Clinical trial NCT03900923
Conditions: ASD Autism Spectrum Disorder
Keywords: cannabidiol (CBD)
Sponsor: NYU Langone Health
Start date: 2019-03-12; Completion date: 2023-05-04
Enrollment: 29 participants; Allocation: NA; Intervention model: SEQUENTIAL

Brief summary:
This is a 6-week open trial to identify the optimal dosing of cannabidiol (CBD) in youth with autism spectrum disorder (ASD) and to identify primary and secondary outcomes for future controlled studies. This study evaluates change in symptoms commonly associated with ASD, as evidence suggests that CBD may be eﬀective in addressing diﬃculties such as irritability and anxiety, while maintaining a benign adverse eﬀect (AE) proﬁle in children and adolescents.

30 male and female participants with ASD between the ages of 7 and 17 years old are being recruited. Participants have ﬂuent speech and an estimated IQ greater than or equal to 80. Study intervention is 98% pure CBD. The CBD is Greenwich Biosciences, Inc.'s 100mg/mL oral solution, brand name EPIDIOLEX. First, a Bayesian optimal interval (BOIN) design was used, such that participants were assigned to cohorts of size 3 receiving doses of 3, 6, or 9 mg/kg/day, depending on the treatment response of participants in prior cohorts.

The BOIN design ended after the fifth cohort of participants, and the two lower doses, 3 and 6 mg/kg/day, were eliminated. The highest dose, 9 mg/kg/day, was not tested. Therefore, in subsequent cohorts, we will be examining 9 mg/kg/day exclusively in up to 15 additional participants with co-occurring ASD and attention-deficit/hyperactivity disorder (ADHD) diagnoses, as this clinical profile appears to most closely resemble youth classified as responders within the BOIN design.

Detailed description:

Arms: arm 1: 98% pure CBD. The CBD will be 100mg/mL oral solution provided by Greenwich Biosciences, Inc.
Interventions: intervention 1: 98% pure CBD
Intervention descriptions: intervention 1: A Bayesian optimal interval (BOIN) design was used, such that participants were assigned to cohorts of size 3 receiving doses of 3, 6, or 9 mg/kg/day, depending on the treatment response of participants in prior cohorts. The BOIN design has ended, and two doses have been tested and eliminated (3 and 6 mg/kg/day). We are now examining 9 mg/kg/day exclusively.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Official Title: 
A Phase 2 Study of Cannabidiol as a New Treatment for Autism 
Spectrum Disorder in Children and Adolescents   
NCT Number: 
NCT03900923 
Study Number: 
18-00250 
Document Type:  
Study Protocol and Statistical Analysis Plan 
Date of the 
Document: 
• 
September 13, 2022 
 
 


A PHASE 2 STUDY OF CANNABIDIOL AS A NEW 
TREATMENT FOR AUTISM SPECTRUM DISORDER IN 
CHILDREN AND ADOLESCENTS [CBD4ASD-open] 
Protocol Number: s18-00250 
National Clinical Trial (NCT) Identified Number:  NCT03900923 
Principal Investigator: Francisco Xavier Castellanos, MD  
<IND/IDE> Sponsor: Department of Child and Adolescent Psychiatry, Hassenfeld 
Children’s Hospital at NYU Langone 
Version Number:  v.1.17 
30 August 2022 
 
Summary of Changes from Previous Version: 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
6.1.2 
We removed sections in 6.1.2. Dosing and 
Administration, asking caregivers to 
provide information on typical eating 
habits at baseline. Caregivers will also no 
longer be requested to provide preferred 
meals with adequate fat content at drug 
administration times. No data on food 
administered with the cannabidiol will be 
collected.  
Preliminary analyses with n=19 showed low inter-
participant variability in caregiver data on dietary intake 
and no appreciable relationships to plasma levels of 
cannabidiol or to outcome measures. Therefore, we will 
stop collecting these data to minimize burden on 
caregivers.  
 


  
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Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................................................. 1 
1 
PROTOCOL SUMMARY ............................................................................................................................... 1 
1.1 
Synopsis ................................................................................................................................................ 1 
1.2 
Schema ................................................................................................................................................. 3 
1.3 
Schedule of Activities (SoA) ............................................................................................................... 4 
2 
INTRODUCTION ............................................................................................................................................ 5 
2.1 
Study Rationale .................................................................................................................................... 5 
2.2 
Background........................................................................................................................................... 6 
2.3 
Risk/Benefit Assessment .................................................................................................................... 8 
2.3.1 
Known Potential Risks ..................................................................................................... 8 
2.3.2 
Known Potential Benefits .............................................................................................. 10 
2.3.3 
Assessment of Potential Risks and Benefits .............................................................. 10 
3 
OBJECTIVES AND ENDPOINTS .............................................................................................................. 12 
4 
STUDY DESIGN ........................................................................................................................................... 13 
4.1 
Overall Design .................................................................................................................................... 13 
4.2 
Scientific Rationale for Study Design.............................................................................................. 13 
4.3 
Justification for Dose ......................................................................................................................... 14 
4.4 
End of Study Definition ..................................................................................................................... 14 
5 
STUDY POPULATION ................................................................................................................................ 14 
5.1 
Inclusion Criteria ................................................................................................................................ 14 
5.2 
Exclusion Criteria ............................................................................................................................... 15 
5.3 
Screen Failures .................................................................................................................................. 16 
5.4 
Strategies for Recruitment and Retention ...................................................................................... 16 
6 
STUDY INTERVENTION ............................................................................................................................ 17 
6.1 
Study Intervention(s) Administration ............................................................................................... 18 
6.1.1 
Study Intervention Description ..................................................................................... 18 
6.1.2 
Dosing and Administration ............................................................................................ 18 
6.2 
Preparation/Handling/Storage/Accountability ................................................................................ 21 
6.2.1 
Acquisition and accountability ...................................................................................... 21 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ................................................ 22 
6.2.3 
Product Storage and Stability ....................................................................................... 22 
6.2.4 
Preparation ...................................................................................................................... 22 
6.3 
Measures to Minimize Bias: Randomization and Blinding ........................................................... 22 
6.4 
Study Intervention Compliance ........................................................................................................ 22 
6.5 
Concomitant Therapy ........................................................................................................................ 22 
6.5.1 
Rescue Medicine ............................................................................................................ 22 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .................................................................................................................... 22 
7.1 
Discontinuation of Study Intervention ............................................................................................. 22 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................................................... 23 
7.3 
Lost to Follow-Up ............................................................................................................................... 24 
8 
STUDY ASSESSMENTS AND PROCEDURES ..................................................................................... 24 
8.1 
Efficacy Assessments ....................................................................................................................... 24 
8.2 
Safety and Other Assessments ....................................................................................................... 27 
8.3 
Adverse Events and Serious Adverse Events ............................................................................... 32 
8.3.1 
Definition of Adverse Events (AE) ............................................................................... 32 


  
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8.3.2 
Definition of Serious Adverse Events (SAE) .............................................................. 32 
8.3.3 
Classification of an Adverse Event .............................................................................. 32 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ....................... 33 
8.3.5 
Adverse Event Reporting .............................................................................................. 34 
8.3.6 
Serious Adverse Event Reporting ............................................................................... 34 
8.3.7 
Reporting Events to Participants ................................................................................. 34 
8.3.8 
Events of Special Interest ............................................................................................. 35 
8.3.9 
Reporting of Pregnancy ................................................................................................ 35 
8.4 
Unanticipated Problems .................................................................................................................... 35 
8.4.1 
Definition of Unanticipated Problems (UP) ................................................................. 35 
8.4.2 
Unanticipated Problem Reporting ................................................................................ 35 
8.4.3 
Reporting Unanticipated Problems to Participants ................................................... 36 
9 
STATISTICAL CONSIDERATIONS .......................................................................................................... 36 
9.1 
Statistical Hypotheses ....................................................................................................................... 36 
9.2 
Sample Size Determination .............................................................................................................. 36 
9.3 
Populations for Analyses .................................................................................................................. 36 
9.4 
Statistical Analyses............................................................................................................................ 36 
9.4.1 
General Approach .......................................................................................................... 36 
9.4.2 
Analysis of the Primary Efficacy Endpoint(s) ............................................................. 36 
9.4.3 
Analysis of the Secondary Endpoint(s) ....................................................................... 37 
9.4.4 
Safety Analyses .............................................................................................................. 37 
9.4.5 
Baseline Descriptive Statistics ..................................................................................... 37 
9.4.6 
Planned Interim Analyses ............................................................................................. 37 
9.4.7 
Sub-Group Analyses ..................................................................................................... 37 
9.4.8 
Tabulation of Individual participant Data .................................................................... 37 
9.4.9 
Exploratory Analyses ..................................................................................................... 38 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................. 38 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ........................................................... 38 
10.1.1 
Informed Consent Process ........................................................................................... 38 
10.1.2 
Study Discontinuation and Closure ............................................................................. 39 
10.1.3 
Confidentiality and Privacy ........................................................................................... 39 
10.1.4 
Future Use of Stored Specimens and Data ............................................................... 40 
10.1.5 
Key Roles and Study Governance .............................................................................. 41 
10.1.6 
Safety Oversight ............................................................................................................. 41 
10.1.7 
Clinical Monitoring .......................................................................................................... 41 
10.1.8 
Quality Assurance and Quality Control ....................................................................... 41 
10.1.9 
Data Handling and Record Keeping ............................................................................ 42 
10.1.10 
Protocol Deviations ........................................................................................................ 42 
10.1.11 
Publication and Data Sharing Policy ........................................................................... 42 
10.1.12 
Conflict of Interest Policy .............................................................................................. 43 
10.2 
Additional Considerations ................................................................................................................. 43 
10.3 
Abbreviations ...................................................................................................................................... 44 
10.4 
Protocol Amendment History ........................................................................................................... 46 
11 
REFERENCES ............................................................................................................................................. 47 
 


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STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with International Conference on Harmonization (ICH) Good 
Clinical Practice (GCP) and the 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 this trial 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  
Title: 
A Phase 2 Study of Cannabidiol as a New Treatment for Autism Spectrum 
Disorder in Children and Adolescents [CBD4ASD-open] 
Study Description: 
We propose a 6-week open trial to identify the optimal dosing of 
cannabidiol (CBD) in youth with autism spectrum disorder (ASD), and to 
guide decisions on the primary outcome for a subsequent double-blind 
randomized clinical trial. As there are currently no effective 
pharmacological interventions for the core symptoms of ASD, we are 
primarily interested in examining the potential for CBD to fill this gap. 
Given emerging literature demonstrating the effectiveness of CBD in 
increasing social responding within mouse models and the proposed 
mechanism of action of CBD mapping on to the leading hypotheses of the 
pathophysiologic processes that may contribute to ASD, CBD could be a 
promising treatment for core symptoms. Further, we will also evaluate 
change in symptoms commonly associated with ASD, as evidence suggests 
that CBD may be effective in addressing difficulties such as irritability and 
anxiety, while maintaining a benign adverse effect (AE) profile in children 
and adolescents. Notably, data are limited in regard to guidelines for most 
promising dose and multiple lines of evidence suggest that an inverted-U 
shaped dose response curve may be present; therefore, exploration of 
optimal dosing is essential and will be conducted in relation to 
improvement in both core and associated symptoms as outlined in this 
protocol in Part 1 of the trial. Following the completion of the BOIN design, 
we will engage in Part 2 of the study, in which we will examine the 
remaining dose (9 mg/kg/day) in a subset of youth with the clinical profile 
that most closely resembles those youth who were categorized as 
responders in Part 1 of the trial.  


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Objectives: 
 
Primary Objective: Determine the optimal dose of CBD in children and 
adolescents with ASD 
 
Secondary Objectives: Examine change in core and associated symptoms, 
and identify the primary outcome measure for a subsequent double-blind 
placebo-controlled randomized clinical trial  
Exploratory Objectives: Assess underlying mechanisms using functional 
magnetic resonance imaging (MRI)  
Endpoints: 
Primary Endpoint: Optimal dose of CBD in children and adolescents with 
ASD, defined as the dose at which the greatest proportion of participants 
respond in an individualized target symptom domain designated for each 
individual prior to beginning CBD treatment 
Secondary Endpoints: Effect sizes of changes in symptoms from baseline of 
measures developed to assess ASD symptoms, symptoms often associated 
with ASD, and global functioning 
Exploratory Endpoints: Effect sizes of changes in MRI signals (i.e., resting-
state functional connectivity) from baseline to the final week of treatment 
Study Population: 
Sample will include 30 male and female participants with ASD between the 
ages of 7 and 17 years old. Participants will have fluent speech and an 
estimated IQ greater than or equal to 80. Individuals of all races and ethnic 
origins are eligible for participation. Following the completion of the BOIN 
design, in Part 2 of the trial, we will recruit youth with clinical profiles that 
most closely resemble youth classified as responders in Part 1 of the trial. 
Phase: 
This is a Phase 2 study.  
Description of 
Sites/Facilities Enrolling 
Participants: 
The study will be conducted at the Child Study Center, Hassenfeld 
Children’s Hospital, NYU Langone Health.  
Description of Study 
Intervention: 
Study intervention will be 98% pure CBD. The CBD will be Greenwich 
Biosciences, Inc.’s 100mg/mL oral solution, brand name Epidiolex (V). A 
Bayesian optimal interval (BOIN) design will be used, such that participants 
will be assigned to cohorts of size 3 receiving doses of 3, 6, or 9 
mg/kg/day, depending on the treatment response of participants in prior 
cohorts.  
Study Duration: 
The duration of the trial is approximately 100 weeks.  
Participant Duration: 
Expected duration of subject participation is 8 to 10 weeks, with in-person 
visits scheduled every other week. Between in-person visits, participants 
will be contacted via secure email and/or phone to assess for the presence 
of AE. 
 
 


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1.2 
SCHEMA 
 
Telephone Pre-screening
Pre-trial
•Interested parents/legal guardians will speak with study staff over the phone to determine basic inclusionary and exclusionary information
•If the caregiver endorses any exclusionary criteria or fails to endorse inclusionary criteria over the phone, cargivers will be informed that the 
study would not be appropriate
•If the parent/legal guardian does not endorse any exclusionary criteria and endorses all inclusionary criteria, the study staff will schedule the 
screening visit
•Of note, if the child does not qualify for the study as a result of pre-screening or the family decides not to proceed with the study after pre-
screening, their data will be discarded and will not be used in this research.
Screening Visit
Pre-trial
•Screen n=5 at a time; total n=50 for screening
•Obtain informed consent and assent and patient history
•Screen potential participants by inclusion and exclusion criteria according to the assessments outlined in the Schedule of Activities (SOA) 
Enrollment/Baseline
Day 0 
•Enroll cohorts of size 3
•Arrive at clinician group consensus on individualized primary target(s) based on results of assessment with parent input
•Administer specified dose of study intervention to the cohort
•Refer to Section 1.3, SOA for battery of baseline assessments
Follow-up phone call
Day 7 +/- 3 days
•Assess for AE
Assessment of study endpoints and safety
Day 14 +/- 3 days
•Administer study intervention
•Refer to Section 1.3, SOA for battery of assessments
Follow-up phone call
Day 21 +/- 3 days
•Assess for AE
Assessment of study endpoints and safety
Day 28 +/- 3 days
•Administer study intervention
•Refer to Section 1.3, SOA for battery of assessments
Follow-up phone call
Day 35 +/- 3 days
•Assess for AE
End of Study Assessments
Day 42 +/- 3 days
•Discontinue study intervention
•Refer to Section 1.3, SOA for battery of assessments
•Group consensus on response to treatment based on the designated target symptom for each study participant
Repeat with subsequent cohorts
Repeat Screening to Day 42
•Following completion of each cohort, a new group of ~5 children will be scheduled for screening
•Enroll subsequent cohort of size 3 and follow the same schedule as above
•Total Enrolled (n = 30; 10 cohorts)
•The dose of each subsequent cohort is determined by the dose response of participants in previous cohorts,  according to the rules detailed 
within the Dosing and Adminstration subsection 


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1.3 
SCHEDULE OF ACTIVITIES (SOA) 
 
Procedures 
Screening 
 
Study Visit 1 
Enrollment/Baseline 
Telephone Follow-Up 
1  
Study Visit 2 
Telephone Follow-Up 
2  
Study Visit 3 
 
Telephone Follow-Up 
3 
Study Visit 4 
Final Study Visit 
2-Week Post-Trial 
Telephone Follow-Up 
4-Week Post-Trial 
Telephone Follow-Up 
6-Week Post-Trial 
Follow-Up 
3-Month Telephone 
Follow-Up(s)c 
Informed consent and assent 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical, Psychiatric, and Treatment history 
X 
 
 
 
 
 
