Conditions: Autism Spectrum Disorder Attention Deficit Hyperactivity Disorder
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 18
Healthy volunteers: no

Brief summary:
Children with comorbid autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) have significantly worse outcomes than those with either ASD alone or ADHD alone. Effective early treatments that account for ADHD symptoms have not been developed for young children with ASD+ADHD. The overarching goals of this randomized, placebo-controlled, phase 2, pilot study are to (1) evaluate a novel early intervention that pharmacologically addresses ADHD symptoms while providing an ASD-targeted behavioral intervention, and (2) identify changes in behavioral and neurophysiological activity that may underlie improved outcomes in children with comorbid ASD and ADHD ages 3-10 years. The primary aim of this study is to evaluate whether a stimulant treatment augments efficacy of an ASD specific form of parent child therapy based on the Early Start Denver Model called ESDM influenced Parent Coaching. Secondary aims are to determine the efficacy of combined intervention in improving ADHD symptoms and the efficacy, safety, and tolerability of Adzenys-XR-ODT in young children with ASD+ADHD. The study will also examine correlations between behavioral changes and state-of-the-art eye-gaze tracking (EGT) and electroencephalographic (EEG) biomarkers to elucidate key ways in which ADHD impacts attentional and neural functioning in ASD+ADHD, and to potentially identify new targets for intervention in children with ASD+ADHD. The study is about 8 months long and will involve screening, baseline assessment followed by 10- 11 weeks of study drug treatment (active or placebo) and 8 sessions of ESDM informed parent coaching beginning after 2 weeks of study drug treatment, primary endpoint assessments at \~11 weeks, AE follow-up by phone at \~week 13 and remote FU 24 weeks after baseline. Eligible participants will be randomly assigned to the active medication or placebo, Between weeks 11 to 24, it is expected that the parent will use the behavioral strategies they were coached in even though they will not receive parent coaching. Participants will be given the option to pursue ADHD medication outside of the research study after week 11 assessments.

Detailed description:
This randomized, placebo-controlled, Phase 2, single site, pilot study will evaluate the developmental impact of combined medication and behavioral treatment (COMB) versus placebo and behavioral treatment (BEH) in children with comorbid ASD +ADHD, who are between 36 and \< 132 months of age. The active medication treatment will be an orally dissolvable, extended release amphetamine preparation (Adzenys-XR-ODT) administered from weeks 0-\~11 and carefully titrated to the optimal dose using an algorithm that considers adverse events and improvement in attention symptoms with a flexible dose range of 1.55mg - 18.6mg/day. The target dose is 12.4mg/day. A placebo, matched to the active medication, will be titrated and adjusted using the same algorithm in the BEH arm. The provided behavioral treatment will be eight \~ hour long parent child therapy sessions of ESDM influenced parent coaching.

Approximately 48 participants will be randomly assigned to either the COMB or BEH treatment arms. To account for possible differences in attrition due to potential poor tolerability of Adzenys-XR-ODT, participants will be randomized in a 7 COMB to 6 BEH ratio. Treatment assignment will be provided by the Data Management and Analysis Core (DMAC)using computer generated algorithms.

The primary analyses will compare changes in outcomes between weeks 0 and 11 weeks. Exploratory analyses will explore changes between weeks 0 and 24.

The primary outcome measure is change in amount and quality of joint engagement between the child and the parent during a semi-structured, 6 minute parent child interaction task (PCIT), which reflects the core symptom domain targeted by P-ESDM: social communication.

Our key secondary outcomes will be changes in 1) the mean of the interview version of the VABS-3 socialization subscale and communication subscale standard scores and 2) clinician ratings of ADHD symptoms using the preschool ADHD-RS.

We will also assess the safety and tolerability of Adzenys-XR-ODT compared to placebo.

Arms:
arm 1: Amphetamine regimen (11 weeks total duration) will begin 2 weeks prior to initiation of ESDM informed parent coaching (8 weekly sessions) and continue through the week 11 endpoint assessment. The drug is an orally dissolvable, extended-release form of d- and l-amphetamine. arm 2: Placebo regimen (11 weeks total duration) will begin 2 weeks prior to initiation of ESDM informed parent coaching (8 weekly sessions) and continue through the week 11 endpoint assessment. The placebo contains no active drug and appears identical to the amphetamine (active drug).

Interventions: intervention 1: Amphetamine intervention 2: ESDM informed parent coaching intervention 3: Placebo Oral Tablet
Intervention descriptions: intervention 1: Study drug will be administered in the morning. Treatment will be initiated at 1 tablet = 3.1 mg or 0 mg of mixed amphetamine. Doses will be flexibly titrated upward and may be decreased or stopped at any time. intervention 2: All participants will receive 8 weekly parent child therapy sessions will be delivered by a therapist trained in parent coaching and ESDM principles and strategies and utilizing a therapy manual,(includes coaching for behavior management and handouts). intervention 3: Matched placebo tablets will be administered in the morning and provided for 11 weeks . The tablets will be titrated in the same way as the active drug and may be stopped at any time.

Protocol document:
Prot_SAP_000.pdf: 
 
 
Protocol Cover Page for ClinicalTrials.Gov Record 
 
 
 
Official Study Title:    Impact of combined medication and behavioral treatment in young 
children with comorbid ASD and ADHD 
NCT #:     NCT03242772 
Duke University Health System (DUHS) Protocol #: Pro00085179 
Document Version Date (DUHS IRB Approval of Protocol): 16-DEC-2021 
Document Name: Main Study Protocol 


A+ Treatment: Impact of combined medication and behavioral treatment for young children with ASD and ADHD    
Protocol Pro00085179, v4.6 
13 December 2021 
 
A+ Treatment v4.6 
13 Dec 2021 
1 
A+ Treatment:  ACE Project 3 
A pilot study of the impact of combination medication and behavioral treatment 
in young children with comorbid ASD and ADHD. 
Duke IRB Protocol Number: Pro00085179 
National Clinical Trial (NCT) Identified Number:  NCT03242772 
Principal Investigator: Dr. Lauren Franz 
IND Exemption Received by Dr. Linmarie Sikich 
 
Funded by:  National Institute of Child Health and Human Development  
Version Number:  v.4.6 
13 DEC 2021 
APPROVED 16 DEC 2021 


A+ Treatment: Impact of combined medication and behavioral treatment for young children with ASD and ADHD    
Protocol Pro00085179, v4.6 
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A+ Treatment v4.6 
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2 
 


A+ Treatment: Impact of combined medication and behavioral treatment for young children with ASD and ADHD    
Protocol Pro00085179, v4.6 
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A+ Treatment v4.6 
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3 
Proposed Changes in this IRB amendment from protocol v 1.0 
Version/Date 
Change 
Brief Rationale 
4.6/ 
December 
13, 2021 
Corrected 
and 
clarified 
designation 
of 
outcomes Table in section 3 and Schedule of 
Activities and other language to reflect Aims 
(Section 2.3) and protocol.  
Wanted to ensure that the outcomes table 
and schedule of activities correctly reflects 
primary outcome, secondary outcome, and 
exploratory outcomes per the specific aims.  
4.5/ April 16, 
2021 
Changed PI from Dr. Geraldine Dawson to 
Dr. Lauren Franz 
Dr. Franz has valuable experience to take 
on the role and this change helps balance 
other PI transitions across the ACE 
program. 
4.4/October 
8, 
2020 
Clarified that Intervention history form at 10 
weeks will ask about interventions over the 
past 10 weeks, and the study staff may ask 
participants about interventions during the 
course of treatment as well.  
Added Stimulant Washout Confirmation 
Form and Condensed Medical History Form 
at Screening.  
Added instance of CGI I&S at Week 24.  
Parenting 
Sense 
of 
Competence 
form 
(baseline and week 10) 
 
Stimulant Washout Form will be used to 
document 
stimulant 
washout 
in 
a 
standardized 
fashion, 
to 
continue 
to 
document this has been done prior to 
medication start; CGI I& S will help 
capture 
changes 
in 
participant 
symptoms/behaviors up through Week 24, 
and Parenting Sense of Competence will 
provide indication of changes in caregiver’s 
sense of efficacy and satisfaction related to 
parenting role during intervention.  
4.3/October 22, 
2019 
• Removed Intervention Log mention in the 
protocol 
• Removal of Selective Serotonin Reuptake 
Inhibitors 
as 
prohibited 
concomitant 
medications 
• Clarified 
visit 
windows 
through 
the 
screening and baseline portion of the study.  
• This is to reflect changes already put in 
place and to represent the Schedule of 
Activities 
• With the expansion of the age group we 
predict more children will be taking 
prescription medications. This removal 
should improve enrollment. 
• This will allow for a more steady stream 
of participants and the ESDM portion of 
the study will be better able to 
accommodate participant schedules 
4.2/September 
12, 2019 
• Removed blood chemistries at baseline visit 
 
 
• Rearranged the timing of physician visits  
 
 
 
 
• Changed the timing of the AE follow-up 
visit 
 
 
• Clarified that all conmeds will be collected 
even if PRN and taken less than 14 days 
 
• Removal will allow more subjects to 
participate due to major obstacle in 
collecting blood in this population 
• This will allow for an in-person visit 
within a week of reaching target dose and 
allow the physician to make dose 
adjustments more readily. 
• This will allow an evaluation of any 
ongoing AEs much sooner and may 
facilitate resolution of AEs 
• This is more in-line with the industry 
standard of collecting ALL conmeds to 
address any potential AE’s in general 
inquiry prompt 
• This is dependent on the type of visit in 
this study and was depicted in the SoA 


A+ Treatment: Impact of combined medication and behavioral treatment for young children with ASD and ADHD    
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A+ Treatment v4.6 
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4 
 
• Clarified when a participant would be lost 
to follow-up   
 
 
• Clarified that at baseline and end of 
assessment time point the ADHD-RS would 
continue to be collected 
previously but was also added to the text 
and refers to the SoA for clarity 
• It was inadvertently left out due to some 
confusion on when the caregiver form 
and 
the 
clinician 
form 
would 
be 
administered but has now been clarified 
in the text 
4.1/August 
08, 
2019 
• Removed lower limit Inclusion Criteria of 
General Conceptual Ability Score having to 
be higher than 60 
• Removed the PAERS form and will replace 
with general AE inquiry 
• Removed CGI-S and I parent form and 
added new Impairment Rating Scale-Parent 
Form (IRS) 
 
• Removal of lower IQ limit in hopes of 
broadening 
eligible 
population 
for 
recruitment 
• Removal of this form will better 
streamline the safety monitoring process 
• The new Impairment Rating Scale-Parent 
Form is a more parent-friendly form than 
the CGI-S 
 
4.0/ 
July 03, 2019 
• Changed Inclusion Criteria to expand age 
range to include children 36 months to 
<132 months of age 
• Removed criteria based on receptive 
language age equivalent 
• Added lower IQ limit of 60 
•  
• Switched primary and secondary end 
points.  Primary end point is PCI Jeri 
Rating to measure joint engagement.  
Secondary end point is Vineland Adaptive 
Behavior Scale – socialization subscale and 
communication subscale. 
• Updated language on exclusion criteria for 
other psychiatric conditions and/or elevated 
symptoms to allow for clinical case review 
and PI decision 
• Updated language on medication inclusion / 
exclusion to allow for meds that address 
sleep disturbances and irritability; and to 
exclude 
other 
stimulants 
and 
anti-
depressants 
• Shortened medication phase 10 weeks. 
• Restructured study visits to allow 2 weeks 
of titration prior to starting behavioral 
intervention 
• Change study visit schedule to  
o 
Diagnostic evaluation 
o 
Med 
screen 
and 
baseline 
assessments 
o 
2 weeks of med/placebo titration 
followed 
by 
8 
weeks 
of 
continued titration/optimal dose 
of med/placebo and behavioral 
intervention sessions 
o 
End point assessments the visit 
• Increased age range is to broaden eligible 
population for recruitment 
• Removing 
receptive 
language 
age 
equivalent 
and 
setting 
lower 
IQ 
requirement is designed to facilitate 
diagnosis of ADHD in children who do 
not 
have 
severe 
developmental 
disabilities 
• Direct observational measure (PCI) will 
be a better indicator of the effects of 
COMB vs. BEH treatment in this study 
timeframe 
• Keeping VABS-3 as key secondary and 
using 
remote 
follow-up 
to 
allow 
sufficient time to observe change in 
response and improvement 
• Broadened language on criteria associated 
with other psychiatric conditions allows 
PI and study team to assess individual 
circumstances and whether conditions 
confound assessments 
• Shortened medication phase is aligned 
with 
stimulant 
trials, 
accommodates 
participant 
engagement, 
and 
allows 
unblinding directly following treatment 
phase 
• Restructured visit schedule encompasses 
all safety precautions in medical exams 
and med titration, in addition to collecting 
assessment data, without overburdening 
family or participant on any given visit 
 
 


A+ Treatment: Impact of combined medication and behavioral treatment for young children with ASD and ADHD    
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5 
following last ESDM-informed 
parent coaching session 
o 
30 day AE follow-up 
o 
Remote follow-up at 24 weeks 
• Changed behavioral intervention from 12 
weekly sessions of P-ESDM including 
curriculum assessment to 8 weekly sessions 
of ESDM-informed parent coaching model 
• Changed 
Schedule 
of 
Activities 
to 
accommodate shorter study duration and 
remove 
midpoint 
assessments 
while 
preserving baseline, end point and follow-
up assessments 
• Changed AE reporting to use PAERS 
system for reporting and tracking 
• AE reporting must occur at each visit and 
may be completed with MD or study 
coordinator 
• Changed study intervention to include 
unblinding of participants to med/placebo 
group immediately following completion of 
end point assessments 
• Added optional follow-up phase for remote 
assessments at 24 weeks after baseline 
assessments 
• Reduced n to 48 participants 
• Remove CPT 
• Add CGI S&I parent report form  
• Adjust 
compensation 
for 
new 
visit 
schedule.  This increases total potential 
compensation to $600. 
 
 
 
 
 
 
 
• 8 sessions of behavioral intervention 
cover of all principles of ESDM model 
without extending medication treatment 
phase unnecessarily 
• SOA includes all baseline and endpoint 
assessments.  Requirement for midpoint 
assessments is no longer relevant as there 
is no need to “re-baseline” following 
medication ramp. 
• PAERS reporting tools are commonly 
used in pediatric clinical drug trials and 
allows for reporting at every visit – both 
physician and therapy led visits. 
• Remote 24 week follow-up creates 
opportunity for additional administration 
of VABS-3 to address secondary aim. 
• Reduced number of participants is 
selected to accommodate remaining grant 
period. 
• Removed CPT as it no longer aligns with 
primary, secondary or exploratory aims. 
• Added CGI S&I parent forms to enable 
tracking at visits that do not include 
physician 
• Increased compensation to adequately 
compensate families for length and 
number of visits 
  
3.0/ 
Oct. 30,2018 
 
 
 
 
 
 
 
 
 
• Changed Inclusion Criteria to include 
children  
--55-72 months with receptive language age 
equivalent of = or  < 72 months, 
--changed exclusion for amount of child 
therapy outside of study to be no time 
limit but stable in amount and dose for 8 
weeks prior to enrollment 
• Will 
provide 
transportation 
to 
those 
children and their families who would not 
otherwise be able to obtain consistent 
transportation. 
• Built in assessment of caregiver fidelity to 
the P-ESDM model within the P-ESDM 
coaching 
sessions.   
zzzz 
• Increase feasibility of recruiting full 
sample size to provide P-ESDM to 
broader array of children, to children 
receiving more intensive therapies not 
specifically focused on reciprocal social 
interactions 
and 
attention.   
a 
• Increase recruitment by making study 
accessible to indigent families who may 
not have access to reliable transportation 
• Provide 
a 
measure 
of 
parent 
responsiveness to coping which we 
expect to be a major component of child 
response to P-ESDM 
• Compliance with DEA requests and 
changes in how study investigational 


A+ Treatment: Impact of combined medication and behavioral treatment for young children with ASD and ADHD    
Protocol Pro00085179, v4.6 
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6 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.0/ 
Sep. 21, 2018 
• Provided more clarification of blinding and 
drug 
accountability 
procedures   
a 
• Moved measures obtained at Week 0 only 
to 1st section of Schedule of Assessments 
• Made visit windows broader  
• Increased initial rate of study drug titration 
• Added Specific Aims Section 
• Changed the primary outcome measure to 
the mean of the VABS socialization and 
communication subscale standard scores 
• Changed key secondary outcomes to 
include JERI ratings  joint attention and 
engagement.   
• Eliminated the week 10 EEG measures. 
• Changed timing and length of P-ESDM 
curriculum 
assessment 
and 
coaching 
sessions.   
• Added 
Sluggish 
Cognitive 
Tempo 
questionnaire weeks 0, 10,24,& 52. 
• Removed ASSIST/READY, added Sense to 
Know 
• Changed 
exclusion 
criteria, 
Leiter 
guidelines & deleted post baseline Leiters, 
& added home videos, childhood behavior 
inventory, 
sensory 
experiences 
questionnaire 
and 
preschool 
executive 
function battery to week 0 
• Changed FDA reporting to reflect IND 
exemption; provided more detail about 
safety reporting, documentation of TEAEs, 
and drug accountability procedures 
• Updated references & corrected clerical 
errors 
materials were supplied. 
• Increase 
clarity   
aa 
• To reduce burden on participants.  
• DSMB suggestion 
• Increase coordination of grant &protocol 
• Changed to reflect specific functional 
areas 
targeted 
by 
P-ESDM.   
a  
• Increased sensitivity vs duration coding 
& alignment across Duke ACE center. 
• Reduce burden & cost. 
• Prevent overlap with week 10, reduce 
burden & assess parent fidelity.  
• Advisory board suggested given potential 
overlap with ASD & ADHD 
• Unable to agree on contract 
• To standardize week 0 assessments with 
A+ Development facilitate centerwide 
comparisons.                                                 
A                                                                   
aaa 
• Revisions necessary as gathered new 
regulatory 
information 
& 
developed 
database & drug blinding procedures.   
A                                                              
aaaa 
• Clerical 
 


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Protocol Pro00085179, 
 
 
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ii 
Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................................................. 1 
1 
PROTOCOL SUMMARY ............................................................................................................................... 1 
1.1 
Synopsis ................................................................................................................................................ 1 
1.2 
Schema ................................................................................................................................................. 5 
1.3 
Schedule Of Activities (SoA) .............................................................................................................. 0 
2 
INTRODUCTION: SCIENTIFIC RATIONALE AND BACKGROUND INFORMATION ........................ 0 
2.1 
Rationale ............................................................................................................................................... 0 
2.2 
Background ........................................................................................................................................... 0 
2.3 
Specific Aims ........................................................................................................................................ 5 
2.4 
Risk/Benefit Assessment .................................................................................................................... 6 
2.4.1 
Known potential risks ....................................................................................................... 7 
2.4.2 
Known potential benefits ................................................................................................. 8 
2.4.3 
Assessment of potential risks and benefits .................................................................. 9 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................................ 9 
4 
STUDY DESIGN ........................................................................................................................................... 12 
4.1 
Overall Design .................................................................................................................................... 12 
4.2 
Scientific Rationale for Study Design .............................................................................................. 13 
4.3 
Justification for Dose ......................................................................................................................... 14 
4.4 
End of Study Definition ..................................................................................................................... 15 
5 
STUDY POPULATION ................................................................................................................................ 16 
5.1 
Inclusion Criteria ................................................................................................................................ 16 
5.2 
Exclusion Criteria ............................................................................................................................... 16 
5.3 
Lifestyle Considerations .................................................................................................................... 17 
5.4 
Screen Failures .................................................................................................................................. 17 
5.5 
Strategies for Recruitment and Retention ...................................................................................... 17 
6 
STUDY INTERVENTION ............................................................................................................................ 19 
6.1 
Study Interventions Administration.................................................................................................. 19 
6.1.1 
Study medication intervention description .................................................................. 19 
6.1.2 
Medication dosing and administration ......................................................................... 19 
6.1.3 
Study Behavioral Intervention Description ................................................................. 20 
6.1.4 
Study intervention groups ............................................................................................. 21 
6.2 
Clinical Trial Supplies Preparation/Handling/Storage/Accountability ......................................... 21 
6.2.1 
Acquisition and accountability ...................................................................................... 22 
6.2.2 
Formulation, appearance, packaging, and labeling .................................................. 24 
6.2.3 
Product storage and stability ........................................................................................ 25 
6.2.4 
Preparation ...................................................................................................................... 25 
6.3 
Measures to Minimize Bias: Randomization And Blinding .......................................................... 26 
6.3.1 
Randomization ................................................................................................................ 26 
6.3.2 
Blinding 26 
6.4 
Study Intervention Compliance ........................................................................................................ 28 
6.5 
Concomitant Therapy ........................................................................................................................ 28 
6.5.1 
Prohibited concomitant therapies ................................................................................ 28 
6.5.2 
Permitted concomitant therapies ................................................................................. 28 
6.5.3 
Rescue medicine ............................................................................................................ 29 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT WITHDRAWAL ..................... 29 
7.1 
Study Halting Rules ........................................................................................................................... 29 
7.2 
Rules for Individual Participant Discontinuation in Study Interventions ..................................... 30 
7.3 
Participant Discontinuation/Withdrawal from the Study ............................................................... 30 
7.4 
Lost to Follow-Up ............................................................................................................................... 30 
8 
STUDY ASSESSMENTS AND PROCEDURES ...................................................................................... 31 
8.1 
Efficacy Assessments ....................................................................................................................... 31 


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8.1.1 
Primary efficacy assessment ........................................................................................ 31 
8.1.2 
Secondary efficacy procedures and assessments .................................................... 32 
8.1.3 
Exploratory objective outcome assessments ............................................................. 32 
8.1.4 
Other supporting behavioral outcome assessments................................................. 33 
8.1.5 
Other descriptive measures obtained only at baseline ............................................. 35 
8.2 
Safety and Other Assessments ....................................................................................................... 36 
8.3 
Adverse Events and Serious Adverse Events ............................................................................... 37 
8.3.1 
Definition of adverse events (AE) ...................................................................... 37 
8.3.2 
Definition of serious adverse events (SAE) ................................................... 37 
8.3.3 
Classification of an adverse event ............................................................................... 38 
8.3.4 
Time period and frequency for event assessment and follow-up.......... 38 
8.3.5 
Adverse event reporting ......................................................................................... 39 
8.3.6 
Serious ADVERSE EVENT REPORTING ........................................................ 39 
8.3.7 
Reporting events to participants .................................................................................. 40 
8.3.8 
Events of special interest .............................................................................................. 40 
8.3.9 
Reporting of pregnancy ................................................................................................. 40 
8.3.10 
Reporting of suspected child abuse or neglect .......................................................... 40 
8.4 
Unanticipated Problems .................................................................................................................... 41 
8.4.1 
Definition of unanticipated problems (UP) .................................................................. 41 
8.4.2 
Unanticipated problem (UP) reporting ........................................................................ 41 
8.4.3 
Reporting unanticipated problems to participants ..................................................... 42 
8.5 
Overall Plan to Protect Patient Safety ............................................................................................ 42 
9 
STATISTICAL CONSIDERATIONS .......................................................................................................... 43 
9.1 
Statistical Hypotheses ....................................................................................................................... 43 
9.2 
Sample Size Determination .............................................................................................................. 44 
9.3 
Populations for Analyses .................................................................................................................. 45 
9.4 
Statistical Analyses ............................................................................................................................ 45 
9.4.1 
General approach .......................................................................................................... 45 
9.4.2 
Analysis of the primary efficacy endpoint ................................................................... 46 
9.4.3 
Analysis of the secondary endpoints ........................................................................... 46 
9.4.4 
Safety analyses .............................................................................................................. 47 
9.4.5 
Baseline descriptive statistics ...................................................................................... 47 
9.4.6 
Planned interim analyses .............................................................................................. 48 
9.4.7 
Sub-group analyses ....................................................................................................... 48 
9.4.8 
Tabulation of individual participant data ..................................................................... 48 
9.4.9 
Exploratory analyses ..................................................................................................... 48 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................. 48 
10.1 
Regulatory, Ethical and Study Oversight Considerations ............................................................ 49 
10.1.1 
Informed consent process ............................................................................................ 49 
10.1.2 
Study discontinuation and closure ............................................................................... 49 
10.1.3 
Confidentiality and privacy ............................................................................................ 50 
10.1.4 
Future use of stored specimens and data .................................................................. 51 
10.1.1 
Safety oversight .............................................................................................................. 51 
10.1.2 
Key roles and study governance ................................................................................. 51 
10.1.3 
Clinical monitoring .......................................................................................................... 52 
10.1.4 
Quality assurance and quality control ......................................................................... 53 
10.1.5 
Data handling and record keeping............................................................................... 53 
10.1.6 
Protocol deviations ......................................................................................................... 54 
10.1.7 
Publication and data sharing policy ............................................................................. 54 
10.1.8 
Conflict of interest policy ............................................................................................... 55 
10.2 
Abbreviations ...................................................................................................................................... 55 
10.3 
Protocol Amendment History ........................................................................................................... 57 
11 
APPENDIX 1: Conmed sheet with washout instructions ........................................................................ 58 


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12 
References .................................................................................................................................................... 60 
 


A+ Treatment: Impact of combined medication and behavioral treatment for young children with ASD and ADHD    
Protocol Pro00085179, 
 
 
A+ Treatment v4.6 
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1 
STATEMENT OF COMPLIANCE 
The study will be carried out in accordance with International Council for Harmonisation Good Clinical 
Practice (ICH GCP) and the following:  
 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR 
Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are responsible 
for the conduct, management, or oversight of NIH-funded clinical trials have completed Human Subjects 
Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both the 
protocol and the consent form must be obtained before any participant is enrolled.  Any amendment to 
the protocol will require review and approval by the IRB before the changes are implemented to the 
study.  In addition, all changes to the consent form will be IRB-approved; a determination will be made 
regarding whether a new consent needs to be obtained from participants who provided consent, using a 
previously approved consent form. 
 
1 
 
PROTOCOL SUMMARY 
1.1 
Synopsis  
 
A+ Treatment: 
 
Impact of combined medication and behavioral treatment for young children 
with Autism Spectrum Disorder (ASD) and Attention Deficit Hyperactivity 
Disorder (ADHD); Duke Autism Center of Excellence (Duke ACE), Project 3; 
Protocol Pro00085179, v1.1 20 August 2018) 
 
 
Study Description: 
This randomized, placebo-controlled, phase 2, pilot study will evaluate the 
developmental impact of combined medication and behavioral treatment 
(COMB) versus placebo and behavioral treatment (BEH) in children with 
comorbid ASD and ADHD, who are between 36 and <132 months of age.  The 
active medication treatment will be an orally dissolvable, extended release 
amphetamine preparation (Adzenys-XR-ODT, (2)) administered following 
baseline assessments for 10 weeks and titrated to the optimal dose.  The 
provided behavioral treatment will be eight ~60-minute sessions in ESDM-
informed parent coaching delivered weekly, beginning 2 weeks after 
medication/placebo administration begins and continuing for 8  consecutive 
weeks.  The implicit behavioral treatment is Early Start Denver Model 
(ESDM)-informed parent coaching implemented within the child’s daily 
schedule by the parent/caregiver. 
 
 
Objectives: 
The overarching goal of A+ Treatment is to evaluate whether combined 
medication and behavioral treatment improves quality of sustained joint 
engagement at 10 weeks after medication baseline.   


A+ Treatment: Impact of combined medication and behavioral treatment for young children with ASD and ADHD    
Protocol Pro00085179, 
 
 
A+ Treatment v4.6 
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Other important objectives are to determine whether the COMB treatment 
improves ADHD ratings and results in greater social communicative 
developmental progress than the behavioral intervention alone.    
Exploratory objectives are to identify potential assessments of overall 
attention, social attention/engagement and/or neurophysiologic biomarkers 
that correlate with greater improvements in social communicative 
development independent of medication group assignment; and to 
determine if there is a difference in social communicative functioning and 
ADHD symptoms in treatment groups 24 weeks after beginning treatment. 
 
 
Primary Endpoint: 
Change in the amount and quality of joint engagement between the child 
and the parent/guardian during a semi-structured 6 minute parent child 
interaction task using the Joint Engagement Rating Inventory (JERI(4)). 
 
 
Key Secondary 
Endpoints 
Change in the Mean of the Vineland Adaptive Behavior Scale - 3rd edition 
(VABS(3)) Socialization subscale standard score and Communication subscale 
standard score (aka Vineland -2DC). 
Preschool and School age ADHD Rating Scale(5) – parent report and MD 
report 
Multiple other assessments will be obtained to provide supportive 
information related to the child’s functioning, general attention, social 
attention, executive functioning, safety, and potential neurophysiologic 
indices of improved social and general attention. 
 
Study Population: 
~ 48 participants who are between 36 months and <132 months of age with 
comorbid ASD and ADHD.   
 
 
   Inclusion criteria 
• 
Provision of a parent/guardian signed and dated informed consent form. 
• 
Stated willingness to comply with all study procedures and availability 
for the duration of the study.  
• 
Aged 36 months and <132 months of age at baseline.   
• 
Diagnosed with both ASD and ADHD based on consensus diagnosis 
informed by results of the Autism Diagnostic Observation Schedule 2nd 
edition (ADOS-2(7)), Autism Diagnostic Interview - Revised (ADI-R(8)), a 
standardized ADHD Diagnostic Interview (9), and the MINI psychiatric 
diagnostic interview. 
• 
In good general health as evidenced by medical history, physical exam 
and review of safety labs and electrocardiogram. 
 
 
   Exclusion Criteria 
• 
Recent use of prohibited psychoactive medication in close proximity of 
baseline assessments. See MOP for specific medications that are 
prohibited and washout procedures.) Use of a monoamine oxidase 


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inhibitor is prohibited within 14 days of baseline.  
• 
Known allergic reactions to amphetamines or components of Adzenys-
XR-ODT.   
• 
Known history of sudden non-ischemic cardiac death in a first or second 
degree family member (sibling, parent, aunt, uncle, cousin or 
grandparent).  
• 
Personal history of significant cardiac abnormalities or disease, 
particularly rhythm abnormalities.  
• 
Significant visual, auditory or motor impairments that would preclude 
participation in ESDM-informed parent coaching or completion of key 
assessments (see MOP for details). 
• 
Inability of the caregiver participating in ESDM-informed parent coaching 
and responding to questionnaires to fluently speak English.  
• 
Parent’s participation in another parent coaching intervention on more 
than a monthly basis that may affect ESDM-informed parent coaching as 
deemed by the PI or clinician.  
• 
Presence of any psychiatric conditions or psychiatric symptoms in 
addition to ASD and ADHD that would confound assessments and/or 
affect participation in the study as deemed by the PI or clinician. See 
MOP for procedures for senior clinician review of psychiatric conditions 
and/or symptoms. 
• 
Known genetic (e.g. Fragile X) or neurological syndrome or condition 
with established link to autism, but not events in which the link to ASD is 
less well known/established (e.g., 16p11.2 CNVs, CHD8 mutations, 
Trisomy 21, 22q deletion syndrome). 
• 
History of epilepsy or seizure disorder (except for history of simple 
febrile seizures or if the child is seizure free - regardless of seizure type - 
for the past year) 
• 
History of neonatal brain damage. (e.g., with diagnoses of hypoxic or 
ischemic event) 
• 
Any known environmental circumstances that is likely to account for the 
clinical presentation of autism in the proband (severe nutritional or 
psychological deprivation etc.) 
• 
Study clinician judgment that it is not in the best interests of the 
participant and/or the study for the child to participate. 
 
