Clinical trial NCT05098509
Conditions: Prader-Willi Syndrome
Sponsor: Radius Pharmaceuticals, Inc.
Start date: 2022-04-13; Completion date: 2022-10-31
Enrollment: 4 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This was a study investigating RAD011 in participants diagnosed with Prader-Willi Syndrome (PWS). The primary objective of the Phase 2 part of this study was to assess the safety and tolerability of multiple dose levels of RAD011 in order to select 1 or 2 dose level(s) for further evaluation in the Phase 3 part of the study. In Phase 3, the primary objective was to assess the effect of RAD011 on hyperphagia-related behavior in participants with PWS.

Detailed description:

Arms: arm 1: Participants were administered 40 mg/kg of RAD011 orally daily with food. arm 2: Participants were administered 20 mg/kg of RAD011 orally daily with food. arm 3: Participants were administered 10 mg/kg of RAD011 orally daily with food. arm 4: Participants were administered a placebo matching to RAD011, orally daily with food.
Interventions: intervention 1: RAD011 intervention 2: Placebo
Intervention descriptions: intervention 1: Cannabidiol Oral Solution (containing synthetic cannabidiol) intervention 2: Matching Placebo for RAD011

Protocol documents:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL 
A Phase 2/3, Randomized, Double-Blind, Placebo-Controlled Study of RAD011 
(Cannabidiol Oral Solution) for the Treatment of Patients with Prader-Willi Syndrome 
This study will be conducted according to the protocol and in compliance with Good Clinical Practice, the 
ethical principles stated in the Declaration of Helsinki, and other applicable regulatory requirements 
Protocol 
Number: 
Protocol SCOUT-015 
Version Number: 
5.0 
IND Number: 
136,374 
Study Sponsor: 
Radius Pharmaceuticals, Inc. (Radius) 
22 Boston Wharf Rd 
7th Floor 
Boston, MA 02210 
Tel: 
; Fax: 
 
Contract 
Research 
Organization 
CTI Clinical Trial & Consulting 
100 E. RiverCenter Blvd. 
Covington, KY 41011 
Key Sponsor  
Contact 
 
 
Medical Monitor 
 
CTI Clinical Trial & Consulting 
Phone: 
  
Fax: 
 
Email: 
 
Version number 
Version date 
5.0 
10 March 2022 
TITLE PAGE 
Disclosure Statement 
This document contains information that is confidential and proprietary to Radius Pharmaceuticals, 
Incorporated (Radius). This information is being provided to you solely for the purpose of evaluation 
and/or conducting a clinical study for Radius. You may disclose the contents of this document only to 
study personnel under your supervision and/or to your Institutional Review Board(s) or Ethics 
Committee(s) who need to know the contents for this purpose and who have been advised on the 
confidential nature of the document. 
NCT #: NCT05098509


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1. 
RADIUS SIGNATURE PAGE  
 
Title 
A Phase 2/3, Randomized, Double-Blind, Placebo-Controlled Study of 
RAD011 (Cannabidiol Oral Solution) for the Treatment of Patients with Prader-
Willi Syndrome 
Protocol Number 
SCOUT-015 
Version Number 
5.0 
Version Date 
10 March 2022 
Amendment 
4 
 
The design of this study as outlined by this protocol has been reviewed and approved by: 
 
 
 
Date  
11-Mar-2022 | 11:12:50 AM EST


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PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
I hereby acknowledge that I have received and read the Investigator’s Brochure, read the 
protocol, appendices, and accessory materials related to Study SCOUT-015, Version 5.0 dated 
10 March 2022, and agree to the following: 
 To conduct this study as described by the protocol and any accessory materials 
 To protect the rights, safety, and welfare of the patients under my care 
 To provide oversight to all personnel to whom study activities have been delegated 
 To control all investigational products provided by the Sponsor and maintain records of 
the disposition of those products 
To conduct the study in accordance with all applicable local and national regulations, the 
requirements of the ethics committee of record for my clinical site, and Good Clinical Practices 
as outlined by ICH E6(R2). 
 To obtain approval for the protocol and all written materials provided to patients prior to 
initiating the study at my site 
 To obtain informed consent – and updated consent in the event of new information or 
amendments – from all patients enrolled at my study site prior to initiating any study 
specific procedures or administering investigational products to those patients 
 To maintain records of each patient’s participation and all data required by the protocol 
 To ensure that the confidential information contained in this document will not be used 
for any purpose other than the evaluation or conduct of the clinical investigation without 
the prior written consent of Radius.  
 
Principal Investigator 
Printed Name: 
Title: 
Institution Address: 
Phone: 
Signature: 
Date (DD Month YYYY): 
 


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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
1. 
RADIUS SIGNATURE PAGE ....................................................................................2 
PRINCIPAL INVESTIGATOR SIGNATURE PAGE ...................................................................3 
TABLE OF CONTENTS .................................................................................................................4 
LIST OF TABLES .........................................................................................................................10 
LIST OF FIGURES .......................................................................................................................11 
LIST OF ABBREVIATIONS ........................................................................................................12 
2. 
SYNOPSIS .................................................................................................................16 
3. 
INTRODUCTION ......................................................................................................26 
3.1. 
Background .................................................................................................................26 
3.1.1. 
Overview of Prader-Willi Syndrome ..........................................................................26 
3.1.2. 
The Endocannabinoid System and Appetite Regulation ............................................27 
3.1.3. 
Overview of RAD011 .................................................................................................28 
3.1.4. 
Summary of Nonclinical Experience ..........................................................................28 
3.1.5. 
Summary of Clinical Experience ................................................................................30 
3.1.5.1 
Phase 2 Study (INS011-16-085) .................................................................................30 
3.1.5.2 
Phase 2 Study Open-Label Extension (INS011-17-115) ............................................31 
3.1.6. 
Pharmacokinetic Experience ......................................................................................31 
3.1.7. 
Potential for Pharmacokinetic Drug-Drug Interactions ..............................................32 
3.2. 
Study Rationale ...........................................................................................................33 
3.2.1. 
Risk-Benefit of RAD011 in Patients with Prader-Willi Syndrome ............................33 
3.2.2. 
Summary of Potential Risks .......................................................................................33 
3.2.2.1 
Potential for Testicular Toxicity .................................................................................33 
3.2.2.2 
Expected Adverse Events ...........................................................................................33 
3.2.3. 
Summary of Potential Benefits ...................................................................................34 
4. 
STUDY OBJECTIVES ..............................................................................................34 
4.1. 
Objectives ...................................................................................................................34 
4.1.1. 
Phase 2 Part .................................................................................................................34 
4.1.1.1 
Primary Objective .......................................................................................................34 
4.1.2. 
Phase 3 Part .................................................................................................................34 
4.1.2.1 
Primary Objective .......................................................................................................34 


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4.1.2.2 
Secondary Objectives .................................................................................................35 
4.1.2.3 
Other Objectives .........................................................................................................35 
5. 
INVESTIGATIONAL PLAN .....................................................................................35 
5.1. 
Overall Study Design ..................................................................................................35 
5.2. 
Scientific Rationale for Study Design ........................................................................42 
5.3. 
Number of Patients .....................................................................................................43 
5.4. 
Replacement of Patients .............................................................................................43 
5.5. 
Investigational Products ..............................................................................................43 
5.6. 
RAD011 Dose Rationale ............................................................................................44 
5.7. 
Dose Reduction Criteria .............................................................................................45 
5.7.1. 
Dose Level (mg/kg/day) Reduction for Tolerability During the Dose 
Escalation Period ........................................................................................................45 
5.7.2. 
Dose Level (mg/kg/day) Reduction for Tolerability During the Maintenance 
Period (Weeks 10 to 34) .............................................................................................45 
5.7.3. 
Total Daily Dose (mg/day) Adjustment for Weight Change During the 
Maintenance Period ....................................................................................................45 
5.8. 
Study Visits and Procedures .......................................................................................46 
5.8.1. 
Study Windows ...........................................................................................................46 
5.8.2. 
Screening Period (3 weeks, Visit 1 [Weeks -3 to 0]) .................................................46 
5.8.2.1 
Visit 1 (Weeks -3 to 0) ................................................................................................46 
5.8.2.2 
Documentation of Genetic Diagnosis of Prader-Willi Syndrome ..............................47 
5.8.3. 
Tolerability Period (6 weeks, Visits 2 to 5 [Weeks 1 to 7]) .......................................47 
5.8.3.1 
Visits 2 to 4 (Weeks 1 to 6) ........................................................................................47 
5.8.4. 
Dose Escalation Period (3 weeks, Visits 5 to 7 [Weeks 7 to 10]) ..............................48 
5.8.4.1 
Visit 5 (End of Screening, Beginning of Dose Escalation Period, Week 7) ..............48 
5.8.4.2 
Visits 6 and 7 (Weeks 8 and 9) ...................................................................................50 
5.8.5. 
Maintenance Period (24 Weeks, Visits 8 to 14 [Weeks 10 to 34]) .............................50 
5.8.5.1 
Visits 8, 10, 12, and 14 (Weeks 10, 19, 27, and 34) ...................................................50 
5.8.5.2 
Visits 9, 11, and 13 (Weeks 15, 24, and 30) ...............................................................51 
5.8.6. 
Taper and Follow-Up Periods (4 Weeks, Visits 14 to 16 [Weeks 34 to 38]) .............52 
5.9. 
Adjustments of Study Assessments for Visits Impacted by COVID-19 ....................52 
5.9.1. 
Schedule of Assessments for the Screening, Tolerability, Dose Escalation, 
Maintenance, Taper, and Follow-Up Periods .............................................................53 
5.10. 
Criteria for Study or Site Termination ........................................................................60 


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6. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................60 
6.1. 
Patient Inclusion Criteria ............................................................................................60 
6.2. 
Patient Exclusion Criteria ...........................................................................................61 
6.3. 
Patient Withdrawal Criteria ........................................................................................62 
6.3.1. 
Discontinuation of Investigational Product ................................................................63 
6.3.2. 
Drug-Induced Liver Injury .........................................................................................63 
6.3.3. 
Patient Withdrawal .....................................................................................................64 
6.3.4. 
Lost to Follow-Up.......................................................................................................65 
6.4. 
Evaluation of Eligibility at the End of the Screening and Tolerability Periods .........65 
6.4.1. 
Screening Period .........................................................................................................65 
6.4.2. 
Tolerability Period ......................................................................................................65 
7. 
TREATMENT OF PATIENTS ..................................................................................66 
7.1. 
Investigational Product Administration ......................................................................66 
7.1.1. 
Tapering of Investigational Product for Patients Entering the Taper and 
Follow-Up Periods ......................................................................................................66 
7.2. 
Concomitant Medications ...........................................................................................66 
7.2.1. 
RAD011 Drug-Drug Interactions Overview ..............................................................66 
7.3. 
RAD011 Precautions ..................................................................................................67 
7.4. 
Treatment Adherence ..................................................................................................67 
7.5. 
Randomization and Blinding ......................................................................................67 
7.5.1. 
Breaking the Blind ......................................................................................................68 
7.6. 
Treatment After the End of the Study .........................................................................68 
8. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................68 
8.1. 
Description of Investigational Product .......................................................................68 
8.2. 
Study Drug Packaging and Labeling ..........................................................................69 
8.3. 
Study Drug Storage .....................................................................................................69 
8.4. 
Study Drug Preparation ..............................................................................................70 
8.5. 
Study Drug Accountability .........................................................................................70 
8.6. 
Study Drug Handling and Disposal ............................................................................70 
9. 
ASSESSMENT OF EFFICACY ................................................................................70 
9.1. 
Primary Efficacy Endpoint (HQ-CT Questionnaire) ..................................................70 
9.2. 
Secondary Efficacy Endpoints ....................................................................................71 
9.2.1. 
Change in Irritability (Irritability subscale of the ABC Questionnaire) .....................71 


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9.2.2. 
Change in Clinician Global Impression of Change in Hyperphagia (CGI-C 
Questionnaire) .............................................................................................................71 
9.2.3. 
Change in Clinician Global Impression of Severity of Hyperphagia (CGI-S 
Questionnaire) .............................................................................................................71 
9.3. 
Other Endpoints ..........................................................................................................72 
9.3.1. 
Change in Caregiver Global Impression of Change in Hyperphagia, Change 
in Caregiver Global Impression of Severity of Hyperphagia, Change in 
Caregiver Global Impression of Change in Irritability  ..............................................72 
9.3.2. 
Change in Overall Behavior (ABC) ...........................................................................72 
9.3.3. 
Change in Sleep (ESS-CHAD Questionnaire) ...........................................................72 
9.3.4. 
Change in Body Mass Index and Weight ...................................................................72 
9.3.5. 
Change in Skin-Picking Behavior ..............................................................................72 
9.3.6. 
Change in Muscle/Fat Composition (DEXA Scan) ....................................................72 
9.4. 
Pharmacokinetic Endpoints ........................................................................................73 
9.5. 
Biomarkers assessments (Phase 3 exploratory) ..........................................................73 
10. 
ASSESSMENT OF SAFETY .....................................................................................73 
10.1. 
Safety Parameters .......................................................................................................73 
10.1.1. 
Demographics and Medical/Surgical/Seizure History ................................................73 
10.1.1.1 
Seizure Patient Impression .........................................................................................73 
10.1.2. 
Vital Signs ..................................................................................................................73 
10.1.3. 
Weight and Height ......................................................................................................73 
10.1.4. 
Physical Examination .................................................................................................74 
10.1.5. 
Electrocardiogram .......................................................................................................74 
10.1.6. 
Columbia Suicide-Severity Rating Scale ....................................................................74 
10.1.7. 
Laboratory Assessments .............................................................................................74 
10.1.8. 
Hepatic Function Testing ............................................................................................74 
10.1.9. 
Estimated Glomerular Filtration Rate .........................................................................75 
10.1.10. 
Urine Drug Screen ......................................................................................................75 
10.1.11. 
Follicle-Stimulating Hormone ....................................................................................75 
10.1.12. 
Pregnancy Screen ........................................................................................................75 
10.1.13. 
Pharmacokinetic Sampling .........................................................................................75 
10.1.14. 
Food Diary ..................................................................................................................77 
10.2. 
Adverse and Serious Adverse Events .........................................................................77 
10.2.1. 
Evaluation of Safety ...................................................................................................77 


