Clinical trial NCT03458416
Conditions: Prader-Willi Syndrome
Sponsor: Radius Pharmaceuticals, Inc.
Start date: 2018-09-06; Completion date: 2019-07-31
Enrollment: 2 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The objective of this study is to assess the long-term safety and tolerability of Cannabidiol Oral Solution (CBD) in participants with Prader-Willi Syndrome.

Detailed description:

Arms: arm 1: Participants will receive total daily doses between 20 milligrams per kilograms per day (mg/kg/day), 30 mg/kg/day, and 40 mg/kg/day. The two equivalent doses will be administered twice a day with a standard meal approximately every 12 hours.
Interventions: intervention 1: Cannabidiol Oral Solution
Intervention descriptions: intervention 1: An oral solution containing pharmaceutical grade cannabidiol (nonplant-based).

Protocol documents:
Prot_000.pdf: 
 
 
 
CLINICAL TRIAL PROTOCOL 
 
 
A Multicenter, Open-Label Study to Assess the Long-Term Safety of 
Pharmaceutical Grade Synthetic Cannabidiol Oral Solution in Patients 
with Prader-Willi Syndrome 
 
Protocol Number: INS011-17-115 
Final Protocol Date: 27 Feb 2018 
Version: 1.0 
Investigational Product: Cannabidiol Oral Solution 
IND Number: IND 136,374 
 
ClinicalTrials.gov ID: NCT03458416 


CLINICAL TRIAL PROTOCOL 
 
A Multicenter, Open-Label Study to Assess the Long-Term Safety of 
Pharmaceutical Grade Synthetic Cannabidiol Oral Solution in Patients 
with Prader-Willi Syndrome 
Protocol Number: INS011-17-115 
Protocol Date: 27 Feb 2018   
Protocol Version: 1.0  
Investigational Product: Cannabidiol Oral Solution 
IND Number: 136,374 
Sponsor: Insys Development Company, Inc.
1333 South Spectrum Blvd, Suite 100 
Chandler, AZ 85286 
Medical Monitor: 
 DO 
Insys Development Company, Inc. 
Sr. Director, Clinical Development/Medical 
Affairs 
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 INS011-17-115 
27 Feb 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 Study to Assess the Long-Term Safety of Pharmaceutical Grade 
Synthetic Cannabidiol Oral Solution in Patients with Prader-Willi Syndrome 
Study center(s): Approximately 10 sites in the US. 
Phase of development: Phase 2  
Objective:  
The objective of this study is to assess the long-term safety and tolerability of Cannabidiol 
Oral Solution (CBD) in patients with Prader-Willi Syndrome. 
Methodology: 
This is a multicenter, open-label study designed to assess long-term safety and tolerability of 
CBD in patients with Prader-Willi Syndrome. Patients must have completed INS011-16-085 
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 this long-term safety study (INS011-17-
115) after completing INS011-16-085 Visit 10 (Study Completion) to avoid interruption of the 
investigational product. Patients will have up to 2 weeks to enroll in INS011-17-115.    
Patients will receive CBD treatment for approximately 48 weeks.   Total daily doses ranging 
from 20 mg/kg/day to 40 mg/kg/day will be administered with standard meal. 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 (6±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. 
INS011-17-115-PWS LTS protocol Final 27Feb2018 | VV-TMF-115256 | 1.0
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Protocol Number INS011-17-115 
27 Feb 2018 
 
 
 
 
 
    CONFIDENTIAL 
 
 
 
 
 
 
                     4 
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 concomitant 
medications. 
• Review of vital signs. 
• Review clinical labs. 
• Urinanalysis (Visit 1 only). 
• Urine pregnancy screening for 
post-menarchal females.  
• Columbia-Suicide Severity 
Rating Scale (C-SSRS).   
• Dispensing CBD.  
• Drug accountability.  
• Review adverse events (AEs).  
• 12-lead ECG  
• Physical examination. 
• Weight. 
• Urine drug screen. 
• Urine pregnancy screen for post-
menarchal females 
At End of Study (Visit 7) or Early Withdrawal, the following assessments will be completed: 
• Review of concomitant 
medications.  
• Review clinical labs 
• 12-lead ECG.  
• Review AEs.  
• Review of vital signs. 
• Drug accountability.  
• Urine drug screen. 
• Urinalysis. 
• Urine pregnancy screen for post-
menarchal females.  
• Physical examination. 
• Weight. 
• Dispensing CBD.  
• Columbia-Suicide Severity Rating Scale 
(C-SSRS).  
• Hyperphagia Questionnaire for Clinical 
Trial (HQ-CT)  
At Taper Period (Visit 8), the following will be completed:  
• Collect CBD.  
• Review AEs. 
At Follow-Up (phone call only), the following assesments will be completed: 
• Review of concomitant medications.  
• Review AEs. 
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Insys Development Company, Inc. 
Protocol Number INS011-17-115 
27 Feb 2018 
 
 
 
 
 
    CONFIDENTIAL 
 
 
 
 
 
 
                     5 
Taper Period  
At the end of the Long-Term Safety study, patients will be tapered off of CBD. The following 
tapering scheme will be utilizied: 40 mg/kg/day will be reduced to 30 mg/kg/day for three 
days, then 30 mg/kg/day will be reduced to 20 mg/kg/day for three days, then discontinued; 
30 mg/kg/day will be reduced to 20 mg/kg/day for three days, then discontinued. 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). Patient will begin tapering the day after 
Visit 7. 
• Patient withdraws early. 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 the End of Study (Visit 7) or Early 
Withdrawal AEs and record concomitant medications.  
Number of patients (planned):  
Approximatley 66 patients who completed INS011-16-085 will be enrolled in the study.  
Diagnosis and main criteria for inclusion:  
Inclusion criteria 
1. Completed activities up to and including Visit 10 (Study Completion) of INS011-16-
085. 
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. If female, is either not of childbearing potential (defined as premenarchal or surgically 
sterile [bilateral tubal ligation, bilateral oophorectomy, or hysterectomy]) or practicing 
one of the following medically acceptable methods of birth control: 
a. Hormonal methods such as oral, implantable, injectable, vaginal ring, or 
transdermal contraceptives for a minimum of 1 full cycle (based on the patient’s 
usual menstrual cycle period) before study drug administration. 
b. Total abstinence from sexual intercourse since the last menses before study drug 
administration. 
c. Intrauterine device. 
d. Double-barrier method (condoms, sponge, or diaphragm with spermicidal jellies or 
 
cream). Growth hormone treatment will be permitted if doses have been stable for 
 
at least 1 month prior to screening. 
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Protocol Number INS011-17-115 
27 Feb 2018 
 
 
 
 
 
    CONFIDENTIAL 
 
 
 
 
 
 
                     6 
4. Psychotropic treatment will be permitted if the subject has been on a stable dose during 
the INS011-16-085 and does not anticipate a dose change during the course of the 
study. 
5. Growth hormone treatment will be permitted if the subject has been on a stable dose 
during INS01-16-085. 
6. Any other treatment including thyroid hormones should be stable prior to entering the 
INS011-17-113 study. 
7. 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. Uncontrolled Type I and Type II Diabetes. 
4. Developed an adverse event thought to be related to CBD in the previous study and the 
investigator determines that continuing treatment with CBD would not be in the best 
interest of the patient. 
5. History of clinically significant gastrointestinal, renal, hepatic, neurologic, 
hematologic, endocrine, oncologic, pulmonary, immunologic, psychiatric, or 
cardiovascular disease, or other condition which would jeopardize safety or impact 
validity of results (per investigator). 
6. Currently taking felbamate. 
7. Compromised respiratory function or severe respiratory insufficiency. 
8. Pregnant or lactating female.. 
9. 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, 20 mg/kg/day, 30 mg/kg/day, and 40 mg/kg/day, divided into 
twice daily doses with standard meal, manufactured for and supplied by Insys Development 
Company, Inc.    
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:  
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Protocol Number INS011-17-115 
27 Feb 2018 
 
 
 
 
 
    CONFIDENTIAL 
 
 
 
 
 
 
                     7 
Not applicable. 
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). 
• Change from baseline in weight. 
Exploratory Efficacy Endpoint 
• Change in total score of the HQ-CT from Baseline to Study Completion/Early 
Withdrawal. 
Baseline is defined as Visit 10 of INS011-16-085. 
Statistical Methods: 
Safety Analysis 
All safety assessments, including AEs, clinical laboratory evaluations, vital signs, 12-lead 
ECGs, and physical examination (including weight) 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. 
• Weight will be listed and 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. 
• 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 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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Protocol Number INS011-17-115 
27 Feb 2018
CONFIDENTIAL
                    
                                8 
Table 1: 
Schedule of Events 
ASSESSMENTS 
SAFETY PERIOD 
 
TAPER PERIOD 
FOLLOW-UP 
PERIODg 
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
Week 48
0-6 Days
30 Days After EOS
Visit Window (Days) 
± 5 
± 5 
± 5 
± 3 
 
± 3 
± 5 
Informed consent ** 
X 
 
 
 
 
 
 
Review of 
inclusion/exclusion 
criteria ** 
X 
 
 
 
 
 
 
C-SSRS 
X 
 
 
X 
X 
 
 
Review concomitant 
medications 
X 
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 
 
 
Urine pregnancy screen 
for post-menarchal 
females 
X 
 
 
X 
X 
 
 
Urine drug screen 
X 
 
 
X 
X 
 
 
Physical examinationd 
X 
X 
X 
X 
X 
 
 
Hyperphagia 
Questionnaire for 
Clinical Trial (HQ-CT) 
 
 
 
X 
X 
 
 
Dosing with Cannabidiol 
Oral Solution 
X  
X 
X 
X 
Xe 
X e 
 
Drug accountability 
X 
X 
X 
X 
X 
X 
 
AEs 
X 
X 
X 
X 
X 
X 
X 
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Protocol Number INS011-17-115 
27 Feb 2018 
CONFIDENTIAL
                                                     9 
ASSESSMENTS 
SAFETY PERIOD 
 
TAPER PERIOD 
FOLLOW-UP 
PERIODg 
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 
Week 48 
 
0-6 Days 
30 Days After EOS 
Visit Window (Days) 
± 5 
± 5 
± 5 
± 3 
 
± 3 
± 5 
End of Study  
 
 
 