 
 
Phase: 
This is a phase 2 pilot study. 
 
Description of Sites 
Enrolling Participants: 
 
Single academic center site in US. 
Description of Study 
Intervention: 
All participants will be randomized to receive flexible dose (1.55 mg to 18.6 
mg/day) Adzenys-XR-ODT extended release, orally dissolvable tablets or 
matched placebo for ~10 weeks following baseline assessments until the end 


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of treatment assessments are completed. Adzenys-XR-ODT or placebo 
treatment will be initiated at 1 tablet (3.1/0 mg/day) for participants 36 to 
<72 months of age, and 2 tablets (6.2/0 mg/day) for participants 72 to < 132 
months of age.  Dose will be flexibly titrated upward to reach a target dose 
of 4 tablets (12.4/0 mg) daily.  If necessary, the dose may be decreased to as 
little as ½ tablet (1.55/0 mg) daily or increased to as many as 6 tablets 
(18.6/0 mg) daily using procedures described in the MOP.  The study drug 
may also be stopped if there are intolerable adverse events. 
In addition, all participants will receive eight consecutive weekly ~60-minute 
ESDM-informed parent coaching sessions following 2 weeks of medication 
titration.  
The two randomized intervention groups will be: 
• COMB in which participants receive flexibly dosed Adzenys-XR-ODT 
(1.55mg – 18.6 mg) each morning between day1 (day following 
completion of baseline and completion of endpoint assessment(10 
weeks) plus eight consecutive weekly ~60 minute ESDM-informed 
parent coaching sessions between day 14 and day 63 of study drug 
treatment. . 
• BEH in which participants receive flexibly dosed Placebo each 
morning between day1 (day following completion of baseline and 
completion 
of 
endpoint 
assessment(10 
weeks) 
plus 
eight 
consecutive weekly ~60 minute ESDM-informed parent coaching 
sessions between day 14 and day 63 of study drug treatment.. 
 
 
 
Participant Duration: 
Total participation is expected to require 30 weeks, including optional 
remote follow-up at 24 weeks after start of medication treatment. The A+ 
Treatment diagnostic and screening visits will generally occur between 1 and 
6 weeks prior to baseline.  After randomization, study-provided medication 
and ESDM-informed parent coaching will be delivered per the Schedule of 
Activities (SOA) for 10 weeks.  Following the endpoint assessment 
participants and parents/guardians will be free to obtain medication or 
behavioral intervention outside of the study, but none will be provided by 
the study team. The final assessment will be obtained at 24 weeks after 
baseline when the parent will be contacted remotely to conduct caregiver-
report assessments of child behavior.  
 
 
 
 


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1.2 
Schema 
 
 
  
 
Figure 1: A+ Treatment Schema  A+ treatment staff will meet with parents/caregivers to explain the 
study and to review the informed consent document with them. Eligibility in the A+ Treatment study will 
include meeting diagnostic, cognitive and age criteria. A+ Treatment staff will obtain an 
electrocardiogram (ECG)and perform other medical assessments necessary to determine eligibility, 
ESDM-informed parent coaching beginning after 2 weeks of study drug titration. Adverse events will be 
evaluated weekly with dose titration as needed. The primary outcome assessments will evaluate change 
between baseline assessments and endpoint assessments, following 10 weeks of study drug and ESDM-
informed parent coaching. In addition, parents will be contacted remotely (via phone/internet) at 24 
weeks following baseline to conduct caregiver-report assessments, to obtain information about the 
course of subsequent developmental and behavioral changes. 
 


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1.3 
Schedule Of Activities (SoA) 
 
Part of Study 
Screening# 
Baseline# 
Study Intervention Period 
Endpt 
FU 
Visits 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
Type 
ADI-R 
Consent and 
Diagnostic 
Diagnostic 
Med Screen 
and Feedback 
Baseline 1 
Baseline 2 and 
Medication 
Titration 
Titration and 
ESDM Week 1 
ESDM Week 
2** 
ESDM Week 3 
ESDM Week 4 
ESDM Week 5 
ESDM Week 6 
ESDM Week 7 
ESDM Week 8 
Endpoint 
Assessments 
2 week AE 
Follow-up 
Remote 
Follow-up 
Typical Week offset from 
med baseline 
-5 
-4 
-3 
-2 
-1 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
12 
24 
Window 
n/a 
n/a 
 
Within 6 months 
 
 
+/-     
3 days 
+/-      
3 days 
+/-      
3 days 
+/-      
3 days  
+/-     
3 days  
+/-     
3 days  
+/-     
3 days  
+/-     
3 days  
+/-     
3 days  
+/-     
3 days 
+/-     
1 wk 
+/-     
1 wk 
 
Within  30 days 
Consent/ 
Diagnostic Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
A 
A 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ADI-R 
A 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
A 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ACE Subject Med History 
 
A 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ACE Family History 
 
A 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Intervention History 
 
A 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vineland-3 parent report 
 
A 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ADOS 
 
A 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cognitive testing DAS-2 
 
A 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBCL 
 
A 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ADHD-RS-parent, 
 
A 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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teacher (optional) 
SRS-2 
 
A 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MINI Kid 7.0.2 
 
 
A 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Spence 
 
 
A 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diagnostic Feedback 
 
 
 
A 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Additional Screening  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Family Hx Cardiac Disease 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Recent & Current Meds  
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Intervention History  
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
PMH, Psychiatric History 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Electrocardiogram 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam, focused 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
Vital signs, height, weight 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Condensed Medical 
History Form 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stimulant Washout 
Confirmation Form 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visits 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
Type 
ADI-R 
Consent and 
Diagnostic 
Diagnostic 
Med Screen 
and Feedback 
Baseline 1 
Baseline 2 and 
Medication 
Titration 
Titration and 
ESDM Week 1 
ESDM Week 2 
ESDM Week 3 
ESDM Week 4 
ESDM Week 5 
ESDM Week 6 
ESDM Week 7 
ESDM Week 8 
Endpoint 
Assessments 
2 week AE 
Follow-up 
Remote 
Follow-up 
Week offset from med 
baseline 
-5 
-4 
-3 
-2 
-1 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
12 
24 
Window 
n/a 
n/a 
within 6 months 
 
+/- 
3days 
+/-     
3 days  
+/-     
3 days  
+/-     
3 days  
+/-     
3 days  
+/-     
3 days  
+/-     
3 days  
+/-     
3 days  
+/-     
3 days 
+/-     
3 days 
+/-     
1 wk 
+/-     
1 wk 
 
Within 30 days 
RANDOMIZATION 
to 
COMB/BEH 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 


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  MD Dispense study pills  
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
Participant takes study 
pills 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
ESDM-informed parent 
coaching 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Monitor  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE Monitoring 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Suicidality Assessment  
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
 
Prescribed dose record 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Medication Accountability  
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
ESDM parent eng rating 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
ESDM coaching fidelity  
 
 
 
 
 
 
 
* 
* 
* 
* 
* 
* 
* 
* 
 
 
 
PRIMARY OUTOME 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PCIT-(allows JERI & Activity 
Video) 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 SECONDARY/Exploratory 
OUTCOMES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ADHD-RS parent/clinician 
report 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Vineland 3-interview 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
CBCL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Eye Gaze Tracking & Sense 
to KnowB  
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
ABC 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
SRS-2 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Childhood Behavior 
Questionnaire 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Leiter –executive function  
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sensory Experiences 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Questionnaire 
Visits 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
Type 
ADI-R 
Consent and 
Diagnostic 
Diagnostic 
Med Screen 
and Feedback 
Baseline 1 
Baseline 2 and 
Medication 
Titration 
Titration and 
ESDM Week 1 
ESDM Week 
2** 
ESDM Week 3 
ESDM Week 4 
ESDM Week 5 
ESDM Week 6 
ESDM Week 7 
ESDM Week 8 
Endpoint 
Assessments 
2 week AE 
Follow-up 
Remote 
Follow-up 
Week offset from med 
baseline 
-5 
-4 
-3 
-2 
-1 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
12 
24 
Window 
n/a 
n/a 
 
Within 6 months 
 
 
+/- 
3days 
+/-     
3 dsys 
+/-     
3 days 
+/-     
3 days 
+/-     
3 days  
+/-     
3 days 
+/-     
3 days 
+/-     
3 days 
+/-     
3 days  
+/-     
3 days 
+/-     
1 wk 
+/-     
1 wk 
 
Within 30 days 
 SECONDARY/Exploratory 
OUTCOMES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Home Video 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sluggish Cognitive Tempo 
Rating  
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
BRIEF  
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
Child Sleep Health 
Questionnaire 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
CGI-S&I clinician report 
 
 
 
 
 
S 
S,I 
S,I 
 
S,I 
 
 
S, I 
 
 
S,I 
 
S,I 
Impairment Rating Scale 
 
 
 
 
 
XB 
F 
F 
F 
F 
F 
F 
F 
F 
F 
F 
 
 
Caregiver Strain 
Questionnaire  
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
Parent Satisfaction 
Questions 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Treatment Guess  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Parenting Sense of 
Competence Form 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
EEG OUTCOMES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Regional Coherence  
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
Interphase Coherence  
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
Evoked response to social  
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
#=Portions of visits may be completed in the context of A+ Assessment or A+ Development in advance of signing consent for A+ Treatment.  If this is the case, medical screening 
would be done after A+ Treatment consent is signed.  In addition, outcome assessments for A+ Treatment may need to be repeated from A+ Development if they have occurred 
more than 3 months previously for EEG,EGT, PCI and more than 1 month previously for parent questionnaires. 
A=Assessments performed as part of eligibility evaluation and diagnostics.  Source documents are submitted and IRB-approved under the A+ Assessment protocol. 
X=Assessments performed as part of the A+ Treatment protocol 
XB=IRS baseline form 
F=IRS follow-up form 
* ESDM coaching fidelity is completed by the clinician for one session for each participant.  The session is selected at random. 
**Physician may attend this visit if deemed necessary. 
S= CGI-S form completed 
I= CGI-I form completed 


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2  
INTRODUCTION: SCIENTIFIC RATIONALE AND BACKGROUND INFORMATION 
 
2.1 
Rationale  
 
The Significance on the Comorbidity of ASD and ADHD 
Autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) are highly 
comorbid, with ~40-60% of children with ASD having co-occurring ADHD and ~18% of children with 
ADHD exhibiting social communication deficits similar to those observed in ASD(11, 12). Multiple studies 
have shown that youth with ASD+ADHD often receive a delayed diagnosis of ASD, have worse clinical 
outcomes, require more restrictive environments and have caregivers experiencing higher levels of 
stress than those without ADHD(13-16). Studies that have examined the shared and distinguishing 
features of ASD and ADHD in school-age children suggest that each disorder is associated with a unique 
profile of attentional, behavioral, affective and cognitive processing problems that impact social 
communication and long term outcomes(17, 18). Specifically, ASD has been associated with difficulties 
in disengaging attention, reduced attention to social stimuli, reduced expression of positive affect and 
deficient early stage neural processing of social information. In contrast, ADHD has been associated with 
difficulties in selective and sustained attention and inhibitory control, challenging behaviors such as 
hyperactivity, increased negative affect, and deficient neural processing of higher order social 
information. Older children with comorbid ASD and ADHD have greater impairments than those with 
either ASD or ADHD alone. Thus, the difficulties typically associated with ADHD are likely to exacerbate 
the attentional, social, affective and neural processing impairments generally associated with ASD, 
leading to significantly greater initial and long-term impairments in children with ASD+ADHD.  We posit 
that co-occurring ADHD symptoms also significantly impair the ability of children with ASD to respond to 
and fully benefit from ASD behavioral interventions, further increasing the functional gap between them 
and their peers with ASD alone throughout development. This idea is supported by a recent study 
reporting decreased efficacy of a social skills intervention for children with ASD+ADHD vs. peers with 
ASD alone or with ASD and comorbid anxiety(16). 
 
Treatment Gaps for Young Children with ASD + ADHD 
The impact of co-occurring ADHD symptoms on response to ASD behavioral intervention has not been 
studied. However, clinical observations suggest that ADHD behaviors significantly slow the pace of 
progress during intervention. Successful treatment depends upon increasing children’s attention to 
social and nonsocial (e.g., toys) stimuli and sustained social engagement, both of which can be disrupted 
by inattention, hyperactivity, and negative affect, all of which are associated with ADHD. In addition, 
there is little information about the efficacy and tolerability of various medications to treat ADHD in 
children with ASD + ADHD. Finally there are few ADHD medications available for children who are not 
able to swallow pills or capsules. 
 
2.2 
Background   
Prevalence 
Approximately half of children with autism spectrum disorder (ASD) have co-occurring attention deficit 
hyperactivity disorder (ADHD)(11, 12). Unfortunately, the long-term outcomes of individuals with 
comorbid ASD and ADHD (ASD+ADHD) are significantly worse than individuals with ASD or ADHD. Those 
with ASD+ADHD are often diagnosed with ASD significantly later and exhibit more behavioral problems, 


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poorer peer relationships and increased use of restricted educational settings(13-15). As described in 
the Duke ACE Overall Research Plan, we hypothesize that these negative outcomes in individuals with 
ASD+ADHD are, in part, the consequence of ADHD symptoms compromising the individual’s ability to 
fully benefit from behavioral interventions for ASD, which all require the interventionist to acquire and 
sustain the child’s attention. Consequently, we hypothesize that effective treatment of co-occurring 
ADHD symptoms will improve developmental and functional outcomes for children with ASD+ADHD. 
 
ADHD Comorbidity with ASD Related to Impaired Verbal Working Memory and Verbal Delayed Recall 
The main manifestations of ASD include impaired social interaction, communication, and restricted and 
repetitive patterns of behaviors. Although ASD is typically an exclusion criteria for ADHD according the 
DSM-5, several studies have reported ADHD symptoms co-occurring in subjects with ASD. A study by 
Andersen et al (19) studied 38 children with high functioning autism (HFA) with (+) and without (-) 
“attention problems” according to the Child Behavior Checklist, 79 with ADHD alone and 50 typically 
developing children. The children were administered a Letter-Number Sequencing test (LNS) where 
children are required to listen to a presentation of alternating letters and digits and afterwards asked to 
recall the numbers in ascending order and the letter in alphabetical order (19). It was found that 
children with HFA+ displayed significant impairment compared to other typically developing children in 
all three neurocognitive measures while those with HFA- only had greater impairments with working 
memory and acquisition measures. In addition, the HFA+ group scored significantly lower than the HFA- 
group and the ADHD group on verbal working memory and delayed recall measures. 
 
Background and Justification for the Interventions and Neural Correlates to be Examined 
Early Start Denver Model (ESDM(20)). ESDM is an empirically-validated, naturalistic, developmental, 
behavioral intervention for children with ASD who have mental ages between 12 and 60 months. 
Intervention strategies are delivered in the context of affectively- and socially-engaged joint activities 
between the child and adult. A key goal is to promote social attention and social engagement as a 
platform for teaching joint attention, imitation, language, motor, cognitive and social skills, and for 
reducing maladaptive, disruptive behaviors. Thus, this intervention provides an ideal context in which to 
evaluate our overall conceptual framework, which posits that ADHD symptoms impede the ability of 
children with ASD to acquire and improve sustained social attention and social engagement. ESDM was 
co-developed by Sally Rogers and Duke ACE Center PI Geraldine Dawson. An RCT demonstrated that, 
when delivered intensively by trained therapists, ESDM results in significant improvements in IQ, 
language, social abilities, and adaptive behavior. It was also found that children who received ESDM 
showed normalized brain activity, reflected in measures of EEG activity during viewing of social 
stimuli(21). ESDM also has been associated with significant reductions in clinician-rated maladaptive 
behaviors, with 68% of children showing reductions by 12 weeks and 79% after ~ 1 year(22).  
 
Parent-delivered 
ESDM 
(P-ESDM) 
A 
parent 
delivered version of ESDM, parts of which will be 
used in this project, also has been developed, 
manualized, and evaluated. After the coach has 
assessed parent goals for their child, the therapist 
coaches that child’s parents on ESDM strategies to 
increase social attention and motivation, social 


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routines, joint activity routines, nonverbal communication, imitation, joint attention, speech 
development, functional and symbolic play skills, and management of challenging behavior in the 
context of parent identified social communication goals. The first study of P-ESDM evaluated the 
benefits of 1 hour/week of parent-coaching for 12 weeks in 8 children with ASD. Parents acquired the 
strategies and achieved fidelity by the 6th week(23). Children demonstrated sustained increases in joint 
attention, social engagement, social initiation, imitation and functional communicative behaviors (Figure 
2).  
Next, a larger (N = 98), NIH-funded RCT was conducted, evaluating the same brief 12-week, 1 hour/week 
of P-ESDM parent coaching vs. treatment-as-usual (TAU) in the community(21). The TAU group received 
significantly more hours of intervention, many of which were delivered by trained professionals. Both 
groups demonstrated similar statistically significant improvements in social symptoms and 
communication abilities, as measured by the ADOS social affect score and the Mullen Scales of Early 
Learning respectively. Parents in the P-ESDM group demonstrated significantly lower levels of parenting 
stress.  A+ Treatment will utilize principles derived from P-ESDM for 8 caregiver coaching sessions. 
Zhou et al. (24) evaluated the effects of a more intense version of P-ESDM that provided 1.5 hours/week 
of parent coaching for 6 months vs. treatment-as-usual in the community.  The control group was 
comprised of children with ASD who did not live near the university where the study was being 
conducted, and, thus, could not feasibly attend weekly treatment.  At baseline, there were no group 
differences in gender, birth history, parental education and income, parental age, or number of siblings. 
With appropriate controls for baseline scores and intervention hours received, the P-ESDM group 
showed significantly greater improvements on the Griffiths Mental Development Scales T-scores in the 
Social (M = 5.4 vs. -4.4; p = 0.001) and Receptive/Expressive Language (M = 20.3 vs. -6.6; p < 0.001) 
domains.  
Research on the developmental impact of the intervention after parent coaching is relatively more 
limited, although the impact of therapist delivered ESDM is typically assessed after 1-2 years and 
benefits appear to increase over time.  
Treatment of ADHD. Multiple treatment guidelines focused on ADHD in children recommend that initial 
treatment include behavioral management. In preschool children, behavioral treatment alone is 
recommended, while in school-aged children combined treatment with a stimulant medication and, if 
there is inadequate response, behavioral treatment is recommended(25).  Although no specific form of 
behavioral treatment is recommended, general principles include: 1) modifying the environment to 
reduce distractions, facilitate organization (a specific logical place for each thing), and increase 
predictability; 2) setting small attainable goals, 3) providing visual tools for assessing progress and on 
task behaviors, 4) rewarding positive behaviors, 5) minimizing reinforcement of negative behaviors and 
6) calm non-punitive discipline.  Although behavioral interventions typically improve problem behaviors 
often associated with ADHD, there is no indication that they directly impact ADHD symptoms. 
Multiple pharmacological treatments for ADHD have been demonstrated to have efficacy.  These 
medications typically fall into the following categories: 1) stimulants within the methylphenidate class or 
the amphetamine class, 2) alpha adrenergic agents which seem especially helpful for hyperactivity, 3) 
norepinephrine reuptake inhibitors (atomoxetine,  a selective norepinephrine reuptake inhibitor with a 
specific indication or venlaflaxine, which inhibits both norepinephrine and serotonin reuptake and does 
not have a specific ADHD indication), and other agents with theoretical actions that might increase 
dopaminergic tone.  Stimulant medications are the mainstay of treatment because they act very quickly, 
have a well-established safety profile and their impact is readily apparent.  Multiple different 
formulations of stimulants have been developed that vary primarily in terms of their formulations 
(liquid, tablet, capsule, transdermal) and their pharmacokinetic properties, generally with the goal of 


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consistent benefit throughout the day with minimal on off periods.  For any given stimulant medication, 
approximately 70% of treated children with ADHD alone will respond.  In the definitive clinical trial of 
methylphenidate and behavioral treatment of ADHD in school-age children the effect size of 
methylphenidate was 0.66 for parents and 1.33 for teachers (26, 27).  Further, ~ 85% of school-aged 
children with ADHD alone will respond to some stimulant medication, suggesting the benefit of trying 
the other stimulant class or a different formulation if the initial stimulant medication is not beneficial. 
Methylphenidate preparations and amphetamine preparations have similar adverse effects, although 
one meta-analysis suggested that amphetamine preparations may be slightly better tolerated (28).  
However, more information is available about the use of methylphenidate preparations in very young 
children and in children with ADHD. 
 
Adverse effects frequently seen during stimulant treatment include: reduced appetite, insomnia, 
emotional lability, increased anxiety and dysphoria, and weight loss.  In trials of Adderall XR (an 
extended release formulation of mixed amphetamine salts that the FDA views as generally equivalent to 
Adzenys-XR-ODT), 2.4% of Adderall treated school-aged children (n=425) with ADHD alone withdrew 
from treatment due to adverse effects compared to 2.7% of placebo treated children (n=259).  Overall, 
in school age children treated with Adderall XR loss of appetite, gastrointestinal distress and insomnia 
are reported in approximately 20% with emotional lability, nervousness, fever, vomiting, nausea, and 
weight loss reported in 4-10%.   Tics are seen infrequently (2).  Long-term follow-up of children with 
ADHD treated with methylphenidate from the NIH funded MTA study has also shown that children who 
remain on stimulant treatment for many years are about 1 inch shorter than their untreated peers (29). 
Infrequent adverse events include seizures, palpitations, increased heart rate, increased blood pressure, 
bad taste in one’s mouth, tiredness, rash, blurred vision, hair loss, prolonged erections and Raynaud’s 
phenomena (pain and vascular constriction in fingers with cold exposure). Highly significant but rare to 
isolated adverse events include possible new or worsening psychosis and/or bipolar disorder, muscle 
breakdown, cardiomyopathy, and sudden cardiac death.  A large FDA funded study examining the rates 
of sudden cardiac death in children treated with stimulants did not find any association of sudden 
cardiac death and stimulant use (30-32).  However, treatment guidelines suggest careful assessment of 
cardiac health prior to stimulant treatment and avoidance of stimulant use in individuals in whom 
tachycardia or increases in blood pressure could be dangerous.   
Mixed amphetamine salts, including Adzenys-XR-ODT, are typically metabolized more quickly in younger 
children than in older children or adults (2).  The rate of metabolism appears to depend upon the weight 
of individuals with metabolism slowing as individuals weigh less.  This is in contrast to methylphenidate 
preparations where older individuals typically metabolize the drug more quickly.   In pharmacokinetic 
studies of Adzenys-XR-ODT 3.1 mg (1 tablet) has dose equivalence to 5mg of mixed amphetamine salts 
and is metabolized in the same way with a peak in adults after a single dose at about 3 hours and return 
to non-detectible levels by ~ 60 hours. Please see Appendix 1 containing the package inserts for Adderall 
XR and Adzenys-XR-ODT for more detailed information.  
 
Pharmacological treatment of ADHD in preschool-age children. The only large trial of ADHD 
medications for preschool children with ADHD was the PATS study (33).  This study, in which the dose 
range was limited by the DSMB, showed that all but the lowest dose of methylphenidate was 
significantly better than placebo at reducing parent and teacher ratings of ADHD with effect sizes of 0.54 
and 0.66 respectively, which is reduced considerably from the effect sizes seen in the MTA, particularly 
for teachers.  In addition, about 10% of the preschool children could not tolerate methylphenidate and 
withdrew.  The most frequent adverse event associated with withdrawal was emotionality or irritability.  


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While appetite loss, stomachaches and insomnia occurred at similar rates as in older children, the 
preschool children also showed high rates of social withdrawal and lethargy (dull/tired/listless) 
compared to periods of placebo treatment.  Further only about 20% showed complete remission of 
ADHD symptoms. 
 
ADHD Medications in children with ASD + ADHD.  Similar to preschool children with ADHD alone, 
school-aged children with ASD+ADHD demonstrate lower rates of response and more frequent adverse 
effects to methylphenidate (34-37). Again mood adverse effects were particularly common and 
approximately 20% of children with ASD +ADHD could not tolerate any of the studied doses.  Further, 
the optimal dose was lower among school-aged children with ASD+ADHD than among similar children 
with ADHD alone.  Subsequently, trials have also shown benefit of atomoxetine and guanfacine 
extended release in school age children with ASD + ADHD(38-42).  In each of these trials the same 
general pattern has been observed.  Specifically, children with ASD+ADHD appear to have more 
frequent adverse events, particularly related to mood stability/irritability, and are modestly less likely to 
respond.   
To date no adequately powered, randomized controlled trials have examined the impact of an ADHD 
medication in preschool children with ASD + ADHD.  However, a small study of 12 preschool children 
with ASD+ADHD using a similar cross-over design as the RUPP MPH study, found that MPH significantly 
reduced ADHD symptoms, with a response rate similar that seen in older children with ASD+ADHD(43).  
Surprisingly, there were fewer dropouts due to intolerable adverse effects among the preschool children 
than the older children with ASD+ADHD.   
 
Impact of ADHD treatment of school-aged children with ASD+ADHD on Core ASD Symptoms.  Relevant 
to the aims of the A+ Treatment study, Jahromi et al.(44) evaluated a subset of 33 school-aged children 
with ASD+ADHD from the pivotal RUPP MPH study using an objective assessment of social 
communication functioning (the Joint Attention Measure from the Early Social Communication Scales, 
known as the JAMES). Optimal dose MPH, compared to placebo, resulted in significantly more joint 
attention initiations and responses during the assessment.  In addition, the children demonstrated less 
negative affect during parent-child interactions while treated with MPH compared to treatment with 
placebo.  These findings with school-age children provide support for our conceptual model and 
hypotheses for A+ Treatment.  
We will examine stimulants due to 1) established efficacy, 2) practice guidelines to use stimulants as the 
first medication option and 3) most importantly, evidence of positive effects on social communication 
(joint attention) in school-age children with ASD+ADHD. 
 
Neural correlates of attentional problems in ADHD and ASD and response to intervention. A growing 
body of evidence suggests that altered neural synchronization is a defining feature of both ADHD and 
ASD(29, 45-50). Studies of EEG connectivity (e.g., EEG coherence)(45) suggest that altered (hyper- or 
hypo) neural connectivity is associated with ADHD and ASD, and characterized by atypical long-range 
connectivity, especially between the frontal and other brain regions. This pattern also has been 
identified via fMRI studies. In addition, individuals with ADHD and those with ASD have been shown to 
exhibit increased variability of neural transmission, a neural signature that has been correlated with 
attentional control(51, 52). Variability in neural transmission can be evaluated via intertrial phase 
coherence (ITPC), a measure of the degree to which the phase (or timing) of the frequency-domain 


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event related component of the EEG signal aligns across trials, independently of amplitude. Using 
measures of ITPC, studies have demonstrated that the event-related brain potential (ERP) responses of 
individuals with ASD and ADHD are less consistent when compared to typically developing controls(51). 
However, some evidence suggests that, in the ASD group, this might be explained by the subgroup of 
individuals with ASD with co-occurring ADHD. Finally, substantial evidence from studies of infants 
through adults conducted by Dawson and Murias, as well as by others, indicates that ASD is associated 
with reduced neurophysiological responses to social stimuli (e.g., faces), as reflected in altered ERPs and 
spectral power(53, 54). Evidence is accumulating that changes in neurophysiologic activity are 
associated with symptomatic responses to pharmacologic, behavioral, and device-related interventions. 
For example, increases in neural connectivity, measured by resting state fMRI, have been demonstrated 
in children with ADHD who were treated with MPH, and also were associated with reductions in ADHD 
symptoms(51). In an RCT, Dawson et al. demonstrated that preschool-age children receiving ESDM 
intervention exhibited normalized neural activity (faster ERP responses, and decreased alpha and 
increased theta spectral power) when viewing social stimuli after receiving intervention(21). 
Improvements in social communication correlated significantly with measures of alpha and theta 
spectral power while viewing faces. Finally, there is evidence of treatment-related changes in intertrial 
phase coherence in children with hearing loss and cochlear implants (55). Specifically, reduced variability 
in neural transmission - increased ITPC - correlated with the amount of time the cochlear implant was 
present and, consequently, the duration of the ability to perceive auditory stimuli. In the present study, 
we will examine whether improvements in ASD and ADHD symptoms (i.e., joint attention, social 
communication functioning, and ADHD-RS scores) are correlated with enhanced (1) long range neural 
connectivity assessed by EEG coherence, (2) neural stability reflected by intertrial phase coherence, and 
(3) neural responsiveness while viewing social (face) stimuli (i.e., shorter ERP latency and increased 
cortical activation reflected in alpha and theta spectral power). Such neurophysiologic changes in 
response to interventions may reflect an underlying neural mechanism of treatment response and 
demonstrate target engagement, as well as a focus for the development of new treatments. 
 
