Conditions: Infantile Spasms
Keywords: GWP42003-P Cannabidiol
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 9
Healthy volunteers: no

Brief summary:
This trial consists of 3 parts: a pilot safety phase, a pivotal randomized controlled phase, and an open-label extension phase. The open-label extension phase only will be described in this record. All participants will receive GWP42003-P.

Detailed description:

Arms:
arm 1: Administered orally, up to the target dose recommended by the data safety monitoring committee.

Participants continue at the target dose, or the highest tolerated dose up to the target dose, for a total of 12 months' treatment.

Interventions: intervention 1: GWP42003-P
Intervention descriptions: intervention 1: Clear, colorless to yellow solution containing cannabidiol dissolved in the excipients sesame oil and anhydrous ethanol with added sweetener (sucralose) and strawberry flavoring.

Protocol document:
Prot_000.pdf: 
Study Code: GWEP15100 
EudraCT Number: 2015-004904-50 
Protocol V3 20Sep16  
A Randomized, Double-blind, Placebo-controlled Trial to Investigate 
the Efficacy and Safety of Cannabidiol (CBD; GWP42003-P) in 
Infants with Infantile Spasms Following an Initial Open-label Pilot 
Study 
Study Code: GWEP15100
EudraCT Number: 2015-004904-50 
CLINICAL PROTOCOL 
GW Research Ltd 
Sovereign House 
Vision Park 
Chivers Way 
Histon 
Cambridge CB24 9BZ 
United Kingdom 
Tel: +44 (0) 1223 266 800 
Fax: +44 (0) 1223 235 667 
Confidentiality Statement 
This document contains confidential information of GW Research Ltd (GW) that 
must not be disclosed to anyone other than the recipient study staff and members of 
the institutional review board or independent ethics committee.  This information 
cannot be used for any purpose other than the evaluation or conduct of the clinical 
investigation without the prior written consent of GW. 
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NCT Number: NCT02953548
This NCT number has been applied to the document for
purposes of posting on clinicaltrials.gov




Study Code: GWEP15100 
EudraCT Number: 2015-004904-50 
Protocol V3 20Sep16  
1 
PROTOCOL SYNOPSIS 
Trial Title 
A Randomized, Double-blind, Placebo-controlled Trial to 
Investigate the Efficacy and Safety of Cannabidiol (CBD; 
GWP42003-P) in Infants with Infantile Spasms Following an 
Initial Open-label Pilot Study.    
Clinical Trial 
Type 
Phase 3. 
Indication 
Infantile spasms (IS). 
Primary Objective Pilot Phase: 
•
To determine the maximum safe, tolerable dose and dosing
regimen of GWP42003-P in infants with IS, to be utilized in
the pivotal phase and open-label extension (OLE).
•
To assess the number and proportion of patients considered
treatment responders, defined as those free of spasms and have
resolution of hypsarrhythmia at the end of the 2-week
treatment period.
Note: Resolution of hypsarrhythmia requires reduction of the
electroencephalography (EEG) background below 300 µV
AND elimination of any electrodecrements or epochs of
discontinuity. Persistence of some background slowing and
interictal epileptiform discharges may be seen and still be
consistent with resolution of hypsarrhythmia.
Pivotal Phase: 
•
To assess the number and proportion of patients considered
treatment responders, defined as those free of spasms and have
resolution of hypsarrhythmia, at the end of the 2-week blinded
treatment period versus placebo.
OLE: 
•
To assess the long term safety of GWP42003-P in infants with
IS.
Secondary 
Objective(s) 
All Phases: 
•
Key: To assess the number and proportion of patients who are
free of clinical spasms, as observed on
video-electroencephalography (video-EEG) at the end of the
treatment period.
•
Key: To assess the number and proportion of patients who
have resolution of hypsarrhythmia, as observed on video-EEG
at the end of the treatment period.
•
To assess changes in spasms and seizure subtypes by caregiver
observation during the treatment period.
•
To determine time to cessation of spasms during the treatment
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Protocol V3 20Sep16  
 
Secondary 
Objective(s) 
(continued) 
period, as determined by caregiver diaries. 
• To explore the effect of GWP42003-P on quality of life. 
Pivotal Phase Only:  
• To assess the safety and tolerability of GWP42003-P. 
• To determine the population pharmacokinetics (POPPK) of 
CBD and its metabolites (6-hydroxy-cannabidiol 
[6-OH-CBD], 7-carboxy-cannabidiol [7-COOH-CBD] and 7-
hydroxy-cannabidiol [7-OH-CBD]). 
OLE Only:  
• To assess the number and proportion of patients who are free 
of spasms and have resolution of hypsarrhythmia, after 3, 6, 9 
and 12 months of treatment.  
• To assess the number and proportion of responders who 
relapse and the time to relapse. 
• To explore the effect of GWP42003-P on growth, adaptive 
behavior and development.  
• To determine the population POPPK of CBD and its 
metabolites (6-OH-CBD, 7-COOH-CBD and 7-OH-CBD). 
Trial Design 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This is a multisite trial to evaluate the efficacy and safety of 
GWP42003-P in patients with IS who have failed to become 
spasm-free following treatment with 1 or more approved IS 
therapies (i.e., any therapy for the treatment of IS approved in 
Europe or the United States (US) [e.g., steroids and/or vigabatrin 
(VGB)]).  All approved therapies must be discussed with the 
patient’s parent(s)/legal representative before the patient is 
considered for the trial (discussions regarding treatment options 
must be documented).   
The trial will comprise of a pilot safety phase, followed by a 
pivotal phase, with a 1 year open-label extension available to all 
patients who complete either phase. The pilot phase will be 
open-label with 2 sequential cohorts of 5 patients (aged between 
6 and 24 months in the first cohort and between 1 and 24 months 
in the second cohort), who will receive GWP42003-P for 2 weeks.  
The pivotal phase will comprise 192 patients, aged 1–24 months, 
who will undergo a 2-week, randomized, placebo-controlled, 
double-blind treatment period.  
An independent data safety monitoring committee (DSMC) will 
be used throughout the study; they will consider safety of the 
patients and will confirm doses and dose regimens to be 
investigated in the pivotal phase, as well as the plans for dose 
titration.  
Patients will enter the pilot and pivotal phase at the respective 
screening visits (Visit 1, Day −7 to Day −1) for assessment of 
eligibility, which includes a prolonged video-EEG.  Patients who 
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Trial Design 
(continued) 
satisfy all eligibility criteria will then be administered 
GWP42003-P (pilot phase) or randomized to GWP42003-P (1 of 
2 dose levels) or placebo at a 1:1:1 ratio (pivotal phase) (Visit 2, 
Day 1 [+3 days]). The High Dose Level will be as recommended 
by the DSMC; the Low Dose Level will be defined as 50% of the 
High Dose Level. Patients in the placebo group will be split into 
2 equivalent cohorts: half receiving Low Dose Level dosing 
volumes and half receiving High Dose Level dosing volumes.  
Following baseline assessments, patients will titrate the 
investigational medicinal product (IMP) in 10 mg/kg/day 
increments to the target dose level (or equivalent volume of 
placebo in the pivotal phase) and will continue at this dose, or the 
highest tolerated dose up to a maximum of 40 mg/kg/day, for the 
remainder of the 2-week treatment phase.  Patients in the pilot 
phase will remain in the clinic as inpatients during the 4-day 
titration period.  If deemed safe by the DSMC, then it is planned 
for those in the pivotal phase to titrate in an outpatient setting.  
Further clinic-based assessments will take place after 3 days’ 
dosing (Visit 3, Day 4 [+1 day]).  All patients in the pilot and 
pivotal phases will return to the clinic after 2 weeks of dosing 
(Visit 4, Day 15 [+3 days]) or earlier if they withdraw 
prematurely.  All patients who complete treatment will then have 
the opportunity to receive GWP42003-P during the subsequent 
OLE phase.  The OLE phase will last for a maximum of 1 year. 
Patients who enter the OLE phase will remain on the same dose 
(pilot phase) or will transition to their target dose of GWP42003-P 
over 4 days in a blinded manner (pivotal phase).  Patients may 
continue at this dose, or the highest tolerated dose up to a 
maximum of 40 mg/kg/day, for the remainder of the OLE phase.  
GWP42003-P may be discontinued at the discretion of the 
investigator.  During the OLE phase, clinic visits will take place 
on Day 19 (Visit 5 [+1 day]), Day 29 (Visit 6 [±3 days]), Day 43 
(Visit 7 [±3 days]), Day 71 (Visit 8 [±3 days]), Day 127 (Visit 9 
[±7 days]), Day 211 (Visit 10 [±7 days]), and on Day 295 
(Visit 11 [±7 days]).  Patients will return to the site for an end of 
OLE treatment visit on Day 379 (Visit 12 [±7 days]) or earlier if 
they withdraw prematurely from the OLE phase.   
Following end of treatment, withdrawal, or discontinuation of 
IMP, all patients will taper the IMP over 10 days followed by 
safety follow-up.  Patient diaries will be completed each day by 
the caregiver during the trial. 
Primary Endpoint  
 
 
 
 
Pilot Phase: 
• To assess the safety as determined by adverse events (AEs), 
clinical laboratory tests, 12-lead electrocardiogram (ECG), 
vital signs and physical examinations during the treatment 
period. 
• The number and proportion of patients who are free of spasms 
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Primary Endpoint 
(continued) 
and have resolution of hypsarrhythmia at the end of the 
2-week treatment period, as determined by video-EEG. 
Pivotal Phase:  
• The number and proportion of patients who are free of spasms 
and have resolution of hypsarrhythmia at the end of the 2-
week treatment period, as determined by video-EEG. 
OLE:  
• To assess the long term safety as determined by AEs, clinical 
laboratory tests, ECG, vital signs and physical examinations 
during the treatment period. 
Secondary 
Endpoint(s) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
All Phases: 
The following endpoints will be analyzed separately for each 
phase: 
• Key: The number and proportion of patients who are free of 
clinical spasms, as observed on video-EEG at the end of the 
treatment period. 
• Key: The number and proportion of patients who have 
resolution of hypsarrhythmia, as observed on video-EEG at 
the end of the treatment period. 
• Changes in spasms and seizure subtypes by caregiver 
observation during the treatment period.  
• Time to cessation of spasms during the treatment period, as 
determined by caregiver diaries. 
• Caregiver Global Impression of Change (CGIC). 
• Physician Global Impression of Change (PGIC). 
Pivotal Phase Only: 
• Safety and tolerability as determined by AEs, clinical 
laboratory tests, ECG, physical examinations and vital signs. 
• Measurement, where possible, of plasma concentrations of 
CBD and its metabolites (6-OH-CBD, 7-COOH-CBD and 
7-OH-CBD) will be investigated using a sparse sampling 
approach, with the aim to define a POPPK model. 
OLE Only:  
• The number and proportion of patients who are free of spasms 
and have resolution of hypsarrhythmia, as determined by 
video-EEG after 3, 6, 9 and 12 months of treatment.  
• Number and proportion of responders with relapse of spasms, 
and the time to relapse, as determined by caregiver diaries. 
• Changes from baseline in length (height), body weight, and 
head circumference. 
• Change from baseline in Vineland Adaptive Behavior Scales, 
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Secondary 
Endpoint(s) 
(Continued) 
Second Edition (Vineland-II) score.  
• Measurement, where possible, of plasma concentrations of 
CBD and its metabolites (6-OH-CBD, 7-COOH-CBD and 
7-OH-CBD) will be investigated using a sparse sampling 
approach, with the aim to define a POPPK model. 
Sample Size 
 
 
 
 
The pilot phase is not powered and comprises 10 patients. 
The pivotal phase will comprise 192 patients.  Patients will be 
randomized to receive 1 of 2 dose levels of GWP42003-P (High 
Dose Level or Low Dose Level), or matching placebo, on a 1:1:1 
basis (64 per treatment group).  Patients in the placebo group will 
be further split into 2 cohorts (32 patients receiving High Dose 
Level volumes and 32 patients receiving Low Dose Level 
volumes), but it is assumed that these 2 cohorts can be pooled for 
the analyses of efficacy.  Assuming a 20% screen failure rate, it is 
expected that approximately 245 patients will need to be screened 
to achieve this target.   
 
 
 
 
 
  This is based on a 2-sided 5% significance level, 
based on a Fisher’s exact test. 
Summary of 
Patient Eligibility 
Criteria 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion Criteria 
For inclusion in the trial, patients must fulfil ALL of the following 
criteria: 
• Pilot phase: Patient is male or female aged 6–24 months 
(inclusive) in the first cohort or aged 1-24 months (inclusive) 
in the second cohort, at the time of consent. 
OR 
Pivotal phase: Patient is male or female aged 1–24 months 
(inclusive) at the time of consent. 
• Patient’s parent(s)/legal representative is willing and able to 
give informed consent for the patient’s participation in the 
trial. 
• Patient and their caregiver are willing and able (in the 
investigator’s opinion) to comply with all trial requirements. 
• Patient is diagnosed with IS (i.e., spasms and hypsarrhythmia 
are still evident on video-EEG at screening). 
Note: To be considered hypsarrhythmia, as defined for use in 
the study, the EEG background must be slowed and have 
multifocal spikes.  In addition, it must be EITHER high 
voltage (above 300 µV) OR have 
electrodecrement/discontinuity.     
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Study Code: GWEP15100 
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Summary of 
Patient Eligibility 
Criteria 
(continued) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• Patient has failed to respond adequately (i.e., spasms and/or 
hypsarrhythmia are observed on video-EEG at screening) 
following treatment with 1 or more approved IS therapies (i.e., 
any therapy for the treatment of IS approved in Europe or the 
US [e.g., steroids and/or VGB]. 
• Patient’s parent(s)/legal representative is willing to allow the 
responsible authorities to be notified of participation in the 
trial, if mandated by local law. 
• Patient’s parent(s)/legal representative is willing to allow the 
patient’s primary care practitioner (if they have one) and 
consultant (if they have one) to be notified of participation in 
the trial, if the primary care practitioner/consultant is different 
to the investigator. 
• All non-pharmacological interventions for epilepsy (including 
ketogenic diet and any neurostimulation devices for epilepsy) 
must have been stable for 2 weeks prior to screening. 
Exclusion Criteria 
The patient may not enter the trial if ANY of the following apply: 
• Patient is currently taking or has taken clobazam or any oral 
mammalian target of rapamycin (mTOR) inhibitor within the 
2 weeks prior to the screening visit. 
• Patient has a QT interval, corrected for heart rate with Bazett’s 
formula (QTcB), of > 460 msec on ECG. 
Note: If the QTcB is above > 460 msec, the investigator 
should repeat the ECG 3 times and contact the GW medical 
monitor, prior to screen failure or entry into the pilot/pivotal 
phase. 
• Patient’s caregiver is currently giving or has given recreational 
or medicinal cannabis, or synthetic cannabinoid-based 
medications, to the patient within the 1 month prior to the 
screening visit, as determined by investigator interview with 
patient’s caregiver. 
• Patient’s caregiver is unwilling to abstain from giving the 
patient (including the patient’s mother abstaining themselves, 
if breastfeeding) recreational or medicinal cannabis, or 
synthetic cannabinoid-based medications (other than the study 
IMP), during the trial, as determined by investigator interview 
with patient’s caregiver. 
• Patient has any known or suspected hypersensitivity to 
cannabinoids or any of the excipients of the IMP(s), such as 
sesame oil. 
• Patient has significantly impaired hepatic function at the 
screening visit, defined as any of the following: 
− Serum alanine aminotransferase (ALT) or aspartate 
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Summary of 
Patient Eligibility 
Criteria 
(continued) 
aminotransferase (AST) > 5 × upper limit of normal 
(ULN). 
− Serum ALT or AST > 3 × ULN and (total bilirubin [TBL] 
> 2 × ULN or international normalized ratio [INR] > 1.5). 
− Serum ALT or AST > 3 × ULN with the presence of 
fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash, and/or eosinophilia (> 5%). 
This criterion can only be confirmed once the laboratory 
results are available; patients must not be allocated any IMP 
prior to this. Note:  If transaminases are elevated, the 
investigator may choose to confirm the transaminase 
elevations by repeat testing during the screening period; 
results should be discussed with the GW medical monitor 
prior to screen failure or entry into the pilot or pivotal phase.  
• Patient has received an IMP as part of a clinical trial within a 
minimum of 5 half-lives prior to the screening visit. 
• Patient has 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 trial, may influence the 
result of the trial, or may affect the patient’s ability to take part 
in the trial. 
• Any abnormalities identified following a physical examination 
of the patient that, in the opinion of the investigator, would 
jeopardize the safety of the patient or confound assessment of 
efficacy if they took part in the trial. 
• Patient has been previously included in the pilot or pivotal 
phase of this trial. 
• Patient has travel outside the country and/or US state of 
residence planned during the trial, unless the patient has 
confirmation that the IMP is permitted in the destination 
country/state. 
Criteria for 
Withdrawal 
 
 
 
 
 
 
 
 
 
 
The patient must be withdrawn from the trial if ANY of the 
following apply: 
• Any issue with eligibility criteria that is considered to 
potentially compromise the safety of the patient. 
• Administrative decision by the investigator, GW, or regulatory 
authority. 
• Protocol deviation that is considered to potentially 
compromise the safety of the patient. 
• Withdrawal of the patient’s parent(s)/legal representative 
consent. 
• QTcB of 500 msec or greater on ECG, or a shift from baseline 
QTcB of 60 msec or greater. 
Note: Prior to withdrawal for the QTcB shifts noted above, the 
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Criteria for 
Withdrawal 
(continued) 
investigator should repeat the ECG 3 times and contact the 
GW medical monitor.  If the above QTcB criteria are 
confirmed, the patient must be withdrawn from the trial. 
• Lost to follow-up. 
• ALT or AST > 3 × ULN with the appearance of fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, 
fever, rash, and/or eosinophilia (> 5%). 
• ALT or AST > 8 × ULN. 
• ALT or AST > 5 × ULN for more than 2 weeks. 
• ALT or AST > 3 × ULN and (TBL > 2 × ULN or INR > 1.5). 
Note: Prior to withdrawal for the transaminase elevations 
noted above, the investigator may choose to confirm the 
transaminase elevations by repeating the following laboratory 
tests within 24 to 48 hours:  ALT, AST, TBL, INR, % 
eosinophils, gamma glutamyl transferase and alkaline 
phosphatase.  Should the above transaminase elevation 
criteria be confirmed, the patient must be withdrawn from 
the trial. 
The patient may also be withdrawn from the trial for ANY of the 
following: 
• Any other issue with eligibility criteria (non-safety related). 
• Any requirement to increase the dose of concomitant AED(s) 
or to add in new AED(s) during the pilot or pivotal phase.  
• If a patient is not showing evidence of benefit during the OLE 
phase (the option of withdrawing from the trial will be 
discussed with the caregiver at each visit). 
• Patient/caregiver non-compliance. 
• AE (including clinically significant laboratory result) which, 
in the opinion of the investigator, would compromise the 
continued safe participation of the patient in the trial. 
Investigational 
Medicinal 
Product: 
Formulation, 
Mode of 
Administration, 
Dose and 
Regimen 
 
 
 
 
 
GWP42003-P: Clear, colorless to yellow solution containing 
100 mg/mL CBD dissolved in the excipients sesame oil and 
anhydrous ethanol (79 mg/mL) with added sweetener (sucralose 
[0.5 mg/mL]) and strawberry flavoring (0.2 mg/mL). 
Placebo to match GWP42003-P: Clear, colorless to yellow 
solution containing the excipients sesame oil and anhydrous 
ethanol (79 mg/mL) with added sweetener (sucralose 
[0.5 mg/mL]) and strawberry flavoring (0.2 mg/mL). 
Mode of administration: Oral.  Dosing via a gastric/nasogastric 
tube (as required) may be considered following approval by the 
GW medical monitor. 
Dose (pilot phase): All patients will titrate up to a target dose of 
40 mg/kg/day over 4 days (10 mg/kg/day) and will continue at this 
dose, or the highest tolerated dose up to 40 mg/kg/day, for the 
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Investigational 
Medicinal 
Product: 
Formulation, 
Mode of 
Administration, 
Dose and 
Regimen 
(continued) 
remainder of the 2-week treatment phase. 
Dose (pivotal phase):  Patients will titrate the IMP to the target 
dose level over 4 days and will continue at this dose, or the 
highest tolerated dose up to the target dose level, for the remainder 
of the blinded treatment phase.  
Dose (OLE phase): Patients will remain on the same dose (pilot 
phase) or will transition to the target dose of GWP42003-P, or the 
highest tolerated dose up to 40 mg/kg/day, over 4 days 
(10 mg/kg/day), in a blinded manner (pivotal phase).  Patients 
may continue at this dose for the remainder of the OLE phase.  
GWP42003-P may be discontinued at any time during the OLE 
phase, at the discretion of the investigator, but patients who have 
become spasm-free and have resolution of hypsarrhythmia will be 
encouraged to continue to attend all subsequent clinic visits. 
Dosage: IMP is taken twice daily (morning and evening), 
maintaining consistency with regard to feeds/meals and other 
concomitant medications, and can be taken with other 
concomitant medications as directed by the investigator.  In the 
event that the IMP is poorly tolerated, dosing may be changed to 
3 times daily (while keeping the equivalent total daily dose), 
following approval by the GW medical monitor.  The 
recommended dosing intervals are: 
• 12-hourly (8-hourly minimum) for twice daily dosing. 
• 6-hourly (minimum) for 3 times daily dosing. 
Control Group 
The control group in the pivotal phase will receive equivalent 
dosing volumes of matching placebo. 
Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pilot and Pivotal Phase 
Visit 1 (Day −7 to Day −1): Screening 
The following will be collected/assessed: 
• Informed consent. 
• Eligibility criteria. 
• Patient demographics. 
• Full medical history. 
• Concomitant medication review. 
• Physical examination (including length [height], body weight, 
and head circumference). 
• Vital signs (including supine blood pressure). 
• ECG. 
• Video-EEG (8–24 hours in duration). 
• Clinical laboratory samples (blood and urine [if possible]) for: 
− Serum biochemistry. 
− Hematology. 
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Procedures 
(continued) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
− Urinalysis. 
To minimize the volume of blood required, serum biochemistry 
and hematology results from samples analyzed up to 3 days prior 
to Visit 1 may be used. 
• AEs. 
• Caregiver paper diary issue and training.  The caregiver will 
be required to record all AEs, concomitant antiepileptic drugs 
(AEDs) and rescue medications, seizures, and spasms from the 
time of consent. 
Patients can be re-screened only once, in exceptional cases, at the 
discretion of the investigator and GW medical monitor. 
Visit 2 (Day 1 [+3 Days])  
The following will be collected/assessed for patients who satisfy 
all eligibility criteria during the screening period: 
• Concomitant medication review. 
• Physical examination (including length [height], body weight, 
and head circumference). 
• Vital signs (including supine blood pressure). 
• CGIC memory aid. 
• PGIC memory aid. 
• Vineland-II. 
• Caregiver diary review for: 
− Spasm/seizure information. 
− Changes in concomitant AEDs. 
− Usage of rescue medication. 
− AEs. 
• AEs. 
• IMP dispensing. 
The first dose of IMP will be taken in the clinic in the morning of 
Day 1 with an ECG assessment between 3 and 5 hours postdose.   
Pivotal phase only: A pharmacokinetic (PK) blood sample will be 
taken any time between 1 and 12 hours postdose, provided the 
risk/benefit outcome is favorable in the investigator’s opinion.  
The PK blood sampling time and time of last dose must be 
recorded. 
Pilot phase only: Following Visit 2, all patients will remain in the 
clinic as inpatients during the 4-day titration period.   
Daily Safety Checks (Day 2 to Day 7 [Inclusive]) 
Caregivers will be asked for information on the following (can be 
conducted by telephone): 
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Procedures 
(continued) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• Spasm/seizure information. 
• Changes in concomitant AEDs. 
• Usage of rescue medication. 
• AEs. 
Visit 3 (Day 4 [+1 Day]) 
The following will be collected/assessed: 
• Concomitant medication review. 
• Vital signs (including supine blood pressure). 
• ECG (prior to the day’s first dose of IMP). 
• Clinical laboratory samples (blood and urine [if possible]) for: 
− Serum biochemistry. 
− Hematology. 
− Urinalysis. 
• Caregiver diary review for: 
− Spasm/seizure information. 
− IMP usage. 
− Changes in concomitant AEDs. 
− Usage of rescue medication. 
− AEs. 
• AEs. 
All patients will take their IMP in the clinic with an additional 
ECG assessment between 3 and 5 hours postdose.  Patients in the 
pilot phase will then be discharged from the clinic. 
Visit 4 (Day 15 [+3 Days]): End of Pilot or Pivotal 
Phase/Withdrawal 
The following will be collected/assessed: 
• Concomitant medication review. 
• Physical examination (including length [height], body weight, 
and head circumference). 
• Vital signs (including supine blood pressure). 
• ECG (prior to the day’s first dose of IMP). 
• Video-EEG (8–24 hours in duration). 
• Clinical laboratory samples (blood and urine [if possible]) for: 
− Serum biochemistry. 
− Hematology. 
− Urinalysis. 
• Pivotal phase only: PK blood sampling (prior to the day’s first 
dose of IMP, provided the risk/benefit outcome is favorable in 
the investigator’s opinion). 
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Procedures 
(continued) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• CGIC. 
• PGIC. 
• Caregiver diary review for: 
− Spasm/seizure information. 
− IMP usage. 
− Changes in concomitant AEDs. 
− Usage of rescue medication. 
− AEs. 
• AEs. 
• IMP compliance. 
• IMP dispensing for transition to the OLE phase, if necessary. 
All patients will take their IMP in the clinic with an additional 
ECG assessment between 3 and 5 hours postdose.   
Pivotal phase only: A further PK blood sample will be taken 
around 2 hours postdose, provided the risk/benefit outcome is 
favorable in the investigator’s opinion. 
OLE Phase 
Following Visit 4, daily safety checks will be made during the 
first week of GWP42003-P dosing. 
Daily Safety Checks (Day 16 to Day 22 [Inclusive]) 
Caregivers will be asked for information on the following (can be 
conducted by telephone): 
• Spasm/seizure information. 
• Changes in concomitant AEDs. 
• Usage of rescue medication. 
• AEs. 
Visit 5 (Day 19 [+1 Day]) 
The following will be collected/assessed: 
• Concomitant medication review. 
• Vital signs (including supine blood pressure). 
• ECG. 
• Clinical laboratory samples (blood and urine [if possible]) for: 
− Serum biochemistry. 
− Hematology. 
− Urinalysis. 
• Caregiver diary review for: 
− Spasm/seizure information. 
− IMP usage. 
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Clinical Protocol Template (Phase 2–4) 
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Study Code: GWEP15100 
EudraCT Number: 2015-004904-50 
Protocol V3 20Sep16  
 
 
Procedures 
(continued) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
− Changes in concomitant AEDs. 
− Usage of rescue medication. 
− AEs. 
• AEs. 
All patients will take their IMP in the clinic.   
Pivotal phase only: Patients transitioning from the pivotal phase to 
the OLE only: A PK blood sample will be taken any time between 
4 and 12 hours postdose, provided the risk/benefit outcome is 
favorable in the investigator’s opinion. 
Visit 6 (Day 29 [±3 Days]) 
The following will be collected/assessed: 
• Concomitant medication review. 
• Physical examination (including length [height], body weight, 
and head circumference). 
• Vital signs (including supine blood pressure). 
• ECG. 
• Video-EEG (8–24 hours in duration). 
• Clinical laboratory samples (blood and urine [if possible]) for: 
− Serum biochemistry. 
− Hematology. 
− Urinalysis. 
• CGIC. 
• PGIC. 
• Caregiver diary review for: 
− Spasm/seizure information. 
− IMP usage. 
− Changes in concomitant AEDs. 
− Usage of rescue medication. 
− AEs. 
• AEs. 
• IMP compliance. 
• IMP dispensing. 
Visit 7 (Day 43 [±3 Days]); Visit 8 (Day 71 [±3 Days]); Visit 9 
(Day 127 [±7 Days]); Visit 10 (Day 211 [±7 Days]); Visit 11 
(Day 295 [±7 Days]); Visit 12 (Day 379 [±7 Days]): End of OLE 
Treatment/Withdrawal 
The following will be collected/assessed at each of the above 
visits: 
• Concomitant medication review. 
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Clinical Protocol Template (Phase 2–4) 
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Study Code: GWEP15100 
EudraCT Number: 2015-004904-50 
Protocol V3 20Sep16  
 
 
Procedures 
(continued) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• Physical examination (including length [height], body weight, 
and head circumference). 
• Vital signs (including supine blood pressure). 
• ECG. 
• Clinical laboratory samples (blood and urine [if possible]) for: 
− Serum biochemistry. 
− Hematology. 
− Urinalysis. 
• CGIC. 
• PGIC. 
• Caregiver diary review for: 
− Spasm/seizure information. 
− IMP usage. 
− Changes in concomitant AEDs. 
− Usage of rescue medication. 
− AEs. 
• AEs. 
• IMP compliance. 
• IMP dispensing (only if necessary at Visit 12). 
The following will also be collected/assessed in addition to the 
above: 
• Video-EEG (8–24 hours in duration) (Visits 7 and 9–12, or on 
withdrawal). 
• Vineland-II (Visits 10 and 12, or on withdrawal). 
Taper Period (10 Days) 
Following end of treatment, discontinuation of IMP, or 
withdrawal, all patients will taper IMP (unless continued dosing is 
not possible due to an AE). 
End of Taper Period Visit (+3 Days) 
The following will be collected/assessed: 
• Concomitant medication review. 
• Physical examination (including length [height], body weight, 
and head circumference). 
• Vital signs (including supine blood pressure). 
• ECG. 
• Clinical laboratory samples (blood and urine [if possible]) for: 
− Serum biochemistry. 
− Hematology. 
− Urinalysis. 
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Page 16 of 143 
Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 


Study Code: GWEP15100 
EudraCT Number: 2015-004904-50 
Protocol V3 20Sep16  
 
 
Procedures 
(continued) 
• Caregiver diary review for: 
− Spasm/seizure information. 
− IMP usage. 
− Changes in concomitant AEDs. 
− Usage of rescue medication. 
− AEs. 
• AEs. 
• IMP compliance. 
Safety Follow-up Period (4 Weeks) 
Following end of dosing (including taper period), all patients will 
commence a 4-week safety follow-up period, which includes 
weekly safety telephone calls followed by a safety follow-up visit. 
Weekly Safety Telephone Calls (±3 Days) 
Caregivers will be asked for information on the following: 
• Spasm/seizure information. 
• Changes in concomitant AEDs. 
• Usage of rescue medication. 
• AEs. 
Safety Follow-up Visit (+3 Days) 
The following will be collected (can be via telephone): 
• Spasm/seizure information. 
• Changes in concomitant AEDs. 
• Usage of rescue medication. 
• AEs. 
The caregiver should return the completed caregiver diary 
following the safety follow-up visit.  
Statistical 
Considerations 
 
 
 
 
 
 
 
 
 
 
The following endpoints will be assessed using appropriate 
statistical tests: 
Primary 
Pilot Phase: 
• Safety as determined by AEs, clinical laboratory tests, ECG, 
vital signs and physical examinations during the treatment 
period. 
• The number and proportion of patients who are free of spasms 
and have resolution of hypsarrhythmia at the end of the 
2-week treatment period, as determined by video-EEG. 
Pivotal Phase:  
• The number and proportion of patients who are free of spasms 
and have resolution of hypsarrhythmia at the end of the initial 
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Clinical Protocol Template (Phase 2–4) 
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Study Code: GWEP15100 
EudraCT Number: 2015-004904-50 
Protocol V3 20Sep16  
 