 
 
 
 
 
 
Administer study intervention 
 
X 
 
X 
 
X 
 
 
 
 
 
 
Concomitant medication review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Physical exam (including height and weight) 
X* 
 
 
 
 
 
 
X 
 
 
 
 
Vital signs 
X* 
X 
 
X* 
 
X* 
 
X 
 
 
 
 
Test of hepatic and hematologic function a 
X 
 
 
 
 
X* 
 
X 
 
 
 
 
Pregnancy test b 
X 
 
 
 
 
 
 
 
 
 
 
 
Plasma for CBD levels 
 
 
 
 
 
 
 
X 
 
 
 
 
Urine drug screen 
X 
 
 
 
 
 
 
 
 
 
 
 
Adverse event review and evaluation  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
UKU Side Effects Rating Scale 
 
 
 
X 
 
X 
 
X 
 
 
 
 
Mock MRI scan 
X 
 
 
 
 
 
 
 
 
 
 
 
MRI 
 
X 
 
 
 
 
 
X 
 
 
 
 
Aberrant Behavior Checklist (ABC) 
 
X• 
 
 
 
 
 
X 
 
 
X 
 
Anxiety, Depression, and Mood Scale (ADAMS) 
 
X• 
 
 
 
 
 
X 
 
 
X 
 
Anxiety Scale for Children – Autism Spectrum 
Disorder – Child version (ASC-ASD-C) 
 
X• 
 
 
 
 
 
X 
 
 
 
 
Anxiety Scale for Children – Autism Spectrum 
Disorder – Parent version (ASC-ASD-P) 
 
X• 
 
 
 
 
 
X 
 
 
X 
 
Autism Diagnostic Observation Schedule – 2nd 
Edition (ADOS-2) 
X* 
 
 
 
 
 
 
 
 
 
 
 
Childhood Autism Rating Scale, 2nd Edition, High 
Functioning (CARS-2-HF) 
X 
 
 
 
 
 
 
 
 
 
 
 
Autism Family Experience Questionnaire (AFEQ) 
 
X• 
 
 
 
 
 
X 
 
 
 
 
Autism Symptom Interview (ASI) 
X 
 
 
 
 
 
 
 
 
 
 
 
Behavioral Inflexibility Scale (BIS) 
 
X• 
 
 
 
 
 
X 
 
 
X 
 
Brief Observation of Social Communication- 
Change (BOSCC) 
 
X 
 
 
 
 
 
X 
 
 
 
 
Clinical Global Impression Scale – Improvement 
(CGI-I) 
 
 
 
 
 
 
 
X 
 
 
 
 
Clinical Global Impression-Severity (CGI-S) 
X 
X 
 
 
 
 
 
X 
 
 
 
 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
X 
X 
 
X 
 
X 
 
X 
 
 
 
 
Computerized Kiddie Schedule for Affective 
Disorders and Schizophrenia (KSADS-COMP) 
X 
 
 
 
 
 
 
 
 
 
 
 
Home Situations Questionnaire – ASD (HSQ-ASD) 
 
X• 
 
 
 
 
 
X 
 
 
X 
 
OSU Autism Clinical Global Impression: Severity 
Subscale 
X 
X 
 
 
 
 
 
X 
 
 
 
 
OSU Autism Clinical Global Impression: 
Improvement Subscale 
 
 
 
 
 
 
 
X 
 
 
 
 
Repetitive Behavior Scale – Revised (RBS-R) 
 
X• 
 
 
 
 
 
X 
 
 
X 
 
Screen for Child Anxiety Related Disorders 
(SCARED), Parent Version 
 
X• 
 
 
 
 
 
X 
 
 
X 
 
Sleep Disturbance Scale for Children (SDSC) 
 
X• 
 
 
 
 
 
X 
 
 
X 
 
Social Responsiveness Scale, 2nd Edition (SRS-2) 
X 
 
 
 
 
 
 
X 
 
 
X 
 
Strengths and Weaknesses of Attention-
Deficit/Hyperactivity Disorder Symptoms and 
Normal Behavior (SWAN) 
 
X• 
 
 
 
 
 
X 
 
 
X 
 
Vineland Adaptive Behavior Scales-3 
Parent/Caregiver Form (Vineland-3) 
 
X• 
 
 
 
 
 
X 
 
 
 
 


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Procedures 
Screening 
 
Study Visit 1 
Enrollment/Baseline 
Telephone Follow-Up 
1  
Study Visit 2 
Telephone Follow-Up 
2  
Study Visit 3 
 
Telephone Follow-Up 
3 
Study Visit 4 
Final Study Visit 
2-Week Post-Trial 
Telephone Follow-Up 
4-Week Post-Trial 
Telephone Follow-Up 
6-Week Post-Trial 
Follow-Up 
3-Month Telephone 
Follow-Up(s)c 
Wechsler Abbreviated Scale of Intelligence, 2nd 
Edition (WASI-II) 
X 
 
 
 
 
 
 
 
 
 
 
 
a: Albumin, alkaline phosphatase, AST, ALT, total bilirubin, LDH, total protein; complete blood count. 
b: Urine pregnancy test (females of childbearing potential) 
c: Parents/guardians will be asked if they can be contacted every 3 months following the completion of the trial to provide data on longer-term behavior 
changes and parental choice in treatment, including whether they pursued continuation of CBD, for up to 1 year.   
*As in-person visits have transitioned to virtual visits following re-initiation after a pause due to the COVID-19 pandemic, select procedures to be completed in 
certain cases (e.g., family prefers to attend in-person visit and agrees to in-person procedures; Week 4 blood draw clinically indicated from baseline 
blood draw results as per clinical judgement of PI) 
•Questionnaires must be completed prior to medication administration; however, caregivers will be given the option to complete them during screening or 
baseline.   
 
2 
 
INTRODUCTION 
 
2.1 
STUDY RATIONALE  
Autism spectrum disorder (ASD), a lifelong profoundly impairing neurodevelopmental disorder, is far 
more common than previously appreciated. Currently, only two medications, risperidone and 
aripiprazole, are Food and Drug Administration (FDA)-approved for treating irritability in pediatric ASD. 
Unfortunately, these medications are associated with significant AE. There are currently no medications 
that target core autism symptoms; however, a wide range of psychotropic medications have been 
applied for either core or associated difficulties with little evidence of effectiveness and numerous AE. 
Regardless of the thin evidence base, up to 65% of patients with ASD have been prescribed at least one 
psychotropic medication, with many taking multiple medications simultaneously. Thus there is a large, 
unmet need for additional treatment options.  
 
Notably, a recent preliminary, retrospective study evaluating the efficacy, safety, and tolerability of 
CBD for ASD found significant improvements in communication problems and reduction in the 
associated symptoms of anxiety, disruptive behaviors, and behavioral outbreaks following treatment 
(1). However, this preliminary study was exploratory, with numerous limitations. Cannabidiol (CBD) was 
also reported to increase social responding in a mouse model of Dravet syndrome (2) and to decrease a 
broad range of behavioral difficulties in a small open study of children and adolescents with Fragile X 
syndrome [http://zynerba.com/zynerba-pharmaceuticals-announces-positive-top-line-results-zyn002-
open-label-phase-2-fab-c-study-children-fragile-x-syndrome/]. Further, CBD decreases anxiety-like 
behaviors in animal studies and shows anxiolytic effects in human trials. Crucially, both open and 
placebo-controlled randomized controlled trials (RCT) have found that CBD is well-tolerated by children 
and adolescents. The combination of a benign AE profile, potential benefits for core and associated 
symptoms, and the lack of alternatives all suggest that CBD should be considered as a potential 
treatment for core and associated ASD symptoms. 
 
The rationale for considering CBD as a therapeutic option for ASD also rests on the leading hypotheses 
of the pathophysiologic processes that may contribute to ASD. These include synaptic 
excitatory/inhibitory (EI) imbalance and low-level chronic inflammation. CBD shows effects to reduce 


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EI imbalance (i.e., three RCTs showing efficacy in patients with Dravet and Lennox Gastaut Syndromes 
and extensive animal models of epilepsy spanning multiple species and epilepsy models) and 
neuroinflammation (3-5).  Additional pathophysiological mechanisms thought to underlie the 
neurobehavioral deficits present in ASD include aberrant synaptic plasticity, immune dysfunction, and 
metabolic disturbances, all of which are susceptible to modulation by the endocannabinoid system 
(ECS) and which are likely influenced by CBD (6).  
 
In summary, CBD appears to address many of the mechanisms that have been implicated in the 
pathophysiology of ASD. Accordingly, this study aims to explore the efficacy of CBD in addressing core 
autism symptoms, as pharmacological treatment options do not exist. We will focus on children and 
adolescents with high-functioning autism (HFA; i.e., those with fluent language and broadly average 
intelligence), as this subpopulation is not often prioritized in pharmacological research, including 
studies currently underway evaluating CBD for ASD. Further, despite often having reduced symptom 
severity compared to lower functioning groups, individuals with HFA continue to experience poor long-
term prognoses, including increased prevalence of psychiatric disorders and heightened under-
/unemployment rates (7, 8).  
 
While we aspire to identify improvement in core symptoms, we recognize that CBD may be beneficial 
for youth with ASD in other ways, specifically by ameliorating common comorbid symptoms (1). 
Because research into the therapeutic benefit of CBD for ASD is in its infancy, it would be inappropriate 
for us to limit this exploratory study to target only core symptoms when improvements in a wide range 
of outcomes could be possible. Therefore, a secondary goal for the study is to identify changes in 
symptoms associated with ASD (e.g., anxiety, irritability), which will enable the selection of primary 
and secondary outcomes to be used in a subsequent double-blind placebo-controlled trial.  
 
Of note, there is limited data available to suggest most promising dosage and there is preliminary 
research evidence suggesting the possibility of nonlinearity in the dose response across a variety of 
outcomes (2, 9). Determining the optimal dose of CBD is essential in maximizing potential for 
treatment of core and associated ASD symptoms. Therefore, we will evaluate varying dose levels by 
implementing an adaptive design to determine at which dose the largest proportion of participants 
respond. The definition of treatment response will be individualized for each participant based upon a 
predetermined target symptom cluster that is considered most interfering at study outset. Lastly, we 
also intend to collect brain MRI data before and after open CBD treatment to provide insights into 
feasibility of incorporating biomarkers into subsequent studies, and potentially yield testable 
hypotheses.  
 
2.2 
BACKGROUND  
The Centers for Disease Control and Prevention (CDC) estimate 1 in 59 children have ASD (10). Autism 
spectrum disorder (ASD) is characterized by core deficits in social communication and interaction and 
the presence of restricted and repetitive behaviors (RRB), and is commonly associated with a range of 
challenging behaviors (e.g., aggression, irritability, tantrums), sleep problems, and comorbid 
psychopathology, all of which entail a high caregiver burden (11-14). Currently, only risperidone and 
aripiprazole are FDA-approved for treating irritability in pediatric ASD, and are associated with 
significant AE (e.g., weight gain, metabolic syndrome, type 2 diabetes, prolactin elevation, development 
of breast tissue, extrapyramidal/movement-related side effects) (15, 16). Beyond risperidone and 
aripiprazole, a wide range of psychotropic medications have been applied to target core and associated 
autism symptoms, including antipsychotics, antidepressants, anticonvulsants, mood stabilizers, 


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stimulants, and alpha-2 agonists. However, findings of effectiveness have been mixed and AE have been 
numerous (17). Despite the thin evidence base, a majority of patients with ASD are or have been 
prescribed at least one psychotropic medication (18). The lack of available evidence-based treatments 
for core and associated symptoms in conjunction with the AE profiles of currently approved treatments 
suggest that there is a large need for additional treatment options. Given emerging literature, CBD may 
be a promising treatment to fill this gap. 
 
Limited research has been conducted examining the use of CBD with the ASD population. There is a 
growing pool of anecdotal evidence suggesting potential benefit; however, no formal studies have been 
conducted. Recently, a preliminary study was presented demonstrating the effects of varying CBD-rich 
strains on the areas of communication, anxiety, behavioral outbreaks, and disruptive behavior in 
approximately 60 children with ASD. Improvements in anxiety were noted in 39% of the sample; 
improvements in communication problems were noted in 47% of the sample; and, improvements in 
behavioral outbreaks were noted in 61% of the sample. Adverse events (AEs) were infrequent and not 
severe (1). While these data are promising, there were numerous limitations and more well-designed 
research is needed to make conclusions about the potential for CBD in ASD.  
 
Outside of the ASD population, CBD has been found to reduce anxiety-like behaviors in animal models 
(19-24) and to reduce anxiety associated with public speaking in humans (9, 25). CBD lacks agonist 
effects at CB1 or CB2 receptors, but acts as an agonist at 5-hydroxytryptophan 1A (5HT1A) receptors 
(21, 22, 24), which are implicated in the anti-anxiety effects of buspirone in ASD (26). With respect to 
social behavior, CBD increased social responding in a mouse model of Dravet syndrome (2) and 
decreased a broad range of behavioral difficulties in a small open study of children and adolescents with 
Fragile X syndrome [http://zynerba.com/zynerba-pharmaceuticals-announces-positive-top-line-results-
zyn002-open-label-phase-2-fab-c-study-children-fragile-x-syndrome/]. Importantly, CBD has largely 
been well-tolerated by pediatric patients (3, 27).  
 
The rationale for considering CBD as a therapeutic option for ASD also rests on the hypothesized 
pathophysiologic processes that may contribute to ASD (28). These include synaptic EI imbalance and 
low-level chronic inflammation. Evidence of EI imbalance, due to abnormal GABAergic or 
glutamatergic neurotransmission has implicated key brain regions, including parietal-occipital and 
frontal cortical regions (29). Abnormalities in EI balance in these regions in animal models can result in 
seizures, in addition to behavioral changes and social dysfunction, including irritability, repetitive and 
disruptive behaviors, and social avoidance and withdrawal. Cannabidiol attenuates seizures in many 
animal models and in human epilepsy; CBD’s impact on seizures and EI imbalance supports its 
potential as a treatment for non-epileptiform dysfunctional mechanisms in ASD that could result in 
increased irritability, repetitive behaviors and social dysfunction (28).  
 
Cannabidiol is a multi-target drug, interacting both with non-endocannabinoid systems and within the 
endocannabinoid system, including inhibition of the equilibrative nucleoside transporter and the 
orphan G-protein-coupled receptor 55 (GPR55) (6, 30-32) modulating the presynaptic release of 
glutamate (33). Besides activating 5HT1A receptors (21, 22, 24, 33-39), CBD inhibits adenosine 
reuptake through multiple mechanisms (40, 41). Cannabidiol may exert some of its effects by 
modulating intracellular calcium flux via GPR55; the voltage dependent anion selective channel protein 
1 (VDAC1); or by reducing neuronal excitability and neuronal transmission, and engaging inflammatory 
pathways by inhibiting adenosine reuptake or modulating the release of pro-inflammatory cytokine 
tumor necrosis factor alpha (TNFα) (41, 42). These multiple effects parallel many of the hypothesized 
molecular mechanisms implicated in the pathophysiology of ASD, i.e., aberrant EI balance (43), 


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immune dysfunction (44, 45), and metabolic disturbances (46). The effects of CBD on EI imbalance are 
a principal focus of the Tsien lab, in collaboration with Devinsky and colleagues. Work in progress 
recently reported at the 2018 NYU Neuroscience Retreat shows that CBD decreases excitability of 
pyramidal neurons and increases inhibitory drive in hippocampal area CA1 (47). Parallel work is also 
revealing that CBD restores EI balance by decreasing excessive excitation and strengthening inhibition 
via antagonism of GPR55 (48).  
 
While research indicates that CBD may be therapeutically beneficial for ASD, there is some evidence to 
suggest the presence of an inverted-U shaped dose response. For instance, Kaplan et al. studied a 
mouse model of Dravet syndrome and found that high doses attenuated seizures but only moderate 
doses improved social interaction deficits (2). Similarly, Zuardi et al. examined the anxiolytic effect of 
CBD during a public speaking task in healthy adults and found that a 300 mg dose reduced anxiety 
more effectively than 100 and 900 mg doses (9). Further support for a potential inverted-U dose 
response curve was provided in a personal communication from Dr. Adi Aran, an Israeli researcher 
conducting the only currently active clinical trial testing CBD for ASD. Dr. Aran reported that of the 
over 300 children with ASD he has treated with CBD, most appear to respond optimally to moderate 
doses (e.g., 5-7 mg/kg/day) and some patients who have had excellent responses on 3-4 mg/kg/day 
have worsened on higher doses (personal communication Dr. Adi Aran, July 3, 2018). 
 
