Sub-study: Feasibility Trial of Adapted ESDM-informed Caregiver Coaching Delivered Remotely for Children With ASD and ADHD
Phase: NA
Conditions: Autism Spectrum Disorder, Adhd
Sponsor: Duke University

Feasibility trial of adapted ESDM informed caregiver coaching delivered remotely for children with ASD 
and ADHD  
 
 
Protocol Pro00085179, v1.4 
17 March 2022 
 
A+ Treatment Sub-study  v.1.3 
1 
A+ Treatment/Feasibility:  ACE Project 3 
Sub-study: Feasibility trial of adapted ESDM-informed caregiver coaching 
delivered remotely for children with ASD and ADHD 
Duke IRB Protocol Number: Pro00085179 
Principal Investigator: Dr. Lauren Franz 
 
Funded by:  National Institute of Child Health and Human Development  
Version Number:  v.1.4 
17 MARCH 2022 
 
NCT05417607 

Feasibility trial of adapted ESDM informed caregiver coaching delivered remotely for children with ASD 
and ADHD  
 
 
Protocol Pro00085179, v1.4 
17 March 2022 
 
A+ Treatment Sub-study  v.1.3 
2 
 
 
Summary of Changes 
 
Version / Date 
Description 
of 
changes 
Rationale 
Date of Approval (iRIS 
version) 
V1.4/17 MAR 2022 
1. The protocol analysis 
section was 
updated/clarified to 
reflect the addition of 
a statistical analysis 
plan for the project. 
Primary outcomes, 
secondary outcomes, 
and exploratory 
outcomes were 
updated to match the 
plan. 
1. The statistical 
analysis plan, 
protocol and CT.gov 
should all be in 
agreement to prevent 
any confusion. 
 
V1.3/12 AUG 2021 
2. Removed 16 week 
physician check in.  
3. Clarified that if there 
is limited internet 
access participants 
can receive coaching 
through telephone 
and record 
interactions for both 
the PCI and ESDM 
sessions and upload 
to Duke BOX.  
4. Removed language 
that is not applicable 
to the protocol 
(section 6.4.1) - this 
section previously 
stated that 
participants will be 
asked to refrain from 
changing the type or 
intensity of other 
behavioral 
interventions during 
the study. 
5. Removed information 
for Scott Kollins as 
former Co-I for the 
2. It does not impact 
the primary or 
secondary outcomes 
for the study and 
data (missed week 16 
physician visits) is 
suggesting that 
participants are 
finding this to be a 
burden.  
3. We would like to 
ensure that parent 
coaching and study 
procedures are 
accessible to study 
participants that are 
unable to obtain 
high-speed internet 
access.  
3.and 4. – No longer 
pertinent to protocol. 
3. was legacy 
language and this is 
a feasibility study so 
medications and 
behavioral 
interventions will not 
be restricted; if there 
20 SEP 2021 

Feasibility trial of adapted ESDM informed caregiver coaching delivered remotely for children with ASD 
and ADHD  
 
 
Protocol Pro00085179, v1.4 
17 March 2022 
 
A+ Treatment Sub-study  v.1.3 
3 
ACE. 
 
is something that 
seriously impedes 
participation, then 
the study PI will take 
appropriate action to 
discontinue, 
withdraw, or provide 
participant with 
feedback on options . 
 
V1.2/16 APR 2021 
1.Primary PI changed 
from Dr. Geraldine 
Dawson to Dr. Lauren 
Franz 
 
2.Updated inclusion 
criterion # 4 to allow 
for tele-ASD-peds 
used in clinic and 
further clarification of 
diagnostic assessment.  
 
3.Removing measures 
from protocol:  CGI-
I&S, ADHD-RS 
(clinician 
administered), and 
Sluggish Cognitive 
Tempo (AOA) 
questionnaire. 
Reducing the number 
of times the ADHD-RS 
(parent) caregiver 
completed form is 
assessed. 
 4.Clarified what 
measures may need to 
be repeated if too 
much time has 
progressed through 
the assessment core 
(see SOA). 
 
5. Clarified 
procedures for 
conducting Qualitative 
Interview and consent 
process with 
1.Dr. 
Franz 
has 
valuable experience to 
take on the PI role and 
this 
change 
helps 
balance 
other 
PI 
transitions across the 
ACE. 
 
2.We are including a 
telehealth 
assessment 
that is standard practice 
being used in younger 
children during COVID 
for ASD diagnosis. 
 
3.These assessments add 
additional time burden 
to the families and we 
feel 
that 
given 
the 
remote nature of the 
study 
they 
are 
not 
required assessments for 
primary end goals.  
 
 
 
 
4.Clarifying in the table 
of assessments what may 
need to be repeated 
 
5. 
The 
qualitative 
interview 
with 
staff, 
clinicians, and coaches 
requires 
a 
consent 
process and outlining of 
ways we will minimize 
bias 
and 
ensure 
24 APR 2021  
(iRIS Version 1.5) 

Feasibility trial of adapted ESDM informed caregiver coaching delivered remotely for children with ASD 
and ADHD  
 
 
Protocol Pro00085179, v1.4 
17 March 2022 
 
A+ Treatment Sub-study  v.1.3 
4 
stakeholders who are 
study staff. 
 
 
 
voluntariness.  
v1.1 / 28 DEC 2020 
Removed 
exclusion 
criterion (#5) which 
was based on presence 
of known genetic or 
other 
neurological 
condition; 
modified 
exclusion #1 to specify 
CNS 
active 
medications (not just 
ADHD 
medications) 
must be stable 4 weeks 
prior to baseline. 
The presence of genetic or 
neurological 
condition 
alone is not expected to 
affect the suitability or 
applicability and potential 
benefit or risk profile of the 
intervention to 
children 
with these characteristics; 
removal 
of 
exclusion 
makes the sample more 
representative. It is ideal 
for 
all 
psychotropic 
medications to not change  
prior to baseline to reduce 
possibility of changes in 
medications/symptoms 
confounding data. 
19 JAN 2021 
(iRIS Version 1.3) 
v1.0 / 07 DEC 2020  
First 
version, 
feasibility sub-study 
Initiating feasibility sub-
study 
16 DEC 2020 
(iRIS version 1.1) 

Feasibility trial of adapted ESDM informed caregiver coaching delivered remotely for children with ASD 
and ADHD 
 
Protocol Pro00085179, 
 
 
A+ Treatment Sub-study  v.1.3 
ii 
Table of Contents 
Table of Contents .................................................................................................................................................... ii 
STATEMENT OF COMPLIANCE ............................................................................................................................. 1 
1 
PROTOCOL SUMMARY ............................................................................................................................... 1 
1.1 
Synopsis ................................................................................................................................................ 1 
1.2 
Schema ................................................................................................................................................. 4 
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 ........................................................................................................................................ 3 
2.4 
Risk/Benefit Assessment .................................................................................................................... 4 
2.4.1 
Known potential risks ....................................................................................................... 4 
2.4.2 
Known potential benefits ................................................................................................. 5 
2.4.3 
Assessment of potential risks and benefits .................................................................. 5 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................................ 6 
4 
STUDY DESIGN ............................................................................................................................................. 7 
4.1 
Overall Design ...................................................................................................................................... 7 
4.2 
Scientific Rationale for Study Design ................................................................................................ 7 
4.3 
Justification for Dose ........................................................................................................................... 8 
4.4 
End of Study Definition ....................................................................................................................... 8 
5 
STUDY POPULATION .................................................................................................................................. 8 
5.1 
Inclusion Criteria .................................................................................................................................. 8 
5.2 
Exclusion Criteria ................................................................................................................................. 8 
5.3 
Lifestyle Considerations ...................................................................................................................... 9 
5.4 
Screen Failures .................................................................................................................................... 9 
5.5 
Strategies for Recruitment and Retention ........................................................................................ 9 
6 
STUDY INTERVENTION ............................................................................................................................ 11 
6.1 
Study Interventions Administration.................................................................................................. 11 
6.1.1 
Study medication intervention description .................................................................. 11 
6.1.2 
Medication dosing and administration ......................................................................... 11 
6.1.3 
Study Behavioral Intervention Description ................................................................. 11 
6.2 
Clinical Trial Supplies Preparation/Handling/Storage/Accountability ......................................... 12 
6.3 
Measures to Minimize Bias: Randomization And Blinding .......................................................... 12 
6.4 
Study Intervention Compliance ........................................................................................................ 12 
6.4.1 
Prohibited concomitant therapies ................................... Error! Bookmark not defined. 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT WITHDRAWAL ..................... 12 
7.1 
Study Halting Rules ........................................................................................................................... 12 
7.2 
Rules for Individual Participant Discontinuation in Study Interventions ..................................... 12 
7.3 
Participant Discontinuation/Withdrawal from the Study ............................................................... 13 
7.4 
Lost to Follow-Up ............................................................................................................................... 13 
8 
STUDY ASSESSMENTS AND PROCEDURES ...................................................................................... 13 
8.1 
Other Assessments ........................................................................................................................... 16 
8.2 
Adverse Events and Serious Adverse Events ............................................................................... 17 
8.2.1 
Definition of adverse events (AE) ...................................................................... 17 
8.2.2 
Definition of serious adverse events (SAE) ................................................... 17 
8.2.3 
Classification of an adverse event ............................................................................... 17 
8.2.4 
Time period and frequency for event assessment and follow-up.......... 18 
8.2.5 
Adverse event reporting ......................................................................................... 18 
8.2.6 
Serious ADVERSE EVENT REPORTING ........................................................ 18 
8.2.7 
Reporting events to participants .................................................................................. 19 

