Clinical trial NCT03355300
Conditions: Childhood Absence Epilepsy
Sponsor: Radius Pharmaceuticals, Inc.
Start date: 2018-02-20; Completion date: 2019-06-28
Enrollment: 11 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary purpose of this study is to assess the long-term safety and tolerability of Cannabidiol Oral Solution (CBD) in pediatric participants with treatment-resistant childhood absence seizures.

Detailed description:

Arms: arm 1: Cannabidiol Oral solution, dose as assigned in INS-17-103.
Interventions: intervention 1: Cannabidiol Oral Solution
Intervention descriptions: intervention 1: An oral solution containing pharmaceutical grade cannabidiol (nonplant-based).

Protocol documents:
Prot_SAP_002.pdf: 
 
 
 
CLINICAL TRIAL PROTOCOL 
 
 
A Multicenter, Open-Label, Flexible Dose Study to Assess the Long-Term Safety of 
Pharmaceutical Grade Synthetic Cannabidiol Oral Solution in Pediatric Patients with 
Treatment-Resistant Childhood Absence Seizures 
 
 
Protocol Number: INS011-17-113 
Final Protocol Date: 23 Aug 2018 
Version: 4.0 
Investigational Product: Cannabidiol Oral Solution 
IND Number: IND 123,120 
 
ClinicalTrials.gov ID: NCT03355300 


CLINICAL TRIAL PROTOCOL 
A Multicenter, Open-Label, Flexible Dose Study to Assess the Long-Term Safety of 
Pharmaceutical Grade Synthetic Cannabidiol Oral Solution in Pediatric Patients with 
Treatment-Resistant Childhood Absence Seizures 
Protocol Number: INS011-17-113 
Protocol Date: 23 Aug 2018 
Protocol Version: 4.0 
Investigational Product: Cannabidiol Oral Solution 
IND Number: 123,120 
Sponsor: Insys Development Company, Inc. 
1333 South Spectrum Blvd, Suite 100 
Chandler, AZ 85286 
Medical Monitor: 
 MD 
Insys Development Company, Inc. 
 Clinical Development 
Phone: 
 
Fax: 
 
Confidentiality Statement 
This study will be performed in compliance with Good Clinical Practices (GCP) and applicable regulatory 
requirements. The confidential information in this document is provided to you as an investigator, 
potential investigator or consultant for review by you, your staff and applicable Independent Ethics 
Committee (IEC) or Institutional Review Board (IRB). It is understood that the information will not be 
disclosed to others without written authorization from Insys Development Company, Inc., except to the 
extent necessary to obtain informed consent from those persons to whom the drug may be administered. 
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Insys Development Company, Inc. 
 
Protocol Number INS011-17-113 
23 Aug 2018 
 
 
 
 
 
 
     CONFIDENTIAL 
 
 
 
 
 
 
                     3 
 
 
PROTOCOL SYNOPSIS 
Name of Sponsor/Company: 
Insys Development Company, Inc. 
Name of Investigational Product: 
Cannabidiol Oral Solution 
Name of Active Ingredient: 
Cannabidiol 
Title of Study:  
A Multicenter, Open-label, Flexible Dose Study to Assess the Long-Term Safety of 
Pharmaceutical Grade Synthetic Cannabidiol Oral Solution in Pediatric Patients with 
Treatment-Resistant Childhood Absence Seizures 
Study center(s): Prospectively 8 sites will screen patients for enrollment 
Phase of development: Phase 2 Long-Term Safety 
Objective:  
The objective of this study is to assess the long-term safety and tolerability of Cannabidiol 
Oral Solution (CBD) in pediatric patients with treatment-resistant Childhood Absence 
Seizures. 
Methodology: 
This is a multicenter, open-label, flexible dose study designed to assess long-term safety and 
tolerability of CBD in doses ranging from 20 mg/kg/day to 40 mg/kg/day in patients with 
treatment-resistant childhood absence seizures. Patients must have completed INS011-17-103 
to be eligible.  
The Investigator will ensure that the patients legal representative [parent(s)/caregiver(s)] will 
receive a copy of the informed consent form for review and provide full informed consent 
prior to study participation. Patients may enroll in the Long-Term Safety study (INS011-17-
113) after completing INS011-17-103 Visit 6 (End of Study) to avoid interruption of the 
investigational product. Patients will have up to 2 weeks to enroll in INS011-17-113.  The first 
visit (Visit 1) for INS011-17-113 will be after the completion of Visit 6 of INS011-17-103.  
Patients will continue to receive CBD treatment for approximately 48 weeks. Patients will 
remain on their previously assigned dose from Study INS011-17-103 or may be titrated up to a 
higher dose level if the Data Monitoring Committee (DMC) has approved the higher dose 
level in INS011-17-103.  If any participant does not enroll within the 2 week window, that 
patient will not be eligible to enroll into the study.  
The study will consist of a Safety Period (48±2 weeks), Taper Period (10±3 days), and a 
Follow-up Period (30±5 days). Treatment visits will be scheduled monthly for the first 
INS011-17-113_CAE LTS_FINAL_23Aug2018 FE | VV-TMF-118587 | 1.0
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Insys Development Company, Inc. 
 
Protocol Number INS011-17-113 
23 Aug 2018 
 
 
 
 
 
 
     CONFIDENTIAL 
 
 
 
 
 
 
                     4 
3 months and then quarterly over the remaining 9 months. All patients will complete a Visit 7 
(End of Study) or Early Withdrawal Visit regardless of when they stop treatment/complete the 
study. A Follow-Up telephone call (Visit 9) will occur 30 days after the end of either the End 
of Study (Visit 7) or Early Withdrawal. 
In this study, all patients will be dosed as follows:  
• Once the informed consent for INS011-17-113 is provided within the required time 
frame, initially the patient will receive the same dose as was administered during 
INS011-17-103.  If tolerability issues occurred during INS011-17-103, the dose can be 
decreased if the dose was greater than 20 mg/kg/day.  If the patient received 20 
mg/kg/day and the physician wants to decrease the dose, the patient should be 
discontinued. 
• Physicians will not increase a patient’s assigned dose until the Data Monitoring 
Committee has deemed that the higher dose is safe in INS011-17-103. Doses of CBD 
may be adjusted at the investigator’s discretion up to a maximum of 40 mg/kg/day. 
• Treatment with established antiepileptic drugs (AEDs) and therapeutic treatments (e.g., 
vagus nerve stimulation [VNS]) may be initiated/continued/adjusted and changes will 
be permitted as necessary based on safety concerns or changes in seizure control. Any 
changes must be documented in the eCRF.   
Patients will be dosed approximately every 12 hours with food to help ensure consistent 
plasma levels are achieved. Patients will be dosed  for 48 weeks during which the investigator 
will assess safety and tolerability. 
Study Assessments 
At Visit 1 (Day 1) and each monthly and quarterly visit, the following assessments will be 
completed: 
• Review of Antiepileptic Drugs 
(AEDs).  
• Review of concomitant 
medications. 
• Review of vital signs. 
• Review clinical labs. 
• Urinanalysis.  
• Physical Examination (including 
height and weight). 
• Brief Neurological Exam.  
• Dispensing CBD.  
• Drug Accountability.  
• Review Adverse Events (AEs).  
• 12-lead ECG. 
 
At End of Study (Visit 7) or Early Withdrawal, the following assessments will be completed: 
• Review of antiepileptic drugs 
(AEDs).  
• Urinalysis. 
• Urine pregnancy screen for post-
menarchal females  
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Protocol Number INS011-17-113 
23 Aug 2018 
 
 
 
 
 
 
     CONFIDENTIAL 
 
 
 
 
 
 
                     5 
• Review of concomitant 
medications.  
• Review clinical labs 
• 12-lead ECG.  
• Review AEs.  
• Review of vital signs 
• Drug Accountability.  
• Physical examination (including 
height and weight). 
• Neurological examination 
• Dispensing CBD.  
• Columbia-Suicide Severity Rating 
Scale (C-SSRS).   
 
At Taper Period (Visit 8), the following assessment will be completed:  
• 
Collect CBD.  
• 
Review AEs. 
At Follow-Up (phone call only), the following assesments will be completed: 
• Review of Antiepileptic Drugs (AEDs).  
• Review of concomitant medications.  
• 
Review AEs. 
Taper Period  
At the end of the Long-Term Safety study, patients will be tapered off of CBD over a 0-10 
days period. The following tapering scheme will be utilizied: 40 mg/kg/day will be reduced to 
30 mg/kg/day for five days, then 20 mg/kg/day for five days, then stop; 30 mg/kg/day will be 
reduced to 20 mg/kg/day for five days, then stop; and doses ≤ 20 mg/kg/day can be 
discontinued without taper. This can be modified by the investigator based upon the patient’s 
response. 
Tapering will occur under the following circumstances: 
• Patient completes Visit 7 (End of Study) of INS011-17-113 
o Patient will begin tapering the day after Visit 7 
• Patient withdraws early 
o Patient will begin tapering the day after they decide to withraw from the trial 
Follow-Up Period  
A Follow-up telephone call will occur 30 days after discontinuation of the study drug to assess 
AEs, AEDs, and record concomitant medications.  
Number of patients (planned):  
Up to 30 patients who completed INS011-17-103 will be enrolled in the study.  
Diagnosis and main criteria for inclusion:  
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Insys Development Company, Inc. 
 
Protocol Number INS011-17-113 
23 Aug 2018 
 
 
 
 
 
 
     CONFIDENTIAL 
 
 
 
 
 
 
                     6 
Inclusion criteria 
1. Completed activities up to and including Visit 6 (End of Study) of INS011-17-103. 
2. Patient and/or parent(s)/caregiver(s) fully comprehend the informed consent form 
(ICF) and assent form, understand all study procedures, and can communicate 
satisfactorily with the investigator and study coordinator, in accordance with 
applicable laws, regulations, and local requirements.  
3. A female patient is eligible to participate in the study if she is: 
a. Premenarchal, or 
b. Of childbearing potential with a negative urine pregnancy test at the Screening 
Visit. If sexually active, she must agree to fulfill one of the following 
requirements: 
i. Complete abstinence from intercourse for ≥ 4 weeks prior to administration of 
the first dose of the investigational product, throughout the Safety 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 intrauterine device [IUD], diaphragm, or 
stable hormonal contraceptive use for at least 3 months before screening and 
through 14 days after study completion). 
4. A sexually active male patient or partner of enrolled patient must be willing to use 
acceptable methods of contraception throughout the study and for 4 weeks after 
completion of study participation or 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 one of the methods listed in criterion #3). 
5. In the opinion of the investigator, the parent(s)/caregiver(s) is (are) willing and able to 
comply with the study procedures and visit schedules, including venipuncture, and the 
visit schedules. 
Exclusion criteria 
1. Patient or parent(s)/caregiver(s) have commitments during the study duration that 
would interfere with attending all study visits. 
2. Experienced an anoxic episode related to study drug requiring resuscitation during the 
previous study. 
3. Developed an adverse event thought to be related to CBD in the previous study and for 
whom the Investigator determines that continuing treatment with CBD would not be in 
the best interest of the patient. 
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Insys Development Company, Inc. 
 
Protocol Number INS011-17-113 
23 Aug 2018 
 
 
 
 
 
 
     CONFIDENTIAL 
 
 
 
 
 
 
                     7 
4. Evidence of other clinically significant disease such as unstable hepatic, 
hematological, renal, cardiovascular, gastrointestinal, immunological, or pulmonary 
diseases or ongoing malignancies. 
5. Compromised respiratory function or severe respiratory insufficiency. 
6. Clinically significant abnormal laboratory values within the past 14 days, including: 
a. Liver function tests (LFTs) such as albumin, direct bilirubin, total bilirubin, 
aspartate aminotransferase (AST), and alanine aminotransferase (ALT) ≥3 times 
the upper limit of normal (ULN). 
7. In the opinion of the investigator, the patient is unsuitable in any other way to 
participate in this study. 
Investigational product, dosage and mode of administration:  
Cannabidiol Oral Solution: an oral solution containing pharmaceutical grade synthetic 
cannabidiol  manufactured and supplied by Insys Development Company, Inc. 
Patients who completed INS011-17-103 will initiate this study on the dose with which they 
were receiving previously (20, 30, or 40 mg/kg/day orally). The total daily dose (mg/kg/day) 
will be administered in two equal doses (mg/kg) twice daily within 30 minutes after a meal. 
Doses of CBD may be adjusted at the investigator’s discretion up to a maximum of 40 
mg/kg/day once the higher dose level has been approved by the DMC in INS011-17-103. 
Patients who withdraw early or complete this study will be tapered off in the following 
manner: 40 mg/kg/day will be reduced to 30 mg/kg/day for five days, then 20 mg/kg/day for 
five days, and then stop; 30 mg/kg/day will be reduced to 20 mg/kg/day for five days, then 
stop; and doses ≤ 20 mg/kg/day can be discontinued without taper. This can be modified by 
the investigator based upon the patient’s response.  
Duration of treatment:  
The maximum duration of the study from Visit 1 (Day 1) to follow-up call will be 
approximately 54 weeks (±3 weeks). 
Reference therapy, dosage and mode of administration:  
Not applicable. 
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Insys Development Company, Inc. 
 
Protocol Number INS011-17-113 
23 Aug 2018 
 
 
 
 
 
 
     CONFIDENTIAL 
 
 
 
 
 
 
                     8 
Criteria for evaluation: 
Safety Endpoints 
• Incidence, type, and severity of AEs and serious adverse events (SAEs) associated 
with Cannabidiol Oral Solution (i.e., treatment-emergent adverse events [TEAEs]). 
• Changes from baseline in vital signs, ECG findings, and laboratory values 
(hematology, chemistry, and urinalysis). 
• Changes from baseline in neurological exam. 
Baseline is defined as Visit 6 of INS011-17-103. 
Statistical Methods: 
Safety Analysis 
All safety assessments, including AEs, clinical laboratory evaluations, vital signs, 12-lead 
ECGs, physical examination (including height and weight), and neurological examinations 
will be listed for each visit. When appropriate, they will be summarized with descriptive 
statistics by age and dose cohort. The Medical Dictionary for Regulatory Activities 
(MedDRA; Version 20.0 or higher) will be used to classify all adverse events with respect to 
system organ class and preferred term. Adverse event summaries will include only TEAEs, 
which will be summarized for each treatment group. 
• Clinical laboratory findings and vital signs will be summarized for all patients for 
observed values and change from baseline. Shifts from baseline to outside normal 
range criteria will also be presented for all patients. 
• The neurological examination results will be listed and summarized descriptively. 
Shifts from baseline according to normal and abnormal criteria will also be 
presented for all patients. 
• Results of physical examinations conducted throughout the study will be presented 
in listings and summarized descriptively. Shifts from baseline according to normal 
and abnormal criteria will also be presented for all patients. 
• Concomitant medications and AEDs will be reported in the data listings. 
• Statistical analyses will be performed using SAS® (Version 9.3 or higher, SAS 
Institute Inc.) or R (Version 3.3 or higher, Roswell Park Cancer Institute).  
Missing Data 
There will be no imputation of the missing values. All assessments will be conducted based on 
all the observed data.   
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Insys Development Company, Inc.      
 
