Clinical trial NCT04745026
Conditions: Autism Spectrum Disorder
Keywords: Cannabidiol oral solution CBD-OS GWP42003-P Children Adolescents
Sponsor: Jazz Pharmaceuticals
Start date: 2021-05-31; Completion date: 2023-12-21
Enrollment: 103 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will be conducted to evaluate the efficacy of GWP42003-P, compared with placebo, in reducing symptom severity in children with Autism Spectrum Disorder (ASD).

Detailed description:

Arms: arm 1: Participants will be stratified based on their age (6 to 11 years old, 12 to 17 years old), use of antipsychotics (on versus off), and region (North America versus Rest of the World) and will be randomized to receive 5 milligrams per kilogram per day (mg/kg/day) GWP42003-P for 1 week and then 10 mg/kg/day GWP42003-P for 11 weeks. arm 2: Participants will be stratified based on their age (6 to 11 years old, 12 to 17 years old), use of antipsychotics (on versus off), and region (North America versus Rest of the World) and will be randomized to receive matching placebo for 12 weeks.
Interventions: intervention 1: GWP42003-P intervention 2: Placebo
Intervention descriptions: intervention 1: GWP42003-P oral solution (100 milligrams per milliliter \[mg/mL\] cannabidiol \[CBD\] in sesame oil with anhydrous ethanol, ethanol \[10% v/v\] sweetener \[sucralose\], and strawberry flavoring), administered twice a day (morning and evening) intervention 2: Oral placebo to match GWP42003-P oral solution containing sesame oil with anhydrous ethanol, sweetener (sucralose), strawberry flavoring, and beta carotene, administered twice a day (morning and evening)

Protocol documents:
Prot_000.pdf: 
Study Code: GWND19189
IND Number: 150775
Protocol Version 2.0, 24 Nov 2020
Confidential
Page 1 of 88
Clinical Protocol Template (Phase 2–4)
V1, 24Sep15
AN EXPLORATORY, PHASE 2, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED TRIAL TO INVESTIGATE THE SAFETY AND EFFICACY OF 
CANNABIDIOL ORAL SOLUTION (GWP42003P; CBD-OS) IN CHILDREN AND 
ADOLESCENTS WITH AUTISM SPECTRUM DISORDER
Study Code: GWND19189
IND Number:
EudraCT Number: 2020-002819-21
CLINICAL PROTOCOL
GW Research Ltd
Sovereign House
Vision Park
Chivers Way
Histon
Cambridge CB24 9BZ
United Kingdom
Tel: +44 (0) 1223 266 800
Fax: +44 (0) 1223 235 667
Confidentiality Statement
This document contains confidential information of GW Research Ltd (GW) that must not be 
disclosed to anyone other than the recipient study staff and members of the institutional review 
board or independent ethics committee.  This information cannot be used for any purpose other 
than the evaluation or conduct of the clinical investigation without the prior written consent of 
GW.


Study Code: GWND19189
IND Number: 150775
Protocol Version 2.0, 24 Nov 2020
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Clinical Protocol Template (Phase 2–4)
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Investigator Agreement
I have read the attached clinical protocol entitled “An exploratory, Phase 2, randomized, 
double-blind, placebo-controlled trial to investigate the safety and efficacy of cannabidiol oral 
solution (GWP42003-P; CBD-OS) in children and adolescents with Autism Spectrum Disorder”,
dated 24 November 2020 and agree to abide by all provisions set forth therein.
I agree to comply with applicable regulatory requirement(s); the US FDA regulations relating to 
GCP and clinical trials, the EU Clinical Trials Directive (2001/20/EC), the EU GCP Directive
(2005/28/EC) and subsequent applicable regulatory/statutory instruments, or the International 
Council for Harmonisation Tripartite Guidelines for GCP where the EU Clinical Trials and GCP 
Directives do not apply, and to complete Form FDA 1572, if required. I accept responsibility for 
the overall medical care of patients during the trial and for all trial-related medical decisions.
I am not aware that any conflicts of interest, financial or otherwise, exist for myself, my spouse 
[or legal partner] and dependent children and agree to confirm this in writing if required and 
update as necessary.
I agree to ensure that the confidential information contained in this document will not be used for 
any purpose other than the evaluation or conduct of the clinical investigation without the prior 
written consent of GW.
Center No:
Print name:
Date:
Principal investigator
(DD Month YYYY)
Signature:
GW Authorization
Print name:
Date:
Medical Director
(DD Month YYYY)
Signature:


Study Code: GWND19189
IND Number: 150775
Protocol Version 2.0, 24 Nov 2020
Confidential
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Clinical Protocol Template (Phase 2–4)
V1, 24Sep15
1
PROTOCOL SYNOPSIS
Trial Title
An exploratory, Phase 2, randomized, double-blind, placebo-controlled trial 
to investigate the safety and efficacy of cannabidiol oral solution 
(GWP42003-P; CBD-OS) in children and adolescents with Autism 
Spectrum Disorder
Clinical Trial 
Type
Phase 2
Indication
Autism Spectrum Disorder
Objectives and 
Endpoints for 
Part B
Efficacy Objective
Efficacy Endpoints
x
To evaluate the efficacy of 
GWP42003-P, compared with 
placebo, in reducing symptom 
severity in children with ASD.
Behavior
x ABC Subscales
Social Communication
x
VABS-3
Overall Condition
x
CGI-I
x
CGI-S
Safety Objective
Safety Endpoints
x
To evaluate the safety of 
GWP42003-P, compared with 
placebo, in children with ASD.
x
AEs.
x
Clinical laboratory 
parameters.
x
Vital signs.
x
Physical examination 
procedures.
x
12-lead ECG.
x
C-SSRS.
 
 
 
 
 
 
 
 
 
 


Study Code: GWND19189
IND Number: 150775
Protocol Version 2.0, 24 Nov 2020
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Clinical Protocol Template (Phase 2–4)
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Trial Design
This is an exploratory, Phase 2, double-blind, randomized, 
placebo-controlled, multisite trial, which will compare the safety and 
efficacy of a 10 mg/kg/day dose of GWP42003-P versus placebo in children 
and adolescents with ASD. 
Patients will be screened and if they meet eligibility criteria, they will be 
randomized to receive GWP42003-P or matching placebo in a 1:1 ratio. 
Patients will be stratified based on their age (6 to 11, 12 to 17), use of 
antipsychotics (on versus off), and region (North America versus Rest of the 
World). Patients will be administered 5 mg/kg/day GWP42003-P or 
matching volumes of placebo for 1 week and then 10 mg/kg/day 
GWP42003-P or matching volumes of placebo for 11 weeks. At the end of 
treatment, patients will taper the medication over 1 week. 
In order to facilitate trial execution in the context of infectious diseases or 
other transmissible conditions (e.g., COVID-19), the trial will involve a 
combination of clinic, remote (including a video call and a home nurse visit) 
and telephone visits, as specified in APPENDIX 1.
Sample Size
160 patients randomized to allow for 144 evaluable patients 
(72 evaluable patients per arm) at trial end. 
Summary of 
Patient Eligibility 
Criteria
Inclusion Criteria
For inclusion in the trial, patients must fulfill ALL of the following criteria:
x
Male or female aged 6 to 17 years (inclusive). 
x
Patient weight is at least 12 kg. 
x
Patients (if possessing adequate understanding, in the investigator’s 
opinion) and their parent(s)/legal representative are willing and able to 
give informed assent and consent for participation in the trial.
x
Patient and their caregiver are willing and able (in the investigator’s 
opinion) to comply with all trial requirements. 
x
Patient has a diagnosis of ASD as per DSM-5 criteria for ASD, 
confirmed by ADOS-2 criteria (conducted within 2 years at the trial 
site or at screening by a qualified assessor). Note: During special 
circumstances (e.g., COVID-19 pandemic) where the ADOS-2 cannot 
be performed due to site restrictions (e.g., mandatory use of face 
masks) and an ADOS-2 conducted within 2 years at the trial site by a 
qualified assessor is not available, eligibility can be confirmed using: 
1) an ADOS-2 performed within 2 years by a qualified assessor 


Study Code: GWND19189
IND Number: 150775
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Clinical Protocol Template (Phase 2–4)
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(external to the site); 2) if 1) is not available, eligibility may be 
confirmed using the ADI-R at screening.
x
CGI-S  4 (moderately ill) at screening and randomization.
x
ABC-I VXEVFDOHVFRUHDWVFUHHQLQJ.
x
,4 at screening, or measured within 1 year of screening, using 
WASI-II.
x
All medications or interventions (including psychosocial interventions, 
dietary supplements, probiotics, speech therapy, etc.) for ASD related 
symptoms must have been stable for 4 weeks prior to screening and 
randomization, and the patient/caregiver should be willing to maintain 
a stable regimen throughout the trial.
x
Patients must have the ability to swallow the IMP, provided as a liquid 
solution.
x
Patient and/or parent(s)/legal representative is willing to allow the 
responsible authorities to be notified of participation in the trial, if 
mandated by local law.
x
Patient and/or parent(s)/legal representative is/are willing to allow the 
patient’s primary care practitioner (if they have one) and consultant (if 
they have one) to be notified of participation in the trial if the primary 
care practitioner/consultant is different from the investigator.
Exclusion Criteria
The patient may not enter the trial if ANY of the following apply:
x
Current diagnosis of bipolar disorder, psychosis, schizophrenia, 
schizoaffective disorder, or major depression (patients with depression 
in remission may be included).
x
Has a diagnosis other than ASD that dominates the clinical 
presentation (e.g., ADHD).
x
Has a progressive neurological condition.
x
Seizures in the past 24 weeks.
x
Changes in anticonvulsive therapy within the last 12 weeks.
x
Currently taking more than 2 AEDs.
x
Taking sirolimus, everolimus, temsirolimus, or tacrolimus.
x
Taking clobazam.
x
Taking omeprazole, lansoprazole, tolbutamide, or warfarin.
x
Taking repaglinide, pioglitazone, rosiglitazone, montelukast, 
bupropion, or efavirenz.
x
Currently using or has used recreational or medicinal cannabis, 
cannabinoid-based medications (including Sativex®, or 
Epidiolex®/Epidyolex®) within the 12 weeks prior to screening and is 
unwilling to abstain for the duration of the trial.


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IND Number: 150775
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Clinical Protocol Template (Phase 2–4)
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x
Patient has any known or suspected hypersensitivity to cannabinoids or 
any of the excipients of the IMP, such as sesame oil.
x
Patient has moderately impaired hepatic function at screening, defined 
as serum ALT or AST > 2 × ULN or TBL > 2 × ULN’
This criterion can only be confirmed once the laboratory results 
are available; patients enrolled into the trial who are later found 
to meet this criterion must be screen-failed.
x
Patient is male and fertile (i.e., after puberty unless permanently sterile 
by bilateral orchidectomy) unless willing to ensure that they use male 
contraception (condom) or remain sexually abstinent during the trial 
and for 12 weeks thereafter.
x
Patient is female and of childbearing potential (i.e., following 
PHQDUFKHDQGXQWLOEHFRPLQJSRVWPHQRSDXVDOIRU 12 consecutive 
months unless permanently sterile by hysterectomy, bilateral 
salpingectomy, or bilateral oophorectomy) unless willing to ensure that 
they use a highly effective method of birth control (e.g., hormonal 
contraception, intrauterine device/hormone-releasing system, bilateral 
tubal occlusion, vasectomized partner, sexual abstinence) during the 
trial and for 12 weeks thereafter.
x
Female patient who is pregnant (positive pregnancy test), lactating or 
planning pregnancy during the course of the trial or within 12 weeks 
thereafter.
x
Patient has received an IMP within the 12 weeks prior to the screening 
visit.
x
Patient had brain surgery or traumatic brain injury within 1 year of 
screening.
x
Patient has any other significant disease or disorder which, in the 
opinion of the investigator, may either put the patient, other 
participants, or site staff at risk because of participation in the trial, 
may influence the result of the trial, or may affect the patient’s ability 
to take part in the trial.
x
Any abnormalities identified following a physical examination of the 
patient that, in the opinion of the investigator, would jeopardize the 
safety of the patient if they took part in the trial.
x
Any history of suicidal behavior (lifelong) or any suicidal ideation of 
type 4 or 5 on the C-SSRS in the last 4 weeks or at screening or 
randomization.
x
Patient has donated blood during the past 12 weeks and is unwilling to 
abstain from donation of blood during the trial.
x
Patient has any known or suspected history of alcohol or substance 
abuse or positive drugs of abuse test at screening (not justified by a 
known concurrent medication).


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IND Number: 150775
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x
Patient has previously been randomized into this trial.
x
Patient has plans to travel outside their country of residence during the 
trial, unless the patient has confirmation that the IMP is permitted in 
the destination country/state.
Criteria for 
Withdrawal
The patient must be withdrawn from the trial if any of the following apply:
x
Administrative decision by the investigator, GW or regulatory 
authority.
x
Did not meet eligibility criteria.
x
Pregnancy.
x
Protocol deviation that is considered to potentially compromise the 
safety of the patient.
x
Withdrawal of patient consent/assent.
x
Withdrawal of parent(s)/legal representative consent.
x
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, and/or 
eosinophilia (> 5%).
x
ALT or AST > 8 × ULN.
x
ALT or AST > 5 × ULN for more than 2 weeks.
x
ALT or AST > 3 × ULN and (TBL > 2 × ULN or INR > 1.5).
x
Note: Prior to treatment discontinuation for the transaminase 
elevations noted above, the investigator may choose to confirm the 
transaminase elevations by repeating the following laboratory tests, tests 
within 24 to 48 hours: ALT, AST, TBL, INR, % eosinophils, gamma-
glutamyl transferase and alkaline phosphatase. Should the above 
transaminase elevation criteria be confirmed, the patient must be 
withdrawn from the trial. In cases where transaminase elevation 
withdrawal criteria are not met or confirmed, the dose of IMP or a 
concomitant medication with known hepatotoxicity may be reduced 
following discussion with the medical monitor.
x
Lost to follow-up.
The patient may also be withdrawn from the trial for any of the following:
x
Patient noncompliance.
x
AE (including clinically significant laboratory result) which, in the 
opinion of the investigator, would compromise the continued safe 
participation of the patient in the trial.
x
Patient cannot tolerate a dose level of 5 mg/kg/day.
x
Any evidence of use of drugs of abuse or drug diversion.
x
Suicidal ideation or behavior of type 4 or 5 during the treatment 
period, as evaluated with the C-SSRS.


Study Code: GWND19189
IND Number: 150775
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Clinical Protocol Template (Phase 2–4)
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Investigational 
Medicinal 
Product: 
Formulation, 
Mode of 
Administration, 
Dose and 
Regimen
GWP42003-P oral solution (100 mg/mL CBD in sesame oil with anhydrous 
ethanol, ethanol (10% v/v) sweetener [sucralose], and strawberry flavoring). 
Mode of administration: to be taken orally b.i.d. (morning and evening) 
using the syringe(s) provided, preferentially with food i.e., within 30 
minutes after the end of a meal/snack. The time of IMP administration in 
relation to food should be kept consistent throughout the trial. Volume of 
IMP to be determined by patient’s weight. 
Control Group 
Placebo to match GWP42003-P oral solution containing sesame oil with 
anhydrous ethanol, sweetener (sucralose), strawberry flavoring, and beta 
carotene. 
Procedures
Before undergoing any assessments or observations, the patient’s 
parent(s)/legal representative is required to give written informed consent. In 
cases where the patient possesses adequate understanding, their assent will 
be taken, along with parental/legal representative consent. 
Screening (Visit 1) assessments/procedures will include: 
x
Informed consent/assent; eligibility criteria checks; demographics; 
medical history. 
x
Concomitant medications/therapies; AE/SAE review.
x
Test for drugs of abuse. 
x
Full physical examinations; including height, weight, and BMI. 
x
12-lead ECG. 
x
Hematology; biochemistry (including liver chemistries); and 
urinalysis. 
x
Serum pregnancy test (WOCBP only). 
x
C-SSRS. 
x
Vital signs. 
x
WASI-II (if required), ADOS-2 (if required, or ADI-R under special 
circumstances). 
x
ABC, CGI-S. 
Treatment Period (Visits 2 to 8) assessments/procedures will include 
(please refer to APPENDIX 1 for frequency of assessments): 
x
Randomization 
x
Concomitant medications/therapies; AE/SAE review
x
Vital signs 
x
Full physical examinations and weight 
x
12-lead ECG
x
Hematology and biochemistry (including liver chemistries) 
x
C-SSRS


Study Code: GWND19189
IND Number: 150775
Protocol Version 2.0, 24 Nov 2020
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Clinical Protocol Template (Phase 2–4)
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x
 ABC, Vineland-3,
 CGI-S, CGI-I, 
x
IMP dispensing
x
IMP review
Note: Visits 3, 4, 6, and 10 are to be conducted by telephone
End of Taper (Visit 9) assessments/procedures will include:
x
Concomitant medications/therapies; AE/SAE review
x
C-SSRS
x
Vital signs
x
Hematology; biochemistry (including liver chemistries); and urinalysis
x
Serum pregnancy test (WOCBP only)
x
IMP review
Follow-up (Visit 10) assessments/procedures will include:
x
Concomitant medications/therapies; AE/SAE review
Additional procedures to screen for the presence of or immunity against 
infectious diseases (such as body temperature, sampling of nasal mucosal 
cells, or serology) may be conducted at screening, at the beginning of each 
visit, or as needed, according to local guidance and policy.
Statistical 
Considerations
All safety and efficacy data will be summarized and analyzed using 
appropriate statistical methods. Questionnaires will be summarized at each 
visit along with the change from baseline, where appropriate. As this is an 
exploratory trial, there will be no type I error adjustments with all hypothesis 
testing performed at a 5% significance level.
Safety 
Monitoring 
Committee
Not applicable.
Sponsor
GW Research Ltd
Sovereign House
Vision Park
Chivers Way
Histon
Cambridge CB24 9BZ
United Kingdom


Study Code: GWND19189
IND Number: 150775
Protocol Version 2.0, 24 Nov 2020
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Clinical Protocol Template (Phase 2–4)
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Figure 1-1
Trial Design and Treatment Schematic


Study Code: GWND19189
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Clinical Protocol Template (Phase 2–4)
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Table of Contents
Title Page................................................................................................................... 1
1
PROTOCOL SYNOPSIS............................................................................... 3
Table of Contents ...................................................................................................11
List of Appendices..................................................................................................16
List of In-text Tables..............................................................................................16
List of In-text Figures ............................................................................................16
List of Abbreviations .............................................................................................17
Definition of Terms................................................................................................20
2
OBJECTIVES AND ENDPOINTS.............................................................21
3
BACKGROUND AND RATIONALE........................................................22
3.1
Disease.......................................................................................................................... 22
3.2
Cannabidiol Background .............................................................................................. 23
3.3
Rationale ....................................................................................................................... 25
3.3.1
Choice of Efficacy and Exploratory Endpoints ......................................................... 25
3.3.2
Choice of Dosing Regimen ........................................................................................ 27
3.3.3
Benefit-Risk ............................................................................................................... 28
3.4
Clinical Hypothesis ...................................................................................................... 29
4
EXPERIMENTAL PLAN............................................................................30
4.1
Trial Design .................................................................................................................. 30
4.2
Number of Centers ....................................................................................................... 31
4.3
Number of Patients ....................................................................................................... 31
5
INVESTIGATIONAL MEDICINAL PRODUCT ....................................32
5.1
GWP42003-P Oral Solution ......................................................................................... 32
5.2
Placebo ......................................................................................................................... 32
5.3
Packaging, Storage and Drug Accountability .............................................................. 32
5.3.1
Packaging and Labeling ............................................................................................. 32
5.3.2
Storage ....................................................................................................................... 33
5.3.3
Supply and Return of Investigational Medicinal Product .......................................... 34
5.3.4
Investigational Medicinal Product Accountability .................................................... 34