Feasibility trial of adapted ESDM informed caregiver coaching delivered remotely for children with ASD 
and ADHD 
 
Protocol Pro00085179, 
 
 
A+ Treatment Sub-study  v.1.3 
iii 
8.2.8 
Reporting of pregnancy ................................................................................................. 19 
8.2.9 
Reporting of suspected child abuse or neglect .......................................................... 19 
8.3 
Unanticipated Problems .................................................................................................................... 19 
8.3.1 
Definition of unanticipated problems (UP) .................................................................. 19 
8.3.2 
Unanticipated problem (UP) reporting ........................................................................ 20 
8.3.3 
Reporting unanticipated problems to participants ..................................................... 20 
8.4 
Overall Plan to Protect Patient Safety ............................................................................................ 20 
9 
STATISTICAL CONSIDERATIONS .......................................................................................................... 21 
9.1 
Sample Size Determination .............................................................................................................. 21 
9.2 
Population for Analysis ..................................................................................................................... 21 
9.3 
Statistical Analyses ............................................................................................................................ 21 
9.3.1 
General approach .......................................................................................................... 21 
9.3.2 
Analysis of the primary efficacy endpoint ................................................................... 22 
9.3.3 
Analysis of the secondary endpoints ........................................................................... 23 
9.3.4 
Safety analyses .............................................................................................................. 23 
9.3.5 
Baseline descriptive statistics ...................................................................................... 23 
9.3.6 
Planned interim analyses .............................................................................................. 23 
9.3.7 
Sub-group analyses ....................................................................................................... 23 
9.3.8 
Exploratory analyses ..................................................................................................... 23 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................. 24 
10.1 
Regulatory, Ethical and Study Oversight Considerations ............................................................ 24 
10.1.1 
Informed consent process ............................................................................................ 24 
10.1.2 
Study discontinuation and closure ............................................................................... 25 
10.1.3 
Confidentiality and privacy ............................................................................................ 25 
10.1.4 
Future use of stored specimens and data .................................................................. 26 
10.1.1 
Safety oversight .............................................................................................................. 27 
10.1.2 
Key roles and study governance ................................................................................. 27 
10.1.3 
Clinical data monitoring ................................................................................................. 27 
10.1.4 
Quality assurance and quality control ......................................................................... 28 
10.1.5 
Data handling and record keeping............................................................................... 28 
10.1.6 
Protocol deviations ......................................................................................................... 29 
10.1.7 
Publication and data sharing policy ............................................................................. 29 
10.1.8 
Conflict of interest policy ............................................................................................... 30 
10.2 
Abbreviations ...................................................................................................................................... 30 
10.3 
Protocol Amendment History ........................................................................................................... 32 
11 
References .................................................................................................................................................... 33 
 

Feasibility trial of adapted ESDM informed caregiver coaching delivered remotely for children with ASD 
and ADHD 
 
Protocol Pro00085179, 
 
 
A+ Treatment Sub-study  v.1.3 
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: 
 
Feasibility trial of adapted ESDM-informed caregiver coaching delivered 
remotely for children with Autism Spectrum Disorder (ASD) and Attention-
Deficit/Hyperactivity Disorder (ADHD); Duke Autism Center of Excellence 
(Duke ACE), Project 3; Protocol Pro00085179, v1.0 23 October 2020) 
 
 
Study Description: 
This study will evaluate the feasibility of adapted ESDM-informed caregiver 
coaching in children with comorbid ASD and ADHD, who are between 36 and 
<132 months of age.  There will be no study provided medication treatment 
in this study.  Children will either be on ADHD medication prescribed by their 
own personal provider or will not be taking any ADHD medication (this will 
be documented by the study).  The provided behavioral treatment will be 
eight ~60-minute sessions in ESDM-informed caregiver coaching remotely 
delivered weekly, for 8 consecutive weeks.  The behavioral treatment is 
provided to children through Early Start Denver Model (ESDM)-informed 
caregiver coaching strategies, implemented within the child’s typical daily 
routine by the caregiver. Pre-baseline procedures included screening and 
eligibility procedures, cognitive & diagnostic assessments. This was followed 
by baseline visit (Week 0), 8 subsequent weekly coaching sessions (Weeks 1 -
8), an endpoint visit (Week 9), and a follow up visit (Week 16).   
 
 
Objectives: 
The overarching goal of A+ Treatment is to evaluate feasibility and gather 

Feasibility trial of adapted ESDM informed caregiver coaching delivered remotely for children with ASD 
and ADHD 
 
Protocol Pro00085179, 
 
 
A+ Treatment Sub-study  v.1.3 
2 
pilot data of remotely-delivered ESDM informed caregiver coaching for 
children with ASD and ADHD which may inform future combination clinical 
trials (pharmacotherapy and behavioral intervention).  
 
 
 
Primary Endpoint:          Using an implementation science approach we will characterize the 
acceptability, appropriateness, feasibility and fidelity of remotely behavioral 
intervention in the following ways: 1. Using 3 pragmatic measures: 
Acceptability of Intervention Measure (AIM), Intervention Appropriateness 
Measure (IAM), and Feasibility of Intervention Measure (FIM). 2. Conducting 
qualitative interviews (caregiver, clinician and staff) of perceptions regarding 
the intervention. 3. Assessing fidelity of intervention delivery, using adapted 
ESDM Fidelity rating scales.  
 
 
 
Key Secondary 
Endpoints 
 
 
 
 
 
 
 
 
 
Other Exploratory 
Endpoints 
 
The proximal outcomes of child and caregiver behaviors and sense of 
competence after the intervention. Key proximal outcomes will be change 
from baseline (pre-intervention) to 9-weeks (post-intervention) in caregiver 
sense of competence measured by the Parent Sense of Competence Scale 
and child behaviors measured by the sum of 4 items from the JERI (Joint 
Engagement, 
Attention 
to 
Caregiver, 
Responsiveness 
to 
Partner’s 
Communication Bids, Fluency and Connectedness) coded by a trained, 
reliable coder who is naïve with respect to whether the observation is from 
baseline our outcome using video-recorded caregiver-child interactions.  
 
Additional exploratory outcomes will be change in caregiver ratings from 
baseline to 9-week in the following measures: a) ADHD-RS ratings of the 
child’s attention; b) Aberrant Behavior Checklist (ABC), including 
inattention/hyperactivity, social withdrawal, stereotypies, irritability, and 
inappropriate speech; c) Social Reciprocity Scale-2 (SRS-2) ratings of child’s 
social communication behavior; d) Caregiver Strain Questionnaire (CSQ) 
ratings of the impact of the child’s condition on the family and caregiver and 
quality-of-life; e) Behavior Rating Inventory of Executive Functions (BRIEF) 
ratings of child’s executive function; and f) Child Behavior Checklist (CBCL) 
ratings of child behavioral and emotional problems. Change from baseline (pre-
intervention) to 16-weeks (8-weeks post-intervention) will be assessed for the VABS-
3 Socialization and Communication Subscale Standard Scores. 
Study Population: 
~ 30-35 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 of parent/guardian to comply with all study 

Feasibility trial of adapted ESDM informed caregiver coaching delivered remotely for children with ASD 
and ADHD 
 
Protocol Pro00085179, 
 
 
A+ Treatment Sub-study  v.1.3 
3 
procedures and availability for the duration of the study.  
• 
Child is between 36 months and <132 months of age at baseline.   
• 
Child has a confirmed DSM-5 diagnosis of both ASD and ADHD, informed 
by results of assessments including: an ASD diagnostic assessment (Brief 
Observation of Symptoms of Autism [BOSA], Autism Diagnostic 
Observation Schedule, 2nd Edition [ADOS-2], or TELE-ASD-PEDS, and if 
applicable the Autism Diagnostic Interview - Revised [ADI-R]) and an 
ADHD diagnostic (a standardized ADHD Diagnostic Interview and the 
MINI psychiatric diagnostic interview). 
 
