Conditions: Prader-Willi Syndrome
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 7
Healthy volunteers: no

Brief summary:
The primary objective of this study is to assess the efficacy of cannabidiol oral solution on hyperphagia-related behavior in patients with Prader-Willi Syndrome (PWS). The secondary objectives of this study are to assess the efficacy, safety and tolerability, impact on quality of life, and impact on physical activity of cannabidiol oral solution in patients with PWS.

Detailed description:

Arms:
arm 1: Cannabidiol oral solution (40 milligram/kilogram/day \[40 mg/kg/day\]) divided into two daily doses with a standard meal arm 2: Matching placebo solution divided into two daily doses with a standard meal

Interventions: intervention 1: Cannabidiol intervention 2: Placebo
Intervention descriptions: intervention 1: Oral solution intervention 2: Matching oral solution

Protocol document:
Prot_000.pdf: 
 
 
 
CLINICAL TRIAL PROTOCOL 
 
 
A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study to Assess 
the Efficacy, Safety, and Tolerability of Cannabidiol Oral Solution for the 
Treatment of Patients with Prader-Willi Syndrome 
 
 
Protocol Number: INS011-16-085 
Final Protocol Date: 12 July 2018 
Version: 2.0 
Investigational Product: Cannabidiol Oral Solution 
IND Number: IND 136,374 
 
ClinicalTrials.gov ID: NCT02844933 


12 Jan 2018 
CONFIDENTIAL 
1 
CLINICAL TRIAL PROTOCOL 
A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study to Assess the 
Efficacy, Safety, and Tolerability of Cannabidiol Oral Solution for the 
Treatment of Patients with Prader-Willi Syndrome 
Protocol Number: INS011-16-085 
Final Protocol Date: 12 Jan 2018 
Protocol Version: 2.0  
Investigational Product: Cannabidiol Oral Solution 
IND Number: IND 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. 
PPD
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12 january 2018
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Insys Development Company, Inc.  
 
 
Protocol Number INS011-16-085 
12 Jan 2018 
    CONFIDENTIAL 
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PROTOCOL SYNOPSIS 
Name of Sponsor/Company: 
Insys Development Company, Inc. 
Name of Investigational Product: 
Cannabidiol Oral Solution 
Name of Active Ingredient: 
Cannabidiol 
Title of Study:  
A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study to Assess the Efficacy, 
Safety, and Tolerability of Cannabidiol Oral Solution for the Treatment of Patients with 
Prader-Willi Syndrome 
Study Center(s): Approximately 10 sites in the US and Canada 
 
Study Period: 
Estimated date first patient enrolled: Mar 2018 
Estimated date last patient completed: Mar 2019 
Phase of Development: Phase 2 
Objectives:  
Primary: 
• To assess the efficacy of Cannabidiol Oral Solution on hyperphagia-related behavior 
in patients with Prader-Willi Syndrome (PWS) as measured by total score of the 
Hyperphagia Questionnaire for Clinical Trials (HQ-CT).   
Secondary:  
• To assess the efficacy of Cannabidiol Oral Solution on the change in total body-
weight in patients with PWS. 
• To assess the responder rate (responder is defined as 6-point decrease on the HQ-CT 
from Baseline to End of Study). 
• To assess the efficacy of Cannabidiol Oral Solution by measuring the changes in 
Patient Global Impression of Change (PGI-C). 
• To assess the safety and tolerability of Cannabidiol Oral Solution in patients with 
PWS. 
• To assess the efficacy of Cannabidiol Oral Solution on eating behavior in patients 
with PWS as measured by the Three Factor Eating Questionnaire-18-item version 
(TFEQ-R18). 
• To assess the impact on Quality of Life in patients with PWS as measured by the 
PROMIS® Life Satisfaction and Positive Affect short-form questionnaires. 


Insys Development Company, Inc.  
 
 
Protocol Number INS011-16-085 
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• To assess the impact on physical activity in patients with PWS as measured by the 
PROMIS Physical Activity and Fatigue questionnaires. 
Exploratory: 
• To assess the efficacy of Cannabidiol Oral Solution on body composition, and bone 
mineral density, as measured by dual-energy X-ray absorptiometry (DEXA).  
Methodology:  
This is a double-blind, randomized, placebo-controlled, Phase 2 clinical trial in patients 
diagnosed with Prader-Willi Syndrome. Patients will receive either Cannabidiol Oral 
Solution (40 mg/kg/day) or placebo with patients randomized in a 1:1 ratio. Randomization 
will be stratified according to use of growth hormone treatment.  
Approximately 66 male and female patients aged 8 to 17 years, inclusive, with a genetically 
confirmed diagnosis of Prader-Willi Syndrome will be enrolled in the study.  
The study will consist of the following six periods: 
• Screening Period (2 weeks) 
• Placebo Lead-In Period (2 weeks) 
• Titration Period (1 week) 
• Maintenance Period (12 weeks) 
• Taper Period (1 week) 
• Follow-Up Period (1 week) 
Patients who meet entry criteria will be assigned to a 2-week single-blind Placebo Lead-In 
Period. Following the placebo single-blind lead-in period, patients will be randomly assigned 
to receive double-blind treatment with either Cannabidiol Oral Solution treatment at a dose of 
40 mg/kg/day or matching placebo divided twice daily with standard meal (a 1-week 
Titration Period followed by a 12-week Maintenance Period). During the Titration Period, 
Cannabidiol Oral Solution will be titrated as follows: Days 1-3: 20 mg/kg/day, Days 4-6: 30 
mg/kg/day, Day 7: 40 mg/kg/day. The Investigator or designee will call on Day 3 and Day 6 
to determine if the patient’s dose may be titrated to the next dose level. If the Investigator 
determines that the patient is unable to tolerate the higher dose, the patient should be 
withdrawn from the study. 
During the Maintenance Period, patients may have their dose of blinded study medication 
adjusted down to 30 mg/kg/day at the discretion of the Investigator or qualified designee 
based on the patient’s tolerability.   
After completion of the study, patients will be offered the opportunity to enroll in an open-
label, long-term safety study. Patients who do not elect to enroll in the long-term safety study 
will be tapered off the study drug over 7 days according to the following schedule: 
40 mg/kg/day to 30 mg/kg/day for 3 days, 30 mg/kg/day to 20 mg/kg/day for 3 days, 
discontinuing the drug on Day 7. A final safety follow-up will be conducted 2 weeks after 
study completion (Visit 10) for patients who do not elect to continue into the long-term safety 
study.  


Insys Development Company, Inc.  
 
 
Protocol Number INS011-16-085 
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Safety assessments for all patients will include medical history, physical examination, vital 
signs (seated blood pressure, pulse rate, temperature, and respiration rate), clinical laboratory 
testing (including a CBC test), 12-lead ECG, urine drug screen (including THC), prior 
medication history, concomitant medication, and AE assessments. 
Blood draws for PK sampling will be taken prior to medication dosing at specific study visits 
for determination of the plasma levels of CBD and 7-OH-CBD. 
Number of patients (planned):  
Approximately 66 male and female patients will be enrolled to have 60 patients (30 patients 
per treatment group) complete the study. 
Diagnosis and main criteria for inclusion:  
Patients will be male and non-pregnant female volunteers between 8 and 17 years of age 
(inclusive) with a genetically confirmed diagnosis of Prader-Willi Syndrome using a standard 
DNA methylation test or fluorescent in situ hybridization, able to understand and provide 
written consent, and who meet all the inclusion and none of the exclusion criteria. 
Inclusion Criteria 
1. 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. 
2. Males and females from 8-17 years of age, inclusive.  
3. Genetically confirmed diagnosis of Prader-Willi Syndrome using standard DNA 
methylation test or fluorescent in situ hybridization. Documentation of genetically 
confirmed diagnosis of Prader-Willi Syndrome is acceptable. 
4. A score of ≥ 10 on the HQ-CT.  
5. A caregiver is available to complete the HQ-CT. 
6. 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). 
7. Adequate renal function, defined as serum creatinine ≤ 1.5 × upper limit of normal 
(ULN) and urine protein/creatinine ratio <0.2.  


Insys Development Company, Inc.  
 
 
Protocol Number INS011-16-085 
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8. Adequate hepatic function, defined as total bilirubin ≤ 1.5 × ULN and Aspartate 
aminotransferase (AST) and Alanine aminotransferase (ALT) levels ≤ 3 × ULN.  
9. Growth hormone treatment will be permitted if doses have been stable for at least 
1 month prior to screening. 
10. Psychotropic treatment will be permitted and should be stable at least 6 weeks prior to 
screening. 
11. Any other treatment including thyroid hormones should be stable for at least 6 weeks 
prior to screening. 
Exclusion Criteria 
1. Known use of cannabis or cannabinoid-containing products for 4 weeks prior to 
baseline.  
2. History of chronic liver disease, such as cirrhosis or chronic hepatitis due to any 
cause, or suspected alcohol abuse.  
3. Use of weight loss agents or drugs known to affect appetite (including glucagon-like 
peptide-1[GLP-1] analogs) within 2 months prior to screening. 
4. Uncontrolled Type I and Type II diabetes.   
5. Currently taking concomitant medications that are strong cytochrome P450 3A4 
(CYP3A4) or CYP2D6 inhibitors; or inducers of CYP3A4- or CYP2D6-sensitive 
substrates with a narrow therapeutic index. 
6. Co-morbid condition or disease (such as respiratory disease, heart disease, or 
psychiatric disorder) diagnosed less than 1 month prior to screening.  
7. History or presence of gastrointestinal or any other condition known to interfere with 
the absorption, distribution, metabolism or excretion of drugs as determined by the 
Investigator.   
8. Patients who have participated in any other trials involving an investigational product 
or device within 30 days of screening or longer as required by local regulations.  
9. Clinically significant abnormalities on ECG at screening or other evidence of heart 
disease as determined by the Investigator.  
10. Has screening systolic blood pressure ≥160 mm Hg and diastolic blood pressure >100 
mm Hg (may be repeated one additional time after 5 minutes’ rest to verify). Patients 
with hypertensive levels lower than those specified may be excluded at the 
Investigator’s discretion if deemed to be in the best interest of the patient.  
11. Currently taking felbamate. 
12. Uncontrolled sleep apnea. 
13. Pregnant or lactating female.  
14. History of hypersensitivity to drugs with a similar chemical structure or class as CBD.  
15. Unwillingness or inability to follow the procedures outlined in the protocol.  


Insys Development Company, Inc.  
 
 
Protocol Number INS011-16-085 
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16. Patient judged by the investigator or sponsor (or designee) as unable to comply with 
the treatment protocol, including appropriate supportive care, follow-up and research 
tests. 
17. Positive drug screen, including THC, at time of screening. 
18. Creatinine clearance test of < 30 mL/min. 
Investigational product, dosage and mode of administration:  
Cannabidiol Oral Solution, 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 screening to follow-up will be approximately 19 
weeks. 
Reference therapy, dosages and modes of administration:  
Matching placebo, divided into twice daily doses with standard meal, manufactured for and 
supplied by Insys Development Company, Inc. 
Criteria for evaluation: 
Efficacy 
Primary efficacy endpoint:   
• Change in the total score of the HQ-CT from Baseline (defined as the score after the 
2-week Placebo Lead-In) through Study Completion (Week 13/Early Withdrawal). 
Secondary efficacy endpoints:   
• Change in total body-weight from Baseline through Study Completion/Early 
Withdrawal. 
• Responder rate (responder is defined as 6-point decrease on the HQ-CT) from 
Baseline through Study Completion). 
• Change in Patient Global Impression of Change (PGI-C). 
• Change in the TFEQ-R18 from Baseline through Study Completion/Early 
Withdrawal. 
• Change in the Quality of Life (PROMIS Life Satisfaction and Positive Affect short 
form pediatric questionnaires) from Baseline through Study Completion/Early 
Withdrawal. 
• Change in physical activity (PROMIS Physical Activity and Fatigue pediatric 
questionnaires) from Baseline through Study Completion/Early Withdrawal. 
Exploratory efficacy endpoint: 
• Change in body composition and bone mineral density from Baseline to Study 
Completion/Early Withdrawal as measured by DEXA. 
Safety 


Insys Development Company, Inc.  
 
 
Protocol Number INS011-16-085 
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The safety endpoints are treatment-emergent AEs (TEAEs), clinical laboratory assessments, 
vital signs (blood pressure, pulse rate, respiration rate, and temperature), 12-lead ECGs, 
physical examination assessments, pregnancy screens, urine drug screen (including THC), 
medical history, and prior and concomitant medications.   
Pharmacokinetic 
• Trough concentrations (Ctrough) of cannabidiol (CBD) and metabolite 7-hydoxy-CBD 
(7-OH CBD) will be used to assess the exposure-response relationship. 
Statistical Methods: 
Sample Size Calculation 
A total of 30 patients per treatment group will provide more than 85% power with an alpha of 
0.05, for a difference in the HQ-CT from Baseline to Week 13 of 5 points with standard 
deviation of 6. Assuming a 20% drop out rate, approximately 66 patients (33 patients per 
arm) will be randomized to achieve 60 (30 patients/arm) completers. 
Analysis Populations 
Statistical analyses will be conducted on the following populations: 
• Safety Population: The Safety Population will include all patients who were treated with 
at least one dose of the study drug. 
• Intent to Treat (ITT) Population: The ITT Population will include all patients who were 
randomized.   
Efficacy Analyses 
The ITT Population will be used for all efficacy analyses. 
The primary efficacy endpoint will be tested using a 2-sided type I error rate of 0.05 The 
primary outcome variable for the study is the change in total score of the HQ-CT from 
Baseline through Study Completion/Early Withdrawal. 
Statistical inference for the primary endpoint and for the secondary endpoints (change in total 
body-weight, responder rate, PGI-C and PGI-S, TFEQ-R18, and PROMIS Life Satisfaction 
and Positive Affect, PROMIS Physical Activity and Fatigue), will be controlled at an overall 
family wise error rate (alpha) of 0.05, 2-sided.  
For continuous endpoints, number of observations, mean, standard deviation (SD), median, 
minimum, and maximum, will be presented as descriptive statistics. For inferential statistics, 
analysis of covariance (ANCOVA) with the baseline value and randomization strata (growth 
hormone treatment) as covariates. 
For categorical endpoints, the number of observations, frequency counts and percentages will 
be presented as descriptive statistics. Fisher’s exact test will be used for inferential statistics.  
Safety Analyses 
The Safety Population will be used for all safety assessments. 
All safety assessments will be descriptive and no inferential statistics are planned. All data 
listings will be provided for protocol specified safety data. The Medical Dictionary for 
Regulatory Activities (MedDRA; Version 20.0 or higher) will be used to classify all adverse 
events with respect to system organ class and preferred term. Adverse event summaries will 
include only TEAEs by treatment group. All clinical laboratory findings and vital signs will 
be summarized for all patients in the safety population for observed values and change from 


Insys Development Company, Inc.  
 
 
Protocol Number INS011-16-085 
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    CONFIDENTIAL 
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baseline. Shifts from baseline according to normal range criteria will also be presented for all 
patients in the safety population. Prior medication and concomitant medications will be 
reported in the data listings.   
Statistical analyses will be performed using SAS® (Version 9.3 or higher, SAS Institute Inc.). 
Pharmacokinetic Analyses   
Exploratory analyses of dose (exposure)-response relationship will be performed. Further 
population PK approach may be used for PK parameter calculations, as appropriate. 
Missing Data 
For efficacy measures, missing data points may be imputed using Jump to Reference as a 
conservative method.  For safety data, there will be no imputation of missing data, and the 
safety assessments will be conducted based on the observed data. 


Insys Development Company, Inc.  
 
 
  
Protocol Number INS011-16-085 
 
12 Jan 2018 
                                                    CONFIDENTIAL  
          
 
 
 
 
 
 
10 
Table 1: 
Schedule of Assessments 
Assessment 
SCREENING 
(2 Weeks) 
SINGLE 
BLIND 
PLACEBO 
LEAD-IN 
(2 Weeks) 
 
DOUBLE-BLIND TREATMENT PHASE 
FOLLOW
-UP 
PERIODb 
(2 Week) 
TITRATION 
PERIODa 
(1 Week) 
MAINTENANCE PERIOD 
(12 Weeks) 
Visit Number 
1 
2 
3 
Baseline 
Call/ 
Email 
4 
5 
6 
7 
8 
9 
10 
Study 
Completion
/            
Early 
Withdrawal 
11 
Study Time Point 
Week  
-4 to -2 
Week  
-2 
Day 1 
Day 
3 & 6 
Day 7 
Week 
3 
Week 
5 
Week 
7 
Week 
9 
Week 
11 
Week  
13 
Week  
15 
Visit Window (Days) 
±3 
±3 
±3 
0 
0 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
Informed consent/assent 
(if appropriate)   
X 
 
 
 
 
 
 
 
 
 
 
 
Medical/surgical history      
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Review of inclusion and 
exclusion criteria                  
X 
 
 
 
 
 
 
 
 
 
 
 
Randomization          
 
 
X 
 
 
 
 
 
 
 
 
 
Physical exam   
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Record vital signs          
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Resting 12-lead ECG      
X 
 
 
 
 
 
X 
 
X 
 
X 
 
Clinical laboratory testsd 
X 
 
 
 
 
X 
 
 
 
 
X 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
X 
 


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Protocol Number INS011-16-085 
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Assessment 
SCREENING 
(2 Weeks) 
SINGLE 
BLIND 
PLACEBO 
LEAD-IN 
(2 Weeks) 
 
DOUBLE-BLIND TREATMENT PHASE 
FOLLOW
-UP 
PERIODb 
(2 Week) 
TITRATION 
PERIODa 
(1 Week) 
MAINTENANCE PERIOD 
(12 Weeks) 
Visit Number 
1 
2 
3 
Baseline 
Call/ 
Email 
4 
5 
6 
7 
8 
9 
10 
Study 
Completion
/            
Early 
Withdrawal 
11 
Study Time Point 
Week  
-4 to -2 
Week  
-2 
Day 1 
Day 
3 & 6 
Day 7 
Week 
3 
Week 
5 
Week 
7 
Week 
9 
Week 
11 
Week  
13 
Week  
15 
Visit Window (Days) 
±3 
±3 
±3 
0 
0 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
Urine dipstick for females 
of childbearing potential 
only      
X 
 
 
 
 
 
 
 
 
 
X 
 
Urine drug screen (drugs 
of abuse including THC) 
X 
 
 
 
 
 
 
 
 
 
 
 
Dosing with Study 
Medication 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dispense/Review/Collect 
study medication  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hyperphagia 
Questionnaire for Clinical 
Trial (HQ-CT) 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Weight 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Three Factor Eating 
Questionnaire (TFEQ-
R18) 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
PROMIS Life 
Satisfaction and Positive 
Affect pediatric short-
form questionnaires 
 
 
X 
 
 
X 
 
 
X 
 
X 
 


Insys Development Company, Inc.  
 