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5.3.5
Post-Trial Provision ................................................................................................... 35
6
PATIENT ELIGIBILITY............................................................................36
6.1
Inclusion Criteria .......................................................................................................... 36
6.2
Exclusion Criteria ......................................................................................................... 36
7
PATIENT ENROLLMENT.........................................................................39
7.1
Treatment Assignment ................................................................................................. 39
8
TREATMENT PROCEDURES..................................................................40
8.1
Investigational Medicinal Product Dosage, Administration and Schedule .................. 40
8.1.1
Dose Administration .................................................................................................. 40
8.1.2
Dose Escalation, Adjustments, and Taper ................................................................. 40
8.2
Concomitant Therapy ................................................................................................... 41
8.3
Prohibited Therapy During Trial Period ...................................................................... 41
8.4
Compliance in Investigational Medicinal Product Administration .............................. 42
8.5
Access to Blinded Treatment Assignment ................................................................... 42
9
TRIAL PROCEDURES ...............................................................................43
9.1
Trial Procedures ........................................................................................................... 44
9.1.1
Informed Consent ...................................................................................................... 44
9.1.2
Contraception Requirements ..................................................................................... 44
9.1.3
Demographics ............................................................................................................ 45
9.1.4
Medical History ......................................................................................................... 45
9.1.5
Concomitant Medications and Interventions ............................................................. 45
9.1.6
Physical Examination ................................................................................................ 45
9.1.7
Vital Signs ................................................................................................................. 45
9.1.8
12-Lead Electrocardiogram ....................................................................................... 46
9.1.9
Clinical Laboratory Sampling.................................................................................... 46
9.1.9.1
Pharmacokinetic Blood Sampling .......................................................................... 48
9.1.10
Randomization and Trial Supply Management System ............................................ 48
9.1.11
Questionnaires and Assessments Completed at Scheduled Visits ............................. 49
9.1.11.1
Wechsler Abbreviated Scale of Intelligence Scale Second Edition ....................... 49
9.1.11.2
Autism Diagnostic Observational Schedule-2 ....................................................... 49
9.1.11.3
Vineland Adaptive Behavior Scales, Third Edition ............................................... 50
9.1.11.4
Aberrant Behavior Checklist .................................................................................. 50


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9.1.11.5
Clinical Global Impressions Questionnaire ........................................................... 50
9.1.11.6
Pediatric Anxiety Rating Scale .............................................................................. 51
9.1.11.7
Repetitive Behavioral Scale-Revised ..................................................................... 51
9.1.11.8
Care-related Quality of Life Questionnaire............................................................ 52
9.1.11.9
Brief Observation of Social Communication and Speech Sample 
Acquisition ............................................................................................................. 52
9.1.11.10
Columbia-Suicide Severity Rating Scale ............................................................... 52
9.1.12
Investigational Medicinal Product Accountability .................................................... 53
9.1.13
Adverse Events .......................................................................................................... 53
9.2
Special Circumstances .................................................................................................. 53
10
WITHDRAWAL...........................................................................................55
11
URGENT SAFETY MEASURES ...............................................................57
12
ADVERSE EVENT REPORTING .............................................................58
12.1
Definitions .................................................................................................................... 58
12.1.1
Adverse Event ............................................................................................................ 58
12.1.2
Investigator ................................................................................................................ 58
12.2
Serious Adverse Events ................................................................................................ 58
12.3
Reporting Procedures for Serious Adverse Events ...................................................... 59
12.4
Pregnancy ..................................................................................................................... 60
12.5
Causality Assessment ................................................................................................... 60
12.6
Reporting Procedures for All Adverse Events ............................................................. 61
12.7
Follow-up Procedures for Adverse Events ................................................................... 63
12.8
Potential Cases of Drug-Induced Liver Injury ............................................................. 63
12.9
Notification of Safety Information to Investigators, Regulatory Authorities 
and IRBs/ECs ............................................................................................................... 64
13
STATISTICAL CONSIDERATIONS........................................................66
13.1
Sample Size, Power and Significance Levels .............................................................. 66
13.2
Interim Analysis ........................................................................................................... 66
13.3
Analysis Sets ................................................................................................................ 67
13.3.1
Protocol Deviations ................................................................................................... 67
13.4
General Considerations ................................................................................................ 67
13.5
Accountability and Background Characteristics .......................................................... 68


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13.5.1
Enrollment and Disposition ....................................................................................... 68
13.5.2
Baseline and Demographic Characteristics ............................................................... 68
13.5.3
Medical History ......................................................................................................... 68
13.5.4
Concomitant Medication ........................................................................................... 68
13.6
Endpoints and Statistical Methods ............................................................................... 68
13.6.1
Efficacy Endpoints ..................................................................................................... 68
13.6.1.1
VABS-3 .................................................................................................................. 68
13.6.1.2
ABC ....................................................................................................................... 69
13.6.1.3
CGI-I and CGI-S .................................................................................................... 69
13.6.2
Exploratory Endpoints ............................................................................................... 70
13.6.2.1
 .............................................................................................. 70
13.6.2.2
 ............................................................................................... 70
13.6.2.3
 ............................................................................................................ 70
13.6.2.4
 ............................................................ 70
13.6.3
Safety ......................................................................................................................... 71
13.6.3.1
Treatment Compliance and Extent of Treatment Exposure ................................... 71
13.6.3.2
Adverse Events....................................................................................................... 71
13.6.3.3
Clinical Laboratory Data ........................................................................................ 72
13.6.3.4
Vital Signs, 12-Lead Electrocardiogram, Physical Examination and Other 
Safety Data ............................................................................................................. 72
14
DATA MONITORING COMMITTEE......................................................73
15
REGULATORY AND ETHICAL OBLIGATIONS.................................74
15.1
Declaration of Helsinki ................................................................................................ 74
15.2
Informed Consent ......................................................................................................... 74
15.3
Institutional Review Board/Independent Ethics Committee ........................................ 74
15.4
Pre-trial Documentation Requirements ........................................................................ 75
15.5
Patient Confidentiality .................................................................................................. 75
16
ADMINISTRATIVE AND LEGAL OBLIGATIONS..............................77
16.1
Protocol Amendments and End of Trial or Termination .............................................. 77
16.2
Trial Documentation and Storage ................................................................................. 77
16.3
Trial Monitoring and Data Collection .......................................................................... 78
16.4
Quality Assurance ........................................................................................................ 79


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16.5
Compensation ............................................................................................................... 79
16.6
Publication Policy......................................................................................................... 79
16.7
Intellectual Property Rights .......................................................................................... 80
16.8
Confidential Information .............................................................................................. 80
17
REFERENCES..............................................................................................81


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List of Appendices
APPENDIX 1
SCHEDULE OF ASSESSMENTS .......................................... 84
APPENDIX 2
TRIAL PERSONNEL .............................................................. 87
Appendix 2.1
Investigator Details .................................................................. 87
Appendix 2.2
Sponsor Contact Details ........................................................... 87
Appendix 2.3
Contract Research Organizations ............................................. 88
List of In-text Tables
Table 5.1-1
Formulation of GWP42003-P Oral Solution ........................... 32
Table 5.2-1
Formulation of Placebo Oral Solution ..................................... 32
Table 9.1-1
Biochemistry, Hematology, Urinalysis, and THC ................... 47
List of In-text Figures
Figure 1-1
Trial Design and Treatment Schematic.................................... 10


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List of Abbreviations
ABC
Aberrant Behavior Checklist Subscales
ABC-I
Aberrant Behavior Checklist Irritability Subscale
ADHD
Attention deficit hyperactivity disorder
ADI-R
Autism Diagnostic Interview, Revised
ADOS-2
Autism Diagnostic Observational Schedule 
AE
Adverse Event
AESI
Adverse Event of Special Interest
AED
Anti-epileptic drug
ALT
Alanine aminotransferase
ANCOVA
Analysis of covariance
ASD
Autism spectrum disorder
AST
Aspartate aminotransferase
BAC
Blood alcohol content
b.i.d
Twice daily
BMI
Body mass index
BUN
Blood urea nitrogen
Ca
Calcium
CB
Cannabinoid
CB1
Cannabinoid receptor type 1
CB2
Cannabinoid receptor type 2 
CBD
Cannabidiol
CBD-OS
GWP42003-P, Cannabidiol oral solution 
CGI
Clinical Global Impressions
CGI-I
Clinical Global Impressions - Improvement
CGI-S
Clinical Global Impressions - Severity
CI
Confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CK
Creatinine kinase


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Cmax
Maximum measured plasma concentration
COVID-19
Corona virus disease-19
CRF
Case report form
CRO
Contract Research Organization
C-SSRS
Columbia-Suicide Severity Rating Scale
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, 5th 
Edition
DS
Dravet syndrome
DMC
Data Monitoring Committee
ECG
12-Lead electrocardiogram
eCRF
Electronic case report form
ECS
Endocannabinoid system
EDC
Electronic data capture
EMA
European Medicines Agency
EOT
End of Treatment
EU
European Union
FAS
Full analysis set
FDA
US Food and Drug Administration
GCP
Good Clinical Practice
GEE
Generalized estimating equation 
GPR55
G protein-coupled receptor 55
GW
GW Research Ltd
HDL
High density lipoprotein
IB
Investigator Brochure
ICF
Informed consent form
ICH
International Council for Harmonisation
IMP
Investigational medicinal product
INR
International normalized ratio
IRB
Institutional Review Board
LGS
Lennox-Gastaut syndrome
LS
The least squares 
MDMA
3,4-Methylenedioxymethamphetamine


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MMRM
Mixed-effects repeated measures model
 
PI
Principal Investigator
PP
Per protocol 
PRN
Packaging reference number
PT/INR
Prothrombin time/International normalized ratio
PVD
Pharmacovigilance Department
RTSM
Randomization and Trial Management System
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SAS®
Statistical Analysis System
SD
Standard deviation
SOC
System organ class
SRS
Social Responsiveness Scale 
SUSAR
Suspected Unexpected Serious Adverse Reaction
TEAE
Treatment-emergent adverse event
TBL
Total Bilirubin
THC
ǻ9-Tetrahydrocannabinol
TRP
Transient receptor potential
ULN
Upper limit of normal
US
United States
USA
United States of America
VABS-3
Vineland Adaptive Behavior Scales, 3rd Ed., comprehensive 
interview form 
VAS
Visual analog scale
VPA
Valproic acid
WASI-II
Wechsler Abbreviated Scale of Intelligence Scale Second 
Edition
WD
Withdrawal
WOCBP
Women of childbearing potential


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Definition of Terms
Term
Definition
Day 1
The day a patient first receives investigational medicinal product in 
this trial.
End of trial
Last patient last visit or last contact, whichever occurs last.
Enrolled patient
Any patient who has provided written informed consent/assent to 
take part in the trial.
International normalized
ratio
A calculation made to standardize prothrombin time.
Investigational medicinal 
product
Term used to describe both investigational active product and 
reference therapy (placebo).
Investigator
Trial principal investigator or a formally delegated trial physician.


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2
OBJECTIVES AND ENDPOINTS
Efficacy Objective 
Efficacy Endpoints
x
To evaluate the efficacy of GWP42003-P, 
compared with placebo, in reducing 
symptom severity in children with ASD.
Social Communication
x
VABS-3
Behavior
x ABC Subscales
Overall Condition
x
CGI-I
x
CGI-S
Safety Objective
Safety Endpoints
x To evaluate the safety of GWP42003-P, 
compared with placebo, in children with 
ASD.
x
AEs.
x
Clinical laboratory parameters.
x
Vital signs.
x
Physical examination procedures.
x
12-lead ECG.
x
C-SSRS.
 
 
 
 
 
 
 
 


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3 
BACKGROUND AND RATIONALE
3.1
Disease
Autism Spectrum Disorder is a lifelong neurodevelopmental disorder characterized by restricted, 
repetitive patterns of behavior and persistent deficits in social communication and interaction. In 
the US, ASD is currently estimated to affect approximately 1 in every 54 children aged 8 years 
and is reported to occur in all racial, ethnic, and socioeconomic groups1. Associated comorbid 
symptoms can include intellectual disability, language impairment, motor abnormalities (for 
example, motor delay, hypotonia, catatonia and deficits in coordination), gastrointestinal 
problems, sleep disorders, psychiatric comorbidities (most commonly anxiety and depression) 
and behavioral dysregulation such as aggression, impulsivity, irritability, and self-injurious 
behavior2. Autism Spectrum Disorder is approximately 4 times more common in boys than in 
girls1.
Autism Spectrum Disorder is diagnosed through developmental screening (18 and 24 months, 
although additional screening might be needed if a child is at high risk for ASD [e.g., an affected 
sibling] or if symptoms are present) and comprehensive diagnostic evaluation. Diagnostic tools 
usually rely on parents’ or caregivers’ descriptions of their child’s development and a 
professional’s observation of the child’s behavior2,3.  
There is currently no single standard treatment for ASD. Current options for these patients 
include early intervention services, behavioral management therapy, education and school-based 
therapies, nutritional therapy, and medication treatment. Medications are often used to manage 
certain behaviors, such as irritability, aggression, and self-injury3,4. To date, the US FDA has 
approved 2 drugs for treating irritability associated with ASD (risperidone [RISPERDAL®] and 
aripiprazole [ABILIFY®]); however, there are no approved drugs for the treatment of the core 
ASD symptoms (repetitive behavior; communication and social issues). Selective serotonin 
reuptake inhibitors (fluoxetine [PROZAC®], fluvoxamine [LUVOX®], sertraline [ZOLOFT®], 
and clomipramine [ANAFRANIL®]) can help to reduce repetitive behaviors and increase social 
contact, yet these drugs carry an FDA black box warning regarding potential increased risk of 
suicidal thoughts or attempts in children and adolescents. Anti-epileptic drugs are also required 
in patients with seizures.


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3.2
Cannabidiol Background
GWP42003-P is the substance code for the IMP, purified CBD under development by GW for 
the treatment of a number of conditions, including childhood onset epileptic syndromes and Rett 
syndrome. 
GWP42003-P is extracted from Cannabis sativa L. plants, has a defined chemical profile, and 
contains consistent levels of CBD as the principal phytocannabinoid. Extracts from these plants 
are processed to yield pure (&%'WKDWW\SLFDOO\FRQWDLQVOHVVWKDQZZ7+&. 
The pure CBD is subsequently dissolved in excipients with added sweetener and flavoring. 
Cannabidiol demonstrates anticonvulsant, antipsychotic, anxiolytic, neuroprotective, antioxidant, 
and anti-inflammatory activity5. Anti-seizure effects of GWP42003-P have been demonstrated in 
clinical trials of childhood onset epilepsies6 and GWP42003-P has received FDA approval and 
by the EMA in the EU for the treatment of seizures associated with LGS or DS in patients 
2 years of age and older (EMA approval is for treatment in conjunction with clobazam).
Cannabidiol possesses very low affinity and lacks appreciable functional activity at CB 
receptors; CB1 and CB26. In addition, CBD does not significantly interact with enzymes 
responsible for the synthesis and degradation of endocannabinoids, at clinically relevant 
concentrations7,8. Other data exist describing the polypharmacology of CBD at multiple 
7-transmembrane receptor systems, ion channels, transporters and enzymes7,8 although this is 
often at concentrations (> 10 M) that are unlikely to be clinically relevant.
At least 2 mechanisms of anticonvulsant action are proposed for CBD. The first is modulation of 
intracellular Ca2+ mobilization via antagonism of GPR55 and/or activation (and subsequent 
desensitization) of TRP channels, particularly TRPV16. The second is inhibition of adenosine 
reuptake6.
Importantly, CBD does not produce THC-like euphoric effects. 
 Cannabidiol oral solution has been studied in placebo-controlled clinical trials as adjunctive 
treatment of seizures associated with LGS and DS and is being used on a compassionate basis, as 
part of a series of expanded access IND applications in variety of refractory epilepsy syndromes, 
mainly in pediatric patients. This meaningful clinical trial exposure has yielded safety data on 
over 1,419 unique patients with epilepsy, with 391 patients with more than 1 year of continuous 
exposure. 
In general, the key risks identified from the clinical development program for LGS and DS are 
broadly expected to be the same for the ASD population – as the patient demographics and 
comorbidities have a significant amount of overlap. It is important to note that several of the key 


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risks for CBD-OS are dose related, as such the lower doses planned for the current trial may 
improve the tolerability of CBD-OS:
Hepatocellular injury is anticipated to be an important risk for CBD-OS in ASD patients, 
although to date the transaminase elevations observed with CBD-OS treatment have generally 
been asymptomatic, with no Hy’s law cases reported from any source. The proposed dose level 
of 10 mg/kg/day may provide an improved tolerability compared to the 10 and 20 mg/kg/day 
doses employed in the LGS and DS program. Furthermore, the transaminase elevations in LGS 
and DS patients were markedly more frequent and of a greater magnitude in patients taking 
concomitant VPA. Of note, VPA use is expected to be less frequent in the ASD population than 
in the LGS and DS populations, providing an additional avenue to an improved tolerability to 
CBD-OS with respect to potential hepatocellular injury. 
Somnolence type events are anticipated to be important risks for CBD-OS in ASD patients; 
however, from experience in LGS and DS patients, such events were manageable, and only a 
minority needed to discontinue CBD-OS. Dose adjustment should help mitigate any events of 
somnolence and sedation if needed. The somnolence may also diminish with repeated dosing 
over time.
Cannabidiol oral solution has been shown to cause loss of weight in clinical trials, however the 
incidence of a significant loss of weight (> 5%) was noted to be similar between the CBD-OS 
dose of 10 mg/kg/day and placebo in placebo-controlled trials. There was no impact on growth, 
as measured through BMI or height in these trials. 
In DS/LGS studies, aggression was reported in 2.2% of patients in the 10 mg/kg/day group while 
irritability was reported in 7.2% of patients in the 10 mg/kg/day group. The majority of cases 
reported were of mild or moderate severity with only few cases leading to withdrawal from these 
trials.
A higher incidence of pneumonia was noted with CBD-OS in LGS and DS controlled trials, 
although incidence does not appear to be dose related, majority of patients has risk factors for 
pneumonia and no plausible mechanism has been identified. 
Rash has been reported more often in CBD-OS patients compared with placebo patients in the 
controlled trials in LGS and DS. Importantly, none showed systemic involvement or involvement 
of mucous membranes; generally, the rash events have been self-limiting without serious 
outcomes. 
For further information on CBD-OS and current safety information please refer to the IB6.


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3.3
Rationale
Available therapies have limited efficacy, and there is no single standard treatment for ASD. 
Both FDA-approved agents (risperidone [RISPERDAL in 2006] and aripiprazole [ABILIFY in 
2009]) are indicated for irritability and associated with potential for neurological and metabolic 
adverse effects; in Europe none of these drugs are specifically approved for use in ASD. There 
are no approved drugs for the treatment of the core ASD symptoms. 
CBD has the potential to modulate some of the pathophysiological mechanisms thought to 
underly ASD. CBD has also shown benefit in a range of pharmacological, brain 
injury-associated and genetic models of relevant medical conditions, which exhibit behavioral
deficits similar to those seen in ASD, including deficits in social behavior, cognition, language, 
motor abnormalities, and seizures6.
There is clinical literature on open-label investigations of cannabinoids extracts, containing CBD 
and THC, in ASD9,10,11,12. Data from these investigations suggest some positive effects on 
behavior however data have generally been collected using non-validated measures, flexible 
dosing schedules and variable cannabinoid content formulations, all of which render the results 
difficult to interpret. To date, data from 1 single placebo-controlled trial of a formulation 
containing CBD and THC in a ratio of 20:1 reported improvement in the SRS and CGI-I9. All 
these investigations have used THC-containing compounds. However, there are known potential 
safety issues associated with administering THC to children13 while administration of 
GWP43002-P has been well tolerated in other pediatric populations. It is therefore important to 
investigate whether GWP43002-P improves symptom severity in children with ASD. 
3.3.1
Choice of Efficacy and Exploratory Endpoints
In this trial, we will evaluate the effect of GWP42003-P on core symptoms ASD and major 
associated symptoms/comorbidities in children and adolescents. 
Efficacy Measures
The core symptoms of autism are the symptoms required for its diagnosis. Per DSM-5, the core 
symptoms cover 2 domains: persistent deficits in social communication and social interaction
AND restricted, repetitive patterns of behavior, interests, or activities. 
Effects on the core symptom ‘persistent deficits in social communication and social interaction’ 
will be evaluated using the Vineland-3. The challenges measuring social communication are well 
reported14. Measures such as the widely used SRS have been shown to be highly susceptible to 
placebo effect, other measures are limited in scope or age range. The Vineland is a well validated 