 
   Exclusion Criteria 
• 
If continuing psychotropic (CNS-active) medications, must not have been 
changed within 4 weeks prior to baseline  
• 
Significant visual, auditory or motor impairments that would preclude 
participation in ESDM-informed caregiver coaching or completion of key 
assessments. 
• 
Inability of the caregiver participating in ESDM-informed caregiver 
coaching and responding to questionnaires to fluently speak English.  
• 
Study clinician judgment that it is not in the best interests of the 
participant and/or the study for the child to participate (including 
presence of psychiatric conditions or psychiatric symptoms in addition to 
ASD and ADHD that in the opinion of the PI or based on senior clinical 
review, would confound assessments and/or affect participation in the 
study).  
 
 
Description of Sites 
Enrolling Participants: 
 
Single academic center site in US. 
Description of Study 
Intervention: 
All participants will receive eight consecutive weekly ~60-minute ESDM-
informed caregiver coaching sessions.  
 
 
Participant Duration: 
Total participation is expected to require a maximum of 20 weeks, including 
optional remote follow-up at 16 weeks. The A+ Treatment diagnostic and 
screening visits will generally occur between 1 and 6 weeks prior to baseline.  
ESDM-informed parent coaching will be delivered per the Schedule of 
Activities (SOA) for 8 weeks. Endpoint assessments will be completed after 
the final coaching visit.  No medication will be provided by the study team. 
The final assessment will be obtained at 16 weeks after baseline.  
 
 
 
 
 
 

Feasibility trial of adapted ESDM informed caregiver coaching delivered remotely for children with ASD 
and ADHD 
 
Protocol Pro00085179, 
 
 
A+ Treatment Sub-study  v.1.3 
4 
 
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 and age criteria. ESDM-informed caregiver coaching begins after baseline 
assessments and will continue for 8 weeks. The primary outcome assessments will evaluate feasibility of 
ESDM-informed caregiver coaching in children ages 3-10. This study will be conducted remotely.  
 
Week -2 to -1 
Week 0 
Weeks 1-8 
Week 9 
 
Week 16 
Screen & Confirm 
Diagnose 
Baseline 
ESDM Sessions 
Endpoint 
 
Remote Follow-up 
Diagnostic 
assessments 
Cognitive testing 
Parent questionnaires 
Vineland-3 parent 
report 
Joint engagement 
Social communication 
ADHD symptoms 
AIM 
Parent questionnaires 
ESDM Caregiver Fidelity 
ESDM Caregiver Self-
Monitoring 
ESDM Coaching Fidelity 
Joint engagement 
Social communication 
ADHD symptoms 
AIM 
Qualitative interview 
Vineland-3 parent report 
Parent questionnaires 
 
 
Social communication 
ADHD symptoms 
Parent Questionnaires 
Vineland-3 parent 
report 
 
 

A+ Treatment: Impact of combined medication and behavioral treatment for young children with ASD and ADHD    
Protocol Pro00085179, 
 
A+ Treatment Sub-study  v.1.3 
0 
1.3 
Schedule Of Activities (SoA) 
 
ACTIVITIES 
Consent &  
Diagnostic 
Confirmation&  & 
Feedback 
Baseline/and 
call with 
Coach 
Coaching W1 
Coaching 
W2 
Coaching 
W3 
Coaching 
W4 
Coaching 
W5 
Coaching 
W6 
Coaching 
W7 
Coaching 
W8 
Endpoint 
Assessments 
Remote 
Follow-
up 
Typical Week offset from 
baselineA 
prior 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
16 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics, ACE subject 
Med Hx, ACE Fam Hx, 
Intervention Hx, ꭞSpence 
X 
 
 
 
 
 
 
 
 
 
 
 
Diagnostic & Cognitive 
testing 
X 
 
 
 
 
 
 
 
 
 
 
 
ESDM-informed caregiver 
coaching 
 
Brief call  
X 
X 
X 
X 
X 
X 
X 
X 
 
 
P-ESDM Caregiver Self-
Monitoring checklist** 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
ESDM coach fidelity * 
 
 
* 
* 
* 
* 
* 
* 
* 
* 
 
 
ESDM caregiver fidelity 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Remote PCIT 
JERI coding of child/ caregiver 
items 
 
X 
 
 
 
 
 
 
 
 
X 
 
Qualitative Interview 
 
 
 
 
 
 
 
 
 
 
X 
 
AIM, IAM, FIM 
 
 
 
 
 
 
 
 
 
 
X 
 
Caregiver Sense of 
Competence Scale 
 
X 
 
 
 
 
 
 
 
 
X 
X 
App S2K 
 
X 
 
 
 
 
 
 
 
 
X 
X 
ABC 
 
X 
 
 
 
 
X 
 
 
 
X 
X 
Vineland-3 parent 
questionnaire 
X 
 
 
 
 
 
 
 
 
 
X 
X 
CBCL 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
ADHD-RS-parent 
X 
 
 
 
 
 
 
 
 
 
X 
X 
SRS-2 
X 
(X)+ 
 
 
 
 
 
 
 
 
X 
X 
Caregiver Strain Questionnaire 
 
X 
 
 
 
 
 
 
 
 
X 
X 
Condensed (non-ASD) Med 
Hx2, AE’s, Con Meds,  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
BRIEF 
X 
(X)+ 
 
 
 
 
 
 
 
 
X 
 
A: no strict window for visits, but ideally post-baseline visits should be done within ± 7 days (relative to visit each time point from baseline);  *: done once randomly 

A+ Treatment: Impact of combined medication and behavioral treatment for young children with ASD and ADHD    
Protocol Pro00085179, 
 
A+ Treatment Sub-study  v.1.3 
1 
during sessions 2-8;  **: completed by caregiver and coach; Green text: measures acquired in ARC and in P3; (X)+: only needs to be done if baseline done more than 
3 months prior; 2: non ASD med history only done at baseline visit & diagnostic confirmation is informed by ARC assessments. Participants typically begin study 
participation within 1-3 months of completing the ARC evaluation (if the participant is eligible). However, we also expect that in some situations, (e.g., due to the 
COVID-19 pandemic) there may be a delay between the ARC evaluation and participation in the A+ Treatment/Feasibility sub-study. If this happens, the following 
assessments and/or parent-report forms may be repeated: 
•If > 2 years since ARC completion: ASD diagnostic assessment (e.g., BOSA, ADOS, TELE-ASD-PEDS) and cognitive assessment (e.g., WPPSI/WISC, DAYC-2, DAS-2, 
Mullen) 
•If > 6 months since ARC completion: CBCL  
•If > 3 months since ARC completion of: SRS-2, VABS, ADHD-RS parent form    

A+ Treatment: Impact of combined medication and behavioral treatment for young children with ASD and ADHD    
Protocol Pro00085179, 
 
A+ Treatment Sub-study  v.1.3 
0 
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, 
poorer peer relationships and increased use of restricted educational settings(13-15). As described in 

A+ Treatment: Impact of combined medication and behavioral treatment for young children with ASD and ADHD    
Protocol Pro00085179, 
 
A+ Treatment Sub-study  v.1.3 
1 
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 criterion 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 
routines, 
joint 
activity 
routines, 
nonverbal 

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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 
consistent benefit throughout the day with minimal on off periods.  For any given stimulant medication, 

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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. 
 
Impact of ADHD treatment of school-aged children with ASD+ADHD on Core ASD Symptoms.  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.   
 
