Conditions: Infantile Spasm
Keywords: Infantile spasm Vigabatrin Cannabidiol oral solution
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 2
Healthy volunteers: no

Brief summary:
The primary purpose of this study was to evaluate the efficacy, safety, and tolerability of Cannabidiol Oral Solution (CBD) as adjunctive therapy with vigabatrin as initial therapy, compared to vigabatrin alone in the treatment of infants newly diagnosed with Infantile Spasms (IS).

Detailed description:
This was a randomized, double-blind, placebo-controlled, parallel-group study in which participants were randomized in a 1:1 ratio to 1 of 2 treatment groups. During the Initial Treatment Period, participants received either vigabatrin plus CBD or vigabatrin plus matching placebo and were dosed approximately every 12 hours, with a meal. This study was comprised of five periods: Screening, Initial Treatment, Extended Treatment, Taper, and Follow up Periods, with a maximum duration of approximately 140 days.

Arms:
arm 1: Participants received up to 40 milligrams per kilogram per day (mg/kg/day) divided twice daily (BID) of CBD with food. Participants also received up to 150 mg/kg/day BID of vigabatrin with food. arm 2: Participants received a matching placebo to CBD with food, and also received up to 150 mg/kg/day BID of vigabatrin with food.

Interventions: intervention 1: Cannabidiol Oral Solution intervention 2: Placebo intervention 3: Vigabatrin
Intervention descriptions: intervention 1: An oral solution containing pharmaceutical grade cannabidiol (nonplant-based). intervention 2: Matching oral solution intervention 3: Powder suspension

Protocol document:
Prot_000.pdf: 
Insys Development Company, Inc. 
Protocol Number INS011-16-082 
CLINICAL TRIAL PROTOCOL 
A Phase 3 Randomized, Double-Blind, Placebo-Controlled, Parallel-Group 
Study to Assess the Efficacy, Safety, and Tolerability of Cannabidiol Oral 
Solution as Adjunctive Therapy with Vigabatrin as Initial Therapy in 
Patients with Infantile Spasms 
Protocol Number: INS011-16-082 
Final Protocol Date: 
Amendment 1 Date: 
Amendment 2 Date: 
12 Jan 2018  
22 Feb 2018 
05 Jul 2018 
Protocol Version: 5.0 
Investigational Product: Cannabidiol Oral Solution 
IND Number: 
EudraCT Number: 
123120 
2018-001523-40 
Sponsor: Insys Development Company, Inc. 
1333 South Spectrum Blvd, Suite 100 
Chandler, AZ 85286 
Medical Monitor: 
 
Insys Development Company, Inc. 
 
Phone: 
 
Fax: 
 
Confidentiality Statement 
This study will be performed in compliance with Good Clinical Practices (GCP) and applicable regulatory 
requirements. The confidential information in this document is provided to you as an investigator, 
potential investigator or consultant for review by you, your staff and applicable Independent Ethics 
Committee (IEC) or Institutional Review Board (IRB). It is understood that the information will not be 
disclosed to others without written authorization from Insys Development Company, Inc., except to the 
extent necessary to obtain informed consent from those persons to whom the drug may be administered. 
NCT#: NCT03421496


10 July 2018


Insys Development Company, Inc.  
 
 
Protocol Number INS011-16-082 
05 Jul 2018 
CONFIDENTIAL  
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PROTOCOL SYNOPSIS 
Name of Sponsor/Company: 
Insys Development Company, Inc. 
Name of Investigational Product: 
Cannabidiol Oral Solution 
Name of Active Ingredient: 
Cannabidiol 
Title of Study:  
A Phase 3 Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Assess the 
Efficacy, Safety, and Tolerability of Cannabidiol Oral Solution as Adjunctive Therapy with Vigabatrin 
as Initial Therapy in Patients with Infantile Spasms 
Study center(s): Approximately 40 sites in the US and ex-US. 
Phase of development: Phase 3 
Objectives: 
Primary 
• To evaluate the efficacy of Cannabidiol Oral Solution as adjunctive therapy with 
vigabatrin as initial therapy in treating patients with Infantile Spasms.  
Secondary 
• To evaluate the continued efficacy of Cannabidiol Oral Solution after the 14-day 
treatment with vigabatrin or vigabatrin plus Cannabidiol Oral Solution is complete. 
• To evaluate the safety and tolerability of Cannabidiol Oral Solution as adjunctive 
therapy with vigabatrin as initial therapy in treating patients with Infantile Spasms. 
Methodology: 
This is a Phase 3, double-blind, placebo-controlled, randomized, multicenter study to evaluate 
the efficacy, safety, and tolerability of Cannabidiol Oral Solution (CBD) as adjunctive therapy 
with vigabatrin as initial therapy, compared to vigabatrin alone in the treatment of infants 
newly diagnosed with Infantile Spasms (IS). Randomization will occur during Visit 2 to one 
of two treatment groups:  
• Treatment with vigabatrin plus  
o CBD 40 mg/kg/day, or 
o Matching CBD 40 mg/kg/day placebo  


Insys Development Company, Inc.  
 
 
Protocol Number INS011-16-082 
05 Jul 2018 
CONFIDENTIAL  
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Approximately 190 patients in total will be enrolled into one of the two treatment arms; 130 
patients in the investigational product arm with 60 patients in the placebo arm. Patients will be 
dosed approximately every 12 hours with meals to help ensure consistent plasma levels are 
achieved and to reduce variability.  
Doses of CBD exceeding 40 mg/kg/day will not be examined in this study. In addition to the 
safety assessments required by the study protocol, the investigator will monitor patients 
throughout the study as recommended in the current approved product label for vigabatrin. 
Study participants will be newly diagnosed pediatric patients age 1 to 24 months (inclusive) 
experiencing infantile spasms who satisfy all inclusion/exclusion criteria. This study will be 
comprised of five periods: Screening, Initial Treatment, Extended Treatment, Taper, and 
Follow-up Periods, with a maximum duration of approximately 140 days.  
Screening Period:  
Each newly diagnosed patient with Infantile Spasms will complete a Screening Period and will 
have up to 14 days to enroll in the study.  
Patients will have a minimum of a 9-hour video-EEG that includes at least one full sleep-wake 
cycle during their Screening Visit to establish their baseline level of infantile spasms and 
hypsarrythmia and a 24-hour video-EEG at Visit 5 (Day 14) of the Initial Treatment Period to 
establish their final level of infantile spasms and hypsarrythmia. A blinded central reader, not 
involved in the study, will evaluate the video-EEGs and determine responder status.  Details 
of the video-EEG assessment will be provided in the video-EEG Charter. The treatment 
response categories are summarized in Table 1 below. In addition, a 9-hour video EEG will be 
conducted during the Extended Treatment Period to confirm parent/caregiver reports of 
relapse. If possible, a 9-hour video EEG will be conducted for patients who have continued 
into the Extended Treatment Period and decided to Early Withdraw. A video EEG is not 
required for patients who decide to withdraw during the Initial Treatment Period. 
Table 1: Video EEG Response Definitions 
Response Category 
Definition 
Complete Response  
Complete resolution of spasms and hypsarrythmia confirmed 
by video EEG  
Partial Response  
Complete resolution of either spasms or hypsarrythmia 
confirmed by video EEG  
Non-Response 
No improvement or worsening of spasms/hypsarrythmia 
burden  
Initial Treatment Period 
• Day 1 (Visit 2): Patients will receive the initial titration dose of vigabatrin 
(50 mg/kg/day divided twice daily [BID]), and either CBD 20 mg/kg/day plus 
matching CBD 20 mg/kg/day placebo or CBD 40 mg/kg/day placebo, each drug 
administered BID for 3 days. 
• Day 4 (Visit 3): Patients will return to the study center to evaluate medical status 
(seizure diary, vital signs, and neurological exam), clinical laboratory assessments, 


Insys Development Company, Inc.  
 
 
Protocol Number INS011-16-082 
05 Jul 2018 
CONFIDENTIAL  
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concomitant medications, height/weight, and assess adverse events (AEs). For those 
patients who tolerate the initial dose, the dose for vigabatrin will be increased to 
100 mg/kg/day (BID), and either CBD 30 mg/kg/day and matching CBD 10 mg/kg/day 
placebo, or CBD 40 mg/kg/day placebo BID for 3 days.  
• Day 7 (Visit 4): Patients will return to the study center to evaluate medical status 
(seizure diary, vital signs, and neurological exam), clinical laboratory assessments, 
concomitant medications, height/weight, and assess AEs.  For those patients who 
tolerate the increased doses, the dose of vigabatrin will be increased to 150 mg/kg/day 
and CBD or CBD placebo to 40 mg/kg/day BID for the remaining 9 days. Vigabatrin, 
CBD, and matching placebo will be administered in a twice daily fashion at 12-hour 
intervals with meals. 
• As part of their standard of care, investigators will assess safety and tolerability of the 
treatment regimens throughout the study period. All subjects will continue treatment 
until confirmation from the central reader on the 24-hour video EEG and clinical 
laboratory results are received. 
Extended Treatment Period 
Following the Initial Treatment Period: 
• Complete Responders will continue receiving their assigned treatments of 
vigabatrin plus either CBD 40 mg/kg/day or matching placebo for 75 days, until 
Week 13 (Day 90) to monitor treatment response.  
• During the Extended Treatment Period, the investigator may reduce the dose of 
CBD or CBD placebo to 30 mg/kg/day for safety or tolerability. If the subjects 
cannot tolerate the 30 mg/kg/day, they will be discontinued from the study 
following the completion of the taper period. 
Partial Responders: 
Partial responders will be offered the opportunity to enroll in an open-label safety study that 
allows investigators to combine standard-of-care treatment with CBD. 
Taper Period 
Following the completion of the Initial Treatment Period (Visit 6), partial responders who do 
not enroll in the open-label safety study and non-responders will have vigabatrin and CBD or 
CBD placebo tapered as follows:  
• Vigabatrin taper: 150 mg/kg/day will be reduced to 100 mg/kg/day for 3 days, then 
the 100 mg/kg/day dose will be reduced to 50 mg/kg/day for 3 days, and then 
discontinued.  
• CBD or CBD Placebo taper: 40 mg/kg/day will be reduced to 30 mg/kg/day for 
three days, then 30 mg/kg/day will be reduced to 20 mg/kg/day for 3 days, and then 
discontinued.  


Insys Development Company, Inc.  
 
 
Protocol Number INS011-16-082 
05 Jul 2018 
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Complete Responders will be tapered off vigabatrin and CBD at the completion of the 
Extended Treatment Period, and all patients will be tapered off at any Early Withdrawal 
Visits, using the same schedules as described above.  
If the investigator decides to continue vigabatrin as a treatment for patients at the end of the 
study or early withdrawal, tapering of vigabatrin will be left to the discretion of the PI. 
CBD requires tapering off at the End of Study or at the Early Withdrawal visit. 
Follow-up Period 
A follow-up phone call will occur for all subjects 30 days after discontinuation of the study 
drug to assess AEs, AETs, and record concomitant medications. 
Study Assessments 
To assess efficacy, a 24-hour video-EEG, daily seizure diaries, meal diary 24 hours prior to 
and through PK blood sampling and investigator Clinical Global Impressions-Global 
Improvement (CGI-I) assessments will be completed and evaluated.  
• A 9-hour video EEG that includes at least one sleep-wake cycle will be completed 
during Screening (Visit 1) and a 24-hour video EEG will be completed Day 14 (Visit 
5) through Day 15 (Visit 6). The EEGs and hypsarrythmia will be evaluated by a 
blinded central reader who is not involved with the study. Further details will be 
provided in the video-EEG Charter.   
• Daily seizure diaries will be completed throughout the Initial and Extended Treatment 
Periods. 
• The CGI-I will be completed by the investigator at Visit 6 of the Initial Treatment 
Period, or at Early Withdrawal. The CGI-S will be completed by the investigator at 
Screening. 
Safety assessments for all patients will include medical history, physical and neurological 
examinations, vital signs (seated or supine blood pressure [depending on patient age and 
ability], pulse rate, temperature, and respiration rate), clinical laboratory testing (hematology, 
chemistry, liver enzymes, and serum bilirubin), prior medication history (assessment of 
past/current AETs and concomitant medications), and AE assessments will be conducted at 
specific visits throughout the study. In addition to the safety assessments required by the study 
protocol, the investigator will monitor patients as recommended in the current FDA-approved 
vigabatrin prescribing information. 
A blood sample for PK analysis of CBD and the metabolite 7-hydoxy-CBD (7-OH-CBD) will 
be obtained on Day 15 prior to the second dose during the 24-hour video-EEG. A meal diary 
will be used to record the type of meals consumed in relation to PK blood draws. 
If a patient discontinues the study prematurely, the investigator’s impression of efficacy and 
tolerability of the study drug, as evaluated by CGI-I, will be assessed and recorded 
immediately before discontinuation. If possible, the parent/caregiver will be encouraged to 
have the patient have an Early Withdrawal video-EEG completed. 


Insys Development Company, Inc.  
 
 
Protocol Number INS011-16-082 
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Number of patients planned: 
Approximately 190 patients (130 patients in the active drug arm and 60 patients in the placebo 
arm).   
Diagnosis and main criteria for inclusion: 
Patients will be male and female patients between 1 and 24 months of age (inclusive), with a 
new clinical diagnosis of Infantile Spasms, confirmed by video-EEG analysis during the 
Screening Period, have adequate renal and hepatic function, and who meet all the inclusion 
and none of the exclusion criteria. Parent(s)/caregiver(s) must be able to understand and 
provide written consent.  
Inclusion criteria   
A patient will be eligible for study participation if the patient meets all of the following 
criteria: 
1. Parent(s)/caregiver(s) fully comprehends and signs the informed consent form, 
understands all study procedures, and can communicate satisfactorily with the 
Investigator and study coordinator, in accordance with applicable laws, regulations, 
and local requirements. 
2. Male or female between 1 month to 24 months of age (inclusive) at time of consent. 
3. Clinical diagnosis of Infantile Spasms, confirmed by video-EEG (including at least one 
cluster of electroclinical spasms [≥3 in any 10-minute epoch] and hypsarrythmia) 
obtained during the Screening Period and read by a central reader. 
4. General good health (defined as the absence of any clinically relevant abnormalities as 
determined by the Investigator) based on physical and neurological examinations, 
medical history, and clinical laboratory values completed during the Screening Visit 
(Visit 1). 
5. In the opinion of the investigator, the parent(s)/caregiver(s) is (are) willing and able to 
comply with the study procedures and visit schedules.  
Exclusion criteria   
A patient must not meet any of the following criteria: 
1. Is considered by the investigator, for any reason (including, but not limited to, the risks 
described as precautions, warnings, and contraindications in the current version of the 
Investigator’s Brochure for Cannabidiol Oral Solution) to be an unsuitable candidate to 
receive the study drug. 
2. Known or suspected allergy to cannabidiol. 
3. History of an allergic reaction or a known or suspected sensitivity to any substance that 
is contained in the investigational product formulation. 
4. Use of any cannabidiol/cannabis product within 30 days of study entry. 
5. Patient is diagnosed or suspected of having tuberous sclerosis. 


Insys Development Company, Inc.  
 
 
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6. Patient has received treatment with either vigabatrin, ACTH, or high-dose steroids 
previously. 
7. Previous or concomitant therapy with felbamate, clobazam, valproic acid, or the 
ketogenic diet. 
8. Patient currently on any disallowed CYP3A4-related medication listed in Appendix 1  
(phenytoin, fluvoxamine, carbamazepine, and St. John’s Wort). 
9. Previously received any investigational drug or device or investigational therapy 
within 30 days before Screening. 
10. Clinically significant abnormal laboratory values, including: liver function tests (LFTs) 
such as albumin, direct bilirubin, total bilirubin, aspartate aminotransferase (AST), and 
alanine aminotransferase (ALT) ≥3 times the upper limit of normal (ULN). The 
investigator may deem the patient eligible if he or she judges the laboratory values to 
be not clinically significant.  
Investigational product, dosage, and mode of administration: 
Cannabidiol Oral Solution, manufactured for and supplied by Insys Manufacturing LLC. 
During the Initial Treatment Period: 20, 30, and 40 mg/kg CBD BID. During the Extended 
Treatment Period: 40 mg/kg CBD BID (or 30 mg/kg if dose is reduced) for Complete 
Responders. 
Duration of treatment: 
The maximum duration of the study from screening to follow-up of AEs will be 
approximately 140 days. 
Reference therapy, dosage, and mode of administration: 
Vigabatrin powder suspension divided twice daily with food, 50 mg/kg/day for 3 days, then 
100 mg/kg/day for 3 days, then 150 mg/kg/day for 9 days.  


Insys Development Company, Inc.  
 
 
Protocol Number INS011-16-082 
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Criteria for evaluation: 
Efficacy 
Primary efficacy endpoint   
• Percent of patients who are considered complete responders, defined as complete 
resolution of spasms and hypsarrhythmia confirmed by 24-hour video EEG from 
Day 14 to Day 15, as determined by the Independent Central Reader. 
Secondary efficacy endpoints   
• Percent of patients with resolution of infantile spasms as assessed by 24-hour 
video EEG from Day 14 to Day 15 (partial response).  
• Percent of patients with resolution of hypsarrhythmia as assessed by 24-hour 
video EEG from Day 14 to Day 15 (partial response). 
• Investigator impression of efficacy and tolerability of study drug (CGI-I) at Visit 6 
(End of Study) or Early Withdrawal. 
• Increase in the number of spasm-free days between Day 1 and Day 15 of the Initial 
Treatment Period, as determined by the seizure diary entries.  
• For patients with a complete response during the Initial Treatment Period who 
continue: percent of patients who relapse during the Extended Treatment Period 
confirmed by video EEG following parent report of relapse, and time to relapse. 
Safety  
The safety endpoints of the study are the incidence of treatment-emergent AEs (TEAEs), 
clinical laboratory assessments, vital signs (blood pressure, pulse rate, respiration rate, and 
temperature), physical and neurological examination assessments, prior and concomitant 
medications, liver enzymes and serum bilirubin. 
Pharmacokinetics 
Trough concentrations (Ctrough) of cannabidiol (CBD) and 7-OH-CBD will be used to assess 
the exposure-response relationship. A meal diary will be used to record the type of meals 
consumed in relation to the PK blood draws. 


Insys Development Company, Inc.  
 
 
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Statistical methods: 
Sample Size Calculation 
A total of 190 patients (130 and 60 patients in the two groups) will provide 80% power with a 
two-sided alpha of 0.05 to detect a difference in response rate, assuming the response with 
vigabatrin alone is 40% and the response with vigabatrin with Cannabidiol Oral Solution is 
60%. 
Analysis Populations 
Statistical analyses will be conducted on the following populations: 
• Safety Population: The Safety Population will include all patients who were treated 
with at least one dose of the study drug. 
• Intent to Treat (ITT) Population: The ITT Population will include all patients who 
were randomized.    
• PK Population: The PK Population will include all patients who were treated with at 
least one dose of the study drug and have at least one usable PK measurement. 
Efficacy Analyses 
The ITT Population will be used for all efficacy analyses in the Initial Treatment Period. 
• For the primary endpoint, a 2-sided Type I error rate of 0.05 will be used.   
• For the secondary efficacy endpoints, to maintain the trial-wise Type I error rate at 
0.05, a fixed sequence multiple comparisons correction with fallback will be used. The 
assignment of alpha levels to hypotheses being tested will be specified in the Statistical 
Analysis Plan. 
• For endpoints that are continuous in nature, the number of observations, mean, median, 
minimum and maximum, and standard deviation (SD) values will be presented as 
descriptive statistics. For inferential statistics, a t-test will be used to compare 
treatment to placebo group.  
• For endpoints that are categorical in nature, frequency, counts, and percentages will be 
presented as descriptive statistics, and a chi-square test will be used for inferential 
statistics. 
Primary Efficacy Analysis 
• Percent of patients with complete resolution of both infantile spasms and 
hypsarrhythmia at Day 15 (complete response) will be compared between vigabatrin 
plus placebo and vigabatrin plus CBD 40 mg/kg/day groups using a chi-square test.     
Secondary Efficacy Analyses 
• Percent of patients who relapse during the Extended Treatment Period will be 
compared between 14-day complete responders receiving vigabatrin + CBD and 
complete responders receiving 14-day vigabatrin + placebo using chi-square test. Time 
to relapse will be described with Kaplan-Meier curves and treatment groups compared 
using a log-rank test. 


Insys Development Company, Inc.  
 
 
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• Percent of patients with complete resolution of infantile spasms at Day 15 will be 
compared between treatment groups using a chi-square test. 
• Percent of patients with complete resolution of hypsarrhythmia at Day 15 will be 
compared between treatment groups using a chi-square test. 
• Investigator impression of efficacy and tolerability of study drug (Clinical Global 
Impression – Global Improvement [CGI-I]) will be compared between treatment 
groups using ANCOVA with baseline CGI-S as a covariate.  
• Reduction in percentage of spasm-free days between the Initial Treatment Period and 
Screening Period will be compared between treatment groups using ANCOVA with 
the Screening Period percent spasm-free days as a covariate.  
Secondary Efficacy Analyses for patients with a complete response during the Initial 
Treatment Period who continue to the Extended Treatment Period: 
• Percent of patients who relapse during the Extended Treatment Period confirmed by 
video-EEG following parent report of relapse.  
• Time to relapse. 
Safety Analyses 
The Safety Population will be used for all safety assessments. All safety assessments will be 
descriptive and no inferential statistics are planned for safety assessments. All data listings 
will be provided for protocol specified safety data.  
• The Medical Dictionary for Regulatory Activities (MedDRA; Version 20.0 or higher) 
will be used to classify all adverse events with respect to system organ class and 
preferred term. Adverse event summaries will include only TEAEs by treatment group.  
• Clinical laboratory findings will be summarized for all patients in the safety population 
for observed values and change from baseline. Shifts from baseline to outside normal 
range criteria will also be presented for all patients in the safety population. 
• Vital signs will be summarized for all patients in the safety population for observed 
values and change from baseline as appropriate. 
• The neurological examination results will be listed and summarized descriptively. 
Shifts from baseline according to normal and abnormal criteria will also be presented 
for all patients in the safety population. 
• Results of physical examinations conducted throughout the study will be presented in 
listings and summarized descriptively. Shifts from baseline according to normal and 
abnormal criteria will also be presented for all patients in the safety population. 
• Prior medication and concomitant medications will be reported in the data listings. 
• Statistical analyses will be performed using SAS® (Version 9.3 or higher, SAS 
Institute Inc.) or R (Version 3.3 or higher, Roswell Park Cancer Institute). 
Pharmacokinetic Analyses 
Exploratory analyses of dose (exposure)-response relationship will be performed.  Further 
population PK approach may be used for PK parameter calculations, as appropriate. 


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Missing Data 
There will be no imputation of the missing values. Patients without a video EEG assessment 
on Days 14-15 will be considered non-responders for all EEG-related endpoints. Percentage of 
spasm-free days will be calculated based on the number of entries (up to 15 days per 
measurement period). A sensitivity analysis may be conducted to assess the impact of the 
missing values on the final analysis.  The sensitivity analyses will be detailed in the SAP. 


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Table 1: 
Schedule of Events 
 
SCREENING 
PERIOD 
INITIAL TREATMENT PERIOD 
EXTENDED TREATMENT 
PERIOD 
 
Taper 
Period 
Follow-
up 
Period 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Early 
Withdrawalm 
6 days 
30 days 
Day 
-14 to -1 
Titration 
Days 1 
Titration 
Day 4 
 
Day 7 
Day 
14a 
Day 15 
EOSb 
(+ 5 
days) 
Week 6 
Week 
10 
Week 
13 
EOSb 
Signed ICF 
X 
 
 
 
 
 
 
 
 
 
 
 
Video-EEG 
Xc 
 
 
 
Xc  Xc 
--------------Xc ---------- 
Xc 
 
 
Review of 
inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Assessment of 
current AETs 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Medical/surgical 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
Seizure Historyd 
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signse 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Clinical Labs 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
 
 
Physical Exam  
X 
 
 
 
 
 
 
 
 
 
 
 
Height/Weight 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Head 
Circumference 
X 
 
 
 
 
X 
 
 
X 
X 
 
 


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SCREENING 
PERIOD 
INITIAL TREATMENT PERIOD 
EXTENDED TREATMENT 
PERIOD 
 
Taper 
Period 
Follow-
up 
Period 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Early 
Withdrawalm 
6 days 
30 days 
Day 
-14 to -1 
Titration 
Days 1 
Titration 
Day 4 
 
Day 7 
Day 
14a 
Day 15 
EOSb 
(+ 5 
days) 
Week 6 
Week 
10 
Week 
13 
EOSb 
Neurological 
Examf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Study Drug Dosing 
 
Xg 
Xh 
 
Xh 
 
Xh 
 
Xi 
Xi 
Xi 
Xi 
Xi 
Xj 
 
Assess AEs 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK blood 
samplingk 
 
 
 
 
 
X 
 
 
 
 
 
 
Investigator CGI-S 
X 
 
 
 
 
 
 
 
 
 
 
 
Investigator CGI-I 
 
 
 
 
 
X 
 
 
 
X 
 
 
Seizure Diaryl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Meal Diaryn 
 
 
 
 
X 
X 
 
 
 
 
 
 
Abbreviations: AE = adverse event; AETs = antiepileptic therapies; CGI-I = Clinical Global Impression-Global Improvement Scale; CGI-S = Clinical Global 
Impression-Severity; EEG = electroencephalography; EOS = End of Study; ICF = informed consent form; PK = pharmacokinetic. 
a Patients will be admitted to the study center as an inpatient on Day 14 and discharged on Day 15 following the completion of End of Study assessments. 
b End of Study assessments will be completed at Day 15 for partial and non-responder patients and Week 13 for patients who complete the extension period of 
the study. 
c Patients will have a minimum of a 9-hour video EEG that includes at least one full sleep-wake cycle during their Screening Visit and a 24-hour video EEG at 
Visit 5 (Day 14 to Day 15) during the Initial Treatment Period. A minimum of 9-hour video-EEG will be performed during the Extended Treatment Period to 


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confirm parent/caregiver report of relapse or complete resolution or at Early Withdrawal for patients who have continued into the Extended Treatment Period. A 
Video EEG is not required for patients who decide to withdraw during the Initial Treatment Period 
d To assess preliminary efficacy, a seizure history will be collected at screening to record the approximate number of seizures in the last 28 days as reported by 
the parent/caregiver. 
e Vital signs will be taken after approximately 5 minutes seated or supine, depending on patient ability. On Day 1(Visit 2), vital signs should be taken predose and 
at 4 hours postdose. On all other days, the assessment will be completed predose.   
f A brief neurological examination will be performed, except for the Screening Visit, Visit 6, Visit 9 and Early Withdrawal which will be a complete neurological 
exam. On Day 4 (Visit 3), and Day 7 (Visit 4) a brief neurological examination will be performed predose and approximately 2 hours following administration of 
the morning dose of the investigational product.  Additional examinations may be performed at the discretion of the investigator.  
g On Day 1 (Visit 2), patients will receive the initial titration dose of vigabatrin (50 mg/kg/day divided twice daily [BID]), and either CBD 20 mg/kg/day plus 
matching CBD 20 mg/kg/day placebo or CBD 40 mg/kg/day placebo, each drug administered twice daily for three days. 
h For those patients who tolerate the initial dose, the dose for vigabatrin will be increased to 100 mg/kg/day [BID], and either CBD 30 mg/kg/day plus matching 
CBD 10 mg/kg/day, or CBD 40 mg/kg/day placebo for 3 days. On Day 7 (Visit 4) the dose of vigabatrin will be increased to 150 mg/kg/day and CBD to 
40 mg/kg/day for the remaining 9 days for subjects who tolerate the previous dose. 
i Complete Responders will continue receiving their assigned treatments of vigabatrin plus either CBD 40 mg/kg/day or matching placebo for 75 days, until 
Week 13 (Day 90) to monitor treatment response. During the extended treatment period the Investigator can only down titrate once to 30 mg/kg/day. 
j All subjects will be tapered off vigabatrin as follows: 150 mg/kg/day will be reduced to 100 mg/kg/day for 3 days then the 100 mg/kg/day will be reduced to 50 
mg/kg/day for 3 days and then discontinued. Similarly, all subjects will be tapered off CBD or CBD Placebo according to the following schedule: 40 mg/kg/day 
will be reduced to 30 mg/kg/day for 3 days, then 30 mg/kg/day will be reduced to 20 mg/kg/day for 3 days, then discontinued. Patients will receive a follow-up 
phone call 4 weeks after completing the tapering.  Drug reconciliation will be completed at the end of study. 
k A blood sample for PK analysis will be obtained on Day 15 prior to the second dose during the 24-hour video EEG.  
l A seizure diary will record daily spasms between Visit 1 and Visit 2. The daily spasm record will continue through the Initial Treatment and Extended 
Treatment Periods, and throughout the Taper period for patients enrolled in the Extended Treatment Period. 
m Patients who discontinue the study drug early should return for the Early Withdrawal Visit.  
n Meal diary must be collected 24 hours prior to and through PK blood sampling on Day 15 (Visit 6). 


