Clinical trial NCT02318602
Conditions: Seizures
Keywords: Lennox-Gastaut syndrome Dravet syndrome Treatment-resistant seizures
Sponsor: INSYS Therapeutics Inc
Start date: 2016-01-08; Completion date: 2017-06-22
Enrollment: 52 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This is a multicenter, open-label trial to assess the long-term safety and efficacy of Cannabidiol Oral Solution as adjunctive therapy for pediatric participants with treatment-resistant seizure disorders, including Lennox-Gastaut syndrome (LGS) or Dravet syndrome (DS). All participants have rolled over from previous trials: INS011-14-029 (NCT02324673) and INS011-15-054 (NCT02551731).

Detailed description:

Arms: arm 1: Participants 1 to\<2 years of age. Participants who completed INS011-14-029 initiated this study on the dose with which they were being treated previously, and dose modifications were made at the Investigator's discretion if tolerability or efficacy issues were observed for a particular participant. The maximum daily dose was 40 mg/kg/day.

Participants who enrolled from INS011-15-054 continued treatment with the dose at which they were being treated previously, and dose modifications were made at the Investigator's discretion if tolerability or efficacy issues were observed for a particular participant.

The total daily dose, milligrams per kilograms per day (mg/kg/day), will be evenly split between morning and evening doses (12 hours apart). If tolerability issues arise, the participant's dose may be changed at the investigator's discretion. arm 2: Participants 2 to \<12 years of age. Participants who completed INS011-14-029 initiated this study on the dose with which they were being treated previously, and dose modifications were made at the Investigator's discretion if tolerability or efficacy issues were observed for a particular participant.The maximum daily dose was 40 mg/kg/day.

Participants who enrolled from INS011-15-054 continued treatment with the dose at which they were being treated previously, and dose modifications were made at the Investigator's discretion if tolerability or efficacy issues were observed for a particular participant.

The total daily dose (mg/kg/day) will be evenly split between morning and evening doses (12 hours apart). If tolerability issues arise, the participant's dose may be changed at the investigator's discretion. arm 3: Participants 12 to \<17 years of age. Participants who completed INS011-14-029 initiated this study on the dose with which they were being treated previously, and dose modifications were made at the Investigator's discretion if tolerability or efficacy issues were observed for a particular participant. The maximum daily dose was 40 mg/kg/day.

Participants who enrolled from INS011-15-054 continued treatment with the dose at which they were being treated previously, and dose modifications were made at the Investigator's discretion if tolerability or efficacy issues were observed for a particular participant.

The total daily dose (mg/kg/day) will be evenly split between morning and evening doses (12 hours apart). If tolerability issues arise, the participant's dose may be changed at the investigator's discretion.
Interventions: intervention 1: Cannabidiol Oral Solution
Intervention descriptions: intervention 1: An oral solution containing pharmaceutical grade cannabidiol (nonplant-based).

Protocol documents:
Prot_000.pdf: 
lnsys Development Company, Inc. 
INS0ll-14-030 Amendment 5
Cannabidiol Oral Solution 
Protocol Title: 
Protocol Number: 
Date of Protocol: 
Amendment 1: 
Amendment 2: 
Amendment 3: 
Amendment 4: 
Administrative Change 1: 
Amendment 5: 
Product: 
IND No.: 
Study Phase: 
Sponsor: 
Medical Monitor: 
Clinical Study Protocol 
A multicenter, open-label, flexible dose study to assess 
the long-term safety of pharmaceutical Cannabidiol Oral 
Solution as an adjunctive treatment for pediatric subjects 
with a treatment-resistant seizure disorder who complete 
INS0ll-14-029 or Part A ofINS0ll-15-054 
INS0ll-14-030 / NCT02318602 
27 October 2014 
11 December 2014 
07 August 2015 
08 April 2016 
05 October 2016 
01 November 2016 
06 March 2017 
Cannabidiol Oral Solution 
123120 
3b 
Insys Development Company, Inc. 
1333 South Spectrum Boulevard, Suite 100 
Chandler, Arizona 85286, US 
 MD 
 
US toll free: 
 
Confidentiality Statement 
This confidential information in this document is provided to you as an Investigator or 
consultant for review by you, your staff, and the applicable Institutional Review Board. 
Your acceptance of this document constitutes agreement that you will not disclose the 
information contained herein to others without written authorization from the Sponsor. 
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Insys Development Company, Inc. 
INS0I 1-14-030 Amendment 5 
Cannabidiol Oral Solution 
Approval Signatures 
PROTOCOL TITLE: 
PROTOCOL NO: 
A multicenter, open-label, flexible dose study to assess the 
long-term safety of pharmaceutical Cannabidiol Oral Solution 
as an adjunctive treatment for pediatric subjects with a 
treatment-resistant seizure disorder who complete INSOl 1-14-
029 or Part A ofINS0l 1-15-054 
INS0l 1-14-030, Amendment 5 
2 
I, the undersigned, have read this protocol and confirm that to the best of my knowledge it 
accurately describes the planned conduct of the study. 
 
 
INSYS Development Company, Inc. 
INSYS Development Company, Inc. 
 