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 suspect 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. Thus, we hypothesize that we 
can intervene to reduce negative outcomes in children with ASD+ADHD by concurrently providing ADHD 
treatment and ASD treatment.  
The overall purpose of this project is inform the most feasible design of a future clinical trial combining 
ADHD treatment with ASD behavioral treatment in children with ASD+ADHD to test our hypotheses.  To 
do this, we are evaluating the feasibility of various trial designs. This sub study will be delivered 
completely remotely and will allow participants and their families to choose whether to treat ADHD 
symptoms or not in consultation with community providers.   
Aim 1. Assess implementation outcomes. Assess acceptability, appropriateness, feasibility, and fidelity 
of remotely delivered ESDM-informed caregiver coaching intervention which has been adapted for older 
children who have comorbid ADHD for delivery over a period of 8 weeks.  Acceptability, 
appropriateness, and feasibility will be quantitatively and qualitatively assessed using 4-item, pragmatic 
scales and individual stakeholder interviews. Fidelity of intervention delivery, the degree to which 
programs are implemented as intended by program developers, is also an important implementation 
outcome. This will be monitored using an adapted version of the Parent Early Start Denver Model (P-
ESDM) Caregiver Fidelity Rating System.  

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Hypothesis: we will be able to determine acceptability, appropriateness, feasibility, and fidelity 
by gathering this outcome data through selected endpoints. 
 
Aim 2: Assess proximal and distal child and caregiver outcomes. Both proximal and distal outcomes will 
be measured. Key proximal outcome will be change from baseline (pre-intervention) to 9-weeks 
(immediately post-intervention) in caregiver sense of competence measured by the Parent Sense of 
Competence Scale and child behaviors measured by the sum of 4 items from the JERI (Joint Engagement, 
Attention to Caregiver, Responsiveness to Partner’s Communication Bids, Fluency and Connectedness) 
coded by a trained, reliable coder who is naïve with respect to whether the observation is from baseline 
our outcome using video-recorded caregiver-child interactions.  
Hypothesis: we will detect proximal changes in child and caregiver interactions and caregiver sense of 
competence. 
 
Exploratory Outcome: In this exploratory outcome we will assess change in caregiver ratings from 
baseline to 9-week in the following measures: a) ADHD-RS ratings of the child’s attention; b) Aberrant 
Behavior Checklist (ABC), including inattention/hyperactivity, social withdrawal, stereotypies, irritability, 
and inappropriate speech; c) Social Reciprocity Scale-2 (SRS-2) ratings of child’s social communication 
behavior; d) Caregiver Strain Questionnaire (CSQ) ratings of the impact of the child’s condition on the 
family and caregiver and quality-of-life; e) Behavior Rating Inventory of Executive Functions (BRIEF) 
ratings of child’s executive function; and f) Child Behavior Checklist (CBCL) ratings of child behavioral and 
emotional problems. Change from baseline (pre-intervention) to 16-weeks (8-weeks post-intervention) will be 
assessed for the VABS-3 Socialization and Communication Subscale Standard Scores. 
 
2.4 
Risk/Benefit Assessment   
 
2.4.1 Known potential risks  
The caregiver coaching, questionnaires, and behavioral assessments to be used in this protocol present 
minimal physical or psychological risk; the probability and magnitude of harm or discomfort anticipated 
are not greater than those ordinarily encountered in daily life or during the performance of routine 
physical or psychological examinations or tests. 
There is a possibility that behavioral assessments and caregiver coaching and other tasks may at times 
cause some children or caregivers to experience fatigue or boredom or frustration. The clinicians and 
study staff are well-trained in working with families and children and have carefully designed activities 
that may be performed remotely through teleconference, telephone, and use of electronic surveys.  
Clinicians and staff will explain activities or tasks to the caregiver by using educational materials, scripts, 
and speaking with them in advance as needed to explain what the remote assessments, interviews, and 
other study measures will entail. Study staff will use understandable language in verbal and written 
communication to help caregivers and the child prepare for visits, explain procedures to their child, and 
to help both the caregiver and child feel as comfortable as possible. Questionnaires and interviews may 
cause parents or children to feel uncomfortable. Breaks will be taken as needed. Participants will be 

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reminded that the assessments can be stopped at any time and their participation is completely 
voluntary. 
 Parents of children with ASD and/or ADHD symptoms may experience stress when results of diagnostic 
and cognitive testing are communicated to them. Before the child participates in the open-label study of 
A+ Treatment, they will have completed assessments with A+ Assessment. An experienced clinician will 
discuss the diagnostic results and any new findings (if applicable) with the family in a sensitive and 
competent manner and, whenever necessary, children will be referred for treatment or/and further 
evaluation at Duke University or in the community, as appropriate. Incidental findings could include 
receiving information about a child’s cognitive functioning or diagnosis that was unexpected by the 
parent.  This information would be explained to the parent by an experienced and licensed psychiatrist 
or psychologist, along with recommendations for services at Duke or in the community, if appropriate. 
Children with ASD and ADHD may exhibit behaviors such as tantrums and other challenging behaviors, 
and can these worsen in severity without appropriate intervention. It is anticipated that these events 
could occur during the course of the study due to the nature of the child’s conditions, and may occur 
during study activities. If they do happen, the study staff will reassure the parent they may take a break 
and coach them as needed to help address the behavior in the moment. Our staff and clinicians are well 
trained to address these difficulties with children with ASD, ADHD, and other developmental conditions.  
 There is a potential risk for a loss of confidentiality due to reasons beyond our control. Our study 
processes and data storage and security methods, overseen by the DMAC, are designed to minimize 
these risks. All information that is collected in connection with this study will remain confidential and 
will only be disclosed as required by U.S. or State law. Examples of information that we are legally 
required to disclose include abuse and neglect of a child. Every foreseeable precaution to protect 
confidentiality will be taken. Nevertheless, despite such precautions, there are always risks to 
confidentiality with participation in any study of this kind as researchers will have access to subjects’ 
medical records and protected health information. 
 
2.4.2 Known potential benefits  
All participants in this trial will receive 8 sessions of ESDM-informed caregiver coaching, a well-accepted 
parent coaching behavioral intervention from expert providers free of charge.  The ESDM-informed 
caregiver coaching is expected to facilitate the caregiver’s use of ESDM behavioral intervention 
strategies in multiple daily living contexts on a daily basis for an extended period. The caregiver 
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.  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 benefits outweigh the risks given that the caregiver can withdraw from the study at any time. They 
can decline to respond to any question or assessment at any time.  

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There is a scarcity of accessible and effective behavioral interventions for individuals with ASD and 
ADHD, and the current pandemic makes access to therapies and support even more challenging. Based 
on extant clinical evidence and empirical data on the positive impact that behavioral intervention and 
parent coaching (in the traditional format) has on child development, family wellbeing, improvement in 
ASD symptoms and daily functioning, it is our hope and belief that participation in the caregiver 
coaching component (remotely) may bring some benefit to the families in this study in both the short 
and long term. The study will also make this form of support and coaching more accessible to families 
that currently do not have such access. If the risks (such as psychological discomfort related to any of 
the assessments) outweigh this benefit for any one individual, they may withdraw at any time without 
any penalty or loss of services they would otherwise have access to. By maintaining contact with 
participants, and conducting assessments and questionnaires designed to measure participant wellbeing 
and symptoms during the course of their participation, study clinicians will be able to help detect and 
determine if it is no longer in the interest of the family to participate. This includes assessment of AEs 
which will allow us to track closely whether any symptoms are worsening or if new ones are to appear. 
Participants will be informed during the consent process and throughout their participation that their 
involvement is always completely voluntary and will always receive support in making decisions that 
beneficial to them and their child.  
 
3 
OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS 
  PRIMARY 
 
Determine implementation 
outcomes including 
acceptability, 
appropriateness, feasibility, 
and fidelity.  
Acceptability, appropriateness, and feasibility will be quantitatively 
and qualitatively assessed using 4-item, pragmatic scales and 
individual stakeholder interviews.  
 
 
 
 
Fidelity of intervention delivery, will be monitored using an adapted 
version of the Parent Early Start Denver Model (P-ESDM) Caregiver 
Fidelity Rating System.  
 