Together this suggests that CBD is a multi-target drug that may address multiple mechanisms implicated 
in the pathophysiology of ASD (49) and common comorbid disorders (50). However, continued study of 
its efficacy for core and associated ASD symptoms is necessary. Because the CBD dose response curve is 
unknown and data suggest the potential for nonlinearity, determining optimal dose is paramount in 
informing future research. Given the preliminary evidence of therapeutic effects across a range of 
domains, selecting primary and secondary outcomes is also essential in the design of a subsequent 
double-blind placebo-controlled trial. In regard to our exploratory objectives, collecting brain MRI data 
before and after the open trial may also provide insights into feasibility of incorporating biomarkers into 
subsequent studies, and potentially will yield testable hypotheses. 
 
2.3 
RISK/BENEFIT ASSESSMENT   
 
2.3.1 KNOWN POTENTIAL RISKS  
Risk of the study intervention 
Cannabidiol (CBD) has been used alone and in combination with tetrahydrocannabinol (THC) in 
numerous clinical trials and is approved with THC to treat spasms in patients with multiple sclerosis in 
more than 20 countries. Scientific studies using only CBD are more limited, involving <10,000 patient-
years, with limited data on long-term AEs. Data from open-label and RCTs in epilepsy reveal a consistent 
profile of AEs (3, 27, 51).  Serious adverse events (SAE) were more common in the CBD group than in the 
placebo groups (e.g., 16% vs. 5%), and AEs led to the withdrawal CBD-treated patients more than those 
in the placebo group (e.g., 8/61 v. 1/60). The large majority of AEs were mild to moderate in severity. 
Adverse effects (AEs) seen more frequently in the CBD group included somnolence (36% in the CBD 
group vs. 10% in the placebo group), loss of appetite (28% vs. 5%), and diarrhea (31% vs. 10%) (3, 27, 52, 
53). Abnormalities of hepatic aminotransferase levels occurred most often in patients taking valproate, 
suggesting an interaction in which CBD may potentiate a valproic acid-induced change in hepatic 
aminotransferase levels (3). Nevertheless, the FDA label for Epidiolex (Reference ID: 4282447) does note 
that the incidence of ALT elevations in patients who were not taking valproate or clobazam was 3%. The 
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or reduction of Epidiolex and/or concomitant valproate in about two-thirds of cases. In about one-third 
of cases, transaminase elevations resolved during continued treatment with Epidiolex, without dose 
reduction.” 
Other AEs reported more frequently in the treatment group include upper respiratory tract infection, 
pyrexia, and vomiting. Possible AEs of CBD that were not more common in the CBD versus placebo 
groups included headache, dizziness, fatigue, oral numbness, dry mouth, neck pain, feeling strange, 
depression, lack of taste or changed taste, feeling weak, falls, shakiness, muscle stiffness, unusual 
dreams, nosebleeds, hot or cold flashes, heartburn, trouble swallowing, and decreased pulse (3, 4, 27, 
52, 54).  
 
Potential drug interactions may occur as CBD is a potent inhibitor of CYP2B6, CYP2C8, CYP2C9, 
CYP2C19, CYP2D6 and CYP3A4, although research is limited on pharmacokinetic interaction with other 
pharmacological agents when CBD serves as the primary cannabinoid in treatment (55).  
 
Given that CBD is extracted from cannabis, one concern could be that individuals who require drug 
testing for employment or school may test positive for cannabinoids. Fortunately, the CBD formulation 
to be administered has an extremely low concentration of Δ9-THC, making it extremely unlikely, albeit 
not impossible, that subjects would test positive for THC while participating in this study.  
 
Other Associated Risks 
MRI: MRI scans are considered a safe way to noninvasively visualize tissue in adults and children. This 
study will be performed on a FDA approved scanner. There are no known significant risks or side effects 
associated with MRI procedures except the risk of metallic projectiles in the magnetic field or metallic 
objects in the body. Some participants report mild discomfort when undergoing magnetic resonance 
scans. Some participants have experienced claustrophobia (fear of enclosed spaces).  
The major risk of having a research brain MRI is the identification of incidental findings, most of which 
turn out to be inconsequential. Nevertheless, being informed of a possible abnormality in a brain scan is 
anxiety provoking. In the largest pediatric brain imaging study to date, of 11,679 children ages 9-10 
years-old, 17.2% had a finding that was judged to not require a referral, 3.7% had incidental findings for 
which referral was considered, and 20 (0.2%) were found to merit considering an immediate referral 
(99). The PI has nearly 30 years’ experience in conducting pediatric neuroimaging studies and has always 
directly communicated any concerning findings to parents/guardians in a sensitive and forthright 
manner.  
The MRI scanner also makes loud knocking or beeping sounds during imaging. Due to the rapid rate of 
change of the magnetic gradients during imaging, peripheral nerve stimulation is a possibility. If this 
happens, participants may feel creeping or tingling sensations, typically along their arms or lower back. 
Dizziness and nausea may occur if participants move their head rapidly in the bore of the magnet. 
Finally, there may be some heating from the radio frequency coils, the cables to the coils, and response 
and physiological monitoring devices. We do not use cables that can conduct electricity in the proximity 
of participants and have had no such untoward events in the past in over 15 years scanning young 
children.  
 
Blood draw: This study involves blood draws, which may cause some discomfort, bruising, or transient 
pain at site of needle entry into the vein as with any blood draw. There is a slight risk of fainting. 
Infection can also occur at site where needle penetrates the skin. 
 


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Pregnancy-related risks: There are no data available on the risks associated with CBD use in pregnancy.  
 
Burden of study time commitment: This proposal calls for participants and their caregivers to return to 
the clinic/attend virtual visits over WebEx regularly and participate in a relatively lengthy battery of 
assessments.  
 
Mandated reporting of suspected child abuse or neglect: As mandated reporters, evidence of 
suspected child abuse or neglect would need to be reported to the appropriate authorities. This 
exception to confidentiality is explicitly provided in the consent document. If required, 
parents/guardians will be informed of the referral.  
 
2.3.2 KNOWN POTENTIAL BENEFITS  
It is possible that some study subjects will experience an improvement in their ASD and related 
symptoms while taking CBD during the study. For participants who experience benefit without 
significant side effects, parents/guardians may elect to continue CBD prescribed by their own physician. 
CBD is now available legally in New York State. It is also possible subjects may not benefit from being in 
this research study. Others with ASD may benefit in the future from what we learn in this study. 
 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
The common AE associated with CBD in previous research are typically mild (e.g., headaches, 
gastrointestinal symptoms), particularly when compared to the AE profile of currently approved 
medications for ASD. Nonetheless, all participants will be closely monitored for AEs during the treatment 
period and assessment of the need for discontinuation of treatment will be conducted as appropriate. 
 
In regard to the potential for drug interaction effects, participants taking medications metabolized 
primarily by CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A4, or CYP2D6 isoenzymes will be excluded. 
Adverse effects related to the interaction between medications will be monitored, including tests of 
hepatic and hematological function at Baseline and at Weeks 6. Further, if a subject’s baseline blood 
draw suggests borderline clinical abnormalities (that did not meet the cutoff for exclusion), they will be 
required to complete a Week 4 blood draw. Since transaminase elevations of greater than 3 times the 
upper level of normal (ULN) (plus elevated bilirubin levels) are significant predictors of severe liver injury 
and given that CBD can cause dose-related elevations in liver transaminases, potential participants with 
elevated baseline transaminase levels greater than 3 times the ULN plus elevations in bilirubin greater 
than 2 times the ULN, will be excluded from trial participation. 
 
Further, while there are no data to suggest 9 mg/kg/day will be associated with increased risk, out of an 
abundance of caution, participants assigned to the highest dose (9 mg/kg/day) will be instructed to take 
half the dose (4.5 mg/kg/day, divided in two doses) per day for the first week of treatment before 
increasing to the full dose to minimize the chance for adverse events upon treatment initiation.  
 
Lastly, if families are concerned about CBD showing up on a urine drug test, the study team will provide 
documentation that the subject is in a research study using a cannabis-related compound that has no 
psychoactive effects. Additionally, we will exclude participants with a history of cannabis usage or 
substance use disorders or a positive urine toxicological screen. 
 
MRI scanning is optional. Participants who have no contraindications for MRI scanning and who agree to 
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screened for previous exposure to metallic fragments and for devices such as electrically, magnetically 
or mechanically activated implants, e.g., cardiac pacemakers, clips on blood vessels in their brain, or 
other metallic objects in their body, e.g., shrapnel, bullets, buckshot, or metal fragments. They will also 
be asked to leave all metallic and magnetic objects in their possession (e.g., keys, jewelry, credit cards) 
outside the magnet room. To manage the noise associated with the scan, earplugs are provided. 
Participants will also be instructed how to use an emergency handheld device to inform the operator if 
they feel discomfort, and/or wish to immediately stop scanning and be removed from the magnet. It is 
worth noting that the MRI scanning environment necessarily predicates the utmost concern for the 
complete comfort of the participant. We emphasize that even slight discomfort tends to result in 
participants moving during the scan, which degrades image quality. Therefore, prior to the imaging 
session, we have participants complete a mock scanner session using an MRI simulator, and also spend 
extra time when we place them on the gantry to make sure they are comfortable, and readjust as 
needed whenever they let us know that they are even slightly uncomfortable. For participants prone to 
fear of tight spaces (claustrophobia), special care will be taken during the mock scanner session to test if 
proceeding with training and the real MRI will be feasible for them. In general, once a participant has 
gotten over the novelty of entering the magnet bore, and has habituated to the knocking noises, the 
main issue is boredom, and staying awake for functional scans. Participants are asked to keep their eyes 
open during resting state scans to facilitate monitoring of wake status. Participants are free to sleep or 
watch a DVD or listen to music during several of the scanning sequences (e.g., structural scans). Given 
that we are using instruments that are calibrated to deliver energy levels judged to be well within safe 
limits, we expect no adverse events. Nonetheless, we will monitor all participants during scanning and 
be available for any follow-up that may be required.  
 
In regard to AE associated with blood draws, the study team will offer EMLA cream to minimize 
discomfort, and precautions will be taken to prevent infection by using sterile technique.  
 
Because risks of CBD use in pregnancy as well as MRI scanning in pregnancy are unknown, all potentially 
fertile subjects are required to use abstinence or a valid method of contraception to participate in the 
study. Menstruating females will undergo urine pregnancy test before initiation of study drug, as well as 
before each MRI scan. If a subject becomes pregnant during the study, she will immediately be 
discontinued from the medication. Subjects who become pregnant during the study, or within 30 days 
after completing the study, will be followed throughout the course of the pregnancy for safety, with the 
subject’s permission and that of her parent/guardian. Information about the risks of the pregnancy and 
the possible effects on the fetus will be provided to support an informed decision in cooperation with the 
treating physician and the obstetrician. Any spontaneous abortion will be classified as a SAE. 
 
Regarding the time commitment of participation, every effort has been made to reduce the time 
burden on participants and caregivers. A majority of the assessments are completed by the caregiver, 
and child assessments are kept to a minimum, with only diagnostic/screening measures completed at 
screening and a brief observational measure (~10-15 minutes) completed twice, at baseline and study 
completion at in-person visits. If virtual visits are conducted, the brief observational measure will not 
be administered and the diagnostic/screening measure will be conducted over WebEx. If needed, 
enrollment/baseline visits can be split into two visits. Caregivers may prefer to attend one of those 
visits (virtually or in-person) without their child to complete their measures. Caregivers will be 
encouraged to complete measures using secure electronic entry as much as possible. To give 
caregivers more flexibility, we will allow them the option to complete measures during the screening 
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ease of scheduling, the participant will be given a window of time around the next visit date of +/-3 
days. Reimbursement for time and travel will also be provided at each visit ($75/each at the 
enrollment/baseline, 4-week and 6-week visits and $40/each for the screening and 2-week visits; $75 
for each MRI scan; an additional $10 will be provided on visits that include blood draws and brain MRIs 
[e.g., Screening Visit, Baseline Visit, Week-4 Visit, Week-6 Visit] to cover additional travel expenses). Of 
note, the time commitment and study burden are similar to those of other ASD treatment studies. 
 
3 
OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 
 
Determine the optimal dose of 
CBD in children and adolescents 
with ASD 
 
Establishment of optimal dose of 
CBD in children and adolescents with 
ASD, defined as the dose at which 
the greatest proportion of 
participants respond. Discussed 
further in the Dosing and 
Administration section, the 
definition of treatment response will 
be individualized for each participant 
based upon a predetermined target 
symptom cluster. 
Identification of the optimal dose 
of CBD (within the range tested) is 
desirable given the insufficient 
research in this area and the 
potential for dose-dependent 
inverted-U effects (2, 9). 
Secondary 
 
 
Identify the primary outcome 
measure for a subsequent double-
blind placebo-controlled RCT  
Change in core and associated 
symptoms from baseline based upon 
measures developed to assess ASD 
symptoms, symptoms often 
associated with ASD, and global 
functioning including: 
- 
ABC Social Withdrawal and 
Irritability Subscales 
- 
ASC-ASD-Child and Parent 
- 
AFEQ 
- 
ADAMS 
- 
BIS 
- 
CGI-I 
- 
CGI-S 
- 
HSQ-ASD 
- 
OSU Autism CGI Severity 
- 
OSU Autism CGI Improvement 
- 
RBS-R  
- 
SCARED 
- 
SDSC  
- 
SRS-2 
- 
SWAN (Part 2 of the trial) 
- 
Vineland-3 
Measures were selected because 
they have been widely used in prior 
trials in ASD (ABC, CGI, HSQ-ASD, 
OSU Autism CGI, RBS-R, SCARED, 
SRS-2, SWAN [Part 2], Vineland-3), 
or have been used in a recent trial 
of CBD in Fragile X syndrome 
(ADAMS) or have been used in 
medication trials more broadly 
(SDSC), or represent new and 
innovative tools available in the 
ASD field (ASC-ASD; AFEQ; BIS).  
Tertiary/Exploratory  
 
 
Assess underlying brain 
mechanisms using MRI 
Change in brain activity, indexed by 
resting-state functional connectivity. 
Otherwise, results will be reported 
Inform the feasibility of 
incorporating biomarkers (e.g., 
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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
qualitatively (conducted at in-person 
visits only, if participants agree) 
connectivity) in our future studies 
and potentially yield testable 
hypotheses.  
 
 
 
4 
STUDY DESIGN  
 
4.1 
OVERALL DESIGN 
The primary objective is to determine the optimal dose of CBD in children and adolescents with ASD; the 
hypothesis is that dose response curve may not be linear and that moderate doses of CBD may be 
therapeutically beneficial for core and associated symptoms in children and adolescents with ASD. The 
second objective of this study is to determine effect sizes for a variety of outcome measures, with the 
longer term goal of facilitating the selection of primary and secondary outcome measures for a 
subsequent placebo-controlled RCT. The third objective is to assess the feasibility of quantifying 
candidate biomarkers (e.g., resting-state functional connectivity) using MRI.  
 
This single group single-site study will seek to enroll youth between the ages of 7 and 17 years who have 
a diagnosis of ASD with broadly average intelligence and who are fluently verbal. An adaptive design will 
be employed to allow for evaluation of optimal dosing while collecting data on core and associated ASD 
symptoms and any Aes that may present. Under the adaptive design algorithm we implemented, we 
ended recruitment after enrolling 15 participants and testing two doses. Given the higher rate of 
response on the higher of the two doses tested (44% vs. 16%), and the suggestion that higher doses of 
CBD may particularly target dopamine type 2 high affinity receptors (D2Rhigh) in the striatum, we have 
modified the study by implementing part 2 (described further on page 17-20), to recruit up to 15 youth 
(within the previously approved total accrual of 30 who would enroll) with clinical profiles that most 
closely resemble youth classified as responders in Part 1 of the trial. 
 
It is important to note that all endpoints in this study are exploratory; the research base is too limited to 
make confident predictions. Nonetheless, given the lack of alternative pharmacological options, the 
benign AE profile, and the potential for CBD to fill this treatment gap, this line of work is necessary to 
direct future research in the field. 
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
Suggested dosing to address psychiatric symptoms may be substantially lower compared to dosing in 
epilepsy studies, which has been the focus of most pediatric CBD research. Further, previous research 
suggests that CBD has dose-dependent effects on social behavior and anxiety. Therefore, prior to 
conducting a double-blind trial, identifying optimal dosage is imperative. The BOIN design was employed 
as our dose finding approach. The BOIN design is flexible and sensitive to nonlinearity, and enables the 
designation of an optimal dose level based upon the proportion of participants who respond to the 
treatment.  
 