X 
Xf 
 
 
** To be completed prior to enrollment into LTS, specifically within the 2-week period that is allotted post completion of Visit 10 (Study Completion) of INS011-16-085. 
a For  patients who enroll within the first 2 weeks after completion of Visit 10 (Study Completion) of INS011-16-085 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 weight, and evaluation of general appearance, skin, eyes, ears, nose, throat, neck, lymph nodes, chest, heart, abdomen, and extremities. 
e 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 30 mg/kg/day for three days, then 30 mg/kg/day will be reduced to 20 mg/kg/day for three days, then discontinued; 30 mg/kg/day will be reduced to 
20 mg/kg/day for three days, then discontinued. This can be modified by the investigator based upon the patient’s response. 
f 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 and concomitant medications. 
gFollow-up Period Visit 9 will be a phone call. 
AE = adverse event.  
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Protocol Number INS011-17-113 
27 Feb 2018 
CONFIDENTIAL
10 
TABLE OF CONTENTS 
PROTOCOL APPROVAL PAGE ...................................................................................................2
PROTOCOL SYNOPSIS ................................................................................................................3
TABLE OF CONTENTS ...............................................................................................................10
List of Tables .................................................................................................................................14
List of Figures ................................................................................................................................14
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................15
1.
INTRODUCTION ......................................................................................................18
1.1.
Cannabidiol .................................................................................................................18
1.1.1.
Mechanism of Action .................................................................................................19
1.1.2.
Metabolism and Potential Drug Interactions ..............................................................19
1.2.
Nonclinical Experience ...............................................................................................19
1.2.1.
Safety ..........................................................................................................................19
1.2.2.
Efficacy .......................................................................................................................20
1.2.2.1.
Single Dose Regimens ................................................................................................20
1.2.2.2.
Multiple Dose Regimens ............................................................................................21
1.3.
Clinical Experience .....................................................................................................21
1.3.1.
Pharmacokinetics ........................................................................................................25
1.3.2.
Overview of Safety .....................................................................................................26
1.3.3.
Clinical Safety Data ....................................................................................................26
1.4.
Prader-Willi Syndrome ...............................................................................................29
1.5.
Dose Selection Rationale ............................................................................................30
1.6.
Summary of Potential Risks and Benefits ..................................................................30
2.
STUDY OBJECTIVE .................................................................................................33
3.
INVESTIGATIONAL PLAN .....................................................................................34
3.1.
Overall Study Design ..................................................................................................34
3.1.1.
Safety Assessments .....................................................................................................34
3.1.2.
Taper Period ................................................................................................................35
3.1.3.
Follow-Up Period .......................................................................................................35
3.2.
Patient Selection .........................................................................................................37
3.2.1.
Inclusion Criteria ........................................................................................................37
3.2.2.
Exclusion Criteria .......................................................................................................37
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Protocol Number INS011-17-115 
27 Feb 2018 
                                        CONFIDENTIAL 
                                            11 
3.3.
Removal of Patients from Therapy or Assessment.....................................................38
3.4.
Dose Adjustment Criteria ...........................................................................................38
3.5.
Stopping Rules ............................................................................................................39
4.
TREATMENTS ..........................................................................................................40
4.1.
Treatments Administered ............................................................................................40
4.2.
Identity of Investigational Product .............................................................................40
4.3.
Selection of Doses in the Study ..................................................................................40
4.4.
Selection and Timing of Dose for Each Patient ..........................................................40
4.5.
Blinding and Unblinding Treatment Assignment .......................................................40
4.6.
Treatment Compliance ................................................................................................40
4.7.
Permitted and Prohibited Therapies ............................................................................41
4.7.1.
Permitted Therapies ....................................................................................................41
4.7.2.
Prohibited Therapies ...................................................................................................41
4.8.
Treatment After the End of Study ..............................................................................41
5.
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................42
5.1.
Labeling and Packaging ..............................................................................................42
5.1.1.
Labeling ......................................................................................................................42
5.1.2.
Packaging ....................................................................................................................42
5.2.
Dispensing and Storage ..............................................................................................42
5.3.
Drug Supply and Accountability ................................................................................43
6.
STUDY ASSESSMENTS ..........................................................................................44
6.1.
Safety Assessments .....................................................................................................44
6.1.1.
Physical Examinations ................................................................................................44
6.1.2.
Vital Signs ..................................................................................................................44
6.1.3.
Electrocardiograms .....................................................................................................44
6.1.4.
Clinical Laboratory Assessments ...............................................................................44
6.1.5.
Columbia Suicide Severity Rating Scale (C-SSRS) ...................................................45
6.1.6.
Concomitant Medications ...........................................................................................45
6.1.7.
Adverse Events and Serious Adverse Events .............................................................45
6.1.7.1.
Definition of Adverse Events .....................................................................................45
6.1.7.2.
Classification of Adverse Events ................................................................................46
6.1.7.3.
Causality/Drug Relationship Assessment ...................................................................46
6.1.7.4.
Definition of Serious Adverse Events ........................................................................47
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                                            12 
6.1.7.5.
Serious Adverse Events Actions Taken ......................................................................47
6.1.7.6.
Serious Adverse Events Outcome at the Time of Last Observation ..........................47
6.1.7.7.
Adverse Event Recording and Reporting ...................................................................47
6.1.7.8.
Adverse Event Follow-Up ..........................................................................................48
6.1.7.9.
Special Considerations ................................................................................................48
6.2.
Efficacy Assessment ...................................................................................................49
7.
STUDY PROCEDURES ............................................................................................50
7.1.
Safety Period ...............................................................................................................50
7.1.1.
Visit 1 (Day 1) ............................................................................................................50
7.1.2.
Monthly (Visits 2, 3, and 4) and Quarterly (Visits 5, and 6) Visits............................50
7.2.
End of Study (Visit 7) or Early Withdrawal ...............................................................51
7.3.
Taper Period (Visit 8) .................................................................................................51
7.4.
Follow-Up Period (Visit 9) .........................................................................................51
8.
STATISTICS ..............................................................................................................52
8.1.
Safety Endpoints .........................................................................................................52
8.2.
Efficacy Endpoint .......................................................................................................52
8.3.
Sample Size Determination ........................................................................................52
8.4.
Analysis Populations ..................................................................................................52
8.5.
Statistical Analyses .....................................................................................................52
8.5.1.
Study Patients and Demographics ..............................................................................52
8.5.1.1.
Disposition and Withdrawals ......................................................................................52
8.5.1.2.
Protocol Deviations ....................................................................................................53
8.5.1.3.
Demographics and Other Baseline Characteristics .....................................................53
8.5.2.
Exposure and Compliance ..........................................................................................53
8.5.3.
Safety and Tolerability Analyses ................................................................................53
8.5.3.1.
Adverse Events ...........................................................................................................53
8.5.3.2.
Clinical Laboratory Evaluations .................................................................................53
8.5.3.3.
Vital Signs ..................................................................................................................53
8.5.3.4.
Electrocardiograms .....................................................................................................53
8.5.3.5.
Physical Examination Findings ..................................................................................54
8.5.3.6.
Columbia Suicide Severity Rating Scale (C-SSRS) ...................................................54
8.5.4.
Interim Analysis ..........................................................................................................54
8.5.5.
Missing Data ...............................................................................................................54
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27 Feb 2018 
                                        CONFIDENTIAL 
                                            13 
9.
STUDY CONDUCT ...................................................................................................55
9.1.
Sponsor and Investigator Responsibilities ..................................................................55
9.1.1.
Sponsor Responsibilities .............................................................................................55
9.1.2.
Investigator Responsibilities .......................................................................................55
9.2.
Site Initiation ..............................................................................................................56
9.3.
Screen Failures ............................................................................................................56
9.4.
Study Documents ........................................................................................................56
9.4.1.
Investigator’s Regulatory Documents ........................................................................56
9.4.2.
Case Report Forms .....................................................................................................56
9.4.3.
Source Documents ......................................................................................................57
9.5.
Study Termination ......................................................................................................57
9.6.
Study Site Closure ......................................................................................................57
9.6.1.
Record Retention ........................................................................................................57
9.6.2.
Laboratory Sample Retention .....................................................................................58
10.
QUALITY CONTROL AND QUALITY ASSURANCE .........................................59
10.1.
Changes To The Protocol ...........................................................................................59
10.2.
Monitoring ..................................................................................................................59
10.3.
Data Review Meeting .................................................................................................59
10.4.
Protocol Violations .....................................................................................................59
10.5.
Quality Assurance Audit .............................................................................................60
11.
REGULATORY AND ETHICAL CONSIDERATIONS ..........................................61
11.1.
Regulatory Authority Approval ..................................................................................61
11.2.
Ethical Conduct of the Study ......................................................................................61
11.3.
Statement of Investigator/Delegation of Authority ....................................................61
11.4.
Patient Informed Consent ...........................................................................................61
11.4.1.
Assent Guidance .........................................................................................................62
11.5.
Investigator Reporting Requirements .........................................................................62
12.
DATA HANDLING AND RECORD KEEPING ......................................................63
12.1.
Data Management .......................................................................................................63
12.2.
Case Report Forms and Source Documents ...............................................................63
12.3.
Documentation and Retention of Essential Documents .............................................63
12.4.
Financial Disclosure ...................................................................................................63
13.
FACILITIES ...............................................................................................................65
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Protocol Number INS011-17-115 
27 Feb 2018 
                                        CONFIDENTIAL 
                                            14 
14.
USE OF INFORMATION AND PUBLICATION POLICY .....................................66
14.1.
Use of Information ......................................................................................................66
14.2.
Publication Policy .......................................................................................................66
15.
REFERENCES ...........................................................................................................67
16.
INVESTIGATOR SIGNATURE PAGE ....................................................................72
List of Tables 
Table 1: 
Schedule of Events .......................................................................................................8
Table 2: 
List of Insys Sponsored Clinical Trials with Cannabidiol Oral Solution ...................24
List of Figures 
Figure 1: 
Study Design Schematic .............................................................................................36
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Protocol Number INS011-17-115 
27 Feb 2018 
                                        CONFIDENTIAL 
                                            15 
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 
ALT 
alanine aminotransferase 
API 
active pharmaceutical ingredient 
AST 
aspartate aminotransferase 
AUC0-t 
area under the plasma concentration-time curve 
AUC0-tau 
area under the plasma concentration-time curve to the end of the 
dosing period 
AUCinf 
area under the plasma concentration-time curve extrapolated to 
infinity 
BMI 
body mass index 
BUN 
blood urea nitrogen 
CB1 
cannabinoid receptor 1 
CB2 
cannabinoid receptor 2 
CBD 
cannabidiol 
CBN 
cannabinol 
CFR 
Code of Federal Regulations 
cGMP 
current Good Manufacturing Practices 
Cmax 
maximum plasma concentration 
Cmax,ss 
maximum plasma concentration at steady state 
CNS 
central nervous system 
CRF 
case report form 
CRO 
contract research organization  
C-SSRS 
Columbia Suicide Severity Rating Scale 
CYP 
cytochrome P450 enzymes 
CYP1A1 
cytochrome P450 1A1 
CYP2C19 
cytochrome P450 2C19 
CYP2C9 
cytochrome P450 2C9 
CYP2D6 
cytochrome P450 2D6 
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conc
d
conc
sma concentrat
d
sma concentrat
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mass index 
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Protocol Number INS011-17-115 
27 Feb 2018 
                                        CONFIDENTIAL 
                                            16 
CYP3A4 
Cytochrome P450 3A4 
CYP3A5 
Cytochrome P450 3A5 
CV% 
coefficient of variation 
DEA 
Drug Enforcement Administration 
ECG 
electrocardiogram 
EDC 
electronic data capture 
EEG 
electroencephalogram 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP-1 
glucagon-like peptide-1 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IFN 
interferon 
IL-2 
interleukin-2 
i.p. 
intraperitoneal  
IP 
investigational product 
IRB 
Institutional Review Board 
LFT 
liver function test 
MedDRA 
Medical Dictionary for Regulatory Activities 
MCT 
medium chain triglycerides 
OH 
hydroxy 
PK 
pharmacokinetic(s) 
pKa 
acid dissociation constant 
PWS 
Prader-Willi Syndrome 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SOP 
standard operating procedure 
TEAE 
treatment-emergent adverse event 
Tmax 
time to maximum plasma concentration 
Δ9-THC 
Δ9-tetrahydrocannabinol 
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Insys Development Company, Inc. 
Protocol Number INS011-17-115 
27 Feb 2018 
                                        CONFIDENTIAL 
                                            17 
THC 
tetrahydrocannabinol 
THCV 
tetrahydrocannabivarin 
ULN 
upper limit of normal 
US 
United States 
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Protocol Number INS011-17-115 
27 Feb 2018 
                                        CONFIDENTIAL 
                                            18 
1. 
INTRODUCTION 
Data presented in this section include overviews from the nonclinical and clinical published 
literature that report on various other formulations of cannabidiol (CBD) (primarily plant-based).  
Analogous studies have not been completed for Cannabidiol Oral Solution, the non-plant-based 
CBD to be investigated in this study. 
There is evidence that CBD may be effective in anxiety, epilepsy, chemotherapy-induced 
peripheral neuropathy, glioblastoma, addiction and drug dependency, post-traumatic stress 
disorder, weight-loss, and appetite regulation. CBD’s effects on appetite, weight regulation, and 
anxiety are of interest to patients with Prader-Willi Syndrome (PWS), the focus of this 
investigation. 
Please see the Investigator’s Brochure (IB) for more information. 
1.1. 
Cannabidiol  
The Cannabidiol is the second most abundant cannabinoid found in the cannabis plant and is 
highly physiologically relevant without the psychoactive sequelae (Pertwee, 2008). In contrast, 
Δ9-tetrahydrocannabinol (Δ9-THC) is the most prevalent and principal psychoactive constituent 
of cannabis (Pertwee, 2008).   
Insys Development Company, Inc. (hereafter referred to as the Sponsor) manufactures a 
synthetic pharmaceutical grade CBD drug substance. It is manufactured in a 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). The active pharmaceutical ingredient is ≥99.5% pure (Sponsor internal 
analysis), can be consistently produced without the concern for contaminants of other 
cannabinoids, is formulated with medium chain triglycerides (MCT) without alcohol specifically 
for pediatric use, and will provide CBD to responsibly investigate the treatment of Prader-Willi 
Syndrome (PWS).  
Cannabis was extensively used as a medicine throughout the developed world in the 19th 
century. However, interest as a medicine declined as cannabis became the most widely used 
illicit recreational drug in the 20th century (Robson, 2014). Since the isolation and elucidation of 
the structure of the main active constituent of cannabis, THC, (Gaoni and Mechoulam, 1964) a 
large number of published articles have investigated its chemistry, biochemistry, pharmacology, 
and clinical effects. The effects of cannabis are not due to THC alone. At least one constituent, 
CBD, was found to have significant pharmacological effects on its own, some of which may 
modify the metabolism and effects of THC (Karniol at al., 1974; Jaeger et al., 1996).   
The endogenous endocannabioid system was first described in the 1990’s as the primary targets 
of THC were sought (Mechoulam and Parker, 2013). Studies in animals have demonstrated an 
effect of CBD on appetite, food consumption, and reward system, from sugar intake felt to 
interact with the endogenous endocannabinoid system’s effects on these activities (Silveira Filho 
and Tufik, 1981; Parsons and Hurd, 2015; Edwards and Abizaid, 2016). In addition, CBD has 
been observed to have anxiolytic and anti-psychotic properties, two comorbidities that are highly 
prevalent in patients with PWS (Whitman and Accardo, 1987; Crippa et al., 2010). Taken 
together, CBD may have an impact on both the hyperphagia-related disorders and subsequent 
obesity related to PWS. 
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binoid found in t
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Insys Development Company, Inc. 
Protocol Number INS011-17-115 
27 Feb 2018 
                                        CONFIDENTIAL 
                                            19 
1.1.1.
Mechanism of Action 
The mode of action of CBD is not fully understood.  While THC is a strong agonist of the 
endogenous cannabinoid receptors 1 (CB1) and 2 (CB2), CBD has only a low-affinity for these 
receptors and is believed to be a non-competitive antagonist/inverse agonist to them both 
(Pertwee, 2008; McPartland, 2015; Laprairie et al., 2015). Instead, CBD has been shown to have 
activities at several other biologically relevant receptors in the brain. For instance, it stimulates 
the vanilloid receptor type 1 (Bisogno et al., 2001) and modulates, without antagonism, both µ- 
and δ-opioid receptors (Kathmann et al., 2006). In addition, CBD has been shown to effect 
bidirectional regulation of intracellular calcium homeostasis via the mitochondrial 
sodium/calcium exchanger (Ryan et al., 2009), have agonistic properties at 5-hydroxytryptamine 
1a (5-HT1a) receptors (Russo et al., 2005), and enhancing endogenous adenosine levels in the 
central nervous system (CNS) by reducing adenosine re-uptake leading to increased activity at 
the adenosine A2a receptor (Carrier et al., 2006; Jones et al., 2012). 
These activities have translated to demonstration of anxiolytic effects in animals (Campos et al., 
2013; Gomes et al., 2013) through activation of the 5-HT1a receptors and followed with 
supportive observations in some human studies (Bergamaschi et al., 2011a; Crippa et al., 2011; 
Almeida et al., 2013). In addition, several investigations have outlined how CBD can affect the 
endogenous cholinergic-dopaminergic reward system suggested by decreases in cue-craving and 
increase in threshold for opioid self-administration (Parsons and Hurd, 2015; Prud'homme et al., 
2015).   
1.1.2. 
Metabolism and Potential Drug Interactions 
The major biotransformation pathway for CBD is similar to that of other cannabinoids and 
mediated by hydroxylation by cytochrome P450 (CYP) proteins (Harvey et al., 1991). 
Cannabidiol is metabolized primarily in the liver by CYP3A4 and to a lesser extent by 
CYP2C19.   
Its interactions with human drug metabolizing enzymes (as a substrate, inhibitor, or inducer) were 
recently reviewed (Stout and Cimino, 2014; Bergamaschi et al, 2011b). Specifically, CBD inhibits 
CYP3A4, CYP3A5, CYP2D6, and CYP1A1 in vitro (Johannessen and Landmark, 2010; Yamaori et al., 
2010, 2011a, 2011b;). It also appears to inhibit CYP2C9 (Yamaori et al., 2012) and the transport protein 
P-glycoprotein (Holland et al., 2006; Zhu et al., 2006).      
Further details may be found in the Investigator’s Brochure (IB).  
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.  
INS011-17-115-PWS LTS protocol Final 27Feb2018 | VV-TMF-115256 | 1.0
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al
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Protocol Number INS011-17-115 
27 Feb 2018 
                                        CONFIDENTIAL 
                                            20 
1.2.2.
Efficacy
There are no prior clinical studies investigating the potential efficacy of cannabidiol in patients 
with Prader-Willi Syndrome. Please refer to Section 1.4 for review of potential clinical efficacy 
of cannabidiol from studies in different patient populations. The following is a review of non-
clinical data on the use of cannabidiol on food and water intake in animals. 
Eight preclinical studies examined the effect of CBD on food and water intake and/or weight 
gain. However, the results were often conflicting based on the dose, dosing regimen, endpoints 
and analyses conducted and suggest a lack of acute effect following starvation, but do suggest a 
sustained effect against hyperphagia-related food intake. 
1.2.2.1.
Single Dose Regimens 
Sofia and Knobloch (1976) looked at the effect of a single dose of CBD (50 mg/kg) given to rats 
intraperitoneally (i.p.) on food and water intake when food plus water, food plus 5% sucrose, or 
food + 20% sucrose was given. They followed the animals out for 6 days after the injections. 
They found that CBD, as well as THC and cannabinol (CBN), led to decreased food intake 
which was maximal the first day and returned to normal by the 5th day. They also noted that the 
effect was greater for food than for the sucrose solutions. They concluded that CBD led to a 
preference for sweet calories and that CBD led to decreased intake. This effect decreased daily 
until it was no longer present, approximately 3-5 days after treatment. 
Silveira Filho and Tufik (1981) noted that intake of food by albino rats was decreased after 
treatment with 30 mg/kg CBD compared with control rats. 
Riedel et al. (2009) studied the effects of a synthetic CB1 antagonist, a phytocannabinoid 
(tetrahydrocannabivarin [THCV]) that acts as a CB1 antagonist, an extract rich in THCV, CBD 
alone, and a combination of the extract with CBD in both a single-dose regimen as well as a 
multiple-dose regimen (over 4 days). In the single dose regimen, mice were administered the 
above in either a fasted state (maximum 24 hours) or a non-fasted state after which they were 
allowed free access to food. As expected, the CB1 antagonists led to a decrease in food uptake 
and weight loss on the day post treatment. An extract rich in THCV did not result in a decline in 
weight that was thought to be due to the small amounts of THC present. While CBD alone at a 
low dose of 10 mg/kg induced a small although non-significant reduction in weight gain, in 
combination with the THCV-rich extract gave a significant suppression of time spent in the food 
zone. The multiple treatments over 4 days gave the same results. 
Scopinho et al. (2011) treated Wistar rats that had free access to food or animals that had been 
fasted for 18 hours with a single i.p. injection of 1, 10, or 20 mg/kg CBD. After 30 minutes, the 
rats were provided food. While CBD alone had no effect on food intake, CBD was able to 
prevent the hyperphagia seen in rats that had also been treated with agonists to CB1 or 5-HT1A 
receptors. 
Farrimond et al. (2012) treated rats with CBD (doses 0.04 mg/kg, 0.44 mg/kg, 4.4 mg/kg) and 
tested later for food intake. Only doses of 4.4 mg/kg demonstrated a statistically significant 
decrease in cumulative food intake when measured over 1-4 hours after treatment. 
INS011-17-115-PWS LTS protocol Final 27Feb2018 | VV-TMF-115256 | 1.0
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od plu
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Protocol Number INS011-17-115 
27 Feb 2018 
                                        CONFIDENTIAL 
                                            21 
1.2.2.2.
Multiple Dose Regimens 
Ignatowska-Jankowska et al. (2011) treated male Wistar rats at an age when body weight is 
rapidly increasing with i.p. injections at doses of 2.5 mg and 5 mg/kg/day for 14 consecutive 
days. The diet provided was standard ad lib rodent chow without prior fasting. Both CBD doses 
produced significant decreases in body weight gain, with the effect produced by the 5 mg/kg 
dose being more pronounced. This effect on weight was blocked, however, by a selective CB2 
antagonist, raising the possibility of more peripheral, non-CNS mechanism.  
Wierucka-Rybak et al. (2014) reported a study where CBD alone or in combination with leptin 
were administered intraperitoneally to Wistar rats for 3 consecutive days and maintained on 
either a high-fat diet or free choice diet consisting of high-sucrose and normal rat chow. 
Interestingly, while CBD seemed to decrease food intake on rats feed high fat diet or standard 
chow, there did not seem to be corresponding decrease in weight after the 4 days of the study. 
Rhesus monkeys treated with oral CBD for 90 consecutive days (30-300 mg/kg/day; 4 
monkeys/sex/dose) to observe toxicities demonstrated a relative dose-dependent decrease in 
weight gain. As it was reported as an observation, it did not merit comment by the authors 
(Rosenkrantz et al., 1981).  
While animal models provide seemingly inconsistent results on the effect of CBD on food intake 
and weight, they nonetheless suggest a potential non-acute effect on appetite and overall food 
consumption. This likely indicates, more than anything, the complex interaction between the 
endocanniboid system with appetite regulation (via the leptin and ghrelin), the endogenous 
reward system mediated by the cholinergic-serotinergic pathway, and metabolic regulation. The 
observation that some studies have demonstrated that CBD up to 80-100 mg/kg had no acute 
(within 24 hours) effect on food consumption in mice and rats, but did so in longer test periods 
provides support for the length of the current study of 12 weeks.   
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.  
INS011-17-115-PWS LTS protocol Final 27Feb2018 | VV-TMF-115256 | 1.0
Approved
ive day
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ive day
a relative d
d
a relative d
did not merit com
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Insys Development Company, Inc. 
Protocol Number INS011-17-115 
27 Feb 2018 
                                        CONFIDENTIAL 
                                            22 
• 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.  
• 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. 
INS011-17-115-PWS LTS protocol Final 27Feb2018 | VV-TMF-115256 | 1.0
Approved
nnab
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variable systemi
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bl
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Insys Development Company, Inc. 
Protocol Number INS011-17-115 
27 Feb 2018 
                                        CONFIDENTIAL 
                                            23 
• 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).   
• 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). 
INS011-17-115-PWS LTS protocol Final 27Feb2018 | VV-TMF-115256 | 1.0
Approved
mina
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mina
itability, on
d
itability, on
ith a genetic muta
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ith a genetic mu
ed). Overall, 91% o
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f
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Insys Development Company, Inc. 
Protocol Number INS011-17-115 
27 Feb 2018 
                                        CONFIDENTIAL 
                                            24 
Clinical data described in the following sections were collected following administration of 
various extracts of CBD as oral solutions or solid formulations. 
Overall, over 100 patients have been treated with Cannabidiol Oral Solution, many for over 48 
weeks, ranging in age from 1-51 years and was generally well-tolerated. A summary of the 
clinical experience is summarized below in Table 2. 
A Phase 1/2 study to assess the pharmacokinetics and safety of multiple doses (10 mg/kg/day, 
20 mg/kg/day, and 40 mg/kg/day) of pharmaceutical Cannabidiol Oral Solution in pediatric 
subjects with treatment-resistant seizure disorders was conducted by the Sponsor (Protocol 
INS011-14-029). This study has been completed and the data were presented. In addition, a long-
term safety study (Protocol INS011-14-030) for subjects who enrolled in the PK study above 
recently completed. 
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 adrenocorticotropic hormone (ACTH) and vigabatrin 
was also conducted and discussed below (Protocol INS011-14-054). 
Two food effect studies of Cannabidiol Oral Solution in normal healthy adults (Protocol INS011-
14-043) and (Protocol INS011-16-093) were also conducted. 
Table 2: 
List of Insys Sponsored Clinical Trials with Cannabidiol Oral Solution 
Study Number 
Study Title 
Study 
Design 
Population 
Number 
of 
Patients 
Study 
Status 
INS011-14-029 
A Phase 1/2 study to assess 
the pharmacokinetics and 
safety of multiple doses of 
pharmaceutical Cannabidiol 
Oral Solution in pediatric 
subjects with treatment-
resistant seizure disorder. 
 