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TABLE OF CONTENTS 
PROTOCOL APPROVAL PAGE ...................................................................................................2 
PROTOCOL SYNOPSIS ................................................................................................................3 
TABLE OF CONTENTS ...............................................................................................................16 
LIST OF TABLES .........................................................................................................................21 
LIST OF FIGURES .......................................................................................................................21 
1. 
INTRODUCTION ......................................................................................................25 
1.1. 
Cannabidiol .................................................................................................................25 
1.1.1. 
Mechanism of Action .................................................................................................25 
1.1.2. 
Metabolism and Potential Drug Interactions ..............................................................25 
1.2. 
Nonclinical Experience ...............................................................................................26 
1.2.1. 
Safety ..........................................................................................................................26 
1.2.2. 
Efficacy in Animal Models of Epilepsy .....................................................................27 
1.3. 
Clinical Experience .....................................................................................................27 
1.3.1. 
Pharmacokinetics ........................................................................................................28 
1.3.2. 
Overview of Safety .....................................................................................................28 
1.3.3. 
Selected Clinical Safety Data .....................................................................................29 
1.3.4. 
Efficacy in Human Epilepsy .......................................................................................31 
1.4. 
Infantile Spasms ..........................................................................................................31 
1.5. 
Study Rationale ...........................................................................................................32 
1.6. 
Summary of Potential Risks and Benefits ..................................................................32 
2. 
STUDY OBJECTIVES ..............................................................................................34 
2.1. 
Primary Objective .......................................................................................................34 
2.2. 
Secondary Objectives .................................................................................................34 
3. 
INVESTIGATIONAL PLAN .....................................................................................35 
3.1. 
Overall Study Design ..................................................................................................35 
3.1.1. 
Initial Treatment Period ..............................................................................................36 
3.1.2. 
Extended Treatment Period ........................................................................................36 
3.1.3. 
Partial Responders ......................................................................................................37 
3.1.4. 
Taper Period ................................................................................................................37 
3.1.5. 
Follow-up Period ........................................................................................................37 
3.2. 
Patient Selection .........................................................................................................39 
3.2.1. 
Inclusion Criteria ........................................................................................................39 


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3.2.2. 
Exclusion Criteria .......................................................................................................39 
3.3. 
Removal of Patients from Therapy or Assessment.....................................................40 
3.4. 
Dose Adjustment Criteria ...........................................................................................40 
3.5. 
Stopping Rules ............................................................................................................41 
4. 
TREATMENTS ..........................................................................................................42 
4.1. 
Treatments Administered ............................................................................................42 
4.1.1. 
Initial Treatment Period ..............................................................................................42 
4.1.2. 
Extended Treatment Period ........................................................................................42 
4.1.3. 
Partial Responders ......................................................................................................42 
4.1.4. 
Taper Period ................................................................................................................42 
4.2. 
Method of Assigning Patients to Treatment Groups ..................................................43 
4.3. 
Blinding and Unblinding Treatment Assignment .......................................................43 
4.4. 
Dose Selection Rationale ............................................................................................44 
4.5. 
Selection and Timing of Dose for Each Patient ..........................................................44 
4.6. 
Treatment Compliance ................................................................................................44 
4.7. 
Permitted and Prohibited Therapies ............................................................................45 
4.7.1. 
Permitted Therapies ....................................................................................................45 
4.7.2. 
Prohibited Therapies ...................................................................................................45 
5. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................46 
5.1. 
Identity of Investigational Product .............................................................................46 
5.2. 
Labeling and Packaging ..............................................................................................46 
5.2.1. 
Labeling ......................................................................................................................46 
5.2.2. 
Packaging ....................................................................................................................46 
5.3. 
Dispensing and Storage ..............................................................................................46 
5.4. 
Drug Accountability ...................................................................................................47 
6. 
STUDY ASSESSMENTS ..........................................................................................48 
6.1. 
Efficacy Assessments .................................................................................................48 
6.2. 
Safety Assessments .....................................................................................................48 
6.2.1. 
Demographics and Medical History ...........................................................................48 
6.2.2. 
Physical Examinations ................................................................................................49 
6.2.3. 
Neurological Examinations ........................................................................................49 
6.2.4. 
Vital Signs ..................................................................................................................49 
6.2.5. 
Clinical Laboratory Assessments ...............................................................................49 


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6.2.5.1. 
Hematology .................................................................................................................49 
6.2.5.2. 
Chemistry ....................................................................................................................49 
6.2.6. 
Adverse Events and Serious Adverse Events .............................................................49 
6.2.6.1. 
Definition of Adverse Events .....................................................................................49 
6.2.6.2. 
Classification of Adverse Events ................................................................................50 
6.2.6.3. 
Causality: Drug Relationship Assessment ..................................................................51 
6.2.6.4. 
Definition of Serious Adverse Events ........................................................................51 
6.2.6.5. 
Actions Taken .............................................................................................................51 
6.2.6.6. 
Outcome at the Time of Last Observation ..................................................................52 
6.2.6.7. 
Adverse Event Recording and Reporting ...................................................................52 
6.2.6.8. 
Adverse Event Follow-Up ..........................................................................................53 
6.2.6.9. 
Monitoring of AEs Potentially Related to Drug Metabolism .....................................53 
6.2.6.10. 
Data Monitoring Committee .......................................................................................53 
6.3. 
Pharmacokinetics Assessments ..................................................................................53 
7. 
STUDY PROCEDURES ............................................................................................54 
7.1. 
Screening Period (Visit 1) ..........................................................................................54 
7.2. 
Assessments and Procedures ......................................................................................55 
7.2.1. 
Initial Treatment Period ..............................................................................................55 
7.2.1.1. 
Visit 2 (Day 1) ............................................................................................................55 
7.2.1.2. 
Day 2 and Day 3 .........................................................................................................55 
7.2.1.3. 
Visit 3 (Day 4) ............................................................................................................55 
7.2.1.4. 
Visit 4 (Day 7) ............................................................................................................56 
7.2.1.5. 
Days 7-15 ....................................................................................................................57 
7.2.1.6. 
Visit 5 (Day 14) ..........................................................................................................57 
7.2.1.7. 
Visit 6 (Day 15, End of Study for the Initial Treatment Period) ................................57 
7.2.2. 
Taper Period ................................................................................................................58 
7.2.3. 
Extended Treatment Period (Visit 7/Week 6, Visit 8/Week 10, and 
Visit 9/Week 13) .........................................................................................................58 
7.2.4. 
Partial Responders ......................................................................................................59 
7.2.5. 
Early Withdrawal Visit ...............................................................................................59 
7.2.6. 
Follow-up Period ........................................................................................................60 
7.2.7. 
Follow-up of Adverse Events .....................................................................................60 
7.3. 
Investigational Product PK Sample ............................................................................60 


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7.4. 
Sample Collection for Patients ...................................................................................60 
8. 
STATISTICS ..............................................................................................................61 
8.1. 
Study Endpoints ..........................................................................................................61 
8.1.1. 
Primary Efficacy Endpoint .........................................................................................61 
8.1.2. 
Secondary Efficacy Endpoints ....................................................................................61 
8.1.3. 
Safety Endpoints .........................................................................................................61 
8.2. 
Sample Size Determination ........................................................................................61 
8.3. 
Analysis Populations ..................................................................................................62 
8.4. 
Statistical Analyses .....................................................................................................62 
8.4.1. 
Study Patients and Demographics ..............................................................................62 
8.4.1.1. 
Disposition and Withdrawals ......................................................................................62 
8.4.1.2. 
Protocol Deviations ....................................................................................................62 
8.4.1.3. 
Demographics and Other Baseline Characteristics .....................................................62 
8.4.2. 
Exposure and Compliance ..........................................................................................63 
8.4.3. 
Efficacy Analyses .......................................................................................................63 
8.4.3.1. 
Primary Efficacy Analysis ..........................................................................................63 
8.4.3.2. 
Secondary Efficacy Analyses .....................................................................................63 
8.4.4. 
Safety and Tolerability Analyses ................................................................................64 
8.4.4.1. 
Adverse Events ...........................................................................................................64 
8.4.4.2. 
Clinical Laboratory Evaluations .................................................................................64 
8.4.4.3. 
Vital Signs ..................................................................................................................65 
8.4.4.4. 
Neurological Examination Findings ...........................................................................65 
8.4.5. 
Pharmacokinetic Analyses ..........................................................................................65 
8.4.6. 
Missing Data ...............................................................................................................65 
9. 
STUDY CONDUCT ...................................................................................................66 
9.1. 
Sponsor and Investigator Responsibilities ..................................................................66 
9.1.1. 
Sponsor Responsibilities .............................................................................................66 
9.1.2. 
Investigator Responsibilities .......................................................................................66 
9.2. 
Site Initiation ..............................................................................................................67 
9.3. 
Screen Failures ............................................................................................................67 
9.4. 
Study Documents ........................................................................................................67 
9.4.1. 
Investigator’s Regulatory Documents ........................................................................67 
9.4.2. 
Case Report Forms .....................................................................................................67 


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9.4.3. 
Source Documents ......................................................................................................68 
9.5. 
Data Quality Control ...................................................................................................68 
9.5.1. 
Monitoring Procedures ...............................................................................................68 
9.5.2. 
Data Management .......................................................................................................68 
9.5.3. 
Quality Assurance/Audit ............................................................................................69 
9.6. 
Study Termination ......................................................................................................69 
9.7. 
Study Site Closure ......................................................................................................69 
9.7.1. 
Record Retention ........................................................................................................69 
9.7.2. 
Pharmacokinetic/Laboratory Sample Retention .........................................................70 
9.8. 
Changes to the Protocol ..............................................................................................70 
9.9. 
Financial Disclosure ...................................................................................................70 
10. 
REGULATORY AND ETHICAL CONSIDERATIONS ..........................................72 
10.1. 
Regulatory Authority Approval ..................................................................................72 
10.2. 
Ethical Conduct of the Study ......................................................................................72 
10.3. 
Statement of Investigator/Delegation of Authority ....................................................72 
10.4. 
Patient Informed Consent ...........................................................................................72 
10.5. 
Investigator Reporting Requirements .........................................................................73 
11. 
USE OF INFORMATION AND PUBLICATION POLICY .....................................74 
11.1. 
Use of Information ......................................................................................................74 
11.2. 
Publication Policy .......................................................................................................74 
12. 
REFERENCES ...........................................................................................................75 
13. 
INVESTIGATOR SIGNATURE PAGE ....................................................................80 
APPENDIX 1. CYP3A4-RELATED PROHIBITED MEDICATIONS.....................................81 


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LIST OF TABLES 
Table 1: 
Schedule of Events .....................................................................................................13 
Table 2: 
Video EEG Response Definitions ..............................................................................36 
Table 3: 
Description of Drug Product (20 mg/kg/day, 30 mg/kg/day, 40 mg/kg/day) .............46 
 
LIST OF FIGURES 
Figure 1:  Study Design Schematic .............................................................................................38 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Abbreviation or Specialist Term 
Explanation 
5-HT1a 
5-hydroxytryptamine 1a 
ACTH 
adrenocorticotropic hormone 
AE 
adverse event 
AET 
anti-epileptic therapy 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
AUC(0-tau) 
area under the plasma concentration-time curve to the end of 
the dosing period 
BUN 
blood urea nitrogen 
CB1 
cannabinoid receptor 1 
CB2 
cannabinoid receptor 2 
CBD 
Cannabidiol 
CFR 
Code of Federal Regulations 
CGI-I 
Clinical Global Impression – Global Improvement 
CGI-S 
Clinical Global Impression – Severity of Illness 
cGMP 
current Good Manufacturing Practices 
Cmax 
maximum plasma concentration 
CNS 
central nervous system 
CRF 
case report form 
CRO 
contract research organization  
CV% 
coefficient of variation 
CYP 
cytochrome P450 
CYP1A1 
Cytochrome P450 1A1 
CYP2C9 
Cytochrome P450 2C9 
CYP2C19 
Cytochrome P450 2C19 
CYP3A4 
Cytochrome P450 3A4 
CYP3A5 
Cytochrome P450 3A5 
DEA 
Drug Enforcement Administration 


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DMC 
Data Monitoring Committee 
eCRF 
electronic case report form 
ECG 
Electrocardiogram 
EDC 
electronic data capture 
ED50 
median effective dose 
EEG 
electroencephalogram 
EENT 
eyes, ears, nose, and throat 
FDA 
Food and Drug Administration 
FSH 
Follicle stimulating hormone 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICD 
informed consent document 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
INR 
international normalized ratio 
IP 
Investigational product 
IRB 
Institutional Review Board 
IS 
Infantile Spasms 
ITT 
Intent to Treat 
IV 
Intravenous 
LDH 
lactate dehydrogenase 
LFTs 
liver function tests 
MCT 
Medium Chain Triglycerides 
MedDRA 
Medical Dictionary for Regulatory Activities 
NOAEL  
No Observed Adverse Effect Level   
OH 
Hydroxy 
PK 
pharmacokinetic(s) 
pKa 
acid dissociation constant 
PT 
preferred term 
RBC 
red blood cell 
SAE 
serious adverse event 


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SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SOC 
System organ class  
SOP 
standard operating procedure 
t½  
terminal phase half-life 
TD50 
median tolerated dose 
TBL 
total bilirubin 
TEAE 
treatment-emergent adverse event 
THC 
tetrahydrocannabinol 
TLFs 
tables, listings, and figures  
tmax 
time to maximum plasma concentration 
ULN 
upper limit of normal 
US 
United States 


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1. 
INTRODUCTION 
Data presented in Section 1.0 include overviews from the nonclinical and clinical published 
literature that reports on various other formulations of cannabidiol (CBD) (primarily plant-
based). Analogous studies have not been completed for Cannabidiol Oral Solution, the 
pharmaceutical grade synthetic CBD to be investigated in this study. 
Please see the Investigator’s Brochure (IB)1 for more information. 
1.1. 
Cannabidiol 
The main active constituent of cannabis, Δ9-tetrahydrocannabinol (Δ9-THC) is the principal 
psychoactive constituent of marijuana. Cannabidiol is the second most abundant cannabinoid and 
highly physiologically relevant, but is non-psychoactive. It has demonstrated a potential benefit 
in treating patients with treatment-resistant epilepsy.2,3,4,5    
Insys Development Company, Inc. (hereafter referred to as the Sponsor) has successfully 
manufactured a pharmaceutical grade, synthetic CBD drug substance. It is manufactured in their 
current Good Manufacturing Practices (cGMP) manufacturing facility. This facility is approved 
by the Drug Enforcement Administration (DEA) and has been inspected by the Food and Drug 
Administration (FDA). This active pharmaceutical ingredient is ≥99.5% pure6 and can be 
consistently produced without the concern for contaminant.  
1.1.1. 
Mechanism of Action 
The mode of action of CBD is not fully understood. The drug substance manifests a low affinity 
for endogenous cannabinoid receptors 1 (CB1) and 2 (CB2). Cannabidiol acts as an indirect 
antagonist of CB1 and inhibits several CB1 mediated ∆9-THC effects.7 It also stimulates the 
vanilloid receptor type 18 and modulates the µ- and δ-opioid receptors.9 It may also increase 
plasma ∆9-THC levels by inhibiting its hepatic microsomal metabolism by competitively binding 
proteins in the cytochrome P450 (CYP) oxidative system.10 Finally, CBD may modulate 
neuronal hyperexcitability through one or more of the following mechanisms: 
• Bidirectional regulation of calcium homeostasis via the mitochondrial 
sodium/calcium exchanger.11  
• Agonistic properties at 5-hydroxytryptamine 1a (5-HT1a) receptors.12 
• Enhancing endogenous adenosine levels in the central nervous system (CNS) by 
reducing adenosine re-uptake.13,14  
Recent studies have shown that CBD dose-dependently increased seizure threshold in wild-type 
mice, an effect that was markedly reduced in transient receptor potential vanilloid 1 (TRPV1) 
channel knockout mice15, and blocked the G protein-coupled receptor-55 (GPR-55) mediated 
increase of miniature excitatory postsynaptic currents (mEPSCs) frequency in CA1 pyramidal 
neurons in healthy and epileptic tissues.16  
1.1.2. 
Metabolism and Potential Drug Interactions 
The major biotransformation pathway for CBD is similar to that of other cannabinoids and 
mediated by hydroxylation by cytochrome P450 (CYP) proteins.17 Its interactions with human 
drug metabolizing enzymes (as a substrate, inhibitor, or inducer) were recently reviewed.18,19    


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Cannabidiol is metabolized primarily in the liver by cytochrome P450 3A4 (CYP3A4) and to a 
lesser extent by cytochrome P450 2C19 (CYP2C19). The effect of cannabidiol on primary fetal 
rat hepatocyte viability was investigated.20 In vitro, hepatocytes showed reduced cell viability, 
inhibited cell growth, and cytoplasmic alterations after 24 hours of exposure to cannabidiol at 
concentrations of 10-4 to 10-3 M. Markers of cell injury increased following treatment of 
cannabidiol at concentrations of 10-4 M (160% of control after 24 hours of exposure) and 
5 x 10-5 M (220% of control after 72 hours). These results correspond to other studies showing 
that cannabidiol is a potent inhibitor of hepatic drug metabolism.21,22,23 Specifically, cannabidiol 
inhibits CYP3A4, cytochrome P450 3A5 (CYP3A5), and cytochrome P450 1A1 (CYP1A1) in 
vitro.24,25,26 It also appears to inhibit cytochrome P450 2C9 (CYP2C9)27 and the transport protein 
p-glycoprotein.28,29  
Cannabidiol likely inhibits drug metabolism when one of its metabolites binds to hepatic 
microsomal CYP proteins.30,31,32,33 Hexobarbital is metabolized by CYP2C9 and the duration of 
sleep induced by hexobarbital may be used as a surrogate for drug metabolism. Using this 
outcome measure, it was shown that suppression of drug metabolism by cannabidiol diminished 
following repeated exposure to the drug substance in rodents.34   
Clinically, oral intake of cannabidiol (100 mg every 4 hours for 5 to 12 days) produced a 36% 
lower clearance and 35% lower volume of distribution of hexobarbital in healthy volunteers.35 
Notably, this study also showed that liver function tests (LFTs) remained normal before and 
during cannabidiol ingestion. Cannabidiol also inhibited barbiturate metabolism in humans to an 
extent substantially greater than that observed for ∆9-THC. Conversely, another study reported 
that oral dosing with cannabidiol (25 mg/kg) did not significantly affect the total clearance, 
volume of distribution, or terminal elimination t1⁄2 of ∆9-THC metabolites.36  
1.2. 
Nonclinical Experience  
1.2.1. 
Safety 
Nonclinical toxicological assessments of CBD conducted by Insys Development Company, Inc. 
thus far have concluded that 600 mg/kg/day exceeded the maximum tolerated dose in adult rats. 
Female rats generally appear to be more sensitive to the effects of CBD (in terms of toxicity) 
than similarly treated males. Because of the microscopic findings in the skin (follicular atrophy) 
noted in both genders at all CBD dose levels, a No Observed (Adverse) Effect Level (NOAEL) 
could not be determined for this study. The main GLP 6-month adult rat and 9-month 
cynomolgus monkey chronic toxicity studies with CBD in Medium Chain Triglycerides (MCT) 
are underway with few clinical signs being observed in either study.   
Observations from single- and repeat-dose toxicology studies in rats and non-human primates 
demonstrate that CBD-induced hypoactivity is transient and does not induce 
psychopharmacological effects37. In rats, inhalation exposure of up to 1.6 mg/kg/day of CBD 
(smoke) once daily for 14 days was associated with a transient dose-related hypoactivity (and 
prostration) and body weight gain was depressed38. The target organ for toxicity was the testes 
(impairment of spermatogenesis and sperm maturation).   
In monkeys, a single intravenous dose of CBD produced dose-related hypoactivity, sedation, and 
prostration.36 Tremors and convulsions occurred at >150 mg/kg and mortality at ≥225 mg/kg 
(associated with respiratory arrest and cardiac failure). Liver weights were increased and testes 


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`weights were decreased in the 200 mg/kg groups. Whether these effects on liver and testes were 
test-article related could not be conclusively determined due to the small sample size. There were 
no other meaningful treatment-related changes in clinical signs, body weight, core body 
temperature, or clinical or gross anatomic pathology.   
In a 90-day repeated-dose oral toxicity study in monkeys, CBD (30 to 300 mg/kg/day) did not 
result in mortality, clinical signs, or adversely affect physiological parameters, body weights or 
gains, food consumption, or ophthalmologic or electrocardiogram (ECG) evaluations.39 Lower 
heart rates were observed in treated males only during the first month. The only target organ 
identified was the testes.  Similar to the observations in rats, lower testes weights were associated 
with dose-related inhibition of spermatogenesis, which did not appear to be reversible within the 
30-day recovery period. The NOAEL in the monkey was determined to be <30 mg/kg/day (<360 
mg/m2/day based on body surface area). 
In rat fertility studies, CBD appears to affect testicular development38,40, and reduce fertility 
(reproductive capacity) of males but not females.41 There were no studies that assessed the 
potential for effects on embryofetal development. The effects of CBD on perinatal and postnatal 
development principally showed effects in the testes of developing male pups.  
It is unclear whether the observed testicular effects on spermatogenesis are reversible or not, as recovery 
periods have not been of sufficient duration to allow recovery of the seminiferous epithelium. 
1.2.2. 
Efficacy in Animal Models of Epilepsy 
Plant-derived cannabidiol shows antiepileptic,42 antipsychotic, anti-dystonic, anti-emetic, and 
anti-inflammatory properties in animal models.43 These models support exploring the use of 
cannabidiol for the treatment of epilepsy.    
As an example, the anticonvulsant activity of oral cannabidiol was investigated in adult rat 
model of seizures (induced by maximal electroshock or audiogenic sources).44 Cannabidiol was 
effective against maximal electroshock-induced seizures (median effective dose [ED50] = 18 
mg/kg), but only minimally effective against audiogenic-induced seizures (ED50 ≥75 mg/kg).  
The neurotoxicity median tolerated dose (TD50) was >100 mg/kg. Cannabidiol co-administered 
with different anti-seizure drugs (e.g., phenytoin or carbamazepine) increased or reduced their 
anticonvulsant activity, indicating that synergism or antagonism with cannabidiol was drug 
specific. 
1.3. 
Clinical Experience  
Clinical data described in the following sections were collected following administration of 
various extracts of cannabidiol as oral solutions or solid formulations. Early reports have 
indicated the cannabinoids, in particular CBD, may be efficacious in treating refractory 
epilepsy.45, 46, 47, 48 In separate Phase 3 studies with a plant-derived purified CBD (Epidiolex®, 
GW Pharmaceuticals), patients with Dravet Syndrome and Lennox-Gastaut Syndrome (LGS) 
treated with 20 mg/kg/day demonstrated a significant decrease in the median monthly seizure 
rate when compared to controls. 


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1.3.1. 
Pharmacokinetics 
In human subjects, the pharmacokinetics (PK) of tetrahydrocannabinol (THC) containing 
cannabinoids varies as a function of its route of administration.   
Pulmonary assimilation of inhaled cannabinoids provides a maximum plasma concentration 
(Cmax) within minutes.   
The PK parameters of cannabidiol were evaluated in a group of five cannabis smokers.42 A high 
plasma clearance (960 to 1560 mL/minute) was calculated. A terminal half-life (t½) was not 
reached at 72 hours, but the available data indicated t½ for cannabidiol of 27 to 35 hours (mean 
of 31 hours) after smoking.21 The distribution volume was estimated to be approximately 
30 L/kg. The mean t½ for cannabidiol is 24 or 31 hours, respectively, when administered 
intravenously (IV) or inhaled.49      
After oral administration of 0.6 mg/kg of cannabidiol in normal subjects, the plasma time 
concentration curves over 6 hours post dosing were similar to that after 0.3 mg/kg of THC.50   
Oral doses of cannabidiol (10 mg/kg/day) once daily for 6 weeks in patients with Huntington’s 
disease resulted in mean weekly plasma concentrations of 5.9 to 11.2 µg/L.51  The volume of 
distribution of cannabidiol was about 30 L/kg greater than for THC, and the plasma clearance 
was similar to that of THC, ranging from 58 to 94 L/hour (960 to 1560 mL/min). After an IV 
dose of 20 mg, the average t1⁄2 for cannabidiol was 24 hours (range of 18 to 33 hours).21,52    
Following oral ingestion, psychotropic effects of THC set in with a delay of 30 to 90 minutes, 
reach their maximum after 2 to 3 hours, depending on the dose and specific effect.   
Following doses of 10 mg cannabidiol in combination with 10.8 mg THC in an oral spray for 9 
consecutive days, mean peak plasma concentrations were 1.14 (0.86) ng/mL for cannabidiol and 
2.72 (1.47) ng/mL for THC. The median time to Cmax (tmax) was 1.27 (range of 0.75 to 2.52) 
hours for cannabidiol and 1.50 (0.75 to 2.50) hours for THC.53   
A Phase 1 clinical study examined the results of sublingual administration of 10 mg THC with 
that of 10 mg THC and 10 mg cannabidiol in cannabis-based medicinal extracts.54 Despite 
administration of equivalent amounts of THC and cannabidiol, lower plasma concentrations of 
cannabidiol were consistently observed. Mean Cmax concentrations for THC, cannabidiol, and 
11-hydroxy (OH)-THC were 4.9, 3.3, and 4.5 ng/mL when 10 mg THC and 10 mg cannabidiol 
were administered. The tmax was approximately 4 hours for all three analytes.   
The systemic availability of cannabidiol administered via the smoking route averages 
approximately 31% with inter-patient variability ranging from 11% to 45%.21 The bioavailability 
of cannabidiol following oral administration is approximately 6%.46 
1.3.2. 
Overview of Safety 
Clinical studies in various human populations indicate that CBD has a favorable side-effect 
profile. Doses as high as 1500 mg are well tolerated.55 No significant reactions or serious adverse 
events (SAEs) have been reported across a wide range of dosages in both acute and chronic 
settings. Bergamaschi et al.19 recently reviewed the safety of CBD in humans examined in 221 
patients across 21 studies. As detailed in the IB1, no significant safety issues were reported. 
Regarding doses of CBD that have been examined in other studies, daily doses of 200 to 300 mg 
CBD (or potentially more) may be safe.2,56 Clinical evaluation and therapeutic ranges of CBD 


Insys Development Company, Inc.                                               Protocol Number INS011-16-082 
05 Jul 2018                                                    CONFIDENTIAL                                                               29  
doses have been reported to be between 10 and 1500 mg/day, with the majority of reports 
evaluating doses in the 300 to 600 mg/day CBD range. Further, between 300 and 1500 mg have 
been used in humans without toxicity or SAEs.45,57,58,59    
1.3.3. 
Selected Clinical Safety Data  
Insys study INS011-14-029 enrolled 62 patients with refractory seizures between 1 and 17 years 
of age. Cannabidiol Oral Solution, 300 mg/mL at doses between 10 mg/kg/day and 40 mg/kg/day 
were generally well tolerated and no patient discontinued. Fifty-two of the 61 patients enrolled 
into a long-term safety study (INS011-14-030). Study INS011-14-030 was a long-term, open-
label, 48-week study for pediatric patients aged 1 year to 17 years with refractory epilepsy who 
participated in the Phase 1/2 Study INS011-14-029.  
Insys recently completed a long-term safety study (INS011-14-030) in pediatric patients with 
refractory epilepsy who participated in the Phase 1/2 PK study (INS011-14-029). This study was 
a long-term, open-label, 48-week study for pediatric subjects aged 1 year to 17 years with 
refractory epilepsy who participated in the Phase 1/2 Study INS011-14-029. A total of 52 
subjects (9 infants, 26 children, and 17 adolescents) were enrolled and received at least one dose 
of the investigational product in this study. Forty-five (86.5%) subjects completed the study 
including follow-up. Seven (13.5%) subjects prematurely discontinued treatment and study 
participation: 2 (3.8%) subjects due to AEs, 3 (5.8%) subjects due to withdrawal of consent, 
1 (1.9%) subject due to death considered not related to investigational product, and 1 (1.9%) 
subject due to other reason (reported lack of efficacy).   
The mean modal dose (defined as the dose with the longest duration) was 24.42 mg/kg/day and 
the mean total duration of study drug was 311.1 days. Overall, 13 subjects (14.4%) had dose 
reductions during the study: 12 subjects (13.3%) had dose reductions due to an AE and 1 subject 
(1.1%) had a dose reduction due to “other” reason. The incidence of dose reductions resulting 
from an AE was higher for subjects who received 40 mg/kg/day (8 subjects, 30.8%) compared 
with subjects who received 20-<30 mg/kg/day (6 subjects, 8.8%) and 30-<40 mg/kg/day (1 
subject, 6.6%). No subjects who received 10-<20 mg/kg/day and no infants had dose reductions. 
The trend was to increase the doses over the course of the study. There were 39 subjects (43.3%) 
who had dose increases during the study. The incidence of dose increases was higher for subjects 
who received 10-<20 mg/kg/day (14 subjects, 100%) compared with subjects who received 20-
<30 mg/kg/day (16 subjects, 47.1%) and 30-<40 mg/kg/day (9 subjects, 56.3%).   
Overall, 47 subjects (90.4%) experienced ≥1 adverse event (AE) during the study. The following 
AEs were reported in at least five subjects during the study:  seizure (16 subjects, 30.8%), upper 
respiratory tract infection (eight subjects, 15.4%), anemia (seven subjects, 13.5%), diarrhea 
(seven subjects, 13.5%), pyrexia (seven subjects, 13.5%), somnolence (seven subjects, 13.5%), 
aggression (five subjects, 9.6%), nasopharyngitis (five subjects, 9.6%), and otitis media (five 
subjects, 9.6%). There were 47 AEs reported for 24 (46.2%) subjects that were considered 
possibly or probably related to the investigational product. The most common possibly or 
probably related AEs reported were anemia (five subjects, 9.6%), somnolence (four subjects, 
7.7%), and weight increased (four subjects, 7.7%). One subject died during the study; the death 
resulted from an SAE of systemic sepsis leading to multi-organ failure and was considered not 
related. Relevant medical history included sodium voltage-gated channel alpha subunit 8 
mutation, patent foramen ovale, tracheomalacia, tracheostomy, gastrostomy, gastroesophageal 


Insys Development Company, Inc.                                               Protocol Number INS011-16-082 
05 Jul 2018                                                    CONFIDENTIAL                                                               30  
reflux disease, global developmental delay, cortical visual impairment, and hypotonia. Overall, 
17 (32.7%) subjects had experienced a total of 37 serious TEAEs. The most frequently reported 
serious TEAEs were seizure (six subjects, 11.5%), status epilepticus (two subjects, 3.8%), and 
mental status changes (two subjects, 3.8%).     
An open-label study of Cannabidiol Oral Solution, 300 mg/mL (20 mg/kg/day and 40 
mg/kg/day) in pediatric patients with infantile spasms refractory to adrenocorticotropic hormone 
(ACTH) and vigabatrin recently was halted due to futility (Protocol INS011-15-054). However, 
the drug was generally well tolerated for doses up to 40 mg/kg/day. A total of nine patients were 
included in the safety analysis. The mean duration of exposure was 29.6 days (min, max: 5, 159). 
Eight patients were treated for approximately 2 weeks at 20 mg/kg/day while the patient who 
was a Complete Responder received 238 days of investigational (IP). She increased her dose to 
40 mg/kg/day at Week 10 and continued that dose until Week 34 when she enrolled into the 
long-term safety study INS011-14-030 to continue treatment. Of the nine patients in the safety 
population, three (33%) had four events: infantile spasms (3) and sedation (1).  
Insys study INS011-15-043 enrolled 24 healthy adults who received a single dose of 20 mg/kg 
Cannabidiol Oral Solution, 300 mg/mL as part of a food effect study (Treatment A= fasted, 
Treatment B= fed). Neutropenia was reported in two subjects [one fed (moderate) and one 
fasting (mild)]. Other AEs (all considered mild) reported in the fasting arm included diarrhea (1), 
dry mouth (1) and nausea (1) and events of diarrhea (2) and flatulence (1) were reported in 
patients in the fed arm. All diarrhea, dry mouth, flatulence, and nausea events were considered 
possibly related to study drug.  No serious AEs or deaths were reported. 
INS011-16-093 was a Phase 1, open-label, randomized, single-dose (10 mg/kg), four-treatment, 
four-sequence, four-period, four-way crossover food effect study of multiple formulations 
[sesame oil-based, 100 mg/mL (fed and fasted), MCT-based, 100 mg/mL (fed), and ethanol-
containing 80 mg/mL (fed)] of Cannabidiol Oral Solution in 8 healthy adult subjects.  No serious 
AEs or AEs that led to subject discontinuation were reported. A total of two AEs were reported 
during the study, both following 10 mg/kg Cannabidiol Oral Solution, 80 mg/mL, administered 
under fed conditions. Two subjects reported mild abdominal pain, and the Investigator judged 
each as possibly related to study treatment. Both AEs resolved in less than 1 day. No AEs were 
related to abnormal laboratory tests, vital signs, ECGs, or physical examinations. 
Safety data from the food effect studies in healthy adult subjects demonstrated that the MCT 
formulations single dose of 20 mg/kg [Cannabidiol Oral Solution, 300 mg/mL (INS011-15-043)] 
and 10 mg/kg/dose [Cannabidiol Oral Solution, 100 mg/mL (INS011-16-093)] was generally 
well tolerated. No AEs were reported for the MCT 100 mg/mL formulation in INS011-16-093) 
and only eight treatment-emergent AEs were reported in INS011-15-043 [three patients fasting 
and four subjects fed (diarrhea and neutropenia)]. The AE of neutropenia was considered not 
related. Although the CBD exposure was much higher in the fed state, there was no significant 
difference in the number of AEs reported between fed and fasted, indicating these higher 
exposures did not lead to higher rates of adverse events.   
The above safety data collected from five clinical studies demonstrate the CBD is generally well 
tolerated for doses up to 40 mg/kg/day and for durations for up to one year. 