 
INSYS Development C~
pany, Inc. 
 MD, PhD 
 
INSYS Development Company, Inc. 
06 March 201 7 
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07/1.4-(c 
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Date 
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Date 
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Insys Development Company, Inc. 
INS0l 1-14-030 Amendment 5 
Cannabidiol Oral Solution 
SYNOPSIS 
Name of Sponsor/Company: 
Insys Development Company, Inc. 
Name of Finished Product: 
Cannabidiol Oral Solution 
Name of Active Ingredient: 
Cannabidiol 
Title of Study: 
A multicenter, open-label, flexible dose study to assess the long-term safety of 
pharmaceutical Cannabidiol Oral Solution as an adjunctive treatment for pediatric 
subjects with a treatment-resistant seizure disorder who complete INS0l 1-14-029 or 
Part A in INS0l 1-15-054 
Phase: 
3b 
Protocol No: 
INS0l 1-14-030 
Study centers: 
Multicenter (approximately 10 sites), United States (US) 
Study duration: Subjects will receive daily oral doses ofCannabidiol Oral Solution for approximately 
48 weeks or until the investigational product is successfully approved for marketing in the US ( whichever 
occurs earlier), inclusive of their treatment on the previous study.- A Final Visit/Discontinuation Visit will be 
completed when the subject completes or stops the study. A Follow-up Visit will be completed 2 weeks after 
the Final Visit/Discontinuation Visit. For subjects enrolling from INS0 11-15-054, their visit entry in 
INS0l 1-14-030 will be determined at the discretion of the sponsor and investigator. Combined study duration 
ofINS0l 1-15-054 and INS0l 1-14-030 will not exceed approximately 48 weeks. 
Objectives: 
• 
To assess the long-term safety ofCannabidiol Oral Solution as an adjunctive treatment for subjects 
with treatment-resistant seizure disorders, including Lennox-Gastaut syndrome (LGS), Dravet 
syndrome (DS) or infantile spasms (IS). 
• 
To establish the continued efficacy of Cannabidiol Oral Solution in maintaining seizure control in 
subjects with treatment-resistant seizures that previously completed INS0l 1-14-029 or Part A (Visit 
6) in INS0l 1-15-054. 
• 
To assess the global status of subjects taking Cannabidiol Oral Solution for an extended period of 
time determined by various qualitative assessments. 
• 
To monitor for changes in plasma levels ofCannabidiol Oral Solution during long-term treatment of 
subjects with treatment-resistant seizure disorders, including LGS, DS or IS. 
• 
Methodology: This is a multicenter, open-label study to assess the long-term safety and efficacy of 
Cannabidiol Oral Solution as adjunctive therapy for pediatric subjects with treatment-resistant 
seizure disorders, including LGS, DS, and IS. Subjects must complete 1 of the following studies to 
be eligible. 
• 
Activities through Day 11 in INS0l 1-14-029 . 
• 
Activities in Part A through Visit 6 in INS0 11-15-054 . 
Eligible subjects will also be medically stable without new, clinically significant comorbidities since the 
Screening Visit in their previous study. 
Subjects should enroll in INS0l 1-14-030 immediately upon completion of the Treatment Period in their 
previous study (to avoid interruption of the investigational product). If rollover does not occur within 
2 weeks after completion of the Treatment Period in their previous study the subjects will need to complete a 
Screening Visit (Visit 1) to confirm continued eligibility. If rollover does occur within 2 weeks after 
completion of the Treatment Period in their previous study Day 11 for INS0l 1-14-029. For subjects enrolling 
from INS0 11-15-054, there should be no interruption of greater than 2 weeks between completing treatment 
in INS0 11-15-054 and initiating treatment in INS0 11-14-030. All assessments for the previous study will be 
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Insys Development Company, Inc. 
INS0l 1-14-030 Amendment 5 
Cannabidiol Oral Solution 
completed prior to administration of the first dose of Cannabidiol Oral Solution in INS0 11-14-030. Data 
from the baseline visit in the subject's previous study will serve as the baseline for INS0l 1-14-030 where 
applicable. Data collected at the Screening Visit (Visit 1) or Visit 2 (Day 1) of this study will also be 
analyzed as a baseline, whichever visit represents the first visit in the INS0 11-14-030 for each respective 
subject, and as described in Section 8.2.2. 
In this study, all subjects will be dosed as follows: 
• 
Subjects who completed INS0l 1-14-029 will initiate this study on the dos~ with which they were 
being treated previously, unless tolerability issues were observed for a particular subject. 
• 
Subjects who enroll from INS0l 1-15-054 will continue treatment with the dose at which they were 
being treated previously, unless tolerability issues were observed for a particular subject. 
• 
Dosing of the investigational product may be adjusted for an individual subject at any time as per 
Investigator opinion should tolerability issues arise. 
Treatment with established antiepileptic drugs (AEDs) will continue without interruption and changes will be 
permitted as necessary based on safety concerns or changes in seizure control. 
Treatment visits will be scheduled weekly at Visits 3 and 4, then monthly for 3 months, and then quarterly 
thereafter. All subjects will complete a Final Visit/Discontinuation Visit regardless of when they stop 
treatment/complete the study. A Follow-up Visit will occur 2 weeks after the Final Visit/Discontinuation 
Visit. For subjects enrolling from INS0 11-15-054, their visit entry in INS0 11-14-030 will be determined at 
the discretion of the sponsor and investigator. Combined study duration ofINS0l l-15-054 and INS0l l-14-
030 will not exceed approximately 48 weeks. 
At each visit, a record of the incidence and severity of adverse events (AEs), treatment-emergent AEs 
(TEAEs), and Serious Adverse Events (SAEs) will be collected and this will serve as a primary outcome 
criterion for this study. Other safety-related parameters such as 12-lead ECG and hematology, chemistry, 
and urinary analyses will also be assessed at specified visits. Determination of trough plasma levels of 
cannabidiol and its 7-0H metabolite will be performed at each visit except at Visits 3 and 4. Information 
regarding diet (including ketogenic diet), time of the closest meal, and time of drug administration will be 
collected. This will support safety monitoring and establish the extent of variability during long-term 
treatment with the investigational product. For subjects taking clobazam, levels of clobazam and its major 
metabolite (norclobazam) will be measured if there are safety concerns. Seizure diaries will be collected to 
assess control of seizures (frequency, duration, and severity) for one week prior to each quarterly visit. 
At each visit except Visits 3 and 4, the following qualitative assessments will be completed: Clinical Global 
Impression oflmprovement (CGI-1), Clinical Global Impression of Severity (CGI-S), Impact of Pediatric 
Epilepsy Scale (IPES), and Columbia-Suicide Severity Rating Scale (C-SSRS) if appropriate. The Vineland 
Adaptive Behavior Scales, Second Edition - Survey Interview Form including the Maladaptive Behavior 
Index (V ABS) will be collected at Visit 2 and visit 10 or early termination. Subjects enrolled from INS0 11-
15-054 will be excluded from IPES, V ABS, and C-SSRS scores evaluation. 
Planned number of subjects: 
Main criteria for inclusion: 
The study will include subjects who completed activities through 
Day 11 in INS0 11-14-029 or Part A (Visit 6) in INS0 11-15-054. The 
estimated maximum number of rollover subjects from these previous 
studies is as follows: 
• 
INS0l 1-14-029: 60 subjects 
• 
INS0l 1-15-054: 20 subjects 
If all subjects are eligible for and elect to continue into INS0 11-14-030, 
the population of this study will be a maximum of 80 subjects. 
1. 
Completed activities through Day 11 in INS0l 1-14-029 or Part 
A (Visit 6) INS0l 1-15-054 
2. 
Informed consent and assent (as applicable) of the subject 
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INS0I 1-14-030 Amendment 5 
Cannabidiol Oral Solution 
Main criteria for exclusion: 
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3. 
4. 
5. 
6. 
l. 
2. 
3. 
4. 
5 
and/or parent(s)/caregiver(s) in accordance with applicable 
laws, regulations, and local requirements 
Medically stable in the opinion of the Investigator. 
a. 
Changes in background AEDs may occur during the 
study as discussed in Section 4.3. Care should be 
taken if patients are on other drugs metabolized by 
CYP enzymes. 
A female subject is eligible to participate in the study if she is: 
a. 
Premenarchal, or 
b. 
Of childbearing potential with a negative serum 
pregnancy test at Screening (only for those subjects 
required to complete the Screening Visit) and a 
negative urine pregnancy test at Visit 2. If sexually 
active, she must fulfill l of the following 
requirements: 
i. 
Complete abstinence from intercourse 
2:4 weeks prior to administration of the first 
dose of the investigational product, 
throughout the Treatment Period, and 
4 weeks after completion or premature 
discontinuation from the investigational 
product, and agreement to use a double-
barrier method if she becomes sexually 
active. 
ii. 
Use of acceptable methods of contraception 
throughout the study and 4 weeks after 
completion or premature discontinuation 
from investigational product. The acceptable 
method of contraception is double barrier 
method (i.e., condom plus spermicide or a 
condom plus diaphragm). 
A sexually active male subject must use acceptable methods of 
contraception throughout the study and for 4 weeks completion 
of study participation or premature discontinuation from 
investigational product. The acceptable methods of birth 
control are abstinence or double barrier birth control (i.e., 
condom plus spermicide or a condom plus diaphragm). 
In the opinion of the Investigator, the subject and/or 
parent(s)/caregiver(s) are able to continue keeping accurate 
seizure diaries. 
Experienced an anoxic episode related to study drug requiring 
resuscitation during their previous study. 
Evidence of other clinically significant disease such as 
unstable hepatic, hematological, renal, cardiovascular, 
gastrointestinal, immunological, or pulmonary diseases or 
ongoing malignancies. 
Compromised respiratory function or severe respiratory 
insufficiency. 
Clinically significant abnormal laboratory values within the 
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Insys Development Company, Inc. 
INS0l 1-14-030 Amendment 5 
Cannabidiol Oral Solution 
Test product, dose and mode of 
administration: 
Reference therapy, dose, and 
mode of administration: 
Endpoints 
past 14 days, including: 
a. 
Liver function tests (LFTs) such as albumin, direct 
bilirubin, total bilirubin, aspartate aminotransferase 
(AST), and alanine aminotransferase (ALT) 2::3 times 
the upper limit of normal (ULN). 
b. 
The investigator may deem the subject eligible if in 
the opinion of the investigator, the clinically 
significant abnormal laboratory values are deemed to 
be acceptable and to not have an impact on subject 
safety. 
5. 
Inadequate supervision by parent(s)/caregiver(s). 
6. 
For appropriate subjects, an affirmative answer to queries 
regarding active suicidal ideation with some intent to act but 
without a specific plan or active suicidal ideation with specific 
plan and intent on the C-SSRS assessment at the 
Screening Visit. Subjects who have significant findings for 
suicidal ideation as assessed by the C-SSRS must be referred 
to the Investigator for follow-up evaluation. 
Cannabidiol Oral Solution: an oral solution containing pharmaceutical 
grade cannabidiol (nonplant-based). 
dose with which they were being treated previously (10, 20, or 
40 mg/kg/day administered in twice daily doses of 5, 10, or 20 mg/kg, 
depending on dose cohort). For subjects enrolling from INS0I 1-15-054 
their dose will be the same as in the previous study (maximum of 
40mg/kg/day). The total daily dose (mg/kg/day) will be administered in 
two equal concentration doses (mg/kg) at 12-hour intervals. 
Dosing of the investigational product may be adjusted at any time based 
on investigators discretion, however maximum daily dose will not 
exceed 40 mg/kg/day. 
Subjects who will not continue to receive Cannabidiol Oral Solution 
under the Investigator IND Expanded Access Program may be tapered 
off based on Investigator's preference and subject's tolerability The 
investigator should ensure that the taper is planned in advance to allow 
sufficient time to complete the taper prior to Visit 10 at 48 weeks (± I 0 
days).The date of entering the Expanded Access Program will be 
documented in the EDC. The timing of administration of the drug with 
regards to food should be consistent throughout the duration of the 
study. 
Not applicable. 
• 
Incidence, type, and severity of AEs and SAEs associated with Cannabidiol Oral Solution as an 
adjunctive treatment for seizures 
• 
Changes from baseline in the previous study in vital signs 
• 
Changes from baseline in the previous study in ECG findings if appropriate 
• 
Changes from baseline in the previous study laboratory values (hematology, chemistry, and 
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Insys Development Company, Inc. 
INSOI 1-14-030 Amendment 5 
Cannabidiol Oral Solution 
urinalysis) 
• 
Trough (steady state) concentrations ofCannabidiol Oral Solution throughout approximately 48 
weeks of continuous exposure, inclusive of the subject's treatment on their previous study 
Efficacy-related Data to be Reported 
• 
Frequency, duration, and severity of seizures (i.e., seizure control). 
• 
Parent(s)/caregiver(s) CGI-I and CGI-S. 
• 
Investigator CGI-I and CGI-SIPES, C-SSRS, and V ABS scores, Subjects enrolled from INS0l 1-15-
054 will be excluded from IPES, V ABS, and C-SSRS scores evaluation. 
Criteria for evaluation: A record of the incidence and severity of treatment-emergent AEs (TEAEs) and 
SAEs throughout the study is the primary criterion. Other safety-related parameters such as 12-lead ECG 
and hematology, chemistry, and urinary analyses will also be assessed. 
Plasma levels of cannabidiol and its 7-hydroxy (OH) metabolite will be evaluated (trough levels). For 
subjects taking clobazam, levels of clobazam and its major metabolite (norclobazam) will be measured if 
there are safety concerns. 
Secondary outcome measures will include control of seizures (frequency, duration, and severity of seizures 
compared to baseline in the previous study), overall changes in global impression assessments by the 
Investigator and parent(s)/caregiver(s) (CGI-I and CGI-S), and change from baseline in IPES, VABS, and C-
SSRS scores, Subjects enrolled from INS0 11-15-054 will be excluded from IPES, V ABS, and C-SSRS 
scores evaluation. 
Statistical methods: The sample size will be determined by the number of subjects that are eligible and 
elect to rollover from INS0 11-14-029 and INS0 11-15-054 into this study. 
Data listings and univariate descriptive summary statistics (number and percentages) will be generated for 
TEAEs and SAEs. The AEs with missing onset dates or AEs with missing onset times occurring on the same 
day as the administration of investigational product will be summarized as TEAEs. Both A Es and SAEs will 
be summarized using the Medical Dictionary for Regulatory Activities (MedDRA). Each verbatim term will 
be mapped to a lower level term, then to a preferred term (PT), and finally to a system organ class (SOC). 
The number and percentage of subjects with ~1 TEAE for each SOC and preferred term will be summarized. 
Laboratory analytes will be summarized as mean change from baseline to endpoint. Shift tables will also be 
produced describing changes from normal to abnormal (high and low) levels or abnormal (high and low) to 
normal levels. 
For each continuous endpoint, descriptive statistics (number, mean, median, minimum, maximum, standard 
deviation [SD], and 95% confidence interval [CI]) will be generated. This analysis will be carried out for the 
change from baseline in frequency, severity, and duration of seizures, IPES, V ABS, and C-SSRS scores, as 
well as parent(s)/caregiver(s) and Investigator CGI-1 and CGI-S. Subjects enrolled from INS0l 1-15-054 will 
be excluded from IPES, V ABS, and C-SSRS scores evaluation. 
Concentrations of cannabidiol and its 7-OH metabolite will be measured at each visit except Visits 3 and 4. 
A descriptive summary of observed blood concentrations (number, mean, median, SD, minimum value, and 
maximum value) will be displayed. 
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Cannabidiol Oral Solution 
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TABLE OF CONTENTS 
APPROVAL SIGNATURES .................................................................................................. 2 
Synopsis ......................................................................................................................... 3 
Table of contents .......................................................................................................... 8 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .................................... 13 
1.0 
INTRODUCTION ..................................................................................................... 16 
1.1 
Cannabidiol .................................................................................................... 16 
1.1.1 
Mechanism of Action ........................................................................ 16 
1.1.2 
Metabolism and Potential Drug Interactions ..................................... 17 
1.1.3 
Nonclinical ........................................................................................ 18 
1.1.3 .1 
Safety ............................................................................... 18 
1.1.3 .2 
Efficacy in Epilepsy Animal Models .............................. 19 
1.1.4 
Clinical .............................................................................................. 19 
1. i .4.1 
Pharma(.;okinetics ............................................................. 19 
1.1.4.2 
Overview of Safety .......................................................... 19 
1.1.4.3 
Efficacy in Human Epilepsy ............................................ 21 
1.1.5 
Previous Studies with the Investigational Product ............................ 21 
1.2 
Pediatric Treatment-Resistant Seizure Disorders ...................................... 22 
1.2.1 
Lennox-Gastaut Syndrome ................................................................ 23 
1.2.2 
Dravet Syndrome ............................................................................... 24 
1.2.3 
Study Population ............................................................................... 24 
1.3 
Study Rationale ..............................................................•............................... 25 
1.4 
Risk-Benefit Analysis ..................................................................................... 25 
1.5 
Compliance ...........................•......................................................................... 26 
2.0 
STUDY OBJECTIVES .................................................................•.•.•.•.......•.•...•..••... 27 
2.1 
Objectives ........................................................................................................ 27 
3.0 
INVESTIGATIONAL PLAN ................................................................................... 28 
3.1 
Summary of Study Design ...•......................................................................... 28 
3.2 
Medical and Safety Data Review .................................................................. 30 
3.3 
Schedule of Events ........................................................................................... 30 
3.4 
Selection of Study Population ....................................................................... 36 
3.4.1 
Inclusion Criteria ............................................................................... 36 
3.4.2 
Exclusion Criteria .............................................................................. 37 
3.4.3 
Subject Withdrawal ........................................................................... 38 
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Cannabidiol Oral Solution 
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4.0 
STUDY TREATMENTS ........................................................................................... 40 
4.1 
Treatments Administered ............................................................................. 40 
4.1.1 
Dose Adjustments .............................................................................. 41 
4.1.2 
Dose Tapering ................................................................................... 41 
4.2 
Identity of Investigational Product .............................................................. 41 
4.2.1 
Storage of the Investigational Product ............................................. .41 
4.3 
Background Therapy ..................................................................................... 42 
4.4 
Packaging and Labelling ............................................................................... 42 
4.5 
Selection of Doses in the Study ..................................................................... 43 
4.6 
Selection and Timing of Dose for Each Subject .......................................... 43 
4. 7 
Method of Assigning Subjects to Treatment Group ................................... 43 
4.8 
Blinding ........................................................................................................... 43 
4.9 
Prior and Concomitant Treatments ............................................................. 44 
4.9.1 
Excluded Medications and Foods ..................................................... .44 
4.9.2 
Allowed Medications ........................................................................ 44 
4.10 
Treatment Compliance .................................................................................. 44 
4.11 
Study Medication Accountability ................................................................. 44 
5.0 
STUDY PROCEDURES ................................................................................................. 46 
5.1 
Screening Period (Visit 1) ............................................................................. 46 
Subjects that do not rollover within 14 days of completing their previous 
study (INS0l 1-14-029) will be required to complete a Screening 
Visit. Subjects who enroll after participating in INS0 11-15-054 
will not need to complete a Screening Visit if less than 14 days 
has elapsed between dosing ............................................................................. 46 
5 .. 2 
Treatment Period .................................................................................................................................................... 47 
5.2.1 
Visit 2 (Day 1) ................................................................................... 48 
5.2.2 
Visits 3 and 4 (Weeks 1 and 2) ±3 days ........................................... .49 
5.2.3 
Visits 5 and 6 (Monthly Visits) ±7 days ............................................ 50 
5.2.4 
Visit 7 (Monthly Visit) ±7 days ........................................................ 50 
5.2.5 
Visits 8 and 9 (Quarterly Visits) ±10 days ........................................ 51 
5.3 
Final Visit/Discontinuation Visit (Visit 10) ±10 days .................................. 53 
5.4 
Follow-up Visit (Visit 11) ±5 days ................................................................ 54 
6.0 
SAFETY, PLASMA LEVEL, AND EFFICACY ASSESSMENTS 
AND ENDPOINTS ............................................................................................................................ 56 
6.1 
Safefy ..................................................................................................................................... 56 
6.1.1 
Adverse Events .................................................................................. 56 
6.1.1.1 
Monitoring of AEs Potentially Related to 
Drug Metabolism ............................................................. 58 
6.1.2 
Reporting of AEs ............................................................................... 59 
6.1.2.1 
Reporting of SAEs to Regulatory Authorities 
and Investigators .............................................................. 61 
6.1.3 
Follow-Up of AEs ............................................................................. 62 
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6.1.4 
Clinical Laboratory Evaluations ........................................................ 62 
6.1.4.1 
Central Laboratory .......................................................... 63 
6.1.5 
Vital Signs, Physical Findings and Other Safety 
Assessments ....................................................................................... 63 
6.1.5.1 
VitalSigns ....................................................................... 63 
6.1.5.2 
Physical and Neurological Examinations ........................ 63 
6.1.5.3 
ECGs ............................................................................... 63 
6.1.5.4 
C-SSRS ............................................................................ 64 
6.1.5.5 
Medical/Surgical History ................................................ 64 
6.1.6 
Safety-related Endpoints ................................................................... 64 
6.2 
Plasma Levels ................................................................................................. 64 
6.2.1 
Plasma Levels-related Endpoint.. ...................................................... 65 
6.3 
Efficacy ........................................................................................................... 65 
6.3.1 
Seizure Control .................................................................................. 65 
6.3.1.1 
Subject Seizure and Dosing Diary Education ................. 66 
6.3.2 
Additional Information to be Recorded in Subject Seizure 
and Dosing Diary ............................................................................... 68 
6.3.3 
Qualitative Assessments .................................................................... 68 
6.3.4 
Efficacy-related Data to be Reported ................................................ 69 
6.4 
Appropriateness of Measurements .................................... ,.. .......................... 69 
7.0 
QUALITY CONTROL AND QUALITY ASSURANCE ....................................... 70 
7.1 
Monitoring ...................................................................................................... 71 
7.2 
Data Management/Coding ............................................................................ 71 
7.3 
Quality Assurance Audit ............................................................................... 73 
8.0 
STATISTICS .............................................................................................................. 74 
8.1 
Determination of Sample Size ....................................................................... 74 
8.2 
General Statistical Considerations ............................................................... 7 4 
8.2.1 
Statistical Methods and Analysis Plan .............................................. 74 
8.2.2 
General .............................................................................................. 74 
8.2.3 
Data to be Analyzed .......................................................................... 75 
8.3 
Statistical Considerations .............................................................................. 75 
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8.3.1 
8.3.2 
8.3.3 
8.3.4 
8.3.5 
8.3.6 
Subject Population for Analysis ........................................................ 75 
Subject Disposition ............................................................................ 75 
Demography and Other Baseline Data .............................................. 76 
Safety Analysis .................................................................................. 76 
8.3.4.1 
AEs .................................................................................. 76 
8.3.4.2 
Clinical Laboratory Evaluations ...................................... 77 
8.3.4.3 
Vital Sign Measurements ................................................ 77 
8.3 .4.4 
ECG Evaluations ............................................................. 77 
Analysis of Cannabidiol and 7-0H Metabolite 
Concentrations ................................................................................... 77 
Efficacy Analysis .............................................................................. 78 
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8.3.6.1 
8.3.6.2 
Seizure-related Data ........................................................ 78 
Qualitative Subject Status Assessments .......................... 78 
8.4 
Interim analysis .............................................................................................. 78 
8.5 
Handling of Missing Values .......................................................................... 78 
9.0 
ETHICS ...................................................................................................................... 79 
9 .1 
Institutional Review Board ........................................................................... 79 
9.2 
Ethical Conduct of the Study ........................................................................ 79 
9.3 
Subject Information and Informed Consent ............................................... 80 
9.3.1 
Subject Assent Guidance ................................................................... 80 
10.0 
STUDY ADMINISTRATION .................................................................................. 81 
10.1 
Data Handling and Record Keeping ............................................................ 81 
10.2 
Direct Access to Source Data/Documents .................................................... 81 
10.3 
Investigator Information ............................................................................... 81 
10.3.1 
10.3.2 
10.3.3 
Investigator Obligations .................................................................... 81 
Protocol Signatures ............................................................................ 82 
Publication Policy .............................................................................. 82 
10.4 
Financing and Insurance ............................................................................... 82 
APPENDIX 1: SIGNATURE OF INVESTIGATOR ........................................................ 83 
REFERENCES ...................................................................................................................... 84 
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LIST OF TABLES 
12 
Table 1 Schedule of Events .................................................................................................... 31 
Table 2 Description of Drug Product.. ................................................................................... .42 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
5-HTia 
AE 
AED 
ADR 
ALT 
API 
AST 
P-hCG 
BUN 
CB1 
CB2 
CBC 
CFR 
CGl-1 
CGI-S 
cGMP 
CHMP 
CNS 
CRO 
CSR 
C-SSRS 
CYP 
CYPlAl 
CYP2C19 
CYP2C9 
CYP3A4 
CYP3A5 
DEA 
DNA 
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Definition 
5-hydroxytryptamine la 
adverse event 
antiepileptic drug 
adverse drug reaction 
alanine aminotransferase 
active pharmaceutical ingredient 
aspartate aminotransferase 
human chorionic gonadotropin 
blood urea nitrogen 
cannabinoid receptor 1 
cannabinoid receptor 2 
complete blood count 
Code of Federal Regulations 
Clinical Global Impression of Improvement 
Clinical Global Impression of Severity 
current Good Manufacturing Practices 
Committee for Medicinal Products for Human Use 
central nervous system 
contract research organization 
clinical study report 
Columbia-Suicide Severity Rating Scale 
cytochrome P450 
Cytochrome P450 lAl 
Cytochrome P450 2C19 
Cytochrome P450 2C9 
Cytochrome P450 3A4 
Cytochrome P450 3A5 
Drug Enforcement Administration 
deoxyribonucleic acid 
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DS 
ECG 
eCRF 
EDso 
EDC 
EEG 
FDA 
FSH 
GCP 
GGT 
IB 
ICF 
ICH 
IEC 
lFN 
IL-2 
IP 
IPES 
IRB 
IV 
LFT 
LGS 
MedDRA 
mRNA 
NICE 
NK 
OH 
PCOS 
PK 
pKa 
PRO 
PT 
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Dravet syndrome 
electrocardiogram 
electronic case report form 
median effective dose 
electronic data capture 
electroencephalogram 
Food and Drug Administration 
follicle-stimulating hormone 
Good Clinical Practice 
gamma glutamyl transferase 
Investigator's Brochure 
informed consent form 
International Conference on Harmonization 
Independent Ethics Committee 
interferon 
interleukin-2 
intraperitoneal 
Impact of Pediatric Epilepsy Scale 
Institutional Review Board 
intravenous 
liver function test 
Lennox-Gastaut Syndrome 
Medical Dictionary for Regulatory Activities 
messenger ribonucleic acid 
National Institutes of Health and Care Excellence 
natural killer 
hydroxy 
polycystic ovarian syndrome 
pharmacokinetics 
acid dissociation constant 
patient reported outcome 
preferred term 
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RBCs 
SAE 
SAP 
SCNlA 
SD 
SMEI 
soc 
SOP 
t112 
TDso 
TEAE 
~ 9-THC 
TLFs 
UK 
ULN 
us 
VABS 
VNS 
WBCs 
WHO-DD 
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red blood cells 
serious adverse event 
Statistical Analysis Plan 
a subunit of the sodium channel, voltage-gated, type 1 
standard deviation 
severe myoclonic epilepsy of infancy 
system organ class 
standard operating procedures 
half-life 
median tolerated dose 
treatment-emergent adverse event 
~ 9 -tetrahydrocannabinol 
tables, listings, and figures 
United Kingdom 
upper limit of normal 
United States 
Vineland Adaptive Behavior Scale, Second Edition - Survey 
Interview Form including the Maladaptive Behavior Index 
vagus nerve stimulation 
white blood cells 
World Health Organization's Drug-Dictionary 
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1.0 
INTRODUCTION 
16 
Data presented in Section 1.0 includes overviews from the nonclinical and clinical published 
literature that reports on various other formulations of cannabidiol (primarily plant-based). 
Analogous studies have not been completed for Cannabidiol Oral Solution, the nonplant-
based cannabidiol 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, ~9-tetrahydrocannabinol (~9-THC) is the principal 
psychoactive constituent of marijuana. Cannabidiol is the second most abundant cannabinoid 
and highly physiologically relevant, but is nonpsychoactive. It has demonstrated a potential 
benefit to 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, nonplant-based cannabidiol (Cannabidiol Oral 
Solution). 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 (API) is ~99.5% pure,6 can be consistently produced without the 
concern for contaminants, and will provide cannabidiol to responsibly treat epilepsy. 
1.1.1 
Mechanism of Action 
The mode of action of cannabidiol is not fully understood. The drug substance manifests a 
low affinity for endogenous cannabinoid receptors 1 (CB1) and 2 (CB2). Cannabidiol acts 
primarily 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 theµ- and o-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.1° Finally, cannabidiol may modulate neuronal hyperexcitability through 1 or more of 
the following mechanisms: 
• 
Bidirectional regulation of calcium homeostasis via the mitochondrial 
sodium/calcium exchanger11 
• 
Agonistic properties at 5-hydroxytryptamine la (5-HT1a) receptors12 
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• 
Enhancing endogenous adenosine levels in the central nervous system (CNS) by 
reducing adenosine re-uptake. 13•14 
1.1.2 
Metabolism and Potential Drug Interactions 
17 
The major biotransformation pathway for cannabidiol is similar to that of other cannabinoids 
and mediated by hydroxylation by CYP proteins. 1s Its interactions with human drug 
metabolizing enzymes (as a substrate, inhibitor, or inducer) were recently reviewed. 16•17 
Details of some interactions may be found below. 
Cannabidiol is metabolized primarily in the liver by cytochrome P 3A4 (CYP3A4) and to a 
lesser extent by cytochrome P450 2Cl 9 (CYP2C19). The effect of cannabidiol on primary 
fetal rat hepatocyte viability was investigated. 18 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. 19,20,21 
Specifically, cannabidiol inhibits CYP3A4, cytochrome P450 3A5 (CYP3A5), and 
cytochrome P450 lAl (CYPlAl) in vitro.22•23•24 It also appears to inhibit 
cytochrome P450 2C9 (CYP2C9)2s and the transport protein p-glycoprotein.26•27 
Cannabidiol likely inhibits drug metabolism when 1 of its metabolites binds to hepatic 
microsomal CYP proteins.28•29•30•31 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. 32 
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 ofhexobarbital in healthy 
volunteers.33 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 119-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 half-
life (t1-2) of /19-THC metabolites.34 It has also been shown that suppression of drug 
metabolism by cannabidiol is diminished following repeated exposure to the drug 
substance.3s 
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1.1.3 
1.1.3.1 
Nonclinical 
Safety 
18 
In a nonclinical setting, single-dose toxicology studies of cannabidiol reveal a relatively safe 
toxicology profile except at very high doses of the drug substance. Repeated dose toxicology 
studies highlight a potential impact of cannabidiol on spermatogenesis, follicle-stimulating 
hormone (FSH) levels, and a subset of immune responses. Full detail of these results may be 
found in the 1B1 and selected data are summarized below. 
• 
In a repeated-dose toxicity study, monkeys treated with oral cannabidiol (0, 30, 100, 
or 300 mg/kg/day), spermatogenesis was inhibited.36 Another study reported 
abnormal sperm in animals exposed to cannabidiol and that paternal exposure to 
cannabidiol is associated with a lower impregnation rate, a 2.3-fold increase in fetal 
loss, and a 5.2-fold increase in postnatal loss.37 
• 
Levels of FSH increased approximately 70% to 100% in Rhesus monkeys dosed with 
100 and 300 mg/kg/day of cannabidiol.38 
• 
Blood sampling following repeated daily injections of 5 mg/kg/day cannabidiol for 
14 days in adult male Wistar rats showed decreased total leukocyte number and total 
numbers ofT and B cells and T helper and T cytotoxic subsets.39 This 
immunosuppressive effect did not affect the total numbers of natural killer (NK) and 