 
Statistical 
Considerations 
(continued) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2-week treatment phase, as determined by video-EEG. 
OLE:  
• To assess the long term safety as determined by AEs, clinical 
laboratory tests, ECG, vital signs and physical examinations 
during the treatment period. 
Secondary 
Pilot Phase Only: 
• The number and proportion of patients who are free of clinical 
spasms, as observed on video-EEG at the end of the treatment 
period. 
• The number and proportion of patients who have resolution of 
hypsarrhythmia as, observed on video-EEG at the end of the 
treatment period. 
• Changes in spasms and seizure subtypes by caregiver 
observation during the treatment period.  
• Time to cessation of spasms during the treatment period, as 
determined by caregiver diaries. 
• CGIC. 
• PGIC. 
Pivotal Phase Only:  
• The number and proportion of patients who are free of clinical 
spasms, as observed on video-EEG at the end of the treatment 
period. 
• The number and proportion of patients with resolution of 
hypsarrhythmia, at the end of the initial 2-week treatment 
phase. 
• Changes in spasms and seizure subtypes during the initial 
2-week treatment phase. 
• Time to cessation of spasms during the treatment period, as 
determined by caregiver diaries. 
• CGIC. 
• PGIC. 
• Safety and tolerability as determined by AEs, clinical 
laboratory tests, ECG, physical examinations and vital signs. 
• Measurement, where possible, of plasma concentrations of 
CBD and its metabolites (6-OH-CBD, 7-COOH-CBD and 
7-OH-CBD) will be investigated using a sparse sampling 
approach, with the aim to define a POPPK model. 
OLE Only:  
• The number and proportion of patients who are free of clinical 
spasms, as observed on video-EEG at the end of the treatment 
period. 
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Page 18 of 143 
Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 


Study Code: GWEP15100 
EudraCT Number: 2015-004904-50 
Protocol V3 20Sep16  
 
 
Statistical 
Considerations 
(continued) 
• The number and proportion of patients who have resolution of 
hypsarrhythmia as, observed on video-EEG at the end of the 
treatment period. 
• Changes in spasms and seizure subtypes by caregiver 
observation during the treatment period.  
• Time to cessation of spasms during the treatment period, as 
determined by caregiver diaries. 
• The number and proportion of patients who are free of spasms 
and have resolution of hypsarrhythmia, as determined by 
video-EEG after 3, 6, 9 and 12 months of treatment.  
• The number and proportion of responders with relapse of 
spasms, and the time to relapse, as determined by caregiver 
diaries. 
• Changes from baseline in length (height), body weight, and 
head circumference. 
• CGIC. 
• PGIC. 
• Change from baseline in Vineland-II score.  
• Measurement, where possible, of plasma concentrations of 
CBD and its metabolites (6-OH-CBD, 7-COOH-CBD and 
7-OH-CBD) will be investigated using a sparse sampling 
approach, with the aim to define a POPPK model. 
To control the type I error, a step-up Hochberg's procedure will be 
used for the primary endpoint of the pivotal phase.  If both of the 
observed p-values from the Low Dose Level and High Dose Level 
comparisons with placebo are < 0.050 in favor of the 
GWP42003-P treatment groups, then both groups would be 
declared statistically significantly better than placebo.  However, 
if the observed p-value is ≥ 0.050 for one GWP42003-P treatment 
group but < 0.025 in favor of the other GWP42003-P treatment 
group, then only the latter GWP42003-P treatment group will be 
declared statistically significantly better than placebo. 
All safety data will be summarized using appropriate statistical 
methods. 
Sponsor 
GW Research Ltd 
Sovereign House 
Vision Park 
Chivers Way 
Histon 
Cambridge CB24 9BZ 
United Kingdom 
 
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Page 19 of 143 
Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 


Study Code: GWEP15100 
EudraCT Number: 2015-004904-50 
Protocol V3 20Sep16  
 
Figure 1-1 
Trial Design and Treatment Schematic: Pilot Phase (two sequential cohorts; Cohort 1 & Cohort 2) 
Completers
Up to 7 days
3 days
GWP42003-P
(40 mg/kg/day)
n=5
Screening 
period
Visit 1
Day −7 to −1
 Visit 21
Day 1
(+3 days)
Visit 4
Day 15
(+3 days)
Visit 3
Day 4
(+1 day)
I
M
P
D
I
S
P
E
N
S
I
N
G
 Cohort 1
(6–24 months)
n=5
S
C
R
E
E
N
I
N
G
11 days
Continue to 
OLE phase
Titration 
period
10 days
End of 
Taper 
Period 
Visit2
E
N
D
O
F
T
A
P
E
R
Safety 
Follow-up 
Visit3
F
O
L
L
O
W
U
P
28 days
Safety
follow-up 
period
Non-
completers 
(Taper period)
E
N
D
O
F
1st
P
H
A
S
E
 Cohort 2
(1–24 months)
n=5
GWP42003-P
(40 mg/kg/day)
n=5
 
1All patients will titrate GWP42003-P in an inpatient setting.  Daily safety checks will be made during the first week (Day 2-7) of IMP dosing (can be conducted by 
telephone). 
2IMP is to be tapered over 10 days following the decision not to enter the OLE phase or withdrawal from the trial (unless continued dosing is not possible due to an AE). 
3For patients who withdraw, the safety follow-up visit is to occur 28 (+3) days after date of final dose (including tapered dose); weekly (±3 days) telephone calls must be 
made during the safety follow-up period. 
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Page 20 of 143 
Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 


Study Code: GWEP15100 
EudraCT Number: 2015-004904-50 
Protocol V3 20Sep16  
 
Figure 1-2 
Trial Design and Treatment Schematic: Pivotal Phase   
Up to 7 days
3 days
GWP42003-P
(High dose level)
n=64
Placebo
(50% High dose level 
volume; 50% Low 
dose level volume)
n=64
Screening 
period
Visit 1
Day −7 to −1
 Visit 21
Day 1
(+3 days)
Visit 4
Day 15
(+3 days)
Visit 3
Day 4
(+1 day)
R
A
N
D
O
M
I
Z
A
T
I
O
N
Pivotal phase
(1–24 months)
n=192
S
C
R
E
E
N
I
N
G
11 days
Titration 
period
Completers
Continue to 
OLE phase
10 days
End of 
Taper 
Period 
Visit2
E
N
D
O
F
T
A
P
E
R
Safety 
Follow-up 
Visit3
F
O
L
L
O
W
U
P
28 days
Safety
follow-up 
period
Non-
completers 
(Taper period)
E
N
D
O
F
1st
P
H
A
S
E
GWP42003-P
(Low dose level)
n=64
 
1Following Visit 2, daily safety checks will be made during the first week (Day 2-7) of blinded IMP dosing (can be conducted by telephone). 
2IMP is to be tapered over 10 days following the decision not to enter the OLE phase or withdrawal from the trial (unless continued dosing is not possible due to an AE). 
3For patients who withdraw, the safety follow-up visit is to occur 28 (+3) days after date of final dose (including tapered dose); weekly (±3 days) telephone calls must be 
made during the safety follow-up period. 
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Page 21 of 143 
Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 


Study Code: GWEP15100 
EudraCT Number: 2015-004904-50 
Protocol V3 20Sep16  
 
Figure 1-3 
Trial Design and Treatment Schematic: Open-label Extension Phase 
4 days
10 days
2 weeks
4 weeks
Visit 5
Day 19
(+1 day)
Visit 6
Day 29
(±3 days)
Visit 7
Day 43
(±3 days)
Visit 8
Day 71
(±3 days)
Visit 9
Day 127
(±7 days)
Visit 10
Day 211
(±7 days)
8 weeks
12 weeks
12 weeks
E
N
D
O
F
T
A
P
E
R
F
O
L
L
O
W
U
P
10 days
28 days
End of 
Taper 
Period
 Visit2
Safety 
Follow-up
 Visit3
Taper
period
Visit 11
Day 295
(±7 days)
 Visit 41
Day 15
(+3 days)
Continued 
dosing
Pilot phase
treatment 
completers
Pivotal phase
treatment 
completers
Blinded 
transition
Safety 
follow-up 
period
12 weeks
Visit 12
Day 379
(±7 days)
GWP42003-P
(target dose)
E
N
D
O
F
T
R
E
A
T
M
E
N
T
1Following Visit 4, daily safety checks will be made during the first week (Day 16-22) of OLE IMP dosing (can be conducted by telephone). 
2IMP is to be tapered over 10 days following discontinuation of IMP, end of treatment, or withdrawal from the trial (unless continued dosing is not possible due to an AE). 
3The safety follow-up visit is to occur 28 (+3) days after date of final dose (including tapered dose); weekly (±3 days) telephone calls must be made during the safety 
follow-up period.
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Page 22 of 143 
Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 


Study Code: GWEP15100 
EudraCT Number: 2015-004904-50 
Protocol V3 20Sep16  
 
Table of Contents 
Title Page ................................................................................................... 1 
1 
PROTOCOL SYNOPSIS ................................................................ 3 
Table of Contents .................................................................................... 23 
List of Appendices................................................................................... 28 
List of In-text Tables .............................................................................. 29 
List of In-text Figures ............................................................................. 30 
List of Abbreviations .............................................................................. 31 
Definition of Terms ................................................................................. 33 
2 
OBJECTIVES ................................................................................ 34 
2.1 
Primary ........................................................................................................ 34 
2.1.1 
Pilot Phase ................................................................................................ 34 
2.1.2 
Pivotal Phase ............................................................................................. 34 
2.1.3 
Open-label Extension ................................................................................ 34 
2.2 
Secondary .................................................................................................... 34 
2.2.1 
All Phases ................................................................................................. 34 
2.2.2 
Pivotal Phase Only .................................................................................... 35 
2.2.3 
Open-label Extension Only ....................................................................... 35 
3 
BACKGROUND AND RATIONALE ......................................... 36 
3.1 
Disease......................................................................................................... 36 
3.2 
GWP42003-P Background .......................................................................... 41 
3.3 
Rationale ...................................................................................................... 42 
3.3.1 
Selection of Study Dose ............................................................................ 43 
3.4 
Clinical Hypothesis ..................................................................................... 44 
4 
EXPERIMENTAL PLAN ............................................................. 45 
4.1 
Trial Design ................................................................................................. 45 
4.1.1 
Primary Endpoint ...................................................................................... 46 
4.1.1.1 
Pilot Phase ............................................................................................. 46 
4.1.1.2 
Pivotal Phase ......................................................................................... 46 
4.1.1.3 
Open-label Extension ............................................................................ 46 
4.1.2 
Secondary Endpoint(s) .............................................................................. 47 
4.1.2.1 
All Phases .............................................................................................. 47 
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Study Code: GWEP15100 
EudraCT Number: 2015-004904-50 
Protocol V3 20Sep16  
 
4.1.2.2 
Pivotal Phase Only ................................................................................ 47 
4.1.2.3 
Open-label Extension Only ................................................................... 47 
4.2 
Number of Sites ........................................................................................... 48 
4.3 
Number of Patients ...................................................................................... 48 
5 
INVESTIGATIONAL MEDICINAL PRODUCT ..................... 49 
5.1 
GWP42003-P Oral Solution ........................................................................ 49 
5.2 
Placebo Oral Solution .................................................................................. 49 
5.3 
Packaging, Storage, and Drug Accountability ............................................ 49 
5.3.1 
Packaging and Labeling ............................................................................ 49 
5.3.2 
Storage ...................................................................................................... 50 
5.3.3 
Supply and Return of Investigational Medicinal Product ......................... 51 
5.3.4 
Investigational Medicinal Product Accountability ................................... 51 
5.3.5 
Post-trial Provision ................................................................................... 52 
6 
PATIENT ELIGIBILITY ............................................................. 53 
6.1 
Inclusion Criteria ......................................................................................... 53 
6.2 
Exclusion Criteria ........................................................................................ 54 
7 
PATIENT ENROLLMENT ......................................................... 56 
7.1 
Treatment Assignment ................................................................................ 56 
7.2 
Randomization............................................................................................. 56 
8 
TREATMENT PROCEDURES ................................................... 57 
8.1 
Investigational Medicinal Product Dosage, Administration, and 
Schedule ...................................................................................................... 57 
8.1.1 
Dose Administration ................................................................................. 57 
8.1.2 
Dose Escalation and Dose Adjustments ................................................... 57 
8.2 
Concomitant Therapy .................................................................................. 59 
8.3 
Prohibited Therapy During Trial Period ..................................................... 60 
8.4 
Compliance in Investigational Medicinal Product Administration ............. 60 
8.5 
Access to Blinded Treatment Assignment (Pivotal Phase Only) ................ 60 
9 
TRIAL PROCEDURES ................................................................ 62 
9.1 
Trial Procedures by Visit ............................................................................. 62 
9.1.1 
Pilot and Pivotal Phase ............................................................................. 62 
9.1.1.1 
Visit 1 (Day −7 to −1): Screening ......................................................... 62 
9.1.1.2 
Visit 2 (Day 1 [+3 Days]) ..................................................................... 63 
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Clinical Protocol Template (Phase 2–4) 
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Study Code: GWEP15100 
EudraCT Number: 2015-004904-50 
Protocol V3 20Sep16  
 
9.1.1.3 
Daily Safety Checks (Day 2 to Day 7 [Inclusive]) ............................... 64 
9.1.1.4 
Visit 3 (Day 4 [+1 Day]) ....................................................................... 64 
9.1.1.5 
Visit 4 (Day 15 [+3 Days]): End of Pilot or Pivotal 
Phase/Withdrawal ................................................................................. 65 
9.1.2 
Open-label Extension Phase ..................................................................... 66 
9.1.2.1 
Daily Safety Checks (Day 16 to Day 22 [Inclusive]) ........................... 68 
9.1.2.2 
Visit 5 (Day 19 [+1 Day]) ..................................................................... 68 
9.1.2.3 
Visit 6 (Day 29 [±3 Days]).................................................................... 69 
9.1.2.4 
Visit 7 (Day 43 [±3 Days]).................................................................... 70 
9.1.2.5 
Visit 8 (Day 71 [±3 Days]).................................................................... 70 
9.1.2.6 
Visit 9 (Day 127 [±7 Days]).................................................................. 71 
9.1.2.7 
Visit 10 (Day 211 [±7 Days])................................................................ 72 
9.1.2.8 
Visit 11 (Day 295 [±7 Days])................................................................ 73 
9.1.2.9 
Visit 12 (Day 379 [±7 Days]): End of OLE 
Treatment/Withdrawal .......................................................................... 74 
9.1.3 
Taper Period (10 Days) ............................................................................. 75 
9.1.3.1 
End of Taper Period Visit (+3 Days) .................................................... 75 
9.1.4 
Safety Follow-up Period (4 Weeks) ......................................................... 76 
9.1.4.1 
Weekly Safety Telephone Calls (±3 Days) ........................................... 76 
9.1.4.2 
Safety Follow-up Visit (+3 Days) ......................................................... 76 
9.2 
Trial Procedure Listing ................................................................................ 77 
9.2.1 
Informed Consent ..................................................................................... 77 
9.2.2 
Interactive Voice Response System/Interactive Web Response 
System....................................................................................................... 77 
9.2.3 
Demographics ........................................................................................... 77 
9.2.4 
Medical History ........................................................................................ 78 
9.2.5 
Concomitant Medication .......................................................................... 78 
9.2.6 
Physical Examination ............................................................................... 78 
9.2.7 
Vital Signs ................................................................................................ 79 
9.2.8 
12-lead Electrocardiogram ........................................................................ 79 
9.2.9 
Video-electroencephalography ................................................................. 79 
9.2.10 
Clinical Laboratory Sampling................................................................... 79 
9.2.11 
Pharmacokinetic Blood Sampling ............................................................ 81 
9.2.12 
Questionnaires Completed at Scheduled Visits ........................................ 82 
9.2.12.1 
Caregiver Global Impression of Change ............................................... 82 
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Study Code: GWEP15100 
EudraCT Number: 2015-004904-50 
Protocol V3 20Sep16  
 
9.2.12.2 
Physician Global Impression of Change ............................................... 82 
9.2.12.3 
Vineland Adaptive Behavior Scales, Second Edition ........................... 82 
9.2.13 
Caregiver Diary ........................................................................................ 83 
9.2.13.1 
Spasm/Seizure Information ................................................................... 83 
9.2.13.2 
Usage of Investigational Medicinal Product ......................................... 83 
9.2.13.3 
Changes in Concomitant Medication .................................................... 83 
9.2.13.4 
Usage of Rescue Medication ................................................................. 83 
9.2.13.5 
Adverse Events...................................................................................... 83 
10 
WITHDRAWAL ............................................................................ 84 
11 
URGENT SAFETY MEASURES ................................................ 86 
12 
ADVERSE EVENT REPORTING .............................................. 87 
12.1 
Definitions ................................................................................................... 87 
12.1.1 
Adverse Event ........................................................................................... 87 
12.1.2 
Investigator ............................................................................................... 87 
12.2 
Serious Adverse Events ............................................................................... 87 
12.3 
Reporting Procedures for Serious Adverse Events ..................................... 88 
12.4 
Causality Assessment .................................................................................. 89 
12.5 
Reporting Procedures for All Adverse Events ............................................ 89 
12.6 
Follow-up Procedures for Adverse Events .................................................. 91 
12.7 
Potential Cases of Drug-Induced Liver Injury ............................................ 92 
12.8 
Notification of Safety Information to Investigators, Regulatory 
Authorities, and IRBs/IECs ......................................................................... 92 
13 
STATISTICAL CONSIDERATIONS ......................................... 95 
13.1 
Sample Size, Power, and Significance Levels ............................................ 95 
13.2 
Interim Analysis .......................................................................................... 95 
13.3 
Analysis Sets ............................................................................................... 95 
13.3.1 
Protocol Deviations .................................................................................. 96 
13.4 
General Considerations ............................................................................... 96 
13.5 
Accountability and Background Characteristics ......................................... 96 
13.5.1 
Enrollment and Disposition ...................................................................... 96 
13.5.2 
Baseline and Demographic Characteristics .............................................. 96 
13.6 
Endpoints and Statistical Methods .............................................................. 96 
13.6.1 
Evaluable Period ....................................................................................... 97 
13.6.2 
Primary Endpoint(s) .................................................................................. 97 
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Study Code: GWEP15100 
EudraCT Number: 2015-004904-50 
Protocol V3 20Sep16  
 
13.6.2.1 
Pilot Phase ............................................................................................. 97 
13.6.2.2 
Pivotal Phase ......................................................................................... 98 
13.6.2.3 
Open-label Extension ............................................................................ 98 
13.6.3 
Secondary Endpoint(s) .............................................................................. 98 
13.6.3.1 
Pilot Phase ............................................................................................. 98 
13.6.3.2 
Pivotal Phase ......................................................................................... 99 
13.6.3.3 
Open-label Extension ............................................................................ 99 
13.6.4 
Pharmacokinetics .................................................................................... 100 
13.6.5 
Safety ...................................................................................................... 100 
13.6.5.1 
Treatment Compliance and Extent of Treatment Exposure ................ 100 
13.6.5.2 
Adverse Events.................................................................................... 100 
13.6.5.3 
Clinical Laboratory Data ..................................................................... 101 
13.6.5.4 
Vital Signs, 12-Lead Electrocardiogram, Physical 
Examination, and Other Safety Data ................................................... 101 
14 
DATA SAFETY MONITORING COMMITTEE ................... 102 
15 
REGULATORY AND ETHICAL OBLIGATIONS ................ 103 
15.1 
Declaration of Helsinki ............................................................................. 103 
15.2 
Informed Consent ...................................................................................... 103 
15.3 
Institutional Review Board/Independent Ethics Committee ..................... 103 
15.4 
Pre-trial Documentation Requirements ..................................................... 104 
15.5 
Patient Confidentiality ............................................................................... 105 
16 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ............. 106 
16.1 
Protocol Amendments and End of Trial or Termination ........................... 106 
16.2 
Trial Documentation and Storage .............................................................. 106 
16.3 
Trial Monitoring and Data Collection ....................................................... 107 
16.4 
Quality Assurance ..................................................................................... 108 
16.5 
Compensation ............................................................................................ 108 
16.6 
Publication Policy...................................................................................... 109 
16.7 
Intellectual Property Rights ....................................................................... 109 
16.8 
Confidential Information ........................................................................... 109 
17 
REFERENCES ............................................................................ 111 
 
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Study Code: GWEP15100 
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List of Appendices 
APPENDIX 1 
SCHEDULE OF ASSESSMENTS ........................................ 116 
APPENDIX 2 
TRIAL PERSONNEL ............................................................ 120 
Appendix 2.1 
Investigator Details ................................................................ 120 
Appendix 2.2 
Sponsor Contact Details ......................................................... 120 
Appendix 2.3 
Contract Research Organizations ........................................... 120 
APPENDIX 3 
QUESTIONNAIRES ............................................................. 122 
Appendix 3.1 
Caregiver Global Impression of Change................................ 122 
Appendix 3.2 
Physician Global Impression of Change ................................ 122 
Appendix 3.3 
Vineland Adaptive Behavior Scales, Second Edition ............ 123 
 
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List of In-text Tables 
Table 5.1-1 
Formulation of GWP42003-P Oral Solution ........................... 49 
Table 5.2-1 
Formulation of Placebo Oral Solution ..................................... 49 
Table 8.1.2-1 
Example Titration Regimen: Pilot and Pivotal Phase .............. 58 
Table 8.1.2-2 
Example Titration Regimen: Transition to the OLE Phase 
(Pivotal Phase Only) ................................................................ 58 
Table 9.2.10-1 
Biochemistry, Hematology, Urinalysis .................................... 80 
 
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List of In-text Figures 
Figure 1-1 
Trial Design and Treatment Schematic: Pilot Phase (two 
sequential cohorts; Cohort 1 & Cohort 2) ................................ 20 
Figure 1-2 
Trial Design and Treatment Schematic: Pivotal Phase ............ 21 
Figure 1-3 
Trial Design and Treatment Schematic: Open-label 
Extension Phase ....................................................................... 22 
 
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List of Abbreviations 
 
6-OH-CBD 
6-hydroxy-cannabidiol 
7-COOH-CBD 7-carboxy-cannabidiol 
7-OH-CBD 
7-hydroxy-cannabidiol 
ACTH 
Adrenocorticotrophic hormone (corticotropin) 
AE 
Adverse event 
AED 
Antiepileptic drug 
ALT 
Alanine amino transaminase or alanine aminotransferase 
AST 
Aspartate amino transaminase or aspartate aminotransferase 
CBD 
Cannabidiol 
CGIC 
Caregiver Global Impression of Change 
CIOMS 
Council for International Organizations of Medical Sciences 
CRF 
Case report form 
CRO 
Contract research organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
DSMC 
Data safety monitoring committee 
EAP 
Expanded access program 
EEG 
Electroencephalography/electroencephalogram 
ECG 
12-lead electrocardiogram 
EU 
European Union 
FDA 
Food and Drug Administration 
GABA 
γ-aminobutyric acid 
GCP 
Good clinical practice 
GW 
GW Research Ltd 
IB 
Investigator brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent ethics committee 
IMP 
Investigational medicinal product 
INR 
International normalized ratio 
IRB 
Institutional review board 
IS 
Infantile spasms 
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ITT 
Intention to treat 
IU 
International units 
IVRS 
Interactive voice response system 
IWRS 
Interactive web response system 
LGS 
Lennox–Gastaut syndrome 
mTOR 
Mammalian target of rapamycin 
µV 
Microvolt 
OLE 
Open-label extension 
PGIC 
Physician Global Impression of Change 
PI 
Principal investigator 
PK 
Pharmacokinetic 
POPPK 
Population pharmacokinetics 
PRN 
Packaging reference number 
PVD 
Pharmacovigilance department 
QTcB 
QT interval corrected for heart rate with Bazett’s formula 
RCT 
Randomized controlled trial 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SUSAR 
Suspected unexpected serious adverse reaction 
TBL 
Total bilirubin 
TEAE 
Treatment-emergent adverse event 
THC 
Δ9-tetrahydrocannabinol 
TSC 
Tuberous sclerosis complex 
ULN 
Upper limit of normal 
US 
United States 
VFD 
Visual field defects 
VGB 
Vigabatrin 
 
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Definition of Terms 
Term 
Definition 
Day 1 
The day a patient first receives investigational medicinal 
product in this trial. 
End of trial 
Last patient last visit or last contact, whichever occurs later. 
Enrolled patient 
Any patient whose parent(s)/legal representative has 
provided written informed consent to take part in the trial. 
Hypsarrhythmia - 
eligibility 
To be considered hypsarrhythmia, as defined for use in the 
study, the electroencephalography (EEG) background must 
be slowed and have multifocal spikes.  In addition, it must be 
EITHER high voltage (above 300 µV) OR have 
electrodecrement/discontinuity.     
Hypsarrhythmia - 
resolution 
Resolution of hypsarrhythmia requires reduction of the EEG 
background below 300 µV AND elimination of any 
electrodecrements or epochs of discontinuity. Persistence of 
some background slowing and interictal epileptiform 
discharges may be seen and still be consistent with 
resolution of hypsarrhythmia. 
International 
normalized ratio 
A calculation made to standardize prothrombin time. 
Investigational 
medicinal product 
Term used to describe both investigational active product 
and reference therapy (placebo). 
Investigator 
Trial principal investigator or a formally delegated study 
physician. 
Status epilepticus  
Any seizure lasting 30 minutes or longer.  
 
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2 
OBJECTIVES 
2.1 
Primary 
2.1.1 
Pilot Phase 
To determine the maximum safe, tolerable dose and dosing regimen of GWP42003-P 
in infants with Infantile Spasms (IS), to be utilized in the pivotal phase and open-label 
extension (OLE).   
To assess the number and proportion of patients considered treatment responders, 
defined as those free of spasms and resolution of hypsarrhythmia, at the end of the 
2-week treatment period. 
Note: Resolution of hypsarrhythmia requires reduction of the electroencephalography 
(EEG) background below 300 µV AND elimination of any electrodecrements or 
epochs of discontinuity. Persistence of some background slowing and interictal 
epileptiform discharges may be seen and still be consistent with resolution of 
hypsarrhythmia. 
2.1.2 
Pivotal Phase 
To assess the number and proportion of patients considered treatment responders, 
defined as those free of spasms and resolution of hypsarrhythmia, at the end of the 
2-week blinded treatment period versus placebo. 
2.1.3 
Open-label Extension 
To assess the long term safety of GWP42003-P in infants with IS. 
2.2 
Secondary 
2.2.1 
All Phases 
Key: To assess the number and proportion of patients who are free of clinical spasms, 
as observed on video-electroencephalography (video-EEG) at the end of the treatment 
period. 
Key: To assess the number and proportion of patients who have resolution of 
hypsarrhythmia, as observed on video-EEG at the end of the treatment period. 
To assess changes in spasms and seizure subtypes by caregiver observation during the 
treatment period.  
To determine time to cessation of spasms during the treatment period, as determined 
by caregiver diaries. 
To explore the effect of GWP42003 P on quality of life. 
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2.2.2 
Pivotal Phase Only 
To determine assess the safety and tolerability of GWP42003-P. 
To determine the population pharmacokinetics (POPPK) of CBD and its metabolites 
(6-hydroxy-cannabidiol [6-OH-CBD], 7-carboxy-cannabidiol [7-COOH-CBD] and 7-
hydroxy-cannabidiol [7-OH-CBD]). 
2.2.3 
Open-label Extension Only 
To assess the number and proportion of patients who are free of spasms and have 
resolution of hypsarrhythmia, after 3, 6, 9 and 12 months of treatment.  
To assess the number and proportion of responders who relapse and the time to 
relapse. 
To explore the effect of GWP42003-P on growth, adaptive behavior and 
development.  
To determine the population pharmacokinetics (POPPK) of CBD and its metabolites 
(6-OH-CBD, 7-COOH-CBD and 7-OH-CBD). 
 