 
Protocol Number INS011-17-113 
23 Aug 2018 
                                           CONFIDENTIAL 
                    
                                9 
Table 1: 
Schedule of Events 
ASSESSMENTS 
SAFETY PERIOD 
 
TAPER PERIOD 
FOLLOW-UP 
PERIODi 
Visit Number 
1a 
2, 3, 4 
(monthly) 
5, 6 
(quarterly) 
7 
(End of Study) 
Early 
Withdrawal 
8 
9 
(Phone Call) 
Study Time Points 
Day 1 
Weeks 4, 8, 12 
Weeks 24, 36 
End of Active 
Treatment (Week 
48) 
 
0-10 Days 
30 Days After EOS 
Visit Window (Days) 
± 5 
± 5 
± 5 
± 3 
 
 
± 5 
Informed consent ** 
 
 
 
 
 
 
 
Review of 
inclusion/exclusion 
criteria ** 
 
 
 
 
 
 
 
C-SSRS 
 
 
 
X 
X 
 
 
Review of AEDs 
X 
X 
X 
X 
X 
 
X 
Review Concomitant 
Medications 
X 
X 
X 
X 
X 
 
X 
Vital Signsb 
X 
X 
X 
X 
X 
 
 
Clinical Labsc 
X 
X 
X 
X 
X 
 
 
12-lead ECG 
X 
X 
X 
X 
X 
 
 
Urinalysis 
X 
X 
X 
X 
X 
 
 
Urine pregnancy screen 
for post-menarchal 
females 
X 
 
 
X 
X 
 
 
Physical Examinationd 
X 
X 
X 
X 
X 
 
 
Brief neurological 
Examinatione 
X 
X 
X 
X 
X 
 
 
Dosing with Cannabidiol 
Oral Solutionf 
X  
X 
X 
X 
Xf 
X g 
 
Drug Accountability 
X 
X 
X 
X 
X 
X 
 
AEs 
X 
X 
X 
X 
X 
X 
X 
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Insys Development Company, Inc. 
                                                                                  Protocol Number INS011-17-113 
23 Aug 2018 
                                        CONFIDENTIAL 
                                                     10 
ASSESSMENTS 
SAFETY PERIOD 
 
TAPER PERIOD 
FOLLOW-UP 
PERIODi 
Visit Number 
1a 
2, 3, 4 
(monthly) 
5, 6 
(quarterly) 
7 
(End of Study) 
Early 
Withdrawal 
8 
9 
(Phone Call) 
Study Time Points 
Day 1 
Weeks 4, 8, 12 
Weeks 24, 36 
End of Active 
Treatment (Week 
48) 
 
0-10 Days 
30 Days After EOS 
Visit Window (Days) 
± 5 
± 5 
± 5 
± 3 
 
 
± 5 
End of Study  
 
 
 
X 
Xh 
 
 
** To be completed prior to enrollment into LTS, specifically within the 2 week period that is allotted post completion of Visit 6 (End of Study) of INS011-17-103. 
a For  patients  who enroll within the first 2 weeks after completion of Visit 6 (End of Study) of INS011-17-103 protocol. 
b Vital signs will be taken after a 5-minute seated rest. 
c If the total bilirubin laboratory value is abnormal, direct bilirubin will be drawn. 
d The physical examination will include height, weight, and evaluation of general appearance, skin, eyes, ears, nose, throat, neck, lymph nodes, chest, heart, abdomen, and 
extremities. 
e A brief neurological examination (mental status, cranial nerves, nystagmus, motor system, sensory system, reflexes, coordination, gait, and station) will be performed at all visits 
f At-home doses will be recorded in the daily medication diary.  
g Following the Safety Period or if the patient withdraws early, the patient will enter a Taper Period. Patients will be tapered off of Cannabidiol Oral Solution as follows: 40 
mg/kg/day will be reduced to 30mg/kg/day for five days, then 20 mg/kg/day for five days, then stop; 30 mg/kg/day for five days wil be reduced to 20 mg/kg/day for five days, then 
stop; 20 mg/kg/day can be discontinued without taper. This can be modified by the investigator based upon the patient’s response. 
h If the patient withdraws prematurely from the Safety Period, all Visit 7 (End of Study) procedures should be conducted. Site staff will follow up with the patient 4 weeks after 
completion of treatment via the telephone to collect information regarding AEs, AEDs, and concomitant medications. 
i Follow-up Period visit (Visit 9) will be a phone call. 
AE = adverse event; AED = anti-epileptic drug;  
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Insys Development Company, Inc.      
 
Protocol Number INS011-17-113 
23 Aug 2018 
CONFIDENTIAL 
11 
TABLE OF CONTENTS 
PROTOCOL APPROVAL PAGE ...................................................................................................2 
PROTOCOL SYNOPSIS ................................................................................................................3 
TABLE OF CONTENTS ...............................................................................................................11 
List of Tables .................................................................................................................................15 
List of Figures ................................................................................................................................15 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................16 
1. 
INTRODUCTION ......................................................................................................19 
1.1. 
Cannabidiol .................................................................................................................19 
1.1.1. 
Mechanism of Action .................................................................................................19 
1.1.2. 
Metabolism and Potential Drug Interactions ..............................................................19 
1.2. 
Nonclinical Experience ...............................................................................................20 
1.2.1. 
Safety ..........................................................................................................................20 
1.2.2. 
Efficacy in Animal Models of Epilepsy .....................................................................20 
1.3. 
Clinical Experience .....................................................................................................20 
1.3.1. 
Overview of Safety .....................................................................................................23 
1.3.2. 
Pharmacokinetics ........................................................................................................23 
1.3.3. 
Clinical Safety Data ....................................................................................................24 
1.3.4. 
Efficacy in Human Epilepsy .......................................................................................25 
1.4. 
Childhood Absence Epilepsy ......................................................................................25 
1.5. 
Dose Selection Rationale ............................................................................................26 
1.6. 
Summary of Potential Risks and Benefits ..................................................................27 
2. 
STUDY OBJECTIVE .................................................................................................29 
3. 
INVESTIGATIONAL PLAN .....................................................................................30 
3.1. 
Overall Study Design ..................................................................................................30 
3.1.1. 
Safety Assessments .....................................................................................................31 
3.1.2. 
Taper Period ................................................................................................................31 
3.1.3. 
Follow-Up Period .......................................................................................................32 
3.2. 
Patient Selection .........................................................................................................34 
3.2.1. 
Inclusion Criteria ........................................................................................................34 
3.2.2. 
Exclusion Criteria .......................................................................................................34 
3.3. 
Removal of Patients from Therapy or Assessment.....................................................35 
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                                            12 
3.4. 
Dose Adjustment Criteria ...........................................................................................35 
3.5. 
Stopping Rules ............................................................................................................36 
4. 
TREATMENTS ..........................................................................................................37 
4.1. 
Treatments Administered ............................................................................................37 
4.2. 
Identity of Investigational Product .............................................................................37 
4.3. 
Method of Assigning Patients to Treatment Groups ..................................................37 
4.4. 
Selection and Timing of Dose for Each Patient ..........................................................37 
4.5. 
Blinding and Unblinding Treatment Assignment .......................................................37 
4.6. 
Treatment Compliance ................................................................................................37 
4.7. 
Permitted and Prohibited Therapies ............................................................................38 
4.7.1. 
Permitted Therapies ....................................................................................................38 
4.7.2. 
Prohibited Therapies ...................................................................................................38 
4.8. 
Treatment After the End of Study ..............................................................................38 
5. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................39 
5.1. 
Labeling and Packaging ..............................................................................................39 
5.1.1. 
Labeling ......................................................................................................................39 
5.1.2. 
Packaging ....................................................................................................................39 
5.2. 
Dispensing and Storage ..............................................................................................39 
5.3. 
Drug Supply and Accountability ................................................................................40 
6. 
STUDY ASSESSMENTS ..........................................................................................41 
6.1. 
Safety Assessments .....................................................................................................41 
6.1.1. 
Physical Examinations ................................................................................................41 
6.1.2. 
Neurological Examinations ........................................................................................41 
6.1.3. 
Vital Signs ..................................................................................................................41 
6.1.4. 
Electrocardiograms .....................................................................................................41 
6.1.5. 
Clinical Laboratory Assessments ...............................................................................41 
6.1.6. 
Columbia Suicide Severity Rating Scale (C-SSRS) ...................................................42 
6.1.7. 
Concomitant Medications ...........................................................................................42 
6.1.8. 
Adverse Events and Serious Adverse Events .............................................................42 
6.1.8.1. 
Definition of Adverse Events .....................................................................................42 
6.1.8.2. 
Classification of Adverse Events ................................................................................43 
6.1.8.3. 
Causality/Drug Relationship Assessment ...................................................................43 
6.1.8.4. 
Definition of Serious Adverse Events ........................................................................44 
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23 Aug 2018 
CONFIDENTIAL         
                                            13 
6.1.8.5. 
Serious Adverse Events Actions Taken ......................................................................44 
6.1.8.6. 
Serious Adverse Events Outcome at the Time of Last Observation ..........................44 
6.1.8.7. 
Adverse Event Recording and Reporting ...................................................................45 
6.1.8.8. 
Adverse Event Follow-Up ..........................................................................................46 
6.1.8.9. 
Special Considerations ................................................................................................46 
7. 
STUDY PROCEDURES ............................................................................................47 
7.1. 
Safety Period ...............................................................................................................47 
7.1.1. 
Visit 1 (Day 1) ............................................................................................................47 
7.1.2. 
Monthly (Visits 2, 3, and 4) and Quarterly (Visits 5 and 6) Visits.............................47 
7.2. 
End of Study (Visit 7) or Early Withdrawal ...............................................................48 
7.3. 
Taper Period (Visit 8) .................................................................................................48 
7.4. 
Follow-Up Period (Visit 9) .........................................................................................48 
8. 
STATISTICS ..............................................................................................................49 
8.1. 
Safety Endpoints .........................................................................................................49 
8.2. 
Sample Size Determination ........................................................................................49 
8.3. 
Analysis Populations ..................................................................................................49 
8.4. 
Statistical Analyses .....................................................................................................49 
8.4.1. 
Study Patients and Demographics ..............................................................................49 
8.4.1.1. 
Disposition and Withdrawals ......................................................................................49 
8.4.1.2. 
Protocol Deviations ....................................................................................................49 
8.4.1.3. 
Demographics and Other Baseline Characteristics .....................................................49 
8.4.2. 
Exposure and Compliance ..........................................................................................50 
8.4.3. 
Safety and Tolerability Analyses ................................................................................50 
8.4.3.1. 
Adverse Events ...........................................................................................................50 
8.4.3.2. 
Clinical Laboratory Evaluations .................................................................................50 
8.4.3.3. 
Vital Signs ..................................................................................................................50 
8.4.3.4. 
Electrocardiograms .....................................................................................................50 
8.4.3.5. 
Physical Examination Findings ..................................................................................51 
8.4.3.6. 
Columbia Suicide Severity Rating Scale (C-SSRS) ...................................................51 
8.4.4. 
Interim Analysis ..........................................................................................................51 
8.4.5. 
Missing Data ...............................................................................................................51 
9. 
STUDY CONDUCT ...................................................................................................52 
9.1. 
Sponsor and Investigator Responsibilities ..................................................................52 
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Insys Development Company, Inc.                                              Protocol Number INS011-17-113 
23 Aug 2018 
CONFIDENTIAL         
                                            14 
9.1.1. 
Sponsor Responsibilities .............................................................................................52 
9.1.2. 
Investigator Responsibilities .......................................................................................52 
9.2. 
Site Initiation ..............................................................................................................53 
9.3. 
Screen Failures ............................................................................................................53 
9.4. 
Study Documents ........................................................................................................53 
9.4.1. 
Investigator’s Regulatory Documents ........................................................................53 
9.4.2. 
Case Report Forms .....................................................................................................53 
9.4.3. 
Source Documents ......................................................................................................54 
9.5. 
Study Termination ......................................................................................................54 
9.6. 
Study Site Closure ......................................................................................................54 
9.6.1. 
Record Retention ........................................................................................................54 
9.6.2. 
Laboratory Sample Retention .....................................................................................55 
10. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................56 
10.1. 
Changes To The Protocol ...........................................................................................56 
10.2. 
Monitoring ..................................................................................................................56 
10.3. 
Data Review Meeting .................................................................................................56 
10.4. 
Protocol Violations .....................................................................................................56 
10.5. 
Quality Assurance Audit .............................................................................................57 
11. 
REGULATORY AND ETHICAL CONSIDERATIONS ..........................................58 
11.1. 
Regulatory Authority Approval ..................................................................................58 
11.2. 
Ethical Conduct of the Study ......................................................................................58 
11.3. 
Statement of Investigator/Delegation of Authority ....................................................58 
11.4. 
Patient Informed Consent ...........................................................................................58 
11.4.1. 
Assent Guidance .........................................................................................................59 
11.5. 
Investigator Reporting Requirements .........................................................................59 
12. 
DATA HANDLING AND RECORD KEEPING ......................................................60 
12.1. 
Data Management .......................................................................................................60 
12.2. 
Case Report Forms and Source Documents ...............................................................60 
12.3. 
Documentation and Retention of Essential Documents .............................................60 
12.4. 
Financial Disclosure ...................................................................................................60 
13. 
FACILITIES ...............................................................................................................62 
14. 
USE OF INFORMATION AND PUBLICATION POLICY .....................................63 
14.1. 
Use of Information ......................................................................................................63 
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Insys Development Company, Inc.                                              Protocol Number INS011-17-113 
23 Aug 2018 
CONFIDENTIAL         
                                            15 
14.2. 
Publication Policy .......................................................................................................63 
15. 
REFERENCES (AVAILABLE UPON REQUEST) ..................................................64 
16. 
INVESTIGATOR SIGNATURE PAGE ....................................................................67 
List of Tables 
Table 1: 
Schedule of Events .......................................................................................................9 
List of Figures 
Figure 1: 
Study Design Schematic .............................................................................................33 
  
