Clinical trial NCT02428205
Conditions: Autism
Sponsor: University of Missouri-Columbia
Start date: 2015-04-01; Completion date: 2022-11-01
Enrollment: 10 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
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:
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.

Arms: arm 1: 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. arm 2: 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.
Interventions: intervention 1: Propranolol intervention 2: Placebo
Intervention descriptions: intervention 1: Participant will receive Propranolol prior to each EIBI session intervention 2: Participant will receive placebo prior to each EIBI session

Protocol documents:
Prot_SAP_000.pdf: 
 
 
MU IRB version: 3/26/2014 
 
Page 1 of 14 
 
 
Date: 03/19/2015   
Version Number: 01 
Principal Investigator: David Beversdorf, MD 
Application Number: 2001935 
Application Title: Combined effects of early behavioral intervention and propranolol on ASD 
 
 
Protocol 
 
1. 
Abstract 
a. Provide no more than a one page research abstract briefly stating the problem, the 
research hypothesis, and the importance of the research. 
 
 
Finding effective treatments is a primary concern for individuals with autism and 
their families. Despite decades of research exploring treatment options, few treatments 
targeting core symptoms of the disorder, such as social communication, exist. Behavioral 
therapy involving intensive, individualized training is the mainstay of treatment for 
autism, but drugs targeting autism symptoms can be an important addition to treatment. 
Explorations of combined treatment approaches, in which drugs are used to augment the 
effects of behavioral therapy, are limited within the context of autism. Additionally, most 
currently available drugs target psychiatric symptoms associated with the disorder, 
including aggression, irritability, and obsessive behaviors, instead of core features. 
 
Previous studies from our laboratory have examined the effects of the beta-
blocker propranolol in adults and adolescents with autism. Propranolol inhibits the action 
of norepinephrine, a brain chemical that drives the stress response, or fight-or-flight, 
system. Heightened stress and anxiety in autism suggest propranolol as a potentially 
beneficial drug for this population. Our previous studies have demonstrated a benefit of 
single doses of propranolol for social functioning, as well as language-related cognitive 
abilities, in autism. We have also observed that participants with greater levels of stress 
reactivity demonstrate greater improvements in social functioning with propranolol, 
suggesting a potential method of predicting treatment response. 
 
In the proposed serial-dose, parallel design study, we plan to explore the effects of 
propranolol in combination with early intensive behavioral intervention in children with 
autism. Propranolol or placebo will be administered at the beginning of behavioral 
intervention sessions in a double-blinded, counterbalanced manner for the course of 
twelve weeks. Outcome measures will include assessments of social functioning, 
language, anxiety, adaptive behaviors, and other autism-related symptoms. This study 
will allow us to examine the effects of propranolol with multiple doses in a trial setting. 
In addition, this will be the first exploration of this drug’s effects in children with autism, 
an important area of study given the benefits of early intervention. Previous studies 
involving pediatric migraine suggest that this drug can be used safely in young children. 
We will also determine whether measures of autonomic nervous system functioning and 
anxiety can predict which individuals will respond best to the drug. In this manner, we 
can begin to optimize and individualize combined treatment approaches for treating core 
symptoms of autism. 


 
 
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2. 
Objectives (include all primary and secondary objectives) 
 
 
We propose to examine the effects of propranolol on social interaction in children 
with autism undergoing early intensive behavioral intervention (EIBI) in a 12-week, 
double-blinded, placebo-controlled pilot trial. We will also assess the effects of this 
combined therapeutic approach on language, anxiety, adaptive behaviors, and other 
autism-related behaviors in these individuals. Lastly, we will investigate how autonomic 
nervous system (ANS) activity, as measured by heart rate variability and pupillary light 
reflex, and baseline anxiety might predict the effects of propranolol on social functioning 
and our other outcome measures. We hypothesize that concomitant administration of 
propranolol will enhance the clinical benefit made through EIBI by improving social 
functioning, language, anxiety, adaptive behaviors, and other autism-related behaviors. 
We predict that this augmentation of EIBI’s effects will only be apparent for the 
propranolol condition of the study. We also expect that ANS activity and anxiety levels 
will predict response to propranolol on our outcome measures. 
 