2.3 
Specific Aims 
 
Approximately half of children with autism spectrum disorder (ASD) have co-occurring attention deficit 
hyperactivity disorder (ADHD)(11, 12). Unfortunately, the long-term outcomes of individuals with 
comorbid ASD and ADHD (ASD+ADHD) are significantly worse than individuals with ASD or ADHD. Those 
with ASD+ADHD are often diagnosed with ASD significantly later and exhibit more behavioral problems, 
poorer peer relationships and increased use of restricted educational settings(13-15). We hypothesize 
that these negative outcomes in individuals with ASD+ADHD are, in part, the consequence of ADHD 
symptoms compromising the individual’s ability to fully benefit from behavioral interventions for ASD, 
which all require the interventionist to acquire and sustain the child’s attention. Consequently, we 
hypothesize that effective treatment of co-occurring ADHD symptoms while receiving ASD behavioral 
intervention will improve developmental and functional outcomes for children with ASD+ADHD. 
The overarching goals of Project 3 are to (1) evaluate a novel behavioral intervention model 
personalized for children with ASD+ADHD that involves pharmacologically addressing ADHD symptoms 
while receiving behavioral intervention, and (2) identify changes in patterns of social attention, social 
interaction, and neurophysiology that may underlie improved treatment outcomes in children with 
ASD+ADHD. We will accomplish these goals by conducting a randomized controlled trial (RCT) evaluating 
whether stimulant treatment augments the benefits of ESDM-informed parent coaching (23, 24). 
Children with ASD+ADHD will be randomized to receive either an extended-release amphetamine 


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product (Adzenys-XR-ODT; AMP) or placebo prior to initiating ESDM-informed parent coaching. The 
flexibly- dosed AMP or placebo will be provided for 10 weeks under double-blind conditions. ESDM-
informed parent coaching will consist of individual parent coaching provided weekly for 8 weeks 
beginning 2 weeks after AMP or placebo is initiated. We will achieve our overall goals with the following 
specific aims:  
Aim 1. Determine whether stimulant medication combined with a parent-delivered behavioral 
intervention (COMB) is more efficacious than behavioral intervention alone (BEH) for improving 
social communication functioning in children with ASD+ADHD. We hypothesize that degree of 
change of child’s joint engagement during parent-child interaction (assessed via the JERI coding 
rating scale) will increase to a greater extent in children receiving COMB compared to those 
receiving BEH. Key secondary outcomes will be the changes in the mean of the Vineland Adaptive 
Behavior Scales-3rd edition Socialization subscale standard score and Communication subscale 
standard score.  
Aim 2. Evaluate the efficacy of AMP vs. placebo for reducing ADHD symptoms in children with 
comorbid ASD+ADHD. We hypothesize that ADHD symptom reduction (assessed via the clinician 
administered Preschool or School age ADHD Rating Scale10, 11) will be greater in children 
receiving AMP than placebo. 
Aim 3 (descriptive). Determine the association between pre- to post-treatment changes in 
behavioral outcomes (social communication functioning - VABS-3 and ADHD symptoms), without 
regard to treatment group, and changes in objective measures of children’s social attention 
(assessed via an eye-gaze tracking biomarker) and social engagement (assessed during a semi-
structured parent-child interaction). We hypothesize that increases in social communication 
functioning and/or reductions in ADHD symptoms will be correlated with a) increases in 
objectively measured attention to social stimuli in eye gaze tracking tasks and b) increases in 
amount, quality and fluency of parent-child joint attention and engagement. 
Aim 4 (exploratory). Determine the association between pre- to post-treatment changes in 
behavioral outcomes (social communication functioning and ADHD symptoms) and changes in 
neuro-physiological activity, as reflected in a) neural connectivity (EEG coherence), b) neural 
stability (inter-trial phase coherence; ITPC), and c) neural responsiveness to social information 
(event-related brain potentials [ERP] to social stimuli). We hypothesize that each of the following 
─ increases in social communication functioning and reductions in ADHD symptoms ─ will be 
positively correlated with enhanced long-range EEG coherence and ITPC, and shorter ERP latency 
and increased cortical activation (reduced alpha and increased theta spectral power) in response 
to social stimuli. 
A+Treatment will provide essential information about the impact of treating co-occurring ADHD on 
response to behavioral intervention which may influence the priority that practitioners place on early 
identification and treatment of ADHD in young children with ASD. By combining the results of Projects 1, 
2, and 3, the Duke ACE Center research program will offer a comprehensive understanding of the impact 
of co-occurring ADHD symptoms on early detection, trajectory, functional outcomes, neural 
mechanisms, and treatment response in young children with ASD. 
 
 
2.4 
Risk/Benefit Assessment   
 


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2.4.1 Known potential risks  
Study Drug: 
The potential risks of participating in this study are primarily related to the use of the active medication 
‒ Adzenys-XR-ODT.  As stated above in section 2.2, these risks are well known from the prolonged use 
of mixed amphetamine salts.  Specifically, adverse effects frequently seen during stimulant treatment 
include: reduced appetite, insomnia, emotional lability, increased anxiety and dysphoria, and weight 
loss.  In trials of Adderall XR (an extended release formulation of mixed amphetamine salts that the FDA 
views as generally equivalent to Adzenys-XR-ODT)(2), 2.4% of Adderall treated school-aged children 
(n=425) with ADHD alone withdrew from treatment due to adverse effects compared to 2.7% of placebo 
treated children (n=259).  Overall, in school age children treated with Adderall XR loss of appetite, 
gastrointestinal distress and insomnia are reported in approximately 20% and emotional lability, 
nervousness, fever, vomiting, nausea, and weight loss reported in 4-10%.   Tics are seen infrequently.  
Long-term follow-up of children with ADHD treated with methylphenidate from the NIH funded MTA 
study (ref) has also shown that children who remain on stimulant treatment for many years are about 1 
inch shorter than their untreated peers.  Infrequent adverse events include seizures, palpitations, 
increased heart rate, increased blood pressure, bad taste in one’s mouth, tiredness, rash, blurred vision, 
hair loss, prolonged erections and Raynaud’s phenomena (pain and vascular constriction in fingers with 
cold exposure).  Highly significant but rare to isolated adverse events include possible new or worsening 
psychosis and/or bipolar disorder, muscle breakdown, cardiomyopathy, and sudden cardiac death.  A 
large FDA funded study examining the rates of sudden cardiac death in children treated with stimulants 
did not find any association of sudden cardiac death and stimulant use.  However, treatment guidelines 
suggest careful assessment of cardiac health prior to stimulant treatment and avoidance of stimulant 
use in individuals in whom tachycardia or increases in blood pressure could be dangerous.  We would 
anticipate that the children in this trial may be more likely to have mood regulation, social withdrawal 
and listlessness adverse effects compared to the school age sample described in the Adzenys-XR-ODT 
label due to their young age and the presence of comorbid ASD.  In clinical practice many of these 
adverse effects are dose related, so the use of a flexible dosing strategy should be beneficial.  
In addition, the active pharmaceutical ingredient ‒ amphetamine salts ‒ can be abused and diverted by 
adults for their own use and thus is a controlled substance.  However, it is extremely unlikely that the 
participants in this trial would abuse the medication due to their young age and high levels of 
supervision.  
 
Rescue Medications: 
Melatonin  Studies of melatonin use for durations up to four years have failed to demonstrate 
significant adverse effects in a variety of pediatric populations(56-58). However, potential side effects 
include suppression of the hypothalamic–gonadal axis (triggering precocious puberty on 
discontinuation) and increased reactivity of the immune system in children on immunosuppressants 
(i.e., corticosteroids) or with immune disorders.  Melatonin has been demonstrated to have benefits on 
sleep latency in children with ASD(56, 57, 59, 60). 
 
Clonidine  Clonidine’s label (www.accessdata.fda.gov/drugsatfda_docs/label/2012/017407s037lbl.pdf) 
(2) indicates most adverse effects are mild and tend to diminish with continued therapy. The most 
frequent, which appear to be dose-related, are dry mouth, occurring in about 40 of 100 patients; 
drowsiness, about 33 in 100; dizziness, about 16 in 100; constipation and sedation, each about 10 in 


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100.  Most adverse effects are mild and tend to diminish with continued therapy. The most frequent 
(which appear to be dose-related) are dry mouth, occurring in about 40 of 100 patients; drowsiness, 
about 33 in 100; dizziness, about 16 in 100; constipation and sedation, each about 10 in 100.  The 
following less frequent adverse experiences have also been reported in patients receiving clonidine 
tablets, but in many cases patients were receiving concomitant medication and a causal relationship has 
not been established: fatigue, fever, headache, pallor, weakness, withdrawal syndrome, a weakly 
positive Coombs’ test and increased sensitivity to alcohol. Cardiovascular adverse events include 
bradycardia, congestive heart failure, electrocardiographic abnormalities (i.e., sinus node arrest, 
junctional bradycardia, sinus bradycardia, high degree AV block and arrhythmias), orthostatic symptoms, 
palpitations, Raynaud’s phenomenon, syncope, and tachycardia. Central nervous system events include 
agitation, anxiety, delirium, delusions, hallucinations (including visual and auditory), insomnia, mental 
depression, nervousness, other behavioral changes, paresthesia, restlessness, sleep disorder, and vivid 
dreams or nightmares. Dermatological events include alopecia, angioneurotic edema, hives, pruritus, 
rash, and urticaria. Gastrointestinal events include abdominal pain, anorexia, constipation, hepatitis, 
malaise, mild transient abnormalities in liver function tests, nausea, parotitis, pseudo-obstruction 
(including colonic pseudo-obstruction), salivary gland pain, and vomiting. Genitourinary symptoms 
include difficulty in micturition, erectile dysfunction, loss of libido, nocturia, and urinary retention. 
Hematologic events include thrombocytopenia. Endocrine and metabolic events include gynecomastia, 
transient elevation of blood glucose or serum creatine phosphokinase, and weight gain. Musculoskeletal 
events include leg cramps and muscle or joint pain. Dryness of the nasal mucosa has been reported.  
Ophthalmological symptoms include accommodation disorder, blurred vision, burning of the eyes, 
decreased lacrimation, and dryness of eyes. 
 
Diphenhydramine Diphenhydramine is usually well tolerated but has been associated with paradoxical 
effects in some young children.  Up to date (61) lists its adverse effects as:  Cardiovascular: Chest 
tightness, extrasystoles, hypotension, palpitations, tachycardia; Central nervous system: Ataxia, chills, 
confusion, dizziness, drowsiness, euphoria, excitement, fatigue, headache, insomnia, irritability, 
nervousness, neuritis, paradoxical excitation, paresthesia, restlessness, sedation, seizure, vertigo; 
Dermatologic: Diaphoresis; Endocrine & metabolic: Menstrual disease (early menses); Gastrointestinal: 
Anorexia, constipation, diarrhea, dry mucous membranes, epigastric distress, nausea, vomiting, 
xerostomia; Genitourinary: Difficulty in micturition, urinary frequency, urinary retention; Hematologic & 
oncologic: Agranulocytosis, hemolytic anemia, thrombocytopenia; Hypersensitivity: Anaphylactic shock; 
Neuromuscular & skeletal: Tremor; Ophthalmic: Blurred vision, diplopia; Otic: Labyrinthitis (acute), 
tinnitus, Respiratory: Constriction of the pharynx, nasal congestion, thickening of bronchial secretions, 
wheezing. 
 
2.4.2 Known potential benefits  
All participants in this trial will receive 8 sessions of ESDM-informed parent coaching, a well-accepted 
parent coaching behavioral intervention from expert providers free of charge.  The ESDM-informed 
parent coaching is expected to facilitate the parents’ use of ESDM behavioral intervention strategies in 
multiple daily living contexts on a daily basis for an extended period. The parent implementation of 
these strategies and techniques is expected to promote the development of participants and to provide 
a sense of self efficacy for participating caregivers.  Such therapy is currently often hard to access in the 
community so immediate access may be of benefit.  In addition, participants will have their ADHD 
symptoms carefully monitored and some will receive a medication that is likely to reduce ADHD 


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symptoms.  It is hypothesized that reduction of ADHD symptoms will improve the participant’s 
receptivity to ESDM-informed parent coaching. Finally, the Vineland Assessments may be useful in 
further treatment and/or educational planning.  However there is no guarantee that any one participant 
will benefit from participation. 
 
2.4.3 Assessment of potential risks and benefits  
The purpose of this trial is to determine whether the benefits of a parent-delivered behavioral 
intervention in children with ASD + ADHD can be improved by providing carefully monitored and flexibly 
dosed stimulant medication (Adzenys-XR-ODT).  If the trial provides evidence that the response to 
behavioral intervention in children with ASD+ADHD is improved by concurrent treatment with ADHD 
medications, it will allow us to personalize treatment for this comorbid population, which typically does 
not benefit as much from behavioral treatment as same aged children with ASD alone.  Further we 
would be able to provide additional guidance regarding the frequency and severity of adverse events in 
this vulnerable population and about the typical medication doses to which they respond.  The 
exploratory eye tracking and neurophysiologic measures may help us further personalize treatment or 
identify potential ways to more objectively assess the benefit from combined medication and behavioral 
treatment. 
 
The primary risks are time-limited adverse events that typically resolve shortly after medication 
discontinuation in children with ADHD alone and in older children with ASD+ADHD.  There is no reason 
to believe that they would be more persistent in this population. The study’s titration schedule and 
flexible dosing should reduce the likelihood of a participant experiencing an adverse event for a 
prolonged period.  In addition, study doctors will be reachable 24 hours a day for emergencies.  
 
3 
OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION 
Aim 1: Determine whether 
stimulant medication 
combined with a parent-
delivered behavioral 
intervention (COMB) is more 
efficacious than the same 
behavioral intervention alone 
(BEH) for improving a core 
ASD symptom - social 
communication functioning. 
 
Primary Outcome: Change in 
JERI ratings of joint attention 
and social engagement 
(fluency and connectedness) 
during a 6 minute, semi-
structured parent child 
interaction task, assessed at 
Baseline and 10 weeks later at 
Endpoint assessments. 
 
Key Secondary Outcome: 
Change in mean of VABS 3 
Socialization and 
Communication subscale 
Standard scores assessed at 
Baseline and 10 weeks later. 
Additional completion at 
ESDM is designed to improve core 
symptoms of ASD and thus lead to 
improved overall functioning of the 
child. The JERI ratings provide for 
objective ratings of parent and child 
engagement that consider both 
duration and quality of behaviors.  
They have been demonstrated to 
distinguish 
between 
diagnostic 
groups and to change with typical 
development. Joint engagement is a 
critical 
aspect 
of 
social 
communication, which is impaired 
in ASD.  The VABS 3(3) provides 
standardized 
measures 
of 
the 
child’s 
actual 
functioning 
as 
reported by the caregiver.  Clinically 


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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION 
remote follow-up 24 weeks 
after baseline (exploratory 
time point). 
meaningful changes in VABS have 
determined a sample of >9000 
individuals with ASD(62).  
Aim 2: Evaluate the efficacy 
of COMB vs. BEH for reducing 
ADHD symptoms in children 
with comorbid ASD+ADHD. 
 
Secondary Outcome: 
Parent/clinician completed 
ADHD Rating Scale (ADHD-
RS)(5, 63) at diagnostic 
assessment (clinician), baseline 
(clinician), and weekly during 
treatment phase.  Additional 
completion at remote follow-
up 24 weeks (exploratory time 
point) after baseline. 
 
Validated scale with parent rating. 
Week 24 visit is remote so clinician 
rated ADHD-RS is not feasible but 
will be administered at baseline 
and end of study assessments 
visits. 
Aim 3: Determine the 
association between changes 
in behavioral outcomes 
(social communication 
functioning and ADHD 
symptoms) without regard to 
treatment group, and 
changes in objective 
measures of social attention 
and social engagement.  
 
 
Secondary Outcome: Eye Gaze 
Tracking (EGT) measures 
during presentation of social 
and nonsocial stimuli at 
baseline (visit 6) and endpoint 
(visit 16) 
 
 
EGT(63) is highly objective and 
quantitative and relatively efficient 
to administer.  Changes have been 
detected 
in 
other 
treatment 
studies. 
 
Aim 4 (Exploratory): 
Determine the association 
between changes in 
behavioral outcomes (social 
and ADHD symptoms) 
independent of treatment 
group and changes in neuro-
physiological activity. 
Exploratory Outcomes 
• SenseToKnow app with 
presentation of social and 
novel stimuli at baseline 
(visit 6) and endpoint (visit 
16) 
• JERI ratings of coordinated 
joint attention and fluency 
and coordination during 
PCIT(4, 64). 
• Video activity monitoring 
during PCIT and structured 
free play assessment. 
• Neural connectivity (EEG 
coherence). 
• Neural stability (intertrial 
phase coherence; ITPC). 
• SenseToKnow 
is 
quantifiable 
measure and relatively easy to 
administer to children at a young 
age. 
• JERI ratings are more sensitive to 
diagnostic 
differences 
than 
duration of joint attention and 
reflects a key ESDM-informed 
parent coaching goal. 
• Noldus 
monitoring 
provides 
precise quantitative measures of 
approach and proximity.(70)  
• EEG 
provides 
an 
objective, 
noninvasive way to assess neural 
functioning 
in 
response 
to 
specific stimuli.  It may provide a 
marker 
for 
prediction 
of 


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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION 
• Neural response to social 
stimuli (evoked response 
potentials; ERP). 
response. Well regulated activity 
between 
different 
cortical 
regions and relative stability in 
responses to repeated stimuli 
during a trial are hypothesized to 
reflect 
increased 
sustained 
attention during task. Extent of 
response to social vs. nonsocial 
stimuli 
likely 
reflects 
social 
attention.  
Other supportive behavioral outcomes (exploratory) 
 
Assess core ASD social 
functions  
 
 
 
• Social Responsiveness Scale-
2 (SRS-2)(66-68) 
 
• Aberrant Behavior Checklist-
2 (ABC)(69, 70) 
 
• Clinical Global Impression  
(CGI)(71) 
 
• Impairment Rating Scale (IRS) 
• Community-normed 
parent 
completed scale evaluating social 
function 
• Parent rating of functions often 
impaired in ASD and widely used 
in ASD pharmacologic trials 
• Clinician rating of overall severity 
of all problematic behaviors and 
of improvement since baseline 
• Parent rating of overall severity of 
all problematic behaviors and of 
improvement 
since 
last 
time 
point. 
 
Assess other aspects of 
attention and executive 
function 
 
• Behavioral Rating Inventory 
of Executive Function 
(BRIEF)(77, 78)  
 
• Sluggish Cognitive Tempo 
Questionnaire (REF).  
• Parent 
report 
measure 
of 
executive functioning 
 
 
• Questionnaire assesses the rate 
with which the child responds 
cognitively, 
which 
may 
be 
misinterpreted as inattention. 
Other Relevant Behaviors 
• Child Behavior Checklist 
(CBCL)(79) 
 
 
 
 
 
 
 
 
 
 
 
• Parent 
report 
measure 
that 
assesses 
a 
wide 
variety 
of 
behaviors in children including 
problematic 
internalizing 
and 
externalizing symptoms.  The 
measure has been validated and 
normed in a large US sample and 
yield a T score with thresholds for 
potential and definite clinical 
concerns 
in 
several 
different 
domains 
including 
atypical 
behavior 
and 
attentional 
problems 


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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION 
• Children’s Sleep Habits 
Questionnaire(80-82) 
• Validated 
parent 
report 
of 
children’s sleep issues 
Caregiver functioning & 
attitudes toward treatment 
• Caregiver strain 
questionnaire (CSQ)(83, 84) 
 
 
• Treatment satisfaction  
• Treatment guess 
• Parent report measure validated 
in parents of children with ASD 
and 
other 
developmental 
disorders. 
• Measures of parent perception of 
treatment 
Safety assessments 
• Adverse effects assessed  
based on 1) spontaneous 
report from 
parent/caregiver; and 2) 
General AE Inquiry from 
coordinator or study 
physician ECG 
• Suicidality assessment 
• Standard approach for evaluating 
adverse 
events 
in 
stimulant 
medication trials  
 
 
• Routine assessment of cardiac 
functioning 
• Assess child safety and suicidality 
in 
conjunction 
with 
AE 
monitoring.  
 
Several other measures will be obtained at baseline only to allow comparison between our sample and 
that of other groups in the A+ Development study.  These include the Leiter attention and memory 
scales in children with IQ ≥ 70, the Childhood Behavior Questionnaire, the Sensory Experiences 
Questionnaire and upload of early home videos if available.  
 
 
 
 
 
 
4 
STUDY DESIGN  
 
4.1 
Overall Design 
 
The overall study design and key outcomes and assessments are shown in the Schema in the synopsis.  
This randomized, placebo-controlled, Phase 2, single site, pilot study will evaluate the developmental 
impact of combined medication and behavioral treatment (COMB) versus placebo and behavioral 
treatment (BEH) in children with comorbid ASD +ADHD, who are 36 and <132 months of age. The active 
medication treatment will be an orally dissolvable, extended release amphetamine preparation 
(Adzenys-XR-ODT) administered from following baseline assessments for 10 weeks (visit 6 – 16) and 
carefully titrated to the optimal dose using an algorithm (see MOP) that considers adverse events and 
improvement in attention symptoms with a flexible dose range of 1.55mg – 18.6mg/day.  The target 
dose is 12.4mg/day.  A placebo, matched to the active medication, will be titrated and adjusted using 
the same algorithm in the BEH arm.  The provided behavioral treatment will be eight consecutive weekly 
~60-minute coaching sessions in ESDM-informed parent coaching delivered beginning after 2 weeks of 


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study drug treatment..  The implicit behavioral intervention is the parent-delivered behavioral 
intervention provided during interactions with the child at home and in the community. The ESDM-
informed parent coaching is a modification of the evidence-based behavioral treatment of ESDM, which 
is typically delivered as 20 hrs/week of 1:1 interaction between the child and a trained therapist over a 
2-year period.  The  ESDM-informed parent coaching modification reduces rigid time demands on 
families and is more likely to be sustainable and available in the current healthcare environment.   
Forty-eight participants will be randomly assigned to either the COMB or BEH treatment arms.  To 
account for possible differences in attrition due to potential poor tolerability of Adzenys-XR-ODT, 
participants will be randomized in a 7 COMB to 6 BEH ratio.  Treatment assignment will be provided by 
the Data Management and Analysis Core (DMAC) using computer generated algorithms.  
The primary analyses will compare changes in outcomes between baseline assessments and endpoint 
assessments, study visits 6 and 16, (a planned duration of ~10 weeks). Exploratory analyses will evaluate 
changes between baseline assessments and remote follow-up with caregivers, study visits 6 and 18, (a 
planned duration of ~ 24 weeks).4.  
The primary outcome measure will be changes in objective JERI ratings made by blinded coders of 
parent-child joint engagement during the semi-structured parent child interaction task (PCIT) and 
clinician ratings of ADHD symptoms.  The JERI ratings use a 7 point ordinal scale that considers both 
amount and quality of joint attention and engagement.  The amount of time spent in coordinated joint 
attention has shown significant differences between two different parent interventions for ASD(Kasari 
et al 2014).  The ratings have been shown to correlate well with time measures but to be more sensitive 
in distinguishing ASD from Down syndrome and typical development and in distinguishing between 
children with increased ASD interventions over time (Adamson 2017; Suma 2016). 
Our key secondary outcome is a change in the mean of the interview version of the VABS-3 Socialization 
subscale and Communication subscale standard scores. These standardized scores have real clinical 
significance, account for the variable rates of change observed developmentally, and reflect the core 
symptom domain targeted by ESDM-informed parent coaching: social communication.  
We also will examine several other supportive behavioral outcomes including parent ratings of social 
functioning (SRS-2), several aberrant behaviors including social withdrawal, attention, irritability, 
repetitive behavior, and abnormal speech (ABC), executive function (BRIEF), parental ratings of ADHD 
symptoms (ADHD-RS-parent) and sluggish cognitive tempo, and caregiver strain (CSQ).  We will also 
assess the safety and tolerability of Adzenys-XR-ODT compared to placebo.   
In subsequent aims, we will examine the relationship between changes in behavioral outcomes 
(independent of treatment group) and more objective measures of attention (eye gaze tracking to social 
stimuli, JERI and video activity measures of overall activity and attention, and parent child interactions 
such as time spent near parent, latency to approach parent).  Finally, we will examine whether 
improvements in ASD and ADHD symptoms are associated with changes in electroencephalographic 
(EEG) neural functioning measures related to enhanced neural connectivity (EEG coherence), neural 
stability (ITPC) and social processing (evoked response potentials (ERPs) and spectral power to faces vs. 
objects). 
 
4.2 
Scientific Rationale for Study Design 
 


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This study is limited to a single site and to comparison of two treatment groups due to the amount of 
funding available.  The intention of the study is not to evaluate the efficacy of the behavioral 
intervention, which is informed by a widely accepted, clinical intervention that has demonstrated 
efficacy compared to usual care treatment that did not include ESDM at the time.  Instead, we are 
testing whether addition of a pharmacological treatment for ADHD alongside ASD specific behavioral 
treatment improves social communicative functioning, a core ASD symptom domain, to a greater extent 
than the ASD behavioral treatment alone in children with both ASD and ADHD.  Our hypothesis, shown 
below, is that children with ASD+ADHD have poorer outcomes than those with ASD alone because their 
ADHD symptoms interfere with their engagement in ASD behavioral interventions. 
 
 
 
Medication treatment is chosen rather than behavioral treatment for ADHD in these children for three 
reasons.  First, the behavioral intervention for ASD –ESDM-informed parent coaching – already 
incorporates the key elements of behavioral treatment for ADHD.  Secondly, behavioral intervention for 
ADHD reduces problem behaviors associated with ADHD, but does not reduce core ADHD symptoms.  
Thirdly, we hypothesize that ADHD symptoms significantly impair the ability of children with ASD + 
ADHD to respond to behavioral interventions as shown below.  The choice of medication to be studied 
was based on four factors.  First, ADHD medication treatment guidelines suggest use of a stimulant prior 
to use of other classes of ADHD medications.  Secondly, the orally dissolvable formulation was well 
suited to the age of the population being studied in contrast to tablets or capsules.  Thirdly, well 
matched placebo was available.  Fourth, examination of an amphetamine preparation would provide 
novel information about a different class of stimulants in children with ASD + ADHD, rather than 
extending existing studies of methylphenidate to a younger population.  
 
All key assessments will be performed by evaluators who are blinded to treatment assignment and who 
do not observe the parent coaching sessions.  The control group is rigorously designed by providing a 
matched placebo so that parental expectations of medication response are minimized.  Prior studies in 
both children with ADHD alone and in children with ASD + ADHD have shown that children treated with 
placebo also show relatively high rates of adverse effects and treatment discontinuation due to adverse 
effects, so it is not likely that the blind will be broken by observation of adverse events.  In addition, 
more objective secondary measures are included.   
 
4.3 
Justification for Dose 
 
Choice of medication Many young children are unable to swallow tablets or capsules, so it was 
necessary to choose an ADHD medication that could be readily taken by the youngest children in the 
study.  Such formulations include liquids, transdermal patches that are often poorly tolerated by 
children with ASD due to sensory issues, or orally dissolvable tablets.  We were fortunate to partner with 
a commercial company who agreed to provide matched placebo at no charge, allowing the study to be 
conducted within available funding limits and to be initiated as quickly as possible without requiring 


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additional time to formulate the placebo.  The use of an extended release formulation is expected to 
minimize rebound effects and to provide more consistent coverage throughout the day, which is 
particularly important since young children with ASD + ADHD are likely to be developing social 
communication skills throughout the day rather than only during specific, time limited structured 
educational activities.  However, we are aware that use of an extended release product may be 
associated with higher rates of insomnia. 
Titration schedule  Overall, dosing will be flexible and guided by safety and efficacy considerations. 
Dosing will be initiated at 3.1 / 0 mg (1 pill; active/placebo assigned groups) daily for participants <72 
months of age, and 6.2 / 0 mg (2 pills; active/placebo assigned groups) for participants 72 months of age 
or older.  Dosage will be increased by 3.1 / 0mg weekly up to the target dose of 12.4 mg/0 mg daily by 
week 4, as tolerated provided there is insufficient benefit at a lower dose (see MOP for more detail).  
Once the target dose has been reached and tolerated for at least 2 weeks, dose increases above the 
target dose may be considered using the same criteria as above.  These dose adjustments may be made 
during unscheduled visits. The maximal dose is 18.6 / 0 mg daily.  The dose can be reduced at any time if 
there are issues with tolerability or if attention and hyperactivity appeared to be reduced to greater 
extent on a lower dose.  The study allows use of ½ a pill in those children who are unable to tolerate a 
3.1 / 0 mg dose.  If 1.55 / 0 mg is not tolerated, the participant will discontinue medication but continue 
to receive ESDM-informed parent coaching.  Since younger children metabolize Adzenys-XR-ODT more 
quickly than older children, we do not anticipate that they will require lower doses than are currently 
planned. 
This is a similar strategy to what is recommended in the label for Adzenys-XR-ODT, which suggests 
initiating dosing with 6.3 mg and increasing the dose increments of 3.1 mg or 6.3 mg at weekly intervals. 
Our target dose of 12.4 mg is less than the recommended maximum dose of 18.8 mg in children 6 to 12 
years old(2).  The study is pursuing a more conservative strategy for the maximum dose due to the 
increased vulnerability of children with ASD + ADHD to adverse effects with other ADHD agents, the 
general observation that most children with ASD + ADHD require lower doses of ADHD medications than 
children with ADHD alone, and the challenges in assessing clinical response in younger children who are 
less often in settings requiring high levels of sustained attention. In addition, we are more interested in 
the effects of medication treatment on ASD-related outcomes, rather than efficacy of the medication 
alone for treating ADHD symptoms. 
This study utilizes only 3.1 / 0 mg tablets to facilitate dose adjustments and simplify medication 
dispensing.     
FDA Regulatory Activities The investigators have received an Investigational New Drug (IND) exemption 
for the study since the results of the study are not intended to change labeling of Adzenys-XR-ODT and 
the use of Adzenys-XR-ODT is not expected to pose a significantly greater risk in this study than when 
used clinically.  Further, the population participating in the trial is not significantly different from that 
indicated in the label, which makes no statement about the presence of comorbid ASD.  The label of 
Adderall, which uses an identical active pharmaceutical ingredient, implies indicated use in children as 
young as 3 years old: 
“Pediatric Use: Long-term effects of amphetamines in children have not been well established. 
Amphetamines are not recommended for use in children under 3 years of age with Attention 
Deficit,” https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/011522s043lbl.pdf. 
 
 
4.4 
End of Study Definition 
 


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A participant is considered to have completed the study if he or she has completed the endpoint 
assessments all phases of the study including visit 16 – endpoint assessments or has been withdrawn 
from both treatment and assessments in the study.  If a participant wishes to stop medication and/or 
behavioral treatment in the study before endpoint assessments, he or she will be requested to complete 
them on schedule if at all possible.   The remote follow-up call at 24 weeks following baseline is optional.  
 
 
5 
STUDY POPULATION 
The planned sample size is 48 children.  There are no limitations related to sex, race or ethnicity.  
 
5.1 
Inclusion Criteria 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
1. Provision of a parent/guardian signed and dated informed consent form. 
2. Stated willingness to comply with all study procedures and availability for the duration of the 
study.  
3. Aged 36 months and <132 months of age at baseline.   
4. Diagnosed with both ASD and ADHD based on consensus diagnosis informed by results of the 
Autism Diagnostic Observation Schedule 2nd edition (ADOS-2(7)), Autism Diagnostic Interview - 
Revised (ADI-R(8)), a standardized ADHD Diagnostic Interview (9), and the MINI psychiatric 
diagnostic interview. 
5. In good general health as evidenced by medical history, physical exam and review of safety labs 
and electrocardiogram. 
5.2 
Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation in this study: 
1. Recent use of prohibited psychoactive medication in close proximity of baseline assessments. See MOP 
for specific medications that are prohibited and washout procedures.) Use of a monoamine oxidase 
inhibitor is prohibited within 14 days of baseline.  
2. Known allergic reactions to amphetamines or components of Adzenys-XR-ODT.   
3. Known history of sudden non-ischemic cardiac death in a first or second degree family member (sibling, 
parent, aunt, uncle, cousin or grandparent).  
4. Personal history of significant cardiac abnormalities or disease, particularly rhythm abnormalities.  
5. Significant visual, auditory or motor impairments that would preclude participation in ESDM-informed 
parent coaching or completion of key assessments (see MOP for details). 
6. Inability of the caregiver participating in ESDM-informed parent coaching and responding to 
questionnaires to fluently speak English.  
7. Parent’s participation in another parent coaching intervention on more than a monthly basis that may 
affect ESDM-informed parent coaching as deemed by the PI or clinician.  
8. Presence of any psychiatric conditions or psychiatric symptoms in addition to ASD and ADHD that would 
confound assessments and/or affect participation in the study as deemed by the PI or clinician. See MOP 
for procedures for senior clinician review of psychiatric conditions and/or symptoms. 
9. Known genetic (e.g. Fragile X) or neurological syndrome or condition with established link to autism, but 
not events in which the link to ASD is less well known/established (e.g., 16p11.2 CNVs, CHD8 mutations, 
Trisomy 21, 22q deletion syndrome). 
10. History of epilepsy or seizure disorder (except for history of simple febrile seizures or if the child is seizure 


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free - regardless of seizure type - for the past year) 
11. History of neonatal brain damage. (e.g., with diagnoses of hypoxic or ischemic event) 
12. Any known environmental circumstances that is likely to account for the clinical presentation of autism in 
the proband (severe nutritional or psychological deprivation etc.) 
13. Study clinician judgment that it is not in the best interests of the participant and/or the study for the child 
to participate. 
 
