Trial of Propranolol in Children and Youth With Autism Spectrum Disorder and Predictors of Response
Phase: EARLY_PHASE1
Conditions: Autism Spectrum Disorder
Sponsor: University of Missouri-Columbia

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Date: 5/16/2017    
Version Number: 6 
Principal Investigator: David Q. Beversdorf, MD 
Application Number: 2005213 
Application Title: Trial of Propranolol in Children and Youth with ASD and Predictors of Response 
 
 
Protocol 
 
 
1. Abstract 
 
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by 
impairments in social communication and restricted, repetitive behaviors, which affects 
approximately 1 in 68 children in the United States. Pharmacotherapies are often a significant 
component of treatment of ASD, but most are directed at psychiatric symptoms, such as 
agitation, anxiety, repetitive and obsessive behaviors, and depression. Evidence for 
pharmacological treatments aimed at improving cognitive aspects of ASD, including language 
and socialization, is not yet established. This is an important area of new investigation. Most 
published studies specifically directed at the cognitive aspects of ASD are small case series 
reports, single dose studies, or small pilot trials. Both social and language benefits have been 
reported in a small, uncontrolled case series of autism patients with the beta-adrenergic 
antagonist, propranolol. Work from our lab has demonstrated benefits in verbal problem-
solving and social interaction with propranolol in adults and adolescents with ASD in double-
blinded placebo-controlled single dose challenge studies. Due to the potential benefits from 
cognitive pharmacotherapy, and evidence suggesting social and language benefits from 
propranolol in ASD, we now wish to determine whether the benefits we observed with single 
doses also occur with repeated doses in a double-blinded placebo-controlled pilot trial. Our 
aim is to examine the effects of serial doses of propranolol on social interaction, as well as on 
language tasks, anxiety, adaptive behaviors, global function in high-functioning children and 
youth with ASD. We will also examine whether response to treatment can be predicted based 
upon markers of anxiety and autonomic nervous system activity. This trial will entail one 15-
week drug period, during which participants will be randomized to take propranolol or 
placebo daily in a double-blinded manner. Participants will also have the option of completing 
a 12-week open label extension during which they will be prescribed propranolol by their 
primary care physician. Successful completion of this work could result in the development of 
a new evidence-based treatment option for core features of ASD, which does not currently 
exist. It may also result in markers to predict who is most likely to respond.  
 
2. Objectives  
 
Our specific aim is to examine the effects of serial doses of propranolol on social interaction, 
and secondarily on language tasks, anxiety, adaptive behaviors, and global function in high 
functioning adults and adolescents with autism in a double-blinded, placebo-controlled trial. 
We will also examine whether response to treatment can be predicted based upon markers of 
autonomic functioning, such as skin conductance, heart rate variability (HRV), and the 
pupillary light reflex (PLR), and whether anxiety can predict treatment response. Our 
hypothesis is that social functioning and language abilities will benefit from serial doses of 
propranolol, as we have demonstrated in previous single-dose studies. We also predict that 

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those with the greatest degree of autonomic dysregulation, or the lowest functional 
connectivity, will demonstrate the greatest benefit from the drug. 
 
3. Background  
 
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) and a potential association between resting autonomic activity, 
assessed via heart rate variability, and response to propranolol on the social task (14). 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 maintained in serial doses in the form of a trial in 
children and youth with autism. 
 
4. Study Procedures 
a. Study design, including the sequence and timing of study procedures   
 
The proposed study is a between-subject, placebo-controlled trial. For the purposes of 
this study, we will recruit two groups of participants—the first being children age 7-14 
with ASD, the second being youth age 15-24 with high functioning ASD. High-
functioning autism is defined in this study by Autism Diagnostic Interview-Revised 
(ADI-R) criteria and Autism Diagnostic Observational Scale (ADOS) criteria for autism, 
and a WASI-II IQ full scale of at least 85. Participants will be screened for this 
information as well as inclusion/exclusion criteria to determine their eligibility to 
participate in this study through their medical record and over the phone prior to 
obtaining written consent. A waiver of documentation consent is requested only for 
these screening purposes and to distribute the Rome IV Diagnostic Questionnaire for 
Pediatric Functional Gastrointestinal Disorders - Child (R4PDQ-Child), (for adults, the 
Rome IV Diagnostic Questionnaire for Adults (R4DQA) will be used), and the 
Gastrointestinal Symptoms Inventory (GSI). Written consent will be obtained prior to 
any other study-related procedures. 
If a prospective participant does not have IQ scores available through the Thompson 
Center database or EMR, such as Powerchart, or if the participant’s scores are not 
reflective of his/her current level of functioning, the WASI-II may be given at the 
beginning of the initial study visit or at a separate visit. The ADI-R may be 
administered to the parent/caregiver of a prospective participant at the beginning of 
the initial study visit or at a separate visit, if the prospective participant does not have 
ADI-R scores from a previous assessment. Prior to participation in the study, informed 

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consent will be obtained from each subject. In addition, the subjects will be informed 
that they can terminate the procedure and exit the study at any time. 
 
Procedure outline for ages 15-24: 
 
General study visit outline: 
Upon study enrollment, participants will be randomized to receive either placebo or 
propranolol via oral capsule, crushed tablet, or liquid daily. The drug dosage will be 
titrated slowly to ensure the drug is tolerated well (detailed titration schedule below). 
The following are brief descriptions of the drugs to be administered: 
 
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], also commonly referred to as a “sugar pill,” is an inactive 
substance that looks like other drugs. 
 
Subjects in the youth age group will undergo magnetic resonance imaging (MRI) before 
initiating drug. (See details below.) 
 
During the study, participants will undergo psychophysiological 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; (2) halfway 
through drug period (approximately week 6); (3) the end of drug period 
(approximately week 12).  
 
Prescription for the drug will be given after the completion of the imaging and baseline 
sessions. 
 
