Clinical trial NCT05288283
Conditions: Seizures Associated With EMAS
Keywords: Epilepsy Seizures Epilepsy with Myoclonic-Atonic Seizures (EMAS) Myoclonic-Atonic Epilepsy Doose syndrome Myoclonic-Astatic epilepsy (MAE) Children Cannabidiol (CBD) GWP42003-P
Sponsor: Jazz Pharmaceuticals
Start date: 2022-10-31; Completion date: 2023-09-28
Enrollment: 3 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary aim of Part A of the study to assess the efficacy and tolerability of GWP42003-P compared to placebo as an adjunctive treatment for children with Epilepsy with myoclonic-atonic seizures (EMAS) -associated seizures.

Part B of this study will be conducted to evaluate the long-term safety and tolerability of GWP42003-P in participants with EMAS.

Detailed description:
The duration of study participation in Part A will be approximately 26 weeks, which includes a 1- to 3-week Screening Period, 4-week Baseline Observation Period, 14-week Dose Optimization Treatment Period, 10-day Taper Period, and a Safety Follow-up Period (4 weeks after end of taper visit). Participants will be randomized centrally in a 1:1 ratio to receive either GWP42003-P or matching placebo. Randomization will be stratified by clobazam use (on/off) and age of seizure onset (3 years of age and younger or older than 3 years of age). Upon completion of the double-blind phase (Part A), participants will have an option to continue in a 54-week open-label extension (Part B).

Arms: arm 1: Participants will be initiated on a dose of GWP42003-P 2.5 milligrams per kilogram (mg/kg) twice a day (BID) (5 mg/kg/day); after 1 week, the dose will be increased to 5 mg/kg BID (10 mg/kg/day). Dose escalation up to a maximum daily dosage of 20 mg/kg/day (in increments of 5 mg/kg/day \[2.5 mg/kg BID\] no more rapidly than every 7 days) may occur after Day 15 based on the investigator's assessment of efficacy, safety and tolerability. arm 2: Participants will receive the matching placebo.
Interventions: intervention 1: GWP42003-P intervention 2: Placebo
Intervention descriptions: intervention 1: oral solution intervention 2: oral solution

Protocol documents:
Prot_SAP_003.pdf: 
Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 1 
TITLE PAGE 
Protocol Title:  
A randomized, double-blind, placebo-controlled, multisite, Phase 3 study to investigate the 
efficacy and safety of cannabidiol oral solution (GWP42003-P) in children and adolescents with 
epilepsy with myoclonic-atonic seizures 
Protocol Number: GWEP20238 
Amendment Number: 2.0 
Product Code: GWP42003-P (cannabidiol oral solution) 
Brief Title:  
A safety and efficacy study of cannabidiol oral solution (GWP42003-P) in children and 
adolescents with epilepsy with myoclonic-atonic seizures between 1 and 18 years of age, 
inclusive. 
Phase: 3 
Sponsor Name: Jazz Pharmaceuticals Inc. on behalf of GW Research Ltd. 
Legal Registered Address: 3170 Porter Drive, Palo Alto, CA 94304. 
Regulatory Agency Identifier Number(s) 
IND: 
 
EudraCT: 2021-003094-61 
Document Version and Approval Date: Amendment 2.0 (Version 4) 
 
 
 
Refer to the final page of this protocol for electronic signature and date of approval. 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 2 
INVESTIGATOR AGREEMENT 
I have read the attached clinical study protocol entitled “A randomized, double-blind, 
placebo-controlled, multisite, Phase 3 study to investigate the efficacy and safety of cannabidiol 
oral solution (GWP42003-P) in children and adolescents with epilepsy with myoclonic-atonic 
seizures” and agree to abide by all provisions set forth therein. 
I agree to comply with the ICH Harmonised Guideline on GCP, Declaration of Helsinki, and 
applicable national or regional regulations/guidelines. 
I agree to complete Form FDA 1572, if required. I accept responsibility for the overall medical 
care of participants during the study and for all study-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  the sponsor. 
Site: 
 
  
 
 
 
  
 
Print name: 
 
 Date: 
 
 
Investigator 
 
 
  
(DD Month YYYY) 
Signature: 
 
  
 
Sponsor Authorization  
Print name: 
 
 Date: 
 
 
 Clinical Development or 
Designee 
 
 
 
 
  
(DD Month YYYY) 
Signature: 
 
  
 
Medical monitor name and contact information can be found in Appendix 1: Study Contacts. 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 3 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date of Issue 
Amendment 2.0 (Version 4) 
Refer to the final page of this protocol for 
electronic signature and date of approval. 
Amendment 1.1 (Version 3) 
25 August 2022 
Amendment 01 (Version 2) 
21 June 2022 
Original Protocol (Version 1) 
13 September 2021 
Amendment 2.0  
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment: 
The overall rationale for the changes implemented in Amendment 2.0 was to ensure alignment of 
study procedures globally and to revise the statistical methodology per the CID meeting outcome 
with the FDA. Specific updates incorporated into Amendment 2.0 are listed below. 
Section # and 
Name 
Description of Change 
Brief Rationale 
Title Page 
10.1.2 Sponsor 
Contact Details 
Updated sponsor name and address. 
Replaced “GW” with “the sponsor” throughout the 
document where applicable. 
For clarification. 
1.1 Synopsis 
2.2 Study 
Rationale 
2.3 Benefit/Risk 
Assessment 
4.2 Scientific 
Rationale for 
Study Design 
6.1 Study 
Intervention(s) 
Administered 
Removed “OS (GWP42003-P)” as study IMP, where 
applicable. 
For correction. 
1.1 Synopsis 
4.2 Scientific 
Rationale for 
Study Design 
Primary aim for Part A updated to focus on efficacy. 
For correction. 




Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 5 
Section # and 
Name 
Description of Change 
Brief Rationale 
1.1 Synopsis Part 
A and Part B 
4.1 Overall 
Design 
Added the following text “if participants discontinue 
treatment prematurely, they should be encouraged to 
complete the end of treatment visit and the taper 
period and remain in the study.” 
For clarification. 
1.1 Synopsis 
4.4 Number of 
Participants 
Reduced maximum sample size from 240 to 120 and 
up to 60 per treatment arm. 
To change study sample 
size after consultation with 
the FDA as part of the FDA 
CID Program. 
Revised to include “interim analyses when 60, 75, 
90, and 105 participants are randomized.” 
To change study sample 
size and interim analysis 
after consultation with the 
FDA as part of the FDA 
CID Program. 
1.1 Synopsis  
5.1 Inclusion 
Criteria  
5.2 Exclusion 
Criteria 
6.8 Concomitant 
Therapy  
Updated inclusion criterion #6, exclusion criterion 
#37, and third bullet point under concomitant 
therapy to shorten the required stability period on a 
ketogenic diet/epilepsy dietary therapy to ≥ 28 days 
prior to starting the baseline period. 
Revised inclusion criterion #7 to “Participant has 
failed ≥ 1 prior ASM due to inadequate seizure 
control.” 
Revised EEG range to > 2.5 to 6 Hz in inclusion 
criterion #8. 
For flexibility and 
clarification in the 
enrollment of targeted 
study population. 
1.2 Schema: Part 
A and Part B 
Replaced both schema with the following updates:  
Part A: n≤12060, AEDsASMs, CBDGWP42003-P, 
and Dose optimized based on efficacy and safety 
Baseline ASMs (n ≤ 60). 
Part B: AEDsASMs 
For correction. 
1.3 SoA 
Removed body weight measurement at the end of 
Taper Period in Part A in consistency with Part B. 
For correction. 
Specified “Section 8.1.4” under “PK blood” for 
reference. 
For clarification. 
Corrected time between End of Taper Period and 
Safety FU Visit in Part B to 28 days instead of 
32 days and day corrected to “376” instead of “380.” 
For correction. 
2.1.2 Study 
Intervention 
Background 
Included “other geographic expansion areas” along 
with US and EU as commercial markets for 
GWP42003-P. 
For clarification. 
4.1 Overall 
Design 
Deleted “A safety follow-up visit (phone call) will 
be conducted 4 weeks after the end-of-taper visit.” 
To remove duplicated 
information. 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 6 
Section # and 
Name 
Description of Change 
Brief Rationale 
5.1 Inclusion 
Criteria 
Removed statement in inclusion criterion #4 that “At 
least 1 myoclonic-atonic seizure is mandatory and 
must be observed during the baseline period.” 
For flexibility in the 
enrollment of the targeted 
study population as the key 
requirement for 
myoclonic-atonic seizures 
can be based on medical 
history to confirm the 
diagnosis of EMAS with 
the existing inclusion 
criteria and does not need 
to be restricted to the 
baseline period. Note that 
independent confirmation 
of the EMAS diagnosis by 
the epilepsy consortium 
remains a requirement. 
Updated inclusion criterion #12 to include “≥ 25 
days of daily Reminder Diary entries” instead of 
“≥ 25 days of entries.” 
To focus eligibility on 
completion of Reminder 
Diary. 
5.2 Exclusion 
Criteria 
6.8 Concomitant 
Therapy  
Added “Is currently treated with 
Epidiolex/Epidyolex or recently received treatment 
with Epidiolex/Epidyolex within 28 days prior to 
screening (Part A Visit 1)” as exclusionary criterion 
# 31.  
For clarity to avoid 
misinterpretation during 
audits/inspection. 
Revised and clarified exclusion criterion # 32 to 
exclude participants who experienced a lack of 
efficacy/poor tolerability to an adequate regimen of 
Epidiolex/Epidyolex and allow consideration of 
participants who discontinued treatment for reasons 
other than safety, tolerability, or lack of efficacy and 
previously received Epidiolex/Epidyolex ≥ 28 days 
prior to screening (Part A Visit 1) after consultation 
with medical monitor/sponsor. 
Revised text under concomitant therapy for the 
following: 
• Any medication or vaccine… or other previous or 
concomitant AEDs that the participant is 
receiving within 3 months of Screening... 
• Additionally, All all AEDASMs, antiepileptic 
therapies, and rescue medications taken during 
the participant’s life or receives during the 
study(previous and/or current use)...” 
For clarification. 
5.2 Exclusion 
Criteria 
Removed exclusion criterion # 33 “treatment with 
general anesthetic in the 28 days prior to screening.” 
For flexibility in the 
enrollment of targeted 
study population. 




Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 8 
TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
INVESTIGATOR AGREEMENT...................................................................................................2 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................3 
1. 
PROTOCOL SUMMARY ..........................................................................................13 
1.1. 
Synopsis ......................................................................................................................13 
1.2. 
Schema ........................................................................................................................22 
1.3. 
Schedule of Activities (SoA) ......................................................................................24 
2. 
INTRODUCTION ......................................................................................................33 
2.1. 
Background .................................................................................................................33 
2.1.1. 
Disease Background ...................................................................................................33 
2.1.2. 
Study Intervention Background ..................................................................................33 
2.2. 
Study Rationale ...........................................................................................................34 
2.3. 
Benefit/Risk Assessment ............................................................................................35 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................36 
3.1. 
Part A ..........................................................................................................................36 
3.2. 
Part B ..........................................................................................................................39 
4. 
STUDY DESIGN .......................................................................................................42 
4.1. 
Overall Design ............................................................................................................42 
4.2. 
Scientific Rationale for Study Design ........................................................................45 
4.2.1. 
Participant Input into Design ......................................................................................46 
4.3. 
Justification for Dose ..................................................................................................46 
4.4. 
Number of Participants ...............................................................................................46 
4.5. 
End of Study Definition ..............................................................................................46 
5. 
STUDY POPULATION .............................................................................................48 
5.1. 
Inclusion Criteria ........................................................................................................48 
5.2. 
Exclusion Criteria .......................................................................................................50 
5.3. 
Lifestyle Considerations .............................................................................................53 
5.3.1. 
Meals and Dietary Restrictions ...................................................................................53 
5.4. 
Screen Failures ............................................................................................................53 
5.4.1. 
Rescreening .................................................................................................................53 
6. 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ........................54 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 9 
6.1. 
Study Intervention(s) Administered ...........................................................................54 
6.2. 
Preparation/Handling/Storage/Accountability ............................................................54 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................................55 
6.3.1. 
Randomization ............................................................................................................55 
6.3.2. 
Blinding ......................................................................................................................55 
6.3.2.1. 
Unblinding ..................................................................................................................55 
6.4. 
Study Intervention Compliance ..................................................................................56 
6.5. 
Dose Modification ......................................................................................................56 
6.6. 
Continued Access to Study Intervention After the End of the Study .........................60 
6.7. 
Treatment of Overdose ...............................................................................................60 
6.8. 
Concomitant Therapy .................................................................................................60 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL .......................................62 
7.1. 
Discontinuation of Study Intervention........................................................................62 
7.2. 
Participant Withdrawal from the Study ......................................................................63 
7.3. 
Lost to Follow up ........................................................................................................64 
8. 
STUDY ASSESSMENTS ..........................................................................................65 
8.1. 
General Assessments ..................................................................................................65 
8.1.1. 
Demographics .............................................................................................................65 
8.1.2. 
Medical History ..........................................................................................................65 
8.1.3. 
Interactive Response Technology ...............................................................................66 
8.1.4. 
Participant eDiary .......................................................................................................66 
8.1.5. 
Confirmation of EMAS Diagnosis and Seizure Classification ...................................67 
8.1.6. 
Investigational Medicinal Product Accountability .....................................................68 
8.2. 
Efficacy Assessments .................................................................................................68 
8.2.1. 
Questionnaires and Assessments Completed at Scheduled Visits ..............................68 
8.2.1.1. 
Columbia-Suicide Severity Rating Scale (4 Years of Age and Older) .......................69 
8.2.1.2. 
Caregiver Global Impression of Change ....................................................................69 
8.2.1.3. 
Physician Global Impression of Change.....................................................................69 
8.2.1.4. 
Caregiver Global Impression of Change in Seizure Duration ....................................69 
8.2.1.5. 
Pediatric Quality of Life Inventory – Epilepsy Module .............................................69 
8.2.1.6. 
Pediatric Quality of Life Inventory – Family Impact Module ....................................70 
8.2.1.7. 
Achenbach Child Behavior Checklist .........................................................................70 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 10 
8.2.1.8. 
Behavior Rating Inventory of Executive Functioning ................................................70 
8.2.1.9. 
Treatment Credibility/Expectancy Questionnaire – Parent Version ..........................70 
8.2.1.10. 
Menstruation ...............................................................................................................71 
8.2.1.11. 
Tanner Staging ............................................................................................................71 
8.3. 
Safety Assessments .....................................................................................................71 
8.3.1. 
Physical Examinations ................................................................................................71 
8.3.2. 
Vital Signs ..................................................................................................................71 
8.3.3. 
Electrocardiograms .....................................................................................................71 
8.3.4. 
Clinical Safety Laboratory Assessments ....................................................................72 
8.3.5. 
Pregnancy Testing ......................................................................................................73 
8.3.6. 
Suicidal Ideation and Behavior Risk Monitoring .......................................................73 
8.4. 
Adverse Events, Serious Adverse Events and Other Safety Reporting ......................73 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE Information .......................74 
8.4.2. 
Method of Detecting AEs and SAEs ..........................................................................74 
8.4.3. 
Follow up of AEs and SAEs .......................................................................................74 
8.4.4. 
Regulatory Reporting Requirements for SAEs ...........................................................74 
8.4.5. 
Pregnancy ...................................................................................................................75 
8.4.6. 
Adverse Events of Special Interest .............................................................................75 
8.5. 
Pharmacokinetic Assessments ....................................................................................75 
8.6. 
Pharmacodynamic Assessment ...................................................................................76 
8.7. 
Genetics Assessment ..................................................................................................76 
8.8. 
Biomarkers ..................................................................................................................76 
8.9. 
Immunogenicity Assessments ....................................................................................76 
8.10. 
Healthcare Resource Utilization .................................................................................76 
8.11. 
Special Circumstances ................................................................................................76 
9. 
STATISTICAL CONSIDERATIONS .......................................................................78 
9.1. 
Statistical Hypotheses .................................................................................................78 
9.2. 
Sample Size Determination ........................................................................................78 
9.3. 
Analysis Sets ...............................................................................................................79 
9.4. 
Statistical Analyses .....................................................................................................79 
9.4.1. 
General Considerations ...............................................................................................79 
9.4.2. 
Primary Endpoint(s) ....................................................................................................80 
9.4.2.1. 
Missing Data ...............................................................................................................81 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 11 
9.4.2.2. 
Sensitivity Analyses ....................................................................................................81 
9.4.3. 
Secondary Endpoint(s) ................................................................................................82 
9.4.3.1. 
Key Secondary Endpoints ...........................................................................................82 
9.4.3.2. 
Other Secondary Efficacy Endpoints ..........................................................................83 
9.4.3.3. 
Safety Secondary Endpoints (Part A Only): ...............................................................83 
 
...........................................................................................84 
9.4.5. 
Safety Analysis ...........................................................................................................85 
9.4.5.1. 
Treatment Compliance and Extent of Treatment Exposure .......................................85 
9.4.5.2. 
Adverse Events ...........................................................................................................85 
9.4.5.3. 
Clinical Laboratory Data ............................................................................................85 
9.4.5.4. 
Vital Signs, ECG, Physical Examination and Other Safety Data ...............................86 
9.4.6. 
Other Analysis ............................................................................................................86 
9.5. 
Interim Analyses .........................................................................................................86 
9.5.1. 
Interim Analysis Review Committee ..........................................................................86 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................87 
10.1. 
Appendix 1: Study Contacts .......................................................................................87 
10.1.1. 
Investigator Details .....................................................................................................87 
10.1.2. 
Sponsor Contact Details .............................................................................................87 
10.1.3. 
Contract Research Organizations ...............................................................................87 
10.2. 
Appendix 2: Regulatory, Ethical, and Study Oversight Considerations ....................88 
10.2.1. 
Regulatory and Ethical Considerations ......................................................................88 
10.2.2. 
Financial Disclosure ...................................................................................................89 
10.2.3. 
Informed Consent/Assent Process ..............................................................................89 
10.2.4. 
Data Protection ...........................................................................................................90 
10.2.5. 
Committees Structure .................................................................................................90 
10.2.5.1. 
The Epilepsy Study Consortium .................................................................................90 
10.2.6. 
Dissemination of Clinical Study Data ........................................................................90 
10.2.7. 
Data Quality Assurance ..............................................................................................91 
10.2.8. 
Source Documents ......................................................................................................91 
10.2.9. 
Study and Site Start and Closure ................................................................................92 
10.2.9.1. 
First Act of Recruitment .............................................................................................92 
10.2.9.2. 
Study/Site Termination ...............................................................................................92 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 12 
10.2.10. 
Publication Policy .......................................................................................................93 
10.3. 
Appendix 3: Clinical Laboratory Tests .......................................................................93 
10.4. 
Appendix 4: AEs and SAEs: Definitions and Procedures for Recording, 
Evaluating, Follow up, and Reporting ........................................................................96 
10.4.1. 
Definition of AE .........................................................................................................96 
10.4.2. 
Definition of SAE .......................................................................................................97 
10.4.3. 
Adverse Events of Special Interest .............................................................................97 
10.4.4. 
Recording and Follow up of AE and/or SAE .............................................................98 
10.4.5. 
Reporting of SAEs ....................................................................................................100 
10.4.6. 
Urgent Safety Measures ............................................................................................100 
10.5. 
Appendix 5: Contraceptive and Barrier Guidance ....................................................101 
10.5.1. 
Definitions ................................................................................................................101 
10.5.2. 
Contraception Guidance ...........................................................................................101 
10.6. 
Appendix 6: Liver Safety: Actions and Follow-up Assessments .............................103 
10.7. 
Appendix 7: Abbreviations and Definitions .............................................................104 
10.8. 
Appendix 8: Protocol Amendment History ..............................................................108 
11. 
REFERENCES .........................................................................................................111 
 
 
LIST OF TABLES 
Table 1: 
Schedule of Activities: Part A ....................................................................................24 
Table 2: 
Schedule of Activities: Part B .....................................................................................29 
Table 3: 
Study Interventions .....................................................................................................54 
Table 4: 
Possible Range of Investigational Medicinal Product Doses During the 
14-Week Treatment Period of Part A .........................................................................57 
Table 5: 
Cross-Titration Scheme from End of 14-Week Treatment Period in Part A to 
Start of Part B .............................................................................................................59 
Table 6: 
Protocol-required Laboratory Tests ............................................................................94 
 