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3 
BACKGROUND AND RATIONALE 
3.1 
Disease 
IS constitutes a distinct form of epilepsy of early infancy characterized by epileptic 
spasms with or without an interictal EEG pattern of hypsarrhythmia1.  The epileptic 
spasms characteristic of IS usually consist of sudden, generally bilateral and 
symmetrical contractions of the muscles of the neck, trunk, and extremities which can 
be accompanied by a brief loss of consciousness.  The spasms can be divided into 
3 types depending on which muscle groups are predominantly affected (flexor, 
extensor, or mixed flexor–extensor).  The most common are mixed flexor–extensor 
spasms and flexor spasms, which account for 50% and 42% of seizures, respectively2.  
Individual spasms are often brief and normally comprise an initial phasic component 
lasting 1–2 seconds followed by a less intense but more sustained tonic contraction3.  
They frequently occur in clusters, which can consist of as few as 2 or > 100 spasms, 
with 3–30 seconds between each individual spasm3,4.  Less common spasms include 
extensor spasms of the legs and spine, simple head nodding, and (rarely) 
asymmetrical spasms1,5.  The most characteristic EEG pattern of IS is 
hypsarrhythmia, which classically consists of random, high-voltage (> 200 μV), 
nonsynchronous spikes and slow-wave activity in all cortical areas that varies from 
moment to moment in duration and location3.  However, in some cases of IS, 
hypsarrhythmia may be modified/atypical or even absent1,6.  Where present, the 
hypsarrhythmic EEG pattern most frequently occurs during non-rapid eye movement 
sleep, and is greatly reduced or absent during clinical attacks of epileptic spasms (ictal 
electrodecrement) and during rapid eye movement sleep1,3.  The association of 
clustered epileptic spasms and hypsarrhythmia, with or without atypical features, 
constitute a subset of IS known as West syndrome1.  Other subsets of IS include IS 
without hypsarrhythmia, in which clustered epileptic spasms occur with no interictal 
hypsarrhythmic EEG pattern, and IS single-spasm variant (with or without 
hypsarrhythmia), in which no clustering of epileptic spasms occurs1.  The incidence 
of IS ranges from 0.16 to 0.42 per 1,000 live births with a prevalence of 1.4–2.0 per 
10,000 children aged 10 years or younger7,8.  Boys are affected slightly more often 
than girls (60:40 ratio)3. 
Although epileptic spasms can arise de novo throughout childhood, the onset of IS 
almost always occurs within the first 2 years of life (90% of patients presenting within 
the first year), with peak onset between 3 and 7 months of age1,3.  In some patients, 
onset of IS may be preceded by diagnosis of early infantile epileptic encephalopathy, 
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also known as Ohtahara syndrome, which presents within the first 3 months of life 
(often within the first 2 weeks) and is associated with a suppression-burst EEG 
pattern9.  Approximately 75% of patients with Ohtahara syndrome progress to 
develop West syndrome within the first 6 months of age10.  However, Ohtahara 
syndrome is very rare and precedes West syndrome in only 2.6% of cases11.  The 
spasms characteristic of IS are refractory to treatment with most conventional 
antiepileptic drugs (AEDs) and although they almost always resolve with time 
(usually by 2 years of age), the long-term prognosis is poor4.  More than half of 
children with IS develop other forms of severe epilepsy such as Lennox–Gastaut 
syndrome (LGS; an epileptic encephalopathy characterized by multiple seizure types 
and a slow spike-and-wave EEG pattern12), and the majority (80–90%) manifest some 
degree of mental retardation, often accompanied by motor- and behavioral problems2. 
IS is associated with a wide range of underlying etiologies and there is growing 
evidence that IS results from disturbances in key genetic pathways of brain 
development13.  One of the most common specific underlying disorders is tuberous 
sclerosis complex (TSC), diagnosed in approximately 5–7% of children with IS14.  
TSC is characterized by the formation of nonmalignant tumors (tubers) in multiple 
organ systems that results from inadequate suppression of mammalian target of 
rapamycin (mTOR) signaling due to inactivating mutations in either of 2 tumor 
suppressor genes (TSC1 and TSC2)15.  Around 40% patients diagnosed with TSC 
present with IS16 and it has been suggested that IS may occur when the mTOR 
pathway is perturbed in a specific neuronal population at a key neurodevelopmental 
stage13.  Other brain malformations, such as lissencephaly, can also underlie IS.  The 
2 genes most commonly associated with classic lissencephaly (PAFAH1B1 and DCX) 
are strongly associated with IS, which is prevalent in up to 80% of children with 
PAFAH1B1 mutations or deletions13.  Both PAFAH1B1 and DCX are expressed in 
inhibitory interneurons; thus, lissencephaly-associated IS may be due to deficits in 
this neuronal population rather than the cortical malformation per se13.  Collectively, 
congenital brain malformations (including TSC) are the underlying etiology in around 
15% of IS cases14.  Congenital chromosomal abnormalities (genomic imbalances) can 
also predispose to IS, the most common being Down syndrome (trisomy 21) which is 
the underlying etiology in approximately 5% of children with IS14.  Inversely, only 
around 3% of Down syndrome patients present with IS17.  With the exception of 
PAFAH1B1 deletion in Miller–Dieker syndrome18, the biological mechanism(s) of IS 
in syndromes of genomic imbalance are not known.  As well as underlying congenital 
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disorders, IS is associated with a range of extrinsic etiologies.  Pre-, peri- and 
postnatal brain injuries, including hypoxic–ischemic encephalopathy, stroke, 
periventricular leukomalacia/hemorrhage, and infection, cumulatively account for 
around one-quarter of cases of IS14.  Other etiologies have been identified, such as 
specific endocrine or metabolic disorders, but these are individually uncommon.  In 
approximately one-third of IS cases no evidence of a neurologic disorder is found14.  
Importantly, the underlying etiology is the most important factor affecting 
developmental outcome19. 
Adrenocorticotrophic hormone (ACTH), also known as corticotropin, is a 
long-established therapy for IS and was approved by the United States (US) Food and 
Drug Administration (FDA) in 2010 (as H.P. Acthar® Gel) as monotherapy in infants 
and children under 2 years of age.  Cosyntropin (known outside the US as 
tetracosactide) is a synthetic alternative and consists of the first 24 amino acids 
occurring in ACTH.  Currently, synthetic ACTH is not approved by the FDA for the 
treatment of IS, although orphan drug designation was granted for tetracosactide (as 
Synacthen® Depot) in 2012.  An early randomized controlled trial (RCT) compared 
ACTH (20–30 international units [IU]/day) with the oral corticosteroid prednisone 
(2 mg/kg/day) in 24 patients with IS20.  In the initial phase of the trial (prior to 
crossover), 5 of the 12 patients (42%) treated with ACTH were both spasm- and 
hypsarrhythmia-free after 2–6 weeks’ treatment compared with 4 of the 12 patients 
(33%) treated with prednisone.  Furthermore, of the 8 non-responders who received 
prednisone, 4 (50%) responded after crossover to ACTH.  A later RCT compared a 
larger dose of ACTH (150 IU/m2/day; n = 15) with prednisone (2 mg/kg/day; n = 14) 
and demonstrated that 87% of patients taking ACTH were both spasm- and 
hypsarrhythmia-free after 2 weeks’ treatment compared with 29% of patients taking 
prednisone21.  Of the 10 non-responders who received prednisone, 9 received ACTH 
and 8 (88%) responded.  Tetracosactide (0.50–0.75 mg [40–60 IU] every 2 days; 
n = 25) was compared with prednisolone (the active form of prednisone; 40–
60 mg/day; n = 30) for the treatment of IS in a later RCT which excluded patients with 
a diagnosis or high risk of TSC22.  After 2 weeks’ treatment, 76% of patients who 
received tetracosactide were spasm-free compared with 70% of patients who received 
prednisolone.  In those for whom it was measured, resolution of hypsarrhythmia 
occurred in 89% of the responders to tetracosactide compared with 71% of the 
responders to prednisolone.  A recent RCT comparing ACTH (40–60 IU every 2 days; 
n = 44) with prednisolone (40–60 mg/day; n = 48) for the treatment of hypsarrhythmia 
in West syndrome not due to TSC demonstrated a significantly greater improvement 
with prednisolone compared with ACTH after 2 weeks’ treatment23.  However, it was 
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recently concluded that the evidence is insufficient to recommend the use of 
prednisolone or other forms of corticosteroids as being as effective as ACTH for the 
short-term treatment of IS24. 
Several trials have compared low-dose ACTH with high-dose ACTH in the treatment 
of IS25,26,27.  One RCT demonstrated that cessation of spasms and disappearance of 
hypsarrhythmia occurred in 14 of 24 patients (58%) treated with low-dose ACTH 
(20–30 IU/day for 2–6 weeks, followed by a 1-week taper period) compared with 
13 of 26 patients (50%) treated with high-dose ACTH (150 IU/m2/day for 3 weeks, 
followed by a 9-week taper period)25.  Similarly, in a separate RCT in 30 children 
with West syndrome, a good initial response was observed in 60% of patients treated 
with low-dose ACTH (0.4 IU/kg/day for 2 weeks, increased to 1.0 IU/kg/day if no 
response was seen, followed by a 2-week taper period) compared with 53% of 
patients treated with high-dose ACTH (50 IU/day for 2 weeks, followed by a 2-week 
taper period)26.  In a RCT comparing low-dose tetracosactide (0.005 mg/kg/day, 
equivalent to 8 IU/kg/day natural ACTH; n = 13) with high-dose tetracosactide 
(0.2 mg/kg/day, equivalent to 40 IU/kg/day natural ACTH; n = 13), 75% of low-dosed 
patients were both spasm- and hypsarrhythmia-free after 2 weeks’ treatment 
compared with 85% of high-dosed patients27.  Due to the similar efficacy between 
doses, it was recently recommended that low-dose ACTH should be considered as an 
alternative to high-dose ACTH for the treatment of IS24.  Although ACTH is the 
preferred treatment for short-term control of IS24,28, side effects are common and 
long-term exposure is associated with serious adverse events (SAEs), including 
fulminant infections secondary to immunosuppression, hypertension, glucosuria and 
metabolic abnormalities3,29.  Furthermore, there is evidence that ACTH may 
contribute to the enlargement of cardiac rhabdomyoma in TSC patients30,31.  ACTH 
treatment is therefore generally short-term (~2 weeks followed by taper) and close 
monitoring is required in TSC patients with cardiac rhabdomyoma.  Relapse rates 
following effective ACTH treatment range from 15–60%5. 
Vigabatrin (VGB) is a newer AED and was approved by the FDA in 2009 (as Sabril®) 
to treat IS in children aged 1 month to 2 years3.  VGB is a structural analog of 
γ-aminobutyric acid (GABA; the major inhibitory neurotransmitter in the brain) that 
irreversibly inhibits GABA-transaminase and thereby increases brain levels of 
GABA32.  The initial, prospective RCT compared VGB (100–150 mg/kg/day) with 
ACTH (10 IU/day) in 42 patients with IS33.  After 20 days’ treatment, 11 of 
23 patients (48%) treated with VGB were spasm-free compared with 14 of 19 patients 
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(74%) treated with ACTH.  Resolution of hypsarrhythmia occurred in 36% of the 
responders to VGB, compared with 78% of the responders to ACTH.  Of note, VGB 
was more effective than ACTH as treatment for cerebral malformations and TSC.  In 
a separate RCT, which compared VGB (150 mg/kg/day; n = 11) with the oral steroid 
hydrocortisone (15 mg/kg/day; n = 11) for the treatment of IS specifically due to TSC, 
100% of patients taking VGB were spasm-free after 1 month’s treatment compared 
with 45% taking hydrocortisone34.  Furthermore, of the non-responders who received 
hydrocortisone, all became spasm-free on switching to VGB therapy.  In contrast, a 
later placebo-controlled trial of VGB as first-line treatment of IS did not include any 
patients with TSC35.  After 5 days’ treatment, 7 of 20 patients (35%) who received 
VGB (50–150 mg/kg/day) were spasm-free compared with 2 of 20 patients (10%) 
who received placebo.  Resolution of hypsarrhythmia occurred in 71% of the 
responders to VGB compared with 50% of the responders to placebo.  Following a 
subsequent open-label phase, 15 patients (42% of those who entered the phase) were 
spasm-free with VGB monotherapy after 6 months’ treatment, 14 of whom 
demonstrated resolution of hypsarrhythmia.  Patients with a diagnosis or high risk of 
TSC were also excluded in a larger RCT comparing VGB (100–150 mg/kg/day; 
n = 52) with tetracosactide (0.50–0.75 mg [40–60 IU] every 2 days; n = 25) or 
high-dose prednisolone (40–60 mg/day; n = 30) for the treatment of IS22.  After 
2 weeks’ treatment, 54% of patients who received VGB were spasm-free compared 
with 73% of patients who received either tetracosactide or prednisolone.  In those for 
whom it was measured, resolution of hypsarrhythmia occurred in 71% of the 
responders to VGB compared with 81% of the responders to hormonal treatment. 
A separate RCT of VGB (18–148 mg/kg/day; n = 142) included 25 patients diagnosed 
with TSC36.  Of these patients, 52% were both spasm- and hypsarrhythmia-free after 
2 weeks’ treatment compared with 16% of patients with other etiologies.  
Furthermore, after 71 days’ treatment, 92% of patients with TSC who began VGB 
therapy were spasm-free compared with 56% of patients with other etiologies, 
although whether these patients received additional treatments during this time is 
unclear.  Following recruitment of more patients into the trial and use of 
intent-to-treat analysis, however, only 21% of patients with TSC could be classed as 
primary responders after 2 weeks’ treatment compared with 9% of patients with other 
etiologies37.  Although VGB is generally well tolerated, long-term treatment with 
VGB is associated with irreversible peripheral visual field defects (VFD), the risk of 
which increases with increasing dose and cumulative exposure32.  The prevalence of 
VGB-associated VFD in children with refractory complex partial seizures is 
approximately 15%; however, a recent study found that 34% of patients who received 
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VGB treatment for IS subsequently developed VFD with TSC patients at higher risk 
(60% developing VFD)38.  Furthermore, relapse rates of up to 63% have been 
reported in the 6 months following effective VGB treatment39.  One RCT followed up 
patients at 4 years of age and demonstrated that for those with no identified etiology, 
psychomotor development scores were significantly lower in those allocated VGB 
compared with those allocated hormonal treatment40.  In light of these clinical data, 
recent guidelines have concluded that VGB is possibly effective in the short-term 
control of IS, especially in the case of TSC, although treatment with ACTH/oral 
steroids may result in a better long-term neurodevelopmental outcome than treatment 
with VGB in children with IS due to unknown etiologies24,28.  Other agents used in 
the treatment of IS include valproic acid, pyridoxine (vitamin B6), nitrazepam, 
zonisamide, topiramate, sulthiame, levetiracetam, lamotrigine, intravenous 
immunoglobulin, thyrotropin-releasing hormone, and ketogenic diet5,24,41.  However, 
there is currently insufficient evidence to determine whether these therapies are 
effective. 
3.2 
GWP42003-P Background 
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 purified (≥ 98%) CBD that typically contains 
less than 0.15% (w/w) Δ9-tetrahydrocannabinol (THC).  The purified 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 comprises 
cannabinoid receptors, endogenous ligands (endocannabinoids), and enzymes for 
endocannabinoid synthesis and degradation.  To date, 2 G-protein-coupled receptors 
for cannabinoids have been identified, designated CB1 receptor and CB2 receptor.  
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 conduction of ion channels and acts on other G-protein-coupled receptors such 
as the transient receptor potential channel TRPV142 and the orphan receptor GPR5543.  
Importantly, CBD lacks the psychoactivity associated with THC.  Further to this, 
CBD has demonstrated anticonvulsant, antipsychotic, anxiolytic, neuroprotective, 
antioxidant and anti-inflammatory activity44.  Data concerning adverse events (AEs) 
of CBD in humans are limited; however, in the small number of placebo-controlled 
trials published to date investigating the anticonvulsant effects of CBD, few side 
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effects have been reported after 4–12 months of 200–300 mg/day CBD44.  A recent 
abstract at the American Epilepsy Society 2015 Annual Meeting described the safety 
profile of GWP42003-P (up to 25 mg/kg/day) in 313 adults and children in a 
compassionate use program in the US45.  The most common AEs (i.e., reported in 
≥ 10% of patients) were somnolence (23%), diarrhea (23%), fatigue (17%), decreased 
appetite (17%), convulsions (17%), and vomiting (10%).  Dropouts due to AEs were 
4%. 
3.3 
Rationale 
The approved pharmacological therapies currently available for IS often produce 
serious adverse effects, and a significant proportion of patients develop 
medically-intractable epilepsy46.  Consequently, there is a clear need for new, safe 
and efficacious pharmaceutical treatments for infantile spasms.  Given the limitations 
of current AEDs, it has been suggested that CBD should be tested for anticonvulsive 
efficacy in RCTs, especially in infantile epileptic syndromes44.  Although there are no 
completed RCTs to date investigating the efficacy of CBD for the treatment of IS, a 
recent parent survey has reported that 92% of children with IS and/or LGS 
experienced a reduction in seizures while taking CBD-enriched cannabis, with 13% 
becoming seizure-free47.  The CBD-enriched cannabis was well-tolerated and 
children often experienced improved sleep, increased alertness, and better mood.  
Moreover, in a recent open-label expanded access program (EAP) of GWP42003-P 
(up to 50 mg/kg/day) in 9 patients with a diagnosis of infantile or epileptic spasms 
(aged 2-16 years), 67% of patients had achieved a > 50% reduction in seizures after 
2 weeks’ treatment, with 33% becoming seizure-free48.   Improvements in alertness, 
verbal capacity/communications, and cognitive availabilities were also reported.  Side 
effects were reported in 90% of patients, yet were alleviated by AED dose 
adjustments without loss of seizure control.  In the recently completed GWEP1332 
trial in Dravet syndrome, the primary efficacy endpoint was a comparison between 
GWP42003-P and placebo measuring the median percentage change in the monthly 
frequency of convulsive seizures during the 14-week treatment period compared with 
the 4-week baseline observation period.  In this study, preliminary data showed 
patients taking GWP42003-P achieved a median reduction in monthly convulsive 
seizures of 39% compared with a reduction on placebo of 13%, which was 
statistically significant (p=0.01).  The trial randomized 120 patients into 2 arms, 
GWP42003-P 20 mg/kg/day (n=61) and placebo (n=59).  GWP42003-P or placebo 
was added to current AED treatment regimens.  On average, patients were taking 
approximately 3 AEDs, having previously tried and failed an average of more than 4 
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other AEDs. The average age of trial participants was 10 years and 30% of patients 
were less than 6 years of age. 
3.3.1 
Selection of Study Dose 
Standard treatment regimens with currently approved IS therapies involve achieving 
high maintenance dose levels rapidly49. For example, VGB is initially given at a dose 
of 50 mg/kg/day and can be titrated by 25–50 mg/kg/day increments every 3 days to a 
maximum dose of 150 mg/kg/day50; both of these doses are approximately 3 times the 
recommended initial and maximal dose of VGB in adults.  Moreover, treatment with 
ACTH, which is injected intramuscularly, begins at the maintenance dose 
immediately (150 IU/m2/day recommended)51.  Consequently, due to the urgency 
required in achieving efficacious doses to treat this population, rapid titration to a 
maximal safe and tolerable maintenance dose is proposed in this trial in infants with 
IS.  The titration regimen proposed for use on this trial was discussed, and agreed, 
with consultants.  Due to the rapid titration of the IMP, all patients in the pilot phase 
will be inpatient during the 4-day titration period.  Following independent data safety 
monitoring committee (DSMC) review, adjustment of doses and dose regimens may 
occur during the trial, as well as plans for the dose titration during the pivotal phase. 
The DSMCs of the GW studies in Dravet syndrome patients (GWEP1332, 
GWEP1424) and LGS patients (GWEP1414, GWEP1423) recommended a target of 
20 mg/kg/day as a safe and tolerable dose during a 14-week treatment period.  The 
lower age limit in these studies is 2 years of age.  Three of the 4 studies are now 
complete; preliminary data from the GWEP1332 trial show GWP42003-P was 
generally well tolerated.  The most common AEs (occurring in greater than 10% of 
GWP42003-P-treated patients [n=61]) were: somnolence, diarrhea, decreased 
appetite, fatigue, pyrexia, vomiting, lethargy, upper respiratory tract infection and 
convulsion.  Of those patients on GWP42003-P for whom an AE was reported, 84% 
of these AEs were mild or moderate.  
Data on the safety of GWP42003-P is also emerging from the physician-initiated EAP 
being conducted in the US as well as other compassionate use worldwide.  This 
program has been running since January 2014 and, at the time of writing, has now 
exposed 693 patients to CBD oral solution.  The last data cut (September 2015) shows 
that the mean maximum exposure achieved in this patient population of refractory 
epilepsies was a daily dose of approximately 25 mg/kg CBD with a maximum dose of 
51 mg/kg in 1 patient.  Among the 350 patients in the safety data set, 47% were taking 
> 20 and ≤ 30 mg/kg/day CBD and 18% taking > 30 and ≤ 50 mg/kg/day CBD.  In 
healthy adults administered doses of up to 1500 mg GWP42003-P twice daily for 
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6 consecutive days with a single morning dose on Day 7, treatment emergent adverse 
events (TEAEs) reported in 95.8% of all subjects were of mild or moderate severity. 
The twice daily dose of 1500 mg equates to 40 mg/kg/day in a 75 kg adult.  In 
addition, 75.0% of subjects administered single doses of up to 6000 mg CBD 
(equivalent to 80 mg/kg in a 75 kg adult) reported TEAEs, all of mild or moderate 
severity.  When 1500 mg GWP42003-P was administered to subjects alongside a high 
fat breakfast, a 4.85-fold increase in the maximum measured plasma concentration 
and a 4.20-fold increase in exposure (measured as area under the concentration-time 
curve calculated to the last observable concentration at time t) for CBD were 
observed.  The extent of the food effect was also reflected in CBD metabolite 
exposure.  The exposure increase coincided with a higher incidence, but no increased 
severity, of TEAEs in the fed compared to the fasted group52. 
In view of the higher metabolic rate of children aged up to 2 years, it has been 
recommended by consultants that dosing should be approximately 30–40% higher 
than that used for patients 2 years and older.  To reflect this, and in light of the 
emerging RCT and EAP data detailed above, a target dose of 40 mg/kg/day is 
proposed in this trial in infants with IS. 
3.4 
Clinical Hypothesis 
The primary clinical hypothesis is that there will be a difference between 
GWP42003-P and placebo during the pivotal phase in their effect on IS, as measured 
by elimination of clinical spasms and hypsarrhythmia. 
This trial will also evaluate the effect of GWP42003-P compared with placebo on 
time to cessation of clinical spasms and changes in other seizure types.  The safety 
and tolerability of GWP42003-P will also be assessed during the pilot phase, pivotal 
phase (compared with placebo) and OLE phase of the trial. 
 
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4 
EXPERIMENTAL PLAN 
4.1 
Trial Design 
This is a multisite trial to evaluate the efficacy and safety of GWP42003-P in patients 
with IS who have failed to become spasm- and hypsarrhythmia-free following 
treatment with 1 or more approved IS therapies (e.g., steroids and/or VGB).  All 
approved therapies must be discussed with the patient’s parent(s)/legal representative 
before the patient is considered for the trial (discussions regarding treatment options 
must be documented).   The trial will comprise of a pilot safety phase, followed by a 
pivotal phase, with a 1 year open-label extension available to all patients who 
complete either phase.  The pilot phase will be open-label with 2 sequential cohorts of 
5 patients, the first cohort aged between 6 and 24 months and the second cohort aged 
between 1 and 24 months, who will receive GWP42003-P for 2 weeks.  The pivotal 
phase will comprise 192 patients, aged 1–24 months, who will undergo a 2-week, 
randomized, placebo-controlled, double-blind treatment period.   
An independent DSMC will be used throughout the study; they will consider safety of 
the patients, and will confirm doses and dose regimens to be investigated in the 
pivotal phase, as well as the plans for dose titration.  If required, following DSMC 
review, adjustment of doses and dose regimens will also take place following the first 
cohort of 5 patients in the pilot phase.  
Patients will enter the pilot and pivotal phases at the respective screening visits 
(Visit 1, Day −7 to −1) for assessment of eligibility, which includes a prolonged 
video-EEG.  Patients who satisfy all eligibility criteria will then be administered 
GWP42003-P (pilot phase) or randomized to GWP42003-P (1 of 2 dose levels) or 
placebo at a 1:1:1 ratio (pivotal phase) (Visit 2, Day 1 [+3 days]).  The High Dose 
Level will be as recommended by the DSMC; the Low Dose Level will be defined as 
50% of the High Dose Level. Patients in the placebo group will be split into 2 
equivalent cohorts: half receiving Low Dose Level dosing volumes and half receiving 
High Dose Level dosing volumes.  Following baseline assessments, patients will 
titrate the IMP in 10 mg/kg/day increments to the target dose level (or equivalent 
volume of placebo in the pivotal phase) and will continue at this dose, or the highest 
tolerated dose up to 40 mg/kg/day, for the remainder of the 2-week treatment phase.  
Patients in the pilot phase will remain in the clinic as inpatients during the 4-day dose 
titration period.  If deemed safe by the DSMC then it is planned for those in the 
pivotal phase to titrate in an outpatient setting.  Further clinic-based assessments will 
take place after 3 days’ dosing (Visit 3, Day 4 [+1 day]).  All patients in the pilot and 
pivotal phases will return to the clinic after 2 weeks’ dosing (Visit 4, Day 15 
[+3 days]) or earlier if they withdraw prematurely.  All patients who complete 
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treatment will then have the opportunity to receive GWP42003-P during the 
subsequent OLE phase.  The OLE phase will last for a maximum of 1 year. 
Patients who enter the OLE phase will remain on the same dose (pilot phase) or will 
transition to their target dose of GWP42003-P over 4 days in a blinded manner 
(pivotal phase).  Patients may continue at this dose, or the highest tolerated dose up to 
40 mg/kg/day, for the remainder of the OLE phase.  GWP42003-P may be 
discontinued at the discretion of the investigator (Section 9.1.2).  During the OLE 
phase, clinic visits will take place on Day 19 (Visit 5 [+1 day]), Day 29 (Visit 6 
[±3 days]), Day 43 (Visit 7 [±3 days]), Day 71 (Visit 8 [±3 days]), Day 127 (Visit 9 
[±7 days]), Day 211 (Visit 10 [±7 days]), and on Day 295 (Visit 11 [±7 days]).  
Patients will return to the site for an end of OLE treatment visit on Day 379 (Visit 12 
[±7 days]) or earlier if they withdraw prematurely from the OLE phase.  Following 
end of treatment, withdrawal, or discontinuation of IMP, all patients will taper the 
IMP over 10 days followed by safety follow-up.  Patient diaries will be completed 
each day by the caregiver during the trial. 
A series of schematic diagrams (Figure 1-1, Figure 1-2, and Figure 1-3), presented at 
the end of Section 1, depict the overall trial design.  More detailed information on 
treatment and trial procedures is provided in Section 8 and Section 9, respectively. 
4.1.1 
Primary Endpoint 
4.1.1.1 
Pilot Phase 
To assess the safety as determined by AEs, clinical laboratory tests, 12-lead 
electrocardiogram (ECG), vital signs and physical examinations during the treatment 
period. 
The number and proportion of patients who are free of spasms and have resolution of 
hypsarrhythmia at the end of the 2-week treatment period, as determined by 
video-EEG. 
4.1.1.2 
Pivotal Phase 
The number and proportion of patients who are free of spasms and have resolution of 
hypsarrhythmia, at the end of the 2-week blinded treatment period, as determined by 
video-EEG. 
4.1.1.3 
Open-label Extension 
To assess the long term safety as determined by AEs, clinical laboratory tests, ECG, 
vital signs and physical examinations during the treatment period. 
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4.1.2 
Secondary Endpoint(s) 
4.1.2.1 
All Phases 
The following endpoints will be analyzed separately for each phase: 
Key: The number and proportion of patients who are free of clinical spasms, as 
observed on video-EEG at the end of the treatment period. 
Key: The number and proportion of patients who have resolution of hypsarrhythmia 
as, observed on video-EEG at the end of the treatment period. 
Changes in spasms and seizure subtypes by caregiver observation during the 
treatment period.  
Time to cessation of spasms during the treatment period, as determined by caregiver 
diaries. 
Caregiver Global Impression of Change (CGIC). 
Physician Global Impression of Change (PGIC). 
4.1.2.2 
Pivotal Phase Only 
Safety and tolerability as determined by AEs, clinical laboratory tests, ECG, physical 
examinations and vital signs. 
Measurement, where possible, of plasma concentrations of CBD and its metabolites 
(6-OH-CBD, 7-COOH-CBD and 7-OH-CBD) will be investigated using a sparse 
sampling approach, with the aim to define a POPPK model. 
4.1.2.3 
Open-label Extension Only 
The number and proportion of patients who are free of spasms and have resolution of 
hypsarrhythmia, as determined by video-EEG after 3, 6, 9 and 12 months of 
treatment.  
The number and proportion of responders with relapse of spasms, and the time to 
relapse, as determined by caregiver diaries. 
Changes from baseline in length (height), body weight, and head circumference. 
Change from baseline in Vineland Adaptive Behavior Scales, Second Edition 
(Vineland II) score.  
Measurement, where possible, of plasma concentrations of CBD and its metabolites 
(6-OH-CBD, 7-COOH-CBD and 7-OH-CBD) will be investigated using a sparse 
sampling approach, with the aim to define a POPPK model. 
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4.2 
Number of Sites 
Approximately 50 sites are expected to participate in this trial.   
Additional sites may be used in order to supplement recruitment. 
4.3 
Number of Patients 
The pilot phase is not powered and comprises 10 patients. 
The pivotal phase will comprise 192 patients.  Patients will be randomized to receive 
1 of 2 dose levels of GWP42003-P (High Dose Level or Low Dose Level), or 
matching placebo on a 1:1:1 basis (64 per treatment group).  Patients in the placebo 
group will be further split into 2 cohorts (32 patients receiving High Dose Level 
dosing volumes and 32 patients receiving Low Dose Level dosing volumes), but it is 
assumed that these 2 cohorts can be pooled for the analyses of efficacy.  Assuming a 
20% screen failure rate, it is expected that approximately 245 patients will need to be 
screened to achieve this target.  Recruitment 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 clear, colorless to yellow 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 
Purified CBD 
100 mg/mL 
Anhydrous ethanol 
79 mg/mL 
Sucralose 
0.5 mg/mL 
Strawberry flavoring 
0.2 mg/mL 
Refined sesame oil 
make up to 1 mL 
 
5.2 
Placebo Oral Solution 
Placebo to match GWP42003-P oral solution is presented as a clear, colorless to 
yellow solution containing 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 
Refined sesame oil 
make up to 1 mL 
 
5.3 
Packaging, Storage, and Drug Accountability 
5.3.1 
Packaging and Labeling  
The IMP will be manufactured, packaged, labeled and/or distributed by G-Pharm or 
delegated contractors in accordance with good manufacturing practice guidelines.  
The IMP will be presented in 100 mL amber glass bottles with child-resistant, 
tamper-evident screw caps, and packed in cartons.  Sufficient IMP will be dispensed 
at Visits 2, 4, 6–11, and for the taper period, if necessary, considering the weight of 
the patient and the length of time until the next visit.  A unique identification number 
will be used to identify each box and the IMP it contains.  The unique identification 
number together with the packaging reference number (PRN) will permit full 
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traceability of manufacture, pack and label activities conducted at or on behalf of 
G-Pharm and the IMP information held on the interactive voice response system 
(IVRS)/interactive web response system (IWRS).  Label text will include the 
following information, as a minimum: 
• Sponsor’s name and address. 
• Product identification (e.g., “GWP42003-P or Placebo”). 
• Concentration/potency. 
• Study code. 
• Batch number. 
• Expiry date. 
• Storage conditions. 
• Instruction: “For clinical trial use only”. 
• Instruction: “Keep out of the sight and reach of children”. 
• Any other information required by local regulatory authorities. 
Directions for use will be provided separately to the patient’s caregiver. 
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.  
Temperature records of the clinical site storage location must be maintained 
(recording a minimum of Monday–Friday, excluding public holidays) from date of 
receipt of first shipment until end of trial dispensing period at each site.  These 
records must contain at least the minimum and maximum daily temperatures and must 
be made available to the appropriate GW personnel for review throughout the trial.  
Temperature during transit of IMP to the site must be checked on receipt and 
compliance/non-compliance to the minimum and maximum recorded. 
Should storage conditions deviate from these specified requirements, the GW study 
monitor must be contacted immediately to confirm if the IMP remains suitable for 
use.  IMP must be placed under quarantine until written confirmation is received that 
the IMP is suitable for use. 
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Caregivers will be provided with instructions regarding home storage requirements 
for the IMP. 
5.3.3 
Supply and Return of Investigational Medicinal Product 
IMP will be transported by G-Pharm or delegated contractors to approved country 
depots and clinical sites in compliance with good distribution practice guidelines.  All 
IMP will be shipped with a product release certificate that includes a physical 
description of the product for confirmation of identity on receipt. 
Once a site has been activated via the IVRS/IWRS at trial initiation, IMP will be 
shipped to the identified responsible person, such as the pharmacist, at the 
investigator’s site, who will check the amount received (against the IVRS/IWRS 
Shipment Request) and condition of the drug (i.e., integrity, physical appearance, 
temperature during transit).  Details of the IMP received will be recorded in the IMP 
accountability record (see Section 5.3.4).  The site will acknowledge the IMP receipt 
via the IVRS/IWRS and will complete any receipt forms required.  IMP will be 
dispensed and returned as detailed in Section 8.4 with further IMP shipments to be 
initiated by IVRS/IWRS.  As directed, all supplies, including unused, partially used, 
or empty containers, will be returned to G-Pharm/depot or destroyed at a 
G-Pharm-approved site 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 
must contain: 
• Study code. 
• PRN, treatment number, date of receipt, and quantity of IMP received. 
• Patient’s trial identification and/or treatment number. 
• Date and quantity of IMP dispensed. 
• The initials of the dispensing/dosing party. 
• Date and quantity of IMP returned to the investigator. 
• IMP expiry dates. 
IMP will be dispensed at Visits 2, 4, 6–11, and for the taper period, if necessary.  
Patients will be asked to return all IMP (used and unused) at each relevant visit 
(Visits 4, 6–12, and the end of taper period visit, if applicable).  The site will check 
the returned IMP against the usage recorded in the paper diary.  Any discrepancies 
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will be discussed with the patient’s caregiver at the time of the visit and documented 
accordingly within the patient’s source documents. 
The investigator must inform GW promptly of all missing or unaccountable IMP. 
A record of returned IMP must be completed and included in the shipment of used 
and unused IMP to the relevant drug distribution depot.  At the end of the trial, a 
record/statement of reconciliation must be completed and provided to GW. 
These inventories must be made available for inspection by an authorized GW 
representative and local officials or regulatory agency inspectors. 
Please refer to the separate pharmacy manual for more detailed information on the 
IMP. 
5.3.5 
Post-trial Provision 
All patients who complete the pilot and pivotal phase of the trial will have the 
opportunity to receive GWP42003-P during the subsequent OLE phase.  The OLE 
phase will last for a maximum of 1 year. 
A summary of the results of this trial will be made available on 
http://www.clinicaltrials.gov and http://www.clinicaltrialsregister.eu/ (as applicable), 
as required by US and European Union (EU) Law. 
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6 
PATIENT ELIGIBILITY 
Investigators are responsible for confirming patient eligibility and will be required to 
maintain a log that includes limited information about all screened patients (initials, 
age, sex; as allowed per local regulations) and outcome of screening. 
6.1 
Inclusion Criteria 
For inclusion in the trial, patients must fulfil ALL of the following criteria: 
6.1.1 Pilot phase: Patient is male or female aged 6–24 months (inclusive) in the 
first cohort or aged 1-24 months (inclusive) in the second cohort, at the 
time of consent. 
OR 
Pivotal phase: Patient is male or female aged 1–24 months (inclusive) at 
the time of consent. 
6.1.2 Patient’s parent(s)/legal representative is willing and able to give informed 
consent for the patient’s participation in the trial (see Section 15.2). 
6.1.3 Patient and their caregiver are willing and able (in the investigator’s 
opinion) to comply with all trial requirements. 
6.1.4 Patient is diagnosed with IS (i.e., clinical spasms and hypsarrhythmia are 
observed on video-EEG at screening). 
Note: To be considered hypsarrhythmia, as defined for use in the study, the 
EEG background must be slowed and have multifocal spikes.  In addition, 
it must be EITHER high voltage (above 300 µV) OR have 
electrodecrement/discontinuity.   
6.1.5 Patient has failed to respond adequately (i.e., clinical spasms and/or 
hypsarrhythmia are still evident on video-EEG at screening) following 
treatment with 1 or more approved IS therapies (i.e., therapy for the 
treatment of IS approved in Europe or the US [e.g., steroids and/or VGB]) 
for the treatment of IS. 
6.1.6 Patient’s parent(s)/legal representative is willing to allow the responsible 
authorities to be notified of participation in the trial, if mandated by local 
law. 
6.1.7 Patient’s parent(s)/legal representative is willing to allow the patient’s 
primary care practitioner (if they have one) and consultant (if they have 
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one) to be notified of participation in the trial, if the primary care 
practitioner/consultant is different to the investigator. 
6.1.8 All non-pharmacological interventions for epilepsy (including ketogenic 
diet and any neurostimulation devices for epilepsy) must have been stable 
for 2 weeks prior to screening. 
6.2 
Exclusion Criteria 
The patient may not enter the trial if ANY of the following apply: 
6.2.1 Patient is currently taking or has taken clobazam or any oral mTOR 
inhibitor within the 2 weeks prior to the screening visit. 
6.2.2 Patient has a QT interval, corrected for heart rate with Bazett’s formula 
(QTcB), of > 460 msec on ECG. 
Note: If the QTcB is above > 460 msec, the investigator should repeat the 
ECG 3 times and contact the GW medical monitor, prior to screen failure 
or entry into the pilot/pivotal phase. 
6.2.3 Patient’s caregiver is currently giving or has given recreational or 
medicinal cannabis, or synthetic cannabinoid-based medications, within 
the 1 month prior to the screening visit, as determined by investigator 
interview with patient’s caregiver. 
6.2.4 Patient’s caregiver is unwilling to abstain from giving the patient 
(including the patient’s mother abstaining themselves, if breastfeeding) 
recreational or medicinal cannabis, or synthetic cannabinoid-based 
medications (other than the study IMP) during the trial, as determined by 
investigator interview with patient’s caregiver. 
6.2.5 Patient has any known or suspected hypersensitivity to cannabinoids or 
any of the excipients of the IMP(s), such as sesame oil. 
6.2.6 Patient has significantly impaired hepatic function at the screening visit, 
defined as any of the following: 
i) 
Serum alanine aminotransferase (ALT) or aspartate aminotransferase 
(AST) > 5 × upper limit of normal (ULN). 
ii) Serum ALT or AST > 3 × ULN and (total bilirubin [TBL] > 2 × ULN 
or international normalized ratio [INR] > 1.5). 
iii) Serum ALT or AST > 3 × ULN with the presence of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, and/or 
eosinophilia (> 5%). 
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This criterion can only be confirmed once the laboratory results are 
available; patients must not be allocated any IMP prior to this.  Note: If 
transaminases are elevated, the Investigator may choose to confirm the 
transaminase elevations by repeat testing during the screening period; 
results should be discussed with the GW medical monitor prior to screen 
failure or entry into the pilot or pivotal phase. 
6.2.7 Patient has received an IMP as part of a clinical trial within a minimum of 
5 half-lives prior to the screening visit. 
6.2.8 Patient has 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 trial, may influence the result of the trial, or may affect 
the patient’s ability to take part in the trial. 
6.2.9 Any abnormalities identified following a physical examination of the 
patient that, in the opinion of the investigator, would jeopardize the safety 
of the patient or confound assessment of efficacy if they took part in the 
trial. 
6.2.10 Patient has been previously included in the pilot or pivotal phase of this 
trial. 
6.2.11 Patient has travel outside the country and/or US state of residence planned 
during the trial, unless the patient has confirmation that the IMP is 
permitted in the destination country/state. 
 