At each study visit, psychophysiological measurements will be performed to assess 
autonomic activity (details below). A small sample of cheek cells will be taken using a 
buccal swab for genetic processing. Behavioral tasks and questionnaires will also be 
performed at each study session, except for the Vineland, which will only be performed 
at baseline and week 12. Different forms of each behavioral task will be used at each of 
the six visits. Questionnaires will remain the same for each visit. (See detailed 
description below.) 
 
Imaging visit specifics: 
The imaging personnel will go over the MRI screening form in detail with the subject 
and give specific instructions on how to safely complete the session. Subjects will also 
be given the option to practice in a mock scanner before the actual scanning session to 
acclimatize them better. The MRI session will consist of a T1 weighted anatomical scan, 
functional MRI (task-based activation), resting state functional connectivity MRI and 
diffusion tensor imaging (DTI). Prior to each scanning session, the subjects will be 
given practice fluency tasks to familiarize with the task. For the semantic word fluency 
task imaging, a block design with two sets of three task blocks (30 seconds) and 4 rest 
blocks (30 seconds) for a total of 3 min 30 sec for each set. During the task block, 
participants will be asked to generate as many words as they can that are related to a 
particular category. The categories used in the scanner will be distinct from the ones 
used on subsequent cognitive testing. Verbal responses will be recorded offline with an 
MRI compatible microphone. The stimuli, presented visually, will be the category 

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(semantic fluency) from which the subject will generate words, which will remain on 
screen for the full 30 seconds. During the rest block, the participants will be asked to 
fixate their eyes on a crosshair in the center of the screen. All stimuli for subject 
instruction will be displayed using an LCD projector (Avotec, Inc.). A laptop computer 
using E-Prime (Version 2.0, Psychological Software Tools, Inc.) will generate the 
stimuli. The second task based activation will have 2 sets of subjects looking at 
emotional faces versus neutral faces versus shapes in a randomized block design 
where each block would last 30 seconds for a total of 3 minutes per set. Images will be 
collected with the 3T Siemens Trio MRI scanner at The University of Missouri Brain 
Imaging Center. High-resolution structural three-dimensional T1-weighted images will 
be acquired for anatomic localization and co-registration of the functional data, using a 
high-resolution sagittal MP-RAGE sequence (TR = 1920 ms; TE = 3.75 ms; 8 degree flip 
angle; in-plane resolution = 1x1 mm; slice thickness = 1mm; number of slices  = 160). 
The BOLD contrast functional data will be collected using a T2*-weighted EPI pulse 
sequence (TR = 2000 ms; TE = 30 ms; 90 degree flip angle; 3.8 x 3.8 mm in-plane 
resolution, slice thickness = 3.8 mm, number of slices = 28), which will be acquired 
parallel to the anterior-posterior commissure plane. The acquisition parameters for 
the resting state functional connectivity MRI (fcMRI) and the ROIs will be identical to 
those with the above described task-based imaging, and the z-transformed correlations 
will be compared similarly for its relationship to response to propranolol.  Diffusion 
tensor imaging (DTI) will be acquired using standard sequences, and fractional 
anisotropy, and mean diffusivity will be calculated to establish white matter integrity 
and how this relates to response to propranolol. A custom VacFix cushion (S&S Par 
Scientific, Inc.) can be used to provide head and upper body restraint. The imaging 
session will last no longer than 1 hour.  
 
Study visit task specifics: 
Measurements will include skin conductance, measured by finger transducers, and 
heart rate variability, measured by electrocardiogram. Two adjustable transducers will 
be placed on the fingers to collect skin conductance data, and three electrodes will be 
placed on the chest in the typical manner, and signal from the transducers and 
electrodes will be amplified by GSR 100C and ECG 100C amplifiers connected to a 
BIOPAC MP150 Data Acquisition System.  Alternatively, for skin conductance, two 
transducers may be placed on the palmar surface of the hand if sufficient data are not 
obtained from the finger transducers. Measurements will be recorded for a period of 8 
minutes, allowing for 3 minutes of acclimation to the equipment. Heart rate and blood 
pressure will also be measured via wrist cuff at each study visit. Respiration will be 
monitored with a BIOPAC TSD201 respiration transducer placed around the abdominal 
area.  The transducer is affixed to an adjustable strap and in non-invasive.  The TSD201 is 
connected to a RSP100C amplifier that is attached to the MP150 system. 
 
Pupillary light reflex (PLR) will be collected at baseline and again at week 12.  PLR is a 
simple functional neurological test that measures the pupil size changes in response to 
a short light flash.  A novel remote PLR system will be used to measure PLR in 
participants.  During the test, the participant will sit comfortably in a chair about 1 m 
from the PLR system.  A movie will be shown on a projector screen behind the PLR 
system to attract the attention of the participant so that the PLR responses can be 
measured. The movie is red-filtered to avoid affecting pupil size. The operator will 
observe the participant’s head and pupil images on the control PC and initialize the 
PLR test at appropriate times. The projector screen will be illuminated using LEDs 
(530nm) to provide stimuli. PLR measurements will be first made with a stimulation 

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intensity of 9.5 cd/m2 in the light-adaptation condition; then the room light will be 
turned off while the participant continues to watch the video for 15 mins; and PLR will 
be then tested again with 0.75 cd/m2 stimulation in dark-adaptation. A total of 10 trials 
will be performed under each stimulation condition, and the multiple measurement 
results will be averaged. Each PLR trial takes 2.5 sec and there is a 25-30 sec interval 
between two trials. The whole PLR test will be completed in about 30 min (including 
15 min dark-adaptation). Breaks will be allowed at the participant’s request.  
The pupil size will be automatically computed using custom software from saved 
image stacks to construct the pupillogram. Initial pupil diameter, the measure most 
closely related to sympathetic and parasympathetic balance, and PLR latency, the 
measure most specific to autism, will be the primary measures of interest. 
 