NK T cells that are responsible for the primary, nonspecific antiviral, and antitumor 
immune response. Mechanistically, 0.5 to 10 µM of cannabidiol suppressed 
interleukin-2 (IL-2) and interferon (IFN)-y messenger ribonucleic acid (mRNA) 
expression, proliferation, and cell surface expression of the IL-2 receptor a chain in 
murine splenocyte cell suspensions. 
• 
Human peripheral lymphocytes cultured with 3 .2 x 1 o-6 M cannabidiol for 72 hours 
did not induce chromosomal aberrations.40 Similarly, treatment with 20 to 250 µM 
cannabidiol did not induce unscheduled deoxyribonucleic acid (DNA) repair 
synthesis in cultured human fibroblasts.41 Cultured lymphocytes harvested from prior 
cannabis users receiving oral doses of 1200 mg/day of cannabidiol for 20 days did 
not show an increase in chromosomal aberrations or sister chromatid exchange. 42 
• 
Intraperitoneal (IP) injection of 1 or 10 mg/kg/day into mice resulted in 2- to 6-fold 
increases in chromosomal and nuclear aberrations in bone marrow cells harvest from 
these mice. 43 
o Conversely, human peripheral lymphocytes cultured with 3.2 x 10·6 M 
cannabidiol for 72 hours did not induce chromosomal aberrations.44 
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Similarly, treatment with 20 to 250 µM cannabidiol did not induce 
unscheduled DNA repair synthesis in cultured human fibroblasts.45 Cultured 
lymphocytes harvested from prior cannabis users receiving oral doses of 
1200 mg/day of cannabidiol for 20 days did not show an increase in 
chromosomal aberrations or sister chromatid exchange.46 
19 
• 
As described in Section 1.1.2, cannabidiol may also affect liver-mediated metabolism 
as a result of its interactions with CYP proteins and p-glycoprotein. 
1.1.3.2 
Efficacy in Epilepsy Animal Models 
Plant-derived cannabidiol shows antiepileptic,47 antipsychotic, antidystonic, anti-emetic, and 
anti-inflammatory properties in animal models.48 These models support exploring the use of 
cannabidiol for the treatment of epilepsy.49 
As an example, the anticonvulsant activity of oral cannabidiol was investigated in adult rat 
model of seizures (induced by maximal electroshock or audiogenic sources). 5° 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 antiseizure drugs (e.g., phenytoin or 
carbamazepine) increased or reduced their anticonvulsant activity, indicating that synergism 
or antagonism with cannabidiol was drug specific. 
1.1.4 
Clinical 
Clinical data described in the following sections were collected following administration of 
various extracts of cannabidiol as oral solutions or solid formulations. 
1.1.4.1 
Pharmacokinetics 
Oral doses of cannabidiol (10 mg/kg/day) once daily for 6 weeks in patients with 
Huntington's disease results in mean weekly plasma concentrations of 5.9 to 11.2 µg/L. 51,52 
The mean t112 for cannabidiol is 24 and 31 hours when administered intravenously (IV) or 
inhaled, respectively, with a range of 18 to 33 hours.53 Cannabidiol is cleared from plasma 
at rates between 960 and 1560 mL/min and the distribution volume is estimated to be 
approximately 30 L/kg.53 
1.1.4.2 
Overview of Safety 
Clinical studies in various human populations indicate that cannabidiol has a favorable side-
effect profile. Doses as high as 1500 mg are well tolerated. 54 No significant reactions or 
serious adverse events (SAEs) have been reported across a wide range of dosages and in both 
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acute and chronic settings. Bergamaschi et al. 17 recently reviewed the safety of cannabidiol 
in humans examined in 221 subjects across 21 studies. As detailed in the IB, no significant 
safety issues were reported. 
20 
Selected studies in which more detailed information regarding safety outcomes are reviewed 
in Section 1.1.4.2.1. 
Regarding doses of cannabidiol that have been examined in other studies, daily doses of 200 
to 300 mg cannabidiol (or potentially more) may be safe.2•58 Clinical evaluation and 
therapeutic ranges of cannabidiol doses have been reported to be between 10 and 
1500 mg/day, with the majority ofreports evaluating doses in the 300 to 600 mg/day 
cannabidiol range. Furthermore, between 300 and 1500 mg have been used in humans 
without toxicity or SAEs. 51 •55•56•57. Cannabidiol PK has not previously been studied in a 
pediatric population. 
1.1.4.2.1 
Selected Detailed Clinical Safety Data 
The following specific examples detail selected studies of the safety of cannabidiol use in 
humans: 
• 
Ten (10) mg/kg daily dosing of cannabidiol was evaluated in a study of 15 subjects 
diagnosed with Huntington's disease.51 Only 15 abnormal clinical laboratory values 
were associated with cannabidiol treatment; these were largely limited to 4 subjects 
and exhibited no obvious pattern. No significant or clinical differences in cannabidiol 
were observed in a cannabis-specific side-effect inventory. 
• 
Chronic oral administration of 10 mg cannabidiol daily for 21 days does not induce 
any changes in neurological (including electroencephalogram [EEG]), clinical 
(including electrocardiogram [ECG]), psychiatric, blood, or urine examinations in 
both healthy volunteers and epileptic patients.2 
• 
Oral administration of cannabidiol in healthy volunteers (3 mg/kg daily for 30 days) 
and in epileptic subjects (200 to 300 mg daily for 135 days) was well tolerated. No 
signs of toxicity or serious side-effects were detected on neurological and physical 
examinations, blood and urine analysis, ECG, or EEG.2•58 
• 
Administration of single and repeated doses of cannabidiol for up to 20 days at a dose 
of 1200 mg/day does not impact pulse rate and blood pressure in human subjects with 
previous experience to cannabis smoking. 59 
• 
Three (3) subjects with treatment-resistant schizophrenia have been dosed with 40 to 
1280 mg/day of cannabidiol for up to 4 weeks without reporting side-effects.60 
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• 
Two (2) subjects diagnosed with bipolar affective disorder did not report adverse 
effects upon receiving 600 to 1200 mg/day of cannabidiol for up to 24 days.61 
1.1.4.3 
Efficacy in Human Epilepsy 
21 
While efficacy is not a primary endpoint for this study (see Section 2.0), several preliminary 
studies of cannabidiol report reductions in seizure activity for a significant subset of subjects. 
Cannabidiol was examined as an adjunctive therapy in 15 subjects with secondary 
generalized epilepsy with temporal focus who were refractory to conventional treatment. 2•3 
The 8 subjects randomized to the active arm received 200 to 300 mg/day of cannabidiol or 
placebo for up to 4.5 months in addition to previously established antiepileptic drugs 
(AEDs).2•58 Subjects tolerated cannabidiol well, with no signs of toxicity or serious side-
effects. Four (4) of the 8 subjects receiving cannabidiol remained almost free of convulsive 
crises throughout the study and 3 others experienced partial improvement. The clinical 
condition of 7 subjects receiving placebo remained unchanged and 1 subject improved. 
Parents of children with treatment-resistant epilepsy have sought cannabidiol-enriched 
cannabis for treatment.4 In a survey, these parents reported dosages of cannabidiol ranging 
from <0.5 to 28.6 mg/kg/day, as per results from medical cannabis testing facilities. Sixteen 
(16; 84%) of the 19 parents eligible to respond to the survey reported a reduction in their 
child's seizure frequency while taking cannabidiol-enriched cannabis. Of these, 2 (11 %) 
reported complete seizure-freedom, 8 (42%) reported >80% reduction in seizure frequency, 
and 6 (32%) reported a 25% to 60% seizure reduction. Reported side-effects included 
fatigue and somnolence. 
Realm Oil is an extract from a strain of cannabis known as Charlotte's Web and contains a 
cannabidiol:~9-THC ratio >20:1. Gedde and Maa5 reported on a small group of pediatric 
subjects diagnosed with various types of epilepsy who took Realm Oil for 2'.:3 months. 
Baseline seizure frequency for these subjects ranged from 5 to 2800 events per week. 
Eight (8; 73%) of these subjects reported a 95% to 100% reduction in seizure occurrence, 
1 (9%) reported 75% reduction, and 2 (18%) reported 20% to 45% reduction. 
1.1.5 
Previous Studies with the lnvestigational Product 
A Phase 1/2 study to examine the pharmacokinetics (PK), safety, and tolerability of 
Cannabidiol Oral Solution in a variety of treatment-resistant seizure disorders (INS0l 1-14-
029) is being conducted. The Sponsor has received an orphan drug designation for 
investigating Cannabidiol Oral Solution in the treatment of Lennox-Gastaut Syndrome (LGS) 
and Dravet Syndrome (DS). Phase 3 studies (INS0 11-14-024 and INS0 11-14-025, 
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22 
respectively) are planned to examine the safety and efficacy of Cannabidiol Oral Solution in 
the treatment of seizures in LGS and DS subjects. 
Subjects who completed INS0l 1-14-029 or Part A in INS0l 1-15-054 and satisfy the 
inclusion/exclusion criteria detailed in Section 3.4 are eligible to participate in this study. 
1.2 
Pediatric Treatment-Resistant Seizure Disorders 
The clinical manifestations of epilepsy are periodic, uncontrolled, convulsive seizures. The 
highest incidence of epilepsy in North America and Europe is in the first 12 months of life 
when 90 to 212 cases per 100,000 individuals are diagnosed. Children diagnosed with 
various types of epilepsy have an increased risk (23% to 34%) of behavioral and cognitive 
symptoms and comorbidities. 62 
As recently reviewed, 62•63 current interventions for pediatric epilepsy patients include the 
following: 
• 
AEDs 
o The FDA has approved multiple medications (i.e.clonazepam, felbamate, 
lamotrigine, topiramate, rufinamide, and clobazam) for adjunctive use in 
pediatric epilepsy. Although not approved in the US, other AEDs that may be 
used in this population include stiripentol. 
• 
Resective surgery for specific types of drug-resistant focal epilepsy ( e.g., Rasmussen 
encephalitis and tuberous sclerosis complex) 
• 
Ketogenic diet or low-glycemic index diet 
• 
Vagus nerve stimulation (VNS). 
Safety and tolerability issues with current AED therapies include the following: 
• 
Valproic acid: weight gain or loss, nausea and vomiting, pancreatitis, liver failure, 
thrombocytopenia, fetal anomalies if used in pregnancy, polycystic ovarian syndrome 
(PCOS), and hair loss 
• 
Clobazam: irritability, sedation, hypotonia, and drooling 
• 
Topiramate: decreased appetite, weight loss, decreased sweating, slowing of verbal 
processing, kidney stones, acidosis, and glaucoma 
• 
Levetiracetam: behavior and mood issues. 
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23 
Additionally, some currently approved AEDs have specific contraindications. For example, 
clobazam is excluded as a therapy for patients with significant liver disease or acute narrow 
angle glaucoma. Some AEDs also carry specialized warnings ( e.g., serious skin reactions 
with clobazam and lamotrigine ). 
In addition to the above tolerability issues, 10% to 40% of patients with epilepsy are 
treatment-resistant.64•65•66 The hallmark of treatment-resistance seizures is the failure of 
2:2 AEDs to control them.67 Patients diagnosed with LGS and DS are frequently treatment-
resistant. These indications will be among those investigated in this study ( among other 
treatment-resistant seizure disorders) and will also be examined in planned Phase 3 studies. 
Data from the current study will inform the dose of the investigational product to be 
examined in the Phase 3 studies. 
1.2.1 
Lennox-Gastaut Syndrome 
A severe childhood epileptic encephalopathy, LGS represents an estimated 1 % to 10% of all 
pediatric epilepsies. This pathology typically develops between 3 and 5 years of age, but can 
arise any time between 1 and 8 years of age. 68 According to the Commission on 
Classification and Terminology of the International League Against Epilepsy, LGS is 
characterized by the following: 
• 
Multiple seizure types, including tonic, atonic, and atypical absence 
o Partial, myoclonic, and generalized tonic-clonic seizures may also be 
observed. 
• 
An EEG pattern with diffuse and slow spike-and-wave complexes (<3 Hz) with 
paroxysmal fast rhythms of 10 to 12 Hz in sleep 
• 
Cognitive dysfunction with psychomotor delay and neuropsychiatric problems 
• 
Frequent lesional etiology 
• 
Later onset than comparable pediatric epilepsies. 
In the United Kingdom (UK), the National Institutes of Health and Care Excellence (NICE) 
guidelines (2012) recommend sodium valproate as first-line treatment for LGS, followed by 
lamotrigine (second-line), rufinamide or topiramate (third-line), and felbamate as a last 
therapeutic option. Typical treatment in the United States (US) follows a similar pattern, 
though there are no specific guidelines in this country due to the heterogeneity of patients. 
Each of FDA-approved AEDs for pediatric epilepsy include LGS as an approved indication 
in their labeling. Only approximately 10% of pediatric LGS patients undergo full seizure 
remission with currently available interventions.69,70 
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1.2.2 
Dravet Syndrome 
24 
A genetic form of pediatric epilepsy, DS occurs in 1 of 20,000 to 40,000 live births. It was 
initially described in 1978 as severe myoclonic epilepsy of infancy (SMEI), and has a high 
rate (15%) of early mortality. 71 Seizures in DS patients typically begin at 5 to 8 months of 
age and are frequently associated with fever in the initial stage of the disease. Seizures may 
be of a variety of types, including: 
• 
Generalized clonic 
• 
Generalized tonic-clonic 
• 
Atypical absence 
• 
Myoclonic 
• 
Focal, with or without secondary generalization 
• 
Tonic (rarely). 
By 2 years of age, many DS patients exhibit other neurologic symptoms, including cognitive 
deficits, lack of attention, and motor dysfunction. 72,73 70% to 80% of patients diagnosed with 
DS exhibit identified mutations in the a subunit of the sodium channel, voltage-gated, 
type 1 (SCNlA) gene.71,74,75 Such mutations are often used to confirm diagnosis. 
In the UK, the NICE guidelines (2012) recommend sodium valproate or topiramate as first-
line treatment for DS, followed by clobazam or stiripentol (second-line). Of the 6 AEDs that 
are FDA-approved for adjunctive use in pediatric epilepsy, none are labeled for the treatment 
of DS. In the US, clinicians may choose to utilize an AED off-label to treat patients with DS 
since there are no approved therapies or treatment algorithms. Typical treatment in the US is 
to maintain patients on a combination ofvalproate with or without topiramate, clobazam, or 
levetiracetam and to use benzodiazepines (e.g., clonazepam, diazepam, lorazepam, or 
midazolam) as rescue therapy. Regardless of the chosen treatment, most cases ofDS are 
refractory to medical management and outcomes are generally poor.76 
1.2.3 
Study Population 
Subjects diagnosed with treatment-resistant seizures to be enrolled in this study must satisfy 
the inclusion/exclusion criteria detailed in Sections 3.4.1 and 3.4.2. 
Subjects will all receive the investigational product in an open-label setting. It is estimated 
that up to 80 subjects will enroll. 
All subjects will be treated in an adjunctive setting. 
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1.3 
Study Rationale 
25 
Treatment-resistant seizure disorders, including LGS,DS and IS, are life-time disorders that 
require prolonged exposure to medications to control seizures. This open-label study will 
assess the long-term safety and seizure control of Cannabidiol Oral Solution as an adjunctive 
therapy for the treatment of treatment-resistant seizures in pediatric subjects, including those 
with LGS, DS or IS. 
Safety endpoints were a focus of INS0l 1-14-029 and INS0l 1-15-054, in which short-term 
dosing with the investigational product was examined. The current study will facilitate the 
monitoring of safety and tolerability during long-term treatment with the investigational 
product. 
1.4 
Risk-Benefit Analysis 
As discussed in Sections 1.1.3 and 1.1.4, numerous nonclinical and clinical studies have 
examined other formulations of cannabidiol. Several areas of potential concern have been 
identified with the use of cannabidiol, especially in nonclinical studies. These include: 
• 
Competitive binding of CYP proteins (thus, an impact on drug metabolism in the 
liver). Cannabidiol is metabolized predominantly by CYP3A4 and CYP2C19, and 
may inhibit these 2 isoenzymes, as well as having small effects on CYP3A5, 
CYPlAl, 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-y. 
Based on recent studies of cannabinoid administration in humans, controlled cannabidiol may 
be safe in humans and animals. However, further studies are needed to investigate these 
reported effects. 
The concomitant medication guidelines and safety monitoring (clinical laboratory, ECG, vital 
signs, and physical and neurological examination assessments) planned for this study (see 
Sections 4.9 and 6.1) are intended to minimize these potential safety risks. Levels of 
cannabidiol and its ?-hydroxy (OH) metabolite in the plasma will also be monitored (see 
Section 6.2). 
Stopping criteria for individual subjects will dictate termination of subject participation 
should a safety issue arise (see Section 3.4.3). 
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26 
This study will allow subjects who previously completed INS0I 1-14-029 or participated in 
INS0I 1-15-054 and completed Part A (visit 6) continued access. This is particularly 
important for those who received therapeutic benefit in terms of seizure control during the 
previous studies. As reviewed in Section 1.2, patients with treatment-resistant seizure 
disorders continue to experience a significant unmet medical need despite ongoing treatment 
with currently available medications and procedures. Devinsky et al. 77 recently noted that 
treatment-resistant seizure disorders are particularly good candidates for cannabidiol 
intervention. 
From a therapeutic perspective, the risk of exacerbating a subject's epilepsy symptoms will 
be minimized by examining the investigational product in an adjunctive setting in 
combination with the subject's established AED(s) treatment regime. Alternations may be 
made to the subject's AED background medication(s) as discussed in Section 4.3. 
In addition to the potential therapeutic benefit noted above, Insys' pharmaceutical grade, 
nonplant-based 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 1'19-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 1'19-THC, herbicides, pesticides, etc. 
1.5 
Compliance 
Each Investigator agrees that the study will be conducted according to the protocol, 
International Conference on Harmonization (ICH), Good Clinical Practice (GCP), and the 
ethical principles that have their origin in the Declaration of Helsinki. The Investigator will 
conduct all aspects of the study in accordance with applicable local law(s) and regulation(s). 
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2.0 
STUDY OBJECTIVES 
2.1 
Objectives 
• 
To assess the long-term safety of Cannabidiol Oral Solution as an adjunctive 
treatment for subjects with treatment-resistant seizure disorders, including LGS, DS 
or IS. 
• 
To establish the continued efficacy of Cannabidiol Oral Solution in maintaining 
seizure control in subjects with treatment-resistant seizures that previously 
completedINS0 11-14-029 or participated in INS0 11-15-054 and complete Part A 
(Visit 6). 
• 
To assess the global status of subjects taking Cannabidiol Oral Solution for an 
extended period of time determined by various qualitative assessments. 
• 
To monitor for changes in plasma levels of cannabidiol and its 7-0H metabolite 
during long-term treatment of subjects with treatment-resistant seizure disorders, 
including LGS, DS or IS. 
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Insys Development Company, Inc. 
INS0l 1-14-030 Amendment 5 
Cannabidiol Oral Solution 
3.0 
INVESTIGATIONAL PLAN 
3.1 
Summary of Study Design 
28 
This is a multicenter, open-label study to assess the long-term safety oflnsys' pharmaceutical 
Cannabidiol Oral Solution as adjunctive therapy for pediatric subjects with treatment-
resistant seizure disorders, including LGS, DS and IS. Plasma levels of cannabidiol and its 
7-OH metabolite and efficacy (seizure control and qualitative assessments of subject global 
status) will also be evaluated, though the latter will not be analyzed as endpoints. 
Subjects must complete 1 of the following studies to be eligible for the current study: 
• 
Activities through Day 11 in INS0 11-14-029 
• 
Activities through Part A (Visit 6) in INS0l 1-15-054. 
Eligible subjects will also be medically stable without new, clinically significant 
inclusion/exclusion criteria in Sections 3 .4.1 and 3 .4.2. 
Subjects should enroll in INS0l 1-14-030 immediately upon completion of the 
Treatment Period in their previous study (to avoid interruption of the investigational 
product). Rollover should occur within 2 weeks after completion of the Treatment Period in 
their previous study or when appropriate. A Screening Visit may be required for subjects that 
do not rollover within 14 days of completing their previous study. 
In this study, subjects will be dosed as described below. 
• 
Subjects who completed INS0l 1-14-029 will initiate this study on the dose with 
which they were being treated previously, unless tolerability issues were observed for 
a particular subject. 
• 
Subjects who completed Part A in INS0l 1-15-054 will continue treatment with the 
dose at which they were being treated previously, unless tolerability issues were 
observed for a particular subject. 
Subjects will receive twice daily oral doses of Cannabidiol Oral Solution as described in 
Section 4.1 for approximately 48 weeks or until the investigational product is successfully 
approved for marketing in the US (whichever occurs earlier), inclusive of their treatment on 
the previous study. For subjects that completed INS0l 1-14-029, 48 weeks of treatment 
would be completed under this protocol. For subjects that participated in INS0l 1-15-054, 
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29 
duration of treatment in INS0l 1-14-030 will be based on the length of time they were 
emolled in INS0l 1-15-054 such that total duration of treatment in both studies combined will 
not exceed approximately 48 weeks. Subjects visit entry into INS0l 1-14-030 will be 
determined at the discretion of the sponsor and the investigator. 
The study will be terminated upon 1 of the following: 
• 
The investigational product is successfully approved for marketing in the US 
• 
Sponsor elects to terminate INS0l 1-14-030. 
Treatment with established background AEDs will continue without interruption and changes 
will be permitted as necessary based on safety concerns or due to changes in seizure control 
as described in Section 4.3. 
As described in Table 1 and Section 5.0, visits will be scheduled at Week 1, Week 2, then 
monthly for 3 months, and then quarterly thereafter. A Screening Visit will be required for 
all subjects that do not rollover within 14 days of completing their previous study. All 
subjects will complete the Final Visit/ Discontinuation Visit regardless of when they stop 
treatment/complete the study. A Follow-up Visit will occur 2 weeks after the Final 
Visit/Discontinuation Visit. 
At each visit, a record of the incidence and severity of adverse events (AEs), treatment-
emergent AEs (TEAEs), and SAEs will be collected and this will serve as a primary outcome 
criterion for this study. Other safety-related parameters such as 12-lead ECG and 
hematology, chemistry, and urinary analyses will also be assessed at specified visits. 
Determination of trough plasma levels of cannabidiol and its 7-0H metabolite will be 
performed at each visit except Visits 3 and 4 (Week 1 and Week 2). This will support safety 
monitoring and establish the extent of variability during long-term treatment with the 
investigational product. For subjects taking clobazam, levels of clobazam and its major 
metabolite (norclobazam) will be measured ifthere are safety concerns. Seizure diaries will 
be reviewed to assess control of seizures (frequency, duration, and severity) throughout the 
duration of the study. 
At each visit except Visits 3 and 4 (Week 1 and Week 2), qualitative assessments will be 
completed as specified in the Schedule of Events (Table 1 ). The Investigator Clinical Global 
Impressions oflmprovement (CGI-I) and Clinical Global Impressions of Severity (CGI-S), 
will be completed for all subjects regardless of chronological and developmental age. Other 
qualitative assessments will be completed in an age-specific manner. This refers to 
developmental age, as discussed below. Specifically: 
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INS0l l-14-030 Amendment 5 
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• 
The Impact of Pediatric Epilepsy Scale (IPES),78•79 is validated for subjects who are 
2 to 16 years of age. Due to developmental delay characteristic of the study 
population, subjects through 18 years of chronological age will complete the IPES. 
Subjects > 18 years of chronological age will not complete the IPES. 
• 
If appropriate, the Columbia-Suicide Severity Rating Scale (C-SSRS) will be 
administered to access suicidality. 
30 
The risk of suicide may be evaluated using the C-SSRS for patients aged >=7 years. Clinical 
impression will be used for patients < 7 years and for patients aged >=7 years with 
development impairment for whom the C-SSRS would be inappropriate. 
The assessments to be completed in this study are discussed in Section 6.0. 
Subject safety will be monitored by a medical and safety data review as described in Section 
3.2. 
3.2 
Medical and Safety Data Review 
The medical and safety data review will be conducted throughout the study in parallel with 
continued subject recruitment, enrollment, and dosing. In addition, the pharmacokineticist 
and statistician may review, as appropriate. Additional experts may be consulted, as 
necessary. 
3.3 
Schedule of Events 
The Schedule of Events may be found in Table 1. 
Subjects should rollover from the previous study as soon as possible following completion of 
Day 11 activities (INSOl 1-14-029) or when appropriate for INSOl 1-15-054 to avoid 
interruption of the investigational product. A Screening Visit may be required for all 
subjects that do not rollover within 14 days of completing their previous study. The duration 
of each subject's treatment will be determined by the duration of treatment the subject 
received in their previous study as described in Section 3 .1. 
Visits will occur weekly for two weeks, monthly for 3 months, and then quarterly thereafter. 
A Screening Period (Visit 1) may be required for all subjects that do not rollover within 14 
days of completing their previous study. All subjects will complete a 
Final Visit/Discontinuation Visit regardless of when they stop treatment/complete the study. 
Discontinuation may occur due to reasons discussed in Sections 3.1 and 3.4.3. A Follow-up 
Visit will occur 2 weeks after the Final Visit/Discontinuation Visit. 
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INS0I 1-14-030 Amendment 5 
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Table 1 Schedule of Events 
Visit 1 (14 
Day 
Screening 
Visit2 
Periodb) 
(Day 1c) 
Assessments a 
Obtain 
informed 
X 
X 
consentt 
Demographics 
X 
X 
Review of 
inclusion/exclus 
X 
X 
ion criteria 
Medical and 
X 
X 
surgical history 
Assessment of 
X 
X 
current AEDs 
Concomitant 
medications 
X 
X 
and procedures 
ECG 
X 
X 
Vital signsg 
X 
X 
Laboratory 
values 
X 
X 
(hematology, 
chemistry)h 
Urinalysisi 
X 
X 
Pregnancy testi 
X 
X 
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Visit3 
(Week 1) 
±3 days 
X 
X 
X 
31 
Treatment Period 
Final Visit / 
Follow-up Visit 
Discontinuation 
Visits 5, 6, & 7 
Visits 8, 9, 
Visitd (Visit 10) 
Two weeks after 
Visit4 
Quarterly: 
Week48 ±10 
(Week 2) 
Monthly: 
(Weeks 24 
dayse (if not 
Final Visit/ 
±3 days 
(Weeks 4, 8 & 
and 36) ±10 
conducted at a 
Discontinuation Visit 
12) ±7 days 
daysd 
normally 
(Visit 11) ±5 days 
scheduled visit) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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INSOI 1-14-030 Amendment 5 
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Visit 1 (14 
Day 
Screening 
Visit2 
Periodb) 
(Day 1c) 
Assessments a 
Physical 
examination 
and 
X 
X 
neurological 
examinationk 
Dispense (D), 
review (R), and 
collect (C) 
subject seizure 
and dosing 
diary1 
Dispense (D) 
and collect (C) 
study drug and 
DIR 
review (R) 
dosing 
procedures 
Administer 
morning dose 
X 
of study drug in 
the clinic 
AEs and SAEs 
X 
X 
Blood draw for 
X 
plasma levels 
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Visit3 
(Week 1) 
±3 days 
D/R/C 
X 
32 
Treatment Period 
Final Visit / 
Follow-up Visit 
Discontinuation 
Visits 5, 6, & 7 
Visits 8, 9, 
Visitd (Visit 10) 
Two weeks after 
Visit4 
Quarterly: 
Week 48 ±10 
(Week 2) 
Monthly: 
(Weeks 24 
dayse (if not 
Final Visit / 
±3 days 
(Weeks 4, 8 & 
and 36) ±10 
conducted at a 
Discontinuation Visit 
12) ±7 days 
daysd 
normally 
(Visit 11) ±5 days 
scheduled visit) 
X 
X 
X 
D 
D/R/C 
RIC 
D/R/C 
D/R/C 
D/R/C 
C 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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33 
Treatment Period 
Final Visit / 
Follow-up Visit 
Discontinuation 
Visit 1 (14 
Visits 5, 6, & 7 
Visits 8, 9, 
Visitd (Visit 10) 
Two weeks after 
Day 
Visit3 
Visit4 
Quarterly: 
Week 48 ±10 
Screening 
Visit 2 
(Week 1) 
(Week 2) 
Monthly: 
(Weeks 24 
dayse (if not 
Final Visit / 
Periodb) 
(Day 1c) 
±3 days 
±3 days 
(Weeks 4, 8 & 
and 36) ±10 
conducted at a 
Discontinuation Visit 
12) ±7 days 
daysd 
normally 
(Visit 11) ±5 days 
Assessments a 
scheduled visit) 
Investigator 
and 
X 
X 
X 
X 
X 
X 
Parent( s )/ca reg 
iver(s) CGI-Sm 
Investigator 
and 
X 
X 
X 
X 
Parent( s )/ca reg 
iver(s) CGl-lm 
IPESn,o 
X 
X 
X 
X 
X 
VABSn, P 
X 
X 
C-SSRSq 
X 
X 
X 
X 
X 
X 
Reminders for 
X 
X 
X 
X 
X 
X 
next visits 
a At Visits 2, 5, 6,7 8,9 and 10 all assessments are to precede administration of the morning dose of the investigational product (i.e., 
the subject should arrive for their study visit without having taken the morning dose of the investigational product). See Section 
5 .1 for more details. 
b A Screening Period (Visit 1) will be required only for all subjects that do not rollover within 14 days of completing their previous 
study. 
cvisit 2 (Day 1) may occur simultaneously with Day 11 from INS0l 1-014-029 or within 14 days of Visit 1 (Screening Visit) for 
INS0l 1-14-030. All assessments (except vital signs) completed within 14 days prior to administration of the first dose of 
Cannabidiol Oral Solution in INS0l 1-14-030 may be used for Visit 2 (Day 1) (to avoid repetition of procedures). 
d Subjects will receive two daily oral doses of Cannabidiol Oral Solution for approximately 48 weeks or until the investigational 
product is successfully approved for marketing in the US (whichever occurs earlier), inclusive of their treatment on the previous 
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34 
study, unless they are discontinued due to a reason described in Section 3.4.3. After 12 weeks, study visits will be completed at a 
quarterly frequency; the definition of quarterly is every 12 weeks (e.g., Weeks 24 and 36). 
e All subjects will complete the Final Visit/ Discontinuation Visit regardless of when they stop treatment/complete the study. 
f The ICF must be completed prior to rollover into INS0l 1-14-030. 
g Vital signs to be assessed are blood pressure, pulse rate, respiratory rate, and temperature. They will be taken after a 5-minute supine 
rest and, if applicable, following simultaneously scheduled ECG meawrements. 
h Fasting is NOT required for collection of plasma levels, hematology and chemistry laboratory samples; whether subject was fasting 
at time of collection should be recorded in the eCRF. Laboratory assessments completed within 14 days prior to administration of 
the first dose of Cannabidiol Oral Solution in INS0l 1-14-030 may be used for Visit 2 (Day 1) (to avoid repetition of procedures). 
i Urinalysis will include macroscopic review; microscopic will be completed if indicated by macroscopic results. Urinalysis completed 
within 14 days prior to administration of the first dose of Cannabidiol Oral Solution in INS0l 1-14-030 may be used for Visit 2 
(Day 1) (to avoid repetition of procedures). 
j The pregnancy test is only required for female subjects of childbearing potential. A serum pregnancy test is required at Screening 
( only for those subjects required to complete the Screening Visit) and urine pregnancy test for all other specified visits. Urine 
pregnancy tests completed within 14 days prior to administration of the first dose of Cannabidiol Oral Solution in INS0 11-14-030 
may be used for Visit 2 (Day 1) (to avoid repetition of procedures). 
k A full physical examination (general appearance, skin, eyes, ears, nose, throat, neck, lymph nodes, chest, heart, abdomen, and 
extremities systems) with neurological examination (developmental age, mental status, cranial nerves, nystagmus, motor system, 
sensory system, reflexes, coordination, gait, and station) will be perfonned at the subject's first visit (Screening or Visit 2. The 
subject's developmental capabilities will be assessed as a part of the neurological examination (in a manner the Investigator sees 
fit) during the Screening Period (Visit 1) or Visit 2 (Day 1) only, whichever visit occurs first for each respective subject. 
A brief neurological examination (mental status, cranial nerves, nystagmus, motor system, sensory system, reflexes, coordination, 
gait, and station) will be performed during other visits. All physical exams will also include an assessment of the subject's height 
and weight. Weight measurements at the quarterly visits may be used to calculate the subject's dose volume. Additional 
examinations may be performed at the discretion of the Investigator. 
1 Seizure diaries will be collected to assess control of seizures (frequency, duration, and severity) for one week prior to each quarterly 
visit. In addition, timing of the administration of the drug and timing and contents of the meals will be collected. 
m For appropriate subjects will complete the CGI-I and CGI-S for themselves. 
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n For subjects who previously completed INS0l 1-14-029, the IPES and VABS that are completed on Visit 2 (Day 1) ofINS0l 1-14-
030 will serve as the baseline. 
Analysis will also be done using the Visit 2 (Day 1) data in INS0l 1-14-030 as the baseline (see 
Section 8.2.2). 
0 The IPES is validated for subjects who are 2 to 16 years of ( developmental) age. Due to developmental delay characteristic of the 
study population, subjects through 18 years of chronological age will complete the IPES,. . Subjects enrolled from INS0 11-15-054 
will be excluded from IPES evaluation. 
P The V ABS is validated for use in subjects from birth to 90 years of age. To be conducted at Visits 2 and 10. Subjects enrolled from 
INS0l 1-15-054 will be excluded from VABS evaluation. 
35 
q The C-SSRS will only be completed for subjects for whom it is appropriate. The suggested age range for the pediatric version of the 
C-SSRS is from middle childhood (typically, around 7 years of age) through onset of adolescence (typically, through 11 years of age). 
However, in the face of cognitive delays, the tool can be suitable in older age groups. The appropriate adult version will be used in 
subjects 12 years of age and older. Subjects enrolled from INS0ll-15-054 will be excluded from C-SSRS scores evaluation. 
rThe Investigator or study center staff will remind the subject and/or parent(s)/caregiver(s) that the subject should not take the 
morning dose of the investigational product prior to assessments/clinic visit on the date of their quarterly study visits. The last 
dose of the investigational product prior to quarterly visits should be administered in the evening the day immediately prior. The 
subject and/or parents(s)/caregiver(s) will also be reminded that the date and time of the evening meal on the day prior to the 
quarterly study visits should be recorded in the subject seizure and dosing diary. 
AE: adverse event; AED: antiepileptic drug; CGI-I: Clinical Global Impression oflmprovement; CGI-S: Clinical Global Impression 
of Severity; C-SSRS: Columbia-Suicide Severity Rating Scale; ECG: electrocardiogram; eCRF: electronic case report form; ICF: 
informed consent form; IPES: Impact of Pediatric Epilepsy Scale; SAE: serious adverse event; VABS: Vineland Adaptive Behavior 
Scales, Second Edition- Survey Interview Form including the Maladaptive Behavior Index (VABS) 
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3.4 
Selection of Study Population 
The study will include subjects who completed activities through Day 11 in INS0l 1-14-029 
or Part A in INS0l 1-15-054. The estimated maximum number of rollover subjects from 
these previous studies is as follows: 
• 
INS0l 1-14-029: 60 subjects 
• 
INS0l 1-15-054: 20 subjects 
36 
If all subjects are eligible for and elect to rollover into INS0l 1-14-030, the population of this 
study will be a maximum of 80 subjects. 
Each subject must satisfy all inclusion/exclusion criteria in Sections 3 .4.1 and 3 .4.2. 
3.4.1 
Inclusion Criteria 
Subjects may be entered in the study only if they meet all of the following criteria: 
1. Cumpldt:<l adivilit:s lhruugh Day 11 in INS0l 1-14-029 ur cumplt:lt:<l Parl A in INS0l 1-
15- 054. 
2. Informed consent and assent (as applicable) of the subject and/or parent(s)/caregiver(s) in 
accordance with applicable laws, regulations, and local requirements. 
3. Medically stable in the opinion of the Investigator. 
4. Changes in background AEDs may occur during the study as discussed in 
Section 4.3. Care should be taken if patients are on other drugs metabolized by CYP 
enzymes. 
5. A female subject is eligible to participate in the study if she is: 
• 
Premenarchal, or 
• 
Of childbearing potential with a negative serum pregnancy test at Screening ( only for 
those subjects required to complete the Screening Visit) and a negative urine 
pregnancy test on Visit 2 (Day 1). If sexually active, she must fulfill I of the 
following requirements: 
i) Complete abstinence from intercourse ~4 weeks prior to administration of the first 
dose of the investigational product, throughout the Treatment Period, and 4 weeks 
after completion or premature discontinuation from the investigational product, 
and agreement to use a double-barrier method if she becomes sexually active. 
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37 