Open 
label 
Pediatric patients 
(1 to 17 years of 
age) with 
refractory epilepsy 
61 
Completed 
INS011-14-030 
A multicenter, open-label, 
flexible dose study to assess 
the long-term safety of 
pharmaceutical Cannabidiol 
Oral Solution as an 
adjunctive treatment for 
pediatric and adult subjects 
with a treatment-resistant 
seizure disorder who 
complete INS011-14-029, 
INS011-024, or INS011-14-
025. 
 
Open 
label 
Pediatric patients 
(1 to 17 years of 
age) with 
refractory epilepsy 
52 
Completed 
INS011-15-043 
An open-label, randomized, 
single-dose, two-period, two-
way crossover food-effect 
study of Cannabidiol Oral 
Solution in healthy subjects. 
Open 
label 
Healthy adults 
24 
Completed 
INS011-17-115-PWS LTS protocol Final 27Feb2018 | VV-TMF-115256 | 1.0
Approved
otropic
d
otropic
S011-14-054
d
S011-14-054
ion in normal healt
ed
ion in normal hea
o conducted. 
ved
o conducted. 
ical Tria
ve
ical Trials with C
ve
ls with C
Study
ov
Study
Design
ov
Design
Pop
v
Pop
v
rov
o assess 
pr
o assess 
etics and 
p
etics and 
ple doses of 
pp
ple doses of 
cal Cannabidiol
pp
cal Cannabidiol
on in 
Ap
on in pediatric
App
pediatric
with treatment
Ap
with treatment-
p
-
nt seizure disorder.
Ap
nt seizure disorder.
Open 
pr
Open 
label
pr
label
ro
ro
ro
pro
A
nter, open
A
nter, open-
A
-la
A
la
tudy 
d
A
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Insys Development Company, Inc. 
Protocol Number INS011-17-115 
27 Feb 2018 
                                        CONFIDENTIAL 
                                            25 
Study Number 
Study Title 
Study 
Design 
Population 
Number 
of 
Patients 
Study 
Status 
INS011-15-054
A Phase 2 study to assess the 
efficacy and safety of 
Cannabidiol Oral Solution 
for the treatment of refractory 
infantile spasms  
Open 
label 
Infants 6 to 36 
months with 
infantile spasms 
refractory to 
ACTH and 
vigabatrin 
9 
Completed 
INS011-16-093 
A Phase 1, open-label, 
randomized, single-dose, 
four-treatment, four-
sequence, four-period, four-
way crossover food effect 
study of multiple 
formulations of Cannabidiol 
Oral Solution in healthy 
subjects. 
Open 
label 
Healthy adults 
8 
Completed 
1.3.1.
Pharmacokinetics 
INS011-14-029 is a completed Phase 1/2 study assessing the pharmacokinetics (PK) and safety of 
multiple doses of pharmaceutical CBD (Cannabidiol Oral Solution, Insys Development Company, Inc.). 
Each cohort of 20 pediatric patients from 1 to 17 years of age was administered 10 mg/kg/day, 20 
mg/kg/day, or 40 mg/kg/day over a period of 10 days. Patients were dosed as inpatients for Days 1 
through 8. Patients were then offered the opportunity to be discharged on Day 8 with readmission on Day 
10 for a final study assessment on Day 11. Cohort 1 received an earlier formulation containing alcohol; 
Cohorts 2 and 3 received a subsequent alcohol-free, medium chain triglyceride (MCT)-containing 
formulation. The study was designed to have adequate representation among three age groups in each 
dosing cohort: infants (1 to <2 yrs: 5 subjects), children (2 to <12 yrs: 9 subjects), and adolescents (12 to 
<18 yrs: 6 subjects). 
Single oral administration of CBD at 5, 10, 20 mg/kg (half of the full daily dose) resulted in mean peak 
levels of about 59, 111, and 232 ng/mL, respectively. 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 twice daily 
doses of 5, 10, 20 mg/kg/day CBD, with typical steady-state peak levels of about 120, 214, and 
427 ng/mL, respectively.  
A dose proportional increase 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 the metabolite 7-OH cannabidiol were 
generally similar to the parent drug. 
The food effect study (Protocol INS011-15-043) demonstrated that when taken within 30 minutes of the 
start of a meal, CBD mean AUC and Cmax were significantly higher with a much improved (lower) 
coefficient of variance and a 6-hour shorter median time to maximum concentration (Tmax). Thus, there is 
a recommendation that all doses be administered within 30 minutes after the start of a meal. 
Insys Study INS011-16-093 examined three different formulations under fed with standard high-fat diet 
and/or fasted conditions: sesame-oil based, 100 mg/mL (fed and fasted), MCT-based, 100 mg/mL (fed) 
and alcohol-containing, 80 mg/mL). An appreciable food effect and lower variability were observed with 
INS011-17-115-PWS LTS protocol Final 27Feb2018 | VV-TMF-115256 | 1.0
Approved
ed
ed
ed
ed
assessing the pharma
ve
assessing the pharma
abidiol Oral Solution
ov
abidiol Oral Solution
to 17 years of age w
rov
to 17 years of age w
od of 10 days. Patien
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od of 10 days. Patien
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he opportunity to be
Day
Day 11. Cohort 1 rece
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11. Cohort 1 rece
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quent alcohol-
pp
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pp
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signed to have adequ
App
signed to have adequ
<2 yrs: 5 subjects), c
App
<2 yrs: 5 subjects), c
of CBD at 5, 10
A
of CBD at 5, 10
A
2 ng/mL, 
A
2 ng/mL, 
ady
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Insys Development Company, Inc. 
Protocol Number INS011-17-115 
27 Feb 2018 
                                        CONFIDENTIAL 
                                            26 
the Cannabidiol Oral Solution (100 mg/mL) in a Sesame Oil Formulation, with mean exposures of 6.9-
fold and 11.9-fold higher, for AUC0-t and Cmax, respectively, relative to the fasted state. All formulations 
(Sesame Oil, Medium Chain Triglyceride, and alcohol-containing) showed similar exposures in the fed 
state. Mean (standard deviation [SD]) AUC0-inf (h*ng/mL) in the fed condition was: 4450 (1130) for 
Sesame Oil based, 4360 (933) for MCT-based, and 4980 (2110) for alcohol-containing. The %CV was 
25.3, 21.4, and 42.3 for Sesame-Oil based, MCT-based, and alcohol-containing, respectively. 
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 INS011-15-043). Thus, similar 
PK parameters are expected to operate over this study’s age range of 8-17 years of age. 
1.3.2.
Overview of Safety 
Clinical data described in the following sections were collected following administration of 
various extracts of CBD as oral solutions or solid formulations. 
Clinical studies in various human populations indicate that CBD has a favorable side-effect 
profile. Doses as high as 1500 mg were well tolerated (Zuardi et al., 1995). No significant 
reactions or serious adverse events (SAEs) have been reported across a wide range of dosages 
and in both acute and chronic settings. Bergamaschi et al. (2011b) recently reviewed the safety 
of CBD in humans examined in 221 subjects across 21 studies. As detailed in the IB, 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 (Cunha et al., 1980; Gloss and Vickery, 2014). 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 
(Consroe et al., 1991; Zuardi et al., 1993, 1995; Borgwardt et al., 2008).    
In Study INS011-14-029 and the subsequent extension study, INS011-14-030, some patients 
received over 3000 mg/day for several months without toxicity or SAE. 
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 (Consroe et al., 1991). 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 (Cunha et al., 1980).  
• 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 
INS011-17-115-PWS LTS protocol Final 27Feb2018 | VV-TMF-115256 | 1.0
Approved
tio
d
tio
that CBD h
d
that CBD h
ed (Zuardi et al., 1
ed
ed (Zuardi et al
been reported acros
ed
been reported acro
aschi et al. (2011b)
ve
aschi et al. (2011b)
across 21 studies. 
ve
across 21 studies. 
n examined in other
rov
n examined in other
fe (Cunha et al., 19
ro
fe (Cunha et al., 19
of CBD doses have 
pro
of CBD doses have 
of reports evaluatin
pr
of reports evaluatin
1500 mg have bee
pp
1500 mg have bee
i et al., 1993, 1995
App
i et al., 1993, 1995
and the subsequen
Ap
and the subsequen
/day for several mo
Ap
/day for several mo
Data
A
Data
d
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Insys Development Company, Inc. 
Protocol Number INS011-17-115 
27 Feb 2018 
                                        CONFIDENTIAL 
                                            27 
toxicity or serious side-effects were detected on neurological and physical examinations, 
blood and urine analysis, ECG, or EEG (Cunha et al., 1980; Gloss and Vickery, 2014). 
• 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 (Gong et al., 1984).  
• 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 (Zuardi et al., 2006).  
• 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 (Zuardi et al., 2010).     
• Insys recently completed a long-term safety study (INS-011-030, 48 weeks) for pediatric 
subjects who were receiving up to 40 mg/kg/day (maximum dose given was 3200 
mg/day) in the Phase 1/2 PK study (Protocol INS011-14-029) and these doses were 
generally well tolerated. 
• There is currently an expanded access program ongoing for the pediatric patients who 
completed the long-term safety study (INS-011-030) and wished to continue on CBD 
therapy. 
In addition to the references cited above, there are recently published studies of CBD treatment 
of refractory epilepsy.  
In an open label study of Epidiolex® (a plant-derived purified CBD), 214 patients suffering from 
different refractory epilepsies were enrolled between January 15, 2014, and January 15, 2015 
(Devinsky et al., 2016). Patients were given oral cannabidiol at 2-5 mg/kg per day, up-titrated 
until intolerance or to a maximum dose of 25 mg/kg or 50 mg/kg per day (dependent on study 
site), for a 12-week treatment period. Titration to a maximum dose of 50 mg/kg per day was 
done in 48 (30%) patients, 23 of whom received a dose of more than 25 mg/kg per day during 
the 12-week treatment period. Of the 214 enrolled patients, 162 (76%) patients who had at least 
12 weeks of follow-up after the first dose of cannabidiol were included in the safety and 
tolerability analysis, 137 (64%) patients were included in the efficacy analysis. 
The most common adverse events reported (in more than 10% of patients) were somnolence 
(n=41, 25%), decreased appetite (n=31, 19%), diarrhea (n=31, 19%), fatigue (n=21, 13%), and 
convulsion (n=18, 11%). Five (3%) patients discontinued treatment because of an adverse event. 
Serious adverse events were reported in 48 (30%) patients, including one death-a sudden 
unexpected death in epilepsy regarded as unrelated to study drug; 20 (12%) patients had severe 
adverse events possibly related to cannabidiol use, the most common of which was status 
epilepticus (n=9 [6%]). 
In a Phase 3 study, 171 patients aged 2 to 55 years with a confirmed diagnosis of drug-resistant 
Lennox–Gastaut Syndrome (LGS) currently uncontrolled on one or more concomitant AEDs 
were randomized into two treatment arms, Epidiolex® 20 mg/kg/day (n=86) or placebo (n=85), 
for a 14-week treatment period (Thiele et al., 2016). Epidiolex® or placebo was added to current 
AED treatment regimens. On average, patients were taking approximately 3 AEDs, having 
previously tried and failed an average of 6 other AEDs. The average age of patients was 15 
years. Epidiolex® was generally well tolerated in this trial. Overall, 86% of all Epidiolex® 
INS011-17-115-PWS LTS protocol Final 27Feb2018 | VV-TMF-115256 | 1.0
Approved
011-
d
011-
ram ongo
ed
ram ongoing for th
ed
ing for
S-011-030) and wi
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were given oral can
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t period. Titration 
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23 of whom receiv
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eriod. Of the 214 e
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after the first dose
Ap
after the first dose
(64%)
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ents r
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Insys Development Company, Inc. 
Protocol Number INS011-17-115 
27 Feb 2018 
                                        CONFIDENTIAL 
                                            28 
patients experienced an adverse event compared with 69% of patients on placebo. The most 
common adverse events (occurring in greater than 10% of Epidiolex®-treated patients) were: 
diarrhea, somnolence, decreased appetite, pyrexia, and vomiting. Twenty patients on 
Epidiolex® experienced a serious adverse event (nine of which were deemed treatment related) 
compared with four patients on placebo (one of which was deemed treatment related). Twelve 
patients on Epidiolex® discontinued treatment due to adverse events compared with one patient 
on placebo. There was one death in the Epidiolex® group, which was considered unrelated to 
treatment. 
In another Phase 3 study, 120 patients aged 2 to 18 years with Dravet Syndrome were 
randomized into two treatment arms, Epidiolex® 20 mg/kg/day (n=61) and placebo (n=59), for a 
14-week treatment period (Devinsky et al., 2017). Epidiolex® or placebo was added to current 
AED treatment regimens. On average, patients were taking approximately three AEDs, having 
previously tried and failed an average of more than four other AEDs. The average age of trial 
participants was 10 years and 30 percent of patients were less than 6 years of age. Epidiolex® 
was generally well tolerated in this study. The most common adverse events (AEs) (occurring in 
greater than ten percent of Epidiolex®-treated patients) were: somnolence, diarrhea, decreased 
appetite, fatigue, pyrexia, vomiting, lethargy, upper respiratory tract infection, and convulsion.  
Ten patients receiving Epidiolex® experienced a serious AE compared with three patients 
receiving placebo. None of these events led to withdrawal from the study and none were 
considered related to the study treatment. 
In Study INS011-14-029, the most common adverse events included somnolence (21.3%), 
diarrhea (16.4%), anemia (18%), psychomotor hyperactivity (8.2%), and flatulence (8.2%).  
Somnolence may have been related to the concomitant administration with the anti-epileptic, 
clobazam, that resulted in increased plasma levels of clobazam due to a unique drug-drug 
interaction. The somnolence improved following dose adjustments. Somnolence was observed in 
only 3.3% of study subjects who were not taking clobazam. In addition, three serious adverse 
events were observed following administration of drug (three were observed after screening but 
before dosing). The first involved the development of a thrombus associated with a peripherally 
inserted central catheter (PICC) line in an infant. The thrombus resolved with treatment without 
any untoward effects. The second involved an apneic episode felt to be related to 
gastroesophageal reflux disease (GIRD) also in an infant. Neither of these SAEs were deemed by 
the investigator to be related to the drug. The third SAE consisted of a drug eruption following 
the final dose of the study that self-resolved without intervention. 
In the long-term safety study, INS014-030, 52 patients continued treatment for approximately 
48 weeks at doses ranging from 10 mg/kg/day to 40 mg/kg/day. Cannabidiol Oral Solution was 