Buccal Swab: To collect a sample, researchers will ask the participant how long since 
their last food or drink to ensure nothing had been consumed for 30 prior to collection. 
Researcher will then scrape the swab firmly against the inside of each cheek 6 times. 
The swab must air-dry for at least two hours after collection. The swab will be stored 
in a -80 degree freezer until processing. These samples will be analyzed to examine 
whether or not different genes are related to symptoms of autism and/or affect how 
people with autism respond to the drug propranolol. 
 
The following assessments will be completed by the participant with ASD: 
1. General Social Outcomes Measure (GSOM): To address our primary outcome 
measure: determining whether our previously reported social effects with single doses 
of propranolol are also observed with serial doses, the General Social Outcomes 
Measure will be administered, as with our previous work with single doses. This is 
designed to allow repeated assessments, consisting of a semi-structured assessment of 
social functioning assessing ability staying on topic, sharing information, reciprocity, 
transitions/interruptions, nonverbal communication, and eye contact, during a semi-
structured conversation with the researcher for Conversational Reciprocity score, as 
developed by Dr. Stichter. In our initial study, we assessed only the Conversational 
Reciprocity portion of the GSOM. We will also secondarily assess the other portions, 
and thus will also obtain scores on Facial Expressions, Social Problem Solving, Affect 
Demonstration, and Emotional Perspective Taking as well, that have been developed in 
the newest version of the GSOM. As our previous study demonstrated effects of single 
doses on the Conversational Reciprocity portion of the GSOM, as well as prediction of 
response based on HRV, this sub-test will be the primary outcome measure for the 
effect of serial doses of propranolol in this study. The utilization of a novel assessment 
is necessary due to the lack of existing measures allowing repeated measure of social 
interaction in the testing environment in response to a treatment. Dr. Stichter designed 
this for serial assessment of response to interventions for this purpose. 
 
2. Social Responsiveness Scale, second edition (SRS-2): 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-2 will be administered. 
3. Anagrams (Youth age group only): Subjects will be given a set of 20 anagram 
tasks (word unscrambling tasks, where letters are rearranged to form a word: IRCKB 
→ BRICK) similar to those used in our previous research.8 As with our previous work, 
a maximum of 120 seconds will be allowed for each anagram. Number solved and 
solution latency (with failed anagrams recorded as 120 seconds) will be recorded. Six 
distinct test versions of equivalent difficulty are available for this task, and additionally 

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they will be presented counterbalanced across the conditions and visits in order to 
further minimize any potential confounding effect of variation in difficulty between 
test versions, as with our previous work. This task has been extensively utilized with 
normative data in our previous work. 
4. Semantic fluency (Youth age group only): Subjects will also be given the word 
fluency task, a widely utilized, validated language task in a variety of populations. 
Subjects will be asked to generate as many words as possible within one minute each 
from 3 different categories (e.g. set1: animals, things to wear, vegetables; set2: drinks, 
things in the kitchen, hobbies). These categories will be distinct from those used in the 
initial fcMRI. Six distinct test versions of equivalent difficulty are also available for this 
task, in addition to the version used during imaging, and they also will be presented 
counterbalanced across the conditions and visits in order to further minimize any 
potential effect of variation in difficulty between test versions, as with our previous 
work. Total number of distinct words (not including proper nouns) will be recorded 
for each session. 
5. Clinical Global Impression of Severity (CGIS), Clinical Global Impression of 
Change (CGIC), Clinical Global Impression of Severity & Change – Anxiety (CGIA), and 
Clinical Global Impression of Severity & Change – Gastrointestinal (CGIG) (purpose- 
overall clinical change, and change in anxiety and gastrointestinal symptoms): These 
tools are semi-structured interviews that are now leading reliable and validated 
primary outcome measures in clinical trials for other cognitive disorders and are 
currently in use in autism clinical trials. 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 the blinded clinician (Dr. Beversdorf) 
will be utilized. Since this reflects change, this will only be done at week 6 and 12 
sessions, not at the beginning. The CGIS is a similar 7-point subjective scale for 
severity, which will be assessed at each time point including at the beginning to 
provide a baseline upon which to base the CGIC. The CGIS, CGIC, as well as the 
subsequent assessments, will provide pilot data to determine the necessary sample 
size for obtaining a significant result utilizing this measure more commonly utilized in 
larger trials.  The CGIA and CGIG severity and change versions will be administered in a 
similar manner to assess changes in anxiety and gastrointestinal symptoms, 
respectively. The purpose of the CGIC, as well as the subsequent assessments, is to 
obtain critical information for optimizing design for future trials utilizing measures 
more commonly used in larger trials. 
6. Autism Impact Measure (AIM) (purpose: autism severity impact): This is a 
tool developed by Drs. Kanne and Mazurek that has been developed to assess the 
impact of the autism-associated behaviors. Subjects are asked a series of 41 questions 
regarding the frequency and the impact, or interference resulting from, a series of 
autism-associated behaviors, in order to determine the impact of these autism 
associated behaviors. Overall impact scores and frequency scores will be obtained 
from this measure. This assessment will be utilized in an exploratory manner as it may 
represent a more sensitive measure for the overall impact of autism than other 
measures focusing on specific aspects, such as behavior. 
7. Clinical Evaluation of Language Fundamentals-5th Edition (CELF-5): The 
CELF-5 is a comprehensive language assessment that is validated across the full range 
of our subjects’ ages and yields a Core Language score in addition to Index scores for 
Receptive Language, Expressive Language, Language Content, and Language Memory, 
and also includes a Pragmatics subtest. 