Insys Development Company, Inc.                                               Protocol Number INS011-16-082 
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1.3.4. 
Efficacy in Human Epilepsy 
Several preliminary studies of CBD report reductions in seizure activity for a significant subset 
of subjects.    
In a recent report, 10 pediatric subjects (3 to 12 years of age) and one adult subject (22 years of 
age) showed reductions in motor seizures (generalized tonic-clonic, tonic, myoclonic, atonic) per 
week. Eight (73%) subjects reported a 95-100% reduction in seizure occurrence, 1 (9%) reported 
75% reduction and 2 (18%) reported 20-45% reductions.60 
In an expanded-access program in 137 patients treated with Epidiolex® (an oil-based CBD 
extract) in the efficacy population, they reported a median reduction in monthly motor seizures 
of 36.5% after 12 weeks of treatment compared to baseline.61 
In a Phase 3 study, 120 patients with Dravet Syndrome were randomized into two treatment 
arms, Epidiolex® 20 mg/kg/day (n=61) and placebo (n=59). Epidiolex® or placebo was added to 
current anti-epileptic drug (AED) treatment regimens62 (GW Pharmaceuticals, Dravet Syndrome 
study). On average, patients were taking approximately 3 AEDs, having previously tried and 
failed an average of more than 4 other AEDs. The average age of trial participants was 10 years 
and 30 percent of patients were less than 6 years of age. The median baseline convulsive seizure 
frequency per month was 13. 
The primary efficacy endpoint was a comparison between Epidiolex® and placebo measuring the 
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, patients taking 
Epidiolex® achieved a significant median reduction in monthly convulsive seizures of 39 percent 
compared with a reduction on placebo of 13 percent (p=0.01). The difference between 
Epidiolex® and placebo emerged during the first month of treatment and was sustained during 
the entire treatment period. 
1.4. 
Infantile Spasms 
Infantile Spasms is a devastating form of epilepsy that typically strikes children in the first year 
of life.62 Usually provoked by one of many structural, genetic, or metabolic etiologies, Infantile 
Spasms manifests with clusters of a distinct seizure-type (spasms), and is often accompanied by 
an EEG pattern known as hypsarrhythmia.63 Unsuccessful treatment, as well as delay in 
definitive treatment, are associated with tremendous reductions in neurodevelopmental 
outcome.64 Among pharmacologic therapies for infantile spasms, hormonal therapies such as 
intramuscular adrenocorticotropic hormone (ACTH, Acthar®)65,66,67 and vigabatrin (Sabril®)68 
are the most efficacious. Almost half of patients either fail first line therapy or relapse after 
initially successful treatment.69 The side-effect profiles of the above therapies are poor: 
vigabatrin is associated with irreversible peripheral visual field defects70,71 and the hormonal 
therapies impart substantial risk of immunosuppression leading to potentially lethal bacterial 
infections (pneumonia, sepsis, meningitis, etc.) as well as hypertension that has been associated 
with cardiac failure. 
Accordingly, there is a tremendous need for safe and effective therapies in the treatment of 
infantile spasms. This need is even more pronounced in those patients who have failed currently 
approved therapies. 


Insys Development Company, Inc.                                               Protocol Number INS011-16-082 
05 Jul 2018                                                    CONFIDENTIAL                                                               32  
1.5. 
Study Rationale 
Therapeutic failure may lead epilepsy patients to try alternative treatments, including 
“recreational drugs” and especially cannabis.72 As summarized in Sections 1.2.1 and 1.3.2, 
nonclinical and clinical data show that cannabidiol has a largely favorable safety profile.  
However, carefully controlled efficacy and safety studies have not been done and the specific 
profile of Cannabidiol Oral Solution has not been examined in infantile spasms.    
The primary purpose of this study is to formally investigate the efficacy and safety of 
Cannabidiol Oral Solution as adjunctive therapy in first-line treatment with vigabatrin to 
determine whether the addition of CBD will either increase the response rate associated with the 
use of vigabatrin alone or reduce the incidence of relapse.   
1.6. 
Summary of Potential Risks and Benefits 
As discussed in Sections 1.2 and 1.3, numerous nonclinical and clinical studies have examined 
other formulations of CBD. Several areas of potential concern have been identified with the use 
of CBD, especially in nonclinical studies. These include:   
• Competitive binding of CYP proteins (thus, an impact on drug metabolism in the 
liver).  
o Cannabidiol is metabolized predominantly by CYP3A4 and CYP 2C19.  
Cannabidiol may inhibit these two isozymes, as well as having small effects on 
CYP3A5, CYP1A1, and CYP2C9. 
• Abnormal spermatogenesis. 
• Abnormal induction of FSH in males. 
• Potential downregulation of immune responses involving the T, B, T-helper, and T 
cytotoxic subsets of leukocytes and/or those dependent on IL-2 or IFN-γ. 
Based on recent studies of cannabinoid administration in humans, controlled CBD may be safe in 
humans and animals. However, further studies are needed to clarify these reported in vitro and in 
vivo side-effects.20  
A Phase 1/2 study to assess the pharmacokinetics and safety of multiple doses of pharmaceutical-
grade synthetic Cannabidiol Oral Solution in 61 pediatric subjects with treatment-resistant 
seizure disorders who were between <2 years of age to 17 years of age was conducted by Insys 
(Protocol INS-011-14-029). Steady-state levels of cannabidiol appeared to be attained with 
approximately 2 to 6 days of repeated BID dosing with Cannabidiol Oral Solution, with 
geometric mean AUC (0-tau) of 507.0 (Cohort 1 [10 mg/kg/day,]) 836.0 (Cohort 2 [20 
mg/kg/day]), and 2108 ng·h/mL (Cohort 3 [40 mg/kg/day]) for all age categories combined. All 
doses of Cannabidiol Oral Solution from 10 mg/kg/day up to 40 mg/kg/day in divided doses 
were generally well tolerated. There were no clinically relevant differences in the AE profile 
among patients in the infant, child, and adolescent age categories. The majority of patients 
reported ≥1 TEAE (most commonly in the system organ classes of gastrointestinal disorders and 
nervous system disorders). 


Insys Development Company, Inc.                                               Protocol Number INS011-16-082 
05 Jul 2018                                                    CONFIDENTIAL                                                               33  
The inclusion/exclusion criteria, concomitant medication guidelines, and safety monitoring (AEs, 
clinical laboratory, vital signs, and physical examination assessments) planned for this study are 
intended to minimize these potential safety risks.   
Criteria for removal of subjects from the study will dictate discontinuation of subject 
participation should a safety issue arise (see Section 3.3).  
Two facets of the current treatment landscape for pediatric patients with infantile spasms support 
the potential benefit for patients in this study. First, as reviewed in Section 1.4, newly diagnosed 
pediatric patients when treated with either ACTH or vigabatrin experience a significant unmet 
medical need despite ongoing treatment because of the limited response rate or the incidence of 
relapse. This study is expected to serve as a critical step in the development of Cannabidiol Oral 
Solution as an adjunctive treatment for pediatric patients who are initially diagnosed with 
infantile spasms.    
Second, pharmaceutical grade synthetic Cannabidiol Oral Solution is expected to have several 
distinct advantages over cannabis plant-derived extracts:  
• Availability of the drug substance does not depend on cannabis plant production.  
o As such, the development of Cannabidiol Oral Solution will not support growth 
and distribution of plants from which marijuana is derived.   
• Manufacture of Cannabidiol Oral Solution does not involve an extraction process 
whereby the derived constituents could also include a significant amount of Δ9-THC.    
o The manufacturing process can be controlled so that mass quantities can be 
produced that are uniform in quality, purity, and consistency and can be delivered 
in known and predetermined quantities. 
• Variability in concentration and constituents should be reduced among batches, which 
may improve safety and tolerability. 
• Reduced concern for contamination by Δ9-THC, herbicides, pesticides, etc. 
  
 


Insys Development Company, Inc.                                               Protocol Number INS011-16-082 
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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
• To evaluate the efficacy of Cannabidiol Oral Solution as adjunctive therapy with 
vigabatrin as initial therapy in treating patients with Infantile Spasms. 
2.2. 
Secondary Objectives 
• To evaluate the continued efficacy of Cannabidiol Oral Solution after the 14-day 
treatment with vigabatrin or vigabatrin plus Cannabidiol Oral Solution is complete. 
• To evaluate the safety and tolerability of Cannabidiol Oral Solution as adjunctive 
therapy with vigabatrin as initial therapy in treating patients with Infantile Spasms.  
 
 


Insys Development Company, Inc.                                               Protocol Number INS011-16-082 
05 Jul 2018                                                    CONFIDENTIAL                                                               35  
3. 
INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design 
This is a Phase 3, double-blind, placebo-controlled, randomized, multicenter study to evaluate 
the efficacy, safety, and tolerability of Cannabidiol Oral Solution (CBD) as adjunctive therapy 
with vigabatrin as initial therapy, compared to vigabatrin alone in the treatment of infants newly 
diagnosed with Infantile Spasms (IS). Randomization will occur during Visit 2 and then 
allocated to one of two treatment groups:  
• Treatment with vigabatrin plus  
• CBD 40 mg/kg/day, or 
• Matching CBD 40 mg/kg/day placebo 
Approximately, 190 patients in total will be enrolled into one of the two treatment arms; 130 
patients in the investigational product arm with 60 patients in the placebo arm. Patients will be 
dosed approximately every 12 hours with meals to help ensure consistent plasma levels are 
achieved and to reduce variability.  
Doses of CBD exceeding 40 mg/kg/day will not be examined in this study. In addition to the 
safety assessments required by the study protocol, the investigator will monitor patients 
throughout the study as recommended in the approved product label for vigabatrin. Study 
participants will be newly diagnosed pediatric patients age 1 to 24 months (inclusive) 
experiencing infantile spasms who satisfy all inclusion/exclusion criteria. This study will be 
comprised of five periods: Screening, Initial Treatment, Extended Treatment, Taper, and Follow-
up Periods, with a maximum duration of approximately 140 days.  
The study design and patient progression through the study is outlined in Figure 1. All screening, 
efficacy, and safety evaluations will be performed according to the schedule of assessments 
summarized in Table 1. 
Each newly diagnosed patient with Infantile Spasms will complete a Screening Period and will 
have up to 14 days to enroll in the study.  
Patients will have a, minimum of a 9-hour video EEG that includes at least one full sleep-wake 
cycle during their Screening Visit to establish their baseline level of infantile spasms and 
hypsarrythmia and a 24-hour video EEG at Visit 5 (Day 14 to Day 15 ) of the Initial Treatment 
Period to establish their final level of infantile spasms and hypsarrythmia. A blinded central 
reader, not involved in the study, will evaluate the video EEGs and determine responder status. 
Details of the video EEG assessment will be provided in the video-EEG Charter. The treatment 
response categories are summarized in Table 2. In addition, a 9-hour video EEG will be 
conducted during the Extended Treatment Period to confirm parent/caregiver report of relapse. If 
possible, a 9-hour video EEG will be conducted for patients who have continued into the 
Extended Treatment Period and decided to Early Withdraw. A video EEG is not required for 
patients who decide to withdraw during the Initial Treatment Period. 
 


Insys Development Company, Inc.                                               Protocol Number INS011-16-082 
05 Jul 2018                                                    CONFIDENTIAL                                                               36  
Table 2: 
Video EEG Response Definitions 
Response Category 
Definition 
Complete Response  
Complete resolution of spasms and hypsarrythmia confirmed 
by video EEG  
Partial Response  
Complete resolution of either spasms or hypsarrythmia 
confirmed by video EEG 
Non-Response 
No improvement or worsening of spasms/hypsarrythmia 
burden  
3.1.1. 
Initial Treatment Period 
• Day 1 (Visit 2): Patients will receive the initial titration dose of vigabatrin (50 
mg/kg/day divided twice daily [BID]), and either CBD 20 mg/kg/day plus matching 
CBD 20 mg/kg/day placebo or CBD 40 mg/kg/day placebo, each drug administered 
BID for 3 days. 
• Day 4 (Visit 3): Patients will return to the study center to evaluate medical status 
(seizure diary, vital signs, and neurological exam), clinical laboratory assessments, 
concomitant medications, height/weight, and assess adverse events (AEs). For those 
patients who tolerate the initial dose, the dose for vigabatrin will be increased to 100 
mg/kg/day BID, and either CBD 30 mg/kg/day and matching CBD placebo 10 
mg/kg/day, or matching CBD 40 mg/kg/day BID placebo for 3 days.  
• Day 7 (Visit 4): Patients will return to the study center to evaluate medical status 
(seizure diary, vital signs, and neurological exam), clinical laboratory assessments, 
concomitant medications, height/weight, and assess AEs.  For those patients who 
tolerate the increased doses, the dose of vigabatrin will be increased to 150 mg/kg/day 
and CBD or CBD placebo to 40 mg/kg/day for the remaining 9 days. Vigabatrin, 
CBD, and matching placebo will be administered in a twice daily fashion at 12-hour 
intervals with meals. 
As part of their standard of care, investigators will assess safety and tolerability of the treatment 
regimens throughout the study period. All subjects will continue on their treatment until 
confirmation from the central reader on the 24-hour video EEG and clinical laboratory results are 
received. 
3.1.2. 
Extended Treatment Period 
Following the Initial Treatment Period:  
• Complete Responders will continue receiving their assigned treatments of vigabatrin 
plus either CBD 40 mg/kg/day or placebo for 75 days, until Week 13 (Day 90), to 
monitor progress for treatment response.  
• During the Extended Treatment Period, the investigator may reduce the dose of CBD 
or CBD placebo to 30 mg/kg/day for safety or tolerability. If the subjects cannot 
tolerate the 30 mg/kg/day, the drug will be discontinued and the patient withdrawn 
from the study following the completion of the taper period. 


Insys Development Company, Inc.                                               Protocol Number INS011-16-082 
05 Jul 2018                                                    CONFIDENTIAL                                                               37  
3.1.3. 
Partial Responders 
• Partial responders will be offered the opportunity to enroll in an open-label safety 
study that allows investigators to combine standard-of-care treatment with CBD. 
3.1.4. 
Taper Period 
Following the completion of the Initial Treatment Period (Visit 6), partial responders who do not 
enroll in the open-label safety study and non-responders will have vigabatrin and CBD tapered as 
follows:  
• Vigabatrin taper: 150 mg/kg/day will be reduced to 100 mg/kg/day for 3 days, then 
the 100 mg/kg/day dose will be reduced to 50 mg/kg/day for 3 days, and then 
discontinued.  
• CBD or CBD Placebo taper: 40 mg/kg/day will be reduced to 30 mg/kg/day for three 
days, then 30 mg/kg/day will be reduced to 20 mg/kg/day for 3 days, and then 
discontinued.  
Complete Responders will be tapered off vigabatrin and CBD or CBD placebo at the completion 
of the Extended Treatment Period, and all patients will be tapered off at any Early Withdrawal 
Visits, using the same schedules as described above.  
If the investigator decides to continue vigabatrin as a treatment for patients after the end of study 
or early withdrawal, tapering of vigabatrin will be left to the discretion of the PI.  
CBD requires tapering off at the End of Study or at the Early Withdrawal visit. 
3.1.5. 
Follow-up Period 
A follow-up phone call will occur for all subjects 30 days after discontinuation of the study drug 
to assess AEs, AETs, and record concomitant medications. 


Insys Development Company, Inc.                                              
 Protocol Number INS011-16-082 
05 Jul 2018                                                              
                     CONFIDENTIAL                                                                                        38  
Figure 1:  
Study Design Schematic 
 
 
 
 
Vigabatrin + 
Matching CBD 
Placebo
9 days
SCREENING
PERIOD
14 days
Vigabatrin + 
CBD 40 mg/kg/d
9 days
EXTENDED 
TREATMENT 
PERIOD
75 days
Titration
6 days
Complete 
Responder?
TAPER 
PERIOD
6 days
FOLLOW-UP
PERIOD
30 days
Y
 N
Partial 
Responder?
INITIAL TREATMENT PERIOD
15 days
OPEN-LABEL 
SAFETY STUDY
INS011-18-120
Y
 N


Insys Development Company, Inc.                                               Protocol Number INS011-16-082 
05 Jul 2018                                           CONFIDENTIAL                                                                         39  
3.2. 
Patient Selection  
Each patient must satisfy all of the following inclusion and exclusion criteria. 
3.2.1. 
Inclusion Criteria 
All patients must satisfy the following criteria to be considered for study participation: 
1. Parent(s)/caregiver(s) fully comprehend and sign the informed consent form, understand 
all study procedures, and can communicate satisfactorily with the investigator and study 
coordinator, in accordance with applicable laws, regulations, and local requirements. 
2. Male or female between 1 months to 24 months of age (inclusive) at time of consent. 
3. Clinical diagnosis of infantile spasms, confirmed by video-EEG analysis (including at 
least one cluster of electroclinical spasms [≥3 in any 10-minute epoch)] and 
hypsarrythmia) obtained during the Screening Period and read by a central reader. 
4. General good health (defined as the absence of any clinically relevant abnormalities as 
determined by the investigator) based on physical and neurological examinations, 
medical history and clinical laboratory values completed during the Screening Visit 
(Visit 1).  
5. In the opinion of the investigator, the parent(s)/caregiver(s) is (are) willing and able to 
comply with the study procedures and visit schedules. 
3.2.2. 
Exclusion Criteria 
Patients will be excluded for any of the following: 
1. Is considered by the investigator, for any reason (including, but not limited to, the risks 
described as precautions, warnings, and contraindications in the current version of the 
Investigator’s Brochure for Cannabidiol Oral Solution) to be an unsuitable candidate to 
receive the study, 
2. Known or suspected allergy to cannabidiol. 
3. History of an allergic reaction or a known or suspected sensitivity to any substance that is 
contained in the investigational product formulation. 
4. Use of any cannabidiol/cannabis product within 30 days of study entry. 
5. Patient is diagnosed or at high risk of having tuberous sclerosis. 
6. Patient has received treatment with either vigabatrin, ACTH, or high-dose steroids 
previously. 
7. Previous or concomitant therapy with felbamate, clobazam, valproic acid, or the 
ketogenic diet. 
8. Patient currently on any disallowed CYP3A4-related medication listed in Appendix 1 
(phenytoin, fluvoxamine, carbamazepine, and St. John’s Wort). 
9. Previously received any investigational drug or device or investigational therapy within 
30 days before Screening. 


Insys Development Company, Inc.                                               Protocol Number INS011-16-082 
05 Jul 2018                                           CONFIDENTIAL                                                                         40  
10. Clinically significant abnormal laboratory values, including: liver function tests (LFTs) 
such as albumin, direct bilirubin, total bilirubin, aspartate aminotransferase (AST), and 
alanine aminotransferase (ALT) ≥3 times the upper limit of normal (ULN). The 
investigator may deem the patient eligible if he or she judges the laboratory values to be 
not clinically significant.  
3.3. 
Removal of Patients from Therapy or Assessment 
Patients will be allowed to discontinue their participation in the study at any time for any reason 
(withdrawal of consent).  
The inclusion/exclusion criteria in Sections 3.2.1 and 3.2.2  are to be followed explicitly. If a 
patient who does not meet enrollment criteria is inadvertently enrolled, that patient should be 
withdrawn from the study and the Sponsor must be contacted.   
In addition, participation in this clinical study may be discontinued by the Investigator or by the 
sponsor for any of the following reasons: 
• Intolerable side effects of the study product. 
• Changes in medical status or medical condition of the patient such that the 
Investigator believes that patient safety will be compromised or that it would be in the 
best interest of the patient to stop treatment.  
• Patient safety or welfare is at risk. 
• Non-compliance with study visits, defined as failure to perform any portion of 
scheduled assessments or procedures. 
• Any unforeseen event that in the opinion of the treating physician and/or the Principal 
Investigator, will prevent the research participant from continuing in this study. 
• Sponsor decides to stop the study. 
In the event of a patient’s withdrawal, the investigator will promptly notify the sponsor. 
Patients who withdraw from the study early will complete an Early Withdrawal Visit. Should 
any patient choose to withdraw early from the study, they will be advised of the safety 
precautions to be taken and will be followed until resolution of any AE or until the unresolved 
AEs are judged by the investigator to have stabilized. 
If a patient discontinues the study prematurely, the investigator’s impression of efficacy and 
tolerability of the study drug, as evaluated by the Clinical Global Impression – Global 
Improvement (CGI-I) assessment, will be assessed and recorded immediately before 
discontinuation. If possible, the parent/caregiver will be encouraged to have an Early Withdrawal 
visit with 9-hour video-EEG. 
3.4. 
Dose Adjustment Criteria 
During the Extended Treatment Period, the investigator may reduce the dose of CBD or CBD 
placebo once from 40 mg/kg/day to 30 mg/kg/day for safety or tolerability. In addition, tapering 
of vigabatrin and CBD will be required as described in Section 3.1.4. 


Insys Development Company, Inc.                                               Protocol Number INS011-16-082 
05 Jul 2018                                           CONFIDENTIAL                                                                         41  
3.5. 
Stopping Rules 
The Investigator reserves the right to terminate the study in the interest of patient safety and 
welfare. The Sponsor reserves the right to terminate the study at any time for administrative 
reasons.  Patients will also be discontinued when their liver enzymes and serum bilirubin reach: 
• ALT or AST > 8 x ULN. 
• ALT or AST > 5 x ULN for more than 2 weeks. 
• ALT or AST > 3 x ULN and (TBL>2 x ULN or INR>1.5). 
• ALT or AST > 3 x ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%). 


Insys Development Company, Inc.                                               Protocol Number INS011-16-082 
05 Jul 2018                                           CONFIDENTIAL                                                                         42  
4. 
TREATMENTS 
4.1. 
Treatments Administered  
4.1.1. 
Initial Treatment Period 
On Day 1 (Visit 2), patients will receive the initial titration dose of vigabatrin (50 mg/kg/day 
divided twice daily [BID]), and either CBD 20 mg/kg/day plus matching CBD 20 mg/kg/day 
placebo or CBD 40 mg/kg/day placebo BID for 3 days. 
Following the 3-day titration, on Day 4 (Visit 3) vigabatrin will be increased to 100 mg/kg/day 
[BID], and either CBD 30 mg/kg/day and matching CBD placebo 10/mg/kg/day or matching 
CBD 40 mg/kg/day placebo BID for 3 days.  
On Day 7 (Visit 4) vigabatrin will be increased to 150 mg/kg/day plus CBD 40 mg/kg/day 
administered twice daily for the remaining 9 days. Placebo patients will receive CBD 
40 mg/kg/day placebo BID for 15 days. All subjects will continue on their treatment at the end of 
study until confirmation from the central reader on the 24-hour video EEG and clinical 
laboratory results are received. 
4.1.2. 
Extended Treatment Period 
Following the Initial Treatment Period:  
• Complete Responders will continue receiving their assigned treatments of vigabatrin 
plus either CBD 40 mg/kg/day or placebo for 75 days, until Week 13 (Day 90), to 
monitor progress for treatment response.  
• During the Extended Treatment Period, the investigator may reduce the dose of CBD 
or CBD placebo to 30 mg/kg/day for safety or tolerability. If the subjects cannot 
tolerate the 30 mg/kg/day, the drug will be discontinued and the patient withdrawn 
from the study following the completion of the Taper Period. 
4.1.3. 
Partial Responders 
• Partial responders will be offered the opportunity to enroll in an open-label safety 
study that allows investigators to combine standard-of-care treatment with CBD.  
4.1.4. 
Taper Period 
Following the completion of the Initial Treatment Period (Visit 6), partial responders who do not 
enroll in the open-label safety study and non-responders will have vigabatrin and CBD or CBD 
placebo tapered as follows:  
• Vigabatrin taper: 150 mg/kg/day will be reduced to 100 mg/kg/day for 3 days, then 
the 100 mg/kg/day dose will be reduced to 50 mg/kg/day for 3 days, and then 
discontinued.  
• CBD or CBD Placebo taper: 40 mg/kg/day will be reduced to 30 mg/kg/day for three 
days, then 30 mg/kg/day will be reduced to 20 mg/kg/day for 3 days, and then 
discontinued.  