ii) Use of acceptable methods of contraception throughout the study and 4 weeks 
after completion or premature discontinuation from investigational product. The 
acceptable method of contraception is double-barrier method (i.e., condom plus 
spermicide or a condom plu~ diaphragm). 
6. A sexually active male subject must use acceptable methods of contraception throughout 
the study and for 4 weeks completion of study participation or premature discontinuation 
from investigational product. The acceptable methods of birth control are abstinence or 
double-barrier birth control (i.e., condom plus spermicide or a condom plus diaphragm). 
7. In the opinion of the Investigator, subject and/or parent(s)/caregiver(s) are able to 
continue keeping accurate seizure diaries. 
3.4.2 
Exclusion Criteria 
Subjects will not be entered in the study for any of the following reasons: 
1. Experienced an anoxic episode related to study drug requiring resuscitation during their 
previous study. 
2. Evidence of other clinically significant disease such as unstable hepatic, hematological, 
renal, cardiovascular, gastrointestinal, immunological, or pulmonary diseases or ongoing 
malignancies. 
3. Compromised respiratory function or severe respiratory insufficiency. 
4. Clinically significant abnormal laboratory values within the past 14 days, including: 
• 
LFTs such as albumin, direct bilirubin, total bilirubin, aspartate aminotransferase 
(AST), and alanine aminotransferase (ALT) 2:3 times the upper limit of normal 
(ULN). 
• 
The investigator may deem the subject eligible if in the opinion of the investigator, 
the clinically significant abnormal laboratory values are deemed to be acceptable and 
to not have an impact on subject safety. 
5. Inadequate supervision by parent(s)/caregiver(s). 
6. For appropriate subjects, an affirmative answer to queries regarding active suicidal 
ideation with some intent to act but without a specific plan or active suicidal ideation 
with specific plan and intent on the C-SSRS assessment at the Screening Visit. Subjects 
who have significant findings for suicidal ideation as assessed by the C-SSRS must be 
referred to the Investigator for follow-up evaluation. 
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3.4.3 
Subject Withdrawal 
All subjects are free to withdraw from participation in the study at any time, for any reason, 
specified or unspecified, and without prejudice to further treatment. 
38 
The criteria for enrollment are to be followed explicitly. If a subject who does not meet 
enrollment criteria is inadvertently enrolled, that subject should be withdrawn from the study 
and the Sponsor must be contacted. An exception may be granted in rare circumstances 
where there is a compelling safety reason to allow the subject to continue. In these rare 
cases, the Investigator must obtain documented approval from the Sponsor to allow the 
subject to continue in the study. 
In addition, subjects will be withdrawn from the study in the following circumstances (i.e., 
stopping criteria): 
• 
The Investigator decides that the subject should be withdrawn for safety 
o If the decision to remove the subject from the study is made because of an 
intolerable AE or a clinically significant laboratory value associated with the 
use of the investigational product, the investigational product is to be 
discontinued, appropriate measures taken, and the Sponsor notified 
immediately. 
• 
Subject is unwilling to continue in the study and/or the subject or caregiver withdraw 
consent 
• 
Lack of compliance with protocol 
• 
Investigator or Sponsor stops the study for any reason 
• 
Subject becomes pregnant 
• 
Laboratory values demonstrate a subject serum ALT or AST level >3 times ULN 
(requires confirmation within 2 days) 
• 
Laboratory values demonstrate a subject serum total bilirubin in excess of >2 times 
the ULN (requires confirmation within 2 days) 
• 
Subject is enrolled in error 
• 
Subject is lost to follow-up. 
o Lost to follow-up will be defined as a subject failing to attend planned study 
visits or to response to contacts by the study center staff contacts after 
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documented 2 attempts and for whom no other contact information is 
available. 
Subjects who discontinue the study early will be asked to complete the 
Final Visit/Discontinuation Visit, with assessments to be completed as indicated in Table 1. 
39 
Subjects may elect to withdraw from study treatment with the possibility of completing 
remaining visits to allow for monitoring until end of study. All data taken through the 
subject withdrawing consent or the Investigator or Sponsor decision to discontinue the study, 
as well as data from the Final Visit/ Discontinuation Visit, will be collected for discontinued 
subjects. 
Subjects who withdraw or are withdrawn from the study will not be replaced. 
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4.0 
STUDY TREATMENTS 
4.1 
Treatments Administered 
The starting dose of the investigational product will be determined by the study previously 
completed by the subject. 
40 
Subjects who completed INS0l 1-14-029 will initiate this study on the dose with which they 
were being treated previously, unless tolerability issues were observed for a particular 
subject. Subjects who completed Part A in INS0l 1-15-054 will continue treatment with the 
dose at which they were being treated previously unless a tolerability issue was observed for 
a particular subject. 
The Sponsor has developed a dronabinol product, which has a similar chemical composition 
to that of Cannabidiol Oral Solution. The 2 compounds differ in that dronabinol has closed 
ring, while the ring is open in Cannabidiol Oral Solution. Data from a single-dose PK study 
Cannabidiol Oral Solution. 
The strength of the investigational product is discussed in Section 4.3. 
Immediately after dosing, the subject will consume an adequate amount of water or clear 
liquid according to the age of the subject. 
• 
For subjects aged <2 years, 4 ounces of water or clear fluid should be offered and the 
amount consumed recorded in the electronic case report form ( eCRF). 
• 
For subjects aged 2 to <12 years, 5 ounces of water should be offered and the amount 
consumed recorded in the electronic case report form ( eCRF). 
• 
For subjects aged ~12 years, 8 ounces of water should be offered and the amount 
consumed recorded in the electronic case report form (eCRF). 
The subject is not required to fast prior to or after dosing. However, the timing of meals with 
regards to drug administration should be consistent throughout the duration of the study. 
Dosing of the investigational product may be increased or decreased based on efficacy and 
tolerability up to a maximum of 40 mg/kg/day. 
The investigational product will be administered in an adjunctive setting and background 
AED medication(s) will be administered as described in Section 4.3. 
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4.1.1 
Dose Adjustments 
41 
IP dose may be adjusted at the investigators discretion. Dose may be adjusted up or down 
based on efficacy, safety or tolerability. All dose changes must be clearly documented in the 
eCRF. Maximum dose must never exceed 40mg/kg/day. 
4.1.2 
Dose Tapering 
If the subject is not going to continue to receive IPoffered under the Investigator IND 
Expanded Access Program, the subject may be tapered off Cannabidiol Oral Solution based 
on the investigator's preference and subject's tolerability. The investigator should ensure 
that the taper is planned well in advance to allow sufficient time to complete the taper prior 
to the Visit 10 at 48 weeks ( ± 10 days). The date of entering the Expanded Access Program 
will be documented in the EDC. 
4.2 
Identity of Investigational Product 
The active pharmaceutical ingredient (API) in Cannabidiol Oral Solution is a nonplant-based, 
pharmaceutical grade 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 10 mL amber glass bottle. More detailed information may be 
found in the IB. 
4.2.1 
Storage of the Investigational Product 
The investigational product will be stored at controlled room temperature (20 to 25 degrees 
Centigrade, 68 to 77 degrees Fahrenheit) at the study center. The product can also be stored 
refrigerated (2 to 8 degrees Centigrade, 36 to 46 degrees Fahrenheit). 
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. 
The DEA regulations detail specific security requirements for storage of the investigational 
product. 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. 
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42 
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. 
The investigational product will be dispensed from a Schedule I licensed study center. 
Study centers are required to provide complete information, including eCRFs and final 
outcomes, on all instances of addiction, abuse, misuse, overdose, drug diversion/drug 
accountability, discrepancies in 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 subjects dropped out of the study. 
4.3 
Background Therapy 
Subjects are allowed to remain on their established AEDs throughout the study. For any 
patient the ketogenic diet and VNS settings may also be adjusted. 
Safety issues may be encountered that are associated with concomitant administration of the 
investigational product with the subject's established AEDs that necessitate an alteration in 
AED medication. AED medication(s), including stopping or starting medication(s), may 
be adjusted throughout the trial to maximize seizure control based on tolerability as 
judged by the investigator. 
The Statistical Analysis Plan (SAP) will address how changes in AED medication(s) will be 
addressed from a biostatistical perspective. 
4.4 
Packaging and La belling 
A description of the drug product may be found in Table 2. The investigational product will 
be supplied in either 10 mL or 30 mL amber glass containers of a 300 mg/mL strength. 
Table 2 Description of Drug Product 
Non-proprietary or common name of drug 
Cannabidiol Oral Solution, 300 mg/mL 
product 
Dosage form 
Oral solution 
Strength 
300 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 
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43 
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. 
4.5 
Selection of Doses in the Study 
For this study, twice daily oral dosing will be initiated as detailed in Section 4.1 based on 
dosing in the subject's previous study. 
Dose reductions of the investigational product may occur due to safety or tolerability 
concerns as described in Section 4 .1.1. and Section 4 .1.2. Dosing of the investigational 
product may also be increased (up to maximum 40 mg/kg/day) for an individual subject as 
per Investigator opinion if there is reason to believe that it is beneficial for the patient. 
4.6 
Selection and Timing of Dose for Each Subject 
Subjects will receive the investigational product twice daily as descried in Section 4.1. 
. 
. 
The subject and/or parent(s)/caregiver(s) will record the date and time for all administrations 
of the investigational product for one week prior to each quarterly visit in the subject 
seizure/dosing diary. On the seizure/dosing diaries parent(s)/caregiver(s) will also record the 
frequency, duration, and severity of seizures for one week prior to each quarterly visit. 
Administration of the investigational product with regards to timing of meals should be 
consistent throughout the study. 
It is recommended that sites call the subject and/or parent(s)/caregiver(s) to remind them to 
start recording seizures and dosing at one week prior to each quarterly visit. 
4. 7 
Method of Assigning Subjects to Treatment Group 
Subjects will be allocated to a dose of the investigational product based on their dosing in the 
previous studies as described in Section 4.1. 
4.8 
Blinding 
The study is open-label; no blinding will be performed. 
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4.9 
Prior and Concomitant Treatments 
4.9.1 
Excluded Medications and Foods 
During the study, subjects are not to receive the following: 
• 
Any cannabinoids ( cannabidiol, !).9-THC, or marijuana) 
• 
Any other investigational drug or investigational device. 
44 
Although they are not prohibited, subjects taking concomitant medications may require that 
the subject is monitored with special care to identify any AEs arising due to the potential for 
altered drug metabolism. This is discussed in detail in Section 6.1.1.1. 
4.9.2 
Allowed Medications 
Any medications ( other than those excluded by the protocol, see Section 4.9 .1) that the 
Investigator considers necessary for a subject's welfare may be given at the Investigator's 
discretion. 
Subjects will remain on established AEDs throughout the duration of the study except as 
described in Section 4.3. Typical AEDs for treatment-resistant seizure disorders are 
discussed in Section 1.2, but background AED medication(s) are not limited to those 
referenced in this protocol. 
4.10 Treatment Compliance 
The subject seizure and dosing diary will include a record of the date and time of each 
administration of the investigational product. Diary data will be collected for one week (7 
days) prior to each quarterly visits. 
Subjects exhibiting poor compliance should be counseled on the importance of good 
compliance to the study dosing regimen. Noncompliance is defined as taking <80% or 
> 120% of the investigational product during any evaluation period (i.e., visit to visit). 
Any departures from the intended regimen must be recorded in the eCRF. 
4.11 Study Medication Accountability 
The Investigator, a member of the investigational staff, or a hospital pharmacist must 
maintain an adequate record of the receipt, distribution, and collection (of unused supplies) 
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of all investigational product using the Drug Accountability Form. These forms must be 
available for inspection at any time. 
All supplies of the investigational product 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 designee. 
45 
If the study is terminated, discontinued, suspended, or completed, all unused supplies of the 
investigational product may be destroyed via the use of a third-party vendor or be returned to 
the Sponsor or a designee after the final drug accountability check has been performed. A 
certificate of destruction will be provided to the Sponsor. 
All regulations issued by the DEA in regards to the accountability of Schedule I medications 
will be followed (e.g., prevention of diversion). 
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5.0 
STUDY PROCEDURES 
46 
Prior to performing any study related procedures or assessments, the Investigator will ensure 
that the subject and/or their parent(s)/caregiver(s) (if applicable) provides written informed 
consent and a pediatric subject provides assent (as appropriate). Subjects and their 
parent(s)/caregiver(s) (if applicable) will receive a copy of the informed consent form (ICF) 
and assent form for review and must provide fully informed consent prior to study 
participation. 
The consent process must be conducted and the ICF signed before any study procedures. 
See Section 9.3 for guidelines regarding subject consent and assent. 
5.1 
Screening Period (Visit 1) 
Subjects that do not rollover within 14 days of completing their previous study (INS0 11-14-
0?Q) urill hP rPrmirPrl tn r.nmnlPtP. ::i ~r.rP.Pnino Vi,;:it ~nhiP.d<;: urhn Pnrnll ::iftP.r n::irtir.in::itino in 
--~ / ··--- -- -·.1.------ -- ----r---- -- ~---------o · ----- ----.,----
··--- --~--- --~--- r------r------c, ---
INSQl 1-15-054 will not need to complete a Screening Visit ifless than 14 days has elapsed 
between dosing. 
The following procedures will be completed only after obtaining informed consent: 
• 
Review of inclusion and exclusion criteria (see Sections 3.4.1 and 3.4.2) 
• 
Record concomitant medications and concomitant procedures 
• 
Obtain a 12-lead ECG 
• 
Record vital signs (blood pressure, heart rate, respiratory rate, and temperature 
measurements) 
• 
Draw blood samples for hematology and chemistry (fasting NOT required) and 
record whether subject was fasting at time of collection in the eCRF 
• 
Obtain a urine sample for urinalysis 
• 
Obtain a blood sample for serum pregnancy test in female subjects of childbearing 
potential 
• 
Perform a complete physical examination (see Section 6.1.5.2), including height and 
weight 
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• 
Perform a neurological examination (see Section 6.1.5 .2), including assessment for 
developmental capabilities 
• 
Record demographic data 
• 
Record medical and surgical history 
• 
Record recent medication history including current AEDs, vitamins, herbal 
preparations, blood products, and over-the-counter drugs 
• 
Record AEs and SAEs 
• 
Administer Investigator CGI-S 
• 
Administer parent(s)/caregiver(s) CGI-S 
o When appropriate, subjects will complete the CGI-S for themselves. 
• 
Administer C-SSRS (if appropriate). 
5.2 
Treatment Period 
47 
Subjects that completed INS0l 1-14-029 will complete this study through the 48 week visit, 
unless they are discontinued due to a reason described in Section 3.4.3, or until the 
investigational product is successfully approved for marketing in the US (whichever occurs 
earlier). For subjects that participated in INS0l 1-15-054 will participate through the Week 48 
visit unless they are discontinued due to a reason described in Section 3.4.3, or until the 
investigational product is successfully approved for marketing in the US (whichever occurs 
earlier); however, the combined treatment duration in INS0l 1-14-030 and INS0l 1-15-054 
will not exceed approximately 48 weeks 
At Visits 2, 8, and 9, all assessments are to precede administration of the morning dose of the 
investigational product. Specifically, the subject will NOT receive the investigational 
product on the morning of Visits 2, 8, and 9 UNTIL all assessments have been completed. 
The morning dose of the investigational product should be administered following 
completion of all assessments. 
Given the timing of study assessments in regards to administration of the investigational 
product and the twice daily dosing of this medication, all visits requiring in-clinic dose 
administration will preferably be scheduled in the morning. Ideally, all assessments should 
be completed before 12 PM (noon) in the time zone of the study center to adhere as closely 
as possible to the 12-hour interval for dosing (see Section 4.6). 
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5.2.1 
Visit 2 (Day 1) 
48 
Since Day 11 for INS0l 1-14-029 may represent the first visit of this study, activities that 
have been carried out in the previous protocol will not be repeated and the data will be used 
in the analysis of both studies provided the assessments are completed within 14 days prior to 
administration of the first dose of Cannabidiol Oral Solution in INS0 11-14-030 (to avoid 
repetition of procedures). Similarly, all assessments completed during the Screening Period 
(Visit 1 ), and within 14 days prior to administration of the first dose of Cannabidiol Oral 
Solution in INS0 11-14-030, may be used for the Visit 2 (Day 1 ), except vital signs. 
If not already completed in the past 14 days, the following procedures will be completed 
PRIOR to administration of the morning dose of the investigational product: 
• 
Obtain informed consent 
o The ICF must be completed prior to any procedures. 
• 
Review of inclusion and exclusion criteria (see Sections 3.4.1 and 3.4.2). 
• 
Record concomitant medications and concomitant procedures. 
• 
Obtain a 12-lead ECG. 
• 
Record vital signs (blood pressure, heart rate, respiratory rate, and temperature 
measurements). Vital signs must be assessed regardless of date of last collection. 
• 
Draw blood samples for hematology and chemistry (fasting NOT required) and 
record whether subject was fasting at time of collection in the eCRF. 
• 
Obtain a urine sample for urinalysis. 
• 
Obtain a urine sample for 
human chorionic gonadotropin (~-hCG) pregnancy test in 
female subjects of childbearing potential. 
• 
Complete blood draw for plasma levels. 
• 
Perform a complete physical examination (see Section 6.1.5.2), including height and 
weight. 
• 
Perform a brief neurology examination (see Section 6.1.5.2). 
• 
Administer morning dose of the investigational product in the clinic. 
• 
Record demographic data. 
• 
Record medical and surgical history. 
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• 
Record and review current AEDs 
• 
Dispense investigational product 
• 
Review of dosing procedures for the investigational product 
• 
Record AEs and SAEs 
• 
Administer Investigator CGI-S 
• 
Administer parent(s)/caregiver(s) CGI-S 
o When appropriate, subjects will complete the CGI-S for themselves. 
• 
Administer IPES 
o The IPES is validated for subjects who are 2 to 16 years of (developmental) 
age. Due to developmental delay characteristic of the study population, 
subjects through 18 years of chronological age will complete the IPES. 
• 
Administer V ABS 
o The VABS is validated for use in subjects from birth to 90 years of age. 
• 
Administer C-SSRS (if appropriate) 
• 
Remind subject/parent(s)/caregiver(s) of next scheduled visit 
5.2.2 
Visits 3 and 4 (Weeks 1 and 2) ±3 days 
The following procedures will be completed: 
• 
Record concomitant medications and concomitant procedures. 
• 
Record vital signs (blood pressure, heart rate, respiratory rate, and temperature 
measurements). 
• 
Record recent medication history including current AEDs, vitamins, herbal 
preparations, blood products, and over-the-counter drugs. 
• 
Dispense and collect investigational product. 
• 
Review of dosing procedures for the investigational product. 
• 
Record AEs and SAEs. 
• 
Remind subject/parent(s)/caregiver(s) of next scheduled visit. 
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Cannabidiol Oral Solution 
5.2.3 
Visits 5 and 6 (Monthly Visits) ±7 days 
Subjects will complete Visits 5 and 6 monthly at Weeks 4 and 8. 
The following procedures will be completed: 
• 
Record concomitant medications and concomitant procedures 
• 
Record vital signs (blood pressure, heart rate, respiratory rate, and temperature 
measurements) 
• 
Record recent medication history including current AEDs, vitamins, herbal 
preparations, blood products, and over-the-counter drugs 
• 
Complete blood draw for plasma levels 
• 
Draw blood samples for hematology and chemistry (fasting NOT required). 
• 
Dispense and collect investigational product 
• 
Review of dosing procedures for the investigational product 
• 
Record AEs and SAEs 
• 
Administer Investigator CGI-1 and CGI-S 
• 
Administer parent(s)/caregiver(s) CGI-1 and CGI-S 
o When appropriate, subjects will complete the CGI-1 and CGI-S for 
themselves. 
• 
Administer IPES 
o The IPES is validated for subjects who are 2 to 16 years of (developmental) 
age. Due to developmental delay characteristic of the study population, 
subjects through 18 years of chronological age will complete the IPES. 
• 
Administer C-SSRS (if appropriate) 
• 
Remind subject/parent(s)/caregiver(s) of next scheduled visit. 
5.2.4 
Visit 7 (Monthly Visit) ±7 days 
Subjects will complete Visit 7 at Week 12. 
The following procedures will be completed: 
• 
Record concomitant medications and concomitant procedures 
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Insys Development Company, Inc. 
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• 
Record vital signs (blood pressure, heart rate, respiratory rate, and temperature 
measurements) 
• 
Dispense subject seizure and dosing diary 
o Re-education of the parent/caregiver and/or subject regarding diary 
completion will be conducted. Diary data will be collected for one week (7 
days) prior to the next visit. 
• 
Record recent medication history including current AEDs, vitamins, herbal 
preparations, blood products, and over-the-counter drugs 
• 
Complete blood draw for plasma levels 
• 
Dispense and collect investigational product 
• 
Review of dosing procedures for the investigational product 
• 
Record AEs and SAEs 
• 
Administer Investigator CGI-1 and CGI-S 
• 
Administer parent(s)/caregiver(s) CGI-1 and CGI-S 
o 
When appropriate, subjects will complete the CGI-1 and CGI-S for 
themselves. 
• 
Administer IPES 
o The IPES is validated for subjects who are 2 to 16 years of (developmental) 
age. Due to developmental delay characteristic of the study population, 
subjects through 18 years of chronological age will complete the IPES. 
• 
Administer C-SSRS (if appropriate) 
5.2.5 
Visits 8 and 9 (Quarterly Visits) ±10 days 
Subjects will complete Visits 8 and 9 quarterly (every 3 months) at Weeks 24 and 36. 
The following procedures will be completed: 
• 
Record concomitant medications and concomitant procedures 
• 
Record vital signs (blood pressure, heart rate, respiratory rate, and temperature 
measurements) 
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Insys Development Company, Inc. 
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• 
Obtain a urine sample for serum ~-hCG pregnancy test in female subjects of 
childbearing potential 
• 
Draw blood samples for hematology and chemistry (fasting NOT required) and 
record whether subject was fasting at time of collection in the eCRF 
• 
Obtain a urine sample for urinalysis 
• 
Complete blood draw for plasma levels 
• 
Perform physical examination (see Section 6.1.5.2), including height and weight 
• 
Perform a brief neurology examination (see Section 6.1.5.2) 
• 
Review subject seizure and dosing diary and collect completed pages 
o Re-education of the parent/caregiver and/or subject regarding diary 
completion will be conducted as needed in the opinion of the Investigator. 
• 
Dispense new subject seizure and dosing diary 
o Diary data will be collected for one week (7 days) prior to the next visit. 
• 
Administer morning dose of the investigational product in the clinic. 
• 
Record recent medication history including current AEDs, vitamins, herbal 
preparations, blood products, and over-the-counter drugs 
• 
Dispense and collect investigational product 
• 
Review of dosing procedures for the investigational product 
• 
Record AEs and SAEs 
• 
Administer Investigator CGI-I and CGI-S 
• 
Administer parent(s)/caregiver(s) CGI-I and CGI-S 
o When appropriate, subjects will complete the CGI-I and CGI-S for 
themselves. 
• 
Administer IPES 
o The IPES is validated for subjects who are 2 to 16 years of (developmental) 
age. Due to developmental delay characteristic of the study population, 
subjects through 18 years of chronological age will complete the IPES. 
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• 
Administer C-SSRS (if appropriate) 
53 
• 
Remind subject/parent(s)/caregiver(s) of next scheduled visit. The 
subject/parent(s)/caregiver(s) should be reminded that the morning dose of the 
investigational product should not be administered prior to study assessments/clinic 
visit on the date of their next study visit and to record the date and time of the evening 
meal on the day prior to the next study visit. 
5.3 
Final Visit/Discontinuation Visit (Visit 10) ±10 days 
Each subject will complete a Final Visit/Discontinuation Visit regardless of when they 
complete/stop the study. Should a subject's participation be terminated according to study 
stopping criteria (see Section 3.4.3), this will be considered a Discontinuation Visit. For 
both, the following procedures will be completed: 
• 
Record recent medication history including current AEDs, vitamins, herbal 
preparations, blood products, and over-the-counter drugs 
• 
Record concomitant medications and concomitant procedures 
• 
Obtain a 12-lead ECG 
• 
Record vital signs (blood pressure, heart rate, respiratory rate, and temperature 
measurements) 
• 
Draw blood samples for hematology and chemistry (fasting NOT required) and 
record whether subject was fasting at time of collection in the eCRF 
• 
Obtain a urine sample for urinalysis 
• 
Obtain a urine sample for serum ~-hCG pregnancy test in female subjects of 
childbearing potential 
• 
Perform physical examination ( see Section 6.1.5 .2), including height and weight 
• 
Perform a brief neurology examination (see Section 6.1.5.2) 
• 
Review and collect subject seizure and dosing diary and collection of completed 
pages, if applicable 
o Diary data will be collected for one week (7 days) prior to Visit 10. 
• 
Collect investigational product 
• 
Record AEs and SAEs 
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• 
Complete blood draw for plasma levels 
• 
Administer Investigator CGI-I and CGI-S 
• 
Administer parent(s)/caregiver(s) CGI-I and CGI-S 
o When appropriate, subjects will complete the CGI-I and CGI-S for 
themselves. 
• 
Administer IPES 
o The IPES is validated for subjects who are 2 to 16 years of (developmental) 
age. Due to developmental delay characteristic of the study population, 
subjects through 18 years of chronological age will complete the IPES. 
• 
Administer V ABS 
o The V ABS is validated for use in subjects from birth to 90 years of age. 
• 
Administer C-SSRS (if appropriate). 
5.4 
Follow-up Visit (Visit 11) ±5 days 
All subjects will complete a Follow-up Visit 2 weeks (±5 days) after the 
Final Visit/Discontinuation Visit. The following activities will be completed: 
• 
Record recent medication history including current AEDs, vitamins, herbal 
preparations, blood products, and over-the-counter drugs 
• 
Record vital signs (blood pressure, heart rate, respiratory rate, and temperature 
measurements) 
• 
Draw blood samples for hematology and chemistry (fasting NOT required) and 
record whether subject was fasting at time of collection in the eCRF 
• 
Obtain a urine sample for urinalysis 
• 
Obtain a urine sample for serum ~-hCG pregnancy test in female subjects of 
childbearing potential 
• 
Perform physical examination (see Section 6.1.5.2), including height and weight 
• 
Perform a brief neurology examination ( see Section 6.1.5 .2) 
• 
Record AEs and SAEs 
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• 
Complete blood draw for plasma levels 
• 
Administer Investigator CGI-I and CGI-S 
• 
Administer parent(s)/caregiver(s) CGI-I and CGI-S 
o When appropriate, subjects will complete the CGI-I and CGI-S for 
themselves. 
• 
Administer IPES 
o The IPES is validated for subjects who are 2 to 16 years of ( developmental) 
age. Due to developmental delay characteristic of the study population, 
subjects through 18 years of chronological age will complete the IPES. 
• 
Administer C-SSRS (if appropriate). 
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6.0 
SAFETY, PLASMA LEVEL, AND EFFICACY 
ASSESSMENTS AND ENDPOINTS 
6.1 
Safety 
A central objective of this study is to investigate the safety and tolerability of the 
investigational product. This will be done by assessment of the following: 
• 
AEs 
56 
o 
Safety evaluation will consist of TEAEs and SAEs graded according to the 
Medical Dictionary for Regulatory Activities (MedDRA), including deaths. 
This will be captured at every subject visit to the study center. Additionally, 
standard laboratory tests (hematology, chemistry, and urinalysis as detailed in 
Section 6.1.4), 12-lead ECGs, physical and neurological examinations, and 
assessment of vital signs will be performed as indicated in Table 1. 
• 
Clinical chemistry and hematology laboratory results 
• 
Urinalysis 
• 
12-lead ECG 
• 
Vital signs (blood pressure, pulse rate, and respiratory rate) 
• 
Physical and neurological examinations 
• 
C-SSRS (if appropriate). 
6.1.1 
Adverse Events 
An Adverse Event (AE) is any untoward medical occurrence in a subject administered a 
pharmaceutical product. It does not necessarily have a causal relationship with this 
treatment. 
Seizures should not be considered an AE unless they differ significantly from the subjects' 
baseline. The onset of a new seizure type, as well as an injury incurred as a result of any 
seizure should be recorded as an AE. 
A SAE is any untoward medical occurrence ( whether considered to be related to 
investigational product or not) that at any dose: 
• 
Results in death 
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• 
Is life-threatening 
o This requires that the subject bt nt a risk of death at the time of the event; it 
does not refer to an event that hypothetically might have caused death if it 
were more severe. 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
o Hospital admissions and/or surgical operations planned before or during a 
study are not considered AEs if the illness or disease existed before the 
subject was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study. 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital abnormality/birth defect 
57 
• 
Other medically significant events, which do not meet any of the criteria above, but 
may jeopardize the subject and may require medical or surgical intervention to 
prevent a serious outcome listed in the definition above ( e.g., blood dyscrasias such as 
anemia requiring blood transfusion). 
An adverse drug reaction (ADR) is defined as all noxious and unintended responses to a 
medicinal product related to any dose. An unexpected ADR is defined as any adverse 
reaction, the nature of which is not consistent with the applicable product information. 
The Investigator is responsible for recording all AEs observed during the study through the 
Follow-up Visit. Each AE will be evaluated for duration, severity, frequency, seriousness, 
and causal relationship to the study treatment. Action taken with the study treatment and 
outcome will also be recorded. 
Definitions for severity and causal relationship to the study treatment are presented below. 
Severity 
The severity of the AE will be characterized as mild, moderate, or severe according to the 
following definitions: 
• 
Mild events are usually transient and do not interfere with the subject's daily 
activities. 
• 
Moderate events introduce a low level of inconvenience or concern to the subject and 
may interfere with daily activities. 
• 
Severe events interrupt the subject's usual daily activity. 
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Relationship 
The Investigator will assess the causal relationship of an AE to the investigational product 
and characterize the AE as unrelated, unlikely, possible, probable, or unknown (unable to 
judge). The following definitions of causality will be used: 
58 
• 
Events can be classified as "unrelated" if there is not a reasonable possibility that the 
study medication caused the AE. 
• 
An "unlikely" relationship suggests that only a remote connection exists between the 
investigational product and the reported AE. With this classification, other 
conditions, including chronic illness, progression or expression of the disease state or 
reaction to concomitant medication, appear to explain the reported AE. 
• 
A "possible" relationship suggests that the association of the AE with the study 
medication is unknown; however, the AE is not reasonably supported by other 
conditions. 
• 
A "probable" relationship suggests that a reasonable temporal sequence of the AE 
with drug administration exists and, in the Investigator's clinical judgment, it is likely 
that a causal relationship exists between the drug administration and the AE. Other 
conditions ( concurrent illness, progression or expression of disease state or 
concomitant medication reactions) do not appear to explain the AE. 
All efforts should be made to classify the AE according to the above categories. The 
category "unknown" (unable to judge) may be used only if the causality is not assessable 
( e.g., because of insufficient evidence, conflicting evidence, conflicting data, or poor 
documentation). 
The frequency of each observed event will be recorded. Clinical actions taken as a result of 
an AEs include pausing, stopping, or delaying dosing of the investigational product. If 
applicable, the resolution of each observed AE will also be recorded; unresolved AEs at the 
time of subject discontinuation will be noted as such. 
6.1.1.1 
Monitoring of AEs Potentially Related to Drug Metabolism 
Cannabidiol inhibits drug metabolism mediated by a subset of CYP proteins (see 
Section 1.1.2). Thus, the Investigator and study center staff should monitor subjects who are 
taking concomitant medications that are metabolized by CYP2C19, CYP2C9, or CYPlAl or 
by p-glycoprotein with special care. Medication(s) that is/are inhibitor(s) or inducer(s) or 
sensitive substrates of CYP3A4 should be monitored with special care. 
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The CYP proteins noted above metabolize a selection of clinically important AEDs. As 
such, subjects should be monitored for AEs that may be related to a change in the 
metabolism of background AEDs. These may include: 
• 
Increases in liver enzymes 
• 
Increases in side effects associated with background AEDs 
• 
Development of new side effects associated with background AEDs. 
59 
Similarly, several AEDs are known inducers of CYP3A4.24 As such, their use may result in 
alterations in the level of the investigational product. Plasma levels of cannabidiol and 7-0H 
cannabidiol will be assessed as described in Section 6.2. 
The Investigator may choose to assess plasma levels of background AEDs with which the 
subject is being treated should AEs arise that may be due to altered metabolism of these 
medications (see above). As noted in Section 4.3, decisions to alter background AED 
medications and dosing due to safety concerns will be considered on a case by case basis. 
6.1.2 
Reporting of AEs 
The AEs and SAEs will be assessed at all study visits. As noted in Section 6.1.6, endpoints 
for this study include the AE/SAE record for each subject. 
At each visit, information regarding AEs will be elicited from subjects by questioning 
conducted by the study center staff and the subject record will be reviewed with the 
parent(s)/caregiver(s) at each visit. The AEs and SAEs will be assessed at study visits 
according to the schedule indicated in Table 1. As noted in Section 6.1.6, endpoints for this 
study include the AE and SAE record for each subject. 
All AEs, regardless of severity or when they occur, are to be recorded on the appropriate AE 
pages ( either serious or nonserious) in the eCRF. The Investigator should complete all the 
details requested including dates of onset, severity, action taken, outcome, and relationship to 
the investigational product. Each event should be recorded separately. 
Any SAE, including death due to any cause, which occurs during this study, whether or not 
related to the investigational product, must be reported immediately (within 24 hours of the 
study center's first knowledge of the event) by fax to the Sponsor or designee. 
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The Sponsor contact information is listed below: 
 RPh 
 