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8. Vineland Adaptive Behavior Scales-Second Edition (VABS-2) (purpose- 
communication, living skills, socialization): The VABS-2 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-2 scores for 
Communication, Daily Living Skills, and Socialization will be monitored in this study. 
9. Aberrant Behavior Checklist (ABC) (purpose- overall behavioral 
disturbances): The ABC is a well validated, reliable, and widely used assessment tool 
for interventions for a range of cognitive disorders. It is a 58-item questionnaire of the 
parent/caregiver, rated on a four-point scale (0=not at all a problem, 3=the problem is 
severe). Items are scored on five subscales: I-Irritability, Agitation, Crying, II-Lethargy, 
Social Withdrawal, III-Stereotypic Behavior, IV-Hyperactivity, Noncompliance, V-
Inappropriate Speech. Each subscale will be utilized in our assessment. It has been 
validated and utilized in a wide range of ages and cognitive conditions including 
autism. It is sensitive to early effects of drugs (within a few weeks) in autism, including 
non-antipsychotic agents. 
10. Gastrointestinal Symptomatology: The Rome IV Diagnostic Questionnaire on 
Pediatric Functional Gastrointestinal Disorders (R4PDQ-child) assesses the frequency, 
severity, and duration of functional GI symptoms in children and adolescents, and 
contains parent/caregiver and self- report versions. For participants age 18 and older, 
the adult version of the Rome IV Diagnostic Questionnaire (R4DQA) may be used.  The 
R4PDQ and/or the R4DQA will be administered at baseline, 6-week, and 12-week 
sessions.  Paper and/or on-line versions of the questionnaire may be utilized.  
Furthermore, the GI Severity Index (GSI) will be administered to the participant or 
their parent/caregiver in-person or over the phone during the baseline, week 1, week 
2, week 6, and week 12 periods. 
11. Pet Demographics Questionnaire (PDQ): The PDQ assesses demographics 
regarding the presence of a pet or pets in the home, and the level of attachment to the 
animals by the participant.  The PDQ will be administered at baseline. 
12. The Companion Animal Bonding Scale (CABS): The CABS is an 8-item scale 
assessing an individuals’ interactions with their companion animal in the home.  The 
CABS will be administered at baseline, 6-weeks, and 12-weeks. 
13. Sympathetic Tone and Anxiety: As above, to determine effects on 
sympathetic tone or anxiety, the HRV, heart rate (via standard electrocardiogram 
procedure using adhesive pads on the chest), skin conductance, blood pressure, PLR 
and SCAS will be repeated at 12 weeks to determine how the effect of treatment on 
these markers relate to response to treatment for the outcomes above. 
14. Salivary Cortisol: To determine the effects on the stress response, salivary 
cortisol samples will be collected immediately when the participant enters the testing 
room and again after administration of the GSOM during the baseline, 6-week, and 12-
week sessions to determine how the effect of treatment on cortisol relates to response 
to treatment for the outcomes above.  Samples will be collected using the Salimetrics 
SalivaBio Children’s Swab (SCS) method and analyzed using enzyme-linked 
immunosorbent assay (ELISA). 
15. Sensory Over-Responsivity: To examine the effects of propranolol on 
sensory over-responsivity, the SenSOR will be administered at baseline, 6-weeks, and 
12-weeks.  The SenSOR is a 76-item yes/no questionnaire examining sensory over-
responsivity in multiple domains. 
 
Our team has experience with all of these assessments from our previous research in 
our single-dose studies with propranolol, as well as with other research. 
  
 
 

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Drug Titration schedule: 
 
This study involves a titration schedule in which participants will begin with small 
doses (single capsules) of the drug and increase to a larger dosage (divided over 3 
capsules) over the course of three weeks. To maintain blinding, participants will be 
given bottles labeled “A” and “B,” containing different doses of propranolol. 
Participants will be given a drug diary to keep track of their doses throughout the 
study. Participants will be asked turn in their drug diary and empty capsule bottles 
after each drug period ends. In addition, participants will be given a personalized 
calendar, marked with labels denoting which pills to take when on each day of the drug 
period. 
 
The drug titration schedule will be as follows for the drug period and its subsequent 
tapering-off period:  
 
Week 1: 40 mg propranolol (1 capsule, nightly) 
Week 2: 80 mg propranolol (2 40mg capsules, morning & night) 
Weeks 3 - 12: 100 mg propranolol (3 capsules, 40 mg/morning, 
20mg/afternoon, & 40mg/night) 
Week 13: 60 mg propranolol (2 capsules, 40 mg/morning & 20mg/night) 
Week 14: 20 mg propranolol (1 capsule, nightly) 
Week 15: no capsules 
[Participants may choose to continue on with open label extension described 
below] 
 
During the titration schedule, heart rate and blood pressure measurements will be 
taken via automated wrist cuff by the participant or parent/caregiver within 48 hours 
after each change in drug dosage. At the initial study visit, participants and/or their 
parent/caregiver will be trained on the use of the wrist cuff or pediatric arm cuff, 
depending on needs of participant, given a sheet of instructions for its use, and given a 
wrist/arm cuff to take home for the duration of the study. A member of the study staff 
will call the family to obtain the heart rate and blood pressure results. If on any 
measurement the heart rate is below 55 for youth or 60 for children or systolic blood 
pressure is below 90 for youth or 80 for children, the PI will be immediately notified, 
and he will call and/or examine the participant to assess his or her condition. At this 
point, the PI may make the decision to have the participant drop back to the previous 
dosage level or to withdraw the participant from the study for safety reasons. A 
member of the study staff will also call the participant to confirm no further problems 
before each increase in dosage. During this call, parts A and B of the Safety Monitoring 
Uniform Research Form (SMURF) will be performed. The SMURF is a rating scale for 
measuring the presence and intensity of medication side effects. Abnormal ratings on 
the SMURF will result in notification of the PI who may then call or examine the 
participant to further assess his/her condition. 
 
 
Study procedure for ages 7-14: 
 
General study procedures: 
 
Procedures for the child age group will be the same as for the youth age group except: 
 
1) Child age group will not participate in the imaging portion of the study. 

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2) Child age group will not complete the anagrams or semantic fluency tasks. 
3) Titration schedule for the child age group is based on weight. 
4) Minimum heart rate allowed for children will be 60 and the minimum systolic 
blood pressure allowed will be 80. 
 