5.3 
Lifestyle Considerations 
None applicable. 
 
5.4 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical trial but are not 
subsequently randomly assigned to the study intervention or included in the modified intent to treat 
analyses. A minimal set of screen failure information is required to ensure transparent reporting of 
screen failure participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements and to respond to queries from regulatory authorities. The following 
information will be collected for all screen failures: demography, reason for screen failure details and 
any serious adverse event (SAE) that occurred while enrolled in the trial. 
Individuals who do not meet the criteria for participation in this trial (screen failure) because of 
concurrent pharmacological or behavioral treatments, a nonfebrile seizure within the six months prior 
to randomization, or a participating caregiver’s inability to fluently speak English may be rescreened 
when the exclusionary criteria has resolved. Rescreened participants should be assigned the same 
participant number as for the initial screening. 
 
5.5 
Strategies for Recruitment and Retention 
The target sample size is 48.  We anticipate that 20% or less of the sample will be female due to the 
lower prevalence of both ASD and ADHD among females.  We expect that Caucasians will be modestly 
overrepresented in the sample due to increased historical comfort with clinical trials than minorities.  
Further, among minorities we anticipate that Hispanic individuals will be most underrepresented in the 
sample due to requirements that the parent participating in ESDM-informed parent coaching be fluent 
in English.  We expect to enroll 2participants per month and a total of 24 per 12 month period; we 
anticipate that 18-22 of these will be randomized and have at least one post baseline assessment.    
Participants will be recruited from A+ Assessment, A+ Health, A+ Development, community 
advertisements and physician contacts.  Recruitment strategies include: developing radio and 
newspaper ads and brochures, using social media, attending community events, delivering community 
talks, meeting with various agencies who provide clinical and educational services for children, 
developing and maintaining active relationships with local autism and ADHD advocacy and support 
groups, and reaching out to community pediatricians, family practice doctors, child psychiatrists and 
psychologists, early intervention programs, and schools to make them aware of the treatment needs of 
children with ASD+ADHD and the availability of A+ Treatment.  We will also approach churches and 
cultural institutions that serve primarily African American, Hispanic and/or Asian populations about 
giving informational talks and providing informational materials to increase minority recruitment. 


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Retention:  A+ Treatment staff including behavioral therapists will maintain regular ongoing contact 
with all participants and their families to facilitate retention and discuss any concerns that may arise.  
We anticipate that any concerns will be adequately addressed during the frequent medication visits and 
the weekly ESDM-informed parent coaching visits.  Every effort will be made to coordinate assessment 
procedures with parent coaching sessions so that families do not have to make additional trips to the 
center.  If necessary, some parts of the diagnostic and major assessment visits can be split into 2 visits 
up to one week apart if the family prefers.  Randomization will not occur until all baseline assessments 
have been completed.  All treatment and follow-up visits will be scheduled as an offset of completion of 
baseline visits and the start of medication. Additional visits with an MD may be scheduled at any time if 
medication concerns arise. In addition, the recruitment core will send birthday/holiday cards, distribute 
newsletters, and e-blasts; provide diagnostic reports that summarize testing results; provide clinical 
referrals; and give regular updates about Duke ACE Center and DCABD research and activities.  
Incentives for Participation:  We will provide participants with $50 for completing each physician visit 
and its associated assessments, for each coaching session, and for the remote follow-up assessment 
completion for a maximum of $600 to help compensate for parental time off work, transportation costs 
and meals during the assessments.  We will provide transportation to those children and their families 
who would not otherwise be able to obtain consistent transportation up to 90 miles. We will also 
provide incentives for children during assessments and provide each child with a certificate when he/she 
completes the study. In addition, the opportunity to receive ESDM-informed parent coaching as part of 
the study without extensive waiting and free of charge is anticipated to be an incentive.  We will also 
provide reports of Vineland and diagnostic assessments to schools and other providers if requested.  
Finally, we will facilitate transfer of care after each participant completes the study.  
Rationale for Selection Criteria:  We have included children between 36 months and < 132 months in 
order to facilitate recruitment.  We excluded children below 36 months chronological age in order to 
ensure that ADHD can be reliably diagnosed. We excluded children with known cardiac disease, 
neurodevelopmental, genetic or environmental factors that are likely the etiology of their ASD, 
uncontrolled seizures, or family history of relevant cardiac disease to reduce risk of adverse events 
associated with stimulant treatment. We review those with >1 comorbid psychiatric conditions in 
addition to ASD+ADHD for inclusion / exclusion because the PATS trial, which examined the response of 
preschool children to methylphenidate, found poorer response was associated with having > 2 
diagnoses in addition to ADHD. We are allowing one additional comorbid diagnosis because studies 
suggest that a substantial percentage of children with ASD+ADHD will have a third psychiatric diagnosis, 
and we would not be able to reach our recruitment goals if these children were excluded. All children 
will be administered the Child Behavior Checklist (CBCL), which is a widely-used, well-normed, and 
empirically validated tool to facilitate diagnosis of other psychiatric problems. If a child has clinically 
elevated scores, this will be followed up with a semi-structured diagnostic interview by an expert 
clinician. 
 
Attrition:  We conservatively estimate that ~15% will not be able to tolerate the lowest dose of 
stimulant medication.  However, we will encourage these children to continue in the study and will 
include them in the modified intent to treat analyses.  To compensate for potential differences in 
attrition in the COMB group compared to the BEH group, 7 participants will be randomized to COMB for 
every 6 participants randomized to BEH.  We expect this to yield very similar sample sizes (~24) in the 
two treatment arms for a per protocol sensitivity analysis.   We expect our low starting dose, slow 
titration schedule and flexible dose strategy to reduce withdrawals due to medication intolerance.  We 
will continue to provide ESDM-informed parent coaching and obtain outcome assessments in children 


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who discontinue study medication treatment.  We will not replace any participants due to medication 
discontinuation. 
 
We acknowledge that some participants may not be able to cooperate sufficiently to acquire usable EGT 
and EEG data. However, based on our extensive past research with severely affected preschool children 
with ASD (some of whom had ADHD), we estimate no more than 10% attrition on these secondary and 
exploratory outcomes due to lack of compliance and expect to have >20 in each group with usable 
biomarker data.  
 
6 
STUDY INTERVENTION 
 
6.1 
Study Interventions Administration 
 
6.1.1 Study medication intervention description 
Active Agent: Adzenys-XR-ODT is an orange flavored, orally disintegrating tablet form of Adderall XR 
(mixed salts of a single-entity amphetamine product extended-release capsules referred to as MAS ER).  
Each 3.1 mg. tablet of Adzenys-XR-ODT contains mixed amphetamine salts equivalent to those in a 5 mg. 
capsule of Adderall XR.  Each lozenge is packaged in a tamper resistant foil package and designed to be 
dissolved on top of the tongue.  The lozenge should not be chewed or crushed.  It should be swallowed 
after dissolving. 
When the New Drug Application (NDA) for Adzenys-XR-ODT was submitted, the FDA permitted the 
manufacturer to rely on efficacy and adverse event data previously submitted in support of the Adderall 
XR NDA and only required demonstration of overlapping pharmacokinetics and animal studies to 
demonstrate an absence of toxicity of the formulation.  Adzenys-XR-ODT has an FDA indication for the 
treatment of ADHD in patients 6 years and older.  Two studies in 4-6 year old children are currently 
underway and anticipated to be completed during 2018.  The FDA has indicated that it does not feel 
trials in 3 year olds are feasible due to challenges in diagnosis.  The U.S. labels for both Adzenys-XR-ODT 
and Adderall XR are included in Appendix 1.   
We are using this commercially available medication in a manner that is consistent with its labeled 
indication, i.e., for the treatment of ADHD.  Some of our participants may be younger than stated on the 
label, but this is consistent with general clinical practice and we will provide updated information for use 
in younger children from the ongoing trials when it becomes available.  We have received an IND 
exemption for use of Adzenys-XR-ODT in this study. 
Control Agent:  The manufacturer of Adzenys-XR-ODT is supplying us with a matched placebo orally 
disintegrating tablet identical in appearance, disintegration characteristics and taste to the active 
medication.  The same low starting dose, slow titration schedule and flexible dosing paradigm will be 
used for placebo as for the active medication.  
 
6.1.2 Medication dosing and administration 
Medication Dosing .  Treatment will be initiated according to the following algorithm according to the 
child’s age.   


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Children ages 3- 5 years, 11 mo:  start at 1 tablet = 3.1 mg or 0 mg of mixed amphetamine daily.  Doses 
will be flexibly titrated upward by 1 tablet (3.1 mg or 0 mg) weekly up to a target dose of 4 tablets= 12.4 
mg or 0 mg of Adzenys-XR-ODT unless there are intolerable adverse events or great improvement in 
ADHD symptoms. Doses may be reduced at any point during the trial (typically in 0.5-1 tablet 
increments) but may be increased only once every week in order to fully assess potential benefits and 
adverse events of the current dose.  
Children ages 6-10 years 11 mo:  start at 2 tablets = 6.2 mg or 0 mg of mixed amphetamine daily.  Doses 
will be flexibly titrated upward by 1 tablet (3.1 mg or 0 mg) weekly up to a target dose of 4 tablets= 12.4 
mg or 0 mg of Adzenys-XR-ODT unless there are intolerable adverse events or great improvement in 
ADHD symptoms. Doses may be reduced at any point during the trial (typically in 0.5-1 tablet 
increments) but, after the first two weeks, may be increased only once every week in order to fully 
assess potential benefits and adverse events of the current dose.  
The allowable dose will range from 1.55/0 mg (1/2 tablet) to 18.6/0 mg (6 tablets) for both groups based 
on clinical improvement and/or judgment of adverse events. 
 Study drug will be administered in the morning. If a participant has not taken the day’s dose by noon, 
the dose should be skipped.  Handouts providing directions for opening the foil packages and placing the 
tablet on the tongue will be provided to each participant’s caregiver.  The 3.1 mg AMP dose has been 
demonstrated to be bioequivalent to, and to have the same pharmacokinetic profile as, 5 mg Adderall 
XR. The 12.4 mg dose is smaller than recommended for children 6-12 years, consistent with what is 
known about tolerability of ADHD medications in young children with ADHD alone and in older children 
with ASD+ADHD.  
Medication discontinuation If a participant cannot tolerate the lowest dose of study drug (1/2 tablet) or 
has an adverse event that the study physician feels precludes ongoing treatment, the participant will 
discontinue study medication, but will continue to receive ESDM-informed parent coaching and to 
participate in study assessments. Participants who have taken fewer than 6 doses of medication during 
the first 2 weeks of the study will be replaced if possible.  
Medication Adherence Medication adherence will be based on pill counts conducted by unblinded staff 
at each physician visit in which the participant’s family remembers to bring in dispensed cartons and 
unblinded staff is available. If unblinded staff is not available or the family does not return the study 
investigational drug treatments and is unable to estimate the number of unused tablets/cards 
remaining, study physician will assume the maximum number of tablets have been used and prescribe 
the corresponding number of cartons.  If unblinded staff were not available at a visit, adherence will be 
determined at the next medication visit when both the cartons are returned and unblinded staff are 
available.   
See section 4.3 for Justification of Medication Dose.  
 
6.1.3 Study Behavioral Intervention Description 
All participants and their caregivers will receive the same behavioral intervention. The therapist will 
discuss and identify appropriate goals for the participant in the first treatment session.   Coaching 
sessions are a modification of the evidence-based behavioral treatment known as ESDM(20), which is 
typically delivered as 20 hrs/week of 1:1 interaction between the child and a trained therapist for a 2 
year period.  ESDM-informed parent coaching modification reduces demands on families and is more 
likely to be available and sustainable in the current healthcare environment.  Each participant and 
his/her caregiver(s) will meet with the behavioral therapist for eight ~60 minute consecutive weekly 


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sessions.  During these sessions, the therapist will coach the parent in developing specific skills and 
strategies to engage the child and promote the child’s social, communicative and cognitive 
development.  Sessions will begin with a free play session in which the therapist will assess parent 
fidelity to and comfort with previously taught strategies.  Then the therapist will check-in with the 
caregiver regarding any issues or successes during the prior week and will review the new 
technique/strategy to be learned and practiced during the session. Subsequently, the caregiver will 
practice of the technique with his/her child with feedback and suggestions as needed from the 
therapist.  At the end of the coaching session, the therapist and the caregiver will discuss potential 
opportunities for utilizing the strategy and other strategies presented in earlier sessions during the 
coming week (homework).  The caregiver will also be provided with a book that describes some 
strategies used in ESDM-informed parent coaching. The caregiver is expected to utilize the strategies 
when interacting with his/her child in naturalistic situations on a daily basis. More than one caregiver 
may attend one or more coaching sessions, but the same caregiver is expected to commit to attending 
all coaching sessions. The therapists will have been trained in ESDM-informed parent coaching by a 
certified ESDM trainer.   
The therapist will not participate in study physician visits or in the majority of assessments.  If the 
therapist becomes aware of a concern or has feedback for the study physician, this may be provided.  If 
the caregiver has concerns about adverse effects, he/she will be directed to the study coordinator to 
facilitate contact with the study MD.  If a parent coaching visit is missed, it can be rescheduled within 
the session window of +/- 3 days.  The total number of parent coaching visits attended will be tracked, 
the parent’s use of ESDM techniques will be assessed at coaching sessions 1-8 by the therapist, and the 
therapist’s fidelity to the parent coaching model will be assessed from a video recording of one random 
sessions during the course of each participant’s treatment by an independent rater. 
Participants who choose to discontinue parent coaching sessions prematurely will be included in the 
modified intent to treat analysis.  Those who do not attend any parent coaching sessions will be 
included in the intent to treat analysis but not in the per protocol sensitivity analysis.  Such participants 
will not be replaced.  
 
6.1.4 Study intervention groups 
The two randomized intervention groups will be: 
• COMB in which participants receive flexibly dosed Adzenys-XR-ODT (1.55mg – 18.6 mg) each 
morning between Visit 6 – Visit 16 (10 weeks) plus eight consecutive weekly ~60 minute ESDM-
informed parent coaching sessions during Visit 8 through Visit 15. 
• BEH in which participants receive flexibly dosed Placebo each morning between Visit 6 – Visit 16 
(10 weeks) plus eight consecutive weekly ~60 minute ESDM-informed parent coaching sessions 
during Visit 8 through Visit 15. 
Treatment will be provided in a double-blind fashion such that none of the study staff whom interact 
with participants and caregivers, therapists who provide parent coaching or the participant’s caregivers 
will be aware of whether the participant is receiving active or placebo study medication.  All involved in 
the study will know the family is receiving ESDM-informed parent coaching. 
 
6.2 
Clinical Trial Supplies Preparation/Handling/Storage/Accountability 
 


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6.2.1 Acquisition and accountability 
See Pharmacy Manual for further details.  Prior to receiving any clinical trial supplies, the Duke ACE 
Center Data Management and Analysis Core (DMAC) will prepare a random, nonsequential list of 6000 
carton #s, each of which is linked to treatment assignment (COMB or BEH).   
Acquisition:  After receiving an appropriately completed DEA 222 form from the study principal 
investigator, Neos Therapeutics will ship specially manufactured lots of Adzenys-XR-ODT 3.1 mg tablets 
and of matched placebo in sealed, plain white cartons containing 12 blister cards of 6 tablets (for a total 
of 72 tablets/carton). The cartons will be marked only with the lot number and expiration date.  The 
individual tablets are packaged in a child-resistant manner, with the lot number printed on the 
packaging of each tablet.  The clinical trial supplies are expected to have an expiration date that is at 
least 24 months after the initial manufacturing date.   
Neos expects to ship clinical trial supplies on at least an annual basis.  The DMAC team and/or unblinded 
research staff will notify the principal investigator when ~30% of the original inventory of either active 
or placebo cartons remains, so that there is sufficient time for NEOS to manufacture new supplies and 
distribute them to the research site upon receiving a DEA 222 form.  Both the DMAC and the unblinded 
research staff will track the inventory and expiration dates of clinical trial supplies.  Separate drawers in 
the locked storage file will be reserved for cartons that expire in 8 weeks, which could be dispensed at 
weeks 0, 6, and 10 weeks, and in 12 weeks, which could be dispensed at week 16. 
 
When Neos therapeutics sends clinical trial supplies, they will also provide a shipping manifest 
documenting the lot #, information about whether the lot contains active or placebo, and the number of 
cartons in each lot shipped.  We anticipate that they will ship two lots simultaneously.  The shipping 
manifest from NEOS will be stored in a separate binder in a locked location accessible only to unblinded 
staff.  When Neos notifies the PI of the maximum number of cartons per lot that will be shipped, the PI 
will notify the DMAC of this number.  The DMAC will refer to the list they prepared prior to the site 
receiving any clinical trial supplies and provide a list of potential carton # labels to the unblinded study 
staff, so that they can prepare the necessary labels.   
 
Accountability and Blinding: 
Overview:  Since the active clinical trial supply (Adzenys XR-ODT/ adderall/ DEA # 1100) is a schedule IIN 
drug, it will be stored in a locked steel file cabinet with no other investigational drug supplies to limit 
access in the Department of Psychiatry, Lakeview Pavillion East Investigation Drug Supplies storage 
room.  This room is behind a locked door requiring an ID badge swipe for entry.  The door the storage 
room is triple locked requiring an ID badge swipe, key (not included as part of the floor master key), and 
individual specific pin # to open.  Only authorized staff participating in this study will have access to the 
key to the file cabinet containing the clinical trial supplies for this study.  Placebo and Active supplies will 
be mixed together and stored in sequential order within the file cabinet after initial labeling.  Separate 
Blinded and Unblinded Inventory Logs, an Unblinded Accountability Log and a Blinded Dispensing Log 
will be maintained.  All entries into any of the logs will require that two staff with the appropriate 
credentials (unblinded or blinded) sign off at the same time.  Blinded inventories will be done on a 
monthly basis.  Unblinded inventories will be done every six months or more frequently if needed.  Only 
unblinded study staff and select Duke ACE Center Data Management and Analyses Core (DMAC) staff 
will have access to Unblinded documents.  Only the unblinded A+ Treatment and DMAC staff will be 
aware of the linkages between specific carton numbers, lot numbers and active/placebo substance 
identities.  Only the unblinded DMAC staff will have access to the file linking subject ID to treatment 
group assignment.  DMAC staff have developed a program that will allow them to monitor the inventory 


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of clinical trial supplies on an ongoing basis and assign the appropriate carton #’s when study staff input 
the subject’s ID number and the number of carton’s prescribed by the study physician.  Once a carton 
has been assigned by the DMAC program, it will be removed from the DMAC inventory.  There will be 
triple accountability and inventory of the clinical trial supplies by the DMAC, unblinded study staff and 
blinded study staff (who will have access only to carton #’s, and not to lot #’s, expiration dates or 
treatment assignment). 
 
Initial receipt: When each lot of active and placebo clinical trial supplies arrives, the DMAC will provide 
the unblinded staff with 2 tables assigning each carton in each lot a unique carton # based on the DMAC 
table linking carton #’s to treatment assignment. Then the unblinded staff will prepare one carton label 
containing study information and a unique carton ID # (carton # label) and a set of labelmaker labels 
containing only the unique carton # to facilitate tracking and accountability of the clinical trial supplies.   
 
After receiving the DMAC tables assigning carton #’s to specific lots, two unblinded staff will verify the 
lot # on the each carton against the DMAC table assigning carton #’s to the lot, then place the carton # 
label over the lot # and expiration date imprinted on the carton.  Two-three of the labels with only the 
unique carton # will be partially taped onto the carton for removal and placement in the Blinded 
Dispensing Log when the carton is dispensed by MD and later when returned by the participant  
 
At the same time, labels with only the carton # will be placed generally as follows (See Pharmacy Manual 
for details): 
 
 
-  1 on the Unblinded DMAC document assigning carton #’s to the specific lot,   
 
 
-  1 in the Unblinded Inventory Log received column, 
 
 
-  1 in the Blinded Inventory Log received column, and  
 
 
-  1 in the Blinded Dispensing Log received column 
The remaining label with only the carton # will be placed in the Unblinded Inventory Log Binder, to be 
used when the carton and any remaining tablets within it are destroyed. 
 
Minimizing the amount of clinical trial supplies dispensed:  The participant’s caregiver will be 
instructed to bring all unused tablets in their original carton and any cartons in which all the tablets have 
been used to the next medication visit, so that staff can be sure they are taking the medication correctly.  
When the caregivers do so, the caregiver and an unblinded staff member will count the number of 
tablets available for ongoing use.  The caregiver will retain control of all opened cartons containing 
unused tablets; cartons that have no unused tablets will be logged on the Blinded Dispensing Log and 
Unblinded Accountability Log as noted below.  Study staff will calculate the percentage of the expected 
number of used tablets and will notify the study physician.  The study physician will address any issues 
related to use of too many or too few tablets and will subtract the number of remaining tablets from the 
number to be dispensed, so that the minimal number of cartons are dispensed.   
 
Dispensing:  At the time of dispensing, study staff will start the DMAC dispensing program, enter the 
subject ID and the number of cartons prescribed by the study physician.  The program will provide a 
printable document with the subject ID, date and the unique carton #’s to be dispensed.  Only full sealed 
cartons will be dispensed; no cartons will be redispensed.  Two study staff will pull the cartons specified 
by the DMAC dispensing program and will verify the carton #’s pulled agree with the DMAC assignment 
sheet.  The printed DMAC assignment, the physician’s order and carton # only labels for each dispensed 
box will be maintained in the subject’s source documentation.  In addition, one of the duplicate carton # 
only labels will be placed in the Blinded Dispensing Log and the date and study ID number of the subject 
to whom it is to be dispensed will be noted and both staff will sign off on the log.  


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Subject Return of Used Cartons:  Participants’ caregivers will be instructed to return the study drug 
cartons to the site after they have used all the tablets in the carton or at the week 249 visit, whichever 
comes first.  When the used carton is returned to the site, another carton # only label will be placed in 
the Blinded Dispensing Log, along with the date it is returned and sign off by two staff members.  As 
soon as possible after return, two unblinded staff will examine the returned cartons, determine whether 
there are remaining unused tablets, document the number of returned unused tables, date returned 
and counted and both will sign off on the Blinded Dispensing Log and the Unblinded Inventory Log.  
Returned clinical trial supplies will be stored in the investigational drug storage room in a locked drawer, 
separate from the drawers containing clinical trial supplies that have not yet been dispensed. 
 
Clinical Trial Supply Destruction:  Two unblinded staff will be responsible for removing expired or 
returned clinical trial supplies from the active clinical supply stock, documenting the removal in the 
Blinded Dispensing Log and Unblinded Destruction Log, and preparing the supplies for destruction.   
 
The unblinded staff will identify which expired/returned tablets contain active medication and transfer 
those materials to a locked safe in the investigational drug storage room prior to transfer to a reverse 
distributor for DEA approved destruction at least one time per year.  Empty cartons and blister cards and 
expired and returned placebo supplies will be disposed of according to Duke University policies for 
biomedical waste.  A carton # only label for each carton destroyed, indicating the number if any unused 
tablets from the carton destroyed or awaiting destruction by the Reverse Distributor will be placed on 
the Unblinded Destruction Log, along with the date of destruction or of transfer to the locked safe. 
When the contents of the locked safe are transferred to the reverse distributor, the total number of 
active tablets transferred will be recorded and the Unblinded Destruction Log updated with 
documentation of receipt by the reverse distributor.    
 
6.2.2 Formulation, appearance, packaging, and labeling 
Formulation and Appearance:  
Adzenys-XR-ODT (amphetamine extended-release orally disintegrating tablet) contains a 3 to 1 ratio of 
d-to l-amphetamine, a central nervous system stimulant. The labeled strengths reflect the amount of 
amphetamine base in Adzenys-XR-ODT whereas the strengths of the (mixed salts of a single-entity 
amphetamine) products are in terms of the amount of amphetamine salts.  Adzenys-XR-ODT is an 
extended-release orally disintegrating tablet containing 50% immediate release and 50% delayed-
release amphetamine for once daily dosing. ADZENYS-XR-ODT also contains the following inactive 
ingredients: Mannitol, Crospovidone, Microcrystalline Cellulose, Methacrylic Acid Copolymer Type A, 
Sodium Polystyrene Sulfonate, Citric Acid, Fructose, Orange Flavor, Colloidal Silicon Dioxide, Triethyl 
Citrate, Sucralose, Lake Blend Orange, Magnesium Stearate, and Polyethylene Glycol.  
Packaging: 
Adzenys-XR-ODT is packaged in child-proof blister packages with a fold line for each tablet that permits 
opening the foil blister containing the tablet.  Twelve blister cards containing 6 tablets each are provided 
in a white carton ~3 inches x 6 inches x 2 inches, which is initially imprinted with a lot number and 
expiration date.  In addition, each tablet containing blister pack has an imprinted lot number on it.  
Labeling:   


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Carton number labels:  Upon receipt at Duke, the DMAC will assign each carton in the lot with a 
unique nonsequential carton number as described in 6.2.1.  Then, the unblinded A+ Treatment 
medication coordinator and supervising, unblinded physician will place a unique, nonsequential 
carton number label over the lot number and expiration date of each carton in the lot. The following 
information will be included: 
Duke Center for Autism and Brain Development 
2608 Erwin Rd, Suite 300 Durham, NC 27705 
Protocol# Pro00085179  NCT03242772  A+Treatment 
LIMITED BY US FEDERAL LAW TO INVESTIGATIONAL USE ONLY 
CARTON #:___________ 
Participant labels:  After the study physician prescribes a specific number of cartons for the specific 
participant and the DMAC program provides the unique carton number(s) to be dispensed, the A+ 
Treatment staff will place a participant label on the carton that includes the dispensing date, the 
participant’s name, the statement that the carton contains Adzenys-XR-ODT 3.1 mg OR 0 mg for 
investigational use only in the A+ Treatment 
study, the instructions for use, an expiration 
date for the participant’s use (generally 
within 2-7 months of dispensing, and never 
longer than the actual expiration date of the 
lot from which it comes) and the study 
emergency phone number to call for urgent 
concerns and the name of the Study Principal 
Investigator. The Participant Label will be 
similar to that shown to the right.  
 
 
 
 
6.2.3 Product storage and stability 
The product tablets are individually packaged in foil blisters of six blisters per blister card.  The blister 
cards protect from light, humidity and crushing. Additional protection from crushing is provided by the 
storage carton. Clinical trial supplies will be stored in a triple-locked, limited access, temperature 
regulated (20oC - 25 oC) investigational drug storage room, in a locked steel cabinet until the blinded A+ 
Treatment physician orders a specific number of cartons be prepared for dispensing to a specific 
participant.  The temperature in the drug storage room will be monitored daily.  The drug storage room 
is located off a hallway that requires a key card for access.  The room itself is triple locked and can’t be 
opened using a master key.  The Access to the drug storage room is limited to fewer than 20 staff 
members within the Duke Psychiatry Department, each of whom must use their badge, a unique pin 
number for the keypad and a key to open the investigational drug storage room.  A separate key (which 
is kept in a locked storage box in a separate location) is required to open the A+ treatment clinical 
supplies storage cabinet.  Other research teams that also utilize the investigational drug storage room 
will not have access to keys for the cabinet in which the A+ Treatment clinical trial supplies are stored.  
Storage will be in accordance with established SOPs and Duke, NC Pharmacy Board, NC DEA and US Drug 
Enforcement Administration regulations for a regulated Schedule IIN drug. All Duke SOP’s for storage 
and use of controlled substances in outpatient clinical trials will be followed precisely.  
 
6.2.4 Preparation 


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The unblinded A+ Treatment medication coordinator will label each carton as above.  Either blinded or 
unblinded staff can utilize the DMAC program to link a specific subject’s ID number with specific carton 
numbers to be dispensed at the visit after receiving the study physician’s prescription.  Once the carton 
numbers are determined, the cartons are pulled and labeled for the specific subject according to the 
study physician’s prescription as described above, the cartons will be given to the study physician for 
dispensing to the subject’s caregiver.  This will be done in accordance with the study physician’s orders 
using established Duke Center for Autism and Brain Development dispensing policies and procedures 
that have been developed in accordance with the Duke Investigational Drug Service.  The blinded study 
coordinator will provide the participant’s caregiver with visual instructions on opening the blister 
packages and letting the tablets dissolve on the participant’s tongue.   
 
6.3 
Measures to Minimize Bias: Randomization And Blinding 
6.3.1 Randomization 
Participants will be randomly assigned to COMB or BEH in a 7:6 ratio using blocks of 13 or 26 
participants.  The DMAC will be responsible for the randomization assignment and linking the subject ID 
and randomization assignment within the DMAC drug inventory program.  The randomization schedule 
will be stratified by chronological age ([36 to 72 months] or [73 to <132 months]) and by nonverbal IQ 
([less than or equal to 69] or [equal to or greater than 70]).  The DMAC will maintain a table linking the 
treatment group to individual medication lot numbers and subsequently to unique carton numbers, 
which will be accessible only to the DMAC unblinded staff member and the unblinded A+ Treatment 
staff.  The DMAC program will provide unique, random, nonsequential carton numbers for dispensation 
to specific participants according to their treatment assignment and the study physician’s prescription 
each time medications are dispensed. 
Participants will be randomized at the week 0 visit after all inclusion/exclusion criteria are confirmed 
and all baseline assessments have been completed.  At that time, the study physician will prescribe the 
initial carton of study medications and the study staff will utilize the DMAC program to obtain a specific 
carton number to dispense.  Two staff members will verify that appropriate carton of study medication 
has been pulled from the inventory, labeled appropriately for the participant and entered into the 
blinded drug accountability log.  A similar process will be followed at subsequent visits with the 
exception that the unblinded A+ Treatment staff will determine the number of unused tablets remaining 
in the carton to assess compliance and ensure that excessive amounts of study drug are not dispensed. 
 