Insys Development Company, Inc. 
Telephone: 
 
Fax: 
 
Email: 
 
60 
All SAEs will be recorded on the SAE Report Form, entered into the electronic data capture 
(EDC) system, and recorded in the source documents. The Investigator must complete, sign, 
and date the SAE Report Form, check that the data are consistent, and send a copy (within 
24 hours, preferably by fax) to the Sponsor or designee list above. 
The report will contain as much available information concerning the SAE to enable the 
Sponsor or designee to file a report, which satisfies regulatory reporting requirements. In 
addition to the initial 24-hour report, a completed, separate SAE Report Form is to be sent to 
thP ~nrm1;1r,r r,r rlP1;11onPP "1i:1 fi:1v r,r mi:111 u,ithin LI.R hrn1r1;1 r.fthP "'""'"t ThP1;1P t1mPl1np1;1 i:1nnh, 
•u- ~!'~ .. 
~• --~•i:,u--
• •- •-•• ~• ....... ., uuu• • 
u~-•~ ~• •u- -
• -u•• •••-~- u•u-uu-~i .t-"•J 
to initial reports of SAEs and to all follow-up reports. 
Criteria for documenting the relationship to the investigational product, severity, and 
outcome will be the same as those previously described. 
All SAEs that are spontaneously reported within 30 days of a subject's last visit are to be 
collected and reported as previously described. 
The information must include at least the following: 
• 
Investigational product 
• 
Study name and code 
• 
Name, address, fax number, email, and telephone number of the reporting 
Investigator 
• 
Subject identification number, initials, and demographics (gender and date of birth) 
• 
Clinical event 
• 
Description of the AE, including 
o Date of onset 
o Treatment (drug, dose, dosage form) 
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o Preliminary classification of causal relationship by the Investigator. 
o Measures taken (i.e., action taken regarding investigational product in direct 
relationship to the AE) 
o Outcome 
• 
If the AE was fatal or life-threatening 
• 
Cause of death (and whether or not the death was related to investigational product) 
• 
Autopsy findings (if available). 
61 
In the case of fatal or life-threatening events, please also immediately report by telephone to 
the Sponsor or designee. 
Additional follow-up information should be completed on an SAE follow-up form with a 
copy sent to the Sponsor or designee and the original placed in the SAE section of the eCRF 
binder. 
In medical emergencies, the Investigator should use medical judgment and remove the 
subject from immediate hazard. The Sponsor or designee will be notified regarding the type 
of emergency and course of action taken and the procedures for SAE reporting will be 
followed, if necessary. 
During a subject's participation in the study, the Investigator or institution will provide 
adequate medical care for any AEs, including clinically significant laboratory values related 
to the study. The Investigator or institution should inform a subject when medical care is 
needed for an intercurrent illness ( clinic, laboratory results, or otherwise) which in the 
opinion of the Investigator should receive medical follow-up. 
6.1.2.1 
Reporting of SAEs to Regulatory Authorities and Investigators 
The Investigators will be responsible for submission of SAEs as required to their Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC). The Investigators should provide 
written documentation of IRB notification for each report to the Sponsor or designee. The 
Sponsor or designee will ensure that all SAEs are reported to the appropriate regulatory 
authorities. 
Any additional local IRB/IEC reporting requirements for SAEs should be observed by the 
study center. 
The Sponsor or its representative will be responsible for notification to regulatory agencies. 
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6.1.3 
Follow-Up of AEs 
Any AEs observed will be followed up 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 or designee within 30 days of the last 
administration of the investigational product. 
6.1.4 
Clinical Laboratory Evaluations 
62 
All clinical laboratory tests will be reviewed for results of potential clinical significance 
throughout the study. The Investigator will evaluate any change in laboratory values. If the 
Investigator determines a laboratory abnormality to be clinically significant, it is considered a 
laboratory AE; however, if the abnormal laboratory value is consistent with a current 
diagnosis, it may be documented accordingly. 
The following laboratory tests will be assessed at the time points specified by Table 1. 
• 
Hematology: complete blood count (CBC) with differential, including platelet count, 
neutrophils, lymphocytes, eosinophils, basophils, monocytes, hemoglobin, and 
hematocrit 
• 
Serum chemistry: total protein, albumin, creatinine, blood urea nitrogen (BUN), uric 
acid, total bilirubin, direct bilirubin, alkaline phosphatase, FSH, AST, ALT, glucose, 
calcium, phosphorus, bicarbonate, chloride, sodium, and potassium 
• 
Urinalysis: specific gravity, pH, color, and presence of white blood cells (WBCs), 
red blood cells (RBCs), and proteins 
• 
~-hCG in urine (pregnancy test) 
LFTs (e.g., albumin, direct and total bilirubin, AST, and ALT) will be closely monitored to 
identify any damage that could be induced by the investigational product. 
Levels of FSH will be monitored as a potential surrogate outcome for gametocyte damage. 
Laboratory values outside the reference limits suspected to be of any clinical significance 
will be repeated. Subjects in whom suspected clinical significance is confirmed will either 
not be included or if already enrolled will be followed until normalization or for as long as 
the Investigator considers necessary. Additional laboratory variables may be performed for 
safety reasons if judged appropriate by the Investigator. Further details are provided in the 
Laboratory Manual. 
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6.1.4.1 
Central Laboratory 
Clinical laboratory tests will be analyzed centrally. Refer to the Laboratory Manual for 
information regarding collection, processing, and analysis of samples. 
6.1.5 
Vital Signs, Physical Findings and Other Safety Assessments 
63 
Vital signs, physical findings, and other safety assessments will be reviewed for results of 
potential clinical significance throughout the study. The Investigator will evaluate any 
changes. If the Investigator determines that a safety assessment is clinically significant, it is 
considered an AE. However, if the finding is consistent with the subject's current diagnoses, 
it may be documented accordingly. 
6.1.5.1 
Vital Signs 
Vital signs (including blood pressure, pulse rate, respiratory rate, and temperature) will be 
recorded at the time points specified by Table 1. 
If clinically significant findings, as determined by the Investigator, occur in any of the vital 
signs measurements, that measurement will be repeated at medically appropriate intervals 
until the value returns to an acceptable range, a specific diagnosis is established, or the 
condition is otherwise explained. 
6.1.5.2 
Physical and Neurological Examinations 
The full physical examination will consist of the following: general appearance, skin, eyes, 
ears, nose, throat, neck, lymph nodes, chest, heart, abdomen, and extremities. All physical 
exams will also include an assessment of the subject's height and weight. 
A brief neurological examination will consist of the following: mental status, cranial nerves, 
nystagmus, motor system, sensory system, reflexes, coordination, gait, and station. 
The subject's developmental capabilities will be assessed as a part of the neurological 
examination (in a manner the Investigator sees fit) during the Screening Period (Visit 1) or 
Visit 2 (Day 1) only, whichever visit occurs first for each respective subject. 
Additional examinations may be performed at the discretion of the Investigator. 
6.1.5.3 
ECGs 
The ECGs will be performed at the time points specified in Table 1. 
Subjects should be supine for 2:5 minutes prior to the assessment. 
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If the first ECG is abnormal, up to an additional 2 repetitions of a specific assessment may be 
performed. 
6.1.5.4 
C-SSRS 
The Columbia-Suicide Rating Scale (C-SSRS) is a prospective assessment tool routinely 
used in studies of drugs with any potential for CNS effects. It captures the occurrence, 
severity, and frequency of suicide-related thoughts and behaviors during the assessment 
period. The risk of suicide will be evaluated using the C-SSRS for patients aged >=7 years. 
Clinical impression will be used for patients < 7 years and for patients with development 
impairment for whom the C-SSRS would be inappropriate. The questionnaires will be 
completed at the time points specified by the schedule of assessments in Table 1. 
6.1.5.5 
Medical/Surgical History 
A complete medical/surgical history will include evaluation (past or present) of the 
following: general, head and neck, eyes, ears, nose, throat, chest/respiratory, 
heart/ cardiovascular, gastrointestinal/liver, gynecological/urogenital, 
musculoskeletal/extremities, skin, neurological/psychiatric, endocrine/metabolic, 
hematological/lymphatic, allergies/drug sensitivities, past surgeries, or any other diseases or 
disorders. 
6.1.6 
Safety-related Endpoints 
The safety-related endpoints are: 
• 
Incidence, type, and severity of AEs and SAEs associated with Cannabidiol Oral 
Solution as an adjunctive treatment for seizures 
• 
Changes from baseline in the previous study in vital signs 
• 
Changes from baseline in the previous study in ECG findings 
• 
Changes from baseline in the previous study laboratory values (hematology, 
chemistry, and urinalysis). 
6.2 
Plasma Levels 
Whole blood will be obtained in a Vacutainer® containing heparin anticoagulant for the 
determination of the plasma levels of cannabidiol and 7-0H cannabidiol in human plasma. 
The sample will be obtained as indicated in Table 1 prior to daily study medication dosing on 
that day. Samples for plasma level assessment of cannabidiol and 7-0H cannabidiol should 
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be collected immediately prior to administration of the morning dose of the investigational 
product on indicated days. 
The following information will be captured for blood sample collection in each subject's 
eCRF: 
• 
Subject number and initials 
65 
• 
Time and date of most recent administration of the investigational product prior to the 
sample collected for plasma level analysis 
• 
Time and date of each blood sample collected for plasma level analysis 
• 
Time and date of subject's ingestion of food (i.e., the evening meal on the day prior to 
each study visit). 
Samples for the determination of the investigational product in human plasma will be 
analyzed by the Sponsor, using an appropriate bioanalytical method. It is anticipated that this 
will include estimates of concentration and trough (steady state) concentration of cannabidiol 
and 7-OH cannabidiol (monthly to quarterly). For subjects taking clobazam, levels of 
clobazam and its major metabolite (norclobazam) will be measured if there are safety 
concerns. 
The analytical method for human plasma will be developed and validated. All samples still 
within the known stability of the investigational product will be analyzed. 
Exploratory plasma samples will be shipped to the Sponsor or the Sponsor-designated 
bioanalytical laboratory. 
6.2.1 
Plasma Levels-related Endpoint 
The plasma level-related endpoint is trough (steady state) concentrations of Cannabidiol Oral 
Solution throughout approximately 48 weeks of continuous exposure or until the 
investigational product is successfully approved for marketing in the US (whichever occurs 
earlier), inclusive of the subject's treatment on their previous study. 
6.3 
Efficacy 
6.3.1 
Seizure Control 
In this study, seizure frequency, duration, and severity will be assessed to monitor seizure 
control achieved by long-term treatment with Cannabidiol Oral Solution. Seizures will be 
observed and recorded using a patient reported outcome (PRO) instrument (i.e., 
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subject/caregiver diaries). The exact format and version(s) of diary to be used will also be 
included in the eCRF. Diaries will be dispensed at Visits 7, 8, and 9 (Weeks 12, 24, and 
36) and reviewed and completed pages collected (if applicable) during each visit. 
For the purposes of this study, only observable seizures will be quantified in the one week 
prior to Visits 8, 9, and 10. All seizures should be recorded by the parent(s)/caregiver(s) 
and/or subject (if applicable) in the diary. 
66 
Given that continuous seizures may be observed in some subjects (i.e., multiple seizures may 
occur without break), it may not be possible to accurately record all seizures for these 
subjects. If necessary, the parent(s)/caregiver(s) or subject (if applicable) will, at a 
minimum, categorize the seizure frequency ( for seizures others than tonic or atonic seizures) 
by range (i.e., diaries will record the count of seizures per day as >50 seizures/day, 20 to 
50 seizures/day, 6 to 19 seizures/day, 1 to 5 seizures/day, or no seizures). 
The subject and/or his/her parent(s)/caregiver(s) are responsible for completing the diary. 
The party who is primarily responsible will be chosen by the Investigator in consultation with 
the subject's parent(s)/caregiver(s). If a pediatric subject will be entering diary data, the 
parent(s)/caregiver(s) should provide guidance and monitor accuracy and completeness. 
6.3.1.1 
Subject Seizure and Dosing Diary Education 
Similar to INS0 11-14-029 and INS0 11-15-054, ongoing training and re-education of the 
parent( s )/caregiver( s) and (if applicable) the subject will occur under the direction of the 
Investigator and Study Coordinator. 
To this end, the Investigator and study center staff are expected to provide appropriate 
(refresher) training to subjects and/or their parent(s)/caregiver(s) regarding data to be 
collected. To satisfy the needs of all seizure-related efficacy endpoints, training will include 
a number of topics: 
• 
Recognition of seizure activity 
o Such training will facilitate the counting of seizures to satisfy the primary 
efficacy endpoint, as well as other efficacy-related endpoints. 
o For the purposes of this study, a seizure will be defined as uncontrolled 
electrical activity in the brain that may produce a physical convulsion, minor 
physical signs, thought disturbances, or a combination of symptoms. 
• 
Recognition of the characteristics of relevant seizure types as described in Section 
6.3.1.1.1 
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• 
Quantification of seizure severity as described in Section 6.3.1.1.3 
• 
Quantification of seizure duration as described in Section 6.3 .1.1.3 
67 
It is anticipated that training on the above topics will allow the parent(s)/caregiver(s) and 
subject (if applicable) to completely and accurately record seizure activity. The Investigator 
is responsible for ensuring that the parent(s)/caregiver(s) and subject (if applicable) are 
properly trained to complete the diary. Competency will be confirmed by review of diary 
entries with parent(s)/caregiver(s) and subject (if applicable) at each study center visit (see 
Table 1) so the Investigator and study center staff can monitor the quality of record-keeping. 
The subject seizure and dosing diary for this study was designed to satisfy current FDA 
guidance regarding PROs (i.e., the Guidance for Industry Patient-Reported Outcome 
Measures: Use in Medical Product Development to Support Labeling Claims). 
6.3.1.1.1 
Seizure Type Identification 
Characteristics of the seizure types to be observed and recorded for efficacy assessments (i.e., 
subject/caregiver diaries) include: 
• 
Tonic: body stiffening, upward deviation of the eyes, pupil dilation, and altered 
respiratory patterns 
• 
Atonic: brief loss of muscle tone and consciousness, that may result in an abrupt fall 
• 
Myoclonic: sudden muscle jerks and including infantile spasms 
• 
Tonic-clonic: jerking preceded by stiffening 
• 
Clonic: repeated jerking 
• 
Absence: lapses of awareness, sometimes with staring 
• 
Febrile: seizure of various types (especially tonic-clonic) associated with high fever 
• 
Focal: typically involving 1 side and/or region of the body, twitching, and grimacing 
• 
Atypical absence: staring (as in an absence seizure), but subject may also be 
somewhat responsive. 
These observable characteristics will be utilized to assist the parents(s)/caregiver(s) and 
subject (if applicable) in categorizing seizures types in the subject seizure and dosing diary. 
The Investigator will fully train the parents(s)/caregiver(s) and subject (if applicable) in 
methods to identify seizure type. 
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6.3.1.1.2 
Seizure Severity Assessment 
Subject/caregiver diaries will also be utilized to record seizure severity. Overall, seizure 
severity will be captured using the CGI-S as described in Section 6.3.3. This scale will be 
completed as noted in Table 1. 
Seizure severity will be determined by the parent(s)/caregiver(s). In the subject seizure and 
dosing diary, the Investigators will work with the parent(s)/caregiver(s) to record an 
assessment of seizure severity based on the following: 
• 
Postictal events and duration 
• 
Occurrence of injuries 
• 
Overall functional impairment. 
The Investigator and study center staff are expected to provide appropriate training to 
subjects and/or the parent(s)/caregiver(s) regarding data to be collected. 
6.3.1.1.3 
Seizure Duration Assessment 
68 
Seizure duration will be quantified by approximate timing by the caregiver or other observer, 
and recorded in the subject seizure and dosing diary. The Investigator and study center staff 
are expected to provide appropriate training to subjects and/or their parent(s)/caregiver(s) 
regarding recording seizure duration. 
6.3.2 
Additional Information to be Recorded in Subject Seizure and Dosing Diary 
The subject seizure and dosing diary will include a record of the date and time of each 
administration of the investigational product in the one week prior to Visits 8, 9, and 10. 
6.3.3 
Qualitative Assessments 
In this study, the global status of each subject will be monitoring using a set of qualitative 
assessment tools administered at specified visits: 
• 
CGI-I 
• 
CGI-S 
• 
IPES 
• 
VABS 
• 
C-SSRS (for subjects ?:.7 years of [ developmental] age). 
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Study center staff will be trained in the administration of these scales during the Investigator 
Meeting(s). 
6.3.4 
Efficacy-related Data to be Reported 
For this study, efficacy data will be collected, analyzed, and reported, but will not be 
considered as study endpoints. These data include the following and will include only data 
collected during this study: 
• 
Frequency, duration, and severity of seizures (i.e., seizure control) 
• 
Parent(s)/caregiver(s) CGI-I and CGI-S 
• 
Investigator CGI-I and CGI-S 
• 
IPES and V ABS scores 
• 
C-SSRS 
The above scales will be administered to subjects as per their chronological or developmental 
age as discussed in Section 3.1. Subjects enrolled from INSOI 1-15-054 will be excluded 
from IPES, V ABS, and C-SSRS scores evaluation. 
6.4 
Appropriateness of Measurements 
All assessments will be performed using methods that are considered standard and 
appropriate. 
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7.0 QUALITY CONTROL AND QUALITY ASSURANCE 
70 
According to the ICH Guidelines of GCP (CPMP/ICH/135/95), the Sponsor is responsible 
for implementing and maintaining quality assurance and quality control systems with written 
standard operating procedures (SOPs). 
Quality control will be applied to each stage of data handling. 
The following steps will be taken to ensure the accuracy, consistency, completeness, and 
reliability of the data: 
• 
Investigator and study center staff familiarity with GCP/ICH 
• 
Investigator Meeting(s), including protocol and study systems training 
• 
Instruction manuals for investigational product, IVRS, EDC, and any other systems 
included in study operation 
= 
• 
Study Center Initiation Visit 
• 
Early study center visit following enrollment of the first subject 
• 
Routine study center monitoring 
• 
Ongoing study center communication and training 
• 
Data management quality control checks 
• 
Continuous data acquisition and cleaning 
• 
Internal review of data 
• 
Quality control check of the final clinical study report (CSR). 
In addition, the Sponsor and/or designee may conduct periodic audits of the study processes, 
including, but not limited to the study center, study center visits, central laboratories, 
vendors, clinical database, and final CSR. When audits are conducted, access must be 
authorized for all study related documents including medical history and concomitant 
medication documentation to authorized Sponsor's representatives and regulatory authorities. 
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7 .1 
Monitoring 
The Sponsor may engage the services of a contract research organization (CRO) to perform 
all monitoring functions within this clinical study. Monitoring will occur according to GCP 
and the designee's monitors will work in accordance with their SOPs and have the same 
rights and responsibilities as monitors from the Sponsor. Monitors will establish and 
maintain regular contact between the Investigator and the Sponsor. 
71 
Monitors will evaluate the competence of the study center, informing the Sponsor about any 
problems relating to facilities, technical equipment or medical staff. During the study, 
monitors will check that written informed consent has been obtained from all subjects 
correctly and that data are recorded correctly and completely. Monitors are also entitled to 
compare entries in eCRFs with corresponding source data and to inform the Investigator of 
any errors or omissions. Monitors will also control adherence to the protocol at the study 
center. They will arrange for the supply of investigational product and ensure appropriate 
storage conditions are maintained. 
Monitoring visits will be conducted according to all applicable regulatory requirements and 
standards. Regular monitoring visits will be made to each center while subjects are enrolled 
in the study. The monitor will make written reports to the Sponsor on each occasion contact 
with the Investigator is made, regardless of whether it is by phone or in person. 
During monitoring visits, all entries in the eCRFs will be compared with the original source 
documents (source data verification). 
7.2 
Data Management/Coding 
Data generated within this study will be handled according to the relevant SOPs of the data 
management and biostatistics departments of the Sponsor or designee. 
A Code of Federal Regulations (CFR) Title 21, Part I I-compliant EDC system will be used 
for this study, meaning that all eCRF data will be entered in electronic forms at the study 
center. The eCRFs will be produced by the Sponsor or designee for each subject. Where 
eCRFs are not possible, the source data will be captured on paper. 
Data collection will be completed by authorized study center staff designated by the 
Investigator. Appropriate training and security measures will be completed with the 
Investigator and all authorized study center staff prior to the study being initiated and any 
data being entered into the system for any study subjects. 
All data must be entered in English. The eCRFs should always reflect the latest observations 
on the subjects participating in the study. Therefore, the eCRFs are to be completed as soon 
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as possible during or after the subject's visit. To avoid inter-observer variability, every effort 
should be made to ensure that the same individual who made the initial baseline 
determinations completes all plasma level and safety evaluations. The Investigator must 
verify that all data entries in the eCRFs are accurate and correct. If some assessments are not 
done, or if certain information is not available or not applicable or unknown, the Investigator 
should indicate this in the eCRF. The Investigator will be required to electronically sign off 
on the clinical data. 
The monitor will review the eCRFs and evaluate them for completeness and consistency. 
The eCRF will be compared with the source documents to ensure that there are no 
discrepancies between critical data. All entries, corrections and alterations are to be made by 
the responsible Investigator or designee. The monitor cannot enter data in the eCRFs. Once 
clinical data of the eCRF have been submitted to the central server, corrections to the data 
fields will be audit trailed, meaning that the reason for change, the name of the person who 
performed the change, together with time and date will be logged. Roles and rights of the 
study center staff responsible for entering the clinical data into the eCRF will be determined 
in advance. If additional corrections are needed, the responsible monitor or Data Manager 
will raise a query in the EDC application. The appropriate study center staff will answer 
queries sent to the Investigator. This will be audit trailed by the EDC application meaning 
that the name of investigational staff, time and date stamp are captured. 
The eCRF is essentially considered a data entry form and should not constitute the original 
( or source) medical records unless otherwise specified. Source documents are all documents 
used by the Investigator or hospital that relate to the subject's medical history, that verify the 
existence of the subject, the inclusion and exclusion criteria and all records covering the 
subject's participation in the study. They include laboratory notes, ECG results, memoranda, 
pharmacy dispensing records, subject files, etc. 
The Investigator is responsible for maintaining source documents. These will be made 
available for inspection by the study monitor at each monitoring visit. The Investigator must 
submit a completed eCRF for each subject who receives investigational product, regardless 
of duration. All supportive documentation submitted with the eCRF, such as laboratory or 
hospital records, should be clearly identified with the study and subject number. Any 
personal information, including subject name, should be removed or rendered illegible to 
preserve individual confidentiality. 
The eCRFs will be automatically appended with the identification of the creator, by means of 
their unique UserID. Specified records will be electronically signed by the Investigator to 
document his/her review of the data and acknowledgement that the data are accurate. This 
will be facilitated by means of the Investigator's unique U serID and password; date and time 
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stamps will be added automatically at time of electronic signature. If an entry on an eCRF 
requires change, the correction should be made in accordance with the relevant software 
procedures. All changes will be fully recorded in a protected audit trail, and a reason for the 
change will be required. 
Concomitant diseases/medical history and AEs will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA). Concomitant medications will be coded using the 
World Health Organization's Drug-Dictionary (WHO-DD). 
7.3 
Quality Assurance Audit 
The study center, the study database, and study documentation may be subject to quality 
assurance audits during the course of the study by the Sponsor or a designee on behalf of the 
Sponsor. In addition, inspections may be conducted by regulatory bodies at their discretion. 
The Investigator will ensure the accuracy, completeness, and timeliness of the data recorded 
for data queries and all required reports according to any instructions provided. 
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8.0 
STATISTICS 
8.1 
Determination of Sample Size 
74 
The sample size will be determined by the number of subjects who are eligible to and elect to 
rollover from INSOl 1-14-029 or INSOl 1-15-054. These studies would contribute up to a 
maximum of 60 and 20 subjects respectively. 
8.2 
General Statistical Considerations 
8.2.1 
Statistical Methods and Analysis Plan 
This section describes the planned statistical analyses in general terms. A complete 
description of the methodology will be specified in the SAP. Any changes in the statistical 
methods described in this protocol that occur prior to database lock will be documented in 
the SAP and will not require a protocol amendment. 
8.2.2 
General 
Since this is an extension study ofINSOl 1-14-029 and INSOl 1-15-054 data for INSOl 1-14-
030 will be presented for the extension period only (i.e., not for the entire period spanning 
INSOl 1-14-029 and INSOl l-15-054 and INSOl 1-14-030 studies). 
Categorical variables will be summarized using frequencies and percentages. Continuous 
variables will be summarized using descriptive statistics (number, mean, standard deviation 
[SD], median, minimum, and maximum). 
Baseline for this study will be the same as that defined in protocols INSO 11-14-029 and 
INSOl 1-15-054, respectively. Additionally, all data from this study will also be compared to 
the intra-study baseline ( data from the subject's first visit [i.e., Visit 1 [Screening] or Visit 2 
[Day 1]). For assessments that were not completed in INSOl l-14-029 (i.e., IPES and 
VABS), the only baseline will be data collected at Visit 2 (Day 1) ofINSOl 1-14-030. (Data 
from subjects enrolling through INSOl 1-15-054 may be excluded from the analysis) 
Data collected at unscheduled time points will not be summarized at the unscheduled time 
points. 
Data will be presented for each dose (10, 20, and 40 mg/kg/day) and for all doses combined 
together (overall), corresponding to the dose at which subject will initiate this study (as 
described in Section 4.1 ). When appropriate, raw data will be presented by visit (Visit 1 
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75 
[Screening], Visit 2 [Day 1], Visit 3 [Week 1], Visit 4 [Week 2], then monthly for 3 months, 
and then quarterly thereafter). 
No statistical hypothesis testing is planned for this study. 
A detailed SAP will be finalized prior to database lock. 
8.2.3 
Data to be Analyzed 
The data will be inspected for inconsistencies by performing validation checks. 
All details regarding the statistical analysis and the preparation of tables, listings, and figures 
(TLFs) will be described in the SAP prepared by the Sponsor or by a designee and approved 
by the Sponsor before database lock. 
8.3 
Statistical Considerations 
8.3.1 
Subject Population for Analysis 
The analysis population will be the Safety Population, which will include all subjects who 
receive 2'.:l dose of the investigational product. In the event that a subject receives treatment 
other than that specified in the protocol, safety analyses will be conducted according to the 
treatment the subject actually received. 
All safety-related endpoints and efficacy-related data will be analyzed using the Safety 
Population. 
8.3.2 
Subject Disposition 
The number of subjects who receive each dose and the duration of exposure will be 
summarized for the Safety Population. 
Prior and concomitant therapies will be listed. The frequency and percentage of subjects 
who use prior or concomitant medication will be summarized by preferred term (PT), 
utilizing WHO-DD definition and treatment regimen for each dose and overall. Concomitant 
medications will also be checked for protocol deviations. 
Subjects who take prohibited concomitant medications will be noted in the summary of 
protocol deviations. 
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8.3.3 
Demography and Other Baseline Data 
76 
Demographic data and subject characteristics will be listed and summarized by dose and for 
all subjects using descriptive statistics (mean, number, SD, median, minimum, and maximum 
values for continuous variables and counts and percentages for categorical variables). 
Past and current medical history will be summarized by dose and overall using the system 
organ class (SOC) as coded using the MedDRA coding dictionary. If both a past and current 
( ongoing) medical condition record are indicated for a condition, the condition will be 
presented under current medical conditions only. 
8.3.4 
Safety Analysis 
The assessment of safety will be based on the analyses of AEs, vital signs, 12-lead ECG, and 
clinical laboratory evaluations. All safety analyses will be performed on the Safety 
Population. Safety endpoints are described in Section 6.1.6. 
8.3.4.1 
AEs 
The TEAEs are defined as AEs that first occw· or worsen in severity after the first 
administration of the investigational product. Such AEs will be coded using the MedDRA 
coding dictionary and will be summarized by presenting the number and percentage of 
subjects having any AE, having an AE in each SOC, and having each individual AE as 
reported by PT. Furthermore, a summary for SAEs and summaries by severity and 
relationship to the investigational product will be presented by dose and overall. The most 
frequent (5%) AEs and drug related AEs will also be provided. 
All percentages will be based on the number of subjects in the Safety Population. 
In the summaries, AEs will be counted only once per subject. If a subject reports the same 
AE more than once, it will be counted with its worst severity and closest relationship to 
investigational product. Only those AEs that begin between start and end of study will be 
summarized. 
The AEs will also be listed by subject and dose. 
Subject death due to any cause and subjects with AEs leading to investigational product 
discontinuation will be listed and summarized by dose and overall. 
The proportion of subjects that discontinue investigational product or experience dose 
interruption due to treatment emergent AEs will be summarized by dose and for all subjects. 
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8.3.4.2 
Clinical Laboratory Evaluations 
Proportions of subjects who develop clinical laboratory result abnormalities of interest will 
be summarized by dose and overall. 
77 
Summary statistics (mean, median, SD, minimum value, and maximum value) over time will 
be presented by dose and overall at each visit for the continuous laboratory parameters. 
Descriptive statistics of changes from baseline by visit will also be presented for each dose 
and for all subjects. 
A frequency table of results of categorical laboratory parameters will be produced. 
Furthermore, laboratory abnormalities will be analyzed by shift tables where each subject 
will be counted only once with the worst grade in the summary tables. 
All laboratory data will be listed with abnormal values flagged. 
8.3.4.3 
Vital Sign Measurements 
Vital signs (including the raw data and the changes from baseline) will be listed and 
summarized over time by visit for each dose and overall. Notable values and changes will be 
tabulated. 
8.3.4.4 
ECG Evaluations 
The ECG evaluations will be summarized by visit for each dose and overall. 
Descriptive statistics (number, mean, SD, median, minimum value, and maximum value) of 
the continuous ECG parameters will be presented at each assessment visit for both raw data 
and change from baseline data, respectively, for each dose and overall. Frequency counts 
will be presented by visit for both change and absolute values for each dose and overall. 
Individual listings presenting subjects with flags will be created for both change and absolute 
values. 
8.3.5 
Analysis of Cannabidiol and 7-0H Metabolite Concentrations 
Cannabidiol and 7-OH cannabidiol concentrations will be measured at baseline, after the first 
dose, and periodically thereafter (see Table 1 and Section 6.2). A descriptive summary of 
observed blood concentration (number, mean, SD, minimum value, and maximum value) 
will be displayed at each interval. 
The plasma concentration data from this study may be combined with data collected in 
INS0l 1-14-029 and INS0l 1-15-054 for population PK model development. An independent 
SAP will detail this analysis. 
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8.3.6 
Efficacy Analysis 
Although these data do not represent endpoints for this long-term safety study (see 
Section 6.3), they will be analyzed and reported: 
• 
Frequency, duration, and severity of seizures (i.e., seizure control) 
• 
Parent(s)/caregiver(s) CGI-I and CGI-S 
• 
Investigator CGI-I and CGI-S 
• 
IPES and V ABS scores 
• 
C-SSRS. 
78 
The above scales will be administered to subjects as per their chronological or developmental 
age as discussed in Section 3 .1. Subjects enrolled from INSO 11-15-054 will be excluded 
from IPES, V ABS, and C-SSRS scores evaluation. 
8.3.6.1 
Seizure-related Data 
All seizure-related parameters (in terms of raw data and percentage change from baseline) 
will be listed and summarized by dose and for all subjects using descriptive statistics (mean, 
number, SD, median, minimum, and maximum values for continuous variables). 
No statistical inferential procedures will be performed. 
8.3.6.2 
Qualitative Subject Status Assessments 
All qualitative subject status assessments (CGI-I, CGI-S, IPES, VABS, and C-SSRS related 
parameters) will be listed and summarized by dose and overall using descriptive statistics 
(mean, number, SD, median, minimum, and maximum values for continuous variables). 
No statistical inferential procedures will be performed. 
8.4 
Interim analysis 
An interim analysis may be conducted if deemed necessary. 
8.5 
Handling of Missing Values 
In general, for all analyses, observed values will be used and no imputation will be made for 
missing values. For specific endpoints and special instances, details for handling missing 
values will be described in the SAP. 
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9.0 
ETHICS 
9.1 
Institutional Review Board 
79 
An IRB/IEC must approve the final protocol, including the final version of the ICF and 
Assent Form and any other written information and/or materials to be provided to the 
subjects. The Investigator will provide the Sponsor or a designee with documentation of IRB 
approval of the protocol and informed consent before the study may begin at the study center. 
The Investigator should submit the written approval to the Sponsor or designee before 
enrolment of any subject into the study. 
The Sponsor or a representative should approve any modifications to the ICF that are needed 
to meet local requirements. 
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 ICF, assent form, or 
amendments to the protocol. 
The Investigator will report promptly to the IRB/IEC, any new information that may 
adversely affect the safety of subjects or the conduct of the study. Similarly, the Investigator 
will submit written summaries of the study status to the IRB/IEC annually, or more 
frequently ifrequested by the IRB/IEC. Upon completion of the study, the Investigator will 
provide the ethics committee with a brief report of the outcome of the study, if required. 
9.2 
Ethical Conduct of the Study 
This study will be conducted and informed consent will be obtained according to the ethical 
principles stated in the Declaration of Helsinki (64th General Assembly, Fortaleza, Brazil, 
October 2013), the applicable guidelines for GCP (Committee for Medicinal Products for 
Human Use [CHMP]/ICH/135/95), or the applicable drug, and data protection laws and 
regulations of the country where the study will be conducted. 
GCP is an international ethical and scientific quality standard for designing, conducting, 
recording and reporting studies that involve the participation of human subjects. The study 
will be conducted in compliance with GCP and the applicable national regulations so as to 
assure that the rights, safety and well-being of the participating study subjects are protected 
consistent with the ethical principles that have their origin in the Declaration of Helsinki. 
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9.3 
Subject Information and Informed Consent 
80 
The ICF will be used to explain the risks and benefits of study participation to the subject in 
simple terms before the subject will be entered into the study. The ICF contains a statement 
that the consent is freely given, that the subject is aware of the risks and benefits of entering 
the study, and that the subject is free to withdraw from the study at any time. Written 
consent must be given by the subject and/or legal representative, after the receipt of detailed 
information on the study. 
The Investigator is responsible for ensuring that informed consent is obtained from each 
subject or legal representative and for obtaining the appropriate signatures and dates on the 
ICF and assent form (if applicable) prior to the performance of any protocol procedures and 
prior to the administration of study medication. The Investigator will provide each subject 
with a copy of the signed and dak<l ICF. 
9.3.1 
Subject Assent Guidance 
This study may enroll children as young as 1 year of age (see Section 3.4.1). The IRB/IEC 
must determine, to the extent required by 45 Cr'R §46.116, that adequate provisions are made 
for soliciting the assent of pediatric subjects (when the IRB/IEC judges that they are capable 
of providing assent), as well as the permission of the parents (45 CFR §46.408). Permission 
means the agreement of parent(s) or guardian to the participation of their child or ward in 
research (45 CFR §46.402(c)). Local and regional/state regulations will also be addressed as 
applicable. 
If the IRB/IEC determines that the capability of some or all of the children is so limited that 
they cannot reasonably be consulted regarding assent, or that the intervention or procedure 
involved in the research holds out a prospect of direct benefit that is important to the health 
or well-being of the children, and is available only in the context of the research, the assent 
of the children is not a necessary condition for proceeding with the research. Even where the 
IRB/IEC determines that the subjects are capable of assenting, the IRB/IEC may still waive 
the assent requirement under certain circumstances in accord with 45 CFR §46.116 and 
45 CFR §46.408(a). 
The IRB/IEC and local regulations will determine the age at which assent of subjects in this 
study will not be required. Informed consent from all parent(s)/caregiver(s) will be required. 
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10.0 STUDY ADMINISTRATION 
10.1 Data Handling and Record Keeping 
81 
It is the Investigator's responsibility to maintain essential study documents (protocol and 
protocol amendments, completed eCRFs, signed ICFs, relevant correspondence, and all other 
supporting documentation). 
The US FDA regulations (21 CFR §312.62[c]) and the ICH Guideline for GCP (see 
Section 4.9 of the guideline) require that records and documents pertaining to the conduct of 
this study and the distribution of investigational product, including eCRFs, ICFs, laboratory 
test results, and medication inventory records, must be retained by the Investigator for 
15 years after the last marketing application approval in an ICH region or after at least 
15 years have elapsed since formal discontinuation of clinical development of the 
investigational will notify the Investigator of these events. 
Subject identification codes (subject names and corresponding study numbers) will be 
retained for this same period of time. These documents may be transferred to another 
responsible party, acceptable to Sponsor, who agrees to abide by the retention policies. 
Written notification of transfer must be submitted to Sponsor. The Investigator must contact 
Sponsor prior to disposing of any study records. No records should be disposed of without 
the written approval of the Sponsor. 
10.2 Direct Access to Source Data/Documents 
The Investigator will prepare and maintain adequate and accurate source documents to record 
all observations and other pertinent data for each subject randomized into the study. 
The Investigator will allow the Sponsor, its designee, study monitors, and authorized 
regulatory authorities to have direct access to all documents pertaining to the study, including 
individual subject medical records, as appropriate. 
10.3 Investigator Information 
10.3.1 
Investigator Obligations 
This study will be conducted in accordance with the ICH Harmonized Tripartite Guideline 
for GCP (1997); the US CFR Title 21 parts 50, 56, and 312; and European Legislation; and 
the ethical principles that have their origin in the Declaration of Helsinki. 
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The Investigator agrees to conduct the clinical study in compliance with this protocol after 
the approval of the protocol by the IRB in compliance with local regulatory requirements. 
The Investigator and the Sponsor will sign the protocol to confirm this agreement. 
10.3.2 
Protocol Signatures 
82 
After reading the protocol, each Investigator will sign the protocol signature page and send a 
copy of the signed page to the Sponsor or its representative (Appendix 1). By signing the 
protocol, the Investigator confirms in writing that he/she has read, understands and will 
strictly adhere to the study protocol and will conduct the study in accordance with ICH 
Tripartite Guidelines for GCP and applicable regulatory requirements. The study will not be 
able to start at any center where the Investigator has not signed the protocol. 
10.3.3 
Publication Policy 
The data generated by this study are confidential information of the Sponsor. The Sponsor 
will make the results of the study publicly available. The publication policy with respect to 
the Investigator and study center will be set forth in the Clinical Trial Agreement. 
10.4 Financing and Insurance 
The Sponsor will provide insurance in accordance with local guidelines and requirements as 
a minimum for the subjects participating in this study. The terms of the insurance will be 
kept in the study files. 
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Appendix 1: Signature of Investigator 
83 
PROTOCOL TITLE: A multicenter, open-label, flexible dose study to assess the long-
term safety of pharmaceutical Cannabidiol Oral Solution as an 
adjunctive treatment for pediatric subjects with a treatment-resistant 
seizure disorder who complete INS0l 1-14-029, or Part A in 
INS0l l-15-054 -
PROTOCOL NO: 
INS0l 1-14-030, Amendment 5 
This protocol is a confidential communication of Insys Development Company, Inc. I 
confirm that I have read this protocol, I understand it, and I will work according to this 
protocol. I will also work consistently with the ethical principles that have their origin in the 
Declaration of Helsinki and that are consistent with good clinical practices and the applicable 
laws and regulations. Acceptance of this document constitutes my agreement that no 
unpublished information contained herein will be published or disclosed without prior 
written approval from Insys Development Company, Inc. 
Instructions to the Investigator: Please SIGN and DATE this signature page. PRINT your name, title, and the 
name of the center in which the study will be conducted. Return the signed copy to Insys Development 
Company, Inc. 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
Signature of Investigator: 
Date: - ----
Printed Name: 
Investigator Title: 
Name/ Address of Center: 
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51 Consroe P, Laguna J, Allender J, et al. Controlled clinical trial of cannabidiol in Huntington's disease. 
Pharmacol Biochem Behav. 1991;40:701-708. 
52 Stott CG, White L, Wright S, Wilbraham D, Guy GW. A phase I study to assess the single and multiple dose 
pharmacokinetics ofTHC/CBD oromucosal spray. Eur J Clin Pharmacol 2013;69: 1135-J 147. 
53 Jones G, Pertwee RG. A metabolic interaction in vivo between cannabidiol and 1 -tetrahydrocannabinol. Br J 
Pharmacol. 1972;45:375-377. 
54 Zuardi AW, Morais SL, Guimaraes FS, Mechoulam R. Antipsychotic effect of cannabidiol. J Clin Psychiatry. 
1995;56:485-486. 
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55 Zuardi AW, Cosme RA, GraeffFG, Guimaraes FS. Effects ofipsapirone and cannabidiol on human 
experimental anxiety. J Psychopharmacol. 1993a;7:82-88. 
56 Borgwardt SJ, Allen P, Bhattacharyya S, et al. Neural Basis ofDelta-9-Tetrahydrocannabinol and 
Cannabidiol: Effects During Response Inhibition. Biol Psychiatry. 2008;64:966-973. 
57 Zuardi AW. Cannabidiol: from an inactive cannabinoid to a drug with wide spectrum of action. Rev Bras 
Psiquiatr. 2008;30:271-280. 
58 Gloss D, Vickrey B. Cannabinoids for epilepsy. Cochrane Database Syst Rev. 2014;5;3:CD009270. 
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59 Gong H Jr, Tashkin DP, Simmons MS, Calvarese B, Shapiro BJ. Acute and subacute bronchial effects of oral 
cannabinoids. Clin Pharmacol and Ther. 1984;35:26-32. 
60 Zuardi AW, Hallak JE, Dursun SM, et al. Cannabidiol monotherapy for treatment-resistant schizophrenia. J 
Psychopharmacol. 2006;20:683-686. 
61 Zuardi A, Crippa J, Dursun S, Morais S, Vilela J, Sanches R, et al. Cannabidiol was ineffective for manic 
episode of bipolar affective disorder. J Psychopharmacol. 2010;24:135-137. 
62 Wilmshurst JM, Berg AT, Lagae L, Newton CR, Cross JH. The challenges and innovations for therapy in 
children with epilepsy. Nat Rev Neurol. 2014;10(5):249-60. 
63 Joshi SM, Singh RK, Shellhaas RA. Advanced Treatments for Childhood Epilepsy. JAMA Pediatr. 
2013;167:76-83. 
64 Hill AJ, Hill TDM, Whalley BJ. The development of cannabinoid based therapies for epilepsy. In: Murillo-
Rodriguez E, ed. Endocannabinoids: Molecular, Pharmacological, Behavioral and Clinical Features. Oak 
Park, IL: Bentham Science Publishers; 2013:164-204. 
65 LaRoche SM, Helmers SL. The new anti-epileptic drugs: scientific review. JAMA. 2004;291:605-614. 
66 Skjei KL and Dlugos DJ. The evaluation of treatment-resistant epilepsy. Semin Pediatr Neurol. 2011 
Sep; 18(3): 150-170. 
67 Kwan P, Arzimanoglou A, Berg AT, et al. Definition of drug resistant epilepsy: consensus proposal by the ad 
hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia. 2010;5 l: 1069-77. 
68 Arzimanoglou A, French J, Blume W, Cross J, Ernst J, Feucht M, et al. Lennox-Gastaut syndrome: a 
consensus approach on diagnosis, assessment, management, and trial methodology. Lancet Neurol. 
2009;8:82-93. 
69 Crumrine P. Management of seizures in Lennox-Gastaut syndrome. Paediatr Drugs. 2011;13:107-118. 
70 Hancock E., Cross H. Treatment ofLennox-Gastaut syndrome. Cochrane Database Syst Rev 
8:2009;CD003277. 
71 Dravet C. The core Dravet syndrome phenotype. Epilepsia. 2011;52(Suppl):3-9. 
72 Casse-Perrot C, WolffM, Dravet C. (2001) Neuropsychological aspects of severe myoclonic epilepsy in 
infancy. In Jambaque I, Lassonde M, Dulac O (Eds). The neuropsychology of childhood epilepsy. Plenum 
Press/Kluwer Academic, New York, pp. 131-140. 
73 WolffM, Casse-Perrot C, Dravet C. Severe myoclonic epilepsy of infants (Dravet syndrome): Natural history 
and neuropsychological findings. Epilepsia. 2006;47(Suppl):45-48. 
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74 Claes L, Del-Favero J, Ceulemans B, Lagae L, Van Broeckhoven C, De Jonghe P. De novo mutations in the 
sodium-channel gene SCNIA cause severe myoclonic epilepsy of infancy. Am J Hum Genet. 
2001 ;68: 1327-1332. 
75 Marini C, Scheffer IE, Nabbout R, Suls A, De Jonghe P, Zara F, Guerrini R. The genetics ofDravet 
syndrome. Epilepsia. 2011;52(Suppl):24-29. 
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76 Scheffer IE. Diagnosis and long-term course ofDravet syndrome. Eur J PaediatrNeurol. 2012;16 Suppl l:S5-
8. 
77 Devinsky 0, Cilio MR, Cross H, Fernandez-Ruiz J, French J, Hill C, et al. Cannabidiol: Pharmacology and 
potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia. 2014;55(6):791-802. 
78 Breau GM, Camfield CS, Camfield PR, Breau LM. Evaluation of the responsiveness of the Impact of 
Pediatric Epilepsy Scale. Epilepsy Behav. 2008; 13 :454-457. 
79 Camfield C, Breau L, Camfield P. Impact of pediatric epilepsy on the family: a new scale for clinical and 
research use. Epilepsia 2001 ;42: 104-112. 
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9.8 
Changes in the Conduct of the Study or Planned Analyses 
9.8.1 
Changes in the Conduct of the Study 
The original protocol dated 27 October 2014 was amended four times.  Protocol 
Amendments 1 and two were instituted before the first subject was enrolled.  Copies of the 
protocol and protocol amendments are provided in Appendix 16.1.1.  Brief summaries of the 
nonadministrative changes are outlined below. 
9.8.1.1 
Protocol Amendment 1 
Amendment 1 dated 11 December 2014 implemented the following changes: 
• 
Updated planned number of subjects to remove eight additional subjects from 
INS011-14-029; 
• 
Modified exclusion criteria as follows:  
− Clarified exclusionary anoxic episodes; 
− Removed exclusion based on neurometabolic, neurodegenerative, or progressive 
neuro-oncological disease;  
− Added exclusion based on suicidal ideation. 
• 
Retitled the Safety Review Committee as a Medical and Safety Data Review; 
• 
Updated the schedule of events to reflect changes to the protocol;  
• 
Clarified that all study procedures performed during scheduled study visits should occur 
prior to administration of study drug; 
• 
Changed Adverse Event guidelines from the Common Terminology Criteria for Adverse 
Events to the MedDRA; 
• 
Added valproic acid and phenobarbital to Appendix 2: CYP3A4-Related Prohibited 
Medications; 
• 
Added all scales to Appendix 4: Scales. 
9.8.1.2 
Protocol Amendment 2 
Amendment 2 dated 07 August 2015 implemented the following changes: 
• 
Clarified study duration to include provision to retain subjects on-study until marketing 
approval in the US; 