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scale with strong reliability that has been widely used in studies in children neurodevelopmental 
disabilities (although the majority of published studies used the previous version Vineland-2). It 
was identified by Anagnostou et al14 as an appropriate measure with conditions with one of the 
limitations being possibly requiring a longer period to show sensitivity to change. Since, the 
Vineland-2, and in particular the socialization and communication domains, were reported to 
detect improvement over a 12-week treatment15. Importantly these 2 domains tackle social and 
communication skills relevant to the ASD population. 
Behavioral aspects, such as aggressive and self-injurious behaviors are amongst the most 
common ASD associated conditions2, as well as those of greatest concern to caregivers16. The 
ABC-I is a well validated questionnaire with excellent reliability17, which will be used to 
evaluate effects in these problem behaviors. The ABC was designed to measure treatment effects 
and has been used extensively in clinical trial in autism and other neurodevelopmental disorders. 
The ABC-I in particular has been shown to be sensitive to treatment change, having been a 
primary endpoint for both risperidone and aripiprazole FDA registration studies. 
The remaining subscale scores of the ABC (social withdrawal, stereotypic behavior, 
hyperactivity/noncompliance, and inappropriate speech) assess other aberrant behaviors relevant 
in ASD.
The CGI-S and CGI-I are widely used outcome measures in clinical trials with well accepted 
face validity18. The CGI-I in particular is known to be sensitive to treatment changes. Being a 
global measure, changes CGI-I reinforce the clinically meaningfulness of changes reported in 
symptom specific outcomes. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3.3.2
Choice of Dosing Regimen
Doses of up to 50 mg/kg/day GWP42003-P have been administered in the GW clinical 
development programs for GWP42003-P. At the time of protocol authoring, a total of 
approximately 4,973 subjects have received GWP42003-P from blinded and open-label GW-
sponsored trials and supportive programs (expanded access and other compassionate use 
programs), including patients with epilepsy (data cutoff date: Feb 2020). From these data sources 
the following warnings and precautions were established: hepatocellular injury, somnolence and 
sedation, suicidal behavior and ideation, hypersensitivity reactions, and withdrawal of AEDs. Of 
note, routine liver monitoring is required with the use of CBD-OS. To date, the available safety 
data collected showed that the reported AEs were usually mild or moderate in severity and 
resolved. There have been few withdrawals due to AEs. 
Efficacy of CBD against cognitive and social behavioral deficits in relevant animal models has 
been found over a range of doses from 2 to 200 mg/kg in a model and endpoint dependent 
manner6, with the top dose of the tested dose range overlapping with the effective anticonvulsive 
dose range of 50 to 200 mg/kg/day in nonclinical models6. It is therefore expected that clinical 
anticonvulsant doses (10 mg/kg/day and 20 mg/kg/day as per studies in LGS or DS patients) 
should provide meaningful exposures to explore efficacy in ASD. 
The doses used across the investigations reported in the literature referencing the use of CBD 
and THC in ASD are variable but mostly fall between 2 and 10 mg/kg/day CBD. In particular, 
the target dose in the randomized, placebo-controlled trial9 was 10 mg/kg day CBD (with a 
maximum CBD daily dose of 420 mg and an average daily dose of 5.5 mg/kg/day). 
The GWND19189 trial will evaluate the efficacy and safety of 10 mg/kg/day CBD-OS (dosed as 
5 mg/kg/day b.i.d.) versus placebo. The dose of 10 mg/kg day was selected as it is within the 


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clinical therapeutic range for GWP42003-P in pediatric epileptic encephalopathies (LGS and 
DS).
The IMP solution contains 7.9% w/v anhydrous ethanol, which is required as sucralose is not 
soluble in sesame oil. The proposed dose of 10 mg/kg/day (administered as 5 mg/kg b.i.d.) will 
result in a BAC of 0.0065 g/L which equates to ethanol ingestion of 3.95 mg/kg. Both these 
amounts are well under the threshold for BAC of 0.125 g/L and ethanol ingestion of 75 mg/kg 
for patients 6 years and older. Twice daily (b.i.d) dosing is recommended for this clinical trial in 
accordance with the approved FDA label for CBD-OS (GWP42003-P) in the treatment of 
seizures associated with LGS or DS in patients 2 years of age and older. Twice daily dosing 
should also minimize the potential risk of acute AEs related to Cmax. Further, peak trough ratios 
would be reduced, and improved patient adherence may reduce the potential clinical risks of a 
 patient/care psychological viewpoint. 
Concomitant administration of CBD-OS with a high fat meal resulted in a predictable increase in 
CBD exposure and less total subject variability. The IMP will therefore be taken preferentially 
with food i.e., within 30 minutes after the end of a meal/snack, and the time of IMP 
administration in relation to food should be kept consistent throughout the trial. 
3.3.3
Benefit-Risk
There are no approved medications for the core symptoms of ASD and there are limited options 
for the management of comorbidities. 
Nonclinical and clinical data indicate that CBD-OS may benefit patients with ASD (see 
Section 3.3).
The key risks identified from the CBD-OS clinical development program for LGS and DS 
(described in Section 3.2) are broadly expected to be the same for the ASD population, as the 
patient demographics and comorbidities have a significant amount of overlap. Importantly, the 
risk of raised transaminases is reduced in the context of this ASD trial, where the lower dose of 
CBD-OS will be used and VPA use is expected to be lower in this population. 
In the context of the anticipated benefit of CBD-OS in ASD patients, the key risks identified 
from the CBD-OS clinical development program in LGS and DS are acceptable given the 
proposed dose level of 10 mg/kg/day and the age range of 6 to 17 years. Thus, the overall 
benefit-risk for the development of CBD-OS in the ASD population is favorable. 


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3.4
Clinical Hypothesis
Treatment with GWP42003-P is associated with improvements in ASD symptom in children and 
adolescents as measured by the mean change in scores of the ABC-I, VABS-3 communication 
and socialization composite.


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4 
EXPERIMENTAL PLAN
4.1
Trial Design
This is an exploratory, Phase 2, double-blind, randomized, placebo-controlled, multisite trial, 
which will compare the safety and efficacy of a 10/mg/kg/day dose of GWP42003-P versus 
placebo in children and adolescents with ASD. 
Patients will be screened and if they meet eligibility criteria will be randomized to receive 
GWP42003-P or matching placebo in a 1:1 ratio. Patients will be stratified based on their age 
(6 to 11, 12 to 17), use of antipsychotics (on versus off), and region (North America versus Rest 
of the World). Patients will be administered 5 mg/kg/day GWP42003-P or matching volumes of 
placebo for 1 week and then 10 mg/kg/day GWP42003-P or matching volumes of placebo for 
11 weeks. At the end of treatment, patients will taper the medication over 1 week.
A schematic (Figure 1-1), presented at the end of Section 1, depicts the overall trial design. More 
detailed information on treatment and trial procedures is provided in Section 8 and Section 9, 
respectively. 
Eligible patients may be randomized 7 to 14 days after the screening visit (Visit 1), once all 
required assessments have been completed and laboratory results have been reviewed; if 
required, screening assessment may be spilt over 2 visits; however both visits must fall into the 
7 to 14 day window prior to randomization (Visit 2). One week and 2 weeks following 
randomization, there will be 2 safety telephone visits (Visit 3 and 4). The patient will return to 
the clinic or video call and home nurse visit, 4 weeks after randomization (Visit 5). Six weeks 
after randomization, there will be another safety call (Visit 6), and then the patient will return for 
a clinic visit or video call visit (Visit 7) 8 weeks after randomization. The end of treatment visit 
will take place 12 weeks after randomization (Visit 8). If at any point it is decided to withdraw a 
patient from the trial, the patient should return to the clinic as soon as possible and complete 
Visit 8 procedures. At Visit 8, patients will commence to taper the medication (unless in case of 
withdrawal the medication was already discontinued or continued dosing is inadvisable, e.g., due 
to an AE). At the end of taper, the patient will return to the clinic or video call and home nurse 
visit (Visit 9). All patients will have a follow-up safety telephone visit, 14 days after Visit 9 or 
Visit 8 (in case the patient did not taper the medication).
Visit windows are allowed as defined in the schedule of assessment. Visit 3, 4, 5, 6, 7, and 
8 days and windows are counted from the day of randomization (Visit 2). Visit 9 day and 
window is counted from the day of Visit 8. Visit 10 day and window is counted from the day of 
Visit 9, or the day of Visit 8 (if the patient did not enter the taper period). 


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4.2
Number of Centers
Approximately 25 centers are expected to participate in this trial. Additional centers may be used 
in order to supplement recruitment. 
4.3
Number of Patients 
It is expected that 188 patients will be screened. With an anticipated screen failure rate of 15%, it 
is expected that 160 patients will be randomized to allow for 144 evaluable patients 
(72 evaluable patients per arm) at trial end. The sample size calculation is explained fully in
Section 13.1. 


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5 
INVESTIGATIONAL MEDICINAL PRODUCT
Please refer to the separate pharmacy manual for more detailed information on the IMP. 
5.1
GWP42003-P Oral Solution
GWP42003-P oral solution contains 100 mg/mL CBD dissolved in the excipients sesame oil and 
anhydrous ethanol (10% v/v), with sweetener (sucralose), and strawberry flavoring (Table 5.1-1).
Table 5.1-1
Formulation of GWP42003-P Oral Solution
Ingredients
Quantity
CBD
100 mg/mL
Anhydrous ethanol
79 mg/mL
Sucralose
0.5 mg/mL
Strawberry flavor
0.2 mg/mL
Refined sesame oil
make up to 1 mL
CBD = cannabidiol
5.2
Placebo
3ODFHERRUDOVROXWLRQFRQWDLQVWKHH[FLSLHQWVVHVDPHRLODQGDQK\GURXVHWKDQROZLWKDGGHGȕ-
carotene, sweetener (sucralose) and strawberry flavoring (Table 5.2-1).
Table 5.2-1
Formulation of Placebo Oral Solution
Ingredients
Quantity
Anhydrous ethanol
79 mg/mL
Sucralose
0.5 mg/mL
Strawberry flavor
0.2 mg/mL
Beta Carotene*
Up to 0.1 mg/mL
Refined sesame oil
make up to 1 mL
* ȕ-Carotene concentration can be varied up to a maximum of 0.01% w/v as required to provide a consistent 
yellow colored solution.
5.3
Packaging, Storage and Drug Accountability
5.3.1
Packaging and Labeling
The IMP will be manufactured, packaged, labeled and/or distributed by G-Pharm or delegated 
contractors. The IMP will be presented in 100 mL amber glass bottles with child resistant screw 
caps and packed in cartons. Sufficient IMP will be dispensed at each relevant visit considering 
the dose group and the weight of the patient. A unique identification number will be used to 
identify each carton and the IMP it contains. The unique identification number together with the 
PRN will permit full traceability of manufacture, pack and label activities conducted at or on 
behalf of GW and the IMP information held on the RTSM system. GW will ensure that all IMP 


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provided is fully labeled and packaged. Label text will include the following information, as a 
minimum:
x
Sponsor’s name and address.
x
Product identification (e.g., “GWP42003-P or Placebo”).
x
Dose and/or Potency (e.g., “100 mg/mL GWP42003-P”).
x
Trial code number.
x
Expiry date.
x
Storage conditions.
x
Instruction: “For clinical trial use only”.
x
Instruction: “Keep out of the reach and sight of children”.
x
Any other information required by local regulatory authorities.
In addition, any local country requirements in accordance with local Drug Law or Regulatory 
Requirement will be included in the final label text.
Directions of use, name, address, and the telephone number of the investigator (or main contact 
for information about the product or the clinical trial) will be provided separately to the 
caregiver. Caregivers will be instructed to retain and carry this information with the patient at all 
times.
5.3.2
Storage
The IMP must be stored 
 
. It must also be kept away from heat and direct sunlight.
The IMP must be stored in compliance with the local regulations for a controlled drug (if 
applicable to country). The sponsor must approve storage location and facilities. Temperature 
records of the clinical center storage location must be maintained (recording a minimum of 
Monday–Friday, excluding public holidays) from date of receipt of first shipment until end of 
trial dispensing period at each center. These records must contain at least the minimum and 
maximum daily temperatures and must be made available to the appropriate GW personnel for 
review throughout the trial. Temperature during transit of IMP to the center must be checked on 
receipt and compliance/noncompliance to the minimum and maximum recorded.
Should storage conditions deviate from these specified requirements, the GW trial monitor must 
be contacted immediately to confirm if the IMP remains suitable for use. IMP must be placed 
under quarantine until written confirmation is received that the IMP is suitable for use.
Caregivers will be provided with instructions regarding home storage requirements for the IMP.


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5.3.3
Supply and Return of Investigational Medicinal Product
At trial initiation and as needed thereafter, IMP will be shipped to the identified responsible 
person, such as the pharmacist, at the investigator’s center, who will check the amount received 
and condition of the drug (i.e., integrity, physical appearance, temperature during transit). Details 
of the IMP received will be recorded in the IMP accountability record (see Section 5.3.4). The 
center will acknowledge the IMP receipt and will complete any receipt forms required. IMP will 
be dispensed and returned as detailed in Section 8.4. As directed, all supplies, including unused, 
partially used, or empty containers, will be returned to GW/depot or destroyed at a GW-approved 
site if agreed in writing by the trial monitor. 
5.3.4
Investigational Medicinal Product Accountability
The investigator has overall responsibility for the accountability of all used and unused IMP. A 
drug accountability record for the IMPs must be kept current and must contain: 
x
Trial code. 
x
PRN, treatment number, date of receipt and quantity of IMP received.
x
Patient’s trial identification and or treatment number. 
x
Date and quantity of IMP dispensed. 
x
The initials of the dispensing/dosing party. 
x
Date and quantity of IMP returned to the investigator. 
x
IMP expiry dates.
Refer to APPENDIX 1 for when IMP will be dispensed. Patients will be asked to return all IMP 
(used and unused) at each relevant visit (APPENDIX 1). The site will check the returned IMP 
against the usage recorded in the medication diary. Any discrepancies will be discussed with the 
caregiver at the time of the visit and documented accordingly within the patient’s source 
documents. 
The investigator must inform GW promptly of all missing or unaccountable IMP. 
A record of returned IMP must be completed and included in the shipment of used and unused 
IMP to the relevant drug distribution depot. At the end of the trial, verification of reconciliation 
will be provided to GW.
These inventories must be made available for inspection by an authorized GW representative and 
local officials or regulatory agency inspectors. 
Please refer to the separate pharmacy manual for more detailed information on the IMP. 


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5.3.5
Post-Trial Provision
No post-trial access to the IMP will be provided.


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6
PATIENT ELIGIBILITY
Investigators are responsible for confirming patient eligibility and will be required to maintain 
information about all screened patients (age, sex; as allowed per local regulations) and outcome 
of screening.
6.1
Inclusion Criteria
For inclusion in the trial patients must fulfill ALL of the following criteria:
6.1.1 Male or female aged 6 to 17 years (inclusive).
6.1.2 Patient weight is at least 12 kg.
6.1.3 Patients (if possessing adequate understanding, in the investigator’s opinion) and their 
parent(s)/legal representative are willing and able to give informed consent for 
participation in the trial.
6.1.4 Patient is/and their caregiver are willing and able (in the investigator’s opinion) to 
comply with all trial requirements.
6.1.5 Patient has a diagnosis of ASD as per DSM-5 criteria for ASD, confirmed by ADOS-2 
criteria (conducted within 2 years at the trial site or at screening by a qualified 
assessor). Note: During special circumstances (e.g., COVID-19 pandemic) where the 
ADOS-2 cannot be performed due to site restrictions (e.g., mandatory use of face 
masks) and an ADOS-2 conducted within 2 years at the trial site by a qualified 
assessor is not available, eligibility can be confirmed using: 1) an ADOS-2 performed 
within 2 years by a qualified assessor external to the site; 2) if 1) is not available,
eligibility may be confirmed using the ADI-R at screening.
6.1.6 CGI-S  4 (moderately ill) at screening and randomization.
6.1.7 ABC-,VXEVFDOHVFRUHDWVFUHHQLQJ.
6.1.8 IQ  70 at screening, measured within 1 year of screening, using WASI-II.
6.1.9
All medications or interventions (including psychosocial interventions, dietary 
supplements, probiotics, speech therapy, etc.) for ASD related symptoms must have 
been stable for 4 weeks prior to screening and randomization, and the 
patient/caregiver should be willing to maintain a stable regimen throughout the trial.
6.1.10 Patient must have the ability to swallow the IMP provided as a liquid solution.
6.1.11 Patient and/or parent(s)/legal representative is willing to allow the responsible 
authorities to be notified of participation in the trial, if mandated by local law.
6.1.12 Patient and/or parent(s)/legal representative is/are willing to allow the patient’s 
primary care practitioner (if they have one) and consultant (if they have one) to be 
notified of participation in the trial if the primary care practitioner/consultant is 
different from the investigator.
6.2
Exclusion Criteria
The patient may not enter the trial if ANY of the following apply:


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6.2.1
Current diagnosis of bipolar disorder, psychosis, schizophrenia, schizoaffective 
disorder or major depression (patients with depression in remission may be included).
6.2.2
Has a diagnosis other than ASD that dominates the clinical presentation (e.g.,
ADHD).
6.2.3
Has a progressive neurological condition.
6.2.4
Seizures in the past 24 weeks.
6.2.5
Changes in anticonvulsive therapy within the last 12 weeks.
6.2.6
Currently taking more than 2 AEDs.
6.2.7
Taking sirolimus, everolimus, temsirolimus, or tacrolimus.
6.2.8
Taking clobazam.
6.2.9
Taking omeprazole, lansoprazole, tolbutamide, or warfarin.
6.2.10 Taking repaglinide, pioglitazone, rosiglitazone, montelukast, bupropion, or efavirenz.
6.2.11 Patient is currently using or has used recreational or medicinal cannabis, cannabinoid-
based medications (including Sativex®, or Epidiolex®/Epidyolex®) within the 
12 weeks prior to screening and is unwilling to abstain for the duration of the trial.
6.2.12 Patient has any known or suspected hypersensitivity to cannabinoids or any of the 
excipients of the IMP, such as sesame oil.
6.2.13 Patient has moderately impaired hepatic function at screening, defined as serum ALT 
or AST > 2 × ULN or TBL > 2 × ULN’.
6.2.14 This criterion can only be confirmed once the laboratory results are available; patients 
enrolled into the trial who are later found to meet this criterion must be screen-failed.
6.2.15 Patient is male and fertile (i.e., after puberty unless permanently sterile by bilateral 
orchidectomy) unless willing to ensure that they use male contraception (condom) or 
remain sexually abstinent during the trial and for 12 weeks thereafter.
6.2.16 Patient is female and of childbearing potential (i.e., following menarche and until 
EHFRPLQJSRVWPHQRSDXVDOIRUFRQVHFXWLYHPRQWKVXQOHVVSHUPDQHQWO\VWHULOHE\
hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) unless willing to 
ensure that they use a highly effective method of birth control (e.g., hormonal 
contraception, intrauterine device/hormone-releasing system, bilateral tubal 
occlusion, vasectomized partner, sexual abstinence) during the trial and for 12 weeks
thereafter.
6.2.17 Female patient who is pregnant (positive pregnancy test), lactating or planning 
pregnancy during the course of the trial or within 12 weeks thereafter.
6.2.18 Patient has received an IMP within the 12 weeks prior to the screening visit.
6.2.19 Patient had brain surgery or traumatic brain injury within 1 year of screening.
6.2.20 Patient has any other significant disease or disorder which, in the opinion of the 
investigator, may either put the patient, other participants, or site staff at risk because 
of participation in the trial, may influence the result of the trial, or may affect the 
patient’s ability to take part in the trial.


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6.2.21 Any abnormalities identified following a physical examination of the patient that, in 
the opinion of the investigator, would jeopardize the safety of the patient if they took 
part in the trial.
6.2.22 Any history of suicidal behavior (lifelong) or any suicidal ideation of type 4 or 5 on 
the C-SSRS in the last 4 weeks or at screening or randomization.
6.2.23 Patient has donated blood during the past 12 weeks and is unwilling to abstain from 
donation of blood during the trial.
6.2.24 Patient has any known or suspected history of alcohol or substance abuse or positive 
drugs of abuse test at screening (not justified by a known concurrent medication).
6.2.25 Patient has previously been randomized into this trial.
6.2.26 Patient has plans to travel outside their country of residence during the trial, unless 
the patient has confirmation that the IMP is permitted in the destination country/state.


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7 
PATIENT ENROLLMENT
Before patients may be entered into the trial, GW requires a copy of the relevant center’s
IRB/EC written approval of the protocol, informed consent/assent forms and other patient
information material. Patients will be considered enrolled in the trial from the time of providing 
written informed consent/assent. All patients and/or parent(s)/legal representatives, where 
appropriate, must personally sign and date the consent/assent and, if allowed per local 
regulations, prior to any procedures being performed (refer to Section 9.1.1 and Section 15.2).
7.1
Treatment Assignment
At the start of Visit 1, enrolled patients will be allocated a unique patient number. After 
confirmation of eligibility at Visit 2, patients will be stratified and randomly allocated to 
GWP42003-P or matching volumes of placebo using the RTSM in a 1:1 ratio. GW will provide 
all IMP in a packed and labeled state and the RTSM will identify the pack number to be 
dispensed to the patient at each relevant visit, according to the treatment assigned in the 
randomization schedule. 