Drug titration schedule for the child age group will be based on weight as follows: 
For patients >50kg:  
Same titration as youth age group 
For patients 40-50kg: 75% youth dosage 
Week 1: 30 mg propranolol (nightly) 
Week 2: 60 mg propranolol (30mg morning & night) 
Weeks 3 - 12: 75 mg propranolol (30 mg/morning, 15mg/afternoon, & 
30mg/night) 
Week 13: 45 mg propranolol (30 mg/morning & 15mg/night) 
Week 14: 15 mg propranolol (nightly) 
Week 15: no medication 
For patients 30-40kg: 50% 
Week 1: 20 mg propranolol (nightly) 
Week 2: 40 mg propranolol (20mg morning & night) 
Weeks 3 - 12: 50 mg propranolol (20 mg/morning, 10mg/afternoon, & 
20mg/night) 
Week 13: 30 mg propranolol (20 mg/morning & 10mg/night) 
Week 14: 10 mg propranolol (nightly) 
Week 15: no medication 
For patients 20-30kg: 25% 
Week 1: 10 mg propranolol (nightly) 
Week 2: 20 mg propranolol (10mg morning & night) 
Weeks 3 - 12: 25 mg propranolol (10 mg/morning, 5mg/afternoon, & 
10mg/night) 
Week 13: 15 mg propranolol (10 mg/morning & 5mg/night) 
Week 14: 5 mg propranolol (nightly) 
Week 15: no medication 
[Participants may choose to continue with open label extension described 
below] 
 
 
Optional Open Label Extension 
Participants will also have the option to participate in an open label extension period 
after week 15 of the study. After at least two weeks taking no initial study medication, 
participants will be prescribed propranolol by their primary care physician, a 
researcher will retake baseline GSOM, SRS, ABC, R4PDQ/R4DQA, and GSI measures, 
and participants will be titrated on the schedule dictated by their age and/or weight. 
After 12 weeks on propranolol, a researcher will take final GSOM, SRS, ABC, 
R4PDQ/R4DQA, and GSI measures. 
 
b. Study duration and number of study visits required of research participants. 
 
Participation in this study will last 15 weeks, with the option to extend another 12 
weeks depending on participation in the open label extension. The youth group will 
have 1 visit to the Brain Imaging Center (lasting approximately 1.5hr), 3 visits to the 
Thompson Center, and an optional 2 visits to the Thompson Center (lasting 

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approximately 2hrs). The child group will not have the visit to the Brain Imaging 
Center. 
 
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 while participants are taking placebo and propranolol 
 
f. Definition of treatment failure or participant removal criteria. 
 
As this is an initial 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 are very low or if the participant is experiencing an 
adverse reaction to the drug the PI will be notified and will examine or speak with the 
participant. 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. 
 
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 
participants will no longer take propranolol or placebo capsules. Participants will 
continue with their routine care as they would have done throughout the study. 
 
5. Inclusion/Exclusion Criteria 
 
Participants 
Youth: 
Inclusion: 
 
 
Autism 
 
 
IQ >= 85 
 
 
Age 15-24yrs 
 
 
Native English speaker 
 
 
General Exclusion: 

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Alpha 2 agonists 
 
 
Non-autism LD (ADHD, dyslexia, etc) 
 
 
Other major psych diagnosis 
 
 
Other neuro diagnosis 
 
 
Major head trauma 
 
 
Reaction to adhesives 
 
 
Drug Exclusions: 
 
 
 
Diabetes 
 
 
 
Reactive airway disease 
 
 
 
Thyroid disease 
 
 
 
Bradyarrhythmias 
 
 
 
Unexplained syncope 
 
 
 
Pregnancy 
 
 
 
Possible interacting drugs 
 
 
 
Underweight 
 
 
 
Imaging Exclusions: 
 
 
 
Metallic implants 
 
 
 
Metal foreign body exposure 
 
 
 
Pacemakers 
 
 
 
Claustrophobia 
 
 
 
Any other MRI exposure risk 
 
 
 
Pregnancy 
 
Children: 
Inclusion: 
 
 
Autism 
 
 
Age 7-14yrs 
 
 
Native English speaker 
 
 
General Exclusion: 
Alpha 2 agonists 
 
 
Other major psych diagnosis 
 
 
Other neuro diagnosis 
 
 
Major head trauma 
 
 
Reaction to adhesives 
 
 
Drug Exclusions: 
 
 
 
Diabetes 
 
 
 
Reactive airway disease 
 
 
 
Thyroid disease 
 
 
 
Bradyarrhythmias 
 
 
 
Unexplained syncope 
 
 
 
Possible interacting drugs 
 
 
 
Underweight (<20kg) 
 
 
Parent/caregiver 
 
 
Inclusion: >=18yo, native English speaker 
 
 
Exclusion: None 
 
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. 
We predict that propranolol’s effects on stress and anxiety will positively impact social 

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and language abilities in individuals with ASD. The dose (starting with 40 mg and 
titrating up to 100 mg) has been previously used in neuropsychiatric populations (15) 
and is within the dosage recommended by the FDA for hypertension. 
 
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. 
 
Previous studies from our laboratory indicate a potential effect of propranolol on social 
and language abilities in adults and adolescents with ASD. Thus, this trial investigation 
will explore the effects of serial doses of propranolol in the same population. 
Participants taking propranolol in this study may be at risk for the side effects 
described below. Measures to maintain the safety of study participants will be further 
discussed below.  Subjects will be encouraged to discuss these with the PI (David Q. 
Beversdorf, MD) and/or their own doctor. Subjects will also be told that there may be 
other side effects that we cannot predict.  
 
c. Justification and safety information if non-FDA approved drugs without an IND will be 
administered.  
 
NA 
 
7. Study Statistics 
a. Primary outcome variable. 
 
We are primarily exploring the effects of propranolol on social abilities, as assessed via 
the GOSM. 
 
b. Secondary outcome variables. 
 