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• 
Updated information regarding formulation of the investigational product; 
• 
Updated the schedule of assessments as follows: 
− Added a review of subject eligibility in the event of a prolonged (> 14-day) gap in 
administration of the investigational product; 
− Removed a subset of qualitative assessments; 
− Updated period in which subject diary data was collected. 
9.8.1.3 
Protocol Amendment 3 
Amendment 3 dated 08 April 2016 implemented the following changes: 
• 
Added Australia as a clinical conduct country; 
• 
Updated inclusion criterion #3 to allow the Investigator to judge medical stability of 
subjects; 
• 
Updated inclusion criterion #4 to note that special monitoring was required for subjects 
taking drugs metabolized by CYP enzymes (see Section 9.4.7.2); 
• 
Updated inclusion criteria #5 and #6 language regarding required contraception; 
• 
Removed eligibility criteria that excluded subjects who were taking concomitant 
medications that are strong CYP3A4 inhibitors or inducers or CYP3A4-sensitive 
substrates with a narrow therapeutic index or who had sleep apnea; 
• 
Updated exclusion criterion #6, schedule of assessments, and throughout protocol to note 
that C-SSSR was to be utilized for appropriate subjects (from a developmental age 
perspective); 
• 
Added that clinical impression of suicidality was to be utilized in place of the C-SSRS for 
subjects < 7 years of age; 
• 
Updated that the dose of the investigational product could be increased to a maximum 
dose of 40 mg/kg/day; 
• 
Updated the schedule of assessments to include collection of plasma level samples for 
Visit 5, Visit 6, and Visit 7; 
• 
Clarified that dose of the investigational product may be adjusted based on changes in 
subject weight; 
• 
Clarified that background AEDs, ketogenic diet, and VNS settings could have been 
adjusted as needed for seizure control and tolerability as per the Investigator’s judgement; 


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• 
Clarified that date and time of administration of the investigational product, and the 
frequency, duration and severity of seizures were only required to be recorded for 
one week prior to Visit 8, Visit 9, and Visit 10; 
• 
Removed the following as prohibited medications and foods:   
− Medication (s) that are strong CYP3A4 inhibitors or inducers or CYP3A4-sensitive 
substrates with a narrow therapeutic index; 
− Corticotrophins; 
− Systemic steroid therapy (excluding inhaled medication for asthma treatment) or any 
other daily medications known to exacerbate epilepsy; 
− Felbamate (if used for at least six months); 
− Consumption of grapefruit, grapefruit juice, Seville oranges, Seville orange 
marmalade, or other products containing grapefruit or Seville oranges. 
• 
Updated to allow for new AEDs to be added to background therapy; 
• 
Clarified that developmental capability, rather than chronological age, were to be used to 
determine whether the subject completed the CGI-S for themselves; 
• 
Updated identifying description of myoclonic seizures. 
9.8.1.4 
Protocol Amendment 4 
Amendment 4 dated 05 October 2016 implemented the following changes: 
• 
Removed Australia as a clinical conduct country; 
• 
Allowed subjects from INS011-15-054 to rollover into this study after completion of 
Part A (Visit 6);  
• 
Removed all references to INS011-14-024 and INS011-14-025; 
• 
Reduced the number of study centers from 45 to 10; 
• 
Allowed study centers to collect diet information, including time of closest meal to 
administration of the investigational product and use of ketogenic diet; 
• 
Added recommendations regarding administration of the investigational product with 
regards to timing of meals; 
• 
Reduced sample size from 232 to 80 subjects; 


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• 
Updated exclusion criterion #4 to allow Investigators to enroll subjects with clinically 
significant abnormal lab values that the Investigator judged acceptable and to have no 
impact on subject safety; 
• 
Allowed Investigators to adjust subject dose at any time as long as the maximum dose did 
not exceed 40 mg/kg/day; 
• 
Excluded subjects enrolling from INS011-15-054 from completing IPES, VABS, and 
C-SSRS evaluations; 
• 
Restricted conduct of the VABS assessment to Visit 2 and Visit 10; 
• 
Added guidance regarding the circumstances under which a seizure was considered an 
AE; 
• 
Removed the following as prohibited medications for subjects diagnosed with DS:   
− Carbamazepine; 
− Eslicarbazepine; 
− Oxcarbazepine; 
− Lamotrigine; 
− Phenytoin. 
9.8.1.5 
Administrative Change 1 
Administrative Change 1 dated 01 November 2016 removed all references to adult subjects 
or subjects > 18 years were removed from the protocol. 
9.8.1.6 
Protocol Amendment 5 
Amendment 5 dated 06 March 2017 implemented the following change: 
• 
Added a description of dose tapering procedures for subjects who were not continuing to 
receive the investigational product under an Investigator IND Expanded Access Program;  
• 
Specified that dose tapering should be planned in advance to allow sufficient time to 
complete the taper prior to Visit 10 at 48 weeks (±10 days). 


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9.8.2 
Changes in the Planned Analyses 
Changes that were made to the planned analyses after the finalization of the SAP were as 
follows: 
• 
Given that an Investigator could have chosen to down-titrate or up-titrate subjects to any 
dose, results were not analyzed and presented “by dose and overall” as was stated in the 
protocol.  On 13 October 2016, it was decided that summaries should only be presented 
by age category and overall as described in Sections 9 to 17 of the SAP 
(Appendix 16.1.9). 

SAP_001.pdf: 
 
16.1.9 
Documentation of Statistical Methods 
Document 
Document Date 
Statistical Analysis Plan 
04 April 2017 
Pharmacokinetic Statistical Analysis Plan 
11 July 2017 
 
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STATISTICAL ANALYSIS PLAN: PROTOCOL INS011-14-030 
Page 1 of 40 
STATISTICAL ANALYSIS PLAN 
INS011-14-030 / NCT02318602
A MULTICENTER, OPEN-LABEL, FLEXIBLE DOSE STUDY TO ASSESS THE LONG-
TERM SAFETY OF PHARMACEUTICAL CANNABIDIOL ORAL SOLUTION AS AN 
ADJUNCTIVE TREATMENT FOR PEDIATRIC SUBJECTS WITH A TREATMENT-
RESISTANT SEIZURE DISORDER WHO COMPLETE INS011-14-029 OR PART A 
OF INS011-15-054 
AUTHOR: 
 
VERSION NUMBER AND DATE: FINAL V1.0, 04APR2017 
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STATISTICAL ANALYSIS PLAN SIGNATURE PAGE 
Statistical Analysis Plan Final v1.0 (Dated 04APR2017) for Protocol INS011-14-030 V5.0 (Dated 06MAR2017). 
 
 
Name 
Signature 
Date 
Author: 
 
 
 
DDMMMYYYY 
 
Position: 
 
 
Company: 
 
 
Upon review of this document, the undersigned approves this version of the Statistical Analysis Plan, authorizing 
that the content is acceptable for the reporting of this study. 
 
Name 
Signature 
Date 
Approved By: 
 
 
DDMMMYYYY 
 
Position: 
 
 
Company: 
Insys Development Company, Inc. 
 
Approved By: 
 PhD 
 
DDMMMYYYY 
 
Position: 
 
 
Company: 
Insys Development Company, Inc. 
 
Approved By: 
 MD, PhD 
 
DDMMMYYYY 
 
Position: 
 
 
Company: 
Insys Development Company, Inc. 
 