3. 
Background (briefly describe pre-clinical and clinical data, current experience with 
procedures, drug or device, and any other relevant information to justify the research) 
 
 
Previous studies support the existence of altered noradrenergic activity in ASD, 
including early studies suggesting increased plasma (1) and urine (2) adrenergic 
metabolites in autism. Additionally, multiple studies indicate that ASD may be 
characterized by hyper-restrictive associative networks (3, 4) which may be related to 
increased noradrenergic signaling (5).These findings suggest the potential benefit of a 
pharmacological agent aimed at the noradrenergic system for this population. 
Propranolol, a centrally and peripherally active nonselective beta-adrenergic antagonist, 
reduces noradrenergic system activity.  This anxiolytic has been used off-label for test 
anxiety (6) and performance anxiety (7) for several decades.  Propranolol was first 
explored within the context of ASD in an uncontrolled case series, which reported 
improvements in language and sociability (8).  Our laboratory has since investigated this 
agent’s effects on a wide range of behaviors known to be affected in ASD, including 
verbal abilities (9, 10), working memory (11), and facial scanning (12) in single-dose 
psychopharmacological challenge studies in adults and adolescents with ASD. Most 
recently, we demonstrated a benefit of a single dose of propranolol on social functioning, 
assessed via conversational reciprocity, in a sample of 20 high-functioning adults and 
adolescents with ASD (13). This study also showed a potential association between 
resting autonomic activity, assessed via heart rate variability, and response to propranolol 
on the social task. These findings suggest a potential benefit of propranolol on core 
features of ASD and that treatment response may be predicted by certain markers. 
Accordingly, further study is necessary to examine if these potential benefits are not only 
maintained in serial doses, but also if these benefits extend to a younger population of 
individuals with autism. Behavioral therapy, including early intensive behavioral 
intervention (EIBI), has been shown to have lasting benefits for social functioning, 
language, and adaptive functioning in ASD. It has also been shown that behavioral 
intervention is more beneficial when introduced early in life; therefore, this critical early 


 
 
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stage following diagnosis would be also an opportune time to integrate pharmacological 
intervention with behavioral therapy to maximize therapeutic benefits. 
 
4. 
Study Procedures 
a. Study design, including the sequence and timing of study procedures   
(distinguish research procedures from those that are part of routine care). 
 
 
 
The proposed study is a 12-week, parallel design, placebo-controlled pilot trial. For 
the purposes of this study, we will recruit 30 participants with ASD aged 3-8 who are 
currently enrolled in an EIBI program. ASD is defined in this study by the DSM-V 
criteria plus Autism Diagnostic Observation Schedule (ADOS) criteria for Autism. 
Participants will be screened for this formation as well as inclusion/exclusion criteria to 
determine their eligibility to participate in this study over the phone prior to obtaining 
written consent. A waiver of documentation of consent is requested for these screening 
purposes only. Written consent will be obtained prior to any other study-related 
procedures. The ADOS may be administered during the initial study visit if a prospective 
participant does not have ADOS scores from a previous assessment. Additionally, an 
intellectual assessment (IQ test), the Differential Ability Scales (DAS), may be 
administered at this time if previous scores do not exist.  
 
 
 
Prior to participation in the study, informed consent will be obtained from both 
parents/legal guardians of the participant, and assent will be obtained from the 
participant. In addition, the parents and participants will be informed that they can 
terminate the procedure and exit the study at any time. 
 
 
 
We will recruit participants during their participation in the EIBI program at the 
Thompson Center or other institutions in Missouri. The EIBI team provides one-on-one 
instruction for individuals with ASD, as they work toward treatment goals of learning 
new skills and minimizing challenging behavior. EIBI staff will be also be blinded to 
drug conditions. Given the highly individualized nature of EIBI, each participant’s 
therapy will differ in frequency of sessions per week and length, as well as defined 
behavioral targets and the methods used to reach them. This variability will be accounted 
for via a stratified randomization approach (see below) as well as statistically during 
analyses after study completion. 
 