Insys Development Company, Inc.                                               Protocol Number INS011-16-082 
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Complete Responders will be tapered off vigabatrin and CBD or CBD placebo at the completion 
of the Extended Treatment Period, and all patients will be tapered off at any Early Withdrawal 
Visits, using the same schedules as described above. If the investigator decides to continue 
vigabatrin as a treatment for patients at the end of study or early withdrawal, tapering of 
vigabatrin will be left to the discretion of the PI.  
CBD requires tapering off at the End of Study or at the Early Withdrawal visit. 
4.2. 
Method of Assigning Patients to Treatment Groups 
Following confirmation of eligibility, patients will be randomized into one of two investigational 
product dose groups (vigabatrin plus CBD 40 mg/kg/day or vigabatrin plus matching placebo).  
The randomization schedule will be computer generated by using a permuted block algorithm 
and will randomly allocate the IP to randomization numbers. The randomization numbers will be 
provided to the drug packager who will prepare blinded drug kits. The randomization schedule 
will be prepared by the sponsor or sponsor’s representative before the start of the study. No one 
involved in the study performance will have access to the randomization schedule before official 
unblinding of treatment assignment. No subject will be randomized into this study more than 
once. 
4.3. 
Blinding and Unblinding Treatment Assignment 
This is a double-blind study with vigabatrin, CBD, and matched CBD placebo components.  
Study centers will be provided with three dosage levels of CBD (20 mg/kg/day, 30 mg/kg/day, 
40 mg/kg/day, and matching placebos) in identical packaging, and three dosage levels of 
vigabatrin (50 mg/kg/day, 100 mg/kg/day, and 150 mg/kg/day), matched with the randomization 
schedule for that center. 
All patients and study personnel involved in the conduct of the study, including data 
management, will be blinded to the Initial Treatment Period. 
Study personnel will endeavor to safeguard the integrity of the study blind to minimize bias in 
the conduct of the study. Treatment unblinding is discouraged if knowledge of the treatment 
assignment will not materially change the planned management of a medical emergency.  
Unblinding will be permitted in a medical emergency that requires immediate knowledge of the 
patient’s treatment assignment. Unblinding should be discussed in advance with the sponsor, 
sponsor’s representative, or medical monitor if possible. For emergency unblinding, study 
personnel will contact the sponsor or sponsor’s representative. If the investigator is not able to 
discuss treatment unblinding in advance, then he or she must notify the sponsor, sponsor’s 
representative, or medical monitor as soon as possible about the unblinding incident without 
revealing the patient’s treatment assignment. The investigator or designee must record the date 
and reason for study unblinding in the source document for that patient. In all cases that are not 
emergencies, the investigator must discuss the event with the sponsor, sponsor’s representative, 
and/or medical monitor prior to unblinding the patient’s treatment assignment. 
If the treatment assignment is unblinded for an individual patient, study personnel will be 
notified of that patient’s treatment assignment without unblinding of the treatment assignments 
for the remaining patients in the study. Thus, the overall study blind will not be compromised. If 
a patient’s treatment assignment is unblinded, he or she may or may not be asked to withdraw 


Insys Development Company, Inc.                                               Protocol Number INS011-16-082 
05 Jul 2018                                           CONFIDENTIAL                                                                         44  
from the study. The investigator will make this decision after consultation with the sponsor, 
sponsor’s representative, or medical monitor. 
4.4. 
Dose Selection Rationale 
As described in Section 1.3.2, data suggest that doses up to 1500 mg/day of other formulations of 
cannabidiol may be safe. These dose levels were selected based on data regarding concentrations 
that have been administered with other cannabidiol products without significant safety concerns 
and accounting for the range of body weights of patients to be enrolled in this study. 
Additionally, doses up to 40 mg/kg/day were administered by the Sponsor in studies INS011-14-
029 and INS011-14-030 and were generally well tolerated. Three infants were dosed initially 
with 40 mg/kg/day in INS011-14-029 and continued on the same dose in INS011-14-030, which 
was a 48-week, long-term safety study. Two of four infants who received 20 mg/kg/day in 
INS011-14-029 titrated their dose from 20 mg/kg/day up to 40 mg/kg/day and continued 
receiving this dose throughout the long-term safety study. No infants had dose reductions in 
INS011-14-029, INS011-14-030, or INS011-15-054, the double refractory infantile spasms 
study. Thus, whether the dose was provided with or without titration, all infants generally 
tolerated the 40 mg/kg/day dose. Thus, these same doses will be administered in this study. 
4.5. 
Selection and Timing of Dose for Each Patient 
Patients will receive vigabatrin and CBD or CBD Placebo twice daily during the 15-day Initial 
Treatment Period as described in Section 4.1. Subsequently, Complete Responders will receive 
CBD or CBD Placebo and/or vigabatrin twice daily during the 75-day Extended Treatment 
Period.  
The date and time of all investigational product administrations will be documented in the case 
report form (CRF). 
4.6. 
Treatment Compliance 
The doses of vigabatrin and CBD or matching placebo will be administered at the study center 
on the days listed in Table 1 under the supervision of the investigator (or a designee). All other 
doses will be administered by a parent or caregiver. 
The Investigator, a member of the investigational staff, or a hospital pharmacist must maintain an 
adequate record of the receipt and distribution of all study medication using the Drug 
Accountability Form. These forms must be available for inspection at any time. 
All supplies of IP should be accounted for at the termination of the study and a written 
explanation provided for any discrepancies. All unused supplies and packaging materials are to 
be inventoried and returned by the Investigator to the Sponsor or a designee. The Investigator is 
not permitted to return or destroy unused clinical drug supplies or packaging materials unless 
authorized by the Sponsor or a designee. 
If the study is terminated, discontinued, suspended, or completed, all unused supplies of the 
investigational product will be returned to the Sponsor or a designee for destruction after the 
final drug accountability check has been performed. Sponsor approval is required prior to drug 
destruction. A certificate of destruction will be provided to the Sponsor. 


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05 Jul 2018                                           CONFIDENTIAL                                                                         45  
All regulations issued by the DEA or per local regulations in ex-US locations concerning the 
accountability of Schedule I medications will be followed (e.g., prevention of diversion). 
4.7. 
Permitted and Prohibited Therapies 
4.7.1. 
Permitted Therapies 
Any medications (other than those excluded by the protocol, see Section 4.7.2) that the 
investigator considers necessary for a patient’s welfare and will not interfere with the 
investigational product may be given at the Investigator’s discretion. 
4.7.2. 
Prohibited Therapies 
During the Screening, Initial Treatment, Extended Treatment, Taper, and Follow-up Periods, 
patients are not to receive the following: 
• Any cannabinoids besides the investigational drug (other formulations of CBD, Δ9-
THC, hemp oil, Realm Oil or marijuana). Exclusion criterion number 4 prohibits use 
within 30 days of study entry. 
• Felbamate. 
• Valproic acid. 
• Clobazam. 
• Corticotrophins. 
• Medication(s) that are strong CYP3A4 inhibitors or inducers or CYP3A4-sensitive 
substrates with a narrow therapeutic index. A list of these medications is provided in 
Appendix 1. 
• Systemic steroid therapy (excluding inhaled medication for asthma treatment). 
• Any other investigational drug or investigational device.  
• Introduction of new anti-epileptic therapies (AETs) during the study is prohibited. 
Patients must refrain from consumption of grapefruit, grapefruit juice, Seville oranges, Seville 
orange marmalade, or other products containing grapefruit or Seville oranges within 3 days of 
the first administration of investigational product and throughout the entire Treatment and Taper 
Periods. 
Although they are not prohibited, patients taking concomitant medications may need to be 
monitored with special care to identify any AEs arising due to the potential for altered drug 
metabolism. This is discussed in detail in Section 6.2.6.9. 


Insys Development Company, Inc.                                               Protocol Number INS011-16-082 
05 Jul 2018                                           CONFIDENTIAL                                                                         46  
5. 
 STUDY DRUG MATERIALS AND MANAGEMENT 
5.1. 
Identity of Investigational Product 
The active pharmaceutical ingredient (API) in Cannabidiol Oral Solution is a pharmaceutical-
grade synthetic cannabidiol manufactured according to cGMP. It is an off-white to pale yellow 
resin or crystal substance that is soluble in several organic solvents with an acid dissociation 
constant (pKa) of 9.64. The solution is a clear, colorless to pale yellow to brown colored solution 
filled into a 30-mL amber glass bottle. More detailed information may be found in the IB. 
5.2. 
Labeling and Packaging 
5.2.1. 
Labeling 
The labels for the investigational product will contain all information according to regulatory 
requirements. 
5.2.2. 
Packaging 
A description of the drug products may be found in Table 3. The investigational product will be 
supplied in 30 mL containers of a 100 mg/mL strength (i.e., 3000 mg per container). 
Table 3: 
Description of Drug Product (20 mg/kg/day, 30 mg/kg/day, 40 mg/kg/day) 
Non-proprietary or common name of drug 
product 
Cannabidiol Oral Solution, 100 mg/mL 
Dosage form 
Oral solution 
Strength 
100 mg/mL 
The investigational product will be clearly marked according to FDA and/or ICH requirements 
regarding use for clinical study investigation only and will be labeled with the investigational 
product name, study reference number, and storage conditions. It is the responsibility of the 
Investigator to ensure that accurate accountability records are maintained throughout the study.  
Study center staff will dispense the investigational product according to the handling 
instructions. 
5.3. 
Dispensing and Storage 
The investigational product will be stored at a controlled room temperature (20 to 25 degrees 
Celsius, 68 to 77 degrees Fahrenheit) or refrigerated (2 to 8 degrees Celsius, 36 to 46 degrees 
Fahrenheit) at the study center.  
The investigational product will be dispensed from a Schedule I licensed study center. Ex- US 
centers must meet local regulations for dispensing investigational product. The investigator will 
provide study medication and exact dosing instructions to parent(s)/caregiver(s) for titration 
doses during Visits 2 and 3 and the full Initial Treatment Period doses during Visit 4 to be 
administered at home. Drug for the extended treatment period will be dispensed after clinical 
laboratory results and 24-hour video EEG readings have been received.  Study drug will be 
stored at room temperature. 


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Cannabis and its constituents (including cannabidiol) are Schedule I controlled substances in the 
United States and subject to all applicable local and federal laws and regulations regarding these 
products. This includes security provisions for storing the controlled substances and for 
dispensing in a manner to prevent diversion. Additionally, the Sponsor or Investigator must 
provide a statement of the quantity to be manufactured and the sources of the chemicals to be 
used or the substance. 
For US sites, the DEA regulations detail specific security requirements for storage of the 
investigational product. For ex-US sites, local regulations must be adhered to and IP must be 
securely locked in a substantially constructed cabinet. Any loss in investigational product must 
be reported to the Sponsor. Licensed practitioners must store controlled substances in a “securely 
locked, substantially constructed cabinet” and must notify the DEA of the theft or significant loss 
of any controlled substances within 1 business day of discovering such loss or theft. 
Furthermore, all practitioners are prohibited from hiring employees who have been convicted of 
a drug-related felony or who have had a DEA registration denied or revoked. 
Investigators are responsible for ensuring that all applicable licensures are in place and storage 
conditions are appropriate.   
Study centers are required to provide complete information, including CRFs and final outcomes, 
on all instances of addiction, abuse, misuse, overdose, drug diversion/drug accountability, 
discrepancies in the amount of the clinical supplies of the investigational product, 
noncompliance, protocol violations, lack of efficacy, individuals lost to follow-up, and any other 
reasons why patients dropped out of the study. 
5.4. 
Drug Accountability 
The Investigator, a member of the investigational staff, or a hospital pharmacist must maintain an 
adequate record of the receipt and distribution of all study medication using the Drug 
Accountability Form. These forms must be available for inspection at any time. 
All supplies of IP should be accounted for at the termination of the study and a written 
explanation provided for discrepancies. All unused supplies and packaging materials are to be 
inventoried and returned to the Sponsor or a designee by the Investigator. The Investigator is not 
permitted to return or destroy unused clinical drug supplies or packaging materials unless 
authorized by the Sponsor or a designee. 
If the study is terminated, discontinued, suspended, or completed, all unused supplies of the 
investigational product will be returned to the Sponsor or a designee for destruction after the 
final drug accountability check has been performed. Sponsor approval is required prior to drug 
destruction. A certificate of destruction will be provided to the Sponsor. 
All regulations issued by the DEA concerning the accountability of Schedule I medications will 
be followed (e.g., prevention of diversion). Ex- US centers will be required to follow local 
regulations. 
 


Insys Development Company, Inc.                                               Protocol Number INS011-16-082 
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6. 
STUDY ASSESSMENTS  
6.1. 
Efficacy Assessments 
To assess the efficacy of Cannabidiol Oral Solution, a 9-hour video-EEG will be completed 
during Screening and a 24-hour video-EEG will be performed from Day 14 (Visit 5) to Day 15.  
During the Extended Treatment Period, a 9-hour video-EEG will be completed to confirm 
parent/caregiver reports of relapse or complete resolution. If possible, a 9-hour video EEG will 
be conducted for patients who have continued into the Extended Treatment Period and decided to 
Early Withdraw. A video EEG is not required for patients who decide to withdraw during the 
Initial Treatment Period. 
The video EEGs should include at least one full wake/sleep cycle. Video EEGs may be first read 
by the investigator. However, no efficacy assessment will be made based on the investigator’s 
reading of the video EEG and this read will not be captured in the database. An Independent 
Central Reader will evaluate all video EEGs in a blinded manner and determine responder status 
for the primary endpoint. Details regarding requirements for the conduction of the video EEG 
and the Independent Central Reader’s review and assessment of the video EEG is outlined in the 
EEG Charter. The treatment response categories are summarized in Table 2. 
• The CGI-S will be completed by the investigator at screening. 
• The CGI-I will be completed by the investigator at Visit 6 of the Initial Treatment Period, 
or the Early Withdrawal Visit. 
• Daily seizure diaries will be completed throughout the Initial and Extended Treatment 
Periods, or the Early Withdrawal Visit.  
If a patient discontinues the study prematurely, the investigator’s impression of efficacy and 
tolerability of the study drug, as evaluated by CGI-I, will be assessed and recorded immediately 
before discontinuation. If possible, the parent/caregiver will be encouraged to have the patient 
have an Early Withdrawal video-EEG completed. 
6.2. 
Safety Assessments 
Safety assessments for all patients will include medical history, physical and neurological 
examinations, vital signs (seated or supine blood pressure [depending on patient age and ability], 
seated blood pressure, pulse rate, temperature, and respiration rate), clinical laboratory testing 
(hematology, chemistry, liver enzymes, and serum bilirubin), prior medication history 
(assessment of past/current AETs and concomitant medications), and AE assessments. The 
safety assessments will be conducted for each patient at specific study Days and Visits, as 
indicated in Table 1. In addition to the safety assessments required by the study protocol, the 
investigator will monitor patients as recommended in the current FDA-approved vigabatrin 
prescribing information. 
6.2.1. 
Demographics and Medical History 
The investigator or designee will record the following information during the Screening Period: 
demographic data, including sex, date of birth, race, ethnicity, medical history, medications 
history, and concomitant medications.  


Insys Development Company, Inc.                                               Protocol Number INS011-16-082 
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6.2.2. 
Physical Examinations 
The first physical examination will include evaluation of general appearance, ears, eyes, nose, 
and throat (EENT), heart, peripheral vasculature, lungs, musculoskeletal system, abdomen, 
endocrine system, and skin. Height/length and weight will be obtained.  Subsequent brief 
physical exams will consist of general appearance, height/length and weight. Head 
circumference will be collected. 
6.2.3. 
Neurological Examinations 
A complete neurological examination will be performed at Screening, Visit 6, Visit 9 and Early 
Withdrawal. This exam will include mental status, visual assessment, nystagmus, cranial nerves, 
motor and sensory systems, reflexes coordination and gait (if applicable based on age). A brief 
neurological exam will be completed at all other visits; this will not include a visual assessment. 
On Day 4 (Visit 3), and Day 7 (Visit 4) a brief neurological examination will be performed 
predose and approximately 2 hours following administration of the morning dose of the 
investigational product. If needed, additional visual assessments, may be performed based on the 
clinical recommendations for patient’s treatment with vigabatrin. 
6.2.4. 
Vital Signs 
Vital signs will consist of seated or supine blood pressure (depending on patient age and ability), 
pulse rate, temperature, and respiration rate measurements.  
Additional vital sign measurements may be performed as deemed medically necessary by 
research personnel. 
6.2.5. 
Clinical Laboratory Assessments 
6.2.5.1. 
Hematology 
Blood samples for the following hematology assessments will be collected: hemoglobin, 
hematocrit, total and differential leukocyte count, red blood cell (RBC), and platelet count. 
6.2.5.2. 
Chemistry 
Blood samples for the following serum chemistry assessments: albumin, blood urea nitrogen 
(BUN), creatinine, total and direct bilirubin, alkaline phosphatase (ALP), aspartate transaminase 
(AST), alanine transaminase (ALT), sodium (Na+), potassium (K+), chloride (Cl-), lactate 
dehydrogenase (LDH), uric acid, glucose, and calcium.  
6.2.6. 
Adverse Events and Serious Adverse Events 
6.2.6.1. 
Definition of Adverse Events 
An AE is defined as any untoward medical occurrence in a patient administered a pharmaceutical 
product during the course of a clinical investigation. An AE can therefore be any unfavorable 
and unintended sign, symptom, or disease temporally associated with the use of an 
investigational product, whether or not thought to be related to the investigational product. 


Insys Development Company, Inc.                                               Protocol Number INS011-16-082 
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Patients will be monitored throughout the study for AEs. Monitoring for treatment-emergent AEs 
(TEAEs) will begin as soon as the patient is dosed. All AEs must be followed until they are 
resolved or stabilized, or until all attempts to determine resolution of the event are exhausted. 
The investigator should use their discretion in ordering additional tests as necessary to monitor 
the progress of such events. 
An AE may be: 
• A new illness, not documented in the patient’s medical history; 
• Worsening of a concomitant illness; 
• An effect of the study medication; it could be an abnormal laboratory value, as well 
as a significant shift from baseline within normal range which the qualified 
investigator or medical qualified designate considers to be clinically important; 
• A combination of two or more of these factors. 
Surgical procedures themselves are not AEs. They are therapeutic measures for conditions that 
required surgery. The condition for which the surgery is required is an AE, if it occurs or is 
detected during the study period. Planned surgical measures permitted by the clinical study 
protocol and the conditions(s) leading to these measures are not AEs, if the condition(s) was 
(were) known before the start of study treatment. In the latter case, the condition should be 
reported as medical history. 
Seizures or worsening seizures are not considered AEs as they are considered part of the 
underlying disease. Injuries that occur as a result of a seizure, such as a broken nose, and new 
seizure types will be considered adverse events. 
Patients will be monitored throughout the study for AEs. All AEs must be followed until they are 
resolved or stabilized, or until all attempts to determine resolution of the event are exhausted. 
The investigator should use his/her discretion in ordering additional tests as necessary to monitor 
the progress of such events. 
Adverse events reported prior to dose administration will be recorded as part of the patient’s 
medical history. 
6.2.6.2. 
Classification of Adverse Events 
Adverse events are to be recorded on the AE page of the patient’s case report form (CRF).  
Severity will be graded according to the following definitions: 
• Mild: The patient experiences awareness of symptoms but these are easily tolerated or 
managed without specific treatment. 
• Moderate: The patient experiences discomfort enough to cause interference with 
usual activity, and/or the condition requires specific treatment. 
• Severe: The patient is incapacitated with inability to work or do usual activity, and/or 
the event requires significant treatment measures. 


Insys Development Company, Inc.                                               Protocol Number INS011-16-082 
05 Jul 2018                                           CONFIDENTIAL                                                                         51  
6.2.6.3. 
Causality: Drug Relationship Assessment 
The relationship of the event to the study drug should be determined by the investigator 
according to the following criteria: 
• Definitely related: The event follows a reasonable temporal sequence from the time of 
drug administration that cannot be explained, follows a known or expected response 
pattern to the study drug, that is confirmed by improvement on stopping and 
reappearance of the event on repeated exposure and that could not be reasonably 
explained by other factors such as the patient’s clinical condition, intercurrent illness, or 
concomitant drugs. 
• Probably related: The event follows a reasonable temporal sequence from the time of 
drug administration, and/or follows a known response pattern to the study drug, and 
cannot be reasonably explained by other factors such as the patient’s clinical condition, 
intercurrent illness, or concomitant drugs. 
• Possibly related: The event follows a reasonable temporal sequence from the time of drug 
administration, and/or follows a known response pattern to the study drug, but could have 
been produced by other factors such as the patient’s clinical condition, intercurrent 
illness, or concomitant drugs. 
• Unlikely related: The event follows little or no temporal sequence from the time of drug 
administration that makes a causal relationship improbable and/or other factors such as 
the patient’s clinical condition, intercurrent illness, or concomitant drugs is a more likely 
alternative. 
• Not related: The event is most likely produced by other factors such as the patient’s 
clinical condition, intercurrent illness, or concomitant drugs, and does not follow a 
known response pattern to the study drug, or the temporal relationship of the event to 
study drug administration makes a causal relationship unlikely. 
6.2.6.4. 
Definition of Serious Adverse Events 
A serious AE (SAE) is any AE that fulfills any of the following criteria, as per 21 CFR 312.32: 
• Results in death; 
• Is life-threatening; 
• Requires in-patient hospitalization or prolongation of existing hospitalization; 
• Results in persistent or significant disability or incapacity; 
• Is a congenital anomaly or birth defect; 
• Is medically significant or requires intervention to prevent one of the outcomes listed 
above. 
Serious AEs will be captured from the time of consent through the end of the study. 
6.2.6.5. 
Actions Taken  
Actions taken may consist of:  


Insys Development Company, Inc.                                               Protocol Number INS011-16-082 
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• None 
• Study drug discontinued 
• Dose modified 
• Required concomitant medication 
• Required procedure 
• Other 
6.2.6.6. 
Outcome at the Time of Last Observation  
The outcome at the time of last observation will be classified as: 
• Recovered/resolved 
• Recovered/resolved with sequelae 
• Not recovered/not resolved 
• Death 
• Unknown 
6.2.6.7. 
Adverse Event Recording and Reporting 
Adverse events will be recorded throughout the study in the source documents and in the CRFs. 
The investigator will rate AEs for seriousness, intensity, causality, action taken, and outcome as 
described in the previous section. 
Expedited reporting is required for serious unexpected adverse drug reactions. Fatal or 
life-threatening unexpected drug reactions must be reported by the Sponsor to regulatory 
agencies no more than 7 days after the Sponsor’s first knowledge of the reaction; followed by as 
complete a report as possible within 8 additional days. Unexpected adverse drug reactions must 
be reported no later than 15 days after the Sponsor’s first knowledge of the reaction. In order to 
comply with these requirements, the investigator or delegate must inform the Sponsor 
immediately upon occurrence of any SAE. The site will complete the SAE Report Form as 
thoroughly as possible and e-mail it to WCT within 24 hours of the investigators first knowledge 
of the event. 
These SAE reports must contain the following information: 
A. Study name/number 
B. Study drug 
C. Investigator details (name, phone, fax, e-mail) 
D. Patient number 
E. Patient initials 
F. Patient demographics 
G. Clinical event 


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1) 
Description 
2) 
Date of onset 
3) 
Treatment (drug, dose, dosage form) 
4) 
Adverse event relationship to study drug 
5) 
Action taken regarding study drug in direct relationship to the AE 
H. If the AE was fatal or life-threatening 
I. 
Cause of death (whether or not the death was related to study drug) 
J. 
Autopsy findings (if available) 
The Sponsor or its representative will be responsible for notification to regulatory agencies. 
6.2.6.8. 
Adverse Event Follow-Up 
All non-serious AEs that are not related or unlikely to be related to study treatment will be 
followed until the end of study participation. All SAEs or AEs that are considered as possibly, 
probably, or definitely related to treatment will be followed until resolution or stabilization. 
6.2.6.9. 
Monitoring of AEs Potentially Related to Drug Metabolism 
Cannabidiol inhibits drug metabolism mediated by a subset of CYP proteins (see Section 
Section 1.1.2). Thus, the Investigator and study center staff should monitor patients who are 
taking concomitant medications that are metabolized by CYP2C19, CYP2C9, CYP3A4, 
CYP1A2 or by P-glycoprotein with special care. Medication(s) that is/are strong inhibitor(s) or 
inducer(s) or sensitive substrates of CYP3A4 are exclusionary and prohibited (see Sections 3.2.2 
and Section 4.7.2). However, patients taking medications that are weak inhibitors or inducers of 
CYP3A4 should be monitored with special care.      
6.2.6.10. Data Monitoring Committee 
The Data Safety Monitoring Committee (DSMC) will consist of a least one physician with 
experience in treating IS subjects and at least one biostatistician. The DSMC ensures that the 
ethical principles are observed and monitors the safety of the subjects. To fulfil its 
responsibilities, the DSMC may have access to the clinical data. The DSMC may also meet on an 
ad hoc basis if needed. The DSMC will be informed to what extent the data and analyses 
provided to them have been quality controlled. Members of the DSMC will not be involved in 
other study-related tasks. The DSMC procedures are described in the Data Monitoring 
Committee Charter. 
6.3. 
Pharmacokinetics Assessments 
A blood sample for PK analysis of CBD and 7-OH-CBD will be obtained on Day 15  just prior 
to the second dose during the 24-hour video EEG. Whole blood will be obtained in a 
Vacutainer® tube containing K2-EDTA as a preservative. 


Insys Development Company, Inc.                                               Protocol Number INS011-16-082 
05 Jul 2018                                           CONFIDENTIAL                                                                         54  
7. 
STUDY PROCEDURES 
The assessments and procedures that will be conducted during this study are summarized in 
Table 1.  
7.1. 
Screening Period (Visit 1) 
Potential study patients will be examined before the start of the study to determine their 
eligibility for participation. Prior to performing any study related procedures or assessments, the 
Investigator will ensure that the patient’s legal representative (parent[s]/caregiver[s]) provides 
written informed consent. Patients and their parent(s)/caregiver(s) will receive a copy of the ICF 
for review and must provide fully informed consent prior to study participation.     
The following screening procedures and assessments are intended to be performed during 
Visit 1, but the patient may return to complete activities, which must be performed within 
14 days of the start of the Initial Treatment Period for all patients. 
• Obtain written informed consent. 
• Review of inclusion and exclusion criteria (see Sections 3.2.1 and 3.2.2). 
• Record demographic data. 
• Record recent and concomitant medication and procedure history including vitamins, 
herbal preparations, blood products, and over-the-counter drugs. All medications 
taken ≤30 days of the Screening Visit must be documented in the concomitant 
medications section of the CRF.  
• Record all prior and current anti-epileptic therapies (AETs, including drugs, 
ketogenic diet, vagal stimulators etc.)    
• Record medical and surgical history.  
• Record the types of seizures and the frequency of infantile spasms occurring ≤28 days 
of the Screening Visit based on parent/caregiver recollection. 
• Record vital signs (seated or supine blood pressure [depending on patient age and 
ability], pulse rate, respiratory rate, and temperature measurements). 
• Draw blood samples for hematology and chemistry. 
o Section 7.4 details the volume of samples to be drawn based on patient age. 
• Perform a complete physical examination (see Section 6.2.2), including height, 
weight, and head circumference. 
• Perform a complete neurological examination (see Section 6.2.3). 
• Perform a minimum of 9-hr video-EEG that includes a full sleep-wake cycle. 
• Completion of investigator CGI-S. 
• Provide daily seizure diary to capture seizure activity (infantile spasms only) between 
visit 1 and visit 2, and train the caregiver to recognize and capture the infantile 
spasms. 


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7.2. 
Assessments and Procedures 
7.2.1. 
Initial Treatment Period  
7.2.1.1. 
Visit 2 (Day 1) 
Once the patient has been approved for the study, they will return to the study clinic where the 
patient will be randomized to the appropriate treatment arm. Patients will receive the titration 
dose of vigabatrin (50 mg/kg/day divided twice daily [BID]), and either CBD 20 mg/kg/day plus 
matching CBD 20 mg/kg/day placebo or CBD 40 mg/kg/day placebo, each drug administered 
twice daily at 12-hour intervals for three days. 
The following procedures and assessments will be performed during Visit 2: 
• Review and record seizure diary. 
• Record concomitant medications  
• Record AEs. 
• Perform a brief neurological examination predose (see Section 6.2.3). 
• Administer the first titration dose of vigabatrin and the Investigational product and 
train caregiver(s) to measure, administer, and record doses. 
• Vital signs will be taken after approximately 5 minutes seated or supine, depending 
on patient ability. Vital signs should be taken predose and at approximately 4 hours 
postdose.   
7.2.1.2. 
Day 2 and Day 3 
• The Investigator or designee will follow up by phone or E-mail for the first three days 
of the Initial Treatment Period, and record any AEs. 
• Administer prescribed titration dose at approximately 12-hour intervals by the 
parent/caregiver.  
• Parent/caregiver should also complete the seizure diary.  
7.2.1.3. 
Visit 3 (Day 4) 
Patients will receive 100 mg/kg/day divided twice daily of vigabatrin and (30 mg/kg/day CBD 
and CBD placebo 10 mg/kg/day or matching CBD 40 mg/kg/day placebo) divided twice daily 
for 3 days, according to the patient's assigned cohort. the following procedures and assessments 
will be performed on Day 4 for all patients prior to IP administration: 
• Record concomitant medications 
• Record vital signs (seated of supine blood pressure [depending on patient age and 
ability], pulse rate, respiratory rate, and temperature)  
• Record height and weight. 
• Perform a brief neurological examination predose (see Section 6.2.3). 


Insys Development Company, Inc.                                               Protocol Number INS011-16-082 
05 Jul 2018                                           CONFIDENTIAL                                                                         56  
• Draw blood samples for hematology and chemistry. 
o Section 7.4 details the volume of samples to be drawn based on patient age. 
• Record AEs. 
• Record and review daily seizure diary.  
• Administer dose of vigabatrin and investigational product 
 The following activities will occur after administration of the morning dose of the 
investigational product: 
• Perform an additional brief neurological examination approximately 2 hours 
postdose. 
• Records AEs. 
Patients will be released from the study center after assessments are complete.  
7.2.1.4. 
Visit 4 (Day 7) 
Patients will receive 150 mg/kg/day divided twice daily of vigabatrin and (40 mg/kg/day CBD 
day or matching CBD placebo) twice daily for 9 days, according to the patient's assigned cohort. 
The following procedures and assessments will be performed on Day 7 for all patients prior to IP 
administration: 
• Record concomitant medications. 
• Record vital signs (seated of supine blood pressure [depending on patient age and 
ability], pulse rate, respiratory rate, and temperature). 
• Record height and weight. 
• Perform a brief neurological examination predose (see Section 6.2.3). 
• Draw blood samples for hematology and chemistry. 
o Section 7.4 details the volume of samples to be drawn based on patient age. 
• Record AEs. 
• Record and review daily seizure diary.  
• Administer dose of vigabatrin and investigational product. 
The following activities will occur after administration of the morning dose of the investigational 
product: 
• Perform an additional brief neurological examination approximately 2 hours 
postdose. 
• Records AEs.  