 
 
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TABLE OF CONTENTS 
1. 
INTRODUCTION ........................................................................................................................................... 10 
2. 
STUDY OBJECTIVES ................................................................................................................................... 10 
2.1. 
Primary Objective................................................................................................................................... 10 
2.2. 
Secondary Objectives ............................................................................................................................. 10 
3. 
STUDY DESIGN ............................................................................................................................................. 10 
3.1. 
General Description ................................................................................................................................ 10 
3.2. 
Schedule of Events ................................................................................................................................. 11 
3.3. 
Changes to Analysis from Protocol .......................................................................................................... 11 
4. 
PLANNED ANALYSES ................................................................................................................................ 12 
4.1. 
Data Monitoring Committee (DMC) ........................................................................................................ 12 
4.2. 
Interim Analysis ..................................................................................................................................... 12 
4.3. 
Final Analysis ......................................................................................................................................... 12 
5. 
ANALYSIS POPULATIONS ........................................................................................................................ 12 
5.1. 
All Subjects Enrolled Population ............................................................................................................. 12 
5.2. 
Safety Analysis Population ..................................................................................................................... 12 
6. 
GENERAL CONSIDERATIONS ................................................................................................................ 13 
6.1. 
Reference Start Date and Study Day ....................................................................................................... 13 
6.2. 
Baseline ................................................................................................................................................. 13 
6.3. 
Retests, Unscheduled Visits and Early Termination Data ......................................................................... 14 
6.4. 
Windowing Conventions ........................................................................................................................ 14 
6.5. 
Statistical Tests ...................................................................................................................................... 15 
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6.6. 
Common Calculations ............................................................................................................................. 15 
6.7. 
Software Version .................................................................................................................................... 15 
7. 
STATISTICAL CONSIDERATIONS ......................................................................................................... 15 
7.1. 
Multicenter Studies ................................................................................................................................ 15 
7.2. 
Missing data ........................................................................................................................................... 15 
7.3. 
Multiple Comparisons/ Multiplicity ........................................................................................................ 15 
7.4. 
Examination of Subgroups ...................................................................................................................... 15 
8. 
OUTPUT PRESENTATIONS ..................................................................................................................... 16 
9. 
DISPOSITION AND WITHDRAWALS ................................................................................................... 16 
10. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ................................................. 17 
10.1. 
Derivations ......................................................................................................................................... 18 
11. 
SURGICAL AND MEDICAL HISTORY ................................................................................................... 18 
12. 
PRIOR AND CONCOMITANT PROCEDURES .................................................................................... 18 
13. 
PRIOR AND CONCOMITANT MEDICATIONS ................................................................................... 19 
14. 
STUDY MEDICATION EXPOSURE ......................................................................................................... 20 
14.1. 
Derivations ......................................................................................................................................... 21 
15. 
STUDY MEDICATION COMPLIANCE ................................................................................................... 21 
15.1. 
Derivations ......................................................................................................................................... 21 
16. 
PHARMACOKINETIC AND EFFICACY OUTCOMES ........................................................................ 21 
16.1. 
Pharmacokinetic ................................................................................................................................. 21 
16.2. 
Efficacy Outcomes .............................................................................................................................. 21 
16.2.1. 
Seizures-Related Data ...............................................................................................................................22 
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16.2.1.1. 
Seizures-Related Variable(s) & Derivation(s) ....................................................................................22 
16.2.1.2. 
Missing Data Methods for Seizures-Related Variable(s) ..................................................................23 
16.2.1.3. 
Analysis of Seizures-Related Variable(s) ...........................................................................................23 
16.2.2. 
Qualitative Subject Status Assessments ...................................................................................................24 
16.2.2.1. 
Qualitative Subject Status Variables & Derivations ..........................................................................24 
16.2.2.2. 
Missing Data Methods for Qualitative Subject Status Variable(s) ....................................................25 
16.2.2.3. 
Analysis of Qualitative Subject Status Variables ...............................................................................25 
17. 
SAFETY OUTCOMES ................................................................................................................................... 26 
17.1. 
Adverse Events ................................................................................................................................... 26 
17.1.1. 
All TEAEs ...................................................................................................................................................26 
17.1.1.1. 
Severity .............................................................................................................................................26 
17.1.1.2. 
Relationship to Study Medication ....................................................................................................26 
17.1.2. 
TEAEs Leading to Interruption of Study Medication.................................................................................27 
17.1.3. 
TEAEs Leading to Discontinuation of Study Medication ...........................................................................27 
17.1.4. 
Serious Adverse Events .............................................................................................................................27 
17.1.5. 
Adverse Events Leading to Death .............................................................................................................27 
17.1.6. 
Adverse Events of Special Interest (AESIs) ................................................................................................27 
17.1.7. 
CTC Grading for Adverse Events ...............................................................................................................27 
17.2. 
Deaths ................................................................................................................................................ 28 
17.3. 
Laboratory Evaluations ....................................................................................................................... 28 
17.3.1. 
Laboratory Reference Ranges and Markedly Abnormal Criteria ..............................................................28 
17.3.2. 
CTC Grading for Laboratory Data ..............................................................................................................29 
17.4. 
ECG Evaluations .................................................................................................................................. 29 
17.4.1. 
ECG Markedly Abnormal Criteria ..............................................................................................................30 
17.5. 
Vital Signs ........................................................................................................................................... 30 
17.5.1. 
Vital Signs Markedly Abnormal Criteria ....................................................................................................31 
17.6. 
Physical and Neurological Examination ............................................................................................... 32 
17.7. 
Columbia Suicide Severity Rating Scale (C-SSRS) and Vineland Adaptive Behavior Scales (VABS) .......... 32 
17.7.1. 
Variables & Derivations ............................................................................................................................32 
17.7.2. 
Missing Data Methods ..............................................................................................................................33 
17.7.3. 
Analysis of Variables .................................................................................................................................33 
18. 
DATA NOT SUMMARIZED OR PRESENTED ..................................................................................... 33 
19. 
REFERENCES ................................................................................................................................................ 35 
APPENDIX 1. PARTIAL DATE CONVENTIONS ......................................................................................... 36 
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Algorithm for Treatment Emergence of Adverse Events: .................................................................................... 36 
Algorithm for Prior / Concomitant Medications: ................................................................................................ 37 
APPENDIX 2. ADVERSE EVENTS OF SPECIAL INTEREST PREFFERED TERMS ....................... 39 
APPENDIX 3. LABORATORY TESTS ............................................................................................................. 39 
 
 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
Abbreviation  
Definition  
ACS 
Abnormal, clinically significant 
AE  
adverse event  
AED  
antiepileptic drug  
ALT  
alanine aminotransferase  
ANCS 
Abnormal, not clinically significant 
AST  
aspartate aminotransferase  
β-hCG  
β human chorionic gonadotropin  
BLQ 
Below the lower limit of quantification 
BUN  
blood urea nitrogen  
CBD 
Cannabidiol 
CGI-I  
Clinical Global Impression of Improvement  
CGI-S  
Clinical Global Impression of Severity  
C-SSRS  
Columbia-Suicide Severity Rating Scale  
CTC 
Common toxicity grading 
CTMS 
Clinical trial management system 
DMC 
Data monitoring committee 
DS  
Dravet syndrome  
ECG  
electrocardiogram  
eCRF  
electronic case report form  
ENR 
Enrolled population 
FSH  
follicle-stimulating hormone  
GGT  
gamma glutamyl transferase  
IP 
Investigational product 
IPES  
Impact of Pediatric Epilepsy Scale  
IS 
infantile spasms 
LFT  
liver function test  
LGS  
Lennox-Gastaut Syndrome  
MedDRA  
Medical Dictionary for Regulatory Activities  
OH  
hydroxy  
PK  
pharmacokinetics  
PRO  
patient reported outcome  
PT  
preferred term  
RBCs  
red blood cells  
SAE  
serious adverse event  
SAF 
Safety population 
SAP  
Statistical Analysis Plan  
SD 
standard deviation 
SOC  
system organ class  
TEAE  
treatment-emergent adverse event  
ULQ 
Above the upper limit of quantification 
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VABS  
Vineland Adaptive Behavior Scale, Second Edition – Survey Interview 
Form including the Maladaptive Behavior Index  
WBCs  
white blood cells  
WHO-DD  
World Health Organization’s Drug-Dictionary  
 
 
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1. INTRODUCTION 
This document describes the rules and conventions to be used in the presentation and analysis of efficacy, plasma 
level, and safety data for Protocol INS011-14-030. It describes the data to be summarized and analyzed, including 
specifics of the statistical analyses to be performed.  
This statistical analysis plan (SAP) is based on protocol version 5.0, dated October 5, 2016. Protocol INS011-14-030 
is a 48-week, phase 3b extension study of Protocols INS011-14-029 and INS011-15-054 Part A.  
2. STUDY OBJECTIVES 
2.1. 
PRIMARY OBJECTIVE 
 
The primary objective is to assess the long-term safety of Cannabidiol (CBD) Oral Solution as an adjunctive 
treatment for subjects with treatment-resistant seizure disorders, including Lennox-Gastaut syndrome (LGS), 
Dravet syndrome (DS) or infantile spasms (IS). 
2.2. 
SECONDARY OBJECTIVES 
The secondary objectives are: 
 
To establish the continued efficacy of Cannabidiol Oral Solution in maintaining seizure control in subjects with 
treatment-resistant seizures that previously completed INS011-14-029 or Part A (Visit 6) in INS011-15-054. 
 
To assess the global status of subjects taking Cannabidiol Oral Solution for an extended period of time 
determined by various qualitative assessments. 
 
To monitor for changes in plasma levels of cannabidiol and its 7-OH metabolite during long-term treatment of 
subjects with treatment-resistant seizure disorders, including LGS, DS and IS. 
3. STUDY DESIGN 
3.1. 
GENERAL DESCRIPTION 
This is a multicenter, open-label, flexible dose study to assess the long-term safety of Insys’ pharmaceutical 
Cannabidiol Oral Solution as adjunctive therapy for pediatric subjects with treatment-resistant seizure disorders, 
including LGS, DS, and IS. Plasma levels of cannabidiol and its 7-OH metabolite and efficacy (seizure control and 
qualitative assessments of subject global status) will also be evaluated, although the latter will not be analyzed as 
endpoints. 
Subjects must complete 1 of the following studies to be eligible for the current study: 
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 
Activities through Day 11 in INS011-14-029 
 
Activities through Part A (Visit 6) in INS011-15-054.   
Eligible subjects will also be medically stable without new, clinically significant comorbidities since the Screening Visit 
in the subject’s previous study and satisfy the inclusion/exclusion criteria in protocol Sections 3.4.1 and 3.4.2.   
Subjects should enroll in INS011-14-030 immediately upon completion of the Treatment Period in their previous 
study (to avoid interruption of the investigational product (IP)). Rollover should occur within 2 weeks after 
completion of the Treatment Period in their previous study or when appropriate. A Screening Visit may be required 
for subjects that do not rollover within 14 days of completing their previous study.   
In this study, subjects will be dosed as described below. 
 
Subjects who completed INS011-14-029 will initiate this study on the dose with which they were being 
treated previously, unless tolerability issues were observed for a particular subject.   
 
Subjects who completed Part A in INS011-15-054 will continue treatment with the dose at which they 
were being treated previously, unless tolerability issues were observed for a particular subject.    
Subjects will receive twice daily oral doses of Cannabidiol Oral Solution for approximately 48 weeks or until the IP is 
successfully approved for marketing in the US (whichever occurs earlier), inclusive of their treatment on the previous 
study.  For subjects that completed INS011-14-029, 48 weeks of treatment would be completed under this protocol.  
For subjects that participated in INS011-15-054, duration of treatment in INS011-14-030 will be based on the length 
of time they were enrolled in INS011-15-054 such that total duration of treatment in both studies combined will not 
exceed approximately 48 weeks. Subjects visit entry into INS011-14-030 will be determined at the discretion of the 
sponsor and the investigator. All subjects will complete the Final Visit/Discontinuation Visit regardless of when they 
stop treatment/complete the study. A Follow-up Visit will occur 2 weeks after the Final Visit/Discontinuation Visit. 
If the subject is not going to continue to receive IP offered under the Investigator IND Expanded Access Program, the 
subject may be tapered off Cannabidiol Oral Solution based on the investigator’s preference and subject’s tolerability.  
The investigator should ensure that the taper is planned well in advance to allow sufficient time to complete the 
taper prior to the Visit 10 at 48 weeks (±10 days). The date of entering the Expanded Access Program will be 
documented in the electronic case report form (eCRF). 
3.2. 
SCHEDULE OF EVENTS 
Schedule of events can be found in Section 3.3 and Table 1 of the protocol. 
3.3. 
CHANGES TO ANALYSIS FROM PROTOCOL 
Given that an Investigator may choose to down-titrate or up-titrate subjects to any dose, results will not be 
analyzed and presented “by dose and overall” as currently stated in the protocol. It has been agreed with Insys 
(13Oct2016) that summaries will only be presented by age category and overall as described in this SAP 
(Sections 9 to 17).  
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4. PLANNED ANALYSES 
The following analysis will be performed for this study: 
 
Final Safety and Efficacy Analysis  
 
An Interim analysis may be conducted if deemed necessary.  
4.1. 
DATA MONITORING COMMITTEE (DMC)  
There will be no DMC for this study. 
4.2. 
INTERIM ANALYSIS  
There are no planned interim analyses for this study which require statistical support. Data management will be 
providing Insys with listings periodically for safety reviews. 
4.3. 
FINAL ANALYSIS  
The final, planned analysis identified in this SAP will be performed by 
 Biostatistics following Database 
Lock.  
5. ANALYSIS POPULATIONS 
Agreement and authorization of subjects included/ excluded from each analysis set will be conducted prior to the 
database lock of the study.  
5.1. 
ALL SUBJECTS ENROLLED POPULATION 
The enrolled population (ENR) will contain all subjects who signed an informed consent form for this study. 
5.2. 
SAFETY ANALYSIS POPULATION 
The safety analysis population (SAF) will contain all subjects in the ENR set who received at least one dose of study 
medication. This is an open-label extension study, so all patients are assigned to receive study medication. 
If there is any doubt whether a subject was treated or not, they will be assumed treated for the purposes of 
analysis.  
All safety and efficacy analyses will be performed on the SAF population. 
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6. GENERAL CONSIDERATIONS 
6.1. 
REFERENCE START DATE AND STUDY DAY 
Study Day will be calculated from the reference start date, and will be used to show start/ stop day of assessments 
and events.  
Reference start date is defined as the day of the first dose of study medication, (Day 1 is the day of the first dose 
of study medication), and will appear in every listing where an assessment date or event date appears. 
 
If the date of the event is on or after the reference date then:  
Study Day = (date of event – reference date) + 1. 
 
If the date of the event is prior to the reference date then:  
Study Day = (date of event – reference date). 
 
In the situation where the event date is partial or missing, the date will appear partial or missing in the listings, and 
Study Day, and any corresponding durations will be presented based on the imputations specified in Appendix 2; 
Partial Date Conventions. 
6.2. 
BASELINE 
For this study, subjects will have 2 different baselines defined as follows: 
 
The first one (Baseline 1) will be the same as that defined in their previous study. This baseline was defines 
in the 029 as “baseline is defined as the last non-missing measurement taken prior to reference start date 
(including unscheduled assessments). In the case where the last non-missing measurement and the 
reference start date coincide, that measurement will be considered prior to baseline.  However, AEs and 
medications commencing on the reference start date will be considered post baseline, unless the start 
time of the AE is known to be prior to the first dosing of the study medication.”  
 
The second one (Baseline 2) will be the intra-study baseline, defined as the last non-missing measurement 
prior to the first dose including pre-dose assessments performed on the reference start date. The intra-
study baseline could correspond to: 
o 
Last assessment from the previous study (e.g. Day 11 for subjects from INS011-14-029) 
o 
Screening (Visit 1) assessment of INS011-14-030 
o 
Data collected at Day 1 (Visit 2) of INS011-14-030 
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6.3. 
RETESTS, UNSCHEDULED VISITS AND EARLY TERMINATION DATA 
For by-visit summaries, data recorded at the nominal visit will be presented. Unscheduled measurements will not 
be included in by-visit summaries, but will contribute to the best/ worst case value where required (e.g. shift table).  
In the case of a retest (same visit number assigned), the earliest available measurement for that visit will be used 
for by-visit summaries.  
If the retest measurement occurs prior to the dosing of the first study medication, the retest measurement will be 
used in the summary statistics if it is the last measurement taken prior to the dose.  The retest measurements will 
not be used in summary statistics for post dose measurements. 
Early termination data will be mapped to the next available visit number for by-visit summaries. 
Listings will include scheduled, unscheduled, retest and early discontinuation data. 
6.4. 
WINDOWING CONVENTIONS  
For seizure data only, as the date only is collected on the Subject Diary - Seizure eCRF page, the time points will be 
assigned to each record considering the following visit windowing:  
Table A: 
Study Day Windows 
Assigned Study Day (Inclusive) 
Target Day 
Week Assigned 
From 
To 
 
 
-14 
-1 
N/A 
Screening 
1 
1 
1 
Day 1 
4 
10 
7 
Week 1 
11 
17 
14 
Week 2 
21 
35 
28 
Week 4 
49 
63 
56 
Week 8 
77 
91 
84 
Week 12 
158 
178 
168 
Week 24 
242 
262 
252 
Week 36 
For the final visit/discontinuation visit, the date should match with the last record from Seizure Diary eCRF page. 
No other visit windowing of scheduled time points will be performed for this study.  Data will be summarized based 
on the planned visit schedule.   
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6.5. 
STATISTICAL TESTS 
No statistical inferential procedures will be performed for this study. 
6.6. 
COMMON CALCULATIONS 
For quantitative measurements, change from baseline will be calculated as: 
 
 
Test Value at Visit X – Baseline Value 
6.7. 
SOFTWARE VERSION 
All safety and efficacy analyses will be conducted using SAS® Version 9.2 or higher (SAS Institute, Inc., Cary, North 
Carolina). 
7. STATISTICAL CONSIDERATIONS 
7.1. 
MULTICENTER STUDIES 
This study will be conducted by multiple investigators at multiple centers within the United States. Center pooling 
will not be carried out for use in analyses for this study. 
7.2. 
MISSING DATA 
For safety and efficacy analyses, observed values will be used and no imputation will be made for missing data. 
Missing dates for Adverse Events (AEs) and concomitant medications will be imputed using the rule provided in 
Appendix 1. If the intensity is missing for any AE, its intensity will be classified as Severe in the summary tables.  If 
the assessment of relationship of the AE to study treatment is missing, it will be classified as Related in the frequency 
table of possible related treatment emergent AEs. 
7.3. 
MULTIPLE COMPARISONS/ MULTIPLICITY 
No adjustment for multiplicity will be performed since the analyses of safety and efficacy endpoints are descriptive. 
7.4. 
EXAMINATION OF SUBGROUPS 
No subgroup analyses will be performed for this study. 
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However analyses will be displayed by age category as follows: 
 
Infants = 1 to <2 years of age 
 
Children = 2 to <12 years of age  
 
Adolescents = 12 to ≤17 years of age  
Age categories are based on the subject’s age at the beginning of their previous study. 
In addition, some relevant results observed during the follow-up period (between the Final visit and the Follow-up 
visit) or assessed at the Follow-up visit will be presented by CBD status (i.e. subjects who continue to receive CBD 
after their Final visit versus those who stop receiving CBD after their Final visit). Such analyses are further described 
in the following sections. 
8. OUTPUT 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 by 
 Biostatistics. 
9. DISPOSITION AND WITHDRAWALS 
All subjects who provide informed consent will be accounted for in this study.  
Subject disposition and withdrawals, and protocol violations, including inclusion and exclusion criteria will be 
presented for the ENR set. 
The table will summarize the following information: 
 
Number of subjects screened  
 
Number of screen failures - overall and by following reasons:  
o 
subject did not meet eligibility criteria 
o 
Withdrew informed consent 
o 
Subject died 
o 
Other 
 
Number of treated subjects (SAF) 
 
Number of subjects in the PK 
 
Number of subjects who completed study including follow-up 
 
Number of subjects who discontinued from treatment (overall and by reasons) 
 
Number of subjects with early discontinuation from study (overall and by reasons) 
For both discontinuation from treatment/study the reasons are as follows: 
o 
Inadvertently enrolled (enrollment criteria not met) 
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o 
Investigator decision 
o 
Adverse Event 
o 
Subject withdrew consent 
o 
Lack of protocol compliance 
o 
Subject attempted suicide or is at risk of suicide 
o 
Sponsor decision 
o 
Subject becomes pregnant 
o 
Abnormal laboratory values 
o 
Lost to follow-up 
o 
Death 
o 
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 
10. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic data and other baseline characteristics will be presented for the SAF by age category and overall.  
No statistical testing will be carried out for demographic or other baseline characteristics. 
The following demographic and other baseline characteristics will be reported for this study: 
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 
Age (years) - calculated relative to date of consent 
 
Gender 
 
Race  
 
Ethnicity 
 
Weight (kg) 
 
Height (cm) 
For height and weight, the baseline value of the previous study will be reported for subjects who were enrolled no 
later than 14 days after they completed their previous study. Otherwise, height and weight will be from the 
screening physical examinations for this study. 
10.1. 
DERIVATIONS 
 
Age (years) =  integer portion [(calculated relative to date of signed informed consent – date of 
birth)/365.25] 
11. SURGICAL AND MEDICAL HISTORY 
Past and current surgical and medical history, as recorded on the Medical and Surgical History eCRF page, will be 
summarized by age category and overall using the System Organ Class (SOC) and Preferred Term (PT) as coded 
using the latest version of the Medical Dictionary for Regulatory Activities (MedDRA).  
Past medical and surgical conditions are those which stop prior to the first dose of study medication. If both a past 
and current (ongoing) medical condition records are indicated for a condition, the condition will be presented 
under current medical conditions only. 
A supportive listing will also be provided. 
12. PRIOR AND CONCOMITANT PROCEDURES 
Prior and concomitant procedures, as collected on the Concomitant Procedure eCRF page, will be summarized for 
the SAF, by age category and overall. They will be presented by PT and coded using the latest version of MedDRA. 
 
‘Prior’ procedures are procedures which started and stopped prior to the first dose of study medication.  
 
‘Concomitant’ procedures are procedures which: 
o 
Started prior to, on or after the first dose of study medication and started no later than 6 days 
following end of study medication (Unless the procedure is related to SAE. In such a case the 
procedure can start within 30 days after last study visit.),  
o 
AND ended on or after the date of first dose of study medication or were ongoing at the end of 
the study. 
 
 ‘Post’ procedures are procedures which started later than 6 days following end of study medication. 
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Prior and concomitant procedures observed during the Follow-up period will also be summarized by CBD status. 
Prior and concomitant procedures will also be listed. 
13. PRIOR AND CONCOMITANT MEDICATIONS 
Prior and concomitant medications, as collected on the Concomitant Medication eCRF page, will be summarized 
for the SAF, by age category and overall. They will be presented by PT and coded using the latest version of the 
World Health Organization Drug Dictionary (WHO-DD). 
See Appendix 1 for handling of partial dates for medications. In the case where it is not possible to define a 
medication as prior, concomitant, or post treatment, the medication will be classified by the worst case (i.e. 
concomitant).  
 
‘Prior’ medications are medications which started and stopped prior to the first dose of study medication.  
 
‘Concomitant’ medications are medications which:  
o 
started prior to, on or after the first dose of study medication and started no later than 6 days 
following end of study medication,  
o 
AND ended on or after the date of first dose of study medication or were ongoing at the end of 
the study. 
 
‘Post’ medications are medications which started more than 6 days following the last dose of study 
medication. 
Prior and concomitant medications observed during the Follow-up period will also be summarized by CBD status. 
Prior and concomitant medications will also be listed. 
 
In addition, AED medication(s), including stopping or starting medication(s), may be adjusted throughout the trial 
to maximize seizure control based on tolerability as judged by the investigator. AEDs are recorded on the 
Concomitant Medication eCRF page where the “Reason for medication” is ticked “Antiepileptic drug (AED)”.  
Changes in AED medication(s) will be analyzed as follows: 
 
The number of different AEDs a subject took during the study will be summarized 
 
A bar chart will present the mean number of seizures versus the number of unique AEDs taken during the 
study for each age category and overall and by type of seizures (separate graphs for tonic and atonic 
seizures).  
 
AEDs will be flagged in the listing for all prior and concomitant medications 
As for overall concomitant medications, incidence of AEDs will be summarized for each PTs by age category and 
overall. 
AEDs observed during the Follow-up period will also be summarized by CBD status.  
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14. STUDY MEDICATION EXPOSURE 
Exposure to study medication in days will be presented for the SAF, by age category and overall. The following 
parameters will be summarized: 
 
Modal dose (defined as the dose with the longest exposure),  
 
Total duration of study medication at any dose 
 
Total duration of each dose 
 
Number of subjects dosed per time points 
The date of first study medication administration will be taken from the Study Drug Administration eCRF page. The 
date of last study medication will be taken from the End of Treatment eCRF page. In the case of missing data on 
these eCRF pages, the Subject Diary – Study Medication Record eCRF page will be used in order to determine the 
first and last date of study medication. 
Interruptions, compliance, and dose changes are not taken into account for duration of exposure.  
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 age category 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 
If a subject experiences several dose modifications for the same reason, he will be counted only once for this 
reason. However, in the case a subject experiences several dose modifications due to different reasons, he will be 
counted once for each reason.   
A supportive listing will display all the relevant administration details including data/time/interval of each 
administration, volume planned/administered, reason if dose not administered and amount of water consumed 
after dosing. 
Exposure data coming from the Subject Diary – Study Medication Record eCRF page will also be listed. 
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14.1. 
DERIVATIONS 
The following derivation will be used to calculate the duration of exposure: 
 
Duration of exposure (days) = date of last study medication administration – date of first study medication 
administration + 1.  
A dose modification is defined as any change in dose, dose interruption or dose permanently discontinued. 
15. STUDY MEDICATION COMPLIANCE  
The starting dose of the study medication will be determined by the study previously completed by the subject. 
Dosing of the study medication may be increased or decreased at any dose based on efficacy and tolerability up to 
a maximum of 40 mg/kg/day. 
Noncompliance is defined as taking <80% or >120% of the study medication during any evaluation period (i.e., visit 
to visit). 
Compliance to study medication will be presented for the SAF. 
15.1. 
DERIVATIONS 
Compliance to study medication will be based on the volume of medication and calculated as follows: 
 
 ”Per Visit” Compliance to study medication will be calculated as follows: 
ୗ୳୫ ୭୤ ୟୢ୫୧୬୧ୱ୲ୣ୰ୣୢ ୴୭୪୳୫ୣୱ ୢ୳୰୧୬୥ ୲୦ୣ ୵ୣୣ୩ ୠୣ୤୭୰ୣ ୚୧ୱ୧୲ ଡ଼
ୗ୳୫ ୭୤ ୮୪ୟ୬୬ୣୢ ୴୭୪୳୫ୣୱ ୢ୳୰୧୬୥ ୲୦ୣ ୵ୣୣ୩ ୠୣ୤୭୰ୣ ୚୧ୱ୧୲ ଡ଼ 
 
x 100 
 
The compliance per visit will be summarized and reasons for which dose not administered will be listed. The 
compliance will be clustered as follows: <50%, [50%; 80%[, [80%; 100%[, [100%; 120%], >120%. 
16. PHARMACOKINETIC AND EFFICACY OUTCOMES  
16.1. 
PHARMACOKINETIC 
PK analyses will be described in a separate SAP. 
 