 
Protocol Number INS011-16-085 
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Assessment 
SCREENING 
(2 Weeks) 
SINGLE 
BLIND 
PLACEBO 
LEAD-IN 
(2 Weeks) 
 
DOUBLE-BLIND TREATMENT PHASE 
FOLLOW
-UP 
PERIODb 
(2 Week) 
TITRATION 
PERIODa 
(1 Week) 
MAINTENANCE PERIOD 
(12 Weeks) 
Visit Number 
1 
2 
3 
Baseline 
Call/ 
Email 
4 
5 
6 
7 
8 
9 
10 
Study 
Completion
/            
Early 
Withdrawal 
11 
Study Time Point 
Week  
-4 to -2 
Week  
-2 
Day 1 
Day 
3 & 6 
Day 7 
Week 
3 
Week 
5 
Week 
7 
Week 
9 
Week 
11 
Week  
13 
Week  
15 
Visit Window (Days) 
±3 
±3 
±3 
0 
0 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
PROMIS Physical 
Activity and Fatigue 
pediatric short-form 
questionnaires 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
Patient Global Impression 
of Severity (PGI-S) 
 
 
X 
 
 
 
 
 
 
 
 
 
Patient Global Impression 
of Change (PGI-C) 
 
 
 
 
 
X 
 
 
X 
 
X 
 
DEXA scane 
 
 
X 
 
 
 
 
 
 
 
X 
 
Columbia Suicide 
Severity Rating Scale (C-
SSRS) 
 
 
X 
 
 
 
 
 
 
 
X 
 
Review of concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review of adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacokineticsc 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
DEXA = Dual energy X-ray absorptiometry; PROMIS = Patient-Reported Outcomes Measurement Information System 
a Titration schedule = Days 1-3: 20 mg/kg/day; Days 4-6: 30 mg/kg/day; Day 7: 40 mg/kg/day. Phone calls will be made at Day 3 and Day 6 to determine if the 
patient’s dose may be  titrated to the next dose level.  


Insys Development Company, Inc.  
 
 
Protocol Number INS011-16-085 
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b The Follow-up Visit is only for patients who do not choose to enroll in the long-term safety study and are tapering off the study drug.  Patients will return to the 
site for assessment of concomitant medications, AEs, and to return and reconcile study drug.  
c Blood draws for trough pharmacokinetic analyses of CBD and metabolite 7-OH-CBD will be collected prior to morning dose at Visit 3 (Baseline) and Visit 6, 8, 
and 10 during the Maintenance Period. 
d Blood and urine samples for hematology, chemistry, and urinalysis will be collected at Screening (visit1), and Study Completion (Visit 10)/Early Withdrawal. 
Blood sample for complete blood count (CBC) will be collected at Week 3 (Visit 5). 
e DEXA scan will be completed on a subset of 20 patients.


Insys Development Company, Inc.  
 
 
Protocol Number INS011-16-085 
 
 
12 Jan 2018 
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14 
TABLE OF CONTENTS 
PROTOCOL APPROVAL PAGE ...................................................................................................2 
PROTOCOL SYNOPSIS ................................................................................................................3 
TABLE OF CONTENTS ...............................................................................................................14 
LIST OF TABLES .........................................................................................................................19 
LIST OF FIGURES .......................................................................................................................19 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................20 
1. 
INTRODUCTION ......................................................................................................23 
1.1. 
Cannabidiol .................................................................................................................23 
1.1.1. 
Mechanism of Action .................................................................................................24 
1.1.2. 
Metabolism and Potential Drug Interactions ..............................................................24 
1.2. 
Nonclinical Experience ...............................................................................................24 
1.2.1. 
Safety ..........................................................................................................................24 
1.2.2. 
Efficacy .......................................................................................................................25 
1.2.2.1. 
Single Dose Regimens ................................................................................................25 
1.2.2.2. 
Multiple Dose Regimens ............................................................................................26 
1.3. 
Clinical Experience .....................................................................................................26 
1.3.1. 
Pharmacokinetics ........................................................................................................28 
1.3.2. 
Overview of Safety .....................................................................................................29 
1.3.3. 
Clinical Safety Data ....................................................................................................29 
1.4. 
Prader-Willi Syndrome ...............................................................................................32 
1.5. 
Dose Selection Rationale ............................................................................................33 
1.6. 
Summary of Potential Risks and Benefits ..................................................................33 
2. 
STUDY OBJECTIVES ..............................................................................................36 
2.1. 
Primary Objective .......................................................................................................36 
2.2. 
Secondary Objectives .................................................................................................36 
2.3. 
Exploratory Objective .................................................................................................36 
3. 
INVESTIGATIONAL PLAN .....................................................................................37 
3.1. 
Overall Study Design ..................................................................................................37 
3.2. 
Patient Selection .........................................................................................................39 
3.2.1. 
Inclusion Criteria ........................................................................................................39 


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3.2.2. 
Exclusion Criteria .......................................................................................................39 
3.3. 
Removal of Patients from Therapy or Assessment.....................................................40 
3.4. 
Premature Patient Withdrawal ....................................................................................41 
3.5. 
Dose Adjustment Criteria ...........................................................................................41 
3.6. 
Stopping Rules ............................................................................................................41 
4. 
TREATMENTS ..........................................................................................................43 
4.1. 
Treatments Administered ............................................................................................43 
4.1.1. 
Screening Period .........................................................................................................43 
4.1.2. 
Placebo Lead-In Period ...............................................................................................43 
4.1.3. 
Titration Period ...........................................................................................................43 
4.1.4. 
Maintenance Period ....................................................................................................43 
4.1.5. 
Taper Period ................................................................................................................43 
4.1.6. 
Follow-Up Period .......................................................................................................44 
4.2. 
Identity of Investigational Product .............................................................................44 
4.3. 
Method of Assigning Patients to Treatment Groups ..................................................44 
4.4. 
Selection and Timing of Dose for Each Patient ..........................................................44 
4.5. 
Blinding and Unblinding Treatment Assignment .......................................................44 
4.6. 
Treatment Compliance ................................................................................................45 
4.7. 
Permitted and Prohibited Therapies ............................................................................45 
4.7.1. 
Permitted Therapies ....................................................................................................45 
4.7.2. 
Prohibited Therapies ...................................................................................................45 
4.8. 
Treatment After End of Study ....................................................................................45 
5. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................46 
5.1. 
Labeling and Packaging ..............................................................................................46 
5.1.1. 
Labeling ......................................................................................................................46 
5.1.2. 
Packaging ....................................................................................................................46 
5.2. 
Dispensing and Storage ..............................................................................................46 
5.3. 
Drug Supply and Accountability ................................................................................47 
6. 
STUDY ASSESSMENTS ..........................................................................................48 
6.1. 
Efficacy Assessments .................................................................................................48 
6.1.1. 
Body Weight Measurements .......................................................................................48 
6.1.2. 
Hyperphagia Questionnaire-Clinical Trial (HQ-CT) ..................................................48 
6.1.3. 
Three Factor Eating Questionnaire (TFEQ-R18) .......................................................48 


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6.1.4. 
Quality of Life (PROMIS Life Satisfaction and Positive Affect) ..............................48 
6.1.5. 
Physical Activity (PROMIS Physical Activity and Fatigue) ......................................48 
6.1.6. 
Dual Energy X-ray Absorptiometry (DEXA) Scan ....................................................48 
6.1.7. 
Patient Global Impression of Severity (PGI-S) ..........................................................49 
6.1.8. 
Patient Global Impression of Change (PGI-C) ...........................................................49 
6.2. 
Safety Assessments .....................................................................................................49 
6.2.1. 
Demographics and Medical History ...........................................................................49 
6.2.2. 
Physical Examinations ................................................................................................49 
6.2.3. 
Vital Signs ..................................................................................................................49 
6.2.4. 
Electrocardiograms .....................................................................................................49 
6.2.5. 
Clinical Laboratory Assessments ...............................................................................50 
6.2.5.1. 
Hematology .................................................................................................................50 
6.2.5.2. 
Chemistry ....................................................................................................................50 
6.2.5.3. 
Urinalysis ....................................................................................................................50 
6.2.5.4. 
Pregnancy Screen (Female Patients) ..........................................................................50 
6.2.5.5. 
Urine Drug Screen ......................................................................................................50 
6.2.5.6. 
Columbia Suicide Severity Rating Scale (C-SSRS) ...................................................50 
6.2.6. 
Adverse Events and Serious Adverse Events .............................................................50 
6.2.6.1. 
Definition of Adverse Events .....................................................................................50 
6.2.6.2. 
Classification of Adverse Events ................................................................................51 
6.2.6.3. 
Causality: Drug Relationship Assessment ..................................................................52 
6.2.6.4. 
Definition of Serious Adverse Events ........................................................................52 
6.2.6.5. 
Serious Adverse Event Actions Taken .......................................................................53 
6.2.6.6. 
Serious Adverse Event Outcome at the Time of Last Observation ............................53 
6.2.6.7. 
Adverse Event Recording and Reporting ...................................................................53 
6.2.6.8. 
Adverse Event Follow-Up ..........................................................................................54 
6.2.6.9. 
Special Considerations ................................................................................................54 
6.2.7. 
Pharmacokinetics Assessments ..................................................................................54 
7. 
STUDY PROCEDURES ............................................................................................55 
7.1. 
Screening ....................................................................................................................55 
7.2. 
Placebo Lead-In Period ...............................................................................................55 
7.2.1. 
Visit 2 (Week -2) ........................................................................................................55 
7.3. 
Titration Period ...........................................................................................................56 


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7.3.1. 
Baseline (Visit 3, Day 1) ............................................................................................56 
7.3.2. 
Visit 4 (Day 7) ............................................................................................................56 
7.4. 
Maintenance Period ....................................................................................................57 
7.4.1. 
Visit 4-9 (Week 3 to 11) .............................................................................................57 
7.4.2. 
Visit 10 (Week 13; Study Completion) or Early Withdrawal ....................................57 
7.5. 
Taper Period ................................................................................................................58 
7.6. 
Follow-Up Period .......................................................................................................58 
7.6.1. 
Visit 11 (Week 15) ......................................................................................................58 
8. 
STATISTICS ..............................................................................................................59 
8.1. 
Efficacy Endpoints ......................................................................................................59 
8.1.1. 
Primary Efficacy Endpoint .........................................................................................59 
8.1.2. 
Secondary Efficacy Endpoints ....................................................................................59 
8.1.3. 
Exploratory Efficacy Endpoint ...................................................................................59 
8.2. 
Safety Endpoints .........................................................................................................59 
8.3. 
Pharmacokinetic Endpoints ........................................................................................59 
8.4. 
Sample Size Determination ........................................................................................60 
8.5. 
Analysis Populations ..................................................................................................60 
8.6. 
Statistical Analyses .....................................................................................................60 
8.6.1. 
Study Patients and Demographics ..............................................................................60 
8.6.1.1. 
Disposition and Withdrawals ......................................................................................60 
8.6.1.2. 
Protocol Deviations ....................................................................................................60 
8.6.1.3. 
Demographics and Other Baseline Characteristics .....................................................60 
8.6.2. 
Exposure and Compliance ..........................................................................................60 
8.6.3. 
Efficacy Analyses .......................................................................................................61 
8.6.3.1. 
Primary Efficacy Analysis ..........................................................................................61 
8.6.3.2. 
Secondary Efficacy Analysis ......................................................................................61 
8.6.3.3. 
Exploratory Efficacy Analysis ....................................................................................61 
8.6.4. 
Safety and Tolerability Analyses ................................................................................61 
8.6.4.1. 
Adverse Events ...........................................................................................................61 
8.6.4.2. 
Clinical Laboratory Evaluations .................................................................................62 
8.6.4.3. 
Vital Signs ..................................................................................................................62 
8.6.4.4. 
Electrocardiograms .....................................................................................................62 
8.6.4.5. 
Physical Examination Findings ..................................................................................62 


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8.6.5. 
Pharmacokinetic Analyses ..........................................................................................63 
8.6.6. 
Missing Data ...............................................................................................................63 
9. 
STUDY CONDUCT ...................................................................................................64 
9.1. 
Sponsor and Investigator Responsibilities ..................................................................64 
9.1.1. 
Sponsor Responsibilities .............................................................................................64 
9.1.2. 
Investigator Responsibilities .......................................................................................64 
9.2. 
Site Initiation ..............................................................................................................64 
9.3. 
Screen Failures ............................................................................................................65 
9.4. 
Study Documents ........................................................................................................65 
9.4.1. 
Investigator’s Regulatory Documents ........................................................................65 
9.4.2. 
Case Report Forms .....................................................................................................65 
9.4.3. 
Source Documents ......................................................................................................65 
9.5. 
Study Termination ......................................................................................................66 
9.6. 
Study Site Closure ......................................................................................................66 
9.6.1. 
Record Retention ........................................................................................................66 
9.6.2. 
Pharmacokinetic/Laboratory Sample Retention .........................................................66 
10. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................67 
10.1. 
Changes to The Protocol .............................................................................................67 
10.2. 
Monitoring ..................................................................................................................67 
10.3. 
Data Review Meeting .................................................................................................67 
10.4. 
Protocol Violations .....................................................................................................67 
10.5. 
Quality Assurance Audit .............................................................................................68 
11. 
REGULATORY AND ETHICAL CONSIDERATIONS ..........................................69 
11.1. 
Regulatory Authority Approval ..................................................................................69 
11.2. 
Ethical Conduct of the Study ......................................................................................69 
11.3. 
Statement of Investigator/Delegation of Authority ....................................................69 
11.4. 
Patient Informed Consent ...........................................................................................69 
11.5. 
Investigator Reporting Requirements .........................................................................70 
12. 
DATA HANDLING AND RECORD KEEPING ......................................................71 
12.1. 
Data Management .......................................................................................................71 
12.2. 
Case Report Forms and Source Documents ...............................................................71 
12.3. 
Documentation and Retention of Essential Documents .............................................71 
12.4. 
Financial Disclosure ...................................................................................................71 


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13. 
FACILITIES ...............................................................................................................73 
14. 
USE OF INFORMATION AND PUBLICATION POLICY .....................................74 
14.1. 
Use of Information ......................................................................................................74 
14.2. 
Publication Policy .......................................................................................................74 
15. 
REFERENCES ...........................................................................................................75 
16. 
INVESTIGATOR AGREEMENT AND SIGNATURE PAGE .................................81 
LIST OF TABLES 
Table 1: 
Schedule of Assessments ............................................................................................10 
Table 2: 
List of Insys Sponsored Clinical Trials with Cannabidiol Oral Solution ...................27 
Table 3: 
Description of Drug Product .......................................................................................46 
 
LIST OF FIGURES 
Figure 1:  Study Design Schematic .............................................................................................38 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Abbreviation or Specialist Term 
Explanation 
5-HT1a 
5-hydroxytryptamine 1a 
ACTH 
adrenocorticotropic hormone  
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
API 
active pharmaceutical ingredient 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
AUCinf 
area under the 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 
CHMP 
Committee for Medicinal Products for Human Use 
Cmax 
maximum plasma concentration 
Ctrough 
plasma trough concentrations 
CNS 
central nervous system 
CRF 
case report form 
CRO 
contract research organization  
C-SSRS 
Columbia Suicide Severity Rating Scale 
CV% 
coefficient of variation 
CYP 
cytochrome P450 
CYP1A1 
Cytochrome P450 1A1 
CYP2C19 
Cytochrome P450 2C19 
CYP2C9 
Cytochrome P450 2C9 


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CYP2D6 
Cytochrome P450 2D6 
CYP3A4 
Cytochrome P450 3A4 
CYP3A5 
Cytochrome P450 3A5 
DBC 
Developmental Behaviour Checklist 
DEA 
Drug Enforcement Administration 
DEXA 
Dual energy X-ray absorptiometry 
DNA 
deoxyribonucleic acid 
DMC 
Data Monitoring Committee 
ECG 
electrocardiogram 
EDC 
electronic data capture 
EEG 
electroencephalogram 
EENT 
eyes, ears, nose, and throat 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GH 
growth hormone 
GLP-1 
glucagon-like peptide-1 
HQ-CT 
Hyperphagia Questionnaire-Clinical Trial 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IFN 
interferon 
IL-2 
interleukin-2 
IP 
intraperitoneal  
IRB 
Institutional Review Board 
MedDRA 
Medical Dictionary for Regulatory Activities 
MCT 
medium chain triglycerides 
MMRM 
mixed model repeated measures 
OH 
hydroxy 
PK 
pharmacokinetic(s) 
pKa 
acid dissociation constant 
PGI-C 
Patient Global Impression of Change 
PGI-S 
Patient Global Impression of Severity 


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PROMIS® 
Patient-Reported Outcomes Measurement Information 
System 
PSG 
polysomnography 
PT 
preferred term 
PWS 
Prader-Willi Syndrome 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SOC 
system organ class 
SOP 
standard operating procedure 
TEAE 
treatment-emergent adverse event 
TFEQ-R18 
Three Factor Eating Questionnaire - 18-item version 
Tmax 
time to maximum plasma concentration 
Δ9-THC 
Δ9-tetrahydrocannabinol 
THC 
tetrahydrocannabinol 
ULN 
upper limit of normal 
US 
United States 
 
 


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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. 
In addition, the unmet medical needs of Prader-Willi Syndrome as well as the rationale for the 
development of Cannabidiol Oral Solution for the treatment of hyperphagia and obesity in this 
syndrome will be presented (See Section 1.4).   
Please see the Investigator’s Brochure (IB) for more information. 
1.1. 
Cannabidiol 
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 


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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. 
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 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 


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highlight a potential impact of CBD on spermatogenesis, follicle-stimulating hormone levels, 
and a subset of immune responses. Full detail of these results may be found in the IB. 
1.2.2. 
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 (IP) 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 
(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 IP 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. 


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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 IP 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 
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. 


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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 
INS011-15-054 
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 
Open 
label 
Healthy adults 
8 
Completed 


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Study Number 
Study Title 
Study 
Design 
Population 
Number 
of 
Patients 
Study 
Status 
Oral Solution in healthy 
subjects. 
1.3.1. 
Pharmacokinetics 
INS011-14-029 is a completed Phase 1/2 study assessing the 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 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, 
100mg/mL (fed) and alcohol-containing, 80 mg/mL). An appreciable food effect and lower 
variability were observed with 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 (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-


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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 
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).  


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• 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® 
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. 


