Combined Effects of Early Behavioral Intervention and Propranolol on ASD

Study Overview
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Brief Summary
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The purpose of this study is to explore the effects of propranolol in combination with early intensive behavioral intervention on social interaction, and secondarily on language, anxiety, adaptive behaviors, and global function in children with autism in a double-blinded, placebo-controlled pilot trial.

Detailed Description
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The investigators' specific aim is to examine the effects of serial doses of propranolol in combination with early intensive behavioral intervention on social interaction, and secondarily on language tasks, anxiety, adaptive behaviors, and global function in children with autism in a double-blinded, placebo-controlled trial. The investigators will also examine whether response to treatment can be predicted based upon markers of autonomic functioning, such as pupillary light reflex and heart rate variability, and whether anxiety predicts treatment response. The investigators' hypothesis is that propranolol will augment the effects of behavioral therapy on social functioning and language abilities. The investigators have demonstrated benefits of propranolol on social functioning and language in previous single-dose studies in adults and adolescents with autism. The investigators also predict that those with the greatest degree of autonomic dysregulation will demonstrate the greatest benefit from the drug.

Official Title
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Combined Effects of Early Behavioral Intervention and Propranolol on ASD

Conditions
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Autism

Intervention / Treatment
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* Drug: Propranolol
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of autism spectrum disorder (ASD), defined in this study by the DSM-V criteria plus Autism Diagnostic Observation Schedule (ADOS) criteria for Autism. Aged 3-8 Participants must also be enrolled in an early behavioral intervention program at the Thompson Center or another institution in Missouri for the duration of the study. Exclusion Criteria: Non-autism learning disability (e.g. dyslexia) Major psychiatric diagnosis (e.g. major depression, schizophrenia, bipolar disorder) Other neurological diagnosis Major head trauma Any of the following exclusionary criteria related to propranolol (diabetes, reactive airway/pulmonary disease, thyroid disease, bradyarrhythmias, unexplained syncope, narrow angle glaucoma, known hypersensitivity/adverse reaction to beta-blockers, potentially interacting drugs, underweight < 15 kg) Any of the following exclusionary criteria related to the use of electrocardiogram (history of rash from adhesives) Any of the following exclusionary criteria related to the pupillary reflex measurement (uncorrectable visual acuity impairment). Participants with a heart rate of less than 60 or a systolic blood pressure of less than 75 at the outset of the study will be excluded.

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 10 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Propranolol arm<br>Propranolol will be administered in the form of a liquid dose via oral syringe by the participants' parent/caregiver an hour before each EIBI session. To minimize risk, the bodyweight adjusted minimum dose of propranolol used safely for test anxiety in healthy adults (10mg) will be used: participants weighing > 30 kg will be given 4 mg, participants weighing 22.5 - 30 kg will be given 3 mg, participants weighing 15 - 22.5 kg will be given 2 mg. Participants weighing < 15 kg will be excluded for safety reasons. | Drug: Propranolol<br>* Participant will receive Propranolol prior to each EIBI session<br>* Other names: Inderal;|
| Placebo Comparator: Placebo arm<br>Placebo will be administered in the form of a liquid dose via oral syringe by the participants' parent/caregiver an hour before each EIBI session.The same bodyweight adjusted doses specified in the propranolol arm will be used for this arm. | Drug: Placebo<br>* Participant will receive placebo prior to each EIBI session<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in General Social Outcome Measure (GSOM) | The GSOM is a brief evaluation tool that measures a participant's level of social functioning and how it changes with intervention. There GSOM includes 4 different tasks: conversational reciprocity, ability to recognize facial expressions, social problem solving, affect demonstration, and emotional perspective taking. The experimenter administers each component of the GSOM to the participant and then scores their responses according to a pre-determined scoring rubric. Each component is scored on a 1-5 or 0 - 2 scale, with higher total scores indicating better social functioning. A video camera will be used to record the participant's behavior during GSOM administration for the purposes of having two independent raters score the tasks after the study session is complete. The video camera will be turned off for the remainder of the study session. A camera will also be used during the affect demonstration task of the GSOM. | Week 1, Week 6, Week 12 | 
| Change in Social Responsiveness Scale (SRS) | This 65-item, parent-report measure asks questions about a participants' social awareness, social information processing, capacity for reciprocal social responses, social anxiety or avoidance, and characteristic autistic preoccupations or traits. | Week 1, Week 6, Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Preschool Anxiety Scale (PAS) | To assess anxiety, the PAS will be completed by the parents/caregivers of participants. This self-report measure yields a total score in addition to six subscales (separation anxiety, social phobia, obsessive compulsive, panic/agoraphobia, physical injury fears, and generalized anxiety). | Week 1, Week 6, Week 12 | 
| Change in Clinical Global Impression of Change (CGIC) scale | To assess overall changes in the participant's ASD-related clinical symptoms, the CGIC will be administered. The CGIC consists of a 7-point subjective scale assessing change from baseline, initially assessed via the the Clinical Global Impression of Severity (CGIS) scale (CGIS). On the CGIC scale, scores of 1, 2, and 3 represent marked, moderate, and mild improvement, respectively. A score of 4 represents no change. Scores of 5, 6, and 7 represent mild, moderate, and marked worsening, respectively. CGIC scores from both the parent/caregiver and a blinded clinician will be utilized. | Baseline, Week 6, Week 12 | 
| Change in Clinical Global Impression of Severity (CGIS) scale | To assess overall severity of a participant's ASD-related clinical symptoms, the CGIS will be administered. The CGIS consists of a 7-point subjective scale assessing symptom severity. On this scale, scores of 1, 2, and 3 represent normal, some presence of symptoms, and mild behavior, respectively. A score of 4 represents moderate behavior. Scores of 5, 6, and 7 represent marked, severe, and among the most severe behavior, respectively. CGIS scores from both the parent/caregiver and a blinded clinician will be utilized. | Week 1, Week 6, Week 12 | 
| Change in Aberrant Behavior Checklist (ABC) | To assess overall behavioral disturbances, a parent/caregiver of the participants will complete ABC. This 58-item questionnaire is a well validated, reliable, and widely used assessment tool for interventions for a range of cognitive disorders. | Week 1, Week 6, Week 12 | 
| Change in Vineland Adaptive Behavior Scales-II (VABS) | To assess overall adaptive functioning, the VABS will be administered in the form of a structured interview with the parent/caregiver. The VABS is a well validated assessment used for the full range of our subjects' ages and yields standard scores in Communication, Daily Living Skills, Socialization, and Motor Skills. VABS scores for Communication, Daily Living Skills, and Socialization will be monitored in this study. | Week 1, Week 6, Week 12 | 
| Change in Autism Impact Measure (AIM) | The AIM will be administered to assess the frequency and impact of a participant's ASD-related symptoms. A parent/caregiver is asked a series of 41 questions regarding the frequency and the impact, or interference resulting from, a series of autism-associated behaviors. Overall impact and frequency scores, as well as subscale scores, will be obtained from this measure. | Week 1, Week 6, Week 12 | 
| Change in Preschool Language Scale (PLS): | To evaluate language, we will administer the PLS, which has been developed for use in younger children (birth through age 7), and is appropriate for children of all ability levels, including nonverbal children. This play-based, interactive assessment is designed to assess receptive and expressive language skills and their change over time. | Week 1, Week 6, Week 12 |