains 65 items rated on a 4-point scale (1/not true to 4/almost always true). Scores are recoded 0-3 and totaled for a raw score. Raw scores are converted to T-scores based on age and sex. T-scores have a population mean of 50 with a standard deviation of 10. T-scores 60-65 indicate mild social impairment, 66-75 moderate deficits, and above 76 severe deficits strongly associated with autism. Higher SRS-2 T-scores indicate greater severity of social impairment. Larger, negative slopes reflect a greater reduction in severity.	Baseline and Week 24 (3-month follow-up)
Secondary	Rate of Change From Baseline in Social Functioning (SRS-2)	The change from baseline in the Social Responsiveness Scale (SRS-2) is represented by the slope of each group. The primary outcome is the difference between groups in this rate of change or the group*time interaction. The SRS-2 is a caregiver reported measure of social behavior in the general population (3-18 yo) used to assess social functioning. The SRS-2 contains 65 items rated on a 4-point scale (1/not true to 4/almost always true). Scores are recoded 0-3 and totaled for a raw score. Raw scores are converted to T-scores based on age and sex. T-scores have a population mean of 50 with a standard deviation of 10. T-scores 60-65 indicate mild social impairment, 66-75 moderate deficits, and above 76 severe deficits strongly associated with autism. Higher SRS-2 T-scores indicate greater severity of social impairment. Larger, negative slopes reflect a greater reduction in severity.	Baseline and Week 24 (3-month follow-up)
Secondary	Change From Baseline in Quality of Life (CGSQ)	The change from baseline in the Caregiver Strain Questionnaire (CGSQ) is represented by the slope of each group. The primary outcome is the difference between groups in this rate of change or the group*time interaction. The CGSQ was used to assess quality of life. The CGSQ is a parent-rated questionnaire designed for parents of children and adolescents with emotional and behavioral disorders. It includes 21 items rated on a 5-point problem scale (1 = not at all to 5 = very much) rating subjective internal, subjective external, and objective strain. A global measure of strain can be calculated by averaging the scores together. Higher CGSQ scores indicate greater strain. Larger, negative slopes reflect a greater reduction in strain (i.e., improvement in score).	Baseline and Week 12 (Endpoint)
Secondary	Rate of Change From Baseline in Quality of Life (CGSQ)	The change from baseline in the Caregiver Strain Questionnaire (CGSQ) is represented by the slope of each group. The primary outcome is the difference between groups in this rate of change or the group*time interaction. The CGSQ was used to assess quality of life. The CGSQ is a parent-rated questionnaire designed for parents of children and adolescents with emotional and behavioral disorders. It includes 21 items rated on a 5-point problem scale (1 = not at all to 5 = very much) rating subjective internal, subjective external, and objective strain. A global measure of strain can be calculated by averaging the scores together. Higher CGSQ scores indicate greater strain. Larger, negative slopes reflect a greater reduction in strain (i.e., improvement in score).	Baseline and Week 12 (Endpoint)
Secondary	Change From Baseline in Quality of Life (CGSQ)	The change from baseline in the Caregiver Strain Questionnaire (CGSQ) is represented by the slope of each group. The primary outcome is the difference between groups in this rate of change or the group*time interaction. The CGSQ was used to assess quality of life. The CGSQ is a parent-rated questionnaire designed for parents of children and adolescents with emotional and behavioral disorders. It includes 21 items rated on a 5-point problem scale (1 = not at all to 5 = very much) rating subjective internal, subjective external, and objective strain. A global measure of strain can be calculated by averaging the scores together. Higher CGSQ scores indicate greater strain. Larger, negative slopes reflect a greater reduction in strain (i.e., improvement in score).	Baseline and Week 16 (1-month follow-up)
Secondary	Rate of Change From Baseline in Quality of Life (CGSQ)	The change from baseline in the Caregiver Strain Questionnaire (CGSQ) is represented by the slope of each group. The primary outcome is the difference between groups in this rate of change or the group*time interaction. The CGSQ was used to assess quality of life. The CGSQ is a parent-rated questionnaire designed for parents of children and adolescents with emotional and behavioral disorders. It includes 21 items rated on a 5-point problem scale (1 = not at all to 5 = very much) rating subjective internal, subjective external, and objective strain. A global measure of strain can be calculated by averaging the scores together. Higher CGSQ scores indicate greater strain. Larger, negative slopes reflect a greater reduction in strain (i.e., improvement in score).	Baseline and Week 16 (1-month follow-up)
Secondary	Change From Baseline in Quality of Life (CGSQ)	The change from baseline in the Caregiver Strain Questionnaire (CGSQ) is represented by the slope of each group. The primary outcome is the difference between groups in this rate of change or the group*time interaction. The CGSQ was used to assess quality of life. The CGSQ is a parent-rated questionnaire designed for parents of children and adolescents with emotional and behavioral disorders. It includes 21 items rated on a 5-point problem scale (1 = not at all to 5 = very much) rating subjective internal, subjective external, and objective strain. A global measure of strain can be calculated by averaging the scores together. Higher CGSQ scores indicate greater strain. Larger, negative slopes reflect a greater reduction in strain (i.e., improvement in score).	Baseline and Week 24 (3-month follow-up)
Secondary	Rate of Change From Baseline in Quality of Life (CGSQ)	The change from baseline in the Caregiver Strain Questionnaire (CGSQ) is represented by the slope of each group. The primary outcome is the difference between groups in this rate of change or the group*time interaction. The CGSQ was used to assess quality of life. The CGSQ is a parent-rated questionnaire designed for parents of children and adolescents with emotional and behavioral disorders. It includes 21 items rated on a 5-point problem scale (1 = not at all to 5 = very much) rating subjective internal, subjective external, and objective strain. A global measure of strain can be calculated by averaging the scores together. Higher CGSQ scores indicate greater strain. Larger, negative slopes reflect a greater reduction in strain (i.e., improvement in score).	Baseline and Week 24 (3-month follow-up)