SECONDARY 
 
Determine proximal changes 
in child and caregiver 
interactions and caregiver 
sense of competence  
A key proximal outcome will be change from baseline (pre-
intervention) to 9-weeks (immediately post-intervention) in 
caregiver sense of competence measured by the Parent Sense of 
Competence Scale and child behaviors measured by the sum of 4 
items from the JERI (Joint Engagement, Attention to Caregiver, 
Responsiveness to Partner’s Communication Bids, Fluency and 
Connectedness).  
 
 
Other Exploratory behavioral outcomes at 9 weeks and 16 weeks 
Assess core ASD social 
• Social Responsiveness Scale-2 (SRS-2)(66-68) 

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OBJECTIVES 
ENDPOINTS 
functions, ADHD symptoms, 
symptoms and adaptive 
functioning  
 
 
 
• Aberrant Behavior Checklist-2 (ABC)(69, 70) 
• ADHD-RS 
• VABS-3  
 
Assess other aspects of 
attention and executive 
function 
• Behavioral Rating Inventory of Executive Function (BRIEF)(77, 78)  
Other Relevant Behaviors 
• Child Behavior Checklist (CBCL)(79) 
Caregiver functioning & 
attitudes toward treatment 
• Caregiver Strain Questionnaire (CSQ)(83, 84) 
 
Safety assessments 
• Treatment emergent adverse effects assessed based on 
spontaneous report from parent/caregiver 
 
 
 
 
4 
STUDY DESIGN  
 
4.1 
Overall Design 
 
The overall study design and key outcomes and assessments are shown in the Schema in the synopsis.   
The provided behavioral treatment will be eight consecutive weekly ~60-minute coaching sessions 
delivered remotely.  The ESDM-informed caregiver coaching is a modification of the evidence-based 
behavioral treatment of ESDM, which is typically delivered as 20 hours/week of 1:1 interaction between 
the child and a trained therapist over a 2-year period.  The ESDM-informed caregiver coaching 
modification reduces rigid time demands on families and is more likely to be sustainable and available in 
the current healthcare environment.  Additionally, the remote implementation of the intervention 
allows this to be utilized in pandemic conditions and in rural communities where it may be difficult to 
travel to an academic center for sessions.  
 
4.2 
Scientific Rationale for Study Design 
 
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 assessing the feasibility of an 
adapted caregiver delivered ESDM behavioral intervention given remotely in children with a dual 
diagnosis of 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. 

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By understanding rates of enrollment, acceptability, appropriateness, and feasibility of a behavioral 
intervention delivered remotely to caregivers of children with both ASD and ADHD we can begin to 
develop a more informed patient centered phase 2 study which would address both a medication 
component and behavioral intervention for the treatment of ASD and ADHD.  
 
4.3 
Justification for Dose 
No study-provided medication 
 
4.4 
End of Study Definition 
 
A participant is considered to have completed the study if he or she has completed the endpoint 
assessments of all phases of the study or has been withdrawn from both treatment and assessments in 
the study.  If a participant chooses to stop behavioral treatment in the study before endpoint 
assessments, he or she will be requested to complete them on schedule if at all possible.   The follow-up 
visit at 16 weeks following baseline is optional.  
 
 
5 
STUDY POPULATION 
The planned sample size is 35 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 of parent/guardian to comply with all study procedures and availability for 
the duration of the study.  
3. Child is between 36 months and <132 months of age at baseline.   
4. Child has a confirmed DSM-5 diagnosis of both ASD and ADHD, informed by results of 
assessments including: an ASD diagnostic assessment (Brief Observation of Symptoms of Autism 
[BOSA], Autism Diagnostic Observation Schedule, 2nd Edition [ADOS-2], or TELE-ASD-PEDS, and 
if applicable the Autism Diagnostic Interview - Revised [ADI-R]) and an ADHD diagnostic (a 
standardized ADHD Diagnostic Interview and the MINI psychiatric diagnostic interview). 
 
5.2 
Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation in this study: 

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1. If continuing psychotropic (CNS-active) medications, must not have been changed within 4 weeks 
prior to baseline.  
2. Significant visual, auditory or motor impairments that would preclude participation in ESDM-
informed parent coaching or completion of key assessments. 
3. Inability of the caregiver participating in ESDM-informed caregiver coaching and responding to 
questionnaires to fluently speak English.  
4. Study clinician judgment that it is not in the best interests of the participant and/or the study for 
the child to participate (including presence of psychiatric conditions or psychiatric symptoms in 
addition to ASD and ADHD that in the opinion of the PI or based on senior clinical review, would 
confound assessments and/or affect participation in the study).  
 
5.3 
Lifestyle Considerations 
None applicable. 
 
5.4 
Screen Failures 
Screen failures are defined as participants who consent to participate in the diagnostic portion and the 
study but are not subsequently enrolled. Individuals who initially express interest but do not consent to 
or attend ARC visits will also be considered as part of the number approached for determining rates of 
enrollment. 
 
5.5 
Strategies for Recruitment and Retention 
The target sample size is 30-35.  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 caregiver coaching be 
fluent in English.  We expect to enroll 1-3 participants per month.    
Participants will be recruited from A+ Assessment, A+ Health, A+ Development, community 
advertisements, medical records, 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 weekly ESDM-informed 
caregiver coaching visits. 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.  In addition, the recruitment core may 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 visit and its 
associated assessments, for each coaching session, and for the remote follow-up assessment completion 
for a maximum of $550 to help compensate for participation in this protocol.  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 caregiver coaching as part 
of the study without extensive waiting and at no cost is anticipated to be an incentive.  We will also 
provide the participant with reports of Vineland and diagnostic assessments if requested.  
Qualitative interviews and surveys with staff, coaches and clinicians: to prevent any undue influence, 
clinicians, coaches and staff will be asked by a non-supervisor team member whether they wish to do 
the qualitative interview/survey, and it will be stressed that they are free to say no, that their decision 
will have no impact on their employment, performance evaluations, or standing, and that they should 
only participate it if they are completely comfortable doing so. Those who do decide to participate in the 
interview and/or survey will not be provided with compensation beyond what they are paid for that 
time as part of their study role (this means the time taken to do the interview and/or survey will be 
done as part of, and will count towards, their regular working hours). To minimize bias when staff, 
clinicians, and coaches share about their experiences and opinions, and to ensure voluntariness in the 
consent process, we plan to have a study team member who is not the interviewee’s supervisor or 
mentor conduct the interview and the consent processes.  
Rationale for Selection Criteria:  We have included children between 36 months and < 132 months of 
age in order to facilitate recruitment.  We excluded children below 36 months’ chronological age in 
order to ensure that ADHD can be reliably diagnosed.  We are allowing additional comorbid diagnoses or 
symptoms because studies suggest that a substantial percentage of children with ASD+ADHD will have a 
third psychiatric diagnosis or other symptoms, and we would not be able to reach our recruitment goals 
if these children were excluded. Additionally, the study will not exclude participants solely on the basis 
of a known genetic or neurological condition, as this would unnecessarily prevent otherwise eligible 
children with ASD and ADHD from participating in and potentially benefiting from this intervention. 
Furthermore, behavioral intervention in not anticipated to pose an additional risk due to these 
characteristics; inclusion will also allow for a more representative sample. Participants may be found 
ineligible if, according to study clinician judgment, it is not in the best interests of the participant and/or 
the study for the child to participate (including presence of psychiatric conditions or psychiatric 
symptoms in addition to ASD and ADHD that in the opinion of the PI or based on senior clinical review, 
would confound assessments and/or affect participation in the study). 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. 
 

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Attrition:  We conservatively estimate that ~15% will not be able to meet the time, technology demands 
of the study.   
 
6 
STUDY INTERVENTION 
 
6.1 
Study Interventions Administration 
 
6.1.1 Study medication intervention description 
No study medication provided. This study will enroll both participants who are on ADHD medication 
(prescribed by a personal provider) or those who chose to not take medication.  
6.1.2 Medication dosing and administration 
No study medication provided. This study will enroll both participants who are on ADHD medication 
(prescribed by personal provider) or those who chose to not take medication. 
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 hours/week of 1:1 interaction between the child and a trained therapist for a 2 
year period.  ESDM-informed caregiver 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 
sessions.  During these sessions, the therapist will coach the caregiver 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 caregiver coaching by a 
certified ESDM trainer.   
If live Zoom recording of ESDM coaching sessions is not feasible (e.g., unstable or there is no high speed 
internet connection), participants will be allowed to record the ESDM sessions on their own device and 
upload the video to a unique Duke BOX link created by the study team for the participant. The ESDM 
sessions may also take place asynchronously (videos recorded before coaching feedback) and done over 
phone instead of Zoom.  Participants will receive verbal and written instructions for how to self-record 
ESDM videos using their own device and upload into Duke BOX. Other strategies may also be used by 

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the team to facilitate access and engagement. For example, a hot spot may be provided to participants if 
they are in remote locations.  
 