 
LIST OF FIGURES 
Figure 1: 
Study Schema: Part A .................................................................................................22 
Figure 2: 
Study Schema: Part B .................................................................................................23 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 13 
1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title:  
A randomized, double-blind, placebo-controlled, multisite, Phase 3 study to investigate the 
efficacy and safety of cannabidiol oral solution (GWP42003-P) in children and adolescents with 
epilepsy with myoclonic-atonic seizures  
Brief Title:  
A safety and efficacy study of cannabidiol oral solution (GWP42003-P) in children and 
adolescents with epilepsy with myoclonic-atonic seizures between 1 and 18 years of age, 
inclusive. 
Phase: 3 
Indication: Treatment of seizures associated with epilepsy with myoclonic-atonic seizures 
(EMAS) syndrome in participants between 1 and 18 years of age, inclusive. 
Study Rationale: 
EMAS, also known as Doose syndrome, myoclonic-astatic epilepsy, or myoclonic-atonic 
epilepsy, is a childhood-onset idiopathic generalized seizure disorder. EMAS is characterized by 
multiple seizure types; however, myoclonic-atonic seizures are the hallmark seizure type and are 
mandatory for the diagnosis of EMAS. 
There are no FDA-approved treatment options specifically for EMAS and its associated primary 
seizure types (ie, myoclonic-atonic and/or atonic and/or myoclonic seizures) and no clear 
consensus treatment guidelines for EMAS. Thus, there is a clear unmet need for the development 
of effective and well-tolerated treatments that target the primary seizures associated with EMAS. 
Based on the results of several Phase 3 studies and open-label studies with GWP42003-P in the 
treatment of other pediatric epilepsy syndromes, GWP42003-P may be an appropriate candidate 
to investigate for the treatment of EMAS. 
Therefore, the primary aim of Part A of the study is to assess the efficacy of GWP42003-P 
compared to placebo as an adjunctive treatment for children with EMAS. The primary aim of 
Part B of the study is to evaluate the long-term safety and tolerability of GWP42003-P in 
participants with EMAS. 
Objectives and Endpoints: 
Part A 
Objectives 
Endpoints 
Primary 
• 
To evaluate the efficacy of GWP42003-P 
compared with placebo in reducing the 
frequency of EMAS-associated seizures 
• 
Change in EMAS-associated seizure 
frequency (myoclonic-atonic, atonic, tonic, 
clonic, or tonic-clonic) during the 14-week 
treatment period compared to baseline 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 14 
Key Secondary 
• 
To evaluate the rate of treatment response to 
GWP42003-P compared with placebo in 
reducing the frequency of EMAS-associated 
seizures 
• 
Proportion of participants who achieve ≥ 50% 
reduction from baseline in EMAS-associated 
seizures over the 14-week treatment period 
• 
To evaluate the effect of GWP42003-P 
compared with placebo on caregiver 
impression of change  
• 
CGIC score at Week 14 
• 
To evaluate the effect of GWP42003-P in 
reducing the frequency of all seizure types 
compared with placebo 
• 
Change in total seizure frequency during the 
14-week treatment period compared to 
baseline 
Secondary 
• 
To evaluate the effect of GWP42003-P 
compared with placebo on physician 
impression of change 
• 
PGIC score at Week 14 
• 
To evaluate the effect of GWP42003-P 
compared with placebo on additional 
antiepileptic measures from daily seizure 
diaries 
• 
Proportion of participants who achieve 
≥ 25%, ≥ 75%, and 100% reduction from 
baseline in EMAS-associated seizures over 
the 14-week treatment period 
• 
Proportion of participants who achieve 
≥ 25%, ≥ 50%, ≥ 75%, and 100% reduction 
from baseline in total seizures over the 
14-week treatment period  
• 
Change from baseline in number of 
EMAS-associated seizure-free days over the 
14-week treatment period  
• 
Proportion of participants with ≥25% and 
≥ 50% reduction in the number of days per 
week with myoclonic seizures during the 
treatment period  
• 
Time to baseline seizure frequency 
• 
To evaluate the safety and tolerability of 
GWP42003-P compared with placebo 
• 
Frequency of TEAEs over the 14-week 
treatment period  
• 
Laboratory tests 
• 
Vital signs 
• 
ECG 
• 
Tanner Staging  
• 
Change in: 
o  C-SSRS ideation score 
o Number of suicide attempts in the 
C-SSRS  


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 15 
 
 
Part B 
Primary 
• 
To evaluate the long-term safety and 
tolerability of GWP42003-P in participants 
with EMAS 
• 
Frequency of TEAEs over the 48-week 
treatment period  
• 
Laboratory tests 
• 
Vital signs 
• 
ECG 
• 
Tanner Staging  
• 
Change in: 
o C-SSRS ideation score 
o Number of suicide attempts in the 
C-SSRS 
Key Secondary 
• 
To evaluate long-term effect of GWP42003-P 
on seizure frequency and additional measures 
• 
Change in EMAS-associated seizure 
frequency (myoclonic-atonic, atonic, tonic, 
clonic, or tonic-clonic) compared to baseline 
• 
Proportion of participants achieving ≥ 50% 
reduction in EMAS-associated seizures 
• 
CGIC score 
• 
Change in total seizure frequency compared 
to baseline 
Secondary 
• 
To evaluate long-term effect of GWP42003-P 
on additional measures 
• 
PGIC score 
• 
Proportion of participants who achieve 
≥ 25%, ≥ 75%, and 100% reduction in 
EMAS-associated seizures from baseline 
• 
Proportion of participants who achieve 
≥ 25%, ≥ 50%, ≥ 75%, and 100% reduction in 
total seizures from baseline 
• 
Proportion of participants with ≥ 25% and 
≥ 50% reductions in the number of days per 
week with myoclonic seizures  
Abbreviations: CGIC = Caregiver Global Impression of Change; C-SSRS = Columbia-Suicide Severity Rating 
Scale; ECG = 12-lead electrocardiogram; EMAS = epilepsy with myoclonic-atonic seizures; PGIC = Physician 
Global Impression of Change; TEAE = treatment-emergent adverse event. 
Estimands (Part A Only) 
The primary estimand for this study is defined by the following 3 components: 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 16 
• Target population: participants with EMAS-associated seizures who have not 
achieved adequate control from other ASMs. 
• Endpoint: change in EMAS-associated seizure frequency during the 14-week 
treatment period compared to baseline. 
• Measure of IMP effect: change in EMAS-associated seizure frequency during the 
treatment period, regardless of any intercurrent events. This measure of effect follows 
the treatment policy strategy for handling intercurrent events. 
The first key secondary estimand for this study is defined as follows: 
• Target population: participants with EMAS-associated seizures who have not 
achieved adequate control from other ASMs.  
• Endpoint: proportion of participants who achieve ≥ 50% reduction from baseline in 
EMAS-associated seizures over the 14-week treatment period. 
• Measure of IMP effect: proportion of responders during the treatment period, 
regardless of any intercurrent events. This measure of effect follows a treatment 
policy strategy for handling intercurrent events. 
The second key secondary estimand for this study is defined as follows: 
• Target population: participants with EMAS-associated seizures who have not 
achieved adequate control from other ASMs.  
• Endpoint: CGIC score at Week 14. 
• Measure of IMP effect: CGIC score at Week 14, regardless of any intercurrent events. 
This measure of effect follows a treatment policy strategy for handling intercurrent 
events. 
The third key secondary estimand for this study is defined as follows: 
• Target population: participants with EMAS-associated seizures who have not 
achieved adequate control from other ASMs.  
• Endpoint: change in total seizure frequency during the 14-week treatment period 
compared to baseline. 
• Measure of IMP effect: change in total seizure frequency during the treatment period, 
regardless of any intercurrent events. This measure of effect follows a treatment 
policy strategy for handling intercurrent events. 
Overall Design: 
• This is a multisite, double-blind, randomized, placebo-controlled, parallel-group 
study (Part A) to evaluate the safety and efficacy of GWP42003-P compared to 
placebo as a treatment for children and adolescents with EMAS, followed by an 
open-label extension phase (Part B).  


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 17 
Part A: 
• The duration of study participation in Part A is approximately 26 weeks, which 
includes a 1- to 3-week screening period, 4-week baseline observation period, 
14-week dose-optimization treatment period, 10-day taper period, and a safety 
follow-up period (4 weeks after end-of-taper visit).  
• After the informed consent/assent form has been signed, participants will be screened 
to enter the study from Day -49 to Day -35 (Visit 1) and commence a 28-day baseline 
period beginning at Day -28 (Visit 2), before returning for a randomization visit and 
treatment initiation (Day 1 [Visit 3]). 
• IMP administration during the 14-week treatment period will follow a flexible 
titration schedule to enable optimization of dosage.  
• Visits 4 to 6 will be conducted as phone visits; Visit 7 will be completed in clinic, and 
Visit 8 will be completed in clinic or at home visit. Participants will then return to the 
study site for an end of treatment visit (Day 99 [Visit 9]). If a participant withdraws 
from the study prematurely (ie, before the end of treatment visit) an early withdrawal 
visit will be conducted, and a safety follow-up phone call will occur 4 weeks after 
their last dose of IMP. If a participant discontinues IMP prematurely, they should be 
encouraged to complete the end of treatment visit and the taper period and remain in 
the study. Participants not continuing to Part B of the study will return to the study 
site again at the end of the 10-day taper period (Day 110 [Visit 10]) and complete a 
phone safety visit at the end of the follow-up period (Day 138 [Visit 11]).  
• Part B will be available to participants who complete Part A of the study and continue 
to meet all eligibility criteria and to participants for whom the investigator feels 
continued treatment in Part B represents a favorable risk-benefit assessment. Rollover 
into Part B should occur on the same day as Part A Day 99 (Visit 9). 
• Unscheduled phone visits can occur at any time throughout Part A, as needed. 
Part B: 
• Part B will evaluate the long-term safety, tolerability, 
 of 
GWP42003-P for a period of 48 weeks in participants with EMAS-associated 
seizures. All participants in Part B will receive GWP42003-P. 
• The duration of study for Part B will be approximately 54 weeks, which includes a 
48-week treatment period (including a 2-week blinded titration [or transition] period 
for all participants), 10-day taper period, and a safety follow-up period (4 weeks after 
end-of-taper visit). 
• Part B will be available to participants who complete Part A of the study and continue 
to meet all eligibility criteria and to participants for whom the investigator feels 
continued treatment in Part B represents a favorable risk-benefit assessment. 
• Participants who continue into Part B of the study will proceed without the Part A 
taper period (Visit 10) and follow-up visit (Visit 11). The Part A end of treatment 
visit (Visit 9) procedures/data will then be utilized for Visit 1 of Part B (ie, the same 
procedures should not be repeated at Visit 9 of Part A and Visit 1 of Part B). If the 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 18 
participant is continuing to Part B, IMP should only be dispensed at Part B Visit 1. If 
the participant is not continuing to Part B, IMP for the taper period will be dispensed 
at Part A Visit 9, as required. 
• Participants who do not enroll in Part B at Visit 9 of Part A will be required to 
complete Part A and continue to an end-of-taper visit (Visit 10) and a follow-up visit 
(Visit 11). 
• In order to maintain consistent exposure to IMP and maintain the integrity of the 
blind, participants will enter a 2-week blinded transition to Part B. Part B IMP will be 
titrated up to 10 mg/kg/day whilst blinded IMP is simultaneously tapered down to 
zero. All participants will complete the transition and enter Part B taking 
GWP42003-P (Section 6.5 Part B) (Table 5). 
• A safety follow-up visit (phone call) will be conducted 4 weeks after the end-of-taper 
visit. If a participant withdraws from the study prematurely (ie, before the end of 
treatment visit), an early withdrawal visit will be conducted, and a safety follow-up 
phone call will occur 4 weeks after their last dose of IMP. Participants who 
discontinue IMP prematurely should be encouraged to complete the end of treatment 
visit and taper period. 
Schematics (Figure 1 for Part A and Figure 2 for Part B), presented in Section 1.2, depict the 
overall study design. A detailed outline of procedures and activities is provided in the Schedule 
of Activities (Table 1 for Part A and Table 2 for Part B). 
Brief Summary: 
The purpose of this study is to assess the change from baseline in seizure frequency of twice 
daily (BID) doses of cannabidiol (CBD; GWP42003-P) compared with placebo in children and 
adolescents with EMAS. Study details include: 
Study Duration: Approximately 80 weeks (Part A: 26 weeks and Part B: 54 weeks) 
Treatment Duration: Up to approximately 66 weeks for Part A and Part B (Part A up to 
16 weeks including the taper period and Part B up to 50 weeks, including the taper period) 
Visit Frequency: Weekly or monthly (study site visits, home visits, or phone visits). 
GWP42003-P is not available through an expanded access program. 
Number of Participants: 
Up to a maximum of 120 participants (up to 60 per treatment arm) will be randomized in Part A 
of this study. 
Summary of Participant Eligibility 
Male/female participants between 1 and 18 years of age, inclusive, with diagnosed EMAS with a 
minimum average frequency of ≥ 2 The Epilepsy Study Consortium-approved, countable, 
EMAS-associated seizures (myoclonic-atonic, atonic, tonic, clonic, or tonic-clonic) per week 
(≥ 8 seizures per month) at baseline, refractory to anticonvulsant treatment (failed ≥ 1 prior 
ASM) and treated with 1 or more ASMs on a stable regimen (≥ 28 days prior to starting the 
baseline period [Part A Visit 2]) or on a stable ketogenic diet/epilepsy dietary therapy (≥ 28 days 
prior to starting the baseline period [Part A Visit 2]) (Section 5.1 and Section 5.2). 






Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 21 
the following for each participant: LOCF, NOCB and the mean daily number of 
seizures during the treatment period based on nonmissing data: 
Number of seizures 
Number of reported days in the eDiary 
− For participants in the active arm who withdraw from the study due to an adverse 
event or lack of efficacy, missing eDiary data will be imputed as the baseline rate 
or the average seizure frequency during the treatment period, whichever is higher. 
• To test the sensitivity of the results of the primary analysis to the degree of borrowing 
introduced by the dynamic borrowing prior, a model similar to the primary analysis 
model will explore a range of degrees of fixed borrowing of the historical data. More 
specifically, the variance of the Bayesian hierarchical distribution specified for the 
treatment effects across populations (Section 9.4.2) will be fixed across a set of 
values specified in the ADR ranging from very low (full borrowing) to very high (no 
borrowing). Summaries of the estimated treatment effect within each sensitivity 
analysis will be provided to assess the robustness of the primary analysis results to the 
degree of borrowing. 
Part B: 
All data collected during this part of the study will be summarized over time using appropriate 
descriptive statistics. Where baseline data are available from Part A, changes from baseline will 
also be presented as appropriate.  
Interim Analyses 
Interim analyses will be performed when 60, 75, 90, and 105 participants are randomized in 
Part A. The maximum sample size will be 120 randomized participants. The interim analyses or 
sample size updates will be based on the Goldilocks methodology in which Bayesian predictive 
probabilities are used to make sample size decisions.  
Data Monitoring/Other Committee:  
An IARC will be responsible for reviewing the data and providing recommendations based on 
the interim analyses of this study (see Section 9.5.1 for details). 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 22 
1.2. 
Schema 
Figure 1: 
Study Schema: Part A 
Abbreviations: ASMs = antiseizure medications; DRF = Diagnostic Review Form; eDiary = electronic diary; SIF = Seizure Identification Form; TESC = The Epilepsy Study Consortium. 
Note: Additional information for dose titration is provided in Section 6.5 and Table 4. 
Visit 2 will occur 14 to 21 days following Visit 1. Visit 2 cannot occur until the site has received final TESC approval of SIF/DRF and eDiary Seizure Classification Report. 
Visit 3 will occur 28 days (+3 days) following Visit 2. 
 
 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 23 
Figure 2: 
Study Schema: Part B 
 
Abbreviations: ASMs = antiseizure medication; WK = week.  
Note: Additional information for dose titration is provided in Section 6.5 and Table 5. 
 




















Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 33 
2. 
INTRODUCTION 
2.1. 
Background 
2.1.1. 
Disease Background 
EMAS, also known as Doose syndrome, myoclonic-astatic epilepsy, or myoclonic-atonic 
epilepsy, is a childhood-onset primary generalized seizure disorder (Zempel 2014). EMAS is 
also classified as a developmental epileptic encephalopathy. Symptoms typically present 
between 1 to 6 years of age, with an estimated 24% of diagnosed children experiencing their first 
afebrile seizure between 1 and 2 years of age (Hinokuma 2020) (Neubauer 2005). EMAS 
represents up to an estimated 2.2% of childhood-onset epilepsies and has an approximate 
incidence rate of 1 in 10,000 children (Neubauer 2005). 
EMAS is characterized by multiple seizure types (myoclonic-atonic, myoclonic, atonic, 
generalized tonic-clonic, atypical absences, and tonic seizures). However, myoclonic-atonic 
seizures are the hallmark seizure type and are mandatory for the diagnosis of EMAS 
(Hinokuma 2020) (Neubauer 2005). Myoclonic-atonic seizures are myoclonic seizures that are 
followed by atonic seizures, which result in drop attacks. Myoclonic seizures specifically 
produce quick, jerking movements (Hinokuma 2020), and atonic seizures cause patients to lose 
tone briefly, causing small drops of the head or trunk. 
The majority of children with EMAS have normal development prior to onset of seizures 
(Moeller 2014) or exhibit only mild developmental/cognitive delays. Moreover, when well 
controlled, up to 90% of patients with EMAS can have normal or mild cognitive impairment 
(Oguni 1992).  
Children with EMAS who develop tonic seizures and whose disease progresses to episodes of 
nonconvulsive status epilepticus, tend to have a poor prognosis that is often accompanied by 
significant developmental delays, cognitive impairment, intractable epilepsy, and intellectual 
disability (Oguni 1992) (Stephani 2006) (Wirrell 2018) (Hinokuma 2020). The most common 
cognitive effects associated with inadequately controlled seizures include deficits in processing 
speed, language, verbal learning, and memory (specifically phonological working memory in 
EMAS patients) (Doose 1992) (Kilaru 2007). Traditional ASM treatment can contribute to these 
cognitive deficits, which can be worsened by drug-drug interactions as many of these patients 
will be on 2 or more ASMs (Kilaru 2007). Many of the clinical features of EMAS are also 
common to LGS, although myoclonic-atonic seizures do not predominantly occur in LGS and 
patients with EMAS are typically developmentally normal with normal EEG background early in 
the course. 
2.1.2. 
Study Intervention Background 
GWP42003-P is the product code for the IMP, purified GWP42003-P, a CBD under 
development by the sponsor for the treatment of a number of conditions. 
CBD is extracted from the Cannabis sativa L. plant as CBD BDS and purified by crystallization 
from solvent to produce the CBD active substance.  