generally safe and well-tolerated. The most frequently reported AEs were seizure, upper 
respiratory tract infection, anemia, diarrhea, pyrexia, somnolence, aggression, nasopharyngitis, 
and otitis media; anemia and somnolence were considered related to study drug. Seventeen 
subjects experienced serious TEAEs; the most frequently reported serious TEAEs were seizure, 
status epilepticus, and mental status changes (all considered unrelated to study drug). These 
events may have been consistent with the subjects’ underlying disease and seizure history. One 
subject died during the study due to systemic sepsis that was considered unrelated to 
investigational product. Dose reductions occurred for 26.9% of the patients; primarily at the 
40 mg/kg/day dose (9/20 patients, 45.0%).   
INS011-17-115-PWS LTS protocol Final 27Feb2018 | VV-TMF-115256 | 1.0
Approved
other 
d
other 
ere less than
d
ere less than
common adverse
ed
common adver
ents) were: somno
ed
ents) were: somn
pper respiratory tra
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A
ond in
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Insys Development Company, Inc. 
Protocol Number INS011-17-115 
27 Feb 2018 
                                        CONFIDENTIAL 
                                            29 
In summary, the safety data to date suggest that cannabidiol can be safely administered to and 
tolerated by medically complex pediatric and adult patients at doses up to 40 mg/kg/day for 
extended periods of time (currently over 48 weeks). Despite the confounding co-administration 
of clobazam in the majority of cases of observed somnolence, CBD should be carefully 
monitored in patients with significant respiratory comorbidities, such as those that occur in 
patients with Prader-Willi Syndrome.
1.4. 
Prader-Willi Syndrome 
Prader-Willi Syndrome (PWS), first described in 1956, is a multifaceted developmental disorder 
and the most common genetic syndrome associated with obesity (Gunay-Aygun et al., 1997; 
McAllister and Whittington, 2011). It is caused by the absent expression of paternally-inherited 
genes in the PWS region on 15q11-q13 (Ledbetter et al., 1981). While it presents with 
generalized hypotonia and developmental delay in infancy, PWS then manifests with 
uncontrollable appetite, hyperphagia, and excessive weight gain leading to severe obesity 
(Grechi et al., 2012).  
Clinically, PWS patients suffer a complex pattern of physical, behavioral, endocrine, and 
intellectual deficiencies. Endocrine abnormalities lead to hypogonadism and short stature. In 
particular, growth hormone deficiency is reported to occur in 40% to 100% of the population 
(Griggs et al., 2015) and is commonly treated with growth hormone (Angulo et al., 2015). 
Behavioral disorders include obsessive compulsive behaviors such as skin picking, hoarding, re-
doing, and repetitive speech (Griggs et al., 2015).  
However, it is the appetite behavior classified as hyperphagia in Prader-Willi Syndrome that is 
the most life threatening (Dykens et al., 2007; Griggs et al., 2015) and until recently, no patient 
lived over the age of 50 due to morbid obesity and its related complications (Aycan et al., 2014). 
The mortality rate in patients with PWS is six times higher than patients with other intellectual 
disabilities (Einfeld and Kavanagh, 2006) and mortality in patients not treated with growth 
hormone was estimated to be 3% per year between the ages of 6 and 56 compared to the general 
population mortality of 0.13% below 55 years. Mortality in Prader-Willi Syndrome below 
5 years of age has not been determined (Eiholzer, 2005).   
Hyperphagic behaviors can also be dangerous in persons who are not obese, with increased risks 
of death due to choking while sneaking food, and gastric perforations after consuming more food 
than usual (Dykens et al., 2007). Approximately 8% of deaths in individuals with PWS are 
reported due to the choking, especially on hot dogs (Stevenson et al., 2007). PWS patients also 
are known to eat discarded (contaminated) food and items that are not for human consumption 
such as pet food, or even non-food items such as paint or paper (Griggs et al., 2015).   
Currently, there are no FDA-approved therapies for the treatment of hyperphagia or obesity in 
patients with PWS. In addition, drugs that have demonstrated efficacy in the past have been 
withdrawn or have significant safety concerns (e.g., rimonabant, beloranib). Therapy consists 
mostly of strict and consistent behavioral controls surrounding eating that prevent independent 
living for adult patients. Recent studies investigating modulation of the endocannabinoid system, 
however, have shown promise.   
The endocannabinoid system appears to be critically involved in the regulation of appetite, body 
weight, metabolism, hypothalamic-pituitary-adrenal axis, and reward brain circuitry (Liu et al., 
INS011-17-115-PWS LTS protocol Final 27Feb2018 | VV-TMF-115256 | 1.0
Approved
y, 
d
y, 
ght gain
d
ght gain
of physica
ed
of physical, behavi
ed
l, beha
es lead to hypogona
ved
es lead to hypogona
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ov
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al., 2015).  
ro
al., 2015).  
classified as hyper
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et al., 2007; Grigg
pr
et al., 2007; Grigg
morbid obesity and
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with PWS is six ti
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with PWS is six ti
avanagh, 2006) and
App
avanagh, 2006) and
to be 3% per year b
Ap
to be 3% per year b
f 0.13% below 55 
Ap
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A
en determined
A
en determined
o be 
A
b
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Insys Development Company, Inc. 
Protocol Number INS011-17-115 
27 Feb 2018 
CONFIDENTIAL 
30 
2005; Edwards and Abizaid, 2016). Endocannabinoid receptor CB1, is widely expressed in the 
central nervous system, autonomic gastric vagus nerve endings of the peripheral nervous system, 
and other key cells involved in body energy metabolism, including adipocytes, hepatocytes, and 
myocytes (Bensaid et al., 2003; Liu et al., 2005; Osei-Hyiaman et al., 2008). In clinical studies, 
compounds with endocannabinoid effects (fenfluramine, rimonabant) have shown significant 
effects on weight and appetite suppression (Pinder et al., 1975; Despres et al., 2005; Pi-Sunyer et 
al., 2006). These effects on appetite also occurred in 19% of epilepsy patients treated with 
Epidiolex® (i.e., cannabidiol extracted from the cannabis plant) during an open-access program 
for patients with pediatric seizure disorder (Devinsky et al., 2016). Because of the well-
characterized orexigenic activity of THC (a strong CB1 agonist), the CB1 antagonist, 
rimonabant, was studied and found to be effective in treating obesity in adults without PWS (Pi-
Sunyer et al., 2006). Both fenfluramine and rimonabant were subsequently withdrawn from the 
market, however, due to unacceptable side effects (McCann et al., 1997).  
CBD is a low-affinity antagonist of CB1, but it may also modulate CB1 receptor signaling 
through its inhibition of the metabolism of the endogenous cannabinoid, anandamide (Ibeas Bih 
et al., 2015; Laprairie et al., 2015). As for appetite, CBD has been shown to decrease food intake 
in rats under stressful conditions and reduce ad lib intake of high-sugar feed when compared to 
vehicle-treated controls (Silveira Filho and Tufik, 1981). In addition, CBD has been shown to 
diminish daily food consumption without affecting daily water intake (Wierucka-Rybak et al., 
2014) as well as inhibited hyperphagia induced by CB1 receptor or 5-hydroxytryptamine (5-
HT1A) serotonin receptor agonists suggesting a role for CBD as a regulator of food intake. 
Perhaps just as importantly, CBD decreases cue-induced craving and reduces the reward induced 
by drugs of abuse by modulating the cholanergic-dopaminergic pathway that may drive such 
behaviors in PWS patients (Von Deneen et al., 2009; Hurd et al., 2015; Parsons and Hurd, 2015).  
Thus, CBD may have potential to address the main medical problems associated with Prader-
Willi Syndrome patients leading to obesity and related mortality. Insys Development Company, 
Inc. (Insys) is manufacturing a pharmaceutical grade synthetic cannabidiol formulation 
(Cannabidiol Oral Solution) to be advanced into clinical development for the treatment of 
hyperphagia behaviors and obesity in patients with Prader-Willi Syndrome. 
1.5. 
Dose Selection Rationale 
Patients total daily dose will range from 20 mg/kg/day, 30 mg/kg/day, and 40 mg/kg/day. Doses 
of CBD may be adjusted at the investigator’s discretion up to a maximum of 40 mg/kg/day. 
Doses greater than 40 mg/kg/day are not allowed. 
1.6.
Summary of Potential Risks and Benefits
As reviewed in Sections 1.2 and 1.3, numerous nonclinical and clinical studies have examined 
other formulations of CBD. Several areas of potential concern have been identified with the use 
of CBD, especially in nonclinical studies. These include:  
•
Competitive binding of CYP proteins (thus, an impact on drug metabolism in the liver).
Cannabidiol is metabolized predominantly by CYP3A4 and CYP 2C19.  Cannabidiol may inhibit
these two isozymes, as well as having small effects on CYP3A5, CYP2D6, CYP1A1, and
CYP2C9.
INS011-17-115-PWS LTS protocol Final 27Feb2018 | VV-TMF-115256 | 1.0
pproved
o
d
o modul
d
modul
enous cannabi
d
enous cannabi
CBD
ed
CBD ha
ed
has
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1981). In additi
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Deneen et 
pr
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i
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Insys Development Company, Inc. 
Protocol Number INS011-17-115 
27 Feb 2018 
                                        CONFIDENTIAL 
                                            31 
• 
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. While further studies are needed to clarify these reported in vitro and in 
vivo side-effects (Braut-Boucher et al., 1986), no infection-related events have been reported in 
recent studies in the pediatric seizure population. 
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 subjects from the study and stopping rules will dictate discontinuation of 
subject participation should a safety issue arise (see Section 3.3 and Section 3.5, respectively).  
The appetite behavior classified as hyperphagia in Prader-Willi Syndrome is the most life 
threatening (Dykens et al., 2007; Griggs et al., 2015) and until recently, no patient lived over the 
age of 50 years due to morbid obesity and the related complications (Aycan et al., 2014). The 
mortality rate in patients with PWS is six times higher than patients with other intellectual 
disabilities (Einfeld and Kavanagh, 2006) and mortality in patients not treated with growth 
hormone was estimated to be 3% per year between the ages of 6 and 56 years compared to the 
general population mortality of 0.13% below 55 years; mortality in Prader-Willi Syndrome 
below 5 years of age has not been determined (Eiholzer, 2005).  
Hyperphagic behaviors can also be dangerous in persons who are not obese, with increased risks 
of death due to choking while sneaking food, and gastric perforations after consuming more food 
than usual (Dykens et al., 2007). Approximately 8% of deaths in individuals with PWS was 
reported due to the choking, especially on hot dogs (Stevenson et al., 2007). Prader-Willi 
Syndrome patients also are known to eat discarded (contaminated) food and items that are not for 
human consumption such as pet food, or even non-food items such as paint or paper (Griggs et 
al., 2015). 
Subjects with PWS continue to experience a significant unmet medical need, especially when it 
comes to hyperphagia behavior and obesity. There are no approved drugs currently to treat these 
behaviors. Fenfluramine demonstrated significant efficacy in Prader-Willi Syndrome patients but 
was removed from the market due to cardiac valve concerns. Rimonabant was approved in the 
EU for obesity and a trial was ongoing in Prader-Willi Syndrome. However, the drug was never 
approved in the US and removed from the market in the EU due to significant psychiatric side 
effects. A trial in PWS, while demonstrating a trend for efficacy was terminated early for safety 
concerns. Currently, Zafgen’s product Beloranib demonstrated significant positive effects on 
weight loss and hyperphagia behavior in patients with Prader-Willi syndrome but is currently on 
hold due to two deaths that were thought to be caused by thrombotic events. Orlistant, locaserin, 
Qsymia, and Contrave have been approved for obesity but not studied in the Prader-Willi 
Syndrome population. Therefore, there continues to be a high unmet need for an efficacious and 
safe treatment for this population.  
Cannabidiol has been safely administered to over 300 medically complex children and was 
generally well-tolerated. The adverse events recorded do not correspond to those encountered by 
previous trials in patients with Prader-Willi syndrome. The anxiolytic effects of CBD and its 
indirect effect on the CB1 receptor suggest an improved side effect profile in this population. 
INS011-17-115-PWS LTS protocol Final 27Feb2018 | VV-TMF-115256 | 1.0
Approved
-
d
-Wi
d
Wi
nd until rec
d
nd until rec
d complications (
d
d complications
gher than patients w
ed
gher than patients
mortality in patients
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mortality in patients
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w 55 years; mortali
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w 55 years; mortali
ined (Eiholzer, 200
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king food, and gastr
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nown to eat discard
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Insys Development Company, Inc. 
Protocol Number INS011-17-115 
27 Feb 2018 
                                        CONFIDENTIAL 
                                            32 
In conclusion, there is both pre-clinical and clinical evidence that affecting the endocannabinoid 
system with cannabidiols, including cannabidiol, may demonstrate a clinically relevant effect on 
the hyperphagia behaviors as well as lead to weight loss in patients with Prader-Willi Syndrome. 
Insys believes that due to the safety and tolerability of cannabidiol demonstrated by the data 
available in the literature and collected by the sponsor, and the life-threatening obesity in Prader-
Willi Syndrome, the demonstration of efficacy and safety of Cannabidiol Oral Solution in this 
population will be a valuable option to treat these patients.   
INS011-17-115-PWS LTS protocol Final 27Feb2018 | VV-TMF-115256 | 1.0
Approved
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Insys Development Company, Inc. 
Protocol Number INS011-17-115 
27 Feb 2018 
                                        CONFIDENTIAL 
                                            33 
2. 
STUDY OBJECTIVE 
The objective of this study is to assess the long-term safety and tolerability of Cannabidiol Oral 
Solution (CBD) in patients with Prader-Willi Syndrome. 
  