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10.2.1.1 
Definition of Adverse Events .....................................................................................78 
10.2.1.2 
Determination of Clinical Significance Must be Made by the Investigator. ..............79 
10.2.1.3 
Definition of a Serious Adverse Event .......................................................................79 
10.2.1.4 
Unexpected Adverse Events .......................................................................................80 
10.2.1.5 
Adverse Events of Special Interest (AESI) ................................................................81 
10.2.2. 
Collection and Recording of Adverse Events .............................................................81 
10.2.3. 
Follow-up of Adverse Events .....................................................................................82 
10.2.4. 
Intensity ......................................................................................................................82 
10.2.5. 
Relationship to Study Drug ........................................................................................83 
10.2.6. 
Study Drug Action taken ............................................................................................83 
10.2.7. 
Adverse Event Outcome .............................................................................................84 
10.2.8. 
Abuse, Misuse, and Overdose ....................................................................................84 
10.2.9. 
Pregnancy ...................................................................................................................85 
10.2.10. 
Study Completion and Post-Investigational Product Treatment ................................85 
10.3. 
Reporting of Serious Adverse Events .........................................................................85 
10.4. 
Data Monitoring Committee .......................................................................................86 
11. 
STATISTICAL CONSIDERATIONS .......................................................................86 
11.1. 
Sample Size Determination ........................................................................................87 
11.2. 
Hyperphagia Questionnaire for Clinical Trials and Prader-Willi Syndrome 
Mean Score .................................................................................................................88 
11.3. 
Change in Hyperphagia Questionnaire for Clinical Trials During Tolerability 
Period Response Evaluation .......................................................................................88 
11.4. 
Statistical Analyses .....................................................................................................88 
11.4.1. 
Populations for Analyses ............................................................................................88 
11.4.2. 
Primary Endpoint ........................................................................................................89 
11.4.3. 
Secondary and Other Endpoints .................................................................................89 
11.4.4. 
Pharmacokinetic Analyses ..........................................................................................90 
11.4.5. 
Safety Analyses ..........................................................................................................90 
12. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................90 
12.1. 
Study Monitoring ........................................................................................................90 
12.2. 
Audits and Inspections ................................................................................................91 
12.3. 
Institutional Review Board and Independent Ethics Committee ................................91 
13. 
ETHICAL AND REGULATORY CONSIDERATIONS ..........................................91 


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13.1. 
Ethics Review .............................................................................................................91 
13.2. 
Ethical Conduct of the Study ......................................................................................92 
13.3. 
Patient Confidentiality ................................................................................................92 
13.4. 
Written Informed Consent/Assent ..............................................................................92 
13.5. 
Financial Disclosure ...................................................................................................93 
14. 
DATA HANDLING AND RECORDKEEPING .......................................................93 
14.1. 
Case Report Form Completion ...................................................................................93 
14.2. 
Inspection of Records .................................................................................................93 
14.3. 
Retention of Records ..................................................................................................94 
14.4. 
Substantial Amendments to the Protocol ....................................................................94 
15. 
PUBLICATION POLICY ..........................................................................................94 
16. 
DISSEMINATION OF STUDY DATA ....................................................................94 
17. 
LIST OF REFERENCES ............................................................................................95 
18. 
APPENDICES ..........................................................................................................100 
APPENDIX 1. SUMMARY OF PROTOCOL CHANGES .....................................................101 
APPENDIX 2. EVALUATION OF SEIZURE HISTORY AND SEIZURE PATIENT 
HISTORY .................................................................................................................108 
Medical History Questionnaire ....................................................................................................108 
Seizure Patient Impression ...........................................................................................................108 
 
 
 
 
 


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LIST OF TABLES 
Table 1: 
Pivotal Toxicology Studies and Safety Margins Over Clinical Exposures at 
10, 20 and 40 mg/kg Twice Daily ..............................................................................29 
Table 2: 
Demographic Data from Phase 2 Study of RAD011 in Prader-Willi 
Syndrome ....................................................................................................................31 
Table 3: 
Pharmacokinetic Parameters of RAD011 (Medium Chain Triglyceride 
Formulation) Administered to Healthy Subjects in a Fed State .................................32 
Table 4: 
Dose Escalation Regimen ...........................................................................................44 
Table 5: 
Dose Level (mg/kg/day) Reduction for Tolerability during the Maintenance 
Period ..........................................................................................................................45 
Table 6: 
Schedule of Assessments – Screening and Tolerability Periods ................................53 
Table 7: 
Schedule of Assessments – Dose Escalation, Maintenance, Taper, and 
Follow-Up Periods ......................................................................................................56 
Table 8: 
Investigational Product ...............................................................................................69 
Table 9: 
Laboratory Analytes ...................................................................................................76 
Table 10: Intensity Classification and Definition of Adverse Events .........................................83 
Table 11: Classification for Study Drug Action Taken with Regards to an Adverse 
Event ...........................................................................................................................84 
Table 12: Classifications for Outcome of an Adverse Event ......................................................84 
Table 13: Summary of Protocol Changes .................................................................................101 
 


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LIST OF FIGURES 
Figure 1: 
Study Design of Phase 2 Study of RAD011 in Prader-Willi Syndrome ....................30 
Figure 2: 
Study Design Schematic – Phase 2 of the Study  .......................................................40 
Figure 3: 
Study Design Schematic – Phase 3 of the Study ........................................................41 
 


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LIST OF ABBREVIATIONS 
 
Acronym 
Definition 
µM 
micromolar 
5-HT1A 
5-hydroxytryptamine 
ABC 
Aberrant Behavior Checklist 
ABC-I 
Aberrant Behavior Checklist – Irritability subscale 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
AUC0-inf 
area under the curve from time 0 to infinity 
BMI 
body mass index 
BP 
blood pressure 
BUN 
blood urea nitrogen 
CaGI-C 
Caregiver Global Impression of Change 
CaGI-S 
Caregiver Global Impression of Severity 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CBC 
complete blood count 
CBD 
cannabidiol  
CB-1  
endocannabinoid receptor 
CFR 
Code of Federal Regulations 
CGI-C 
Clinical Global Impression of Change  
CGI-S 
Clinical Global Impression of Severity  
CI 
confidence interval 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
Cmax 
maximal concentration 
CLB 
clobazam  
COS 
cannabidiol oral solution 
CRO 
contract research organization 
CYP 
cytochrome P450 
D 
day 


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Acronym 
Definition 
DEXA 
dual-energy X-ray absorptiometry 
DMC 
Data Monitoring Committee 
DNA 
deoxyribonucleic acid  
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
EOS 
end of study 
ESS-CHAD 
Epworth Sleepiness Scale for Children and Adolescents 
EU 
European Union 
F 
female 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
FU 
follow-up 
GCP 
Good Clinical Practices 
GGT 
gamma-glutamyl transferase 
GH 
growth hormone 
GMP 
Good Manufacturing Practices 
HbA1c 
glycosylated hemoglobin 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HQ-CT 
Hyperphagia Questionnaire for Clinical Trials 
HR 
heart rate 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Institutional Ethics Committee 
INR 
international normalized ratio 
IP 
Investigational Product 
IRB 
Institutional Review Board 
ISF 
Investigator Site File 
ITT 
intent-to-treat 


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Acronym 
Definition 
IUD 
intrauterine device 
IUS 
intrauterine hormone-releasing system 
LTE 
long-term extension 
M 
male 
MCT 
medium chain triglycerides 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
mITT 
modified intent-to-treat 
MMRM 
mixed model for repeated measures 
nCLB 
norclobazam 
NOAEL 
no-observed-adverse-effect-level 
OTcF 
QT interval corrected with Fridericia’s Formula 
PCP 
phencyclidine 
PK 
pharmacokinetic 
PP 
per protocol 
PPARγ 
peroxisome proliferator-activated receptor γ 
PT 
prothrombin time 
PWS 
Prader-Willi Syndrome 
RAND 
randomization 
RBC 
red blood cells 
RDW  
red cell distribution width 
RR 
respiratory rate 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SOC 
System Organ Class 
SOP 
standard operating procedures 
SUSAR 
suspected unexpected serious adverse reaction 
T1/2 
half-life 
Tmax 
time to maximal concentration 
TBD 
to be determined 


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Acronym 
Definition 
TEAE 
treatment-emergent adverse event 
THC 
tetrahydrocannabinol  
TMF 
Trial Master File 
UGT 
5'-diphospho-glucuronosyltransferase 
ULN 
upper limit of normal 
US 
United States 
W 
week 
WBC 
white blood cells 
WOCBP 
women of childbearing potential 


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2. 
SYNOPSIS 
Name of Sponsor/Company: Radius Pharmaceuticals, Inc. (Radius) 
Name of Finished Drug: RAD011 (Cannabidiol Oral Solution) 100 mg/mL 
Name of Active Ingredient: Cannabidiol (CBD)  
Title of Study: A Phase 2/3, Randomized, Double-Blind, Placebo Controlled Study of RAD011 
(Cannabidiol Oral Solution) for the Treatment of Patients with Prader-Willi Syndrome 
Phase of Development: Phase 2/3 
Study Center(s): Approximately 38 sites (20 NA, 18 non-NA) 
Number of Patients Randomized (Planned): Ages 12 to 65 years (Phases 2 and 3): ~191 patients 
 
Ages 8 to <12 years (Phase 3): ~30 patients  
Objective: The primary objective of the Phase 2 part of this study is to assess the safety and 
tolerability of multiple doses levels of RAD011 in order to select 1 or 2 dose level(s) to further 
evaluate in the Phase 3 part of the study. The primary objective of the Phase 3 part of this study is to 
assess the effect of RAD011 on hyperphagia-related behavior in patients with Prader-Willi Syndrome 
(PWS). 
Design and Methodology:  
This is a seamless Phase 2/3, double-blind, randomized, placebo-controlled clinical study in patients 
diagnosed with PWS. Following consent (or legal guardian consent and patient assent as appropriate), 
patients will be screened for eligibility to participate in this study.  
The study will consist of six similar periods for the Phase 2 and Phase 3 parts of the study: 
1. Screening Period (3 weeks) 
a. Review of eligibility prior to proceeding to the Tolerability Period 
2. Tolerability Period (6 weeks) 
a. Determination of randomization eligibility † 
3. Dose Escalation Period (3 weeks) 
4. Maintenance Period (24 weeks) ‡ 
5. Taper Period (2 weeks)‡ 
6. Follow-Up Period (2 weeks)‡. 
†Patients who do not meet criteria for randomization eligibility will not be randomized to study 
SCOUT-015.  
‡All patients participating in the Maintenance Period may be offered participation in the long-term 
extension study (SCOUT-016). Patients who do not enroll in the SCOUT-016 study will have their 
investigational product (RAD011 or placebo [IP]) tapered off over 2 weeks (14 days), followed by a 
2-week (14-day) safety follow-up. 
After approximately 45 patients complete 4 weeks of the Maintenance Period of the Phase 2 part of 
the study, the Data Monitoring Committee (DMC) will meet to review safety and tolerability data and 
to recommend 1 or 2 RAD011 dose level(s) for evaluation in the Phase 3 part of the study.  
Screening Period (3 weeks, Visit 1 [Weeks -3 to 0]): 
Phase 2 and Phase 3 Parts of the study 
All patients with a signed informed consent/assent will undergo Screening assessments. Screening 
assessments will include a full medical history and physical exam, a review of documentation of PWS 


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diagnosis, an electrocardiogram (ECG), laboratory and questionnaire assessments (including the 
HQ-CT). To be eligible for the Tolerability Period, patients must meet the following criterion:  
• 
Mean HQ-CT score ≥13 
Patients not meeting Inclusion/Exclusion criteria for entry in the study will not be eligible for the 
study and may not be screened again. Caregivers will be required to either assist the patient or 
complete the questionnaires on behalf of the patient. The same caregiver should be available 
throughout the study to help in completing the questionnaires for purposes of consistency. 
 