 
Upon study enrollment, participants will be randomized to receive either placebo or 
propranolol for a period of 12 weeks during the study. Drug randomization will be 
counterbalanced to ensure that half of the participants will receive placebo and the other 
half will receive propranolol. Randomization will also be double-blinded so that neither 
participants nor the researchers performing analysis will be aware of the identity of the 
drug being administered. As participants will be receiving varying levels of intensity of 
EIBI (number of hours per week), randomization will also be stratified according to 
different levels of intensity to ensure approximately equal distribution of EIBI intensity 
between the two drug groups. 
 
The following are brief descriptions of the drugs to be administered: 


 
 
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Propranolol [pro-pran’-o-lol] blocks the brain’s and body’s use of norepinephrine 
both centrally and peripherally and also is commonly used to decrease high blood 
pressure.    
 
Placebo [pla-see’-bo] is a physiologically inactive suspension that looks like other 
drugs.  
 
 
Drug administration: 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. Drug 
administration will begin after the first (baseline) study visit. To minimize risk, the 
bodyweight adjusted minimum dose of propranolol used safely for test anxiety in healthy 
adults (10mg) will be used (see table below): 
 
 
 
 
 
 
This more cautious dosing strategy will be utilized for safety purposes, as children may 
be less able to report potential side effects. Participants weighing less than 15kg will be 
excluded for safety reasons. 
 
 
Heart rate and blood pressure monitoring: 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. 
Heart rate and blood pressure will also be measured via wrist cuff at each study visit. If 
on any measurement the heart rate or systolic blood pressure is abnormal, the PI will be 
immediately notified. At this point, the PI may withdraw the participant from the study 
for safety reasons.  
 
 
During the study, participants will undergo ANS activity and behavioral assessments 
(discussed below) at three separate study visits at the following time points: (1) prior to 
drug administration, for establishment of a baseline (week 0); (2) at approximately week 
6; and (3) at the end of week 12. Each study visit is expected to last approximately an 
hour and half. 
 
 
ANS Measurements: At each study visit, ANS measurements will be performed to 
assess autonomic activity. Heart rate variability (HRV), measured via electrocardiogram, 
will be used to assess sympathetic and parasympathetic nervous system activity. 
Electrodes will be placed on the chest region in the typical manner, and signal from the 
electrodes will be amplified by an ECG 100C module connected to a BIOPAC MP150 
data acquisition system. Measurements will be recorded for a period of 8 minutes, 
allowing for 3 minutes of acclimation to the equipment.  
 
We will also evaluate ANS activity via the pupillary light reflex (PLR), a simple 
functional neurological test measuring pupil constriction and recovery in response to 
stimulation via a short light flash. During the test, the participant will sit comfortably in a 
Bodyweight (kg) 
Dose (mg) 
> 30 
4 
22.5 - 30 
3 
15 - 22.5 
2 
< 15 
N/A 


 
 
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chair or will be seated on a parent’s lap about 1 m from the PLR system. A red-filtered 
movie will be shown on a projector screen behind the PLR system to attract the 
participant’s attention. During the test, participants’ PLR will be assessed in both light- 
and dark-adapted conditions. A total of 10 trials, each lasting 2.5 sec followed by a 25-30 
sec interval, will be performed for each stimulation condition. 
 
 
Behavioral Assessments: Behavioral tasks and questionnaires will also be performed 
at each study session. The following assessments will be completed by the participant 
with ASD: 
 
(1) 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. Both video 
recordings and photographs will be anonymized and coded. Parents of the participants 
will complete a release for video recordings and photographs during the enrollment 
process. 
 
(2) Preschool Language Scale, fourth edition (PLS-4): To evaluate language, we 
will administer the PLS-4, 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. 
 
 
 
The following assessments/questionnaires will be completed by a parent or caregiver 
of the participant with ASD: 
 
(1) Comprehensive Review of Systems: At the initial study session only, 
participants’ parents/caregivers will complete a detailed questionnaire about their 
child’s physical and psychological condition, any surgeries or hospitalizations they 
have had, and any medications they are taking. This questionnaire is for the purpose 
of maintaining the safety of participants, as the study staff and PI will compare any 
subsequent symptoms participants report with those listed on this initial review of 
systems. 
 
