Clinical trial NCT02224573
Conditions: Epilepsy Dravet Syndrome Lennox-Gastaut Syndrome
Keywords: Cannabidiol CBD GWP42003-P GWPCARE5
Sponsor: GW Research Ltd
Start date: 2015-06-11; Completion date: 2020-09-24
Enrollment: 681 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
To investigate the potential antiepileptic effects of cannabidiol (GWP42003-P) in children and adults with Dravet or Lennox-Gastaut syndromes.

Detailed description:
This is a multi-center, open-label extension study for participants with Dravet syndrome or Lennox-Gastaut syndrome who have previously participated in double-blind, placebo-controlled clinical studies of GWP42003-P (Core Studies: GWEP1332A \[NCT02091206\], GWEP1332B \[NCT02091375\], GWEP1424 \[NCT02224703\], GWEP1414 \[NCT02224560\], GWEP1424 \[NCT02224703\], and GWEP1423 \[NCT02224690\]). The first participant was enrolled into the open-label extension study after the Data Safety Monitoring Committee reviewed the safety data from Part A of study GWEP1332.

Arms: arm 1: None
Interventions: intervention 1: GWP42003-P
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_000.pdf: 
Study Code: GWEP1415 
EudraCT Number: 2014-001834-27 
Protocol V18 (USA ONLY) 25Apr18 
 
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TITLE: An open label extension study to investigate the safety of 
cannabidiol (GWP42003-P; CBD) in children and adults with 
inadequately controlled Dravet or Lennox-Gastaut Syndromes. 
 
STUDY CODE: GWEP1415 
EudraCT NUMBER: 2014-001834-27 
 
COUNTRY-SPECIFIC PROTOCOL 
 
GW RESEARCH LTD 
SOVEREIGN HOUSE 
VISION PARK 
CHIVERS WAY 
HISTON 
CAMBRIDGE CB24 9BZ 
UNITED KINGDOM 
TEL: +44 (0)1223 266 800 
FAX: +44 (0)1223 235 667 
 
Confidentiality Statement 
This document contains confidential information of GW Research Ltd (GW) that 
must not be disclosed to anyone other than the recipient study staff and members of 
the Institutional Review Board/Independent Ethics Committee.  This information 
cannot be used for any purpose other than the evaluation or conduct of the clinical 
investigation without the prior written consent of GW. 


Study Code: GWEP l415 
EudraCT Number: 2014-001834-27 
Protocol V 18 (USA ONLY) 25Aprl 8 
Investigator Agreement 
GW 
pharmaceuticals 
1 have read the attached protocol entitled "An open label extension study to 
investigate the safety of cannabidiol (GWP42003-P; CBD) in children and adults with 
inadequately controlled Dravet or Lennox-Gastaut Syndromes", dated 25 April 2018 
and agree to abide by all provisions set forth therein. 
I agree to comply with applicable regulatory requirement(s); the FDA regulations 
relating to good clinical practice and clinical trials, and the European Union (EU) 
Clinical Trials Directive 2001/20/EC and subsequent applicable regulatory/statutory 
instruments, or the International Conference on Harmonization Tripartite Guideline 
on Good Clinical Practice (ICH GCP) where the EU Clinical Trials Directive does not 
apply and to complete a Form 1572 ifrequired. 
I am not aware that any conflicts of interest, financial or otherwise, exist for myself, 
my spquse [or legal partner] and dependent children and agree to confirm this in 
writing if required and update as necessary. 
1 agree to ensure that the confidential information contained in this document will not 
be used for any purpose other than the evaluation or conduct of the clinical 
investigation without the prior written consent of GW. 
Center No: 
Print Name: 
Date: 
Principal Investigator 
(DD Month YYYY) 
Signature: 
GW Authorization 
Print Name: 
Date: 
(DD Month YYYY) 
Signature: 
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Study Code: GWEP1415 
EudraCT Number: 2014-001834-27 
Protocol V18 (USA ONLY) 25Apr18 
 
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1 
PROTOCOL SYNOPSIS 
Study Title 
An open label extension study to investigate the safety of 
cannabidiol (GWP42003-P; CBD) in children and adults with 
inadequately controlled Dravet or Lennox-Gastaut Syndromes. 
Clinical Study 
Type 
Phase 3 Study. 
Indication 
Dravet Syndrome (DS) or Lennox-Gastaut Syndrome (LGS). 
Primary 
Objective 
To evaluate the long-term safety and tolerability of GWP42003-P, 
as adjunctive treatment, in children and adults with inadequately 
controlled DS or LGS. 
Secondary 
Objective(s) 
All Patients: 
To evaluate the effect of GWP42003-P, as adjunctive treatment, 
on: 
 Quality of life. 
 Adaptive behavior. 
 Need for hospitalizations due to epilepsy. 
 Usage of rescue medication. 
 Maintenance of seizure frequency reduction and freedom from 
seizures during the open label extension (OLE) study. 
 Frequency of total and subtypes of seizures. 
 Change in duration of subtypes of seizures. 
 Number of episodes of status epilepticus. 
 Cognitive function. 
 Growth and development. 
 Menstruation cycles (in females). 
 Signals indicating drug abuse liability of GWP42003-P. 
DS Patients Only: 
To evaluate the effect of GWP42003-P, as adjunctive treatment, 
on: 
 Total convulsive seizure frequency. 
 Total non-convulsive seizure frequency. 
 Number of patients convulsive seizure-free. 
 Responder rate (defined in terms of percentage reduction in 
total convulsive seizure frequency). 
LGS Patients Only: 
To evaluate the effect of GWP42003-P, as adjunctive treatment, 
on: 
 Drop seizure frequency. 


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 Non-drop seizure frequency. 
 Number of patients drop seizure-free. 
 Responder rate (defined in terms of percentage reduction in 
drop seizure frequency). 
Study Design 
This is a multi-center, OLE study for patients with DS or LGS 
who have completed the double-blind, placebo-controlled, clinical 
studies with GWP42003-P (Core Studies).  The study consists of a 
titration period and a maintenance period, followed by a 10-day 
taper period. 
Titration Period: All patients will titrate up to 10–20 mg/kg/day 
GWP42003-P using a recommended titration schedule.  It is 
advised that the Investigator considers monitoring hepatic function 
(alanine aminotransferase [ALT], aspartate aminotransferase 
[AST], total bilirubin [TBL] and international normalized ratio 
[INR] levels) during the titration period for patients taking 
concomitant antiepileptic drugs (AEDs) that are known to be 
associated with hepatic injury or failure.  To minimize any 
elevations in hepatic function markers the titration period can be 
extended and the dosage of a concomitant AED and/or 
GWP42003-P may be adjusted at the discretion of the 
Investigator.  If there is intolerance during titration, the patient 
may be maintained on a dose below 10–20 mg/kg/day.  A titration 
rate faster than recommended may be considered if there is an 
increase in seizures, following consultation with the GW Research 
Ltd (GW) medical monitor. 
Maintenance Period: Patients will continue dosing at doses up to 
10–20 mg/kg/day.  However, Investigators may decrease the dose 
if a patient experiences intolerance, or increase the dose if required 
for better seizure control, until the optimal dose is found.  The 
Investigator may schedule additional clinic visits to facilitate dose 
adjustments, e.g., when increasing doses above 20 mg/kg/day.  
Patients whose dose has been decreased can have their dose 
increased again provided there is adequate tolerance.  The 
maximum dose patients can receive will be 30 mg/kg/day 
(51 mg/kg/day is the maximum dose safely used in the USA 
Intermediate Expanded Access Investigational New Drug Program 
[EAP] to date, with a mean dose of 24 mg/kg/day [n = 59]).  Dose 
increases above 20 mg/kg/day are recommended to be done 
slowly, with maximum increments of 2.5 mg/kg every 5–7 days.  
If seizure freedom is achieved with use of GWP42003-P during 
the study, the Investigator can consider reducing the dose of 
concomitant AEDs after consultation with the GW medical 
monitor. 
Study Completion: The maximum duration of this OLE study 
will be 4 years (208 weeks after Visit 1).  
 A patient with at least 2 years’ participation in the OLE 


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(≥ 104 weeks after Visit 1) will complete the OLE phase 
when GWP42003-P is approved in their indication and is 
commercially available.  Patients will complete an 
unscheduled ‘End of treatment’ visit to transition from 
OLE to commercial product.  The timing will vary per 
patient and is projected to begin in February 2019.    
 A patient with less than 2 years’ participation in the OLE 
when GWP42003-P is approved in their indication and is 
commercially available will continue the OLE phase until 
reaching a maximum of 2 years’ (104 weeks after Visit 1) 
OLE treatment, at which point an unscheduled ‘End of 
Treatment’ visit will be conducted.  The unscheduled ‘End 
of Treatment’ visit will be conducted no earlier than 
730 days after Visit 1. 
 A patient who does not continue treatment with 
GWP42003-P will commence the 10-day taper period 
(down-titrating 10% per day for 10 days) and complete an 
‘End of Taper Period’ visit followed by a Follow-up visit 
(which can be by telephone) 4 weeks later. 
Interim Analysis: At least one interim analysis will be conducted 
to support New Drug Application and Marketing Authorization 
Application filings.  Further interim analyses may be conducted as 
required. 
Primary Endpoint The safety of GWP42003-P will be assessed by the adverse event 
(AE) profile and by evaluating changes in the following, relative 
to the pre-randomization baseline of the Core Study: 
 Vital signs. 
 Physical examination (including height and body weight). 
 12-lead electrocardiogram (ECG). 
 Columbia-Suicide Severity Rating Scale (C-SSRS) score. 
 Cannabis Withdrawal Scale (CWS) or Pediatric Cannabinoid 
Withdrawal Scale (PCWS) score, as appropriate. 
 Clinical laboratory parameters. 
The CWS will be administered to patients aged 18 and older while 
the PCWS will be administered to patients aged 4–17 (inclusive). 
The Children’s C-SSRS will be used for patients aged 6–18 
(inclusive) while the C-SSRS will be used for patients aged 19 and 
older. 
Secondary 
Endpoint(s) 
All Patients: 
 Change in quality of life as measured with Quality of Life in 
Childhood Epilepsy (QOLCE) if 18 years of age or younger, 
or Quality of Life in Epilepsy (QOLIE) if 19 years of age or 
older, relative to the pre-randomization baseline of the Core 


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Study, if assessed during the Core Study. 
 Change in Subject/Caregiver Global Impression of Change 
(S/CGIC), relative to the pre-randomization baseline of the 
Core Study. 
 Change in adaptive behavior as measured with the Vineland 
Adaptive Behavior Scales, Second Edition (Vineland-II), 
relative to the pre-randomization baseline of the Core Study, if 
assessed during the Core Study. 
 Change in the number of inpatient epilepsy-related 
hospitalizations (number of hospitalizations due to epilepsy in 
each 28-day period), relative to the pre-randomization baseline 
of the Core Study. 
 Change in the use of rescue medication (number of days used 
in each 28-day period), relative to the pre-randomization 
baseline of the Core Study. 
 Maintenance of seizure frequency reduction and freedom from 
seizures during the OLE study. 
 Percentage change in the frequency of total seizures, relative to 
the pre-randomization baseline of the Core Study. 
 Number of patients considered treatment responders, defined 
as those with a ≥ 25%, ≥ 50%, ≥ 75%, or 100% reduction in 
total seizures, relative to the pre-randomization baseline of the 
Core Study. 
 Number of patients experiencing a > 25% worsening, − 25 to 
+ 25% no change, 25–50% improvement, 50–75% 
improvement or > 75% improvement in total seizures, relative 
to the pre-randomization baseline of the Core Study. 
 Percentage change in the frequencies of subtypes of seizures, 
relative to the pre-randomization baseline of the Core Study. 
 
Changes in duration of seizure subtypes as assessed by the 
Subject/Caregiver Global Impression of Change in Seizure 
Duration (S/CGICSD), relative to the pre-randomization 
baseline of the Core Study. 
 Change in the number of episodes of status epilepticus, 
relative to the pre-randomization baseline of the Core Study. 
 Change in cognitive function as measured with a cognitive 
assessment battery, relative to the pre-randomization baseline 
of the Core Study, if assessed during the Core Study. 
 Change in growth and development for patients less than 
18 years of age by measurement of height, weight, insulin-like 
growth factor-1 (IGF-1) levels and Tanner Staging (for 
patients aged 10–17 [inclusive], or earlier if clinically 
indicated by onset of menarche or other signs of precocious 
puberty), relative to the pre-randomization baseline of the Core 


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Study. 
 Effects on menstruation cycles (in females). 
 Drug abuse liability, as measured by AEs of abuse potential, 
drug accountability and Study Medication Use and Behavior 
Survey in patients aged 12 and older. 
DS Patients Only: 
 Percentage change in total convulsive seizure frequency, 
relative to the pre-randomization baseline of the Core Study. 
 Percentage change in total non-convulsive seizure frequency, 
relative to the pre-randomization baseline of the Core Study. 
 Number of patients considered treatment responders, defined 
as those with a ≥ 25%, ≥ 50%, ≥ 75%, or 100% reduction in 
convulsive seizures, relative to the pre-randomization baseline 
of the Core Study. 
 Number of patients experiencing a > 25% worsening, − 25 to 
+ 25% no change, 25–50% improvement, 50–75% 
improvement or > 75% improvement in convulsive seizures, 
relative to the pre-randomization baseline of the Core Study. 
LGS Patients Only: 
 Percentage change in the number of drop seizures, relative to 
the pre-randomization baseline of the Core Study. 
 Percentage change in the number of non-drop seizures, relative 
to the pre-randomization baseline of the Core Study. 
 Number of patients considered treatment responders, defined 
as those with a ≥ 25%, ≥ 50%, ≥ 75%, or 100% reduction in 
drop seizures, relative to the pre-randomization baseline of the 
Core Study. 
 Number of patients experiencing a > 25% worsening, − 25 to 
+ 25% no change, 25–50% improvement, 50–75% 
improvement or > 75% improvement in drop seizures, relative 
to the pre-randomization baseline of the Core Study. 
Sample Size 
All patients who wish to continue on Investigational Medicinal 
Product (IMP) from the populations included in the double-blind 
Phase 2 and Phase 3 studies in DS and LGS.  Approximately 
680 patients will be enrolled. 
Summary of 
Patient 
Eligibility 
Criteria 
Inclusion (ALL must be fulfilled): 
 Patient has completed the treatment phase of their Core Study. 
 Patient and/or parent(s)/legal representative must be willing 
and able to give informed consent/assent for participation in 
the study. 
 Patient and their caregiver must be willing and able (in the 
Investigator’s opinion) to comply with all study requirements. 


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 Patient and/or parent(s)/legal representative is willing to allow 
his or her primary care practitioner and consultant to be 
notified of participation in the study. 
Exclusion (if ANY apply): 
 Patient is currently using or has in the past used recreational or 
medicinal cannabis, or synthetic cannabinoid-based 
medications (including Sativex®) within the 3 months prior to 
study entry, not including IMP received during the Core study. 
 Patient is unwilling to abstain from using recreational or 
medicinal cannabis, or synthetic cannabinoid-based 
medications (including Sativex) during the study. 
 Patient has a history of symptoms (e.g., dizziness, 
light-headedness, blurred vision, palpitations, weakness, 
syncope) related to a drop in blood pressure due to postural 
changes. 
 Any history of suicidal behavior or any suicidal ideation of 
type 4 or 5 on the C-SSRS at Visit 1. 
 Patient has been part of a clinical trial involving an IMP during 
the inter-study period. 
 Patient has previously been enrolled and dosed in this study. 
 Female patient is of child bearing potential or male patient’s 
partner is of child bearing potential; unless willing to ensure 
that they or their partner use highly effective contraception for 
the duration of the study and for 3 months thereafter.  Highly 
effective methods of contraception are defined as those, alone 
or in combination, that result in a low failure rate (i.e., less 
than 1% per year) when used consistently and correctly.  Such 
methods include hormonal contraceptives, intrauterine 
devices/hormone-releasing systems, bilateral tubal occlusion, 
vasectomized partner or sexual abstinence. 
 Female patient who is pregnant (positive pregnancy test), 
lactating or planning pregnancy during the course of the study 
and for 3 months thereafter. 
 Any other significant disease or disorder which, in the opinion 
of the Investigator, may either put the patient at risk because of 
participation in the study, may influence the result of the study, 
or affect the patient’s ability to participate in the study. 
 Following a physical examination the patient has any 
abnormalities that, in the opinion of the Investigator, would 
prevent the patient from safe participation in the study. 
 Patient is unwilling to abstain from donation of blood during 
the study. 
 Patient has significantly impaired hepatic function at the ‘End 
of Treatment’ visit of their Core Study or at Visit 1 if 


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re-assessed, defined as any of the following: 
 ALT or AST > 5 × upper limit of normal (ULN). 
 ALT or AST > 3 × ULN and (TBL > 2 × ULN or INR 
> 1.5). 
 ALT or AST > 3 × ULN with the presence of fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, 
fever, rash, and/or eosinophilia (> 5%). 
If the Core Study ‘End of Treatment’/‘End of Taper Period’ visit 
assessments or Visit 1 re-assessments (as applicable) raise any 
safety concerns, the Investigator should consider whether it will be 
appropriate for the patient to continue to participate in the OLE 
study, or if the patient should be withdrawn. 
Criteria for 
Withdrawal 
The patient must be withdrawn from the study if any of the 
following apply: 
 Administrative decision by the Investigator, GW, or a 
Regulatory Authority. 
 Pregnancy. 
 Protocol deviation that is considered to potentially 
compromise the safety of the patient. 
 Withdrawal of patient consent/assent. 
 Withdrawal of parent(s)/legal representative consent. 
 Lost to follow-up. 
 ALT or AST > 3 × ULN and (TBL > 2 × ULN or INR > 1.5). 
 ALT or AST > 3 × ULN with the appearance 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 more than 2 weeks.  
Note:  Prior to withdrawal for the transaminase elevations 
noted above, the Investigator may choose to confirm the 
transaminase elevations by repeating the following laboratory 
tests within 24 to 48 hours:  ALT, AST, TBL, INR, 
% eosinophils, gamma glutamyl transferase and alkaline 
phosphatase.  Should the above transaminase elevation 
criteria be confirmed, the patient must be withdrawn from 
the trial. 
Patients may also be withdrawn from the study for any of the 
following: 
 Patient non-compliance. 
 AE which, in the opinion of the Investigator, would 
compromise the continued safe participation of the patient in 
the study. 


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 Any evidence of drug abuse or diversion. 
 Suicidal ideation or behavior of type 4 or 5 during the 
treatment period, as evaluated with the C-SSRS. 
Investigational 
Medicinal 
Product: Dosage, 
Regimen, 
Formulation and 
Mode of 
Administration 
GWP42003-P oral solution (100 mg/mL CBD in sesame oil with 
anhydrous ethanol, added sweetener [sucralose] and strawberry 
flavoring). 
Dosage: Patients will titrate up to 10–20 mg/kg/day GWP42003-P.  
Patients will then remain at this dose until the ‘End of Treatment’ 
visit, with the option for doses to be increased (up to 
30 mg/kg/day, maximum) or decreased, if deemed necessary by 
the Investigator.  Following the ‘End of Treatment’/Withdrawal 
visit, doses of IMP will be down-titrated at home (10% per day for 
10 days) until the ‘End of Taper Period’ visit. 
IMP will be taken twice daily (morning and evening).  
Control Group 
Not applicable. 
Procedures 
Visit 1 (Day 1): Every effort should be made for this visit to take 
place on the same day as the ‘End of Treatment’ visit or up to 
7 (+ 3) days after the ‘End of Treatment’ visit of the Core Study.  
If this is not possible then patients can still enter the OLE study by 
passing the screening procedures at Visit 1.  All patients will be 
instructed to begin titration of OLE IMP in the evening of Visit 1 
(Day 1).  Patients with no gap in IMP dosing between the Core 
Study and the OLE (including tapered dose) will take their final 
dose of Core Study IMP in the morning of Visit 1.  Any OLE 
procedures that were not assessed during the Core Study should 
first be assessed at Visit 1, with the exception of the cognitive 
assessment battery. 
For patients enrolling immediately from the Core Study into 
the OLE (same day): The following data collected at the ‘End of 
Treatment’ visit of the Core Study will also be considered as 
Visit 1 data: vital signs, physical examination (including height 
and body weight), details of menstruation (for females), Tanner 
Staging (for patients aged 10–17 [inclusive], or earlier if clinically 
indicated by onset of menarche or other signs of precocious 
puberty), ECG, clinical laboratory samples (including serum 
IGF-1 levels [patients less than 18 years of age] and pregnancy 
test [if appropriate]), Interactive Voice Response System (IVRS) 
and paper diary information from the previous study (including 
information regarding seizures, AEs, usage of rescue medication, 
concomitant AEDs, IMP dosing), epilepsy-related hospitalizations, 
concomitant medications and/or changes to medication, C-SSRS, 
QOLCE/QOLIE, Vineland-II, cognitive assessment battery 
(participating centers only), S/CGIC and S/CGICSD.  A 
pregnancy test (if appropriate) must be conducted using a urine 
dipstick to confirm eligibility. 


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Hepatic function must be confirmed before OLE dosing 
commences.  In order to confirm normal hepatic function, an 
additional blood sample must be taken to analyze ALT, AST, TBL 
and INR at a local laboratory.  
For patients enrolling from the taper period of the Core Study 
(1–7 [+ 3] days post ‘End of Treatment’ visit): At Visit 1, 
patients should have their Core Study ‘End of Taper Period’ 
assessments made.  These data, along with all other data collected 
at the ‘End of Treatment’ visit of the Core Study, will also be 
considered as Visit 1 data.  A pregnancy test (if appropriate) must 
be conducted using a urine dipstick to confirm eligibility.  Hepatic 
function must be confirmed before OLE dosing commences.  In 
order to confirm normal hepatic function, an additional blood 
sample may be taken to analyze ALT, AST, TBL and INR at a 
local laboratory. 
For patients with any gap in IMP dosing between the Core 
Study and the OLE: At Visit 1, all aforementioned procedures 
must be re-assessed, with the exception of the cognitive 
assessment battery.  A pregnancy test (if appropriate) must be 
conducted using a urine dipstick to confirm eligibility. 
Hepatic function must be confirmed before OLE dosing 
commences.  In order to confirm normal hepatic function, an 
additional blood sample must be taken to analyze ALT, AST, TBL 
and INR at a local laboratory. 
All patients or their caregivers will receive a 2-week supply of 
GWP42003-P together with a titration schedule.  If an 
unacceptable AE develops at any time during titration, dosing 
should initially be suspended or amended, at the Investigator’s 
discretion, as appropriate, until the event has resolved or is well 
tolerated.  It is advised that the Investigator considers monitoring 
hepatic function (ALT, AST, TBL and INR levels) during the 
titration period for patients taking AEDs that are known to be 
associated with hepatic injury or failure.  To minimize any 
elevations in hepatic function markers the titration period can be 
extended and the dosage of a concomitant AED and/or 
GWP42003-P may be adjusted at the discretion of the 
Investigator.  If there is intolerance during titration, the patient 
may be maintained on a dose below 10–20 mg/kg/day.  A titration 
rate faster than recommended may be considered if there is an 
increase in seizures, following consultation with the GW medical 
monitor. 
Patients or their caregivers will be given a paper diary to record 
information regarding AEs, usage of rescue medication, 
concomitant AEDs and IMP dosing during the time they are on 
treatment.  In addition, patients/caregivers will be instructed to 
complete a weekly seizure reporting diary until the ‘End of 


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Treatment’/Withdrawal visit using the IVRS. 
Visit 2 (Day 15 ± 3), Visit 3 (Day 29 ± 3): The following 
assessments will be made: vital signs, physical examination 
(including height and body weight) and ECG.  Clinical laboratory 
samples (urine [where possible] and blood) will be taken for 
hematology, biochemistry and urinalysis.  The patient’s IVRS 
report and paper diary will be reviewed and the information 
recorded along with information regarding AEs, IMP, 
epilepsy-related hospitalizations, concomitant medications and/or 
changes to medication.  The Investigator must assess adherence to 
the titration/dosing regimen. 
A 2-week supply of IMP will be issued to the patient/caregiver on 
Day 15. 
An 8-week supply of IMP will be issued to the patient/caregiver 
on Day 29. 
A safety telephone call must be made every 4 weeks (± 7 days) 
after Visit 3 to assess AEs, epilepsy-related hospitalizations, 
concomitant medications and/or changes to medication.  In 
addition, during titration of doses above 20 mg/kg/day, safety 
telephone calls must be made every 7 days (± 3 days) until stable 
dosing is achieved. 
Visit 4 (Day 85  ± 3): The following assessments will be made: 
vital signs, physical examination (including height and body 
weight) and ECG.  Clinical laboratory samples (urine [where 
possible] and blood) will be taken for hematology, biochemistry 
and urinalysis.  The patient’s IVRS report and paper diary will be 
reviewed and the information recorded along with information 
regarding AEs, IMP, epilepsy-related hospitalizations, 
concomitant medications and/or changes to medication.  The 
Investigator must assess adherence to the dosing regimen. 
A 12-week supply of IMP will be issued to the patient/caregiver. 
Following Visit 4, safety telephone calls must be made every 
4 weeks (± 7 days) to assess AEs, epilepsy-related 
hospitalizations, concomitant medications and/or changes to 
medication.  In addition, during titration of doses above 
20 mg/kg/day, safety telephone calls must be made every 7 days 
(± 3 days) until stable dosing is achieved. 
Visit 5 (24 weeks ±7 days) and Visit 6 (36 weeks ± 7 days): 
The following assessments will be made: vital signs, physical 
examination (including height and body weight), ECG, C-SSRS, 
Vineland-II, QOLCE/QOLIE, S/CGIC and S/CGICSD.  Clinical 
laboratory samples (urine [where possible] and blood) will be 
taken for hematology, biochemistry and urinalysis.  The patient’s 
IVRS report and paper diary will be reviewed and the information 
recorded along with information regarding AEs, IMP, epilepsy-
related hospitalizations, concomitant medications and/or changes 


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to medication.  The Investigator must assess adherence to the 
dosing regimen. 
Patients/caregivers will receive a 12-week supply of IMP at 
Visits 5 and 6. 
Between Visits 5 and 6, safety telephone calls must be made every 
4 weeks (± 7 days) to assess AEs, epilepsy-related 
hospitalizations, concomitant medications and/or changes to 
medication.  In addition, during titration of doses above 
20 mg/kg/day, safety telephone calls must be made every 7 days 
(± 3 days) until stable dosing is achieved. 
Visit 7 (48 weeks ± 7 days): The following assessments will be 
made: vital signs, physical examination (including height and 
body weight), effects on menstruation cycles (for females), Tanner 
Staging (for patients aged 10–17 [inclusive], or earlier if clinically 
indicated by onset of menarche or other signs of precocious 
puberty), ECG, C-SSRS, Vineland-II, cognitive assessment battery 
(participating centers only), QOLCE/QOLIE, S/CGIC and 
S/CGICSD.  Clinical laboratory samples (urine [where possible] 
and blood) will be taken for determination of serum IGF-1 levels 
(for patients less than 18 years of age), pregnancy (if appropriate, 
using a serum sample), hematology, biochemistry and urinalysis.  
The patient’s IVRS report and paper diary will be reviewed and 
the information recorded along with information regarding AEs, 
IMP, epilepsy-related hospitalizations, concomitant medications 
and/or changes to medication.  The Investigator must assess 
adherence to the dosing regimen. 
The cognitive assessment battery will only be administered at a 
sub-group of centers that have the expertise to conduct the 
assessments (ideally before any other study procedures but can be 
completed on a separate day, if necessary, within 3 days of the 
visit) and will only be administered to patients who underwent 
cognitive testing during their Core Study. 
A 14-week supply of IMP will be issued to the patient/caregiver. 
Following Visit 7, safety telephone calls must be made every 
4 weeks (± 7 days) to assess AEs, epilepsy-related 
hospitalizations, concomitant medications and/or changes to 
medication.  In addition, during titration of doses above 
20 mg/kg/day, safety telephone calls must be made every 7 days 
(± 3 days) until stable dosing is achieved. 
At least 1 dispensing appointment will be scheduled to occur 
between Visits 7 and 8.  The dispensing appointment date(s) will 
be calculated from Visit 7.  At each dispensing appointment 
caregivers will be dispensed with sufficient IMP to be 
administered until the next scheduled appointment.  Patients need 
not attend the dispensing appointments. 
 