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7 
PATIENT ENROLLMENT 
Before patients may be entered into the trial, GW requires a copy of the relevant site’s 
institutional review board (IRB) or independent ethics committee (IEC) written 
approval of the protocol, informed consent form (ICF), and other patient information 
material.  Patients will be considered enrolled in the trial from the time written 
informed consent is provided.  The patient’s parent(s)/legal representative must 
personally sign and date the ICF prior to any procedures being performed (refer to 
Section 9.2.1 and Section 15.2). 
7.1 
Treatment Assignment 
At the start of Visit 1, patients will be allocated a unique patient number using an 
IVRS/IWRS.  After confirmation of eligibility at Visit 2, patients will be assigned 
GWP42003-P (pilot phase) or randomly allocated to GWP42003-P or matching 
placebo (pivotal phase) using the IVRS/IWRS.  G-Pharm or delegated contractors will 
provide all IMP in a packed and labeled state and the IVRS/IWRS will identify the 
pack number to be dispensed to the patient at each relevant visit, according to the 
treatment assigned in the randomization schedule. 
7.2 
Randomization 
For the pivotal phase, the allocation of IMP to treatment number will be done 
according to a randomization schedule produced by an independent statistician.  The 
randomization schedule will be held centrally by GW or delegated contractor and not 
divulged to any other person involved in the trial until the database has been locked 
and unblinding authorized by the relevant GW personnel.  For access to blinded 
treatment assignment, see Section 8.5. 
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8 
TREATMENT PROCEDURES 
8.1 
Investigational Medicinal Product Dosage, Administration, and 
Schedule 
The use of placebo in the current trial is deemed necessary to determine the efficacy 
and safety of the current intervention, since one or more approved interventions have 
already been tried and have failed to alleviate the patient’s symptoms.  For details 
regarding IMP formulations, see Section 5. 
8.1.1 
Dose Administration 
The IMP will be administered orally by the patient’s caregiver twice each day 
(morning and evening), maintaining consistency with regard to feeds/meals and other 
concomitant medications, using the syringe(s) provided.  Dosing via a 
gastric/nasogastric tube (as required) may be considered following approval by the 
GW medical monitor; details of dose administration via the gastric/nasogastric tube 
will be provided in a separate pharmacy manual.  The IMP may be taken with other 
concomitant medications, as directed by the investigator.  In the event that the IMP is 
poorly tolerated, dosing may be changed to 3 times daily (while keeping the 
equivalent total daily dose) following approval by the GW medical monitor.  The 
recommended dosing intervals are: 
• 12-hourly (8-hourly minimum) for twice daily dosing. 
• 6-hourly (minimum) for 3 times daily dosing. 
8.1.2 
Dose Escalation and Dose Adjustments 
All patients will be weighed during each clinic visit where IMP is dispensed (i.e., no 
physical exam performed at Visit 3 [Day 4] or Visit 5 [Day 19]).  The volumes of 
IMP solution to be taken each day during the titration periods, and for the remainder 
of each phase of the trial, will be calculated and provided to the patient’s caregiver.  If 
an unacceptable AE develops at any time during the titration periods, dosing should 
initially be amended or suspended, at the investigator’s discretion, until the event has 
resolved or is well tolerated.  During the maintenance periods, patients should 
continue on a stable dosing regimen at the target dose.  However, if the patient is not 
able to tolerate the target dose, the investigator may consider temporarily or 
permanently reducing the dose or dosage for the remainder of the maintenance period. 
Eligible patients will be assigned GWP42003-P (pilot phase) or randomly allocated to 
GWP42003-P or matching placebo (pivotal phase) and will titrate the IMP over 
4 days according to the titration regimen, an example titration regimen up to 
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40 mg/kg/day over 4 days is shown in Table 8.1.2-1.  Patients in the pilot phase will 
remain in the clinic as inpatients during the 4-day titration period.  If the DSMC 
confirms it is safe then patients in the pivotal phase will titrate the IMP as outpatients. 
For the pivotal phase there will be 2 dose levels; the High Dose Level will be as 
recommended by the DSMC, the Low Dose Level will be defined as 50% of the High 
Dose Level.  Patients in the placebo group will be split into 2 equivalent cohorts: half 
receiving Low Dose Level dosing volumes and half receiving High Dose Level 
dosing volumes.  In both phases, daily safety checks will be made during the first 
week of IMP dosing.   
Table 8.1.2-1 
Example Titration Regimen: Pilot and Pivotal Phase 
 Day  
 IMP Dosage1 
 Total Daily IMP Dose2 
1 
5 mg/kg (am/pm) 
10 mg/kg 
2 
10 mg/kg (am/pm) 
20 mg/kg 
3 
15 mg/kg (am/pm) 
30 mg/kg 
4 onwards 
20 mg/kg (am/pm) 
40 mg/kg 
1Volumes of IMP to be taken each day will be calculated using the patient’s weight and the required 
dose. 
2Patients may taper to and remain on a lower dose if unable to tolerate the target dose. 
Patients from the pivotal phase who enter the OLE will taper their blinded IMP while 
simultaneously titrating their OLE IMP (GWP42003-P) over 4 days according to the 
titration regimen, an example titration regimen up to 40 mg/kg/day over 4 days is 
shown in Table 8.1.2-2.  No further titration will be required for patients in the pilot 
phase; they will remain on the same GWP42003-P dose going into the OLE phase.  
Daily safety checks will be made during the first week of OLE IMP dosing.  
GWP42003-P may be discontinued at any time during the OLE phase, at the 
discretion of the investigator (see Section 9.1.2). 
Table 8.1.2-2 
Example Titration Regimen: Transition to the OLE Phase 
(Pivotal Phase Only) 
Day 
Blinded IMP 
Dosage1 
OLE IMP 
Dosage1 
Total Daily IMP 
Dose (Patients 
Randomized to 
Placebo)2 
Total Daily IMP 
Dose (Patients 
Randomized to 
GWP42003-P)2 
15 
20 mg/kg (am/pm) 
0 
0 
40 mg/kg 
16 
15 mg/kg (am/pm) 
5 mg/kg (am/pm) 
10 mg/kg 
40 mg/kg 
17 
10 mg/kg (am/pm) 10 mg/kg (am/pm) 
20 mg/kg 
40 mg/kg 
18 
5 mg/kg (am/pm) 
15 mg/kg (am/pm) 
30 mg/kg 
40 mg/kg 
19 onwards 
0 
20 mg/kg (am/pm) 
40 mg/kg 
40 mg/kg 
1Volumes of IMP to be taken each day will be calculated using the patient’s weight and the required 
dose. 
2Patients may taper to and remain on a lower dose if unable to tolerate the target dose. 
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Following the end of treatment, all patients will commence a taper period (tapering 
10% per day for 10 days).  Patients who withdraw early should also begin the taper 
period following the withdrawal visit (unless continued dosing is not possible due to 
an AE).  Patients who discontinue IMP during the OLE phase should also begin the 
taper period following the investigator’s decision to discontinue.  The IVRS/IWRS 
will generate the patient’s daily IMP dosing volumes for the 10-day taper period. 
8.2 
Concomitant Therapy 
All non-pharmacological interventions for epilepsy (including ketogenic diet and any 
neurostimulation devices for epilepsy) must have been stable for at least 2 weeks prior 
to screening and must remain stable throughout the pilot and pivotal phases of the 
trial.  During the screening period, patients should continue to take their current IS 
therapy at a stable dose.  After starting treatment, and during the pilot and pivotal 
phase, every effort should be made to keep the patient’s current IS therapy stable; 
current therapy may be tapered or stopped, in response to AEs, at the discretion of the 
investigator.  Increases in the dose of existing concomitant AEDs or commencement 
of new AEDs are not allowed during the pilot or pivotal phases, and should the 
investigator deem that an increase in concomitant AED or new AED be needed, the 
subject may need to be withdrawn from the trial (see Section 10).  During the OLE, in 
response to AEs or if there are symptoms of toxicity due to a suspected drug-drug 
interaction, the investigator may decrease the dose of GWP42003-P or other 
concomitant AEDs following discussion with the GW medical monitor.  Any request 
for an increase in concomitant AED dose, or addition of a new AED in the OLE must 
be discussed with the GW medical monitor prior to implementing, and will be based 
on confirmation of benefit over risk of continued treatment with or discontinuation of 
GWP42003-P.  It should be noted that there is the potential for drug-drug interactions 
with strong inhibitors/inducers of CYP3A4 or CYP2C19; if alternatives cannot be 
found these should be co-administered with caution and monitoring as clinically 
indicated.  Monitoring of concomitant AEDs may be requested by the investigator as 
clinically indicated.  Any AED monitoring should be documented in the CRF.  
Further information on drug interactions can be found in the Investigator Brochure 
(IB)53. 
As the risk of hepatotoxicity with valproate is high in the trial population, 
investigators should pay particular attention to liver enzyme levels in patients who are 
taking valproate concomitantly. 
The use of rescue medication is allowed if clinically indicated.  Any medication, other 
than the IMP, taken during the trial must be recorded on the case report form (CRF). 
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8.3 
Prohibited Therapy During Trial Period 
The following medications are prohibited both prior to and during the trial, as stated 
below.  However, any patients taking these medications after starting treatment on the 
trial should not be withdrawn from the trial unless there are safety concerns.  If 
applicable, the possible effects of these medications on the trial endpoints will be 
considered during the assessment of the evaluable period (see Section 13.6.1). 
• Any new non-pharmacological interventions for epilepsy (including ketogenic 
diet and any neurostimulation devices for epilepsy) or changes in regimen 
during the pilot and pivotal phases of the trial (and within the 2 weeks prior to 
the screening visit). 
• Clobazam and oral mTOR inhibitors during the pilot and pivotal phase of the 
trial (and within the 2 weeks prior to the screening visit). 
• Recreational or medicinal cannabis, or synthetic cannabinoid-based 
medications (and within the 1 month prior to the screening visit). 
• Any other IMP taken as part of a clinical trial (and within a minimum of 
5 half-lives prior to the screening visit). 
Furthermore, any increases to existing AEDs or commencement of new AEDs during 
the pilot or pivotal phase may result in the patient being withdrawn from the trial. 
8.4 
Compliance in Investigational Medicinal Product Administration 
The patient’s caregiver will record IMP intake on each treatment day in the paper 
diary.  Caregivers should return all IMP (used and unused) at each of Visits 4, 6–12, 
and the end of taper period visit, if applicable.  The diary-reported dosing information 
will be checked and any discrepancies discussed with the patient’s caregiver at the 
time of the visit and documented accordingly within the patient’s source documents.  
Records of IMP accountability will be maintained according to Section 5.3.4. 
8.5 
Access to Blinded Treatment Assignment (Pivotal Phase Only) 
The identity of IMP assigned to patients in the pivotal phase will be held by the 
IVRS/IWRS.  The principal investigator (PI) at each site, or his/her designee, is 
responsible for ensuring that information on how to access the IVRS/IWRS for an 
individual patient is available to the relevant staff in case of an emergency and 
unblinding is required.  A patient’s treatment assignment should only be unblinded 
when knowledge of the treatment is essential to make a decision on the medical 
management of the patient.  Unblinding for any other reason will be considered a 
protocol deviation. 
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The investigator is encouraged to contact GW to discuss the rationale for unblinding 
prior to doing so.  However, to prevent delays to the investigator or medical personnel 
responding to a potentially emergent situation, unblinding of trial medication will not 
be dependent upon the investigator receiving approval from 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 1 working day of the 
event and must document the time, date and reason(s) for unblinding in the patient’s 
medical notes and on the CRF. 
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9 
TRIAL PROCEDURES 
A list of the required trial 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 CRF. 
The location of the source data for the following procedures will be documented, per 
site, in a signed source data verification plan; for further details see Section 16.2. 
9.1 
Trial Procedures by Visit 
Patients and their parent(s)/legal representative will be invited to take part in the trial 
and will be issued with the parent(s)/legal representative information and ICF.  
Following adequate time to discuss the trial with the investigator, nurse, relatives, or 
caregiver, as wished, patients of those parent(s)/legal representatives who provide 
written informed consent will be screened for entry into the trial. 
9.1.1 
Pilot and Pivotal Phase 
9.1.1.1 
Visit 1 (Day −7 to −1): Screening 
Following collection of parent(s)/legal representative informed consent 
(Section 9.2.1), patients will be assigned a unique patient number using an 
IVRS/IWRS (Section 9.2.2).  The following will then be collected/assessed within a 
screening period which must be no more than 7 days in duration, during which time 
patients must continue to take their current IS therapy at a stable dose: 
• Eligibility criteria (Section 6). 
• Patient demographics (Section 9.2.3). 
• Full medical history (Section 9.2.4). 
• Concomitant medication review (Section 9.2.5). 
• Physical examination (Section 9.2.6). 
• Vital signs (Section 9.2.7). 
• ECG (Section 9.2.8). 
• Video-EEG (Section 9.2.9). 
• Clinical laboratory samples (blood and urine [if possible]; Section 9.2.10) for: 
− Serum biochemistry. 
− Hematology. 
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− Urinalysis. 
To minimize the volume of blood required, serum biochemistry and 
hematology results from samples analyzed up to 3 days prior to Visit 1 may be 
used. 
• AEs (Section 12). 
• Caregiver paper diary issue and training (Section 9.2.13). The caregiver will 
be required to record all AEs, concomitant AEDs and rescue medications, 
seizures, and spasms from the time of consent. 
Patients can be re-screened only once, in exceptional cases, at the discretion of the 
investigator and GW medical monitor. 
9.1.1.2 
Visit 2 (Day 1 [+3 Days]) 
This visit will occur up to 7 (+3) days after Visit 1 (screening).  Patients who satisfy 
all eligibility criteria (Section 6) during the screening period will be assigned 
GWP42003-P (pilot phase) or randomly allocated to GWP42003-P or matching 
placebo (pivotal phase) using the IVRS/IWRS (Section 9.2.2).  Eligible patients must 
begin treatment within 7 days of their video-EEG screening assessment.  The 
following will be collected/assessed prior to the patient receiving IMP: 
• Concomitant medication review (Section 9.2.5). 
• Physical examination (Section 9.2.6). 
• Vital signs (Section 9.2.7). 
• CGIC memory aid (Section 9.2.12.1). 
• PGIC memory aid (Section 9.2.12.2). 
• Vineland-II (Section 9.2.12.3). 
• Caregiver diary review (Section 9.2.13) for: 
− Spasm/seizure information. 
− Changes in concomitant AEDs. 
− Usage of rescue medication. 
− AEs. 
•  AEs (Section 12). 
Patients will receive sufficient IMP for 2 weeks of dosing.  Patients in the pilot phase 
will remain in the clinic as inpatients during the 4-day titration period.  For all 
patients, the first dose of IMP will be taken in the clinic on the morning of Day 1 with 
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an ECG assessment between 3 and 5 hours postdose (Section 9.2.8).  For patients 
involved in the pivotal phase of the trial, a PK blood sample will be taken, provided 
the risk/benefit outcome is favorable in the investigator’s opinion (Section 9.2.11).  If 
a PK blood sample is collected, the investigator must note the sampling time and the 
dosing times of IMP and of any concomitant AEDs taken that day and the previous 
day.  Patients will titrate to their target dose of GWP42003-P (or equivalent volume of 
placebo in the pivotal phase; Section 8.1.2) and will continue at this dose, or the 
highest tolerated dose up to 40 mg/kg/day, for the remainder of the 2-week treatment 
phase.  During this time, the patient’s current IS therapy may be continued or tapered, 
at the discretion of the investigator.  All non-pharmacological interventions for 
epilepsy (including ketogenic diet and any neurostimulation devices for epilepsy) 
must remain stable during the pilot and pivotal phases of the trial.  Following Visit 2, 
daily safety checks will be made during the first week of IMP dosing. 
9.1.1.3 
Daily Safety Checks (Day 2 to Day 7 [Inclusive]) 
Safety checks will be made daily (including weekends, where possible) from Day 2 to 
Day 7 (inclusive). Safety checks can be conducted by telephone (where applicable 
they will be incorporated into scheduled visits, e.g., Visit 3 [Day 4]).  During each 
safety check, caregivers will be asked about the following, along with confirmation 
that the relevant details have been recorded in the caregiver diary: 
• Spasm/seizure information. 
• Changes in concomitant AEDs. 
• Usage of rescue medication. 
• AEs. 
Confirmation that the safety check has taken place will be recorded in the CRF.   
9.1.1.4 
Visit 3 (Day 4 [+1 Day]) 
This visit will occur 3 (+1) days after Visit 2.  The following will be 
collected/assessed: 
• Concomitant medication review (Section 9.2.5). 
• Vital signs (Section 9.2.7). 
• ECG (prior to the day’s first dose of IMP; Section 9.2.8). 
• Clinical laboratory samples (blood and urine [if possible]; Section 9.2.10) for: 
− Serum biochemistry. 
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− Hematology. 
− Urinalysis. 
• Caregiver diary review (Section 9.2.13) for: 
− Spasm/seizure information. 
− IMP usage. 
− Changes in concomitant AEDs. 
− Usage of rescue medication. 
− AEs. 
• AEs (Section 12). 
All patients will take their IMP in the clinic with an additional ECG assessment 
between 3 and 5 hours postdose (Section 9.2.8).  Patients in the pilot phase will then 
be discharged from the clinic. 
9.1.1.5 
Visit 4 (Day 15 [+3 Days]): End of Pilot or Pivotal 
Phase/Withdrawal 
This visit will occur 14 (+3) days after Visit 2 or earlier if the patient withdraws from 
the pilot or pivotal phase of the trial.  The following will be collected/assessed: 
• Concomitant medication review (Section 9.2.5). 
• Physical examination (Section 9.2.6). 
• Vital signs (Section 9.2.7). 
• ECG (prior to the day’s first dose of IMP; Section 9.2.8). 
• Video-EEG (Section 9.2.9). 
• Clinical laboratory samples (blood and urine [if possible]; Section 9.2.10) for: 
− Serum biochemistry. 
− Hematology. 
− Urinalysis. 
• Pivotal phase only: PK blood sampling (prior to the day’s first dose of IMP, 
provided the risk/benefit outcome is favorable in the investigator’s opinion; 
Section 9.2.11). 
• CGIC (Section 9.2.12.1). 
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• PGIC (Section 9.2.12.2). 
• Caregiver diary review (Section 9.2.13) for: 
− Spasm/seizure information. 
− IMP usage. 
− Changes in concomitant AEDs. 
− Usage of rescue medication. 
− AEs. 
• AEs (Section 12). 
Patients will take their IMP in the clinic with an additional ECG assessment between 
3 and 5 hours postdose (Section 9.2.8).  For patients involved in the pivotal phase of 
the trial, a further PK blood sample will be taken, provided the risk/benefit outcome is 
favorable in the investigator’s opinion (Section 9.2.11).  If PK blood samples are 
collected, the investigator must note the sampling times and the dosing times of the 
IMP and of any concomitant AEDs taken that day and the previous day.  All IMP will 
be collected and compliance reviewed. 
Patients who have successfully completed the pilot or pivotal phase will have the 
opportunity to receive GWP42003-P during the subsequent OLE phase at Visit 4.  
Patients from the pilot phase who enter the OLE phase will remain at the target dose 
which was reached during the pilot phase.  Patients from the pivotal phase who enter 
the OLE phase will receive sufficient blinded IMP for tapering along with sufficient 
OLE IMP (GWP42003-P) for simultaneous titration and subsequent dosing for 
2 weeks.  All patients in the pivotal phase who enter the OLE phase will transition to 
the target dose of GWP42003-P (in a blinded manner; Section 8.1.2) and may 
continue at this dose, or the highest tolerated dose up to 40 mg/kg/day, for the 
remainder of the OLE phase.  Following Visit 4, daily safety checks will be made 
during the first week of GWP42003-P dosing. 
For patients who withdraw early, the IVRS/IWRS will be contacted to confirm 
withdrawal from the trial.  Patients who opt not to enter the OLE phase or who 
withdraw from the pilot or pivotal phase early should begin the taper period, if 
possible (Section 9.1.3), and sufficient IMP will be dispensed. 
9.1.2 
Open-label Extension Phase 
The OLE phase will last for a maximum of 1 year. 
During the OLE phase, GWP42003-P may be discontinued by the investigator if: 
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• The patient has become spasm-free, as determined by clinical assessment by 
the investigator. 
OR 
• The patient is not perceived to be receiving any benefit from GWP42003-P, as 
determined by clinical assessment by the investigator. 
For any patients who have their IMP discontinued by the investigator, the 
IVRS/IWRS will be contacted to confirm IMP discontinuation.  All patients should 
commence the taper period, if possible (Section 9.1.3), and sufficient IMP will be 
dispensed if required. 
If the investigator decides to discontinue GWP42003-P following resolution of 
spasms, the parent(s)/legal representative will be encouraged to allow the patient to 
remain in the trial to complete the remaining assessments.  The investigator must 
contact the GW medical monitor to discuss the discontinuation process, including the 
subsequent assessments to be conducted. 
If the investigator decides to discontinue GWP42003-P because the patient is not 
perceived to be receiving any benefit from GWP42003-P, the patient will not be 
asked to complete the remaining trial assessments and will be withdrawn from the 
trial as per Section 10 (withdrawal to be registered in the IVRS/IWRS). 
Patients who have not demonstrated complete resolution of spasms but are perceived 
to be receiving some benefit from GWP42003-P may remain in the OLE and receive 
other concomitant medications during the OLE phase.  The option of withdrawal from 
the trial will be discussed with the caregiver at each visit. 
In cases of relapse, patients may restart IMP only if ALL of the following criteria are 
fulfilled: 
• The patient had their IMP discontinued by the investigator due to resolution of 
spasms. 
• The patient has remained in the trial to complete the remaining assessments. 
• The decision to restart IMP is discussed with the GW medical monitor. 
The IVRS/IWRS will then be contacted to confirm restart of IMP.  Patients restarting 
IMP will re-titrate to their target dose of GWP42003-P and may continue at this dose, 
or the highest tolerated dose up to 40 mg/kg/day, for the remainder of the OLE phase.  
The next scheduled clinic visit will then be performed according to the Schedule of 
Assessments (APPENDIX 1). 
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9.1.2.1 
Daily Safety Checks (Day 16 to Day 22 [Inclusive]) 
Safety checks will be made daily (including weekends, where possible) from Day 16 
to Day 22 (inclusive). Safety checks can be conducted by telephone (where applicable 
they will be incorporated into scheduled visits, e.g.. Visit 5 [Day 19]).  During each 
safety check, caregivers will be asked about the following, along with confirmation 
that the relevant details have been recorded in the caregiver diary: 
• Spasm/seizure information. 
• Changes in concomitant AEDs. 
• Usage of rescue medication. 
• AEs. 
Confirmation that the safety check has taken place will be recorded in the CRF. 
9.1.2.2 
Visit 5 (Day 19 [+1 Day]) 
This visit will occur 18 (+1) days after Visit 2.  The following will be 
collected/assessed: 
• Concomitant medication review (Section 9.2.5). 
• Vital signs (Section 9.2.7). 
• ECG (Section 9.2.8). 
• Clinical laboratory samples (blood and urine [if possible]; Section 9.2.10) for: 
− Serum biochemistry. 
− Hematology. 
− Urinalysis. 
• Caregiver diary review (Section 9.2.13) for: 
− Spasm/seizure information. 
− IMP usage. 
− Changes in concomitant AEDs. 
− Usage of rescue medication. 
− AEs. 
• AEs (Section 12). 
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All patients will take their IMP in the clinic.  For patients transitioning from the 
pivotal phase to the OLE a PK blood sample will be taken, provided the risk/benefit 
outcome is favorable in the investigator’s opinion (Section 9.2.11).  If a PK blood 
sample is collected, the investigator must note the sampling time and the dosing times 
of IMP and of any concomitant AEDs taken that day. 
9.1.2.3 
Visit 6 (Day 29 [±3 Days]) 
This visit will occur 28 (±3) days after Visit 2.  Collection of Visit 6 assessments 
earlier than Day 29 (i.e., on Day 26, 27, or 28) must only occur if there have been no 
witnessed spasms over the preceding 48 hours (minimum).  The following will be 
collected/assessed: 
• Concomitant medication review (Section 9.2.5). 
• Physical examination (Section 9.2.6). 
• Vital signs (Section 9.2.7). 
• ECG (Section 9.2.8). 
• Video-EEG (Section 9.2.9). 
• Clinical laboratory samples (blood and urine [if possible]; Section 9.2.10) for: 
− Serum biochemistry. 
− Hematology. 
− Urinalysis. 
• CGIC (Section 9.2.12.1). 
• PGIC (Section 9.2.12.2). 
• Caregiver diary review (Section 9.2.13) for: 
− Spasm/seizure information. 
− IMP usage. 
− Changes in concomitant AEDs. 
− Usage of rescue medication. 
− AEs. 
• AEs (Section 12). 
All IMP will be collected and compliance reviewed.  Patients will then receive 
sufficient IMP for 2 weeks’ dosing. 
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9.1.2.4 
Visit 7 (Day 43 [±3 Days]) 
This visit will occur 42 (±3) days after Visit 2.  The following will be 
collected/assessed: 
• Concomitant medication review (Section 9.2.5). 
• Physical examination (Section 9.2.6). 
• Vital signs (Section 9.2.7). 
• ECG (Section 9.2.8). 
• Video-EEG (Section 9.2.9). 
• Clinical laboratory samples (blood and urine [if possible]; Section 9.2.10) for: 
− Serum biochemistry. 
− Hematology. 
− Urinalysis. 
• CGIC (Section 9.2.12.1). 
• PGIC (Section 9.2.12.2). 
• Caregiver diary review (Section 9.2.13) for: 
− Spasm/seizure information. 
− IMP usage. 
− Changes in concomitant AEDs. 
− Usage of rescue medication. 
− AEs. 
• AEs (Section 12). 
All IMP will be collected and compliance reviewed.  Patients will then receive 
sufficient IMP for 4 weeks’ dosing. 
9.1.2.5 
Visit 8 (Day 71 [±3 Days]) 
This visit will occur 70 (±3) days after Visit 2.  The following will be 
collected/assessed: 
• Concomitant medication review (Section 9.2.5). 
• Physical examination (Section 9.2.6). 
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• Vital signs (Section 9.2.7). 
• ECG (Section 9.2.8). 
• Clinical laboratory samples (blood and urine [if possible]; Section 9.2.10) for: 
− Serum biochemistry. 
− Hematology. 
− Urinalysis. 
• CGIC (Section 9.2.12.1). 
• PGIC (Section 9.2.12.2). 
• Caregiver diary review (Section 9.2.13) for: 
− Spasm/seizure information. 
− IMP usage. 
− Changes in concomitant AEDs. 
− Usage of rescue medication. 
− AEs. 
• AEs (Section 12). 
All IMP will be collected and compliance reviewed.  Patients will then receive 
sufficient IMP for 8 weeks of dosing. 
9.1.2.6 
Visit 9 (Day 127 [±7 Days]) 
This visit will occur 126 (±7) days after Visit 2.  The following will be 
collected/assessed: 
• Concomitant medication review (Section 9.2.5). 
• Physical examination (Section 9.2.6). 
• Vital signs (Section 9.2.7). 
• ECG (Section 9.2.8). 
• Video-EEG (Section 9.2.9). 
• Clinical laboratory samples (blood and urine [if possible]; Section 9.2.10) for: 
− Serum biochemistry. 
− Hematology. 
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− Urinalysis. 
• CGIC (Section 9.2.12.1). 
• PGIC (Section 9.2.12.2). 
• Caregiver diary review (Section 9.2.13) for: 
− Spasm/seizure information. 
− IMP usage. 
− Changes in concomitant AEDs. 
− Usage of rescue medication. 
− AEs. 
• AEs (Section 12). 
All IMP will be collected and compliance reviewed.  Patients will then receive 
sufficient IMP for 12 weeks of dosing. 
9.1.2.7 
Visit 10 (Day 211 [±7 Days]) 
This visit will occur 210 (±7) days after Visit 2.  The following will be 
collected/assessed: 
• Concomitant medication review (Section 9.2.5). 
• Physical examination (Section 9.2.6). 
• Vital signs (Section 9.2.7). 
• ECG (Section 9.2.8). 
• Video-EEG (Section 9.2.9). 
• Clinical laboratory samples (blood and urine [if possible]; Section 9.2.10) for: 
− Serum biochemistry. 
− Hematology. 
− Urinalysis. 
• CGIC (Section 9.2.12.1). 
• PGIC (Section 9.2.12.2). 
• Vineland-II (Section 9.2.12.3). 
• Caregiver diary review (Section 9.2.13) for: 
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− Spasm/seizure information. 
− IMP usage. 
− Changes in concomitant AEDs. 
− Usage of rescue medication. 
− AEs. 
• AEs (Section 12). 
All IMP will be collected and compliance reviewed.  Patients will then receive 
sufficient IMP for 12 weeks of dosing. 
9.1.2.8 
Visit 11 (Day 295 [±7 Days]) 
This visit will occur 294 (±7) days after Visit 2.  The following will be 
collected/assessed: 
• Concomitant medication review (Section 9.2.5). 
• Physical examination (Section 9.2.6). 
• Vital signs (Section 9.2.7). 
• ECG (Section 9.2.8). 
• Video-EEG (Section 9.2.9). 
• Clinical laboratory samples (blood and urine [if possible]; Section 9.2.10) for: 
− Serum biochemistry. 
− Hematology. 
− Urinalysis. 
• CGIC (Section 9.2.12.1). 
• PGIC (Section 9.2.12.2). 
• Caregiver diary review (Section 9.2.13) for: 
− Spasm/seizure information. 
− IMP usage. 
− Changes in concomitant AEDs. 
− Usage of rescue medication. 
− AEs. 
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• AEs (Section 12). 
All IMP will be collected and compliance reviewed.  Patients will then receive 
sufficient IMP for 12 weeks of dosing. 
9.1.2.9 
Visit 12 (Day 379 [±7 Days]): End of OLE 
Treatment/Withdrawal 
This visit will occur 378 (±7) days after Visit 2 or earlier if the patient withdraws 
from the OLE phase of the trial.  The following will be collected/assessed: 
• Concomitant medication review (Section 9.2.5). 
• Physical examination (Section 9.2.6). 
• Vital signs (Section 9.2.7). 
• ECG (Section 9.2.8). 
• Video-EEG (Section 9.2.9). 
• Clinical laboratory samples (blood and urine [if possible]; Section 9.2.10) for: 
− Serum biochemistry. 
− Hematology. 
− Urinalysis. 
• CGIC (Section 9.2.12.1). 
• PGIC (Section 9.2.12.2). 
• Vineland-II (Section 9.2.12.3). 
• Caregiver diary review (Section 9.2.13) for: 
− Spasm/seizure information. 
− IMP usage. 
− Changes in concomitant AEDs. 
− Usage of rescue medication. 
− AEs. 
• AEs (Section 12). 
All IMP will be collected and compliance reviewed.  For patients who withdraw 
early, the IVRS/IWRS will be contacted to confirm withdrawal from the trial.  All 
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patients should commence the taper period, if possible (Section 9.1.3), and sufficient 
IMP will be dispensed. 
9.1.3 
Taper Period (10 Days) 
Following end of treatment, all patients will taper the IMP 10% per day over 10 days.  
Patients who withdraw early should also begin the taper period following the 
appropriate withdrawal visit (unless continued dosing is not possible due to an AE).  
Patients who discontinue IMP during the OLE phase should also begin the taper 
period following the investigator’s decision to discontinue.  The IVRS/IWRS will 
generate the patient’s daily IMP dosing volumes for the 10-day taper period, during 
which time paper diary information will continue to be recorded. 
9.1.3.1 
End of Taper Period Visit (+3 Days) 
This visit will occur 10 (+3) days after the end of treatment/withdrawal visit (if IMP is 
tapered).  For patients who begin to taper IMP, but subsequently withdraw/do not 
complete the full taper period, this visit should occur on the final day of dosing, or as 
soon as possible after this date.  The following will be collected/assessed: 
• Concomitant medication review (Section 9.2.5). 
• Physical examination (Section 9.2.6). 
• Vital signs (Section 9.2.7). 
• ECG (Section 9.2.8). 
• Clinical laboratory samples (blood and urine [if possible]; Section 9.2.10) for: 
− Serum biochemistry. 
− Hematology. 
− Urinalysis. 
• Caregiver diary review (Section 9.2.13) for: 
− Spasm/seizure information. 
− IMP usage. 
− Changes in concomitant AEDs. 
− Usage of rescue medication. 
− AEs. 
• AEs (Section 12). 
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All IMP will be collected and compliance reviewed. 
9.1.4 
Safety Follow-up Period (4 Weeks) 
Following end of dosing (including taper period), all patients will commence a 
4-week safety follow-up period to ascertain the status of AEs continuing after 
cessation of IMP or any new AEs commencing after discontinuation.  Patients who 
discontinue IMP during the OLE phase should begin the safety follow-up period 
following the end of the taper period.  During the safety follow-up period, paper diary 
information will continue to be recorded. 
9.1.4.1 
Weekly Safety Telephone Calls (±3 Days) 
Safety telephone calls will be made weekly (±3 days) from the date of final dosing 
until the safety follow-up visit, or until the next scheduled clinic visit for patients 
remaining in the trial following discontinuation of IMP by the investigator.  During 
each safety telephone call, caregivers will be asked for information on the following: 
• Spasm/seizure information. 
• Changes in concomitant AEDs. 
• Usage of rescue medication. 
• AEs. 
9.1.4.2 
Safety Follow-up Visit (+3 Days) 
This visit will occur 28 (+3) days after the end of taper period visit or date of final 
dosing, and can be conducted over the telephone.  The following will be collected: 
• Spasm/seizure information. 
• Changes in concomitant AEDs. 
• Usage of rescue medication. 
• AEs. 
The caregiver should return the completed caregiver diary following the safety 
follow-up visit. 
All causally related AEs that result in a patient’s premature termination from the trial 
or are present at the end of the trial should be followed up until a satisfactory 
resolution occurs; that is, until the AE resolves or is considered clinically 
insignificant, or until the investigator is satisfied that the AE is not related to IMP and 
needs no further investigation. 
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9.2 
Trial Procedure Listing 
9.2.1 
Informed Consent 
The parent(s)/legal representative of the patient must personally sign and date the 
IRB/IEC-approved ICF before any trial-specific procedures are performed or any 
patient-related data is recorded for the trial.  GW requires a physician to be present for 
consent and to sign the consent form also.  The original signed ICF should be retained 
and a copy provided to the patient’s parent(s)/legal representative.  The patient’s 
parent(s)/legal representatives will be given the option of being informed about the 
summary outcome and results of the trial as part of the ICF.  For further details, see 
Section 15.2. 
9.2.2 
Interactive Voice Response System/Interactive Web Response 
System 
The IVRS/IWRS will be used to assign patients to treatment groups, manage IMP 
supply, and to provide treatment allocation information in the event of patient 
unblinding (pivotal phase only). 
A member of the trial team must contact the IVRS/IWRS at each clinic visit in order 
to: 
• Obtain a patient number (Visit 1). 
• Assign GWP42003-P (pilot phase) or randomize a patient (pivotal phase) 
(Visit 2). 
• Obtain dispensing information (Visits 2, 4, 6–11, and for the taper period, if 
necessary). 
• Provide IMP discontinuation/IMP restart/completion/taper/premature 
termination information. 
Training will be given to all sites prior to the start of the trial. 
9.2.3 
Demographics 
The following information will be obtained for each patient (as allowed per local 
regulations): 
• Date of birth. 
• Sex. 
• Race. 
• Date of onset of IS. 
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• Gestational age at birth. 
• Birthweight. 
9.2.4 
Medical History 
The following medical history will be obtained for each patient: 
• Prior and current seizures/spasms. 
• Prior AEDs/steroids. 
• Prior IS treatment details (all approved therapies must be discussed with the 
patient’s parent(s)/legal representative before the patient is considered for the 
trial; discussions regarding treatment options must be documented). 
• Presence of abnormal EEG patterns that are consistent with IS, including 
hypsarrhythmia. 
• Neuroimaging history. 
• Unequivocally normal development at onset of IS. 
• Etiologic classification of IS: 
• idiopathic (genetic). 
• symptomatic (structural / metabolic). 
• cryptogenic (unknown). 
In addition, any relevant, significant medical history will be obtained, and is defined 
as any condition or disease that: 
• May affect the condition under study. 
• Is ongoing on entry into the trial. 
9.2.5 
Concomitant Medication 
Details of all current and prior medication, including AEDs/steroids, will be obtained.  
Any changes in concomitant medication during the trial must be recorded on the CRF 
at trial visits.  Refer to Section 8.2 and Section 8.3 for further information. 
9.2.6 
Physical Examination 
Physical examinations will include length (height), body weight, and head 
circumference measurements. 
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9.2.7 
Vital Signs 
Vital signs measurements (systolic and diastolic blood pressure, pulse rate, body 
temperature and respiratory rate), taken in a supine position at rest for 5 minutes, will 
be completed alongside the physical examination.  The methods/procedures employed 
for vital signs measurements must be consistent throughout the trial, where possible.  
Any deviation in methods used must be reported to the study monitor. 
9.2.8 
12-lead Electrocardiogram  
ECG recordings will be performed after 5 minutes in a supine position.  A physician 
must review the ECG immediately (annotated, signed and dated) and any abnormal 
findings considered to indicate significant medical history or AEs must be recorded 
appropriately on the CRF.  Additional ECG measurements can be taken at any time 
during the trial, if clinically indicated. 
9.2.9 
Video-electroencephalography 
Prolonged video-EEG monitoring (minimum 8 hours in duration, extendable to 
24 hours) will be performed to document clinical spasms and EEG patterns consistent 
with IS.  At least 1 full sleep-wake cycle must be observed during each video-EEG 
assessment.  The investigator must review the video-EEG during screening to confirm 
eligibility, during which time patients must continue to take their current IS therapy at 
a stable dose.  If no clinical spasms and hypsarrhythmia are observed during the initial 
8-hour recording at screening, every effort should be taken to extend monitoring up to 
a maximum of 24 hours to confirm eligibility, if the site has the capability.  Eligible 
patients must begin treatment within 7 days of their video-EEG screening assessment.  
In addition to being read at the trial site, all video-EEG recordings will be centrally 
read retrospectively (see APPENDIX 2 for further details regarding the central 
reader).  The assessment by the central reader for the video-EEG assessment 
screening will be considered final.  Any video-EEG findings considered to represent 
an AE must be documented on the CRF.   
9.2.10 
Clinical Laboratory Sampling 
Due to the nature of the disease being studied, and the need for prompt treatment of 
patients, it will be necessary to use local laboratories for the clinical laboratory 
aspects of the trial. 
Urine samples (provided urine can be obtained) will be analyzed at the trial site by 
use of a dipstick with any relevant findings being sent for further urinalysis at a local 
laboratory (urinalysis, microscopy, culture and sensitivity, as applicable). 
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Clinical laboratory sample parameters required from the local laboratories are detailed 
in Table 9.2.10-1. 
 