6.3.2 Blinding 
Blinding of Study Medications: 
The placebo used in this study is manufactured by NEOS Therapeutics, the maker of Adzenys-XR-ODT, 
and appears identical in appearance and taste to the active Adzenys-XR-ODT.  NEOS Therapeutics will 
ship both the active and placebo tablets, which will be identifiable by their unique lot numbers as 
indicated on the shipping inventory form, directly to the unblinded A+ Treatment Clinical Supply 
Manager, who will be responsible for labeling each carton with a unique non-sequential carton number 
prior to storing them in our existing temperature-controlled, triple-locked drug storage room in 
accordance with established SOPs and Duke, NC Pharmacy Board and US Drug Enforcement 
Administration Regulations for a regulated Schedule IIN drug.  


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Limited Unblinded Staff: 
Only two to three designated unblinded staff members (one person from the Data Analysis and 
Management Core [DMAC] and the Project 3 unblinded Clinical Supply Manager and supervising 
unblinded physician) will know whether a given lot contains placebo or active tablets. The lot number 
will be covered after verification by two unblinded staff members with a unique carton number to 
reduce the potential of accidental unblinding.  PDFs of the shipping manifests reporting the active or 
placebo contents of specific cartons will be stored in a password protected file on a separate computer 
drive from all other study files and the originals will be stored in a locked cabinet accessible only by the 
unblinded Clinical Supply Manager.   
These unblinded staff will have no interaction with participants and will be thoroughly trained in the 
importance of maintaining the blind by not discussing any subject-specific information with other staff 
members, including the study coordinator, EGT/ EEG assistants, study staff involved in coding of the 
Parent Child Interaction Task, behavioral therapists, and study physicians.  
 
Potential Unblinding Due to Adverse Effects:   
Prior trials of Adderall XR have demonstrated fairly similar rates of the most common adverse events 
among active and placebo groups. The frequent adverse events of insomnia, stomach upset or pain, 
decreased appetite, anxiety and mood lability are even more frequently seen in young children with ASD 
than in children with ADHD.  Because these adverse events are so common in preschool children with 
ASD who are not treated with medications, it is unlikely that occurrence of an adverse event would 
unblind the study clinician.  Further the collection of multiple different types of outcome measures 
(clinician rated, parent rated, observed during structured interactions and rated by evaluators not 
involved in the interaction, and objective and neural measures) should minimize the likelihood of results 
being skewed by adverse events.  Further, behavioral treatments like those provided in ESDM-informed 
parent coaching contain the elements of behavioral treatments that are sometimes beneficial in ADHD 
treatment.  Thus an improvement in symptoms would be unlikely to be ascribed to the medication 
alone.  
 
Situations When Blinded Treatment Assignment Would Be Revealed:  
Most emergency medical situations would not necessitate revelation of the study treatment assignment 
because there is not a specific antidote to the active study medication and the active study medication 
could simply be held due to the relatively short half-life.  If the emergency medical situation might be 
related to study medication (e.g. anaphylactic reaction), the study medication treatment would be 
stopped regardless of whether the treatment contained active or placebo treatment while parent 
coaching would continue.   However, if the treating clinician for the medical emergency felt that it was 
absolutely essential to determine whether the participant was taking active medication, the study 
physician would call the unblinded A+ Treatment Clinical Supply manager and request that the clinical 
supply manager reveal the treatment assignment directly to the outside clinician responding to the 
medical emergency.  In such cases, medication treatment would be discontinued for the remainder of 
the trial although parent coaching would continue.  The outside clinician would be requested not to 
reveal the identity of study medication treatment to the family and the family would be asked not to 
discuss their suspicions about the treatment identity with the A+ Treatment staff.  


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Approximately 2 weeks after the endpoint assessments all participants’ caregivers will be notified of 
their child’s treatment assignment. Those who wish to continue medication treatment will be referred 
to a physician who is not involved in the study for ongoing medication treatment. 
 
 
6.4 
Study Intervention Compliance 
Study drug compliance will be determined by comparing the number of tablets that should have been 
taken with the difference between the number of tablets dispensed less the number of tablets the 
caregiver reports were wasted (spit out, dropped etc.) and the number of tablets unopened in the 
blister packs.  This will be expressed as percent compliance. 
 
% compliance = Number dispensed – (number reported wasted + number remaining in blister package unopened) 
       
 
      Number of pills prescribed per day * Number of days since dispensing)  
Parent coaching session compliance will be assessed by determining the number of sessions attended.   
We will not measure the amount of time the caregiver spends engaged in using ESDM strategies due to 
burden on caregivers and expected low quality of the data.  
 
6.5 
Concomitant Therapy 
6.5.1 Prohibited concomitant therapies 
Participants will be asked to refrain from taking any of the following medications throughout the course 
of the trial.  Those who do take such medications will be excluded from the per protocol population. 
• 
Monoamine oxidase inhibitors including rasagiline (Azilect), selegiline (Eldepryl, Zelapar), 
isocarboxazid (Marplan), phenelzine (Nardil), and tranylcypromine (Parnate). 
• 
Other medication treatments for ADHD including any other sort of stimulant MAS ER salts, lis-
dexamphetamine(Vyvanse), methylphenidate products, atomoxetine (Strattera), amantadine 
(Symmetrel), memantine, buproprion (Wellbutrin), venlaflaxine (Effexor), omega 3 fatty acids, 
Vayarin. 
• 
Participants will be asked to refrain from changing the type or intensity of other behavioral 
interventions obtained during the eight weeks preceding Week 0 of the study through the Week 9 
assessment in the study.  The amount and type of other behavioral interventions will not be 
restricted in order to increase feasibility of recruiting the full sample. 
• 
Participant’s caregivers will be asked to refrain from more than one other parent coaching 
intervention provided no more than 1x per month.  Those participants whose caretakers do engage 
in more than one other parent coaching session per month will be excluded from the study per 
protocol population. 
 
6.5.2 Permitted concomitant therapies 
Participants may receive the following therapies and still be considered as complying with the study 
protocol.  The study physician will determine if any additional monitoring is required if a permitted 
concomitant medication is used. 


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• 
Aripiprazole (Abilify) or risperidone (Risperdal) prescribed for the treatment of irritability in ASD 
• 
Melatonin or immediate release clonidine prescribed for the treatment of insomnia 
• 
Special diets  
• 
Antibiotics for treatment of acute infections 
• 
Antipyretics such as acetaminophen and ibuprofen 
• 
Antianxiety medications for medical procedures such as phlebotomy, but not within 2 hours 
prior to outcome assessments other than safety labs.  (In such cases all of the behavioral and neural 
assessments should be performed prior to the safety blood draw or the blood draw should be 
performed at a separate time.  
• 
Asthma medications 
• 
Gastrointestinal medications 
• 
Any behavioral intervention delivered to the participant inside a school or daycare setting or 
that is provided outside a school or daycare setting that has been of the same type and intensity for 
8 weeks prior to the Week 0 assessments.   
• 
Any behavioral intervention changes for either the parent or child during the first 9 weeks of the 
study are discouraged, but are not prohibited. 
The concomitant medication Case Report Form (CRF) will report all those prescription medications, 
over-the-counter medications and supplements taken. Doses will not be reported.  The Intervention 
History CRF will track hours and types of behavioral interventions received. Intervention history form at 
10 weeks will ask about interventions over the past 10 weeks, and the study staff may ask participants 
about interventions during the course of treatment as well. 
 
6.5.3 Rescue medicine 
Insomnia  The study physician will be permitted to prescribe melatonin ≤ 6mg/night, immediate release 
clonidine ≤ 0.2mg/night or diphenhydramine ≤ 12.5mg/night for insomnia that is not responsive to 
reductions in the dose of study medication and behavioral interventions, if desired by the participant’s 
caregivers.  This medication will be recorded on the case report form.   
These rescue medications will not be provided or paid for by the study. The rescue medications will  be 
recorded on the case report forms.  
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT WITHDRAWAL 
7.1 
Study Halting Rules 
The DSMB may choose to halt the study at any time they feel there is significant risk to participants as a 
result of study procedures or as a result of the safety profile of the study medication treatments (active 
Adzenys-XR-ODT or placebo), study behavioral treatment (ESDM-informed parent coaching), or of 
specific study assessments.  Of these situations, concerns about the safety profile of study medication 
treatments is most likely to occur, since the behavioral treatment is well accepted in the community and 
does not appear to have specific safety concerns and the assessments are used in a wide variety of 


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studies of young children with ASD and have never been shown previously to result in significant safety 
risks.  
In addition, we will place the study on hold and request DSMB review for safety concerns if we note that 
the proportion of participants withdrawing from active medication treatment in either treatment arm is 
greater than 40% and more than 3x that of the other treatment arm.  This is a study interruption rule ‒ 
“halting” rule ‒, although the final decision to stop the study or change study procedures will be made 
by the DSMB and/or IRB. 
 
7.2 
Rules for Individual Participant Discontinuation in Study Interventions 
Participants’ caregivers may choose to discontinue the study drug intervention and/or the behavioral 
parent coaching intervention at any time for any reason.  Similarly the study physician or therapist may 
choose to withdraw the participant at any time if the physician or therapist feels that it is not in the 
participant’s best interest to continue.  
In addition, if the participant has intolerable adverse events that have not sufficiently resolved even on 
the lowest available dose of study medication (1/2 tablet daily = 1.55 mg / 0 mg Adzenys-XR-ODT) or are 
so medically serious that dose reduction is not in the best interests of the child in the study physician’s 
or caregiver’s opinion, the participant will be withdrawn from study medication treatment., In any of 
these cases, every effort will be made to encourage the participant and his/her caregiver to complete 
the outcome assessments according to the study schedule.  A+ Treatment staff will continue to assess 
safety and adverse events for up to 30 days following discontinuation or until the adverse event has 
resolved or stabilized.  
 
7.3 
Participant Discontinuation/Withdrawal from the Study 
Participants are free to withdraw from participation in the study at any time. 
An investigator may discontinue or withdraw a participant from the study for the following reasons: 
• 
Significant study intervention non-compliance,  
• 
If any clinical adverse event (AE), or other medical condition or situation occurs such 
that continued participation in the study would not be in the best interest of the 
participant, 
• 
The entire study has been halted. 
The reason for participant discontinuation or withdrawal from the study will be recorded on the End of 
Study CRF.  Participants who are randomized but do not receive the study intervention may be replaced 
if feasible.  Participants who receive at least one component of the study intervention (medication or 
behavioral) and subsequently withdraw, or are withdrawn or discontinued from the study, will not be 
replaced. 
 
7.4 
Lost to Follow-Up 
A participant will be considered lost to follow-up if he or she fails to attend planned study visits over the 
time period described in the SoA under window and is unable to be contacted by the study site staff 
after 3 attempts by 2 methods including email and phone.  


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The following actions must be taken if a participant fails to return to the clinic for a required study visit: 
• 
The site will attempt to contact the participant by phone, email and/or regular return 
receipt mail at least 3 separate times over the period window (see SOA).  These contacts 
will be recorded on the appropriate study CRF.  
• 
If the study staff is able to reach the participant’s caregiver, staff will counsel the 
participant’s caregiver on the importance of maintaining the assigned visit schedule and 
ascertain if the participant’s caregiver wishes to and is able to continue in the study.  If 
the caregiver is willing to continue, study medication visits will be rescheduled as soon 
as possible.  Study behavioral parent coaching visits will be resumed as soon as possible.  
Missed sessions will not be rescheduled outside the session window of +/- 3 days. 
• 
If the study staff is able to reach the caregiver, every effort will be made to encourage 
the participant’s caregiver to participate in the final outcome assessment.  
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
8.1 
Efficacy Assessments  
8.1.1 Primary efficacy assessment  
 
Procedures: 
We will utilize a semi-structured Parent Child Interaction Task (PCIT) modified by DeVito et al., 2016, 
personal communication) to assess several key behaviors using a standard set of materials in a 
naturalistic setting.  Children and their parents are observed during a series of 2-6 minute scenarios that 
include 1) staff instructions to the child to not touch a particular toy that is placed separately from other 
toys, 2) child independent play while parent is busy, 3) a six minute parent-child free play session, and 4) 
a parent structured “clean up” period at the end.  These specific scenarios will allow assessment of the 
child’s ability to attend to directions, inhibit impulses, attend to and comply with requested tasks, 
hyperactivity, and child approach to the parent and to rate child, parent and dyadic behavior.  All 
sessions will be video taped using two research assistant-controlled cameras in the room designed to 
capture as much of the child and parent’s behaviors simultaneously as possible and a fixed, ceiling-
mounted, wide angle camera (Ethovision) that inputs the resulting video into an automatic analysis 
program (Noldus software) to track child and parent proximity and the child’s movements within regions 
of interest in the room across time.  Many ratings and objective measures from the PCIT will be derived, 
but we will only analyze two ratings from the Joint Engagement Rating Inventory (JERI) Ratings of 
parent child joint attention and engagement developed by Adamson and colleagues (164) and adapted 
as needed for the study in collaboration with her group as key primary outcomes.   
The JERI rating system considers both duration and quality of behaviors.  It correlates well with time 
spent in specific engagement states and appears to be more sensitive in distinguishing diagnostic groups 
and change than simply determining the total time spent in particular engagement states (Adamson 
2012; Suma 2017).  Raters blinded to treatment status will be trained to reliability by a trainer from 
Adamson’s group and Dr. Devito.  In addition, ~15% of videos from each rater will be coded by another 
rater and the gold standard rater on an ongoing basis to ensure that interrater reliability is maintained.  
We are focusing on two specific JERI ratings, but there are several other ratings from the JERI that may 
be of interest in the future. 


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Social related measures from the Noldus system include the time until the child approaches the parent, 
proportion of time spent in proximity of the parent, percent of time spent neither in proximity of toys or 
parent and compliance with instructions during the clean-up activity including latency to help and 
percent of time spent helping with clean-up.   
Multiple ADHD related measures can be derived from the Noldus system during PCIT. Physical activity 
measures include total minutes in physical activity and total distance traveled.  Inhibition control 
measures are based on Noldus tracking of interactions with the forbidden toy, and will include the 
latency to first touch of toy, number of touches of toy, and total proportion of time spent touching the 
forbidden toy. 
Two JERI ratings of social communication will be considered as the primary outcome measures. One of 
these will focus on joint attention. The other will focus on the coordination and fluency of parent child 
joint engagement.   
8.1.2 Secondary efficacy procedures and assessments 
 
Key Secondary Efficacy Assessments: 
Vineland Adaptive Behavior Scale (VABS) Mean of the Standard Scores of the socialization and 
communication subscales is a key secondary outcome.  This measure will assess how the participant 
actually has been functioning over the preceding month with regard to communication and social 
behaviors.  The VABS-3(3) comprehensive form will be administered as a semi-structured interview by a 
trained and research reliable staff member according to the specifications in the Manual of Procedures 
(MOP).  The standard score is based on the participant’s age and is normed from a large sample of 
typically developing children.  The standard score has a mean of 100 and a standard deviation of 15.  
The minimally clinically significant change on the VABS adaptive behavior composite and standard 
scores for each of the subscales within individuals with ASD has recently been determined (Chatham et 
al., 2017).  
In addition, the Preschool or School age ADHD Rating Scale – clinician rating (P-ADHD- RS-C) will be 
used as the measure to assess ADHD symptoms in aim 2.  It will be based on all information available to 
the clinician including review of parent ratings, parent interview, participant exam and unstructured 
observations during the visit. At the remote follow-up assessment (24 weeks following baseline), the 
parent rating of the P-ADHD-RS will be used to assess ADHD symptoms since the visit is conducted 
remotely. The parent version of the P-ADHD-RS contains the same questions as the clinician rating.  
 
8.1.3 Exploratory objective outcome assessments  
Objective Measures of Social Attention during Eye Gaze Tracking.  These will include time in seconds 
and percent of total looking time spent looking at social stimuli.  Eye gaze tracking (EGT) will be recorded 
using a Tobii system.  The system utilizes near-infrared illumination to create reflections on the eyes that 
can be tracked with high accuracy. Near-infrared light can be found in our natural environment, for 
instance in candle lights, fires, and in the sun where the IR light is invisible or viewed as white light. All 
Tobii Eye Trackers have been tested and approved by certified labs according to the European standard 
for optical radiation hazards of different lamps and lamp systems, IEC/EN 62471. Light emission that 
meets this standard is not harmful to the human eye. Eye-tracking systems are completely non-
intrusive, and do not require the subject to wear any equipment (such as a helmet, eyeglasses or facial 
markers). No apparatus is connected to the participants.  The participants will be shown videos of 


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various social and non-social stimuli as well as dynamic videos that contain both socially relevant and 
non-socially relevant stimuli.  Regions of interest will be used to define the social and nonsocial stimuli.  
The total amount of time looking at the screen, looking at the social stimuli, looking at nonsocial stimuli, 
latency to looking at each type of stimuli for the first time and number of fixations on each type of 
stimuli will be recorded.  The analyzed variables will reflect change between baseline and final outcome 
/ endpoint assessments (10 weeks apart). 
SenseToKnow. Children may complete this task which is delivered on a mobile device which uses 
computer vision analysis to code visual attention and affective expressions in response to brief videos 
presented on the device. Stimuli consist of a series of video clips including toys that make noise, a man 
blowing bubbles, bubbles cascading and popping, and a puppy video with unexpected events. Children 
will sit on the parent’s/guardian’s lap or a chair with the mobile device at eye level for the child. Children 
will watch videos and play games that are presented on the mobile device. Overall, the entire task will 
take approximately 10-15 minutes. Children will be allowed to take breaks between videos and games as 
needed. A research assistant will be present at all times to answer questions. 
EEG Measures of Neurophysiologic Activity. Brain activity will be examined using high-density EEG 
recordings. We will record EEGs in the neurophysiology laboratory at the Duke Center for Autism and 
Brain Development. The technique of measuring brain activity with EEG is completely non-invasive and 
involves the use of a light net of damp electrodes (128 Ag/AgCl electrodes encased in soft sponges and 
soaked in a saline solution). Before EEG testing begins, participants are familiarized with the laboratory 
and equipment. Participants will be seated in a comfortable chair, and the elastic net will be place over 
their head and secured with a chinstrap.  Preparation (placing of the net and ensuring that electrodes 
are properly aligned) takes approximately 5 minutes. All participants will be given an appropriate 
explanation of the procedure before it takes place and will be given an opportunity to examine the 
materials and equipment. The experimenter, as well as parent if desired, will remain in the room with 
the participant at all times. A second experimenter will monitor the EEG recording and behavior of the 
participant via a video link from an adjoining room. We will record EEG continuously while the 
participant watches various videos (e.g. of brightly colored geometric shapes, models displaying 
emotional faces, an hour glass), or listens to sounds. The session will be videotaped to monitor the 
participant’s affect during the EEG. The EEG will be preprocessed to remove artifacts.  We will examine 
regional connectivity, interphase stability and total spectral power during evoked electrical responses to 
social stimuli. Due to the intensive time and staff demands of the EEG assessments, they will be 
obtained only at baseline and endpoint.  
 
8.1.4 
OTHER SUPPORTING BEHAVIORAL OUTCOME ASSESSMENTS 
• Aberrant Behavior Checklist – 2nd Edition Community Version (ABC) is a parent report measure that 
was initially developed for use with intellectually disabled children and adults in residential settings 
but has been validated for use with individuals with ASD living in the community.  Reference values 
are available from large samples of individuals with ASD.  The ABC includes 5 subscales: irritability, 
attention, lethargy/social withdrawal, repetitive behaviors, and abnormal language.  Each of the 40 
items is rated from 0 – not at all a problem to 3 – very much a problem.  Respondents are asked to 
rate behaviors in comparison to typically developing individuals.  The ABC will be obtained at 
baseline and endpoint. 
• Behavior Rating Inventory of Executive Function (BRIEF) The BRIEF is a caregiver report measure 
that assesses age appropriate executive function behaviors for children. The preschool BREIF is for 
children between 3 years and 5 years 11 months and the BREIF 2 is designed for children 6 and 


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older.  The same version of the BRIEF will be used at baseline and endpoint to assess changes over 
time.  The following domains will be examined: inhibition, shifting, emotional control, working 
memory and planning.   
• Caregiver Strain Questionnaire (CSQ) The CSQ is a caregiver completed measure with 21 questions 
assessing the impact of a child with a developmental disorder or behavioral disorder on the caregiver 
and the rest of the family.  Questions are rated on a 5 point scale from not at all a problem to very 
much a problem. In the original version one item relating to your child is reverse scored.  We will use 
a version in which the question is rephrased to avoid reverse scoring.  The scale has 3 subscales: 
objective, internalizing and externalizing.   It takes about 5 minutes to complete. 
• Child Behavior Checklist (CBCL) The CBCL is a caregiver- completed scale that assesses problem 
behaviors using a 3 point scale  (not true, somewhat or sometimes true, and very true or often true) 
over the prior two months.  The preschool version is designed for children 1.5 to 5 years and 
contains 99 items.  The school age version is designed for children 6-17 and contains 118 items.  The 
behavioral domains that are assessed include Emotionally Reactive; Anxious/Depressed; Somatic 
Complaints; Withdrawn; Attention Problems; Aggressive Behavior and, in the older version, sleep 
problems. There are also DSM-oriented scales that are consistent with DSM-5 diagnostic categories. 
Depressive Problems; Anxiety Problems; Autism Spectrum Problems; Attention Deficit/Hyperactivity 
Problems; Oppositional Defiant Problems. The scale is standardized to provide a mean T score of 50 
with a standard deviation of 10.  Higher scores reflect more impairment. It has been studied in 
samples of both school-aged and preschool children with ASD, other psychiatric disorders and 
typical 
development(85, 
86). 
It 
takes 
about 
15 
min 
to 
complete. 
http://www.aseba.org/preschool.html 
• Children’s Sleep Habits Questionnaire abbreviated (CSHQ) This caregiver report measure assesses 
the sleep habits of children 4-10 years old.  33 items are rated on a three point scale.  The scale 
reports  on sleep domain scale scores: (1) bedtime resistance, (2) sleep duration, (3) parasomnias, (4) 
sleep-disordered breathing, (5) night awakenings, (6) daytime sleepiness, (7) sleep anxiety, and (8) 
sleep onset delay.  It takes about 5 min to complete. 
• Clinical Global Impressions Scale (CGI) is a clinician rated measure of overall clinical severity and 
improvement that compares to typically developing individuals of a similar age using anchored 
descriptions.  The severity score (CGI-S) ranges from 1- no clinical problem to 7- among the most 
severely ill; the improvement score (CGI-I) ranges from 1- very much improved to 7 – very much 
worse, both as compared to baseline.  Four CGI measures will be used focusing on 1) overall 
functioning that includes the impact of the child’s ASD + ADHD as well all associated and comorbid 
problems, Social communication behaviors, 2) ADHD symptoms only, 3) social communication 
behaviors, and 4) restricted and repetitive behaviors and interests.  The CGI will be assessed by the 
study physician at physician and at the endpoint visit.  The CGI raters will be trained by the PI and 
reliability will be established using a set of vignettes.  Raters will be considered to be reliable if they 
are in exact agreement with half of the gold standard ratings and within 1 point of the gold standard 
on the other half of the ratings.  Reliability will be reassessed annually by coding additional vignettes 
or double coding observed or taped participant visits. 
• Impairment Rating Scale (IRS) is a parent reported measure that quantifies impairment present in a 
child’s life in both school and non-school settings. The scale ranges from 1 – No challenge; definitely 
does not need treatment/special services to 7 – Extreme challenge; definitely needs 
treatment/special services. The IRS will be assessed at the ESDM informed coaching visits during 
weeks 2-8. 


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• Satisfaction Questionnaire  The satisfaction questionnaire includes 4 questions asking about the 
caregiver’s impression of the quality of treatment received during the study, the extent to which the 
caregiver believes her/his child and she/he as the caregiver benefited from the study treatment, and 
the caregiver’s impression of participating in research assessments.  It takes about 2 minutes to 
complete and will be done with the endpoint assessments. 
• Sluggish Cognitive Tempo Questionnaire is a caregiver completed questionnaire that assesses 15 
items (Becker et al 2017) that reflect daydreaming, low physical and cognitive energy and challenges 
in maintaining focus on ones thoughts, which have been conceptualized as sluggish cognitive tempo 
historically.  These symptoms, which are highly comorbid with the inattention symptoms of ADHD, 
can be reliably distinguished from nine key symptoms of inattention within ADHD on the Child 
Adolescent Behavior Inventory.  Some of these symptoms also overlap with symptoms sometimes 
associated with ASD such as stares blankly into space, gets lost in own thoughts and spaces out.  
However, studies have suggested that when ADHD symptoms and ASD symptoms are statistically 
controlled, SCT is independently associated with greater social dysfunction and more internalizing 
symptoms. The questionnaire will be completed at baseline and endpoint. 
• Social Responsiveness Scale- Revised (SRS-2) is a parent report version characterizing various social 
and repetitive behaviors associated with ASD.  The scale’s 65 items are rated between 1 and 4 and 
typically can be completed within 10 minutes.  It is designed for use in children between the ages of 
2 ½  – 18 years.  It contains subscales assessing social awareness, social cognition, social 
communication, social motivation, and restricted and repetitive behaviors. The measure has been 
standardized on a large sample including individuals with typical development and demonstrated to 
be distributed along a continuum.  Threshold scores suggestive of ASD have been determined 
separately for boys and girls. Participants between ages 2.5 and <4 years will receive the Preschool 
SRS-2, and those ages 4 and above will be asked to complete SRS-2 School age version.  The SRS will 
be obtained at baseline and endpoint.  
• Treatment guess questionnaire  The caregiver, parent coach and study doctor will indicate whether 
s/he thinks the child was receiving active medication during the trial at the endpoint assessment 
before unblinding.  
 
8.1.5 Other descriptive measures obtained only at baseline 
• Children’s Behavior Questionnaire Short Form (Rothbart, 2000; Rothbart et al 2001,) is a caregiver 
report measure designed to provide a detailed assessment of temperament in children 3 to 7 years 
of age. Individual differences are assessed on 15 primary temperament characteristics indicating 
three broad dimensions of temperament: Extraversion/Surgency, Negative Affectivity, and Effortful 
Control.  Temperment characteristics on the CBQ have been linked with subsequent 
psychopathology, including negative affectivity and ADHD.   
• Home Video Tape Upload, typically of the child’s first birthday or an occasion that involves clear 
social expectations and interactions with others, will be requested at baseline. 
• Leiter Attention and Memory Scales (Roid et al. 2013) The Leiter is a standardized nonverbal 
assessment with 3 subscales: cognition, attention and memory and examiner ratings of various 
aspects of the child’s behaviors (not standardized).   The attention and memory component includes 
five subtests: two measure nonverbal attention; two measure memory; and one measures cognitive 
interference (nonverbal Stroop test). It takes about 30 minutes to administer and will be obtained in 
participants with IQ’ ≥ 70, only at baseline. 


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• The Sensory Experiences Questionnaire, version 3.0 (Baranek 1999, 2006) is a 105 item caregiver 
report measure designed to characterize sensory features in children 2-12 years old. It has been 
shown to have good discriminate validity between children with ASD, intellectual disability and 
typical development and also has good test-retest reliability. (Baranek et al., 2006; Little et al., 
2011). 
• 
The Parenting Sense of Competence scale (Gibaud-Wallston & Wandersman, 1978) measures 
parental competence along two dimensions: Satisfaction and Efficacy. It is a 17 item Likert-scale 
questionnaire (on a 6 point scale ranging from strongly agree [1] to strongly disagree [6]), with ten 
questions under Satisfaction (examining the caregiver’s anxiety, motivation and frustration) and 
seven under Efficacy (which looks at the caregiver’s competence, capability levels, and problem-
solving abilities in their role). The scale can also be scored as a 16-point scale (where the last 
question isn’t used). This measure will examine changes in participant’s parental competence before 
and after the study and will be administered at baseline and week 10. 
 
8.2 
Safety and Other Assessments 
• ACE Medical and family history forms-Caregivers will be administered  the ACE  Subject  Medical 
History   Questionnaire,  and  the   ACE   Family   Medical   History   Questionnaire at the screening 
visit. These forms collect medical history and current status so that our physicians can have a basis 
for on-going questions as needed. The ACE Subject Medical History Questionnaire will provide a 
detailed developmental history and systematic review of problems in each body system using a 
standardized data dictionary shared across all ACE funded projects. The ACE Family Medical History 
Questionnaire elicits the developmental and neuropsychiatric history of parents, full- and half-
siblings in a similar standardized and shared format. The study physician will review the ACE Subject 
Medical History and ACE Family Medical History forms completed by the A+ Assessment Core prior 
to interviewing and examining the participant and his/her parents.  
• Cardiovascular History Form- The study physician will ask the caregivers about family medical 
history of cardiovascular problems or malformations and subject history of cardiac congenital 
malformations, hypertension, arrhythmia, fainting spells and chest pain to get an idea of cardiac 
history or current issues that could be problematic.  
• Electocardiogram (ECG)-The child will be administered an ECG at Screening, which will be read by a 
pediatric cardiologist at screening only to rule out any heart complications prior to randomization. 
The physician may decide to request additional ECGs, if warranted at any point of the study.  
• Physical examination The ACE Physical Exam form containing standardized data elements will be 
completed at baseline and endpoint. At subsequent physician visits, a more targeted brief physical 
exam will be performed.  
• Vital signs Vital signs including height, weight, pulse, and blood pressure will be taken at each in-
person visit and reviewed by the study physician. Recognition of clinically relevant changes, 
patterns, or trends in vital signs and growth indices will be facilitated by use of a "vital signs log" that 
contains all measurements over the study for a particular participant. 
• Assessment of adverse events At each visit, the participant’s caregiver will be asked an open-ended 
question about new medical/behavioral problems or significant worsening of existing problems. 
Responses to these will be reviewed by study staff and the study physician to determine whether 
any further action is necessary to mitigate risks. Any treatment emergent adverse events (i.e. events 


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not included in past medical history or present at baseline or events that significantly increase in 
intensity rating from the intensity at baseline or in the PMH) will be recorded.   Upon resolution of 
the AE or at the end of the study, each problems relatedness to the study interventions is assessed.  
The adverse event form will include information about intensity, start and stop dates, action taken, 
relatedness to study and status of AE when it resolves or at the endpoint assessment. 
• Suicidality Assessment At each physician visit, a child suicidality assessment form will be given. A 
clinician/physician will assess the appropriateness of directing the questions to the participant based 
on age, verbal ability, cognitive functioning, overall functioning, behavior, willingness, etc.  
Concomitant Medication Log: At the first visit, the physician will make a list of any medications the 
subject is currently taking. The physician or study staff will record ANY changes to the subjects’ 
medications and dietary supplements throughout the course of the study.  
 