Participants will be asked at enrollment/screening/ ARC about access to internet and familiarity with 
technologies in order to help with planning of A+ Treatment sessions and internet/technology access 
needs. 
 
The total number of caregiver coaching visits attended will be tracked, the parent’s use of ESDM 
techniques will be assessed at coaching sessions 1-8 by the therapist (scale of 1-3), 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. 
 
6.2 
Clinical Trial Supplies Preparation/Handling/Storage/Accountability 
 
 
No study medication provided. This study will enroll both participants who are on ADHD medication 
(prescribed by personal provider) or those who chose to not take medication. 
 
6.3 
Measures to Minimize Bias: Randomization And Blinding 
All participants will be treated openly with caregiver coaching with no randomization occurring and no 
blinding occurring. If participants choose to take ADHD medications that will be done separately from 
the study with no randomization or specific rules for treatment. 
 
6.4 
Study Intervention Compliance 
No study medication provided. This study will enroll both participants who are on ADHD medication 
(prescribed by personal provider) or those who chose to not take medication.  
 
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 study behavioral treatment (ESDM-informed caregiver 
coaching), or of specific study assessments.  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 studies of young children with ASD and have never been shown previously to result in 
significant safety risks we expect there will be very low risk for study halting due to safety concerns.  
 
7.2 
Rules for Individual Participant Discontinuation in Study Interventions 

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Participants’ caregivers may choose to discontinue the study behavioral caregiver 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.  
 
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 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.   
 
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 and is unable to be contacted by the study site staff after 3 attempts 
by 2 methods including email and phone.  
The following actions must be taken if a participant fails to attend required study visit: 
• 
The site will attempt to contact the participant’s caregiver 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.  
• 
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 behavioral caregiver 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 
 
• 
Acceptability of Intervention Measure (AIM), Intervention Appropriateness Measure (IAM), and 
Feasibility of Intervention Measure (FIM). (Weiner et al., 2017) These measures have been 
administered to a wide range of stakeholders to determine the extent to which they believe an 
intervention or implementation strategy is acceptable, appropriate, and feasible. Readability is at 
the 5th grade level. Higher scores indicate greater acceptability, appropriateness, and feasibility. The 

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AIM, IAM, and FIM have demonstrated content validity, discriminant content validity, reliability, 
structural validity, structural invariance, known-groups validity, and responsiveness to change. This 
measure will be completed with participants who enroll in the study, as well as coaches, clinicians, 
and support staff who consent to conduct the Qualitative Interview and AIM-IAM-FIM survey. 
 
• 
Two Early Start Denver Model (ESDM) fidelity scales will be utilized in this study: (1) ESDM 
Coaching Fidelity Rating System; and the (2) Parent Early Start Denver Model (P-ESDM) Caregiver 
Fidelity Rating System. The ESDM Coaching Fidelity Rating System evaluates 14 coaching behaviors 
during the caregiver coaching sessions. Items are individually rated with a Likert-type rating scale 
with values that vary from 1 to 4, with higher scores reflecting a greater degree of fidelity. A portion 
of the items evaluate specific activities within the intervention session (e.g., warm-up activity, 
coaching on the topic) and the remaining items assess coaching characteristics which are evaluated 
across the entire session (e.g., reflective, nonjudgmental). The P-ESDM Caregiver Fidelity Scale 
provides a method for assessing the fidelity with which a caregiver is using ESDM principles in a joint 
activity routine with their young child. The 13 item rating scale includes ratings of performance from 
1 to 3. 
 
• 
Caregiver Sense of Competence Scale (also known as Parenting Sense of Competence) is a caregiver 
self-report measure that was initially developed by Gibaud-Wallston and Wandersman (1978) and 
was translated and revised by Johnston and Marsh (1989) to assess parenting sense of competence 
in 3-17-year-old children.  It is a 16 item 6-point Likert scale questionnaire with ratings ranging from 
strongly agree (1) to strongly disagree.  It includes 2 validated factors: satisfaction (9 items) and 
efficacy (7 items).  Several of the items are reverse coded (highlighted in yellow on the form).  There 
is an optional 17th question about the reward of being a good parent/caregiver.  
 
• 
Vineland Adaptive Behavior Scales—Third Edition (Vineland-3). This assessment examines the 
child’s adaptive functioning. These are day to day behaviors one uses to live and get along in the 
world. There are several domains including: Communication, Daily Living Skills, Socialization, Motor 
Skills, and Maladaptive Behaviors. The Parent/Caregiver Forms are administered through Q-global 
Remote On-Screen Administration (ROSA). 
 
• 
Parent-Child Interaction Task (PCIT) is a remote six-minute free play task between a caregiver and 
child that serves as a naturalistic, observational measure of social engagement and dyadic 
interaction. Eight standardized toy categories are designated for this task, with toys being selected 
for each category from those available in the family’s home. The PCIT is conducted remotely via a 
secure Zoom recording in the family’s home. The PCIT consists of a pre-visit Zoom call with the 
caregiver, and then the separate PCIT session with the caregiver and child. During the pre-visit call, 
the examiner and caregiver work together to select toys for each category; to determine the best 
location in the home for the PCIT session; to determine the recording device and best camera angles 
for the recording; and to review the general plan for the PCIT session. The PCIT remote recording 
session involves a review of the room setup with the caregiver and instructions for just the 
caregiver, followed by the 6-minute play session with the caregiver and parent. After recording PCIT 
sessions, videos will be quality reviewed and trimmed. Behavioral coding of trimmed videos using 
selected items from the Joint Engagement Rating Inventory (JERI) will be conducted in Noldus 
Observer XT software. If live Zoom recording of PCI sessions is not feasible (e.g., unstable or there is 
no high speed internet connection), participants will be allowed to record the PCI videos sessions on 
their own device and upload the video to a unique Duke BOX link created by the study team for the 

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participant. The PCI sessions may also take place asynchronously (videos recorded before coaching 
feedback) and done over phone instead of Zoom.  Participants will receive verbal and written 
instructions for how to self-record PCI videos using their own device and upload into Duke BOX. 
Other strategies may also be used by the team to facilitate access and engagement. For example, a 
hot spot may be provided to participants if they are in remote locations. 
 
• 
Qualitative interview with stakeholders. Questions in the interview will be tailored to stakeholder 
group (Caregivers, Coaches, Clinicians, or Staff) and will be informed by previous studies that have 
examined barriers and facilitators during the implementation of a new treatment approach. 
Interviews will be conducted with caregivers after they have completed coaching sessions and with 
coaches and staff once they delivered the intervention and supported coaching activities. For study 
coaches, clinicians, and/or staff who are interviewed, they will be consented by the regulatory 
coordinator or other trained person who is not the PI and does not have a supervisory or mentoring 
relationship with the interviewee. Similarly, the interviewer will also be a trained individual who is 
not a supervisor or mentor of the interviewee. This will help ensure that the consent is voluntary 
and minimize bias in the answers and feedback given during the interview. A separate, IRB-approved 
consent form will be used for consenting staff, clinicians, and coaches who give their permission to 
complete the Qualitative Interview and AIM-IAM-FIM survey.  
 
• 
The Preschool or School age ADHD Rating Scale –  the parent rating version of the ADHD-RS will be 
used to assess ADHD symptoms.  
 
• 
SenseToKnow (S2K). Children may complete this task remotely (app) . The app 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 caregiver’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. During the S2K administration, the app generates a video and audio 
recording of the child’s responses to the stimuli in the movies. All sensor information gathered on 
the iPhone or iPad will be collected. At the completion of the S2K administration, either the study 
staff or the parent/caregiver will upload the saved recording of the enrolled participant to a secure 
study database for analysis. 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 
available to answer questions. 
 
• 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 BRIEF is for 
children between 3 years and 5 years 11 months and the BRIEF-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 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 
• 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. Caregivers of 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.  
 