Table 9.2.10-1 
Biochemistry, Hematology, Urinalysis 
Biochemistry 
(Serum)1 
Hematology 
(Whole Blood)1 
Urinalysis 
(Urine)1 
Essential Parameters2 
Alanine aminotransferase 
Hematocrit 
Glucose 
Alkaline phosphatase 
Hemoglobin 
Nitrites 
Aspartate aminotransferase 
Mean corpuscular hemoglobin 
pH 
Creatinine 
Platelets 
Protein 
Gamma-glutamyl transferase 
Red blood cell count 
White blood cells 
Potassium 
White blood cell count with 
automated differential 
 
Sodium 
 
 
Triglycerides 
 
 
Total bilirubin 
 
 
Urea (blood urea nitrogen)  
 
 
Additional Parameters3 
Albumin  
Mean cell volume 
 
Calcium  
 
 
Creatinine clearance 
 
 
Prothrombin time (plasma) 
 
 
Total protein 
 
 
1Refer to the laboratory manual. 
2Analyzed as a priority. 
3Analyzed in addition to the essential parameters, wherever possible. 
To minimize the volume of blood required, serum biochemistry and hematology 
results from samples analyzed up to 3 days prior to Visit 1 may be used for screening 
purposes.  The samples must be analyzed at the same local laboratory that is being 
used for the clinical laboratory aspects of the trial.  
All laboratory results will be reviewed and the reports signed and dated by an 
investigator.  Any results considered to be of clinical significance must be addressed 
and followed up as clinically appropriate.  All laboratory results must be documented 
on the CRF.  For reporting and follow-up of potential cases of drug-induced liver 
injury, see Section 12.7. 
Repeat samples will be taken, if required, for clinical follow-up or if the sample is lost 
or damaged.  Any abnormal end of treatment clinical laboratory result of clinical 
significance must be repeated at regular intervals until it returns to normal, or until an 
investigator is satisfied that the abnormality is not related to the IMP and needs no 
further investigation.  The maximum amount of blood taken in any 24-hour period, 
including PK blood samples, will be 3 mL/kg of body weight and will not exceed a 
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total of 50 mL within any 8-week period54.  A separate laboratory manual will 
provide guidance on the priority of blood samples to be taken in relation to the 
maximum permitted blood volumes.  The caregiver must be advised that it may not be 
safe for the patient to undertake further blood tests within 1 month of any trial-related 
blood draws and to inform the investigator if the patient suffered any blood loss 
during the 1 month period leading up to a planned blood draw. 
9.2.11 
Pharmacokinetic Blood Sampling  
Blood samples may be taken from patients involved in the pivotal phase, and 
progressing to the OLE from the pivotal phase, for the determination of CBD and its 
metabolites (6-OH-CBD, 7-COOH-CBD, and 7-OH-CBD) to provide an 
understanding of the PK of CBD.  In addition, an exploration of the relationship 
between plasma levels of CBD with safety and efficacy may be performed.   In this 
trial, a sparse sampling approach will be employed to minimize the impact on patients 
in terms of potential discomfort and to keep the blood volume taken as low as 
practicable.  Suggested sampling times are as follows: 
• Day 1: between 1 and 12 hours after the day’s first dose of IMP. 
• Day 15: prior to the day’s first dose of IMP and around 2 hours postdose. 
• Day 19: between 4 and 12 hours after the day’s first dose of IMP (only for 
patients in the pivotal phase who transition to the OLE). 
These sampling times should be considered optimal; however, since the data will be 
fitted to a population PK model developed from other clinical trials, the investigator 
should use their discretion regarding sampling time to minimize distress/discomfort to 
the patient.  IMP dosing time and blood sampling time should be recorded accurately.  
The dosing time of any concomitant AEDs and timing of feeds/meals should also be 
recorded. 
Analysis of all PK samples will be conducted at a central bioanalytical laboratory.  
Blood sample volume requirements and processing procedures will also be detailed in 
a separate laboratory manual; the maximum amount of blood taken in a single draw 
for PK analyses will be approximately 1 mL.  The maximum number of PK blood 
draws will be determined by the criteria stated in Section 9.2.10.  The caregiver must 
be advised that it may not be safe for the patient to undertake further blood tests 
within 1 month of any trial-related blood draws and to inform the investigator if the 
patient suffered any blood loss during the 1-month period leading up to a planned 
blood draw. 
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9.2.12 
Questionnaires Completed at Scheduled Visits  
With the exception of the PGIC, all questionnaires should be completed by the main 
caregiver.  In situations where this is not possible, this information must be captured 
over the telephone, ideally on the day of the visit or otherwise within 3 days.  The 
same person should complete the questionnaires in order to maintain consistency.  
Copies of questionnaires can be found in APPENDIX 3. 
9.2.12.1 
Caregiver Global Impression of Change 
The CGIC comprises a single question to be rated on a 7-point scale: 
“Since the patient started treatment, please assess the status of the 
patient’s overall condition (comparing their condition now to their 
condition before treatment) using the scale below.” 
The markers are: “Very Much Improved”; “Much Improved”; “Slightly Improved”; 
“No Change”; “Slightly Worse”; “Much Worse”; “Very Much Worse”. 
The caregiver will be asked to record the status of the patient’s overall condition at 
Visit 2 (Day 1, i.e., prior to commencement of IMP) as a memory aid for subsequent 
visits. 
9.2.12.2 
Physician Global Impression of Change 
The PGIC comprises the same, single question as the CGIC (Section 9.2.12.1) to be 
rated on the same, 7-point scale by the investigator.  The investigator will be asked to 
record the status of the patient’s overall condition at Visit 2 (Day 1, i.e., prior to 
commencement of IMP) as a memory aid for subsequent visits. 
9.2.12.3 
Vineland Adaptive Behavior Scales, Second Edition 
The Vineland-II55 is an individually administered instrument for assessing adaptive 
behaviors and is widely used in pediatric clinical trials due to its applicability to 
children of all ages and developmental levels.  The Vineland-II will be completed by 
the caregiver using a rating scale.  Due to the possibility of cognitive/developmental 
delay, caregivers should start the assessment at the lowest age, irrespective of the 
patient’s actual age. 
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9.2.13 
Caregiver Diary 
Caregivers will be instructed how to complete a paper diary and will be asked to 
record the following patient information daily throughout the trial.  Caregivers must 
bring the paper diary to each clinic visit for review by the investigator. 
9.2.13.1 
Spasm/Seizure Information 
The caregiver must record whether the patient had any episodes of spasms and/or 
other subtypes of epileptic seizure on a daily basis. 
9.2.13.2 
Usage of Investigational Medicinal Product 
Information on IMP intake on each treatment day must be recorded by the caregiver.  
IMP administration compliance checks will be conducted according to Section 8.4. 
9.2.13.3 
Changes in Concomitant Medication 
Any changes in the patient’s concomitant medication (including AEDs/steroids) or IS 
therapies must be recorded by the caregiver.  Any changes in concomitant medication 
during the trial must be recorded on the CRF at trial visits. 
9.2.13.4 
Usage of Rescue Medication 
Details of each administration of rescue medication must be recorded by the caregiver 
(drug name and dose level).  The use of any rescue medication during the trial must 
be recorded on the CRF at trial visits. 
9.2.13.5 
Adverse Events 
Details of any AEs must be recorded by the caregiver.  Refer to Section 12 for 
definitions, procedures and further information on AE reporting. 
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10 
WITHDRAWAL 
In accordance with the Declaration of Helsinki56, the International Conference on 
Harmonisation (ICH) Tripartite Guideline for GCP Topic E6(R1)57, the FDA 
regulations relating to GCP and clinical trials58,59,60, the EU Clinical Trials 
Directive61, the EU GCP Directive62 and/or other applicable regulations, a patient has 
the right to withdraw from the trial at any time and for any reason, with no obligation 
to provide a reason, and without prejudice to his or her future medical care by the 
physician or at the institution. 
The patient must be withdrawn from the trial if any of the following apply: 
• Any issue with eligibility criteria that is considered to potentially compromise 
the safety of the patient. 
• Administrative decision by the investigator, GW, or a regulatory authority. 
• Protocol deviation that is considered to compromise potentially the safety of 
the patient. 
• Withdrawal of the patient’s parent(s)/legal representative consent. 
• QTcB of 500 msec or greater on ECG, or a shift from baseline QTcB of 
60 msec or greater. 
Note: Prior to withdrawal for the QTcB shifts noted above, the investigator 
should repeat the ECG three times and contact the GW medical monitor.  If 
the above QTcB criteria are confirmed, the patient must be withdrawn from 
the trial.   
• Lost to follow-up. 
• ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, 
right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia 
(> 5%). 
• ALT or AST > 8 × ULN. 
• ALT or AST > 5 × ULN for more than 2 weeks. 
• ALT or AST > 3 × ULN and (TBL > 2 × ULN or INR > 1.5). 
Note: Prior to withdrawal for the transaminase elevations noted above, the 
Investigator may choose to confirm the transaminase elevations by repeating the 
following laboratory tests within 24 to 48 hours: ALT, AST, TBL, INR, % eosinophils, 
gamma glutamyl transferase and alkaline phosphatase.  Should the above 
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transaminase elevation criteria be confirmed, the patient must be withdrawn from 
the trial. 
Patients may also be withdrawn from the trial for any of the following: 
• Any other issue with eligibility criteria (non-safety related). 
• Any requirement to increase the dose of concomitant AED(s) or to add in new 
AED(s) during the pilot or pivotal phase.  
• If a patient is not showing evidence of benefit during the OLE phase (the 
option of withdrawing from the trial will be discussed with the caregiver at 
each visit). 
• Patient/caregiver non-compliance. 
• AE (including clinically significant laboratory result) which, in the opinion of 
the investigator, would compromise the continued safe participation of the 
patient in the trial. 
Should a patient’s parent(s)/legal representative request or decide to withdraw the 
patient from the trial, all efforts must be made to complete and report the observations 
as thoroughly as possible up to the date of withdrawal.  Patients who are withdrawn 
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 (end of pilot or 
pivotal phase/withdrawal) or Visit 12 (end of OLE treatment/withdrawal), as 
appropriate, should be conducted if possible.  If the tapered dose is administered, 
caregivers should continue to complete the paper diary and return for the end of taper 
period visit, if possible.  For patients who begin to taper IMP but are subsequently 
withdrawn, the end of taper period visit assessments (including ECG and clinical 
laboratory sampling) should be conducted, if possible; this visit should occur on the 
final day of dosing or as soon as possible after this date.  Patients who are withdrawn 
due to an AE should be followed up according to Section 12.6.  All information 
should be reported on the applicable CRF pages (refer to Section 9.2).  Wherever 
possible, a safety follow-up visit should take place 28 days after the last dose of IMP 
(refer to Section 9.1.4.2).  If the parent(s)/legal representative of withdrawing patients 
decline to give a reason for withdrawal of consent, the investigator must respect these 
wishes. 
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11 
URGENT SAFETY MEASURES 
The sponsor and investigator may take appropriate urgent safety measures in order to 
protect the patients of a clinical trial against any immediate hazard to their health or 
safety.  If such measures are taken by the investigator they must notify GW 
immediately or at least within 24 hours of awareness.  GW will report urgent safety 
measures to regulatory authorities by telephone within 24 hours of awareness, 
wherever possible, and will provide a written report to the regulatory authorities and 
IRB/IEC within 3 days. 
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12 
ADVERSE EVENT REPORTING 
12.1 
Definitions 
12.1.1 
Adverse Event 
For the purposes of this trial an AE is defined as: 
Any new unfavorable/unintended signs/symptoms (including abnormal laboratory 
findings when relevant), or diagnosis or worsening of a pre-existing condition, which 
occurs following screening (Visit 1) and at any point up to the post-treatment, safety 
follow-up visit, which may or may not be considered to be related to the IMP.  Any 
event that is the result of a trial procedure must be recorded as an AE. 
Surgical/Investigational procedures are not AEs.  The medical reason for the 
procedure is the AE.  Elective hospitalizations for pre-trial existing conditions or 
elective procedures are not AEs.  The exception may be if the patient has an AE 
during hospitalization which prolongs their scheduled hospital stay in which case it 
would be considered a SAE (refer to Section 12.2). 
If reporting a fatal event, the SAE term should be the underlying cause of the death 
(e.g., disease or medical condition leading to death). 
12.1.2 
Investigator 
The term investigator refers to the trial PI or a formally delegated 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 medicine is 
developed (e.g., change in dose, population, monitoring need, consent forms).  This is 
particularly true for events that threaten life or function.  Such SAEs will be reported 
promptly to regulatory authorities, applicable IRBs/IECs and investigators (expedited 
reporting) by GW. 
An AE must only be classed as serious, i.e., a SAE, when the event falls into one of 
the following criteria: 
• Results in death. 
• Is life-threatening*. 
• Requires inpatient hospitalization or prolongation of existing hospitalization. 
• Results in persistent or significant disability/incapacity. 
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• Is a congenital anomaly/birth defect. 
• Is 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. 
The sponsor considers all convulsive and non-convulsive status epilepticus events 
to be medically significant and should be reported to the Sponsor as medically 
significant SAEs 
12.3 
Reporting Procedures for Serious Adverse Events 
All SAEs occurring during the trial must be reported to GW with any other supporting 
information and recorded in the AE section of the CRF.  Any ongoing SAEs should 
be followed up until resolution wherever possible.  For all deaths, the working 
diagnosis or cause of death as stated on a death certificate, available autopsy reports 
and relevant medical reports should be sent to GW promptly. 
All SAEs must be reported directly to the GW Pharmacovigilance Department 
(PVD) within 24 hours of discovery or notification of the event.  All SAE 
information must be recorded in the SAE report forms provided in the site files and 
faxed to the GW PVD (see APPENDIX 2).  Additional information received for a 
case (follow-up or corrections to the original case) need to be detailed on a new SAE 
report form, signed/dated and faxed to the GW PVD and the AE section of the CRF 
must be updated. 
Any other problem discovered after the safety follow-up visit which is deemed to be 
an unexpected safety issue and is likely to have an impact on patients who have taken 
part in the trial must be treated as an SAE and reported to the GW PVD.  Such 
post-trial SAEs do not need to be recorded on the patient’s CRF if editing rights to the 
CRF have been removed due to final trial data lock.  GW PVD may request safety 
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follow-up information after the final trial visit in order to investigate a potential safety 
issue. 
Contact details for the GW PVD are provided at the front of the site files for all trial 
sites, and upon the GW SAE report form. 
12.4 
Causality Assessment 
Causality assessment is required for all AEs and SAEs.  Causality assessment must 
only be assigned by the investigator.  All cases judged as having a reasonable 
suspected causal relationship to the IMP must be reported as such.  The expression 
“reasonable causal relationship” is meant to convey in general that there are facts 
(evidence) or arguments to suggest a causal relationship. 
The following question which must be answered by the investigator for all AEs is 
used to capture the reasonable causal relationship of an event to the IMP: 
“In your opinion is there a plausible relationship to the IMP?” The answer is either 
“yes” or “no”. 
Events that start before the first dose of IMP (pre-treatment) should be considered as 
not causally related.  Where a pre-treatment event worsens in severity following the 
first dose of IMP, a new event record should be entered into the CRF. 
Considering the explanation given above, investigators are strongly encouraged to 
express their opinion on what the cause of an AE might be.  For individual patients, 
the investigator is usually in the best position to assess the underlying suspected cause 
of an AE.  For all AEs and especially SAEs, it is important that the investigator assess 
not only the possible role of the IMP but also other potential contributing factors.  
Factors for consideration of the underlying cause may include: 
• Medical and disease history. 
• Lack of efficacy/worsening of treated condition. 
• Concomitant or previous treatment. 
• Withdrawal of IMP. 
• Protocol-related procedure. 
12.5 
Reporting Procedures for All Adverse Events 
All AEs (including SAEs) occurring during the trial will be reported on the running 
logs in the AE section of the CRF.  This includes all events from the time following 
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screening (Visit 1) up to and including the post-treatment follow-up visit, whether or 
not attributed to IMP and observed by the investigator or patient. 
The following information will need to be provided for all AEs: 
A) Adverse Event (Diagnosis or Syndrome if Known, or Signs and Symptoms) 
Where the investigator cannot determine a diagnosis, signs or symptoms should be 
recorded in the AE section of the 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, 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. 
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If the severity of an AE fluctuates day-to-day, e.g., a headache or constipation, the 
change in severity should not be recorded each time; instead, only the worst observed 
severity should be recorded with AE start and stop dates relating to the overall event 
duration, regardless of severity. 
A severe AE is not the same as a SAE.  For example, a patient may have severe 
vomiting but the event does not result in any of the SAE criteria above.  Therefore, it 
should not be classed as serious. 
E) Causality 
See Section 12.4 above. 
F) Action Taken with Trial Medication 
This question refers to the action taken with the IMP due to an AE.  The action with 
the IMP must be classed as: 
• None. 
• Dose reduced temporarily. 
• Dose reduced. 
• Trial medication interrupted. 
• Trial medication stopped. 
12.6 
Follow-up Procedures for Adverse Events 
The investigator may be asked to provide follow-up information to the GW PVD for 
any AEs reported or during the investigation of potential safety issues.  Such requests 
for additional safety information may occur after the safety follow-up visit (i.e., after 
the trial). 
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’s 
parent(s)/legal representative may also voluntarily withdraw the patient from 
treatment due to what he or she perceives as an intolerable AE.  Further details of 
withdrawal are presented in Section 10.  If either of these occurs, the patient must 
undergo an end of treatment assessment and be given appropriate care under medical 
supervision until symptoms cease or the condition becomes stable.  If a safety concern 
is identified following withdrawal of a patient, GW may contact the investigator for 
additional follow-up information. 
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12.7 
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 starting treatment that meets the criteria for the selected 
laboratory parameters as follows:  
• ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, 
right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia 
(> 5%). 
• ALT or AST > 8 × ULN. 
• ALT or AST > 5 × ULN for more than 2 weeks. 
• ALT or AST > 3 × ULN and (TBL > 2 × ULN or INR > 1.5). 
These reports must be sent to the GW PVD using the fax number for SAE reporting 
(see APPENDIX 2) within 24 hours of becoming aware of the results.  In addition, 
please send a copy of the patient’s baseline laboratory results with all reports to the 
GW PVD. 
Abnormal values in AST and/or ALT concurrent with abnormal elevations in TBL 
that meet the criteria outlined above are considered potential cases of drug-induced 
liver injury and will be considered as protocol-defined criteria for withdrawal and 
important medical events.  The investigator will arrange for the patient to return to the 
investigational site as soon as possible (within 24 to 48 hours of notice of abnormal 
results) for repeat assessment of ALT, AST, TBL, alkaline phosphatase and 
gamma-glutamyl transferase levels, detailed history and physical examination.  
Patients should be followed in this way until all abnormalities have normalized (in the 
investigator’s opinion) or returned to the baseline state, however, if the above 
transaminase elevation criteria are confirmed by the first set of follow-up laboratory 
tests, the patient must be withdrawn from the trial. 
Elevations in ALT or AST > 3 × ULN or TBL > 2 × ULN alone are not considered 
potential cases of drug-induced liver injury, but will be followed as detailed above, 
within 72 hours’ notice of abnormal results.   
12.8 
Notification of Safety Information to Investigators, Regulatory 
Authorities, and IRBs/IECs 
In accordance with the EU Clinical Trials Directive61, relevant parts of the FDA Code 
of Federal Regulations63, and any national regulations, GW will inform investigators, 
regulatory authorities and relevant IRBs/IECs of all relevant safety information.  This 
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will include the reporting of relevant SAEs and all suspected unexpected serious 
adverse reactions (SUSARs). 
This information will be provided through 3 sources: 
1. IB53: a compilation of the clinical and non-clinical safety data available on the 
IMP that is relevant to the trial.  The IB is updated annually. 
2. Development core safety information: this document forms the safety section 
of the IB53, or is updated as an addendum to the IB53.  This document is 
revised if necessary, when new important safety information becomes 
available (potentially up to a few times a year). 
3. Council for International Organizations of Medical Sciences (CIOMS) reports: 
these reports are issued every time a SUSAR is reported to GW.  They provide 
information on individual case reports and are sent to all the regulatory 
authorities, the relevant central IRBs/IECs which have approved the trial and 
investigators.  As required, the investigator should notify their regional 
IRBs/IECs 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 US, investigators are normally required to report promptly to their IRBs all 
unanticipated problems involving risks to patients, or others, including AEs that 
should be considered unanticipated problems.  Based on current FDA guidance58 the 
following clarification is provided in determining what constitutes an unanticipated 
problem: 
In general, an AE observed during the conduct of a trial should be considered an 
unanticipated problem involving risk to patients and reported to the IRB, only if it 
were unexpected, serious, and would have implications for the conduct of the trial 
(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 trial cannot be 
understood. 
The FDA guidance63 states that, accordingly, to satisfy the investigator’s obligation to 
notify the IRB of unanticipated problems, any investigators participating in a multisite 
trial may rely on the sponsor’s assessment and provide to the IRB a report of the 
unanticipated problem prepared by the sponsor. 
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GW will inform investigators, regulatory authorities and relevant IRBs/IECs of any 
safety issues or case reports that are considered to be unanticipated and provide such 
reports as mentioned above.  It should be noted that a single SUSAR report notified to 
investigators in the trial does not necessarily constitute an unanticipated problem 
unless identified by GW in the submission cover letter. 
As a minimum, the recipient will be sent all of the above and relevant updates 
between the period from ethical approval and final database lock. 
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13 
STATISTICAL CONSIDERATIONS 
13.1 
Sample Size, Power, and Significance Levels 
The pilot phase is not powered and comprises 10 patients.  Both cohorts in the pilot 
phase will comprise 5 patients, the first cohort aged between 6 and 24 months and the 
second cohort aged between 1 and 24 months, who will all receive GWP42003-P. 
The pivotal phase will comprise 192 patients, aged 1–24 months, who will be 
randomized to receive 1 of 2 dose levels of GWP42003-P (High Dose Level or Low 
Dose Level) or matching placebo on a 1:1:1 basis (64 per treatment group).  Patients 
in the placebo group will be further split into 2 cohorts (32 patients receiving Low 
Dose Level dosing volumes and 32 patients receiving High Dose Level dosing 
volumes), but it is assumed that these 2 cohorts can be pooled for the analyses of 
efficacy.   
Assuming a 20% screen failure rate, it is expected that approximately 245 patients 
will need to be screened to achieve this target (202 patients included in the pilot and 
pivotal phases in total).   
 