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 34 
Nonclinical pharmacology studies conducted by the sponsor have identified antiepileptic, 
anti-inflammatory, neuroprotective, and antipsychotic activities for CBD. 
A large body of nonclinical toxicity data on purified CBD and CBD BDS suggests a good safety 
profile for CBD and a wide safety margin between the proposed clinical dose of CBD and the 
dose at which toxicity is noted. 
There is an adequate margin of safety for CBD at a daily dose of up to 25 mg/kg/day in a 
pediatric and adult population. 
A single ascending-dose study has been conducted where 4 groups of 6 healthy participants 
received single oral doses of either 1500, 3000, 4500, or 6000 mg GWP42003-P (GWEP1544). 
Each single oral dose was well or moderately well tolerated. 
The sponsor has performed a number of clinical studies to investigate a range of possible 
indications for GWP42003-P. These include 5 positive pivotal studies that have supported its 
commercialization in the US, EU, and other geographic expansion areas as an ASM. 
2.2. 
Study Rationale 
There are no FDA-approved treatment options specifically for EMAS and its associated primary 
seizure types (ie, myoclonic-atonic and/or atonic and/or myoclonic seizures) and no clear 
consensus treatment guidelines for EMAS. Drug resistance to ASMs in children with EMAS is 
common and patients typically fail an average of 5 ASMs (Doose 1970) (Oguni 1992). While 
several ASMs, including valproic acid, clobazam, clonazepam, and levetiracetam have been 
reported to be beneficial, none of these agents have been evaluated in randomized, controlled 
studies in patients with EMAS. Furthermore, most of these ASMs have also been associated with 
safety and tolerability issues, such as sedation, ataxia, and cognitive impairment (Menlove 2015). 
Valproic acid may have the best efficacy for controlling myoclonic seizures, but it is associated 
with additional safety and tolerability issues (eg, risk for hepatotoxicity, teratogenicity, alopecia, 
etc.). EMAS is considered challenging to treat and often requires patients to tolerate 
difficult-to-maintain ketogenic diets (Goldberg 2001). Despite all the treatment options with 
ASMs and ketogenic diet, 20 to 50% of patients will not respond to treatment and only 50% will 
become seizure free (Kelley 2010) (Helmstaedter 2020). Thus, there is a clear unmet need for the 
development of effective and well-tolerated treatments that target the primary seizures associated 
with EMAS. 
Based on the results of several Phase 3 studies and open-label studies with GWP42003-P in the 
treatment of other pediatric epilepsy syndromes, GWP42003-P may be an appropriate candidate 
to investigate for the treatment of EMAS. Results of 5 Phase 3 randomized, double-blind, 
placebo-controlled studies show robust efficacy of GWP42003-P for treatment of seizures 
associated with LGS (Devinsky 2018a) (Thiele 2018), DS (Devinsky 2017) (Miller 2020), and 
TSC (Thiele 2020b). These effects were sustained with long-term therapy up to 1.5 years 
(Devinsky 2016). There is also strong preclinical (Gofshteyn 2017) (Hess 2016) and real-world 
evidence (Devinsky 2016) (Devinsky 2018b) (Szaflarski 2018) (Thiele 2020a) suggesting that 
GWP42003-P might have antiepileptic properties that target a broad range of seizure types. 
GWP42003-P was also used in patients with treatment-resistant epilepsies other than those 
already approved by the FDA, including EMAS, as part of an investigator-initiated, 
FDA-authorized EAP. Interim safety and efficacy data collected as part of open-label studies of 




Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 36 
3. 
OBJECTIVES AND ENDPOINTS 
3.1. 
Part A 
 
Primary 
• 
To evaluate the efficacy of GWP42003-P 
compared with placebo in reducing the 
frequency of EMAS-associated seizures 
• 
Change in EMAS-associated seizure 
frequency (myoclonic-atonic, atonic, tonic, 
clonic, or tonic-clonic) during the 14-week 
treatment period compared to baseline 
Key Secondary 
• 
To evaluate the rate of treatment response to 
GWP42003-P compared with placebo in 
reducing the frequency of EMAS-associated 
seizures 
• 
Proportion of participants who achieve ≥ 50% 
reduction from baseline in EMAS-associated 
seizures over the 14-week treatment-period 
• 
To evaluate the effect of GWP42003-P 
compared with placebo on caregiver 
impression of change 
• 
CGIC score at Week 14 
• 
To evaluate the effect of GWP42003-P in 
reducing the frequency of all seizure types 
compared with placebo 
• 
Change in total seizure frequency during the 
14-week treatment period compared to 
baseline 
Secondary 
• 
To evaluate the effect of GWP42003-P 
compared with placebo on physician 
impression of change 
• 
PGIC score at Week 14 
• 
To evaluate the effect of GWP42003-P 
compared with placebo on additional 
antiepileptic measures from daily seizure 
diaries 
• 
Proportion of participants who achieve 
≥ 25%, ≥ 75%, and 100% reduction from 
baseline in EMAS-associated seizures over 
the 14-week treatment period 
• 
Proportion of participants who achieve 
≥ 25%, ≥ 50%, ≥ 75%, and 100% reduction 
from baseline in total seizures over the 
14-week treatment period 
• 
Change from baseline in number of 
EMAS-associated seizure-free days over the 
14-week treatment period 
• 
Proportion of participants with ≥ 25% and 
≥ 50% reduction in the number of days per 
week with myoclonic seizures during the 
treatment period 




Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 38 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 39 
3.2. 
Part B 
Primary 
• 
To evaluate the long-term safety and 
tolerability of GWP42003-P in participants 
with EMAS 
• 
Frequency of TEAEs over the 48-week 
treatment period  
• 
Laboratory tests 
• 
Vital signs 
• 
ECG 
• 
Tanner Staging  
• 
Change in: 
o C-SSRS ideation score 
o Number of suicide attempts in the 
C-SSRS 
Key Secondary 
• 
To evaluate long-term effect of GWP42003-P 
on seizure frequency and additional measures 
• 
Change in EMAS-associated seizure 
frequency (myoclonic-atonic, atonic, tonic, 
clonic, or tonic-clonic) compared to baseline 
• 
Proportion of participants achieving ≥ 50% 
reduction in EMAS-associated seizures 
• 
CGIC score  
• 
Change in total seizure frequency compared 
to baseline 
Secondary 
• 
To evaluate long-term effect of GWP42003-P 
on additional measures 
• 
PGIC score 
• 
Proportion of participants who achieve 
≥ 25%, ≥ 75%, and 100% reduction in 
EMAS-associated seizures from baseline 
• 
Proportion of participants who achieve 
≥ 25%, ≥ 50%, ≥ 75%, and 100% reduction in 
total seizures from baseline 
• 
Proportion of participants with ≥ 25% and 
≥ 50% reduction in the number of days per 
week with myoclonic seizures  




Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 41 
The first key secondary estimand for this study is defined as follows: 
• Target population: participants with EMAS-associated seizures who have not 
achieved adequate control from other ASMs.  
• Endpoint: proportion of participants who achieve ≥ 50% reduction from baseline in 
EMAS-associated seizures over the 14-week treatment period. 
• Measure of IMP effect: proportion of responders during the treatment period, 
regardless of any intercurrent events. This measure of effect follows a treatment 
policy strategy for handling intercurrent events. 
The second key secondary estimand for this study is defined as follows: 
• Target population: participants with EMAS-associated seizures who have not 
achieved adequate control from other ASMs.  
• Endpoint: CGIC score at Week 14. 
• Measure of IMP effect: CGIC score at Week 14, regardless of any intercurrent events. 
This measure of effect follows a treatment policy strategy for handling intercurrent 
events. 
The third key secondary estimand for this study is defined as follows: 
• Target population: participants with EMAS-associated seizures who have not 
achieved adequate control from other ASMs.  
• Endpoint: change in total seizure frequency during the 14-week treatment period 
compared to baseline. 
• Measure of IMP effect: change in total seizure frequency during the treatment period, 
regardless of any intercurrent events. This measure of effect follows a treatment 
policy strategy for handling intercurrent events. 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 42 
4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a multisite, double-blind, randomized, placebo-controlled, parallel-group study to 
evaluate the efficacy and safety of GWP42003-P compared to placebo as a treatment for children 
and adolescents with EMAS, followed by an OLE phase. The study will consist of 2 parts: 
Part A: 
The duration of study participation is approximately 26 weeks, which includes a 1- to 3-week 
screening period, 4-week baseline observation period, 14-week dose-optimization treatment 
period, 10-day taper period, and a safety follow-up period (4 weeks after end of taper visit). 
After the ICF has been signed, participants will be screened to enter the study from Day -49 to 
Day -35 (Visit 1) and commence a 28-day baseline period beginning at Day -28 (Visit 2), before 
returning for a randomization visit and treatment initiation (Day 1 [Visit 3]).  
On Day -28 (Visit 2), participants who continue to meet eligibility criteria will be contacted by 
phone and commence a 28-day baseline period, before returning for a randomization visit and 
treatment initiation (Day 1 [Visit 3]). 
On Day 1 (Visit 3), participants will be randomized centrally in a 1:1 ratio to receive either 
GWP42003-P or matching placebo. Randomization will be stratified by clobazam use (on/off) 
and age of seizure onset (3 years of age and younger or older than 3 years of age). 
IMP administration during the 14-week treatment period will follow a flexible titration schedule 
to enable optimization of dosage:  
• Participants will be initiated on a dose of 2.5 mg/kg BID (5 mg/kg/day) on Day 1 
(Visit 3), and after 1 week, the dose will be increased to 5 mg/kg BID (10 mg/kg/day) 
at the Day 8 (Visit 4) phone visit. 
• For participants who are tolerating the IMP at 5 mg/kg BID (10 mg/kg/day) and 
require further reduction of seizures, investigators may choose to increase their 
dosage up to a maximum dosage of 10 mg/kg BID (20 mg/kg/day). The decision to 
titrate above 5 mg/kg BID (10 mg/kg/day) should be based on the observed efficacy, 
safety, and tolerability of the participant (including review of laboratory values) per 
the clinical judgement of the investigator. 
• Starting at the Day 15 (Visit 5) phone visit, investigators have the option to titrate 
participants no more rapidly than 2.5 mg/kg BID (5 mg/kg/day) every 7 days, up to a 
maximum daily dosage of 20 mg/kg/day. The investigator will determine if further 
dose adjustments are warranted during unscheduled phone visits and/or scheduled 
clinic visits throughout the remainder of the 14-week treatment period. If dose change 
is warranted outside of a scheduled visit, the caregiver should be contacted by phone 
prior to making any dose increases above 10 mg/kg/day to assess the appropriateness 
of the dose increase based on the participant’s reported clinical response and ensure 
the caregiver has received the updating dosing schedule reflecting the new target 
dose. This contact should be documented as an unscheduled phone visit in the eCRF. 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 43 
• After Day 15 (Visit 5) phone visit, if in the investigator’s opinion, a participant is 
experiencing a clinically meaningful improvement in EMAS-associated seizures, the 
investigator can choose to continue treatment at the participant’s current dosage and 
may re-consider an increase in the dosage of IMP at either a later study visit, or at any 
time between study visits, as described above. 
• If a participant reports any tolerability issues related to IMP, the investigator can also 
decrease a participant’s current dosage. Dose decreases to below 10 mg/kg/day, based 
on safety and tolerability may occur at any time. Investigators should regularly 
monitor a participant’s response to treatment and re-evaluate the need for adjustments 
to dosage (ie, increase, maintain, or decrease) at the next study visit, if applicable. 
The rationale for any dosage changes will be documented in the appropriate eCRF. 
Participants will complete weekly scheduled phone visits at Day 8 (Visit 4), Day 15 (Visit 5), 
and Day 22 (Visit 6) and complete an in-clinic visit at Day 29 (Visit 7) and an in-clinic or home 
visit for review of symptoms and safety laboratory tests and to return/dispense IMP at 
Day 57 (Visit 8). Participants will then return to the study site for an end of treatment visit 
(Day 99 [Visit 9]). If a participant withdraws from the study prematurely (ie, before the end of 
treatment visit), an early withdrawal visit will be conducted, and a safety follow-up phone call 
will occur 4 weeks after their last dose of IMP. If a participant discontinues IMP prematurely, 
they should be encouraged to complete the end of treatment visit and the taper period and remain 
in the study. 
Participants not continuing to Part B will return to the study site again at the end of the 10-day 
taper period (Day 110 [Visit 10]) and will complete a phone safety visit at the end of the 
follow-up period (Day 138 [Visit 11]).  
Part B will be available to participants who complete Part A of the study and continue to meet all 
eligibility criteria and to participants for whom the investigator feels continued treatment in 
Part B represents a favorable risk-benefit assessment. Rollover into Part B should occur on the 
same day as Part A Day 99 (Visit 9). 
Unscheduled phone visits can occur at any time throughout Part A, as needed. 
AE, concomitant medication, and rescue medication eDiaries will be completed each day during 
the screening period, baseline observation period, treatment period, and taper period beginning at 
screening (Visit 1). 
Seizure eDiaries will be completed each day during the screening period, baseline observation 
period, and treatment period beginning at screening (Visit 1). 
IMP dosing eDiaries will be completed each day during the titration, treatment, and taper periods 
beginning at randomization (Visit 3). 
Food eDiaries will be completed for approximately 24 hours prior to each visit where PK blood 
samples will be collected beginning approximately 24 hours prior to randomization (Visit 3). 
Part B: 
Part B will evaluate the long-term safety, tolerability, 
 of GWP42003-P 
for a period of 48 weeks in participants with EMAS-associated seizures. All participants in 
Part B will receive GWP42003-P. 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 44 
The duration of study for Part B will be approximately 54 weeks, which includes a 48-week 
treatment period (including a 2-week blinded titration [or transition] period for all participants), 
10-day taper period, and a safety follow-up period (4 weeks after end-of-taper visit). 
Part B will be available to participants who complete Part A of the study and continue to meet all 
eligibility criteria and to participants for whom the investigator feels continued treatment in 
Part B represents a favorable risk-benefit assessment. 
Participants who continue into Part B of the study will proceed without the Part A taper period 
(Visit 10) and follow-up visit (Visit 11). The Part A end of treatment visit (Visit 9) 
procedures/data will then be utilized for Visit 1 of Part B (ie, the same procedures should not be 
repeated at Visit 9 of Part A and Visit 1 of Part B). If the participant is continuing to Part B, IMP 
should only be dispensed at Part B Visit 1. If the participant is not continuing to Part B, IMP for 
the taper period will be dispensed at Part A Visit 9, as required. 
Participants who do not enroll in Part B at Visit 9 of Part A will be required to complete an 
end-of-taper visit (Visit 10) and a follow-up visit (Visit 11). 
In order to maintain consistent exposure to IMP and maintain the integrity of the blind, 
participants will enter a 2-week blinded transition to Part B. Part B IMP will be titrated up to 
10 mg/kg/day whilst blinded IMP is simultaneously tapered down to zero. All participants will 
complete the transition and enter Part B taking GWP42003-P (Section 6.5 Part B) (Table 5). 
Investigators have the option to titrate participants no more rapidly than 2.5 mg/kg BID 
(5 mg/kg/day) every 7 days, up to a maximum daily dosage of 20 mg/kg/day. 
After Part B Week 2 (Visit 3), for some participants in whom a more rapid titration from 10 to 
20 mg/kg/day is warranted, the dosage may be increased no more frequently than every other day 
following consultation with the medical monitor and/or sponsor representative.  
If any safety/tolerability issues, investigators can decide to maintain or decrease dosage. 
After Part B Week 14 (Visit 7), serum transaminases and total bilirubin levels should be 
evaluated within 1 month following changes in GWP42003-P dosage and in medications that are 
known to impact the liver. 
• As much as possible, laboratory assessments should be done centrally via IQVIA 
Mobile Health Solutions (if done locally, laboratory results should be filed in source 
documents and any abnormal and clinically significant results should be recorded as 
AEs) 
A safety follow-up visit (phone call) will be conducted 4 weeks after the end-of-taper visit. If a 
participant withdraws from the study prematurely (ie, before the end of treatment visit), an early 
withdrawal visit will be conducted, and a safety follow-up phone call will occur 4 weeks after 
their last dose of IMP. Participants who discontinue IMP prematurely should be encouraged to 
complete the end of treatment visit and taper period. 
Unscheduled phone visits can occur at any time during Part B, as needed. 
During Part B, eDiaries will be completed at least weekly. No food eDiary is required for Part B. 
Schematics (Figure 1 for Part A and Figure 2 for Part B), presented in Section 1.2, depicts the 
overall trial design. A detailed outline of procedures and activities is provided in the SoA 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 45 
(Table 1 for Part A and Table 2 for Part B). More detailed information on treatment and study 
procedures is provided in Section 6 and Section 8, respectively. 
4.2. 
Scientific Rationale for Study Design 
EMAS is characterized by multiple seizure types (myoclonic-atonic, myoclonic, atonic, 
generalized tonic-clonic, atypical absences, and tonic seizures), with myoclonic-atonic seizures 
being the hallmark seizure type and mandatory for the diagnosis of EMAS (Hinokuma 2020) 
(Kelley 2010) (Neubauer 2005). There are no FDA-approved treatment options specifically for 
EMAS and its associated primary seizure types (ie, atonic and/or myoclonic seizures), and no 
clear consensus treatment guidelines for EMAS. Drug resistance to ASMs in children with 
EMAS is common and patients are typically exposed to and fail an average of 5 ASMs 
(Doose 1970) (Oguni 1992). While several ASMs have been reported to be beneficial, none of 
these agents have been evaluated in randomized, controlled studies in EMAS patient. 
Furthermore, most of these ASMs have also been associated with safety and tolerability issues, 
such as sedation, ataxia, and cognitive impairment (Menlove 2015). EMAS is considered 
challenging to treat, often requiring patients to tolerate difficult-to-maintain ketogenic diets 
(Goldberg 2001). Despite all the treatment options with ASMs and ketogenic diet, 20 to 50% of 
patients do not respond to treatment and only 50% become seizure-free (Helmstaedter 2020) 
(Kelley 2010). Thus, there is a clear unmet need for the development of effective and 
well-tolerated treatments that target the primary seizures associated with EMAS.  
Based on the results of several Phase 3 studies and open-label studies with GWP42003-P in the 
treatment of other pediatric epilepsy syndromes, GWP42003-P may be an appropriate candidate 
to investigate for the treatment of EMAS. Results of 5 Phase 3 randomized, double-blind, 
placebo controlled studies show robust efficacy of GWP42003-P for treatment of seizures 
associated with LGS (Devinsky 2018a) (Thiele 2018), DS (Devinsky 2017) (Miller 2020), and 
TSC (Thiele 2020b). The anticonvulsant efficacy of GWP42003-P was durable as effects were 
sustained up to 1.5 years (Devinsky 2016).  
GWP42003-P was also investigated in patients with other treatment-resistant epilepsies in the 
investigator initiated, FDA authorized EAP (including those with EMAS). Interim safety and 
efficacy results from the EAP uphold the finding that GWP42003-P produces clinically 
significant reductions in seizures when used as an add-on ASM treatment (McCagh 2009) 
(Wu 2020). Thus, there is direct evidence supporting that GWP42003-P can be an effective 
therapy for treatment of EMAS associated seizures. 
Given the extensive clinical study results that have established the safety and efficacy profile of 
GWP42003-P as an anticonvulsant therapy and its potential to address the existing unmet need in 
the EMAS, the primary aim of Part A of the study is to assess the efficacy of GWP42003-P 
compared to placebo as an adjunctive treatment for children with EMAS. The primary aim of 
Part B of the study is to evaluate the long-term safety and tolerability of GWP42003-P in 
participants with EMAS. 
The choice of a flexible dosing approach was based on results of the Phase 3 studies for DS, 
LGS, and TSC with GWP42003-P. These studies suggest that participants randomized to lower 
maximum dosages of GWP42003-P (eg, 10 mg/kg/day) experienced a similar magnitude of 
reductions in seizures to those treated with higher dosages of GWP42003-P (eg, 20, 25, and 
50 mg/kg/day). Likewise, participants randomized to higher doses of GWP42003-P in clinical 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 46 
studies report significantly greater side effects compared to those randomized to lower doses. 
However, given the variability in dose-response to GWP42003-P, it is possible that AEs 
observed with higher doses of GWP42003-P could be mitigated if participants are only titrated 
when clinically indicated. The choice of treatment length was determined based on previous 
studies of GWP42003-P, which have demonstrated that onset of treatment effect occurs rapidly 
(approximately within the 1 to 2 weeks of treatment) and maximum efficacy is attained at around 
1 month of treatment. Based on these results, it is not scientifically warranted to extend the 
treatment phase past the length of historic studies (14 weeks). 
4.2.1. 
Participant Input into Design 
Representatives from patient organizations were consulted to ensure the patient and caregiver 
perspectives were implemented in the design of this clinical study. 
4.3. 
Justification for Dose 
The IMP, GWP42003-P, is FDA approved for the treatment of DS and LGS up to a maximum 
maintenance dosage of 20 mg/kg/day and for the treatment of TSC up to a recommended 
maintenance dosage of 25 mg/kg/day. It has also been prescribed by physicians for treatment of 
patients with intractable epilepsy resulting from a variety of etiologies as part of the investigator 
initiated, FDA authorized EAP Investigational New Drug studies in daily dosages up to 
50 mg/kg/day (median daily dosage of 25 mg/kg/day). Based on safety results from previous 
studies and because the current study is designed to allow for individualized dosing, a daily 
maximum dosage of 20 mg/kg/day GWP42003-P was selected.  
All participants will be randomized to the IMP for administration during the 14-week treatment 
period that will follow a flexible titration schedule. Refer to Section 6.5 for details on dose 
modification. 
Investigators may decrease daily dosage any time if a participant experiences intolerance. 
Participants whose dosage has been decreased can have their dosage increased again if the 
tolerability improves. 
4.4. 
Number of Participants 
In Part A, up to a maximum of 120 participants (up to 60 per treatment arm) will be randomly 
assigned to IMP (ie, randomized) in Part A of the study. The final sample size is dependent on 
the results from interim analyses when 60, 75, 90 and 105 participants are randomized (see 
Section 9.2 and Section 9.5 for sample size calculation assumptions).  
Note: “Enrolled” means a participant’s or their caregiver’s agreement to participate in a clinical 
study following completion of the informed consent process. 
4.5. 
End of Study Definition 
The end of the study is defined as the date of the last participant’s final completed scheduled 
visit or last completed study assessment, whichever occurs last.  
A participant is considered to have completed the entire study if he/she has completed all phases 
of Part A and Part B of the study including the last scheduled visit or the last scheduled 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 47 
assessment shown in the SoA for Part B (Section 1.3). If a participant completes Part A and does 
not continue to Part B, he/she will be considered to have completed only Part A.  