Tolerability Period (6 weeks, Visits 2 to 5 [Weeks 1 to 7]) 
Phase 2 and Phase 3 of the study 
Patients who meet the eligibility criteria will undergo a 6-week Tolerability Period. During this 
Period, all patients will receive placebo at a dose of 0.1 mL/kg/day to assess tolerability of the 
formulation without active CBD and give patients time to adjust to study procedures and future IP 
administration. Patients unable to tolerate the 0.1 mL/kg/day dose level will be withdrawn from the 
study. 
Patients/caregivers will also complete serial HQ-CT questionnaires at 2-week intervals. At the end of 
the 6-week Tolerability Period and prior to randomization, patient randomization eligibility based on 
tolerability and HQ-CT scores will be evaluated. To be eligible for randomization, patients must meet 
both of the following criteria:  
• 
Mean HQ-CT score ≥13 obtained from prior HQ-CT scores 
• 
Decrease from the Tolerability Period to the Screening Period in HQ-CT score ≤7 points 
Patients who do not meet criteria for randomization eligibility will not be randomized to study 
SCOUT-015.  
 
Randomization (Visit 5 [Week 7]) 
Phase 2 of the study 
Following the Tolerability Period, patients meeting randomization eligibility criteria will be 
randomized to 1 of 6 groups (3 active and 3 placebo with the ratio of 2:2:2:1:1:1): low dose 
(10 mg/kg/day [0.1 mL/kg/day]) RAD011, mid dose (20 mg/kg/day [0.2 mL/kg/day]) RAD011, high 
dose (40 mg/kg/day [0.4 mL/kg/day]) RAD011, low volume (0.1 mL/kg/day) placebo, mid volume 
(0.2 mL/kg/day) placebo, or high volume (0.4 mL/kg/day) placebo divided twice daily. 
Phase 3 of the study 
Following review of the Phase 2 safety and tolerability data by the DMC, 1 or 2 dose level(s) will be 
recommended for further development and assessment in the Phase 3 part of the study. 
 
Dose Escalation Period (3 weeks, Visits 5 to 7 [Weeks 7 to 9]) 
Phase 2 of the study 
After completing the Screening and Tolerability Periods, all randomized patients will be initiated on 
the IP 10 mg/kg/day (0.1 mL/kg/day) for a period of 1 week at Visit 5 (Week 7). Patients randomized 
to low dose or low volume IP (10 mg/kg/day) will continue at a dose of 10 mg/kg/day 
(0.1 mL/kg/day) until the end of Visit 7 (Week 9). Patients randomized to mid dose or mid volume IP 
(20 mg/kg/day) will have their dose increased to 20 mg/kg/day (0.2 mL/kg/day) at Visit 6 (Week 8) 
and will continue at that dose until the end of Visit 7 (Week 9). Patients randomized to high dose or 
high volume IP (40 mg/kg/day) will have their dose increased to 20 mg/kg/day (0.2 mL/kg/day) at 
Visit 6 (Week 8) and to 40 mg/kg/day (0.4 mL/kg/day) at Visit 7 (Week 9).  


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The Investigator, or designee, will contact patients/caregivers by phone call, video call, email, or 
other remote means of communication at Visits 6 (Week 8) and 7 (Week 9) to determine if the 
patient’s dose may be escalated to the next dose level. Dose reductions will not be allowed during the 
Dose Escalation Period. Patients unable to tolerate their assigned dose level(s) during the Dose 
Escalation Period will be withdrawn from the study. 
Phase 3 of the study 
After completing the Screening and Tolerability Periods, all patients will be initiated on 10 mg/kg/day 
IP (0.1 mL/kg/day) for a period of 1 week at Visit 5 (Week 7). Dose escalation will occur as in the 
Phase 2 of the study, according to the DMC-recommended Phase 3 dose level(s).  
The Investigator, or designee, will contact patients/caregivers by phone call, video call, email, or 
other remote means of communication at Visits 6 (Week 8) and 7 (Week 9) to determine if the 
patient’s dose may be escalated to the next dose level. Dose reductions will not be allowed during the 
Dose Escalation Period. If a patient cannot be escalated to the next dose level, the patient will be 
discontinued from the study. 
 
Maintenance Period (24 weeks, Visits 8 to 14 [Weeks 10 to 34]) 
Phase 2 and Phase 3 of the study 
After completing the 3-week Dose Escalation Period, patients will enter the 24-week Maintenance 
Period. 
Some patients may have their dose adjusted based on tolerability during the Maintenance Period. 
After completion of the Maintenance Period, patients may be offered the opportunity to enroll in the 
long-term extension study (SCOUT-016). Patients who do not elect to enroll will be tapered off the 
IP. 
 
Taper Period (14 days, Visit 14 [Week 34]) and Follow-up Period (14 days, Visits 15 and 16 [Weeks 
36 and 38]) 
Patients who do not enroll in the long-term extension study (SCOUT-016) will have their IP tapered 
off over 14 days according to the following schedule: the IP should be decreased by 50% during the 
first 7 days, followed by an additional 50% during the following 7 days, and then discontinued. The 
taper schedule may be modified at the discretion of the Investigator but cannot be extended to a total 
period lasting more than 14 days. A final follow up will be conducted 2 weeks after the last dose of IP 
for patients who are tapered off. 
 
A schematic representation of the Phase 2 and Phase 3 of the study is provided in the figures below:  


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Study Design Schematic – Phase 2 of the Study 
 
* Patients assigned to placebo will include low, mid, and high volume placebo to match active drug and will be 
combined for statistical analysis. 
 
Study Design Schematic – Phase 3 of the Study  
*Patients assigned to placebo will be further broken down to achieve balanced exposure between placebo and 
RAD011 patients. The number of doses to be studied will be determined by the DMC’s safety review.  
Diagnosis and Main Criteria for Inclusion:  
Inclusion criteria: 
To be eligible for this study, patients must meet all of the following inclusion criteria: 
1. Presence of a parent/legal guardian that is able to consent for their participation. 
Parent/caregiver/legal guardian can complete the required assessments throughout the study. 
Patient Consent/Assent will be obtained if the patient is 8 years of age or older and has the 
mental capacity to understand and sign a written consent/assent form and/or give verbal 
assent 
2. Males and females between: 
a. Phase 2: 12 and 65 years of age (inclusive) at time of consent/assent 
b. Phase 3: 8 and 65 years of age (inclusive) at time of consent/assent 
3. Documentation of genetically confirmed PWS diagnosis 


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4. If a caregiver helps in completing the HQ-CT or other questionnaires, the same caregiver is 
available to complete the questionnaire throughout the duration of the study 
5. 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 up to 4 weeks after the last dose of 
RAD011 or placebo: 
a. Double barrier method (i.e., condom plus occlusive cap (diaphragm or cervical/vault 
caps), condom or occlusive cap plus spermicide) 
b. Hormonal methods such as oral, implantable, injectable, vaginal ring, or transdermal 
contraceptives at a stable dose for a minimum of 1 full cycle (based on the patient’s 
usual menstrual cycle period) before IP administration 
c. Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS) 
d. If not using hormonal contraceptives or IUD or IUS, then all male partners 
throughout the study must have been vasectomized and have received medical 
assessment of the surgical success 
6. If male, is vasectomized and has received medical assessment of the surgical success or 
agrees to use an approved method of contraception (double barrier method as described in 
Inclusion Criterion 5, female partner’s use of an IUD or IUS [in place at least 12 weeks prior 
to dosing], oral contraceptives or female partner who is surgically sterile or 2 years 
postmenopausal) and agrees to use this method for 4 weeks after last administration of 
RAD011 or placebo 
7. If receiving growth hormone (GH), psychotropic therapy, metabolic treatments that could 
affect appetite (including metformin), and other treatment including thyroid hormone, must 
be on the same medication and stable dose for at least 90 days prior to consent/assent 
8. Any non-medical interventions (eg, counseling, behavior modification) should be stable for at 
least 90 days prior to consent/assent 
9. HQ-CT eligibility automatically calculated in the electronic data capture (EDC) system: 
a. Visit 2 
i. Patients with a mean HQ-CT score ≥13 (from Visit 1 and Visit 2) will be 
eligible to continue in the Tolerability Period 
b. Visit 5 
i. Patients with a mean HQ-CT score ≥13 (from Visit 3, Visit 4 and Visit 5) 
will be eligible for randomization, and  
ii. Patients with a decrease in HQ-CT score (from Tolerability Period to the 
Screening Period) ≤7 will be eligible for randomization 
Exclusion criteria: 
Patients meeting any of the following criteria will be excluded from the study: 
1. Hypersensitivity or intolerance to CBD, or any other excipients used in the RAD011 
preparation 
2. Known use of cannabis or cannabinoid containing products (including topical products) 
within 90 days prior to consent/assent 
3. History of chronic liver disease, such as cirrhosis or chronic hepatitis due to any cause 
4. Positive urine test for drugs of abuse, including tetrahydrocannabinol (THC), or known 
history of drug, alcohol, or substance abuse 


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5. Use of prescription or over-the-counter weight loss agents within 90 days prior to 
consent/assent 
6. Implementation of new food restrictions or environmental restrictions within 90 days of 
consent/assent 
7. Any significant comorbid condition or disease: 
a. Respiratory disease, heart disease, or psychiatric disorder which in the opinion of the 
Investigator would preclude the patient from participating or 
b. Uncontrolled type 1 or type 2 diabetes as determined by the Investigator or 
c. Clinically significant ECG abnormalities or other evidence of clinically significant 
heart disease as determined by the Investigator or 
d. Uncontrolled sleep apnea as determined by the Investigator or 
e. Neutropenia with neutrophil counts <1,000 /microL (grade 3 or grade 4 neutropenia 
as defined by CTCAE v5.0) or 
f. History or presence of gastrointestinal disorders or any other condition known to 
interfere with the absorption, distribution, metabolism, or excretion of drugs taken 
orally as determined by the Investigator 
8. QT interval corrected for heart rate (HR) according to Fridericia's formula (QTcF) meeting 
the following criteria: 
a. For males and females aged 8 to <20 years: QTcF >439 msec  
b. For males aged 20 to 65 years: QTcF >450 msec  
c. For females aged 20 to 65 years; QTcF >470 msec 
9. At consent/assent, patients with age-matched hypertensive levels of systolic and/or diastolic 
blood pressure may be excluded at the Investigator’s discretion if deemed to be in the best 
interest of the patient. 
10. Pregnant (determined by a positive serum pregnancy test) or lactating female 
11. Unwillingness or inability to follow the procedures outlined in the protocol 
12. Estimated glomerular filtration rate <30 mL/min/1.73m2 or protein/creatinine ratio ≥0.4 
13. Bilirubin >1.5 × upper limit of normal (ULN), or aspartate aminotransferase (AST), alanine 
aminotransferase (ALT) >3 × ULN, or international normalized ratio (INR) >1.5 × ULN 
14. 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 
15. Other genetic, hormonal, chromosomal, cognitive, or behavioral impairment 
16. If living in a group home, patient spends less than 25 waking hours with their caregiver per 
week.  
17. Significant risk of committing suicide based on history, routine psychiatric examination, or 
based on the Investigator's judgment 
18. Participation in any other study involving an investigational product or device within 4 weeks 
or 5 half-lives (whichever is longer) of consent/assent or longer as required by local 
regulations 
Investigational Product, Dosage, and Mode of Administration:  
RAD011 (Cannabidiol Oral Solution) 100 mg/mL, 10 mg/kg/day to 40 mg/kg/day, administered 
orally in two divided doses 
Duration of Study Participation:  
37 to 40 weeks 


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Reference Therapy, Dosage, and Mode of Administration:  
Placebo (medium-chain triglyceride vehicle used in RAD011 formulation) 
Criteria for Evaluation:  
Primary objective 
The primary objective of the Phase 2 of this study is to assess the safety and tolerability of multiple 
doses levels of RAD011 in order to select 1 or 2 dose level(s) to further evaluate in the Phase 3 of the 
study. 
The primary objective of the Phase 3 of this study is to assess the effect of RAD011 on 
hyperphagia-related behavior in patients with PWS. 
Secondary objectives 
The secondary objectives are to assess the following: 
• 
Effect of RAD011 on irritability 
• 
Effect of RAD011 on Clinician Global Impression of Change (CGI-C) in Hyperphagia 
• 
Effect of RAD011 on Clinician Global Impression of Severity (CGI-S) of Hyperphagia  
• 
Safety and tolerability of RAD011 
Other objectives 
The other objectives of this study are to assess the: 
• 
Effect of RAD011 on Caregiver Global Impression of Change (CaGI-C) in Hyperphagia 
• 
Effect of RAD011 on Caregiver Global Impression of Severity (CaGI-S) of Hyperphagia  
• 
Effect of RAD011 on Caregiver Global Impression of Change (CaGI-C) in Irritability 
• 
Effect of RAD011 on overall behavior 
• 
Effect of RAD011 on sleep 
• 
Effect of RAD011 on body mass index (BMI) and weight 
• 
Effect of RAD011 on skin-picking behavior 
• 
Effect of RAD011 on total muscle/fat composition (performed at selected United States [US] 
sites) 
Endpoints: 
Primary efficacy endpoint: 
• 
Change in HQ-CT scores from Baseline through End of Study/Week 34 Visit for RAD011 
compared to placebo 
Secondary efficacy endpoints: 
• 
Change in PWS-associated Irritability from Baseline through End of Study/Week 34 Visit 
using the Aberrant Behavior Checklist (ABC) questionnaire – Irritability subscale (ABC-I) 
for RAD011 compared to placebo 
• 
Change in hyperphagia as defined by the Clinician Global Impression of Change (CGI-C) in 
Hyperphagia through End of Study/Week 34 Visit 
• 
Change in Clinician Global Impression of Severity (CGI-S) of Hyperphagia from Baseline 
through End of Study/Week 34 Visit 
Other endpoints: 
• 
Change in hyperphagia as defined by the Caregiver Global Impression of Change (CaGI-C) 
in Hyperphagia response through End of Study/Week 34 Visit for RAD011 compared to 
placebo 