Insys Development Company, Inc.                                               Protocol Number INS011-16-082 
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7.2.1.5. 
Days 7-15  
• Patients will receive 150 mg/kg/day divided twice daily of vigabatrin and (40 mg/kg/day 
CBD or matching CBD placebo) from Day 7 through Day 15. Doses will be administered 
at approximately 12-hour intervals by the parent/caregiver.  
• Parent/caregiver should complete the seizure diary daily and note any adverse events. 
The investigator or designee will follow up by phone or e-mail on Days 9 to 11. 
7.2.1.6. 
Visit 5 (Day 14) 
On Day 14, patients will be admitted to the study center before the morning administration of 
vigabatrin and the investigational product and assessments. The following assessments will be 
completed PRIOR to administration of the morning dose of vigabatrin and the investigational 
product: 
• Record concomitant medications.  
• Record vital signs (seated or supine blood pressure [depending on patient age and 
ability], pulse rate, respiratory rate, and temperature measurements). 
• Record height and weight. 
• Perform a brief neurological examination (see Section 6.2.3). 
• Record AEs. 
• Record and review daily seizure diary.  
• Start meal diary collection. 
. The following assessments will be completed after administration of the morning doses of 
vigabatrin and the investigational product: 
• Start the 24-hour video EEG assessment. 
7.2.1.7. 
Visit 6 (Day 15, End of Study for the Initial Treatment Period) 
The following activities will occur on Day 15, at approximately 24 hours post the Day 14 
morning dose: 
• Complete the 24-hour video EEG assessment. 
• Record concomitant medications and AETs 
• Record vital signs (seated or supine blood pressure [depending on patient age and 
ability], pulse rate, respiratory rate, and temperature measurements). 
• Record height and weight and head circumference. 
• Perform a complete neurological examination (see Section 6.2.3). 
• Draw blood samples for hematology, chemistry and PK analysis. PK analysis will be 
obtained on Day 15 just prior to the second dose during the 24-hour video EEG. 
o Section 7.4 details the volume of samples to be drawn based on patient age. 


Insys Development Company, Inc.                                               Protocol Number INS011-16-082 
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• Record and review daily seizure diary. 
• Record AEs. 
• Completion of investigator CGI-I.  
• Complete meal diary collection. 
• Administer dose of vigabatrin and investigational product 
Patients will be discharged from the study center after assessments are complete. Subjects will 
continue treatment until confirmation of treatment response after 24-hour video EEG and clinical 
laboratory results are received. 
7.2.2. 
Taper Period 
Following the completion of the Initial Treatment Period (Visit 6), partial responders who do not 
enroll in the open-label safety study and non-responders will have vigabatrin and CBD or CBD 
placebo tapered as follows: 
• Vigabatrin taper: 150 mg/kg/day will be reduced to 100 mg/kg/day for 3 days, then 100 
mg/kg/day will be reduced to 50 mg/kg/day for 3days and then discontinued.  
• CBD or CBD placebo taper: CBD: 40 mg/kg/day will be reduced to 30 mg/kg/day for 3 
days, 30 mg/kg/day will be reduced to 20 mg/kg/day for 3 days, and then discontinued.  
Complete Responders will be tapered off vigabatrin and CBD or CBD placebo at the completion 
of the Extended Treatment Period, and all patients will be tapered off at any Early Withdrawal 
Visits, using the same schedules as described above.  
If the investigator decided to continue vigabatrin as a treatment for patients at the end of the 
study of at early withdrawal, tapering of vigabatrin will be left to the discretion of the PI.  
CBD requires tapering off at the End of Study or at the Early Withdrawal visit. The following 
assessments will be performed during this period: 
• Concomitant medications and AETs.  
• Administer dose of vigabatrin and investigational product 
• Record AEs. 
• Record and review daily seizure diary. 
7.2.3. 
Extended Treatment Period (Visit 7/Week 6, Visit 8/Week 10, and 
Visit 9/Week 13) 
Following the Initial Treatment Period, Complete Responders will continue receiving their 
assigned treatments of vigabatrin plus either CBD 40 mg/kg/day or matching placebo for 
75 days, until Week 13 (Day 90).  
The following assessments and procedures will be completed at Visit 7 (Week 6), Visit 8 
(Week 10), and Visit 9 (End of Study; Week 13): 
• Record concomitant medications and AETs.  


Insys Development Company, Inc.                                               Protocol Number INS011-16-082 
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• Record vital signs (seated or supine blood pressure ([depending on patient age and 
ability)], pulse rate, respiratory rate, and temperature measurements). 
• Record height, weight  
• Head circumference (Visit 9, Week 13) 
• Perform a brief neurological examination for Visits 7 and 8 and complete 
neurological exam for Visit 9 (EOS) (see Section 6.2.3) 
• Record AEs. 
• Administer dose of vigabatrin and investigational product 
• Draw blood samples for hematology and chemistry. 
o Section 7.4 details the volume of samples to be drawn based on patient age. 
• Record and review daily seizure diary. 
In addition, a 9-hour video EEG will be performed to confirm parent/caregiver report of relapse. 
All patients will begin tapering off CBD and vigabatrin at the end of this period (Visit 9; see 
Section 7.2.2). 
7.2.4. 
Partial Responders 
Partial responders will be offered the opportunity to enroll in an open-label safety study that 
allows investigators to combine standard-of-care treatment with CBD or up to .. 
7.2.5. 
Early Withdrawal Visit  
Should a patient’s participation be terminated prior to Day 14 or Day 90 for any reason (see 
Section 3.3), an Early Withdrawal Visit will be completed. The following procedures will be 
completed: 
• Record concomitant medications and AETs. 
• Record vital signs (seated or supine blood pressure ([depending on patient age and 
ability)], pulse rate, respiratory rate, and temperature measurements). 
• Record height and weight and head circumference. 
• Record and review daily seizure diary. 
• Perform a complete neurological examination (see Section 6.2.3). 
• Complete investigator CGI-I. 
• Record AEs. 
• Perform 9-hour video EEG, if possible only for patients that continued into the 
Extended Treatment Period. 
• Draw blood samples for hematology and chemistry.  
o Section 7.4 details the volume of samples to be drawn based on patient age. 


Insys Development Company, Inc.                                               Protocol Number INS011-16-082 
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All patients will begin tapering off investigational product and vigabatrin at this visit (see 
Section 7.2.2). 
7.2.6. 
Follow-up Period 
A follow-up phone call will occur for all subjects 30 days after discontinuation of the study drug 
to assess AEs, AETs, and record concomitant medications. 
7.2.7. 
Follow-up of Adverse Events 
Any AEs observed from the Screening Visit until the end of the study will be followed to 
resolution. Resolution means that the subject has returned to a baseline state of health or the 
Investigator does not expect any further improvement or worsening of the AE. All AEs that 
occur after the subject completed a clinical study should also be reported to the Sponsor within 
30 days of the last dose of study drug. 
7.3. 
Investigational Product PK Sample   
A blood sample for PK analysis of CBD and 7-OH-CBD will be obtained while inpatient on 
Visit 6 (Day 15, EOS) just prior to the second dose during the 24-hour video EEG. A meal-diary 
will need to be completed on Visit 5 (Day 14) and Visit 6 (Day 15).  
7.4. 
Sample Collection for Patients  
The frequency for PK and safety laboratory samples has been adjusted to avoid excessive blood 
loss in a subset of patients. Multiple standards may be used to determine maximum acceptable 
blood loss in a clinical study. In this study, sample volumes will be adjusted for patients based on 
age to ensure that an excessive amount of blood is not removed. Two (2) metrics that are used to 
determine this volume are discussed below. 
• As per the requirements of the Office for Human Research Protections, no more than 
3 mL/kg per 8-week period should be removed.   
• As per the National Institutes of Health, no more than 7 mL/kg per 6-week period 
should be removed. 
Given the duration of this study, this effectively means that blood loss should not exceed 
approximately 3 mL/kg of body weight per patient for the entire study. 


Insys Development Company, Inc.                                               Protocol Number INS011-16-082 
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8. 
STATISTICS  
The detailed descriptions of statistical analysis methods and data conventions will be in a 
separate document, the Statistical Analysis Plan (SAP). Any post-hoc analyses will be identified 
in the final clinical study report. This section presents general information about statistical 
considerations and concepts such as randomization, statistical power, and sample size. There will 
also be a brief discussion on analysis methodology, as well as some data conventions. 
8.1. 
Study Endpoints 
8.1.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint in this study is: 
• 
Percent of patients who are considered complete responders, defined as complete resolution 
of spasms and hypsarrhythmia, confirmed by 24-hour video EEG from Day 14 to Day 15, as 
determined by the Independent Central Reader. 
8.1.2. 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints in the Initial Treatment Period of this study are: 
• Percent of patients with resolution of infantile spasms as assessed by 24-hour 
video EEG from Day 14 to Day 15 (partial response).  
• Percent of patients with resolution of hypsarrhythmia as assessed by 24-hour 
video EEG from Day 14 to Day 15 (partial response). 
• Investigator impression of efficacy and tolerability of study drug (CGI-I) at Visit 6 
(End of Study), or Early Withdrawal. 
• Increase in the number of spasm-free days between Day 1 and Day 15 of the Initial 
Treatment Period, as determined by the seizure diary entries. 
• For patients with a complete response during the Initial Treatment Period who 
continue: percent of patients who relapse during the Extended Treatment Period 
confirmed by video EEG following parent report of relapse, and time to relapse. 
8.1.3. 
Safety Endpoints 
The safety endpoints of this study are the incidence of treatment-emergent AEs (TEAEs), clinical 
laboratory assessments, vital signs (blood pressure, pulse rate, respiration rate, and temperature), 
physical and neurological examination assessments, medical history, and prior and concomitant 
medications, liver enzymes, and serum bilirubin. 
8.2. 
Sample Size Determination 
A total of 190 patients (130 and 60 patients in the two groups) will provide 80% power with a 
two-sided alpha of 0.05 to detect a difference in response rate, assuming the response with 
vigabatrin alone is 40% and the response with vigabatrin with Cannabidiol Oral Solution is 60%.   


Insys Development Company, Inc.                                               Protocol Number INS011-16-082 
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8.3. 
Analysis Populations 
Statistical analysis will be done on the following populations: 
• Intent to Treat (ITT) Population: The ITT Population will include all patients who 
were randomized.   
• Safety Population: The Safety Population will include all patients who were treated 
with at least one dose of the study drug.  Patients will be analyzed according to the 
actual treatment they receive.   
• PK Population: The PK Population will include all patients who were treated with at 
least one dose of the study drug and have at least one usable PK measurement. 
8.4. 
Statistical Analyses 
The results of this study will be reported using summary tables, listings, and figures (TLFs), as 
appropriate. Continuous variables will be summarized using descriptive statistics (sample size 
[n], mean, standard deviation [SD], coefficient of variation [CV%; as appropriate], median, 
minimum, maximum, and geometric mean and geometric CV% [as appropriate for PK 
parameters]). Categorical variables will be summarized by presenting the number (frequency) 
and percentage in each category. Differences between treatment groups will be assessed by 
ANCOVA for continuous variables and a chi-square test for categorical variables. Pearson’s 
correlation will be used to quantify the relationship between covariates of interest, and logistic 
regression may be used to simultaneously assess the relationship of multiple variables on 
treatment response (if enrollment provides sufficient sample size). Time to Relapse will be 
described with Kaplan-Meier Curves and treatment groups compared with a log-rank test. 
8.4.1. 
Study Patients and Demographics 
8.4.1.1. 
Disposition and Withdrawals 
The numbers of patients randomized, completing, and withdrawing, along with reasons for 
withdrawal, will be tabulated overall and by treatment group. The number of patients in each 
analysis population will be reported. 
8.4.1.2. 
Protocol Deviations 
Protocol deviations will be identified and listed. 
8.4.1.3. 
Demographics and Other Baseline Characteristics 
These analyses will be conducted for the safety populations. 
Demographic and baseline characteristics (including sex, age, gender, ethnicity, race, 
height/length, and weight) will be summarized by descriptive statistics. No formal statistical 
analyses will be performed. Medical history and clinical laboratory test results will be listed. 
Prior and concomitant medications will be summarized by the number and percentage of patients 
taking each medication. They will also be classified by using the World Health Organization 
Drug Dictionary Anatomical Therapeutic Chemical classes and preferred terms. 


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8.4.2. 
Exposure and Compliance 
The exposure to study medication will be summarized by descriptive statistics. 
8.4.3. 
Efficacy Analyses 
A 9-hour video EEG will be conducted during the Screening Period (Baseline) and a 24-hour 
video EEG will be conducted from Day 14 to Day 15 of the Initial Treatment Period. In addition, 
to confirm parent/caregiver report of relapse or complete resolution a 9-hour video EEG will be 
conducted during the Extended Treatment Period. For each video EEG, the number of spasms 
will be counted and the presence of hypsarrhythmia determined. Change from Baseline for each 
measure will be summarized by the median difference. Patients will be defined as having 
Complete Response, Partial Response, or Non-Response on Day 15 as defined in Table 2, the 
percentage of patients who achieve a Complete Response and Partial Responders in each 
treatment arm will be compared using a chi-square test. 
The results of the CGI-I assessments will be listed and summarized by descriptive statistics as 
appropriate. The responses to the seizure diary will also be summarized by dose level and 
scheduled time point. All efficacy summaries will be based on the ITT Population. 
Details of these summaries will be provided in the SAP. For all inferential statistical tests, a 
2-sided type I error rate of 0.05 will be used throughout.  
For the secondary efficacy endpoints, to maintain the trial-wise type I error rate at 0.05, a fixed 
sequence multiple comparisons correction with fallback will be used. The assignment of alpha 
levels to hypotheses being tested will be specified in the SAP. 
For endpoints that are continuous in nature number, the number of observations, mean, median, 
minimum and maximum, and standard deviation (SD) values will be presented as descriptive 
statistics. For inferential statistics:  
• If the normality assumption is met, analysis of covariance (ANCOVA) using the 
baseline value as a covariate will be used.  
• If the normality assumption is not met, a rank-ANCOVA analysis i.e., an ANCOVA 
analysis on rank-transformed data or other non-parametric methods will be used.  
• Time to event analyses will be described with Kaplan-Meier curves and treatment 
groups compared with log-rank tests. 
For endpoints that are categorical in nature, frequency, counts, and percentages will be presented 
as descriptive statistics, and a chi-square test will be used for inferential statistics. 
8.4.3.1. 
Primary Efficacy Analysis 
• Percent of patients with complete resolution of both infantile spasms and 
hypsarrhythmia at Day 15 (complete response) will be compared between vigabatrin 
plus placebo and vigabatrin plus CBD 40 mg/kg/day groups using a chi square test.   
8.4.3.2. 
Secondary Efficacy Analyses 
•  Percent of patients who relapse during the Extended Treatment Period will be 
compared between 14-day vigabatrin + CBD responders and 14-day vigabatrin + 


Insys Development Company, Inc.                                               Protocol Number INS011-16-082 
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placebo responders using a chi-square test. Time to relapse will be described with 
Kaplan-Meier curves and treatment groups compared using a log-rank test. 
• Percent of patients with complete resolution of infantile spasms at Day 15 will be 
compared between treatment groups using a chi-square test. 
• Percent of patients with complete resolution of hypsarrhythmia at Day 15 using a 
chi-square test. 
• Investigator impression of efficacy and tolerability of study drug (Clinical Global 
Impression – Global Improvement [CGI-I]) will be compared between treatment 
groups using ANCOVA with baseline CGI-S as a covariate. 
• Percent reduction in spasm-free days between the Initial Treatment Period and 
Screening Period will be compared between treatment groups using ANCOVA with 
the baseline score as a covariate. 
Secondary efficacy analyses for patients with a complete response during the Initial Treatment 
Period who continue to the Extended Treatment Period: 
• Percent of patients who relapse during the Extended Treatment Period confirmed by 
video EEG following parent report of relapse.  
• Time to relapse. 
8.4.4. 
Safety and Tolerability Analyses 
The Safety Population will be used for all safety assessments. All safety assessments will be 
descriptive and no inferential statistics are planned for safety assessments. All data listings will 
be provided for protocol specified safety data. 
8.4.4.1. 
Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA, version 20.0) will be used to 
classify all AEs. Adverse event summaries will include only treatment-emergent AEs (TEAEs) 
by treatment group. Treatment-emergent adverse events (TEAEs) are defined as AEs that first 
occurred or worsened during the indicated treatment phase. 
The number and percentage of patients with TEAEs will be summarized by system organ class 
(SOC) and preferred term (PT). Summaries of AEs by severity and relationship to the study 
treatment will also be provided. Serious adverse events (SAEs) and AEs resulting in 
discontinuation will be summarized separately in a similar manner. Patient listings of AEs and 
SAEs will be produced. 
8.4.4.2. 
Clinical Laboratory Evaluations 
For the continuous laboratory parameters, descriptive statistics will be presented for values 
collected at Screening, Initial and Extended Treatment, and End of Study/Early Withdrawal 
Visits, and for the changes from baseline to End of Study/Early Withdrawal. 


Insys Development Company, Inc.                                               Protocol Number INS011-16-082 
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8.4.4.3. 
 Vital Signs 
For blood pressure, pulse rate, temperature, and respiration rate, descriptive statistics will be 
presented for values collected at Screening, Initial and Extended Treatment, End of Study /Early 
Withdrawal, and Follow-up Visits, and for the changes from baseline to End of Study /Early 
Withdrawal. 
8.4.4.4. 
Neurological Examination Findings 
Brief neurological examinations will be presented as the number and percentage of patients that 
have normal or abnormal results at Screening (complete exam), Initial and Extended Treatment, 
End of Study, Visit 6 and Visit 9 (complete exam), Early Withdrawal (complete exam), and 
Follow-up Visits. 
8.4.5. 
Pharmacokinetic Analyses 
Exploratory analyses of dose (exposure) will be performed.  Further population PK approach 
may be used for PK parameter calculations, as appropriate. 
8.4.6. 
Missing Data 
There will be no imputation of the missing values. Patients without a video EEG assessment on 
Days 14-15 will be considered non-responders for all EEG-related endpoints. Percentage of 
spasm-free days will be calculated based on the number of entries (up to 15 days per 
measurement period). A sensitivity analysis may be conducted to assess the impact of the 
missing values on the final analysis.  The sensitivity analyses will be detailed in the SAP.   


Insys Development Company, Inc.                                               Protocol Number INS011-16-082 
05 Jul 2018                                           CONFIDENTIAL                                                                         66  
9. 
STUDY CONDUCT 
Steps to ensure the accuracy and reliability of data include the selection of qualified investigators 
and appropriate study sites, review of protocol procedures with the investigator and associated 
personnel prior to the study, periodic monitoring visits, and meticulous data management. 
9.1. 
Sponsor and Investigator Responsibilities 
9.1.1. 
Sponsor Responsibilities 
The sponsor, and/or sponsor’s representative is obligated to conduct the study in accordance with 
strict ethical and data privacy principles. The sponsor reserves the right to withdraw a patient 
from the study, to terminate participation of a study site at any time, and/or to discontinue the 
study. 
The sponsor, or sponsor’s representative, agrees to provide the investigator with sufficient 
material and support to permit the investigator to conduct the study according to the study 
protocol. 
9.1.2. 
Investigator Responsibilities 
By signing the Investigator’s Agreement, the investigator indicates that she/he has carefully read 
the protocol, fully understands the requirements, and agrees to conduct the study in accordance 
with the procedures and requirements described in this protocol. 
The investigator also agrees to conduct this study in accordance with all laws, regulations, and 
guidelines of the pertinent regulatory authorities, including and in accordance with the April 
1996 International Conference on Harmonisation (ICH) Guidance for Industry E6 Good Clinical 
Practice (GCP) and in agreement with the 1996 Version of the Declaration of Helsinki. 
Furthermore, the investigator agrees to abide by the EU General Data Protection Regulations. 
While delegation of certain aspects of the study to sub-investigators and study coordinators is 
appropriate, the investigator will remain personally accountable for closely overseeing the study 
and for ensuring compliance with the protocol and all applicable regulations and guidelines. The 
investigator is responsible for maintaining a list of all persons that have been delegated study-
related responsibilities (e.g., sub-investigators and study coordinators) and their specific study-
related duties. 
Investigators should ensure that all persons who have been delegated study-related 
responsibilities are adequately qualified and informed about the protocol, IPs, and their specific 
duties within the context of the study. Investigators are responsible for providing Insys with 
documentation of the qualifications, GCP training, and research experience for themselves and 
their staff as required by the sponsor and the relevant governing authorities. 
To ensure compliance with the guidelines, the study will be audited by an independent person. 
The investigator agrees, by written consent to this protocol, to cooperate fully with compliance 
checks by allowing access to all study documentation by authorized individuals. 


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9.2. 
Site Initiation 
Study personnel may not screen or enroll patients into the study until after receiving notification 
from the sponsor or sponsor’s representative that the study can be initiated at the study site. The 
study site will not be authorized for study initiation until: 
• The study site has received the appropriate institutional review board (IRB) approval 
for the protocol and the appropriate informed consent form. 
•  All regulatory documents have been submitted to and approved by the sponsor or 
sponsor’s representative. 
• The study site has a clinical trial agreement in place. 
9.3. 
Screen Failures 
Patients who fail inclusion and/or exclusion criteria may be re-screened based on prior investigator and 
Sponsor approval. 
9.4. 
Study Documents 
All documentation and material provided by the sponsor, or sponsor’s representative for this 
study are to be retained in a secure location and treated as confidential material. 
9.4.1. 
Investigator’s Regulatory Documents 
The regulatory documents must be received from the investigator and reviewed and approved by 
the sponsor or sponsor’s representative before the study site can initiate the study and before the 
sponsor, or sponsor’s representative, will authorize shipment of IP to the study site. Copies of the 
investigator’s regulatory documents must be retained at the study site in a secure location. 
Additional documents, including a copy of the protocol and applicable amendment(s), the IB, 
CRF/electronic case report form (eCRF) completion guidelines, copies of regulatory references, 
copies of IRB correspondence, and IP accountability records should also be retained as part of 
the investigator’s regulatory documents. It is the investigator’s responsibility to ensure that 
copies of all required regulatory documents are organized, current, and available for inspection. 
9.4.2. 
Case Report Forms 
By signing the Investigator’s Agreement (Section 13), the investigator agrees to maintain 
accurate CRFs/eCRFs and source documentation as part of the case histories for all patients who 
sign an informed consent form (ICF). 
Case report forms are considered confidential documents and should be handled and stored 
accordingly. The sponsor, or sponsor’s representative, will provide the necessary training on the 
use of the specific CRFs/eCRF system used during the study to ensure that the study information 
is captured accurately and appropriately. 
To ensure data accuracy, CRF/eCRF data for individual patient visits should be completed as 
soon as possible after the visit. All requested information must be entered in the CRF/electronic 
data capture (EDC) system according to the completion guidelines provided by the sponsor, or 
sponsor’s representative. 


Insys Development Company, Inc.                                               Protocol Number INS011-16-082 
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9.4.3. 
Source Documents 
All information recorded in the CRF/EDC system must be supported by corresponding source 
documentation. Examples of acceptable source documentation include, but are not limited to, 
hospital records, clinic and office charts, laboratory notes, and recorded data from automated 
instruments, memoranda, and pharmacy dispensing records. 
During the study, select CRF/eCRF data may be used as original data collection tools as long as 
a description of this documentation process is maintained in the investigator’s study files. 
Clinical laboratory data required by the protocol will be electronically transferred from the local 
laboratory to the sponsor or the sponsor’s representative. A paper copy of the laboratory results 
will be provided to the study site and should be retained with each patient’s source data. 
All documents pertaining to the study, including a copy of the approved protocol, copy of the 
ICD, completed CRFs, source documents, drug accountability and retention records, and other 
study related documents will be retained in the permanent archives of the study site. These will 
be available for inspection at any time by the Sponsor or the FDA. Per 21 CFR 312, record 
retention for this study is required for a period of two years following the date on which this 
study agent is approved by the FDA for the marketing purposes that were the patient of this 
investigation; or, if no application is to be filed or if the application is not approved for such 
indication, until two years following the date on which the entire study is completed, terminated, 
or discontinued, and the FDA is notified. 
The investigator will provide direct access to source data and documents for trial related 
monitoring, audits, IEC/IRB review, and regulatory requirements. 
9.5. 
Data Quality Control 
9.5.1. 
Monitoring Procedures 
The investigator will permit the site monitor to review trial data as frequently as is deemed 
necessary to ensure data are being recorded in an adequate manner and protocol adherence is 
satisfactory. The investigator will access medical records for the monitor to verify CRF entries. 
The investigator, as part of his or her responsibilities, is expected to cooperate with the sponsor 
or its designee in ensuring the trial adheres to GCP requirements. The investigator may not 
recruit patients into the study until such time that a site visit has been conducted. 
9.5.2. 
Data Management 
The CRO will be responsible for activities associated with the data management of this study. 
The standard procedures for handling and processing records will be followed per GCP and the 
CRO’s standard operating procedures (SOPs). A comprehensive Data Management Plan will be 
developed including a data management overview, database contents, annotated CRF and 
consistency checks. 
Study site personnel will be responsible for providing resolutions to all data queries. The 
investigator will be required to document electronic data review to ensure the accuracy of the 
corrected and/or clarified data. 
The sponsor will review all data reported in CRFs of all patients before database lock. The data 
review meeting determines whether or not all enrolled patients can be included in the analysis 


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05 Jul 2018                                           CONFIDENTIAL                                                                         69  
population according to the specified definition of analysis populations and evaluates whether or 
not medical decisions of the Investigator were appropriate for important data affecting the safety 
and efficacy endpoint. 
9.5.3. 
Quality Assurance/Audit 
This study will be subject to audit by the sponsor, CRO, or designee. 
The sponsor or sponsor’s representative may conduct audits on a selection of study sites, 
requiring access to patient notes, study documentation, and facilities or laboratories used for the 
study. 
The study site, facilities, all data (including source data), and documentation will be made 
available for audit by quality assurance auditors and for IRB or regulatory authorities according 
to GCP guidelines. The investigator agrees to cooperate with the auditor during the visit and will 
be available to supply the auditor with CRFs or other files necessary to conduct that audit. Any 
findings will be strictly confidential. 
If a regulatory authority informs the investigator that it intends to conduct an inspection, the 
investigator shall notify sponsor or sponsor’s representative immediately. 
9.6. 
Study Termination 
The study may be terminated at the sponsor’s discretion at any time and for any reason. Study 
sites may be asked to have all patients currently participating in the study complete all of the 
assessments for the telephone follow-up call. 
In the event of study discontinuation, study sites may be asked to have all patients currently 
participating in the study complete all of the assessments for the Early Withdrawal Visit. 
9.7. 
Study Site Closure 
At the end of the study, all study sites will be closed. The sponsor or sponsor’s representative 
may terminate participation of a study site at any time. Examples of conditions that may require 
premature termination of a study site include, but are not limited to, the following: 
• Noncompliance with the protocol and/or applicable regulations and guidelines. 
• Inadequate patient enrollment. 
9.7.1. 
Record Retention 
The investigator shall retain and preserve one copy of all data generated in the course of the 
study, specifically including, but not limited to, those defined by GCP as essential until the 
following occur: 
• At least 2 years after the last marketing authorization for the investigational product 
(IP) has been approved or the sponsor has discontinued its research with the IP, or 
• At least 2 years have elapsed since the formal discontinuation of clinical development 
of the IP 
These documents should be retained for a longer period, however, if required by the applicable 
regulatory requirement(s) or if needed by the sponsor. 


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Insys will keep personal data for no longer than reasonably necessary for our ongoing course of 
study, regulatory filing, and for record keeping purposes and in case of any legal claims of 
complaints. 
Furthermore, EU citizens of residents have the following rights under the GDPR (unless subject 
to an exemption): 
• The right to request a copy of your personal data which Insys holds about you 
• The right to request that Insys corrects any personal data if it is found to be inaccurate 
or out of date 
• The right to request your personal data is erased where it is no longer necessary for 
Insys to retain such data 
• The right to withdraw your consent to the processing at any time 
• The right to request that Insys provide you, as the data subject, with your personal 
data and where possible, to transmit that data directly to another data controller 
• The right, where there is a dispute in relation to the accuracy or processing of your 
personal data, to request a restriction is placed on further processing 
• The right to lodge a complaint with governmental agencies or Data Protection 
Authorities as provided for in the GDPR. 
9.7.2. 
Pharmacokinetic/Laboratory Sample Retention 
Laboratory samples may be used for purposes related to this research. The samples will be stored 
until the sponsor has determined that specimens are no longer needed and the decision has been 
made that none of the samples needs to be reanalyzed. In addition, identifiable samples can be 
destroyed at any time at the request of the patient. 
9.8. 
Changes to the Protocol 
The investigator may not deviate from the protocol without a formal protocol amendment 
established and approved by the appropriate IEC/IRB, except when necessary to eliminate 
immediate hazards to the patient or when the change involves only logistical or administrative 
aspects of the study. Any deviation may result in patient withdrawal from the study and 
rendering that patient not available for data evaluation. 
The Investigator or sub-investigator should document any deviation from the protocol and the 
reason. If the Investigator performs a deviation from the protocol or a change of the protocol to 
eliminate an immediate hazard(s) to patients, the record should be immediately submitted to the 
sponsor, the Clinical Research Unit (CRU), and the IRB by the Investigator. The IRB will 
provide expedited review and approval. After the Investigator has obtained approval of the IRB, 
the Investigator should obtain written permission of the CRU and written agreement of the 
sponsor. 
9.9. 
Financial Disclosure 
These issues will be addressed in a separate agreement between the sponsor and the Investigator. 
The US FDA Financial Disclosure by Clinical Investigators (21 Code of Federal Regulations 
[CFR] 54) regulations require sponsors to obtain certain financial information from investigators 


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05 Jul 2018                                           CONFIDENTIAL                                                                         71  
participating in covered clinical studies; each investigator and sub-investigator is required to 
provide the required financial information and to promptly update Insys Development Company, 
Inc., with any relevant changes to their financial information throughout the course of the clinical 
study and for up to one year after its completion. This rule applies to all investigators and sub-
investigators participating in covered clinical studies to be submitted to the FDA in support of an 
application for market approval. 


