Clinical trial NCT02564952
Conditions: Epilepsy
Keywords: Cannabidiol (CBD) GWP42003-P Clobazam Epidiolex
Sponsor: Jazz Pharmaceuticals
Start date: 2016-03-11; Completion date: 2017-06-07
Enrollment: 18 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study consisted of 2 parts: a double-blind (DB) phase and an open-label extension (OLE) phase. Only the OLE phase is described in this record. The OLE phase was a safety study. All participants received GWP42003-P initially titrated to 20 milligrams (mg)/kilograms (kg)/day; however, investigators subsequently decreased or increased the participant's dose to a maximum of 30 mg/kg/day (no minimum).

Detailed description:

Arms: arm 1: Participants who transferred from the DB phase (NCT02565108) to the OLE (still blinded at that stage) tapered off their GWP42003-P or placebo treatment by reducing their maintenance dose by 10% per day and concomitantly titrating GWP42003-P to 20 mg/kg/day initially for the OLE; doses could then be adjusted up or down, dependent on investigator opinion, to a maximum of 30 mg/kg/day GWP42003-P.

Clobazam (CLB) was administered in line with the physician's preferred CLB dosing regimen for each participant.
Interventions: intervention 1: GWP42003-P intervention 2: Clobazam
Intervention descriptions: intervention 1: GWP42003-P was presented as an oral solution containing 100 mg/milliliter (mL) cannabidiol (CBD) in the excipients sesame oil and anhydrous ethanol (79 mg/mL) with added sweetener (0.5 mg/mL sucralose) and strawberry flavoring (0.2 mg/mL). Participants received up to a maximum of 30 mg/kg/day. intervention 2: Participants were taking CLB upon entry into the OLE phase of the trial. CLB was not an investigational medicinal product (IMP) for the OLE phase and was not administered by the Sponsor, but was administered at the physician's discretion, as required for each participant. CLB could be stopped, if clinically indicated, without impact on analysis.

Protocol documents:
Prot_000.pdf: 
Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Version 1 Date 26 Jan 15 
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TITLE: A PHASE II, SINGLE-BLIND, PLACEBO-CONTROLLED STUDY 
TO INVESTIGATE POSSIBLE DRUG-DRUG INTERACTIONS BETWEEN 
CLOBAZAM AND CANNABIDIOL (GWP42003-P) 
STUDY CODE: GWEP1428 
EudraCT NUMBER: 2014-002942-33 
GW RESEARCH LTD 
SOVEREIGN HOUSE, VISION PARK 
HISTON, CAMBRIDGE 
CAMBS, CB24 9BZ 
TEL: 
   FAX: 
Confidentiality Statement 
This document contains confidential information of GW Research Ltd that must not 
be disclosed to anyone other than the recipient study staff and members of the 
Institutional Review Board.  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 Research Ltd. 
PPD
PPD
NCT Number: DBL Part NCT02565108
 
           OLE Part NCT02564952


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
GV\1 
· Version 1 Date 26 Jan 15 
pharmaceuticals 
Investigator Agreement 
I have read the attached protocol entitled "A phase II, single-blind, placebo-controlled 
study to investigate possible drug-drug interactions between clobazam and 
cannabidiol (GWP42003-P)", dated 26 January 2015 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 Harmonisation Tripartite Guideline on 
Good Clinical Practice (ICH GCP) where the EU Directive does not apply and to 
complete a Form 1572 if required. 
I am not aware that any conflicts of interest, financial or otherwise, exist for myself, 
my spouse [or legal partner] and dependent children and agree to confirm this in 
writing if required and update as necessary. 
I agree to ensure that the confidential information contained in this document will not 
be used for any purpose other than the evaluation or conduct of the clinical 
investigation without the prior written consent of GW Research Ltd. 
Centre No: 
Print Name: 
Date: 
Principal Investigator 
(DD Month YYYY) 
Signature: 
GW Authorization 
Print Name: 
Date: 
rJ. + J,.fA) 2o I) 
(DD Month YYYY) 
Clinical Manager 
Signature: 
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PPD
PPD


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1. 
PROTOCOL SYNOPSIS 
Study Title 
A phase 2, single-blind, placebo-controlled study to investigate 
possible drug-drug interactions between clobazam and cannabidiol 
(GWP42003-P) 
Clinical Study 
Type 
Phase 2 
Indication 
Epilepsy 
Primary Objective 
To determine whether cannabidiol (CBD) affects the pharmacokinetic 
(PK) profile of clobazam (CLB) and its primary metabolite N-
desmethylclobazam (N-CLB). 
Secondary 
Objective(s) 
To assess the safety and tolerability of CBD in the presence of CLB. 
Study Design 
This is a phase 2, single-blind, placebo-controlled study in 20 patients. 
• All patients will be given placebo first followed by CBD during the 
course of the study. Patients will receive placebo in the first part of 
the single-blind phase (Days 2 to 26) and CBD during the second 
part of the single-blind phase (Day 27 onwards). 
• 
At the end of the treatment period, patients will be given the option 
of continuing onto an open-label extension (OLE) period if the 
investigator and patient both agree that it is in their best interests. 
Doses may be adjusted up or down, dependent on investigator 
opinion, to a maximum of 30 mg/kg/day CBD. The OLE will last 
for a maximum of one year or until marketing authorization is 
granted; whichever is earlier. 
• 
Patients that do not continue onto the OLE will taper off of CBD 
over a 10 day period and will have a telephone follow-up visit four 
weeks after the end of taper day on Day 89. 
• Day 1 (Visit 2), patients will not be dosed with investigational 
medicinal product (IMP) but will continue to take CLB at a stable 
dose. 
• Day 2 (Visit 2), patients will begin the up-titration with placebo to 
an equivalent maintenance dose of 20 mg/kg/day over a period of 
10 days (Days 2 to 11). 
• After up-titration with placebo, the patients will remain on the 
maintenance dose for 14 days (Days 12 to 25). 
• On Day 27 (Visit 3), patients will begin the up-titration with CBD 
to the maintenance dose of 20 mg/kg/day over a period of 10 days 
(Days 27 to 36). 
• After up-titration with CBD, the patients will remain on the 
maintenance dose for a further 14 days (Day 37 to 51). 
• On Day 52 (Visit 4), patients will be invited to receive CBD in the 


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OLE period. If the patient enters the OLE period of the study, the 
patient will continue to take CBD as advised by the investigator. 
• If the patient does not enter the OLE period of the study, the patient 
will taper off of CBD by reducing the dose by approximately 10% 
of the maintenance dose each day until dosing has ceased, with end 
of taper on Day 61 (Visit 5). 
PK samples will be taken on the day of enrollment (Visit 2, Day 1), 
after completing 14 days treatment on placebo (Visit 3, Day 26) and 
prior to starting on CBD, and after the completing 14 days treatment on 
CBD (Visit 4, Day 451). The PK assessments will therefore capture the 
following combinations of CLB and IMP: 
• First PK Assessment: CLB only. 
• Second PK Assessment: CLB and placebo. 
• Third PK Assessment: CLB and CBD. 
Each PK assessment should be performed at time points in respect to a 
morning dose of CLB. The time points are as follows: Pre-dose, 
15 min, 30 min, 1h, 1.5h, 2h, 4h, 6h, 12h and 24h. It is expected that 
the patient will continue to take their CLB as advised by their physician 
and PK assessments will be scheduled in order to accommodate this 
dosing schedule. The IMP should be taken twice daily immediately 
following their CLB dose. 
PK assessments will analyze the amount of CLB, the CLB primary 
metabolite N-CLB, CBD and CBD major metabolites. 
Patients will be required to keep a paper diary to note the time and dose 
of IMP and CLB administration each morning and evening and to 
record any adverse events (AEs) that may occur whilst receiving IMP 
and any other medications. Patients will also be requested to record the 
number and type of seizures for each day whilst on the study. 
Primary Endpoint 
The primary endpoints of the study are the PK parameters (Cmax, tmax, 
AUC(0–∞) AUC(0–t), t½) of the following analytes: 
• CLB 
• N-desmethylclobazam (N-CLB) 
• CBD 
• CBD major metabolites 
Secondary 
Endpoint(s) 
To assess the safety and tolerability of CBD compared with placebo 
when taken in combination with CLB. Safety and tolerability will be 
assessed using the following parameters: 
• AEs 
• 12-lead Electrocardiogram (ECG) 
• Clinical laboratory parameters (clinical chemistry, hematology and 
urinalysis) 
• Vital signs 
• Columbia-Suicide Severity Rating Scale (C-SSRS) 
• Seizure Frequency 


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Sample Size 
A total of 20 patients will be enrolled in this study. Recruitment for the 
study will be competitive between participating sites. There is no 
formal sample size: Calculation and analysis is descriptive only. 
Summary of 
Participant 
Eligibility Criteria 
For inclusion in the study patients must fulfil ALL of the following 
criteria: 
• Male or female patients aged 18 to 55 years inclusive. 
• Patient must have epilepsy as determined by the investigator and be 
taking CLB. 
• Patient must have a documented magnetic resonance 
imaging/computerized tomography of the brain that ruled out a 
progressive neurologic condition. 
• Patient must have experienced at least one seizure of any type (i.e., 
tonic-clonic, tonic, clonic, atonic seizures) within the two months 
prior to randomization. 
• Patients must be taking CLB and no more than two other anti-
epileptic drugs (AEDs) during the course of the study. 
• AED(s), including CLB, must be stable for four weeks prior to 
screening and regimen must remain stable throughout the duration 
of the blinded phase of the study. 
• Intervention with vagus nerve stimulation and/or ketogenic diet 
must be stable for four weeks prior to baseline and patient/caregiver 
must be willing to maintain a stable regimen throughout the 
duration of the study. 
• Patients must abstain from alcohol during the single-blind phase of 
the study. 
• Patient and/or legal representative is available to attend all PK visits 
within the required visit window. 
• Patient and/or legal representative must be willing and able to give 
informed consent for participation in the study 
• Patient and/or legal representative must be willing and able (in the 
investigator’s opinion) to comply with all study requirements. 
• Patient is willing for his or her name to be notified to the 
responsible authorities for participation in this study, as applicable. 
• Patient is willing to allow his or her primary care practitioner and 
consultant, if appropriate, to be notified of participation in the 
study. 
 
Exclusion: The patient may not enter the study if ANY of the following 
apply: 
• Patient has clinically significant unstable medical conditions other 
than epilepsy. 


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• Patients on CLB at doses above 20 mg per day. 
• Patients taking CLB intermittently as rescue medication. 
• Patient has a history of symptoms (e.g., dizziness, light-headedness, 
blurred vision, palpitations, weakness, syncope) related to a drop in 
blood pressure (BP) due to postural changes. 
• Any history of suicidal behavior or any suicidal ideation of type 
four or five on the C-SSRS in the last month or at screening. 
• Patient has had clinically relevant symptoms or a clinically 
significant illness in the four weeks prior to screening or 
enrollment, other than epilepsy. 
• Patient has consumed alcohol during the seven days prior to 
enrollment and is unwilling to abstain for the duration of the study. 
• Patient is currently using or has in the past used recreational or 
medicinal cannabis, or synthetic cannabinoid based medications 
(including Sativex®) within the three months prior to study entry. 
• Patient has any known or suspected history of any drug abuse or 
addiction. 
• Patient is unwilling to abstain from recreational or medicinal 
cannabis, or synthetic cannabinoid based medications (including 
Sativex) for the duration for the study. 
• Patient has consumed grapefruit or grapefruit juice seven days prior 
to enrollment and is unwilling to abstain from drinking grapefruit 
juice within seven days of PK visits. 
• Patient has any known or suspected hypersensitivity to 
cannabinoids or any of the excipients of the IMP, e.g., sesame oil 
• Female patients must have a negative pregnancy test and be willing 
and able to use a reliable method of contraception throughout the 
trial and for three months after last dose. In the context of this trial, 
an effective method is defined as those which result in low failure 
rate (i.e., less than 1% per year) when used consistently and 
correctly such as: combined or progesterone only oral 
contraceptives, intrauterine device, intrauterine hormone-releasing 
system, bilateral tubal occlusion, vasectomized partner or sexual 
abstinence. 
• Female patient who is pregnant, lactating or planning pregnancy 
during the course of the study and for three months thereafter. 
• Patients who have received an IMP within the 12 weeks prior to the 
screening visit. 
• 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 
the patient’s ability to participate in the study. 
• Following a physical examination, the patient has any abnormalities 


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that, in the opinion of the investigator would prevent the participant 
from safe participation in the study. 
• Patient has significantly impaired hepatic function, as determined at 
screening or enrollment (Alanine aminotransferase [ALT] >5 × 
upper limit of normal [ULN] or total bilirubin [TBL] >2 × ULN) 
OR the ALT or Aspartate aminotransferase (AST) >3 × ULN and 
(TBL >2 × ULN or international normalized ratio [INR] >1.5).  
This criterion can only be confirmed once the laboratory results are 
available; patients randomized into the study who are later found to 
meet this criterion must be withdrawn from the study. 
• Unwilling to abstain from donation of blood during the study. 
• Travel outside the country of residence planned during the study. 
• Patients previously enrolled into this study. 
Criteria for 
Withdrawal 
Patients must be withdrawn from the study if any of the following 
apply: 
• Administrative decision by the investigator or GW Research Ltd or 
Regulatory Authority. 
• Pregnancy. 
• Protocol deviation that is considered to potentially compromise the 
safety of the patient. 
• Withdrawal of patient consent. 
• Withdrawal of legal representative consent. 
• Lost to follow up. 
• ALT >3 × ULN 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 two weeks. 
 
Patients may also be withdrawn from the study if any of the following 
apply: 
• Patient non-compliance. 
• AE, which in the investigator’s opinion, 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 four or five during the 
treatment period, as evaluated with the C-SSRS. 
Investigational 
Medicinal Product: 
GWP42003-P oral solution (100 mg/mL CBD in sesame oil with 
anhydrous ethanol, added sweetener (sucralose) and strawberry 


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Dosage, Regimen, 
Formulation and 
Mode of 
Administration 
flavoring). 
Placebo oral solution containing the excipients sesame oil and 
anhydrous ethanol with added sweetener (sucralose) and strawberry 
flavoring. 
The IMP should be taken orally as per intended commercial therapeutic 
use. 
IMP will be taken twice daily (morning and evening) following the 
dose schedule below: 
• Day 2 (Visit 2), patients will begin the up-titration with placebo to 
an equivalent maintenance dose of 20 mg/kg/day over a period of 
10 days (Days 2 to 11). 
• After up-titration with placebo, the patients will remain on the 
maintenance dose for 14 days (Days 12 to 25). 
• On Day 27 (Visit 3), patients will begin the up-titration with CBD 
to the maintenance dose of 20 mg/kg/day over a period of 10 days 
(Days 27 to 36). 
• After up-titration with CBD, the patients will remain on the 
maintenance dose for a further 14 days (Day 37 to 50). 
Please refer to Table 8.1-1 for details of the up-titration doses for CBD 
and placebo for each of the ten days. 
On Day 52 (Visit 4), patients will be invited to receive CBD in the 
open label extension (OLE) period. If the patient enters the OLE period 
of the study, the patient will continue to take CBD as advised by the 
investigator. 
Control Group 
All patients will receive placebo in the first part of the single-blind 
phase (Days 2 to 26) and CBD during the second part of the single-
blind phase (Day 27 onwards).There is no separate control group. 
Procedures 
VISIT 1 - Screening (Day -7) 
The following observations will be made at Visit 1: demographics, 
medical history (including seizure information since diagnosis, history 
of epilepsy-specific genetic testing and all prior AEDs taken), 
concomitant medications (including AEDs), physical examination 
(including height and body weight), ECG and vital signs. 
Clinical laboratory samples (blood and urine) will be taken for 
hematology, biochemistry, urinalysis and a pregnancy test (using a 
serum sample, if appropriate). The laboratory results should be 
available within 3-5 working days after Visit 1. If the results show a 
patient is ineligible, the patient will not be enrolled into the study. The 
C-SSRS will be administered. 
Patients who satisfy all inclusion and none of the exclusion criteria 
specified in Section 6 will be assigned a unique patient number and 
then begin the seven day baseline period. Patients or their caregivers 
will be given a paper diary to record daily seizure information, rescue 
medication, concomitant AEDs and AEs; and will be instructed on how 


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to do so. The investigator must record the patient’s attendance at the 
visit and confirm the outcome of screening on the CRF.  
VISIT 2 - Enrollment (Day 1) +3 days window 
This visit will occur 7 days after Visit 1. 
The following observations will be made at Visit 2: concomitant 
medications, (including AEDs), physical examination (including height 
and body weight), ECG, vital signs, review of seizure diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for 
hematology, biochemistry and urinalysis. The C-SSRS will be 
administered. The investigator must record the patient’s attendance at 
the visit, and confirm the outcome of the visit prior to enrollment. 
Following enrollment patients will begin the PK sampling process. 
Blood samples will be taken for analysis of plasma concentrations of 
CLB, N-CLB, CBD and CBD major metabolites. A baseline PK 
sample will be taken before the patient takes their morning dose of 
CLB. Further samples will then be taken at the following times relative 
to the CLB dose: 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 
4 hours, 6 hours and 12 hours. Patients will either remain in clinic 
overnight throughout this PK sampling process or return to the clinic 
on Day 2 ahead of additional sample collection. 
VISIT 2 - Enrollment (Day 2) 
This is the second part of the two day enrollment visit. The final PK 
sample will be collected 24 hours after the Day 1 morning CLB dose. 
Following completion of the PK sampling process the following 
observations will be made on Day 2: concomitant medications 
(including AEDs), physical examination (including height and body 
weight), vital signs, and AEs. 
IMP will be dispensed and both the morning dose of CLB and of IMP 
will be taken in clinic. Patients and/or their caregivers will be provided 
with individual dosing schedules as described in Section 8.1. Each 
patient will then receive their IMP for the 10 day titration period 
followed by the 14 day maintenance period. Patients, or their 
caregivers, will be instructed on how to record the diary information. 
VISIT 3 - Day 26 ±3 days window 
This visit will occur 25 days after Visit 2, Day 1 (enrollment). Patients 
will return all used and unused IMP. The following observations will 
be made at Visit 3 (Day 26): concomitant medications (including 
AEDs), physical examination (including height and body weight), 
ECG, vital signs, review of seizure diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for 
hematology, biochemistry and urinalysis. The C-SSRS will be 
administered. 
Blood samples will be taken for analysis of plasma concentrations of 


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CLB, N-CLB, CBD and CBD major metabolites. A baseline PK 
sample will be taken before the patient takes their morning dose of 
CLB, followed immediately by their dose of IMP. Further samples will 
then be taken at the following times relative to the CLB dose: 
15  minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours 
and 12 hours. Patients are expected to remain in clinic throughout this 
PK sampling process. 
The investigator must assess adherence to the dosing regimen and 
recording of rescue medications by reviewing the patient’s diary. 
VISIT 3 - Day 27 
This is the second part of the two day visit. The final PK sample will be 
collected 24 hours after the Day 25 morning CLB dose. 
Following completion of the PK sampling process the following 
observations will be made on Day 27: concomitant medications 
(including AEDs), physical examination (including height and body 
weight), vital signs, and AEs. 
IMP will be dispensed and both the morning dose of CLB and of IMP 
will be taken in clinic. Patients and/or their caregivers will be provided 
with individual dosing schedules as described in Section 8.1. Each 
patient will then receive their IMP for the 10 day titration period 
followed by the 14 day maintenance period.  
VISIT 4 - Day 51 ±3 days window 
This visit will occur 50 days after Visit 2, Day 1 (enrollment). Patients 
will return all used and unused IMP. The following observations will 
be made at Visit 4 (Day 51): concomitant medications (including 
AEDs), physical examination (including height and body weight), 
ECG, vital signs, review of seizure diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for 
hematology, biochemistry and urinalysis. The C-SSRS will be 
administered. The investigator must record the patient’s attendance at 
the visit and the outcome. 
Blood samples will be taken for analysis of plasma concentrations of 
CLB, N-CLB, CBD and CBD major metabolites. A baseline PK 
sample will be taken before the patient takes their morning dose of 
CLB, followed immediately by their dose of IMP. Further samples will 
then be taken at the following times relative to the CLB dose: 
15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours and 
12 hours. Patients are expected to remain in clinic throughout this PK 
sampling. 
The investigator must assess adherence to the dosing regimen and 
recording of rescue medications by reviewing the patient’s diary. 
VISIT 4 - Day 52  
This is the second part of the two day visit. The final PK sample will be 


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collected 24 hours after the Day 51 morning CLB dose. 
Following completion of the PK sampling process the following 
observations will be made on Day 52: concomitant medications 
(including AEDs), physical examination (including height and body 
weight), vital signs, and AEs. 
At the end of the blinded phase of the study on Day 52, providing the 
investigator and patient both agree, patients will be invited to continue 
taking IMP and to enter the OLE. 
Patients who enter the OLE will be dispensed CBD on Day 52. The 
dose may be adjusted up or down by the investigator from the 
maintenance dose of 20 mg/kg/day in the blinded phase to a maximum 
of 30 mg/kg/day in the OLE. Patients and/or their caregivers will be 
provided with individual dosing schedules as described in Section 8.1.  
Patients who do not enter the OLE will begin a 10 day taper period 
during which they will taper off their daily dose of IMP. The daily dose 
will be reduced by 10% of the maintenance dose per day and treatment 
will end on Day 60. 
Patients Not Entering OLE 
VISIT 5 – Day 61 (End of Taper) +3 days window 
This visit will occur 60 days after Visit 2, Day 1 (enrollment) for those 
patients who do not enter the OLE. 
All IMP (used and unused) will be collected and a check of the 
returned IMP against usage must be made. A physical examination 
(including height and body weight) and vital signs will be assessed and 
the C-SSRS will be administered. 
Clinical laboratory samples (blood and urine) will be taken for 
hematology, biochemistry and urinalysis and a review of concomitant 
medications (including AEDs) and AEs will be completed. Patient 
diaries will be collected. 
SAFETY FOLLOW-UP CALL - Day 89 ±3 days 
This visit is required for patients who do not enter the OLE study on 
Day 52, or who withdraw from the study early. This visit should occur 
four weeks (±3 days) after Visit 5, or withdrawal from treatment, and 
can be conducted over the telephone. The following observations will 
be made on Day 89: concomitant medications (including AEDs) and 
AEs. 
Patients Entering OLE 
Patients who enter the OLE will be dispensed IMP at Visit 4 (Day 52) 
and will have regular clinic visits for a maximum of one year or earlier 
(if marketing authorization is granted or the patient withdraws). The 
visit schedule is calculated relative to Visit 4 (Day 52). 


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VISIT 5 (OLE) – Two Weeks ±3 days 
This visit will occur two weeks after Visit 4 (Day 51). Patients will 
return all used and unused IMP. The following observations will be 
made at Visit 5 (OLE): concomitant medications (including AEDs), 
physical examination (including height and body weight), ECG, vital 
signs, review of seizure diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for 
hematology, biochemistry and urinalysis. The C-SSRS will be 
administered. The investigator must record the patient’s attendance at 
the visit and the outcome. 
The investigator must assess adherence to the dosing regimen and 
recording of rescue medications by reviewing the patient’s diary. 
VISIT 6 (OLE) – One Month ±3 days 
This visit will occur one month after Visit 4 (Day 51). Patients will 
return all used and unused IMP. The following observations will be 
made at Visit 6 (OLE): concomitant medications (including AEDs), 
physical examination (including height and body weight), ECG, vital 
signs, review of seizure diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for 
hematology, biochemistry and urinalysis. The C-SSRS will be 
administered. The investigator must record the patient’s attendance at 
the visit and the outcome. 
The investigator must assess adherence to the dosing regimen and 
recording of rescue medications by reviewing the patient’s diary. 
VISIT 7 (OLE) – Two Months ±3 days 
This visit will occur two months after Visit 4 (Day 51). Patients will 
return all used and unused IMP. The following observations will be 
made at Visit 7 (OLE): concomitant medications (including AEDs), 
physical examination (including height and body weight), ECG, vital 
signs, review of seizure diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for 
hematology, biochemistry and urinalysis. The C-SSRS will be 
administered. The investigator must record the patient’s attendance at 
the visit and the outcome. 
The investigator must assess adherence to the dosing regimen and 
recording of rescue medications by reviewing the patient’s diary. 
VISIT 8 (OLE) - Three Months ±7 days 
This visit will occur three months after Visit 4 (Day 51). Patients will 
return all used and unused IMP. The following observations will be 
made at Visit 8 (OLE): concomitant medications (including AEDs), 
physical examination (including height and body weight), ECG, vital 
signs, review of seizure diary and AEs. 


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Clinical laboratory samples (blood and urine) will be taken for 
hematology, biochemistry and urinalysis. The C-SSRS will be 
administered. The investigator must record the patient’s attendance at 
the visit and the outcome. 
The investigator must assess adherence to the dosing regimen and 
recording of rescue medications by reviewing the patient’s diary. 
VISIT 9 (OLE) - Six Months ±7 days 
This visit will occur six months after Visit 4 (Day 51). Patients will 
return all used and unused IMP. The following observations will be 
made at Visit 9 (OLE): concomitant medications (including AEDs), 
physical examination (including height and body weight), ECG, vital 
signs, review of seizure diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for 
hematology, biochemistry and urinalysis. The C-SSRS will be 
administered. The investigator must record the patient’s attendance at 
the visit and the outcome. 
The investigator must assess adherence to the dosing regimen and 
recording of rescue medications by reviewing the patient’s diary. 
VISIT 10 (OLE) - Nine Months ±7 days 
This visit will occur nine months after Visit 4 (Day 51). Patients will 
return all used and unused IMP. The following observations will be 
made at Visit 10 (OLE): concomitant medications (including AEDs), 
physical examination (including height and body weight), ECG, vital 
signs, review of seizure diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for 
hematology, biochemistry and urinalysis. The C-SSRS will be 
administered. The investigator must record the patient’s attendance at 
the visit and the outcome. 
The investigator must assess adherence to the dosing regimen and 
recording of rescue medications by reviewing the patient’s diary. 
VISIT 11 – Twelve Months (OLE End of Treatment) ±7 days 
This visit will occur twelve months after Visit 4 (Day 51). Patients will 
return all used and unused IMP. The following observations will be 
made at Visit 11 (OLE): concomitant medications (including AEDs), 
physical examination (including height and body weight), ECG, vital 
signs, review of seizure diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for 
hematology, biochemistry and urinalysis. The C-SSRS will be 
administered. The investigator must record the patient’s attendance at 
the visit and the outcome. 
The investigator must assess adherence to the dosing regimen and 
recording of rescue medications by reviewing the patient’s diary. 
Starting at Visit 11, patients will begin to taper down their IMP dose. 


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The dose will be reduced by 10% of their OLE maintenance dose per 
day. 
VISIT 12 - OLE End of taper +3 days 
This visit will be ten days after Visit 11. All IMP (used and unused) 
will be collected and a check of the returned IMP against usage must be 
made. A physical examination (including height and body weight), 
ECG and vital signs will be assessed and the C-SSRS will be 
administered. 
Clinical laboratory samples (blood and urine) will be taken for 
hematology, biochemistry and urinalysis and a review of concomitant 
medications (including AEDs) and AEs will be completed. Patient 
diaries will be collected and reviewed. 
SAFETY FOLLOW-UP CALL (OLE) 
This visit will occur one month after the OLE End of Taper and can be 
conducted over the telephone. The following observations will be made 
during the follow up call: concomitant medications (including AEDs) 
and AEs. 
Statistical 
Considerations 
Plasma concentration data will be analyzed to estimate 
pharmacokinetic endpoints Cmax, AUC(0–t), AUC(0–∞) of the following 
analytes CLB, N-CLB, CBD and major metabolites. 
In order to assess whether the presence of CBD alters the PK profile of 
CLB or N-CLB, a standard 90% confidence interval (CI) approach for 
the between group ratios of geometric means of Cmax AUC(0–t), and 
AUC(0–∞) will be done on logarithm scale using a linear mixed effect 
model with treatment (CBD or placebo) as fix effect and subject as a 
random effect. The no-effect boundary will be set between 0.5 and 2.0 
and if the 90% CI for the ratio of the geometric means of a PK variable 
falls within the interval [0.5, 2.0], a lack of meaningful effect will be 
declared. 
Descriptive summaries (means and standard deviations or counts [%] 
as appropriate) will be presented for all secondary endpoints (adverse 
events, laboratory data, vital signs, physical examination, C-SSRS and 
seizure frequency) for each phase of the study. 
Sponsor 
Sovereign House 
Vision Park 
Histon 
Cambridge CB24 9BZ 
United Kingdom 
 


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Figure 1-1 
Study Design and Treatment Schema 
 
S 
C 
R 
E 
E 
N 
I 
N 
G 
E 
N 
R 
O 
L 
L 
M 
E 
N 
T 
Single Blind Phase: 
Placebo Phase 
Placebo 
(N=20, All patients) 
Single Blind Phase: 
Active Phase 
GWP42003-P Oral 
Solution 
(100mg/mL bd) 
(N=20, All patients) 
E 
N 
D 
 
O 
F 
 
B 
L 
I 
N 
D 
E 
D 
 
T 
R 
E 
A 
T 
M 
E 
N 
T 
Visit 1 
Day -7 
 
Visit 2 
Day 1/2 
(+3 d) 
Visit 3 
Day 26/27 
(±3 d) 
Visit 4 
Day 51/52 
(±3 d) 
E 
N 
D 
  
O 
F 
  
T 
A 
P 
E 
R 
 
10 Day Taper
Patients not 
entering the 
OLE 
Patients entering the OLE 
S 
A 
F 
E 
T 
Y 
 
F 
O 
L 
L 
O 
W 
 
U 
P 
10 Day 
Up-Titration 
14 Day 
Maintenance 
10 Day 
Up-Titration 
14 Day 
Maintenance 
Visit 5 
Day 61 
Visit 6 
Day 89 
28 day FU 
(±3 d) 
7 days 
24 days 
24 days 
10 days 
28 days 


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Figure 1-2 
Study Design and Treatment Schema  
 
Patients  
entering 
from 
 the 
‘Single  
Blind 
Phase’ 
Visit 5 OLE 
2 weeks 
(±3 d) 
Visit 7 OLE 
2 months 
(±3 d) 
Visit 6 OLE 
1 month 
(±3 d) 
Visit 8 OLE 
3 months 
(±7 d) 
Visit 9 OLE 
6 months 
(±7 d) 
Visit 11 OLE 
12 months 
(±7 d) 
Visit 10 OLE 
9 months 
(±7 d) 
Visit 12 OLE 
 
E 
N 
D 
  
O 
F 
  
T 
A 
P 
E 
R 
Visit 13 OLE 
28 day FU 
(±3 d) 
S 
A 
F 
E 
T 
Y 
 
F 
O 
L 
L 
O 
W 
 
U 
P 
Open-Label Extension Phase: 
GWP42003-P Oral Solution 
(100mg/mL bd) 
10 
Day 
Taper 
2 weeks 
from V4 
2 weeks 
1 month 
1 month 
3 months 
3 months 
3 months 
10 days 
18 days 


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Table of Contents 
Title Page ................................................................................................... 1 
1. 
PROTOCOL SYNOPSIS ................................................................ 3 
Table of Contents .................................................................................... 17 
Table of Appendices ............................................................................... 22 
List of In-text Tables .............................................................................. 23 
List of In-text Figures ............................................................................. 24 
List of Abbreviations .............................................................................. 25 
Definition of Terms ................................................................................. 27 
2. 
OBJECTIVES ................................................................................ 28 
2.1 
Primary ........................................................................................................ 28 
2.2 
Secondary .................................................................................................... 28 
3. 
BACKGROUND AND RATIONALE ......................................... 28 
3.1 
Disease......................................................................................................... 28 
3.2 
GWP42003-P Background .......................................................................... 28 
3.3 
Rationale ...................................................................................................... 29 
3.3.1 
Selection of Study Doses .......................................................................... 30 
3.4 
Clinical Hypothesis ..................................................................................... 31 
4. 
EXPERIMENTAL PLAN ............................................................. 31 
4.1 
Study Design ............................................................................................... 31 
4.1.1 
Primary Endpoint ...................................................................................... 33 
4.1.2 
Secondary Endpoint(s) .............................................................................. 33 
4.2 
Number of Centers ...................................................................................... 33 
4.3 
Number of Patients ...................................................................................... 33 
5. 
INVESTIGATIONAL MEDICINAL PRODUCT ..................... 33 
5.1 
GWP42003-P Oral Solution ........................................................................ 34 
5.2 
Placebo Oral Solution .................................................................................. 34 
5.3 
Packaging, Storage and Drug Accountability ............................................. 34 
5.3.1 
Packaging and Labelling ........................................................................... 34 
5.3.2 
Storage ...................................................................................................... 35 
5.3.3 
Supply and Return of Investigational Medicinal Product ......................... 35 
5.3.4 
Investigational Medicinal Product Accountability ................................... 35 


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6. 
PARTICIPANT ELIGIBILITY ................................................... 36 
6.1 
Inclusion Criteria ......................................................................................... 36 
6.2 
Exclusion Criteria ........................................................................................ 37 
7. 
PATIENT ENROLLMENT ......................................................... 39 
7.1 
Treatment Assignment ................................................................................ 39 
7.2 
Randomization............................................................................................. 39 
8. 
TREATMENT PROCEDURES ................................................... 40 
8.1 
Investigational Medicinal Product Dosage, Administration and 
Schedule ...................................................................................................... 40 
8.1.1 
Dose Administration ................................................................................. 40 
8.1.2 
Dose Escalation and Dose Adjustments ................................................... 40 
8.2 
Concomitant Therapy .................................................................................. 41 
8.3 
Prohibited Therapy During Study Period .................................................... 41 
8.4 
Compliance in Investigational Medicinal Product Administration ............. 42 
8.5 
Access to Blinded Treatment Assignment .................................................. 42 
9. 
STUDY PROCEDURES ............................................................... 43 
9.1 
Study Procedure Listing .............................................................................. 43 
9.1.1 
Contraception ............................................................................................ 43 
9.1.2 
Informed Consent ..................................................................................... 43 
9.1.3 
Demographics ........................................................................................... 43 
9.1.4 
Medical History ........................................................................................ 44 
9.1.5 
Concomitant Medication .......................................................................... 44 
9.1.6 
Physical Examination ............................................................................... 44 
9.1.7 
Vital Signs ................................................................................................ 44 
9.1.8 
12-Lead Electrocardiogram ...................................................................... 44 
9.1.9 
Clinical Laboratory Sampling................................................................... 44 
9.1.10 
Pharmacokinetic Analyses ........................................................................ 46 
9.1.11 
Columbia Suicide Severity Rating Scale .................................................. 46 
9.1.12 
Patient Diary ............................................................................................. 47 
9.1.13 
Investigational Medicinal Product Accountability ................................... 47 
9.1.14 
Adverse Events ......................................................................................... 47 
9.2 
Study Procedures by Visit ........................................................................... 48 
9.2.1 
Single Blind Phase .................................................................................... 48 


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9.2.1.1 
Visit 1 (Day −7, Screening) .................................................................. 48 
9.2.1.2 
Visit 2 .................................................................................................... 49 
9.2.1.2.1 
Visit 2 (Day 1) – Enrollment (+3 days) ............................................. 49 
9.2.1.2.2 
Visit 2 (Day 2) - Enrollment .............................................................. 49 
9.2.1.3 
Visit 3 .................................................................................................... 49 
9.2.1.3.1 
Visit 3 (Day 25) (±3 days) ................................................................. 49 
9.2.1.3.2 
Visit 3 (Day 26) ................................................................................. 50 
9.2.1.4 
Visit 4 .................................................................................................... 50 
9.2.1.4.1 
Visit 4 (Day 50) (±3 days) ................................................................. 50 
9.2.1.4.2 
Visit 4 (Day 50) ................................................................................. 51 
9.2.1.5 
Visit 5 (Patients not entering OLE) (+3 days) ...................................... 51 
9.2.1.6 
Safety Follow up Call (Day 87) (±3 days) ............................................ 52 
9.2.2 
Open Label Extension ............................................................................... 52 
9.2.2.1 
Visit 5 (Open Label Extension) - Two Weeks (±3 days) ...................... 52 
9.2.2.2 
Visit 6 (Open Label Extension) - One Month (±3 days) ....................... 52 
9.2.2.3 
Visit 7 (Open Label Extension) - Two Months (±3 days) .................... 52 
9.2.2.4 
Visit 8 (Open Label Extension) - Three Months (±7 days) .................. 53 
9.2.2.5 
Visit 9 (Open Label Extension) - Six Months (±7 days) ...................... 53 
9.2.2.6 
Visit 10 (Open Label Extension) - Nine Months (±7 days) .................. 53 
9.2.2.7 
Visit 11 (Open Label Extension End of Treatment) - Twelve 
Months (±7 days) .................................................................................. 54 
9.2.2.8 
Visit 12 (Open Label Extension End of Taper) .................................... 54 
9.2.2.9 
Safety Follow Up Call (±3 days) .......................................................... 54 
10. 
WITHDRAWAL ............................................................................ 54 
11. 
URGENT SAFETY MEASURES ................................................ 56 
12. 
ADVERSE EVENT REPORTING .............................................. 56 
12.1 
Definitions ................................................................................................... 56 
12.1.1 
Adverse Event ........................................................................................... 56 
12.1.2 
Investigator ............................................................................................... 56 
12.2 
Serious Adverse Events ............................................................................... 56 
12.3 
Reporting Procedures for Serious Adverse Events ..................................... 57 
12.4 
Pregnancy .................................................................................................... 58 
12.5 
Causality Assessment .................................................................................. 58 


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12.6 
Reporting Procedures for All Adverse Events ............................................ 59 
12.7 
Follow up Procedures for Adverse Events .................................................. 61 
12.8 
Reporting Clinically Significant Laboratory Results .................................. 61 
12.9 
Notification of Safety Information to Investigators, Regulatory 
Authorities and Ethics Committees. ............................................................ 62 
13. 
STATISTICAL CONSIDERATIONS ......................................... 64 
13.1 
Sample Size, Power and Significance Levels ............................................. 64 
13.2 
Interim Analysis .......................................................................................... 64 
13.3 
Analysis Sets ............................................................................................... 64 
13.3.1 
Safety Set .................................................................................................. 64 
13.3.2 
Pharmacokinetic Analysis Set .................................................................. 64 
13.3.3 
Protocol Deviations .................................................................................. 64 
13.4 
General Considerations ............................................................................... 64 
13.5 
Accountability and Background Characteristics ......................................... 65 
13.5.1 
Enrolment and Disposition ....................................................................... 65 
13.5.2 
Baseline and Demographic Characteristics .............................................. 65 
13.5.3 
Medical History ........................................................................................ 65 
13.5.4 
Concomitant Medication .......................................................................... 65 
13.6 
Endpoints and Statistical Methods .............................................................. 65 
13.6.1 
Primary Endpoint(s) .................................................................................. 65 
13.6.2 
Secondary Endpoint(s) .............................................................................. 65 
13.6.3 
Pharmacokinetics ...................................................................................... 65 
13.6.4 
Safety ........................................................................................................ 67 
13.6.4.1 
Treatment Compliance and Extent of Treatment Exposure .................. 67 
13.6.4.2 
Adverse Events...................................................................................... 67 
13.6.4.3 
Clinical Laboratory Data ....................................................................... 67 
13.6.4.4 
Columbia-Suicide Severity Rating Scale, Vital Signs, 12-lead 
Electrocardiogram, Physical Examination and Other Safety Data ....... 67 
13.6.4.5 
Seizure Data .......................................................................................... 68 
14. 
DATA SAFETY MONITORING COMMITTEE ..................... 68 
15. 
REGULATORY AND ETHICAL OBLIGATIONS .................. 69 
15.1 
Declaration of Helsinki ............................................................................... 69 
15.2 
Informed Consent ........................................................................................ 69 
15.3 
Institutional Review Board/Ethics Committee ............................................ 69 


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15.4 
Pre-Study Documentation Requirements .................................................... 70 
15.5 
Participant Confidentiality .......................................................................... 70 
16. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ............... 72 
16.1 
Protocol Amendments and End of Study or Termination ........................... 72 
16.2 
Study Documentation and Storage .............................................................. 72 
16.3 
Study Monitoring and Data Collection ....................................................... 73 
16.4 
Quality Assurance ....................................................................................... 75 
16.5 
Compensation .............................................................................................. 75 
16.6 
Publication Policy........................................................................................ 75 
16.7 
Intellectual Property Rights ......................................................................... 76 
16.8 
Confidential Information ............................................................................. 76 
17. 
REFERENCES .............................................................................. 77 


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Table of Appendices 
APPENDIX 1. 
Schedule of Assessments 
80 
APPENDIX 2. 
Study Personnel 
83 
Appendix 3.1 
Investigator Details 
83 
Appendix 3.2 
Sponsor Contact Details 
83 
 
 


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List of In-text Tables 
Table 3.3.1-1 
Epidiolex Adverse Events ........................................................ 31 
Table 5.1-1 
Formulation of GWP42003-P Oral Solution ........................... 34 
Table 5.2-1 
Formulation of Placebo Oral Solution ..................................... 34 
Table 8.1-1 
Dose Titration Regimen* ......................................................... 41 
Table 9.1-1 
Hematology, Biochemistry, Urinalysis and THC Screen ........ 45 
 
 
 


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List of In-text Figures 
Figure 1-1 
Study Design and Treatment Schema  
 
 
15 
 


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List of Abbreviations 
AE 
Adverse Event 
AEDs 
Antiepileptic Drugs 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC(0–∞) 
The area under the plasma concentration versus time curve from 
zero to ‘t’ calculated as AUC(0–t) plus the extrapolated amount 
from time ‘t’ to infinity 
AUC(0–t) 
The area under the plasma concentration versus time curve, from 
time zero to ‘t’ (where t = the final time of positive detection) as 
calculated by the linear trapezoidal method 
BP 
Blood Pressure 
CLB 
Clobazam 
CBD 
Cannabidiol 
CI 
Confidence Interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CLB 
Clobazam 
Cmax 
Maximum measured plasma concentration 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DILI 
Drug-Induced Liver Injury 
EC 
Ethics Committee 
ECG 
12-lead Electrocardiogram 
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 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug 
INR 
International Normalized Ratio 


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IRB 
Institutional Review Board 
ITT 
Intention to Treat 
IVRS 
Interactive Voice Response System 
LOCF 
Last Observation Carried Forward 
MMRM 
Mixed-effects Model Repeated Measures 
N-CLB 
N-desmethylclobazam 
OLE 
Open label extension 
PBPK 
Physiologically-based pharmacokinetic interactions 
PI 
Principal Investigator 
PP 
Per Protocol 
PVD 
Pharmacovigilance Department 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
t½ 
Half-life 
TBL 
Total bilirubin 
THC 
∆9-tetrahydrocannabinol 
tmax 
Time to the maximum measured plasma concentration 
ULN 
Upper Limit of Normal 
USA 
United States of America 
VNS 
Vagus Nerve Stimulation 
 


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Definition of Terms 
Term 
Definition 
Baseline period 
The seven-day period from screening (Visit 1) to enrollment 
(Visit 2). 
Convulsive seizures 
Tonic-clonic, tonic, clonic or atonic seizures. 
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 is enrolled and begins PK sampling. 
End of treatment 
Completion of the treatment period (Visit 5 or Visit 11) or 
withdrawal. 
End of study 
Last patient’s last visit / last contact. 
IMP 
Investigational Medicinal Product (Study Medication). Used 
to describe both investigational active product and reference 
therapy (placebo). 
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. 
Partial seizures 
Partial (focal) seizures occur when the electrical activity 
remains in a limited area of the brain. 
Status epilepticus 
Seizures lasting for 30 minutes or longer. 
Sub-types of seizures 
Seizure sub-types can be tonic, clonic, tonic-clonic, atonic, 
myoclonic, absence (typical and atypical), countable partial 
and other partial. 
 


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2. 
OBJECTIVES 
2.1 
Primary 
To determine whether cannabidiol (CBD) affects the pharmacokinetic (PK) profile of 
clobazam (CLB) and its primary metabolite N-desmethylclobazam (N-CLB). 
2.2 
Secondary 
To assess the safety and tolerability of CBD in the presence of CLB. 
3. 
BACKGROUND AND RATIONALE 
3.1 
Disease 
Epilepsy is a common disorder1. Approximately 1% of the world’s population is 
chronically affected by epilepsy2. It shows no particular geographic distribution and 
the gender distribution is more or less equal. The incidence of epilepsy is greater in 
childhood and in elderly people2,3,4,5. Focal seizures represent the most frequent 
seizure type (around 60% of all cases of epilepsy, and a substantial percentage of 
them are not well controlled)6. 
Overall, and despite the introduction of a substantial number of new antiepileptic 
drugs (AEDs) in the last two decades, around 30% of patients remain refractory to 
currently available treatment7,8,9. In addition, most currently approved AEDs are 
associated with significant motor and cognitive adverse reactions10,11. 
Currently available AEDs each belong to one of a large number of different classes. 
The principal targets for existing AEDs tend to be either modulators of voltage-
dependent ion channels, enhancers of inhibitory neurotransmission, and attenuators of 
excitatory neurotransmission, with the aim being to reduce neuronal 
excitotoxicity12,13. 
3.2 
GWP42003-P Background 
The cannabis plant (Cannabis sativa L.) produce trichomes that synthesize a large 
number of pharmacologically active compounds called phytocannabinoids. The most 
abundant of these are Δ9-tetrahydrocannabinol (THC) and 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 


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these plants are processed to yield pure (>98%) CBD that typically contains less than 
0.5% (w/w) THC. 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 conductance and acts on other G-protein-coupled receptors such as 
the transient receptor potential channel TRPV114 and the orphan receptor GPR5515. 
Importantly, in contrast to THC, CBD lacks detectable psychoactivity. CBD has 
demonstrated anticonvulsant, antipsychotic, anxiolytic, neuroprotective, antioxidant 
and anti-inflammatory activity16. Very little data concerning 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 humans17. 
3.3 
Rationale 
CBD has shown therapeutic potential as an AED, with preclinical studies 
demonstrating anticonvulsant effects in a number of animal models of seizure16,18,19. 
Although no placebo-controlled trials have been completed to date, 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 either >80% reduction in seizure frequency or complete seizure 
freedom20. The CBD-enriched cannabis was behaviorally well tolerated and children 
often experienced improved sleep, increased alertness and better mood. There has 
been a program of expanded access by GW Pharma Ltd (GWP) in the USA, primarily 
in children with severe epilepsy, that has shown encouraging reports of reductions in 
multiple seizure types with good tolerability in 151 exposures21. 
Population-based studies of drug utilization demonstrate that 19-24% of patients with 
epilepsy use polytherapy with AEDs22,23,24. In recent studies of children and adults 
with refractory epilepsy, 64 % used polytherapy with two or more AEDs, resulting in 
a considerable risk of interactions25,26. CLB is a widely used AED, prescribed with 
other medication(s) to control seizures in adults and children two years of age and 
older who have Lennox-Gastaut syndrome (a disorder that causes seizures and often 


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developmental delays). The pharmacological action of CLB is to decrease abnormal 
electrical activity in the brain via allosteric activation of the ligand-gated γ-
aminobutyric acid (A) receptor. 
CLB is in a class of medications called benzodiazepines. Similar to other 
benzodiazepine medications, clobazam is metabolized by cytochrome P450 (CYP450) 
enzymes (mainly in the liver). This metabolism results in the formation of an active 
metabolite N-desmethylclobazam (N-CLB), amongst others. 
Cytochrome P450 enzymes are a family of heme-containing enzymes responsible for 
the metabolism of over half of all prescribed medications and interactions with these 
enzymes are the major source of physiologically-based pharmacokinetic (PBPK) 
interactions between drugs. It is anticipated that patients taking CBD may also be 
taking clobazam and as CBD has been shown to both inhibit CYP450 enzymes in 
vitro (Ki CYP3A4 = 1.5 μM) and induce CYP450 enzymes in vitro (EC50 CYP3A4 
= 1.2 μg/mL) a possibility of a pharmacokinetic (PK) interaction between CBD and 
clobazam exists. Furthermore, CLB has been shown to undergo PBPK interactions 
with other AED medications via both CYP induction (such as with felbamate where 
the formation of the active metabolite of clobazam, N-CLB was increased several-
fold27) and also CYP inhibition (such as with stiripentol where serum concentrations 
of CLB were increased and metabolites decreased28,29,30). Given the high likelihood 
that patients prescribed CBD will also be using clobazam, it is the aim and purpose of 
this study to determine whether a PK interaction between CBD and CLB exists. 
3.3.1 
Selection of Study Doses 
Doses up to 800 mg CBD per day for up to eight weeks have been well tolerated in 
adults in GW Research Ltd (GW) clinical study GWMD09112, which, assuming an 
average weight of 70 kg, equates to a daily dose of 11.4 mg/kg. In the literature, doses 
of CBD have been given up to 1500 mg CBD per day for four weeks in adults, which, 
in a 70 kg human equates to a daily dose of 21.4 mg/kg CBD. 
Data on the safety of CBD is emerging from the physician-initiated Epidiolex® 
Expanded Access Program being conducted in the USA. This program has been 
running since January 2014 and at the time of writing had data on 63 patients. The 
mean maximum exposure achieved in this patient population of refractory epilepsies 
was a daily dose of 24.4 mg/kg (n=59 patients) with a maximum dose of 51 mg/kg in 
one patient. Please see below for a break-down of the groups: 
• ≤ 20 mg/kg CBD n=13 (21%) 
• >20 mg/kg ≤ 30 mg/kg CBD n=40 (64%) 
• >30 mg/kg ≤ 40 mg/kg CBD n=4 (6%) 


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• >40 mg/kg CBD n=2 (3%) 
• Dose not reported n=4(6%) 
11 patients had a daily CBD dose of >25 mg/kg, of which five did not report any 
adverse events (AEs). Of note, the patient who received 51 mg/kg did not have any 
AEs at this dose. The remaining six patients experienced AEs as documented in the 
Table 3.3.1-1below: 
Table 3.3.1-1 
Epidiolex Adverse Events 
Adverse Event Term 
Number of Events 
Loose stools / urgent bowel 
movements 
2 
Increase in seizures 
2 
Drowsiness 
1 
Aspiration pneumonia 
1 
Lethargy 
1 
Decreased appetite 
1 
Dyskinesia 
1 
Urinary tract infection 
1 
Based on the above, a daily dose up to 20 mg/kg/day (given as two divided doses) has 
been selected for the CBD dose in the current study, including a titration period with 
daily increments of 2.5 mg/kg and 5 mg/kg. At the end of the treatment period, 
patients will be given the option of continuing onto an open label extension (OLE) 
period if the investigator and patient both agree that it is in their best interest. During 
the OLE doses may be adjusted up or down, dependent on investigator opinion, to a 
maximum daily dose of 30 mg/kg CBD. 
3.4 
Clinical Hypothesis 
CBD can act as both a CYP inhibitor and inducer in human hepatocytes in vitro. 
Therefore, the potential for PK interactions with other drugs that are metabolized by 
CYP450 enzymes exists. The hypothesis is that the in vivo PK of CLB and its major 
metabolite (N-CLB) may be altered (increased or decreased) by the chronic 
administration of CBD. 
4. 
EXPERIMENTAL PLAN 
4.1 
Study Design 
This phase 2, placebo-controlled study consists of a 52 day, single-blind phase 
followed by an optional maximum one year OLE. Patients will continue to take CLB 
as advised by their physician for the duration of the study. The IMP will be taken 
twice daily immediately after their CLB dose. 


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Patients will enter the study and begin a 10 day placebo titration phase. During this 
period patients will be up-titrated to an equivalent maintenance dose of 20 mg/kg/day. 
Patients will continue to take this maintenance dose of placebo for 14 days (Days 12 
to 26). 
On Day 27 patients will begin a 10 day CBD titration phase. During this period 
patients will be up-titrated to a maintenance dose of 20 mg/kg/day CBD. Patients will 
continue to take this maintenance dose for 14 days (Days 37 to 50). 
Upon completion of the single blind phase of the study (Day 52) patients will be 
invited to receive CBD during the OLE phase. If a patient enters the OLE they will 
continue to take CBD as advised by the investigator. If a patient chooses not to enter 
the OLE, and/or the investigator does not feel it is in their best interests, they will 
taper off their CBD treatment by reducing their maintenance dose by 10% per day 
until dosing has ceased. For those patients not entering the OLE, dosing will end on 
Day 60 and they will receive a telephone follow-up visit four weeks after the end of 
IMP dosing (Day 89). 
PK samples will be taken on three occasions during the single blind phase of the 
study: 
• Day 1 (Visit 2) before beginning treatment (patients will be taking CLB only). 
• Day 26 (Visit 3) following 14 days of placebo maintenance (patients will be 
taking CLB and placebo). 
• Day 51 (Visit 4) following 14 days of CBD maintenance (patients will be 
taking CLB and CBD). 
Ten samples will be taken during each PK assessment. PK samples should be taken at 
time points in respect to the morning dose of CLB. The time points are as follows: 
Pre-dose, 15min, 30min, 1h, 1.5h, 2h, 4h, 6h, 12h and 24h. PK samples will be 
quantitatively analyzed for CLB, N-CLB (primary metabolite of CLB), CBD and 
CBD major metabolites. 
Patients should try to be consistent in the timing of their food intake in relation to 
dosing throughout the single blind phase of the study. 
Upon entry into the OLE the dose of CBD may be adjusted up or down to a maximum 
of 30 mg/kg/day. The OLE will last for a maximum of one year or until marketing 
authorization is granted; whichever is earlier. 
Patients will be required to keep a paper diary to note the time and dose of IMP and 
CLB administration each morning and evening and to record any AEs that may occur 
whilst receiving IMP and any other medications. Patients will also be required to 
record the number and type of seizures for each day whilst on the study. 


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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 are 
provided in Section 7 and Section 9 respectively. 
4.1.1 
Primary Endpoint 
The primary endpoints of the study are the PK parameters (Cmax, tmax, AUC(0–∞) 
AUC(0–t), t½) of the following analytes: 
• CLB 
• N-desmethylclobazam (N-CLB) 
• CBD 
• CBD major metabolites 
4.1.2 
Secondary Endpoint(s) 
To assess the safety and tolerability of CBD compared with placebo when taken in 
combination with CLB. Safety and tolerability will be assessed using the following 
parameters: 
• AEs 
• 12-lead Electrocardiogram (ECG) 
• Clinical laboratory parameters (clinical chemistry, hematology and urinalysis) 
• Vital signs 
• Columbia-Suicide Severity Rating Scale (C-SSRS) 
• Seizure Frequency 
4.2 
Number of Centers 
An estimated number of two centers is expected to participate in this study. 
4.3 
Number of Patients 
A total of 20 patients will be enrolled into the study. Recruitment for the study will be 
competitive between participating sites. 
The sample size calculation is explained fully in Section 13.1. 
5. 
INVESTIGATIONAL MEDICINAL PRODUCT 
Please refer to the separate Pharmacy Manual for more detailed information on the 
IMP. 


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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 
Placebo Oral Solution 
Placebo oral solution contains the excipients sesame oil and anhydrous ethanol with 
added sweetener (sucralose) and strawberry flavoring Table 5.2-1. 
Table 5.2-1 
Formulation of Placebo Oral Solution 
Material 
Quantity 
Anhydrous ethanol 
79 mg/mL 
Sucralose 
0.5 mg/mL 
Strawberry flavoring 
0.2 mg/mL 
Sesame oil 
make up to 1 mL 
5.3 
Packaging, Storage and Drug Accountability 
5.3.1 
Packaging and Labelling  
The IMP will be manufactured and packaged by 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 weight of each patient. 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 labelled and packaged. Label text will comply with European Union 
(EU) guidance on Good Manufacturing Practice, Annex 13 Labelling and will be fully 
described in the separate Pharmacy Manual. 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 investigator, or main 
contact for information about the product or the clinical trial, will be provided 
separately to the patient. 


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5.3.2 
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. 
5.3.3 
Supply and Return of Investigational Medicinal Product 
Once a site has been activated 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 and the condition of the drug. Details of the IMP received will be recorded in 
the IMP accountability record. The site will acknowledge IMP receipt and will 
complete any receipt forms required. IMP will be dispensed and returned as detailed 
in Section 5.3.4 with further IMP shipments to be requested as necessary. 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. 
5.3.4 
Investigational Medicinal Product Accountability 
The investigator has overall responsibility for the accountability of all used and 
unused IMP. A drug accountability record for the IMPs must be kept current and 
should contain: 
• 
The dates and quantities of IMP received from GWP. 
• 
Patient’s identification. 
• 
Date and quantity of IMP dispensed. 
• 
The initials of the dispenser. 
• 
Date and quantity of IMP returned to the investigator/pharmacy. 


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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 authorized GW or GWP 
representatives and local officials or regulatory agency inspectors. 
Please refer to the separate Pharmacy Manual for more detailed information on the 
IMP. 
6. 
PARTICIPANT ELIGIBILITY 
Investigators will be required to maintain a log that includes limited information about 
all screened patients (initials, age, and gender; as allowed per local regulations) and 
outcome of screening. 
6.1 
Inclusion Criteria 
For inclusion in the study patients must fulfil ALL of the following criteria: 
6.1.1 
Male or female patients aged 18 to 55 years inclusive. 
6.1.2 
Patient must have epilepsy as determined by the investigator and be taking 
CLB. 
6.1.3 
Patient must have a documented magnetic resonance imaging/computerized 
tomography of the brain that ruled out a progressive neurologic condition. 
6.1.4 
Patient must have experienced at least one seizure of any type (i.e., tonic-
clonic, tonic, clonic, atonic seizures) within the two months prior to 
randomization. 
6.1.5 
Patients must be taking CLB and no more than two other AEDs during the 
course of the study. 
6.1.6 
AED(s), including CLB, must be stable for four weeks prior to screening 
and regimen must remain stable throughout the duration of the blinded 
phase of the study. 
6.1.7 
Intervention with vagus nerve stimulation (VNS) and/or ketogenic diet 
must be stable for four weeks prior to baseline and patient/caregiver must 
be willing to maintain a stable regimen throughout the duration of the 
study. 
6.1.8 
Patients must abstain from alcohol during the single-blind phase of the 
study. 
6.1.9 
Patient and/or legal representative is available to attend all PK visits within 
the required visit window. 
6.1.10 
Patient and/or legal representative must be willing and able to give 
informed consent for participation in the study 
6.1.11 
Patient and/or legal representative must be willing and able (in the 
investigator’s opinion) to comply with all study requirements. 


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6.1.12 
Patient is willing for his or her name to be notified to the responsible 
authorities for participation in this study, as applicable. 
6.1.13 
Patient is willing to allow his or her primary care practitioner and 
consultant, if appropriate, 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 has clinically significant unstable medical conditions other than 
epilepsy. 
6.2.2 
Patients on CLB at doses above 20 mg per day. 
6.2.3 
Patients taking CLB intermittently as rescue medication. 
6.2.4 
Patient has a history of symptoms (e.g., dizziness, light-headedness, blurred 
vision, palpitations, weakness, syncope) related to a drop in blood pressure 
(BP) due to postural changes. 
6.2.5 
Any history of suicidal behavior or any suicidal ideation of type four or five 
on the C-SSRS in the last month or at screening. 
6.2.6 
Patient has had clinically relevant symptoms or a clinically significant 
illness in the four weeks prior to screening or enrollment, other than 
epilepsy. 
6.2.7 
Patient has consumed alcohol during the seven days prior to enrollment and 
is unwilling to abstain for the duration of the study. 
6.2.8 
Patient is currently using or has in the past used recreational or medicinal 
cannabis, or synthetic cannabinoid based medications (including Sativex®) 
within the three months prior to study entry. 
6.2.9 
Patient has any known or suspected history of any drug abuse or addiction. 
6.2.10 
Patient is unwilling to abstain from recreational or medicinal cannabis, or 
synthetic cannabinoid based medications (including Sativex) for the 
duration for the study. 
6.2.11 
Patient has consumed grapefruit or grapefruit juice seven days prior to 
enrollment and is unwilling to abstain from drinking grapefruit juice within 
seven days of PK visits. 
6.2.12 
Patient has any known or suspected hypersensitivity to cannabinoids or any 
of the excipients of the IMP, e.g., sesame oil. 
6.2.13 
Female patients must have a negative pregnancy test and be willing and 
able to use a reliable method of contraception throughout the trial and for 
three months after last dose. In the context of this trial, an effective method 
is defined as those which result in low failure rate (i.e., less than 1% per 
year) when used consistently and correctly such as: combined or 
progesterone only oral contraceptives, intrauterine device, intrauterine 
hormone-releasing system, bilateral tubal occlusion, vasectomized partner 
or sexual abstinence. The use of hormonal contraception must be 
supplemented with a barrier method (preferably male condom). 


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6.2.14 
Female patient who is pregnant, lactating or planning pregnancy during the 
course of the study and for three months thereafter. 
6.2.15 
Patients who have received an IMP within the 12 weeks prior to the 
screening visit. 
6.2.16 
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 the patient’s ability to 
participate in the study. 
6.2.17 
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. 
6.2.18 
Patient has significantly impaired hepatic function, as determined at 
screening or enrollment (Alanine aminotransferase [ALT] >5 × upper limit 
of normal [ULN] or total bilirubin [TBL] >2 × ULN) OR the ALT or 
Aspartate aminotransferase (AST) >3 × ULN and (TBL >2 × ULN or 
international normalized ratio [INR] >1.5). This criterion can only be 
confirmed once the laboratory results are available; patients randomized 
into the study who are later found to meet this criterion must be withdrawn 
from the study. 
6.2.19 
Unwilling to abstain from donation of blood during the study. 
6.2.20 
Travel outside the country of residence planned during the study. 
6.2.21 
Patients previously enrolled into this study. 
 


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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 forms and other patient information material. 
Patients will be considered enrolled in the study from the time of providing written 
informed consent. All patients, or legal representatives, where appropriate, must 
personally sign and date the consent form prior to any procedures being performed 
(refer to Section 9.1.2 and Section 15.2). 
7.1 
Treatment Assignment 
At the start of Visit 1, patients will be allocated a unique patient number, consisting of 
a four digit GW center number and a three digit patient identification number. The 
three digit patient number will be assigned in ascendant numerical order at each site. 
The unique patient number will be preceded by a unique letter. For example, 
P1234001, denoting patient 001 at site 1234. GWP will provide all IMP packed and 
labelled. Following enrollment at Visit 2, patients will be allocated a pre-packed 
numbered IMP. 
7.2 
Randomization 
This is a single-blind study with all patients following the same treatment regimen. 
 
 


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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 either the active 
pharmaceutical ingredient and excipients (in the case of GWP42003-P) or only 
excipients (in the case of placebo). For details regarding IMP formulations, see 
Section 5. 
The IMP will consist of two types of medication: 
• GWP42003-P Oral Solution containing 100 mg/mL CBD. 
• Placebo Oral Solution containing excipients. 
All patients will be weighed during Visit 2 and the daily volumes of IMP solution to 
be taken during the titration period, and for the remainder of the study, will be 
calculated and provided to the patient and/or caregiver. Further information on 
dispensing procedures will be provided in a separate Pharmacy Manual. 
Each patient will take their first dose of IMP at Visit 2, Day 2 in the clinic. Patients 
not entering the OLE will take their final maintenance dose of IMP at Visit 4 (Day 51) 
in the clinic. Patients entering the OLE will take their final dose of IMP at Visit 11 
(one year after the end of the blinded phase of the study) or sooner (if marketing 
authorization is granted within one year). 
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 should be taken 
immediately after the patient’s usual CLB administration. The IMP should be 
swallowed, as per the intended commercial therapeutic route, and may be taken with 
other concomitant medications, as directed by the investigator. 
8.1.2 
Dose Escalation and Dose Adjustments 
Patients will enter the single blind phase of the study and will be up-titrated over ten 
days (Day 2 to Day 11) to an equivalent maintenance dose of placebo of 
20 mg/kg/day. From Day 27 to Day 36 patients will be up-titrated to a maintenance 
dose of 20 mg/kg/day CBD. The titration regimen is described in Table 8.1-1. 
For those patients who do not enter the OLE the dose of CBD will taper off over 10 
days beginning on Day 52. The patient will reduce the dose by 10% of the 
maintenance dose each day and treatment will end on Day 60. 


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For patients who enter the OLE the maintenance dose of CBD may be adjusted up or 
down, depending on investigator opinion, to a maximum of 30 mg/kg/day. 
Table 8.1-1 
Dose Titration Regimen* 
Day - Placebo 
Day - CBD 
Dose Level 
(CBD or equivalent 
placebo) 
2 
26 
2.5 mg/kg 
3 
27 
2.5 mg/kg 
4 
28 
5.0 mg/kg 
5 
29 
5.0 mg/kg 
6 
30 
7.5 mg/kg 
7 
31 
7.5 mg/kg 
8 
32 
10.0 mg/kg 
9 
33 
10.0 mg/kg 
10 
34 
15.0 mg/kg 
11 
35 
15.0 mg/kg 
12 onwards 
36 onwards 
20.0 mg/kg 
*IMP is to be taken twice daily. Total daily doses are shown. 
8.2 
Concomitant Therapy 
Doses of any concomitant AEDs, including CLB, must have been stable for at least 
four weeks prior to screening and must remain stable throughout the study period. 
The use of rescue medication is allowed if necessary. The use of oxygen may be 
considered as rescue medication if used as required. Any medication, other than the 
IMP, taken during the study must be recorded on the Case Report Form (CRF). 
Any non-pharmacological therapies (e.g., ketogenic diet, VNS) must also be stable up 
to four weeks prior to baseline and throughout the duration of the study. 
8.3 
Prohibited Therapy During Study Period 
The following medications are prohibited for the duration of the study starting from 
acquisition of patient consent. However, any patients taking these medications after 
screening 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. 
• Any new medications or interventions for epilepsy (including ketogenic diet 
and VNS) or changes in dosage. 
• Patients should not take any more than three AEDs inclusive of CLB. 
• Recreational or medicinal cannabis or synthetic cannabinoid based 
medications (including Sativex) within three months prior to or during the 
study. 
• Any other IMP taken as part of a clinical trial within six months or during the 
study. 


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8.4 
Compliance in Investigational Medicinal Product Administration 
Patients or their caregivers will record the total volume of IMP, administered on each 
treatment day, using the paper diary and will be asked to return all IMP (used and 
unused) at each subsequent visit. The site will check the returned IMP against the 
usage recorded in the diary and the projected usage. 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. 
Records of IMP accountability will be maintained according to Section 5.3.4. 
8.5 
Access to Blinded Treatment Assignment 
This is a single blind study. The identity of IMP assigned to patients will be known to 
the PI and the GWEP1428 study team at each site but will not be known by the 
patients. 


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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 
9.1.1 
Contraception 
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 effective contraception for the 
duration of the study and for three months thereafter. A highly effective method of 
birth control is defined as those which result in a low failure rate (i.e., less than 1% 
per year) when used consistently and correctly such combined or progesterone only 
oral contraceptives, intrauterine device, intrauterine hormone-releasing system, 
bilateral tubal occlusion, vasectomized partner or sexual abstinence6. Abstinence, as 
referenced above, 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. The use of hormonal contraception must be supplemented 
with a barrier method (preferably male condom). 
9.1.2 
Informed Consent 
Adult patients with an adequate level of understanding must personally sign and date 
the IRB/EC approved informed consent form before any study specific procedures are 
performed or any patient related data is recorded for the study. For adult patients with 
an insufficient level of understanding of what is proposed, only personal legal 
representative consent will be sought. The informed consent process should be 
documented within the patient notes. 
GW requires a physician to be present for consent and to also sign the consent forms. 
9.1.3 
Demographics 
Patient demographics will be recorded at Visit 1. The following information will be 
obtained for each patient: date of birth, gender and ethnic origin (if allowed per local 
regulations). 


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9.1.4 
Medical History 
Relevant, significant medical history (including seizure information since diagnosis, 
history of epilepsy-specific genetic testing and all prior AEDs taken) will be obtained 
during Visit 1 and is defined as any condition or disease that: 
• May affect the condition under study. 
• Is ongoing on entry into the study. 
9.1.5 
Concomitant Medication 
Details of all current and recent medication (i.e., taken within the previous 28 days) 
including AEDs will be recorded at the screening visit (Visit 1) and reviewed at each 
subsequent visit. AEDs used during the study should be maintained at a stable dose. 
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 the 
screening visit, as defined in Section 8.3. 
9.1.6 
Physical Examination 
A physical examination will be performed at the screening visit (Visit 1) to ensure 
that the patient is eligible to enter the study. To ensure patient safety, further physical 
examinations will be performed at every hospital visit. Physical examinations will 
include height and body weight measurements. 
9.1.7 
Vital Signs 
Vital sign measurements, taken after five minutes rest in a sitting position, will be 
completed alongside the physical examination at all visits. Postural BP will be 
assessed after five minutes in supine position and, if possible, two minutes in standing 
position. The pulse rate must also be measured as part of the vital sign assessments. 
BP and pulse rate must be recorded using the same arm throughout the study. 
9.1.8 
12-Lead Electrocardiogram 
An ECG will be performed, after five minutes in supine position, at all hospital visits. 
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 be undertaken at all hospital visits and will include hematology, 
biochemistry, and urinalysis (provided urine can be obtained, with the exception of 


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screening where a urine sample for THC screen must be obtained). A serum 
pregnancy test (if appropriate) will also be performed at Visit 1. 
Urine samples for biochemistry will be analyzed at the study center by use of a 
dipstick with any relevant findings being sent for further laboratory based urinalysis 
(urinalysis, microscopy, culture and sensitivity, as applicable). 
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 9.1-1.  
Table 9.1-1 
Hematology, Biochemistry, Urinalysis and THC Screen 
Biochemistry 
(serum) 
Hematology 
(whole blood) 
Urinalysis 
(urine) 
Pregnancy 
Test 
THC screen 
(urine) 
Alanine aminotransferase 
(ALT) 
Hematocrit 
Bilirubin 
Serum 
THC 
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 
 
 
 
 
Potassium 
 
 
 
 
Prolactin 
 
 
 
 
Prothrombin time (plasma) 
 
 
 
 
Sodium 
 
 
 
 
Total bilirubin (TBL) 
 
 
 
 
Total protein 
 
 
 
 
Urea 
 
 
 
 
 
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 (DILI). All laboratory results considered by the investigator 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 


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investigator is satisfied that the abnormality is not related to the IMP and needs no 
further investigation. 
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 
them 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 in the four weeks 
prior to screening. 
9.1.10 
Pharmacokinetic Analyses 
The plasma concentration/time curves of CLB, N-CLB, CBD and CBD major 
metabolites will be assessed at Visit 2 (Day 1 and Day 2), Visit 3 (Day 26 and Day 
27) and Visit 4 (Day 51 and Day 52). Patients will be given their daily dose of 
clobazam at a scheduled time during Visit 2, Visit 3 and Visit 4 and the IMP 
immediately afterwards (Visit 3 and Visit 4 only) to facilitate the accurate timing of 
blood samples required for PK analysis. Blood samples will be taken by either direct 
venipuncture or an indwelling cannula inserted into a forearm vein at the following 
times: Pre-dose and, 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 
hours, 12 hours and 24 hours after dosing. The timing of each PK sample will be 
relative to the morning dose of CLB. 
The pre-dose blood sample will be taken within 30 minutes prior to dosing. The 
allowable window for post-dose blood sample collection is ±2 minutes up to and 
including 1 hour post-dose, ±5 minutes from 1.5 hours up to and including 6 hours 
post-dose and ±1 hour at 12 hours and 24 hours post-dose. 
In the event of an AE that, in the opinion of the investigator, is related to a 
concomitant AED, additional blood samples may be collected. 
Analysis of all PK samples will be conducted at a central clinical laboratory. Sample 
volume requirements and processing procedures will be detailed in a separate 
laboratory manual. 
9.1.11 
Columbia Suicide Severity Rating Scale  
The C-SSRS is to be completed by the investigator or his/her qualified designee at all 
hospital visits. Qualified designee is defined as physician, osteopath, nurse 
practitioner, clinical psychologist or physician’s assistant who is licensed and has 
completed the C-SSRS training within the last two years. It is a brief standardized 
measure that uniquely assesses the essential information (behavior, ideation, lethality 
and severity) and distinguishes between suicidal occurrences and non-suicidal self-


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injury. The survey should be completed by the same assessor, where possible, 
throughout the study. 
If the investigator or his/her qualified designee feel that the patient is either unable to 
answer the questions presented in C-SSRS, or that the questions are causing undue 
stress to the patient, the questionnaire may be skipped and this must be documented in 
the patient notes. 
9.1.12 
Patient Diary 
Patients or their caregivers will be instructed on how to complete a paper diary and 
will be asked to record information daily in it. The number and type of seizures as 
well as information on AEs, concomitant AEDs and rescue medication will be 
collected each day from screening (Visit 1) until completion of dosing or withdrawal. 
Information on IMP intake will also be recorded each day from enrollment (Visit 2) 
until completion of dosing or withdrawal. 
9.1.13 
Investigational Medicinal Product Accountability 
IMP will be dispensed at each of the following visits during the single blind phase: 
• 
Visit 2 (Day 2) 
• 
Visit 3 (Day 26) 
• 
Visit 4 (Day 51) 
IMP will be dispensed at each of the following visits for patients entering the OLE: 
• 
Visit 5 (Two weeks) 
• 
Visit 6 (One month) 
• 
Visit 7 (Two months) 
• 
Visit 8 (Three months) 
• 
Visit 9 (Six months) 
• 
Visit 10 (Nine months) 
• 
Visit 11 (12 months) 
Patients will be asked to return all IMP (used and unused) to each relevant visit 
(Visits 2 to 12). The site will check the returned IMP against the usage recorded in the 
paper diary. Any discrepancies will be discussed with the patient/caregiver and 
documented accordingly within the patient’s source documents. 
9.1.14 
Adverse Events 
Any adverse changes in the patient’s medical condition, following completion of the 
consent form by the patient, will be recorded on the CRF as AEs, questioning the 


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patient further if necessary. 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. 
*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. 
Serious Adverse Events (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. 
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. 
9.2 
Study Procedures by Visit 
Patients and their caregivers will be invited to participate in the study and will be 
issued with the patient information and informed consent or the personal legal 
representative information and informed consent (refer to Section 9.1.2 and 
Section 15.2). Following adequate time to discuss the study with the investigator, 
nurse, relatives or caregiver, patients/legal representatives who provide written 
informed consent at Visit 1 will be screened for entry into the study. 
9.2.1 
Single Blind Phase 
9.2.1.1 
Visit 1 (Day −7, Screening) 
The following observations will be made at Visit 1: demographics, medical history 
(including seizure information since diagnosis, history of epilepsy-specific genetic 
testing and all prior AEDs taken), concomitant medications (including AEDs), 
physical examination (including height and body weight), ECG and vital signs. 
Clinical laboratory samples (blood and urine) will be taken for hematology, 
biochemistry, urinalysis and a pregnancy test (using a serum sample, if appropriate). 
The laboratory results should be available within 3-5 working days after Visit 1. If the 
results show a patient is ineligible, the patient will not be enrolled into the study. The 
C-SSRS will be administered. 
Patients who satisfy all inclusion and none of the exclusion criteria specified in 
Section 6 will be assigned a unique patient number and then begin the seven day 
baseline period. Patients or their caregivers will be given a paper diary to record daily 
seizure information, rescue medication, concomitant AEDs and AEs; and will be 


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instructed on how to do so. The investigator must record the patient’s attendance at 
the visit and confirm the outcome of screening on the CRF.  
9.2.1.2 
Visit 2 
9.2.1.2.1 
Visit 2 (Day 1) – Enrollment (+3 days) 
This visit will occur 7 days after Visit 1. 
The following observations will be made at Visit 2: concomitant medications, 
(including AEDs), physical examination (including height and body weight), ECG, 
vital signs and review of seizure diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for hematology, 
biochemistry and urinalysis. The C-SSRS will be administered. The investigator must 
record the patient’s attendance at the visit, and confirm the outcome of the visit prior 
to enrollment. 
Following enrollment patients will begin the PK sampling process. Blood samples 
will be taken for analysis of plasma concentrations of CLB, N-CLB, CBD and CBD 
major metabolites. A baseline PK sample will be taken before the patient takes their 
morning dose of CLB. Further samples will then be taken at the following times 
relative to the CLB dose: 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 
6 hours and 12 hours. Patients will either remain in clinic overnight throughout this 
PK sampling process or return to the clinic on Day 2 ahead of additional sample 
collection. 
9.2.1.2.2 
Visit 2 (Day 2) - Enrollment 
This is the second part of the two day enrollment visit. The final PK sample will be 
collected 24 hours after the Day 1 morning CLB dose. 
Following completion of the PK sampling process the following observations will be 
made on Day 2: concomitant medications (including AEDs), physical examination 
(including height and body weight), vital signs, and AEs. 
IMP will be dispensed and both the morning dose of CLB and of IMP will be taken in 
clinic. Patients and/or their caregivers will be provided with individual dosing 
schedules as described in Section 8.1.2. Each patient will then receive their IMP for 
the 10 day titration period followed by the 14 day maintenance period. Patients, or 
their caregivers, will be instructed on how to record the diary information. 
9.2.1.3 
Visit 3 
9.2.1.3.1 
Visit 3 (Day 26) (±3 days) 
This visit will occur 25 days after Visit 2, Day 1 (enrollment). Patients will return all 
used and unused IMP. The following observations will be made at Visit 3 (Day 26): 


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concomitant medications (including AEDs), physical examination (including height 
and body weight), ECG, vital signs, review of seizure diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for hematology, 
biochemistry and urinalysis. The C-SSRS will be administered. 
Blood samples will be taken for analysis of plasma concentrations of CLB, N-CLB, 
CBD and CBD major metabolites. A baseline PK sample will be taken before the 
patient takes their morning dose of CLB, followed immediately by their dose of IMP. 
Further samples will then be taken at the following times relative to the CLB dose: 
15  minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours and 12 hours. 
Patients are expected to remain in clinic throughout this PK sampling process. 
The investigator must assess adherence to the dosing regimen and recording of rescue 
medications by reviewing the patient’s diary. 
9.2.1.3.2 
Visit 3 (Day 27) 
This is the second part of the two day visit. The final PK sample will be collected 
24 hours after the Day 26 morning CLB dose. 
Following completion of the PK sampling process the following observations will be 
made on Day 27: concomitant medications (including AEDs), physical examination 
(including height and body weight), vital signs, and AEs. 
IMP will be dispensed and both the morning dose of CLB and of IMP will be taken in 
clinic. Patients and/or their caregivers will be provided with individual dosing 
schedules as described in Section 8.1.2. Each patient will then receive their IMP for 
the 10 day titration period followed by the 14 day maintenance period. Patients or 
their caregivers will be instructed how to record the diary information. 
9.2.1.4 
Visit 4 
9.2.1.4.1 
Visit 4 (Day 51) (±3 days) 
This visit will occur 50 days after Visit 2, Day 1 (enrollment). Patients will return all 
used and unused IMP. The following observations will be made at Visit 4 (Day 51): 
concomitant medications (including AEDs), physical examination (including height 
and body weight), ECG, vital signs, review of seizure diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for hematology, 
biochemistry and urinalysis. The C-SSRS will be administered. The investigator must 
record the patient’s attendance at the visit and the outcome. 
Blood samples will be taken for analysis of plasma concentrations of CLB, N-CLB, 
CBD and CBD major metabolites. A baseline PK sample will be taken before the 
patient takes their morning dose of CLB, followed immediately by their dose of IMP. 


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Further samples will then be taken at the following times relative to the CLB dose: 
15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours and 12 hours. 
Patients are expected to remain in clinic throughout this PK sampling. 
The investigator must assess adherence to the dosing regimen and recording of rescue 
medications by reviewing the patient’s diary. 
9.2.1.4.2 
Visit 4 (Day 52) 
This is the second part of the two day visit. The final PK sample will be collected 
24 hours after the Day 51 morning CLB dose. 
Following completion of the PK sampling process the following observations will be 
made on Day 52: concomitant medications (including AEDs), physical examination 
(including height and body weight), vital signs, and AEs. 
At the end of the blinded phase of the study on Day 52, providing the investigator and 
patient both agree, patients will be invited to continue taking IMP and to enter the 
OLE. 
Patients who enter the OLE will be dispensed CBD on Day 52. The dose may be 
adjusted up or down by the investigator from the maintenance dose of 20 mg/kg/day 
in the blinded phase to a maximum of 30 mg/kg/day in the OLE. Patients and/or their 
caregivers will be provided with individual dosing schedules as described in 
Section 8.1.2. Patients, or their caregivers, will be instructed how to record the diary 
information. 
Patients who do not enter the OLE will begin a 10 day taper period during which they 
will taper off their daily dose of IMP. The daily dose will be reduced by 10% of the 
maintenance dose per day and treatment will end on Day 60. 
9.2.1.5 
Visit 5 (Patients not entering OLE) (+3 days) 
This visit will occur 60 days after Visit 2, Day 1 (enrollment) for those patients who 
do not enter the OLE. 
All IMP (used and unused) will be collected and a check of the returned IMP against 
usage must be made. A physical examination (including height and body weight) and 
vital signs will be assessed and the C-SSRS will be administered. 
Clinical laboratory samples (blood and urine) will be taken for hematology, 
biochemistry and urinalysis and a review of concomitant medications (including 
AEDs) and AEs will be completed. Patient diaries will be collected. 


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9.2.1.6 
Safety Follow up Call (Day 89) (±3 days) 
This visit is required for patients who do not enter the OLE study on Day 50, or who 
withdraw from the study early. This visit should occur four weeks after Visit 5, (±3 
days) or withdrawal from treatment, and can be conducted over the telephone. The 
following observations will be made on Day 89: concomitant medications (including 
AEDs) and AEs. 
9.2.2 
Open Label Extension 
Patients who enter the OLE will be dispensed IMP at Visit 4 (Day 52) and will have 
regular clinic visits for a maximum of one year or earlier (if marketing authorization 
is granted or the patient withdraws). The visit schedule is calculated relative to Visit 4 
(Day 51). 
9.2.2.1 
Visit 5 (Open Label Extension) - Two Weeks (±3 days) 
This visit will occur two weeks after Visit 4 (Day 51). Patients will return all used and 
unused IMP. The following observations will be made at Visit 5 (OLE): concomitant 
medications (including AEDs), physical examination (including height and body 
weight), ECG, vital signs, review of seizure diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for hematology, 
biochemistry and urinalysis. The C-SSRS will be administered. The investigator must 
record the patient’s attendance at the visit and the outcome. 
The investigator must assess adherence to the dosing regimen and recording of rescue 
medications by reviewing the patient’s diary. 
9.2.2.2 
Visit 6 (Open Label Extension) - One Month (±3 days) 
This visit will occur one month after Visit 4 (Day 51). Patients will return all used and 
unused IMP. The following observations will be made at Visit 6 (OLE): concomitant 
medications (including AEDs), physical examination (including height and body 
weight), ECG, vital signs, review of seizure diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for hematology, 
biochemistry and urinalysis. The C-SSRS will be administered. The investigator must 
record the patient’s attendance at the visit and the outcome. 
The investigator must assess adherence to the dosing regimen and recording of rescue 
medications by reviewing the patient’s diary. 
9.2.2.3 
Visit 7 (Open Label Extension) - Two Months (±3 days) 
This visit will occur two months after Visit 4 (Day 51). Patients will return all used 
and unused IMP. The following observations will be made at Visit 7 (OLE): 


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concomitant medications (including AEDs), physical examination (including height 
and body weight), ECG, vital signs, review of seizure diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for hematology, 
biochemistry and urinalysis. The C-SSRS will be administered. The investigator must 
record the patient’s attendance at the visit and the outcome. 
The investigator must assess adherence to the dosing regimen and recording of rescue 
medications by reviewing the patient’s diary. 
9.2.2.4 
Visit 8 (Open Label Extension) - Three Months (±7 days) 
This visit will occur three months after Visit 4 (Day 51). Patients will return all used 
and unused IMP. The following observations will be made at Visit 8 (OLE): 
concomitant medications (including AEDs), physical examination (including height 
and body weight), ECG, vital signs, review of seizure diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for hematology, 
biochemistry and urinalysis. The C-SSRS will be administered. The investigator must 
record the patient’s attendance at the visit and the outcome. 
The investigator must assess adherence to the dosing regimen and recording of rescue 
medications by reviewing the patient’s diary. 
9.2.2.5 
Visit 9 (Open Label Extension) - Six Months (±7 days) 
This visit will occur six months after Visit 4 (Day 51). Patients will return all used 
and unused IMP. The following observations will be made at Visit 9 (OLE): 
concomitant medications (including AEDs), physical examination (including height 
and body weight), ECG, vital signs, review of seizure diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for hematology, 
biochemistry and urinalysis. The C-SSRS will be administered. The investigator must 
record the patient’s attendance at the visit and the outcome. 
The investigator must assess adherence to the dosing regimen and recording of rescue 
medications by reviewing the patient’s diary. 
9.2.2.6 
Visit 10 (Open Label Extension) - Nine Months (±7 days) 
This visit will occur nine months after Visit 4 (Day 51). Patients will return all used 
and unused IMP. The following observations will be made at Visit 10 (OLE): 
concomitant medications (including AEDs), physical examination (including height 
and body weight), ECG, vital signs, review of seizure diary and AEs. 


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Clinical laboratory samples (blood and urine) will be taken for hematology, 
biochemistry and urinalysis. The C-SSRS will be administered. The investigator must 
record the patient’s attendance at the visit and the outcome. 
The investigator must assess adherence to the dosing regimen and recording of rescue 
medications by reviewing the patient’s diary. 
9.2.2.7 
Visit 11 (Open Label Extension End of Treatment) - Twelve 
Months (±7 days) 
This visit will occur twelve months after Visit 4 (Day 51). Patients will return all used 
and unused IMP. The following observations will be made at Visit 11 (OLE): 
concomitant medications (including AEDs), physical examination (including height 
and body weight), ECG, vital signs, review of seizure diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for hematology, 
biochemistry and urinalysis. The C-SSRS will be administered. The investigator must 
record the patient’s attendance at the visit and the outcome. 
The investigator must assess adherence to the dosing regimen and recording of rescue 
medications by reviewing the patient’s diary. 
Starting at Visit 11, patients will begin to taper down their IMP dose. The dose will be 
reduced by 10% of their OLE maintenance dose per day. 
9.2.2.8 
Visit 12 (Open Label Extension End of Taper) 
This visit will be ten days after Visit 11. All IMP (used and unused) will be collected 
and a check of the returned IMP against usage must be made. A physical examination 
(including height and body weight), ECG and vital signs will be assessed and the C-
SSRS will be administered. 
Clinical laboratory samples (blood and urine) will be taken for hematology, 
biochemistry and urinalysis and a review of concomitant medications (including 
AEDs) and AEs will be completed. Patient diaries will be collected and reviewed. 
9.2.2.9 
Safety Follow Up Call (±3 days) 
This visit will occur one month after the OLE End of Taper and can be conducted 
over the telephone. The following observations will be made during the follow up 
call: concomitant medications (including AEDs) and AEs. 
10. WITHDRAWAL 
In accordance with the Declaration of Helsinki31, the FDA regulations relating to 
good clinical practice (GCP) and clinical trials32,33,34, the EU Clinical Trials Directive 


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(2001/20/EC)35 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. 
• Withdrawal of legal representative consent. 
• Lost to follow up. 
• ALT >3 × ULN 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 two weeks. 
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 four or five during the treatment period, 
as evaluated with the C-SSRS. 
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 Visit 4 (if the withdrawal is during the blinded phase) or Visit 11 (if the 
withdrawal is during the OLE) should be conducted if possible. If the tapered dose is 
administered, patients should return for Visit 5 (if withdrawal is during the blinded 
phase) or Visit 12 (if the withdrawal is during the OLE) if possible. Wherever 
possible, the safety follow-up visit should be conducted 28 days from the date of the 
last dose of IMP. Patients withdrawing due to an AE should be followed up according 
to Section 12.7. All information should be reported on the applicable CRF pages 


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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 three days. 
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 screening (Visit 1) throughout the study and up to the post treatment, safety 
follow-up visit (28 days after last dose of IMP), 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 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 forms). This is 
particularly true for events that threaten life or function. Such SAEs will be reported 


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promptly to Regulatory/Competent Authorities, applicable IRB/ECs and Investigators 
(expedited reporting) by GW. 
An AE must only be classed as serious i.e., an 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. 
• 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 visit (Visit 13 for patients entering the OLE and Visit 6 for those 


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patients that are not entering the OLE). If the investigator subsequently becomes 
aware of any deaths or a 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. 
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 study medication 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 study medication: 
“In your opinion is there a plausible relationship to the study medication?” The 
answer is “yes” or “no”. 
Events that start before the first dose of study medication (pre-treatment) should be 
considered as not causally related. Where a pre-treatment event worsens in severity 
following the first dose of study medication, a new event record should be entered 
into the CRF. 


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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 study medication but also competing etiological 
factors as the underlying cause. Factors for consideration may include: 
• Medical history. 
• Lack of efficacy/worsening of treated condition. 
• Concomitant or previous treatment. 
• Withdrawal of study medication. 
• Protocol-related procedure. 
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 
screening (Visit 1) to post study follow-up (Visit 13 for patients entering the OLE and 
Visit 6 for those patients that are not entering the OLE). 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. 


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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 for the 
following categories: 
• Recovered. 
• Recovered with sequelae. 
• Continuing. 
• 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. 


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• 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 occurs, 
the patient must undergo an end of treatment assessment and be given appropriate 
care under medical supervision until symptoms cease or the condition becomes stable. 
12.8 
Reporting Clinically Significant Laboratory Results 
All investigational sites 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 two 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 DILI 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 hours of notice of abnormal results) for repeat assessment, 
detailed history and physical examination. Patients should be followed until all 
abnormalities have normalized (in the investigator’s opinion) or returned to the 
baseline state. 


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12.9 
Notification of Safety Information to Investigators, Regulatory 
Authorities and Ethics Committees. 
In accordance with the EU Clinical Trials Directive35, relevant parts of the FDA Code 
of Federal Regulations 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 three sources: 
• Investigator Brochure36: 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 
participants. The IB is updated annually. 
• Development Core Safety Information: this document actually forms the 
Safety Section of the IB36, or is updated as an appendix of the IB36. This 
document is revised if necessary, when new important safety information 
becomes available (potentially up to a few times a year). 
• 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 IRB/EC 
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 guidance32 
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, 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 guidance37 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/EC’s) 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 ethics approval and final database lock. 


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13. 
STATISTICAL CONSIDERATIONS 
A statistical analysis plan (SAP) will be produced prior to the database lock and 
analysis of the study. Any deviations from the original SAP will be described in the 
final clinical study report. 
13.1 
Sample Size, Power and Significance Levels 
A total of 20 patients will be enrolled in this study. There is no formal sample size: 
Calculation and analysis is descriptive only. 
13.2 
Interim Analysis 
An interim analysis will be conducted at the end of the Single Blind phase of the 
study and may also be considered during the OLE phase, if long term data is required 
to support New Drug Application/Marketing Authorization Application submissions. 
13.3 
Analysis Sets 
13.3.1 
Safety Set 
All subjects who are treated and receive at least one dose of IMP will be included. 
The Safety set is the primary analysis set for all safety endpoints. 
13.3.2 
Pharmacokinetic Analysis Set  
All subjects who are treated and receive at least one dose of IMP and who provide 
some on-treatment data will be included. 
The PK analysis set is the primary analysis set for all PK endpoints. 
13.3.3 Protocol Deviations 
Any protocol deviations will be listed and reasons for exclusion from the analysis 
populations 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 in each category. Summaries will be presented for data 
recorded pre-treatment, during each 25 day dosing phase (placebo and CBD) and 
during the OLE phase separately. 


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13.5 
Accountability and Background Characteristics 
13.5.1 Enrolment and Disposition 
All patients (screened, treated, completing the study and those prematurely terminated 
IMP) will be accounted for in the enrolment 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 and the types of seizures currently 
experienced by the patients. 
13.5.4 Concomitant Medication 
Concomitant medications taken prior to and during the study will be summarized, by 
medication class and active ingredients. Summaries of medications taken during the 
IMP treatment phases and during OLE will be presented separately. 
13.6 
Endpoints and Statistical Methods 
13.6.1 Primary Endpoint(s) 
The primary endpoints of the study are the pharmacokinetic parameters (Cmax, tmax, 
AUC(0–∞), AUC(0–t), t½) of the following analytes: 
• CLB 
• N-desmethylclobazam (N-CLB) 
• CBD 
• CBD major metabolites 
13.6.2 Secondary Endpoint(s) 
The secondary endpoints of the study are the safety parameters (see Section 13.6.5). 
13.6.3 Pharmacokinetics 
Calculation of PK parameters will be based on actual blood sampling times [h] 
(relative to the corresponding administration time) rounded to two decimal digits with 
negative pre-dose times set to zero. Plasma concentrations of CLB, N-CLB, CBD and 


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the major metabolites will be displayed graphically, summarized and listed. For 
descriptive statistics, values below the lower limit of quantification of the assay 
(LLOQ) will be excluded from any calculations. Descriptive statistics of 
concentrations will be calculated if at least half of the individual data points that have 
been measured are equal to or above the LLOQ. 
For calculation of the PK parameters, the following rules will be applied: 
At time zero and at time points in the lag-time between time zero and the first 
quantifiable concentration, concentrations below the LLOQ will be set to zero. All 
other concentrations below the LLOQ will not be used in calculations. 
Variables derived from plasma concentrations: 
• Concentration maximum (Cmax): Highest observed plasma concentration of the 
measured concentration-time profile. Dimension: [amount / volume]. 
• Terminal half-life t½= ln(2)/λz. 
• The rate constant of the terminal phase λz will be determined by linear 
regression of log-transformed concentration data after the time of maximum 
concentration. A sequence of terminal elimination rate constants will be 
created by linear regression. Linear regressions are repeated using the last 
three points with a quantifiable concentration, the last four points, the last five 
points etc. For each regression, an adjusted R2 is computed. The regression 
with the largest adjusted R2 is selected to estimate the terminal half-life. 
Dimension: [time]. 
• Area under the concentration-time curve from administration until the last 
sampling point (t) equal or above the LLOQ AUC(0–t) will be calculated by the 
linear trapezoidal formula. Dimension: [time • amount / volume]. 
• Area under the concentration-time curve extrapolated to infinity: AUC(0–∞) = 
AUC(0–t) + Clast/λz and Clast is the concentration observed at the last time point 
with a quantifiable concentration, λz refers to the terminal elimination rate 
constant. Dimension: [time • amount / volume]. 
• Time of maximum concentrations: Tmax will be taken as the time after 
administration at which Cmax occurs. Dimension: [time]. 
• PK parameters for each analyte will be summarized for the two treatment 
phases of the study separately, as appropriate. 
• In order to assess whether the presence of CBD alters the PK profile of CLB 
(or N-CLB), a standard 90% confidence interval (CI) approach for the 
between group ratios of geometric means of Cmax, AUC(0–t), and AUC(0–∞) will 
be carried on logarithm scale using a linear mixed effect model with treatment 
(CBD or placebo) as fix effect and subject as a random effect. The no-effect 
boundary will be set between 0.5 and 2.0 and if the 90% CI for the ratio of the 
geometric means of a PK variable falls within the interval [0.5, 2.0], a lack of 
meaningful effect will be declared. 


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13.6.4 Safety 
13.6.4.1 
Treatment Compliance and Extent of Treatment Exposure 
Treatment compliance and exposure to treatment will be summarized for each phase 
of the study separately. 
13.6.4.2 
Adverse Events 
AEs will be coded according to the Medical Dictionary for Regulatory Activities 
dictionary. 
A treatment emergent AE is one that started, or worsened in severity or seriousness, 
following the first dose of IMP. 
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. Summaries will be provided for each phase of the 
study separately. 
The following summaries will be produced: 
• 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. 
13.6.4.3 
Clinical Laboratory Data 
Clinical laboratory data at screening and at the end of each 24 day treatment phase 
and the change from baseline to end of treatment (OLE) 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. 
13.6.4.4 
Columbia-Suicide Severity Rating Scale, Vital Signs, 12-lead 
Electrocardiogram, Physical Examination and Other Safety 
Data 
The C-SSRS, vital signs, ECG and physical examination data will be summarized at 
screening, at the end of each 24 day treatment phase and during the OLE treatment 
period using appropriate summary statistics. Changes in the vital signs from baseline 
to end of each treatment phase will also be summarized. 


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13.6.4.5 
Seizure Data 
Seizure data collected during each 24 day treatment phase and during the OLE phase 
of the study will be summarized using appropriate summary statistics. 
14. 
DATA SAFETY MONITORING COMMITTEE 
GW does not plan to use an independent data safety monitoring committee as part of 
this study. 


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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 
the31,35and the clinical trial regulations adopting European Commission Directives 
into national legislation38,39,40. 
15.2 
Informed Consent 
Initial master informed consent forms will be provided to the investigator to prepare 
the informed consent documents to be used at his or her center. The GW Clinical 
Manager will communicate updates to the templates by letter. The written informed 
consent 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 from the patient or 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, or their legal representative, should have ample time for 
review to consider the information provided before giving written consent; more 
specific definitions of ample time may be in force if required by IRB/ECs or local 
regulations. 
The acquisition of informed consent should be documented in the patient’s medical 
records and the informed consent form should be signed and personally dated by the 
patient or legal representative (as applicable) and by the person who conducted the 
informed consent discussion. GW also requires a physician to be present for consent 
and to sign the consent forms as well. The original signed informed consent forms 
should be retained and a copy provided to the patient or legal representative. 
15.3 
Institutional Review Board/Ethics Committee 
A copy of the protocol, proposed informed consent 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 forms before enrollment of 
patients into the study and shipment of IMP. 
The investigator must submit and, where necessary, obtain approval from the IRB/EC 
for all subsequent protocol amendments and changes to the informed consent 


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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 for entry into the study: 
• Signed and dated protocol signature page. 
• Copy of approved informed consent forms and other patient information 
material. 
• Copy of the IRB/EC approval of the protocol, informed consent forms and 
other patient information material. 
• Up to date curricula 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 
trials32,33,34,41, the EU Clinical Trials Directive35, or International Conference 
on Harmonization Tripartite Guideline for Good Clinical Practice (ICH 
GCP)42 where the EU 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 
Participant 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 ethnic origin (if allowed per 
local regulations) and a patient study number only. Documents that are not for 
submission to GW, e.g., signed informed consent forms should be kept in strict 
confidence by the investigator. 
In compliance with the FDA regulations relating to good clinical practice and clinical 
trials32,33,34,41, and the EU Clinical Trials Directive35/ICH GCP Guidelines42, it is 


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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 documents. The IRB/EC and Competent Authorities must be 
informed of all amendments and give approval for any substantial amendments prior 
to implementation. The investigator must send a copy of the approval letter from the 
IRB/EC to GW. Amendments for administrational changes can be submitted to the 
IRB/EC for information only. 
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. In the rare situations of this happening, 
then the source data from the CRF should be transcribed in the patient’s notes with 
appropriate signature and date to provide a full audit trail. 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. 
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 8.242), 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 forms and 
supporting copies of source documentation. 


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• 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. 
• 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, paper 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 two 
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 two 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 1643). 
GW will inform the investigators for each site 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 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. 


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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 five working days after 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 regulations32,33,34,41, the ICH GCP 
Guideline42, and all other applicable regulatory requirements35,42, 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. 