Our secondary outcome variables include, effects on anxiety (assessed via the SCAS, 
and salivary cortisol), language abilities (assessed via anagrams and semantic fluency 
tasks), adaptive/global functioning (assessed via the Vineland), and change in clinical 
impression/impact of ASD symptoms (assessed via CGIC, CGIS, SRS, ABC, and AIM).   
Effects of propranolol on gastrointestinal functioning, as measured by the R4PDQ-
child/R4DQA and the GSI will be assessed to obtain pilot data.  Furthermore, effects of 
propranolol on bonding with a pet in the home will be assessed. 
 
c. Statistical plan including sample size justification and interim data analysis. 
 
The analysis for the primary outcome (GSOM) will be a two-factor ANOVA with 
repeated measures on one factor (Time) and so this is the model we base our sample 
size estimates on. Sample size estimation for a repeated measures model is complex 
and requires considerable prior information to be well informed. Not only is the 
expected configuration of means needed but also information on an appropriate 
covariance structure for the ANOVA residuals. For purposes of sample size 
calculations, we assumed a first-order autoregressive (AR) model for the residuals 
with ρ = 0.20. Perhaps because the time between pre- and post-propranolol 
measurements was very short in the pilot study the correlation was 0.74, and so the 
assumption of an AR process with ρ = 0.20 seems to be a reasonably pessimistic 
assumption for sample size purposes. We further assume that in the control group 

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mean GSOM will be stable over the 12 weeks of the study and in the propranolol group 
the mean improvement in GSOM score at 6 and 12 weeks will be one-half and one-
standard deviation above baseline. In our pilot work we saw about 0.375 of a standard 
deviation improvement on the GSOM with only a single dose so we feel these are both 
meaningful and plausible expectations for change. Thus when testing at the 0.05 level 
of significance, a sample size of 40 subjects per group (pooled across Aim 1a and b to 
maximize the power for the main effect of propranolol on GSOM in this parallel design 
study) will provide better than 80% power to detect a statistically significant Time by 
Group interaction and similar power for the follow-up within- and between-group 
pairwise comparisons. Prior experience with ASD subjects leads us to expect a high 
level of motivation and compliance, but to protect against potential drop out will 
recruit 48 subjects per group, i.e. approximately 20% loss to follow-up. The sampling 
plan will be stratified to provide balanced sample to within each age group, with half of 
the sample representing adults and adolescents and half younger ASD subjects. 
 
The imaging data acquired will be analyzed using Statistical Parametric Mapping (SPM) 
and FMRIB Software Libraries (FSL) (FMRIB, UK), adjusted for acquisition delay, 
corrected for motion artifacts, co-registered to the mean image and registered to the 
Montreal Neurological Institute (MNI) template and smoothed with a Gaussian spatial 
smoothing function (with a FWHM of 5 mm). Specially designed processing pipelines 
will be used to account for subject motion-related error during the assessment of 
resting state functional connectivity. Group analyses will be performed for both the 
task based activation studies and functional connectivity data and the activation maps 
will be superimposed on the standard template.  
 
Functional connectivity will be determined using average time-courses of all activated 
voxels in the regions-of-interest (ROI) and the linear associations of the temporal 
activation patterns in each ROI pair. The four a priori regions of interest for the word 
fluency task are the right and left inferior frontal, left parietal and left middle temporal 
areas. Subsequently, Fisher’s z transformations will be applied to assess statistical 
significance in the comparison of the observed correlations. Mean connectivity across 
all ROI pairs activated with the language tasks will be the measure utilized to 
determine relationship to response with propranolol. Fractional anisotropy, and radial 
and axial mean diffusivity will be calculated from the DTI session to establish white 
matter integrity and how it relates to response to propranolol.  
 
For PLR, the pupil size will be automatically computed using custom software from 
saved image stacks to construct the pupillogram. The following basic PLR parameters 
will be recorded for each measurement: initial pupil diameter (D0), maximal 
constriction diameter (Dm), relative constriction (A), PLR latency (tL), constriction time 
(tC), recovery time (tR), constriction velocity and recovery velocity. The mean value of 
each PLR parameter will be calculated at all stimulus conditions, and entered into the 
regression analysis.  Participants with uncorrectable visual acuity issues will be 
excluded from this aspect of the study. Initial pupil diameter, the measure most closely 
related to sympathetic and parasympathetic balance, and PLR latency, the measure 
most specific to autism, will be the primary measures of interest. 
 
For skin conductance, heart-rate variability, heart rate, and blood pressure, regression 
will be used to determine the relationship between performance on the GSOM and 
autonomic nervous system functioning. 
 

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d. Early stopping rules. 
 
As this is an initial 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 to stop the study early. However, this is not expected to occur given the well-
established minimal side effects known to be associated with this drug. 
 
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 and an MRI scan.  
 
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. 
Side Effect 
Frequency 
Severity 
Bradycardia (abnormally slow heart action) 
Common 
Mild 
Fatigue (extreme tiredness) 
Common 
Mild 
Dizziness 
Common 
Mild 
Hypotension (abnormally low blood pressure) 
Common 
Moderate 
Light headedness 
Occasional 
Mild 
Constipation 
Uncommon 
Mild 
Paresthesia (abnormal sensation, typically tingling or 
pricking) of hands  
Rare 
Mild 
Vivid dreams 
Rare 
Mild 
Dry eyes 
Rare 
Mild 
Urticaria (hives) 
Rare 
Mild 
Diarrhea 
Rare 
Mild 
Abdominal cramping 
Rare 
Mild 
Nausea 
Rare 
Mild 
Epigastric distress (Upper abdominal pain) 
Rare 
Mild 
Impotence (inability to achieve or maintain an erection) 
Rare 
Mild 
Nightmares 
Rare 
Mild 
Depression 
Rare 
Moderate 
Lassitude (lack of energy) 
Rare 
Moderate 
Weakness 
Rare 
Moderate 
Visual disturbances 
Rare 
Moderate 
Hallucinations (experience of something that is not actually 
present) 
Rare 
Moderate 