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10. 
REGULATORY AND ETHICAL CONSIDERATIONS 
10.1. 
Regulatory Authority Approval 
The investigator will ensure that the protocol and consent forms are reviewed and approved by 
the appropriate Independent Ethics Committee/Institutional Review Board (IEC/IRB) prior to the 
start of any study procedures. The IEC/IRB will be appropriately constituted and will perform its 
functions in accordance with Food and Drug Administration (FDA) regulations, International 
Conference on Harmonization (ICH) good clinical practice (GCP) guidelines, and local 
requirements as applicable. 
In addition, the IRB will approve all protocol amendments (except for logistical or administrative 
changes), written informed consent documents and document updates, patient recruitment 
procedures, written information to be provided to the patients, available safety information, 
information about payment and compensation available to patients, the investigator’s curriculum 
vitae and/or other evidence of qualifications, and any other documents requested by the IRB/IEC 
and regulatory authority, as applicable. 
The Investigator will supply documentation to the Sponsor or designee of required IRB/IEC 
annual renewal of the protocol, and any approvals of revisions to the consent form, or 
amendments to the protocol. 
10.2. 
Ethical Conduct of the Study 
The study will be conducted in accordance with the Declaration of Helsinki and GCP according 
to ICH guidelines. Specifically, the study will be conducted under a protocol reviewed by an IRB 
or IEC; the study will be conducted by scientifically and medically qualified persons; the 
benefits of the study are in proportion to the risks; the rights and welfare of the patients will be 
respected; the physicians conducting the study do not find the hazards to outweigh the potential 
benefits; and each patient will give his or her written, informed consent before any protocol-
driven tests or evaluations are performed. 
10.3. 
Statement of Investigator/Delegation of Authority 
As a condition for conducting the clinical investigation, the Principal Investigator will sign the 
FDA Form 1572, Statement of Investigator (21 Code of Federal Regulations [CFR] Part 312). 
The Principal Investigator will ensure that all persons assisting with the trial are adequately 
qualified, informed about the protocol, any amendments to the protocol, the study treatments, 
and their trial-related duties and functions. The qualified investigator will maintain a list of 
sub-investigator and other appropriately qualified persons to whom to delegate significant 
trial-related duties. Should the qualified investigator delegate the supervision of the 
investigational product administration to a designated person, this individual must have the 
appropriate medical qualifications to effectively conduct or supervise any potential resuscitation 
procedures. 
10.4. 
Patient Informed Consent 
The Investigator is responsible for ensuring that informed consent is obtained from each 
parent/caregiver or legal representative and for obtaining the appropriate signatures and dates on 


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the consent form form (if applicable) prior to the performance of any protocol procedures and 
prior to the administration of study medication.     
The investigator or his/her designee will inform the parent/caregiver or legal guardian of all 
aspects pertaining to their participation in the study. The process for obtaining informed consent 
will be in accordance with all applicable regulatory requirements (e.g., CFR Part 50 and ICH E6 
Section 4.8). The investigator or his/her designee and the parent/caregiver or legal guardian must 
both sign and date the informed consent document (ICD) before the patient can participate in the 
study. The parent/caregiver or legal guardian will receive a copy of the signed and dated form, 
and the original will be retained in the site’s study records. The decision to participate in the 
study that is made by the parent/caregiver or legal guardian is entirely voluntary. The 
investigator or his/her designee must emphasize to the parent/caregiver or legal guardian that 
consent for study participation may be withdrawn at any time without penalty or loss of benefits 
to which the patient is otherwise entitled. If the ICD is amended during the study the investigator 
must follow all applicable regulatory requirements pertaining to approval of the amended ICD by 
the IEC/IRB, and use of the amended form, including the necessity of re-consenting ongoing 
patients.    
10.5. 
Investigator Reporting Requirements 
In accordance with applicable local regulatory requirements, the investigator may be obligated to 
provide periodic safety updates on the conduct of the study at his/her site and notification of 
study closure to the IRB. Such periodic safety updates and notifications are the responsibility of 
the investigator and not of Insys or its delegate. 
 
 
 
 


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11. 
USE OF INFORMATION AND PUBLICATION POLICY 
11.1. 
Use of Information 
All information concerning Cannabidiol Oral Solution and Insys Development Company’s 
operations, such as Insys’ patent applications, formulas, manufacturing processes, basic scientific 
data, or formulation information, supplied by Insys Development Company and not previously 
published, is considered confidential information. 
This confidential information shall remain the sole property of Insys Development Company, 
shall not be disclosed to others without the written consent of Insys Development Company, and 
shall not be used except in the performance of this study. 
The investigator will maintain a confidential patient identification code list of all patients 
enrolled in the study (by name and patient number). This list will be maintained at the site, and 
will not be retrieved by Insys. 
11.2. 
Publication Policy 
Insys Development Company, Inc. will retain ownership of all data. All proposed publications 
based on this study will be subject to the sponsor’s approval requirements. 


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05 Jul 2018                                           CONFIDENTIAL                                                                         75  
12. 
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effects of cannabinoids on P-glycoprotein transport and expression in multidrug resistant 
cells. Biochem Pharmacol. 2006; 71:1146-1154. 


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30. Bornheim LM, Everhart ET, Li J, Correia MA. Induction and genetic regulation of mouse 
hepatic cytochrome P450 by cannabidiol. Biochem Pharmacol. 1994; 48: 161-171. 
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37. Borys HK, Ingall GB, Karler R. Development of tolerance to the prolongation of 
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cannabinoids to rhesus monkeys. Toxicol Appl Pharmacol. 1981; 58: 118-131. 
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41. Dalterio S, Badr F, Bartke A, Mayfield D. Cannabinoids in male mice: effects on fertility 
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43. Mechoulam R, Hanus L. Cannabidiol: an overview of some chemical and 
pharmacological aspects. Part I: chemical aspects. Chem Phys Lipids. 2002; 121: 35-43. 
44. Consroe P, Wolkin A. Cannabidiol - antiepileptic drug comparisons and inter-actions in 
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45. Cunha JM, Carlini EA, Pereira AE, et al. Chronic administration of cannabidiol to 
healthy volunteers and epileptic patients. Pharmacol. 1980; 21: 175-85. 
46. Carlini EA, Cunha JM. Hypnotic and antiepileptic effects of cannabidiol. J Clin 
Pharmacol. 1981; 21: 417S-427S.    


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47. Porter BE, Jacobson C. Report of a parent survey of cannabidiol-enriched cannabis use in 
pediatric treatment-resistant epilepsy.  Epilepsy Behav. 2013; 29: 574-577. 
48. Devinsky O, Marsh E, Friedman D, et al. Cannabidiol in patients with treatment-resistant 
epilepsy: an open-label interventional trial. Lancet Neurol. 2016; 15: 270-8. 
49. Agurell S, Halldin M, Lindgren JE, et al. Pharmacokinetics and metabolism of delta 1-
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kinetics of deuterium-labelled cannabidiol in man after smoking and intravenous 
administration. Biomed Environ Mass Spectrom. 1986; 13: 77-83. 
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54. Guy GW, Robson P. A Phase I, double blind, three-way crossover study to assess the 
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60. Gedde MM, Maa E.  Whole cannabis extract of high concentration cannabidiol may calm 
seizures in highly refactory pediatric epilepsies.  2013; America Epilepsy Society 
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61. Devinsky O, Cross JH, Laux L, et al. Trial of cannabidiol for drug-resistant seizures in 
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62. Shields WD. Infantile spasms: little seizures, BIG consequences. Epilepsy Curr. 2006; 6: 
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11(2): 91-93. 


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13. 
INVESTIGATOR SIGNATURE PAGE 
 
TITLE:  
A Phase 3 Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group Study to Assess the Efficacy, Safety and 
Tolerability of Cannabidiol Oral Solution as Adjunctive Therapy 
with Vigabatrin as Initial Therapy in Patients with Infantile 
Spasms 
PROTOCOL NUMBER: 
INS011-16-082 
PHASE OF STUDY: 
Phase 3 
PROTOCOL DATE: 
05 Jul 2018 
STUDY SPONSOR: 
Insys Development Company, Inc 
1333 South Spectrum Blvd, Suite 100 
Chandler, AZ 85286 
 
 
 
 
PRINCIPAL INVESTIGATOR COMMITMENT: 
I, the undersigned Principal Investigator, submit this statement of commitment as evidence that I 
understand my responsibilities pursuant to the Code of Federal Regulations (21 CFR § 312.60 
through § 312.70, 21 CFR § 11, 50, 54, 56) and ICH E6 Good Clinical Practice guidelines, as 
well as with any and all applicable federal, state and/or local laws and regulations, and agree to 
conduct the study in accordance with the protocol referenced herein. 
 
 
 
 
 
Principal Investigator Printed Name 
 
 
 
 
 
Principal Investigator Signature 
 
Date 
 
 


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05 Jul 2018                                           CONFIDENTIAL                                                                         81  
APPENDIX 1. 
CYP3A4-RELATED PROHIBITED MEDICATIONS 
Example of prohibited medications (list is not exhaustive). 
1. Strong inhibitors 
• Boceprevir 
• Clarithromycin 
• Conivaptan 
• Valproic acid 
• Grapefruit juice 
• Indinavir 
• Itraconazole 
• Ketoconazole 
• Lopinavir/ritonavir 
• Mibefradil 
• Nefazodone 
• Nelfinavir 
• Posaconazole 
• Saquinavir 
• Telaprevir 
• Telithromycin 
• Voriconazole 
2. Strong inducers 
• Avasimibe 
• Carbamazepine 
• Phenobarbital 
• Phenytoin 
• Rifampin 
• St. John’s Wort 
3. Sensitive substrates with a narrow therapeutic index 
• Alfentanil 
• Astemizole 
• Cisapride 


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05 Jul 2018                                           CONFIDENTIAL                                                                         82  
• Cyclosporine 
• Dihydroergotamine 
• Ergotamine 
• Fentanyl 
• Pimozide 
• Quinidine 
• Sirolimus 
• Tacrolimus 
• Terfenadine 
 

SAP_001.pdf: 
Insys Development Company, Inc. 
Statistical Analysis Plan: INS011-16-082 
1 
STATISTICAL ANALYSIS PLAN 
PHASE 3 
VERSION: 0.1 
DATE OF PLAN: 
30 OCT 2017 
BASED ON: 
INS011-16-082 v2.0 
26 Oct 2017 
STUDY DRUG:  
PROTOCOL NUMBER: 
2.0 
STUDY TITLE: 
A PHASE 3 RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
PARALLEL-GROUP STUDY TO ASSESS THE EFFICACY, SAFETY, AND 
TOLERABILITY OF CANNABIDIOL ORAL SOLUTION AS ADJUNCTIVE THERAPY 
WITH VIGABATRIN AS INITIAL THERAPY IN INFANTS WITH INFANTILE 
SPASMS 
SPONSOR: 
Insys Development Company, Inc. 
1333 South Spectrum Blvd, Suite 100 
Chandler, AZ 85286 
This study is being conducted in compliance with good clinical practice, including the archiving 
of essential documents. 
NCT#: NCT03421496


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Statistical Analysis Plan: INS011-16-082 
 
 
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SIGNATURE PAGE 
 
 
This document has been prepared and/or reviewed by: 
 
 
 
 
 
 
 
Insys Development Company, Inc.{Sponsor 
Name} 
 
Signature 
 
Date 
 
 
 
 
 
<<Printed Name>>, <<Title>> 
Insys Development Company, Inc. 
 
Signature 
 
Date 
 
This document has been reviewed and accepted by: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Insys Development Company, Inc. 
 
Signature 
 
Date 
 


Insys Development Company, Inc. 
 
 
Statistical Analysis Plan: INS011-16-082 
 
 
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              3         
TECHNICAL SUMMARY REPORT (TSR) 
 
Name of Sponsor/Company 
{Sponsor Name} 
Individual Study Table Referring 
to Part of the Dossier: 
Volume: 
(For National Authority Use 
Only): 
Name of Investigational Product: 
Cannabidiol Oral Solution 
Page: 
 
Name of Active Ingredient: 
Cannabidiol 
 
 
Title of Study: A Phase 3 Randomized, Double-Blind, Placebo-Controlled, Parallel-Group 
Study to Assess the Efficacy, Safety, and Tolerability of Cannabidiol Oral Solution as 
Adjunctive Therapy with Vigabatrin as Initial Therapy in Infants with Infantile Spasms 
Investigators: 
Approximately 35 sites in the US, Canada, and Australia. 
Studied period (years): 
Estimated Date of first patient in 
(FPI): 
Estimated Date of last patient in 
(LPI):   
Phase of development: 3 
Objectives: 
Primary: 
• To evaluate the efficacy of Cannabidiol Oral Solution as adjunctive therapy with 
vigabatrin as initial therapy in treating patients with Infantile Spasms.  
Secondary 
• to evaluate the continued efficacy of the combination treatment of Vigabatrin plus 
CBD after the initial 14 days. 
•  To evaluate the safety and tolerability of Cannabidiol Oral Solution as adjunctive 
therapy with vigabatrin as initial therapy in treating patients with Infantile Spasms. 
 


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Methodology: 
This is a Phase 3, double-blind, placebo-controlled, randomized, multicenter study to evaluate 
the efficacy, safety, and tolerability of Cannabidiol Oral Solution (CBD) as adjunctive therapy 
with Vigabatrin as initial therapy, compared to Vigabatrin alone in the treatment of infants 
newly diagnosed with Infantile Spasms (IS). Randomization will be stratified by 
developmental impairment (high or low) as determined by the investigator during Screening 
Visit 1 and then allocated to one of two treatment groups:  
• Treatment with vigabatrin plus 
 CBD 40 mg/kg/day, or 
 Matching CBD 40 mg/kg/day placebo  
One hundred eighty patients in total will be enrolled into one of the two treatment arms: 120 
patients in the investigational product arm and 60 patients in the placebo arm. Patients will be 
dosed approximately every 12 hours with food to help ensure consistent plasma levels are 
achieved.  
In addition to the safety assessments required by the study protocol, the investigator will 
monitor patients throughout the study as recommended in the current approved product label 
for Vigabatrin. Study participants will be newly diagnosed pediatric patients age 3 to 12 
months (inclusive) experiencing infantile spasms who satisfy all inclusion/exclusion criteria. 
This study will be comprised of five periods: Screening, Initial Treatment, Extended 
Treatment, Taper, and Follow-up Periods, with a maximum duration of approximately 137 
days.  
Each newly diagnosed patient with Infantile Spasms will complete a Screening Period for up 
to 14 (± 5) days.  
Patients will have an overnight, minimum of a 9-hour video-EEG that includes at least one full 
sleep-wake cycle during their Screening Visit to establish their baseline level of infantile 
spasms and hypsarrythmia or a pattern of epileptic encephalopathy, and a 24-hour video-EEG 
at Visit 4 (Day 13) of the Initial Treatment Period to establish their final level of infantile 
spasms and hypsarrythmia. During the Extended Treatment Period, a 9-hour video-EEG will 
be conducted to confirm parent/caregiver report of relapse or resolution. 
Initial Treatment Period 
At the Baseline Visit (Visit 2, Day 1), patients will receive the titration dose of Vigabatrin 
(50 mg/kg/day divided twice daily [BID]), and either CBD 20 mg/kg/day plus matching CBD 
20 mg/kg/day placebo or CBD 40 mg/kg/day placebo, each drug administered twice daily for 
three days. 
On Day 4 (Visit 3), patients will return to the study center to evaluate medical status (seizure 
diary, vital signs, and neurological exam), clinical laboratory assessments, and assess adverse 
events (AEs), then increase Vigabatrin to 100 mg/kg/day, and CBD or matching CBD placebo 
to 40 mg/kg/day for 11 days. Vigabatrin, CBD, and matching placebo will be administered in 
a twice daily fashion at 12-hour intervals. As part of their standard of care, the investigator 
will assess safety and tolerability during the first three days of the Initial Treatment Period. 


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Patients will be dosed for a total of 14 days during which the investigator will assess 
tolerability and efficacy.  
Extended Treatment Period 
Following the Initial Treatment Period, Complete and Partial Responders in the treatment arm 
will continue receiving CBD 40 mg/kg/day and Vigabatrin for 76 days, until Week 13 (Day 
90) to monitor progress for treatment response. Complete and Partial Responders in the 
placebo arm will continue receiving Vigabatrin during the Extended Treatment Period. Non-
responders will be tapered off Vigabatrin and CBD as specified in the Protocol. 
Taper Period 
Following the completion of the Initial Treatment Period (Visit 5), all non-responders 
receiving Vigabatrin will be tapered off. Similarly, all non-responders receiving CBD will be 
tapered off according to the protocol. Patients will also be tapered off Vigabatrin and CBD at 
the completion of the Extended Treatment Period or at Early Withdrawal Visits.  
Follow-up Period 
A follow-up phone call will occur 30 days after discontinuation of the study drug to assess 
AEs, AEDs, and record concomitant medications. 
Study Assessments 
To assess efficacy, a 9-hour video-EEG that includes at least one sleep-wake cycle, a 24-hour 
video-EEG, daily seizure diaries, and investigator Clinical Global Impressions-Global 
Improvement (CGI-I) assessments will be completed and evaluated.  
• A 9-hour video EEG that includes at least one sleep-wake cycle will be completed 
during Screening (Visit 1) and a 24-hour video EEG will be completed at Visit 5.  
• Daily seizure diaries will be completed throughout the Initial and Extended 
Treatment Periods. The daily record will ask: “How many spasms did the patient 
have today?” 
• The CGI-I will be completed by the investigator at Visit 5 of the Initial Treatment 
Period, or at Early Withdrawal. 
Safety assessments for all patients will include medical history, physical examination, vital 
signs (seated blood pressure, pulse rate, temperature, and respiration rate), clinical laboratory 
testing (hematology, chemistry, and urinalysis), prior medication history (assessment of 
past/current AEDs and concomitant medications), and AE assessments will be conducted at 
specific visits throughout the study.  
If a patient discontinues the study prematurely, the parent’s impression of efficacy and 
tolerability of the study drug, as evaluated by CGI-I, will be assessed and recorded 
immediately before discontinuation. If possible, the parent/caregiver will be encouraged to 
have the patient have an Early Withdrawal video-EEG completed. 
Number of patients (planned):  
Approximately 180 patients (120 patients in the active drug arm and 60 patients in the placebo arm).   


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Diagnosis and main criteria for inclusion:  
Patients will be male and female patients between 3 and 12 months of age (inclusive), with a 
new clinical diagnosis of Infantile Spasms, confirmed by video-EEG analysis during the 
Screening Period, have adequate renal and hepatic function and who meet all the inclusion and 
none of the exclusion criteria. Parent(s)/caregiver(s) must be able to understand and provide 
written consent. 
Investigational product, dosage, and mode of administration:  
Cannabidiol Oral Solution or Placebo (IP).  Initial dose of the IP will be either matching CBD 
placebo 20 mg/kg/day or CBD 20 mg/kg/day for 3 days, after which the dose of IP will be 
adjusted to the final dose of CBD or CBD placebo 40 mg/kg/day divided twice daily for 
11 days, manufactured for and supplied by Insys Development Company, Inc. Following the 
completion of the 14-day Initial Treatment Period, Complete and Partial Responders will 
receive CBD 40 mg/kg/day for 76 days during the Extended Treatment Period. 
Duration of treatment:  
The maximum duration of the study from screening to follow-up of AEs will be approximately 144 
days. 
Reference therapies, dosage and mode of administration:  
Vigabatrin powder suspension divided twice daily with food, 50 mg/kg/day for 3 days, then 100 
mg/kg/day for 11 days. 


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Criteria for evaluation: 
Efficacy 
Primary efficacy endpoint   
• Percent of patients who are considered complete responders, defined as complete 
resolution of spasms and hypsarrhythmia or a pattern of epileptic encephalopathy 
confirmed by 24-hour video-EEG from Day 13 to Day 14, as determined by the 
Independent Central Reader. 
Secondary efficacy endpoints   
• Percent of patients with resolution of infantile spasms as assessed by 24-hour 
video-EEG from Day 13 to Day 14 (partial response).  
• Percent of patients with resolution of hypsarrhythmia or pattern of epipleptic 
encephalopathy as assessed by 24-hour video-EEG from Day 13 to Day 14 (partial 
response). 
• Investigator impression of efficacy and tolerability of study drug (CGI-I) at Visit 5 
(End of Study) or Early Withdrawal. 
• Percent reduction in spasm-free days between the Initial Treatment Period (Days 1 
to 14) and Screening Period (Days -14 to -1), as determined by the seizure diary 
entries. 
• For patients with a complete response during the Initial Treatment Period who 
continue: percent of patients who relapse during the Extended Treatment Period 
confirmed by video-EEG following parent report of relapse, and time to relapse. 
• For patients with partial response during the Initial Treatment Period who continue: 
percent of patients who achieve complete response during the Extended Treatment 
Period, confirmed by video-EEG following parent report, and time to complete 
response. 
Safety  
The safety endpoints of the study are the incidence of treatment-emergent AEs (TEAEs), 
clinical laboratory assessments, vital signs (blood pressure, pulse rate, respiration rate, and 
temperature), physical and neurological examination assessments, prior and concomitant 
medications. 
Pharmacokinetic 
Trough concentrations (Ctrough) of cannabidiol (CBD) and metabolite 7-hydoxy-CBD (7-OH-
CBD) will be used to assess the exposure-response relationship. 


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Statistical methods: 
Sample Size Calculation 
A total of 180 patients (120 and 60 patients in the two groups) will provide 80% power with a 
two-sided alpha of 0.05 to detect a difference in response rate, assuming the response with 
vigabatrin alone is 40% and the response with vigabatrin with Cannabidiol Oral Solution is 
62%. 
Analysis Populations 
Statistical analyses will be conducted on the following populations: 
• Safety Population: The Safety Population will include all patients who were treated 
with at least one dose of the study drug. 
• Intent to Treat (ITT) Population: The ITT Population will include all patients who 
were randomized.   
Efficacy Analyses 
The ITT Population will be used for all efficacy analyses. 
• For the primary endpoint, a 2-sided Type I error rate of 0.05 will be used.   
• For the secondary efficacy endpoints, to maintain the trial-wise Type I error rate at 
0.05, False Discovery Rate multiple comparisons correction will be used. 
• For endpoints that are continuous in nature, the number of observations, mean, 
median, minimum and maximum, and standard deviation (SD) values will be 
presented as descriptive statistics. For inferential statistics, a t-test or ANCOVA 
will be used to compare treatment to placebo group.  
• For endpoints that are categorical in nature, frequency, counts, and percentages will 
be presented as descriptive statistics, and Fisher’s exact test, Cochran-Maentel-
Haenzel, or logit model will be used for inferential statistics as appropriate. 
Primary Efficacy Analysis 
• Percent of patients with resolution of both infantile spasms and hypsarrhythmia or 
a pattern of epileptic encephalopathy at Day 14 (complete response) will be 
compared between Vigabatrin plus Placebo and Vigabatrin plus CBD 40 
mg/kg/day groups using Fisher’s exact test.     
Secondary Efficacy Analyses 
• Percent of patients with resolution of infantile spasms at Day 14 will be compared 
between treatment groups using Fisher’s exact test. 
• Percent of patients with resolution of hypsarrhythmia or a pattern of epileptic 
encephalopathy at Day 14 will be compared between treatment groups using 
Fisher’s exact test. 
• Investigator impression of efficacy and tolerability of study drug (Clinical Global 
Impression – Global Improvement (CGI-I) will be compared between treatment 
groups using a t-test. 


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• Percent reduction in spasm-free days between the Initial Treatment Period (Days 1 
to 14) and Screening Period (Days -14 to -1) will be compared between treatment 
groups using ANCOVA with the baseline score as a covariate. 
• Percent of patients who relapse during the Extended Treatment Period will be 
compared between 14-day Vigabatrin + CBD responders and 14-day Vigabatrin + 
placebo responders using Fisher’s exact test. Time to relapse will be calculated 
with Kaplan-Meier curves and compared using a log-rank test. 
• Percent of patients with partial response at Day 14 who achieve complete response 
during the Extended Treatment Period will be compared using Fisher’s exact test. 
Time to complete response will be calculated with Kaplan-Meier curves and 
compared using a log-rank test. 
Safety Analyses 
The Safety Population will be used for all safety assessments. All safety assessments will be 
descriptive and no inferential statistics are planned for safety assessments. All data listings 
will be provided for protocol specified safety data.  
• The Medical Dictionary for Regulatory Activities (MedDRA; Version 20.0 or 
higher) will be used to classify all adverse events with respect to system organ 
class and preferred term. Adverse event summaries will include only TEAEs by 
treatment group.  
• Clinical laboratory findings will be summarized for all patients in the safety 
population for observed values and change from baseline. Shifts from baseline to 
outside normal range criteria will also be presented for all patients in the safety 
population. 
• Vital signs will be summarized for all patients in the safety population for observed 
values and change from baseline as appropriate. 
• The neurological examination results will be listed and summarized descriptively. 
Shifts from baseline according to normal and abnormal criteria will also be 
presented for all patients in the safety population. 
• Results of physical examinations conducted throughout the study will be presented 
in listings and summarized descriptively. Shifts from baseline according to normal 
and abnormal criteria will also be presented for all patients in the safety population. 
• Prior medication and concomitant medications will be reported in the data listings. 
• Statistical analyses will be performed using SAS® (Version 9.3 or higher, SAS 
Institute Inc.) or R (Version 3.3 or higher, Roswell Park Cancer Institute). 
Pharmacokinetic Analyses 
Exploratory analyses of dose (exposure)-response relationship will be performed. Further 
population PK approach may be used for PK parameter calculations, as appropriate. 
Missing Data 
There will be no imputation of the missing values. All assessments will be conducted based on 
all observed data. A sensitivity analysis may be conducted to assess the impact of the missing 
values on the final analysis. The sensitivity analyses will be detailed in the SAP. 