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• 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. 
16.4 
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. 
16.5 
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. 
16.6 
Publication Policy 
GW recognizes that there is a responsibility under the regulatory guidelines to ensure 
that results of scientific interest arising from this clinical 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 


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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 six months from the date of first submission to them in order to allow them to 
take steps to protect proprietary information where applicable. 
16.7 
Intellectual Property Rights 
All Intellectual Property Rights owned by or licensed to either GW or the PIs, other 
than those arising from the clinical 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. 
16.8 
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. REFERENCES 
1 
Bergen DC.  Preventable neurological diseases worldwide.  Neuroepidemiology, 
1998, 17(2): 67-73. 
2 
Sander JW.  The epidemiology of epilepsy revisited.  Curr Opin Neurol, 2003, 
16(2): 165-170. 
3 
MacDonald BK, Cockerell OC, Sander JW and Shorvon SD.  The incidence and 
lifetime prevalence of neurological disorders in a prospective community-based 
study in the UK.  Brain, 2000, 123(4): 665-676. 
4 
Forsgren L, Beghi E, Oun A and Sillanpää M.  The epidemiology of epilepsy in 
Europe – a systematic review.  Eur J Neurol, 2005, 12(4): 245-253. 
5 
Duncan JS, Sander JW, Sisodiya SM and Walker MC.  Adult epilepsy.  The 
Lancet, 2006, 367(9516): 1087-1100. 
6 
Committee for medicinal products for human use. Guideline on clinical 
investigation of medicinal products in the treatment of epileptic disorders, 22 July 
2010, CHMP/EWP/566/98 Rev.2/Corr. 
7 
Sander JS.  Some aspects of prognosis in the epilepsies: a review.  Epilepsia, 
1993, 34(6): 1007-1016. 
8 
Kwan P and Brodie MJ.  Early Identification of Refractory Epilepsy.  N Engl J 
Med, 2000, 342(5): 314-319. 
9 
Kwan P and Brodie MJ.  Emerging drugs for epilepsy.  Expert Opin Emer Drugs, 
2007, 12(3): 407-422. 
10 Schachter SC.  Currently available antiepileptic drugs.  Neurotherapeutics, 2007, 
4(1): 4-11. 
11 Martin J.  British National Formulary. 2013, Pharmaceutical Press London. 
12 Bialer M and White HS.  Key factors in the discovery and development of new 
antiepileptic drugs.  Nat Rev Drug Discov, 2010, 9(1): 68-82. 
13 Czapiński P, Blaszczyk B and Czuczwar SJ.  Mechanisms of action of 
antiepileptic drugs.  Curr Top  Med Chem, 2005, 5(1): 3-14. 
14 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. 
15 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. 
16 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. 
17 Zuardi AW, Morais SL, Guimarães FS, Mechoulam R. Antipsychotic effect of 
cannabidiol. J Clin Psychiatry 1995;56(10):485-6. 
18 Jones NA, Hill AJ, Smith I, Bevan SA, Williams CM, Whalley BJ et al. 
Cannabidiol displays antiepileptiform and antiseizure properties in vitro and in 
vivo. J Pharmacol Exp Ther 2010;332(2):569-77. 


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19 Jones NA, Glyn SE, Akiyama S, Hill TD, Hill AJ, Weston SE et al. Cannabidiol 
exerts anti-convulsant effects in animal models of temporal lobe and partial 
seizures. Seizure 2012;21(5):344-52. 
20 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. 
21 Gover J, Schultz, S. GW Pharmaceuticals announces new physician reports of 
Epidiolex treatment effect in children and young adults with treatment-resistant 
epilepsy [press release]. United Kingdom: GW Pharma Ltd; 2014 Oct 14. 
22 Johannessen Landmark C, Larsson PG, Rytter E, Johannessen SI. Antiepileptic 
drugs in epilepsy and other disorders: a population-based study of prescriptions. 
Epilepsy Res. 2009, 87(1):31-39 
23 Tsiropoulos I, Gichangi A, Andersen M, Bjerrum L, Gaist D, Hallas J. Trends in 
utilization of anti-epileptic drugs in Denmark. Acta Neurol. Scand. 2006, 113, 
405-411 
24 van de Vrie-Hoekstra NW, de Vries TW, van den Berg PB, Brouwer OF, de Jong-
van den Berg LT. Antiepileptic drug utilization in children from 1997-2005 - a 
study from the Netherlands. Eur J Clin Pharmacol. 2008, 64: 1013-1020. 
25 Johannessen Landmark C, Rytter E, Johannessen SI. Clinical use of antiepileptic 
drugs at a referral centre for epilepsy. Seizure. 2007, 16:356-364 
26 Rytter E, Johannessen Landmark C, Johannessen SI. Antiepileptic drug treatment 
of children at a referral centre for epilepsy - does admission make a difference? 
Seizure. 2009, 18:573-579 
27 Contin M, Riva R, Albani F, Baruzzi A. Effect of felbamate on clobazam and its 
metabolite kinetics in patients with epilepsy. Ther Drug Monit. 1999, 21:604-608 
28 Levy RH, Lin HS, Blehaut HM, Tor JA. Pharmacokinetics of stiripentol in normal 
man: evidence of non-linearity. J Clin Pharmacol. 1983, 23 (11-12):523-533. 
29 Tran A, Vauzelle-Kervroedan F, Rey E, Pous G, d´Athis P, Chiron C, Dulac O, 
Renard F, Olive G. Effect of stiripentol on carbamazepine plasma concentration 
and metabolism in epileptic children. Eur J Clin Pharmacol. 1996, 50:497-500. 
30 Trojnar MK, Wojtal K, Trojnar MP, Czuczwar SJ. Stiripentol. A novel 
antiepileptic drug. Pharmacol Rep. 2005, 57:154-160. 
31 World Medical Association Declaration of Helsinki — Ethical principles for 
medical research involving human subjects. October 2013. 
32 U.S. Food and Drug Administration Code of Federal Regulations Title 21 (Food 
and Drugs) Part 50 — Protection of human subjects. April 2014. 
33 U.S. Food and Drug Administration Code of Federal Regulations Title 21 (Food 
and Drugs) Part 312 — Investigational New Drug application. April 2014. 
34 U.S. Food and Drug Administration Code of Federal Regulations Title 21 (Food 
and Drugs) Part 56 — Institutional Review Boards. April 2014. 
35 Directive 2001/20/EC  of the European Parliament and of the Council of 04 April 
2001 on the approximation of the laws, regulations and administrative provisions 
of the Member States relating to the implementation of good clinical practice in 
the conduct of clinical trials on medicinal products for human use. Official Journal 
of the European Communities L 121, 1/5/2001 p. 34–44. 


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36 Investigator Brochure — CBD medicine. GW Pharma Ltd. Edition 7, August 
2014. 
37 U.S. Food and Drug Administration guidance for clinical Investigators, Sponsors, 
and IRBs: Adverse Event reporting to IRBs — Improving human subject 
protection. January 2009. 
38 UK Statutory Instrument 2004/1031 — The medicines for human use (clinical 
trials) regulations 2004. May 2004. 
39 UK Statutory Instrument 2006/1928 — The medicines for human use (clinical 
trials) amendment regulations 2006. August 2006. 
40 UK Statutory Instrument 2006/2984 — The medicines for human use (clinical 
trials) amendment (No.2) regulations 2006. December 2006. 
41 U.S. Food and Drug Administration Code of Federal Regulations Title 21 (Food 
and Drugs) Part 11 — Electronic records; electronic signatures (Subpart B — 
Electronic records). April 2014. 
42 International Conference on Harmonisation Topic E6(R1): Guideline for good 
clinical practice — Note for guidance on good clinical practice 
(CPMP/ICH/135/95). July 2002. 
43 Commission Directive 2005/28/EC of 08 April 2005 laying down the principles 
and detailed guidelines for GCP as regards investigational medicinal products for 
human use, as well as the requirements for authorisation of the manufacturing or 
importation of such products. Official Journal of the European Union L 91, 
9/4/2005 p. 13–19. 
 
 
 
 
 
 
 
 
 
 


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APPENDIX 1. SCHEDULE OF ASSESSMENTS 
Visit Number 
Day 
(Visit Window) 
Visit 1 
Day -7 
 
Visit 2 
Day 1 
(+ 3 days) 
Visit 2 
Day 2 
 
Visit 3 
Day 26 
(± 3 days) 
Visit 3 
Day 27 
 
Visit 4 
Day 51 
(± 3 days) 
Visit 4 
Day 52 
 
Visit 5* 
End of Taper 
 
Visit 6* 
4wk SFU 
(± 3 days) 
Informed consent 
X 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
X 
 
 
 
 
 
 
 
Enrollment 
 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Paper diary training 
X 
 
X 
 
 
 
 
 
 
Concomitant medications 
(including AEDs) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
(including height and body 
weight) 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECG 
X 
X 
 
X 
 
X 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
 
AEs 
 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical laboratory blood 
sampling  
X 
X 
 
X 
 
X 
 
X 
 
Clinical laboratory urine 
sampling (dipstick 
urinalysis) 
X 
X 
 
X 
 
X 
 
X 
 
Alcohol/THC test 
X 
 
 
 
 
 
 
 
 
Pregnancy test (if 
appropriate) 
X 
 
 
 
 
 
 
 
 
Pharmacokinetic blood 
sampling**  
 
X 
X 
X 
X 
X 
X 
 
 
C-SSRS 
X 
X 
 
X 
 
X 
 
X 
 
Patient diary review 
 
X 
 
X 
 
X 
 
X 
 


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Visit Number 
Day 
(Visit Window) 
Visit 1 
Day -7 
 
Visit 2 
Day 1 
(+ 3 days) 
Visit 2 
Day 2 
 
Visit 3 
Day 26 
(± 3 days) 
Visit 3 
Day 27 
 
Visit 4 
Day 51 
(± 3 days) 
Visit 4 
Day 52 
 
Visit 5* 
End of Taper 
 
Visit 6* 
4wk SFU 
(± 3 days) 
(seizures, AE information, 
concomitant AEDs, rescue 
medication, IMP dosing) 
IMP dispensing 
 
 
X 
 
X 
 
X 
 
 
Collection of IMP 
 
 
 
X 
 
X 
 
X 
 
IMP compliance review 
 
 
 
X 
 
X 
 
X 
 
* Patients not entering the OLE 
**PK Sampling time points are as follows: Pre-dose and 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 12 hours and 24 hours after 
dosing. For the second and third PK visits the patient should take the IMP immediately after their daily dose of CLB. 
 
 


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Open Label Extension Schedule of Assessments 
 
 
 
Visit Number 
Day 
(Visit Window) 
Visit 5 
2 Weeks 
(+ 3 days) 
Visit 6 
1 Month 
(± 3 days) 
Visit 7 
2 Months 
 (± 3 days) 
Visit 8 
3 Months 
(± 7 days) 
Visit 9 
6 Months 
 (± 7 days) 
Visit 10 
9 Months 
(± 7 days) 
Visit 11 
12 Months 
 (± 7 days) 
Visit 12 
End of 
Taper 
 
Visit 13 
4wk SFU 
(± 3 days) 
Paper diary training 
 
 
 
 
 
 
 
 
 
Concomitant medications 
(including AEDs) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
(including height and 
body weight) 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECG 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical laboratory blood 
sampling  
X 
X 
X 
X 
X 
X 
X 
X 
 
Clinical laboratory urine 
sampling (dipstick 
urinalysis) 
X 
X 
X 
X 
X 
X 
X 
X 
 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
X 
 
Patient diary review 
(seizures, AE 
information, concomitant 
AEDs, rescue medication, 
IMP dosing) 
X 
X 
X 
X 
X 
X 
X 
X 
 
IMP dispensing 
X 
X 
X 
X 
X 
X 
X 
 
 
Collection of IMP 
X 
X 
X 
X 
X 
X 
X 
X 
 
IMP compliance review 
X 
X 
X 
X 
X 
X 
X 
X 
 


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APPENDIX 2. STUDY PERSONNEL 
Appendix 3.1 
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 3.2 
Sponsor Contact Details 
Pharmacovigilance Department — SAE Reporting: 
Fax: 
 
USA Toll Free Fax: 
 
Tel: 
 
Sponsor: 
GW Research Ltd 
Sovereign House 
Vision Park 
Histon 
Cambridge CB24 9BZ 
United Kingdom 
Tel: 
 
Fax: 
 
Medical Monitor 
EU 
 
  
Tel: 
 
Mobile:
 
Clinical Project Manager/Clinical Operations 
Director: 
GW Research Ltd 
Sovereign House 
Vision Park 
Histon 
Cambridge CB24 9BZ 
United Kingdom 
Tel: 
 
Fax: 
 
Clinical Trials Supplies: 
GW Pharma Ltd 
Tel: 
 
Fax: 
 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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TITLE: A phase 2, double-blind, randomized, placebo-controlled study to investigate 
possible drug-drug interactions between clobazam and cannabidiol (GWP42003-P) 
STUDY CODE: GWEP1428 
EudraCT NUMBER: 2014-002942-33 
 
PROTOCOL AMENDMENT NUMBER: 1  
 
to be incorporated into the Protocol, creating 
PROTOCOL VERSION 2, DATE 09 JUL 2015 
 
 
 
 
GW RESEARCH LTD 
SOVEREIGN HOUSE 
VISION PARK 
CHIVERS WAY 
HISTON 
CAMBRIDGE CB24 9BZ 
UNITED KINGDOM 
TEL: 
   FAX: 
 
 
 
 
 
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. 
PPD
PPD


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1. 
PROTOCOL SYNOPSIS 
Study Title  
A phase 2, double-blind, randomized, placebo-controlled study to 
investigate possible drug-drug interactions between clobazam and 
cannabidiol (GWP42003-P) 
Indication 
Epilepsy 
Study Design 
This is a phase 2, double-blind, randomized, placebo-controlled study in 
20 patients. 
• Patients will be randomized in a 4:1 ratio to receive 20 mg/kg 
cannabidiol (CBD) or placebo from days 2 to 33.  
• 
At the end of the treatment period, patients will be given the option of 
continuing onto an open label extension (OLE) period if the investigator 
and patient both agree that it is in their best interests. Doses may be 
adjusted up or down, dependent on investigator opinion, to a maximum 
of 30 mg/kg/day GWP42003-P. The OLE will last for a maximum of 
one year or until marketing authorization is granted; whichever is 
earlier. 
• 
Patients that do not continue onto the OLE will taper off of GWP42003-
P over a 10 day period and will have a telephone follow-up visit four 
weeks after the end of taper day on Day 71. 
• Day 1 (Visit 2), patients will not be dosed with GWP42003-P/placebo 
but will continue to take CLB at a stable dose. 
• Day 2 (Visit 2), patients will begin the up-titration with GWP42003-P or 
placebo to a maintenance dose or an equivalent maintenance dose of 
20 mg/kg/day over a period of 10 days (Days 2 to 11). 
• Day 12 (Visit 3), patients will attend the study site to check safety and 
compliance. 
• After up-titration with GWP42003-P or placebo, the patients will remain 
on the maintenance dose for 21 days (Days 12 to 32). 
• On Day 34 (Visit 4), patients will be invited to receive GWP42003-P in 
the OLE period. If the patient enters the OLE period of the study, the 
patient will continue to take GWP42003-P as advised by the 
investigator. 
• If the patient does not enter the OLE period of the study, the patient will 
taper off of GWP42003-P by reducing the dose by approximately 10% 
of the maintenance dose each day until dosing has ceased, with end of 
taper on Day 43 (Visit 5). 
Pharmacokinetic (PK) samples will be taken on the day of enrollment 
(Visit 2, Day 1) and after completing 21 days treatment on GWP42003-P or 
placebo (Visit 4, Day 33). The PK assessments will therefore capture the 
following combinations of CLB and GWP42003-P: 
• First PK Assessment: CLB only. 
• Second PK Assessment: CLB and GWP42003-P or placebo. 
Each PK assessment should be performed at time points in respect to a 


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morning dose of CLB. The time points are as follows: Pre-dose, 15 min, 
30 min, 1h, 1.5h, 2h, 4h, 6h, 12h and 24h. It is expected that the patient will 
continue to take their CLB as advised by their physician and PK 
assessments will be scheduled in order to accommodate this dosing 
schedule. The GWP42003-P/placebo should be taken twice daily 
immediately following their CLB dose. 
PK assessments will analyze the amount of CLB, the CLB primary 
metabolite N-CLB, CBD, CBD major metabolites, ∆9-tetrahydrocannabinol 
(THC) and THC major metabolites. Patients will be required to keep a paper 
diary to note the time and dose of GWP42003-P and CLB administration 
each morning and evening and to record any adverse events (AEs) that may 
occur whilst receiving investigational medicinal product (IMP) and any 
other medications. Patients will also be requested to record the number and 
type of seizures for each day whilst on the study. 
Sponsor 
GW Research Ltd 
Sovereign House 
Vision Park 
Chivers Way 
Histon 
Cambridge CB24 9BZ 
United Kingdom 
 


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2. 
TABLE OF CONTENTS 
1. 
PROTOCOL SYNOPSIS 
2 
2. 
TABLE OF CONTENTS 
4 
2.1 
Table of Appendices 
4 
3. 
RATIONALE 
4 
3.1 
Study Design 
4 
3.2 
Procedures 
5 
3.3 
Investigational Medicinal Product 
5 
3.3.1 
Clobazam 
5 
3.3.2 
Cannabidiol/Placebo                                                                            5 
3.4 
Secondary Endpoints 
6 
3.5 
Inclusion/Exclusion/Withdrawal Criteria 
6 
3.6 
Clarification of Liver Function Testing 
6 
3.7 
Administrative Changes 
6 
4. 
IMPLEMENTATION OF THE AMENDMENT 
6 
5. 
PRESENTATION OF AMENDED TEXT 
7 
2.1 
Table of Appendices 
 
49 
APPENDIX 1.1
 
53 
APPENDIX 1.2
 
54 
APPENDIX 1.3
 
55 
APPENDIX 1.4
 
3. 
RATIONALE 
This protocol amendment 1 will be incorporated into the Protocol creating Protocol 
Version 2, date 09 Jul 15) addresses the following issue(s): 
3.1 
Study Design 
The study design has been amended as follows: 
• Changed from a single-blind to a double-blind randomized design. Participants will 
be randomized in a 4:1 ratio to receive either GWP42003-P or placebo. This allows 
for the removal of one of the pharmacokinetic (PK) time points, therefore being of 
less burden to participants whilst maintaining the same outcome of the study. 
• Increased screening period from 7 to 14 days to provide more flexibility to sites and 
participants. 
• Increased maintenance period of the double-blind phase of the study from 14 to 
21 days. Clobazam takes up to 14 days to reach steady state; therefore, increasing the 


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maintenance period to 21 days will ensure steady state has been achieved following 
the introduction of GWP42003-P or placebo. 
• Visit 3 will be a site visit 12 days in to the treatment period to ensure participants 
have titrated up to the required dose and to check if they have experienced any 
adverse events (AEs) following introduction of the GWP42003-P/placebo. 
• Visit 6 (safety follow up phone call) has changed from day 89 to day 71 due to the 
study design changes discussed above. 
3.2 
Procedures 
The following procedures have been added to the protocol: 
• A serum alcohol test will be performed at Visits 1, 2 and 4 to capture alcohol levels 
at the time of the PK draws as well as at screening.  
• An additional blood sample will be taken at Visit 2 for genetic testing subject to 
additional consent being obtained from the participant. Genetic testing will be 
conducted to look at the CYP450 genes, with particular focus on CYP2C19 and 
CYP3A4, involved in the metabolization of anti-epileptic drugs (AEDs) and 
GWP42003-P.  
• Guidance on monitoring human abuse liability via AEs and drug accountability 
throughout the study. In addition to ongoing reporting of such events, a Study 
Medication Use and Behavior Survey will be completed at the final dosing visit 
(Visit 5 or 12). 
The following procedure has been removed from the protocol: 
• Measurement of height at Visits 2 to 12 inclusive. It is not envisaged that a patient’s 
height will change significantly during their participation in the study; therefore, it is 
an unnecessary burden to the patient. 
3.3 
Investigational Medicinal Product 
3.3.1 
Clobazam 
In order to comply with a request received from the Medicines & Healthcare products 
Regulatory Agency, for the purposes of this study, Clobazam is now described as an 
investigational medicinal product (IMP) for the blinded phase of the study. References to 
IMP have been amended to GWP42003-P/placebo throughout the protocol where needed. 
3.3.2 
Cannabidiol/Placebo 
• Color of GWP42003-P has been included. 
• Guidance has been provided on the reduction of the GWP42003-P/placebo dose if 
AEs, which are attributable to the IMP or concomitant AEDs, occur during titration.  
• References to ‘CBD’ have been updated throughout the protocol, as required, to 
reflect the product code GWP42003-P instead. In the interests of brevity, these 
changes have not been captured within section 5 of this amendment. 


Study Code: GWEP1428 
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Date 09 Jul 15 
 
 
 
 
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3.4 
Secondary Endpoints 
The following secondary endpoints have been added: 
• PK parameters of ∆9-tetrahydrocannabinol (THC) and THC major metabolites. 
• Safety assessment to assess drug abuse liability.  
3.5 
Inclusion/Exclusion/Withdrawal Criteria 
The inclusion/exclusion/withdrawal criteria have been updated as follows: 
• Inclusion criterion regarding seizure type has been updated to specify the type of 
seizure a patient must have experienced to allow their inclusion into the study. 
• Inclusion criteria regarding intervention with vagus nerve stimulation and ketogenic 
diet and alcohol consumption have been clarified that these should be stable 
throughout the blinded section of the study.   
• Exclusion criterion regarding contraception has been updated to factor in male 
patients. 
• Exclusion criterion regarding pregnancy has been updated to clarify that this must be 
confirmed by a positive pregnancy test. 
• Withdrawal criterion added to specify that if any other IMP is taken as part of any 
other clinical trial during the study, the patient must be withdrawn. 
3.6 
Clarification of Liver Function Testing 
• Additional details have been included regarding follow-up of elevated liver enzyme 
levels that do not meet the criteria for drug-induced liver injury (DILI). 
• Section 12.8 has been re-titled as the text within concerns potential cases of DILI 
only. 
• The eligibility criterion regarding impaired hepatic function has been amended to 
bring into line with the criteria for DILI. 
3.7 
Administrative Changes 
Minor spelling/formatting/consistency/administrative issues have been corrected. (NB. in the 
interest of brevity, minor changes to grammar and punctuation are not captured in this 
amendment document). 
4. 
IMPLEMENTATION OF THE AMENDMENT 
This amendment will be issued as Protocol Version 2, Date 09 Jul 2015.  It will be kept in 
the study master file at GW and in each investigator and pharmacy site file, if applicable. 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Date 09 Jul 15 
 
 
 
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Page 7 of 60 
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5. 
PRESENTATION OF AMENDED TEXT 
The text will be amended as follows: 
Protocol Section 
Number, 
Heading and 
Page Number 
Original Wording from Protocol Version 1,  
Dated 26 Jan 15 
(Deleted wording is struck through and in bold)  
Revised Wording from Protocol Amendment 1 
(Protocol Version 2, Dated 09 Jul 15)  
(Revised wording is underscored and in bold)  
Rationale for 
the 
amendment.  
Investigator 
Agreement, pg 
2; Section 1, 
Protocol 
Synopsis, Study 
Title, pg 3 
 
A phase 2, single-blind, placebo-controlled study to 
investigate possible drug-drug interactions between 
clobazam and cannabidiol (GWP42003-P) 
 
A phase 2, double-blind, randomized, placebo-
controlled study to investigate possible drug-drug 
interactions between clobazam and cannabidiol 
(GWP42003-P) 
 
 
See section 3.1 
Title page, pg 1 
A phase II, single-blind, placebo-controlled study to 
investigate possible drug-drug interactions between 
clobazam and cannabidiol (GWP42003-P) 
A phase 2, double-blind, randomized, placebo-
controlled study to investigate possible drug-drug 
interactions between clobazam and cannabidiol 
(GWP42003-P) 
See section 3.7 
Cover Page, pg 1 
GW RESEARCH LTD 
SOVEREIGN HOUSE,  
VISION PARK,  
HISTON,  
CAMBRIDGE 
CAMBS, CB24 9BZ 
GW RESEARCH LTD 
SOVEREIGN HOUSE,  
VISION PARK,  
CHIVERS WAY 
HISTON,  
CAMBRIDGE 
CB24 9BZ 
See section 3.7 
Cover Page, pg 1 
Confidentiality 
Statement 
This document contains confidential information of 
GW Research Ltd that must not be disclosed to 
anyone other than the recipient study staff and 
members of the Institutional Review Board. 
This document contains confidential information of 
GW Research Ltd that must not be disclosed to 
anyone other than the recipient study staff and 
members 
of 
the 
Institutional 
Review 
Board/Independent Ethics Committee. 
See section 3.7 
Section 1, 
Protocol 
Synopsis, Study 
This is a phase 2, single-blind, placebo-controlled 
study in 20 patients. 
• All patients will be given placebo first followed 
This is a phase 2, double-blind, randomized, 
placebo-controlled study in 20 patients. 
• Patients will be randomized in a 4:1 ratio to 
See section 3.1  
 
 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Date 09 Jul 15 
 
 
 
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Protocol Section 
Number, 
Heading and 
Page Number 
Original Wording from Protocol Version 1,  
Dated 26 Jan 15 
(Deleted wording is struck through and in bold)  
Revised Wording from Protocol Amendment 1 
(Protocol Version 2, Dated 09 Jul 15)  
(Revised wording is underscored and in bold)  
Rationale for 
the 
amendment.  
Design, pg 3 
by CBD during the course of the study. Patients 
will receive placebo in the first part of the 
single-blind phase (Days 2 to 26) and CBD 
during the second part of the single-blind phase 
(Day 27 onwards). 
• (…) 
• Patients that do not continue onto the OLE will 
taper off of CBD over a 10 day period and will 
have a telephone follow-up visit four weeks after 
the end of taper day on Day 89. 
(…) 
receive 20 mg/kg GWP42003-P or placebo from 
days 2 to 33. 
 
 
 
• (…) 
• Patients that do not continue onto the OLE will 
taper off of GWP42003-P over a 10 day period 
and will have a telephone follow-up visit four 
weeks after the end of taper day on Day 71. 
(…) 
 
 
 
 
 
 
See section 
3.3.2 
Section 1, 
Protocol 
Synopsis, Study 
Design, pg 3 
(…) 
• Day 1 (Visit 2), patients will not be dosed with 
investigational medicinal product (IMP) but will 
continue to take CLB at a stable dose. 
(…) 
(…) 
• Day 1 (Visit 2), patients will not be dosed with 
GWP42003-P/placebo but will continue to take 
CLB at a stable dose. 
(…) 
See section 
3.3.1 
 
Section 1, 
Protocol 
Synopsis, Study 
Design, pg 3 
 
 
 
 
 
 
 
 
 
 
 
(…) 
• Day 2 (Visit 2), patients will begin the up-titration 
with placebo to an equivalent maintenance dose of 
20 mg/kg/day over a period of 10 days (Days 2 to 
11). 
 
 
• After up-titration with placebo, the patients will 
remain on the maintenance dose for 14 days (Days 
12 to 25). 
• On Day 27 (Visit 3), patients will begin the up-
titration with CBD to the maintenance dose of 
20 mg/kg/day over a period of 10 days (Days 27 
to 36). 
• After up-titration with CBD, the patients will 
remain on the maintenance dose for a further 
(…) 
• Day 2 (Visit 2), patients will begin the up-titration 
with GWP42003-P or placebo to a maintenance 
dose or an equivalent maintenance dose of 20 
mg/kg/day over a period of 10 days (Days 2 to 11). 
• Day 12 (Visit 3), patients will attend the study 
site to check safety and compliance. 
• After up-titration with GWP42003-P or placebo, 
the patients will remain on the maintenance dose 
for 21 days (Days 12 to 32). 
 
 
 
 
 
 
See section 3.1  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Date 09 Jul 15 
 
 
 
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Protocol Section 
Number, 
Heading and 
Page Number 
Original Wording from Protocol Version 1,  
Dated 26 Jan 15 
(Deleted wording is struck through and in bold)  
Revised Wording from Protocol Amendment 1 
(Protocol Version 2, Dated 09 Jul 15)  
(Revised wording is underscored and in bold)  
Rationale for 
the 
amendment.  
Section 1, 
Protocol 
Synopsis, Study 
Design, pg 3 
14 days (Day 37 to 51). 
• On Day 52 (Visit 4), patients will be invited to 
receive CBD in the OLE period. (…) 
• If the patient does not enter the OLE period (…) 
with end of taper on Day 61 (Visit 5). 
PK samples will be taken on the day of enrollment 
(Visit 2, Day 1), after completing 14 days treatment 
on placebo (Visit 3, Day 26) and prior to starting on 
CBD, and after the completing 14 days treatment 
on CBD (Visit 4, Day 451). The PK assessments will 
therefore capture the following combinations of CLB 
and IMP: 
• First PK Assessment: CLB only. 
• Second PK Assessment: CLB and placebo. 
• Third PK Assessment: CLB and CBD. 
(…) 
 
• On Day 34 (Visit 4), patients will be invited to 
receive GWP42003-P in the OLE period. (…) 
• If the patient does not enter the OLE period (…) 
with end of taper on Day 43 (Visit 5). 
PK samples will be taken on the day of enrollment 
(Visit 2, Day 1) and after completing 21 days 
treatment on GWP42003-P or placebo (Visit 4, Day 
33). The PK assessments will therefore capture the 
following combinations of CLB and GWP42003-P: 
• First PK Assessment: CLB only. 
• Second PK Assessment: CLB and GWP42003-P 
or placebo. 
(…) 
 
 
 
See section 3.1 
 
 
 
 
 
 
 
 
 
 
 
Section 1, 
Protocol 
Synopsis, Study 
Design, pg 3-4 
(…) 
The IMP should be taken twice daily immediately 
following their CLB dose. 
PK assessments will analyze (…) CBD and CBD 
major metabolites. Patients will be required to keep a 
paper diary to note the time and dose of IMP and 
CLB administration each morning and evening and to 
record any adverse events (AEs) that may occur whilst 
receiving IMP (…) 
(…) 
The GWP42003-P/placebo should be taken twice 
daily immediately following their CLB dose. 
PK assessments will analyze (…) CBD, CBD major 
metabolites, ∆9-tetrahydrocannabinol (THC) and 
THC major metabolites. Patients will be required to 
keep a paper diary to note the time and dose of 
GWP42003-P and CLB administration each morning 
and evening and to record any adverse events (AEs) 
that may occur whilst receiving investigational 
medicinal product (IMP) (…) 
See section 
3.3.1 and 3.4  
 
Section 1, 
Protocol 
Synopsis, 
Secondary 
(…) 
 
(…) 
• Abuse liability 
 
PK parameters (Cmax, tmax, AUC(0–∞), AUC(0–t), 
See section 3.4 


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Date 09 Jul 15 
 
 
 
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Protocol Section 
Number, 
Heading and 
Page Number 
Original Wording from Protocol Version 1,  
Dated 26 Jan 15 
(Deleted wording is struck through and in bold)  
Revised Wording from Protocol Amendment 1 
(Protocol Version 2, Dated 09 Jul 15)  
(Revised wording is underscored and in bold)  
Rationale for 
the 
amendment.  
Endpoint(s), 
pg 4-5 
t½) of the following analytes: 
• THC  
• THC major metabolites 
Section 1, 
Protocol 
Synopsis, 
Summary of 
Participant 
Eligibility 
Criteria, pg 5-6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(…) 
• Patient must have experienced at least one seizure 
of any type (i.e., tonic-clonic, tonic, clonic, atonic 
seizures) within the two months prior to 
randomization. 
 
 
 
 
(…) 
• Intervention with vagus (…) throughout the 
duration of the study. 
• Patients must abstain from alcohol during the 
single-blind phase of the study. 
(…) 
• Patient has consumed alcohol during the seven 
days prior to enrollment and is unwilling to abstain 
for the duration of the study. 
(…) 
• Female patients must have a negative pregnancy 
test and be willing and able to use a reliable 
method of contraception throughout the trial and 
for three months after last dose. In the context of 
this trial, an effective method is defined as those 
which result in low failure rate (i.e., less than 1% 
per year) when used consistently and correctly 
such as: combined or progesterone only oral 
contraceptives, intrauterine device, intrauterine 
hormone-releasing system, bilateral tubal 
(…) 
• Patient must have experienced at least one seizure 
of any type (i.e., convulsive: tonic-clonic, tonic, 
clonic, atonic; focal: focal seizures with retained 
consciousness and a motor component,  focal 
seizures with impaired consciousness or focal 
seizures evolving to bilateral secondary 
generalization) within the two months prior to 
randomization. 
(…) 
• Intervention with vagus (…) throughout the 
blinded phase of the study. 
• Patients must abstain from alcohol during the 
blinded phase of the study. 
(…) 
• Patient has consumed alcohol during the seven 
days prior to enrollment and is unwilling to abstain 
during the blinded phase of the 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 three 
months thereafter. Highly effective methods of 
contraception are defined as those, alone or in 
combination, that result in a low failure rate (i.e., 
See section 3.5 
 
 
 
 
 
 
 
 
 
 
See section 3.5 
 
 
 
See section 3.5 
 
 
 
 
See section 3.5 
 
 
 
 
 
 
 


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Date 09 Jul 15 
 
 
 
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Protocol Section 
Number, 
Heading and 
Page Number 
Original Wording from Protocol Version 1,  
Dated 26 Jan 15 
(Deleted wording is struck through and in bold)  
Revised Wording from Protocol Amendment 1 
(Protocol Version 2, Dated 09 Jul 15)  
(Revised wording is underscored and in bold)  
Rationale for 
the 
amendment.  
Section 1, 
Protocol 
Synopsis, 
Summary of 
Participant 
Eligibility 
Criteria, pg 6-7 
occlusion, vasectomized partner or sexual 
abstinence.  
 
 
 
• Female patient who is pregnant, lactating (…) 
(…) 
• Patient has significantly impaired hepatic function, 
as determined at screening or enrollment (Alanine 
aminotransferase [ALT] >5 × upper limit of 
normal [ULN] or total bilirubin [TBL] >2 × 
ULN) OR the ALT or Aspartate 
aminotransferase (AST) >3 × ULN and (TBL >2 
× ULN or international normalized ratio [INR] 
>1.5). 
(…) 
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 (…) 
(…) 
• Patient has significantly impaired hepatic function 
at screening (Visit 1) or enrollment (Visit 2), 
defined as any of the following: 
- 
Alanine aminotransferase (ALT) or 
Aspartate aminotransferase (AST) >5 × 
upper limit of normal (ULN). 
- 
ALT or AST >3 × ULN and total 
bilirubin (TBL) >2 × ULN or 
international normalized ratio (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%). 
(…) 
 
 
 
 
 
 
See section 3.5 
 
 
See section 3.6 
Section 1, 
Protocol 
Synopsis, 
Criteria for 
Withdrawal, 
pg 8 
(…) 
 
(…) 
• Any other IMP is taken as part of a clinical trial 
during the study. 
See section 3.5 
Section 1, 
Protocol 
GWP42003-P oral solution (100 mg/mL CBD in 
sesame oil with anhydrous ethanol, added sweetener 
GWP42003-P oral solution (100 mg/mL CBD in 
sesame oil with anhydrous ethanol, added sweetener 
See section 
3.3.2 


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Date 09 Jul 15 
 
 
 
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Protocol Section 
Number, 
Heading and 
Page Number 
Original Wording from Protocol Version 1,  
Dated 26 Jan 15 
(Deleted wording is struck through and in bold)  
Revised Wording from Protocol Amendment 1 
(Protocol Version 2, Dated 09 Jul 15)  
(Revised wording is underscored and in bold)  
Rationale for 
the 
amendment.  
Synopsis, 
Investigational 
Medicinal 
Product: Dosage, 
Regimen, 
Formulation and 
Mode of 
Administration, 
pg 8 
(sucralose) and strawberry flavoring). 
(…) 
 
 
(sucralose) and strawberry flavoring), pale yellow in 
color. 
(…) 
 
Section 1, 
Protocol 
Synopsis, 
Investigational 
Medicinal 
Product: Dosage, 
Regimen, 
Formulation and 
Mode of 
Administration, 
pg 8 
(…) 
• Day 2 (Visit 2), patients will begin the up-titration 
with placebo to an equivalent maintenance dose of 
20 mg/kg/day (…) 
 
• After up-titration with placebo, the patients will 
remain on the maintenance dose for 14 days (Days 
12 to 25). 
• On Day 27 (Visit 3), patients will begin the up-
titration with CBD to the maintenance dose of 
20 mg/kg/day over a period of 10 days (Days 27 
to 36). 
• After up-titration with CBD, the patients will 
remain on the maintenance dose for a further 
14 days (Day 37 to 50). 
Please refer to Table 8.1-1 for details of the up-
titration doses for CBD and placebo for each of the 
ten days. 
On Day 52 (Visit 4), patients will be invited to receive 
CBD in the open label extension (OLE) period. (…) 
(…) 
• Day 2 (Visit 2), patients will begin the up-titration 
with GWP42003-P or placebo to a maintenance 
dose or an equivalent maintenance dose of 
20 mg/kg/day (…) 
• After up-titration with GWP42003-P or placebo, 
the patients will remain on the maintenance dose 
for 21 days (Days 12 to 32). 
 
 
 
 
 
 
Please refer to Table 8.1.2-1 for details of the up-
titration doses for GWP42003-P and placebo for the 
ten day taper period. 
On Day 34 (Visit 4), patients will be invited to receive 
GWP42003-P in the OLE period. (…) 
 
See section 3.1 
 
 
 
 
 
 
 
 
 
 
 
 
 
See section 3.7, 
3.3.2 and 
section 3.1 
Section 1, 
Protocol 
(…) 
(…) 
Clobazam will be an IMP for the blinded section of 
See section 
3.3.1 


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Protocol Section 
Number, 
Heading and 
Page Number 
Original Wording from Protocol Version 1,  
Dated 26 Jan 15 
(Deleted wording is struck through and in bold)  
Revised Wording from Protocol Amendment 1 
(Protocol Version 2, Dated 09 Jul 15)  
(Revised wording is underscored and in bold)  
Rationale for 
the 
amendment.  
Synopsis, 
Investigational 
Medicinal 
Product: Dosage, 
Regimen, 
Formulation and 
Mode of 
Administration, 
pg 8 
the study. The patients’ own supply of Clobazam 
will be used. 
Section 1, 
Protocol 
Synopsis, 
Control Group, 
pg 8 
All patients will receive placebo in the first part of 
the single-blind phase (Days 2 to 26) and CBD 
during the second part of the single-blind phase 
(Day 27 onwards).There is no separate control 
group. 
The control group will receive an equal volume of 
matching placebo. 
See section 3.1 
Section 1, 
Protocol 
Synopsis, 
Procedures, 
pg 8-9 
VISIT 1 - Screening (Day -7) 
The following observations (…) ECG and vital signs. 
Clinical laboratory samples (blood and urine) will be 
taken for hematology, biochemistry, urinalysis (…) 
(…) 
 
Patients who satisfy all inclusion (…) and then begin 
the seven day baseline period. 
(…) 
This visit will occur 7 days after Visit 1. 
 
VISIT 1 - Screening (Day -14 to -7) 
The following observations (…) ECG, vital signs and 
AEs. Clinical laboratory samples (blood and urine) 
will be taken for hematology, biochemistry, alcohol 
testing, THC testing, urinalysis (…) 
(…) 
Patients who satisfy all inclusion (…) and then begin 
the baseline period. 
(…) 
This visit will occur 7-14 days after Visit 1. 
 
See section 3.1  
 
 
See section 3.1 
and 3.7 
 
See section 3.1 
 
 
See section 3.1 
Section 1, 
Protocol 
Synopsis, 
Procedures, pg 9 
VISIT 2 - Enrollment (Day 1) +3 days window  
(…) 
The following observations will be made at Visit 2: 
(…) physical examination (including height and body 
weight, review of seizure diary and AEs. Clinical 
laboratory samples (blood and urine) will be taken for 
VISIT 2 - Enrollment (Day 1) +3 days window 
(…) 
The following observations will be made at Visit 2: 
(…) physical examination (including body weight), 
review of patient diary and AEs. Clinical laboratory 
samples (blood and urine) will be taken for 
See section 3.7 
and 3.2  
‘Seizure’ diary 
replaced with 
‘patient’ diary 
(throughout) as 


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Protocol Section 
Number, 
Heading and 
Page Number 
Original Wording from Protocol Version 1,  
Dated 26 Jan 15 
(Deleted wording is struck through and in bold)  
Revised Wording from Protocol Amendment 1 
(Protocol Version 2, Dated 09 Jul 15)  
(Revised wording is underscored and in bold)  
Rationale for 
the 
amendment.  
hematology, biochemistry and urinalysis. 
(…) 
hematology, biochemistry, alcohol testing and 
urinalysis. 
(…) 
 
the diary 
includes 
multiple items, 
not just seizure 
information. 
 
Section 1, 
Protocol 
Synopsis, 
Procedures, pg 9 
(…) 
 
(…) 
(…) 
Blood samples will also be taken for genetic testing 
if additional consent has been obtained. 
(…) 
See section 3.2 
 
Section 1, 
Protocol 
Synopsis, 
Procedures, pg 9 
(…) 
Blood samples will be taken for analysis of plasma 
concentrations of CLB, N-CLB, CBD and CBD 
major metabolites. 
(…) 
 
(…) 
Blood samples will be taken for analysis of plasma 
concentrations of CLB, N-CLB, CBD, CBD, major 
metabolites, THC and THC major metabolites. 
(…) 
 
See section 3.4 
 
Section 1, 
Protocol 
Synopsis, 
Procedures, pg 
9-10 
VISIT 2 - Enrollment (Day 2) 
(…)Following completion of the PK sampling process 
(...), physical examination (including height and body 
weight), vital signs, and AEs.  
IMP will be dispensed and both the morning dose of 
CLB and of IMP will be taken in clinic. (…) Each 
patient will then receive their IMP for the 10 day 
titration period followed by the 14 day maintenance 
period. 
(…) 
VISIT 2 - Enrollment (Day 2) 
(…)Following completion of the PK sampling process 
(...), physical examination (including body weight), 
vital signs and AEs.  
GWP42003-P/placebo will be dispensed and both the 
morning dose of CLB and GWP42003-P/placebo will 
be taken in clinic. (…) Each patient will then receive 
their GWP42003-P/placebo for the 10 day titration 
period followed by the 21 day maintenance period. 
(…) 
 
 
See section 3.2 
and section 3.7 
 
See section 
3.3.1 
See section 3.1  
  
Section 1, 
Protocol 
Synopsis, 
Procedures, 
pg 10 
(…) 
 
(…) 
(…) 
VISIT 3 – Day 12 +3 day window 
This visit will occur 11 days after Visit 2, Day 1 
(enrollment). Patients will return all used and 
unused GWP42003-P/placebo. The following 
See section 3.1 


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Protocol Section 
Number, 
Heading and 
Page Number 
Original Wording from Protocol Version 1,  
Dated 26 Jan 15 
(Deleted wording is struck through and in bold)  
Revised Wording from Protocol Amendment 1 
(Protocol Version 2, Dated 09 Jul 15)  
(Revised wording is underscored and in bold)  
Rationale for 
the 
amendment.  
observations will be made at Visit 3: concomitant 
medications (including AEDs), physical 
examination (including body weight), ECG, vital 
signs, AEs and review of patient diary completion. 
Clinical laboratory samples (blood and urine) will 
be taken for hematology, biochemistry and 
urinalysis. The C-SSRS will be administered. 
(…) 
Section 1, 
Protocol 
Synopsis, 
Procedures, 
pg 10 
(…) 
VISIT 3 - Day 26 ±3 days window 
This visit will occur 25 days after Visit 2, Day 1 
(enrollment). Patients will return all used and unused 
IMP. The following observations will be made at 
Visit 3 (Day 26): (…) physical examination (including 
height and body weight), ECG, vital signs, review of 
seizure diary and AEs. Clinical laboratory samples 
(blood and urine) will be taken for hematology, 
biochemistry and urinalysis. 
(…) 
(…) 
VISIT 4 - Day 33 ±3 days window 
This visit will occur 32 days after Visit 2, Day 1 
(enrollment). Patients will return all used and unused 
GWP42003-P/placebo. The following observations 
will be made at Visit 4 (Day 33): (…) physical 
examination (including body weight), ECG, vital 
signs, review of patient diary and AEs. Clinical 
laboratory samples (blood and urine) will be taken for 
hematology, biochemistry, alcohol testing and 
urinalysis. 
(…) 
 
See section 3.1 
 
See section 
3.3.1 
See section 3.1  
 
See section 3.7 
 
See section 3.2 
Section 1, 
Protocol 
Synopsis, 
Procedures, 
pg 10 
(…) 
Blood samples will be taken for analysis of plasma 
concentrations of CLB, N-CLB, CBD and CBD 
major metabolites. A baseline PK sample will be 
taken before the patient takes their morning dose of 
CLB, followed immediately by their dose of IMP. 
(…) 
 
(…) 
Blood samples will be taken for analysis of plasma 
concentrations of CLB, N-CLB, CBD, CBD major 
metabolites, THC and THC major metabolites. A 
baseline PK sample will be taken before the patient 
takes their morning dose of CLB, followed 
immediately by their dose of GWP42003-P/placebo. 
(…) 
 
 
 
See section 3.4 
 
 
See section 
3.3.1 
Section 1, 
Protocol 
Synopsis, 
(…) 
VISIT 3 - Day 27 
(…) 
(…) 
VISIT 4 - Day 34 
(…) 
See section 3.1 
and section 3.2 
 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Date 09 Jul 15 
 
 
 
Confidential 
 
Page 16 of 60 
Template: 031213 
Protocol Section 
Number, 
Heading and 
Page Number 
Original Wording from Protocol Version 1,  
Dated 26 Jan 15 
(Deleted wording is struck through and in bold)  
Revised Wording from Protocol Amendment 1 
(Protocol Version 2, Dated 09 Jul 15)  
(Revised wording is underscored and in bold)  
Rationale for 
the 
amendment.  
Procedures, 
pg 10 
 
 
 
 
Section 1, 
Protocol 
Synopsis, 
Procedures, 
pg 10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The final PK sample will be collected 24 hours after 
the Day 25 morning CLB dose. 
Following completion of the PK sampling process the 
following observations will be made on Day 27: 
(…).physical examination (including height and body 
weight), vital signs, and AEs. 
IMP will be dispensed and both the morning dose 
of CLB and of IMP will be taken in clinic. Patients 
and/or their caregivers will be provided with 
individual dosing schedules as described in Section 
8.1. Each patient will then receive their IMP for 
the 10 day titration period followed by the 14 day 
maintenance period. 
VISIT 4 - Day 51 ±3 days window 
This visit will occur 50 days after Visit 2, Day 1 
(enrollment). Patients will return all used and 
unused IMP. The following observations will be 
made at Visit 4 (Day 51): concomitant medications 
(including AEDs), physical examination (including 
height and body weight), ECG, vital signs, review 
of seizure diary and AEs. 
Clinical laboratory samples (blood and urine) will 
be taken for hematology, biochemistry and 
urinalysis. The C-SSRS will be administered. The 
investigator must record the patient’s attendance 
at the visit and the outcome. 
Blood samples will be taken for analysis of plasma 
concentrations of CLB, N-CLB, CBD and CBD 
major metabolites. A baseline PK sample will be 
taken before the patient takes their morning dose 
of CLB, followed immediately by their dose of 
The final PK sample will be collected 24 hours after 
the Day 33 morning CLB dose. 
Following completion of the PK sampling process the 
following observations will be made on Day 34:(…) 
physical examination (including body weight), vital 
signs, and AEs. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
See section 3.1 
and section 3.2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Date 09 Jul 15 
 
 
 
Confidential 
 
Page 17 of 60 
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Protocol Section 
Number, 
Heading and 
Page Number 
Original Wording from Protocol Version 1,  
Dated 26 Jan 15 
(Deleted wording is struck through and in bold)  
Revised Wording from Protocol Amendment 1 
(Protocol Version 2, Dated 09 Jul 15)  
(Revised wording is underscored and in bold)  
Rationale for 
the 
amendment.  
Section 1, 
Protocol 
Synopsis, 
Procedures, 
pg 10 
IMP. Further samples will then be taken at the 
following times relative to the CLB dose: 15 
minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 
hours, 6 hours and 12 hours. Patients are expected 
to remain in clinic throughout this PK sampling. 
The investigator must assess adherence to the 
dosing regimen and recording of rescue 
medications by reviewing the patient’s diary. 
VISIT 4 - Day 52  
This is the second part of the two day visit. The 
final PK sample will be collected 24 hours after the 
Day 51 morning CLB dose. 
Following completion of the PK sampling process 
the following observations will be made on Day 52: 
concomitant medications (including AEDs), 
physical examination (including height and body 
weight), vital signs, and AEs. 
At the end of the blinded phase of the study on Day 
52 providing the investigator and patient both agree, 
patients will be invited to continue taking IMP and to 
enter the OLE. 
Patients who enter the OLE will be dispensed CBD on 
Day 52.  
(…) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
On Day 34, providing the investigator and patient 
both agree, patients will be invited to continue taking 
GWP42003-P and to enter the OLE. 
Patients who enter the OLE will be dispensed 
GWP42003-P on Day 34.  
(…) 
 
See section 3.1 
and section 3.2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
See section 3.1 
and 3.3.1 
 
 
Section 1, 
Protocol 
Synopsis, 
Procedures, 
pg 11 
(…) 
Patients who do not enter the OLE will begin a 10 day 
taper period during which they will taper off their 
daily dose of IMP. The daily dose will be reduced by 
10% of the maintenance dose per day and treatment 
will end on Day 60. 
(…) 
(…) 
Patients who do not enter the OLE will begin a 10 day 
taper period during which they will taper off their 
daily dose of GWP42003-P. The daily dose will be 
reduced by 10% of the maintenance dose per day and 
treatment will end on Day 42. 
(…) 
 
 
 
See section 
3.3.1 
See section 3.1 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Date 09 Jul 15 
 
 
 
Confidential 
 
Page 18 of 60 
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Protocol Section 
Number, 
Heading and 
Page Number 
Original Wording from Protocol Version 1,  
Dated 26 Jan 15 
(Deleted wording is struck through and in bold)  
Revised Wording from Protocol Amendment 1 
(Protocol Version 2, Dated 09 Jul 15)  
(Revised wording is underscored and in bold)  
Rationale for 
the 
amendment.  
Section 1, 
Protocol 
Synopsis, 
Procedures, 
pg 11 
(…) 
VISIT 5 – Day 61 (End of Taper) +3 days window 
This visit will occur 60 days after Visit 2, Day 1 
(enrollment) for those patients who do not enter the 
OLE. 
All IMP (used and unused) will be collected and a 
check of the returned IMP against usage must be 
made. A physical examination (including height and 
body weight) and vital signs (…) 
(…) 
 
 
 
(…) 
(…) 
VISIT 5 – Day 43 (End of Taper) +3 days window 
This visit will occur 42 days after Visit 2, Day 1 
(enrollment) for those patients who do not enter the 
OLE. 
All GWP42003-P/placebo (used and unused) will be 
collected and a check of the returned 
GWP42003-P/placebo against usage must be made. 
A physical examination (including body weight), 
ECG and vital signs (…) The trained investigator or 
study coordinator will complete the Study 
Medication Use and Behavior Survey as an 
interview with the patient/caregiver.  
(…) 
 
 
See section 3.1 
 
 
See section 
3.3.1 
 
 
See section 3.2 
To be 
consistent with 
Visit 12 ECG 
See section 3.2 
Section 1, 
Protocol 
Synopsis, 
Procedures, 
pg 11 
(…) 
SAFETY FOLLOW-UP CALL - Day 89 ±3 days 
This visit is required for patients who do not enter the 
OLE study on Day 52, or who withdraw from the 
study early.  
(…) 
 
The following observations will be made on Day 89: 
(…) 
(…) 
VISIT 6 - SAFETY FOLLOW-UP CALL - Day 71 
±3 days 
This visit is required for patients who do not enter the 
OLE study on Day 34, or who withdraw from the 
study early.  
(…) 
The following observations will be made on Day 71: 
(…) 
 
See section 3.1 
Section 1, 
Protocol 
Synopsis, 
Procedures, 
pg 11 
(…) 
 
 
 
 
 
 
(…) 
At the point of entry to the OLE, patients will be 
transitioned to the OLE treatment over a 10 day 
period in order to maintain blinding.  
 
 
 
 
To provide 
clarity over 
how patients 
will transition 
from the 
blinded to 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Date 09 Jul 15 
 
 
 
Confidential 
 
Page 19 of 60 
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Protocol Section 
Number, 
Heading and 
Page Number 
Original Wording from Protocol Version 1,  
Dated 26 Jan 15 
(Deleted wording is struck through and in bold)  
Revised Wording from Protocol Amendment 1 
(Protocol Version 2, Dated 09 Jul 15)  
(Revised wording is underscored and in bold)  
Rationale for 
the 
amendment.  
Patients who enter the OLE will be dispensed IMP at 
Visit 4 (Day 52) (…) The visit schedule is calculated 
relative to Visit 4 (Day 52). 
(…) 
Patients who enter the OLE will be dispensed IMP at 
Visit 4 (Day 34) (…) The visit schedule is calculated 
relative to Visit 4 (Day 34). 
(…) 
OLE. 
See section 3.1 
Section 1, 
Protocol 
Synopsis, 
Procedures, 
pg 11-13 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
VISIT 5 (OLE) – Two Weeks ±3 days 
This visit will occur two weeks after Visit 4 (Day 51). 
(…) physical examination (including height and body 
weight), ECG, vital signs, review of seizure diary and 
AEs. (…) 
VISIT 6 (OLE) – One Month ±3 days 
This visit will occur one month after Visit 4 (Day 51). 
(…) physical examination (including height and body 
weight), ECG, vital signs, review of seizure diary and 
AEs.(…) 
VISIT 7 (OLE) – Two Months ±3 days 
This visit will occur two months after Visit 4 (Day 
51). (…) physical examination (including height and 
body weight), ECG, vital signs, review of seizure 
diary and AEs.(…) 
VISIT 8 (OLE) - Three Months ±7 days 
This visit will occur three months after Visit 4 (Day 
51). (…) physical examination (including height and 
body weight), ECG, vital signs, review of seizure 
diary and AEs. (…) 
VISIT 9 (OLE) - Six Months ±7 days 
This visit will occur six months after Visit 4 (Day 51). 
(…) physical examination (including height and body 
weight), ECG, vital signs, review of seizure diary and 
AEs. (…) 
VISIT 10 (OLE) - Nine Months ±7 days 
This visit will occur nine months after Visit 4 (Day 
VISIT 5 (OLE) – Two Weeks ±3 days 
This visit will occur two weeks after Visit 4 (Day 34). 
(…) physical examination (including body weight), 
ECG, vital signs, review of patient diary and AEs. 
(…) 
VISIT 6 (OLE) – One Month ±3 days 
This visit will occur one month after Visit 4 (Day 34). 
(…) physical examination (including body weight), 
ECG, vital signs, review of patient diary and AEs. 
(…) 
VISIT 7 (OLE) – Two Months ±3 days 
This visit will occur two months after Visit 4 (Day 
34). (…) physical examination (including body 
weight), ECG, vital signs, review of patient diary and 
AEs.(…) 
VISIT 8 (OLE) - Three Months ±7 days 
This visit will occur three months after Visit 4 (Day 
34). (…) physical examination (including height and 
body weight), ECG, vital signs, review of patient 
diary and AEs. (…) 
VISIT 9 (OLE) - Six Months ±7 days 
This visit will occur six months after Visit 4 (Day 34). 
(…) physical examination (including body weight), 
ECG, vital signs, review of patient diary and AEs. 
(…) 
VISIT 10 (OLE) - Nine Months ±7 days 
This visit will occur nine months after Visit 4 (Day 
See section 3.1, 
3.2 and 3.7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
See section 3.1, 
3.2 and 3.7 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Date 09 Jul 15 
 
 
 
Confidential 
 
Page 20 of 60 
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Protocol Section 
Number, 
Heading and 
Page Number 
Original Wording from Protocol Version 1,  
Dated 26 Jan 15 
(Deleted wording is struck through and in bold)  
Revised Wording from Protocol Amendment 1 
(Protocol Version 2, Dated 09 Jul 15)  
(Revised wording is underscored and in bold)  
Rationale for 
the 
amendment.  
Section 1, 
Protocol 
Synopsis, 
Procedures, 
pg 11-13 
51). (…) physical examination (including height and 
body weight), ECG, vital signs, review of seizure 
diary and AEs. (…) 
VISIT 11 – Twelve Months (OLE End of Treatment) 
±7 days 
This visit will occur twelve months after Visit 4 (Day 
51). (…) physical examination (including height and 
body weight), ECG, vital signs, review of seizure 
diary and AEs. 
(…) 
34). (…) physical examination (including body 
weight), ECG, vital signs, review of patient diary and 
AEs.(…) 
VISIT 11 – Twelve Months (OLE End of Treatment) 
±7 days 
This visit will occur twelve months after Visit 4 (Day 
34). (…) physical examination (including body 
weight), ECG, vital signs, review of patient diary and 
AEs. 
(…) 
See section 3.1, 
3.2 and 3.7 
Section 1, 
Protocol 
Synopsis, 
Procedures, 
pg 13-14 
(…) 
VISIT 12 - OLE End of taper +3 days 
(…) A physical examination (including height and 
body weight), (...) 
 
 
 
(…) 
SAFETY FOLLOW-UP CALL (OLE) 
(…) 
(…) 
VISIT 12 - OLE End of taper +3 days 
(…) A physical examination (including body weight), 
(...) 
The trained investigator or study coordinator will 
complete the Study Medication Use and Behavior 
Survey as an interview with the patient/caregiver. 
(…) 
VISIT 13 - SAFETY FOLLOW-UP CALL (OLE) 
(…) 
 
 
See section 3.2 
 
See section 3.2 
 
 
 
See section 3.7 
Section 1, 
Protocol 
Synopsis, 
Procedures, 
pg 14 
 
 
 
 
 
 
(…) 
(…) 
Monitoring of Drug Abuse Liability  
During the routine collection of AEs in this study, 
if AEs are reported which can illuminate an abuse 
potential signal (specific AEs detailed in Section 
9.1.16.1.1), 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 discussions of the event(s) with the 
patient/caregiver. 
See section 3.2 
 
 
 
  
 
 
 
 
 
 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Date 09 Jul 15 
 
 
 
Confidential 
 
Page 21 of 60 
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Protocol Section 
Number, 
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Page Number 
Original Wording from Protocol Version 1,  
Dated 26 Jan 15 
(Deleted wording is struck through and in bold)  
Revised Wording from Protocol Amendment 1 
(Protocol Version 2, Dated 09 Jul 15)  
(Revised wording is underscored and in bold)  
Rationale for 
the 
amendment.  
Section 1, 
Protocol 
Synopsis, 
Procedures, 
pg 14 
The second trigger that will require the 
investigator or study coordinator to discuss abuse 
potential signals with the patient/caregiver is drug 
accountability issues regarding overuse of the IMP 
or missing IMP 
bottles. 
Irrespective of the above, all patients/caregivers 
will be interviewed at their final dosing visit or 
withdrawal visit 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. 
See section 3.2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 1, 
Protocol 
Synopsis, 
Statistical 
Considerations, 
pg 14 
Plasma concentration data will be analyzed to estimate 
pharmacokinetic endpoints Cmax, AUC(0–t), AUC(0–
∞) of the following analytes CLB, N-CLB, CBD and 
major metabolites. 
(…) 
(…) In order to assess (…) linear mixed effect model 
with treatment (CBD or placebo) as fix effect (…) 
(…) 
Plasma concentration data will be analyzed to estimate 
PK endpoints Cmax, tmax, AUC(0–t), AUC(0–∞) and 
t½ of the following analytes: CLB, N-CLB, CBD, 
CBD major metabolites, THC and THC major 
metabolites. 
(…) 
(…) In order to assess (…) linear mixed effect model 
with treatment (CLB or CLB+CBD) as a fixed effect 
(…) 
(…) 
 
See section 3.7 
 
See section 3.4 
 
 
 
See section 3.1 
and section 3.7 
Section 1, 
Protocol 
Synopsis, 
Sovereign House 
Vision Park 
Histon 
GW Research Ltd 
Sovereign House 
Vision Park 
Added sponsor 
name and 
corrected 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Date 09 Jul 15 
 
 
 
Confidential 
 
Page 22 of 60 
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Protocol Section 
Number, 
Heading and 
Page Number 
Original Wording from Protocol Version 1,  
Dated 26 Jan 15 
(Deleted wording is struck through and in bold)  
Revised Wording from Protocol Amendment 1 
(Protocol Version 2, Dated 09 Jul 15)  
(Revised wording is underscored and in bold)  
Rationale for 
the 
amendment.  
Sponsor, pg 14 
Cambridge CB24 9BZ 
United Kingdom 
Chivers Way 
Histon 
Cambridge CB24 9BZ 
United Kingdom 
sponsor 
address. 
Section 1, Figure 
1-1, Figure 1-2, 
Study Design 
and Treatment 
Schema, 
pg 16-17 
<< Note: See Appendix 1.1 for detailed changes >> 
 
<< Note: See Appendix 1.1 for detailed changes >> 
 
See section 3.1 
Section 1, List of 
Abbreviations, 
pg 26–27 
 
(...) 
(...) 
AUC (0–∞) 
The area under the plasma 
concentration versus time curve 
from zero to ‘t’ calculated as 
AUC(0–t) plus the extrapolated 
amount from time ‘t’ to infinity  
(...) 
(...) 
DILI 
Drug-Induced Liver Injury 
EC 
Ethics Committee 
(...) 
(...) 
t½ 
Half-life 
(...) 
(...) 
 
(...) 
(...) 
AUC (0–∞) 
Area under the concentration time 
curve from zero to infinity with 
extrapolation  
of the terminal phase 
EC 
Ethics Committee 
(...) 
(...) 
t½ 
Terminal half-life 
(...) 
(...) 
 
 
 
 
 
See section 3.7 
 
 
 
See section 3.7 
Section 1, 
Definition of 
Terms, pg 28 
(…) 
Baseline period      The seven-day period from 
screening (Visit 1) to enrollment (Visit 2). 
(…) 
End of treatment      Completion of the treatment 
period (Visit 5 or Visit 11) or withdrawal. 
(…) 
(…) 
Baseline period      The period from screening (Visit 
1) to enrollment (Visit 2). 
 
(…) 
End of treatment      Completion of the treatment 
period (Visit 5 or Visit 12) or withdrawal.(…) 
See section 3.1 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Date 09 Jul 15 
 
 
 
Confidential 
 
Page 23 of 60 
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Protocol Section 
Number, 
Heading and 
Page Number 
Original Wording from Protocol Version 1,  
Dated 26 Jan 15 
(Deleted wording is struck through and in bold)  
Revised Wording from Protocol Amendment 1 
(Protocol Version 2, Dated 09 Jul 15)  
(Revised wording is underscored and in bold)  
Rationale for 
the 
amendment.  
Section 3.3, 
Rationale, pg 31 
(…) 
(…) active metabolite N-desmethylclobazam (N-
CLB), amongst others. 
(…) 
(…) 
(…) active metabolite N-CLB, amongst others. 
(…) 
See section 3.7 
Section 3.3.1, 
Selection of 
Study Doses, 
pg 32 
(…) 
• >20 mg/kg ≤ 30 mg/kg CBD n=40 (64%) 
• >30 mg/kg ≤ 40 mg/kg CBD n=4 (6%) 
(...) 
11 patients had a daily CBD dose of (...). 
(…) 
• >20 mg/kg - ≤30 mg/kg GWP42003-P n=40 (64%) 
• >30 mg/kg - ≤40 mg/kg GWP42003-P n=4 (6%) 
(...) 
Eleven patients had a daily GWP42003-P dose of 
(...). 
 
See section 3.7 
Section 4.1, 
Study Design, 
pg 32–33 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This phase 2, placebo-controlled study consists of a 52 
day, single-blind phase followed by an optional 
maximum one year OLE.  
(…) 
The IMP will be taken twice daily immediately after 
their CLB dose. (…)   
Patients will enter the study and begin a 10 day 
placebo titration phase. During this period patients 
will be up-titrated to an equivalent maintenance dose 
of 20 mg/kg/day. Patients will continue to take this 
maintenance dose of placebo for 14 days (Days 12 to 
26). 
On Day 27 patients will begin a 10 day CBD 
titration phase. During this period patients will be 
up-titrated to a maintenance dose of 20 mg/kg/day 
CBD. Patients will continue to take this 
maintenance dose for 14 days (Days 37 to 50). 
Upon completion of the single blind phase of the 
study (Day 52) patients will be invited to receive 
CBD during the OLE phase.  
(…) 
This phase 2, placebo-controlled study consists of a 
34 day, double-blind phase followed by an optional 
maximum one year OLE.  
(…) 
GWP42003-P /placebo will be taken twice daily 
immediately after their CLB dose. (…)   
Patients will enter the study and begin a 10 day 
GWP42003-P or placebo titration phase. During this 
period patients will be up-titrated to a maintenance 
dose or equivalent of 20 mg/kg/day. Patients will 
continue to take this maintenance dose of 
GWP42003-P or placebo for 21 days (Days 12 to 32). 
 
 
 
Upon completion of the treatment period (Day 34) 
patients will be invited to receive GWP42003-P 
during the OLE phase.  
 
 
(…) 
See section 3.1 
 
 
 
See section 
3.3.1 
See section 3.1 
 
 
 
 
 
 
 
 
See section 3.1 
 
 
 
 
 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Date 09 Jul 15 
 
 
 
Confidential 
 
Page 24 of 60 
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Protocol Section 
Number, 
Heading and 
Page Number 
Original Wording from Protocol Version 1,  
Dated 26 Jan 15 
(Deleted wording is struck through and in bold)  
Revised Wording from Protocol Amendment 1 
(Protocol Version 2, Dated 09 Jul 15)  
(Revised wording is underscored and in bold)  
Rationale for 
the 
amendment.  
Section 4.1, 
Study Design, 
pg 32–33 
If a patient chooses not to enter the OLE, (…) they 
will taper off their CBD treatment (…). For those 
patients not entering the OLE, dosing will end on Day 
60 and they will receive a telephone follow-up visit 
four weeks after the end of IMP dosing (Day 89). 
PK samples will be taken on three occasions during 
the single blind phase of the study: 
(…) 
• Day 26 (Visit 3) following 14 days of placebo 
maintenance (patients will be taking CLB and 
placebo). 
• Day 51 (Visit 4) following 14 days of CBD 
maintenance (patients will be taking CLB and 
CBD). 
(…) 
PK samples will be quantitatively analyzed for CLB, 
N-CLB (primary metabolite of CLB), CBD and 
CBD major metabolites. 
Patients should try to be consistent in the timing of 
their food intake in relation to dosing throughout the 
single blind phase of the study. 
Upon entry into the OLE the dose of CBD may be 
adjusted up or down to a maximum of 30 mg/kg/day. 
(…) 
 
More detailed information on treatment and study 
procedures are provided in Section 7 and Section 9 
respectively. 
If a patient chooses not to enter the OLE, (…) they 
will taper off their GWP42003-P/placebo treatment 
(…). For those patients not entering the OLE, dosing 
will end on Day 43 and they will receive a telephone 
follow-up visit four weeks after the end of 
GWP42003-P/placebo dosing (Day 71). 
PK samples will be taken on two occasions during the 
blinded phase of the study: 
(…) 
• Day 33 (Visit 4) following 21 days of GWP42003-
P or placebo maintenance (patients will be taking 
CLB and GWP42003-P or placebo). 
(…) 
 
 
PK samples will be quantitatively analyzed for CLB, 
N-CLB, CBD, CBD major metabolites, THC and 
THC major metabolites. 
Patients should try to be consistent in the timing of 
their food intake in relation to dosing throughout the 
blinded phase of the study. 
Upon entry into the OLE the dose of GWP42003-P 
and other AEDs may be adjusted up or down to a 
maximum of 30 mg/kg/day. 
(…) 
More detailed information on treatment and study 
procedures are provided in Section 8 and Section 9 
respectively. 
See section 3.1 
 
 
See section 3.1 
See section 
3.3.1 
See section 3.1 
 
 
 
 
 
 
 
 
See section 3.4 
 
 
 
See section 3.1 
See section 3.7 
 
 
 
See section 3.7 
Section 4.1.1, 
Primary 
Endpoint, pg 34 
(…) 
• N-desmethylclobazam (N-CLB) 
(…) 
(…) 
• N-CLB 
(…) 
See section 3.7 
 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Date 09 Jul 15 
 
 
 
Confidential 
 
Page 25 of 60 
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Protocol Section 
Number, 
Heading and 
Page Number 
Original Wording from Protocol Version 1,  
Dated 26 Jan 15 
(Deleted wording is struck through and in bold)  
Revised Wording from Protocol Amendment 1 
(Protocol Version 2, Dated 09 Jul 15)  
(Revised wording is underscored and in bold)  
Rationale for 
the 
amendment.  
Section 4.1.2, 
Secondary 
Endpoints, pg 34 
(…) 
(…) 
• Abuse liability 
PK parameters (Cmax, tmax, AUC(0–∞),AUC(0–t), 
t½) of the following analytes: 
• THC  
• THC major metabolites 
See section 3.4 
Section 4.2, 
Number of 
Centers, pg 34 
An estimated number of two centers is expected to 
participate in this study. 
An estimated number of seven centers are expected to 
participate in this study. 
More centers 
required to 
conduct this 
study. 
Section 5.1, 
GWP42003-P 
Oral Solution, 
pg 35 
GWP42003-P oral solution is presented as an oily 
solution (…) 
(…) 
GWP42003-P oral solution is presented as a pale 
yellow oily solution (…) 
(…) 
See section 
3.3.2 
Section 5.3, 
Packaging, 
Storage and 
Drug 
Accountability 
(Cannabidiol/ 
Placebo), pg 35 
5.3 Packaging, Storage and Drug Accountability  
5.3 Packaging, Storage and Drug Accountability 
(Cannabidiol/Placebo) 
See section 
3.3.1 
Section 5.4, 
Clobazam, pg 37 
N/A 
5.4 Clobazam 
Patients will use their own supply of Clobazam 
throughout the study. Clobazam usage will be 
recorded by the investigator. Clobazam is only an 
IMP for the blinded phase of the study.     
See section 
3.3.1 
Section 6.1, 
Inclusion 
Criteria, 
pg 37-38 
(…) 
6.1.4 
Patient must have experienced at least one 
seizure of any type (i.e., tonic-clonic, tonic, clonic, 
atonic seizures) within the two months prior to 
(…) 
6.1.4 
Patient must have experienced at least one 
seizure of any type (i.e., convulsive: tonic-clonic, 
tonic, clonic, atonic; focal: focal seizures with 
See section 3.5 
 
 
 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Date 09 Jul 15 
 
 
 
Confidential 
 
Page 26 of 60 
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Protocol Section 
Number, 
Heading and 
Page Number 
Original Wording from Protocol Version 1,  
Dated 26 Jan 15 
(Deleted wording is struck through and in bold)  
Revised Wording from Protocol Amendment 1 
(Protocol Version 2, Dated 09 Jul 15)  
(Revised wording is underscored and in bold)  
Rationale for 
the 
amendment.  
Section 6.1, 
Inclusion 
Criteria, 
pg 37-38 
 
randomization. 
(…) 
 
 
 
6.1.8 
Patients must abstain from alcohol during the 
single-blind phase of the study. 
(…) 
retained consciousness and a motor component,  
focal seizures with impaired consciousness, focal 
seizures evolving to bilateral secondary 
generalization) within the two months prior to 
randomization. 
(…) 
6.1.8 
Patients must abstain from alcohol during the 
blinded phase of the study. 
(…) 
 
See section 3.5 
 
 
 
 
See section 3.1 
Section 6.2, 
Exclusion 
Criteria, 
pg 38-39 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(…) 
6.2.7 
Patient has consumed alcohol during the 
seven days prior to enrollment and is unwilling to 
abstain for the duration of the study. 
(…) 
6.2.13 Female patients must have a negative 
pregnancy test and be willing and able to use a 
reliable method of contraception throughout the 
trial and for three months after last dose. In the 
context of this trial, an effective method is defined as 
those which result in low failure rate (i.e., less than 
1% per year) when used consistently and correctly 
such as: combined or progesterone only oral 
contraceptives, intrauterine device, intrauterine 
hormone-releasing system, bilateral tubal occlusion, 
vasectomized partner or sexual abstinence.  
 
 
 
6.2.14 Female patient who is pregnant, lactating (…) 
(…) 
6.2.18 Patient has significantly impaired hepatic 
function, as determined at screening or enrollment 
(…) 
6.2.7 
Patient has consumed alcohol during the 
seven days prior to enrollment and is unwilling to 
abstain during the blinded phase of the study. 
(…) 
6.2.13 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 three 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. 
6.2.14 Female patient who is pregnant (positive 
pregnancy test), lactating (…) 
(…) 
6.2.18 Patient has significantly impaired hepatic 
See section 3.5 
 
 
 
 
See section 3.5 
 
 
 
 
 
 
 
 
 
 
 
 
See section 3.5 
 
 
 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Date 09 Jul 15 
 
 
 
Confidential 
 
Page 27 of 60 
Template: 031213 
Protocol Section 
Number, 
Heading and 
Page Number 
Original Wording from Protocol Version 1,  
Dated 26 Jan 15 
(Deleted wording is struck through and in bold)  
Revised Wording from Protocol Amendment 1 
(Protocol Version 2, Dated 09 Jul 15)  
(Revised wording is underscored and in bold)  
Rationale for 
the 
amendment.  
Section 6.2, 
Exclusion 
Criteria, 
pg 38-39 
 
(Alanine aminotransferase [ALT] >5 × upper limit of 
normal [ULN] or total bilirubin [TBL] >2 × ULN) 
OR the ALT or Aspartate aminotransferase (AST) 
>3 × ULN and (TBL >2 × ULN or international 
normalized ratio [INR] >1.5). (…) 
(…) 
 
function at screening (Visit 1) or enrollment (Visit 2), 
defined as any of the following: 
- Alanine aminotransferase (ALT) or Aspartate 
aminotransferase (AST) >5 × upper limit of 
normal (ULN). 
- ALT or AST >3 × ULN and total bilirubin (TBL) 
>2 × ULN or international normalized ratio (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%). 
(…) 
See section 3.6 
 
See section 3.6 
 
 
See section 3.6 
 
 
See section 3.6 
Section 7.1, 
Treatment 
Assignment, 
pg 40 
(…) 
GWP will provide all IMP packed and labelled. 
(…) 
(…) 
GWP will provide all GWP42003-P/placebo packed 
and labelled. 
(…) 
See section 
3.3.1 
Section 7.2, 
Randomization, 
pg 40 
This is a single-blind study with all patients 
following the same treatment regimen. 
This is a double-blind study. Patients will be 
randomised in a 4:1 ratio to receive 20 mg/kg 
GWP42003-P or placebo. 
See section 3.1 
Section 8.1, 
Investigational 
Medicinal 
Product Dosage, 
Administration 
and Schedule, 
pg 41 
The IMP will be presented as an oral solution 
containing either the active pharmaceutical 
ingredient and excipients (in the case of 
GWP42003-P) or only excipients (in the case of 
placebo). For details regarding IMP formulations, 
see Section 5. 
The IMP will consist of two types of medication: 
• GWP42003-P Oral Solution containing 100 
mg/mL CBD. 
• Placebo Oral Solution containing excipients. 
 
 
 
 
 
 
The IMP will consist of three types of medication: 
• GWP42003-P Oral Solution containing 100 
mg/mL CBD. 
• Placebo Oral Solution containing excipients. 
• Clobazam (patient supplied). 
 
See section 
3.3.2 
 
 
 
See section 
3.3.1 
 
See section 
3.3.1 
 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Date 09 Jul 15 
 
 
 
Confidential 
 
Page 28 of 60 
Template: 031213 
Protocol Section 
Number, 
Heading and 
Page Number 
Original Wording from Protocol Version 1,  
Dated 26 Jan 15 
(Deleted wording is struck through and in bold)  
Revised Wording from Protocol Amendment 1 
(Protocol Version 2, Dated 09 Jul 15)  
(Revised wording is underscored and in bold)  
Rationale for 
the 
amendment.  
 
 
 
 
 
 
 
All patients will be weighed during Visit 2 and the 
daily volumes of IMP solution to be taken (…) 
(…) 
 
Each patient will take their first dose of IMP at Visit 
2, Day 2 in the clinic. Patients not entering the OLE 
will take their final maintenance dose of IMP at Visit 
4 (Day 51) in the clinic. 
(…) 
The GWP42003-P/placebo will be presented as an 
oral solution containing either the active 
pharmaceutical ingredient and excipients (in the 
case of GWP42003-P) or only excipients (in the 
case of placebo). For details regarding 
GWP42003-P/placebo formulations, see Section  5. 
 
All patients will be weighed during the study visits 
and the daily volumes of GWP42003-P/placebo 
solution to be taken (…) 
(…) 
Each patient will take their first dose of 
GWP42003-P/placebo at Visit 2, Day 2 in the clinic. 
Patients not entering the OLE will take their final 
maintenance dose of GWP42003-P/placebo at Visit 4 
(Day 33) in the clinic.  
(…) 
Patients will use their own supply of Clobazam 
throughout the study. Patients will continue on the 
dose that they were on at screening for the blinded 
phase of the study. Clobazam will only be an IMP 
for the blinded section of the study. 
See section 
3.3.2 
 
 
 
 
 
See section 3.7 
See section 
3.3.1 
 
See section 
3.3.1 
 
See section 
3.3.1 and 3.1 
 
See section 
3.3.1 
Section 8.1.1, 
Dose 
Administration, 
pg 41 
The IMP will be administered orally (…) The IMP 
should be taken immediately after the patient’s usual 
CLB administration. The IMP should be swallowed, 
(…) 
(…) 
GWP42003-P/placebo will be administered orally 
(…) GWP42003-P/placebo should be taken 
immediately after the patient’s usual CLB 
administration. The GWP42003-P/placebo should be 
swallowed, (…) 
(…) 
See section 
3.3.1 
Protocol Section 
8.1.2, Dose 
Escalation and 
Patients will enter the single blind phase of the study 
and will be up-titrated over ten days (Day 2 to Day 
11) to an equivalent maintenance dose of placebo of 
Patients will enter the blinded phase of the study and 
will be up-titrated over ten days (Day 2 to Day 11) to 
a maintenance dose or equivalent of 
See section 
3.3.1 
 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Date 09 Jul 15 
 
 
 
Confidential 
 
Page 29 of 60 
Template: 031213 
Protocol Section 
Number, 
Heading and 
Page Number 
Original Wording from Protocol Version 1,  
Dated 26 Jan 15 
(Deleted wording is struck through and in bold)  
Revised Wording from Protocol Amendment 1 
(Protocol Version 2, Dated 09 Jul 15)  
(Revised wording is underscored and in bold)  
Rationale for 
the 
amendment.  
Dose 
Adjustments, 
pg 41-43 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
20 mg/kg/day. From Day 27 to Day 36 patients will 
be up-titrated to a maintenance dose of 20 
mg/kg/day CBD. (…) 
For those patients who do not enter the OLE the 
dose of CBD will taper off over 10 days beginning 
on Day 52. The patient will reduce the dose by 
10% of the maintenance dose each day and 
treatment will end on Day 60. 
For patients who enter the OLE the maintenance 
dose of CBD may be adjusted up or down, 
depending on investigator opinion, to a maximum 
of 30 mg/kg/day. 
 
<< Note: For changes to Table 8.1-1: See Appendix 
1.2 >> 
GWP42003-P/placebo of 20 mg/kg/day. If 
GWP42003-P is not tolerated then the dose can be 
reduced accordingly at the discretion of the 
investigator. (…) 
 
 
<<Note: For changes to Table 8.1.2-1: See Appendix 
1.2 >> 
 
The titration regimen defined above should be 
followed to the maximum dose (20 mg/kg/day).  
Should an AE occur during titration which is 
attributable to IMP or concomitant AED, then 
IMP dose should be reduced to the next lower dose. 
Any other changes in concomitant AED therapy 
should be reviewed with the medical monitor 
before being initiated. 
For those patients who do not enter the OLE the 
dose of GWP42003-P/placebo will taper off over 
10 days beginning on Day 34. The patient will 
reduce the dose by 10% of the maintenance dose 
each day and treatment will end on Day 43. 
Patients who enter the OLE period will be 
transitioned to the OLE treatment over a 10-day 
period in order to maintain blinding, 
simultaneously down-titrating blinded 
GWP42003-P/placebo whilst up-titrating open-
label GWP42003-P. As such, patients who were 
taking GWP42003-P during the blinded period will 
maintain their 20 mg/kg/day dose throughout the 
transition from the blinded period into the OLE 
 
 
 
 
 
 
 
 
 
See section 
3.3.1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Date 09 Jul 15 
 
 
 
Confidential 
 
Page 30 of 60 
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Protocol Section 
Number, 
Heading and 
Page Number 
Original Wording from Protocol Version 1,  
Dated 26 Jan 15 
(Deleted wording is struck through and in bold)  
Revised Wording from Protocol Amendment 1 
(Protocol Version 2, Dated 09 Jul 15)  
(Revised wording is underscored and in bold)  
Rationale for 
the 
amendment.  
Protocol Section 
8.1.2, Dose 
Escalation and 
Dose 
Adjustments, 
pg 41-43 
period and patients who received placebo during 
the blinded period up-titrate slowly to the 
20 mg/kg/day dose in the OLE period. After this 
has taken place, the maintenance dose of 
GWP42003-P may be adjusted up or down at the 
discretion of the investigator to a maximum of 
30 mg/kg/day (no minimum). 
See section 
3.3.1 
Section 8.2, 
Concomitant 
Therapy, pg 43 
Doses of any concomitant AEDs, (…) must remain 
stable throughout the study period. 
(…) 
Doses of any concomitant AEDs, (…) must remain 
stable throughout the blinded phase of the study. If 
there are symptoms of toxicity suspected to be 
from a drug interaction, the investigator may 
adjust GWP42003-P/placebo or the CLB or other 
AEDs after discussion with the medical monitor. 
(…) 
See section 
3.3.2 
Section 8.3, 
Prohibited 
Therapy During 
Study Period, 
pg 43 
(…) 
• Any other IMP taken as part of a clinical trial 
within six months or during the study. 
(…) 
If any other IMP is taken as part of a clinical trial 
within twelve weeks of the screening visit or during 
the study, the patient must be withdrawn from this 
study. 
See section 3.5 
Section 8.5, 
Access to 
Blinded 
Treatment 
Assignment, 
pg 44 
 
 
 
 
 
 
This is a single blind study. The identity of IMP 
assigned to patients will be known to the PI and the 
GWEP1428 study team at each site but will not be 
known by the patients. 
The identity of IMP assigned to patients will be 
held by the IVRS. The principal investigator (PI) 
at each center is responsible for all trial-related 
medical decisions and is responsible for ensuring 
that information on how to access the IVRS is 
available to the relevant staff in case of an 
emergency and unblinding is required. A patient’s 
treatment assignment must only be unblinded 
when knowledge of the treatment is essential to 
make a decision on the medical management of the 
patient. Unblinding for any other reason will be 
considered a protocol deviation. 
See section 3.1 
 
 
 
 
 
 
 
 
 
 
 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Date 09 Jul 15 
 
 
 
Confidential 
 
Page 31 of 60 
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Protocol Section 
Number, 
Heading and 
Page Number 
Original Wording from Protocol Version 1,  
Dated 26 Jan 15 
(Deleted wording is struck through and in bold)  
Revised Wording from Protocol Amendment 1 
(Protocol Version 2, Dated 09 Jul 15)  
(Revised wording is underscored and in bold)  
Rationale for 
the 
amendment.  
Section 8.5, 
Access to 
Blinded 
Treatment 
Assignment, 
pg 44 
The investigator is encouraged to contact GW to 
discuss the rationale for unblinding. However, to 
prevent delays to the investigator or medical 
personnel responding to a potentially emergent 
situation, unblinding of study medication will not 
be dependent upon the investigator receiving 
approval from GW (i.e., the investigator will be 
able to obtain the code break information 
independent of contacting GW). 
If the investigator does unblind they must contact 
GW within one working day of the event and must 
document the time, date and reasons for 
unblinding in the patient’s CRF. 
See section 3.1 
Section 9.1.1, 
Contraception, 
pg 45 
(…) the patient must have agreed that if they or their 
partner are of child-bearing potential they are willing 
to use effective contraception (…) when used 
consistently and correctly such combined or 
progesterone (…) 
 
(…) the patient must have agreed that if they or their 
partner are of child-bearing potential they are willing 
to use highly effective contraception (…) when used 
consistently and correctly such as combined or 
progesterone (…) 
 
See section 3.5  
Section 9.1.3, 
Demographics, 
pg 45 
Section 15.5 
Participant 
Confidentiality, 
pg 77 
(…) ethnic origin (…) 
(…) race (…) 
See section 3.7 
Section 9.1.6, 
Physical 
Examination, 
pg 46 
 
(…) Physical examinations will include height and 
body weight measurements. 
(…) Physical examinations will include height (at 
screening) and body weight measurements. 
See section 3.7 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Date 09 Jul 15 
 
 
 
Confidential 
 
Page 32 of 60 
Template: 031213 
Protocol Section 
Number, 
Heading and 
Page Number 
Original Wording from Protocol Version 1,  
Dated 26 Jan 15 
(Deleted wording is struck through and in bold)  
Revised Wording from Protocol Amendment 1 
(Protocol Version 2, Dated 09 Jul 15)  
(Revised wording is underscored and in bold)  
Rationale for 
the 
amendment.  
Section 9.1.9, 
Clinical 
Laboratory 
Sampling, pg 47 
 
 
 
 
 
 
 
 
Section 9.1.9, 
Clinical 
Laboratory 
Sampling, pg 47 
(…) 
 
(…) 
Table 9.1-1 Hematology, Biochemistry, Urinalysis 
and THC Screen 
 
Biochemistry 
(serum) 
(...) 
(...) 
(...) 
Urea 
 
 
 
(...) 
See Section 12.8 for guidance on evaluation of 
potential drug-induced liver injury (DILI). (...) 
(…) A serum alcohol test will be performed at 
Visits 1, 2 and 4. (…) 
(…) 
Table 9.1.9-1 Hematology, Biochemistry, Urinalysis 
and THC Screen 
 
Biochemistry 
(serum) 
(...) 
(...) 
(...) 
Urea (BUN) 
 
Triglycerides 
 
 
(...) 
See Section 12.8 for guidance on evaluation of 
potential drug-induced liver injury. (...) 
See section 3.2 
 
 
See section 3.7 
 
 
 
 
 
 
See section 3.7 
 
 
See section 3.7 
Section 9.1.10, 
Pharmacokinetic 
Analyses, pg 48 
The plasma concentration/time curves of CLB, N-
CLB, CBD and CBD major metabolites will be 
assessed at Visit 2 (Day 1 and Day 2), Visit 3 (Day 26 
and Day 27) and Visit 4 (Day 51 and Day 52). 
Patients will be given their daily dose of clobazam at a 
scheduled time during Visit 2, Visit 3 and Visit 4 and 
the IMP immediately afterwards (Visit 3 and Visit 4 
only) (…) 
(…) 
The plasma concentration/time curves of CLB, N-
CLB, CBD, CBD major metabolites, THC and THC 
major metabolites will be assessed at Visit 2 (Day 1 
and Day 2) and Visit 4 (Day 33 and Day 34). Patients 
will be given their daily dose of clobazam at a 
scheduled time during Visit 2 and Visit 4 and the 
GWP42003-P/placebo immediately afterwards (Visit 
4 only) (…) 
(…) 
See section 3.4  
 
 
See section 3.1 
 
 
 
Section 9.1.11, 
Genetic Testing, 
pg 48 
N/A 
9.1.11 Genetic Testing 
Genetic testing will only be conducted if specific 
consent is obtained from the participant. There is a 
separate informed consent form for this. 
Genetic testing will be conducted to look at the 
genes, CYP 2C19 and CYP 3A4, involved in the 
See section 3.2 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Date 09 Jul 15 
 
 
 
Confidential 
 
Page 33 of 60 
Template: 031213 
Protocol Section 
Number, 
Heading and 
Page Number 
Original Wording from Protocol Version 1,  
Dated 26 Jan 15 
(Deleted wording is struck through and in bold)  
Revised Wording from Protocol Amendment 1 
(Protocol Version 2, Dated 09 Jul 15)  
(Revised wording is underscored and in bold)  
Rationale for 
the 
amendment.  
metabolization of AEDs and GWP42003-P.     
Section 9.1.14, 
Investigational 
Medicinal 
Product 
Accountability, 
pg 49 
IMP will be dispensed at each of the following visits 
during the single blind phase: 
• Visit 2 (Day 2) 
• Visit 3 (Day 26) 
• Visit 4 (Day 51) 
(…) 
GWP42003-P/placebo will be dispensed at each of 
the following visits during the blinded phase: 
• Visit 2 (Day 2) 
• Visit 4 (Day 34) 
(…) 
See section 3.1 
Section 9.1.15, 
Adverse Events, 
pg 50 
(…) 
(…) 
Refer to Section 9.1.16.1.1 for the list of 
‘Triggering AEs of Interest’ associated with 
monitoring of drug abuse liability. 
See section 3.4 
Section 9.1.16, 
Monitoring of 
Drug Abuse 
Liability, pg 50 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N/A 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.1.16 Monitoring of Drug Abuse Liability 
There are two 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 (Visit 5 or Visit 12) or 
withdrawal visit 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. 
See section 3.2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Date 09 Jul 15 
 
 
 
Confidential 
 
Page 34 of 60 
Template: 031213 
Protocol Section 
Number, 
Heading and 
Page Number 
Original Wording from Protocol Version 1,  
Dated 26 Jan 15 
(Deleted wording is struck through and in bold)  
Revised Wording from Protocol Amendment 1 
(Protocol Version 2, Dated 09 Jul 15)  
(Revised wording is underscored and in bold)  
Rationale for 
the 
amendment.  
Section 9.1.16.1, 
Monitoring of 
Adverse Events, 
pg 51 
Section 
9.1.16.1.1, List of 
‘Triggering 
Adverse Events 
of Interest’ pg 51 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N/A 
 
 
 
 
N/A 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.1.16.1 Monitoring of Adverse Events 
AE information will be collected according to 
Section 9.1.15. 
 
9.1.16.1.1 
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. 
• 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 
See section 3.2 
 
 
 
 
 
 
 
 
 
See section 3.2 
See section 3.2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Date 09 Jul 15 
 
 
 
Confidential 
 
Page 35 of 60 
Template: 031213 
Protocol Section 
Number, 
Heading and 
Page Number 
Original Wording from Protocol Version 1,  
Dated 26 Jan 15 
(Deleted wording is struck through and in bold)  
Revised Wording from Protocol Amendment 1 
(Protocol Version 2, Dated 09 Jul 15)  
(Revised wording is underscored and in bold)  
Rationale for 
the 
amendment.  
 
 
Section 
9.1.16.1.2, 
Supplemental 
Adverse Event 
Form, pg 51 
 
 
 
 
 
 
 
 
 
 
 
Section 9.1.16.2, 
Monitoring 
Drug 
Accountability 
Discrepancies, 
pg 52 
 
 
 
 
 
 
 
 
 
 
N/A 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N/A 
 
 
 
 
 
 
 
 
 
 
 
 
the purposes of this study. 
 
9.1.16.1.2 
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. 
 
9.1.16.2 
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 reported within the paper 
diary. 
• At any time that the site is informed by the 
patient/caregiver about any overuse of IMP, 
suspected misuse, abuse, or diversion. 
 
See section 3.2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
See section 3.2 
 
 
 
 
 
 
 
 
 
 
 
 
 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Date 09 Jul 15 
 
 
 
Confidential 
 
Page 36 of 60 
Template: 031213 
Protocol Section 
Number, 
Heading and 
Page Number 
Original Wording from Protocol Version 1,  
Dated 26 Jan 15 
(Deleted wording is struck through and in bold)  
Revised Wording from Protocol Amendment 1 
(Protocol Version 2, Dated 09 Jul 15)  
(Revised wording is underscored and in bold)  
Rationale for 
the 
amendment.  
Section 
9.1.16.2.1, List of 
‘Triggering 
Drug 
Accountability 
Discrepancies’, 
pg 52 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 9.16.2.2, 
Supplemental 
Drug 
Accountability 
Form, pg 53 
 
 
 
 
 
 
 
 
N/A 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N/A 
 
 
 
 
 
 
 
 
 
9.1.16.2.1 
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, according to the paper diary. 
• Returned IMP supply with evidence of 
tampering.  
• Greater than the target daily dose as recorded 
in the paper diary. 
 
9.1.16.2.2 
Supplemental Drug Accountability 
Form 
This form consists of eight 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 
See section 3.2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
See section 3.2 
 
 
 
 
 
 
 
 
 
 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Date 09 Jul 15 
 
 
 
Confidential 
 
Page 37 of 60 
Template: 031213 
Protocol Section 
Number, 
Heading and 
Page Number 
Original Wording from Protocol Version 1,  
Dated 26 Jan 15 
(Deleted wording is struck through and in bold)  
Revised Wording from Protocol Amendment 1 
(Protocol Version 2, Dated 09 Jul 15)  
(Revised wording is underscored and in bold)  
Rationale for 
the 
amendment.  
Section 9.16.2.2, 
Supplemental 
Drug 
Accountability 
Form, pg 53 
 
 
 
 
 
 
Section 9.1.16.3, 
Site 
Classification 
Form, pg 53 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 9.16.4, 
Study 
N/A 
 
 
 
 
 
 
 
 
 
 
N/A 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N/A 
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 or placebo, not 
other concomitant medications). 
 
9.1.16.3 
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. 
 
9.1.16.4 
Study Medication Use and 
 
 
 
 
 
 
 
 
 
 
 
 
See section 3.2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Date 09 Jul 15 
 
 
 
Confidential 
 
Page 38 of 60 
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Protocol Section 
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Page Number 
Original Wording from Protocol Version 1,  
Dated 26 Jan 15 
(Deleted wording is struck through and in bold)  
Revised Wording from Protocol Amendment 1 
(Protocol Version 2, Dated 09 Jul 15)  
(Revised wording is underscored and in bold)  
Rationale for 
the 
amendment.  
Medication Use 
and Behavior 
Survey, pg 53 
 
 
 
 
 
 
 
 
 
 
 
 
Section 9.16.5, 
Adjudication 
Committee – 
Assessment of 
Abuse Potential 
of GWP42003-P, 
pg 54 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N/A 
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 (Visit 5 or Visit 12) or withdrawal visit. 
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 in the study and 
not only those that have reported a triggering AE 
or drug accountability discrepancy. 
 
9.1.16.5 
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. Only 
data from patients who have completed the study 
will be assessed.  
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 
See section 3.2 
 
 
 
 
 
 
 
 
 
 
 
 
 
See section 3.2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Date 09 Jul 15 
 
 
 
Confidential 
 
Page 39 of 60 
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Protocol Section 
Number, 
Heading and 
Page Number 
Original Wording from Protocol Version 1,  
Dated 26 Jan 15 
(Deleted wording is struck through and in bold)  
Revised Wording from Protocol Amendment 1 
(Protocol Version 2, Dated 09 Jul 15)  
(Revised wording is underscored and in bold)  
Rationale for 
the 
amendment.  
Section 9.16.5, 
Adjudication 
Committee – 
Assessment of 
Abuse Potential 
of GWP42003-P, 
pg 54 
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. 
<< Note: For details of Figure 9-1 see Appendix 1.3 
>> 
See section 3.2 
 
 
 
 
 
 
 
 
 
See section 3.2 
Section 9.2.1 
Double Blind 
Phase, pg 56 
9.2.1 
Single Blind Phase 
9.2.1 
Double Blind Phase 
See section 3.1 
Section 9.2.1.1 
Visit 1 (Day -14 
to -7, Screening), 
pg 56 
9.2.1.1 Visit 1 (Day −7, Screening) 
The following observations (…) ECG and vital signs. 
 