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8 
TREATMENT PROCEDURES
8.1 
Investigational Medicinal Product Dosage, Administration and Schedule
For details regarding IMP formulations, see Section 5. 
8.1.1
Dose Administration
GWP42003-P or placebo will be administered orally b.i.d. (morning and evening) using the 
syringe(s) provided, preferentially with food i.e., within 30 minutes after the end of a 
meal/snack. The first dose of GWP42003-P or placebo is taken at home in the evening. The time 
of IMP administration in relation to food should be kept consistent throughout the trial. Volume 
of IMP to be determined by patient’s weight. 
The daily volumes of IMP solution to be taken will be calculated based on the patients’ weight 
and the dosing schedule will be provided to the caregiver. 
8.1.2
Dose Escalation, Adjustments, and Taper
Patients will be administered 5 mg/kg/day GWP42003-P or matching volumes of placebo for 
1 week and then 10 mg/kg/day GWP42003-P or matching volumes of placebo for 11 weeks. 
If an unacceptable AE develops at any time during the dose escalation or treatment periods, 
dosing should be reduced, at the investigator’s discretion and in a blinded manner, until the event 
has resolved or is well tolerated. The end of treatment taper schedule should be used to guide 
dose adjustment. If required, dosing may be suspended. Patients whose dose has been decreased 
should have their dose increased again, if the tolerability improves. Patients unable to tolerate the 
target dose may stay at a lower dose. If a patient cannot tolerate a dose of 5 mg/kg/day, the 
investigator should discuss with the medical monitor whether patient continuation in the trial is 
recommended. Single dose volumes must be at least 0.1 mL. 
Transaminase elevations should be medically managed by the investigator either by reducing the 
IMP dose or, following discussion with the medical monitor, by reducing concomitant 
medications judged to be causing the elevation (as per Section 10). For potential cases of 
drug-induced liver injury see Section 12.9. 
Dose adjustments should be discussed with the GW medical monitor. The final decision 
regarding dose adjustments should be taken by the investigator. 
At the end of treatment, patients will taper the medication in steps of -2.5 mg/kg/day every 
2 days. 


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8.2
Concomitant Therapy
It is theoretically possible that GWP42003-P may modify the metabolism of other drugs 
(including AEDs) administered concurrently and there remains the possibility of 
pharmacological interactions between GWP42003-P and other concurrently administered drugs. 
Doses of any concomitant medications for ASD related symptoms must have been stable for at 
least 4 weeks prior to screening and must remain stable throughout the blinded trial period. If 
there are side-effects suspected of being related to a drug-drug interaction, the investigator must 
contact the medical monitor to discuss best management. Decisions should be based on clinical 
symptoms and not plasma levels of concomitant medications. Further information on drug 
interactions can be found in the IB6. Dose reductions for concomitant medications for ASD 
related symptoms are permitted on clinical grounds (e.g., due to AEs or transaminase elevations 
not meeting withdrawal criteria specified in Section 10 and Section 12.8 following discussion 
with the medical monitor). 
Any non-pharmacological therapies (e.g., psychosocial interventions, dietary supplements, 
probiotics, speech therapy, etc.) must also be stable up to 4 weeks prior to screening and 
throughout the duration of the trial. 
All medications and non-pharmacological therapies, other than the IMP, taken during the trial
must be recorded on the CRF. 
8.3
Prohibited Therapy During Trial Period
The following medications are prohibited for the duration of the trial beginning from the date of 
the screening visit. However, any patients taking these medications after randomization should 
not be discontinued from treatment unless there are safety concerns. 
Care should be taken with drugs, or their metabolites, that are cytochrome P450 2C19 substrates, 
such as N-desmethylclobazam and are excluded as indicated below. Care should also be taken 
with drugs, or their metabolites, that are solely or primarily metabolized by UDP-
glucuronosyltransferase 1A9 and 2B7. 


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x
Sirolimus, everolimus, temsirolimus, or tacrolimus. 
x
Clobazam. 
x
Omeprazole or lansoprazole. 
x
Tolbutamide or warfarin. 
x
Repaglinide, pioglitazone, rosiglitazone, montelukast, bupropion, or efavirenz. 
x
Any new medications or interventions for ASD related symptoms or changes in dosage, 
within 4 weeks or during the trial. 
x
Recreational or medicinal cannabis or cannabinoid-based medications (including Sativex, 
Epidiolex/Epidyolex) within the 12 weeks prior to or during the trial. 
x
Any other IMP taken as part of a clinical trial within the 12 weeks prior to or during the 
trial. 
8.4
Compliance in Investigational Medicinal Product Administration
The caregiver will record the volume of solution on each treatment day in the diary. 
Patients should return all IMP (used and unused) at Visits 5, 8, and 9. The diary-reported dosing 
information will be checked and any discrepancies discussed with the caregiver at the time of the 
visit and documented accordingly within the patient’s source documents. 
Records of IMP accountability will be maintained according to Section 5.3.4. 
8.5
Access to Blinded Treatment Assignment
The identity of IMP assigned to patients will be held by the RTSM system. The PI at each site, or 
his/her designee, is responsible for ensuring that information on how to access the RTSM system 
is available to the relevant staff in case of an emergency and unblinding is required. A patient’s 
treatment assignment should only be unblinded when knowledge of the treatment is essential to 
make a decision on the medical management of the patient. Unblinding for any other reason will 
be considered a protocol deviation. 
The investigator is encouraged to contact the medical monitor to discuss the rationale for 
unblinding prior to doing so. However, to prevent delays to the investigator or medical personnel 
responding to a potentially emergent situation, unblinding of trial medication will not be 
dependent upon the investigator receiving approval from the medical monitor (i.e., the 
investigator will be able to obtain the code break information independent of contacting the 
medical monitor).
If the investigator does unblind, they must contact the medical monitor within 1 working day of 
the event and must document the time, date and reason(s) for unblinding in the patient’s medical 
notes and on the eCRF.


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9 
TRIAL PROCEDURES
In order to facilitate trial execution in the context of infectious diseases or other transmissible 
conditions (e.g., COVID-19), the trial will involve a combination of clinic, remote (including a 
video call and a home nurse visit) and telephone visits, as specified in APPENDIX 1. The 
investigator will determine in discussion with the caregiver by visit 2 which visits will be 
performed at clinic or remotely. If at any point there is motive for concern (e.g., AE of concern, a 
score of 4 or 5 in the C-SSRS) the patient should attend the clinic for further assessment (either 
for a scheduled visit or for an unscheduled visit). Unscheduled visits and assessments may be 
performed in the event of a safety concern, as deemed necessary by the investigator. Data from 
any unscheduled visits or assessments should be reported on the unscheduled visits eCRF. 
When remote visits are agreed these may require (as per visit schedule): 
x
A home nurse visit to collect blood and urine samples (including urine dipstick), and vital 
signs. 
x
A video call with the child and the caregiver to review IMP usage, adverse events, changes 
in concomitant medications, perform clinical interviews (C-SSRS and Vineland-3), and 
patient observation for assessment of CGI-S and CGI-I. 
x
The caregiver to complete the caregiver questionnaires electronically (ABC and 
). 
x
IMP review by the home nurse or over the video call and IMP secure delivery/collection.
All events must take place within the protocol window; further guidance will be provided in a 
site manual. 
A list of the required trial procedures is provided in the subsections that follow; refer also to the 
schedule of assessments (APPENDIX 1). 
Patient functional assessments, i.e., the WASI-II, ADOS-2, 
 
 should be performed prior to any invasive assessments being carried out. All 
assessments should reflect the patient’s regular state; therefore, it should be ensured the patient 
had adequate time to settle prior to each assessment.
Assessments or tests that are not done and examinations that are not conducted must be reported 
as such on the electronic CRF.
The location of the source data for study procedures will be documented, per center, and filed in
the trial file; for further details see Section 16.2. 


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9.1
Trial Procedures 
9.1.1
Informed Consent
The parent(s)/legal representative of minor patients must personally sign and date the IRB/EC
approved ICF before any trial-specific procedures are performed or any patient-related data is 
recorded for the trial. In addition, assent will be taken (if allowed per local regulations) along 
with parent(s)/legal representative consent, using IRB/EC-approved forms. It is expected that the 
majority of patients will have sufficient understanding to provide assent; if the investigator 
assesses the patient as not having sufficient understanding or communication ability to provide 
assent, this must be clearly recorded in the patient notes. The explicit wish of a minor, who is 
capable of forming an opinion and assessing the information provided, to refuse participation in 
or to be withdrawn from the clinical trial at any time must be considered by the investigator. 
Investigators must record in the patient notes any reason(s) why a minor is unable to sign a form.
The original signed ICF should be retained and a copy provided to the patient and/or 
parent(s)/legal representative. Patients/parent(s)/legal representative will be given the option of 
being informed about the summary outcome and results of the trial as part of the ICF. For further 
details, see Section 15.2. 
9.1.2
Contraception Requirements
To be eligible for the trial, female patients of childbearing potential (i.e., following menarche and 
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hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) must have agreed that they are 
willing to use highly effective contraception for the duration of the trial and for 12 weeks 
thereafter. Highly effective methods of contraception are defined as those, alone or in 
combination, that result in a low failure rate (i.e., less than 1% per year) when used consistently 
and correctly20. Such methods include hormonal contraception (the use of hormonal 
contraception must be supplemented with a barrier method [preferably male condom]), an 
intrauterine device/hormone-releasing system, bilateral tubal occlusion, vasectomized partner 
(provided that partner is the sole sexual partner of the trial patient and that the vasectomized 
partner has received medical assessment of the surgical success), or sexual abstinence21. 
To be eligible for the trial, male patients who are fertile (i.e., after puberty unless permanently 
sterile by bilateral orchidectomy) must have agreed that they are willing to use male 
contraception (condom) or remain sexually abstinent during the trial and for 12 weeks thereafter. 
Abstinence, as referenced above, is only acceptable as true abstinence, i.e., when this is in line 
with the preferred and usual lifestyle of the patient. Periodic abstinence (calendar, 


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symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and 
the lactational amenorrhea method are not acceptable methods of contraception21. 
9.1.3
Demographics
The following information will be obtained for each patient: date of birth, sex, race, and ethnicity 
(as allowed per local regulations). Details informing amount of time spent with main caregiver 
will also be collected. 
9.1.4
Medical History
Relevant, significant medical history will be obtained at Screening (Visit 1) and is defined as any 
condition or disease that: 
x
May affect the condition under study. 
x
Is ongoing on entry into the trial. 
x
Suspected or confirmed COVID-19 infection (or other significant infectious diseases) 
within 1 year prior to Screening (Visit 1). 
x
Information on ASD history, including known etiologies, will be recorded. 
9.1.5
Concomitant Medications and Interventions
Details of all current and recent medication/therapy (i.e., taken within the 14 days prior to the 
initial screening visit) will be recorded. All medications and interventions for ASD related 
symptoms must remain at stable doses throughout the trial; however, doses may be changed in 
response to a safety concern. Interventions would include special diets. 
Any changes in concomitant medication or interventions during the trial must be recorded on the 
CRF at trial visits. Patients should stop taking any prohibited therapy prior to the screening visit, 
as defined in Section 8.3. 
Testing for drugs of abuse will be performed at screening (Visit 1). 
9.1.6
Physical Examination
Physical examinations will include height (measured once), body weight measurements, and 
BMI (Visit 1 only). 
9.1.7
Vital Signs
Vital sign measurements (body temperature, pulse rate, respiration rate), including blood 
pressure taken in a sitting position at rest for 5 minutes. Blood pressure must be recorded using 
the same arm throughout the trial, where possible. 


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9.1.8
12-Lead Electrocardiogram
A 12-lead ECG will be performed after 5 minutes in a supine position. A physician must review 
the ECG immediately (annotated, signed and dated) and any abnormal findings considered to 
indicate significant medical history or AEs must be recorded appropriately on the CRF. 
Additional ECG measurements can be taken at any time during the trial, if clinically indicated.
9.1.9
Clinical Laboratory Sampling
The investigator should use their judgment and knowledge of the patient to determine when best 
to collect the blood and urine samples in order to mitigate the risk that invasive procedures may 
cause the patient to become stressed, thereby affecting the results of other assessments.
Laboratory tests will include hematology, biochemistry, coagulation (Visit 1 only; thereafter 
only as an unscheduled assessment if ALT or AST > 3 × ULN) and urinalysis (provided urine 
can be obtained). Blood sample volume requirements and processing procedures will be detailed 
in a separate laboratory manual. 
Urine samples for biochemistry will be analyzed at the trial site (or by the home nurse) by use of 
a dipstick with any relevant findings being sent for further urinalysis at the central laboratory 
(urinalysis, microscopy, culture, and sensitivity, as applicable). In cases where urine samples 
cannot be analyzed at the site (or by the home nurse) due to local regulations, a full set of urine 
samples should be sent to the central laboratory for analysis. Urine sample volume requirements 
and processing procedures will be detailed in a separate laboratory manual.
Urine samples for drugs of abuse will be sent to the central laboratory. 
The investigator and trial monitor will be provided with a list of the normal ranges used by the 
testing laboratory for all variables assayed during the trial and a statement of accreditation (or 
similar) for the laboratory. Clinical laboratory sample parameters are detailed in Table 9.1-1. 


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Table 9.1-1
Biochemistry, Hematology, Urinalysis, and THC
Biochemistry
(Serum)a
Hematology
(Whole Blood)a
Coagulation
(plasma)a,b
Urinalysis
(Urine)c
Pregnancy 
Test 
(Serum)a
Drugs of Abuse
(Urine)a
Alanine 
aminotransferase (ALT)
Hematocrit
Prothrombin 
time 
(PT/INR) 
Bilirubin
Serum
Amphetamines
Albumin
Hemoglobin
Blood
Barbiturates
Alkaline phosphatase
Mean cell volume
Glucose
Benzodiazepine
Aspartate 
aminotransferase (AST)
Mean corpuscular 
hemoglobin
Ketones
Cannabinoids
Calcium
Platelets
Protein
Cocaine
Creatinine
Red blood cell count
Nitrites
Methadone
Creatinine clearance
White blood cell count 
with automated 
differential
pH
Opiates
Creatine kinase (CK)
Specific 
gravity
MDMA
Gamma-glutamyl 
transferase
Urobilinogen
Methamphetamines
Glucose
White blood 
cells
Oxycodone
HDL-cholesterol
Phencyclidine
Potassium
Tricyclic 
antidepressants
Prolactin
Sodium
Total bilirubin
Total protein
Triglycerides
Urea (blood urea 
nitrogen [BUN])
HDL = high density lipoprotein; INR = international normalized ratio; 
MDMA = 3,4-methylenedioxymethamphetamine: THC = tetrahydrocannabidiol. 
a Analyzed at a central laboratory.
b Tested at Visit 1 only; thereafter only as an unscheduled assessment only if ALT or AST > 3 × ULN
c Analyzed at the trial site (or by the home nurse) by use of a dipstick (if allowed per local regulations).
Investigators at trial sites will be notified of safety laboratory test results. All laboratory results 
will be reviewed, and the reports signed and dated by an investigator. Any results considered to 
be of clinical significance must be addressed and followed up as clinically appropriate. The 
results of drugs of abuse screening will be reported back to the trial center for confirmation of 
eligibility. All laboratory results considered to represent an AE must be documented on the CRF. 
For reporting and follow-up of potential cases of drug-induced liver injury, see Section 12.7. 
Repeat samples will be taken, if required, for clinical follow-up or if the sample is lost or 
damaged. Any abnormal end of treatment clinical laboratory result of clinical significance must 
be repeated at regular intervals until it returns to normal, or until an investigator is satisfied that 


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the abnormality is not related to the IMP and needs no further investigation. Blood sample 
volume requirements and processing procedures will be detailed in a separate laboratory manual; 
the maximum amount of blood taken during the course of the trial will not exceed 3 mL/kg of 
body weight within any 8-week period.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.1.10
Randomization and Trial Supply Management System
The RTSM system will be used to assign patients to treatment arms, manage IMP supply, and to 
provide treatment allocation information in the event of patient unblinding. The RTSM system 
information can be accessed via the eCRF. A member of the trial team must register in the eCRF 
at clinic visits in order to:
x
Obtain a patient number.
x
Randomize a patient.
x
Obtain dispensing information.


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Training will be given to all sites prior to the start of the trial.
9.1.11
Questionnaires and Assessments Completed at Scheduled Visits
Caregiver-completed questionnaires should be completed by an identified main caregiver, 
nominated at Visit 1. The main caregiver should be able to assess the patient based on daily 
contact and be able to attend clinic and video call visits. For both caregiver-completed and 
investigator-completed questionnaires, the same assessors should answer/complete the 
questionnaires/assessments throughout the trial to maintain consistency. Investigators must be 
suitably qualified to perform each assessment/administer each questionnaire. Caregiver 
questionnaires are to be completed electronically at site or at home. Physician 
interviews/assessments are to be completed at site or over a video call. Visit 2 and Visit 8 
assessments should always be completed at site.
If at any point of the trial the main caregiver cannot attend a visit (and this cannot be avoided),
an alternate or backup caregiver may be used. This should only be done if all other options for 
the primary caregiver (i.e., scheduling issues) have been exhausted. The alternative caregiver 
should not complete the 
.
9.1.11.1
Wechsler Abbreviated Scale of Intelligence Scale Second Edition
Patient direct assessment.
An IQ score DWVFUHHQLQJ is required for eligibility, measured using WASI-II within 1 year 
of screening. If a score within 1 year of screening is not available the WASI-II will be conducted 
at the screening visit. The WASI-II provides a brief, reliable measure of cognitive ability suitable 
for individuals ages 6 to 90 years. The 2-subset form will be used. It evaluates Vocabulary and 
Matrix Reasoning and provides an estimate of general cognitive ability.
The WASI-II (2-subset form) will be administered by and experienced and suitable qualified 
assessor
9.1.11.2
Autism Diagnostic Observational Schedule-2
Patient direct assessment.
The ADOS-2 provides an accurate assessment and diagnosis of ASD across all ages, 
developmental levels and language skills. It is a semi-structured assessment of communication, 
social interaction, play, and restricted and repetitive behaviors. It presents various activities that 
elicit behaviors directly related to a diagnosis of ASD. By observing and coding these behaviors, 
the test user can obtain information that informs diagnosis, treatment planning, and educational 
placement. The ADOS-2 consists of 5 modules, each of which is appropriate for children and 


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adults of differing developmental and language levels, ranging from nonverbal to verbally fluent. 
The individual being evaluated is given only one module. The appropriate module is selected and 
administered depending on the individual’s verbal ability. The manual provides guidelines for 
selecting the most appropriate module and general instructions for administration and scoring 
and interpreting an individual’s results. The ADOS-2 must be performed face-to-face without the 
use of face masks, coverings, or shields. The ADOS-2 requires 40 to 60 minutes to administer. 
The ADOS-2 will be administered by an experienced and suitably qualified assessor. (Unless 
records of an ADOS-2 performed at the trial site within 2 years are available, in which case it 
does not need to be carried out at screening). 
9.1.11.3
Vineland Adaptive Behavior Scales, Third Edition
The Vineland-3 measures the personal and social skills of individuals from birth through 
adulthood. Because adaptive behavior refers to an individual’s typical performance of the day-to-
day activities required for personal and social sufficiency, these scales assess what a person does, 
rather than what he or she can do. The Vineland-3 assesses adaptive behavior in 3 domains: 
Communication, Daily Living Skills, and Socialization. Each domain is comprised of 
3 subdomains: receptive expression and written (communication); personal, domestic and 
community (daily living skills); Interpersonal relationships, play and leisure and copying skills 
(socialization). There are several administration formats available. In this trial, the 
comprehensive review form will be used. The interview will be performed by an experienced 
suitably trained assessor. 
9.1.11.4
Aberrant Behavior Checklist
The ABC was designed to assess the presence and severity of various problem behaviors 
commonly observed in individuals diagnosed with intellectual and developmental16. It contains 
items that resolve onto 5 subscales: Irritability (15 items); Social Withdrawal (16 items); 
Stereotypic Behavior (7 items); Hyperactivity/Noncompliance (16 items); and Inappropriate 
Speech (4 items). Each item is scored as 0 (never a problem), 1 (slight problem), 2 (moderately 
serious problem), or 3 (severe problem). 
The ABC will be completed by the caregiver.
9.1.11.5
Clinical Global Impressions Questionnaire
The CGI questionnaire was developed as a clinical trial measure to provide a brief, stand-alone 
assessment of the clinician’s view of the patient’s global functioning prior to and after initiating 
a trial medication18. 