(2) Interval Medical History Questionnaire: Participants’ parents/caregivers will 
complete a questionnaire about any side effects their child has experienced since the 
previous study visit, any new medical or psychiatric diagnoses, and any concomitant 
medications they are taking or have added since the last study visit, and whether they 
have visited a doctor’s office or hospital since their last study visit. This questionnaire 
is for the purpose of maintaining the safety of participants, as the study staff and PI 


 
 
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will need to ensure that each participant is not experiencing any adverse events 
throughout the study. 
 
(3) Demographic questionnaire: A questionnaire ascertaining a participant’s 
personal and family demographic information, such as race/ethnicity, handedness, 
and socioeconomic status, will be completed by the parent/caregiver at the initial 
study visit only. 
 
(4) Social Responsiveness Scale, second edition (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. Depending on the 
child’s age, the preschool or school-age version of the SRS will be administered. 
 
(5) Clinical Global Impression of Change (CGIC) and Clinical Global Impression 
of Severity (CGIS) scales: To assess overall changes in the participant’s ASD-related 
clinical symptoms, the CGIC and CGIS will be administered. The CGIC consists of a 
7-point subjective scale assessing change from baseline. On this 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. The CGIS is a similar 7-point subjective scale for severity. 
 
(6) 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. 
 
(7) 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. 
 
(8) Aberrant Behavior Checklist (ABC): To assess overall behavioral 
disturbances, a parent/caregiver of the participants will complete the ABC. This 58-
item questionnaire is a well validated, reliable, and widely used assessment tool for 
interventions for a range of cognitive disorders. 
 
(9) Preschool Anxiety Scale (PAS): To assess anxiety, the PAS will be completed 
by a parent/caregiver. This 34-item parent-report questionnaire, adapted from the 
Spence Children’s Anxiety Scale (SCAS), yields a total score and five subscale 
scores based on DSM-IV anxiety disorder structure (separation anxiety, social phobia, 
obsessive-compulsive disorder, and generalized anxiety), as well as fears related to 
physical injury. 
 
 
We will also make efforts to gain the input of participants’ parents/caregivers at the 
outset as well as completion of the study. This will involve the completion of a survey 
upon study enrollment asking about potential outcomes the parent/caregiver wishes to 
explore (e.g., gastrointestinal symptoms) in this study. Any suggestions that are not 
already incorporated to the study and are deemed appropriate and necessary by the PI will 


 
 
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be submitted to the HS IRB as an amendment. Additionally, after completing the study, 
the participants’ parents/caregivers will be asked to complete an exit survey, asking about 
their child’s experience of the study and if they have any suggestions for future studies of 
a similar nature. This survey will be given to parents/caregivers to complete at the end of 
the final study visit or mailed when necessary. 
 
We will also make efforts to inform families of the progress of this study via 
newsletters containing enrollment updates and new (non-study related) findings and news 
in autism research sent via email on a quarterly basis. Each newsletter will be submitted 
to the HS IRB for approval prior to being sent out. 
 
 
b. Study duration and number of study visits required of research participants. 
 
Participation in this study will last 12 weeks and will involve 3 visits to the 
Thompson Center for Autism & Neurodevelopmental Disorders lasting approximately an 
hour and a half each. If a private room is not available at the Thompson Center when a 
participant’s visit needs to be scheduled, the visit will take place at the Center for 
Translational Neuroscience (M741) in the Medical Sciences Building instead. 
 
c. Blinding, including justification for blinding or not blinding the trial, if applicable. 
 
This study will be double-blinded for the purposes of removing any bias that 
could be introduced if either the researchers or the study participants are aware of which 
drug they are taking at a given time. Blinding of the drugs will be conducted by the 
University Hospital’s Investigational Pharmacy. In the case of emergency, the PI and 
research staff running study sessions will have access to unblinding information in the 
form of a sealed envelope. 
 
d. Justification of why participants will not receive routine care or will have current 
therapy stopped. 
 
Routine care for this population will not be affected by this study. Participants 
will be able to continue routine care, including behavioral therapy or other medications. 
Potential participants taking medications that are exclusionary for this study will not be 
enrolled. 
 
e. Justification for inclusion of a placebo or non-treatment group. 
 