Clinical laboratory samples (blood and urine) will be 
taken for hematology, biochemistry, urinalysis (…) 
(…) 
 
Patients who satisfy all inclusion (…) and then begin 
the seven day baseline period. 
(…) 
9.2.1.1 Visit 1 (Day −14 to −7, Screening) 
The following observations (…) ECG, vital signs and 
AEs. 
Clinical laboratory samples (blood and urine) will be 
taken for hematology, biochemistry, alcohol testing, 
THC testing, urinalysis (…) 
(…) 
Patients who satisfy all inclusion (…) and then begin 
the baseline period. 
(…) 
See section 3.1 
 
 
See section 3.2 
and 3.7 
 
 
See section 3.1 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Date 09 Jul 15 
 
 
 
Confidential 
 
Page 40 of 60 
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Protocol Section 
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Page Number 
Original Wording from Protocol Version 1,  
Dated 26 Jan 15 
(Deleted wording is struck through and in bold)  
Revised Wording from Protocol Amendment 1 
(Protocol Version 2, Dated 09 Jul 15)  
(Revised wording is underscored and in bold)  
Rationale for 
the 
amendment.  
Section 9.2.1.2.1 
Visit 2 (Day 1) – 
Enrollment (+3 
days), pg 56-57 
This visit will occur 7 days after Visit 1. 
The following observations will be made at Visit 2: 
(…) physical examination (including height and body 
weight), ECG, vital signs and review of seizure diary 
and AEs. 
Clinical laboratory samples (blood and urine) will be 
taken for hematology, biochemistry and urinalysis.  
Blood samples will be taken for analysis of plasma 
concentrations of CLB, N-CLB, CBD and CBD 
major metabolites. 
(…) 
This visit will occur 7–14 days after Visit 1. 
The following observations will be made at Visit 2: 
(…) physical examination (including body weight), 
ECG, vital signs and review of patient diary and AEs. 
Clinical laboratory samples (blood and urine) will be 
taken for hematology, biochemistry, alcohol testing 
and urinalysis. Blood samples will also be taken for 
genetic testing if additional consent has been 
obtained. 
(…) 
Blood samples will be taken for analysis of plasma 
concentrations of CLB, N-CLB, CBD, CBD major 
metabolites, THC and THC major metabolites. 
(…) 
See section 3.1  
 
See section 3.2 
See section 3.7 
 
See section 3.2 
 
 
 
 
 
 
See section 3.4   
Section 9.2.1.2.2 
Visit 2 (Day 2) – 
Enrollment, 
pg 57 
(…) 
(…) physical examination (including height and body 
weight), vital signs, and AEs.  
IMP will be dispensed and both the morning dose of 
CLB and of IMP will be taken in clinic. (…)  Each 
patient will then receive their IMP for the 10 day 
titration period followed by the 14 day maintenance 
period. (…) 
(…) 
(…) physical examination (including body weight), 
vital signs and AEs.  
GWP42003-P/placebo will be dispensed and both the 
morning dose of CLB and of GWP42003-P/placebo 
will be taken in clinic. (…)  Each patient will then 
receive their GWP42003-P/placebo for the 10 day 
titration period followed by the 21 day maintenance 
period. (…) 
 
See section 3.7 
 
See section 
3.3.1 
 
 
See section 3.1 
Section 9.2.1.3 
Visit 3 (Day 12 
+3 days), pg 57 
 
 
 
 
 
9.2.1.3 Visit 3 
9.2.1.3.1 
Visit 3 (Day 26) (±3 days) 
This visit will occur 25 days after Visit 2, Day 1 
(enrollment). Patients will return all used and unused 
IMP. The following observations will be made at Visit 
3 (Day 26): concomitant medications (including 
AEDs), physical examination (including height and 
body weight), ECG, vital signs, review of seizure 
9.2.1.3 Visit 3 (Day 12 +3 days) 
This visit will occur 11 days after Visit 2, Day 1 
(enrollment). Patients will return all used and unused 
IMP. The following observations will be made at Visit 
3 (Day 12): concomitant medications (including 
AEDs), physical examination (including body 
weight), ECG, vital signs, AEs and review of patient 
diary completion. 
See section 3.1 
and section 3.2 
 
 
 
 
 
 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Date 09 Jul 15 
 
 
 
Confidential 
 
Page 41 of 60 
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Protocol Section 
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Page Number 
Original Wording from Protocol Version 1,  
Dated 26 Jan 15 
(Deleted wording is struck through and in bold)  
Revised Wording from Protocol Amendment 1 
(Protocol Version 2, Dated 09 Jul 15)  
(Revised wording is underscored and in bold)  
Rationale for 
the 
amendment.  
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 9.2.1.3 
Visit 3 (Day 12 
+3 days), pg 57 
diary and AEs. 
Clinical laboratory samples (blood and urine) will be 
taken for hematology, biochemistry and urinalysis. 
The C-SSRS will be administered. 
Blood samples will be taken for analysis of plasma 
concentrations of CLB, N-CLB, CBD and CBD 
major metabolites. A baseline PK sample will be 
taken before the patient takes their morning dose 
of CLB, followed immediately by their dose of 
IMP. Further samples will then be taken at the 
following times relative to the CLB dose: 15 
minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 
hours, 6 hours and 12 hours. Patients are expected 
to remain in clinic throughout this PK sampling 
process. 
The investigator must assess adherence to the 
dosing regimen and recording of rescue 
medications by reviewing the patient’s diary. 
9.2.1.3.2 
Visit 3 (Day 27) 
This is the second part of the two day visit. The 
final PK sample will be collected 24 hours after the 
Day 26 morning CLB dose. 
Following completion of the PK sampling process 
the following observations will be made on Day 27: 
concomitant medications (including AEDs), 
physical examination (including height and body 
weight), vital signs, and AEs. 
IMP will be dispensed and both the morning dose 
of CLB and of IMP will be taken in clinic. Patients 
and/or their caregivers will be provided with 
individual dosing schedules as described in Section 
Clinical laboratory samples (blood and urine) will be 
taken for hematology, biochemistry and urinalysis. 
The C-SSRS will be administered. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
See section 3.1 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Date 09 Jul 15 
 
 
 
Confidential 
 
Page 42 of 60 
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Protocol Section 
Number, 
Heading and 
Page Number 
Original Wording from Protocol Version 1,  
Dated 26 Jan 15 
(Deleted wording is struck through and in bold)  
Revised Wording from Protocol Amendment 1 
(Protocol Version 2, Dated 09 Jul 15)  
(Revised wording is underscored and in bold)  
Rationale for 
the 
amendment.  
8.1.2. Each patient will then receive their IMP for 
the 10 day titration period followed by the 14 day 
maintenance period. Patients or their caregivers 
will be instructed how to record the diary 
information. 
Section 9.2.1.4.1 
Visit 4 (Day 33 
±3 days), pg 57 
 
 
 
 
 
 
Section 9.2.1.4.1 
Visit 4 (Day 33 
±3 days), pg 57 
9.2.1.4.1 
Visit 4 (Day 51) (±3 days) 
This visit will occur 50 days after Visit 2, Day 1 
(enrollment). Patients will return all used and unused 
IMP. The following observations will be made at 
Visit 4 (Day 51): (…) physical examination (including 
height and body weight), ECG, vital signs, review of 
seizure diary and AEs. Clinical laboratory samples 
(blood and urine) will be taken for hematology, 
biochemistry and urinalysis. 
(…)The investigator must record the patient’s 
attendance at the visit and the outcome. 
Blood samples will be taken for analysis of plasma 
concentrations of CLB, N-CLB, CBD and CBD 
major metabolites. A baseline PK sample will be 
taken before the patient takes their morning dose of 
CLB, followed immediately by their dose of IMP.  
(…) 
9.2.1.4.1 
Visit 4 (Day 33) (±3 days) 
This visit will occur 32 days after Visit 2, Day 1 
(enrollment). Patients will return all used and unused 
GWP42003-P/placebo. The following observations 
will be made at Visit 4 (Day 33): (…) physical 
examination (including body weight), ECG, vital 
signs, review of patient diary and AEs. Clinical 
laboratory samples (blood and urine) will be taken for 
hematology, biochemistry, alcohol testing, and 
urinalysis. 
(…) 
Blood samples will be taken for analysis of plasma 
concentrations of CLB, N-CLB, CBD, CBD major 
metabolites, THC and THC major metabolites. A 
baseline PK sample will be taken before the patient 
takes their morning dose of CLB, followed 
immediately by their dose of GWP42003-P/placebo.  
(…) 
See section 3.1 
 
 
 
 
See section 3.7 
and section 3.2 
 
See section 3.2 
 
 
 
See section 3.4 
 
See section 
3.3.1 
Section 9.2.1.4.2 
Visit 4 (Day 34), 
pg 58 
 
 
 
 
 
9.2.1.4.2 
Visit 4 (Day 52) 
(…) The final PK sample will be collected 24 hours 
after the Day 51 morning CLB dose. 
Following completion of the PK sampling process the 
following observations will be made on Day 52: (…) 
physical examination (including height and body 
weight), vital signs, and AEs. 
At the end of the blinded phase of the study on Day 
9.2.1.4.2 
Visit 4 (Day 34) 
(…) The final PK sample will be collected 24 hours 
after the Day 33 morning CLB dose. 
Following completion of the PK sampling process the 
following observations will be made on Day 34: (…) 
physical examination (including body weight), vital 
signs and AEs. 
At the end of the blinded phase of the study on Day 
See section 3.1 
 
 
 
 
See section 3.2 
 
 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Date 09 Jul 15 
 
 
 
Confidential 
 
Page 43 of 60 
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Protocol Section 
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Page Number 
Original Wording from Protocol Version 1,  
Dated 26 Jan 15 
(Deleted wording is struck through and in bold)  
Revised Wording from Protocol Amendment 1 
(Protocol Version 2, Dated 09 Jul 15)  
(Revised wording is underscored and in bold)  
Rationale for 
the 
amendment.  
Section 9.2.1.4.2 
Visit 4 (Day 34), 
pg 58 
52, providing the investigator and patient both agree, 
patients will be invited to continue taking IMP and to 
enter the OLE. 
Patients who enter the OLE will be dispensed CBD on 
Day 52. (…) 
(…) 
 
 
Patients who do not enter the OLE will begin a 10 day 
taper period during which they will taper off their 
daily dose of IMP. The daily dose will be reduced by 
10% of the maintenance dose per day and treatment 
will end on Day 60. 
34, providing the investigator and patient both agree, 
patients will be invited to continue taking 
GWP42003-P and to enter the OLE. 
Patients who enter the OLE will be dispensed 
GWP42003-P on Day 34. At the point of entry to 
the OLE, patients will be transitioned to the OLE 
treatment over a 10 day period in order to 
maintain blinding. (…) 
(…) 
Patients who do not enter the OLE will begin a 10 day 
taper period during which they will taper off their 
daily dose of GWP42003-P/placebo. The daily dose 
will be reduced by 10% of the maintenance dose per 
day and treatment will end on Day 42. 
To provide 
clarity over 
how patients 
will transition 
from the 
blinded to 
OLE. 
See section 
3.3.1 
See section 3.1 
Section 9.2.1.5 
Visit 5 (Patients 
not entering 
Open Label 
Extension) (Day 
43 +3 days), 
pg 58-59 
9.2.1.5 Visit 5 (Patients not entering OLE) (+3 days) 
This visit will occur 60 days after Visit 2, Day 1 
(enrollment) for those patients who do not enter the 
OLE. 
All IMP (used and unused) will be collected and a 
check of the returned IMP against usage must be 
made. A physical examination (including height and 
body weight) and vital signs (…)  
(…) 
9.2.1.5 Visit 5 (Patients not entering Open Label 
Extension) (Day 43 +3 days) 
This visit will occur 42 days after Visit 2, Day 1 
(enrollment) for those patients who do not enter the 
OLE. 
All GWP42003-P/placebo (used and unused) will be 
collected and a check of the returned GWP42003-
P/placebo against usage must be made. A physical 
examination (including body weight), ECG and vital 
signs (…) The trained investigator or study 
coordinator will complete the Study 
Medication Use and Behavior Survey as an 
interview with the patient/caregiver. 
(…) 
See section 3.1  
 
 
 
See section 
3.3.1 
 
See section 3.2 
To be 
consistent with 
visit 12 ECG 
 
See section 3.2 
Section 9.2.1.6 
Visit 6 - Safety 
Follow up Call 
9.2.1.6 Safety Follow up Call (Day 89) (±3 days) 
This visit is required for patients who do not enter the 
OLE study on Day 50, or who withdraw from the 
9.2.1.6 Visit 6 - Safety Follow up Call (Day 71) (±3 
days) 
This visit is required for patients who do not enter the 
See section 3.1 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Date 09 Jul 15 
 
 
 
Confidential 
 
Page 44 of 60 
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Protocol Section 
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Page Number 
Original Wording from Protocol Version 1,  
Dated 26 Jan 15 
(Deleted wording is struck through and in bold)  
Revised Wording from Protocol Amendment 1 
(Protocol Version 2, Dated 09 Jul 15)  
(Revised wording is underscored and in bold)  
Rationale for 
the 
amendment.  
(Day 71) (±3 
days), pg 59 
study early.  
(…) 
The following observations will be made on Day 89: 
(...) 
OLE study on Day 34, or who withdraw from the 
study early.  
(…) 
The following observations will be made on Day 71: 
(…) 
Section 9.2.2 
Open Label 
Extension, pg 59 
Patients who enter the OLE will be dispensed IMP at 
Visit 4 (Day 52) (…). The visit schedule is calculated 
relative to Visit 4 (Day 51). 
Patients who enter the OLE will be dispensed IMP at 
Visit 4 (Day 34) (…).  The visit schedule is calculated 
relative to Visit 4 (Day 34). 
See section 3.1 
Section 9.2.2.1 
Visit 5 (Open 
Label Extension) 
- Two Weeks (±3 
days), pg 59 
This visit will occur two weeks after Visit 4 (Day 51).  
(…)The following observations will be made at Visit 
5 (OLE): (...), physical examination (including height 
and body weight) (...) 
This visit will occur two weeks after Visit 4 (Day 34).  
(…)The following observations will be made at Visit 
5 (OLE): (...), physical examination (including body 
weight) (...) 
See section 3.1 
and section 3.2 
Section 9.2.2.2 
Visit 6 (Open 
Label Extension) 
– One Month (±3 
days), pg 59 
This visit will occur one month after Visit 4 (Day 51).  
(…) The following observations will be made at Visit 
6 (OLE): (...), physical examination (including height 
and body weight) (...) 
This visit will occur one month after Visit 4 (Day 34).  
(…)The following observations will be made at Visit 
6 (OLE): (...), physical examination (including body 
weight) (...) 
See section 3.1 
and section 3.2 
Section 9.2.2.3 
Visit 7 (Open 
Label Extension) 
– Two Months 
(±3 days), pg 60 
This visit will occur two months after Visit 4 (Day 
51).(…) The following observations will be made at 
Visit 7 (OLE): (...), physical examination (including 
height and body weight) (...) 
This visit will occur two months after Visit 4 (Day 
34).(…) The following observations will be made at 
Visit 7 (OLE): (...), physical examination (including 
body weight) (...) 
See section 3.1 
and section 3.2 
Section 9.2.2.4 
Visit 8 (Open 
Label Extension) 
– Three Months 
(±3 days), pg 60 
This visit will occur three months after Visit 4 (Day 
51).(…) The following observations will be made at 
Visit 8 (OLE): (...), physical examination (including 
height and body weight) (...) 
This visit will occur three months after Visit 4 (Day 
34). (…) The following observations will be made at 
Visit 8 (OLE): (...), physical examination (including 
body weight) (...) 
See section 3.1 
and section 3.2 
Section 9.2.2.5 
Visit 9 (Open 
Label Extension) 
This visit will occur six months after Visit 4 (Day 51). 
(…)The following observations will be made at Visit 
9 (OLE): (...), physical examination (including height 
This visit will occur six months after Visit 4 (Day 34). 
(…)The following observations will be made at Visit 
9 (OLE): (...), physical examination (including body 
See section 3.1 
and section 3.2 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Date 09 Jul 15 
 
 
 
Confidential 
 
Page 45 of 60 
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Protocol Section 
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Page Number 
Original Wording from Protocol Version 1,  
Dated 26 Jan 15 
(Deleted wording is struck through and in bold)  
Revised Wording from Protocol Amendment 1 
(Protocol Version 2, Dated 09 Jul 15)  
(Revised wording is underscored and in bold)  
Rationale for 
the 
amendment.  
– Six Months (±3 
days), pg 60 
and body weight) (...) 
weight) (...) 
Section 9.2.2.6 
Visit 10 (Open 
Label Extension) 
– Nine Months 
(±3 days), pg 61 
This visit will occur nine months after Visit 4 (Day 
51).(…) The following observations will be made at 
Visit 10 (OLE): (...), physical examination (including 
height and body weight) (...) 
This visit will occur nine months after Visit 4 (Day 
34).(…) The following observations will be made at 
Visit 10 (OLE): (...), physical examination (including 
body weight) (...) 
See section 3.1 
and section 3.2 
Section 9.2.2.7 
Visit 11 (Open 
Label Extension) 
– Twelve Months 
(±3 days), pg 61 
This visit will occur twelve months after Visit 4 (Day 
51).(…) The following observations will be made at 
Visit 11 (OLE): (...), physical examination (including 
height and body weight) (...) 
This visit will occur twelve months after Visit 4 (Day 
34).(…) The following observations will be made at 
Visit 11 (OLE): (...), physical examination (including 
body weight) (...) 
See section 3.1 
and section 3.2 
Section 9.2.2.8 
Visit 12 (Open 
Label Extension 
End of Taper), 
pg 61 
(…) 
A physical examination (including height and body 
weight) (...) 
 
 
(…) 
(…)  
A physical examination (including body weight) (...) 
The trained investigator or study coordinator will 
complete the Study Medication Use and Behavior 
Survey as an interview with the patient/caregiver. 
(…) 
 
See section 3.2 
 
See section 3.2 
Section 10 
WITHDRAWAL, 
pg 62 
(…) 
 
(…) 
(…) 
• Any other IMP is taken as part of a clinical trial 
during the study. 
(…) 
See section 3.5 
Section 12.8, 
Potential Cases 
of Drug Induced 
Liver Injury, 
pg 68-69 
12.8 
Reporting Clinically Significant 
Laboratory Results 
(…) DILI (...) for repeat assessment, detailed history 
(…) 
 
 
12.8 
Potential Cases of Drug Induced Liver 
Injury 
(…) drug-induced liver injury (...) for repeat 
assessment of ALT, AST, TBL and alkaline 
phosphatase levels, detailed history (…) 
 
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 
See section 3.6 
 
 
 
 
 
See section 3.6 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Date 09 Jul 15 
 
 
 
Confidential 
 
Page 46 of 60 
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Protocol Section 
Number, 
Heading and 
Page Number 
Original Wording from Protocol Version 1,  
Dated 26 Jan 15 
(Deleted wording is struck through and in bold)  
Revised Wording from Protocol Amendment 1 
(Protocol Version 2, Dated 09 Jul 15)  
(Revised wording is underscored and in bold)  
Rationale for 
the 
amendment.  
detailed above, within 72 hours’ notice of 
abnormal results. If the participant cannot return 
to the investigational center, repeat assessments 
may be done at a local laboratory and the results 
sent to GW PVD. 
Section 13.2 
Interim 
Analysis, pg 71 
An interim analysis will be conducted at the end of the 
Single Blind phase (…) 
An interim analysis will be conducted at the end of the 
Double Blind phase (…) 
See section 3.1 
Section 13.6.1 
Primary 
Endpoint(s), 
pg 72 
(…) 
The primary endpoints of the study are the 
pharmacokinetic parameters (...) 
• N-desmethylclobazam (N-CLB) 
(…) 
(…) 
The primary endpoints of the study are the PK 
parameters (...) 
• N-CLB 
(…) 
 
See section 3.7 
Section 13.6.2 
Secondary 
Endpoint(s), 
pg 72 
The secondary endpoints of the study are the safety 
parameters (see Section 13.6.5). 
The secondary endpoints of the study are the safety 
parameters (see Section 13.6.4) and the PK 
parameters (Cmax, tmax, AUC(0–∞), AUC(0–t), t½) of 
the following analytes: 
• THC 
• THC major metabolites 
 
See section 3.7 
 
See section 3.4 
Section 13.6.3 
Pharmacokinetics 
pg 73-74 
(…)Plasma concentrations of CLB, N-CLB, CBD and 
the major metabolites will be (…) 
(…) 
• In order to assess (…) mixed effect model with 
treatment (CBD or placebo) as fix effect (…) 
(…)Plasma concentrations of CLB, N-CLB, CBD, 
CBD major metabolites, THC and THC major 
metabolites will be (…) 
(…) 
• In order to assess (…) mixed effect model with 
treatment (CLB or CLB+CBD) as a fixed effect 
(…) 
 
 
See section 3.4 
and 3.1 
 
See Section 3.7 
Section 13.6.4.3 
Clinical 
Laboratory Data 
pg 74 
Clinical laboratory data at screening and at the end of 
each 24 day treatment phase (…) 
Clinical laboratory data at screening and at the end of 
the 31 day treatment phase (…) 
See section 3.1 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Date 09 Jul 15 
 
 
 
Confidential 
 
Page 47 of 60 
Template: 031213 
Protocol Section 
Number, 
Heading and 
Page Number 
Original Wording from Protocol Version 1,  
Dated 26 Jan 15 
(Deleted wording is struck through and in bold)  
Revised Wording from Protocol Amendment 1 
(Protocol Version 2, Dated 09 Jul 15)  
(Revised wording is underscored and in bold)  
Rationale for 
the 
amendment.  
Section 13.6.4.4 
Columbia-Suicide 
Severity Rating 
Scale, Vital Signs, 
12-lead 
Electrocardiogra
m, Physical 
Examination and 
Other Safety Data 
pg 75 
(…) at the end of each 24 day treatment phase (…) 
(…) at the end of the 31 day treatment phase (…) 
See section 3.1 
Section 13.6.4.5 
Seizure Data 
pg 75 
(…) collected during each 24 day treatment phase 
(…) 
(…) collected during the 31 day treatment phase (…) 
See section 3.1 
APPENDIX 1, 
Schedule of 
Assessments, 
pg 86 
<< Note: See Appendix 1.4 for detailed changes >> 
 
<< Note: See Appendix 1.4 for detailed changes >> 
 
See section 3.1 
and 3.2 
Appendix 3.2, 
Sponsor Contact 
Details, pg 90-91 
 
 
 
 
 
 
 
 
 
 
 
 
(...) 
(...) 
Sponsor: 
GW Research Ltd 
Sovereign House 
Vision Park 
Histon 
Cambridge 
CB24 9BZ 
United Kingdom 
 
Medical Monitor 
(...) 
Clinical Project 
GW Research Ltd 
 
(...) 
(...) 
Sponsor: 
GW Research Ltd 
Sovereign House 
Vision Park 
Chivers Way 
Histon 
Cambridge 
CB24 9BZ 
United Kingdom 
 
Medical Monitor 
(...) 
 
 
 
 
 
 
See section 3.7 
 
 
 
 
 
 
Back up USA 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Date 09 Jul 15 
 
 
 
Confidential 
 
Page 48 of 60 
Template: 031213 
Protocol Section 
Number, 
Heading and 
Page Number 
Original Wording from Protocol Version 1,  
Dated 26 Jan 15 
(Deleted wording is struck through and in bold)  
Revised Wording from Protocol Amendment 1 
(Protocol Version 2, Dated 09 Jul 15)  
(Revised wording is underscored and in bold)  
Rationale for 
the 
amendment.  
Appendix 3.2, 
Sponsor Contact 
Details, pg 90-91 
Manager/Clinical 
Operations 
Director: 
Sovereign House 
Vision Park 
Histon 
Cambridge CB24 9BZ 
United Kingdom 
(...) 
(...) 
 
 
USA 
 
 
Tel:
 
Mobile: 
 
Clinical Project 
Manager/Clinical 
Operations 
Director: 
GW Research Ltd 
Sovereign House 
Vision Park 
Chivers Way 
Histon 
Cambridge CB24 9BZ 
United Kingdom 
(...) 
(...) 
study 
medic 
added 
as 
a 
contact 
 
 
 
 
 
 
 
See section 3.7 
 
 
PPD
PPD
PPD
PPD
PPD


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Date 09 Jul 15 
 
 
 
Confidential 
 
Page 49 of 60 
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APPENDIX 1.1
Study Design and Treatment Schema (Protocol V1 / Figure 1-1) 
 
S 
C 
R 
E 
E 
N 
I 
N 
G 
E 
N 
R 
O 
L 
L 
M 
E 
N 
T 
Single Blind Phase: 
Placebo Phase 
Placebo 
(N=20, All patients) 
Single Blind Phase: 
Active Phase 
GWP42003-P Oral 
Solution 
(100mg/mL bd) 
(N=20, All patients) 
E 
N 
D 
 
O 
F 
 
B 
L 
I 
N 
D 
E 
D 
 
T 
R 
E 
A 
T 
M 
E 
N 
T 
Visit 1 
Day -7 
 
Visit 2 
Day 1/2 
(+3 d) 
Visit 3 
Day 26/27 
(±3 d) 
Visit 4 
Day 51/52 
(±3 d) 
E 
N 
D 
  
O 
F 
  
T 
A 
P 
E 
R 
 
10 Day Taper 
Patients not 
entering the 
OLE 
Patients entering the OLE 
S 
A 
F 
E 
T 
Y 
 
F 
O 
L 
L 
O 
W 
 
U 
P 
10 Day 
Up-Titration 
14 Day 
Maintenanc
10 Day 
Up-Titration 
14 Day 
Maintenanc
Visit 5 
Day 61 
Visit 6 
Day 89 
28 day FU 
(±3 d) 
7 days 
24 days 
24 days 
10 days 
28 days 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Date 09 Jul 15 
 
 
 
Confidential 
 
Page 50 of 60 
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Study Design and Treatment Schema (Protocol V2 / Figure 1-1)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
S 
C 
R 
E 
E 
N 
I 
N 
G 
E 
N 
R 
O 
L 
L 
M 
E 
N 
T 
E 
N 
D 
  
O 
F 
  
B 
L 
I 
N 
D 
E 
D 
  
T 
R 
E 
A 
T 
M 
E 
N 
T 
Visit 1 
Day -14 to -7 
  
Visit 2 
Day 1/2 
(+3 d) 
Visit 4 
Day 33/34 
(±3 d) 
E 
N 
D 
  
O 
F 
  
T 
A 
P 
E 
R 
10 Day Taper 
Patients not 
entering the 
OLE 
Patients entering the OLE 
S 
A 
F 
E 
T 
Y 
  
F 
O 
L 
L 
O 
W 
  
U 
P 
10 Day 
Up-Titration 
21 Day 
Maintenance 
Visit 5 
Day 43 
Visit 6 
Day 71 
28 day FU 
(±3 d) 
7-14 days 
31 days 
10 days 
28 days 
Placebo  
N=4 
GWP42003-P Oral 
Solution 
(100 mg/mL bd) 
N=16 
Visit 3 
Day 12 
(+3 d) 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Date 09 Jul 15 
 
 
 
Confidential 
 
Page 51 of 60 
Template: 031213 
 
Study Design and Treatment Schema (Protocol V1 / Figure 1-2) 
 
 
 
Patients  
entering 
from 
 the 
‘Single  
Blind 
Phase’ 
Visit 5 OLE 
2 weeks 
(±3 d) 
Visit 7 OLE 
2 months 
(±3 d) 
Visit 6 OLE 
1 month 
(±3 d) 
Visit 8 OLE 
3 months 
(±7 d) 
Visit 9 OLE 
6 months 
(±7 d) 
Visit 11 OLE 
12 months 
(±7 d) 
Visit 10 OLE 
9 months 
(±7 d) 
Visit 12 OLE 
 
E 
N 
D 
  
O 
F 
  
T 
A 
P 
E 
R 
Visit 13 OLE 
28 day FU 
(±3 d) 
S 
A 
F 
E 
T 
Y 
 
F 
O 
L 
L 
O 
W 
 
U 
P 
Open-Label Extension Phase: 
GWP42003-P Oral Solution 
(100mg/mL bd) 
10 
Day 
Taper 
2 weeks 
from V4 
2 weeks 
1 month 
1 month 
3 months 
3 months 
3 months 
10 days 
18 days 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Date 09 Jul 15 
 
 
 
Confidential 
 
Page 52 of 60 
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Study Design and Treatment Schema (Protocol V2 / Figure 1-2) 
Patients  
entering 
from 
 the  
blinded 
phase 
Visit 5 OLE 
2 weeks 
(±3 d) 
Visit 7 OLE 
2 months 
(±3 d) 
Visit 6 OLE 
1 month 
(±3 d) 
Visit 8 OLE 
3 months 
(±7 d) 
Visit 9 OLE 
6 months 
(±7 d) 
Visit 11 OLE 
12 months 
(±7 d) 
Visit 10 OLE 
9 months 
(±7 d) 
Visit 12 OLE 
 
E 
N 
D 
  
O 
F 
  
T 
A 
P 
E 
R 
Visit 13 OLE 
28 day FU 
(±3 d) 
S 
A 
F 
E 
T 
Y 
 
F 
O 
L 
L 
O 
W 
 
U 
P 
Open Label Extension Phase: 
GWP42003-P Oral Solution 
(100 mg/mL bd) 
10 
Day 
Taper 
2 weeks 
from V4 
2 weeks 
1 month 
1 month 
3 months 
3 months 
3 months 
10 days 
28 days 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Date 09 Jul 15 
 
 
 
Confidential 
 
Page 53 of 60 
  
APPENDIX 1.2
Dose Titration Regimen (Protocol V1 / Table 8.1-1) 
Table 8.1-1 
Dose Titration Regimen* 
Day - Placebo 
Day - CBD 
Dose Level 
(CBD or equivalent 
placebo) 
2 
26 
2.5 mg/kg 
3 
27 
2.5 mg/kg 
4 
28 
5.0 mg/kg 
5 
29 
5.0 mg/kg 
6 
30 
7.5 mg/kg 
7 
31 
7.5 mg/kg 
8 
32 
10.0 mg/kg 
9 
33 
10.0 mg/kg 
10 
34 
15.0 mg/kg 
11 
35 
15.0 mg/kg 
12 onwards 
36 onwards 
20.0 mg/kg 
*IMP is to be taken twice daily. Total daily doses are shown. 
 
Dose Titration Regimen (Protocol V2 / Table 8.1.2-1) 
Table 8.1.2-1 Dose Up-Titration Regimen* 
Day - GWP42003-P/Placebo 
(Blinded Period) 
Day - GWP42003-P only 
(OLE**) 
Dose Level 
(GWP42003-P or equivalent 
placebo) 
2 
34 
2.5 mg/kg 
3 
35 
2.5 mg/kg 
4 
36 
5.0 mg/kg 
5 
37 
5.0 mg/kg 
6 
38 
7.5 mg/kg 
7 
39 
7.5 mg/kg 
8 
40 
10.0 mg/kg 
9 
41 
10.0 mg/kg 
10 
42 
15.0 mg/kg 
11 
43 
15.0 mg/kg 
12 onwards 
44 onwards 
20.0 mg/kg 
* GWP42003-P /placebo is to be taken twice daily. Total daily doses are shown. 
** Only patients who were taking placebo during the double-blind period will up-titrate according to 
this schedule during the OLE period. Those taking GWP42003-P during the double-blind period will 
down-titrate their blinded IMP whilst simultaneously up-titrating with GWP42003-P, thus maintaining a 
daily dose of 20 mg/kg/day GWP42003-P throughout. 
 
 
 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Date 09 Jul 15 
 
 
 
Confidential 
 
Page 54 of 60 
  
APPENDIX 1.3
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 
 
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.  
Stage 5 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Date 09 Jul 15 
 
 
 
Confidential 
 
Page 55 of 60 
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APPENDIX 1.4
Schedule of Assessments Blinded Phase (Protocol V1 / Appendix 1) 
Visit Number 
Day 
(Visit Window) 
Visit 1 
Day -7 
 
Visit 2 
Day 1 
(+ 3 days) 
Visit 2 
Day 2 
 
Visit 3 
Day 26 
(± 3 days) 
Visit 3 
Day 27 
 
Visit 4 
Day 51 
(± 3 days) 
Visit 4 
Day 52 
 
Visit 5* 
End of Taper 
 
Visit 6* 
4wk SFU 
(± 3 days) 
Informed consent 
X 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
X 
 
 
 
 
 
 
 
Enrollment 
 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Paper diary training 
X 
 
X 
 
 
 
 
 
 
Concomitant medications 
(including AEDs) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
(including height and body 
weight) 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECG 
X 
X 
 
X 
 
X 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
 
AEs 
 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical laboratory blood 
sampling  
X 
X 
 
X 
 
X 
 
X 
 
Clinical laboratory urine 
sampling (dipstick 
urinalysis) 
X 
X 
 
X 
 
X 
 
X 
 
Alcohol/THC test 
X 
 
 
 
 
 
 
 
 
Pregnancy test (if 
appropriate) 
X 
 
 
 
 
 
 
 
 
Pharmacokinetic blood 
sampling**  
 
X 
X 
X 
X 
X 
X 
 
 
C-SSRS 
X 
X 
 
X 
 
X 
 
X 
 
Patient diary review 
 
X 
 
X 
 
X 
 
X 
 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Date 09 Jul 15 
 
 
 
Confidential 
 
Page 56 of 60 
Template: 031213 
Visit Number 
Day 
(Visit Window) 
Visit 1 
Day -7 
 
Visit 2 
Day 1 
(+ 3 days) 
Visit 2 
Day 2 
 
Visit 3 
Day 26 
(± 3 days) 
Visit 3 
Day 27 
 
Visit 4 
Day 51 
(± 3 days) 
Visit 4 
Day 52 
 
Visit 5* 
End of Taper 
 
Visit 6* 
4wk SFU 
(± 3 days) 
(seizures, AE information, 
concomitant AEDs, rescue 
medication, IMP dosing) 
IMP dispensing 
 
 
X 
 
X 
 
X 
 
 
Collection of IMP 
 
 
 
X 
 
X 
 
X 
 
IMP compliance review 
 
 
 
X 
 
X 
 
X 
 
* Patients not entering the OLE 
**PK Sampling time points are as follows: Pre-dose and 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 12 hours and 24 hours after dosing. For 
the second and third PK visits the patient should take the IMP immediately after their daily dose of CLB. 
 
 
 
 
 
 
 
 
 
 
 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Date 09 Jul 15 
 
 
 
Confidential 
 
Page 57 of 60 
Template: 031213 
Schedule of Assessments Blinded Phase (Protocol V2 / Appendix 1) 
Visit Number 
Day 
(Visit Window) 
Visit 1 
Day -14 to -7 
 
Visit 2 
Day 1 
(+ 3 days) 
Visit 2 
Day 2 
 
Visit 3 
Day 12 
(+ 3 days) 
Visit 4 
Day 33 
(± 3 days) 
Visit 4 
Day 34 
 
Visit 5* 
End of Taper 
 
Visit 6* 
4wk SFU 
(± 3 days) 
Informed consent 
X 
 
 
 
 
 
 
 
Eligibility criteria 
X 
X 
 
 
 
 
 
 
Enrollment 
 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
Paper diary training 
X 
 
X 
 
 
 
 
 
Concomitant medications 
(including AEDs) 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
(including height and body 
weight)♥  
X 
X 
X 
X 
X 
X 
X 
 
ECG 
X 
X 
 
X 
X 
 
X 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical laboratory blood 
sampling  
X 
X 
 
X 
X 
 
X 
 
Clinical laboratory urine 
sampling (dipstick 
urinalysis) 
X 
X 
 
X 
X 
 
X 
 
THC test 
X 
 
 
 
 
 
 
 
Alcohol Test 
X 
X 
 
 
X 
 
 
 
Pregnancy test (if 
appropriate) 
X 
 
 
 
 
 
 
 
Pharmacokinetic blood 
sampling**  
 
X 
X 
 
X 
X 
 
 
Sample for Genetic 
Testing*** 
 
X 
 
 
 
 
 
 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Date 09 Jul 15 
 
 
 
Confidential 
 
Page 58 of 60 
Template: 031213 
Visit Number 
Day 
(Visit Window) 
Visit 1 
Day -14 to -7 
 
Visit 2 
Day 1 
(+ 3 days) 
Visit 2 
Day 2 
 
Visit 3 
Day 12 
(+ 3 days) 
Visit 4 
Day 33 
(± 3 days) 
Visit 4 
Day 34 
 
Visit 5* 
End of Taper 
 
Visit 6* 
4wk SFU 
(± 3 days) 
C-SSRS 
X 
X 
 
X 
X 
 
X 
 
Patient diary review 
(seizures, AE information, 
concomitant AEDs, rescue 
medication, IMP dosing) 
 
X 
 
X 
X 
 
X 
 
IMP dispensing 
 
 
X 
 
 
X 
 
 
Collection of IMP 
 
 
 
X 
X 
 
X 
 
IMP compliance review 
 
 
 
X 
X 
 
X 
 
Study Medication Use and 
Behavior Survey 
 
 
 
 
 
 
X 
 
* Patients not entering the OLE 
**PK Sampling time points are as follows: Pre-dose and 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 12 hours and 24 hours after dosing. For 
the second PK visit the patient should take the GWP42003-P/placebo immediately after their daily dose of CLB. 
*** Samples for genetic testing will only be taken if additional consent is obtained. 
♥ Patients height measured at Visit 1 only. 
 
 
 
 
 
 
 
 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Date 09 Jul 15 
 
 
 
Confidential 
 
Page 59 of 60 
Template: 031213 
Open Label Extension Schedule of Assessments (Protocol V1 / Appendix1) 
 
 
 
Visit Number 
Day 
(Visit Window) 
Visit 5 
2 Weeks 
(+ 3 days) 
Visit 6 
1 Month 
(± 3 days) 
Visit 7 
2 Months 
 (± 3 days) 
Visit 8 
3 Months 
(± 7 days) 
Visit 9 
6 Months 
 (± 7 days) 
Visit 10 
9 Months 
(± 7 days) 
Visit 11 
12 Months 
 (± 7 days) 
Visit 12 
End of Taper 
 
Visit 13 
4wk SFU 
(± 3 days) 
Paper diary training 
 
 
 
 
 
 
 
 
 
Concomitant medications 
(including AEDs) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
(including height and 
body weight) 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECG 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical laboratory blood 
sampling  
X 
X 
X 
X 
X 
X 
X 
X 
 
Clinical laboratory urine 
sampling (dipstick 
urinalysis) 
X 
X 
X 
X 
X 
X 
X 
X 
 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
X 
 
Patient diary review 
(seizures, AE information, 
concomitant AEDs, rescue 
medication, IMP dosing) 
X 
X 
X 
X 
X 
X 
X 
X 
 
IMP dispensing 
X 
X 
X 
X 
X 
X 
X 
 
 
Collection of IMP 
X 
X 
X 
X 
X 
X 
X 
X 
 
IMP compliance review 
X 
X 
X 
X 
X 
X 
X 
X 
 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Date 09 Jul 15 
 
 
 
Confidential 
 
Page 60 of 60 
Template: 031213 
Open Label Extension Schedule of Assessments (Protocol V2/ Appendix1) 
 
 
 
 
Visit Number 
Day 
(Visit Window) 
Visit 5 
2 Weeks 
(+ 3 days) 
Visit 6 
1 Month 
(± 3 days) 
Visit 7 
2 Months 
 (± 3 days) 
Visit 8 
3 Months 
(± 7 days) 
Visit 9 
6 Months 
 (± 7 days) 
Visit 10 
9 Months 
(± 7 days) 
Visit 11 
12 Months 
 (± 7 days) 
Visit 12 
End of Taper 
 
Visit 13 
4wk SFU 
(± 3 days) 
Paper diary training 
 
 
 
 
 
 
 
 
 
Concomitant medications 
(including AEDs) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
(including weight) 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECG 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical laboratory blood 
sampling  
X 
X 
X 
X 
X 
X 
X 
X 
 
Clinical laboratory urine 
sampling (dipstick 
urinalysis) 
X 
X 
X 
X 
X 
X 
X 
X 
 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
X 
 
Patient diary review 
(seizures, AE information, 
concomitant AEDs, rescue 
medication, IMP dosing) 
X 
X 
X 
X 
X 
X 
X 
X 
 
IMP dispensing 
X 
X 
X 
X 
X 
X 
X 
 
 
Collection of IMP 
X 
X 
X 
X 
X 
X 
X 
X 
 
IMP compliance review 
X 
X 
X 
X 
X 
X 
X 
X 
 
Study Medication Use 
and Behavior Survey 
 
 
 
 
 
 
 
X 
 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Version 2 Date 09 Jul 15 
 
 
 
 
 
 
Confidential  
Page 1 of 91  
Template: 271112 
 
TITLE: A PHASE2, DOUBLE-BLIND, RANDOMIZED, 
PLACEBO-CONTROLLED STUDY TO INVESTIGATE POSSIBLE 
DRUG-DRUG INTERACTIONS BETWEEN CLOBAZAM AND 
CANNABIDIOL (GWP42003-P) 
 
STUDY CODE: GWEP1428 
 
EudraCT NUMBER: 2014-002942-33 
 
 
 
GW RESEARCH LTD 
SOVEREIGN HOUSE,  
VISION PARK,  
CHIVERS WAY 
HISTON,  
CAMBRIDGE 
CB24 9BZ 
TEL: 
   FAX: 
 
 
 
 
Confidentiality Statement 
This document contains confidential information of GW Research Ltd 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 Research Ltd. 
PPD
PPD


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Version 2 Date 09 Jul 15 
Investigator Agreement 
G\1\1 
pharmaceuticals 
I have read the attached protocol entitled "A phase 2, double-blind, randomized, 
placebo-controlled study to investigate possible drug-drug interactions between 
clobazam and cannabidiol (GWP42003-P)", dated version 2 date 09 Jul15 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 Directive does not apply and to 
complete a Form 1572 if required. 
I am not aware that any conflicts of interest, financial or otherwise, exist for myself, 
my spouse [or legal partner] and dependent children and agree to confirm this in 
writing if required and update as necessary. 
I agree to ensure that the confidential information contained in this document will not 
be used for any purpose other than the evaluation or conduct of the clinical 
investigation without the prior written consent of GW Research Ltd. 
Center No: 
Print Name: 
Date: 
Principal Investigator 
(DD Month YYYY) 
Signature: 
GW Authorization 
Print Name: 
Date: 
Clinical Manag
Signature: 
(DD Month YYYY) 
Confidential 
Page 2 of91 
Template: 271112 
PPD
PPD


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Version 2 Date 09 Jul 15 
 
 
 
 
Confidential  
Page 3 of 91  
Template: 271112 
1. 
PROTOCOL SYNOPSIS 
Study Title 
A phase 2, double-blind, randomized, placebo-controlled study to 
investigate possible drug-drug interactions between clobazam and 
cannabidiol (GWP42003-P) 
Clinical Study 
Type 
Phase 2 
Indication 
Epilepsy 
Primary Objective 
To determine whether GWP42003-P affects the pharmacokinetic (PK) 
profile of clobazam (CLB) and its primary metabolite 
N-desmethylclobazam (N-CLB). 
Secondary 
Objective(s) 
To assess the safety and tolerability of GWP42003-P in the presence of 
CLB. 
Study Design 
This is a phase 2, double-blind, randomized, placebo-controlled study 
in 20 patients. 
• Patients will be randomized in a 4:1 ratio to receive 20 mg/kg 
GWP42003-P or placebo from days 2 to 33.  
• 
At the end of the treatment period, patients will be given the option 
of continuing onto an open label extension (OLE) period if the 
investigator and patient both agree that it is in their best interests. 
Doses may be adjusted up or down, dependent on investigator 
opinion, to a maximum of 30 mg/kg/day GWP42003-P. The OLE 
will last for a maximum of one year or until marketing 
authorization is granted; whichever is earlier. 
• 
Patients that do not continue onto the OLE will taper off of 
GWP42003-P over a 10 day period and will have a telephone 
follow-up visit four weeks after the end of taper day on Day 71. 
• Day 
1 
(Visit 
2), 
patients 
will 
not 
be 
dosed 
with 
GWP42003-P/placebo but will continue to take CLB at a stable 
dose. 
• Day 2 (Visit 2), patients will begin the up-titration with 
GWP42003-P or placebo to a maintenance dose or an equivalent 
maintenance dose of 20 mg/kg/day over a period of 10 days (Days 
2 to 11). 
• Day 12 (Visit 3), patients will attend the study site to check safety 
and compliance. 
• After up-titration with GWP42003-P or placebo, the patients will 
remain on the maintenance dose for 21 days (Days 12 to 32). 
• On Day 34 (Visit 4), patients will be invited to receive 
GWP42003-P in the OLE period. If the patient enters the OLE 
period of the study, the patient will continue to take GWP42003-P 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Version 2 Date 09 Jul 15 
 
 
 
 
Confidential  
Page 4 of 91  
Template: 271112 
as advised by the investigator. 
• If the patient does not enter the OLE period of the study, the patient 
will taper off of GWP42003-P by reducing the dose by 
approximately 10% of the maintenance dose each day until dosing 
has ceased, with end of taper on Day 43 (Visit 5). 
PK samples will be taken on the day of enrollment (Visit 2, Day 1) and 
after completing 21 days treatment on GWP42003-P or placebo (Visit 
4, Day 33). The PK assessments will therefore capture the following 
combinations of CLB and GWP42003-P: 
• First PK Assessment: CLB only. 
• Second PK Assessment: CLB and GWP42003-P or placebo. 
Each PK assessment should be performed at time points in respect to a 
morning dose of CLB. The time points are as follows: Pre-dose, 
15 min, 30 min, 1h, 1.5h, 2h, 4h, 6h, 12h and 24h. It is expected that 
the patient will continue to take their CLB as advised by their physician 
and PK assessments will be scheduled in order to accommodate this 
dosing schedule. The GWP42003-P/placebo should be taken twice 
daily immediately following their CLB dose. 
PK assessments will analyze the amount of CLB, the CLB primary 
metabolite N-CLB, CBD, CBD major metabolites, 
∆9-tetrahydrocannabinol (THC) and THC major metabolites. Patients 
will be required to keep a paper diary to note the time and dose of 
GWP42003-P and CLB administration each morning and evening and 
to record any adverse events (AEs) that may occur whilst receiving 
investigational medicinal product (IMP) and any other medications. 
Patients will also be requested to record the number and type of 
seizures for each day whilst on the study. 
Primary Endpoint 
The primary endpoints of the study are the PK parameters (Cmax, tmax, 
AUC(0–∞) AUC(0–t), t½) of the following analytes: 
• CLB 
• N-desmethylclobazam (N-CLB) 
• CBD 
• CBD major metabolites 
Secondary 
Endpoint(s) 
To assess the safety and tolerability of GWP42003-P compared with 
placebo when taken in combination with CLB. Safety and tolerability 
will be assessed using the following parameters: 
• AEs 
• 12-lead Electrocardiogram (ECG) 
• Clinical laboratory parameters (clinical chemistry, hematology and 
urinalysis) 
• Vital signs 
• Columbia-Suicide Severity Rating Scale (C-SSRS) 
• Seizure Frequency 
• Abuse liability 


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PK parameters (Cmax, tmax, AUC(0–∞), AUC(0–t), t½) of the following 
analytes: 
• THC  
• THC major metabolites 
Sample Size 
A total of 20 patients will be enrolled in this study. Recruitment for the 
study will be competitive between participating sites. There is no 
formal sample size: Calculation and analysis is descriptive only. 
Summary of 
Participant 
Eligibility Criteria 
For inclusion in the study patients must fulfil ALL of the following 
criteria: 
• Male or female patients aged 18 to 55 years inclusive. 
• Patient must have epilepsy as determined by the investigator and be 
taking CLB. 
• Patient must have a documented magnetic resonance 
imaging/computerized tomography of the brain that ruled out a 
progressive neurologic condition. 
• Patient must have experienced at least one seizure of any type (i.e., 
convulsive: tonic-clonic, tonic, clonic, atonic; focal: focal seizures 
with retained consciousness and a motor component, focal seizures 
with impaired consciousness focal seizures evolving to bilateral 
secondary generalization) within the two months prior to 
randomization. 
• Patients must be taking CLB and no more than two other 
anti-epileptic drugs (AEDs) during the course of the study. 
• AED(s), including CLB, must be stable for four weeks prior to 
screening and regimen must remain stable throughout the duration 
of the blinded phase of the study. 
• Intervention with vagus nerve stimulation and/or ketogenic diet 
must be stable for four weeks prior to baseline and patient/caregiver 
must be willing to maintain a stable regimen throughout the blinded 
phase of the study. 
• Patients must abstain from alcohol during the blinded phase of the 
study. 
• Patient and/or legal representative is available to attend all PK visits 
within the required visit window. 
• Patient and/or legal representative must be willing and able to give 
informed consent for participation in the study 
• Patient and/or legal representative must be willing and able (in the 
investigator’s opinion) to comply with all study requirements. 
• Patient is willing for his or her name to be notified to the 
responsible authorities for participation in this study, as applicable. 
• Patient is willing to allow his or her primary care practitioner and 


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consultant, if appropriate, to be notified of participation in the 
study. 
 
Exclusion: The patient may not enter the study if ANY of the following 
apply: 
• Patient has clinically significant unstable medical conditions other 
than epilepsy. 
• Patients on CLB at doses above 20 mg per day. 
• Patients taking CLB intermittently as rescue medication. 
• Patient has a history of symptoms (e.g., dizziness, light-headedness, 
blurred vision, palpitations, weakness, syncope) related to a drop in 
blood pressure (BP) due to postural changes. 
• Any history of suicidal behavior or any suicidal ideation of type 
four or five on the C-SSRS in the last month or at screening. 
• Patient has had clinically relevant symptoms or a clinically 
significant illness in the four weeks prior to screening or 
enrollment, other than epilepsy. 
• Patient has consumed alcohol during the seven days prior to 
enrollment and is unwilling to abstain during the blinded phase of 
the study. 
• Patient is currently using or has in the past used recreational or 
medicinal cannabis, or synthetic cannabinoid based medications 
(including Sativex®) within the three months prior to study entry. 
• Patient has any known or suspected history of any drug abuse or 
addiction. 
• Patient is unwilling to abstain from recreational or medicinal 
cannabis, or synthetic cannabinoid based medications (including 
Sativex) for the duration for the study. 
• Patient has consumed grapefruit or grapefruit juice seven days prior 
to enrollment and is unwilling to abstain from drinking grapefruit 
juice within seven days of PK visits. 
• Patient has any known or suspected hypersensitivity to 
cannabinoids or any of the excipients of the IMP, e.g., sesame oil 
• 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 three 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 


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or planning pregnancy during the course of the study and for three 
months thereafter. 
• Patients who have received an IMP within the 12 weeks prior to the 
screening visit. 
• 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 
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 participant 
from safe participation in the study. 
• Patient has significantly impaired hepatic function at screening 
(Visit 1) or enrollment (Visit 2), defined as any of the following: 
- 
Alanine aminotransferase (ALT) or Aspartate aminotransferase 
(AST) >5 × upper limit of normal (ULN). 
- 
ALT or AST >3 × ULN and total bilirubin (TBL) >2 × ULN or 
international normalized ratio (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%).  
This criterion can only be confirmed once the laboratory results are 
available; patients randomized into the study who are later found to 
meet this criterion must be withdrawn from the study. 
• Unwilling to abstain from donation of blood during the study. 
• Travel outside the country of residence planned during the study. 
• Patients previously enrolled into this study. 
Criteria for 
Withdrawal 
Patients must be withdrawn from the study if any of the following 
apply: 
• Administrative decision by the investigator or GW Research Ltd or 
Regulatory Authority. 
• Pregnancy. 
• Protocol deviation that is considered to potentially compromise the 
safety of the patient. 
• Withdrawal of patient consent. 
• Withdrawal of legal representative consent. 
• Lost to follow up. 
• ALT >3 × ULN 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%). 


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• ALT or AST >8 × ULN. 
• ALT or AST >5 × ULN for more than two weeks. 
• Any other IMP is taken as part of a clinical trial during the study.  
 
Patients may also be withdrawn from the study if any of the following 
apply: 
• Patient non-compliance. 
• AE, which in the investigator’s opinion, 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 four or five 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), pale yellow in color. 
Placebo oral solution containing the excipients sesame oil and 
anhydrous ethanol with added sweetener (sucralose) and strawberry 
flavoring. 
The IMP should be taken orally as per intended commercial therapeutic 
use. 
IMP will be taken twice daily (morning and evening) following the 
dose schedule below: 
• Day 2 (Visit 2), patients will begin the up-titration with 
GWP42003-P or placebo to a maintenance dose or an equivalent 
maintenance dose of 20 mg/kg/day over a period of 10 days (Days 
2 to 11). 
• After up-titration with GWP42003-P or placebo, the patients will 
remain on the maintenance dose for 21 days (Days 12 to 32). 
Please refer to Table 8.1.2-1 for details of the up-titration doses for 
GWP42003-P and placebo for the ten day taper period. 
On Day 34 (Visit 4), patients will be invited to receive GWP42003-P in 
the OLE period. If the patient enters the OLE period of the study, the 
patient will continue to take GWP42003-P as advised by the 
investigator. 
Clobazam will be an IMP for the blinded section of the study. The 
patients’ own supply of Clobazam will be used. 
Control Group 
The control group will receive an equal volume of matching placebo. 
Procedures 
VISIT 1 - Screening (Day -14 to -7) 
The following observations will be made at Visit 1: demographics, 
medical history (including seizure information since diagnosis, history 
of epilepsy-specific genetic testing and all prior AEDs taken), 
concomitant medications (including AEDs), physical examination 


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(including height and body weight), ECG, vital signs and AEs. 
Clinical laboratory samples (blood and urine) will be taken for 
hematology, biochemistry, alcohol testing, THC testing, urinalysis and 
a pregnancy test (using a serum sample, if appropriate). The laboratory 
results should be available within 3-5 working days after Visit 1. If the 
results show a patient is ineligible, the patient will not be enrolled into 
the study. The C-SSRS will be administered. 
Patients who satisfy all inclusion and none of the exclusion criteria 
specified in Section 6 will be assigned a unique patient number and 
then begin the baseline period. Patients or their caregivers will be given 
a paper diary to record daily seizure information, rescue medication, 
concomitant AEDs and AEs; and will be instructed on how to do so. 
The investigator must record the patient’s attendance at the visit and 
confirm the outcome of screening on the CRF.  
VISIT 2 - Enrollment (Day 1) +3 days window 
This visit will occur 7-14 days after Visit 1. 
The following observations will be made at Visit 2: concomitant 
medications, (including AEDs), physical examination (including body 
weight), ECG, vital signs, review of patient diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for 
hematology, biochemistry, alcohol testing and urinalysis. Blood 
samples will also be taken for genetic testing if additional consent has 
been obtained. The C-SSRS will be administered. The investigator 
must record the patient’s attendance at the visit, and confirm the 
outcome of the visit prior to enrollment. 
Following enrollment patients will begin the PK sampling process. 
Blood samples will be taken for analysis of plasma concentrations of 
CLB, N-CLB, CBD, CBD major metabolites, THC and THC major 
metabolites. A baseline PK sample will be taken before the patient 
takes their morning dose of CLB. Further samples will then be taken at 
the following times relative to the CLB dose: 15 minutes, 30 minutes, 
1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours and 12 hours. Patients will 
either remain in clinic overnight throughout this PK sampling process 
or return to the clinic on Day 2 ahead of additional sample collection. 
VISIT 2 - Enrollment (Day 2) 
This is the second part of the two day enrollment visit. The final PK 
sample will be collected 24 hours after the Day 1 morning CLB dose. 
Following completion of the PK sampling process the following 
observations will be made on Day 2: concomitant medications 
(including AEDs), physical examination (including body weight), vital 
signs and AEs. 
GWP42003-P/placebo will be dispensed and both the morning dose of 
CLB and GWP42003-P/placebo will be taken in clinic. Patients and/or 
their caregivers will be provided with individual dosing schedules as 


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described in Section 8.1. Each patient will then receive their 
GWP42003-P/placebo for the 10 day titration period followed by the 
21 day maintenance period. Patients, or their caregivers, will be 
instructed on how to record the diary information. 
VISIT 3 – Day 12 +3 day window 
This visit will occur 11 days after Visit 2, Day 1 (enrollment). Patients 
will return all used and unused GWP42003-P/placebo. The following 
observations will be made at Visit 3: concomitant medications 
(including AEDs), physical examination (including body weight), 
ECG, vital signs, AEs and review of patient diary completion. 
Clinical laboratory samples (blood and urine) will be taken for 
hematology, biochemistry and urinalysis. The C-SSRS will be 
administered. 
VISIT 4 - Day 33 ±3 days window 
This visit will occur 32 days after Visit 2, Day 1 (enrollment). Patients 
will return all used and unused GWP42003-P/placebo. The following 
observations will be made at Visit 4 (Day 33): concomitant medications 
(including AEDs), physical examination (including body weight), 
ECG, vital signs, review of patient diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for 
hematology, biochemistry, alcohol testing and urinalysis. The C-SSRS 
will be administered. 
Blood samples will be taken for analysis of plasma concentrations of 
CLB, N-CLB, CBD, CBD major metabolites, THC and THC major 
metabolites. A baseline PK sample will be taken before the patient 
takes their morning dose of CLB, followed immediately by their dose 
of GWP42003-P/placebo. Further samples will then be taken at the 
following times relative to the CLB dose: 15 minutes, 30 minutes, 
1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours and 12 hours. Patients are 
expected to remain in clinic throughout this PK sampling process. 
The investigator must assess adherence to the dosing regimen and 
recording of rescue medications by reviewing the patient’s diary. 
VISIT 4 - Day 34 
This is the second part of the two day visit. The final PK sample will be 
collected 24 hours after the Day 33 morning CLB dose. 
Following completion of the PK sampling process the following 
observations will be made on Day 34: concomitant medications 
(including AEDs), physical examination (including body weight), vital 
signs and AEs. 
On Day 34, providing the investigator and patient both agree, patients 
will be invited to continue taking GWP42003-P and to enter the OLE. 
Patients who enter the OLE will be dispensed GWP42003-P on Day 34. 
The dose may be adjusted up or down by the investigator from the 


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maintenance dose of 20 mg/kg/day in the blinded phase to a maximum 
of 30 mg/kg/day in the OLE. Patients and/or their caregivers will be 
provided with individual dosing schedules as described in Section 8.1.  
Patients who do not enter the OLE will begin a 10 day taper period 
during which they will taper off their daily dose of GWP42003-P. The 
daily dose will be reduced by 10% of the maintenance dose per day and 
treatment will end on Day 42. 
Patients Not Entering OLE 
VISIT 5 – Day 43 (End of Taper) +3 days window 
This visit will occur 42 days after Visit 2, Day 1 (enrollment) for those 
patients who do not enter the OLE. 
All GWP42003-P/placebo (used and unused) will be collected and a 
check of the returned GWP42003-P/placebo against usage must be 
made. A physical examination (including body weight), ECG and vital 
signs will be assessed and the C-SSRS will be administered. The 
trained investigator or study coordinator will complete the Study 
Medication Use and Behavior Survey as an interview with the 
patient/caregiver. 
Clinical laboratory samples (blood and urine) will be taken for 
hematology, biochemistry and urinalysis and a review of concomitant 
medications (including AEDs) and AEs will be completed. Patient 
diaries will be collected. 
VISIT 6 - SAFETY FOLLOW-UP CALL - Day 71 ±3 days 
This visit is required for patients who do not enter the OLE study on 
Day 34, or who withdraw from the study early. This visit should occur 
four weeks (±3 days) after Visit 5, or withdrawal from treatment, and 
can be conducted over the telephone. The following observations will 
be made on Day 71: concomitant medications (including AEDs) and 
AEs. 
Patients Entering OLE 
At the point of entry to the OLE, patients will be transitioned to the 
OLE treatment over a 10 day period in order to maintain blinding. 
Patients who enter the OLE will be dispensed IMP at Visit 4 (Day 34) 
and will have regular clinic visits for a maximum of one year or earlier 
(if marketing authorization is granted or the patient withdraws). The 
visit schedule is calculated relative to Visit 4 (Day 34). 
VISIT 5 (OLE) – Two Weeks ±3 days 
This visit will occur two weeks after Visit 4 (Day 34). Patients will 
return all used and unused IMP. The following observations will be 
made at Visit 5 (OLE): concomitant medications (including AEDs), 
physical examination (including body weight), ECG, vital signs, review 
of patient diary and AEs. 


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Clinical laboratory samples (blood and urine) will be taken for 
hematology, biochemistry and urinalysis. The C-SSRS will be 
administered. The investigator must record the patient’s attendance at 
the visit and the outcome. 
The investigator must assess adherence to the dosing regimen and 
recording of rescue medications by reviewing the patient’s diary. 
VISIT 6 (OLE) – One Month ±3 days 
This visit will occur one month after Visit 4 (Day 34). Patients will 
return all used and unused IMP. The following observations will be 
made at Visit 6 (OLE): concomitant medications (including AEDs), 
physical examination (including body weight), ECG, vital signs, review 
of patient diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for 
hematology, biochemistry and urinalysis. The C-SSRS will be 
administered. The investigator must record the patient’s attendance at 
the visit and the outcome. 
The investigator must assess adherence to the dosing regimen and 
recording of rescue medications by reviewing the patient’s diary. 
VISIT 7 (OLE) – Two Months ±3 days 
This visit will occur two months after Visit 4 (Day 34). Patients will 
return all used and unused IMP. The following observations will be 
made at Visit 7 (OLE): concomitant medications (including AEDs), 
physical examination (including body weight), ECG, vital signs, review 
of patient diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for 
hematology, biochemistry and urinalysis. The C-SSRS will be 
administered. The investigator must record the patient’s attendance at 
the visit and the outcome. 
The investigator must assess adherence to the dosing regimen and 
recording of rescue medications by reviewing the patient’s diary. 
VISIT 8 (OLE) - Three Months ±7 days 
This visit will occur three months after Visit 4 (Day 34). Patients will 
return all used and unused IMP. The following observations will be 
made at Visit 8 (OLE): concomitant medications (including AEDs), 
physical examination (including body weight), ECG, vital signs, review 
of patient diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for 
hematology, biochemistry and urinalysis. The C-SSRS will be 
administered. The investigator must record the patient’s attendance at 
the visit and the outcome. 
The investigator must assess adherence to the dosing regimen and 
recording of rescue medications by reviewing the patient’s diary. 


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VISIT 9 (OLE) - Six Months ±7 days 
This visit will occur six months after Visit 4 (Day 34). Patients will 
return all used and unused IMP. The following observations will be 
made at Visit 9 (OLE): concomitant medications (including AEDs), 
physical examination (including body weight), ECG, vital signs, review 
of patient diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for 
hematology, biochemistry and urinalysis. The C-SSRS will be 
administered. The investigator must record the patient’s attendance at 
the visit and the outcome. 
The investigator must assess adherence to the dosing regimen and 
recording of rescue medications by reviewing the patient’s diary. 
VISIT 10 (OLE) - Nine Months ±7 days 
This visit will occur nine months after Visit 4 (Day 34). Patients will 
return all used and unused IMP. The following observations will be 
made at Visit 10 (OLE): concomitant medications (including AEDs), 
physical examination (including body weight), ECG, vital signs, review 
of patient diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for 
hematology, biochemistry and urinalysis. The C-SSRS will be 
administered. The investigator must record the patient’s attendance at 
the visit and the outcome. 
The investigator must assess adherence to the dosing regimen and 
recording of rescue medications by reviewing the patient’s diary. 
VISIT 11 – Twelve Months (OLE End of Treatment) ±7 days 
This visit will occur twelve months after Visit 4 (Day 34). Patients will 
return all used and unused IMP. The following observations will be 
made at Visit 11 (OLE): concomitant medications (including AEDs), 
physical examination (including body weight), ECG, vital signs, review 
of patient diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for 
hematology, biochemistry and urinalysis. The C-SSRS will be 
administered. The investigator must record the patient’s attendance at 
the visit and the outcome. 
The investigator must assess adherence to the dosing regimen and 
recording of rescue medications by reviewing the patient’s diary. 
Starting at Visit 11, patients will begin to taper down their IMP dose. 
The dose will be reduced by 10% of their OLE maintenance dose per 
day. 
VISIT 12 - OLE End of taper +3 days 
This visit will be ten days after Visit 11. All IMP (used and unused) 
will be collected and a check of the returned IMP against usage must be 


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made. A physical examination (including body weight), ECG and vital 
signs will be assessed and the C-SSRS will be administered. The 
trained investigator or study coordinator will complete the Study 
Medication Use and Behavior Survey as an interview with the 
patient/caregiver. 
Clinical laboratory samples (blood and urine) will be taken for 
hematology, biochemistry and urinalysis and a review of concomitant 
medications (including AEDs) and AEs will be completed. Patient 
diaries will be collected and reviewed. 
VISIT 13 - SAFETY FOLLOW-UP CALL (OLE) 
This visit will occur one month after the OLE End of Taper and can be 
conducted over the telephone. The following observations will be made 
during the follow up call: concomitant medications (including AEDs) 
and AEs. 
Monitoring of Drug Abuse Liability  
During the routine collection of AEs in this study, if AEs are reported 
which can illuminate an abuse potential signal (specific AEs detailed 
in Section 9.1.16.1.1), 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 
discussions of the event(s) with the patient/caregiver. 
The second trigger that will require the investigator or study 
coordinator to discuss abuse potential signals with the patient/caregiver 
is drug accountability issues regarding overuse of the IMP or missing 
IMP bottles. 
Irrespective of the above, all patients/caregivers will be interviewed at 
their final dosing visit or withdrawal visit 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 
Plasma concentration data will be analyzed to estimate PK endpoints 
Cmax, tmax, AUC(0–t), AUC(0–∞) and t½ of the following analytes: CLB, 
N-CLB, CBD, CBD major metabolites, THC and THC major 
metabolites. 
In order to assess whether the presence of CBD alters the PK profile of 
CLB or N-CLB, a standard 90% confidence interval (CI) approach for 
the between group ratios of geometric means of Cmax AUC(0–t), and 
AUC(0–∞) will be done on logarithm scale using a linear mixed effect 
model with treatment (CLB or CLB+GWP42003-P) as a fixed effect 
and subject as a random effect. The no-effect boundary will be set 
between 0.5 and 2.0 and if the 90% CI for the ratio of the geometric 


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means of a PK variable falls within the interval [0.5, 2.0], a lack of 
meaningful effect will be declared. 
Descriptive summaries (means and standard deviations or counts [%] 
as appropriate) will be presented for all secondary endpoints (adverse 
events, laboratory data, vital signs, physical examination, C-SSRS and 
seizure frequency) for each phase of the study. 
Sponsor 
GW Research Ltd 
Sovereign House 
Vision Park 
Chivers Way 
Histon 
Cambridge CB24 9BZ 
United Kingdom 


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Figure 1-1 
Study Design and Treatment Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
S 
C 
R 
E 
E 
N 
I 
N 
G 
E 
N 
R 
O 
L 
L 
M 
E 
N 
T 
E 
N 
D 
  
O 
F 
  
B 
L 
I 
N 
D 
E 
D 
  
T 
R 
E 
A 
T 
M 
E 
N 
T 
Visit 1 
Day -14  
to -7 
Visit 2 
Day 1/2 
(+3 d) 
Visit 4 
Day 33/34 
(±3 d) 
E 
N 
D 
  
O 
F 
  
T 
A 
P 
E 
R 
10 Day Taper 
Patients not 
entering the 
OLE 
Patients entering the OLE 
S 
A 
F 
E 
T 
Y 
  
F 
O 
L 
L 
O 
W 
  
U 
P 
10 Day 
Up-Titration 
21 Day 
Maintenance 
Visit 5 
Day 43 
Visit 6 
Day 71 
28 day FU 
(±3 d) 
7-14 days 
31 days 
10 days 
28 days 
Placebo  
N=4 
GWP42003-P Oral 
Solution 
(100 mg/mL bd) 
N=16 
Visit 3 
Day 12 
(+3 d) 


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Figure 1-2 
Study Design and Treatment Schema  
 
Patients  
entering 
from 
 the  
blinded 
phase 
Visit 5 OLE 
2 weeks 
(±3 d) 
Visit 7 OLE 
2 months 
(±3 d) 
Visit 6 OLE 
1 month 
(±3 d) 
Visit 8 OLE 
3 months 
(±7 d) 
Visit 9 OLE 
6 months 
(±7 d) 
Visit 11 OLE 
12 months 
(±7 d) 
Visit 10 OLE 
9 months 
(±7 d) 
Visit 12 OLE 
 
E 
N 
D 
  
O 
F 
  
T 
A 
P 
E 
R 
Visit 13 OLE 
28 day FU 
(±3 d) 
S 
A 
F 
E 
T 
Y 
 
F 
O 
L 
L 
O 
W 
 
U 
P 
Open Label Extension Phase: 
GWP42003-P Oral Solution 
(100 mg/mL bd) 
10 
Day 
Taper 
2 weeks 
from V4 
2 weeks 
1 month 
1 month 
3 months 
3 months 
3 months 
10 days 
28 days 


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Table of Contents 
Title Page ................................................................................................... 1 
1. 
PROTOCOL SYNOPSIS ................................................................ 3 
Table of Contents .................................................................................... 18 
Table of Appendices ............................................................................... 23 
List of In-text Tables .............................................................................. 24 
List of In-text Figures ............................................................................. 25 
List of Abbreviations .............................................................................. 26 
Definition of Terms ................................................................................. 28 
2. 
OBJECTIVES ................................................................................ 29 
2.1 
Primary ........................................................................................................ 29 
2.2 
Secondary .................................................................................................... 29 
3. 
BACKGROUND AND RATIONALE ......................................... 29 
3.1 
Disease......................................................................................................... 29 
3.2 
GWP42003-P Background .......................................................................... 29 
3.3 
Rationale ...................................................................................................... 30 
3.3.1 
Selection of Study Doses .......................................................................... 31 
3.4 
Clinical Hypothesis ..................................................................................... 32 
4. 
EXPERIMENTAL PLAN ............................................................. 32 
4.1 
Study Design ............................................................................................... 32 
4.1.1 
Primary Endpoint ...................................................................................... 34 
4.1.2 
Secondary Endpoint(s) .............................................................................. 34 
4.2 
Number of Centers ...................................................................................... 34 
4.3 
Number of Patients ...................................................................................... 34 
5. 
INVESTIGATIONAL MEDICINAL PRODUCT ..................... 34 
5.1 
GWP42003-P Oral Solution ........................................................................ 35 
5.2 
Placebo Oral Solution .................................................................................. 35 
5.3 
Packaging, Storage and Drug Accountability (Cannabidiol/Placebo) ........ 35 
5.3.1 
Packaging and Labelling ........................................................................... 35 
5.3.2 
Storage ...................................................................................................... 36 
5.3.3 
Supply and Return of Investigational Medicinal Product ......................... 36 
5.3.4 
Investigational Medicinal Product Accountability ................................... 36 


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5.4 
Clobazam ..................................................................................................... 37 
6. 
PARTICIPANT ELIGIBILITY ................................................... 37 
6.1 
Inclusion Criteria ......................................................................................... 37 
6.2 
Exclusion Criteria ........................................................................................ 38 
7. 
PATIENT ENROLLMENT ......................................................... 40 
7.1 
Treatment Assignment ................................................................................ 40 
7.2 
Randomization............................................................................................. 40 
8. 
TREATMENT PROCEDURES ................................................... 41 
8.1 
Investigational Medicinal Product Dosage, Administration and 
Schedule ...................................................................................................... 41 
8.1.1 
Dose Administration ................................................................................. 41 
8.1.2 
Dose Escalation and Dose Adjustments ................................................... 42 
8.2 
Concomitant Therapy .................................................................................. 43 
8.3 
Prohibited Therapy During Study Period .................................................... 43 
8.4 
Compliance in Investigational Medicinal Product Administration ............. 43 
8.5 
Access to Blinded Treatment Assignment .................................................. 44 
9. 
STUDY PROCEDURES ............................................................... 45 
9.1 
Study Procedure Listing .............................................................................. 45 
9.1.1 
Contraception ............................................................................................ 45 
9.1.2 
Informed Consent ..................................................................................... 45 
9.1.3 
Demographics ........................................................................................... 45 
9.1.4 
Medical History ........................................................................................ 46 
9.1.5 
Concomitant Medication .......................................................................... 46 
9.1.6 
Physical Examination ............................................................................... 46 
9.1.7 
Vital Signs ................................................................................................ 46 
9.1.8 
12-Lead Electrocardiogram ...................................................................... 46 
9.1.9 
Clinical Laboratory Sampling................................................................... 46 
9.1.10 
Pharmacokinetic Analyses ........................................................................ 48 
9.1.11 
Genetic Testing ......................................................................................... 48 
9.1.12 
Columbia Suicide Severity Rating Scale .................................................. 49 
9.1.13 
Patient Diary ............................................................................................. 49 
9.1.14 
Investigational Medicinal Product Accountability ................................... 49 
9.1.15 
Adverse Events ......................................................................................... 50 


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9.1.16 
Monitoring of Drug Abuse Liability......................................................... 50 
9.1.16.1 
Monitoring of Adverse Events .............................................................. 51 
9.1.16.1.1 
List of ‘Triggering Adverse Events of Interest’ ................................ 51 
9.1.16.1.2 
Supplemental Adverse Event Form ................................................... 51 
9.1.16.2 
Monitoring Drug Accountability Discrepancies ................................... 52 
9.1.16.2.1 
List of ‘Triggering Drug Accountability Discrepancies’ .................. 52 
9.1.16.2.2 
Supplemental Drug Accountability Form ......................................... 53 
9.1.16.3 
Site Classification Form ........................................................................ 53 
9.1.16.4 
Study Medication Use and Behavior Survey ........................................ 53 
9.1.16.5 
Adjudication Committee — Assessment of Abuse Potential of 
GWP42003-P ........................................................................................ 54 
9.2 
Study Procedures by Visit ........................................................................... 56 
9.2.1 
Double Blind Phase .................................................................................. 56 
9.2.1.1 
Visit 1 (Day −14 to −7, Screening) ....................................................... 56 
9.2.1.2 
Visit 2 .................................................................................................... 56 
9.2.1.2.1 
Visit 2 (Day 1) – Enrollment (+3 days) ............................................. 56 
9.2.1.2.2 
Visit 2 (Day 2) - Enrollment .............................................................. 57 
9.2.1.3 
Visit 3 (Day 12 +3 days) ....................................................................... 57 
9.2.1.4 
Visit 4 .................................................................................................... 57 
9.2.1.4.1 
Visit 4 (Day 33) (±3 days) ................................................................. 57 
9.2.1.4.2 
Visit 4 (Day 34) ................................................................................. 58 
9.2.1.5 
Visit 5 (Patients not entering Open Label Extension) (Day 43 +3 
days) ...................................................................................................... 58 
9.2.1.6 
Visit 6 - Safety Follow up Call (Day 71) (±3 days) .............................. 59 
9.2.2 
Open Label Extension ............................................................................... 59 
9.2.2.1 
Visit 5 (Open Label Extension) - Two Weeks (±3 days) ...................... 59 
9.2.2.2 
Visit 6 (Open Label Extension) - One Month (±3 days) ....................... 59 
9.2.2.3 
Visit 7 (Open Label Extension) - Two Months (±3 days) .................... 60 
9.2.2.4 
Visit 8 (Open Label Extension) - Three Months (±7 days) .................. 60 
9.2.2.5 
Visit 9 (Open Label Extension) - Six Months (±7 days) ...................... 60 
9.2.2.6 
Visit 10 (Open Label Extension) - Nine Months (±7 days) .................. 61 
9.2.2.7 
Visit 11 (Open Label Extension End of Treatment) - Twelve 
Months (±7 days) .................................................................................. 61 
9.2.2.8 
Visit 12 (Open Label Extension End of Taper) .................................... 61 


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9.2.2.9 
Safety Follow Up Call (±3 days) .......................................................... 62 
10. 
WITHDRAWAL ............................................................................ 62 
11. 
URGENT SAFETY MEASURES ................................................ 63 
12. 
ADVERSE EVENT REPORTING .............................................. 63 
12.1 
Definitions ................................................................................................... 63 
12.1.1 
Adverse Event ........................................................................................... 63 
12.1.2 
Investigator ............................................................................................... 64 
12.2 
Serious Adverse Events ............................................................................... 64 
12.3 
Reporting Procedures for Serious Adverse Events ..................................... 64 
12.4 
Pregnancy .................................................................................................... 65 
12.5 
Causality Assessment .................................................................................. 65 
12.6 
Reporting Procedures for All Adverse Events ............................................ 66 
12.7 
Follow up Procedures for Adverse Events .................................................. 68 
12.8 
Potential Cases of Drug Induced Liver Injury............................................. 68 
12.9 
Notification of Safety Information to Investigators, Regulatory 
Authorities and Ethics Committees. ............................................................ 69 
13. 
STATISTICAL CONSIDERATIONS ......................................... 71 
13.1 
Sample Size, Power and Significance Levels ............................................. 71 
13.2 
Interim Analysis .......................................................................................... 71 
13.3 
Analysis Sets ............................................................................................... 71 
13.3.1 
Safety Set .................................................................................................. 71 
13.3.2 
Pharmacokinetic Analysis Set .................................................................. 71 
13.3.3 
Protocol Deviations .................................................................................. 71 
13.4 
General Considerations ............................................................................... 71 
13.5 
Accountability and Background Characteristics ......................................... 72 
13.5.1 
Enrollment and Disposition ...................................................................... 72 
13.5.2 
Baseline and Demographic Characteristics .............................................. 72 
13.5.3 
Medical History ........................................................................................ 72 
13.5.4 
Concomitant Medication .......................................................................... 72 
13.6 
Endpoints and Statistical Methods .............................................................. 72 
13.6.1 
Primary Endpoint(s) .................................................................................. 72 
13.6.2 
Secondary Endpoint(s) .............................................................................. 72 
13.6.3 
Pharmacokinetics ...................................................................................... 73 


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13.6.4 
Safety ........................................................................................................ 74 
13.6.4.1 
Treatment Compliance and Extent of Treatment Exposure .................. 74 
13.6.4.2 
Adverse Events...................................................................................... 74 
13.6.4.3 
Clinical Laboratory Data ....................................................................... 74 
13.6.4.4 
Columbia-Suicide Severity Rating Scale, Vital Signs, 12-lead 
Electrocardiogram, Physical Examination and Other Safety Data ....... 75 
13.6.4.5 
Seizure Data .......................................................................................... 75 
14. 
DATA SAFETY MONITORING COMMITTEE ..................... 75 
15. 
REGULATORY AND ETHICAL OBLIGATIONS .................. 76 
15.1 
Declaration of Helsinki ............................................................................... 76 
15.2 
Informed Consent ........................................................................................ 76 
15.3 
Institutional Review Board/Ethics Committee ............................................ 76 
15.4 
Pre-Study Documentation Requirements .................................................... 77 
15.5 
Participant Confidentiality .......................................................................... 77 
16. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ............... 79 
16.1 
Protocol Amendments and End of Study or Termination ........................... 79 
16.2 
Study Documentation and Storage .............................................................. 79 
16.3 
Study Monitoring and Data Collection ....................................................... 80 
16.4 
Quality Assurance ....................................................................................... 82 
16.5 
Compensation .............................................................................................. 82 
16.6 
Publication Policy........................................................................................ 82 
16.7 
Intellectual Property Rights ......................................................................... 83 
16.8 
Confidential Information ............................................................................. 83 
17. 
REFERENCES .............................................................................. 84 


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Table of Appendices 
APPENDIX 1. 
Schedule of Assessments 
87 
APPENDIX 2. 
Study Personnel 
90 
Appendix 3.1 
Investigator Details 
90 
Appendix 3.2 
Sponsor Contact Details 
90 
 
 


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List of In-text Tables 
Table 3.3.1-1 
Epidiolex Adverse Events ........................................................ 32 
Table 5.1-1 
Formulation of GWP42003-P Oral Solution ........................... 35 
Table 5.2-1 
Formulation of Placebo Oral Solution ..................................... 35 
Table 8.1.2-1 
Dose Up-Titration Regimen* ................................................... 42 
Table 9.1.9-1 
Hematology, Biochemistry, Urinalysis and THC Screen ........ 47 
 
 
 


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List of In-text Figures 
Figure 1-1 
Study Design and Treatment Schema ...................................... 16 
Figure 1-2 
Study Design and Treatment Schema ...................................... 17 
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 ....................................... 55 
 


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List of Abbreviations 
AE 
Adverse Event 
AEDs 
Antiepileptic Drugs 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC(0–∞) 
Area under the concentration time curve from zero to infinity with 
extrapolation of the terminal phase 
AUC(0–t) 
The area under the plasma concentration versus time curve, from 
time zero to ‘t’ (where t = the final time of positive detection) as 
calculated by the linear trapezoidal method 
BP 
Blood Pressure 
CLB 
Clobazam 
CBD 
Cannabidiol 
CI 
Confidence Interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CLB 
Clobazam 
Cmax 
Maximum measured plasma concentration 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
EC 
Ethics Committee 
ECG 
12-lead Electrocardiogram 
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 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ITT 
Intention to Treat 


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IVRS 
Interactive Voice Response System 
LOCF 
Last Observation Carried Forward 
MMRM 
Mixed-effects Model Repeated Measures 
N-CLB 
N-desmethylclobazam 
OLE 
Open label extension 
PBPK 
Physiologically-based pharmacokinetic interactions 
PI 
Principal Investigator 
PP 
Per Protocol 
PVD 
Pharmacovigilance Department 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
t½ 
Terminal half-life 
TBL 
Total bilirubin 
THC 
∆9-tetrahydrocannabinol 
tmax 
Time to the maximum measured plasma concentration 
ULN 
Upper Limit of Normal 
USA 
United States of America 
VNS 
Vagus Nerve Stimulation 
 


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Definition of Terms 
Term 
Definition 
Baseline period 
The period from screening (Visit 1) to enrollment (Visit 2). 
Convulsive seizures 
Tonic-clonic, tonic, clonic or atonic seizures. 
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 is enrolled and begins PK sampling. 
End of treatment 
Completion of the treatment period (Visit 5 or Visit 12) or 
withdrawal. 
End of study 
Last patient’s last visit / last contact. 
IMP 
Investigational Medicinal Product (Study Medication). Used 
to describe both investigational active product and reference 
therapy (placebo). 
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. 
Partial seizures 
Partial (focal) seizures occur when the electrical activity 
remains in a limited area of the brain. 
Status epilepticus 
Seizures lasting for 30 minutes or longer. 
Sub-types of seizures 
Seizure sub-types can be tonic, clonic, tonic-clonic, atonic, 
myoclonic, absence (typical and atypical), countable partial 
and other partial. 
 


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2. 
OBJECTIVES 
2.1 
Primary 
To determine whether GWP42003-P affects the pharmacokinetic (PK) profile of 
clobazam (CLB) and its primary metabolite N-desmethylclobazam (N-CLB). 
2.2 
Secondary 
To assess the safety and tolerability of GWP42003-P in the presence of CLB. 
3. 
BACKGROUND AND RATIONALE 
3.1 
Disease 
Epilepsy is a common disorder1. Approximately 1% of the world’s population is 
chronically affected by epilepsy2. It shows no particular geographic distribution and 
the gender distribution is more or less equal. The incidence of epilepsy is greater in 
childhood and in elderly people2,3,4,5. Focal seizures represent the most frequent 
seizure type (around 60% of all cases of epilepsy, and a substantial percentage of 
them are not well controlled)6. 
Overall, and despite the introduction of a substantial number of new antiepileptic 
drugs (AEDs) in the last two decades, around 30% of patients remain refractory to 
currently available treatment7,8,9. In addition, most currently approved AEDs are 
associated with significant motor and cognitive adverse reactions10,11. 
Currently available AEDs each belong to one of a large number of different classes. 
The principal targets for existing AEDs tend to be either modulators of voltage-
dependent ion channels, enhancers of inhibitory neurotransmission, and attenuators of 
excitatory neurotransmission, with the aim being to reduce neuronal 
excitotoxicity12,13. 
3.2 
GWP42003-P Background 
The cannabis plant (Cannabis sativa L.) produce trichomes that synthesize a large 
number of pharmacologically active compounds called phytocannabinoids. The most 
abundant of these are Δ9-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 


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these plants are processed to yield pure (>98%) CBD that typically contains less than 
0.5% (w/w) THC. 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 conductance and acts on other G-protein-coupled receptors such as 
the transient receptor potential channel TRPV114 and the orphan receptor GPR5515. 
Importantly, in contrast to THC, CBD lacks detectable psychoactivity. CBD has 
demonstrated anticonvulsant, antipsychotic, anxiolytic, neuroprotective, antioxidant 
and anti-inflammatory activity16. Very little data concerning 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 humans17. 
3.3 
Rationale 
CBD has shown therapeutic potential as an AED, with preclinical studies 
demonstrating anticonvulsant effects in a number of animal models of seizure16,18,19. 
Although no placebo-controlled trials have been completed to date, 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 either >80% reduction in seizure frequency or complete seizure 
freedom20. The CBD-enriched cannabis was behaviorally well tolerated and children 
often experienced improved sleep, increased alertness and better mood. There has 
been a program of expanded access by GW Pharma Ltd (GWP) in the USA, primarily 
in children with severe epilepsy, that has shown encouraging reports of reductions in 
multiple seizure types with good tolerability in 151 exposures21. 
Population-based studies of drug utilization demonstrate that 19-24% of patients with 
epilepsy use polytherapy with AEDs22,23,24. In recent studies of children and adults 
with refractory epilepsy, 64 % used polytherapy with two or more AEDs, resulting in 
a considerable risk of interactions25,26. CLB is a widely used AED, prescribed with 
other medication(s) to control seizures in adults and children two years of age and 
older who have Lennox-Gastaut syndrome (a disorder that causes seizures and often 


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developmental delays). The pharmacological action of CLB is to decrease abnormal 
electrical activity in the brain via allosteric activation of the ligand-gated γ-
aminobutyric acid (A) receptor. 
CLB is in a class of medications called benzodiazepines. Similar to other 
benzodiazepine medications, clobazam is metabolized by cytochrome P450 (CYP450) 
enzymes (mainly in the liver). This metabolism results in the formation of an active 
metabolite N-CLB, amongst others. 
Cytochrome P450 enzymes are a family of heme-containing enzymes responsible for 
the metabolism of over half of all prescribed medications and interactions with these 
enzymes are the major source of physiologically-based pharmacokinetic (PBPK) 
interactions between drugs. It is anticipated that patients taking GWP42003-P may 
also be taking clobazam and as CBD has been shown to both inhibit CYP450 
enzymes in vitro (Ki CYP3A4 = 1.5 μM) and induce CYP450 enzymes in vitro (EC50 
CYP3A4 = 1.2 μg/mL) a possibility of a pharmacokinetic (PK) interaction between 
CBD and clobazam exists. Furthermore, CLB has been shown to undergo PBPK 
interactions with other AED medications via both CYP induction (such as with 
felbamate where the formation of the active metabolite of clobazam, N-CLB was 
increased several-fold27) and also CYP inhibition (such as with stiripentol where 
serum concentrations of CLB were increased and metabolites decreased28,29,30). 
Given the high likelihood that patients prescribed CBD will also be using clobazam, it 
is the aim and purpose of this study to determine whether a PK interaction between 
CBD and CLB exists. 
3.3.1 
Selection of Study Doses 
Doses up to 800 mg GWP42003-P per day for up to eight weeks have been well 
tolerated in adults in GW Research Ltd (GW) clinical study GWMD09112, which, 
assuming an average weight of 70 kg, equates to a daily dose of 11.4 mg/kg. In the 
literature, doses of GWP42003-P have been given up to 1500 mg GWP42003-P per 
day for four weeks in adults, which, in a 70 kg human equates to a daily dose of 
21.4 mg/kg GWP42003-P. 
Data on the safety of GWP42003-P is emerging from the physician-initiated 
Epidiolex® Expanded Access Program being conducted in the USA. This program has 
been running since January 2014 and at the time of writing had data on 63 patients. 
The mean maximum exposure achieved in this patient population of refractory 
epilepsies was a daily dose of 24.4 mg/kg (n=59 patients) with a maximum dose of 
51 mg/kg in one patient. Please see below for a break-down of the groups: 
• ≤20 mg/kg GWP42003-P n=13 (21%) 


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• >20 mg/kg - ≤30 mg/kg GWP42003-P n=40 (64%) 
• >30 mg/kg - ≤40 mg/kg GWP42003-P n=4 (6%) 
• >40 mg/kg GWP42003-P n=2 (3%) 
• Dose not reported n=4(6%) 
Eleven patients had a daily GWP42003-P dose of >25 mg/kg, of which five did not 
report any adverse events (AEs). Of note, the patient who received 51 mg/kg did not 
have any AEs at this dose. The remaining six patients experienced AEs as 
documented in the Table 3.3.1-1below: 
Table 3.3.1-1 
Epidiolex Adverse Events 
Adverse Event Term 
Number of Events 
Loose stools / urgent bowel 
movements 
2 
Increase in seizures 
2 
Drowsiness 
1 
Aspiration pneumonia 
1 
Lethargy 
1 
Decreased appetite 
1 
Dyskinesia 
1 
Urinary tract infection 
1 
Based on the above, a daily dose up to 20 mg/kg/day (given as two divided doses) has 
been selected for the GWP42003-P dose in the current study, including a titration 
period with daily increments of 2.5 mg/kg and 5 mg/kg. At the end of the treatment 
period, patients will be given the option of continuing onto an open label extension 
(OLE) period if the investigator and patient both agree that it is in their best interest. 
During the OLE doses may be adjusted up or down, dependent on investigator 
opinion, to a maximum daily dose of 30 mg/kg GWP42003-P. 
3.4 
Clinical Hypothesis 
CBD can act as both a CYP inhibitor and inducer in human hepatocytes in vitro. 
Therefore, the potential for PK interactions with other drugs that are metabolized by 
CYP450 enzymes exists. The hypothesis is that the in vivo PK of CLB and its major 
metabolite (N-CLB) may be altered (increased or decreased) by the chronic 
administration of GWP42003-P. 
4. 
EXPERIMENTAL PLAN 
4.1 
Study Design 
This phase 2, placebo-controlled study consists of a 34 day, double-blind phase 
followed by an optional maximum one year OLE. Patients will continue to take CLB 


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as advised by their physician for the duration of the study. GWP42003-P/placebo will 
be taken twice daily immediately after their CLB dose. 
Patients will enter the study and begin a 10 day GWP42003-P or placebo titration 
phase. During this period patients will be up-titrated to a maintenance dose or 
equivalent of 20 mg/kg/day. Patients will continue to take this maintenance dose of 
GWP42003-P or placebo for 21 days (Days 12 to 32). 
Upon completion of the treatment period (Day 34) patients will be invited to receive 
GWP42003-P during the OLE phase. If a patient enters the OLE they will take 
GWP42003-P as advised by the investigator. If a patient chooses not to enter the 
OLE, and/or the investigator does not feel it is in their best interests, they will taper 
off their GWP42003-P/placebo treatment by reducing their maintenance dose by 10% 
per day until dosing has ceased. For those patients not entering the OLE, dosing will 
end on Day 43 and they will receive a telephone follow-up visit four weeks after the 
end of GWP42003-P/placebo dosing (Day 71). 
PK samples will be taken on two occasions during the blinded phase of the study: 
• Day 1 (Visit 2) before beginning treatment (patients will be taking CLB only). 
• Day 33 (Visit 4) following 21 days of GWP42003-P or placebo maintenance 
(patients will be taking CLB and GWP42003-P or placebo). 
Ten samples will be taken during each PK assessment. PK samples should be taken at 
time points in respect to the morning dose of CLB. The time points are as follows: 
Pre-dose, 15min, 30min, 1h, 1.5h, 2h, 4h, 6h, 12h and 24h. PK samples will be 
quantitatively analyzed for CLB, N-CLB, CBD, CBD major metabolites, THC and 
THC major metabolites. 
Patients should try to be consistent in the timing of their food intake in relation to 
dosing throughout the blinded phase of the study. 
Upon entry into the OLE the dose of GWP42003-P and other AEDs may be adjusted 
up or down to a maximum of 30 mg/kg/day. The OLE will last for a maximum of one 
year or until marketing authorization is granted; whichever is earlier. 
Patients will be required to keep a paper diary to note the time and dose of IMP and 
CLB administration each morning and evening and to record any AEs that may occur 
whilst receiving IMP and any other medications. Patients will also be required to 
record the number and type of seizures for each day whilst on the study. 
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 are 
provided in Section 8 and Section 9 respectively. 


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4.1.1 
Primary Endpoint 
The primary endpoints of the study are the PK parameters (Cmax, tmax, AUC(0–∞), 
AUC(0–t), t½) of the following analytes: 
• CLB 
• N-CLB 
• CBD 
• CBD major metabolites 
4.1.2 
Secondary Endpoint(s) 
To assess the safety and tolerability of GWP42003-P compared with placebo when 
taken in combination with CLB. Safety and tolerability will be assessed using the 
following parameters: 
• AEs 
• 12-lead Electrocardiogram (ECG) 
• Clinical laboratory parameters (clinical chemistry, hematology and urinalysis) 
• Vital signs 
• Columbia-Suicide Severity Rating Scale (C-SSRS) 
• Seizure Frequency 
• Abuse Liability 
 
PK parameters (Cmax, tmax, AUC(0–∞), AUC(0–t), t½) of the following analytes: 
• THC 
• THC major metabolites 
4.2 
Number of Centers 
An estimated number of seven centers are expected to participate in this study. 
4.3 
Number of Patients 
A total of 20 patients will be enrolled into the study. Recruitment for the study will be 
competitive between participating sites. 
The sample size calculation is explained fully in Section 13.1. 
5. 
INVESTIGATIONAL MEDICINAL PRODUCT 
Please refer to the separate Pharmacy Manual for more detailed information on the 
IMP. 


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5.1 
GWP42003-P Oral Solution 
GWP42003-P oral solution is presented as a pale yellow 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 
Placebo Oral Solution 
Placebo oral solution contains the excipients sesame oil and anhydrous ethanol with 
added sweetener (sucralose) and strawberry flavoring Table 5.2-1. 
Table 5.2-1 
Formulation of Placebo Oral Solution 
Material 
Quantity 
Anhydrous ethanol 
79 mg/mL 
Sucralose 
0.5 mg/mL 
Strawberry flavoring 
0.2 mg/mL 
Sesame oil 
make up to 1 mL 
5.3 
Packaging, 
Storage 
and 
Drug 
Accountability 
(Cannabidiol/Placebo) 
5.3.1 
Packaging and Labelling  
The IMP will be manufactured and packaged by 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 weight of each patient. 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 labelled and packaged. Label text will comply with European Union 
(EU) guidance on Good Manufacturing Practice, Annex 13 Labelling and will be fully 
described in the separate Pharmacy Manual. In addition, any local country 
requirements in accordance with local drug law or regulatory requirement will be 
included in the final label text. 


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Directions of use, name, address and telephone number of investigator, or main 
contact for information about the product or the clinical trial, will be provided 
separately to the patient. 
5.3.2 
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. 
5.3.3 
Supply and Return of Investigational Medicinal Product 
Once a site has been activated 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 and the condition of the drug. Details of the IMP received will be recorded in 
the IMP accountability record. The site will acknowledge IMP receipt and will 
complete any receipt forms required. IMP will be dispensed and returned as detailed 
in Section 5.3.4 with further IMP shipments to be requested as necessary. 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. 
5.3.4 
Investigational Medicinal Product Accountability 
The investigator has overall responsibility for the accountability of all used and 
unused IMP. A drug accountability record for the IMPs must be kept current and 
should contain: 
• The dates and quantities of IMP received from GWP. 
• Patient’s identification. 
• Date and quantity of IMP dispensed. 
• The initials of the dispenser. 


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• Date and quantity of IMP returned to the investigator/pharmacy. 
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 authorized GW or GWP 
representatives and local officials or regulatory agency inspectors. 
Please refer to the separate Pharmacy Manual for more detailed information on the 
IMP. 
5.4 
Clobazam 
Patients will use their own supply of Clobazam throughout the study. Clobazam usage 
will be recorded by the investigator. Clobazam is only an IMP for the blinded phase 
of the study. 
6. 
PARTICIPANT ELIGIBILITY 
Investigators will be required to maintain a log that includes limited information about 
all screened patients (initials, age, and gender; as allowed per local regulations) and 
outcome of screening. 
6.1 
Inclusion Criteria 
For inclusion in the study patients must fulfil ALL of the following criteria: 
6.1.1 
Male or female patients aged 18 to 55 years inclusive. 
6.1.2 
Patient must have epilepsy as determined by the investigator and be taking 
CLB. 
6.1.3 
Patient must have a documented magnetic resonance imaging/computerized 
tomography of the brain that ruled out a progressive neurologic condition. 
6.1.4 
Patient must have experienced at least one seizure of any type (i.e., 
convulsive: tonic-clonic, tonic, clonic, atonic; focal: focal seizures with 
retained consciousness and a motor component, focal seizures with 
impaired consciousness focal seizures evolving to bilateral secondary 
generalization) within the two months prior to randomization.  
6.1.5 
Patients must be taking CLB and no more than two other AEDs during the 
course of the study. 
6.1.6 
AED(s), including CLB, must be stable for four weeks prior to screening 
and regimen must remain stable throughout the duration of the blinded 
phase of the study. 
6.1.7 
Intervention with vagus nerve stimulation (VNS) and/or ketogenic diet 
must be stable for four weeks prior to baseline and patient/caregiver must 


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be willing to maintain a stable regimen throughout the blinded phase of the 
study. 
6.1.8 
Patients must abstain from alcohol during the blinded phase of the study. 
6.1.9 
Patient and/or legal representative is available to attend all PK visits within 
the required visit window. 
6.1.10 
Patient and/or legal representative must be willing and able to give 
informed consent for participation in the study 
6.1.11 
Patient and/or legal representative must be willing and able (in the 
investigator’s opinion) to comply with all study requirements. 
6.1.12 
Patient is willing for his or her name to be notified to the responsible 
authorities for participation in this study, as applicable. 
6.1.13 
Patient is willing to allow his or her primary care practitioner and 
consultant, if appropriate, 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 has clinically significant unstable medical conditions other than 
epilepsy. 
6.2.2 
Patients on CLB at doses above 20 mg per day. 
6.2.3 
Patients taking CLB intermittently as rescue medication. 
6.2.4 
Patient has a history of symptoms (e.g., dizziness, light-headedness, blurred 
vision, palpitations, weakness, syncope) related to a drop in blood pressure 
(BP) due to postural changes. 
6.2.5 
Any history of suicidal behavior or any suicidal ideation of type four or five 
on the C-SSRS in the last month or at screening. 
6.2.6 
Patient has had clinically relevant symptoms or a clinically significant 
illness in the four weeks prior to screening or enrollment, other than 
epilepsy. 
6.2.7 
Patient has consumed alcohol during the seven days prior to enrollment and 
is unwilling to abstain during the blinded phase of the study. 
6.2.8 
Patient is currently using or has in the past used recreational or medicinal 
cannabis, or synthetic cannabinoid based medications (including Sativex®) 
within the three months prior to study entry. 
6.2.9 
Patient has any known or suspected history of any drug abuse or addiction. 
6.2.10 
Patient is unwilling to abstain from recreational or medicinal cannabis, or 
synthetic cannabinoid based medications (including Sativex) for the 
duration for the study. 
6.2.11 
Patient has consumed grapefruit or grapefruit juice seven days prior to 
enrollment and is unwilling to abstain from drinking grapefruit juice within 
seven days of PK visits. 
6.2.12 
Patient has any known or suspected hypersensitivity to cannabinoids or any 
of the excipients of the IMP, e.g., sesame oil. 


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6.2.13 
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 three 
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.  
6.2.14 
Female patient who is pregnant (positive pregnancy test), lactating or 
planning pregnancy during the course of the study and for three months 
thereafter. 
6.2.15 
Patients who have received an IMP within the 12 weeks prior to the 
screening visit. 
6.2.16 
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 the patient’s ability to 
participate in the study. 
6.2.17 
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. 
6.2.18 
Patient has significantly impaired hepatic function at screening (Visit 1) or 
enrollment (Visit 2), defined as any of the following:  
- 
Alanine aminotransferase (ALT) or Aspartate aminotransferase (AST) 
>5 × upper limit of normal (ULN). 
- 
ALT or AST >3 × ULN and total bilirubin (TBL) >2 × ULN or 
international normalized ratio (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%).  
This criterion can only be confirmed once the laboratory results are 
available; patients randomized into the study who are later found to meet 
this criterion must be withdrawn from the study. 
6.2.19 
Unwilling to abstain from donation of blood during the study. 
6.2.20 
Travel outside the country of residence planned during the study. 
6.2.21 
Patients previously enrolled into this study. 
 


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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 forms and other patient information material. 
Patients will be considered enrolled in the study from the time of providing written 
informed consent. All patients, or legal representatives, where appropriate, must 
personally sign and date the consent form prior to any procedures being performed 
(refer to Section 9.1.2 and Section 15.2). 
7.1 
Treatment Assignment 
At the start of Visit 1, patients will be allocated a unique patient number, consisting of 
a four digit GW center number and a three digit patient identification number. The 
three digit patient number will be assigned in ascendant numerical order at each site. 
The unique patient number will be preceded by a unique letter. For example, 
P1234001, denoting patient 001 at site 1234. GWP will provide all 
GWP42003-P/placebo packed and labelled. Following enrollment at Visit 2, patients 
will be allocated a pre-packed numbered IMP. 
7.2 
Randomization 
This is a double-blind study. Patients will be randomized in a 4:1 ratio to receive 
20 mg/kg GWP42003-P or placebo. 
 
 


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8. 
TREATMENT PROCEDURES 
8.1 
Investigational Medicinal Product Dosage, Administration and 
Schedule 
The IMP will consist of three types of medication: 
• GWP42003-P Oral Solution containing 100 mg/mL CBD. 
• Placebo Oral Solution containing excipients. 
• Clobazam (patient supplied). 
The GWP42003-P/placebo will be presented as an oral solution containing either the 
active pharmaceutical ingredient and excipients (in the case of GWP42003-P) or only 
excipients (in the case of placebo). For details regarding GWP42003-P/placebo 
formulations, see Section 5. 
All patients will be weighed during the study visits and the daily volumes of 
GWP42003-P/placebo solution to be taken during the titration period, and for the 
remainder of the study, will be calculated and provided to the patient and/or caregiver. 
Further information on dispensing procedures will be provided in a separate 
Pharmacy Manual. 
Each patient will take their first dose of GWP42003-P/placebo at Visit 2, Day 2 in the 
clinic. Patients not entering the OLE will take their final maintenance dose of 
GWP42003-P/placebo at Visit 4 (Day 33) in the clinic. Patients entering the OLE will 
take their final dose of IMP at Visit 11 (one year after the end of the blinded phase of 
the study) or sooner (if marketing authorization is granted within one year). 
Patients will use their own supply of Clobazam throughout the study. Patients will 
continue on the dose that they were on at screening for the blinded phase of the study. 
Clobazam will only be an IMP for the blinded section of the study.    
8.1.1 
Dose Administration 
GWP42003-P/placebo will be administered orally by the patient or their caregiver 
twice each day (morning and evening) using the syringe(s) provided. 
GWP42003 P/placebo should be taken immediately after the patient’s usual CLB 
administration. The GWP42003-P/placebo should be swallowed, as per the intended 
commercial therapeutic route, and may be taken with other concomitant medications, 
as directed by the investigator. 