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The CGI questionnaire is split into 2 scales; the CGI-S scale and the CGI-I scale. The CGI-S is a 
7-point scale that requires the clinician to rate the severity of the patient's illness at the time of 
assessment, relative to the clinician’s experience with patients who have the same diagnosis. The 
clinician is asked: Considering your total clinical experience with this particular population, 
how ill is the patient at this time? This is rated as: 1 = normal, not at all ill; 2 = borderline ill; 
3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; or 7 = extremely ill.
The second section, the CGI-I, is a 7-point scale that requires the clinician to assess how much 
the patient’s illness has improved or worsened relative to a baseline state at the beginning of the 
intervention. The clinician is asked: Compared to the patient’s condition at admission to the 
project, how much has the patient changed? This is rated as: 1 = very much improved; 2 = much 
improved; 3 = minimally improved; 4 = no change; 5 = minimally worse; 6 = much worse; or 
7 = very much worse. 
The CGI will be completed by the investigator. 
At Visits 5 and 7 the CGI-I may be performed over a video call. The investigator must ensure, in 
collaboration with the caregiver, that there is sufficient opportunity to observe and assess the 
patient over the video call. The investigator may prompt the caregiver to interact with the child 
to facilitate assessment, to mimic as much as possible a clinic assessment. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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9.1.11.10
Columbia-Suicide Severity Rating Scale
The C-SSRS supports suicide risk assessment through a series of simple, plain-language 
questions which answers help users identify whether someone is at risk for suicide, assess the 
severity and immediacy of that risk, and gauge the level of support that the person needs. It is 
completed as an interview covering whether and when they have thought about suicide 
(ideation), what actions they have taken, and when, to prepare for suicide and whether and when 
they attempted suicide or began a suicide attempt that was either interrupted by another person or 
stopped of their own volition. 
Suicidality will be assessed by using the C-SSRS via interview with the patient or, if the patient 
is not being cooperative, interview with the patient’s caregiver assistance. If the interview is 
carried out with the caregiver this must be recorded and justified in the patient notes. 


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It is expected that some patient may engage in non-suicidal self-harming behavior. Self-harming 
behavior is not per se an exclusion or withdrawal criteria unless it is carried out with suicidal 
intent. However, if an increase in non-suicidal self-harming behavior if observed this should be 
reported and an adverse event and the investigator should consider if it is safe for the patient to 
continue in the trial.
The C-SSRS is to be completed by the investigator or a delegate who has completed the C-SSRS 
training within the past 2 years or has continually administered the C-SSRS assessments 
throughout this trial since obtaining the training certificate.
9.1.12 
Investigational Medicinal Product Accountability
Records of IMP accountability will be maintained according to Section 5.3.4. 
9.1.13
Adverse Events
Any adverse changes in the patient’s medical condition, following completion of the consent 
form by the caregiver, will be recorded on the eCRF as AEs, after questioning the caregiver 
further if necessary. All AEs occurring during the trial, whether attributed to the IMP or not, 
observed by the investigator, or reported by the caregiver, will be recorded in the eCRF. 
Any AE which meets SAE criteria should be reported as a SAE. 
SAEs must be reported to GW PVD within 24 hours of discovery or notification of the event via 
recording in the eCRF. 
Adverse events inferring to hepatic enzymes increased, rash, pneumonia, cognitive disorders and 
self-injurious ideation or intentional self-injury may be considered as AESI by GW PVD and 
additional information may be requested during follow-up. 
Refer to Section 12 for definitions, procedures and further information on AE reporting. 
9.2
Special Circumstances
During special circumstances (e.g., COVID-19 pandemic), the specific guidance from local 
public health and other competent authorities regarding the protection of individuals’ welfare 
must be applied. In cases where patients are not able to perform all protocol-defined assessments 
due to special circumstances, the investigator must discuss with the medical monitor potential 
mitigation approaches. 


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For the duration of such special circumstances, the following measures may be implemented for 
enrolled patients: 
x
Where the ADOS-2 cannot be performed due to site restrictions (e.g., mandatory use of 
face masks), and an ADOS-2 conducted within 2 years at the trial site by a qualified 
assessor is not available, eligibility can be confirmed using: 1) an ADOS-2 performed 
within 2 years by a qualified assessor external to the site; 2) if 1) is not available, eligibility 
may be confirmed using the ADI-Rat screening.
x
Visits or assessments may take place in a different location or by different means (e.g., by 
video call) than defined in the protocol. 
x
Biological samples may be collected and analyzed at a different location than defined in the 
protocol. Biological samples should not be collected if they cannot be processed in a timely 
manner or appropriately stored until shipping/processing. 
x
Where required, in order to collect the biological samples, safety assessments (e.g., ECG, 
vital signs), or efficacy assessments as defined in the protocol, visit windows may be 
extended up to a maximum length of 14 days. 
x
If despite best efforts a safety assessment cannot be performed, the investigator must 
review the benefit-risk for patient continuation in the trial and record this in the medical 
records.
The rationale (e.g., the specific limitation imposed by the special circumstances that led to the 
inability to perform the protocol-specified assessment) and outcome of the discussion with the 
medical monitor will be documented in the medical record. Information on how each visit was 
performed will be recorded in the eCRF.


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10
WITHDRAWAL
In accordance with the Declaration of Helsinki25, the ICH Tripartite Guideline for GCP Topic 
E6(R1)26, the FDA regulations relating to GCP and clinical trials27,28,29, the EU Clinical Trials 
Directive30, the EU Good Clinical Practice/GCP Directive31 and/or other applicable regulations, 
a patient has the right to withdraw from the trial at any time and for any reason, with no 
obligation to provide a reason, and without prejudice to his or her future medical care by the 
physician or at the institution. 
The patient must be withdrawn from the trial if any of the following apply: 
x
Administrative decision by the investigator, GW, or a regulatory authority. 
x
Did not meet eligibility criteria.
x
Pregnancy. 
x
Protocol deviation that is considered to compromise potentially the safety of the patient. 
x
Withdrawal of patient consent/assent. 
x
Withdrawal of parent(s)/legal representative consent. 
x
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%).
x
ALT or AST > 8 × ULN.
x
ALT or AST > 5 × ULN for more than 2 weeks.
x
ALT or AST > 3 × ULN and (TBL > 2 × ULN or INR > 1.5). 
Note: Prior to treatment discontinuation for the transaminase elevations noted above, the 
investigator may choose to confirm the transaminase elevations by repeating the following 
laboratory tests, tests within 24 to 48 hours: ALT, AST, TBL, INR, % eosinophils, gamma-
glutamyl transferase, and alkaline phosphatase. Should the above transaminase elevation 
criteria be confirmed, the patient must be withdrawn from the trial. In cases where 
transaminase elevation withdrawal criteria are not met or confirmed, the dose of IMP or a 
concomitant medication with known hepatotoxicity may be reduced following discussion 
with the medical monitor.
x
Lost to follow-up. 
Patients may also be withdrawn from the trial for any of the following: 
x
Patient non-compliance.
x
AE (including clinically significant laboratory result) which, in the opinion of the 
investigator, would compromise the continued safe participation of the patient in the trial. 
x
Patient cannot tolerate a dose level of 5 mg/kg/day. 
x
Any evidence of use of drugs of abuse or drug diversion. 
x
Suicidal ideation or behavior of type 4 or 5 during the treatment period, as evaluated with 
the C-SSRS. 


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Should a patient request or decide to withdraw from the trial, all efforts must be made to 
complete and report the observations as thoroughly as possible up to the date of withdrawal. 
Patients withdrawing due to an AE should be followed up according to Section 12.7. All 
information should be reported on the applicable CRF pages. A safety follow-up visit should 
take place 14 days after last dose of IMP. If withdrawing patients decline to give a reason for 
withdrawal of consent, the investigator must respect the patient’s wishes.


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11
URGENT SAFETY MEASURES
The sponsor and investigator may take appropriate urgent safety measures in order to protect the 
patients of a clinical trial against any immediate hazard to their health or safety. If such measures 
are taken by the investigator, they must notify GW immediately or at least within 24 hours of 
awareness. GW will report urgent safety measures to regulatory authorities by telephone within 
24 hours of awareness, wherever possible, and will provide a written report to the regulatory 
authorities and IRB/EC within 3 days.


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12
ADVERSE EVENT REPORTING
12.1
Definitions
12.1.1
Adverse Event
For the purposes of this trial an AE is defined as:
Any new unfavorable/unintended signs/symptoms (including abnormal laboratory findings when 
relevant), or diagnosis or worsening of a pre-existing condition, which occurs following 
screening and at any point up to the post-treatment, safety follow-up visit, which may or may not 
be considered to be related to the IMP. Any event that is the result of a trial procedure must be 
recorded as an AE. 
Surgical/Investigational procedures are not AEs. The medical reason for the procedure is the AE. 
Elective hospitalizations for pre-trial existing conditions or elective procedures are not AEs. The 
exception may be if the patient has an AE during hospitalization which prolongs their scheduled 
hospital stay in which case it would be considered a SAE (refer to Section 12.2). 
If reporting a fatal event, the SAE term should be the underlying cause of the death (e.g., disease 
or medical condition leading to death). 
12.1.2
Investigator
The term investigator refers to the trial PI or a formally delegated trial physician. 
12.2
Serious Adverse Events
During clinical investigations, AEs may occur which, if suspected to be IMP-related, might be 
significant enough to lead to important changes in the way the IMP is developed (e.g., change in 
dose, population, monitoring need, consent forms). This is particularly true for events that 
threaten life or function. Such SAEs will be reported promptly to regulatory authorities, 
applicable IRBs/ECs and investigators (expedited reporting) by GW. 
An AE must only be classed as serious, i.e., a SAE, when the event falls into one of the 
following criteria:
x
Results in death. 
x
Is life-threatening*. 
x
Requires inpatient hospitalization or prolongation of existing hospitalization. 
x
Results in persistent or significant disability/incapacity. 
x
Is a congenital anomaly/birth defect. 
x
Is medically significant**. 


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*The term “life-threatening” in the definition of “serious” refers to an event in which the patient
was at risk of death at the time of the event; it does not refer to an event which, hypothetically,
might have caused death if it were more severe.
**Medical and scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations. Important medical events may not be immediately life-threatening 
or result in death or hospitalization but may jeopardize the patient or may require intervention to 
prevent one of the other outcomes listed in the definition above. These should also usually be 
considered serious. Examples of such events are intensive treatment in an emergency room or at 
home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalization, development of drug dependency or drug abuse, or positive COVID-19 test.
12.3
Reporting Procedures for Serious Adverse Events
All SAEs occurring during the trial must be reported to GW with any other supporting 
information and recorded in the AE section of the eCRF. Any ongoing SAEs should be followed 
up until resolution wherever possible. For all deaths, the working diagnosis or cause of death as 
stated on a death certificate, available autopsy reports and relevant medical reports should be 
sent to GW promptly.
All SAEs must be recorded in the eCRF within 24 hours of discovery or notification of the 
event. GW PVD will be automatically notified that an SAE has been recorded. Any additional 
information required for a case (follow-up or corrections to the original case) will be requested 
by GW PVD through eCRF queries.
The investigator should continue to document all AEs which occur up to the last formal 
follow-up observational period. If the investigator subsequently becomes aware of any deaths or 
a new IMP-related SAE after the last formal follow-up period of the trial, these should still be 
reported to the GW PVD.
Any other problem discovered after the follow-up visit which is deemed to be an unexpected 
safety issue and is likely to have an impact on patients who have taken part in the trial must be 
treated as an SAE and reported to the GW PVD. Such post-trial SAEs do not need to be recorded 
on the patient’s eCRF if editing rights to the eCRF have been removed due to final trial data 
lock. GW PVD may request safety follow-up information after the final trial visit in order to 
investigate a potential safety issue.
Contact details for the GW PVD are provided at the front of the center files for all trial centers.


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12.4
Pregnancy
Any patient, or patient’s partner, who becomes pregnant while receiving the IMP, or within 
90 days of the last dose of IMP, must be reported to the GW PVD using the GW Pregnancy 
Monitoring forms provided. Where possible, the investigator should provide the outcome of the 
pregnancy. All pregnancies must be recorded in the eCRF within 24 hours of becoming aware. 
The GW PVD will be automatically notified that a pregnancy has been recorded. Any additional 
information required for a case (follow-up or corrections to the original case) will be requested 
by GW PVD through eCRF queries where data is entered in EDC. The investigator is not obliged 
to actively monitor for any pregnancies that commence more than 90 days after the final dose of 
IMP. However, if the investigator becomes aware of a new pregnancy outside this time limit, 
then he/she should report it as above. The GW PVD will follow-up for all pregnancy outcomes.
12.5
Causality Assessment
Causality assessment is required for all AEs and SAEs. Causality assessment must only be 
assigned by the investigator. All cases judged as having a reasonable suspected causal 
relationship to the IMP must be reported as such. The expression “reasonable causal 
relationship” is meant to convey in general that there are facts (evidence) or arguments to 
suggest a causal relationship.
The following question which must be answered by the investigator for all AEs is used to capture 
the reasonable causal relationship of an event to the IMP:
“In your opinion is there a plausible relationship to the IMP?” The answer is either “yes” or
“no”.
Events that start before the first dose of IMP (pre-treatment) should be considered as not causally 
related. Where a pre-treatment event worsens in severity following the first dose of IMP, a new 
event record should be entered into the eCRF.
Considering the explanation given above, investigators are strongly encouraged to express their 
opinion on what the cause of an AE might be. For individual patients, the investigator is usually 
in the best position to assess the underlying suspected cause of an AE. For all AEs and especially
SAEs, it is important that the investigator assess not only the possible role of the IMP but also 
other potential contributing factors. Factors for consideration of the underlying cause may 
include:


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x
Medical and disease history.
x
Lack of efficacy/worsening of treated condition.
x
Concomitant or previous treatment.
x
Withdrawal of IMP.
x
Protocol-related procedure.
12.6
Reporting Procedures for All Adverse Events
All AEs (including SAEs) occurring during the trial will be reported on the running logs in the 
AE section of the eCRF. This includes all events from the time following screening up to and 
including the post-trial follow-up visit, whether or not attributed to IMP and observed by the 
investigator or patient.
The following information will need to be provided for all AEs:
A)
Adverse Event (Diagnosis or Syndrome if Known, or Signs and Symptoms)
Where the investigator cannot determine a diagnosis, signs or symptoms should be recorded in 
the AE section of the eCRF. Once a diagnosis has been determined the AE section of eCRF must 
be updated to reflect the diagnosis in replacement of the original symptoms. In circumstances 
where only a provisional diagnosis is possible (working diagnosis), the eCRF must be updated to 
reflect the provisional diagnosis in replacement of the original symptoms. In some circumstances 
it may be relevant for the investigator to include the symptoms alongside the diagnosis in the 
verbatim event description. However, the diagnosis (full or provisional) should be clearly stated,
e.g., fever and malaise due to respiratory tract infection.
B)
Adverse Event Start Date and Stop Date
The start and stop dates of the event must be provided. All AEs require these fields to be 
completed in full. Partial dates or missing dates are not normally acceptable and significant effort 
must be undertaken to obtain any unknown information. If a precise date is not known an 
estimated date should be provided instead. When a complete date cannot be given, record as 
much information as possible (i.e., month and year or, in exceptional circumstances, just year). 
When the actual start date becomes known the eCRF must be updated to replace the previously 
recorded date.


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C)
Outcome
The outcome of the event must be recorded accurately and classified into one for the following 
categories:
x
Recovered/Resolved. 
x
Recovered/Resolved with Sequelae. 
x
Not Recovered/Not Resolved. 
x
Fatal. 
D)
Severity
When describing the severity of an AE the terms mild, moderate, or severe should be used. 
Clinical judgment should be used when determining which severity applies to any AE. 
If the severity of an AE fluctuates day-to-day, e.g., a headache or constipation, the change in 
severity should not be recorded each time; instead, only the worst observed severity should be 
recorded with AE start and stop dates relating to the overall event duration, regardless of 
severity. 
A severe AE is not the same as a SAE. For example, a patient may have severe vomiting, but the 
event does not result in any of the SAE criteria above. Therefore, it should not be classed as 
serious. 
The severity of an AE will be recorded as one of the following: 
x
Mild: easily tolerated, does not interfere with normal daily activities, does not require 
intervention. 
x
Moderate: causes some interference with daily activities; minimal, local or non-invasive 
intervention indicated. 
x
Severe: daily activities limited or completely halted; intervention indicated.
E)
Causality
See Section 12.6 above. 
F)
Action Taken with Trial Medication
This question refers to the action taken with the IMP due to an AE. The action with the IMP 
must be classed as:
x
Dose Not Changed. 
x
Dose Reduced. 
x
Drug Interrupted. 
x
Drug Withdrawn. 


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12.7
Follow-up Procedures for Adverse Events
The investigator may be asked to provide follow-up information to the GW PVD for any AEs 
reported or during the investigation of potential safety issues. Such requests for additional safety 
information may occur after a patient has finished a trial. 
Additional information may also be requested by GW PVD if a patient experiences any adverse 
events that is considered an AESI, these include any events that may infer to hepatic enzymes 
increased, rash, pneumonia, cognitive disorders and self-injurious ideation or intentional self-
injury. 
AEs considered related to the IMP by the investigator or the sponsor should be followed up until 
resolution or the event is considered stable. 
It will be left to the investigator’s clinical judgment whether an AE is of sufficient severity to 
require the patient’s removal from treatment. A patient may also voluntarily withdraw from 
treatment due to what he or she perceives as an intolerable AE. Further details of withdrawal are 
presented in Section 10. If either of these occurs, the patient must undergo an end of treatment 
assessment and be given appropriate care under medical supervision until symptoms cease or the 
condition becomes stable. If a safety concern is identified following withdrawal of a patient, GW 
may contact the investigator for additional follow-up information. 
12.8
Potential Cases of Drug-Induced Liver Injury
All investigational centers are required to submit to the GW PVD the laboratory results for any 
patient after randomization that meets the criteria for the selected laboratory parameters as 
follows: 
x
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%).
x
ALT or AST > 8 × ULN.
x
ALT or AST > 5 × ULN for more than 2 weeks.
x
ALT or AST > 3 × ULN and (TBL > 2 × ULN or INR > 1.5). 
These reports must be sent to the GW PVD via email for SAE reporting (see APPENDIX 2) 
within 24 hours of becoming aware of the results. In addition, please send a copy of the patient’s 
baseline laboratory results with all reports to the GW PVD.
Abnormal values in AST and/or ALT concurrent with abnormal elevations in TBL that meet the 
criteria outlined above are considered potential cases of drug-induced liver injury and will be 
considered as protocol-defined criteria for withdrawal and important medical events. The 
investigator will arrange for the patient to return to the investigational center as soon as possible 


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(within 24 hours of notice of abnormal results) for repeat assessment of ALT, AST, TBL, 
alkaline phosphatase and gamma-glutamyl transferase levels, detailed history and physical 
examination; patients should be followed in this way until all abnormalities have normalized (in 
the investigator’s opinion) or returned to the baseline state. 
Elevations in ALT or AST > 3 × ULN or TBL > 2 × ULN alone are not considered potential 
cases of drug-induced liver injury, but will be followed as detailed above, within 72 hours’ 
notice of abnormal results. If the patient cannot return to the investigational center, repeat 
assessments may be done at a local laboratory and the results sent to GW PVD. 
12.9
Notification of Safety Information to Investigators, Regulatory Authorities 
and IRBs/ECs
In accordance with the EU Clinical Trials Directive30, relevant parts of the FDA Code of Federal 
Regulations32 and any national regulations, GW will inform investigators, regulatory authorities 
and relevant IRBs/ECs of all relevant safety information. This will include the reporting of 
relevant SAEs and all SUSARs. 
This information will be provided through 3 sources: 
1) IB6: a compilation of the clinical and nonclinical safety data available on the IMP that is 
relevant to the trial. The IB is updated annually or when important new safety 
information becomes available. 
2) Development core safety information: this document forms the safety section of the IB6, 
or is updated as an addendum to the IB6. This document is revised if necessary, when 
new important safety information becomes available (potentially up to a few times a 
year).
3) CIOMS reports: these reports are issued every time a SUSAR is reported to GW. They 
provide information on individual case reports and are sent to all the regulatory 
authorities, the relevant central ECs which have approved the trial and investigators. As 
required, the investigator should notify their regional IRBs/ECs of SAEs or SUSARs
occurring at their center and other AE reports, i.e., CIOMS reports and any additional 
safety documentation received from GW, in accordance with local procedures.
In the USA, investigators are normally required to report promptly to their IRBs/ECs all 
unanticipated problems involving risks to patients, or others, including AEs that should be 
considered unanticipated problems. Based on current FDA guidance28 the following clarification 
is provided in determining what constitutes an unanticipated problem: 
In general, an AE observed during the conduct of a trial should be considered an unanticipated 
problem involving risk to patients and reported to the IRB/EC, only if it were unexpected, 
serious, and would have implications for the conduct of the trial (e.g., requiring a significant, and 


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usually safety-related, change in the protocol such as revising inclusion/exclusion criteria or 
including a new monitoring requirement, informed consent, or IB). An individual AE occurrence 
ordinarily does not meet these criteria because, as an isolated event, its implications for the trial
cannot be understood. 
The FDA guidance32 states that, accordingly, to satisfy the investigator’s obligation to notify the 
IRB/EC of unanticipated problems, any investigators participating in a multicenter trial may rely 
on the sponsor’s assessment and provide to the IRB/EC a report of the unanticipated problem 
prepared by the sponsor. 
GW will inform investigators, regulatory authorities and relevant IRBs/ECs of any safety issues 
or case reports that are considered to be unanticipated and provide such reports as mentioned 
above. It should be noted that a single SUSAR report notified to investigators in the trial does not 
necessarily constitute an unanticipated problem unless identified by GW in the submission cover 
letter.
As a minimum, the recipient will be sent all of the above and relevant updates between the 
period from ethical approval and final database lock. 