INS011-17-115-PWS LTS protocol Final 27Feb2018 | VV-TMF-115256 | 1.0
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Insys Development Company, Inc. 
Protocol Number INS011-17-115 
27 Feb 2018 
                                        CONFIDENTIAL 
                                            34 
3. 
INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design 
This is a multicenter, open-label study designed to assess long-term safety and tolerability of 
CBD in patients with Prader-Willi Syndrome. Patients must have completed INS011-16-085 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 this long-term safety study (INS011-17-115) after 
completing INS011-16-085 Visit 10 (Study Completion) to avoid interruption of the 
investigational product. Patients will have up to 2 weeks to enroll in INS011-17-115.    
Patients will receive CBD treatment for approximately 48 weeks. Total daily doses ranging from 
20 mg/kg/day to 40 mg/kg/day will be administered with standard meal. 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 (6±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. 
Once the informed consent for INS011-17-115 is provided within the required time frame, the 
patient will receive a total daily dose ranging from 20mg/kg/day to 40mg/kg/day.   
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. 
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 INS011-17-115. 
• 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 (Visit 1 only), urine preganacy screen, 
urine drug screen, weight and physical examination. 
• Review concomitant medication and adverse events (AEs). 
• 12-lead ECG.
INS011-17-115-PWS LTS protocol Final 27Feb2018 | VV-TMF-115256 | 1.0
Approved
w
d
w
h standa
d
h standa
l not be eligibl
d
l not be eligib
eeks), Taper Period
ed
eeks), Taper Perio
scheduled monthly
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scheduled monthly
All patients will com
ve
All patients will com
en they stop treatm
ov
en they stop treatm
days after the end o
ov
days after the end o
011-17-115 is prov
pro
011-17-115 is prov
ose ranging from 2
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ose ranging from 2
mately every 12 ho
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inated upon one of
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inated upon one of
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ate
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Insys Development Company, Inc. 
Protocol Number INS011-17-115 
27 Feb 2018 
                                        CONFIDENTIAL 
                                            35 
• Columbia-Suicide Severity Rating Scale (C-SSRS) will be used for children and 
adolesents aged 7 to 17 years, if appropriate. 
• Dispensing CBD. 
• Drug accountability. 
At Visit 7 (End of Study) or Early Withdrawal Visits the following assessments will be 
completed: 
• Review vital signs, clinical labs, ECG, urinalysis, urine preganacy screen, urine drug 
screen, weight and physical examination. 
• Review concomitant medication and adverse events (AEs). 
•
12-lead ECG.
• Columbia-Suicide Severity Rating Scale (C-SSRS) will be used for children and 
adolesents aged 7 to 17 years, if appropriate. 
• Hyperphagia Questionnaire for Clinical Trial (HQ-CT). 
• Dispensing CBD. 
• 
Drug accountability. 
All AEs that arise during the Safety, Taper, and Follow-up Periods will be documented. 
3.1.2. 
Taper Period 
At the end of the Long-Term Safety study patients will be tapered off of CBD over a 0-6 day 
period. The following tapering scheme will be utilizied: 40 mg/kg/day will be reduced to 30 
mg/kg/day for three days, then 30 mg/kg/day will be reduced to 20 mg/kg/day for three days and 
then discontinued; 30 mg/kg/day will be reduced to 20 mg/kg/day for three days and then 
discontinued. 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). Patient will begin tapering the day after Visit 7. 
• Patient withdraws early. Patient will begin tapering the day after the investigatory has 
been informed of the decision to withdraw from the trial. 
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 and record concomitant medications. 
INS011-17-115-PWS LTS protocol Final 27Feb2018 | VV-TMF-115256 | 1.0
proved
RS) will b
d
RS) will b
rial (HQ
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rial (HQ-
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Insys Development Company, Inc.      
 
 
Protocol Number INS011-17-115 
27 Feb 2018  
                                                                          CONFIDENTIAL
 
 
 
 
 
 
 
 
 
36 
Figure 1: Study Design Schematic 
SAFETY
PERIOD
48 weeks
INS011-16-085
COMPLETED
FOLLOW-UP
PERIOD
30 days
TAPER
PERIOD
6 days
INELIGIBLE 
≤ 14 days since 
completed?
Y
N
 
INS011-17-115-PWS LTS protocol Final 27Feb2018 | VV-TMF-115256 | 1.0
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ed
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Insys Development Company, Inc.      
 
Protocol Number INS011-17-115 
27 Feb 2018 
CONFIDENTIAL
37 
3.2. 
Patient Selection  
3.2.1.
Inclusion Criteria 
Patients must meet all of the following inclusion criteria: 
1. Completed all activities through Visit 10 (Study Completion) of INS011-16-085. 
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. If female, is either not of childbearing potential (defined as premenarchal or surgically 
sterile [bilateral tubal ligation, bilateral oophorectomy, or hysterectomy]) or practicing 
one of the following medically acceptable methods of birth control: 
a. Hormonal methods such as oral, implantable, injectable, vaginal ring, or transdermal 
contraceptives for a minimum of 1 full cycle (based on the patient’s usual menstrual 
cycle period) before study drug administration. 
b. Total abstinence from sexual intercourse since the last menses before study drug 
administration. 
c. Intrauterine device. 
d. Double-barrier method (condoms, sponge, or diaphragm with spermicidal jellies or 
cream). 
4. Psychotropic treatment will be permitted if the subject has been on a stable dose during 
the INS011-16-085 and does not anticipate a dose change during the course of the study. 
5. Growth hormone treatment will be permitted if the subject has been on a stable dose 
during INS01-16-085. 
6. Any other treatment including thyroid hormones should be stable prior to entering the 
INS011-17-115 study. 
7. 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. 
3. Uncontrolled Type I and Type II diabetes. 
INS011-17-115-PWS LTS protocol Final 27Feb2018 | VV-TMF-115256 | 1.0
pproved
ds o
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ds o
le, injectable
d
le, injectable
ycle (based on the
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Insys Development Company, Inc.                                              Protocol Number INS011-17-115 
27 Feb 2018 
CONFIDENTIAL         
                                            38 
4. 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. 
5. History of clinically significant gastrointestinal, renal, hepatic, neurologic, hematologic, 
endocrine, oncologic, pulmonary, immunologic, psychiatric, or cardiovascular disease, or 
other condition which would jeopardize safety or impact validity of results (per 
investigator).   
6. Currently taking felbamate. 
7. Compromised respiratory function or severe respiratory insufficiency. 
8. Pregnant or lactating female. 
9. 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.  
• Pregnancy.  
• Relevant non-compliance with the protocol. 
• Any use of marijuana, confirmed by a positive drug screen for THC. 
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 
Patients may have their dose of study medication adjusted down once from 40 mg/kg/day to 30 
mg/kg/day or 30 mg/kg/day to 20 mg/kg/day at the discretion of the Investigator or qualified 
designee based on the patient’s tolerability. If the lower dose is not tolerated, the drug will be 
discontinued and the patient will be withdrawn from the study. 
All dose changes must be clearly documented in the eCRF.
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Insys Development Company, Inc.                                              Protocol Number INS011-17-115 
27 Feb 2018
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 39 
3.5. 
Stopping Rules 
The Investigator reserves the right to terminate the study in the interest of patient safety and 
welfare. The Sponsor reserves the right to terminate the study at any time for administrative 
reasons. Patients will also be discontinued when their liver enzymes and serum bilirubin reach: 
• ALT or AST > 8 x ULN. 
• ALT or AST > 5 x ULN for more than 2 weeks. 
• ALT or AST > 3 x ULN and (TU>2 x ULN or INR>1.5). 
• ALT or AST > 3 x ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%). 
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Insys Development Company, Inc.                                              Protocol Number INS011-17-115 
27 Feb 2018
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 40 
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 between 20 mg/kg/day, 30 mg/kg/day, and 40 mg/kg/day will be administered 
with standard 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. 
4.3. 
Selection of Doses in the Study 
Patients total daily dose will ranging from 20 mg/kg/day, 30 mg/kg/day, and 40 mg/kg/day. 
Doses of CBD may be adjusted at the investigator’s discretion up to a maximum of 40 
mg/kg/day. Doses greater than 40 mg/kg/day are not allowed 
4.4. 
Selection and Timing of Dose for Each Patient 
Once the informed consent for INS011-17-115 is provided, patients will initiate this long-term 
safety study.  Total daily dose will range from 20 mg/kg/day, 30 mg/kg/day, and 40 mg/kg/day. 
Patients will take each dose approximately every 12 hours with standard meal 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 
INS011-17-115-PWS LTS protocol Final 27Feb2018 | VV-TMF-115256 | 1.0
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Insys Development Company, Inc.                                              Protocol Number INS011-17-115 
27 Feb 2018
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 41 
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. 
Growth hormone, thyroid hormone, and psychotropic medications are permitted, provided they 
meet the stability requirements described in the inclusion criteria.   
Adjustments to growth hormone and thyroid hormone medications are permitted as needed based 
on weight. Laboratory assessments for IGF-1/BP3 are required one month after any changes to 
growth hormone medication, and assessments for FT4 and TSH are required one month after any 
changes to thyroid hormone medication. No changes to psychotropic medications are allowed.
4.7.2.
Prohibited Therapies 
During the Safety, Taper, and Follow-up Periods, patients are not to receive the following: 
• Any cannabinoids other than study medication (CBD, Δ9-THC, hemp oil, Realm Oil or 
marijuana). 
• Felbamate. 
• Use of weight loss agents or drugs known to affect appetite (including glucagon-like 
peptide-1[GLP-1] analogs).   
• Any other investigational drug or investigational device.  
• Medication that are strong inhibitors/inducers/ sensitive substrates with a narrow 
therapeutic index for P450 3A4 (CYP3A4), CYP2D6, CYP3A4, or CYP2D6. 
Although they are not prohibited, patients taking concomitant medications may require that the 
patient is 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 3-6 day period 
(see Section 3.1.2).  
INS011-17-115-PWS LTS protocol Final 27Feb2018 | VV-TMF-115256 | 1.0
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Insys Development Company, Inc.                                              Protocol Number INS011-17-115 
27 Feb 2018
CONFIDENTIAL
 42 
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 IB 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. 
INS011-17-115-PWS LTS protocol Final 27Feb2018 | VV-TMF-115256 | 1.0
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Insys Development Company, Inc.                                              Protocol Number INS011-17-115 
27 Feb 2018
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 43 
Investigators are responsible for ensuring that all applicable licensures are in place and storage 
conditions are appropriate.   
Doses of Cannabidiol Oral Solution 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). 
 