A placebo arm of this study will allow for statistical comparisons between 
behavioral performance for participants who are taking placebo versus propranolol. The 
parallel design of the trial will involve half of the participants receiving propranolol and 
the other half receiving placebo. Drug randomization will be counterbalanced. 
 
f. Definition of treatment failure or participant removal criteria. 
 
As this is a pilot trial exploring the effects of propranolol on social and language 
abilities, there are no behavioral endpoints that we would consider treatment failure. 
However, for the safety of the participants, if at any measurement taken, a participant’s 
heart rate or blood pressure is abnormal or if the participant is experiencing an adverse 
reaction to the drug the PI will be immediately notified. At that point, if the PI determines 
it is necessary, the participant will be instructed to discontinue taking the drug and will be 
removed from the study.  


 
 
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g. Description of what happens to participants receiving therapy when study ends or if a 
participant’s participation in the study ends prematurely. 
 
When the study ends or if a participant’s participation ends prematurely, the 
participant will no longer take propranolol or placebo. Participants will continue with 
their routine care as they would have done throughout the study. 
 
5. 
Inclusion/Exclusion Criteria 
Inclusion criteria:  
 
For participants with autism: Individuals with ASD aged 3-8. ASD is defined in 
this study by the DSM-V criteria plus Autism Diagnostic Observation Schedule (ADOS) 
criteria for Autism. Participants must also be enrolled in an EIBI program at the 
Thompson Center or another institution in Missouri for the duration of the study. 
 
For parent/caregiver of participant with autism: Minimum age of 18, no maximum age. 
 
Exclusion criteria:  
 
For participants with autism: 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), or any of the following exclusionary 
criteria related to the pupillary response 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. 
 
For parent/caregiver of participant with autism: No exclusionary criteria. 
 
6. 
Drugs/ Substances/ Devices 
a. The rationale for choosing the drug and dose or for choosing the device to be used. 
 
 
Propranolol is a beta-adrenergic antagonist that dampens the stress response 
system. Previous studies from our laboratory indicate a potential effect of propranolol on 
social and language abilities in adults and adolescents with ASD. This pilot trial 
investigation will explore the effects of serial doses of propranolol in children with 
autism who are concurrently undergoing EIBI. We predict that propranolol’s effects on 
stress and anxiety will positively impact social and language abilities in children with 
ASD and augment the effects of EIBI.  
 
b. Justification and safety information if FDA approved drugs will be administered for 
non-FDA approved indications or if doses or routes of administration or participant 
populations are changed. 
 
Propranolol is part of established care for treating pediatric migraine (14, 15, 16) 
and infantile hemangioma (17, 18), demonstrating its safety for this population. To 


 
 
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minimize risk, the doses to be used for children in the present study were selected as the 
bodyweight adjusted minimum dose safely used in otherwise healthy adults for test 
anxiety. The typical doses for test anxiety in adults (10mg) are lower than those for 
cardiac indications (starting dose for hypertension is 40mg). Participants taking 
propranolol in this study may be at risk for the side effects described below. 
Parents/caregivers and the participants will also be told that there may be other side 
effects that we cannot predict. Measures to maintain the safety of study participants will 
be further discussed below.  Parents/caregivers of participants will be encouraged to 
discuss these with the PI (David Q. Beversdorf, MD) and/or their own doctor. 
 
c. Justification and safety information if non-FDA approved drugs without an IND will 
be administered.  
 
 
N/A 
 
7. 
Study Statistics 
a. Primary outcome variable. 
 
We are primarily exploring the effects of propranolol on social abilities, as 
assessed via the GOSM and the SRS. 
 
b. Secondary outcome variables. 
 
Our secondary outcome variables include effects on anxiety (assessed via the 
PAS), language abilities (assessed via the PLS-4), adaptive/global functioning (assessed 
via the Vineland), and change in clinical impression/impact of ASD symptoms (assessed 
via CGIC, CGIS, ABC, and AIM). 
 
c. Statistical plan including sample size justification and interim data analysis. 
 
