Cannabinoid Therapy in Medically Refractory Pediatric Epilepsy - Phase 1: Dosing and Tolerability Study of a Cannabidiol-Rich Whole Plant Extract of Cannabis.
Phase: PHASE1
Conditions: Epilepsy
Sponsor: The Hospital for Sick Children

                                                                                                                                       NCT number: 02983695 
 
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Clinical Research Protocol -    
 
Cannabinoid therapy in medically refractory pediatric epilepsy – 
Phase 1: Dosing and tolerability study of a Cannabidiol-rich whole 
Cannabis plant extract. 
Study Site:  
The Hospital for Sick Children  
Toronto, Ontario 
 
Principal Investigator: 
Dr. O Carter Snead III 
 
Lead Co-Investigator:  
Dr Bláthnaid McCoy  
 
Co-Investigators:  
Maria Zak NP, Dr. Katia Sinopoli PhD CPsych and Laura Wang (Pharmacist), Dr Kenda 
Alhadid 
Study product: 
TIL-TC150 Oil  
 
 

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Study product Vendor: 
Tilray 
 
 
Study Funding: 
 
Tilray, the Little Rocky Fund (via Sick Kids Foundation) 
 

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TABLE OF CONTENTS 
 
Study Summary Table 
1. Background and Rationale 
2. Study Objectives 
3. Study Design 
4. Selection and Withdrawal of Subjects 
5. Study Treatment and Study Procedures 
6. Assessment of Efficacy 
7. Assessment of Safety and Adverse Events 
8. Statistical Plan and Analysis 
9. Source Data/Documents Access 
10. Quality Control Procedures 
11. Study Ethics 
12. Data Handling and Record Keeping 
13. Trial Registration 
14. Publication policy 
15. References 
16. Supplemental Information 

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List of Abbreviations 
AED  
Anti-epileptic drug 
CBD  
Cannabidiol 
CBG  
Cannabigerol 
CBDV  
Cannabidivarin     
CBC  
Cannabichromene 
CYP  
Cytochrome P 
GABA  
Gamma-aminobutyric Acid 
LFP 
 
Local field potential 
LFT 
 
Liver function tests 
MES  
Maximal Electroshock 
PESQ  
Pediatric Epilepsy Side Effects Questionnaire 
PTZ 
 
Pentylenetetrazol 
QOLCE 
Quality of Life in Childhood Epilepsy Questionnaire 
SUDEP 
Sudden Unexplained Death in Epilepsy 
THC  
Delta-9-Tetrahydrocannabidiol 
VNS  
Vagus nerve stimulator 
 

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Study Summary 
Title 
Cannabinoid Therapy in Medically Refractory Pediatric Epilepsy – 
Phase 1: Dosing and Tolerability Study of a Cannabidiol-Rich 
Whole Plant Extract of Cannabis. 
Short Title 
Cannabinoid Therapy for Pediatric Epilepsy 
Phase 
1 
Methodology 
Open-label Intervention 
Study Duration 
20 weeks to primary analysis with continued follow-up until 64 
weeks completed 
Study Center 
The Hospital for Sick Children, Toronto Ontario 
Objectives 
To determine the tolerability and optimal dose of 50:1 ratio 
CBD:THC Cannabis extract as an adjunct treatment in children 
with severe drug resistant epilepsy 
Number of Subjects 
20 
Diagnosis and Main 
Inclusion Criteria 
Patients with Dravet Syndrome 
Between ages of 1 and 18 years old male or female 
Must have failed 2 AEDs at therapeutic doses and be on current 
regimen of 1-4 AEDs which have been stable doses for 4 weeks 
Study Product, Dose, 
Route, Regimen 
TIL-TC150 Oil is the study product 
The active ingredients in TIL-TC150 Oil are THC and CBD, 
present in a 1:50 ratio. These active ingredients are derived from 
Cannabis sativa L. strains produced by Tilray and suspended in a 
grape seed oil. This suspension is administered at a dose of 
2mg/kg/day CBD divided BID and titrated up to a maximal dose of 
16mg/kg/day CBD (or maximal tolerated). 
Duration of Administration 
Study period: primary safety and outcome data at 20 weeks with 
longer follow-up of safety and tolerability in those who chose to 
continue after the 20-week period and will be followed up to 64 
weeks. 
Reference Therapy 
None 
Statistical methodology 
The primary aims of this study are to determine the maximal 
tolerated dose of TIL-TC150 Oil Cannabis Extract in children with 
drug resistant epilepsies.  Descriptive statistics will be used to 
quantify the frequency and severity of adverse events that are 

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reported for the various dosages that are employed 
 
1. Background 
1.1 Introduction 
This is a single center study to ascertain dosing and tolerability of add-on (i.e., in 
addition to their standard anti-epileptic therapy) Cannabidiol in children between 12 
months and 18 years with treatment-resistant epilepsy due to Dravet syndrome. Dravet 
syndrome is a devastating syndrome which causes medication resistant epilepsy 
associated with significant cognitive morbidity and frequent seizures [1-7]. In addition to 
the significant morbidity, children with refractory epilepsy are at risk of seizure-related 
mortality and Sudden Unexpected Death in an Epilepsy Patient (SUDEP) [8]. The risk of 
SUDEP in treatment resistant epilepsy is 1 in 150 [9]. The current armory of anti-
epileptic drugs, dietary therapy and the Vagal Nerve Stimulator (VNS) device are not 
always successful in achieving seizure control. The healthcare costs of childhood-onset 
treatment resistant epilepsy are well established [10, 11]. In Dravet syndrome the 
severity of the epilepsy often requires frequent emergency department attendances, 
and hospital admissions.  
Rationale for this study  
The availability of a treatment to reduce the seizure frequency in children with Dravet 
syndrome (thus reducing hospital admissions) and to provide the chance of improved 
long term cognitive outcome, hence reducing the need for lifelong neurodisability 
service availability, would lead to significant savings in healthcare expenditure [12]. 
In addition, it is scientifically plausible that this study product would have efficacy in 
treating seizures in Dravet syndrome. In 80% of cases of Dravet syndrome a causative 
genetic mutation is detected in a Sodium channel coding gene (SCN1a mutation). 
Cannabinoids CBD and CBG have been shown to be potent sodium channel blockers in 
both human and animal models. 

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1.2 Investigational Product 
The physiochemical characteristics of THC and CBD are detailed in Table 1.  
Table 1: Drug Substance Common Name  
delta-9-tetrahydrocannabinol (THC) and 
cannabidiol (CBD)  
Chemical Name  
THC: IUPAC ID: (−)-trans-Δ9-
tetrahydrocannabinol; IUPAC ID: (−)-
(6aR,10aR)-6,6,9-trimethyl- 3-pentyl-
6a,7,8,10a-tetrahydro- 6H-benzo[c]chromen-
1-ol.  
CBD: IUPAC ID: 2-[(1R,6R)-6-isopropenyl-3-
methylcyclohex-2-en-1-yl]-5-pentylbenzene-
1,3-diol.  
Appearance  
THC: Light yellow resinous oil; CBD: Light 
yellow resinous oil  
Molecular Formula  
THC: C21H30O2; CBD: C21H30O2  
Molecular Mass  
THC: 314.47; CBD: 314.47  
Solubility  
THC: Soluble in methanol, ethanol, acetone, 
chloroform, and dichloromethane. Insoluble in 
water.  
CBD: Soluble in methanol, ethanol, acetone, 
chloroform, light petroleum, and 
dichloromethane. Insoluble in water.  
Tilray TIL-TC150 is formulated with THC and CBD in grape seed oil at strengths of 2 
mg/ml and 100 mg/ml, respectively. The product is formulated with standard 
pharmaceutical excipients. 
TIL-TC150 Oil is packaged in 25 ml Type III amber glass stopper bottles with a 
polypropylene cap and a fill of 20.0 ml. The oil drug product is stored at room 
temperature with a 6 months expiration. 
.
 