The BOIN design allowed us to test the intermediate dose (n=9) and the low dose (n=6) and to observe a 
non-significantly higher rate of response (44%) on the intermediate dose than on the low dose (16%). 
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severe adverse events or need to discontinue treatment) and the suggestion that higher doses of CBD 
may particularly target striatal D2Rhigh receptors, we have modified the second part of the trial to 
administer only the still untested 9 mg/kg/day dose, and to focus on participants who present with both 
ASD and ADHD, as they appear to be the ones most likely to be classified as responders in part 1. This is 
described in further detail on pages 17-20.  
  
4.3 
JUSTIFICATION FOR DOSE 
Chronic CBD dosing up to 1500 mg/day has been reported to be tolerated well without AE (60-63); 
minor AE were reported after CBD use in children with epilepsy being treated with multiple other 
medications in doses up to 50 mg/kg/day (3, 27). Accordingly, we believe an upper limit of 9 mg/kg/day 
orally in our dose finding approach is reasonable and safe. Our proposed dosage range is substantially 
lower than most pediatric studies registered in ClinicalTrials.gov (accessed on 06 February 2018). Our 
dose range (3-9 mg/kg/day) is comparable to the only ongoing study specifically addressing behavioral 
symptoms in ASD (NCT02956226; dose range 1 mg/kg/day to 10 mg/kg/day). As mentioned, participants 
assigned to the highest dose (9 mg/kg/day) will be instructed to take half the dose (4.5 mg/kg/day, 
divided in two doses) per day for the first week of treatment before increasing to the full dose to 
minimize the chance for adverse events upon treatment initiation. This will go into effect when the next 
cohort of participants begin treatment with CBD; therefore, all participants who have already been 
enrolled will not be re-consented or informed of the changes.  
 
The BOIN design, discussed in detail within the Dosing and Administration section of the protocol, was 
informed by the observation of dose-dependent inverted-U effects on social behavior in a mouse model 
of Dravet syndrome in which social effects were observed at lower doses than anti-seizure effects (2), the 
increased efficacy of CBD in reducing anxiety during a public speaking task at a moderate dose compared 
to a low and high dose (9), and correspondence with Dr. Adi Aran regarding his clinical experiences in 
prescribing CBD to address associated symptoms of ASD. As noted, now that we’ve obtained data from 
15 participants on the low and intermediate doses by implementing the BOIN design, we propose to test 
the remaining 9 mg/kg/day dose in up to 15 participants – within the originally approved accrual ceiling 
of 30.  
 
Drs. Castellanos and Devinsky, the multiple PIs, and co-I’s Drs. Friedman, Hirsch and Nishawala will 
review all data relating to safety and tolerability throughout the study, after every cohort of three, 
to monitor study conduct and assess participant safety throughout the dosage period of 
approximately 6 weeks. This will be conducted through clinical evaluations at enrollment/baseline and 
final visits, with weekly consultation via WebEx and telephone follow-up calls in between. 
 
4.4 
END OF STUDY DEFINITION 
A participant is considered to have completed the study if he or she has completed all phases of the 
study including the last in-person visit (Visit 4 shown in the SOA, Section 1.3). 
 
5 
STUDY POPULATION 
 
5.1 
INCLUSION CRITERIA 
Patients who will be selected for this study will meet the following criteria: 
• 
Male or female pediatric outpatients aged between and including 7 to 17.9 years old 
• 
Diagnosis of ASD confirmed by the ADOS-2 or CARS-2-HF and DSM-5 criteria 


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• 
Part 2: Diagnosis of ADHD confirmed by clinician review of the K-SADS-COMP 
• 
SRS-2 Total T-score of 66 or higher  
• 
CGI-S score of 4 or higher  
• 
Physical exam and laboratory results that are within normal range for their age 
• 
Fluent speech 
• 
Estimated IQ of at least 80  
• 
Presence of a parent/legal guardian who is able to consent for their participation and complete 
assessments regarding the child’s development and behavior throughout the study  
- 
Child Assent will be obtained. 
 
5.2 
EXCLUSION CRITERIA 
Patients cannot be included in the study if: 
• 
History of active seizure disorder or epilepsy; patients seizure free for > 5 years off of 
antiepileptic drugs and other than uncomplicated febrile seizures are not excluded 
• 
History or current evidence of significantly impaired liver function, defined as 1) Alanine 
aminotransferase (ALT) and/or aspartate aminotransferase (AST) > 5 × upper limit of normal 
(ULN); 2) ALT or AST > 3 × ULN with concomitant total bilirubin > 2.0 × ULN; or 3) ALT or AST ≥ 3 
× ULN with the appearance of fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash, and/or eosinophilia.  
• 
Exposure to any investigational agent in the 30 days prior to initiation of trial 
• 
Treatment with CBD or other cannabinoid within the previous two months 
• 
Current use of medications metabolized primarily by CYP2B6, CYP2C8, CYP2C9, CYP2C19, 
CYP3A4, or CYP2D6 isoenzymes. Methylphenidate is not contraindicated as it is rapidly and 
extensively metabolized by carboxylesterase CES1A1 to ritalinic acid, which has little to no 
pharmacologic activity per DrugBank (accessed 1/31/19: www.DrugBank.ca/drugs)D800422).  
• 
History of drug abuse including marijuana/cannabis use in the past 3 months 
• 
Positive urine sample results from drug screening indicating presence of the following drugs: 
THC, opiates, methamphetamine, or cocaine  
• 
Diagnosis of a known genetic disorder (e.g., Prader-Willi Syndrome, Angelman Syndrome, etc.). 
• 
Active suicidality (ideation and plan) is present 
• 
A current psychiatric diagnosis of bipolar disorder, major depressive disorder (MDD), psychosis, 
schizophrenia, or post-traumatic stress disorder (PTSD) 
- 
These patients will be excluded due to potential confounding results. 
• 
Pregnant or lactating patients or patients who will not agree to be abstinent or use 
contraception 
- 
CBD has not been studied in pregnant or lactating females. 
• 
A medical condition that severely impacts the subject’s ability to participate in the study, 
interferes with the conduct of the study, confounds interpretation of study results or endangers 
the subject’s well-being 
• 
Diagnosis of Rett Syndrome or Childhood Disintegrative Disorder or marked sensory impairment 
such as deafness or blindness 
• 
Subjects who have had changes in allied health therapies, behavioral or educational 
interventions within 4 weeks prior to initiation of trial, other than those associated with school 
holidays 
• 
Subjects who have had changes in non-exclusionary psychotropic medications within 4 weeks of 
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Lifestyle Considerations 
During this study, participants are asked to: 
• 
Refrain from making changes in allied health therapies, behavioral or educational interventions 
• 
Refrain from making changes in non-exclusionary psychotropic medication (e.g., 
methylphenidate) regimen or dosage 
• 
Abstain from illicit drugs, particularly THC, opiates, methamphetamine and cocaine  
• 
Use abstinence or use a valid method of contraception 
 
If prohibited medication, treatment, or practices are indicated during the trial, the participant will be 
withdrawn from the trial. Notably, if the patient/caregiver states they plan to discontinue exclusionary 
medications to participate in the trial, they will be required to do so under the care of their treating 
physician, and will remain under that clinician’s care during the titration/discontinuation and 
throughout their participation in this study.  
 
Importantly, participants will be screened for contraindications to MRI scanning (e.g., metal implants, 
pacemakers, metal foreign bodies, pregnancy). They will not be permitted to undergo optional scanning 
if they meet a condition that is contraindicated.   
  
5.3 
SCREEN FAILURES 
Screen failures are defined as participants who consent to participate in the clinical trial but do not enter 
the study. A minimal set of screen failure information is required to ensure transparent reporting of 
screen failure participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any SAE. 
 
Individuals who do not meet the criteria for participation in this trial (screen failure) because of a 
modifiable factor (e.g., changed treatment regimen 3 weeks prior to screening) may be rescreened. 
Rescreened participants should be assigned the same participant number as for the initial screening. 
 
5.4 
STRATEGIES FOR RECRUITMENT AND RETENTION 
Recruitment will occur through the NYU Langone Child Study Center and Comprehensive Epilepsy 
Center. Both sites have a good track record for recruitment of participants with ASD, and will use all 
successful recruitment methods as previously demonstrated, including use of a study flyer that will 
be available in the lobbies of the Child Study Center and the Comprehensive Epilepsy Center as well 
as published online. We expect to accrue the sample of 30 within 22 months of study initiation. If 
accrual slows at any time point during the study, additional staff effort and resources will be 
dedicated to recruitment efforts including attendance at autism support groups and events and the 
use of tools such as google search engine optimization. We will also employ an EHR query through 
NYU Langone Health’s DataCore for individuals with an ASD diagnosis and will contact these 
individuals using the IRB-approved direct mail text (see 18-00250 direct mail recruitment 
notification). Only the pIs, co-I’s, and other research personnel listed on the study will have access to 
information regarding potential participants. 
 
Interested parents/legal guardians will speak with study staff over the phone for the purpose of 
screening to determine basic inclusionary and exclusionary information prior to scheduling a 
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inclusionary criteria over the phone, then the study staff will inform them that the study would not 
be appropriate. If the parent/legal guardian does not endorse any exclusionary criteria and endorses 
all inclusionary criteria, then the study staff will schedule the screening visit. Of note, if the child 
does not qualify for the study as a result of pre-screening or the family decides not to proceed with 
the study after pre-screening, their data will be discarded and will not be used in this research. We 
aim to obtain complete datasets from at least 30 child and adolescent participants with HFA. To 
reach this number, we anticipate enrolling up to 50 children for in-person screening visits to assess 
variables related to inclusionary and exclusionary criteria. Approximately five children will be 
screened for eligibility to enter each cohort of size 3. Therefore, screening visits will be scheduled 
across time, as each prior cohort approaches participation completion.  
 
We will recruit and include both males and females. The male to female prevalence ratio for ASD 
without intellectual disability is estimated at approximately 5:1 (10); therefore, we will aim to recruit 
at least 15% female participants (n=4 to enroll; n=8 to screen) by prioritizing prospective female 
participants. In regard to age, this study is intended to examine the CBD dose response in a child and 
adolescent population. Therefore, youth aged 7 years to before their 18th birthday at the time of 
projected end of the trial will be recruited to participate. We aim to recruit participants across this 
age range to ensure representation of developmental stages. Finally, individuals of all races and 
ethnic origins are eligible for participation in this study. Based upon the demographics of prior ASD 
study samples at the NYU Child Study Center, we expect approximately 15% of participants to self-
identify as Hispanic/Latino, and racial composition of participants to be approximately 64% 
Caucasian, 20% African American or Black, 4% Asian, 1% Native Hawaiian or Other Pacific Islander, 
<1% American Indian, and 10% more than one race.  
 
This trial focuses on children and adolescents with HFA because of the greater potential for benefit 
in ASD core and associated symptoms in children and adolescents than in adults, balanced with the 
relatively low AE profile of CBD. The lower age limit is defined by feasibility of obtaining cooperation 
for extensive study procedures. In compliance with IRB standards for research with vulnerable 
populations, a description of risks and benefits is included in the protocol. We will not enroll 
emancipated minors or mature minors and will therefore require written consent by a parent or 
legal guardian as well as child assent, in accordance with IRB regulation.  
 
Parents/guardians of participants will be compensated for study participation, subject to IRB 
approval, at the rate of $75/visit for the enrollment/baseline, week-4 and final visits, and $40/visit 
for the other two visits. If they agree to participate in optional MRI scanning, they will also be 
compensated $75 for each scan. A $10 stipend will also be provided for visits that include blood 
draws and MRI scans (e.g., Screening Visit, Baseline Visit, Week-4 Visit if indicated, Week-6 Visit) to 
cover any additional travel expenses. This practice is standard for research projects which require 
substantial effort, and serves to distinguish research from standard clinical practice.  
 
In addition to compensation and because the study will occur across approximately 10 weeks, 
participants will receive visit reminders to enhance participant retention. Further, multiple methods 
including telephone calls and secure email will be used for contacting participants throughout the 
study.  
 
6 
STUDY INTERVENTION 
 


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6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
 
6.1.1 STUDY INTERVENTION DESCRIPTION 
Pure CBD is extracted from the plant Cannabis sativa. The most common elements for potential 
therapeutic use extracted from this plant include Δ9-THC and CBD. Tetrahydrocannabinol (THC) is the 
main psychoactive element found in Cannabis sativa, while CBD has no psychoactive properties. Pure 
CBD can be found as a white crystalline solid. Figure 1 shows its chemical structure. 
 
 
 
 
Figure 1. Cannabidiol Structure 
 
The CBD will be Greenwich Biosciences, Inc.’s formulation of 100 mg/mL purified oral solution, 
dissolved in the excipients sesame oil and anhydrous ethanol with added sweetener (sucralose) and 
strawberry flavoring. The drug is formulated from extracts prepared from Cannabis sativa L. plants 
that have a defined chemical profile and contain consistent levels of CBD as the principal 
phytocannabinoid. Extracts from these plants are processed to yield pure (>95%) CBD that typically 
contains less than 0.5% (w/w) THC.  
 
Cannabidiol is excreted in the urine and feces. The plasma peaks vary significantly between individuals 
but are typically between 1 to 3 hours (52). The half-life has been reported to be 2-5 days (64).  
6.1.2 DOSING AND ADMINISTRATION 
In regard to drug administration, participants will be required to take Epidiolex with food. Of note, 
symptoms of food selectivity and food refusal are seen frequently in ASD (65). Therefore, if caregivers 
report that their child has initial difficulties accepting the CBD, the study clinicians will work on 
increasing participant tolerance and acceptance of the CBD through the use of standard behavioral 
intervention strategies for up to one week. If the participant continues to reject the dose he/she was 
assigned after one week of trial initiation, he/she will be withdrawn from the study. 
 
Related to dosing, in Part 1 of the study, we employed the BOIN design (66, 67) in the first five cohorts 
of this open trial to estimate the optimal dose. The BOIN design was selected because it is more flexible 
than the traditional 3+3 design and possesses superior operating characteristics that are comparable to 
those of the more complex model-based designs, such as the continual reassessment method (CRM) 
(68). 
 


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We defined a target response rate for the optimal dose is 𝜙𝜙= 0.60 and a maximum sample size of 30. 
We enrolled and treated participants in cohorts of size 3. The trial design was implemented through the 
following three steps: 
1. 
Participants in the first cohort were treated at Dose Level 2 (see Table 1). 
2. 
To assign a dose to the next cohort of participants, we conducted dose escalation/de-escalation 
according to the rule displayed in Table 2, which minimizes the probability of incorrect dose 
assignment with response rates of 𝜙𝜙1 = 0.684 and 𝜙𝜙2 = 0.52 designated as the uncertainty 
interval. When using Table 2, please note the following: 
a. 
"Eliminate" means that we eliminate the current dose from the trial to prevent treating 
any future participants at this dose because the response rate is too low. 
b. 
When we eliminate a dose, automatically de-escalate the dose to the next lower level.  
c. 
If none of the actions (i.e., escalation, de-escalation or elimination) is triggered, we treat 
the new participants at the current dose. 
d. 
If the current dose is the lowest dose and the rule indicates dose de-escalation, treat the 
new participants at the lowest dose. 
e. 
If the current dose is the highest dose and the rule indicates dose escalation, treat the new 
participants at the highest dose. 
3. 
Repeat step 2 until the maximum sample size of 30 is reached. 
Table 1. Dose levels 
Dose Level 1 
Dose Level 2 
Dose Level 3 
3 mg/kg/day 
6 mg/kg/day 
9 mg/kg/day 
  
Table 2. Dose escalation/de-escalation/elimination rules for the BOIN Design and results in the first 5 
cohorts 
 Cohort 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Number of participants treated 
at the current dose 
3 
6 
9 
12 
15 
18 
21 
24 
27 
30 
Dose administered (mg/kg/d) 
6 
6 
3 
3 
6 
- 
- 
- 
- 
- 
Cumulative N of respondents 
1 
3 
4 
4 
5 
- 
- 
- 
- 
- 
Escalate if # of responses >= 
3 
5 
7 
9 
11 
13 
15 
17 
19 
21 
Deescalate if # of responses <= 
NA 
3 
4 
6 
7 
9 
10 
12 
14 
15 
Eliminate if # of responses <= 
NA 
1 
2 
4 
5 
7 
8 
10 
12 
13 
For purposes of the study design, participants were categorized as either “responders” or “non-
responders” at the end of the 6-week intervention phase in order to determine the dose level for the 
following cohort. This categorization was based upon the following procedures.  
- 
After completing and meeting eligibility criteria, study staff (including child psychologists 
and psychiatrists with expertise in ASD and comorbid symptoms) met to consensus on an 
individualized, primary outcome variable for each participant at the enrollment/baseline 
visit. The primary target was what is most interfering in the child’s functioning at the 
time of assessment and chosen based upon informant report, scores from a battery of 
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domains, and clinical observations. Clinician consensus also yielded a Clinical Global 
Impression-Severity (CGI-S) score to represent the study team’s impression of the 
participant’s current severity of illness. 
- 
After the final study visit, study staff met again to consensus on the degree of 
improvement observed in the predetermined primary outcome variable for each child. A 
CGI-S score was also determined. Definitions of response and non-response are provided 
below. 
 