 
 
  
This is based on a 2-sided 5% significance level, based on a Fisher’s exact test. 
13.2 
Interim Analysis 
No formal interim analysis will be conducted.  A review of safety and efficacy data 
will be conducted after the end of the pilot phase, and blinded data review(s) may be 
conducted to support IMP clinical development.  However, for the pivotal phase, it is 
anticipated that the database will be locked and treatment unblinded, prior to the 
completion of the OLE phase. 
13.3 
Analysis Sets 
Statistical analysis will be performed according to a statistical analysis plan (SAP) .  
Details of any deviations from the SAP will be documented in the clinical study 
report. 
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There will be 3 analysis sets for this trial: 
Pilot or Pivotal Phase Safety 
All patients exposed to at least 1 dose of IMP during the pilot or pivotal phase will 
be used for summaries of the safety endpoints during both phases. 
OLE Phase Safety 
All patients exposed to at least 1 dose of IMP during the OLE phase will be used 
for summaries of the safety endpoints during the OLE phase. 
Intention to Treat (ITT) 
All patients in the pivotal phase who are randomized and receive IMP will be 
included and analyzed according to their randomized treatment group.  The ITT 
analysis set is the primary analysis set for all efficacy endpoints. 
13.3.1 
Protocol Deviations 
Protocol deviations will be listed and reasons for exclusion from the analysis sets 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.  Categorical variables will be summarized showing the number and 
percentage of patients falling into each category. 
13.5 
Accountability and Background Characteristics 
13.5.1 
Enrollment and Disposition 
All patients (screened, treated, entering the OLE, prematurely terminating IMP) will 
be accounted for in the enrollment and disposition summary tables. 
13.5.2 
Baseline and Demographic Characteristics 
Baseline characteristics, including demographics, medical history, and concomitant 
medications will be summarized by treatment group and overall as appropriate. 
13.6 
Endpoints and Statistical Methods 
For the pivotal phase, only data from this phase will be used for analysis of the 
primary and secondary endpoints; data from the pilot phase may be used in 
subsequent sensitivity analyses.  Data from all phases will be used for a number of 
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descriptive summaries for certain endpoints.  All safety endpoints for the phases of 
the trial will be summarized as detailed in Section 13.6.5 below. 
For the pivotal phase of the trial, statistical hypothesis testing will be performed on 
the secondary endpoints as appropriate.   
Since there is a single primary analysis endpoint for the pivotal phase, no formal 
adjustment of statistical significance for multiple testing on multiple endpoints is 
required, although such multiplicity should be allowed for when interpreting the 
results for secondary endpoints.  However, there are 3 treatments, so multiple 
significance testing will occur when making comparisons between the treatments; the 
major comparisons of interest are those between each of the GWP42003-P dose levels 
and placebo.  To control the type I error, a step-up Hochberg's procedure will be used 
for the primary endpoint of the pivotal phase.  If both of the observed p-values from 
the Low Dose Level and High Dose Level comparisons with placebo are < 0.050 in 
favor of the GWP42003-P treatment groups, then both groups would be declared 
statistically significantly better than placebo.  However, if the observed p-value is 
≥ 0.050 for one GWP42003-P treatment group but < 0.025 in favor of the other 
GWP42003-P treatment group, then only the latter GWP42003-P treatment group will 
be declared statistically significantly better than placebo. 
13.6.1 
Evaluable Period 
The start of the evaluable period (Day 1) is defined as the first day the patient took 
IMP in the trial or the day of randomization/initial assignment of IMP if this date is 
unknown.  The end of the evaluable period for the pilot or pivotal phase is defined as 
the last day on which the study IMP was taken during the pilot or pivotal phase.  The 
end of the evaluable period for the OLE phase is defined as the last day on which a 
study-related assessment was undertaken during the OLE phase as opposed to the last 
day on which the study IMP was taken.  This is to allow data collected after 
discontinuation of the study IMP due to resolution of spasms to form part of the 
evaluable period. 
13.6.2 
Primary Endpoint(s) 
13.6.2.1 
Pilot Phase 
The following endpoints will be analyzed descriptively only: 
• 
Safety as determined by AEs, clinical laboratory tests, ECG, vital signs and 
physical examinations during the treatment period (see Section 13.6.5) 
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• 
The number and proportion of patients who are free of spasms and have 
resolution of hypsarrhythmia at the end of the 2-week treatment period, as 
determined by video-EEG. 
13.6.2.2 
Pivotal Phase 
The number and proportion of patients who are free of spasms and have resolution of 
hypsarrhythmia at the end of the initial 2-week treatment phase, will be analyzed by 
treatment group using a chi-square test.  However, if the number of patients in either 
of the treatment groups is less than 5 then a Fisher’s exact test will be performed 
instead. 
Patients who withdraw from the trial or patients who do not have a video EEG 
performed at the end of the 2-week treatment period will be included in the primary, 
and key secondary analyses as not being free of spasms and not having resolution of 
hypsarrhythmia. 
Details of sensitivity analyses due to missing data and handling of patients potentially 
receiving rescue medication will be fully detailed in the SAP prior to unblinding. 
13.6.2.3 
Open-label Extension 
To assess the long term safety as determined by AEs, clinical laboratory tests, ECG, 
vital signs and physical examinations during the treatment period (see Section 13.6.5). 
13.6.3 
Secondary Endpoint(s) 
13.6.3.1 
Pilot Phase 
For the pilot phase, the following secondary endpoints will be analyzed descriptively 
only: 
• The number and proportion of patients who are free of clinical spasms, as 
observed on video-EEG at the end of the treatment period. 
• The number and proportion of patients who have resolution of 
hypsarrhythmia, as observed on video-EEG at the end of the treatment period. 
• Changes in spasms and seizure subtypes by caregiver observation during the 
treatment period.  
• Time to cessation of spasms during the treatment period, as determined by 
caregiver diaries. 
• CGIC. 
• PGIC. 
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Safety data is detailed in Section 13.6.5 below. 
13.6.3.2 
Pivotal Phase 
For the pivotal phase, the number and proportion of patients who are free of clinical 
spasms, and the proportion of patients with resolution of hypsarrhythmia at the end of 
the initial 2-week treatment phase, will be analyzed by treatment group using a 
chi-square test.  However, if the number of patients in either of the treatment groups is 
less than 5 then a Fisher’s exact test will be performed instead. 
Changes in spasms and seizure subtypes during the initial 2-week treatment phase will 
be analyzed descriptively only. 
The time to cessation of spasms during the initial 2-week treatment phase will be 
calculated as the number of days from first dose of IMP to the first day in which no 
spasms were recorded in the patient diary.  Patients who do not have cessation of 
spasms by Visit 4 will be censored on the day of Visit 4.  The time to cessation of 
spasms will be analyzed descriptively as well as with a log-rank test. 
The CGIC and PGIC will be analyzed by treatment group using ordinal logistic 
regression, including treatment group as a factor and sex as a covariate in the model. 
Safety and tolerability as determined by AEs, clinical laboratory tests, 12-lead 
electrocardiogram (ECG), physical examinations and vital signs. 
Measurement where possible of plasma concentrations of CBD and its major 
metabolites (7-OH-CBD, 6-OH-CBD, and 7-COOH-CBD) will be investigated using 
a sparse sampling approach, with the aim to define a POPPK model. 
13.6.3.3 
Open-label Extension 
For the OLE phase, the following secondary endpoints will be analyzed descriptively 
only: 
• The number and proportion of patients who are free of clinical spasms, as 
observed on video-EEG at the end of the treatment period. 
• The number and proportion of patients who have resolution of hypsarrhythmia 
as, observed on video-EEG at the end of the treatment period. 
• Changes in spasms and seizure subtypes by caregiver observation during the 
treatment period.  
• Time to cessation of spasms during the treatment period, as determined by 
caregiver diaries. 
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• The number and proportion of patients who are free of spasms and have 
resolution of hypsarrhythmia, as determined by video-EEG after 3, 6, 9 and 
12 months of treatment.  
• The number and proportion of responders with relapse of spasms, and the time 
to relapse, as determined by caregiver diaries. 
• Changes from baseline in length (height), body weight, and head 
circumference. 
• CGIC. 
• PGIC.  
• Change from baseline in Vineland-II score. 
Safety data is detailed in Section 13.6.5 below. 
Measurement, where possible, of plasma concentrations of CBD and its major 
metabolites (7-OH-CBD, 6-OH-CBD, and 7-COOH-CBD) will be investigated using 
a sparse sampling approach, with the aim to define a POPPK model. 
13.6.4 
Pharmacokinetics 
Where possible, POPPK analyses for CBD and its metabolites (6-OH-CBD, 
7-OH-CBD, and 7-COOH-CBD) will be conducted using results from analysis of 
sparse samples collected during the pivotal phase of the trial. 
13.6.5 
Safety 
13.6.5.1 
Treatment Compliance and Extent of Treatment Exposure 
Treatment compliance and exposure to treatment will be summarized for each phase 
of the trial separately. 
13.6.5.2 
Adverse Events 
AEs will be coded according to the Medical Dictionary for Regulatory Activities 
dictionary. 
A TEAE is one that started, or worsened in severity or seriousness, following the first 
dose of IMP. 
Descriptive presentations of TEAEs will be given by preferred term and system organ 
class for the safety analysis set for each phase of the trial separately.  The number of 
patients reporting at least 1 TEAE will be provided. 
The following summaries will be produced: 
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• All-causality TEAEs. 
• Treatment-related TEAEs. 
• All-causality TEAEs by severity. 
• All-causality TEAEs by sex. 
• All-causality serious TEAEs. 
• Treatment-related serious TEAEs. 
• TEAEs reported as leading to permanent cessation of study treatment. 
• Treatment-related TEAEs reported as leading to permanent cessation of study 
treatment. 
• Fatal TEAEs. 
13.6.5.3 
Clinical Laboratory Data 
For each phase of the trial, clinical laboratory data at screening, during and at the end 
of treatment, and the change from baseline to end of treatment will be summarized for 
the safety analysis set using appropriate summary statistics.  Categorical shift tables 
will also be presented, showing the numbers of patients with values outside the 
normal range. 
13.6.5.4 
Vital Signs, 12-Lead Electrocardiogram, Physical 
Examination, and Other Safety Data 
For each phase of the trial, vital signs, ECG, and physical examination data will be 
summarized at screening, baseline, and at each time point during the treatment period 
using appropriate summary statistics.  Changes in the vital signs from baseline to end 
of treatment will also be summarized. 
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14 
DATA SAFETY MONITORING COMMITTEE 
An independent DSMC will be used in this trial. 
The DSMC will comprise a minimum of 4 members and will include an independent 
pediatric epileptologist and an independent pediatrician. 
The DSMC will review safety data from the initial 2-week treatment phase of patients 
in the pilot phase, (once patients in cohort 1 and cohort 2 have completed Day 15).  
Following these reviews the DSMC will recommend whether it is safe to continue, 
modify, or stop the trial.  
The DSMC will also review blinded safety data from the initial 2-week treatment 
phase of patients in the pivotal phase and will recommend whether to continue, 
modify, or stop the trial. 
Ad hoc meetings may also take place based on new and/or unexpected safety signals, 
to enable DSMC members to discuss and provide recommendations.  
Details of the composition and standard operating procedures of the DSMC will be 
detailed in a separate charter. 
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15 
REGULATORY AND ETHICAL OBLIGATIONS 
15.1 
Declaration of Helsinki 
The investigator will ensure that this trial is conducted in full conformity with the 
current version and subsequent amendments of the Declaration of Helsinki56, the ICH 
Tripartite Guideline for GCP Topic E6(R1)57, the EU Clinical Trials Directive61, the 
EU GCP Directive62 and the clinical trial regulations adopting European Commission 
Directives into national legislation64,65,66,67,68. 
15.2 
Informed Consent 
An initial generic ICF will be prepared by GW and provided to the investigator, who 
will tailor this for their site by adding the site’s contact details and by using headed 
paper.  The GW clinical manager will communicate updates to the template by letter.  
The written informed consent document should be prepared in the language(s) of the 
potential patient population. 
Before a patient’s involvement in the trial, the investigator is responsible for obtaining 
written informed consent from the patient’s parent(s)/legal representative after 
adequate explanation of the aims, methods, anticipated benefits and potential hazards 
of the trial and before any trial-specific procedures are performed or any 
patient-related data are recorded for the trial.  All approved IS therapies must be 
discussed with the patient’s parent(s)/legal representative.  It will be clearly explained 
to the patient’s parent(s)/legal representative that initiation with the next recognized 
IS therapy may be delayed by participating in this trial.  The patient’s parent(s)/legal 
representative must have ample time to consider the information provided before 
giving written consent.  More specific definitions of ‘ample time’ may be in force if 
required by IRBs/IECs or local regulations. 
The acquisition of informed consent must be documented in the patient’s medical 
records and the ICF must be signed and personally dated by the patient’s 
parent(s)/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 form.  The original signed ICF should be retained and a copy 
provided to the patient’s parent(s)/legal representative. 
15.3 
Institutional Review Board/Independent Ethics Committee 
A copy of the protocol, proposed ICF, master ICF, other parent(s)/legal representative 
information material, any proposed advertising material, and any further 
documentation requested must be submitted to the IRB/IEC for written approval.  GW 
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must receive a copy of the written approval of the appropriate version of the protocol 
and ICF before recruitment of patients into the trial and shipment of IMP. 
The investigator must submit and, where necessary, obtain approval from the 
IRB/IEC for all subsequent protocol amendments and changes to the informed 
consent document.  The investigator must notify the IRB/IEC of deviations from the 
protocol, SAEs occurring at the site and other AE reports received from GW, in 
accordance with local procedures. 
The investigator will be responsible for obtaining ongoing IRB/IEC approval/renewal 
throughout the duration of the trial.  Copies of the investigator’s reports and the 
IRB/IEC continuance of approval must be sent to GW. 
15.4 
Pre-trial Documentation Requirements 
The investigator is responsible for forwarding the following documents to GW for 
review before allowing any parent(s)/legal representative of patients to consent for 
entry into the trial: 
• Signed and dated protocol signature page. 
• Copy of IRB/IEC-approved ICF (including version number and date) and 
other patient information material. 
• Copy of the IRB/IEC approval of the protocol, ICF (including version number 
and date) 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/IEC composition and/or written statement of the IRB/IEC in 
compliance with the FDA regulations relating to GCP and clinical 
trials58,59,60,69, the EU Clinical Trials Directive61, the EU GCP Directive62, or 
the ICH Tripartite Guidelines for GCP Topic E6(R1)57 where the EU Clinical 
Trials and GCP Directives do not apply. 
• Signed and dated laboratory normal ranges and documentation of laboratory 
certification (or equivalent) unless using central laboratory arranged by GW. 
• Signed and dated clinical trial agreement (including patient/investigator 
indemnity insurance and financial agreement). 
• Form FDA 1572, if required. 
• Drug Enforcement Administration license, if required. 
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• Completed financial disclosure statements for the PI and all sub-investigators, 
if relevant. 
GW will ensure that the site is informed of when screening of patients can commence. 
15.5 
Patient Confidentiality 
The investigator must ensure that the patient’s anonymity is maintained.  In the CRFs 
or other documents submitted to GW, patients should be identified by their initials 
and race (if allowed per local regulations) and their trial patient number only.  
Documents that are not for submission to GW, e.g., signed ICFs, should be kept in 
strict confidence by the investigator.  Video recordings will be taken of patients as 
part of the video-EEG assessments; the information will be kept confidential and 
secure, and will be used only for the purpose for which it was collected (informed 
consent will be taken in relation to this). 
In compliance with the FDA regulations relating to GCP and clinical trials58,59,60,69, 
and the EU Clinical Trials Directive61/ICH Tripartite Guidelines for GCP Topic 
E6(R1)57, it is required that the investigator and institution permit authorized 
representatives of the company, the regulatory authorities and the IRB/IEC have 
direct access to review the patient’s original medical records for verification of 
trial-related procedures and data.  Direct access includes examining, analyzing, 
verifying and reproducing any records and reports that are important to the evaluation 
of the trial.  The investigator is obligated to inform the patient that his/her trial-related 
records will be reviewed by the above named representatives without violating the 
confidentiality of the patient. 
All information concerning the IMP and operations of GW such as patent 
applications, formulae, manufacturing processes, basic scientific data or formulation 
information supplied to the investigator by the company and not previously published 
is considered confidential by the company and shall remain the sole property of the 
company.  The investigator will agree to use this information only in accomplishing 
the trial and will not use it for any other purposes without the written consent of the 
company. 
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16 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
16.1 
Protocol Amendments and End of Trial or Termination 
Protocol amendments must be made only with the prior approval of GW.  Agreement 
from the investigator must be obtained for all protocol amendments and amendments 
to the informed consent document.  The IRB/IEC and regulatory authorities must be 
informed of all amendments and give approval for any substantial amendments.  
Amendments for administrational changes can be submitted to the IRB/IEC for 
information only.  The investigator must send a copy of the approval letter from the 
IRB/IEC to GW. 
Both GW and the investigator reserve the right to terminate the trial, according to the 
clinical trial agreement.  The investigator must notify the IRB/IEC in writing of the 
trial’s completion or early termination and send a copy of the notification to GW. 
16.2 
Trial Documentation and Storage 
The investigator must maintain a list of appropriately qualified persons to whom 
he/she has delegated trial duties.  All persons authorized to make entries in and/or 
corrections to CRFs will be included on the GW Delegation of Authority and 
Signature form. 
Source documents are original documents, data and records containing all 
protocol-specified information from which the patient’s CRF data are obtained.  
These include, but are not limited to, hospital records, clinical and office charts, 
laboratory and pharmacy records, diaries, microfiches, radiographs and 
correspondence.  A source data verification plan, identifying the source for each data 
point at each site, will be agreed with each site prior to patient recruitment.  In the rare 
situations of data being recorded directly into the CRF in error, then the source data 
from the CRF should be transcribed into the patient’s notes with appropriate signature 
and date to provide a full audit trail. 
The investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all trial-related, essential documentation (as outlined in 
the ICH Tripartite Guidelines for GCP Topic R6(R1)57, Section 8.2), 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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• Trial files containing the protocol with all amendments, IB, copies of pre-trial 
documentation (see Section 15.4) and all correspondence to and from the 
IRB/IEC and GW. 
• Enrollment log of all patients whose parent(s)/legal representative gave 
consent to take part in the trial. 
• Screening and recruitment log of all patients screened and whether or not they 
were recruited into the trial (i.e., randomized/assigned GWP42003-P and/or 
dosed with IMP). 
• Proof of receipt, IMP accountability record, return of IMP for destruction, 
final IMP reconciliation statement and all drug-related correspondence. 
In addition, all original source documents supporting entries in the CRFs and diary 
data must be maintained and be readily available. 
Following completion or termination of a clinical trial, GW will initiate proper 
archive of clinical trial-related documentation and electronic records generated by the 
investigator and/or GW.  All clinical trial-related documents and electronic records 
will be retained within an archiving system for a period dependent upon need and for 
a minimum of 25 years.  Essential documents must be retained until at least 2 years 
after the last approval of a marketing application in an ICH region and until there are 
no pending or contemplated marketing applications in an ICH region, or until at least 
2 years have elapsed since the formal discontinuation of clinical development of the 
IMP.  These documents must be retained for a longer period, however, if required by 
the applicable regulatory requirements62 or if needed by GW. 
GW will inform the investigators for each site in writing of the need for record 
retention.  No trial document may be destroyed without prior written agreement 
between GW and the investigator.  Should the investigator wish to assign the trial 
records to another party or move them to another location, he/she must notify GW in 
writing of the new responsible person and/or the new location. 
16.3 
Trial Monitoring and Data Collection 
The GW representative and regulatory authority inspectors are responsible for 
contacting and visiting the investigator for the purpose of inspecting the facilities and, 
upon request, inspecting the various records of the trial, e.g., CRFs and other pertinent 
data, provided that patient confidentiality is respected. 
The GW study monitor, or designee, is responsible for inspecting the CRFs and 
available diary data at regular intervals throughout the trial to verify adherence to the 
protocol, completeness, accuracy and consistency of the data and adherence to local 
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regulations on the conduct of clinical research.  The study monitor must have access 
to patient medical records and other trial-related records needed to verify the entries 
on the CRFs. 
The investigator agrees to cooperate with the study monitor to ensure that any 
problems detected in the course of these monitoring visits are resolved. 
To ensure the quality of clinical data across all patients and sites, 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 regulations58,59,60,69, ICH Tripartite 
Guidelines for GCP Topic E6(R1)57 and all other applicable regulatory requirements.  
To resolve any questions arising from the clinical data management review process, 
data queries and/or site notifications will be sent to the site for completion and then 
returned to GW or the CRO, as applicable. 
16.4 
Quality Assurance 
In accordance with the FDA regulations58,59,60,69, EU Clinical Trials Directive61/ICH 
Tripartite Guidelines for GCP Topic E6(R1)57 and the sponsor’s audit plans, 
representatives from GW’s Clinical Quality Assurance Department may select this 
trial for audit.  Inspection of site facilities, e.g., pharmacy, drug storage areas, 
laboratories, and review of trial-related records will occur to evaluate the trial conduct 
and compliance with the protocol, the EU Clinical Trials Directive61/ICH Tripartite 
Guidelines for GCP Topic E6(R1)57 and applicable regulatory requirements. 
16.5 
Compensation 
GW will indemnify the investigator and the trial site in the event of any claim in 
respect of personal injury arising due to a patient’s involvement in the trial, providing 
that the trial protocol has been adhered to.  This would include claims arising out of or 
relating to the administration of the IMP or any clinical intervention or procedure 
provided for or required by the protocol to which the clinical trial patient would not 
otherwise have been exposed, providing there is no evidence of negligence on behalf 
of the investigator or their team.  GW will not be liable for any claims arising from 
negligence on the part of the investigator or their team. 
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16.6 
Publication Policy 
GW recognizes that there is a responsibility under the regulatory guidelines to ensure 
that results of scientific interest arising from this clinical trial are appropriately 
published and disseminated.  They will coordinate this dissemination and may solicit 
input and assistance from the chief/principal investigators.  A summary of the results 
of this trial will be made available on http://www.clinicaltrials.gov and 
http://www.clinicaltrialsregister.eu/ (as applicable), as required by US and EU Law. 
The raw data from this trial may be obtained by the PIs or by their steering committee 
representatives on request.  Should they wish, PIs are allowed to conduct their own 
analyses and are permitted to present such information along with methods and results 
of the clinical trial at symposia, national or regional professional meetings and to 
publish it in theses or dissertations.  If video-EEG data are presented, the identity of 
the patient must be obscured. 
All publications, e.g., manuscripts, abstracts, oral/slide presentations or book chapters 
based on this trial, must be submitted to the GW Medical Writing Department and, as 
applicable, GW Publication Committee for corporate review before release.  To 
ensure adequate time for GW to make comments and suggestions where pertinent, all 
such material should be submitted to them at least 60 days prior to the date for 
submission for publication, public dissemination, or review by a publication 
committee.  The PIs must then incorporate all reasonable comments made by GW into 
the publication. 
GW also reserves the right to delay the submission of such information by a period of 
up to 6 months from the date of first submission to them in order to allow them to take 
steps to protect proprietary information where applicable. 
16.7 
Intellectual Property Rights 
All intellectual property rights owned by or licensed to either GW or the PIs, other 
than those arising from the clinical trial, will remain their property.  All intellectual 
property rights arising out of the clinical trial will vest in or be exclusively licensed to 
GW and, as such, the PI must promptly disclose all knowledge to GW and refrain 
from using such knowledge without the prior written consent of GW. 
16.8 
Confidential Information 
GW and the PI must ensure that only personnel directly concerned with the trial are 
party to confidential information and that any information coming to either party 
about the other during the course of the trial must be kept strictly confidential and 
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must not be disclosed to any third party or made use of without the prior written 
consent of the other. 
 
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17 
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Study Code: GWEP15100 
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 APPENDIX 1 
SCHEDULE OF ASSESSMENTS 
 
Pilot or Pivotal phase 
Open-Label Extension Phase 
 
 
Visit Number 
Day 
(Visit Window) 
 Visit 1  
Day −7 
to −1 
 Visit 21 
Day 1 
(+3 days) 
 Visit 3  
Day 4 
(+1 day) 
 Visit 42 
Day 15 
(+3 days) 
 Visit 5  
Day 19 
(+1 day) 
 Visit 6  
Day 29 
(±3 days) 
 Visit 7  
Day 43 
(±3 days) 
 Visit 8  
Day 71 
(±3 days) 
 Visit 9  
Day 127 
(±7 days) 
 Visit 10  
Day 211 
(±7 days) 
 Visit 11  
Day 295 
(±7 days) 
 Visit 12  
Day 379 
(±7 days) 
End of 
Taper 
Period 
Visit3 
(+3 days) 
Safety 
Follow-
up 
Visit4 
(+3 days) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient number 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
 X5 
 
 
 
 
 
 
 
 
 
 
 
 
Start of IMP 
dosing 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inpatient stay 
(pilot phase only) 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medication review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical 
examination 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECG 
X 
 X6 
 X7 
 X7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Video-EEG 
(8–24 hours) 
X 
 
 
X 
 
X 
X 
 
X 
X 
X 
X 
 
 
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Study Code: GWEP15100 
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Protocol V3 20Sep16  
 
 
Pilot or Pivotal phase 
Open-Label Extension Phase 
 
 
Visit Number 
Day 
(Visit Window) 
 Visit 1  
Day −7 
to −1 
 Visit 21 
Day 1 
(+3 days) 
 Visit 3  
Day 4 
(+1 day) 
 Visit 42 
Day 15 
(+3 days) 
 Visit 5  
Day 19 
(+1 day) 
 Visit 6  
Day 29 
(±3 days) 
 Visit 7  
Day 43 
(±3 days) 
 Visit 8  
Day 71 
(±3 days) 
 Visit 9  
Day 127 
(±7 days) 
 Visit 10  
Day 211 
(±7 days) 
 Visit 11  
Day 295 
(±7 days) 
 Visit 12  
Day 379 
(±7 days) 
End of 
Taper 
Period 
Visit3 
(+3 days) 
Safety 
Follow-
up 
Visit4 
(+3 days) 
Clinical laboratory 
sampling 
(blood/urine) 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK blood 
sampling8 
 
X 
 
X 
X 
 
 
 
 
 
 
 
 
 
Caregiver paper 
diary 
issue/training 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
CGIC 
 
 X9 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
PGIC 
 
 X9 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Vineland-II 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
 
IMP dispensing10 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
IMP compliance 
review 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Caregiver diary 
review 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Spasm/seizure 
information 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IMP usage11 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
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Study Code: GWEP15100 
EudraCT Number: 2015-004904-50 
Protocol V3 20Sep16  
 
 
Pilot or Pivotal phase 
Open-Label Extension Phase 
 
 
Visit Number 
Day 
(Visit Window) 
 Visit 1  
Day −7 
to −1 
 Visit 21 
Day 1 
(+3 days) 
 Visit 3  
Day 4 
(+1 day) 
 Visit 42 
Day 15 
(+3 days) 
 Visit 5  
Day 19 
(+1 day) 
 Visit 6  
Day 29 
(±3 days) 
 Visit 7  
Day 43 
(±3 days) 
 Visit 8  
Day 71 
(±3 days) 
 Visit 9  
Day 127 
(±7 days) 
 Visit 10  
Day 211 
(±7 days) 
 Visit 11  
Day 295 
(±7 days) 
 Visit 12  
Day 379 
(±7 days) 
End of 
Taper 
Period 
Visit3 
(+3 days) 
Safety 
Follow-
up 
Visit4 
(+3 days) 
Changes in 
concomitant 
AEDs 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Usage of rescue 
medication 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AEs 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1All patients in the pilot phase will titrate GWP42003-P in an inpatient setting.  In both phases (pilot and pivotal), daily safety checks will be made during the first week of 
IMP dosing (can be conducted by telephone).  Each safety check will conduct the same assessments as listed for safety follow-up visit. 
2Daily safety checks will be made during the first week of OLE IMP dosing (can be conducted by telephone).  Each safety check will conduct the same assessments as 
listed for safety follow-up visit. 
3IMP is to be tapered over 10 days following discontinuation of IMP, end of treatment, or withdrawal (unless continued dosing is not possible due to an AE). 
4Safety follow-up visit is to occur 28 (+3) days after date of final dose (including tapered dose); weekly (±3 days) telephone calls must be made during the follow-up 
period.  Each safety telephone call will conduct the same assessments as listed for safety follow-up visit. 
5Based on assessment of clinical laboratory and video-EEG results. 
6ECG to be performed between 3 and 5 hours after the day’s first dose of IMP only. 
7ECG to be performed both prior to the day’s first dose of IMP and between 3 and 5 hours after this dose. 
8Only for patients involved in the pivotal phase, and progressing to the OLE from the pivotal phase. To be conducted only if the risk/benefit outcome is favorable, in the 
investigator’s opinion. 
9Memory aid only (worksheet completed). 
10If necessary, IMP will also be dispensed for taper period. 
11IMP usage to be recorded on a dosing schedule which will form part of the paper diary 
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Study Code: GWEP15100 
EudraCT Number: 2015-004904-50 
Protocol V3 20Sep16  
 
 APPENDIX 2 
TRIAL PERSONNEL 
Appendix 2.1 
Investigator Details 
At the time of protocol production, the participating investigators had not been 
confirmed.  A list of all investigators will be maintained within the GW master files 
(electronically and added to the trial master file at the end of the trial). 
Appendix 2.2 
Sponsor Contact Details 
Pharmacovigilance Department — SAE Reporting: 
Fax:
 
US Toll-free Fax: 
 
Tel: 
 
Sponsor: 
GW Research Ltd 
Sovereign House 
Vision Park 
Chivers Way 
Histon 
Cambridge CB24 9BZ 
United Kingdom 
Tel: +44 (0) 1223 266 800 
Fax: +44 (0) 1223 235 667 
Medical Advisor & Clinical Project Manager: 
Please refer to the Sponsor and 
Related Contact Details form in 
the trial site file. 
Clinical Trial Supplies: 
G-Pharm Ltd 
Tel: 
 
Fax: 
 
 
Appendix 2.3 
Contract Research Organizations 
Details of the contract research organizations, clinical and bioanalytical laboratories, 
and central EEG reader for the trial are provided below.  A corresponding list will be 
maintained within the GW master files (electronically and added to the trial master 
file at the end of the trial). 
Video-EEG vendor 
Lifelines Neurodiagnostic Systems Inc. 
411 Edwardsville Road 
Troy, IL 62294 
US 
Central Video-EEG reader  
 
Chief of the Division of Pediatric Neurology  
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 of the Neurosciences Institute 
Children’s Hospital Los Angeles 
4650 Sunset Boulevard 
Los Angeles, CA 90027 
US 
Contract Data Management 
Cytel Inc 
ICC, Bat, C, 2nd Floor 
Route de Pré Bois  
20 C.P. 1839 
1215 Geneva 15 
Switzerland 
Central Laboratory(Central AED & 
CBD PK) 
Managed from:  
Covance Clinical Laboratory Services  
7 Rue Moïse-Marcinhes  
1217 Geneva 
Switzerland 
 
Sample analysis will be carried out at: 
Covance Laboratories Ltd 
Otley Road 
Harrogate  
North Yorkshire  
HG3 1PY 
UK 
Contract IVRS Provider 
PAREXEL Informatics  
Castle Wharf  
4 Canal Street 
Nottingham 
NG1 7EH 
UK 
 
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Study Code: GWEP15100 
EudraCT Number: 2015-004904-50 
Protocol V3 20Sep16  
 
 APPENDIX 3 
QUESTIONNAIRES 
Appendix 3.1 
Caregiver Global Impression of Change 
An example of the CGIC questionnaire, to be completed by the caregiver, is given 
below. 
 