To determine the appropriate sample size for this study, we conducted a power 
analysis based on effect size estimates on our previous study examining the effects of 
propranolol on social functioning in ASD. The power analysis indicated that a sample 
size of 20 would achieve a proposed power of 0.80 at the significance level of α = .05. 
Behavioral assessments will be compared across study time points and between drugs 
(propranolol and placebo) using repeated measures multivariate analyses of variance 
(MANOVAs). We will use simple linear regressions to determine whether variability in 
baseline autonomic nervous system functioning or anxiety serve as markers to predict 
treatment response. Interim data analysis will only be conducted for the purposes of 
presenting preliminary data at academic conferences. The investigational pharmacy will 
assist in unblinding collected data for these preliminary analyses, keeping investigators 
blinded throughout the study. 
 
 
 
d. Early stopping rules. 
 
As this is a pilot trial exploring the effects of propranolol on social and language 
abilities, there are no behavioral endpoints that we could consider treatment success or 
failure prior to the completion of the study, thus we would not stop the study based on 
early evidence of treatment efficacy or futility. If safety becomes a concern due to side 
effects associated with propranolol, the PI (in consultation with the HS IRB) may decide 


 
 
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to stop the study early. However, this is not expected to occur given the minimal side 
effects known to be associated with this drug at these doses. 
 
8. 
Risks 
a. Medical risks, listing all procedures, their major and minor risks and expected 
frequency. 
 
The medical risks participants may encounter are those associated with taking the 
drugs used in this study. Below are the descriptions and side effects associated with each 
drug: 
 
Propranolol [pro-pran’-o-lol] is commonly used to decrease high blood pressure. 
This drug can cause problems for persons with depression, diabetes, thyroid disease, 
very slow heart rates, very low blood pressure, fluid in the lungs from heart failure, 
and asthma. The side effects related to this drug are given below. These symptoms are 
most present within 5 hours of the drug administration. None of these symptoms will 
be present once the single dose is washed out of the system, which can take up to 24 
hours. 
•Very Likely: Decreased Blood Pressure and/or Slow Heart Rate 
•Less Likely: Decreased Sex Drive or Impotence 
•Rare: Abdominal Cramps, Diarrhea, Constipation, Fatigue, Depression, Vivid 
Dreaming and/or Tingling Sensations 
•Rare but more Serious Side Effects: Insomnia, Nausea, Hypersensitivity/Allergy, 
Dizziness, Drowsiness or Lightheadedness, Very Slow or Uneven Heartbeats, 
Swelling of Ankles/Feet and/or Difficulty Breathing 
 
Placebo [pla-see’-bo] is a physiologically inactive suspension that looks like other 
drugs. The placebo doses will not have any risk associated with their administration. 
 
Participants may also encounter minor risks associated with the adhesives used to 
collect ANS data via electrocardiogram. Participants may develop a small rash where 
the sensors attach to their chest. If this occurs, the rash normally subsides shortly after 
the study visit. Participants and their parents/caregivers will be asked to notify a 
member of the study staff or the PI if the rash persists. 
 
There are also psychological risks of boredom and probing for personal and/or 
sensitive information in the tasks and questionnaires the participants will complete as 
part of this study. 
 
There is the potential risk of a loss of privacy, in which information related to 
participants’ autism diagnosis and their answers to the tasks and questionnaires being 
administered will be obtained.  
 
b. Steps taken to minimize the risks. 
 
Strict adherence to the exclusionary criteria of this study will minimize the chance 
of enrolling participants who might be put at risk by taking propranolol. Before 
enrollment in the study, the PI (a licensed physician) will meet in person with prospective 


 
 
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participants and their parents/caregivers to evaluate their ability to safely take part in this 
study. Upon enrollment in the study, participants’ parent/caregiver will be given a 
business card containing contact information for lead study staff and the PI in case of 
questions and/or emergency. Additionally, one week after the initiation of drug 
administration (at approximately week 1), a member of the study staff will call the 
participants’ parents/caregiver to inquire about any possible side effects associated with 
the drug (listed above). Any reports of adverse response to the drug will be 
communicated to the study PI. 
 
Given the chance of unforeseen side effects associated with the drug in 
participants who met criteria for participating in the study, monitoring of heart rate and 
blood pressure will occur at each of three study visits. If on any measurement the heart 
rate or systolic blood pressure is abnormal, the PI will be immediately notified. At this 
point, the PI may withdraw the participant from the study for safety reasons. 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. 
 