Response: In the absence of dose limiting effects, a Clinical Global Impression Scale – 
Improvement (CGI-I) score of 1 (very much improved) or 2 (much improved) determined 
by consensus based upon clinical judgment, informant report, and change in scores on 
measures (using the Reliable Change Index when possible) relevant to the 
predetermined primary outcome. 
 
Non-response: no-to-minimal therapeutic benefit captured by a CGI-I score of 3 
(minimally improved) or greater (i.e., no change or any worsening) determined by 
consensus as indicated above, and/or severe AE, defined as severe cognitive or 
behavioral toxicity, impaired liver and renal function, or impaired hematopoiesis that is 
deemed to be potentially or likely related to study medication (also see section 8.3.2), 
causing early discontinuation of study intervention. 
While applying a uniform statistically derived algorithm for defining treatment response and non-
response for all patients would have been preferable, the above procedures were implemented given 
the exploratory nature of the study and the wide range of therapeutic effects that CBD may exert. The 
intent of this exploratory study has been to provide the foundation for a well-defined subsequent RCT.  
Over the first 15 participants, we have identified five as responders, for an overall response rate of 33%, 
and a response rate of 4/9 = 44% on 6 mg/kg/day, as opposed to the 60% rate anticipated on the 
optimal dose. The response rate on 3 mg/kg/day was 1/6 = 16%. Per the BOIN design that we 
implemented, we have excluded both the 6 mg/kg/day and 3 mg/kg/day dose for further testing. We 
believe that it would be scientifically valuable to test the 9 mg/kg/day dose on the remaining 15 
participants that were originally approved for this open trial. The purpose would be to further confirm 
the overall safety of the AE profile – which is likely given the pediatric experience with 10 mg/kg/day 
and 20 mg/kg/day in patients with refractory epilepsy who are more medically fragile. It has also been 
hypothesized that higher doses of CBD may have preferential effects on D2high receptors in the striatum. 
If so, that might explain why all five responders had ASD, as well as ADHD.  
Accordingly, we now request that we amend the open trial to test only the dose of 9 mg/kg/day and 
that we require the combination of ASD and ADHD for inclusion. All other aspects of the trial would be 
unchanged, other than adding the Strengths and Weaknesses of Attention-Deficit/Hyperactivity 
Disorder Symptoms and Normal Behavior (SWAN) as a dimensional measure of ADHD and completing 
the K-SADS-COMP at the screening visit rather than the baseline/enrollment visit so that the study 
clinicians can confirm the presence of an ADHD diagnosis.  


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Given our experience with the first 15 participants, we anticipate that at least 1/3 will be classified as 
responders. If none of the first 6 participants on 9 mg/kg/day are responders, then we would eliminate 
the dose and terminate the trial. A low, non-zero response rate, as shown below in Table 3, would also 
determine terminating the trial, as it would be tantamount to evidence that the optimal dose was 6 
mg/kg/day, our initial starting dose.  
Table 3. Dose elimination rules for cohorts 6 to 10  
 Cohort 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Number of participants to be 
treated at the current dose 
3 
6 
9 
12 
15 
18 
21 
24 
27 
30 
Dose administered (mg/kg/d) 
6 
6 
3 
3 
6 
9 
9 
9 
9 
9 
Cumulative N of respondents 
1 
3 
4 
4 
5 
- 
- 
- 
- 
- 
Terminate if # of responses <= 
 
 
 
 
 
NA 
5 
6 
7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thus, we propose to enroll at least six more participants on the dose of 9 mg/kg/day. If none of them 
respond, the cumulative number of respondents would remain 5, and we will discontinue the trial; if at 
least 1 responds within the first 6, we will enroll 3 additional participants. If the total number of 
responders remains 6, we will discontinue the trial. If the number of responders is 7 or more after 9 
participants are enrolled, we will enroll an additional 3 participants for a total of 12 on this dose. If the 
number of responders does not increase beyond a total of 7, we will terminate due to likely futility.   
Table 4 provides the operating characteristics of this design extension for a variety of true response 
rates. 
Table 4. Operating characteristics of 9 mg/kg/day evaluation 
 
Dose 1 
Dose 2 
Dose 3 
Dose 4 
Dose 5 
True response rate 
0.1 
0.2 
0.3 
0.4 
0.5 
Probability of early termination(%) 
90.4 
60.8 
31.0 
11.9 
3.5 
 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
 
6.2.1 ACQUISITION AND ACCOUNTABILITY 
The drug will be shipped to the responsible person, such as the PI, who will check the amount received 
and the condition of the drug.  Details of the drug received will be recorded in an accountability record. 
We will acknowledge drug receipt to Greenwich Biosciences, Inc. and will complete any receipt forms 
required.  As directed in the investigational brochure, all supplies, including unused, partially used, or 
empty containers, will be returned to Greenwich Biosciences, Inc. or destroyed at the center if agreed in 
writing by the study monitor. 


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6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
The CBD will be packaged as Epidiolex (V), 100mg/mL oral solution in a 100 mL bottle. Each bottle of 
100mg/mL solution will contain 100 mL of oral CBD solution. The CBD will be shipped in separate 
subject-specific boxes from Greenwich Biosciences, Inc. The subject drug kits will contain a 100mL 
amber glass bottle of 100 mg/mL CBD in sesame oil vehicle with sucralose sweetener and strawberry 
flavoring. The bottle will have a child-resistant cap. The bottles will be in a white cardboard carton with 
cardboard insert. The outer sides of carton will bear a label with appropriate instructions. The box will 
also contain a graduated oral syringe for accurate dosing administration and a patient information 
leaflet. Label text will comply with European Union (EU) guidance on Good Manufacturing Practice, 
Annex 13 Labelling.   
 
6.2.3 PRODUCT STORAGE AND STABILITY 
The CBD will be stored in a locked file-cabinet inside a locked office at room temperature. The CBD must 
be stored in temperatures less than 30°C, with limited access to light. 
 
6.2.4 PREPARATION 
Not applicable.  
 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
Not applicable.  
 
6.4 
STUDY INTERVENTION COMPLIANCE 
Adherence to protocol will be assessed by requiring a participant drug log in which dose and time of 
administration will be recorded by the parent/guardian.  
 
6.5 
CONCOMITANT THERAPY 
 For this protocol, concomitant pharmacologic, educational, behavioral, and/or dietary therapies will be 
reviewed at each contact. Concomitant therapies will be reported in the Case Report Form (CRF). The 
subjects will be asked to continue any non-exclusionary psychopharmacologic (i.e., stimulant such as 
methylphenidate), educational, behavioral, and/or dietary interventions that were stable for 4 weeks 
prior to initiation of trial and to maintain them stable through the trial. Change in outside therapy, 
including pharmacological treatment, could skew results. Any participant who experiences a change of 
services (other than those associated with school holidays) will be withdrawn from the study as per the 
PI. 
 
6.5.1 RESCUE MEDICINE 
  Not applicable.  
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
A participant may be discontinued from the study intervention at any time if the participant or 
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continue. Study intervention may be discontinued following parental withdrawal of consent, failure to 
remain compliant with study procedures, protocol violation requiring discontinuation, or SAE. If a 
participant must discontinue the study treatment, the method of CBD discontinuation will be 
determined based on type of reaction and/or reason for withdrawal. For example, if the participant 
experiences a rapidly progressive rash it would lead to abrupt cessation of CBD, but if participant 
experiences excess tiredness, CBD would be tapered off. A discussion of the method of cessation will 
occur between the participant and/or participant’s parent/legal guardian and the physician.  
 
If a participant requires discontinuation of CBD due to AEs, the participant will be considered a “non-
responder.” Participants who are discontinued from study intervention will receive the 3-month follow-
up telephone call to gather descriptive information about current functioning and treatment choice.  
 
While there will be no temporary discontinuations on the basis of AE, participants may experience a 
temporary discontinuation if a follow-up session is not attended within the +/- 3 day timeframe. In this 
case, the investigator will determine how to proceed based on report of effects and AEs, and results 
from safety assessments. If all variables indicate good tolerability, continuation will occur. The 
participant’s participation in the trial will be extended by one week to ensure that data has been 
collected across three time points after enrollment/baseline. If AE is a concern, the investigator will 
determine if any change in participant management is needed. 
 
The data to be collected at the time of study intervention discontinuation will include the following: 
• 
Physical exam and vital signs 
• 
Clinical labs (i.e., test of hepatic and hematological function including total bilirubin; plasma for 
CBD levels)  
• 
AE review and evaluation 
• 
MRI 
• 
Standardized measures of symptom improvement (i.e., ABC, ADAMS, ASC-ASD-Child, ASC-ASD-
Parent, AFEQ, BIS, CGI-I, CGI-S, HSQ-ASD, OSU Autism CGI-I, OSU Autism CGI-S, RBS-R, SCARED, 
SDSC, SRS-2, SWAN [Part 2], Vineland-3) 
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
A participant may be discontinued from study treatment at any time if the participant or participant’s 
legal guardian or the investigator feels that it is not in the subject’s best interest to continue. The 
following is a list of possible reasons for study treatment discontinuation: 
• 
Parental/guardian withdrawal of consent 
• 
Subject is not compliant with study procedures 
• 
Protocol violation requiring discontinuation of study treatment 
• 
SAE, including significant toxicity such as severe cognitive or behavioral toxicity, impaired liver 
function, or impaired hematopoiesis that is deemed to be potentially or likely related to study 
medication 
 
If subject must come off of study treatment, the method of CBD discontinuation will be determined 
based on type of reaction and/or reason for withdrawal. For example, if the participant experiences a 
rapidly progressive rash it would lead to abrupt cessation of CBD, but if participant experiences excess 
tiredness, CBD would be tapered off. A discussion of the method of cessation will occur between the 
participant and/or participant’s parent/legal guardian and the physician.  
 


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Subjects for whom a parent/guardian has signed the informed consent form, who have received the 
study intervention, and subsequently withdraw, or are withdrawn or discontinued from the study will 
not be replaced. 
 
7.3 
LOST TO FOLLOW-UP 
A participant will be considered lost to follow-up if he or she fails to return for 2 or more scheduled visits 
and is unable to be contacted by the study site staff.  
 
The following actions must be taken if a participant fails to return to the clinic for a required study visit: 
• 
The site will attempt to contact the participant and reschedule the missed visit within a week +/- 
3 days and counsel the participant on the importance of maintaining the assigned visit schedule 
and ascertain if the participant wishes to and/or should continue in the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, 3 telephone calls, secure email, 
and, if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts will be documented in the participant’s medical 
record or study file.  
• 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 
EFFICACY ASSESSMENTS  
Primary Endpoint  
Treatment response will be determined according to the Clinical Global Impression Scale – 
Improvement (CGI-I), based upon clinical judgment and scores from relevant measures within the 
Secondary Endpoints subsection:  
• 
Clinical Global Impression Scale – Improvement (CGI-I): The CGI-I is a clinician rated global 
measure of improvement and is made up of a 7-point scale where: 1=very much improved, 
2=much improved, 3=minimally improved, 4=no change, 5=minimally worse, 6=much worse, 
and 7=very much worse (69). The CGI-I has been used as an outcome measure in multiple 
clinical psychopharmacology trials and will be completed through expert consensus, including a 
team of child psychologists and psychiatrists with expertise in ASD, based upon scores from 
relevant measures and clinical judgment. This will be completed at the final study visit (Week 
6). 
 
Secondary Endpoints – Symptom Measurement  
Autism Measures  
• 
Behavioral Inflexibility Scale (BIS): The BIS is a newly developed parent-report measure 
designed to assess rigid patterns of behavior, commonly associated with ASD, in children and 
adolescents 3-18 years of age. The BIS includes 38 items rated on a 6-point Likert scale where 
0=Not at all a problem and 5=Very severe or extreme problem. Psychometric properties 
resulting from initial evaluations of the measure are strong (70). The BIS will be completed by 
caregivers at the enrollment/baseline visit (or at the screening visit), at the final study visit 
(Week 6), and 6 weeks after medication discontinuation (optional).     


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• 
OSU Autism Clinical Global Impression-Severity and Improvement Subscales: The OSU Autism 
CGI-Severity and Improvement scales are adapted versions of the classic CGI-S and CGI-I 
developed by the OSU Research Unit on Pediatric Psychopharmacology (RUPP) to better 
account for autism symptoms in clinician ratings. The indications are more directly and 
specifically related to ASD compared to those in the CGI. Importantly, the OSU Autism CGI has 
been found reliable when used by experienced clinicians (73). The OSU Autism CGI-S will be 
completed by the research team at the enrollment/baseline visit and final visit (Week 6) to 
obtain an estimate of severity of ASD symptoms. The OSU Autism CGI-I will be completed in 
the final visit (Week 6) by the research team to quantify improvement in core ASD symptoms 
only. These uses are differentiated from our use of the CGI-S and the CGI-I in the current study, 
as both the CGI-S and CGI-I will be used to assign ratings to each participant’s individualized 
target symptom domain whereas the OSU Autism CGI-S and OSU Autism CGI-I ratings will 
relate to ASD symptoms only.    
• 
Repetitive Behavior Scale-Revised (RBS-R): The RBS-R is a questionnaire used to measure the 
range of RRBs expressed by individuals with ASD. The RBS-R consists of six subscales covering a 
range of RRB subtypes including: Stereotyped Behavior, Self-injurious Behavior, Compulsive 
Behavior, Routine Behavior, Sameness Behavior, and Restricted Behavior. The subscales have 
no overlap of item content, permitting differential identification and scoring of discrete 
varieties of RRB. The presence and frequency of behaviors are rated on a 4-point scale (ranging 
from 0=behavior does not occur to 3=behavior occurs and is a severe problem) (74-76). The 
RBS-R will be completed by caregivers at the enrollment/baseline visit (or at the screening 
visit), at the final study visit (Week 6), and 6 weeks after medication discontinuation (optional), 
and takes approximately 20 minutes to complete.  
• 
Social Responsiveness Scale, 2nd Edition (SRS-2), School-Age Form: The SRS-2 is a measure of 
social impairment related to ASD in children aged 4 to 18 years old. Five domains are assessed 
including: Social Awareness, Social Cognition, Social Communication, Social Motivation, and 
Restricted Interests and Repetitive Behavior. Items are scored on a 4-point scale (ranging from 
1=not true to 4=almost always true). Excellent psychometric properties have been previously 
established for the SRS for use in children and adults (77, 78). The SRS-2 will be administered at 
screening and at the final study visit (Week 6), and 6 weeks after medication discontinuation 
(optional). The SRS-2 takes approximately 20 minutes to complete. 
Measures of Associated Symptoms 
• 
Aberrant Behavior Checklist (ABC) – Irritability and Social Withdrawal Subscales: The ABC was 
designed to measure behavior problems in individuals with developmental disabilities and 
ASD through informant report. The subscales of the ABC include: Irritability, Social 
Withdrawal, Stereotypic Behavior, Hyperactivity/Noncompliance, and Inappropriate Speech. 
Items are rated on a 4-point scale (ranging from 0=no problem at all to 3 = problem is severe 
in degree) (79-81). The ABC has been used in multiple ASD trials to measure changes in 
irritability and social withdrawal, with success. It will be completed by caregivers at the 
enrollment/baseline visit (or at the screening visit), the final study visit (Week 6), and 6 weeks 
after medication discontinuation (optional), and takes approximately 20 minutes to complete. 
• 
Anxiety, Depression and Mood Scale (ADAMS): The ADAMS was developed to provide a 
psychometrically sound instrument for quantifying anxiety, depression and mood disorders 
among individuals with intellectual disabilities above age 10 (82). It contains 55 symptom 
items that resolve into five subscales labeled: Manic/Hyperactive Behavior, Depressed Mood, 
Social Avoidance, General Anxiety, and Compulsive Behavior. The ADAMS total score was the 
top-line outcome measure in the previously mentioned pilot trial of CBD in FXS. The ADAMS 
will be administered at the enrollment/baseline visit (or at the screening visit), at the final 