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13
STATISTICAL CONSIDERATIONS
Further details of the proposed statistical analysis will be documented in SAP, which will be 
finalized prior to unblinding of the trial. Any deviations from the original SAP will be described 
in the final clinical study report.
13.1
Sample Size, Power and Significance Levels
Approximately 160 patients will be randomized to receive GWP42003-P or matching volume of 
placebo on a 1:1 basis. 
This is an exploratory trial with interest in multiple efficacy endpoints therefore, a formal power 
calculation was not performed, however a sample size was informed by data available in the 
literature for the 2 measures with the highest level of validation, VABS15 and ABC-I33.
Assuming a common standard deviation for data of 8.46 and using a 2-sided hypothesis test at a 
Į-level, a total sample size of 160 patients randomized to allow for 144 evaluable patients 
(72 patients per arm) at trial end will provide 80% power to detect a significant result assuming a 
WUXHWUHDWPHQWGLIIHUHQFHRIௗSRLQWVIRUWKH9$%6-3 score in change from baseline to end of 
treatment between GWP42003-P and placebo. Allowing for a 10% drop-out rate, a minimum of 
160 patients need to be randomized into the trial. Depending on the drop-out rate during the trial, 
this number may be increased to ensure a minimum of 144 evaluable patients at Week 12.
The size of this trial is more than enough to ensure > 99% power on the ABC-I scale assuming a 
common standard deviation for data of 8.27 with a true treatment difference in change from 
baseline to end of treatment between GWP42003-P and placebo of -8.26 and using a 2-sided 
K\SRWKHVLVWHVWDWDĮ-level. As this is an exploratory trial, no adjustments for the type I error 
were considered for these calculations. 
13.2
Interim Analysis
Interim evaluations for futility and superiority may be performed as part of DMC operations (see 
Section 14).   
Bayesian analysis of the key variables of interest may be performed to evaluate the probability 
that GWP42003-P is different than placebo. Details of the evaluation criteria will be provided in 
a separate Statistical Analysis or Simulation plan. 


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13.3
Analysis Sets
The following analysis sets will be used for the statistical analysis:
Full Analysis Set
All patients who are randomized and receive at least 1 dose of IMP in the trial will be 
included and analyzed according to their randomized treatment arm.
The FAS is the primary analysis set for all efficacy endpoints.
Safety Analysis Set
All patients who receive at least 1 dose of IMP in the trial will be included and analyzed 
according to the treatment received. Only patients for whom it has been confirmed that they 
did not take any IMP will be excluded from this safety analysis set. This analysis set will be 
used to report the safety data.
Per Protocol Analysis Set
If there are a sufficient number of significant protocol deviations in the trial, a PP analysis set 
may also be presented. The PP set is defined as:
All patients that are a subset of the FAS who have no major protocol deviations deemed to 
compromise the assessment of efficacy. Major protocol deviations will be identified and fully 
defined prior to unblinding of the trial. The PP analyses will only be conducted on efficacy 
endpoints.
Analysis sets will be identified prior to the unblinding of the trial data.
13.3.1
Protocol Deviations
Protocol deviations will be listed and reasons for exclusion from the analysis sets (for major 
protocol deviations) will be summarized.
13.4
General Considerations
Unless stated otherwise, continuous variables will be summarized showing the number of non-
missing values (n), mean, SD, median, minimum and maximum and categorical variables will be 
summarized showing the number and percentage of patients falling in each category. Unless 
otherwise specified, tables will be summarized by randomized treatment group.
For clinic visit-based endpoints (unless otherwise specified), baseline is defined as the last record 
or measure collected prior to the first dose of IMP in the treatment period.


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13.5
Accountability and Background Characteristics
13.5.1
Enrollment and Disposition
All patients (screened, randomized, withdrawn, etc.) will be accounted for in the enrollment and 
disposition summary tables.
13.5.2
Baseline and Demographic Characteristics
Age, sex, race, and ethnicity (as per local data protection laws in each specific country) and any
other demographic or baseline characteristics will be summarized by treatment arm, using 
appropriate summary statistics.
There will be no formal comparison of baseline data; that is, no statistical hypothesis testing.
13.5.3
Medical History
Previous and current medical conditions (including details of ASD history) will be summarized 
by SOC by treatment arm.
13.5.4
Concomitant Medication
Concomitant medications taken prior to and during the trial will be summarized separately by 
treatment arm, medication class, and active ingredients. Non-pharmacologic therapies and 
therapeutic diets will be summarized by treatment arm.
13.6
Endpoints and Statistical Methods
Statistical hypothesis testing will be performed on the efficacy and exploratory endpoints as 
appropriate with no inferential statistical decision drawn as this is an exploratory trial. For each 
endpoint, GWP42003-P will be compared against placebo.
All safety data will be summarized using appropriate statistical methods.
13.6.1
Efficacy Endpoints
13.6.1.1
VABS-3
The VABS-3 social and communication composite (arithmetic mean of the social and 
communication domain scores), the adaptive behavior composite, and individual domain scores 
will be analyzed. The VABS social and communication composite score is a key interest.
The change from baseline in social and communication composite score for VABS-3 will be 
summarized by treatment arm and visit.


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The change from baseline in social and communication composite score for VABS-3 will be 
analyzed in the final analysis using an MMRM model. The corresponding model will include 
randomization stratification factors, baseline composite score, visit, treatment arm, visit by 
treatment arm interaction as fixed effects, and visit repeated within each patient as a repeated 
effect. An unstructured covariance matrix will be used to estimate the variance-covariance 
structure within patients across time points. If convergence is not obtained, then other covariance 
structures to be used will be specified in the SAP. Objective criteria for assessing normality 
assumptions and proposed alternative analyses will be specified in the SAP. 
A Bayesian evaluation will also be carried out on the final data (see also Section 13.2).
From this analysis the LS mean estimates for each treatment arm at each visit, along with the 
standard error and 95% CIs will be presented separately. In addition, estimates of the treatment 
difference at each visit will be presented along with standard errors of the difference and 95% 
CIs. The main comparison of interest is the estimate of the treatment difference at Week 12. 
The change from baseline in adaptive behavior composite score and for each individual domain 
will be summarized and analyzed as described above for the social and communication 
composite score.
13.6.1.2
ABC
All ABC subscales will be analyzed. The ABC-I subscale is of key interest.
ABC-I subscale scores will be summarized by treatment arm and visit together with the 
corresponding change from baseline scores.
The change from baseline in ABC-I scores will be analyzed separately using a similar model as 
the one described for the social and communications composite endpoint. 
The other ABC subscales will be summarized and analyzed as described for the ABC-I subscale. 
13.6.1.3
CGI-I and CGI-S 
Counts and proportion of patients within each category for the CGI-I and CGI-S scores will be 
produced separately by treatment arm and visit. These data will be analyzed separately using a 
GEE model approach. The model will include CGI-I as the dependent variable, with treatment 
arm and stratification factors as fixed effects and baseline response as a covariate. The model 
will also include a repeated statement that allows to model the correlation of the dependent 
variable at different time points. A similar model will be fitted to the CGI-S data.
Proportion of patients at Week 12 ‘minimally’, ‘much’ or ‘very much’ improved, as well as 
‘much’ or ‘very much’ improved, on the CGI-I score will be summarized by treatment arm and 


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will be analyzed using a logistic regression model with responder (improved/not improved) as 
the dependent variable, with treatment arm and stratification factors as fixed effects and baseline 
response as a covariate. The associated odds ratios together with the corresponding 95% CIs and 
p-values will be presented.
 
 
 
 
 
 
 
 
 
 
 
 


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13.6.3
Safety
The following safety endpoints are used to support the safety objective and will be evaluated 
based on SAS®. For each endpoint, GWP42003-P will be compared with placebo as described in 
the following sections:
x
AEs.
x
Clinical laboratory parameters.
x
Vital signs.
x
Physical examination procedures.
x
12-lead ECG.
x
C-SSRS.
All safety endpoints will be summarized by treatment received using appropriate statistical 
methods.
13.6.3.1
Treatment Compliance and Extent of Treatment Exposure
Treatment compliance and exposure to treatment will be summarized.
13.6.3.2
Adverse Events
AEs will be coded according to the Medical Dictionary for Regulatory Activities dictionary.
A TEAE is one that started, or worsened in severity or seriousness, following the first dose of 
IMP.
Descriptive presentations of TEAEs will be given by preferred term and SOC for the safety 
analysis set. The number of patients reporting at least 1 TEAE will be provided. AEs will be 
summarized in terms of the number of patients with at least 1 event (N) and the percentage of 
patients with at least 1 event (%).
The following summaries will be produced as a minimum:
x
All-causality TEAEs.
x
Treatment-related AEs.
x
All-causality TEAEs by maximal severity.
x
All-causality serious TEAEs.
x
Treatment-related serious TEAEs.
x
TEAEs reported as leading to permanent cessation of IMP.
x
Fatal TEAEs.


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13.6.3.3
Clinical Laboratory Data
Clinical laboratory data will be summarized at screening, baseline, and at each time point during 
the treatment period using appropriate summary statistics. Categorical shift tables will be 
presented, showing the numbers of patients with values outside the normal range. Change from 
baseline will also be summarized by visit.
13.6.3.4
Vital Signs, 12-Lead Electrocardiogram, Physical Examination and 
Other Safety Data
Vital signs, ECG, physical examination data will be summarized for the safety analysis set, at 
screening, baseline and at each time point during the treatment period using appropriate 
summary statistics. Changes in the vital signs from baseline to end of treatment will also be 
summarized.


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14
DATA MONITORING COMMITTEE
A Data Monitoring Committee will be setup for ongoing unblinded data review. The DMC will 
not include any members of the study team. Operations and constitution of the DMC will be 
detailed in a separate charter.


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15
REGULATORY AND ETHICAL OBLIGATIONS
15.1
Declaration of Helsinki
The investigator will ensure that this trial is conducted in full conformity with the current version 
and subsequent amendments of the Declaration of Helsinki34, the ICH Tripartite Guideline for 
GCP Topic E6(R1)26, the EU Clinical Trials Directive30, the EU GCP Directive31 and the 
clinical trial regulations adopting European Commission Directives into national 
legislation35,36,37,38. 
15.2
Informed Consent
An initial generic ICF/Initial master informed consent/assent forms will be prepared by GW or 
delegate and provided to the investigator, who will tailor this for their center by adding the 
center’s contact details and by using headed paper. The clinical manager or delegate will 
communicate updates to the template by letter. The written informed consent/assent documents 
should be prepared in the language(s) of the potential patient population. 
Before a patient’s involvement in the trial, the investigator is responsible for obtaining written 
informed consent/assent (if allowed per local regulations and if applicable) from the patient
along with written parent(s)/legal representative consent after adequate explanation of the aims, 
methods, anticipated benefits and potential hazards of the trial and before any trial-specific 
procedures are performed or any patient-related data are recorded for the trial. The patient and/or 
parent(s)/legal representative must have ample time to consider the information provided before 
giving written consent. More specific definitions of ‘ample time’ may be in force if required by 
IRBs/ECs or local regulations. 
The acquisition of informed consent/assent must be documented in the patient’s medical records 
and the ICF must be signed and personally dated by the patient and/or parent(s)/legal 
representative (as applicable) and by the person who conducted the informed consent/assent
discussion. The original signed ICF/assent should be retained and a copy provided to the patient
and/or parent(s)/legal representative. 
15.3
Institutional Review Board/Independent Ethics Committee
A copy of the protocol, proposed ICF, master ICF, other patient information material, any 
proposed advertising material and any further documentation requested must be submitted to the
IRB/EC for written approval. GW must receive a copy of the written approval of the appropriate 
version of the protocol and ICF before recruitment of patients into the trial and shipment of IMP. 


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The investigator must submit and, where necessary, obtain approval from the IRB/EC for all 
subsequent protocol amendments and changes to the informed consent document. The 
investigator must notify the IRB/EC of deviations from the protocol, SAEs occurring at the 
center and other AE reports received from GW, in accordance with local procedures.
The investigator will be responsible for obtaining annual/ongoing IRB/EC approval/renewal 
throughout the duration of the trial. Copies of the investigator’s reports and the IRB/EC
continuance of approval must be sent to GW. 
15.4
Pre-trial Documentation Requirements
The investigator is responsible for forwarding the following documents to GW for review before 
allowing any patients to consent for entry into the trial: 
x Signed and dated protocol signature page. 
x Copy of IRB/EC-approved ICF (including version number and date) and other patient
information material.
x Copy of the IRB/EC approval of the protocol, ICF forms (including version number and 
date) and other patient information material.
x Up to date curricula vitae and medical licenses (as per local regulations) of the PI and all 
sub-investigators.
x The IRB/EC composition and/or written statement of the IRB/EC in compliance with the 
FDA regulations relating to GCP and clinical trials27,28,29,39, the EU Clinical Trials 
Directive30, the EU GCP Directive31, or the ICH Tripartite Guidelines for GCP Topic 
E6(R1)20 where the EU Clinical Trials and GCP Directives do not apply. 
x Signed and dated laboratory normal ranges and documentation of laboratory certification 
(or equivalent) unless using central laboratory arranged by GW. 
x Signed and dated clinical trial agreement (including investigator indemnity insurance and 
financial agreement).
x Form FDA 1572 or equivalent, if required. 
x Completed financial disclosure statements for the PI and all sub-investigators, if relevant.
GW will ensure that the center is informed of when screening of patients can commence. 
15.5
Patient Confidentiality
The investigator must ensure that the patient’s anonymity is maintained. In the eCRFs or other 
documents submitted to GW, patients should be identified by their patient number and their trial
screening number only. Documents that are not for submission to GW, e.g., signed ICF, should 
be kept in strict confidence by the investigator. 


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In compliance with the FDA regulations relating to GCP and clinical trials27,28,29,39 and the EU 
Clinical Trials Directive30/ICH Tripartite Guidelines for GCP Topic E6(R1)26, it is required that 
the investigator and institution permit authorized representatives of the company, the regulatory 
authorities and the IRB/EC have direct access to review the patient’s original medical records for 
verification of trial-related procedures and data. Direct access includes examining, analyzing, 
verifying and reproducing any records and reports that are important to the evaluation of the trial. 
The investigator is obligated to inform the patient that his/her trial-related records will be 
reviewed by the above-named representatives without violating the confidentiality of the patient. 
All information concerning the IMP and operations of GW such as patent applications, formulae, 
manufacturing processes, basic scientific data or formulation information supplied to the 
investigator by the company and not previously published is considered confidential by the 
company and shall remain the sole property of the company. The investigator will agree to use 
this information only in accomplishing the trial and will not use it for any other purposes without 
the written consent of the company. 


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16
ADMINISTRATIVE AND LEGAL OBLIGATIONS
16.1
Protocol Amendments and End of Trial or Termination
Protocol amendments must be made only with the prior approval of GW. Agreement from the 
investigator must be obtained for all protocol amendments and amendments to the informed 
consent document. The IRB/EC and regulatory authorities must be informed of all amendments 
and give approval for any substantial amendments. Amendments for administrational changes 
can be submitted to the IRB/EC for information only. The investigator must send a copy of the 
approval letter from the IRB/EC to GW.
Both GW and the investigator reserve the right to terminate the trial, according to the clinical 
trial agreement. The investigator must notify the IRB/EC in writing of the trial’s completion or 
early termination and send a copy of the notification to GW. 
16.2
Trial Documentation and Storage
The investigator must maintain a list of appropriately qualified persons to whom he/she has 
delegated trial duties. All persons authorized to make entries in and/or corrections to CRFs will 
be included on the delegation log. 
Source documents are original documents, data and records containing all protocol-specified 
information from which the patient’s CRF data are obtained. These include, but are not limited 
to, hospital records, clinical and office charts, laboratory and pharmacy records, diaries, 
microfiches, radiographs and correspondence. The source for each data point will be agreed with 
each center prior to patient recruitment. In the rare situations of data being recorded directly into 
the CRF in error, then the source data from the CRF should be transcribed into the patient’s notes 
with appropriate signature and date to provide a full audit trail. 
The investigator and trial staff are responsible for maintaining a comprehensive and centralized
filing system of all trial-related, essential documentation (as outlined in the ICH Tripartite 
Guidelines for GCP Topic R6[R1]26, Section 8.2), suitable for inspection at any time by 
representatives from GW and/or applicable regulatory authorities. Elements should include: 
x
Patient files containing completed CRFs, ICF forms and supporting copies of source 
documentation. 
x
Trial files containing the protocol with all amendments, IB, copies of pre-trial
documentation (see Section 15.4) and all correspondence to and from the IRB/EC and GW.
x
Enrollment log of all patients who consented to take part in the trial. 
x
Screening and recruitment log of all patients screened and whether or not they were 
recruited into the trial (i.e., randomized and/or dosed with IMP). 


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x
Proof of receipt, IMP accountability record, return of IMP for destruction, final IMP
reconciliation statement and all drug-related correspondence.
In addition, all original source documents supporting entries in the eCRFs, and diary data must 
be maintained and be readily available.
Following completion or termination of a clinical trial, GW will initiate proper archive of clinical 
trial-related documentation and electronic records generated by the investigator and/or GW. All 
clinical trial-related documents and electronic records will be retained within an archiving 
system for a period dependent upon need and for a minimum of 25 years. Essential documents 
must be retained until at least 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 IMP. These documents must be retained for a longer period, however, if required by the 
applicable regulatory requirements31 or if needed by GW. 
GW will inform the investigators for each center in writing of the need for record retention. No 
trial document may be destroyed without prior written agreement between GW and the 
investigator. Should the investigator wish to assign the trial records to another party or move 
them to another location, he/she must notify GW in writing of the new responsible person and/or 
the new location. 
16.3
Trial Monitoring and Data Collection
The GW representative and regulatory authority inspectors are responsible for contacting and 
visiting the investigator for the purpose of inspecting the facilities and, upon request, inspecting 
the various records of the trial, e.g., CRFs and other pertinent data, provided that patient
confidentiality is respected.
The GW trial monitor, or designee, is responsible for inspecting (on site or remotely) the CRFs 
and available diary data at regular intervals throughout the trial to verify adherence to the 
protocol, completeness, accuracy and consistency of the data and adherence to local regulations 
on the conduct of clinical research. The trial monitor must have (direct or remote) access to 
patient medical records and other trial-related records needed to verify the entries on the CRFs. 
The investigator agrees to cooperate with the trial monitor to ensure that any problems detected 
in the course of these monitoring visits are resolved. 
To ensure the quality of clinical data across all patients and centers, a clinical data management 
review will be performed on patient data received at GW or a CRO. During this review, patient
data will be checked for consistency, omissions and any apparent discrepancies. In addition, the 
data will be reviewed for adherence to the protocol and FDA regulations27,28,29,39, ICH Tripartite 


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Guidelines for GCP Topic E6(R1)26 and all other applicable regulatory requirements. To resolve 
any questions arising from the clinical data management review process, data queries and/or 
center notifications will be sent to the center for completion and then returned to GW or the 
CRO, as applicable. 
16.4
Quality Assurance
In accordance with the FDA regulations27,28,29, EU Clinical Trials Directive30/ICH Tripartite 
Guidelines for GCP Topic E6(R1)26 and the sponsor’s audit plans, representatives from GW’s 
Clinical Quality Assurance Department may select this trial for audit. Inspection of center
facilities, e.g., pharmacy, drug storage areas, laboratories, and review of trial-related records will 
occur to evaluate the trial conduct and compliance with the protocol, the EU Clinical Trials 
Directive30/ICH Tripartite Guidelines for GCP Topic E6(R1)26 and applicable regulatory 
requirements.
16.5
Compensation
GW will indemnify the investigator and the trial center in the event of any claim in respect of 
personal injury arising due to a patient’s involvement in the trial, providing that the trial protocol 
has been adhered to. This would include claims arising out of or relating to the administration of 
the IMP or any clinical intervention or procedure provided for or required by the protocol to 
which the clinical trial patient would not otherwise have been exposed, providing there is no 
evidence of negligence on behalf of the investigator or their team. GW will not be liable for any 
claims arising from negligence on the part of the investigator or their team.
16.6
Publication Policy
GW recognizes that there is a responsibility under the regulatory guidelines to ensure that results 
of scientific interest arising from this clinical trial are appropriately published and disseminated. 
They will coordinate this dissemination and may solicit input and assistance from the 
chief/principal investigators. A summary of the results of this trial will be made available on 
http://www.clinicaltrials.gov and http://www.clinicaltrialsregister.eu/ (as applicable), as required 
by US and EU Law.
The raw data from this trial may be obtained by the PIs or by their steering committee 
representatives on request. Should they wish, PIs are allowed to conduct their own analyses and 
are permitted to present such information along with methods and results of the clinical trial at 
symposia, national or regional professional meetings and to publish it in theses or dissertations. 