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8.1.2 
Dose Escalation and Dose Adjustments 
Patients will enter the blinded phase of the study and will be up-titrated over ten days 
(Day 2 to Day 11) to a maintenance dose or equivalent of GWP42003-P/placebo of 
20 mg/kg/day. If GWP42003-P is not tolerated then the dose can be reduced 
accordingly at the discretion of the investigator. The titration regimen is described in 
Table 8.1.2-1. 
Table 8.1.2-1 Dose Up-Titration Regimen* 
Day - GWP42003-P/Placebo 
(Blinded Period) 
Day - GWP42003-P only 
(OLE**) 
Dose Level 
(GWP42003-P or equivalent 
placebo) 
2 
34 
2.5 mg/kg 
3 
35 
2.5 mg/kg 
4 
36 
5.0 mg/kg 
5 
37 
5.0 mg/kg 
6 
38 
7.5 mg/kg 
7 
39 
7.5 mg/kg 
8 
40 
10.0 mg/kg 
9 
41 
10.0 mg/kg 
10 
42 
15.0 mg/kg 
11 
43 
15.0 mg/kg 
12 onwards 
44 onwards 
20.0 mg/kg 
*GWP42003-P /placebo is to be taken twice daily. Total daily doses are shown. 
** Only patients who were taking placebo during the double-blind period will up-titrate according to 
this schedule during the OLE period. Those taking GWP42003-P during the double-blind period will 
down-titrate their blinded IMP whilst simultaneously up-titrating with GWP42003-P, thus maintaining 
a daily dose of 20 mg/kg/day GWP42003-P throughout. 
The titration regimen defined above should be followed to the maximum dose 
(20 mg/kg/day). Should an AE occur during titration which is attributable to IMP or 
concomitant AED, then IMP dose should be reduced to the next lower dose. Any 
other changes in concomitant AED therapy should be reviewed with the medical 
monitor before being initiated. 
For those patients who do not enter the OLE the dose of GWP42003-P/placebo will 
taper off over 10 days beginning on Day 34. The patient will reduce the dose by 10% 
of the maintenance dose each day and treatment will end on Day 43. 
Patients who enter the OLE period will be transitioned to the OLE treatment over a 
10-day period in order to maintain blinding, simultaneously down-titrating blinded 
GWP42003-P /placebo whilst up-titrating open-label GWP42003-P. As such, patients 
who were taking GWP42003-P during the blinded period will maintain their 
20 mg/kg/day dose throughout the transition from the blinded period into the OLE 
period and patients who received placebo during the blinded period up-titrate slowly 
to the 20 mg/kg/day dose in the OLE period. After this has taken place, the 


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maintenance dose of GWP42003-P may be adjusted up or down at the discretion of 
the investigator to a maximum of 30 mg/kg/day (no minimum). 
8.2 
Concomitant Therapy 
Doses of any concomitant AEDs, including CLB, must have been stable for at least 
four weeks prior to screening and must remain stable throughout the blinded phase of 
the study. If there are symptoms of toxicity suspected to be from a drug interaction, 
the investigator may adjust GWP42003-P/placebo or the CLB or other AEDs after 
discussion with the medical monitor. 
The use of rescue medication is allowed if necessary. The use of oxygen may be 
considered as rescue medication if used as required. Any medication, other than the 
IMP, taken during the study must be recorded on the Case Report Form (CRF). 
Any non-pharmacological therapies (e.g., ketogenic diet, VNS) must also be stable up 
to four weeks prior to baseline and throughout the duration of the study. 
8.3 
Prohibited Therapy During Study Period 
The following medications are prohibited for the duration of the study starting from 
acquisition of patient consent. However, any patients taking these medications after 
screening 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. 
• Any new medications or interventions for epilepsy (including ketogenic diet 
and VNS) or changes in dosage. 
• Patients should not take any more than three AEDs inclusive of CLB. 
• Recreational or medicinal cannabis or synthetic cannabinoid based 
medications (including Sativex) within three months prior to or during the 
study. 
If any other IMP is taken as part of a clinical trial within twelve weeks of the 
screening visit or during the study, the patient must be withdrawn from this study.  
8.4 
Compliance in Investigational Medicinal Product Administration 
Patients or their caregivers will record the total volume of IMP, administered on each 
treatment day, using the paper diary and will be asked to return all IMP (used and 
unused) at each subsequent visit. The site will check the returned IMP against the 
usage recorded in the diary and the projected usage. Any discrepancies will be 
discussed with the patient/caregiver and documented accordingly within the patient’s 
source documents. 


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The investigator must inform GW promptly of all missing or unaccountable IMP. 
Records of IMP accountability will be maintained according to Section 5.3.4. 
8.5 
Access to Blinded Treatment Assignment 
The identity of IMP assigned to patients will be held by the IVRS. The principal 
investigator (PI) at each center is responsible for all trial-related medical decisions 
and is responsible for ensuring that information on how to access the IVRS is 
available to the relevant staff in case of an emergency and unblinding is required. A 
patient’s treatment assignment must only be unblinded when knowledge of the 
treatment is essential to make a decision on the medical management of the patient. 
Unblinding for any other reason will be considered a protocol deviation. 
The investigator is encouraged to contact GW to discuss the rationale for unblinding. 
However, to prevent delays to the investigator or medical personnel responding to a 
potentially emergent situation, unblinding of study medication will not be dependent 
upon the investigator receiving approval from GW (i.e., the investigator will be able 
to obtain the code break information independent of contacting GW). 
If the investigator does unblind they must contact GW within one working day of the 
event and must document the time, date and reasons for unblinding in the patient’s 
CRF. 


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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 
9.1.1 
Contraception 
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 three months thereafter. A highly effective method of 
birth control is defined as those which result in a low failure rate (i.e., less than 1% 
per year) when used consistently and correctly such as combined or progesterone only 
oral contraceptives, intrauterine device, intrauterine hormone-releasing system, 
bilateral tubal occlusion, vasectomized partner or sexual abstinence6. Abstinence, as 
referenced above, 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. The use of hormonal contraception must be supplemented 
with a barrier method (preferably male condom). 
9.1.2 
Informed Consent 
Adult patients with an adequate level of understanding must personally sign and date 
the IRB/EC approved informed consent form(s) before any study specific procedures 
are performed or any patient related data is recorded for the study. For adult patients 
with an insufficient level of understanding of what is proposed, only personal legal 
representative consent will be sought. The informed consent process should be 
documented within the patient notes. 
GW requires a physician to be present for consent and to also sign the consent forms. 
9.1.3 
Demographics 
Patient demographics will be recorded at Visit 1. The following information will be 
obtained for each patient: date of birth, gender and race (if allowed per local 
regulations). 


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9.1.4 
Medical History 
Relevant, significant medical history (including seizure information since diagnosis, 
history of epilepsy-specific genetic testing and all prior AEDs taken) will be obtained 
during Visit 1 and is defined as any condition or disease that: 
• May affect the condition under study. 
• Is ongoing on entry into the study. 
9.1.5 
Concomitant Medication 
Details of all current and recent medication (i.e., taken within the previous 28 days) 
including AEDs will be recorded at the screening visit (Visit 1) and reviewed at each 
subsequent visit. AEDs used during the study should be maintained at a stable dose. 
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 the 
screening visit, as defined in Section 8.3. 
9.1.6 
Physical Examination 
A physical examination will be performed at the screening visit (Visit 1) to ensure 
that the patient is eligible to enter the study. To ensure patient safety, further physical 
examinations will be performed at every hospital visit. Physical examinations will 
include height (at screening) and body weight measurements. 
9.1.7 
Vital Signs 
Vital sign measurements, taken after five minutes rest in a sitting position, will be 
completed alongside the physical examination at all visits. Postural BP will be 
assessed after five minutes in supine position and, if possible, two minutes in standing 
position. The pulse rate must also be measured as part of the vital sign assessments. 
BP and pulse rate must be recorded using the same arm throughout the study. 
9.1.8 
12-Lead Electrocardiogram 
An ECG will be performed, after five minutes in supine position, at all hospital visits. 
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 be undertaken at all hospital visits and will include hematology, 
biochemistry, and urinalysis (provided urine can be obtained, with the exception of 


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screening where a urine sample for THC screen must be obtained). A serum alcohol 
test will be performed at Visits 1, 2 and 4. A serum pregnancy test (if appropriate) 
will also be performed at Visit 1. 
Urine samples for biochemistry will be analyzed at the study center by use of a 
dipstick with any relevant findings being sent for further laboratory based urinalysis 
(urinalysis, microscopy, culture and sensitivity, as applicable). 
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.  
Table 9.1.9-1 
Hematology, Biochemistry, Urinalysis and THC Screen 
Biochemistry 
(serum) 
Hematology 
(whole blood) 
Urinalysis 
(urine) 
Pregnancy 
Test 
THC screen 
(urine) 
Alanine aminotransferase 
(ALT) 
Hematocrit 
Bilirubin 
Serum 
THC 
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 
 
 
 
 
Potassium 
 
 
 
 
Prolactin 
 
 
 
 
Prothrombin time (plasma) 
 
 
 
 
Sodium 
 
 
 
 
Total bilirubin (TBL) 
 
 
 
 
Total protein 
 
 
 
 
Urea (BUN) 
 
 
 
 
Trigylcerides 
 
 
 
 
 
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 by the investigator 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 


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investigator is satisfied that the abnormality is not related to the IMP and needs no 
further investigation. 
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 
them 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 in the four weeks 
prior to screening. 
9.1.10 
Pharmacokinetic Analyses 
The plasma concentration/time curves of CLB, N-CLB, CBD, CBD major 
metabolites, THC and THC major metabolites will be assessed at Visit 2 (Day 1 and 
Day 2) and Visit 4 (Day 33 and Day 34). Patients will be given their daily dose of 
clobazam at a scheduled time during Visit 2 and Visit 4 and the GWP42003-
P/placebo immediately afterwards (Visit 4 only) to facilitate the accurate timing of 
blood samples required for PK analysis. Blood samples will be taken by either direct 
venipuncture or an indwelling cannula inserted into a forearm vein at the following 
times: Pre-dose and, 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 
6 hours, 12 hours and 24 hours after dosing. The timing of each PK sample will be 
relative to the morning dose of CLB. 
The pre-dose blood sample will be taken within 30 minutes prior to dosing. The 
allowable window for post-dose blood sample collection is ±2 minutes up to and 
including 1 hour post-dose, ±5 minutes from 1.5 hours up to and including 6 hours 
post-dose and ±1 hour at 12 hours and 24 hours post-dose. 
In the event of an AE that, in the opinion of the investigator, is related to a 
concomitant AED, additional blood samples may be collected. 
Analysis of all PK samples will be conducted at a central clinical laboratory. Sample 
volume requirements and processing procedures will be detailed in a separate 
laboratory manual. 
9.1.11 
Genetic Testing 
Genetic testing will only be conducted if specific consent is obtained from the 
participant. There is a separate informed consent form for this. 
Genetic testing will be conducted to look at the CYP450 genes, with particular focus 
on CYP 2C19 and CYP 3A4, involved in the metabolization of AEDs and 
GWP42003-P.     


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9.1.12 
Columbia Suicide Severity Rating Scale  
The C-SSRS is to be completed by the investigator or his/her qualified designee at all 
hospital visits. Qualified designee is defined as physician, osteopath, nurse 
practitioner, clinical psychologist or physician’s assistant who is licensed and has 
completed the C-SSRS training within the last two years. It is a brief standardized 
measure that uniquely assesses the essential information (behavior, ideation, lethality 
and severity) and distinguishes between suicidal occurrences and non-suicidal 
self-injury. The survey should be completed by the same assessor, where possible, 
throughout the study. 
If the investigator or his/her qualified designee feel that the patient is either unable to 
answer the questions presented in C-SSRS, or that the questions are causing undue 
stress to the patient, the questionnaire may be skipped and this must be documented in 
the patient notes. 
9.1.13 
Patient Diary 
Patients or their caregivers will be instructed on how to complete a paper diary and 
will be asked to record information daily in it. The number and type of seizures as 
well as information on AEs, concomitant AEDs and rescue medication will be 
collected each day from screening (Visit 1) until completion of dosing or withdrawal. 
Information on IMP intake will also be recorded each day from enrollment (Visit 2) 
until completion of dosing or withdrawal. 
9.1.14 
Investigational Medicinal Product Accountability 
GWP42003-P/placebo will be dispensed at each of the following visits during the 
blinded phase: 
• Visit 2 (Day 2) 
• Visit 4 (Day 34) 
IMP will be dispensed at each of the following visits for patients entering the OLE: 
• Visit 5 (Two weeks) 
• Visit 6 (One month) 
• Visit 7 (Two months) 
• Visit 8 (Three months) 
• Visit 9 (Six months) 
• Visit 10 (Nine months) 
• Visit 11 (12 months) 


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Patients will be asked to return all IMP (used and unused) to each relevant visit 
(Visits 2 to 12). The site will check the returned IMP against the usage recorded in the 
paper diary. Any discrepancies will be discussed with the patient/caregiver and 
documented accordingly within the patient’s source documents. 
9.1.15 
Adverse Events 
Any adverse changes in the patient’s medical condition, following completion of the 
consent form by the patient, will be recorded on the CRF as AEs, questioning the 
patient further if necessary. 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. 
*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. 
Serious Adverse Events (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. 
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 9.1.16.1.1 for the list of ‘Triggering AEs of Interest’ associated with 
monitoring of drug abuse liability.  
 
9.1.16 
Monitoring of Drug Abuse Liability 
There are two 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 (Visit 5 or Visit 12) or withdrawal visit 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. 


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9.1.16.1 
Monitoring of Adverse Events 
AE information will be collected according to Section 9.1.15.  
 
9.1.16.1.1 
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. 
• 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. 
 
9.1.16.1.2 
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. 
 


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9.1.16.2 
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 reported within the paper diary. 
• At any time that the site is informed by the patient/caregiver about any 
overuse of IMP, suspected misuse, abuse, or diversion. 
 
9.1.16.2.1 
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, according to the paper diary. 
• Returned IMP supply with evidence of tampering.  
• Greater than the target daily dose as recorded in the paper diary. 
 
 


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9.1.16.2.2 
Supplemental Drug Accountability Form 
This form consists of eight 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 or placebo, 
not other concomitant medications). 
 
9.1.16.3 
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. 
 
9.1.16.4 
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 (Visit 5 or Visit 12) or withdrawal visit. 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 in 
the study and not only those that have reported a triggering AE or drug accountability 
discrepancy. 
 


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9.1.16.5 
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. Only data from 
patients who have completed the study will be assessed.  
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  
 
 
 
 
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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9.2 
Study Procedures by Visit 
Patients and their caregivers will be invited to participate in the study and will be 
issued with the patient information and informed consent or the personal legal 
representative information and informed consent (refer to Section 9.1.2 and 
Section 15.2). Following adequate time to discuss the study with the investigator, 
nurse, relatives or caregiver, patients/legal representatives who provide written 
informed consent at Visit 1 will be screened for entry into the study. 
9.2.1 
Double Blind Phase 
9.2.1.1 
Visit 1 (Day −14 to −7, Screening) 
The following observations will be made at Visit 1: demographics, medical history 
(including seizure information since diagnosis, history of epilepsy-specific genetic 
testing and all prior AEDs taken), concomitant medications (including AEDs), 
physical examination (including height and body weight), ECG, vital signs and AEs. 
Clinical laboratory samples (blood and urine) will be taken for hematology, 
biochemistry, alcohol testing, THC testing, urinalysis and a pregnancy test (using a 
serum sample, if appropriate). The laboratory results should be available within 3-5 
working days after Visit 1. If the results show a patient is ineligible, the patient will 
not be enrolled into the study. The C-SSRS will be administered. 
Patients who satisfy all inclusion and none of the exclusion criteria specified in 
Section 6 will be assigned a unique patient number and then begin the baseline period. 
Patients or their caregivers will be given a paper diary to record daily seizure 
information, rescue medication, concomitant AEDs and AEs; and will be instructed 
on how to do so. The investigator must record the patient’s attendance at the visit and 
confirm the outcome of screening on the CRF.  
9.2.1.2 
Visit 2 
9.2.1.2.1 
Visit 2 (Day 1) – Enrollment (+3 days) 
This visit will occur 7–14 days after Visit 1. 
The following observations will be made at Visit 2: concomitant medications, 
(including AEDs), physical examination (including body weight), ECG, vital signs 
and review of patient diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for hematology, 
biochemistry, alcohol testing and urinalysis. Blood samples will also be taken for 
genetic testing if additional consent has been obtained. The C-SSRS will be 
administered. The investigator must record the patient’s attendance at the visit, and 
confirm the outcome of the visit prior to enrollment. 


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Following enrollment patients will begin the PK sampling process. Blood samples 
will be taken for analysis of plasma concentrations of CLB, N-CLB, CBD, CBD 
major metabolites, THC and THC major metabolites. A baseline PK sample will be 
taken before the patient takes their morning dose of CLB. Further samples will then 
be taken at the following times relative to the CLB dose: 15 minutes, 30 minutes, 
1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours and 12 hours. Patients will either remain 
in clinic overnight throughout this PK sampling process or return to the clinic on 
Day 2 ahead of additional sample collection. 
9.2.1.2.2 
Visit 2 (Day 2) - Enrollment 
This is the second part of the two day enrollment visit. The final PK sample will be 
collected 24 hours after the Day 1 morning CLB dose. 
Following completion of the PK sampling process the following observations will be 
made on Day 2: concomitant medications (including AEDs), physical examination 
(including body weight), vital signs and AEs. 
GWP42003-P/placebo will be dispensed and both the morning dose of CLB and of 
GWP42003-P/placebo will be taken in clinic. Patients and/or their caregivers will be 
provided with individual dosing schedules as described in Section 8.1.2. Each patient 
will then receive their GWP42003-P/placebo for the 10 day titration period followed 
by the 21 day maintenance period. Patients, or their caregivers, will be instructed on 
how to record the diary information. 
9.2.1.3 
Visit 3 (Day 12 +3 days) 
This visit will occur 11 days after Visit 2, Day 1 (enrollment). Patients will return all 
used and unused GWP42003-P/placebo. The following observations will be made at 
Visit 3 (Day 12): concomitant medications (including AEDs), physical examination 
(including body weight), ECG, vital signs, AEs and review of patient diary 
completion. 
Clinical laboratory samples (blood and urine) will be taken for hematology, 
biochemistry and urinalysis. The C-SSRS will be administered. 
9.2.1.4 
Visit 4 
9.2.1.4.1 
Visit 4 (Day 33) (±3 days) 
This visit will occur 32 days after Visit 2, Day 1 (enrollment). Patients will return all 
used and unused GWP42003-P/placebo. The following observations will be made at 
Visit 4 (Day 33): concomitant medications (including AEDs), physical examination 
(including body weight), ECG, vital signs, review of patient diary and AEs. 


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Clinical laboratory samples (blood and urine) will be taken for hematology, 
biochemistry, alcohol testing, and urinalysis. The C-SSRS will be administered.  
Blood samples will be taken for analysis of plasma concentrations of CLB, N-CLB, 
CBD, CBD major metabolites, THC and THC major metabolites. A baseline PK 
sample will be taken before the patient takes their morning dose of CLB, followed 
immediately by their dose of GWP42003-P/placebo. Further samples will then be 
taken at the following times relative to the CLB dose: 15 minutes, 30 minutes, 1 hour, 
1.5 hours, 2 hours, 4 hours, 6 hours and 12 hours. Patients are expected to remain in 
clinic throughout this PK sampling. 
The investigator must assess adherence to the dosing regimen and recording of rescue 
medications by reviewing the patient’s diary. 
9.2.1.4.2 
Visit 4 (Day 34) 
This is the second part of the two day visit. The final PK sample will be collected 
24 hours after the Day 33 morning CLB dose. 
Following completion of the PK sampling process the following observations will be 
made on Day 34: concomitant medications (including AEDs), physical examination 
(including body weight), vital signs and AEs. 
At the end of the blinded phase of the study on Day 34, providing the investigator and 
patient both agree, patients will be invited to continue taking GWP42003-P and to 
enter the OLE. 
Patients who enter the OLE will be dispensed GWP42003-P on Day 34. At the point 
of entry to the OLE, patients will be transitioned to the OLE treatment over a 10 day 
period in order to maintain blinding. The dose may be adjusted up or down by the 
investigator from the maintenance dose of 20 mg/kg/day in the blinded phase to a 
maximum of 30 mg/kg/day in the OLE. Patients and/or their caregivers will be 
provided with individual dosing schedules as described in Section 8.1.2. Patients, or 
their caregivers, will be instructed how to record the diary information. 
Patients who do not enter the OLE will begin a 10 day taper period during which they 
will taper off their daily dose of GWP42003-P/placebo. The daily dose will be 
reduced by 10% of the maintenance dose per day and treatment will end on Day 42. 
9.2.1.5 
Visit 5 (Patients not entering Open Label Extension) (Day 43 
+3 days) 
This visit will occur 42 days after Visit 2, Day 1 (enrollment) for those patients who 
do not enter the OLE. 


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All GWP42003-P/placebo (used and unused) will be collected and a check of the 
returned GWP42003-P/placebo against usage must be made. A physical examination 
(including body weight), ECG and vital signs will be assessed and the C-SSRS will be 
administered. The trained investigator or study coordinator will complete the Study 
Medication Use and Behavior Survey as an interview with the patient/caregiver. 
Clinical laboratory samples (blood and urine) will be taken for hematology, 
biochemistry and urinalysis and a review of concomitant medications (including 
AEDs) and AEs will be completed. Patient diaries will be collected. 
9.2.1.6 
Visit 6 - Safety Follow up Call (Day 71) (±3 days) 
This visit is required for patients who do not enter the OLE study on Day 34, or who 
withdraw from the study early. This visit should occur four weeks after Visit 5, 
(±3 days) or withdrawal from treatment, and can be conducted over the telephone. 
The following observations will be made on Day 71: concomitant medications 
(including AEDs) and AEs. 
9.2.2 
Open Label Extension 
Patients who enter the OLE will be dispensed IMP at Visit 4 (Day 34) and will have 
regular clinic visits for a maximum of one year or earlier (if marketing authorization 
is granted or the patient withdraws). The visit schedule is calculated relative to Visit 4 
(Day 34). 
9.2.2.1 
Visit 5 (Open Label Extension) - Two Weeks (±3 days) 
This visit will occur two weeks after Visit 4 (Day 34). Patients will return all used and 
unused IMP. The following observations will be made at Visit 5 (OLE): concomitant 
medications (including AEDs), physical examination (including body weight), ECG, 
vital signs, review of seizure diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for hematology, 
biochemistry and urinalysis. The C-SSRS will be administered. The investigator must 
record the patient’s attendance at the visit and the outcome. 
The investigator must assess adherence to the dosing regimen and recording of rescue 
medications by reviewing the patient’s diary. 
9.2.2.2 
Visit 6 (Open Label Extension) - One Month (±3 days) 
This visit will occur one month after Visit 4 (Day 34). Patients will return all used and 
unused IMP. The following observations will be made at Visit 6 (OLE): concomitant 
medications (including AEDs), physical examination (including body weight), ECG, 
vital signs, review of seizure diary and AEs. 


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Clinical laboratory samples (blood and urine) will be taken for hematology, 
biochemistry and urinalysis. The C-SSRS will be administered. The investigator must 
record the patient’s attendance at the visit and the outcome. 
The investigator must assess adherence to the dosing regimen and recording of rescue 
medications by reviewing the patient’s diary. 
9.2.2.3 
Visit 7 (Open Label Extension) - Two Months (±3 days) 
This visit will occur two months after Visit 4 (Day 34). Patients will return all used 
and unused IMP. The following observations will be made at Visit 7 (OLE): 
concomitant medications (including AEDs), physical examination (including body 
weight), ECG, vital signs, review of seizure diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for hematology, 
biochemistry and urinalysis. The C-SSRS will be administered. The investigator must 
record the patient’s attendance at the visit and the outcome. 
The investigator must assess adherence to the dosing regimen and recording of rescue 
medications by reviewing the patient’s diary. 
9.2.2.4 
Visit 8 (Open Label Extension) - Three Months (±7 days) 
This visit will occur three months after Visit 4 (Day 34). Patients will return all used 
and unused IMP. The following observations will be made at Visit 8 (OLE): 
concomitant medications (including AEDs), physical examination (including body 
weight), ECG, vital signs, review of seizure diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for hematology, 
biochemistry and urinalysis. The C-SSRS will be administered. The investigator must 
record the patient’s attendance at the visit and the outcome. 
The investigator must assess adherence to the dosing regimen and recording of rescue 
medications by reviewing the patient’s diary. 
9.2.2.5 
Visit 9 (Open Label Extension) - Six Months (±7 days) 
This visit will occur six months after Visit 4 (Day 34). Patients will return all used 
and unused IMP. The following observations will be made at Visit 9 (OLE): 
concomitant medications (including AEDs), physical examination (including body 
weight), ECG, vital signs, review of seizure diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for hematology, 
biochemistry and urinalysis. The C-SSRS will be administered. The investigator must 
record the patient’s attendance at the visit and the outcome. 


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The investigator must assess adherence to the dosing regimen and recording of rescue 
medications by reviewing the patient’s diary. 
9.2.2.6 
Visit 10 (Open Label Extension) - Nine Months (±7 days) 
This visit will occur nine months after Visit 4 (Day 34). Patients will return all used 
and unused IMP. The following observations will be made at Visit 10 (OLE): 
concomitant medications (including AEDs), physical examination (including body 
weight), ECG, vital signs, review of seizure diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for hematology, 
biochemistry and urinalysis. The C-SSRS will be administered. The investigator must 
record the patient’s attendance at the visit and the outcome. 
The investigator must assess adherence to the dosing regimen and recording of rescue 
medications by reviewing the patient’s diary. 
9.2.2.7 
Visit 11 (Open Label Extension End of Treatment) - Twelve 
Months (±7 days) 
This visit will occur twelve months after Visit 4 (Day 34). Patients will return all used 
and unused IMP. The following observations will be made at Visit 11 (OLE): 
concomitant medications (including AEDs), physical examination (including body 
weight), ECG, vital signs, review of seizure diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for hematology, 
biochemistry and urinalysis. The C-SSRS will be administered. The investigator must 
record the patient’s attendance at the visit and the outcome. 
The investigator must assess adherence to the dosing regimen and recording of rescue 
medications by reviewing the patient’s diary. 
Starting at Visit 11, patients will begin to taper down their IMP dose. The dose will be 
reduced by 10% of their OLE maintenance dose per day. 
9.2.2.8 
Visit 12 (Open Label Extension End of Taper) 
This visit will be ten days after Visit 11. All IMP (used and unused) will be collected 
and a check of the returned IMP against usage must be made. A physical examination 
(including body weight), ECG and vital signs will be assessed and the C-SSRS will be 
administered. The trained investigator or study coordinator will complete the Study 
Medication Use and Behavior Survey as an interview with the patient/caregiver. 
Clinical laboratory samples (blood and urine) will be taken for hematology, 
biochemistry and urinalysis and a review of concomitant medications (including 
AEDs) and AEs will be completed. Patient diaries will be collected and reviewed. 


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9.2.2.9 
Safety Follow Up Call (±3 days) 
This visit will occur one month after the OLE End of Taper and can be conducted 
over the telephone. The following observations will be made during the follow up 
call: concomitant medications (including AEDs) and AEs. 
10. WITHDRAWAL 
In accordance with the Declaration of Helsinki31, the FDA regulations relating to 
good clinical practice (GCP) and clinical trials32,33,34, the EU Clinical Trials Directive 
(2001/20/EC)35 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. 
• Withdrawal of legal representative consent. 
• Lost to follow up. 
• ALT >3 × ULN 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 two weeks. 
• Any other IMP is taken as part of a clinical trial during the study.  
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 four or five during the treatment period, 
as evaluated with the C-SSRS. 
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 


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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 Visit 4 (if the withdrawal is during the blinded phase) or Visit 11 (if the 
withdrawal is during the OLE) should be conducted if possible. If the tapered dose is 
administered, patients should return for Visit 5 (if withdrawal is during the blinded 
phase) or Visit 12 (if the withdrawal is during the OLE) if possible. Wherever 
possible, the safety follow-up visit should be conducted 28 days from the date of the 
last dose of IMP. Patients withdrawing due to an AE should be followed up according 
to Section 12.7. All information should be reported on the applicable CRF pages 
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 three days. 
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 screening (Visit 1) throughout the study and up to the post treatment, safety 
follow-up visit (28 days after last dose of IMP), 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). 


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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 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 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., an 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. 
• 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 


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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 visit (Visit 13 for patients entering the OLE and Visit 6 for those 
patients that are not entering the OLE). If the investigator subsequently becomes 
aware of any deaths or a 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. 
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 study medication must be reported as such. The 


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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 study medication: 
“In your opinion is there a plausible relationship to the study medication?” The 
answer is “yes” or “no”. 
Events that start before the first dose of study medication (pre-treatment) should be 
considered as not causally related. Where a pre-treatment event worsens in severity 
following the first dose of study medication, 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 study medication but also competing etiological 
factors as the underlying cause. Factors for consideration may include: 
• Medical history. 
• Lack of efficacy/worsening of treated condition. 
• Concomitant or previous treatment. 
• Withdrawal of study medication. 
• Protocol-related procedure. 
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 
screening (Visit 1) to post study follow-up (Visit 13 for patients entering the OLE and 
Visit 6 for those patients that are not entering the OLE). 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: 


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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 for the 
following categories: 
• Recovered. 
• Recovered with sequelae. 
• Continuing. 
• 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 
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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 occurs, 
the patient must undergo an end of treatment assessment and be given appropriate 
care under medical supervision until symptoms cease or the condition becomes stable. 
12.8 
Potential Cases of Drug Induced Liver Injury   
All investigational sites 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 two weeks. 


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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 hours of notice of abnormal results) 
for repeat assessment of ALT, AST, TBL and alkaline phosphatase levels, detailed 
history and physical examination. Patients should be followed until all abnormalities 
have normalized (in the investigator’s opinion) or returned to the baseline state. 
Elevations in ALT or AST >3 × ULN or TBL >2 × ULN alone are not considered 
potential cases of drug-induced liver injury, but will be followed as detailed above, 
within 72 hours’ notice of abnormal results. If the participant cannot return to the 
investigational center, repeat assessments may be done at a local laboratory and the 
results sent to GW PVD. 
12.9 
Notification of Safety Information to Investigators, Regulatory 
Authorities and Ethics Committees. 
In accordance with the EU Clinical Trials Directive35, relevant parts of the FDA Code 
of Federal Regulations 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 three sources: 
• Investigator Brochure36: 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 
participants. The IB is updated annually. 
• Development Core Safety Information: this document actually forms the 
Safety Section of the IB36, or is updated as an appendix of the IB36. This 
document is revised if necessary, when new important safety information 
becomes available (potentially up to a few times a year). 
• 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 IRB/EC 
of SAEs or SUSARs occurring at their site and other AE reports, i.e., CIOMS 


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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 guidance32 
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, 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 guidance37 states that, accordingly, to satisfy the investigator’s obligation to 
notify the IRB of unanticipated problems, any investigators participating in a 
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/EC’s) 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 ethics approval and final database lock. 


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13. 
STATISTICAL CONSIDERATIONS 
A statistical analysis plan (SAP) will be produced prior to the database lock and 
analysis of the study. Any deviations from the original SAP will be described in the 
final clinical study report. 
13.1 
Sample Size, Power and Significance Levels 
A total of 20 patients will be enrolled in this study. There is no formal sample size: 
Calculation and analysis is descriptive only. 
13.2 
Interim Analysis 
An interim analysis will be conducted at the end of the Double Blind phase of the 
study and may also be considered during the OLE phase, if long term data is required 
to support New Drug Application/Marketing Authorization Application submissions. 
13.3 
Analysis Sets 
13.3.1 
Safety Set 
All subjects who are treated and receive at least one dose of IMP will be included. 
The Safety set is the primary analysis set for all safety endpoints. 
13.3.2 
Pharmacokinetic Analysis Set  
All subjects who are treated and receive at least one dose of IMP and who provide 
some on-treatment data will be included. 
The PK analysis set is the primary analysis set for all PK endpoints. 
13.3.3 Protocol Deviations 
Any protocol deviations will be listed and reasons for exclusion from the analysis 
populations 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 in each category. Summaries will be presented for data 
recorded pre-treatment, during each 25 day dosing phase (placebo and GWP42003-P) 
and during the OLE phase separately. 


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13.5 
Accountability and Background Characteristics 
13.5.1 Enrollment and Disposition 
All patients (screened, treated, completing the study and those 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 and the types of seizures currently 
experienced by the patients. 
13.5.4 Concomitant Medication 
Concomitant medications taken prior to and during the study will be summarized, by 
medication class and active ingredients. Summaries of medications taken during the 
IMP treatment phases and during OLE will be presented separately. 
13.6 
Endpoints and Statistical Methods 
13.6.1 Primary Endpoint(s) 
The primary endpoints of the study are the PK parameters (Cmax, tmax, AUC(0–∞), 
AUC(0–t), t½) of the following analytes: 
• CLB 
• N-CLB 
• CBD 
• CBD major metabolites 
13.6.2 Secondary Endpoint(s) 
The secondary endpoints of the study are the safety parameters (see Section 13.6.4) 
and the PK parameters (Cmax, tmax, AUC(0–∞), AUC(0–t), t½) of the following analytes: 
• THC 
• THC major metabolites 


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13.6.3 Pharmacokinetics 
Calculation of PK parameters will be based on actual blood sampling times [h] 
(relative to the corresponding administration time) rounded to two decimal digits with 
negative pre-dose times set to zero. Plasma concentrations of CLB, N-CLB, CBD, 
CBD major metabolites, THC and THC major metabolites will be displayed 
graphically, summarized and listed. For descriptive statistics, values below the lower 
limit of quantification of the assay (LLOQ) will be excluded from any calculations. 
Descriptive statistics of concentrations will be calculated if at least half of the 
individual data points that have been measured are equal to or above the LLOQ. 
For calculation of the PK parameters, the following rules will be applied: 
At time zero and at time points in the lag-time between time zero and the first 
quantifiable concentration, concentrations below the LLOQ will be set to zero. All 
other concentrations below the LLOQ will not be used in calculations. 
Variables derived from plasma concentrations: 
• Concentration maximum (Cmax): Highest observed plasma concentration of the 
measured concentration-time profile. Dimension: [amount / volume]. 
• Terminal half-life t½= ln(2)/λz. 
• The rate constant of the terminal phase λz will be determined by linear 
regression of log-transformed concentration data after the time of maximum 
concentration. A sequence of terminal elimination rate constants will be 
created by linear regression. Linear regressions are repeated using the last 
three points with a quantifiable concentration, the last four points, the last five 
points etc. For each regression, an adjusted R2 is computed. The regression 
with the largest adjusted R2 is selected to estimate the terminal half-life. 
Dimension: [time]. 
• Area under the concentration-time curve from administration until the last 
sampling point (t) equal or above the LLOQ AUC(0–t) will be calculated by the 
linear trapezoidal formula. Dimension: [time • amount / volume]. 
• Area under the concentration-time curve extrapolated to infinity: AUC(0–∞) = 
AUC(0–t) + Clast/λz and Clast is the concentration observed at the last time point 
with a quantifiable concentration, λz refers to the terminal elimination rate 
constant. Dimension: [time • amount / volume]. 
• Time of maximum concentrations: Tmax will be taken as the time after 
administration at which Cmax occurs. Dimension: [time]. 
• PK parameters for each analyte will be summarized for the two treatment 
phases of the study separately, as appropriate. 
• In order to assess whether the presence of CBD alters the PK profile of CLB 
(or N-CLB), a standard 90% confidence interval (CI) approach for the 
between group ratios of geometric means of Cmax, AUC(0–t), and AUC(0–∞) will 
be carried on logarithm scale using a linear mixed effect model with treatment 


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(CLB or CLB+CBD) as a fixed effect and subject as a random effect. The no-
effect boundary will be set between 0.5 and 2.0 and if the 90% CI for the ratio 
of the geometric means of a PK variable falls within the interval [0.5, 2.0], a 
lack of meaningful effect will be declared. 
13.6.4 Safety 
13.6.4.1 
Treatment Compliance and Extent of Treatment Exposure 
Treatment compliance and exposure to treatment will be summarized for each phase 
of the study separately. 
13.6.4.2 
Adverse Events 
AEs will be coded according to the Medical Dictionary for Regulatory Activities 
dictionary. 
A treatment emergent AE is one that started, or worsened in severity or seriousness, 
following the first dose of IMP. 
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. Summaries will be provided for each phase of the 
study separately. 
The following summaries will be produced: 
• 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. 
13.6.4.3 
Clinical Laboratory Data 
Clinical laboratory data at screening and at the end of the 31 day treatment phase and 
the change from baseline to end of treatment (OLE) 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. 


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13.6.4.4 
Columbia-Suicide Severity Rating Scale, Vital Signs, 12-lead 
Electrocardiogram, Physical Examination and Other Safety 
Data 
The C-SSRS, vital signs, ECG and physical examination data will be summarized at 
screening, at the end of the 31 day treatment phase and during the OLE treatment 
period using appropriate summary statistics. Changes in the vital signs from baseline 
to end of each treatment phase will also be summarized. 
13.6.4.5 
Seizure Data 
Seizure data collected during the 31 day treatment phase and during the OLE phase of 
the study will be summarized using appropriate summary statistics. 
14. 
DATA SAFETY MONITORING COMMITTEE 
GW does not plan to use an independent data safety monitoring committee as part of 
this study. 


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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 
the31,35and the clinical trial regulations adopting European Commission Directives 
into national legislation38,39,40. 
15.2 
Informed Consent 
Initial master informed consent forms will be provided to the investigator to prepare 
the informed consent documents to be used at his or her center. The GW Clinical 
Manager will communicate updates to the templates by letter. The written informed 
consent 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 from the patient or 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, or their legal representative, should have ample time for 
review to consider the information provided before giving written consent; more 
specific definitions of ample time may be in force if required by IRB/ECs or local 
regulations. 
The acquisition of informed consent should be documented in the patient’s medical 
records and the informed consent form should be signed and personally dated by the 
patient or legal representative (as applicable) and by the person who conducted the 
informed consent discussion. GW also requires a physician to be present for consent 
and to sign the consent forms as well. The original signed informed consent forms 
should be retained and a copy provided to the patient or legal representative. 
15.3 
Institutional Review Board/Ethics Committee 
A copy of the protocol, proposed informed consent 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 forms before enrollment of 
patients into the study and shipment of IMP. 
The investigator must submit and, where necessary, obtain approval from the IRB/EC 
for all subsequent protocol amendments and changes to the informed consent 


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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 for entry into the study: 
• Signed and dated protocol signature page. 
• Copy of approved informed consent forms and other patient information 
material. 
• Copy of the IRB/EC approval of the protocol, informed consent forms and 
other patient information material. 
• Up to date curricula 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 
trials32,33,34,41, the EU Clinical Trials Directive35, or International Conference 
on Harmonization Tripartite Guideline for Good Clinical Practice (ICH 
GCP)42 where the EU 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 
Participant 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 forms should be kept in strict confidence by the 
investigator. 
In compliance with the FDA regulations relating to good clinical practice and clinical 
trials32,33,34,41, and the EU Clinical Trials Directive35/ICH GCP Guidelines42, it is 


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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 documents. The IRB/EC and Competent Authorities must be 
informed of all amendments and give approval for any substantial amendments prior 
to implementation. The investigator must send a copy of the approval letter from the 
IRB/EC to GW. Amendments for administrational changes can be submitted to the 
IRB/EC for information only. 
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. In the rare situations of this happening, 
then the source data from the CRF should be transcribed in the patient’s notes with 
appropriate signature and date to provide a full audit trail. 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. 
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 8.242), 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 forms and 
supporting copies of source documentation. 


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• 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. 
• 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, paper 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 two 
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 two 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 1643). 
GW will inform the investigators for each site 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 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. 


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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 five working days after 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 regulations32,33,34,41, the ICH GCP 
Guideline42, and all other applicable regulatory requirements35,42, 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. 


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• 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. 
16.4 
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. 
16.5 
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. 
16.6 
Publication Policy 
GW recognizes that there is a responsibility under the regulatory guidelines to ensure 
that results of scientific interest arising from this clinical 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 


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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 six months from the date of first submission to them in order to allow them to 
take steps to protect proprietary information where applicable. 
16.7 
Intellectual Property Rights 
All Intellectual Property Rights owned by or licensed to either GW or the PIs, other 
than those arising from the clinical 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. 
16.8 
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. REFERENCES 
1 
Bergen DC.  Preventable neurological diseases worldwide.  Neuroepidemiology, 
1998, 17(2): 67-73. 
2 
Sander JW.  The epidemiology of epilepsy revisited.  Curr Opin Neurol, 2003, 
16(2): 165-170. 
3 
MacDonald BK, Cockerell OC, Sander JW and Shorvon SD.  The incidence and 
lifetime prevalence of neurological disorders in a prospective community-based 
study in the UK.  Brain, 2000, 123(4): 665-676. 
4 
Forsgren L, Beghi E, Oun A and Sillanpää M.  The epidemiology of epilepsy in 
Europe – a systematic review.  Eur J Neurol, 2005, 12(4): 245-253. 
5 
Duncan JS, Sander JW, Sisodiya SM and Walker MC.  Adult epilepsy.  The 
Lancet, 2006, 367(9516): 1087-1100. 
6 
Committee for medicinal products for human use. Guideline on clinical 
investigation of medicinal products in the treatment of epileptic disorders, 22 July 
2010, CHMP/EWP/566/98 Rev.2/Corr. 
7 
Sander JS.  Some aspects of prognosis in the epilepsies: a review.  Epilepsia, 
1993, 34(6): 1007-1016. 
8 
Kwan P and Brodie MJ.  Early Identification of Refractory Epilepsy.  N Engl J 
Med, 2000, 342(5): 314-319. 
9 
Kwan P and Brodie MJ.  Emerging drugs for epilepsy.  Expert Opin Emer Drugs, 
2007, 12(3): 407-422. 
10 Schachter SC.  Currently available antiepileptic drugs.  Neurotherapeutics, 2007, 
4(1): 4-11. 
11 Martin J.  British National Formulary. 2013, Pharmaceutical Press London. 
12 Bialer M and White HS.  Key factors in the discovery and development of new 
antiepileptic drugs.  Nat Rev Drug Discov, 2010, 9(1): 68-82. 
13 Czapiński P, Blaszczyk B and Czuczwar SJ.  Mechanisms of action of 
antiepileptic drugs.  Curr Top  Med Chem, 2005, 5(1): 3-14. 
14 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. 
15 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. 
16 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. 
17 Zuardi AW, Morais SL, Guimarães FS, Mechoulam R. Antipsychotic effect of 
cannabidiol. J Clin Psychiatry 1995;56(10):485-6. 
18 Jones NA, Hill AJ, Smith I, Bevan SA, Williams CM, Whalley BJ et al. 
Cannabidiol displays antiepileptiform and antiseizure properties in vitro and in 
vivo. J Pharmacol Exp Ther 2010;332(2):569-77. 


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19 Jones NA, Glyn SE, Akiyama S, Hill TD, Hill AJ, Weston SE et al. Cannabidiol 
exerts anti-convulsant effects in animal models of temporal lobe and partial 
seizures. Seizure 2012;21(5):344-52. 
20 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. 
21 Gover J, Schultz, S. GW Pharmaceuticals announces new physician reports of 
Epidiolex treatment effect in children and young adults with treatment-resistant 
epilepsy [press release]. United Kingdom: GW Pharma Ltd; 2014 Oct 14. 
22 Johannessen Landmark C, Larsson PG, Rytter E, Johannessen SI. Antiepileptic 
drugs in epilepsy and other disorders: a population-based study of prescriptions. 
Epilepsy Res. 2009, 87(1):31-39 
23 Tsiropoulos I, Gichangi A, Andersen M, Bjerrum L, Gaist D, Hallas J. Trends in 
utilization of anti-epileptic drugs in Denmark. Acta Neurol. Scand. 2006, 113, 
405-411 
24 van de Vrie-Hoekstra NW, de Vries TW, van den Berg PB, Brouwer OF, de Jong-
van den Berg LT. Antiepileptic drug utilization in children from 1997-2005 - a 
study from the Netherlands. Eur J Clin Pharmacol. 2008, 64: 1013-1020. 
25 Johannessen Landmark C, Rytter E, Johannessen SI. Clinical use of antiepileptic 
drugs at a referral centre for epilepsy. Seizure. 2007, 16:356-364 
26 Rytter E, Johannessen Landmark C, Johannessen SI. Antiepileptic drug treatment 
of children at a referral centre for epilepsy - does admission make a difference? 
Seizure. 2009, 18:573-579 
27 Contin M, Riva R, Albani F, Baruzzi A. Effect of felbamate on clobazam and its 
metabolite kinetics in patients with epilepsy. Ther Drug Monit. 1999, 21:604-608 
28 Levy RH, Lin HS, Blehaut HM, Tor JA. Pharmacokinetics of stiripentol in normal 
man: evidence of non-linearity. J Clin Pharmacol. 1983, 23 (11-12):523-533. 
29 Tran A, Vauzelle-Kervroedan F, Rey E, Pous G, d´Athis P, Chiron C, Dulac O, 
Renard F, Olive G. Effect of stiripentol on carbamazepine plasma concentration 
and metabolism in epileptic children. Eur J Clin Pharmacol. 1996, 50:497-500. 
30 Trojnar MK, Wojtal K, Trojnar MP, Czuczwar SJ. Stiripentol. A novel 
antiepileptic drug. Pharmacol Rep. 2005, 57:154-160. 
31 World Medical Association Declaration of Helsinki — Ethical principles for 
medical research involving human subjects. October 2013. 
32 U.S. Food and Drug Administration Code of Federal Regulations Title 21 (Food 
and Drugs) Part 50 — Protection of human subjects. April 2014. 
33 U.S. Food and Drug Administration Code of Federal Regulations Title 21 (Food 
and Drugs) Part 312 — Investigational New Drug application. April 2014. 
34 U.S. Food and Drug Administration Code of Federal Regulations Title 21 (Food 
and Drugs) Part 56 — Institutional Review Boards. April 2014. 
35 Directive 2001/20/EC  of the European Parliament and of the Council of 04 April 
2001 on the approximation of the laws, regulations and administrative provisions 
of the Member States relating to the implementation of good clinical practice in 
the conduct of clinical trials on medicinal products for human use. Official Journal 
of the European Communities L 121, 1/5/2001 p. 34–44. 


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36 Investigator Brochure — CBD medicine. GW Pharma Ltd. Edition 7, August 
2014. 
37 U.S. Food and Drug Administration guidance for clinical Investigators, Sponsors, 
and IRBs: Adverse Event reporting to IRBs — Improving human subject 
protection. January 2009. 
38 UK Statutory Instrument 2004/1031 — The medicines for human use (clinical 
trials) regulations 2004. May 2004. 
39 UK Statutory Instrument 2006/1928 — The medicines for human use (clinical 
trials) amendment regulations 2006. August 2006. 
40 UK Statutory Instrument 2006/2984 — The medicines for human use (clinical 
trials) amendment (No.2) regulations 2006. December 2006. 
41 U.S. Food and Drug Administration Code of Federal Regulations Title 21 (Food 
and Drugs) Part 11 — Electronic records; electronic signatures (Subpart B — 
Electronic records). April 2014. 
42 International Conference on Harmonisation Topic E6(R1): Guideline for good 
clinical practice — Note for guidance on good clinical practice 
(CPMP/ICH/135/95). July 2002. 
43 Commission Directive 2005/28/EC of 08 April 2005 laying down the principles 
and detailed guidelines for GCP as regards investigational medicinal products for 
human use, as well as the requirements for authorisation of the manufacturing or 
importation of such products. Official Journal of the European Union L 91, 
9/4/2005 p. 13–19. 
 
 
 
 
 
 
 
 
 
 


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APPENDIX 1. SCHEDULE OF ASSESSMENTS 
Visit Number 
Day 
(Visit Window) 
Visit 1 
Day -14 to -7 
 
Visit 2 
Day 1 
(+ 3 days) 
Visit 2 
Day 2 
 
Visit 3 
Day 12 
(+ 3 days) 
Visit 4 
Day 33 
(± 3 days) 
Visit 4 
Day 34 
 
Visit 5* 
End of Taper 
 
Visit 6* 
4wk SFU 
(± 3 days) 
Informed consent 
X 
 
 
 
 
 
 
 
Eligibility criteria 
X 
X 
 
 
 
 
 
 
Enrollment 
 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
Paper diary training 
X 
 
X 
 
 
 
 
 
Concomitant medications 
(including AEDs) 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
(including height and body 
weight)♥ 
X 
X 
X 
X 
X 
X 
X 
 
ECG 
X 
X 
 
X 
X 
 
X 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical laboratory blood 
sampling  
X 
X 
 
X 
X 
 
X 
 
Clinical laboratory urine 
sampling (dipstick 
urinalysis) 
X 
X 
 
X 
X 
 
X 
 
THC test 
X 
 
 
 
 
 
 
 
Alcohol Test 
X 
X 
 
 
X 
 
 
 
Pregnancy test (if 
appropriate) 
X 
 
 
 
 
 
 
 
Pharmacokinetic blood 
sampling**  
 
X 
X 
 
X 
X 
 
 


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Visit Number 
Day 
(Visit Window) 
Visit 1 
Day -14 to -7 
 
Visit 2 
Day 1 
(+ 3 days) 
Visit 2 
Day 2 
 
Visit 3 
Day 12 
(+ 3 days) 
Visit 4 
Day 33 
(± 3 days) 
Visit 4 
Day 34 
 
Visit 5* 
End of Taper 
 
Visit 6* 
4wk SFU 
(± 3 days) 
Sample for Genetic 
Testing*** 
 
X 
 
 
 
 
 
 
C-SSRS 
X 
X 
 
X 
X 
 
X 
 
Patient diary review 
(seizures, AE information, 
concomitant AEDs, rescue 
medication, IMP dosing) 
 
X 
 
X 
X 
 
X 
 
IMP dispensing 
 
 
X 
 
 
X 
 
 
Collection of IMP 
 
 
 
X 
X 
 
X 
 
IMP compliance review 
 
 
 
X 
X 
 
X 
 
Study Medication Use and 
Behavior Survey 
 
 
 
 
 
 
X 
 
* Patients not entering the OLE 
**PK Sampling time points are as follows: Pre-dose and 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 12 hours and 24 hours after 
dosing. For the second PK visit the patient should take the GWP42003-P/placebo immediately after their daily dose of CLB. 
*** Samples for genetic testing will only be taken if additional consent is obtained. 
♥ Patients height measured at Visit 1 only. 
 
 


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Open Label Extension Schedule of Assessments 
 
 
Visit Number 
Day 
(Visit Window) 
Visit 5 
2 Weeks 
(+ 3 days) 
Visit 6 
1 Month 
(± 3 days) 
Visit 7 
2 Months 
 (± 3 days) 
Visit 8 
3 Months 
(± 7 days) 
Visit 9 
6 Months 
 (± 7 days) 
Visit 10 
9 Months 
(± 7 days) 
Visit 11 
12 Months 
 (± 7 days) 
Visit 12 
End of 
Taper 
 
Visit 13 
4wk SFU 
(± 3 days) 
Paper diary training 
 
 
 
 
 
 
 
 
 
Concomitant medications 
(including AEDs) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
(including weight) 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECG 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical laboratory blood 
sampling  
X 
X 
X 
X 
X 
X 
X 
X 
 
Clinical laboratory urine 
sampling (dipstick 
urinalysis) 
X 
X 
X 
X 
X 
X 
X 
X 
 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
X 
 
Patient diary review 
(seizures, AE 
information, concomitant 
AEDs, rescue medication, 
IMP dosing) 
X 
X 
X 
X 
X 
X 
X 
X 
 
IMP dispensing 
X 
X 
X 
X 
X 
X 
X 
 
 
Collection of IMP 
X 
X 
X 
X 
X 
X 
X 
X 
 
IMP compliance review 
X 
X 
X 
X 
X 
X 
X 
X 
 
Study Medication Use 
and Behavior Survey 
 
 
 
 
 
 
 
X 
 


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APPENDIX 2. STUDY PERSONNEL 
Appendix 3.1 
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 3.2 
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: 
 
Fax: 
 
Medical Monitor 
EU 
 
  
Tel: 
 
Mobile:
 
USA 
 
 
Tel: 
 
Mobile: 
  
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Version 2 Date 09 Jul 15 
 
 
 
 
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Clinical Project Manager/Clinical Operations 
Director: 
GW Research Ltd 
Sovereign House 
Vision Park 
Chivers Way 
Histon 
Cambridge CB24 9BZ 
United Kingdom 
Tel: 
 
Fax: 
 
Clinical Trials Supplies: 
GW Pharma Ltd 
Tel: 
 
Fax: 
 
 
 
 
 
 
PPD
PPD
PPD
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Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Version 1 Date 08 Oct 15 
 
 
 
 
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TITLE: A phase 2, double-blind, randomized, placebo-controlled study to investigate 
possible drug-drug interactions between clobazam and cannabidiol (GWP42003-P) 
STUDY CODE: GWEP1428 
EudraCT NUMBER: 2014-002942-33 
 
PROTOCOL AMENDMENT NUMBER: 2  
 
to be incorporated into the Protocol, creating 
PROTOCOL VERSION 3, DATE 08 OCT 2015 
 
 
 
 
GW RESEARCH LTD 
SOVEREIGN HOUSE 
VISION PARK 
CHIVERS WAY 
HISTON 
CAMBRIDGE CB24 9BZ 
UNITED KINGDOM 
TEL: 
   FAX: 
 
 
 
 
 
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. 
PPD
PPD


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Version 1 Date 08 Oct 15 
 
 
 
 
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1. 
PROTOCOL SYNOPSIS 
Study Title  
A phase 2, double-blind, randomized, placebo-controlled study to 
investigate possible drug-drug interactions between clobazam and 
cannabidiol (GWP42003-P) 
Indication 
Epilepsy 
Study Design 
This is a phase 2, double-blind, randomized, placebo-controlled study in 
20 patients. 
• Patients will be randomized in a 4:1 ratio to receive 20 mg/kg 
cannabidiol (CBD) or placebo from days 2 to 33.  
• 
At the end of the treatment period, patients will be given the option of 
continuing onto an open label extension (OLE) period if the investigator 
and patient both agree that it is in their best interests. Doses may be 
adjusted up or down, dependent on investigator opinion, to a maximum 
of 30 mg/kg/day GWP42003-P. The OLE will last for a maximum of 
one year or until marketing authorization is granted; whichever is 
earlier. 
• 
Patients that do not continue onto the OLE will taper off of GWP42003-
P over a 10 day period and will have a telephone follow-up visit four 
weeks after the end of taper day on Day 71. 
• Day 1 (Visit 2), patients will not be dosed with GWP42003-P/placebo 
but will continue to take CLB at a stable dose. 
• Day 2 (Visit 2), patients will begin the up-titration with GWP42003-P or 
placebo to a maintenance dose or an equivalent maintenance dose of 
20 mg/kg/day over a period of 10 days (Days 2 to 11). 
• Day 12 (Visit 3), patients will attend the study site to check safety and 
compliance. 
• After up-titration with GWP42003-P or placebo, the patients will remain 
on the maintenance dose for 21 days (Days 12 to 32). 
• On Day 34 (Visit 4), patients will be invited to receive GWP42003-P in 
the OLE period. If the patient enters the OLE period of the study, the 
patient will continue to take GWP42003-P as advised by the 
investigator. 
• If the patient does not enter the OLE period of the study, the patient will 
taper off of GWP42003-P by reducing the dose by approximately 10% 
of the maintenance dose each day until dosing has ceased, with end of 
taper on Day 43 (Visit 5). 
Pharmacokinetic (PK) samples will be taken on the day of enrollment 
(Visit 2, Day 1) and after completing 21 days treatment on GWP42003-P or 
placebo (Visit 4, Day 33). The PK assessments will therefore capture the 
following combinations of CLB and GWP42003-P: 
• First PK Assessment: CLB only. 
• Second PK Assessment: CLB and GWP42003-P or placebo. 
Each PK assessment should be performed at time points in respect to a 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Version 1 Date 08 Oct 15 
 
 
 
 
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morning dose of CLB. The time points are as follows: Pre-dose, 15 min, 
30 min, 1h, 1.5h, 2h, 4h, 6h, 12h and 24h. It is expected that the patient will 
continue to take their CLB as advised by their physician and PK 
assessments will be scheduled in order to accommodate this dosing 
schedule. The GWP42003-P/placebo should be taken twice daily 
immediately following their CLB dose. 
PK assessments will analyze the amount of CLB, the CLB primary 
metabolite N-CLB, CBD, CBD major metabolites, ∆9-tetrahydrocannabinol 
(THC) and THC major metabolites, valproate, stiripentol, levetiracetam and 
topiramate. Patients will be required to keep a paper diary to note the time 
and dose of GWP42003-P and CLB administration each morning and 
evening and to record any adverse events (AEs) that may occur whilst 
receiving investigational medicinal product (IMP) and any other 
medications. Patients will also be requested to record the number and type 
of seizures for each day whilst on the study. 
Sponsor 
GW Research Ltd 
Sovereign House 
Vision Park 
Chivers Way 
Histon 
Cambridge CB24 9BZ 
United Kingdom 
 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
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2. 
TABLE OF CONTENTS 
1. 
PROTOCOL SYNOPSIS 
2 
2. 
TABLE OF CONTENTS 
4 
2.1 
Table of Appendices 
4 
3. 
RATIONALE 
5 
3.1 
Secondary Endpoints 
5 
3.2 
Exclusion/Withdrawal Criteria 
5 
3.3 
Laboratory tests 
5 
3.4 
Procedures 
5 
3.5 
Administrative Changes 
6 
4. 
IMPLEMENTATION OF THE AMENDMENT 
6 
5. 
PRESENTATION OF AMENDED TEXT 
7 
 
LIST OF APPENDICES 
Appendix 1 Changes to Protocol Table 8.1.2-1 ................................................................. 14 
 
 
 


Study Code: GWEP1428 
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3. 
RATIONALE 
This protocol amendment 2 (will be incorporated into the Protocol creating Protocol 
Version 3, date 08 Oct 15) addresses the following issue(s): 
3.1 
Secondary Endpoints 
A blood draw for CYP2C19 and CPY3A4 genotype analysis was added in protocol 
amendment 1. The analysis for these samples is added in protocol amendment 2 as a 
secondary endpoint. 
3.2 
Exclusion/Withdrawal Criteria 
The following exclusion/withdrawal criteria have been added / amended: 
• Addition of exclusion criterion: Patients taking felbamate for less than 1 year prior to 
screening. Aplastic anemia and liver toxicity with felbamate has the greatest risk in 
the first year of treatment, therefore exclusion criterion added to mitigate that risk. 
• Amended exclusion criterion regarding travel outside of the country of residence to 
clarify that this is allowed if the patient has confirmation that the IMP is permitted in 
the destination country. 
• Addition of exclusion criterion: Patient has a prolonged QTcB (>450 msec for males 
and >470 msec for females). Exclusion criterion added as a safety precaution as a 
formal QTc study has not yet been completed with GWP42003-P.  
• 
Addition of withdrawal criterion: Significant change in QTcB (>60 msec) from the previous 
ECG or absolute QTcB of >500msec.Withdrawal criterion added as a safety 
precaution as a formal QTc study has not yet been completed with GWP42003-P.  
3.3 
Laboratory tests 
The following changes have been made to the laboratory tests and PK analyses: 
• PK analysis for CBD, CBD major metabolites, THC and THC major metabolites will 
not be conducted on the visit 2 blood samples as patients will not have been exposed 
to CBD at this point. 
• PK analysis to be done at visit 2 and visit 4 for stiripentol, valproate, levetiracetam 
and topiramate if the patient is taking any of these. 
• In cases of elevated liver enzymes, the patient must come back into site for repeat 
testing. Gamma-glutamyl transferase has been added as an analyte to the required 
analytes to be tested at the recommendation of the FDA. 
 
3.4 
Procedures 
The following clarifications have been made to the study procedures: 
• On the enrollment visit (visit 2, day 2), patients must remain in clinic for at least 
30 minutes to monitor for any adverse reactions. 


Study Code: GWEP1428 
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• For the PK visits, clarification has been added that the evening dose of 
GWP42003-P/placebo and any AEDs the patient is taking must be taken after the 12 
hour PK blood draw. 
• Clarification that the dose of GWP42003-P can only be adjusted to 30 mg/kg/day 
from visit 5 onwards rather than visit 4 onwards. This is to allow all patients time to 
have been titrated up to 20 mg/kg/day of GWP42003-P prior to any further dose 
increases. 
3.5 
Administrative Changes 
Minor spelling/formatting/consistency/administrative issues have been corrected (NB. in the 
interest of brevity, minor changes to grammar and punctuation are not captured in this 
amendment document). 
4. 
IMPLEMENTATION OF THE AMENDMENT 
This amendment will be issued as Protocol Version 3, Date 08 Oct 2015.  It will be kept in 
the study master file at GW and in each investigator and pharmacy site file, if applicable. 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Date 09 Jul 15 
 
 
 
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5. 
PRESENTATION OF AMENDED TEXT 
The text will be amended as follows: 
Protocol Section 
Number, 
Heading and 
Page Number 
Original Wording from Protocol Version 2,  
Dated 09 Jul 15 
(Deleted wording is struck through and in bold)  
Revised Wording from Protocol Amendment 2 
(Protocol Version 3, Dated 08 Oct 15)  
(Revised wording is underscored and in bold)  
Rationale for 
the 
amendment.  
Protocol 
Synopsis, Study 
Design, p 4 
 
(…) 
PK assessments will analyze the amount of CLB, the 
CLB primary metabolite N-CLB, CBD, CBD major 
metabolites, ∆9 tetrahydrocannabinol (THC) and 
THC major metabolites. (…) 
 
(…) 
PK assessments will analyze the amount of CLB, the 
CLB primary metabolite N-CLB, CBD, CBD major 
metabolites, ∆9 tetrahydrocannabinol (THC), THC 
major metabolites, valproate (VPA), stiripentol 
(STP), levetiracetam (LEV) and topiramate (TPM) 
(…) 
 
 
See section 3.3 
Protocol 
Synopsis, 
Secondary 
Endpoint(s), p 5 
 
(…) 
 
(…) 
(…) 
• 
CYP2C19 and CPY3A4 patient genotype 
analysis 
(…) 
See section 3.1 
Protocol 
Synopsis, 
Summary of 
Participant 
Eligibility 
Criteria, p 5 
 
(…) 
• 
Patient and/or legal representative is 
available to attend all PK visits within the 
required visit window. 
(…) 
 
 
 
(…) 
 
 
(…) 
• 
Patient is available to attend all PK visits 
within the required visit window. 
 
(…) 
• 
Patient is taking felbamate and they have 
been taking it for less than one year prior 
to screening. 
(…) 
• 
Patient has a prolonged QTcB  (>450 msec 
for males and >470 msec for females). 
 
Patient must 
attend PK 
visits.  
 
 
See section 3.2 
 
 
 
See section 3.2 
 


Study Code: GWEP1428 
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Protocol Section 
Number, 
Heading and 
Page Number 
Original Wording from Protocol Version 2,  
Dated 09 Jul 15 
(Deleted wording is struck through and in bold)  
Revised Wording from Protocol Amendment 2 
(Protocol Version 3, Dated 08 Oct 15)  
(Revised wording is underscored and in bold)  
Rationale for 
the 
amendment.  
(…) 
• 
Travel outside the country of residence 
planned during the study. 
(…) 
(…) 
• 
Travel outside the country of residence 
planned during the study, unless the patient 
has confirmation that the IMP is permitted 
in the destination country/state. 
(…) 
 
 
See section 3.2 
Protocol 
Synopsis, 
Criteria for 
Withdrawal, p 8 
 
(…) 
 
 
 
(…) 
(…) 
• 
Significant change in QTcB (> 60 msec) 
from the previous ECG or absolute QTcB 
of > 500 msec. 
(…) 
 
See section 3.2 
Protocol 
Synopsis, 
Procedures, p 9-
12 
 
(…) 
Blood samples will be taken for analysis of plasma 
concentrations of CLB, N-CLB, CBD, CBD major 
metabolites, THC and THC major metabolites. (…)  
(…) 
 
 
 
 
(…) 
Blood samples will be taken for analysis of plasma 
concentrations of CLB, N-CLB, CBD, CBD major 
metabolites, THC and THC major metabolites. (…)  
(…) 
 
 
 
The dose may be adjusted up or down by the 
investigator from the maintenance dose of 20 
(…) 
Blood samples will be taken for analysis of plasma 
concentrations of CLB, N-CLB, VPA, STP, LEV and 
TPM. (…) The evening dose of any AEDs must be 
taken after the 12 hour PK blood sample. (…) 
(…) 
Following administration of GWP42003-P/placebo, 
patients must remain in clinic for at least 30 
minutes to monitor for any adverse reactions. 
(…) 
Blood samples will be taken for analysis of plasma 
concentrations of CLB, N-CLB, VPA, STP, LEV, 
TPM, CBD, CBD major metabolites, THC and THC 
major metabolites (…) The evening dose of 
GWP42003-P/placebo and any AEDs must be 
taken after the 12 hour PK blood sample. (…) 
(…) 
 
 
 
See section 3.3 
 
See section 3.4 
 
 
See section 3.4 
 
 
 
 
See section 3.3 
 
See section 3.4 
 
 
 
See section 3.4 
 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Date 09 Jul 15 
 
 
 
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Protocol Section 
Number, 
Heading and 
Page Number 
Original Wording from Protocol Version 2,  
Dated 09 Jul 15 
(Deleted wording is struck through and in bold)  
Revised Wording from Protocol Amendment 2 
(Protocol Version 3, Dated 08 Oct 15)  
(Revised wording is underscored and in bold)  
Rationale for 
the 
amendment.  
mg/kg/day in the blinded phase to a maximum of 
30 mg/kg/day in the OLE. Patients and/or their 
caregivers will be provided with individual dosing 
schedules as described in Section 8.1. 
(…) 
 
 
 
 
 
(…) 
 
 
 
 
(…) 
The GWP42003-P dose may be adjusted up or 
down by the investigator from the maintenance 
dose of 20 mg/kg/day achieved at the end of the 10-
day transition period, up to a maximum of 
30 mg/kg/day in the OLE period.   
(…) 
 
 
 
 
 
See section 3.4 
Protocol 
Synopsis, 
Statistical 
Considerations, 
p 15 
 
Plasma concentration data will be analyzed to estimate 
PK endpoints Cmax, tmax, AUC(0–t), AUC(0–∞) and t½ of the 
following analytes: CLB, N-CLB, CBD, CBD major 
metabolites, THC and THC major metabolites. 
(…) 
 
Plasma concentration data will be analyzed to estimate 
PK endpoints Cmax, tmax, AUC(0–t), AUC(0–∞) and t½ of the 
following analytes: CLB, N-CLB, VPA, STP, LEV, 
TPM, CBD, CBD major metabolites, THC and THC 
major metabolites. 
(…) 
 
See section 3.3 
Protocol List of 
Abbreviations, 
p26 
(...) 
(...) 
 
(...) 
(...) 
CYP 
Cytochrome P450 
(...) 
(...) 
LEV 
Levetiracetam 
(...) 
(...) 
QTcB  Heart rate corrected QT interval using 
Bazett’s formula 
(...) 
(...) 
SFU 
Safety follow up 
STP 
Stiripentol 
(...) 
(...) 
 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Date 09 Jul 15 
 
 
 
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Protocol Section 
Number, 
Heading and 
Page Number 
Original Wording from Protocol Version 2,  
Dated 09 Jul 15 
(Deleted wording is struck through and in bold)  
Revised Wording from Protocol Amendment 2 
(Protocol Version 3, Dated 08 Oct 15)  
(Revised wording is underscored and in bold)  
Rationale for 
the 
amendment.  
TPM 
Topiramate 
(...) 
(...) 
VPA 
Valproate 
(...) 
(...) 
Protocol Section 
4.1, Study 
Design, p 33 
 
(…) 
PK samples will be quantitatively analyzed for CLB, 
N-CLB, CBD, CBD major metabolites, THC and 
THC major metabolites. 
(…) 
(…) 
PK samples will be quantitatively analyzed for CLB, 
N-CLB, 
valproate 
(VPA), 
stiripentol 
(STP),  
levetiracetam (LEV) and topiramate (TPM) at 
Visit 2  and CLB, N-CLB, VPA, STP, LEV, TPM, 
CBD, CBD major metabolites, THC and THC major 
metabolites at Visit 4. 
(…) 
See section 3.3 
Protocol Section 
4.2, Secondary 
Endpoint(s), p 
34 
 
(…) 
 
 
(…) 
(…) 
• 
CYP2C19 and CPY3A4 patient genotype 
analysis 
(…) 
See section 3.1 
Protocol Section 
6.1.9, Inclusion 
Criteria, p 38 
 
 
Patient and/or legal representative is available to 
attend all PK visits within the required visit window. 
Patient is available to attend all PK visits within the 
required visit window. 
Patient must 
attend PK 
visits.  
 
Protocol Section 
6.2, Exclusion 
Criteria, p 39 
 
(…) 
 
 
(…) 
 
 
(…) 
Travel outside the country of residence planned during 
the study. 
(…) 
(…) 
Patient is taking felbamate and they have been 
taking it for less than one year prior to screening. 
(…) 
Patient has a prolonged QTcB (> 450 msec for 
males and > 470 msec for females). 
(…) 
Travel outside the country of residence planned during 
the study, unless the patient has confirmation that 
the IMP is permitted in the destination 
 
See section 3.2 
 
 
See section 3.2 
 
 
See section 3.2 


Study Code: GWEP1428 
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Date 09 Jul 15 
 
 
 
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Protocol Section 
Number, 
Heading and 
Page Number 
Original Wording from Protocol Version 2,  
Dated 09 Jul 15 
(Deleted wording is struck through and in bold)  
Revised Wording from Protocol Amendment 2 
(Protocol Version 3, Dated 08 Oct 15)  
(Revised wording is underscored and in bold)  
Rationale for 
the 
amendment.  
country/state. 
(…) 
Protocol Section 
7.1, Treatment 
Assigment, p 41 
 
(…) 
For example, P1234001, denoting patient 001 at site 
1234. 
(…) 
(…) 
For example, W1234001, denoting patient 001 at site 
1234. 
(…) 
Unique letter at 
the start of 
patient number 
has been 
confirmed as 
W. 
Protocol Section 
8.1.2, Dose 
Escalation and 
Dose 
Adjustments, p 
43 
 
<<Note: For changes to Table 8.1.2-1: See Appendix 
1>> 
<<Note: For changes to Table 8.1.2-1: See Appendix 
1 >> 
 
 
Up-titration 
regimen when 
transitioning to 
the OLE is 
different to the 
up-titration 
regimen at days 
2-11. 
Protocol Section 
8.1.2, Dose 
Escalation and 
Dose 
Adjustments, p 
44 
 
(…) 
After this has taken place, the maintenance dose of 
GWP42003-P may be (…) 
 
(…) 
After this has taken place after Visit 5, the 
maintenance dose of GWP42003-P may be (…) 
 
See section 3.4 
 
Protocol Section 
9.1.10, 
Pharmacokinetic 
Analyses, p 49 
 
The plasma concentration/time curves of CLB, N-
CLB, CBD, CBD major metabolites, THC and 
THC major metabolites will be assessed at Visit 2 
(Day 1 and Day 2) and Visit 4 (Day 33 and Day 34). 
(…) 
The plasma concentration/time curves of CLB, N-
CLB, VPA, STP, LEV and TPM will be assessed at 
Visit 2 (Day 1 and Day 2) and CLB, N-CLB, VPA, 
STP, LEV, TPM, CBD, CBD major metabolites, 
THC and THC major metabolites at Visit 4 (Day 
33 and Day 34). 
(…) 
See section 3.3 
Protocol Section 
(…) 
(…) 
 


Study Code: GWEP1428 
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Protocol Section 
Number, 
Heading and 
Page Number 
Original Wording from Protocol Version 2,  
Dated 09 Jul 15 
(Deleted wording is struck through and in bold)  
Revised Wording from Protocol Amendment 2 
(Protocol Version 3, Dated 08 Oct 15)  
(Revised wording is underscored and in bold)  
Rationale for 
the 
amendment.  
9.2.1.2.1, Visit 2 
(Day 1) – 
Enrollment (+3 
days), p 58 
 
Blood samples will be taken for analysis of plasma 
concentrations of CLB, N-CLB, CBD, CBD major 
metabolites, THC and THC major metabolites.(…) 
(…) 
Blood samples will be taken for analysis of plasma 
concentrations of CLB, N-CLB, VPA, STP, LEV and 
TPM. (…) The evening dose of any AEDs must be 
taken after the 12 hour PK blood sample. 
(…) 
See section 3.3 
 
See section 3.4 
Protocol Section 
9.2.1.2.2, Visit 2 
(Day 2) – 
Enrollment, p 58 
 
(…) 
 
 
 
(…) 
(…) 
Following administration of GWP42003-P/placebo, 
patients must remain in clinic for at least 30 
minutes to monitor for any adverse reactions. 
(…) 
 
See section 3.4 
Protocol Section 
9.2.1.4.1, Visit 4 
(Day 33) (±3 
days), p 59 
 
(…) 
Blood samples will be taken for analysis of plasma 
concentrations of CLB, N-CLB, CBD, CBD major 
metabolites, THC and THC major metabolites. (…) 
(…) 
(…) 
Blood samples will be taken for analysis of plasma 
concentrations of CLB, N-CLB, VPA, STP, LEV, 
TPM, CBD, CBD major metabolites, THC and THC 
major metabolites. (…) The evening dose of 
GWP42003-P/placebo and any AEDs must be 
taken after the 12 hour PK blood sample. 
(…) 
 
 
See section 3.3 
 
 
See section 3.4 
Protocol Section 
9.2.1.4.2, Visit 4 
(Day 34), p 59 
 
(…) 
The dose may be adjusted up or down by the 
investigator from the maintenance dose of 20 
mg/kg/day in the blinded phase to a maximum of 
30 mg/kg/day in the OLE. Patients and/or their 
caregivers will be provided with individual dosing 
schedules as described in Section 8.1.2. Patients, or 
their caregivers, will be instructed how to record 
the diary information. 
(…) 
(…) 
(…) 
 
See section 3.4 
Protocol Section 
9.2.2.1, Visit 5 
(…) 
(…) 
(…) 
The GWP42003-P dose may be adjusted up or 
 
See section 3.4 


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Protocol Section 
Number, 
Heading and 
Page Number 
Original Wording from Protocol Version 2,  
Dated 09 Jul 15 
(Deleted wording is struck through and in bold)  
Revised Wording from Protocol Amendment 2 
(Protocol Version 3, Dated 08 Oct 15)  
(Revised wording is underscored and in bold)  
Rationale for 
the 
amendment.  
(Open Label 
Extension) – 
Two Weeks (±3 
days), p 60 
 
down by the investigator from the maintenance 
dose of 20 mg/kg/day achieved at the end of the 10-
day transition period, up to a maximum of 
30 mg/kg/day in the OLE period.   
(…) 
 
Protocol Section 
10, Withdrawal, 
p 63 
 
(…) 
 
 
(…) 
(…) 
• Significant change in QTcB (> 60 msec) from the 
previous ECG or absolute QTcB of > 500 msec. 
(…) 
 
See section 3.2 
Protocol Section 
12.8, Potential 
Cases of Drug 
Induced Liver 
Injury, p 70 
 
(…) 
The investigator will arrange for the patient to return 
to the investigational site as soon as possible (within 
24 hours of notice of abnormal results) for repeat 
assessment of ALT, AST, TBL and alkaline 
phosphatase levels, (…) 
(…) 
(…) 
The investigator will arrange for the patient to return 
to the investigational site as soon as possible (within 
24 hours of notice of abnormal results) for repeat 
assessment of ALT, AST, TBL, alkaline phosphatase 
and gamma-glutamyl transferase levels, (…) 
(…) 
 
See section 3.3 
Protocol Section 
13.6.3, 
Pharmacokinetic
s, p 74 
 
(…) 
Plasma concentrations of CLB, N-CLB, CBD, CBD 
major metabolites, THC and THC major metabolites 
(…) 
(…) 
(…) 
Plasma concentrations of CLB, N-CLB, VPA, STP, 
LEV, TPM, CBD, CBD major metabolites, THC and 
THC major metabolites (…) 
(…) 
 
See section 3.3 
Protocol Section 
16.2, Study 
Documentation 
and Storage, p 
80 
 
(…) 
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. 
(…) 
(…) 
All clinical trial related documents and electronic 
records will be retained within an archiving system for 
a period dependent upon need and for a minimum of 
25 years. 
(…) 
 
Update to GW 
Standard 
Operating 
Procedure 
 


Study Code: GWEP1428 
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Appendix 1 
Changes to Protocol Table 8.1.2-1 
 
Dose Titration Regimen (Protocol V2 / Table 8.1.2-1) 
Table 8.1.2-1 Dose Up-Titration Regimen* 
Day - GWP42003-P/Placebo 
(Blinded Period) 
Day - GWP42003-P only 
(OLE**) 
Dose Level 
(GWP42003-P or equivalent 
placebo) 
2 
34 
2.5 mg/kg 
3 
35 
2.5 mg/kg 
4 
36 
5.0 mg/kg 
5 
37 
5.0 mg/kg 
6 
38 
7.5 mg/kg 
7 
39 
7.5 mg/kg 
8 
40 
10.0 mg/kg 
9 
41 
10.0 mg/kg 
10 
42 
15.0 mg/kg 
11 
43 
15.0 mg/kg 
12 onwards 
44 onwards 
20.0 mg/kg 
* GWP42003-P /placebo is to be taken twice daily. Total daily doses are shown. 
** Only patients who were taking placebo during the double-blind period will up-titrate according to this schedule during the OLE period. Those taking GWP42003-P 
during the double-blind period will down-titrate their blinded IMP whilst simultaneously up-titrating with GWP42003-P, thus maintaining a daily dose of 20 mg/kg/day 
GWP42003-P throughout. 
 
 
 
 


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Dose Titration Regimen (Protocol V3 / Table 8.1.2-1) 
Table 8.1.2-1 Dose Up-titration Regimen* 
Day - GWP42003-P/Placebo 
(Blinded Period) 
Dose Level 
(GWP42003-P or equivalent 
placebo) 
Day - GWP42003-P only 
(OLE**) 
Dose Level 
GWP42003-P  
2 
2.5 mg/kg 
34 
2.0 mg/kg 
3 
2.5 mg/kg 
35 
4.0 mg/kg 
4 
5.0 mg/kg 
36 
6.0 mg/kg 
5 
5.0 mg/kg 
37 
8.0 mg/kg 
6 
7.5 mg/kg 
38 
10.0 mg/kg 
7 
7.5 mg/kg 
39 
12.0 mg/kg 
8 
10.0 mg/kg 
40 
14.0 mg/kg 
9 
10.0 mg/kg 
41 
16.0 mg/kg 
10 
15.0 mg/kg 
42 
18.0 mg/kg 
11 
15.0 mg/kg 
43 
20.0 mg/kg 
12 onwards 
20.0 mg/kg 
44 onwards 
20.0 mg/kg*** 
* GWP42003-P /placebo is to be taken twice daily. Total daily doses are shown. 
** Only patients who were taking placebo during the double-blind period will up-titrate according to this schedule during the OLE period. Those taking GWP42003-P 
during the double-blind period will down-titrate their blinded IMP whilst simultaneously up-titrating with GWP42003-P, thus maintaining a daily dose of 
20 mg/kg/day GWP42003-P throughout. 
*** The GWP42003-P dose of 20 mg/kg/day can be adjusted during the OLE period, after Visit 5, at the investigator’s discretion: up to a maximum dose of 
30 mg/kg/day. It may also be adjusted down (no minimum). 
 
 
 


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TITLE: A PHASE2, DOUBLE-BLIND, RANDOMIZED, 
PLACEBO-CONTROLLED STUDY TO INVESTIGATE POSSIBLE 
DRUG-DRUG INTERACTIONS BETWEEN CLOBAZAM AND 
CANNABIDIOL (GWP42003-P) 
 
STUDY CODE: GWEP1428 
 
EudraCT NUMBER: 2014-002942-33 
 
 
 
GW RESEARCH LTD 
SOVEREIGN HOUSE,  
VISION PARK,  
CHIVERS WAY 
HISTON,  
CAMBRIDGE 
CB24 9BZ 
TEL: 
   FAX: 
 
 
 
 
Confidentiality Statement 
This document contains confidential information of GW Research Ltd 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 Research Ltd. 
PPD
PPD


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Version 3 Date 08 Oct 15 
Investigator Agreement 
G\1\1 
pharmaceuticals 
I have read the attached protocol entitled "A phase 2, double-blind, randomized, 
placebo-controlled study to investigate possible drug-drug interactions between 
clobazam and cannabidiol (GWP42003-P)", dated version 3 date 08 Oct 15 and agree 
to abide by all provisions set forth therein. 
I agree to comply with applicable regulatory requirements, 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 Directive does not apply and to 
complete a Form 1572 if required. 
I am not aware that any conflicts of interest, financial or otherwise, exist for myself, 
my spouse [or legal partner] and dependent children and agree to confirm this in 
writing if required and update as necessary. 
I agree to ensure that the confidential information contained in this document will not 
be used for any purpose other than the evaluation or conduct of the clinical 
investigation without the prior written consent of GW Research Ltd. 
Center No: 
Print Name: 
Principal Investigator 
Signature: 
GW Authorization 
Print Name: 
Clinical Manag
Signature: 
Confidential 
Page 2 of93 
Date: 
(DD Month YYYY) 
Date: DB (!JeT 2_ors-
(DD Month YYYY) 
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PPD
PPD


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1. 
PROTOCOL SYNOPSIS 
Study Title 
A phase 2, double-blind, randomized, placebo-controlled study to 
investigate possible drug-drug interactions between clobazam and 
cannabidiol (GWP42003-P) 
Clinical Study 
Type 
Phase 2 
Indication 
Epilepsy 
Primary Objective 
To determine whether GWP42003-P affects the pharmacokinetic (PK) 
profile of clobazam (CLB) and its primary metabolite 
N-desmethylclobazam (N-CLB). 
Secondary 
Objective(s) 
To assess the safety and tolerability of GWP42003-P in the presence of 
CLB. 
Study Design 
This is a phase 2, double-blind, randomized, placebo-controlled study 
in 20 patients. 
• Patients will be randomized in a 4:1 ratio to receive 20 mg/kg 
GWP42003-P or placebo from days 2 to 33.  
• 
At the end of the treatment period, patients will be given the option 
of continuing onto an open label extension (OLE) period if the 
investigator and patient both agree that it is in their best interests. 
Doses may be adjusted up or down, dependent on investigator 
opinion, to a maximum of 30 mg/kg/day GWP42003-P. The OLE 
will last for a maximum of one year or until marketing 
authorization is granted; whichever is earlier. 
• 
Patients that do not continue onto the OLE will taper off of 
GWP42003-P over a 10 day period and will have a telephone 
follow-up visit four weeks after the end of taper day on Day 71. 
• Day 
1 
(Visit 
2), 
patients 
will 
not 
be 
dosed 
with 
GWP42003-P/placebo but will continue to take CLB at a stable 
dose. 
• Day 2 (Visit 2), patients will begin the up-titration with 
GWP42003-P or placebo to a maintenance dose or an equivalent 
maintenance dose of 20 mg/kg/day over a period of 10 days (Days 
2 to 11). 
• Day 12 (Visit 3), patients will attend the study site to check safety 
and compliance. 
• After up-titration with GWP42003-P or placebo, the patients will 
remain on the maintenance dose for 21 days (Days 12 to 32). 
• On Day 34 (Visit 4), patients will be invited to receive 
GWP42003-P in the OLE period. If the patient enters the OLE 
period of the study, the patient will continue to take GWP42003-P 


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as advised by the investigator. 
• If the patient does not enter the OLE period of the study, the patient 
will taper off of GWP42003-P by reducing the dose by 
approximately 10% of the maintenance dose each day until dosing 
has ceased, with end of taper on Day 43 (Visit 5). 
PK samples will be taken on the day of enrollment (Visit 2, Day 1) and 
after completing 21 days treatment on GWP42003-P or placebo 
(Visit 4, Day 33). The PK assessments will therefore capture the 
following combinations of CLB and GWP42003-P: 
• First PK Assessment: CLB only. 
• Second PK Assessment: CLB and GWP42003-P or placebo. 
Each PK assessment should be performed at time points in respect to a 
morning dose of CLB. The time points are as follows: Pre-dose, 
15 min, 30 min, 1h, 1.5h, 2h, 4h, 6h, 12h and 24h. It is expected that 
the patient will continue to take their CLB as advised by their physician 
and PK assessments will be scheduled in order to accommodate this 
dosing schedule. The GWP42003-P/placebo should be taken twice 
daily immediately following their CLB dose. 
PK assessments will analyze the amount of CLB, the CLB primary 
metabolite N-CLB, CBD, CBD major metabolites, 
∆9-tetrahydrocannabinol (THC), THC major metabolites, valproate 
(VPA), stiripentol (STP),  levetiracetam (LEV) and topiramate (TPM). 
Patients will be required to keep a paper diary to note the time and dose 
of GWP42003-P and CLB administration each morning and evening 
and to record any adverse events (AEs) that may occur whilst receiving 
investigational medicinal product (IMP) and any other medications. 
Patients will also be requested to record the number and type of 
seizures for each day whilst on the study. 
Primary Endpoint 
The primary endpoints of the study are the PK parameters (Cmax, tmax, 
AUC(0–∞) AUC(0–t), t½) of the following analytes: 
• CLB 
• N-desmethylclobazam (N-CLB) 
• CBD 
• CBD major metabolites 
Secondary 
Endpoint(s) 
To assess the safety and tolerability of GWP42003-P compared with 
placebo when taken in combination with CLB. Safety and tolerability 
will be assessed using the following parameters: 
• AEs 
• 12-lead electrocardiogram (ECG) 
• Clinical laboratory parameters (clinical chemistry, hematology 
and urinalysis) 
• Vital signs 
• Columbia-Suicide Severity Rating Scale (C-SSRS) 
• Seizure frequency 


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• Abuse liability 
• CYP2C19 and CPY3A4 patient genotype analysis 
 
PK parameters (Cmax, tmax, AUC(0–∞), AUC(0–t), t½) of the following 
analytes: 
• THC  
• THC major metabolites 
Sample Size 
A total of 20 patients will be enrolled in this study. Recruitment for the 
study will be competitive between participating sites. There is no 
formal sample size: Calculation and analysis is descriptive only. 
Summary of 
Participant 
Eligibility Criteria 
For inclusion in the study patients must fulfil ALL of the following 
criteria: 
• Male or female patients aged 18 to 55 years inclusive. 
• Patient must have epilepsy as determined by the investigator and be 
taking CLB. 
• Patient must have a documented magnetic resonance 
imaging/computerized tomography of the brain that ruled out a 
progressive neurologic condition. 
• Patient must have experienced at least one seizure of any type (i.e., 
convulsive: tonic-clonic, tonic, clonic, atonic; focal: focal seizures 
with retained consciousness and a motor component, focal seizures 
with impaired consciousness focal seizures evolving to bilateral 
secondary generalization) within the two months prior to 
randomization. 
• Patients must be taking CLB and no more than two other 
anti-epileptic drugs (AEDs) during the course of the study. 
• AED(s), including CLB, must be stable for four weeks prior to 
screening and regimen must remain stable throughout the duration 
of the blinded phase of the study. 
• Intervention with vagus nerve stimulation and/or ketogenic diet 
must be stable for four weeks prior to baseline and patient/caregiver 
must be willing to maintain a stable regimen throughout the blinded 
phase of the study. 
• Patients must abstain from alcohol during the blinded phase of the 
study. 
• Patient is available to attend all PK visits within the required visit 
window. 
• Patient and/or legal representative must be willing and able to give 
informed consent for participation in the study. 
• Patient and/or legal representative must be willing and able (in the 
investigator’s opinion) to comply with all study requirements. 


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• Patient is willing for his or her name to be notified to the 
responsible authorities for participation in this study, as applicable. 
• Patient is willing to allow his or her primary care practitioner and 
consultant, if appropriate, to be notified of participation in the 
study. 
 
Exclusion: The patient may not enter the study if ANY of the following 
apply: 
• Patient has clinically significant unstable medical conditions other 
than epilepsy. 
• Patients on CLB at doses above 20 mg per day. 
• Patients taking CLB intermittently as rescue medication. 
• Patient has a history of symptoms (e.g., dizziness, light-headedness, 
blurred vision, palpitations, weakness, syncope) related to a drop in 
blood pressure (BP) due to postural changes. 
• Any history of suicidal behavior or any suicidal ideation of type 
four or five on the C-SSRS in the last month or at screening. 
• Patient has had clinically relevant symptoms or a clinically 
significant illness in the four weeks prior to screening or 
enrollment, other than epilepsy. 
• Patient has consumed alcohol during the seven days prior to 
enrollment and is unwilling to abstain during the blinded phase of 
the study. 
• Patient is currently using or has in the past used recreational or 
medicinal cannabis, or synthetic cannabinoid based medications 
(including Sativex®) within the three months prior to study entry. 
• Patient has any known or suspected history of any drug abuse or 
addiction. 
• Patient is unwilling to abstain from recreational or medicinal 
cannabis, or synthetic cannabinoid based medications (including 
Sativex) for the duration of the study. 
• Patient has consumed grapefruit or grapefruit juice seven days prior 
to enrollment and is unwilling to abstain from drinking grapefruit 
juice within seven days of PK visits. 
• Patient has any known or suspected hypersensitivity to 
cannabinoids or any of the excipients of the IMP, e.g., sesame oil. 
• 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 three 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 


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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 three 
months thereafter. 
• Patients who have received an IMP within the 12 weeks prior to the 
screening visit. 
• Patient is taking felbamate and they have been taking it for less than 
one year prior to screening. 
• 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 
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 participant 
from safe participation in the study. 
• Patient has significantly impaired hepatic function at screening 
(Visit 1) or enrollment (Visit 2), defined as any of the following: 
- 
Alanine aminotransferase (ALT) or Aspartate aminotransferase 
(AST) >5 × upper limit of normal (ULN). 
- 
ALT or AST >3 × ULN and total bilirubin (TBL) >2 × ULN or 
international normalized ratio (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%).  
This criterion can only be confirmed once the laboratory results are 
available; patients randomized into the study who are later found to 
meet this criterion must be withdrawn from the study. 
• Patient has a prolonged QTcB  (> 450 msec for males and 
> 470 msec for females). 
• Unwilling to abstain from donation of blood during the study. 
• Travel outside the country of residence planned during the study, 
unless the patient has confirmation that the IMP is permitted in the 
destination country/state. 
• Patients previously enrolled into this study. 
Criteria for 
Withdrawal 
Patients must be withdrawn from the study if any of the following 
apply: 
• Administrative decision by the investigator or GW Research Ltd or 
Regulatory Authority. 
• Pregnancy. 
• Protocol deviation that is considered to potentially compromise the 
safety of the patient. 


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• Withdrawal of patient consent. 
• Withdrawal of legal representative consent. 
• Lost to follow up. 
• ALT >3 × ULN 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 two weeks. 
• Any other IMP is taken as part of a clinical trial during the study.  
• Significant change in QTcB (> 60 msec) from the previous ECG or 
absolute QTcB of > 500 msec. 
 
Patients may also be withdrawn from the study if any of the following 
apply: 
• Patient non-compliance. 
• AE, which in the investigator’s opinion, 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 four or five 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), pale yellow in color. 
Placebo oral solution containing the excipients sesame oil and 
anhydrous ethanol with added sweetener (sucralose) and strawberry 
flavoring. 
The IMP should be taken orally as per intended commercial therapeutic 
use. 
IMP will be taken twice daily (morning and evening) following the 
dose schedule below: 
• Day 2 (Visit 2), patients will begin the up-titration with 
GWP42003-P or placebo to a maintenance dose or an equivalent 
maintenance dose of 20 mg/kg/day over a period of 10 days (Days 
2 to 11). 
• After up-titration with GWP42003-P or placebo, the patients will 
remain on the maintenance dose for 21 days (Days 12 to 32). 
Please refer to Table 8.1.2-1 for details of the up-titration doses for 
GWP42003-P and placebo for the ten day taper period. 
On Day 34 (Visit 4), patients will be invited to receive GWP42003-P in 
the OLE period. If the patient enters the OLE period of the study, the 


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patient will continue to take GWP42003-P as advised by the 
investigator. 
CLB will be an IMP for the blinded section of the study. The patient’s 
own supply of CLB will be used. 
Control Group 
The control group will receive an equal volume of matching placebo. 
Procedures 
VISIT 1 - Screening (Day -14 to -7) 
The following observations will be made at Visit 1: demographics, 
medical history (including seizure information since diagnosis, history 
of epilepsy-specific genetic testing and all prior AEDs taken), 
concomitant medications (including AEDs), physical examination 
(including height and body weight), ECG, vital signs and AEs. 
Clinical laboratory samples (blood and urine) will be taken for 
hematology, biochemistry, alcohol testing, THC testing, urinalysis and 
a pregnancy test (using a serum sample, if appropriate). The laboratory 
results should be available within 3-5 working days after Visit 1. If the 
results show a patient is ineligible, the patient will not be enrolled into 
the study. The C-SSRS will be administered. 
Patients who satisfy all inclusion and none of the exclusion criteria 
specified in Section 6 will be assigned a unique patient number and 
then begin the baseline period. Patients or their caregivers will be given 
a paper diary to record daily seizure information, rescue medication, 
concomitant AEDs and AEs; and will be instructed on how to do so. 
The investigator must record the patient’s attendance at the visit and 
confirm the outcome of screening on the CRF.  
VISIT 2 - Enrollment (Day 1) +3 days window 
This visit will occur 7-14 days after Visit 1. 
The following observations will be made at Visit 2: concomitant 
medications, (including AEDs), physical examination (including body 
weight), ECG, vital signs, review of patient diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for 
hematology, biochemistry, alcohol testing and urinalysis. Blood 
samples will also be taken for genetic testing if additional consent has 
been obtained. The C-SSRS will be administered. The investigator 
must record the patient’s attendance at the visit, and confirm the 
outcome of the visit prior to enrollment. 
Following enrollment patients will begin the PK sampling process. 
Blood samples will be taken for analysis of plasma concentrations of 
CLB, N-CLB, VPA, STP, LEV and TPM. A baseline PK sample will 
be taken before the patient takes their morning dose of CLB. Further 
samples will then be taken at the following times relative to the CLB 
dose: 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 
hours and 12 hours. The evening dose of any AEDs must be taken after 
the 12 hour PK blood sample. Patients will either remain in clinic 
overnight throughout this PK sampling process or return to the clinic 


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on Day 2 ahead of additional sample collection. 
VISIT 2 - Enrollment (Day 2) 
This is the second part of the two day enrollment visit. The final PK 
sample will be collected 24 hours after the Day 1 morning CLB dose. 
Following completion of the PK sampling process the following 
observations will be made on Day 2: concomitant medications 
(including AEDs), physical examination (including body weight), vital 
signs and AEs. 
GWP42003-P/placebo will be dispensed and both the morning dose of 
CLB and GWP42003-P/placebo will be taken in clinic. Following 
administration of GWP42003-P/placebo, patients must remain in clinic 
for at least 30 minutes to monitor for any adverse reactions. Patients 
and/or their caregivers will be provided with individual dosing 
schedules as described in Section 8.1. Each patient will then receive 
their GWP42003-P/placebo for the 10 day titration period followed by 
the 21 day maintenance period. Patients, or their caregivers, will be 
instructed on how to record the diary information. 
VISIT 3 – Day 12 +3 day window 
This visit will occur 11 days after Visit 2, Day 1 (enrollment). Patients 
will return all used and unused GWP42003-P/placebo. The following 
observations will be made at Visit 3: concomitant medications 
(including AEDs), physical examination (including body weight), 
ECG, vital signs, AEs and review of patient diary completion. 
Clinical laboratory samples (blood and urine) will be taken for 
hematology, biochemistry and urinalysis. The C-SSRS will be 
administered. 
VISIT 4 - Day 33 ±3 days window 
This visit will occur 32 days after Visit 2, Day 1 (enrollment). Patients 
will return all used and unused GWP42003-P/placebo. The following 
observations will be made at Visit 4 (Day 33): concomitant medications 
(including AEDs), physical examination (including body weight), 
ECG, vital signs, review of patient diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for 
hematology, biochemistry, alcohol testing and urinalysis. The C-SSRS 
will be administered. 
Blood samples will be taken for analysis of plasma concentrations of 
CLB, N-CLB, VPA, STP, LEV, TPM, CBD, CBD major metabolites, 
THC and THC major metabolites. A baseline PK sample will be taken 
before the patient takes their morning dose of CLB, followed 
immediately by their dose of GWP42003-P/placebo. Further samples 
will then be taken at the following times relative to the CLB dose: 
15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours and 
12 hours. The evening dose of GWP42003-P/placebo and any AEDs 
must be taken after the 12 hour PK blood sample. Patients are expected 


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to remain in clinic throughout this PK sampling process. 
The investigator must assess adherence to the dosing regimen and 
recording of rescue medications by reviewing the patient’s diary. 
VISIT 4 - Day 34 
This is the second part of the two day visit. The final PK sample will be 
collected 24 hours after the Day 33 morning CLB dose. 
Following completion of the PK sampling process the following 
observations will be made on Day 34: concomitant medications 
(including AEDs), physical examination (including body weight), vital 
signs and AEs. 
On Day 34, providing the investigator and patient both agree, patients 
will be invited to continue taking GWP42003-P and to enter the OLE. 
Patients who enter the OLE will be dispensed GWP42003-P on Day 34. 
Patients who do not enter the OLE will begin a 10 day taper period 
during which they will taper off their daily dose of GWP42003-P. The 
daily dose will be reduced by 10% of the maintenance dose per day and 
treatment will end on Day 42. 
Patients Not Entering OLE 
VISIT 5 – Day 43 (End of Taper) +3 days window 
This visit will occur 42 days after Visit 2, Day 1 (enrollment) for those 
patients who do not enter the OLE. 
All GWP42003-P/placebo (used and unused) will be collected and a 
check of the returned GWP42003-P/placebo against usage must be 
made. A physical examination (including body weight), ECG and vital 
signs will be assessed and the C-SSRS will be administered. The 
trained investigator or study coordinator will complete the Study 
Medication Use and Behavior Survey as an interview with the 
patient/caregiver. 
Clinical laboratory samples (blood and urine) will be taken for 
hematology, biochemistry and urinalysis and a review of concomitant 
medications (including AEDs) and AEs will be completed. Patient 
diaries will be collected. 
VISIT 6 - SAFETY FOLLOW-UP CALL - Day 71 ±3 days 
This visit is required for patients who do not enter the OLE study on 
Day 34, or who withdraw from the study early. This visit should occur 
four weeks (±3 days) after Visit 5, or withdrawal from treatment, and 
can be conducted over the telephone. The following observations will 
be made on Day 71: concomitant medications (including AEDs) and 
AEs. 
Patients Entering OLE 
At the point of entry to the OLE, patients will be transitioned to the 


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OLE treatment over a 10 day period in order to maintain blinding. 
Patients who enter the OLE will be dispensed IMP at Visit 4 (Day 34) 
and will have regular clinic visits for a maximum of one year or earlier 
(if marketing authorization is granted or the patient withdraws). The 
visit schedule is calculated relative to Visit 4 (Day 34). 
VISIT 5 (OLE) – Two Weeks ±3 days 
This visit will occur two weeks after Visit 4 (Day 34). Patients will 
return all used and unused IMP. The following observations will be 
made at Visit 5 (OLE): concomitant medications (including AEDs), 
physical examination (including body weight), ECG, vital signs, review 
of patient diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for 
hematology, biochemistry and urinalysis. The C-SSRS will be 
administered. The investigator must record the patient’s attendance at 
the visit and the outcome. 
The investigator must assess adherence to the dosing regimen and 
recording of rescue medications by reviewing the patient’s diary. 
The GWP42003-P dose may be adjusted up or down by the investigator 
from the maintenance dose of 20 mg/kg/day achieved at the end of the 
10-day transition period, up to a maximum of 30 mg/kg/day in the OLE 
period.   
VISIT 6 (OLE) – One Month ±3 days 
This visit will occur one month after Visit 4 (Day 34). Patients will 
return all used and unused IMP. The following observations will be 
made at Visit 6 (OLE): concomitant medications (including AEDs), 
physical examination (including body weight), ECG, vital signs, review 
of patient diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for 
hematology, biochemistry and urinalysis. The C-SSRS will be 
administered. The investigator must record the patient’s attendance at 
the visit and the outcome. 
The investigator must assess adherence to the dosing regimen and 
recording of rescue medications by reviewing the patient’s diary. 
VISIT 7 (OLE) – Two Months ±3 days 
This visit will occur two months after Visit 4 (Day 34). Patients will 
return all used and unused IMP. The following observations will be 
made at Visit 7 (OLE): concomitant medications (including AEDs), 
physical examination (including body weight), ECG, vital signs, review 
of patient diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for 
hematology, biochemistry and urinalysis. The C-SSRS will be 
administered. The investigator must record the patient’s attendance at 
the visit and the outcome. 