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Figure 1. Cannabidiol Structure 
CBD is highly lipid soluble and is a potent inhibitor of CYP2B6, CYP2C8, CYP2C9, 
CYP2C19, and CYP3A4. The effects of other concomitant drug levels metabolized 
by these enzyme systems are not known. CBD is excreted in the urine and faeces. 
The plasma peaks vary significantly between individuals but are typically between 1 
to 2 hours. The CBD levels are detected up to 8 hours post administration. The 
adverse drug reactions of CBD that have been indicated in trials include headache, 
dizziness, fatigue, loss of appetite, oral numbness, dry mouth, neck pain, feeling 
strange, depression, lack of taste or changed taste, gastrointestinal disturbances, 
feeling weak, falls, shakiness, muscle stiffness, unusual dreams, nose bleeds, hot or 
cold flashes, and heartburn.  
Cannabinoids: Increases in systolic BP over time (Sativex = 3 hrs), and decreases in 
diastolic BP with noted heart rate increase (Sativex = 4-8 hrs) [1] However, this is 
anticipated to be due to the THC content. Much of the published data refers to 
Sativex which contains 50% THC and many of the adverse effects are considered in 
keeping with the psychoactive THC effects. 
Phytocannabinoids exhibit very low mammalian toxicity, and mixtures of 
cannabinoids are less toxic than pure THC. [2] Therefore, a mixture of other 
cannabinoids (terpenoids, etc.) may also reduce any potential toxicity issues due to 
having a high CBD product.  
The following are the most common side effects of AEDs and/or high-THC cannabis. 
However, since our product is very low in THC we anticipate that these will be minor 
or rare: 
- 
Dizziness, somnolence, fatigue, irritability, ataxia, blurred vision, diplopia 
vision, rashes, and motor incoordination / falls. 
- 
Gastrointestinal (anorexia, loss of appetite, nausea, vomiting, and weight 
loss).Psychiatric and behavioural adverse reactions such as aggression, 
hostility, irritability, anger, and homicidal ideation / threats. 

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1.3 Preclinical Data 
There have been a number of studies published reporting the anti-convulsant effect of 
CBD using the mouse model. Izquierdo et al used a maximal electroshock (MES) model 
to induce seizures in mice and found CBD to be protective against the maximal 
electroshock (MES) model of generalized seizures with an ED50 (effective dose for 50% 
of group) of 3 mg/kg CBD [13]. Chesher et al used the MES model and 
Pentylenetetrazole (PTZ) induced seizure model in mice and found CBD of 50-200 
mg/kg orally exhibited no anti-convulsant effects in either model [14, 15]. However, 
there was no data on the pharmacokinetics for oral CBD making the results difficult to 
interpret. In mice, CBD has been found to be an effective and relatively potent anti-
convulsant in the MES model with ED50 values of 12 mg/kg. In these mice models, CBD 
enhanced the anti-convulsant potencies of phenytoin and phenobarbital. However, CBD 
diminished effects of clonazepam and ethosuximide. 
Karler et al studied the occurrence of tolerance in CBD’s (120 mg/kg) anti-convulsant 
effects in electrically-induced seizure models [16]. Mice were dosed repeatedly for 3-4 
days with CBD, phenytoin, and phenobarbital and no change in their anti-convulsant 
sensitivity was found in MES models compared to those dosed acutely. Repeated 
dosing increased sensitivity of CBD in 6 Hz electroshock-threshold test. 
Another study found that CBD (0.3-3 mg/kg) raised the threshold required to produce 
epileptic after-discharges recorded by chronically implanted electrodes in electrically 
kindled limbic seizures in rats [17]. This is consistent with the known effects of 
phenytoin in this model. However, CBD also decreased the after-discharge amplitude, 
duration, and propagation in this model, similar to the effects of ethosuximide. The 
group concluded that “CBD was the most efficacious of the drugs tested against limbic 
after-discharges and convulsions.” 
CBD was evaluated in many different seizure models and found to be an effective anti-
convulsant in MES and all of the GABA inhibition-based models [18].  

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Recently, Jones et al reported significant anti-epileptiform and anti-convulsant activity 
with in vitro and in vivo models [19, 20]. Using spontaneous epileptiform local field 
potentials (LFPs) models they found that in vitro CBD decreased epileptiform LFP burst 
amplitude and duration. In addition, CBD had significant anti-convulsant effects against 
PTZ- induced acute, generalized seizures, pilocarpine-induced temporal lobe seizures 
and penicillin-induced partial seizures in their rats.   
 
1.4 Clinical Data to Date 
A Cochrane Report from 2012 compiled studies on cannabinoids for epilepsy [21]. This 
report included 4 clinical studies where CBD was used to treat epilepsy. In 1978, a 
study by Mechoulam et al randomized 9 adult patients to either 200mg of CBD (4 
patients) or placebo (5 patients) [22]. All patients had uncontrolled temporal lobe 
epilepsy and had failed treatment with multiple medications. Two of the four patients 
treated with CBD over the 3 month trial became seizure free for duration and 1 patient 
showed partial improvement. However, none of the 5 patients receiving placebo 
experienced a reduction in seizures. There were no toxic effects observed. 
Cuhna et al studied 15 adult patients with treatment resistant secondary generalized 
epilepsy [23].Each participant had at least 1 generalized convulsion per week. They 
were randomly divided into 2 groups and treated with either placebo (8 patients) or 200-
300 mg of CBD (7 patients) daily up to 18 weeks. One patient was transferred to the 
treatment group after one month. Four of eight patients in the CBD group became 
almost seizure free, and three of the eight experienced a partial reduction in seizures. 
Only one of seven patients in the placebo group experienced seizure reduction. The 
most commonly reported side effect was somnolence and no patients reported 
psychotropic effects. All patients remained on their previously prescribed anti-epileptic 
drugs (AED) throughout the trial. 
Ames et al performed a placebo-controlled trial of 12 institutionalized, intellectually 
disabled patients with frequent seizures uncontrolled on conventional AEDs [24]. The 

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patients were divided into 2 groups by unclear method. The treatment group was given 
300 mg cannabidiol daily for 1 week then 200 mg daily for 3 weeks. At the study’s 
conclusion there were no statistically significant differences between the 2 groups. The 
only immediate side effect reported was mild drowsiness. The specific details of the 
study were lacking on seizure frequencies and other parameters. There was no 
indication that patients continued on their AED medication during the study. 
Trembly et al [25] conducted a cross-over design in which 12 patients with incompletely 
controlled epilepsy received their standard AEDs for 3 months and then a placebo for 6 
months. Patients’ AEDs could change in this period only. The 12 patients were then 
randomized to placebo or cannabidiol 100 mg 3 times a day for 6 months. After this 
period, those on the active treatment switched to the placebo and those on the placebo 
switched to the active treatment for another 6 months. The study concluded with all 
patients receiving neither placebo nor treatment for 3 months. The study’s published 
abstract did not report any statistical analysis. The only reported results were no 
discernible effect on the Minnesota Multiphasic Personality Inventory (MMPI), Beck 
depression inventory, trail making test, and finger tapping test. This same study was 
later summarized in a book chapter by Consroe in 1992 [26]. This summary reported 
that there were only 10 patients and that Trembly reported no effects on seizure pattern, 
character, or frequency. Cochrane was unsuccessful in contacting Trembly’s group for 
clarification. 
Dr. Porter and Dr. Jacobson of Stanford University conducted a survey of parents to 
learn about their experience with CBD.  They surveyed 19 parents to determine their 
observations about the effect or lack of effect of CBD on their children’s seizure 
frequency. The children ranged in age from 2 to 16 years old and had Dravet syndrome 
(13), Doose syndrome (3), and one each with myoclonic astatic epilepsy, Lennox-
Gastaut syndrome, and idiopathic epilepsy. The children experienced a wide variety of 
seizure types and had unsuccessfully trialed an average of 12 AEDs before their 
parents began cannabidiol-enriched cannabis treatment. The doses of cannabidiol the 
parents reported administering to their children ranged from less than 0.5 mg/kg/day to 