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• 
Change in Caregiver Global Impression of Severity (CaGI-S) of Hyperphagia from Baseline 
through End of Study/Week 34 Visit 
• 
Change in irritability as defined by the Caregiver Global Impression of Change (CaGI-C) in 
Irritability through End of Study/Week 34 Visit 
• 
Change in overall behavior from Baseline through End of Study/Week 34 Visit using the 
ABC questionnaire subscales for RAD011 compared to placebo  
• 
Change in sleep from Baseline through End of Study/Week 34 Visit using the Epworth 
Sleepiness Scale for Children and Adolescents (ESS-CHAD) for RAD011 compared to 
placebo 
• 
Change in weight and BMI from Baseline through End of Study/Week 34 for RAD011 
compared to placebo 
• 
Change in skin picking behavior using the Skin Picking Questionnaire from Baseline through 
End of Study/Week 34 for RAD011 compared to placebo 
• 
Change in muscle/fat composition using a dual-energy X-ray absorptiometry (DEXA) scan 
from Randomization through End of Study/Week 34 for RAD011 compared to placebo 
Pharmacokinetic endpoints 
Throughout the study, plasma samples will be collected to establish the PK profile of CBD and 
2 metabolites, 7-OH-CBD and 7-COOH-CBD in patients with PWS. Furthermore, an exposure 
response analysis using CBD and 7-OH-CBD concentrations as well as a population PK model will 
be derived from the data. 
 
Safety and Tolerability Endpoints: 
Treatment-emergent adverse events, vital signs (blood pressure, HR, body temperature, respiratory 
rate, oxygen saturation), ECGs, and laboratory tests (chemistry, hematology, coagulation, and 
urinalysis)  
Sample Size and Power Calculation: 
DMC Recommendation of Two RAD011 Doses 
For the primary efficacy analysis, a total of 150 patients (50 patients per treatment group) aged 12 to 
65 years will provide 90% power to compare each dose group vs. placebo with a two-sided alpha of 
0.025. The study is powered to detect a difference in the HQ-CT from Baseline to Week 34 of 
5 points with a standard deviation of 7 points. The 0.05 Type 1 error is split equally between groups 
(low dose and high dose). The low- and high-volume placebo groups will be combined for all 
comparisons to placebo. Assuming a 15% post-randomization dropout rate, approximately 
176 patients (~59 patients per treatment group) will be evaluated for the primary efficacy analysis.  
Thus, if the DMC recommends two RAD011 doses for Phase 3 of the study, approximately a total of 
191 patients (target approximately 200 patients) aged 12 to 65 years will be randomized in this study. 
The 191 reflects 176 patients required for primary efficacy analysis plus 15 patients randomized in 
the Phase 2 part of the study to the dose not selected for the Phase 3 part of the study. 
Assuming a 20% pre-randomization eligibility failure rate (including HQ-CT eligibility criteria), 
approximately 240 patients will be enrolled in the Screening Period. An additional 10 patients per 
treatment group aged 8 to <12 years may be allowed to participate in the Phase 3 part of the study and 
will be randomized in a way to obtain a balanced number of patients on RAD011 (at dose levels 
recommended by the DMC) and placebo. Patients aged 8 to <12 will not be included in the primary 
efficacy analysis.  
 


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DMC Recommendation of One RAD011 Dose 
For the primary efficacy analysis, a total of 100 patients (50 patients per treatment group) aged 12 to 
65 years will provide 94% power to compare active vs. placebo with a two-sided alpha of 0.05. The 
study is powered to detect a difference in the HQ-CT from Baseline to Week 34 of 5 points with a 
standard deviation of 7 points. Assuming a 15% post-randomization dropout rate, approximately 
118 patients (~59 patients per treatment group) will be evaluated for the primary efficacy analysis.  
Thus, if the DMC recommends one RAD011 dose for the Phase 3 part of the study, approximately 
148 patients (target approximately 150 patients) aged 12 to 65 years will be randomized in this study. 
The 148 reflects 118 patients required for primary efficacy analysis plus 30 patients randomized in 
the Phase 2 part of the study to the two doses not selected for the Phase 3 part of the study. 
Assuming a 20% pre-randomization eligibility failure rate (including HQ-CT eligibility criteria), 
approximately 185 patients will be enrolled into the Screening Period. An additional 10 patients per 
treatment group aged 8 to <12 years may be allowed to participate in the Phase 3 part of the study and 
will be randomized in a way to obtain a balanced number of patients on RAD011 (at dose level 
recommended by the DMC) and placebo. Patients aged 8 to <12 will not be included in the primary 
efficacy analysis. 
Statistical Methods: 
Analysis Populations: 
The following patient populations will be defined for analysis: 
 
Safety Population: the Safety Population will include all randomized patients who were 
treated with at least one dose of IP 
 
Intent-to-Treat (ITT) Population: the ITT Population will include all randomized patients 
 
Modified ITT (mITT) Population: the mITT Population will include all patients aged ≥12 
years who were randomized, received at least 1 dose of IP, had at least 1 post-randomization 
HQ-CT questionnaire completed, and were randomized to receive the dose level(s) 
recommended for development in the Phase 3 part of the study, including patients in the 
Phase 2 part of the study who received the chosen dose level(s) 
 
Per Protocol (PP) Population: the PP Population will include all patients aged ≥12 years who 
were randomized, received at least 1 dose of IP, completed Week 34 without significant 
protocol deviations that were prospectively defined to impact efficacy (see SAP) and received 
the dose level(s) recommended for development in the Phase 3 part of the study, including 
patients in Phase 2 of the study who received the chosen dose level(s) 
 
Pharmacokinetic (PK) Evaluable Population: the PK Evaluable Population will include all 
patients who received at least 1 dose of IP and underwent at least 1 PK sample collection.  
 
Efficacy Analyses: 
The primary endpoint, change in HQ-CT score from Baseline to End of Study (Week 34), will be 
analyzed for the mITT population based on the treatment policy estimand using a mixed model for 
repeated measures (MMRM) with change in HQ-CT score as the response variable and randomization 
assignment, Baseline HQ-CT score and stratification variables (age [≥16 or <16 years] at 
randomization and GH treatment at randomization [yes/no]) and time × treatment interaction as fixed 
effects. Patient will be included as a random effect with an unstructured covariance matrix. A 
multiple imputation will be used for missing data. Baseline will be defined as the mean HQ-CT score 
(Visit 1, Visit 2). 
 


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DMC Recommendation of two RAD011 Doses 
The primary comparison will be mean change in HQ-CT as calculated via least square means 
comparing RAD011 low dose vs. placebo and RAD011 high dose vs. placebo at Week 34. Low dose 
and high dose groups will be compared to placebo at the two-sided 0.025 level so overall Type 1 error 
is maintained at two-sided 0.05 level. 
 
DMC Recommendation of one RAD011 Dose 
The primary comparison will be mean change in HQ-CT as calculated via least square means 
comparing RAD011 vs. placebo at Week 34. RAD011 will be compared to placebo at the two-
sided 0.05 level. 
Pharmacokinetic Analyses: 
All PK analyses will be described in the pharmacokinetic analysis plan prior to performing statistical 
analyses. A pharmacodynamic analysis may be completed to evaluate exposure with efficacy and 
safety. 
 
Safety Analyses: 
The Safety Population will be used for all safety assessments. Safety assessments will be based on 
adverse events (AEs), Columbia-Suicide Severity Rating Scale (C-SSRS), vital signs, ECGs, and 
laboratory assessments. All analyses of safety will be described in the Statistical Analysis Plan (SAP). 
All safety assessments will be descriptive, and no inferential statistics will be performed. All data 
listings will be provided for protocol specified safety data. The Medical Dictionary for Regulatory 
Activities will be used to classify all AEs with respect to System Organ Class (SOC) and preferred 
term. Adverse event summaries will include only treatment-emergent adverse events (TEAEs) by 
treatment group. Assessment of severity and relationship will also be presented. Adverse events 
leading to study discontinuation will also be summarized by SOC, Preferred Term, severity, and 
relationship. 
The C-SSRS will be used to evaluate suicidal ideation and intensity of ideation. Ideation and intensity 
will be grouped by categories, with separate groupings for the Baseline/Screening and the “Since Last 
Visit” questionnaires. 
Clinical laboratory and vital signs will be summarized for the Safety Population for observed values 
and change from Baseline. Shifts from Baseline according to normal range criteria will also be 
presented for all patients in the Safety Population. 
 


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3. 
INTRODUCTION 
3.1. 
Background 
3.1.1. 
Overview of 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, 1997; 
McAllister, 2011). It is caused by the absent expression of paternally inherited genes in the PWS 
region on chromosome 15q11-q13 (Ledbetter, 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 (Elena, 2012). Obesity is the 
major cause of death in adults with PWS (Laurance, 1981).  
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 (GH) deficiency is reported to occur in 40% to 100% of the 
population with PWS (Griggs, 2015) and is commonly treated with GH (Angulo, 2015). 
Behavioral disorders include obsessive compulsive behaviors such as skin picking, hoarding, 
redoing, and repetitive speech (Griggs, 2015).  
However, it is the appetite behavior classified as hyperphagia in PWS that is the most life 
threatening (Dykens, 2007; Griggs, 2015). Until recently, no patient survived over the age of 50 
due to morbid obesity and its related complications (Aycan, 2014). The mortality rate in patients 
with PWS is 6 times higher than patients with other intellectual disabilities (Einfeld, 2006) and 
mortality in patients not treated with GH was estimated to be 3% per year between the ages of 6 
and 56 compared to the general population yearly mortality of 0.13% below 55 years.  
Hyperphagic behaviors can also be dangerous in persons who are relatively slim, with increased 
risks of death due to choking while sneaking food, and gastric perforations after consuming more 
food than usual (Dykens, 2007). Approximately 8% of deaths in individuals with PWS was 
reported due to choking (Stevenson, 2007). PWS patients are also known to eat discarded 
(contaminated) food and items that are not intended for human consumption such as pet food, or 
non-food items, such as paint or paper (Griggs, 2015). 
The treatment of PWS is currently based on treating the symptoms of the disorder as they arise. 
Growth hormone deficiency is present in almost all children and many adults with PWS. In 
multiple studies, GH has been found to be beneficial for those with PWS (Passone, 2020). In 
June of 2000, GH was approved by Food and Drug Administration (FDA) in the United States 
(US) for use in patients with PWS. Growth hormone is effective in increasing height, decreasing 
body fat, increasing muscle mass, improving weight distribution, increasing stamina, and 
increasing bone mineral density (Goldstone, 2008; McCandless, 2011). 
Despite GH treatment, many challenging symptoms associated with PWS remain difficult to 
treat. The inability to control food intake is often the biggest obstacle keeping those with PWS 
from living independently. Although the hyperphagia has been well identified and there exists a 
well-validated hyperphagia questionnaire (Hyperphagia Questionnaire for Clinical Trials 
[HQ-CT]), there is no current therapeutic that effectively controls hyperphagia (Dykens, 2007). 
Therefore, strict environmental control and constant supervision are the only means to prevent 


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life-threatening overeating and extreme obesity at present. A well-balanced diet, along with 
careful control of the environment to minimize uncontrolled access to food is the main 
recommendation provided by the Foundation for PWS Research (https://www.fpwr.org/prader-
willi-syndrome-diagnosis-treatments). 
The greatest unmet medical need in PWS is to address hyperphagia, low energy expenditure, and 
the progression to obesity, morbid obesity, diabetes and their resulting cardiovascular 
complications. Prader-Willi Syndrome-related anxiety, irritability and other behavioral issues are 
also among the unmet needs of individuals with PWS. Safe and efficacious therapies are needed 
to address hyperphagia and other prominent symptoms in patients with PWS. 
3.1.2. 
The Endocannabinoid System and Appetite Regulation 
The endocannabinoid system appears to be critically involved in the regulation of appetite, body 
weight, metabolism, hypothalamic-pituitary-adrenal axis, and reward brain circuitry in both 
animals and humans (Edwards, 2016; Parsons, 2015). The 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, 2003; Liu, 2005; Osei-Hyiaman, 2008). Several 
nonclinical studies have suggested an effect of cannabidiol (CBD) on appetite, such as a decrease 
in food intake without a decrease in water intake (Farrimond, 2012; Silveira Filho, 1981). In 
addition, CBD has been shown to block the hyperphagia associated with CB1 and 
5-hydroxytryptamine (5-HT1A) agonists (Scopinho, 2011) and cause weight loss via its activity 
on peripheral CB2 receptors (Ignatowska-Jankowska, 2011). Furthermore, CBD may reduce the 
resultant hyperphagia associated with sweet food (Silveira Filho, 1981).  
Cannabidiol is a low-affinity antagonist of CB1, and may also modulate CB1 receptor signaling 
through its inhibition of the metabolism of the endogenous cannabinoid, anandamide (Ibeas Bih, 
2015; Laprairie, 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, 1981). In addition, CBD has been shown to diminish 
daily food consumption without affecting daily water intake (Wierucka-Rybak, 2014) as well as 
inhibited hyperphagia induced by CB1 receptor or 5-HT1A serotonin receptor agonists, 
suggesting a role for CBD as a regulator of food intake. 
In vitro studies with CBD and some other cannabinoids used in high concentrations have also 
been shown to activate peroxisome proliferator-activated receptor γ (PPARγ), possibly through 
direct binding. Peroxisome proliferator-activated receptor γ involvement may contribute to the 
weight control mechanism of CBD (Booz, 2011). 
Clinically, while no studies have investigated the effect of CBD in patients with PWS, a 
multi-center clinical study of plant-derived CBD in pediatric epilepsy reported appetite 
suppression in 19% of patients (Devinsky, 2016). Because of the well-characterized orexigenic 
activity of tetrahydrocannabinol (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, 
2006). Rimonabant demonstrated suppression of appetite (Seely, 2012) and was subsequently 
approved in the European Union (EU) for the treatment of obesity; however, psychiatric side 
effects led to the drugs withdrawal from the market. The demonstrated effect of the cannabinoid 