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The investigator must assess adherence to the dosing regimen and 
recording of rescue medications by reviewing the patient’s diary. 
VISIT 8 (OLE) - Three Months ±7 days 
This visit will occur three months after Visit 4 (Day 34). Patients will 
return all used and unused IMP. The following observations will be 
made at Visit 8 (OLE): concomitant medications (including AEDs), 
physical examination (including body weight), ECG, vital signs, review 
of patient diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for 
hematology, biochemistry and urinalysis. The C-SSRS will be 
administered. The investigator must record the patient’s attendance at 
the visit and the outcome. 
The investigator must assess adherence to the dosing regimen and 
recording of rescue medications by reviewing the patient’s diary. 
VISIT 9 (OLE) - Six Months ±7 days 
This visit will occur six months after Visit 4 (Day 34). Patients will 
return all used and unused IMP. The following observations will be 
made at Visit 9 (OLE): concomitant medications (including AEDs), 
physical examination (including body weight), ECG, vital signs, review 
of patient diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for 
hematology, biochemistry and urinalysis. The C-SSRS will be 
administered. The investigator must record the patient’s attendance at 
the visit and the outcome. 
The investigator must assess adherence to the dosing regimen and 
recording of rescue medications by reviewing the patient’s diary. 
VISIT 10 (OLE) - Nine Months ±7 days 
This visit will occur nine months after Visit 4 (Day 34). Patients will 
return all used and unused IMP. The following observations will be 
made at Visit 10 (OLE): concomitant medications (including AEDs), 
physical examination (including body weight), ECG, vital signs, review 
of patient diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for 
hematology, biochemistry and urinalysis. The C-SSRS will be 
administered. The investigator must record the patient’s attendance at 
the visit and the outcome. 
The investigator must assess adherence to the dosing regimen and 
recording of rescue medications by reviewing the patient’s diary. 
VISIT 11 – Twelve Months (OLE End of Treatment) ±7 days 
This visit will occur twelve months after Visit 4 (Day 34). Patients will 
return all used and unused IMP. The following observations will be 
made at Visit 11 (OLE): concomitant medications (including AEDs), 


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physical examination (including body weight), ECG, vital signs, review 
of patient diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for 
hematology, biochemistry and urinalysis. The C-SSRS will be 
administered. The investigator must record the patient’s attendance at 
the visit and the outcome. 
The investigator must assess adherence to the dosing regimen and 
recording of rescue medications by reviewing the patient’s diary. 
Starting at Visit 11, patients will begin to taper down their IMP dose. 
The dose will be reduced by 10% of their OLE maintenance dose per 
day. 
VISIT 12 - OLE End of taper +3 days 
This visit will be ten days after Visit 11. All IMP (used and unused) 
will be collected and a check of the returned IMP against usage must be 
made. A physical examination (including body weight), ECG and vital 
signs will be assessed and the C-SSRS will be administered. The 
trained investigator or study coordinator will complete the Study 
Medication Use and Behavior Survey as an interview with the 
patient/caregiver. 
Clinical laboratory samples (blood and urine) will be taken for 
hematology, biochemistry and urinalysis and a review of concomitant 
medications (including AEDs) and AEs will be completed. Patient 
diaries will be collected and reviewed. 
VISIT 13 - SAFETY FOLLOW-UP CALL (OLE) 
This visit will occur one month after the OLE End of Taper and can be 
conducted over the telephone. The following observations will be made 
during the follow up call: concomitant medications (including AEDs) 
and AEs. 
Monitoring of Drug Abuse Liability  
During the routine collection of AEs in this study, if AEs are reported 
which can illuminate an abuse potential signal (specific AEs detailed in 
Section 9.1.16.1.1), 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 
discussions of the event(s) with the patient/caregiver. 
The second trigger that will require the investigator or study 
coordinator to discuss abuse potential signals with the patient/caregiver 
is drug accountability issues regarding overuse of the IMP or missing 
IMP bottles. 
Irrespective of the above, all patients/caregivers will be interviewed at 
their final dosing visit or withdrawal visit 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 


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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 
Plasma concentration data will be analyzed to estimate PK endpoints 
Cmax, tmax, AUC(0–t), AUC(0–∞) and t½ of the following analytes: CLB, 
N-CLB, VPA, STP, LEV, TPM, CBD, CBD major metabolites, THC 
and THC major metabolites. 
In order to assess whether the presence of CBD alters the PK profile of 
CLB or N-CLB, a standard 90% confidence interval (CI) approach for 
the between group ratios of geometric means of Cmax AUC(0–t), and 
AUC(0–∞) will be done on logarithm scale using a linear mixed effect 
model with treatment (CLB or CLB+GWP42003-P) as a fixed effect 
and subject as a random effect. The no-effect boundary will be set 
between 0.5 and 2.0 and if the 90% CI for the ratio of the geometric 
means of a PK variable falls within the interval [0.5, 2.0], a lack of 
meaningful effect will be declared. 
Descriptive summaries (means and standard deviations or counts [%] 
as appropriate) will be presented for all secondary endpoints (adverse 
events, laboratory data, vital signs, physical examination, C-SSRS and 
seizure frequency) for each phase of the study. 
Sponsor 
GW Research Ltd 
Sovereign House 
Vision Park 
Chivers Way 
Histon 
Cambridge CB24 9BZ 
United Kingdom 


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Figure 1-1 
Study Design and Treatment Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
S 
C 
R 
E 
E 
N 
I 
N 
G 
E 
N 
R 
O 
L 
L 
M 
E 
N 
T 
E 
N 
D 
  
O 
F 
  
B 
L 
I 
N 
D 
E 
D 
  
T 
R 
E 
A 
T 
M 
E 
N 
T 
Visit 1 
Day -14  
to -7 
Visit 2 
Day 1/2 
(+3 d) 
Visit 4 
Day 33/34 
(±3 d) 
E 
N 
D 
  
O 
F 
  
T 
A 
P 
E 
R 
10 Day Taper 
Patients not 
entering the 
OLE 
Patients entering the OLE 
S 
A 
F 
E 
T 
Y 
  
F 
O 
L 
L 
O 
W 
  
U 
P 
10 Day 
Up-Titration 
21 Day 
Maintenance 
Visit 5 
Day 43 
Visit 6 
Day 71 
28 day FU 
(±3 d) 
7-14 days 
31 days 
10 days 
28 days 
Placebo  
N=4 
GWP42003-P Oral 
Solution 
(100 mg/mL bd) 
N=16 
Visit 3 
Day 12 
(+3 d) 


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Figure 1-2 
Study Design and Treatment Schema  
 
Patients  
entering 
from 
 the  
blinded 
phase 
Visit 5 OLE 
2 weeks 
(±3 d) 
Visit 7 OLE 
2 months 
(±3 d) 
Visit 6 OLE 
1 month 
(±3 d) 
Visit 8 OLE 
3 months 
(±7 d) 
Visit 9 OLE 
6 months 
(±7 d) 
Visit 11 OLE 
12 months 
(±7 d) 
Visit 10 OLE 
9 months 
(±7 d) 
Visit 12 OLE 
 
E 
N 
D 
  
O 
F 
  
T 
A 
P 
E 
R 
Visit 13 OLE 
28 day FU 
(±3 d) 
S 
A 
F 
E 
T 
Y 
 
F 
O 
L 
L 
O 
W 
 
U 
P 
Open Label Extension Phase: 
GWP42003-P Oral Solution 
(100 mg/mL bd) 
10 
Day 
Taper 
2 weeks 
from V4 
2 weeks 
1 month 
1 month 
3 months 
3 months 
3 months 
10 days 
28 days 


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Table of Contents 
Title Page ................................................................................................... 1 
1. 
PROTOCOL SYNOPSIS ................................................................ 3 
Table of Contents .................................................................................... 18 
Table of Appendices ............................................................................... 23 
List of In-text Tables .............................................................................. 24 
List of In-text Figures ............................................................................. 25 
List of Abbreviations .............................................................................. 26 
Definition of Terms ................................................................................. 28 
2. 
OBJECTIVES ................................................................................ 29 
2.1 
Primary ........................................................................................................ 29 
2.2 
Secondary .................................................................................................... 29 
3. 
BACKGROUND AND RATIONALE ......................................... 30 
3.1 
Disease......................................................................................................... 30 
3.2 
GWP42003-P Background .......................................................................... 30 
3.3 
Rationale ...................................................................................................... 31 
3.3.1 
Selection of Study Doses .......................................................................... 32 
3.4 
Clinical Hypothesis ..................................................................................... 33 
4. 
EXPERIMENTAL PLAN ............................................................. 34 
4.1 
Study Design ............................................................................................... 34 
4.1.1 
Primary Endpoint ...................................................................................... 35 
4.1.2 
Secondary Endpoint(s) .............................................................................. 35 
4.2 
Number of Centers ...................................................................................... 35 
4.3 
Number of Patients ...................................................................................... 36 
5. 
INVESTIGATIONAL MEDICINAL PRODUCT ..................... 37 
5.1 
GWP42003-P Oral Solution ........................................................................ 37 
5.2 
Placebo Oral Solution .................................................................................. 37 
5.3 
Packaging, Storage and Drug Accountability (Cannabidiol/Placebo) ........ 37 
5.3.1 
Packaging and Labelling ........................................................................... 37 
5.3.2 
Storage ...................................................................................................... 38 
5.3.3 
Supply and Return of Investigational Medicinal Product ......................... 38 
5.3.4 
Investigational Medicinal Product Accountability ................................... 38 


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5.4 
Clobazam ..................................................................................................... 39 
6. 
PARTICIPANT ELIGIBILITY ................................................... 39 
6.1 
Inclusion Criteria ......................................................................................... 39 
6.2 
Exclusion Criteria ........................................................................................ 40 
7. 
PATIENT ENROLLMENT ......................................................... 42 
7.1 
Treatment Assignment ................................................................................ 42 
7.2 
Randomization............................................................................................. 42 
8. 
TREATMENT PROCEDURES ................................................... 43 
8.1 
Investigational Medicinal Product Dosage, Administration and 
Schedule ...................................................................................................... 43 
8.1.1 
Dose Administration ................................................................................. 43 
8.1.2 
Dose Escalation and Dose Adjustments ................................................... 44 
8.2 
Concomitant Therapy .................................................................................. 45 
8.3 
Prohibited Therapy During Study Period .................................................... 45 
8.4 
Compliance in Investigational Medicinal Product Administration ............. 45 
8.5 
Access to Blinded Treatment Assignment .................................................. 46 
9. 
STUDY PROCEDURES ............................................................... 47 
9.1 
Study Procedure Listing .............................................................................. 47 
9.1.1 
Contraception ............................................................................................ 47 
9.1.2 
Informed Consent ..................................................................................... 47 
9.1.3 
Demographics ........................................................................................... 47 
9.1.4 
Medical History ........................................................................................ 48 
9.1.5 
Concomitant Medication .......................................................................... 48 
9.1.6 
Physical Examination ............................................................................... 48 
9.1.7 
Vital Signs ................................................................................................ 48 
9.1.8 
12-Lead Electrocardiogram ...................................................................... 48 
9.1.9 
Clinical Laboratory Sampling................................................................... 48 
9.1.10 
Pharmacokinetic Analyses ........................................................................ 50 
9.1.11 
Genetic Testing ......................................................................................... 50 
9.1.12 
Columbia Suicide Severity Rating Scale .................................................. 51 
9.1.13 
Patient Diary ............................................................................................. 51 
9.1.14 
Investigational Medicinal Product Accountability ................................... 51 
9.1.15 
Adverse Events ......................................................................................... 52 


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9.1.16 
Monitoring of Drug Abuse Liability......................................................... 52 
9.1.16.1 
Monitoring of Adverse Events .............................................................. 53 
9.1.16.1.1 
List of ‘Triggering Adverse Events of Interest’ ................................ 53 
9.1.16.1.2 
Supplemental Adverse Event Form ................................................... 53 
9.1.16.2 
Monitoring Drug Accountability Discrepancies ................................... 54 
9.1.16.2.1 
List of ‘Triggering Drug Accountability Discrepancies’ .................. 54 
9.1.16.2.2 
Supplemental Drug Accountability Form ......................................... 55 
9.1.16.3 
Site Classification Form ........................................................................ 55 
9.1.16.4 
Study Medication Use and Behavior Survey ........................................ 55 
9.1.16.5 
Adjudication Committee — Assessment of Abuse Potential of 
GWP42003-P ........................................................................................ 56 
9.2 
Study Procedures by Visit ........................................................................... 58 
9.2.1 
Double Blind Phase .................................................................................. 58 
9.2.1.1 
Visit 1 (Day −14 to −7, Screening) ....................................................... 58 
9.2.1.2 
Visit 2 .................................................................................................... 58 
9.2.1.2.1 
Visit 2 (Day 1) – Enrollment (+3 days) ............................................. 58 
9.2.1.2.2 
Visit 2 (Day 2) - Enrollment .............................................................. 59 
9.2.1.3 
Visit 3 (Day 12 +3 days) ....................................................................... 59 
9.2.1.4 
Visit 4 .................................................................................................... 59 
9.2.1.4.1 
Visit 4 (Day 33) (±3 days) ................................................................. 59 
9.2.1.4.2 
Visit 4 (Day 34) ................................................................................. 60 
9.2.1.5 
Visit 5 (Patients not entering Open Label Extension) (Day 43 +3 
days) ...................................................................................................... 60 
9.2.1.6 
Visit 6 - Safety Follow up Call (Day 71) (±3 days) .............................. 61 
9.2.2 
Open Label Extension ............................................................................... 61 
9.2.2.1 
Visit 5 (Open Label Extension) - Two Weeks (±3 days) ...................... 61 
9.2.2.2 
Visit 6 (Open Label Extension) - One Month (±3 days) ....................... 62 
9.2.2.3 
Visit 7 (Open Label Extension) - Two Months (±3 days) .................... 62 
9.2.2.4 
Visit 8 (Open Label Extension) - Three Months (±7 days) .................. 62 
9.2.2.5 
Visit 9 (Open Label Extension) - Six Months (±7 days) ...................... 62 
9.2.2.6 
Visit 10 (Open Label Extension) - Nine Months (±7 days) .................. 63 
9.2.2.7 
Visit 11 (Open Label Extension End of Treatment) - Twelve 
Months (±7 days) .................................................................................. 63 
9.2.2.8 
Visit 12 (Open Label Extension End of Taper) .................................... 63 


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9.2.2.9 
Safety Follow Up Call (±3 days) .......................................................... 64 
10. 
WITHDRAWAL ............................................................................ 64 
11. 
URGENT SAFETY MEASURES ................................................ 65 
12. 
ADVERSE EVENT REPORTING .............................................. 65 
12.1 
Definitions ................................................................................................... 65 
12.1.1 
Adverse Event ........................................................................................... 65 
12.1.2 
Investigator ............................................................................................... 66 
12.2 
Serious Adverse Events ............................................................................... 66 
12.3 
Reporting Procedures for Serious Adverse Events ..................................... 67 
12.4 
Pregnancy .................................................................................................... 67 
12.5 
Causality Assessment .................................................................................. 68 
12.6 
Reporting Procedures for All Adverse Events ............................................ 68 
12.7 
Follow up Procedures for Adverse Events .................................................. 70 
12.8 
Potential Cases of Drug Induced Liver Injury............................................. 70 
12.9 
Notification of Safety Information to Investigators, Regulatory 
Authorities and Ethics Committees. ............................................................ 71 
13. 
STATISTICAL CONSIDERATIONS ......................................... 73 
13.1 
Sample Size, Power and Significance Levels ............................................. 73 
13.2 
Interim Analysis .......................................................................................... 73 
13.3 
Analysis Sets ............................................................................................... 73 
13.3.1 
Safety Set .................................................................................................. 73 
13.3.2 
Pharmacokinetic Analysis Set .................................................................. 73 
13.3.3 
Protocol Deviations .................................................................................. 73 
13.4 
General Considerations ............................................................................... 73 
13.5 
Accountability and Background Characteristics ......................................... 74 
13.5.1 
Enrollment and Disposition ...................................................................... 74 
13.5.2 
Baseline and Demographic Characteristics .............................................. 74 
13.5.3 
Medical History ........................................................................................ 74 
13.5.4 
Concomitant Medication .......................................................................... 74 
13.6 
Endpoints and Statistical Methods .............................................................. 74 
13.6.1 
Primary Endpoint(s) .................................................................................. 74 
13.6.2 
Secondary Endpoint(s) .............................................................................. 74 
13.6.3 
Pharmacokinetics ...................................................................................... 75 


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13.6.4 
Safety ........................................................................................................ 76 
13.6.4.1 
Treatment Compliance and Extent of Treatment Exposure .................. 76 
13.6.4.2 
Adverse Events...................................................................................... 76 
13.6.4.3 
Clinical Laboratory Data ....................................................................... 76 
13.6.4.4 
Columbia-Suicide Severity Rating Scale, Vital Signs, 12-lead 
Electrocardiogram, Physical Examination and Other Safety Data ....... 77 
13.6.4.5 
Seizure Data .......................................................................................... 77 
14. 
DATA SAFETY MONITORING COMMITTEE ..................... 77 
15. 
REGULATORY AND ETHICAL OBLIGATIONS .................. 78 
15.1 
Declaration of Helsinki ............................................................................... 78 
15.2 
Informed Consent ........................................................................................ 78 
15.3 
Institutional Review Board/Ethics Committee ............................................ 78 
15.4 
Pre-Study Documentation Requirements .................................................... 79 
15.5 
Participant Confidentiality .......................................................................... 79 
16. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ............... 81 
16.1 
Protocol Amendments and End of Study or Termination ........................... 81 
16.2 
Study Documentation and Storage .............................................................. 81 
16.3 
Study Monitoring and Data Collection ....................................................... 82 
16.4 
Quality Assurance ....................................................................................... 84 
16.5 
Compensation .............................................................................................. 84 
16.6 
Publication Policy........................................................................................ 84 
16.7 
Intellectual Property Rights ......................................................................... 85 
16.8 
Confidential Information ............................................................................. 85 
17. 
REFERENCES .............................................................................. 86 


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Table of Appendices 
APPENDIX 1. 
Schedule of Assessments 
89 
APPENDIX 2. 
Study Personnel 
92 
Appendix 3.1 
Investigator Details 
92 
Appendix 3.2 
Sponsor Contact Details 
92 
 
 


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List of In-text Tables 
Table 3.3.1-1 
Epidiolex Adverse Events ........................................................ 33 
Table 5.1-1 
Formulation of GWP42003-P Oral Solution ........................... 37 
Table 5.2-1 
Formulation of Placebo Oral Solution ..................................... 37 
Table 8.1.2-1 
Dose Up-titration Regimen* .................................................... 44 
Table 9.1.9-1 
Hematology, Biochemistry, Urinalysis and THC Screen ........ 49 
 
 
 


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List of In-text Figures 
Figure 1-1 
Study Design and Treatment Schema ...................................... 16 
Figure 1-2 
Study Design and Treatment Schema ...................................... 17 
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 ....................................... 57 
 


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List of Abbreviations 
AE 
Adverse Event 
AEDs 
Antiepileptic Drugs 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC(0–∞) 
Area under the concentration time curve from zero to infinity with 
extrapolation of the terminal phase 
AUC(0–t) 
The area under the plasma concentration versus time curve, from 
time zero to ‘t’ (where t = the final time of positive detection) as 
calculated by the linear trapezoidal method 
BP 
Blood Pressure 
CBD 
Cannabidiol 
CI 
Confidence Interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CLB 
Clobazam 
Cmax 
Maximum measured plasma concentration 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CYP 
Cytochrome P450 
EC 
Ethics Committee 
ECG 
12-lead electrocardiogram 
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 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ITT 
Intention to Treat 


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IVRS 
Interactive Voice Response System 
LEV 
Levetiracetam 
LOCF 
Last Observation Carried Forward 
MMRM 
Mixed-effects Model Repeated Measures 
N-CLB 
N-desmethylclobazam 
OLE 
Open label extension 
PBPK 
Physiologically-based pharmacokinetic interactions 
PI 
Principal Investigator 
PP 
Per Protocol 
PVD 
Pharmacovigilance Department 
QTcB 
Heart rate corrected QT interval using Bazett’s formula 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SFU 
Safety follow up 
STP 
Stiripentol 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
t½ 
Terminal half-life 
TBL 
Total bilirubin 
THC 
∆9-tetrahydrocannabinol 
tmax 
Time to the maximum measured plasma concentration 
TPM 
Topiramate 
ULN 
Upper Limit of Normal 
USA 
United States of America 
VNS 
Vagus Nerve Stimulation 
VPA 
Valproate 
 


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Definition of Terms 
Term 
Definition 
Baseline period 
The period from screening (Visit 1) to enrollment (Visit 2). 
Convulsive seizures 
Tonic-clonic, tonic, clonic or atonic seizures. 
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 is enrolled and begins PK sampling. 
End of treatment 
Completion of the treatment period (Visit 5 or Visit 12) or 
withdrawal. 
End of study 
Last patient’s last visit / last contact. 
IMP 
Investigational Medicinal Product (Study Medication). Used 
to describe both investigational active product and reference 
therapy (placebo). 
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. 
Partial seizures 
Partial (focal) seizures occur when the electrical activity 
remains in a limited area of the brain. 
Status epilepticus 
Seizures lasting for 30 minutes or longer. 
Sub-types of seizures 
Seizure sub-types can be tonic, clonic, tonic-clonic, atonic, 
myoclonic, absence (typical and atypical), countable partial 
and other partial. 
 


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2. 
OBJECTIVES 
2.1 
Primary 
To determine whether GWP42003-P affects the pharmacokinetic (PK) profile of 
clobazam (CLB) and its primary metabolite N-desmethylclobazam (N-CLB). 
2.2 
Secondary 
To assess the safety and tolerability of GWP42003-P in the presence of CLB. 
 
 


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3. 
BACKGROUND AND RATIONALE 
3.1 
Disease 
Epilepsy is a common disorder1. Approximately 1% of the world’s population is 
chronically affected by epilepsy2. It shows no particular geographic distribution and 
the gender distribution is more or less equal. The incidence of epilepsy is greater in 
childhood and in elderly people2,3,4,5. Focal seizures represent the most frequent 
seizure type (around 60% of all cases of epilepsy, and a substantial percentage of 
them are not well controlled)6. 
Overall, and despite the introduction of a substantial number of new antiepileptic 
drugs (AEDs) in the last two decades, around 30% of patients remain refractory to 
currently available treatment7,8,9. In addition, most currently approved AEDs are 
associated with significant motor and cognitive adverse reactions10,11. 
Currently available AEDs each belong to one of a large number of different classes. 
The principal targets for existing AEDs tend to be either modulators of voltage-
dependent ion channels, enhancers of inhibitory neurotransmission, and attenuators of 
excitatory neurotransmission, with the aim being to reduce neuronal 
excitotoxicity12,13. 
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 Δ9-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 
0.5% (w/w) THC. 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 


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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 conductance and acts on other G-protein-coupled receptors such as 
the transient receptor potential channel TRPV114 and the orphan receptor GPR5515. 
Importantly, in contrast to THC, CBD lacks detectable psychoactivity. CBD has 
demonstrated anticonvulsant, antipsychotic, anxiolytic, neuroprotective, antioxidant 
and anti-inflammatory activity16. Very little data concerning 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 humans17. 
3.3 
Rationale 
CBD has shown therapeutic potential as an AED, with preclinical studies 
demonstrating anticonvulsant effects in a number of animal models of seizure16,18,19. 
Although no placebo-controlled trials have been completed to date, 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 either > 80% reduction in seizure frequency or complete 
seizure freedom20. The CBD-enriched cannabis was behaviorally well tolerated and 
children often experienced improved sleep, increased alertness and better mood. 
There has been a program of expanded access by GW Pharma Ltd (GWP) in the USA, 
primarily in children with severe epilepsy, that has shown encouraging reports of 
reductions in multiple seizure types with good tolerability in 151 exposures21. 
Population-based studies of drug utilization demonstrate that 19-24% of patients with 
epilepsy use polytherapy with AEDs22,23,24. In recent studies of children and adults 
with refractory epilepsy, 64 % used polytherapy with two or more AEDs, resulting in 
a considerable risk of interactions25,26. CLB is a widely used AED, prescribed with 
other medication(s) to control seizures in adults and children two years of age and 
older who have Lennox-Gastaut syndrome (a disorder that causes seizures and often 
developmental delays). The pharmacological action of CLB is to decrease abnormal 
electrical activity in the brain via allosteric activation of the ligand-gated 
γ-aminobutyric acid (A) receptor. 
CLB is in a class of medications called benzodiazepines. Similar to other 
benzodiazepine medications, CLB is metabolized by cytochrome P450 (CYP) 
enzymes (mainly in the liver). This metabolism results in the formation of an active 
metabolite N-CLB, amongst others. 


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CYP enzymes are a family of heme-containing enzymes responsible for the 
metabolism of over half of all prescribed medications and interactions with these 
enzymes are the major source of physiologically-based pharmacokinetic (PBPK) 
interactions between drugs. It is anticipated that patients taking GWP42003-P may 
also be taking CLB and as CBD has been shown to both inhibit CYP450 enzymes in 
vitro (Ki CYP3A4 = 1.5 μM) and induce CYP450 enzymes in vitro (EC50 CYP3A4 
= 1.2 μg/mL) a possibility of a pharmacokinetic (PK) interaction between CBD and 
CLB exists. Furthermore, CLB has been shown to undergo PBPK interactions with 
other AED medications via both CYP induction (such as with felbamate where the 
formation of the active metabolite of CLB, N-CLB was increased several-fold27) and 
also CYP inhibition (such as with stiripentol where serum concentrations of CLB 
were increased and metabolites decreased28,29,30). Given the high likelihood that 
patients prescribed CBD will also be using CLB, it is the aim and purpose of this 
study to determine whether a PK interaction between CBD and CLB exists. 
3.3.1 
Selection of Study Doses 
Doses up to 800 mg GWP42003-P per day for up to eight weeks have been well 
tolerated in adults in GW Research Ltd (GW) clinical study GWMD09112, which, 
assuming an average weight of 70 kg, equates to a daily dose of 11.4 mg/kg. In the 
literature, doses of GWP42003-P have been given up to 1500 mg GWP42003-P per 
day for four weeks in adults, which, in a 70 kg human equates to a daily dose of 
21.4 mg/kg GWP42003-P. 
Data on the safety of GWP42003-P is emerging from the physician-initiated 
Epidiolex® Expanded Access Program being conducted in the USA. This program has 
been running since January 2014 and at the time of writing had data on 63 patients. 
The mean maximum exposure achieved in this patient population of refractory 
epilepsies was a daily dose of 24.4 mg/kg (n=59 patients) with a maximum dose of 
51 mg/kg in one patient. Please see below for a breakdown of the groups: 
• ≤20 mg/kg GWP42003-P n=13 (21%) 
• >20 mg/kg - ≤30 mg/kg GWP42003-P n=40 (64%) 
• >30 mg/kg - ≤40 mg/kg GWP42003-P n=4 (6%) 
• >40 mg/kg GWP42003-P n=2 (3%) 
• Dose not reported n=4 (6%) 
Eleven patients had a daily GWP42003-P dose of >25 mg/kg, of which five did not 
report any adverse events (AEs). Of note, the patient who received 51 mg/kg did not 
have any AEs at this dose. The remaining six patients experienced AEs as 
documented in the Table 3.3.1-1 below: 


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Table 3.3.1-1 
Epidiolex Adverse Events 
Adverse Event Term 
Number of Events 
Loose stools / urgent bowel 
movements 
2 
Increase in seizures 
2 
Drowsiness 
1 
Aspiration pneumonia 
1 
Lethargy 
1 
Decreased appetite 
1 
Dyskinesia 
1 
Urinary tract infection 
1 
Based on the above, a daily dose up to 20 mg/kg/day (given as two divided doses) has 
been selected for the GWP42003-P dose in the current study, including a titration 
period with daily increments of 2.5 mg/kg and 5 mg/kg. At the end of the treatment 
period, patients will be given the option of continuing onto an open label extension 
(OLE) period if the investigator and patient both agree that it is in their best interest. 
During the OLE doses may be adjusted up or down, dependent on investigator 
opinion, to a maximum daily dose of 30 mg/kg GWP42003-P. 
3.4 
Clinical Hypothesis 
CBD can act as both a CYP inhibitor and inducer in human hepatocytes in vitro. 
Therefore, the potential for PK interactions with other drugs that are metabolized by 
CYP450 enzymes exists. The hypothesis is that the in vivo PK of CLB and its major 
metabolite (N-CLB) may be altered (increased or decreased) by the chronic 
administration of GWP42003-P. 
 
 


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4. 
EXPERIMENTAL PLAN 
4.1 
Study Design 
This phase 2, placebo-controlled study consists of a 34 day, double-blind phase 
followed by an optional maximum one year OLE. Patients will continue to take CLB 
as advised by their physician for the duration of the study. GWP42003-P/placebo will 
be taken twice daily immediately after their CLB dose. 
Patients will enter the study and begin a 10 day GWP42003-P or placebo titration 
phase. During this period patients will be up-titrated to a maintenance dose or 
equivalent of 20 mg/kg/day. Patients will continue to take this maintenance dose of 
GWP42003-P or placebo for 21 days (Days 12 to 32). 
Upon completion of the treatment period (Day 34) patients will be invited to receive 
GWP42003-P during the OLE phase. If a patient enters the OLE they will take 
GWP42003-P as advised by the investigator. If a patient chooses not to enter the 
OLE, and/or the investigator does not feel it is in their best interests, they will taper 
off their GWP42003-P/placebo treatment by reducing their maintenance dose by 10% 
per day until dosing has ceased. For those patients not entering the OLE, dosing will 
end on Day 43 and they will receive a telephone follow-up visit four weeks after the 
end of GWP42003-P/placebo dosing (Day 71). 
PK samples will be taken on two occasions during the blinded phase of the study: 
• Day 1 (Visit 2) before beginning treatment (patients will be taking CLB only). 
• Day 33 (Visit 4) following 21 days of GWP42003-P or placebo maintenance 
(patients will be taking CLB and GWP42003-P or placebo). 
Ten samples will be taken during each PK assessment. PK samples should be taken at 
time points in respect to the morning dose of CLB. The time points are as follows: 
Pre-dose, 15min, 30min, 1h, 1.5h, 2h, 4h, 6h, 12h and 24h. PK samples will be 
quantitatively analyzed for CLB, N-CLB, valproate (VPA), stiripentol (STP),  
levetiracetam (LEV) and topiramate (TPM) at Visit 2  and CLB, N-CLB, VPA, STP, 
LEV, TPM, CBD, CBD major metabolites, THC and THC major metabolites at 
Visit 4. 
Patients should try to be consistent in the timing of their food intake in relation to 
dosing throughout the blinded phase of the study. 
Upon entry into the OLE the dose of GWP42003-P and other AEDs may be adjusted 
up or down to a maximum of 30 mg/kg/day. The OLE will last for a maximum of one 
year or until marketing authorization is granted; whichever is earlier. 


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Patients will be required to keep a paper diary to note the time and dose of IMP and 
CLB administration each morning and evening and to record any AEs that may occur 
whilst receiving IMP and any other medications. Patients will also be required to 
record the number and type of seizures for each day whilst on the study. 
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 are 
provided in Section 8 and Section 9 respectively. 
4.1.1 
Primary Endpoint 
The primary endpoints of the study are the PK parameters (Cmax, tmax, AUC(0–∞), 
AUC(0–t), t½) of the following analytes: 
• CLB 
• N-CLB 
• CBD 
• CBD major metabolites 
4.1.2 
Secondary Endpoint(s) 
To assess the safety and tolerability of GWP42003-P compared with placebo when 
taken in combination with CLB. Safety and tolerability will be assessed using the 
following parameters: 
• AEs 
• 12-lead electrocardiogram (ECG) 
• Clinical laboratory parameters (clinical chemistry, hematology and urinalysis) 
• Vital signs 
• Columbia-Suicide Severity Rating Scale (C-SSRS) 
• Seizure frequency 
• Abuse liability 
• CYP2C19 and CPY3A4 patient genotype analysis 
 
PK parameters (Cmax, tmax, AUC(0–∞), AUC(0–t), t½) of the following analytes: 
• THC 
• THC major metabolites 
4.2 
Number of Centers 
An estimated number of seven centers are expected to participate in this study. 


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4.3 
Number of Patients 
A total of 20 patients will be enrolled into the study. Recruitment for the study will be 
competitive between participating sites. 
The sample size calculation is explained fully in Section 13.1. 
 
 


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5. 
INVESTIGATIONAL MEDICINAL PRODUCT 
Please refer to the separate Pharmacy Manual for more detailed information on the 
IMP. 
5.1 
GWP42003-P Oral Solution 
GWP42003-P oral solution is presented as a pale yellow 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 
Placebo Oral Solution 
Placebo oral solution contains the excipients sesame oil and anhydrous ethanol with 
added sweetener (sucralose) and strawberry flavoring Table 5.2-1. 
Table 5.2-1 
Formulation of Placebo Oral Solution 
Material 
Quantity 
Anhydrous ethanol 
79 mg/mL 
Sucralose 
0.5 mg/mL 
Strawberry flavoring 
0.2 mg/mL 
Sesame oil 
make up to 1 mL 
5.3 
Packaging, Storage and Drug Accountability 
(Cannabidiol/Placebo) 
5.3.1 
Packaging and Labelling  
The IMP will be manufactured and packaged by 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 weight of each patient. 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 labelled and packaged. Label text will comply with European Union 
(EU) guidance on Good Manufacturing Practice, Annex 13 Labelling and will be fully 
described in the separate Pharmacy Manual. In addition, any local country 


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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 investigator, or main 
contact for information about the product or the clinical trial, will be provided 
separately to the patient. 
5.3.2 
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. 
5.3.3 
Supply and Return of Investigational Medicinal Product 
Once a site has been activated 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 and the condition of the drug. Details of the IMP received will be recorded in 
the IMP accountability record. The site will acknowledge IMP receipt and will 
complete any receipt forms required. IMP will be dispensed and returned as detailed 
in Section 5.3.4 with further IMP shipments to be requested as necessary. 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. 
5.3.4 
Investigational Medicinal Product Accountability 
The investigator has overall responsibility for the accountability of all used and 
unused IMP. A drug accountability record for the IMPs must be kept current and 
should contain: 
• The dates and quantities of IMP received from GWP. 


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• Patient’s identification. 
• Date and quantity of IMP dispensed. 
• The initials of the dispenser. 
• Date and quantity of IMP returned to the investigator/pharmacy. 
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 authorized GW or GWP 
representatives and local officials or regulatory agency inspectors. 
Please refer to the separate Pharmacy Manual for more detailed information on the 
IMP. 
5.4 
Clobazam 
Patients will use their own supply of CLB throughout the study. CLB usage will be 
recorded by the investigator. CLB is only an IMP for the blinded phase of the study. 
6. 
PARTICIPANT ELIGIBILITY 
Investigators will be required to maintain a log that includes limited information about 
all screened patients (initials, age, and gender; as allowed per local regulations) and 
outcome of screening. 
6.1 
Inclusion Criteria 
For inclusion in the study patients must fulfil ALL of the following criteria: 
6.1.1 
Male or female patients aged 18 to 55 years inclusive. 
6.1.2 
Patient must have epilepsy as determined by the investigator and be taking 
CLB. 
6.1.3 
Patient must have a documented magnetic resonance imaging/computerized 
tomography of the brain that ruled out a progressive neurologic condition. 
6.1.4 
Patient must have experienced at least one seizure of any type (i.e., 
convulsive: tonic-clonic, tonic, clonic, atonic; focal: focal seizures with 
retained consciousness and a motor component, focal seizures with 
impaired consciousness focal seizures evolving to bilateral secondary 
generalization) within the two months prior to randomization.  
6.1.5 
Patients must be taking CLB and no more than two other AEDs during the 
course of the study. 
6.1.6 
AED(s), including CLB, must be stable for four weeks prior to screening 
and regimen must remain stable throughout the duration of the blinded 
phase of the study. 


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6.1.7 
Intervention with vagus nerve stimulation (VNS) and/or ketogenic diet 
must be stable for four weeks prior to baseline and patient/caregiver must 
be willing to maintain a stable regimen throughout the blinded phase of the 
study. 
6.1.8 
Patients must abstain from alcohol during the blinded phase of the study. 
6.1.9 
Patient is available to attend all PK visits within the required visit window. 
6.1.10 
Patient and/or legal representative must be willing and able to give 
informed consent for participation in the study 
6.1.11 
Patient and/or legal representative must be willing and able (in the 
investigator’s opinion) to comply with all study requirements. 
6.1.12 
Patient is willing for his or her name to be notified to the responsible 
authorities for participation in this study, as applicable. 
6.1.13 
Patient is willing to allow his or her primary care practitioner and 
consultant, if appropriate, 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 has clinically significant unstable medical conditions other than 
epilepsy. 
6.2.2 
Patients on CLB at doses above 20 mg per day. 
6.2.3 
Patients taking CLB intermittently as rescue medication. 
6.2.4 
Patient has a history of symptoms (e.g., dizziness, light-headedness, blurred 
vision, palpitations, weakness, syncope) related to a drop in blood pressure 
(BP) due to postural changes. 
6.2.5 
Any history of suicidal behavior or any suicidal ideation of type four or five 
on the C-SSRS in the last month or at screening. 
6.2.6 
Patient has had clinically relevant symptoms or a clinically significant 
illness in the four weeks prior to screening or enrollment, other than 
epilepsy. 
6.2.7 
Patient has consumed alcohol during the seven days prior to enrollment and 
is unwilling to abstain during the blinded phase of the study. 
6.2.8 
Patient is currently using or has in the past used recreational or medicinal 
cannabis, or synthetic cannabinoid based medications (including Sativex®) 
within the three months prior to study entry. 
6.2.9 
Patient has any known or suspected history of any drug abuse or addiction. 
6.2.10 
Patient is unwilling to abstain from recreational or medicinal cannabis, or 
synthetic cannabinoid based medications (including Sativex) for the 
duration of the study. 
6.2.11 
Patient has consumed grapefruit or grapefruit juice seven days prior to 
enrollment and is unwilling to abstain from drinking grapefruit juice within 
seven days of PK visits. 
6.2.12 
Patient has any known or suspected hypersensitivity to cannabinoids or any 
of the excipients of the IMP, e.g., sesame oil. 


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6.2.13 
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 three 
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.  
6.2.14 
Female patient who is pregnant (positive pregnancy test), lactating or 
planning pregnancy during the course of the study and for three months 
thereafter. 
6.2.15 
Patients who have received an IMP within the 12 weeks prior to the 
screening visit. 
6.2.16 
Patient is taking felbamate and they have been taking it for less than 
one year prior to screening. 
6.2.17 
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 the patient’s ability to 
participate in the study. 
6.2.18 
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. 
6.2.19 
Patient has significantly impaired hepatic function at screening (Visit 1) or 
enrollment (Visit 2), defined as any of the following:  
- 
Alanine aminotransferase (ALT) or Aspartate aminotransferase (AST) 
> 5 × upper limit of normal (ULN). 
- 
ALT or AST > 3 × ULN and total bilirubin (TBL) >2 × ULN or 
international normalized ratio (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%).  
This criterion can only be confirmed once the laboratory results are 
available; patients randomized into the study who are later found to meet 
this criterion must be withdrawn from the study. 
6.2.20 
Patient has a prolonged QTcB (> 450 msec for males and > 470 msec for 
females).  
6.2.21 
Unwilling to abstain from donation of blood during the study. 
6.2.22 
Travel outside the country of residence planned during the study, unless the 
patient has confirmation that the IMP is permitted in the destination 
country/state. 
6.2.23 
Patients previously enrolled into this study. 
 


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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 forms (ICFs) and other patient information material. 
Patients will be considered enrolled in the study from the time of providing written 
informed consent. All patients, or legal representatives, where appropriate, must 
personally sign and date the consent form prior to any procedures being performed 
(refer to Section 9.1.2 and Section 15.2). 
7.1 
Treatment Assignment 
At the start of Visit 1, patients will be allocated a unique patient number, consisting of 
a four digit GW center number and a three digit patient identification number. The 
three digit patient number will be assigned in ascendant numerical order at each site. 
The unique patient number will be preceded by a unique letter. For example, 
W1234001, denoting patient 001 at site 1234. GWP will provide all 
GWP42003-P/placebo packed and labelled. Following enrollment at Visit 2, patients 
will be allocated a pre-packed numbered IMP. 
7.2 
Randomization 
This is a double-blind study. Patients will be randomized in a 4:1 ratio to receive 
20 mg/kg GWP42003-P or placebo. 
 
 


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8. 
TREATMENT PROCEDURES 
8.1 
Investigational Medicinal Product Dosage, Administration and 
Schedule 
The IMP will consist of three types of medication: 
• GWP42003-P oral solution containing 100 mg/mL CBD. 
• Placebo oral solution containing excipients. 
• CLB (patient supplied). 
The GWP42003-P/placebo will be presented as an oral solution containing either the 
active pharmaceutical ingredient and excipients (in the case of GWP42003-P) or only 
excipients (in the case of placebo). For details regarding GWP42003-P/placebo 
formulations, see Section 5. 
All patients will be weighed during the study visits and the daily volumes of 
GWP42003-P/placebo solution to be taken during the titration period, and for the 
remainder of the study, will be calculated and provided to the patient and/or caregiver. 
Further information on dispensing procedures will be provided in a separate 
Pharmacy Manual. 
Each patient will take their first dose of GWP42003-P/placebo at Visit 2, Day 2 in the 
clinic. Patients not entering the OLE will take their final maintenance dose of 
GWP42003-P/placebo at Visit 4 (Day 33) in the clinic. Patients entering the OLE will 
take their final dose of IMP at Visit 11 (one year after the end of the blinded phase of 
the study) or sooner (if marketing authorization is granted within one year). 
Patients will use their own supply of CLB throughout the study. Patients will continue 
on the dose that they were on at screening for the blinded phase of the study. CLB 
will only be an IMP for the blinded section of the study.    
8.1.1 
Dose Administration 
GWP42003-P/placebo will be administered orally by the patient or their caregiver 
twice each day (morning and evening) using the syringe(s) provided. 
GWP42003 P/placebo should be taken immediately after the patient’s usual CLB 
administration. The GWP42003-P/placebo should be swallowed, as per the intended 
commercial therapeutic route, and may be taken with other concomitant medications, 
as directed by the investigator. 


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8.1.2 
Dose Escalation and Dose Adjustments 
Patients will enter the blinded phase of the study and will be up-titrated over ten days 
(Day 2 to Day 11) to a maintenance dose or equivalent of GWP42003-P/placebo of 
20 mg/kg/day. If GWP42003-P is not tolerated then the dose can be reduced 
accordingly at the discretion of the investigator. The titration regimen is described in 
Table 8.1.2-1. 
Table 8.1.2-1 Dose Up-titration Regimen* 
Day - GWP42003-
P/Placebo (Blinded 
Period) 
Dose Level 
(GWP42003-P or 
equivalent placebo) 
Open label 
Extension** 
(GWP42003-P only)  
Day  
Dose Level 
GWP42003-P  
2 
2.5 mg/kg 
34 
2.0 mg/kg 
3 
2.5 mg/kg 
35 
4.0 mg/kg 
4 
5.0 mg/kg 
36 
6.0 mg/kg 
5 
5.0 mg/kg 
37 
8.0 mg/kg 
6 
7.5 mg/kg 
38 
10.0 mg/kg 
7 
7.5 mg/kg 
39 
12.0 mg/kg 
8 
10.0 mg/kg 
40 
14.0 mg/kg 
9 
10.0 mg/kg 
41 
16.0 mg/kg 
10 
15.0 mg/kg 
42 
18.0 mg/kg 
11 
15.0 mg/kg 
43 
20.0 mg/kg 
12 onwards 
20.0 mg/kg 
44 
20.0 mg/kg*** 
* GWP42003-P /placebo is to be taken twice daily. Total daily doses are shown. 
** Only patients who were taking placebo during the double-blind period will up-titrate according to 
this schedule during the OLE period. Those taking GWP42003-P during the double-blind period will 
down-titrate their blinded IMP whilst simultaneously up-titrating with GWP42003-P, thus maintaining 
a daily dose of 20 mg/kg/day GWP42003-P throughout. 
*** The GWP42003-P dose of 20 mg/kg/day can be adjusted during the OLE period, after Visit 5, at 
the investigator’s discretion: up to a maximum dose of 30 mg/kg/day. It may also be adjusted down (no 
minimum). 
The titration regimen defined above should be followed to the maximum dose 
(20 mg/kg/day). Should an AE occur during titration which is attributable to IMP or 
concomitant AED, then IMP dose should be reduced to the next lower dose. Any 
other changes in concomitant AED therapy should be reviewed with the medical 
monitor before being initiated. 
For those patients who do not enter the OLE the dose of GWP42003-P/placebo will 
taper off over 10 days beginning on Day 34. The patient will reduce the dose by 10% 
of the maintenance dose each day and treatment will end on Day 43. 
Patients who enter the OLE period will be transitioned to the OLE treatment over a 
10-day period in order to maintain blinding, simultaneously down-titrating blinded 
GWP42003-P /placebo whilst up-titrating open-label GWP42003-P. As such, patients 


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who were taking GWP42003-P during the blinded period will maintain their 
20 mg/kg/day dose throughout the transition from the blinded period into the OLE 
period and patients who received placebo during the blinded period up-titrate slowly 
to the 20 mg/kg/day dose in the OLE period. After this has taken place after Visit 5, 
the maintenance dose of GWP42003-P may be adjusted up or down at the discretion 
of the investigator to a maximum of 30 mg/kg/day (no minimum). 
8.2 
Concomitant Therapy 
Doses of any concomitant AEDs, including CLB, must have been stable for at least 
four weeks prior to screening and must remain stable throughout the blinded phase of 
the study. If there are symptoms of toxicity suspected to be from a drug interaction, 
the investigator may adjust GWP42003-P/placebo or the CLB or other AEDs after 
discussion with the medical monitor. 
The use of rescue medication is allowed if necessary. The use of oxygen may be 
considered as rescue medication if used as required. Any medication, other than the 
IMP, taken during the study must be recorded on the Case Report Form (CRF). 
Any non-pharmacological therapies (e.g., ketogenic diet, VNS) must also be stable up 
to four weeks prior to baseline and throughout the duration of the study. 
8.3 
Prohibited Therapy During Study Period 
The following medications are prohibited for the duration of the study starting from 
acquisition of patient consent. However, any patients taking these medications after 
screening 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. 
• Any new medications or interventions for epilepsy (including ketogenic diet 
and VNS) or changes in dosage. 
• Patients should not take any more than three AEDs inclusive of CLB. 
• Recreational or medicinal cannabis or synthetic cannabinoid based 
medications (including Sativex) within three months prior to or during the 
study. 
If any other IMP is taken as part of a clinical trial within twelve weeks of the 
screening visit or during the study, the patient must be withdrawn from this study.  
8.4 
Compliance in Investigational Medicinal Product Administration 
Patients or their caregivers will record the total volume of IMP, administered on each 
treatment day, using the paper diary and will be asked to return all IMP (used and 
unused) at each subsequent visit. The site will check the returned IMP against the 


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usage recorded in the diary and the projected usage. 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. 
Records of IMP accountability will be maintained according to Section 5.3.4. 
8.5 
Access to Blinded Treatment Assignment 
The identity of IMP assigned to patients will be held by the IVRS. The principal 
investigator (PI) at each center is responsible for all trial-related medical decisions 
and is responsible for ensuring that information on how to access the IVRS is 
available to the relevant staff in case of an emergency and unblinding is required. A 
patient’s treatment assignment must only be unblinded when knowledge of the 
treatment is essential to make a decision on the medical management of the patient. 
Unblinding for any other reason will be considered a protocol deviation. 
The investigator is encouraged to contact GW to discuss the rationale for unblinding. 
However, to prevent delays to the investigator or medical personnel responding to a 
potentially emergent situation, unblinding of study medication will not be dependent 
upon the investigator receiving approval from GW (i.e., the investigator will be able 
to obtain the code break information independent of contacting GW). 
If the investigator does unblind they must contact GW within one working day of the 
event and must document the time, date and reasons for unblinding in the patient’s 
CRF. 


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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 in 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 
9.1.1 
Contraception 
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 three months thereafter. A highly effective method of 
birth control is defined as those which result in a low failure rate (i.e., less than 1% 
per year) when used consistently and correctly such as combined or progesterone only 
oral contraceptives, intrauterine device, intrauterine hormone-releasing system, 
bilateral tubal occlusion, vasectomized partner or sexual abstinence6. Abstinence, as 
referenced above, 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. The use of hormonal contraception must be supplemented 
with a barrier method (preferably male condom). 
9.1.2 
Informed Consent 
Adult patients with an adequate level of understanding must personally sign and date 
the IRB/EC approved ICF(s) before any study specific procedures are performed or 
any patient related data is recorded for the study. For adult patients with an 
insufficient level of understanding of what is proposed, only personal legal 
representative consent will be sought. The informed consent process should be 
documented within the patient notes. 
GW requires a physician to be present for consent and to also sign the ICFs. 
9.1.3 
Demographics 
Patient demographics will be recorded at Visit 1. The following information will be 
obtained for each patient: date of birth, gender and race (if allowed per local 
regulations). 


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9.1.4 
Medical History 
Relevant, significant medical history (including seizure information since diagnosis, 
history of epilepsy-specific genetic testing and all prior AEDs taken) will be obtained 
during Visit 1 and is defined as any condition or disease that: 
• May affect the condition under study. 
• Is ongoing on entry into the study. 
9.1.5 
Concomitant Medication 
Details of all current and recent medication (i.e., taken within the previous 28 days) 
including AEDs will be recorded at the screening visit (Visit 1) and reviewed at each 
subsequent visit. AEDs used during the study should be maintained at a stable dose. 
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 the 
screening visit, as defined in Section 8.3. 
9.1.6 
Physical Examination 
A physical examination will be performed at the screening visit (Visit 1) to ensure 
that the patient is eligible to enter the study. To ensure patient safety, further physical 
examinations will be performed at every hospital visit. Physical examinations will 
include height (at screening) and body weight measurements. 
9.1.7 
Vital Signs 
Vital sign measurements, taken after five minutes rest in a sitting position, will be 
completed alongside the physical examination at all visits. Postural BP will be 
assessed after five minutes in supine position and, if possible, two minutes in standing 
position. The pulse rate must also be measured as part of the vital sign assessments. 
BP and pulse rate must be recorded using the same arm throughout the study. 
9.1.8 
12-Lead Electrocardiogram 
An ECG will be performed, after five minutes in supine position, at all hospital visits. 
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 be undertaken at all hospital visits and will include hematology, 
biochemistry, and urinalysis (provided urine can be obtained, with the exception of 


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screening where a urine sample for THC screen must be obtained). A serum alcohol 
test will be performed at Visits 1, 2 and 4. A serum pregnancy test (if appropriate) 
will also be performed at Visit 1. 
Urine samples for biochemistry will be analyzed at the study center by use of a 
dipstick with any relevant findings being sent for further laboratory based urinalysis 
(urinalysis, microscopy, culture and sensitivity, as applicable). 
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.  
Table 9.1.9-1 
Hematology, Biochemistry, Urinalysis and THC Screen 
Biochemistry 
(serum) 
Hematology 
(whole blood) 
Urinalysis 
(urine) 
Pregnancy 
Test 
THC screen 
(urine) 
Alanine aminotransferase 
(ALT) 
Hematocrit 
Bilirubin 
Serum 
THC 
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 
 
 
 
 
Potassium 
 
 
 
 
Prolactin 
 
 
 
 
Prothrombin time (plasma) 
 
 
 
 
Sodium 
 
 
 
 
Total bilirubin (TBL) 
 
 
 
 
Total protein 
 
 
 
 
Urea (BUN) 
 
 
 
 
Trigylcerides 
 
 
 
 
 
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 by the investigator 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 


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investigator is satisfied that the abnormality is not related to the IMP and needs no 
further investigation. 
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 
them 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 in the four weeks 
prior to screening. 
9.1.10 
Pharmacokinetic Analyses 
The plasma concentration/time curves of CLB, N-CLB, VPA, STP, LEV and TPM 
will be assessed at Visit 2 (Day 1 and Day 2) and CLB, N-CLB, VPA, STP, LEV, 
TPM, CBD, CBD major metabolites, THC and THC major metabolites at Visit 4 
(Day 33 and Day 34). Patients will be given their daily dose of CLB at a scheduled 
time during Visit 2 and Visit 4 and the GWP42003-P/placebo immediately afterwards 
(Visit 4 only) to facilitate the accurate timing of blood samples required for PK 
analysis. Blood samples will be taken by either direct venipuncture or an indwelling 
cannula inserted into a forearm vein at the following times: Pre-dose and, 15 minutes, 
30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 12 hours and 24 hours after 
dosing. The timing of each PK sample will be relative to the morning dose of CLB. 
The pre-dose blood sample will be taken within 30 minutes prior to dosing. The 
allowable window for post-dose blood sample collection is ±2 minutes up to and 
including 1 hour post-dose, ±5 minutes from 1.5 hours up to and including 6 hours 
post-dose and ±1 hour at 12 hours and 24 hours post-dose. 
In the event of an AE that, in the opinion of the investigator, is related to a 
concomitant AED, additional blood samples may be collected. 
Analysis of all PK samples will be conducted at a central clinical laboratory. Sample 
volume requirements and processing procedures will be detailed in a separate 
laboratory manual. 
9.1.11 
Genetic Testing 
Genetic testing will only be conducted if specific consent is obtained from the 
participant or their legal representative. There is a separate ICF for this. 
Genetic testing will be conducted to look at the CYP450 genes, with particular focus 
on CYP 2C19 and CYP 3A4, involved in the metabolization of AEDs and 
GWP42003-P.     


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9.1.12 
Columbia Suicide Severity Rating Scale  
The C-SSRS is to be completed by the investigator or his/her qualified designee at all 
hospital visits. Qualified designee is defined as physician, osteopath, nurse 
practitioner, clinical psychologist or physician’s assistant who is licensed and has 
completed the C-SSRS training within the last two years. It is a brief standardized 
measure that uniquely assesses the essential information (behavior, ideation, lethality 
and severity) and distinguishes between suicidal occurrences and non-suicidal 
self-injury. The survey should be completed by the same assessor, where possible, 
throughout the study. 
If the investigator or his/her qualified designee feel that the patient is either unable to 
answer the questions presented in C-SSRS, or that the questions are causing undue 
stress to the patient, the questionnaire may be skipped and this must be documented in 
the patient notes. 
9.1.13 
Patient Diary 
Patients or their caregivers will be instructed on how to complete a paper diary and 
will be asked to record information daily in it. The number and type of seizures as 
well as information on AEs, concomitant AEDs and rescue medication will be 
collected each day from screening (Visit 1) until completion of dosing or withdrawal. 
Information on IMP intake will also be recorded each day from enrollment (Visit 2) 
until completion of dosing or withdrawal. 
9.1.14 
Investigational Medicinal Product Accountability 
GWP42003-P/placebo will be dispensed at each of the following visits during the 
blinded phase: 
• Visit 2 (Day 2) 
• Visit 4 (Day 34) 
IMP will be dispensed at each of the following visits for patients entering the OLE: 
• Visit 5 (Two weeks) 
• Visit 6 (One month) 
• Visit 7 (Two months) 
• Visit 8 (Three months) 
• Visit 9 (Six months) 
• Visit 10 (Nine months) 
• Visit 11 (12 months) 


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Patients will be asked to return all IMP (used and unused) to each relevant visit 
(Visits 2 to 12). The site will check the returned IMP against the usage recorded in the 
paper diary. Any discrepancies will be discussed with the patient/caregiver and 
documented accordingly within the patient’s source documents. 
9.1.15 
Adverse Events 
Any adverse changes in the patient’s medical condition, following completion of the 
consent form by the patient, will be recorded on the CRF as AEs, questioning the 
patient further if necessary. 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. 
*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. 
Serious Adverse Events (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. 
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 9.1.16.1.1 for the list of ‘Triggering AEs of Interest’ associated with 
monitoring of drug abuse liability.  
 
9.1.16 
Monitoring of Drug Abuse Liability 
There are two 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 (Visit 5 or Visit 12) or withdrawal visit 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. 


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9.1.16.1 
Monitoring of Adverse Events 
AE information will be collected according to Section 9.1.15.  
 
9.1.16.1.1 
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. 
• 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. 
 
9.1.16.1.2 
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. 
 


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9.1.16.2 
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 reported within the paper diary. 
• At any time that the site is informed by the patient/caregiver about any 
overuse of IMP, suspected misuse, abuse, or diversion. 
 
9.1.16.2.1 
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, according to the paper diary. 
• Returned IMP supply with evidence of tampering.  
• Greater than the target daily dose as recorded in the paper diary. 
 
 


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9.1.16.2.2 
Supplemental Drug Accountability Form 
This form consists of eight 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 or placebo, 
not other concomitant medications). 
 
9.1.16.3 
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. 
 
9.1.16.4 
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 (Visit 5 or Visit 12) or withdrawal visit. 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 in 
the study and not only those that have reported a triggering AE or drug accountability 
discrepancy. 
 


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9.1.16.5 
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. Only data from 
patients who have completed the study will be assessed.  
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  
 
 
 
 
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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9.2 
Study Procedures by Visit 
Patients and their caregivers will be invited to participate in the study and will be 
issued with the patient information and informed consent or the personal legal 
representative information and informed consent (refer to Section 9.1.2 and 
Section 15.2). Following adequate time to discuss the study with the investigator, 
nurse, relatives or caregiver, patients/legal representatives who provide written 
informed consent at Visit 1 will be screened for entry into the study. 
9.2.1 
Double Blind Phase 
9.2.1.1 
Visit 1 (Day −14 to −7, Screening) 
The following observations will be made at Visit 1: demographics, medical history 
(including seizure information since diagnosis, history of epilepsy-specific genetic 
testing and all prior AEDs taken), concomitant medications (including AEDs), 
physical examination (including height and body weight), ECG, vital signs and AEs. 
Clinical laboratory samples (blood and urine) will be taken for hematology, 
biochemistry, alcohol testing, THC testing, urinalysis and a pregnancy test (using a 
serum sample, if appropriate). The laboratory results should be available within 3-5 
working days after Visit 1. If the results show a patient is ineligible, the patient will 
not be enrolled into the study. The C-SSRS will be administered. 
Patients who satisfy all inclusion and none of the exclusion criteria specified in 
Section 6 will be assigned a unique patient number and then begin the baseline period. 
Patients or their caregivers will be given a paper diary to record daily seizure 
information, rescue medication, concomitant AEDs and AEs; and will be instructed 
on how to do so. The investigator must record the patient’s attendance at the visit and 
confirm the outcome of screening on the CRF.  
9.2.1.2 
Visit 2 
9.2.1.2.1 
Visit 2 (Day 1) – Enrollment (+3 days) 
This visit will occur 7–14 days after Visit 1. 
The following observations will be made at Visit 2: concomitant medications, 
(including AEDs), physical examination (including body weight), ECG, vital signs 
and review of patient diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for hematology, 
biochemistry, alcohol testing and urinalysis. Blood samples will also be taken for 
genetic testing if additional consent has been obtained. The C-SSRS will be 
administered. The investigator must record the patient’s attendance at the visit, and 
confirm the outcome of the visit prior to enrollment. 


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Following enrollment patients will begin the PK sampling process. Blood samples 
will be taken for analysis of plasma concentrations of CLB, N-CLB, VPA, STP, LEV 
and TPM. A baseline PK sample will be taken before the patient takes their morning 
dose of CLB. Further samples will then be taken at the following times relative to the 
CLB dose: 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours and 
12 hours. The evening dose of any AEDs must be taken after the 12 hour PK blood 
sample. Patients will either remain in clinic overnight throughout this PK sampling 
process or return to the clinic on Day 2 ahead of additional sample collection. 
9.2.1.2.2 
Visit 2 (Day 2) - Enrollment 
This is the second part of the two day enrollment visit. The final PK sample will be 
collected 24 hours after the Day 1 morning CLB dose. 
Following completion of the PK sampling process the following observations will be 
made on Day 2: concomitant medications (including AEDs), physical examination 
(including body weight), vital signs and AEs. 
GWP42003-P/placebo will be dispensed and both the morning dose of CLB and of 
GWP42003-P/placebo will be taken in clinic. Following administration of 
GWP42003-P/placebo, patients must remain in clinic for at least 30 minutes to 
monitor for any adverse reactions. Patients and/or their caregivers will be provided 
with individual dosing schedules as described in Section 8.1.2. Each patient will then 
receive their GWP42003-P/placebo for the 10 day titration period followed by the 
21 day maintenance period. Patients, or their caregivers, will be instructed on how to 
record the diary information. 
9.2.1.3 
Visit 3 (Day 12 +3 days) 
This visit will occur 11 days after Visit 2, Day 1 (enrollment). Patients will return all 
used and unused GWP42003-P/placebo. The following observations will be made at 
Visit 3 (Day 12): concomitant medications (including AEDs), physical examination 
(including body weight), ECG, vital signs, AEs and review of patient diary 
completion. 
Clinical laboratory samples (blood and urine) will be taken for hematology, 
biochemistry and urinalysis. The C-SSRS will be administered. 
9.2.1.4 
Visit 4 
9.2.1.4.1 
Visit 4 (Day 33) (±3 days) 
This visit will occur 32 days after Visit 2, Day 1 (enrollment). Patients will return all 
used and unused GWP42003-P/placebo. The following observations will be made at 


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Visit 4 (Day 33): concomitant medications (including AEDs), physical examination 
(including body weight), ECG, vital signs, review of patient diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for hematology, 
biochemistry, alcohol testing, and urinalysis. The C-SSRS will be administered.  
Blood samples will be taken for analysis of plasma concentrations of CLB, N-CLB, 
VPA, STP, LEV, TPM, CBD, CBD major metabolites, THC and THC major 
metabolites. A baseline PK sample will be taken before the patient takes their 
morning dose of CLB, followed immediately by their dose of GWP42003-P/placebo. 
Further samples will then be taken at the following times relative to the CLB dose: 
15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours and 12 hours. The 
evening dose of GWP42003-P/placebo and any AEDs must be taken after the 12 hour 
PK blood sample.  Patients are expected to remain in clinic throughout this PK 
sampling. 
The investigator must assess adherence to the dosing regimen and recording of rescue 
medications by reviewing the patient’s diary. 
9.2.1.4.2 
Visit 4 (Day 34) 
This is the second part of the two day visit. The final PK sample will be collected 
24 hours after the Day 33 morning CLB dose. 
Following completion of the PK sampling process the following observations will be 
made on Day 34: concomitant medications (including AEDs), physical examination 
(including body weight), vital signs and AEs. 
At the end of the blinded phase of the study on Day 34, providing the investigator and 
patient both agree, patients will be invited to continue taking GWP42003-P and to 
enter the OLE. 
Patients who enter the OLE will be dispensed GWP42003-P on Day 34. At the point 
of entry to the OLE, patients will be transitioned to the OLE treatment over a 10 day 
period in order to maintain blinding.  
Patients who do not enter the OLE will begin a 10 day taper period during which they 
will taper off their daily dose of GWP42003-P/placebo. The daily dose will be 
reduced by 10% of the maintenance dose per day and treatment will end on Day 42. 
9.2.1.5 
Visit 5 (Patients not entering Open Label Extension) (Day 43 
+3 days) 
This visit will occur 42 days after Visit 2, Day 1 (enrollment) for those patients who 
do not enter the OLE. 


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All GWP42003-P/placebo (used and unused) will be collected and a check of the 
returned GWP42003-P/placebo against usage must be made. A physical examination 
(including body weight), ECG and vital signs will be assessed and the C-SSRS will be 
administered. The trained investigator or study coordinator will complete the Study 
Medication Use and Behavior Survey as an interview with the patient/caregiver. 
Clinical laboratory samples (blood and urine) will be taken for hematology, 
biochemistry and urinalysis and a review of concomitant medications (including 
AEDs) and AEs will be completed. Patient diaries will be collected. 
9.2.1.6 
Visit 6 - Safety Follow up Call (Day 71) (±3 days) 
This visit is required for patients who do not enter the OLE study on Day 34, or who 
withdraw from the study early. This visit should occur four weeks after Visit 5, 
(±3 days) or withdrawal from treatment, and can be conducted over the telephone. 
The following observations will be made on Day 71: concomitant medications 
(including AEDs) and AEs. 
9.2.2 
Open Label Extension 
Patients who enter the OLE will be dispensed IMP at Visit 4 (Day 34) and will have 
regular clinic visits for a maximum of one year or earlier (if marketing authorization 
is granted or the patient withdraws). The visit schedule is calculated relative to Visit 4 
(Day 34). 
9.2.2.1 
Visit 5 (Open Label Extension) - Two Weeks (±3 days) 
This visit will occur two weeks after Visit 4 (Day 34). Patients will return all used and 
unused IMP. The following observations will be made at Visit 5 (OLE): concomitant 
medications (including AEDs), physical examination (including body weight), ECG, 
vital signs, review of seizure diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for hematology, 
biochemistry and urinalysis. The C-SSRS will be administered. The investigator must 
record the patient’s attendance at the visit and the outcome. 
The investigator must assess adherence to the dosing regimen and recording of rescue 
medications by reviewing the patient’s diary. 
The GWP42003-P dose may be adjusted up or down by the investigator from the 
maintenance dose of 20 mg/kg/day achieved at the end of the 10-day transition period, 
up to a maximum of 30 mg/kg/day in the OLE period.   


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9.2.2.2 
Visit 6 (Open Label Extension) - One Month (±3 days) 
This visit will occur one month after Visit 4 (Day 34). Patients will return all used and 
unused IMP. The following observations will be made at Visit 6 (OLE): concomitant 
medications (including AEDs), physical examination (including body weight), ECG, 
vital signs, review of seizure diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for hematology, 
biochemistry and urinalysis. The C-SSRS will be administered. The investigator must 
record the patient’s attendance at the visit and the outcome. 
The investigator must assess adherence to the dosing regimen and recording of rescue 
medications by reviewing the patient’s diary. 
9.2.2.3 
Visit 7 (Open Label Extension) - Two Months (±3 days) 
This visit will occur two months after Visit 4 (Day 34). Patients will return all used 
and unused IMP. The following observations will be made at Visit 7 (OLE): 
concomitant medications (including AEDs), physical examination (including body 
weight), ECG, vital signs, review of seizure diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for hematology, 
biochemistry and urinalysis. The C-SSRS will be administered. The investigator must 
record the patient’s attendance at the visit and the outcome. 
The investigator must assess adherence to the dosing regimen and recording of rescue 
medications by reviewing the patient’s diary. 
9.2.2.4 
Visit 8 (Open Label Extension) - Three Months (±7 days) 
This visit will occur three months after Visit 4 (Day 34). Patients will return all used 
and unused IMP. The following observations will be made at Visit 8 (OLE): 
concomitant medications (including AEDs), physical examination (including body 
weight), ECG, vital signs, review of seizure diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for hematology, 
biochemistry and urinalysis. The C-SSRS will be administered. The investigator must 
record the patient’s attendance at the visit and the outcome. 
The investigator must assess adherence to the dosing regimen and recording of rescue 
medications by reviewing the patient’s diary. 
9.2.2.5 
Visit 9 (Open Label Extension) - Six Months (±7 days) 
This visit will occur six months after Visit 4 (Day 34). Patients will return all used 
and unused IMP. The following observations will be made at Visit 9 (OLE): 


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concomitant medications (including AEDs), physical examination (including body 
weight), ECG, vital signs, review of seizure diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for hematology, 
biochemistry and urinalysis. The C-SSRS will be administered. The investigator must 
record the patient’s attendance at the visit and the outcome. 
The investigator must assess adherence to the dosing regimen and recording of rescue 
medications by reviewing the patient’s diary. 
9.2.2.6 
Visit 10 (Open Label Extension) - Nine Months (±7 days) 
This visit will occur nine months after Visit 4 (Day 34). Patients will return all used 
and unused IMP. The following observations will be made at Visit 10 (OLE): 
concomitant medications (including AEDs), physical examination (including body 
weight), ECG, vital signs, review of seizure diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for hematology, 
biochemistry and urinalysis. The C-SSRS will be administered. The investigator must 
record the patient’s attendance at the visit and the outcome. 
The investigator must assess adherence to the dosing regimen and recording of rescue 
medications by reviewing the patient’s diary. 
9.2.2.7 
Visit 11 (Open Label Extension End of Treatment) - Twelve 
Months (±7 days) 
This visit will occur twelve months after Visit 4 (Day 34). Patients will return all used 
and unused IMP. The following observations will be made at Visit 11 (OLE): 
concomitant medications (including AEDs), physical examination (including body 
weight), ECG, vital signs, review of seizure diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for hematology, 
biochemistry and urinalysis. The C-SSRS will be administered. The investigator must 
record the patient’s attendance at the visit and the outcome. 
The investigator must assess adherence to the dosing regimen and recording of rescue 
medications by reviewing the patient’s diary. 
Starting at Visit 11, patients will begin to taper down their IMP dose. The dose will be 
reduced by 10% of their OLE maintenance dose per day. 
9.2.2.8 
Visit 12 (Open Label Extension End of Taper) 
This visit will be ten days after Visit 11. All IMP (used and unused) will be collected 
and a check of the returned IMP against usage must be made. A physical examination 
(including body weight), ECG and vital signs will be assessed and the C-SSRS will be 


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administered. The trained investigator or study coordinator will complete the Study 
Medication Use and Behavior Survey as an interview with the patient/caregiver. 
Clinical laboratory samples (blood and urine) will be taken for hematology, 
biochemistry and urinalysis and a review of concomitant medications (including 
AEDs) and AEs will be completed. Patient diaries will be collected and reviewed. 
9.2.2.9 
Safety Follow Up Call (±3 days) 
This visit will occur one month after the OLE End of Taper and can be conducted 
over the telephone. The following observations will be made during the follow up 
call: concomitant medications (including AEDs) and AEs. 
10. WITHDRAWAL 
In accordance with the Declaration of Helsinki31, the FDA regulations relating to 
good clinical practice (GCP) and clinical trials32,33,34, the EU Clinical Trials Directive 
(2001/20/EC)35 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. 
• Withdrawal of legal representative consent. 
• Lost to follow up. 
• ALT >3 × ULN 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 two weeks. 
• Any other IMP is taken as part of a clinical trial during the study.  
• Significant change in QTcB (> 60 msec) from the previous ECG or absolute 
QTcB of > 500 msec.  
Patients may also be withdrawn from the study for any of the following: 
• Patient non-compliance. 


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• 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 four or five during the treatment period, 
as evaluated with the C-SSRS. 
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 Visit 4 (if the withdrawal is during the blinded phase) or Visit 11 (if the 
withdrawal is during the OLE) should be conducted if possible. If the tapered dose is 
administered, patients should return for Visit 5 (if withdrawal is during the blinded 
phase) or Visit 12 (if the withdrawal is during the OLE) if possible. Wherever 
possible, the safety follow-up visit should be conducted 28 days from the date of the 
last dose of IMP. Patients withdrawing due to an AE should be followed up according 
to Section 12.7. All information should be reported on the applicable CRF pages 
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 three days. 
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 screening (Visit 1) throughout the study and up to the post treatment, safety 
follow-up visit (28 days after last dose of IMP), which may or may not be considered 


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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 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 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., an 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. 
• 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 


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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 visit (Visit 13 for patients entering the OLE and Visit 6 for those 
patients that are not entering the OLE). If the investigator subsequently becomes 
aware of any deaths or a 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. 
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 


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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 study medication 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 study medication: 
“In your opinion is there a plausible relationship to the study medication?” The 
answer is “yes” or “no”. 
Events that start before the first dose of study medication (pre-treatment) should be 
considered as not causally related. Where a pre-treatment event worsens in severity 
following the first dose of study medication, 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 study medication but also competing etiological 
factors as the underlying cause. Factors for consideration may include: 
• Medical history. 
• Lack of efficacy/worsening of treated condition. 
• Concomitant or previous treatment. 
• Withdrawal of study medication. 
• Protocol-related procedure. 
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 
screening (Visit 1) to post study follow-up (Visit 13 for patients entering the OLE and 
Visit 6 for those patients that are not entering the OLE). whether or not attributed to 
IMP and observed by the investigator or patient. 


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*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 for the 
following categories: 
• Recovered. 
• Recovered with sequelae. 
• Continuing. 
• 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 
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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 occurs, 
the patient must undergo an end of treatment assessment and be given appropriate 
care under medical supervision until symptoms cease or the condition becomes stable. 
12.8 
Potential Cases of Drug Induced Liver Injury   
All investigational sites 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). 


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• 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 two 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 hours of notice of abnormal results) 
for repeat assessment of ALT, AST, TBL, alkaline phosphatase and gamma-glutamyl 
transferase levels, detailed history and physical examination. Patients should be 
followed until all abnormalities have normalized (in the investigator’s opinion) or 
returned to the baseline state. 
Elevations in ALT or AST >3 × ULN or TBL >2 × ULN alone are not considered 
potential cases of drug-induced liver injury, but will be followed as detailed above, 
within 72 hours’ notice of abnormal results. If the participant cannot return to the 
investigational center, repeat assessments may be done at a local laboratory and the 
results sent to GW PVD. 
12.9 
Notification of Safety Information to Investigators, Regulatory 
Authorities and Ethics Committees. 
In accordance with the EU Clinical Trials Directive35, relevant parts of the FDA Code 
of Federal Regulations 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 three sources: 
• Investigator Brochure36: 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 
participants. The IB is updated annually. 
• Development Core Safety Information: this document actually forms the 
Safety Section of the IB36, or is updated as an appendix of the IB36. This 


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document is revised if necessary, when new important safety information 
becomes available (potentially up to a few times a year). 
• 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 IRB/EC 
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 guidance32 
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, 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 guidance37 states that, accordingly, to satisfy the investigator’s obligation to 
notify the IRB of unanticipated problems, any investigators participating in a 
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/EC’s) 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 ethics approval and final database lock. 


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13. 
STATISTICAL CONSIDERATIONS 
A statistical analysis plan (SAP) will be produced prior to the database lock and 
analysis of the study. Any deviations from the original SAP will be described in the 
final clinical study report. 
13.1 
Sample Size, Power and Significance Levels 
A total of 20 patients will be enrolled in this study. There is no formal sample size: 
Calculation and analysis is descriptive only. 
13.2 
Interim Analysis 
An interim analysis will be conducted at the end of the Double Blind phase of the 
study and may also be considered during the OLE phase, if long term data is required 
to support New Drug Application/Marketing Authorization Application submissions. 
13.3 
Analysis Sets 
13.3.1 
Safety Set 
All subjects who are treated and receive at least one dose of IMP will be included. 
The Safety set is the primary analysis set for all safety endpoints. 
13.3.2 
Pharmacokinetic Analysis Set  
All subjects who are treated and receive at least one dose of IMP and who provide 
some on-treatment data will be included. 
The PK analysis set is the primary analysis set for all PK endpoints. 
13.3.3 Protocol Deviations 
Any protocol deviations will be listed and reasons for exclusion from the analysis 
populations 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 in each category. Summaries will be presented for data 
recorded pre-treatment, during each 25 day dosing phase (placebo and GWP42003-P) 
and during the OLE phase separately. 


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13.5 
Accountability and Background Characteristics 
13.5.1 Enrollment and Disposition 
All patients (screened, treated, completing the study and those 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 and the types of seizures currently 
experienced by the patients. 
13.5.4 Concomitant Medication 
Concomitant medications taken prior to and during the study will be summarized, by 
medication class and active ingredients. Summaries of medications taken during the 
IMP treatment phases and during OLE will be presented separately. 
13.6 
Endpoints and Statistical Methods 
13.6.1 Primary Endpoint(s) 
The primary endpoints of the study are the PK parameters (Cmax, tmax, AUC(0–∞), 
AUC(0–t), t½) of the following analytes: 
• CLB 
• N-CLB 
• CBD 
• CBD major metabolites 
13.6.2 Secondary Endpoint(s) 
The secondary endpoints of the study are the safety parameters (see Section 13.6.4) 
and the PK parameters (Cmax, tmax, AUC(0–∞), AUC(0–t), t½) of the following analytes: 
• THC 
• THC major metabolites 


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13.6.3 Pharmacokinetics 
Calculation of PK parameters will be based on actual blood sampling times [h] 
(relative to the corresponding administration time) rounded to two decimal digits with 
negative pre-dose times set to zero. Plasma concentrations of CLB, N-CLB, VPA, 
STP, LEV, TPM, CBD, CBD major metabolites, THC and THC major metabolites 
will be displayed graphically, summarized and listed. For descriptive statistics, values 
below the lower limit of quantification of the assay (LLOQ) will be excluded from 
any calculations. Descriptive statistics of concentrations will be calculated if at least 
half of the individual data points that have been measured are equal to or above the 
LLOQ. 
For calculation of the PK parameters, the following rules will be applied: 
At time zero and at time points in the lag-time between time zero and the first 
quantifiable concentration, concentrations below the LLOQ will be set to zero. All 
other concentrations below the LLOQ will not be used in calculations. 
Variables derived from plasma concentrations: 
• Concentration maximum (Cmax): Highest observed plasma concentration of the 
measured concentration-time profile. Dimension: [amount / volume]. 
• Terminal half-life t½= ln(2)/λz. 
• The rate constant of the terminal phase λz will be determined by linear 
regression of log-transformed concentration data after the time of maximum 
concentration. A sequence of terminal elimination rate constants will be 
created by linear regression. Linear regressions are repeated using the last 
three points with a quantifiable concentration, the last four points, the last five 
points etc. For each regression, an adjusted R2 is computed. The regression 
with the largest adjusted R2 is selected to estimate the terminal half-life. 
Dimension: [time]. 
• Area under the concentration-time curve from administration until the last 
sampling point (t) equal or above the LLOQ AUC(0–t) will be calculated by the 
linear trapezoidal formula. Dimension: [time • amount / volume]. 
• Area under the concentration-time curve extrapolated to infinity: AUC(0–∞) = 
AUC(0–t) + Clast/λz and Clast is the concentration observed at the last time point 
with a quantifiable concentration, λz refers to the terminal elimination rate 
constant. Dimension: [time • amount / volume]. 
• Time of maximum concentrations: Tmax will be taken as the time after 
administration at which Cmax occurs. Dimension: [time]. 
• PK parameters for each analyte will be summarized for the two treatment 
phases of the study separately, as appropriate. 
• In order to assess whether the presence of CBD alters the PK profile of CLB 
(or N-CLB), a standard 90% confidence interval (CI) approach for the 
between group ratios of geometric means of Cmax, AUC(0–t), and AUC(0–∞) will 


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be carried on logarithm scale using a linear mixed effect model with treatment 
(CLB or CLB+CBD) as a fixed effect and subject as a random effect. The no-
effect boundary will be set between 0.5 and 2.0 and if the 90% CI for the ratio 
of the geometric means of a PK variable falls within the interval [0.5, 2.0], a 
lack of meaningful effect will be declared. 
13.6.4 Safety 
13.6.4.1 
Treatment Compliance and Extent of Treatment Exposure 
Treatment compliance and exposure to treatment will be summarized for each phase 
of the study separately. 
13.6.4.2 
Adverse Events 
AEs will be coded according to the Medical Dictionary for Regulatory Activities 
dictionary. 
A treatment emergent AE is one that started, or worsened in severity or seriousness, 
following the first dose of IMP. 
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. Summaries will be provided for each phase of the 
study separately. 
The following summaries will be produced: 
• 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. 
13.6.4.3 
Clinical Laboratory Data 
Clinical laboratory data at screening and at the end of the 31 day treatment phase and 
the change from baseline to end of treatment (OLE) 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. 


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13.6.4.4 
Columbia-Suicide Severity Rating Scale, Vital Signs, 12-lead 
Electrocardiogram, Physical Examination and Other Safety 
Data 
The C-SSRS, vital signs, ECG and physical examination data will be summarized at 
screening, at the end of the 31 day treatment phase and during the OLE treatment 
period using appropriate summary statistics. Changes in the vital signs from baseline 
to end of each treatment phase will also be summarized. 
13.6.4.5 
Seizure Data 
Seizure data collected during the 31 day treatment phase and during the OLE phase of 
the study will be summarized using appropriate summary statistics. 
14. 
DATA SAFETY MONITORING COMMITTEE 
GW does not plan to use an independent data safety monitoring committee as part of 
this study. 


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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 
the31,35and the clinical trial regulations adopting European Commission Directives 
into national legislation38,39,40. 
15.2 
Informed Consent 
Initial master ICFs will be provided to the investigator to prepare the informed 
consent documents to be used at his or her center. The GW Clinical Manager will 
communicate updates to the templates by letter. The written informed consent 
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 from the patient or 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, or their legal representative, should have ample time for 
review to consider the information provided before giving written consent; more 
specific definitions of ample time may be in force if required by IRB/ECs or local 
regulations. 
The acquisition of informed consent should be documented in the patient’s medical 
records and the ICF should be signed and personally dated by the patient or legal 
representative (as applicable) and by the person who conducted the informed consent 
discussion. GW also requires a physician to be present for consent and to sign the 
consent forms as well. The original signed ICFs should be retained and a copy 
provided to the patient or legal representative. 
15.3 
Institutional Review Board/Ethics Committee 
A copy of the protocol, proposed ICFs, 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 ICFs before enrollment of patients into the study and 
shipment of IMP. 
The investigator must submit and, where necessary, obtain approval from the IRB/EC 
for all subsequent protocol amendments and changes to the informed consent 
documents. The investigator should notify the IRB/EC of deviations from the protocol 


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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 for entry into the study: 
• Signed and dated protocol signature page. 
• Copy of approved ICFs and other patient information material. 
• Copy of the IRB/EC approval of the protocol, ICFs and other patient 
information material. 
• Up to date curricula 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 
trials32,33,34,41, the EU Clinical Trials Directive35, or International Conference 
on Harmonization Tripartite Guideline for Good Clinical Practice (ICH 
GCP)42 where the EU 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 
Participant 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 ICFs should be kept in strict confidence by the investigator. 
In compliance with the FDA regulations relating to good clinical practice and clinical 
trials32,33,34,41, and the EU Clinical Trials Directive35/ICH GCP Guidelines42, 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 


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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 documents. The IRB/EC and Competent Authorities must be 
informed of all amendments and give approval for any substantial amendments prior 
to implementation. The investigator must send a copy of the approval letter from the 
IRB/EC to GW. Amendments for administrational changes can be submitted to the 
IRB/EC for information only. 
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. In the rare situations of this happening, 
then the source data from the CRF should be transcribed in the patient’s notes with 
appropriate signature and date to provide a full audit trail. 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. 
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 8.242), suitable for inspection at any time by representatives from GW 
and/or applicable regulatory authorities. Elements should include: 
• Patient files containing completed CRFs, ICFs and supporting copies of source 
documentation. 


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• 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. 
• 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, paper 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 25 years. Essential documents should be retained until at least two 
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 two 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 1643). 
GW will inform the investigators for each site 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 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. 


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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 five working days after 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 regulations32,33,34,41, the ICH GCP 
Guideline42, and all other applicable regulatory requirements35,42, 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. 


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• 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. 
16.4 
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. 
16.5 
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. 
16.6 
Publication Policy 
GW recognizes that there is a responsibility under the regulatory guidelines to ensure 
that results of scientific interest arising from this clinical 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 


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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 six months from the date of first submission to them in order to allow them to 
take steps to protect proprietary information where applicable. 
16.7 
Intellectual Property Rights 
All Intellectual Property Rights owned by or licensed to either GW or the PIs, other 
than those arising from the clinical 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. 
16.8 
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. REFERENCES 
1 
Bergen DC.  Preventable neurological diseases worldwide.  Neuroepidemiology, 
1998, 17(2): 67-73. 
2 
Sander JW.  The epidemiology of epilepsy revisited.  Curr Opin Neurol, 2003, 
16(2): 165-170. 
3 
MacDonald BK, Cockerell OC, Sander JW and Shorvon SD.  The incidence and 
lifetime prevalence of neurological disorders in a prospective community-based 
study in the UK.  Brain, 2000, 123(4): 665-676. 
4 
Forsgren L, Beghi E, Oun A and Sillanpää M.  The epidemiology of epilepsy in 
Europe – a systematic review.  Eur J Neurol, 2005, 12(4): 245-253. 
5 
Duncan JS, Sander JW, Sisodiya SM and Walker MC.  Adult epilepsy.  The 
Lancet, 2006, 367(9516): 1087-1100. 
6 
Committee for medicinal products for human use. Guideline on clinical 
investigation of medicinal products in the treatment of epileptic disorders, 22 July 
2010, CHMP/EWP/566/98 Rev.2/Corr. 
7 
Sander JS.  Some aspects of prognosis in the epilepsies: a review.  Epilepsia, 
1993, 34(6): 1007-1016. 
8 
Kwan P and Brodie MJ.  Early Identification of Refractory Epilepsy.  N Engl J 
Med, 2000, 342(5): 314-319. 
9 
Kwan P and Brodie MJ.  Emerging drugs for epilepsy.  Expert Opin Emer Drugs, 
2007, 12(3): 407-422. 
10 Schachter SC.  Currently available antiepileptic drugs.  Neurotherapeutics, 2007, 
4(1): 4-11. 
11 Martin J.  British National Formulary. 2013, Pharmaceutical Press London. 
12 Bialer M and White HS.  Key factors in the discovery and development of new 
antiepileptic drugs.  Nat Rev Drug Discov, 2010, 9(1): 68-82. 
13 Czapiński P, Blaszczyk B and Czuczwar SJ.  Mechanisms of action of 
antiepileptic drugs.  Curr Top  Med Chem, 2005, 5(1): 3-14. 
14 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. 
15 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. 
16 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. 
17 Zuardi AW, Morais SL, Guimarães FS, Mechoulam R. Antipsychotic effect of 
cannabidiol. J Clin Psychiatry 1995;56(10):485-6. 
18 Jones NA, Hill AJ, Smith I, Bevan SA, Williams CM, Whalley BJ et al. 
Cannabidiol displays antiepileptiform and antiseizure properties in vitro and in 
vivo. J Pharmacol Exp Ther 2010;332(2):569-77. 


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19 Jones NA, Glyn SE, Akiyama S, Hill TD, Hill AJ, Weston SE et al. Cannabidiol 
exerts anti-convulsant effects in animal models of temporal lobe and partial 
seizures. Seizure 2012;21(5):344-52. 
20 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. 
21 Gover J, Schultz, S. GW Pharmaceuticals announces new physician reports of 
Epidiolex treatment effect in children and young adults with treatment-resistant 
epilepsy [press release]. United Kingdom: GW Pharma Ltd; 2014 Oct 14. 
22 Johannessen Landmark C, Larsson PG, Rytter E, Johannessen SI. Antiepileptic 
drugs in epilepsy and other disorders: a population-based study of prescriptions. 
Epilepsy Res. 2009, 87(1):31-39 
23 Tsiropoulos I, Gichangi A, Andersen M, Bjerrum L, Gaist D, Hallas J. Trends in 
utilization of anti-epileptic drugs in Denmark. Acta Neurol. Scand. 2006, 113, 
405-411 
24 van de Vrie-Hoekstra NW, de Vries TW, van den Berg PB, Brouwer OF, de Jong-
van den Berg LT. Antiepileptic drug utilization in children from 1997-2005 - a 
study from the Netherlands. Eur J Clin Pharmacol. 2008, 64: 1013-1020. 
25 Johannessen Landmark C, Rytter E, Johannessen SI. Clinical use of antiepileptic 
drugs at a referral centre for epilepsy. Seizure. 2007, 16:356-364 
26 Rytter E, Johannessen Landmark C, Johannessen SI. Antiepileptic drug treatment 
of children at a referral centre for epilepsy - does admission make a difference? 
Seizure. 2009, 18:573-579 
27 Contin M, Riva R, Albani F, Baruzzi A. Effect of felbamate on clobazam and its 
metabolite kinetics in patients with epilepsy. Ther Drug Monit. 1999, 21:604-608 
28 Levy RH, Lin HS, Blehaut HM, Tor JA. Pharmacokinetics of stiripentol in normal 
man: evidence of non-linearity. J Clin Pharmacol. 1983, 23 (11-12):523-533. 
29 Tran A, Vauzelle-Kervroedan F, Rey E, Pous G, d´Athis P, Chiron C, Dulac O, 
Renard F, Olive G. Effect of stiripentol on carbamazepine plasma concentration 
and metabolism in epileptic children. Eur J Clin Pharmacol. 1996, 50:497-500. 
30 Trojnar MK, Wojtal K, Trojnar MP, Czuczwar SJ. Stiripentol. A novel 
antiepileptic drug. Pharmacol Rep. 2005, 57:154-160. 
31 World Medical Association Declaration of Helsinki — Ethical principles for 
medical research involving human subjects. October 2013. 
32 U.S. Food and Drug Administration Code of Federal Regulations Title 21 (Food 
and Drugs) Part 50 — Protection of human subjects. April 2014. 
33 U.S. Food and Drug Administration Code of Federal Regulations Title 21 (Food 
and Drugs) Part 312 — Investigational New Drug application. April 2014. 
34 U.S. Food and Drug Administration Code of Federal Regulations Title 21 (Food 
and Drugs) Part 56 — Institutional Review Boards. April 2014. 
35 Directive 2001/20/EC  of the European Parliament and of the Council of 04 April 
2001 on the approximation of the laws, regulations and administrative provisions 
of the Member States relating to the implementation of good clinical practice in 
the conduct of clinical trials on medicinal products for human use. Official Journal 
of the European Communities L 121, 1/5/2001 p. 34–44. 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Version 3 Date 08 Oct 15 
 
 
 
 
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36 Investigator Brochure — CBD medicine. GW Pharma Ltd. Edition 7, August 
2014. 
37 U.S. Food and Drug Administration guidance for clinical Investigators, Sponsors, 
and IRBs: Adverse Event reporting to IRBs — Improving human subject 
protection. January 2009. 
38 UK Statutory Instrument 2004/1031 — The medicines for human use (clinical 
trials) regulations 2004. May 2004. 
39 UK Statutory Instrument 2006/1928 — The medicines for human use (clinical 
trials) amendment regulations 2006. August 2006. 
40 UK Statutory Instrument 2006/2984 — The medicines for human use (clinical 
trials) amendment (No.2) regulations 2006. December 2006. 
41 U.S. Food and Drug Administration Code of Federal Regulations Title 21 (Food 
and Drugs) Part 11 — Electronic records; electronic signatures (Subpart B — 
Electronic records). April 2014. 
42 International Conference on Harmonisation Topic E6(R1): Guideline for good 
clinical practice — Note for guidance on good clinical practice 
(CPMP/ICH/135/95). July 2002. 
43 Commission Directive 2005/28/EC of 08 April 2005 laying down the principles 
and detailed guidelines for GCP as regards investigational medicinal products for 
human use, as well as the requirements for authorisation of the manufacturing or 
importation of such products. Official Journal of the European Union L 91, 
9/4/2005 p. 13–19. 
 
 
 
 
 
 
 
 
 
 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Version 3 Date 08 Oct 15 
 
 
 
 
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Template: 271112 
APPENDIX 1. SCHEDULE OF ASSESSMENTS 
Visit Number 
Day 
(Visit Window) 
Visit 1 
Day -14 to -7 
 
Visit 2 
Day 1 
(+ 3 days) 
Visit 2 
Day 2 
 
Visit 3 
Day 12 
(+ 3 days) 
Visit 4 
Day 33 
(± 3 days) 
Visit 4 
Day 34 
 
Visit 5* 
End of Taper 
 
Visit 6* 
4wk SFU 
(± 3 days) 
Informed consent 
X 
 
 
 
 
 
 
 
Eligibility criteria 
X 
X 
 
 
 
 
 
 
Enrollment 
 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
Paper diary training 
X 
 
X 
 
 
 
 
 
Concomitant medications 
(including AEDs) 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
(including height and body 
weight)♥ 
X 
X 
X 
X 
X 
X 
X 
 
ECG 
X 
X 
 
X 
X 
 
X 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical laboratory blood 
sampling  
X 
X 
 
X 
X 
 
X 
 
Clinical laboratory urine 
sampling (dipstick 
urinalysis) 
X 
X 
 
X 
X 
 
X 
 
THC test 
X 
 
 
 
 
 
 
 
Alcohol Test 
X 
X 
 
 
X 
 
 
 
Pregnancy test (if 
appropriate) 
X 
 
 
 
 
 
 
 
Pharmacokinetic blood 
sampling**  
 
X 
X 
 
X 
X 
 
 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Version 3 Date 08 Oct 15 
 
 
 
 
Confidential  
Page 90 of 93  
Template: 271112 
Visit Number 
Day 
(Visit Window) 
Visit 1 
Day -14 to -7 
 
Visit 2 
Day 1 
(+ 3 days) 
Visit 2 
Day 2 
 
Visit 3 
Day 12 
(+ 3 days) 
Visit 4 
Day 33 
(± 3 days) 
Visit 4 
Day 34 
 
Visit 5* 
End of Taper 
 
Visit 6* 
4wk SFU 
(± 3 days) 
Sample for Genetic 
Testing*** 
 
X 
 
 
 
 
 
 
C-SSRS 
X 
X 
 
X 
X 
 
X 
 
Patient diary review 
(seizures, AE information, 
concomitant AEDs, rescue 
medication, IMP dosing) 
 
X 
 
X 
X 
 
X 
 
IMP dispensing 
 
 
X 
 
 
X 
 
 
Collection of IMP 
 
 
 
X 
X 
 
X 
 
IMP compliance review 
 
 
 
X 
X 
 
X 
 
Study Medication Use and 
Behavior Survey 
 
 
 
 
 
 
X 
 
* Patients not entering the OLE 
**PK Sampling time points are as follows: Pre-dose and 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 12 hours and 24 hours after 
dosing. For the second PK visit the patient should take the GWP42003-P/placebo immediately after their daily dose of CLB. 
*** Samples for genetic testing will only be taken if additional consent is obtained. 
♥ Patients height measured at Visit 1 only. 
 