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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%).   
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, cannabidiol should be carefully 
monitored in patients with significant respiratory comorbidities, such as those that occur in 
patients with Prader-Willi Syndrome. 


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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., 
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 


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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, 1980). 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 
Doses up to 40 mg/kg/day were administered in the Phase 1/2 PK study (Protocol INS011-14-
029) and the long-term safety study (Protocol INS011-14-030). The maximum dose given was 
3200 mg/day in an adolescent. These doses were generally well tolerated even without titration. 
Because the Prader-Willi patients enrolled in this study will be obese and there were concerns 
that distribution to fat would decrease the effective dose in these subjects, the maximum 
tolerated dose identified in the previous PK and safety study will be given. To maximize 
tolerability, a one-week titration period is included in this study (initial dose of 20 mg/kg/day for 
3 days, followed by 30 mg/kg/day for 3 days, and then 40 mg/kg/day starting on Day 7 and 
continuing through the duration of the study). 
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. 
• 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. 


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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 3.6, 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 et al., 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. 
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 


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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.   
 


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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
The primary objective of this study is: 
• To assess the efficacy of Cannabidiol Oral Solution on hyperphagia-related behavior in 
patients with Prader-Willi Syndrome (PWS) as measured by total score of the 
Hyperphagia Questionnaire for Clinical Trials (HQ-CT).   
2.2. 
Secondary Objectives 
The secondary objectives of this study are: 
• To assess the efficacy of Cannabidiol Oral Solution on the change in total body weight in 
patients with PWS. 
• To assess the responder rate (responder is defined as 6-point decrease on the HQ-CT 
from Baseline to End of Study). 
• To assess the efficacy of Cannabidiol Oral Solution by measuring the changes in Patient 
Global Impression of Change (PGI-C). 
• To assess the safety and tolerability of Cannabidiol Oral Solution in patients with PWS.  
• To assess the efficacy of Cannabidiol Oral Solution on eating behavior in patients with 
PWS as measured by the Three Factor Eating Questionnaire -18-item version (TFEQ-
R18). 
• To assess the impact on Quality of Life in patients with PWS as measured by the 
PROMIS Life Satisfaction and Positive Affect pediatric short-form questionnaires. 
• To assess the impact on physical activity in patients with PWS as measured by the 
PROMIS Physical Activity and Fatigue questionnaires. 
2.3. 
Exploratory Objective 
The exploratory objective of this study is:  
• To assess the efficacy of Cannabidiol Oral Solution on body composition and bone 
mineral density, as measured by dual-energy X-ray absorptiometry (DEXA). 


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3. 
INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design 
This is a double-blind, randomized, placebo-controlled, Phase 2 clinical trial in patients 
diagnosed with Prader-Willi Syndrome. Patients will receive either Cannabidiol Oral Solution 
(40 mg/kg/day) or placebo with patients randomized in a 1:1 ratio. Randomization will be 
stratified according to use of growth hormone treatment.  
Approximately 66 male and female patients aged 8 to 17 years, inclusive, with a genetically 
confirmed diagnosis of Prader-Willi Syndrome will be enrolled in the study.  
The study will consist of the following six periods: 
• Screening Period (2 weeks) 
• Placebo Lead-In Period (2 weeks) 
• Titration Period (1 week) 
• Maintenance Period (12 weeks) 
• Taper Period (1 week) 
• Follow-Up Period (1 week) 
Patients who meet entry criteria will be assigned to a 2-week single-blind Placebo Lead-In 
Period. Following the placebo single-blind lead-in period, patients will be randomly assigned to 
receive double-blind treatment with either Cannabidiol Oral Solution treatment at a dose of 
40 mg/kg/day or matching placebo divided twice daily with standard meal (a 1-week Titration 
Period followed by a 12-week Maintenance Period). During the Titration Period, Cannabidiol 
Oral Solution will be titrated as follows: Days 1-3: 20 mg/kg/day, Days 4-6: 30 mg/kg/day, Day 
7: 40 mg/kg/day. The Investigator or designee will call on Day 3 and Day 6 to determine if the 
patient’s dose may be titrated to the next dose level.  If the Investigator determines that the 
patient is unable to tolerate the higher dose, the patient should be withdrawn from the study.   
During the Maintenance Period, patients may have their dose of blinded study medication 
adjusted down to 30 mg/kg/day at the discretion of the Investigator or qualified designee based 
on the patient’s tolerability. 
After completion of the study, patients will be offered an opportunity to enroll into an open-
label, long-term safety study. Patients who do not elect to enroll in the long-term safety study 
will be titrated off the study drug over 7 days according to the following schedule: 40 mg/kg/day 
to 30 mg/kg/day for 3 days, to 20 mg/kg/day for 3 days, and then discontinue the drug on Day 7. 
A final safety follow-up phone call will be placed 2 weeks after study completion (Visit 10) for 
patients who do not elect to continue into the long-term safety study and whose AEs have not 
resolved prior to the last visit.  
The study design and patient progression through the study is outlined in Figure 1. 
All screening, efficacy, and safety evaluations will be performed according to the schedule of 
assessments summarized in Table 1.


Insys Development Company, Inc.                                              
 Protocol Number INS011-16-085 
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Figure 1:  
Study Design Schematic 
 
Screening
(2 weeks)
Placebo 
Lead-In
Period
(2 weeks)
Titration 
Period
(1 week)
Maintenance 
Period
(12 weeks)
Long-term 
Safety 
Taper Period    
(1 week)
Follow-up 
Period
(1 week)
Long-term 
Safety Study
Y
N
 
 
 
 
 


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3.2. 
Patient Selection  
3.2.1. 
Inclusion Criteria 
All patients must satisfy the following criteria to be considered for study participation: 
1. 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. 
2. Males and females from 8-17 years of age, inclusive.  
3. Genetically confirmed diagnosis of Prader-Willi Syndrome using standard DNA 
methylation test or fluorescent in situ hybridization. Documentation of genetically 
confirmed diagnosis of Prader-Willi Syndrome is acceptable. 
4. A score of ≥ 10 on the HQ-CT. 
5. A caregiver is available to complete the HQ-CT. 
6. 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.   
7. Adequate renal function, defined as serum creatinine ≤1.5 × upper limit of normal (ULN) 
and urine protein/creatinine ratio <0.2.  
8. Adequate hepatic function, defined as total bilirubin ≤ 1.5 × ULN and aspartate 
aminotransferase (AST) and Alanine aminotransferase (ALT) levels ≤ 3 × ULN.  
9. Growth hormone treatment will be permitted if doses have been stable for at least 
1 month prior to screening. 
10. Psychotropic treatment will be permitted and should be stable at least 6 weeks prior to 
screening. 
11. Any other treatment including thyroid hormones should be stable for at least 6 weeks 
prior to screening. 
3.2.2. 
Exclusion Criteria 
Patients will be excluded for any of the following: 


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1. Known use of cannabis or cannabinoid-containing products for 4 weeks prior to baseline.  
2. History of chronic liver disease, such as cirrhosis or chronic hepatitis due to any cause, or 
suspected alcohol abuse.  
3. Use of weight loss agents or drugs known to affect appetite (including glucagon-like 
peptide-1[GLP-1] analogs) within 2 months prior to screening. 
4. Uncontrolled Type I and Type II diabetes.   
5. Currently taking concomitant medications that are strong cytochrome P450 3A4 
(CYP3A4) or CYP2D6 inhibitors; or inducers of CYP3A4- or CYP2D6-sensitive 
substrates with a narrow therapeutic index. 
6. Co-morbid condition or disease (such as respiratory disease, heart disease, or psychiatric 
disorder) diagnosed less than 1 month prior to screening.  
7. History or presence of gastrointestinal or any other condition known to interfere with the 
absorption, distribution, metabolism or excretion of drugs as determined by the 
Investigator.   
8. Patients who have participated in any other trials involving an investigational product or 
device within 30 days of screening or longer as required by local regulations.  
9. Clinically significant abnormalities on ECG at screening or other evidence of heart 
disease as determined by the Investigator.  
10. Has screening systolic blood pressure ≥160 mm Hg and diastolic blood pressure >100 
mm Hg (may be repeated one additional time after 5 minutes’ rest to verify). Patients 
with hypertensive levels lower than those specified may be excluded at the Investigator’s 
discretion if deemed to be in the best interest of the patient.  
11. Currently taking felbamate. 
12. Uncontrolled sleep apnea. 
13. Pregnant or lactating female.  
14. History of hypersensitivity to drugs with a similar chemical structure or class as CBD.  
15. Unwillingness or inability to follow the procedures outlined in the protocol.  
16. Patient judged by the investigator or sponsor (or designee) as unable to comply with the 
treatment protocol, including appropriate supportive care, follow-up and research tests. 
17. Positive drug screen, including THC, at time of screening. 
18. Creatinine clearance test of < 30 mL/min. 
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. 


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• 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. 
Patients who are withdrawn from the study may be replaced at the discretion of the Sponsor. 
3.4. 
Premature Patient Withdrawal 
All patients will be advised that they are free to withdraw from participation in this study at any 
time, for any reason, and without prejudice. Every reasonable attempt should be made by the 
investigator to keep patients in the study. However, patients must be withdrawn from the study if 
they withdraw consent to participate. Investigators must attempt to contact patients who fail to 
attend scheduled visits by telephone or other means to exclude the possibility of an AE being the 
cause of withdrawal. Should this be the cause, the AE must be documented, reported, and 
followed as described in Section 6.2.6. The sponsor reserves the right to request the withdrawal 
of a patient due to protocol violations (i.e., terminating investigational product treatment and/or 
procedures) or other reasons. 
The investigator also has the right to withdraw patients from the study at any time for lack of 
therapeutic effect that is intolerable or otherwise unacceptable to the patient, for intolerable or 
unacceptable AEs, intercurrent illness, noncompliance with study procedures, administrative 
reasons, or in the investigator’s opinion, to protect the patient’s best interest. 
If a patient is withdrawn before completing the study, the reason for withdrawal and the date of 
discontinuation will be recorded on the appropriate case report form (CRF). Whenever possible 
and reasonable, the evaluations that were to be conducted at the completion of the study should 
be performed at the time of premature discontinuation. 
3.5. 
Dose Adjustment Criteria 
During the Maintenance Period, patients may have their dose of blinded study medication 
adjusted down to 30 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. 
3.6. 
 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: 


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• 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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4. 
TREATMENTS 
4.1. 
Treatments Administered 
4.1.1. 
Screening Period 
No study medication will be provided in the Screening Phase. 
4.1.2. 
Placebo Lead-In Period 
Patients will be required to complete a single blind placebo lead-in period. Patients will receive a 
matching placebo of Cannabidiol Oral Solution 40 mg/kg/day divided into twice daily dose with 
standard meal for 2 weeks. 
4.1.3. 
Titration Period 
At Visit 3 (Baseline), eligible patients will enter a 1-week Titration Period and will be 
randomized in a 1:1 ratio to receive Cannabidiol Oral Solution (40 mg/kg/day) or matching 
Placebo twice daily.  
Titration will begin at 20 mg/kg/day divided into twice daily dose with standard meal for 3 days. 
If the 20 mg/kg/day dose of study medication has been well tolerated, patients will increase the 
dose of study medication to 30 mg/kg/day divided into twice daily doses with standard meal for 
3 days. If the 30 mg/kg/day dose of study medication has been well-tolerated, patients will up 
titrate to the maximum dose of 40 mg/kg/day and start the 12-week Maintenance Period.  
If the initial 20 mg/kg/day or the 30/mg/kg/day dose of study medication was NOT 
well-tolerated, patients will be discontinued from the study.  
4.1.4. 
Maintenance Period 
At Visit 4, patients will enter a 12-week Maintenance Period and continue taking Cannabidiol 
Oral Solution or matching placebo divided into twice daily dose with standard meal.   
Patients may have their dose of study medication adjusted down by one dose level on one 
occasion at the discretion of the Investigator, or qualified designee. If the 40 mg/kg/day dose of 
study medication was NOT well tolerated, patients may have their dose of study medication 
adjusted to 30 mg/kg/day. If patients are unable to tolerate the 30 mg/kg/day dose of study 
medication, the drug will be discontinued and the patient will be withdrawn from the study. 
4.1.5. 
Taper Period 
Following the completion of the Maintenance Period (Visit 10), patients will have the option to 
continue treatment in an open-label long-term safety study. Patients who choose to enroll in the 
long-term safety study will not have a follow-up visit. Patients who do not choose to enroll in the 
long-term safety study will taper the dose of study medication according to the following 
schedule: 40 mg/kg/day dose 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 dose will be 
reduced to 20 mg/kg/day for three days and then discontinued.  


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4.1.6. 
Follow-Up Period  
A follow-up visit call will occur within 2 weeks after study completion. No study medication 
will be provided during this time. 
4.2. 
Identity of Investigational Product 
The active pharmaceutical ingredient (API) in Cannabidiol Oral Solution is a synthetic, 
pharmaceutical grade 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. 
Method of Assigning Patients to Treatment Groups 
Following the 2-week Placebo Lead-In Period of the study, patients will be randomized in a 1:1 
ratio, using a web-based randomization system. The randomization will be stratified according to 
growth hormone treatment (yes/no).   
4.4. 
Selection and Timing of Dose for Each Patient 
Patients will receive Cannabidiol Oral Solution or matching placebo twice daily with standard 
meal as described in Section 4.1. The date and time of all investigational product administrations 
will be documented in the CRF. 
4.5. 
Blinding and Unblinding Treatment Assignment 
In the double-blind treatment period of the study, all patients and study personnel involved in the 
conduct of the study, including data management, will be blinded to treatment assignment with 
the exception of a specified unblinded statistical programmer from the sponsor or sponsor’s 
representative who will have access to the randomization codes. The unblinded study personnel 
will not otherwise participate in study procedures or data analysis before unblinding of the study 
data to all study-related personnel. 
Study personnel will endeavor to safeguard the integrity of the study blind to minimize bias in 
the conduct of the study. Treatment unblinding is discouraged if knowledge of the treatment 
assignment will not materially change the planned management of a medical emergency. 
Unblinding will be permitted in a medical emergency that requires immediate knowledge of the 
patient’s treatment assignment. If a medical emergency occurs and unblinding is required, the 
site will contact IXRS for drug assignment. Unblinding should be discussed in advance with the 
sponsor, sponsor’s representative, or medical monitor if possible. For emergency unblinding, 
study personnel will contact the sponsor or sponsor’s representative. If the investigator is not 
able to discuss treatment unblinding in advance, the sponsor or sponsor’s representative must be 
notified, or medical monitor as soon as possible about the unblinding incident without revealing 
the patient’s treatment assignment. The investigator or designee must record the date and reason 
for study unblinding in the source document for that patient. In all cases that are not 
emergencies, the investigator must discuss the event with the sponsor, sponsor’s representative, 
and/or medical monitor prior to unblinding the patient’s treatment assignment. 


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If the treatment assignment is unblinded for an individual patient, study personnel will be 
notified of that patient’s treatment assignment without unblinding of the treatment assignments 
for the remaining patients in the study. Thus, the overall study blind will not be compromised. If 
a patient’s treatment assignment is unblinded, he or she may or may not be asked to withdraw 
from the study. The investigator will make this decision after consultation with the sponsor, 
sponsor’s representative, or medical monitor. 
4.6. 
Treatment Compliance 
The prescribed dosage, timing, and mode of administration of Cannabidiol Oral Solution may 
not be changed unless a safety concern or toxicity is identified for a patient.  
Patient compliance will be calculated during Placebo Lead-In Period. Patients taking too much or 
too little study medication should be re-educated on the proper use of study medication. Non-
compliance (<80% or >100%) should be evaluated by the Investigator for the need to withdraw 
the patient. The Investigator should discuss the case with the Medical Monitor.  
4.7. 
Permitted and Prohibited Therapies 
4.7.1. 
Permitted Therapies 
Any medications (other than those excluded by the protocol, see Section 4.7.2) that the 
Investigator considers necessary for a patient’s welfare and will not interfere with the 
investigational product may be given at the Investigator’s discretion. 
4.7.2. 
Prohibited Therapies 
During the Screening, Placebo Lead-In, Titration, Treatment, 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 End of Study 
After completion of the study, patients will be offered the chance to enroll into an open-label, 
long-term safety study. Patients who choose to enroll in the long-term safety study will not have 
a follow-up visit. Patients who do not choose to enroll in the long-term safety study will be 
tapered off study medication and complete a follow-up visit approximately 2 weeks after study 
completion. 


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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 
A description of the drug product may be found in Table 3. The investigational product will be 
supplied in 30 mL containers of a 100 mg/mL strength (i.e., 3000 mg per container). 
Table 3: 
Description of Drug Product 
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 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 
Investigational product 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 patient 
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. 


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Investigators are responsible for ensuring that all applicable licensures are in place and storage 
conditions are appropriate.   
Doses of Cannabidiol Oral Solution will be dispensed 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 by 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). 
 


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6. 
STUDY ASSESSMENTS  
6.1. 
Efficacy Assessments 
The efficacy assessments to be performed throughout the study are: 
6.1.1. 
Body Weight Measurements 
Body weight measurements will be obtained in the fasted, voided state at each Visit (Screening, 
Placebo Lead-In, Baseline, Week 1, Week 3, Week 5, Week 7, Week 9, Week 11, and Study 
Completion/Early Withdrawal (Week 13). 
6.1.2. 
Hyperphagia Questionnaire-Clinical Trial (HQ-CT)  
The HQ-CT will be completed at each Visit (Screening, Placebo Lead-In, Baseline, Week 1, 
Week 3, Week 5, Week 7, Week 9, Week 11, and Study Completion/Early Withdrawal 
(Week 13). 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).   
6.1.3. 
Three Factor Eating Questionnaire (TFEQ-R18)  
The TFEQ-R18 will be completed at Visits 3, 5, 8, and 10 (Baseline, Week 3, Week 9, and Study 
Completion/Early Withdrawal [Week 13], respectively). The TFEQ-R18 consists of 18 items 
designed to assess three dimensions of eating behavior: Cognitive Restraint, Uncontrolled 
Eating, and Emotional Eating (Karlsson et al., 2000).  
6.1.4. 
Quality of Life (PROMIS Life Satisfaction and Positive Affect)  
The PROMIS Life Satisfaction and Positive Affect pediatric short-form questionnaires will be 
completed at Visits 3, 5, 8, and 10 (Baseline, Week 3, Week 9, and Study Completion/Early 
Withdrawal [Week 13], respectively). These questionnaires are designed to determine the 
patient’s own judgement concerning their satisfaction with their life currently and are appropriate 
for children and adolescents. 
6.1.5. 
Physical Activity (PROMIS Physical Activity and Fatigue) 
The PROMIS Physical Activity and Fatigue pediatric short-form questionnaires will be 
completed at Visits 3, 5, 8, and 10 (Baseline, Week 3, Week 9, and Study Completion/Early 
Withdrawal [Week 13], respectively).  These questionnaires are designed to determine the 
patient’s physical activity and are appropriate for children and adolescents. 
6.1.6. 
Dual Energy X-ray Absorptiometry (DEXA) Scan  
Changes in body composition (total fat/lean body mass/bone mineral content) will be measured 
at Visit 3 and Visit 10 (Baseline and Study Completion/Early Withdrawal [Week 13], 
respectively). Lean body mass (LBM) will be calculated as fat free mass (FFM) minus bone 
mineral content. Fat percentage will be expressed as percentage of total body mass. 