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study visit (Week 6), and 6 weeks after medication discontinuation (optional). It takes 
approximately 10 minutes to complete. 
• 
Anxiety Scale for Children – Autism Spectrum Disorder – Child and Parent versions (ASC-ASD):  
The ASD-ASD was developed as the first anxiety measure specifically designed to detect 
symptoms in youth with ASD. Psychometrics of this new measure are promising (83). Both the 
parent and child versions are 24 items in length, making up four subscales: Performance 
Anxiety, Uncertainty, Anxious Arousal, and Separation Anxiety. The ASC-ASD-Parent and the 
ASC-ASD-Child will be administered at the enrollment/baseline visit (or at the screening visit) 
and final visit (Week 6) and both take approximately 15 minutes to complete. The ASC-ASD-
Parent will also be administered 6 weeks after medication discontinuation (optional). 
• 
Computerized Kiddie Schedule for Affective Disorders and Schizophrenia (KSADS-COMP): The 
KSADS-COMP is a DSM-5 based instrument administered by a secure web-based computer 
program to parents/guardians derived from the KSADS (85). The responses and the 
algorithmically determined presumptive diagnoses are then immediately provided for follow-
up and clarification, as needed, by a licensed clinician. The KSADS-COMP will be used in the 
current study to allow for further clinical characterization of the sample and will be 
administered to caregivers online at the enrollment/baseline visit (or at the screening visit).  
In Part 2 of the trial, the K-SADS-COMP will be administered at the screening visit and will also 
be used to confirm the presence of an ADHD diagnosis.  
• 
Home Situations Questionnaire – Modified for ASD (HSQ-ASD): The HSQ-ASD is a 24-item 
questionnaire that measures behavioral noncompliance in everyday settings for children with 
ASD (86). The HSQ-ASD is a modified version of the HSQ (87), a measure that was initially 
designed for assessing noncompliance in children with disruptive behavior disorders. In its 
modified form, the HSQ-ASD includes an additional 7 items that address a broader range of 
situations in which children with ASD may display noncompliance and consists of two 12-item 
factors: Socially Inflexible and Demand Specific. To complete the form, caregivers indicate 
whether the child has a problem with compliance in each situation and, if so, to rate the 
severity of non-compliance on a 1–9 Likert scale. Higher scores indicate greater non-
compliance. The HSQ-ASD will be completed by caregivers at the enrollment/baseline visit (or 
at the screening visit) and the final study visit (Week 6), and 6 weeks after medication 
discontinuation (optional), and takes approximately 10 minutes to complete. 
• 
Screen for Child Anxiety Related Disorders (SCARED), Parent Version: The SCARED, Parent 
Version is a parent report measure with strong psychometrics developed to measure child 
anxiety symptoms. Subscales include Somatic Symptoms/Panic Disorder, Generalized Anxiety 
Disorder, Separation Anxiety, Social Phobia, and School Phobia. Research exists 
demonstrating the utility of the SCARED for assessing anxiety in the ASD population (88). The 
SCARED, Parent Version takes approximately 10 minutes to complete and will be 
administered to parents/guardians at the enrollment/baseline visit (or at the screening visit), 
at the final study visit (Week 6), and 6 weeks after medication discontinuation (optional). 
• 
The Sleep Disturbance Scale for Children (SDSC): The SDSC is an informant-report measure 
designed to assess the most common areas of sleep disorders in childhood and adolescence 
(89). The SDSC has six subscales including Disorders of Initiating and Maintaining Sleep, Sleep 
Breathing Disorders, Disorders of Arousal, Sleep Wake Transition Disorders, Disorders of 
Excessive Somnolence, and Sleep Hyperhydrosis. The SDSC takes approximately 10–15 
minutes to complete and will be administered to caregivers of participants at the 
enrollment/baseline visit (or at the screening visit) and at the final study visit (Week 6), and 6 
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• 
Strengths and Weakness of Attention-Deficit/Hyperactivity Disorder Symptoms and Normal 
Behavior Scale (SWAN):  The SWAN is a parent report measure designed to assess symptoms 
of ADHD in children and adolescents. The SWAN consists of 18 items that make up two 
subscales (i.e., ADHD-Inattentive and ADHD-Hyperactive/Impulsive). The SWAN takes 
approximately 10 minutes to complete and will be administered to caregivers at the 
baseline/enrollment visit (or at the screening visit) and the final study visit (Week 6) and 6 
weeks after medication discontinuation (optional) during Part 2 of the trial.   
• 
Vineland Adaptive Behavior Scales, Third Edition (Vineland-3), Parent/Caregiver Form: The 
Vineland-3 is frequently used to measure adaptive functioning across the areas of 
communication, daily living skills, socialization, motor skills, and maladaptive behavior (90). 
The Parent/Caregiver form is an informant-based questionnaire assessing three core domains 
(i.e., Communication, Daily Living Skills, and Socialization) and two optional domains (i.e., 
Motor Skills and Maladaptive Behavior). The core domains sum to a total Adaptive Behavior 
Composite. The Vineland-3 Parent/Caregiver Form was designed to assess the functioning of 
individuals 3 years of age or older and takes approximately 15 minutes to complete. The 
Vineland-3 will be administered at the baseline/enrollment visit (or at the screening visit) and 
the final visit. Because “high functioning autism” is often a misnomer, in that children with 
ASD with average to above average IQ and language skills often experience substantial 
functional impairments (96), the Vineland-3 will provide further characterization of the 
sample in addition to serving as an outcome measure. 
General Functioning 
• 
Autism Family Experience Questionnaire (AFEQ): The AFEQ was developed to measure the 
impact of autism interventions on family experience and quality of life. Recent research on 
the AFEQ demonstrated the measure was sensitive to change in response to intervention in 
young children with ASD (91). The measure includes 48 items that make up four domains: 
Parent, Family, Child Development, and Child Symptoms. Ratings on each item can also be 
summed to equal a total score. The AFEQ will be administered to parents at the 
enrollment/baseline visit (or at the screening visit) and at the final visit (Week 6) and takes 
about 15 minutes to complete.  
• 
Clinical Global Impression-Severity (CGI-S): The CGI-S reflects clinician impression of the 
participant’s current severity of illness on a 7-point scale ranging from 1=not at all ill to 
7=among the most extremely ill (69). The CGI-S will be completed by the evaluating clinician 
at the screening visit, and by clinician consensus at the enrollment/baseline visit and the final 
study visit (Week 6).  
 
Given the extent of the information we are requesting from caregivers, rating scales will be available to 
complete online from home during the time period between the screening and enrollment/baseline 
visits, and in the sixth week of treatment up until the final study visit. Caregivers can choose to complete 
these forms in the clinic or online. Caregivers can choose to complete these forms prior to their child 
being found eligible for participation, in the case the additional time makes completion of the measures 
more feasible for the caregiver and scheduling of subsequent visits more efficient. An eligible child will 
not be administered the study drug until all forms are submitted. If the caregiver does not complete the 
forms prior to coming to the final study visit, all forms must be completed at the clinic during that visit.  
 
8.2 
SAFETY AND OTHER ASSESSMENTS 
Prior to the in-person portions of the screening visit, patients and caregivers will be consented and an 
interview will be conducted regarding medical, psychiatric, and treatment history relevant to the 


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exclusionary criteria virtually over WebEx. If families prefer to do the full visit in person, 
parents/guardians will then be set up in a room to complete necessary parent-report measures. 
Otherwise, they will be instructed to complete these online. Child testing will be conducted. The 
Wechsler Abbreviated Scale of Intelligence, Second Edition (WASI-II) and the Autism Diagnostic 
Observation Schedule, Second Edition (ADOS-2) or Childhood Autism Rating Scale, 2nd Edition, High 
Functioning version (CARS-2-HF) will be administered to ensure patients meet inclusionary criteria for 
ASD symptom score, language requirements, and IQ. The CGI-S will be completed by the evaluating 
clinician. These tests are discussed below.  
 
Screening measures  
• 
Autism Diagnostic Observation Schedule – 2 (ADOS-2): The ADOS-2 is a diagnostic tool used to 
document the presence of ASD. During a semi-structured evaluation, the individual is observed 
in a naturalistic social situation and assessed across areas of social communication, imagination, 
and RRBs. The ADOS includes four modules for use with different age groups and language 
levels; Modules 3 or 4 will be used in this study. The appropriate module of the ADOS will be 
administered by a certified rater at screening (92, 93). If the potential participant has been 
administered the ADOS assessment in the past and results are documented, given the 
substantial stability in ADOS scores across time, there will be no requirement to repeat it. The 
ADOS-2 takes approximately 45 minutes to complete and will only occur at the screening visit. 
Total scores must be at or above 7 to participate in the study.  
• 
Autism Symptom Interview (ASI): The ASI is a brief interview derived from the Autism Diagnostic 
Interview-Revised (ADI-R); the ASI offers improved efficiency while maintaining sound 
psychometric properties (94). The ASI takes approximately 45 minutes and includes questions 
about current and past symptoms consistent with ASD. The ASI will be used in conjunction with 
other interviews, scores from the ADOS-2 and SRS-2, and clinical judgment to confirm ASD 
diagnoses by the DSM-5 diagnostic criteria at the screening visit. 
• 
Childhood Autism Rating Scale, 2nd Edition, High Functioning (CARS-2-HF): The CARS-2-HF is 
similar to the ADOS and is a commonly used diagnostic tool to document the presence of ASD in 
children and adolescents over the age of 6 with broadly average IQ and verbal language. 
Because the ADOS cannot be administered validly over WebEx or when wearing personal 
protective equipment, we will administer the CARS-2-HF to participants that do not have 
documentation of a previous ADOS assessment. The CARS offers more flexibility than the ADOS, 
as the ADOS requires standardized materials and scripted activities. The psychologists on the 
team were trained by the developers of the CARS on virtual administration of the instrument, 
and activities completed within the CARS were adapted, so that administration is similar across 
participants and clinicians. Participants must score in the mild-to-moderate or severe symptoms 
of ASD range.  
• 
Computerized Kiddie Schedule for Affective Disorders and Schizophrenia (KSADS-COMP): As 
described above, in Part 2 of the trial, the K-SADS-COMP will be administered at the screening 
visit and will also be used to confirm the presence of an ADHD diagnosis. 
• 
Wechsler Abbreviated Scale of Intelligence, Second Edition (WASI-II): The WASI-II was designed 
to swiftly and accurately assess cognitive functioning and has strong psychometric properties 
(95).The WASI-II, Two-Subtest Form will be administered in this study to obtain data on 
intellectual ability. This form consists of two subtests (i.e., Vocabulary and Matrix Reasoning) 
and takes approximately 10-20 minutes to complete. This will only be completed at screening. 
Estimated IQ must be at or above 80 to participate in the trial. As with the ADOS-2, the WASI-II 
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professional and was documented within the previous 3 years of the screening visit or when the 
child was 6 years of age or older.   
• 
Clinical Global Impression-Severity (CGI-S): Information regarding the CGI-S is provided within 
Section 8.1 Secondary Study Endpoints. Within the screening visit, patients must receive a 
rating of 4 (Moderately Ill) or higher on the CGI-S to participate in the trial.  
• 
Social Responsiveness Scale, 2nd Edition (SRS-2), School-Age Form: Information regarding the 
SRS-2 is provided within Section 8.1 Secondary Study Endpoints. Patients must receive a total 
T-score of 66 to meet inclusionary criteria for participation in the study. 
 
Further, in the case of virtual visits for participants who do not have prior documentation of an ADOS 
assessment, because confirming a diagnosis of ASD virtually is understudied, we will follow up cases for 
which clinicians report substantial uncertainty by administering a complete Autism Diagnostic Interview-
Revised (ADI-R), the gold standard interview instrument for ASD that takes 1-3 hours to administer. 
 
Following the child testing, the clinician will score the child and parent measures to determine if 
benchmarks for eligibility were met. If participants continue to be eligible for participation, a medical 
exam will be conducted. Patients will receive a brief physical exam, vital sign assessment, a blood draw, 
a urine drug screen, and, if female, a pregnancy test to further evaluate eligibility criteria. In the case of 
virtual visits, the urine drug screen and pregnancy test if applicable will be mailed to participating 
families and we will ask parents to collect urine and then test the urine over WebEx with a study team 
member “assisting” virtually. We will also accept a note from the child’s pediatrician reporting that the 
child is in good health and is medically cleared to participate, rather than requiring a separate in-person 
physical exam. We will not collect vital signs during these virtual visits, as we did not detect any 
differences in heart rate or blood pressure in response to CBD administration in the first cohort of 
participants. We have also not noted any reports in the literature on such effects. To participate in the 
study, patients’ vital signs and results from their tests of hepatic and hematologic function must be 
within the normal range for their age. Specifically, patients with baseline elevations greater than 3 times 
the upper limit of normal (UNL) in alanine aminotransferase (ALT) and/or aspartate aminotransferase 
(AST) or elevations of total bilirubin greater than 2 times the ULN will be excluded. Patients will be 
excluded if they have a positive urine sample results from drug screening indicating presence of THC, 
opiates, methamphetamine or cocaine. Patients will also be excluded if pregnant. See table listing 
screening visit below.  
 
Tasks 
Assessments 
Inclusionary/Exclusionary Criteria 
Gather history 
Medical History 
 
History of active seizure disorder/epilepsy 
 
Known genetic disorder 
 
Diagnosis of Rett syndrome or Childhood Disintegrative 
Disorder 
 
Marked sensory impairment (e.g., blindness, hearing 
impairment) 
 
Pregnant or lactating 
 
Current use of medications metabolized primarily by CYP2B6, 
CYP2C8, CYP2C9, CYP2C19, CYP3A4, or CYP2D6 isoenzymes 
 
Refusal to remain abstinent or use contraception 
Psychiatric History 
 
Current psychiatric diagnosis of bipolar disorder, MDD, 
psychosis, schizophrenia, PTSD or active suicidality (ideation 
and plan) 


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History of drug abuse in the past 3 months 
Treatment History 
 
Stable interventions (i.e., allied health therapies, behavioral, 
educational, non-exclusionary antidepressant or stimulant 
medication/dosing of medication) for 4 weeks prior to 
randomization/for the duration of the study 
 
Prior treatment with CBD or an endocannabinoid treatment 
 
Current treatment with valproate or clobazam or other 
antiepileptic medication 
 
Exposure to investigational agent in 30 days prior to 
randomizations 
Developmental 
and Psychiatric 
Evaluation 
WASI-II  
 
Estimated IQ ≥ 80 
ADOS-2 
 
Qualify for administration of Module 3 or Module 4 
(Indicating presence of fluent speech) 
 
Meets or exceeds autism spectrum cutoff on ADOS or CARS-
2-HF 
SRS-2 
 
Total T-score ≥ 66 
CGI-S 
 
Score ≥ 4 
K-SADS-COMP (Part 2) 
 
Presence of ADHD diagnosis confirmed by clinician review of 
K-SADS-COMP results 
Medical 
Examination 
Physical Exam (Vital 
Signs, Height, Weight) 
 
Personal physician provides documentation indicating the 
participant is in good health to participate in the trial or 
physical exam results within normal limits or results of 
physical exam conducted by study PI within normal limits 
 
 AST, ALT are less than 3 times the ULN and total bilirubin is 
less than 2 times ULN 
Clinical Labs 
 
Results that are within normal range for age 
Drug screen 
 
Positive urine sample results from drug screening indicating 
presence of: THC, opiates, methamphetamine or cocaine 
Pregnancy test 
 
Positive results of pregnancy test 
 
Patients’ parents/guardians will be notified about eligibility for the study and enrollment procedures 
within about 1 week following the receipt of all measures. As mentioned, patients will be screened at 
different times according to each cohort start date. We estimate screening approximately 5 children at a 
time to secure a cohort of size 3. After a patient is found eligible, the enrollment/baseline visit will be 
scheduled in accordance with the availability of cohort “slots” and family availability. If more than 8 
weeks elapses following their screening visit, we will confirm continued eligibility by scheduling a 
telephone appointment. This provision for the possibility of extended time allows for an eligible 
participant to be assigned to a cohort that follows the one they were screened for. This will be 
important in the case that 5 children were screened for a cohort (as described) but more than 3 were 
eligible. It could also come into play when the family’s anticipated schedule will conflict with trial 
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children within a cohort of size 3 could begin the trial without all three participants in the cohort having 
been recruited. This will minimize asking families to defer changes in treatment while waiting for a 
cohort to be established. Decisions regarding termination or continuation of Part 2 of the trial will still 
depend on the result of each three participant cohort, even if not performed contemporaneously.  
 
Through the trial, safety will be assessed regularly using the assessment strategies listed below.  
 