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28.6 mg/kg/day. The doses of THC contained within those samples were reported to 
range from 0 to 0.8 mg/kg/day. The parents obtained dosage information by having their 
preparations tested at commercial medical cannabis testing facilities. Seizure frequency 
prior to administered cannabidiol-enriched cannabis ranged from 2 per week to 250 per 
day.  
Validation of the survey was achieved by giving the same survey to a similar group of 
parents to enquire about effects of an AED approved in Europe for Dravet Syndrome, 
stiripentol (STP). Sixteen of 19 parents (84%) reported a reduction in their child’s 
seizure frequency. Two parents reported their child become seizure-free after more than 
4 months on cannabidiol-enriched cannabis. Of the remaining 14 parents, 8 reported 
greater than 80% reduction in seizure frequency, 3 reported greater than 50% 
reduction, and 3 reported greater than 25% reduction. Three parents reported no 
change in seizure frequency. Twelve parents were able to wean their child off of another 
AED after starting cannabidiol-enriched cannabis. Other beneficial effects of 
cannabidiol-enriched cannabis included better mood (15/19, 79%), increased alertness 
(14/19, 74%), better sleep (13/19, 68%), and decreased self-stimulation (6/19, 32%). 
The only negative effects reported were drowsiness (7/19, 37%) and fatigue (3/19, 
16%). While this data does contain some limitations, such as lack of control data, lack of 
randomization and blinding, and uncertainty of artisanal preparation dosages, it does 
lend hope that CBD may be a useful pharmaceutical alternative to existing therapies in 
drug resistant epilepsy and sheds light on what tolerated doses are being used 
experimentally. 
There have also been clinical studies on chronic dosing of CBD in other disease states. 
CBD was evaluated for symptomatic efficacy and safety in 15 neuroleptic-free patients 
with Huntington’s Disease. Oral CBD (10 mg/kg/day) or placebo (sesame oil) was 
administered for 6 weeks and the effects were evaluated weekly under a double blind, 
randomized crossover design. The CBD was found to show no significant or clinical 
difference compared to placebo in Cannabis side effect inventory, clinical lab tests, or 
other safety outcome measures [27]. A published case report of a 19-year-old 

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diagnosed with schizophrenia had severe side effects after treatment with conventional 
antipsychotics, but showed significant improvement of symptoms with no adverse 
effects after 4 weeks of inpatient treatment with CBD in increasing doses up to 1500 
mg/day [28]. CBD monotherapy was administered to 3 patients with treatment-resistant 
schizophrenia with starting dose at 40 mg/day and increased to 1280 mg/day up to 4 
weeks with no side effects reported [29]. Lastly, 2 patients with bipolar affective disorder 
received CBD of 600-1200 mg/day for up to 24 days with no side effects at any dose 
[30]. 
GW Pharma has a product called Sativex ® Oromucosal Spray that has been approved 
in over 20 countries as an adjunct medication for symptom improvement in patients with 
spasticity from multiple sclerosis (MS). These patients had not shown an improvement 
in spasticity with other anti-spasticity medications and showed significant improvement 
during initial trials with Sativex. It contains 27 mg/mL of THC and 25 mg/mL of CBD. 
The dosing is administered as a spray (each spray is 0.1 ml and contains 2.5 mg of 
CBD/ 2.7mg of THC). The recommended dosages are one spray twice daily (5mg of 
CBD/ 5.4mg of THC per day) at initiation and titration according to effect to 4-8 sprays 
per day (10 mg CBD/ 10.8 mg THC – 20 mg CBD / 21.6 mg THC). The most common 
adverse reactions to Sativex are dizziness, nausea, fatigue, dry mouth, and 
somnolence. While it is believed that most of these adverse effects are mostly like from 
the THC component of the Sativex, it has still been approved as safe and effective. 
Sativex was originally approved in Canada in 2005 and since then there have been 16 
periodic safety update reports (PSURs). During that time, 5,472 patients were exposed 
to Sativex and the benefit-risk evaluation for Sativex continues to be unchanged. There 
have been no safety concerns identified and Sativex continues to remain well tolerated. 
Therefore, even in the presence of THC, CBD-containing compounds have been proven 
to be well tolerated and safe. 
Recently a retrospective review was undertaken in an attempt to provide guidance on 
the safety and efficacy of CBD [31]. 11 patients with intractable epilepsy (Dravet, Doose 
and similar) were identified ranging in age from 6 months to 21 years.  All 11 patients 

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were observed to have significant reduction in seizures after 3 months. The range of 
seizure reduction was found to be 55% to 100% with a mean of 90%.  10 of 11 patients 
experienced 80% or more seizure reduction, and 3 of 11 patients were seizure free after 
3 months of therapy. The average dose giving maximal improvement at 3 months was 5 
mg CBD/lb/day (range: 2-8 mg CBD/lb/day or 1-3.6 mg/kg/day).  Families reported no 
adverse effects attributed to the high CBD, low THC extract therapy. Several families 
reported an increase in adverse events from concurrent AEDs, including irritability and 
increased seizure activity, when therapy was added. Families reported that titrating 
down doses of concurrent AEDs while continuing therapy resolved adverse events and 
improved seizure control. 
The CBD/epilepsy landscape was further changed dramatically in December 2015 with 
the publication by Devinsky and colleagues [32] of an open-label trial of CBD, in over 
200 patients (aged 1–30 years) with severe, intractable, childhood-onset, treatment 
resistant epilepsy, in 11 epilepsy centers across the United States. Open label add-on 
study, 11 centers across US between 2014-2015.  The CBD used in this study was a 
99% pure oil-based cannabidiol extract of constant composition (Epidiolex, GW 
Pharmaceuticals, London, UK), in a 100 mg per mL preparation, so 100:1 ratio of CBD: 
THC. Their results showed an average reduction from 30 seizures a month to 16 
seizures a month. There were 5 participants who were free from motor sz at the end of 
the 12 weeks. They titrated doses up to 25mg/kg/day without patients withdrawing due 
to side effects. They noted that side effects of GI disturbance (diarrhea) were more 
likely at higher doses, and they titrated up to 25mg/kg/day. 
Health Canada has approved a cannabis extract oil of 18:1 ratio CBD:THC and 20:1 
CBD:THC for sale to patients of all ages (Cannimed licensed producers). Given the 
recent data on CBD:THC at a 100:1 ratio from Devinsky et al (Epidiolex)[32], we feel 
dosing and safety for a 50:1 CBD:THC cannabis extract product in our study product is 
the appropriate next step. This ratio allows us to maximize the CBD dosing, while 
ensuring exposure to lower THC dosing than products currently licensed for sale to 
patients in Canada. 