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Insys Development Company, Inc.                                              Protocol Number INS011-17-113 
23 Aug 2018 
CONFIDENTIAL         
                                            16 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Abbreviation or Specialist Term 
Explanation 
5-HT1a 
5-hydroxytryptamine 1a 
ACTH 
adrenocorticotropic hormone 
AE 
adverse event 
AEDs 
anti-epileptic drugs 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
API 
active pharmaceutical ingredient 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
AUC0-t 
area under the concentration-time curve from 0 (predose) to 
the last quantifiable concentration 
BMI 
body mass index 
BID 
bis in die (twice a day) 
BUN 
blood urea nitrogen 
CAE 
childhood absence epilepsy1A1 
CB1 
cannabinoid receptor 1 
CB2 
cannabinoid receptor 2 
CBD 
cannabidiol 
CFR 
Code of Federal Regulations 
cGMP 
current Good Manufacturing Practices 
CLB 
clobazam 
Cmax 
maximum plasma concentration 
Ctrough 
plasma trough concentrations 
CNS 
central nervous system 
CRF 
case report form 
CRA 
clinical research associate 
CRO 
contract research organization  
C-SSRS 
Columbia Suicide Severity Rating Scale 
CV% 
coefficient of variation 
CYP 
cytochrome P450 
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Insys Development Company, Inc.                                              Protocol Number INS011-17-113 
23 Aug 2018 
CONFIDENTIAL         
                                            17 
Abbreviation or Specialist Term 
Explanation 
CYP1A1 
Cytochrome P450 1A1 
CYP2C19 
Cytochrome P450 2C19 
CYP2C9 
Cytochrome P450 2C9 
CYP3A4 
Cytochrome P450 3A4 
CYP3A5 
Cytochrome P450 3A5 
DEA 
Drug Enforcement Administration 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EEG 
electroencephalogram 
EENT 
eyes, ears, nose, and throat 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICD 
informed consent document 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IFN 
interferon 
IL-2 
interleukin-2 
IP 
Investigational product 
IRB 
Institutional Review Board 
LDH 
lactate dehydrogenase 
MCT 
medium chain triglycerides 
MedDRA 
Medical Dictionary for Regulatory Activities 
OH 
hydroxy 
PK 
pharmacokinetic(s) 
pKa 
acid dissociation constant 
PT 
preferred term 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
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Insys Development Company, Inc.                                              Protocol Number INS011-17-113 
23 Aug 2018 
CONFIDENTIAL         
                                            18 
Abbreviation or Specialist Term 
Explanation 
SOP 
standard operating procedure 
t½ 
elimination half-life 
TEAE 
treatment-emergent adverse event 
Tmax 
time to maximum plasma concentration 
Δ9-THC 
Δ9-tetrahydrocannabinol 
THC 
tetrahydrocannabinol 
US 
United States 
VNS 
vagus nerve stimulation 
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Insys Development Company, Inc.                                              Protocol Number INS011-17-113 
23 Aug 2018 
CONFIDENTIAL         
                                            19 
1. 
INTRODUCTION 
Data presented in this section include overviews from the nonclinical and clinical published 
literature that reports on various other formulations of cannabidiol (CBD) (primarily plant-
based). Analogous studies have not been completed for Cannabidiol Oral Solution, the synthetic 
pharmaceutical grade CBD to be investigated in this study. 
Please see the Investigator’s Brochure (IB)1 for more information. 
1.1. 
Cannabidiol  
The main active constituent of cannabis, Δ9-tetrahydrocannabinol (Δ9-THC) is the principal 
psychoactive constituent of marijuana. Cannabidiol is nonpsychoactive and the second most 
abundant cannabinoid. 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, synthetic CBD drug substance. It is manufactured in 
Insys’ current Good Manufacturing Practices (cGMP) manufacturing facility. This facility is 
approved by the Drug Enforcement Administration (DEA) and has been inspected by the Food 
and Drug Administration (FDA). This active pharmaceutical ingredient is ≥ 99.5% pure6 and can 
be consistently produced without concern for contaminant.  
1.1.1. 
Mechanism of Action 
The mode of action of CBD is not fully understood. The drug substance manifests a low affinity 
for endogenous cannabinoid receptors 1 (CB1) and 2 (CB2). Cannabidiol acts as an indirect 
antagonist of CB1 and inhibits several CB1 mediated ∆9-THC effects.7 It also stimulates the 
vanilloid receptor type 18 and modulates the µ- and δ-opioid receptors.9 It may also increase 
plasma ∆9-THC levels by inhibiting hepatic microsomal metabolism through competitively 
binding proteins in the cytochrome P450 (CYP) oxidative system.10 Finally, CBD may modulate 
neuronal hyperexcitability through one or more of the following mechanisms: 
• Bidirectional regulation of calcium homeostasis via the mitochondrial 
sodium/calcium exchanger.11  
• Agonistic properties at 5-hydroxytryptamine 1a (5-HT1a) receptors.12 
• Enhancing endogenous adenosine levels in the central nervous system (CNS) by 
reducing adenosine re-uptake.13,14  
1.1.2. 
Metabolism and Potential Drug Interactions 
The major biotransformation pathway for CBD is similar to that of other cannabinoids and mediated by 
hydroxylation with cytochrome P450 (CYP) proteins.15 Its interactions with human drug metabolizing 
enzymes (as a substrate, inhibitor, or inducer) were recently reviewed.16,17  
Cannabidiol is metabolized primarily in the liver by CYP3A4 and to a lesser extent by CYP2C19. 
Specifically, CBD inhibits CYP3A4, CYP3A5, and CYP1A1 in vitro.18,19,20 It also appears to inhibit 
CYP2C921 and the transport protein P-glycoprotein. 22,23     
Further details may be found in the Investigator’s Brochure (IB).1 
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Insys Development Company, Inc.                                              Protocol Number INS011-17-113 
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CONFIDENTIAL         
                                            20 
1.2. 
Nonclinical Experience 
1.2.1. 
Safety 
In a nonclinical setting, single-dose toxicology studies of CBD reveal a relatively safe toxicology 
profile except at very high doses of the drug substance. Repeated dose toxicology studies 
highlight a potential impact of CBD on spermatogenesis, follicle-stimulating hormone levels, 
and a subset of immune responses.  
Full detail of these results may be found in the IB.1 
1.2.2. 
Efficacy in Animal Models of Epilepsy 
Plant-derived CBD studies show antiepileptic,24 antipsychotic, anti-dystonic, anti-emetic, and 
anti-inflammatory properties in animal models.25 These models support exploring the use of 
CBD for the treatment of epilepsy.26    
The anticonvulsant activity of oral CBD was investigated in an adult rat model of seizures 
(induced by maximal electroshock or audiogenic sources).27 Cannabidiol was effective against 
maximal electroshock-induced seizures (median effective dose [ED50] = 18 mg/kg), but only 
minimally effective against audiogenic-induced seizures (ED50 ≥75 mg/kg). The neurotoxicity 
median tolerated dose (TD50) was >100 mg/kg. Cannabidiol co-administered with different anti-
seizure drugs (e.g., phenytoin or carbamazepine) increased or reduced their anticonvulsant 
activity, indicating that synergism or antagonism with CBD was drug specific. 
1.3. 
Clinical Experience 
A Phase 1/2 study to assess the pharmacokinetics (PK) and safety of multiple doses 
(10 mg/kg/day, 20 mg/kg/day, and 40 mg/kg/day) of pharmaceutical grade, synthetic 
Cannabidiol Oral Solution in 61 pediatric patients with treatment-resistant seizure disorders aged 
1 year to 17 years has been completed by the Sponsor (Protocol INS011-14-029). Patients were 
exposed for a period of approximately 11 days before qualifying to participate in the long-term 
extension study (INS011-14-030). Analyses demonstrated that: 
• Cannabidiol levels on Day 10 appeared to increase proportionally with weight-based 
dose across the dosing cohorts, notwithstanding the two different formulations of the 
investigational product.   
• Steady-state levels of cannabidiol appeared to be attained with approximately 2 to 6 
days of repeated BID dosing with Cannabidiol Oral Solution, with geometric mean 
area under the concentration-time curve in plasma during a dosing interval (AUC(0-
tau)) of 507.0 (Cohort 1 [10 mg/kg/day]), 836.0 (Cohort 2 [20 mg/kg/day]), and 
2108 ng∙h/mL (Cohort 3 [40 mg/kg/day]) for all age categories combined.  
• Geometric mean maximum plasma concentrations (Cmax) of cannabidiol at 
steady-state were 91.0 (Cohort 1 [10 mg/kg/day]), 126.0 (Cohort 2 [20 mg/kg/day]), 
and 314.5 ng/mL (Cohort 3 [40 mg/kg/day]) for all age categories combined.  
• Median time to maximum plasma concentration of cannabidiol at steady-state ranged 
from 2.0 to 3.0 hours for all age categories combined.  
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Insys Development Company, Inc.                                              Protocol Number INS011-17-113 
23 Aug 2018 
CONFIDENTIAL         
                                            21 
• Geometric means of cannabidiol apparent terminal half-life (t1/2) ranged from 19.5 to 
29.6 hours following a single dose of Cannabidiol Oral Solution for all age categories 
combined. 
• Accumulation in cannabidiol exposures was approximately 3- to 4-fold for all age 
categories combined. Dosing cohort total geometric means ranged from 2.6 to 3.1 for 
accumulation ratio for Cmax and from 3.6 to 4.4 for accumulation ratio for AUC(0-tau). 
• Most of the dosing cohort’s total variability in cannabidiol exposures after repeated 
dosing (Day 10) was lower than Day 1. Single and repeated administrations of 
Cannabidiol Oral Solution resulted in highly variable systemic exposures of 
cannabidiol. 
• There were no apparent formulation-related differences observed in terms of t1/2, 
dose-normalized exposures, and variability. 
• There were no clear trends for age-related differences in cannabidiol exposures, but 
exposure in infants tended to be lower than that in children and adolescents, 
approximately half at the highest dose (40 mg/kg/day).  
• Approximately 50% of subjects enrolled were receiving clobazam. Clobazam and 
cannabidiol have a reciprocal drug-drug interaction leading to the increased mean 
exposures of both cannabidiol (approximately 2.5-fold), and clobazam as well as 
norclobazam (approximately 3-fold) at the highest dose (40 mg/kg/day). 
• No apparent gender differences were observed for cannabidiol pharmacokinetics 
(PK). 
• Pharmacokinetic results for 7-hydroxy cannabidiol and its statistical evaluations 
generally reflected those observed for parent cannabidiol. 
• There were no quantifiable levels Δ9-THC and 11-hydroxy-Δ9-THC measured 
following cannabidiol dosing.  
• All doses of the investigational product were generally well-tolerated, although 
dose-titration was not employed. Dose-dependent adverse events (AEs) that occurred 
in multiple dosing cohorts and increased as the dose of the investigational product 
increased included diarrhea, flatulence, weight increase, somnolence, and 
psychomotor hyperactivity. Events of somnolence were potentially also related to 
concomitant use of clobazam with the investigational product, but this was not 
formally investigated in this study.  
• There were no clinically relevant differences in the AE profile among subjects in the 
infant, child, and adolescent age categories. 
• Serious adverse events were reported rarely and were consistent with underlying 
disease or procedures. 
• Although this was not designed as an efficacy study, parent(s)/caregiver(s) and 
investigators both reported notable reductions in severity of mental illness (Clinical 
Global Impression of Severity) and improvement in global subject status (Clinical 
Global Impression of Improvement).   
INS011-17-113_CAE LTS_FINAL_23Aug2018 FE | VV-TMF-118587 | 1.0
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Insys Development Company, Inc.                                              Protocol Number INS011-17-113 
23 Aug 2018 
CONFIDENTIAL         
                                            22 
• The average change in weekly seizure rates (seizures of all types) was variable across 
subjects, dosing cohorts, and over time. Although the mean change in the weekly rate 
of tonic seizures at the end of the study compared with baseline generally decreased 
in a potentially dose-dependent manner, no pattern was observed for the other types 
of seizures reported. It was thought that tonic seizures were most representative of 
seizure control in this study.  
In addition, a long-term safety study (Protocol INS011-14-030) for subjects enrolled in the PK 
study above was recently completed. Fifty-two of 61 subjects from INS011-14-029 enrolled; 45 
subjects completed the study. There were seven early termination subjects (two for withdrawal of 
consent, two for AEs of aggressions and sleepiness/irritability, one for the SAE of worsening 
seizures, one for lack of efficacy, and one subject with a genetic mutation died from systemic 
sepsis and multi-organ failure considered nonrelated). Overall, 91% of the subjects were taking 
doses greater than 20 mg/kg/day, with 38% of subjects tolerating 40 mg/kg/day. The most 
common drug-related AEs reported were anemia (5 subjects), somnolence (4 subjects), and 
weight increased (4 subjects). However, the weight increases ranged from a little over 2 lbs to 
approximately 7 lbs. 
During the study, trough PK values were drawn and interim PK data for CBD and 7-OH CBD 
from Visit 5 (Week 4) to Visit 8 (Week 24) were analyzed. Dose-normalized mean trough CBD 
concentrations ranged from 11.9 to 16 (ng/mL)/(mg/kg), showing relatively stable levels for up 
to 6 months dosing Cannabidiol Oral Solution at various dose levels. After one month of dosing, 
there did not appear to be much accumulation, even though early accumulation had likely 
happened when compared with INS011-14-029 results. High variability in trough CBD 
concentrations was observed, but the extent of variability between visits was similar as reported 
in the previous 029 study. 
An open-label study of Cannabidiol Oral Solution (20 mg/kg/day and 40 mg/kg/day) in pediatric 
subjects with infantile spasms refractory to ACTH and vigabatrin recently was halted due to 
futility (Protocol INS011-15-054) because only one out of nine patients achieved a complete 
response. 
A food effect study of Cannabidiol Oral Solution in normal healthy adults (Protocol INS011-15-
043) recently completed and the results are presented in the IB. Analysis demonstrated 
significantly higher CBD levels when administered with food.  
INS011-16-093 evaluated the effect of food on the bioavailability of multiple test formulations 
of Cannabidiol Oral Solution: MCT Oil formulation (100 mg/mL), Sesame Seed Oil formulation 
(100 mg/ml), and alcohol-containing formulation (80 mg/mL). The Sesame Oil formulation was 
studied both after subjects were fed a high fat diet and after a fast; the other formulations were 
tested after a high-fat diet. CBD Cmax was approximately 12.3-fold higher after administration of 
food compared to fasting. Comparing the Sesame Oil fasting levels to the fed formulations there 
was a 12.7-fold higher CBD Cmax (MCT formulation) and 11.2-fold higher Cmax (alcohol-
containing formulation). 
Clinical data described in the following sections were collected following administration of 
various extracts of CBD as oral solutions or solid formulations. 
INS011-17-113_CAE LTS_FINAL_23Aug2018 FE | VV-TMF-118587 | 1.0
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ler
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Insys Development Company, Inc.                                              Protocol Number INS011-17-113 
23 Aug 2018 
CONFIDENTIAL         
                                            23 
1.3.1. 
Overview of Safety 
Clinical studies in various human populations indicate that CBD has a favorable side-effect 
profile. Doses as high as 1500 mg are well tolerated.28 No significant reactions or serious adverse 
events (SAEs) have been reported across a wide range of dosages in both acute and chronic 
settings.  Bergamaschi et al.17 recently reviewed the safety of CBD in humans and examined 221 
subjects across 21 studies. As detailed in the IB1, no significant safety issues were reported. 
Regarding doses of CBD that have been examined in other studies, daily doses of 200 to 300 mg 
CBD (or potentially more) may be safe.2,29 Clinical evaluation and therapeutic ranges of CBD 
doses have been reported to be between 10 and 1500 mg/day, with the majority of reports 
evaluating doses in the 300 to 600 mg/day CBD range. Furthermore, between 300 and 1500 mg 
have been used in humans without toxicity or SAEs.30,31,32    
1.3.2. 
Pharmacokinetics 
Study INS011-14-029 is a Phase 1/2 study assessing the PK and safety of multiple doses of 
CBD.  In this recently completed PK trial using synthetic CBD (Cannabidiol Oral Solution, Insys 
Development Company, Inc.), each cohort consisted of 20 pediatric subjects from 1 to 17 years 
of age who received 10 mg/kg/day, 20 mg/kg/day, or 40 mg/kg/day over a period of 10 days. 
Subjects were dosed as in-subjects for Day 1 through Day 8. Subjects were then offered the 
opportunity to be discharged on Day 8 with readmission on Day 10 and a final study visit on 
Day 11. Cohort 1 received a formulation containing alcohol; Cohorts 2 and 3 received the final 
alcohol-free formulation containing medium chain triglycerides (MCT) oil. It was designed to 
have three age groups consisting of infants (1-2 yrs: 5 subjects), children (2 to <12 yrs: 9 
subjects), and adolescents (12 to <17 yrs: 6 subjects) in each cohort. 
Single oral administration of CBD at 5, 10, 20 mg/kg per dose resulted in mean peak levels of 
about 59, 111, and 232 ng/mL, respectively, and terminal half-life value of about 17 to 29 hours.  
The PK of CBD in different age groups was comparable at each dose level. Steady-state seemed 
to be achieved within 2 to 4 days after daily dose of 10, 20, 40 mg/kg/day CBD, with typical 
steady-state peak levels of about 120, 214, and 427 ng/mL, respectively, and a terminal half-life 
of 4 to 9 hours on Day 10.  
Dose proportional increases in CBD exposures on Day 10 was clearly observed in mean Cmax,ss 
and AUCtau even if two different formulations were used in the study. Accumulation after 
repeated doses was about 2-fold. Plasma levels of 7-hydoxy (7-OH) CBD were generally similar 
to the parent drug. 
Cannabidiol and clobazam (CLB) appear to have a drug-drug interaction based on the observed 
plasma levels of both drugs: Increase in mean exposures of clobazam on Day 10 by cannabidiol 
was shown in a dose-dependent matter (×1.2, × 1.5, × 2.6 of clobazam for 10, 20, 40 mg/kg/day 
CBD, respectively). Similarly, mean N-desmethyl CLB plasma levels following 20 or 
40 mg/kg/day of CBD were increased by CBD. 
However, there were appreciable changes in cannabidiol exposures on Day 10 only at the highest 
CBD dose (40 mg/kg/day), but not in the lower doses, with co-administration of clobazam.  
The food effect study (Protocol INS011-15-043) demonstrated a 15 to 18-fold and 85-fold higher 
AUC and Cmax, respectively, in the fed state versus the fasting state after a single administration 
of 20 mg/kg Cannabidiol Oral Solution (300 mg/mL) in healthy adults. Inter-subject variability 
INS011-17-113_CAE LTS_FINAL_23Aug2018 FE | VV-TMF-118587 | 1.0
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he PK and sa
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Insys Development Company, Inc.                                              Protocol Number INS011-17-113 
23 Aug 2018 
CONFIDENTIAL         
                                            24 
was dramatically reduced with food: 55%CV from 125% for Cmax and 35%CV from 78% for 
AUC0-inf. Median time to maximum cannabidiol exposure (Tmax) occurred approximately 6 hours 
earlier under fed conditions compared to that after fasted conditions (6.00 h Fed vs. 12.00 h 
Fasted). The highest exposures with food in terms of AUC and Cmax were 24040 h·ng/mL and 
4190 ng/mL, respectively. 
INS011-16-093 evaluated the effect of food on the bioavailability of multiple test formulations 
of Cannabidiol Oral Solution: MCT Oil formulation (100 mg/mL), Sesame Seed Oil formulation 
(100 mg/ml), and alcohol-containing formulation (80 mg/mL). The Sesame Oil formulation was 
studied both after subjects were fed a high fat diet and after a fast; the other formulations were 
tested after a high-fat diet. CBD Cmax was approximately 12.3-fold higher after administration of 
food compared to fasting. Comparing the Sesame Oil fasting levels to the fed formulations there 
was a 12.7-fold higher CBD Cmax (MCT formulation) and 11.2-fold higher Cmax (alcohol-
containing formulation). 
As a comparison, mean peak and total exposures in all age groups (Protocol INS011-14-029) on 
Day 10 were within 16 to 36% to dose-adjusted exposures in fed adults (Protocol INS011-14-
029). 
1.3.3. 
Clinical Safety Data 
The following specific examples detail selected studies of the safety of CBD use in humans: 
• Daily dosing of 10 mg/kg CBD was evaluated in a study of 15 subjects diagnosed 
with Huntington's disease.30 Only 15 abnormal clinical laboratory values were 
associated with CBD treatment; these were largely limited to 4 subjects and exhibited 
no obvious pattern. No significant or clinical differences in CBD were observed in a 
cannabis-specific side-effect inventory. 
• Chronic oral administration of 10 mg CBD 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 subjects.2  
• Oral administration of CBD 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.2,29 
• Administration of single and repeated doses of CBD 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.34  
• Three subjects with treatment-resistant schizophrenia have been dosed with 40 to 
1280 mg/day of CBD for up to 4 weeks without reporting side-effects.35 
• Two subjects diagnosed with bipolar affective disorder did not report adverse effects 
upon receiving 600 to 1200 mg/day of CBD for up to 24 days.36     
• In addition, a long-term safety study (Protocol INS011-14-030) for subjects enrolled 
in the PK study above was recently completed. Fifty-two of 61 subjects from INS011-
INS011-17-113_CAE LTS_FINAL_23Aug2018 FE | VV-TMF-118587 | 1.0
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age group
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Insys Development Company, Inc.                                              Protocol Number INS011-17-113 
23 Aug 2018 
CONFIDENTIAL         
                                            25 
14-029 enrolled; 45 subjects completed the study. There were seven early termination 
subjects (two for withdrawal of consent, two for AEs of aggressions and 
sleepiness/irritability, one for the SAE of worsening seizures, one for lack of efficacy, 
and one subject with a genetic mutation died from systemic sepsis and multi-organ 
failure considered nonrelated). Overall, 91% of the subjects were taking doses greater 
than 20 mg/kg/day, with 38% of subjects tolerating 40 mg/kg/day. The most common 
drug-related AEs reported were anemia (5 subjects), somnolence (4 subjects), and 
weight increased (4 subjects). However, the weight increases ranged from a little over 
2 lbs to approximately 7 lbs.  
1.3.4. 
Efficacy in Human Epilepsy 
Several preliminary studies of CBD report reductions in seizure activity for a significant subset 
of subjects.    
Plant-derived CBD 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 
eight subjects randomized to the active arm received 200 to 300 mg/day of CBD or placebo for 
up to 4.5 months in addition to previously established antiepileptic drugs (AEDs).2,29 Subjects 
tolerated CBD well, with no signs of toxicity or serious side-effects. Four of the eight subjects 
receiving CBD remained almost free of convulsive crises throughout the study and three others 
experienced partial improvement. The clinical condition of seven subjects receiving placebo 
remained unchanged and one subject improved.   
Parents of children with treatment-resistant epilepsy have sought CBD-enriched cannabis for 
treatment.4 In a survey, these parents reported dosages of CBD ranging from <0.5 to 
28.6 mg/kg/day, as per results from medical cannabis testing facilities. Sixteen (84%) of the 
19 parents eligible to respond to the survey reported a reduction in their child's seizure frequency 
while taking CBD-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 
CBD:∆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 ≥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. 
1.4. 
Childhood Absence Epilepsy 
Although there are currently two drugs approved for childhood absence epilepsy (CAE), 
valproate and ethosuximide, neither are ideal. Valproate has potentially serious side effects, 
including weight gain, polycystic ovary disease, liver failure, and significant teratogenic effects. 
Ethosuximide does not control general tonic-clonic seizures that can co-exist with CAE. In a 
recent study comparing ethosuximide, valproic acid, and lamotrigine, freedom from failure rates 
where treatment failure was defined as persistence of absence seizures at Week 16 or 20, a 
generalized tonic-clonic seizure at any time, excessive drug-related systemic toxicity, dose-
limiting toxicity after a single downward dose modification, or withdrawal initiated by the parent 
INS011-17-113_CAE LTS_FINAL_23Aug2018 FE | VV-TMF-118587 | 1.0
proved
rapy in 15
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Insys Development Company, Inc.                                              Protocol Number INS011-17-113 
23 Aug 2018 
CONFIDENTIAL         
                                            26 
or physician, was 53% (ethosuximide), 58% (valproic acid), and 29% (lamotrigine).37 Therefore, 
there is still an unmet need for more effective anti-epileptic drugs with less side effects for these 
seizures. As CBD has been demonstrated to be effective in the treatment of cortical mediated 
epileptic encephalopathies,38 Insys is proposing a multiple-site, open-label, dose-finding proof of 
concept study of Cannabidiol Oral Solution for the treatment of refractory childhood absence 
epilepsy.  
1.5. 
Dose Selection Rationale 
Patients will initiate this long-term safety study on the final dose of Cannabidiol Oral Solution 
administered during the Phase 2 Study INS011-17-103.  
Patients will not increase their assigned dose until the Data Monitoring Committee has approved 
the higher dose level in INS011-17-103. Doses of CBD may be adjusted at the investigator’s 
discretion up to a maximum of 40 mg/kg/day. 
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Insys Development Company, Inc.      
 