At each study visit taking place at the Thompson Center for Autism & 
Neurodevelopmental Disorders or the Center for Translational Neuroscience, a member 
of the study staff will first confirm with the participant and his/her parent/caregiver that 
no changes in the participant’s physical condition have occurred since he/she met with 
the PI in person. A medical and pharmaceutical history will also be obtained to ensure the 
participant’s condition has not changed in a way that would increase the risk of taking 
propranolol. Any new symptoms or diagnoses will be reported to the PI, who will follow-
up with the participant and parent/caregiver if necessary.  
 
Participants with previously documented history of rash from adhesives will be 
excluded from the study. This will minimize the risks associated with the ANS 
measurements taken during the study sessions. 
 
To minimize the risk of boredom, participants will be given the opportunity to 
take breaks and ask any questions they have. 
 
To minimize the risk of probing for personal and/or sensitive information, testing 
will take place in a private room at the Thompson Center. If participants have difficulty 
with disclosure of information on some surveys, they will be reminded that their answers 
will be kept securely and are confidential. 
 
To minimize the risk of loss of privacy, the data will be coded, password-
protected, and stored separately from the consent and screening forms in a locked filing 
cabinet. However, in the unfortunate event that a loss of privacy occurs, it is possible that 
information related to a participant's autism diagnosis and performance on the tests being 
administered will be obtained. 
 
c. Plan for reporting unanticipated problems or study deviations. 
 
Any unanticipated problems or study deviations will be immediately reported to 
the PI and HS IRB via an Event Report for further investigation.  
 
d. Legal risks such as the risks that would be associated with breach of confidentiality. 
 
The risk of loss of privacy is minimized as the data will be coded, password-
protected, and stored separately from the consent and screening forms in a locked 
filing cabinet. However, in the unfortunate event that a loss of privacy occurs, it is 


 
 
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Page 12 of 14 
 
possible that information related to a participant's autism diagnosis and performance 
on the tests being administered will be obtained. 
 
e. Financial risks to the participants. 
 
There are no expected financial risks associated with this study. However, in the 
event of an injury associated with the study, participants may be responsible for 
paying for medical expenses associated with that injury. This determination would be 
made in consultation with the University of Missouri Risk Management Officer. 
 
9. 
Benefits 
a. Description of the probable benefits for the participant and for society. 
 
It is possible that participants may experience benefit on the behavioral 
assessments of social functioning, language abilities, anxiety, and global and adaptive 
functioning in the propranolol condition. Otherwise, there are no direct benefits to the 
participant. If propranolol is shown to improve ASD-related symptoms, with the greatest 
benefits being for those with the greatest dysregulation in autonomic activity, 
propranolol may be used to treat others with similar conditions. 
 
10. 
Payment and Remuneration 
a. Detail compensation for participants including possible total compensation, proposed 
bonus, and any proposed reductions or penalties for not completing the protocol. 
 
Participants will be compensated $25.00 for each completed study visit they 
complete, for a total of $75.00 if they complete all three study visits.  Furthermore, 
participants will be compensated $25.00 for diagnostic testing, if needed, via the Autism 
Diagnostic Observation Schedule (ADOS) and $25.00 for IQ testing, if needed, via the 
Differential Ability Scales (DAS). If a participant lives more than 50 miles from 
Columbia, MO, the family will be eligible for a flat rate of $75 per visit to offset of costs 
of travel to the Thompson Center. If a family is eligible for travel funds, they could be 
paid a maximum of $225 for travel-related expenses. Payments will be mailed in the 
form of a check within approximately one month after each study visit. 
 
11. 
Costs 
a. Detail costs of study procedure(s) or drug (s) or substance(s) to participants and 
identify who will pay for them. 
 
All test procedures, materials, and medications are paid for by the study. The only 
expected direct cost to the participants will be transportation to and from the Thompson 
Center for Autism & Neurodevelopmental Disorders or Center for Translational 
Neuroscience if the family lives within 50 miles of Columbia, MO. Participants’ 
parents/caregivers may also be responsible for costs incurred in the research for ancillary 
resources, such as medical treatment, psychological counseling, emergency services or 
concomitant medications. 
 