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system in appetite control supports the development of CBD for the treatment of hyperphagia in 
patients with PWS. 
Based on experience of the effect of modifying the endocannabinoid system via the CB1 receptor 
in animals (Riedel, 2009) and in obese humans (rimonabant) (Pi-Sunyer, 2006), the significant 
decrease in risk of obesity in chronic cannabis users despite the known effect of THC to 
stimulate the appetite (Le Strat, 2011; Penner, 2013), the significant reported adverse events 
(AE) of weight loss and appetite suppression in epilepsy patients treated with a plant-derived 
CBD (EPIDIOLEX®) (Devinsky, 2016), and the dose-dependent effect on weight seen in the 
long-term safety study INS011-14-030 (Section 3.1.5), Radius is studying RAD011 in patients 
with PWS for the treatment of hyperphagia. 
3.1.3. 
Overview of RAD011 
Cannabidiol is a non-psychoactive physiologically relevant phytocannabinoid isomer of THC. 
RAD011 is a synthetic CBD formulated as a 100 mg/mL oral solution with medium chain 
triglycerides (MCT) that overcomes the need for ethanol to solubilize CBD in an oral solution 
presentation. 
3.1.4. 
Summary of Nonclinical Experience 
Nonclinical information is available from RAD011 studies, and the label of the FDA approved 
botanical extract CBD product, EPIDIOLEX. 
The completed RAD011 toxicology studies include chronic toxicology studies, 6-month rat and 
9-month monkey with 28-day recovery phases, juvenile rat toxicology studies, dose range-
finding and 6-week with 5-month recovery, and a full battery of genotoxicity studies (Ames Test, 
in vitro micronucleus and in vivo micronucleus assays). The genotoxicity studies were negative 
and the chronic and juvenile toxicology studies demonstrated that RAD011 was well-tolerated 
with sufficient safety margins over the anticipated clinical exposures (Table 1). 
In summary, the RAD011 nonclinical program supports chronic dosing in PWS patients at doses 
of 20 mg/kg/day and 40 mg/kg/day. 
The EPIDIOLEX US Package summarizes the nonclinical findings on in vitro metabolism, 
reproductive, developmental, fertility, and abuse-related toxicology studies. 
Cannabidiol is metabolized in the liver and the gut (primarily in the liver) by cytochrome P450 
(CYP) 2C19 and CYP3A4 enzymes, and uridine 5'-diphospho-glucuronosyltransferase 
(UGT) 1A7, UGT1A9, and UGT2B7 isoforms. Cannabidiol has the potential for inactivation of 
CYP450 isozymes and therefore has the potential to induce drug‑ drug interactions. 
Oral administration of CBD to pregnant rats throughout the period of organogenesis resulted in 
embryofetal mortality at the highest dose (250 mg/kg/day) tested. There were no other drug-
related maternal or developmental effects. Oral administration of CBD (125 mg/kg/day) to 
pregnant rabbits throughout organogenesis resulted in decreased fetal body weights and 
increased fetal structural variations at the highest dose (125 mg/kg/day) tested, which was also 
associated with maternal toxicity.  


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Table 1: 
Pivotal Toxicology Studies and Safety Margins Over Clinical Exposures at 10, 20 and 40 mg/kg Twice Daily 
Nonclinical experience 
Study 
Study 
Number 
Species/ 
Strain 
NOAEL 
(mg/kg/day) 
Cmax 
(ng/mL) 
AUC 
(hr*ng/mL) 
Safety 
Margin: Cmax 
(fold) 
Safety 
Margin: AUC 
(fold) 
Route of 
Administration 
6-month rat 
2508-001-
003 
Rat/Sprague Dawley 
70 
2683M 
8403F 
32492M 
77407F 
13-46 
20-95 
Gavage 
9-month 
monkey 
2508-001-
001 
Monkey/ 
Cynomolgus 
100 
374M 
140F 
6093M 
1723F 
0.6-2 
1.4-7 
Gavage 
6-week 
juvenile rat 
20096193 
Rat 
140 
2610M 
3640F 
34300M 
50500F 
6-30 
13-87 
Gavage 
Clinical Study Experience 
Study Number 
Population 
Total Daily Dosea 
(mg/kg/day) 
Cmax 
(ng/mL) 
AUC 
(hr*ng/mL) 
 
 
Route of 
Administration 
INS011-14-029 
Pediatric patients with 
treatment-resistant 
seizures 
10 
119.6 
581.6 
-- 
-- 
Oral solution 
20 
220.0 
1098 
-- 
-- 
40 
426.8 
2708 
-- 
-- 
Abbreviations: AUC = area under the curve; Cmax = maximal concentration; F = female; M = male; NOAEL = no-observed-adverse-effect-level. 
a Total daily doses were divided in approximately 2 equal doses administered twice daily. 


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When CBD was orally administered to rats throughout pregnancy and lactation, decreased 
growth, delayed sexual maturation, neurobehavioral changes (decreased activity), and adverse 
effects on male reproductive organ development (small testes in adult offspring) and fertility 
were observed in the offspring at the mid (150 mg/kg/day) and high (250 mg/kg/day) dose. 
These effects occurred in the absence of maternal toxicity. 
Oral administration of CBD (evaluated in doses up to 250 mg/kg/day) to male and female rats, 
prior to and throughout mating and continuing in females during early gestation, produced no 
adverse effects on fertility. 
Animal abuse-related studies show that CBD does not produce cannabinoid-like behavioral 
responses, including generalization to THC in a drug discrimination study; and animal self-
administration studies, which suggests that it does not produce rewarding effects. 
3.1.5. 
Summary of Clinical Experience 
Two clinical studies have been initiated with RAD011 in patients with PWS. Both were 
terminated early due to reasons other than safety. 
3.1.5.1 
Phase 2 Study (INS011-16-085) 
A Phase 2 study of the compound entitled, “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” was initiated by a previous Sponsor 
(Insys Therapeutics) with the study design provided in Figure 1. 
 
Figure 1: 
Study Design of Phase 2 Study of RAD011 in Prader-Willi Syndrome 
 
Abbreviation: CBD = cannabidiol. 
The study planned to enroll 66 patients but was terminated prematurely due to the closure of 
Insys Therapeutics, under circumstances unrelated to the study with 7 patients enrolled. Of these 
7 patients, 4 patients received RAD011 and 3 received placebo. The baseline demographics of 
the population are described in Table 2. 


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Table 2: 
Demographic Data from Phase 2 Study of RAD011 in Prader-Willi 
Syndrome 
 
Cannabidiol 
N=4 
Placebo 
N=3 
Median age (years) 
(range) 
14.5 
(11.0 to 16.0) 
12 
(8.0 to 15.5) 
Male:Female 
2:2 
2:1 
Baseline Weight (kg) 
Median (range) 
88.4 
(47.9 to 112.4) 
56.7 
(45.5 to 109.7) 
Growth Hormone Use 
2 (50%) 
2 (67%) 
 
The primary endpoint of this Phase 2 study was to assess the efficacy of Cannabidiol Oral 
Solution (COS) on hyperphagia related behavior in patients with PWS as measured by the 
change in HQ-CT scale. A secondary endpoint assessed the effect of COS on weight in patients 
with PWS.  
Despite the abbreviated nature of the Phase 2 study, mean duration of exposure was 9-weeks, the 
data are directionally supportive of reducing hyperphagia with an approximate 6.5-point 
reduction in the HQ-CT scale. Treatment with RAD011 was also well tolerated with the most 
frequent AEs of diarrhea, rash, and abdominal cramping. 
3.1.5.2 
Phase 2 Study Open-Label Extension (INS011-17-115) 
A Phase 2 study entitled, “A Multicenter, Open Label Study to Assess the Long Term Safety of 
Pharmaceutical Grade Synthetic Cannabidiol Oral Solution in Patients with Prader-Willi 
Syndrome” was initiated by a previous Sponsor (Insys Therapeutics). Patients had to have 
completed INS011-16-085 to be eligible. Approximately 66 male and female patients aged 8 to 
17 years, inclusive, with a genetically confirmed diagnosis of PWS were planned to be enrolled 
in the study. All patients were to receive COS at 40 mg/kg/day, divided into two daily doses with 
standard meals, for up to 48 weeks.  
This study was terminated prematurely due to the closure of Insys Therapeutics, under 
circumstances unrelated to the study, with 2 patients enrolled. Each patient experienced at least 
one AE. Both patients experienced diarrhea and one patient experienced a seizure (also occurred 
on placebo in study INS011-16-085). 
No deaths, serious adverse events (SAE), or discontinuations were reported during the study. No 
clinically meaningful changes in laboratory, vital sign, or electrocardiogram (ECG) parameters 
were observed during the study. 
3.1.6. 
Pharmacokinetic Experience 
Three studies have characterized the pharmacokinetics (PK) and additional details on the PK 
studies can be found in the Investigator’s Brochure. Overall conclusions from the PK studies 
include: 


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 Cannabidiol Oral Solution, 100 mg/mL is a suitable formulation for use in clinical 
investigations of CBD, ensuring better, faster, and less variable systemic exposure with 
food. Exposure is expected to be dose proportional- under the fed state (enabling 
comparison between two formulations). Administration of cannabidiol under fed 
conditions may be optimal to achieve consistent exposure in patients. A PK study was 
completed in healthy volunteers in a fed state with the 100 mg/mL formulation. 
Parameters for time to maximal concentration (Tmax), Cmax, AUC, and half-life (T1/2) are 
provided in Table 3. 
 Steady state- levels of CBD appeared to be attained with approximately 2 to 6 days of 
repeated dosing, with median CBD time to Cmax of 2 to 3 hours for pediatric patients. 
Repeated twice daily administrations of COS resulted in highly variable systemic 
exposures of CBD with some accumulation (approximately 3- to 4-fold). There were no 
clear trends for age related differences in CBD peak exposures; however, exposures in 
infants tended to be lower than older age groups. 
 
Table 3: 
Pharmacokinetic Parameters of RAD011 (Medium Chain Triglyceride 
Formulation) Administered to Healthy Subjects in a Fed State 
Parameter 
Cannabidiol 100 mg/kg MCT in Fed State 
 
N 
Mean 
SD 
CV% 
Tmax (h)a 
8 
6.00 (2.5,12.0) 
Cmax (ng/mL) 
8 
878 
322 
36.7 
AUC0-inf 
(h*ng/mL)b 
5 
4360 
933 
21.4 
T1/2 (h)b 
5 
14.0 
1.30 
9.3 
Abbreviations: AUC0-inf = area under the curve from time 0 to infinity; Cmax = maximal concentration; 
MCT = medium chain triglycerides; T1/2 = half-life; Tmax = time to maximal concentration. 
a Tmax presented as median (min, max). 
b λ2 acceptance criteria was not met for some subjects. 
 