Protocol Number INS011-17-113 
 
23 Aug 2018 
CONFIDENTIAL 
27 
1.6. 
Summary of Potential Risks and Benefits 
As reviewed in Section 1.2 and Section 1.3, numerous nonclinical and clinical studies have 
examined other formulations of CBD. Several areas of potential concern have been identified 
with the use of CBD, especially in nonclinical studies. These include:   
• Competitive binding of CYP proteins (thus, an impact on drug metabolism in the 
liver). Cannabidiol is metabolized predominantly by CYP3A4 and CYP 2C19.  
Cannabidiol may inhibit these 2 isozymes, as well as having small effects on 
CYP3A5, CYP1A1, and CYP2C9. 
• Potential downregulation of immune responses involving the T, B, T-helper, and T 
cytotoxic subsets of leukocytes and/or those dependent on IL-2 or IFN-γ. 
Based on recent studies of cannabinoid administration in humans, controlled CBD may be safe in 
humans and animals. However, further studies are needed to clarify these reported in vitro and in 
vivo side-effects.39  
The inclusion/exclusion criteria, concomitant medication guidelines, and safety monitoring (AEs, 
clinical laboratory, vital signs, ECG, and physical examination assessments) planned for this 
study are intended to minimize these potential safety risks.   
Criteria for removal of patients from the study will dictate discontinuation of patient 
participation should a safety issue arise (see Section 3.3).  
Two facets of the current treatment landscape for pediatric patients with treatment-resistant 
absence seizures support the potential benefit for patients in this study. First, pediatric patients 
with treatment-resistant absence seizures continue to experience a significant unmet medical 
need despite ongoing treatment with currently available medications and procedures. Patients 
included in this study may potentially benefit from treatment with Cannabidiol Oral Solution.  
Devinsky et al.40 recently noted that pediatric patients with treatment-resistant seizures are 
particularly good candidates for CBD intervention. Data reviewed in Section 1.2.2  and 
Section 1.3.4 demonstrate that CBD has shown preliminary efficacy in treating epilepsy in 
several early-stage nonclinical and clinical studies, respectively. This study is expected to serve 
as a critical step in the development of Cannabidiol Oral Solution as a treatment for refractory 
childhood absence epilepsy.   
Second, synthetic pharmaceutical grade 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. As 
such, the development of Cannabidiol Oral Solution will not support growth and 
distribution of plants from which marijuana is derived.   
• Manufacture of Cannabidiol Oral Solution does not involve an extraction process 
whereby the derived constituents could also include a significant amount of Δ9-THC. 
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. 
INS011-17-113_CAE LTS_FINAL_23Aug2018 FE | VV-TMF-118587 | 1.0
proved
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Insys Development Company, Inc.                                              Protocol Number INS011-17-113 
23 Aug 2018 
CONFIDENTIAL         
                                            28 
• Reduced concern for contamination by Δ9-THC, herbicides, pesticides, etc. 
  
 
 
INS011-17-113_CAE LTS_FINAL_23Aug2018 FE | VV-TMF-118587 | 1.0
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Insys Development Company, Inc.                                              Protocol Number INS011-17-113 
23 Aug 2018 
CONFIDENTIAL         
                                            29 
2. 
STUDY OBJECTIVE 
The objective of this study is to assess the long-term safety and tolerability of Cannabidiol Oral 
Solution (CBD) in pediatric patients with treatment-resistant Childhood Absence Seizures. 
  