Study Code: GWEP1415 
EudraCT Number: 2014-001834-27 
Protocol V18 (USA ONLY) 25Apr18 
 
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Visit 8 (76 weeks ± 7 days): 
The same assessments and review procedures will be made as at 
Visits 2, 3, 4, 5 and 6. 
A 14-week supply of IMP will be issued to the patient/caregiver.  
Following Visit 8, safety telephone calls must be made every 
4 weeks (± 7 days) to assess AEs, epilepsy-related 
hospitalizations, concomitant medications and/or changes to 
medication.  In addition, during titration of doses above 
20 mg/kg/day, safety telephone calls must be made every 7 days 
(± 3 days) until stable dosing is achieved. 
At least 1 dispensing appointment will be scheduled to occur 
between Visits 8 and 9.  The dispensing appointment date(s) will 
be calculated from Visit 8.  At each dispensing appointment 
caregivers will be dispensed with sufficient IMP to be 
administered until the next scheduled appointment.  Patients need 
not attend the dispensing appointments. 
Visit 9 (104 weeks ± 7 days): 
The same assessments and review procedures will be made as at 
Visit 7. 
A 14-week supply of IMP will be issued to the patient/caregiver.  
Following Visit 9, safety telephone calls must be made every 
4 weeks (± 7 days) to assess AEs, epilepsy-related 
hospitalizations, concomitant medications and/or changes to 
medication.  In addition, during titration of doses above 
20 mg/kg/day, safety telephone calls must be made every 7 days 
(± 3 days) until stable dosing is achieved. 
At least 1 dispensing appointment will be scheduled to occur 
between Visits 9 and 10.  The dispensing appointment date(s) will 
be calculated from Visit 9.  At each dispensing appointment 
caregivers will be dispensed with sufficient IMP to be 
administered until the next scheduled appointment.  Patients need 
not attend the dispensing appointments. 
Visit 10 (132 weeks ± 7 days): 
The same assessments and review procedures will be made as at 
Visits 2, 3, 4, 5, 6 and 8. 
A 14-week supply of IMP will be issued to the patient/caregiver.  
Following Visit 10, safety telephone calls must be made every 
4 weeks (± 7 days) to assess AEs, epilepsy-related 
hospitalizations, concomitant medications and/or changes to 
medication.  1In addition, during titration of doses above 
20 mg/kg/day, safety telephone calls must be made every 7 days 
(± 3 days) until stable dosing is achieved. 
At least 1 dispensing appointment will be scheduled to occur 
between Visit 10 and Visit 11.  The dispensing appointment 
date(s) will be calculated from Visit 10.  At each dispensing 


Study Code: GWEP1415 
EudraCT Number: 2014-001834-27 
Protocol V18 (USA ONLY) 25Apr18 
 
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appointment caregivers will be dispensed with sufficient IMP to 
be administered until the next scheduled appointment.  Patients 
need not attend the dispensing appointments. 
Visit 11 (156 weeks ± 7 days): 
The same assessments and review procedures will be made as at 
Visit 7 and Visit 9. 
A 14-week supply of IMP will be issued to the patient/caregiver.  
Following Visit 11, safety telephone calls must be made every 
4 weeks (± 7 days) to assess AEs, epilepsy-related 
hospitalizations, concomitant medications and/or changes to 
medication.  In addition, during titration of doses above 
20 mg/kg/day, weekly safety telephone calls must be made every 7 
days (± 3 days) until stable dosing is achieved. 
At least 1 dispensing appointment will be scheduled to occur 
between Visits 11 and 12.  The dispensing appointment date(s) 
will be calculated from Visit 11.  At each dispensing appointment 
caregivers will be dispensed with sufficient IMP to be 
administered until the next scheduled appointment.  Patients need 
not attend the dispensing appointments. 
Visit 12 (184 weeks ± 7 days): 
The same assessments and review procedures will be made as at 
Visits 2, 3, 4, 5, 6, 8 and 10. 
A 14-week supply of IMP will be issued to the patient/caregiver.  
Following Visit 12, safety telephone calls must be made every 
4 weeks (± 7 days) to assess AEs, epilepsy-related 
hospitalizations, concomitant medications and/or changes to 
medication.  In addition, during titration of doses above 
20 mg/kg/day, safety telephone calls must be made every 7 days 
(± 3 days) until stable dosing is achieved. 
At least 1 dispensing appointment will be scheduled to occur 
between Visit 12 and ‘End of Treatment’ visit.  The dispensing 
appointment date(s) will be calculated from Visit 12.  At each 
dispensing appointment caregivers will be dispensed with 
sufficient IMP to be administered until the next scheduled 
appointment.  Patients need not attend the dispensing 
appointments. 
End of Treatment/Withdrawal, End of Taper and Follow-up 
Visits 
End of Treatment/Withdrawal Visit:  
This visit will take place after a maximum of 4 years’ (208 weeks 
after Visit 1) treatment (as detailed below), or following early 
withdrawal from the study.  
 A patient with at least 2 years’ participation in the OLE 
(≥ 104 weeks after Visit 1) will complete the OLE phase 
when GWP42003-P is approved in their indication and is 


Study Code: GWEP1415 
EudraCT Number: 2014-001834-27 
Protocol V18 (USA ONLY) 25Apr18 
 
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commercially available.  Patients will complete an 
unscheduled ‘End of Treatment’ visit to transition from 
OLE to commercial product.  The timing will vary per 
patient and is projected to begin in February 2019. 
 A patient with less than 2 years’ participation in the OLE 
when GWP42003-P is approved in their indication and is 
commercially available will continue the OLE phase until 
reaching a maximum of 2 years’ OLE treatment, at which 
point an unscheduled ‘End of Treatment’ visit will be 
conducted.  The unscheduled ‘End of Treatment’ visit will 
be conducted no earlier than 730 days after Visit 1. 
 Patients who do not continue treatment with GWP42003-P 
will be scheduled for an ‘End of Taper’ visit.  
The following assessments will be made: vital signs, physical 
examination (including height and body weight), effects on 
menstruation cycles (for females), Tanner Staging (for patients 
aged 10–17 [inclusive], or earlier if clinically indicated by onset of 
menarche or other signs of precocious puberty), ECG, C-SSRS, 
Vineland-II, cognitive assessment battery (participating centers 
only), QOLCE/QOLIE, S/CGIC and S/CGICSD.  Clinical 
laboratory samples (urine [where possible] and blood) will be 
taken for determination of serum IGF-1 levels (for patients less 
than 18 years of age), pregnancy (if appropriate, using a serum 
sample), hematology, biochemistry and urinalysis.  The patient’s 
IVRS report and paper diary will be reviewed and the information 
recorded along with information regarding AEs, IMP, 
epilepsy-related hospitalizations, concomitant medications and/or 
changes to medication.  The Investigator must assess adherence to 
the dosing regimen. 
The cognitive assessment battery will only be administered at a 
sub-group of centers that have the expertise to conduct the 
assessments (ideally before any other study procedures but can be 
completed on a separate day, if necessary, within 3 days of the 
visit) and will only be administered to patients who underwent 
cognitive testing during their Core Study. 
Patients who do not immediately continue to use GWP42003-P 
will then commence a taper period (down-titrating 10% per day 
for 10 days).  Additional IMP will be dispensed, if required.  
Patients who withdraw early should also begin the taper period 
following the Withdrawal visit (unless continued dosing is not 
possible due to an AE).  The IVRS will generate the patient’s daily 
IMP dosing volumes for the 10-day taper period, during which 
time diary information will continue to be recorded in the paper 
diary.  Following the ‘End of Treatment’/Withdrawal visit, the 
IVRS seizure reporting diary should only be completed on the day 
before the ‘End of Taper Period’ visit and on the day before the 
Follow-up visit. 


Study Code: GWEP1415 
EudraCT Number: 2014-001834-27 
Protocol V18 (USA ONLY) 25Apr18 
 
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End of Taper Period Visit: This visit will take place 10 (+ 3) 
days after the ‘End of Treatment’ visit or Withdrawal visit for 
patients who withdraw early or who do not transition to 
commercial product. For patients who begin to taper IMP but 
subsequently withdraw/do not complete the full taper period, this 
visit should occur on the final day of dosing or as soon as possible 
after this date. 
The following assessments will be made: vital signs, physical 
examination (including height and body weight), CWS/PCWS and 
C-SSRS.  In addition, the following assessments will be made for 
patients who do not transition to commercial product or withdraw 
early and taper IMP (including withdrawal during the taper 
period): ECG and clinical laboratory samples (blood and urine for 
hematology, biochemistry and urinalysis).  The patient’s IVRS 
report and paper diary will be reviewed and the information 
recorded along with information regarding AEs, IMP, epilepsy-
related hospitalizations, concomitant medications and/or changes 
to medication.  The Investigator must assess adherence to the 
dosing regimen.  Following the ‘End of Taper Period’ visit (or 
date of final dosing), the IVRS seizure reporting diary should only 
be completed on the day before the Follow-up visit. 
Post-Taper Safety Telephone Call: A safety telephone call must 
be made 2 weeks (± 3 days) after the ‘End of Taper Period’ visit or 
date of final dosing.  Patients or their caregivers will be asked for 
information on AEs, epilepsy-related hospitalizations, concomitant 
medications and/or changes to medication.  The CWS/PCWS will 
be administered as well.  Following this call, the IVRS seizure 
reporting diary should only be completed on the day before the 
Follow-up visit. 
Follow-up Visit: For patients who withdraw or complete, but do 
not wish to continue to use GWP42003-P, a safety follow-up visit 
will be performed 4 weeks (+ 3 days) after the patient’s last dose 
(including final taper period dose).  This visit can be conducted 
over the telephone.  During this visit/call, caregivers will be asked 
for information on AEs, epilepsy-related hospitalizations, 
concomitant medications and/or changes to medication.  The 
CWS/PCWS will be administered as well. 
Monitoring of Drug Abuse Liability (for Patients 12 Years of 
Age and Older) 
During the routine collection of AEs in this study, if AEs are 
reported which can illuminate an abuse potential signal, then the 
Investigator or study coordinator is required to complete an 
additional Supplemental Adverse Event Form and a Site 
Classification Form (Investigator only) following further 
discussion of the event(s) with the patient/caregiver. 
The second trigger that will require the Investigator or study 


Study Code: GWEP1415 
EudraCT Number: 2014-001834-27 
Protocol V18 (USA ONLY) 25Apr18 
 
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coordinator to discuss abuse potential signals with the 
patient/caregiver is drug accountability issues regarding overuse of 
the IMP or missing bottles. 
Irrespective of the above, all patients/caregivers will be 
interviewed at their final dosing visit (‘End of 
Treatment’/Withdrawal visit or ‘End of Taper Period’ visit, as 
applicable) and a Study Medication Use and Behavior Survey will 
be completed by the Investigator or study coordinator. 
A formal Adjudication Committee will be appointed and assigned 
to this initiative to classify triggered cases.  The Adjudication 
Committee will meet on a periodic basis to review and assess all 
of the information collected on triggered cases. 
Statistical 
Considerations 
All data collected during this study will be summarized across 
time, using appropriate statistical methods.  Where baseline data 
are available from the Core Studies (seizure information, C-SSRS, 
quality of life assessments, Vineland-II, cognitive assessment 
battery, other measures of safety [vital signs, clinical laboratory 
samples]), changes from baseline will also be presented.  
Summaries will be presented overall as well as for the different 
etiologies (DS and LGS) separately.  Descriptive statistical 
methods will be used throughout.  There will be no formal 
hypothesis testing. 
Sponsor 
GW Research Ltd 
Sovereign House  
Vision Park 
Chivers Way 
Histon 
Cambridge CB24 9BZ 
United Kingdom 
 


Study Code: GWEP1415 
EudraCT Number: 2014-001834-27 
Protocol V18 (USA ONLY) 25Apr18 
 
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Figure 1-1 
Study Design and Treatment Schema 
Visit 1
Day 1
Visit 2
Day 15 
(±3 days)
Visit 3§ 
Day 29 
(±3 days)
Follow-up
Visit**
(+3 days)
End of 
Taper 
Visit#
(+3 days)
End of 
Treatment 
Visit¶ 
Visit 4§ 
Day 85 
(-3 days)
Visit 5§ 
24 weeks 
(±7 days)
Visit 6§ 
36 weeks 
(±7 days)
Visit 7§ 
48 weeks 
(±7  days)
Visit 9§ 
104 
weeks 
(±7 days)
C
O
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E 
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Y
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Titration
 Period
Taper
 Period
2 weeks
2 weeks 8 weeks
12 weeks
12 weeks 12 weeks
28 weeks
≤ 10 days
4 weeks
Visit 11§ 
156 weeks 
 (±7 days)
Visit 12§ 
184 weeks 
(±7 days)
A
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24 weeks
24 weeks
Δ
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Visit 8§ 
76 weeks 
(±7 days)
A
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Visit 10§ 
132 
weeks 
(±7 days)
A
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28 weeks
28 weeks
28 weeks
 
* All patients will be instructed to begin titration of OLE IMP in the evening of Visit 1 (Day 1).  Patients with no gap in IMP dosing between the Core Study and the OLE 
(including tapered dose) will take their final dose of Core Study IMP in the morning of Visit 1. 
§ Between visits, safety telephone calls must be made every 4 weeks (± 7 days).  In addition, during titration of doses above 20 mg/kg/day, safety telephone calls must be made 
every 7 days (± 3 days) until stable dosing is achieved.  All safety telephone calls will assess AEs, epilepsy-related hospitalizations, concomitant medications and/or changes 
to medication. 
Δ IMP dispensing appointments will take place between all visits after Visit 7, 14 weeks following the previous visit. 
¶ ‘End of Treatment’ visit will occur after a maximum of 4 years’ treatment (208 weeks after Visit 1), following early withdrawal from the study, or following an unscheduled 
‘End of Treatment’ visit conducted no earlier than 730 days after Visit 1. 
# Following the ‘End of Taper Period’ visit (or date of final dosing), a safety telephone call must be made 2 weeks (± 3 days) later to collect seizure information, administer the 
CWS/PCWS and to assess AEs, epilepsy-related hospitalizations, concomitant medications and/or changes to medication. 


Study Code: GWEP1415 
EudraCT Number: 2014-001834-27 
Protocol V18 (USA ONLY) 25Apr18 
 
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** Can be conducted by telephone. 


Study Code: GWEP1415 
EudraCT Number: 2014-001834-27 
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Table of Contents 
Title Page ........................................................................................................ 1 
1 
PROTOCOL SYNOPSIS ..................................................................... 3 
Table of Contents ......................................................................................... 21 
List of Appendices........................................................................................ 26 
List of In-text Tables ................................................................................... 27 
List of In-text Figures .................................................................................. 28 
List of Abbreviations ................................................................................... 29 
Definition of Terms ...................................................................................... 31 
2 
OBJECTIVES ..................................................................................... 32 
2.1 
Primary ..............................................................................................................32 
2.2 
Secondary ..........................................................................................................32 
3 
BACKGROUND AND RATIONALE .............................................. 34 
3.1 
Disease...............................................................................................................34 
3.2 
GWP42003-P Background ................................................................................38 
3.3 
Rationale ............................................................................................................38 
3.3.1 
Selection of Study Dose ..................................................................................39 
3.4 
Clinical Hypothesis ...........................................................................................40 
4 
EXPERIMENTAL PLAN .................................................................. 41 
4.1 
Study Design .....................................................................................................41 
4.1.1 
Primary Endpoint ............................................................................................42 
4.1.2 
Secondary Endpoint(s) ....................................................................................43 
4.2 
Number of Centers ............................................................................................44 
4.3 
Number of Patients ............................................................................................44 
5 
INVESTIGATIONAL MEDICINAL PRODUCT .......................... 45 
5.1 
GWP42003-P Oral Solution ..............................................................................45 
5.2 
Packaging, Storage and Drug Accountability ...................................................45 
5.2.1 
Packaging and Labeling ..................................................................................45 
5.2.2 
Storage ............................................................................................................46 
5.2.3 
Supply and Return of Investigational Medicinal Product ...............................46 
5.2.4 
Investigational Medicinal Product Accountability .........................................46 


Study Code: GWEP1415 
EudraCT Number: 2014-001834-27 
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6 
PATIENT ELIGIBILITY .................................................................. 48 
6.1 
Inclusion Criteria ...............................................................................................48 
6.2 
Exclusion Criteria ..............................................................................................48 
7 
PATIENT ENROLLMENT .............................................................. 50 
7.1 
Treatment Assignment ......................................................................................50 
8 
TREATMENT PROCEDURES ........................................................ 51 
8.1 
Investigational Medicinal Product Dosage, Administration and 
Schedule ............................................................................................................51 
8.1.1 
Dose Administration .......................................................................................51 
8.1.2 
Dose Escalation, Dose Adjustments and Down-Titration ..............................51 
8.2 
Concomitant Therapy ........................................................................................52 
8.3 
Prohibited Therapy During Study Period ..........................................................53 
8.4 
Compliance in Investigational Medicinal Product Administration ...................53 
9 
STUDY PROCEDURES .................................................................... 54 
9.1 
Study Procedure Listing ....................................................................................54 
9.1.1 
Informed Consent/Assent ...............................................................................54 
9.1.2 
Demographics .................................................................................................55 
9.1.3 
Medical History ..............................................................................................55 
9.1.4 
Inpatient Epilepsy-Related Hospitalizations ...................................................55 
9.1.5 
Concomitant Medication ................................................................................55 
9.1.6 
Physical Examination .....................................................................................56 
9.1.7 
Vital Signs ......................................................................................................56 
9.1.8 
12-Lead Electrocardiogram ............................................................................56 
9.1.9 
Clinical Laboratory Sampling .........................................................................56 
9.1.10 
Interactive Voice Response System ................................................................58 
9.1.11 
Questionnaires and Assessments Completed at Scheduled Visits ..................58 
9.1.11.1 
Vineland Adaptive Behavior Scales (Second Edition) ...............................58 
9.1.11.2 
Quality of Life in Childhood Epilepsy (18 Years of Age and 
Younger) or Quality Life in Epilepsy (19 Years of Age and Older) ..........58 
9.1.11.3 
Subject/Caregiver Global Impression of Change ........................................59 
9.1.11.4 
Subject/Caregiver Global Impression of Change in Seizure 
Duration ......................................................................................................59 
9.1.11.5 
Columbia-Suicide Severity Rating Scale (Six Years of Age and 
Older) ..........................................................................................................60 


Study Code: GWEP1415 
EudraCT Number: 2014-001834-27 
Protocol V18 (USA ONLY) 25Apr18 
 
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9.1.11.6 
Cognitive Assessment Battery ....................................................................60 
9.1.11.7 
Cannabis Withdrawal Scale (18 Years and Above) or Pediatric 
Cannabinoid Withdrawal Scale (4–17 Years) .............................................62 
9.1.11.8 
Menstruation ...............................................................................................63 
9.1.11.9 
Tanner Staging ............................................................................................63 
9.1.12 
Patient Diary ...................................................................................................64 
9.1.13 
Investigational Medicinal Product Accountability .........................................64 
9.1.14 
Adverse Events ...............................................................................................64 
9.1.15 
Monitoring of Drug Abuse Liability (for Patients 12 Years of Age 
and Older) .......................................................................................................65 
9.1.15.1 
Monitoring of Adverse Events ....................................................................65 
9.1.15.1.1 
List of ‘Triggering Adverse Events of Interest’ ......................................65 
9.1.15.1.2 
Supplemental Adverse Event Form .........................................................66 
9.1.15.2 
Monitoring Drug Accountability Discrepancies .........................................66 
9.1.15.2.1 
List of ‘Triggering Drug Accountability Discrepancies’ ........................66 
9.1.15.2.2 
Supplemental Drug Accountability Form ...............................................67 
9.1.15.3 
Site Classification Form ..............................................................................67 
9.1.15.4 
Study Medication Use and Behavior Survey ..............................................67 
9.1.15.5 
Adjudication Committee: Assessment of Abuse Potential of 
GWP42003-P ..............................................................................................68 
9.2 
Study Procedures by Visit .................................................................................69 
9.2.1 
Visit 1 (Day 1) ................................................................................................70 
9.2.2 
Visit 2 (Day 15) ..............................................................................................72 
9.2.3 
Visit 3 (Day 29) ..............................................................................................72 
9.2.4 
Visit 4 (Day 85) ..............................................................................................73 
9.2.5 
Visit 5 and 6 (24-36 weeks) ............................................................................73 
9.2.6 
Visit 7 (48 weeks) ...........................................................................................74 
9.2.7 
Visit 8 (76 weeks) ...........................................................................................75 
9.2.8 
Visit 9 (104 weeks) .........................................................................................76 
9.2.9 
Visit 10 (132 weeks) .......................................................................................77 
9.2.10 
Visit 11 (156 weeks) .......................................................................................77 
9.2.11 
Visit 12 (184 weeks) .......................................................................................78 
9.2.12 
End of Treatment/Withdrawal Visit ...............................................................79 
9.2.13 
End of Taper Period Visit ...............................................................................80 


Study Code: GWEP1415 
EudraCT Number: 2014-001834-27 
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9.2.14 
Post-Taper Safety Telephone Call ..................................................................81 
9.2.15 
Follow-up Visit ...............................................................................................81 
9.2.16 
Safety Telephone Calls ...................................................................................81 
10 
WITHDRAWAL ................................................................................. 82 
11 
URGENT SAFETY MEASURES ..................................................... 84 
12 
ADVERSE EVENT REPORTING ................................................... 85 
12.1 
Definitions .........................................................................................................85 
12.1.1 
Adverse Event .................................................................................................85 
12.1.2 
Investigator .....................................................................................................85 
12.2 
Serious Adverse Events .....................................................................................85 
12.3 
Reporting Procedures for Serious Adverse Events ...........................................86 
12.4 
Pregnancy ..........................................................................................................87 
12.5 
Causality Assessment ........................................................................................87 
12.6 
Reporting Procedures for All Adverse Events ..................................................88 
12.7 
Follow-up Procedures for Adverse Events ........................................................89 
12.8 
Potential Cases of Drug-Induced Liver Injury ..................................................90 
12.9 
Notification of Safety Information to Investigators, Regulatory 
Authorities and Ethics Committees ...................................................................91 
13 
STATISTICAL CONSIDERATIONS .............................................. 93 
13.1 
Sample Size, Power and Significance Levels ...................................................93 
13.2 
Interim Analysis ................................................................................................93 
13.3 
Analysis Sets .....................................................................................................93 
13.3.1 
Protocol Deviations ........................................................................................93 
13.4 
General Considerations .....................................................................................93 
13.5 
Accountability and Background Characteristics ...............................................94 
13.5.1 
Enrollment and Disposition ............................................................................94 
13.5.2 
Baseline and Demographic Characteristics ....................................................94 
13.5.3 
Medical History ..............................................................................................94 
13.5.4 
Concomitant Medication ................................................................................94 
13.6 
Endpoints and Statistical Methods ....................................................................94 
13.6.1 
Evaluable Period .............................................................................................94 
13.6.2 
Primary Endpoint(s) ........................................................................................94 
13.6.2.1 
Adverse Events ...........................................................................................94 


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13.6.2.2 
Clinical Laboratory Data .............................................................................95 
13.6.2.3 
Vital Signs, 12-lead Electrocardiogram, Physical Examination and 
Other Safety Data ........................................................................................95 
13.6.2.4 
Columbia-Suicide Severity Rating Scale Data ...........................................96 
13.6.2.5 
Cannabis Withdrawal Scale and Pediatric Cannabinoid 
Withdrawal Scale Data ................................................................................96 
13.6.3 
Secondary Endpoint(s) ....................................................................................96 
14 
DATA SAFETY MONITORING COMMITTEE .......................... 99 
15 
REGULATORY AND ETHICAL OBLIGATIONS ..................... 100 
15.1 
Declaration of Helsinki ...................................................................................100 
15.2 
Informed Consent/Assent ................................................................................100 
15.3 
Institutional Review Board/Ethics Committee ................................................100 
15.4 
Pre-Study Documentation Requirements ........................................................101 
15.5 
Patient Confidentiality .....................................................................................101 
16 
ADMINISTRATIVE AND LEGAL OBLIGATIONS .................. 103 
16.1 
Protocol Amendments and End of Study or Termination ...............................103 
16.2 
Study Documentation and Storage ..................................................................103 
16.3 
Study Monitoring and Data Collection ...........................................................104 
16.4 
Electronic Data Collected by the Interactive Voice Response System ...........106 
16.5 
Quality Assurance ...........................................................................................106 
16.6 
Compensation ..................................................................................................106 
16.7 
Publication Policy............................................................................................107 
16.8 
Intellectual Property Rights .............................................................................107 
16.9 
Confidential Information .................................................................................107 
17 
REFERENCES ................................................................................. 108 
 


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List of Appendices 
APPENDIX 1 
SCHEDULE OF ASSESSMENTS ..................................... 114 
APPENDIX 2 
STUDY PERSONNEL......................................................... 118 
Appendix 2.1 
Investigator Details .............................................................. 118 
Appendix 2.2 
Sponsor Contact Details ...................................................... 118 
APPENDIX 3 
TANNER STAGING ........................................................... 119 
APPENDIX 4 
TITRATION REGIMEN .................................................... 122 
 


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List of In-text Tables 
Table 5.1-1 
Formulation of GWP42003-P Oral Solution ........................... 45 
Table 9.1.9-1 
Hematology, Biochemistry and Urinalysis .............................. 57 
Table 9.1.11.6-1 
Neuropsychological Protocol for Epilepsy Patients 
Treated with Cannabidiol - Patient Measures .......................... 62 
Table 9.1.11.6-2 
Neuropsychological Protocol for Epilepsy Patients 
Treated with Cannabidiol - Parent Measures ........................... 62 
 


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List of In-text Figures 
Figure 1-1 
Study Design and Treatment Schema ...................................... 19 
Figure 9-1 
Flow Diagram for Identifying and Evaluating Clinical 
Trial Adverse Event Data Through Systematic 
Categorization, Tabulation and Analysis which can 
Illuminate an Abuse Potential Signal (for Patients 
12 Years of Age and Older) ..................................................... 69 
 


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List of Abbreviations 
AE 
Adverse Event 
AEDs 
Antiepileptic drugs 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
CBD 
Cannabidiol 
CGIC 
Caregiver Global Impression of Change 
CGICSD 
Caregiver Global Impression of Change in Seizure Duration 
CIOMS 
Council for International Organizations of Medical Sciences 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CWS 
Cannabis Withdrawal Scale 
DS 
Dravet syndrome 
DSMC 
Data Safety Monitoring Committee 
EAP 
Intermediate Expanded Access Investigational New Drug Program 
EC 
Ethics Committee 
ECG 
12-lead Electrocardiogram 
EEG 
Electroencephalogram 
EU 
European Union 
GCP 
Good Clinical Practice 
GW 
GW Research Ltd 
GWP 
GW Pharma Ltd 
IB 
Investigator Brochure 
ICH GCP 
International Conference on Harmonization Tripartite Guideline for 
Good Clinical Practice 
IGF-1 
Insulin-like growth factor-1 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IVRS 
Interactive Voice Response System 
LGS 
Lennox-Gastaut syndrome 


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OLE 
Open label extension 
PCWS 
Pediatric Cannabinoid Withdrawal Scale 
PI 
Principal Investigator 
PVD 
Pharmacovigilance Department 
QOLCE 
Quality of Life in Childhood Epilepsy 
QOLIE 
Quality of Life in Epilepsy 
S/CGIC 
Subject/Caregiver Global Impression of Change 
S/CGICSD 
Subject/Caregiver Global Impression of Change in Seizure Duration  
SGIC 
Subject Global Impression of Change 
SGICSD 
Subject Global Impression of Change in Seizure Duration  
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TBL 
Total Bilirubin 
THC 
Δ9-tetrahydrocannabinol 
ULN 
Upper limit of normal 
Vineland-II Vineland Adaptive Behavior Scales, Second Edition 
VPA 
Valproic Acid 
 


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Definition of Terms 
Term 
Definition 
Baseline 
The 28-day period of the Core Study from screening to 
randomization.  
Convulsive seizures 
Tonic-clonic, tonic, clonic or atonic seizures. 
Core Study 
A double-blind, randomized, placebo-controlled, parallel 
group study of GWP42003-P in patients with DS or LGS. 
Countable partial seizures Partial/focal seizures with a motor or behavioral 
component that allow such seizures to be easily identified 
and hence counted. 
Day 1 
The day a patient first receives investigational medicinal 
product in this study. 
Drop seizure 
An attack or spell (atonic, tonic or tonic-clonic) involving 
the entire body, trunk or head that led or may have led to a 
fall, injury, slumping in a chair or hitting the patient’s head 
on a surface. 
Enrolled patient 
Patient is considered enrolled in the study from the time of 
providing written informed consent/assent. 
End of treatment 
A maximum of 4 years’ (208 weeks after Visit 1) 
treatment. 
End of study 
Last patient last visit or last contact, whichever occurs last. 
IMP 
Investigational Medicinal Product (Study Medication). 
INR 
International Normalized Ratio (INR) is a calculation 
made to standardize prothrombin time. 
Investigator 
Study Principal Investigator or a formally delegated study 
physician. 
Non-convulsive seizures Myoclonic, partial or absence seizures. 
Non-drop seizures 
Seizures that would not result in a fall or drop attack. 
Status epilepticus 
Any seizure lasting for 30 minutes or longer. 
Subtypes of seizures 
Protocol seizure subtypes can be atonic, tonic, clonic, 
tonic-clonic, myoclonic, absence, countable partial and 
other partial. 
 