16.2. 
EFFICACY OUTCOMES 
Efficacy related data do not represent endpoints for this long-term safety study but they will be recorded and 
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analyzed in terms of: 
 
Control of seizures (frequency, duration, and severity of seizures compared to each baseline as defined 
Section 6.2) 
 
Qualitative subject status (CGI-S, CGI-I, IPES) 
The analysis of efficacy-related data will be performed for the SAF. 
No statistical inferential procedures will be performed. 
16.2.1. SEIZURES-RELATED DATA 
In this study, seizure frequency, duration, and severity will be assessed to monitor seizure control achieved by 
long-term treatment with Cannabidiol Oral Solution. Seizures will be observed and recorded using a patient 
reported outcome (PRO) instrument (i.e., subject/caregiver diaries). Seizures are collected at week 24, week 36 
and final visit and they will be compared to the baseline from the previous study. 
16.2.1.1. Seizures-Related Variable(s) & Derivation(s) 
The following variables will be used to assess the control of seizures: 
 
Type of seizures: 
o 
Tonic: body stiffening, upward deviation of the eyes, pupil dilation, and altered respiratory 
patterns  
o 
Atonic: brief loss of muscle tone and consciousness, that may result in an abrupt fall  
o 
Myoclonic: sudden muscle jerks and including infantile spasms  
o 
Tonic-clonic: jerking preceded by stiffening  
o 
Clonic: repeated jerking  
o 
Absence: lapses of awareness, sometimes with staring  
o 
Febrile: seizure of various types (especially tonic-clonic) associated with high fever  
o 
Focal: typically involving 1 side and/or region of the body, twitching, and grimacing  
o 
Atypical absence: staring (as in an absence seizure), but subject may also be somewhat 
responsive.  
 
Seizure frequency: 
For tonic and atonic seizures, the number of seizures will be recorded. For other types of seizures, the frequency 
will be reported by range as follows: 
o 
None  
o 
1 to 5 seizures  
o 
6 to 19 seizures  
o 
20 to 50 seizures  
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o 
> 50 seizures. 
 
Seizure severity: 
The assessment of seizure severity will be recorded by the parent(s)/caregiver(s) in the subject seizure and dosing 
diary. Seizure severity will be categorized as: 
o 
Mild 
o 
Moderate 
o 
Severe 
Overall seizure severity will be captured using the CGI-S as described in Section 16.2.2. 
 
Seizure duration: 
The approximate timing of seizure will be recorded by the parent(s)/caregiver(s) in the subject seizure and dosing 
diary. 
16.2.1.2. Missing Data Methods for Seizures-Related Variable(s) 
All data will be evaluated as observed; no imputation method for missing values will be used.  
The eCRF includes the following question on each study day: “Did the subject experience any seizures?”. If the 
response to this question is no, it will be assumed that the subject does not have any seizures on that day.  If the 
question is not answered, it will be not assumed that the subject does not have any seizures that day (i.e., it will 
be assumed that the question is inadvertently not answered). 
16.2.1.3. Analysis of Seizures-Related Variable(s) 
Seizure-related parameters will be summarized as follows: 
 
Number of subjects (and corresponding percentage) that experienced, by maximum severity, a tonic and 
atonic seizure, per time point and age category. 
 
Descriptive statistics (n, mean, SD, median, minimum, and maximum) of the actual number and duration 
of tonic and atonic seizures, by time point and age category. 
 
Descriptive statistics (n, mean, SD, median, minimum, and maximum) of the change from baseline in the 
number and duration of tonic and atonic seizures, by time point and age category. 
 
Number of subjects by maximum severity, maximum number of seizures and seizure duration for each 
other types of seizures by time point and age category.  
 
For each tonic and atonic seizure type, figures will display: 
o 
Number of seizures per subjects over time by age category 
o 
Average number of seizures over time by age category and by modal dose category, where modal 
doses will be clustered as follows: ]0;10], ]10;20], ]20;30], ]30;40]. 
Supportive listings will also be performed for tonic and atonic seizures, and for other types of seizures separately. 
The listings will include all the related data recorded in the Subject Diary – Seizure Record eCRF page. 
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16.2.2. QUALITATIVE SUBJECT STATUS ASSESSMENTS 
16.2.2.1. Qualitative Subject Status Variables & Derivations 
The following parameters will be used to assess the qualitative status of subjects: 
 
Summary and change from baseline in global impression assessments by the Investigator and 
parent(s)/caregiver(s) 
o 
Clinical Global Impression of Severity (CGI-S) 
o 
Clinical Global Impression of Improvement (CGI-I) 
 
Change from baseline in scores for: 
o 
Impact of Pediatric Epilepsy Scale (IPES)  
 
For subjects who previously completed INS011-14-029, the IPES that are completed on Visit 2 (Day 1) of INS011-
14-030 will serve as the baseline. Analysis will also be done using the Visit 2 (Day 1) data in INS011-14-030 as the 
baseline. 
The schedule of assessments is provided in Table 1 of the protocol. Subjects enrolled from INS011-15-054 will be 
excluded from IPES scores evaluation. 
For CGI-S, the assessment for each subject by time point will be recorded on a scale of 1 to 7: 
 
1 = Normal 
 
2 = Borderline  
 
3 = Mild  
 
4 = Moderate  
 
5 = Marked  
 
6 = Severe  
 
7 = Most extreme.  
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. 
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The IPES is validated for subjects who are 2 to 16 years of age. Due to developmental delay characteristic of the study 
population, subjects through 18 years of chronological age will complete the IPES.  
The IPES is an 11-item questionnaire in which parents rate the degree to which their child’s epilepsy has affected 
major aspects of their family and child’s health-related quality of life. This includes the impact on their child’s overall 
health, relationships, social life, academics, self-esteem, family activities, and the parents’ own hopes for their child’s 
future. Each item is scored on a four point scale: 
 
0 = Not at all (epilepsy does not affect the area in question) 
 
1 = A little 
 
2 = Some 
 
3 = A lot (epilepsy greatly affects functioning in the given area) 
All of the items are then added to produce an IPES total score. The IPES also includes a numeric scale of the child’s 
overall quality of life ranging from 1 = “Poor” to 6 = “Excellent”. 
 
16.2.2.2. Missing Data Methods for Qualitative Subject Status Variable(s) 
All data will be evaluated as observed; no imputation method for missing values will be used.  A subject who 
withdraws prior to the last planned observation in a trial period will be included in the analyses up to the time of 
withdrawal (for any reason).  Missing data will result in a reduced sample size for that variable/parameter. 
16.2.2.3. Analysis of Qualitative Subject Status Variables 
The qualitative subject status will be summarized as follows: 
 
Number of subjects (and corresponding percentage) along the 7-point scale by time point and age 
category separately for CGI-S and CGI-I completed by the parent(s)/caregiver(s) and the Investigator 
 
Shift from baseline in CGI-S score over time separately as regards if it’s completed by the 
parent(s)/caregiver(s) or the Investigator  
 
Descriptive statistics (n, mean, SD, median, minimum, and maximum) over time and by age category of 
the actual numeric score and the change from baseline for CGI-S completed by the parent(s)/caregiver(s) 
and the Investigator 
 
Descriptive statistics (n, mean, SD, median, minimum, and maximum) over time and by age category of 
the actual numeric score for CGI-I completed by the parent(s)/caregiver(s) and the Investigator 
 
Descriptive statistics (n, mean, SD, median, minimum, and maximum) over time and by age category of 
actual scores and the change from baseline for the different items of IPES 
 
For each change/shift from baseline analysis, the two baselines, as defined Section 6.2, will be used in separate 
tables. 
Each of the above items will also be summarized by CBD status for results observed at the Follow-up visit. 
Results for each assessment will be listed separately to support these tables. 
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17. SAFETY OUTCOMES 
All outputs for safety outcomes will be based on the SAF.  
There will be no statistical comparisons between the treatment groups for safety data.  
17.1. 
ADVERSE EVENTS 
Adverse Events (AEs) will be coded using the latest version of MedDRA central coding dictionary. 
Treatment emergent adverse events (TEAEs) are defined as AEs that first occur or worsen in severity after the first 
administration of the study medication. 
See Appendix 1 for handling of partial dates for AEs.  In the case where it is not possible to define an AE as 
treatment emergent or not, the AE will be classified by the worst case; i.e. treatment emergent.  
An overall summary of number of subjects within each of the categories described in the sub-section below, will 
be provided as specified in the templates. In the summaries, AEs will be counted only once per subject. Only those 
AEs that begin between start and end of study will be summarized. 
Each summary described in Adverse Event section (except Section 17.1.2 and Section 17.1.3) will be repeated for 
TEAEs observed during the Follow-up period and presented by CBD status.  
Listings will include TEAEs and Non-TEAEs. 
17.1.1. ALL TEAES  
TEAEs will be summarized by presenting the number and percentage of subjects having any TEAE, having any TEAE 
in each SOC, and having each individual TEAE as reported by PT. Furthermore, summaries by severity and 
relationship to the study medication will be presented according to the definition below. The most frequent (at 
least 5%) TEAEs and drug related TEAEs will also be provided. 
For each summary, TEAEs will be reported by age category. 
17.1.1.1. Severity 
Severity is classed as mild/ moderate/ severe (increasing severity). TEAEs starting after the first dose of study 
medication with a missing severity will be classified as severe. If a subject reports a TEAE more than once within 
that SOC/ PT, the AE with the worst case severity will be used in the corresponding severity summaries. 
17.1.1.2. Relationship to Study Medication 
Relationship, as indicated by the Investigator, is classed as “unrelated”, ”unlikely”, “possible”, “probable” 
(increasing severity of relationship), or “unknown”. A ”related” TEAE is defined as a TEAE with a relationship to 
study medication as a ”possible” or ”probable” relationship to study medication. TEAEs with a missing relationship 
to study medication will be regarded as a “probable” relationship to study medication. If a subject reports the 
same AE more than once within that SOC/ PT, the AE with the worst case relationship to study medication will be 
used in the corresponding relationship summaries.  
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17.1.2. TEAES LEADING TO INTERRUPTION OF STUDY MEDICATION 
TEAEs leading to interruption of study medication will be identified by a response of “Dose interrupted” for the 
“Action taken with study medication” question on the AE page of the eCRF. For TEAEs leading to interruption of 
study medication, summaries of incidence rates (frequencies and percentages) by SOC and PT will be prepared. 
Such TEAEs will also be listed separately. 
17.1.3. TEAES LEADING TO DISCONTINUATION OF STUDY MEDICATION 
TEAEs leading to permanent discontinuation of study medication will be identified by a response of “Dose 
discontinued” for the “Action taken with study medication” question on the AE page of the eCRF. For TEAEs leading 
to discontinuation of study medication, summaries of incidence rates (frequencies and percentages) by SOC and 
PT will be prepared. Such TEAEs will also be listed separately. 
17.1.4. SERIOUS ADVERSE EVENTS 
Serious adverse events (SAEs) are those events recorded as ”Serious” on the Adverse Events page of the (e)CRF. A 
summary of serious TEAEs by SOC and PT will be prepared. SAEs will also be listed separately. 
17.1.5. ADVERSE EVENTS LEADING TO DEATH 
TEAEs leading to Death are those events which are recorded as ”Fatal” on the Adverse Events page of the eCRF. A 
summary of TEAEs leading to death by SOC and PT will be prepared. Such TEAEs will also be listed separately. 
17.1.6. ADVERSE EVENTS OF SPECIAL INTEREST (AESIS) 
AESIs identified in Appendix 2 will be listed and summarized as follows:  
 
AESIs by SOC and PT 
 
AESIs by SOC, PT and relationship to study drug 
 
Related AESIs by SOC, PT and maximum severity 
Two other events are of special interest and will be reported separately as follows: 
 
The relation between Somnolence event and the administration of Clobazam will be summarized. 
 
Subjects with Anemia events will be listed (values of hemoglobin, hematocrit and erythrocytes will be 
reported over time) 
17.1.7. CTC GRADING FOR ADVERSE EVENTS 
No CTC grading is required for this study.  
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17.2. 
DEATHS 
If any subjects die during the study, as recorded on the “Death Details” page of the eCRF, the information will be 
summarized and listed.  
Primary reason for death will also be summarized by CBD status for deaths observed during the Follow-up period. 
CBD status will be flagged in the listing. 
17.3. 
LABORATORY EVALUATIONS 
Results from the central laboratory will be included in the reporting of this study for Hematology, Serum Chemistry, 
and Urinalysis. A list of laboratory assessments to be included in the outputs is included in 
Appendix 3. 
Data will be provided and presented in Standard International (SI) units.   
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. 
The following summaries will be provided for laboratory data: 
 
Actual and change from baseline results will be summarized by time point and age category (for 
quantitative measurements) using descriptive statistics 
 
Shift from baseline according to normal range criteria (for quantitative measurements and categorical 
measurements as described in Section 17.3.1) by time point and age category 
 
Proportion of subjects who develop clinical laboratory result abnormalities of interest as described in 
Section 17.3.1  
Each laboratory result will be compared, separately, to the both baselines as defined Section 6.2. 
Each laboratory result measured at the Follow-up visit will also be summarized (as described above) by CBD status.  
All laboratory data will be listed with abnormal values flagged. 
Data from Urine Pregnancy Test and Blood Draw for Plasma Level eCRF page will also be listed. 
17.3.1. LABORATORY REFERENCE RANGES AND MARKEDLY ABNORMAL CRITERIA 
Quantitative laboratory measurements will be compared with the relevant laboratory reference ranges in SI units 
and categorized as: 
 
Low: Below the lower limit of the laboratory reference range (LLN).  
 
Normal: Within the laboratory reference range (upper and lower limit included). 
 
High: Above the upper limit of the laboratory reference range (ULN). 
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In addition to the high and low quantitative laboratory assignments (as identified by means of the laboratory 
reference ranges), markedly abnormal values for liver function tests (LFTs) will also be identified and summarized by 
time point and age category for: 
 
Alanine aminotransferase (ALT) level >3 times ULN  
 
Aspartate aminotransferase (AST) level >3 times ULN 
 
Total bilirubin in excess of >2 times ULN 
Markedly abnormal values for LFTs observed at the Follow-up visit will also be summarized by CBD status. 
17.3.2. CTC GRADING FOR LABORATORY DATA  
Laboratory measurements will not be graded using the Common Toxicity grading (CTC) system. 
17.4. 
ECG EVALUATIONS 
Results from the central electrocardiogram (ECG) review will be included in the reporting of this study. If the first 
ECG is abnormal, up to an additional 2 repetitions of a specific assessment may be performed. ECG will be 
evaluated at Screening (for subjects who did not meet the rollover timing criteria, see Section 6.2), Day 1 and at 
Final Visit/Discontinuation Visit.  
The following ECG parameters will be reported for this study: 
 
HR (Ventricular rate) (bpm) 
 
PR Interval (msec) 
 
QRS Interval (msec) 
 
QT Interval (msec) 
 
QTcF Interval (msec) [QT interval corrected by Fridericia] 
 
RR Interval (msec) 
 
Rhythm  
o 
Sinus rhythm 
o 
Atrial fibrillation 
o 
Other 
 
Overall assessment of ECG (Investigator’s judgment): 
o 
Normal 
o 
Abnormal, Not Clinically Significant (ANCS) 
o 
Abnormal, Clinically Significant (ACS) 
Handling of retests values is described Section 6.3. 
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The following summaries will be provided for ECG data: 
 
Frequency counts and shift from baseline by age category (for qualitative measurements) in separate 
tables 
 
Summary of absolute results and change from baseline by age category (for quantitative measurements) 
in separate tables 
 
Absolute value and change from baseline according to markedly abnormal criteria and age category as 
described in Section 17.4.1 
 
Listing of all data with flag for subjects meeting markedly abnormal criteria for absolute values and for 
change from baseline 
Each ECG result will be compared to the both baselines as defined Section 6.2. 
17.4.1. ECG MARKEDLY ABNORMAL CRITERIA 
Markedly abnormal quantitative ECG measurements will be identified in accordance with the following predefined 
markedly abnormal criteria and summarized by time point and age category for QT interval and QTcF parameters. 
 
Absolute values for QT interval and QTcF will be classified as: 
o 
> 450 msec  
o 
> 480 msec  
o 
> 500 msec 
 
Change from Baseline for QT interval and QTcF will be classified as: 
o 
>30 msec increase from baseline 
o 
>60 msec increase from baseline 
17.5. 
VITAL SIGNS 
The following Vital Signs measurements will be reported at each visit:  
 
Systolic Blood Pressure (mmHg) 
 
Diastolic Blood Pressure (mmHg) 
 
Pulse Rate (bpm) 
 
Respiratory Rate (breaths/min) 
 
Temperature (⁰C) 
If clinically significant findings, as determined by the Investigator, occur in any of the vital signs measurements, 
that measurement will be repeated at medically appropriate intervals until the value returns to an acceptable 
range, a specific diagnosis is established, or the condition is otherwise explained. 
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The following summaries will be provided for vital signs data: 
 
Actual and change from baseline by time point and age category 
 
Incidence of markedly abnormal values  
 
All vital signs will be listed 
Each vital sign result will be compared to the both baselines as defined Section 6.2. 
Each vital sign result measured at the Follow-up visit will also be summarized (as described above) by CBD status.  
In addition, the subject weight will be summarized in terms of both: 
 
Change from baseline across each visit 
 
Change from baseline to Follow-up visit by CBD status 
The corresponding listing will also be provided including the flag for CBD status. 
17.5.1. 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 
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 
Respiratory rate will be classified as Low and High according to the following age-dependent ranges (Low for values 
under the range and High for values above the range): 
Age Category 
Normal Respiratory Rate Range (Breaths Per 
Minute) 
< 3 years  
 
20-30 bpm 
3 -< 6 years 
20-25 bpm 
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6 -< 12 years  
14-22 bpm 
≥ 12 years 
12-18 bpm 
 
17.6. 
PHYSICAL AND NEUROLOGICAL EXAMINATION  
The full physical examination will consist of the following: general appearance, skin, eyes, ears, nose, throat, neck, 
lymph nodes, chest, heart, abdomen, and extremities. All physical exams will also include an assessment of the 
subject’s height and weight.  
A brief neurological examination will consist of the following: mental status, cranial nerves, nystagmus, motor 
system, sensory system, reflexes, coordination, gait, and station.  
The subject’s developmental capabilities will be assessed as a part of the neurological examination (in a manner the 
Investigator sees fit) during the Screening Period (Visit 1) or Visit 2 (Day 1) only, whichever visit occurs first for each 
respective subject.  
Additional examinations may be performed at the discretion of the Investigator. 
The following summary will be produced separately for physical and neurological examination: 
 
Number and percentage of subjects with the results (normal/ANCS/ACS) by time point and age category 
 
Shifts from baseline according to normal/ANCS/ACS criteria by time point and age category 
 
Supportive listings will also be provided 
17.7. COLUMBIA SUICIDE SEVERITY RATING SCALE (C-SSRS) AND VINELAND 
ADAPTIVE BEHAVIOR SCALES (VABS) 
17.7.1. VARIABLES & DERIVATIONS 
The 2 following scales will be analyzed in term of change from baseline in scores: 
o 
Vineland Adaptive Behavior Scales, Second Edition – Survey Interview Form including the 
Maladaptive Behavior Index (VABS)  
o 
Columbia-Suicide Severity Rating Scale (C-SSRS)  
For subjects who previously completed INS011-14-029, the VABS that are completed on Visit 2 (Day 1) of INS011-
14-030 will serve as the baseline. Analysis will also be done using the Visit 2 (Day 1) data in INS011-14-030 as the 
baseline. 
The schedule of assessments is provided in Table 1 of the protocol. Subjects enrolled from INS011-15-054 will be 
excluded from VABS and C-SSRS scores evaluation. 
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The VABS is validated for use in subjects from birth to 90 years of age. For the first items the raw score is collected, 
whereas for the Maladaptive Behavior Critical Items, both frequency and severity will be recorded as follows: 
Frequency: 
 
0 = Never 
 
1 = Sometimes 
 
2 = Usually 
Severity rating: 
 
S = Severe 
 
M = Moderate 
The C-SSRS will evaluate the risk of suicide for patients aged >=7 years. Clinical impression will be used for patients 
< 7 years or for patients >=7 years with development impairment for whom the C-SSRS would be inappropriate. 
The appropriate C-SSRS adult version will be used in subjects 12 years of age and older. 
17.7.2. MISSING DATA METHODS  
All data will be evaluated as observed; no imputation method for missing values will be used.  A subject who 
withdraws prior to the last planned observation in a trial period will be included in the analyses up to the time of 
withdrawal (for any reason).  Missing data will result in a reduced sample size for that variable/parameter. 
17.7.3. ANALYSIS OF VARIABLES 
The qualitative subject status will be summarized as follows: 
 
Descriptive statistics (n, mean, SD, median, minimum, and maximum) over time and by age category of 
actual scores and the change from baseline for each quantitative items of VABS 
 
Number of subjects (and corresponding percentage) per frequency level and per severity scale for each 
Maladaptive Behavior Critical Items of VABS over time reported by age category 
 
Number of subjects (and corresponding percentage) over time and by age category per answer (Y/N) for 
each questions of the C-SSRS “suicidal ideation” item 
 
Number of subjects (and corresponding percentage) over time and by age category per answer (Y/N) for 
each questions of the C-SSRS “suicidal behavior” item 
For change from baseline analysis, the two baselines, as defined Section 6.2, will be used in separate tables. 
Each of the above items will also be summarized by CBD status for results observed at the Follow-up visit. 
Results for each assessment will be listed separately to support these tables. 
18. DATA NOT SUMMARIZED OR PRESENTED 
The other variables and/or domains not summarized or presented are: 
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 
Comments 
These domains and/or variables will not be summarized or presented, but will be available in the clinical study 
database, SDTM and/or ADaM datasets. 
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19. REFERENCES  
 
 
 
 
 
 
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APPENDIX 1. PARTIAL DATE CONVENTIONS 
Imputed dates will NOT be presented in the listings. 
ALGORITHM FOR TREATMENT EMERGENCE OF ADVERSE EVENTS: 
START DATE 
STOP DATE 
ACTION 
Known 
Known 
If start date < study med start date, then not TEAE 
If start date >= study med start date, then TEAE 
 
Partial 
If start date < study med start date, then not TEAE 
If start date >= study med start date, then TEAE 
 
Missing 
If start date < study med start date, then not TEAE 
If start date >= study med start date, then TEAE 
 
 
 
Partial, 
but 
known 
components show that it 
cannot be on or after study 
med start date 
Known 
Not TEAE 
 
Partial 
Not TEAE 
 
Missing 
Not TEAE 
 
 
 
Partial, could be on or after 
study med start date 
Known 
If stop date < study med start date, then not TEAE 
If stop date >= study med start date, then TEAE 
 
Partial 
Impute stop date as latest possible date (i.e. last day of 
month if day unknown or 31st December if day and month 
are unknown), then: 
If stop date < study med start date, then not TEAE 
If stop date >= study med start date, then TEAE 
 
Missing 
Assumed TEAE 
 
 
 
Missing 
Known 
If stop date < study med start date, then not TEAE 
If stop date >= study med start date, then TEAE 
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START DATE 
STOP DATE 
ACTION 
 
Partial 
Impute stop date as latest possible date (i.e. last day of 
month if day unknown or 31st December if day and month 
are unknown), then: 
If stop date < study med start date, then not TEAE 
If stop date >= study med start date, then TEAE 
 
Missing 
Assumed TEAE 
 
ALGORITHM FOR PRIOR / CONCOMITANT MEDICATIONS:  
START DATE 
STOP DATE 
ACTION 
Known 
Known 
If stop date < study med start date, assign as prior  
If stop date >= study med start date and start date <= end of treatment, 
assign as concomitant  
If stop date >= study med start date and start date > end of treatment, 
assign as post study  
 
Partial 
Impute stop date as latest possible date (i.e. last day of month if day 
unknown or 31st December if day and month are unknown), then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date and start date <= end of treatment, 
assign as concomitant 
If stop date >= study med start date and start date > end of treatment, 
assign as post treatment 
 
Missing 
If stop date is missing could never be assumed a prior medication 
If start date <= end of treatment, assign as concomitant 
If start date > end of treatment, assign as post treatment 
 
 
 
Partial 
Known 
Impute start date as earliest possible date (i.e. first day of month if day 
unknown or 1st January if day and month are unknown), then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date and start date <= end of treatment, 
assign as concomitant 
If stop date >= study med start date and start date > end of treatment, 
assign as post treatment 
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Effective Date: 01May2012 
 
 
 
STATISTICAL ANALYSIS PLAN: PROTOCOL INS011-14-030 
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START DATE 
STOP DATE 
ACTION 
 
Partial 
Impute start date as earliest possible date (i.e. first day of month if day 
unknown or 1st January if day and month are unknown) and impute stop 
date as latest possible date (i.e. last day of month if day unknown or 31st 
December if day and month are unknown), then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date and start date <= end of treatment, 
assign as concomitant 
If stop date >= study med start date and start date > end of treatment, 
assign as post treatment 
 
Missing 
Impute start date as earliest possible date (i.e. first day of month if day 
unknown or 1st January if day and month are unknown), then: 
If stop date is missing could never be assumed a prior medication 
If start date <= end of treatment, assign as concomitant 
If start date > end of treatment, assign as post treatment 
 
 
 
Missing 
Known 
If stop date < study med start date, assign as prior 
If stop date >= study med start date, assign as concomitant 
Cannot be assigned as ‘post treatment’ 
 
Partial 
Impute stop date as latest possible date (i.e. last day of month if day 
unknown or 31st December if day and month are unknown), then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date, assign as concomitant 
Cannot be assigned as ‘post treatment’ 
 
Missing 
Assign as concomitant 
 
 
 
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APPENDIX 2. ADVERSE EVENTS OF SPECIAL INTEREST PREFFERED TERMS 
 
Anemia; 
 
Diarrhea; 
 
Fatigue; 
 
Blood FSH decreased; 
 
Blood FSH increased; 
 
Weight decreased; 
 
Weight increased; 
 
Decreased appetite; 
 
Hypersomnia; 
 
Lethargy; 
 
Sedation; 
 
Seizure; 
 
Somnolence; 
 
Status epilepticus; 
 
Aggression; 
 
Agitation; 
 
Irritability; 
 
Acute respiratory failure; 
 
Dyspnea; 
 
Respiratory arrest. 
APPENDIX 3. LABORATORY TESTS 
Analytical Testing 
Hematology 
white blood cells, red blood cells, platelet count, 
neutrophils, lymphocytes, eosinophils, basophils, 
monocytes, hemoglobin, and hematocrit 
Serum Chemistry 
total protein, albumin, creatinine, Blood urine nitrogen 
(BUN), uric acid, total bilirubin, direct bilirubin, alkaline 
phosphatase, FSH, AST, ALT, glucose, calcium, 
phosphorus, bicarbonate, chloride, sodium, and 
potassium  
Urinalysis 
specific gravity, pH, color, and presence of white blood 
cells (WBCs), red blood cells (RBCs), and proteins  
Pregnancy test 
β human chorionic gonadotripin (β-hCG) in urine 
 
 
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