INS011-17-113_CAE LTS_FINAL_23Aug2018 FE | VV-TMF-118587 | 1.0
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Insys Development Company, Inc.                                              Protocol Number INS011-17-113 
23 Aug 2018 
CONFIDENTIAL         
                                            30 
3. 
INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design 
This is a multicenter, open-label, flexible dose study designed to assess the long-term safety and  
tolerability of CBD in doses ranging from 20 mg/kg/day to 40 mg/kg/day in patients with 
treatment-resistant childhood absence seizures. Patients must have completed INS011-17-103 to 
be eligible.  
The Investigator will ensure that the patients legal representative [parent(s)/caregiver(s)] will 
receive a copy of the informed consent form for review and provide full informed consent prior 
to study participation.  
Patients should enroll in Long-Term Safety Study (INS011-17-113) after completing Study 
INS011-17-103 Visit 6 (End of Study) to avoid interruption of the investigational product. 
Patients will have up to 2 weeks to enroll in INS011-17-113.  The first visit (Visit 1) for INS011-
17-113 will be after the completion of Visit 6 of INS011-17-103.  
Patients will continue to receive CBD treatment for approximately 48 weeks. Patients will 
remain on their assigned dose or may be titrated up to a higher dose level if the Data Monitoring 
Committee has approved the higher dose level in INS011-17-103.  If any participant does not 
enroll within the 2 week window, the patient will not be eligible to enroll into the study.  
The study will consist of a Safety Period (48±2 weeks), Taper Period (10±3 days), and a Follow-
up Period (30±5 days). Treatment visits will be scheduled monthly for the first 3 months and 
then quarterly over the remaining 9 months. All patients will complete a Visit 7 (End of Study) 
or Early Withdrawal Visit regardless of when they stop treatment/complete the study. A Follow-
Up telephone call (Visit 9) will occur 30 days after the end of either the End of Study (Visit 7) or 
Early Withdrawal. 
In this study, all patients will be dosed as follows:  
• Once the informed consent for INS011-17-113 is provided within the required time 
frame, initially the patient will receive the same dose as was administered during 
INS011-17-103.  If tolerability issues occurred during INS011-17-103, the dose can be 
decreased if the dose was greater than 20 mg/kg/day.  If the patient received 20 
mg/kg/day and the physician wants to decrease the dose, the patient should be 
discontinued. 
• Physicians will not increase a patient’s assigned dose until the Data Monitoring 
Committee has deemed that the higher dose is safe in INS011-17-103. Doses of CBD 
may be adjusted at the investigator’s discretion up to a maximum of 40 mg/kg/day. 
• Treatment with established antiepileptic drugs (AEDs) and therapeutic treatments (e.g., 
vagus nerve stimulation [VNS]) may be initiated/continued/adjusted and changes will be 
permitted as necessary based on safety concerns or changes in seizure control. Any 
changes must be documented in the eCRF.   
Patients will be dosed approximately every 12 hours with food to help ensure consistent plasma 
levels are achieved. Patients will be dosed  for 48 weeks during which the investigator will 
assess safety and tolerability. 
INS011-17-113_CAE LTS_FINAL_23Aug2018 FE | VV-TMF-118587 | 1.0
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Insys Development Company, Inc.                                              Protocol Number INS011-17-113 
23 Aug 2018 
CONFIDENTIAL         
                                            31 
The study will be terminated upon one of the following: 
• The investigational product is successfully approved for marketing in the US. 
• Sponsor elects to terminate INS011-17-113. 
• The patient has received 48 weeks of treatment. 
3.1.1. 
Safety Assessments  
At Visit 1 (Day 1) and each monthly and quarterly visit, the following assessments will be 
completed: 
• Review vital signs, clinical labs, ECG, urinalysis, and physical examination (including 
height and weight). Refer to Section 6.1. 
• Review adverse events (AEs). Refer to Section 6.1.8. 
• 12-lead ECG. 
• Brief neurological exam. Refer to Section 6.1.2. 
At Visit 7 (End of Study) or Early Withdrawal Visits the following assessments will be 
completed: 
• Columbia-Suicide Severity Rating Scale (C-SSRS) will be used for children and 
adolesents aged 7 to 17 years, if appropriate. Refer to Section 6.1.6. 
• Review vital signs, clinical labs, ECG, urinalysis, and physical examination (including 
height and weight). Refer to Section 6.1. 
• Review AEs. Refer to Section 6.1.8. 
• Brief neurological exam. Refer to Section 6.1.2. 
All AEs that arise during the Safety, Taper, and Follow-up Periods will be documented. Overall, 
patient safety will be reviewed as described in Section 10.3. 
3.1.2. 
Taper Period 
At the end of the Long-Term Safety study patients will be tapered off of CBD over a 0-10 days 
period. The following tapering scheme will be utilizied: 40 mg/kg/day will be reduced to 30 
mg/kg/day for five days, then 20mg/kg/day for five days; 30mg/kg/day will be reduced to 
20mg/kg/day for five days; and doses ≤ 20 mg/kg/day can be discontinued without taper. This 
can be modified by the investigator based upon the patient’s response 
Tapering will occur under the following circumstances: 
• Patient completes Visit 7 (End of Study) of INS011-17-113. 
o Patient will begin tapering the day after Visit 7. 
• Patient withdraws early. 
o Patient will begin tapering the day after the investigatory has been informed of the 
decision to withdraw from the trial. 
INS011-17-113_CAE LTS_FINAL_23Aug2018 FE | VV-TMF-118587 | 1.0
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Insys Development Company, Inc.                                              Protocol Number INS011-17-113 
23 Aug 2018 
CONFIDENTIAL         
                                            32 
3.1.3. 
Follow-Up Period 
A follow-up telephone call (Visit 9) will occur 30 days after the Visit 7 (End of Study) or Early 
Withdrawal to assess AEs, AEDs, and record concomitant medications. 
INS011-17-113_CAE LTS_FINAL_23Aug2018 FE | VV-TMF-118587 | 1.0
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Insys Development Company, Inc.      
 
 
Protocol Number INS011-17-113 
23 Aug 2018 
                                                                          CONFIDENTIAL 
 
 
 
 
 
 
 
 
 
33 
Figure 1: Study Design Schematic 
SAFETY
PERIOD
48 weeks
INS011-17-103
COMPLETED
FOLLOW-UP
PERIOD
30 days
TAPER
PERIOD
10 days
INELIGIBLE 
≤ 14 days since 
completed?
Y
N
 
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Insys Development Company, Inc. 
 
Protocol Number INS011-17-113 
 
 
 
23 Aug 2018 
CONFIDENTIAL 
 34 
3.2. 
Patient Selection  
3.2.1. 
Inclusion Criteria 
Patients must meet all of the following inclusion criteria: 
1. Completed all activities through Visit 6 (End of Study) of INS011-17-103. 
2. Patient and/or parent(s)/caregiver(s) fully comprehend the informed consent form (ICF) 
and assent form, understand all study procedures, and can communicate satisfactorily 
with the investigator and study coordinator, in accordance with applicable laws, 
regulations, and local requirements. 
3. A female patient is eligible to participate in the study if she is: 
a. Premenarchal, or 
b. Of childbearing potential with a negative urine pregnancy test at the Screening Visit. 
If sexually active, she must agree to fulfill one of the following requirements: 
i. Complete abstinence from intercourse for ≥ 4 weeks prior to administration of the 
first dose of the investigational product, throughout the Safety 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 intrauterine device [IUD], diaphragm, or stable 
hormonal contraceptive use for at least 3 months before screening and through 14 
days after study completion). 
4. A sexually active male patient or partner of enrolled patient must be willing to use 
acceptable methods of contraception throughout the study and for 4 weeks after 
completion of study participation or 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 one of the methods listed in criterion #3). 
5. In the opinion of the investigator, the parent(s)/caregiver(s) is (are) willing and able to 
comply with the study procedures and visit schedules, including venipuncture, and the 
visit schedules. 
3.2.2. 
Exclusion Criteria 
Patients will be excluded for any of the following: 
1. Patient or parent(s)/caregiver(s) have daily commitments during the study duration that 
would interfere with attending all study visits. 
2. Experienced an anoxic episode related to study drug requiring resuscitation during their 
previous study. 
INS011-17-113_CAE LTS_FINAL_23Aug2018 FE | VV-TMF-118587 | 1.0
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Insys Development Company, Inc. 
 
Protocol Number INS011-17-113 
 
 
 
23 Aug 2018 
CONFIDENTIAL 
 35 
3. Developed an adverse event thought to be related to CBD in the previous study and for 
whom the Investigator determines that continuing treatment with CBD would not be in 
the best interest of the patient. 
4. Evidence of other clinically significant disease such as unstable hepatic, hematological, 
renal, cardiovascular, gastrointestinal, immunological, or pulmonary diseases or ongoing 
malignancies. 
5. Compromised respiratory function or severe respiratory insufficiency. 
6. Clinically significant abnormal laboratory values within the past 14 days, including: 
a. Liver function tests (LFTs) such as albumin, direct bilirubin, total bilirubin, aspartate 
aminotransferase (AST), and alanine aminotransferase (ALT) ≥ 3 times the upper 
limit of normal (ULN). 
7. In the opinion of the investigator, the patient is unsuitable in any other way to participate 
in this study. 
3.3. 
Removal of Patients from Therapy or Assessment 
Patients will be allowed to discontinue their participation in the study at any time for any reason 
(withdrawal of consent). Furthermore, participation in this clinical study may be discontinued by 
the investigator or by the sponsor for any of the following reasons: 
• Intolerable side effects of the study product. 
• Changes in medical status or medical condition of the patient such that the 
investigator believes that patient safety will be compromised or that it would be in the 
best interest of the patient to stop treatment.  
• Patient safety or welfare is at risk. 
• Non-compliance with study visits, defined as failure to perform any portion of 
scheduled assessments or procedures. 
• Any unforeseen event that in the opinion of the treating physician and/or the Principal 
investigator, will prevent the research participant from continuing in this study. 
• Sponsor decides to stop the study. 
In the event of a patient’s withdrawal, the investigator will promptly notify the sponsor. Every 
effort will be made to complete the end-of-study assessments. 
Should any patient choose to withdraw early from the study, they will be advised of the safety 
precautions to be taken and will be followed until resolution of any AE or until the unresolved 
AEs are judged by the investigator to have stabilized. 
3.4. 
Dose Adjustment Criteria 
Doses of CBD may be adjusted at the investigator’s discretion up to a maximum of 40 
mg/kg/day only if the Data Monitoring Committee has approved the higher dose level in 
INS011-17-103. Doses greater than 40 mg/kg/day are not allowed. All dose changes must be 
clearly documented in the eCRF. 
INS011-17-113_CAE LTS_FINAL_23Aug2018 FE | VV-TMF-118587 | 1.0
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Insys Development Company, Inc. 
 
Protocol Number INS011-17-113 
 
 
 
23 Aug 2018 
CONFIDENTIAL 
 36 
Antiepileptic drugs (AEDs) or therapies (e.g., VNS and ketogenic diet) may be initiated, 
discontinued or dose adjusted as needed. Any changes must be documented in the eCRF. 
3.5. 
Stopping Rules 
The investigator reserves the right to terminate the study in the interests of patient safety and 
welfare. The Sponsor reserves the right to terminate the study at any time for administrative 
reasons. 
Patients will also be discontinued from the study if they meet the following criteria: 
• ALT or AST > 3 x ULN with (or the appearance of) fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, and/or eosinophilia >5% 
• ALT or AST > 8 x ULN 
• ALT or AST > 5 x ULN for more than 2 weeks 
• ALT or AST > 3 x ULN and bilirubin > 2 x ULN or INR > 1.5 
For patients meeting the above criteria, the investigator will arrange for the patient to return to 
the investigational site as soon as possible (within 24 hours of notice of abnormal results) for 
repeat assessment of ALT, AST, bilirubin, and alkaline phosphatase (ALP), detailed history, and 
physical examination. Patients will be followed until all abnormalities have normalized (in the 
investigator’s opinion) or returned to the baseline state. If the patient is unable to return to the 
investigational site, repeat assessments may be performed at a local laboratory.  
INS011-17-113_CAE LTS_FINAL_23Aug2018 FE | VV-TMF-118587 | 1.0
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Insys Development Company, Inc. 
 
Protocol Number INS011-17-113 
 
 
 
23 Aug 2018 
CONFIDENTIAL 
 37 
4. 
TREATMENTS 
4.1. 
Treatments Administered 
Patients or parent/caregiver will be reminded how to measure, take their dose, and record their 
dose in the dosing diary when the IP is dispensed for the first time. 
Total daily doses ranging from 20 mg/kg/day to 40 mg/kg/day will be administered with food, 
within 30 minutes after a meal, in two equivalent daily doses approximately every 12 hours. 
4.2. 
Identity of Investigational Product  
The active pharmaceutical ingredient (API) in Cannabidiol Oral Solution is a pharmaceutical 
grade synthetic CBD 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-brown colored solution (CBD 
concentration of 100 mg/mL) filled into a 30 mL amber glass vial. More detailed information 
may be found in the IB.1 
4.3. 
Method of Assigning Patients to Treatment Groups 
Patients will be allocated to a dose of the investigational product based on their dosing in the 
previous study INS011-17-103. 
4.4. 
Selection and Timing of Dose for Each Patient 
Once the informed consent for INS011-17-113 is provided, patients will initiate this long-term 
safety study on the final dose of CBD administered during the study INS011-17-103 Visit 6 (End 
of Study).  Subsequently, the dose may be increased to a maximum of 40 mg/kg/day only if the 
higher dose level has been approved by the Data Monitoring Committee in INS011-17-103. 
Patients will take each dose approximately every 12 hours with food in order to ensure consistent 
plasma levels are achieved. The date and time of all investigational product administrations will 
be documented in the case report form (CRF). 
4.5. 
Blinding and Unblinding Treatment Assignment 
Not applicable. This is an open-label study. 
4.6. 
Treatment Compliance 
The prescribed dosage, timing, and mode of administration of IP may not be changed except as 
directed by the investigator.  
The investigator, a member of the investigational staff, or a hospital pharmacist must maintain an 
adequate record of the receipt and distribution of all study medication using the Drug 
Accountability Form. These forms must be available for inspection at any time. 
All supplies of IP should be accounted for at the termination of the study and a written 
explanation provided for discrepancies. All used and unused supplies, and packaging materials 
are to be inventoried and returned to the Sponsor or a designee by the investigator. The 
INS011-17-113_CAE LTS_FINAL_23Aug2018 FE | VV-TMF-118587 | 1.0
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Insys Development Company, Inc. 
 
Protocol Number INS011-17-113 
 
 
 
23 Aug 2018 
CONFIDENTIAL 
 38 
investigator is not permitted to return or destroy unused clinical drug supplies or packaging 
materials unless authorized by the Sponsor or a designee. 
If the study is terminated, discontinued, suspended, or completed, all used and 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 concerning the accountability of Schedule I medications will 
be followed (e.g., prevention of diversion). 
4.7. 
Permitted and Prohibited Therapies 
4.7.1. 
Permitted Therapies 
Any medications (other than those excluded by the protocol, see Section 4.7.2) that the 
investigator considers necessary for a patient’s welfare and will not interfere with the 
investigational product may be administered at the investigator’s discretion. 
4.7.2. 
Prohibited Therapies 
During the Safety, Taper, and Follow-up Periods, patients are not to receive the following: 
• Any cannabinoids besides the study drug (cannabidiol, Δ9-THC, hemp oil, Realm Oil 
or marijuana). 
• Phenytoin, fluvoxamine, carbamazepine, or St. John’s Wort. 
• Medications that are strong inhibitors/inducers/sensitive substrates with a narrow 
therapeutic index for CYP3A4, CYP2C9, or CYP2C19, with the exception of 
Valproic Acid.   
• Any other investigational drug or investigational device.  
Although they are not prohibited, patients taking concomitant medications may need to be 
monitored with special care to identify any AEs arising due to the potential for altered drug 
metabolism. 
4.8. 
Treatment After the End of Study 
After the Safety Period, patients will have their taper schedule initiated over a 0-10 days period.  
INS011-17-113_CAE LTS_FINAL_23Aug2018 FE | VV-TMF-118587 | 1.0
Approved
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Insys Development Company, Inc. 
 
Protocol Number INS011-17-113 
 
 
 
23 Aug 2018 
CONFIDENTIAL 
 39 
5. 
STUDY DRUG MATERIALS AND MANAGEMENT 
5.1. 
Labeling and Packaging 
5.1.1. 
Labeling 
The labels for the investigational product will contain all information according to regulatory 
requirements. 
5.1.2. 
Packaging 
The investigational product will be supplied in 30 mL containers of a 100 mg/mL strength (i.e., 
3000 mg per container). 
Non-proprietary or common name of 
drug product 
Cannabidiol Oral Solution, 100 mg/mL 
Dosage form 
Oral solution 
Strength 
100 mg/mL 
Please refer to the Cannabidiol Oral Solution IB1 for additional information on the drug 
formulation.   
The investigational product will be clearly marked according to FDA and/or ICH requirements 
regarding use for clinical study investigation only and will be labeled with the investigational 
product name, study reference number, storage conditions, and expiry date. It is the 
responsibility of the investigator to ensure that accurate accountability records are maintained 
throughout the study. Study center staff will dispense the investigational product according to the 
handling instructions. 
5.2. 
Dispensing and Storage 
IP will be stored at controlled room temperature (20 to 25 degrees Celsius, 68 to 77 degrees 
Fahrenheit) at the study centers. 
Cannabis and its constituents (including CBD) are Schedule I controlled substances 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 one business day of discovering such loss or theft. Furthermore, all 
practitioners are prohibited from hiring employees who have been convicted of a drug-related 
felony or who have had a DEA registration denied or revoked. 
INS011-17-113_CAE LTS_FINAL_23Aug2018 FE | VV-TMF-118587 | 1.0
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Insys Development Company, Inc. 
 