Safety assessment  
• 
Brief physical examination (e.g., height and weight) to be completed at screening and Week 6. 
To minimize the time spent in in-person visits given the risks presented by COVID-19, and allow 
families the option to complete as much as possible virtually, we will accept documentation 
from the participant’s physician stating that the participant is in good health to participate in the 
trial to replace the physical exam at screening. The Week 6 physical examination will be 
conducted by the study team. 
• 
Vital signs (e.g., temperature, pulse, respirations, blood pressure) to be completed at each in-
person visit. We will not collect vital signs during virtual visits (e.g., screening, Week 2, Week 4), 
as we did not detect any differences in heart rate or blood pressure in response to CBD 
administration in the first cohort of participants. We have also not noted any reports in the 
literature on such effects. Vital signs will be collected at baseline/enrollment and Week 6 visits. 
• 
Test of hepatic and hematological function to be completed at screening, Week 4 and Week 6. 
To reduce in-person visits, we will make decisions regarding the necessity of a Week 4 blood 
draw on an individual basis. If a subject’s baseline blood draw suggests borderline clinical 
abnormalities (that did not meet the cutoff for exclusion), they will be required to complete a 
Week 4 blood draw at the outpatient lab out of an abundance of caution. Otherwise, blood 
draws will be limited to two – one at baseline and one at the final visit (Week 6) – rather than 
three. 
• 
Plasma for quantifying CBD levels to be completed at Weeks 6. 
• 
AE report: UKU Side Effects Rating Scale – Patient Version (97) to be completed by 
parent/guardian at the Week 2, Week 4, and Week 6 visits. The participant will also be involved 
in these interviews when appropriate. Each UKU Side Effects Rating Scale will be reviewed by 
the PI. Symptoms of possible hepatic injury (i.e., fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever or rash) will be specifically queried. 
• 
Columbia-Suicide Severity Rating Scale (98) to be completed by the participant at screening, 
baseline/enrollment, Week 2, Week 4, and Week 6 visits and reviewed by the PI. The C-SSRS is a 
brief assessment of suicidal ideation and behavior validated for use across the lifespan; the C-
SSRS maintains strong psychometric properties (98). Screening for suicidality is necessary given 
that Epidiolex is classified within the anti-epileptic drug (AED) class, and AEDs have been shown 
to increase the risk of suicidal thoughts or behavior. 
 
Exploratory endpoints 
To examine potential underlying brain mechanisms related to CBD, the proposed study will use MRI to 
inform the feasibility of incorporating biomarkers (e.g., resting-state functional connectivity) in our 
future studies and potentially yield testable hypotheses. 
 
During the screening visit, to effectively acclimate the child to the MR environment, we use an MR 
simulator. Habituating children in an MRI simulator minimizes data loss, which is pivotal for obtaining 
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prepare the child for the scanning experience. Our team has a long track-record of obtaining high-quality 
imaging data in neurodevelopmental disorders, including ADHD and autism, with children as young as 5 
years old.  
 
Following the mock scan, a scan will be scheduled for the Baseline visit. Imaging will be performed using 
scanning equipment which have been FDA-approved for clinical and research scans as minimal risk 
devices. No exogenous contrast agent will be used in any imaging sequence. At the beginning of the 
scan session, participants will be familiarized with the scanning environment and the research team, 
while the imaging procedures are being carefully explained. The Social Story will be read aloud again. 
The research staff will conduct a metal screening interview with the parent(s) to ensure MRI safety and 
will use a hand-held metal detector to search for any metal on the participant (and the parent, if they 
plan on entering the scanner suite while the child is being set-up). Additionally, female participants who 
have begun menstruation will be instructed to take a urine pregnancy test to ensure lack of pregnancy. 
If there are no contraindications, participants will be brought into the MRI room. The research staff will 
place earplugs, headphones, pneumatic belt, and finger transducer on the child and have them lay down 
on the scanner table. The participant will be positioned on their back on the scanner gantry with head 
straight aligned with the middle of the coil. The radio frequency imaging coil, which obtains the imaging 
data, will be positioned in front of the child’s face. All participants will be asked to limit head motion. 
Foam padding will be used for comfort and to comfortably restrict head motion. Once the child is 
comfortable, we will slide the scanner table into the magnet and begin scanning. Between each scan, 
the child will be in contact with the research staff through a microphone mounted in the MRI scanner. 
While scanning is on, it gets loud, thus the speaker is turned off and we will not be able to hear the child. 
This is why the child will have a handheld squeeze-ball device to let the operator know if they wish to 
immediately stop scanning and be removed from the magnet. Upon being squeezed, the squeeze-ball 
emits a loud sound in the operator room to notify the research staff who will immediately stop the scan. 
We spend time during the mock MRI to instruct and coach the child of these procedures so they will be 
well prepared before the MRI scan. 
 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 
Adverse event (AE) means any untoward medical occurrence associated with the use of an intervention 
in humans, whether or not considered intervention-related (21 CFR 312.32 (a)). 
 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
An AE or suspected adverse reaction is considered "serious" if, in the view of the investigator it results in 
any of the following outcomes: death, a life-threatening adverse event, inpatient hospitalization or 
prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of 
the ability to conduct normal life functions, or a congenital anomaly/birth defect. Important medical 
events that may not result in death, be life-threatening, or require hospitalization may be considered 
serious when, based upon appropriate medical judgment, they may jeopardize the participant and may 
require medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse. 
 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 


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8.3.3.1 SEVERITY OF EVENT 
For AEs not included in the protocol defined grading system, the following guidelines will be used to 
describe severity.  
 
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities.  
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating.  Of note, the term “severe” does not necessarily equate to “serious”. 
 
8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION 
All AEs must have their relationship to study intervention assessed by the clinician who examines and 
evaluates the participant based on temporal relationship and his/her clinical judgment. The degree of 
certainty about causality will be graded using the categories below. In a clinical trial, the study product 
must always be suspect.  
 
• 
Related – The AE is known to occur with the study intervention, there is a reasonable possibility 
that the study intervention caused the AE, or there is a temporal relationship between the study 
intervention and event. Reasonable possibility means that there is evidence to suggest a causal 
relationship between the study intervention and the AE. 
• 
Not Related – There is not a reasonable possibility that the administration of the study 
intervention caused the event, there is no temporal relationship between the study intervention 
and event onset, or an alternate etiology has been established. 
 
8.3.3.3 EXPECTEDNESS  
The PI will be responsible for determining whether an AE was 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. 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
The occurrence of an AE or SAE may come to the attention of study personnel during study visits and 
interviews of a study participant presenting for medical care. 
 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate case report form (CRF). Information to be collected includes event description, time of 
onset, clinician’s assessment of severity, relationship to study product (assessed only by those with the 
training and authority to make a diagnosis), and time of resolution/stabilization of the event. All AEs 
occurring while on study must be documented appropriately regardless of relationship. All AEs will be 
followed to adequate resolution. 
 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any 
time during the study, it will be recorded as an AE.  
 


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Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
 
The PI will record all reportable events with start dates occurring any time after informed consent is 
obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study participation. At 
each study visit, the investigator will inquire about the occurrence of AE/SAEs since the last visit.  Events 
will be followed for outcome information until resolution or stabilization. 
 
8.3.5 ADVERSE EVENT REPORTING  
The study clinician will immediately report to the IRB any adverse event, whether or not considered 
study intervention related, including those listed in the protocol or investigator brochure and must 
include an assessment of whether there is a reasonable possibility that the study intervention caused 
the event. Disease related events (DRE), such as behavioral disruptions (e.g., tantrums) will not be 
reported as AE, unless their severity or frequency far surpasses their prior levels.   
 
All AEs will be followed until satisfactory resolution or until the site investigator deems the event to be 
chronic or the participant is stable.  
 
The investigator will be responsible for notifying the FDA of any unexpected or suspected severe 
adverse reaction as soon as possible, but in no case later than 7 calendar days after the investigator’s 
initial receipt of the information.  In addition, the investigator must notify FDA and all participating 
investigators in an Investigational New Drug (IND) safety report of potential serious risks, from clinical 
trials or any other source, as soon as possible, but in no case later than 15 calendar days after the 
investigator determines that the information qualifies for reporting. 
 
8.3.6 SERIOUS ADVERSE EVENT REPORTING  
The study clinician will immediately report to the IRB any serious adverse event, whether or not 
considered study intervention related, including those listed in the protocol and must include an 
assessment of whether there is a reasonable possibility that the study intervention caused the event.  
 
All SAEs will be followed until satisfactory resolution or until the site investigator deems the event to be 
chronic or the participant is stable.  
 
The investigator will be responsible for notifying the FDA of any unexpected fatal or life-threatening 
suspected adverse reaction as soon as possible, but in no case later than 7 calendar days after the 
investigator’s initial receipt of the information.  In addition, the investigator must notify FDA and all 
participating investigators in an IND safety report of potential serious risks, from clinical trials or any 
other source, as soon as possible, but in no case later than 15 calendar days after the investigator 
determines that the information qualifies for reporting. 
 
8.3.7 REPORTING EVENTS TO PARTICIPANTS  
Parents/guardians will be informed about AEs and SAEs, and study-related results on an individual level. 
Similarly, parents/guardians will be informed of incidental findings that may emerge from study 
procedures. A summary of study participation will be provided at the conclusion of each participant’s 
treatment, including any incidental findings of clinical relevance. Parents/guardians will be given the 
opportunity to discuss any such results directly with the investigational team.    


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8.3.8 EVENTS OF SPECIAL INTEREST  
Not applicable.  
 
8.3.9 REPORTING OF PREGNANCY  
Because risks of CBD use in pregnancy are unknown, all participants are required to use abstinence or 
use a valid method of contraception to participate in the study. Menstruating females will undergo urine 
pregnancy tests at the screening visit to ensure participant safety. If a participant becomes pregnant 
during the study, she will immediately be discontinued from the medication. Participants who become 
pregnant during the study, or within 30 days after completing the study, will be followed throughout the 
course of the pregnancy for safety, with the participant’s permission and that of her parent/guardian. 
Information about the risks of the pregnancy and the possible effects on the fetus will be provided to 
support an informed decision in cooperation with the treating physician and the obstetrician. Any 
spontaneous abortion will be classified as a serious adverse event. Pregnancy of a participant will be 
reported to study leadership and the IRB. 
 
8.4 
UNANTICIPATED PROBLEMS 
 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
The Office for Human Research Protections (OHRP) considers unanticipated problems (UP) involving 
risks to participants or others to include, in general, any incident, experience, or outcome that meets all 
of the following criteria: 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the IRB-approved research protocol and 
informed consent document; and (b) the characteristics of the participant population being 
studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
 
 
8.4.2  UNANTICIPATED PROBLEM REPORTING  
The investigator will report UPs to the reviewing IRB. 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. 
 
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• 
UPs that are SAEs will be reported to the IRB within 7 calendar days of the investigator 
becoming aware of the event.  
• 
Any other UP will be reported to the IRB within 14 days of the investigator becoming aware of 
the problem.  
• 
All UPs should be reported to appropriate institutional officials (as required by an institution’s 
written reporting procedures), the supporting agency head (or designee), and the OHRP within 
30 days of the IRB’s receipt of the report of the problem from the investigator. 
 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
Parents/guardians will be informed any UPs on an individual level. Parents/guardians will be given the 
opportunity to discuss any concerns regarding UPs directly with the investigational team.    
 
9 
STATISTICAL CONSIDERATIONS  
 
9.1 
STATISTICAL HYPOTHESES 
The hypothesis of this phase 2 open trial is that moderate doses of CBD may be therapeutically 
beneficial for core and/or associated symptoms in children and adolescents with ASD. 
 
9.2 
SAMPLE SIZE DETERMINATION 
No statistical methods were used to determine the sample size for this study. The total number of 
participants expected to participate at NYU Child Study Center and Comprehensive Epilepsy Center is 30. 
 
9.3 
POPULATIONS FOR ANALYSES 
Participants included within the analysis datasets include all participants in the trial, including both 
responders and non-responders, to examine efficacy at varying doses as well as safety and tolerability 
across the whole sample.  
 
9.4 
STATISTICAL ANALYSES 
 
9.4.1 GENERAL APPROACH 
The primary aim of this study is to determine the optimal dose of CBD in children and adolescents with 
ASD. Therefore, to increase sensitivity in capturing a nonlinear dose response, we will employ the BOIN 
design as discussed above. After the trial is completed, we will select the optimal dose based on isotonic 
regression as specified in Liu and Yuan (66).  
 
9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
We will select as the optimal dose the dose for which the isotonic estimate of the response rate is 
closest to the target response rate. If there are ties, we will select the higher dose level when the 
isotonic estimate is lower than the target response rate and we will select the lower dose level when the 
isotonic estimate is greater than or equal to the target response rate. 
 
As mentioned, response rate will be determined by the proportion of participants classified as 
responders. A treatment response is defined as a CGI-I score of 1 or 2 on the individualized, 
predetermined primary outcome variable, whereas a nonresponse is a CGI-I score of 3 or greater. Scores 
on the CGI-I will be determined by clinician consensus.  


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Table 5 shows the operating characteristics of a 5-dose BOIN design based on 1000 simulations. The 
operating characteristics show that the design selects the true optimal dose, if any, with high probability 
and allocates more participants to the dose levels with the response rate closest to the target of 0.6. 
Please refer to Tables 3 and 4 for the design and statistical expectations relevant to Part 2 of the study. 
 
Table 5. Operating characteristics of the BOIN design: Part 1 
 
Dose 1 
Dose 2 
Dose 3 
Dose 4 
Dose 5 
# of Participants 
% Early Stopping 
True Response 
Rate 
0.4 
0.5 
0.6 
0.55 
0.45 
 
 
Selection % 
17.1 
9.3 
21.8 
22.0 
1.7 
 
28.1 
# Participants 
treated  
5.84 
4.39 
10.55 
5.36 
0.86 
27 
 
 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
Our secondary objective is to quantify the effect size of changes in a wide range of candidate measures 
that may reveal response to CBD. Effect sizes and 95% confidence intervals will be reported for all 
measures obtained at enrollment/baseline and at the final visit (or last observation, in cases of early 
termination).  
 
9.4.4 SAFETY ANALYSES 
Safety endpoints will be analyzed as summary statistics during treatment and as change scores from 
baselines. Adverse events will be coded per the Medical Dictionary for Regulatory Activities (MedDRA). 
Each AE will be counted once only for a given participant. Adverse events will be presented in terms of 
severity, frequency, and relationship of AEs to study intervention by System Organ Class (SOC) and 
preferred term groupings. For each AE, start date, stop date, severity, relationship, expectedness, 
outcome, and duration will be reported. Adverse events leading to premature discontinuation from the 
study intervention and serious treatment-emergent AEs will be presented either in a table. The 
information included here should be consistent with the information contained within Section 8.2, 
Safety and Other Assessments. 
 
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
The demographic characteristics and the baseline measurements of all participants will be summarized 
using standard descriptive statistics (e.g., means, medians, standard deviations, and ranges for 
continuous variables and frequencies for categorical variables).  
 
9.4.6 PLANNED INTERIM ANALYSES  
After each cohort completes participation in the 6-week treatment period, classification of participants 
as “responders” or “non-responders” will occur based upon the definitions provided above. The 
subsequent cohort will be administered the dose level indicated given the response of the previous 
cohorts.  
 
9.4.7 SUB-GROUP ANALYSES 
Not applicable.  
 
9.4.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
Individual participant data will be listed by measure and time point. 


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9.4.9 EXPLORATORY ANALYSES 
The objective of obtaining MRI data is to determine the feasibility of obtaining possible biomarkers of 
treatment response in children and adolescents with ASD and to conduct preliminary analyses, if 
sufficient data are collected. For all participants who agree to undergo MRI before and after treatment 
with Epidiolex, resting-state functional connectivity analyses will be conducted. 
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
10.1.1 INFORMED CONSENT PROCESS 
 
10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
Consent forms describing in detail the study intervention, study procedures, and risks are given to the 
parents/guardians of participants and written documentation of informed consent is required prior to 
starting intervention/administering study intervention. The consent and assent materials are submitted 
with this protocol. 
 
10.1.1.2 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 will be IRB-approved 
and the participant’s parent/guardian will be asked to read and review the document. The research staff 
will explain the research study to the participant’s parent/guardian and answer any questions that may 
arise. A verbal explanation will be provided in terms suited to the participant’s parent/guardian 
comprehension of the purposes, procedures, and potential risks of the study and of their rights as 
research participants. Participants and their parent/guardian will have the opportunity to carefully 
review the written consent form and ask questions prior to signing. The participants and their 
parent/guardian should have the opportunity to discuss the study with their family or surrogates or 
think about it prior to agreeing to participate. The participant’s parent/guardian will sign the informed 
consent document prior to any procedures being done specifically for the study. Participants and their 
parent/guardian must be informed that participation is voluntary and that they may withdraw from the 
study at any time, without prejudice. A copy of the informed consent document will be given to the 
participant’s parent/guardian for their records. The informed consent process will be conducted and 
documented in the source document (including the date), and the form signed, before the participant 
undergoes any study-specific procedures. The rights and welfare of the participants will be protected by 
emphasizing to them that the quality of their medical care will not be adversely affected if they decline 
to participate in this study. 
 