 
INS011-17-115-PWS LTS protocol Final 27Feb2018 | VV-TMF-115256 | 1.0
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Insys Development Company, Inc.                                              Protocol Number INS011-17-115 
27 Feb 2018
CONFIDENTIAL
 44 
6. 
STUDY ASSESSMENTS 
6.1. 
Safety Assessments 
For all patients physical 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. 
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. 
6.1.3. 
Electrocardiograms 
A resting 12-lead ECG will be conducted during Visit 1 (Day 1), all monthly & quarterly visits, 
and Visit 7 (End of Study) or Early Withdrawal. 
6.1.4. 
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 (Visit 1 and Visit 7 or Early Withdrawal only): 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. 
A urine drug screen (amphetamines, barbiturates, benzodiazepines, cocaine, opiates, 
phencyclidine, and tetrahydrocannabinol) will be performed during at Visit 1 and Visit 7 (End of 
Study) or Early Withdrawal. 
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. 
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Insys Development Company, Inc.                                              Protocol Number INS011-17-115 
27 Feb 2018
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 45 
6.1.5.
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. The questionnaire will be completed 
during Visit 1 (Day 1) and at the end of the Safety Period (Visit 7) or Early Withdrawal Visit. 
Patients who have significant findings for suicidal ideation as assessed by the C-SSRS must be 
referred to the investigator for follow-up evaluation.  
6.1.6. 
Concomitant Medications 
Will be assessed at all visits. 
6.1.7. 
Adverse Events and Serious Adverse Events 
6.1.7.1. 
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 
(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. 
INS011-17-115-PWS LTS protocol Final 27Feb2018 | VV-TMF-115256 | 1.0
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Insys Development Company, Inc.                                              Protocol Number INS011-17-115 
27 Feb 2018
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 46 
The investigator should use his/her discretion in ordering additional tests as necessary to monitor 
the progress of such events. 
Adverse events reported prior to dose administration will be recorded as part of the patient’s 
medical history. 
6.1.7.2.
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. 
6.1.7.3.
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 
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. 
INS011-17-115-PWS LTS protocol Final 27Feb2018 | VV-TMF-115256 | 1.0
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Insys Development Company, Inc.                                              Protocol Number INS011-17-115 
27 Feb 2018
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 47 
6.1.7.4.
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. 
6.1.7.5.
Actions Taken 
Actions taken may consist of: 
•
None 
• Study drug discontinued 
• Dose modified 
• Required concomitant medication 
• Required procedure 
• Other 
6.1.7.6.
Outcome at the Time of Last Observation 
The outcome at the time of last observation will be classified as: 
• Recovered/resolved 
• Recovered/resolved with sequelae 
• Not recovered/not resolved 
• Death 
• Unknown 
6.1.7.7. 
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 
INS011-17-115-PWS LTS protocol Final 27Feb2018 | VV-TMF-115256 | 1.0
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Insys Development Company, Inc.                                              Protocol Number INS011-17-115 
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 48 
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) 
J. 
Autopsy findings (if available) 
The Sponsor or its representative will be responsible for notification to regulatory agencies. 
6.1.7.8.
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. 
6.1.7.9.
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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dosage form) 
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6.2. 
Efficacy Assessment 
The HQ-CT will be completed at the Study Completion/Early Withdrawal. The questionnaire 
assesses food-related problem behaviors and consists of three factors: Hyperphagic Drive 
(internal consistency 0.76), Hyperphagic Behavior (internal consistency 0.80) and Hyperphagic 
Severity (internal consistency 0.60). It is a 13-item parent completed questionnaire (Fehnel et al., 
2015). 
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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: 
• Obtain written informed consent/assent (if appropriate). 
• Review of inclusion and exclusion assessment. 
• Review/assess concomitant medications. 
• Record vital signs  (seated blood pressure, pulse rate, temperature, and respiration rate). 
• Collect blood samples for clinical labs (chemistry and hematology) 
• Collect urine sample for urinalysis, urine drug screen, and urine dipstick pregnancy test 
(all female patients of childbearing potential).  
• Perform resting 12-lead ECG.
• Perform physical examinations. 
• Record weight. 
• Dispense CBD. 
• 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 concomitant medications. 
• Record vital signs  (seated blood pressure, pulse rate, temperature, and respiration rate). 
• Collect blood samples for clinical labs (chemistry and hematology) 
• Perform resting 12-lead ECG.
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• Perform physical examinations. 
• Record weight. 
• Collect/review/dispense CBD. 
• Perform drug accountability. 
• Review AEs. 
7.2. 
End of Study (Visit 7) or Early Withdrawal 
The following procedures and assessments will be performed: 
• Review/assess concomitant medications. 
• Record vital signs  (seated blood pressure, pulse rate, temperature, and respiration rate). 
• Collect blood samples for clinical labs (chemistry and hematology) 
• Collect urine sample for urinalysis, urine drug screen, and urine dipstick pregnancy test 
(all female patients of childbearing potential).  
• Perform resting 12-lead ECG.
• Perform physical examinations. 
• Record weight. 
• Complete the HQ-CT. 
• Collect/review CBD. 
• Perform drug accountability. 
• Review AEs. 
• 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 study via the telephone to collect information regarding AEs and 
concomitant medications. 
7.3.
Taper Period (Visit 8) 
The following procedures and assessments will be performed: 
• Collect CBD.  
• Review concomitant medication and 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):  
• Review/assess concomitant medications and review AEs. 
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try and hem
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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 
10 of INS011-16-085.  
• 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, ECG findings, and laboratory values 
(hematology, chemistry, and urinalysis). 
• Change from baseline in weight. 
8.2. 
Efficacy Endpoint 
•
Change in the total score of the HQ-CT from Baseline to Study Completion/Early 
Withdrawal. 
Details of the exploratory analysis of this endpoint will be provided in the Statistical Analysis 
Plan. 
8.3. 
Sample Size Determination 
The sample size is based on successful completion of INS011-16-085, with a maximum of 
66 patients.  
8.4.
Analysis Populations
Statistical analsysis will be conducted on all enrolled patients. 
8.5. 
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. 
8.5.1. 
Study Patients and Demographics 
8.5.1.1. 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. 
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8.5.1.2. Protocol Deviations 
Protocol deviations will be identified and classified as minor or major and listed. 
8.5.1.3. 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 
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. 
8.5.2. 
Exposure and Compliance 
The exposure to study medication will be summarized by descriptive statistics. Any compliance 
deviations will be listed. 
8.5.3. 
Safety and Tolerability Analyses 
No formal inferential analyses will be conducted for safety variables.  Data listings will be 
provided for protocol-specified safety data.  
8.5.3.1. 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. 
8.5.3.2. 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.  
8.5.3.3. 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. 
8.5.3.4. Electrocardiograms 
For the continuous ECG parameters, descriptive statistics will be presented for values collected 
at all study visits, and for the changes from Baseline to End of Study/Early Withdrawal. 
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descriptive statis
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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]). 
8.5.3.5.
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.  
8.5.3.6.
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 Visit 1 
(Day 1) and End of Study/Early Withdrawal Visits. 
8.5.4. 
Interim Analysis 
No interim analyses are planned. 
8.5.5. 
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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ia may not be rescr
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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 
INS011-17-115-PWS LTS protocol Final 27Feb2018 | VV-TMF-115256 | 1.0
proved
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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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and fac
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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 
INS011-17-115-PWS LTS protocol Final 27Feb2018 | VV-TMF-115256 | 1.0
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to 
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other docum
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other docum
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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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oved
or all of th
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12. 
DATA HANDLING AND RECORD KEEPING 
The Contract Research Organization (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 standard operating procedures (SOPs). A comprehensive Data Management Plan will be 
developed including a data management overview, database contents, annotated CRF and 
consistency checks. Study site personnel will be responsible for providing resolutions to all data 
queries. The investigator will be required to document electronic data review to ensure the 
accuracy of the corrected and/or clarified data. 
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 
INS011-17-115-PWS LTS protocol Final 27Feb2018 | VV-TMF-115256 | 1.0
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ocuments
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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 
Selection of specific study vendors is pending. 
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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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lis
d
lis
wnership of all data
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wnership of all data
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nsor’s approval requ
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15. 
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Quevedo J, Roesler R, Schröder N, Nardi AE, Martín-Santos R, Hallak JE, Zuardi AW, Crippa 
JA. Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naive 
social phobia patients. Neuropsychopharmacology 2011a; 36(6): 1219-26. 
Bergamaschi MM, Queiroz RH, Zuardi AW, Crippa JA. Safety and side-effects of cannabidiol, a 
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INS011-17-115-PWS LTS protocol Final 27Feb2018 | VV-TMF-115256 | 1.0
Approved
a DC, D
d
a DC, D
-Santos R, Ha
d
-Santos R, Ha
mulated public spe
ed
mulated public sp
gy
gy 2011a; 36(6): 12
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Crippa JA. Safety a
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2011b; 6: 237-249
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2011b; 6: 237-249
t al. Molecular targ
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ceptors and on the c
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01; 134: 845-852. 
pro
01; 134: 845-852. 
aryya S, et al. Neur
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ponse inhibition. 
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ponse inhibition. B
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fferent cell culture 
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fferent cell culture 
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Palazuelos J, Fog
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Palazuelos J, Fog
eira FA, Guz
A
eira FA, Guz
nically 
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nically
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proved
ight into the co
d
ight into the co
modulating brain re
ed
modulating brain 
Willi Syndrome. 
ve
Willi Syndrome. Ho
e
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ader-
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acology
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pproved
20
d
20
, Edition 8.0
d
, Edition 8.0
cyclospor
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cyclosporine and te
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microsomes. 
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microsomes. Xeno
d
Xeno
drug interactions – 
ve
drug interactions – 
8: 254-267.  
ov
8: 254-267.  
Cannabidiol exerts a
ov
Cannabidiol exerts a
eizures. 
ro
eizures. Seizure.
ro
Seizure. 20
o
20
ski N, Pfeferman A
pp
ski N, Pfeferman A
App
annibinol in man. 
App
annibinol in man. E
p
E
dmer A, Trankle C
Ap
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receptors.
Ap
receptors.
A
Naunyn
Ap
Naunyn
M, Kelly MEM
A
M, Kelly MEM
annabino
A
annabino
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mice. Br J Pharmacol. 2009; 156: 1154–1166. 
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cannabinoids to rhesus monkeys. Toxicol  Appl  Pharmacol. 1981; 58: 118-131. 
Russo EB, Burnett A, Hall B, Parker KK. Agonistic properties of cannabidiol at 5-HT1A 
receptors. Neurochem Res. 2005; 30: 1037-1043. 
Ryan D, Drysdale AJ, Lafourcade C, Pertwee RG, Platt B. Cannabidiol targets mitochondria to 
regulate intracellular Ca2+ levels. J Neurosci. 2009; 29: 2053-2063. 
Scopinho AA, Guimarães FS, Corrêa FMA, Resstel LBM. Cannabidiol inhibits the hyperphagia 
induced by cannabinoid-1 or serotonin-1A receptor agonists. Pharmacol Biochem Behav. 2011; 
98: 268–272. 
Sofia RD, Knobloch LC. Comparative effects of various naturally occurring cannabinoids on 
food, sucrose and water consumption by rats. Pharmacol Biochem Behav. 1976; 4: 591-599. 
Stevenson DA, Heinemann J, Angulo M, et al. Gastric rupture and necrosis in Prader-Willi 
Syndrome. Pediatr Gastroenterol Nutr. 2007; 45: 272–274. 
Stout SM, Cimino NM. Exogenous cannabinoids as substrates, inhibitors, and inducers of human 
drug metabolizing enzymes: a systematic review. Drug Metab Rev. 2014; 46: 86-95. 
INS011-17-115-PWS LTS protocol Final 27Feb2018 | VV-TMF-115256 | 1.0
Approved
abo
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Insys Development Company, Inc.                                              Protocol Number INS011-17-115 
27 Feb 2018
CONFIDENTIAL
 71 
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phytocannabinoids, cannabidiol and cannabinol, as isoform-selective and potent inhibitors of 
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potent atypical inhibitor for CYP2D6. Drug Metab Dispos. 2011b; 39(11): 2049-56. 
Zhu HJ, Wang JS, Markowitz JS, et al. Characterization of P-glycoprotein inhibition by major 
cannabinoids from marijuana. J Pharmacol Exp Ther. 2006; 317: 850-857. 
Zuardi A, Crippa J, Dursun S, Morais S, Vilela J, Sanches R, et al. Cannabidiol was ineffective 
for manic episode of bipolar affective disorder. J Psychopharmacol. 2010; 24: 135-137. 
Zuardi AW, Cosme RA, Graeff FG, Guimarães FS. Effects of ipsapirone and cannabidiol on 
human experimental anxiety. J Psychopharmacol. 1993; 7: 82-88. 
Zuardi AW, Hallak JE, Dursun SM, et al. Cannabidiol monotherapy for treatment-resistant 
schizophrenia. J Psychopharmacol. 2006; 20: 683-686. 
Zuardi AW, Morais SL, Guimarães FS, Mechoulam R. Antipsychotic effect of cannabidiol. 
J Clin Psychiatry. 1995; 56: 485-486. 
INS011-17-115-PWS LTS protocol Final 27Feb2018 | VV-TMF-115256 | 1.0
Approved
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Insys Development Company, Inc.                                              Protocol Number INS011-17-115 
27 Feb 2018
CONFIDENTIAL
 72 
16. 
INVESTIGATOR SIGNATURE PAGE 
PROTOCOL TITLE: A Multicenter, Open-Label Study to Assess the Long-Term Safety of 
Pharmaceutical Grade Synthetic Cannabidiol Oral Solution in Patients with Prader-Willi 
Syndrome 
PROTOCOL NO: INS011-17-115 
This protocol is a confidential communication of Insys Development Company, Inc. I confirm 
that I have read this protocol, I understand it, and I will work according to this protocol. I will 
also work consistently with the ethical principles that have their origin in the Declaration of 
Helsinki and that are consistent with good clinical practices and the applicable laws and 
regulations. Acceptance of this document constitutes my agreement that no unpublished 
information contained herein will be published or disclosed without prior written approval from 
Insys Development Company, Inc. 
1) I have received and reviewed the Investigator’s Brochure for Cannabidiol Oral Solution. 
2) I agree to conduct the study outlined above according to the terms and conditions of the 
Protocol INS011-17-115, GCP guidelines, and with applicable regulatory requirements. 
3) I agree to maintain the confidentiality of all information received or developed in connection 
with this protocol. 
4) I agree to permit representatives of Insys Development Company, Inc. and their designated 
representatives to perform trial-related monitoring and auditing, including auditing of the 
IRB and regulatory documents, by providing direct access to all source data and documents. 
 
Signature of Investigator:  
Printed Name:  
Date:  
Investigator Title:  
Address:  
INS011-17-115-PWS LTS protocol Final 27Feb2018 | VV-TMF-115256 | 1.0
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SAP_001.pdf: 
 
 
 
 
 Statistical Analysis Plan 
 
A Multicenter, Open-Label Study to Assess the Long-Term Safety of 
Pharmaceutical Grade Synthetic Cannabidiol Oral Solution in Patients 
with Prader-Willi Syndrome 
 
Protocol Number: INS011-17-115 
Final Protocol Date: 04 Oct 2018 
Version: 1.0 
Investigational Product: Cannabidiol Oral Solution 
IND Number: IND 136,374 
 
ClinicalTrials.gov ID: NCT03458416 


Statistical Analysis Plan  
Sponsor Name: Insys Development Company, Inc. 
Sponsor Protocol ID: INS011-17-115 
 
Covance Study ID: 000000163385 
COVANCE INC. CONFIDENTIAL 
Document Date: 04 October 2018
Page 1 of 22
 
 
ST-AD-008 version 04 
Statistical Analysis Plan 
 
Insys Development Company, Inc. 
Protocol No.: INS011-17-115 
A Multicenter, Open-Label, Study to Assess the 
Long-Term Safety of Pharmaceutical Grade 
Synthetic Cannabidiol Oral Solution in Patients with 
Prader-Willi Syndrome 
Covance Study ID: 000000163385
Document Version: Final 1.0 
Document Date: 04 Oct 2018 
Covance Inc. CDCS 
Clinical Development Commercialization Services 
 
INS011-17-115 Statistical Analysis Plan Final 2018_10_04_signed | VV-TMF-115504 | 1.0
Approved
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y ID: 00000016
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00000016
nt Version:
ov
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Statistical Analysis Plan  
Sponsor Name: Insys Development Company, Inc. 
Sponsor Protocol ID: INS011-17-115 
 
Covance Study ID: 000000163385 
COVANCE INC. CONFIDENTIAL 
Document Date: 04 October 2018
Page 2 of 22
 
 
ST-AD-008 version 04 
Table of Contents 
1. 
Source Documents ................................................................................. 7 
2. 
Protocol Details ..................................................................................... 7 
2.1 
Study Objectives................................................................................. 7 
2.2 
Overall Study Design ........................................................................... 7 
2.3 
Sample Size and Power ....................................................................... 8 
3. 
Efficacy and Safety Variables................................................................... 8 
3.1 
Safety Endpoints ................................................................................. 8 
3.2 
Efficacy Endpoint ................................................................................ 8 
4. 
Analysis populations ............................................................................... 8 
4.1 
All Enrolled Population ......................................................................... 8 
4.2 
Special Subpopulations ........................................................................ 9 
5. 
DATA Handling ...................................................................................... 9 
5.1 
Time points and Visit Windows ............................................................. 9 
5.2 
Handling of Dropouts, Missing Data, and Outliers .................................... 9 
6. 
Statistical Methods ............................................................................... 10 
6.1 
General Principles ............................................................................. 10 
6.2 
Subject Disposition and Data Sets Analyzed ......................................... 11 
6.3 
Protocol Deviations ........................................................................... 12 
6.4 
Demographics and Other Baseline Characteristics ................................. 12 
6.4.1 
Medical or Surgical History ................................................................................................. 12 
6.4.2 
Prior and Concomitant Medications ................................................................................... 12 
6.5 
Measurements of Treatment Compliance .............................................. 13 
6.6 
Efficacy ............................................................................................ 13 
6.6.1 
Exploratory Efficacy Analysis ............................................................................................... 14 
6.6.2 
Sensitivity Analysis .............................................................................................................. 14 
6.6.3 
Secondary Efficacy Analysis ................................................................................................ 14 
6.6.4 
Subgroup Analysis ............................................................................................................... 14 
6.6.5 
Columbia Suicide Severity Rating Scale .............................................................................. 14 
6.7 
Safety ............................................................................................. 15 
6.7.1 
Extent of Exposure .............................................................................................................. 15 
INS011-17-115 Statistical Analysis Plan Final 2018_10_04_signed | VV-TMF-115504 | 1.0
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Statistical Analysis Plan  
Sponsor Name: Insys Development Company, Inc. 
Sponsor Protocol ID: INS011-17-115 
 
Covance Study ID: 000000163385 
COVANCE INC. CONFIDENTIAL 
Document Date: 04 October 2018
Page 3 of 22
 
 
ST-AD-008 version 04 
6.7.2 
Adverse Events .................................................................................................................... 15 
6.7.3 
Laboratory Evaluations ....................................................................................................... 17 
6.7.4 
Vital Signs ............................................................................................................................ 18 
6.7.5 
Electrocardiograms ............................................................................................................. 18 
6.7.6 
Physical Examination ........................................................................................................... 19 
6.8 
Interim Analysis................................................................................ 19 
7. 
Changes in Planned Analysis ................................................................. 19 
8. 
Data Issues......................................................................................... 19 
9. 
References .......................................................................................... 19 
Appendix A: Schedule of Events ..................................................................... 21 
 
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Statistical Analysis Plan  
Sponsor Name: Insys Development Company, Inc. 
Sponsor Protocol ID: INS011-17-115 
 
Covance Study ID: 000000163385 
COVANCE INC. CONFIDENTIAL 
Document Date: 04 October 2018
Page 4 of 22
 
 
ST-AD-008 version 04 
 
INS011-17-115 Statistical Analysis Plan Final 2018_10_04_signed | VV-TMF-115504 | 1.0
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Statistical Analysis Plan  
Sponsor Name: Insys Development Company, Inc. 
Sponsor Protocol ID: INS011-17-115 
 
Covance Study ID: 000000163385 
COVANCE INC. CONFIDENTIAL 
Document Date: 04 October 2018
Page 5 of 22
 
 
ST-AD-008 version 04 
Reviewers
The following reviews of the SAP were conducted: 
Version History  
Version # 
Description of Changes 
Version Date 
Final 1.0 
4 October 2018 
 