 


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2 
OBJECTIVES 
2.1 
Primary 
To evaluate the long term safety and tolerability of GWP42003-P, as adjunctive 
treatment, in children and adults with inadequately controlled Dravet Syndrome (DS) 
or Lennox-Gastaut Syndrome (LGS). 
2.2 
Secondary 
All Patients: 
To evaluate the effect of GWP42003-P, as adjunctive treatment, on: 
 Quality of life. 
 Adaptive behavior. 
 Need for hospitalizations due to epilepsy. 
 Usage of rescue medication. 
 Maintenance of seizure frequency reduction and freedom from seizures during 
the open label extension (OLE) study. 
 Frequency of total and subtypes of seizures. 
 Change in duration of subtypes of seizures. 
 Number of episodes of status epilepticus. 
 Cognitive function. 
 Growth and development. 
 Menstruation cycles (in females). 
 Signals indicating drug abuse liability of GWP42003-P. 
DS Patients Only: 
To evaluate the effect of GWP42003-P, as adjunctive treatment, on: 
 Total convulsive seizure frequency. 
 Total non-convulsive seizure frequency. 
 Number of patients convulsive seizure-free. 
 Responder rate (defined in terms of percentage reduction in total convulsive 
seizure frequency). 
LGS Patients Only: 
To evaluate the effect of GWP42003-P, as adjunctive treatment, on: 
 Drop seizure frequency. 
 Non-drop seizure frequency. 
 Number of patients drop seizure-free. 


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 Responder rate (defined in terms of percentage reduction in drop seizure 
frequency). 
 
 
 


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3 
BACKGROUND AND RATIONALE 
3.1 
Disease 
DS, also known as Severe Myoclonic Epilepsy in Infancy, and LGS are two rare 
forms of severe epilepsy with onset in early childhood.  DS and LGS each have an 
incidence of around 1 in 40–50,0001,2,3 and account for 1.4% and 4.3% of childhood 
epilepsies, respectively4,5.  Both DS and LGS are considered epileptic 
encephalopathies in which the epileptic activity contributes to mental 
deterioration/stagnation and behavioral disorders with a high proportion of patients 
being drug-resistant.  DS and LGS differ in seizure types, age of onset and 
electroencephalogram (EEG) features. 
In DS, onset usually occurs between 4 and 8 months of age and manifests typically as 
a prolonged (> 15 min) clonic, generalized or unilateral convulsive seizure, often 
triggered by fever, that can evolve into status epilepticus6,7,8.  After a typical period of 
2 weeks to 2 months, further febrile seizures occur and afebrile seizures begin to 
appear.  In addition to the above convulsive seizures, myoclonic seizures, tonic-clonic 
seizures, focal seizures, atypical absences and obtundation statuses (in which 
consciousness is impaired) appear between the ages of 1 and 4 years.  Episodes of 
convulsive or non-convulsive status epilepticus may also occur.  Despite the frequent 
occurrence of convulsive seizures, interictal EEG recordings are generally normal 
during the first 6 months following onset of DS.  However, background EEG activity 
tends to slow as the disease develops and EEG spike-waves with ≥ 3 Hz frequency are 
often observed during massive myoclonic seizures6,9.  Significant developmental 
delay becomes apparent from the second year onwards and associated 
neuropsychological disturbances, such as attention deficit/hyperactivity disorder, are 
common6,7,8. 
The onset of LGS usually occurs between 3 and 5 years of age and is characterized by 
the presence of multiple seizure types (predominantly tonic, atonic and atypical 
absence seizures), slow (≤ 2.5 Hz) EEG spike-waves with abnormal background 
activity when awake and fast (10–20 Hz) polyspikes during sleep10,11,12.  Other 
seizure types can occur in LGS, including generalized tonic-clonic, focal and 
myoclonic seizures.  The diagnostic clinical and EEG features of LGS may not be 
present at the time of onset of LGS and it sometimes evolves from other early-onset 
epileptic encephalopathies.  It is suggested that approximately 20% of LGS cases are 
preceded by West syndrome (peak onset 4–7 months), which itself can evolve from 
Ohtahara syndrome (onset within 1 month of birth)12.  Due to this etiology, 20–60% 


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of LGS patients already have delayed cognitive development at onset of LGS10.  In 
cryptogenic cases of LGS (25–30% of all cases) development appears normal prior to 
the onset of the first seizures, yet cognitive impairment is apparent in 75–95% of all 
LGS patients by 5 years post-onset10.  As with DS, various behavioral and psychiatric 
comorbidities are often seen in LGS patients, including attention deficit/hyperactivity 
disorder, anxiety, aggressive behavior, psychosis and depression10,12.  Generally, both 
LGS and DS are more prevalent in boys. 
Genetic analyses have revealed that more than 70% of patients with DS have 
mutations in the voltage-gated sodium channel 1 subunit gene 
(SCN1A)13,14,15,16,17,18.  SCN1A encodes the pore-forming subunit of the NaV1.1 
voltage-gated sodium channel and there are currently more than 700 published 
SCN1A mutations, 90% of which occur in DS patients19.  Most SCN1A mutations in 
DS patients arise de novo, although approximately 5% of cases involve inheritance of 
familial SCN1A mutations from a mildly affected parent20,21,22,23.  More than 20% of 
patients with DS have no detectable mutations in SCN1A and it is possible that many 
of these patients harbor mutations in regulatory elements located outside coding 
regions.  Additional genes in which mutations cause DS include PCDH1924,25, 
GABRG226, SCN1B27 and SCN2A28, although very few cases have been reported.  
Genetic factors are regarded to be less important in LGS as approximately 75% of 
cases are symptomatic with underlying cerebral malformation, hypoxic–ischemic 
injury, tuberous sclerosis or metabolic disease11,12.  However, a genetic predisposition 
has been hypothesized to underlie cryptogenic cases of LGS29 and a variant of the 
mitochondrial MTND1 gene has recently been associated with LGS evolving from 
West syndrome30.  Furthermore, in a cohort of LGS and West syndrome patients, de 
novo mutations have recently been found in the genes GABRB3 and ALG13, as well 
as in several genes regulated by the fragile X protein31. 
DS and LGS are two of the most pharmacoresistant forms of epilepsy, with all seizure 
types extremely refractory to conventional antiepileptic drugs (AEDs).  Sodium 
valproate (valproic acid [VPA]) is often used to prevent the initial recurrent 
convulsive seizures and benzodiazepines (e.g., diazepam, midazolam, clonazepam or 
clobazam) are frequently co-administered to limit the duration of long-lasting seizures 
and frequency of drop attacks.  In most cases however, the relief provided by these 
agents is insufficient10,32,33.  Two randomized, double-blind, dose-ranging studies 
evaluated the safety and efficacy of clobazam as adjunctive therapy for drop seizures 
in LGS patients34,35.  In the first study, which compared 2 doses of clobazam, two 


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thirds of patients in the high dose group (1.0 mg/kg/day, n = 36) experienced ≥ 75% 
reduction in weekly drop seizures after 4 weeks’ stable dosing, compared with one 
quarter of patients in the low dose group (0.25 mg/kg/day, n = 32).  Moreover, 22% of 
patients in the high dose group achieved drop seizure freedom compared with 6% of 
patients in the low dose group34.  In the second study, which compared 3 doses of 
clobazam with placebo, 78% of patients in the high dose group (1.0 mg/kg/day, 
n = 49) achieved a ≥ 50% reduction in drop seizures after 12 weeks’ stable dosing, 
compared with 32% of patients taking placebo (n = 57)35.  Eligible patients from both 
of these trials were then given the opportunity to continue receiving clobazam as 
adjunctive treatment for LGS in an OLE study36,37.  Of the patients who had a ≥ 50% 
reduction in drop seizures after 3 months’ continuing treatment, 86% maintained this 
degree of drop seizure reduction at Year 3, and 47% were drop seizure free37.  
Following the results of the 2 randomized trials, clobazam (under the name Onfi) was 
later approved by the FDA in 2011 as add-on therapy for LGS patients aged 2 years 
and older. 
Lamotrigine has been shown to reduce the frequency of all seizure types in LGS, with 
one third of patients receiving lamotrigine achieving a > 50% reduction at 16 weeks 
compared with 16% receiving placebo38.  Similarly, more than half of LGS patients 
taking lamotrigine experienced a > 50% reduction in seizures at 12 weeks when 
compared with placebo in a 2-period, within-patient crossover study39.  Lamotrigine 
can paradoxically worsen seizures in DS patients however40 and all sodium channel 
blockers are best avoided in DS patients.  Potassium bromide can be effective at 
controlling seizures in DS, with over half of patients achieving a > 50% reduction and 
30% becoming seizure-free at 3 months41.  However, this compound has no effect on 
focal and tonic seizures (hence it is not used in LGS) and any initial efficacy is often 
not maintained long term33,41. 
To date, the only AED that has proved efficacious in the treatment of DS in 
placebo-controlled, double-blind trials is stiripentol42,43.  In these studies, stiripentol 
was administered as adjunctive therapy to VPA and clobazam.  At least two thirds of 
patients experienced a > 50% reduction in seizure frequency in the stiripentol arms of 
these studies versus < 10% of patients in the placebo arms42,43.  A subsequent 
meta-analysis of these studies showed that stiripentol reduced the overall seizure rate 
by 70%44.  Both the frequency and duration of seizures remained significantly 
reduced at a median of 2.9 years’ follow-up, with the greatest efficacy observed in 
infants41.  Both short term and long term benefits of stiripentol as adjunctive therapy 


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have also been demonstrated in an open label study of Japanese DS patients, with 
responder rates of 61% and 48% at 6 weeks and 6 months, respectively45.  Stiripentol 
is generally well tolerated and can improve seizure control in DS patients receiving 
pharmacotherapy other than VPA and/or clobazam45,46. 
Topiramate and levetiracetam are 2 further AEDs that have undergone preliminary 
trials as adjunctive therapy in DS and LGS patients.  In 3 open label studies, more 
than half of DS patients receiving topiramate as add-on therapy achieved a > 50% 
reduction in seizure frequency, with 17% becoming seizure-free for at least 4 months 
in all cases47,48,49.  In the only randomized placebo-controlled trial of adjunctive 
topiramate use in LGS to date, one third of patients taking topiramate achieved a 
> 50% reduction in drop attacks and tonic–clonic seizures at 11 weeks compared with 
8% taking placebo50.  As such, topiramate was approved by the FDA in 2001 as 
add-on therapy for LGS patients 2 years of age and older.  Two subsequent long term 
open label studies showed that 55% and 40% of LGS patients experienced a 50% 
reduction in drop attacks at 6 and 16 months, respectively51,52.  Open label trials of 
levetiracetam have demonstrated similar results, with approximately two thirds of DS 
and LGS patients experiencing a 50—100% reduction in tonic–clonic seizures at 
12 weeks and 12 months, respectively53,54.  However, tonic seizure frequency in LGS 
patients remained unchanged. 
Following preliminary trials, felbamate and rufinamide have also been approved as 
add-on therapy for treatment of LGS.  Felbamate was approved by the FDA for the 
treatment of LGS after a randomized controlled study demonstrated a 19% overall 
decrease in the total frequency of seizures in LGS patients receiving felbamate at 
10 weeks compared with a 4% increase in the placebo group55.  Similarly, rufinamide 
was granted FDA approval after a placebo-controlled, double-blind study showed 
there was a 33% overall reduction in all seizures experienced by LGS patients taking 
rufinamide at 12 weeks compared with a 12% reduction in patients taking placebo56.  
These newer AEDs therefore appear promising for the management of seizures in DS 
and LGS; however, larger randomized placebo-controlled studies are required to 
accurately assess their efficacy in the treatment of these syndromes.  
Non-pharmacological treatments of DS and LGS have also demonstrated benefit as 
adjunctive therapy to AEDs, including vagus nerve stimulation57,58,59 and the 
introduction of a ketogenic diet60,61,62,63.  Despite the therapies listed above, DS and 
LGS remain 2 of the most pharmacoresistant epilepsy syndromes.  Consequently, 
there is a clear need for new, efficacious pharmaceutical treatments. 


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3.2 
GWP42003-P Background 
The cannabis plant (Cannabis sativa L.) produces trichomes that synthesize a large 
number of pharmacologically active compounds called phytocannabinoids.  The most 
abundant of these are 9-tetrahydrocannabinol (THC) and cannabidiol (CBD), 
although the amounts and proportions of the various phytocannabinoids in each plant 
vary by strain and can be adjusted by breeding. 
The Investigational Medicinal Product (IMP), GWP42003-P, is formulated from 
extracts prepared from Cannabis sativa L. plants that have a defined chemical profile 
and contain consistent levels of CBD as the principal phytocannabinoid.  Extracts 
from these plants are processed to yield pure (≥ 98%) CBD that typically contains less 
than 0.15% (w/w) THC (for oral formulations).  The pure CBD is subsequently 
dissolved in excipients with added sweetener and flavoring. 
The pharmacological effects of phytocannabinoids are thought to be mediated 
primarily via their interaction with the endocannabinoid system, which consists of 
cannabinoid receptors, endogenous ligands (endocannabinoids) and enzymes for 
endocannabinoid synthesis and degradation.  Two G-protein-coupled receptors for 
cannabinoids have so far been identified, designated cannabinoid CB1 and CB2 
receptors.  CBD does not bind to either of these receptors with any great affinity but 
does modulate the metabolizing enzymes of the endocannabinoid system.  CBD also 
affects ion channel conductances and acts on other G-protein-coupled receptors such 
as the transient receptor potential channel TRPV164 and the orphan receptor GPR5565.  
Importantly, CBD generally lacks detectable psychoactivity as found with THC.  
CBD has demonstrated anticonvulsant, antipsychotic, anxiolytic, neuroprotective, 
antioxidant and anti-inflammatory activity66.  Very little data concerning adverse 
events (AEs) of CBD in humans exists to date.  However, doses of up to 1500 mg 
CBD per day are reported to be well tolerated in humans67. 
3.3 
Rationale 
Given the limitations of current synthetic AEDs, it has been hypothesized that CBD 
can be tested for efficacy in children with pharmacoresistant epilepsy68.  A recent 
parent survey has reported that 84% of children with treatment-resistant epilepsy 
experienced a reduction in seizures while taking CBD-enriched cannabis, with over 
half of those reporting > 80% reduction in seizure frequency69.  The majority of 
children had been diagnosed with DS, two thirds of which experienced ≥ 50% 
reduction in seizure frequency with one patient (8.3%) achieving complete seizure 
freedom.  The only child diagnosed with LGS achieved a > 80% reduction in seizure 


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frequency.  The CBD-enriched cannabis was behaviorally well tolerated and children 
often experienced improved sleep, increased alertness and better mood. 
The current study will provide free access to GWP42003-P for patients with DS or 
LGS who have completed the double-blind, placebo-controlled, clinical studies of 
GWP42003-P (Core Studies).  The study will also assess the long term safety and 
efficacy of GWP42003-P when taken as adjunctive therapy for DS and LGS. 
3.3.1 
Selection of Study Dose 
Doses up to 800 mg CBD per day for up to 8 weeks have been well tolerated in adults 
in GW Research Ltd (GW) clinical study GWMD0911270, which, assuming an 
average weight of 70 kg, equates to 11.4 mg/kg.  In the literature, doses of CBD have 
been given up to 1500 mg CBD per day for 4 weeks in adults67, which, in a 70 kg 
human, equates to a daily dose of 21.4 mg/kg CBD. 
At the time of dose selection, GWP42003-P was being used by physicians for 
treatment of patients with intractable epilepsy resulting from a variety of etiologies in 
a number of open Individual Expanded Access Investigational New Drug (IND) 
studies and open Intermediate Expanded Access IND studies.  In the ongoing 
Individual Expanded Access IND studies, the initial dosing had been cautious 
(100 mg [morning] + 150 mg [afternoon/evening]), progressively increasing to 
400 mg CBD/day; doses up to 22 mg/kg per day had been well tolerated in an 
individual pediatric patient.  The Sponsor was not aware of any safety issues arising 
from the dosing used in the Individual Expanded Access INDs.  Treatment has also 
begun in the Intermediate Expanded Access INDs.  Based on the above, a daily 
maximum dose of 20 mg/kg CBD (given as 2 divided doses) was selected for the 
Phase 2 study in patients with DS (GWEP1332 Part A).  At the end of Part A of the 
GWEP1332 study a Data Safety Monitoring Committee (DSMC) recommended the 
20 mg/kg/day maximum dose and titration schedule for all subsequent studies, 
including this OLE (see APPENDIX 4).  During the maintenance phase, Investigators 
may decrease the dose if a patient experiences intolerance, or increase the dose if 
required for better seizure control, until the optimal dose is found.  The Investigator 
may schedule additional clinic visits during the maintenance period to facilitate dose 
adjustments, e.g., when increasing doses above 20 mg/kg/day.  Patients whose dose 
has been decreased can have their dose increased again, if the tolerability improves. 
The maximum dose patients can receive during the OLE maintenance phase will be 
30 mg/kg/day.  This was based on data from the Intermediate Expanded Access IND 
program (EAP), at the time of initiation of GWEP1415.  The Sponsor reviews all 
safety information on an ongoing basis from the patients in all of the Expanded 


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Access INDs regarding GWP42003-P.  Please refer to the Development Core Safety 
Information71 for the most current safety data.  At the initiation of GWEP1415, the 
maximum dose used to date in the EAP was 51 mg/kg/day, with a mean dose of 
24 mg/kg/day and 64% of doses falling within the 20-30 mg/kg/day range. 
3.4 
Clinical Hypothesis 
Pre-clinical studies have shown CBD to have anti-seizure and antiepileptic activity in 
a range of models.  Anecdotal evidence and some literature reports69 suggest that 
CBD is an effective AED in children with DS or LGS as discussed in Section 3.3.  
The hypothesis underlying this study is that CBD has a positive risk/benefit outcome 
in the adjunctive treatment of DS and LGS. 
 
 
 
 
 


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4 
EXPERIMENTAL PLAN 
4.1 
Study Design 
This is a multi-center, OLE study for patients with DS or LGS who have completed 
the double-blind, placebo-controlled, clinical studies of GWP42003-P (Core Studies).  
The study consists of a titration period and a maintenance period, followed by a 
10-day taper period. 
Titration Period: All patients will titrate up to 10–20 mg/kg/day GWP42003-P using 
a recommended titration schedule (see APPENDIX 4).  It is advised that the 
Investigator considers monitoring hepatic function (alanine aminotransferase [ALT], 
aspartate aminotransferase [AST], total bilirubin [TBL] and international normalized 
ratio [INR] levels) during the titration period for patients taking concomitant AEDs 
that are known to be associated with hepatic injury or failure.  To minimize any 
elevations in hepatic function markers the titration period can be extended and the 
dosage of a concomitant AED and/or GWP42003-P may be adjusted at the discretion 
of the Investigator.  If there is intolerance during titration, the patient may be 
maintained on a dose below 10–20 mg/kg/day.  A titration rate faster than 
recommended may be considered if there is an increase in seizures, following 
consultation with the GW medical monitor. 
Maintenance Period: Patients will continue dosing at 10–20 mg/kg/day.  However, 
Investigators may decrease the dose if the patient experiences intolerance, or increase 
the dose if required for better seizure control, until the optimal dose is found.  The 
Investigator may schedule additional clinic visits to facilitate dose adjustments e.g., 
when increasing doses above 20 mg/kg/day.  Patients whose dose has been decreased 
can have their dose increased again provided there is adequate tolerance.  The 
maximum dose patients can receive will be 30 mg/kg/day (51 mg/kg/day is the 
maximum dose safely used in the USA EAP to date with a mean dose of 
24 mg/kg/day [n = 59]).  Dose increases above 20 mg/kg/day are recommended to be 
done slowly, with maximum increments of 2.5 mg/kg every 5–7 days.  If seizure 
freedom is achieved with use of GWP42003-P during the study, the Investigator can 
consider reducing the dose of concomitant AEDs after consultation with the GW 
medical monitor. 
Study Completion: The maximum duration of this OLE study will be 4 years 
(208 weeks after Visit 1).   
 A patient with at least 2 years’ participation in the OLE (≥ 104 weeks after 
Visit 1) will complete the OLE phase when GWP42003-P is approved in their 
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unscheduled ‘End of treatment’ visit to transition from OLE to commercial 
product.  The timing will vary per patient and is projected to begin in February 
2019.    
 A patient with less than 2 years’ participation in the OLE when GWP42003-P 
is approved in their indication and is commercially available will continue the 
OLE phase until reaching a maximum of 2 years’ (104 weeks after Visit 1) 
OLE treatment, at which point an unscheduled ‘End of Treatment’ visit will be 
conducted.  The unscheduled ‘End of Treatment’ visit will be conducted no 
earlier than 730 days after Visit 1. 
 A patient who does not continue treatment with GWP42003-P will commence 
the 10-day taper period (down-titrating 10% per day for 10 days) and complete 
an ‘End of Taper Period’ visit followed by a Follow-up visit (which can be by 
telephone) 4 weeks later. 
Interim Analysis: At least one interim analysis will be conducted to support New 
Drug Application and Marketing Authorization Application filings.  Further interim 
analyses may be conducted as required. 
A study schema (Figure 1-1), presented at the end of Section 1, depicts the overall 
study design.  More detailed information on treatment and study procedures is 
provided in Section 8 and Section 9, respectively, and is summarized in 
APPENDIX 1. 
4.1.1 
Primary Endpoint 
The safety of GWP42003-P will be assessed by the AE profile and by evaluating 
changes in the following, relative to the pre-randomization baseline of the Core 
Study:  
 Vital signs. 
 Physical examination (including height and body weight). 
 12-lead electrocardiogram (ECG). 
 Columbia-Suicide Severity Rating Scale (C-SSRS) score. 
 Cannabis Withdrawal Scale (CWS) score or Pediatric Cannabinoid 
Withdrawal Scale (PCWS) score, as appropriate. 
 Clinical laboratory parameters. 
The CWS will be administered to patients aged 18 and older while the PCWS will be 
administered to patients aged 4–17 (inclusive). 
The Children’s C-SSRS will be used for patients aged 6–18 (inclusive) and the 
C-SSRS will be used for patients aged 19 and older. 


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4.1.2 
Secondary Endpoint(s) 
All Patients: 
 Change in quality of life as measured with Quality of Life in Childhood 
Epilepsy (QOLCE) if 18 years of age or younger, or Quality of Life in 
Epilepsy (QOLIE) if 19 years of age or older, relative to the 
pre-randomization baseline of the Core Study, if assessed during the Core 
Study. 
 Change in Subject/Caregiver Global Impression of Change (S/CGIC), relative 
to the pre-randomization baseline of the Core Study. 
 Change in adaptive behavior as measured with the Vineland Adaptive 
Behavior Scales, Second Edition (Vineland-II), relative to the 
pre-randomization baseline of the Core Study, if assessed during the Core 
Study. 
 Change in the number of inpatient epilepsy-related hospitalizations (number of 
hospitalizations due to epilepsy in each 28-day period), relative to the 
pre-randomization baseline of the Core Study. 
 Change in the use of rescue medication (number of days used in each 28-day 
period), relative to the pre-randomization baseline of the Core Study. 
 Maintenance of seizure frequency reduction and freedom from seizures during 
the OLE study. 
 Percentage change in the frequency of total seizures, relative to the 
pre-randomization baseline of the Core Study. 
 Number of patients considered treatment responders, defined as those with a 
≥ 25%, ≥ 50%, ≥ 75%, or 100% reduction in total seizures, relative to the 
pre-randomization baseline of the Core Study. 
 Number of patients experiencing a > 25% worsening, − 25 to + 25% no 
change, 25–50% improvement, 50–75% improvement or > 75% improvement 
in total seizures, relative to the pre-randomization baseline of the Core Study. 
 Percentage change in the frequencies of subtypes of seizures, relative to the 
pre-randomization baseline of the Core Study. 
 Changes in duration of seizure subtypes as assessed by the Subject/Caregiver 
Global Impression of Change in Seizure Duration (S/CGICSD), relative to the 
pre-randomization baseline of the Core Study. 
 Change in the number of episodes of status epilepticus, relative to the 
pre-randomization baseline of the Core Study. 
 Change in cognitive function as measured with a cognitive assessment battery, 
relative to the pre-randomization baseline of the Core Study, if assessed during 
the Core Study. 
 Change in growth and development for patients less than 18 years of age by 
measurement of height, weight, insulin-like growth factor-1 (IGF-1) levels and 
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indicated by onset of menarche or other signs of precocious puberty), relative 
to the pre-randomization baseline of the Core Study. 
 Effects on menstruation cycles (in females). 
 Drug abuse liability, as measured by AEs of abuse potential, drug 
accountability and Study Medication Use and Behavior Survey in patients 
aged 12 and older. 
DS Patients Only: 
 Percentage change in total convulsive seizure frequency, relative to the 
pre-randomization baseline of the Core Study. 
 Percentage change in total non-convulsive seizure frequency, relative to the 
pre-randomization baseline of the Core Study. 
 Number of patients considered treatment responders, defined as those with a 
≥ 25%, ≥ 50%, ≥ 75%, or 100% reduction in convulsive seizures, relative to 
the pre-randomization baseline of the Core Study. 
 Number of patients experiencing a > 25% worsening, − 25 to + 25% no 
change, 25–50% improvement, 50–75% improvement or > 75% improvement 
in convulsive seizures, relative to the pre-randomization baseline of the Core 
Study. 
LGS Patients Only: 
 Percentage change in the number of drop seizures, relative to the 
pre-randomization baseline of the Core Study. 
 Percentage change in the number of non-drop seizures, relative to the 
pre-randomization baseline of the Core Study. 
 Number of patients considered treatment responders, defined as those with a 
≥ 25%, ≥ 50%, ≥ 75%, or 100% reduction in drop seizures, relative to the 
pre-randomization baseline of the Core Study. 
 Number of patients experiencing a > 25% worsening, − 25 to + 25% no 
change, 25–50% improvement, 50–75% improvement or > 75% improvement 
in drop seizures, relative to the pre-randomization baseline of the Core Study. 
4.2 
Number of Centers 
Approximately 70 centers are expected to participate in this study. 
4.3 
Number of Patients 
All patients who wish to continue on IMP from the populations included in the 
double-blind Phase 2 and Phase 3 Core Studies in DS and LGS.  Approximately 
680 patients will be enrolled.  Patients are considered enrolled in the study from the 
time of providing written informed consent/assent. 
 