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1.5 Dose Rationale 
Chronic CBD dosing up to 1500 mg/day is described in published literature with no 
adverse effects. In addition, the report by Drs. Porter and Jacobson from a parent 
survey of children (2-16 years of age) receiving Cannabinoid with high CBD content up 
to doses of 28.6 mg/kg/day showed that it was well tolerated. In addition, a recent 
pediatric report [31] described a good clinical effect with doses between 1-3.6 
mg/kg/day. In Devinsky et al study they descried tolerance of up to 25mg/kg/day of their 
Epidiolex compound. Somnolence was reported in 25%. At doses of CBD above 
15mg/kg/day diarrhea (19% at any dose) and weight loss (6%) were reported. No 
patients wanted to discontinue despite the frequent side effects. Therefore, we feel the 
dosing titration protocol of up to 16 mg/kg/day of CBD is reasonable and safe in this 
population of children with treatment-resistant epilepsy. 
Study investigators will review all data relating to safety and tolerability throughout the 
study, after every third patient has been treated, to monitor study conduct and assess 
patient safety throughout the dosage period of 4 months. This review of data will be 
conducted by regular clinical evaluations at baseline, every 2 weeks for the first month, 
monthly for 4 months (to interim outcome stage) then once every 3 months thereafter 
(for those choosing to continue therapy). CBD will be started at 2mg/kg/day CBD and 
titrated slowly by 2mg/kg/day CBD every 7 days until 16mg/kg/day CBD is reached (or 
maximal tolerated dose clinically). Patients will also be assessed for concomitant AED 
levels at baseline and maximal tolerated CBD dose. These concomitant AEDs will be 
adjusted by the study team as necessary based on the level and signs/symptoms of 
toxicity or decline in seizure control. Patients will also be monitored via telephone or 
email in between in-person visits. 
1.6 Study Population 
Our target population is children with treatment-resistant epilepsy due to Dravet 
syndrome. Dravet syndrome may be clinically suspected by evaluation of the clinical 

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history and EEG (sleep recording within 12 months of study enrollment), and the 
diagnosis will be confirmed genetically (up to 80% of children with Dravet syndrome are 
positive for a mutation in the SCN1A gene).   
Clinical features suggestive of Dravet syndrome –  
Normal early development prior to seizure onset 
Seizure onset in the first year of life 
Febrile and afebrile seizures – often prolonged and unilateral clonic or tonic-clonic 
Seizure types evolve to include myoclonic, atypical absence, and focal clonic seizure 
types 
Seizures typically refractory to AED 
Cognitive delay begins typically during second year of life, with marked slowing of 
development typically between 2-4 years, which may plateau thereafter. 
EEG features suggestive of Dravet syndrome – 
Early EEG may be normal 
As epilepsy progresses EEG shows focal, generalized and multifocal interictal 
epileptiform discharges. 
The background may show generalized slowing in line with clinical seizure frequency. 
 
In order to recruit patients, we will forward study information to all hospital pediatric 
neurologists at our institution by email. In addition, we will write to the referring 
community neurologists in the Greater Toronto Area (GTA) or local referring centres 
who care for children with complex epilepsy inviting them to refer children with Dravet 
syndrome for consideration for enrollment to attend a clinic visit with the study 
investigator team at our institution to learn more about the study and potential 

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enrollment. Referring physicians will be asked to confirm that referred families have 
ascertained to hear more about the study. When seen at a clinic visit the study details 
will be explained to them by one of the investigator team (a physician or NP)  
1.7 Research Risks and Benefits 
1.7.1 Risk of Study Product 
Cannabinoids have not been extensively studied and therefore like with any drug, not all 
risks are known. The possible adverse drug reactions may include headache, dizziness, 
fatigue, drowsiness, somnolence, loss of appetite, oral numbness, dry mouth, neck 
pain, feeling strange, depression, lack of taste or changed taste, GI disturbances, 
feeling weak, falls, shakiness, muscle stiffness, unusual dreams, nose bleeds, hot or 
cold flashes, and heartburn. All patients will be closely monitored for adverse events 
during titration and treatment period. Dose and/or frequency may be adjusted as 
appropriate. 
From the study recently published by Devinsky et al, [32] their prominent side effects 
were somnolence (25%), diarrhea (19% at least one episode however only 2% were 
classified as a serious adverse event of diarrhea), weight loss, weight gain, fatigue 
(13%). Status epilepticus was reported in 6% (9 participants) during their study, 
however it is difficult to ascertain whether this was related to therapy or in keeping with 
their inherent risk of status epilepticus due to their refractory epilepsy 
Potential drug interactions may occur as CBD is a potent inhibitor of CYP2B6, CYP2C8, 
CYP2C9, CYP2C19, and CYP3A4. The effects of other concomitant AED and other 
drug levels metabolized by these enzyme systems are not fully known, but it may 
increase their levels leading to potential toxicities. Therefore, AED plasma levels will be 
measured at baseline and at day 28 following first CBD dose. AEDs may be adjusted as 
needed based on signs and symptoms of toxicity and/or changes in drug levels. 
1.7.2 Potential Benefits 

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The potential benefits of this study include the possibility of reduced seizure frequency 
due to the addition of a high CBD low THC whole plant extract option to the patient’s 
current AED regimen. We hope that knowledge gained about high CBD and low THC 
whole plant extract dosing and tolerability during this study will benefit all study 
participants’ quality of life by reducing their seizure frequency. The data from Devinsky 
et al open-label study [32] suggest that CBD might significantly “reduce seizure 
frequency and might have an adequate safety profile in children and young adults with 
highly treatment-resistant epilepsy”. Epidiolex is now an orphan drug in the United 
States to be used for medically refractory childhood onset epilepsy. However, to date 
this compound is not available in Canada. 
 
1.8 Compliance Statement 
This document is a clinical research protocol for a human research study. This study will 
be conducted in accordance with the protocol, applicable Health Canada regulatory 
guidelines, international standards of Good Clinical Practice, and institutional research 
policies and procedures. 
 
2. Study Objectives 
The primary objective is to establish the safe dosing and tolerability of TIL-TC150, a 
CBD rich cannabis plant extract administered as an oral solution for children with severe 
refractory epilepsy. Dosing safety will be measured by blood work evaluation of renal, 
hematologic and hepatic function and of AED levels, by parent/caregiver report, by 
physician assessment, and by assessing caregiver reported tolerability and the 
Pediatric Epilepsy Side Effects Questionnaire (PESQ).   
As secondary measures we will also assess: 

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1. The impact of therapy on quality of life using the Quality of Life in Childhood 
Epilepsy (QOLCE) questionnaire and on everyday behaviours using the Vineland 
Adaptive Behavior Scales, Second Edition. 
2. Change in seizure frequency from baseline using the following measures: 
Parent-reported seizure diary 
24 hour Ambulatory EEG study (measurements: (a) percentage change in 
electrographic seizure frequency and (b) using spike detection software we will 
measure the percentage change in interictal activity during the recording) 
Number of episodes of Status Epilepticus – defined as convulsive seizure lasting 
longer than 10 minutes 
Frequency of use of rescue medications (Lorazepam, Midazolam, or Diazepam). 
Number of visits to emergency department / hospitalizations with seizures 
 
 
3. Study Design 
The study is a Phase 1 dosing and tolerability study of TIL-TC150. TIL-TC150 will be 
administered to 20 children with Dravet syndrome by the investigator team who will 
closely follow them for the duration of the study. 
3.1 Pre-intervention period (4 weeks) 
This period is the first four weeks after the patient is enrolled. Once enrolled, the 
participant’s legal guardian will be educated about maintaining a detailed seizure diary 
during this 4 week period to allow baseline analysis of seizure frequency. As an 
objective measure of seizure frequency, during this 4 week period all enrolled 

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participants with undergo a 24 hour ambulatory EEG study to also assess ictal and 
interictal epileptiform activity.  
3.2 Intervention period (20 weeks) 
Following the pre-intervention assessment of baseline seizure frequency, the participant 
will commence TIL-TC150 product. The initial dose is 2mg/kg/day CBD divided twice 
daily with weekly titration as described below in section 5. Study treatment will be 
increased each week as tolerated by 2mg/kg/day CBD. Week 8 should be the last 
increase if the participant increases by this schedule. The maximal dose is 
16/mg/kg/day CBD.  
During this time there will be regular communication and clinic visits with the 
investigator team, as detailed in section 5. Once 16 weeks of therapy have been 
completed, participants will enter a 4 week interim analysis period, during which time 
they continue the TIL-TC150 at an unchanged does and a 4 week seizure diary and a 
24 hour ambulatory EEG recording will be performed and compared with the pre-
intervention seizure frequency. 
This primary outcome data regarding safety, tolerability, dosing and secondary seizure 
outcomes will be reported at this time point. 
3.3 Longitudinal safety and tolerability (44 weeks) 
For those participants who chose to continue TIL-TC150 therapy after the initial 
intervention period, they will be followed by the investigator team in clinic at 3 monthly 
intervals to assess for any tolerability and safety issues that arise with more prolonged 
therapy. They will be followed to 64 weeks.  
Once the participant is stable on the therapy the frequency of visits and phone calls may 
be reduced at the discretion of the investigator team in conjunction with discussion with 
participant family. 
3.4 Primary Study Endpoint 

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The primary endpoint is establishing the maximal safely tolerated dose of TIL-TC150 in 
our study population. 
 