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All publications, e.g., manuscripts, abstracts, oral/slide presentations or book chapters based on 
this trial, must be submitted to the GW Medical Affairs Department and, as applicable, GW 
Publication Committee for corporate review before release. To ensure adequate time for GW to 
make comments and suggestions where pertinent, all such material should be submitted to them 
at least 60 days prior to the date for submission for publication, public dissemination, or review 
by a publication committee. The PIs must then incorporate all reasonable comments made by 
GW into the publication.
GW also reserves the right to delay the submission of such information by a period of up to 
6 months from the date of first submission to them in order to allow them to take steps to protect 
proprietary information where applicable.
16.7
Intellectual Property Rights
All intellectual property rights owned by or licensed to either GW or the PIs, other than those 
arising from the clinical trial, will remain their property. All intellectual property rights arising 
out of the clinical trial will vest in or be exclusively licensed to GW and, as such, the PI must 
promptly disclose all knowledge to GW and refrain from using such knowledge without the prior 
written consent of GW.
16.8
Confidential Information
GW and the PI must ensure that only personnel directly concerned with the trial are party to 
confidential information and that any information coming to either party about the other during 
the course of the trial must be kept strictly confidential and must not be disclosed to any third 
party or made use of without the prior written consent of the other.


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REFERENCES
1
Maenner MJ, Shaw KA, Baio J, et al. Prevalence of Autism Spectrum Disorder Among 
Children Aged 8 Years - Autism and Developmental Disabilities Monitoring Network, 11 
Sites, United States, 2016. MMWR Surveill Summ 2020; 69 (4): 1–12.
2
Lai MC, Lombardo MV, Baron-Cohen S. Autism. Lancet, 2014;383:896-910.
3
Howes OD, Rogdaki M, Findon JL, et al. Autism Spectrum Disorder: consensus guidelines 
on assessment, treatment and research from the British Association for Psychopharmacology. 
J Psychopharmacol. 2018 January;32(1):3–29. doi:10.1177/0269881117741766.
4
Sharma SR, Gonda X, Tarazi FI. Autism Spectrum Disorder: Classification, diagnosis and 
therapy. Pharma Thera. 2018;190:91–104.
5
dos Santos RG, Hallak JEC, Leite JP, Zuardi AW, Crippa JAS. Phytocannabinoids and 
epilepsy. J Clin Pharm Ther 2015;40(2):135–43.
6
Investigator’s Brochure — CBD medicine. GW Research Ltd. Edition 12.1. October 2019.
7
Ibeas Bih C, Chen T, Nunn A, Bazelot M, Dallas M, Whalley B. Molecular Targets of 
Cannabidiol in Neurological Disorders. Neurotherapeutics. 2015;12(4):699-730.
8
Turner SE, Williams CM, Iversen L, Whalley BJ.  Molecular pharmacology of 
phytocannabinoids. Prog Chem Org Nat Prod. 2017; 103: 61–101
9
Aran A, Cassuto H, Lubotzky A, Wattad N, Hazan E. Brief Report: Cannabidiol-rich 
cannabis in children with autism spectrum disorder and severe behavioral problems—a 
retrospective feasibility study. 2018; J Autism Dev Disord; https://doi.org/10.1007/s10803-
018-3808-2
10 Barchel D,  Stolar O, De-Haan T, et al. Oral cannabidiol use in children with autism
spectrum disorder to treat related symptoms and co-morbidities. 2019; Front. Pharmacol. 
9:1521.
11 Bar-Lev Schleider L, Mechoulam R, Saban N, et al. Real life experience of medical cannabis 
treatment in autism: analysis of safety and efficacy. www.nature.com/Scientific Reports. 
2019; 9:200 DOI:10.1038/s41598-018-37570-y.
12 Kurz R and Blaas K. Use of dronabinol (delta-9-THC) in autism: A prospective single-case-
study with an early infantile autistic child. Cannabinoids 2010;5(4):4–6.
13 Arseneault L, Cannon M, Poulton R, et al., Cannabis use in adolescence and risk for adult 
psychosis: longitudinal prospective study, BMJ. 2002; 325(7374):1212–3.
14 Anagnostou E, Jones N, Huerta M, et al. Measuring social communication behaviors as a 
treatment endpoint in individuals with autism spectrum disorder. Autism, 2015; 19(5) 622–
36.
15 Bolognani F, del Valle Rubido M, Squassante L, et al. A phase 2 clinical trial of a 
vasopressin V1a receptor antagonist shows improved adaptive behaviors in men with autism 
spectrum disorder. Sci. Transl. Med., 2019;11: eaat7838.
16 Aman  MG and Singh NN.  Aberrant Behaviour Checklist Manual, second edition. 2017.


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17 The Voice of The Patient, Autism, Report Date: January 2018: 
https://www.fda.gov/media/111099/download.
18 Guy W. ECDEU Assessment manual for psychopharmacology. Revised, 1976.
19 Lecavalier L, Wood JJ, Halladay AK, et al. Measuring anxiety as a treatment endpoint in 
youth with autism spectrum disorder.J Autism Dev Disord. 2014 May; 44(5): 1128–43.doi: 
0.1007/s10803-013-1974-9
20 ICH Harmonised Tripartite Guideline: Guidance on Nonclinical Safety Studies for the 
Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals 
M3(R2). June 2009.
21 Clinical Trial Facilitation Group: Recommendations related to contraception and pregnancy 
testing in clinical trials.  September 2014.
22 Lam KSL, Aman MG. The Repetitive Behavior Scale-Revised: Independent Validation in 
Individuals with Autism Spectrum Disorders. J Autism Dev Disord. 2007;37:855-856. doi 
10.1007/s10803-006-0213-z
23 Bodfish JW, Symons FJ, Parker DE, Lewis MH. Varieties of repetitive behavior in autism: 
comparisons to mental retardation. J Autism Dev Disord, 2000; 30(3):237–43.
24 Hoefman R, Payakachat N, van Exel J, et al. Caring for a child with autism spectrum disorder 
and parents’ quality of life: Application of the CarerQol. J Autism Dev Disord. 2014 August; 
44 (8):1933–45.
25 World Medical Association Declaration of Helsinki - Ethical Principles for Medical Research 
Involving Human Subjects. October 2013.
26 ICH Harmonised Guideline: Integrated addendum to ICH E6(R1) Guideline for Good 
Clinical Practice E6(R2). November 2016.
27 US Food and Drug Administration Code of Federal Regulations Title 21 (Food and Drugs) 
Part 312—Investigational New Drug Application. 01 April 2014.
28 US Food and Drug Administration Code of Federal Regulations Title 21 (Food and Drugs) 
Part 50-Protection of Human Subjects.  April 2018.
29 US Food and Drug Administration Code of Federal Regulations Title 21 (Food and Drugs) 
Part 56-Institutional Review Boards.  April 2018.
30 Directive 2001/20/EC of the European Parliament and of the Council of 04 April 2001 on the 
approximation of the laws, regulations and administrative provisions of the Member States 
relating to the implementation of good clinical practice in the conduct of clinical trials on 
medicinal products for human use.  Official Journal of the European Communities L 121, 
1/5/2001 p. 34–44.
31 Commission Directive 2005/28/EC of 08 April 2005 laying down the principles and detailed 
guidelines for GCP as regards investigational medicinal products for human use, as well as 
the requirements for authorisation of the manufacturing or importation of such products.  
Official Journal of the European Union L 91, 9/4/2005 p. 13–19.
32 US Food and Drug Administration Guidance for Clinical Investigators, Sponsors, and IRBs.  
Adverse Event Reporting to IRBs- Improving Human Subject Protection.  January 2009.


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33 Fung LK, Mahajan R, Nozzolillo A, et al. Pharmacologic treatment of severe irritability and 
problem behaviors in autism: a systematic review and meta-analysis. Pediatrics, 
2016;137(s2):e20152851K.
34 World Medical Association Declaration of Helsinki - Ethical Principles for Medical Research 
Involving Human Subjects. October 2013.
35 UK Statutory Instrument 2004 No. 1031: The Medicines for Human Use (Clinical Trials) 
Regulations 2004.  May 2004.
36 UK Statutory Instrument 2012 No. 1916: The Human Medicines Regulations 2012.  August 
2012.
37 UK Statutory Instrument 2006 No. 1928: The Medicines for Human Use (Clinical Trials) 
Amendment Regulations 2006.  August 2006. 
38 UK Statutory Instrument 2008 No. 941: The Medicines for Human Use (Clinical Trials) and 
Blood Safety and Quality (Amendment) Regulations 2008.  May 2008.
39 US Food and Drug Administration Code of Federal Regulations Title 21 (Food and Drugs) 
Part 11-Electronic records; Electronic signatures (Subpart B—Electronic Records). April 
2018.


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Clinical Protocol Template (Phase 2–4)
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APPENDIX 1
SCHEDULE OF ASSESSMENTS
Schedule of Assessments
Period
Screening
Treatment Period
End of 
Taper
Follow-upn
Visit
Visit 1a
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6 
Visits 
7
Visit 8
EoT/WD
Visit 9
Visit 10
Visit Type
Clinic
Clinic
Telephone
Telephone
Clinic or 
Video 
Call and 
Home 
Nurse*
Telephone
Clinic or 
Video 
Call 
Clinic
Clinic or 
Video 
Call and 
Home 
Nurse*
Telephone
Day
-14 to -7
1
7 (± 3)
14 (± 3)
29 (± 
3)
43 (± 3)
57 (± 
3)
85 (± 3)
V8 + 7 
(+ 3)
V9 + 14 
(+ 3)
Informed consent/assent
X
Demographics
X
Medical historyb
X
Inclusion and exclusion criteria
X
X
AE review
X
X
X
X
X
X
X
X
X
X
SAE review
X
X
X
X
X
X
X
X
X
X
Concomitant medication reviewc
X
X
X
X
X
X
X
X
X
X
Test for drugs of abuse
X
C-SSRS
X
X
X
X
X
X
Vital signsd
X
X
X
X
X
Full physical examination 
X
X
Height
X
Weight
X
X
BMI
X
12-lead ECGe
X
X
Safety laboratory assessmentsf
X
X
If not 
tapering
X
Urinalysisg
X
If not 
tapering
X


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Clinical Protocol Template (Phase 2–4)
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Period
Screening
Treatment Period
End of 
Taper
Follow-upn
Visit
Visit 1a
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6 
Visits 
7
Visit 8
EoT/WD
Visit 9
Visit 10
Visit Type
Clinic
Clinic
Telephone
Telephone
Clinic or 
Video 
Call and 
Home 
Nurse*
Telephone
Clinic or 
Video 
Call 
Clinic
Clinic or 
Video 
Call and 
Home 
Nurse*
Telephone
Serum pregnancy test (WOCBP 
only)
X
If not 
tapering
X
Trial treatment
X
X
X
X
X
X
X
X
Randomizationi
X
WASI-II (if required) l
X
ADOS-2 (if required)
X
ABCj
X
X
X
X
X
Vineland-3j,k
X
X
X
X
CGI-Sk
X
X
X
X
X
CGI-Ik
X
X
X
IMP dispensingm
X
X
X
IMP review
X
X
X
Dosing diary completion (daily)
X
IMP dosing compliance reviewo
X
X
X
X
X
X
Abbreviations: ABC = Aberrant Behavior Checklist; ADOS-2 = Autism Diagnostic Observational Schedule; AE = adverse events; 
 
CGI-I = Clinical Global Impression Improvement; CGI-
S = Clinical Global Impression Severity; C-SSRS = Columbia-Suicide Severity Rating Scale; DSM-5 = Diagnostic and Statistical Manual of Mental Disorders, 
5th Edition; ECG = 12-lead electrocardiogram; EoT = End of Treatment; IMP = investigational medicinal product accountability; 
 


Study Code: GWND19189
IND Number: 150775
Protocol Version 2.0, 24 Nov 2020
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Clinical Protocol Template (Phase 2–4)
V1, 24Sep15
 RTSM = Randomization and Trial Management System; SAE = serious 
adverse events; WASI-II = Wechsler Abbreviated Scale of Intelligence Scale Second Edition; WD = withdrawal; WOCBP = women of childbearing potential. 
* For visits carried out remotely, home nurse assessments include: collection of blood and urine samples (including urine dipstick), and vital signs. 
a Screening procedures may be performed over 2 days, if needed; both days must fall within the -14 to -7 day window.
b Relevant, significant medical history will be obtained and is defined as any condition or disease that may affect the condition under study, is ongoing on 
entry into the trial, and information on ASD history, including known etiologies. Patient has a diagnosis of ASD as per DSM-5 criteria for ASD, confirmed 
by ADOS-2 criteria (conducted within 2 years at the trial site or at screening).
c All current and recent medication/therapy, i.e., taken within 14 days prior to the initial screening visit. All medications and interventions for ASD related 
symptoms must remain at stable doses throughout the trial; however, doses may be changed in response to a safety concern. 
d Includes body temperature, pulse rate, and respiration rate and blood pressure taken in a sitting position at rest for 5 minutes.
e Performed after 5 minutes in a supine position and reviewed by a physician. 
f Includes hematology and biochemistry (including liver chemistries). Coagulation only at Visit 1; thereafter only as an unscheduled assessment if ALT or 
AST > 3 × ULN). If the patient in not tapering (and therefore will not attend Visit 9), clinical laboratory sampling is to be carried out at Visit 8. Details are 
provided in Table 9.1-1.
g Urinalysis to be performed provided urine can be obtained. Urine samples for biochemistry will be analyzed at the trial site (or by the home nurse) by use of 
a dipstick with any relevant findings being sent for further urinalysis at the central laboratory (urinalysis, microscopy, culture and sensitivity, as applicable). 
Details are provided in Table 9.1-1.
h TKHVDPSOHPXVWEHFROOHFWHGKRXUVíKRXUVVLQFHODst IMP dose and before the patient’s next dose. The time of sample collection, the time of 
previous IMP dose, and time and type of meal (snack, standard meal, high fat) consumed by the patient closest to the previous IMP dose will be collected.. 
To minimize discomfort samples should be collected together with the safety laboratory sample collection.
i The RTSM system will be used to assign patients to treatment arms, including randomization.
j Caregivers questionnaires are to be completed by an identified main caregiver (nominated at Visit 1. The same identified caregiver is to complete the clinical 
interviews (Vineland-3 and 
).
k Investigator questionnaires/interviews are to be completed for each patient by the same investigator (CGI-S, CGI-I, Vineland-3, and 
).
l  Patients functional assessments, i.e., the WASI-II, ADOS-2, 
 should be performed prior to any invasive assessments 
being carried out. All assessments should reflect the patient’s regular state; therefore, it should be ensured the patient had adequate time to settle prior to 
each assessment. WASI-II required if score within 1 year of screening is not available. ADOS-2 required if not performed at the trial site within 2years. 
During special circumstances (e.g., COVID-19 pandemic) where the ADOS-2 cannot be performed due to site restrictions (e.g., mandatory use of face 
masks), eligibility can be confirmed using the Autism Diagnostic Interview, Revised (ADI-R).
m In cases where Visits 5, or 9 are carried out at home, secure IMP delivery and collection will be organized. 
n  If the patient did not enter the Taper Period, then Safety Follow-up occurs 14 days after Visit 8.
o  Dosing diary (completion and volumes taken) and time of IMP taken in relation to food will be reviewed


Study Code: GWND19189
IND Number: 150775
Protocol Version 2.0, 24 Nov 2020
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Clinical Protocol Template (Phase 2–4)
V1, 24Sep15
APPENDIX 2
TRIAL PERSONNEL
Appendix 2.1
Investigator Details
At the time of protocol production, the participating investigators have not been confirmed. A list 
of all investigators will be maintained within the GW master files (electronically and added to 
the trial master file at the end of the trial).
Appendix 2.2
Sponsor Contact Details
Pharmacovigilance Department — SAE Reporting:
Fax: +44 (0)1223 233 319
USA Toll-free Fax:
+1-866-234-1751
Tel: +44 (0)1223 233 410
Sponsor:
GW Research Ltd
Sovereign House
Vision Park
Chivers Way
Histon
Cambridge CB24 9BZ
United Kingdom
Tel: +44 (0) 1223 266 800
Fax: +44 (0) 1223 235 667
Medical Advisor, 24 hour Emergency Contact Number
& Clinical Project Manager:
Please refer to the sponsor and 
Related Contact Details form in the 
trial center file.
Clinical Trial Supplies:
G-Pharm Ltd
Tel: +44 (0) 1795 435 029
Fax: +44 (0) 1795 475 439
At the time of protocol production, the CROs, and the clinical and bioanalytical laboratories for 
the trial had not been confirmed. A corresponding list will be maintained within the GW master 
files (electronically and added to the trial master file at the end of the trial):
Medical Advisor & Clinical Project Manager:
Please refer to the sponsor and 
Related Contact Details form in the 
trial site file.
Clinical Trial Supplies:
G-Pharm Ltd
Tel: +44 (0) 1795 435 029
Fax: +44 (0) 1795 475 439


Study Code: GWND19189
IND Number: 150775
Protocol Version 2.0, 24 Nov 2020
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Clinical Protocol Template (Phase 2–4)
V1, 24Sep15
Appendix 2.3
Contract Research Organizations
IQVIA Biotech LLC
Registered Address
IQVIA Biotech Ltd.
500 Brook Drive, Reading, RG2 6UU
Main Office Address
1700 Perimeter Park Drive
Morrisville, NC USA 27560-8404

SAP_001.pdf: 


Jazz Pharmaceuticals / Protocol: GWND19189
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Page 2 of 31
Signature Page
This document has been prepared by:
Study Biostatistician Biostatistics, 
Data Science.
Jazz Pharmaceuticals, Inc.
Signature
Date
This document has been reviewed and approved by:
Biostatistician
Associate Director, Biostatistics, 
Data Science
Jazz Pharmaceuticals, Inc.
Sig
Clinical Lead
Director, Global Clinical Lead 
Translational Medicine, 
Neuroscience Clinical 
Development
Jazz Pharmaceuticals, Inc.
Sig
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Jazz Pharmaceuticals / Protocol: GWND19189 
 
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ULN  
Upper limit of normal  
VABS-3  
Vineland Adaptive Behavior Scales, 3rd Ed., comprehensive interview 
form  
VAS  
Visual analog scale  
WASI-II  
Wechsler Abbreviated Scale of Intelligence Scale Second Edition  
WD  
Withdrawal  
 
 
 
 
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CONTENTS 
1.Introduction ............................................................................................................. 7 
2.Protocol Objectives and Endpoints.......................................................................... 7 
3.Study Design ........................................................................................................... 8 
3.1 Design Overview ........................................................................................ 8 
3.2 Sample Size ............................................................................................... 9 
3.3 Treatment Randomization ........................................................................ 10 
3.4 Assessment Schedule .............................................................................. 10 
3.5 Interventions ............................................................................................. 10 
4.General Study Level Considerations ..................................................................... 11 
4.1 Data Sources ........................................................................................... 11 
4.2 Definition of Baseline and Change from Baseline .................................... 11 
4.3 Study Day ................................................................................................. 11 
4.4 Analysis Visit Window .............................................................................. 11 
4.5 Missing Data and Partial Dates ................................................................ 11 
4.6 Multiple Study Centers ............................................................................. 12 
5.Statistical Analysis ................................................................................................. 12 
5.1 Hypothesis testing .................................................................................... 12 
5.2 Analysis Populations ................................................................................ 12 
5.2.1 
Screened Analysis Set ...................................................................... 13 
5.2.2 
Full Analysis Set (FAS) ..................................................................... 13 
5.2.3 
Safety Analysis Set ........................................................................... 13 
5.2.4 
Per Protocol (PP) Analysis Set .......................................................... 13 
5.2.5 
................................................................................. 14 
6.Data Display Characteristics ................................................................................. 14 
6.3 Subject Accountability .............................................................................. 14 
6.3.1 
Disposition ......................................................................................... 14 
6.3.2 
Subject Characteristics ...................................................................... 15 
6.3.3 
Protocol Deviations and Population Inclusions .................................. 16 
7.Efficacy Analyses .................................................................................................. 16 
7.1 Statistical Models ..................................................................................... 16 
7.1.1 
MMRM analysis ................................................................................. 16 
7.1.2 
GEE model ........................................................................................ 17 
7.1.3 
Logistic regression model .................................................................. 17 
7.1.4 
ANCOVA model ................................................................................ 18 
7.1.5 
Bayesian analysis .............................................................................. 18 
7.2 Efficacy endpoints .................................................................................... 18 
7.2.1 
Vineland Adaptive Behavior Scales, 3rd Edition (VABS-3) ............... 18 
7.2.2 
Aberrant Behavior Checklist (ABC) ................................................... 19 
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4. General Study Level Considerations 
 
4.1 Data Sources 
 
Data are recorded on electronic case report forms (eCRFs). Central laboratory data and 
 
 will be provided via electronic data transfers. Electronic devices are used to capture dosing 
diary, medications, and questionnaire data. 
 