8.3 
Adverse Events and Serious Adverse Events 
8.3.1 Definition of adverse events (AE) 
Adverse event means any untoward medical occurrence associated with the use of an intervention in 
humans, whether or not considered intervention-related (21 CFR 312.32a).  Adverse events will be 
specifically elicited using the open ended queries. Adverse events may also include abnormal medically 
concerning laboratory or ECG findings obtained during the course of the study as the result of the 
participant’s routine medical care or study assessments.   
In this trial we are eliciting all AE’s using open-ended queries, but analyses will focus only on Treatment 
Emergent AE’s (TEAE’s).  Medical and behavioral conditions that are present at screening and/or 
baseline will only be considered treatment emergent adverse events if their severity increases 
significantly after the participant has taken at least one dose of study treatment.  Intermittent 
conditions such as seasonal allergies will only be considered TEAEs, if the severity or frequency is 
significantly greater than at their most intense during the previous two years.   
If a TEAE occurs, its relationship to study product (assessed only by those with the training and authority 
to make a diagnosis, which would include MD, DDS, DMD, PA, Nurse, Nurse Practitioner or DO), and 
resolution/stabilization will be coded at the resolution of the event or end of the subject’s participation 
through week 24 of the study.  All TEAEs occurring while on study must be documented appropriately 
regardless of relationship.  If a TEAE is a severe adverse event rating of “Severe” and an Unexpected 
Problem (UP-no prior history of issue/not commonly seen in autistic patients and not described as a risk 
of the treatment), the UP form must be completed.  If a TEAE is a Serious Adverse Event (SAE - see 
below), but not an UP, the SAE description completed. 
 
8.3.2 Definition of serious adverse events (SAE)  
An adverse event (AE) is considered "serious" if, in the view of the investigator, it results in any of the 
following outcomes: death, imminent threat of death, inpatient overnight hospitalization or 
prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of 
the ability to conduct normal life functions, or a congenital anomaly/birth defect.  Important medical 
events that may not result in death, be life-threatening, or require hospitalization may be considered 
serious when, based upon appropriate medical judgment, they may jeopardize the participant and may 
require medical or surgical intervention to prevent one of the outcomes listed in this definition.  


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8.3.3 Classification of an adverse event 
Intensity of Event: 
• 
Mild: Mild events require minimal or no treatment and do not significantly interfere with the 
subject’s daily activities for more than a day or two. 
• 
Moderate: Moderate events lead to consideration of medical evaluation or treatment and 
typically cause some significant interference with functioning for multiple days. 
• 
Severe: Severe events prevent a subject’s usual daily activity for an extending period of time and 
are usually incapacitating.  Medical evaluation and treatment are generally required if such 
treatment exists.  
• 
Extreme: Life threatening events pose imminent and substantial risk of dying or require urgent 
intervention to prevent risk of dying.  
 
 
Relationship to Study Intervention: 
The study physician will assess the relationship between each TEAE to the study interventions and 
procedures based on his/her knowledge of similar medical events, the study procedures and the 
temporal relationship between the study treatment/procedure and emergence of the TEAE.  All TEAEs 
regardless of the relationship between the AE and study treatment will be reported.  The degree of 
certainty about relatedness will be graded using the categories below. 
• 
Yes/Definitely related (certainly related): The adverse event and administration of the study 
drug are related in time, and a direct association can be demonstrated. There is clear evidence 
to suggest a causal relationship, and other possible contributing factors can be ruled out. The 
AE, including an abnormal laboratory test result, occurs in a plausible time relationship to study 
intervention administration and cannot be explained by concurrent disease or other exposures. 
The response to withdrawal of the study intervention (dechallenge) should be clinically 
plausible. The event must be pharmacologically or phenomenologically definitive, with use of a 
satisfactory rechallenge procedure if necessary. 
• 
No (unrelated): The AE is clearly explained by another cause not related to the study 
intervention. The AE is completely independent of study intervention administration, and/or 
evidence exists that the event is definitely related to another etiology.  
Expectedness: 
The study PI will be responsible for determining whether an AE is expected or unexpected.  An AE will be 
considered unexpected if the nature, severity, or frequency of the event is not consistent with the risk 
information previously described for the study intervention or procedure or with typical experiences of 
children. See package insert for detailed information pertaining to what AEs may be expected with 
Adzenys-XR-ODT extended release, orally dissolvable tablets.  
 
8.3.4 Time period and frequency for event assessment and follow-up 


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The occurrence of a treatment emergent adverse event (TEAE) or serious adverse event (SAE) may come 
to the attention of study personnel during study visits or contacts with other medical providers caring 
for the study participant, or in the context of other contacts between the participant, his/her caregivers 
and study staff.  All non-serious TEAEs will be followed up until satisfactory resolution, the site 
investigator determines the TEAE to be chronic or the child completes participation in week 9 of the 
study.  All SAEs will be followed until satisfactory resolution or until the site investigator deems the 
event to be chronic or the participant is stable.  
 
8.3.5 Adverse event reporting  
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured in the 
through a general AE inquiry. Information to be collected includes event description, clinician’s 
assessment of intensity, relationship to study product (assessed only by those with the training and 
authority to make a diagnosis) AEs will be followed to adequate resolution or the completion of the 
child’s week 9 visit in the study. Any medical condition that is present at the time that the participant is 
screened or at the week 0 visit will be considered as past medical history and not reported as a 
treatment emergent AE. However, if the study participant’s condition deteriorates at any time during 
the study, that is, there is an increase in the condition’s intensity rating, it will be considered a TEAE. 
 
8.3.6 Serious ADVERSE EVENT REPORTING  
An SAE is defined as an AE that meets certain conditions as defined in section 8.3.2.  As soon as study 
staff become aware of a possible SAE, they will notify the study physician or study PI.   
The study physician or PI will review and evaluate the potential SAE, obtaining external medical records 
and requesting the participant attend an unscheduled physician visit as needed to determine whether or 
not the event is an SAE. 
If the event is an SAE:, 
• 
The study PI and ACE Center PIs will be notified within 24 hours. 
• 
The study medical monitor will be notified within 14 days 
• 
Record event on the appropriate SAE CRF 
• 
follow through resolution (study clinician), updating as needed 
 
Timeline for reporting of SAEs is: 
• 
Medical Monitor: The PI will report all SAEs to the medical monitor within 14 days of becoming 
aware of the SAE and receive acknowledgment that she/he has reviewed them.  
• 
DSMB: The PI will report SAEs that are considered possibly related to study treatment to the 
DSMB within 14 days of being made aware of their occurrence.  
• 
IRB: SAEs will be reported to the IRB in the context of the annual report or within 14 days of 
being made aware of the SAE’s occurrence if it is considered related and unexpected or results 
in death. 


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• 
FDA:  This study has received an IND exemption, so there is no mandated reporting required.  
However, if the SAE results in death, is related and unexpected the SAE will be reported using 
FDA’s public Adverse Event Reporting System (FAERS) within 7 days. If the SAE does not result in 
death, but is both related and unexpected it will be reported using FAERS within 14 days of 
becoming aware of the SAE. 
• 
NICHD:  The ACE center co-PIs and study PI will report SAES that result in death to the NICHD 
program officer within 48 hours of becoming aware of the event, regardless of whether the SAE 
was related or expected.  If SAE does not result in death or permanent disability, but is 
considered related and unexpected, we will report it to the NICHD program officer within 
14days of becoming aware of the SAE.  SAEs that are not considered related or unexpected will 
be reported in annual progress reports. 
• 
Neos Therapeutics:  within 7 days if the SAE results in death and is considered related to treatment 
and within 14 days if the SAE does not result in death and is considered related to treatment. 
 
8.3.7 Reporting events to participants  
If any information emerges that the DSMB or IRB concludes significantly changes the risk: benefit profile 
of participation in the study, the information will be incorporated into a revised informed consent 
document for approval by the IRB and the caregivers of participants who are still active in the study will 
be reconsented with IRB approved revised consent at the earliest possible opportunity.  
 
8.3.8 Events of special interest  
Cardiac Monitoring. Based on the patient’s age, gender, and height percentile, we have adapted blood 
pressure parameters where blood pressures above or below the set threshold will prompt the PI or 
study physician to consider doing a repeat ECG. These parameters were derived from the National High 
Blood Pressure Education Program Working Group on High Blood Pressure in Children and 
Adolescents(88). We have likewise adapted parameters from Pediatric cardiology for practitioners(50) 
and Normal ECG standards for infants and children (89) to establish heart rate guidelines where patients 
whose heart rate is above or below these thresholds will be considered for an ECG at every visit. Finally, 
we will incorporate clinical signs and symptoms of cardiac risk into our clinical medical assessment.  The 
SLAES also specifically queries for the presence of syncope, dizziness, palpitations, shortness of breath, 
and bradycardia or tachycardia. Family cardiac history will also be collected and assessed by a physician 
before starting the study.  
 
8.3.9 Reporting of pregnancy  
Not-applicable due to age of participants. 
 
8.3.10 Reporting of suspected child abuse or neglect  
If any member of the study staff has significant concerns that a participant may be being abused or 
neglected, they will discuss it with the study PI.  The study PI will attempt to obtain any additional 
information felt necessary to clarify the situation.  If after this there is still concern about abuse or 
neglect, the PI will contact child protective services and file a report.   


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8.4 
Unanticipated Problems 
8.4.1 Definition of unanticipated problems (UP) 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all of the 
following criteria: 
• 
Unexpected in terms of nature, severity, or frequency given both the research procedures that 
are described in the protocol-related documents, and the characteristics of the participant 
population being studied; 
• 
Related or possibly related to participation in the research and 
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
 
8.4.2  Unanticipated problem (UP) reporting  
The UP report will include the following information: 
• Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number; 
• A detailed description of the event, incident, experience, or outcome;  
• An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP;  
• A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP. 
Timelines for reporting the UP are listed below.  The FDA and IRB require different reporting based on 
the characteristics of the UP as noted below. 
• Study PI within 24 hours of staff suspecting a UP 
• ACE Center co-PIs within 7 days of the Study PI confirming a UP has occurred. 
• Medical Monitor: The study PI will report all UPs to the medical monitor within 14 days and 
receive acknowledgment that she/he has reviewed them.  
• DSMB: The ACE co-PIs and the study PI will report UPs that are considered possibly related to 
study treatment to the DSMB within 14 days of being made aware of their occurrence.   
• FDA: Only those UP’s that are also SAEs will be reported to the FDA using the FAERS. Timelines 
for reporting to the FDA follow. 
 
Fatal or life threatening unanticipated problems in 7 days 
 
Non-fatal/non-life threatening unanticipated problem in 14 days 
• IRB: The PI is responsible for reporting unanticipated problems according to the time frames 
below. 
 
Unanticipated Problems that are also SAEs within 7 days of becoming aware of the 
event.  
 
Any other Unanticipated Problem within 14 days of becoming aware of the problem. 


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• 
Neos Therapeutics:  within 14 days of becoming aware of the UP. 
 
8.4.3 Reporting unanticipated problems to participants  
The informed consent document for the study will be revised to reflect the UP.  After IRB approval of the 
revised informed consent document is received, all participants who are continuing to be treated within 
A+ Treatment will be reconsented.  In addition, all participants who do not have a previously scheduled 
appointment within 2 weeks of the approval of the revised informed consent document will be notified 
by phone, email or mail that the UP has occurred and that a revised consent form now exists.  They will 
be asked to contact study staff if they wish to discuss the event prior to the next scheduled study visit 
 
8.5 
Overall Plan to Protect Patient Safety 
Frequent monitoring by study physician Participant safety will be monitored at an individual level by 
the treating study physician through review of the caregiver medical and behavioral checklist, vital signs 
and labs, as well as systematic interview elicitation of potential medical and behavioral problems via the 
SLAES and regular physical and psychiatric exams during scheduled visits, which are more frequent than 
is typical with community care.  In addition, caregivers will have access to a study physician 24hrs/day by 
contacting the study coordinator during regular business hours and using the emergency phone number 
after business hours.  Additional appointments and laboratory or ECG assessments can be provided at 
any time according to the treating study doctor’s clinical judgment.   
 
Flexible dosing, which includes a 1.55mg dose, is allowed to address dosing-related adverse effects.  In 
addition, participants who are not able to tolerate this small dose are allowed to completely discontinue 
study medication while continuing participation in assessments and parent coaching.   
 
Rescue medication is provided for significant insomnia, which is one of the most common and 
problematic adverse effects of stimulant medications. 
 
Medical Monitor The study will also provide for additional oversight via a medical monitor who reviews 
SAEs and unexpected problems and who will be available to the study clinicians upon request to discuss 
safety concerns. 
 
Data Safety and Monitoring Board (DSMB) The study will have a three person data and safety 
monitoring board that reviews the initial protocol prior to any participant being enrolled.  After the first 
participant has been randomized until the last participant has completed the week 24 visit, the DSMB 
will meet a minimum of two times a year to review the study’s progress and the safety of randomized 
participants.  Specifically, the following will be reviewed at each meeting: 
1. 
enrollment and randomization as compared to proposed enrollment and randomization,  
2. 
SAEs and UPs with any resulting changes in study procedures or consents, 
3. 
participant discontinuation of study medication, study withdrawals, and study completions 


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4. 
adverse events separated by system organ class, severity and relatedness, 
5. 
changes in laboratory and ECG assessments between screen and week 24 and TEAE related 
laboratory and ECG assessments,  
6. 
protocol deviations and 
7. 
status of data entry. 
Reports related to participant safety will be separated into two groups but the treatment identity of 
each group will not be disclosed by the unblinded statistician/programmer unless requested by the 
DSMB.  The DSMB may also request additional reports or additional meetings.  The membership of the 
DSMB includes two child psychiatrists who are experts in psychopharmacological treatments for ASD 
and conducting clinical trials in ASD and a statistician. The DSMB will determine at each meeting 
whether there are any concerns, especially with regard to safety, that lead the board to conclude that 
the study should be suspended or that the protocol should be amended to provide greater protections 
for subjects.  The DSMB may also raise concerns or provide suggestions to improve recruitment or 
procedures for the trial.  The DSMB charter, which lists its current members, is included as a appendix.  
 
9 
STATISTICAL CONSIDERATIONS  
9.1 
Statistical Hypotheses 
Primary Analysis:  Efficacy of COMB vs BEH: We hypothesize that, in children 36 to <132 months old 
with comorbid ASD+ADHD, COMB ‒ stimulant medication provided during 10 weeks, including 8 weeks 
of ESDM-informed parent coaching ‒ will demonstrate greater improvements in the degree of child 
joint attention and fluency and coordination of parent child joint engagement as measured by the JERI 
coding rating scale and the mean of the VABS Socialization and Communication domain standard 
scores than BEH ‒ placebo medication provided during 10 weeks, including 8 weeks of ESDM-informed 
parent coaching.  The significance level will be set at p < 0.05.  An exploratory analysis will explore 
changes between week 0 and week 24. 
 
Secondary Analysis: Efficacy of Adzenys-XR-ODT vs Placebo:  We hypothesize that in 36 to <132  month 
old children with ASD + ADHD, ADHD symptom reduction (assessed via changes in the clinician-
administered preschool or school age ADHD Rating Scale will be significantly greater in children 
receiving Adzenys-XR-ODT than in children receiving matched placebo in the 24 week duration between 
baseline and remote follow-up assessments..  
 
Exploratory Hypotheses are primarily descriptive and will not be corrected for multiple comparisons. 
• 
Determine the Efficacy of COMB vs BEH on supportive measures of ASD related symptoms:  We 
will compare the COMB and BEH groups with regard to changes between baseline and endpoint 
assessments (an 10 week duration) in the following outcomes: JERI ratings of coordinated joint 
attention and of fluency and coordination of engagement during the PCIT free play task, 
proportion of time spent near caregiver in the PCIT video activity recording, social attention 
assessed via EGT and via ERP to social stimuli, SRS-2 total, ABC-social withdrawal and repetitive 
behavior subscale scores, and CGI scores for overall functioning, social communication and 


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repetitive behaviors.  We will also compare week 24 scores controlling for baseline on the 
following parent report measures: SRS-2, ABC, and VABS (caregiver report form).   
• 
Determine the Efficacy of COMB vs BEH on supportive measures of ADHD, sluggish cognitive 
tempo and executive functioning:  We will compare the COMB and BEH groups with regard to 
changes between baseline and endpoint assessments (an 10 week duration) in the parent rated 
ADHD-RS, SCT questionnaire, the inattention subscale of the ABC and the CBCL, , and time spent 
moving during the video activity monitoring.  We will examine changes in the BRIEF, ABC and 
parent rated ADHD-RS between baseline and endpoint assessments (an 10 week duration).  
• 
Determine the Efficacy of COMB vs BEH on supportive measures of caregiver strain and 
treatment satisfaction between baseline and endpoint assessments (an 10 week duration).. 
• 
Determine if there is a correlation between reductions in ADHD symptoms measured by the 
ADHD-RS and measures of social communication and executive functioning.  We will initially 
focus on the changes in the VABS adaptive behavior composite standard score, objective 
measures from the PCIT as a function of changes in the ADHD-RS.  We will subsequently 
examine changes across the study period  or the SRS-2 and the BRIEF. 
• 
Determine if there is a correlation between changes in VABS mean Socialization and 
Communication standard scores, JERI ratings of parent child joint attention and coordination 
and fluency of engagement and ADHD-RS scores and changes in neural connectivity, neural 
stability and neural response to social stimuli between weeks 0 and 10 and weeks 0 and 24.  
We hypothesize that each of the following ─ increases in social communication functioning, 
increases in ratings of coordinated joint attention and fluency and coordination of engagement, 
and reductions in ADHD symptoms ─ will be positively correlated with increases in EEG 
coherence and ITPC, and with shorter ERP latency and increased cortical activation (reduced 
alpha and increased theta spectral power) in response to social stimuli.  
 
9.2 
Sample Size Determination 
The power calculation is based on the primary hypothesis that COMB treatment will result in 
improvement in the degree of child joint attention and fluency and coordination of parent child joint 
engagement as measured by the JERI coding rating scale at week 9 that is significantly greater than the 
change seen in the BEH treatment group.  A moderate effect size (ES) of 0.50 is estimated. This estimate 
is based on prior information about the impact of P-ESDM on VABS Adaptive Behavior Composite in 
toddlers at risk for ASD after 12 weeks of active parent coaching(21), the benefits of ESDM on young 
children with ASD(20), and the interfering impact of ADHD on response to social skills interventions in 
older children with ASD + ADHD(16).  Specifically in the study of toddlers at risk for ASD, who would be 
expected to be more likely to show improvement than young children who actually have ASD, the 
improvement in the VABS Adaptive Behavior Composite was less than one point after 12 weeks of P-
ESDM.  In the pivotal study of ESDM in children with ASD who were ~ 2 years old when starting 
intervention, both the intervention and the community control groups showed a reduction in the VABS 
Adaptive Behavior Composite after one year, though the reduction in the ESDM group was about 50% 
that of the control group.  Further by year 2, the ESDM group’s score was reversing whereas the control 
group’s score continued to worsen.  Finally, we expect that ESDM-informed parent coaching will have 
limited impact in children with comorbid ASD + ADHD due to the interference with engagement in 
treatment related to ADHD symptoms. 


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Power estimates were derived empirically via simulation in SAS 9.4.  We modeled the VABS Adaptive 
Behavior Composite for simplicity rather than the mean of the standard scores for the Socialization and 
Communication domain scores.  A mean baseline composite score of 72.0 was assumed for both 
treatment groups (based on data from Chatham et al 2017(62)), with an improvement in control group 
of 2.0 points by week 52. For the active treatment group, an improvement of 4.5 additional points was 
assumed by week 52, for an estimated ES of 0.50. Attrition by week 52 was estimated at 10%, and 
incorporated missing values in the simulated data based on a uniform pattern of 5% missing by week 12, 
5% by week 24, and 10% missing by week 52. In sample size calculations for longitudinal studies, it is 
also necessary to include information about the correlation structure both between patients and within 
patients over time. The variance components were conservatively estimated assuming a total standard 
deviation of 9.0 and a within-individual correlation of 0.75 among repeated ABC Composite scores. After 
generating 1,000 simulated datasets under these assumptions, a longitudinal regression model 
(described in section 9.4 below) was fit to each simulated dataset and assessed the effect of interest 
using two-sided tests with a Type I error rate of 0.05. For a total sample size of 76 and within-individual 
correlation of 0.75, the empirical power estimate is 92.7%. 
 
9.3 
Populations for Analyses 
The Primary Analysis Population will include all randomized participants who have taken at least one 
dose of study medication and have completed at least one post-baseline ADHD-RS assessment.  This is a 
modified intent to treat analysis dataset. 
The Safety Population will include all randomized participants who have taken at least one dose of 
study medication and whose caregiver has provided adverse events information at least one time after 
randomization. 
The Per Protocol Population will include all participants who have continued to take study medication 
throughout the 10 weeks, who have completed 6 of 8 parent coaching sessions and have completed the 
Vineland and ADHD-RS assessments at baseline and remote-followup assessment. 
 
9.4 
Statistical Analyses 
9.4.1 General approach 
We will conduct preliminary checks to identify potential outliers and missing data that will guide the 
choice of models for our formal analyses. We then will address the primary and secondary analyses 
using the general linear model (GLM), which includes linear, logistic, and Poisson regression models, 
which allow random effects models. We will turn then to the other aims, which examine whether 
changes in biomarkers (EGT and EEG) are associated with changes in behavioral functioning. We also will 
examine clinically meaningful and potentially useful subgroupings such as age, gender, and IQ. We plan 
to do extensive exploratory data analysis which includes the use of dimensionality reduction techniques, 
such as factor analysis and principal components analysis, model selection procedures to identify the 
most appropriate covariates to include, and the use of modern clustering methods to try to identify 
homogeneous subgroups that warrant further study of their characteristics. As part of the study design, 
efforts will be made to collect all outcomes on all randomized participants, even when treatment is 
prematurely terminated.   
A final statistical analysis plan will be developed and signed prior to final database lock. 


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9.4.2 Analysis of the primary efficacy endpoint 
JERI ratings  The primary endpoints are the JERI ratings of parent child joint attention and fluency 
and coordination of parent child joint engagement.  They will be analyzed using a similar approach 
to the primary outcome measure.  Tests will be two-sided, and a P value of less than 0.05 will be 
considered to indicate statistical significance, even though we anticipate some correlation between 
the two ratings. 
 
9.4.3 Analysis of the secondary endpoints 
The analyses of the secondary endpoints will be independent of the results of the primary endpoint.   
The mean of the VABS Socialization and Communication Subscale standard scores will be derived from 
the age standardized scores for the Socialization and Communication subscales, calculated from the 
Vineland Manual or, for the caregiver report at 24 weeks after baseline, by Q-data.  The age 
standardized score has a mean of 100 and a standard deviation of 15.  The VABS has predefined rules for 
data imputation such that if there are more than 2 missing values in a subdomain, the subdomain is 
considered invalid, and if there are two or fewer missing values they are converted to scores of 1.  
The VABS standard scores are continuous scales.  In this study, we will examine the co-efficients of 
change over time with repeated measures using time as a continuous variable across the period from 0-
10 weeks).  The minimal clinically important difference in children has been determined to be between 
2.3 and 2.7 by Chatham et al. 2017(62).    
The analyses will compare the COMB group and the BEH group.  The primary analysis will utilize the 
primary analysis group; a sensitivity analysis will utilize the per protocol data set.  Exploratory analyses 
will also consider the effects of age, sex and IQ.   
Longitudinal regression models will be used to examine mean differences in the continuous outcomes 
including the VABS between the two randomized treatment groups at each assessment visit. Each 
regression model includes indicators of time (assessment visit), group assignment, sex and all time-by-
group interaction terms. Residual error terms will be assumed to follow a mean-zero, normal 
distribution with an unstructured covariance structure used to capture the within-person correlation 
over time. The fitted models will be used to report mean scores at each assessment visit and make 
inferences about between-groups comparisons at the final assessment visits (week 24 – in person visit, 
and week 52 – remote assessment- primary). Tests will be two-sided, and a P value of less than 0.05 will 
be considered to indicate statistical significance. The sequential Dunnett test will be used to control the 
overall (familywise) error rate. Longitudinal models will be fit using PROC MIXED in SAS Statistical 
Software, Version 9.4 (SAS Institute, Cary, NC).  
Presentation of results will include p-values and 95% confidence intervals for the least mean square 
values at weeks 0, 10, 24. To enhance interpretation of the results, we will calculate the number needed 
to treat (NNT) using a binary indicator of response. For the continuous outcomes, we will calculate 
standardized between-group mean differences at the week 10, 24 and 52 visits. 
ADHD-RS  Is a continuous measure which consists of the sum of scores on each of 18 questions within 
the scale, ranging between 0 (not at all) and 3 (very often).  The instructions for the measure will be 
adjusted to report on the prior week rather than the prior 6 months as in the initial measure.  Different 
normative values are utilized with boys and girls.  Clinically significant scores in boys are 14 for 


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inattention items (odd numbered items) and 17 for hyperactivity/impulsivity items (even numbered 
items).  Clinically significant thresholds in girls are 12 for inattention items and 14 for 
hyperactivity/impulsivity items.  A supportive exploratory analysis will examine change to a nonclinically 
significant score at 24 weeks after baseline.   
The statistical approach will be similar to that for the primary outcome variable with the exception of a 
categorical presentation of above and below ADHD criteria in the supportive exploratory analyses.  
Specifically, longitudinal regression models will be used to examine mean differences in the continuous 
outcome of ADHD-RS scores between the two randomized treatment groups at each assessment visit. 
Each regression model includes indicators of time (assessment visit), group assignment, sex and all time-
by-group interaction terms. Residual error terms will be assumed to follow a mean-zero, normal 
distribution with an unstructured covariance structure used to capture the within-person correlation 
over time. The fitted models will be used to report mean scores at each assessment visit and make 
inferences about between-groups comparisons at the final assessment visits (visit 16 – in person visit, 
and visit 18 – remote assessment). Tests will be two-sided, and a P value of less than 0.05 will be 
considered to indicate statistical significance. The sequential Dunnett test will be used to control the 
overall (familywise) error rate. Longitudinal models will be fit using PROC MIXED in SAS Statistical 
Software, Version 9.4 (SAS Institute, Cary, NC).  
Presentation of results will include p-values and 95% confidence intervals for the least mean square 
values at baseline, endpoint, and remote follow-up timepoints (visit 6, 10 weeks later at visit 16, and 24 
weeks after baseline at visit 18). To enhance interpretation of the results, we will calculate the number 
needed to treat (NNT) using a binary indicator of response.   
Since ADHD-RS ratings are considered to be independent of the mean of the VABS standard scores for 
the Socialization and Communication domains and we will separately examine the correlation between 
changes in each of these two measures with other more objective measures of social communication 
and attention in Aim 3, we will not correct for multiple comparisons in the analysis of the ADHD-RS.  
Finally, for children who complete the SenseToKnow application, data collected will include: audio and 
video recordings tracking movement, facial expressions, vocalizations, and device information which 
includes accelerometer, gyroscope and tactile response data. 
 
9.4.4 Safety analyses 
We will report the percent of participants who have vital sign abnormalities in the two treatment 
groups. The specific thresholds for reporting are presented in the MOP.  In addition, we will present the 
mean and standard deviation of changes between baseline and endpoint in BMI percentile for age and 
gender, blood pressure percentiles, and absolute values of each laboratory value studied.  
All AE’s will be coded to MedDRA terms by the project staff and physician.   Each AE will be counted 
once only for a given participant. TEAEs will be presented by System Organ Class (SOC) and preferred 
term groupings, severity, proportion of group experiencing the TEAE, and % of each TEAE that was 
judged to be related to treatment.  Adverse events leading to premature discontinuation from the study 
intervention and serious treatment-emergent AEs will be presented as a listing by treatment group.  
 
9.4.5 Baseline descriptive statistics 


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Intervention groups will be compared on baseline characteristics, including demographics, ADOS 
severity scores, cognitive function, adaptive behavior scores, ADHD-RS scores using descriptive statistics 
of mean value, standard deviation and range. Inferential statistics will be used. 
 
9.4.6 Planned interim analyses  
No interim analyses are planned.  
For each DSMB report, we will determine the proportion of participants in the COMB group and in the 
BEH group who withdraw due to adverse events and lack of efficacy.  We will also present a tabulation 
of TEAEs within each of the treatment groups by severity and system organ class.   
 
9.4.7 Sub-group analyses 
We will not conduct any inferential subgroup analyses.  If subgroup analyses are done, they will be 
purely non-inferential and hypotheses generating, given that this is a pilot study with a small sample size 
that is unlikely to have subgroups of sufficient size to draw meaningful conclusions.  
 
9.4.8 Tabulation of individual participant data 
Individual participant data will not be tabulated.  
 
9.4.9 Exploratory analyses 
Overall, exploratory endpoints focusing on supportive behavioral measures of autism symptoms, ADHD 
symptoms, and caregiver perceptions will be analyzed using the above methods for the primary and 
secondary analyses.  
However, relationships between changes in EGT and EEG biomarkers and changes in outcomes will be 
analyzed slightly differently. The general framework for addressing the relationship between changes in 
biomarkers (e.g. EGT, EEG) and changes in outcome (VABS standard scores, ADHD symptoms) in children 
with ASD+ADHD (Aims 3 and 4) also will be the GLM. GLMs handle group comparisons and correlational 
analyses using a common framework while controlling for important sources of heterogeneity in our 
design, such as age, gender, and IQ. The primary variables of interest, EGT variables (e.g., % time gazing 
at actress) and EEG (e.g., amplitudes, latencies, power, coherence and ITPC), will be modeled as a 
function of task condition and treatment group, controlling for relevant covariates. By using 
standardized versions of the measures, we will be able to interpret model coefficients as partial 
correlations. A similar approach will be used to examine relationships between changes in social 
engagement measured via PCIT coding and video activity monitoring, and outcomes.   
These outcomes are primarily descriptive and will not be subject to multiple comparison corrections or 
strict p value criteria to assess significance.  
 
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 


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10.1 Regulatory, Ethical and Study Oversight Considerations 
10.1.1 Informed consent process 
Consent/Assent Provided to Participants.  Consent forms describing in detail the study 
intervention, study procedures, and risks are given to the participant’s caregiver and documentation of 
informed consent is required prior to starting intervention/administering study intervention.  Informed 
assent is not required of the participants due to their developmental status.  The informed consent 
document for the preliminary screening study (A+ Assessment) and this study (A+ Treatment) are 
included in the appendices.  These materials will be provided to the participants’ caregivers when they 
express interest in the study and will be discussed with them as described below.  
Consent Procedures and Documentation: Informed consent is a process that is initiated prior to 
the individual’s agreeing to participate in the study and continues throughout the individual’s study 
participation. Consent forms and consent procedures will be Institutional Review Board (IRB)-approved. 
The participant’s caregiver(s) will be asked to read and review the document with sufficient time 
allowed prior to meeting with study staff.  If the caregiver is still interested in participating or has 
questions that may influence his/her willingness to participate, the study coordinator and/or co-
investigator or one of the study physicians will explain the research study to the participant and answer 
any questions that may arise. A verbal explanation will be provided in terms suited to the caregiver’s 
comprehension of the purposes, procedures, and potential risks of the study and of their and their 
child’s rights as research participants.  A study physician will always be available to potential 
participants’ caregivers to answer any questions. The caregiver will be encouraged to discuss the study 
with their family or their child’s current providers prior to agreeing to participate.  
If the potential participant’s caregivers want the child to participate in the study, the caregiver(s) will 
sign the informed consent document prior to any procedures being done specifically for the study. 
Participants and their caregivers will be informed that participation is voluntary and that they may 
withdraw from the study at any time, without prejudice. A copy of the signed informed consent 
document will be given to the participants for their records.  The informed consent process, including 
the date the documents are signed, will be conducted as per existing Standard Operating Procedures 
(SOPs) and documented in the source documents, before the participant undergoes any study-specific 
procedures.  
 