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6.1.7. 
Patient Global Impression of Severity (PGI-S) 
The Patient Global Impression of Severity will be completed at Visit 3 (Baseline). The 
questionnaire consists of 1-item designed to assess the patient’s impression of disease severity. 
6.1.8. 
 Patient Global Impression of Change (PGI-C) 
The Patient Global Impression of Change will be completed at Visit 5, 8, and 10 (Week 3, 
Week 9, and Study Completion/Early Withdrawal [Week 13], respectively). The questionnaire 
consists of one item designed to assess the patient’s impression of change. 
6.2. 
Safety Assessments 
Safety assessments for all patients will include medical history, physical examination, vital signs 
(seated blood pressure, pulse rate, temperature, and respiration rate), clinical laboratory testing 
(including CBC), 12-lead ECG, urine drug screen (including THC), prior medication history, 
concomitant medication, and AE assessments. 
6.2.1. 
Demographics and Medical History 
Each potential study participant will have the following assessments by the Investigator or 
designee within 2 weeks prior to the Placebo Lead-in Period: medical history and demographic 
data, including sex, age, race, ethnicity, body weight (kg), height (cm), and BMI (kg/m2). 
6.2.2. 
Physical Examinations 
A physical examination will be conducted for every patient at every visit: Screening (Visit 1), 
Placebo Lead-In (Visit 2), Baseline (Visit 3), Titration Period (Visit 4), Maintenance Period 
(Visits 5, 6, 7, 8, 9), and Study Completion/Early Withdrawal (Visit 10) Visits. The examination 
will include evaluation of ears, eyes, nose, and throat (EENT), heart, peripheral vasculature, 
lungs, musculoskeletal system, abdomen, neurologic function, endocrine system, and skin. 
6.2.3. 
Vital Signs 
Vital signs (seated blood pressure, pulse rate, temperature and respiration rate) will be measured 
at every visit: Screening (Visit 1), Placebo Lead-In (Visit 2), Baseline (Visit 3), Titration Period 
(Visit 4), Maintenance Period (Visits 5, 6, 7, 8, 9), and Study Completion/Early Withdrawal 
(Visit 10) Visits.  
Additional vital sign measurements may be performed as deemed medically necessary by 
research personnel.  
6.2.4. 
Electrocardiograms 
A resting 12-lead ECG will be conducted for every patient at the Screening (Visit 1), 
Maintenance Period (Visits 6, 8), and Study Completion/Early Withdrawal (Visit 10) Visits. 


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6.2.5. 
Clinical Laboratory Assessments 
6.2.5.1. 
Hematology 
Blood samples for the following hematology assessments will be collected at the Screening 
(Visit 1), and Study Completion/Early Withdrawal (Visit 10) Visits: hemoglobin, hematocrit, 
total and differential leukocyte count, red blood cell (RBC), and platelet count. 
6.2.5.2. 
A sample for complete blood count (CBC) will be collected at Week 3 (Visit 
5).Chemistry 
Blood samples for the following serum chemistry assessments will be collected at the Screening 
(Visit 1), and Study Completion/Early Withdrawal (Visit 10) Visits: 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.  
6.2.5.3. 
Urinalysis 
Urine samples for the following assessments will be collected at the Screening (Visit 1) and 
Study Completion/Early Withdrawal (Visit 10) Visits: 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. 
6.2.5.4. 
Pregnancy Screen (Female Patients) 
A urine dipstick pregnancy test will be performed on all female patients at the Screening 
(Visit 1) and Study Completion/Early Withdrawal (Visit 10) Visits. A positive pregnancy test 
will result in screening failure or the patient being withdrawn from the study. 
6.2.5.5. 
Urine Drug Screen 
A urine sample for the following assessments will be collected at Screening (Visit 1): 
amphetamines, barbiturates, benzodiazepines, cocaine, opiates, phencyclidine, and 
tetrahydrocannabinol. 
6.2.5.6. 
Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is a prospective assessment tool routinely used in studies of drugs with any 
potential for CNS effects. It captures the occurrence, severity, and frequency of suicide-related 
thoughts and behaviors during the assessment period. For patients aged 7 to 17 years and if the 
developmental level is appropriate, the questionnaire will be completed at Baseline (Visit 3) and 
Visit 10 (Week 13) or the Early Withdrawal Visit.  
6.2.6. 
Adverse Events and Serious Adverse Events 
6.2.6.1. 
Definition of Adverse Events 
An AE is defined as any untoward medical occurrence in a patient administered a pharmaceutical 
product during the course of a clinical investigation. An AE can therefore be any unfavorable 


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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 
(TEAEs) will begin as soon as the patient is dosed. All AEs must be followed until they are 
resolved or stabilized, or until all attempts to determine resolution of the event are exhausted. 
The investigator should use their discretion in ordering additional tests as necessary to monitor 
the progress of such events. 
An AE may be: 
• A new illness, not documented in the patient’s medical history; 
• Worsening of a concomitant illness; 
• An effect of the study medication; it could be an abnormal laboratory value, as well as a 
significant shift from baseline within normal range which the qualified investigator or 
medical qualified designate considers to be clinically important; 
• A combination of two or more of these factors. 
Surgical procedures themselves are not AEs. They are therapeutic measures for conditions that 
require 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. 
Weight gain or loss will not be recorded as an AE. Hyperphagia behaviors and skin picking will 
not be recorded as AEs; however, any other behaviors may be recorded as AEs based on the 
Investigator’s opinion. 
Patients will be monitored throughout the study for AEs. All AEs must be followed until they are 
resolved or stabilized, or until all attempts to determine resolution of the event are exhausted. 
The investigator should use his/her discretion in ordering additional tests as necessary to monitor 
the progress of such events. 
Adverse events reported prior to dose administration will be recorded as part of the patient’s 
medical history. 
6.2.6.2. 
Classification of Adverse Events 
Adverse events are to be recorded on the AE page of the patient’s case report form (CRF).  
Severity will be graded according to the following definitions: 
• Mild: The patient experiences awareness of symptoms but these are easily tolerated or 
managed without specific treatment. 
• Moderate: The patient experiences discomfort enough to cause interference with usual 
activity, and/or the condition requires specific treatment. 
• Severe: The patient is incapacitated with inability to work or do usual activity, and/or the 
event requires significant treatment measures. 


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Action taken will be categorized as none, study drug discontinued, dose modified, required 
concomitant medication, required procedure, or other. 
Event outcome at resolution or time of last follow-up will recorded as event resolved, resolved 
with sequelae, ongoing, or death. 
6.2.6.3. 
Causality: Drug Relationship Assessment 
The relationship of the event to the study drug should be determined by the investigator 
according to the following criteria: 
• Definitely related: The event follows a reasonable temporal sequence from the time of 
drug administration that cannot be explained, follows a known or expected response 
pattern to the study drug, that is confirmed by improvement on stopping and 
reappearance of the event on repeated exposure and that could not be reasonably 
explained by other factors such as the patient’s clinical condition, intercurrent illness, or 
concomitant drugs. 
• 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. 
6.2.6.4. 
Definition of Serious Adverse Events 
A serious AE (SAE) is any AE that fulfills any of the following criteria, as per 21 CFR 312.32: 
• Results in death; 
• Is life-threatening; 
• Requires in-patient hospitalization or prolongation of existing hospitalization; 
• Results in persistent or significant disability or incapacity; 
• Is a congenital anomaly or birth defect; 
• Is medically significant or requires intervention to prevent one of the outcomes listed 
above. 


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Serious AEs will be captured from the time of consent through the end of the study. 
6.2.6.5. 
Serious Adverse Event Actions Taken  
Actions taken may consist of: 
• None: No action taken 
• Treatment: Standard of care measures instituted 
• Drug withdrawn: Study medication was permanently discontinued because of the AE 
• Unknown: Not known, not observed, not recorded, or refused 
6.2.6.6. 
Serious Adverse Event Outcome at the Time of Last Observation  
The outcome at the time of last observation will be classified as: 
• Recovered/resolved 
• Recovered/resolved with sequelae 
• Not recovered/not resolved 
• Death 
• Unknown 
6.2.6.7. 
Adverse Event Recording and Reporting 
Adverse events will be recorded throughout the study in the source documents and in the CRFs. 
The investigator will rate AEs for seriousness, intensity, causality, action taken, and outcome as 
described in the previous section. 
Expedited reporting is required for serious unexpected adverse drug reactions. Fatal or 
life-threatening unexpected drug reactions must be reported by the Sponsor to regulatory 
agencies no more than 7 days after the Sponsor’s first knowledge of the reaction; followed by as 
complete a report as possible within 8 additional days. Unexpected adverse drug reactions must 
be reported no later than 15 days after the Sponsor’s first knowledge of the reaction. In order to 
comply with these requirements, the investigator or delegate must inform the Sponsor 
immediately upon occurrence of any SAE. The site will complete the SAE Report Form as 
thoroughly as possible and e-mail it to Insys or designee within 24 hours of the investigators first 
knowledge of the event. Details will be provided in the safety monitoring plan. 
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 


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3) 
Treatment (drug, dose, dosage form) 
4) 
Adverse event relationship to study drug 
5) 
Action taken regarding study drug in direct relationship to the AE 
H. If the AE was fatal or life-threatening 
I. 
Cause of death (whether or not the death was related to study drug) 
J. 
Autopsy findings (if available) 
The Sponsor or its representative will be responsible for notification to regulatory agencies. 
6.2.6.8. 
Adverse Event Follow-Up 
All non-serious AEs that are not related or unlikely to be related to study treatment will be 
followed until the end of study participation. All SAEs or AEs that are considered as possibly, 
probably, or definitely related to treatment will be followed until resolution or stabilization. 
6.2.6.9. 
Special Considerations 
Cannabidiol inhibits drug metabolism mediated by a subset of CYP proteins (see Section 1.1.2). 
Thus, the Investigator and study center staff should monitor patients who are taking concomitant 
medications that are metabolized by CYP2C19, CYP2C9, CYP2D6, CYP3A4, CYP1A2 or by P-
glycoprotein with special care.     
6.2.7. 
Pharmacokinetics Assessments 
Blood draws for PK sampling will be taken at each visit during the Baseline (Visit 3), 
Maintenance Period (Visits 6 and 8), and Study Completion/Early Withdrawal (Visit 10).  
Whole blood will be obtained in a K2-EDTA Vacutainer® tube for the determination of the 
plasma levels of CBD and 7-OH-CBD. The blood sample will be obtained prior to study 
medication dosing.   
 


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7. 
STUDY PROCEDURES 
The assessments and procedures that will be conducted during this study are summarized 
in Table 1.  
7.1. 
Screening 
Potential study patients will be examined before the start of the study to determine their 
eligibility for participation. Informed consent must be obtained and signed before initiation of 
screening activities. The following screening procedures and assessments must be performed 
within 2 weeks before study enrollment and initiation of the Placebo Lead-in Period. 
• Obtain written informed consent/assent (if appropriate). 
• Review of inclusion and exclusion assessment. 
• Record medical history and demographics. 
• Perform a complete physical examination. 
• Clinical laboratory tests (clinical chemistry, hematology, and urinalysis). 
• Perform resting 12-lead ECG. 
• Urine drug screen (drugs of abuse including THC). 
• Record vital signs (seated blood pressure, pulse rate, temperature, and respiration rate).  
• Urine dipstick pregnancy test (all female patients of childbearing potential).  
• Record weight. 
• Complete the HQ-CT. 
• Review concomitant medications. 
• Review AEs. 
7.2. 
Placebo Lead-In Period 
7.2.1. 
Visit 2 (Week -2) 
Patients who complete all Screening assessments and meet the study entry criteria will be 
assigned to the Placebo Lead-In Period. The following procedures and assessments will be 
performed at Visit 2: 
• Perform a complete physical examination. 
• Record vital signs (seated blood pressure, pulse rate, temperature, and respiration rate). 
• Dispense study medication. 
• Record weight. 
• Complete the HQ-CT. 
• Review concomitant medications. 


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• Review AEs. 
7.3. 
Titration Period 
7.3.1. 
Baseline (Visit 3, Day 1) 
At Visit 3 (Baseline), eligible patients will be randomized and enter a 1 week Titration Period. 
The following procedures and assessments will be performed at Baseline (Visit 3): 
• Randomization. 
• Perform a complete physical examination. 
• Record vital signs (seated blood pressure, pulse rate, temperature, and respiration rate). 
• Collect/review/dispense study medication. 
• Record weight. 
• Complete the HQ-CT. 
• Complete the TFEQ-R18. 
• Complete the PROMIS Life Satisfaction and Positive Affect questionnaires. 
• Complete the PROMIS Physical Activity and Fatigue questionnaires. 
• Complete PGI-S. 
• Perform DEXA scan. 
• Complete the C-SSRS. 
• Take PK sample blood draw. 
• Review concomitant medications. 
• Review AEs. 
Titration will begin at 20 mg/kg/day divided into twice daily dose with standard meal for 3 days. 
If the 20 mg/kg/day dose of study medication has been well tolerated, patient will increase the 
dose of study medication by 1 dose level to 30 mg/kg/day divided into twice daily dose with 
standard meal for 3 days. If the 30 mg/kg/day dose of study medication has been well-tolerated, 
patient will up titrate to the maximum dose of 40 mg/kg/day and start the 12-week Maintenance 
Period.  
If the initial 20 mg/kg/day or the 30/mg/kg/day doses of study medication were NOT 
well-tolerated, the drug will be discontinued and the patient withdrawn from the study.  
The Investigator or designee will call on Day 3 and Day 6 to determine if the patient’s dose may 
be titrated to the next dose level. 
7.3.2. 
Visit 4 (Day 7) 
The following procedures and assessments will be performed at Visit 4: 
• Perform a complete physical examination. 


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• Record vital signs (seated blood pressure, pulse rate, temperature, and respiration rate). 
• Collect/review/dispense study medication. 
• Record weight. 
• Complete the HQ-CT.  
• Review concomitant medications. 
• Review AEs. 
7.4. 
Maintenance Period 
Patients will be administered 40 mg/kg/day or matching placebo, divided twice daily for 12 
weeks. If unacceptable adverse reactions are observed at 40 mg/kg/day, treatment may be 
decreased to 30 mg/kg/day. If the lower dose is not tolerated, the drug will be discontinued and 
the patient will be withdrawn from the study. 
7.4.1. 
Visit 4-9 (Week 3 to 11) 
The following procedures and assessments will be performed at each of Visits 5-9 (unless 
otherwise specified) during this period: 
• Perform a complete physical examination. 
• Record vital signs (seated blood pressure, pulse rate, temperature, and respiration rate). 
• Perform resting 12-lead ECG (Visit6/Week 5 and Visit 8/Week 9 only). 
• Collect/review/dispense study medication. 
• Record weight. 
• Complete the HQ-CT. 
• Complete the TFEQ-R18 (Visit 5/Week 3 and Visit 8/Week 9). 
• Complete the PROMIS Life Satisfaction and Positive Affect questionnaires (Visit 
5/Week 3 and Visit 8/Week 9). 
• Complete the PROMIS Physical Activity and Fatigue questionnaires (Visit 5/Week 3 and 
Visit 8/Week 9). 
• Complete PGI-C (Visit 5/Week 3 and Visit 8/Week 9). 
• CBC assessment (Visit 5/Week 3). 
• PK sample blood draws (Visit 6/Week 5 and Visit 8/Week 9). 
• Review concomitant medications. 
• Review AEs. 
7.4.2. 
Visit 10 (Week 13; Study Completion) or Early Withdrawal 
The following procedures and assessments will be performed at Visit 10 or following patient 
withdrawal: 


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• Perform a complete physical examination. 
• Record vital signs (seated blood pressure, pulse rate, temperature, and respiration rate). 
• 12-lead ECG. 
• Clinical laboratory tests (clinical chemistry, hematology, and urinalysis). 
• Urine dipstick pregnancy test (all female patients of childbearing potential). 
• Collect/review/dispense study medication. 
• Record weight. 
• Complete the HQ-CT 
• Complete the TFEQ-R18. 
• Complete the PROMIS Life Satisfaction and Positive Affect questionnaires (Visit 
5/Week 3 and Visit 8/Week 9). 
• Complete the PROMIS Physical Activity and Fatigue questionnaires (Visit 5/Week 3 and 
Visit 8/Week 9). 
• Complete PGI-C. 
• DEXA scan. 
• Complete the C-SSRS. 
• PK sample blood draw. 
• Review concomitant medications. 
• Review AEs. 
7.5. 
Taper Period 
After completion of the study, patients will be offered an opportunity to enroll in an open-label, 
long-term safety study. Patients who choose to enroll in the long-term safety study will not have 
a follow-up visit. Patients who do not elect to enroll in the long-term safety study will be titrated 
off the study drug over 7 days according to the following schedule: 40 mg/kg/day to 
30 mg/kg/day for 3 days, to 20 mg/kg/day for 3 days, and then discontinue the drug on Day 7.  
7.6. 
Follow-Up Period 
7.6.1. 
Visit 11 (Week 15) 
For patients who do not choose to enroll in the long-term safety study, the following assessments 
will be performed:  
• Collect/review study medication. 
• Review concomitant medications. 
• Review AEs. 
Patients who enroll in the long-term safety study do not complete the Follow-Up Visit.  