 


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5 
INVESTIGATIONAL MEDICINAL PRODUCT 
Please refer to the separate Pharmacy Manual for more detailed information on the 
IMP. 
5.1 
GWP42003-P Oral Solution 
GWP42003-P oral solution is presented as an oily solution containing 100 mg/mL 
CBD dissolved in the excipients sesame oil and anhydrous ethanol with added 
sweetener (sucralose) and strawberry flavoring (Table 5.1-1). 
Table 5.1-1 
Formulation of GWP42003-P Oral Solution 
Material 
Quantity 
CBD 
100 mg/mL 
Anhydrous ethanol 
79 mg/mL 
Sucralose 
0.5 mg/mL 
Strawberry flavoring 
0.2 mg/mL 
Sesame oil 
make up to 1 mL 
 
5.2 
Packaging, Storage and Drug Accountability 
5.2.1 
Packaging and Labeling  
The IMP will be manufactured and packaged by GW Pharma Ltd (GWP).  It will be 
distributed by GWP or delegated contractors.  The IMP will be presented in 100 mL 
amber glass bottles with child-resistant caps and packed in cartons.  Sufficient IMP 
will be dispensed at each visit considering the decided dose as per the Investigator’s 
discretion and weight of each patient.  An Interactive Voice Response System (IVRS) 
will be utilized, where a unique pack identification number will be used to identify 
each box and the medication it contains.  The pack numbers will cross check with the 
batch numbers held at GWP.  GWP will ensure that all IMP provided is fully labeled 
and packaged.  Label text will comply with European Union (EU) guidance on Good 
Manufacturing Practice, Annex 13.  In addition, any local country requirements in 
accordance with local Drug Law or Regulatory Requirement will be included in the 
final label text. 
Directions of use, name, address and telephone number of the Investigator or main 
contact for information about the product or the clinical trial will be provided 
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5.2.2 
Storage 
The IMP must be stored upright at room temperature (< 30C) and must not be 
refrigerated or frozen.  It must also be kept away from heat and direct sunlight. 
The IMP must be stored in compliance with the local regulations for a controlled drug 
(if applicable to country).  The sponsor must approve storage location and facilities. 
Should storage conditions deviate from these specified requirements, the GW study 
monitor should be contacted immediately to confirm if the IMP remains suitable for 
use.  IMP should be placed under quarantine until confirmation is received that IMP is 
suitable for use. 
Temperature records of the storage location must be maintained on a daily basis (a 
minimum of Monday–Friday, excluding public holidays) from date of receipt of first 
shipment until end of study dispensing period at each site.  These records must 
contain at least the minimum and maximum daily temperatures and should be made 
available to the appropriate GW personnel for review throughout the study. 
Patients or their caregivers will be provided with instructions regarding IMP home 
storage requirements. 
5.2.3 
Supply and Return of Investigational Medicinal Product 
Once a site has been activated via the IVRS at study initiation, IMP will be shipped to 
a responsible person, such as the pharmacist, at the Investigator’s center, who will 
check the amount received (against the IVRS Shipment Request) and the condition of 
the drug.  Details of the IMP received will be recorded in the IMP accountability 
record (see Section 5.2.4).  The site will acknowledge IMP receipt via the IVRS and 
will complete any receipt forms required.  IMP will be dispensed and returned as 
detailed in Section 8.4 with further IMP shipments to be initiated by the IVRS.  As 
directed, all supplies, including unused, partially used, or empty containers, will be 
returned to GWP or destroyed at the center if agreed in writing by the study monitor. 
5.2.4 
Investigational Medicinal Product Accountability 
The Investigator has overall responsibility for the accountability of all used and 
unused IMP.  A drug accountability record for the IMP must be kept current and 
should contain: 
 The dates and quantities of IMP received from GWP. 
 Patient’s identification. 
 Date and quantity of IMP dispensed. 


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 The initials of the dispenser. 
 Date and quantity of IMP returned to the Investigator/pharmacy, if 
appropriate. 
 
A record of returned IMP must be completed and included in the shipment of used 
and unused IMP to GWP.  At the end of the study a record/statement of reconciliation 
must be completed and provided to GWP. 
These inventories must be made available for inspection by an authorized GW or 
GWP representative and local officials or regulatory agency inspectors. 
Please refer to the separate Pharmacy Manual for more detailed information on the 
IMP. 
 
 
 
 


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6 
PATIENT ELIGIBILITY 
Investigators will be required to maintain a log that includes limited information about 
all enrolled patients (initials, date of birth, sex; as allowed per local regulations) and 
outcome of applicable screening. 
6.1 
Inclusion Criteria 
For inclusion in the study patients must fulfill ALL of the following criteria: 
6.1.1 
Patient has completed the treatment phase of their Core Study. 
6.1.2 
Patient and/or parent(s)/legal representative must be willing and able to 
give informed consent/assent for participation in the study (see 
Section 15.2). 
6.1.3 
Patient and their caregiver must be willing and able (in the 
Investigator’s opinion) to comply with all study requirements. 
6.1.4 
Patient and/or parent(s)/legal representative is willing to allow his or her 
primary care practitioner and consultant to be notified of participation in 
the study. 
6.2 
Exclusion Criteria 
The patient may not enter the study if ANY of the following apply: 
6.2.1 
Patient is currently using or has in the past used recreational or 
medicinal cannabis, or synthetic cannabinoid-based medications 
(including Sativex®) within the 3 months prior to study entry, not 
including IMP received during the Core study. 
6.2.2 
Patient is unwilling to abstain from using recreational or medicinal 
cannabis, or synthetic cannabinoid-based medications (including 
Sativex) during the study. 
6.2.3 
Patient has a history of symptoms (e.g., dizziness, light-headedness, 
blurred vision, palpitations, weakness, syncope) related to a drop in 
blood pressure due to postural changes. 
6.2.4 
Any history of suicidal behavior or any suicidal ideation of type 4 or 5 
on the C-SSRS at Visit 1. 
6.2.5 
Patient has been part of a clinical trial involving an IMP during the 
inter-study period. 
6.2.6 
Patient has previously been enrolled and dosed in this study. 
6.2.7 
Female patient is of child bearing potential or male patient’s partner is 
of child bearing potential; unless willing to ensure that they or their 
partner use highly effective contraception for the duration of the study 
and for 3 months thereafter.  Highly effective methods of contraception 
are defined as those, alone or in combination, that result in a low failure 
rate (i.e. less than 1% per year) when used consistently and correctly.  
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devices/hormone-releasing systems, bilateral tubal occlusion, 
vasectomized partner or sexual abstinence. 
6.2.8 
Female patient who is pregnant (positive pregnancy test), lactating or 
planning pregnancy during the course of the study and for 3 months 
thereafter. 
6.2.9 
Any other significant disease or disorder which, in the opinion of the 
Investigator, may either put the patient at risk because of participation in 
the study, may influence the result of the study, or affect the patient’s 
ability to participate in the study. 
6.2.10 Following a physical examination the patient has any abnormalities that, 
in the opinion of the Investigator, would prevent the patient from safe 
participation in the study. 
6.2.11 Patient is unwilling to abstain from donation of blood during the study. 
6.2.12 Patient has significantly impaired hepatic function at the ‘End of 
Treatment’ visit of their Core Study or at Visit 1 if re-assessed, defined 
as any of the following: 
i) 
ALT or AST > 5 × upper limit of normal (ULN). 
ii) 
ALT or AST > 3 × ULN and (TBL > 2 × ULN or INR > 1.5). 
iii) ALT or AST > 3 × ULN with the presence of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (> 5%). 
If the Core Study ‘End of Treatment’/‘End of Taper Period’ visit assessments or 
Visit 1 re-assessments (as applicable) raise any safety concerns, the Investigator 
should consider whether it will be appropriate for the patient to continue to participate 
in the OLE study, or if the patient should be withdrawn. 
 
 
 


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7 
PATIENT ENROLLMENT 
Before patients may be entered into the study, GW requires a copy of the relevant 
center’s Ethics Committee (EC) or Institutional Review Board (IRB) written approval 
of the protocol, informed consent/assent form and other patient information material.  
Patients will be considered enrolled in the study from the time of providing written 
informed consent/assent.  All patients and/or parent(s)/legal representatives, where 
appropriate, must personally sign and date the consent/assent form prior to any 
procedures being performed (refer to Section 9.1.1 and Section 15.2). 
7.1 
Treatment Assignment 
As this is a single-group OLE study, all patients will receive GWP42003-P.  Patients 
will not be informed of their allocated treatment group in the Core Study.  Patients 
will retain the patient number allocated to them during the Core Study. 
 
 
 
 


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8 
TREATMENT PROCEDURES 
8.1 
Investigational Medicinal Product Dosage, Administration and 
Schedule 
The IMP will be presented as an oral solution containing 100 mg/mL CBD and 
excipients.  For details regarding IMP formulation see Section 5. 
8.1.1 
Dose Administration 
The IMP will be administered orally by the patient or their caregiver twice each day 
(morning and evening) using the syringe(s) provided.  The IMP will be swallowed 
and may be taken with other concomitant medications, as directed by the Investigator. 
Dosing through gastrostomy/nasogastric tubes may be allowed after consultation with 
the GW medical monitor.  Alteration in dosing frequency may also be considered 
after consultation with the GW medical monitor. 
8.1.2 
Dose Escalation, Dose Adjustments and Down-Titration 
The titration regimen is shown in APPENDIX 4.  All patients will titrate up to a target 
dose of 10–20 mg/kg/day GWP42003-P.   
Patients will be weighed at each study visit.  During Visit 1, the daily volumes of IMP 
solution to be taken during the titration period will be calculated via the IVRS and the 
dosing regimen provided to the patient and/or caregiver.  Patients should aim to 
achieve the target dose before the end of the 2-week titration period; however, 
Investigators may decrease the dose if a patient experiences intolerance, or increase 
the dose if required for better seizure control, until the optimal dose is found.  The 
titration period will be considered 2 weeks long to ensure most patients have achieved 
stable dosing from Visit 2 onwards (maintenance period).  The rate of titration should 
be adjusted based on the specific needs of an individual patient.  It is advised that the 
Investigator considers monitoring hepatic function (ALT, AST, TBL and INR levels) 
during the titration period for patients taking AEDs that are known to be associated 
with hepatic injury or failure.  To minimize any elevations in hepatic function markers 
the titration period can be extended and the dosage of a concomitant AED and/or 
GWP42003-P may be adjusted at the discretion of the Investigator.  If there is 
intolerance during titration, the patient may be maintained on a dose below 
10-20 mg/kg/day.  A titration rate faster than recommended may be considered if 
there is an increase in seizures, following consultation with the GW medical monitor.  
Further information on dispensing procedures will be provided in a separate 
Pharmacy Manual. 


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If an unacceptable AE develops at any time during titration, dosing should initially be 
suspended or amended, at the Investigator’s discretion, as appropriate, until the event 
has resolved or is well tolerated.  During the maintenance period, Investigators may 
decrease the dose if a patient experiences intolerance, or increase the dose if required 
for better seizure control, until the optimal dose is found.  The Investigator may 
schedule additional clinic visits during the maintenance period to facilitate dose 
adjustments, e.g., when increasing doses above 20 mg/kg/day.  Patients whose dose 
has been decreased can have their dose increased again provided there is adequate 
tolerance.  Dose increases above 20 mg/kg/day are recommended to be done slowly, 
with maximum increments of 2.5 mg/kg every 5–7 days.  The maximum dose patients 
can receive will be 30 mg/kg/day. 
For patients who do not immediately continue to use GWP42003-P following the 
‘End of Treatment’ visit, IMP will be down-titrated at home (10% per day for 
10 days).  Additional IMP will be dispensed, if required.  Patients who withdraw early 
should also begin the taper period following the Withdrawal visit (unless continued 
dosing is not possible due to an AE).  The IVRS will generate the patient’s daily IMP 
dosing volumes for the 10-day taper period, during which time IVRS and diary 
information will continue to be recorded. 
8.2 
Concomitant Therapy 
It is theoretically possible that GWP42003-P may modify the metabolism of other 
drugs (including AEDs) administered concurrently and there remains the possibility 
of pharmacological interactions between GWP42003-P and other concurrently 
administered drugs.  Concomitant AED plasma level monitoring may be conducted if 
deemed necessary.  However, if drug-drug interactions are suspected or observed, the 
Investigator must contact the GW medical monitor to discuss best management, but 
the expectation is that decisions should be based on clinical symptoms and not plasma 
levels of AEDs.  Further information on drug interactions can be found in the 
Investigator Brochure (IB)71.   
It is advised that the Investigator considers monitoring hepatic function (ALT, AST, 
TBL and INR levels) during the titration period for patients taking AEDs that are 
known to be associated with hepatic injury or failure.  To minimize any elevations in 
hepatic function markers the titration period can be extended and the dosage of a 
concomitant AED and/or GWP42003-P may be adjusted at the discretion of the 
Investigator.  If there is intolerance during titration, the patient may be maintained on 
a dose below 10–20 mg/kg/day.  A titration rate faster than recommended may be 
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medical monitor.  If seizure freedom is achieved with use of GWP42003-P during the 
study, the Investigator can consider reducing the dose of concomitant AEDs after 
consultation with the GW medical monitor.  Additional new AEDs are not allowed to 
be added but may be considered on a case-by-case basis after consultation with the 
GW medical monitor.   
Rescue medication is allowed when necessary.  Any medication, other than the IMP, 
taken during the study must be recorded on the Case Report Form (CRF). 
8.3 
Prohibited Therapy During Study Period 
The following medications are prohibited for the duration of the study starting from 
acquisition of patient consent/assent.  However, any patients taking these medications 
after enrollment should not be withdrawn from the study unless there are safety 
concerns.  If applicable, the possible effects of these medications on the primary 
endpoint will be considered during the assessment of the evaluable period (see 
Section 13.6.1). 
 Recreational or medicinal cannabis, or synthetic cannabinoid-based 
medications (including Sativex), other than the IMP, within the inter-study 
period or during the study. 
 Any other IMP taken as part of a clinical trial within the inter-study period or 
during the study. 
8.4 
Compliance in Investigational Medicinal Product Administration 
The IMP is dispensed to the patient at each study visit except the ‘End of Taper 
Period’ visit and the Follow-up visit.  If necessary, additional IMP will be dispensed 
at dose-adjustment clinic visits scheduled by the Investigator.  IMP will be dispensed 
at the ‘End of Treatment’/Withdrawal visit only if required for the 10-day taper 
period.  Patients or their caregivers will confirm the daily dose has been administered 
using the paper diary.  Patients will be asked to return all IMP (used and unused) at 
each subsequent visit.  Any discrepancies will be discussed with the patient/caregiver 
and documented accordingly within the patient’s source documents. 
The Investigator must inform GW promptly of all missing or unaccountable IMP. 
Refer to Section 9.1.15.2.1 for the list of ‘Triggering Drug Accountability 
Discrepancies’ associated with monitoring of drug abuse liability. 
Records of IMP accountability will be maintained according to Section 5.2.4. 
 
 


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9 
STUDY PROCEDURES 
A list of the required study procedures is provided in the subsections that follow; refer 
also to the Schedule of Assessments (APPENDIX 1).  Assessments or tests that are 
not done and examinations that are not conducted must be reported as such on the 
CRFs. 
The location of the source data for the following procedures will be documented, per 
center, in a signed ‘Source Data Verification’ plan; for further details see 
Section 16.2. 
9.1 
Study Procedure Listing 
To be eligible for the study, the patient must have agreed that if they or their partner 
are of child bearing potential they are willing to use highly effective contraception for 
the duration of the study and for 3 months thereafter.  Highly effective methods of 
contraception are defined as those, alone or in combination, that result in a low failure 
rate (i.e., less than 1% per year) when used consistently and correctly 
(CPMP/ICH/286/95 mod)72.  Such methods include hormonal contraceptives, 
intrauterine devices/hormone-releasing systems, bilateral tubal occlusion, 
vasectomized partner or sexual abstinence.  Abstinence is only acceptable as true 
abstinence: when this is in line with the preferred and usual lifestyle of the patient; 
periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception.  Female 
patients of child bearing potential must test negative for pregnancy to be eligible for 
the study. 
9.1.1 
Informed Consent/Assent 
The parent(s)/legal representative of minor patients must personally sign and date the 
EC/IRB approved consent form before any study specific procedures are performed or 
any patient related data are recorded for the study.  In addition, in cases where the 
patient possesses adequate understanding, assent will be taken along with 
parent(s)/legal representative consent, using EC/IRB approved assent forms.  Assent 
is defined as the minor’s permission or affirmative agreement to participate in the 
study.  The explicit wish of a minor, who is capable of forming an opinion and 
assessing the information provided, to refuse participation in, or to be withdrawn 
from, the clinical trial at any time must be considered by the Investigator. 
Adult patients with an adequate level of understanding must personally sign and date 
the EC/IRB approved informed consent form before any study specific procedures are 
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with an insufficient level of understanding of what is proposed, only parent(s)/legal 
representative consent will be sought. 
For patients who go from being a minor to an adult (as per the country or state’s 
age-of-majority regulation) during the course of the study, an informed consent form 
will be signed if the patient possesses adequate understanding to do so. 
GW requires a physician to be present for consent and assent and to sign the consent 
and assent forms also. 
9.1.2 
Demographics 
The following demographic information collected for the Core Study will be used for 
the current study: date of birth, sex and race (as allowed per local regulations). 
9.1.3 
Medical History 
Medical history collected for the Core Study will be used for the current study.  New 
information about relevant, significant medical history discovered during/after the 
Core Study will be collected and is defined as any condition or disease that: 
 May affect the condition under study. 
 Is ongoing on entry into the study. 
9.1.4 
Inpatient Epilepsy-Related Hospitalizations 
The number of inpatient hospitalizations that are, in the Investigator’s opinion, due to 
epilepsy will be recorded in the patient’s CRF and through the Serious Adverse Event 
(SAE) reporting process. 
9.1.5 
Concomitant Medication 
Details of all current medication, including AEDs, recorded at the end of the Core 
Study (‘End of Treatment’, ‘End of Taper Period’ or Follow-up visit, as applicable) 
and medications, including AEDs, taken during the last 2 weeks of the inter-study 
period (“prior medications”) will also be recorded for the current study and at each 
subsequent study visits.  Any changes in concomitant medication during the study 
must be recorded in the CRF at study visits.  Patients should stop taking any 
prohibited therapy prior to enrollment, as defined in Section 8.3. 
If seizure freedom is achieved with use of GWP42003-P during the study, the 
Investigator can consider reducing the dose of concomitant AEDs after consultation 
with the GW medical monitor. 


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9.1.6 
Physical Examination 
Physical examinations will include height and body weight measurements. 
9.1.7 
Vital Signs 
Vital sign measurements, taken in a sitting position at rest for 5 minutes, will be 
completed alongside the physical examination.  Blood pressure must be recorded 
using the same arm throughout the study. 
9.1.8 
12-Lead Electrocardiogram  
An ECG will be performed, after 5 minutes in a supine position.  A physician must 
review the ECG and any abnormal findings considered to indicate significant medical 
history or AEs must be recorded appropriately in the CRF.  Additional ECG 
measurements can be taken at any time during the study, if clinically indicated. 
9.1.9 
Clinical Laboratory Sampling 
Laboratory tests will include hematology, biochemistry and urinalysis (provided urine 
can be obtained).  Analysis of all clinical blood samples and pregnancy tests (using 
serum at the ‘End of Treatment’/Withdrawal visit) will be conducted at a central 
clinical laboratory.  However, in order to confirm normal hepatic function before OLE 
dosing commences, an additional blood sample may be taken to analyze ALT, AST, 
TBL and INR at a local laboratory. 
Urine samples for biochemistry will be analyzed at the study center by use of a 
dipstick with any relevant findings being sent for further urinalysis at the central 
laboratory (urinalysis, microscopy, culture and sensitivity, as applicable).  Urine 
pregnancy tests (using a dipstick) will be performed at the study center at Visit 1.  In 
cases where urine samples cannot be analyzed at site due to local regulations, a full 
set of urine samples should be sent to the central laboratory for analysis. 
The Investigator and study monitor will be provided with a list of the normal ranges 
used by the testing laboratory for all variables assayed during the study and a 
statement of accreditation (or similar) for the laboratory.  Clinical laboratory sample 
parameters are detailed in Table 9.1.9-1. 
Throughout the study additional blood samples may be collected for measurement of 
plasma concentrations of concomitant AEDs.  The decision on whether or not to 
assess plasma concentrations of concomitant AEDs will be left to the Investigator’s 
clinical judgment.  Analysis may be done at local or central laboratories and data 


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collected in the CRF.  Central laboratory analysis results will not be released to the 
Investigator. 
Table 9.1.9-1 
Hematology, Biochemistry and Urinalysis 
Biochemistry 
(serum) 
Hematology 
(whole blood) 
Urinalysis 
(urine) 
Pregnancy Test 
Alanine 
aminotransferase 
(ALT) 
Hematocrit 
Bilirubin 
(Serum or Urine) 
Albumin 
Hemoglobin 
Blood 
 
Alkaline phosphatase 
Mean cell volume 
Glucose 
 
Aspartate 
aminotransferase 
(AST) 
Mean corpuscular 
hemoglobin 
Ketones 
 
Calcium 
Platelets 
Nitrites 
 
Creatinine 
Red blood cell count 
pH 
 
Estimates of 
glomerular filtration 
rate 
White blood cell count 
with automated 
differential 
Protein 
 
Gamma glutamyl 
transferase 
 
Specific gravity 
 
Glucose 
 
Urobilinogen 
 
HDL-cholesterol 
 
 
 
Insulin-like growth 
factor-1 (IGF-1) 
 
 
 
Potassium 
 
 
 
Prolactin 
 
 
 
Prothrombin time 
(plasma) 
 
 
 
Sodium 
 
 
 
Total bilirubin (TBL) 
 
 
 
Total protein 
 
 
 
Triglycerides 
 
 
 
Urea (blood urea 
nitrogen [BUN]) 
 
 
 
Investigators at study centers will be notified of safety laboratory test results.  All 
laboratory results will be reviewed and the reports signed by an Investigator.  Any 
results considered to be of clinical significance must be addressed and followed up as 
clinically appropriate.  See Section 12.8 for guidance on evaluation of potential 
drug-induced liver injury.  All laboratory results considered to represent an AE must 
be documented on the CRF. 
Repeat samples will be taken, if required, for clinical follow-up or if the sample is lost 
or damaged.  Any abnormal end of treatment clinical laboratory result of clinical 
significance must be repeated at regular intervals until it returns to normal, or until an 
Investigator is satisfied that the abnormality is not related to the IMP and needs no 
further investigation. 


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Sample volume requirements and processing procedures will be detailed in a separate 
laboratory manual.  The patient/caregiver must be advised that it may not be safe for 
the patient to undertake further blood tests within one month of any study-related 
blood draws and to inform the Investigator if they suffered any blood loss during the 
one-month period leading up to a planned blood draw. 
9.1.10 
Interactive Voice Response System 
The IVRS will be used to collect patient reported diary data (refer to Section 9.1.12) 
and to manage IMP supply.  A member of the study team must contact the IVRS at 
each clinic visit in order to obtain dispensing information and to provide 
completion/taper/premature termination information. 
9.1.11 
Questionnaires and Assessments Completed at Scheduled 
Visits  
Questionnaires should be completed by the patient or the caregiver, as appropriate.  
The same person should complete/answer the questionnaires/assessments in order to 
maintain consistency.  The C-SSRS will be administered by a trained rater. 
9.1.11.1 
Vineland Adaptive Behavior Scales (Second Edition) 
The Vineland-II is an individually administered instrument for assessing adaptive 
behaviors.  Communication, Daily Living Skills, Socialization, and Motor Skills will 
be assessed by the caregiver using a rating scale.  Vineland-II assessments will be 
performed for all patients irrespective of whether or not they completed the 
Vineland-II during their Core Study. 
9.1.11.2 
Quality of Life in Childhood Epilepsy (18 Years of Age and 
Younger) or Quality Life in Epilepsy (19 Years of Age and 
Older) 
The QOLCE and the QOLIE are composed of 16 and 31 subscales, respectively, 
assessing 7 domains of Health Related Quality of Life (physical function, social 
function, emotional well-being, cognition, behavior, general health and general 
quality of life).  The QOLCE (and QOLIE, if completed by the caregiver) must be 
completed by a person who interacts with the patient on a consistent, daily basis.  
Quality of life assessments will be performed for all patients irrespective of whether 
or not they completed during their Core Study.  The questionnaires should take 20–30 
minutes to complete. 


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9.1.11.3 
Subject/Caregiver Global Impression of Change 
The S/CGIC, as appropriate, will be performed for all patients irrespective of whether 
or not it was completed during their Core Study.  The patient or patient’s caregiver 
will use the description of their/the patient’s overall condition made during the Core 
Study (prior to commencement of IMP).  If the memory aid is not available from the 
Core Study then the patient/caregiver will be asked to write a brief description from 
memory, if possible, at Visit 1 as an aid for subsequent visits.  It is preferred that the 
same person performs this assessment at each visit. 
The CGIC comprises the following question to be rated on a 7-point scale: 
 Since your child started treatment, please assess the status of your child’s 
overall condition (comparing their condition now to their condition before 
treatment) using the scale below. 
The SGIC comprises the following question to be rated on a 7-point scale: 
 Since you started treatment, please assess the status of your overall condition 
(comparing your condition now to your condition before treatment) using the 
scale below. 
The markers are: Very Much Improved; Much Improved; Slightly Improved; No 
Change; Slightly Worse; Much Worse; Very Much Worse. 
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 
3 days. 
9.1.11.4 
Subject/Caregiver Global Impression of Change in Seizure 
Duration 
The S/CGICSD comprises a question to be rated on a 3-point scale for each seizure 
subtype: 
CGICSD: 
 Since the patient started treatment, please assess the average duration of the 
patient’s seizures (comparing their condition now to their condition before 
treatment at the Baseline of the Core Study) using the scale below. 
SGICSD: 
 Since you started treatment, please assess the average duration of your 
seizures (comparing their condition now to their condition before treatment at 
the Baseline of the Core Study) using the scale below. 