 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Version 3 Date 08 Oct 15 
 
 
 
 
Confidential  
Page 91 of 93  
Template: 271112 
Open Label Extension Schedule of Assessments 
 
 
Visit Number 
Day 
(Visit Window) 
Visit 5 
2 Weeks 
(± 3 days) 
Visit 6 
1 Month 
(± 3 days) 
Visit 7 
2 Months 
 (± 3 days) 
Visit 8 
3 Months 
(± 7 days) 
Visit 9 
6 Months 
 (± 7 days) 
Visit 10 
9 Months 
(± 7 days) 
Visit 11 
12 Months 
 (± 7 days) 
Visit 12 
End of 
Taper 
 
Visit 13 
4wk SFU 
(± 3 days) 
Paper diary training 
 
 
 
 
 
 
 
 
 
Concomitant medications 
(including AEDs) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
(including weight) 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECG 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical laboratory blood 
sampling  
X 
X 
X 
X 
X 
X 
X 
X 
 
Clinical laboratory urine 
sampling (dipstick 
urinalysis) 
X 
X 
X 
X 
X 
X 
X 
X 
 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
X 
 
Patient diary review 
(seizures, AE 
information, concomitant 
AEDs, rescue medication, 
IMP dosing) 
X 
X 
X 
X 
X 
X 
X 
X 
 
IMP dispensing 
X 
X 
X 
X 
X 
X 
X 
 
 
Collection of IMP 
X 
X 
X 
X 
X 
X 
X 
X 
 
IMP compliance review 
X 
X 
X 
X 
X 
X 
X 
X 
 
Study Medication Use 
and Behavior Survey 
 
 
 
 
 
 
 
X 
 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Version 3 Date 08 Oct 15 
 
 
 
 
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APPENDIX 2. STUDY PERSONNEL 
Appendix 3.1 
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 3.2 
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: 
 
Fax: 
 
Medical Monitor 
EU 
 
  
Tel: 
 
Mobile:
 
USA 
 
 
Tel: 
 
Mobile: 
  
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
Version 3 Date 08 Oct 15 
 
 
 
 
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Clinical Project Manager/Clinical Operations 
Director: 
GW Research Ltd 
Sovereign House 
Vision Park 
Chivers Way 
Histon 
Cambridge CB24 9BZ 
United Kingdom 
Tel: 
 
Fax: 
 
Clinical Trials Supplies: 
GW Pharma Ltd 
Tel: 
 
Fax: 
 
 
 
 
 
 
PPD
PPD
PPD
PPD


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
V1 04Feb16 
 
Confidential 
Page 1 of 13 
Clinical Protocol Amendment Template 
V1, 24Sep15 
TITLE: A phase 2, double-blind, randomized, placebo-controlled 
study to investigate possible drug-drug interactions between 
clobazam and cannabidiol (GWP42003-P) 
Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
CLINICAL PROTOCOL AMENDMENT NUMBER: 3 
to be incorporated into the Protocol, creating 
CLINICAL PROTOCOL VERSION 4, 
DATE 04 FEB 16 
GW Research Ltd 
Sovereign House 
Vision Park 
Chivers Way 
Histon 
Cambridge CB24 9BZ 
United Kingdom 
Tel: 
 
Fax: 
 
Confidentiality Statement 
This document contains confidential information of GW Research Ltd (GW) that 
must not be disclosed to anyone other than the recipient study staff and members of 
the institutional review board or independent ethics committee.  This information 
cannot be used for any purpose other than the evaluation or conduct of the clinical 
investigation without the prior written consent of GW. 
PPD
PPD


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
V1 04Feb16 
 
Confidential 
Page 2 of 13 
Clinical Protocol Amendment Template 
V1, 24Sep15 
1 
PROTOCOL SYNOPSIS 
Study Title  
A phase 2, double-blind, randomized, placebo-controlled study to 
investigate possible drug-drug interactions between clobazam and 
cannabidiol (GWP42003-P). 
Indication 
Epilepsy 
Study Design 
This is a phase 2, double-blind, randomized, placebo-controlled study in 
20 patients. 
• Patients will be randomized in a 4:1 ratio to receive 20 mg/kg 
GWP42003-P or placebo from days 2 to 33.  
• 
At the end of the treatment period, patients will be given the option of 
continuing onto an open label extension (OLE) period if the investigator 
and patient both agree that it is in their best interests.  Doses may be 
adjusted up or down, dependent on investigator opinion, to a maximum 
of 30 mg/kg/day GWP42003-P.  The OLE will last for a maximum of 
one year or until marketing authorization is granted; whichever is 
earlier. 
• 
Patients that do not continue onto the OLE will taper off of 
GWP42003-P over a 10 day period and will have a telephone follow-up 
visit four weeks after the end of taper day on Day 71. 
• Day 1 (Visit 2), patients will not be dosed with GWP42003-P/placebo 
but will continue to take clobazam (CLB) at a stable dose. 
• Day 2 (Visit 2), patients will begin the up-titration with GWP42003-P or 
placebo to a maintenance dose or an equivalent maintenance dose of 
20 mg/kg/day over a period of 10 days (Days 2 to 11). 
• Day 12 (Visit 3), patients will attend the study site to check safety and 
compliance. 
• After up-titration with GWP42003-P or placebo, the patients will remain 
on the maintenance dose for 21 days (Days 12 to 32). 
• On Day 34 (Visit 4), patients will be invited to receive GWP42003-P in 
the OLE period.  If the patient enters the OLE period of the study, the 
patient will continue to take GWP42003-P as advised by the 
investigator. 
• If the patient does not enter the OLE period of the study, the patient will 
taper off of GWP42003-P by reducing the dose by approximately 10% 
of the maintenance dose each day until dosing has ceased, with end of 
taper on Day 43 (Visit 5). 
Pharmacokinetic (PK) samples will be taken on the day of enrollment 
(Visit 2, Day 1) and after completing 21 days treatment on GWP42003-P or 
placebo (Visit 4, Day 33).  The PK assessments will therefore capture the 
following combinations of CLB and GWP42003-P: 
• First PK Assessment: CLB only. 
• Second PK Assessment: CLB and GWP42003-P or placebo. 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
V1 04Feb16 
 
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Clinical Protocol Amendment Template 
V1, 24Sep15 
Each PK assessment should be performed at time points in respect to a 
morning dose of CLB.  The time points are as follows: Pre-dose, 15 min, 
30 min, 1 h, 1.5 h, 2 h, 4 h, 6 h, 12 h and 24 h.  It is expected that the patient 
will continue to take their CLB as advised by their physician and PK 
assessments will be scheduled in order to accommodate this dosing 
schedule.  The GWP42003-P/placebo should be taken twice daily 
immediately following their CLB dose. 
PK assessments will analyze the amount of CLB, the CLB primary 
metabolite N-desmethylclobazam, cannabidiol (CBD), CBD major 
metabolites, ∆9-tetrahydrocannabinol (THC) and THC major metabolites, 
valproate (VPA), stiripentol (STP), levetiracetam (LEV) and topiramate 
(TPM).  Patients will be required to keep a paper diary to note the time and 
dose of GWP42003-P and CLB administration each morning and evening 
and to record any adverse events that may occur whilst receiving 
investigational medicinal product and any other medications.  Patients will 
also be requested to record the number and type of seizures for each day 
whilst on the study. 
Sponsor 
GW Research Ltd 
Sovereign House 
Vision Park 
Chivers Way 
Histon 
Cambridge CB24 9BZ 
United Kingdom 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
V1 04Feb16 
 
Confidential 
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Clinical Protocol Amendment Template 
V1, 24Sep15 
Table of Contents 
Title Page ................................................................................................... 1 
1 
PROTOCOL SYNOPSIS ................................................................ 2 
Table of Contents ...................................................................................... 4 
List of Appendices..................................................................................... 5 
2 
RATIONALE ................................................................................... 6 
2.1 
Inclusion Criteria ........................................................................................... 6 
2.2 
Procedures ..................................................................................................... 6 
2.3 
Administrative Changes ................................................................................ 6 
3 
IMPLEMENTATION OF THE AMENDMENT ......................... 7 
4 
PRESENTATION OF AMENDED TEXT ................................... 8 
5 
REFERENCES .............................................................................. 11 
 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
V1 04Feb16 
 
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Clinical Protocol Amendment Template 
V1, 24Sep15 
List of Appendices 
APPENDIX 1 
Schedule of Assessments ......................................................... 12 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
V1 04Feb16 
 
Confidential 
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Clinical Protocol Amendment Template 
V1, 24Sep15 
2 
RATIONALE 
This clinical protocol amendment 3 (will be incorporated into the Protocol creating 
Clinical Protocol Version 4 Date 04 February 2016) addresses the following issue(s): 
2.1 
Inclusion Criteria 
The following inclusion criterion, relating to age limit, has been amended: 
• Inclusion criterion 6.1.1 has been amended to increase the upper age limit to 
65, to expand the study to more patients. 
2.2 
Procedures 
The following clarifications have been made to the study procedures: 
• For patients entering the OLE, it has been clarified that they must remain in 
clinic for at least 30 minutes following administration of GWP42003-P as this 
may be their first exposure to the study drug if they had previously been taking 
placebo. 
• In the OLE, it has been clarified that 1 month is equal to 28 days or 4 weeks 
for the purpose of scheduling.  
2.3 
Administrative Changes 
Administrative updates have been made throughout the protocol (N.B. in the interest 
of brevity, minor changes to grammar, punctuation or formatting are not captured in 
this amendment document). 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
V1 04Feb16 
 
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Clinical Protocol Amendment Template 
V1, 24Sep15 
3 
IMPLEMENTATION OF THE AMENDMENT 
The changes detailed in this amendment will be issued as Clinical Protocol Version 4, 
Date 04 February 2016.  It will be kept in the trial master file at GW as well as in each 
investigational center file and, if applicable, pharmacy site file. 
 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
V1 04Feb16 
 
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Clinical Protocol Amendment Template 
V1, 24Sep15 
4 
PRESENTATION OF AMENDED TEXT 
The text will be amended as follows: 
Revised Protocol 
Section Number, 
Heading and 
Page Number 
Original Wording from Clinical Protocol Version 
3, Dated 08 Oct 15 
(Deleted wording is struck through and in bold)  
Revised Wording from Clinical Protocol 
Amendment 3 (Clinical Protocol Version 4, Dated 
04 Feb 16)  
(Revised wording is underscored and in bold)  
Rationale for 
the 
Amendment  
Protocol 
Synopsis, 
Summary of 
Participant 
Eligibility 
Criteria, pg 5 
(…) 
Male or female patients aged 18 to 55 years inclusive. 
(…) 
 
(…) 
Male or female patients aged 18 to 65 years inclusive. 
(…) 
 
 
See Section 2.1 
Protocol 
Synopsis, 
Procedures, 
pg 11 
 
 
 
 
 
 
(…) 
Patients who enter the OLE will be dispensed 
GWP42003-P on Day 34. 
(…) 
 
 
 
 
 
 
(…) 
Patients who enter the OLE will be dispensed 
GWP42003-P on Day 34 and the first dose will be 
taken in clinic.  Following administration of 
GWP42003-P, patients must remain in clinic for at 
least 30 minutes to monitor for any adverse 
reactions. 
(…) 
 
 
 
See Section 2.2 
 
 
 
 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
V1 04Feb16 
 
Confidential 
Page 9 of 13 
Clinical Protocol Amendment Template 
V1, 24Sep15 
Revised Protocol 
Section Number, 
Heading and 
Page Number 
Original Wording from Clinical Protocol Version 
3, Dated 08 Oct 15 
(Deleted wording is struck through and in bold)  
Revised Wording from Clinical Protocol 
Amendment 3 (Clinical Protocol Version 4, Dated 
04 Feb 16)  
(Revised wording is underscored and in bold)  
Rationale for 
the 
Amendment  
Protocol 
Synopsis, 
Procedures, 
pg 12 
This visit will occur one month after Visit 4 (Day 34). 
(…) 
 
This visit will occur one month (one month is 
considered as 28 days) after Visit 4 (Day 34). 
(…) 
See Section 2.2 
Protocol 
Section 6.1, 
Inclusion 
Criteria, pg 39 
(…) 
Male or female patients aged 18 to 55 years inclusive. 
(…) 
(…) 
Male or female patients aged 18 to 65 years inclusive. 
(…) 
 
See Section 2.1 
Protocol 
Section 9.2.1.4.2, 
Visit 4 (Day 34), 
pg 60  
(…) 
Patients who enter the OLE will be dispensed 
GWP42003-P on Day 34. 
(…) 
(…) 
Patients who enter the OLE will be dispensed 
GWP42003-P on Day 34 and the first dose will be 
taken in clinic.  Following administration of 
GWP42003-P, patients must remain in clinic for at 
least 30 minutes to monitor for any adverse 
reactions. 
(…) 
 
See Section 2.2 
Protocol Section 
9.2.2.2, Visit 6 
(Open Label 
Extension) – One 
This visit will occur one month after Visit 4 (Day 34). 
(…) 
(…) 
This visit will occur one month (one month is 
considered as 28 days) after Visit 4 (Day 34). (…) 
(…) 
See Section 2.2 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
V1 04Feb16 
 
Confidential 
Page 10 of 13 
Clinical Protocol Amendment Template 
V1, 24Sep15 
Revised Protocol 
Section Number, 
Heading and 
Page Number 
Original Wording from Clinical Protocol Version 
3, Dated 08 Oct 15 
(Deleted wording is struck through and in bold)  
Revised Wording from Clinical Protocol 
Amendment 3 (Clinical Protocol Version 4, Dated 
04 Feb 16)  
(Revised wording is underscored and in bold)  
Rationale for 
the 
Amendment  
Month 
(± 3 days), pg 62 
APPENDIX 1, 
Schedule of 
Assessments, 
pg 92 
<< Note: See Appendix 1 for detailed changes >> 
 
<< Note: See Appendix 1 for detailed changes >> 
 
See Section 2.2 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
V1 04Feb16 
 
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Clinical Protocol Amendment Template 
V1, 24Sep15 
5 
REFERENCES 
N/A


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
V1 04Feb16 
 
Confidential 
Page 12 of 13 
Clinical Protocol Amendment Template 
V1, 24Sep15 
 APPENDIX 1 
SCHEDULE OF ASSESSMENTS 
Open Label Extension Schedule of Assessments (Protocol V3/ Appendix1) 
Visit Number 
Day 
(Visit Window) 
Visit 5 
2 Weeks 
(+ 3 days) 
Visit 6 
1 Month 
(± 3 days) 
Visit 7 
2 Months 
 (± 3 days) 
Visit 8 
3 Months 
(± 7 days) 
Visit 9 
6 Months 
 (± 7 days) 
Visit 10 
9 Months 
(± 7 days) 
Visit 11 
12 Months 
 (± 7 days) 
Visit 12 
End of Taper 
 
Visit 13 
4wk SFU 
(± 3 days) 
Paper diary training 
 
 
 
 
 
 
 
 
 
Concomitant medications 
(including AEDs) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
(including weight) 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECG 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical laboratory blood 
sampling  
X 
X 
X 
X 
X 
X 
X 
X 
 
Clinical laboratory urine 
sampling (dipstick 
urinalysis) 
X 
X 
X 
X 
X 
X 
X 
X 
 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
X 
 
Patient diary review 
(seizures, AE information, 
concomitant AEDs, rescue 
medication, IMP dosing) 
X 
X 
X 
X 
X 
X 
X 
X 
 
IMP dispensing 
X 
X 
X 
X 
X 
X 
X 
 
 
Collection of IMP 
X 
X 
X 
X 
X 
X 
X 
X 
 
IMP compliance review 
X 
X 
X 
X 
X 
X 
X 
X 
 
Study Medication Use and 
Behavior Survey 
 
 
 
 
 
 
 
X 
 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
V1 04Feb16 
 
Confidential 
Page 13 of 13 
Clinical Protocol Amendment Template 
V1, 24Sep15 
Open Label Extension Schedule of Assessments (Protocol V4/ Appendix1) 
* For the purpose of scheduling, each month is considered as 4 weeks (28 days). 
 
Visit Number 
Day 
(Visit Window) 
Visit 5 
2 Weeks 
(+ 3 days) 
Visit 6 
1 Month 
(± 3 days) 
Visit 7 
2 Months 
 (± 3 days) 
Visit 8 
3 Months 
(± 7 days) 
Visit 9 
6 Months 
 (± 7 days) 
Visit 10 
9 Months 
(± 7 days) 
Visit 11 
12 Months 
 (± 7 days) 
Visit 12 
End of Taper 
 
Visit 13 
4wk SFU 
(± 3 days) 
Paper diary training 
 
 
 
 
 
 
 
 
 
Concomitant medications 
(including AEDs) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
(including weight) 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECG 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical laboratory blood 
sampling  
X 
X 
X 
X 
X 
X 
X 
X 
 
Clinical laboratory urine 
sampling (dipstick 
urinalysis) 
X 
X 
X 
X 
X 
X 
X 
X 
 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
X 
 
Patient diary review 
(seizures, AE information, 
concomitant AEDs, rescue 
medication, IMP dosing) 
X 
X 
X 
X 
X 
X 
X 
X 
 
IMP dispensing 
X 
X 
X 
X 
X 
X 
X 
 
 
Collection of IMP 
X 
X 
X 
X 
X 
X 
X 
X 
 
IMP compliance review 
X 
X 
X 
X 
X 
X 
X 
X 
 
Study Medication Use and 
Behavior Survey 
 
 
 
 
 
 
 
X 
 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
V4 04Feb16 
 
 
 
 
 
 
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TITLE: A PHASE2, DOUBLE-BLIND, RANDOMIZED, 
PLACEBO-CONTROLLED STUDY TO INVESTIGATE POSSIBLE 
DRUG-DRUG INTERACTIONS BETWEEN CLOBAZAM AND 
CANNABIDIOL (GWP42003-P) 
 
STUDY CODE: GWEP1428 
 
EudraCT NUMBER: 2014-002942-33 
 
 
 
GW RESEARCH LTD 
SOVEREIGN HOUSE,  
VISION PARK,  
CHIVERS WAY 
HISTON,  
CAMBRIDGE 
CB24 9BZ 
TEL: 
   FAX: 
 
 
 
 
Confidentiality Statement 
This document contains confidential information of GW Research Ltd 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 Research Ltd. 
PPD
PPD


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
V4 04Febl6 
Investigator Agreement 
G\1\1 
pharmaceuticals 
I have read the attached protocol entitled "A phase 2, double-blind, randomized, 
placebo-controlled study to investigate possible drug-drug interactions between 
clobazam and cannabidiol (GWP42003-P)", dated version 4 date 04 Feb 16 and agree 
to abide by all provisions set forth therein. 
I agree to comply with applicable regulatory requirements, the FDA regulations 
relating to good clinical practice and clinical trials and the European Union (EU) 
Clinical Trials Directive (200 1 /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 Directive does not apply and to 
complete a Form 1572 if required. 
I am not aware that any conflicts of interest, financial or otherwise, exist for myself, 
my spouse [or legal partner] and dependent children and agree to con finn this in 
writing if required and update as necessary. 
I agree to ensure that the confidential information contained in this document will not 
be used for any purpose other than the evaluation or conduct of the clinical 
investigation without the prior written consent of GW Research Ltd. 
Center No: 
Print Name: 
Date: 
Principal Investigator 
(DD Month YYYY) 
Signature: 
GW Authorization 
Print Name: 
Date: 0 f 
r)__o / {. · 
Clinical 
Signature: 
(DD Month YYYY) 
Confidential 
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PPD
PPD


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
V4 04Feb16 
 
 
 
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1. 
PROTOCOL SYNOPSIS 
Study Title 
A phase 2, double-blind, randomized, placebo-controlled study to 
investigate possible drug-drug interactions between clobazam and 
cannabidiol (GWP42003-P). 
Clinical Study 
Type 
Phase 2 
Indication 
Epilepsy 
Primary Objective 
To determine whether GWP42003-P affects the pharmacokinetic (PK) 
profile of clobazam (CLB) and its primary metabolite 
N-desmethylclobazam (N-CLB). 
Secondary 
Objective(s) 
To assess the safety and tolerability of GWP42003-P in the presence of 
CLB. 
Study Design 
This is a phase 2, double-blind, randomized, placebo-controlled study 
in 20 patients. 
• Patients will be randomized in a 4:1 ratio to receive 20 mg/kg 
GWP42003-P or placebo from days 2 to 33.  
• 
At the end of the treatment period, patients will be given the option 
of continuing onto an open label extension (OLE) period if the 
investigator and patient both agree that it is in their best interests. 
Doses may be adjusted up or down, dependent on investigator 
opinion, to a maximum of 30 mg/kg/day GWP42003-P.  The OLE 
will last for a maximum of one year or until marketing 
authorization is granted; whichever is earlier. 
• 
Patients that do not continue onto the OLE will taper off of 
GWP42003-P over a 10 day period and will have a telephone 
follow-up visit four weeks after the end of taper day on Day 71. 
• Day 
1 
(Visit 
2), 
patients 
will 
not 
be 
dosed 
with 
GWP42003-P/placebo but will continue to take CLB at a stable 
dose. 
• Day 2 (Visit 2), patients will begin the up-titration with 
GWP42003-P or placebo to a maintenance dose or an equivalent 
maintenance dose of 20 mg/kg/day over a period of 10 days (Days 
2 to 11). 
• Day 12 (Visit 3), patients will attend the study site to check safety 
and compliance. 
• After up-titration with GWP42003-P or placebo, the patients will 
remain on the maintenance dose for 21 days (Days 12 to 32). 
• On Day 34 (Visit 4), patients will be invited to receive 
GWP42003-P in the OLE period.  If the patient enters the OLE 
period of the study, the patient will continue to take GWP42003-P 


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as advised by the investigator. 
• If the patient does not enter the OLE period of the study, the patient 
will taper off of GWP42003-P by reducing the dose by 
approximately 10% of the maintenance dose each day until dosing 
has ceased, with end of taper on Day 43 (Visit 5). 
PK samples will be taken on the day of enrollment (Visit 2, Day 1) and 
after completing 21 days treatment on GWP42003-P or placebo 
(Visit 4, Day 33).  The PK assessments will therefore capture the 
following combinations of CLB and GWP42003-P: 
• First PK Assessment: CLB only. 
• Second PK Assessment: CLB and GWP42003-P or placebo. 
Each PK assessment should be performed at time points in respect to a 
morning dose of CLB.  The time points are as follows: Pre-dose, 
15 min, 30 min, 1 h, 1.5 h, 2 h, 4 h, 6 h, 12 h and 24 h.  It is expected 
that the patient will continue to take their CLB as advised by their 
physician and PK assessments will be scheduled in order to 
accommodate this dosing schedule.  The GWP42003-P/placebo should 
be taken twice daily immediately following their CLB dose. 
PK assessments will analyze the amount of CLB, the CLB primary 
metabolite N-CLB, CBD, CBD major metabolites, 
∆9-tetrahydrocannabinol (THC), THC major metabolites, valproate 
(VPA), stiripentol (STP), levetiracetam (LEV) and topiramate (TPM).  
Patients will be required to keep a paper diary to note the time and dose 
of GWP42003-P and CLB administration each morning and evening 
and to record any adverse events (AEs) that may occur whilst receiving 
investigational medicinal product (IMP) and any other medications.  
Patients will also be requested to record the number and type of 
seizures for each day whilst on the study. 
Primary Endpoint 
The primary endpoints of the study are the PK parameters (Cmax, tmax, 
AUC(0–∞) AUC(0–t), t½) of the following analytes: 
• CLB 
• N-CLB 
• CBD 
• CBD major metabolites 
Secondary 
Endpoint(s) 
To assess the safety and tolerability of GWP42003-P compared with 
placebo when taken in combination with CLB.  Safety and tolerability 
will be assessed using the following parameters: 
• AEs 
• 12-lead electrocardiogram (ECG) 
• Clinical laboratory parameters (clinical chemistry, hematology 
and urinalysis) 
• Vital signs 
• Columbia-Suicide Severity Rating Scale (C-SSRS) 
• Seizure frequency 


Study Code: GWEP1428 
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• Abuse liability 
• CYP2C19 and CPY3A4 patient genotype analysis 
 
PK parameters (Cmax, tmax, AUC(0–∞), AUC(0–t), t½) of the following 
analytes: 
• THC  
• THC major metabolites 
Sample Size 
A total of 20 patients will be enrolled in this study.  Recruitment for the 
study will be competitive between participating sites.  There is no 
formal sample size: Calculation and analysis is descriptive only. 
Summary of 
Participant 
Eligibility Criteria 
For inclusion in the study patients must fulfil ALL of the following 
criteria: 
• Male or female patients aged 18 to 65 years inclusive. 
• Patient must have epilepsy as determined by the investigator and be 
taking CLB. 
• Patient must have a documented magnetic resonance 
imaging/computerized tomography of the brain that ruled out a 
progressive neurologic condition. 
• Patient must have experienced at least one seizure of any type (i.e., 
convulsive: tonic-clonic, tonic, clonic, atonic; focal: focal seizures 
with retained consciousness and a motor component, focal seizures 
with impaired consciousness focal seizures evolving to bilateral 
secondary generalization) within the two months prior to 
randomization. 
• Patients must be taking CLB and no more than two other 
antiepileptic drugs (AEDs) during the course of the study. 
• AED(s), including CLB, must be stable for four weeks prior to 
screening and regimen must remain stable throughout the duration 
of the blinded phase of the study. 
• Intervention with vagus nerve stimulation and/or ketogenic diet 
must be stable for four weeks prior to baseline and patient/caregiver 
must be willing to maintain a stable regimen throughout the blinded 
phase of the study. 
• Patients must abstain from alcohol during the blinded phase of the 
study. 
• Patient is available to attend all PK visits within the required visit 
window. 
• Patient and/or legal representative must be willing and able to give 
informed consent for participation in the study. 
• Patient and/or legal representative must be willing and able (in the 
investigator’s opinion) to comply with all study requirements. 


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• Patient is willing for his or her name to be notified to the 
responsible authorities for participation in this study, as applicable. 
• Patient is willing to allow his or her primary care practitioner and 
consultant, if appropriate, to be notified of participation in the 
study. 
 
Exclusion: The patient may not enter the study if ANY of the following 
apply: 
• Patient has clinically significant unstable medical conditions other 
than epilepsy. 
• Patients on CLB at doses above 20 mg per day. 
• Patients taking CLB intermittently as rescue medication. 
• Patient has a history of symptoms (e.g., dizziness, light-headedness, 
blurred vision, palpitations, weakness, syncope) related to a drop in 
blood pressure (BP) due to postural changes. 
• Any history of suicidal behavior or any suicidal ideation of type 
four or five on the C-SSRS in the last month or at screening. 
• Patient has had clinically relevant symptoms or a clinically 
significant illness in the four weeks prior to screening or 
enrollment, other than epilepsy. 
• Patient has consumed alcohol during the seven days prior to 
enrollment and is unwilling to abstain during the blinded phase of 
the study. 
• Patient is currently using or has in the past used recreational or 
medicinal cannabis, or synthetic cannabinoid based medications 
(including Sativex®) within the three months prior to study entry. 
• Patient has any known or suspected history of any drug abuse or 
addiction. 
• Patient is unwilling to abstain from recreational or medicinal 
cannabis, or synthetic cannabinoid based medications (including 
Sativex) for the duration of the study. 
• Patient has consumed grapefruit or grapefruit juice seven days prior 
to enrollment and is unwilling to abstain from drinking grapefruit 
juice within seven days of PK visits. 
• Patient has any known or suspected hypersensitivity to 
cannabinoids or any of the excipients of the IMP, e.g., sesame oil. 
• 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 three 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 


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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 three 
months thereafter. 
• Patients who have received an IMP within the 12 weeks prior to the 
screening visit. 
• Patient is taking felbamate and they have been taking it for less than 
one year prior to screening. 
• 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 
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 participant 
from safe participation in the study. 
• Patient has significantly impaired hepatic function at screening 
(Visit 1) or enrollment (Visit 2), defined as any of the following: 
- 
Alanine aminotransferase (ALT) or Aspartate aminotransferase 
(AST) > 5 × upper limit of normal (ULN). 
- 
ALT or AST > 3 × ULN and total bilirubin (TBL) > 2 × ULN 
or international normalized ratio (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%).  
This criterion can only be confirmed once the laboratory results are 
available; patients randomized into the study who are later found to 
meet this criterion must be withdrawn from the study. 
• Patient has a prolonged QTcB (> 450 msec for males 
and > 470 msec for females). 
• Unwilling to abstain from donation of blood during the study. 
• Travel outside the country of residence planned during the study, 
unless the patient has confirmation that the IMP is permitted in the 
destination country/state. 
• Patients previously enrolled into this study. 
Criteria for 
Withdrawal 
Patients must be withdrawn from the study if any of the following 
apply: 
• Administrative decision by the investigator or GW Research Ltd or 
Regulatory Authority. 
• Pregnancy. 
• Protocol deviation that is considered to potentially compromise the 
safety of the patient. 


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• Withdrawal of patient consent. 
• Withdrawal of legal representative consent. 
• Lost to follow up. 
• ALT > 3 × ULN 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 two weeks. 
• Any other IMP is taken as part of a clinical trial during the study.  
• Significant change in QTcB (> 60 msec) from the previous ECG or 
absolute QTcB of > 500 msec. 
 
Patients may also be withdrawn from the study if any of the following 
apply: 
• Patient non-compliance. 
• AE, which in the investigator’s opinion, 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 four or five 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), pale yellow in color. 
Placebo oral solution containing the excipients sesame oil and 
anhydrous ethanol with added sweetener (sucralose) and strawberry 
flavoring. 
The IMP should be taken orally as per intended commercial therapeutic 
use. 
IMP will be taken twice daily (morning and evening) following the 
dose schedule below: 
• Day 2 (Visit 2), patients will begin the up-titration with 
GWP42003-P or placebo to a maintenance dose or an equivalent 
maintenance dose of 20 mg/kg/day over a period of 10 days (Days 
2 to 11). 
• After up-titration with GWP42003-P or placebo, the patients will 
remain on the maintenance dose for 21 days (Days 12 to 32). 
Please refer to Table 8.1.2-1 for details of the up-titration doses for 
GWP42003-P and placebo for the ten day taper period. 
On Day 34 (Visit 4), patients will be invited to receive GWP42003-P in 
the OLE period.  If the patient enters the OLE period of the study, the 


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patient will continue to take GWP42003-P as advised by the 
investigator. 
CLB will be an IMP for the blinded section of the study.  The patient’s 
own supply of CLB will be used. 
Control Group 
The control group will receive an equal volume of matching placebo. 
Procedures 
VISIT 1 - Screening (Day -14 to -7) 
The following observations will be made at Visit 1: demographics, 
medical history (including seizure information since diagnosis, history 
of epilepsy-specific genetic testing and all prior AEDs taken), 
concomitant medications (including AEDs), physical examination 
(including height and body weight), ECG, vital signs and AEs. 
Clinical laboratory samples (blood and urine) will be taken for 
hematology, biochemistry, alcohol testing, THC testing, urinalysis and 
a pregnancy test (using a serum sample, if appropriate).  The laboratory 
results should be available within 3-5 working days after Visit 1.  If the 
results show a patient is ineligible, the patient will not be enrolled into 
the study.  The C-SSRS will be administered. 
Patients who satisfy all inclusion and none of the exclusion criteria 
specified in Section 6 will be assigned a unique patient number and 
then begin the baseline period.  Patients or their caregivers will be 
given a paper diary to record daily seizure information, rescue 
medication, concomitant AEDs and AEs; and will be instructed on how 
to do so.  The investigator must record the patient’s attendance at the 
visit and confirm the outcome of screening on the CRF.  
VISIT 2 - Enrollment (Day 1) + 3 days window 
This visit will occur 7–14 days after Visit 1. 
The following observations will be made at Visit 2: concomitant 
medications, (including AEDs), physical examination (including body 
weight), ECG, vital signs, review of patient diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for 
hematology, biochemistry, alcohol testing and urinalysis.  Blood 
samples will also be taken for genetic testing if additional consent has 
been obtained.  The C-SSRS will be administered.  The investigator 
must record the patient’s attendance at the visit, and confirm the 
outcome of the visit prior to enrollment. 
Following enrollment patients will begin the PK sampling process.  
Blood samples will be taken for analysis of plasma concentrations of 
CLB, N-CLB, VPA, STP, LEV and TPM.  A baseline PK sample will 
be taken before the patient takes their morning dose of CLB.  Further 
samples will then be taken at the following times relative to the CLB 
dose: 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 
6 hours and 12 hours.  The evening dose of any AEDs must be taken 
after the 12 hour PK blood sample.  Patients will either remain in clinic 
overnight throughout this PK sampling process or return to the clinic 


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on Day 2 ahead of additional sample collection. 
VISIT 2 - Enrollment (Day 2) 
This is the second part of the two day enrollment visit.  The final PK 
sample will be collected 24 hours after the Day 1 morning CLB dose. 
Following completion of the PK sampling process the following 
observations will be made on Day 2: concomitant medications 
(including AEDs), physical examination (including body weight), vital 
signs and AEs. 
GWP42003-P/placebo will be dispensed and both the morning dose of 
CLB and GWP42003-P/placebo will be taken in clinic.  Following 
administration of GWP42003-P/placebo, patients must remain in clinic 
for at least 30 minutes to monitor for any adverse reactions.  Patients 
and/or their caregivers will be provided with individual dosing 
schedules as described in Section 8.1.  Each patient will then receive 
their GWP42003-P/placebo for the 10 day titration period followed by 
the 21 day maintenance period.  Patients, or their caregivers, will be 
instructed on how to record the diary information. 
VISIT 3 – Day 12 + 3 day window 
This visit will occur 11 days after Visit 2, Day 1 (enrollment).  Patients 
will return all used and unused GWP42003-P/placebo.  The following 
observations will be made at Visit 3: concomitant medications 
(including AEDs), physical examination (including body weight), 
ECG, vital signs, AEs and review of patient diary completion. 
Clinical laboratory samples (blood and urine) will be taken for 
hematology, biochemistry and urinalysis.  The C-SSRS will be 
administered. 
VISIT 4 - Day 33 ± 3 days window 
This visit will occur 32 days after Visit 2, Day 1 (enrollment).  Patients 
will return all used and unused GWP42003-P/placebo.  The following 
observations will be made at Visit 4 (Day 33): concomitant medications 
(including AEDs), physical examination (including body weight), 
ECG, vital signs, review of patient diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for 
hematology, biochemistry, alcohol testing and urinalysis.  The C-SSRS 
will be administered. 
Blood samples will be taken for analysis of plasma concentrations of 
CLB, N-CLB, VPA, STP, LEV, TPM, CBD, CBD major metabolites, 
THC and THC major metabolites.  A baseline PK sample will be taken 
before the patient takes their morning dose of CLB, followed 
immediately by their dose of GWP42003-P/placebo.  Further samples 
will then be taken at the following times relative to the CLB dose: 
15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours and 
12 hours.  The evening dose of GWP42003-P/placebo and any AEDs 
must be taken after the 12 hour PK blood sample.  Patients are expected 


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to remain in clinic throughout this PK sampling process. 
The investigator must assess adherence to the dosing regimen and 
recording of rescue medications by reviewing the patient’s diary. 
VISIT 4 - Day 34 
This is the second part of the two day visit.  The final PK sample will 
be collected 24 hours after the Day 33 morning CLB dose. 
Following completion of the PK sampling process the following 
observations will be made on Day 34: concomitant medications 
(including AEDs), physical examination (including body weight), vital 
signs and AEs. 
On Day 34, providing the investigator and patient both agree, patients 
will be invited to continue taking GWP42003-P and to enter the OLE. 
Patients who enter the OLE will be dispensed GWP42003-P on Day 34 
and the first dose will be taken in clinic.  Following administration of 
GWP42003-P, patients must remain in clinic for at least 30 minutes to 
monitor for any adverse reactions.   
Patients who do not enter the OLE will begin a 10 day taper period 
during which they will taper off their daily dose of GWP42003-P.  The 
daily dose will be reduced by 10% of the maintenance dose per day and 
treatment will end on Day 42. 
Patients Not Entering OLE 
VISIT 5 – Day 43 (End of Taper) + 3 days window 
This visit will occur 42 days after Visit 2, Day 1 (enrollment) for those 
patients who do not enter the OLE. 
All GWP42003-P/placebo (used and unused) will be collected and a 
check of the returned GWP42003-P/placebo against usage must be 
made.  A physical examination (including body weight), ECG and vital 
signs will be assessed and the C-SSRS will be administered.  The 
trained investigator or study coordinator will complete the Study 
Medication Use and Behavior Survey as an interview with the 
patient/caregiver. 
Clinical laboratory samples (blood and urine) will be taken for 
hematology, biochemistry and urinalysis and a review of concomitant 
medications (including AEDs) and AEs will be completed.  Patient 
diaries will be collected. 
VISIT 6 - SAFETY FOLLOW-UP CALL - Day 71 ± 3 days 
This visit is required for patients who do not enter the OLE study on 
Day 34, or who withdraw from the study early.  This visit should occur 
four weeks (± 3 days) after Visit 5, or withdrawal from treatment, and 
can be conducted over the telephone.  The following observations will 
be made on Day 71: concomitant medications (including AEDs) and 
AEs. 


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Patients Entering OLE 
At the point of entry to the OLE, patients will be transitioned to the 
OLE treatment over a 10 day period in order to maintain blinding.  
Patients who enter the OLE will be dispensed IMP at Visit 4 (Day 34) 
and will have regular clinic visits for a maximum of one year or earlier 
(if marketing authorization is granted or the patient withdraws).  The 
visit schedule is calculated relative to Visit 4 (Day 34). 
VISIT 5 (OLE) – Two Weeks ± 3 days 
This visit will occur two weeks after Visit 4 (Day 34).  Patients will 
return all used and unused IMP.  The following observations will be 
made at Visit 5 (OLE): concomitant medications (including AEDs), 
physical examination (including body weight), ECG, vital signs, review 
of patient diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for 
hematology, biochemistry and urinalysis.  The C-SSRS will be 
administered.  The investigator must record the patient’s attendance at 
the visit and the outcome. 
The investigator must assess adherence to the dosing regimen and 
recording of rescue medications by reviewing the patient’s diary. 
The GWP42003-P dose may be adjusted up or down by the investigator 
from the maintenance dose of 20 mg/kg/day achieved at the end of the 
10-day transition period, up to a maximum of 30 mg/kg/day in the OLE 
period.   
VISIT 6 (OLE) – One Month ± 3 days 
This visit will occur one month (one month is considered as 28 days) 
after Visit 4 (Day 34).  Patients will return all used and unused IMP.  
The following observations will be made at Visit 6 (OLE): concomitant 
medications (including AEDs), physical examination (including body 
weight), ECG, vital signs, review of patient diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for 
hematology, biochemistry and urinalysis.  The C-SSRS will be 
administered.  The investigator must record the patient’s attendance at 
the visit and the outcome. 
The investigator must assess adherence to the dosing regimen and 
recording of rescue medications by reviewing the patient’s diary. 
VISIT 7 (OLE) – Two Months ± 3 days 
This visit will occur two months after Visit 4 (Day 34).  Patients will 
return all used and unused IMP.  The following observations will be 
made at Visit 7 (OLE): concomitant medications (including AEDs), 
physical examination (including body weight), ECG, vital signs, review 
of patient diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for 


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hematology, biochemistry and urinalysis.  The C-SSRS will be 
administered.  The investigator must record the patient’s attendance at 
the visit and the outcome. 
The investigator must assess adherence to the dosing regimen and 
recording of rescue medications by reviewing the patient’s diary. 
VISIT 8 (OLE) - Three Months ± 7 days 
This visit will occur three months after Visit 4 (Day 34).  Patients will 
return all used and unused IMP.  The following observations will be 
made at Visit 8 (OLE): concomitant medications (including AEDs), 
physical examination (including body weight), ECG, vital signs, review 
of patient diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for 
hematology, biochemistry and urinalysis.  The C-SSRS will be 
administered.  The investigator must record the patient’s attendance at 
the visit and the outcome. 
The investigator must assess adherence to the dosing regimen and 
recording of rescue medications by reviewing the patient’s diary. 
VISIT 9 (OLE) - Six Months ± 7 days 
This visit will occur six months after Visit 4 (Day 34).  Patients will 
return all used and unused IMP.  The following observations will be 
made at Visit 9 (OLE): concomitant medications (including AEDs), 
physical examination (including body weight), ECG, vital signs, review 
of patient diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for 
hematology, biochemistry and urinalysis.  The C-SSRS will be 
administered.  The investigator must record the patient’s attendance at 
the visit and the outcome. 
The investigator must assess adherence to the dosing regimen and 
recording of rescue medications by reviewing the patient’s diary. 
VISIT 10 (OLE) - Nine Months ± 7 days 
This visit will occur nine months after Visit 4 (Day 34).  Patients will 
return all used and unused IMP.  The following observations will be 
made at Visit 10 (OLE): concomitant medications (including AEDs), 
physical examination (including body weight), ECG, vital signs, review 
of patient diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for 
hematology, biochemistry and urinalysis.  The C-SSRS will be 
administered.  The investigator must record the patient’s attendance at 
the visit and the outcome. 
The investigator must assess adherence to the dosing regimen and 
recording of rescue medications by reviewing the patient’s diary. 
VISIT 11 – Twelve Months (OLE End of Treatment) ± 7 days 


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This visit will occur twelve months after Visit 4 (Day 34).  Patients will 
return all used and unused IMP.  The following observations will be 
made at Visit 11 (OLE): concomitant medications (including AEDs), 
physical examination (including body weight), ECG, vital signs, review 
of patient diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for 
hematology, biochemistry and urinalysis.  The C-SSRS will be 
administered.  The investigator must record the patient’s attendance at 
the visit and the outcome. 
The investigator must assess adherence to the dosing regimen and 
recording of rescue medications by reviewing the patient’s diary. 
Starting at Visit 11, patients will begin to taper down their IMP dose.  
The dose will be reduced by 10% of their OLE maintenance dose per 
day. 
VISIT 12 - OLE End of taper + 3 days 
This visit will be ten days after Visit 11.  All IMP (used and unused) 
will be collected and a check of the returned IMP against usage must be 
made.  A physical examination (including body weight), ECG and vital 
signs will be assessed and the C-SSRS will be administered.  The 
trained investigator or study coordinator will complete the Study 
Medication Use and Behavior Survey as an interview with the 
patient/caregiver. 
Clinical laboratory samples (blood and urine) will be taken for 
hematology, biochemistry and urinalysis and a review of concomitant 
medications (including AEDs) and AEs will be completed.  Patient 
diaries will be collected and reviewed. 
VISIT 13 - SAFETY FOLLOW-UP CALL (OLE) 
This visit will occur one month after the OLE End of Taper and can be 
conducted over the telephone.  The following observations will be 
made during the follow up call: concomitant medications (including 
AEDs) and AEs. 
Monitoring of Drug Abuse Liability  
During the routine collection of AEs in this study, if AEs are reported 
which can illuminate an abuse potential signal (specific AEs detailed in 
Section 9.1.16.1.1), 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 
discussions of the event(s) with the patient/caregiver. 
The second trigger that will require the investigator or study 
coordinator to discuss abuse potential signals with the patient/caregiver 
is drug accountability issues regarding overuse of the IMP or missing 
IMP bottles. 
Irrespective of the above, all patients/caregivers will be interviewed at 
their final dosing visit or withdrawal visit and a Study Medication Use 


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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 
Plasma concentration data will be analyzed to estimate PK endpoints 
Cmax, tmax, AUC(0–t), AUC(0–∞) and t½ of the following analytes: CLB, 
N-CLB, VPA, STP, LEV, TPM, CBD, CBD major metabolites, THC 
and THC major metabolites. 
In order to assess whether the presence of CBD alters the PK profile of 
CLB or N-CLB, a standard 90% confidence interval (CI) approach for 
the between group ratios of geometric means of Cmax AUC(0–t), and 
AUC(0–∞) will be done on logarithm scale using a linear mixed effect 
model with treatment (CLB or CLB+GWP42003-P) as a fixed effect 
and subject as a random effect.  The no-effect boundary will be set 
between 0.5 and 2.0 and if the 90% CI for the ratio of the geometric 
means of a PK variable falls within the interval [0.5, 2.0], a lack of 
meaningful effect will be declared. 
Descriptive summaries (means and standard deviations or counts [%] 
as appropriate) will be presented for all secondary endpoints (adverse 
events, laboratory data, vital signs, physical examination, C-SSRS and 
seizure frequency) for each phase of the study. 
Sponsor 
GW Research Ltd 
Sovereign House 
Vision Park 
Chivers Way 
Histon 
Cambridge CB24 9BZ 
United Kingdom 


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Figure 1-1 
Study Design and Treatment Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
S 
C 
R 
E 
E 
N 
I 
N 
G 
E 
N 
R 
O 
L 
L 
M 
E 
N 
T 
E 
N 
D 
  
O 
F 
  
B 
L 
I 
N 
D 
E 
D 
  
T 
R 
E 
A 
T 
M 
E 
N 
T 
Visit 1 
Day -14  
to -7 
Visit 2 
Day 1/2 
(+3 d) 
Visit 4 
Day 33/34 
(±3 d) 
E 
N 
D 
  
O 
F 
  
T 
A 
P 
E 
R 
10 Day Taper 
Patients not 
entering the 
OLE 
Patients entering the OLE 
S 
A 
F 
E 
T 
Y 
  
F 
O 
L 
L 
O 
W 
  
U 
P 
10 Day 
Up-Titration 
21 Day 
Maintenance 
Visit 5 
Day 43 
Visit 6 
Day 71 
28 day FU 
(±3 d) 
7-14 days 
31 days 
10 days 
28 days 
Placebo  
N=4 
GWP42003-P Oral 
Solution 
(100 mg/mL bd) 
N=16 
Visit 3 
Day 12 
(+3 d) 


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Figure 1-2 
Study Design and Treatment Schema  
 
Patients  
entering 
from 
 the  
blinded 
phase 
Visit 5 OLE 
2 weeks 
(±3 d) 
Visit 7 OLE 
2 months 
(±3 d) 
Visit 6 OLE 
1 month 
(±3 d) 
Visit 8 OLE 
3 months 
(±7 d) 
Visit 9 OLE 
6 months 
(±7 d) 
Visit 11 OLE 
12 months 
(±7 d) 
Visit 10 OLE 
9 months 
(±7 d) 
Visit 12 OLE 
 
E 
N 
D 
  
O 
F 
  
T 
A 
P 
E 
R 
Visit 13 OLE 
28 day FU 
(±3 d) 
S 
A 
F 
E 
T 
Y 
 
F 
O 
L 
L 
O 
W 
 
U 
P 
Open Label Extension Phase: 
GWP42003-P Oral Solution 
(100 mg/mL bd) 
10 
Day 
Taper 
2 weeks 
from V4 
2 weeks 
1 month 
1 month 
3 months 
3 months 
3 months 
10 days 
28 days 


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Table of Contents 
Title Page ................................................................................................... 1 
1. 
PROTOCOL SYNOPSIS ................................................................ 3 
Table of Contents .................................................................................... 18 
Table of Appendices ............................................................................... 23 
List of In-text Tables .............................................................................. 24 
List of In-text Figures ............................................................................. 25 
List of Abbreviations .............................................................................. 26 
Definition of Terms ................................................................................. 28 
2. 
OBJECTIVES ................................................................................ 29 
2.1 
Primary ........................................................................................................ 29 
2.2 
Secondary .................................................................................................... 29 
3. 
BACKGROUND AND RATIONALE ......................................... 30 
3.1 
Disease......................................................................................................... 30 
3.2 
GWP42003-P Background .......................................................................... 30 
3.3 
Rationale ...................................................................................................... 31 
3.3.1 
Selection of Study Doses .......................................................................... 32 
3.4 
Clinical Hypothesis ..................................................................................... 33 
4. 
EXPERIMENTAL PLAN ............................................................. 34 
4.1 
Study Design ............................................................................................... 34 
4.1.1 
Primary Endpoint ...................................................................................... 35 
4.1.2 
Secondary Endpoint(s) .............................................................................. 35 
4.2 
Number of Centers ...................................................................................... 35 
4.3 
Number of Patients ...................................................................................... 36 
5. 
INVESTIGATIONAL MEDICINAL PRODUCT ..................... 37 
5.1 
GWP42003-P Oral Solution ........................................................................ 37 
5.2 
Placebo Oral Solution .................................................................................. 37 
5.3 
Packaging, Storage and Drug Accountability (Cannabidiol/Placebo) ........ 37 
5.3.1 
Packaging and Labelling ........................................................................... 37 
5.3.2 
Storage ...................................................................................................... 38 
5.3.3 
Supply and Return of Investigational Medicinal Product ......................... 38 
5.3.4 
Investigational Medicinal Product Accountability ................................... 38 


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5.4 
Clobazam ..................................................................................................... 39 
6. 
PARTICIPANT ELIGIBILITY ................................................... 39 
6.1 
Inclusion Criteria ......................................................................................... 39 
6.2 
Exclusion Criteria ........................................................................................ 40 
7. 
PATIENT ENROLLMENT ......................................................... 42 
7.1 
Treatment Assignment ................................................................................ 42 
7.2 
Randomization............................................................................................. 42 
8. 
TREATMENT PROCEDURES ................................................... 43 
8.1 
Investigational Medicinal Product Dosage, Administration and 
Schedule ...................................................................................................... 43 
8.1.1 
Dose Administration ................................................................................. 43 
8.1.2 
Dose Escalation and Dose Adjustments ................................................... 44 
8.2 
Concomitant Therapy .................................................................................. 45 
8.3 
Prohibited Therapy During Study Period .................................................... 45 
8.4 
Compliance in Investigational Medicinal Product Administration ............. 45 
8.5 
Access to Blinded Treatment Assignment .................................................. 46 
9. 
STUDY PROCEDURES ............................................................... 47 
9.1 
Study Procedure Listing .............................................................................. 47 
9.1.1 
Contraception ............................................................................................ 47 
9.1.2 
Informed Consent ..................................................................................... 47 
9.1.3 
Demographics ........................................................................................... 47 
9.1.4 
Medical History ........................................................................................ 48 
9.1.5 
Concomitant Medication .......................................................................... 48 
9.1.6 
Physical Examination ............................................................................... 48 
9.1.7 
Vital Signs ................................................................................................ 48 
9.1.8 
12-Lead Electrocardiogram ...................................................................... 48 
9.1.9 
Clinical Laboratory Sampling................................................................... 48 
9.1.10 
Pharmacokinetic Analyses ........................................................................ 50 
9.1.11 
Genetic Testing ......................................................................................... 50 
9.1.12 
Columbia Suicide Severity Rating Scale .................................................. 51 
9.1.13 
Patient Diary ............................................................................................. 51 
9.1.14 
Investigational Medicinal Product Accountability ................................... 51 
9.1.15 
Adverse Events ......................................................................................... 52 


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9.1.16 
Monitoring of Drug Abuse Liability......................................................... 52 
9.1.16.1 
Monitoring of Adverse Events .............................................................. 53 
9.1.16.1.1 
List of ‘Triggering Adverse Events of Interest’ ................................ 53 
9.1.16.1.2 
Supplemental Adverse Event Form ................................................... 53 
9.1.16.2 
Monitoring Drug Accountability Discrepancies ................................... 54 
9.1.16.2.1 
List of ‘Triggering Drug Accountability Discrepancies’ .................. 54 
9.1.16.2.2 
Supplemental Drug Accountability Form ......................................... 55 
9.1.16.3 
Site Classification Form ........................................................................ 55 
9.1.16.4 
Study Medication Use and Behavior Survey ........................................ 55 
9.1.16.5 
Adjudication Committee — Assessment of Abuse Potential of 
GWP42003-P ........................................................................................ 56 
9.2 
Study Procedures by Visit ........................................................................... 58 
9.2.1 
Double Blind Phase .................................................................................. 58 
9.2.1.1 
Visit 1 (Day −14 to −7, Screening) ....................................................... 58 
9.2.1.2 
Visit 2 .................................................................................................... 58 
9.2.1.2.1 
Visit 2 (Day 1) – Enrollment (+3 days) ............................................. 58 
9.2.1.2.2 
Visit 2 (Day 2) - Enrollment .............................................................. 59 
9.2.1.3 
Visit 3 (Day 12 +3 days) ....................................................................... 59 
9.2.1.4 
Visit 4 .................................................................................................... 59 
9.2.1.4.1 
Visit 4 (Day 33) (±3 days) ................................................................. 59 
9.2.1.4.2 
Visit 4 (Day 34) ................................................................................. 60 
9.2.1.5 
Visit 5 (Patients not entering Open Label Extension) (Day 43 +3 
days) ...................................................................................................... 61 
9.2.1.6 
Visit 6 - Safety Follow up Call (Day 71) (±3 days) .............................. 61 
9.2.2 
Open Label Extension ............................................................................... 61 
9.2.2.1 
Visit 5 (Open Label Extension) - Two Weeks (±3 days) ...................... 61 
9.2.2.2 
Visit 6 (Open Label Extension) - One Month (±3 days) ....................... 62 
9.2.2.3 
Visit 7 (Open Label Extension) - Two Months (±3 days) .................... 62 
9.2.2.4 
Visit 8 (Open Label Extension) - Three Months (±7 days) .................. 62 
9.2.2.5 
Visit 9 (Open Label Extension) - Six Months (±7 days) ...................... 63 
9.2.2.6 
Visit 10 (Open Label Extension) - Nine Months (±7 days) .................. 63 
9.2.2.7 
Visit 11 (Open Label Extension End of Treatment) - Twelve 
Months (±7 days) .................................................................................. 63 
9.2.2.8 
Visit 12 (Open Label Extension End of Taper) .................................... 64 


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9.2.2.9 
Safety Follow Up Call (±3 days) .......................................................... 64 
10. 
WITHDRAWAL ............................................................................ 64 
11. 
URGENT SAFETY MEASURES ................................................ 65 
12. 
ADVERSE EVENT REPORTING .............................................. 66 
12.1 
Definitions ................................................................................................... 66 
12.1.1 
Adverse Event ........................................................................................... 66 
12.1.2 
Investigator ............................................................................................... 66 
12.2 
Serious Adverse Events ............................................................................... 66 
12.3 
Reporting Procedures for Serious Adverse Events ..................................... 67 
12.4 
Pregnancy .................................................................................................... 68 
12.5 
Causality Assessment .................................................................................. 68 
12.6 
Reporting Procedures for All Adverse Events ............................................ 69 
12.7 
Follow up Procedures for Adverse Events .................................................. 70 
12.8 
Potential Cases of Drug Induced Liver Injury............................................. 71 
12.9 
Notification of Safety Information to Investigators, Regulatory 
Authorities and Ethics Committees. ............................................................ 71 
13. 
STATISTICAL CONSIDERATIONS ......................................... 74 
13.1 
Sample Size, Power and Significance Levels ............................................. 74 
13.2 
Interim Analysis .......................................................................................... 74 
13.3 
Analysis Sets ............................................................................................... 74 
13.3.1 
Safety Set .................................................................................................. 74 
13.3.2 
Pharmacokinetic Analysis Set .................................................................. 74 
13.3.3 
Protocol Deviations .................................................................................. 74 
13.4 
General Considerations ............................................................................... 74 
13.5 
Accountability and Background Characteristics ......................................... 75 
13.5.1 
Enrollment and Disposition ...................................................................... 75 
13.5.2 
Baseline and Demographic Characteristics .............................................. 75 
13.5.3 
Medical History ........................................................................................ 75 
13.5.4 
Concomitant Medication .......................................................................... 75 
13.6 
Endpoints and Statistical Methods .............................................................. 75 
13.6.1 
Primary Endpoint(s) .................................................................................. 75 
13.6.2 
Secondary Endpoint(s) .............................................................................. 75 
13.6.3 
Pharmacokinetics ...................................................................................... 76 


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13.6.4 
Safety ........................................................................................................ 77 
13.6.4.1 
Treatment Compliance and Extent of Treatment Exposure .................. 77 
13.6.4.2 
Adverse Events...................................................................................... 77 
13.6.4.3 
Clinical Laboratory Data ....................................................................... 77 
13.6.4.4 
Columbia-Suicide Severity Rating Scale, Vital Signs, 12-lead 
Electrocardiogram, Physical Examination and Other Safety Data ....... 78 
13.6.4.5 
Seizure Data .......................................................................................... 78 
14. 
DATA SAFETY MONITORING COMMITTEE ..................... 78 
15. 
REGULATORY AND ETHICAL OBLIGATIONS .................. 79 
15.1 
Declaration of Helsinki ............................................................................... 79 
15.2 
Informed Consent ........................................................................................ 79 
15.3 
Institutional Review Board/Ethics Committee ............................................ 79 
15.4 
Pre-Study Documentation Requirements .................................................... 80 
15.5 
Participant Confidentiality .......................................................................... 80 
16. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ............... 82 
16.1 
Protocol Amendments and End of Study or Termination ........................... 82 
16.2 
Study Documentation and Storage .............................................................. 82 
16.3 
Study Monitoring and Data Collection ....................................................... 83 
16.4 
Quality Assurance ....................................................................................... 85 
16.5 
Compensation .............................................................................................. 85 
16.6 
Publication Policy........................................................................................ 85 
16.7 
Intellectual Property Rights ......................................................................... 86 
16.8 
Confidential Information ............................................................................. 86 
17. 
REFERENCES .............................................................................. 87 


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Table of Appendices 
APPENDIX 1. 
Schedule of Assessments 
90 
APPENDIX 2. 
Study Personnel 
93 
Appendix 3.1 
Investigator Details 
93 
Appendix 3.2 
Sponsor Contact Details 
93 
 
 


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List of In-text Tables 
Table 3.3.1-1 
Epidiolex Adverse Events ........................................................ 33 
Table 5.1-1 
Formulation of GWP42003-P Oral Solution ........................... 37 
Table 5.2-1 
Formulation of Placebo Oral Solution ..................................... 37 
Table 8.1.2-1 
Dose Up-titration Regimen* .................................................... 44 
Table 9.1.9-1 
Hematology, Biochemistry, Urinalysis and THC Screen ........ 49 
 
 
 


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List of In-text Figures 
Figure 1-1 
Study Design and Treatment Schema ...................................... 16 
Figure 1-2 
Study Design and Treatment Schema ...................................... 17 
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 ....................................... 57 
 


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List of Abbreviations 
AE 
Adverse Event 
AEDs 
Antiepileptic Drugs 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC(0–∞) 
Area under the concentration time curve from zero to infinity with 
extrapolation of the terminal phase 
AUC(0–t) 
The area under the plasma concentration versus time curve, from 
time zero to ‘t’ (where t = the final time of positive detection) as 
calculated by the linear trapezoidal method 
BP 
Blood Pressure 
CBD 
Cannabidiol 
CI 
Confidence Interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CLB 
Clobazam 
Cmax 
Maximum measured plasma concentration 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CYP 
Cytochrome P450 
EC 
Ethics Committee 
ECG 
12-lead electrocardiogram 
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 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ITT 
Intention to Treat 


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IVRS 
Interactive Voice Response System 
LEV 
Levetiracetam 
LOCF 
Last Observation Carried Forward 
MMRM 
Mixed-effects Model Repeated Measures 
N-CLB 
N-desmethylclobazam 
OLE 
Open label extension 
PBPK 
Physiologically-based pharmacokinetic interactions 
PI 
Principal Investigator 
PP 
Per Protocol 
PVD 
Pharmacovigilance Department 
QTcB 
Heart rate corrected QT interval using Bazett’s formula 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SFU 
Safety follow up 
STP 
Stiripentol 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
t½ 
Terminal half-life 
TBL 
Total bilirubin 
THC 
∆9-tetrahydrocannabinol 
tmax 
Time to the maximum measured plasma concentration 
TPM 
Topiramate 
ULN 
Upper Limit of Normal 
USA 
United States of America 
VNS 
Vagus Nerve Stimulation 
VPA 
Valproate 
 


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Definition of Terms 
Term 
Definition 
Baseline period 
The period from screening (Visit 1) to enrollment (Visit 2). 
Convulsive seizures 
Tonic-clonic, tonic, clonic or atonic seizures. 
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 is enrolled and begins PK sampling. 
End of treatment 
Completion of the treatment period (Visit 5 or Visit 12) or 
withdrawal. 
End of study 
Last patient’s last visit / last contact. 
IMP 
Investigational Medicinal Product (Study Medication). Used 
to describe both investigational active product and reference 
therapy (placebo). 
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. 
Partial seizures 
Partial (focal) seizures occur when the electrical activity 
remains in a limited area of the brain. 
Status epilepticus 
Seizures lasting for 30 minutes or longer. 
Sub-types of seizures 
Seizure sub-types can be tonic, clonic, tonic-clonic, atonic, 
myoclonic, absence (typical and atypical), countable partial 
and other partial. 
 


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2. 
OBJECTIVES 
2.1 
Primary 
To determine whether GWP42003-P affects the pharmacokinetic (PK) profile of 
clobazam (CLB) and its primary metabolite N-desmethylclobazam (N-CLB). 
2.2 
Secondary 
To assess the safety and tolerability of GWP42003-P in the presence of CLB. 
 
 


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3. 
BACKGROUND AND RATIONALE 
3.1 
Disease 
Epilepsy is a common disorder1.  Approximately 1% of the world’s population is 
chronically affected by epilepsy2.  It shows no particular geographic distribution and 
the gender distribution is more or less equal.  The incidence of epilepsy is greater in 
childhood and in elderly people2,3,4,5.  Focal seizures represent the most frequent 
seizure type (around 60% of all cases of epilepsy, and a substantial percentage of 
them are not well controlled)6. 
Overall, and despite the introduction of a substantial number of new antiepileptic 
drugs (AEDs) in the last two decades, around 30% of patients remain refractory to 
currently available treatment7,8,9.  In addition, most currently approved AEDs are 
associated with significant motor and cognitive adverse reactions10,11. 
Currently available AEDs each belong to one of a large number of different classes.  
The principal targets for existing AEDs tend to be either modulators of 
voltage-dependent ion channels, enhancers of inhibitory neurotransmission, and 
attenuators of excitatory neurotransmission, with the aim being to reduce neuronal 
excitotoxicity12,13. 
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 Δ9-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 0.5% (w/w) THC.  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 


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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 conductance and acts on other G-protein-coupled receptors such as 
the transient receptor potential channel TRPV114 and the orphan receptor GPR5515.  
Importantly, in contrast to THC, CBD lacks detectable psychoactivity.  CBD has 
demonstrated anticonvulsant, antipsychotic, anxiolytic, neuroprotective, antioxidant 
and anti-inflammatory activity16.  Very little data concerning 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 humans17. 
3.3 
Rationale 
CBD has shown therapeutic potential as an AED, with preclinical studies 
demonstrating anticonvulsant effects in a number of animal models of seizure16,18,19.  
Although no placebo-controlled trials have been completed to date, 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 either > 80% reduction in seizure frequency or complete 
seizure freedom20.  The CBD-enriched cannabis was behaviorally well tolerated and 
children often experienced improved sleep, increased alertness and better mood.  
There has been a program of expanded access by GW Pharma Ltd (GWP) in the USA, 
primarily in children with severe epilepsy, that has shown encouraging reports of 
reductions in multiple seizure types with good tolerability in 151 exposures21. 
Population-based studies of drug utilization demonstrate that 19–24% of patients with 
epilepsy use polytherapy with AEDs22,23,24.  In recent studies of children and adults 
with refractory epilepsy, 64% used polytherapy with two or more AEDs, resulting in a 
considerable risk of interactions25,26.  CLB is a widely used AED, prescribed with 
other medication(s) to control seizures in adults and children two years of age and 
older who have Lennox-Gastaut syndrome (a disorder that causes seizures and often 
developmental delays).  The pharmacological action of CLB is to decrease abnormal 
electrical activity in the brain via allosteric activation of the ligand-gated 
γ-aminobutyric acid (A) receptor. 
CLB is in a class of medications called benzodiazepines.  Similar to other 
benzodiazepine medications, CLB is metabolized by cytochrome P450 (CYP) 
enzymes (mainly in the liver).  This metabolism results in the formation of an active 
metabolite N-CLB, amongst others. 


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CYP enzymes are a family of heme-containing enzymes responsible for the 
metabolism of over half of all prescribed medications and interactions with these 
enzymes are the major source of physiologically-based pharmacokinetic (PBPK) 
interactions between drugs.  It is anticipated that patients taking GWP42003-P may 
also be taking CLB and as CBD has been shown to both inhibit CYP450 enzymes in 
vitro (Ki CYP3A4 = 1.5 μM) and induce CYP450 enzymes in vitro (EC50 CYP3A4 
= 1.2 μg/mL) a possibility of a pharmacokinetic (PK) interaction between CBD and 
CLB exists.  Furthermore, CLB has been shown to undergo PBPK interactions with 
other AED medications via both CYP induction (such as with felbamate where the 
formation of the active metabolite of CLB, N-CLB was increased several-fold27) and 
also CYP inhibition (such as with stiripentol where serum concentrations of CLB 
were increased and metabolites decreased28,29,30).  Given the high likelihood that 
patients prescribed CBD will also be using CLB, it is the aim and purpose of this 
study to determine whether a PK interaction between CBD and CLB exists. 
3.3.1 
Selection of Study Doses 
Doses up to 800 mg GWP42003-P per day for up to eight weeks have been well 
tolerated in adults in GW Research Ltd (GW) clinical study GWMD09112, which, 
assuming an average weight of 70 kg, equates to a daily dose of 11.4 mg/kg.  In the 
literature, doses of GWP42003-P have been given up to 1500 mg GWP42003-P per 
day for four weeks in adults, which, in a 70 kg human equates to a daily dose of 
21.4 mg/kg GWP42003-P. 
Data on the safety of GWP42003-P is emerging from the physician-initiated 
Epidiolex® Expanded Access Program being conducted in the USA.  This program 
has been running since January 2014 and at the time of writing had data on 63 
patients.  The mean maximum exposure achieved in this patient population of 
refractory epilepsies was a daily dose of 24.4 mg/kg (n=59 patients) with a maximum 
dose of 51 mg/kg in one patient.  Please see below for a breakdown of the groups: 
• ≤ 20 mg/kg GWP42003-P n=13 (21%) 
• > 20 mg/kg–≤ 30 mg/kg GWP42003-P n=40 (64%) 
• > 30 mg/kg–≤ 40 mg/kg GWP42003-P n=4 (6%) 
• > 40 mg/kg GWP42003-P n=2 (3%) 
• Dose not reported n=4 (6%) 
Eleven patients had a daily GWP42003-P dose of > 25 mg/kg, of which five did not 
report any adverse events (AEs).  Of note, the patient who received 51 mg/kg did not 
have any AEs at this dose.  The remaining six patients experienced AEs as 
documented in the Table 3.3.1-1 below: 


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Table 3.3.1-1 
Epidiolex Adverse Events 
Adverse Event Term 
Number of Events 
Loose stools / urgent bowel 
movements 
2 
Increase in seizures 
2 
Drowsiness 
1 
Aspiration pneumonia 
1 
Lethargy 
1 
Decreased appetite 
1 
Dyskinesia 
1 
Urinary tract infection 
1 
Based on the above, a daily dose up to 20 mg/kg/day (given as two divided doses) has 
been selected for the GWP42003-P dose in the current study, including a titration 
period with daily increments of 2.5 mg/kg and 5 mg/kg.  At the end of the treatment 
period, patients will be given the option of continuing onto an open label extension 
(OLE) period if the investigator and patient both agree that it is in their best interest.  
During the OLE doses may be adjusted up or down, dependent on investigator 
opinion, to a maximum daily dose of 30 mg/kg GWP42003-P. 
3.4 
Clinical Hypothesis 
CBD can act as both a CYP inhibitor and inducer in human hepatocytes in vitro.  
Therefore, the potential for PK interactions with other drugs that are metabolized by 
CYP450 enzymes exists.  The hypothesis is that the in vivo PK of CLB and its major 
metabolite (N-CLB) may be altered (increased or decreased) by the chronic 
administration of GWP42003-P. 
 
 


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4. 
EXPERIMENTAL PLAN 
4.1 
Study Design 
This phase 2, placebo-controlled study consists of a 34 day, double-blind phase 
followed by an optional maximum one year OLE.  Patients will continue to take CLB 
as advised by their physician for the duration of the study.  GWP42003-P/placebo will 
be taken twice daily immediately after their CLB dose. 
Patients will enter the study and begin a 10 day GWP42003-P or placebo titration 
phase.  During this period patients will be up-titrated to a maintenance dose or 
equivalent of 20 mg/kg/day.  Patients will continue to take this maintenance dose of 
GWP42003-P or placebo for 21 days (Days 12 to 32). 
Upon completion of the treatment period (Day 34) patients will be invited to receive 
GWP42003-P during the OLE phase.  If a patient enters the OLE they will take 
GWP42003-P as advised by the investigator.  If a patient chooses not to enter the 
OLE, and/or the investigator does not feel it is in their best interests, they will taper 
off their GWP42003-P/placebo treatment by reducing their maintenance dose by 10% 
per day until dosing has ceased.  For those patients not entering the OLE, dosing will 
end on Day 43 and they will receive a telephone follow-up visit four weeks after the 
end of GWP42003-P/placebo dosing (Day 71). 
PK samples will be taken on two occasions during the blinded phase of the study: 
• Day 1 (Visit 2) before beginning treatment (patients will be taking CLB only). 
• Day 33 (Visit 4) following 21 days of GWP42003-P or placebo maintenance 
(patients will be taking CLB and GWP42003-P or placebo). 
Ten samples will be taken during each PK assessment. PK samples should be taken at 
time points in respect to the morning dose of CLB. The time points are as follows: 
Pre-dose, 15 min, 30 min, 1 h, 1.5 h, 2 h, 4 h, 6 h, 12 h and 24 h.  PK samples will be 
quantitatively analyzed for CLB, N-CLB, valproate (VPA), stiripentol (STP),  
levetiracetam (LEV) and topiramate (TPM) at Visit 2  and CLB, N-CLB, VPA, STP, 
LEV, TPM, CBD, CBD major metabolites, THC and THC major metabolites at 
Visit 4. 
Patients should try to be consistent in the timing of their food intake in relation to 
dosing throughout the blinded phase of the study. 
Upon entry into the OLE the dose of GWP42003-P and other AEDs may be adjusted 
up or down to a maximum of 30 mg/kg/day.  The OLE will last for a maximum of one 
year or until marketing authorization is granted; whichever is earlier. 


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Patients will be required to keep a paper diary to note the time and dose of IMP and 
CLB administration each morning and evening and to record any AEs that may occur 
whilst receiving IMP and any other medications.  Patients will also be required to 
record the number and type of seizures for each day whilst on the study. 
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 are 
provided in Section 8 and Section 9 respectively. 
4.1.1 
Primary Endpoint 
The primary endpoints of the study are the PK parameters (Cmax, tmax, AUC(0–∞), 
AUC(0–t), t½) of the following analytes: 
• CLB 
• N-CLB 
• CBD 
• CBD major metabolites 
4.1.2 
Secondary Endpoint(s) 
To assess the safety and tolerability of GWP42003-P compared with placebo when 
taken in combination with CLB.  Safety and tolerability will be assessed using the 
following parameters: 
• AEs 
• 12-lead electrocardiogram (ECG) 
• Clinical laboratory parameters (clinical chemistry, hematology and urinalysis) 
• Vital signs 
• Columbia-Suicide Severity Rating Scale (C-SSRS) 
• Seizure frequency 
• Abuse liability 
• CYP2C19 and CPY3A4 patient genotype analysis 
 
PK parameters (Cmax, tmax, AUC(0–∞), AUC(0–t), t½) of the following analytes: 
• THC 
• THC major metabolites 
4.2 
Number of Centers 
An estimated number of seven centers are expected to participate in this study. 


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4.3 
Number of Patients 
A total of 20 patients will be enrolled into the study.  Recruitment for the study will 
be competitive between participating sites. 
The sample size calculation is explained fully in Section 13.1. 
 
 


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5. 
INVESTIGATIONAL MEDICINAL PRODUCT 
Please refer to the separate Pharmacy Manual for more detailed information on the 
IMP. 
5.1 
GWP42003-P Oral Solution 
GWP42003-P oral solution is presented as a pale yellow 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 
Placebo Oral Solution 
Placebo oral solution contains the excipients sesame oil and anhydrous ethanol with 
added sweetener (sucralose) and strawberry flavoring Table 5.2-1. 
Table 5.2-1 
Formulation of Placebo Oral Solution 
Material 
Quantity 
Anhydrous ethanol 
79 mg/mL 
Sucralose 
0.5 mg/mL 
Strawberry flavoring 
0.2 mg/mL 
Sesame oil 
make up to 1 mL 
5.3 
Packaging, Storage and Drug Accountability 
(Cannabidiol/Placebo) 
5.3.1 
Packaging and Labelling  
The IMP will be manufactured and packaged by 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 weight of each patient.  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 labelled and packaged.  Label text will comply with 
European Union (EU) guidance on Good Manufacturing Practice, Annex 13 Labelling 
and will be fully described in the separate Pharmacy Manual.  In addition, any local 


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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 investigator, or main 
contact for information about the product or the clinical trial, will be provided 
separately to the patient. 
5.3.2 
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. 
5.3.3 
Supply and Return of Investigational Medicinal Product 
Once a site has been activated 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 and the condition of the drug.  Details of the IMP received will be recorded 
in the IMP accountability record.  The site will acknowledge IMP receipt and will 
complete any receipt forms required.  IMP will be dispensed and returned as detailed 
in Section 5.3.4 with further IMP shipments to be requested as necessary.  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. 
5.3.4 
Investigational Medicinal Product Accountability 
The investigator has overall responsibility for the accountability of all used and 
unused IMP.  A drug accountability record for the IMPs must be kept current and 
should contain: 
• The dates and quantities of IMP received from GWP. 


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• Patient’s identification. 
• Date and quantity of IMP dispensed. 
• The initials of the dispenser. 
• Date and quantity of IMP returned to the investigator/pharmacy. 
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 authorized GW or GWP 
representatives and local officials or regulatory agency inspectors. 
Please refer to the separate Pharmacy Manual for more detailed information on the 
IMP. 
5.4 
Clobazam 
Patients will use their own supply of CLB throughout the study.  CLB usage will be 
recorded by the investigator.  CLB is only an IMP for the blinded phase of the study. 
6. 
PARTICIPANT ELIGIBILITY 
Investigators will be required to maintain a log that includes limited information about 
all screened patients (initials, age, and gender; as allowed per local regulations) and 
outcome of screening. 
6.1 
Inclusion Criteria 
For inclusion in the study patients must fulfil ALL of the following criteria: 
6.1.1 
Male or female patients aged 18 to 65 years inclusive. 
6.1.2 
Patient must have epilepsy as determined by the investigator and be taking 
CLB. 
6.1.3 
Patient must have a documented magnetic resonance imaging/computerized 
tomography of the brain that ruled out a progressive neurologic condition. 
6.1.4 
Patient must have experienced at least one seizure of any type (i.e., 
convulsive: tonic-clonic, tonic, clonic, atonic; focal: focal seizures with 
retained consciousness and a motor component, focal seizures with 
impaired consciousness focal seizures evolving to bilateral secondary 
generalization) within the two months prior to randomization.  
6.1.5 
Patients must be taking CLB and no more than two other AEDs during the 
course of the study. 
6.1.6 
AED(s), including CLB, must be stable for four weeks prior to screening 
and regimen must remain stable throughout the duration of the blinded 
phase of the study. 


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6.1.7 
Intervention with vagus nerve stimulation (VNS) and/or ketogenic diet 
must be stable for four weeks prior to baseline and patient/caregiver must 
be willing to maintain a stable regimen throughout the blinded phase of the 
study. 
6.1.8 
Patients must abstain from alcohol during the blinded phase of the study. 
6.1.9 
Patient is available to attend all PK visits within the required visit window. 
6.1.10 
Patient and/or legal representative must be willing and able to give 
informed consent for participation in the study 
6.1.11 
Patient and/or legal representative must be willing and able (in the 
investigator’s opinion) to comply with all study requirements. 
6.1.12 
Patient is willing for his or her name to be notified to the responsible 
authorities for participation in this study, as applicable. 
6.1.13 
Patient is willing to allow his or her primary care practitioner and 
consultant, if appropriate, 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 has clinically significant unstable medical conditions other than 
epilepsy. 
6.2.2 
Patients on CLB at doses above 20 mg per day. 
6.2.3 
Patients taking CLB intermittently as rescue medication. 
6.2.4 
Patient has a history of symptoms (e.g., dizziness, light-headedness, blurred 
vision, palpitations, weakness, syncope) related to a drop in blood pressure 
(BP) due to postural changes. 
6.2.5 
Any history of suicidal behavior or any suicidal ideation of type four or five 
on the C-SSRS in the last month or at screening. 
6.2.6 
Patient has had clinically relevant symptoms or a clinically significant 
illness in the four weeks prior to screening or enrollment, other than 
epilepsy. 
6.2.7 
Patient has consumed alcohol during the seven days prior to enrollment and 
is unwilling to abstain during the blinded phase of the study. 
6.2.8 
Patient is currently using or has in the past used recreational or medicinal 
cannabis, or synthetic cannabinoid based medications (including Sativex®) 
within the three months prior to study entry. 
6.2.9 
Patient has any known or suspected history of any drug abuse or addiction. 
6.2.10 
Patient is unwilling to abstain from recreational or medicinal cannabis, or 
synthetic cannabinoid based medications (including Sativex) for the 
duration of the study. 
6.2.11 
Patient has consumed grapefruit or grapefruit juice seven days prior to 
enrollment and is unwilling to abstain from drinking grapefruit juice within 
seven days of PK visits. 
6.2.12 
Patient has any known or suspected hypersensitivity to cannabinoids or any 
of the excipients of the IMP, e.g., sesame oil. 


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6.2.13 
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 three 
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.  
6.2.14 
Female patient who is pregnant (positive pregnancy test), lactating or 
planning pregnancy during the course of the study and for three months 
thereafter. 
6.2.15 
Patients who have received an IMP within the 12 weeks prior to the 
screening visit. 
6.2.16 
Patient is taking felbamate and they have been taking it for less than 
one year prior to screening. 
6.2.17 
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 the patient’s ability to 
participate in the study. 
6.2.18 
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. 
6.2.19 
Patient has significantly impaired hepatic function at screening (Visit 1) or 
enrollment (Visit 2), defined as any of the following:  
- 
Alanine aminotransferase (ALT) or Aspartate aminotransferase 
(AST) > 5 × upper limit of normal (ULN). 
- 
ALT or AST > 3 × ULN and total bilirubin (TBL) > 2 × ULN or 
international normalized ratio (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%).  
This criterion can only be confirmed once the laboratory results are 
available; patients randomized into the study who are later found to meet 
this criterion must be withdrawn from the study. 
6.2.20 
Patient has a prolonged QTcB (> 450 msec for males and > 470 msec for 
females).  
6.2.21 
Unwilling to abstain from donation of blood during the study. 
6.2.22 
Travel outside the country of residence planned during the study, unless the 
patient has confirmation that the IMP is permitted in the destination 
country/state. 
6.2.23 
Patients previously enrolled into this study. 
 


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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 forms (ICFs) and other patient information material. 
Patients will be considered enrolled in the study from the time of providing written 
informed consent.  All patients, or legal representatives, where appropriate, must 
personally sign and date the consent form prior to any procedures being performed 
(refer to Section 9.1.2 and Section 15.2). 
7.1 
Treatment Assignment 
At the start of Visit 1, patients will be allocated a unique patient number, consisting of 
a four digit GW center number and a three digit patient identification number.  The 
three digit patient number will be assigned in ascendant numerical order at each site.  
The unique patient number will be preceded by a unique letter.  For example, 
W1234001, denoting patient 001 at site 1234.  GWP will provide all 
GWP42003-P/placebo packed and labelled.  Following enrollment at Visit 2, patients 
will be allocated a pre-packed numbered IMP. 
7.2 
Randomization 
This is a double-blind study.  Patients will be randomized in a 4:1 ratio to receive 
20 mg/kg GWP42003-P or placebo. 
 
 


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8. 
TREATMENT PROCEDURES 
8.1 
Investigational Medicinal Product Dosage, Administration and 
Schedule 
The IMP will consist of three types of medication: 
• GWP42003-P oral solution containing 100 mg/mL CBD. 
• Placebo oral solution containing excipients. 
• CLB (patient supplied). 
The GWP42003-P/placebo will be presented as an oral solution containing either the 
active pharmaceutical ingredient and excipients (in the case of GWP42003-P) or only 
excipients (in the case of placebo).  For details regarding GWP42003-P/placebo 
formulations, see Section 5. 
All patients will be weighed during the study visits and the daily volumes of 
GWP42003-P/placebo solution to be taken during the titration period, and for the 
remainder of the study, will be calculated and provided to the patient and/or caregiver. 
Further information on dispensing procedures will be provided in a separate 
Pharmacy Manual. 
Each patient will take their first dose of GWP42003-P/placebo at Visit 2, Day 2 in the 
clinic.  Patients not entering the OLE will take their final maintenance dose of 
GWP42003-P/placebo at Visit 4 (Day 33) in the clinic.  Patients entering the OLE 
will take their final dose of IMP at Visit 11 (one year after the end of the blinded 
phase of the study) or sooner (if marketing authorization is granted within one year). 
Patients will use their own supply of CLB throughout the study.  Patients will 
continue on the dose that they were on at screening for the blinded phase of the study. 
CLB will only be an IMP for the blinded section of the study.    
8.1.1 
Dose Administration 
GWP42003-P/placebo will be administered orally by the patient or their caregiver 
twice each day (morning and evening) using the syringe(s) provided. 
GWP42003 P/placebo should be taken immediately after the patient’s usual CLB 
administration.  The GWP42003-P/placebo should be swallowed, as per the intended 
commercial therapeutic route, and may be taken with other concomitant medications, 
as directed by the investigator. 


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8.1.2 
Dose Escalation and Dose Adjustments 
Patients will enter the blinded phase of the study and will be up-titrated over ten days 
(Day 2 to Day 11) to a maintenance dose or equivalent of GWP42003-P/placebo of 
20 mg/kg/day.  If GWP42003-P is not tolerated then the dose can be reduced 
accordingly at the discretion of the investigator.  The titration regimen is described in 
Table 8.1.2-1. 
Table 8.1.2-1 Dose Up-titration Regimen* 
Day - GWP42003-
P/Placebo (Blinded 
Period) 
Dose Level 
(GWP42003-P or 
equivalent placebo) 
Open label 
Extension** 
(GWP42003-P only)  
Day  
Dose Level 
GWP42003-P  
2 
2.5 mg/kg 
34 
2.0 mg/kg 
3 
2.5 mg/kg 
35 
4.0 mg/kg 
4 
5.0 mg/kg 
36 
6.0 mg/kg 
5 
5.0 mg/kg 
37 
8.0 mg/kg 
6 
7.5 mg/kg 
38 
10.0 mg/kg 
7 
7.5 mg/kg 
39 
12.0 mg/kg 
8 
10.0 mg/kg 
40 
14.0 mg/kg 
9 
10.0 mg/kg 
41 
16.0 mg/kg 
10 
15.0 mg/kg 
42 
18.0 mg/kg 
11 
15.0 mg/kg 
43 
20.0 mg/kg 
12 onwards 
20.0 mg/kg 
44 
20.0 mg/kg*** 
* GWP42003-P /placebo is to be taken twice daily.  Total daily doses are shown. 
** Only patients who were taking placebo during the double-blind period will up-titrate according to 
this schedule during the OLE period.  Those taking GWP42003-P during the double-blind period will 
down-titrate their blinded IMP whilst simultaneously up-titrating with GWP42003-P, thus maintaining 
a daily dose of 20 mg/kg/day GWP42003-P throughout. 
*** The GWP42003-P dose of 20 mg/kg/day can be adjusted during the OLE period, after Visit 5, at 
the investigator’s discretion: up to a maximum dose of 30 mg/kg/day.  It may also be adjusted down 
(no minimum). 
The titration regimen defined above should be followed to the maximum dose 
(20 mg/kg/day).  Should an AE occur during titration which is attributable to IMP or 
concomitant AED, then IMP dose should be reduced to the next lower dose.  Any 
other changes in concomitant AED therapy should be reviewed with the medical 
monitor before being initiated. 
For those patients who do not enter the OLE the dose of GWP42003-P/placebo will 
taper off over 10 days beginning on Day 34.  The patient will reduce the dose by 10% 
of the maintenance dose each day and treatment will end on Day 43. 
Patients who enter the OLE period will be transitioned to the OLE treatment over a 
10-day period in order to maintain blinding, simultaneously down-titrating blinded 
GWP42003-P /placebo whilst up-titrating open-label GWP42003-P.  As such, patients 


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who were taking GWP42003-P during the blinded period will maintain their 
20 mg/kg/day dose throughout the transition from the blinded period into the OLE 
period and patients who received placebo during the blinded period up-titrate slowly 
to the 20 mg/kg/day dose in the OLE period.  After this has taken place after Visit 5, 
the maintenance dose of GWP42003-P may be adjusted up or down at the discretion 
of the investigator to a maximum of 30 mg/kg/day (no minimum). 
8.2 
Concomitant Therapy 
Doses of any concomitant AEDs, including CLB, must have been stable for at least 
four weeks prior to screening and must remain stable throughout the blinded phase of 
the study.  If there are symptoms of toxicity suspected to be from a drug interaction, 
the investigator may adjust GWP42003-P/placebo or the CLB or other AEDs after 
discussion with the medical monitor. 
The use of rescue medication is allowed if necessary.  The use of oxygen may be 
considered as rescue medication if used as required.  Any medication, other than the 
IMP, taken during the study must be recorded on the Case Report Form (CRF). 
Any non-pharmacological therapies (e.g., ketogenic diet, VNS) must also be stable up 
to four weeks prior to baseline and throughout the duration of the study. 
8.3 
Prohibited Therapy During Study Period 
The following medications are prohibited for the duration of the study starting from 
acquisition of patient consent.  However, any patients taking these medications after 
screening 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. 
• Any new medications or interventions for epilepsy (including ketogenic diet 
and VNS) or changes in dosage. 
• Patients should not take any more than three AEDs inclusive of CLB. 
• Recreational or medicinal cannabis or synthetic cannabinoid based 
medications (including Sativex) within three months prior to or during the 
study. 
If any other IMP is taken as part of a clinical trial within twelve weeks of the 
screening visit or during the study, the patient must be withdrawn from this study.  
8.4 
Compliance in Investigational Medicinal Product Administration 
Patients or their caregivers will record the total volume of IMP, administered on each 
treatment day, using the paper diary and will be asked to return all IMP (used and 
unused) at each subsequent visit.  The site will check the returned IMP against the 


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usage recorded in the diary and the projected usage.  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. 
Records of IMP accountability will be maintained according to Section 5.3.4. 
8.5 
Access to Blinded Treatment Assignment 
The identity of IMP assigned to patients will be held by the IVRS.  The principal 
investigator (PI) at each center is responsible for all trial-related medical decisions 
and is responsible for ensuring that information on how to access the IVRS is 
available to the relevant staff in case of an emergency and unblinding is required.  A 
patient’s treatment assignment must only be unblinded when knowledge of the 
treatment is essential to make a decision on the medical management of the patient.  
Unblinding for any other reason will be considered a protocol deviation. 
The investigator is encouraged to contact GW to discuss the rationale for unblinding.  
However, to prevent delays to the investigator or medical personnel responding to a 
potentially emergent situation, unblinding of study medication will not be dependent 
upon the investigator receiving approval from GW (i.e., the investigator will be able 
to obtain the code break information independent of contacting GW). 
If the investigator does unblind they must contact GW within one working day of the 
event and must document the time, date and reasons for unblinding in the patient’s 
CRF. 


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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 in 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 
9.1.1 
Contraception 
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 three months thereafter.  A highly effective method 
of birth control is defined as those which result in a low failure rate (i.e., less than 1% 
per year) when used consistently and correctly such as combined or progesterone only 
oral contraceptives, intrauterine device, intrauterine hormone-releasing system, 
bilateral tubal occlusion, vasectomized partner or sexual abstinence6.  Abstinence, as 
referenced above, 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.  The use of hormonal contraception must be supplemented 
with a barrier method (preferably male condom). 
9.1.2 
Informed Consent 
Adult patients with an adequate level of understanding must personally sign and date 
the IRB/EC approved ICF(s) before any study specific procedures are performed or 
any patient related data is recorded for the study.  For adult patients with an 
insufficient level of understanding of what is proposed, only personal legal 
representative consent will be sought.  The informed consent process should be 
documented within the patient notes. 
GW requires a physician to be present for consent and to also sign the ICFs. 
9.1.3 
Demographics 
Patient demographics will be recorded at Visit 1.  The following information will be 
obtained for each patient: date of birth, gender and race (if allowed per local 
regulations). 


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9.1.4 
Medical History 
Relevant, significant medical history (including seizure information since diagnosis, 
history of epilepsy-specific genetic testing and all prior AEDs taken) will be obtained 
during Visit 1 and is defined as any condition or disease that: 
• May affect the condition under study. 
• Is ongoing on entry into the study. 
9.1.5 
Concomitant Medication 
Details of all current and recent medication (i.e., taken within the previous 28 days) 
including AEDs will be recorded at the screening visit (Visit 1) and reviewed at each 
subsequent visit.  AEDs used during the study should be maintained at a stable dose. 
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 the 
screening visit, as defined in Section 8.3. 
9.1.6 
Physical Examination 
A physical examination will be performed at the screening visit (Visit 1) to ensure 
that the patient is eligible to enter the study.  To ensure patient safety, further physical 
examinations will be performed at every hospital visit.  Physical examinations will 
include height (at screening) and body weight measurements. 
9.1.7 
Vital Signs 
Vital sign measurements, taken after five minutes rest in a sitting position, will be 
completed alongside the physical examination at all visits.  Postural BP will be 
assessed after five minutes in supine position and, if possible, two minutes in standing 
position.  The pulse rate must also be measured as part of the vital sign assessments. 
BP and pulse rate must be recorded using the same arm throughout the study. 
9.1.8 
12-Lead Electrocardiogram 
An ECG will be performed, after five minutes in supine position, at all hospital visits. 
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 be undertaken at all hospital visits and will include hematology, 
biochemistry, and urinalysis (provided urine can be obtained, with the exception of 


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screening where a urine sample for THC screen must be obtained).  A serum alcohol 
test will be performed at Visits 1, 2 and 4.  A serum pregnancy test (if appropriate) 
will also be performed at Visit 1. 
Urine samples for biochemistry will be analyzed at the study center by use of a 
dipstick with any relevant findings being sent for further laboratory based urinalysis 
(urinalysis, microscopy, culture and sensitivity, as applicable). 
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.  
Table 9.1.9-1 
Hematology, Biochemistry, Urinalysis and THC Screen 
Biochemistry 
(serum) 
Hematology 
(whole blood) 
Urinalysis 
(urine) 
Pregnancy 
Test 
THC screen 
(urine) 
Alanine aminotransferase 
(ALT) 
Hematocrit 
Bilirubin 
Serum 
THC 
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 
 
 
 
 
Potassium 
 
 
 
 
Prolactin 
 
 
 
 
Prothrombin time (plasma) 
 
 
 
 
Sodium 
 
 
 
 
Total bilirubin (TBL) 
 
 
 
 
Total protein 
 
 
 
 
Urea (BUN) 
 
 
 
 
Trigylcerides 
 
 
 
 
 
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 by the investigator 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 


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investigator is satisfied that the abnormality is not related to the IMP and needs no 
further investigation. 
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 
them 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 in the four weeks 
prior to screening. 
9.1.10 
Pharmacokinetic Analyses 
The plasma concentration/time curves of CLB, N-CLB, VPA, STP, LEV and TPM 
will be assessed at Visit 2 (Day 1 and Day 2) and CLB, N-CLB, VPA, STP, LEV, 
TPM, CBD, CBD major metabolites, THC and THC major metabolites at Visit 4 
(Day 33 and Day 34).  Patients will be given their daily dose of CLB at a scheduled 
time during Visit 2 and Visit 4 and the GWP42003-P/placebo immediately afterwards 
(Visit 4 only) to facilitate the accurate timing of blood samples required for PK 
analysis.  Blood samples will be taken by either direct venipuncture or an indwelling 
cannula inserted into a forearm vein at the following times: Pre-dose and, 15 minutes, 
30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 12 hours and 24 hours after 
dosing.  The timing of each PK sample will be relative to the morning dose of CLB. 
The pre-dose blood sample will be taken within 30 minutes prior to dosing.  The 
allowable window for post-dose blood sample collection is ± 2 minutes up to and 
including 1 hour post-dose, ± 5 minutes from 1.5 hours up to and including 6 hours 
post-dose and ± 1 hour at 12 hours and 24 hours post-dose. 
In the event of an AE that, in the opinion of the investigator, is related to a 
concomitant AED, additional blood samples may be collected. 
Analysis of all PK samples will be conducted at a central clinical laboratory.  Sample 
volume requirements and processing procedures will be detailed in a separate 
laboratory manual. 
9.1.11 
Genetic Testing 
Genetic testing will only be conducted if specific consent is obtained from the 
participant or their legal representative.  There is a separate ICF for this. 
Genetic testing will be conducted to look at the CYP450 genes, with particular focus 
on CYP 2C19 and CYP 3A4, involved in the metabolization of AEDs and 
GWP42003-P.     


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9.1.12 
Columbia Suicide Severity Rating Scale  
The C-SSRS is to be completed by the investigator or his/her qualified designee at all 
hospital visits.  Qualified designee is defined as physician, osteopath, nurse 
practitioner, clinical psychologist or physician’s assistant who is licensed and has 
completed the C-SSRS training within the last two years.  It is a brief standardized 
measure that uniquely assesses the essential information (behavior, ideation, lethality 
and severity) and distinguishes between suicidal occurrences and non-suicidal 
self-injury.  The survey should be completed by the same assessor, where possible, 
throughout the study. 
If the investigator or his/her qualified designee feel that the patient is either unable to 
answer the questions presented in C-SSRS, or that the questions are causing undue 
stress to the patient, the questionnaire may be skipped and this must be documented in 
the patient notes. 
9.1.13 
Patient Diary 
Patients or their caregivers will be instructed on how to complete a paper diary and 
will be asked to record information daily in it.  The number and type of seizures as 
well as information on AEs, concomitant AEDs and rescue medication will be 
collected each day from screening (Visit 1) until completion of dosing or withdrawal. 
Information on IMP intake will also be recorded each day from enrollment (Visit 2) 
until completion of dosing or withdrawal. 
9.1.14 
Investigational Medicinal Product Accountability 
GWP42003-P/placebo will be dispensed at each of the following visits during the 
blinded phase: 
• Visit 2 (Day 2) 
• Visit 4 (Day 34) 
IMP will be dispensed at each of the following visits for patients entering the OLE: 
• Visit 5 (Two weeks) 
• Visit 6 (One month) 
• Visit 7 (Two months) 
• Visit 8 (Three months) 
• Visit 9 (Six months) 
• Visit 10 (Nine months) 
• Visit 11 (12 months) 


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Patients will be asked to return all IMP (used and unused) to each relevant visit 
(Visits 2 to 12).  The site will check the returned IMP against the usage recorded in 
the paper diary.  Any discrepancies will be discussed with the patient/caregiver and 
documented accordingly within the patient’s source documents. 
9.1.15 
Adverse Events 
Any adverse changes in the patient’s medical condition, following completion of the 
consent form by the patient, will be recorded on the CRF as AEs, questioning the 
patient further if necessary.  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. 
*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. 
Serious Adverse Events (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. 
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 9.1.16.1.1 for the list of ‘Triggering AEs of Interest’ associated with 
monitoring of drug abuse liability.  
 
9.1.16 
Monitoring of Drug Abuse Liability 
There are two 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 (Visit 5 or Visit 12) or withdrawal visit 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. 


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9.1.16.1 
Monitoring of Adverse Events 
AE information will be collected according to Section 9.1.15.  
 
9.1.16.1.1 
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. 
• 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. 
 
9.1.16.1.2 
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. 
 


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9.1.16.2 
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 reported within the paper diary. 
• At any time that the site is informed by the patient/caregiver about any 
overuse of IMP, suspected misuse, abuse, or diversion. 
 
9.1.16.2.1 
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, according to the paper diary. 
• Returned IMP supply with evidence of tampering.  
• Greater than the target daily dose as recorded in the paper diary. 
 
 


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9.1.16.2.2 
Supplemental Drug Accountability Form 
This form consists of eight 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 or placebo, 
not other concomitant medications). 
 
9.1.16.3 
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. 
 
9.1.16.4 
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 (Visit 5 or Visit 12) or withdrawal visit.  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 in 
the study and not only those that have reported a triggering AE or drug accountability 
discrepancy. 
 


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9.1.16.5 
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.  Only data from 
patients who have completed the study will be assessed.  
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  
 
 
 
 
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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9.2 
Study Procedures by Visit 
Patients and their caregivers will be invited to participate in the study and will be 
issued with the patient information and informed consent or the personal legal 
representative information and informed consent (refer to Section 9.1.2 and 
Section 15.2).  Following adequate time to discuss the study with the investigator, 
nurse, relatives or caregiver, patients/legal representatives who provide written 
informed consent at Visit 1 will be screened for entry into the study. 
9.2.1 
Double Blind Phase 
9.2.1.1 
Visit 1 (Day −14 to −7, Screening) 
The following observations will be made at Visit 1: demographics, medical history 
(including seizure information since diagnosis, history of epilepsy-specific genetic 
testing and all prior AEDs taken), concomitant medications (including AEDs), 
physical examination (including height and body weight), ECG, vital signs and AEs. 
Clinical laboratory samples (blood and urine) will be taken for hematology, 
biochemistry, alcohol testing, THC testing, urinalysis and a pregnancy test (using a 
serum sample, if appropriate).  The laboratory results should be available within 3-5 
working days after Visit 1.  If the results show a patient is ineligible, the patient will 
not be enrolled into the study.  The C-SSRS will be administered. 
Patients who satisfy all inclusion and none of the exclusion criteria specified in 
Section 6 will be assigned a unique patient number and then begin the baseline period. 
Patients or their caregivers will be given a paper diary to record daily seizure 
information, rescue medication, concomitant AEDs and AEs; and will be instructed 
on how to do so.  The investigator must record the patient’s attendance at the visit and 
confirm the outcome of screening on the CRF.  
9.2.1.2 
Visit 2 
9.2.1.2.1 
Visit 2 (Day 1) – Enrollment (+ 3 days) 
This visit will occur 7–14 days after Visit 1. 
The following observations will be made at Visit 2: concomitant medications, 
(including AEDs), physical examination (including body weight), ECG, vital signs 
and review of patient diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for hematology, 
biochemistry, alcohol testing and urinalysis.  Blood samples will also be taken for 
genetic testing if additional consent has been obtained.  The C-SSRS will be 
administered.  The investigator must record the patient’s attendance at the visit, and 
confirm the outcome of the visit prior to enrollment. 


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Following enrollment patients will begin the PK sampling process.  Blood samples 
will be taken for analysis of plasma concentrations of CLB, N-CLB, VPA, STP, LEV 
and TPM.  A baseline PK sample will be taken before the patient takes their morning 
dose of CLB.  Further samples will then be taken at the following times relative to the 
CLB dose: 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours and 
12 hours.  The evening dose of any AEDs must be taken after the 12 hour PK blood 
sample.  Patients will either remain in clinic overnight throughout this PK sampling 
process or return to the clinic on Day 2 ahead of additional sample collection. 
9.2.1.2.2 
Visit 2 (Day 2) - Enrollment 
This is the second part of the two day enrollment visit.  The final PK sample will be 
collected 24 hours after the Day 1 morning CLB dose. 
Following completion of the PK sampling process the following observations will be 
made on Day 2: concomitant medications (including AEDs), physical examination 
(including body weight), vital signs and AEs. 
GWP42003-P/placebo will be dispensed and both the morning dose of CLB and of 
GWP42003-P/placebo will be taken in clinic. Following administration of 
GWP42003-P/placebo, patients must remain in clinic for at least 30 minutes to 
monitor for any adverse reactions.  Patients and/or their caregivers will be provided 
with individual dosing schedules as described in Section 8.1.2. Each patient will then 
receive their GWP42003-P/placebo for the 10 day titration period followed by the 
21 day maintenance period. Patients, or their caregivers, will be instructed on how to 
record the diary information. 
9.2.1.3 
Visit 3 (Day 12 +3 days) 
This visit will occur 11 days after Visit 2, Day 1 (enrollment).  Patients will return all 
used and unused GWP42003-P/placebo.  The following observations will be made at 
Visit 3 (Day 12): concomitant medications (including AEDs), physical examination 
(including body weight), ECG, vital signs, AEs and review of patient diary 
completion. 
Clinical laboratory samples (blood and urine) will be taken for hematology, 
biochemistry and urinalysis. The C-SSRS will be administered. 
9.2.1.4 
Visit 4 
9.2.1.4.1 
Visit 4 (Day 33) (± 3 days) 
This visit will occur 32 days after Visit 2, Day 1 (enrollment).  Patients will return all 
used and unused GWP42003-P/placebo.  The following observations will be made at 


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Visit 4 (Day 33): concomitant medications (including AEDs), physical examination 
(including body weight), ECG, vital signs, review of patient diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for hematology, 
biochemistry, alcohol testing, and urinalysis.  The C-SSRS will be administered.  
Blood samples will be taken for analysis of plasma concentrations of CLB, N-CLB, 
VPA, STP, LEV, TPM, CBD, CBD major metabolites, THC and THC major 
metabolites.  A baseline PK sample will be taken before the patient takes their 
morning dose of CLB, followed immediately by their dose of GWP42003-P/placebo. 
Further samples will then be taken at the following times relative to the CLB dose: 
15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours and 12 hours.  
The evening dose of GWP42003-P/placebo and any AEDs must be taken after the 
12 hour PK blood sample.  Patients are expected to remain in clinic throughout this 
PK sampling. 
The investigator must assess adherence to the dosing regimen and recording of rescue 
medications by reviewing the patient’s diary. 
9.2.1.4.2 
Visit 4 (Day 34) 
This is the second part of the two day visit.  The final PK sample will be collected 
24 hours after the Day 33 morning CLB dose. 
Following completion of the PK sampling process the following observations will be 
made on Day 34: concomitant medications (including AEDs), physical examination 
(including body weight), vital signs and AEs. 
At the end of the blinded phase of the study on Day 34, providing the investigator and 
patient both agree, patients will be invited to continue taking GWP42003-P and to 
enter the OLE. 
Patients who enter the OLE will be dispensed GWP42003-P on Day 34 and the first 
dose will be taken in clinic.  Following administration of GWP42003-P, patients must 
remain in clinic for at least 30 minutes to monitor for any adverse reactions.  At the 
point of entry to the OLE, patients will be transitioned to the OLE treatment over a 10 
day period in order to maintain blinding.  
Patients who do not enter the OLE will begin a 10 day taper period during which they 
will taper off their daily dose of GWP42003-P/placebo.  The daily dose will be 
reduced by 10% of the maintenance dose per day and treatment will end on Day 42. 


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9.2.1.5 
Visit 5 (Patients not entering Open Label Extension) (Day 43 
+ 3 days) 
This visit will occur 42 days after Visit 2, Day 1 (enrollment) for those patients who 
do not enter the OLE. 
All GWP42003-P/placebo (used and unused) will be collected and a check of the 
returned GWP42003-P/placebo against usage must be made.  A physical examination 
(including body weight), ECG and vital signs will be assessed and the C-SSRS will be 
administered.  The trained investigator or study coordinator will complete the Study 
Medication Use and Behavior Survey as an interview with the patient/caregiver. 
Clinical laboratory samples (blood and urine) will be taken for hematology, 
biochemistry and urinalysis and a review of concomitant medications (including 
AEDs) and AEs will be completed.  Patient diaries will be collected. 
9.2.1.6 
Visit 6 - Safety Follow up Call (Day 71) (± 3 days) 
This visit is required for patients who do not enter the OLE study on Day 34, or who 
withdraw from the study early.  This visit should occur four weeks after Visit 5, 
(± 3 days) or withdrawal from treatment, and can be conducted over the telephone. 
The following observations will be made on Day 71: concomitant medications 
(including AEDs) and AEs. 
9.2.2 
Open Label Extension 
Patients who enter the OLE will be dispensed IMP at Visit 4 (Day 34) and will have 
regular clinic visits for a maximum of one year or earlier (if marketing authorization 
is granted or the patient withdraws).  The visit schedule is calculated relative to Visit 
4 (Day 34). 
9.2.2.1 
Visit 5 (Open Label Extension) - Two Weeks (± 3 days) 
This visit will occur two weeks after Visit 4 (Day 34).  Patients will return all used 
and unused IMP.  The following observations will be made at Visit 5 (OLE): 
concomitant medications (including AEDs), physical examination (including body 
weight), ECG, vital signs, review of seizure diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for hematology, 
biochemistry and urinalysis.  The C-SSRS will be administered.  The investigator 
must record the patient’s attendance at the visit and the outcome. 
The investigator must assess adherence to the dosing regimen and recording of rescue 
medications by reviewing the patient’s diary. 


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The GWP42003-P dose may be adjusted up or down by the investigator from the 
maintenance dose of 20 mg/kg/day achieved at the end of the 10-day transition period, 
up to a maximum of 30 mg/kg/day in the OLE period.   
9.2.2.2 
Visit 6 (Open Label Extension) - One Month (± 3 days) 
This visit will occur one month (one month is considered as 28 days) after Visit 4 
(Day 34).  Patients will return all used and unused IMP.  The following observations 
will be made at Visit 6 (OLE): concomitant medications (including AEDs), physical 
examination (including body weight), ECG, vital signs, review of seizure diary and 
AEs. 
Clinical laboratory samples (blood and urine) will be taken for hematology, 
biochemistry and urinalysis.  The C-SSRS will be administered.  The investigator 
must record the patient’s attendance at the visit and the outcome. 
The investigator must assess adherence to the dosing regimen and recording of rescue 
medications by reviewing the patient’s diary. 
9.2.2.3 
Visit 7 (Open Label Extension) - Two Months (± 3 days) 
This visit will occur two months after Visit 4 (Day 34).  Patients will return all used 
and unused IMP.  The following observations will be made at Visit 7 (OLE): 
concomitant medications (including AEDs), physical examination (including body 
weight), ECG, vital signs, review of seizure diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for hematology, 
biochemistry and urinalysis.  The C-SSRS will be administered.  The investigator 
must record the patient’s attendance at the visit and the outcome. 
The investigator must assess adherence to the dosing regimen and recording of rescue 
medications by reviewing the patient’s diary. 
9.2.2.4 
Visit 8 (Open Label Extension) - Three Months (± 7 days) 
This visit will occur three months after Visit 4 (Day 34).  Patients will return all used 
and unused IMP.  The following observations will be made at Visit 8 (OLE): 
concomitant medications (including AEDs), physical examination (including body 
weight), ECG, vital signs, review of seizure diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for hematology, 
biochemistry and urinalysis.  The C-SSRS will be administered.  The investigator 
must record the patient’s attendance at the visit and the outcome. 
The investigator must assess adherence to the dosing regimen and recording of rescue 
medications by reviewing the patient’s diary. 