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8. 
STATISTICS  
The detailed descriptions of statistical analysis methods and data conventions will be in a 
separate document, the Statistical Analysis Plan (SAP). Any post-hoc analyses will be identified 
in the final clinical study report. This section presents general information about statistical 
considerations and concepts such as randomization, statistical power, and sample size. There will 
also be a brief discussion on analysis methodology and data conventions. 
8.1. 
Efficacy Endpoints 
8.1.1. 
Primary Efficacy Endpoint 
• Change in the total score of the HQ-CT from Baseline (defined as the score after the 
Placebo Lead-In Period) through Study Completion (Week 13/Early Withdrawal).  
8.1.2. 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints in this study are: 
• Change in total body-weight from Baseline through Study Completion/Early Withdrawal. 
• Responder rate (responder is defined as 6-point decrease on the HQ-CT from Baseline 
through Study Completion). 
• Change in Patient Global Impression of Change and Severity (PGI-C). 
• Change in the TFEQ-R18 from Baseline through Study Completion/Early Withdrawal. 
• Change in Quality of Life (PROMIS Life Satisfaction and Positive Affect questionnaires) 
from Baseline through Study Completion/Early Withdrawal. 
• Change in physical activity (PROMIS Physical Activity and Fatigue questionnaires) from 
Baseline through Study Completion/Early Withdrawal. 
8.1.3. 
Exploratory Efficacy Endpoint 
• Change in body composition from Baseline to Study Completion/Early Withdrawal as 
measured by DEXA. 
8.2. 
Safety Endpoints 
The safety endpoints are treatment-emergent AEs (TEAEs), clinical laboratory assessments, vital 
signs (blood pressure, pulse rate, respiration rate, and temperature), 12-lead ECGs, physical 
examination assessments, pregnancy screens, urine drug screen (including THC), medical 
history, and prior and concomitant medications. 
8.3. 
Pharmacokinetic Endpoints 
The secondary efficacy endpoints in this study are: 
• Trough concentrations (Ctrough) of CBD and metabolite 7-OH-CBD will be used to assess 
the exposure-response relationship. 


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8.4. 
Sample Size Determination 
A total of 30 patients per treatment group will provide more than 85% power with an alpha of 
0.05, for a difference in the HQ-CT from Baseline to Week 13 of 5 points with standard 
deviation of 6. Assuming a 20% drop out rate, approximately 66 patients (33 patients per arm) 
will be randomized to achieve 60 (30 patients/arm) completers. 
8.5. 
Analysis Populations 
Statistical analysis will be done on the following populations: 
• Intent to Treat (ITT) Population: The ITT Population will include all patients who were 
randomized. The ITT Population will be used for all efficacy analyses. 
• Safety Population: The Safety Population will include all patients who were treated with 
at least one dose of the study drug. The Safety Population will be used for all safety 
assessments. 
8.6. 
Statistical Analyses 
8.6.1. 
Study Patients and Demographics 
Analysis Treatment group will be defined by the modal dose of study drug (dose group the 
patient took for the longest period). 
8.6.1.1. 
Disposition and Withdrawals 
The numbers of patients randomized, completing, withdrawing, and reasons for withdrawal, will 
be tabulated overall and by treatment group. The number of patients in each analysis population 
will be reported.  
8.6.1.2. 
Protocol Deviations 
Protocol deviations will be identified and listed. 
8.6.1.3. 
Demographics and Other Baseline Characteristics 
Descriptive analyses will be conducted for the safety population. 
Demographic and baseline characteristics (including sex, age, gender, ethnicity, race, and 
weight, and BMI) will be summarized by descriptive statistics. No formal statistical analyses will 
be performed. Medical history, clinical laboratory test results, and ECG assessments will be 
listed. 
Prior and concomitant medications will be summarized by the number and percentage of patients 
taking each medication. They will also be classified by using the World Health Organization 
Drug Dictionary Anatomical Therapeutic Chemical classes and preferred terms. 
8.6.2. 
Exposure and Compliance 
The total exposure to study medication will be summarized by descriptive statistics by treatment 
group.  


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8.6.3. 
Efficacy Analyses 
Statistical inference for the primary endpoint and for key secondary endpoints will be controlled 
at an overall family wise error rate (alpha) of 0.05, 2-sided. For continuous endpoints, number of 
observations, mean, standard deviation (SD), median, minimum and maximum will be presented 
as descriptive statistics. For inferential statistics, analysis of covariance (ANCOVA) with the 
baseline value and randomization strata (growth hormone treatment) as covariates t will be used. 
For multiple values, a repeated measures analysis will be performed. For categorical endpoints, 
the number of observations, frequency counts and percentages will be presented as descriptive 
statistics, and Fisher’s exact test will be used for inferential statistics.  
8.6.3.1. 
Primary Efficacy Analysis 
The primary outcome variable for the study is the change in total score of the HQ-CT from 
Baseline through Study Completion/Early Withdrawal.  The primary efficacy endpoint will be 
tested using a 2-sided type I error rate of 0.05. 
8.6.3.2. 
Secondary Efficacy Analysis 
The secondary endpoints, which will be assessed inferentially, are change in total body-weight, 
response rate, PGI-C, TFEQ-R18, PROMIS Life Satisfaction and Positive Affect, PROMIS 
Physical Activity and Fatigue.   
8.6.3.3. 
Exploratory Efficacy Analysis 
The exploratory variable is the change in body composition (total fat/lean body mass/bone 
mineral content) from Baseline to Study Completion/ Early Withdrawal as measured by DEXA. 
Lean body mass (LBM) will be calculated as fat free mass (FFM) minus bone mineral content. 
Fat percentage will be expressed as percentage of total body mass. This analysis will be 
conducted using a pre-defined subset of approximately 20 patients. 
8.6.4. 
Safety and Tolerability Analyses 
All safety assessments will be descriptive and no inferential statistics are planned. All data 
listings will be provided for protocol specified safety data.  
8.6.4.1. 
Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA, version 20.0) will be used to 
classify all AEs. Adverse event summaries will include only treatment-emergent AEs (TEAEs). 
Treatment-emergent adverse events (TEAEs) are defined as AEs that first occurred or worsened 
during the indicated treatment period. 
The number and percentage of patients with TEAEs will be summarized by system organ class 
(SOC) and preferred term (PT). Summaries of AEs by severity and relationship to the study 
treatment will also be provided. Serious adverse events (SAEs) and AEs resulting in 
discontinuation will be summarized separately in a similar manner. Patient listings of AEs and 
SAEs will be produced. 


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8.6.4.2. 
Clinical Laboratory Evaluations 
For the continuous laboratory parameters, descriptive statistics will be presented for values 
collected at Screening and Study Completion/Early Withdrawal Visits, and for the changes from 
Screening to Study Completion/Early Withdrawal. 
8.6.4.3. 
 Vital Signs 
For blood pressure, pulse rate, temperature, and respiration rate, descriptive statistics will be 
presented for values collected during Screening, Placebo Lead-In, Titration, Treatment, 
Maintenance, and Follow-Up periods, and for the changes from Baseline to Study 
Completion/Early Withdrawal. 
8.6.4.4. 
Electrocardiograms 
For the continuous ECG parameters, descriptive statistics will be presented for values collected 
during Screening, and Treatment Period Visits, and for the changes from Screening to Study 
Completion/Early Withdrawal.  
The following ECG parameters will be reported for this study: HR (Ventricular rate) (bpm), PR 
Interval (msec), QRS Interval (msec), QT Interval (msec), QTcF Interval (msec) (QT interval 
corrected by Fridericia), RR Interval (msec), Rhythm (Sinus rhythm, Atrial fibrillation, Other), 
Overall assessment of ECG (Normal, Abnormal, Not Clinically Significant [ANCS], Abnormal, 
Clinically Significant [ACS]). 
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 
Study Completion/Early Withdrawal (normal; abnormal, NCS; or abnormal, clinically significant 
[CS]). 
8.6.4.5. 
Physical Examination Findings 
Physical examination body systems will be presented as the number and percentage of patients 
that have normal or abnormal results at Screening, Placebo Lead-In, Titration, Treatment, 
Maintenance, and Follow-Up periods. The following body systems will be included:  
• EENT (Eyes, Ears, Nose, Throat) 
• Heart  
• Peripheral vasculature  
• Lungs  
• Musculoskeletal system  
• Abdomen  
• Neurologic function  
• Endocrine system  
• Skin 


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8.6.5. 
Pharmacokinetic Analyses 
Exploratory analysis of dose (exposure)-response relationship will be performed using trough 
concentrations and efficacy/safety endpoints. Further population PK approach may be used for 
PK parameter calculations, as appropriate. 
8.6.6. 
Missing Data 
For safety data, there will be no imputation of missing data, and the safety assessments will be 
conducted based on the observed data. 
For efficacy measures, missing data points may be imputed using Jump to Reference as a 
conservative method.  
 


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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 the protocol has been 
carefully read, the requirements are fully understood, 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 Insys with 
documentation of the qualifications, GCP training, and research experience for themselves and 
their staff as required by the sponsor and the relevant governing authorities. 
To ensure compliance with the guidelines, the study will be audited by an independent person. 
The investigator agrees, by written consent to this protocol, to cooperate fully with compliance 
checks by allowing access to all study documentation by authorized individuals. 
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: 


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• The study site has received the appropriate institutional review board (IRB) approval for 
the protocol and the appropriate informed consent form. 
• All regulatory documents have been submitted to and approved by the sponsor or 
sponsor’s representative. 
• The study site has a clinical trial agreement in place. 
9.3. 
Screen Failures 
Patients who fail inclusion and/or exclusion criteria may 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 IP to the study site. Copies of the 
investigator’s regulatory documents must be retained at the study site in a secure location. 
Additional documents, including a copy of the protocol and applicable amendment(s), the IB, 
CRF/electronic case report form (eCRF) completion guidelines, copies of regulatory references, 
copies of IRB correspondence, and IP accountability records should also be retained as part of 
the investigator’s regulatory documents. It is the investigator’s responsibility to ensure that 
copies of all required regulatory documents are organized, current, and available for inspection. 
9.4.2. 
Case Report Forms 
By signing the Investigator’s Agreement (Section 16), 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 
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. 


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During the study, select CRF/eCRF data may be used as original data collection tools as long as 
a description of this documentation process is maintained in the investigator’s study files. 
Clinical laboratory data required by the protocol will be electronically transferred from the local 
laboratory to the sponsor or the sponsor’s representative. A paper copy of the laboratory results 
will be provided to the study site and should be retained with each patient’s source data. 
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 in the course of the 
study, specifically including, but not limited to, those defined by GCP as essential until the 
following occur: 
• At least 2 years after the last marketing authorization for the investigational product (IP) 
has been approved or the sponsor has discontinued its research with the IP, or 
• At least 2 years have elapsed since the formal discontinuation of clinical development of 
the IP 
These documents should be retained for a longer period, however, if required by the applicable 
regulatory requirement(s) or if needed by the sponsor. 
9.6.2. 
Pharmacokinetic/Laboratory Sample Retention 
Laboratory samples may be used for purposes related to this research. The samples will be stored 
until the sponsor has determined that specimens are no longer needed and the decision has been 
made that none of the samples needs to be reanalyzed. In addition, identifiable samples can be 
destroyed at any time at the request of the patient. 


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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 
The investigator may not deviate from the protocol without a formal protocol amendment 
established and approved by the appropriate IEC/IRB, except when necessary to eliminate 
immediate hazards to the patient or when the change involves only logistical or administrative 
aspects of the study. Any deviation may result in patient withdrawal from the study and 
rendering that patient not available for data evaluation. 
10.2. 
Monitoring 
The investigator will permit the site monitor to review trial data as frequently as is deemed 
necessary to ensure data are being recorded in an adequate manner and protocol adherence is 
satisfactory. The investigator will access medical records for the monitor to verify CRF entries. 
The investigator, as part of his or her responsibilities, is expected to cooperate with the sponsor 
or its designee in ensuring the trial adheres to GCP requirements. The investigator may not 
recruit patients into the study until such time that a site visit has been conducted. 
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 or not 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 
and efficacy endpoint. 
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 
eliminate an immediate hazard(s) to patients, the record should be immediately submitted to the 
sponsor, the Clinical Research Unit (CRU), and the IRB by the Investigator 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. 


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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 patient to audit by the sponsor, CRO, or designee. 
The sponsor or sponsor’s representative may conduct audits on a selection of study sites, 
requiring access to patient notes, study documentation, and facilities or laboratories used for the 
study. 
The study site, facilities, all data (including source data), and documentation will be made 
available for audit by quality assurance auditors and for IRB or regulatory authorities according 
to GCP guidelines. The investigator agrees to cooperate with the auditor during the visit and will 
be available to supply the auditor with CRFs or other files necessary to conduct that audit. Any 
findings will be strictly confidential. 
If a regulatory authority informs the investigator that it intends to conduct an inspection, the 
investigator shall notify sponsor or sponsor’s representative immediately. 


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11. 
REGULATORY AND ETHICAL CONSIDERATIONS 
11.1. 
Regulatory Authority Approval 
The investigator will ensure that the protocol, consent and assent forms are reviewed and 
approved by the appropriate Independent Ethics Committee/Institutional Review Board 
(IEC/IRB) prior to the start of any study procedures. The IEC/IRB will be appropriately 
constituted and will perform its functions in accordance with Food and Drug Administration 
(FDA) regulations, International Conference on Harmonization (ICH) good clinical practice 
(GCP) guidelines, and local requirements as applicable. 
In addition, the IRB will approve all protocol amendments (except for logistical or administrative 
changes), written informed consent documents and document updates, patient recruitment 
procedures, written information to be provided to the patients, available safety information, 
information about payment and compensation available to patients, the investigator’s curriculum 
vitae and/or other evidence of qualifications, and any other documents requested by the IRB/IEC 
and regulatory authority, as applicable. 
The Investigator will supply documentation to the Sponsor or designee of required IRB/IEC 
annual renewal of the protocol, and any approvals of revisions to the consent form, assent form, 
or amendments to the protocol. 
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 is responsible for ensuring that informed consent is obtained from each patient 
or legal representative and for obtaining the appropriate signatures and dates on the consent form 


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and assent form (if applicable) prior to the performance of any protocol procedures and prior to 
the administration of study medication.     
The investigator or his/her designee will inform the 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 the patient 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 
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 IEC/IRB, 
and use of the amended form, including the necessity of re-consenting ongoing patients. 
11.5. 
Investigator Reporting Requirements 
In accordance with applicable local regulatory requirements, the investigator may be obligated to 
provide periodic safety updates on the conduct of the study at his/her site and notification of 
study closure to the IRB. Such periodic safety updates and notifications are the responsibility of 
the investigator and not of Insys or its delegate. 
 
 


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12. 
DATA HANDLING AND RECORD KEEPING 
The CRO will be responsible for data management and analysis. The procedures will be 
specified in the Data Management Plan. 
12.1. 
Data Management 
The CRO will be responsible for activities associated with the data management of this study. 
The standard procedures for handling and processing records will be followed per GCP and the 
CRO’s SOPs. A comprehensive Data Management Plan will be developed including a data 
management overview, database contents, annotated CRF and consistency checks. 
Study site personnel will be responsible for providing resolutions to all data queries. The 
investigator will be required to document electronic data review to ensure the accuracy of the 
corrected and/or clarified data. 
12.2. 
Case Report Forms and Source Documents 
The CRFs will be supplied by the CRO data management services. The complete CRFs will be 
reviewed, signed, and dated by the qualified investigator and a copy returned to the Sponsor with 
the final report. 
Source documents are defined as original documents, data, and records. This may include 
hospital records, clinical and office charts, laboratory data/information, patients’ diaries or 
evaluation checklists, pharmacy dispensing and other records, recorded data from automated 
instruments, microfiches, photographic negatives, microfilm or magnetic media and/or x rays. 
12.3. 
Documentation and Retention of Essential Documents 
All documents pertaining to the study, including a copy of the approved protocol, copy of the 
ICD, completed CRFs, source documents, drug accountability and retention records, and other 
study related documents will be retained in the permanent archives of the study site. These will 
be available for inspection at any time by the Sponsor or the FDA. Per 21 CFR 312, record 
retention for this study is required for a period of two years following the date on which this 
study agent is approved by the FDA for the marketing purposes that were the patient of this 
investigation; or, if no application is to be filed or if the application is not approved for such 
indication, until two years following the date on which the entire study is completed, terminated, 
or discontinued, and the FDA is notified. 
The investigator will provide direct access to source data and documents for trial related 
monitoring, audits, IEC/IRB review, and regulatory requirements. 
12.4. 
Financial Disclosure 
These issues will be addressed in a separate agreement between the sponsor and the Investigator. 
The US FDA Financial Disclosure by Clinical Investigators (21 Code of Federal Regulations 
[CFR] 54) regulations require sponsors to obtain certain financial information from investigators 
participating in covered clinical studies; each investigator and sub-investigator is required to 
provide the required financial information and to promptly update Insys Development Company, 
Inc., with any relevant changes to their financial information throughout the course of the clinical 


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study and for up to one year after its completion. This rule applies to all investigators and sub-
investigators participating in covered clinical studies to be submitted to the FDA in support of an 
application for market approval. 
 
 
 
 
 


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13. 
FACILITIES  
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 patient to the sponsor’s approval requirements. 