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 48 
5. 
STUDY POPULATION 
Investigators are responsible for confirming participant eligibility and will be required to 
maintain a log that includes limited information about all screened participants (initials, date of 
birth, and sex [as allowed per local regulations]) and outcome of screening. 
Prospective approval of protocol deviations or waivers related to recruitment and eligibility 
criteria are not permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if ALL of the following criteria apply: 
Age and Sex 
1. Participant must be male or female between 1 and 18 years of age, inclusive, at the 
time of initial informed consent/assent. 
2. Participant must weigh at least 10 kg. 
Type of Participant  
3. Participant has a current diagnosis of EMAS, also known as Doose syndrome, 
myoclonic-astatic epilepsy, or myoclonic-atonic epilepsy, consistent with the ILAE 
guidelines. Presence of myoclonic-atonic seizures is mandatory to support a diagnosis 
of EMAS as determined by medical history and independent approval by TESC. 
4. Participant experiences a minimum average frequency of ≥ 2 TESC-approved, 
countable, EMAS-associated seizures (myoclonic-atonic, atonic, tonic, clonic, or 
tonic-clonic) per week (≥ 8 seizures per month), as reported in the baseline seizure 
eDiary from baseline (Part A Visit 2) until the evening prior to randomization (Part A 
Visit 3).  
5. Participant’s initial seizure onset occurred from ≥ 6 months to < 6 years of age, with 
normal or mildly impaired/delayed neurodevelopment reported prior to onset of 
seizures. During the first year of seizure onset, the majority of seizures experienced by 
the participant were myoclonic-atonic seizures or generalized tonic-clonic seizures as 
determined by medical history. 
6. Participant is currently treated with 1 or more ASMs on a stable regimen (≥ 28 days 
prior to starting the baseline period [Part A Visit 2]) or on a stable ketogenic 
diet/epilepsy dietary therapy (≥ 28 days prior to starting the baseline period [Part A 
Visit 2]) and no changes to treatment are planned for the duration of the study. 
7. Participant has failed ≥ 1 prior ASM due to inadequate seizure control. 
8. Participant is able to provide a historical EEG report, which was performed within 
12 months of screening (Part A Visit 1), or is willing to complete an EEG at screening 
(Part A Visit 1), that confirms a > 2.5 to 6 Hz generalized spike-and-slow-wave or 
polyspike-and-slow-wave pattern. 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 49 
Sex and Contraceptive/Barrier Requirements 
9. Contraceptive use by male and female participants should be consistent with Clinical 
Trial Facilitation Group guidelines and any applicable local regulations regarding the 
methods of contraception for those participating in clinical studies. 
Male participants: 
− Fertile male participants with partners of CBP must be willing to use a male 
barrier method of contraception in addition to a second method of acceptable 
contraception used by their female of CBP partners, from the time of screening 
(Part A Visit 1) until 3 months after the follow-up visit, as detailed in 
Section 10.5 (Appendix 5). 
Female participants of CBP: 
− Will not be pregnant or lactating and have a confirmed negative highly 
sensitive serum pregnancy test at screening (Part A Visit 1). 
− Must also have a confirmed negative urine pregnancy test prior to receiving 
their first dose of blinded IMP at Part A Visit 3. 
− Who are continuing to Part B must have a confirmed negative urine pregnancy 
test prior to receiving their first dose of open-label GWP42003-P at Part B 
Visit 1. 
− Must be willing to use a highly effective method of contraception from the time 
of signing the ICF until 3 months after the follow-up visit, as detailed in 
Section 10.5 (Appendix 5). 
Informed Consent/Assent 
10. Participant or participant’s caregiver(s) (according to local laws) is/are willing and able 
to give signed informed consent/assent for participation in the study including 
compliance with the requirements and restrictions listed in the ICF and in 
Section 10.2.3. 
11. Participant’s caregiver(s) are willing to allow the responsible authorities to be notified 
of participation in the study, if mandated by local law. 
12. Participant’s caregiver completes ≥ 25 days of daily Reminder Diary entries during the 
first 28 days of the baseline period. 
Part B Only: 
13. Has completed Part A of this study. 
14. Was compliant with all requirements of Part A (eg, dosing, seizure eDiary, 
visits/procedures), in the clinical judgement of the investigator and/or sponsor. 
 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 50 
5.2. 
Exclusion Criteria 
Participants are excluded from the study if ANY of the following criteria apply: 
Medical Conditions 
15. Has a history of psychogenic non-epileptic seizures that confounds the assessment of 
the primary efficacy measure. 
16. Has clinically significant unstable medical condition(s), other than EMAS. 
17. Has a clinically significant illness in the 28 days prior to screening (Part A Visit 1) or 
randomization (Part A Visit 3), other than epilepsy, which in the opinion of the 
investigator could affect seizure frequency. 
18. Has presence of focal seizures or persistent focal epileptiform discharges on EEG. 
19. Has a history of infantile spasms. 
20. Has moderate to severe neurocognitive and/or developmental delay prior to seizure 
onset.  
21. Has a progressive neurological condition. 
22. Has known or suspected hypersensitivity to cannabinoids or any of the excipients of 
GWP42003-P such as sesame oil. 
23. Is unwilling or unable to remain stable on concurrent ASMs throughout the study.  
24. Has, in the opinion of the investigator, clinically significant abnormalities in the ECG 
measured at screening (Part A Visit 1), or any concurrent cardiovascular conditions, 
which will interfere with the ability to read their ECGs. 
25. Has significantly impaired hepatic function at the screening visit (Part A Visit 1) or 
prior to dosing, defined as any of the following: 
− ALT or AST > 5 × ULN  
− TBL (serum total bilirubin) > 1.5 × ULN or INR > 1.5. Note that for 
participants diagnosed with Gilbert’s disease, TBL > 3.0 × ULN and/or direct 
bilirubin > 1 × ULN are exclusionary.  
− Serum ALT or AST ≥ 3 × ULN with the presence of fatigue, nausea, vomiting, 
right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%). 
− Elevated ALT or AST at screening (Part A Visit 1), should be discussed with 
the medical monitor prior to randomization (Part A Visit 3); the medical 
monitor may allow for a confirmatory re-draw prior to randomization. 
This criterion can only be confirmed once the laboratory results are available.  
26. Has clinically significant impaired renal function at screening (Part A Visit 1), as 
evidenced by an estimated glomerular filtration rate (Schwartz equation) < 60 mL/min.  


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 51 
27. Is a female participant of CBP, who is pregnant (positive pregnancy test), lactating or 
planning pregnancy during the course of the study and for 3 months thereafter. 
28. Participant has any known or suspected history of alcohol or substance use disorder. 
29. Any clinically significant abnormalities identified following a physical examination or 
laboratory assessments of the participant that, in the opinion of the investigator, would 
jeopardize the safety of the participant if they take part in the study. 
30. Participant has any other clinically significant disease or disorder which, in the opinion 
of the investigator, may either put the participant, other participants, or site staff at risk 
because of participation in the study, may influence the result of the study, or may 
affect the participant’s ability to take part in the study. 
Prior Therapy 
31. Is currently treated with Epidiolex/Epidyolex or recently received treatment with 
Epidiolex/Epidyolex within 28 days prior to screening (Part A Visit 1). 
32. Has experienced a lack of efficacy and/or poor tolerability to an adequate treatment 
regimen of Epidiolex/Epidyolex based on medical history and the clinical judgment of 
the investigator. Participants who discontinued treatment for reasons other than safety, 
tolerability, or lack of efficacy and previously received Epidiolex/Epidyolex ≥ 28 days 
prior to screening (Part A Visit 1) may be eligible for the study after consultation with 
the medical monitor and/or sponsor representative. 
33. Has a change in anticonvulsant therapies within 28 days of starting the baseline period 
(Part A Visit 2), including ASMs or settings on vagal nerve stimulator. 
34. Has any planned clinical interventions or intends to change any or all medications that 
may impact seizures during the study. 
35. Has undergone surgery for epilepsy in the 6 months prior to screening (Part A Visit 1). 
36. Is being considered for epilepsy surgery or any procedure involving general anesthesia 
during the study. 
37. Has initiated a ketogenic diet within 28 days prior to starting the baseline period 
(Part A Visit 2). Participants who are stable on a ketogenic diet for ≥ 28 days and 
willing to remain on a stable epilepsy dietary therapy (eg, ketogenic diet, Atkins diet, 
low glycemic index diet) during the study, are eligible for inclusion. 
38. Has initiated felbamate within 12 months prior to screening (Part A Visit 1). 
Participants who are stable on a felbamate for ≥ 12 months are eligible for inclusion. 
39. Is currently being treated with or had previously (within 3 months prior to screening 
[Part A Visit 1]) received intravenous immunoglobulin treatment or plasma exchange 
for the treatment of seizures. 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 52 
Prior/Concurrent Clinical Study Experience 
40. Has participated in a clinical study involving administration of an IMP (new chemical 
entity) or medical device (eg, vagal nerve stimulator) within 28 days prior to screening 
(Part A Visit 1). 
41. Has previously been randomized, completed, or withdrawn from this study. 
Alcohol and Drugs 
42. Is currently using a drug of abuse or current nonprescribed use of any prescription 
drug. 
43. Is currently using or has used recreational or medicinal cannabis, cannabinoid-based 
medications, products, or supplements (botanical or synthetic) within 28 days prior to 
screening (Part A Visit 1).  
44. Mother (if breastfeeding the participant) is currently using or has used recreational or 
medicinal cannabis, cannabinoid-based medications, products, or supplements 
(botanical or synthetic) within 28 days of screening (Part A Visit 1). 
Other Exclusions 
45. History of suicidal behavior, current suicidal risk as determined from history, or 
presence of active suicidal ideation as indicated by a positive response to Item 4 or 
Item 5 on the C-SSRS. The C-SSRS criterion applies only to participants 4 to 18 years 
of age. 
46. Is unwilling or unable to comply with all study requirements, including accurate eDiary 
completion.  
47. Participants who, in the opinion of the investigator (or designee), should not participate 
in this study. 
48. Has travel planned outside their country of residence during the study, unless the 
participant has confirmation that the IMP is permitted in the destination country and all 
stops along the way. 
Part B Only: 
49. Has significantly impaired hepatic function at Part A Visit 9, defined as any of the 
following: 
− ALT or AST > 5 × ULN  
− TBL (serum total bilirubin) > 1.5 × ULN or INR > 1.5. Note that for 
participants diagnosed with Gilbert’s disease, TBL > 3.0 × ULN and/or direct 
bilirubin > 1 × ULN are exclusionary.  
− Serum ALT or AST ≥ 3 × ULN with the presence of fatigue, nausea, vomiting, 
right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%). 
The medical monitor may allow for a confirmatory re-draw prior to rollover. 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 53 
50. Meets any exclusion criteria at Part B Visit 1. 
 
 
5.3. 
Lifestyle Considerations 
Note: Restrictions that apply to the period before the first admission are described in Section 5.1 
and Section 5.2. 
5.3.1. 
Meals and Dietary Restrictions 
The caregiver will record the date, time, and meal type (eg, high-fat meal [dairy or meat], 
standard meal [fruit or vegetable], or other [if not fitting into one of the categories above]) for all 
meals consumed by the participant within 24 hours prior to PK collection.  
5.4. 
Screen Failures 
Screen failures are defined as participants who consent/assent to participate in the clinical study 
but are not subsequently randomly assigned to the IMP. Documentation of screening failures will 
be collected and recorded in the eCRF. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure participants to meet the Consolidated Standards of 
Reporting Trials publishing requirements and to respond to queries from regulatory authorities. 
Minimal information includes demography, screen failure details, eligibility criteria, AEs, and 
any SAE. 
5.4.1. 
Rescreening 
Participants who do not meet the criteria for participation in this study (screen failure), or who 
could not be randomized within the screening/baseline window for logistical reasons, may be 
rescreened once at the discretion of the investigator or designee and after consultation with the 
medical monitor and/or sponsor representative. Rescreened participants must first be registered 
as screen failures in the eCRF and subsequently registered as rescreens in the eCRF. Once the 
participant is registered as rescreened, a new screening window will begin. For all rescreens, all 
screening procedures, including ICF, must be repeated. Sites should discuss planned rescreens 
with the medical monitor prior to rescreening (Part A Visit 1). 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 54 
6. 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY 
Study intervention is defined as any IMP or placebo intended to be administered to a study 
participant according to the study protocol. 
6.1. 
Study Intervention(s) Administered 
 