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TABLE OF CONTENTS 
TECHNICAL SUMMARY REPORT (TSR) ..................................................................................3 
LIST OF ABBREVIATIONS ........................................................................................................15 
1. 
INTRODUCTION ......................................................................................................17 
2. 
STUDY OBJECTIVES ..............................................................................................18 
2.1. 
Primary Objective .......................................................................................................18 
2.2. 
Secondary Objectives .................................................................................................18 
3. 
STUDY DESIGN .......................................................................................................19 
3.1. 
Summary of Study Design ..........................................................................................19 
3.2. 
Selection of Study Population ....................................................................................21 
3.2.1. 
Inclusion Criteria ........................................................................................................21 
3.2.2. 
Exclusion Criteria .......................................................................................................22 
3.3. 
Sample Size Calculation .............................................................................................23 
4. 
STUDY DURATION AND VISIT SCHEDULE ......................................................24 
4.1. 
Screening Period (Visit 1) ..........................................................................................24 
4.2. 
Initial Treatment Period (Visits 2, 3, 4, and 5) ...........................................................24 
4.2.1. 
Visit 2 (Day 1) ............................................................................................................24 
4.2.2. 
Visit 3 (Day 4) ............................................................................................................24 
4.2.3. 
Visit 4 (Day 13) ..........................................................................................................25 
4.2.4. 
Visit 5 (Day 14) ..........................................................................................................25 
4.3. 
Extended Treatment Period (Week 6, Week 10, and Week 13) .................................25 
4.4. 
Early Withdrawal Visit ...............................................................................................25 
4.5. 
Follow-up Period ........................................................................................................25 
5. 
CLINICAL ASSESSMENTS .....................................................................................26 
5.1. 
Demographics and Medical History ...........................................................................26 
5.2. 
Efficacy Assessments .................................................................................................26 
5.2.1. 
Video-EEG .................................................................................................................26 
5.2.2. 
CGI-I ...........................................................................................................................26 
5.2.3. 
Seizure Diary ..............................................................................................................26 
5.3. 
Safety Assessments .....................................................................................................26 
5.3.1. 
Physical Examination .................................................................................................26 
5.3.2. 
Neurological Examinations ........................................................................................27 


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5.3.3. 
Vital Signs ..................................................................................................................27 
5.3.4. 
Clinical Laboratory Assessments ...............................................................................27 
6. 
DEFINITIONS AND CONVENTIONS ....................................................................28 
6.1. 
General Summary Table and Individual Subject Data Listing Considerations ..........28 
6.2. 
Calculations Using Dates ............................................................................................28 
6.3. 
Baseline .......................................................................................................................28 
6.3.1. 
Visit Windows Relative to the First Dose of Study Medication ................................28 
6.4. 
Analysis Populations ..................................................................................................29 
6.4.1. 
Safety Population ........................................................................................................29 
6.4.2. 
Intent to Treat Population ...........................................................................................29 
6.4.3. 
PK Analysis Population ..............................................................................................29 
6.4.4. 
Handling of Missing Values .......................................................................................29 
7. 
DATA PRESENTATIONS AND DATA MANAGEMENT.....................................30 
7.1. 
Data Presentations ......................................................................................................30 
7.2. 
Data Management .......................................................................................................30 
7.3. 
General Post Text Summary Table and Individual Subject Data Listing 
Format Considerations ................................................................................................30 
8. 
PATIENT DISPOSITION AND PROFILE OF SCREEN FAILURES.....................31 
8.1. 
Patient Accounting ......................................................................................................31 
8.1.1. 
Patient Accounting by Treatment Group ....................................................................32 
8.1.2. 
Patient Distribution by Investigator ............................................................................32 
8.2. 
Screen Failure .............................................................................................................32 
9. 
BASELINE SUBJECT DATA ...................................................................................33 
9.1. 
Baseline Demographic and Physical Characteristics ..................................................33 
9.2. 
Medical History and Medical Conditions Present at Entry ........................................33 
9.3. 
Prior Medication History and Medications Present at Entry ......................................33 
9.3.1. 
Non-Diagnosis Related Prior Medication History ......................................................33 
9.3.2. 
Prior Diagnosis Related Medication History ..............................................................33 
9.3.3. 
Missing and Partially Missing Start and Stop Dates ..................................................33 
9.4. 
Baseline Physical Examination ...................................................................................34 
9.5. 
Baseline Vital Signs ....................................................................................................34 
9.6. 
Baseline Laboratory Data ...........................................................................................34 
9.7. 
Baseline Primary and Secondary Efficacy Evaluations ..............................................34 


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9.7.1. 
Imputation for Missing Data .......................................................................................35 
10. 
EFFICACY .................................................................................................................36 
10.1. 
General Considerations ...............................................................................................36 
10.2. 
Testing Statistical Assumptions Including Comparability at Baseline .......................36 
10.3. 
Statement of the Null and Alternate Hypotheses ........................................................36 
10.3.1. 
Primary Efficacy Endpoint .........................................................................................36 
10.3.2. 
Secondary Efficacy Endpoints ....................................................................................37 
10.4. 
Subgroup Analyses .....................................................................................................38 
10.5. 
Multiple Comparisons and Multiplicity ......................................................................38 
10.6. 
Analysis of the Primary Efficacy Endpoints ..............................................................38 
10.6.1. 
Primary Efficacy Analysis ..........................................................................................38 
10.6.2. 
Presentation of the Primary Efficacy Results .............................................................39 
10.7. 
Analysis of the Secondary Efficacy Endpoints ..........................................................39 
10.7.1. 
Secondary Efficacy Endpoints ....................................................................................39 
10.7.2. 
Presentation of the Secondary Efficacy Results .........................................................40 
10.8. 
Summary of Reasons for Efficacy Non-evaluability/Exclusion from Efficacy 
Analyses ......................................................................................................................40 
11. 
SAFETY AND TOLERABILITY ..............................................................................41 
11.1. 
Overall Summary of Tolerability ................................................................................41 
11.2. 
Adverse Event Preferred Term and Body/Organ System Summary Tables ...............41 
11.2.1. 
Summaries of Adverse Event Incidence Rates for All Subjects .................................41 
11.2.2. 
Missing and Partial AE Onset Dates ..........................................................................41 
11.2.3. 
Summaries of Adverse Incidence Rates for Serious Adverse Events (SAE), 
Adverse Event Dropouts, and Death ..........................................................................42 
11.3. 
Total Duration of Therapy, Average Daily Dose, Maximum Daily Dose, 
Final Daily Dose of Study Medication, and Compliance ...........................................42 
11.4. 
Concomitant and Other Medications ..........................................................................43 
11.4.1. 
Missing and Partial Concomitant and Other Medication Start and Stop Dates ..........43 
11.5. 
Routine Laboratory Data ............................................................................................43 
11.6. 
Vital Signs ..................................................................................................................43 
11.6.1. 
Vital Signs Markedly Abnormal Criteria ...................................................................43 
11.7. 
Physical Examination .................................................................................................44 
11.8. 
Neurological Examination ..........................................................................................44 


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11.9. 
PK Results ..................................................................................................................44 
11.10. 
Study Termination Status ...........................................................................................44 
12. 
INTERIM ANALYSES ..............................................................................................45 
13. 
REFERENCES ...........................................................................................................46 
14. 
APPENDIX .................................................................................................................47 
14.1. 
Sample Table of Contents for Data Listings ...............................................................47 
14.2. 
Sample Table of Contents for Data Display Summaries ............................................48 
 
 


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LIST OF TABLES 
Table 1: 
List of Abbreviations ..................................................................................................15 
Table 2: 
Visit windows and target days ....................................................................................28 
Table 3: 
Calculation of missing or partially missing dates .......................................................29 
 


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LIST OF ABBREVIATIONS 
Table 1: 
List of Abbreviations 
Abbreviation or Specialist Term 
Explanation 
AE 
adverse event 
AED 
anti-epileptic drug 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
BMI 
body mass index 
BUN 
blood urea nitrogen 
CBD 
cannabidiol 
CFR 
Code of Federal Regulations 
CGI-I 
Clinical Global Impression – Global Improvement 
cGMP 
current Good Manufacturing Practices 
Ctrough 
plasma trough concentrations 
CRF 
case report form 
CRO 
contract research organization  
CV% 
coefficient of variation 
CYP 
cytochrome P450 
CYP1A1 
Cytochrome P450 1A1 
CYP2C19 
Cytochrome P450 2C19 
CYP2C9 
Cytochrome P450 2C9 
CYP3A4 
Cytochrome P450 3A4 
CYP3A5 
Cytochrome P450 3A5 
DEA 
Drug Enforcement Administration 
DMC 
Data Monitoring Committee 
eCRF 
electronic case report form 
ECG 
electrocardiogram 
EDC 
electronic data capture 
EEG 
electroencephalogram 
EENT 
eyes, ears, nose, and throat 
FDA 
Food and Drug Administration 


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GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
IA 
Interim Analysis 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICD 
informed consent document 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IP 
Investigational product 
IRB 
Institutional Review Board 
IS 
Infantile Spasms 
ITT 
Intent to Treat 
LFTs 
liver function tests 
MedDRA 
Medical Dictionary for Regulatory Activities 
NOAEL  
No Observed Adverse Effect Level   
OH 
hydroxy 
PK 
pharmacokinetic(s) 
PT 
preferred term 
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SOC 
System organ class  
SOP 
standard operating procedure 
TEAE 
treatment-emergent adverse event 
TLFs 
tables, listings, and figures  
tmax 
time to maximum plasma concentration 
ULN 
upper limit of normal 
US 
United States 
VNS 
vagus nerve stimulation  
 


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1. 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the planned analyses and data 
displays to be included in the Clinical Study Report (CSR) for Protocol INS011-16-082. 
Protocol Revision Chronology: 
INS011-16-082 
30 Oct 2017 
V2.0 
 
 
 
This SAP was developed per guidance documents ICH E9, Statistical Principles for Clinical 
Trials-v1.0. and ICH E9(R1): Addendum to Statistical Principles for Clinical Trials Final 
Concept Paper. 
All decisions regarding final analysis, as defined in this SAP, will be made prior to Database 
Lock (unblinding) of the study data. Further information can be found in the protocol. 
 
The statistical analysis plan (SAP) is based on:  
• Protocol No. INS011-16-082, dated October 30, 2017. 
• ICH guidelines E4 and E9 (Statistical Principles for Clinical Trials).  
• Discussions with the FDA.  
The purpose of this document is to provide details on study populations and on how the variables 
will be derived, how missing data will be handled as well as details on statistical methods to be 
used to analyze the safety and efficacy data for Study Protocol No. INS011-16-082. 
The document may evolve over time, for example, to reflect the requirements of protocol 
amendments or regulatory requests. However, the final SAP must be finalized, approved by the 
Sponsor, and placed on file before the database is locked. Deviations from the final approved 
plan will be noted in the clinical study report. 
 


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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
• To evaluate the efficacy of Cannabidiol Oral Solution as adjunctive therapy with 
vigabatrin as initial therapy in treating patients with Infantile Spasms.  
2.2. 
Secondary Objectives 
• to evaluate the continued efficacy of the combination treatment of Vigabatrin plus 
CBD after the initial 14 days.  
• To evaluate the safety and tolerability of Cannabidiol Oral Solution as adjunctive 
therapy with vigabatrin as initial therapy in treating patients with Infantile Spasms. 


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3. 
STUDY DESIGN 
3.1. 
Summary of Study Design 
This is a Phase 3, double-blind, placebo-controlled, randomized, multicenter study to evaluate 
the efficacy, safety, and tolerability of Cannabidiol Oral Solution (CBD) as adjunctive therapy 
with Vigabatrin as initial therapy, compared to Vigabatrin alone in the treatment of infants newly 
diagnosed with Infantile Spasms (IS). Randomization will be stratified by developmental 
impairment (high or low) as determined by the investigator during Screening Visit 1 and then 
allocated to one of two treatment groups:  
• Treatment with Vigabatrin plus  
• CBD 40 mg/kg/day, or 
• Matching CBD 40 mg/kg/day placebo  
One hundred eighty patients in total will be enrolled into one of the two treatment arms: 120 
patients in the investigational product arm and 60 patients in the placebo arm. Patients will be 
dosed approximately every 12 hours with food.  
Study participants will be newly diagnosed pediatric patients age 3 to 12 months (inclusive) 
experiencing infantile spasms who satisfy all inclusion/exclusion criteria. This study will be 
comprised of five periods: Screening, Initial Treatment, Extended Treatment, Taper, and Follow-
up Periods, with a maximum duration of approximately 137 days.  
Each newly diagnosed patient with Infantile Spasms will complete a Screening Period for up to 
14 (± 5) days.  
Patients will have an overnight, minimum of a 9-hour video-EEG that includes at least one full 
sleep-wake cycle during their Screening Visit to establish their baseline level of infantile spasms 
and hypsarrythmia or a pattern of epileptic encephalopathy, and a 24-hour video-EEG at Visit 4 
(Day 13) of the Initial Treatment Period to establish their final level of infantile spasms and 
hypsarrythmia. During the Extended Treatment Period, a 9-hour video-EEG will be conducted to 
confirm parent/caregiver report of relapse or resolution. 
Initial Treatment Period 
At the Baseline Visit (Visit 2, Day 1), patients will receive the titration dose of Vigabatrin (50 
mg/kg/day divided twice daily [BID]), and either CBD 20 mg/kg/day plus matching CBD 20 
mg/kg/day placebo or CBD 40 mg/kg/day placebo, each drug administered twice daily for three 
days. 
On Day 4 (Visit 3), patients will return to the study center to evaluate medical status (seizure 
diary, vital signs, and neurological exam), clinical laboratory assessments, and assess adverse 
events (AEs), then increase Vigabatrin to 100 mg/kg/day, and CBD or matching CBD placebo to 
40 mg/kg/day for 11 days. Vigabatrin, CBD, and matching placebo will be administered in a 
twice daily fashion at 12 hour intervals. As part of their standard of care, the investigator will 
assess safety and tolerability during the first three days of the Initial Treatment Period. Patients 


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will be dosed for a total of 14 days during which the investigator will assess tolerability and 
efficacy.  
Extended Treatment Period 
Following the Initial Treatment Period, Complete and Partial Responders in the treatment arm 
will continue receiving CBD 40 mg/kg/day and Vigabatrin for 76 days, until Week 13 (Day 90) 
to monitor progress for treatment response. Complete and Partial Responders in the placebo arm 
will continue receiving Vigabatrin during the Extended Treatment Period. Non-responders will 
be tapered off Vigabatrin and CBD as specified in the Protocol. 
Taper Period 
Following the completion of the Initial Treatment Period (Visit 5), all non-responders receiving 
Vigabatrin will be tapered. Similarly, all non-responders receiving CBD will be tapered off 
according to the protocol. Patients will also be tapered off Vigabatrin and CBD at the completion 
of the Extended Treatment Period or Early Withdrawal Visits.  
Follow-up Period 
A follow-up phone call will occur 30 days after discontinuation of the study drug to assess AEs, 
AEDs, and record concomitant medications. 
Study Assessments 
To assess efficacy, a 9-hour video-EEG that includes at least one sleep-wake cycle, a 24-hour 
video-EEG, daily seizure diaries, and investigator Clinical Global Impressions-Global 
Improvement (CGI-I) assessments will be completed and evaluated.  
• A 9-hour video EEG that includes at least one sleep-wake cycle will be completed during 
Screening (Visit 1), and a 24-hour video EEG will be completed at Visit 5.  
• Daily seizure diaries will be completed throughout the Initial and Extended Treatment 
Periods. The daily record will ask: “How many spasms did the patient have today?” 
• The CGI-I will be completed by the investigator at Visit 5 of the Initial Treatment Period, 
or at Early Withdrawal. 
Safety assessments for all patients will include medical history, physical examination, vital signs 
(seated blood pressure, pulse rate, temperature, and respiration rate), clinical laboratory testing 
(hematology, chemistry, and urinalysis), prior medication history (assessment of past/current 
AEDs and concomitant medications), and AE assessments will be conducted at specific visits 
throughout the study.  
If a patient discontinues the study prematurely, the parent’s impression of efficacy and 
tolerability of the study drug, as evaluated by CGI-I, will be assessed and recorded immediately 


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before discontinuation. If possible, the parent/caregiver will be encouraged to have the patient 
have an Early Withdrawal video-EEG completed. 
 
 
Figure 1:  
Study Design Schematic 
 
3.2. 
Selection of Study Population 
3.2.1. 
Inclusion Criteria 
Diagnosis and main criteria for inclusion:  
Patients will be male and female patients between 3 and 12 months of age (inclusive), with a new 
clinical diagnosis of Infantile Spasms, confirmed by video-EEG analysis during the Screening 
Period, have adequate renal and hepatic function and who meet all the inclusion and none of the 
exclusion criteria. Parent(s)/caregiver(s) must be able to understand and provide written consent.  
All patients must satisfy the following criteria to be considered for study participation: 
Vigabatrin + 
Matching 
Placebo
11 days
SCREENING
PERIOD
14 days
Vigabatrin + 
CBD 40 mg/kg/d
11 days
EXTENDED 
TREATMENT 
PERIOD
76 days
Titration
3 days
CR or PR?
TAPER 
PERIOD
3 days
FOLLOW-UP
PERIOD
30 days
Y
 N
INITIAL TREATMENT PERIOD
14 days
CR = complete responder; PR = partial responder 


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1. Parent(s)/caregiver(s) fully comprehend and sign the informed consent form, understand 
all study procedures, and can communicate satisfactorily with the investigator and study 
coordinator, in accordance with applicable laws, regulations, and local requirements. 
2. Male or female between 3 months to 12 months of age (inclusive) at time of consent. 
3. Clinical diagnosis of infantile spasms, confirmed by video-EEG analysis (including at 
least one cluster of electroclinical spasms [≥3 in any 10-minute epoch)], hypsarrythmia or 
a pattern of epileptic encephalopathy) obtained during the Screening Period and read by 
the Investigator. 
4. General good health (defined as the absence of any clinically relevant abnormalities as 
determined by the investigator) based on physical and neurological examinations, 
medical history and clinical laboratory values completed during the Screening Visit 
(Visit 1).  
5. In the opinion of the investigator, the parent(s)/caregiver(s) is (are) willing and able to 
comply with the study procedures and visit schedules. 
 
3.2.2. 
Exclusion Criteria 
Patients will be excluded for any of the following: 
1. Is considered by the investigator, for any reason (including, but not limited to, the risks 
described as precautions, warnings, and contraindications in the current version of the 
Investigator’s Brochure for Cannabidiol Oral Solution) to be an unsuitable candidate to 
receive the study, 
2. Known or suspected allergy to Cannabidiol Oral Solution. 
3. History of an allergic reaction or a known or suspected sensitivity to any substance that is 
contained in the investigational product formulation. 
4. Use of any cannabidiol/cannabis product within 30 days of study entry. 
5. Patient is diagnosed or at high risk of having tuberous sclerosis. 
6. Patient has received treatment with either vigabatrin, ACTH, or high-dose steroids 
previously. 
7. Previous or concomitant therapy with felbamate, clobazam, valproic acid, or the 
ketogenic diet. 
8. Positive drug screen for THC. 
9. Patient currently on any disallowed CYP3A4-related medication listed in  
Appendix 1 of the protocol (phenytoin, fluvoxamine, carbamazepine, and St. John’s 
Wort). 
10. Previously received any investigational drug or device or investigational therapy within 
30 days before Screening. 


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11. Clinically significant abnormal laboratory values, including: liver function tests (LFTs) 
such as albumin, direct bilirubin, total bilirubin, aspartate aminotransferase (AST), and 
alanine aminotransferase (ALT) ≥3 times the upper limit of normal (ULN).  
12. The investigator may deem the patient eligible if he or she judges the laboratory values to 
be not clinically significant.  
3.3. 
Sample Size Calculation 
A total of 180 patients (120 patients in the 40 mg/kg/day arm and 60 patients in the placebo arm) 
will provide 80% power with a two-sided alpha of 0.05, assuming the response with vigabatrin 
alone is 40% and the response with vigabatrin with Cannabidiol Oral Solution is 62%. 


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4. 
STUDY DURATION AND VISIT SCHEDULE 
This study will be comprised of 5 periods: a Screening Period (up to 14 days), Initial Treatment 
Period (14 days), Extended Treatment Period (9 weeks), a Taper Period (3 days) for patients who 
elect not to enroll in the open-label long-term safety study, and a Follow-up Period (30±7 days). 
The maximum study duration is expected to be approximately 144 days.   
4.1. 
Screening Period (Visit 1) 
 
The following screening procedures and assessments are intended to be performed during 
Visit 1, but the patient may return to complete activities, which must be performed within 14 
days of the start of the Initial Treatment Period for all patients: written informed consent is 
obtained and inclusion and exclusion criteria reviewed, demographic data, recent concomitant 
medication and procedures, medical and surgical history, seizure frequency history occurring 
≤28 days of the Screening Visit, patient risk of developmental impairment, adverse events (AEs), 
and vital signs (blood pressure, pulse rate, respiratory rate, and temperature measurements) will 
be recorded. 
Urine (for urinalysis) and blood samples (for hematology, chemistry, and drug screen) will be 
obtained.   
 
A complete physical examination (including height, weight, and head circumference) and brief 
neurological examination will be performed.  
 
A 9-hr video-EEG (includes a full sleep-wake cycle) and a daily seizure diary will be provided. 
 
4.2. 
Initial Treatment Period (Visits 2, 3, 4, and 5) 
 
4.2.1. 
Visit 2 (Day 1) 
During Visit 2, the patient will be randomized and receive the titration doses of Vigabatrin and 
CBD or matched placebo. AEs will be recorded. 
 
4.2.2. 
Visit 3 (Day 4) 
During Visit 4, a brief neurological examination will be performed and blood samples will be 
taken for hematology and chemistry. The following assessments will be recorded: height and 
weight, vital signs, concomitant medications and procedures, AEs, and daily seizure diary. 
 
The patient will have their full study dose of Vigabatrin and CBD or matched placebo dispensed 
and the morning dose of the investigational product will be administered. After administration of 
the morning dose, the patient will remain at the study center for 4 hours.  Additional brief 
neurological examinations will be performed at 2 and 4 hours postdose, and vital signs will be 
recorded at 4 hours postdose. AEs and SAEs will be recorded. 
 


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4.2.3. 
Visit 4 (Day 13) 
On Day 13, patients will be admitted to the study center before the morning administration of the 
investigational product.  The following assessments will be completed PRIOR to administration 
of the morning dose of the investigational product: record concomitant medications and 
procedures, vital signs, height and weight, draw blood samples, brief neurological examination, 
AEs, and daily seizure diary.  
The morning dose will be administered following the assessments listed above, AEs will be 
recorded, and the 24-hour video-EEG assessment will be started. 
 
4.2.4. 
Visit 5 (Day 14) 
The following activities will occur on Day 14, at approximately 24 hours post the Day 13 
morning dose: finish the 24-hour video-EEG assessment; assessment of current AEDs, record 
concomitant medications and procedures, vital signs, height and weight, review daily seizure 
diary, and AEs; draw blood samples (for hematology, chemistry and PK), perform a brief 
neurological examination, and completion of investigator CGI-I.  
 
4.3. 
Extended Treatment Period (Week 6, Week 10, and Week 13) 
Following the Initial Treatment Period, Complete and Partial Responders will continue receiving 
CBD 40 mg/kg/day and/or vigabatrin for 76 days, until Week13 (Day 90). 
 
The following assessments and procedures will be completed at Visit 6 (Week 6), Visit 7 (Week 
10), and Visit 8 (End of Study; Week 13): record concomitant medications and procedures, vital 
signs, AEs, and review daily seizure diary; draw blood samples for hematology and chemistry; 
perform a brief neurological examination, and complete the investigator CGI-I.  
 
In addition, a 9-hour video-EEG will be performed to confirm parent/caregiver report of relapse. 
All patients will begin tapering off CBD and Vigabatrin at the end of this period. 
 
4.4. 
Early Withdrawal Visit 
Should a patient’s participation be terminated prior to Day 14 or Day 90 for any reason, an Early 
Withdrawal Visit will be completed.  The following procedures will be completed: record 
concomitant medications and procedures, vital signs, height and weight, review daily seizure 
diary, and AEs; draw blood samples for hematology and chemistry; perform a brief neurological 
examination; perform a 9-hour video-EEG (if possible) and complete investigator CGI-I. 
All patients will begin tapering off CBD and Vigabatrin at this visit. 
4.5. 
Follow-up Period 
A follow-up phone call will occur 30 days after discontinuation of the study drug to assess AEs, 
AEDs, and record concomitant medications. 


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5. 
CLINICAL ASSESSMENTS 
5.1. 
Demographics and Medical History 
The Investigator or designee will record the following information during the Screening Period: 
demographic data, including sex, date of birth, race, ethnicity, medical history, medications 
history, and concomitant medications.  
5.2. 
Efficacy Assessments 
5.2.1. 
Video-EEG 
Video-EEGs performed during the Screening Visit and Visit 4 to Visit 5 (Day 13 and Day 14), 
and during the Extended Treatment Period to confirm parent reports of relapse or seizure 
cessation.  Data collected include: Presence of spasms (Y/N), Number of spasms, and presence of 
Hypsarrhythmia (Y/N), presence of epileptic encephalopathy (Y/N). 
 
5.2.2. 
CGI-I 
Clinical Global Impression of Improvement (CGI-I) will be completed by the investigator at 
Visit 5 (Treatment Period Day 14).  CGI-I will be completed by the investigator, if possible, 
during the Early Withdrawal Visit or by the parent is a Visit is not completed. 
The CGI-I assessment for each subject will also be a scale of 1 to 7: 
• 1 = Very much improved  
• 2 = Much improved  
• 3 = Minimally improved  
• 4 = No change  
• 5 = Minimally worse  
• 6 = Much worse  
• 7 = Very much worse. 
 
5.2.3. 
Seizure Diary 
The seizure diary records the date, the number of spasms observed each day, and current dose of 
medications. 
 
5.3. 
Safety Assessments 
5.3.1. 
Physical Examination 
The physical examination during the Screening Visit will include evaluation of general 
appearance, ears, eyes, nose, and throat (EENT), heart, peripheral vasculature, lungs, 


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musculoskeletal system, abdomen, neurologic function, endocrine system, and skin, assessed as 
‘normal’ or ‘abnormal’. Height/length and weight will be obtained.   
5.3.2. 
Neurological Examinations 
The brief neurological examination will assess mental status, cranial nerves, nystagmus, motor 
system, sensory system, reflexes, coordination, gait, and station (normal/abnormal). 
5.3.3. 
Vital Signs 
Vital signs will consist of seated or supine blood pressure (depending on patient age and ability), 
pulse rate, temperature, and respiration rate measurements. The most recent valid measurement 
prior to first dose of study medications will be defined as the Baseline measure. 
5.3.4. 
Clinical Laboratory Assessments 
Blood samples will be collected during the Screening Visit and Visits 3 through 8, and at the 
Early Withdrawal Visit. 
5.3.4.1. 
Hematology 
Blood samples for the following hematology assessments will be collected: hemoglobin, 
hematocrit, total and differential leukocyte count, red blood cell (RBC), and platelet count. 
5.3.4.2. 
Chemistry 
Blood samples will be collected for the following serum chemistry assessments: albumin, blood 
urea nitrogen (BUN), creatinine, total bilirubin, alkaline phosphatase (ALP), aspartate 
transaminase (AST), alanine transaminase (ALT), sodium (Na+), potassium (K+), chloride (Cl-), 
lactate dehydrogenase (LDH), uric acid, glucose, and calcium.  
5.3.4.3. 
Drug Screen 
A blood sample will be collected during the Screening Visit for a drug screen, which will test for 
presence of amphetamines, barbiturates, tricyclic antidepressants, cocaine, methadone, 
morphine, 3,4-methylenedioxymethamphetamine (ecstasy), THC, phencyclidine, cotinine, 
alcohol, and opiates. 
5.3.4.4. 
Urinalysis 
Urine will be collected during the Screening Visit for the following urinalysis assessments: pH, 
specific gravity, protein, glucose, ketones, bilirubin, blood, nitrite, leukocyte esterase, and 
urobilinogen.  


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6. 
DEFINITIONS AND CONVENTIONS 
6.1. 
General Summary Table and Individual Subject Data Listing 
Considerations 
Tables and data listings will be prepared using SAS Version 9.3 or higher. 
A patient’s Baseline value will be the last measurement taken prior to treatment. For any 
variable with Change From Baseline (CFB) calculated, CFB will be calculated as: 
CFB = Post-Baseline value – Baseline value. 
6.2. 
Calculations Using Dates 
Age will be calculated as: 
Age = Integer((Date of enrollment – Date of Birth)/365.25) 
Study Day will be calculated as 
 
 
Study Day = Integer(Date of Event  - Day 1 of Treatment) + 1 
6.3. 
Baseline 
The Baseline value for any measurement will be the most recent valid value prior to the first 
dose of study medication. 
6.3.1. 
Visit Windows Relative to the First Dose of Study Medication 
 
Table 2: 
Visit windows and target days 
Visit 
Relative Target Day 
Visit Window 
Visit 1 (Screening) 
-14 
-14 – -1 
Visit 2  
Day 1 
1 
Visit 3 
4 
4 
Visit 4 
13 
13 
Visit 5 (End of Study) 
14 
14 
Visit 6 
Week 6 
 
Visit 7 
Week 10 
 
Visit 8 (End of Study) 
Week 13 
 
Early Withdrawal 
 
 
Taper Period  
 
3 days 
Followup Period 
 
30 days 


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6.4. 
Analysis Populations 
6.4.1. 
Safety Population 
 
The Safety Analysis Population will include all subjects who were treated with at least one dose 
of the study drug. The Safety Analysis Population will be used for all safety assessments. 
6.4.2. 
Intent to Treat Population  
The Intent to Treat (ITT) Population will include all subjects who randomized. The ITT will be 
used for all efficacy assessments. 
6.4.3. 
PK Analysis Population 
The PK Analysis Population will include all subjects who were treated with at least one dose of 
the study drug and have at least one usable plasma concentration measurement. 
6.4.4. 
Handling of Missing Values 
There will be no imputation of the missing values. All assessments will be conducted based on 
all observed data.  A sensitivity analysis will be conducted to assess the impact of the missing 
values on the final analysis.   
Partial missing dates will be imputed as described in Table 3. After following these imputation 
rules, if the start date is imputed as a date after the end date, the start date will be set to the end 
date to provide a positive duration for the event incidence.   
 
Table 3: 
Calculation of missing or partially missing dates 
Missing Start 
Date Portion 
Prior to 
Treatment 
Same as Treatment Start 
Date 
After Treatment 
Start Date 
Day Month and Year < 
Month and Year of first 
treatment: 
 
Day = 1 
Month and Year = Month 
and Year of first treatment: 
 
Day = Day of first 
treatment 
Month and Year > 
Month and Year of 
First Treatment: 
 
Day = 1 
Day and 
Month 
Year < Year of first 
treatment: 
 
Day = 1, 
Month = July 
Year = Year of first 
treatment: 
 
Day = Day of first 
treatment,  
Month = Month of first 
treatment 
Year > Year of first 
treatment: 
 
Day = 1,  
Month = January 
Day, Month, 
and Year 
To be conservative, completely missing start dates will be set to the date of 
first treatment 
 


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7. 
DATA PRESENTATIONS AND DATA MANAGEMENT 
7.1. 
Data Presentations 
The templates provided with this SAP describe the presentations for this study and therefore the 
format and content of the summary tables, figures and listings to be provided. 
7.2. 
Data Management 
Data management for this study will be the responsibility of the CRO as described in the Data 
Management Plan. 
7.3. 
General Post Text Summary Table and Individual Subject Data 
Listing Format Considerations 
 


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8. 
PATIENT DISPOSITION AND PROFILE OF SCREEN 
FAILURES 
The number of patients in the ITT and Safety Analysis Population will be summarized along 
with reasons for early discontinuation from the study. A summary table of protocol deviations 
will also be presented. All protocol deviations along with patient’s eligibility criteria will be 
listed for the Safety Analysis Population. 
Discontinuation reasons are as follows: 
• Inadvertently enrolled (enrollment criteria not met) 
• Investigator decision 
• Adverse Event 
• Subject withdrew consent 
• Lack of protocol compliance 
• Subject attempted suicide or is at risk of suicide 
• Sponsor decision 
• Subject becomes pregnant 
• Abnormal laboratory values 
• Lost to follow-up 
• Death 
• Other 
The following important (clinically) protocol deviations, as identified in the clinical trial 
management system (CTMS), will be summarized: 
• Administrative Criteria 
• Eligibility and Entry Criteria 
• IP Compliance 
• Informed Consent 
• Laboratory Assessment Criteria 
• Serious AE Criteria 
• Study Procedures Criteria 
• Regulatory or Ethics Approvals Criteria 
• Visit Scheduled Criteria 
• Other Criteria 
Supportive listings will also be provided: 
• Allocation to treatment 
• Protocol deviations 
• Subjects eligibility criteria 
 
8.1. 
Patient Accounting  
Patients who are randomized will be listed and summarized including number of patients 
randomized (ITT), treated (Safety Population), in PK Population, and number and reason for 
discontinuation.  