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16. 
INVESTIGATOR AGREEMENT AND SIGNATURE PAGE 
 
PROTOCOL TITLE: A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study to 
Assess the Efficacy, Safety, and Tolerability of Cannabidiol Oral Solution for the Treatment of 
Patients with Prader-Willi Syndrome 
PROTOCOL NO: INS011-16-085 
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 INS011-16-085, 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:  
 

SAP_001.pdf: 
 
 
 
Statistical Analysis Plan 
 
 
 
A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study to Assess 
the Efficacy, Safety, and Tolerability of Cannabidiol Oral Solution for the 
Treatment of Patients with Prader-Willi Syndrome 
 
 
Protocol Number: INS011-16-085 
Final Protocol Date: 9 July 2018 
Version: 1.0 
Investigational Product: Cannabidiol Oral Solution 
IND Number: IND 136,374 
 
ClinicalTrials.gov ID: NCT02844933 


Statistical Analysis Plan  
 
Sponsor Name: Insys Development Company, Inc. 
Sponsor Protocol ID: INS011-16-085 
           Covance Study ID: 000000163564 
 
COVANCE INC. CONFIDENTIAL 
Document Date: 9 July 2018 
 
ST-AD-008 version 04 
18 September 2017 
 
 
Insys Development Company, Inc. 
Protocol No.: INS011-16-085 
A Randomized, Double-Blind, Placebo-Controlled, Phase 2 
Study to Assess the Efficacy, Safety and Tolerability of 
Cannabidiol Oral Solution for the Treatment of Patients 
with Prader-Willi Syndrome 
 
 
Covance Study ID: 000000163564 
 
 
Statistical Analysis Plan 
 
 
 
Document Version: Final 1.0 
Document Date: 9 July 2018 
 
 
Author: 
 and 
 
 
 
 
Covance Inc. CDCS 
INS011-16-085 Statistcal Analysis Plan Final 2018_07_09_signed | VV-TMF-113510 | 1.0
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Statistical Analysis Plan  
 
Sponsor Name: Insys Development Company, Inc. 
Sponsor Protocol ID: INS011-16-085 
 
Covance Study ID: 000000163564 
 
COVANCE INC. CONFIDENTIAL 
Document Date: 9 July 2018 
 
Page 2 of 39 
 
 
ST-AD-008 version 04 
Clinical Development Commercialization Services 
 
Table of Contents 
1. 
Source Documents ................................................................................. 9 
2. 
Protocol Details ..................................................................................... 9 
2.1 
Study Objectives................................................................................. 9 
2.1.1 
Primary Objective .................................................................................................................. 9 
2.1.2 
Secondary Objectives ............................................................................................................ 9 
2.1.3 
Exploratory Objective.......................................................................................................... 10 
2.2 
Overall Study Design ......................................................................... 10 
2.3 
Sample Size and Power ..................................................................... 11 
3. 
Efficacy and Safety Endpoints ................................................................ 11 
3.1 
Primary Efficacy Endpoint(s)............................................................... 11 
3.2 
Secondary Efficacy Endpoints ............................................................. 12 
3.3 
Exploratory Efficacy Endpoint ............................................................. 12 
3.4 
Safety Endpoints ............................................................................... 12 
4. 
Pharmacokinetic Endpoints ................................................................... 12 
5. 
Analysis populations ............................................................................. 13 
5.1 
Intent-to-treat Population .................................................................. 13 
5.2 
Safety Population .............................................................................. 13 
5.3 
Per Protocol Population ...................................................................... 13 
5.3.1 
Important Protocol Deviations Leading to Exclusion from the PP Population Analysis ..... 13 
5.4 
DEXA Population ............................................................................... 14 
5.5 
PK Population ................................................................................... 15 
6. 
DATA Handling .................................................................................... 15 
6.1 
Time points and Visit Windows ........................................................... 15 
6.2 
Handling of Dropouts, Missing Data, and Outliers .................................. 15 
6.2.1 
Observed Cases Analysis ..................................................................................................... 16 
6.2.2 
Jump to Reference .............................................................................................................. 16 
7. 
Statistical Methods ............................................................................... 16 
INS011-16-085 Statistcal Analysis Plan Final 2018_07_09_signed | VV-TMF-113510 | 1.0
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Statistical Analysis Plan  
 
Sponsor Name: Insys Development Company, Inc. 
Sponsor Protocol ID: INS011-16-085 
 
Covance Study ID: 000000163564 
 
COVANCE INC. CONFIDENTIAL 
Document Date: 9 July 2018 
 
Page 3 of 39 
 
 
ST-AD-008 version 04 
7.1 
General Principles ............................................................................. 16 
7.2 
Subject Disposition and Data Sets Analyzed ......................................... 18 
7.3 
Protocol Deviations ........................................................................... 19 
7.4 
Demographics and Other Baseline Characteristics ................................. 19 
7.4.1 
Patient Global Impression of Severity (PGI-S) ..................................................................... 20 
7.4.2 
Medical or Surgical History ................................................................................................. 20 
7.4.3 
Previous and Concomitant Medications ............................................................................. 20 
7.5 
Measurements of Treatment Compliance .............................................. 21 
7.6 
Efficacy ............................................................................................ 21 
7.6.1 
Primary Efficacy Analysis ..................................................................................................... 21 
7.6.2 
Sensitivity Analysis .............................................................................................................. 22 
7.6.3 
Multiplicity .......................................................................................................................... 22 
7.6.4 
Secondary Efficacy Analysis ................................................................................................ 23 
7.6.5 
Subgroup Analysis ............................................................................................................... 25 
7.6.6 
Exploratory Efficacy Analysis ............................................................................................... 25 
7.6.7 
Columbia Suicide Severity Rating Scale .............................................................................. 25 
7.7 
Safety ............................................................................................. 26 
7.7.1 
Extent of Exposure .............................................................................................................. 26 
7.7.2 
Adverse Events .................................................................................................................... 26 
7.7.3 
Laboratory Evaluations ....................................................................................................... 28 
7.7.4 
Vital Signs ............................................................................................................................ 29 
7.7.5 
Electrocardiograms ............................................................................................................. 29 
7.7.6 
Physical Examination ........................................................................................................... 30 
7.8 
PK Analysis ...................................................................................... 30 
7.9 
Interim Analysis................................................................................ 30 
8. 
Changes in Planned Analysis ................................................................. 30 
9. 
Data Issues......................................................................................... 30 
10. 
References .......................................................................................... 32 
Appendix A: Visit Schedule Chart ................................................................... 33 
Appendix B: Scoring of the TFEQ-R18 ............................................................. 37 
Appendix C: Scoring of the PROMIS® Questionnaires ........................................ 38 
INS011-16-085 Statistcal Analysis Plan Final 2018_07_09_signed | VV-TMF-113510 | 1.0
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Statistical Analysis Plan  
 
Sponsor Name: Insys Development Company, Inc. 
Sponsor Protocol ID: INS011-16-085 
 
Covance Study ID: 000000163564 
 
COVANCE INC. CONFIDENTIAL 
Document Date: 9 July 2018 
 
Page 6 of 39 
 
 
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 
9 July 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 
Internal draft 
1.0 
Covance 
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 
INS011-16-085 Statistcal Analysis Plan Final 2018_07_09_signed | VV-TMF-113510 | 1.0
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Ap
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Statistical Analysis Plan  
 
Sponsor Name: Insys Development Company, Inc. 
Sponsor Protocol ID: INS011-16-085 
 
Covance Study ID: 000000163564 
 
COVANCE INC. CONFIDENTIAL 
Document Date: 9 July 2018 
 
Page 7 of 39 
 
 
ST-AD-008 version 04 
Glossary of Abbreviations 
 
Abbreviation 
Term 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine transaminase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate transaminase 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index 
CBD 
Cannabidiol 
CI 
Confidence Interval 
CRF 
Case report form 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CTMS 
Clinical Trials Management System 
DEXA 
Dual energy X-ray absorptiometry 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
HQ-CT 
Hyperphagia Questionnaire for Clinical Trials 
IMP 
Investigational medicinal product 
ITT 
Intent-to-treat 
IWRS 
Interactive web response system 
LDH 
Lactate dehydrogenase 
LS 
Least squares 
MAR 
Missing at random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed effects model for repeated measures 
MNAR 
Missing not at random 
PGI-C 
Patient Global Impression of Change 
PGI-S 
Patient Global Impression of Severity 
INS011-16-085 Statistcal Analysis Plan Final 2018_07_09_signed | VV-TMF-113510 | 1.0
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Statistical Analysis Plan  
 
Sponsor Name: Insys Development Company, Inc. 
Sponsor Protocol ID: INS011-16-085 
 
Covance Study ID: 000000163564 
 
COVANCE INC. CONFIDENTIAL 
Document Date: 9 July 2018 
 
Page 8 of 39 
 
 
ST-AD-008 version 04 
PK 
Pharmacokinetic 
PP 
Per-protocol  
PROMIS® 
Patient-Reported Outcomes Measurement Information System 
PT 
Preferred term 
PWS 
Prader-Willi syndrome 
QTcF 
Fridericia corrected QT interval 
SAP 
Statistical analysis plan 
SD 
Standard Deviation 
SOC 
System Organ Class 
TEAE 
Treatment emergent adverse event 
TESAE 
Treatment emergent serious adverse event 
TFEQ-R18 
Three Factor Eating Questionnaire – 18-item version 
TFLs 
Tables, Figures and Listings 
THC 
Tetrahydrocannabinol 
 
 
INS011-16-085 Statistcal Analysis Plan Final 2018_07_09_signed | VV-TMF-113510 | 1.0
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Statistical Analysis Plan  
 
Sponsor Name: Insys Development Company, Inc. 
Sponsor Protocol ID: INS011-16-085 
 
Covance Study ID: 000000163564 
 
COVANCE INC. CONFIDENTIAL 
Document Date: 9 July 2018 
 
Page 9 of 39 
 
 
ST-AD-008 version 04 
1. Source Documents 
The Statistical Analysis Plan (SAP) was written based on the following 
documentation: 
Document 
Date 
Version 
Protocol Amendment 1 
18 May 2018 
3.0 
eCRF 
31 May 2018 
1.0 
 
2. Protocol Details 
2.1 Study Objectives 
2.1.1 Primary Objective 
The primary objective of this study is to assess the efficacy of Cannabidiol Oral 
Solution on hyperphagia-related behavior in patients with Prader-Willi Syndrome 
(PWS) as measured by the total score of the Hyperphagia Questionnaire for Clinical 
Trials (HQ-CT). 
2.1.2 Secondary Objectives 
The secondary objectives of this study are: 
 
To assess the efficacy of Cannabidiol Oral Solution on the change in total body 
weight in patients with PWS. 
 
To assess the responder rate (responder is defined as a 6-point decrease on 
the HQ-CT from Baseline to End of Study). 
 
To assess the efficacy of Cannabidiol Oral Solution by measuring Patient Global 
Impression of Change (PGI-C). 
 
To assess the safety and tolerability of Cannabidiol Oral Solution in patients 
with PWS. 
 
To assess the efficacy of Cannabidiol Oral Solution on eating behavior in 
patients with PWS as measured by the Three Factor Eating Questionnaire -18-
item version (TFEQ-R18). 
 
To assess the impact on Quality of Life in patients with PWS as measured by 
the PROMIS® Life Satisfaction and Positive Affect short-form questionnaires. 
 
To assess the impact on physical activity in patients with PWS as measured by 
the PROMIS® Physical Activity and Fatigue questionnaires. 
INS011-16-085 Statistcal Analysis Plan Final 2018_07_09_signed | VV-TMF-113510 | 1.0
Approved
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Statistical Analysis Plan  
 
Sponsor Name: Insys Development Company, Inc. 
Sponsor Protocol ID: INS011-16-085 
 
Covance Study ID: 000000163564 
 
COVANCE INC. CONFIDENTIAL 
Document Date: 9 July 2018 
 
Page 10 of 39 
 
 
ST-AD-008 version 04 
2.1.3 Exploratory Objective 
The exploratory objective of this study is to assess the efficacy of Cannabidiol Oral 
Solution on body composition and bone mineral density, as measured by dual-
energy X-ray absorptiometry (DEXA). 
2.2 Overall Study Design 
This study is a double-blind, randomized, placebo-controlled, Phase 2 clinical trial in 
patients aged 8 to 17 years inclusive, with a genetically confirmed diagnosis of 
PWS.   
Approximately 66 patients will be randomized in a 1:1 ratio to receive either: 
 
Cannabidiol Oral Solution (40 mg/kg/day) divided into twice daily doses with 
standard meal 
 
Matching placebo, divided into twice daily doses with standard meal  
Randomization will be stratified according to use of growth hormone (Yes, No). 
Patients will participate in the study for approximately 19 weeks.  The study will 
consist of the following 6 periods: 
 
Screening Period (2 weeks) 
 
Placebo Lead-in Period (2 weeks) 
 
Titration Period (1 week) 
 
Maintenance Period (12 weeks) 
 
Taper Period (1 week) 
 
Follow-up Period (1 week) 
Eligible patients will be assigned to a 2-week single-blind placebo lead-in period 
after which they will be randomly assigned to receive double-blind treatment with 
either Cannabidiol Oral Solution (40 mg/kg/day) or matching placebo (a 1-week 
Titration Period followed by a 12-week Maintenance Period).  During the Titration 
Period Cannabidiol Oral Solution will be titrated as follows: Days 1-3: 20 
mg/kg/day, Days 4-6: 30 mg/kg/day, Day 7: 40 mg/kg/day. 
During the Maintenance Period, patients may have their dose of blinded study 
medication adjusted down to 30 mg/kg/day at the discretion of the investigator or 
qualified designee based on the patient’s tolerability. 
After completion of the study, patients will be offered an opportunity to enroll into 
an open-label, long-term safety study.  Patients who do not elect to enroll in the 
long-term safety study will be titrated off study drug over 7 days and a final safety 
follow-up phone call will be placed 2 weeks after study completion for patients who 
do not elect to continue in the long-term safety study. 
INS011-16-085 Statistcal Analysis Plan Final 2018_07_09_signed | VV-TMF-113510 | 1.0
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Statistical Analysis Plan  
 
Sponsor Name: Insys Development Company, Inc. 
Sponsor Protocol ID: INS011-16-085 
 
Covance Study ID: 000000163564 
 
COVANCE INC. CONFIDENTIAL 
Document Date: 9 July 2018 
 
Page 11 of 39 
 
 
ST-AD-008 version 04 
The study design is depicted in Figure 1.  
 
 All screening, efficacy and safety evaluations will be performed according to the 
schedule of assessments summarized in Appendix A. 
2.3 Sample Size and Power 
A total of 30 patients per treatment group will provide at least 85% power with an 
alpha of 0.05, to detect a difference in the change in HQ-CT from Baseline to Week 
13 of 5 points with a standard deviation of 6.  Assuming a 20% drop out rate, 
approximately 66 patients (33 patients per arm) will be randomized to achieve 60 
(30 patients per arm) completers. 
3. Efficacy and Safety Endpoints 
3.1 Primary Efficacy Endpoint(s) 
The primary efficacy endpoint for this study is change in the total score of the HQ-
CT from Baseline (defined as the score after the Placebo lead-in period) through 
Study Completion (Week 13/Early Withdrawal).  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 then obtained by summing the responses to each item, yielding a total 
HQ-CT score that can range from 0 to 36 (Fehnel, et al., 2015). 
INS011-16-085 Statistcal Analysis Plan Final 2018_07_09_signed | VV-TMF-113510 | 1.0
Appro
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Statistical Analysis Plan  
 
Sponsor Name: Insys Development Company, Inc. 
Sponsor Protocol ID: INS011-16-085 
 
Covance Study ID: 000000163564 
 
COVANCE INC. CONFIDENTIAL 
Document Date: 9 July 2018 
 
Page 12 of 39 
 
 
ST-AD-008 version 04 
3.2 Secondary Efficacy Endpoints 
The secondary efficacy endpoints in this study are: 
•   Change in total body-weight from Baseline through Study Completion/Early 
Withdrawal. 
•   Responder rate (responder is defined as 6-point decrease on the HQ-CT from 
Baseline through Study Completion). 
•   Patient Global Impression of Change and Severity. 
•   Change in the TFEQ-R18 from Baseline through Study Completion/Early 
Withdrawal.  The TFEQ-R18 yields scores for 3 subscales: cognitive restraint, 
uncontrolled eating and emotional eating (Karlsson et al., 2000).  The scores 
for each subscale will be analyzed separately. 
•   Change in Quality of Life (PROMIS® Life Satisfaction and Positive Affect 
questionnaires) from Baseline through Study Completion/Early Withdrawal. 
•   Change in physical activity (PROMIS® Physical Activity and Fatigue 
questionnaires) from Baseline through Study Completion/Early Withdrawal. 
 
Methods for scoring the TFEQ-R18 and the PROMIS® questionnaires are provided in  
Appendix B and Appendix C respectively. 
3.3 Exploratory Efficacy Endpoint 
The exploratory efficacy endpoint is change in body composition from Baseline to 
Study Completion/Early Withdrawal as measured by DEXA. 
3.4  Safety Endpoints 
The safety endpoints of this study are: 
 
Treatment-emergent adverse events (TEAEs) 
 
Clinical laboratory assessments 
 
Vital signs (blood pressure, pulse rate, respiration rate and temperature) 
 
12-lead ECGs 
 
Physical examination assessments 
 
Pregnancy screens 
 
Urine drug screen (including THC) 
 
Medical history  
 
Prior and concomitant medications. 
4. Pharmacokinetic Endpoints 
The pharmacokinetic (PK) endpoints of this study are trough concentrations (Ctrough) 
of cannabidiol (CBD) and metabolite 7-OH-CBD which will be used to assess the 
exposure-response relationship.   
INS011-16-085 Statistcal Analysis Plan Final 2018_07_09_signed | VV-TMF-113510 | 1.0
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Statistical Analysis Plan  
 
Sponsor Name: Insys Development Company, Inc. 
Sponsor Protocol ID: INS011-16-085 
 
Covance Study ID: 000000163564 
 
COVANCE INC. CONFIDENTIAL 
Document Date: 9 July 2018 
 
Page 13 of 39 
 
 
ST-AD-008 version 04 
5. Analysis Populations 
Unless otherwise stated, all efficacy analyses will be performed on the Intent-to-
treat (ITT) population.  A supportive analysis of the primary endpoint will also be 
performed on the Per-protocol (PP) population.  All safety analyses will be 
performed on the safety population.  Analyses of the DEXA endpoints will be 
performed on the DEXA population. The analysis of the PK endpoints will be 
performed on the PK population. 
5.1 Intent-to-treat Population 
The ITT population will consist of all randomized patients.  ITT patients are 
analyzed according to their randomized treatment. 
5.2 Safety Population 
The Safety population includes all randomized patients treated with at least one 
dose of the study drug during the double-blind treatment period.  Safety patients 
are analyzed according to their actual treatment received. 
5.3 Per Protocol Population 
The PP population will consist of all patients in the ITT population who do not have 
any important protocol deviations leading to exclusion from the PP population.   
Protocol deviations are defined as any change, divergence, or departure from the 
study design or procedures defined in the study protocol. Important protocol 
deviations are a subset of protocol deviations and may significantly impact the 
correctness, accuracy, and/or reliability of the study data or that may significantly 
affect a subject’s rights, safety, or well-being. Section 5.3.1 details the deviations. 
All important and non-important protocol deviations are defined in a protocol 
deviations list which includes details about escalation requirements and whether 
they are detected via monitoring or programming.   
5.3.1 Important Protocol Deviations Leading to Exclusion from the PP 
Population Analysis 
Only the important protocol deviations considered as having a major effect on the 
collection or interpretation of the efficacy data will lead to complete exclusion of 
patients from the PP population.   
For the purposes of this study, the following criteria have been identified as 
important protocol deviations leading to exclusion from the PP population as it is 
considered that the occurrences of any of these criteria might have an important 
influence on the primary efficacy endpoint:   
INS011-16-085 Statistcal Analysis Plan Final 2018_07_09_signed | VV-TMF-113510 | 1.0
proved
nt.
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ions leading to e
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Statistical Analysis Plan  
 
Sponsor Name: Insys Development Company, Inc. 
Sponsor Protocol ID: INS011-16-085 
 
Covance Study ID: 000000163564 
 
COVANCE INC. CONFIDENTIAL 
Document Date: 9 July 2018 
 
Page 14 of 39 
 
 
ST-AD-008 version 04 
Table 1: Important Protocol Deviations Leading to Exclusion from the PP Population 
Type 
Important Protocol Deviation 
Leading to Exclusion from the 
PP Population 
Method of Identification 
Non-
compliance 
during the 
double-
blind 
treatment 
phase 
Patients who had low study drug 
compliance (e.g. repeated 
occurrence of compliance < 90%) 
Programmable check based on the 
exposure and drug accountability data. 
 