Protocol Number INS011-17-113 
 
 
 
23 Aug 2018 
CONFIDENTIAL 
 40 
Investigators are responsible for ensuring that all applicable licensures are in place and storage 
conditions are appropriate.   
Doses of IP will be administered from the Schedule I-licensed study center.   
The study centers are required to provide complete information, including case report forms 
(CRFs) 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 patients dropped out of the study. 
5.3. 
Drug Supply and Accountability 
The investigator, a member of the investigational staff, or a hospital pharmacist must maintain an 
adequate record of the receipt and distribution of all study medication using the Drug 
Accountability Form. These forms must be available for inspection at any time. 
All supplies of Cannabidiol Oral Solution should be accounted for at the termination of the study 
and a written explanation provided for discrepancies. All unused supplies and packaging 
materials are to be inventoried and returned to the Sponsor or a designee by the investigator. The 
investigator is not permitted to return or destroy unused clinical drug supplies or packaging 
materials unless authorized by the Sponsor or a designee. 
If the study is terminated, discontinued, suspended, or completed, all unused supplies of the 
investigational product 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 concerning the accountability of Schedule I medications will 
be followed (e.g., prevention of diversion). 
 
 
INS011-17-113_CAE LTS_FINAL_23Aug2018 FE | VV-TMF-118587 | 1.0
Approved
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Insys Development Company, Inc. 
 
Protocol Number INS011-17-113 
 
 
 
23 Aug 2018 
CONFIDENTIAL 
 41 
6. 
STUDY ASSESSMENTS 
6.1. 
Safety Assessments 
For all patients physical examination, brief neurological examination, vital signs (seated blood 
pressure, pulse rate, temperature, and respiration rate), clinical laboratory testing (hematology, 
chemistry, and urinalysis), 12-lead ECG, concomitant medication, C-SSRS, and AE assessments 
(including TEAEs and SAEs). 
6.1.1. 
Physical Examinations 
A physical examination (evaluation of general appearance, skin, eyes, ears, nose, throat, neck, 
lymph nodes, chest, heart, abdomen, and extremities) will be conducted for every patient during 
the Visit 1 (Day 1), all monthly and quarterly visits, and Visit 7 (End of Study) or Early 
Withdrawal.  
6.1.2. 
Neurological Examinations 
A brief neurological examination (mental status, cranial nerves, nystagmus, motor system, 
sensory system, reflexes, coordination, gait, and station) will be conducted for Visit 1 (Day 1), 
all monthly and quarterly visits, and Visit 7 (End of Study) or Early Withdrawal.  
6.1.3. 
Vital Signs 
Vital signs (seated blood pressure, pulse rate, temperature and respiration rate) will be measured 
during Visit 1 (Day 1), all monthly & quarterly visits, and Visit 7 (End of Study) or Early 
Withdrawal. Additional vital sign measurements may be performed as deemed medically 
necessary by research personnel. 
6.1.4. 
Electrocardiograms 
A resting 12-lead ECG will be conducted for every patient at Visit 1 (Day 1), all monthly & 
quarterly visits, and Visit 7 (End of Study) or Early Withdrawal. 
6.1.5. 
Clinical Laboratory Assessments 
Blood samples for hematology and chemistry assessments and urine sample for urinalysis will be 
collected during Visit 1 (Day 1), all monthly & quarterly visits, and Visit 7 (End of Study) or 
Early Withdrawal.  
• Hematology: hemoglobin, hematocrit, total and differential leukocyte count, red 
blood cell (RBC), and platelet count. 
• Chemistry: albumin, blood urea nitrogen (BUN), creatinine, total bilirubin, alkaline 
phosphatase (ALP), aspartate transaminase (AST), alanine transaminase (ALT), 
sodium (Na+), potassium (K+), chloride (Cl-), lactate dehydrogenase (LDH), uric acid, 
glucose, and calcium.  
• Urinalysis: pH, specific gravity, protein, glucose, ketones, bilirubin, blood, nitrite, 
leukocyte esterase, and urobilinogen. If protein, occult blood, nitrite, or leukocyte 
esterase values are out of range a microscopic examination will be performed. 
INS011-17-113_CAE LTS_FINAL_23Aug2018 FE | VV-TMF-118587 | 1.0
Approved
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Insys Development Company, Inc. 
 
Protocol Number INS011-17-113 
 
 
 
23 Aug 2018 
CONFIDENTIAL 
 42 
A urine dipstick pregnancy test will be performed on all female post-menarchal patients during at 
Visit 1 and Visit 7 (End of Study) or Early Withdrawal. 
6.1.6. 
Columbia Suicide Severity Rating Scale (C-SSRS) 
The 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. For patients aged 7 to 17 years and if the 
developmental level is appropriate, the questionnaire will be completed at the end of the Safety 
Period (Visit 7) or Early Withdrawal. For patients who are less than 7 years or for whom the 
C-SSRS is inappropriate due to the patient’s developmental functioning, a clinical assessment 
will be made following FDA guidelines. 
(https://www.fda.gov/downloads/drugs/guidances/ucm225130.pdf). 
Patients who have significant findings for suicidal ideation as assessed by the C-SSRS must be 
referred to the investigator for follow-up evaluation.  
6.1.7. 
Concomitant Medications 
Will be assessed at all visits. 
6.1.8. 
Adverse Events and Serious Adverse Events 
6.1.8.1. 
Definition of Adverse Events 
An AE is defined as any untoward medical occurrence in a patient administered a pharmaceutical 
product during the course of a clinical investigation. An AE can therefore be any unfavorable 
and unintended sign, symptom, or disease temporally associated with the use of an 
investigational product, whether or not thought to be related to the investigational product. 
Patients will be monitored throughout the study for AEs. Monitoring for treatment-emergent AEs 
will begin as soon as the patient is dosed. All AEs must be followed until they are resolved or 
stabilized, or until all attempts to determine resolution of the event are exhausted. The 
investigator should use their discretion in ordering additional tests as necessary to monitor the 
progress of such events. 
An AE may be: 
• A new illness, not documented in the patient’s s medical history; 
• Worsening of a concomitant illness; 
• An effect of the study medication; it could be an abnormal laboratory value, as well 
as a significant shift from baseline within normal range which the qualified 
investigator or medical qualified designate considers to be clinically important; 
• A combination of two or more of these factors. 
Surgical procedures themselves are not AEs. They are therapeutic measures for conditions that 
required surgery. The condition for which the surgery is required is an AE, if it occurs or is 
detected during the study period. Planned surgical measures permitted by the clinical study 
protocol and the conditions(s) leading to these measures are not AEs, if the condition(s) was 
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 43 
(were) known before the start of study treatment. In the latter case, the condition should be 
reported as medical history. 
Absence seizures will not be considered AEs. However, new seizure types and injury resulting 
from a seizure will be captured as AEs. 
Patients will be monitored throughout the study for AEs. All AEs must be followed until they are 
resolved or stabilized, or until all attempts to determine resolution of the event are exhausted. 
The investigator should use his/her discretion in ordering additional tests as necessary to monitor 
the progress of such events. 
Adverse events reported prior to dose administration will be recorded as part of the patient’s 
medical history. 
Previous clinical trial experience has shown that somnolence, diarrhea, and transaminase 
elevations may be associated with CBD treatment. Therefore, Insys Development Company has 
identified these as Adverse Events of Special Interest. 
6.1.8.2. 
Classification of Adverse Events 
Adverse events are to be recorded on the AE page of the patient’s case report form (CRF).  
Severity will be graded according to the following definitions: 
• Mild: The patient experiences awareness of symptoms but these are easily tolerated or 
managed without specific treatment. 
• Moderate: The patient experiences discomfort enough to cause interference with 
usual activity, and/or the condition requires specific treatment. 
• Severe: The patient is incapacitated with inability to work or do usual activity, and/or 
the event requires significant treatment measures. 
Action taken will be categorized as none, study drug discontinued, dose modified, required 
concomitant medication, required procedure, or other. 
Event outcome at resolution or time of last follow-up will recorded as event resolved, resolved 
with sequelae, ongoing, or death. 
6.1.8.3. 
Causality/Drug Relationship Assessment 
The relationship of the event to the study drug should be determined by the investigator 
according to the following criteria:  
• Definitely related: The event follows a reasonable temporal sequence from the time of 
drug administration that cannot be explained, follows a known or expected response 
pattern to the study drug, that is confirmed by improvement on stopping and 
reappearance of the event on repeated exposure and that could not be reasonably 
explained by other factors such as the patient’s clinical condition, intercurrent illness, 
or concomitant drugs. 
• Not related: The event is most likely produced by other factors such as the patient’s 
clinical condition, intercurrent illness, or concomitant drugs, and does not follow a 
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Protocol Number INS011-17-113 
 
 
 
23 Aug 2018 
CONFIDENTIAL 
 44 
known response pattern to the study drug, or the temporal relationship of the event to 
study drug administration makes a causal relationship unlikely. 
• Possibly related: The event follows a reasonable temporal sequence from the time of 
drug administration, and/or follows a known response pattern to the study drug, but 
could have been produced by other factors such as the patient’s clinical condition, 
intercurrent illness, or concomitant drugs. 
• Unlikely related: The event follows little or no temporal sequence from the time of 
drug administration that makes a causal relationship improbable and/or other factors 
such as the patient’s clinical condition, intercurrent illness, or concomitant drugs is a 
more likely alternative. 
• Probably related: The event follows a reasonable temporal sequence from the time of 
drug administration, and/or follows a known response pattern to the study drug, and 
cannot be reasonably explained by other factors such as the patient’s clinical 
condition, intercurrent illness, or concomitant drugs. 
6.1.8.4. 
Definition of Serious Adverse Events 
A serious AE (SAE) is any AE that fulfills any of the following criteria, as per 21 CFR 312.32: 
• Results in death; 
• Is life-threatening; 
• Requires in-patient hospitalization or prolongation of existing hospitalization; 
• Results in persistent or significant disability or incapacity; 
• Is a congenital anomaly or birth defect; 
• Is medically significant or requires intervention to prevent one of the outcomes listed 
above. 
Serious AEs will be captured from the time of consent through the end of the study. 
6.1.8.5. 
Serious Adverse Events Actions Taken 
Actions taken may consist of: 
• None: No action taken 
• Treatment: Standard of care measures instituted 
• Drug withdrawn: Study medication was permanently discontinued because of the AE 
• Unknown: Not known, not observed, not recorded, or refused 
6.1.8.6. 
Serious Adverse Events Outcome at the Time of Last Observation 
The outcome at the time of last observation will be classified as: 
• Recovered/resolved 
• Recovered/resolved with sequelae 
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Protocol Number INS011-17-113 
 
 
 
23 Aug 2018 
CONFIDENTIAL 
 45 
• Not recovered/not resolved 
• Death 
• Unknown 
6.1.8.7. 
Adverse Event Recording and Reporting 
Adverse events will be recorded throughout the study in the source documents and in the CRFs. 
The investigator will rate AEs for seriousness, intensity, causality, action taken, and outcome as 
described in the previous section. 
Expedited reporting is required for serious unexpected adverse drug reactions. Fatal or 
life-threatening unexpected drug reactions must be reported by the Sponsor to regulatory 
agencies no more than 7 days after the Sponsor’s first knowledge of the reaction; followed by as 
complete a report as possible within 8 additional days. Unexpected drug reactions must be 
reported no later than 15 days after the Sponsor’s first knowledge of the reaction. In order to 
comply with these requirements, the investigator or delegate must inform the Sponsor 
immediately upon occurrence of any SAE. The site will complete the SAE Report Form as 
thoroughly as possible and e-mail it to Insys within 24 hours of the investigators first knowledge 
of the event. 
Sponsor contact information is listed below: 
Insys Development Company, Inc.  
Email: clinicalpv@insysrx.com  
These SAE reports must contain the following information: 
A. Study name/number 
B. Study drug 
C. Investigator details (name, phone, fax, e-mail) 
D. Patient number 
E. Patient initials 
F. Patient demographics 
G. Clinical event 
1) 
Description 
2) 
Date of onset 
3) 
Treatment (drug, dose, dosage form) 
4) 
Adverse event relationship to study drug 
5) 
Action taken regarding study drug in direct relationship to the AE 
H. If the AE was fatal or life-threatening 
I. 
Cause of death (whether or not the death was related to study drug) 
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Protocol Number INS011-17-113 
 
 
 
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CONFIDENTIAL 
 46 
J. 
Autopsy findings (if available) 
The Sponsor or its representative will be responsible for notification to regulatory agencies. 
6.1.8.8. 
Adverse Event Follow-Up 
All non-serious AEs that are not related or unlikely to be related to study treatment will be 
followed until the end of study participation. All SAEs or AEs that are considered as possibly, 
probably, or definitely related to treatment will be followed until resolution or stabilization. 
6.1.8.9. 
Special Considerations 
Cannabidiol inhibits drug metabolism mediated by a subset of CYP proteins (see Section 
Section 1.1.2). Thus, the investigator and study center staff should monitor patients who are 
taking concomitant medications that are metabolized by CYP2C19, CYP2C9, CYP2D6, 
CYP3A4, CYP1A2, or by P-glycoprotein with special care..  
 