Appendix 3.2 
Physician Global Impression of Change 
An example of the PGIC questionnaire, to be completed by the investigator, is given 
below. 
 
 
 
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Appendix 3.3 
Vineland Adaptive Behavior Scales, Second Edition 
A sample of the Vineland-II questionnaire is given below: 
 
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Study Code: GWEP15100 
EudraCT Number: 2015-004904-50 
Protocol Amendment 2, V2 18Oct16 
 
 
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2 
RATIONALE 
This clinical protocol amendment 2 (will be incorporated into the protocol creating 
Clinical Protocol Version 3, Date 20 September 2016) addresses the following 
issue(s):Compliance with U.S. Regulatory Requirements 
In order to comply with requests received from the United States Food and Drug 
Administration (FDA), the protocol has been amended as follows: 
2.1.1 
Extend Age Range in the Pilot Phase; Second Cohort 
As the pivotal trial involves patients from 1 month to 24 months, the age range in 
cohort 2 of the pilot phase will be extended from 6 months to 24 months to 1 month to 
24 months.  The inclusion criterion has been updated. 
2.1.2 
Clarification of Allowable Changes in Concomitant 
Medications 
The FDA suggested that allowing increased doses of patients’ infantile spasm (IS) 
therapy may make the treatment effects of GWP42003-P difficult to interpret.  The 
following clarifications have therefore been made: 
 During the pilot and pivotal phase, every effort should be made to keep the 
patient’s current IS therapy stable; current therapy may be tapered, in response 
to AEs, at the discretion of the investigator. 
 Increases in the dose of existing concomitant AEDs or commencement of new 
AEDs are not allowed during the pilot or pivotal phases. 
 During the OLE, in response to AEs or if there are symptoms of toxicity due 
to a suspected drug-drug interaction, the investigator may adjust the dose of 
GWP42003-P or other concomitant AEDs following discussion with the GW 
medical monitor. 
 In Section 8.3, text has been added to prohibit any increases to existing AEDs 
or commencement of new AEDs during the pilot or pivotal phase. 


Study Code: GWEP15100 
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Protocol Amendment 2, V2 18Oct16 
 
 
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2.1.3 
Utilization of Central Video Electroencephalography Readings  
The FDA queried how the central video-electroencephalography (EEG) reader would 
be used in practice.  They stated that, for enrollment, the study should use a single 
expert central reader to adjudicate the presence of hypsarrhythmia and wanted to 
understand the process for disagreements between local and central EEG readings. In 
response to this, the following clarifications have been made within the protocol: 
 Provided details of the Central Reader in Appendix 2.3. 
 Stated that the retrospective assessment of the video-EEGs by the central 
reader will be considered final. 
2.1.4 
Statistical Considerations 
To clarify how dropouts/missing data will be handled in the analyses, Section 13.6.2.2 
has been updated: 
 Details of sensitivity analyses due to missing data and handling of patients 
potentially receiving rescue medication will be fully detailed in the statistical 
analysis plan prior to unblinding. 
2.1.5 
Data Safety Monitoring Committee 
The protocol has been updated to include: 
 Statement that ad hoc meetings of the Data Safety Monitoring Committee will 
take place based on new or unexpected safety signals. 
2.2 
Inclusion/Exclusion Criteria 
 Clarification that approved IS therapies include therapies that have been 
approved in the United States or Europe. 
 Clarification that if a patient has a QT interval, corrected for heart rate with 
Bazett’s formula (QTcB) of > 460 msec on ECG, the investigator should 
repeat the ECG 3 times and contact the GW medical monitor, prior to screen 
failure or entry into the pilot/pivotal phase. 


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Protocol Amendment 2, V2 18Oct16 
 
 
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 The previous use of the terms “enrolled/randomized” for patients entering the 
pilot/pivotal phases conflicted with the definition of an enrolled patient in the 
clinical protocol (which is that any patient whose parent(s)/legal representative 
has provided written informed consent to take part in the trial).  Therefore, the 
protocol wording has been updated as follows to avoid any misunderstanding : 
 Any patient who has previously been included in the pilot or pivotal 
phase of this trial will be excluded. 
 Confirmation of elevations in transaminase levels will be required prior 
to screen failure or entry into the pilot or pivotal phase. 
2.3 
Withdrawal Criteria 
Following questions from investigators regarding the QTcB withdrawal criterion, the 
following clarification has been included: 
 If a patient has a QTcB of 500 msec or greater on ECG, or a shift from 
baseline of 60 msec or greater, the ECG should be repeated 3 times.  If the 
QTcB criteria are confirmed then the patient should be withdrawn from the 
trial. 
 Clarification that any requirement to increase the dose of concomitant AED(s) 
or add in new AED(s) may result in the patient being withdrawn from the trial. 
2.4 
Procedures 
The following changes have been made: 
 During a UK site visit, the site asked whether laboratory results prior to 
screening could be taken into account to reduce the amount of blood that 
needs to be taken.  In line with this, the protocol now states that to minimize 
the volume of blood required, serum biochemistry and hematology results 
from samples analyzed up to 3 days prior to Visit 1 may be used.  The samples 
must be analyzed at the same local laboratory that is being used for the clinical 
laboratory aspects of the trial. 
 To allow limited rescreening of patients, a statement has been included such 
that, in exceptional circumstances, rescreening may be allowed following 
discussions with the GW medical monitor. 


Study Code: GWEP15100 
EudraCT Number: 2015-004904-50 
Protocol Amendment 2, V2 18Oct16 
 
 
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2.5 
Changes to Information Recorded in the Paper Diary 
The following changes have been made to reduce unnecessary caregiver burden: 
 Epilepsy interventions will not be recorded in the paper diary, only 
concomitant AEDs and rescue medications.   
 Only the drug name and dose level of each rescue medication administration 
will be required, not the number of times administered each day. 
2.6 
Minor Corrections and Clarifications 
The following minor corrections/clarifications have been made to the protocol: 
 Addition of transaminases into the abbreviations list for ALT and AST since 
GW approved global abbreviations list now allows both aminotransferase and 
transaminase in reference to these enzymes. 
 Addition of statistical analysis plan into the abbreviations list. 
 Updated information has been provided on completed GW studies, Expanded 
Access Program and Compassionate Use programs. 
 Complete edit/reordering of the information presented within sections 13.6.2.2 
through to 13.6.3.3 to ensure the relevant text correctly applies to each section. 
 Alignment of wording between trial objectives, trial endpoints and statistical 
endpoints. 
 The list of contract research organizations, clinical and bioanalytical 
laboratories and central EEG reader has been updated with current details. 
 Clarification of the days where safety checks should be made during IMP 
dosing in pilot, pivotal and open-label extension phases. 
 Reference list has been updated to include new reference (GWEP1544 CSR) 
and updated citations for CBD Investigator Brochure (Edition 9) and US FDA 
CFR Title 21. 
 A copy of the Vineland-II questionnaire has been included for reference. 
 Minor spelling/grammatical corrections have been made to improve 
consistency but these are not captured within this amendment document. 
 
 
 


Study Code: GWEP15100 
EudraCT Number: 2015-004904-50 
Protocol Amendment 1 V1 31May16 
 
 
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2 
RATIONALE 
This clinical protocol amendment 1 (will be incorporated into the protocol 
creating Clinical Protocol Version 2, Date 31 May 2016) addresses the following 
issue(s):Compliance with U.S. Regulatory Requirements 
In response to comments received from the United States Food and Drug 
Administration (FDA), the protocol has been amended as follows: 
2.1.1 
Revised Clinical Phase and Overall Design 
The trial phase has been revised from phase 2 to phase 3, and the design has been 
updated to reflect this.  The trial will now comprise an initial open-label safety 
study comprising 2 cohorts of 5 patients (pilot phase), followed by a phase 3 
efficacy study (pivotal phase).  The 1 year open-label extension (OLE) will be 
open to patients who complete either phase.   
Due to this change, the trial title, objectives, endpoints and patient numbers have 
been adjusted accordingly. 
2.1.2 
Use of a Data Safety Monitoring Committee 
As the trial involves a vulnerable pediatric population, an independent data safety 
monitoring committee (DSMC) will be used.  The DSMC will be used 
throughout the study and will consider safety of the patients, and confirm doses 
and dose regimens to be investigated in the pivotal phase.  If required, following 
DSMC review, adjustment of doses and dose regimens will also take place 
following the first cohort of 5 patients in the pilot phase. 
2.1.3 
Addition of a Pilot Phase to Confirm Safety 
Due to the lack of safety data in infants under 2 years of age, safety will be 
confirmed in a small group of patients in a hospital environment (pilot phase) 
before proceeding to the pivotal investigations.  Therefore, the trial will be 
performed as 2 separate phases (pilot and pivotal) which will be run sequentially.  
All patients in the pilot phase will receive GWP42003-P (open-label) while all 
patients in the pivotal phase will be randomly allocated to GWP42003-P (1 of 2 
dose levels) or matching placebo in a double-blind manner.  As infants younger 
than 6 months are particularly vulnerable, all patients in the pilot phase will be 
over 6 months of age.  The pivotal phase will only be enrolled after the DSMC 


Study Code: GWEP15100 
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has reviewed data from the pilot phase and has confirmed that there are no safety 
issues.   
Due to the rapid titration of the investigational medicinal product (IMP), all 
patients in the pilot phase will remain in the clinic as inpatients during the 4-day 
titration period.  In both phases, compulsory clinic-based assessments will take 
place at the end of the titration period (i.e., Day 4) and OLE transition period 
(i.e., Day 19).  In addition, daily safety checks will be made during the first week 
of IMP dosing during the pilot and pivotal phases (i.e., Days 1–7) and during the 
first week of OLE IMP dosing (i.e., Days 16–22). 
2.1.4 
Discussion of Approved Treatments for Infantile Spasms 
Prior to Enrollment 
Due to the ethical issues regarding the enrollment of patients who have not failed 
all approved infantile spasms (IS) treatments, all approved therapies and 
treatment options must be discussed with the caregiver before the patient is 
considered for the trial. 
2.1.5 
Evaluation of Clinical Response and Continued Benefit 
As it is unclear what length of treatment is optimal for IS, patients will be 
evaluated for clinical response by video-electroencephalogram (video-EEG) after 
1 month of treatment and approximately every 3 months thereafter during the 
OLE phase.  In addition, as only patients who show evidence of benefit should 
continue to be treated with GWP42003-P during the OLE phase, any patients 
who do not will be withdrawn from the trial.  Patients who have not 
demonstrated complete resolution of IS, but have shown some benefit of 
treatment, may remain in the trial, but may receive other concomitant 
medications during the OLE phase.  The option of withdrawing from the trial 
will be discussed with caregivers at each visit. 
2.1.6 
Clarification of Video-EEG Evaluation 
The protocol has been updated to clarify that it is important for at least one full 
sleep-wake cycle to be observed in each video-EEG assessment.  In addition, any 
video-EEG findings considered to represent an adverse event must be 
documented on the case report form. 


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2.1.7 
Monitoring Plasma Levels of Concomitant Antiepileptic 
Drugs 
Since potential drug-drug interactions are still being evaluated for GWP42003-P, 
concomitant antiepileptic drug (AED) levels will be checked with clinical 
laboratory evaluation, as clinically indicated by symptoms of toxicity.  In 
addition, as the risk of hepatotoxicity with valproate may be high in the proposed 
patient population, the protocol provides guidance for investigators to pay 
particular attention to liver enzyme levels in patients who are taking valproate. 
2.1.8 
Clarification of Cannabidiol Metabolites 
The protocol has been updated to clarify that the following metabolites of CBD 
will be assessed: 
• 6-hydroxy-cannabidiol (6-OH-CBD). 
• 7-hydroxy-cannabidiol (7-OH-CBD). 
• 7-carboxy-cannabidiol (7-COOH-CBD). 
2.2 
Duration of Open-label Extension Phase 
The OLE phase of the trial will last for a maximum of 1 year in all cases, as 
GWP42003-P will continue to be supplied irrespective of marketing 
authorization. 
2.3 
Clarification of Procedures Following the Investigator’s 
Decision to Discontinue GWP42003-P During the Open-
label Extension Phase 
The protocol has been updated to clarify that the investigator may consider 
discontinuing IMP during the OLE phase if the patient has become spasm-free 
and that the patient’s parent(s)/legal representative will be encouraged to allow 
the patient to remain in the trial to complete the remaining assessments (up to 
1 year).  Instructions are provided regarding the discontinuation process as well 
as on restarting GWP42003-P in cases of relapse. 
2.4 
Revised Eligibility Criteria 
The eligibility criterion excluding patients who have received an IMP within the 
3 months prior to the screening visit has been revised to clarify that IMP relates 
to any product received as part of a clinical trial (as opposed to the off-label use 


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of a licensed drug).  In addition, due to the urgency of establishing effective 
treatment in this patient population, the minimum time required before these 
patients may be considered eligible for this trial has been changed to 5 half-lives 
prior to the screening visit.  Similarly, the minimum time required before patients 
who have used cannabis/cannabinoids has been reduced to 1 month prior to the 
screening visit. 
2.5 
Clarification of Withdrawal Criterion 
Due to the potential impact on the intention to treat population, the criterion 
regarding withdrawal of patients who do not continue to meet the eligibility 
criteria has been revised to clarify that patients must be withdrawn only if there 
are safety concerns; patients may be withdrawn if the concerns are non-safety 
related. 
2.6 
Revised Pharmacokinetic Blood Sampling Times 
Since safety blood samples will be taken on Day 4 and Day 19, the proposed 
pharmacokinetic (PK) blood sampling times have been revised to ensure that the 
maximum amount of blood taken will not exceed a total of 50 mL within the 
initial 8-week period of the trial.  Additionally, PK sampling will only take place 
during the pivotal phase. 
2.7 
Removal of Caregiver Impression of IMP Palatability 
Questionnaire 
The Caregiver Impression of IMP Palatability questionnaire has been removed 
from the trial, as minimal feedback is expected in this patient population as it will 
be difficult to determine due to the age of the patients.  
2.8 
Removal of THC Testing 
Δ9-tetrahydrocannabinol (THC) testing has been removed from the trial, to 
reduce the burden on the patient and caregiver.  Furthermore, rapid decision 
making and treatment is needed for this patient population, and this testing would 
add additional complexity while being of minimal benefit in this patient 
population. 


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2.9 
Citation of Recently Disseminated Data 
The protocol has been updated to include citations of GWP42003-P safety and 
efficacy data presented at the American Epilepsy Society 69th Annual 
Meeting1,2. 
2.10 
Patient Confidentiality 
The protocol has been updated to clarify that all video-EEG recordings will be 
kept confidential and secure, and that the patient’s anonymity must be 
maintained if data are presented. 
2.11 
Minor Corrections and Clarifications 
The following minor corrections/clarifications have been made to the protocol: 
• Only patients who complete the pilot or pivotal phase will have the 
opportunity to continue to the OLE phase; those who withdraw early are 
ineligible. 
• Since absorption of topical mammalian target of rapamycin (mTOR) 
inhibitors is lower than oral formulations, only oral mTOR inhibitors may 
not be used. 
• The eligibility criterion regarding breastfeeding has been combined with 
the criterion regarding abstention.  
• The physical description of the IMP has been updated to “clear, colorless 
to yellow solution”. 
• The information to be recorded in the paper diary has been added to the 
synopsis for clarity. 
• The full 4-week safety follow-up period concludes with the safety 
follow-up visit. 
• Caregivers will record IMP intake in the paper diary but will not be 
required to record the volume of IMP administered on each treatment 
day. 
• The assessments listed as bullet points in Section 9.1.1.2 (Visit 2 [Day 1]) 
must be conducted prior to receiving the first dose of IMP. 


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• The timings of any PK blood draws must be recorded, as well as IMP 
dosing time and the timing of concomitant AEDs and feeds/meals around 
the time of PK sampling. 
• Vital signs and clinical laboratory samples must be assessed/collected on 
Day 4. 
• In the OLE phase, all visit days and visit windows are in relation to 
Visit 2. 
• Medical history includes prior and current seizures/spasms. 
• The laboratory manual should be referred to for analysis of clinical 
laboratory samples. 
• Since local laboratories will be used, all laboratory results must be 
documented on the case report form. 
• The dose and number of times rescue medication is given each day will 
be recorded in the paper diary. 
• The patient’s parent(s)/legal representative would voluntarily withdraw 
the patient (rather than the patient withdrawing themself, due to their 
age). 
• All statistical analyses will be conducted at the 5% level of significance. 
• The end of the evaluable period for the OLE phase is defined as the last 
day on which a study-related assessment was undertaken during the OLE 
phase as opposed to the last day on which the study IMP was taken. 
• Participation in the trial would not delay initiation with the next 
recognized IS therapy if the patient had failed all recognized IS therapies 
at enrollment. 
• IMP will not be dispensed at the end of OLE treatment/withdrawal visit 
unless required for the taper period. 
• Investigator Global Impression of Change (IGIC) is updated to Physician 
Global Impression of Change (PGIC) for consistency with other GW 
trials. 
• Only a patient number will be used (screening numbers will not be 
utilized). 


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• Definition of status epilepticus has been added. Additionally, convulsive 
and non-convulsive status epilepticus events are considered to be 
medically significant and should be reported to the sponsor as medically 
significant serious adverse events. 
• The caregiver should return the completed caregiver diary following the 
safety follow-up visit. 
• Guidance regarding transaminase levels, laboratory testing and 
withdrawals. 
• Preliminary data from the recently completed GW trial GWEP1332 
(Dravet) added.  
• Daily safety checks (Day 2 to 7 [inclusive] and Day 16 to 22 [inclusive]) 
to be made daily (including weekends, if possible), and where applicable 
they will be incorporated into scheduled visits (e.g., Day 4 and Day 19). 
• Provision for transaminase levels to be repeat tested prior to enrollment 
/randomization/withdrawal, in case of elevated levels as specified in the 
exclusion criterion and the withdrawal section. 
3 
IMPLEMENTATION OF THE AMENDMENT 
The changes detailed in this amendment will be issued as Clinical Protocol 
Version 2, Date 31 May 2016.  It will be kept in the trial master file (TMF) at 
GW as well as in each investigational site file and, if applicable, pharmacy site 
file. 
 
Section 4 (Presentation of Amended Text) is not included in this amendment 
document.  The justification is as follows; Version 1 of the GWEP15100 Clinical 
Protocol was used for an initial submission to the FDA.  Following feedback 
from the FDA significant changes have been made to protocol Version 1, 
including conversion of the trial from phase 2 to phase 3, increasing the trial’s 
complexity.  Due to the significant number of changes an agreement has been 
reached between GW Clinical Quality Assurance, Medical Writing and the 
Clinical Operations departments that the full details of all the amended text will 
not be documented here, but a summary of, and the rationale for, the changes will 
be outlined in Section 2 above.  For documentation purposes, a track changed 

SAP_001.pdf: 
Confidentiality 
This document is confidential and proprietary property of WinSanTor, Inc. and to be used only as authorized by 
GW Research Ltd.  No part is to be reproduced, disclosed to others, or quoted without prior written authorization 
from GW Research Ltd. 
STATISTICAL ANALYSIS PLAN 
GWEP15100 
 A Randomized, Double-blind, Placebo-controlled Trial to Investigate the 
Efficacy and Safety of Cannabidiol (CBD; GWP42003-P) in Infants with 
Infantile Spasms Following an Initial Open-label Pilot Study 
Study Code: 
(Protocol Version Date) 
GWEP15100  
September 20, 2016 
EudraCT Number: 
2015-004904-50 
Name of Test Drug: 
Cannabidiol (CBD; GWP42003-P) 
Phase: 
3 
Methodology: 
Open-label 
Sponsor: 
GW Research Ltd 
Sovereign House 
Vision Park 
Chivers Way 
Histon 
Cambridge CB24 9BZ 
United Kingdom 
Sponsor Representative: 
 
Head of Biometrics 
Document Date: 
25SEP2019 
Document Version: 
1.0 
NCT Number: NCT02953548
This NCT number has been applied to the document for
purposes of posting on clinicaltrials.gov


Protocol Title: 
Sponsor: 
Study Code: 
EudraCT Number: 
Document Date/Version: 
.... 
r: 
Principal Biostatistician 
Cytel, Inc. 
675 Massachusetts Avenue 
Cambridge, MA 02139 
SIGNATURE PAGE 
A Randomized, Double-blind, Placebo-controlled 
Trial to Investigate the Efficacy and Safety of 
Cannabidiol (CBD; GWP42003-P) in Infants with 
Infantile Spasms Following an Initial Open-label Pilot 
Study 
GW Research Ltd 
Sovereign House 
Vision Park 
Chivers Way 
Histon 
Cambridge CB24 9BZ 
United Kingdom 
GWEPl5100 
2015-004904-50 
25SEP2019/V1.0 
Sponsor Approval 
By signing this document, I acknowledge that I have read the document and approve of the 
planned statistical analyses described herein. I agree that the planned statistical analyses are 
appropriate for this study, are in accordance with the study objectives, and are consistent with 
the statistical methodology described in the protocol, clinical development plan, and all 
applicable regulatory guidances and guidelines. 
I have discussed any questions I have regarding the contents of this document with the 
biostatistical 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). 


I 
\ 'I ! 
'i l 
) 
I. l 
t 
f 
-: 
Head of Biometrics 
GW Research Ltd 
Sovereign House 
Vision Parle 
Chivers Way 
Histon 
Cambridge CB24 9BZ 
United Kingdom 
GW Researrh lid 
Study Code: GWEP15100 
EudraCT Number: 2015-004904-50 
25SEP2019 


GW Research Ltd 
Study Code: GWEP15100 
EudraCT Number: 2015-004904-50 
25SEP2019 
 
 
CONFIDENTIAL 
 4 
TABLE OF CONTENTS 
Section 
Page 
1. 
INTRODUCTION AND OBJECTIVES OF ANALYSIS .......................................... 7 
1.1. 
Introduction ...................................................................................................... 7 
1.2. 
Objectives of Statistical Analysis ..................................................................... 7 
1.2.1. 
Pilot Phase ........................................................................................... 7 
1.2.2. 
OLE Phase ........................................................................................... 7 
2. 
STUDY DESIGN ......................................................................................................... 9 
2.1. 
Synopsis of Study Design.................................................................................. 9 
2.2. 
Randomization Methodology ......................................................................... 10 
2.3. 
Stopping Rules and Unblinding ..................................................................... 10 
2.4. 
Study Procedures............................................................................................ 11 
2.5. 
Primary Endpoints ......................................................................................... 14 
2.5.1. 
Pilot Phase ......................................................................................... 14 
2.6. 
Secondary Endpoints...................................................................................... 14 
3. 
Subject Populations ................................................................................................... 16 
3.1. 
Population Definitions .................................................................................... 16 
3.2. 
Protocol Deviations......................................................................................... 16 
4. 
Statistical Methods ..................................................................................................... 17 
4.1. 
Sample Size Justification ................................................................................ 17 
4.2. 
General Statistical Methods and Data Handling ........................................... 17 
4.2.1. 
General methods ................................................................................ 17 
4.2.2. 
Computing Environment .................................................................... 17 
4.2.3. 
Methods of Pooling Data ................................................................... 17 
4.2.4. 
Adjustments for Covariates and Stratification .................................... 17 
4.2.5. 
Multiple Comparisons/Multiplicity .................................................... 17 
4.2.6. 
Subpopulations .................................................................................. 17 
4.2.7. 
Withdrawals, Dropouts, Loss to Follow-up ........................................ 17 
4.2.8. 
Missing, Unused, and Spurious Data .................................................. 17 
4.2.9. 
Baseline Definition ............................................................................ 19 
4.2.10. 
Visit Windows ................................................................................... 19 


GW Research Ltd 
Study Code: GWEP15100 
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25SEP2019 
 
 
CONFIDENTIAL 
 5 
Section 
Page 
4.3. 
Interim Analyses ............................................................................................. 19 
4.4. 
Subject Disposition ......................................................................................... 19 
4.5. 
Demographic and Baseline Characteristics ................................................... 19 
4.6. 
Medical History .............................................................................................. 19 
4.7. 
Efficacy Analyses ............................................................................................ 19 
4.7.1. 
Primary Efficacy Variables ................................................................ 20 
4.7.2. 
Key Secondary Efficacy Variables ..................................................... 20 
4.7.3. 
Secondary Efficacy Variables ............................................................ 20 
4.8. 
Safety Analyses ............................................................................................... 21 
4.8.1. 
Extent of Exposure and Compliance to Study Treatment .................... 21 
4.8.2. 
Adverse Events .................................................................................. 21 
4.8.3. 
Laboratory Data ................................................................................. 22 
4.8.4. 
Vital Signs and Physical Examinations .............................................. 22 
4.8.5. 
Electrocardiogram.............................................................................. 23 
4.8.6. 
Prior and Concomitant Medications ................................................... 23 
5. 
CHANGES TO PLANNED ANALYSES .................................................................. 24 
6. 
CLINICAL STUDY REPORT APPENDICES ........................................................ 25 
6.1. 
Planned Tables ............................................................................................... 25 
6.2. 
Planned Listings ............................................................................................. 26 
 
LIST OF IN-TEXT TABLES 
Table 
Page 
Table 1 
Schedule of Assessments ............................................................................................ 11 
 
 


GW Research Ltd 
Study Code: GWEP15100 
EudraCT Number: 2015-004904-50 
25SEP2019 
 
 
CONFIDENTIAL 
 6 
ABBREVIATIONS 
Abbreviation 
Definition 
6-OH-CBD 
6-hydroxy-cannabidiol 
7-COOH-CBD 
7-carboxy -cannabidiol 
7-OH-CBD 
7-hydroxy -cannabidiol 
AE 
Adverse event 
AED 
Antiepileptic drug 
ATC 
Anatomic therapeutic class 
BMI 
Body mass index 
CBD 
Cannabidiol 
CGIC 
Caregiver Global Impression of Change 
CRF 
Case report form 
CSR 
Clinical study report 
DSMC 
Data safety monitoring committee 
ECG 
12-lead electrocardiogram 
EEG 
Electroencephalography/electroencephalogram 
GW 
GW Research Ltd 
ICH 
International Conference on Harmonisation 
IMP 
Investigational medicinal product 
INR 
International normalized ratio 
MedDRA 
Medical Dictionary for Regulatory Activities 
OLE 
Open-label extension 
PGIC 
Physician Global Impression of Change 
POPPK 
Population pharmacokinetics 
PT 
Preferred term 
QTcB 
QT interval corrected for heart rate with Bazett’s formula 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SOC 
System organ class 
TBL 
Total bilirubin 
TEAE 
Treatment emergent adverse event 
ULN 
Upper limit of normal 
VGB 
Vigabatrin 
WHO-DD 
World Health Organization Drug Dictionary 


GW Research Ltd 
Study Code: GWEP15100 
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25SEP2019 
 
 
CONFIDENTIAL 
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1. 
INTRODUCTION AND OBJECTIVES OF ANALYSIS 
1.1. 
Introduction 
This document presents the abbreviated statistical analysis plan (SAP) for GW Research Ltd, 
Study GWEP15100: A Randomized, Double-blind, Placebo-controlled Trial to Investigate the 
Efficacy and Safety of Cannabidiol (CBD; GWP42003-P) in Infants with Infantile Spasms 
Following an Open-label Pilot Study. It contains the analysis details and methodology of the 
open-label pilot and extension phases of the study only. 
This SAP is based on protocol V3 dated September 20, 2016 and 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 trial. 
This SAP also will outline any differences in the currently planned analytical objectives relative 
to those planned in the study protocol. 
1.2. 
Objectives of Statistical Analysis 
1.2.1. 
Pilot Phase 
1.2.1.1. 
Primary Objective 
• To determine the maximum safe, tolerable dose and dosing regimen of GWP42003-P in 
infants with IS, to be utilized in the pivotal phase and open-label extension (OLE). 
• To assess the number and proportion of patients considered treatment responders, defined 
as those free of spasms and have resolution of hypsarrhythmia at the end of the 2-week 
treatment period. 
1.2.1.2. 
Secondary Objectives 
• Key: To assess the number and proportion of patients who are free of clinical spasms, as 
observed on video-electroencephalography (video-EEG) at the end of the treatment 
period. 
• Key: To assess the number and proportion of patients who have resolution of 
hypsarrhythmia, as observed on video-EEG at the end of the treatment period. 
• To assess changes in spasms and seizure subtypes by caregiver observation during the 
treatment period. 
• To determine time to cessation of spasms during the treatment period, as determined by 
caregiver diaries. 
• To explore the effect of GWP42003-P on quality of life. 
 