 
10.1.2 Study discontinuation and closure 
Individual Participant Discontinuation  Please see section 7 for a full description of situations in which 
an individual might discontinue participation in the trial and for reasons why the entire study might be 
stopped.  Briefly, individual participants may discontinue study treatment and/or participation in study 
assessments at any time without providing any reason for doing so.  If participants/participant 
caregivers wish to discontinue participation in study interventions, they will be strongly encouraged to 
continue participation in other aspects of study interventions (e.g. discontinue study medication 
treatment but continue parent coaching) and/or study assessments.  Similarly, if the study physicians 
feel it is in the best interests of the participant to discontinue some aspect of the study treatments or 
study assessments, they will be encouraged to have the participant continue other aspects of the study.  
If a participant is discontinued from the trial, the study team will provide and facilitate referrals to other 
appropriate clinicians for ongoing treatment.  


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Suspension of the entire study  This study may be temporarily suspended or prematurely terminated if 
there is sufficient reasonable cause.  We plan to suspend enrollment of new participants, if the 
proportion of participants withdrawing from one treatment arm is greater than 40% and more than 3x 
that of the other treatment arm, until the DSMB reaches a decision regarding continuation of the study.   
In addition, the study might be interrupted or prematurely terminated in the following situations or 
other as yet unanticipated situations.   
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Withdrawal of financial support of the trial 
• 
Determination that a sufficient sample can’t be recruited.  
If the concerns leading to study interruption can be satisfactorily addressed, the study may resume with 
the consent of the sponsor, IRB and/or Food and Drug Administration (FDA).] 
Written notification, documenting the reason for study suspension or termination, will be provided by 
the suspending or terminating party to the investigator and, if applicable, funding agency or DSMB.  
Subsequently, the study PI will provide written notification documenting the reason for study 
suspension or termination to the study participants, funding agency or DSMB as applicable, FDA, drug 
manufacturer and IRB.  If possible and if there are not safety concerns, the active participants in the 
study will complete their participation.  Study participants will have the opportunity to contact the PI 
and other study staff to further discuss the decision to suspend the trial if they wish.  
 
10.1.3 Confidentiality and privacy  
Participant confidentiality and privacy is strictly held in trust by the study team, the sponsor and 
regulatory authorities.  Confidentiality is extended to cover testing of biological samples in addition to 
the clinical information relating to participants.  All research activities will be conducted in as private a 
setting as possible. 
In this study, a strict separation will be maintained between information that contains information that 
is personally identifiable (such as the study consent form and information used to obtain a GUID) and 
the data that will be analyzed from the study.  In all data, participants will be identified by a unique 
subject ID.  Some derived data required in this study requires information about the participant’s age 
(birthdate) and gender but will not be linked to other potentially identifying information such as initials 
or address.  All data will be housed in secure locations, that are double password protected. 
The study monitor, other authorized representatives of Duke University and/or the National Institute of 
Child Health and Human Development (study sponsor), representatives of the Institutional Review 
Board (IRB), FDA or pharmaceutical company supplying study product may inspect all documents and 
records required to be maintained by the investigator, including but not limited to, study source 
documents, medical records and pharmacy records for the participants in this study.  
The study participant’s contact information will be securely stored at the site for internal use during the 
study and until the final results of the study have been shared with the participants and/or their 
caregivers.  At the end of the study, all records will continue to be kept in a secure location for as long a 
period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements.  


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In this study, data identified only by the participant’s globally unique identifier (GUID) will be uploaded 
into the National Database for Autism Research (NDAR) to facilitate additional analyses and discoveries 
to improve the understanding and care of individuals with ASD.   
Mobile devices will be used to deliver/use the applications developed for this study. The mobile devices 
(SenseToKnow app) assigned to each study for use during the visits are Duke-owned. Participant data 
will be stored on the study device(s), which will be handled by trained study staff. 
Data that is collected by the SenseToKnow app will be stored locally on the devices until data is securely 
moved to Fileshare. PHI stored on the device will be automatically erased immediately after data 
transfer to the secure database is completed by a trained staff member. 
The devices will be hardened according to guidelines from the Office of IT Security. For additional 
security we will add a user password to this application so that no one other than those that were given 
the password set on the device can have access to this data through the device itself. 
Security for the mobile device-based application will be taken care of by using 'iOS Keychain' security 
features. This will enable the storage of video and test data on device in a space that only the 
application has access to. No other application will be able to access this data including the camera roll 
or video viewer. Video and test files will be saved in the application directory and not with the rest of 
the multimedia. For device offloading, all the data saved will be encrypted so that only agents with the 
correct decryption will be able to view the test data and videos located in the folder after downloading 
the encrypted files. Data will be transferred every night when the mobile device is charging to a local 
Duke server using native iOS SSL features, which will enable us to securely transfer files over the internet 
and data will be deleted once uploaded to the Duke server. 
To further protect the privacy of study participants, a Certificate of Confidentiality will be issued by the 
National Institutes of Health (NIH).  This certificate protects identifiable research information from 
forced disclosure. It allows the investigator and others who have access to research records to refuse to 
disclose identifying information on research participation in any civil, criminal, administrative, legislative, 
or other proceeding, whether at the federal, state, or local level. By protecting researchers and 
institutions from being compelled to disclose information that would identify research participants, 
Certificates of Confidentiality help achieve the research objectives and promote participation in studies 
by helping assure confidentiality and privacy to participants. 
 
10.1.4 Future use of stored specimens and data  
We do not plan to collect any specimens that will used in the future.  The data collected in this study will 
be transferred to NDAR as described above, but will not be able to linked to a specific individual.  
 
10.1.1 Safety oversight 
There will be a medical monitor and DSMB to oversee the safety of participants in the study as described 
in section 8.5.  All of these individuals are independent of Duke University and of the study.  In addition, 
the study will be reviewed annually and more often if needed by the IRB and the FDA.   
 
10.1.2 Key roles and study governance 
Principal Investigator 
Medical Monitor 
Center  PI 
Center Co-PI 


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10.1.3 
Clinical monitoring 
The Duke ACE center Data Management and Analysis Core (DMAC) will undertake monitoring of this 
study using multiple procedures.  First, data that is directly entered into the database will be checked for 
completeness by study staff during the in person visit related to the caregiver report.  If items are left 
blank or are inconsistent the caregiver will be asked to clarify and complete the items in question.  
Caregivers will be urged not to leave any questions unanswered.   
Data generated by study staff on paper forms will be double data entered.  The DMAC will identify any 
inconsistencies in the doubly entered data points and a third person will resolve discrepancies and/or 
contact the appropriate study staff to clarify the data.   
The Duke ACE Center DMAC will implement many data validation rules ((e.g., blank but required entries, 
out-of-range values, and skip patterns), that will be enforced by the EDC system during data entry. 
Other, more complex error conditions will be checked using custom error-check programs. 
Inconsistencies in data patterns across forms will be used to identify complex errors or confirm validity 
of data. For example, values on the spontaneous language item on the ADI-R are compared to ADOS-2 
module to ensure validity of measures employed with each subject. The DMAC will continually monitor 
data quality as data are entered using a module named the Data Anomaly Detection and Resolution 
Module (DAD-RM), which we have successfully deployed in other studies. The DAD-RM system 
integrates built-in EDC data validity rules with external rules of arbitrary complexity to produce a 
database of potential data problems ("logical queries") that must be resolved by study staff and 
approved and documented by the DMAC. Using the DAD-RM system, project coordinators and the 
DMAC will be able to review all data query records via the Portal website. Each record must be 
annotated and marked as either resolved by data update, approved as an extreme value, or 
unrecoverable. The DAD-RM error checks and database update will be run daily, providing studies the 
opportunity to address data issues early when the probability of resolution is highest. We will resolve 
individual and recurring problems with the data entry system during DMAC weekly staff meetings. These 
meetings will be used to discuss and resolve issues and answer operational concerns, such as data entry 
questions, use of technologies, and EDC. Dr. Compton will manage the data resolution process and host 
training sessions as needed. Procedures regarding QC will be performed to address inconsistencies that 
emerge following data validation processes and work with study staff to address data quality issues and 
to refine the data collection and reporting process.  
Dr. Lauren Franz,  MBChB, 
MPH 
Laura Politte, MD 
Geraldine Dawson, PhD 
Scott Kollins, PhD 
Duke University 
School of Medicine 
Wake Med 
Duke University 
School of Medicine 
Duke University 
School of Medicine 
2608 Erwin Rd, suite 300 
Durham, NC 27705 
 
2608 Erwin Rd, suite 300 
Durham, NC 27705 
2608 Erwin Rd, suite 
300 
Durham, NC 27705 
Office: 919 681-0023 
617-710-5701 
919 668 0070 
919 681 0014 
lauren.franz@duke.edu 
 
lpolitte@gmail.com 
 
Geraldine.dawson@duke.edu 
Scott.kollins@duke.edu 


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In addition, the Duke ACE Center Regulatory Coordinator will conduct periodic audits during the course 
of the trial.  During these audits, she will monitor all regulatory documents, documentation of protocol 
deviations and violations, and correlations between randomly chosen source documents and the data 
base.  
 
10.1.4 Quality assurance and quality control 
All entered data will be subject to Quality Assurance (QA) Measures.  QA processes will be overseen by 
the Administrative Core, in collaboration with Dr. Dawson.  All study staff will be trained on center-wide 
Standard Operating Procedures (SOPs), approving and tracking SOP deviations, Good Clinical Practice 
(GCP) and human subjects research training. The Data Management and Analysis Core will provide the 
Administrative Core with information regarding timeliness of data submission from the study, protocol 
deviations and missing data, and NDAR submissions. This information will help identify areas of 
deficiency, aspects of GCP that need reinforcement, or additional training that may be required. If these 
steps do not correct deficits or GCP concerns, steps may be taken to discipline, relocate, or replace a 
staff member or modify study procedures.  The Administrative Core staff will work closely with the 
DMAC, which will oversee consistent application of scientific standards and methodological rigor for 
data collection, processing, entry, cleaning, and analytics. The DMAC will be responsible for study 
specific QC for all behavioral, questionnaire, EEG, EGT, and biosample data. This will be accomplished by 
the development of well-defined procedures, intensive training of staff, and Manual of Procedures 
(MOPs) with detailed instructions for procedures involved in data acquisition, processing, and upload to 
the Data Management and Analysis Core. Fidelity to research procedures will be accomplished by the 
development of well-defined protocols, intensive reliability training, regular in-person meetings to avoid 
drift, and internal audits. Protocol-specific training will be based on the delegated role of investigators 
and staff as defined in delegation of responsibility logs.  
 
10.1.5 Data handling and record keeping  
Data Collection and Management Responsibilities. Data collection is the responsibility of the clinical 
trial staff at the site under the supervision of the project lead, Dr. Dawson.  Dr. Dawson is responsible for 
ensuring the accuracy, completeness, legibility, and timeliness of the data reported. 
Hardcopies of the study visit worksheets will be used as source document worksheets for recording data 
obtained by study staff for each participant enrolled in the study.  Data recorded in the electronic case 
report form (eCRF) derived from source documents should be consistent with the data recorded on the 
source documents.  
Clinical data (including adverse events (AEs), concomitant medications, and expected adverse reactions 
data) and clinical laboratory data will be entered into the redcap database designed and provided by the 
Duke ACE Center DMAC, a 21 CFR Part 11-compliant data capture system.   The data system includes 
password protection and internal quality checks, such as automatic range checks, to identify data that 
appear inconsistent, incomplete, or inaccurate. Clinical data will be double entered directly from the 
source documents.   
The participants’ caregivers will receive emails from the study team/DMAC notifying them when they 
should complete rating scales online via RedCAP or Q-global.  If a caregiver does not wish to utilize the 
electronic rating scales, study staff will either complete the rating scale with them over the phone or 
provide them with a paper copy of the rating scale to complete.  


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At each assessment point, the study staff will document whether any assessments were not completed 
and the reason for noncompletion. 
The Duke Autism Center DMAC will provide Dr. Dawson with a listing of expected but not entered data 
at least monthly.  
Study Records Retention:  All records will be retained for at least 2 years following publication of the 
final manuscript related to the study or for at least 3 years after submission of the study’s Federal 
Financial Report submission.   
 
10.1.6 Protocol deviations  
A protocol deviation is any noncompliance with the clinical trial protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP), or Manual of Procedures (MOP) requirements. The 
noncompliance may be either on the part of the participant, the investigator, or the study site staff. As a 
result of deviations, corrective actions are to be developed by the site and implemented promptly.  
These practices are consistent with ICH GCP:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
The study staff will record any deviations as they happen and/or as they become aware of the deviation.  
Such deviations will include assessments occurring outside the allowed windows, failure to complete 
scheduled assessments, study medication dosing that is not consistent with the protocol, and issues 
with documenting consent.  Study staff will also document the reason(s) for the deviation and the 
corrective actions that will be put into place to prevent future deviations.  In addition, the DMAC will 
provide a listing of all study visits that occur outside of specified study windows, any medication doses 
that are outside the allowed range (0 tablets to 6 tablets), and any increases in study medication that 
are made prior to the prescribed schedule (eg. within less than 14 days of the most recent dose increase 
unless there has been an interruption in dosing or a dose decrease due to concerns about a TEAE).  All 
protocol deviations during the prior year will be reported to the IRB in the annual report.   
Protocol violations will consist of inclusion of ineligible participants, medication dispensing errors (eg. 
the wrong study treatment), and unblinding of participants or blinded study staff.   Protocol violations 
will be reported to Dr. Dawson, the DMAC and the Duke Center for Autism Administrative Core within 
14 days of becoming aware of the event.  Subsequently, procedures must be put into place as soon as 
possible and within an additional 14 days to prevent similar events in the future.  The IRB and DSMB will 
be notified of all protocol deviations at the time of the next scheduled report or sooner if there are 
safety concerns associated with the deviation.   
 
10.1.7 Publication and data sharing policy 
Every effort will be made to publish the results of this study in a peer reviewed journal as soon as 
possible after completion of the study.  Authorship of resulting papers will be as inclusive as possible.  If 
there are confilicts about authorship, the Duke ACE Center Executive committee will resolve the 
conflicts in accordance with the center’s publication policies.   


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National Institutes of Health (NIH) Public Access Policy, which ensures that the public has access to the 
published results of NIH funded research. It requires scientists to submit final peer-reviewed journal 
manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for 
publication. 
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded 
Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. As 
such, this trial will be registered at ClinicalTrials.gov, and results information from this trial will be 
submitted to ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-
reviewed journals.  Data from this study may be requested by other researchers 3 years after the 
completion of the primary endpoint by contacting Dr. Dawson or the Duke Center of Autism.  Further, all 
data will be uploaded into the National Database for Autism Research (NDAR) for use by other 
investigators according to the specific agreement between NDAR and the Duke ACE Center.   
Genomic data will not be generated by this study.  
 
10.1.8 Conflict of interest policy 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical.  Therefore, any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a 
way that is appropriate to their participation in the design and conduct of this trial.  The Duke ACE 
Center Administrative Core, in conjunction with the NICHD and Duke University School of Medicine, has 
established policies and procedures for all study group members to disclose all conflicts of interest and 
will establish a mechanism for the management of all reported dualities of interest. 
 
10.2 Abbreviations 
The list below includes abbreviations utilized in this protocol.  
 
ABC 
Aberrant Behavior Checklist 
ACE 
Autism Center of Excellence 
ADHD 
Attention Deficit Hyperactivity Disorder 
ADHD-RS 
Preschool Attention Deficit Hyperactivity Disorder Rating Scale 
ADI-R 
Autism Diagnostic Interview - Revised 
ADOS 
Autism Diagnostic Observation Schedule 
AE 
Adverse Event 
ASD 
Autism Spectrum Disorder 
BRIEF 
Behavior Rating Inventory of Executive Function 
CBCL 
Child Behavior Checklist 
CFR 
Code of Federal Regulations 
CGI 
Clinical Global Impressions Scale 
CMP 
Clinical Monitoring Plan 
COC 
Certificate of Confidentiality 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
CSHQ 
Children’s Sleep Habits Questionnaire 
CSQ 
Caregiver Strain Questionnaire 


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DAS 
Differential Abilities Scale 
DMAC 
Data Management and Analysis Core  
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
EEG 
Electroencephalogram 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
ICH 
International Conference on Harmonisation 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
IRS 
Impairment Rating Scale 
ITT 
Intention-To-Treat 
JERI 
Joint Engagement Rating Inventory 
LSMEANS 
Least-squares Means 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
NICHD  
National Institutes of Child Health & Human Development 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SCT 
Sluggish Cognitive Tempo Questionnaire 
SOA 
Schedule of Activities 
SOP 
Standard Operating Procedure 
SRS-2 
Social Responsiveness Scale – 2nd edition 
TEAE 
Treatment Emergent Adverse Event 
UP 
Unanticipated Problem 
US 
United States 
VABS 
Vineland Adaptive Behavior Scales – 3rd edition 
 


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10.3 PROTOCOL AMENDMENT HISTORY 
The table below is intended to capture changes of IRB-approved versions of the protocol, including a 
description of the change and rationale. A copy of Summary of Changes table for the current amendment 
follows the Protocol Title Page.  
Version/Date 
Change 
Brief Rationale 
1.1/Aug. 30, 2018 • Added Specific Aims section 
 
• Changed the primary outcome measure to the 
mean 
of 
the 
VABS 
socialization 
and 
communication subscale standard scores 
• Changed key secondary outcomes to include 
JERI ratings coordinated joint attention and 
fluency and coordination of engagement.  
• Eliminated the week 10 EEG measures. 
• Changed timing and length of P-ESDM 
curriculum assessment and coaching sessions.  
 
• Added Sluggish Cognitive Tempo questionnaire 
weeks 0, 10,24,& 52. 
• Removed ASSIST/READY; added Sense to 
Know 
• Changed exclusion criteria, Leiter guidelines & 
deleted post baseline Leiters, & added home 
videos, childhood behavior inventory, sensory 
experiences questionnaire preschool executive 
function battery,& to week 0 
• Changed FDA reporting to reflect IND 
exemption; provided more detail about safety 
reporting, documentation of TEAEs, and drug 
accountability procedures 
• Updated references & corrected clerical errors 
• Increase concordance between grant 
and protocol. 
• Changed to reflect specific functional 
areas targeted by P-ESDM. 
 
• Increased sensitivity vs duration coding 
& alignment across ACE centers.  
 
• Reduce burden & cost. 
• Prevent 
overlap 
with 
week 
10 
assessments, reduce burden & assess 
parent fidelity.  
• Advisory 
board 
suggested 
given 
potential overlap with ASD & ADHD 
• Unable to work out contract 
• To standardize week 0 assessments 
with 
A+ 
Development 
facilitate 
centerwide comparisons. 
 
• Revisions necessary as obtained new 
regulatory information & developed 
database & drug blinding procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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11 APPENDIX 1: CONMED SHEET WITH WASHOUT INSTRUCTIONS 
 
A+ STUDY CONCOMITANT MEDICATIONS 
Medication 
A+ Treatment 
A+ Development Only 
Clonidine  
(Kapvay, Catapres) 
Allowed 
Prohibited unless only taking at 
night for sleep. (May wean down to 
night-time use only in order to 
participate.) 
Guanfacine  
(Intuniv (XR), Tenex (IR)) 
 
 
 
Allowed 
 
Washout for 24 hours 
Aripiprazole 
(Abilify) 
Allowed 
Allowed 
Atomoxetine  
(Stratterra) 
Up to 3 weeks 
(10-14 days to 
wean off high 
doses, followed 
by 1 week to 
see if tolerable 
if not can 
continue.) 
 
PI/clinician judgement on a case by 
case basis. 
Amphetamine  
(Adzenys ER, Adzenys XR-ODT, Dynavel XR, Mydayis) 
Washout 1 
week for 
immediate 
release (IR). 
Washout for 24 hours. 
Dexmethylphenidate 
 (Focalin IR & LA) 
Dextroamphetamine/amphetamine salt  
(Adderall IR & XR) 
Dextroamphetamine, damphetamine  
(Dexedrine, Dextrosta, Procentrat, Zenzedi) 
Lisdexamphetamine  
(Vyvanse) 
Methylphenidate  
(Aptensio XR, Concerta, Cotempla XR-ODT, Daytrana, Desoxyn, 
Metadate, Methylin, Quillichew, Quillivant, Ritalin, Ritalin LA) 


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Pemoline  
(Cylert) 
Risperidone 
(Risperdal) 
Allowed 
Allowed 
 
 
The following medications will be assessed on a case by case basis: Wellbutrin (bupropion), Effexor (venlaflaxine), 
Desipramine, Amitriptyline, Nortriptyline, Amantadine (Symmetrel), Memantine (Namenda),  
MAO-I’s require 14 day washout prior to A+ Treatment Baseline: Isocarboxazid (Marplan), Phenelzine (Nardil), 
Selegiline (Emsam), Tranylcypromine (Parnate)  


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ICF_001.pdf: 
 
 
Informed Consent Form Cover Page for ClinicalTrials.Gov Record 
 
 
 
Official Study Title:    Impact of combined medication and behavioral treatment in young 
children with comorbid ASD and ADHD 
NCT #:     NCT03242772 
Duke University Health System (DUHS) Protocol #: Pro00085179 
Document Version Date (DUHS IRB Reference Date of Consent Form): 24-APR-2021 
Document Name/Consent Type: Minor Main Study consent 


Consent to Participate in a Research Study
A+ Treatment
Duke Center for Autism Research Program
Page 1 of 19
Parent/Guardian*Initials_________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
Concise Summary
The purpose of this research study (A+ Treatment) is to determine whether a combined therapy (an 
investigational stimulant drug and a behavioral intervention based on parent coaching designed for 
children with Autism Spectrum Disorder (ASD) can improve behavioral and developmental 
functioning of children with Attention Deficit Hyperactivity Disorder (ADHD) and ASD more than a 
placebo and the same behavioral intervention for ASD. The parent coaching intervention is based on 
a model called “Early Start Denver Model” (ESDM) which involves strategies that can be used during 
daily activities to promote social interaction, language, and behavioral regulation (e.g. reduce 
tantrums).  Participants will first complete screening and a behavioral assessment that includes a 
blood draw, physical exam, collection of medical and behavioral information, questionnaires, and 
activities measuring attention, brain activity, and social interaction. 
If eligible for the study, children will be assigned by a computer (that doesn’t consider any personal 
information about them) to receive either the investigational medication or placebo, both which are in 
tablet form, dissolve in the mouth, and are called “study drug” in the rest of this form. The entire study 
is about 3 months with an optional follow-up remote questionnaire assessment. After receiving a 
diagnostic and cognitive assessment and medical/behavioral assessment visit (about 3 weeks), for 
the next 8 weeks, your child will receive either behavioral intervention plus the medication or 
behavioral intervention plus placebo. During the 10 weeks of treatment, your doctor will adjust your 
child’s medication if needed and regularly assess any side effects.  The behavioral intervention will 
be weekly 1-hour sessions of ESDM-based parent coaching. A week after completing the behavioral 
intervention, your child will participate in another behavioral assessment, described in more detail 
below. There are optional follow-up parent questionnaires that can be completed remotely at 24 
weeks. 
Possible risks include potential side effects from the active drug including common side effects such 
as loss of appetite, trouble sleeping, stomach pain, nausea, vomiting, nervousness and fever and 
very rare side effects including fast or irregular heartbeat, prolonged erections, seizures or 
hallucinations. 
Potential benefits: Your child may benefit by receiving diagnostic and cognitive evaluations that are 
conducted as part of this study. Your family could also benefit from the ESDM-based parent 
coaching. The study drug may or may not reduce some of your child’s ADHD symptoms. It is more 
likely that the active study drug will reduce ADHD symptoms than the placebo study drug.  
If you are interested in learning more about this study, please continue to read below.
INTRODUCTION
You and your child are being asked to take part in this research study because your child is 
enrolled in the Duke Autism Center of Excellence (“Duke ACE Center”) research program and 
you have expressed interest participating in the A+ Treatment study for children with ASD and 
ADHD.
DUHS IRB
IRB NUMBER: Pro00085179
IRB REFERENCE DATE: 04/24/2021
IRB EXPIRATION DATE: 04/04/2022


Consent to Participate in a Research Study
A+ Treatment
Duke Center for Autism Research Program
Page 2 of 19
Parent/Guardian*Initials_________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
Please read this consent form carefully and take your time making a decision. The nature of 
the study, including the risks and benefits, are explained below. Please ask the staff member 
who provided this consent form to explain any words or information that you do not clearly 
understand.  
Participation in a research study is always completely voluntary. If you do agree to have your 
child participate, you can change your mind and may withdraw your child from the study at any 
time. Any services that your child receives through a Duke University-affiliated (or non-Duke 
affiliated) clinic or primary care provider will not be affected by your decision about your child’s 
participation in this study. We encourage you to talk with your family and friends before you 
and your child decide to take part in this research study. Please tell the study doctor or study 
staff if your child is taking part in another research study.
This part of the Duke ACE Center program is called the “A+ Treatment Study” and it is 
overseen by Dr. Lauren Franz, the study’s Principal Investigator, and Dr. Tara Chandrasekhar, 
the study’s physician. The A+ Treatment Project and the Duke ACE Center are sponsored by a 
grant from the National Institutes of Health (NIH). Portions of Dr. Franz’s and Dr. 
Chandrasekhar’s and their research team’s salaries are by this grant.
WHO WILL BE MY CHILD’S DOCTOR ON THIS STUDY?
If you and your child decide to participate, Dr. Franz, Dr. Chandrasekhar, or one of the other 
study doctors will be your child’s study doctor and may be in contact with your child’s regular 
health care provider (if you choose) throughout the time that you and your child are in the 
study and afterwards, if needed.
WHY IS THIS STUDY BEING DONE?
Approximately half of children with ASD also have ADHD. We are studying whether the 
combination of parent-coaching behavioral intervention and a stimulant drug that helps 
children focus (Adzenys®XR-ODT) can improve ASD and ADHD symptoms for young children 
with both ADHD and ASD more than behavioral intervention alone. 
Adzenys®XR-ODT has been approved by the U.S. Food and Drug Administration (FDA) to 
help children with ADHD alone in patients ages 6 and above. It has not yet been studied in 
children younger than 6 years old. The Adzenys®XR-ODT is identical to another stimulant 
drug, Adderall, which has been approved by the FDA for children without specifying age and 
has been used for many years. The goal of this study is to help doctors in the future better 
treat children with both ASD and ADHD.
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY?
Approximately 48 children and their parent(s) will take part in this study at Duke. 
DUHS IRB
IRB NUMBER: Pro00085179
IRB REFERENCE DATE: 04/24/2021
IRB EXPIRATION DATE: 04/04/2022


Consent to Participate in a Research Study
A+ Treatment
Duke Center for Autism Research Program
Page 3 of 19
Parent/Guardian*Initials_________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
WHAT IS INVOLVED IN THE STUDY?
If you agree for you and your child to be in this study, you will be asked to sign and date this 
consent form.
The Duke A+ Treatment study will evaluate your child’s health, social and language abilities, 
brain activity, and how they interact with you and play. There will be 12 in-person visits to our 
clinic. The visits and study activities are described below. At 24 weeks, you will have the option 
to fill out some questionnaires about your child’s behavior remotely (you do not need to come 
to the university). 
Visits will include diagnostic and cognitive assessments to determine preliminary eligibility for 
A+ Treatment as well as a health screener to see if you and your child can participate in our 
study. The health screener will be its own separate visit outlined below.
Health Screener
You and your child will be asked to come to the clinic and a doctor will decide if your child is 
eligible for the treatment part of the study. This visit will take around 4-6 hours. 
o
The doctor will collect some medical and behavioral information about your family and 
your child and problems your child may be having. 
o
We will measure your child’s heart rate, blood pressure, weight, height and temperature. 
o
We will measure the electrical activity in your child's heart to make sure your child's 
heart is healthy. This test is called an Electrocardiography (ECG) and it will record the 
electrical activity of your child’s heart through small electrode patches that a research 
staff member will attach to the skin of his/her chest, arms, and/or legs.
After this visit and the cognitive and diagnostic assessments, if the study doctor decides that 
your child can be in the study and you wish to participate; you and your child will be enrolled 
into the study. 
Visits 4 - 12
At the next visit your child will be assigned by a computer that does not consider any personal 
information about your child to receive either placebo or Adzenys®XR-ODT (extended release 
orally-disintegrated tablet) for 10 weeks. A placebo is an inactive substance given in the same 
form as the active study drug. The placebo tablet will look and taste exactly the same as the 
active medication. These tablets are placed on your child's tongue and will melt within 1-2 
minutes. Slightly more kids will be assigned to receive the study drug with the active 
medication than with the placebo. Your child will have approximately a 54% chance of 
receiving the study drug. Neither you nor the study doctor will know what your child receives. 
However, in the event of an emergency, your child’s study doctor will have the ability to find out 
which group your child is in if he/she feels that knowing that information will affect your child’s 
care during the emergency. In the rest of this consent form both placebo and active study drug 
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(Adzenys®XR-ODT) will be called the “study drug”. Once the study drug treatment period is 
complete, one of our unblinded study team members will contact you to tell you if your child 
was on the medication or placebo so you can better make decisions about continuation of care 
for your child.
Approximately 2 weeks later, you will begin 8 weekly 1- hour sessions of ESDM Informed 
Parent Coaching.  During these visits, the doctor and research staff will meet with you to 
monitor the drug and any side effects.  A week (Visit 12) after completing the ESDM Informed 
Parent Coaching sessions, your child will be assessed again using the same assessments that 
were completed at baseline, including collection of medical and behavioral information, 
questionnaires, and activities measuring attention, brain activity, and social interaction. 
Study Drug Monitoring
During the first several weeks after receiving medication, the study doctor will start at a low 
dose of study drug (Adzenys®XR-ODT or placebo-ODT) and slowly increase the dose until the 
best dose is reached for your child. You and your child will be coming to the clinic or receiving 
phone calls and/or emails by the study doctor and/or study staff to make sure your child is not 
having any problems with the study drug during this time. If you or your child feels the study 
drug is causing problems or is not helpful at any time, you are not obligated to continue to take 
the study drug.  You and your child also have the option of continuing the behavioral 
intervention and assessment visits, even though you stop the study medication. Or you and 
your child can stop the study completely.
To monitor how your child is doing on the study drug, the following things will occur:

The research staff will monitor your child’s heart rate, blood pressure, height and 
weight.