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Disorientation (mental confusion about time, place or 
identity) 
Rare 
Moderate 
Emotional lability (excessive emotional reactivity and 
frequent mood changes) 
Rare 
Moderate 
Slightly clouded sensorium (inability to think clearly or 
concentrate) 
Rare 
Moderate 
Decreased performance on neuropsychometrics (tests to 
assess psychological functioning) 
Rare 
Moderate 
Peyronie’s disease (scar tissue inside the penis causing 
curved, painful erections) 
Rare 
Moderate 
Allergy 
Rare 
Serious 
Catatonia (inability to move normally) 
Rare 
Serious 
Intensification of AV block (Worsening of a type of heart 
block) 
Rare 
Serious 
Arterial insufficiency (slowing or stopping of blood flow 
through arteries (blood vessels)) 
Rare 
Serious 
Alopecia (sudden hair loss with one or more circular patches) 
Very rare 
Mild 
Exfoliative dermatitis (reddening and scaling of skin) 
Very rare 
Moderate 
Psoriasisform rashes (plaque-like rashes) 
Very rare 
Moderate 
Vomiting 
Very rare 
Moderate 
Amnesia (partial or total loss of memory) 
Very rare 
Serious 
Erythema multiforme (bulls-eye-shaped lesions on skin) 
Very rare 
Serious 
SLE-like reaction (a disorder where the body mistakenly 
attacks healthy tissues in the body) 
Very rare 
Serious 
Congestive heart failure (inefficient pumping of the heart) 
Very Rare 
Severe 
Stevens Johnson Syndrome (disorder of skin and mucous 
membranes) 
Extremely Rare 
Serious 
Agranulocytosis (deficiency of granulocytes in blood; 
increased vulnerability to infection) 
Extremely rare 
Serious 
Nonthrombocytopenic purpura (spontaneous bruising 
without decrease in levels of blood cells that prevent 
bleeding) 
Extremely rare 
Serious 
Thrombocytopenic purpura (low levels of blood cells that 
prevent bleeding) 
Extremely rare 
Serious 
Toxic Epidermal Necrolysis (skin condition) 
Extremely Rare 
Life threatening 
Mesenteric arterial thrombosis  (injury of the small intestine 
due to lack of blood supply) 
Extremely rare 
Life threatening 
Ischemic colitis (injury of the large intestine due to lack of 
blood supply) 
Extremely rare 
Life threatening 
 
 
Placebo [pla-see’-bo] : Also known as a “sugar pill.” The placebo capsules contain 
lactose, necessitating the exclusion of any potential participants who have extreme 
lactose allergies.  
 
Below are the risks associated with MRI scan: 
 
Unlike x-rays or CT-scans, MRI does not involve any ionizing radiation.  However, the 
tasks may cause some fatigue similar to reading a book or doing homework.  
Participants may also experience discomfort from lying still.   

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The safety of MRI has been evaluated over the past 20 years and no short-term effects 
have been observed.  However, the long-term effects of MRI on the body are not fully 
known.  Some individuals with claustrophobia (fear of closed or confining spaces) may 
find the MRI equipment too confining 
 
The MRI scanner makes sounds variously described as “thumping”, “pounding”, 
“banging”, “chirping” and “buzzing”; these sounds can be loud.  Participants will be 
required to wear protective earplugs and headphones during scanning to reduce the 
noise.   
 
The MR imaging in this study is being performed at a research dedicated scanner and 
the personnel performing the imaging are not Licensed or Trained Diagnosticians or 
Clinicians. The testing performed in this project is not intended to find abnormalities, 
and the images or data collected do not comprise a diagnostic or clinical study. The 
Investigators and the University of Missouri are not responsible for failing to find 
abnormalities. However, on occasion the Investigators may perceive possible 
abnormalities. When this occurs, the Brain Imaging Center will consult with a 
Specialist. If the Specialist determines that additional inquiry is warranted, a staff 
person from the Brain Imaging Center will contact the participant. In such case, 
participants are advised to consult with a Licensed Physician to determine whether 
further examination or treatment would be prudent. The Investigators, Specialist, 
Brain Imaging Center and the University of Missouri are not responsible for any 
decision made with regard to examination or treatment. Because the images collected 
for this research project do not comprise a diagnostic or clinical study, the images will 
not be made available for diagnostic or clinical purposes. 
 
No short-term effects to a fetus from this procedure have been observed.  However, the 
long-term effects of MRI on the fetus are not fully known.  Therefore, participants will 
be screened for pregnancy before imaging.  
 
Participants cannot have an MRI if they have any metal in or near the brain such as an 
aneurysm clip or a cochlear implant, or other contra-indicated implants such as a 
pacemaker for the heart or metal-containing prostheses (like a ‘stent’ or a heart valve, 
hearing aids, etc.).  For example, welders and metal workers may be at risk for a MRI 
because they may have gotten small metal fragments in their eyes.  This would be 
dangerous inside the magnet. There are also possible risks for participants if metal 
objects are drawn to the magnet while a participant is within or near the bore.  
Accordingly, participants will be asked to leave all jewelry and metal objects outside of 
the testing area.  No loose metal objects will be allowed near the magnet.  Many items 
of clothing contain metal hooks, wires, etc. and some of these cannot be worn in the 
MRI device. Clean garments will be provided in this case. 
 
There may be some unanticipated risks or side effects involved with participation in 
this research study.  Since 1981, there is no evidence that high magnetic fields 
endanger health on a short or long term basis. Therefore, the potential health risk is 
thought to be minimal, if any. 
 
Other potential risks:  
 

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Participants may also encounter minor risks associated with the adhesives used to 
collect psychophysiological 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 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 participants to evaluate their ability to safely take part in this study. Upon 
enrollment in the study, participants will be given a business card containing contact 
information for lead study staff and the PI in case of questions and/or emergency. 
 