Errors in 
treatment 
allocation 
Patients who receive the wrong 
treatment at 1 or more study visit 
due to packaging or dispensing 
errors 
Programmatic check based on the 
unblinded IWRS database after the study 
is unblinded.  The check will be 
performed by comparing the kit number 
assigned by IWRS to the patient at a 
particular visit against the kit number 
actually used. 
CTMS 
Covance Clinical will provide the 
list of protocol deviations based on 
the clinical monitoring. 
Manual review: The list will be reviewed 
and the important protocol deviations 
that will lead to exclusion from the PP 
population will be identified. 
 
As defined in Table 1, the majority of the important protocol deviations leading to 
exclusion from the PP population will be determined programmatically from the 
data.  Those criteria which require clinical or medical monitoring interpretation will 
be reviewed prior to database lock. 
All important protocol deviations leading to exclusion from the PP population 
occurring during the study will be reviewed and approved by Insys prior to 
database lock and unblinding.  Should additional important protocol deviations 
leading to exclusion from the PP population, not anticipated at the time of preparing 
this SAP, be identified during the study (and prior to unblinding) they will be 
documented in a SAP amendment and included in all relevant protocol deviation 
reviews and approvals. 
5.4 DEXA Population 
The DEXA population is a pre-defined subpopulation of approximately 20 patients 
from the ITT population for whom changes in body composition (total fat, lean body 
mass and bone mineral content) are assessed via DEXA scans. 
INS011-16-085 Statistcal Analysis Plan Final 2018_07_09_signed | VV-TMF-113510 | 1.0
Approved
Programm
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PPD


Statistical Analysis Plan  
 
Sponsor Name: Insys Development Company, Inc. 
Sponsor Protocol ID: INS011-16-085 
 
Covance Study ID: 000000163564 
 
COVANCE INC. CONFIDENTIAL 
Document Date: 9 July 2018 
 
Page 15 of 39 
 
 
ST-AD-008 version 04 
5.5 PK Population 
The PK population will include patients who receive at least one dose of CBD and 
who have at least one usable CBD plasma concentration measurement. 
6. DATA Handling 
6.1 Time points and Visit Windows 
Day 1 is defined as the date of first dose of double blind treatment.  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. 
For all populations, 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. 
6.2 Handling of Dropouts, Missing Data, and Outliers 
Missing data will not be imputed for the safety analyses.  Safety 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. 
INS011-16-085 Statistcal Analysis Plan Final 2018_07_09_signed | VV-TMF-113510 | 1.0
pproved
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PPD


Statistical Analysis Plan  
 
Sponsor Name: Insys Development Company, Inc. 
Sponsor Protocol ID: INS011-16-085 
 
Covance Study ID: 000000163564 
 
COVANCE INC. CONFIDENTIAL 
Document Date: 9 July 2018 
 
Page 16 of 39 
 
 
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. 
6.2.1 Observed Cases Analysis 
A mixed effects model for repeated measurements (MMRM) will be used to analyze 
the primary and continuous secondary efficacy endpoints.  This model is based on 
the assumption that the missing data follow a missing at random (MAR) mechanism 
and uses only observed data.  There are no imputations of missing data for this 
analysis. 
6.2.2 Jump to Reference 
A reference-based multiple imputation approach, jump to reference, may be used 
as a sensitivity analysis of the primary efficacy endpoint.  This analysis is based on 
the assumption that the missing data follow a missing not at random (MNAR) 
mechanism.  For this analysis, it is assumed that the distribution of values at future 
visits for patients in the CBD treatment group who discontinue early is similar to 
that of patients with observed data in the control arm. 
No rules for outlier detection are planned. 
7. Statistical Methods 
7.1 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). 
 
 
INS011-16-085 Statistcal Analysis Plan Final 2018_07_09_signed | VV-TMF-113510 | 1.0
Approved
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PPD


Statistical Analysis Plan  
 
Sponsor Name: Insys Development Company, Inc. 
Sponsor Protocol ID: INS011-16-085 
 
Covance Study ID: 000000163564 
 
COVANCE INC. CONFIDENTIAL 
Document Date: 9 July 2018 
 
Page 17 of 39 
 
 
ST-AD-008 version 04 
 
The following principles will be applied to all TFLs unless otherwise stated: 
Principle 
Value 
Significant tests 
Two-sided and use a 5% significance level for main 
effects and 10% significance level for interaction 
terms 
Treatment group labels and order 
presented 
Listings:  
Placebo 
Cannabidiol Oral Solution (30 mg/kg/day) 
Cannabidiol Oral Solution (40 mg/kg/day) 
Tables: 
Placebo 
CBD (30 mg/kg/day) 
CBD (40 mg/kg/day) 
All CBD 
Total 
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) 
Median 
Minimum  
Maximum 
INS011-16-085 Statistcal Analysis Plan Final 2018_07_09_signed | VV-TMF-113510 | 1.0
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Oral Solut
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PPD


Statistical Analysis Plan  
 
Sponsor Name: Insys Development Company, Inc. 
Sponsor Protocol ID: INS011-16-085 
 
Covance Study ID: 000000163564 
 
COVANCE INC. CONFIDENTIAL 
Document Date: 9 July 2018 
 
Page 18 of 39 
 
 
ST-AD-008 version 04 
Principle 
Value 
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 
Date Format 
DDMMMYYYY 
Baseline is defined as the last scheduled or unscheduled measurement collected 
prior to first dose of double-blind investigational medicinal product (IMP) treatment.  
Only data from scheduled post-baseline visits will be included in analyses and 
summary tables, all visit data will be listed. 
7.2 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: 
 
screened; 
 
entered placebo lead-in period; 
 
screened and not randomized; 
 
randomized (i.e. entered the titration period); 
 
randomized and not treated with double-blind treatment; 
 
treated with double-blind treatment; 
 
entered the maintenance period; 
 
entered the taper period; 
INS011-16-085 Statistcal Analysis Plan Final 2018_07_09_signed | VV-TMF-113510 | 1.0
pproved
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PPD


Statistical Analysis Plan  
 
Sponsor Name: Insys Development Company, Inc. 
Sponsor Protocol ID: INS011-16-085 
 
Covance Study ID: 000000163564 
 
COVANCE INC. CONFIDENTIAL 
Document Date: 9 July 2018 
 
Page 19 of 39 
 
 
ST-AD-008 version 04 
 
continued to the long-term safety study; 
 
included in each study population (Safety, ITT, PP, DEXA, PK). 
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 randomization by site will also be provided by treatment 
group and overall for the ITT population.  Inclusion/exclusion criteria not met will 
be listed for all screened patients.  
In addition, a summary table and listing will be produced for discrepancies between 
the stratification factors in the database and IWRS.  This will be produced for the 
ITT population. 
A listing of study drug kit numbers and assignments will be produced. 
7.3 Protocol Deviations 
All important protocol deviations leading to exclusion from the PP population (see 
Section 5.3.1) will be summarized by treatment group for the ITT population.  The 
deviations will be identified before data are unblinded. 
All protocol deviations will be listed. 
7.4 Demographics and Other Baseline Characteristics 
Demographic and baseline characteristics will be listed and summarized by 
treatment group and overall for the ITT population.  Standard descriptive statistics 
will be presented for: 
 
age (years) [calculated as (screening visit date – date of birth)/365.25 and 
reported as whole 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 Screening visit; 
 
body mass index (kg/m2) (derived on eCRF);  
 
randomization strata of growth hormone treatment (Yes, No). 
No formal tests of statistical significance will be performed on the demographic and 
baseline data.   
INS011-16-085 Statistcal Analysis Plan Final 2018_07_09_signed | VV-TMF-113510 | 1.0
Approved
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PPD


Statistical Analysis Plan  
 
Sponsor Name: Insys Development Company, Inc. 
Sponsor Protocol ID: INS011-16-085 
 
Covance Study ID: 000000163564 
 
COVANCE INC. CONFIDENTIAL 
Document Date: 9 July 2018 
 
Page 20 of 39 
 
 
ST-AD-008 version 04 
Other baseline measurements, such as vital signs and ECG, will be summarized by 
treatment group with the post-baseline measurements. 
7.4.1 Patient Global Impression of Severity (PGI-S) 
Patient Global Impression of Severity (PGI-S) is assessed at Baseline and is a single 
item questionnaire where patients are asked to rate the severity of their condition.  
The response to this assessment ranges from 1: “Normal” to 7: “Extremely ill (I am 
more sick/ill than I have ever been”.  PGI-S response will be summarized by 
treatment group using standard descriptive statistics.  In addition, the number and 
percentage of patients selecting each response will be summarized. 
7.4.2 Medical or Surgical History 
Medical or surgical history will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) [Version 21.0 (or a later version if updated during the study)].  
All medical or surgical history will be listed, and the number and percentage of 
patients with any medical or surgical history will be summarized for the ITT 
population by system organ class (SOC) and preferred term (PT) for each treatment 
group and overall.   
7.4.3 Previous and Concomitant Medications 
Medications received prior to or concomitantly with treatment will be coded by 
Covance using the WHODrug 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 taken prior to the first dose date of double-blind IMP 
treatment.  
Concomitant medications are those with a start date on or after the first dose date 
of double-blind IMP treatment, or those with a start date before the first dose date  
of double-blind IMP treatment and a stop date on or after the first dose date of 
double blind treatment or ongoing at the end of the 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 the ITT 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. 
INS011-16-085 Statistcal Analysis Plan Final 2018_07_09_signed | VV-TMF-113510 | 1.0
proved
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PPD


Statistical Analysis Plan  
 
Sponsor Name: Insys Development Company, Inc. 
Sponsor Protocol ID: INS011-16-085 
 
Covance Study ID: 000000163564 
 
COVANCE INC. CONFIDENTIAL 
Document Date: 9 July 2018 
 
Page 21 of 39 
 
 
ST-AD-008 version 04 
7.5 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 
Safety 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 
Safety population.   
All study drug administration and drug accountability data will be listed in full. 
7.6 Efficacy 
All statistical inference will be based on a comparison of the placebo and all CBD 
treatment groups.  Descriptive statistics for efficacy endpoints will be based on all 
treatment groups, i.e. placebo, CBD (30 mg/kg/day), CBD (40 mg/kg/day), all CBD 
and total. 
7.6.1 Primary Efficacy Analysis 
The primary endpoint, change in total HQ-CT score from Baseline through Study 
Completion/Early Withdrawal, will be assessed using MMRM. 
The MMRM model will include change in total HQ-CT score at each scheduled visit, 
fixed factors for treatment group, time (study week), randomization strata of 
growth hormone treatment (yes, no), a treatment-by-time interaction term, and 
baseline total HQ-CT as a covariate.  A contrast will be specified for the primary 
analysis time point of Study Completion/Early Withdrawal. 
All patients in the ITT population with non-missing total baseline HQ-CT score and 
at least one non-missing post-baseline HQ-CT score will be included in the analysis 
model.  The MMRM will use observed data only, no imputations of missing data will 
be performed.  Stratification factors as used in the IWRS randomization will be 
INS011-16-085 Statistcal Analysis Plan Final 2018_07_09_signed | VV-TMF-113510 | 1.0
Approved
will also
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PPD


Statistical Analysis Plan  
 
Sponsor Name: Insys Development Company, Inc. 
Sponsor Protocol ID: INS011-16-085 
 
Covance Study ID: 000000163564 
 
COVANCE INC. CONFIDENTIAL 
Document Date: 9 July 2018 
 
Page 22 of 39 
 
 
ST-AD-008 version 04 
included. An unstructured covariance matrix will be used to model the residuals 
over time within each patient.  However, in the event that the model does not 
converge, the following matrices will be used in order until the model converges: 
Toeplitz, first-order autoregressive and compound symmetry.  The least squares 
(LS) means and their associated 95% confidence intervals (CIs) and p-values will 
be presented for each treatment group, as well as the LS mean difference, its 95% 
CI and the comparison p-value. 
Graphical presentations of total HQ-CT scores by treatment and visit will be used to 
examine trends over time, displaying the LS means together with their associated 
95% CIs. 
In addition, total HQ-CT scores and changes from baseline will be summarized by 
treatment group and visit using standard descriptive statistics. 
This analysis will be repeated for all patients in the per protocol population. 
7.6.2 Sensitivity Analysis 
The MMRM is based on the assumption that missing data follow a MAR mechanism.   
A sensitivity analysis, based on the assumption that the missing data are MNAR, 
may be performed for the primary endpoint.  The implementation of this analysis 
will depend on the extent and pattern of missing data and as such, it may not be 
used.  For this sensitivity analysis, missing values will be imputed using jump to 
reference where it is assumed that following early discontinuation, the values for 
patients in the CBD group at future visits will follow the same distribution as the 
values of patients in the placebo group. 
Each of the complete datasets will be analyzed using an Analysis of Covariance 
(ANCOVA) model which will model the change in total HQ-CT score from Baseline to 
Study Completion/Early Withdrawal and which will include fixed factors for 
treatment group and randomization strata of growth hormone treatment (yes, no), 
and baseline HQ-CT total score as a covariate.  The results from the analyses of 
each complete dataset will then be combined using Rubin’s method. 
LS means and the LS mean difference between all CBD and placebo will be 
presented together with the relevant 95% CIs and p-values.   
7.6.3 Multiplicity 
Statistical inference for the primary endpoint and for the secondary endpoints 
[change in total body weight, responder rate, PGI-C, TFEQ-R18 (3 subscales), 
PROMIS® Life Satisfaction and Positive Affect (2 separate scores) and PROMIS® 
Physical Activity and Fatigue (2 separate scores)] will be controlled at an overall 
family wise error rate of α =0.05 using a gatekeeping approach.  Using this 
INS011-16-085 Statistcal Analysis Plan Final 2018_07_09_signed | VV-TMF-113510 | 1.0
ved
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PPD


Statistical Analysis Plan  
 
Sponsor Name: Insys Development Company, Inc. 
Sponsor Protocol ID: INS011-16-085 
 
Covance Study ID: 000000163564 
 
COVANCE INC. CONFIDENTIAL 
Document Date: 9 July 2018 
 
Page 23 of 39 
 
 
ST-AD-008 version 04 
approach, the hypotheses associated with the secondary endpoints will only be 
tested if the null hypothesis for the primary endpoint is rejected (i.e. if p<0.05 for 
the primary endpoint). 
In this instance, the 10 hypotheses corresponding to the secondary endpoints will 
be tested using the Hochberg procedure.  The 10 p-values resulting from the 
inferential analyses of the secondary endpoints will be ordered from largest to 
smallest and will be compared with alpha critical values of α, α/2, α/3, … α/(10-1).  
The largest p-value is then compared with α.  If this p-value is not less than α, 
proceed to the second largest p-value and compared it with α/2.  Testing continues 
sequentially in this manner until a p-value for an endpoint is statistically significant.  
Once a p-value is statistically significant, conclude that the treatment effect for that 
endpoint and all endpoints with smaller p-values are statistically significant.   
7.6.4 Secondary Efficacy Analysis 
The analyses of the secondary efficacy endpoints will be based on the placebo and 
all CBD treatment groups in the ITT population.  Descriptive statistics for the 
secondary efficacy endpoints will be based on all treatment groups, i.e. placebo, 
CBD (30 mg/kg/day), CBD (40 mg/kg/day), all CBD and total. 
Listings of secondary efficacy endpoint data will be produced for the ITT population. 
7.6.4.1 
Change in Total Body Weight 
Change from Baseline to Study Completion/Early Withdrawal in body weight will be 
analyzed using the MMRM method described for the primary efficacy endpoint.  The 
MMRM model will include change in total body weight at each scheduled visit, fixed 
factors for treatment group, time (study week), randomization strata of growth 
hormone treatment (yes, no), a treatment-by-time interaction term, and baseline 
total body weight as a covariate. 
LS means and the LS mean difference between all CBD and placebo will be 
presented together with the relevant 95% CIs and p-values.  In addition, LS means 
and the 95% CIs will be plotted by treatment group and visit.  
7.6.4.2 
Responder Rate 
A responder is defined as a 6-point decrease in HQ-CT total score from Baseline to 
Study Completion/Early Withdrawal.  The responder rate data will be analyzed 
using Fisher’s exact test and patients with missing HQ-CT score at Study 
Completion/Early Withdrawal will be treated as non-responders. 
The proportion of responders and non-responders will be presented by treatment 
group, together with the difference in proportion, its associated 95% CI and the 
INS011-16-085 Statistcal Analysis Plan Final 2018_07_09_signed | VV-TMF-113510 | 1.0
Approved
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PPD


Statistical Analysis Plan  
 
Sponsor Name: Insys Development Company, Inc. 
Sponsor Protocol ID: INS011-16-085 
 
Covance Study ID: 000000163564 
 
COVANCE INC. CONFIDENTIAL 
Document Date: 9 July 2018 
 
Page 24 of 39 
 
 
ST-AD-008 version 04 
comparison p-value from the Fishers exact test. The proportion of responders will 
be plotted by treatment group and visit. 
7.6.4.3 
PGI-C 
PGI-C will be analyzed using the MMRM method described for the primary efficacy 
endpoint, which will include PGI-C at each scheduled visit, fixed factors for 
treatment group, time (study week), randomization strata of growth hormone 
treatment (yes, no), a treatment-by-time interaction term, and PGI-S score at 
baseline as a covariate. 
LS means, the LS mean difference between all CBD and placebo, as well as the 
relevant 95% CIs and p-values will be presented.  A plot of the LS means and their 
associated 95% CIs by treatment group and visit will be produced.  
7.6.4.4 
Change TFEQ-R18 
Change from Baseline to Study Completion/Early Withdrawal in each TFEQ-R18 
subscale will be analyzed using the MMRM method described for the primary 
efficacy endpoint.  For each subscale, the MMRM model will include change in TFEQ-
R18 subscale score at each scheduled visit, fixed factors for treatment group, time 
(study week), randomization strata of growth hormone treatment (yes, no), a 
treatment-by-time interaction term, and baseline TFEQ-R18 subscale score as a 
covariate. 
LS means and the LS mean difference between all CBD and placebo will be 
presented together with the relevant 95% CIs and p-values.  In addition, LS means 
and the 95% CIs will be plotted by treatment group and visit.  
7.6.4.5 
Change in Quality of Life 
Quality of life will be assessed using the PROMIS® Life Satisfaction and Positive 
Affect short-form questionnaires.  Change in PROMIS® Life Satisfaction from 
Baseline to Study Completion/Early Withdrawal and change in PROMIS® Positive 
Affect from Baseline to Study Completion/Early Withdrawal will be analyzed 
separately using the MMRM described for the analysis of the primary endpoint.   
The MMRM analysis described for the primary endpoint will be used to analyze the 
change in PROMIS® score (Life Satisfaction or Positive Affect) from Baseline to 
Study Completion/Early Withdrawal.  For each analysis, change in PROMIS® score 
(Life Satisfaction or Positive Affect) at each visit will be included in the model, 
together with fixed factors for treatment group, time (study week), randomization 
strata of growth hormone treatment (yes, no), a treatment-by-time interaction 
INS011-16-085 Statistcal Analysis Plan Final 2018_07_09_signed | VV-TMF-113510 | 1.0
roved
d.  A pl
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Statistical Analysis Plan  
 