8.1 
Other Assessments 
• ACE Medical and Family History forms: Caregivers will be administered the ACE Subject Medical 
History   Form, and the   ACE   Family   Medical   History Form at the screening visit. The ACE Subject 
Medical History Form 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 Form 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.  

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• 
The Condensed (non-ASD) Medical History Form is completed at Baseline and Weeks 1-9. It is 
similar to that used by physicians during routine clinical visits and in clinical trials.  It is focused on 
issues that aren’t clearly related to the etiology of ASD and that may inform assessment of adverse 
events during the course of the trial.  
 
• Assessment of adverse events: AEs are collected at Baseline and Weeks 1-9. At each of these time 
points, 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 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 Week 9, 
each problem’s relatedness to the study interventions will be assessed.  The adverse event form will 
include information about intensity, start and stop dates, relatedness to study procedures and 
status of AE when it resolves or at Week 9. 
• 
Concomitant Medication Log: At the first visit (Baseline), the physician will make a list of any 
medications the subject is currently taking. The concomitant medication log will also be completed 
at each of the Weeks 1-9 time points. 
 
8.2 
Adverse Events and Serious Adverse Events 
8.2.1 Definition of adverse events (AE) 
Adverse event means any untoward medical/legal occurrence that happens during the course of the 
study, whether or not the medical occurrence is considered intervention-related (21 CFR 312.32a).  
Adverse events will be specifically elicited using open ended queries. If an AE has a severe adverse event 
rating of “Severe” and is an Unexpected Problem (UP) (meaning a problem not previously seen or 
expected in children with ASD and ADHD), then the event must be documented and reported as a UP 
(see below, 8.3.2),.  If a TEAE is a Serious Adverse Event (SAE), but not an UP, the SAE will be 
documented and reported accordingly (see below, 8.2.6).   
 
8.2.2 Definition of serious adverse events (SAE)  
An adverse event (AE) is considered "serious" if 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 an offspring’s 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.  
8.2.3 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. 

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• 
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 extended period of time and 
are usually incapacitating during that period.  Medical evaluation and treatment are generally 
required if such treatment exists.  
 
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 with ASD.  
 
8.2.4 Time period and frequency for event assessment and follow-up 
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 other contacts with participants or 
communication from other medical providers caring for the study participant.  All non-serious TEAEs will 
be followed up until satisfactory resolution 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.  
 
8.2.5 Adverse event reporting  
All AEs not meeting the criteria for SAEs will be captured in the through a general AE inquiry. 
Information to be collected initially includes event description, clinician’s assessment of intensity, 
relationship to study procedures (note NO study medication provided). If the event has resolved that 
will also be collected.  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 unless there is a significant increase in the condition’s intensity leading to a change in the intensity 
rating.   
 
8.2.6 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 and study PI.   
The study physician or PI will review and evaluate the potential SAE, obtaining external medical records 
if possible.  
If the event is deemed to be an SAE: 
• 
The ACE Center PIs will be notified within 24 hours. 
• 
Record event in a NTF 

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• 
The study clinician (MD)will follow the trajectory of the SAE until it is resolved or deemed to be 
clinically stable or for 1 month following the week 16 visit. 
 
Timeline for reporting of SAEs is: 
• 
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. 
• 
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 14 
days of becoming aware of the SAE.  SAEs that are not considered related or unexpected will be 
reported in annual progress reports. 
 
8.2.7 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.  
 
8.2.8 Reporting of pregnancy  
Not-applicable due to age of participants. 
 
8.2.9 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.   
 
8.3 
Unanticipated Problems 
8.3.1 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: 

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• 
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. 
 
8.3.2  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. 
• 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.   
• 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. 
 
8.3.3 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. 
 
8.4 
Overall Plan to Protect Patient Safety 
 

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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 enrolled and started the study, until the last participant has completed the week 16 visit, 
the DSMB will meet a minimum of two times a year to review the study’s progress and the safety.  
Specifically, the following will be reviewed at each meeting: 
1. 
enrollment as compared to proposed enrollment,  
2. 
SAEs and UPs with any resulting changes in study procedures or consents, 
3. 
participant discontinuation, study withdrawals, and study completions 
4. 
adverse events separated by system organ class, severity and relatedness, 
5. 
protocol deviations  
 
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.   
 
9 
STATISTICAL CONSIDERATIONS  
9.1 
Sample Size Determination 
Since this is a feasibility study not an efficacy trial, the sample size was determined based on expected 
ability to recruit during the period of the study. 
 
 
9.2 
Population for Analysis 
The primary analysis population will include all participants. 
The safety population will include all participants  
 
9.3 
Statistical Analyses 
9.3.1 General approach 
We will conduct preliminary checks to identify potential outliers and missing data. We also will examine 
clinically meaningful subgroupings such as age, gender, and IQ. As part of the study design, efforts will 
be made to collect all outcomes on all participants, even when behavioral intervention is prematurely 
terminated.   
A final statistical analysis plan will be developed and signed prior to final database lock. 
 

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9.3.2 Analysis of the primary efficacy endpoint 
The primary feasibility analysis will focus on the Acceptability of Intervention Measure (AIM), 
Intervention Appropriateness Measure (IAM), and Feasibility of Intervention Measure (FIM). These 
measures can be administered to a wide range of stakeholders to determine the extent to which they 
believe an intervention or implementation strategy is acceptable, appropriate, and feasible. Readability 
is at the 5th grade level. Higher scores indicate greater acceptability, appropriateness, and feasibility. 
The AIM, IAM, and FIM have demonstrated content validity, discriminant content validity, reliability, 
structural validity, structural invariance, known-groups validity, and responsiveness to change. Means 
and standard deviations will be reported for the AIM, IAM, and FIM. Descriptive statistics on caregiver 
completion rates for the 8-session treatment program will be reported.  
Acceptability, appropriateness and feasibility will also be assessed qualitatively with stakeholder 
individual interviews. In the field of implementation science, qualitative methods are frequently used to 
shed light on key implementation challenges8. Questions in the interview guide will be tailored to 
stakeholder group (Caregivers, Coaches, Clinicians, or Staff) and will be informed by previous studies 
that have examined barriers and facilitators during the implementation of a new treatment approach9-11. 
Interviews will be conducted with caregivers after they have completed coaching sessions and with 
coaches, clinicians, and staff once they have delivered the intervention and supported coaching 
activities for a 6-month period. Qualitative analysis will use an iterative coding and review process 
informed by grounded theory12. To minimize bias and protect privacy, personal names and direct 
identifiers in transcripts of the interviews will be replaced with a code or descriptor. Qualitative data will 
initially be coded independently by two team members at a general level in order to condense data into 
analyzable units. Responses will be assigned codes based on a priori or emergent themes. 
Disagreements will be resolved by reviewing transcripts and additional discussion. A final list of codes 
will be developed through consensus. Axial coding will then be used to generate categories arranged in 
a treelike structure connecting segments into separate nodes, describing the relationship between 
codes and subcategories. Nodes and trees will be used to create a taxonomy of themes including a 
priori, emergent and new categories. Qualitative coding will then be quantified using frequency counts 
to identify primary themes. Participant quotes from individual interviews will inform assessments of 
acceptability, appropriateness, and feasibility of the adapted coaching approach. 
Fidelity of intervention delivery, the degree to which programs are implemented as intended by 
program developers, is an important implementation outcome because it can moderate the effect of an 
intervention on targeted health outcomes2,4. When interventions are adapted to fit a new target 
population, delivery setting, location or organization, maintaining intervention fidelity is of particular 
importance. Fidelity of caregiver implementation of ESDM strategies will be assessed quantitatively, 
using an adapted version of the Parent Early Start Denver Model (P-ESDM) Caregiver Fidelity Rating 
System. The P-ESDM Caregiver Fidelity Scale provides a method for assessing the fidelity with which a 
caregiver is using ESDM principles in a joint activity routine with their young child. The 13 item rating 
scale includes ratings of performance from 1 to 5.  Observations will be coded from video-recorded 
caregiver-child interactions completed at baseline (pre-intervention) and at 9-weeks (post-intervention), 
by certified ESDM therapists who are naïve with respect to whether they are coding the baseline or 9-
week observation. Tabular and graphical summaries of pre and post caregiver implementation fidelity 
will be generated to assess the degree to which the average in the cohort changes over time. Inference 
on pre-post change will be based on paired t-tests or, if the assumptions are found to be untenable, the 
Wilcoxon signed rank test for paired samples. 
 