 
Given the chance of unforeseen side effects associated with the drug in participants 
who met criteria for participating in the study, regular monitoring of heart rate and 
blood pressure will occur throughout the study. During titration of the drug from the 
initial to the full dose, heart rate and blood pressure measurements will be taken via 
wrist cuff or pediatric arm cuff by the participant or parent/caregiver within 48 hours 
after each change in drug dosage. A member of the study staff will call the family to 
obtain these results. If on any measurement the heart rate is below 55 (60 for children) 
or systolic blood pressure is below 90 (80 for children), the PI will be immediately 
notified, and he will call and/or examine the participant to assess his or her condition. 
At this point, the PI may make the decision to have the participant drop back to the 
previous dosage level or to withdraw the participant from the study for safety reasons. 
A member of the study staff will also call the participant to confirm no further 
problems before each increase in dosage. During this call, the SMURF will be 
performed, and blood pressure and heartrate will be taken. Abnormal ratings on the 
SMURF or too low blood pressure or heartrate will result in notification of the PI who 
may then call or examine the participant to further assess his/her condition.  
 
 
At each study visit taking place at the Thompson Center for Autism & 
Neurodevelopmental Disorders, a member of the study staff will first confirm that 
there are no changes in the participant’s physical condition 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 if necessary. Blood pressure and heart rate will also be 
measured at each of these study visits.  
 

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To minimize risk associated with MRI, all participants will be screened to ensure they 
do not meet any exclusionary conditions, and scrubs and a metal detecting wand will 
be available to prevent metal from being introduced into the scanning room. 
 
 
Participants with previously documented history of rash from adhesives will be 
excluded from the study. This will minimize the risks associated with the 
psychophysiological 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 secure 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. Risks specific to genetic testing 
When disease, including autism, is tied to genetic abnormalities, this can create 
problems for families with regards to obtaining insurance coverage. To keep this from 
happening, the results of the genetic analysis through buccal swab will not be given to 
anyone outside of the research team. Also, a Federal law, called the Genetic 
Information Nondiscrimination Act (GINA), generally makes it illegal for health 
insurance companies, group health plans, and most employers to discriminate based 
on genetic information. 
 
However, this Federal law does not protect participants or their families against 
genetic discrimination by companies that sell life insurance, disability insurance, or 
long-term care insurance. Also, GINA does not prohibit discrimination of individuals 
with a genetic disorder that has been diagnosed. However, in order to do everything 
possible to prevent genetic discrimination, the results of the DNA test will NOT be 
given to anyone outside the study staff. This means that it will not be made available to 
participants or their family members, their private physician, employer, insurance 
company or any other party as allowed by law.   
 
d. 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.  
 
The Research Monitor, John Hall, MD, is responsible to oversee the safety of the 
research and report observations/findings to the IRB or a designated institutional 
official. The Research Monitor will review all unanticipated problems involving risks to 
subjects or others associated with the protocol and provide an independent report of 
the event to the IRB. The Research Monitor may discuss the research protocol with the 
investigators; shall have authority to stop a research protocol in progress, remove 
individual human subjects from a research protocol, and take whatever steps are 
necessary to protect the safety and well-being of human subjects until the IRB can 

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assess the monitor's report; and shall have the responsibility to promptly report their 
observations and findings to the IRB or other designated official and the HRPO. 
 
e. 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 possible that 
information related to a participant's autism diagnosis and performance on the tests 
being administered will be obtained. 
 
f. 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. 
 
All participants will be receiving medical surveillance beyond the standard of care with 
frequent call checks for symptoms and blood pressure checks throughout 
participation. Participants will also be receiving behavioral and psychological 
assessments beyond general standard of care. 
 
Also, there is evidence that serial doses of propranolol will be beneficial for people 
with autism in the realm of social interaction and anxiety (13, 14, 16). Therefore, 
participants taking propranolol (including those one the placebo arm who choose to 
take part in the open label extension) have the potential for direct benefit. Beyond that, 
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 maximum total of $125.00 if they complete all five study visits.  The final payment 
of $25.00 will be authorized once the participant returns the heart rate and blood 
pressure cuff to a member of the study staff. Participants in youth age group can also 
receive $50.00 for completing the fMRI session. If a participant lives more than 50 
miles from the Thompson Center in for Autism & Neurodevelopmental Disorders in 
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. Payments will be made in cash at the end of 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. 

MU IRB version:  3/26/2014 
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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. Participants 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.  
 
(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 speech and social behaviors in 8 autistic adults. Journal of Autism and Developmental 
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. 
 

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(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. 
 
(13) Zamzow RM, Ferguson BJ, Stichter, JP, Porges, EC, Ragsdale, AS, Lewis, ML, & 
Beversdorf, DQ.  Effects of propranolol on conversational reciprocity in autism 
spectrum disorder: a pilot, double-blind, single-dose, psychopharmacological challenge 
study.  Psychopharmacology (Berl). 2016; 233(7), 1171-8. 
 
(14) Zamzow RM, Ferguson BJ, Hegarty II JP, Lewis, ML, Ragsdale, AS, Christ, SE, 
Stichter JP, Beversdorf DQ. Effects of a beta-adrenergic antagonist on social and 
cognitive functioning in autism spectrum disorder. Poster Presentation at the 
International Meeting For Autism Research Annual Meeting, Atlanta, Georgia (2014). 
 
(15) Kampman KM, Dackis C, Lynch KG, Pettinati H, Tirado C, Gariti P, Sparkman T, 
Atzram M, O’Brien CP. A double-blind, placebo-controlled trial of amantadine, 
propranolol, and their contribution for the treatment of cocaine dependence in 
patientswith severe cocaine withdrawal symptoms. Drug Alcohol Depend 84:129-137 
(2006). 
 
(16) Ratey, J. J., Bemporad, J., Sorgi, P., Bick, P., Polakoff, S., O'Driscoll, G., & Mikkelsen, E. 
(1987). Brief report: open trial effects of beta-blockers on speech and social behaviors 
in 8 autistic adults. Journal of autism and developmental disorders, 17(3), 439-446.