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The markers are: Average duration of seizures has decreased; Average duration of 
seizures has stayed the same; Average duration of seizures has increased. 
The patient/caregiver would have been asked to assess and note the average duration 
of the patient’s seizures at the Baseline of the Core Study as a memory aid for 
subsequent visits.  If the memory aid is not available from the Baseline of the Core 
Study then the patient/caregiver should do this from memory, if possible, and 
complete a memory aid at Visit 1. 
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 
3 days. 
9.1.11.5 
Columbia-Suicide Severity Rating Scale (Six Years of Age 
and Older) 
The definitions of behavioral suicidal events used in this scale are based on those used 
in the Columbia-Suicide History Form.  Questions are asked on suicidal behavior, 
suicidal ideation and intensity of ideation.  Questioning will be in relation to the last 
assessment (Since Last Visit). 
The C-SSRS is to be completed by the Investigator or his/her qualified designee at 
every visit as indicated in the Schedule of Assessments (see APPENDIX 1); 
“qualified designee” is defined as anyone who has completed the C-SSRS training 
within the past 2 years.  The survey should be completed by the same assessor, where 
possible, throughout the study.  The Children’s C-SSRS will be used for patients aged 
6–18 (inclusive) while the C-SSRS will be used for patients aged 19 and older.  For 
patients that become 6 years old during this OLE trial, the Children’s Baseline 
C-SSRS (employing questions in relation to lifetime experience) should be completed 
at the next trial visit.  Questioning at all subsequent visits will be in relation to the last 
assessment (Children’s Since Last Visit). 
9.1.11.6 
Cognitive Assessment Battery 
The items that comprise the cognitive assessment battery are age specific.  The age of 
the patient at entry will be the age used when choosing the items to be administered.  
Children and adults are to complete the battery as able.  It is expected that a number 
of patients will only be able to complete part of the battery and some may not be able 
to complete any of it.  Parents and/or caregivers are to complete certain items.  The 
cognitive assessment battery items will only be administered at a sub-group of centers 
that have the expertise to conduct the assessments (ideally before any other study 
procedures but can be completed on a separate day, if necessary, within 3 days of the 
visit).  Each assessment will need to be conducted by an experienced 


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psychometrician.  A summary of the battery is as shown below in Table 9.1.11.6-1 
and Table 9.1.11.6-2.  Items will only be administered to patients who underwent 
cognitive testing during their Core Study. 


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Table 9.1.11.6-1 
Neuropsychological Protocol for Epilepsy Patients Treated 
with Cannabidiol - Patient Measures 
Function 
Patient Measures 
Age 
Range 
Approximate 
Administration Time 
for Psychometrician 
Intelligence 
IQ 
WPPSI-4 Vocabulary, Matrix Reasoning 
2;6 - 5;11 
years 
30 minutes  
WASI-2 Vocabulary, Matrix Reasoning 
(Including Wechsler: ‘Digit Span’ 
subtest from WISC-4 and WAIS-4; 
‘Coding’ subtest from WISC-4 & WAIS-
4; ‘Bug Search’ from WPPSI-4) 
6 - adult 
45 minutes 
Attention/Executive 
Trail Making 
Trail Making Test D-KEFS 
9 - adult 
5 minutes 
Language 
Naming  
Fluency 
 
Expressive One-Word Picture 
Vocabulary Test-4th Ed 
2 - adult 
5 minutes 
NEPSY-2 Word Generation 
2 - 5 years 
5 minutes 
F-A-S and Animals 
6 - adult 
5 minutes 
Visual-Spatial 
VMI 
Developmental Test of Visual Motor 
Integration-6 
2 - adult 
5 minutes 
Fine Motor Speed 
Pegs 
Purdue Pegboard 
4 - adult 
5 minutes 
 
Table 9.1.11.6-2 
Neuropsychological Protocol for Epilepsy Patients Treated 
with Cannabidiol - Parent Measures 
Function 
Parent Measures 
Age 
Range 
Approximate 
Administration Time 
for Parents 
Executive 
Behavior Rating Inventory of Executive 
Function  
(Parent and Teacher) 
3 - 21 
years 
10 minutes 
Attention 
 
ADHD Checklist  
(Parent and Teacher) 
All ages 
5 minutes 
Mood/Anxiety 
BASC-2 
(Parent and Teacher) 
3 - 21 
years 
20 minutes 
Free-form Report 
Behavior Report Form 
(Parent and Teacher) 
All ages 
5 minutes 
 
9.1.11.7 
Cannabis Withdrawal Scale (18 Years and Above) or 
Pediatric Cannabinoid Withdrawal Scale (4–17 Years)  
The CWS is to be administered to patients 18 years of age and above.  It is a 19-item 
scale with each item (withdrawal symptom) measured on a 0–10 NRS (0 = Not at all; 
5 = Moderately; 10 = Extremely).  The patient or their caregiver is asked to record the 
extent to which each withdrawal symptom was experienced in the last 24 hours and 
also to rate the negative impact on normal daily activities (i.e., 2 separate scores are 
recorded for each item using the same 0–10 NRS).  Scores are summed over the 
19 items for each measure. 


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The PCWS is to be administered to patients aged 4 to 17 years of age (inclusive).  It 
was developed from the 19-item validated CWS (adults) that assesses mood, 
behavioral and physical symptoms associated with cannabis, which was based on the 
Marijuana Withdrawal Checklist.  The modified 10-item PCWS was developed from 
a low literacy version of the CWS.  Symptoms specific to adult cannabis withdrawal 
have been removed and the wording has been amended to be comprehensible to 
children of the specified age range. 
Ratings are based on a 4-point scale where 0 = none, 1 = a little bit, 2 = quite a bit, 
and 3 = a lot.  This rating scale has been compacted from the original 11-point Likert 
scale used for the CWS in order to simplify the range of options to consider for 
potential intellectually disabled children.  The PCWS was designed with epileptic 
children in mind as a tool to assess the safety of cannabinoid medications with respect 
to the stimulation of cannabinoid withdrawal syndrome when medications are 
withdrawn.  As there may be a wide range of intellectual or developmental difficulties 
in severely epileptic children, from no intellectual or developmental impairment to 
extreme, the PCWS has been designed to be administered by a treating clinician, 
either directly to the child, or to the parent or caregiver of the child, reflecting on the 
child’s symptoms within the chosen timeframe. 
The CWS or PCWS, as appropriate, would have been used at the Baseline of the Core 
Study to establish a baseline score for this current study, GWEP1415. 
Assessments will be conducted only if patients are of an appropriate age (4 years of 
age and older). 
9.1.11.8 
Menstruation 
For female patients, details of menstruation recorded during the Core Study (including 
whether the patient is menstruating and any changes in normal menstrual cycles) will 
continue to be assessed. 
9.1.11.9 
Tanner Staging 
The pubic hair growth (both sexes), genital (males only) and breast (females only) 
development of all adolescent patients (i.e., 10 to less than 18 years of age at the time 
of signing the informed consent/assent form, or earlier if clinically indicated by onset 
of menarche or other signs of precocious puberty) will be assessed using Tanner 
Staging (see APPENDIX 3).  The patients will undergo a discreet physical 
examination and assigned a value under each category of Pubic Hair Growth (both 
sexes), Genitals (male patients only), and Breasts (female patients only).  Once a 
patient reaches a score of “V” (i.e., 5), the examination need not be performed again. 


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9.1.12 
Patient Diary 
Seizure information (number and type of seizures) will continue to be collected 
through an IVRS telephone diary, completed weekly until the ‘End of 
Treatment’/Withdrawal visit.  In addition, patients/caregivers will be instructed to 
complete the diary using IVRS at the following times: 
 Once on the day before the ‘End of Taper Period’ visit. 
 Once on the day before the Follow-up visit. 
The patient or their caregiver will also continue to complete a paper diary daily to 
record daily usage of IMP, rescue medication, concomitant AEDs and AEs.  Adequate 
training will be provided to the patient/caregiver in order to ensure data is being 
accurately collated via IVRS and paper diaries. 
9.1.13 
Investigational Medicinal Product Accountability 
IMP will be dispensed at each visit except the ‘End of Taper Period’ visit and the 
Follow-up visit.  IMP will also be dispensed between visits from Visit 7 through to 
the ‘End of Treatment’ visit.  If necessary, additional IMP will be dispensed at 
dose-adjustment clinic visits scheduled by the Investigator.  IMP will be dispensed at 
the ‘End of Treatment’/Withdrawal visit only if required for the 10-day taper period.  
Patients/caregivers will be asked to return all IMP (used and unused) at each 
subsequent visit.  Any discrepancies will be discussed with the patient/caregiver and 
documented accordingly within the patient’s source documents. 
Refer to Section 9.1.15.2.1 for the list of ‘Triggering Drug Accountability 
Discrepancies’ associated with monitoring of drug abuse liability. 
9.1.14 
Adverse Events 
Any adverse changes in the patient’s medical condition, following completion of the 
consent/assent form by the patient, will be recorded on the CRF as AEs, questioning 
the patient further if necessary.  Any AEs that are continuing from the Core Study will 
be carried over into the OLE study and transcribed in the CRF, only becoming 
classified as treatment emergent if they worsen.  All AEs occurring during the study, 
whether or not attributed to the IMP, observed by the Investigator or reported by the 
patient will be recorded in the CRF. 
SAEs must be reported to GW Pharmacovigilance Department (PVD) within 24 hours 
of discovery or notification of the event, and recorded in the CRF. 
Refer to Section 12 for definitions, procedures and further information. 


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The number of inpatient hospitalizations that are, in the Investigator’s opinion, due to 
epilepsy will be recorded in the patient’s CRF and through the SAE reporting process. 
Refer to Section 9.1.15.1.1 for the list of ‘Triggering AEs of Interest’ associated with 
monitoring of drug abuse liability. 
9.1.15 
Monitoring of Drug Abuse Liability (for Patients 12 Years of 
Age and Older) 
There are 2 triggers that will require the Investigator or study coordinator to discuss 
abuse potential signals with the patient or their caregiver.  These are either AEs of 
interest that may be reported by the patient/caregiver, or drug accountability issues 
regarding overuse of the IMP or missing bottles.  Different questionnaires will be 
completed by the site depending upon which trigger occurs (see Figure 9-1).  
Irrespective of the above, all patients/caregivers will be interviewed at their final 
dosing visit (‘End of Treatment’/Withdrawal visit or ‘End of Taper Period’ visit, as 
applicable) and a Study Medication Use and Behavior Survey will be completed by 
the Investigator or study coordinator.  Investigators and study coordinators will be 
provided with training on how to complete and perform the processes outlined in this 
section.  This training must be completed and documented by the relevant site staff 
prior to implementation at site. 
9.1.15.1 
Monitoring of Adverse Events 
AE information will be collected according to Section 9.1.14. 
9.1.15.1.1 
List of ‘Triggering Adverse Events of Interest’ 
During the collection of AEs, if the patient reports an AE consistent with any of the 
following categories, then the Investigator or study coordinator is required to 
complete an additional Supplemental Adverse Event Form and a Site Classification 
Form (Investigator only) following further discussion of the event(s) with the patient 
or their caregiver.  The categories are: 
 Euphoria or inappropriate elation. 
 Inappropriate laughter or exhilaration. 
 Mood changes. 
 Drunk, high or intoxicated. 
 Hallucinations (visual or auditory), dissociations, disorientation, agitation. 
 Disturbance in cognition, memory, or attention. 
 Drug abuse. 
 Drug withdrawal or drug withdrawal syndrome. 


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 Addiction. 
 Overdose. 
 Misuse of IMP. 
 Thoughts of suicide, attempted suicide or suicide. 
An AE that is consistent with the above categories will be known as a ‘triggering AE 
of interest’ for the purposes of this study. 
9.1.15.1.2 
Supplemental Adverse Event Form 
This form consists of 15 questions regarding the AE and use of IMP.  It is completed 
as part of an interview with the patient/caregiver when a triggering AE of interest is 
reported.  It is important that this is completed by a trained Investigator or study 
coordinator with the patient/caregiver present.  The answers on the Supplemental 
Adverse Event Form will then be transcribed into the patient’s CRF for the study.  If 
the Supplemental Adverse Event Form cannot be completed at the time the triggering 
AE of interest is reported, then the site should contact the patient/caregiver to obtain 
the required answers as soon as possible. 
9.1.15.2 
Monitoring Drug Accountability Discrepancies 
Any time after enrollment until final collection of study data, drug accountability 
discrepancies are monitored as follows:  
 At routine Drug Accountability collection times: 
the site personnel will collect the IMP clinical supplies and make sure the 
usage is in line with the expectations. 
 At any time that the site is informed by either the IVRS or by the 
patient/caregiver about any overuse of IMP, suspected misuse, abuse, or 
diversion. 
9.1.15.2.1 
List of ‘Triggering Drug Accountability Discrepancies’ 
If there are any discrepancies in drug accountability as outlined by the criteria below, 
known as ‘triggering drug accountability discrepancies’, then the trained Investigator 
or study coordinator will complete a Supplemental Drug Accountability Form and 
Site Classification Form (Investigator only) following further discussion of the 
event(s) with the patient/caregiver.  The triggering drug accountability discrepancies 
are as follows: 
 Missing bottle(s). 
 Compliance issues where one or more bottles are used compared to what was 
the expected use. 
 Returned IMP supply with evidence of tampering. 


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 Greater than the target daily dose. 
9.1.15.2.2 
Supplemental Drug Accountability Form 
This form consists of 8 questions regarding various aspects of drug accountability and 
patient usage.  It is completed as part of an interview with the patient/caregiver when 
a triggering drug accountability discrepancy is identified.  It is important that this is 
completed by a trained Investigator or study coordinator with the patient/caregiver 
present.  The answers on the Supplemental Drug Accountability Form will then be 
transcribed into the patient’s CRF for the study.  The accountability reporting 
procedures will still occur.  If the Supplemental Drug Accountability Form cannot be 
completed at the time the triggering drug accountability discrepancy is identified, then 
the site should contact the patient/caregiver by telephone to obtain the required 
answers as soon as possible.  (Note: IMP refers to GWP42003-P, not other 
concomitant medications). 
9.1.15.3 
Site Classification Form 
The Investigator should review the applicable Supplemental Adverse Event Form or 
Supplemental Drug Accountability Form, and then complete the Site Classification 
Form.  For each Supplemental Adverse Event Form or Supplemental Drug 
Accountability Form completed, there should be an associated Site Classification 
Form. 
The Site Classification Form requires the Investigator to assign the finding to an 
appropriate classification and then to also assign the possible relationship to the IMP.  
The Investigator is also required to indicate the level of the certainty of the 
classification.  The answers from the Site Classification Form will then be transcribed 
into the patient’s CRF for the study. 
9.1.15.4 
Study Medication Use and Behavior Survey 
This form consists of 18 questions regarding the use of the IMP.  The trained 
Investigator or study coordinator will complete this survey as an interview with the 
patient/caregiver at the final dosing visit (‘End of Treatment’/Withdrawal visit or 
‘End of Taper Period’ visit, as applicable).  The answers on the Study Medication Use 
and Behavior Survey will then be transcribed into the patient’s CRF for the study. 
The Study Medication Use and Behavior Survey will be completed for all patients 
12 years of age and older in the study and not only those that have reported a 
triggering AE or drug accountability discrepancy. 


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9.1.15.5 
Adjudication Committee: Assessment of Abuse Potential of 
GWP42003-P  
A formal Adjudication Committee will be appointed and assigned to this initiative to 
classify triggered cases.  The Adjudication Committee will meet on a periodic basis to 
review and assess all of the information collected on triggered cases. 
A detailed charter will be agreed, which will describe the roles, responsibilities and 
duties of the members of Adjudication Committee.  The Committee will review all of 
the information collected in the process and in the assessment of the abuse potential of 
GWP42003-P, such as:  
 All triggering AE information. 
 Supplemental Adverse Event Form (if applicable). 
 All triggering drug accountability discrepancies. 
 Supplemental Drug Accountability Form (if applicable). 
 Site Classification Form. 
 Study Medication Use and Behavioral Survey. 
 Additional information from site(s) as requested by the Committee. 
The Adjudication Committee will assess all of the information.  It will form a position 
on the classification of each event and will write a study-related report, detailing the 
conclusions and recommendations. 
The overall process is summarized in Figure 9-1. 


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Figure 9-1 
Flow Diagram for Identifying and Evaluating Clinical Trial 
Adverse Event Data Through Systematic Categorization, 
Tabulation and Analysis which can Illuminate an Abuse 
Potential Signal (for Patients 12 Years of Age and Older) 
 
 
 
9.2 
Study Procedures by Visit 
Patients and their parent(s)/legal representative will be invited to participate in the 
study and will be issued with the patient information and informed assent or the 
Stage 1 
Patients with ‘Triggering 
Adverse Events of Interest’ 
Patients with ‘Triggering Drug 
Accountability Discrepancy’ 
All 
patients 
When a Triggering Adverse Event 
of Interest is identified, a patient 
interview is conducted with the 
Supplemental Adverse Event 
Form and, if applicable, the 
Supplemental Drug 
Accountability Form. 
When a Triggering Drug 
Accountability discrepancy is 
identified, a patient interview is 
conducted with the Supplemental 
Drug Accountability Form and, 
if applicable, the Supplemental 
Adverse Event Form. 
Investigator completes a Site Classification Form after supplemental 
information is collected, drug accountability evaluated, and the patient 
evaluated.  One Site Classification Form is completed per Supplemental 
Adverse Event Form or Drug Accountability Form. 
Stage 2 
Stage 3 
Site completes Study Medication Use and Behavior Survey at end of dosing. 
Stage 4 
Adjudication Committee 
Evaluates all of the information collected (as detailed above in stages 1–4) in the 
assessment of the abuse potential of GWP42003-P and completes a report. 
 Committee submits a report to GW. 
Stage 5 


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patient/parent(s)/legal representative information and informed consent (as 
applicable).  Following adequate time to discuss the study with the Investigator, 
nurse, relatives or caregiver, patients/parent(s)/legal representatives who provide 
written informed consent/assent at Visit 1 will be enrolled into the study. 
9.2.1 
Visit 1 (Day 1) 
Every effort should be made for this visit to take place on the same day as the ‘End of 
Treatment’ visit or up to 7 (+ 3) days after the ‘End of Treatment’ visit of the Core 
Study.  If this is not possible then patients can still enter the OLE study by passing the 
screening procedures at Visit 1.  All patients will be instructed to begin titration of 
OLE IMP in the evening of Visit 1 (Day 1) (APPENDIX 4).  Patients with no gap in 
IMP dosing between the Core Study and the OLE (including tapered dose) will take 
their final dose of Core Study IMP in the morning of Visit 1. 
Any OLE procedures that were not assessed during the Core Study should first be 
assessed at Visit 1, with the exception of the cognitive assessment battery. 
For patients enrolling immediately from the Core Study into the OLE (same 
day): The following data collected at the ‘End of Treatment’ visit of the Core Study 
will also be considered as Visit 1 data: vital signs, physical examination (including 
height and body weight), details of menstruation (for females), Tanner Staging (for 
patients aged 10–17 [inclusive], or earlier if clinically indicated by onset of menarche 
or other signs of precocious puberty), ECG, clinical laboratory samples (including 
serum IGF-1 levels [patients less than 18 years of age] and pregnancy test [if 
appropriate]), IVRS and paper diary information from the previous study (including 
information regarding seizures, AEs, usage of rescue medication, concomitant AEDs, 
IMP dosing), epilepsy-related hospitalizations, concomitant medications and/or 
changes to medication, C-SSRS, QOLCE/QOLIE, Vineland-II, cognitive assessment 
battery (participating centers only), S/CGIC and S/CGICSD.  A pregnancy test (if 
appropriate) must be conducted using a urine dipstick to confirm eligibility. 
Hepatic function must be confirmed before OLE dosing commences.  In order to 
confirm normal hepatic function, an additional blood sample must be taken to analyze 
ALT, AST, TBL and INR at a local laboratory. 
For patients enrolling from the taper period of the Core Study (1–7 [+ 3] days 
post ‘End of Treatment’ visit): At Visit 1, patients should have their Core Study 
‘End of Taper Period’ assessments made.  These data, along with all other data 
collected at the ‘End of Treatment’ visit of the Core Study, will also be considered as 
Visit 1 data.  A pregnancy test (if appropriate) must be conducted using a urine 
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Hepatic function must be confirmed before OLE dosing commences.  In order to 
confirm normal hepatic function, an additional blood sample may be taken to analyze 
ALT, AST, TBL and INR at a local laboratory. 
For patients with any gap in IMP dosing between the Core Study and the OLE: 
At Visit 1, all aforementioned procedures must be re-assessed, with the exception of 
the cognitive assessment battery.  A pregnancy test (if appropriate) must be conducted 
using a urine dipstick to confirm eligibility. 
Eligibility will be assessed according to the entry criteria, as specified in Section 6.  
Hepatic function must be confirmed before OLE dosing commences.  In order to 
confirm normal hepatic function an additional blood sample must be taken to analyze 
ALT, AST, TBL and INR at a local laboratory. 
Eligible patients or their caregivers will receive sufficient IMP for 2 weeks’ home 
dosing together with a titration schedule provided via the IVRS.  If an unacceptable 
AE develops at any time during titration, dosing should initially be suspended or 
amended, at the Investigator’s discretion, until the event has resolved or is well 
tolerated.  It is advised that the Investigator considers monitoring hepatic function 
(ALT, AST, TBL and INR levels) during the titration period for patients taking AEDs 
that are known to be associated with hepatic injury or failure.  To minimize any 
elevations in hepatic function markers the titration period can be extended and the 
dosage of a concomitant AED and/or GWP42003-P may be adjusted at the discretion 
of the Investigator.  If there is intolerance during titration, the patient may be 
maintained on a dose below 10–20 mg/kg/day.  A titration rate faster than 
recommended may be considered if there is an increase in seizures, following 
consultation with the GW medical monitor. 
Patients or their caregivers will be given a paper diary to record information regarding 
AEs, IMP, usage of rescue medication, concomitant AEDs and amount of IMP intake 
during the time they are on treatment.  In addition, patients/caregivers will be 
instructed to complete a weekly seizure reporting diary until the ‘End of 
Treatment’/Withdrawal visit using the IVRS. 
The Investigator should review the laboratory results as soon as these become 
available.  If the results raise any safety concerns, the Investigator should consider 
whether it will be appropriate for the patient to continue to participate in the extension 
study, or if the patient should be withdrawn. 


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In order to complete the S/CGIC, the patient/caregiver is to compare to the memory 
aid from the Baseline of the Core Study.  If the memory aid is not available from the 
Baseline of the Core Study then the patient/caregiver should do this from memory, if 
possible, and complete a memory aid at Visit 1. 
In order to complete the S/CGICSD, the patient/caregiver would have been asked to 
assess and note the average duration of the patient’s seizures at the Baseline of the 
Core Study as a memory aid for subsequent visits.  If the memory aid is not available 
from the Baseline of the Core Study then the patient/caregiver should do this from 
memory, if possible, and complete a memory aid at Visit 1. 
9.2.2 
Visit 2 (Day 15) 
Visit 2 will take place 14 days after Visit 1.  A visit window of ± 3 days from the 
scheduled visit date is permitted, but it is preferred that the visit is performed on the 
scheduled visit day where possible. 
The following assessments will be made at Visit 2: vital signs, physical examination 
(including height and body weight) and ECG.  Clinical laboratory samples (blood and 
urine [where possible]) will be taken for hematology, biochemistry and urinalysis.  
The patient’s IVRS report and paper diary will be reviewed and the information 
recorded along with information regarding AEs, IMP, epilepsy-related 
hospitalizations, concomitant medications and/or changes to medication.  The 
Investigator must assess adherence to the titration regimen. 
All IMP (used and unused) will be collected and a check of the returned IMP against 
usage should be made.  Patients/caregivers will then receive a 2-week supply of IMP. 
During titration of doses above 20 mg/kg/day, safety telephone calls must be made 
every 7 days (± 3 days) until stable dosing is achieved.  During these calls, caregivers 
will be asked for information on AEs, epilepsy-related hospitalizations, concomitant 
medications and/or changes to medication. 
9.2.3 
Visit 3 (Day 29) 
Visit 3 will take place 14 days after Visit 2 (28 days after Visit 1).  A visit window of 
± 3 days from the scheduled visit date is permitted, but it is preferred that the visit is 
performed on the scheduled visit day where possible. 
The following assessments will be made at Visit 3: vital signs, physical examination 
(including height and body weight) and ECG.  Clinical laboratory samples (blood and 
urine [where possible]) will be taken for hematology, biochemistry and urinalysis.  
The patient’s IVRS report and paper diary will be reviewed and the information 


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recorded along with information regarding AEs, IMP, epilepsy-related 
hospitalizations, concomitant medications and/or changes to medication.  The 
Investigator must assess adherence to the dosing regimen. 
All IMP (used and unused) will be collected and a check of the returned IMP against 
usage should be made.  Patients/caregivers will then receive an 8-week supply of 
IMP. 
A safety telephone call must be made 4 weeks (± 7 days) after Visit 3.  In addition, 
during titration of doses above 20 mg/kg/day, safety telephone calls must be made 
every 7 days (± 3 days) until stable dosing is achieved.  During these calls, caregivers 
will be asked for information on AEs, epilepsy-related hospitalizations, concomitant 
medications and/or changes to medication. 
9.2.4 
Visit 4 (Day 85) 
Visit 4 will take place 8 weeks after Visit 3 (84 days after Visit 1).  A visit window of 
± 3 days from the scheduled visit date is permitted, but it is preferred that the visit is 
performed on the scheduled visit day where possible. 
The following assessments will be made at Visit 4: vital signs, physical examination 
(including height and body weight) and ECG.  Clinical laboratory samples (blood and 
urine [where possible]) will be taken for hematology, biochemistry and urinalysis.  
The patient’s IVRS report and paper diary will be reviewed and the information 
recorded along with information regarding AEs, IMP, epilepsy-related 
hospitalizations, concomitant medications and/or changes to medication.  The 
Investigator must assess adherence to the dosing regimen. 
All IMP (used and unused) will be collected and a check of the returned IMP against 
usage should be made.  Patients/caregivers will then receive a 12-week supply of 
IMP. 
Following Visit 4, safety telephone calls must be made every 4 weeks (± 7 days).  In 
addition, during titration of doses above 20 mg/kg/day, safety telephone calls must be 
made every 7 days (± 3 days) until stable dosing is achieved.  During these calls, 
caregivers will be asked for information on AEs, epilepsy-related hospitalizations, 
concomitant medications and/or changes to medication. 
9.2.5 
Visit 5 and 6 (24-36 weeks)   
Visit 5 will take place 12 weeks after Visit 4 (24 weeks after Visit 1).  Visit 6 will 
then take place 12 weeks later (36 weeks after Visit 1).  A visit window of ± 7 days 


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from the scheduled visit dates is permitted, but it is preferred that the visit is 
performed on the scheduled visit day where possible. 
The following assessments will be made at visits 5 and 6: vital signs, physical 
examination (including height and body weight) and ECG, C-SSRS, Vineland-II, 
QOLCE/QOLIE, S/CGIC and S/CGICSD.  Clinical laboratory samples (urine [where 
possible] and blood) will be taken for hematology, biochemistry and urinalysis.  The 
patient’s IVRS report and paper diary will be reviewed and the information recorded 
along with information regarding AEs, IMP, epilepsy-related hospitalizations, 
concomitant medications and/or changes to medication.  The Investigator must assess 
adherence to the dosing regimen. 
All IMP (used and unused) will be collected and a check of the returned IMP against 
usage should be made. 
Patients/caregivers will then receive a 12-week supply of IMP at Visits 5 and 6. 
Following Visits 5 and 6, safety telephone calls must be made every 4 weeks 
(± 7 days) to assess AEs, epilepsy-related hospitalizations, concomitant medications 
and/or changes to medication.  In addition, during titration of doses above 
20 mg/kg/day, safety telephone calls must be made every 7 days (± 3 days) until 
stable dosing is achieved.  
9.2.6 
Visit 7 (48 weeks)  
Visit 7 will take place 12 weeks after Visit 6 (48 weeks after Visit 1).  A visit window 
of ± 7 days from the scheduled visit date is permitted, but it is preferred that the visit 
is performed on the scheduled visit day where possible. 
The following assessments will be made: vital signs, physical examination (including 
height and body weight), effects on menstruation cycles (for females), Tanner Staging 
(for patients aged 10–17 [inclusive], or earlier if clinically indicated by onset of 
menarche or other signs of precocious puberty), ECG, C-SSRS, Vineland-II, cognitive 
assessment battery (participating centers only), QOLCE/QOLIE, S/CGIC and 
S/CGICSD.  Clinical laboratory samples (urine [where possible] and blood) will be 
taken for determination of serum IGF-1 levels (for patients less than 18 years of age), 
pregnancy (if appropriate, using a serum sample), hematology, biochemistry and 
urinalysis.  The patient’s IVRS report and paper diary will be reviewed and the 
information recorded along with information regarding AEs, IMP, epilepsy-related 
hospitalizations, concomitant medications and/or changes to medication.  The 
Investigator must assess adherence to the dosing regimen. 