1.2.2. 
OLE Phase 
1.2.2.1. 
Primary Objective 
• To assess the long term safety of GWP42003-P in infants with IS. 


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Study Code: GWEP15100 
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CONFIDENTIAL 
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1.2.2.2. 
Secondary Objectives 
• Key: To assess the number and proportion of patients who are free of clinical spasms, as 
observed on video-electroencephalography (video-EEG) at the end of the treatment 
period. 
• Key: To assess the number and proportion of patients who have resolution of 
hypsarrhythmia, as observed on video-EEG at the end of the treatment period. 
• To assess changes in spasms and seizure subtypes by caregiver observation during the 
treatment period. 
• To determine time to cessation of spasms during the treatment period, as determined by 
caregiver diaries. 
• To explore the effect of GWP42003-P on quality of life. 
• To assess the number and proportion of patients who are free of spasms and have 
resolution of hypsarrhythmia, after 3, 6, 9 and 12 months of treatment. 
• To assess the number and proportion of responders who relapse and the time to relapse. 
• To explore the effect of GWP42003-P on growth, adaptive behavior and development. 
• To determine the population POPPK of CBD and its metabolites (6-OH-CBD, 7-COOH-
CBD and 7-OH-CBD) 
 


GW Research Ltd 
Study Code: GWEP15100 
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2. 
STUDY DESIGN 
2.1. 
Synopsis of Study Design 
This is a multisite trial to evaluate the efficacy and safety of GWP42003-P in patients with IS 
who have failed to become spasm- and hypsarrhythmia-free following treatment with 1 or more 
approved IS therapies (e.g., steroids and/or VGB). All approved therapies must be discussed with 
the patient’s parent(s)/legal representative before the patient is considered for the trial 
(discussions regarding treatment options must be documented). The trial will comprise of a pilot 
safety phase, followed by a pivotal phase, with a 1 year OLE extension available to all patients 
who complete either phase. The pilot phase will be open-label with 2 sequential cohorts of 5 
patients, the first cohort aged between 6 and 24 months and the second cohort aged between 1 
and 24 months, who will receive GWP42003-P for 2 weeks. The pivotal phase will comprise 192 
patients, aged 1–24 months, who will undergo a 2-week, randomized, placebo-controlled, 
double-blind treatment period. 
An independent DSMC will be used throughout the study; they will consider safety of the 
patients, and will confirm doses and dose regimens to be investigated in the pivotal phase, as 
well as the plans for dose titration. If required, following DSMC review, adjustment of doses and 
dose regimens will also take place following the first cohort of 5 patients in the pilot phase. 
Patients will enter the pilot and pivotal phases at the respective screening visits (Visit 1, Day −7 
to −1) for assessment of eligibility, which includes a prolonged video-EEG. Patients who satisfy 
all eligibility criteria will then be administered GWP42003-P (pilot phase) or randomized to 
GWP42003-P (1 of 2 dose levels) or placebo at a 1:1:1 ratio (pivotal phase) (Visit 2, Day 1 [+3 
days]). The High Dose Level will be as recommended by the DSMC; the Low Dose Level will 
be defined as 50% of the High Dose Level. Patients in the placebo group will be split into 2 
equivalent cohorts: half receiving Low Dose Level dosing volumes and half receiving High Dose 
Level dosing volumes. Following baseline assessments, patients will titrate the investigational 
medicinal product (IMP) in 10 mg/kg/day increments to the target dose level (or equivalent 
volume of placebo in the pivotal phase) and will continue at this dose, or the highest tolerated 
dose up to 40 mg/kg/day, for the remainder of the 2-week treatment phase. Patients in the pilot 
phase will remain in the clinic as inpatients during the 4-day dose titration period. If deemed safe 
by the DSMC then it is planned for those in the pivotal phase to titrate in an outpatient setting. 
Further clinic-based assessments will take place after 3 days’ dosing (Visit 3, Day 4 [+1 day]). 
All patients in the pilot and pivotal phases will return to the clinic after 2 weeks’ dosing (Visit 4, 
Day 15 [+3 days]) or earlier if they withdraw prematurely. All patients who complete treatment 
will then have the opportunity to receive GWP42003-P during the subsequent OLE phase. The 
OLE phase will last for a maximum of 1 year. 
Patients who enter the OLE phase will remain on the same dose (pilot phase) or will transition to 
their target dose of GWP42003-P over 4 days in a blinded manner (pivotal phase). Patients may 
continue at this dose, or the highest tolerated dose up to 40 mg/kg/day, for the remainder of the 
OLE phase. GWP42003-P may be discontinued at the discretion of the investigator. During the 
OLE phase, clinic visits will take place on Day 19 (Visit 5 [+1 day]), Day 29 (Visit 6 [±3 days]), 
Day 43 (Visit 7 [±3 days]), Day 71 (Visit 8 [±3 days]), Day 127 (Visit 9 [±7 days]), Day 211 


GW Research Ltd 
Study Code: GWEP15100 
EudraCT Number: 2015-004904-50 
25SEP2019 
 
 
CONFIDENTIAL 
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(Visit 10 [±7 days]), and on Day 295 (Visit 11 [±7 days]). Patients will return to the site for an 
end of OLE treatment visit on Day 379 (Visit 12 [±7 days]) or earlier if they withdraw 
prematurely from the OLE phase. Following end of treatment, withdrawal, or discontinuation of 
IMP, all patients will taper the IMP over 10 days followed by safety follow-up. Patient diaries 
will be completed each day by the caregiver during the trial. 
2.2. 
Randomization Methodology 
The pilot and OLE phases of this study are single-arm and open-label with no randomization. After 
confirmation of eligibility at Visit 2, all patients are assigned GWP42003-P in the pilot phase and 
continue on this same treatment in the OLE phase. 
2.3. 
Stopping Rules and Unblinding 
The patient must be withdrawn from the trial if ANY of the following apply: 
• Any issue with eligibility criteria that is considered to potentially compromise the safety 
of the patient. 
• Administrative decision by the investigator, GW, or regulatory authority. 
• Protocol deviation that is considered to potentially compromise the safety of the patient. 
• Withdrawal of the patient’s parent(s)/legal representative consent. 
• QTcB of 500 msec or greater on ECG, or a shift from baseline QTcB of 60 msec or 
greater. 
• Lost to follow-up.  
• ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%).  
• ALT or AST > 8 × ULN.  
• ALT or AST > 5 × ULN for more than 2 weeks.  
ALT or AST > 3 × ULN and (TBL > 2 × ULN or INR > 1.5). The patient may also be withdrawn 
from the trial for ANY of the following:  
• Any other issue with eligibility criteria (non-safety related).  
• Any requirement to increase the dose of concomitant AED(s) or to add in new AED(s) 
during the pilot or pivotal phase.  
• If a patient is not showing evidence of benefit during the OLE phase (the option of 
withdrawing from the trial will be discussed with the caregiver at each visit).  
• Patient/caregiver non-compliance.  
• AE (including clinically significant laboratory result) which, in the opinion of the 
investigator, would compromise the continued safe participation of the patient in the trial.  
There is no blinding necessary for the pilot and OLE phases so unblinding procedures will not 
apply. 
 


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Study Code: GWEP15100 
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2.4. 
Study Procedures 
The schedule of assessments, as outlined in the study protocol, is provided in Table 1. 
Table 1 
Schedule of Assessments 
 
Pilot or Pivotal phase 
Open-Label Extension Phase 
 
 
Visit Number 
Day 
(Visit Window) 
Visit 1 
Day -7 
to -1 
Visit 21 
Day 1 
(+3 
days) 
Visit 3 
Day 4 
(+1 
day) 
Visit 42 
Day 15 
(+3 
days) 
Visit 5 
Day 19 
(+1 
day) 
Visit 6 
Day 29 
(±3 
days) 
Visit 7 
Day 43 
(±3 
days) 
Visit 8 
Day 71 
(±3 
days) 
Visit 9 
Day 127 
(±7 
days) 
Visit 10 
Day 211 
(±7 
days) 
Visit 11 
Day 295 
(±7 
days) 
Visit 12 
Day 379 
(±7 
days) 
End of 
Taper 
Period 
Visit3 (+3 
days) 
Safety 
Follow-up 
Visit4 (+3 
days) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient number 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
X5 
 
 
 
 
 
 
 
 
 
 
 
 
Start of IMP dosing 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inpatient stay (pilot 
phase only) 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medication review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 


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Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECG 
X 
X6 
X7 
X7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Video-EEG (8-24 
hours) 
X 
 
 
X 
 
X 
X 
 
X 
X 
X 
X 
 
 
Clinical laboratory 
sampling 
(blood/urine) 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK blood sampling8 
 
X 
 
X 
X 
 
 
 
 
 
 
 
 
 
Caregiver paper 
diary issue/training 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
CGIC 
 
X9 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
PGIC 
 
X9 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Vineland-II 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
 
IMP dispensing10 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
IMP compliance 
review 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Caregiver diary 
review 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Spasm/seizure 
information 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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IMP usage11 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Changes in 
concomitant AEDs 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Usage of rescue 
medication 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AEs 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1All patients in the pilot phase will titrate GWP42003-P in an inpatient setting. In both phases (pilot and pivotal), daily safety checks will be made during the first 
week of IMP dosing (can be conducted by telephone). Each safety check will conduct the same assessments as listed for safety follow-up visit.  
2Daily safety checks will be made during the first week of OLE IMP dosing (can be conducted by telephone). Each safety check will conduct the same 
assessments as listed for safety follow-up visit.  
3IMP is to be tapered over 10 days following discontinuation of IMP, end of treatment, or withdrawal (unless continued dosing is not possible due to an AE).  
4Safety follow-up visit is to occur 28 (+3) days after date of final dose (including tapered dose); weekly (±3 days) telephone calls must be made during the 
follow-up period. Each safety telephone call will conduct the same assessments as listed for safety follow-up visit.  
5Based on assessment of clinical laboratory and video-EEG results.  
6ECG to be performed between 3 and 5 hours after the day’s first dose of IMP only.  
7ECG to be performed both prior to the day’s first dose of IMP and between 3 and 5 hours after this dose.  
8Only for patients involved in the pivotal phase, and progressing to the OLE from the pivotal phase. To be conducted only if the risk/benefit outcome is 
favorable, in the investigator’s opinion.  
9Memory aid only (worksheet completed).  
10If necessary, IMP will also be dispensed for taper period.  
11IMP usage to be recorded on a dosing schedule which will form part of the paper diary


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2.5. 
Primary Endpoints 
The following endpoints will be analyzed descriptively only: 
2.5.1. 
Pilot Phase 
• Safety as determined by AEs, clinical laboratory tests, ECG, vital signs and physical 
examinations during the treatment period  
• The number and proportion of patients who are free of spasms and have resolution of 
hypsarrhythmia at the end of the 2-week treatment period, as determined by video-EEG. 
2.5.2. 
OLE Phase 
• To assess the long term safety as determined by AEs, clinical laboratory tests, ECG, vital 
signs and physical examinations during the treatment period.  
2.6. 
Secondary Endpoints 
2.6.1. 
Pilot Phase 
For the pilot phase, the following secondary endpoints will be analyzed descriptively only: 
• The number and proportion of patients who are free of clinical spasms, as observed on 
video-EEG at the end of the treatment period. 
• The number and proportion of patients who have resolution of hypsarrhythmia, as 
observed on video-EEG at the end of the treatment period. 
• Changes in spasms and seizure subtypes by caregiver observation during the treatment 
period. 
• Time to cessation of spasms during the treatment period, as determined by caregiver 
diaries. 
• CGIC. 
• PGIC. 
2.6.2. 
OLE Phase 
For the OLE phase, the following secondary endpoints will be analyzed descriptively only: 
  
• The number and proportion of patients who are free of clinical spasms, as observed on 
video-EEG at the end of the treatment period. 
• The number and proportion of patients who have resolution of hypsarrhythmia as, observed 
on video-EEG at the end of the treatment period. 
• Changes in spasms and seizure subtypes by caregiver observation during the treatment 
period. 
• Time to cessation of spasms during the treatment period, as determined by caregiver 
diaries. 
• The number and proportion of patients who are free of spasms and have resolution of 
hypsarrhythmia, as determined by video-EEG after 3, 6, 9 and 12 months of treatment. 


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• The number and proportion of responders with relapse of spasms, and the time to relapse, 
as determined by caregiver diaries. 
• Changes from baseline in length (height), body weight, and head circumference. 
• CGIC. 
• PGIC. 
• Change from baseline in Vineland-II score. 
 


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3. 
SUBJECT POPULATIONS 
3.1. 
Population Definitions 
The following analysis sets will be evaluated and used for presentation and analysis of the data: 
• Pilot Phase Safety: All patients exposed to at least 1 dose of IMP during the pilot phase 
will be used for summaries of the safety endpoints during the pilot phase. 
• OLE Phase Safety: All patients exposed to at least 1 dose of IMP during the OLE phase 
will be used for summaries of the safety endpoints during the OLE phase. 
3.2. 
Protocol Deviations 
All protocol deviations will be listed and reasons for exclusion from the analysis sets will be 
summarized. 


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4. 
STATISTICAL METHODS 
4.1. 
Sample Size Justification 
The pilot phase of the study is not powered and comprises of 9 patients. 
4.2. 
General Statistical Methods and Data Handling 
4.2.1. 
General methods 
All output will be incorporated into Microsoft 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, 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, minimum and maximum values will be presented. 
Given that only the pilot and OLE phases will be analyzed in this study, there will be no formal 
hypothesis testing. Descriptive statistics will be used in the analyses. Data from the pilot and 
OLE phases will be presented together in the same outputs, unless otherwise noted. All 
tabulations will display one treatment column since the pilot and OLE phases only consist of one 
open-label treatment group.  
4.2.2. 
Computing Environment 
All descriptive statistical analyses will be performed using SAS statistical software (Version 9.4 
or higher), unless otherwise noted.  Medical History and adverse events will be coded using 
Medical Dictionary for Regulatory Activities (MedDRA) version 19.0. Concomitant medications 
will be coded using World Health Organization Drug Dictionary (WHO-DD, Q2.2016).  
4.2.3. 
Methods of Pooling Data 
Not applicable to the present study. 
4.2.4. 
Adjustments for Covariates and Stratification 
No formal statistical analysis that adjusts for possible covariate effects is planned. 
4.2.5. 
Multiple Comparisons/Multiplicity 
Multiplicity is not of concern for this study with a descriptive interpretation. 
4.2.6. 
Subpopulations 
No analyses of subgroups of subjects are planned. 
4.2.7. 
Withdrawals, Dropouts, Loss to Follow-up 
Subjects who withdraw from the study will not be replaced.  
4.2.8. 
Missing, Unused, and Spurious Data 
In general, there will be no substitutions made to accommodate missing data points.  All data 
recorded on the CRF will be included in data listings that will accompany the clinical study 
report.   


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4.2.8.1. 
Adverse Events Onset Date 
In the case an AE onset date is missing or partially missing, an imputation needs to be done to determine 
if the event is to be classified as occurring during the treatment period. 
If an onset date is completely missing (or the year is missing), the derived onset date will be calculated 
as the first non-missing valid (actual) date from the following list (in order of precedence): 
- 
First active study medication date 
- 
Consent date 
- 
If a valid non-missing date is not available for any of these dates, the derived onset date 
will be set to missing. 
If an onset date is incomplete, the derived onset date will be calculated using the following algorithm: 
Calculate a surrogate date as the first non-missing valid date from the following list (in order of 
precedence): 
- 
First active study medication date 
- 
Consent date 
- 
If a valid non-missing date is not available for any of these dates, the surrogate date will 
be set to missing. 
Based on the information provided, set the initial derived date to the earliest possible date. If only a year is 
provided, set the derived date to January first of that year. If a year and month is provided, set the derived 
date to the first day of that month. 
If the surrogate date is non-missing then: 
• 
If the derived date is on or after the surrogate date use the derived date as calculated 
• 
If the derived date is prior to the surrogate date and the surrogate date is consistent with the 
partial data provided for the onset date, use the surrogate date as the derived date 
• 
If the derived date is prior to the surrogate date and the surrogate date is not consistent with the 
partial data provided for the onset date then set the derived onset date to be the latest possible 
date based on the partial onset date information provided. If only a year is provided, set the 
derived date to December 31st of that year. If a year and month is provided, set the derived 
date to the last day of that month. 
If all dates used to determine the surrogate date are missing, then based on the information provided, set 
the derived date to the earliest possible date. If only a year is provided, set the derived date to January first 
of that year. If a year and month is provided, set the derived date to the first day of that month.  
4.2.8.2. 
  Adverse Events End Date 
A missing or incomplete end date of an AE will be imputed according to the following conventions: 
• 
If an end date is missing, the derived end date will be set to missing 
• 
If an end date is incomplete, set the derived end date to be the latest possible date based on the 
partial onset date information provided. If only a year is provided, set the derived date to 
December 31st of that year. If a year and month is provided, set the derived date to the last day 
of that month. 


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4.2.8.3. 
 Adverse Events Severity and Relationship 
The missing AE severity will be imputed to be “severe” and the missing AE relationship to study drug 
will be imputed to be “definitely related”. 
4.2.9. 
Baseline Definition 
Unless otherwise noted, baseline (for both the pilot and OLE phases) is defined as the data most recently 
collected prior to the first IMP dosing start date/time in the pilot phase. If the timing of some data 
collection is not recorded, it will be assumed that the assessment at the first dosing date is performed as 
planned, i.e. prior to dosing in the pilot phase. 
4.2.10. 
Visit Windows 
Any clinical domains that are displayed by visit will be shown by nominal study visit. 
4.3. 
Interim Analyses 
An interim analysis is not planned for this study. 
4.4. 
Subject Disposition 
All patients (enrolled, screened, treated, entering the OLE, prematurely terminating IMP) will be 
accounted for in the enrollment and disposition summary tables. 
A tabulation of subject disposition will be displayed, including the number enrolled, the number 
screened, reasons for screen failure, the number randomized, the number that completed the pilot 
phase and the number that entered the open label extension phase. 
A listing of screen failures and a listing of study completion information, including the primary 
reason for study withdrawal, if applicable, will be presented by cohort and subject. 
4.5. 
Demographic and Baseline Characteristics 
Demographic data, including gestational age, birth weight, age at informed consent, sex and race, 
will be summarized using descriptive statistics. For continuous variables, mean, standard 
deviation, median, minimum, and maximum will be presented. For categorical variables, N and 
% will be presented. 
Demographic and baseline data will also be provided in data listings by cohort and site.  
4.6. 
Medical History 
Previous and current significant non-epilepsy medical history will be summarized using System 
Organ Class (SOC) and Preferred Term (PT). 
Non-epilepsy medical history data will also be provided in data listings by cohort and site. 
4.7. 
Efficacy Analyses 
Efficacy analysis will be conducted using the Safety Analysis Set. 


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4.7.1. 
Primary Efficacy Variables 
4.7.1.1. 
Treatment Responders 
The number and proportion of patients who are considered treatment responders will be 
summarized descriptively separately for each phase. Treatment responders are defined as those 
free of spasms and have resolution of hypsarrhythmia at the end of the 2-week treatment period, 
as determined by video-EEG.  Resolution of hypsarrhythmia requires reduction of the EEG 
background below 300 µV and elimination of any electrodecrements or epochs of discontinuity. 
Persistence of some background slowing and interictal epileptiform discharges may be seen and 
still be consistent with resolution of hypsarrythmia. 
4.7.2. 
Key Secondary Efficacy Variables 
4.7.2.1. 
Clinical Spasms 
The number and proportion of patients who are free of spasms, as observed on video-EEG at the 
end of the treatment period, as observed on video-EEG at the end of the treatment period, and 
after 3, 6, 9, and 12 months of treatment will be summarized separately for each phase. 
4.7.2.2. 
Hypsarrhythmia 
The number and proportion of patients who have resolution of hypsarrhythmia, as observed on 
video-EEG at the end of the treatment period, and after 3, 6, and 12 months of treatment will be 
summarized separately for each phase. 
4.7.3. 
Secondary Efficacy Variables 
4.7.3.1. 
Changes in Spasms and Seizure Subtypes 
Caregivers will be instructed to record whether the patient had any episodes of spasms and/or 
other subtypes of epileptic seizure on a daily basis. The number and percentage of subjects who 
experienced spasms and other seizure subtypes (ie-Tonic, Clonic, Tonic-Clonic, Atonic, 
Myoclonic, Focal, Absence) during the treatment period will be summarized for each phase by 
visit. 
4.7.3.2. 
Caregiver Global Impression of Change (CGIC) 
The CGIC comprises a single question to be rated on a 7-point scale: “Since the patient started 
treatment, please assess the status of the patient’s overall condition (comparing their condition 
now to their condition before treatment) using the scale below.” 
The markers are: “Very Much Improved”; “Much Improved”; “Slightly Improved”; “No 
Change”; “Slightly Worse”; “Much Worse”; “Very Much Worse”. 
The caregiver will be asked to record the status of the patient’s overall condition at Visit 2 (Day 
1, prior to commencement of IMP) as a memory aid for subsequent visits.  
The number and percentage of subjects in each response category will be presented by visit for 
both phases combined. 


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4.7.3.3. 
Physician Global Impression of Change (PGIC) 
The PGIC comprises the same single question as the CGIC to be rated on the same, 7-point scale 
by the investigator.  The investigator will be asked to record the status of the patients’ overall 
condition at Visit 2 as a memory aid for subsequent visits. 
The number and percentage of subjects in each response category will be presented by visit for 
both phases combined. 
4.7.3.4. 
Vineland Adaptive Behavior Scales, Second Edition (Vineland-II) 
The Vineland-II is an individually administered instrument for assessing adaptive behaviors and 
is widely used in pediatric clinical trials due to its applicability to children of all ages and 
developmental levels.  The Vineland-II will be completed by the caregiver using a rating scale.  
Due to the possibility of cognitive/developmental delay, caregivers should start the assessment at 
the lowest age, irrespective of the patient’s actual age. The Vineland-II consists of 5 domains 
(communication, daily living skills, socialization, motor skills, and maladaptive behavior) with 
items that are rated as 0=Never, 1=Sometimes or Partially, or 2=Usually. The Vineland-II scores 
will be calculated as the sum of all individual item scores across all scales. 
Observed and change from baseline in Vineland-II scores will be summarized descriptively by 
visit for the OLE phase only. 
4.8. 
Safety Analyses 
Safety analyses will be conducted using the Safety Analysis Set.  
4.8.1. 
Extent of Exposure and Compliance to Study Treatment 
Descriptive statistics will be produced to describe the exposure and compliance to the IMP. The 
duration of exposure, and percent of treatment compliance will be summarized separately by 
phase. 
Duration of exposure in the will be calculated for each subject by counting days where the study 
medication was actually taken (i.e., overall treatment duration - number of days a subject missed 
all doses of study medication). If a subject took at least one dose of study medication on a study 
day, then the subject will be counted as having received study medication on that day. 
Overall percent compliance will be calculated and summarized as follows: duration of exposure / 
overall treatment duration x 100. 
4.8.2. 
Adverse Events 
Adverse events will be coded using the latest version of MedDRA and displayed in tables and 
listings using SOC and PT. 
Analyses of AEs will be performed for those events that are considered treatment emergent AEs 
(TEAEs), where treatment emergent is defined as any adverse event that started, or worsened in 
severity or seriousness, following the first dose of IMP.   
The number and percentage of subjects with the following AEs will be summarized: 
• All-causality TEAEs 
• Treatment-related TEAEs 


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• All-causality TEAEs by severity 
• All-causality TEAEs by sex 
• All-causality non-serious TEAEs 
• All-causality serious TEAEs 
• Treatment-related serious TEAEs 
• TEAEs reported as leading to permanent cessation of study treatment 
• Treatment-related TEAEs reported as leading to permanent cessation of study treatment 
• Fatal TEAEs. 
In these tabulations, each subject will contribute only once (i.e., the most related occurrence or 
the most intense occurrence) to each of the incidence rates in the descriptive analysis, regardless 
of the number of episodes. No formal hypothesis-testing analysis of adverse events incidence 
rates will be performed.   
All adverse events occurring on study will be listed by cohort and subject. Listings will also be 
provided for the following: subject deaths; SAEs; and adverse events leading to withdrawal of 
study drug.  
4.8.3. 
Laboratory Data 
For each phase of the trial, clinical laboratory data (hematology and biochemistry) at screening, 
during and at the end of treatment, and the change from baseline to end of treatment will be 
summarized for the safety analysis set using descriptive statistics. Categorical shift tables will 
also be presented, showing the numbers of patients with values outside the normal range and 
values outside of toxicity limits for hematology and biochemistry data. 
All hematology, biochemistry and urinalysis laboratory data will be provided in data listings. 
The values that are below the lower limit or above the upper limit of the reference range and 
values that are outside of toxicity ranges will be flagged. 
GW Toxicity criteria will be summarized for the following lab tests only: 
• >3xULN for ALT and AST; 
• >2xULN for TBL. 
4.8.4. 
Vital Signs and Physical Examinations 
Vital signs measurements (systolic and diastolic blood pressure, pulse rate, body temperature, 
respiratory rate, height, weight, BMI, and head circumference), taken in a supine position at rest 
for 5 minutes, will be completed alongside the physical examination. 
Physical examinations will include length (height), body weight, and head circumference 
measurements.  
Vital signs and physical examination data will be summarized at screening, baseline, and at each 
time point during the treatment period using descriptive statistics.  Changes in the vital signs 
from baseline to end of treatment will also be summarized. 


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All vital sign and physical examination measurements will be presented in data listings. 
4.8.5. 
Electrocardiogram 
ECG recordings (ventricular rate, PR duration, QRS duration, QT duration, and QTCB) will be 
performed after 5 minutes in a supine position. A physician must review the ECG immediately 
(annotated, signed and dated) and any abnormal findings considered to indicate significant 
medical history or AEs must be recorded appropriately on the CRF. Additional ECG 
measurements can be taken at any time during the trial, if clinically indicated.  
ECG data will be summarized at screening, baseline, and at each time point during the treatment 
period using descriptive statistics. 
All ECG measurements will be presented in a data listing. 
4.8.6. 
Prior and Concomitant Medications 
Prior medications are those the subject used prior to the start date/time of IMP administration. 
Concomitant medications are those the subject used on or after the start date/time of IMP 
administration. No imputation of medication start/end dates or times will be performed.  If a 
medication date or time is missing or partially missing and it cannot be determined whether it 
was taken prior or concomitantly, it will be considered a concomitant medication. 
Prior antiepileptic medications and therapies along with concomitant antiepileptic therapies and 
medications, rescue medications, and all other medications will be coded using the WHO-DD. 
Results will be tabulated by Anatomic Therapeutic Class (ATC) and PT. 
The use of prior and concomitant medications will be included in data listings by cohort and 
subject. 


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5. 
CHANGES TO PLANNED ANALYSES 
Since this trial only included patients from the open-label pilot study, the details and analyses of 
the pivotal phase of the study mentioned in the protocol were omitted from this SAP.  
 


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6. 
CLINICAL STUDY REPORT APPENDICES 
6.1. 
Planned Tables 
Table 1.1 Summary of Patient Disposition – All Screened Subjects 
Table 1.2 Summary of Protocol Deviations – All Enrolled Subjects 
Table 2.1 Summary of Demographic Data – Safety 
Table 3.1  Summary of Previous Significant Non-Epilepsy Medical or Surgical History Now Resolved 
– Safety 
Table 3.2  Summary of Significant Non-Epilepsy Medical or Surgical History - Current Conditions – 
Safety 
Table 4.1 Summary of Prior Antiepileptic Medications and Therapies - Safety 
Table 4.2 Summary of Concomitant Antiepileptic Therapies – Safety 
Table 4.3 Summary of Concomitant Antiepileptic Medications – Safety 
Table 4.4 Summary of Concomitant Rescue Medications – Safety 
Table 4.5 Summary of Other Concomitant Medications – Safety 
Table 7.1 Summary of Exposure and Compliance to Study Treatment – Pilot Phase - Safety 
Table 7.2 Summary of Exposure and Compliance to Study Treatment – OLE Phase - Safety 
Table 8.1.1 Proportion of Treatment Responders – Pilot Phase – Safety 
Table 8.1.2 Proportion of Treatment Responders – OLE Phase – Safety 
Table 9.1.1 Proportion of Spasms and Seizure Subtypes by Caregiver Observation – Pilot Phase – 
Safety 
Table 9.1.2 Proportion of Spasms and Seizure Subtypes by Caregiver Observation – OLE Phase – 
Safety 
Table 9.2.1 Summary of CGIC Scores – Pilot and OLE Phase – Safety 
Table 9.2.2 Summary of PGIC Scores – Pilot and OLE Phase – Safety 
Table 9.3 Summary of Vineland Adaptive Behavior Scales Change from Baseline by Visit – OLE 
Phase – Safety 
Table 11.1.1 Overview of Adverse Events – Pilot Phase – Safety 
Table 11.1.2 Overview of Adverse Events – OLE Phase – Safety  
Table 11.2.1 Treatment-Emergent Adverse Events by System Organ Class and Preferred Term – Pilot 
Phase – Safety 
Table 11.2.2 Treatment-Emergent Adverse Events by System Organ Class and Preferred Term – OLE 
Phase – Safety 
Table 11.3.1 Treatment Related Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term – Pilot Phase – Safety 
Table 11.3.2 Treatment Related Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term – OLE Phase – Safety 
Table 11.4.1 Treatment-Emergent Adverse Events by System Organ Class and Preferred Term and 
Severity – Pilot Phase – Safety 
Table 11.4.2 Treatment-Emergent Adverse Events by System Organ Class and Preferred Term and 
Severity – OLE Phase – Safety 
Table 11.5.1 Treatment-Emergent Adverse Events by System Organ Class and Preferred Term and 
Sex – Pilot Phase – Safety 
Table 11.5.2 Treatment-Emergent Adverse Events by System Organ Class and Preferred Term and 
Sex – OLE Phase – Safety 


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Table  11.6.1: Non-Serious Treatment Emergent Adverse Events by System Organ Class and 
Preferred Term for Subjects and Events – Pilot Phase – Safety 
Table  11.6.2: Non-Serious Treatment Emergent Adverse Events by System Organ Class and 
Preferred Term for Subjects and Events – OLE Phase – Safety 
Table 12.1.1 Serious Treatment-Emergent Adverse Events by System Organ Class and Preferred Term 
– Pilot Phase – Safety 
Table 12.1.2 Serious Treatment-Emergent Adverse Events by System Organ Class and Preferred Term 
– OLE Phase – Safety 
Table 12.2.1 Treatment Related Serious Treatment-Emergent Adverse Events by System Organ Class 
and Preferred Term – Pilot Phase – Safety 
Table 12.2.2 Treatment Related Serious Treatment-Emergent Adverse Events by System Organ Class 
and Preferred Term – OLE Phase – Safety 
Table 12.3.1 Treatment-Emergent Adverse Events Leading to Study Drug Discontinuation by System 
Organ Class and Preferred Term – Pilot Phase – Safety 
Table 12.3.2 Treatment-Emergent Adverse Events Leading to Study Drug Discontinuation by System 
Organ Class and Preferred Term – OLE Phase – Safety 
Table 12.4.1 Treatment Related Treatment-Emergent Adverse Events Leading to Study Drug 
Discontinuation by System Organ Class and Preferred Term – Pilot Phase – Safety 
Table 12.4.2 Treatment Related Treatment-Emergent Adverse Events Leading to Study Drug 
Discontinuation by System Organ Class and Preferred Term – OLE Phase – Safety 
Table 12.5.1 Fatal Treatment-Emergent Adverse Events by System Organ Class and Preferred Term – 
Pilot Phase – Safety 
Table 12.5.2 Fatal Treatment-Emergent Adverse Events by System Organ Class and Preferred Term – 
OLE Phase – Safety 
Table 13.1.1 Summary of Laboratory Test Results and Change from Baseline by Visit – Hematology – 
Pilot and OLE Phase - Safety 
Table 13.1.2 Summary of Laboratory Test Results and Change from Baseline by Visit – Chemistry – 
Pilot and OLE Phase – Safety 
Table 14.1 Summary of Vital Signs Results and Change from Baseline by Visit – Pilot and OLE Phase 
– Safety 
Table 14.2 Summary of Physical Examination Results and Change from Baseline by Visit – Pilot and 
OLE Phase – Safety 
Table 14.3.2 Summary of ECG Results and Change from Baseline by Visit – Pilot and OLE Phase – 
Safety 
Table 13.2.1 Hematology Shift Table Based on Reference Ranges – Pilot and OLE Phase – Safety 
Table 13.2.2 Chemistry Shift Table Based on Reference Ranges – Pilot and OLE Phase – Safety 
Table 13.2.3 Chemistry Shift Table Based on Toxicity Limits – Pilot and OLE Phase – Safety 
 
6.2. 
Planned Listings 
Listing 1.1 Patient Disposition – Screening Failures 
Listing 1.2 Patient Disposition - All Enrolled Patients 
Listing 1.3 Visit Dates - All Enrolled Patients 
Listing 1.4 Protocol Deviations - All Enrolled Patients 
Listing 3.1 Demographic Data – Safety 
Listing 4.1 Non-Epilepsy Medical or Surgical History - Safety 


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Listing 4.2 Prior Antiepileptic Medications and Therapies - Safety 
Listing 5.1 Concomitant Antiepileptic Medications and Therapies – Safety 
Listing 8.1 Clinical Spasms and Seizures - Safety 
Listing 8.2 CGIC, PGIC and Vineland-II Data – Safety 
Listing 11.1 Adverse Events – Safety 
Listing 13.1 Laboratory Parameters – Hematology – Safety 
Listing 13.2 Laboratory Parameters – Biochemistry – Safety 
Listing 13.3 Laboratory Parameters – Urinalysis – Safety 
Listing 14.1 Vital Signs and Physical Examinations – Safety 
Listing 14.2 ECG Parameters – Safety