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9.2.2.5 
Visit 9 (Open Label Extension) - Six Months (± 7 days) 
This visit will occur six months after Visit 4 (Day 34).  Patients will return all used 
and unused IMP.  The following observations will be made at Visit 9 (OLE): 
concomitant medications (including AEDs), physical examination (including body 
weight), ECG, vital signs, review of seizure diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for hematology, 
biochemistry and urinalysis.  The C-SSRS will be administered.  The investigator 
must record the patient’s attendance at the visit and the outcome. 
The investigator must assess adherence to the dosing regimen and recording of rescue 
medications by reviewing the patient’s diary. 
9.2.2.6 
Visit 10 (Open Label Extension) - Nine Months (± 7 days) 
This visit will occur nine months after Visit 4 (Day 34).  Patients will return all used 
and unused IMP.  The following observations will be made at Visit 10 (OLE): 
concomitant medications (including AEDs), physical examination (including body 
weight), ECG, vital signs, review of seizure diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for hematology, 
biochemistry and urinalysis.  The C-SSRS will be administered.  The investigator 
must record the patient’s attendance at the visit and the outcome. 
The investigator must assess adherence to the dosing regimen and recording of rescue 
medications by reviewing the patient’s diary. 
9.2.2.7 
Visit 11 (Open Label Extension End of Treatment) - Twelve 
Months (± 7 days) 
This visit will occur twelve months after Visit 4 (Day 34).  Patients will return all 
used and unused IMP.  The following observations will be made at Visit 11 (OLE): 
concomitant medications (including AEDs), physical examination (including body 
weight), ECG, vital signs, review of seizure diary and AEs. 
Clinical laboratory samples (blood and urine) will be taken for hematology, 
biochemistry and urinalysis.  The C-SSRS will be administered.  The investigator 
must record the patient’s attendance at the visit and the outcome. 
The investigator must assess adherence to the dosing regimen and recording of rescue 
medications by reviewing the patient’s diary. 
Starting at Visit 11, patients will begin to taper down their IMP dose.  The dose will 
be reduced by 10% of their OLE maintenance dose per day. 


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9.2.2.8 
Visit 12 (Open Label Extension End of Taper) 
This visit will be ten days after Visit 11.  All IMP (used and unused) will be collected 
and a check of the returned IMP against usage must be made.  A physical examination 
(including body weight), ECG and vital signs will be assessed and the C-SSRS will be 
administered.  The trained investigator or study coordinator will complete the Study 
Medication Use and Behavior Survey as an interview with the patient/caregiver. 
Clinical laboratory samples (blood and urine) will be taken for hematology, 
biochemistry and urinalysis and a review of concomitant medications (including 
AEDs) and AEs will be completed.  Patient diaries will be collected and reviewed. 
9.2.2.9 
Safety Follow Up Call (± 3 days) 
This visit will occur one month after the OLE End of Taper and can be conducted 
over the telephone.  The following observations will be made during the follow up 
call: concomitant medications (including AEDs) and AEs. 
10. WITHDRAWAL 
In accordance with the Declaration of Helsinki31, the FDA regulations relating to 
good clinical practice (GCP) and clinical trials32,33,34, the EU Clinical Trials Directive 
(2001/20/EC)35 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. 
• Withdrawal of legal representative consent. 
• Lost to follow up. 
• ALT > 3 × ULN 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 two weeks. 
• Any other IMP is taken as part of a clinical trial during the study.  


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• Significant change in QTcB (> 60 msec) from the previous ECG or absolute 
QTcB of > 500 msec.  
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 four or five during the treatment period, 
as evaluated with the C-SSRS. 
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 Visit 4 (if the withdrawal is during the blinded phase) or Visit 11 (if the 
withdrawal is during the OLE) should be conducted if possible.  If the tapered dose is 
administered, patients should return for Visit 5 (if withdrawal is during the blinded 
phase) or Visit 12 (if the withdrawal is during the OLE) if possible.  Wherever 
possible, the safety follow-up visit should be conducted 28 days from the date of the 
last dose of IMP.  Patients withdrawing due to an AE should be followed up 
according to Section 12.7.  All information should be reported on the applicable CRF 
pages 
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 three 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 screening (Visit 1) throughout the study and up to the post treatment, safety 
follow-up visit (28 days after last dose of IMP), 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 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 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., an 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. 


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• Is a congenital anomaly/birth defect. 
• 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 visit (Visit 13 for patients entering the OLE and Visit 6 for those 
patients that are not entering the OLE).  If the investigator subsequently becomes 
aware of any deaths or a 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 study medication 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 study medication: 
“In your opinion is there a plausible relationship to the study medication?” The 
answer is “yes” or “no”. 
Events that start before the first dose of study medication (pre-treatment) should be 
considered as not causally related.  Where a pre-treatment event worsens in severity 
following the first dose of study medication, 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 study medication but also competing etiological 
factors as the underlying cause.  Factors for consideration may include: 
• Medical history. 
• Lack of efficacy/worsening of treated condition. 
• Concomitant or previous treatment. 


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• Withdrawal of study medication. 
• Protocol-related procedure. 
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 
screening (Visit 1) to post study follow-up (Visit 13 for patients entering the OLE and 
Visit 6 for those patients that are not entering the OLE). 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 for the 
following categories: 


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• Recovered. 
• Recovered with sequelae. 
• Continuing. 
• 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 


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AE, further details of withdrawal are presented in Section 10.  If either of these 
occurs, the patient must undergo an end of treatment assessment and be given 
appropriate care under medical supervision until symptoms cease or the condition 
becomes stable. 
12.8 
Potential Cases of Drug Induced Liver Injury   
All investigational sites 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 two 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 hours of notice of abnormal results) 
for repeat assessment of ALT, AST, TBL, alkaline phosphatase and gamma-glutamyl 
transferase levels, detailed history and physical examination.  Patients should be 
followed until all abnormalities have normalized (in the investigator’s opinion) or 
returned to the baseline state. 
Elevations in ALT or AST > 3 × ULN or TBL > 2 × ULN alone are not considered 
potential cases of drug-induced liver injury, but will be followed as detailed above, 
within 72 hours’ notice of abnormal results.  If the participant cannot return to the 
investigational center, repeat assessments may be done at a local laboratory and the 
results sent to GW PVD. 
12.9 
Notification of Safety Information to Investigators, Regulatory 
Authorities and Ethics Committees. 
In accordance with the EU Clinical Trials Directive35, relevant parts of the FDA Code 
of Federal Regulations and any national regulations, GW will inform investigators, 


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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 three sources: 
• Investigator Brochure36: 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 
participants.  The IB is updated annually. 
• Development Core Safety Information: this document actually forms the 
Safety Section of the IB36, or is updated as an appendix of the IB36.  This 
document is revised if necessary, when new important safety information 
becomes available (potentially up to a few times a year). 
• 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 
IRB/EC 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 guidance32 
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, 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 guidance37 states that, accordingly, to satisfy the investigator’s obligation to 
notify the IRB of unanticipated problems, any investigators participating in a 
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/EC’s) of any 
safety issues or case reports that are considered to be unanticipated and provide such 


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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 ethics approval and final database lock. 


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13. 
STATISTICAL CONSIDERATIONS 
A statistical analysis plan (SAP) will be produced prior to the database lock and 
analysis of the study.  Any deviations from the original SAP will be described in the 
final clinical study report. 
13.1 
Sample Size, Power and Significance Levels 
A total of 20 patients will be enrolled in this study.  There is no formal sample size: 
Calculation and analysis is descriptive only. 
13.2 
Interim Analysis 
An interim analysis will be conducted at the end of the Double Blind phase of the 
study and may also be considered during the OLE phase, if long term data is required 
to support New Drug Application/Marketing Authorization Application submissions. 
13.3 
Analysis Sets 
13.3.1 
Safety Set 
All subjects who are treated and receive at least one dose of IMP will be included. 
The Safety set is the primary analysis set for all safety endpoints. 
13.3.2 
Pharmacokinetic Analysis Set  
All subjects who are treated and receive at least one dose of IMP and who provide 
some on-treatment data will be included. 
The PK analysis set is the primary analysis set for all PK endpoints. 
13.3.3 Protocol Deviations 
Any protocol deviations will be listed and reasons for exclusion from the analysis 
populations 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 in each category.  Summaries will be presented for data 
recorded pre-treatment, during each 25 day dosing phase (placebo and GWP42003-P) 
and during the OLE phase separately. 


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13.5 
Accountability and Background Characteristics 
13.5.1 Enrollment and Disposition 
All patients (screened, treated, completing the study and those 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 and the types of seizures currently 
experienced by the patients. 
13.5.4 Concomitant Medication 
Concomitant medications taken prior to and during the study will be summarized, by 
medication class and active ingredients.  Summaries of medications taken during the 
IMP treatment phases and during OLE will be presented separately. 
13.6 
Endpoints and Statistical Methods 
13.6.1 Primary Endpoint(s) 
The primary endpoints of the study are the PK parameters (Cmax, tmax, AUC(0–∞), 
AUC(0–t), t½) of the following analytes: 
• CLB 
• N-CLB 
• CBD 
• CBD major metabolites 
13.6.2 Secondary Endpoint(s) 
The secondary endpoints of the study are the safety parameters (see Section 13.6.4) 
and the PK parameters (Cmax, tmax, AUC(0–∞), AUC(0–t), t½) of the following analytes: 
• THC 
• THC major metabolites 


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13.6.3 Pharmacokinetics 
Calculation of PK parameters will be based on actual blood sampling times [h] 
(relative to the corresponding administration time) rounded to two decimal digits with 
negative pre-dose times set to zero.  Plasma concentrations of CLB, N-CLB, VPA, 
STP, LEV, TPM, CBD, CBD major metabolites, THC and THC major metabolites 
will be displayed graphically, summarized and listed.  For descriptive statistics, values 
below the lower limit of quantification of the assay (LLOQ) will be excluded from 
any calculations.  Descriptive statistics of concentrations will be calculated if at least 
half of the individual data points that have been measured are equal to or above the 
LLOQ. 
For calculation of the PK parameters, the following rules will be applied: 
At time zero and at time points in the lag-time between time zero and the first 
quantifiable concentration, concentrations below the LLOQ will be set to zero.  All 
other concentrations below the LLOQ will not be used in calculations. 
Variables derived from plasma concentrations: 
• Concentration maximum (Cmax): Highest observed plasma concentration of the 
measured concentration-time profile. Dimension: [amount / volume]. 
• Terminal half-life t½= ln(2)/λz. 
• The rate constant of the terminal phase λz will be determined by linear 
regression of log-transformed concentration data after the time of maximum 
concentration.  A sequence of terminal elimination rate constants will be 
created by linear regression.  Linear regressions are repeated using the last 
three points with a quantifiable concentration, the last four points, the last five 
points etc.  For each regression, an adjusted R2 is computed.  The regression 
with the largest adjusted R2 is selected to estimate the terminal half-life. 
Dimension: [time]. 
• Area under the concentration-time curve from administration until the last 
sampling point (t) equal or above the LLOQ AUC(0–t) will be calculated by the 
linear trapezoidal formula. Dimension: [time • amount / volume]. 
• Area under the concentration-time curve extrapolated to infinity: AUC(0–∞) = 
AUC(0–t) + Clast/λz and Clast is the concentration observed at the last time point 
with a quantifiable concentration, λz refers to the terminal elimination rate 
constant. Dimension: [time • amount / volume]. 
• Time of maximum concentrations: Tmax will be taken as the time after 
administration at which Cmax occurs. Dimension: [time]. 
• PK parameters for each analyte will be summarized for the two treatment 
phases of the study separately, as appropriate. 
• In order to assess whether the presence of CBD alters the PK profile of CLB 
(or N-CLB), a standard 90% confidence interval (CI) approach for the 
between group ratios of geometric means of Cmax, AUC(0–t), and AUC(0–∞) will 


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be carried on logarithm scale using a linear mixed effect model with treatment 
(CLB or CLB+CBD) as a fixed effect and subject as a random effect.  The no-
effect boundary will be set between 0.5 and 2.0 and if the 90% CI for the ratio 
of the geometric means of a PK variable falls within the interval [0.5, 2.0], a 
lack of meaningful effect will be declared. 
13.6.4 Safety 
13.6.4.1 
Treatment Compliance and Extent of Treatment Exposure 
Treatment compliance and exposure to treatment will be summarized for each phase 
of the study separately. 
13.6.4.2 
Adverse Events 
AEs will be coded according to the Medical Dictionary for Regulatory Activities 
dictionary. 
A treatment emergent AE is one that started, or worsened in severity or seriousness, 
following the first dose of IMP. 
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. Summaries will be provided for each phase of the 
study separately. 
The following summaries will be produced: 
• 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. 
13.6.4.3 
Clinical Laboratory Data 
Clinical laboratory data at screening and at the end of the 31 day treatment phase and 
the change from baseline to end of treatment (OLE) 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. 


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13.6.4.4 
Columbia-Suicide Severity Rating Scale, Vital Signs, 12-lead 
Electrocardiogram, Physical Examination and Other Safety 
Data 
The C-SSRS, vital signs, ECG and physical examination data will be summarized at 
screening, at the end of the 31 day treatment phase and during the OLE treatment 
period using appropriate summary statistics.  Changes in the vital signs from baseline 
to end of each treatment phase will also be summarized. 
13.6.4.5 
Seizure Data 
Seizure data collected during the 31 day treatment phase and during the OLE phase of 
the study will be summarized using appropriate summary statistics. 
14. 
DATA SAFETY MONITORING COMMITTEE 
GW does not plan to use an independent data safety monitoring committee as part of 
this study. 


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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 
the31,35and the clinical trial regulations adopting European Commission Directives 
into national legislation38,39,40. 
15.2 
Informed Consent 
Initial master ICFs will be provided to the investigator to prepare the informed 
consent documents to be used at his or her center.  The GW Clinical Manager will 
communicate updates to the templates by letter.  The written informed consent 
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 from the patient or 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, or their legal representative, should have ample time for 
review to consider the information provided before giving written consent; more 
specific definitions of ample time may be in force if required by IRB/ECs or local 
regulations. 
The acquisition of informed consent should be documented in the patient’s medical 
records and the ICF should be signed and personally dated by the patient or legal 
representative (as applicable) and by the person who conducted the informed consent 
discussion.  GW also requires a physician to be present for consent and to sign the 
consent forms as well.  The original signed ICFs should be retained and a copy 
provided to the patient or legal representative. 
15.3 
Institutional Review Board/Ethics Committee 
A copy of the protocol, proposed ICFs, 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 ICFs before enrollment of patients into the study and 
shipment of IMP. 
The investigator must submit and, where necessary, obtain approval from the IRB/EC 
for all subsequent protocol amendments and changes to the informed consent 
documents.  The investigator should notify the IRB/EC of deviations from the 


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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 for entry into the study: 
• Signed and dated protocol signature page. 
• Copy of approved ICFs and other patient information material. 
• Copy of the IRB/EC approval of the protocol, ICFs and other patient 
information material. 
• Up to date curricula 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 
trials32,33,34,41, the EU Clinical Trials Directive35, or International Conference 
on Harmonization Tripartite Guideline for Good Clinical Practice (ICH 
GCP)42 where the EU 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 
Participant 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 ICFs should be kept in strict confidence by the investigator. 
In compliance with the FDA regulations relating to good clinical practice and clinical 
trials32,33,34,41, and the EU Clinical Trials Directive35/ICH GCP Guidelines42, 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 


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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 documents.  The IRB/EC and Competent Authorities must be 
informed of all amendments and give approval for any substantial amendments prior 
to implementation.  The investigator must send a copy of the approval letter from the 
IRB/EC to GW.  Amendments for administrational changes can be submitted to the 
IRB/EC for information only. 
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.  In the rare situations of this happening, 
then the source data from the CRF should be transcribed in the patient’s notes with 
appropriate signature and date to provide a full audit trail.  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. 
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 8.242), suitable for inspection at any time by representatives from GW 
and/or applicable regulatory authorities.  Elements should include: 
• Patient files containing completed CRFs, ICFs and supporting copies of source 
documentation. 


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• 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. 
• 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, paper 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 25 years.  Essential documents should be retained until at least two 
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 two 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 1643). 
GW will inform the investigators for each site 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 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. 


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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 five working days after 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 regulations32,33,34,41, the ICH GCP 
Guideline42, and all other applicable regulatory requirements35,42, 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. 


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• 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. 
16.4 
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. 
16.5 
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. 
16.6 
Publication Policy 
GW recognizes that there is a responsibility under the regulatory guidelines to ensure 
that results of scientific interest arising from this clinical 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 


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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 six months from the date of first submission to them in order to allow them to 
take steps to protect proprietary information where applicable. 
16.7 
Intellectual Property Rights 
All Intellectual Property Rights owned by or licensed to either GW or the PIs, other 
than those arising from the clinical 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. 
16.8 
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. REFERENCES 
1 
Bergen DC.  Preventable neurological diseases worldwide.  Neuroepidemiology, 
1998, 17(2): 67-73. 
2 
Sander JW.  The epidemiology of epilepsy revisited.  Curr Opin Neurol, 2003, 
16(2): 165-170. 
3 
MacDonald BK, Cockerell OC, Sander JW and Shorvon SD.  The incidence and 
lifetime prevalence of neurological disorders in a prospective community-based 
study in the UK.  Brain, 2000, 123(4): 665-676. 
4 
Forsgren L, Beghi E, Oun A and Sillanpää M.  The epidemiology of epilepsy in 
Europe – a systematic review.  Eur J Neurol, 2005, 12(4): 245-253. 
5 
Duncan JS, Sander JW, Sisodiya SM and Walker MC.  Adult epilepsy.  The 
Lancet, 2006, 367(9516): 1087-1100. 
6 
Committee for medicinal products for human use. Guideline on clinical 
investigation of medicinal products in the treatment of epileptic disorders, 22 July 
2010, CHMP/EWP/566/98 Rev.2/Corr. 
7 
Sander JS.  Some aspects of prognosis in the epilepsies: a review.  Epilepsia, 
1993, 34(6): 1007-1016. 
8 
Kwan P and Brodie MJ.  Early Identification of Refractory Epilepsy.  N Engl J 
Med, 2000, 342(5): 314-319. 
9 
Kwan P and Brodie MJ.  Emerging drugs for epilepsy.  Expert Opin Emer Drugs, 
2007, 12(3): 407-422. 
10 Schachter SC.  Currently available antiepileptic drugs.  Neurotherapeutics, 2007, 
4(1): 4-11. 
11 Martin J.  British National Formulary. 2013, Pharmaceutical Press London. 
12 Bialer M and White HS.  Key factors in the discovery and development of new 
antiepileptic drugs.  Nat Rev Drug Discov, 2010, 9(1): 68-82. 
13 Czapiński P, Blaszczyk B and Czuczwar SJ.  Mechanisms of action of 
antiepileptic drugs.  Curr Top  Med Chem, 2005, 5(1): 3-14. 
14 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. 
15 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. 
16 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. 
17 Zuardi AW, Morais SL, Guimarães FS, Mechoulam R. Antipsychotic effect of 
cannabidiol. J Clin Psychiatry 1995;56(10):485-6. 
18 Jones NA, Hill AJ, Smith I, Bevan SA, Williams CM, Whalley BJ et al. 
Cannabidiol displays antiepileptiform and antiseizure properties in vitro and in 
vivo. J Pharmacol Exp Ther 2010;332(2):569-77. 


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19 Jones NA, Glyn SE, Akiyama S, Hill TD, Hill AJ, Weston SE et al. Cannabidiol 
exerts anti-convulsant effects in animal models of temporal lobe and partial 
seizures. Seizure 2012;21(5):344-52. 
20 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. 
21 Gover J, Schultz, S. GW Pharmaceuticals announces new physician reports of 
Epidiolex treatment effect in children and young adults with treatment-resistant 
epilepsy [press release]. United Kingdom: GW Pharma Ltd; 2014 Oct 14. 
22 Johannessen Landmark C, Larsson PG, Rytter E, Johannessen SI. Antiepileptic 
drugs in epilepsy and other disorders: a population-based study of prescriptions. 
Epilepsy Res. 2009, 87(1):31-39 
23 Tsiropoulos I, Gichangi A, Andersen M, Bjerrum L, Gaist D, Hallas J. Trends in 
utilization of anti-epileptic drugs in Denmark. Acta Neurol. Scand. 2006, 113, 
405-411 
24 van de Vrie-Hoekstra NW, de Vries TW, van den Berg PB, Brouwer OF, de Jong-
van den Berg LT. Antiepileptic drug utilization in children from 1997-2005 - a 
study from the Netherlands. Eur J Clin Pharmacol. 2008, 64: 1013-1020. 
25 Johannessen Landmark C, Rytter E, Johannessen SI. Clinical use of antiepileptic 
drugs at a referral centre for epilepsy. Seizure. 2007, 16:356-364 
26 Rytter E, Johannessen Landmark C, Johannessen SI. Antiepileptic drug treatment 
of children at a referral centre for epilepsy - does admission make a difference? 
Seizure. 2009, 18:573-579 
27 Contin M, Riva R, Albani F, Baruzzi A. Effect of felbamate on clobazam and its 
metabolite kinetics in patients with epilepsy. Ther Drug Monit. 1999, 21:604-608 
28 Levy RH, Lin HS, Blehaut HM, Tor JA. Pharmacokinetics of stiripentol in normal 
man: evidence of non-linearity. J Clin Pharmacol. 1983, 23 (11-12):523-533. 
29 Tran A, Vauzelle-Kervroedan F, Rey E, Pous G, d´Athis P, Chiron C, Dulac O, 
Renard F, Olive G. Effect of stiripentol on carbamazepine plasma concentration 
and metabolism in epileptic children. Eur J Clin Pharmacol. 1996, 50:497-500. 
30 Trojnar MK, Wojtal K, Trojnar MP, Czuczwar SJ. Stiripentol. A novel 
antiepileptic drug. Pharmacol Rep. 2005, 57:154-160. 
31 World Medical Association Declaration of Helsinki — Ethical principles for 
medical research involving human subjects. October 2013. 
32 U.S. Food and Drug Administration Code of Federal Regulations Title 21 (Food 
and Drugs) Part 50 — Protection of human subjects. April 2014. 
33 U.S. Food and Drug Administration Code of Federal Regulations Title 21 (Food 
and Drugs) Part 312 — Investigational New Drug application. April 2014. 
34 U.S. Food and Drug Administration Code of Federal Regulations Title 21 (Food 
and Drugs) Part 56 — Institutional Review Boards. April 2014. 
35 Directive 2001/20/EC  of the European Parliament and of the Council of 04 April 
2001 on the approximation of the laws, regulations and administrative provisions 
of the Member States relating to the implementation of good clinical practice in 
the conduct of clinical trials on medicinal products for human use. Official Journal 
of the European Communities L 121, 1/5/2001 p. 34–44. 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
V4 04Feb16 
 
 
 
 
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36 Investigator Brochure — CBD medicine. GW Pharma Ltd. Edition 7, August 
2014. 
37 U.S. Food and Drug Administration guidance for clinical Investigators, Sponsors, 
and IRBs: Adverse Event reporting to IRBs — Improving human subject 
protection. January 2009. 
38 UK Statutory Instrument 2004/1031 — The medicines for human use (clinical 
trials) regulations 2004. May 2004. 
39 UK Statutory Instrument 2006/1928 — The medicines for human use (clinical 
trials) amendment regulations 2006. August 2006. 
40 UK Statutory Instrument 2006/2984 — The medicines for human use (clinical 
trials) amendment (No.2) regulations 2006. December 2006. 
41 U.S. Food and Drug Administration Code of Federal Regulations Title 21 (Food 
and Drugs) Part 11 — Electronic records; electronic signatures (Subpart B — 
Electronic records). April 2014. 
42 International Conference on Harmonisation Topic E6(R1): Guideline for good 
clinical practice — Note for guidance on good clinical practice 
(CPMP/ICH/135/95). July 2002. 
43 Commission Directive 2005/28/EC of 08 April 2005 laying down the principles 
and detailed guidelines for GCP as regards investigational medicinal products for 
human use, as well as the requirements for authorisation of the manufacturing or 
importation of such products. Official Journal of the European Union L 91, 
9/4/2005 p. 13–19. 
 
 
 
 
 
 
 
 
 
 


Study Code: GWEP1428 
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V4 04Feb16 
 
 
 
 
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APPENDIX 1. SCHEDULE OF ASSESSMENTS 
Visit Number 
Day 
(Visit Window) 
Visit 1 
Day -14 to -7 
 
Visit 2 
Day 1 
(+ 3 days) 
Visit 2 
Day 2 
 
Visit 3 
Day 12 
(+ 3 days) 
Visit 4 
Day 33 
(± 3 days) 
Visit 4 
Day 34 
 
Visit 5* 
End of Taper 
 
Visit 6* 
4wk SFU 
(± 3 days) 
Informed consent 
X 
 
 
 
 
 
 
 
Eligibility criteria 
X 
X 
 
 
 
 
 
 
Enrollment 
 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
Paper diary training 
X 
 
X 
 
 
 
 
 
Concomitant medications 
(including AEDs) 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
(including height and body 
weight)♥ 
X 
X 
X 
X 
X 
X 
X 
 
ECG 
X 
X 
 
X 
X 
 
X 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical laboratory blood 
sampling  
X 
X 
 
X 
X 
 
X 
 
Clinical laboratory urine 
sampling (dipstick 
urinalysis) 
X 
X 
 
X 
X 
 
X 
 
THC test 
X 
 
 
 
 
 
 
 
Alcohol Test 
X 
X 
 
 
X 
 
 
 
Pregnancy test (if 
appropriate) 
X 
 
 
 
 
 
 
 
Pharmacokinetic blood 
sampling**  
 
X 
X 
 
X 
X 
 
 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
V4 04Feb16 
 
 
 
 
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Visit Number 
Day 
(Visit Window) 
Visit 1 
Day -14 to -7 
 
Visit 2 
Day 1 
(+ 3 days) 
Visit 2 
Day 2 
 
Visit 3 
Day 12 
(+ 3 days) 
Visit 4 
Day 33 
(± 3 days) 
Visit 4 
Day 34 
 
Visit 5* 
End of Taper 
 
Visit 6* 
4wk SFU 
(± 3 days) 
Sample for Genetic 
Testing*** 
 
X 
 
 
 
 
 
 
C-SSRS 
X 
X 
 
X 
X 
 
X 
 
Patient diary review 
(seizures, AE information, 
concomitant AEDs, rescue 
medication, IMP dosing) 
 
X 
 
X 
X 
 
X 
 
IMP dispensing 
 
 
X 
 
 
X 
 
 
Collection of IMP 
 
 
 
X 
X 
 
X 
 
IMP compliance review 
 
 
 
X 
X 
 
X 
 
Study Medication Use and 
Behavior Survey 
 
 
 
 
 
 
X 
 
* Patients not entering the OLE 
**PK Sampling time points are as follows: Pre-dose and 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 12 hours and 24 hours after 
dosing.  For the second PK visit the patient should take the GWP42003-P/placebo immediately after their daily dose of CLB. 
*** Samples for genetic testing will only be taken if additional consent is obtained. 
♥ Patients height measured at Visit 1 only. 
 
 


Study Code: GWEP1428 
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V4 04Feb16 
 
 
 
 
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Open Label Extension Schedule of Assessments 
* For the purpose of scheduling, each month is considered as 4 weeks (28 days). 
Visit Number 
Day 
(Visit Window) 
Visit 5 
2 Weeks 
(± 3 days) 
Visit 6 
1 Month 
(± 3 days) 
Visit 7 
2 Months 
 (± 3 days) 
Visit 8 
3 Months 
(± 7 days) 
Visit 9 
6 Months 
 (± 7 days) 
Visit 10 
9 Months 
(± 7 days) 
Visit 11 
12 Months 
 (± 7 days) 
Visit 12 
End of 
Taper 
 
Visit 13 
4wk SFU 
(± 3 days) 
Paper diary training 
 
 
 
 
 
 
 
 
 
Concomitant medications 
(including AEDs) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
(including weight) 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECG 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical laboratory blood 
sampling  
X 
X 
X 
X 
X 
X 
X 
X 
 
Clinical laboratory urine 
sampling (dipstick 
urinalysis) 
X 
X 
X 
X 
X 
X 
X 
X 
 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
X 
 
Patient diary review 
(seizures, AE 
information, concomitant 
AEDs, rescue medication, 
IMP dosing) 
X 
X 
X 
X 
X 
X 
X 
X 
 
IMP dispensing 
X 
X 
X 
X 
X 
X 
X 
 
 
Collection of IMP 
X 
X 
X 
X 
X 
X 
X 
X 
 
IMP compliance review 
X 
X 
X 
X 
X 
X 
X 
X 
 
Study Medication Use 
and Behavior Survey 
 
 
 
 
 
 
 
X 
 


Study Code: GWEP1428 
EudraCT Number: 2014-002942-33 
V4 04Feb16 
 
 
 
 
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APPENDIX 2. STUDY PERSONNEL 
Appendix 3.1 
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 3.2 
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: 
 
Fax: 
 
Medical Monitor 
EU 
 
  
Tel: 
 
Mobile:
 
USA 
 
 
Tel: 
 
Mobile: 
  
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


Study Code: GWEP1428 
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V4 04Feb16 
 
 
 
 
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Clinical Project Manager/Clinical Operations 
Director: 
GW Research Ltd 
Sovereign House 
Vision Park 
Chivers Way 
Histon 
Cambridge CB24 9BZ 
United Kingdom 
Tel: 
 
Fax: 
 
Clinical Trials Supplies: 
GW Pharma Ltd 
Tel: 
 
Fax: 
 
 
 
 
 
 
PPD
PPD
PPD
PPD

SAP_001.pdf: 
Confidentiality 
This document is confidential and proprietary property of GW Pharmaceuticals and to be used only as authorized 
by GW Pharmaceuticals.  No part is to be reproduced, disclosed to others, or quoted without prior written 
authorization from GW Pharmaceuticals 
STATISTICAL ANALYSIS PLAN 
Protocol GWEP1428  
EudraCT Number: 2014-002942-33 
A PHASE 2, DOUBLE-BLIND, RANDOMIZED, PLACEBO-
CONTROLLED STUDY TO INVESTIGATE POSSIBLE DRUG-DRUG 
INTERACTIONS BETWEEN CLOBAZAM AND CANNABIDIOL 
(GWP42003-P) 
Protocol Number: 
(Version Date) 
GWEP1428 
Version 4 (04-Feb-2016) 
Name of Test Drug: 
Cannabidiol (GWP42003-P) 
Phase: 
2 
Methodology: 
Double-Blind, Randomized, Placebo-Controlled 
Sponsor: 
GW Research Ltd 
Sovereign House, Vision Park, 
Chivers Way, 
Histon, Cambridge 
CB24 9BZ,  
Tel: 
 Fax: 
Sponsor Representative: 
Document Date: 
23 September 2016 
Document Version: 
1.0 
PPD
PPD
PPD
NCT Number:  
 
       DBL Part - NCT02565108
 
 
 
 
       OLE Part - NCT02564952


Protocol Title: 
Sponsor: 
Protocol Number: 
Document DateNersion: 
Cytel, Inc. Author: 
 
Cytel, Inc. 
20 route de Pre-Bois 
CH -1216 Cointrin 
SIGNATURE PAGE 
GW Phnnnnceu/icals 
Protocol GJI'EP14211 
SAP ll?rsion /_0- 23 SEP 21116 
A PHASE2, DOUBLE-BLIND, RANDOMIZED, 
PLACEBO-CONTROLLED STUDY TO 
INVESTJGATE POSSlBLE DRUG-DRUG 
INTERACTIONS BETWEEN CLOBAZAM AND 
CANNABIDIOL (GWP42003-P) 
GW Research Ltd 
Sovereign House, Vision Park, 
Chivers Way, 
Histon, Cambridge 
CB249BZ, 
Tel: 
 Fax: 
 
Protocol GWEP1428 
EudraCT Number: 2014-002942-33 
Sponsor Approval 
By signing this document I acknowledge that I have read the document and approve of the 
planned tatistical analyses described herein. 1 agree that the planned statistical analyses are 
appropriate for this study, are in accordance with the study objectives, and are consistent with 
the tatislicalmethodology described in the protocol, clinical development plan, and all 
applicable regulatory guidance -and guidelines. 
I have discussed any questions I have regarding the contents ofthis document with the 
biostatistica1 author. 
I also understand that any subsequent changes to the planned statistical analyses, as described 
herein, may have a regulatory impact and/or result in timeline adjustments. All changes to the 
planned analyses will be described in the clinical study report (CSR). 
Sponsor Signatory: 
 
GW Research Ltd 
Histon, Cambridge, UK 
CB24 9BZ 
Date: 23S.EP2-0l6 
CONFIDENTIAL 
PPD
PPD
PPD
PPD
PPD
PPD


GW Pharmaceuticals 
Protocol GWEP1428  
SAP version 1.0 - 23 SEP 2016 
CONFIDENTIAL 
3 
TABLE OF CONTENTS 
Section 
Page 
1. 
INTRODUCTION AND OBJECTIVES OF ANALYSIS ............................................ 8 
1.1. 
Introduction .......................................................................................................... 8 
1.2. 
Objectives of Statistical Analysis ........................................................................ 8 
Objectives of the study........................................................................................... 8 
Objectives of the statistical analysis plan (SAP) ................................................... 8 
2. 
STUDY DESIGN .............................................................................................................. 9 
2.1. 
Synopsis of Study Design ..................................................................................... 9 
2.2. 
Randomization Methodology .............................................................................. 9 
2.3. 
Stopping Rules and Unblinding ........................................................................ 10 
2.4. 
Study Procedures ............................................................................................... 10 
2.5. 
Efficacy, Pharmacokinetic and Safety Variables ............................................ 14 
Primary Endpoint(s) ............................................................................................. 14 
Secondary Endpoint(s) ......................................................................................... 14 
3. 
Patient POPULATIONS ............................................................................................... 15 
3.1. 
Population Definitions ....................................................................................... 15 
Screened Population............................................................................................. 15 
Safety Population ................................................................................................. 15 
PK Population ...................................................................................................... 15 
Open-Label Extension Population ....................................................................... 15 
3.2. 
Protocol Deviations/Violations .......................................................................... 16 
4. 
STATISTICAL METHODS ......................................................................................... 17 
4.1. 
Sample Size Justification ................................................................................... 17 
4.2. 
General Statistical Methods and Data Handling ............................................ 17 
General Methods .................................................................................................. 17 
Computing Environment ...................................................................................... 17 
Methods of Pooling Data ..................................................................................... 17 
Adjustments for Covariates.................................................................................. 17 
Multiple Comparisons/Multiplicity ..................................................................... 17 
Withdrawals, Dropouts, Loss to Follow-up ......................................................... 17 
Missing, Unused, and Spurious Data ................................................................... 18 


GW Pharmaceuticals 
Protocol GWEP1428  
SAP version 1.0 - 23 SEP 2016 
CONFIDENTIAL 
4 
Section 
Page 
Visit Windows ..................................................................................................... 18 
Handling of partially missing dates ..................................................................... 18 
4.3. 
Interim Analyses ................................................................................................ 18 
4.4. 
Patient Disposition ............................................................................................. 18 
4.5. 
Demographic and Baseline Characteristics ..................................................... 20 
Demographics ...................................................................................................... 20 
Medical History ................................................................................................... 20 
Prior Medications ................................................................................................. 21 
Other Baseline Characteristics ............................................................................. 21 
4.6. 
Efficacy Evaluation ............................................................................................ 21 
4.7. 
Pharmacokinetic Evaluations ........................................................................... 22 
Reporting of Pharmacokinetic Parameters (CLB/CBD/THC) ............................. 22 
Reporting of Pharmacokinetic Parameters (Other Drugs) ................................... 23 
4.8. 
Safety Analyses ................................................................................................... 24 
Treatment Compliance and Extent of Treatment Exposure ................................. 24 
Adverse Events .................................................................................................... 24 
Laboratory Data ................................................................................................... 26 
Vital Signs, Physical Examinations and Blood Pressure ..................................... 27 
Electrocardiogram ................................................................................................ 27 
Concomitant Medications .................................................................................... 27 
C-SSRS 28 
Genotype .............................................................................................................. 29 
Abuse liability ...................................................................................................... 29 
Patient Diary ........................................................................................................ 29 
Seizure Frequency ................................................................................................ 29 
5. 
CHANGES TO PLANNED ANALYSES .................................................................... 30 
6. 
REFERENCES ............................................................................................................... 31 
7. 
APPENDICES ................................................................................................................ 32 
7.1. 
Statistical Tables/Listings and Figures to be Generated ................................ 32 
7.2. 
Toxicity criteria for laboratory parameters .................................................... 34 
7.3. 
Study Design ....................................................................................................... 36 
 


GW Pharmaceuticals 
Protocol GWEP1428  
SAP version 1.0 - 23 SEP 2016 
CONFIDENTIAL 
5 
LIST OF IN-TEXT TABLES 
Table 
Page 
Table 1 
Schedule of Assessments................................................................................................. 11 
Table 2 
Pharmacokinetic parameters ............................................................................................ 14 
Table 3 
Hematology, Biochemistry, Urinalysis and THC Screen* .............................................. 26 
 


GW Pharmaceuticals 
Protocol GWEP1428  
SAP version 1.0 - 23 SEP 2016 
CONFIDENTIAL 
6
ABBREVIATIONS 
 
Abbreviation 
Definition 
AE 
Adverse Event 
AEDs 
Antiepileptic Drugs 
AUC(0–∞) 
Area under the concentration time curve from to infinity with 
extrapolation of the terminal phase 
AUC(0–t) 
 
Area under the concentration time curve, from time zero to ‘t’ 
(where t = the final time of positive detection) as calculated by the 
linear trapezoidal method 
CBD 
Cannabidiol 
CI 
Confidence Interval 
CLB 
Clobazam 
Cmax 
Maximum plasma concentration 
CRF 
Case Report Form 
CS 
Clinically Significant 
CSR 
Clinical Study Report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CV 
Coefficient of variation 
CYP 
Cytochrome P450 
DB 
Double-Blind 
ECG 
12-Lead Electrocardiogram 
EEG 
Electroencephalography 
GW 
GW Research Ltd 
GWP 
GW Pharma Ltd 
IMP 
Investigational Medicinal Product 
LEV 
Levetiracetam 
LLOQ 
Lower Limit of Quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
N-CLB 
N-desmethylclobazam 
OLE 
Open Label Extension 
PK 
Pharmacokinetic 
Q1 
First Quartile 
Q3 
Third Quartile 


GW Pharmaceuticals 
Protocol GWEP1428  
SAP version 1.0 - 23 SEP 2016 
CONFIDENTIAL 
7 
Abbreviation 
Definition 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation  
SFU 
Safety Follow Up 
SOC 
System Organ Class 
STP 
Stiripentol 
t½ 
Terminal half-life 
TBL 
Total bilirubin 
THC 
9-tetrahydrocannabinol 
Tmax 
Time to maximum plasma concentration 
TPM 
Topiramate 
VPA 
Valproate 
WHO 
World Health Organization 
λz 
Terminal elimination rate constant 
 


GW Pharmaceuticals 
Protocol GWEP1428  
SAP version 1.0 - 23 SEP 2016 
CONFIDENTIAL 
8 
1. 
INTRODUCTION AND OBJECTIVES OF ANALYSIS 
1.1. 
Introduction 
GWP42003-P is formulated from extracts prepared from Cannabis sativa L. plants that have a 
defined chemical profile and contain consistent levels of cannabidiol (CBD) as the principal 
phytocannabinoid. Clobazam (CLB) is a widely used antiepileptic drug (AED), prescribed with 
other medication(s) to control seizures in adults and children two years of age and older who 
have Lennox-Gastaut syndrome (a disorder that causes seizures and often developmental 
delays). CLB is in a class of medications called benzodiazepines. Similar to other 
benzodiazepine medications, CLB is metabolized by cytochrome P450 (CYP) enzymes (mainly 
in the liver). This metabolism results in the formation of an active metabolite N-
desmethylclobazam (N-CLB), amongst others.  
CBD can act as both a CYP inhibitor and inducer in human hepatocytes in vitro. Therefore, the 
potential for pharmacokinetic (PK) interactions with other drugs that are metabolized by CYP 
enzymes exists. The hypothesis is that the in vivo PK of CLB and its major metabolite (N-CLB) 
may be altered (increased or decreased) by the chronic administration of GWP42003-P. 
GWEP1428 is a phase 2, double-blind (DB), randomized, placebo-controlled study to 
investigate possible drug-drug interactions between CLB and CBD (GWP42003-P) in patients 
with epilepsy. 
 
1.2. 
Objectives of Statistical Analysis 
Objectives of the study 
Primary 
To determine whether GWP42003-P affects the PK profile of CLB and its primary metabolite 
N-CLB. 
Secondary 
To assess the safety and tolerability of GWP42003-P in the presence of CLB. 
Objectives of the statistical analysis plan  
This statistical analysis plan (SAP) is designed to outline the methods to be used in the analysis 
of study data in order to answer the study objective(s).  Populations for analysis, data handling 
rules, statistical methods, and formats for data presentation are provided.  The statistical 
analyses and summary tabulations described in this SAP will provide the basis for the results 
sections of the clinical study report (CSR) for this study. 
This SAP covers the two analyses planned, at the end of the DB period and the end of the study 
(see 4.3). The SAP describes analyses planned for both periods. For the first analysis, at the end 
of the DB period, all data from post-DB period will be absent from the outputs.  
This SAP will also outline any differences in the currently planned analytical objectives relative 
to those planned in the study protocol. 
This SAP has been prepared in conjunction with the protocol version 04 (date: 04-February-
2016). 


GW Pharmaceuticals 
Protocol GWEP1428  
SAP version 1.0 - 23 SEP 2016 
CONFIDENTIAL 
9 
2. 
STUDY DESIGN 
2.1. 
Synopsis of Study Design 
This phase 2, placebo-controlled study consists of a 34-day, DB phase followed by an optional 
maximum one year open label extension (OLE). Patients will continue to take CLB as advised 
by their physician for the duration of the study. GWP42003-P/placebo will be taken twice daily 
immediately after their CLB dose. 
Patients will enter the study and begin a 10-day GWP42003-P or placebo titration phase. During 
this period patients will be up-titrated to a maintenance dose. Patients will continue to take this 
maintenance dose of GWP42003-P or placebo for 21 days (Days 12 to 32). 
Upon completion of the treatment period (Day 34) patients will be invited to receive 
GWP42003-P during the OLE phase. If a patient enters the OLE they will take GWP42003-P as 
advised by the investigator. If a patient chooses not to enter the OLE, and/or the investigator 
does not feel it is in their best interests, they will taper off their GWP42003-P/placebo treatment 
by reducing their maintenance dose by 10% per day until dosing has ceased. For those patients 
not entering the OLE, dosing will end on Day 43 and they will receive a telephone follow-up 
visit four weeks after the end of GWP42003-P/placebo dosing (Day 71). 
PK samples will be taken on two occasions during the blinded phase of the study: 
 Day 1/2 (Visit 2) before beginning of treatment (patients will be taking CLB only). 
 Day 33/34 (Visit 4) following 21 days of GWP42003-P or placebo maintenance (patients 
will be taking CLB and GWP42003-P or placebo). 
Ten samples will be taken during each PK assessment. PK samples should be taken at time 
points in respect to the morning dose of CLB. The time points are as follows: Pre-dose, 15min, 
30min, 1h, 1.5h, 2h, 4h, 6h, 12h and 24h. PK samples will be quantitatively analyzed for CLB, 
N-CLB, valproate (VPA), stiripentol (STP),  levetiracetam (LEV) and topiramate (TPM) at Visit 
2 and CLB, N-CLB, VPA, STP, LEV, TPM, CBD, CBD major metabolites, THC (9-
tetrahydrocannabinol) and THC major metabolites at Visit 4. 
Upon entry into the OLE, the dose of GWP42003-P and other AEDs may be adjusted up or 
down to a maximum of 30 mg/kg/day. The OLE will last for a maximum of one year or until 
marketing authorization is granted; whichever is earlier. 
Patients will be required to keep a paper diary to note the time and dose of IMP and CLB 
administration each morning and evening and to record any AEs that may occur whilst receiving 
IMP and any other medications. Patients will also be required to record the number and type of 
seizures for each day whilst on the study. 
Study schemas depicting the overall study design are presented in Figure 7-1 and Figure 7-2, 
Appendix 7.3.  
 
2.2. 
Randomization Methodology 
This is a DB study. Patients will be randomized in a 4:1 ratio to receive 20 mg/kg GWP42003-P 
or placebo.  
A total of 20 patients will be enrolled into the study.  


GW Pharmaceuticals 
Protocol GWEP1428  
SAP version 1.0 - 23 SEP 2016 
CONFIDENTIAL 
10 
2.3. 
Stopping Rules and Unblinding 
A patient’s treatment assignment must only be unblinded when knowledge of the treatment is 
essential to make a decision on the medical management of the patient. Unblinding for any other 
reason will be considered a protocol deviation. 
2.4. 
Study Procedures 
The schedule of assessments, as outlined in the study protocol, is provided in Table 1.


GW Pharmaceuticals 
Protocol GWEP1428  
SAP version 1.0 - 23 SEP 2016 
CONFIDENTIAL 
11 
Table 1 
Schedule of Assessments 
Visit Number 
Day 
(Visit Window) 
Visit 1 
Day -14 to -7 
 
Visit 2 
Day 1 
(+ 3 days) 
Visit 2 
Day 2 
 
Visit 3 
Day 12 
(+ 3 days) 
Visit 4 
Day 33 
(± 3 days) 
Visit 4 
Day 34 
 
Visit 5* 
End of Taper 
 
Visit 6* 
4wk SFU 
(± 3 days) 
Informed consent 
X 
 
 
 
 
 
 
 
Eligibility criteria 
X 
X 
 
 
 
 
 
 
Enrolment 
 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
Paper diary training 
X 
 
X 
 
 
 
 
 
Concomitant medications 
(including AEDs) 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
(including height and body 
weight)♥ 
X 
X 
X 
X 
X 
X 
X 
 
ECG 
X 
X 
 
X 
X 
 
X 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical laboratory blood 
sampling  
X 
X 
 
X 
X 
 
X 
 
Clinical laboratory urine 
sampling (dipstick urinalysis) 
X 
X 
 
X 
X 
 
X 
 
THC test 
X 
 
 
 
 
 
 
 
Alcohol Test 
X 
X 
 
 
X 
 
 
 


GW Pharmaceuticals 
Protocol GWEP1428  
SAP version 1.0 - 23 SEP 2016 
CONFIDENTIAL 
12 
Visit Number 
Day 
(Visit Window) 
Visit 1 
Day -14 to -7 
 
Visit 2 
Day 1 
(+ 3 days) 
Visit 2 
Day 2 
 
Visit 3 
Day 12 
(+ 3 days) 
Visit 4 
Day 33 
(± 3 days) 
Visit 4 
Day 34 
 
Visit 5* 
End of Taper 
 
Visit 6* 
4wk SFU 
(± 3 days) 
Pregnancy test (if 
appropriate) 
X 
 
 
 
 
 
 
 
Pharmacokinetic blood 
sampling**  
 
X 
X 
 
X 
X 
 
 
Sample for Genetic 
Testing*** 
 
X 
 
 
 
 
 
 
C-SSRS 
X 
X 
 
X 
X 
 
X 
 
Patient diary review 
(seizures, AE information, 
concomitant AEDs, rescue 
medication, IMP dosing) 
 
X 
 
X 
X 
 
X 
 
IMP dispensing 
 
 
X 
 
 
X 
 
 
Collection of IMP 
 
 
 
X 
X 
 
X 
 
IMP compliance review 
 
 
 
X 
X 
 
X 
 
Study Medication Use and 
Behaviour Survey 
 
 
 
 
 
 
X 
 
* Patients not entering the OLE 
**PK Sampling time points are as follows: Pre-dose and 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 12 hours and 24 hours after 
dosing. For the second PK visit the patient should take the GWP42003-P/placebo immediately after their daily dose of CLB. 
*** Samples for genetic testing will only be taken if additional consent is obtained. 
♥ Patients height measured at Visit 1 only. 
 
 


GW Pharmaceuticals 
Protocol GWEP1428  
SAP version 1.0 - 23 SEP 2016 
CONFIDENTIAL 
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Open Label Extension Schedule of Assessments 
Visit Number 
Day 
(Visit Window) 
Visit 5 
2 Weeks 
(± 3 days) 
Visit 6 
1 Month 
(± 3 days) 
Visit 7 
2 Months 
 (± 3 days) 
Visit 8 
3 Months 
(± 7 days) 
Visit 9 
6 Months 
 (± 7 days) 
Visit 10 
9 Months 
(± 7 days) 
Visit 11 
12 Months 
 (± 7 days) 
Visit 12 
End of 
Taper 
Visit 13 
4wk SFU 
(± 3 days) 
Paper diary training 
 
 
 
 
 
 
 
 
 
Concomitant medications 
(including AEDs) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
(including weight) 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECG 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical laboratory blood 
sampling  
X 
X 
X 
X 
X 
X 
X 
X 
 
Clinical laboratory urine 
sampling (dipstick urinalysis) 
X 
X 
X 
X 
X 
X 
X 
X 
 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
X 
 
Patient diary review 
(seizures, AE information, 
concomitant AEDs, rescue 
medication, IMP dosing) 
X 
X 
X 
X 
X 
X 
X 
X 
 
IMP dispensing 
X 
X 
X 
X 
X 
X 
X 
 
 
Collection of IMP 
X 
X 
X 
X 
X 
X 
X 
X 
 
IMP compliance review 
X 
X 
X 
X 
X 
X 
X 
X 
 
Study Medication Use and 
Behaviour Survey 
 
 
 
 
 
 
 
X 
 


GW Pharmaceuticals 
Protocol GWEP1428  
SAP version 1.0 - 23 SEP 2016 
CONFIDENTIAL 
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2.5. 
Efficacy, Pharmacokinetic and Safety Variables 
Primary Endpoint(s) 
The primary endpoints of the study are the PK parameters of the following analytes: 
 CLB 
 N-CLB 
 CBD 
 CBD major metabolites 
 
Blood samples will be collected as outlined in Table 1. The PK parameters will be determined 
as outlined in Table 2.  
Table 2 
Pharmacokinetic parameters 
PK parameters 
Description 
Cmax 
Maximum measured plasma concentration 
tmax 
Time to the maximum measured plasma concentration 
AUC(0–∞) 
Area under the concentration time curve from zero to infinity with 
extrapolation of the terminal phase 
AUC(0–t) 
The area under the plasma concentration versus time curve, from time 
zero to ‘t’ (where t = the final time of positive detection) as calculated by 
the linear trapezoidal method 
t½ 
Terminal half-life 
  
Secondary Endpoint(s) 
To assess the safety and tolerability of GWP42003-P compared with placebo when taken in 
combination with CLB. Safety and tolerability will be assessed using the following parameters: 
 Adverse Events (AEs) 
 12-lead electrocardiogram (ECG) 
 Clinical laboratory parameters (clinical chemistry, hematology and urinalysis) 
 Vital signs 
 Columbia-Suicide Severity Rating Scale (C-SSRS) 
 Seizure frequency 
 Abuse liability 
 CYP2C19 and CYP3A4 patient genotype analysis 
PK parameters (Cmax, tmax, AUC(0–∞), AUC(0–t), t½) of the following analytes: 
 THC 
 THC major metabolites 


GW Pharmaceuticals 
Protocol GWEP1428  
SAP version 1.0 - 23 SEP 2016 
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3. 
PATIENT POPULATIONS 
3.1. 
Population Definitions 
The following patient populations will be evaluated and used for presentation and analysis of 
the data: 
Screened Population 
All patients enrolled in the study (with an assigned patient number), irrespective of whether the 
patient completed the screening period or not, or was a screening failure. 
The Screened Population is the primary analysis set for disposition. 
Safety Population 
All patients enrolled in the study who are treated and receive at least one dose of IMP will be 
included. 
The Safety Population is the primary analysis set for all safety endpoints reported during the DB 
phase of the study. Analyses are done using actual treatment received (placebo or GWP42003-
P) and not randomized treatment. 
Pharmacokinetic Population 
All patients enrolled in the study who are treated and receive at least one dose of IMP 
(GWP42003-P or placebo) and who provide some on-treatment data will be included. On-
treatment data is defined as sufficient PK concentration data to derive PK parameters at day 1/2 
(visit 2) and day 33/34 (visit 4). 
The PK population is the primary analysis set for all PK endpoints. 
Open Label Extension Population 
The OLE population includes all patients enrolled in the extension phase of the study who took 
at least one dose of IMP from Visit 4 (Day 34) onwards. The OLE population will be used to 
provide long-term safety summaries of IMP use. Patients will be analyzed according to the 
treatment they actually received during the DB treatment period. 
The analysis sets to be used for analyses are described in the table below. All listings will be 
presented using the screened population with flags indicating inclusion in other populations. 
 
Analyses 
Screened  
Pharmacokinetic 
(Double-Blind) 
Safety 
(Double-
Blind) 
Open-
Label 
Extension 
Patient Disposition  
 
 
 
 
Demographics 
 
 
 
 
Baseline (Prior 
Medications and 
Medical History) 
 
 
 
 
Compliance and 
 
 
 
 


GW Pharmaceuticals 
Protocol GWEP1428  
SAP version 1.0 - 23 SEP 2016 
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Exposure 
Pharmacokinetics 
 
 
 
 
Adverse Events 
(AEs) and Serious 
Adverse Events 
(SAEs) 
 
 
 
 
Laboratory 
Parameters 
 
 
 
 
ECG 
 
 
 
 
Physical 
Examination 
 
 
 
 
Vital Signs 
 
 
 
 
Concomitant 
Medications 
 
 
 
 
C-SSRS 
 
 
 
 
Genotype 
 
 
 
 
Abuse liability 
 
 
 
 
Seizure Frequency  
 
 
 
 
 
3.2. 
Protocol Deviations/Violations 
The sponsor, or designee, will be responsible for producing the final protocol 
deviation/violation file (formatted as an Excel file or SAS dataset). This file will be finalized 
prior to hard database lock. 


GW Pharmaceuticals 
Protocol GWEP1428  
SAP version 1.0 - 23 SEP 2016 
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4. 
STATISTICAL METHODS 
4.1. 
Sample Size Justification 
A total of 20 patients will be enrolled in this study. There is no formal sample size. Calculation 
and analysis are descriptive only. 
4.2. 
General Statistical Methods and Data Handling 
General Methods 
All output will be incorporated into Word files, sorted and labeled according to the International 
Conference on Harmonisation (ICH) recommendations, and formatted to the appropriate page 
size(s). 
Tabulations will be produced for appropriate demographic, baseline, PK and safety parameters.  
For categorical variables, summary tabulations of the number and percentage within each 
category (with a category for missing data) of the parameter will be presented.  For continuous 
variables, the mean, median, standard deviation, Q1, Q3, minimum and maximum values will be 
presented.   
Summaries will be presented for data recorded pre-treatment, during the DB phase and during 
the OLE phase separately. Of note, tapering periods following DB or OLE are not included in 
the DB and OLE periods respectively, but as part of the safety follow-up. 
In general, summaries for the Safety and the OLE populations will be presented by treatment 
group from the DB phase (placebo and GWP42003-P).  
Listings will include all patients with flags for the populations and be sorted by actual treatment 
(normally randomized treatment), patient number, study period and time point (where 
applicable).  
Computing Environment 
All descriptive statistical analyses will be performed using SAS statistical software (Version 9.2 
or later), unless otherwise noted.  Medical History and AEs will be coded using Medical 
Dictionary for Regulatory Activities (MedDRA), Version 18.1.  Medications will be coded 
using World Health Organization (WHO) Drug Dictionary Enhanced, 01 June 2014.  
Versions of dictionaries will be indicated in the footnote of the relevant tables. 
Methods of Pooling Data 
Not applicable to the present study. 
Adjustments for Covariates 
No formal statistical analysis that adjusts for possible covariate effects is planned. 
Multiple Comparisons/Multiplicity 
Multiplicity is not of concern for this study with a descriptive interpretation. 
Withdrawals, Dropouts, Loss to Follow-up 
Patients who withdraw from the study will not to be replaced. 


GW Pharmaceuticals 
Protocol GWEP1428  
SAP version 1.0 - 23 SEP 2016 
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Missing, Unused, and Spurious Data 
In general, there will be no substitutions made to accommodate missing data points unless 
otherwise specified.  All data recorded on the CRF will be included in data listings that will 
accompany the clinical study report.   
Visit Windows 
No visit windows will be used. Unscheduled measurements will be included in the listings. With 
the exception of unscheduled measurements used for baseline, or unscheduled measurements 
used to define worst outcome within a time period, unscheduled measurements will be excluded 
from the descriptive statistics and statistical analysis. 
Actual dates and times will be used for PK analyses rather than nominal days and times. 
Handling of Partially Missing Dates  
For event dates relating to seizure information since diagnosis, history of epilepsy and prior 
AEDs, if the date is recorded as a complete date it will be used. If the date is recorded as an 
incomplete date, it will be imputed as follows: if the day and month are missing and the year is 
recorded, then the day and month are imputed to be 15 and June; if the day is missing and the 
month and year are recorded, then the day is imputed to be 15; if the day and year are recorded 
and the month is missing, then the month is imputed to be June. If the year is missing, then the 
date is left as missing. 
Estimation of other event dates, such as AEs start and stop dates is given in the applicable 
section below. 
Key Definitions 
Baseline measurements are defined as the last available measurements obtained during the 
screening period, prior to first IMP dose administration. 
DB period starts with the date/time of first dose (inclusive) and ends at the DB phase 
completion date or date of first dose in the OLE, whichever occurs later. 
The date of first dose in the OLE is the start of the OLE period which ends at the OLE phase 
completion date. 
For the purpose of study reporting, tapering period is considered as part of the safety follow-up.  
 
4.3. 
Interim Analyses 
The first analysis will be conducted at the end of the DB phase of the study. Final analysis will 
occur at the end of the study. Analysis may also be considered during the OLE phase, if long 
term data is required to support New Drug Application/Marketing Authorization Application 
submissions. 
4.4. 
Patient Disposition 
The number of patients enrolled by country and site will be summarized for the screened 
population. United Kingdom sites numbers are 
 other sites 
 are from Spain.  
PPD
PPD


GW Pharmaceuticals 
Protocol GWEP1428  
SAP version 1.0 - 23 SEP 2016 
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Patient disposition will be summarized overall and by treatment arm, for the screened 
population, including the following information: 
 Number of patients screened 
o Number of patients not randomized (screen failure) and reasons 
o Number of patients randomized 
o Number of patients randomized and treated 
 
 Number of patients who completed the DB period 
o Number of patients continuing in OLE period 
o Number of patients continuing to the taper period 
o Number of patients not continuing in OLE or Taper, and reasons 
 
 Number of patients who did not complete the DB period and reasons 
o Number of patients continuing in the taper period 
 Number of patients who completed the taper period 
 Number of patients who did not complete the taper period and reasons 
o Number of patients not continuing in the taper period 
 
 Number of patients that entered OLE period 
o Number of patients who completed the OLE period 
 Number of patients continuing to the taper period 
 Number of patients not continuing in taper period, and reasons 
 
o Number of patients who did not complete the OLE period and reasons 
 Number of patients continuing in the taper period 
 Number of patients who completed the taper period 
 Number of patients who did not complete the taper period and 
reasons 
The number of patients at each visit will be summarized. An overview of the number of patients 
included in each population together with reason for exclusion will be produced. 
A by-patient listing of study completion information, including the reason for premature study 
withdrawal, if applicable, will be presented. Information on informed consent for the study and 
genetic testing will also be included. 
Protocol deviations identified in the study will be listed, including violation from entry criteria 
(inclusion/exclusion criteria). No per-protocol population will be used in this analysis. 


GW Pharmaceuticals 
Protocol GWEP1428  
SAP version 1.0 - 23 SEP 2016 
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4.5. 
Demographic and Baseline Characteristics 
Demographic, prior medications, medical history and other baseline information will be 
summarized for the safety population using descriptive statistics.   
Data will also be provided in listings. 
Demographics 
Demographic characteristics will be summarized using the following variables:  
o 
Age at informed consent (years) 
o 
Sex: male, female  
o 
Race (CRF categories) 
o 
Height (cm) 
o 
Weight (kg) at Visit 1 
o 
Body Mass Index (BMI in kg/m2) at Visit 1 
 
Note that if weight is missing at Visit 1, the first available weight taken after is to be used. 
Age is derived as (date of informed consent – date of birth + 1)/365.25. 
BMI is derived as the weight (kg)/(height[m] × height[m]). 
 
Medical History 
Data collected as part of the following CRF pages will be listed: 
1. History of seizures no longer occurring (including also patient's age when seizure type 
last occurred) 
2. History of current seizures (including also patient's age at onset of seizure type) 
3. Electroencephalography (EEG) history 
4. Neuroimaging history 
5. Genetic testing history (including genetic testing informed consent) 
6. History of antiepileptic medications and therapies 
7. Non-epilepsy medical history 
The following variables, from the domain above, will be summarized in a baseline disease 
characteristics table: 
 Seizure type no longer occurring 
 Current seizure types 
 Number of patients who ever had abnormal EEG, and seizure type 
 Number of patients who ever had an abnormal neuroimaging test (regardless of 
neuroimaging method) 
 Number of patients who had genetic testing performed in the past 


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Number and percentages of patients having had at least one non-epilepsy medical history are 
presented by system organ class (SOC) and individual preferred term within each SOC. SOCs 
are sorted by descending order of frequency. If the frequencies of SOCs are the same, 
alphabetical order is used. The same rule applies for preferred terms within SOC.  
Previous use of cannabis will be summarized in a table including the following variables: 
previous use (Yes, No), Time since last use (in months, continuous and categorical [≤ 3 months; 
> 3 months]) and frequency (once per year, up to 12 times per year, more than 12 times per 
year). 
Time since last use (in months) is derived as the (date of informed consent – date of last use + 
1)/30.5. In order to flag potential deviation from exclusion criteria 8 (worst case approach), the 
following imputation is done in case of partial/missing date of last use, for patients that reported 
previous use of cannabis: 
 If the year is missing, the year of the informed consent is used. 
 If the month is missing: 
o If the year is the same as the year of informed consent, the month of informed 
consent is used. 
o If the year is prior to the year of informed consent, the month of December is 
used. 
 If the day is missing: 
o If the year and month are the same as the year and month of informed consent, 
the day of informed consent is used. 
o If the year is the same year of informed consent, but month is before the last day 
of the month is used. 
o If the year and month is prior to the year and month of informed consent, the last 
day of the month is used. 
 
Prior Medications 
See section 4.8 for a description of prior medications summaries.  
Other Baseline Characteristics 
Not applicable. 
 
4.6. 
Efficacy Evaluation 
Not applicable 


GW Pharmaceuticals 
Protocol GWEP1428  
SAP version 1.0 - 23 SEP 2016 
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4.7. 
Pharmacokinetic Evaluations 
PK analyses will be conducted using the PK Population. All PK tables, listings and figures from 
this sub-section will be presented by treatment group (GWP42003-P/Placebo). Subgroup 
analyses might be performed on an ad-hoc basis. 
The plasma concentration/time curves of CLB, N-CLB, VPA, STP, LEV and TPM will be 
assessed at Visit 2 (Day 1 and Day 2) and CLB, N-CLB, VPA, STP, LEV, TPM, CBD, CBD 
major metabolites, THC and THC major metabolites at Visit 4 (Day 33 and Day 34). Patients 
will be given their daily dose of CLB at a scheduled time during Visit 2 and Visit 4 and the 
GWP42003-P/placebo immediately afterwards (Visit 4 only) to facilitate the accurate timing of 
blood samples required for PK analysis.  
The PK assessments will therefore capture the following combinations of CLB and GWP42003-
P: 
 First PK Assessment: CLB only (Visit 2: Days 1 and 2) 
 Second PK Assessment: CLB and GWP42003-P/Placebo (Visit 4: Days 33 and 34) 
Blood samples will be taken at the following times: Pre-dose and, 15 minutes, 30 minutes, 
1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 12 hours and 24 hours after dosing. The timing of 
each PK sample will be relative to the morning dose of CLB. 
PK variables listed in Table 2 will be calculated using standard non-compartmental methods and 
provided by an external partner. 
Reporting of Pharmacokinetic Parameters (CLB/CBD/THC) 
Plasma Concentration 
Plasma concentrations of CLB, N-CLB, CBD, CBD major metabolites (6-OH-CBD, 7-COOH-
CBD and 7-OH-CBD), THC and THC major metabolites (11-OH-THC and 11-COOH-THC) 
will be displayed graphically, summarized and listed.  
Plasma concentration will be summarized by visit, for CLB, CBD, THC and their major 
metabolites. The following descriptive statistics will be presented for plasma concentrations 
obtained at each nominal time point: n (number of non-missing observations), arithmetic mean, 
SD, median, Q1, Q3, minimum, and maximum.  
Nominal sampling times will be used in the table summaries and figures of plasma 
concentrations. Figures will plot the mean concentration by treatment group and assessment 
time (4 lines, GWP42003-P/Placebo × First/Second PK assessment period). 
Handling of Values Below the LLOQ 
For descriptive statistics, values below the lower limit of quantification of the assay (LLOQ) 
will be set to LLOQ/2. 
All PK concentrations below the LLOQ will be labeled as such in the concentration data 
listings. Missing samples will be reported as no sample ("NS") and excluded from analysis.  


GW Pharmaceuticals 
Protocol GWEP1428  
SAP version 1.0 - 23 SEP 2016 
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PK parameters 
All PK parameters will be listed by patient and summarized by treatment group and PK 
assessment period. 
Statistical Analysis of Drug-Drug Interaction 
The following descriptive statistics will be presented in summary tables: n (number of non-
missing observations), arithmetic mean, median, Q1, Q3, minimum, maximum, geometric 
mean, geometric CV, where GCV%=SQRT(es²-1)*100 and s is the standard deviation of the 
log-transformed values. 
In order to assess whether the presence of CBD alters the PK profile of CLB (or N-CLB), a 
standard 90% confidence interval (CI) approach for the between time point ratios of geometric 
means of Cmax, AUC(0–t), and AUC(0–∞) will be carried on logarithmic scale using a linear mixed 
effect model. The no-effect boundary will be set between 0.5 and 2.0 and if the 90% CI for the 
ratio of the geometric means of a PK variable falls within the interval [0.5, 2.0], a lack of 
meaningful effect will be declared. 
Estimates will be back transformed to provide summaries on the original scale. 
The model will include a fixed effect term for PK assessment period. An unstructured 
covariance matrix will be used. Kenward and Roger's method will be used to calculate the 
denominator degrees of freedom for the fixed effects. 
The following SAS code can be used as reference: 
PROC MIXED; 
CLASS usubjid period; 
BY treatment; 
MODEL logvar= period /DDFM=KR; 
REPEATED / Subject=usubjid type=un; 
LSMEANS period / CL ALPHA=0.05; 
ESTIMATE 'difference'   period 1 -1   / CL ALPHA=0.1; 
RUN; 
Data will be examined for departures from the assumptions of the statistical model(s) as 
appropriate; e.g., heteroscedasticity, non-normality of the error terms. Distribution-free methods 
may be used if a serious departure from the assumptions of the model(s) is observed. 
For the descriptive statistics of PK parameters for Clobazam and N-desmethyl-Clobazam, Cmax 
and AUCs will be dose normalized as Cmax divided by the dose (expressed in mg/kg) and AUC 
divided by the dose. 
Reporting of Pharmacokinetic Parameters (Other Drugs) 
Plasma concentration and PK parameters for VPA, STP, LEV and TPM will be summarized 
descriptively similarly to CLB. However, the drug-drug interaction will not be formally 
assessed (PROC MIXED).  
The plasma concentrations and PK parameters will be summarized by treatment using the 
following drug categories and patients:  
 VPA alone vs. VPA + CBD for patients with at least one dose of VPA during DB period 


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 STP alone vs. STP + CBD for patients with at least one dose of STP during DB period 
 LEV alone vs. LEV + CBD for patients with at least one dose of LEV during DB period 
 TPM alone vs. TPM + CBD for patients with at least one dose of TPM during DB period 
 
4.8. 
Safety Analyses 
Safety analyses will be conducted using the Safety population for DB period and the OLE 
population for the extension period.   
Treatment Compliance and Extent of Treatment Exposure  
Treatment compliance and exposure to treatment will be summarized for each phase of the 
study separately.  
Compliance is taken from the CRF page IMP compliance review and reported by period as: 
 "Compliant": if, for all assessments done in the period: 
o The response to the question 'Did the patient comply with the dosing scheduled' 
is answered 'Yes' and, 
o The response to the question 'Does the actual IMP usage reflect the expected 
amount used as per the dosing scheduled' is answered 'Yes' and, 
o The response to the question 'Were there some signals of potential abuse since 
last visit' is answered 'No' 
 "Not compliant": if the response to the 2 first questions above was 'No' at least once or 
the response to the third question is 'Yes' at least once. 
 "Unknown" otherwise 
 
Duration of Treatment  
Duration on DB treatment is defined as the difference between the last dose (as reported in the 
CRF page End of DB study outcome) minus the date of first dose of study medication (as 
reported in the Study medication CRF page) +1. 
Similar definition is to be used for the duration of treatment in the taper and in the OLE periods. 
Treatment compliance and exposure will be summarized in a table. All IMP drug usage data 
will be listed (CRF page: Study Medication, IMP compliance review). 
 
Adverse Events 
AEs will be coded using the MedDRA (Version 18.1) and displayed in tables and listings using 
SOC and Preferred Term. 
Analyses of AEs will be performed for those events that are considered treatment emergent, 
where treatment emergent AE is defined as one that started, or worsened in severity or 
seriousness following the first dose of IMP. 
AE classification 


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AEs which occurred during the study will be classified into three periods: pre-study, DB phase 
emergent, and OLE phase emergent.  
The classification of each AE is performed by comparing the onset of the AE to drug intake as 
follows:  
 Pre-study: AE with onset prior to the first dose of the study, or if no dose is taken, or 
stop date is before first dose 
 Treatment-emergent: AE that occurred after the first dose or the same day as the first 
dose are considered treatment emergent AEs and further classified as: 
o DB phase emergent: if onset less than the first dose of the OLE period (if 
applicable).  
o OLE phase emergent: if onset greater than or equal to the first dose of OLE (if 
applicable). 
For patients who did not enter the OLE phase, AE can only be assigned to pre-study or DB 
periods.  
If the AE start date is missing or recorded as a partial date, the AE will be reported in the 
appropriate period using available start date information and stop date, if present. 
AEs are summarized by patient incidence rates. The number of patients reporting at least one 
AE will be provided i.e. a patient contributes only once to the count for a given AE (overall, 
SOC or preferred term). Summaries will be provided for each phase of the study separately on 
the safety population and the OLE population respectively. 
The following summaries will be produced: 
 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. 
In the tabulations by severity, each patient will contribute only once to each of the incidence 
rates by using the worse severity (within the period of interest). 
All AEs occurring on study will be listed in patient data listings. 
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 AE 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. 


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 Hallucinations (visual or auditory), dissociations, disorientation, agitation. 
 Disturbance in cognition, memory, or attention. 
 Drug abuse. 
 Drug withdrawal or drug withdrawal syndrome. 
 Addiction. 
 Overdose. 
 Misuse of IMP. 
 Thoughts of suicide, attempted suicide or suicide. 
 
Treatment-emergent AEs defined as “triggering events of interest” (see above) will also be 
tabulated and listed separately. 
 
Character Presentation of Event Dates in Listings/datasets 
The AE start/end date text (i.e., the character presentation) is the recorded AE start/end date if 
the AE start/end date is recorded as a complete date. If the AE start/end date is partially known, 
the partial date information that is available for the AE start/end day, start/end month, or the 
start/end year is used, where missing date parts are indicated with dashes (-). 
If the AE start/end date is completely unknown, the AE start/end date text is left blank. 
Note: within the dataset of adverse events, partial dates will be presented using the earliest start 
date possible and latest possible end date, with a flag detailing the level of imputation (day or 
month).  
  
Laboratory Data 
Clinical laboratory sample parameters are detailed in Table 3.  
Table 3 
Hematology, Biochemistry, Urinalysis and THC Screen 
Biochemistry 
(serum) 
Hematology 
(whole blood) 
Urinalysis 
(urine) 
Pregnancy 
Test 
THC screen 
(urine) 
Alanine aminotransferase  
Hematocrit 
Bilirubin 
Serum 
THC 
Albumin 
Hemoglobin 
Blood 
 
 
Alkaline phosphatase 
Mean cell volume 
Glucose 
 
 
Aspartate aminotransferase  
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 
 
 


GW Pharmaceuticals 
Protocol GWEP1428  
SAP version 1.0 - 23 SEP 2016 
CONFIDENTIAL 
27 
Table 3 
Hematology, Biochemistry, Urinalysis and THC Screen 
Biochemistry 
(serum) 
Hematology 
(whole blood) 
Urinalysis 
(urine) 
Pregnancy 
Test 
THC screen 
(urine) 
Glucose 
 
Urobilinogen 
 
 
HDL-cholesterol 
 
 
 
 
Potassium 
 
 
 
 
Prolactin 
 
 
 
 
Prothrombin time (plasma) 
 
 
 
 
Sodium 
 
 
 
 
Total bilirubin (TBL) 
 
 
 
 
Total protein 
 
 
 
 
Urea (BUN) 
 
 
 
 
Triglycerides 
 
 
 
 
Note: In addition, an alcohol test will be performed on Visit 1, Visit 2 and Visit 4 (refer to Table 1)  
 
Clinical laboratory values will be expressed using conventional SI units. 
The actual value and change from baseline to each on study evaluation will be summarized for 
biochemistry, hematology and urinalysis for the Safety (DB period) and the OLE (OLE period) 
populations. For all post-baseline time points, the original assessment for any given time point 
will be used in the data summaries.  In the event of repeat values, the last non-missing value per 
study day/time will be used.  
All other laboratory values (baseline pregnancy, baseline THC screen test, and alcohol test 
results at each time point) will be presented within the listing only.  
Categorical shift tables to all visits will also be presented, showing the numbers of patients with 
values outside the normal range for the Safety (DB period) and the OLE populations.  
All laboratory data will be provided in data listings. 
Vital Signs, Physical Examinations and Blood Pressure 
For vital signs (pulse rate, respiratory rate and temperature), physical examination (weight) and 
blood pressure, the actual value and change from baseline to each on study evaluation will be 
summarized for the Safety (DB period) and the OLE (OLE period) populations in one table. 
By-patient listings of measurements will be presented. 
12-lead Electrocardiogram 
ECG results and change from baseline will be summarized descriptively at each study visit. All 
ECG data for each patient will be provided in data listings. 
Concomitant Medications 
Concomitant AED (as reported in the Concomitant AED dosing CRF page) are summarized in a 
table and listing. 


GW Pharmaceuticals 
Protocol GWEP1428  
SAP version 1.0 - 23 SEP 2016 
CONFIDENTIAL 
28 
Prior and concomitant medications will be coded using the WHO Drug Dictionary Enhanced. 
Results will be tabulated for each period of use (see below) by Anatomic Therapeutic Class 
(ATC) level 2 and preferred term. 
The use of concomitant medications will be included in by-patient data listing. 
Medications taken during the study will be classified according to the start/end dates. 
Concomitant medications that were administered on or after the first study dose date or that 
were administered before the first study dose date and are ongoing are considered on treatment 
concomitant medications (other medications are considered prior medications) and further 
categorized as: 
 Baseline ongoing: A concomitant medication with a start date prior to the date of the first 
study dose date. 
 DB Treatment Period: A concomitant medication with a start/end date on or after the 
date of the first study dose date and with a start/end date before the start of OLE or with a 
start date before the date of the first study dose date and is ongoing. 
 Extension Phase: A concomitant medication with a start date on or after the start of OLE 
or with a start date before the start of OLE and an end date after the start of OLE or is 
ongoing. 
 
C-SSRS 
The Columbia–Suicide Severity Rating Scale (C-SSRS) is an assessment tool that evaluates 
suicidal ideation and behavior.  
The following outcomes are C-SSRS categories and have binary responses (yes/no).  
 Category 1 – Wish to be Dead 
 Category 2 – Non-specific Active Suicidal Thoughts 
 Category 3 – Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
 Category 4 – Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
 Category 5 – Active Suicidal Ideation with Specific Plan and Intent 
 Category 6 – Preparatory Acts or Behavior 
 Category 7 – Aborted Attempt 
 Category 8 – Interrupted Attempt 
 Category 9 – Actual Attempt (non-fatal) 
 Category 10 – Completed Suicide 
Self-injurious behavior without suicidal intent is also a C-SSRS outcome (although not suicide-
related) and has a binary response (yes/no).  
Suicidal ideation is defined as a 'yes' answer to any one of the five suicidal ideation questions 
(categories 1-5). 


GW Pharmaceuticals 
Protocol GWEP1428  
SAP version 1.0 - 23 SEP 2016 
CONFIDENTIAL 
29 
Suicidal behavior is defined as a 'yes' answer to any one of the five suicidal ideation questions 
(categories 6-10). 
Suicidal ideation or behavior is defined as a 'yes' answer to any one of the 10 categories. 
The 10 C-SSRS categories, Self-injurious behavior, Suicidal ideation, Suicidal behavior and 
Suicidal ideation or behavior will be summarized for each period separately. For each item and 
period, the number of patients with at least once a response 'yes' will be presented.  
 
Genotype 
A listing of available genotype analyses will be provided.  
 
Abuse liability 
The following listings will be provided:  
 Study Medication Use and Behavior Survey 
 Supplemental AE Form 
 Supplemental Drug Accountability Form 
 Site Classification Form 
 
Patient Diary  
Unless already listed elsewhere, data from patient diaries will be listed.  
 
Seizure Frequency 
Seizure frequency during a period is defined as the total number of seizures divided by the total 
number of reported days in the diary. Any intermittent missing data for the number of seizures 
arising from unreported days in diary will not be imputed. 
Summary statistics for the seizure frequency, absolute and percentage change from screening 
will be presented for the DB period only using the safety population. The number of patients 
experiencing percent changes >25% worsening, −25 to +25% no change, 25–50% improvement, 
50–75% improvement or >75% improvement in seizure frequency will also be displayed. 
Data from all periods will be listed. 


GW Pharmaceuticals 
Protocol GWEP1428  
SAP version 1.0 - 23 SEP 2016 
CONFIDENTIAL 
30 
5. 
CHANGES TO PLANNED ANALYSES 
As of this date, there have been no changes between the protocol-defined statistical analyses and 
those presented in this statistical plan. 


GW Pharmaceuticals 
Protocol GWEP1428  
SAP version 1.0 - 23 SEP 2016 
CONFIDENTIAL 
31 
6. 
REFERENCES 
Not Applicable 


GW Pharmaceuticals 
Protocol GWEP1428  
SAP version 1.0 - 23 SEP 2016 
CONFIDENTIAL 
32 
7. 
APPENDICES 
7.1. 
Statistical Tables to be Generated, CRF data 
This list is only indicative and might be modified. 
1. Subject disposition, visit 
attendance, protocol 
violations 
1.1 Patients screened by country and site 
 
Screened population 
1.2 Patient disposition 
 
Screened population 
1.3 Number of patients by visits 
 
Screened population 
2. Summary of analysis sets Screened population 
 
Screened population 
3. Summary of 
demographics 
Safety population 
 
Safety population 
4. Baseline disease 
characteristics 
4.1 Epilepsy characteristics 
 
Safety population 
4.2 Previous use of cannabis 
 
Safety population 
5. Non-epilepsy medical 
history 
 
 
Safety population 
6. Concomitant medications 6.1 Medications ongoing at baseline 
 
Safety population 
6.2 Medications concomitant to DB treatment period 
 
Safety population 
7. Compliance 
 
 
Safety population 
8. PK 
Note: 2 tables per PK assessment (1 descriptive of PK concentration, 1 for analysis of PK 
parameters) 
PK population 
9. PD 
NA 
 
 
10. Exposure 
 
 
Safety population 
11. Adverse events 
11.1 Treatment-emergent AEs 
 
Safety population 
11.2 Treatment-emergent related Aes 
 
Safety population 
11.3 Treatment-emergent AEs by maximum severity 
 
Safety population 
12. Serious and other 
significant adverse events  
11.4 Treatment-emergent SAEs 
 
Safety population 
11.5 Treatment-emergent related SAEs 
 
Safety population 
11.6 Treatment-emergent AEs reported as leading to 
permanent cessation of study treatment 
 
Safety population 
11.7 All fatal AEs 
 
Safety population 
11.8 Triggering adverse events 
 
Safety population 
13. Laboratory evaluations  13.1 Biochemistry 
13.1.1 Values and changes by visit 
Safety population 
13.1.2 Shift based on reference ranges Safety population 
13.1.3 Shift based on toxicity limits 
Safety population 
13.2 Hematology 
13.1.1 Values and changes by visit 
Safety population 
13.1.2 Shift based on reference ranges Safety population 
13.1.3 Shift based on toxicity limits 
Safety population 
13.3 Urinalysis 
13.1.1 Values and changes by visit 
Safety population 
13.1.2 Shift based on reference ranges Safety population 


GW Pharmaceuticals 
Protocol GWEP1428  
SAP version 1.0 - 23 SEP 2016 
CONFIDENTIAL 
33 
14. Vital signs, other 
physical findings and other 
observations related to 
safety 
14.1 Vital signs 
14.1.1 Value by visit 
Safety population 
14.1.2 Change by visit 
Safety population 
14.2 ECG 
14.2.1 Value by visit 
Safety population 
14.2.2 Change by visit 
Safety population 
14.3 C-SSRS 
Safety population 
 
14.4 Seizure data 
Safety population 
 
 
 
 
 
 
 
 
 


GW Pharmaceuticals 
Protocol GWEP1428  
SAP version 1.0 - 23 SEP 2016 
CONFIDENTIAL 
34 
 
7.2. 
Toxicity criteria for laboratory parameters 
The toxicity criteria that will be used to identify abnormal laboratory parameters are presented in Table 4 and Table 5. 
Table 4 
Toxicity Criteria for Biochemistry Parameters 
Parameter 
Toxicity Decrease 
Toxicity Increase 
Chloride 
0.96xLL 
1.04xUL 
Calcium 
0.89xLL 
1.16xUL 
Sodium 
0.96xLL 
1.04xUL 
Potassium 
0.90xLL 
1.10xUL 
Glucose (mmol/L) 
3.2 
16 
Phosphate 
0.79xLL 
 
Cholesterol 
0.85xLL 
1.6xUL 
ASAT (SGOT) 
 
2.6xUL 
ALAT (SGPT) 
 
2.6xUL 
Lactate Dehydrogenase (LDH) 
 
2.6xUL 
Alkaline phosphatase 
 
2.6xUL 
Gamma GT 
 
2.6xUL 
Bilirubin 
 
1.26xUL 
Albumin 
0.84xLL 
 
Total protein 
0.84xLL 
1.16xUL 
Urea 
 
2.6xUL 
Blood urea nitrogen (BUN) 
 
2.6xUL 
Creatinine 
 
2.6xUL 
Uric acid 
 
1.16xUL 
UL = upper limit of reference range 
LL = lower limit of reference range 
 
 
 
 
 
 
 
 


GW Pharmaceuticals 
Protocol GWEP1428  
SAP version 1.0 - 23 SEP 2016 
CONFIDENTIAL 
35 
 
 
 
Table 5 
Toxicity Criteria for Hematology Parameters 
Parameter 
Toxicity Decrease 
Toxicity Increase 
Hemoglobin (g/dL) 
9.4 
 
Hematocrit (%) 
28 
 
Red cell count 
0.84xLL 
 
Mean corpuscular volume 
0.84xLL 
1.11xUL 
Mean corpuscular hemoglobin 
0.84xLL 
 
Mean corpuscular hemoglobin concentration 
0.84xLL 
 
Platelets (x10^9/L) 
74 
 
Prothrombin time 
 
>1.5xUL 
Prothrombin ratio 
 
>1.5xUL 
Total white blood cell count (x10^9/L) 
2.9 
21 
Total neutrophil count (x10^9/L) 
1.36 
14.7 
Segmented neutrophil count (x10^9/L) 
0.75 
12.3 
Eosinophils (x10^9/L) 
 
1.5 
Basophils (x10^9/L) 
 
0.31 
Monocytes (x10^9/L) 
 
2.1 
Lymphocytes (x10^9/L) for patients <18 years 
(auto hematology) 
1.0 
 
Lymphocytes (x10^9/L) for patients <18 years 
(manual hematology) 
0.2 
 
Lymphocytes (x10^9/L) for patients ≥18 years 
0.2 
 
Promyelocytes 
 
1.1 
Metamyelocytes (x10^9/L) 
 
1.1 
Myclocytes (x10^9/L) 
 
1.1 
UL = upper limit of reference range 
LL = lower limit of reference range 
 
 


GW Pharmaceuticals 
Protocol GWEP1428  
SAP version 1.0 - 23 SEP 2016 
CONFIDENTIAL 
36 
7.3. 
Study Design 
Figure 7-1 
Study Design and Treatment Schema (first part) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10 Day 
T
Patients not 
entering the 
OLE 
21 Day 
Maintenance 
28 days 
S 
C 
R 
E 
E 
N 
I 
N 
G 
E 
N 
R 
O 
L 
L 
M 
E 
N 
T 
E 
N 
D 
  
O 
F 
  
B 
L 
I 
N 
D 
E 
D 
  
T 
R 
E 
A 
T 
M 
E 
N 
T 
Visit 1 
Day -14  
to -7 
Visit 2 
Day 1/2 
(+3 d) 
Visit 4 
Day 33/34 
(±3 d) 
E 
N 
D 
  
O 
F 
  
T 
A 
P 
E 
R 
Patients entering the OLE 
S 
A 
F 
E 
T 
Y 
  
F 
O 
L 
L 
O 
W 
  
U 
P 
10 Day 
Up-
Titration 
Visit 5 
Day 43 
Visit 6 
Day 71 
28 day FU 
(±3 d) 
7-14 days 
31 days 
10 days 
Placebo  
N=4 
GWP42003-P Oral 
Solution 
(100 mg/mL bd) 
N=16 
Visit 3 
Day 12 
(+3 d) 


GW Pharmaceuticals 
Protocol GWEP1428  
SAP version 1.0 - 23 SEP 2016 
CONFIDENTIAL 
37 
Figure 7-2 
Study Design and Treatment Schema (second part) 
 
 
 
 
 
 
Patients  
entering  
from 
 the  
blinded 
phase 
Visit 5 OLE 
2 weeks 
(±3 d) 
Visit 7 OLE 
2 months 
(±3 d) 
Visit 6 OLE 
1 month 
(±3 d) 
Visit 8 OLE 
3 months 
(±7 d) 
Visit 9 OLE 
6 months 
(±7 d) 
Visit 11 OLE 
12 months 
(±7 d) 
Visit 10 OLE 
9 months 
(±7 d) 
Visit 12 OLE 
 
E 
N 
D 
  
O 
F 
  
T 
A 
P 
E 
R 
Visit 13 OLE 
28 day FU 
(±3 d) 
S 
A 
F 
E 
T 
Y 
 
F 
O 
L 
L 
O 
W 
 
U 
P 
Open Label Extension Phase: 
GWP42003-P Oral Solution 
(100 mg/mL bd) 
10 
Day 
Taper 
2 weeks 
from V4 
2 weeks 
1 month 
1 month 
3 months 
3 months 
3 months 
10 days 
28 days 


GW Pharmaceuticals 
Protocol GWEP1428  
SAP version 1.0 - 23 SEP 2016 
CONFIDENTIAL 
38 
7.4. 
Examples of outputs 
 
1. Subject disposition, visit attendance, protocol violations  
1.1 Disposition by periods  
Screened population  
Country  
Site 
Placebo       
N=xx 
Subjects  
n    % 
GWP         
N=x 
Subjects  
n    % 
All patients   
N=xx 
Subjects  
n    % 
 
All countries 
      xx (xxx.x) 
       x (xxx.x) 
      xx (xxx.x) 
 
Spain 
       x ( xx.x) 
       x ( xx.x) 
      xx ( xx.x) 
       
       x ( xx.x) 
       x ( xx.x) 
       x ( xx.x) 
       
       x ( xx.x) 
       x ( xx.x) 
       x ( xx.x) 
 
United Kingdom 
       x ( xx.x) 
       x ( xx.x) 
      xx ( xx.x) 
       
       x ( xx.x) 
       x ( xx.x) 
       x ( xx.x) 
       
       x (  x.x) 
 
       x (  x.x) 
       
       x ( xx.x) 
       x ( xx.x) 
       x ( xx.x) 
       
       x ( xx.x) 
       x ( xx.x) 
       x ( xx.x) 
Output ID: T-DISP1 DDMMMYY 
Z:\GWPHARMA\GWEP1428\DB\BIOSTATISTICS\PRODUCTION\TABLES\PGM\T-DISP1.sas 
                                                                                     
         Page 1 of 1 
 
 
 
 
 
 
 
 
 
 
 
PPD
PPD


GW Pharmaceuticals 
Protocol GWEP1428  
SAP version 1.0 - 23 SEP 2016 
CONFIDENTIAL 
39 
1. Subject disposition, visit attendance, protocol violations  
1.1 Disposition by periods  
Screened population  
Statistics 
Placebo 
 (N=xx)  
 n    (%) 
GWP 
 (N=xx)  
 n    (%) 
Total 
 (N=xx)  
 n    (%) 
 
Screened subjects 
  xx (xxx.x) 
   x (xxx.x) 
  xx (xxx.x) 
 
  Screen failure 
 
   x ( xx.x) 
   x (  x.x) 
     -> Withdrew Consent 
 WAS AFRAID OF POSSIBLE SIDE 
EFFECTS.) 
 
   x ( xx.x) 
   x (  x.x) 
 
  Randomized 
  xx (xxx.x) 
   x ( xx.x) 
  xx ( xx.x) 
 
  Randomized and treated subjects 
  xx (xxx.x) 
   x ( xx.x) 
  xx ( xx.x) 
 
 
 
 
     Completed the DB period 
  xx ( xx.x) 
   x (xxx.x) 
  xx ( xx.x) 
     Did not complete the DB period 
   x ( xx.x) 
 
   x ( xx.x) 
       Patient,legal representative withdrew consent to 
participate 
   x ( xx.x) 
 
   x ( xx.x) 
       Other 
   x ( xx.x) 
 
   x ( xx.x) 
Output ID: T-DISP2 DDMMMYY 
Z:\GWPHARMA\GWEP1428\DB\BIOSTATISTICS\PRODUCTION\TABLES\PGM\T-DISP2.sas 
                                                                                                                 
     Page 1 of 1 
 
 
 
 
 
 
 
 
 
 
 
PPD


GW Pharmaceuticals 
Protocol GWEP1428  
SAP version 1.0 - 23 SEP 2016 
CONFIDENTIAL 
40 
 
1. Subject disposition, visit attendance, protocol violations  
1.1 Number of patients by visits  
Screened population  
Parameters 
Placebo 
 (N=xx)  
 n    (%) 
GWEP 
 (N=x)  
 n    (%) 
Total 
 (N=xx)  
 n    (%) 
 
V1 (Day -14 to -7) 
  xx (xxx.x) 
   x (xxx.x) 
  xx (xxx.x) 
 
V2 (Day 1) 
  xx (xxx.x) 
   x ( xx.x) 
  xx ( xx.x) 
 
V2 (Day 2) 
  xx (xxx.x) 
   x ( xx.x) 
  xx ( xx.x) 
 
V3 (Day 12) 
  xx (xxx.x) 
   x ( xx.x) 
  xx ( xx.x) 
 
V4 (Day 33) 
  xx (xxx.x) 
   x ( xx.x) 
  xx ( xx.x) 
 
V4 (Day 34) 
  xx ( xx.x) 
   x ( xx.x) 
  xx ( xx.x) 
 
V5 DB (End of Taper after DB 
period) 
 
 
 
 
V6 DB (SFU after DB period) 
   x ( xx.x) 
 
   x (  x.x) 
 
V5 (OLE Week 2) 
   x ( xx.x) 
   x ( xx.x) 
   x ( xx.x) 
 
V6 (OLE Month 1) 
   x (  x.x) 
 
   x (  x.x) 
 
V7 (OLE Month 2) 
   x (  x.x) 
   x ( xx.x) 
   x (  x.x) 
 
V8 (OLE Month 3) 
 
 
 
 
V9 (OLE Month 6) 
 
 
 
 
V10 (OLE Month 9) 
 
 
 
 
V11 (OLE Month 12) 
   x (  x.x) 
 
   x (  x.x) 
Output ID: T-DISP3 DDMMMYY 
Z:\GWPHARMA\GWEP1428\DB\BIOSTATISTICS\PRODUCTION\TABLES\PGM\T-DISP3.sas 
                                                                                               
         Page 1 of 2 
 


GW Pharmaceuticals 
Protocol GWEP1428  
SAP version 1.0 - 23 SEP 2016 
CONFIDENTIAL 
41 
 
1. Subject disposition, visit attendance, protocol violations  
1.1 Number of patients by visits  
Screened population  
Parameters 
Placebo 
 (N=xx)  
 n    (%) 
GWEP 
 (N=x)  
 n    (%) 
Total 
 (N=xx)  
 n    (%) 
 
V12 (End of Taper after OLE period) 
 
 
 
 
V13 (SFU after OLE period) 
 
 
 
Output ID: T-DISP3 DDMMMYY 
Z:\GWPHARMA\GWEP1428\DB\BIOSTATISTICS\PRODUCTION\TABLES\PGM\T-DISP3.sas 
                                                                                               
         Page 2 of 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


GW Pharmaceuticals 
Protocol GWEP1428  
SAP version 1.0 - 23 SEP 2016 
CONFIDENTIAL 
42 
 
 
2. Summary of analysis sets  
Screened population  
Statistics 
Placebo 
 (N=xx)  
 n    (%) 
GWEP 
 (N=x)  
 n    (%) 
Total 
 (N=xx)  
 n    (%) 
 
Screened 
  xx (xxx.x) 
   x (xxx.x) 
  xx (xxx.x) 
 
Safety Population 
  xx (xxx.x) 
   x ( xx.x) 
  xx ( xx.x) 
 
Pharmacokinetic Population 
 
 
 
 
OLE Population 
   x ( xx.x) 
   x ( xx.x) 
  xx ( xx.x) 
Output ID: T-DISP4 DDMMMYY 
Z:\GWPHARMA\GWEP1428\DB\BIOSTATISTICS\PRODUCTION\TABLES\PGM\T-DISP4.sas 
                                                                                               
         Page 1 of 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


GW Pharmaceuticals 
Protocol GWEP1428  
SAP version 1.0 - 23 SEP 2016 
CONFIDENTIAL 
43 
 
 
3. Summary of demographics  
Safety population  
Parameters 
Statistics 
Placebo 
 (N=xx) 
GWEP 
 (N=x) 
Total 
 (N=xx) 
Age 
N (missing) 
xx (x) 
x (x) 
xx (x) 
Mean (SD) 
xx.xx (x.xx) 
xx.xx (x.xx) 
xx.xx (x.xx) 
Median 
xx.xx 
xx.xx 
xx.xx 
Q1 ; Q3 
xx.xx ; xx.xx 
xx.xx ; xx.xx 
xx.xx ; xx.xx 
Min ; Max 
xx.x ; xx.x 
xx.x ; xx.x 
xx.x ; xx.x 
Sex 
N (missing) 
xx (x) 
x (x) 
xx (x) 
Male 
   x ( xx.x) 
   x ( xx.x) 
  xx ( xx.x) 
Female 
   x ( xx.x) 
   x ( xx.x) 
  xx ( xx.x) 
Race 
N (missing) 
xx (x) 
x (x) 
xx (x) 
White 
  xx ( xx.x) 
   x (xxx.x) 
  xx ( xx.x) 
Other 
   x (  x.x) 
 
   x (  x.x) 
Height (cm) 
N (missing) 
xx (x) 
x (x) 
xx (x) 
Mean (SD) 
xxx.xx (xx.xx) 
xxx.xx (x.xx) 
xxx.xx (x.xx) 
Median 
xxx.xx 
xxx.xx 
xxx.xx 
Q1 ; Q3 
xxx.xx ; xxx.xx 
xxx.xx ; xxx.xx 
xxx.xx ; xxx.xx 
Min ; Max 
xxx.x ; xxx.x 
xxx.x ; xxx.x 
xxx.x ; xxx.x 
Weight (kg) at Visit 
1 
N (missing) 
xx (x) 
x (x) 
xx (x) 
Mean (SD) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
Median 
xx.xx 
xx.xx 
xx.xx 
Q1 ; Q3 
xx.xx ;  xx.xx 
xx.xx ;  xx.xx 
xx.xx ;  xx.xx 
Min ; Max 
xx.x ; xxx.x 
xx.x ; xxx.x 
xx.x ; xxx.x 
Output ID: T-DM DDMMMYY 
Z:\GWPHARMA\GWEP1428\DB\BIOSTATISTICS\PRODUCTION\TABLES\PGM\T-DM.sas 
                                                                                        Page 1 of 2 
 
 
 
 
 


GW Pharmaceuticals 
Protocol GWEP1428  
SAP version 1.0 - 23 SEP 2016 
CONFIDENTIAL 
44 
 
3. Summary of demographics  
Safety population  
Parameters 
Statistics 
Placebo 
 (N=xx) 
GWEP 
 (N=x) 
Total 
 (N=xx) 
Body Mass Index 
(kg/m2) at Visit 1 
N (missing) 
xx (x) 
x (x) 
xx (x) 
Mean (SD) 
xx.xx (x.xx) 
xx.xx (x.xx) 
xx.xx (x.xx) 
Median 
xx.xx 
xx.xx 
xx.xx 
Q1 ; Q3 
xx.xx ; xx.xx 
xx.xx ; xx.xx 
xx.xx ; xx.xx 
Min ; Max 
xx.x ; xx.x 
xx.x ; xx.x 
xx.x ; xx.x 
Output ID: T-DM DDMMMYY 
Z:\GWPHARMA\GWEP1428\DB\BIOSTATISTICS\PRODUCTION\TABLES\PGM\T-DM.sas 
                                                                                        Page 2 of 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


GW Pharmaceuticals 
Protocol GWEP1428  
SAP version 1.0 - 23 SEP 2016 
CONFIDENTIAL 
45 
 
 
4. Baseline disease characteristics  
4.1 Epilepsy characteristics  
Safety population  
Statistics 
Placebo      
N=xx 
Subjects  
n    % 
GWEP        
N=x 
Subjects  
n    % 
All patients   
N=xx 
Subjects  
n    % 
Ever Had Abnormal EEG? ->Yes 
      xx ( xx.x)        x ( xx.x)       xx ( xx.x) 
Ever Had Abnormal Neuroimaging History? ->Yes 
       x ( xx.x)        x ( xx.x)        x ( xx.x) 
Ever Had Genetic Testing? ->Yes 
       x (  x.x)        x (  x.x)        x (  x.x) 
History Of Current Seizures 
      xx ( xx.x)        x ( xx.x)       xx ( xx.x) 
       Absence or Atypical absence 
       x (  x.x)        x ( xx.x)        x (  x.x) 
       Atonic 
       x (  x.x)        x (  x.x)        x (  x.x) 
       Complex Partial Seizure (Focal 
Dyscognitive) 
       x ( xx.x)        x ( xx.x)       xx ( xx.x) 
       Generalized Tonic Clonic Convulsion 
       x (  x.x)        x (  x.x)        x (  x.x) 
       Other 
       x (  x.x)        x ( xx.x)        x (  x.x) 
       Secondarily Generalized Tonic Clonic 
(Evolving to bilateral convulsive seizure from 
partial (focal) seizure) 
       x ( xx.x)        x (  x.x)        x ( xx.x) 
       Tonic 
       x (  x.x)        x (  x.x)        x (  x.x) 
History Of Seizures No Longer Occurring 
       x ( xx.x)        x (  x.x)        x ( xx.x) 
       Atonic 
       x (  x.x) 
 
       x (  x.x) 
       Complex Partial Seizure (Focal 
Dyscognitive) 
       x (  x.x) 
 
       x (  x.x) 
       Generalized Tonic Clonic Convulsion 
       x (  x.x) 
 
       x (  x.x) 
       Secondarily Generalized Tonic Clonic 
(Evolving to bilateral convulsive seizure from 
partial (focal) seizure) 
       x (  x.x)        x (  x.x)        x (  x.x) 
Output ID: T-EPIL DDMMMYY 
Z:\GWPHARMA\GWEP1428\DB\BIOSTATISTICS\PRODUCTION\TABLES\PGM\T-EPIL.sas 
                                                                                            Page 1 of 1 
 