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9.3.3 Analysis of the secondary endpoints 
Proximal child and caregiver outcomes. A key proximal outcome will be change from baseline (pre-
intervention) to 9-weeks (immediately post-intervention) in caregiver ) sense of competence measured 
by the Parent Sense of Competence Scale and child behaviors measured by the sum of 4 items from the 
JERI (Joint Engagement, Attention to Caregiver, Responsiveness to Partner’s Communication Bids, 
Fluency and Connectedness) coded by a trained, reliable coder who is naïve with respect to whether the 
observation is from baseline our outcome using video-recorded caregiver-child interactions.  
Aim 2 data analysis: Quantitative measures, including participant demographics, will be summarized 
using descriptive statistics. Means and standard deviations will be reported for continuous measures, 
and frequency and percentages are reported for categorical variables. Tabular and graphical summaries 
of each outcome measure at each assessment point will be generated to assess the degree to which the 
average in the cohort changes over time (e.g. boxplots of VABS-3 Communication at baseline and follow 
up). Inference on pre-post change will be based on paired t-tests or, if the assumptions are found to be 
untenable, the Wilcoxon signed rank test. 
9.3.4 Safety analyses 
There is no study provided medication in this sub-study. However, AEs will be collected. Each AE will be 
counted once only for a given participant. TEAEs will be presented by severity.   
 
9.3.5 Baseline descriptive statistics 
Baseline descriptive statistics will include demographics, ADOS/BOSA severity scores, cognitive function, 
adaptive behavior scores, ADHD-RS scores using descriptive statistics of mean value, standard deviation 
and range.  
 
9.3.6 Planned interim analyses  
No interim analyses are planned.  
 
9.3.7 Sub-group 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.  
 
9.3.8 Exploratory analyses 
Additional Exploratory proximal and distal outcomes of interest include: a) caregiver ADHD-RS ratings of 
the child’s attention. b) Aberrant Behavior Checklist (ABC), including inattention/hyperactivity, social 
withdrawal, stereotypies, irritability, and inappropriate speech; c) Social Reciprocity Scale-2 (SRS-2) 
ratings of child’s social communication behavior; d) Caregiver Strain Questionnaire (CSQ) ratings of the 
impact of the child’s condition on the family and caregiver and quality-of-life; e) Behavior Rating 
Inventory of Executive Functions (BRIEF) ratings of child’s executive function; and f) Child Behavior 

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Checklist (CBCL) ratings of child behavioral and emotional problems. Our analysis will focus on graphical 
displays, which will be complemented by appropriate inferential statistical procedures. For the graphical 
displays, we will visualize the distribution of proximal and distal outcome measures in histograms to 
better understand the shape and spread of the distribution of each. In terms of inference, between 
group change at proximal and distal time points will be based on between group t-tests or, if the 
assumptions are found to be untenable, the Mann-Whitney U test. Whilst statistical inference is 
valuable, we anticipate that we will elicit most information through careful data visualization. Change 
from baseline (pre-intervention) to 16-weeks (8-weeks post-intervention) will be assessed for the VABS-3 
Socialization and Communication Subscale Standard Scores.   
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
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.  DUHS IRB approved informed 
consent documents will be used for the preliminary screening study (A+ Assessment) and this study (A+ 
Treatment).  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 Guidance Documents and study 
MOPs, and documented in the source documents, before the participant undergoes any study-specific 
procedures. REDCap will be utilized to conduct and document the consent process remotely. A 
teleconference meeting will be set up to review the consent form with the parent prior to signing the 
eConsent electronically. The consent process with staff, coaches and/or clinicians who elect to 
participate in the Qualitative Interview and AIMS-IAM-FIM survey, will be done by trained team 

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members who are not that person’s supervisor or mentor, in order to minimize bias. Voluntariness will 
be stressed throughout the process.  
 
 
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 caregiver 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.  
Suspension of the entire study.  This study may be temporarily suspended or prematurely terminated if 
there is sufficient reasonable cause.  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 funding agency, and 
regulatory authorities. All staff completing study activities remotely will utilize spaces that protect the 
privacy of participants and will use the security settings as dictated by the software and applicable OIT 
guidelines, including password protecting teleconference meetings. Participants will also be informed of 
these measures and encouraged to use spaces that protect their privacy while engaging in remote study 
activities, such as interviews or behavioral coaching.  

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Various documentation practices are maintained throughout each level of data collection and 
processing to maintain participant confidentiality. These practices are regularly checked though Quality 
Assurance practices. Documents containing personally identifiable information (such as the study 
consent forms and forms containing information used to generate a GUID) and documents containing 
study data will be stored in separate physical locations. Electronic files stored in the study server or on 
the study databases may directly or indirectly link personal information and identifiers with study data 
by being stored in the same electronic file or folder, or by being associated with the same record and ID. 
Any linkage and use of PHI will be based on the minimum necessary information to conduct the research 
activities and data collection and processing in an effective, secure, and valid manner. Participants will 
be identified by a unique subject ID (which will be used in place of names) in data collection forms. 
Some assessments and derived data in this study require information about the participant’s age 
(birthdate) and gender but will not be linked to other identifying information such as full names or 
address.  All data will be housed in secure locations.  
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), may inspect all documents and records required to be maintained by the investigator, 
including but not limited to, study source documents, medical 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.  
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.   
To complete the SenseToKnow app, participants will be asked to use their own or a borrowed 
iPhone/iPad. Alternatively, they may borrow a Duke-owned device. Participant data will be stored on 
the device(s) and securely uploaded to the study database. Participants who complete this measure will 
receive instructions on how to complete the measure, including any security settings in place (e.g., 
receiving a link and password). The study’s physicians will be available to address any clinical concerns 
that arise during the course of the study and that may be related to the conduct of the study.  If a 
concern is voiced by the participant or guardian, the physician will evaluate it and advise the caregiver 
as to whether or not it is likely to be related 
To further protect the privacy of study participants, this study adheres to the Certificate of 
Confidentiality issued by the 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.  

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10.1.1 Safety oversight 
There will be a DSMB to oversee the safety of participants in the study as described in section 8.4.  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.   
 
10.1.2 Key roles and study governance 
 
 
10.1.3 
Clinical data 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. 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 
Principal Investigator 
Center  PI 
 
Geraldine Dawson, PhD 
Geraldine Dawson, PhD 
 
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 
 
919 668 0070 
919 668 0070 
 
Geraldine.dawson@duke.edu 
 
Geraldine.dawson@duke.edu 
 
 

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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.  
In addition, the Duke ACE Center Regulatory Coordinator will conduct periodic monitoring during the 
course of the trial.  During these times, 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 
Guidance Documents, tracking 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 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 monitoring and quality assurance. 
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 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 or virtual electronic copies 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 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 

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and internal quality checks, such as automatic range checks, to identify data that appear inconsistent, 
incomplete, or inaccurate.  
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.  
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, 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 study will keep a listing of all study visits that occur outside of specified 
study windows.  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.   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 

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there are conflicts about authorship, the Duke ACE Center Executive Committee will resolve the conflicts 
in accordance with the Center’s publication policies.   
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 for 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.  Data 
generated by Qualitative Interviews and surveys conducted with staff, clinicians and/or coaches will not 
be submitted to NDAR. 
Genomic data will not be generated by this study.  
 
10.1.8 Conflict of interest policy 
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 
AE 
Adverse Event 
AIM 
Acceptability of Intervention Measure  
ASD 
Autism Spectrum Disorder 
BRIEF 
Behavior Rating Inventory of Executive Function 
CBCL 
Child Behavior Checklist 
CFR 
Code of Federal Regulations 
CMP 
Clinical Monitoring Plan 
CNS 
Central Nervous System 
COC 
Certificate of Confidentiality 

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CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
CSHQ 
Children’s Sleep Habits Questionnaire 
CSQ 
Caregiver Strain Questionnaire 
DMAC 
Data Management and Analysis Core  
DSMB 
Data Safety Monitoring Board 
FDA 
Food and Drug Administration 
FIM 
Feasibility of Intervention Measure  
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
IAM 
Intervention Appropriateness Measure  
ICH 
International Council for Harmonisation 
IRB 
Institutional Review Board 
IRS 
Impairment Rating Scale 
JERI 
Joint Engagement Rating Inventory 
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 
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.  
 
 

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