Name and Title  
 Role 
Version Last 
Reviewed 
Company/ 
Organization 
Peer Review 
Statistician 
Internal draft 
1.0 
Covance 
Lead Programmer 
Internal draft 
1.0 
Covance 
Project Manager / 
Clinical Team Lead 
Internal draft 
1.0 
Covance 
Project Physician 
Internal draft 
1.0 
Covance 
Client Approver 
Sponsor draft 
2.0 
Insys 
Client Approver 
Sponsor draft 
2.0 
Insys 
Client Approver 
Sponsor draft 
2.0 
Insys 
INS011-17-115 Statistical Analysis Plan Final 2018_10_04_signed | VV-TMF-115504 | 1.0
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Statistical Analysis Plan  
Sponsor Name: Insys Development Company, Inc. 
Sponsor Protocol ID: INS011-17-115 
 
Covance Study ID: 000000163385 
COVANCE INC. CONFIDENTIAL 
Document Date: 04 October 2018
Page 6 of 22
 
 
ST-AD-008 version 04 
Glossary of Abbreviations
Abbreviation 
Term 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ANOVA 
Analysis of Variance 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index 
BP 
Blood Pressure 
CBD 
Cannabidiol Oral Solution 
C-CASA
Columbia Classification Algorithm of Suicide Assessment 
CI 
Confidence Interval 
CRF 
Case Report form 
eCRF 
Electronic Case Report Form 
C-SSRS
Columbia Suicide Severity Rating Scale 
ECG 
Electrocardiogram 
HQ-CT 
Hyperphagia Questionnaire for Clinical Trials 
HR 
Heart Rate 
IMP 
Investigational Medicinal Product 
MedDRA 
Medical Dictionary for Regulatory Activities 
LS 
Least Squares 
PT 
Preferred Term 
PWS 
Prader-Willi Syndrome 
QTcF 
Fridericia corrected QT interval 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
TESAE 
Treatment Emergent Serious Adverse Event 
TFLs 
Tables, Figures and Listings 
INS011-17-115 Statistical Analysis Plan Final 2018_10_04_signed | VV-TMF-115504 | 1.0
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Treatment Emer
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Statistical Analysis Plan  
Sponsor Name: Insys Development Company, Inc. 
Sponsor Protocol ID: INS011-17-115 
 
Covance Study ID: 000000163385 
COVANCE INC. CONFIDENTIAL 
Document Date: 04 October 2018
Page 7 of 22
 
 
ST-AD-008 version 04 
1. Source Documents 
The Statistical Analysis Plan (SAP) was written based on the following 
documentation: 
Document 
Date 
Version 
Protocol 
27 February 2018 
1.0 
eCRF 
25 July 2018
1.0 
2. Protocol Details 
2.1 Study Objectives 
The objective of this study is to assess the long-term safety and tolerability of 
Cannabidiol Oral Solution (CBD) in patients with Prader-Willi Syndrome (PWS). 
2.2 Overall Study Design 
This is a multicenter, open-label study designed to assess long-term safety and 
tolerability of CBD in patients with PWS.  Patients must have completed INS011-16-
085 to be eligible for this study. 
Patients may enroll in this long-term safety study after completing INS011-16-085 
Visit 10 (Study Completion) to avoid interruption of the investigational medicinal 
product (IMP).  Patients will have up to 2 weeks to enroll in INS011-17-115.  If a 
patient does not enroll within the 2-week window, they will not be eligible to enroll 
into the study. 
Patients will receive CBD treatment for approximately 48 weeks.  Total daily doses 
ranging from 20 mg/kg/day to 40 mg/kg/day will be administered with standard 
meal. Patients may have their dose of study medication adjusted down once from 
40 mg/kg/day to 30 mg/kg/day or from 30 mg/kg/day to 20 mg/kg/day at the 
discretion of the Investigator or qualified designee based on the patient’s 
tolerability.  If the lower dose is not tolerated, the drug will be discontinued and the 
patient will be withdrawn from the study. 
The study consists of a Safety Period (48 ± 2 weeks), Taper Period (6 ± 3 days), 
and a Follow-up Period (30 ± 5 days).   
The study design is presented in Figure 1. 
INS011-17-115 Statistical Analysis Plan Final 2018_10_04_signed | VV-TMF-115504 | 1.0
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Statistical Analysis Plan  
Sponsor Name: Insys Development Company, Inc. 
Sponsor Protocol ID: INS011-17-115 
 
Covance Study ID: 000000163385 
COVANCE INC. CONFIDENTIAL 
Document Date: 04 October 2018
Page 8 of 22
 
 
ST-AD-008 version 04 
All screening, efficacy and safety evaluations will be performed according to the 
schedule of assessments presented in Appendix A. 
2.3 Sample Size and Power 
The sample size is based on successful completion of INS011-16-085, with a 
maximum of 66 patients. 
3. Efficacy and Safety Variables 
3.1 Safety Endpoints 
The safety endpoints for this study are: 
• 
Incidence, type and severity of adverse events (AEs) and serious adverse events 
(SAEs) associated with CBD, i.e. treatment emergent adverse events (TEAEs) 
• 
Changes from baseline in vital signs, physical exam, ECG findings and laboratory 
values (hematology, chemistry and urinalysis) 
• 
Change from baseline in weight 
3.2 Efficacy Endpoint 
The efficacy endpoint for this study is the change in total score of the hyperphagia 
questionnaire for clinical trials (HQ-CT) from Baseline to Study Completion/Early 
Withdrawal, where baseline is defined as Visit 10 of INS011-16-085.  The HQ-CT is 
a 9-item questionnaire and the response for each item ranges from 0 (for 
responses such as “Not at all” or “Never”) to 4 (for responses such as “Several 
times”).  The total HQ-CT score is calculated by adding the responses to each item, 
thereby yielding a total HQ-CT score which can range from 0 to 36  (Fehnel, et al., 
2015). 
4. Analysis populations 
4.1 All Enrolled Population 
All patients enrolled will be included in the all enrolled population. 
INS011-17-115 Statistical Analysis Plan Final 2018_10_04_signed | VV-TMF-115504 | 1.0
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Statistical Analysis Plan  
Sponsor Name: Insys Development Company, Inc. 
Sponsor Protocol ID: INS011-17-115 
 
Covance Study ID: 000000163385 
COVANCE INC. CONFIDENTIAL 
Document Date: 04 October 2018
Page 9 of 22
 
 
ST-AD-008 version 04 
4.2 Special Subpopulations 
Not applicable. 
5. DATA Handling 
5.1 Time points and Visit Windows 
Day 1 is defined as the date of enrollment onto INS011-17-115 study.  Relative 
days after Day 1 are calculated as (assessment date – Day 1 date) + 1.  Relative 
days prior to Day 1 are calculated as (assessment date – Day 1 date).  The day 
prior to Day 1 is Day -1.  
All data will be analyzed using nominal study visits as defined in the Study Schedule 
(see Appendix A).  No visit windows will be applied for summary and analysis. 
Multiple visits within the same protocol-defined scheduled window (see Appendix A) 
will be dealt with as follows: 
• 
If multiple scheduled visits occur within a single protocol-defined visit window 
then the visit closest to the target day of the visit window will be used in the 
analysis.  In cases where the measurements are equal distances from the 
target day, the later visit will be used in the analysis. 
5.2 Handling of Dropouts, Missing Data, and Outliers 
There will be no imputation of missing data. All summaries will be based on 
observed data only.  
For adverse events (AEs) with missing or partial start date: 
• 
If the partial onset date does not indicate whether the AE started prior to or 
after the end of the treatment-emergent period (last dose of double-blind 
treatment plus 14 days), the AE will be classified as treatment-emergent.   
• 
If the AE onset date is partial or missing, the AE end date will be considered.  If 
the AE end date is partial and the partial end date does not indicate that the AE 
ended prior to the start of double-blind treatment, the AE will be classified as 
treatment-emergent.    
In the event that a partial date for concomitant medication is available, this partial 
information will be used as follows: 
•
If the partial start date does not indicate whether the medication started prior to 
or after double-blind treatment, the medication will be classified as both prior 
and concomitant. 
INS011-17-115 Statistical Analysis Plan Final 2018_10_04_signed | VV-TMF-115504 | 1.0
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Statistical Analysis Plan  
Sponsor Name: Insys Development Company, Inc. 
Sponsor Protocol ID: INS011-17-115 
 
Covance Study ID: 000000163385 
COVANCE INC. CONFIDENTIAL 
Document Date: 04 October 2018
Page 10 of 22
 
 
ST-AD-008 version 04 
• 
If the partial end date does not indicate that the medication ended prior to the 
start of double-blind treatment, the medication will be classified as both prior 
and concomitant.  
The imputations for AEs and medications are for categorization purposes only and 
will not be used in listings. 
6. Statistical Methods 
6.1 General Principles 
All data processing, summarization and analyses will be performed using Covance’s 
SAS Environment / Version 9.4 (or later) of the SAS statistical software package. 
The analysis treatment group will be defined by the modal dose of study drug (dose 
of the study drug that the patient took for the longest period). 
The following principles will be applied to all TFLs unless otherwise stated: 
Principle 
Value 
Significant tests 
Two-sided and use a 5% significance level  
Treatment group labels 
and order presented 
Listings:  
Cannabidiol Oral Solution (20mg/kg/day) 
Cannabidiol Oral Solution (30 mg/kg/day) 
Cannabidiol Oral Solution (40 mg/kg/day) 
Tables: 
CBD (20 mg/kg/day) 
CBD (30 mg/kg/day) 
CBD (40 mg/kg/day) 
All CBD 
Tables 
Data in summary tables presented by treatment group 
and visit (where applicable)
Listings 
All data collected presented by 
Treatment group 
Patient 
Visit (where applicable) 
Date; 
unless otherwise specified 
Descriptive summary 
statistics for continuous 
variables 
Number of patients/observations (n) 
Mean 
Standard deviation (SD) 
INS011-17-115 Statistical Analysis Plan Final 2018_10_04_signed | VV-TMF-115504 | 1.0
ved
he m
d
he m
ongest pe
d
ongest pe
TFLs unless oth
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TFLs unless o
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use a 5% significa
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use a 5% significa
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ol Oral Solution (2
ov
ol Oral Solution (2
bidiol Oral Solution
ro
bidiol Oral Solution
nabidiol Oral Solut
pr
nabidiol Oral Solut
ables:
pp
ables:
CBD
Ap
CBD (20 mg/kg
App
(20 mg/kg
CBD (30 mg/
Ap
CBD (30 mg/
Ap
CBD (40 m
A
CBD (40 m
All CBD
A
All CBD
ve
A
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Statistical Analysis Plan  
Sponsor Name: Insys Development Company, Inc. 
Sponsor Protocol ID: INS011-17-115 
 
Covance Study ID: 000000163385 
COVANCE INC. CONFIDENTIAL 
Document Date: 04 October 2018
Page 11 of 22
 
 
ST-AD-008 version 04 
Principle 
Value 
Median 
Minimum  
Maximum 
Descriptive summary 
statistics for categorical 
variables 
Frequency counts and percentages [n (%)] 
Denominator for 
percentages 
Number of patients in the analysis population, unless 
stated otherwise in table shell(s)
Include “Missing” as 
category 
Yes, when the number missing is greater than zero for at 
least one treatment group 
Display for 0 
percentages 
Leave blank 
Display to one more 
decimal place than 
collected value 
Mean 
Mean Difference 
Median 
Percentages  
Display to two more 
decimal places than 
collected value 
Standard Deviation 
Confidence Interval 
Limit of precision for 
displays 
3 decimal places 
Baseline is defined as Visit 10 of INS011-16-085. 
6.2 Subject Disposition and Data Sets Analyzed 
Patient disposition will be listed and summarized by treatment group and overall 
and will include the number and percentage of patients: 
• 
Entered Safety Period  
• 
Completed Study 
• 
Entered Taper Period 
• 
Entered Follow-up Period 
In addition, the number and percentage of patients who complete the study and 
who discontinue early, including a breakdown of the primary reasons for 
discontinuation from the study will be presented. 
A summary of patient enrollment by site will also be provided by treatment group 
and overall for the enrolled population.   
A listing of study drug bottle numbers and assignments will be produced. 
 
INS011-17-115 Statistical Analysis Plan Final 2018_10_04_signed | VV-TMF-115504 | 1.0
Approved
ation
v
ation
Interval
ov
Interval
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al places
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al places
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Statistical Analysis Plan  
Sponsor Name: Insys Development Company, Inc. 
Sponsor Protocol ID: INS011-17-115 
 
Covance Study ID: 000000163385 
COVANCE INC. CONFIDENTIAL 
Document Date: 04 October 2018
Page 12 of 22
 
 
ST-AD-008 version 04 
6.3 Protocol Deviations
All important protocol deviations will be listed and summarized by treatment group 
for the enrolled population. 
6.4 Demographics and Other Baseline Characteristics 
Demographic and baseline characteristics will be listed and summarized by 
treatment group and overall for enrolled population.  Standard descriptive statistics 
will be presented for the continuous variables of: 
• 
age (years) ; 
• 
gender (Male, Female); 
• 
ethnicity (Hispanic or Latino, Not Hispanic or Latino, Unknown); 
• 
race (White, Black or African American, Asian, American Indian or Alaska 
Native, Native Hawaiian or other Pacific Islander, Other);  
• 
weight (kg) at Day 1 visit; 
• 
height (cm) at Day 1 Visit; 
• 
body mass index (kg/m2) (derived on eCRF); 
No formal tests of statistical significance will be performed on the demographic and 
baseline data.   
Other baseline measurements, such as vital signs and ECG, will be summarized by 
treatment group with the post-baseline measurements. 
6.4.1 Medical or Surgical History 
Medical or surgical history will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) [Version 21.1 (or a later version if updated during the study)].  
All medical history or surgical history will be listed, and the number and percentage 
of patients with any medical or surgical history will be summarized for all enrolled 
population by system organ class (SOC) and preferred term (PT) for each treatment 
group and overall.   
6.4.2 Prior and Concomitant Medications 
Medications received prior to or concomitantly with treatment will be coded by 
Covance using the WHO Drug Dictionary [Version March 2018 (or a later version if 
updated during the study)], Anatomical Therapeutic Chemical (ATC) Classification 
codes.  
Prior medications and concomitant medications are defined as follows: 
Prior medications are those prior to the first dose date of IMP treatment on INS011-
16-085. 
INS011-17-115 Statistical Analysis Plan Final 2018_10_04_signed | VV-TMF-115504 | 1.0
Approved
 o
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d
n, Asian, 
fic Islander, O
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fic Islander, 
erived on eCRF);
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pr
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ost
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Ap
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PPD


Statistical Analysis Plan  
Sponsor Name: Insys Development Company, Inc. 
Sponsor Protocol ID: INS011-17-115 
 
Covance Study ID: 000000163385 
COVANCE INC. CONFIDENTIAL 
Document Date: 04 October 2018
Page 13 of 22
 
 
ST-AD-008 version 04 
Concomitant medications are those with a start date on or after the first dose date 
of IMP treatment on INS011-16-085, or those with a start date before the first dose 
date of IMP treatment and a stop date on or after the first dose date of IMP 
treatment or ongoing end of study. 
If a medication cannot be classified as “prior” or “concomitant” after applying 
imputation rules for missing/incomplete dates, it will be classified as concomitant. 
Prior medications and concomitant medications will be listed together and 
summarized separately for enrolled population. 
The number and percentage of patients using each medication will be displayed 
together with the number and percentage of patients using at least one medication 
within each therapeutic class (ATC-Level 2), chemical subgroup (ATC-Level 4), and 
generic term. 
6.5 Measurements of Treatment Compliance 
Percentage compliance is calculated based on the study drug administration page 
as follows: 
100 × 
# doses taken
Expected # doses (based on visit days) , 
where # doses taken = # of the “yes” responses to “Was AM dose taken?” and 
“Was PM dose taken?”  
Percentage compliance will be summarized descriptively by treatment group for the 
enrolled population. 
The following percentage compliance categories will also be presented: 
• 
<90.0% 
• 
≥90.0% and ≤110.0% 
• 
>110.0% 
In addition, summary statistics of the weights of bottles dispensed and returned, as 
well as the volume administered, will be presented by treatment group for the 
enrolled population.   
All study drug administration and drug accountability data will be listed in full. 
6.6 Efficacy  
All statistical inference will be based on a comparison of the CBD treatment groups.  
Descriptive statistics for efficacy endpoints will be based on all treatment groups, 
i.e. CBD (20 mg/kg/day), CBD (30 mg/kg/day), CBD (40 mg/kg/day), and all CBD. 
INS011-17-115 Statistical Analysis Plan Final 2018_10_04_signed | VV-TMF-115504 | 1.0
Approved
mica
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Compliance
ed
Compliance
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# doses taken
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# doses taken
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the “yes” respo
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the “yes” respo
ll be summarized
pp
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Ap
tage compliance 
Ap
tage compliance 
%
A
%
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Statistical Analysis Plan  
Sponsor Name: Insys Development Company, Inc. 
Sponsor Protocol ID: INS011-17-115 
 