Table 3: 
Study Interventions 
ARM Name 
GWP42003-P 
Placebo 
Intervention Name 
GWP42003-P 
Placebo 
Type  
Drug 
Drug 
Dose Formulation 
CBD dissolved in the excipients sesame 
oil and anhydrous ethanol (10% v/v), 
with sweetener (sucralose), and 
strawberry flavoring 
The excipients sesame oil and 
anhydrous ethanol (10% v/v), with 
sweetener (sucralose), strawberry 
flavoring, and beta carotene 
Unit Dose Strength(s) 
100 mg/mL CBD 
n/a 
Dosage Level(s) 
5 mg/kg/day (2.5 mg/kg BID) up to a 
maximum of 20 mg/kg/day 
0.05 mL/kg/day up to a maximum of 
0.2 mL/kg/day 
Route of Administration 
Oral 
Oral 
Use 
Experimental 
Placebo comparator 
IMP or non-IMP 
IMP 
IMP  
Sourcing 
Provided centrally by the sponsor 
Provided centrally by the sponsor 
Packaging and Labeling 
IMP will be provided in bottles with 
syringes for administration. Each bottle 
will be labeled as required per country 
requirement. 
IMP will be provided in bottles with 
syringes for administration. Each bottle 
will be labeled as required per country 
requirement. 
Current/Former Names 
or Alias 
Cannabidiol 
n/a 
Abbreviations: BID = twice daily; CBD = cannabidiol; IMP = investigational medicinal product; n/a = not 
applicable; OS = oral solution. 
6.2. 
Preparation/Handling/Storage/Accountability 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all IMP received and any discrepancies are reported and resolved 
before use of the IMP. 
Only participants randomized to receive IMP in the study may receive IMP and only authorized 
site staff may supply or administer IMP. All IMP must be stored in a secure, environmentally 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 55 
controlled, and monitored (manual or automated) area in accordance with the labeled storage 
conditions with access limited to the investigator and authorized site staff. 
For self-administration of IMP, participants/caregivers will be provided with bottle(s) containing 
the oral dosing solution along with oral syringes. Participants/caregivers will be trained, during 
Visit 3 at the study site, to self-administer IMP orally or with gastrostomy or nasogastric tubes 
BID (eg, morning and evening) preferably about the same time each day, consistently with or 
without food. Participants/caregivers will be provided with clear instructions for the dose 
escalation and taper dosing periods of the study via a printed dosing schedule and will record 
usage of IMP as part of the IMP dosing eDiary to aid in compliance. 
Where required by local regulations, IMP may be dispensed more frequently than outlined in the 
schedule of assessments by completion of an unscheduled dispensing visit. 
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for IMP accountability, reconciliation, and record maintenance (ie, receipt, 
reconciliation, and final disposition records). 
Further guidance and information for the final disposition of unused IMP are provided in the 
pharmacy manual or other specified location. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
6.3.1. 
Randomization 
All participants will be centrally assigned to randomized IMP using an IRT (RTSM). Before the 
study is initiated, the log-in information and directions for the IRT will be provided to each site. 
Refer to Section 8.1.3 for details on the IRT. 
Training will be given to all sites prior to the start of the study. 
The IMP will be dispensed at the study visits summarized in the SoA (Section 1.3).  
Returned IMP should not be re-dispensed to the participants. 
6.3.2. 
Blinding 
At the start of Part A, participants will be randomly assigned in a 1:1 ratio to receive 
GWP42003-P or matching placebo. Investigators will remain blinded to each participant’s 
assigned IMP throughout the course of the study. 
Participants entering Part B of the study, will first complete a 2-week blinded titration phase. 
Following the blinded titration phase, participants will start open-label treatment with 
GWP42003-P. 
6.3.2.1. 
Unblinding 
The IRT will be programmed with blind-breaking instructions. In case of an emergency, the 
investigator has the sole responsibility for determining if unblinding of a participants’ IMP 
assignment is warranted. Participant safety must always be the first consideration in making such 
a determination. Unblinding for any other reason will be considered a protocol deviation. If the 
investigator decides that unblinding is warranted, the investigator should make every effort to 
contact the sponsor prior to unblinding a participant’s IMP assignment unless this could delay 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 56 
emergency treatment of the participant. If a participant’s IMP assignment is unblinded, the 
sponsor must be notified within 24 hours after breaking the blind. The date and reason that the 
blind was broken must be recorded in the source documentation and eCRF, as applicable. 
Sponsor safety staff may unblind the IMP assignment for any participant with an SAE. The study 
team will remain blinded to IMP assignment. If the SAE requires that an expedited regulatory 
report be sent to one or more regulatory agencies, a copy of the report may be sent to 
investigators in accordance with local regulations and/or sponsor policy. Reason for unblinding 
and date must be recorded/documented appropriately per study documentation process. 
6.4. 
Study Intervention Compliance 
When participants are dosed at the site, they will receive IMP directly from the investigator or 
designee, under medical supervision. The date and time of each dose administered in the clinic 
will be recorded in the IMP dosing eDiary. The dose of IMP and study participant identification 
will be confirmed at the time of dosing. 
Compliance with IMP will be reviewed during phone visits by direct questioning and review of 
completed IMP dosing eDiary. However, IMP compliance cannot be fully assessed during phone 
visits since bottle(s) will not be returned. Possible deviation(s) from the prescribed dosing 
regimen should be discussed with the caregiver (eg, re-training provided) and documented in the 
source documents. 
Compliance with IMP will be assessed at each visit where IMP is returned, as part of 
accountability assessment. Compliance will be assessed by direct questioning, counting returned 
bottle(s), review of completed IMP dosing eDiary, measurement of the IMP used from each 
bottle compared to expected usage, etc. during the site visits and documented in the source 
documents and eCRF. Significant deviation(s) from the prescribed dosage regimen should be 
recorded as protocol deviations as outlined within the pharmacy manual. 
A record of the quantity of IMP dispensed to and administered by each participant must be 
maintained and reconciled with IMP and compliance records. IMP start and stop dates, including 
dates for IMP dosing delays and/or dose adjustments, will also be recorded. 
6.5. 
Dose Modification 
Body weight will be used to calculate the IMP dose. Body weight will be confirmed prior to IMP 
dose calculation. If a visit is being done at home, the last available clinic weight will be used to 
calculate the dose.  
Refer to the “CBD Dose Adjustment” section of the current approved GWP42003-P IB for 
detailed information regarding potential drug interactions and associated dose modifications. 
Part A: 
On Day 1 (Visit 3) of treatment with IMP, participants will be initiated on a dose of 2.5 mg/kg 
BID (5 mg/kg/day), and after 1 week, the dose will be increased to 5 mg/kg BID (10 mg/kg/day) 
at the Day 8 (Visit 4) phone visit.  
For participants who are tolerating the IMP at 5 mg/kg BID (10 mg/kg/day) and require further 
reduction of seizures, investigators may choose to increase their dosage up to a maximum dosage 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 57 
of 10 mg/kg BID (20 mg/kg/day). The decision to titrate above 5 mg/kg BID (10 mg/kg/day) 
should be based on the observed efficacy, safety, and tolerability of the participant (including 
review of laboratory values) per the clinical judgement of the investigator. 
Starting at the Day 15 (Visit 5) phone visit, investigators have the option to titrate participants no 
more rapidly than every 7 days by an additional 2.5 mg/kg BID (5 mg/kg/day) up to a maximum 
daily dosage of 20 mg/kg/day. The investigator will determine if further dose adjustments are 
warranted during unscheduled phone visits and/or scheduled phone or clinic visits throughout the 
remainder of the 14-week treatment period. If dose change is warranted outside of a scheduled 
visit, the caregiver should be contacted by phone prior to making any dose increases above 
10 mg/kg/day to assess the appropriateness of the dose increase based on the participant’s 
reported clinical response and ensure the caregiver has received the updated dosing schedule 
reflecting the new target dose. This contact should be documented as an unscheduled phone visit 
in the eCRF. 
After the Day 15 (Visit 5) phone visit, if in the investigator’s opinion, a participant is 
experiencing a clinically meaningful improvement in EMAS-associated seizures, the investigator 
can choose to continue treatment at the participant’s current dosage and may re-consider an 
increase in the dosage of IMP at either a later study visit, or at any time between study visits, as 
described above.  
If a participant reports any tolerability issues related to IMP, the investigator can also decrease a 
participant’s current dosage. Dose decreases to below 10 mg/kg/day, based on safety and 
tolerability may occur at any time. The caregiver should be contacted by phone prior to making 
any dose decreases below 10 mg/kg/day. Investigators should regularly monitor a participant’s 
response to treatment and re-evaluate the need for adjustments to dosage (ie, increase, maintain, 
or decrease) at the next study visit, if applicable. Dose decreases below 10 mg/kg/day may occur 
in decrements of 2.5 or 5 mg/kg/day based on the clinical judgment of the investigator. 
Table 4: 
Possible Range of Investigational Medicinal Product Doses During the 
14-Week Treatment Period of Part A 
Day 
Morning Dose 
(mg/kg) 
Evening Dose 
(mg/kg) 
Total Daily Dose 
(mg/kg/day) 
1-7 
2.5 
2.5 
5 
8-14 
5 
5 
10 
15-21 
5 or 7.5 
5 or 7.5 
10 or 15 
22-56 
5, 7.5, or 10* 
5, 7.5, or 10* 
10, 15, or 20* 
57-84 
5, 7.5, or 10* 
5, 7.5, or 10* 
10, 15, or 20* 
85-98 
5, 7.5, or 10* 
5, 7.5, or 10* 
10, 15, or 20* 
* The maximum dosage (or dosage equivalent) that could be administered by this point or subsequent points. 
Note: The dose ranges in the table serve as guidance only. Slight differences in dosage timing are allowed. 
At the End of Treatment visit for Part A, participants who complete the treatment period, 
continue to meet all Part B eligibility criteria, and for participants whom the investigator feels 
continued treatment in an extension trial represents a favorable risk-benefit assessment for the 
participant will be offered the option to enroll in Part B. 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 58 
Part B 
Participants eligible to participate in Part B of the study will not be required to complete the 
Part A taper period (Visit 10) or follow-up visit (Visit 11). The Part A end of treatment visit 
(Visit 9) procedures/data should be utilized for Visit 1 of Part B (ie, the same procedures should 
not be repeated at Visit 9 of Part A and Visit 1 of Part B). If the participant is continuing to 
Part B, the IMP should only be dispensed at Part B Visit 1. If the participant is not continuing to 
Part B, the IMP for the taper period will be dispensed at Part A Visit 9, as required. 
In order to maintain consistent exposure to IMP and maintain the integrity of the blind, 
participants will enter a 2-week blinded titration (or transition) to Part B. Part B IMP will be 
increased to 10 mg/kg/day whilst blinded IMP is simultaneously tapered down to zero. If a 
participant completes Part A on a dose < 10 mg/kg/day and continues into Part B, they can 
transition to Part B and remain at a lower GWP42003-P dosage following approval from the 
medical monitor and/or sponsor representative. After Week 2 (Visit 3), investigators will then 
have the option to titrate participants no more rapidly than every 7 days by an additional 
2.5 mg/kg BID (5 mg/kg/day) up to a maximum daily dosage of 20 mg/kg/day (Table 5). 
After Week 2 (Visit 3), it is recommended that the GWP42003-P dosage should be increased no 
more rapidly than 5 mg/kg/day (2.5 mg/kg BID) every 7 days. However, for some participants in 
whom a more rapid titration from 10 to 20 mg/kg/day is warranted, the dosage may be increased 
no more frequently than every other day following consultation with the medical monitor and/or 
sponsor representative.  
If any safety/tolerability issues, investigators can decide to maintain or decrease dosage. 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 59 
Table 5: 
Cross-Titration Scheme from End of 14-Week Treatment Period in Part A to Start of Part B 
Study 
Part/ 
Visit 
Visit 
Type 
Study 
Day 
GWP42003-P 10 mg/kg/day 
GWP42003-P 15 mg/kg/day 
GWP42003-P 20 mg/kg/day 
Placebo 
Blinded 
(mg/kg/
day) 
OL 
(mg/kg/
day) 
Total 
Dose 
(mg/kg/
day) 
Blinded 
(mg/kg/
day) 
OL 
(mg/kg/
day) 
Total 
Dose 
(mg/kg/
day) 
Blinded 
(mg/kg/
day) 
OL 
(mg/kg/
day) 
Total 
Dose 
(mg/kg
/day) 
Blinded 
(mg/kg/
day) 
OL 
(mg/kg
/day) 
Total 
Dose 
(mg/kg
/day) 
Part A 
Visit 9 
C 
99 
10 
0 
10 
15 
0 
15 
20 
0 
20 
0 
0 
0 
Part B 
Visit 1 
C 
1–7 
5 
5 
10 
10 
5 
15 
15 
5 
20 
0 
5 
5 
Part B 
Visit 2 
P 
8–14  
0 
10 
10 
5 
10 
15 
10 
10 
20 
0 
10 
10 
Part B 
Visit 3 
P 
15–21  
- 
10 or 15 
10 or 15 
0 
10 or 15 
10 or 15 
5 
10 or 
15 
15 or 
20 
0 
10 or 
15 
10 or 
15 
Part B 
Visit 4 
P 
22–28 
- 
10, 15, 
or 20 
10, 15, 
or 20 
- 
10, 15, 
or 20 
10, 15, 
or 20 
0 
10, 15, 
or 20 
10, 15, 
or 20 
0 
10, 15, 
or 20 
10, 15, 
or 20 
Abbreviations: C = clinic; OL = open-label; P = phone. 
 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 60 
6.6. 
Continued Access to Study Intervention After the End of the Study 
There is no plan to provide continued access to IMP after the end of the study. 
6.7. 
Treatment of Overdose 
For this study, any dose of IMP > 20 mg/kg within a 24-hour period may be considered an 
overdose, based on investigator’s or sponsor’s discretion. 
In the event of overdose, the participant should be treated symptomatically (supportive 
management) according to local guidelines and in line with the current approved version of the 
IB. 
In the event of an overdose, the investigator should: 
• Closely monitor the participant for any AE/SAE including any laboratory 
abnormalities as clinically indicated. 
• Contact the medical monitor as soon as possible. 
• Evaluate the participant to determine, in consultation with the medical monitor (when 
possible), whether the IMP should be interrupted or whether the dose should be 
reduced. 
• Document the quantity of the excess dose as well as the duration of the overdose. 
• Instructions on missed doses and/vomiting will be included in a separate pharmacy 
manual. 
6.8. 
Concomitant Therapy 
Caution should always be exercised when allowing administration of concomitant therapies 
according to the individual profile and clinical risk-benefit assessment. Key restrictions on 
concomitant therapies that apply to the period before screening and during the study are briefly 
summarized below. Additional restrictions and details are described further in Section 5.1 and 
Section 5.2. 
• Current treatment with 1 or more ASMs or a vagal nerve stimulator are allowed; 
change in anticonvulsant therapies (including ASMs or vagal nerve stimulator 
settings) are not permitted within 28 days of starting the baseline period (Part A Visit 
2), and no changes to these therapies should be planned for the duration of the study. 
• Previous treatment with felbamate within 12 months prior to screening (Part A 
Visit 1) is prohibited. However, participants who are stable on felbamate for 
≥ 12 months are eligible. 
• Current therapy with ketogenic diet/epilepsy dietary therapy is allowed as long as 
dietary therapy has been stable (≥ 28 days prior to starting the baseline period [Part A 
Visit 2]) and no changes to therapy are planned for the duration of the study. 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 61 
• Current therapy with Epidiolex/Epidyolex or recent treatment with 
Epidiolex/Epidyolex within 28 days prior to screening (Part A Visit 1) is not 
permitted. 
• Previous treatment with Epidiolex/Epidyolex that resulted in a lack of efficacy and/or 
poor tolerability is prohibited. However, participants who discontinued treatment for 
reasons other than safety, tolerability, or lack of efficacy and previously received 
Epidiolex/Epidyolex ≥28 days prior to screening (Part A Visit 1) may be eligible for 
the study after consultation with the medical monitor and/or sponsor representative. 
• Current use or recent use (within 28 days prior to screening [Part A Visit 1]) of 
recreational or medicinal cannabis, cannabinoid-based medications, products, or 
supplements (botanical or synthetic) is prohibited. 
• If the study participant is being breastfed, current use or recent use (within 28 days 
prior to screening [Part A Visit 1]) by the mother of recreational or medicinal 
cannabis, cannabinoid-based medications, products, or supplements (botanical or 
synthetic) is prohibited. 
Any vaccination related to SARS-CoV-2 (COVID-19) that was received within the last 
12 months prior to screening (Part A Visit 1) or during the study should be recorded as 
concomitant medication. The information recorded should include the vaccine manufacturer and 
the dates of administration; differing start and end dates if more than 1 dose is received. 
Any medication or vaccine (including over-the-counter or prescription medicines, recreational 
drugs, vitamins, and/or herbal supplements) that the participant is receiving within 3 months of 
screening (Part A Visit 1) or receives during the study must be recorded along with: 
• Reason for use. 
• Dates of administration including start and end dates. 
• Dosage information including dose and frequency. 
Additionally, all ASMs, antiepileptic therapies, and rescue medications taken during the 
participant’s life (previous and/or current use) will be recorded in the eCRF and reviewed at each 
subsequent visit.  
The medical monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
It is possible that GWP42003-P oral solution may modify the metabolism of other drugs 
(including other ASMs) administered concurrently and there remains the possibility of 
pharmacological interactions between GWP42003-P oral solution and other concurrently 
administered drugs. Detailed information on potential drug interactions can be found in the 
current approved GWP42003-P IB in the “CBD Dose Adjustment” section. 
Concomitant ASM dose reductions are permitted on clinical grounds (eg, due to AEs or 
transaminase elevations not meeting withdrawal criteria specified in Section 7.1) following 
discussion with the medical monitor. 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 62 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
Participants have the right to withdraw from the IMP and/or other protocol-required therapies, 
protocol procedures, or the study as a whole at any time and for any reason without prejudice to 
their future medical care by the physician or at the institution. 
The investigator can withdraw a participant(s) from IMP, and/or other protocol-required 
therapies, protocol procedures, or the study as a whole at any time prior to study completion for 
the reasons listed in Section 7.1 and Section 7.2. 
7.1. 
Discontinuation of Study Intervention 
Reasons for removal from IMP include any of the following: 
• Participants may decline to continue receiving IMP or other protocol-required 
therapies or procedures at any time during the study. 
− Participants who choose to discontinue IMP or other protocol-required therapies 
or procedures should not be automatically removed from the study. Whenever 
safe and feasible, and in agreement with the sponsor, the participants should 
remain in the respective part of the study to ensure safety surveillance and 
collection of outcome data. Specifically, participants who discontinue IMP 
prematurely in Part A of the study will not be enrolled in Part B. 
− The investigator is to discuss with the participant the appropriate processes for 
discontinuation from IMP or other protocol-required therapies. The investigator 
must discuss with the participant the possibilities for continuation of activities 
described in the SoA (Table 1 and Table 2) and must document this decision in 
the eCRF. 
• Decision by investigator. 
• Decision by sponsor. 
• Withdrawal by participant/caregiver/legal representative. 
• Lack of efficacy. 
• Change in compliance with any inclusion/exclusion criterion that is clinically relevant 
and affects participant safety, as determined by the investigator (or designee). 
• Protocol deviation that is considered to potentially compromise the safety of the 
participant. 
• Noncompliance with IMP. 
• Noncompliance with study assessments. 
• Pregnancy. 
• Liver Chemistry - Discontinuation of IMP for abnormal liver tests is required by the 
investigator when a participant meets one of the following conditions outlined or in 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 63 
the presence of abnormal liver chemistries not meeting protocol-specified stopping 
rules if the investigator believes that it is in best interest of the participant.  
− Serum ALT or AST > 3 × ULN with the presence of fatigue, nausea, vomiting, 
right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%). 
− ALT or AST > 8 × ULN. 
− ALT or AST > 5 × ULN for > 2 weeks. 
− ALT or AST > 3 × ULN and (TBL > 2 × ULN or INR > 1.5). 
− Note: Refer to Section 10.6 (Appendix 6) for information on follow up for 
clinically significant liver results. 
• Any evidence of drug abuse or diversion. 
• Suicidal behavior or Serious suicidal ideation during the treatment period, defined as 
Item 4 or Item 5 on the C-SSRS. 
• An AE (including clinically significant laboratory result) which, in the opinion of the 
investigator, would compromise the continued safe administration of IMP to the 
participant in the study. 
7.2. 
Participant Withdrawal from the Study 
A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety, behavioral, or 
compliance reasons. 
• The participant will be permanently discontinued both from the IMP and from the 
study at that time. 
• If a participant is withdrawn from the study, the study monitor will be informed 
immediately. If there is a medical reason for withdrawal, the participant will be 
followed up by the investigator until satisfactory health has returned. 
• All efforts must be made to complete and report the observations as thoroughly as 
possible up to the date of withdrawal.  
• Participants withdrawing due to an AE should be followed up according to 
Section 10.4.4. All information should be reported on the applicable eCRF pages 
(refer to Section 8). A safety follow-up visit should take place ±7 days after last dose 
of IMP (refer to Table 1 and Table 2). If withdrawing participants decline to give a 
reason for withdrawal of consent, the investigator must respect the participant’s 
wishes. 
• If the participant withdraws consent for disclosure of future information, the sponsor 
may retain and continue to use any data collected before such a withdrawal of 
consent. 
• If a participant withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site study 
records. 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 64 
Reasons for removal of a participant from the study are: 
• Decision by investigator. 
• Decision by sponsor. 
• Lack of efficacy. 
• AE. 
• Withdrawal by participant/caregiver/legal representative. 
• Death. 
• Lost to follow up. 
7.3. 
Lost to Follow up 
A participant will be considered lost to follow-up if he or she fails to return for scheduled visits 
and/or is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study. 
• Before a participant is deemed lost to follow up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.  
• Site personnel, or an independent third party, will attempt to collect the vital status of 
the participant within legal and ethical boundaries for all participants randomized, 
including those who did not get the IMP. Public sources may be searched for vital 
status information. If vital status is determined as deceased, this will be documented, 
and the participant will not be considered lost to follow up. Sponsor personnel will 
not be involved in any attempts to collect vital status information. 
Discontinuation of specific sites or of the study as a whole are handled as part of Section 10.2.9. 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 65 
8. 
STUDY ASSESSMENTS 
Study procedures and their timing are summarized in the SoA (Section 1.3).  
• Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue IMP. 
• Adherence to the study design requirements, including those specified in the 
SoA (Section 1.3), is essential and required for study conduct. 
• All screening evaluations must be completed in the source records and reviewed to 
confirm that potential participants meet all eligibility criteria. The investigator will 
maintain a screening log to record details of all participants screened and 
confirmation of eligibility or record reasons for screening failure, in the eCRF as 
applicable. 
• Safety/Laboratory/analyte results that could unblind the study will not be reported to 
investigational sites or other blinded personnel until the study has been unblinded. 
8.1. 
General Assessments 
8.1.1. 
Demographics 
At screening (Part A Visit 1), the following information will be obtained for each participant: 
age, sex, race, ethnic origin (if allowed per local regulation or if otherwise supported by the 
scientific rationale). 
8.1.2. 
Medical History 
Full medical history, including perinatal history, and EEG report (historical EEG report can be 
used to determine eligibility at screening if performed within the past 12 months prior to 
screening [Part A Visit 1]) will be obtained during screening and is defined as any condition or 
disease that meets any of the following criteria:  
• May affect the condition under study. 
• Including complete seizure history, developmental history, lifetime history of 
epilepsy, history of status epilepticus, and any hospitalizations. 
• Is ongoing on entry into the study. 
• Has occurred within 1 year prior to screening (Part A Visit 1). 
• Suspected or confirmed COVID-19 infection (or other significant communicable 
diseases) within 1 year prior to screening (Part A Visit 1). 
• Information required for TESC confirmation of EMAS diagnosis and/or seizure 
classification, including but not limited to lifetime imaging history, EEG history, 
genetic testing history, etc. 
• Gastrostomy or nasogastric tube placement. 
• Prior cannabis use. 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 66 
• Historical vaccinations. 
8.1.3. 
Interactive Response Technology 
The IRT (RTSM) will be used to assign participants to treatment groups, manage IMP supply, 
and to provide treatment allocation information in the event of participant unblinding. The 
RTSM will be integrated with Rave electronic data capture. 
A member of the study team must register in the eCRF at each clinic visit in order to: 
• Obtain a participant’s number at screening (Part A Visit 1). 
• Randomize a participant (Part A Visit 3). 
• Obtain dispensing information on day of visit (Part A Visits 3, 7, 8, and 9; Part B 
Visits 1, 5, 6, 7, 8, and 10). If required for home health visits, dispensing information 
may be obtained 1 day prior to visit.  
• Provide completion/taper/premature termination information (after Part A Visit 3). 
Training will be given to all sites prior to the start of the study. 
8.1.4. 
Participant eDiary 
An eDiary will be completed throughout the study, until the end of the taper period (Part A 
Visit 10; Part B Visit 11) or early withdrawal visit (Part A Visit 9; Part B Visit 10). If the 
participant is provided with a site-provisioned eDiary, the device must be returned to the site at 
the last clinic visit. A back-up plan to record eDiary data will be in place in case of any device 
failure. 
Caregivers will record the following information in the eDiary: 
• AEs, concomitant medications, rescue medication, and seizures (including type, 
number, and days with status epilepticus) beginning at screening (Part A Visit 1). 
• Food eDiary module beginning approximately 24 hours prior to randomization 
(Part A Visit 3) and 24 hours prior to Part A Visit 9 (or End of Treatment Visit if the 
participant discontinues treatment prior to Part A Visit 9) – details of each meal 
consumed by the participant within approximately 24 hours prior to PK collection, 
including the date, time, and meal type: 
− High fat meal (dairy or meat) 
− Standard meal (fruit or vegetable) 
Other (if not fitting into one of the categories above) 
• IMP dosing eDiary module beginning at randomization (Part A Visit 3) – IMP usage, 
including dose time, volume administered, and consistency of IMP dosing with 
respect to mealtimes.  
Caregivers will be instructed to immediately contact the investigator by phone to discuss any 
changes in their child’s health (possible AEs), changes in concomitant medications, including 
ASMs, use of rescue medication, and days with status epilepticus or potential new seizure types. 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 67 
All eDiary entries will be reviewed and discussed with the caregiver for verification during 
participant phone or clinic visits. This review will be documented in the source and eCRF. 
• For the AE, concomitant medication, and rescue medication eDiaries, details on AEs, 
changes in concomitant medications, including ASMs and use of rescue medication 
will be recorded within the source documents and eCRF.  
• For the seizure eDiary, any days with status epilepticus will be recorded in the source 
and reported as an SAE; any potential new seizure types will be recorded in the 
source and reported to TESC for adjudication. New seizure types may be added to the 
eCRF as expected seizure types following TESC approval. 
8.1.5. 
Confirmation of EMAS Diagnosis and Seizure Classification 
To ensure accurate diagnosis of EMAS according to ILAE criteria (International League Against 
Epilepsy 2012) (Trinka 2015), investigators will collect lifetime developmental and lifetime 
seizure history during screening (Part A Visit 1) using the SIF/DRF and eDiary Seizure 
Classification Report. 
Caregivers will begin reporting seizures to the seizure eDiary immediately following screening 
(Part A Visit 1) and will continue reporting seizures to the seizure eDiary for the remainder of 
the study. 
The investigator will submit the completed SIF/DRF and eDiary Seizure Classification Report 
directly to TESC within 24 hours (1 business day) of screening (Part A Visit 1), where possible. 
TESC may ask the investigator for additional information to assist in their decision. The 
Epilepsy Study Consortium decision will be made within 14 days of receipt of all required 
information and written approval of the SIF/DRF and eDiary Seizure Classification Report must 
be received by the investigator before the baseline (Part A Visit 2) can occur. 
At baseline (Part A Visit 2), the investigator will contact the caregiver by phone for seizure 
classification training (eg, to review TESC-approved eDiary Seizure Classification Report and 
train the caregiver to identify, count and report the participant’s TESC-approved seizures to the 
seizure eDiary). Only seizures reported from the start of baseline (Part A Visit 2) will be used for 
the participant’s baseline seizure count.  
Only seizures that are recognizable and countable will be reported by caregivers for this study. 
The following ILAE seizure subtypes may be collected in the eDiary: 
• Primary endpoint EMAS-associated seizures: 
− Myoclonic-atonic 
− Atonic 
− Tonic 
− Clonic 
− Tonic–clonic 
• Secondary endpoint seizures: 
− Myoclonic seizures 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 68 
− Total Seizures (primary endpoint seizures and other seizures) 
 