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8.1.1. 
Patient Accounting by Treatment Group 
Patients who are randomized will be listed and summarized by treatment group including 
number of patients randomized (ITT Population), treated (Safety Population), in PK Population,  
and number and reason for discontinuation. 
8.1.2. 
Patient Distribution by Investigator 
Patients who are randomized will be listed and summarized by investigator, including number of 
patients randomized (ITT Population), treated (Safety Population), in PK Population, and 
number and reason for discontinuation. 
8.2. 
Screen Failure 
Patients who fail screening and are not eligible for the study will not be entered into the database. 
 


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9. 
BASELINE SUBJECT DATA 
9.1. 
Baseline Demographic and Physical Characteristics 
Demographic and baseline characteristics (including age in months, gender, race, ethnicity, 
length, weight, BMI, head circumference, video-EEG results) will be summarized for both the 
Safety and ITT Populations. All demographic and baseline characteristics along with body mass 
index (BMI) will be listed for the Safety Population.  
9.2. 
Medical History and Medical Conditions Present at Entry 
Medical and surgical history will be coded using the MedDRA, version 20.0 or above, and will 
be summarized by system organ class and preferred term for the Safety Population. 
Development will be summarized as ‘high’ or ‘low’ risk of developmental impairment as defined 
by the International Collaborative Infantile Spasms Study (ICISS) for the Safety Population. 
ICISS criteria include the presence or absence of the following factors that increase the risk of 
developmental impairment: chromosomal abnormality or clinical syndrome, neonatal 
encephalopathy with seizures, and cerebral palsy or developmental impairment diagnosed before 
onset of spasms. 
9.3. 
Prior Medication History and Medications Present at Entry 
Prior and concomitant medications will be coded using World Health Organization Drug 
Dictionary (WHO-DD), version March 2017 and will be summarized separately by preferred 
term for the Safety Population. The details of medication and foods excluded from the study are 
presented in the protocol. At each level of summarization, subjects reporting more than one 
medication will be counted only once. 
Summary tables and listings will include Baseline assessment data.  
9.3.1. 
Non-Diagnosis Related Prior Medication History 
Prior non-diagnosis related medications are classified as medications which stopped before the 
date of first dose of study medication while concomitant medications are medications started 
prior to, on or after the first dose of study medication, and ended on or after the date of first dose 
of study medication or were ongoing at the end of the study. At each level of summarization, 
subjects reporting more than one medication will be counted only once. Summary tables and 
listings will include Baseline assessment data.  
9.3.2. 
Prior Diagnosis Related Medication History 
Patients with prior anti-epileptic drug administration will be excluded from this study. 
9.3.3. 
Missing and Partially Missing Start and Stop Dates 
Imputation of missing dates is described in Section 6.4.4.  


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9.4. 
Baseline Physical Examination 
Results of the Screening Visit complete physical examination will be listed and summarized by 
treatment group for both the Safety and Efficacy Population. General appearance, ears, eyes, 
nose, and throat (EENT), heart, peripheral vasculature, lungs, musculoskeletal system, abdomen, 
neurologic function, endocrine system, and skin will be assessed and summarized as ‘normal’ or 
‘abnormal’. Height/length and weight will be summarized and BMI calculated. 
9.5. 
Baseline Vital Signs 
Baseline Vital Signs will be defined as the most recent valid measurement taken before receiving 
the first dose of medication during Visit 3 (Treatment Period Day 1). Vital signs will be 
summarized for both the Safety and ITT Population. Vital signs will consist of blood pressure, 
pulse rate, temperature, and respiration rate measurements.  
9.6. 
Baseline Laboratory Data 
Results of the Screening Visit laboratory values will be summarized for both the Safety and ITT 
Population. Hematology assessments include: hemoglobin, hematocrit, total and differential 
leukocyte count, red blood cell (RBC), and platelet count. Serum chemistry assessments include: 
albumin, blood urea nitrogen (BUN), creatinine, total bilirubin, alkaline phosphatase (ALP), 
aspartate transaminase (AST), alanine transaminase (ALT), sodium (Na+), potassium (K+), 
chloride (Cl-), lactate dehydrogenase (LDH), uric acid, glucose, and calcium.  
The results of the Screening Visit drug screen will be listed for the Safety Population, to include 
amphetamines, barbiturates, tricyclic antidepressants, cocaine, methadone, morphine, 3,4-
methylenedioxymethamphetamine (ecstasy), THC, phencyclidine, cotinine, alcohol, and opiates. 
Presence of any drugs will be considered a screen failure. 
Urinalysis will only be assessed during the Screening Visit and will summarized for both the 
Safety and ITT Population. Urine assessments include: pH, specific gravity, protein, glucose, 
ketones, bilirubin, blood, nitrite, leukocyte esterase, and urobilinogen. If protein, occult blood, 
nitrite, or leukocyte esterase values are out of range a microscopic examination will be 
performed and results provided as a listing. 
 
9.7. 
Baseline Primary and Secondary Efficacy Evaluations 
The primary objective of this study is to evaluate the efficacy of Cannabidiol Oral Solution as 
adjunct therapy to vigabatrin in treating infantile spasms.  Efficacy will be evaluated using the 
following primary and secondary endpoints. 
Primary Efficacy Analysis 
• Percent of patients with resolution of both infantile spasms and hypsarrhythmia or a 
pattern of epileptic encephalopathy at Day 14 (complete response) will be compared 
between Vigabatrin plus Placebo and Vigabatrin plus CBD 40 mg/kg/day groups.     


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Secondary Efficacy Analyses 
• Percent of patients with resolution of infantile spasms at Day 14 will be compared 
between treatment groups. 
• Percent of patients with resolution of hypsarrhythmia or a pattern of epileptic 
encephalopathy at Day 14 will be compared between treatment. 
• Investigator impression of efficacy and tolerability of study drug (Clinical Global 
Impression – Global Improvement (CGI-I) will be compared between treatment 
groups. 
• Percent reduction in spasm-free days between the Initial Treatment Period (Days 1 to 
14) and Screening Period (Days -14 to -1) will be compared between treatment 
groups. 
• Percent of patients who relapse during the Extended Treatment Period will be 
compared between 14-day Vigabatrin + CBD responders and 14-day Vigabatrin + 
placebo responders. Time to relapse will be calculated and compared. 
• Percent of patients with partial response at Day 14 who achieve complete response 
during the Extended Treatment Period will be compared. Time to complete response 
will be calculated and compared. 
 
Baseline Video-EEG results (Presence of spasms, number of spasms, and presence of 
hypsarrhythmia, presence of epileptic encephalopathy) will be summarized by treatment group 
for both Awake and Sleep periods. 
Historical seizure history will be recorded during the Screening Visit based on parent/caregiver 
recollection. Baseline percent of spasm-free days will be calculated using the seizure diary 
collected during the Screening Period and summarized by treatment arm.  
9.7.1. 
Imputation for Missing Data 
No imputation of missing values is planned for this study.  Missing or partially missing dates 
will be imputed as described in 6.4.4. 


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10. 
EFFICACY  
10.1. 
General Considerations 
The results of this study will be reported using summary tables, listings, and figures (TLFs), as 
appropriate. Continuous variables will be summarized using descriptive statistics: sample size 
(n), mean, standard deviation (SD), or coefficient of variation (CV %) as appropriate, median, 
interquartile range, minimum and maximum. Categorical variables will be summarized by 
presenting the number (frequency) and percentage in each category. 
10.2. 
Testing Statistical Assumptions Including Comparability at Baseline 
The statistical assumptions of ANCOVA are: 
• Normally distributed response 
• Homogeneity of variance 
• Independence and linear relationship between the dependent variables and the 
covariates 
• Homogeneity of regression slopes 
These assumptions will be assessed using boxplots, Q-Q plots, and scatter plots with regression 
lines for each treatment group.  If interaction between the independent variables is suspected, 
interaction terms will be tested in the regression model.  The additional assumption of random 
independent samples is insured by the use of a randomized, double-blind experimental design. 
Comparability at Baseline will be assessed by comparison of treatment groups for the Baseline 
values using ANCOVA or Fisher’s Exact Test.  Potentially important imbalances between 
treatment groups will be assessed for their impact on efficacy analysis by including them as 
covariates in a linear mixed model and possible supportive sub-group analyses, as appropriate. 
Patients will be randomized to treatment group stratified by developmental status.  
Comparability of strata will be assessed by comparison of strata within treatment groups using 
ANCOVA and Fisher’s exact test. If significant differences in the efficacy endpoints are found 
between strata, a stratified analysis will be performed.  Otherwise, data from each strata will be 
pooled and presented as overall differences between treatment groups. 
 
10.3. 
Statement of the Null and Alternate Hypotheses 
10.3.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint in this study is: 
• Percent of patients who are considered complete responders, defined as complete 
resolution of spasms and hypsarrhythmia or a pattern of epileptic encephalopathy 


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confirmed by 24-hour video-EEG from Day 13 to Day 14, as determined by the 
Independent Central Reader. 
Null hypothesis: There is no difference in the percent of patients defined as complete 
responders between treatment groups. 
Alternative hypothesis: Treatment groups have significantly different percent of 
complete responders. 
10.3.2. 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints: 
• Percent of patients with absence of infantile spasms as assessed by 24-hour video-
EEG from Day 13 to Day 14 (partial response).  
Null hypothesis: There is no difference in the percent of patients with absence of 
infantile spasms between treatment groups. 
Alternative hypothesis: Treatment groups have significantly different percentage of 
patients with absence of infantile spasms. 
• Percent of patients with absence of hypsarrhythmia or pattern of epipleptic 
encephalopathy as assessed by 24-hour video-EEG from Day 13 to Day 14 (partial 
response). 
Null hypothesis: There is no difference in the percent of patients with hypsarrhythmia 
or pattern of epipleptic encephalopathy at Baseline but absence of hypsarrhythmia or 
pattern of epipleptic encephalopathy at Day 13 to Day 14 between treatment groups. 
Alternative hypothesis: Treatment groups have significantly different percent of 
patients with hypsarrhythmia at Baseline but absence of hypsarrhythmia at Day 14 to 
Day 15. 
• Investigator impression of efficacy and tolerability of study drug (CGI-I) at End of 
Study/Early Withdrawal (Visit 5). 
Null hypothesis: There is no difference in the mean CGI-I score between treatment 
groups. 
Alternative hypothesis: Treatment groups have significantly different mean CGI-I 
score. 
• Percent reduction in spasm-free days between the Initial Treatment Period (Days 1 to 
14) and Screening Period (Days -14 to -1), as determined by the seizure diary entries. 
Null hypothesis: There is no difference in the percent reduction in spasm-free days 
between treatment groups. 
Alternative hypothesis: Treatment groups have significantly different percent 
reduction in spasm-free days. 
• For patients with a complete response during the Initial Treatment Period who 
continue: percent of patients who relapse during the Extended Treatment Period 
confirmed by video-EEG following parent report of relapse, and time to relapse. 


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1. Null hypothesis: there is no difference in the relapse rate between Vigabatrin + 
Placebo Responders and Vigabatrin + CBD Responders. 
Alternative Hypothesis: The relapse rate is different Vigabatrin + Placebo 
Responders and Vigabatrin + CBD Responders. 
2. Null hypothesis: there is no difference in time to relapse between Vigabatrin + 
Placebo Responders and Vigabatrin + CBD Responders. 
Alternative Hypothesis: The time to relapse is different Vigabatrin + Placebo 
Responders and Vigabatrin + CBD Responders. 
 
• For patients with partial response during the Initial Treatment Period who continue: 
percent of patients who achieve complete response during the Extended Treatment 
Period, confirmed by video-EEG following parent report, and time to complete 
response. 
1. Null hypothesis: there is no difference in the percentage of patients achieving 
complete response in the Extended Treatment Period between Vigabatrin + 
Placebo Partial Responders and Vigabatrin + CBD Partial Responders. 
Alternative Hypothesis: The percentage of patients achieving complete 
response in the Extended Treatment Period is different Vigabatrin + Placebo 
Partial Responders and Vigabatrin + CBD Partial Responders. 
2. Null hypothesis: there is no difference in time to complete response between 
Vigabatrin + Placebo Partial Responders and Vigabatrin + CBD Partial 
Responders. 
Alternative Hypothesis: The time to complete response is different Vigabatrin 
+ Placebo Partial Responders and Vigabatrin + CBD Partial Responders. 
 
10.4. 
Subgroup Analyses 
No subgroup analysis is planned. However, if significant differences in efficacy endpoints are 
observed between developmentally normal vs. delayed patients, stratified analysis will be 
performed. 
10.5. 
Multiple Comparisons and Multiplicity 
No multiple comparisons are planned for analysis of the Primary Efficacy Endpoint.  Secondary 
Endpoints will have an FDR correction applied to control the overall q = 0.05. 
10.6. 
Analysis of the Primary Efficacy Endpoints 
The primary efficacy endpoint will be assessed on the ITT population. 
10.6.1. 
Primary Efficacy Analysis 
The primary efficacy endpoint in this study is: 


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 Percent of patients who are considered complete responders, defined as complete 
resolution of spasms and hypsarrhythmia or a pattern of epileptic encephalopathy. 
The percent of complete responders will be calculated for each treatment group and compared 
using Fisher’s exact test. 
10.6.2. 
Presentation of the Primary Efficacy Results 
Percent of patients considered complete responders in each treatment group will be reported in a 
table. The p-value for difference between groups will be presented.   
10.7. 
Analysis of the Secondary Efficacy Endpoints 
10.7.1. 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints in this study are: 
 Percent of patients with resolution of infantile spasms as assessed by 24-hour video-
EEG from Day 13 to Day 14 (partial response).  
 Percent of patients with resolution of hypsarrhythmia or pattern of epipleptic 
encephalopathy as assessed by 24-hour video-EEG from Day 13 to Day 14 (partial 
response). 
 Investigator impression of efficacy and tolerability of study drug (CGI-I) at Visit 5 
(End of Study) or Early Withdrawal. 
 Percent reduction in spasm-free days between the Initial Treatment Period (Days 1 to 
14) and Screening Period (Days -14 to -1), as determined by the seizure diary entries. 
 For patients with a complete response during the Initial Treatment Period who 
continue: percent of patients who relapse during the Extended Treatment Period 
confirmed by video-EEG following parent report of relapse, and time to relapse. 
 For patients with partial response during the Initial Treatment Period who continue: 
percent of patients who achieve complete response during the Extended Treatment 
Period, confirmed by video-EEG following parent report, and time to complete 
response. 
Percentage of patients with partial response will be compared for each endpoint between 
treatment groups using Fisher’s exact test. 
Parent impression of efficacy and tolerability as measured by Clinical Global Impression –
Global Improvement Scale (CGI-I) will be summarized by visit and status of response 
(complete/partial and no response). Appropriate summary statistics will be displayed and the 
CGI-I will also be analyzed as a continuous scale: 
1 = Very much improved 
2 = Much improved 
3 = Minimally improved 
4 = No change 


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5 = Minimally worse 
6 = Much worse 
7 = Very much worse 
Percent reduction in spasm-free days, will be calculated for each treatment group. Treatment 
groups will be compared using ANCOVA with baseline number of spasm-free days as a 
covariate. 
Percent of Responders who relapse and Partial Responders who achieve complete response 
during the Extended Treatment Period will be compared between treatment groups using Fisher’s 
exact test.  Time to relapse and time to complete response will be visualized using Kaplan-Meier 
curves and compared with log-rank tests. 
 
10.7.2. 
Presentation of the Secondary Efficacy Results 
 Percentage of Partial Responders at Day 14 will be summarized by treatment group and 
developmental stage, and the p-value presented. CGI-I results will be summarized as a frequency 
table and the mean and median score with the p-value. Percent change in spasm-free days, 
relapse rate, and rate of partial to complete response will be summarized by treatment group and 
p-value.  Time to relapse and time to complete response will be presented by treatment group as 
Kaplan-Meier curves and p-value for log-rank test. 
10.8. 
Summary of Reasons for Efficacy Non-evaluability/Exclusion from 
Efficacy Analyses 
If any patient is excluded from either the Safety or ITT Population, these will be presented in a 
listing with the reason for exclusion. 


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11. 
SAFETY AND TOLERABILITY 
 
11.1. 
Overall Summary of Tolerability 
The secondary objective of the study is to evaluate the safety and tolerability of Cannabidiol Oral 
Solution as adjunctive therapy with either vigabatrin or ACTH as initial therapy in treating 
patients with Infantile Spasms. This objective will be met by assessment of the following: 
• Treatment-emergent AEs (TEAEs) and SAEs graded according to the Medical 
Dictionary for Regulatory Activities (MedDRA version 19.0 or above). These will be 
captured at every patient visit to the study center. 
• Liver function tests. 
• Complete blood counts. 
• Concomitant medications 
• Vital signs (temperature, blood pressure, pulse rate, and respiratory rate). 
• Physical and neurological examinations. 
Collection and monitoring of these data are detailed in Sections 6.2.1 through 6.2.5 of the 
protocol. 
11.2. 
Adverse Event Preferred Term and Body/Organ System Summary 
Tables 
Treatment Emergent Adverse Events (TEAEs) are defined as AEs that first occurred or worsened 
after the first administration of the investigational product. Adverse events are considered 
treatment-related if the relationship to study drug is related. A missing relationship will be 
imputed as related to study drug and included in the summary. 
11.2.1. 
Summaries of Adverse Event Incidence Rates for All Subjects 
Overall summary of TEAE’s will be summarized by any TEAE, treatment-related TEAE, 
treatment-related and severe TEAE, TEAE leading to study drug discontinuation, any serious 
TEAE, any serious and treatment related TEAE and TEAE resulting in death. Summaries of AEs 
will include incidence of TEAEs and treatment-related TEAEs by MedDRA preferred term (PT) 
and system organ class (SOC). The TEAEs will also be summarized by severity, PT, and SOC. 
Subjects reporting more than one TEAE are counted once in each category at the maximum 
severity. 
AEs with a start date during the study will be summarized. Listings of all AEs, AEs leading to 
discontinuation of the study, SAEs, and deaths, if any, will be provided. 
11.2.2. 
Missing and Partial AE Onset Dates 
Imputation of missing and partial dates is described in Section 6.4.4. 


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11.2.3. 
Summaries of Adverse Incidence Rates for Serious Adverse Events (SAE), 
Adverse Event Dropouts, and Death 
Any SAE, dropouts, or death related to the study drug will be listed in a table by treatment 
group. 
11.3. 
Total Duration of Therapy, Average Daily Dose, Maximum Daily 
Dose, Final Daily Dose of Study Medication, and Compliance 
Exposure to study medication in days will be presented for the Safety Population, by treatment 
category and overall. Patients are expected to complete the study drug as prescribed, however, if 
safety or tolerability issues arise the patient will be counted as a treatment failure and 
discontinued. The following parameters will be summarized by assigned treatment group: 
• Total duration of study medication at any dose 
• Number and percent of patients who received their full randomized dose for the 
duration of the study 
• Compliance with prescribed dosing (Number and percent of patients who had at least 
one dose modification, changed, interrupted, or permanently discontinued) 
Interruptions, compliance, and dose changes are not included in the calculation of duration of 
exposure. Total duration of study medication is defined as the number of days between date of 
first study medication administration to date of last study medication administration + 1. 
The corresponding listing will present first/last dose dates, does the subject complete the 
treatment duration, reason for end of treatment and duration of exposure (days). 
In addition, dose modifications will be summarized by treatment and overall in terms of: 
• 
Number of subjects with at least one dose modification (as defined Section 14.1) 
• 
Number of subjects with at least one dose changed 
• 
Number of subjects with at least one dose interrupted 
• 
Number of subjects with dose permanently discontinued 
• 
Number of subjects per reason of dose modification 
o 
Adverse event 
o 
Lack of efficacy 
o 
PK-analysis result 
o 
Other 
A patient who experiences several dose modifications for the same reason will be counted only 
once for this reason. A patient who experiences several dose modifications due to different 
reasons will be counted once for each reason.   
 


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11.4. 
Concomitant and Other Medications 
Concomitant Medications will be summarized using WHO-DD version March 2017 preferred 
terms (PT). Any medication/therapy that stops at or after this time or with missing stop dates is 
considered concomitant medication/therapy.  Listings and summaries will be presented 
separately for the Safety Population. 
11.4.1. 
Missing and Partial Concomitant and Other Medication Start and Stop Dates 
Imputation of missing and partial dates is described in Section 6.4.4. 
11.5. 
Routine Laboratory Data 
Clinical laboratory findings will be summarized for all subjects in the Safety Population for 
observed values and change from baseline by visit. Shifts from baseline according to normal 
range criteria will also be presented for all subjects in the Safety Population.  
Quantitative laboratory measurements reported as “< X”, i.e. below the lower limit of 
quantification (BLQ), or “> X”, i.e. above the upper limit of quantification (ULQ), will be 
converted to X for the purpose of quantitative summaries, but will be presented as recorded, i.e. 
as “< X” or “> X” in the listings. 
For Hematology the following parameters will be summarized: Platelet Count, White Blood Cell 
Count (WBC), Neutrophils (Percent), Neutrophils (Absolute), Lymphocytes (Percent), 
Lymphocytes (Absolute), Eosinophils (Percent), Eosinophils (Absolute), Basophils (Percent), 
Basophils (Absolute), Monocytes (Percent), Monocytes (Absolute), Hemoglobin and Hematocrit. 
For Serum Chemistry the following parameters will be summarized: Total Protein, Albumin, 
Creatinine, Blood Urea Nitrogen, Uric Acid, Total Bilirubin, Direct Bilirubin, Alkaline 
Phosphatase, Asparate aminotransferase (AST), Alanine aminotransferase (ALT), Gamma 
glutamyl transferase (GGT), FSH, Glucose, Calcium, Chloride, Bicarbonate, Sodium, Potassium 
and Phosphorus. 
The clinical laboratory data for each visit will be listed and summarized. 
11.6. 
Vital Signs 
Vital signs will be summarized for all subjects in the Safety Analysis Population for observed 
values and change from baseline as appropriate by visit for the following parameters: Systolic 
Blood Pressure, Diastolic Blood Pressure, Pulse Rate, Respiratory Rate, and Temperature. 
Shifts from baseline according to normal and abnormal criteria will also be presented for all 
subjects the Safety Population. 
11.6.1. 
Vital Signs Markedly Abnormal Criteria 
Markedly abnormal quantitative Vital Signs measurements will be identified in accordance with 
the following predefined markedly abnormal criteria: 
Variable 
Unit 
Low 
High 
SBP 
mmHg 
≤ 90 mmHg AND change from 
baseline ≤ -20 mmHg 
≥ 180 mmHg AND change 
from baseline ≥ 20 mmHg 


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Variable 
Unit 
Low 
High 
DBP 
mmHg 
≤ 50 mmHg AND change from 
≤ -15 mmHg 
≥ 105 mmHg AND change 
from baseline ≥ 15 mmHg 
Heart rate 
Bpm 
≤ 50 bpm AND change from 
baseline ≤ -15 bpm 
≥ 120 bpm AND change from 
baseline ≥ 15 bpm 
Body 
temperature 
˚C 
NA 
≥ 38.3 ˚C AND change from 
baseline ≥ 1.1 ˚C 
 
11.7. 
Physical Examination 
Physical examination at Screening will be summarized as percent of patients with ‘normal’ vs. 
‘abnormal’ findings for the following body systems: General Appearance, Skin, Eyes, Ears, 
Nose, Throat, Neck, Lymph Nodes, Chest, Heart, Abdomen, Extremities, Neurological Systems, 
and Other. Abnormal findings will be presented as a listing. 
 
11.8. 
Neurological Examination 
Neurological examination results at Screening will be summarized as percent of patients with 
‘normal’ vs. ‘abnormal’ findings for mental status, cranial nerves, nystagmus, motor system, 
sensory system, reflexes, coordination, gait, and station.  
Shifts from baseline according to normal and abnormal criteria will also be presented for all 
subjects the Safety Population for each visit. Abnormal findings will be presented as a listing. 
11.9. 
PK Results 
Trough values from the PK analysis obtained at Visit 5 will be presented as a listing and 
summarized by treatment arm and Response status (defined from the 24-hour video-EEG 
performed from Day 13 to Day 14). 
11.10. 
Study Termination Status 
Study completion/termination status will be listed for each patient, including reasons (if 
applicable) for early termination. 


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12. 
INTERIM ANALYSES 
No interim analysis is planned. 
 


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13. 
REFERENCES 
1. US Federal Register. (1998) International Conference on Harmonization; Guidance for 
Industry: Statistical Principles for Clinical Trials. Department of Health and Human Services: 
Food and Drug Administration.  Federal Register, Vol. 63, No. 179, September 16, 1998, 
page 49583. 
 
2. US Federal Register. (1996) International Conference on Harmonization; Guidance for 
Industry: Structure and Content of Clinical Study Reports. Department of Health and Human 
Services: Food and Drug Administration.  Federal Register Vol. 61, July 17, 1996, page 
37320.  
 
3. Guidance for Industry (2014) Analgesic Indications: Developing Drug and Biological 
Products  -  Draft Guidance.  Department of Health and Human Services: Food and Drug 
Administration.  Center for Drug Evaluation and Research (CDER) February 2014 
Clinical/Medical. 


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14. 
APPENDIX 
14.1. 
Sample Table of Contents for Data Listings 
 
Title 
Population 
 
Comments 
Study Population Section 
9.1.1 
Patient Enrollment and Randomization 
All 
Unique 
9.1.2 
Patient Disposition 
All 
Unique 
9.1.3 
Subjects who did not Satisfy Inclusion/Exclusion Criteria (if 
applicable) 
Screening 
Failure 
 
 
Protocol Deviations 
Safety 
Unique 
10.1.1 
Demographics and Baseline Characterics 
Safety 
 
10.2.1 
Medical/Surgical History 
Safety 
 
10.3.1 
Prior and Concomitant Medications 
Safety 
 
10.3.2 
Non-Medication Therapy 
Safety 
 
10.6.1 
Serology Laboratory and Pregnancy Test Results 
Safety 
 
10.6.2 
Urine Drug Screen 
Safety 
 
12.3.1 
Study Drug Administration 
Safety 
 
12.3.2 
Drug Accountability 
Safety 
 
12.2.1 
All Treatment Emergent Adverse Events (TEAEs) 
Safety 
 
12.2.2 
Treatment Related TEAEs 
Safety 
 
12.2.3 
Serious TEAEs 
Safety 
 
12.2.4 
Deaths 
Safety 
 
12.2.5 
TEAEs Leading to Premature Study Discontinuation 
Saftey 
 
12.6.1 
Chemistry Laboratory Results 
Safety 
 
12.6.2 
Hematology Laboratory Results 
Safety 
 
12.6.3 
Urinalysis Laboratory Results 
Safety 
 
12.7.1 
Vital Signs 
Safety 
 
12.8.1 
Physical Examinations 
Safety 
 
12.9.1 
Neurological Examinations 
Safety 
 
 
 
 
 
 
 
 
 
 


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14.2. 
Sample Table of Contents for Data Display Summaries 
 
Title 
Population 
 
Comments 
Study Population Section 
9.1.1 
Summary of Subject Disposition 
Randomized 
Unique 
7.4.1 
Summary of Analysis Populations 
Randomized 
Unique 
10.1.1 
Summary of Demographic Characteristics 
Safety 
Unique 
10.1.2 
Summary of Demographic Characteristics 
ITT 
Repeat 9.3.1 
Efficacy Section  
 
 
Figures 
 
 
11.7.1 
Correlation between trough plasma drug levels and response  
ITT 
Unique 
11.6.2 
 
ITT 
Unique 
Tables 
 
 
11.6.1 
Summary of Complete Responders 
ITT 
Unique 
11.7.1 
Summary of Partial Response – absence of spasms 
ITT 
Unique 
11.7.2 
Summary of Partial Response – absence of hypsarrhythmia 
ITT 
 
11.7.3 
Summary of Investigator CGI-I at End of Study/Early 
Withdrawal 
ITT 
Unique 
13.1 
Median Reduction in Seizure Burden and Percent of Spasm-Free 
Days 
ITT 
Unique 
 
 
ITT 
Unique 
Safety Section 
12.3.1 
Summary of Exposure to Dronabinol Oral Solution by Treatment 
Group 
Safety 
Unique 
12.2.1 
Summary of Adverse Events by Treatment Group 
Safety 
Unique 
12.2.2 
Summary of Death and Serious Adverse Events by Treatment 
Group 
Safety 
Unique 
12.2.4 
Summary of Drug-Related Adverse Events by Treatment Group 
Safety 
Unique 
12.6.1 
Listing of Subjects Who Became Pregnant During the Study 
Safety 
Unique 
12.6.2 
Summary of Actual Values and Changes from Baseline in 
Clinical Chemistry Data by Treatment Group and Study Time 
Safety 
Unique 
12.6.3 
Summary of Actual Values and Changes from Baseline in 
Hematology Data by Study Time 
Safety 
Unique 
12.7.1 
Summary of Actual Values and Changes from Baseline in Vital 
Signs by Treatment Group and Study Time 
Safety 
Unique 
12.8.1 
Summary of Physical Examination Results 
 
 
12.9.1 
Summary of ECG Data 
Safety 
Unique