3.1.7. 
Potential for Pharmacokinetic Drug-Drug Interactions 
In vitro studies using human liver microsomes or recombinant CYP enzymes have shown CBD 
to be a potent mechanism-based inhibitor of human CYP1A1 and can inhibit to a lesser extent 
(by >15-fold) CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 
independent of metabolism (Yamaori, 2014). The half maximal inhibitory concentration values 
for CBD using recombinant human CYP1A1 was 0.671 μM without pre-incubation and 0.0678 
μM with a 20-minute pre-incubation. It was proposed that the methyl resorcinol structure in CBD 
may be required for CYP1A1 inactivation. 
Clinically, CBD (600 mg/day PO; i.e. 10 mg/kg/day) given for 5 to 12 days yielded a 36% 
decrease in the clearance and a 35% decrease in the volume of distribution of hexobarbital in 
normal patients (Benowitz, 1980). Cannabidiol inhibited barbiturate metabolism to an extent 


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substantially greater than that observed for ∆9-THC. In another clinical study, oral dosing with 
CBD (1500 mg or 25 mg/kg) to patients did not significantly affect the total clearance, volume of 
distribution, or terminal elimination half-lives of ∆9-THC metabolites (Hunt, 1981). 
In a clinical report of 13 patients with refractory epilepsy receiving co-administration of 
clobazam (CLB) and EPIDIOLEX, the mean (± standard deviation [SD]) increase in CLB levels 
was 60 ± 80% (95% confidence interval (CI) [-2-91%]) at 4 weeks, the mean increase in 
norclobazam (nCLB), the major metabolite, was 500 ± 300% (95% CI [+90-610%]) at 4 weeks 
(Geffrey, 2015). Since CLB is metabolized by CYP3A4 to nCLB which is then metabolized by 
CYP2C19, this confirms the in vitro studies. 
After analysis of the PK data from INS011-14-029, approximately 50% of the patients enrolled 
were also receiving CLB. In these patients, co-administration of CBD and CLB resulted in 
increased levels of CBD (by approximately 2.5-fold), as well as increased levels of CLB and 
nCLB (by approximately 2.5-fold), compared with patients not taking CLB. 
As expected, based on the findings above, because CBD is metabolized by CYP3A4 and 
CYP2C19, it may act as a competitive inhibitor and increase levels of other drugs also 
metabolized by these enzymes. Therefore, care should be taken when CBD is given in 
conjunction with other drugs metabolized by the CYP system. 
3.2. 
Study Rationale 
The rationale for development of RAD011 for the treatment of hyperphagia in patients with PWS 
is based on preliminary evidence from a prematurely terminated Phase 2 study as well as reports 
of appetite reduction and weight loss as an AE in epilepsy studies with RAD011 and other 
cannabidiol products.  
In addition, in the open label study of EPIDIOLEX for the treatment of refractory seizures in 
patients aged between 1 and 30 years old (Devinsky, 2016), 19% of patients experienced AE of 
decreased appetite, second only to somnolence (25%).  
3.2.1. 
Risk-Benefit of RAD011 in Patients with Prader-Willi Syndrome 
3.2.2. 
Summary of Potential Risks 
3.2.2.1 
Potential for Testicular Toxicity 
The effects of CBD and cannabinoids on male fertility are summarized in more detail in the 
Investigator’s Brochure.  
3.2.2.2 
Expected Adverse Events 
The most common AEs in study INS011-14-029 were somnolence and diarrhea. In 85% of the 
cases of somnolence observed, there was concomitant use of CLB, resulting in elevated levels. 
These events all resolved with reduction of dose of CLB and/or CBD. Thus, caution should be 
used in patients taking CLB. 
One SAE occurred in Study INS011-14-029 of an infant developing a thrombosis associated 
with a peripherally inserted central catheter. The thrombosis resolved without incident with 
treatment. While this SAE was felt to be not related to cannabidiol, given the increased risk for 


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thrombosis in PWS patients, CBD should be used with caution in the presence of an indwelling 
catheter. 
Review of the final safety data from the recently completed long-term safety study 
INS011-14-030 has not identified any safety signals not seen with INS011-14-029. 
Two adult patients in Study INS011-15-043 developed self-limited, uncomplicated mild/moderate 
neutropenia that was possibly related to the use of cannabidiol. Caution should be taken in 
patients at risk for neutropenia from other causes, such as concomitant medications. No patient 
on the MCT-based formulation at 100 mg/mL reported an AE in the study INS016-093. 
3.2.3. 
Summary of Potential Benefits 
The appetite behavior classified as hyperphagia in PWS is the most life threatening (Dykens, 
2007; Griggs, 2015) and until recently, no patient lived over the age of 50 due to morbid obesity 
and its related complications (Aycan, 2014). The mortality rate in patients with PWS is six times 
higher than patients with other intellectual disabilities (Einfeld, 2006) and mortality in patients 
not treated with GH 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. The results from the abbreviated 
Phase 2 study in individuals with PWS, along with the clinical findings of a decrease in appetite 
and weight loss across other indications, and the nonclinical evidence, supports targeting the 
endocannabinoid system with cannabidiol to treat hyperphagia. Radius believes that this 
evidence along with the safety and tolerability of the synthetic COS, RAD011, further supports 
exploration of RAD011 in individuals with PWS to address hyperphagia and alter the subsequent 
morbid obesity and related complications. 
4. 
STUDY OBJECTIVES 
4.1. 
Objectives 
4.1.1. 
Phase 2 Part 
4.1.1.1 
Primary Objective 
The primary objective of the Phase 2 part of this study is to assess the safety and tolerability of 
multiple doses levels of RAD011 in order to select 1 or 2 dose level(s) to further evaluate in the 
Phase 3 part of the study. 
4.1.2. 
Phase 3 Part 
4.1.2.1 
Primary Objective 
The primary objective* of the Phase 3 part of this study is to assess the effect of RAD011 on 
hyperphagia-related behavior in patients with PWS. 
*The Phase 3 part of the study will include all patients from the Phase 2 part of the study who were treated with 
dose level(s) selected for development in the Phase 3 part of the study. 


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4.1.2.2 
Secondary Objectives 
The secondary objectives* are to assess the following: 
 Effect of RAD011 on irritability 
 Effect of RAD011 on Clinician Global Impression of Change (CGI-C) in Hyperphagia 
 Effect of RAD011 on Clinician Global Impression of Severity (CGI-S) of Hyperphagia  
 Safety and tolerability of RAD011. 
*The Phase 3 part of the study will include all patients from the Phase 2 part of the study who were treated with 
dose level(s) selected for development in the Phase 3 part of the study. 
4.1.2.3 
Other Objectives  
The other objectives* of this study are to assess the: 
 Effect of RAD011 on Caregiver Global Impression of Change (CaGI-C) in Hyperphagia 
 Effect of RAD011 on Caregiver Global Impression of Severity (CaGI-S) of Hyperphagia  
 Effect of RAD011 on Caregiver Global Impression of Change (CaGI-C) in Irritability  
 Effect of RAD011 on overall behavior 
 Effect of RAD011 on sleep 
 Effect of RAD011 on body mass index (BMI) and weight 
 Effect of RAD011 on skin-picking behavior 
 Effect of RAD011 on total muscle/fat composition (performed at selected US sites). 
*The Phase 3 part of the study will include all patients from the Phase 2 part of the study who were treated with 
dose level(s) selected for development in the Phase 3 part of the study. 
5. 
INVESTIGATIONAL PLAN 
5.1. 
Overall Study Design 
This is a seamless Phase 2/3, double-blind, randomized, placebo-controlled clinical study in 
patients diagnosed with PWS. Following consent (or legal guardian consent and patient assent as 
appropriate), patients will be screened for eligibility to participate in this study.  
The Phase 2 portion of the study is to assess safety and tolerability. Dose safety and tolerability 
decisions will be made in Phase 2. All patients randomized to placebo and to the selected dose 
level(s) for Phase 3 evaluation will be included in the Phase 3 efficacy evaluation. 
The study will consist of the following six similar periods for Phase 2 and Phase 3 of the study: 
1. Screening Period (3 weeks) 
a. Review of eligibility prior to proceeding to the Tolerability Period 
2. Tolerability Period (6 weeks) 


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a. Determination of randomization eligibility† 
3. Dose Escalation Period (3 weeks) 
4. Maintenance Period (24 weeks)‡ 
5. Taper Period (2 weeks)‡ 
6. Follow-Up Period (2 weeks)‡. 
†Patients who do not meet criteria for randomization eligibility will not be randomized to study 
SCOUT-015.  
‡All patients participating in the Maintenance Period may be offered participation in the 
long-term extension study (SCOUT-016). Patients who do not enroll in the SCOUT-016 study 
will have their IP tapered over 2 weeks (14 days), followed by a 2-week (14-day) safety follow-
up. 
After approximately 45 patients complete 4 weeks of the Maintenance Period of the Phase 2 part 
of the study, the Data Monitoring Committee (DMC) will meet to review safety and tolerability 
data and to recommend 1 or 2 RAD011 dose level(s) for evaluation in the Phase 3 part of the 
study. Details regarding the dose selection for the Phase 3 part of the study will be described in 
the DMC charter. 
A schematic overview of the study is presented in Figure 2 for the Phase 2 part, and in Figure 3 
for the Phase 3 part. 
Screening Period (3 weeks, Visit 1 [Weeks -3 to 0]) 
Phase 2 and Phase 3 of the study 
All patients with a signed informed consent/assent will undergo Screening assessments. 
Screening assessments will include a full medical history and physical exam, a review of 
documentation of PWS diagnosis, an ECG, laboratory assessments, and questionnaires 
(including the HQ-CT) as described in Section 5.8.2. To be eligible for the Tolerability Period, 
patients must meet the following criterion:  
 Mean HQ-CT score ≥13 obtained from HQ-CT scores as defined in Section 6.4. 
Patients not meeting Inclusion/Exclusion criteria for entry in the study will not be eligible for the 
study and may not be screened again. Caregivers will be required either to assist the patient or 
complete the questionnaires on behalf of the patient. The same caregiver should be available 
throughout the study to help in completing the questionnaires for purposes of consistency. 
Tolerability Period (6 weeks, Visits 2 to 5 [Weeks 1 to 7]) 
Phase 2 and Phase 3 of the study 
Patients who meet the eligibility criteria will undergo a 6-week Tolerability Period. During this 
Period, all patients will receive placebo at a dose of 0.1 mL/kg/day to assess tolerability of the 
formulation without active CBD and give patients time to adjust to study procedures and future 


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IP administration. Patients unable to tolerate the 0.1 mL/kg/day dose level will be withdrawn 
from the study. 
Patients/caregivers will also complete serial HQ-CT questionnaires at 2-week intervals. At the 
end of the 6-week Tolerability Period and prior to randomization, patient randomization 
eligibility based on tolerability and HQ-CT scores will be evaluated. To be eligible for 
randomization, patients must meet both of the following HQ-CT criteria:  
 Mean HQ-CT score ≥13 obtained from HQ-CT scores as defined in Section 6.4 
 Decrease from the Tolerability Period to the Screening Period in HQ-CT score ≤7 points 
as defined in Section 6.4. 
Patients who do not meet criteria for randomization eligibility will not be randomized to study 
SCOUT-015.  
Randomization (Visit 5 [Week 7]) 
Phase 2 of the study 
Following the Tolerability Period, patients meeting randomization eligibility criteria will be 
randomized to 1 of 6 groups (3 active to 3 placebo with the ratio of 2:2:2:1:1:1): low dose 
(10 mg/kg/day [0.1 mL/kg/day]) RAD011, mid dose (20 mg/kg/day [0.2 mL/kg/day]) RAD011, 
high dose (40 mg/kg/day [0.4 mL/kg/day]) RAD011, low volume (0.1 mL/kg/day) placebo, mid 
volume (0.2 mL/kg/day) placebo, or high volume (0.4 mL/kg/day) placebo divided in two daily 
doses. Additional details are provided in Section 7.5. 
Phase 3 of the study 
Following review of Phase 2 safety and tolerability data by the DMC (Section 10.4), 1 or 2 dose 
level(s) will be recommended for further development and assessment in Phase 3 of the study. 
Therefore, following the Tolerability Period, patients meeting randomization eligibility criteria 
will be randomized in a way to obtain a balanced number of patients on RAD011 and placebo to 
receive double-blind treatment with Investigational Product (IP) at dose levels recommended by 
the DMC. Additional details are provided in Section 7.5. 
Dose Escalation Period (3 weeks, Visits 5 to 7 [Weeks 7 to 9]) 
Phase 2 of the study 
After completing the Screening and Tolerability Periods, all randomized patients will be initiated 
on IP (RAD011 or placebo) 10 mg/kg/day (0.1 mL/kg/day) for a period of 1 week at Visit 5 
(Week 7). Patients randomized to low dose or low volume IP (10 mg/kg/day) will continue at a 
dose of 10 mg/kg/day (0.1 mL/kg/day) until the end of Visit 7 (Week 9). Patients randomized to 
mid dose or mid volume IP (20 mg/kg/day) will have their dose increased to 20 mg/kg/day 
(0.2 mL/kg/day) at Visit 6 (Week 8) and will continue at that dose until the end of Visit 7 
(Week 9). Patients randomized to high dose or high volume IP (40 mg/kg/day) will have their 
dose increased to 20 mg/kg/day (0.2 mL/kg/day) at Visit 6 (Week 8) and to 40 mg/kg/day 
(0.4 mL/kg/day) at Visit 7 (Week 9).  
Details of the dose escalation schema are provided in Table 4. Patients’ weight at Visit 5 (Last 
Tolerability Period visit / first Dose Escalation Period visit) will be used to determine the 