Covance Study ID: 000000163385 
COVANCE INC. CONFIDENTIAL 
Document Date: 04 October 2018
Page 14 of 22
 
 
ST-AD-008 version 04 
6.6.1 Exploratory Efficacy Analysis 
Total HQ-CT scores and changes from baseline will be summarized by treatment 
group and visit using standard descriptive statistics. 
6.6.2 Sensitivity Analysis 
Not applicable. 
6.6.3 Secondary Efficacy Analysis 
Not applicable. 
6.6.4 Subgroup Analysis
Not applicable. 
6.6.5 Columbia Suicide Severity Rating Scale 
Responses Columbia Suicide Severity Rating Scale (C-SSRS) will be listed 
separately for the adult and child-completed assessments.  The listings will be 
based on the enrolled population.  
C-SSRS will be categorized based on the Columbia Classification Algorithm of 
Suicide Assessment (C-CASA) categories 1, 2, 3, 4 and 7 as follows (Gassmann-
Mayer, et al., 2011): 
Event code 
C-CASA event 
C-SSRS eventa 
1 
Suicide completed 
Completed suicide 
2 
Suicide attempt 
Actual attempt 
3 
Preparatory actions towards 
imminent suicidal behaviour 
(including interrupted attempt 
or aborted attempt) 
Interrupted attempt 
Aborted attempt 
Preparatory acts or behavior 
4 
Suicidal ideation
Subscale code and event: 
1. Wish to be dead 
2. Non-specific active suicidal 
thoughts 
3. Active suicidal ideation with 
any methods (not plan) 
without intent to act 
4. Active suicidal ideation with 
some intent to act, without 
specific plan 
5. Active suicidal ideation with 
any specific plan and intent 
7 
Self-injurious behavior 
Has the subject engaged in non-
INS011-17-115 Statistical Analysis Plan Final 2018_10_04_signed | VV-TMF-115504 | 1.0
Approved
Scale
d
Scale
g Scale (C
ed
g Scale (C-
ed
-SSRS
d
SSR
ted assessments
ve
ted assessments
n the Columbia C
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egories 1, 2, 3, 4
ro
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nt
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pp
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p
e attempt
App
e attempt
App
Ap
paratory
Ap
paratory actions
Ap
actions
A
minent suicidal
A
minent suicidal
ding interr
A
ding interr
ed att
A
ed att
Ap
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Statistical Analysis Plan  
Sponsor Name: Insys Development Company, Inc. 
Sponsor Protocol ID: INS011-17-115 
 
Covance Study ID: 000000163385 
COVANCE INC. CONFIDENTIAL 
Document Date: 04 October 2018
Page 15 of 22
 
 
ST-AD-008 version 04 
without suicidal intent 
suicidal self-injurious behavior? 
aAn event corresponds to a “yes” response to the C-SSRS question. 
C-SSRS will be summarized as dichotomous endpoints corresponding to the C-CASA 
categories at Visit 1 and End of Study/Early Withdrawal Visits. 
6.7 Safety 
6.7.1 Extent of Exposure 
Duration of exposure will be defined in days as: 
(date of last dose – date of first dose) + 1. 
Duration of exposure will be summarized using descriptive statistics for each 
treatment group for the enrolled population. 
6.7.2 Adverse Events 
All AEs recorded on the eCRF will be coded using the MedDRA dictionary [Version 
21.1 (or a later version if updated during the study)] and classified as treatment – 
emergent AEs (TEAEs) as follows: 
• 
TEAEs are events with start date on or after the date of first dose of IMP and 
up to 14 days after the last dose of IMP or events with start date prior to the 
date of first dose of IMP whose severity worsens on or after the date of first 
dose of IMP on INS011-17-115.  
All AE data will be listed by treatment group.  Treatment-emergence status will be 
flagged in the listing. In addition, corresponding listings of treatment-emergent 
serious AEs (TESAEs), AEs leading to permanent discontinuation of IMP and AEs 
resulting in death will be produced. AE ongoing or worsened from INS011-16-085 
will be listed.  
Summary tables of TEAEs by treatment group and overall will be produced for the 
enrolled population. No statistical comparisons of AEs between treatment groups 
will be performed. 
The severity of all AEs is recorded as mild, moderate, or severe.  If severity is 
missing for a TEAE, it will be considered severe.  
The relationship between an AE and IMP treatment is assessed as definite, 
probable, possible, unlikely or not related.  A treatment-related AE is an AE 
considered by the investigator as definitely, possibly, or probably related to IMP 
treatment or with unknown/missing relationship to IMP treatment.   
An overview table will summarize the number and percentage of patients with at 
least one of the following TEAEs, where patients with more than one TEAE in a 
particular category are counted only once in that category: 
INS011-17-115 Statistical Analysis Plan Final 2018_10_04_signed | VV-TMF-115504 | 1.0
Approved
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Statistical Analysis Plan  
Sponsor Name: Insys Development Company, Inc. 
Sponsor Protocol ID: INS011-17-115 
 
Covance Study ID: 000000163385 
COVANCE INC. CONFIDENTIAL 
Document Date: 04 October 2018
Page 16 of 22
 
 
ST-AD-008 version 04 
• 
any TEAE;  
• 
TEAE by severity (mild, moderate, severe); 
• 
treatment-related TEAE;  
• 
severe treatment-related TEAE; 
• 
TESAE;  
• 
TESAE by severity; 
• 
treatment-related TESAE; 
• 
TEAE leading to study drug discontinuation.  
The overview table will be repeated to summarize the number of TEAEs (displaying 
the number and percentage of observed events). 
The number and percentage of patients reporting each AE will be summarized by 
System Organ Class (SOC) and Preferred Term (PT) for all enrolled patients.  Tables 
will be sorted alphabetically by SOC.  PTs will be sorted by descending overall total.  
The following summaries will be produced: 
• 
TEAEs, by SOC and PT; 
• 
TEAEs related to IMP treatment, by SOC and PT; 
• 
TEAEs by relationship to IMP treatment, by SOC and PT; 
• 
TEAEs by maximum severity, by SOC and PT; 
• 
TEAEs related to IMP treatment by maximum severity, by SOC and PT; 
• 
TEAEs causing discontinuation from IMP treatment, by SOC and PT; 
• 
TEAEs related to IMP treatment causing discontinuation from IMP treatment, 
by SOC and PT; 
• 
TESAEs, by SOC and PT; 
• 
TESAEs related to IMP treatment, by SOC and PT; 
• 
TEAEs leading to death, by SOC and PT. 
In the above summaries, patients with more than one TEAE within a particular SOC 
are counted only once for that SOC.  Similarly, patients with more than one TEAE 
within a particular PT are counted only once for that PT.  For summaries by 
maximum severity, patients with multiple TEAEs within a particular SOC or PT will 
be counted under the category of their most severe TEAE within that SOC or PT.  
TEAEs with missing intensity/severity will be included (as severe) in the overall 
count of patients with TEAEs, but will not be included in the counts of patients with 
TEAEs within a SOC or PT.  
INS011-17-115 Statistical Analysis Plan Final 2018_10_04_signed | VV-TMF-115504 | 1.0
Approved
e th
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porting each AE
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App
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Ap
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A
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A
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Statistical Analysis Plan  
Sponsor Name: Insys Development Company, Inc. 
Sponsor Protocol ID: INS011-17-115 
 
Covance Study ID: 000000163385 
COVANCE INC. CONFIDENTIAL 
Document Date: 04 October 2018
Page 17 of 22
 
 
ST-AD-008 version 04 
6.7.3 Laboratory Evaluations 
6.7.3.1 
Standard Safety Laboratory Panel 
Data for the following hematology, blood chemistry, and urinalysis analytes 
received from central laboratory will be listed and summarized by treatment group 
and visit.  If data for any additional analytes are also received or recorded, then 
these will be listed only. 
Hematology 
Serum Chemistry 
Urinalysis 
Hemoglobin 
Hematocrit 
Total Leukocyte Count 
Differential Leukocyte Count 
Red Blood Cell Count 
Platelets 
Neutrophils (abs, %) 
Lymphocytes (abs, %) 
Monocytes (abs, %) 
Eosinophils (abs, %) 
Basophils (abs, %) 
White Blood Count 
 
 
Albumin 
Blood Urea Nitrogen 
Creatinine 
Total Bilirubin 
Alkaline Phosphatase (ALP) 
Aspartate Transaminase (AST) 
Alanine Transaminase (ALT) 
Sodium 
Potassium 
Chloride 
Lactate Dehydrogenase (LDH) 
Uric Acid 
Glucose 
Calcium 
pH 
Specific Gravity 
Protein 
Glucose 
Ketones 
Bilirubin 
Blood 
Nitrite 
Leukocyte Esterase 
Urobilinogen 
Color and Clarity 
Microscopic 
Urine T. Protein, 
Random 
Urine Creatinine, 
Random 
All laboratory data will be reported in conventional units.  Out-of-reference-range 
values will be flagged as high (H) or low (L) in the listings.  
For analysis purposes, values preceded by a “<” or a “>”sign (i.e. those below or 
above the limits of quantification) will be considered equal to the lower or upper 
limit of quantification, respectively. 
Laboratory and urinalysis data will be summarized by visit using standard 
descriptive statistics for the enrolled population.  Changes from baseline will also be 
summarized. 
For hematology and serum chemistry, shift tables presenting movement in and out 
of reference ranges from baseline to each scheduled post-baseline visit will be 
INS011-17-115 Statistical Analysis Plan Final 2018_10_04_signed | VV-TMF-115504 | 1.0
Approved
tase (ALP)
ed
tase (ALP)
nsaminase (AST)
ve
nsaminase (AST)
ansaminase (ALT)
ve
ansaminase (ALT)
ssium
r
ssium
hloride
pr
hloride
Lactate Dehydro
pp
Lactate Dehydro
Uric Acid
App
Uric Acid
Glucose
Ap
Glucose
C
Ap
Calcium
Ap
alcium
Ap
Ap
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Statistical Analysis Plan  
Sponsor Name: Insys Development Company, Inc. 
Sponsor Protocol ID: INS011-17-115 
 
Covance Study ID: 000000163385 
COVANCE INC. CONFIDENTIAL 
Document Date: 04 October 2018
Page 18 of 22
 
 
ST-AD-008 version 04 
provided for each treatment group.  Corresponding shift tables will be produced for 
urinalysis. 
6.7.3.2 
Urine Drug Screen 
A urine sample for the following assessments will be collected at study entry and 
end of study/early withdrawal: amphetamines, barbiturates, benzodiazepines, 
cocaine, opiates, phencyclidine and tetrahydrocannabinol.  
Results from the urine drug screen will be listed for the enrolled population. 
6.7.3.3 
Urine Pregnancy Test 
A urine dipstick pregnancy test will be performed on all female post-menarchal 
patients at Visit 1 and Visit 7 (End of Study) or early withdrawal. 
Pregnancy screen results will be listed for the enrolled population. 
6.7.4 Vital Signs 
The following vital signs will be listed and summarized by treatment group and visit. 
• 
systolic blood pressure (mmHg); 
• 
diastolic blood pressure (mmHg); 
• 
pulse rate (bpm);  
• 
body temperature (°C); 
• 
respiratory rate (breaths/min); 
• 
weight (kg) 
• 
height (m) 
• 
BMI (kg/m2). 
Vital signs data and changes from baseline in vital signs will be summarized by visit 
using standard descriptive statistics for the enrolled population. Shift tables will also 
be presented from baseline to outside normal range criteria. 
All vital sign data collected for the enrolled population will be listed. 
6.7.5 Electrocardiograms 
The following quantitative ECG measurements will be taken during the study: 
• 
Heart rate (bpm); 
• 
PR interval (msec); 
• 
QRS interval (msec); 
• 
QT interval (msec); 
INS011-17-115 Statistical Analysis Plan Final 2018_10_04_signed | VV-TMF-115504 | 1.0
ved
arly 
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arly 
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App
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Statistical Analysis Plan  
Sponsor Name: Insys Development Company, Inc. 
Sponsor Protocol ID: INS011-17-115 
 
Covance Study ID: 000000163385 
COVANCE INC. CONFIDENTIAL 
Document Date: 04 October 2018
Page 19 of 22
 
 
ST-AD-008 version 04 
• 
QTcF interval (msec) 
• 
RR interval (msec). 
An overall Investigator assessment of ECG will be provided (categories “normal”, 
“abnormal, not clinically significant” and “abnormal, clinically significant”). 
The ECG measurements and changes from baseline in ECG will be listed and 
summarized by treatment group and visit using standard descriptive statistics for 
the enrolled population.  
The Investigator assessment will be listed and the number and percentage of 
patients within each assessment category will be tabulated by treatment group and 
visit for the enrolled population. Shifts from baseline at each post-baseline visit will 
be presented. 
A listing of ECG measurements and findings will be produced for all enrolled 
patients. 
6.7.6 Physical Examination 
Physical examination results (normal/abnormal) and details of abnormalities 
(Abnormal, Not Clinically Significant and Abnormal, Clinically Significant) will be 
listed for all enrolled patients. 
For each physical examination body system, the number and percentage of patients 
with abnormalities at baseline and post-baseline will be summarized by treatment 
group for the All Enrolled Population. Shifts from baseline according to normal and 
abnormal criteria will also be presented for all patients 
6.8 Interim Analysis 
No interim analysis will be performed for this study. 
7. Changes in Planned Analysis 
Not applicable. 
8. Data Issues 
Not applicable. 
9. References 
Fehnel, S., Brown, T. M., Nelson, L., Chen, A., Roof, E., Kim, D. D., et al. (2015). 
Development of the hyperphagia questionnaire for use in Prader-Willi 
syndrome clinical trials. Presented at ISPOR 20th Annual International 
Meeting.  
INS011-17-115 Statistical Analysis Plan Final 2018_10_04_signed | VV-TMF-115504 | 1.0
Approved
ngs will be pr
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Statistical Analysis Plan  
Sponsor Name: Insys Development Company, Inc. 
Sponsor Protocol ID: INS011-17-115 
 
Covance Study ID: 000000163385 
COVANCE INC. CONFIDENTIAL 
Document Date: 04 October 2018
Page 20 of 22
 
 
ST-AD-008 version 04 
Gassmann-Mayer, C., Jiang, K., McSorley, P., Arani, R., DuBrava, S., Suryawanshi, 
S., et al. (2011). Clinical and statistical assessment of suicidal ideation and 
behavior in pharmaceutical trials. Clinical Pharmacology and Therapeutics, 
90(4), 554-560. 
 
 
 
INS011-17-115 Statistical Analysis Plan Final 2018_10_04_signed | VV-TMF-115504 | 1.0
Approved
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Statistical Analysis Plan 
Sponsor Name: Insys Development Company, Inc. 
Sponsor Protocol ID: INS011-17-115 
 
Covance Study ID: 000000163385 
COVANCE INC. CONFIDENTIAL 
Document Date: 04 October 2018
Page 21 of 22
 
 
 
 
ST-AD-008 version 04 
Appendix A: Schedule of Events
 
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Statistical Analysis Plan 
Sponsor Name: Insys Development Company, Inc. 
Sponsor Protocol ID: INS011-17-115 
 
Covance Study ID: 000000163385 
COVANCE INC. CONFIDENTIAL 
Document Date: 04 October 2018
Page 22 of 22
 
 
 
 
ST-AD-008 version 04 
INS011-17-115 Statistical Analysis Plan Final 2018_10_04_signed | VV-TMF-115504 | 1.0
App
App
Approved
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