The study doctor and or study staff will ask you and your child about any possible 
benefits or bad effects or other problems that your child may have experienced while 
taking the drug.

The study doctor will perform a physical exam to identify any potential side effects from 
the study medication.

You will be asked to rate your child’s attention in a number of different areas to help the 
study doctor determine the potential benefits of the study medication.
Then the study doctor will talk to you about options related to your child’s dose of the study 
drug, trying to find the dose that results in the most improvement of ADHD symptoms and the 
fewest side effects. We hope that we will be able to identify the best dose of study medication 
2-3 weeks after dispensing the study drug..
Parent-Delivered Early Start Denver Model (P-ESDM) – Informed Coaching
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A therapist trained in parent coaching of ESDM will meet with you and your child 8 times, once 
a week, for about 60 minutes to coach you in the use of strategies to promote social and 
language abilities and behavioral regulation (e.g. reduce tantrums).  Another family member 
may also attend these sessions, but it is important that you come to each therapy visit. This is 
to ensure that you learn how all the different ESDM Informed Parent Coaching strategies work 
together and so that the therapist and you can work together to learn which strategies work 
best for you and to try to make strategies that are more challenging easier to use. 
ESDM Informed Parent Coaching is a therapy developed from an evidence-based form of 
behavioral therapy called ESDM that uses principles of Applied Behavior Analysis (ABA) to 
promote language, social interaction, and behavioral regulation. During each coaching 
session, the therapist will check in with how things are going with your child, briefly talk about 
the strategies to be learned and practiced during that coaching session, and then give you 
feedback as you work with your child trying the strategy and other techniques. Finally, towards 
the end of the appointment, you and the therapist will talk about specific things to try during the 
next week. 
Assessment Visits
You and your child will complete several questionnaires and activities to help us understand 
how your child is progressing in paying attention to things going on around him/her, social and 
language skills, and behavior. These physician visits will take around 3-4 hours. These 
activities are described below. They will be repeated 1 week after completing 8 weeks of 
ESDM Informed Parent Coaching. It is important that you, not some other caretaker, complete 
these forms and come to these visits so that we can see and measure the changes in your 
child over time as accurately as possible. 

Questionnaires and Interviews
o
Prior to starting treatment and after completing behavioral therapy, you will be 
asked to complete a set of questionnaires (sent electronically or completed in 
person), which include questions about your child’s social skills, language, 
emotional expression, interests, and other behaviors, such as sleep habits.  
Some of these will also ask how you and your child are feeling and doing, and 
about your experiences in the study.  
o
There will also be parent interviews where we will ask you about the behaviors 
that you observe your child doing regularly in your home where we can’t observe 
your child ourselves.

Assessment of social interaction, communication, and attention 
o
Your child will participate in activities that involve playing with toys and observing 
how he/she responds to the examiner. Some of these activities will be audio- and 
video-taped so we can be sure each examiner is interacting in the same way as 
the other examiners.
DUHS IRB
IRB NUMBER: Pro00085179
IRB REFERENCE DATE: 04/24/2021
IRB EXPIRATION DATE: 04/04/2022


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
Other assessments of social interaction and communication. We will audio- and 
video-tape most of these interactions so we can go back and count how often specific 
behaviors occur to get more precise measurements that might show change over time
o
We will observe and videotape how your child naturally plays with you and a 
specific set of toys.
o
We will measure how you and your child moves about in the room using a video 
tracking camera, called EthoVision® XT.
o
We will measure where your child is looking while he/she is watching movies 
shown on a special computer monitor. The camera that records where your child 
is looking is called Tobii TX300.
o
You and your child may view a set of short engaging videos on an iPhone or 
tablet, and the camera on the iPhone or tablet will record your child’s facial 
expressions and responses to the videos.

Brain activity
o
Before treatment begins and one week after completing behavioral intervention, , 
we will measure your child’s brain activity using EEG recordings to see if and 
how your child’s brain activity changes when watching either pictures of faces or 
pictures of objects. A net made of a set of wet sponges will be placed on your 
child’s head while your child watches a TV screen that will show short videos with 
pictures and sounds, each video lasting about 5 minutes with breaks between 
each video.
At 24 weeks, you will have the option of completing additional questionnaires about your 
child’s behavior remotely either through a phone call or e-mail (at home).
The study doctor may determine that additional visits, procedures or tests are clinically 
necessary even though they are not specifically listed as part of the study in order to be sure 
your child is receiving the best possible medical care. You can refuse the study doctor’s 
recommendations for these things, but refusal may affect you and your child’s participation in 
the study and could result in you and your child being taken out of the study. 
Future Contact
If you enroll your child in the Duke ACE program you may receive the following information 
occasionally:

Information cards via email (or mail, with pre-stamped envelope) to inform us of any 
changes in your contact information (address, e-mail address, and/or phone number),

Newsletters to update you on ongoing activities of the Duke ACE Center,

Holiday and birthday cards,

Invitations to special community events hosted by the Center (such as sports clinics and 
artwork contests),
DUHS IRB
IRB NUMBER: Pro00085179
IRB REFERENCE DATE: 04/24/2021
IRB EXPIRATION DATE: 04/04/2022


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
Information about other research-related opportunities, including the Registry for Autism 
Research.
Contact with the A+ Treatment Study Team
The study will use email (acetreatment@duke.edu) to communicate with you about visit 
scheduling and follow-ups as needed. Because using your personal e-mail does not provide a 
completely secure and confidential means of communication, please do not use it if you wish 
to keep your communication private.  Instead, let us know and we will communicate with you 
only through the telephone or Duke MyChart. You may also call the study physician, Dr. Tara 
Chandrasekhar at (919)-627-1652.
Video and Audio Recording Activities
Audio and video recordings of assessments of you and your child (e.g., in behavioral, play-
based activities, or interviews conducted with you and/or your child) will be used for data 
analysis, and quality monitoring.
If you agree, these videotapes may also be used for training and/or educational purposes. 
Please indicate your choice by writing your initials next to your selection below (this will not 
affect the participation of you and your child in the study).
_____ Yes, I agree to allow my and my child’s videotaped session to be used for training 
purposes.
_____ Yes, I agree to allow my and my child’s videotaped session to be used for educational 
purposes.
OR
_____ No, I do not agree to allow my and my child’s videotaped session to be used for training 
and/or educational purposes.
HOW LONG WILL I BE IN THIS STUDY?
Total participation is expected to require 12 weeks plus an optional remote visit with 
questionnaires at 24 weeks. 
WHAT ARE THE RISKS OF THE STUDY?
Risks of Active Study Drug
As a result of your participation in this study, your child may be at risk for the following side-
effects from the active study drug. You should discuss these with the study doctor and, if you 
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want, with your child’s regular health care provider. Adzenys®XR-ODT may cause some, all or 
none of the side-effects listed below.
More common  

Loss of appetite

Trouble sleeping

Weight loss

Abdominal pain

Nausea

Vomiting

Nervousness

Fever
Less Likely 

Irregular heartbeat

Other heart-related problems like high blood pressure

Seizures

Hair loss

Blurred vision

Tics

Hallucinations

Prolonged erections
Controlled Drug
A. Adzenys®XR-ODT is under Schedule II in the FDA’s list of controlled substances. This 
means that:The drug or other substances have a high potential for abuse
B. The drug or other substances have currently accepted medical use in treatment in the 
United States, or currently accepted medical use with severe restrictions
C. Abuse of the drug or other substances may lead to severe psychological or physical 
dependence
Therefore, for you and your child’s safety we ask that under no circumstances that this drug be 
given to anyone else, including yourself. We will be closely monitoring the number of tablets 
we give you for your child at each visit and the number of tablets returned to our clinic at each 
medication visit, to be sure your child is taking the medication as directed. If you have any 
issues over the course of the study, please do not hesitate to contact either the study 
coordinators, Dr. Franz at (919) 681-0023, or the study physician, Dr. Chandrasekhar at (919)-
627-1652.
For more information on the FDA’s list of controlled substances please follow the link provided:
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https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=1308.
Risks of Placebo
There is a possibility that the study drug and/or placebo won’t reduce your child’s ADHD 
symptoms and/or won’t help your child respond better to ESDM Informed Parent Coaching.  
This possibility may be greater with the placebo study drug than the active study drug, but this 
has not been tested/seen in young children with both ADHD and ASD. There is also the 
possibility that if your child weren’t in the study and took a different medication or treatment for 
ADHD symptoms that your child would respond better to that medication or have fewer side 
effects with that medication or treatment than with the study drug.  Currently there are no 
medications that are proven to improve the fundamental challenges with social communication 
and repetitive behaviors in ASD. This is why we encourage you to work with a doctor outside 
the study if you want to look into other treatments for ADHD or ASD after week 24 of the study.
Risk of Discontinuing Prior Medication
Any ADHD medication in the form of stimulants, or atomoxetine, must be discontinued prior to 
starting the study medication. Of course, discontinuing any prescribed medication entails some 
risk. There is a possibility that there will be an increase in ADHD symptoms. If these symptoms 
become intolerable at any point, please do not hesitate to contact us, as consent for study is 
an ongoing process. Dr. Franz or the study physician will be available to discuss with you 
whether the potential benefits of being in the trial (outlined below) outweigh the benefits of 
restarting your child’s prior medication or obtaining other community based behavioral 
treatments. If you still feel restarting medication will be the best option for your child, you can 
withdraw from the study knowing that this does not keep your child from receiving other 
services from Duke outside of the study.
Other Medicine

The study physician may prescribe melatonin (6mg/night) if your child is still having 
trouble sleeping even with a reduction in dose of the study medication and if you want to 
do this. Melatonin is a hormone that your body produces naturally to help control 
sleep/wake cycles. Melatonin is sometimes taken as a dietary supplement in a pill or 
readily dissolvable form to help people with trouble sleeping. Although studies with 
melatonin have shown no serious adverse effects, there are a few possible side effects:
o
Melatonin can make symptoms of depression worse
o
Melatonin can raise blood pressure in people who are taking other medications
o
Using melatonin might increase the risk of having a seizure

If melatonin doesn’t help your child sleep better and you want to try a different 
medication to help with sleep, the study physician may prescribe either a drug called 
clonidine or one called diphenhydramine, also known as Benadryl. Clonidine is a 
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IRB REFERENCE DATE: 04/24/2021
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medicine that can be used for high blood pressure or during the day for ADHD.  
However, it tends to cause sleepiness, so many doctors use it to help children sleep. 
Clonidine can have the following side effects
o
Drowsiness
o
Dizziness
o
Tiredness
o
Irritability
o
Light headedness
o
Lower heart rate
o
Lower blood pressure
o
High blood pressure if suddenly discontinue clonidine

Diphenhydramine is an antihistamine used to relieve allergy and cold symptoms.  It is also 
shown to help people relax and fall asleep. Common side effects of diphenhydramine 
include:
o
Drowsiness
o
Dizziness
o
Constipation
o
Upset stomach
o
Blurred vision
o
Dry mouth 

Clonazepam is an anti-anxiety medication.  Common side effects of clonazepam include:
o
Drowsiness
o
Poor coordination
o
Unsteadiness while walking
o
Depression
If your child is prescribed melatonin, clonidine, clonazepam or diphenhydramine, it will not be 
provided for or paid by the study.
Drug and Food Interactions
For your child’s safety, you must tell the study doctor about all the prescribed medical foods 
and drugs, herbal products, over-the-counter (OTC) drugs, vitamins, natural remedies, and 
alcohol that your child is taking before you start the study and before starting to take any of 
these products while you are on the study.
We will watch over your child closely by checking your child’s vital signs at each visit. We will 
initially check your child's heart activity and ensure it is healthy. At visits we will also be 
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monitoring any problems with the study drug your child may have and perform regular physical 
exams.
  
Risks of Electrocardiogram (ECG)
Possible side effects of the ECG are skin irritation, itching, and redness from the ECG 
electrode pads. Let the study coordinator or physician know of any previous skin conditions or 
discomfort your child might have before the pads are applied.
 
Other Risks
There is a possibility that you or your child may become frustrated during study tasks. We will 
try to make the tasks and task directions as easy as possible. Your child can take as many 
breaks as he/she needs during assessments. Some of the questions we will ask you or your 
child as part of this study may make you or your child feel uncomfortable. You or your child 
may refuse to answer any of the questions and you or your child may take a break at any time 
during the study. You or your child may stop your participation in this study at any time.
There is also the potential risk of loss of confidentiality. Every effort will be made to keep your 
information confidential; however, this cannot be guaranteed.  
Risks related to your child’s ASD and ADHD
Your child may experience a worsening of symptoms that may be because of their condition 
alone, or because they are not taking their regular medicine, or because of a lot of other 
factors that may not be related to this study. This may be more likely if your child is taking the 
placebo study drug rather than the active study drug. The study doctor will try to minimize 
these risks by carefully monitoring your child during the study. In cases of severe worsening of 
symptoms that place your child or those around him/her at risk, your child may require 
inpatient hospitalization. If the study doctor feels that your child is at serious risk for hurting 
him/herself or others, he/she can ask a judge to allow your child to be hospitalized against your 
and/or your child’s will. 
There may be risks, discomforts, drug interactions or side effects that are not yet known.
ARE THERE BENEFITS TO TAKING PART IN THE STUDY?
If you and your child agree to take part in this study, your child may benefit by receiving some 
of the diagnostic and cognitive evaluations that are conducted as part of this study. Your family 
could also benefit from the ESDM informed parent coaching and learning how to use strategies 
for promoting social skills, language, and behavioral regulation. 
It is also possible that the study medication may help improve some of your child’s ADHD 
symptoms. However, we will not be providing the study drug after the last in-person visit, the 
study doctor will discuss whether you want to continue to pursue ADHD treatment for your 
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IRB REFERENCE DATE: 04/24/2021
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child. If you do, we will be happy to provide a referral to a medical provider not associated with 
the study. 
There are still potential benefits if your child is in the placebo group. Your child will still be 
receiving a parent-coaching behavioral therapy along with other behavioral assessments as 
previously mentioned. If at any point you feel that restarting prior ADHD medication will be 
more beneficial to your child than continuing participation in the study drug treatment portion of 
the study, we hope you will continue to participate in the remaining efficacy assessments in the 
trial. We will stop providing the study drug to your child if you choose to pursue other 
medication treatments for ADHD for your child outside the study, but will continue to provide 
parent coaching if you agree to participate in ongoing efficacy and safety assessments.
Finally, we also hope that in the future the information learned from this study will benefit other 
people with both ASD and ADHD.  
WHAT ALTERNATIVES ARE THERE TO PARTICIPATION IN THIS STUDY?
Instead of being in this study, you and your child have the following alternatives: 

Other early intervention therapy for ASD

Other medication or behavior therapy for ADHD in young children

Have your child try medicine for associated symptoms, such as anxiety or 
irritability
Please talk to your child’s doctor about these and perhaps other options.
WILL MY CHILD’S INFORMATION BE KEPT CONFIDENTIAL?
Participation in research involves some loss of privacy. This study will collect information that 
might directly identify you and your child, such as names, dates of birth, addresses and health 
related information. We understand that information about you and your child’s health is 
personal, and we are committed to protecting the privacy of that information. We will do our 
best to make sure that information about you and your child is kept confidential, but we cannot 
guarantee total confidentiality. You and your child’s personal information may be viewed by 
individuals involved in this research and may be seen by people including those collaborating, 
funding, and regulating the study. Collaborators include individuals who are not part of Duke 
University. We will share only the minimum information in order to conduct the research. You 
and your child’s personal information may also be given out if required by U.S. or State law. 
Examples of information that we are legally required to disclose include abuse or neglect of a 
child.
As part of the study, results of your child’s study-related data and procedures may be reported 
to the NIH and its affiliates. In addition, your child’s records may be reviewed in order to meet 
federal or state regulations. Reviewers may include representatives from the Food and Drug 
Administration (FDA), representatives and affiliates of the NIH, and the Duke University Health 
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System Institutional Review board, and others as appropriate. If any of these groups review 
your child’s research record, they may need to review your child’s entire medical records.
The Duke ACE Center will use a third-party web-based application called Q-Global from 
Pearson, Inc. to collect data and score the responses for one of the questionnaires in this 
study. To properly score this assessment, only your child’s date of birth and his/her study ID 
will be entered along with your responses. The minimal amount of information will be submitted 
over a secure (industry-standard Secure Socket Layer (SSL)) Internet connection to Q-Global 
for purposes of accurately scoring the questionnaire. The information provided to Q-Global is 
subject to its terms of use. The Q-Global web-based platform is secure (data is encrypted 
using industry-standard SSL technology and compliant with established HIPAA Security 
Regulations as well as changes to HITECH Act effective March 2013 which applies to 
Business Associates to health care providers). However, as with any website platform or 
software, there may be potential security risks and Duke cannot guarantee that the website is 
free of risk.
Except when required by law, and as otherwise explained in this consent document, you or 
your child will not be identified by name, address, telephone number, or any other direct 
personal identifier in records disclosed outside of Duke University Health System (DUHS). All 
data can only be accessed by a secure password which will be locked away by authorized 
personnel. The database will be stored on a secure server at the Duke School of Medicine. 
Study team members are required to log in with a unique username and password to access 
the study database. Before being granted access to the study database, staff complete training 
on protecting confidentiality and sign confidentiality agreements. The database will include all 
the information that we collect during the course of the study and it will also include information 
such as your child’s date of birth, gender, and date of each study visit. It also will contain your 
child’s name and contact information in a dashboard.  All hard copies of your child’s records 
will be kept in locked file cabinets. Only people who need access to your child’s data to do their 
job will have access to it. Any paper records will be stored in locked office.
This project is part of a larger set of projects that are part of the Duke Autism Center of 
Excellence funded by the National Institute of Child Health and Human Development. Data 
collected by this study will be shared with investigators who are part of the Duke Autism Center 
of Excellence. This will allow us to learn more by combining data across different projects that 
are part of the Duke Autism Center of Excellence program.
Some information collected about your child in this research study will be used only for the 
study and will be kept in a research study record separate from your child’s medical record. 
Some research information may also be part of your child’s medical record.  You and your 
child will only have access to information about whether your child received the placebo or the 
study drug during the randomized double-blind portion of the study after all participants have 
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completed the research study and the main study results have been analyzed.  Some research 
information such as test results and psychological assessment reports will be available to your 
physicians if needed for your child’s care.
The study results will be retained in your child’s research record for six years after the study is 
completed or until your child reaches the age of 21, whichever is longer.  At that time either the 
research information not already in your child's medical record will be destroyed or information 
identifying your child will be removed from such study results at DUHS.  Any research 
information in your child's medical record will be kept indefinitely.
This information may be further disclosed by NIMH (National Institute of Mental Health), the 
funding agency of this study. If disclosed by the funding agency, the information is no longer 
covered by federal privacy regulations. If this information is disclosed to outside reviewers for 
audit purposes, it may be further disclosed by them and may not be covered by federal privacy 
regulations. NIMH is a part of the NIH.
While the information and data resulting from this study may be presented at scientific 
meetings or published in a scientific journal, your and your child’s name or other personal 
information will not be revealed.
Some people or groups who receive your and your child’s health information might not have to 
follow the same privacy rules. Once your and your child’s information is shared outside of 
Duke, we cannot guarantee that it will remain private. If you decide to share your or your 
child’s private information with anyone not involved in the study, the federal law designed to 
protect your and your child’s health information privacy may no longer apply to the information 
you have shared.  Other laws may or may not protect sharing of private health information.
NDAR
Data from this study may be submitted to the National Data for Autism Research (NDAR). 
NDAR is a data repository run by the NIMH that allows researchers studying children’s health 
to collect and share de-identified information with each other. A data repository is a large 
database where information from many studies is stored and managed. De-identified 
information means that all personal information (such as name, address, and phone number) 
is removed and replaced with a code number. With an easier way to share, researchers hope 
to learn new and important things about children’s health more quickly than before. 
During and after the study, we will send de-identified information to NDAR. Other researchers 
nationwide can then file an application with the NIMH to obtain access to your or your child’s 
de-identified study data for research purposes. Experts at the NIMH who know how to protect 
health and science information will look at every request carefully to minimize risks to your 
privacy. 
DUHS IRB
IRB NUMBER: Pro00085179
IRB REFERENCE DATE: 04/24/2021
IRB EXPIRATION DATE: 04/04/2022


Consent to Participate in a Research Study
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Parent/Guardian*Initials_________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
You may not benefit directly from allowing your information to be shared with NDAR. The 
information provided to NDAR may help researchers around the world treat future children and 
adults with mental illnesses so that they have better outcomes. NIMH will also report to 
Congress and on its web site about the different studies that researchers are conducting using 
NDAR data. However, you will not be contacted directly about the data you contributed to 
NDAR. 
You may decide now or later that you do not want to share your or your child’s information 
using NDAR. If so, contact Dr. Franz and she or a research study staff member will tell NDAR, 
which can stop sharing the research information. However, NDAR cannot take back 
information that was shared before you changed your mind. If you would like more information 
about NDAR, this is available on-line at http://data-archive.nimh.gov.
Duke Patient
As part of this study, your child will become a Duke patient. Dr. Franz and her study team will 
ask your child to have certain tests. Some of these tests and/or procedures would have been 
done as part of your child’s regular care. She will use these test results both to treat your child 
and to complete this research. These test results will be recorded in your child’s medical 
record and will be reported to the research team and representatives and affiliates of the 
funding agency.  Some results of tests and studies done solely for this research study and not 
as part of your child’s regular care will be included in your child’s medical record.
Other Disclosures
A pediatric cardiologist (heart doctor) will review your child’s ECG to determine if there might 
be possible concerns about your child’s heart beat based on your child’s age. When we collect 
your child’s blood for general blood safety assessments, we will send the blood to an external 
laboratory called Laboratory Corporation of America Holdings, more commonly known as 
Labcorp. Labcorp will also need access to your child’s date of birth in order to ensure that the 
results they report are accurate. 
Neither the pediatric cardiologist nor Labcorp will receive any identifying information other than 
your child’s date of birth. They will not have your child’s name, medical record number or any 
other information. 
Certificate of Confidentiality
The Department of Health and Human Services (HHS) has issued a Certificate of 
Confidentiality to further protect your privacy.  With this Certificate, the investigators may not 
disclose research information that may identify you in any Federal, State, or local civil, criminal, 
administrative, legislative, or other proceedings, unless you have consented for this use. 
DUHS IRB
IRB NUMBER: Pro00085179
IRB REFERENCE DATE: 04/24/2021
IRB EXPIRATION DATE: 04/04/2022


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Parent/Guardian*Initials_________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
Research information protected by this Certificate cannot be disclosed to anyone else who is 
not connected with the research unless:  
1) There is a law that requires disclosure (such as to report child abuse or communicable 
diseases but not for legal proceedings); 
2) You have consented to the disclosure, including for your medical treatment; or 
3) The research information is used for other scientific research, as allowed by federal 
regulations protecting research subjects. 
Disclosure is required, however, for audit or program evaluation requested by the agency that 
is funding this project or for information that is required by the FDA.
You should understand that a Confidentiality Certificate does not prevent you or a member of 
your family from voluntarily releasing information about yourself or your involvement in this 
research. If you want your research information released to an insurer, medical care provider, 
or any other person not connected with the research, you must provide consent to allow the 
researchers to release it. This means that you and your family must also actively protect your 
own privacy.
Finally, you should understand that the investigator is not prevented from taking steps, 
including reporting to authorities, to prevent serious harm to yourself or others.
WHAT ARE THE COSTS TO YOU?
There will be no additional costs to you or your child as a result of being in this study.  
However, routine medical care for your child’s condition (care your child would have received 
whether or not your child was in this study) will be charged to you or your insurance company.  
You may wish to contact your insurance company to discuss this further. If anti-anxiety 
medication is requested by the parent/caregiver for the child’s blood draw, you will need to pick 
this up before the visit at your pharmacy after our study doctor has prescribed it.  In order to 
make sure that tests and studies done solely for research purposes are charged correctly, we 
will carefully monitor your Duke Hospital and Clinic charges as long as you are participating in 
this study.  These tests and studies are not a part of routine care, and people who are not part 
of the study do not usually have them performed.  Please ask Dr. Chandrasekhar or another 
study doctor if you would like to know more about which tests and studies are being done 
solely for research purposes.
The study drug will be provided free of charge for your child’s use in this study up until week 
10.  At the conclusion of the first phase of the study (week 10), or if you or your child decide to 
withdraw from the study, you must return all unused study drug to Dr. Chandrasekhar or 
DUHS IRB
IRB NUMBER: Pro00085179
IRB REFERENCE DATE: 04/24/2021
IRB EXPIRATION DATE: 04/04/2022


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DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
another study doctor. Dr. Chandrasekhar or another study doctor may request that you and 
your child return to complete the tests that would ordinarily occur when a person completes the 
study. If you decide at the end of the 10-week period/end of study that you wish to continue 
using the drug or put your child on the study drug, we will be happy to provide a referral to a 
another care physician not associated with the study. We will not be providing the ADHD drug 
nor will we provide any more coaching after study completion. 
WHAT ABOUT COMPENSATION?
You and your child will be compensated up to a total of $600 for participating in this study. You 
will be reimbursed $50 for each of the 12 visits (health screener, physician visits, and ESDM 
Informed Parent Coaching visits). Participants will be compensated ($50) for the optional 
follow-up questionnaires at week 24. Transportation costs ( within a 2 hour driving distance 1-
way) can also be provided on a case by case basis, to reliably get to study visits if necessary.
Payment received as compensation for participation in research is considered taxable income 
to the research subject. If payment to an individual totals $600 or more in any one calendar 
year, Duke University is required to report this information to the Internal Revenue Service 
(IRS). Research subject payments to a non-employee of Duke University adding up to $600 or 
more during any calendar year will result in a 1099 (Miscellaneous Income) form being issued 
to the individual and a copy sent to the IRS.
WHAT ABOUT RESEARCH RELATED INJURIES?
Immediate necessary medical care is available at Duke University Medical Center in the event 
that your child is injured as a result of your child’s participation in this research study. However, 
there is no commitment by Duke University, Duke University Health System, Inc., or your Duke 
physicians to provide monetary compensation or free medical care to you in the event of a 
study-related injury.
For questions about the study or research-related injury, contact Dr. Franz at (919) 681-0023 
or Dr. Chandrasekhar at (919)-681-0018 during regular business hours and (919)-627-1652 for 
Dr. Chandrasekhar after hours and on weekends and holidays.
WHAT ABOUT MY RIGHTS TO DECLINE PARTICIPATION OR WITHDRAW FROM THE 
STUDY?
You and your child may choose not to be in the study, or, if you and your child agree to be in 
the study, you or your child may withdraw from the study at any time. If you or your child 
withdraw from the study, no new data about your child will be collected for study purposes 
other than data needed to keep track of your child’s withdrawal, unless the data concern an 
adverse event related to the study.  If such an adverse event occurs, we may need to review 
your child’s entire medical record.  All data that have already been collected for study 
purposes, and any new information about an adverse event related to the study, will be 
DUHS IRB
IRB NUMBER: Pro00085179
IRB REFERENCE DATE: 04/24/2021
IRB EXPIRATION DATE: 04/04/2022


Consent to Participate in a Research Study
A+ Treatment
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Parent/Guardian*Initials_________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
included in the research database. All data that have already been collected will be kept solely 
for study purposes and will be sent to the study sponsor.
You or your child’s decision not to participate or to withdraw from the study will not involve any 
penalty or loss of benefits to which you and your child are entitled, and will not affect your 
child’s access to health care at Duke. Signing this consent form is not a condition for receiving 
any medical care outside the study. However, if you or your child decides to stop participating 
in the study, we encourage you to talk to your child’s doctor first. If you do decide to withdraw, 
we ask that you contact Dr. Franz in writing and let her know that you are withdrawing from the 
study. Her email address is: lauren.franz@duke.edu and her phone number is (919) 681-0023. 
If you use email please be aware that you may be at potential risk for a loss of confidentiality 
because email is not a secure means of communication.
In addition, you must return all unused study drug to the study physician, Dr. Chandrasekhar, 
or her staff. She may also ask you and your child to complete the tests that would ordinarily 
occur when a person completes the study.
Your child’s study doctor may decide to discontinue your child’s participation in this study if 
your child’s condition gets worse, if your child has serious side effects, or if your child’s study 
doctor determines that it is no longer in your child’s best interest to continue. The funding 
agency or regulatory agencies may stop this study at any time without your or your child’s 
consent. Reasons why this might occur include because your child has had an unexpected 
reaction, or has failed to follow instructions, or because the entire study has been stopped. If 
this occurs, you will be notified and your child’s study doctor will discuss other options with 
you.
If you do not sign this consent form and your child is a Duke patient, your child will continue to 
receive care from your healthcare provider, but not as a part of this study.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify your child. At most, the 
Web site will include a summary of the results. You can search this Web site at any time.
WHOM DO I CALL IF I HAVE QUESTIONS OR PROBLEMS?
For questions about the study or a research-related injury, or if you have problems, concerns, 
questions or suggestions about the research, Dr. Franz at (919) 681-0023 or (919)-627-1652 
for Dr. Chandrasekhar (another doctor on the study) after hours and on weekends and 
holidays.
DUHS IRB
IRB NUMBER: Pro00085179
IRB REFERENCE DATE: 04/24/2021
IRB EXPIRATION DATE: 04/04/2022


Consent to Participate in a Research Study
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*
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
For questions about your or your child’s rights as a research participant, or to discuss 
problems, concerns or suggestions related to the research, or to obtain information or offer 
input about the research, contact the Duke University Health System Institutional Review 
Board (IRB) Office at (919) 668-5111.
STATEMENT OF CONSENT
"The purpose of this study, procedures to be followed, risks and benefits have been explained 
to me. I have been allowed to ask the questions I have, and my questions have been 
answered to my satisfaction.  I have been told whom to contact if I have additional questions.  I 
have read this consent form and agree to participate and allow my child to be in this study with 
the understanding that I may withdraw him/her or myself at any time. We have discussed the 
study with my child, who agrees to be in the study. I have been told that I will be given either a 
paper signed copy of this consent form or an electronic version, which will be sent to the email 
address (es) I choose to include below." 
__________________________________________
___________     ____________
Signature of Parent/Guardian #1
Date
   Time
__________________________________________
Name of Parent/Guardian #1
__________________________________________
___________     ____________
Signature of Parent/Guardian #2 (if applicable)
Date
   Time
__________________________________________
Name of Parent/Guardian #2
(if applicable)
__________________________________________
___________     ____________
Signature of Person Obtaining Consent
Date
   Time
__________________________________________
Name of Person Obtaining Consent
DUHS IRB
IRB NUMBER: Pro00085179
IRB REFERENCE DATE: 04/24/2021
IRB EXPIRATION DATE: 04/04/2022