4. Selection and Withdrawal of Participants 
4.1 Inclusion Criteria 
Participants selected for the study must meet the following criteria: 
1. Age between 12 months and 18 years 
2. Parent/ legal guardian informed consent obtained 
3. Clinical and EEG (sleep recording within 12 months of study enrollment) 
characteristics of Dravet Syndrome and confirmatory genetic mutation result  
4. Medication-resistant epilepsy – with failure to achieve seizure control with at least 
2 appropriate AEDs at therapeutic doses 
5. Clinically apparent seizures (excluding myoclonic and absence) occurring at least 
twice per week 
6. Agreed diary compliance and clinical compliance with current prescribed therapy 
7. Concomitant AED medication dosing stable during 4 week pre-intervention 
period. Ketogenic diet regime and VNS device settings must be stable for 3 
months prior to pre-intervention period. 
8. Ability to tolerate administration of medication orally or via percutaneous feeding 
tube (PEG). 
9. Negative urinary pregnancy test for all female participants of child bearing age 

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10. Was never on Cannabinoid therapy or have not been treated with Cannabinoid 
products for at least last 60 days (confirmed by negative urine test for 
Tetrahydrocannabidiol (THC), only for those who had been treated with CBD). 
4.2 Exclusion Criteria 
Children may not be included in the study if: 
1. Under 12 months, over 18 years 
2. Co-morbid renal, liver or cardiac disease 
3. Any evidence of underlying inborn error of metabolism (mitochondrial disease) 
4. No clinically apparent seizures, or less than 1 per week 
5. Previous significant drug reaction (i.e. Stevens Johnson Syndrome, Significant 
angioedema causing airway compromise) 
6. Any known or suspected family history of schizophrenia or other psychotic 
illness, or known schizophrenia in a first degree relative 
7. Known sensitivity or allergic reaction to cannabinoids. 
8. Currently taking any Cannabinoid products. 
9. Any planned surgical or other intervention or travel during the intervention period. 
10. Any inability to understand/speak English. 
 
4.3 Recruitment 
20 participants will be recruited by the study investigators from their epilepsy clinics at 
The Hospital for Sick Children.  During a routine visit, patients/parents/caregivers that 
meet criteria for the study will be asked if they would like to participate in the study. If 
they are interested in participation then eligibility will be assessed using our inclusion 

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and exclusion criteria. Patients who have previously been treated with a Cannabinoid 
product, must have stopped taking it at least 60 days before enrolment, and they will be 
asked for a urine test (5-10 ml) to assess for the presence of Tetrahydrocannabidiol 
(THC) in urine. A negative urine test for THC will confirm their eligibility to the study. 
There is published clinical trial evidence for epidiolex (a cannabinoid product) as an 
anti-epileptic agent, and Health Canada approved Cannabinoid product use over a year 
ago, therefore many families have tried this product, and it is not feasible to expect CBD 
naïve participants, nor is it necessary. A washout period is sufficient. A wash out period 
of 60 days allows for all of the administered cannabinoid products to be eliminated from 
the participant’s body.  All genders and ethnicities will be included between ages of one 
and eighteen years. The physician will explain the study during the routine visit. If the 
patient/parent/caregiver agrees, they will be given the informed consent documents to 
read and sign. Only the Principal Investigator, Sub-Investigators, and other research 
personnel listed on the study will have access to participant’s research files. 
4.4 Withdrawal from the study 
4.4.1 When and How to Withdraw 
Study participant may withdraw or be withdrawn from the study at any time if the 
participant, parent/caregiver, or Investigators feel it is not in the participant’s best 
interest to continue. Study participation may be discontinued in the following 
circumstances: 
1. Parent/ legal guardian withdrawal of consent 
2. Participant non-compliance with study procedures  
3. Serious adverse events, including significant toxicity, impaired liver or renal 
function, or impaired hematopoeisis 
4. Exacerbation of seizures not attributable to another factor 

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5. Interaction with participant concomitant AED regimen causing unacceptable 
toxicity 
Once the study withdrawal is decided, the termination of treatment is determined 
based on reason for withdrawal. For example if participant has a severe allergic 
reaction with rapidly progressive rash the treatment would be abruptly stopped, 
whereas if the participant experiences excessive somnolence, the treatment may be 
withdrawn in a gradual way. This determination will be made on an individual basis 
by study team in consultation with participant and participant’s parent/caregiver. 
4.4.2 Data Collection  
For all participants who withdraw from the study we will invite them to attend a clinic 
evaluation within 4 weeks of withdrawal +/- 2 weeks. During this visit we will document: 
their dose reached, reasons for withdrawal, adverse events, seizure diary and PESQ 
will be assessed, patients will have a physical and neurological examination and AED 
trough levels and routine bloodwork (CBC, LFT, Renal profile). 
4.4.3 Replacement  
Participants will not be replaced following withdrawal in the study 
4.4.4 Follow-up  
Every participant will be followed closely throughout the study and if a withdrawal occurs 
contact will be made with participant and they will be invited to attend a final clinic visit 
as described above. If the participant cannot be contacted after 4 phone calls, a letter 
requesting the participant’s parent / legal guardian to contact the study investigator 
team will be sent to participant household. 
 
 
 

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5. Study Treatment 
5.1 Study Drug 
Tilray TIL-TC150 is formulated with THC and CBD in grape seed oil at strengths of 2 
mg/ml and 100 mg/ml, respectively. The product is formulated with standard 
pharmaceutical excipients.  The active ingredients in TIL-TC150 Oil are THC and CBD, 
present in a 1:50 ratio. These active ingredients are derived from Cannabis sativa L. 
strains produced by Tilray, a federally-licensed producer and distributor of medical 
cannabis under Health Canada’s Marijuana for Medical Purposes Regulations. The 
details of extraction and formulation are laid out in the Tilray investigators brochure (part 
of submission) 
 
5.2 Treatment Regimen 
Each participant will start the treatment with a dose of 2mg/kg/day CBD given in two 
equal doses each day. The first dose will be given during the Baseline (Week 0) visit. 
Following this dose the participant will be observed by study personnel for a period of 2 
hours. The participant’s parent/legal guardian will increase the participant’s dose by 
2mg/kg/day CBD every 7 days as tolerated, to a maximal dose of 16mg/kg/day CBD. 
Once optimal dose is determined for each participant they may continue the treatment 
for the duration of study follow-up and thereafter it will be continued if wished by 
participants. 
5.3 Concomitant treatments 
Participants will be taking concomitant AED, perhaps 1-4 AEDs. In addition they may 
have a VNS device inserted or be on the ketogenic diet. We require that their current 
regime is stable prior to initiation – 4 weeks for AED and 3 months for VNS and 
ketogenic diet. All concomitant anti-epileptic treatments are to be continued during the 
intervention period. Participants who are currently taking AEDs where trough levels can 

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routinely be assessed, will have levels assessed at interval throughout the study 
intervention period (as per the detailed schedule) to ensure safety.  
5.3 Compliance Monitoring 
Study drug compliance will be assessed by clinic evaluations and the follow-up phone 
calls and emails as outlined in earlier section. In addition we will ask dispensing hospital 
research pharmacist to measure the mls remaining in their bottle of Cannabinoid when 
they return to collect a next prescription. Any participant who is not compliant with the 
study treatment regime will be withdrawn from the study. 
5.4 Enrollment 
All participants meeting inclusion and exclusion criteria will be invited to enroll during a 
clinic visit at The Hospital for Sick Children with the study investigator team. The 
participant’s legal guardian/parent will be given a consent form to read and the study will 
be explained to them by a physician member of the study team. Given the level of 
intellectual impairment associated with Dravet syndrome, we do not anticipate a 
participant will have capacity to consent or assent to participation in the study and thus 
a single parent/legal guardian consent form has been created.   
 