12. 
References 
a.   List of references supporting research question. 
 
 


 
 
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(1) Lake C, Ziegler MG, Murphy DL. Increased norepinephrine levels and decreased 
dopamine-β-hydroxylase activity in primary autism. Archives of General Psychiatry. 
1977;34(5):553-6. 
 
(2) Martineau J, Barthélémy C, Jouve J, Muh J-P, LeLord G. Monoamines (serotonin and 
catecholamines) and their derivatives in infantile autism: Age-related changes and drug 
effects. Developmental Medicine & Child Neurology. 1992;34(7):593-603. 
 
(3) Beversdorf D, Narayanan A, Hillier A, Hughes J. Network model of decreased 
context utilization in autism spectrum disorder. Journal of Autism and Developmental 
Disorders. 2007;37(6):1040-8. 
 
(4) Beversdorf DQ, Smith BW, Crucian GP, et al. Increased discrimination of “false 
memories” in autism spectrum disorder. Proceedings of the National Academy of 
Sciences. 2000;97(15):8734-7. 
 
(5) Hasselmo ME. Noradrenergic suppression of synaptic transmission may influence 
cortical signal-to-noise ratio. Journal of the American Physiological Society. 
1997;77(6):3326-3339.  
 
(6) Faigel HC. The effect of beta blockade on stress-induced cognitive dysfunction in 
adolescents. Clinical pediatrics. 1991;30(7):441-5. 
 
(7) Laverdure B, Boulenger JP. Beta-blocking drugs and anxiety: A proven therapeutic 
value. L'Encephale. 1991;17(5):481-92. 
 
(8) Ratey J, Bemporad J, Sorgi P, et al. Brief report: Open trial effects of beta-blockers on 
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Disorders. 1987;17(3):439-46. 
 
(9) Beversdorf DQ, Carpenter AL, Miller RF, Cios JS, Hillier A. Effect of propranolol on 
verbal problem solving in autism spectrum disorder. Neurocase. 2008;14(4):378-83. 
 
(10) Beversdorf DQ, Saklayen S, Higgins KF, Bodner KE, Kanne SM, Christ SE. Effect 
of propranolol on word fluency in autism. Cognitive and Behavioral Neurology. 
2011;24(1):11-7. 
 
(11) Bodner KE, Beversdorf DQ, Saklayen SS, Christ SE. Noradrenergic moderation of 
working memory impairments in adults with autism spectrum disorder. Journal of the 
International Neuropsychological Society. 2012;18(3):556-64. 
 
(12) Zamzow RM, Christ SE, Saklayen SS, et al. Effect of propranolol on facial scanning 
in autism spectrum disorder: A preliminary investigation. Journal of Clinical and 
Experimental Neuropsychology. 2014:1-15. 
 


 
 
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(13) Zamzow RM, Ferguson BJ, Hegarty II JP, Stichter JP, Beversdorf DQ. Effects of 
beta-adrenergic antagonism on a measure of social functioning in autism spectrum 
disorder. Biological Psychiatry. (In prep). 
 
(14) Eiland, L. S., Jenkins, L. S., & Durham, S. H. (2007). Pediatric migraine: 
Pharmacologic agents for prophylaxis. Annals of Pharmacotherapy, 41, 1181-1190. 
 
(15) Ashrafi MR, Shabanian R, Zamani GR, et al. (2005). Sodium valproate versus 
propranolol in paediatric migraine prophylaxis. European Journal of Paediatric 
Neurology, 9, 333-338. 
 
(16) Bidabadi E, Mashouf M. (2010). A randomized trial of propranolol versus sodium 
valproate for the prophylaxis of migraine in pediatric patients. Pediatr Drugs, 12, 269-
275. 
 
(17) Léauté-Labrèze C, de la Roque ED, Hubiche T, et al. (2008). Propranolol for severe 
hemangiomas of infancy. New England Journal of Medicine, 358, 2649-2651. 
 
(18) Sans V, de la Roque ED, Berge J, et al. (2009). Propranolol for severe infantile 
hemangiomas: Follow-up report. Pediatrics, 124, 423-431.