Section 16.3 of the protocol provides additional details describing data collection. 
 
4.2 Definition of Baseline and Change from Baseline 
 
Baseline for analysis purposes is defined as the last available observation prior to the first 
administration of the study drug at home in the evening of Visit 2.  
 
4.3 Study Day 
 
Study day 1 is defined as the date of the first dose, and the day immediately prior to study day 1 
is study day -1. For any events on or after the first administration of the study drug, study day is 
calculated as:  
event date – date of first administration of study drug + 1. 
For any events before the first administration date, study day is calculated as: 
event date – date of first administration of study drug.  
 
4.4 Analysis Visit Window 
 
No analysis visit windowing will be performed for this study. 
 
For by-visit summaries, data recorded at the nominal visit will be presented. Subjects who 
withdraw early will be mapped to the nearest scheduled visit considering missed previous visits 
(if previous visit is not missing, then consider the next visit). Unscheduled measurements will 
not be included in by-visit summaries but will contribute to the baseline timepoint (if baseline is 
missing) and/or worst-case value where required (e.g. shift tables or summaries involving worst-
case values at any time post-Baseline). 
 
Listings will include scheduled, unscheduled, retest and early discontinuation data. 
 
4.5 Missing Data and Partial Dates 
 
Unless stated otherwise, missing data will not be replaced with imputed values.  
 
Partial start or stop dates (month or day) are allowed on CRF for adverse events, concomitant 
medication, antipsychotic medication, and medical history. An entry for the year is required in 
the eCRF system for each of these dates. Only the month and day may be entered as unknown. 
Dates from these forms will be reported in listings as collected. Every effort will be made to 
query missing dates. 
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For records with a partial start date, the following procedure will be employed in determining if 
an AE is treatment emergent AE: 
x 
Dates with missing day and non-missing month will be assumed to occur on the first day of 
the non-missing month, except for assessments/events occurring in the first month of 
dosing, in which case the date will be the first day of dosing. 
x 
Dates with missing month will be assumed to occur on the first day of the non-missing year 
(i.e. January 1), except for assessments/events occurring in the first year of dosing, in which 
case the date will be the first day of dosing. 
 
 
4.6 Multiple Study Centers 
 
The study will be conducted at multiple centers in North America and Rest of the World. Data 
from all sites will be pooled for all analyses. For efficacy analyses, region (North America, Rest 
of the World) will be included as a stratification factor. 
 
 
5. Statistical Analysis 
 
 
5.1 Hypothesis testing  
 
Statistical hypothesis testing will be performed on the efficacy and exploratory endpoints as 
appropriate with no inferential statistical decision drawn as this is an exploratory trial.  Statistical 
hypotheses will be tested using 2-sided tests at a 5% significance level. P-values and 95% 
confidence intervals will be provided where appropriate. 
 
5.2 Analysis Populations  
 
Five analysis populations will be defined for use with various analyses. Table 2 illustrates the 
relationship between each population and the analyses for which the data from the population 
will be used. 
 
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of the number and percentage of subjects experiencing a particular disposition event, per 
treatment arm and in total, with number of randomized subjects in the respective treatment 
group, and in total, used as the denominator for the percentage calculation. Number of subjects 
enrolled, but not randomized, as well as number of subjects with a certain reason for not being 
randomized will only be displayed for all subjects combined, with no percentage calculated.  The 
number and percentage of subjects discontinuing treatment and discontinuing study due to 
COVID-19 will also be presented. 
 
The disposition data mentioned above will be listed for all patients. 
 
 
6.3.2 Subject Characteristics 
 
Data collected about the following subject characteristics at the Baseline visit (Visit 2) will be 
summarized for populations as in Table 2. 
 
Demographics  
The following demographic and baseline characteristics data will be summarized by treatment 
group and overall using the safety set. 
Demographic characteristics: age at randomization, age group ( 6 to 11, 12 to 17), sex at birth, if 
female, childbearing potential, race and ethnicity. 
Baseline characteristics: height (cm), weight (kg), body mass index (BMI) (kg/m2). use of 
antipsychotics, region and WASI-II (verbal comprehension index score (VCI); perceptual 
reasoning index score (PRI); intelligent quotient score (FSIQ-2)). 
 
Medical history 
 
Previous and current medical conditions (excluding autism history) will be summarized as the 
numbers and percentages of subjects for the FAS by system organ class (SOC) and preferred 
term (PT). 
 
Autism history and diagnosis 
 
Autism diagnosis will be summarized for the FAS as per eCFR form “Autism History” and in 
addition, assessment used to confirm diagnosis (ADOS-2, ADI-R).  Time since initial diagnosis 
(number of years from date of original diagnosis to the date of informed consent/assent) will 
also be presented. 
 
x ADOS-2. Module administered; Social Affect Total; RBR/RRB Total; Overall Total; 
x 
ADOS-2 Comparison Score; ADOS-2 Classification.  
x 
ADI-R. Scores for A, B, C, D. 
Autism history events will be summarized as per cetegories presented in the eCRF.  
 
 
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Main caregiver and caregiver update  
Caregiver information as collected at Visit 1 on the “Main Caregiver” eCRF will be summarized 
using FAS. Changes to caregiver collected at each visit will be summarise and also will present 
how many patients had changed the caregiver. 
 
6.3.3 Protocol Deviations and Population Inclusions 
 
All screened patients will be displayed in a listing that includes eligibility for each analysis set, 
protocol version for which patient was enrolled, dates of informed consent/assent and 
screening. 
 
All protocol deviations are recorded in the Clinical Trial Management System, InfoLink2, and will 
be included in a data listing of deviations.  
 
Major protocol deviations resulting in FAS subjects being excluded from the PP set will be 
summarized by deviation category. 
 
7. Efficacy Analyses  
 
Efficacy analyses, constituting the comparison of GWP42003-P against placebo in reducing 
symptom severity in children with ASD, will use data from the FAS and the PP analysis set as 
specified in Table 2.  
 
Statistical hypothesis testing will be performed with no inferential statistical decision drawn as 
this is an exploratory trial. Unless otherwise specified, for all analyses for which a statistical test 
is performed, the null hypothesis corresponds to no difference between GWP42003-P and 
Placebo treatment arms.   
 
Example SAS-codes provided may be modified without amendment to this SAP. 
 
7.1 Statistical Models 
 
7.1.1 MMRM analysis 
 
The change from baseline of the VABS, ABC and RBS endpoints will be analyzed using an 
MMRM model. The corresponding model will include randomization stratification factors, 
baseline score, visit, treatment arm, visit by treatment arm interaction, visit by baseline 
interaction as fixed effects, and visit repeated within each patient as a repeated effect. 
 
LS mean estimates for each treatment arm at each visit, along with the standard error and 95% 
CI will be presented separately. In addition, estimates of the treatment difference at each visit 
will be presented along with standard errors of difference and 95% CIs. The main comparison of 
interest is the estimate of the treatment difference at Week 12 (Visit 8).  
 
The following provides sample code for implementing MMRM analysis using compound symetry 
covariance matrix: 
 
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7.1.4 ANCOVA model 
 
An ANCOVA model with randomization stratification factors and treatment arm as factors and 
baseline score as a covariate will be used to analyze change from baseline to Week 12. The LS 
mean estimates for each treatment arm will be displayed together with standard errors and their 
corresponding 95% CIs. Treatment differences with 95% CIs will also be produced. 
 
The following provides sample code for implementing ANCOVA analysis: 
 
ods output lsmeans=lsmeans diffs=diffs; 
proc mixed data=test; 
class trt randager randrgn randpsy; 
model chg = base trt randager randrgn randpsy / ddfm=kr cl 
alpha=0.05 solution; 
lsmeans trt / cl diff; 
run; 
     
 
 
7.1.5 Bayesian analysis 
 
Bayesian analysis on the final data will be carried out as described in interim analysis plan.  
 
 
7.2 Efficacy endpoints 
 
 
7.2.1 Vineland Adaptive Behavior Scales, 3rd Edition (VABS-3) 
 
The Vineland-3 assesses adaptive behavior in 3 domains: Communication, Daily Living Skills, 
and Socialization. Each domain has 3 subdomains: receptive, expressive, written 
(Communication domain); personal, domestic, community (Daily Living Skills domain); 
interpersonal relationships, play and leisure, coping skills (Socialization domain). The 
assessment are done at Visit 2, Visit 5, Visit 7, and Visit 8 EoT/WD.  
 
Subdomain and domain scores will be calculated in the Rater Station. The Chronological Age at 
baseline is used to derived scores for the Vineland-3 throughout the study.  
The social and communication composite score is a key interest and will be calculated as the 
arithmetic mean of the Socialization and Communication domain scores. 
 
The adaptive behavior composite score is calculated as arithmetic mean of all 3 domain scores. 
 
The change from baseline in subdomain, domain and composite scores will be summarized by 
visit. The change from baseline in social and communication composite score, adaptive 
behavior composite score, and individual domain scores will be analyzed using an MMRM 
model. Multiple analyses will carryout by including all observed data and using per protocol set.  
Normality assumption will be tested for Social and communication composite using Q-Q plot. 
 
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7.2.2 Aberrant Behavior Checklist (ABC) 
 
The ABC contains items that resolve into 5 subscales: Irritability (15 items); Social Withdrawal 
(16 items); Stereotypic Behavior (7 items); Hyperactivity/Noncompliance (16 items); and 
Inappropriate Speech (4 items). Each item is scored as 0 (never a problem), 1 (slight problem), 
2 (moderately serious problem), or 3 (severe problem). The assessment is done by the 
caregiver at Visit 1 (Screening), Visit 2, Visit 5, Visit 7, and Visit 8 EoT/WD.  
 
Subscale score is calculated as the sum of the items belonging to each subscale. ABC-I 
(Irritability) subscale score is of the key interest. 
 
Subscale 
Items 
ABC-I (Irritability) 
2, 4, 8, 10, 14, 19, 25, 29, 34, 36, 41, 47, 50, 52, 57 
Social Withdrawal 
3, 5, 12, 16,, 20, 23, 26, 30, 32, 27, 40, 42, 43, 53, 55, 58 
Stereotypic Behavior 
6, 11, 17, 27, 35, 45, 49 
Hyperactivity/Noncompliance 
1, 7, 13, 15, 18, 21, 24, 28, 31, 38, 39, 44, 48, 52, 54, 56 
Inappropriate Speech 
9, 22, 33, 46 
 
The change from baseline in ABC-I and other subscale scores will be summarized by visit.  
MMRM analysis as described in Section 7.2 will be used to analyze the change from baseline in 
ABC-I and other subscale scores.  
 
Multiple analyses will carryout by including all observed data and using per protocol set.  
Normality assumption will be tested for ABC-I (irritability) score using Q-Q plot. 
 
 
7.2.3    Clinical Global Impression – Severity and Improvement (CGI-S and CGI-I) 
 
The CGI-S is a 7-point scale that requires the clinician to rate the severity of the patient's illness 
at the time of assessment, relative to the clinician’s experience with patients who have the same 
diagnosis. The clinician is asked: Considering your total clinical experience with this particular 
population, how ill is the patient at this time? This is rated as: 1 = normal, not at all ill; 2 = 
borderline ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; or 7 = extremely ill. 
The questionnaire is done at Visit 1 (Screening), Visit 2, Visit 5, Visit 7 and Visit 8 EoT/WD. 
 
The CGI-I is a 7-point scale that requires the clinician to assess how much the patient’s illness 
has improved or worsened relative to a baseline state at the beginning of the intervention. The 
clinician is asked: Compared to the patient’s condition at admission to the project, how much 
has the patient changed? This is rated as: 1 = very much improved; 2 = much improved; 3 = 
minimally improved; 4 = no change; 5 = minimally worse; 6 = much worse; or 7 = very much 
worse. 
 
The questionnaire is done at Visit 5, Visit 7 and Visit 8 EoT/WD. 
 
The frequency and proportions of patients within each category for the CGI-S and CGI-I scores 
will be produced separately by visit.  
 
A GEE model will be fitted, for CGI-I (or change from baseline CGI-S) as the dependent 
variable, visit, treatment arm, stratification factors, baseline into visit interaction and treatment 
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Dose compliance based on Diary 
Number of doses administered, as reported in the diary, and dose compliance percentage will 
be summarized overall and separately for treatment and taper period  
Dose compliance based on Diary (%) is calculated by: 
Number of doses administered * 100/ number of diary entries (am+pm) 
 
Dose compliance based on CRF 
Total expected volume since last dispensation, total volume actually taken since last 
dispensation and derived dose compliance (%) are captured on CRF at Visit 5, Visit 8 EoT/WD, 
and Visit 9/End of Taper; derived dose compliance will be summarized for each period.  
 
Number and percentage of subjects compliant will be summarized for each period by treatment 
group and overall for following groups; 
Compliant: ≥75% to ≤125% 
Minor Compliance Deviations 50-75 & 125-50 
Major Compliance deviations:  <50 and >150 
Consistency of dose administration in relation to meal timing (Yes, No) by visit will be 
summarized separately. 
 
Dose adjustment and suspension 
The number and percent of subjects with any dose adjustment (overall and by reason) as 
collected on Investigator Dose Adjustment CRF will be summarized.  
 
 
8.2 Adverse Events 
 
Adverse events will be collected from the date caregiver signs informed consent form up to the 
post-treatment safety follow-up visit. All AEs occurring during the trial, whether attributed to the 
IMP or not, observed by the investigator, or reported by the caregiver, will be recorded in the 
eCRF. AEs will be coded using the latest version of  MedDRA at the time of reportig, 
associating lower-level terms with preferred terms and system organ classes by the primary 
hierarchy. Treatment-emergent AEs (TEAEs) are AEs that started, or worsened in severity or 
seriousness, following the first dose of IMP. 
 
An AE profile for the Safety analysis set will be provided, which summarizes the subject 
incidence by treatment received, for the following information: 
x 
Any TEAEs 
x 
TEAEs related to treatment 
x 
Serious TEAEs 
x 
Serious TEAEs related to treatment 
x 
TEAEs leading to withdrawal of IMP 
x 
TEAEs related to treatment leading to withdrawal of IMP 
x 
TEAE leading to death 
 
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AE summaries will include TEAEs. AE descriptions will be presented by decreasing frequency 
across all patients for a given SOC and Preferred Term. The tables will display counts and 
percentages of subjects who reported at least one AE in each system organ class represented 
in the AE data. Within each system organ class, the tables will display the counts and 
percentages of subjects reporting at least one AE, as designated by the preferred terms.  
 
The following AE summaries will be produced: 
x 
TEAEs by SOC and PT 
x 
TEAEs related to treatment by SOC and PT. This table will include TEAEs that have a 
plausible relationship to the IMP as assessed by the investigator.  
x 
TEAEs by SOC, PT, and maximum severity. On this table, treatment groups will be 
subdivided into three potential grades of AE severity— Mild, Moderate, Severe. TEAEs 
missing a severity grade will be imputed as ‘Severe’. 
x 
TEAEs by SOC, PT, and sex 
x 
TEAEs by SOC, PT, and time of first onset (<1 week, 1-<4 weeks, 4-<12 weeks, >=12 
weeks) 
x 
TEAEs by SOC, PT, and time to AE resolution (<1 week, 1 week, 2 weeks, 3 weeks, 4 
weeks, >=5 weeks, ongoing). 
x 
Serious TEAEs by SOC and PT 
x 
Serious TEAEs related to treatment by SOC and PT. The same approach applies as 
described for TEAEs related to treatment. 
x 
TEAEs leading to study withdrawal  by SOC and PT. This subset includes “Study 
Discontinuation” due to TEAEs. 
x 
TEAEs leading to withdrawal of IMP by SOC and PT. This subset includes TEAEs with an 
Action Taken of “Drug Withdrawn.” Withdrawal means permanent discontinuation of IMP. 
x 
Treatment related TEAEs leading to withdrawal of IMP by SOC and PT. This subset 
includes TEAEs with an Action Taken of “Drug Withdrawn.” Withdrawal means permanent 
discontinuation of IMP. 
x 
TEAEs leading to dose reductions by SOC and PT. This subset includes TEAEs with an 
Action Taken of “Dose Reduced.” 
x 
TEAEs related to treatment leading to dose reductions by SOC and PT. This subset 
includes TEAEs with an Action Taken of “Dose Reduced.” 
x 
TEAEs leading to dose reductions and are resolved by SOC and PT. This subset includes 
TEAEs with an Action Taken of “Dose Reduced” and Outcome “Recovered/Resolved” or 
“Recovered/Resolved with Sequelae”.    
x 
TEAEs leading to dose interruptions by SOC and PT. This subset includes TEAEs with an 
Action Taken of “Dose Interrupted.” 
x 
TEAEs related to treatment leading to dose interruptions by SOC and PT. This subset 
includes TEAEs with an Action Taken of “Dose Interrupted.” 
x 
TEAEs leading to dose interruptions and are resolved by SOC and PT. This subset includes 
TEAEs with an Action Taken of “Dose Interrupted” and Outcome “Recovered/Resolved” or 
“Recovered/Resolved with Sequelae”. 
x 
Fatal TEAEs by SOC and PT. This subset includes TEAEs with Outcome “Fatal”. 
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8.5 Physical Examination 
 
Physical examination findings for Visit 1 and Visit 8 EoT/WD, will be summarized as recorded. 
Height, weight, and BMI will be summarized as continuous variables. Categories of findings 
(normal, abnormal, not evaluated) on physical examination will be summarized as frequency 
and percentages.   
 
 
8.6 12-lead ECG 
 
A 12-lead ECG will be performed at Visit 1 and Visit 8 EoT/WD. Summaries of actual values and 
changes from baseline will be presented. 
 
Marked abnormalities will be summarized, using a similar approach as described in Section 8.4. 
 
Table 3 Marked abnormalities for 12-lead ECG 
Parameter (unit) 
Observed Values 
QTcF (msec) 
> 450 
> 480 
> 500 
 
 
8.7 C-SSRS 
 
The C-SSRS is a suicide risk assessment performed by the investigator at Visit 1 (Screening), 
Visit 2, Visit 5, Visit 7, Visit 8 EoT/WD, and Visit 9. 
 
The number and percent of subjects with suicidal ideation by category, suicidal behavior by 
category and/or self-injurious behavior without suicidal intent will be tabulated. Percentages will 
be based on the number of subjects with at least one post-baseline C-SSRS assessment.  
 
Shift from baseline showing any change in suicidal ideation and suicidal behavior will be 
provided. Subjects will be summarized under the worst of the following three categories: 1) No 
suicidal ideation of behavior; 2) suicidal ideation only; 3) suicidal ideation and behavior.  
 
 
8.8 Concomitant Medications and Concomitant Therapy 
 
Concomitant medications (CMs) will be coded using the September 2020 version of WHO Drug. 
Prior medications include any medications taken and stopped prior to start of treatment. 
Concomitant medications are defined as any medications that are ongoing or with stop dates on 
or after date of first IMP. 
 
CM summary tables will display the anatomical main class of each coded CM and, within that, 
the pharmacological subgroup (3rd level) of the coded CM. Summary tables will display counts 
and percentages of subjects who reported using at least 1 CM in each represented 
pharmacological subgroup by treatment arm. 
 
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The following will be summarized: 
x 
Prior (including antipsychotic) medications   
x 
Concomitant (excluding antipsychotic) medications  
x 
Concomitant antipsychotic medications 
x 
Non-pharmacologic therapies and therapeutic diets prior and during the trial. These will be 
summarized by treatment arm. 
 
The listing of CMs will display entries from Concomitant Medications and Concomitant 
Antipsychotic Medications forms, ordered within subject by the “Start Date.” The listing will 
display the recorded term from the CRF and the WHO Drug pharmacological subgroup. 
 
 
8.9 Pregnancy monitoring 
 
All female subjects of childbearing potential will take a pregnancy test at Visit 1 (Screening), 
Visit 8 EoT/WD if not tapering, and Visit 9. The test results are reported together with laboratory 
test results.  
The information collected on Pregnancy Monitoring and Pregnancy Outcome CRFs will be 
displayed separately in listings. 
 
 
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