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The cognitive assessment battery will only be administered at a sub-group of centers 
that have the expertise to conduct the assessments (ideally before any other study 
procedures but can be completed on a separate day, if necessary, within 3 days of the 
visit) and will only be administered to patients who underwent cognitive testing 
during their Core Study. 
A 14-week supply of IMP will be issued to the patient/caregiver. 
Following Visit 7, safety telephone calls must be made every 4 weeks (± 7 days) to 
assess AEs, epilepsy-related hospitalizations, concomitant medications and/or 
changes to medication.  In addition, during titration of doses above 20 mg/kg/day, 
safety telephone calls must be made every 7 days (± 3 days) until stable dosing is 
achieved. 
At least 1 dispensing appointment will be scheduled to occur between Visits 7 and 8.  
The dispensing appointment date(s) will be calculated from Visit 7.  At each 
dispensing appointment caregivers will be dispensed with sufficient IMP to be 
administered until the next scheduled appointment.  Patients need not attend the 
dispensing appointments. 
9.2.7 
Visit 8 (76 weeks) 
Visit 8 will take place 28 weeks after Visit 7 (76 weeks after Visit 1).  A visit window 
of ± 7 days from the scheduled visit date is permitted, but it is preferred that the visit 
is performed on the scheduled visit day where possible. 
The following assessments will be made: vital signs, physical examination (including 
height and body weight), ECG, C-SSRS, Vineland-II, QOLCE/QOLIE, S/CGIC and 
S/CGICSD.  Clinical laboratory samples (urine [where possible] and blood) will be 
taken for hematology, biochemistry and urinalysis.  The patient’s IVRS report and 
paper diary will be reviewed and the information recorded along with information 
regarding AEs, IMP, epilepsy-related hospitalizations, concomitant medications 
and/or changes to medication.  The Investigator must assess adherence to the dosing 
regimen. 
A 14-week supply of IMP will be issued to the patient/caregiver. 
Following Visit 8, safety telephone calls must be made every 4 weeks (± 7 days) to 
assess AEs, epilepsy-related hospitalizations, concomitant medications and/or 
changes to medication.  In addition, during titration of doses above 20 mg/kg/day, 
safety telephone calls must be made every 7 days (± 3 days) until stable dosing is 
achieved. 


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At least 1 dispensing appointment will be scheduled to occur between Visit 8 and 
Visit 9.  The dispensing appointment date(s) will be calculated from Visit 8.  At each 
dispensing appointment caregivers will be dispensed with sufficient IMP to be 
administered until the next scheduled appointment.  Patients need not attend the 
dispensing appointments. 
9.2.8 
Visit 9 (104 weeks) 
Visit 9 will take place 28 weeks after Visit 8 (104 weeks after Visit 1).  A visit 
window of ± 7 days from the scheduled visit date is permitted, but it is preferred that 
the visit is performed on the scheduled visit day where possible. 
The following assessments will be made: vital signs, physical examination (including 
height and body weight), effects on menstruation cycles (for females), Tanner Staging 
(for patients aged 10–17 [inclusive], or earlier if clinically indicated by onset of 
menarche or other signs of precocious puberty), ECG, C-SSRS, Vineland-II, cognitive 
assessment battery (participating centers only), QOLCE/QOLIE, S/CGIC and 
S/CGICSD.  Clinical laboratory samples (urine [where possible] and blood) will be 
taken for determination of serum IGF-1 levels (for patients less than 18 years of age), 
pregnancy (if appropriate, using a serum sample), hematology, biochemistry and 
urinalysis.  The patient’s IVRS report and paper diary will be reviewed and the 
information recorded along with information regarding AEs, IMP, epilepsy-related 
hospitalizations, concomitant medications and/or changes to medication.  The 
Investigator must assess adherence to the dosing regimen. 
The cognitive assessment battery will only be administered at a sub-group of centers 
that have the expertise to conduct the assessments (ideally before any other study 
procedures but can be completed on a separate day, if necessary, within 3 days of the 
visit) and will only be administered to patients who underwent cognitive testing 
during their Core Study. 
A 14-week supply of IMP will be issued to the patient/caregiver. 
Following Visit 9, safety telephone calls must be made every 4 weeks (± 7 days) to 
assess AEs, epilepsy-related hospitalizations, concomitant medications and/or 
changes to medication.  In addition, during titration of doses above 20 mg/kg/day, 
safety telephone calls must be made every 7 days (± 3 days) until stable dosing is 
achieved. 
At least 1 dispensing appointment will be scheduled to occur between Visits 9 and 10.  
The dispensing appointment date(s) will be calculated from Visit 9.  At each 
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administered until the next scheduled appointment.  Patients need not attend the 
dispensing appointments. 
9.2.9 
Visit 10 (132 weeks) 
Visit 10 will take place 28 weeks after Visit 9 (132 weeks after Visit 1).  A visit 
window of ± 7 days from the scheduled visit date is permitted, but it is preferred that 
the visit is performed on the scheduled visit day where possible. 
The following assessments will be made: vital signs, physical examination (including 
height and body weight), ECG, C-SSRS, Vineland-II, QOLCE/QOLIE, S/CGIC and 
S/CGICSD.  Clinical laboratory samples (urine [where possible] and blood) will be 
taken for hematology, biochemistry and urinalysis.  The patient’s IVRS report and 
paper diary will be reviewed and the information recorded along with information 
regarding AEs, IMP, epilepsy-related hospitalizations, concomitant medications 
and/or changes to medication.  The Investigator must assess adherence to the dosing 
regimen. 
A 14-week supply of IMP will be issued to the patient/caregiver. 
Following Visit 10, safety telephone calls must be made every 4 weeks (± 7 days) to 
assess AEs, epilepsy-related hospitalizations, concomitant medications and/or 
changes to medication.  In addition, during titration of doses above 20 mg/kg/day, 
safety telephone calls must be made every 7 days (± 3 days) until stable dosing is 
achieved. 
At least 1 dispensing appointment will be scheduled to occur between Visit 10 and 
‘End of Treatment’ visit.  The dispensing appointment date(s) will be calculated from 
Visit 10.  At each dispensing appointment caregivers will be dispensed with sufficient 
IMP to be administered until the next scheduled appointment.  Patients need not 
attend the dispensing appointments. 
9.2.10 
Visit 11 (156 weeks) 
Visit 11 will take place 24 weeks after Visit 10 (156 weeks after Visit 1).  A visit 
window of ± 7 days from the scheduled visit date is permitted, but it is preferred that 
the visit is performed on the scheduled visit day where possible. 
The following assessments will be made: vital signs, physical examination (including 
height and body weight), effects on menstruation cycles (for females), Tanner Staging 
(for patients aged 10–17 [inclusive], or earlier if clinically indicated by onset of 
menarche or other signs of precocious puberty), ECG, C-SSRS, Vineland-II, cognitive 
assessment battery (participating centers only), QOLCE/QOLIE, S/CGIC and 


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S/CGICSD.  Clinical laboratory samples (urine [where possible] and blood) will be 
taken for determination of serum IGF-1 levels (for patients less than 18 years of age), 
pregnancy (if appropriate, using a serum sample), hematology, biochemistry and 
urinalysis.  The patient’s IVRS report and paper diary will be reviewed and the 
information recorded along with information regarding AEs, IMP, epilepsy-related 
hospitalizations, concomitant medications and/or changes to medication.  The 
Investigator must assess adherence to the dosing regimen. 
The cognitive assessment battery will only be administered at a sub-group of centers 
that have the expertise to conduct the assessments (ideally before any other study 
procedures but can be completed on a separate day, if necessary, within 3 days of the 
visit) and will only be administered to patients who underwent cognitive testing 
during their Core Study. 
A 14-week supply of IMP will be issued to the patient/caregiver. 
Following Visit 11, safety telephone calls must be made every 4 weeks (± 7 days) to 
assess AEs, epilepsy-related hospitalizations, concomitant medications and/or 
changes to medication.  In addition, during titration of doses above 20 mg/kg/day, 
safety telephone calls must be made every 7 days (± 3 days) until stable dosing is 
achieved. 
At least 1 dispensing appointment will be scheduled to occur between Visits 11 and 
12.  The dispensing appointment date(s) will be calculated from Visit 11.  At each 
dispensing appointment caregivers will be dispensed with sufficient IMP to be 
administered until the next scheduled appointment.  Patients need not attend the 
dispensing appointments. 
9.2.11 
Visit 12 (184 weeks) 
Visit 12 will take place 28 weeks after Visit 11 (184 weeks after Visit 1).  A visit 
window of ± 7 days from the scheduled visit date is permitted, but it is preferred that 
the visit is performed on the scheduled visit day where possible. 
The following assessments will be made: vital signs, physical examination (including 
height and body weight), ECG, C-SSRS, Vineland-II, QOLCE/QOLIE, S/CGIC and 
S/CGICSD.  Clinical laboratory samples (urine [where possible] and blood) will be 
taken for hematology, biochemistry and urinalysis.  The patient’s IVRS report and 
paper diary will be reviewed and the information recorded along with information 
regarding AEs, IMP, epilepsy-related hospitalizations, concomitant medications 
and/or changes to medication.  The Investigator must assess adherence to the dosing 
regimen. 


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A 14-week supply of IMP will be issued to the patient/caregiver. 
Following Visit 12, safety telephone calls must be made every 4 weeks (± 7 days) to 
assess AEs, epilepsy-related hospitalizations, concomitant medications and/or 
changes to medication.  In addition, during titration of doses above 20 mg/kg/day, 
safety telephone calls must be made every 7 days (± 3 days) until stable dosing is 
achieved. 
At least 1 dispensing appointment will be scheduled to occur between Visit 12 and 
‘End of Treatment’ visit.  The dispensing appointment date(s) will be calculated from 
Visit 12.  At each dispensing appointment caregivers will be dispensed with sufficient 
IMP to be administered until the next scheduled appointment.  Patients need not 
attend the dispensing appointments. 
9.2.12 
End of Treatment/Withdrawal Visit 
This visit will take place after a maximum of 4 years’ (208 weeks after Visit 1) 
treatment (as detailed below), or following early withdrawal from the study.  
 A patient with at least 2 years’ participation in the OLE (≥ 104 weeks after 
Visit 1) will complete the OLE phase when GWP42003-P is approved in their 
indication and is commercially available.  Patients will complete an 
unscheduled ‘End of Treatment’ visit to transition from OLE to commercial 
product.  The timing will vary per patient and is projected to begin in February 
2019. 
 A patient with less than 2 years’ participation in the OLE when GWP42003-P 
is approved in their indication and is commercially available will continue the 
OLE phase until reaching a maximum of 2 years’ OLE treatment, at which 
point an unscheduled ‘End of Treatment’ visit will be conducted.  The 
unscheduled ‘End of Treatment’ visit will be conducted no earlier than 
730 days after Visit 1. 
 Patients who do not continue treatment with GWP42003-P will be scheduled 
for an ‘End of Taper’ visit.  
The following assessments will be made at the ‘End of Treatment’/Withdrawal visit: 
vital signs, physical examination (including height and body weight), effects on 
menstruation cycles (for females), Tanner Staging (for patients aged 10–17 
[inclusive], or earlier if clinically indicated by onset of menarche or other signs of 
precocious puberty), ECG, C-SSRS, Vineland-II, cognitive assessment battery 
(participating centers only), QOLCE/QOLIE, S/CGIC and S/CGICSD.  Clinical 
laboratory samples (blood and urine [where possible]) will be taken for determination 
of serum IGF-1 levels (for patients less than 18 years of age), hematology, 


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biochemistry, a pregnancy test (if appropriate, using a serum sample) and urinalysis.  
The patient’s IVRS report and paper diary will be reviewed and the information 
recorded along with information regarding AEs, IMP, epilepsy-related 
hospitalizations, concomitant medications and/or changes to medication.  The 
Investigator must assess adherence to the dosing regimen. 
The cognitive assessment battery items will only be administered at a sub-group of 
centers that have the expertise to conduct the assessments (ideally before any other 
study procedures but can be completed on a separate day, if necessary, within 3 days 
of the visit) and will only be administered to patients who underwent cognitive testing 
during their Core Study. 
All IMP (used and unused) will be collected and a check of the returned IMP against 
usage should be made.  For patients who withdraw early or who do not transition to 
commercial product, the IVRS will be contacted to confirm withdrawal from the 
study.  For patients who immediately continue to use GWP42003-P following the 
‘End of Treatment’ visit, the IVRS will be contacted to confirm the patient’s 
completion of this study and the paper diaries will be collected.  For patients 12 years 
of age and older, the trained Investigator or study coordinator will complete the Study 
Medication Use and Behavior Survey as an interview with the patient/caregiver. 
For patients who do not immediately continue to use GWP42003-P following the 
‘End of Treatment’ visit, IMP will be down-titrated at home (10% per day for 
10 days).  Additional IMP will be dispensed, if required.  Patients who withdraw early 
should also begin the taper period following the Withdrawal visit (unless continued 
dosing is not possible due to an AE).  The IVRS will generate the patient’s daily IMP 
dosing volumes for the 10-day taper period, during which time diary information will 
continue to be recorded in the paper diary. 
Following the ‘End of Treatment’/Withdrawal visit, the IVRS seizure reporting diary 
should only be completed on the day before the ‘End of Taper Period’ visit and on the 
day before the Follow-up visit. 
9.2.13 
End of Taper Period Visit 
This visit will take place 10 (+ 3) days after the ‘End of Treatment’ visit or 
Withdrawal visit for patients who withdraw early or who do not transition to 
commercial product.  For patients who begin to taper IMP but subsequently 
withdraw/do not complete the full taper period, this visit should occur on the final day 
of dosing or as soon as possible after this date. 


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The following assessments will be made: vital signs, physical examination (including 
height and body weight), CWS/PCWS and C-SSRS.  In addition, the following 
assessments will be made for patients who do not transition to commercial product or 
withdraw early and taper IMP (including withdrawal during the taper period): ECG 
and clinical laboratory samples (blood and urine for hematology, biochemistry and 
urinalysis).  The patient’s IVRS report and paper diary will be reviewed and the 
information recorded along with information regarding AEs, IMP, epilepsy-related 
hospitalizations, concomitant medications and/or changes to medication.  The 
Investigator must assess adherence to the dosing regimen. 
All IMP (used and unused) will be collected and a check of the returned IMP against 
usage should be made.  For patients 12 years of age and older, the trained Investigator 
or study coordinator will complete the Study Medication Use and Behavior Survey as 
an interview with the patient/caregiver. 
Following the ‘End of Taper Period’ visit (or date of final dosing), the IVRS seizure 
reporting diary should only be completed on the day before the Follow-up visit. 
9.2.14 
Post-Taper Safety Telephone Call 
A safety telephone call must be made 2 weeks (± 3 days) after the ‘End of Taper 
Period’ visit or date of final dosing.  Patients or their caregivers will be asked for 
information on AEs, epilepsy-related hospitalizations, concomitant medications 
and/or changes to medication.  The CWS/PCWS will be administered as well. 
Following this call, the IVRS seizure reporting diary should only be completed on the 
day before the Follow-up visit. 
9.2.15 
Follow-up Visit 
This visit is required for patients who withdraw from the study or complete treatment 
but do not wish to continue to use GWP42003-P.  The Follow-up visit will be 
performed 4 weeks (+ 3 days) after the patient’s last dose of GWP42003-P (including 
final taper period dose) and can be conducted over the telephone.  During this 
visit/call, caregivers will be asked for information on AEs, epilepsy-related 
hospitalizations, concomitant medications and/or changes to medication.  The 
CWS/PCWS will also be administered. 
9.2.16 
Safety Telephone Calls 
From Visit 3 until the ‘End of Treatment’ visit, safety telephone calls must be made 
every 4 weeks (± 7 days).  In addition, during titration of doses above 20 mg/kg/day, 
safety telephone calls must be made every 7 days (± 3 days) until stable dosing is 


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achieved.  All safety telephone calls will assess AEs, epilepsy-related hospitalizations, 
concomitant medications and/or changes to medication. 
A post-taper safety telephone call must also be made (see Section 9.2.14). 
10 
WITHDRAWAL 
In accordance with the Declaration of Helsinki73, the FDA regulations relating to 
good clinical practice (GCP) and clinical trials74,75,76, the EU Clinical Trials Directive 
2001/20/EC77 and/or other applicable regulations, a patient has the right to withdraw 
from the study at any time and for any reason without prejudice to his or her future 
medical care by the physician or at the institution. 
The patient must be withdrawn from the study if any of the following apply: 
 Administrative decision by the Investigator, GW, or a Regulatory Authority. 
 Pregnancy. 
 Protocol deviation that is considered to potentially compromise the safety of 
the patient. 
 Withdrawal of patient consent/assent. 
 Withdrawal of parent(s)/legal representative consent. 
 Lost to follow-up. 
 ALT or AST > 3  ULN and (TBL > 2  ULN or INR > 1.5).  
 ALT or AST > 3  ULN with the appearance 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 more than 2 weeks. 
Note: Prior to withdrawal for the transaminase elevations noted above, the 
Investigator may choose to confirm the transaminase elevations by repeating the 
following laboratory tests within 24 to 48 hours: ALT, AST, TBL, INR, 
% eosinophils, gamma glutamyl transferase and alkaline phosphatase.  Should the 
above transaminase elevation criteria be confirmed, the patient must be 
withdrawn from the trial. 
Patients may also be withdrawn from the study for any of the following: 
 Patient non-compliance. 
 AE which, in the opinion of the Investigator, would compromise the continued 
safe participation of the patient in the study. 
 Any evidence of drug abuse or diversion. 
 Suicidal ideation or behavior of type 4 or 5 during the treatment period, as 
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Should a patient request or decide to withdraw from the study, all efforts must be 
made to complete and report the observations as thoroughly as possible up to the date 
of withdrawal.  Patients who withdraw should have their dose of IMP tapered 
gradually (10% each day) over a period of 10 days, beginning at the time the decision 
is made to discontinue.  In some cases, tapering the dose of IMP may be inadvisable 
(e.g., continued dosing is not possible due to an AE).  The decision on whether or not 
to taper IMP will be left to the Investigator’s clinical judgment.  All assessments 
required at the ‘End of Treatment’/Withdrawal visit should be conducted if possible.  
If the tapered dose is administered, patients should continue to complete the IVRS and 
paper diary and return for the ‘End of Taper Period’ visit, if possible.  For patients 
who begin to taper IMP but subsequently withdraw, the ‘End of Taper Period’ 
assessments (including ECG and clinical laboratory sampling) should be conducted, if 
possible; this visit should occur on the final day of dosing or as soon as possible after 
this date.  Patients withdrawing due to an AE should be followed up according to 
Section 12.7 safety follow-up visit.  All information should be reported on the 
applicable CRF pages (refer to Section 9.1).  Wherever possible, the safety follow-up 
visit should take place 4 weeks from the date of the last dose of IMP (refer to 
Section 9.2.15). 
 
 
 
 


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


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12 
ADVERSE EVENT REPORTING 
12.1 
Definitions 
12.1.1 
Adverse Event 
For the purposes of this study an AE is defined as: 
Any new unfavorable/unintended signs/symptoms (including abnormal laboratory 
findings), or diagnosis or worsening of a pre-existing condition, which is present 
following enrollment (Visit 1) and the post treatment, safety Follow-up visit, which 
may or may not be considered to be related to the IMP.  Any event that is the result of 
a study procedure must be recorded as an AE. 
Surgical/Investigational procedures are not AEs.  The medical reason for the 
procedure is the AE.  Elective hospitalizations for pre-study existing conditions or 
elective procedures are not AEs.  The exception may be if the patient has an AE 
during hospitalization which prolongs their scheduled hospital stay in which case it 
would be considered a SAE (refer to Section 12.2). 
If reporting a fatal event, the SAE term should be the underlying cause of the death 
(e.g., disease or medical condition leading to death). 
12.1.2 
Investigator 
The term Investigator refers to the study principal Investigator (PI) or a formally 
delegated study physician. 
12.2 
Serious Adverse Events 
During clinical investigations, AEs may occur which, if suspected to be IMP-related, 
might be significant enough to lead to important changes in the way the IMP is 
developed (e.g., change in dose, population, monitoring need, consent/assent forms).  
This is particularly true for events that threaten life or function.  Such SAEs will be 
reported promptly to Regulatory/Competent Authorities, applicable IRB/ECs and 
Investigators (expedited reporting) by GW. 
An AE must only be classed as serious, i.e., a SAE, when the event falls into one of 
the following criteria: 
 Results in death. 
 Is life-threatening.* 
 Requires inpatient hospitalization or prolongation of existing hospitalization. 
 Results in persistent or significant disability/incapacity. 
 Is a congenital anomaly/birth defect. 


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 Medically significant.** 
* The term “life-threatening” in the definition of “serious” refers to an event in which 
the patient was at risk of death at the time of the event; it does not refer to an event, 
which hypothetically might have caused death if it were more severe. 
** Medical and scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations.  Important medical events may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the patient or may require intervention to prevent one of the other outcomes listed in 
the definition above.  These should also usually be considered serious.  Examples of 
such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; or 
development of drug dependency or drug abuse. 
12.3 
Reporting Procedures for Serious Adverse Events 
All SAEs occurring during the study must be reported to GW with any other 
supporting information and recorded in the AE section of the CRF.  Any on-going 
SAEs should be followed up until resolution wherever possible.  For all deaths, the 
working diagnosis or cause of death as stated on a death certificate, available autopsy 
reports and relevant medical reports should be sent to GW promptly. 
All SAEs must be reported directly to GW PVD within 24 hours of discovery or 
notification of the event.  All SAE information must be recorded on the SAE forms 
provided in the site files and faxed to GW PVD.  Additional information received for 
a case (follow-up or corrections to the original case) need to be detailed on a new 
SAE form, signed/dated and faxed to the GW PVD and the AE section of the CRF 
must be updated. 
The Investigator should continue to document all AEs which occur up to the last 
formal follow-up observational period (Follow-up visit).  If the Investigator 
subsequently becomes aware of any new IMP-related SAE after the last formal 
follow-up period of the study, these should still be reported to the GW PVD. 
Any other problem discovered outside these time limits which is deemed to be an 
unexpected safety issue and is likely to have an impact on patients who have 
participated in the study, then these should be treated as an SAE and reported to GW 
PVD.  Such post study SAEs do not need to be recorded on the patient’s CRF if 
editing rights to the CRF have been removed. 


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Contact details for the GW PVD are provided at the front of the site files for all study 
centers, and upon the GW SAE Report form. 
12.4 
Pregnancy 
Any patient, or patient’s partner, who has become pregnant whilst receiving IMP, or 
within 90 days of last dose of IMP, must be reported to the GW PVD within 24 hours 
of first awareness.  Please use the GW Pregnancy Monitoring Forms provided.  
Where possible the Investigator should provide the outcome of the pregnancy. 
The Investigator is not obliged to actively monitor for any pregnancies that commence 
more than 90 days after the final dose of IMP.  However, if the Investigator becomes 
aware of a new pregnancy outside this time limit then they should report it as above.  
GW PVD will follow up for all pregnancy outcomes. 
12.5 
Causality Assessment 
Causality assessment is required for all AEs and SAEs.  Causality assessment must 
only be assigned by the Investigator.  All cases judged as having a reasonable 
suspected causal relationship to the IMP must be reported as such.  The expression 
“reasonable causal relationship” is meant to convey in general that there are facts 
(evidence) or arguments to suggest a causal relationship. 
The following question which must be answered by the Investigator for all AEs is 
used to capture the reasonable causal relationship of an event to the IMP: 
“In your opinion is there a plausible relationship to the IMP?”  The answer is “yes”, 
or “no”. 
Where a pre-treatment event worsens in severity following the first dose of IMP a 
new event record should be entered into the CRF. 
Considering the explanation given above, Investigators are strongly encouraged to 
express their opinion on what the cause of an AE might be.  For individual patients, 
the Investigator is usually in the best position to assess the underlying suspected cause 
of an AE.  For all AEs and especially SAEs, it is important that the Investigator assess 
not only the possible role of the IMP but also competing etiological factors as the 
underlying cause.  Factors for consideration may include: 
 Medical and disease history. 
 Lack of efficacy/worsening of treated condition. 
 Concomitant or previous treatment. 
 Withdrawal of IMP. 
 Protocol-related procedure. 


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12.6 
Reporting Procedures for All Adverse Events 
All AEs (including SAEs) occurring during the study will be reported on the running 
logs in the AE section of the CRF.  This includes all events from the time following 
enrollment (Visit 1) to post study follow-up (Follow-up visit), whether or not 
attributed to IMP and observed by the Investigator or patient. 
For the patient’s expected seizure types, these do not routinely require documentation 
as AEs.  However, any worsening, including change in the pattern or severity of 
seizures must be documented as an AE.  Any AE which meets SAE criteria should 
still be reported as a SAE. 
The following information will need to be provided for all AEs: 
A) Adverse Event (Diagnosis or Syndrome if Known, or Signs and Symptoms) 
Where the Investigator cannot determine a diagnosis, signs or symptoms should be 
recorded on the AE section of the CRF.  Once a diagnosis has been determined the 
AE section of CRF must be updated to reflect the diagnosis in replacement of the 
original symptoms.  In circumstances, where only a provisional diagnosis is possible 
(working diagnosis), the CRF must be updated to reflect the provisional diagnosis in 
replacement of the original symptoms.  In some circumstances it may be relevant for 
the Investigator to include the symptoms alongside the diagnosis in the verbatim event 
description.  However, the diagnosis (full or provisional) should be clearly stated e.g., 
fever and malaise due to a respiratory tract infection. 
B) Adverse Event Start Date and Stop Date 
The start and stop dates of the event must be provided.  All AEs require these fields to 
be completed in full.  Partial dates or missing dates are not normally acceptable and 
significant effort must be undertaken to obtain any unknown information.  If a precise 
date is not known an estimated date should be provided instead.  When a complete 
date cannot be given then record as much information as possible (i.e., month and 
year or in exceptional circumstances just year).  When the actual start date becomes 
known the CRF must be updated to replace the previously recorded date. 
C) Outcome 
The outcome of the event must be recorded accurately and classified into one of the 
following categories: 
 Recovered. 
 Recovered with sequelae. 
 Continuing. 