  
 
 
 
 
 
 
 
 
• Status epilepticus (any seizure lasting 30 minutes or longer)  
− Convulsive status epilepticus  
− Non-convulsive status epilepticus 
8.1.6. 
Investigational Medicinal Product Accountability 
Records of IMP accountability will be maintained according to Section 6.2 and Section 6.4. 
8.2. 
Efficacy Assessments 
Planned time points for all efficacy assessments are provided in the SoA (Section 1.3). 
8.2.1. 
Questionnaires and Assessments Completed at Scheduled Visits  
Non-investigator/physician-facing questionnaires should be completed by the main caregiver. 
The questionnaires will be captured using an electronic system. The same person should 
complete the questionnaires/assessments throughout the study to maintain consistency. If the 
main caregiver is not available at the appropriate visit, then this information can be captured over 
the telephone, ideally on the day of the visit or otherwise within ± 7 days. Because participants in 
this study are expected to be experiencing varying degrees of cognitive impairment or delay 
related to their seizure history, only completion of caregiver-facing questionnaires are expected 
for this study. 
Investigator/physician-facing questionnaires should be completed by the appropriate rater and 
data will be recorded in an electronic system, ideally on the day of the visit or otherwise within 
± 7 days. The same person should complete the questionnaires/assessments throughout the study 
to maintain consistency. 
The participant’s age at Part A Visit 1 will be used to determine which questionnaires should be 
completed for the duration of the trial. Questionnaires should only be administered to study 
participants who satisfy minimum age requirements at screening (Part A Visit 1). Questionnaires 
completed during screening (Part A Visit 1) will be considered as baseline. 
Questionnaires should be completed prior to any invasive procedures (eg, blood draws, ECG, 
EEG, etc.) that may affect the caregiver’s responses to the questionnaires. 
Questionnaires will only be administered if a translation is available in the caregiver’s native 
language. 






Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 71 
recoded to a 9-point scale before summarizing the scales. The CEQ-P will only be administered 
if a translation is available in the caregiver’s native language and should take 5 minutes to 
complete. 
8.2.1.10. Menstruation 
Caregivers will be asked if the female participant is menstruating, and details will be recorded as 
part of their randomization visit (Part A Visit 3); any changes in normal cycles will be captured 
at Part A Visit 9 (Day 99)/Part B Visit 1 and Part B Visit 10. 
8.2.1.11. Tanner Staging 
The pubic hair growth (both sexes), genital (males only), and breast (females only) development 
of all adolescent participants (ie, 10 to 17 years of age at the time the ICF is signed, or earlier if 
clinically indicated by onset of menarche or other signs of precocious puberty) will be assessed 
by the investigator or his/her qualified delegate using Tanner Staging (Carel 2008). The 
participants will undergo a discreet physical examination and be assigned a value under each 
category of Pubic Hair Growth (both sexes), Genitals (male participants only), and Breasts 
(female participants only). 
Once a participant reaches a score of V (ie, 5), the examination need not be performed again. 
8.3. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (see Section 1.3). 
8.3.1. 
Physical Examinations 
A physical examination (including height, length, head circumference, and weight) will be 
performed at the time points specified in the SoA (see Section 1.3). 
8.3.2. 
Vital Signs 
Vital signs will be measured in a supine position after 5 minutes rest in a quiet setting without 
distractions (eg, television, mobile phones) and will include body temperature, systolic and 
diastolic blood pressure, pulse rate, and respiratory rate. As part of screening procedures and at 
each clinic visit, blood pressure and pulse rate will also be taken after 2 minutes in a standing 
position (if it is possible for the participant to stand), following supine measurements. All 
measurements will be performed singly and repeated once if outside the relevant clinical 
reference range. Blood pressure must be recorded using the same arm throughout the study, 
where possible.  
Additional vital signs measurements may be taken during the study, if clinically indicated. 
8.3.3. 
Electrocardiograms 
ECG will be obtained as outlined in the SoA (see Section 1.3) using an ECG machine that 
automatically calculates the heart rate and measures PR, QRS, QT, and corrected QT interval 
with Bazett correction intervals.  
An ECG will be performed after 5 minutes in a supine position. A physician must review the 
ECG in a timely manner and any clinically significant abnormal findings considered to indicate 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 72 
significant medical history or AEs must be recorded appropriately on the eCRF. Additional ECG 
measurements can be taken at any time during the study, if clinically indicated. 
8.3.4. 
Clinical Safety Laboratory Assessments 
See Section 10.3 (Appendix 3) for the list of clinical laboratory tests to be performed and the 
SoA (Section 1.3) for the timing and frequency.  
In participants with clinical risk factors for hepatocellular injury, re-assessment of laboratory 
safety parameters (biochemistry, coagulation, urinalysis, and hematology), including review of 
results should be completed up to 14 days prior to randomization (Part A Visit 3) to verify 
eligibility for the study. The investigator should use his/her clinical judgement along with 
screening assessments and consider the participant’s risk factors to determine whether to 
re-check biochemistry and coagulation during the baseline period. Possible risk factors include 
but are not limited to concurrent use of valproic acid or ketogenic diet, a recent infection or 
illness, a history of elevated liver enzymes, elevated liver enzymes during the previous study 
visit, or any other relevant signs or symptoms that could indicate the participant is experiencing 
abnormal liver function. If re-assessment of laboratory parameters (biochemistry, hematology, 
urinalysis, and coagulation) is completed within 14 days of randomization (Part A Visit 3), 
testing at randomization (Part A Visit 3) does not need to be performed. 
In the absence of clinical risk factors, per the clinical judgement of the investigator, 
re-assessment of laboratory parameters are not required. The laboratory results from Part A 
Visit 1 will serve as Part A baseline values. Part A Visit 9 laboratory results will serve as Part B 
baseline values. 
*Re-assessment of biochemistry and coagulation at Part A Day 57 (Visit 8) is required if there 
has been an adjustment to the participant’s dose of IMP following Part A Day 29 (Visit 7) and/or 
the participant is on concurrent valproic acid and/ or participant had elevated transaminases 
during previous visits.  
The investigator must review the laboratory report, document this review, and record any 
clinically significant changes (in the investigator’s opinion) occurring during the study as an AE. 
The laboratory reports must be filed with the source documents.  
All laboratory tests with values considered clinically significantly abnormal during participation 
in the study should be repeated until the values normalize, return to baseline, or are no longer 
considered clinically significant by the investigator or medical monitor or until values stabilize. 
If clinically significant values do not return to normal/baseline within a period judged reasonable 
by the investigator, the etiology should be identified, and the sponsor notified. 
All protocol-required laboratory tests, as defined in Section 10.3 (Appendix 3), must be 
conducted in accordance with the laboratory manual and the SoA (Section 1.3). 
If laboratory values from non-protocol-specified laboratory tests performed at the institution’s 
local laboratory require a change in participant management or are considered clinically 
significant by the investigator (eg, SAE or AE or dose modification), then the results would be 
captured as AEs and appropriate follow-up actions/measures taken, if needed. 
Blood sample volume requirements and processing procedures will be detailed in a separate 
laboratory manual; the maximum cumulative amount of blood taken in any 4-week period, 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 73 
including PK blood samples, will be 2.55 mL/kg of body weight and will not exceed a total of 
50 mL within any 8-week period (Howie 2011), taking into account possible repeat tests. The 
participant/caregiver must be advised that it may not be safe for the participant to undertake 
further blood tests within 1 month of any study-related blood draws and to inform the 
investigator if they suffered any blood loss during the 1-month period leading up to a planned 
blood draw. 
8.3.5. 
Pregnancy Testing 
Refer to Section 5.1 inclusion criteria for pregnancy testing entry criteria. 
Pregnancy testing (serum or urine) should be conducted for women of CBP as detailed in the 
SoA (Section 1.3). 
Additional serum or urine pregnancy tests may be performed, as determined necessary by the 
investigator or required by local regulation, to establish the absence of pregnancy at any time 
during the participant’s participation in the study. 
8.3.6. 
Suicidal Ideation and Behavior Risk Monitoring 
ASMs are associated with an increased risk of suicidal ideation or behavior.  
Participants with EMAS may occasionally develop suicidal ideation or behavior. 
Participants being treated with IMP should be monitored appropriately and observed closely for 
suicidal ideation and behavior or any other unusual changes in behavior, especially at the 
beginning and end of the course of IMP, or at the time of dose changes, either increases or 
decreases. All factors contributing to suicidal ideation or behavior should be evaluated and 
consideration should be given to discontinuation of the IMP.  
Baseline assessment of suicidal ideation and behavior will be monitored during the study using 
C-SSRS or clinical interview if C-SSRS is not appropriate. 
8.4. 
Adverse Events, Serious Adverse Events and Other Safety Reporting 
The definitions of AEs and SAEs can be found in Section 10.4 (Appendix 4). 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up all AEs or SAEs, considered related to the IMP or study procedures, or that caused the 
participant to discontinue the IMP until resolution or the event is considered stable (see 
Section 7). 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in 
Section 10.4 (Appendix 4). 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 74 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE Information 
All AEs*, including SAEs, will be collected from the signing of the ICF until the follow-up visit 
(Visit 11 for Part A and Visit 12 for Part B) as specified in the SoA (Section 1.3) or end of the 
participant’s participation in the study. 
Medical occurrences that begin before the start of IMP but after obtaining informed 
consent/assent will be reported as non-TEAE. 
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours of becoming aware of the SAE as indicated in 
Section 10.4 (Appendix 4). The investigator will submit any updated SAE data to the sponsor 
within 24 hours of it being available. 
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion of 
the study participation. However, if the investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the IMP or study participation, the investigator must promptly notify the 
sponsor. 
* For the participant’s expected seizure types, these do not routinely require documentation as 
AEs. However, any clinically significant worsening, including a clinically significant change in 
the pattern or severity of seizures from baseline, must be documented as an AE. 
8.4.2. 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.4.3. 
Follow up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs, and AEs of special interest (as defined in 
Section 10.4.3), will be followed until resolution, stabilization, the event is otherwise explained, 
or the participant is lost to follow-up (as defined in Section 7.3). Further information on 
follow-up procedures is provided in Section 10.4.4. 
8.4.4. 
Regulatory Reporting Requirements for SAEs 
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of an IMP 
under clinical investigation are met. 
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of an IMP under clinical investigation. The sponsor will 
comply with country-specific regulatory requirements relating to safety reporting to the 
regulatory authority, IRB/IEC, and investigators. 
An investigator who receives an investigator safety report describing an SAE or other specific 
safety information (eg, summary or listing of SAEs) from the sponsor will review and then file it 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 75 
along with the IB/package insert and will notify the IRB/IEC, if appropriate according to local 
requirements. 
Investigator safety reports must be prepared for suspected unexpected serious adverse reactions 
according to local regulatory requirements and sponsor policy and forwarded to investigators as 
necessary. 
8.4.5. 
Pregnancy 
Details of all pregnancies in female participants and, if indicated, female partners of male 
participants will be collected after the ICF has been signed and until 3 months after the follow-up 
visit (Part B Visit 11 or Part A Visit 12 [if the participant does not continue to Part B]). 
If a pregnancy is reported, the investigator will record pregnancy information on the appropriate 
form and submit it to the sponsor within 24 hours of learning of the female participant or female 
partner of male participant pregnancy. 
The investigator is not obliged to actively monitor for any pregnancies that commence more than 
3 months after the follow-up visit. However, if the investigator becomes aware of a new 
pregnancy outside this time limit, then they should report it as above. The sponsor PVD will 
follow-up for all pregnancy outcomes. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be reported as an AE or SAE. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs and will be reported as such. 
The participant/pregnant female partner (after obtaining the necessary signed informed 
consent/assent from the female partner) will be followed to determine the outcome of the 
pregnancy. The investigator will collect follow-up information on the participant/pregnant 
female partner and the neonate for 6 months after birth, and the information will be forwarded to 
the sponsor. 
Any post-study pregnancy-related SAE considered reasonably related to the IMP by the 
investigator will be reported to the sponsor as described in Section 8.4.4. While the investigator 
is not obligated to actively seek this information in former study participants/pregnant female 
partner, he or she may learn of an SAE through spontaneous reporting. 
Any female participant who becomes pregnant while participating in the study will discontinue 
IMP or be withdrawn from the study. 
8.4.6. 
Adverse Events of Special Interest 
See Section 10.4.3. 
8.5. 
Pharmacokinetic Assessments 
PK assessments will only be performed for Part A of the study. Plasma samples will be collected 
from all participants for measurement of plasma concentrations of CBD and its major 
metabolites as specified in the SoA (Section 1.3) as follows:  
• Pre-dose (within 60 minutes prior to the morning dose of IMP). 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 76 
• Post-dose (3 hours [±1 hour]) following morning dose of IMP). 
Instructions for the collection and handling of biological samples will be provided by the 
sponsor. The actual date and time (24-hour clock time) of each sample will be recorded. 
Samples will be used to evaluate the PK of CBD and its major metabolites.  
IMP concentration information that may unblind the study will not be reported to investigative 
sites or blinded personnel until the study has been unblinded. 
The maximum amount of blood taken for PK analysis will be approximately 4 mL. 
Caregivers will record the date, time, and meal type (eg, high fat meal [dairy or meat], standard 
meal [fruit or vegetable] or other [if not fitting into one of the categories above]) for all meals 
consumed by the participant within 24 hours prior to PK collection. 
Analysis of all PK samples will be conducted at a central bioanalytical laboratory and additional 
details are provided in the laboratory manual. 
8.6. 
Pharmacodynamic Assessment 
Pharmacodynamic parameters are not evaluated in this study. 
8.7. 
Genetics Assessment 
In Part A, samples for epilepsy gene panel analysis will be collected at the time point indicated in 
the SoA (Section 1.3), if the participant/caregiver/legal representative provides consent/assent.  
Participation is optional. Participants who do not wish to participate in the genetic research may 
still participate in the study. 
Details on processes for collection, shipment, storage, and destruction of these samples can be 
found in a separate laboratory manual. No genetic samples will be retained following the 
analysis.  
8.8. 
Biomarkers 
Biomarkers are not evaluated in this study. 
8.9. 
Immunogenicity Assessments 
Immunogenicity assessments are not evaluated in this study. 
8.10. 
Healthcare Resource Utilization 
Healthcare resource utilization parameters are not evaluated in this study. 
8.11. 
Special Circumstances 
During special circumstances (eg, 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 participants are not able to perform all protocol-defined assessments due 
to special circumstances, the investigator must discuss with the medical monitor potential 
mitigation approaches.  


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 77 
For the duration of such special circumstances, the following measures may be implemented for 
enrolled participants:  
• Visits may be done by a telephone call, other means of virtual contact or home visit, 
if appropriate.  
• Participant and/or clinician-rated outcomes assessments may be done by 
videoconference, telephone call, other means of virtual contact, if possible. 
• An alternative approach for IMP dispensing, secure delivery, and collection may be 
sought. 
• Visits may take place in a different location than defined in the protocol. If this is not 
feasible, then the visit may take place virtually with documentation of the means of 
communication (eg, phone call or videoconference).  
• 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.  
• If it is not possible to collect the biological samples or safety assessments (eg, ECG, 
vital signs) within the interval predefined in the protocol (see the SoA [Section 1.3]), 
then the interval may be extended up to a maximum duration of 7 days.  
• If a safety assessment cannot be performed within the modified window, the 
investigator must review the benefit-risk for participant continuation in the study and 
record this in the medical records. 
The rationale (eg, the specific reasons behind the changes) 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. 






Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 80 
minimum (min), and maximum (max). Categorical variables will be summarized by the 
frequency and proportion of participants falling into each category. 
For plasma concentration data and PK parameters, geometric mean, CV, and geometric CV will 
also be computed.  
Unless stated otherwise, baseline is defined as the last record or measurement collected prior to 
the first dose of IMP on Day 1 (Part A Visit 3). Baseline for Part B is the same as the baseline for 
Part A. 
9.4.2. 
Primary Endpoint(s) 
Part A: 
The primary efficacy endpoint is EMAS-associated seizure frequency (myoclonic-atonic, atonic, 
tonic, clonic, or tonic clonic) over the 14-week treatment period. 
The primary estimand for this study is defined by the following 3 components: 
• Target population: participants with EMAS-associated seizures who have not 
achieved adequate control from other ASMs. 
• Endpoint: change in EMAS-associated seizure frequency during the 14-week 
treatment period compared to baseline. 
• Measure of IMP effect: change in EMAS-associated seizure frequency during the 
treatment period, regardless of any intercurrent events. This measure of effect follows 
the treatment policy strategy for handling intercurrent events. 
The analysis of the primary efficacy endpoint will utilize Bayesian methodology to borrow 
external data from the historical pivotal studies in DS, LGS, and TSC. Active treatment groups 
will be pooled across doses within each indication to achieve a single estimated historical 
treatment effect for each indication. A Bayesian hierarchical model that dynamically determines 
the amount of information to be “borrowed” from the historical studies in the estimation of the 
treatment effect in the EMAS population will be used (Viele 2014).  
For the primary efficacy analysis, a single Bayesian hierarchical linear model will be applied as 
specified in the interim analysis SAP, SAP, and ADR to the 4 populations (DS, LGS, TSC, and 
EMAS). The model will include a population-specific intercept, a population-specific treatment 
effect, an adjustment for prespecified baseline covariates (log baseline seizure frequency, age at 
onset of seizures, and clobazam use), and a shared residual error. Prior distributions are 
prespecified for each of the model parameters. A Bayesian hierarchical distribution is specified 
for the treatment effects across populations, in which each study-specific treatment effect has a 
normal distribution centered on a grand overall treatment effect. A prior on the variance of this 
distribution will be specified to induce dynamic borrowing of the data from the previous pivotal 
trials in DS, LGS and TSC, in which the degree of similarity of the EMAS observed data relative 
to the historical data influences the magnitude of borrowing. Markov-Chain Monte Carlo 
methods will be used to estimate the Bayesian posterior distribution for parameters in the 
primary analysis model. Statistical inference and hypothesis testing will be conducted on the 
EMAS-specific treatment effect parameter corresponding to the primary efficacy hypothesis (ie, 
ratio of the change in seizure frequency between GWP42003-P and placebo). Complete details 
will be provided in the interim analysis SAP, SAP, and ADR. 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 81 
Part B: 
No primary efficacy endpoint is defined for Part B of the study. The primary objective for Part B 
is to evaluate the long-term safety and tolerability of GWP42003-P, evaluated by assessing the 
frequency of TEAEs; laboratory tests; vital signs; ECGs; Tanner Staging, and C-SSRS results. 
Data will be presented as per Section 9.4.5. 
9.4.2.1. 
Missing Data 
To ensure consistency with the previous pivotal trials in DS, LGS and TSC, missing data will be 
imputed using methodology implemented in the previous pivotal trials. More specifically, for 
participants missing seizure data due to withdrawal or intercurrent events, a 28-day average is 
imputed for each participant as 
Number of seizures recorded in the period for participant
Number of days that seizure data was recorded for participant in the period × 28 
The change in seizure frequency from baseline is calculated using the imputed value.  
9.4.2.2. 
Sensitivity Analyses 
The following sensitivity analyses will be conducted for the primary endpoint: 
• Primary endpoint analysis repeated using the following imputation methods for 
missing eDiary data during the treatment period only: 
− Any intermittent missing data for the number of seizures arising from unreported 
days in the eDiary will be imputed using the worst (highest number of seizures) of 
the following for each participant: LOCF, NOCB, and the mean daily number of 
seizures during the treatment period based on nonmissing data: 
Number of seizures 
Number of reported days in the eDiary 
− For participants in the active arm who withdraw from the study due to an adverse 
event or lack of efficacy, missing eDiary data will be imputed as the baseline rate 
or the average seizure frequency during the treatment period, whichever is higher. 
• To test the sensitivity of the results of the primary analysis to the degree of borrowing 
introduced by the dynamic borrowing prior, a model similar to the primary analysis 
model will explore a range of degrees of fixed borrowing of the historical data. More 
specifically, the variance of the Bayesian hierarchical distribution specified for the 
treatment effects across populations (Section 9.4.2) will be fixed across a set of 
values specified in the ADR ranging from very low (full borrowing) to very high (no 
borrowing). Summaries of the estimated treatment effect within each sensitivity 
analysis will be provided to assess the robustness of the primary analysis results to the 
degree of borrowing. 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 82 
9.4.3. 
Secondary Endpoint(s) 
The following endpoints will be compared by treatment group over the treatment period: 
9.4.3.1. 
Key Secondary Endpoints 
• Proportion of participants who achieve ≥ 50% reduction from baseline in 
EMAS-associated seizures 
• CGIC score. 
• Change in total seizure frequency compared to baseline 
• Change in EMAS-associated seizure frequency compared to baseline (Part B only) 
Part A: 
The first key secondary estimand for this study is defined as follows: 
• Target population: participants with EMAS-associated seizures who have not 
achieved adequate control from other ASMs.  
• Endpoint: proportion of participants who achieve ≥ 50% reduction from baseline in 
EMAS-associated seizures over the 14-week treatment period. 
• Measure of IMP effect: proportion of responders during the treatment period, 
regardless of any intercurrent events. This measure of effect follows a treatment 
policy strategy for handling intercurrent events. 
The second key secondary estimand for this study is defined as follows: 
• Target population: participants with EMAS-associated seizures who have not 
achieved adequate control from other ASMs.  
• Endpoint: CGIC score at Week 14. 
• Measure of IMP effect: CGIC score at Week 14, regardless of any intercurrent events. 
This measure of effect follows a treatment policy strategy for handling intercurrent 
events. 
The third key secondary estimand for this study is defined as follows: 
• Target population: participants with EMAS-associated seizures who have not 
achieved adequate control from other ASMs.  
• Endpoint: change in total seizure frequency during the 14-week treatment period 
compared to baseline. 
• Measure of IMP effect: change in total seizure frequency during the treatment period, 
regardless of any intercurrent events. This measure of effect follows a treatment 
policy strategy for handling intercurrent events. 
For the first key secondary endpoint, a binary indicator for response (at least a 50% reduction 
from baseline in seizure frequency over the 14-week treatment period) equaling either 1 or 0, a 
single Bayesian hierarchical logistic regression model will be applied to the 4 populations (DS, 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 83 
LGS, TSC, and EMAS). The model will take a form similar to the primary analysis model. 
Complete details will be provided in the ADR. 
For CGIC, a Bayesian hierarchical ordinal logistic regression model will be applied to the 
4 populations. This model will take a form similar to the primary analysis model and will be 
detailed in the ADR. 
Change in total seizure frequency will be analyzed in the same way as the primary endpoint. Full 
details will be provided in the ADR.  
Part B: 
Key secondary endpoints for Part B (long term) will be descriptive, with no formal statistical 
inference, and will be summarized by treatment group over time, using appropriate summary 
statistics. 
9.4.3.2. 
Other Secondary Efficacy Endpoints 
• PGIC score 
• Proportion of participants who achieve ≥ 25%, ≥ 75%, and 100% reduction from 
baseline in EMAS-associated seizures 
• Proportion of participants who achieve ≥ 25%, ≥ 50%, ≥ 75%, and 100% reduction 
from baseline in total seizures 
• Change from baseline in number of EMAS-associated seizure-free days (Part A only) 
• Time to baseline seizure frequency (Part A only) 
• Proportion of participants with ≥ 25% and ≥ 50% reduction in the number of days per 
week with myoclonic seizures during the treatment period 
Secondary endpoints will be summarized by treatment group over time using appropriate 
descriptive statistics for Part A and Part B. 
9.4.3.3. 
Safety Secondary Endpoints (Part A Only): 
• Frequency of TEAEs over the 14-week treatment period 
• Laboratory tests 
• Vital signs 
• ECG 
• Tanner Staging 
• Change in  
− C-SSRS ideation score 
− Number of suicide attempts in the C-SSRS 
Safety data for Part A will be presented as per Section 9.4.5. 






Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 86 
9.4.5.4. 
Vital Signs, ECG, Physical Examination and Other Safety Data 
Vital signs, ECG, physical examination, and C-SSRS data will be summarized for the safety 
analysis set at screening, baseline, and each time point during the treatment period using 
appropriate descriptive statistics. Changes from baseline to each post-baseline visit will also be 
summarized for vital signs and ECG. 
9.4.6. 
Other Analysis 
Following completion of Part A of the study, data will be cleaned and an analysis of all Part A 
data will be conducted. The SAP will describe the planned analyses in greater detail. 
9.5. 
Interim Analyses  
Interim analyses will be performed when 60, 75, 90, and 105 participants are randomized in 
Part A. The maximum sample size will be 120 randomized participants. The interim analyses or 
sample size updates will be based on the Goldilocks methodology (Broglio 2014) (Saville 2014) 
in which Bayesian predictive probabilities are used to make sample size decisions. Complete 
details of the interim analyses will be provided in the interim analysis SAP and ADR.  
9.5.1. 
Interim Analysis Review Committee 
An independent statistician will perform the interim analysis and the IARC will make one of 
3 possible recommendations to the sponsor: 1) stop accrual for expected success and conduct the 
primary analysis after all randomized participants have 14-week follow-up; 2) a nonbinding 
recommendation to stop the study for futility; or 3) continue enrolling to the next interim 
analysis or maximum sample size. A full detailed description of how the interim analyses will be 
conducted (eg, logistics, results delivery) will be documented in an IARC charter. 
Blinding 
In order to maintain study blinding, the interim analyses will be conducted by an unblinded 
statistical team independent from the day-to-day operational team. Enrollment will not be paused 
during the interim analysis. Interim analyses results will be shared only with the IARC, which 
will make a recommendation to the sponsor according to the prespecified adaptive algorithm. 
The sponsor will be provided the general IARC recommendation regarding sample size, but not 
the details of the interim analysis (eg, model results, treatment effects, posterior probabilities). 




Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 88 
 
 
 
 
 
 
 
 
 
Testing Lab: 
  
  
 
 
 
Bioanalytical Laboratory  
  
  
  
  
 
10.2. 
Appendix 2: Regulatory, Ethical, and Study Oversight 
Considerations 
10.2.1. 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines. 
• Applicable ICH Guidelines including ICH E6(R2). 
• Applicable laws and regulations. 
The protocol, protocol amendments, ICF, IB, and other relevant documents (eg, advertisements) 
must be submitted to an IRB/IEC and reviewed and approved by the IRB/IEC before the study is 
initiated. 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 89 
Protocol amendments must be made only with the prior approval of the sponsor. Agreement 
from the investigator must be obtained for all protocol amendments and amendments to the 
informed consent/assent documents. The IRB/IEC and regulatory authorities must be informed 
of all amendments and give approval for any substantial amendments, except for changes 
necessary to eliminate an immediate hazard to study participants. Amendments for 
administrational changes can be submitted to the IRB/IEC for information only. The investigator 
must send a copy of the approval letter from the IRB/IEC to the sponsor. 
The investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC. Note that in some regions this may be the sponsor’s 
responsibility. 
• Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures. 
• Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR (if applicable), ICH guidelines, the IRB/IEC, European 
Directive 2001/20/EC (including amendments since 2001), Directive 2005/28/EC for 
clinical studies (if applicable), and all other applicable local regulations. 
10.2.2. 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
10.2.3. 
Informed Consent/Assent Process 
• The investigator or his/her representative will explain the nature of the study to the 
participant and answer all questions regarding the study. 
• Participants must be informed that their participation is voluntary, and they are free to 
withdraw at any time. Participants or their caregivers will be required to sign a 
study-specific statement of informed consent/assent that meets the requirements of 
21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act requirements, where applicable, General Data Protection 
Regulation, and the IRB/IEC or study site. 
• The medical record must include a statement that written informed consent/assent 
was obtained, and the date the written consent/assent was obtained, before the 
participant completes any protocol-specific screening procedures or any IMPs are 
administered. The authorized person obtaining the informed consent/assent must also 
sign and date the ICF. 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 90 
• If in the investigator’s opinion, a participant lacks the cognitive capacity to provide 
assent, this should be documented in the participant’s source documents and consent 
should be obtained from the caregiver in accordance with local regulations.  
• For participants who are able to provide assent, the caregiver must also provide 
written consent in accordance with local regulations. 
• Participants must be re-consented to the most current version of the ICF(s) during 
their participation in the study per IRB/IEC requirements. 
• A copy of the completed ICF(s) must be provided to the participant. 
10.2.4. 
Data Protection 
• Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier only; 
participant names or any information which would make the participant identifiable 
will not be transferred to the sponsor. 
• The participant must be informed that his/her personal study-related data will be used 
by the sponsor in accordance with local data protection law. The level of disclosure 
must also be explained to the participant who will be required to give consent for 
their data to be used as described in the informed consent/assent.  
• The participant must be informed that his/her medical records may be examined by 
clinical quality assurance auditors, clinical study monitors, or other authorized 
personnel appointed by the sponsor, by appropriate IRB/IEC members, and by 
inspectors from regulatory authorities. 
10.2.5. 
Committees Structure 
10.2.5.1. The Epilepsy Study Consortium 
An independent The Epilepsy Study Consortium (TESC) will be instated to confirm EMAS 
diagnosis and verify the ILAE seizure types of screened participants prior to start of the baseline 
period (Part A Visit 2). See Section 8.1.4 and Section 8.1.5. 
Details of the composition and standard operating procedures of TESC will be detailed in a 
separate charter. 
10.2.6. 
Dissemination of Clinical Study Data 
The sponsor recognizes that there is a responsibility under the regulatory guidelines to ensure 
that results of scientific interest arising from this clinical study 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 study will be made available on 
http://www.clinicaltrials.gov and http://www.clinicaltrialsregister.eu/ (as applicable), as required 
by US and EU law. 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 91 
10.2.7. 
Data Quality Assurance 
• All participant data relating to the study will be recorded on eCRF unless transmitted 
to the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the eCRF. 
• Guidance on completion of eCRFs will be provided in the study eCRF completion 
guidelines. 
• The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• Quality tolerance limits will be predefined in the Risk Management Plan to identify 
systematic issues that can impact participant safety and/or reliability of study results. 
These predefined parameters will be monitored during the study and important 
deviations from the Quality Tolerance Limits and remedial actions taken will be 
summarized in the Clinical Study Report. 
• Monitoring details describing strategy (eg, risk-based initiatives in operations and 
quality such as risk management and mitigation strategies and analytical risk-based 
monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site 
monitoring) are provided in the clinical monitoring plan. 
• The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 
• The sponsor assumes accountability for actions delegated to other individuals 
(eg, contract research organizations). 
• Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the investigator for 25 years after study completion unless 
local regulations or institutional policies require a longer retention period. No records 
may be destroyed without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. 
10.2.8. 
Source Documents 
• Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site. 
• Data entered in the eCRF that are transcribed from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available. 
• Definition of what constitutes source data can be found in a source data verification 
plan. 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 92 
• The investigator must maintain accurate documentation (attributable, legible, 
contemporaneous, original, accurate and complete, consistent, enduring, and available 
[ALCOA+] source data) that supports the information entered in the eCRF. 
• Study monitors will perform (on-site or remotely) ongoing source data verification to 
confirm that data entered into the eCRF by authorized site personnel are accurate, 
complete, and verifiable from source documents; that the safety and rights of 
participants are being protected; and that the study is being conducted in accordance 
with the currently approved protocol and any other study agreements, ICH GCP, and 
all applicable regulatory requirements. 
10.2.9. 
Study and Site Start and Closure 
10.2.9.1. First Act of Recruitment 
The first act of recruitment is when the first participant signs the ICF and will be the study start 
date. 
10.2.9.2. Study/Site Termination 
The sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
For study termination: 
• Discontinuation of further IMP development. 
For site termination: 
• Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines. 
• Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the investigator. 
• Planned target number of participants achieved earlier than expected. 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up. 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 93 
10.2.10. 
Publication Policy 
• All information concerning the IMP and operations of the sponsor such as patent 
applications, formulae, manufacturing processes, basic scientific data or formulation 
information supplied to the investigator by the sponsor and not previously published 
is considered confidential by the sponsor and shall remain the sole property of the 
sponsor. The investigator will agree to use this information only in accomplishing the 
study and will not use it for any other purposes without the written consent of the 
sponsor. 
• The raw data generated by a site from this study may be obtained from the sponsor by 
the site or the investigator on request. Should they wish, investigators are allowed to 
conduct their own analyses on data generated at their own site and are permitted to 
present or publish such information in accordance with the relevant terms set out in 
the clinical study agreement. No single site publication may precede a multisite 
publication.  
• All publications, eg, manuscripts, abstracts, oral/slide presentations, or book chapters 
based on this study, must be submitted to the sponsor Medical Affairs Department 
and, as applicable, the sponsor Publication Committee for corporate review before 
release. To ensure adequate time for the sponsor 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 principal investigators must then incorporate all 
reasonable comments made by the sponsor into the publication. 
• The sponsor 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. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
10.3. 
Appendix 3: Clinical Laboratory Tests 
• The tests detailed in Table 6 will be performed by the central laboratory, wherever 
possible. 
• Local laboratory results are only required in the event that the central laboratory 
results are not available in time for either IMP administration and/or response 
evaluation. Additionally, if the local laboratory results are used to make either an IMP 
decision or response evaluation, the results must be recorded in the source documents. 
All abnormal, clinically significant lab results obtained locally would be captured as 
AE’s and appropriate follow-up actions/measures taken, if needed. 
• Protocol-specific requirements for inclusion or exclusion of participants are detailed 
in Section 5 of the protocol. 
• Refer to Section 8.3.4 for more detail. 
 
 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 94 
Table 6: 
Protocol-required Laboratory Tests 
Biochemistry 
(Serum) 
Hematology 
(Whole Blood)  
Urinalysis 
(Urine)a,b,d 
Hormone Panel (Serum) 
(CBP only) 
ALT 
Albumin 
ALP 
AST 
Calcium 
Creatininee 
Creatine Kinase 
Direct bilirubin 
GGT 
Potassium 
LDL cholesterol 
HDL cholesterol 
LDH 
Total cholesterol 
Sodium 
TBL 
Total protein 
Urea (blood urea nitrogen) 
Glucose 
Chloride 
Triglycerides 
Inorganic phosphate 
IGF-1 
Hematocrit 
Hemoglobin 
MCV 
MCH 
Platelets 
RBC count 
WBC count with 
automated differential 
Neutrophilsc 
Lymphocytesc 
Monocytesc 
Eosinophilsc 
Basophilsc 
 
Blood 
Glucose 
Nitrites 
pH 
Protein 
WBCs 
Specific gravity 
Ketones 
Urobilinogen 
Bilirubin 
Pregnancy test (human 
chorionic gonadotropin) 
(female participants of 
CBP only) 
Pregnancy test (human 
chorionic gonadotropin) 
Coagulation 
INR 
Other 
Genetic testing 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
CBP = childbearing potential; GGT = gamma-glutamyl transferase; HDL = high-density lipoprotein; 
IGF-1 = insulin-like growth factor-1; INR = international normalized ratio; LDH = lactate dehydrogenase; 
LDL = low-density lipoprotein; MCH = mean corpuscular hemoglobin; MCV = mean corpuscular volume; 
RBC = red blood cell; TBL = total bilirubin; WBC = white blood cell. 
Note: Investigators must document their review of each laboratory safety report. 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 95 
a Analyzed at the study site using an automated analyzer/urine dipstick. 
b In accordance with clinical laboratory or local standard procedures, urine microscopy/sediment examinations will 
only be performed if there is an abnormality in urinalysis. 
c Absolute and % of total WBC will be measured. 
d Urinalysis will be completed where urine collection is possible. 
e Estimated glomerular filtration rate will be calculated using the Schwartz equation.












Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 101 
10.5. 
Appendix 5: Contraceptive and Barrier Guidance 
10.5.1. 
Definitions 
Female Participants of Nonchildbearing Potential (NCBP) 
Female participants in the following categories are considered as NCBP: 
1) Participants who are premenarchal. 
2) Premenopausal female with permanent infertility due to one of the following (for the 
purpose of this study): 
a) Documented hysterectomy 
b) Documented bilateral salpingectomy 
c) Documented bilateral oophorectomy 
• For individuals with permanent infertility due to an alternate medical cause other than the 
above, (eg, Mullerian agenesis, androgen insensitivity, gonadal dysgenesis), investigator 
discretion should be applied to determining study entry. 
3) Postmenopausal female with documentation of cessation of menses for ≥ 12 consecutive 
months without an alternative medical cause. 
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
Female Participants of Childbearing Potential  
Female participants are considered of childbearing potential (fertile): 
• From the time of menarche until becoming postmenopausal (ie, documentation of 
cessation of menses for ≥ 12 consecutive months without an alternative medical cause) 
unless permanently sterile (as described above as NCBP). 
Infertile Male Participants 
A man is considered infertile when permanently sterile following bilateral orchidectomy, or any 
other documented cause of infertility. 
Fertile Male Participants 
A man is considered fertile after puberty unless permanently sterile as described above. 
10.5.2. 
Contraception Guidance 
CONTRACEPTIVESa, ALLOWED DURING THE STUDY INCLUDE: 
Highly Effective Methodsb That Have Low User Dependency Failure rate of < 1% per year 
when used consistently and correctly. 
• Implantable progestogen-only hormone contraception associated with inhibition of 
ovulationc 
• Intrauterine device. 
• Intrauterine hormone-releasing system. 
• Bilateral tubal occlusion. 
• Azoospermic partner (vasectomized or due to a medical cause). 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 102 
Azoospermia is a highly effective contraceptive method provided that the partner is the 
sole sexual partner of the woman of childbearing potential and the absence of sperm 
has been confirmed. If not, an additional highly effective method of contraception 
should be used. Spermatogenesis cycle is approximately 90 days. 
Note: documentation of azoospermia for a male participant can come from the site 
personnel’s review of the participant’s medical records, medical examination, or 
medical history interview. 
Highly Effective Methodsb That Are User Dependent Failure rate of < 1% per year when 
used consistently and correctly. 
• Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulationc 
– oral 
– intravaginal 
– transdermal 
• Progestogen-only hormone contraception associated with inhibition of ovulationc 
– oral 
– injectable 
• Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the IMP. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of 
the study and the preferred and usual lifestyle of the participant. 
a) Contraceptive use by male or female participants should also be consistent with local regulations regarding the 
use of contraceptive methods for those participating in clinical studies. 
b) Failure rate of < 1% per year when used consistently and correctly. Typical use failure rates differ from those 
when used consistently and correctly. 
c.) Male condoms must be used in addition to hormonal contraception. If locally required, in accordance with 
Clinical Trial Facilitation Group guidelines, acceptable contraceptive methods are limited to those which 
inhibit ovulation as the primary mode of action. 
Note: Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhea method are not acceptable methods of contraception for this study. 
Male condom and female condom should not be used together (due to risk of failure from friction). 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 103 
10.6. 
Appendix 6: Liver Safety: Actions and Follow-up Assessments  
All investigational sites are required to submit to the sponsor PVD the laboratory results for any 
participant after randomization that meets the criteria for the selected laboratory parameters as 
follows: 
• Serum ALT or AST > 3 × ULN with the presence of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%). 
• ALT or AST > 8 × ULN. 
• ALT or AST > 5 × ULN for > 2 weeks. 
• ALT or AST > 3 × ULN and (TBL > 2 × ULN or INR > 1.5). 
These reports must be sent to the sponsor PVD using the fax number or by e-mail for SAE 
reporting within 24 hours of becoming aware of the results. In addition, please send a copy of the 
participant’s baseline laboratory results with all reports to the sponsor PVD. 
Abnormal values in AST and/or ALT with or without concurrent 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 as soon as possible (within 24 hours of notice of abnormal results) 
for repeat assessment of ALT, AST, TBL, INR, full blood count (and differential count), 
eosinophil counts, ALP, and GGT levels, creatine kinase levels, detailed history, and physical 
examination. Participants should be followed with frequent (every 48 to 72 hours) repeat clinical 
laboratory assessments and any other appropriate assessments 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 participant is no longer at the investigational site, repeat 
assessments may be performed at a local laboratory and the results sent to the sponsor PVD. 
Refer to Section 7 for study withdrawal/discontinuation criteria.


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 104 
10.7. 
Appendix 7: Abbreviations and Definitions  
List of Abbreviations and Definitions of Terms 
AE 
Adverse event 
ADR 
Adaptive Design Report 
ASM 
Antiseizure medication (former terminology was antiepileptic drug 
[AED]) 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
BDS 
Botanical Drug Substance 
BID 
Twice daily 
 
 
C 
Clinic 
 
 
CBD 
Cannabidiol 
CBD-OS 
Cannabidiol oral solution 
CBP 
Childbearing potential 
CEQ-P 
Treatment Credibility/Expectancy Questionnaire and Parent Version 
CFR 
Code of Federal Regulations 
CGIC 
Caregiver Global Impression of Change score 
 
 
CID 
Complex Innovative Trial Design 
COVID-19 
Coronavirus disease 2019 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CV 
Coefficient of variation 
Day 1 
The day a participant first receives IMP in this study. 
DRF 
Diagnostic Review Form 
DS 
Dravet syndrome 
E/W 
Early withdrawal 
EAP 
Expanded access program 
EC 
Ethics Committee 
ECG 
12-lead electrocardiogram 
eCRF 
Electronic case report form 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 105 
eDiary 
Electronic diary 
EAP 
Expanded access program 
EEG 
Electroencephalogram 
EMAS 
Epilepsy with myoclonic-atonic seizures 
End of study 
Date of the last participant’s final completed scheduled visit or last 
completed study assessment, whichever occurs last 
Enrolled participant 
Any participant who has provided written informed consent/assent to 
take part in the study 
EOT 
End of treatment 
EU 
European Union 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
E/W 
Early withdrawal 
FDA 
Food and Drug Administration 
FU 
Follow-up 
GCP 
Good clinical practice 
GGT 
Gamma-glutamyl transferase 
GW 
GW Research Ltd 
HDL 
High-density lipoprotein 
 
 
IARC 
Interim Analysis Review Committee 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IGF-1 
insulin-like growth factor-1 
ILAE 
International League Against Epilepsy 
IMP 
Investigational medicinal product; term used to describe both 
investigational active product and reference therapy (placebo). 
INR 
International normalized ratio; a calculation made to standardize 
prothrombin time. 
Investigator 
Study principal investigator or a formally delegated study physician. 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 106 
ITT 
Intention to Treat 
LDH 
Lactate dehydrogenase 
LDL 
Low-density lipoprotein 
LGS 
Lennox Gastaut syndrome 
LOCF 
Last observation carried forward 
MCH 
Mean corpuscular hemoglobin 
MCV 
Mean corpuscular volume 
N/A 
Not applicable 
NCBP 
Nonchild bearing potential 
NOCB 
Next observation carried backward 
OL 
Open-label 
OLE 
Open-label extension 
OS 
Oral solution 
P 
Phone 
Participant 
Any participant enrolled in the study. 
 
 
 
 
PGIC 
Physician Global Impression of Change 
PK 
Pharmacokinetic(s) 
PVD 
Pharmacovigilance department 
RBC 
Red blood cell 
RTSM 
Randomization and Trial Supply Management 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
Screen failure 
Participants who consent/assent to participate in the clinical study but 
are not subsequently randomized 
Status epilepticus 
Any seizure lasting 30 minutes or longer 
SIF 
Seizure Identification Form 
SoA 
Schedule of activities 
Start of the study 
The date the first participant signs the informed consent/assent form 
TBL 
Total bilirubin 
TEAE 
Treatment-emergent adverse event 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 107 
TESC 
The Epilepsy Study Consortium 
Treatment duration 
The length of time the IMP will be administered. 
Study duration 
The maximum length of time a participant can be in the study. 
Study intervention 
Investigational medicinal product(s), marketed product(s), or placebo, 
intended to be administered to a study participant per protocol. 
TSC 
Tuberous sclerosis complex 
ULN 
Upper limit of normal 
US 
United States 
WBC 
White blood cell 
wks 
Weeks 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 108 
10.8. 
Appendix 8: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents. 
DOCUMENT HISTORY 
Document 
Date of Issue 
Amendment 1.1 (Version 3) 
25 August 2022 
Amendment 01 (Version 2) 
21 June 2022 
Original Protocol (Version 1) 
13 September 2021 
Amendment 1.1 (25 August 2022) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment: 
The overall rationale for the changes implemented in Amendment 1.1 was to ensure alignment 
between study procedures and Italy Regulatory Agency guidance. Specific updates incorporated 
into Amendment 1.1 are listed below. Minor editorial changes are not presented. 
Section # and 
Name 
Description of Change 
Brief Rationale 
1.3 Schedule of 
Activities 
(SoA) 
SoA: Part B: added physical 
examination for Week 14 (Month 3 
visit) and Week 24 (Month 6 visit) study 
visits. 
To have closer timelines for physical 
examination in Part B of the study. 
SoA: Part A and Part B: under column 
for “Notes” specified that height, length, 
and head circumference will be 
measured during physical examination. 
To clarify that where physical 
examination appears now or was added, 
assessments for height, length, and head 
circumference will also occur. 
SoA: Part A and Part B: removed row 
for “Height/length.” 
For clarity since details regarding 
assessments for height, length, and head 
circumference during physical 
examination were included under 
column for “Notes.” 
SoA: Part B Table Note: Text added 
specifying that “height, length, and head 
circumference will be collected at 
remote visits.” 
To clarify that these measurements will 
be collected during remote visits. 
2.3 Benefit/Risk 
Assessment  
Added a link to Section 2.2 (Study 
Rationale). 
To outline the potential benefits of 
GWP42003-P. 
Added statement regarding favorable 
benefit-risk profile of GWP42003-P. 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 109 
Section # and 
Name 
Description of Change 
Brief Rationale 
5.1 Inclusion 
Criteria  
#2: An additional inclusion criterion 
specifying “minimum body weight 
required for eligibility” has been added. 
To keep the blood volume within the 
maximum limits allowed during the 
study. 
5.2 Exclusion 
Criteria 
#25: Specified estimated glomerular 
filtration rate (Schwartz equation) 
< 60 mL/min. 
To provide clarification per Health 
Authority request. 
8.3.1 Physical 
Examinations 
Specified that height, length, and head 
circumference will be collected during 
physical examinations. 
Table 6 
Footnote “e” added to specify that 
estimated glomerular filtration rate will 
be calculated using the Schwartz 
equation. 
Amendment 01 (21 June 2022) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment: 
The overall rationale for the changes implemented in Amendment 01 was to ensure alignment 
between study procedures and Medicines and Healthcare products Regulatory Agency guidance. 
Specific updates incorporated into Amendment 01 are listed below. Minor editorial changes are 
not presented. 
Section # and 
Name 
Description of Change 
Brief Rationale 
1.1 Synopsis  
Revised the erroneous “yes” to “no” to 
accurately indicate that a Data 
Monitoring Committee (DMC) will not 
be utilized in this study. 
To clarify no DMC will be employed in 
this study. 
2.2 Study 
Rationale,  
4.2 Scientific 
Rationale for 
Study Design, 
and 4.3 
Justification 
for Dose  
Revised description of the expanded 
access program (EAP) to indicate it was 
initiated by the investigator and 
authorized by the Food and Drug 
Administration. 
To describe the nature of the EAP. 
5.2 Exclusion 
Criteria  
Revised exclusion criterion for serum 
total bilirubin (TBL) from ≥ 2 × upper 
limit of normal (ULN) to > 1.5 × ULN. 
Also specified exclusionary TBL 
(> 3 × ULN) and/or direct bilirubin 
To update TBL and direct bilirubin 
exclusion criteria, particularly as they 
relate to participants with Gilbert’s 
disease. 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 110 
Section # and 
Name 
Description of Change 
Brief Rationale 
(> 1 × ULN) for participants diagnosed 
with Gilbert’s disease. 
6.5 Dose 
Modification  
Inserted reference to the “CBD Dose 
Adjustment” section of the current 
approved GWP42003-P Investigator’s 
Brochure (IB). 
To provide reference to the IB, where 
detailed information regarding potential 
drug interactions and associated dose 
modifications may be found. 
6.8 
Concomitant 
Therapy  
Added details regarding key restrictions 
on concomitant therapies. Also inserted 
reference to the “CBD Dose Adjustment” 
section of the current approved 
GWP42003-P IB. 
To clarify restrictions regarding 
concomitant medications and provide 
reference to the IB, where detailed 
guidance on potential drug interactions 
may be found.  
10.5.1 
Definitions (in 
Appendix 5: 
Contraceptive 
and Barrier 
Guidance)  
Added definition of postmenopausal 
female. 
To provide clarity regarding the definition 
of postmenopausal status. 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 111 
11. 
REFERENCES 
Broglio KR, Connor JT, Berry SM (2014). Not too big, not too small: a Goldilocks approach to 
sample size selection. Journal of Biopharmaceutical Statistics. 24, 687-705. 
Carel J-C, Leger J (2008). Clinical practice. Precocious puberty. The New England Journal of 
Medicine. 358(22), 2366-77. 
Devinsky O (2003). Psychiatric comorbidity in patients with epilepsy: implications for diagnosis 
and treatment. Epilepsy & Behavior: E&B. 4 Suppl 4, S2-10. 
Devinsky O, Cross JH, Laux L, et al. (2017). Trial of Cannabidiol for Drug-Resistant Seizures in 
the Dravet Syndrome. The New England Journal of Medicine. 376(21), 2011-20. 
Devinsky O, Marsh E, Friedman D, et al. (2016). Cannabidiol in patients with treatment-resistant 
epilepsy: an open-label interventional trial. The Lancet Neurology. 15(3), 270-8. 
Devinsky O, Patel AD, Cross JH, et al. (2018a). Effect of Cannabidiol on Drop Seizures in the 
Lennox-Gastaut Syndrome. The New England Journal of Medicine. 378(20), 1888-97. 
Devinsky O, Verducci C, Thiele EA, et al. (2018b). Open-label use of highly purified CBD 
(Epidiolex®) in patients with CDKL5 deficiency disorder and Aicardi, Dup15q, and Doose 
syndromes. Epilepsy & Behavior: E&B. 86, 131-7. 
Doose H (1992). Myoclonic-astatic epilepsy. Epilepsy Res Suppl. 6, 163-8. 
Doose H, Gerken H, Leonhardt R, Völzke E, Völz C (1970). Centrencephalic myoclonic-astatic 
petit mal. Clinical and genetic investigation. Neuropadiatrie. 2(1), 59-78. 
Gofshteyn JS, Wilfong A, Devinsky O, et al. (2017). Cannabidiol as a Potential Treatment for 
Febrile Infection-Related Epilepsy Syndrome (FIRES) in the Acute and Chronic Phases. Journal 
of Child Neurology. 32(1), 35-40. 
Goldberg JF, Burdick KE (2001). Cognitive side effects of anticonvulsants. The Journal of 
Clinical Psychiatry. 62 Suppl 14, 27-33. 
Helmstaedter C, Witt J-A (2020). Anticonvulsant Drugs and Cognition, in: Riederer, P, Laux, G, 
Mulsant, B, Le, W, Nagatsu, T (Eds.), NeuroPsychopharmacotherapy. Springer International 
Publishing, Cham, pp. 1-12. 
Hess EJ, Moody KA, Geffrey AL, et al. (2016). Cannabidiol as a new treatment for drug-
resistant epilepsy in tuberous sclerosis complex. Epilepsia. 57(10), 1617-24. 
Hinokuma N, Nakashima M, Asai H, et al. (2020). Clinical and genetic characteristics of patients 
with Doose syndrome. Epilepsia Open. 5(3), 442-50. 
Howie SR (2011). Blood sample volumes in child health research: review of safe limits. Bulletin 
of the World Health Organization. 89, 46-53. 
Hulse D, Harvey AS, Freeman JL, et al. (2020). Clinical application of the PedsQL Epilepsy 
 
 
International League Against Epilepsy (ILAE) Diagnostic Manual (2012). Available from: 
https://www.epilepsydiagnosis.org/syndrome/epilepsy-myoclonic-atonic-overview.html 
(accessed 11 February 2020). 
Karakis I, Cole AJ, Montouris GD, et al. (2014). Caregiver burden in epilepsy: determinants and 
impact. Epilepsy Res Treat. 2014, 808421. 
Kelley SA, Kossoff EH (2010). Doose syndrome (myoclonic-astatic epilepsy): 40 years of 
progress. Developmental Medicine & Child Neurology. 52(11), 988-93. 
Kilaru S, Bergqvist AGC (2007). Current treatment of myoclonic astatic epilepsy: clinical 
experience at the Children's Hospital of Philadelphia. Epilepsia. 48(9), 1703-7. 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 112 
Kwan P, Brodie MJ (2001). Neuropsychological effects of epilepsy and antiepileptic drugs. 
Lancet. 357(9251), 216-22. 
McCagh J, Fisk JE, Baker GA (2009). Epilepsy, psychosocial and cognitive functioning. 
Epilepsy Research. 86(1), 1-14. 
Mehta CR, Pocock SJ (2011). Adaptive increase in sample size when interim results are 
promising: a practical guide with examples. Statistics in Medicine. 30(28), 3267-84. 
Menlove L, Reilly C (2015). Memory in children with epilepsy: a systematic review. Seizure. 25, 
126-35. 
Miller I, Scheffer IE, Gunning B, et al. (2020). Dose-Ranging Effect of Adjunctive Oral 
Cannabidiol vs Placebo on Convulsive Seizure Frequency in Dravet Syndrome: A Randomized 
Clinical Trial. JAMA Neurology. 77(5), 613-21. 
Modi AC, Junger KF, Mara CA, et al. (2017). Validation of the PedsQL Epilepsy Module: A 
pediatric epilepsy-specific health-related quality of life measure. Epilepsia. 58(11), 1920-30. 
Moeller F, Groening K, Moehring J, et al. (2014). EEG-fMRI in myoclonic astatic epilepsy 
(Doose syndrome). Neurology. 82(17), 1508-13. 
Neubauer BA, Hahn A, Doose H, Tuxhorn I (2005). Myoclonic-astatic epilepsy of early 
childhood--definition, course, nosography, and genetics. Adv Neurol. 95, 147-55. 
Oguni H, Fukuyama Y, Imaizumi Y, Uehara T (1992). Video-EEG analysis of drop seizures in 
myoclonic astatic epilepsy of early childhood (Doose syndrome). Epilepsia. 33(5), 805-13. 
Saville BR, Connor JT, Ayers GD, Alvarez J (2014). The utility of Bayesian predictive 
probabilities for interim monitoring of clinical trials. Clinical Trials. 11(4), 485-93. 
Stephani U (2006). The natural history of myoclonic astatic epilepsy (Doose syndrome) and 
Lennox-Gastaut syndrome. Epilepsia. 47 Suppl 2, 53-5. 
Szaflarski JP, Bebin EM, Comi AM, et al. (2018). Long-term safety and treatment effects of 
cannabidiol in children and adults with treatment-resistant epilepsies: Expanded access program 
results. Epilepsia. 59(8), 1540-8. 
Thiele E, Bebin EM, Filloux F, et al. (2020a). Long-term Safety and Efficacy of Cannabidiol 
(CBD) for the Treatment of Seizures in Patients with Tuberous Sclerosis Complex (TSC) in an 
Open-label Extension (OLE) Trial (GWPCARE6), The American Academy of Neurology 
Annual Meeting. 
Thiele EA, Bebin EM, Bhathal H, et al. (2020b). Add-On Cannabidiol Treatment for Drug-
Resistant Seizures in Tuberous Sclerosis Complex: A Placebo-Controlled Randomized Clinical 
Trial. JAMA Neurology. 
Thiele EA, Marsh ED, French JA, et al. (2018). Cannabidiol in patients with seizures associated 
with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled 
phase 3 trial. Lancet. 391(10125), 1085-96. 
Trinka E, Cock H, Hesdorffer D, et al. (2015). A definition and classification of status 
epilepticus--Report of the ILAE Task Force on Classification of Status Epilepticus. Epilepsia. 
56(10), 1515-23. 
Varni JW, Burwinkle TM, Seid M, Skarr D (2003). The PedsQL 4.0 as a pediatric population 
health measure: feasibility, reliability, and validity. Ambul Pediatr. 3(6), 329-41. 
Viele K, Berry S, Neuenschwander B, Amzal B, Chen F, et al. (2014) Use of historical control 
data for assessing treatment effects in clinical trials. Pharmaceutical Statistics. 13(1), 41-54.  
Wirrell EC, Vanderwiel AJ, Nickels L, Vanderwiel SL, Nickels KC (2018). Impact of Prior 
Authorization of Antiepileptic Drugs in Children With Epilepsy. Pediatric Neurology. 83, 38-41. 


Jazz Pharmaceuticals 
Protocol GWEP20238 
GWP42003-P 
Protocol Amendment 2.0 
 
CONFIDENTIAL 
Page 113 
Wu J, Cock H, Devinsky O, et al. (2020). Time to Onset of Cannabidiol (CBD) Treatment Effect 
and Resolution of Adverse Events (AEs) in the Tuberous Sclerosis Complex (TSC) Phase 3 
Randomized Controlled Trial (GWPCARE6), The American Academy of Neurology Annual 
Meeting. 
Zempel JM, Mano T (2014). Myoclonic atonic epilepsy: another generalized epilepsy syndrome 
that is "not so" generalized. Neurology. 82(17), 1486-7. 
 


Signature Page for GWEP20238 Global Protocol Amendment 2.0 (VV-CLIN-017004)
Signature Page for GWEP20238 Global Protocol Amendment 2.0 (VV-CLIN-017004)
Approval Task - Approval of Document
Signing Verdict/Reason: I Approved This Document
23-Apr-2023 17:33:34 GMT+0000