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Protocol Number INS011-17-113 
 
 
 
23 Aug 2018 
CONFIDENTIAL 
 47 
7. 
STUDY PROCEDURES 
Prior to performing any study related procedures or assessments, the Investigator will ensure that 
the patients and/or their parent(s)/caregiver(s) (if applicable) provide written informed consent 
and that the perdiatric patient provides assent (as appropriate). Patients and their 
parent(s)/caregiver(s) (if applicable) will receive a copy of the informed consent form (ICF) and 
asent 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 11.4 for guidelines regarding patient consent and assent. 
The assessments and procedures that will be conducted during this study are summarized in 
Table 1. 
7.1. 
Safety Period 
7.1.1. 
Visit 1 (Day 1) 
The following procedures and assessments will be performed: 
• Review/Assess past/current AEDs and concomitant medications. 
• Record vital signs, collect blood samples for clinical labs, and collect urine sample 
for urinalysis. 
• Urine dipstick pregnancy test (all female patients of childbearing potential).  
• Perform physical and brief neurological examinations. 
• 12-lead ECG. 
• Collect/review/dispense CBD (dose may be modified up to 40 mg/kg/day at 
investigator’s discretion). 
• Perform drug accountability. 
• Review AEs. 
7.1.2. 
Monthly (Visits 2, 3, and 4) and Quarterly (Visits 5 and 6) Visits  
The following procedures and assessments will be performed: 
• Review/Assess past/current AEDs and concomitant medications. 
• Record vital signs, collect blood samples for clinical labs, complete 12-lead ECG, and 
collect urine sample for urinalysis. 
• Perform physical and brief neurological examinations. 
• Collect/review/dispense CBD (dose may be modified up to 40 mg/kg/day at 
investigator’s discretion). 
• Perform drug accountability. 
• Review AEs. 
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Protocol Number INS011-17-113 
 
 
 
23 Aug 2018 
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7.2. 
End of Study (Visit 7) or Early Withdrawal 
The following procedures and assessments will be performed: 
• Review/assess past/current AEDs and concomitant medications. 
• Record vital signs, collect blood samples for clinical labs, complete 12-lead ECG, and 
collect urine sample for urinalysis.  
• Perform physical and brief neurological examinations. 
• Collect/review CBD (dose may be modified up to 40 mg/kg/day at investigator’s 
discretion). 
• Perform drug accountability. 
• Review AEs. 
• Complete C-SSRS. 
• Urine dipstick pregnancy test (all female patients of childbearing potential).  
• Dispense CBD for Taper Period. 
• End of Study assessments (If the patient withdraws prematurely from the Safety 
Period, all Visit 7 (End of Study) procedures should be conducted. Site staff will 
follow-up with the patient 4 weeks after completion of treatment via the telephone to 
collect information regarding AEs, AEDs, and concomitant medications. 
7.3. 
Taper Period (Visit 8) 
The following procedures and assessments will be performed: 
• Collect CBD.  
• Review AEs. 
7.4. 
Follow-Up Period (Visit 9) 
The following assessments will be performed by phone call 30 days after Visit 7 (End of Study) 
the last study dose:  
• Review/assess past/current AEDs and concomitant medications. 
• Review AEs. 
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Protocol Number INS011-17-113 
 
 
 
23 Aug 2018 
CONFIDENTIAL 
 49 
8. 
STATISTICS 
8.1. 
Safety Endpoints 
Changes in safety endpoints will be reported as mean/median change from baseline at relevant 
time points and as a listing of events that fall outside normal limits. Baseline is defined as Visit 6 
of INS011-17-103.  
• Incidence, type, and severity of AEs and serious adverse events (SAEs) associated 
with Cannabidiol Oral Solution (i.e., treatment-emergent adverse events [TEAEs]). 
• Changes from baseline in vital signs, physical exam (including height and weight), 
ECG findings, and laboratory values (hematology, chemistry, and urinalysis). 
• Changes from baseline in neurological exam. 
8.2. 
Sample Size Determination 
The sample size is based on successful completion of INS011-17-103, with a maximum of 
30 patients.  
8.3. 
Analysis Populations 
Statistical analsysis will be conducted on all enrolled patients. 
8.4. 
Statistical Analyses 
This section presents a summary of the planned statistical analyses. A Statistical Analysis Plan 
(SAP) that describes the details of the analyses to be conducted will be finalized prior to database 
lock. 
Summary statistics will be provided for the variables described as follows. For continuous 
variables, these statistics will typically include the number of patients, mean, standard deviation, 
median, minimum, and maximum. For categorical variables, these statistics will typically include 
the number and percentage of patients in each category. 
8.4.1. 
Study Patients and Demographics 
8.4.1.1. Disposition and Withdrawals 
The numbers of patients entering, completing, and withdrawing, along with reasons for 
withdrawal, will be tabulated overall and by modal dose group. For each patient, the modal dose 
is the dose with the longest exposure during the study. 
8.4.1.2. Protocol Deviations 
Protocol deviations will be identified and classified as minor or major and listed. 
8.4.1.3. Demographics and Other Baseline Characteristics 
Demographic and baseline characteristics (including age, gender, race, weight, height, and BMI) 
will be summarized by for the overall population by descriptive statistics. No formal statistical 
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Protocol Number INS011-17-113 
 
 
 
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CONFIDENTIAL 
 50 
analyses will be performed. Medical history, clinical laboratory test results, and ECG 
assessments will be listed and summarized by descriptive statistics. 
Prior and concomitant medications will be summarized by the number and percentage of patients 
taking each medication. They will also be classified by using the World Health Organization 
Drug Dictionary Anatomical Therapeutic Chemical classes and preferred terms. 
8.4.2. 
Exposure and Compliance 
The exposure to study medication will be summarized by descriptive statistics. Any compliance 
deviations will be listed. 
8.4.3. 
Safety and Tolerability Analyses 
No formal inferential analyses will be conducted for safety variables.  Data listings will be 
provided for protocol-specified safety data.  
8.4.3.1. Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA, version 20.0 or higher) will be 
used to classify all AEs. Adverse event summaries will include only TEAEs, which will be 
summarized for each modal dose group. For each patient, the modal dose is the dose with the 
longest exposure during the study. 
The number and percentage of patients with AEs will be displayed for each treatment group by 
system organ class and preferred term. Summaries of AEs by severity and relationship to the IP 
will also be provided. Serious AEs (SAEs) and AEs resulting in discontinuation will be 
summarized separately in a similar manner.  Patient listings of AEs and SAEs will be produced. 
8.4.3.2. Clinical Laboratory Evaluations 
For the continuous laboratory parameters, descriptive statistics will be presented for values 
collected at all study visits as indicated in Table 1.  
8.4.3.3.  Vital Signs 
For blood pressure, pulse rate, temperature, and respiration rate, descriptive statistics will be 
presented for values collected at all study visits as indicated in Table 1. 
8.4.3.4. Electrocardiograms 
For the continuous ECG parameters, descriptive statistics will be presented for values collected 
at each visit, and for the changes from Baseline to End of Study/Early Withdrawal. 
Additionally, the number and percentage of patients will be presented as shift tables for the 
overall interpretation from Screening (normal or abnormal, not clinically significant [NCS]) to 
End of Study/Early Withdrawal (normal; abnormal, NCS; or abnormal, clinically significant 
[CS]). 
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Protocol Number INS011-17-113 
 
 
 
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8.4.3.5. Physical Examination Findings 
Physical examination body systems will be presented as the number and percentage of patients 
that have normal or abnormal results at each visit. The examination will include evaluation of 
height, weight, general appearance, skin, eyes, ears, nose, throat, neck, lymph nodes, chest, heart, 
abdomen, and extremities.  
8.4.3.6. Columbia Suicide Severity Rating Scale (C-SSRS) 
C-SSRS categorization based on Columbia Classification Algorithm of Suicide Assessment 
(C-CASA) categories 1, 2, 3, 4, and 7 will be summarized as dichotomous endpoints at End of 
Study/Early Withdrawal Visits. 
8.4.4. 
Interim Analysis 
No Interim analyses are planned. 
8.4.5. 
Missing Data 
There will be no imputation of the missing values. All assessments will be conducted based on 
all the observed data.   
 
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9. 
STUDY CONDUCT 
Steps to ensure the accuracy and reliability of data include the selection of qualified investigators 
and appropriate study sites, review of protocol procedures with the investigator and associated 
personnel prior to the study, periodic monitoring visits, and meticulous data management. 
9.1. 
Sponsor and Investigator Responsibilities 
9.1.1. 
Sponsor Responsibilities 
The sponsor, and/or sponsor’s representative is obligated to conduct the study in accordance with 
strict ethical principles. The sponsor reserves the right to withdraw a patient from the study, to 
terminate participation of a study site at any time, and/or to discontinue the study. 
The sponsor, or sponsor’s representative, agrees to provide the investigator with sufficient 
material and support to permit the investigator to conduct the study according to the study 
protocol. 
9.1.2. 
Investigator Responsibilities 
By signing the Investigator’s Agreement, the investigator indicates that she/he has carefully read 
the protocol, fully understands the requirements, and agrees to conduct the study in accordance 
with the procedures and requirements described in this protocol. 
The investigator also agrees to conduct this study in accordance with all laws, regulations, and 
guidelines of the pertinent regulatory authorities, including and in accordance with the April 
1996 International Conference on Harmonisation (ICH) Guidance for Industry E6 Good Clinical 
Practice (GCP) and in agreement with the 1996 Version of the Declaration of Helsinki. While 
delegation of certain aspects of the study to sub-investigators and study coordinators is 
appropriate, the investigator will remain personally accountable for closely overseeing the study 
and for ensuring compliance with the protocol and all applicable regulations and guidelines. The 
investigator is responsible for maintaining a list of all persons that have been delegated study-
related responsibilities (e.g., sub-investigators and study coordinators) and their specific study-
related duties. 
Investigators should ensure that all persons who have been delegated study-related 
responsibilities are adequately qualified and informed about the protocol, IPs, and their specific 
duties within the context of the study. Investigators are responsible for providing CRO with 
documentation of the qualifications, GCP training, and research experience for themselves and 
their staff as required by the sponsor and the relevant governing authorities. 
To ensure compliance with the guidelines, the study will be audited by an independent person. 
The investigator agrees, by written consent to this protocol, to cooperate fully with compliance 
checks by allowing access to all study documentation by authorized individuals. 
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9.2. 
Site Initiation 
Study personnel may not screen or enroll patients into the study until after receiving notification 
from the sponsor or sponsor’s representative that the study can be initiated at the study site. The 
study site will not be authorized for study initiation until: 
• The study site has received the appropriate institutional review board (IRB) approval 
for the protocol and the appropriate informed consent form (ICF). 
•  All regulatory documents have been submitted to and approved by the sponsor or 
sponsor’s representative. 
• The study site has a clinical trial agreement in place. 
• Study site personnel, including the investigator, have participated in a study initiation 
meeting. 
9.3. 
Screen Failures 
Patients who fail inclusion and/or exclusion criteria may not be rescreened for the study. 
9.4. 
Study Documents 
All documentation and material provided by the sponsor, or sponsor’s representative for this 
study are to be retained in a secure location and treated as confidential material. 
9.4.1. 
Investigator’s Regulatory Documents 
The regulatory documents must be received from the investigator and reviewed and approved by 
the sponsor or sponsor’s representative before the study site can initiate the study and before the 
sponsor, or sponsor’s representative, will authorize shipment of investigational product (IP) to 
the study site. Copies of the investigator’s regulatory documents must be retained at the study 
site in a secure location. Additional documents, including a copy of the protocol and applicable 
amendment(s), the IB, CRF/electronic case report form (eCRF) completion guidelines, copies of 
regulatory references, copies of IRB correspondence, and IP accountability records should also 
be retained as part of the investigator’s regulatory documents. It is the investigator’s 
responsibility to ensure that copies of all required regulatory documents are organized, current, 
and available for inspection. 
9.4.2. 
Case Report Forms 
By signing the Investigator’s Agreement, the investigator agrees to maintain accurate 
CRFs/eCRFs and source documentation as part of the case histories for all patients who sign an 
ICF. 
Case report forms are considered confidential documents and should be handled and stored 
accordingly. The sponsor, or sponsor’s representative, will provide the necessary training on the 
use of the specific CRFs/eCRF system used during the study to ensure that the study information 
is captured accurately and appropriately. 
To ensure data accuracy, CRF/eCRF data for individual patient visits should be completed as 
soon as possible after the visit. All requested information must be entered in the CRF/electronic 
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data capture (EDC) system according to the completion guidelines provided by the sponsor, or 
sponsor’s representative. 
9.4.3. 
Source Documents 
All information recorded in the CRF/EDC system must be supported by corresponding source 
documentation. Examples of acceptable source documentation include, but are not limited to, 
hospital records, clinic and office charts, laboratory notes, and recorded data from automated 
instruments, memoranda, and pharmacy dispensing records. 
During the study, select CRF/eCRF data may be used as original data collection tools as long as 
a description of this documentation process is maintained in the investigator’s study files. 
Clinical laboratory data required by the protocol will be electronically transferred from the 
central laboratory to the sponsor or the sponsor’s representative. A paper copy of the laboratory 
results will be provided to the study site and should be retained with each patient’s source data. 
The investigator will provide direct access to source data and documents for trial-related 
monitoring, audits, IEC/IRB review, and regulatory requirements. 
9.5. 
Study Termination 
The study may be terminated at the sponsor’s discretion at any time and for any reason. Study 
sites may be asked to have all patients currently participating in the study complete all of the 
assessments for the telephone follow-up call. 
In the event of study discontinuation, study sites may be asked to have all patients currently 
participating in the study complete all of the assessments for the Early Withdrawal Visit. 
9.6. 
Study Site Closure 
At the end of the study, all study sites will be closed. The sponsor or sponsor’s representative 
may terminate participation of a study site at any time. Examples of conditions that may require 
premature termination of a study site include, but are not limited to, the following: 
• Noncompliance with the protocol and/or applicable regulations and guidelines 
• Inadequate patient enrollment 
9.6.1. 
Record Retention 
The investigator shall retain and preserve one copy of all data generated during the course of the 
study, specifically including, but not limited to, those defined by GCP as essential until the 
following occur: 
• At least 2 years after the last marketing authorization for the Investigational Product 
has been approved or the sponsor has discontinued its research with the 
Investigational Product, or 
• At least 2 years have elapsed since the formal discontinuation of clinical development 
of the Investigational Product 
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These documents should be retained for a longer period, however, if required by the applicable 
regulatory requirement(s) or if needed by the sponsor. 
9.6.2. 
Laboratory Sample Retention 
Laboratory samples may be used for purposes related to this research. The samples will be stored 
until the sponsor has determined that specimens are no longer needed and the decision has been 
made that none of the samples needs to be reanalyzed. In addition, identifiable samples can be 
destroyed at any time at the request of the patient. 
 