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patient’s actual doses (mL/day) to be administered from Visit 5 (Week 7) through completion of 
the maintenance phase Visit 14 (Week 34).  
The Investigator, or designee, will contact patients/caregivers by phone call, video call, email, or 
other remote means of communication at Visits 6 (Week 8) and 7 (Week 9) to determine if the 
patient’s dose may be escalated to the next dose level. Dose reductions will not be allowed 
during the Dose Escalation Period. If a patient cannot be escalated to the next dose level, the 
patient will be discontinued from the study.  
Phase 3 of the study 
After completing the Screening and Tolerability Periods, all patients will be initiated on 
10 mg/kg/day IP (0.1 mL/kg/day) for a period of 1 week at Visit 5 (Week 7).  
The dose escalation schema for the DMC-recommended Phase 3 dose level(s) will follow the 
same dose escalation schedule as in the Phase 2 part of the study. Details of the dose escalation 
schema are provided in Table 4. Patients’ weight at Visit 5 (Last Tolerability Period visit / first 
Dose Escalation Period visit) will be used to determine the patient’s actual doses (mL/day) to be 
administered from Visit 5 (Week 7) through Visit 14 (Week 34).  
The Investigator, or designee, will contact patients/caregivers by phone call, video call, email, or 
other remote means of communication at Visits 6 (Week 8) and 7 (Week 9) to determine if the 
patient’s dose may be escalated to the next dose level. Dose reductions will not be allowed 
during the Dose Escalation Period. If a patient cannot be escalated to the next dose level, the 
patient will be discontinued from the study.  
Maintenance Period (24 weeks, Visits 8 to 14 [Weeks 10 to 34]) 
Phase 2 and Phase 3 of the study 
After completing the 3-week Dose Escalation Period, patients will enter the 24-week 
Maintenance Period. Patients’ weight at Visit 5 (last Tolerability Period visit / first Dose 
Escalation Period visit) will be used to determine the patient’s actual doses (mL/day) to be 
administered between Visits 8 (Week 10) and 14 (Week 34). 
Some patients may have their dose adjusted based on tolerability during the Maintenance Period 
as detailed in Section 5.7.2.  
After completion of the Maintenance Period, patients may be offered the opportunity to enroll in 
the long-term extension study (SCOUT-016). Patients who do not elect to enroll will be tapered 
off the IP.  
Taper Period (14 days, Visit 14 [Week 34]) and Follow-up Period (14 days, Visits 15 and 16 
[Weeks 36 and 38]) 
Patients who do not enroll in the long-term extension study (SCOUT-016) will have their IP 
tapered off over 14 days according to the following schedule: the IP should be decreased by 50% 
during the first 7 days, followed by an additional 50% during the following 7 days and then 
discontinued. The taper schedule may be modified at the discretion of the Investigator but cannot 


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be extended to a total period lasting more than 14 days. A final follow-up will be conducted 
2 weeks after the last dose of IP for patients who are tapered off as described in Section 5.8.6. 
 


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Figure 2: 
Study Design Schematic – Phase 2 of the Study  
   
Abbreviations: DMC = Data Monitoring Committee; FU = follow-up; LTE = long-term extension; RAND = randomization. 
*Patients assigned to placebo will include low, mid, and high volume placebo to match active drug and will be combined for statistical analysis. 
 
 


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Figure 3: 
Study Design Schematic – Phase 3 of the Study  
Abbreviations: FU = follow-up; LTE = long-term extension; RAND = randomization; TBD = to be determined. 
* Patients assigned to placebo will be further broken down to achieve balanced exposure between placebo and RAD011 patients. Patients in the placebo group 
(matching volume) will be combined for statistical analysis. 
 


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5.2. 
Scientific Rationale for Study Design 
Despite a large safety database with a well-characterized safety profile and dose-response 
relationship of EPIDIOLEX in multiple indications, data on safety and efficacy of CBD remains 
limited in patients with PWS. However, as PWS is a rare disease with significant unmet needs, 
multiple large-scale studies would be impractical and may delay access to efficacious therapies.  
Therefore, this study is designed as a seamless Phase 2/3 study to assess safety and tolerability of 
multiple candidate doses in Phase 2 of the study (10 to 40 mg/kg/day), followed by Phase 3 of 
the study. In Phase 3 of the study, 1 or 2 candidate dose level(s) will be recommended by the 
DMC for further development and assessment based on safety and tolerability data. This 
approach will allow a streamlined way to confirm the safety and tolerability profile of RAD011 
in patients with PWS while limiting the number of patients exposed to lesser tolerated doses. In 
addition, data from patients who participated in Phase 2 of the study in the dose group(s) chosen 
for continued development and assessment in Phase 3 of the study will contribute to the overall 
intent-to-treat (ITT) population. This, in turn, allows for more efficient recruitment in this rare 
disease population. 
The double-blind design will minimize patient and Investigator bias, whereas the placebo control 
will allow better delineation of efficacy and safety profiles of RAD011. The use of placebo 
groups in this study is acceptable as there are no FDA approved treatments for hyperphagia in 
patients with PWS. In addition, the IP will be administered in addition to standard of care 
therapy, which can include GH supplementation and any additional behavioral interventions that 
have been implemented and maintained stable throughout the study.  
The 3-week Screening Period and the 6-week Tolerability Period will allow for the 
characterization of HQ-CT scores and help minimize potential bias in patient/caregiver 
completion of the HQ-CT questionnaire. These Periods will result in the exclusion of patients 
with too low mean scores or significant changes from Screening to the end of the Tolerability 
Period without any active treatment. The 6-week duration of the Tolerability Period will be 
sufficient to evaluate the HQ-CT scores and the tolerability of the MCT vehicle used in the 
RAD011 formulation. The use of inactive treatment periods in PWS studies is common as there 
is a recognized variability in hyperphagia behavior and HQ-CT response behaviors.  
Once randomized, patients will enter the 3-week Dose Escalation Period followed by a 24-week 
Maintenance Period. This combined 26-week treatment period was designed to allow for 
potential placebo effect to wane and allow for the evaluation of separation of effects between 
placebo and RAD011 groups.  
The target population for this study has also been carefully selected to include patients with 
moderate to severe hyperphagia (HQ-CT scores ≥13) (Fehnel, 2015). This is in line with baseline 
severity in other PWS development programs. In terms of age, the primary efficacy analysis will 
be based on the modified ITT (mITT) population (Section 11.4.1) which comprises patients aged 
12 to 65 years. However, as the median age of transition into Phase 3 hyperphagia is 8 years 
(interquartile range of 5 to 13 years), patients aged 8 to <12 years may also benefit from 
efficacious hyperphagia management (Miller, 2011). However, since a significant proportion of 
patients below the age of 12 years may not have established hyperphagia because developmental 
milestones may significantly affect food-seeking behaviors and environmental interactions, and 


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because families are in the process of instating environmental controls, hyperphagia may not be 
well established or stable prior to 12 years of age. Inconsistent, less severe, or unestablished 
hyperphagia may therefore render efficacy assessment impossible. In addition, the population 
aged <12 years with severe hyperphagia remains limited, thereby enhancing the difficulty of 
recruiting such patients. For these reasons, and given the small sample size of Phase 2 of the 
study, patients aged 8 to <12 years of age will not be included in Phase 2 of the study, but will be 
allowed to randomize in Phase 3 of the study in order to obtain safety and preliminary efficacy 
data. 
5.3. 
Number of Patients 
The total number of patients for the study will depend on the number of doses recommended by 
the DMC. 
If the DMC recommends two RAD011 doses for Phase 3 of the study, approximately a total of 
191 male and female patients aged 12 to 65 years (approximate target of 200 patients) will be 
randomized in this study. Up to approximately 30 patients aged 8 to <12 years will be allowed to 
randomize in the Phase 3 part of the study in order to obtain safety and preliminary efficacy data. 
If the DMC recommends one RAD011 dose for Phase 3 of the study, approximately a total of 
148 male and female patients aged 12 to 65 years (approximate target of 150 patients) will be 
randomized in this study. An additional 20 patients aged 8 to <12 years will be allowed to 
randomize in Phase 3 of the study in order to obtain safety and preliminary efficacy data.  
Additional information on sample size estimation is provided in Section 11.1. 
5.4. 
Replacement of Patients 
Patients who are randomized but do not receive a dose of assigned IP due to withdrawal of 
consent/assent or other reasons may be replaced. Any patients receiving at least 1 dose of IP will 
not be replaced and will be included in study analyses. 
5.5. 
Investigational Products 
Once randomized, patients will receive their assigned IP, defined as RAD011 or placebo, and 
enter a Dose Escalation Period as defined in Table 4. Additional information on IP and IP 
preparation are presented in Section 6.4 and in the Pharmacy Manual. 


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Table 4: 
Dose Escalation Regimen 
Group for 
Analysis 
Dosing Group 
Target dose 
Visit 5 
Week 7 
Visit 6 
Week 8 
Visit 7 
Week 9 
RAD011 low 
dose 
RAD011 low dose 
(10 mg/kg/day = 0.1 mL/kg/day) 
10 mg/kg/day 
0.1 mL/kg/day 
10 mg/kg/day 
0.1 mL/kg/day 
10 mg/kg/day 
0.1 mL/kg/day 
RAD011 mid 
dose 
RAD011 mid dose 
(20 mg/kg/day = 0.2 mL/kg/day) 
10 mg/kg/day 
0.1 mL/kg/day 
20 mg/kg/day 
0.2 mL/kg/day 
20 mg/kg/day 
0.2 mL/kg/day 
RAD011 high 
dose 
RAD011 high dose 
(40 mg/kg/day = 0.4 mL/kg/day) 
10 mg/kg/day 
0.1 mL/kg/day 
20 mg/kg/day 
0.2 mL/kg/day 
40 mg/kg/day 
0.4 mL/kg/day 
Placebo 
Placebo low volume 
(0.1 mL/kg/day) 
0.1 mL/kg/day 
0.1 mL/kg/day 
0.1 mL/kg/day 
Placebo mid volume 
(0.2 mL/kg/day) 
0.1 mL/kg/day 
0.2 mL/kg/day 
0.2 mL/kg/day 
Placebo high volume 
(0.4 mL/kg/day) 
0.1 mL/kg/day 
0.2 mL/kg/day 
0.4 mL/kg/day 
 
5.6. 
RAD011 Dose Rationale 
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, 1995). No significant reactions or 
SAEs have been reported across a wide range of dosages, nor have they been reported in acute or 
chronic settings. Bergamaschi and collaborators (Bergamaschi, 2011) recently reviewed the 
safety of CBD in humans examined in 221 patients across 21 studies. 
Regarding doses of CBD that have been examined in other studies, daily doses of 200 to 300 mg 
CBD (or potentially more) are typical (Cunha, 1980; Gloss, 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 (Borgwardt, 
2008; Consroe, 1991; Zuardi, 1993; Zuardi, 1995).  
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 
dose escalation. Because PWS patients enrolled in this Phase 2/3 study may be obese and there 
may be concerns that distribution of RAD011 to fat would decrease the effective dose in these 
patients, the maximum tolerated dose identified in the previous PK and safety studies 
(40 mg/kg/day) will be given. To maximize tolerability, all patients will be initiated on 
10 mg/kg/day (0.1 mL/kg/day) IP for a period of 1 week. Patients randomized to the low dose 
(10 mg/kg/day [0.1 mL/kg/day]) will continue at that dose for Weeks 8 and 9. Patients 
randomized to the mid dose groups will be escalated to 20 mg/kg/day (0.2 mL/kg/day) on 
Week 8 and remain at that dose through Week 9. Patients randomized to the high dose groups 


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(40 mg/kg/day [0.4 mL/kg/day]) will have their dose escalated to 20 mg/kg/day (0.2 mL/kg/day) 
on Week 8 and have a further dose escalation to 40 mg/kg/day (0.4 mL/kg/day) on Week 9.  
5.7. 
Dose Reduction Criteria 
All patients will receive a dose on a mg/kg/day basis, and dose reductions will be allowed per the 
criteria below.  
5.7.1. 
Dose Level (mg/kg/day) Reduction for Tolerability During the Dose Escalation 
Period 
Dose reductions for tolerability are not allowed during the Dose Escalation Period. Patients 
unable to tolerate their assigned dose level(s) during the Dose Escalation Period will be 
withdrawn from the study. 
5.7.2. 
Dose Level (mg/kg/day) Reduction for Tolerability During the Maintenance 
Period (Weeks 10 to 34) 
In the event that a patient does not tolerate their assigned dose level on a mg/kg/day basis during 
the Maintenance Period, the Investigator may decrease the patient’s dose by 25% at any time 
during the Maintenance Period after consultation with the Sponsor as detailed in Table 5. 
Patients undergoing a dose reduction may not have their dose increased back to their originally 
assigned dose. If a second dose reduction is required for tolerability during the Maintenance 
Period, the patient should be discontinued from the study in consultation with the Sponsor.  
 
Table 5: 
Dose Level (mg/kg/day) Reduction for Tolerability during the Maintenance 
Period 
Dose Prior to Performing Dose Reduction 
Dose Following Dose Reduction (25% Decrease)  
10 mg/kg/day 
0.1 mL/kg/day 
7.5 mg/kg/day 
0.075 mL/kg/day 
20 mg/kg/day 
0.2 mL/kg/day 
15 mg/kg/day 
0.15 mL/kg/day 
40 mg/kg/day 
0.4 mL/kg/day 
30 mg/kg/day 
0.3 mL/kg/day 
 
Reasons for dose reduction due to tolerability may include, but are not limited to, diarrhea, 
somnolence, lethargy, hepatotoxicity, insomnia, psychomotor hyperactivity, aggression, anemia, 
and ataxia. 
5.7.3. 
Total Daily Dose (mg/day) Adjustment for Weight Change During the 
Maintenance Period 
All patients will be dosed using their actual body weight at Visit 5 (Week 7), and this dose will 
be maintained through the course of the study. 