5.5 Pre-Intervention Period (4 weeks) 
Once enrolled, the pre-intervention period begins. Participants will be seen and baseline 
physical and neurological examination performed. Medical information regarding 
seizures, medications, birth and development will also be collected. Participant parent / 
legal guardian will be instructed to keep a daily seizure diary for the next four weeks 
which will be used as a measure of baseline seizure frequency.  Seizure diary will be 
kept by participant’s parent/ legal guardian for the duration of the study follow-up period 
also. Seizure frequency for each seizure type will be recorded at baseline. Seizure 
types will be classified prior to study entry.  

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A. Diary: Seizure frequency and type will be monitored and recorded in a 
participant’s daily diary. Participant’s parent/caregiver will report the seizure 
frequency, type, number of episodes of Status Epilepticus, use of rescue 
medication and attendance to ER/ hospitalizations. 
B. Prolonged EEG study: During the pre-intervention period each participant will 
have a 24 hour ambulatory EEG recording performed to enable objective 
measurement of a 24 hour sample of electrographic activity – ictal and interictal, 
which will be reported by a certified experienced Clinical Neurophysiologist who 
is not part of the investigator team. 
C. Vineland Adaptive Behaviour Scale, Second Edition: this is a standardized parent 
interview that will take 20-60 minutes to complete either in person at the clinic or 
by telephone prior to starting the TIL-TC150. The interview will also be completed 
again at the primary evaluation period (week 16-20) and again during the 
longitudinal follow-up (52-64 weeks). This will be done by a clinical research 
assistant, under supervision of a clinical neuropsychologist (Dr. K Sinopoli, 
CPsych). Parents will be provided with a research report detailing the 
assessment findings at study completion. 
5.6 Intervention Period – and Primary Evaluation (20 weeks) 
Week 0: (Baseline): A neurological and physical exam (including measurement of vital 
signs) will be performed and the participant will be weighed. The parent / legal guardian 
will complete the QOLCE. During this visit their seizure diary will be evaluated and 
bloodwork will be performed for baseline measures (Complete blood count, LFT (AST 
ALT, gamma GT, bilirubin), renal profile (electrolytes, creatinine and urea), and AED 
trough levels). The participant’s parent/legal guardian will be instructed on dosing and 
twice daily administration of TIL-TC150. Each participant will start TIL-TC150at an initial 
dose of 2mg/kg/day CBD in 2 equally divided doses, this will be added to their current 
anti-epileptic drug therapy regimen. They will be advised to increase the dose of the 
study treatment after 7 days by 2mg/kg/day CBD. The study pharmacist will be present 

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at the first clinic visit to review dosing schedule, administration and pharmacy 
dispensing procedures.  In addition study pharmacist will be available during the study 
period to provide education and support to families. The first dose will be administered 
in clinic and the participant will be observed for a period of 2 hours by study personnel 
to evaluate for any adverse events.   
Week 2: Participant to return to The Hospital for Sick Children. Study treatment 
increased as tolerated by 2mg/kg/day CBD, neurological and physical exam will be 
performed and the participant will be weighed, and seizure diary evaluated. Medical 
history including concomitant medications will be reviewed. The Pediatric Epilepsy Side 
Effect Questionnaire (PESQ) will be completed by participant’s parent/legal guardian to 
assess for any adverse events and tolerability. 
Week 4: Participant to return to The Hospital for Sick Children. Study treatment 
increased as tolerated by 2mg/kg/day CBD, neurological and physical examination will 
be performed, weight recorded, seizure diary evaluated. Bloodwork performed (CBC, 
LFT, Renal profile, AED trough levels). Medical history including concomitant 
medications will be reviewed. The Pediatric Epilepsy Side Effect Questionnaire (PESQ) 
will be completed by participant’s parent/ legal guardian to assess for any adverse 
events and tolerability. 
Week 8: Participant to return to The Hospital for Sick Children. Study treatment 
increased as tolerated by 2mg/kg/day CBD, neurological and physical examination will 
be performed, weight recorded, seizure diary evaluated. Medical history including 
concomitant medications will be reviewed. If at maximally tolerated study treatment 
dose as determined by study team, then bloodwork will be performed (CBC, LFT, and 
Renal profile and trough AED levels) and QOLCE completed by caregiver/parent. The 
Pediatric Epilepsy Side Effect Questionnaire (PESQ) will be completed by parent/legal 
guardian to assess for any adverse events and tolerability. 
Week 12: Participant to return to The Hospital for Sick Children for clinical evaluation, 
which includes an interview to assess current clinical condition, any participant, parent/ 

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legal guardian concerns related to TIL-TC150and assess for any adverse effects and 
tolerability by interview. A neurological and physical examination will be performed, 
weight recorded, seizure diary evaluated. Medical history including concomitant 
medications will be reviewed. Participant should be on maximal dose of 8mg/kg/day or 
max tolerated dose now, or on maximally tolerated dose (as determined by study team). 
If at maximally tolerated study treatment dose as determined by study team, then 
bloodwork will be performed (CBC, LFT, and Renal profile and trough AED levels). The 
Pediatric Epilepsy Side Effect Questionnaire (PESQ) will be completed by participant 
parent / legal guardian to assess for any adverse events and tolerability. 
Week 16: Participant to return to The Hospital for Sick Children for clinical evaluation, 
neurological and physical examination will be performed, weight recorded, and seizure 
diary will be evaluated. Medical history including concomitant medications will be 
reviewed.  If target dose only reached at this stage blood work to be done now, if 
previously performed at target or maximally tolerated doses no need to repeat. The 
Pediatric Epilepsy Side Effect Questionnaire (PESQ) will be completed by participant 
parent/legal guardian to assess for any adverse events and tolerability and QOLCE 
completed by caregiver/parent between weeks 16 – 20. In addition, the family will be 
contacted by clinical psychology to complete a follow-up Vineland adaptive behaviour 
assessment to measure any changes in behaviour. 
Between week 16 and 20 an ambulatory EEG study will be performed at maximal study 
treatment doses and the completed seizure diary will be collected.  
5.7 Longitudinal safety and tolerability phase (44 weeks) 
This is a continuation of the study beyond the initial 20-week intervention to continue to 
assess participants who chose to continue with TIL-TC150therapy beyond the primary 
analysis period.  
Week 28: Participant to return for clinical evaluation (including physical and neurological 
examination) as they have decided to continue TIL-TC150. Their dose will be 
16mg/kg/day CBD divided twice daily or their individual maximally tolerated dose during 