 
 
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10. 
QUALITY CONTROL AND QUALITY ASSURANCE 
The sponsor or its designee will implement and maintain quality control and quality assurance 
procedures with written standard operating procedures to ensure the study is conducted and data 
are generated, documented, and reported in compliance with the protocol, GCP, and applicable 
regulatory requirements. This trial will be conducted in accordance with the provisions of the 
Declaration of Helsinki (October 1996) and all revisions thereof, and in accordance with the 
FDA CFR 312.50 and 312.56, and with the ICH guidelines on GCP (CPMP/ICH/135/95). 
10.1. 
Changes To The Protocol 
Only Insys may modify the protocol. Amendments to the protocol will be made only after 
consultation and agreement between the sponsor and the investigator. The only exception is 
when the investigator assesses a patient’s safety will be compromised without immediate action. 
In these circumstances, immediate approval of the chairman of the IEC/IRB must be sought, and 
the investigator should inform the sponsor and the full IEC/IRB within 5 working days after the 
emergency occurred. All amendments that have an impact on patient risk or the study objectives, 
or require revision of the informed consent form, must receive approval from the IEC/IRB prior 
to their implementation. 
10.2. 
Monitoring 
The sponsor or sponsor’s representative will conduct site visits to monitor the study and ensure 
compliance with the protocol, GCP, and applicable regulations and guidelines. The assigned 
clinical research associate(s) (CRA[s]) will visit the investigator and study site at periodic 
intervals and maintain periodic communication. The investigator agrees to allow the CRA(s) and 
other authorized sponsor/contract research organization (CRO) personnel access. The CRA(s) 
will maintain current personal knowledge of the study through observation, review of study 
records and source documentation, and discussion of the conduct of the study with the 
investigator and staff. 
10.3. 
Data Review Meeting 
The sponsor will review all data reported in CRFs of all patients before database lock. The data 
review meeting determines whether all enrolled patients can be included in the analysis 
population according to the specified definition of analysis populations and evaluates whether or 
not medical decisions of the investigator were appropriate for important data affecting the safety 
endpoints. 
10.4. 
Protocol Violations  
The investigator will conduct the study in compliance with the protocol approved by the IRB. 
Modifications to the protocol should not be performed without agreement of both the 
investigator and the sponsor. Changes to the protocol will require written IRB approval prior to 
implementation, except when the modification is needed to eliminate an immediate hazard(s) to 
patients. 
The investigator or sub-investigator should document any deviation from the protocol and the 
reason. If the investigator performs a deviation from the protocol or a change of the protocol to 
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eliminate an immediate hazard(s) to patients, the record should be immediately submitted to the 
sponsor, the CRU, and the IRB by the investigator and the IRB will provide expedited review 
and approval. After the investigator has obtained approval of the IRB, the investigator should 
obtain written permission of the CRU and written agreement of the sponsor. 
When deviation from the protocol is required to eliminate immediate hazard(s) to patients, the 
investigator will contact the sponsor, if circumstances permit, to discuss the planned course of 
action. Any deviations from the protocol must be fully documented in the CRF and source 
documentation. 
10.5. 
Quality Assurance Audit 
This study will be subject to audit by the sponsor, CRO, or designee. 
The sponsor or sponsor’s representative may conduct audits on a selection of study sites, 
requiring access to patient notes, study documentation, and facilities or laboratories used for the 
study. 
The study site, facilities, all data (including source data), and documentation will be made 
available for audit by quality assurance auditors and for IRB or regulatory authorities according 
to GCP guidelines. The investigator agrees to cooperate with the auditor during the visit and will 
be available to supply the auditor with CRFs or other files necessary to conduct that audit. Any 
findings will be strictly confidential. 
If a regulatory authority informs the investigator that it intends to conduct an inspection, the 
investigator shall notify sponsor or sponsor’s representative immediately. 
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11. 
REGULATORY AND ETHICAL CONSIDERATIONS 
11.1. 
Regulatory Authority Approval 
The investigator will ensure that the protocol and consent form are reviewed and approved by the 
appropriate Independent Ethics Committee/Institutional Review Board (IEC/IRB) prior to the 
start of any study procedures. The IEC/IRB will be appropriately constituted and will perform its 
functions in accordance with Food and Drug Administration (FDA) regulations, International 
Conference on Harmonization (ICH) good clinical practice (GCP) guidelines, and local 
requirements as applicable. 
In addition, the IRB will approve all protocol amendments (except for logistical or administrative 
changes), written informed consent documents and document updates, patient recruitment 
procedures, written information to be provided to the patients, available safety information, 
information about payment and compensation available to patients, the investigator’s curriculum 
vitae and/or other evidence of qualifications, and any other documents requested by the IRB/IEC 
and regulatory authority, as applicable. 
11.2. 
Ethical Conduct of the Study 
The study will be conducted in accordance with the Declaration of Helsinki and GCP according 
to ICH guidelines. Specifically, the study will be conducted under a protocol reviewed by an IRB 
or IEC; the study will be conducted by scientifically and medically qualified persons; the 
benefits of the study are in proportion to the risks; the rights and welfare of the patients will be 
respected; the physicians conducting the study do not find the hazards to outweigh the potential 
benefits; and each patient will give his or her written, informed consent before any protocol-
driven tests or evaluations are performed. 
11.3. 
Statement of Investigator/Delegation of Authority 
As a condition for conducting the clinical investigation, the Principal Investigator will sign the 
FDA Form 1572, Statement of Investigator (21 Code of Federal Regulations [CFR] Part 312). 
The Principal Investigator will ensure that all persons assisting with the trial are adequately qualified, 
informed about the protocol, any amendments to the protocol, the study treatments, and their trial-related 
duties and functions. The qualified investigator will maintain a list of sub-investigator and other 
appropriately qualified persons to whom to delegate significant trial-related duties. Should the qualified 
investigator delegate the supervision of the investigational product administration to a designated person, 
this individual must have the appropriate medical qualifications to effectively conduct or supervise any 
potential resuscitation procedures. 
11.4. 
Patient Informed Consent 
The investigator or his/her designee will inform the patient of all aspects pertaining to their 
participation in the study. The process for obtaining patient informed consent will be in 
accordance with all applicable regulatory requirements (e.g., CFR Part 50 and ICH E6 Section 
4.8). The investigator or his/her designee and the patient must both sign and date the informed 
consent document (ICD) before they can participate in the study. The patient will receive a copy 
of the signed and dated form, and the original will be retained in the site’s study records. The 
decision to participate in the study that is made by the patient is entirely voluntary. The 
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investigator or his/her designee must emphasize to the patient that consent for study participation 
may be withdrawn at any time without penalty or loss of benefits to which the patient is 
otherwise entitled. If the ICD is amended during the study the investigator must follow all 
applicable regulatory requirements pertaining to approval of the amended ICD by the IRB, and 
use of the amended form, including the necessity of re-consenting ongoing patients. 
11.4.1. 
Assent Guidance 
The IRB/IEC must determine, to the extent required by 45 CFR 46.116, that adequate provisions 
are made for soliciting the assent of pediatric patients (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 patients 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 patients in this study will not be 
required.  Informed consent from all parent(s)/caregiver(s) will be required. 
11.5. 
Investigator Reporting Requirements 
In accordance with applicable local regulatory requirements, the investigator may be obligated to 
provide periodic safety updates on the conduct of the study at his/her site and notification of 
study closure to the IRB. Such periodic safety updates and notifications are the responsibility of 
the investigator and not of Insys or its delegate. 
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12. 
DATA HANDLING AND RECORD KEEPING 
The CRO will be responsible for data management and analysis. The procedures will be 
specified in the Data Management Plan. 
12.1. 
Data Management 
The CRO will be responsible for activities associated with the data management of this study. 
The standard procedures for handling and processing records will be followed per GCP and the 
CRO’s SOPs. A comprehensive Data Management Plan will be developed including a data 
management overview, database contents, annotated CRF and consistency checks. Study site 
personnel will be responsible for providing resolutions to all data queries. The investigator will 
be required to document electronic data review to ensure the accuracy of the corrected and/or 
clarified data. 
12.2. 
Case Report Forms and Source Documents 
The CRFs will be supplied by the CRO data management services. The complete CRFs will be 
reviewed, signed, and dated by the qualified investigator and a copy returned to the Sponsor with 
the final report. 
Source documents are defined as original documents, data, and records. This may include 
hospital records, clinical and office charts, laboratory data/information, patients’ diaries or 
evaluation checklists, pharmacy dispensing and other records, recorded data from automated 
instruments, microfiches, photographic negatives, microfilm or magnetic media and/or x rays. 
12.3. 
Documentation and Retention of Essential Documents 
All documents pertaining to the study, including a copy of the approved protocol, copy of the 
ICD, completed CRFs, source documents, drug accountability and retention records, and other 
study related documents will be retained in the permanent archives of the study site. These will 
be available for inspection at any time by the Sponsor or the FDA. Per 21 CFR 312, record 
retention for this study is required for a period of two years following the date on which this 
study agent is approved by the FDA for the marketing purposes that were the subject of this 
investigation; or, if no application is to be filed or if the application is not approved for such 
indication, until two years following the date on which the entire study is completed, terminated, 
or discontinued, and the FDA is notified. 
The investigator will provide direct access to source data and documents for trial related 
monitoring, audits, IEC/IRB review, and regulatory requirements. 
12.4. 
Financial Disclosure 
These issues will be addressed in a separate agreement between the sponsor and the investigator. 
The US FDA Financial Disclosure by Clinical Investigators (21 Code of Federal Regulations 
[CFR] 54) regulations require sponsors to obtain certain financial information from investigators 
participating in covered clinical studies; each investigator and sub-investigator is required to 
provide the required financial information and to promptly update Insys Development Company, 
Inc., with any relevant changes to their financial information throughout the course of the clinical 
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study and for up to one year after its completion. This rule applies to all investigators and sub-
investigators participating in covered clinical studies to be submitted to the FDA in support of an 
application for market approval. 
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13. 
FACILITIES 
Clinical Laboratory: Medpace 
5375 Medpace Way 
Cincinnati, OH 45227 
Data Management: PRA Health Sciences 
4130 Park Lake Avenue, Suite 400 
Raleigh, NC 27612 
Statistical Services: PRA Health Sciences 
4130 Park Lake Avenue, Suite 400 
Raleigh, NC 27612 
Pharmacovigilance:  PRA Health Sciences 
4130 Park Lake Avenue, Suite 400 
Raleigh, NC 27612 
 
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14. 
USE OF INFORMATION AND PUBLICATION POLICY 
14.1. 
Use of Information 
All information concerning Cannabidiol Oral Solution and Insys Development Company’s 
operations, such as Insys’ patent applications, formulas, manufacturing processes, basic scientific 
data, or formulation information, supplied by Insys Development Company and not previously 
published, is considered confidential information. 
This confidential information shall remain the sole property of Insys Development Company, 
shall not be disclosed to others without the written consent of Insys Development Company, and 
shall not be used except in the performance of this study. 
The investigator will maintain a confidential patient identification code list of all patients 
enrolled in the study (by name and patient number). This list will be maintained at the site, and 
will not be retrieved by Insys. 
14.2. 
Publication Policy 
Insys Development Company, Inc. will retain ownership of all data. All proposed publications 
based on this study will be subject to the sponsor’s approval requirements. 
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15. 
REFERENCES (AVAILABLE UPON REQUEST) 
1. Investigator’s Brochure  for Cannabidiol Oral Solution, Edition 8.0, 05 Oct 2017. 
2. Cunha JM, Carlini EA, Pereira AE, Ramos OL, Pimentel C, Gagliardi R, et al. Chronic 
administration of cannabidiol to healthy volunteers and epileptic patients. Pharmacol. 
1980; 21: 175-185. 
3. Carlini EA, Cunha JM. Hypnotic and antiepileptic effects of cannabidiol. J Clin 
Pharmacol. 1981; 21: 417S-427S. 
4. Porter BE, Jacobson C. Report of a parent survey of cannabidiol-enriched cannabis use in 
pediatric treatment-resistant epilepsy. Epilepsy Behav. 2013; 29: 574-577. 
5. Gedde MM, Maa E. Whole cannabis extract of high concentration cannabidiol may calm 
seizures in highly refractory pediatric epilepsies. America Epilepsy Society Meeting 2013; 
abstract: 3.300. 
6. Sponsor’s internal documentation of analysis. 
7. Zuardi AW, Shirakawa I, Finkelfarb E, Karniol IG. Action of cannabidiol on the anxiety 
and other effects produced by delta 9-THC in normal subjects. Psychopharmacology 
1982; 76: 245-250. 
8. Bisogno T, Hanus L, De Petrocellis L, et al. Molecular targets for cannabidiol and its 
synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and 
enzymatic hydrolysis of anandamide. Br J Pharmacol. 2001; 134: 845-852. 
9. Kathmann M, Flau K, Redmer A, Trankle C, Schlicker E. Cannabidiol is an allosteric 
modulator at mu- and delta-opioid receptors. Naunyn Schmiedebergs Arch Pharmacol. 
2006; 372: 354-361. 
10. Bornheim LM, Grillo MP. Characterization of cytochrome P450 3A inactivation by 
cannabidiol: possible involvement of cannabidiol-hydroxyquinone as a P450 inactivator. 
Chem Res Toxicol. 1998; 11: 1209 1216. 
11. Ryan D, Drysdale AJ, Lafourcade C, Pertwee RG, Platt B. Cannabidiol targets 
mitochondria to regulate intracellular Ca2+ levels. J Neurosci. 2009; 29: 2053-2063. 
12. Russo EB, Burnett A, Hall B, Parker KK. Agonistic properties of cannabidiol at 5-HT1A 
receptors. Neurochem Res. 2005; 30: 1037-1043. 
13. Carrier EJ, Auchampach JA, Hillard CJ. Inhibition of an equilibrative nucleoside 
transporter by cannabidiol: a mechanism of cannabinoid immunosuppression. Proc Natl 
Acad Sci US. 2006; 103: 7895-7900. 
14. Jones NA, Glyn SE, Akiyama S, et al. Cannabidiol exerts anti-convulsant effects in 
animal models of temporal lobe and partial seizures. Seizure. 2012; 21: 344-352. 
15. Harvey DJ, Samara E, Mechoulam R. Comparative metabolism of cannabidiol in dog, rat 
and man. Pharmacol Biochem Behav. 1991; 40: 523-532. 
16. Stout SM, Cimino NM. Exogenous cannabinoids as substrates, inhibitors, and inducers of 
human drug metabolizing enzymes: a systematic review. Drug Metab Rev. 2014 Feb; 46: 
86-95. 
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17. Bergamaschi MM, Queiroz RH, Zuardi AW, Crippa JA. Safety and side-effects of 
cannabidiol, a cannabis sativa constituent. Curr Drug Saf. 2011b; 6: 237-249. 
18. Yamaori S, Ebisawa J, Okushima Y, Yamamoto I, Watanabe K. Potent inhibition of 
human cytochrome P450 3A isoforms by cannabidiol: role of phenolic hydroxyl groups 
in the resorcinol moiety. Life Sci. 2011; 88: 730-736. 
19. Yamaori S, Kushihara M, Yamamoto I, Watanabe K. Characterization of major 
phytocannabinoids, cannabidiol and cannabinol, as isoform-selective and potent 
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CONFIDENTIAL 
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Protocol Number INS011-17-113 
 
 
 
23 Aug 2018 
CONFIDENTIAL 
 67 
16. 
INVESTIGATOR SIGNATURE PAGE 
 
TITLE:  
 
A Multicenter, Open-Label, Flexible Dose Study to Assess the 
Long-Term Safety of Pharmaceutical Grade Synthetic 
Cannabidiol Oral Solution in Pediatric Patients with Treatment-
Resistant Childhood Absence Seizures 
PROTOCOL NUMBER: 
INS011-17-113 
PHASE OF STUDY: 
Phase 2 Long-Term Safety Study 
PROTOCOL DATE: 
23 Aug 2018  
STUDY SPONSOR: 
Insys Development Company, Inc. 
1333 South Spectrum Blvd, Suite 100 
Chandler, AZ 85286 
 
 
 
 
PRINCIPAL INVESTIGATOR COMMITMENT: 
 
I, the undersigned Principal Investigator, submit this statement of commitment as evidence that I 
understand my responsibilities pursuant to the Code of Federal Regulations (21 CFR § 312.60 
through § 312.70, 21 CFR § 11, 50, 54, 56) and ICH E6 Good Clinical Practice guidelines, as 
well as with any and all applicable federal, state and/or local laws and regulations, and agree to 
conduct the study in accordance with the protocol referenced herein. 
 
 
 
 
 
 
 
Principal Investigator Printed Name 
 
 
 
 
 
Principal Investigator Signature 
 
Date 
 
 
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applicable federal,
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applicable federal,
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