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 Patient died. 
D) Severity 
When describing the severity of an AE the terms mild, moderate, or severe should be 
used.  Clinical judgment should be used when determining which severity applies to 
any AE. 
If the severity of an AE fluctuates day-to-day, for example, a headache or 
constipation, the change in severity should not be recorded each time, instead only the 
worst observed severity should be recorded with AE start and stop dates relating to 
the overall event duration regardless of severity. 
A severe AE is not the same as a SAE.  For example, a patient may have severe 
vomiting but the event does not result in any of the SAE criteria above.  Therefore it 
should not be classed as serious. 
E) Causality 
See Section 12.5 above. 
F) Action Taken with Study Medication 
This question refers to the action taken with the IMP due to an AE.  The action with 
the IMP must be classed as: 
 None. 
 Dose reduced temporarily. 
 Dose reduced. 
 Study medication interrupted. 
 Study medication stopped. 
12.7 
Follow-up Procedures for Adverse Events 
The Investigator may be asked to provide follow-up information to the GW PVD for 
any AEs reported. 
AEs considered related to the IMP by the Investigator or the Sponsor should be 
followed up until resolution or the event is considered stable. 
It will be left to the Investigator’s clinical judgment whether or not an AE is of 
sufficient severity to require the patient’s removal from treatment.  A patient may also 
voluntarily withdraw from treatment due to what he or she perceives as an intolerable 
AE, further details of withdrawal are presented in Section 10.  If either of these 
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appropriate care under medical supervision until symptoms cease or the condition 
becomes stable. 
12.8 
Potential Cases of Drug-Induced Liver Injury 
All investigational centers are required to submit to the GW PVD the laboratory 
results for any patient after randomization that meet the criteria for the selected 
laboratory parameters as follows:  
 ALT or AST > 3  ULN and (TBL > 2  ULN or INR > 1.5). 
 ALT or AST > 3  ULN with the appearance 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 more than 2 weeks. 
These reports must be sent to the GW PVD using the same fax number for SAE 
reporting within 24 hours of becoming aware of the results.  In addition, please send a 
copy of the patient’s baseline laboratory results with all reports to GW PVD. 
Abnormal values in AST and/or ALT concurrent with abnormal elevations in TBL 
that meet the criteria outlined above are considered potential cases of drug-induced 
liver injury and will be considered as protocol defined criteria for withdrawal and 
important medical events.  The Investigator will arrange for the patient to return to the 
investigational site as soon as possible (within 24-48 hours of notice of abnormal 
results) for repeat assessment of ALT, AST, TBL, alkaline phosphatase and gamma 
glutamyl transferase, detailed history and physical examination.  Patients should be 
followed in this way until all abnormalities have normalized (in the Investigator’s 
opinion) or returned to the baseline state; however, if the above transaminase 
elevation criteria are confirmed by the first set of follow-up laboratory tests, the 
patient must be withdrawn from the trial. 
Elevations in ALT or AST > 3 × ULN or TBL > 2 × ULN alone are not considered 
potential cases of drug-induced liver injury, but will be followed as detailed above, 
within 72 hours’ notice of abnormal results.  If the patient cannot return to the 
investigational site, repeat assessments may be done at a local laboratory and the 
results sent to GW PVD. 


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12.9 
Notification of Safety Information to Investigators, Regulatory 
Authorities and Ethics Committees 
In accordance with the EU Clinical Trials Directive77, relevant parts of the FDA Code 
of Federal Regulations78 and any national regulations, GW will inform Investigators, 
regulatory authorities and relevant IRB/ECs of all relevant safety information.  This 
will include the reporting of relevant SAEs and all Suspected Unexpected Serious 
Adverse Drug Reactions (SUSARs). 
This information will be provided through 3 sources: 
1) IB71: a compilation of the clinical and non-clinical safety data available on the 
IMP that is relevant to the study on the IMP in human patients.  The IB is 
updated annually. 
2) Development Core Safety Information: this document actually forms the 
Safety Section of the IB71, or is updated as an appendix of the IB71.  This 
document is revised if necessary, when new important safety information 
becomes available (potentially up to a few times a year). 
3) Council for International Organizations of Medical Sciences (CIOMS) reports: 
these reports are issued every time a SUSAR is reported to GW.  They provide 
information on individual case reports and are sent to all the regulatory 
authorities, the relevant central IRB/ECs which have approved the study and 
Investigators.  As required, the Investigator should notify their regional ECs of 
SAEs or SUSARs occurring at their site and other AE reports, i.e., CIOMS 
reports and any additional safety documentation received from GW, in 
accordance with local procedures. 
In the USA, Investigators are normally required to promptly report to their IRBs all 
unanticipated problems involving risks to human patients, or others, including AEs 
that should be considered unanticipated problems.  Based on current FDA guidance74 
the following clarification is provided in determining what constitutes an 
unanticipated problem: 
In general, an AE observed during the conduct of a study should be considered an 
unanticipated problem involving risk to human patients, and reported to the IRB, only 
if it were unexpected, serious, and would have implications for the conduct of the 
study (e.g., requiring a significant, and usually safety-related, change in the protocol 
such as revising inclusion/exclusion criteria or including a new monitoring 
requirement, informed consent/assent, or IB).  An individual AE occurrence 
ordinarily does not meet these criteria because, as an isolated event, its implications 
for the study cannot be understood. 
The FDA guidance78 states that, accordingly, to satisfy the Investigator’s obligation to 
notify the IRB of unanticipated problems, any Investigators participating in a 


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multicenter study may rely on the Sponsor’s assessment and provide to the IRB a 
report of the unanticipated problem prepared by the Sponsor. 
GW will inform Investigators (regulatory authorities and applicable IRB/ECs) of any 
safety issues or case reports that are considered to be unanticipated and provide such 
reports as mentioned above.  It should be noted that a single SUSAR report notified to 
Investigators in the study does not necessarily constitute an unanticipated problem 
unless identified by GW in the submission cover letter. 
As a minimum, the recipient will be sent all of the above and relevant updates 
between the period from ethical approval and final database lock. 
 
 
 


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13 
STATISTICAL CONSIDERATIONS 
A statistical analysis plan (SAP) will be produced prior to carrying out the database 
hard lock.  Any deviations from the original SAP will be described in the final clinical 
study report. 
13.1 
Sample Size, Power and Significance Levels 
As this is an open label safety study, there is no formal sample size calculation.  All 
patients who wish to continue on IMP from the populations included in the 
double-blind Phase 2 and Phase 3 Core Studies in DS and LGS will be eligible for 
inclusion.  Approximately 680 patients will be enrolled. 
All data collected during this study will be summarized across time, using appropriate 
descriptive statistical methods.  There will be no formal hypothesis testing. 
13.2 
Interim Analysis 
At least one interim analysis will be conducted to support New Drug Application and 
Marketing Authorization Application filings.  Further interim analyses may be 
conducted as required. 
13.3 
Analysis Sets 
For this study, there will be only one analysis set: 
Safety 
All patients who receive at least one dose of IMP in the study will be included.  Only 
patients for whom it has been confirmed that they did not take any IMP will be 
excluded from this safety analysis set. 
13.3.1 
Protocol Deviations 
Protocol deviations will be listed and reasons for excluding any data from the analysis 
population will be summarized. 
13.4 
General Considerations 
Unless stated otherwise, continuous variables will be summarized showing the 
number of non-missing values (n), mean, standard deviation, median, minimum and 
maximum and categorical variables will be summarized showing the number and 
percentage of patients falling into each category.  Summaries will be presented overall 
as well as for the different etiologies (DS and LGS) separately. 


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13.5 
Accountability and Background Characteristics 
13.5.1 
Enrollment and Disposition 
All patients (screened, enrolled, prematurely terminated IMP) will be accounted for in 
the enrollment and disposition summary tables. 
13.5.2 
Baseline and Demographic Characteristics 
Age, sex, race (as allowed per local regulations) and any other demographic or 
baseline characteristics will be summarized, using appropriate summary statistics. 
13.5.3 
Medical History 
Previous and current medical conditions will be summarized by system organ class, 
including details of the duration of epilepsy, the types of seizures and seizure duration 
currently experienced by the patients. 
13.5.4 
Concomitant Medication 
Concomitant medications taken 2 weeks prior to and during the study will be 
summarized separately, by medication class and active ingredients. 
13.6 
Endpoints and Statistical Methods 
13.6.1 
Evaluable Period 
All data collected during this study will be summarized across time, using appropriate 
descriptive statistical methods.  Where baseline data are available from the Core 
Studies (such as seizure frequencies, quality of life assessments, Vineland-II, other 
measures of safety [such as vital signs, clinical laboratory samples]), changes from 
pre-randomization baseline of the Core Study will also be presented.  Treatment 
compliance and exposure to treatment will also be summarized. 
13.6.2 
Primary Endpoint(s) 
The primary endpoint is the AE profile and other safety assessments reported during 
the study. 
13.6.2.1 
Adverse Events 
AEs will be coded according to the Medical Dictionary for Regulatory Activities 
dictionary. 


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A treatment emergent AE is one that started, worsened in severity or seriousness, 
following the first dose of IMP in this study.  Any AEs that are continuing from the 
Core Study will be carried over into the OLE study and transcribed in the CRF, only 
becoming classified as treatment emergent if they worsen. 
Descriptive presentations of treatment emergent AEs will be given by preferred term 
and system organ class for the safety analysis set.  The number of patients reporting at 
least one AE will be provided. 
The following summaries will be produced: 
 Pre-existing AEs. 
 All-causality AEs. 
 Treatment related AEs. 
 All-causality AEs by severity. 
 All-causality serious AEs. 
 Treatment related serious AEs. 
 AEs reported as leading to permanent cessation of study treatment. 
 Fatal AEs. 
13.6.2.2 
Clinical Laboratory Data 
Clinical laboratory data from Central Laboratory obtained at baseline (Core Studies), 
screening (OLE Visit 1), during treatment and at the end of treatment and the change 
from baseline (Core Studies), during and at the end of treatment will be summarized 
for the safety analysis set using appropriate summary statistics.  Categorical shift 
tables will also be presented, showing the numbers of patients with values outside the 
normal range at each clinic visit. 
In order only to confirm normal hepatic function before OLE dosing commences, an 
additional blood sample may be taken at Visit 1 to analyze ALT, AST, TBL and INR 
at a local laboratory.  These data will only be used for eligibility determination. 
13.6.2.3 
Vital Signs, 12-lead Electrocardiogram, Physical 
Examination and Other Safety Data 
Vital signs, ECG and physical examination data will be summarized at baseline (Core 
Studies), screening (OLE Visit 1) and at each time point during the treatment period 
using appropriate summary statistics.  Changes in the vital signs from baseline (Core 
Studies) during and at the end of treatment will also be summarized.  Study 
Medication Use and Behavior Survey data will be summarized using appropriate 
summary statistics. 


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13.6.2.4 
Columbia-Suicide Severity Rating Scale Data 
C-SSRS data will be summarized at baseline (Core Studies), screening (OLE Visit 1) 
and at each time point during the treatment period (including the taper period) using 
appropriate summary statistics.  Changes from baseline (Core Studies) during and at 
the end of treatment will also be summarized. 
13.6.2.5 
Cannabis Withdrawal Scale and Pediatric Cannabinoid 
Withdrawal Scale Data 
CWS/PCWS data will be summarized at baseline (Core Studies), the OLE end of 
taper period, 2 weeks after the OLE end of taper period and at OLE follow-up using 
appropriate summary statistics.  Changes from baseline (Core Studies) following 
cessation of treatment will also be summarized. 
13.6.3 
Secondary Endpoint(s) 
All Patients: 
 Change in quality of life as measured with QOLCE if 18 years of age or 
younger, or QOLIE if 19 years of age or older, relative to the 
pre-randomization baseline of the Core Study, if assessed during the Core 
Study. 
 Change in S/CGIC, relative to the pre-randomization baseline of the Core 
Study. 
 Change in adaptive behavior as measured with the Vineland-II, relative to the 
pre-randomization baseline of the Core Study, if assessed during the Core 
Study. 
 Change in the number of inpatient epilepsy-related hospitalizations (number of 
hospitalizations due to epilepsy in each 28-day period), relative to the 
pre-randomization baseline of the Core Study. 
 Change in the use of rescue medication (number of days used in each 28-day 
period), relative to the pre-randomization baseline of the Core Study. 
 Maintenance of seizure frequency reduction and freedom from seizures during 
the OLE study. 
 Percentage change in the frequency of total seizures, relative to the 
pre-randomization baseline of the Core Study. 
 Number of patients considered treatment responders, defined as those with a 
≥ 25%, ≥ 50%, ≥ 75%, or 100% reduction in total seizures, relative to the 
pre-randomization baseline of the Core Study. 
 Number of patients experiencing a > 25% worsening, − 25 to + 25% no 
change, 25–50% improvement, 50–75% improvement or > 75% improvement 
in total seizures, relative to the pre-randomization baseline of the Core Study. 
 Percentage change in the frequencies of subtypes of seizures, relative to the 
pre-randomization baseline of the Core Study. 


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 Changes in duration of seizure subtypes as assessed by the S/CGICSD, 
relative to the pre-randomization baseline of the Core Study. 
 Change in the number of episodes of status epilepticus, relative to the 
pre-randomization baseline of the Core Study. 
 Change in cognitive function as measured with a cognitive assessment battery, 
relative to the pre-randomization baseline of the Core Study, if assessed during 
the Core Study. 
 Change in growth and development for patients less than 18 years of age by 
measurement of height, weight, IGF-1 levels and Tanner Staging (for patients 
aged 10–17 [inclusive], or earlier if clinically indicated by onset of menarche 
or other signs of precocious puberty), relative to the pre-randomization 
baseline of the Core Study. 
 Effects on menstruation cycles (in females). 
 Drug abuse liability, as measured by AEs of abuse potential, drug 
accountability and Study Medication Use and Behavior Survey in patients 
aged 12 and older. 
DS Patients Only: 
 Percentage change in total convulsive seizure frequency, relative to the 
pre-randomization baseline of the Core Study. 
 Percentage change in total non-convulsive seizure frequency, relative to the 
pre-randomization baseline of the Core Study. 
 Number of patients considered treatment responders, defined as those with a 
≥ 25%, ≥ 50%, ≥ 75%, or 100% reduction in convulsive seizures, relative to 
the pre-randomization baseline of the Core Study. 
 Number of patients experiencing a > 25% worsening, − 25 to + 25% no 
change, 25–50% improvement, 50–75% improvement or > 75% improvement 
in convulsive seizures, relative to the pre-randomization baseline of the Core 
Study. 
LGS Patients Only: 
 Percentage change in the number of drop seizures, relative to the 
pre-randomization baseline of the Core Study. 
 Percentage change in the number of non-drop seizures, relative to the 
pre-randomization baseline of the Core Study. 
 Number of patients considered treatment responders, defined as those with a 
≥ 25%, ≥ 50%, ≥ 75%, or 100% reduction in drop seizures, relative to the 
pre-randomization baseline of the Core Study. 
 Number of patients experiencing a > 25% worsening, − 25 to + 25% no 
change, 25–50% improvement, 50–75% improvement or > 75% improvement 
in drop seizures, relative to the pre-randomization baseline of the Core Study. 


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These will be summarized across time, using appropriate statistical methods.  
Descriptive statistical methods will be used throughout.  There will be no formal 
hypothesis testing. 
 
 
 


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14 
DATA SAFETY MONITORING COMMITTEE 
This study will not use a DSMC.  
 
 
 
 


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15 
REGULATORY AND ETHICAL OBLIGATIONS 
15.1 
Declaration of Helsinki 
The Investigator will ensure that this study is conducted in full conformity with the 
Declaration of Helsinki73, EU Clinical Trials Directive77 and the clinical trial 
regulations adopting European Commission Directives into national legislation79,80,81. 
15.2 
Informed Consent/Assent 
Initial master informed consent and assent forms will be provided to the Investigator 
to prepare the informed consent/assent documents to be used at his or her center.  The 
GW Clinical Manager will communicate updates to the template by letter.  The 
written informed consent/assent documents should be prepared in the language(s) of 
the potential patient population. 
Before a patient’s participation in the trial, the Investigator is responsible for 
obtaining written informed consent/assent from the patient and/or parent(s)/legal 
representative after adequate explanation of the aims, methods, anticipated benefits 
and potential hazards of the study and before any protocol specific screening 
procedures or any IMPs are administered.  The patient and parent(s)/legal 
representative should have ample time for review to consider the information 
provided before giving written consent/assent; more specific definitions of ample time 
may be in force if required by ECs/IRBs or local regulations. 
The acquisition of informed consent/assent should be documented in the patient’s 
medical records and the informed consent/assent forms should be signed and 
personally dated by the patient and/or parent(s)/legal representative (as applicable) 
and by the person who conducted the informed consent/assent discussion.  GW also 
requires a physician to be present for consent/assent and to sign the consent/assent 
forms as well.  The original signed informed consent/assent forms should be retained 
and a copy provided to the patient and/or parent(s)/legal representative. 
15.3 
Institutional Review Board/Ethics Committee 
A copy of the protocol, proposed informed consent/assent forms, other patient 
information material, any proposed advertising material and any further 
documentation requested must be submitted to the IRB/EC for written approval.  GW 
must receive a copy of the written approval of the protocol and informed 
consent/assent forms before enrollment of patients into the study and shipment of 
IMP. 


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The Investigator must submit and, where necessary, obtain approval from the IRB/EC 
for all subsequent protocol amendments and changes to the informed consent/assent 
documents.  The Investigator should notify the IRB/EC of deviations from the 
protocol or SAEs occurring at the center and other AE reports received from GW, in 
accordance with local procedures. 
The Investigator will be responsible for obtaining on-going IRB/EC approval/renewal 
throughout the duration of the study.  Copies of the Investigator’s reports and the 
IRB/EC continuance of approval must be sent to GW. 
15.4 
Pre-Study Documentation Requirements 
The Investigator is responsible for forwarding the following documents to GW for 
review before allowing any patients to consent/assent for entry into the study: 
 Signed and dated protocol signature page. 
 Copy of approved informed consent/assent forms and other patient 
information material. 
 Copy of the IRB/EC approval of the protocol, informed consent/assent forms 
and other patient information material. 
 Up to date curriculum vitae and medical licenses (as per local regulations) of 
the PI and all sub-Investigators. 
 The IRB/EC composition and/or written statement of the IRB/EC in 
compliance with the FDA regulations relating to GCP and clinical 
trials74,75,76,82, the EU Clinical Trials Directive77, or International Conference 
on Harmonization Tripartite Guideline for Good Clinical Practice (ICH 
GCP)83 where the EU Clinical Trials Directive does not apply. 
 Signed laboratory normal ranges and documentation of laboratory certification 
(or equivalent) unless using central laboratory arranged by GW. 
 Signed clinical trial agreement (including patient/Investigator indemnity 
insurance and financial agreement). 
 FDA 1572 form. 
 Completed financial disclosure statements for the PI and all sub-Investigators 
if relevant. 
15.5 
Patient Confidentiality 
The Investigator must ensure that the patient’s anonymity is maintained.  On the 
CRFs and within the databases used to collect the trial data or other documents 
submitted to GW, patients should be identified by their initials and race (if allowed 
per local regulations) and a patient study number only.  Documents that are not for 
submission to GW, e.g., signed informed consent/assent forms, should be kept in 
strict confidence by the Investigator. 


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In compliance with the FDA regulations relating to GCP and clinical trials74,75,76,82, 
and the EU Clinical Trials Directive77/ICH GCP Guidelines83, it is required that the 
Investigator and institution permit authorized representatives of the company, the 
regulatory agencies and the IRB/EC direct access to review the patient’s original 
medical records for verification of study-related procedures and data.  Direct access 
includes examining, analyzing, verifying and reproducing any records and reports that 
are important to the evaluation of the study.  The Investigator is obligated to inform 
the patient that his/her study-related records will be reviewed by the above named 
representatives without violating the confidentiality of the patient. 
All information concerning the IMP and operations of GW such as patent 
applications, formulae, manufacturing processes, basic scientific data or formulation 
information supplied to the Investigator by the company and not previously published 
is considered confidential by the company and shall remain the sole property of the 
company.  The Investigator will agree to use this information only in accomplishing 
the study and will not use it for any other purposes without the written consent of the 
company.  
 
 
 


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16 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
16.1 
Protocol Amendments and End of Study or Termination 
Protocol amendments must be made only with the prior approval of GW.  Agreement 
from the Investigator must be obtained for all protocol amendments and amendments 
to the informed consent/assent documents.  The IRB/EC must be informed of all 
amendments and give approval for any substantial amendments.  Amendments for 
administrational changes can be submitted to the IRB/EC for information only.  The 
Investigator must send a copy of the approval letter from the IRB/EC to GW. 
Both GW and the Investigator reserve the right to terminate the study, according to 
the clinical trial agreement.  The Investigator should notify the IRB/EC in writing of 
the study’s completion or early termination and send a copy of the notification to GW. 
16.2 
Study Documentation and Storage 
The Investigator should maintain a list of appropriately qualified persons to whom 
he/she has delegated study duties.  All persons authorized to make entries and/or 
corrections on CRFs will be included on the GW delegation of authority and signature 
form. 
Source documents are original documents, data and records from which the patient’s 
CRF data are obtained.  These include, but are not limited to, hospital records, clinical 
and office charts, laboratory and pharmacy records, diaries, electronic data captured 
by IVRS, microfiches, radiographs and correspondence.  CRF entries may be 
considered source data if the CRF is the site of the original recording, that is, there is 
no other written or electronic record of data.  A source data verification plan, 
identifying the source for each data point at each site, will be agreed with each site 
prior to patient recruitment.  In the rare situations of data being recorded directly into 
the CRF in error, then the source data from the CRF should be transcribed into the 
patient’s notes with appropriate signature and date to provide a full audit trail. 
The Investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related, essential documentation (as outlined in 
ICH E6 Section 8.283), suitable for inspection at any time by representatives from GW 
and/or applicable regulatory authorities.  Elements should include: 
 Patient files containing completed CRFs, informed consent/assent forms and 
supporting copies of source documentation. 
 Study files containing the protocol with all amendments, IB, copies of pre-
study documentation (see Section 15.4) and all correspondence to and from 
the IRB/EC and GW. 


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 Proof of receipt, IMP accountability record, return of IMP for destruction, 
final IMP reconciliation statement and all drug related correspondence. 
In addition, all original source documents supporting entries on the CRFs, diary data 
and electronic data captured by IVRS must be maintained and be readily available. 
Following completion or termination of a clinical study GW will initiate proper 
archive of clinical study-related documentation and electronic records generated by 
the Investigator and/or GW.  All clinical trial related documents and electronic 
records will be retained within an archiving system for a period dependent upon need 
and for a minimum of 20 years.  Essential documents should be retained until at least 
2 years after the last approval of a marketing application in an ICH region and until 
there are no pending or contemplated marketing applications in an ICH region or at 
least 2 years have elapsed since the formal discontinuation of clinical development of 
the IMP.  These documents should be retained for a longer period however if required 
by the applicable regulatory requirements or if needed by GW (EU Directive 
2005/28/EC Chapter 4 Trial Master File and Archiving Article 1684). 
GW will inform the Investigators for each center in writing of the need for record 
retention.  No study document should be destroyed without prior written agreement 
between GW and the Investigator.  Should the Investigator wish to assign the study 
records to another party or move them to another location, he/she must notify GW in 
writing of the new responsible person and/or the new location. 
16.3 
Study Monitoring and Data Collection 
The GW representative and regulatory authority inspectors are responsible for 
contacting and visiting the Investigator for the purpose of inspecting the facilities and, 
upon request, inspecting the various records of the study for example, CRFs and other 
pertinent data provided that patient confidentiality is respected. 
The GW study monitor, or designee, is responsible for inspecting the CRFs and 
available IVRS/diary data at regular intervals throughout the study to verify 
adherence to the protocol, completeness, accuracy and consistency of the data and 
adherence to local regulations on the conduct of clinical research.  The study monitor 
should have access to patient medical records and other study-related records needed 
to verify the entries on the CRFs. 
The Investigator agrees to co-operate with the study monitor to ensure that any 
problems detected in the course of these monitoring visits are resolved. 
The Investigator is responsible for ensuring the data recorded in the CRFs are 
accurate and complete.  The CRF should be completed within 5 working days after 


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the patient’s visit and before review by the study monitor.  Queries generated by GW 
or its representative are to be answered within a similar period of time.  Shorter 
periods of time may apply during specific situations such as interim analysis or final 
database cleaning. 
All handwritten medical records should be filled out with a black or blue ball-point 
pen and must be legible.  Corrections to paper forms will be made by a single line 
stroke through the error and insertion of the correction above or beside the error.  The 
change must be initialed and dated by the Investigator or a member of the study staff 
authorized by the Investigator.  No correction fluid or tape may be used.  The PI will 
sign and date the indicated places on the CRF.  These signatures will indicate that the 
PI inspected or reviewed the data on the CRF, the data queries and the site 
notifications and agrees with the content. 
To ensure the quality of clinical data across all patients and centers, a clinical data 
management review will be performed on patient data received at GW or a contract 
research organization (CRO).  During this review, patient data will be checked for 
consistency, omissions and any apparent discrepancies.  In addition, the data will be 
reviewed for adherence to the protocol and FDA regulations74,75,76,82, the ICH GCP 
Guideline83, and all other applicable regulatory requirements; to resolve any questions 
arising from the clinical data management review process, data queries and/or center 
notifications will be sent to the center for completion and then returned to GW or the 
CRO, as applicable. 
GW’s or the CRO’s Clinical Data Management Department will correct the following 
issues in CRFs without any notification to site staff: 
 Misspellings that do not change the meaning of the word, excluding AEs and 
medications. 
 Date errors that occur at the end of the year and into the New Year. 
 Temperature unit errors (Fahrenheit vs Centigrade). 
 Weight unit errors (pounds vs kilograms) if a baseline weight has been 
established. 
 Administrative data, for example, event names for unscheduled visits or 
retests. 
 Clarifying “other, specify” if data are provided for example, race, physical 
exam. 
 If a YES or NO question for example, ‘Were there any AEs?’ is left blank yet 
AEs are listed on the CRF, YES will be entered in the blank. 
 Correct CRF page numbers. 