 
 


GW Pharmaceuticals 
Protocol GWEP1428  
SAP version 1.0 - 23 SEP 2016 
CONFIDENTIAL 
46 
 
 
 
11. Adverse events  
11.1 Treatment-emergent AEs  
Safety population  
Statistics 
Placebo      
N=xx 
Subjects  
n    % 
GWEP        
N=x 
Subjects  
n    % 
All patients   
N=xx 
Subjects  
n    % 
Subject with at least one adverse event 
      xx ( xx.x)        x ( xx.x)       xx ( xx.x) 
Gastrointestinal disorders 
       x ( xx.x)        x ( xx.x)        x ( xx.x) 
       Diarrhoea 
       x ( xx.x)        x ( xx.x)        x ( xx.x) 
       Nausea 
       x ( xx.x)        x ( xx.x)        x ( xx.x) 
       Vomiting 
       x (  x.x)        x ( xx.x)        x ( xx.x) 
       Abdominal pain 
       x (  x.x) 
 
       x (  x.x) 
       Dyspepsia 
 
       x ( xx.x)        x (  x.x) 
Nervous system disorders 
       x ( xx.x)        x ( xx.x)        x ( xx.x) 
       Dizziness 
       x (  x.x)        x ( xx.x)        x ( xx.x) 
       Sedation 
       x (  x.x)        x ( xx.x)        x ( xx.x) 
       Somnolence 
       x (  x.x)        x ( xx.x)        x ( xx.x) 
       Aphasia 
 
       x ( xx.x)        x (  x.x) 
       Dysarthria 
 
       x ( xx.x)        x (  x.x) 
       Headache 
       x (  x.x) 
 
       x (  x.x) 
       Hypersomnia 
 
       x ( xx.x)        x (  x.x) 
       Lethargy 
       x (  x.x) 
 
       x (  x.x) 
       Memory impairment 
       x (  x.x) 
 
       x (  x.x) 
       Seizure cluster 
       x (  x.x) 
 
       x (  x.x) 
       Speech disorder 
 
       x ( xx.x)        x (  x.x) 
Skin and subcutaneous tissue disorders 
       x ( xx.x)        x ( xx.x)        x ( xx.x) 
       Dermatitis 
       x ( xx.x) 
 
       x ( xx.x) 
       Petechiae 
 
       x ( xx.x)        x (  x.x) 
       Rash 
 
       x ( xx.x)        x (  x.x) 
       Rash maculo-papular 
       x (  x.x) 
 
       x (  x.x) 
       Rash pruritic 
 
       x ( xx.x)        x (  x.x) 
Output ID: T-AE DDMMMYY 
Z:\GWPHARMA\GWEP1428\DB\BIOSTATISTICS\PRODUCTION\TABLES\PGM\T-AE.sas 
                                                                                           Page 1 of xx 


GW Pharmaceuticals 
Protocol GWEP1428  
SAP version 1.0 - 23 SEP 2016 
CONFIDENTIAL 
47 
 
 
 
14. Vital signs, other physical findings and other observations related to safety  
14.1 Vital signs  
14.1.1 Value by visit  
Safety population  
Parameter 
Visit 
Statistics 
Placebo 
 (N=xx)  
 n    (%) 
GWEP 
 (N=x)  
 n    (%) 
Total 
 (N=xx)  
 n    (%) 
 
VS/BP/PE 
indicative of 
medical 
condition? 
Anytime post 
baseline 
N 
xx 
x 
xx 
Yes 
 
   x ( xx.x) 
   x ( xx.x) 
No 
  xx (xxx.x) 
   x ( xx.x) 
  xx ( xx.x) 
 
Weight (kg) 
V1: Day -14 to -7 
N 
xx 
x 
xx 
Mean (SD) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
Median 
xx.xx 
xx.xx 
xx.xx 
Q1 ; Q3 
xx.xx ;  xx.xx 
xx.xx ;  xx.xx 
xx.xx ;  xx.xx 
Min ; Max 
xx.x ; xxx.x 
xx.x ; xxx.x 
xx.x ; xxx.x 
 
 
V2: Day 1 
N 
xx 
x 
xx 
Mean (SD) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
Median 
xx.xx 
xx.xx 
xx.xx 
Q1 ; Q3 
xx.xx ;  xx.xx 
xx.xx ;  xx.xx 
xx.xx ;  xx.xx 
Min ; Max 
xx.x ; xxx.x 
xx.x ; xxx.x 
xx.x ; xxx.x 
 
 
V2: Day 2 
N 
xx 
x 
xx 
Mean (SD) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
Median 
xx.xx 
xx.xx 
xx.xx 
Q1 ; Q3 
xx.xx ;  xx.xx 
xx.xx ;  xx.xx 
xx.xx ;  xx.xx 
Min ; Max 
xx.x ; xxx.x 
xx.x ; xxx.x 
xx.x ; xxx.x 
 
etc… 
etc… 
N 
xx 
x 
xx 
Mean (SD) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
Median 
xx.xx 
xx.xx 
xx.xx 
Q1 ; Q3 
xx.xx ;  xx.xx 
xx.xx ;  xx.xx 
xx.xx ;  xx.xx 
Min ; Max 
xx.x ; xxx.x 
xx.x ; xxx.x 
xx.x ; xxx.x 


GW Pharmaceuticals 
Protocol GWEP1428  
SAP version 1.0 - 23 SEP 2016 
CONFIDENTIAL 
48 
Parameter 
Visit 
Statistics 
Placebo 
 (N=xx)  
 n    (%) 
GWEP 
 (N=x)  
 n    (%) 
Total 
 (N=xx)  
 n    (%) 
VS=Vital Signs; BP=Blood Pressure; PE=Physical Examination 
Output ID: T-VS DDMMMYY 
Z:\GWPHARMA\GWEP1428\DB\BIOSTATISTICS\PRODUCTION\TABLES\PGM\T-VS.sas 
                                                                                           Page 1 of xx 
 


Data Management Plan 
Customer: GW Research Ltd 
Quanticate Project Number: Q_02553 
Protocol Number: GWEP1428                   Version 3.0 Approved 
Date:  01 Nov 2016 
 
ATTACHMENT NO.: CDM-ATT-008 VERSION: 6.0 
 
PAGE 1 OF 33 
COPYRIGHT © QUANTICATE LTD 
 
CONFIDENTIAL 
 
 
GWEP1428 
 
 
 
A PHASE 2, DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED STUDY TO INVESTIGATE 
POSSIBLE DRUG-DRUG INTERACTIONS BETWEEN CLOBAZAM AND CANNABIDIOL (GWP42003-P) 
 
DATA MANAGEMENT PLAN 
 
 
 
Author: 
 
Job Title: 
 
 
 
PPD
PPD


,. 
Data Management Plan 
Q Quanticate 
Customer: GW Research Ltd 
Protocol Number: GWEP1428 
Version 3.0 Approved 
Quanticate Project Number: 0_02553 
Data: 01 Nov 2016 
1 
Approval Form 
QUANTlCATE AUTHOR 
Name: 
 
Position: 
 
QUANTICATE REVIEW 
Name: 
 
Position: 
 
QUANTICATE REVIEW 
Name: 
 
Position: 
 
Signature 
GW RESEARCH LTD APPROVAL 
Name: 
 
Position: 
 
GW RESEARCH LTD APPROVAL 
Name: 
 
Position: 
 
ATTACHMENTNO.: COM-ATT-008VERSION:6.0 
COPYRIGHT C QUANnCATE LTD 
OZ NOV :2-blb 
Date 
Ci KJ::;/ CJOib ' 
Date 
Date 
Date 
o · z. I\A'2J rz O\ -6 
PAGE20F33 
CONFIDENTIAL 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


Data Management Plan 
Customer: GW Research Ltd 
Quanticate Project Number: Q_02553 
Protocol Number: GWEP1428                   Version 3.0 Approved 
Date:  01 Nov 2016 
 
ATTACHMENT NO.: CDM-ATT-008 VERSION: 6.0 
 
PAGE 3 OF 33 
COPYRIGHT © QUANTICATE LTD 
 
CONFIDENTIAL 
 
2 
Table of Contents 
1 
Approval Form.............................................................................................................. 2 
2 
Table of Contents ......................................................................................................... 3 
3 
Version Controlled Document Log .............................................................................. 5 
4 
Glossary of Abbreviations ............................................................................................ 5 
5 
Outline Description of the Protocol .............................................................................. 8 
5.1 
Distribution List ........................................................................................................ 8 
5.2 
Data Management Plan Objectives and Administration ......................................... 8 
5.3 
Project Outline ......................................................................................................... 9 
5.4 
Project Personnel .................................................................................................... 9 
6 
Scope of Work Defined Within the Data Management Plan ....................................... 9 
7 
Timelines ....................................................................................................................10 
8 
Project-Specific Guidelines for the Completion of Tasks ..........................................11 
8.1 
CRF Design ...........................................................................................................11 
8.2 
Database Design ...................................................................................................11 
8.3 
CRF Transport .......................................................................................................12 
8.4 
CRF Receipt ..........................................................................................................12 
8.5 
CRF Tracking ........................................................................................................13 
8.6 
Expected Pages ....................................................................................................15 
8.6.1 Blinded Phase: ..................................................................................................15 
8.6.2 Blinded Diary Pages: ........................................................................................16 
8.6.3 OLE Phase: .......................................................................................................16 
8.6.4 OLE Diary Pages: .............................................................................................16 
8.6.5 Questionnaires ..................................................................................................17 
8.6.6 Screen Failure Patients ....................................................................................17 
8.7 
CRF Storage ..........................................................................................................17 
8.8 
Data Entry and Verification ....................................................................................18 
8.8 
Data Validation ......................................................................................................19 
8.9 
Discrepancy Management ....................................................................................20 
8.10 Translation .............................................................................................................22 
8.11 Data Editing ...........................................................................................................22 
8.12 Protocol Deviations................................................................................................23 
8.13 Laboratory/ External IWRS and Quality of Life Data Handling .............................23 
8.13.1 External Vendors ..............................................................................................24 
8.14 Medical Coding ......................................................................................................26 
8.15 Serious Adverse Event/ Reconciliation .................................................................27 
8.16 File Notes ...............................................................................................................28 
8.17 Investigator Comments .........................................................................................28 
8.18 Quality Control .......................................................................................................28 
8.19 Database Lock.......................................................................................................29 
8.20 Database Unlock ...................................................................................................29 
8.21 Export ....................................................................................................................30 


Data Management Plan 
Customer: GW Research Ltd 
Quanticate Project Number: Q_02553 
Protocol Number: GWEP1428                   Version 3.0 Approved 
Date:  01 Nov 2016 
 
ATTACHMENT NO.: CDM-ATT-008 VERSION: 6.0 
 
PAGE 4 OF 33 
COPYRIGHT © QUANTICATE LTD 
 
CONFIDENTIAL 
8.22 Screen Failures .....................................................................................................30 
8.23 Control of the DMP ................................................................................................31 
9 
Appendix 1 .................................................................................................................32 
9.1 
SOPs to be Followed.............................................................................................32 
9.1.1 Quanticate SOPs: .............................................................................................32 
 


Data Management Plan 
Customer: GW Research Ltd 
Quanticate Project Number: Q_02553 
Protocol Number: GWEP1428                   Version 3.0 Approved 
Date:  01 Nov 2016 
 
ATTACHMENT NO.: CDM-ATT-008 VERSION: 6.0 
 
PAGE 5 OF 33 
COPYRIGHT © QUANTICATE LTD 
 
CONFIDENTIAL 
 
3 
Version Controlled Document Log 
Effective Date 
Version 
Change 
29Feb2016 
Approved 1.0 
Approved Version 
20Sep2016 
Approved 2.0 
Personnel updates 
01Nov2016 
Approved 3.0 
Updated Section 8.9 Discrepancy Management 
 
4 
Glossary of Abbreviations 
ACRF 
Annotated Case Report Form 
AE  
Adverse Event 
AED 
Antiepileptic Drugs 
CAB 
Cognitive Assessment Battery 
CDASH 
Clinical Data Acquisition Standards Harmonization 
CDC 
Clinical Data Co-ordinator 
CDISC 
Clinical Data Interchange Standards Consortium 
CDM 
Clinical Data Management/Manager 
CGIC 
Caregiver Global Impression Of Change 
CGICSD 
Caregiver Global Impression Of Change in Seizure Duration 
CM  
Concomitant Medication 
CPM 
Clinical Project Manager 
CRA 
Clinical Research Associate 
CSR 
Clinical Study Report 
CRF 
Case Report Form 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CWS 
Cannabis Withdrawal Scale 
DBA 
Database Administrator 
DCF 
Data Clarification Form 
DCI 
Data Collection Instrument 
DEC 
Data Entry Clerk 


Data Management Plan 
Customer: GW Research Ltd 
Quanticate Project Number: Q_02553 
Protocol Number: GWEP1428                   Version 3.0 Approved 
Date:  01 Nov 2016 
 
ATTACHMENT NO.: CDM-ATT-008 VERSION: 6.0 
 
PAGE 6 OF 33 
COPYRIGHT © QUANTICATE LTD 
 
CONFIDENTIAL 
DEG 
Data Entry Guidelines 
DMP 
Data Management Plan 
DS 
Dravet Syndrome 
DSD 
Database Specification Document 
DSMC 
Data Safety Monitoring Committee 
DVG 
Discrete Value Groups 
DVP 
Data Validation Plan 
DVS 
Data Validation Specification 
EDTS 
Electronic Data Transfer Specifications 
FPFV 
First Patient First Visit 
GCP 
Good Clinical Practice 
GW 
GW Research Ltd 
HLGT 
Higher Level Group Term 
HLT 
Higher Level Term 
ICH 
International Conference on Harmonisation 
IMP 
Investigational Medicinal Product 
IS 
Information Systems 
IWRS 
Interactive Web Response System 
LCDM 
Lead Clinical Data Manager 
LLT 
Lowest Level Term 
MEDDRA 
Medical Dictionary for Regulatory Activities 
MH 
Medical History 
OC 
Oracle Clinical 
PCWS 
Pediatric Cannabis Withdrawal Scale 
PK 
Pharmacokinetics 
PDF 
Portable Document Format 
PDM 
Project Data Manager 
PI 
Principal Investigator 
PT 
Preferred Term 
PVD 
Pharmacovigilance Department 
QC 
Quality Control 


Data Management Plan 
Customer: GW Research Ltd 
Quanticate Project Number: Q_02553 
Protocol Number: GWEP1428                   Version 3.0 Approved 
Date:  01 Nov 2016 
 
ATTACHMENT NO.: CDM-ATT-008 VERSION: 6.0 
 
PAGE 7 OF 33 
COPYRIGHT © QUANTICATE LTD 
 
CONFIDENTIAL 
QOLCE 
Quality of Life in Childhood Epilepsy 
QOLIE 
Quality of Life in Epilepsy 
SAE 
Serious Adverse Event 
SAS 
Statistical Analysis Software 
SEC 
Self Evident Corrections 
SF 
Screen Failure 
SGIC 
Subject Global Impression of Change 
SGICSD 
Subject Global Impression of Change in Seizure Duration 
SMF 
Study Master File 
SMUBS 
Study Medication Use and Behavior Survey 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
UAT 
User Acceptance Testing 
TMS 
Thesaurus Management System 
WHO-DD 
WHO Drug Dictionary 
 


Data Management Plan 
Customer: GW Research Ltd 
Quanticate Project Number: Q_02553 
Protocol Number: GWEP1428                   Version 3.0 Approved 
Date:  01 Nov 2016 
 
ATTACHMENT NO.: CDM-ATT-008 VERSION: 6.0 
 
PAGE 8 OF 33 
COPYRIGHT © QUANTICATE LTD 
 
CONFIDENTIAL 
5 
Outline Description of the Protocol 
This is a phase 2, double-blind, randomized, placebo-controlled study in 20 patients.  
Patients will be randomized in a 4:1 ratio to receive 20 mg/kg GWP42003-P or 
placebo from days 2 to 33. At the end of the treatment period, patients will be given 
the option of continuing onto an open label extension (OLE) period if the investigator 
and patient both agree that it is in their best interests. Doses may be adjusted up or 
down, dependent on investigator opinion, to a maximum of 30 mg/kg/day 
GWP42003-P. The OLE will last for a maximum of one year or until marketing 
authorization is granted; whichever is earlier. Patients that do not continue onto the 
OLE will taper off of GWP42003-P over a 10 day period and will have a telephone 
follow-up visit four weeks after the end of taper day on Day 71. 
 
5.1 
Distribution List 
 
GW Clinical Project Manager (CPM) 
 
GW Lead Clinical Data Manager (CDM) 
 
Quanticate Project Data Manager (PDM) 
 
Quanticate Lead Clinical Data Manager (LCDM) 
A copy of the signed Data Management Plan (DMP), amendments, and related 
documents will be filed in the Study Master File (SMF) by the LCDM or designee, the 
Quanticate project team will be informed of the location. A copy will be forwarded to GW 
Research Ltd. These are the authorised copies. Any copies taken of these documents 
are not authorised or version controlled. 
5.2 
Data Management Plan Objectives and Administration 
This DMP is intended to document, describe and define all Clinical Data Management 
(CDM) processing activities for the project. It will provide a detailed description of all 
data related procedures and processes. Quanticate CDM staffs are responsible for the 
initiation, production, review and maintenance of the DMP. 
Quanticate has been contracted to perform the CDM tasks for this project that are listed 
in section 6 of this DMP. These include data review and validation of data with a final 
project endpoint of a clean database.  
Data processing activities will not be started on a project until the DMP has been 
authorised by GW. 


Data Management Plan 
Customer: GW Research Ltd 
Quanticate Project Number: Q_02553 
Protocol Number: GWEP1428                   Version 3.0 Approved 
Date:  01 Nov 2016 
 
ATTACHMENT NO.: CDM-ATT-008 VERSION: 6.0 
 
PAGE 9 OF 33 
COPYRIGHT © QUANTICATE LTD 
 
CONFIDENTIAL 
5.3 
Project Outline 
This project will be conducted from the planning phase through database close over 
the course of approximately 2 years. The estimated patient enrolment is 20 patients. 
The first patient was enrolled in the third week of Jan 2016. The first CRF pages 
should arrive at Quanticate by the last week of February 2016. The last CRF should 
arrive in-house by last week of June 2016. Database lock is planned to occur 4 
weeks after last CRF data for each part is received in house. 
5.4 
Project Personnel 
The CDM team will be lead by a LCDM who, in conjunction with the PDM are 
responsible for the accuracy and timelines of the project. The LCDM is responsible for 
ensuring that the data management activities throughout the project are adequately 
resourced and that the resource on the project has been trained on the study 
requirements, the systems used and the Standard Operating Procedures (SOP) 
appropriately. 
6 
Scope of Work Defined Within the Data Management Plan 
 
CRF Design 
 
Database Design 
 
CRF Receipt 
 
CRF Logging/Tracking 
 
CRF Storage 
 
Data Entry 
 
Data Validation 
 
Laboratory Data Handling 
 
External Data Handling (e.g. PK) 
 
Medical Coding 
 
Serious Adverse Events (SAE) Reconciliation 
 
Discrepancy Management 
 
Data Clarification Form (DCF) Process 
 
Database Editing 


Data Management Plan 
Customer: GW Research Ltd 
Quanticate Project Number: Q_02553 
Protocol Number: GWEP1428                   Version 3.0 Approved 
Date:  01 Nov 2016 
 
ATTACHMENT NO.: CDM-ATT-008 VERSION: 6.0 
 
PAGE 10 OF 33 
COPYRIGHT © QUANTICATE LTD 
 
CONFIDENTIAL 
 
File Notes 
 
Quality Control 
 
Control of the DMP 
7 
Timelines 
Timelines and assignments will be reviewed by the project team and will be discussed 
at regular team meetings. All deliverables will be sent to GW unless otherwise specified. 
It is essential that modifications to activities, such as responsibilities and timings, be 
communicated as soon as they are known as this could affect current project scope 
thus potentially resulting in out of scope activities. 
Timelines will be discussed by the PDM and the GW Lead Data Manager and the CPM 
on a regular basis, and will be stored electronically in the project area 
S:\Q_048\Q_02553\GWEP1428\Data Management\Documents\Timelines. 
The clinical monitoring of the project will be performed by GW. It is their responsibility to 
provide the LCDM with the patient enrolment list and the monitoring schedule on a 
monthly basis to allow accurate estimates of CRF workflow. 
The CRF design will be finalised and available for data to be entered into before the first 
patient is enrolled. 
Once the CRF is finalised, the database will be built. 
Once the CRF is finalised the creation of the following documents will commence: 
 
Data Validation Plan (DVP) 
 
Final Data Quality Control (QC) Plan 
 
Electronic Laboratory Data Transfer Specifications 
 
Data Entry Guidelines (DEG) 
The DEG must be approved prior to the start of data entry. The DVP must be authorised 
by GW prior to commencing programming of the data validation checks. The QC Plan 
must be authorised by GW prior to the start of database lock procedures. 
GW’s SAE Reconciliation and Coding Plan will be referenced for SAE Reconciliation 
and Coding activities. 
Transfer specifications for external data received electronically will be produced prior to 
the first load of data being received by Quanticate. For GWEP1428 electronic data will 


Data Management Plan 
Customer: GW Research Ltd 
Quanticate Project Number: Q_02553 
Protocol Number: GWEP1428                   Version 3.0 Approved 
Date:  01 Nov 2016 
 
ATTACHMENT NO.: CDM-ATT-008 VERSION: 6.0 
 
PAGE 11 OF 33 
COPYRIGHT © QUANTICATE LTD 
 
CONFIDENTIAL 
be transferred to Quanticate from ACM-pivotal Global Central Laboratory, LGC Group, 
Covance and Parexel.  
8 
Project-Specific Guidelines for the Completion of Tasks 
The project specific guidelines for this project are written in accordance with Quanticate 
SOPs. 
8.1 
CRF Design 
The CRF has been designed by Quanticate on receipt of the final, signed protocol in 
accordance with CDM-SOP-004. 
8.2 
Database Design 
The database will be built by Quanticate in Oracle Clinical (OC) v4.5. This application is 
compliant with ICH GCP and 21 CFR part 11. This is a system based in Oracle which 
has been validated according to Quanticate CMP-SOP-012 'Validation of Computerised 
Systems'. 
Database naming conventions will be based on CDISC CDASH standards unless 
otherwise specified by the customer. 
Access will only be granted to personnel specifically assigned to this project, with 
access authorised by the LCDM or designee. Specific access is assigned by the CDM 
programmer via the study access form. The access level is specified on the form and 
granted as per the role requirement. 
An annotated CRF (aCRF) and a Database Specification Document (DSD) will be 
prepared to define the database format, and these will document the database 
structure. The aCRF and DSD will form part of the SMF. 
Full quality control of the database will be performed prior to release of the database for 
testing. This will be performed by 100% QC of the Discrete Value Groups (DVG), 
Questions, Question groups, and Data Collection Instruments (DCI) in the database 
against the aCRF. The database will not be released for testing until all issues identified 
during the QC have been resolved as per CDM-SOP-001 ’Database Design’. 
User Acceptance Testing (UAT) of the database will be carried out by entering test 
patient data. During entry, the data entry screens will be checked to ensure the 
collection of all required data and that all variables are of adequate length and 
appropriate type and have been correctly assigned. Any database updates identified will 
be actioned and QC’d before the database is released for production data entry.  


Data Management Plan 
Customer: GW Research Ltd 
Quanticate Project Number: Q_02553 
Protocol Number: GWEP1428                   Version 3.0 Approved 
Date:  01 Nov 2016 
 
ATTACHMENT NO.: CDM-ATT-008 VERSION: 6.0 
 
PAGE 12 OF 33 
COPYRIGHT © QUANTICATE LTD 
 
CONFIDENTIAL 
8.3 
CRF Transport 
CRFs will be couriered from the Site/Clinical Research Associate (CRA) to the 
designated Quanticate office at the following address: 
For All sites:  
  
 
 
 
Quanticate  
 
 
Quanticate 
Bevan House  
 
 
Bevan House  
Bancroft Court  
 
 
Bancroft Court  
Bancroft 
 
 
 
Bancroft   
HITCHIN  
 
 
 
HITCHIN  
Herts  
 
 
 
Herts  
SG5 1LH  
 
 
 
SG5 1LH  
T. 
 
 
T. 
 
 
Each batch of CRFs will be accompanied by an inventory document listing the contents 
of the container (site ID, patient ID, visits, pages or DCF numbers, and any non-CRF 
related study documents such as laboratory reports). GW’s Transmittal Form will be 
used for this purpose. 
The CRA will notify the PDM and LCDM of the expected arrival of the data by email. 
It is the responsibility of the CRAs to ensure that any CRFs sent to Quanticate have 
been signed by appropriately authorised site staff. 
The Clinical Data Co-ordinator (CDC) will acknowledge the arrival of the CRFs with the 
CRA 
The LCDM will inform the CRA if the pages are not received. 
8.4 
CRF Receipt 
Quanticate will expect to receive the top copies (originals) only of the Main CRF pages 
and bottom copies of the questionnaire pages. 
The CDC will check the CRFs against the inventory provided on the GW transmittal 
form. Any discrepancies between the inventory and the documents received will be 
noted and the appropriate CRA informed. A signed and dated inventory will be returned 
to the sender by fax or scanned image/PDF and emailed within two working days of 
receipt of the CRFs. The original inventory will be filed in the SMF. 
If more than one copy of the CRF is received (original and working copy) then both 
copies will be noted in the inventory form that is sent back to the CRA. The pages will 
PPD
PPD
PPD
PPD


Data Management Plan 
Customer: GW Research Ltd 
Quanticate Project Number: Q_02553 
Protocol Number: GWEP1428                   Version 3.0 Approved 
Date:  01 Nov 2016 
 
ATTACHMENT NO.: CDM-ATT-008 VERSION: 6.0 
 
PAGE 13 OF 33 
COPYRIGHT © QUANTICATE LTD 
 
CONFIDENTIAL 
be split, and the copy/copies that should not have been sent will be returned to the 
CRA. 
8.5 
CRF Tracking 
The CDC will set up and maintain the logging and tracking spreadsheet in Microsoft 
Excel. 
The study number, site number and patient number will be checked manually on all 
pages received to ensure all the correct pages are with the correct CRF. Any errors in 
the header data will be noted GW’s Transmittal Form. 
Each CRF should also be manually checked to ensure the pages are in the correct 
order, and any other documents (laboratory reports, DCFs) are at the front of the CRF. 
Missing page reports will be run periodically and issued to the CPM. If patient 
confidential information (i.e. name, telephone number, national insurance number) are 
recorded on the CRF or associated documents, a copy of the page will be taken, the 
confidential information will be blacked out on the copy with permanent marker and the 
page scanned. The scanned page will replace the scan of the original page. The LCDM 
will inform GW and the person who sent the documents to inform them of the action 
taken. The original page will be returned to the CRA for redacting. 
Any scanned copies of the original CRF or associated documents will be deleted from 
CRF storage or electronic systems (including any back up process in place). The CRF 
or associated documents which have had the confidential information removed will be 
scanned again and the usual process will be followed to enter the data into the 
database. 
If the confidential information from CRF or associated documents has already been 
entered into the database (or any other electronic systems) then the data must be 
deleted from the database (including audit trail and any back up process in place) 
immediately once it is noted.  
The LCDM will inform GW in writing either in an email or a file note to confirm the above 
steps have been taken. 
Any additional information not recorded on the CRF e.g. on any form of sticky note will 
be ignored (not tracked or data entered). Any additional information must be recorded 
on the actual CRF or DCF. 
CRFs should be logged as follows: 
X 
received 
XB 
received blank page (also used for received blank pages that are not 
expected 


Data Management Plan 
Customer: GW Research Ltd 
Quanticate Project Number: Q_02553 
Protocol Number: GWEP1428                   Version 3.0 Approved 
Date:  01 Nov 2016 
 
ATTACHMENT NO.: CDM-ATT-008 VERSION: 6.0 
 
PAGE 14 OF 33 
COPYRIGHT © QUANTICATE LTD 
 
CONFIDENTIAL 
PC 
received photocopy page 
PCB received photocopy of page that contains no data 
M 
missing page (noted as sent but not received) 
There may be more than 1 line per patient, in the Excel tracker. A new line is created 
each time a new batch of data is received. 
The first page of all unused visits should be provided to Quanticate for all patients 
who terminate the study early. The page should have the header details completed 
with the rest of the page struck through. In addition the page should be initialled and 
dated. A comment along the lines of: “the patient did not complete visit X no further 
CRF pages completed for this visit” or similar should be annotated onto the CRF 
page. 
 
Where multiple visits are not completed the sites will be instructed to record a comment 
stating “the patient did not complete visits X, Y and Z, no further CRF pages will be 
completed”. 
 
In all cases at least one AE, Concomitant Medication (CM) and general comments page 
must be sent to Quanticate. If the pages do not contain any data, the header should be 
completed, the page struck through and a comment along the lines of “no data expected 
for this page” or similar should be annotated onto the CRF page. 
 
If additional pages are used (Non- Epilepsy Medical History, Concomitant Medications, 
Adverse Events, Comments etc.), these will be numbered as 2.1 for first repeat for Non-
Epilepsy Medical History, AE.1 for first repeat for Adverse Event, AED.1 for Concomitant 
Antiepileptic Medications, MED.1 for first repeat for other concomitant medications etc. 
Only completed additional pages are should be sent to Quanticate. 
The CRF modules that have an additional page contain a check box that should be 
completed if an additional page is used (located at the bottom of the page). Quanticate 
will reconcile this field with the actual pages received from the site. 
Scanned CRF pages should only be sent to Quanticate prior to an Interim Analysis (to 
support New Drug Application and Marketing Authorization Application filing). Original 
pages should still be collected and issued to Quanticate. Quanticate will reconcile the 
original page against the scanned page and update the database if required. 
The tracking spreadsheet will be located on the Quanticate network, and can be 
accessed by all Quanticate sites as required. Tracking reports will be sent to GW on a 
weekly basis. 
 


Data Management Plan 
Customer: GW Research Ltd 
Quanticate Project Number: Q_02553 
Protocol Number: GWEP1428                   Version 3.0 Approved 
Date:  01 Nov 2016 
 
ATTACHMENT NO.: CDM-ATT-008 VERSION: 6.0 
 
PAGE 15 OF 33 
COPYRIGHT © QUANTICATE LTD 
 
CONFIDENTIAL 
8.6 
Expected Pages 
For GWEP1428, the following pages are expected for randomized patients as 
mandatory minimum for the Blinded and OLE phases: 
8.6.1 Blinded Phase: 
Study period Visit 1 
Page 1-16 
Study period Visit 2 
Page 17-29 
Study period Visit 3 
Page 30-34 
Study period Visit 4 
Page 35-48 
Study period Visit 5 * 
Page 49-57 
Study period Safety Telephone Call (Visit 
6)* 
Page 58 
Site Classification Form** 
SCF_ 
Supplemental Drug Accountability Form** 
SDAF_ 
Supplemental Adverse Event Form** 
SAEF1_ , SAEF2_ 
Study Medication Dose Adjustment Log 
DAL_ 
Concomitant Antiepileptic Medications 
AED_ 
Concomitant Antiepileptic Rescue 
Medications 
RM_ 
Other Concomitant Medications 
MED_ 
Concomitant Antiepileptic Therapies 
AET_ 
Adverse Events 
AE_ 
Investigator’s Signature Page 
SIGN 
 
 * Study period visit 5 and study period safety telephone call (visit 6) needs to be updated for Non-OLE 
patients only. 
** Page required only if the trigger question on study medication pages indicate that the page is needed. 
*** The following non mandatory pages may also be received if applicable: unscheduled visit (U1-U5); 
general comments page (GC_)


Data Management Plan 
Customer: GW Research Ltd 
Quanticate Project Number: Q_02553 
Protocol Number: GWEP1428                   Version 3.0 Approved 
Date:  01 Nov 2016 
 
ATTACHMENT NO.: CDM-ATT-008 VERSION: 6.0 
 
PAGE 16 OF 33 
COPYRIGHT © QUANTICATE LTD 
 
CONFIDENTIAL 
 
8.6.2 Blinded Diary Pages:  
 
Epilepsy Daily Diary Record 
Pages 9-10; 15-16; 22-27; 32-33* 
 
*None OLE patients only. 
8.6.3 OLE Phase: 
Study period Visit 5 
Page 1 – 6 
Study period Visit 6 
Page 7 – 12 
Study period Visit 7  
Page 13 – 18 
Study period Visit 8 
Page 19 – 24 
Study period Visit 9 
Page 25 – 30 
Study period Visit 10 
Page 31 – 36  
Study period Visit 11 
Page 37 – 43  
Study period Visit 12 
Page 44 – 52  
Study period Visit 13  
Page 53 
Site Classification Form* 
SCF_ 
Supplemental Drug Accountability Form* 
SDAF_ 
Supplemental Adverse Event Form** 
SAEF1_ , SAEF2_ 
Concomitant Antiepileptic Medications 
AED_ 
Concomitant Antiepileptic Rescue 
Medications 
RM_ 
Other Concomitant Medications 
MED_ 
Concomitant Antiepileptic Therapies 
AET_ 
Adverse Events 
AE_ 
Investigator’s Signature Page 
SIGN 
 
* Page required only if the trigger question on study medication pages indicate that the page is needed. 
** The following non mandatory pages may also be received if applicable: unscheduled visit (U1-U5); 
general comments page (GC_) 
 
8.6.4 OLE Diary Pages:  
Epilepsy Daily Diary Record 
Pages 9-11; 16-18; 26-30; 38-43; 57-
71; 85-99; 113-127; 132-133 
 


Data Management Plan 
Customer: GW Research Ltd 
Quanticate Project Number: Q_02553 
Protocol Number: GWEP1428                   Version 3.0 Approved 
Date:  01 Nov 2016 
 
ATTACHMENT NO.: CDM-ATT-008 VERSION: 6.0 
 
PAGE 17 OF 33 
COPYRIGHT © QUANTICATE LTD 
 
CONFIDENTIAL 
8.6.5 Questionnaires 
The following questionnaires will be used in this study for both blinded and OLE phase: 
Columbia Suicide Severity Rating Scale 
[Adult (C-SSRS)] 
Blinded: Visit 1, Visit 2, Visit 3, Visit 4,Visit 5, 
OLE: Visit 5 , Visit 6, Visit 7, Visit 8 Visit 9, 
Visit 10, Visit 11, Visit 12 
Study Medication Use & Behaviour 
Survey (SMUBS) 
SMUBS Page 1 & 2, Blinded: visit 5; 
OLE: Visit 12 
 
 
8.6.6 Screen Failure Patients 
For patients who are not randomized (screen-failures) only the following pages are 
expected: 
 
- 
Study period Visit 1 (page 1) 
- 
Screen Failure page (SF) 
- 
Adverse Events (AE.1) the “None” box should be ticked if no AEs were 
reported 
- 
Investigator signature page 
 
Any other pages received will be tracked but the data will not be entered. Missing 
page queries for screen failure patients will only be issued if any of the pages 
mentioned above are not received. 
 
8.7 
CRF Storage 
 
CRFs maintained by Quanticate will be kept in a secure, limited-access, storage area. 
CRF pages will be filed such that all data for each patient will be stored together in page 
order. Laboratory reports and other related project documents will be stored at the front 
of the CRF. CRFs will be stored in the project-specific section of the storage area in 
patient numerical order. 
Removal of the CRFs or any project related file will be documented in the CRF tracking 
log, kept in the storage area, to ensure they can be easily found if required. 
All CRF pages will be scanned, and the scanned images stored on the designated 
project area on the Quanticate network. The pages will be grouped by patient as they 
are scanned and will be scanned upon arrival at the designated Quanticate office. The 
file will be named according to patient number and the pages received e.g. If pages 11-
20 are received for patient 002 from site 0001 for visits 3 and 4 the file name will be 
CRF0001002_p11 to 20.  


Data Management Plan 
Customer: GW Research Ltd 
Quanticate Project Number: Q_02553 
Protocol Number: GWEP1428                   Version 3.0 Approved 
Date:  01 Nov 2016 
 
ATTACHMENT NO.: CDM-ATT-008 VERSION: 6.0 
 
PAGE 18 OF 33 
COPYRIGHT © QUANTICATE LTD 
 
CONFIDENTIAL 
8.8 
Data Entry and Verification 
Once data have been tracked the data entry team are informed that the CRFs are ready 
for entry.  
The first pass Data Entry Clerk (DEC) will perform first pass entry using the ‘Initial Log-In 
and Entry’ option. 
All data in the CRF will be double data entered in Oracle Clinical v4.5 (OC) with ‘DCI 
book on’ as described in the project-specific DEG. The DEG includes conventions for 
missing/partial dates, times, other variables, or if a whole page/visit is “Not Done” or 
blank. Data Entry will not commence until the DEG is finalised and approved by the 
LCDM and GW. 
Personnel using the system have an individual username and password. The system 
logs the data entry personnel (Pass 1 User and Pass 2 User) for each module. 
Changes made to the database during editing are clearly indicated by an electronic 
audit trail and is available to all personnel assigned to the project with access to the OC 
project database. 
The CRF data are entered as seen, without interpretation or modification (unless 
directed by the DEG or Self Evident Corrections [SEC]), into the data entry system 
(Pass 1 User), then a second entry with verification is entered by another, independent 
data entry clerk (Pass 2 User) into the system. 
Reconciliation of Pass 1 and Pass 2 data entry will be carried out by an independent 
user within OC. Data points with a discrepancy between Pass 1 and Pass 2 will be 
highlighted within OC and can be corrected during reconciliation of the Data entry.  
If the investigator has entered extraneous comments on the CRF page, these will be 
entered as seen by the first pass data entry clerk using ‘Investigator comments’. 
If the data are unclear the first pass data entry clerk will raise an ‘Operator Comment’ to 
create a manual discrepancy for the CDM to review. 
The LCDM will run a listing periodically to identify if two CRF pages with identical header 
information are entered into the project database. It will then be the LCDM’s (or 
designee’s) responsibility to review the issue and, under Key Changes, delete/amend 
the duplicate record, as applicable. 
Once a batch of data entry has been completed, the LCDM (or designee) will check for 
any CRF pages which have a status of either ‘Received’,’ Pass 1 started’, ‘Pass 1 
complete’ or ‘Pass 2 started’ any outstanding data entry issues and will be actioned and 
confirmation of any blank pages received obtained if required. 
The OC database is automatically updated to show the entry status of each CRF. 


Data Management Plan 
Customer: GW Research Ltd 
Quanticate Project Number: Q_02553 
Protocol Number: GWEP1428                   Version 3.0 Approved 
Date:  01 Nov 2016 
 
ATTACHMENT NO.: CDM-ATT-008 VERSION: 6.0 
 
PAGE 19 OF 33 
COPYRIGHT © QUANTICATE LTD 
 
CONFIDENTIAL 
If repeated errors are encountered in the CRFs during data entry, the DEC must inform 
the LCDM so that GW can be informed, the database can be changed, or the DEGs 
can be updated. Site staff will be instructed on the changes to the guidelines by the GW 
project team, to facilitate a smoother data entry process. 
The LCDM or designee will perform a 100% QC of the first patient entered for each 
DEC (number of CRF pages to be selected for QC depends on the project size). The 
LCDM will inform the DECs of any consistent errors. 
8.8 
Data Validation 
Once a batch of data has been double entered, electronic checks will be run across the 
whole database on a daily basis. 
Data validation is performed as detailed in the ‘Data Validation Plan’ (CDM-ATT-068). 
This details all of the validation checks that will be performed on the data, the 
discrepancy message that the investigator/user will see and the type of check 
(univariate, multivariate, SAS check, listing) and these are agreed between GW and 
Quanticate prior to the start of validation check programming. 
The DVP will consist of: 
Univariate Checks: 
 
Electronic (Univariate) Checks (U): these checks are created at database build and 
will fire for missing data, or indicator questions that have been specified in the DVP or 
for data entered in the incorrect format (text in numerical fields or incorrect field length 
etc.). These will fire at the data entry stage. 
Validation Procedures: 
 
Electronic (Multivariate) Checks (E): Automated checks (validation procedures) 
programmed in PL/SQL within Oracle Clinical. These are for checking data within 
datasets and for simple cross-dataset checks. These will be run overnight during the 
scheduled batch validation sessions or as required by study personnel with the 
relevant access. 
 
Programmed Manual Checks (M): Programs producing discrepancies for manual 
review where programming of edit checks would not be possible. These will be run 
overnight during the scheduled batch validation sessions or as required by project 
personnel with the relevant access. 
 
Listings (L): These are run across data where the programming of checks will be too 
complex, e.g. comparison of Concomitant Medication start dates with Medical History 
and Adverse Events. These are run at intervals throughout the duration of the project. 


Data Management Plan 
Customer: GW Research Ltd 
Quanticate Project Number: Q_02553 
Protocol Number: GWEP1428                   Version 3.0 Approved 
Date:  01 Nov 2016 
 
ATTACHMENT NO.: CDM-ATT-008 VERSION: 6.0 
 
PAGE 20 OF 33 
COPYRIGHT © QUANTICATE LTD 
 
CONFIDENTIAL 
The DVP will be approved by before programming of validations and listings begins. 
Validation checks are written in OC. Programs are validated with test data. The purpose 
of the test data is to enter both valid and invalid data values to ensure that the 
validations catch all errors and are only seen by the site when expected. The test data 
will be single data-entered and the validations will be run on the data. Once the 
validations are executed, errors are generated for each patient. These errors will be 
reviewed for any potential programming errors which will be fixed prior to the validations 
being used in production mode 
Once in production, the validation checks are run on the whole master database. An 
error message will be created for any items that fail a validation check. This message is 
stored in the OC discrepancy management system, together with information to identify 
the record (site, patient, visit and field name etc.). The system is designed so that 
should an item that fails a validation check be edited and it is still invalid, a new error 
message will be generated the next time the validations are run because the value of 
the item has changed. 
 
SAS checks/listings/programmed manual checks: Checks across different types of 
data or CRF pages that are not possible to cross-check electronically and/or require 
manual interpretation of the data before a query can be raised. 
 
Electronic checks: Programmed by the CDM Programmer, which are run at intervals 
during the project, to check for any missing data, data inconsistencies and out-of-
range values etc. 
 
Self-Evident Corrections (SEC): These will be actioned when an obvious error has 
been made and does not require any interpretation of the data on the CRF by the 
observer or the error can be resolved by referring to other CRF pages. 
The DVP will be approved by GW before programming of checks and listings begins. 
The list of SECs requires approval from the Principal Investigator (PI). 
Validation procedures will be tested against test data, created by a CDM (or designee) 
to confirm that each check is accurate and generates appropriate discrepancies. 
Batch validations will be set to run periodically throughout the project. Additional batch 
validations may be performed until no new discrepancies are generated and all existing 
discrepancies have been resolved. 
8.9 
Discrepancy Management 
Discrepancies can be generated several different ways. All discrepancies will be stored 
in the discrepancy database regardless of how they are generated. The methods of 
generating discrepancies are as follows: 


Data Management Plan 
Customer: GW Research Ltd 
Quanticate Project Number: Q_02553 
Protocol Number: GWEP1428                   Version 3.0 Approved 
Date:  01 Nov 2016 
 
ATTACHMENT NO.: CDM-ATT-008 VERSION: 6.0 
 
PAGE 21 OF 33 
COPYRIGHT © QUANTICATE LTD 
 
CONFIDENTIAL 
 
Univariate: Created by OC during data entry when the entry in the field is not as 
expected, e.g. the field length or format of the entry is incorrect. 
 
Indicator: Created as part of the Database build - normally set up for key questions on 
repeating groups i.e. yes/no on Medical History – when a response is expected but 
not present, or vice versa. 
 
Manual: Created by data entry as an operator comment or by a CDM after review of 
SAS output, listings, data QC etc. 
 
Multivariate: Created by running the validation checks over the database in a batch 
validation session. Batch validations run on data which have been double data 
entered and have a page status of ‘Complete’. 
 
TMS (Thesaurus Management System): Created from the Coding application when 
the coder designates a term as un-codable and requiring a discrepancy. The 
discrepancies created in this way will be transferred to the discrepancy database 
during batch validation. 
The OC discrepancy database will be used to store and track discrepancies. OC will 
assign a unique identification number to each discrepancy (i.e. DISC ID). All new 
discrepancies in the discrepancy database will have a status of ‘Unreviewed’ (i.e. 
requires action by a CDM) and these will all be reviewed by a CDM or designee to 
decide the action required. Once the action is decided, the status of the discrepancy will 
be amended: 
 
Investigator Review: Requires review and resolution by Investigator DCF sent to site. 
 
DM Review: Requires review by LCDM. 
 
Resolved: Discrepancy is no longer open, resolution has been provided by either an 
allowable change or change/confirmation provided by a resolved discrepancy by the 
Investigator. (This status will not be allocated until after the database update has been 
performed). 
Closed: Data has changed and is no longer discrepant. 
Quanticate will not raise any queries for Concomitant Medications and Adverse Events 
where both the stop date and on-going are blank until the original pages are received. 
 
DCFs will be created from the discrepancy database and will contain discrepancies 
which require Investigator review. Please note that a DCF may contain more than one 
discrepancy. Once created DCFs will have a unique number and have the status of 
‘Created’. The DCFs will be sent to the CRA as a PDF, and the DCF status will be 
amended to ‘Sent’. 
Original, resolved, signed DCFs will be returned to Quanticate Hitchin office on an on-
going basis prior to the end of the project. In any circumstance where the original ‘wet-


Data Management Plan 
Customer: GW Research Ltd 
Quanticate Project Number: Q_02553 
Protocol Number: GWEP1428                   Version 3.0 Approved 
Date:  01 Nov 2016 
 
ATTACHMENT NO.: CDM-ATT-008 VERSION: 6.0 
 
PAGE 22 OF 33 
COPYRIGHT © QUANTICATE LTD 
 
CONFIDENTIAL 
ink’, resolved, signed DCFs are not available, scanned copies will be accepted in place 
of the originals. 
It is the responsibility of the CRAs to ensure that any DCFs returned to Quanticate have 
been signed by appropriate, authorised site staff.  
On receipt of the DCFs they will be checked to ensure that they have been signed and 
answered, and then the DCF status will be updated to ‘Received’. If the DCF has not 
been signed or answered, it will be returned to CRA. 
It will be the responsibility of the LCDM to notify GW and/or the CRA of receipt of any 
unresolved DCFs or DCFs outstanding for more than 28 days. Monthly standard DCF 
status reports will be sent to GW. 
8.10 Translation 
Quanticate will work with TransPerfect to obtain translations of the comments recorded 
on the questionnaires (and CRFs/diaries if required).  
TransPerfect and Quanticate will follow the process outlined below: 
1. Pages requiring translation will be identified during the CRF tracking process 
2. Quanticate to upload photocopied documents on to Trial Interactive 
3. TransPerfect will translate, edit, and proofread the indicated handwritten 
portions of text 
4. Formatting and Redacting of content in scope will take place 
5. Quality Review and Certification (if necessary) 
6. Final Deliverable in Microsoft word or PDF format uploaded to Trial Interactive 
7. CRF data entered into the clinical database 
8. Project Feedback  
 
TransPerfect contact details: 
 
 
TransPerfect Life Sciences 
45 Moorfields 
5th Floor 
London 
EC2Y 9AE 
Tel: 
 
Email: 
 
8.11 Data Editing 
Edits to the data in the database may be necessary as an action to a DCF, operator 
comment, data entry error, self evident correction or quality control finding. 
PPD
PPD
PPD
PPD


Data Management Plan 
Customer: GW Research Ltd 
Quanticate Project Number: Q_02553 
Protocol Number: GWEP1428                   Version 3.0 Approved 
Date:  01 Nov 2016 
 
ATTACHMENT NO.: CDM-ATT-008 VERSION: 6.0 
 
PAGE 23 OF 33 
COPYRIGHT © QUANTICATE LTD 
 
CONFIDENTIAL 
SECs will be actioned when an obvious error has been made and does not require any 
interpretation of the data on the CRF by the observer, or the error can be resolved by 
referring to other CRF pages. The SEC document requires approval from the PI from 
each site. No SECs will be actioned from a site until the approved list has been received 
from that site by the Quanticate CDM. 
Edits to the data in the database have a full electronic audit trail, allowing a complete 
record of amendments to the database to be recorded. 
A reason for change is required every time an update to the data is made. If the update 
was actioned from a discrepancy, the DCF ID will be recorded in the comments field as 
the reason for the update. If the update was actioned from a SEC, the SEC ID will be 
recorded in the comments field as the reason for the update. 
A sample of edits to the data in the database will be QC’d. Depending on the number of 
errors found in the edits, approximately 10% of updates to the database from DCF 
answers will be QC’d. The first batch of DCFs updated will be QC’d and a random 
sample of DCFs will be QC’d over the duration of the project. If more than 1% of errors 
are found in the edits, further QC of edits will be performed. 
8.12 Protocol Deviations 
Information on Protocol Deviations (PD) will be collected by both the CRAs and 
Quanticate CDM. 
 CRAs will record any PD into the monitoring visit reports; the report reviewer collates 
this information into a central log. 
 The log will be shared with Quanticate at regular intervals during the study.  
 Quanticate will review the log and use it to close the queries that are related to PD.  
 Quanticate will capture any PDs mentioned on the DCF e.g. approved out of window 
visit dates in a log. This log will be reviewed against the PDs log from CRAs and 
ensure that duplicate PDs are not collected (i.e. remove any PDs from DM log if they 
are already present in CRA log).  
 Quanticate will produce a listing of PDs from the comments page, where PD is 
ticked upon GW request. 
 
GW will combine PDs received from CRAs and Quanticate CDM at the end of the study, 
any duplicates will be removed and a final log will be created. 
8.13 Laboratory/ External IWRS and Quality of Life Data Handling 
In addition to CRF data, central laboratory data, external IWRS data, Diary Pages and 
Questionnaire data are expected for each patient. Questionnaire data will be received 
as paper copies and will be double entered into the OC database as specified in the 
DEG. The laboratory data including PK will be received as datasets from Covance, 


Data Management Plan 
Customer: GW Research Ltd 
Quanticate Project Number: Q_02553 
Protocol Number: GWEP1428                   Version 3.0 Approved 
Date:  01 Nov 2016 
 
ATTACHMENT NO.: CDM-ATT-008 VERSION: 6.0 
 
PAGE 24 OF 33 
COPYRIGHT © QUANTICATE LTD 
 
CONFIDENTIAL 
ACM-Pivotal Global Central Laboratory and LGC Group. IWRS data will be received as 
datasets from Parexel.  
Central lab data and external IWRS data will be received electronically in GW compliant 
format. This data will not be entered into OC database. The process for receipt and 
handling electronic data will be documented in the Electronic Data Transfer 
Specifications (EDTS). 
Questionnaire:  
Minimal queries will be raised on questionnaire data. Missing and inconsistent data 
within the forms will not be queried; the only issues to be queried will be missing 
questionnaire pages, and inconsistent header data. 
 
Electronic Data Transfer:  
Details of the process of laboratory data handling and IWRS data handling will be 
discussed with GW, ACM-Pivotal Global Central Laboratory, LGC Group, Parexel and 
Covance and upon agreement will be documented in the EDTS. 
 
8.13.1 
External Vendors 
The following laboratory groups will be responsible for collecting, analysing and reporting 
results accordingly: 
ACM-Pivotal Global Central Laboratory 
 
ACM Global Central Laboratory 
23 Hospital Fields Road 
York 
YO10 4DZ 
UK 
Direct Dial: 
 
Office: 
 Fax: 
 
 
ACM Global Central laboratory will be supplying the Biochemistry, Haematology, 
Urinalysis, Pregnancy test and Urine drug screen data. The blinded data will be 
reconciled before the database lock. 
PPD
PPD
PPD
PPD
PPD


Data Management Plan 
Customer: GW Research Ltd 
Quanticate Project Number: Q_02553 
Protocol Number: GWEP1428                   Version 3.0 Approved 
Date:  01 Nov 2016 
 
ATTACHMENT NO.: CDM-ATT-008 VERSION: 6.0 
 
PAGE 25 OF 33 
COPYRIGHT © QUANTICATE LTD 
 
CONFIDENTIAL 
LGC Group  
 
Newmarket Road 
Fordham 
CB7 5WW 
UK 
Tel: 
 (Office) 
Tel 
 (Direct) 
 
 
LGC Group will provide the Plasma Cannabinoid data. The unblinded data will be 
received once the database is locked (i.e. when the access to database is revoked or set 
to read-only for all users). This data should only be sent to GW upon confirmation from 
GW statistician that the trial has been unblinded.  
Covance  
 
Covance Laboratories Limited 
Otley Road,  
Harrogate,  
North Yorkshire,  
HG3 1PY,  
UK 
Tel: 
 
  
 
Covance will provide the Plasma AED and THC data. The unblinded data will be received 
once the database is locked (i.e. when the access to database is revoked or set to read-
only for all users). This data should only be sent to GW upon confirmation from GW 
statistician that the trial has been unblinded.  
 
PAREXEL: 
 
Castle Wharf,  
4 Canal Street,  
Nottingham,  
NG1 7EH  
Tel: 
 
 
 
Parexel will be providing the IWRS, and patient enrolment data. The unblinded data will 
be received once the database is locked (i.e. when the access to database is revoked or 
set to read-only for all users). This data should only be sent to GW upon confirmation that 
the trial has been unblinded.  
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


Data Management Plan 
Customer: GW Research Ltd 
Quanticate Project Number: Q_02553 
Protocol Number: GWEP1428                   Version 3.0 Approved 
Date:  01 Nov 2016 
 
ATTACHMENT NO.: CDM-ATT-008 VERSION: 6.0 
 
PAGE 26 OF 33 
COPYRIGHT © QUANTICATE LTD 
 
CONFIDENTIAL 
Transfer specifications and transfer schedules will be created and authorised by 
Quanticate and the relevant external vendor prior to receipt of the first live data transfer 
being issued to Quanticate. 
The external data sources will be responsible for the quality and completeness of their 
data. Cumulative transfers will be received. 
Quanticate will be responsible for: 
 Reconciliation of external header data (patient number/visit date and time where 
collected) against CRF data. 
 Reconciliation of external demography data (date of birth/sex) against CRF data. 
 Ensuring external data are present for every sample date/time indicated on the CRF. 
Quanticate will not be responsible for: 
 Checking that all protocol specified parameters are present. 
 Amending database structure if not received in the format specified in the Transfer 
Specifications. 
Discrepancies between the external data and the CRF data will be queried to the 
investigator. If the CRF data are incorrect, these will be updated. If the external data are 
incorrect the query resolution will be forwarded to the external data source vendor for 
resolution. The original DCF resolution will be retained by Quanticate. 
No hardcopy printouts of any kind are expected for tracking. No investigator comments, 
flags or CS/NCS attributions on laboratory data are expected for data entry. 
8.14 Medical Coding 
Adverse Events, Medical History (MH) and Concomitant Medications will be coded 
using TMS v4.6 in OC. 
Detailed coding conventions are provided in the GW SAE Reconciliation and Coding 
Plan. 
The coding will be performed using the following dictionaries: 
 
WHODD version June 2014 for CM. ATC coding will be performed as part of the CM 
coding. Up to fourth level ATC coding will be provided as well as the ATC Code level 
breakdown. 


Data Management Plan 
Customer: GW Research Ltd 
Quanticate Project Number: Q_02553 
Protocol Number: GWEP1428                   Version 3.0 Approved 
Date:  01 Nov 2016 
 
ATTACHMENT NO.: CDM-ATT-008 VERSION: 6.0 
 
PAGE 27 OF 33 
COPYRIGHT © QUANTICATE LTD 
 
CONFIDENTIAL 
 
MedDRA version 18.1 for AE and MH. Coding will be performed using the 5 coding 
levels in MedDRA (Lowest Level Term [LLT], Preferred Term [PR], Higher Level Term 
[HLT], Higher Level Group Term [HLGT] and System Organ Class [SOC]). 
If the dictionaries are updated to an updated version during the study lifetime, any 
differences found between previous and current versions of the dictionary shall require 
to be reviewed.  
It is anticipated that the majority of terms will be coded automatically in TMS. Terms 
requiring manual coding will be handled as specified in GW SAE Reconciliation and 
Coding Plan. 
All query resolutions requiring update will be updated in the OC database using a 
modified verbatim term field. The updated modified terms will then appear for coding in 
a later coding cycle. No changes to the verbatim term will be made on the OC database 
unless confirmed by the investigator. All queries raised in TMS are linked to OC and 
exported during the nightly scheduled batch validation sessions. 
Coding will be performed on an on-going basis but at a minimum after 75% and 100% 
of the data has been double data entered. 
Listings will be generated during the coding process for the LCDM to check for 
appropriate coding consistency. The following listings may be generated for each type 
of term coded: 
 
Listing by unique verbatim terms 
 
Listing by unique coded terms 
 
Listing by body system or drug classification 
Quanticate will QC the manual coding for consistency and reasonability prior to 
forwarding to GW for medical review. Medical review of the coding will be the 
responsibility of GW. During medical review of the coding, changes may be requested. 
These will be updated within the coding application. The revised coding will then be 
available for re-review. The changes are recorded using a paper and electronic audit 
trail. 
Medical review of the coding by a medical monitor and approval of the coding will be 
required from GW and designated medically qualified reviewer, prior to database lock. 
8.15 Serious Adverse Event/ Reconciliation 
Details of the process of the SAE reconciliation have been discussed with the GW 
Pharmacovigilance Department (PVD) and are recorded in the GW SAE Reconciliation 
and Coding Plan. 


Data Management Plan 
Customer: GW Research Ltd 
Quanticate Project Number: Q_02553 
Protocol Number: GWEP1428                   Version 3.0 Approved 
Date:  01 Nov 2016 
 
ATTACHMENT NO.: CDM-ATT-008 VERSION: 6.0 
 
PAGE 28 OF 33 
COPYRIGHT © QUANTICATE LTD 
 
CONFIDENTIAL 
Any SAEs reported to GW PVD during the study will be reconciled with the CRF 
database according to the GW SAE Reconciliation and Coding Plan. 
The SAE forms will be received by GW PVD and the data on these forms will be 
entered by GW PVD onto the SAE database. The SAE forms will not be entered into the 
Quanticate clinical database. 
8.16 File Notes 
File Notes are records of data handling issues which were not anticipated at the 
planning stage of the trial, and their solutions. 
8.17 Investigator Comments 
Any additional information such as free-standing notes on the CRF or comments in the 
query replies that cannot be entered into the data fields database will be documented in 
the Investigator Comments during the course of the project. These will be captured in 
the database but will not be reviewed by clinical data management and will only be used 
by the CDM department as a tool to reduce query numbers.  
8.18 Quality Control 
At the start of the processing phase of the project the LCDM or designee will select CRF 
pages on which to perform a 100% QC on entered data and the LCDM will inform the 
DECs of any consistent errors. 
The end of project QC that will be performed on the database is described in detail in 
the QC Plan and will be approved by GW. This plan must be finalised prior to database 
lock. 
The end of project QC process can begin when a patient’s data are deemed clean (all 
data for that patient is entered, validation completed, database edits completed, no 
medical coding queries outstanding, and no SAE reconciliation queries outstanding). 
The database QC is performed by competent members of CDM who have had little or 
no involvement in the project, where possible. 
CDM Programmers are responsible for producing the list of randomly-selected patient 
numbers for the QC sample and for producing the QC listings. 
Quanticate will assess discrepancies in terms of their possible cause in order to identify 
whether they are systematic, and therefore require a specific course of action. All 
findings will be documented on the ‘Final Data Quality Control Form’ (CDM-ATT-022) 
and all errors will be corrected on the database. Any corrections will be QC’d before 
database lock. Please refer to the QC Plan for a definition of an error. 


Data Management Plan 
Customer: GW Research Ltd 
Quanticate Project Number: Q_02553 
Protocol Number: GWEP1428                   Version 3.0 Approved 
Date:  01 Nov 2016 
 
ATTACHMENT NO.: CDM-ATT-008 VERSION: 6.0 
 
PAGE 29 OF 33 
COPYRIGHT © QUANTICATE LTD 
 
CONFIDENTIAL 
The QC findings will be summarised in a ‘Final Data Quality Control Report’ 
(CDM-ATT-021) which will be sent to GW for approval. If for any reason it fails the QC 
process (with an error rate above the agreed rate specified in the QC Plan) GW will be 
notified and a plan of action will be proposed. 
8.19 Database Lock 
The following criteria must be met prior to database lock. (Please refer the ‘Database 
Lock Checklist’ [CDM-ATT-035] for a full list of procedures to be completed prior to 
database lock). 
 
All patient data has been double-data-entered and validated. 
 
All queries have been resolved or signed off. 
 
All electronic checks and SAS listings have been re-run against the data and no new 
queries were generated. 
 
All external electronic data has been imported with no new errors. 
 
All coding has been reviewed and approved by GW. 
 
All SAE reconciliation has been reviewed and approved by GW. 
 
All the Investigator signature pages (signed and dated by the Investigator) have been 
received for all patients. 
 
GW has authorised the database lock. 
The final database QC will be performed to calculate the final error rate. Once the final 
database QC has been completed and the error rate is acceptable, the LCDM will 
request the lock of the database, upon which write-access will be removed from all 
CDM personnel. Written confirmation of database lock, including date and time of lock, 
will be sent to GW. 
The locked raw data will be extracted and mapped, where necessary, to GW standards 
prior to transfer to GW. 
8.20 Database Unlock 
A database which was locked and released for analysis will usually only be unlocked if 
an error is identified which would: 
 
Significantly affect the statistical outcome of the analysis of key efficacy parameters. 
 
Change the safety profile of the study data. 


Data Management Plan 
Customer: GW Research Ltd 
Quanticate Project Number: Q_02553 
Protocol Number: GWEP1428                   Version 3.0 Approved 
Date:  01 Nov 2016 
 
ATTACHMENT NO.: CDM-ATT-008 VERSION: 6.0 
 
PAGE 30 OF 33 
COPYRIGHT © QUANTICATE LTD 
 
CONFIDENTIAL 
If a request is received to unlock a clinical database or amend locked datasets, the 
Head of CDM and the GW CPM must document their authorisation to re-open the 
database/amend the data in clinical database using ‘Database Unlock Authorisation 
Form’ (CDM-ATT-037). The request and approval must include the reason and rationale 
for unlocking the database/amending the data in clinical database. The request and 
approval must be maintained in compliance with GEN-SOP-024 (‘Study Master File’). 
The database will be unlocked by the Database Administrator (DBA) by changing 
the access profile on receipt of ‘Database Unlock Authorisation Form’ (CDM-ATT-
037). 
 
 
Study folders will be unlocked by the Quanticate Information Systems (IS) department 
on receipt of the ‘Database Unlock Authorisation Form’ (CDM-ATT-037).  
 
Data corrections will be made in accordance with CDM-SOP-008 (‘Editing Data’). A 
QC check will be performed to ensure that only approved changes to the data were 
actioned. This will be documented by the LCDM in compliance with GEN-SOP-024 
(‘Study Master File’). Changes that are made must be documented in an audit trail.  
The database will be re-locked following completion of ‘Database Lock Authorisation 
Form’ (CDM-ATT-036) 
8.21 Export 
Exports of data will occur at the following time points: 
 Test transfer following initial data entry into production database. In the event of 
any errors, further test transfers may be required. 
 5 transfers of the exported data from the clinical database will be provided to 
GW. Each transfer will be sent only following a documented request from GW. 
 Upon written request from GW, the final database, following database lock. The 
data extracts include data extracted from the clinical database and any external 
data. 
Data extracts include data extracted from the clinical database and any external data. 
All exported datasets will be in PC SAS v9.1 in the Quanticate format as per the 
aCRF/DSD. The datasets will be made available to GW via Quanticate’s online portal 
(QuantiCliQ). The CRFs and SMF will be sent to GW within 3 months of the completion 
of the final Clinical Study Report (CSR) and once all CDM invoices have been settled. 
8.22 Screen Failures 
The following pages will be collected and databased for screen failure patients: Page 1, 
Screen failure page (SF), AE page (if any occurred) and the Investigator signature page. 
These pages will be tracked and stored with the completed CRF’s in the designated 


Data Management Plan 
Customer: GW Research Ltd 
Quanticate Project Number: Q_02553 
Protocol Number: GWEP1428                   Version 3.0 Approved 
Date:  01 Nov 2016 
 
ATTACHMENT NO.: CDM-ATT-008 VERSION: 6.0 
 
PAGE 31 OF 33 
COPYRIGHT © QUANTICATE LTD 
 
CONFIDENTIAL 
project storage area. Limited checks will be performed for screen failure patients are 
defined in the DVP. 
 
8.23 Control of the DMP 
Each new version of the DMP will be reviewed by a suitably qualified member of CDM 
and authorised before it is issued to the individuals defined in the distribution list (section 
5). A copy of the updated authorised document will be stored in the SMF in addition to 
the original copy. 


Data Management Plan 
Customer: GW Research Ltd 
Quanticate Project Number: Q_02553 
Protocol Number: GWEP1428                   Version 3.0 Approved 
Date:  01 Nov 2016 
 
ATTACHMENT NO.: CDM-ATT-008 VERSION: 6.0 
 
PAGE 32 OF 33 
COPYRIGHT © QUANTICATE LTD 
 
CONFIDENTIAL 
 
9 
Appendix 1 
9.1 
SOPs to be Followed 
9.1.1 Quanticate SOPs: 
Number 
Title 
Version 
CDM-SOP-001 
Database Design 
5.0 
CDM-SOP-002 
Data Management Plan 
4.0 
CDM-SOP-003 
Data Entry 
5.0 
CDM-SOP-004 
Case Report Form Design 
4.0 
CDM-SOP-005 
Medical Coding 
4.0 
CDM-SOP-006 
Data Validation 
5.0 
CDM-SOP-007 
Discrepancy Management 
5.0 
CDM-SOP-008 
Editing Data 
4.0 
CDM-SOP-010 
Final Data Quality Control 
4.0 
CDM-SOP-011 
CRF Logging and Tracking 
6.0 
CDM-SOP-012 
Database Lock and Unlock 
6.0 
CDM-SOP-013 
Serious Adverse Event Reconciliation 
4.0 
CDM-SOP-014 
Laboratory Data Handling 
3.0 
CDM-SOP-017 
Database Administration 
5.0 
GEN-SOP-004 
Document Management and Version Control 
5.0 
GEN-SOP-013 
Data Transfer 
2.0 
GEN-SOP-015 
Good Document Practice 
2.0 
GEN-SOP-017 
Company Communication  
3.0 
GEN-SOP-018 
Escalation and Documentation of Project Issues 
1.0 
GEN-SOP-019 
Records Retention and Return to Customer 
3.0 
GEN-SOP-022 
Final Inspection of Quality Control Documentation Prior to 
Release of Product to the Customer 
4.0 
GEN-SOP-024 
Study Master File 
1.0 
 


Data Management Plan 
Customer: GW Research Ltd 
Quanticate Project Number: Q_02553 
Protocol Number: GWEP1428                   Version 3.0 Approved 
Date:  01 Nov 2016 
 
ATTACHMENT NO.: CDM-ATT-008 VERSION: 6.0 
 
PAGE 33 OF 33 
COPYRIGHT © QUANTICATE LTD 
 
CONFIDENTIAL 
The current version of these SOPs will be adhered to throughout the duration of the 
project. An SOP deviation will be created to explain why updated versions of SOPs are 
not being adhered to (if applicable). 
Updated versions of these SOPs (if applicable) will be adhered to and the customer will 
be informed of changes between previous and updated SOPs. New versions of SOPs 
will be inserted in to the SOP table above. 
 
 


Final Data Quality Control Plan 
Customer: GW Research Ltd 
Quanticate Project Number: Q_02553 
Protocol Number: GWEP1428 
Version: 3 Approved 
Date: 23 Sep 2016 
 
ATTACHMENT NO.: CDM-ATT-020 VERSION 5.0 
 
PAGE 1 OF 19 
COPYRIGHT © QUANTICATE LTD 
 
CONFIDENTIAL 
 
 
GWEP1428 
 
A PHASE 2, DOUBLE-BLIND, RANDOMIZED, PLACEBO-
CONTROLLED STUDY TO INVESTIGATE POSSIBLE DRUG-
DRUG INTERACTIONS BETWEEN CLOBAZAM AND 
CANNABIDIOL (GWP42003-P) 
 
FINAL DATA QUALITY CONTROL PLAN 
 
 
 
 
Author: 
 
Job Title: 
 
 
 
 
 
PPD
PPD


Final Data Quality Control Plan 
Q Quanticate 
Customer: GIN ResearM ltd 
Ptotocol Number: GWEP1428 
1 
Approval Form 
QUANTICATE AUTHOR 
Name: 
 
Position: 
 
QU.ANTICATE REVIEW 
Name: 
 
Position: 
 
QUANTICATE REVIEW 
Name: 
 
GW RESEARCH l TO APPROVAL 
Name: 
 
Position: 
 
AiTACHMENT NO.: OJM.ATI -020 VERSION 5.0 
COPYRIGHT C QUAN'TlCATE l.TD 
Quantlcate Project Number. 0_02553 
Version: 3 Approved 
Date: 23 Sep 2016 
2.1-
2ol" 
Date 
2.)-S €.('- UJ{, 
Oale 
PAGE20F19 
CONFIOENTlAI.. 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


Final Data Quality Control Plan 
Customer: GW Research Ltd 
Quanticate Project Number: Q_02553 
Protocol Number: GWEP1428 
Version: 3 Approved 
Date: 23 Sep 2016 
 
ATTACHMENT NO.: CDM-ATT-020 VERSION 5.0 
 
PAGE 3 OF 19 
COPYRIGHT © QUANTICATE LTD 
 
CONFIDENTIAL 
2 
Table of Contents 
1 
Approval Form.............................................................................................................. 2 
2 
Table of Contents ......................................................................................................... 3 
3 
Version Controlled Document Log .............................................................................. 4 
4 
Glossary of Terms ........................................................................................................ 4 
5 
Final Data Quality Control ............................................................................................ 5 
5.1 
Critical Item QC ....................................................................................................... 5 
5.2 
Random Selection QC ..........................................................................................18 
5.3 
Definition of an Error ..............................................................................................19 
 
 
 
 
 
 
 
 
 
 
 
 
 


Final Data Quality Control Plan 
Customer: GW Research Ltd 
Quanticate Project Number: Q_02553 
Protocol Number: GWEP1428 
Version: 3 Approved 
Date: 23 Sep 2016 
 
ATTACHMENT NO.: CDM-ATT-020 VERSION 5.0 
 
PAGE 4 OF 19 
COPYRIGHT © QUANTICATE LTD 
 
CONFIDENTIAL 
3 
Version Controlled Document Log 
Effective Date 
Version 
Change 
29 Aug 2016 
1.0 
First Issued. 
13 Sep 2016 
2.0 
Datasets GNIC, EX, EXADEX, EXAD were added to 
Critical QC  
Datasets SMUBQS, SMUB, SF, DIDI, CHK, 
DASCDASC, DASC, DASP, AESP were added to 
Random QC. 
23 Sep 2016 
3.0 
From Page 11 ‘Was the dose of IMP adjusted by the 
Investigator?” was removed as not applicable for this 
study 
Added CONCOMITANT ANTIEPILEPTIC 
MEDICATIONS (Page AED._) 
Added additional datasets names to Random Selection 
QC  
 
4 
Glossary of Terms 
CRF 
Case Report Form 
DCF 
Data Clarification Form 
DCM 
Data Collection Module 
QC 
Quality Control 
 
 
 
 


Final Data Quality Control Plan 
Customer: GW Research Ltd 
Quanticate Project Number: Q_02553 
Protocol Number: GWEP1428 
Version: 3 Approved 
Date: 23 Sep 2016 
 
ATTACHMENT NO.: CDM-ATT-020 VERSION 5.0 
 
PAGE 5 OF 19 
COPYRIGHT © QUANTICATE LTD 
 
CONFIDENTIAL 
5 
Final Data Quality Control 
The following Quality Control will be performed on the data in the database in 
accordance with CDM-SOP-010 (‘Final Data Quality Control’) and prior to database lock 
being declared. 
5.1 
Critical Item QC 
100% of the data indicated below as being critical items, including query updates and 
any other relevant documentation, will be checked against the data in the database. All 
findings will be documented on the ‘Final Data Quality Control Form’ (CDM-ATT-022) 
and corrected. All updates will be checked by an appropriately qualified member of 
Quanticate Clinical Data Management independent of the person who performed the 
update. 
Section 
DCM 
OC SAS Name 
GW SAS Name 
INFORMED CONSENT (Page B1) 
Date of informed consent  
SV[1] 
INFORDN 
INFORMDN 
 
 
 
 
GENETIC TESTING INFORMED CONSENT (Page B1)  
 
Was informed consent for genetic testing 
obtained? 
GNIC 
ICGYN 
 
ICGYN 
 
Date of informed consent for genetic 
testing 
GNIC 
ICGDT 
ICGDT 
 
 
 
 
DEMOGRAPHICS (Page B1) 
Date of birth  
DM[1] 
DOB 
DOB 
Sex  
DM[1] 
SEX 
SEX 
Race  
DM[1] 
RACE 
RACE 
Other, Specify:  
DM[1] 
RACETX 
RACETX 


Final Data Quality Control Plan 
Customer: GW Research Ltd 
Quanticate Project Number: Q_02553 
Protocol Number: GWEP1428 
Version: 3 Approved 
Date: 23 Sep 2016 
 
ATTACHMENT NO.: CDM-ATT-020 VERSION 5.0 
 
PAGE 6 OF 19 
COPYRIGHT © QUANTICATE LTD 
 
CONFIDENTIAL 
GENETIC TESTING HISTORY(Page B6)  
 
Has the patient had genetic testing 
performed in the past?  
MHGN 
MH_YN 
MH_YN 
Test name  
 
MHGN 
MHTERM 
MHTERM 
Was a mutation found?  
 
MHGN 
MUTNYN 
MUTNYN 
If yes, list the specific mutation(s) 
MHGN 
MUTNSPC 
MUTNSPC 
Did either parent have the mutation?  
 
MHGN 
PRMUTN 
PRMUTN 
Were they mosaic for the mutation?  
 
MHGN 
MSCMUTN 
MSCMUTN 
Additional genetic testing history page  
 
MHGN 
MHADD 
MHADD 
If tested off-site, has the report from 
the genetic testing center been 
received and filed?
MHGN 
GENTYN 
GENTYN 
Was a genome wide SNP array 
performed?  
MHGN 
SNPYN 
SNPYN 
If yes, please record any abnormal 
results below 
MHGN 
SNPSPC 
SNPSPC 
Was an epilepsy gene panel 
performed?  
MHGN 
EPLSYN 
EPLSYN 
If yes, please record any abnormal 
results below 
MHGN 
EPLSSPC 
EPLSSPC 
Was a whole exome sequencing 
performed?  
MHGN 
EXOMYN 
EXOMYN 
If yes, please record any abnormal 
results below 
MHGN 
EXOMSPC 
EXOMSPC 
PHYSICAL EXAMINATION (Pages B18, B26, B31, B36, B44, B50, O2, O8, O14, O20, 
O26, O32, O38, O45) 
Were any of the results of Physical 
examination indicative of a medical 
condition? 
PE 
PEMC 
PEMC 
Height 
PE 
HEIGHT 
HEIGHT 
Weight 
PE 
WEIGHT 
WEIGHT 


Final Data Quality Control Plan 
Customer: GW Research Ltd 
Quanticate Project Number: Q_02553 
Protocol Number: GWEP1428 
Version: 3 Approved 
Date: 23 Sep 2016 
 
ATTACHMENT NO.: CDM-ATT-020 VERSION 5.0 
 
PAGE 7 OF 19 
COPYRIGHT © QUANTICATE LTD 
 
CONFIDENTIAL 
INCLUSION CRITERIA (Page 14) 
Inclusion Criteria 
INC 
INC # 1-13 
INC 1-13 
 
EXCLUSION CRITERIA (Page 15,16) 
 Exclusion Criteria 
EXC 
EXC # 1-23 
EXC 1-23 
VITAL SIGNS (Pages B10,B18, B26, B31, B36, B44, B50, O2, O8, O14, O20, O26, 
O32, O38, O45,) 
Pulse rate 
VS 
PULSE 
PULSE 
Respiratory rate 
VS 
RESP 
RESP 
Temperature 
VS 
TEMP 
TEMP 
BLOOD PRESSURE (Pages B10,B18, B26, B31, B36, B44, B50, O2, O8, O14, O20, 
O26, O32, O38, O45) 
Arm used 
VS 
VSARM 
VSARM 
Sitting Blood Pressure 
VS 
VSSISYS 
VSSISYS 
Sitting Blood Pressure 
VS 
VSSIDIA 
VSSIDIA 
Supine Blood Pressure 
VS 
VSSPSYS 
VSSPSYS 
Supine Blood Pressure 
VS 
VSSPDIA 
VSSPDIA 
Standing Blood Pressure 
VS 
VSSTSYS 
VSSTSYS 
Standing Blood Pressure 
VS 
VSSTDIA 
VSSTDIA 
Are any of the vital signs or blood 
pressure results indicative of a medical 
condition? 
VS 
VSMC 
VSMC 
 
 
 
 
 
 
 
 


Final Data Quality Control Plan 
Customer: GW Research Ltd 
Quanticate Project Number: Q_02553 
Protocol Number: GWEP1428 
Version: 3 Approved 
Date: 23 Sep 2016 
 
ATTACHMENT NO.: CDM-ATT-020 VERSION 5.0 
 
PAGE 8 OF 19 
COPYRIGHT © QUANTICATE LTD 
 
CONFIDENTIAL 
12-LEAD ELECTROCARDIOGRAM (Pages B11, B19, B32, B37, B51, O3, O9, O15, 
O21, O27, O33, O39, O46) 
Date of 12- Lead ECG  
ECG 
ECGDN 
ECGDN 
Rhythm  
ECG 
EGABN 
EGABN 
Comments  
ECG 
ABNCOM 
ABNCOM 
Ventricular Rate  
ECG 
EGVR 
EGVR 
PR Interval  
ECG 
EGPR 
EGPR 
QRS duration  
ECG 
EGQRS 
EGQRS 
QT Interval  
ECG 
EGQT 
EGQT 
QTcB  
ECG 
EGQTCB 
EGQTCB 
ST or T-wave changes  
ECG 
EGST 
EGST 
Comments  
ECG 
ECGCOM 
ECGCOM 
Abnormality  
ECG 
EGCND 
EGCND 
Infarct pattern / R-wave progression  
ECG 
EGINF 
EGINF 
Are any of the results indicative of a 
medical condition?  
ECG 
ECGMC 
ECGMC 
STUDY MEDICATION (Pages B29, B40, B46)  
 
Date of administration 
EX 
EXDT 
EXDT 
Time of administration (morning dose) 
EX 
EXAMTM 
EXAMTM 
Time of administration (evening dose) 
EX 
EXPMTM 
EXPMTM 
Time of First dose of Study Medication 
EX 
EXTM 
EXTM 


Final Data Quality Control Plan 
Customer: GW Research Ltd 
Quanticate Project Number: Q_02553 
Protocol Number: GWEP1428 
Version: 3 Approved 
Date: 23 Sep 2016 
 
ATTACHMENT NO.: CDM-ATT-020 VERSION 5.0 
 
PAGE 9 OF 19 
COPYRIGHT © QUANTICATE LTD 
 
CONFIDENTIAL 
CLINICAL LABORATORY BLOOD AND URINE SAMPLING (Pages B12, B20, B33, 
B38, B52, O4, O10, O16, O22, O28, O34, O40, O47) 
Have blood samples been taken?  
LB 
LBBLOOD 
LBBLOOD 
If no, reason 
LB 
BLDSPC 
BLDSPC 
Has a urine sample for urinalysis been 
taken?  
LB 
LBURINE 
LBURINE 
If no, reason 
LB 
URNSPC 
URNSPC 
Are any of the urinalysis or blood results 
indicative of a medical condition?  
LB 
LBRESMC 
LBRESMC 
Are any of the urinalysis or blood results 
indicative of an Adverse Event? 
LB 
LBRESMC 
LBRESMC 
Was a urine sample collected for THC?  
LB 
LBTHC 
LBTHC  
Is a repeat blood sample required? 
LB 
LBREPYN 
LBREPYN 
Date repeat blood sample taken  
LB 
LBREPDN 
LBREPDN 
Is a repeat urine sample required?  
LB 
REPURYN 
REPURYN 
Date repeat urine sample taken  
LB 
REPURDN 
REPURDN 
Is the patient of child bearing potential?  
LB 
LBPOTYN 
LBPOTYN 
Was a urinalysis sample sent for further 
analysis to central lab? 
LB 
LBURCL 
LBURCL 
Results of serum pregnancy test (for 
patient of child bearing potential) 
LB 
PRGRES 
PRGRES 
 
Was a blood sample collected for 
serum alcohol testing? 
LB 
LBALCYN 
LBALCYN 
Result of serum alcohol test 
LB 
ALCRES 
ALCRES 
Was a blood sample collected for 
genetic testing? 
LB 
LBGENYN 
LBGENYN 


Final Data Quality Control Plan 
Customer: GW Research Ltd 
Quanticate Project Number: Q_02553 
Protocol Number: GWEP1428 
Version: 3 Approved 
Date: 23 Sep 2016 
 
ATTACHMENT NO.: CDM-ATT-020 VERSION 5.0 
 
PAGE 10 OF 19 
COPYRIGHT © QUANTICATE LTD 
 
CONFIDENTIAL 
COMPLETION OF QUESTIONNAIRES (COLUMBIA –SUICIDE SEVERITY RATING 
SCALE (C-SSRS) (Page B13, B21, B34, B39, B53, 05, O11, O17,O23, O29, O35, O41, 
O48) 
Has the C-SSRS been completed? 
QSYN 
CSSR_YN 
CSSR_YN 
STUDY MEDICATION DOSE ADJUSTMENT LOG (Page DAL) 
Study medication dose adjustments 
made during the study? 
EXAD 
EXYN 
EXYN 
Date of adjustment 
EXADEX 
EXADDT 
EXADDT 
Dose adjusted to 
EXADEX 
EXDOSE 
EXDOSE 
Dose units 
EXADEX 
EXDOSU 
EXDOSU 
Reason for dose adjustment 
EXADEX 
EXADJ 
EXADJ 
Reason for dose adjustment: Other 
specify 
EXADEX 
EXSPC 
EXSPC 
AE number 
EXADEX 
AENUM 
AENUM 
Additional study medication dose 
adjustment page 
EXAD 
EXADD 
EXADD 
PHARMACOKINETIC BLOOD SAMPLING (Page B23,B27,B41,B45,)  
Time-point  
 
LBPK 
LBTPT 
LBTPT 
Collection date  
 
LBPK 
LBDT 
LBDT 


Final Data Quality Control Plan 
Customer: GW Research Ltd 
Quanticate Project Number: Q_02553 
Protocol Number: GWEP1428 
Version: 3 Approved 
Date: 23 Sep 2016 
 
ATTACHMENT NO.: CDM-ATT-020 VERSION 5.0 
 
PAGE 11 OF 19 
COPYRIGHT © QUANTICATE LTD 
 
CONFIDENTIAL 
Collection time  
 
LBPK 
LBDM 
LBDM 
Not done  
 
LBPK 
LBND 
LBND 
Comments 
 
LBPK 
LBCOM 
LBCOM 
STUDY MEDICATION (Pages B29, B40, B46, B54, O6, O12, O18, O24, O30, O36, 
O42, O49) 
Was medication dispensed? 
DA 
MEDDIS 
MEDDIS 
Number packs (bottles) dispensed at this 
visit 
DA 
DADISP 
DADISP 
Was the first dose of study medication 
administered on site? 
DA 
FSTDOS 
FSTDOS 
If no, specify 
DA 
FSTSPC 
FSTSPC 
Time of first dose of study 
medication 
DA 
DOSETM 
DOSETM 
Was IMP returned? 
DA 
DARETURN 
DARETUN 
Was IMP returned? (Blinded medication) DA 
BLDRYN 
BLDRYN 
If yes, how many packs/bottles (used 
and unused) were returned? 
DA 
BLDRET 
BLDRET 
Was IMP returned? (OLE medication) 
DA 
OLERYN 
OLERYN 
If yes, how many packs/bottles (used 
and unused) were returned? 
DA 
OLERET 
OLERET 
Does the actual IMP usage reflects the 
expected amount used as per dosing 
schedule??  
DA 
DAUSED 
DAUSED 
If no please record 
DA 
DACOM 
DACOM 
Were there some signals of potential 
abuse since last visit? 
DA 
DASPAB 
DASPAB 


Final Data Quality Control Plan 
Customer: GW Research Ltd 
Quanticate Project Number: Q_02553 
Protocol Number: GWEP1428 
Version: 3 Approved 
Date: 23 Sep 2016 
 
ATTACHMENT NO.: CDM-ATT-020 VERSION 5.0 
 
PAGE 12 OF 19 
COPYRIGHT © QUANTICATE LTD 
 
CONFIDENTIAL 
Were the two doses of study 
medication administered on site? 
DA 
DAADM 
DAADM 
If no, specify 
DA 
FSTSPC 
FSTSPC 
Was medication dispensed? 
DA 
MEDDIS 
MEDDIS 
Number of packs (bottles )dispensed at 
this visit 
DA 
DADISP 
DADISP 
IMP COMPLIANCE REVIEW (Pages B30, 35, 49, O1, O7, O13, O19, O25, O31, O37, 
O44) 
Did the patient comply with the dosing 
schedule? 
IMP 
DACOMP 
DACOMP 
CONCOMITANT RESCUE MEDICATIONS (Page RM._) 
Has the patient taken any rescue 
medication in the 14 days prior to 
screening Visit or during the course of 
the study?  
CM 
CM_YN 
CM_YN 
Generic name  
CM 
CMTRT 
CMTRT 
Brand name  
CM 
CMBRDNM 
CMBRDNM 
Dose  
CM 
CMDSTXT 
CMDSTXT 
Units  
CM 
CMDOSU 
CMDOSU 
Route  
CM 
CMROUTE 
CMROUTE 
Frequency  
CM 
CMDOSFR 
CMDOSFR 
Start date  
CM 
CMSTDT 
CMSTDT 
Stop date  
CM 
CMENDT 
CMENDT 
Continuing at the end of the study? 
CM 
CMONGO 
CMONGO 
Reason 
CM 
CMREAS 
CMREAS 
Additional other concomitant medication 
page  
CM 
CMADD 
CMADD 


Final Data Quality Control Plan 
Customer: GW Research Ltd 
Quanticate Project Number: Q_02553 
Protocol Number: GWEP1428 
Version: 3 Approved 
Date: 23 Sep 2016 
 
ATTACHMENT NO.: CDM-ATT-020 VERSION 5.0 
 
PAGE 13 OF 19 
COPYRIGHT © QUANTICATE LTD 
 
CONFIDENTIAL 
OTHER CONCOMITANT MEDICATIONS (MED._) 
Has the patient taken any other 
concomitant medications in the 14 days 
prior to the screening visit or during the 
course of the study?  
CM 
CM_YN 
CM_YN 
Medication name(Generic name)  
CM 
CMTRT 
CMTRT 
Indication 
CM 
CMINDC 
CMINDC 
Dose  
CM 
CMDSTXT 
CMDSTXT 
Units  
CM 
CMDOSU 
CMDOSU 
Route  
CM 
CMROUTE 
CMROUTE 
Frequency  
CM 
CMDOSFR 
CMDOSFR 
Start date  
CM 
CMSTDT 
CMSTDT 
Stop date  
CM 
CMENDT 
CMENDT 
Continuing at the end of the study?  
CM 
CMONGO 
CMONGO 
Additional other concomitant medication 
page  
CM 
CMADD 
CMADD 
CONCOMITANT ANTIEPILEPTIC MEDICATIONS (Page AED._) 
Has the patient taken any concomitant 
antiepileptic medications (excluding 
rescue medications) in the 14? 
CM 
CM_YN 
CM_YN 
 
Generic name  
 
CM 
CMTRT 
CMTRT 
Brand name 
 
CM 
CMBRDNM 
CMBRDNM 
Dose 
CM 
CMDSTX 
CMDSTX 
Units 
CM 
CMDOSU 
CMDOSU 


Final Data Quality Control Plan 
Customer: GW Research Ltd 
Quanticate Project Number: Q_02553 
Protocol Number: GWEP1428 
Version: 3 Approved 
Date: 23 Sep 2016 
 
ATTACHMENT NO.: CDM-ATT-020 VERSION 5.0 
 
PAGE 14 OF 19 
COPYRIGHT © QUANTICATE LTD 
 
CONFIDENTIAL 
Route 
CM 
CMROUT 
CMROUT 
Frequency 
CM 
CMDOSFR 
CMDOSFR 
Start date 
CM 
CMSTDT 
CMSTDT 
Stop date 
CM 
CMENDT 
CMENDT 
Reason  
CM 
CMREAS 
CMREAS 
AE number 
CM 
AENUM 
AENUM 
Specify Comment 
CM 
CMSPC 
CMSPC 
Continuing at the end of study 
CM 
CMONGO 
CMONGO 
Additional other concomitant medication 
page  
CM 
CMADD 
CMADD 
CONCOMITANT ANTI EPILEPTIC THERAPIES (Page AET._) 
Has the patient used a ketogenic diet in 
the 4 weeks prior to Visit 1 or during the 
course of the study?  
CM 
CM_YN 
CM_YN 
If yes, start date: 
CM 
CMSTDT 
CMSTDT 
If yes, stop date:  
CM 
CMENDT 
CMENDT 
Ongoing  
CM 
CMONGO 
CMONGO 
Has the patient used VNS in the 4 
weeks prior to Visit 1 or during the 
course of the study?  
CM 
CM_YN 
CM_YN 
If yes, start date:  
CM 
CMSTDT 
CMSTDT 
If yes, stop date:  
CM 
CMENDT 
CMENDT 
Ongoing  
CM 
CMONGO 
CMONGO 
Additional other concomitant medication 
page 
CM 
CMADD 
CMADD 


Final Data Quality Control Plan 
Customer: GW Research Ltd 
Quanticate Project Number: Q_02553 
Protocol Number: GWEP1428 
Version: 3 Approved 
Date: 23 Sep 2016 
 
ATTACHMENT NO.: CDM-ATT-020 VERSION 5.0 
 
PAGE 15 OF 19 
COPYRIGHT © QUANTICATE LTD 
 
CONFIDENTIAL 
ADVERSE EVENTS (Page AE.1 and AE._) 
Adverse Event  
AE 
AETERM 
AETERM 
Start date  
AE 
AESTDT 
AESTDT 
Stop date  
AE 
AEENDT 
AEENDT 
Duration  
AE 
AEDURTM 
AEDURTM 
Outcome  
AE 
AEOUT 
AEOUT 
Severity  
AE 
AESEV 
AESEV 
Plausible relationship to Study  
Medication  
AE 
AEREL 
AEREL 
Action taken with Study  
Medication  
AE 
AEACN 
AEACN 
Serious Adverse Event  
AE 
AESER 
AESER 
Additional Adverse Event page  
AE 
AEADD 
AEADD 
END OF BLINDED PHASE STUDY OUTCOME (Page B48) 
Date of blinded phase completion or 
withdrawal   
DSTR 
DSSTDT 
DSSTDT 
Did the patient complete the blinded 
phase as planned? 
DSTR 
TRTYN 
TRTYN 
Date of last dose 
DSTR 
DSLSTDT 
DSLSTDT 
Is the patient continuing to the open 
label extension? 
DSTR 
CONTOPN 
CONTOPN 
If no, state reason 
DSTR 
CONTSPC 
CONTSPC 
Is the patient continuing to taper period?  DSTR 
CONTAP 
CONTAP 
If No, state reason 
DSTR 
TAPSPC 
TAPSPC 


Final Data Quality Control Plan 
Customer: GW Research Ltd 
Quanticate Project Number: Q_02553 
Protocol Number: GWEP1428 
Version: 3 Approved 
Date: 23 Sep 2016 
 
ATTACHMENT NO.: CDM-ATT-020 VERSION 5.0 
 
PAGE 16 OF 19 
COPYRIGHT © QUANTICATE LTD 
 
CONFIDENTIAL 
Specify the treatment option the patient 
will receive 
DSTR 
TRTOPT 
TRTOPT 
If other, specify 
DSTR 
TRTSPC 
TRTSPC 
Primary Reason for Withdrawal 
DSTR 
DSTERM 
DSTERM 
Corresponding AE number(s) 
DSTR 
OCAEITX 
OCAEITX 
Patient and/or legal representative 
withdrew consent to participate, specify 
DSTR 
OCCOSTX 
OCCOSTX 
Patient met (protocol specified) 
withdrawal criteria, Specify criteria 
DSTR 
OCPROTX 
OCPROTX 
Patient was withdrawn from participation 
by the Investigator , Specify 
DSTR 
OCINVTX 
OCINVTX 
Specify 
DSTR 
DSSPEC 
DSSPEC 
STUDY OUTCOME – TREATMENT PHASE (Page O43) 
Date of treatment phase completion or 
withdrawal   
DSTR 
DSSTDT 
DSSTDT 
Did the patient complete the treatment 
phase as planned?  
DSTR 
TRTYN 
TRTYN 
Date of last dose 
DSTR 
DSLSTDT 
DSLSTDT 
Is the patient continuing to taper period?  DSTR 
CONTAP 
CONTAP 
If No, state reason  
DSTR 
TAPSPC 
TAPSPC 
Is the patient going to receive a 
Treatment option? 
DSTR 
TRTOPT 
TRTOPT 
If yes, 
DSTR 
TRTSPC 
TRTSPC 
Primary Reason for Withdrawal  
DSTR  
DSTERM 
DSTERM 
Corresponding AE number(s)  
DSTR 
OCAEITX 
OCAEITX 


Final Data Quality Control Plan 
Customer: GW Research Ltd 
Quanticate Project Number: Q_02553 
Protocol Number: GWEP1428 
Version: 3 Approved 
Date: 23 Sep 2016 
 
ATTACHMENT NO.: CDM-ATT-020 VERSION 5.0 
 
PAGE 17 OF 19 
COPYRIGHT © QUANTICATE LTD 
 
CONFIDENTIAL 
Patient or parent/legal representative 
withdrew consent to participate  
Specify  
DSTR 
OCCOSTX 
OCCOSTX 
Patient met (protocol specified) 
withdrawal criteria  
Specify criteria  
DSTR 
OCPROTX 
OCPROTX 
Other, Specify  
DSTR 
DSSPEC 
DSSPC 
END OF TAPER STUDY OUTCOME (Page B57, O52) 
Date of last taper dose  
DSTP 
DSLSTDT 
DSLSTDT 
Was the taper period completed?  
DSTP 
TAPYN 
TAPPYN 
Specify the treatment option the patient 
will receive 
DSTP 
TRTOPT 
TRTOPT 
Other, specify 
DSTP 
TRTSPC 
TRTSPC 
Primary Reason for not completing the 
taper period 
DSTP  
DSTERM 
DSTERM 
Adverse event number(s) 
DSTP 
OCAEITX 
OCAEITX 
Patient withdrew consent to participate  
Specify  
DSTP 
OCCOSTX 
OCCOSTX 
Patient met (protocol specified) 
withdrawal criteria  
Specify criteria  
DSTP 
OCPROTX 
OCPROTX 
Patient was withdrawn from participation 
by the Investigator  
Specify  
DSTP 
OCINVTX 
OCINVTX 
Other, Specify  
 
DSTR 
DSSPEC 
DSSPC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Final Data Quality Control Plan 
Customer: GW Research Ltd 
Quanticate Project Number: Q_02553 
Protocol Number: GWEP1428 
Version: 3 Approved 
Date: 23 Sep 2016 
 
ATTACHMENT NO.: CDM-ATT-020 VERSION 5.0 
 
PAGE 18 OF 19 
COPYRIGHT © QUANTICATE LTD 
 
CONFIDENTIAL 
5.2 
Random Selection QC 
A random selection of the subjects in the project database will have the non-critical CRF 
data (and related documents such as Data Clarification Forms, Self Evident 
Corrections, Data Entry Guidelines) checked against the database. Data received as 
electronic copies from third-party providers/vendors will not be QC’d. 
Non Critical CRF datasets: 
Datasets 
Description 
MHEE 
Electroencephalography (EEG) History  
MHNR 
Neuroimaging History  
CMAE 
& CMAECM 
 
History of Anti-Epileptic Medications (AEDs) And Therapies  
MHSZ(1) 
& MHSZMH 
 
History of Seizures no longer occurring 
MHSZ(2) 
& MHSZMH 
 
History of Current Seizures 
MH 
&MHMH 
 
Non-Epilepsy Medical History 
CANN 
Previous Use Of Cannabis  
DIYN 
Patient Diary 
CSSR 
Columbia-Suicide Severity Rating Scale (C-SSRS)  
SV 
Visit dates 
INV 
Investigator signature and date 
FUP & FUPFUP 
Telephone Follow-up, Safety Telephone Follow-up 
CO 
& COCO 
 
General Comments 
DIDI 
Epilepsy Daily Diary Record  
CHK 
Has the patient had a change in any medication or therapies/AE since 
the previous visit? 
SF 
Screen Failure 
SMUB & 
SMUBQS 
 
Study Medication Use & Behaviour Survey  
DASP 
Supplemental Drug Accountability Form  
AESP 
Supplemental Adverse Event Form 
DASC & 
DASCDASC 
 
Site Classification Form  


Final Data Quality Control Plan 
Customer: GW Research Ltd 
Quanticate Project Number: Q_02553 
Protocol Number: GWEP1428 
Version: 3 Approved 
Date: 23 Sep 2016 
 
ATTACHMENT NO.: CDM-ATT-020 VERSION 5.0 
 
PAGE 19 OF 19 
COPYRIGHT © QUANTICATE LTD 
 
CONFIDENTIAL 
The number of subjects selected is determined by the total number of subjects in the 
project: 
 
For 100 subjects or less: 10% of the number of subjects (n) in the project, with a 
minimum of 3 subjects. 
 
For over 100 subjects: square root of the number of subjects, plus one. i.e. (√n)+1. 
Subjects will be selected using the RANUNI random function within SAS. 20 subjects 
are planned for this project; therefore a planned 3 subjects will be selected randomly for 
the QC process. The subject numbers of the selected subjects will be recorded in the 
‘Final Data Quality Control Report’ (CDM-ATT-021). 
All findings will be documented on the 'Final Data Quality Control Form’ (CDM-ATT-022) 
and corrected. All updates will be checked by an appropriately qualified member of 
Quanticate Clinical Data Management independent of the person who performed the 
update to assess if the finding is an error. 
In order for the database to be released for analysis, an error rate of the Quanticate 
standard of less than or equal to 0.05% must be obtained calculated as: 
100
*
 
reviewed
 
Points
 
Data
 
of
Number 
 
Total
(N)
 
Errors
 
of
Number 
 
Total
 
The number of errors will be totalled and expressed as a percentage of the total (non-
critical) variables audited. This error rate will then be applied to the database as a whole. 
If the Final Data QC fails, i.e. the error rate is greater than the Quanticate standard of 
less than or equal to 0.05% the customer will be informed and a further random sample 
of subject CRFs will be QC’d. The error rate is re-calculated and re-assessed on the 
new random sample. 
 
5.3 
Definition of an Error 
An error is: 
 
Any discrepancy between the CRF data and the data in the database where there 
is no documentation (e.g. DCF, Data Entry Guidelines, SEC) to support the 
discrepancy, except, spelling and/or punctuation mistakes which do not affect the 
meaning of the text. 
 
Incorrect updating of a DCF or incorrect implementation of a global ruling or 
incorrect application of a Self Evident Correction.