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the intervention period. Their seizure diary will be reviewed. The Pediatric Epilepsy Side 
Effect Questionnaire (PESQ) will be completed to assess for any adverse events and 
tolerability and QOLCE completed by caregiver/parent. 
Week 40: Participant to return for clinical evaluation (including physical and neurological 
examination) and seizure diary reviewed. The Pediatric Epilepsy Side Effect 
Questionnaire (PESQ) will be completed by participant parent/legal guardian to assess 
for any adverse events and tolerability. Bloodwork will be performed once to check 
CBC, LFT, and Renal profile and trough AED levels during weeks 40-64. 
Week 52: Participant to return for clinical evaluation (including physical and neurological 
examination) and seizure diary reviewed. The Pediatric Epilepsy Side Effect 
Questionnaire (PESQ) will be completed by participant parent/ legal guardian to assess 
for any adverse events and tolerability and QOLCE completed by caregiver/parent. 
Bloodwork will be performed to check CBC, LFT, and Renal profile and trough AED 
levels. If the blood work is done at week 40, then no need to repeat. 
Week 64: Participant to return for clinical evaluation (including physical and neurological 
examination) and seizure diary reviewed. The Pediatric Epilepsy Side Effect 
Questionnaire (PESQ) will be completed to assess for any adverse events and 
tolerability by caregiver/parent. For families who choose to continue therapy for the 
longer term, they will be invited to complete a Vineland assessment during 52-64 weeks 
by the psychology team in our study to measure any changes in behaviour. Bloodwork 
will be performed to check CBC, LFT, and Renal profile and trough AED levels. If the 
blood work is done at week 40 or 52, then no need to repeat. 
After this time point participants will resume care with their regular pediatric neurologist. 
Written communication regarding their therapy and current dosing will be forwarded by 
the study investigators to this physician. In addition, the study team will be available by 
telephone or email to provide support to physicians as participants’ transition back to 
their care; in particular should they have any questions about TIL-TC150.  

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For the weeks of the study that the participants are not being evaluated in person at The 
Hospital for Sick Children, follow-up emails and/or phone calls will be made. This 
communication will occur in between the clinical visits for the intervention period - week 
1, 3, 5, 6, 7, 10, 14, and 18. Participant’s parent/ legal guardian will be asked about their 
child’s dosage to ensure correct titration or if already at maximal study protocol dose (as 
determined during the intervention period) how they are tolerating it. Adverse events 
and concomitant medications will always be assessed and any concerns participant, 
parent/caregiver may have will be addressed. 
The study participant will be given a window of +/- 3 days around the timing of each 
study visit during the intervention period and +/- 14 days for the post-intervention 
longitudinal visit scheduling. 
 
5.8 Schedule of Events table: 
Study 
Period 
Week # 
Participant/ study team interaction 
TIL-TC150Dose 
Pre-
Intervention 
Period 
-4 
 
Clinic visit – education, baseline physical and 
neurological review and urine test for THC for 
those only who have not been on 
cannabinoids for at least last 60 days. 
None 
Baseline 
analysis 
-4 to 0 
Participant parent/legal guardian completion 
of seizure diary; 24 hour ambulatory EEG, 
psychologist will arrange for parent/caregiver 
to complete a Vineland assessment 
None 
Intervention 
period 
0 
Clinic visit – education, weight, physical and 
neurological review; baseline bloodwork; 
collection of baseline seizure diary; education 
regarding dosing of study product; parent to 
complete baseline QOLCE 
Starting at 2mg/kg/day CBD 
divided in 2 equal doses; first 
dose given in clinic with 2 
hours of observation post-
dose. 
1 
Telephone and/ or email contact by study 
team to determine dosing and tolerability 
Once tolerance ensured, 
increase dose to 4mg/kg/day 
CBD divided twice daily 

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2 
Clinic visit – tolerance review, adverse 
events,; physical and neurological exam; 
parent/legal guardian to complete PESQ; 
seizure diary review 
Once tolerance ensured, 
increase to 6mg/kg/day CBD 
divided twice daily  
3 
Telephone and/ or email contact by study 
team to determine dosing and tolerability 
Once tolerance ensured, 
increase to 8mg/kg/day CBD 
divided twice daily 
4 
Clinic visit – tolerance review, adverse 
events; physical and neurological exam; 
parent/legal guardian to complete PESQ; 
seizure diary review; bloodwork 
Once tolerance ensured, 
increase to 10mg/kg/day CBD 
divided twice daily 
5 
Telephone and/ or email contact by study 
team to determine dosing and tolerability 
Once tolerance ensured, 
increase to 12mg/kg/day CBD 
divided twice daily 
6 
Telephone and/ or email contact by study 
team to determine dosing and tolerability 
Once tolerance ensured, 
increase to 14mg/kg/day CBD 
divided twice daily 
7 
Telephone and/ or email contact by study 
team to determine dosing and tolerability 
Once tolerance ensured, 
increase to 16mg/kg/day CBD 
divided twice daily 
8 
Clinic visit – tolerance review, adverse 
events; physical and neurological exam; 
parent/legal guardian to complete PESQ and 
QOLCE; seizure diary review; bloodwork 
performed once child is at target / maximal 
tolerated dose (any stage from week 8-16) 
If tolerated, dose to continue 
at 16mg/kg/day CBD divided 
twice daily  
10 
Telephone and/ or email contact by study 
team to determine dosing and tolerability 
If tolerated, dose to continue 
at 16mh/kg/day CBD divided 
twice daily 
12 
Clinic visit – tolerance review, adverse 
events; physical and neurological exam; 
parent/legal guardian to complete PESQ; 
seizure diary review; bloodwork performed 
once at target / maximal tolerated dose (if 
not done previously) 
If tolerated, dose to continue 
at 16mg/kg/day CBD divided 
twice daily 
14 
Telephone and/ or email contact by study 
team to determine dosing and tolerability 
If tolerated, dose to continue 
at 16mg/kg/day CBD divided 
twice daily 

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16 
Clinic visit – tolerance review, adverse 
events; physical and neurological exam; 
parent/legal guardian to complete PESQ and 
QOLCE; seizure diary review; bloodwork 
performed once at target / maximal tolerated 
dose (if not done previously) 
If tolerated, dose to continue 
at 16mg/kg/day CBD divided 
twice daily 
Primary 
Analysis 
16-20 
Telephone and/ or email contact by study 
team at 18 weeks to determine dosing and 
tolerability 
Psychologist will arrange for parent/caregiver 
to complete a Vineland assessment 
Participant parent/legal guardian completion 
of seizure diary during this 4 weeks; 24 hour 
ambulatory EEG. Collection of seizure diary 
reported seizure frequency. 
If tolerated, dose to continue 
at 16mg/kg/day CBD divided 
twice daily 
 
 
20 
If tolerated, and participant parent/legal guardian wishes to continue study 
product dose to continue at 16mg/kg/day CBD divided twice daily 
 
 
Longitudinal 
follow-up 
period 
28 
Clinic visit – tolerance review; physical and 
neurological exam; parent/legal guardian to 
complete PESQ and QOLCE; seizure diary 
review; 
If tolerated, and participant 
parent/legal guardian wishes 
to continue, dose to continue 
at 16mg/kg/day CBD divided 
twice daily 
40 
Clinic visit – tolerance review; physical and 
neurological exam; parent/legal guardian to 
complete PESQ; seizure diary review; 
Follow up bloodwork performed once (any 
stage from week 40-64) 
If tolerated, and participant 
parent/legal guardian wishes 
to continue, dose to continue 
at 16mg/kg/day CBD divided 
twice daily 
52 
Clinic visit – tolerance review; physical and 
neurological exam; parent/legal guardian to 
complete PESQ and QOLCE; seizure diary 
review; 
Follow up blood work performed once (if not 
done previously) 
During 52-64 weeks psychologist will arrange 
for parent/caregiver to complete a Vineland 
If tolerated, and participant 
parent/legal guardian wishes 
to continue, dose to continue 
at 16mg/kg/day CBD divided 
twice daily 

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assessment 
64 
Clinic visit – tolerance review; physical and 
neurological exam; parent/legal guardian to 
complete PESQ; seizure diary review 
 
Follow up blood work performed once (if not 
done previously) 
 
If tolerated, and participant 
parent/legal guardian wishes 
to continue, dose to continue 
at 16mg/kg/day CBD divided 
twice daily 
 