Sponsor Name: Insys Development Company, Inc. 
Sponsor Protocol ID: INS011-16-085 
 
Covance Study ID: 000000163564 
 
COVANCE INC. CONFIDENTIAL 
Document Date: 9 July 2018 
 
Page 25 of 39 
 
 
ST-AD-008 version 04 
term, and baseline PROMIS® score (Life Satisfaction or Positive Affect) as a 
covariate. 
The resulting LS means, LS mean difference between all CBD and placebo, 95% CIs 
and corresponding p-values will be presented.  LS means and the 95% CIs will be 
plotted by treatment group and visit.  
7.6.4.6 
Change in Physical Activity 
Physical Activity will be assessed using the PROMIS® Physical Activity and Fatigue 
questionnaires.  Change in PROMIS® Physical Activity from Baseline to Study 
Completion/Early Withdrawal and change in PROMIS® Fatigue from Baseline to 
Study Completion/Early Withdrawal will be analyzed separately using the MMRM 
described for the analysis of the primary endpoint.   
For each analysis, change in PROMIS® score (Physical Activity or Fatigue) from 
Baseline to Study Completion/Early Withdrawal, the MMRM model will include 
change in PROMIS® score (Physical Activity or Fatigue) at each scheduled visit, 
fixed factors for treatment group, time (study week), randomization strata of 
growth hormone treatment (yes, no), a treatment-by-time interaction term, and 
baseline PROMIS® score (Physical Activity or Fatigue) as a covariate. 
LS means and the LS mean difference between all CBD and placebo will be 
presented together with the relevant 95% CIs and the comparison p-value.  In 
addition, LS means and the 95% CIs will be plotted by treatment group and visit.  
7.6.5 Subgroup Analysis 
Not applicable. 
7.6.6 Exploratory Efficacy Analysis 
The exploratory efficacy analysis will be based on the DEXA population.  Total fat, 
fat free mass, bone mineral content and lean body mass, together with changes 
from baseline will be summarized by treatment group and visit using standard 
descriptive statistics. 
All DEXA scan data will be listed. 
7.6.7 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 ITT population. 
INS011-16-085 Statistcal Analysis Plan Final 2018_07_09_signed | VV-TMF-113510 | 1.0
Approved
yzed se
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Statistical Analysis Plan  
 
Sponsor Name: Insys Development Company, Inc. 
Sponsor Protocol ID: INS011-16-085 
 
Covance Study ID: 000000163564 
 
COVANCE INC. CONFIDENTIAL 
Document Date: 9 July 2018 
 
Page 26 of 39 
 
 
ST-AD-008 version 04 
7.7 Safety 
7.7.1 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 Safety population. 
7.7.2 Adverse Events 
All AEs recorded on the eCRF will be coded using the MedDRA dictionary [Version 
21.0 (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 double-
blind IMP and up to 14 days after the last dose of double blind IMP or events 
with start date prior to the date of first dose of double-blind IMP whose 
severity worsens on or after the date of first dose of double-blind IMP.  
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. 
Summary tables of TEAEs by treatment group and overall will be produced for the 
Safety 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: 
 
any TEAE;  
 
TEAE by severity (mild, moderate, severe); 
 
treatment-related TEAE;  
 
severe treatment-related TEAE; 
INS011-16-085 Statistcal Analysis Plan Final 2018_07_09_signed | VV-TMF-113510 | 1.0
proved
udy)]
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Statistical Analysis Plan  
 
Sponsor Name: Insys Development Company, Inc. 
Sponsor Protocol ID: INS011-16-085 
 
Covance Study ID: 000000163564 
 
COVANCE INC. CONFIDENTIAL 
Document Date: 9 July 2018 
 
Page 27 of 39 
 
 
ST-AD-008 version 04 
 
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 the Safety population.  
Tables will be sorted alphabetically by SOC.  PTs will be sorted by descending 
overall total.  The following summaries will be produced: 
 
AEs occurring in the run-in period, by SOC and PT; 
 
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.  
INS011-16-085 Statistcal Analysis Plan Final 2018_07_09_signed | VV-TMF-113510 | 1.0
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PT
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Statistical Analysis Plan  
 
Sponsor Name: Insys Development Company, Inc. 
Sponsor Protocol ID: INS011-16-085 
 
Covance Study ID: 000000163564 
 
COVANCE INC. CONFIDENTIAL 
Document Date: 9 July 2018 
 
Page 28 of 39 
 
 
ST-AD-008 version 04 
7.7.3 Laboratory Evaluations 
7.7.3.1 
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 Safety population.  Changes from baseline will also be 
summarized. 
INS011-16-085 Statistcal Analysis Plan Final 2018_07_09_signed | VV-TMF-113510 | 1.0
Approved
atase (ALP)
ed
atase (ALP)
ansaminase (AST)
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ansaminase (AST)
ransaminase (ALT
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m
assium
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Chloride
p
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Lactate Dehydr
pp
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Uric Acid
Ap
Uric Acid
Glucose
Ap
Glucose
Calciu
A
Calciu
A
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Statistical Analysis Plan  
 
Sponsor Name: Insys Development Company, Inc. 
Sponsor Protocol ID: INS011-16-085 
 
Covance Study ID: 000000163564 
 
COVANCE INC. CONFIDENTIAL 
Document Date: 9 July 2018 
 
Page 29 of 39 
 
 
ST-AD-008 version 04 
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 
provided for each treatment group.  Corresponding shift tables will be produced for 
urinalysis. 
7.7.3.2 
Urine Drug Screen 
A urine sample for the following assessments will be collected at the Screening 
visit: amphetamines, barbiturates, benzodiazepines, cocaine, opiates, phencyclidine 
and tetrahydrocannabinol.  
Results from the urine drug screen will be listed for the Safety population. 
7.7.3.3 
Urine Pregnancy Test 
A urine dipstick pregnancy test will be performed on all female patients at the 
Screening visit. 
Pregnancy screen results will be listed for the Safety population 
7.7.4 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); 
 
respiratory rate (breaths/min); 
 
body temperature (°C); 
 
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 Safety population.   
All vital sign data collected for the Safety population will be listed. 
7.7.5 Electrocardiograms 
The following quantitative ECG measurements will be taken during the study: 
 
heart rate (bpm); 
 
PR interval (msec); 
 
QRS interval (msec); 
INS011-16-085 Statistcal Analysis Plan Final 2018_07_09_signed | VV-TMF-113510 | 1.0
roved
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Ap
ure (°C)
A
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Ap
;
A
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Statistical Analysis Plan  
 
Sponsor Name: Insys Development Company, Inc. 
Sponsor Protocol ID: INS011-16-085 
 
Covance Study ID: 000000163564 
 
COVANCE INC. CONFIDENTIAL 
Document Date: 9 July 2018 
 
Page 30 of 39 
 
 
ST-AD-008 version 04 
 
QT interval (msec); 
 
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 Safety 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 Safety population. Shifts from baseline at each post-baseline visit will 
be presented. 
A listing of ECG measurements and findings will be produced for the Safety 
population. 
7.7.6 Physical Examination 
Physical examination results (normal/abnormal) and details of abnormalities will be 
listed for the Safety population. 
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 Safety Population. 
7.8 PK Analysis 
One pre-dose sample at Baseline, Week 5, Week 9 and Study Completion/Early 
Withdrawal will be drawn for the determination of the plasma levels of CBD and 7-
OH-CBD.  The analysis of the PK data has been described in a separate PK SAP. 
All PK data will be listed. 
7.9 Interim Analysis 
No interim analysis will be performed for this study.  
8. Changes in Planned Analysis 
Not applicable. 
9. Data Issues 
Not applicable. 
INS011-16-085 Statistcal Analysis Plan Final 2018_07_09_signed | VV-TMF-113510 | 1.0
pproved
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Statistical Analysis Plan  
 
Sponsor Name: Insys Development Company, Inc. 
Sponsor Protocol ID: INS011-16-085 
 
Covance Study ID: 000000163564 
 
COVANCE INC. CONFIDENTIAL 
Document Date: 9 July 2018 
 
Page 31 of 39 
 
 
ST-AD-008 version 04 
 
 
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Statistical Analysis Plan  
 
Sponsor Name: Insys Development Company, Inc. 
Sponsor Protocol ID: INS011-16-085 
 
Covance Study ID: 000000163564 
 
COVANCE INC. CONFIDENTIAL 
Document Date: 9 July 2018 
 
Page 32 of 39 
 
 
ST-AD-008 version 04 
 
10. References 
 
de Lauzon, B., Romon, M., Deschamps, V., Lafay, L., Borys, J., Karlsson, J., et al. 
(2004). The Three-Factor Eating Questionnaire-R18 is Able to Distinguish 
among Different Eating Patterns in a General Population. Journal of Nutrition, 
134, 2372-2380. 
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.  
Karlsson, J., Persson, L.-O., Sjöström, L., & Sullivan, M. (2000). Psychometric 
properties and factor structure of the Three-Factor Eating Questionnaire 
(TFEQ) in obese men and women. Results from the Swedish Obese Subjects 
(SOS) study. International Journal of Obesity, 24, 1715-1725. 
Stone, A. A., Broderick, J. E., Junghaenel, D. U., Schneider, S., & Schwartz, J. E. 
(2016). PROMIS fatigue, pain intensity, pain tnterference, pain behavior, 
physical function, depression, anxiety, and anger scales demonstrate 
ecological validity. Journal of Clinical Epidemiology, 74, 194-206. 
Varni, J. W., Magnus, B., Stucky, B. D., Liu, Y., Quinn, H., Thissen, D., et al. 
(2014). Psychometric properties of the PROMIS® pediatric scales: precision, 
stability and comparison of different scoring and administration options. 
Quality of Life Research, 23(4), 1233-1243. 
 
 
 
INS011-16-085 Statistcal Analysis Plan Final 2018_07_09_signed | VV-TMF-113510 | 1.0
Approved
naire
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unghaenel, D. U.
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Journal of Clinic
App
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B., Stucky, B. D
Ap
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Statistical Analysis Plan  
 
Sponsor Name: Insys Development Company, Inc. 
Sponsor Protocol ID: INS011-16-085 
           Covance Study ID: 000000163564 
COVANCE INC. CONFIDENTIAL 
Document Date: 9 July 2018 
 
ST-AD-008 version 04 
18 September 2017 
Appendix A: Visit Schedule Chart 
 
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Statistical Analysis Plan  
 
Sponsor Name: Insys Development Company, Inc. 
Sponsor Protocol ID: INS011-16-085           
Covance Study ID: 000000163564 
 
COVANCE INC. CONFIDENTIAL 
Document Date: 9 July 2018 
 
Page 34 of 39 
 
ST-AD-008 version 04 
 
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Statistical Analysis Plan  
 
Sponsor Name: Insys Development Company, Inc. 
Sponsor Protocol ID: INS011-16-085           
Covance Study ID: 000000163564 
 
COVANCE INC. CONFIDENTIAL 
Document Date: 9 July 2018 
 
Page 35 of 39 
 
ST-AD-008 version 04 
 
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Statistical Analysis Plan  
 
Sponsor Name: Insys Development Company, Inc. 
Sponsor Protocol ID: INS011-16-085           
Covance Study ID: 000000163564 
 
COVANCE INC. CONFIDENTIAL 
Document Date: 9 July 2018 
 
Page 36 of 39 
 
ST-AD-008 version 04 
 
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Statistical Analysis Plan  
 
Sponsor Name: Insys Development Company, Inc. 
Sponsor Protocol ID: INS011-16-085 
 
Covance Study ID: 000000163564 
 
COVANCE INC. CONFIDENTIAL 
Document Date: 9 July 2018 
 
ST-AD-008 version 04 
18 September 2017 
Appendix B: Scoring of the TFEQ-R18 
The TFEQ-R18 assessment is comprised of 3 subscales:  
 
Cognitive restraint: items 2, 11, 12, 15, 16 and 18 
 
Uncontrolled eating: items 1, 4, 5, 7, 8, 9, 13, 14 and 17 
 
Emotional eating: items 3, 6 and 10 
The TFEQ-R18 responses are scored following the method described by de Lauzon, 
et al. (2004). Responses to items 1-17 are given a score between 1 and 4. For item 
18, scores ranging from 1-2 are coded as 1, scores ranging from 3-4 are coded 2, 
scores ranging from 5-6 are coded 3 and scores ranging from 7-8 are coded 4. 
The score for each subscale is obtained by summing the scores for each of the 
items included in that subscale.  The raw scores are then transformed so that the 
resulting scores range from 0 - 100.  The transformation is performed using the 
following formula: 
 
raw score - lowest possible raw score
possible score range
× 100 
 
In instances where patients do not answer all of the questions, scores for each 
subscale will be imputed provided the patient answered at least half of the items for 
that particular subscale.  The imputed score for that subscale is obtained by 
calculating the mean score for the items the patient responded to within that 
subscale and imputing that mean score for the items in that subscale with missing 
responses. 
Higher scores for each of the 3 subscales correspond to greater cognitive restraint, 
greater uncontrolled eating and greater emotional eating.  
 
 
INS011-16-085 Statistcal Analysis Plan Final 2018_07_09_signed | VV-TMF-113510 | 1.0
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Statistical Analysis Plan  
 
Sponsor Name: Insys Development Company, Inc. 
Sponsor Protocol ID: INS011-16-085           
Covance Study ID: 000000163564 
 
 
COVANCE INC. CONFIDENTIAL 
Document Date: 9 July 2018 
 
Page 38 of 39 
 
 
ST-AD-008 version 04 
Appendix C: Scoring of the PROMIS® Questionnaires 
The PROMIS® pediatric assessments are scored to yield standardized T-scores 
which have a mean of 50 and a standard deviation of 10 relative to the general 
population.   For example, if a patient has a T-score of 60 for fatigue, they are 
reporting fatigue that is one standard deviation higher than that of the general 
population average. 
Details on the validation of the assessments can be found in Varni, et al. (2014) 
and Stone, et al. (2016).  
The PROMIS® instruments offer a scoring service, the HealthMeasures Scoring 
Service (https://www.assessmentcenter.net/ac_scoringservice), which 
accommodates missing data in instances when patients fail to respond to all of the 
items for a  particular instrument.  The PROMIS® instruments are scored using 
item-level calibrations and the scoring service uses the responses to each item for 
each participant, as well as item response theory, to generate a standardized T-
score for each participant. Item response theory is a family of mathematical models 
which assigns unique values to each item based on how likely people with different 
levels of a particular measured trait are to endorse that item.   
Responses to each of the PROMIS® instruments (life satisfaction, positive affect, 
physical activity and fatigue) will be read into the HealthMeasures Scoring Service 
tool in a .csv file where the first column is the patient ID (PIN), the second column 
is the assessment number (Assmnt, e.g. 1 for first assessment and 2 for second 
assessment) and the remaining columns correspond to the unique question 
numbers for that particular instrument. 
The scoring service then produces a spreadsheet with the T-scores that will be used 
for the analyses of the PROMIS® outcomes. 
 
 
 
INS011-16-085 Statistcal Analysis Plan Final 2018_07_09_signed | VV-TMF-113510 | 1.0
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instrumen
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pp
e) will be read in
he first column is
pp
he first column is
ber (Assmnt, e.g
App
ber (Assmnt, e.g
remaining colum
Ap
remaining colum
A
rticular instrum
Ap
rticular instrum
 produc
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 produc
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Statistical Analysis Plan  
 
Sponsor Name: Insys Development Company, Inc. 
Sponsor Protocol ID: INS011-16-085 
 
 
Covance Study ID: 000000163564 
COVANCE INC. CONFIDENTIAL 
Document Date: 9 July 2018 
 
ST-AD-008 version 04 
18 September 2017 
The formats for the .csv files for each instrument are given below. 
Life Satisfaction (PROMIS Ped SF v1.0 – Life Satisfaction 8a): 
PIN 
Assmnt 
SWB_LS_046R1 SWB_LS_048R1 SWB_LS_051R1 SWB_LS_019R1 SWB_LS_004R1 SWB_LS_003R1 SWB_LS_006R1 SWB_LS_055R1 
xxxxxx 
x 
x 
x 
x 
x 
x 
x 
x 
x 
xxxxxx 
x 
x 
x 
x 
x 
x 
x 
x 
x 
xxxxxx 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Positive Affect (PROMIS Ped SF v1.0 – Positive Affect 8a): 
PIN
Assmnt 
SWB_P_027R1 
SWB_P_025R1 
SWB_P_026R1 
SWB_P_029R1 
SWB_P_037R1 
SWB_P_049R1 
SWB_P_001R1 
SWB_P_004R1 
xxxxxx 
x 
x 
x 
x 
x 
x 
x 
x 
x 
xxxxxx 
x 
x 
x 
x 
x 
x 
x 
x 
x 
xxxxxx 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Physical Activity (PROMIS Ped SF v1.0 – Physical Activity 8a): 
 
PIN
Assmnt 
PAC_M_009R1 PAC_M_105R1 PAC_M_002R1 PAC_M_008R1 PAC_M_010R1 PAC_M_011R1 PAC_M_114R1 PAC_M_134R1 
xxxxxx 
x 
x 
x 
x 
x 
x 
x 
x 
x 
xxxxxx 
x 
x 
x 
x 
x 
x 
x 
x 
x 
xxxxxx 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Fatigue (PROMIS Ped SF v2.0 – Fatigue 10a): 
PIN
Assmnt 
4239aR2r 
4212R1r 
4213R1r 
2876R1r 
4221R1r 
4220R1r 
4210R2r 
4241R2r 
4208bR2r 
4196R1r 
xxxxxx 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
xxxxxx 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
xxxxxx 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
INS011-16-085 Statistcal Analysis Plan Final 2018_07_09_signed | VV-TMF-113510 | 1.0
Approved
a):
a):
SWB_P_029R1
ve
SWB_P_029R1
SWB_P
e
SWB_P
x
x
x
r
x
x
x
pr
x
v1.0
Ap
v1.0 –
p
– Physical Activ
Appr
Physical Activ
_105R1
A
_105R1
PAC_M_002R1
App
PAC_M_002R1
x
A
x
x
A
x
x
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