Importantly, while the COVID-19 pandemic still presents a risk to participants and staff, we will reduce 
the number of required in-person visits and instead conducting those visits virtually over WebEx. All 
procedures in the screening visit, with the exception of the blood draw, will be conducted virtually and 
will continue to be conducted virtually based on individual family preferences. Therefore, our written 
consent/assent processes will be conducted via WebEx, albeit in the same way it would be done in 
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encouraged to review it. At the beginning of the virtual screening visit, while sharing the consent form 
on the screen, the research staff member will explain the research study to the participant’s 
parent/guardian and answer any questions that may arise. A verbal explanation will be provided in 
terms suited to the participant’s parent/guardian’s comprehension of the purposes, procedures, and 
potential risks of the study and of their rights as research participants. A research staff member will also 
meet with the child participant on WebEx to review the age-appropriate assent form in the same way. 
Participants and their parent/guardian will have the opportunity to carefully review the assent and 
consent forms and ask questions prior to signing electronically. To adjust the consenting process for 
virtual administration, we will present the consent and assent forms and collect signatures through 
REDCap survey. Parents will be provided REDCap links to the consent and assent forms so they can 
follow along while the research team reviews study procedures and can then provide signatures 
indicating consent/assent. A copy of the signed consent form on REDCap will be provided electronically 
to the participant’s parent/guardian for their records.   
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause. Written notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to study participants, investigators, and regulatory 
authorities. If the study is prematurely terminated or suspended, the PI will promptly inform study 
participants, the IRB and will provide the reason(s) for the termination or suspension. Study participants 
will be contacted, as applicable, and be informed of changes to study visit schedule. 
  
Circumstances that may warrant termination or suspension of the study include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination that the primary endpoint has been met 
• 
Determination of futility 
 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, 
and satisfy the IRB and/or FDA. 
 
10.1.3 CONFIDENTIALITY AND PRIVACY  
Participant confidentiality and privacy is strictly held in trust by the participating investigators and their 
staff. This confidentiality is extended to cover testing of biological samples and genetic tests (if any) in 
addition to the clinical information relating to participants. Therefore, the study protocol, 
documentation, data, and all other information generated will be held in strict confidence. No 
information concerning the study or the data will be released to any unauthorized third party without 
prior written approval of the IRB.  
 
All research activities will be conducted in as private a setting as possible. 
 
Representatives of the IRB, regulatory agencies or pharmaceutical company supplying study product 
may inspect all documents and records required to be maintained by the investigator, including but not 
limited to, medical records (office, clinic, or hospital) and pharmacy records for the participants in this 
study. The clinical study site will permit access to such records. 
 


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The study participant’s contact information will be securely stored at each clinical site for internal use 
during the study. 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 or Institutional policies. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be transmitted to and stored at the NYU Child Study Center. This will not include the participant’s 
contact or identifying information. Rather, individual participants and their research data will be 
identified by a unique study identification number. The study data entry and study management 
systems used by clinical sites and by NYU Child Study Center research staff will be secured and password 
protected. At the end of the study, all study databases will be de-identified and archived at the NYU 
Child Study Center. 
 
Audio/visual recordings of the BOSCC took place prior to discontinuing its administration due to the 
COVID-19 pandemic, as they are required to be able to score the behaviors during the interview to 
assess quantitatively whether social communication ability has changes. These recordings were labeled 
only with the participant’s study identification number and will be kept in the Investigator's files. The 
video may show the participant’s face, and if his/her name is spoken during the session, it will be 
recorded as part of the video. Parents were made aware of this, and consent was attained specifically 
for audio/visual recording. It was our intention to pursue expert analysis of these recording, if and when 
available, from the developer, Dr. Catherine Lord, world-renown researcher and expert in autism 
evaluation, and her team at UCLA. This coding service as well as the coding scheme for the BOSCC are 
currently being established. We expect that they will become available within the next year or so while 
this study is still active. Because coding of videos is not absolutely necessary until the end of this trial, 
we are fairly confident that UCLA will have finalized this service in time to pursue expert analysis of our 
complete dataset. For context, seeking these services from Dr. Lord’s team is essential; the BOSCC is a 
novel measure and evaluating change in the subtle symptoms of high-functioning autism is complex. 
Observational measurement of change will likely be unmanageable without their support. Further, using 
outside coders will allow for blinding of observers who will not be informed about whether the video 
they are coding is the first administration from the enrollment/baseline visit or the second 
administration from the final visit. This blinding would not be possible if coding was completed 
internally. Importantly, Dr. Lord and her team would not have access to these recordings until proper 
IRB-approved protocols and contracts are in place at both institutions, and the investigators on the 
current study will provide all documentation necessary to the NYULH IRB prior to initiating the 
consultative relationship with UCLA. Once the coding service has been approved and ready to be 
implemented, we will submit a Modification to include these intentions in the audio/visual recording 
consent form and informed consent form, to enable participants to consent to the recordings knowing 
of our intention to obtain authorized expert assistance to analyze the videos at a later date. Following 
the onset of the COVID-19 pandemic, we discontinued administration of the BOSCC. We will not 
administer the BOSCC for the remainder of the trial, as the requirement for participants and staff to 
have effective face masks during COVID makes it impractical to perform the BOSCC. 
 
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
Data collected for this study will be analyzed and stored at the NYU Child Study Center, Department of 
Child and Adolescent Psychiatry, Hassenfeld Children’s Hospital at NYU Langone. Sample storage is not 
currently planned.  
 


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10.1.5 KEY ROLES AND STUDY GOVERNANCE 
Provide the name and contact information of the Principal Investigator and the Medical Monitor. 
Principal Investigator 
Medical Monitor 
F. Xavier Castellanos, MD  
Melissa Nishawala, MD 
Child Study Center, Department of Child and 
Adolescent Psychiatry, Hassenfeld Children’s 
Hospital at NYU Langone 
Child Study Center, Department of Child and 
Adolescent Psychiatry, Hassenfeld Children’s 
Hospital at NYU Langone 
One Park Avenue, 7th Floor, New York, NY 10016 
One Park Avenue, 7th Floor, New York, NY 10016 
646-754-5194 
646-754-4880 
francisco.castellanos@nyulangone.org    
melissa.nishawala@nyulangone.org 
 
 
Co-Principal Investigator 
Orrin Devinsky, MD  
Comprehensive Epilepsy Center 
NYU Langone Health 
223 East 34th Street, New York, NY 10016 
646-558-0803 
orrin.devinsky@nyulangone.org    
 
 
10.1.6 SAFETY OVERSIGHT 
Safety oversight will be under the direction of a Clinical Monitoring Committee (CMC), chaired by Glenn 
Hirsch, MD, and composed of the PI, F. X. Castellanos, MD, Co-PI Orrin Devinsky, MD, and co-I Daniel 
Friedman, MD. All are free of conflict of interest. The CMC will assess safety and efficacy data every third 
participant. Data reviewed will include all adverse event forms as well as primary and secondary 
outcome measures for each participant in the cohort.  
 
 
10.1.7 CLINICAL MONITORING 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct of 
the trial is in compliance with the currently approved protocol/amendment(s), with ICH GCP, and with 
applicable regulatory requirements.  
 
• 
The PI will conduct the monitoring, on-site, frequency early, for initial assessment and training 
as well as throughout the study, every three participants. Monitoring will be comprehensive 
(100% data verification). Monitoring reports will be maintained in the study binder.  
• 
Reports of the Clinical Monitoring Committee will be sent to the IRB at least annually at the 
time of continuing review. 
• 
Independent audits will not be conducted as this is an open trial.  
 
 
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 


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Quality control (QC) procedures will be implemented beginning with the data entry system and data QC 
checks that will be run on the database will be generated. Any missing data or data anomalies will be 
communicated to the PI for clarification/resolution. 
 
10.1.9 DATA HANDLING AND RECORD KEEPING  
 
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site 
investigator. The investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. 
 
All source documents should be completed in a neat, legible manner to ensure accurate interpretation 
of data.   
 
Hardcopies of the study visit worksheets will be provided for use as source document worksheets for 
recording data 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.  
 
We will use a 21 CFR Part 11-compliant web application, Research Electronic Data Capture (REDCap) for 
data collection and management. REDCap is already implemented for several research studies across 
NYU Langone and can be programmed to meet the needs of this protocol.  
10.1.9.2 STUDY RECORDS RETENTION  
Study documents will be retained for a minimum of 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing applications in an 
ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical development 
of the study intervention. These documents will be retained for a longer period, however, if required by 
local regulations.  
 
10.1.10 
PROTOCOL DEVIATIONS  
A protocol deviation is any noncompliance with the clinical trial protocol, 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.  
 
Protocol deviations will be sent to the reviewing IRB per its policy.  
 
Of note, protocol deviations resulting from mitigation strategies applied during the COVID-19 
pandemic will be reported at time of next continuing review. 
 
10.1.11 
PUBLICATION AND DATA SHARING POLICY 


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This study will be conducted in accordance with the following publication and data sharing policies and 
regulations: 
 
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 from other researchers 6 years after the 
completion of the primary endpoint by contacting Francisco Xavier Castellanos.  
 
 
10.1.12 
CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical.  Therefore, any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a 
way that is appropriate to their participation in the design and conduct of this trial. The study leadership 
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 ADDITIONAL CONSIDERATIONS 
Not applicable. 
 


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10.3 ABBREVIATIONS 
 
ABC 
Aberrant Behavior Checklist 
ADAMS 
Anxiety, Depression and Mood Scale 
ADOS-2 
Autism Diagnostic Observation Schedule, Second Edition 
AFEQ 
Autism Family Experience Questionnaire  
ASC-ASD-C 
Anxiety Scale for Children – Autism Spectrum Disorder-Child Version 
ASD-ASD-P 
Anxiety Scale for Children – Autism Spectrum Disorder-Parent Version 
ASI 
Autism Symptom Interview 
AE 
Adverse Event 
ASD 
Autism Spectrum Disorder 
BIS 
Behavioral Inflexibility Scale 
BNE 
Bureau of Narcotic Enforcement 
BOIN 
Bayesian optimal interval 
BOSCC 
Brief Observation of Social Communication – Change 
CARS-2-HF 
Childhood Autism Rating Scale, 2nd Edition, High Functioning Version 
CBD 
Cannabidiol 
CDC 
Centers for Disease Control and Prevention 
CFR 
Code of Federal Regulations 
CGI-I 
Clinical Global Impression Scale – Improvement 
CGI-S 
Clinical Global Impression Scale-Severity 
Co-I 
Co-Investigator 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
CRM 
Continual Reassessment Method 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DRE 
Disease-Related Event 
EI 
Excitatory/Inhibitory 
EC 
Eyes Closed 
eCRF 
Electronic Case Report Forms 
ECS 
Endocannabinoid System 
EEG 
Electroencephalogram 
EO 
Eyes Open 
EU 
European Union  
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HFA 
High-Functioning Autism 
HSQ-ASD 
Home Situations Questionnaire – Modified for ASD 
ICH 
International Conference on Harmonisation  
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
K-SADS-COMP 
Computerized Kiddie Schedule for Affective Disorders and Schizophrenia  
MDD 
Major Depressive Disorder 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
MOP 
Manual of Procedures 
NCT 
National Clinical Trial 
NIH  
National Institutes of Health 
OHRP 
Office for Human Research Protections 


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OSU Autism 
CGI 
Ohio State University Autism Clinical Global Impressions 
PI 
Principal Investigator 
PTSD 
Post-Traumatic Stress Disorder 
QC 
Quality Control 
RCT 
Randomized Controlled Trial 
RBS-R 
Repetitive Behavior Scale-Revised 
REDCap 
Research Electronic Data Capture 
RRB 
Restricted and Repetitive Behaviors 
SAE 
Serious Adverse Event 
SCARED 
Screen for Child Anxiety Related Disorders 
SDSC 
Sleep Disturbance Scale for Children  
SOA 
Schedule of Activities 
SOC 
System Organ Class 
SRS-2 
Social Responsiveness Scale, Second Edition 
SWAN 
Strengths and Weaknesses of Attention-Deficit/Hyperactivity Disorder Symptoms and Normal 
Behavior 
THC 
Tetrahydrocannabinol 
UP 
Unanticipated Problem 
US 
United States 
Vineland-3 
Vineland Adaptive Behavior Scales, Third Edition 
WASI-II 
Wechsler Abbreviated Scale of Intelligence, Second Edition 
 
 
 
 


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10.4 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 Summary of Changes table for the current amendment is 
located in the Protocol Title Page.  
 
Version 
Date 
Description of Change  
Brief Rationale 
18-
00250_MOD02 
04/03/2019 
ABI was removed; SRS-2 cutoff was 
changed from a t-score of 65 to 66. 
Typos in the ICF/Assent corrected. 
Two staff added to study. 
The ABI covers the same 
constructs as another study 
measure (SRS-2). The SRS-2 
cutoff better aligns with the 
clinical impairment ranges. 
18-
00250_MOD03 
04/10/2019 
A co-investigator was added to the 
protocol (Judith Bluvstein, MD).  
N/A 
18-
00250_MOD04 
06/04/2019 
Added HSQ-ASD; changed details 
regarding urine drug test; added 
clause about discontinuing 
exclusionary medications to 
participate; provided more explicit 
definition of “prior chronic 
treatment of CBD or other 
cannabinoid”  
HSQ-ASD is commonly used in 
RCTs; new drug test 
procedures more in line with 
age group studied; clause 
added to improve safety 
monitoring; more objectivity in 
the definition of CBD use was 
required. 
18-
00250_MOD05 
07/05/2019 
Added $10 stipend to cover travel 
costs for visits with blood draw; 
mechanism for determining 
eligibility with brief updating 
session in cases when the screening 
visit occurs >8 weeks before 
initiation of treatment; rate of 
recruitment changed 
Participants have to travel 
several blocks from the clinic 
to the hospital; given the 
adaptive design, it is possible 
patients are screened more 
than 8 weeks prior to their 
enrollment/baseline visit; 
recruitment rate previously 
indicated did not correspond 
with study design 
18-
00250_MOD06 
12/19/2019 
Instruments were added (ASC-ASD-
Parent and Child Versions; OSU 
Autism Clinical Global Impressions: 
Severity and Improvement 
Subscales), and one will replace a 
previous measure (AFEQ to replace 
PedsQL). We are to use the Reliable 
Change Index to measure change in 
scores on measures pre- and post-
treatment. We made the supports 
used to increase compliance with 
EEG procedures less specific. 
Measures will more 
comprehensively capture 
constructs of interest. Reliable 
change index measures clinical 
significance. Changes to EEG 
supports will allow for more 
flexibility to individualize our 
strategies. 
18-
00250_MOD07 
01/17/2020 
An additional parent-report 
measure was added (Behavioral 
Inflexibility Scale). In the EEG 
procedure, we will ask subjects to 
The measure was added to 
more comprehensively assess 
constructs of interest. One-
minute recordings reported in 


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undergo a consecutive series of six 
two-minute, rather than one-
minute recording periods. We will 
no longer change the instructions 
of the questionnaires to fit the time 
frame. The blood chemistry CRF 
was edited. 
the original protocol 
represents an error; two-
minute recordings is accurate. 
The blood chemistry CRF was 
edited to improve 
relevance/utility to the study.  
18-
00250_MOD08 
01/23/2020 
A research associate was added to 
the protocol. 
--- 
18-
00250_MOD09 
02/23/2020 
ASI was added. Two telephone 
follow-ups were added 2- and 4- 
weeks after participants complete 
the intervention phase. At 6 weeks, 
caregivers will be given the option 
to complete informant-report 
measures. 
The ASI will provide greater 
standardization in the way 
clinicians inquire about current 
and past ASD symptoms. The 
follow-ups at 2, 4, and 6-weeks 
post intervention will provide 
information about any 
discontinuation effects. 
18-
00250_MOD11 
03/27/2020 
A financial disclosure section was 
added to the informed consent 
form. 
Edits were made in line with 
instructions provided by CIMU. 
18-
00250_MOD12 
06/23/2020 
The consenting/assenting process 
will be completed online over 
WebEx. 
Limit participant and staff 
potential exposure to COVID-
19.  
18-
0050_MOD13 
8/28/2020 
Added inquiry about allergies to 
pre-screen; removed CCC-2; 
Vineland-3 only to be given at 
baseline 
Save time if child had allergies 
prohibited participation in 
trial. Measure changes to 
reduce burden on parents. 
 
 
 
 
 
 
 
 
 
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