NB*  At all periods during the study there will be study personnel available 24 hours 
through the main hospital switch board by telephone pager system for participant, 
parent/legal guardian should they have any concerns or queries out of hours or outside 
of these contact times. 
NB Should clinical concern arise during reviews about potential toxicity (clinical 
evidence of accentuated AED action such as somnolence, change in mentation 
etc), a further blood draw may be performed to evaluate trough AED level (for 
AED where trough routinely assessed). 
6. Assessment of Efficacy 
6.1 Specification of Efficacy Parameters 
This is a phase 1 dosing and tolerability study. Efficacy of CBD is not a primary 
outcome. However, as a secondary outcome we will report change in seizure frequency, 
severity by parent/caregiver reporting and change in EEG by objective prolonged 24 
hour recording prior to and at maximal dose of intervention.  
6.2 Methods of Assessing 
Seizure frequency is measured by parent/caregiver in a daily diary. This will be 
reviewed at each clinic visit and during each phone call/email to track change and 
ensure compliance with reporting. Seizure severity will be measured by frequency of 

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rescue medication administration, frequency of status epilepticus and frequency of ER 
attendance /hospitalization, recorded in a daily diary. In addition to this baseline 
analysis of EEG will be performed for each participant using an ambulatory EEG 
recording for 24 hours. Pre-intervention ictal and interictal EEG patterns will be 
compared with a post-intervention study (once maximal dose of treatment has been 
achieved). EEG analysis will be performed by 2 board certified 
electroencephalographers (part of the study team) at the end of the primary intervention 
period.  They will report all EEG studies blinded to whether the recording is performed 
pre- or post therapy. They will record the number of electrographic seizures during the 
study and use spike detection software to provide an objective measure of the 
percentage of interictal activity during each study. 
7. Assessment of Safety and Adverse Events 
7.1 Specification of Safety Parameters 
Each participant will be carefully screened for suitability prior to commencement of the 
intervention. If the study team feels that any pre-existing conditions place the participant 
at risk they will be excluded from participation. Once enrolled in the study each 
participant and parent/legal guardian will receive education regarding the administration, 
dosing and schedule of the study treatment from the study investigator physician, study 
nurse and the study pharmacist. This information will be reviewed and dosing schedule 
re-evaluated at every clinic visit and phone call / email follow up. During each clinic visit 
there will be an evaluation of tolerability of the study treatment and of possible adverse 
events.   
If at any stage during the study any adverse events are suspected they will immediately 
be evaluated by study team. The adverse event reporting period is from the initiation of 
the study treatment until the end of study treatment follow-up. 
An adverse event is any symptom, sign, illness or experience that develops or worsens 
in severity during the course of the study. Intercurrent illness or injuries should be 
regarded as adverse events. Abnormal results of diagnostic procedures are considered 

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adverse events, if the abnormality leads to study withdrawal, is associated with clinical 
signs or symptoms, leads to additional treatment or diagnostic tests, is considered by 
the study team to be of clinical significance or is considered a serious adverse event.  
 
A serious adverse event is one which is:  
• fatal 
• life-threatening 
• requires hospitalization or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event (not immediately life-threatening but of significant clinical 
importance) 
All adverse events that do not meet the criteria for seriousness should be considered 
non-serious adverse events. 
 
7.2 Methods of assessing 
During the intervention period and follow-up there will be regular clinic review and 
telephone/email evaluation of the participant to assess tolerability of the study treatment 
and screen for any adverse events. This will be done by direct questioning of 
participant, parent/caregiver at each review. In addition the study team will perform a 
physical and neurological examination of participant at each clinic review. Every clinic 
visit we will ask parent/ caregiver to complete a side effect questionnaire (PESQ 
questionnaire) and study team will review the daily seizure diary. In addition at regular 

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intervals during the study the participant will have bloodwork to evaluate hematopoeisis, 
liver and renal function and trough AED levels.  
7.3 Recording Procedures 
At each contact with study participant the study team will evaluate for potential adverse 
events as specified above. Information on all adverse events will be recorded 
immediately in source document (medical chart) and in the specific adverse event case 
report form (CRF). All relevant symptoms, signs, and abnormal diagnostic tests will be 
recorded in the source documents also. 
 
 
7.4 Reporting Procedures 
Adverse Event Reporting to the SickKids REB and to Health Canada 
All adverse events will be reported to The Hospital for Sick Children Research Ethics 
Board according to The Hospital for Sick Children’s Adverse Event Reporting 
Requirements. All serious, unexpected adverse drug reactions (S-UADR) will be 
reported to Health Canada within 15 calendar days or for death or life‐threatening 
events, within 7 calendar days. In the latter case, a follow‐up report must be filed within 
8 calendar days. Adverse reactions will be managed according to The Hospital for Sick 
Children’s standard clinical management practices. Each ADR which is subject to 
expedited reporting should be reported individually in accordance with the data 
element(s) specified in the Health Canada/ICH Guidance Document E2A: Clinical 
Safety Data Management Definitions and Standards for Expedited Reporting. 
 
7.5 Adverse Event Follow-up 
The clinical course of each adverse event encountered will be followed by the study 
team until resolution, stabilization, or until determined that study participation is not 

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causative. Serious adverse events that are ongoing at the end of the study period will 
continue to be followed until they are either resolved, or in the opinion of the Principal 
Investigator, the participant is medically stable and does not require further follow-up or 
the participant is deemed lost to follow-up. Any serious adverse event that occurs after 
the intervention period, but is deemed by the study team as possibly related to 
participation will be recorded and reported also.  
 
8. Statistics 
8.1 Statistical Method 
This is an observational study. The primary aims of this study are to determine the 
tolerability of the study treatment in a cohort of children with mediation resistant epilepsy 
due to Dravet syndrome. As such, there are no formal statistical methods required, 
rather descriptive statistics will be presented to quantify dosing tolerability and 
frequency of adverse events. All participants will be analyzed regardless of dose 
achieved or duration of study completed, according to intention to treat analysis. The 
study data will be entered into the REDCap database for analysis. 
 8.2 Sample Size 
No sample size calculation was employed. An intermediate sample size of convenience 
is selected, with 20 participants expected to be recruited from a single site. 
 
9. Source Data/Documents Access 
The study investigator team will permit trial-related monitoring, audits, REB review, and 
regulatory inspections, providing direct access to source data/documents.  
 
 

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10. Quality Control Procedures 
The study pharmacist will oversee the dispensing of the study treatment to the 
participant parent/caregiver and keep documentation of this. Study investigators will 
document all clinical details throughout the study in CRFs and in source documentation. 
Principal investigator will make time to review the documentation, source documentation 
and ensure that it is readily available for any reviewing agency at any time. In addition 
study investigator team will ensure confidentiality is maintained throughout the data 
process. This will be overseen by study Principal Investigator as detailed below.   
 
11. Study Ethics 
This study is conducted in accordance with applicable Health Canada regulations and 
international standards of Good Clinical Practice, and applicable institutional policies 
and procedures. 
12. Data Handling and Record Keeping 
12.1 Confidentiality 
Study participant medical information will be recorded for this study. Any participant 
identifier information and personal health information will be stored in a locked filing 
cabinet in a locked office at The Hospital for Sick Children and only the investigational 
team will have access to this.  
12.2 Data Storage 
Relevant study records will be archived for 25 years following completion of the study, 
as per the requirements of Health Canada’s Food & Drug Act, Division 5.   
13. Trial Registration 
This trial will be registered with the U.S. National Institutes of Health ClinicalTrials.gov, 
which is a registry of federally and privately supported clinical trials conducted in the 

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United States and around the world. The registration will not include any identifiable 
participant data.  
14. Publication policy 
On completion of the study the enrolled participant data will be reported and this report 
submitted for publication in an appropriate medical journal.  

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