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16.4 
Electronic Data Collected by the Interactive Voice Response 
System 
Source data for the assessments collected via the IVRS will be managed by the 
service provider in accordance with GCP and in adherence to a quality management 
system.  All data will be stored in a secure (for example, redundant hardware, 
password control, limited physical access to servers), fully audit trailed environment 
with appropriate industry standard back-up and off-site storage practices. 
Access for patients providing assessments and Investigators will be authenticated and 
meet industry standards and comply with FDA 21 CFR part 11 (subpart B – 
Electronic Records) requirements82. 
After database lock all Investigators will receive a certified copy of all the IVRS 
assessment data.  These data will be in an agreed, read-only format with a covering 
letter explaining the content of the data, a quality statement from the IVRS provider 
and the Investigator’s responsibilities. 
Regulatory and Sponsor auditors will have the ability to review but not modify the 
IVRS data via an agreed means of access. 
16.5 
Quality Assurance 
In accordance with the FDA regulations, EU Clinical Trials Directive/ICH GCP and 
the Sponsor’s audit plans, representatives from GW’s Clinical Quality Assurance 
Department may select this study for audit.  Inspection of site facilities for example, 
pharmacy, drug storage areas, laboratories and review of study-related records will 
occur to evaluate the study conduct and compliance with the protocol, as per the EU 
Clinical Trials Directive/ICH GCP and applicable regulatory requirements. 
16.6 
Compensation 
GW will indemnify the Investigator and the study site in the event of any claim in 
respect of personal injury arising due to a patient’s participation in the study, 
providing that the study protocol has been adhered to.  This would include claims 
arising out of or relating to the administration of the IMP or any clinical intervention 
or procedure provided for or required by the protocol to which the clinical study 
patient would not otherwise have been exposed providing there is no evidence of 
negligence on behalf of the Investigator or their team.  GW will not be liable for any 
claims arising from negligence on the part of the Investigator or their team. 


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16.7 
Publication Policy 
GW 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 co-ordinate this dissemination and may solicit 
input and assistance from the chief/PIs.  A summary of the results of this study will be 
made available on http://www.ClinicalTrials.gov, as required by U.S. Law. 
The raw data from this study may be obtained by the PIs or by their steering 
committee representatives on request.  Should they wish, PIs are allowed to conduct 
their own analysis and are permitted to present such information along with methods 
and results of the clinical study at symposia, national or regional professional 
meetings, and to publish it in theses or dissertations. 
All publications e.g., manuscripts, abstracts, oral/slide presentations or book chapters 
based on this study, must be submitted to GW Medical Writing Department and, as 
applicable, GW Publication Committee for review before release.  To ensure adequate 
time for GW to make comments and suggestions where pertinent, all such material 
should be submitted to them at least 60 days prior to the date for submission for 
publication, public dissemination, or review by a publication committee.  The PIs 
must then incorporate all reasonable comments made by GW into the publication. 
GW also reserve the right to delay the submission of such information by a period of 
up to 6 months from the date of first submission to them in order to allow them to take 
steps to protect proprietary information where applicable. 
16.8 
Intellectual Property Rights 
All Intellectual Property Rights owned by or licensed to either GW or the PIs, other 
than those arising from the clinical study, will remain their property.  All Intellectual 
Property Rights arising out of the clinical study will vest in or be exclusively licensed 
to GW and as such, the PI should promptly disclose all knowledge to GW and refrain 
from using such knowledge without the prior written consent of GW. 
16.9 
Confidential Information 
GW and the PI should ensure that only personnel directly concerned with the study 
should be party to confidential information and that any information coming to either 
party about the other during the course of the study should be kept strictly confidential 
and should not be disclosed to any third party or made use of without the prior written 
consent of the other. 
 
 


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17 
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39 Eriksson AS, Nergårdh A, Hoppu K. The efficacy of lamotrigine in children and 
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41 Lotte J, Haberlandt E, Neubauer B, Staudt M, Kluger GJ. Bromide in patients with 
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42 Perez J, Chiron C, Musial C, Rey E, Blehaut H, d'Athis P et al. Stiripentol: 
efficacy and tolerability in children with epilepsy. Epilepsia 1999;40(11):1618–
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43 Chiron C, Marchand MC, Tran A, Rey E, d'Athis P, Vincent J et al. Stiripentol in 
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44 Kassaï B, Chiron C, Augier S, Cucherat M, Rey E, Gueyffier F et al. Severe 
myoclonic epilepsy in infancy: a systematic review and a meta-analysis of 
individual patient data. Epilepsia 2008;49(2):343–8. 
45 Inoue Y, Ohtsuka Y, Oguni H, Tohyama J, Baba H, Fukushima K et al. Stiripentol 
open study in Japanese patients with Dravet syndrome. Epilepsia 
2009;50(11):2362–8. 
46 Wirrell EC, Laux L, Franz DN, Sullivan J, Saneto RP, Morse RP et al. Stiripentol 
in Dravet syndrome: results of a retrospective U.S. study. Epilepsia 
2013;54(9):1595–604. 


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47 Nieto-Barrera M, Candau R, Nieto-Jimenez M, Correa A, del Portal LR. 
Topiramate in the treatment of severe myoclonic epilepsy in infancy. Seizure 
2000;9(8):590–4. 
48 Coppola G, Capovilla G, Montagnini A, Romeo A, Spanò M, Tortorella G et al. 
Topiramate as add-on drug in severe myoclonic epilepsy in infancy: an Italian 
multicenter open trial. Epilepsy Res 2002;49(1):45–8. 
49 Kröll-Seger J, Portilla P, Dulac O, Chiron C. Topiramate in the treatment of 
highly refractory patients with Dravet syndrome. Neuropediatrics 
2006;37(6):325–9. 
50 Sachdeo RC, Glauser TA, Ritter F, Reife R, Lim P, Pledger G. A double-blind, 
randomized trial of topiramate in Lennox-Gastaut syndrome. Neurology 
1999;52(9):1882–7. 
51 Glauser TA, Levisohn PM, Ritter F, Sachdeo RC. Topiramate in Lennox-Gastaut 
syndrome: open-label treatment of patients completing a randomized controlled 
trial. Epilepsia 2000;41(Suppl 1):S86–90. 
52 Coppola G, Caliendo G, Veggiotti P, Romeo A, Tortorella G, De Marco P et al. 
Topiramate as add-on drug in children, adolescents and young adults with 
Lennox-Gastaut syndrome: an Italian multicentric study. Epilepsy Res 2002;51(1–
2):147–53. 
53 De Los Reyes EC, Sharp GB, Williams JP, Hale SE. Levetiracetam in the 
treatment of Lennox-Gastaut syndrome. Pediatr Neurol 2004;30(4):254–6. 
54 Striano P, Coppola A, Pezzella M, Ciampa C, Specchio N, Ragona F et al. An 
open-label trial of levetiracetam in severe myoclonic epilepsy of infancy. 
Neurology 2007;69(3):250–4. 
55 Ritter FJ, Leppik IE, Dreifuss FE, Rak I, Santilli N, Homzie R et al. Efficacy of 
felbamate in childhood epileptic encephalopathy (Lennox-Gastaut syndrome). N 
Engl J Med 1993;328(1):29–33. 
56 Glauser T, Kluger G, Sachdeo R, Krauss G, Perdomo C, Arroyo S. Rufinamide 
for generalized seizures associated with Lennox-Gastaut syndrome. Neurology 
2008;70(21):1950–8. 
57 Cersósimo RO, Bartuluchi M, Fortini S, Soraru A, Pomata H, Caraballo RH. 
Vagus nerve stimulation: effectiveness and tolerability in 64 paediatric patients 
with refractory epilepsies. Epileptic Disord 2011;13(4):382–8. 
58 Zamponi N, Passamonti C, Cappanera S, Petrelli C. Clinical course of young 
patients with Dravet syndrome after vagal nerve stimulation. Eur J Paediatr 
Neurol 2011;15(1):8–14. 
59 Lancman G, Virk M, Shao H, Mazumdar M, Greenfield JP, Weinstein S et al. 
Vagus nerve stimulation vs. corpus callosotomy in the treatment of Lennox-
Gastaut syndrome: a meta-analysis. Seizure. 2013;22(1):3–8. 
60 Caraballo RH, Cersósimo RO, Sakr D, Cresta A, Escobal N, Fejerman N. 
Ketogenic diet in patients with Dravet syndrome. Epilepsia 2005;46(9):1539–44. 
61 Kang HC, Kim YJ, Kim DW, Kim HD. Efficacy and safety of the ketogenic diet 
for intractable childhood epilepsy: Korean multicentric experience. Epilepsia 
2005;46(2):272–9. 


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62 Caraballo RH. Nonpharmacologic treatments of Dravet syndrome: focus on the 
ketogenic diet. Epilepsia 2011;52(Suppl 2):79–82. 
63 Nabbout R, Copioli C, Chipaux M, Chemaly N, Desguerre I, Dulac O et al. 
Ketogenic diet also benefits Dravet syndrome patients receiving stiripentol: a 
prospective pilot study. Epilepsia 2011;52(7):e54–7. 
64 Bisogno T, Hanus L, De Petrocellis L, Tchilibon S, Ponde DE, Brandi I et al. 
Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid 
VR1 receptors and on the cellular uptake and enzymatic hydrolysis of 
anandamide. Br J Pharmacol. 2001 Oct;134(4):845–52. 
65 Whyte LS, Ryberg E, Sims NA, Ridge SA, Mackie K, Greasley PJ et al. The 
putative cannabinoid receptor GPR55 affects osteoclast function in vitro and bone 
mass in vivo. Proc Natl Acad Sci U S A 2009;106(38):16511–6. 
66 Pertwee RG. The pharmacology and therapeutic potential of cannabidiol. In: Di 
Marzo V, editor. Cannabinoids. New York: Kluwer Academic/Plenum publishers; 
2004. p. 32–83. 
67 Zuardi AW, Morais SL, Guimarães FS, Mechoulam R. Antipsychotic effect of 
cannabidiol. J Clin Psychiatry 1995;56(10):485–6. 
68 Cortesi M, Fusar-Poli P. Potential therapeutical effects of cannabidiol in children 
with pharmacoresistant epilepsy. Med Hypotheses 2007;68(4):920–1. 
69 Porter BE, Jacobson C. Report of a parent survey of cannabidiol-enriched 
cannabis use in pediatric treatment-resistant epilepsy. Epilepsy Behav 
2013;29(3):574–7. 
70 GWMD09112 Clinical Study Report. A randomized, partially-blind, placebo-
controlled, pilot, dose-ranging study to assess the effect of Cannabidiol (CBD) on 
liver fat levels in subjects with fatty liver disease. 28 November 2013. 
71 Investigator Brochure - CBD Medicine.  GW Pharma Ltd, September 2017, 
Edition 10. 
72 Topic M 3 Non-Clinical Safety Studies for the Conduct of Human Clinical Trials 
for Pharmaceuticals Note for Guidance on Non-Clinical Safety Studies for the 
Conduct of Human Clinical Trials for Pharmaceuticals (CPMP/ICH/286/95 - 
Mod) November 2000. 
73 World Medical Association Declaration of Helsinki. Ethical Principles for 
Medical Research Involving Human Subjects, October 2013, Fortaleza. 
74 FDA 21 CFR Part 50 (Protection of Human Subjects). 01 April 2014. 
75 FDA 21 CFR Part 312 (Investigational New Drug Application). 01 April 2014. 
76 FDA 21 CFR Part 56 (Institutional Review Boards). 01 April 2014. 
77 The Directive 2001/20/EC of the European Parliament and of Council of 04 April 
2001. 
78 Guidance for Clinical Investigators, Sponsors, and IRBs.  Adverse Event 
Reporting for IRBs- Improving Human Subject Protection. FDA January 2009. 
79 UK Statutory Instrument No.1031, The Medicines for Human Use (Clinical 
Trials) Regulations 2004 (Available on file at GW). 
80 UK Statutory Instrument No.1928, The Medicines for Human Use (Clinical 
Trials) Amendment Regulations 2006 (Available on file at GW).  


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81 UK Statutory Instrument No.1031, The Medicines for Human Use (Clinical 
Trials) Regulations Amendment No2. 2006 (Available on file at GW). 
82 FDA 21 CFR Part 11 (Subpart B - Electronic Records). 01 April 2014. 
83 ICH Topic E 6 Guideline for Good Clinical Practice.  Note for Guidance on Good 
Clinical Practice (CPMP/ICH/135/95) July 1996. 
84 The Directive 2005/28/EC of the European Parliament and of Council of 09 April 
2005.  Chapter 4 Trial Master File and Archiving Article 16. 
85 Carel J-C, Léger J. Clinical practice. Precocious puberty. N Engl J Med 
2008;358(22):2366–77. 


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APPENDIX 1 SCHEDULE OF ASSESSMENTS 
Visit(s) 
1* 
2, 3, 
4** 
5 & 6** 
 
7** 
Disp
ense 
8** 
Disp
ense 
9** 
Disp
ense 
10** 
Disp
ense 
11** 
Disp
ense 
12** 
Disp
ense 
End of 
Treat
ment 
End of 
Taper 
Safety Call Follow-up 
(Tel.) 
Day/Week 
 
(Visit window) 
Day 
1 
Days 
15, 
29, 8
5 
(± 3 
days) 
Weeks 
24 & 3
6 
(± 7 
days) 
Week 
48 
(± 7 
days) 
 
Week 
76 
(± 7 
days) 
 
Week 
104 
(± 7 
days) 
 
Week 
132 
(± 7 
days) 
 
Week 
156 
(± 7 
days) 
 
Week 
184 
(± 7 
days) 
 
*** 
Up to 
10 
days 
later 
(+ 3 
days) 
2 weeks 
after End 
of Taper 
(± 3 days) 
4 weeks 
after End of 
Taper 
(+ 3 days) 
Informed 
consent/assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ 
Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical 
History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AEs 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Inpatient 
epilepsy-
related 
hospitalization
s 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Concomitant 
medications 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Physical 
examination 
(including 
height and 
body weight) 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
 
Vital signs 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
 
ECG 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X♦ 
 
 
Clinical 
laboratory 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X♦ 
 
 


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Visit(s) 
1* 
2, 3, 
4** 
5 & 6** 
 
7** 
Disp
ense 
8** 
Disp
ense 
9** 
Disp
ense 
10** 
Disp
ense 
11** 
Disp
ense 
12** 
Disp
ense 
End of 
Treat
ment 
End of 
Taper 
Safety Call Follow-up 
(Tel.) 
Day/Week 
 
(Visit window) 
Day 
1 
Days 
15, 
29, 8
5 
(± 3 
days) 
Weeks 
24 & 3
6 
(± 7 
days) 
Week 
48 
(± 7 
days) 
 
Week 
76 
(± 7 
days) 
 
Week 
104 
(± 7 
days) 
 
Week 
132 
(± 7 
days) 
 
Week 
156 
(± 7 
days) 
 
Week 
184 
(± 7 
days) 
 
*** 
Up to 
10 
days 
later 
(+ 3 
days) 
2 weeks 
after End 
of Taper 
(± 3 days) 
4 weeks 
after End of 
Taper 
(+ 3 days) 
blood 
sampling  
Clinical 
laboratory 
urine sampling 
(dipstick 
urinalysis)§ 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X♦ 
 
 
Pregnancy test 
(if 
appropriate)§ 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
  
 
 
Vineland-II 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
S/CGIC† 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
S/CGICSD†  
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
QOLCE or 
QOLIE 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
Cognitive 
assessment 
battery¶ 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Menstruation 
question 
(females) 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Tanner 
Staging and 
IGF-1 levels♥ 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
C-SSRS‡ 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
 
CWS/PCWS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 


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Visit(s) 
1* 
2, 3, 
4** 
5 & 6** 
 
7** 
Disp
ense 
8** 
Disp
ense 
9** 
Disp
ense 
10** 
Disp
ense 
11** 
Disp
ense 
12** 
Disp
ense 
End of 
Treat
ment 
End of 
Taper 
Safety Call Follow-up 
(Tel.) 
Day/Week 
 
(Visit window) 
Day 
1 
Days 
15, 
29, 8
5 
(± 3 
days) 
Weeks 
24 & 3
6 
(± 7 
days) 
Week 
48 
(± 7 
days) 
 
Week 
76 
(± 7 
days) 
 
Week 
104 
(± 7 
days) 
 
Week 
132 
(± 7 
days) 
 
Week 
156 
(± 7 
days) 
 
Week 
184 
(± 7 
days) 
 
*** 
Up to 
10 
days 
later 
(+ 3 
days) 
2 weeks 
after End 
of Taper 
(± 3 days) 
4 weeks 
after End of 
Taper 
(+ 3 days) 
Study 
Medication 
Use and 
Behavior 
Survey# 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Patient diary 
review 
(seizures, AE 
information, 
concomitant 
AEDs, rescue 
medication, 
IMP dosing)£ 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
(seizure 
details) 
X 
(seizure 
details) 
IMP 
dispensing£ 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Return of 
IMP£ 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
IMP 
compliance 
review£ 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
 
* All patients will be instructed to begin titration of OLE IMP in the evening of Visit 1 (Day 1).  Patients with no gap in IMP dosing between the Core Study 
and the OLE (including tapered dose) will take their final dose of Core Study IMP in the morning of Visit 1.  Any OLE procedures that were not assessed 
during the Core Study should first be assessed at Visit 1, with the exception of the cognitive assessment battery. 
For patients enrolling immediately from the Core Study into the OLE (same day): All data collected at the ‘End of Treatment’ visit of the Core Study will 
also be considered as Visit 1 data.  Hepatic function must be confirmed before OLE dosing commences.  In order only to confirm normal hepatic function, 
an additional blood sample must be taken to analyze ALT, AST, TBL and INR at a local laboratory. 
For patients enrolling from the taper period of the Core Study (1–7 [+ 3] days post ‘End of Treatment’ visit): Patients should have their Core Study ‘End of 
Taper Period’ assessments made; these data, along with all other data collected at the ‘End of Treatment’ visit of the Core Study, will be considered as Visit 
1 data.  Hepatic function must be confirmed before OLE dosing commences.  In order only to confirm normal hepatic function, an additional blood sample 


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may be taken to analyze ALT, AST, TBL and INR at a local laboratory. 
For patients with any gap in IMP dosing between the Core Study and the OLE: All procedures must be re-assessed, with the exception of the cognitive 
assessment battery.  Hepatic function must be confirmed before OLE dosing commences.  In order only to confirm normal hepatic function, an additional 
blood sample must be taken to analyze ALT, AST, TBL and INR at a local laboratory. 
** From Visit 3 until the ‘End of Treatment’ visit, safety telephone calls must be made every 4 weeks (± 7 days).  In addition, during titration of doses above 
20 mg/kg/day, safety telephone calls must be made every 7 days (± 3 days) until stable dosing is achieved.  All safety telephone calls will assess AEs, 
epilepsy-related hospitalizations, concomitant medications and/or changes to medication. 
*** ‘End of Treatment’ visit will occur after a maximum of 4 years’ (208 weeks from Visit 1) treatment, when GWP42003-P is approved in their indication 
and is commercially available (as an unscheduled ‘End of Treatment’ visit as detailed below), or following the early withdrawal from the study.  Patients 
who complete treatment but do not immediately continue to use GWP42003-P will commence a 10-day IMP taper period.  Patients who withdraw early 
should commence the 10-day IMP taper period, if possible. 
• A patient with at least 2 years’ participation in the OLE (≥ 104 weeks after Visit 1) will complete the OLE phase when GWP42003-P is approved in their 
indication and is commercially available.  Patients will complete an unscheduled ‘End of Treatment’ visit to transition from OLE to commercial product.  
The timing will vary per patient and is projected to begin in February 2019.     
• A patient with less than 2 years’ (104 weeks after Visit 1) participation in the OLE when GWP42003-P is approved in their indication and is 
commercially available will continue on the OLE phase until reaching a maximum of 2 years’ OLE treatment, at which point an unscheduled ‘End of 
Treatment’ visit will be conducted.  The unscheduled End of Treatment visit will be conducted no earlier than 730 days after Visit 1. 
• Patients who do not continue treatment with GWP42003-P will be scheduled for an ‘End of Taper’ visit. 
♦ Only required for patients who withdraw from the study early. 
§ Urine sample taken if possible.  Pregnancy test: Urine test at Visit 1, serum test at ‘End of Treatment’/Withdrawal visit. 
† Patient/Caregiver is to compare to the memory aid from the Baseline of the Core Study.  If the memory aid is not available from the Baseline of the Core 
Study then the patient/caregiver should do this from memory, if possible, and complete a memory aid at Visit 1. 
¶ Only for patients who underwent cognitive testing during their Core Study.  To be performed at the ‘End of Treatment’/Withdrawal visit only.  The 
cognitive assessment battery will only be administered at participating centers. 
♥ Tanner Staging to be assessed in all adolescent patients (i.e., 10 to less than 18 years of age at the time of signing the informed consent form, or earlier if 
clinically indicated by onset of menarche or other signs of precocious puberty).  IGF-1 level testing to be conducted in all patients less than 18 years of age. 
‡ For patients that become 6 years old during this OLE trial, the Children’s Baseline C-SSRS (employing questions in relation to lifetime experience) should 
be completed at the next trial visit.  Questioning at all subsequent visits will be in relation to the last assessment (Children’s Since Last Visit). 
# To be performed at final dosing visit (‘End of Treatment’/Withdrawal visit or ‘End of Taper Period’ visit, as applicable) for patients 12 years of age and 
older. 
£ IVRS will be used to collect patient reported seizure information and to manage IMP supply.  A member of the study team must contact the IVRS at each 
assessment/dispensing visit in order to obtain dispensing information and to provide completion/taper/premature termination information. 
 
Tel. Visit can be conducted by telephone.


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APPENDIX 2 STUDY PERSONNEL 
Appendix 2.1 
Investigator Details 
At the time of protocol production, the participating Investigators had not been 
confirmed.  A list of all Investigators will be maintained within the GW Master Files 
(electronically and added to the Trial Master File at the end of the study). 
Appendix 2.2 
Sponsor Contact Details 
Pharmacovigilance Department — SAE Reporting: 
Fax:
 
USA Toll Free Fax: 
 
Tel: 
 
Sponsor: 
GW Research Ltd 
Sovereign House 
Vision Park 
Chivers Way 
Histon 
Cambridge CB24 9BZ 
United Kingdom 
Tel: +44 (0) 1233 266 800  
Fax: +44 (0) 1223 235 667 
Medical Monitor: 
 
 
 
Tel: 
  
Cell: 
 
Clinical Project Manager/Clinical Operations 
Director: 
GW Research Ltd 
Sovereign House 
Vision Park 
Chivers Way 
Histon 
Cambridge CB24 9BZ 
United Kingdom 
Tel: +44 (0)1223 266 800 
Fax: +44 (0)1223 235 667 
Clinical Trials Supplies: 
GW Pharma Ltd 
Tel: 
 
Fax: 
 


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APPENDIX 3 TANNER STAGING 
(Reproduced with permission from the New England Journal of Medicine85.) 
The following is to be completed for all female adolescent patients (i.e., 10 to less 
than 18 years of age at the time of signing the informed consent/assent form, or earlier 
if clinically indicated by onset of menarche or other signs of precocious puberty). 
Female Development & Pubic Hair 
 
Please check the box next to the most appropriate stage; in the event that qualifying 
characteristics are not within the same stage, defer to the lesser stage as the overall 
Tanner Score. 
Tanner Stage 1 (Prepubertal, typically 10 years and younger) 
 No glandular tissue; areola follows the skin contours of the chest. 
 No pubic hair at all. 
Tanner Stage 2 (10–11.5 years) 
 Breast bud forms, with small area of surrounding glandular tissue; areola 
begins to widen. 
 Small amount of long, downy hair with slight pigmentation on the labia 
majora. 


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Tanner Stage 3 (11.5–13 years) 
 Breast begins to become more elevated, and extends beyond the borders of the 
areola, which continues to widen but remains in contour with surrounding 
breast. 
 Hair becomes more coarse and curly and begins to extend laterally. 
Tanner Stage 4 (13–15 years) 
 Increased breast size and elevation; areola and papilla form a secondary 
mound projecting from the contour of the surrounding breast. 
 Adult-like hair quality, extending across pubis but sparing medial thighs. 
Tanner Stage 5 (15+ years) 
 Breast reaches final adult size; areola returns to contour of the surrounding 
breast, with a projecting central papilla. 
 Hair extends to medial surface of the thighs. 
 
The following is to be completed for all male adolescent patients (i.e., 10 to less than 
18 years of age at the time of signing the informed consent/assent form, or earlier if 
clinically indicated by signs of precocious puberty). 
Male Genital Development & Pubic Hair 
 
Please check the box next to the most appropriate stage. 
Tanner Stage 1 (Prepubertal, typically 9 years and younger) 
 Testicular volume less than 1.5 mL; small penis of 3 cm or less. 
 No pubic hair at all. 
Tanner Stage 2 (9–11 years) 
 Testicular volume between 1.6 and 6 mL; skin on scrotum thins, reddens and 
enlarges; penis length unchanged. 


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 Small amount of long, downy hair with slight pigmentation at the base of the 
penis and scrotum. 
Tanner Stage 3 (11–12.5 years) 
 Testicular volume between 6 and 12 mL; scrotum enlarges further; penis 
begins to lengthen to about 6 cm. 
 Hair becomes more coarse and curly and begins to extend laterally. 
Tanner Stage 4 (12.5–14 years) 
 Testicular volume between 12 and 20 mL; scrotum enlarges further and 
darkens; penis increases in length to 10 cm and circumference. 
 Adult-like hair quality, extending across pubis but sparing medial thighs. 
Tanner Stage 5 (14+ years) 
 Testicular volume greater than 20 mL; adult scrotum and penis of 15 cm in 
length. 
 Hair extends to medial surface of the thighs. 


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APPENDIX 4 TITRATION REGIMEN 
Dose Titration Regimen* 
Day 
OLE IMP Dosage 
Total Daily OLE IMP Dose 
1 
1.25 mg/kg (pm) 
1.25 mg/kg 
2 
1.25 mg/kg bid (am/pm) 
2.50 mg/kg 
3 
2.50 mg/kg bid (am/pm) 
5.00 mg/kg 
4 
2.50 mg/kg bid (am/pm) 
5.00 mg/kg 
5 
3.75 mg/kg bid (am/pm) 
7.50 mg/kg 
6 
3.75 mg/kg bid (am/pm) 
7.50 mg/kg 
7 
5.00 mg/kg bid (am/pm) 
10.00 mg/kg 
8 
5.00 mg/kg bid (am/pm) 
10.00 mg/kg 
9 
7.50 mg/kg bid (am/pm) 
15.00 mg/kg 
10 
7.50 mg/kg bid (am/pm) 
15.00 mg/kg 
11 
10.00 mg/kg bid (am/pm) 
20.00 mg/kg 
12 
10.00 mg/kg bid (am/pm) 
20.00 mg/kg 
13 
10.00 mg/kg bid (am/pm) 
20.00 mg/kg 
14 
10.00 mg/kg bid (am/pm) 
20.00 mg/kg 
* It is advised that the Investigator considers monitoring hepatic function (ALT, AST, TBL and INR 
levels) during the titration period for patients taking AEDs that are known to be associated with 
hepatic injury or failure.  To minimize any elevations in hepatic function markers the titration 
period can be extended and the dosage of a concomitant AED and/or GWP42003-P may be 
adjusted at the discretion of the Investigator.  If there is intolerance during titration, the patient 
may be maintained on a dose below 10–20 mg/kg/day.  A titration rate faster than recommended 
may be considered if there is an increase in seizures, following consultation with the GW medical 
monitor. 
Emerging clinical data suggest that benefit may be seen in patients in the range of 10–20 mg/kg/day. 
 
 
 
 
 
 
 
 
 

SAP_001.pdf: 
St u d y G W E P 1 4 1 5  
P hase  3 , 2 5 -Fe b -2 0 2 1  
Pr o d uct: G W P 4 2 0 0 3 - P  
 G W Researc h Lt d . 
 
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A p pe n di x 1. 9  
D oc u m e nt ati o n of St atistic al Met h o ds  
Statistical A nal ysis P la n Date d 0 6 N o ve m b er 2 0 2 0