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5.8. 
Study Visits and Procedures 
A summary of the study assessments is described below. More information is provided in the 
Study Operations Manual.  
5.8.1. 
Study Windows 
All study visits will have a ± 3 day study window, except for Visit 1 (Screening) which must 
happen 3 weeks (21 days) prior to Visit 2. 
5.8.2. 
Screening Period (3 weeks, Visit 1 [Weeks -3 to 0]) 
The Screening Period will occur 3 weeks (21 days) prior to initiation of the Tolerability Period. 
The Schedule of Assessments table for the Screening Period is presented in Table 6. Assessments 
may occur over multiple days, but the HQ-CT and Aberrant Behavior Checklist (ABC) 
questionnaires must be completed a minimum of 14 days prior to Visit 2. 
5.8.2.1 
Visit 1 (Weeks -3 to 0) 
The following assessments must be performed in person during Visit 1: 
 Informed consent by the patient, or informed consent by the parent and assent by the 
patient if aged <18 years prior to conducting any study procedures. The signed and dated 
consent form will be kept by the Principal Investigator and a signed and dated copy 
provided to the patient 
 Review of Inclusion/Exclusion criteria 
o Patients must fulfill all Inclusion/Exclusion criteria to be eligible to continue in 
the Tolerability Period 
 Collection of full medical/surgical history, seizure history, and confirmation of PWS 
genetic diagnosis including genetic subtypes 
 Collection of demographics 
 Review of prior/concomitant medications 
 Start collection/recording of AEs 
 Weight and height  
 Vital signs, including, blood pressure (BP), heart rate (HR), temperature, respiratory rate 
(RR), and oxygen saturation 
 Complete physical examination 
 Completion of the HQ-CT, CaGI-S Hyperphagia, and ABC questionnaires 
o To complete the questionnaires, the same caregiver should be available 
throughout the study to complete the questionnaires with the patient 
o Must be completed a minimum of 14 days prior to Visit 2 
 Resting 12-lead ECG in the supine position 


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 Collection of laboratory samples 
o Serum pregnancy test for females of childbearing potential only, to be performed 
centrally 
o Urine drug screen for drugs of abuse including THC 
o Urinalysis 
o Chemistry (renal and liver function panels), 
o Hematology 
o Glycosylated hemoglobin (HbA1c) 
o Prothrombin time (PT)/international normalized ratio (INR) 
o Serologies for hepatitis B virus (HBV), hepatitis C virus (HCV), and human 
immunodeficiency virus (HIV) 
o Follicle stimulating hormone (FSH) for menopausal females only 
o Appetite hormones (including insulin, ghrelin, and leptin). Ghrelin samples will 
only be collected for Phase 3 patients at sites where proper collection is feasible.  
o Biomarker samples. Biomarker assessments will only be performed in patients 
enrolled in the Phase 3 part of the study and be optional. Biomarker assessments 
will not be conducted in the Phase 2 part of the study  
 Review of eligibility 
o Review of eligibility at Visit 1 includes all inclusion and exclusion criteria with 
the exception of HQ-CT. Eligibility related to HQ-CT scores will be assessed at 
Visit 2 and Visit 5 (Section 6.4). 
5.8.2.2 
Documentation of Genetic Diagnosis of Prader-Willi Syndrome 
The proof of prior genetic diagnosis of PWS should be provided as part of the source records and 
used to assess Inclusion/Exclusion criteria. Type(s) of test(s) used (such as deoxyribonucleic acid 
[DNA] methylation assays, in situ hybridization, etc.) as well as the identified variants (deletion, 
disomy, imprinting defect, etc.) should be documented, whenever available. 
5.8.3. 
Tolerability Period (6 weeks, Visits 2 to 5 [Weeks 1 to 7]) 
The Schedule of Assessments table for the Tolerability Period is provided in Table 6. Prior to 
initiating dosing of patients at Visit 2 of the Tolerability Period, patients/caregivers must 
complete the HQ-CT questionnaire and have met the defined HQ-CT criteria (Section 6.4). 
Patients who do not meet criteria for randomization eligibility will not be randomized to study 
SCOUT-015.  
5.8.3.1 
Visits 2 to 4 (Weeks 1 to 6) 
The following assessments must be performed in person during Visits 2 to 4 (Weeks 1 to 6): 
 Review of concomitant medications 


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 Review of AEs 
 Weight and height 
 Vital signs, including, BP, HR, temperature, RR, and oxygen saturation 
 Completion of the HQ-CT questionnaire 
o The same caregiver should be available throughout the study to complete the 
questionnaires with the patient 
o At Visit 2, HQ-CT must be completed pre-dose 
 Review of HQ-CT questionnaire scores for eligibility (Visit 2 only) 
o The electronic data capture (EDC) system will automatically calculate mean 
HQ-CT score from Visit 1 and Visit 2. Patients with a mean HQ-CT score ≥13 
will be eligible to continue in the Tolerability Period. Further details are described 
in Section 6.4 
 Completion of the and Epworth Sleepiness Scale for Children and Adolescents 
(ESS-CHAD), CGI-S Hyperphagia, Skin Picking, and Columbia Suicide Severity Rating 
Scale (C-SSRS) questionnaires (predose-, only to be performed at Visit 2) 
 Placebo dispensing (Visit 2 only) 
 Placebo dosing (Visit 2 only) 
 Drug accountability (only Visits 3 and 4) 
 Food Diary Reminder and Food Diary Distribution (only Visit 4). 
5.8.4. 
Dose Escalation Period (3 weeks, Visits 5 to 7 [Weeks 7 to 10]) 
The Schedule of Assessments table for the Dose Escalation Period is provided in Table 7. 
5.8.4.1 
Visit 5 (End of Screening, Beginning of Dose Escalation Period, Week 7) 
The following assessments must be performed in person during Visit 5 (Week 7). All 
assessments must be performed prior to dosing on Visit 5, unless specified otherwise. Prior to 
assessing randomization eligibility, patients/caregivers must complete the HQ-CT. 
 Review of concomitant medications 
 Review of AEs 
 Weight and height 
 Vital signs, including BP, HR, temperature, RR, and oxygen saturation 
 Complete physical examination 
 Completion of the HQ-CT questionnaire (pre-dose) 
o The same caregiver should be available throughout the study to complete the 
questionnaires with the patient 
o HQ-CT must be completed prior to randomization 


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 Review of HQ-CT questionnaire scores and Inclusion/Exclusion criteria for eligibility 
o The EDC system will automatically calculate mean HQ-CT score from Visit 3, 
Visit 4 and Visit 5 inclusively. Patients with a mean HQ-CT score ≥13 will be 
eligible for randomization. Patients not eligible for randomization because of a 
HQ-CT score <13 will not have the opportunity to participate in the long-term 
extension study (SCOUT-016) 
o The EDC system will also automatically calculate the change in HQ-CT score 
from Visit 2 (beginning of the Tolerability Period) to Visit 5 (end of the 
Tolerability Period/Beginning of Dose Escalation Period) inclusively. Patients 
must have a decrease in HQ-CT score ≤7 to be eligible for randomization and able 
to proceed to the Dose Escalation Period. Further details are defined in 
Section 6.4 
o Laboratory values collected prior to visit 5 should be used to assess eligibility 
o Patients meeting all inclusion and exclusion criteria should proceed to 
randomization.  
o Completion of the C-SSRS questionnaire (predose) 
 Randomization 
 Completion of the ABC, ESS-CHAD, CGI-S Hyperphagia, CaGI-S Hyperphagia, and 
Skin Picking questionnaires 
 Resting 12-lead ECG in the supine position 
 Collection of laboratory samples (Section 10.1) 
o Urinalysis 
o Urine dipstick pregnancy test for females of childbearing potential only to be 
performed locally 
o Urine drug screen for drugs of abuse including THC 
o Chemistry panels (renal and liver function panels) 
o Hematology 
o Appetite hormones (including insulin, ghrelin, and leptin) Ghrelin samples will 
only be collected for Phase 3 patients at sites where proper collection is feasible.  
 Pharmacokinetic sample (Section 10.1.13) 
o Blood draws for PK analyses of CBD, 7-OH-CBD, and 7-COOH-CBD will be 
drawn at the same time as the other laboratory samples. Time of sampling will be 
recorded 
 Food diary collection 
 Drug Accountability 
 Investigational product (IP) dispensing 


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 Dosing of IP after randomization, to be completed in clinic 
 Dual-energy X-ray absorptiometry (DEXA) scan 
o To be performed at certain US sites only 
o Can be performed before or after dosing of IP, within ± 7 days of Visit 5. 
5.8.4.2 
Visits 6 and 7 (Weeks 8 and 9) 
The following assessments must be performed (remotely or in person) during Visits 6 and 7 
(Weeks 8 and 9): 
 Review of concomitant medications 
 Review of AEs 
 Food Diary Reminder and Food Diary Distribution (Visit 7 only): patients will be 
instructed to record the time of their evening and morning doses of study medication on 
the night prior to and the day of their next clinic visit with the type of meal administered. 
5.8.5. 
Maintenance Period (24 Weeks, Visits 8 to 14 [Weeks 10 to 34]) 
The Schedule of Assessments table for the Maintenance Period is provided in Table 7. 
5.8.5.1 
Visits 8, 10, 12, and 14 (Weeks 10, 19, 27, and 34) 
The following assessments must be performed in person during Visits 8, 10, 12, and 14 
(Weeks 10, 19, 27, and 34): 
 Review of concomitant medications 
 Review of AEs 
 Weight and height 
 Vital signs, including BP, HR, temperature, RR, and oxygen saturation 
 Abbreviated, symptom-directed physical examination 
 Completion of the HQ-CT, C-SSRS, CGI-S Hyperphagia, CaGI-S Hyperphagia and ABC 
questionnaires 
o The same caregiver should be available throughout the study to complete the 
questionnaires with the patients 
 Visits 10 and 14 only: completion of the ESS-CHAD and Skin Picking questionnaires 
 Resting 12-lead ECG in the supine position (except Visit 12) 
 Collection of laboratory samples (Section 10.1) 
o Urinalysis  
o Urine dipstick pregnancy test for females of childbearing potential only, to be 
performed locally 
o Chemistry panels (renal and liver function panels) 


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o Hematology 
o Glycosylated hemoglobin at Visits 8, 12, and 14 only 
o Appetite hormones (including insulin, ghrelin, and leptin). Ghrelin samples will 
only be collected for Phase 3 patients at sites where proper collection is feasible. 
To be collected at Visits 8, 12, and 14 only 
o  Pharmacokinetic sample at Visits 8, 12, and 14 only (Section 10.1.13) 
 Blood draws for PK analyses of CBD, 7-OH-CBD, and 7-COOH-CBD 
will be drawn at the same time as the other laboratory samples. The time 
of sampling will be recorded, with the exception of Visit 8 (Week 10). 
Pharmacokinetic sampling on Visit 8 should occur within 6 ± 2 hours of 
dose. The food diary completed prior to each Visit 8, 12, and 14 will be 
collected prior to the blood draw.  
 Food diary collection (Visits 8, 12, and 14 only): patients will have been instructed to 
record the time of their evening and morning doses of study medication on the night prior 
to and the day of their Visits 8, 12, and 14, with the type of meal administered 
 Drug accountability 
 Dispensing of IP (at Visit 14, only dispense if the patient proceeds to the Taper Period) 
 Visit 14 only: completion of the CGI-C Hyperphagia, CaGI-C Irritability, and CaGI-C 
questionnaires, and patient’s impression of seizures 
 Visit 14 only: Biomarker samples. Biomarker assessments will only be performed in 
patients enrolled in the Phase 3 part of the study and be optional. Biomarker assessments 
will not be conducted in the Phase 2 part of the study)  
 Visit 14 only: Dual-energy X-ray absorptiometry (DEXA) scan 
o To be performed at certain US sites only 
o Can be performed before or after dosing of IP, within ± 7 days of Visit 14 
 Patients may be offered enrollment in the long-term extension study (SCOUT-016) 
(Visit 14 only). 
5.8.5.2 
Visits 9, 11, and 13 (Weeks 15, 24, and 30) 
The following assessments must be performed (remotely or in person) during Visits 9, 11, and 13 
(Weeks 15, 24, and 30): 
 Review of concomitant medications 
 Review of AEs 
 Food diary reminder and food diary distribution (Visits 11 and 13 only). Patients will be 
instructed to complete a food diary and record the time of their evening and morning 
doses of study medication on the night prior to and the day of their next clinic visit 
 Dispensing of IP 


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5.8.6. 
Taper and Follow-Up Periods (4 Weeks, Visits 14 to 16 [Weeks 34 to 38])  
Following completion of the Maintenance Period, patients may be offered enrollment in the 
long-term extension study (SCOUT-016). Patients who elect not to enroll in the long-term 
extension study will undergo a 2-week Taper Period (14 days) followed by a 2-week Follow-Up 
Period (14 days), as detailed in Table 7 and Section 7.1.1.long-term extension study 
SCOUT-016, the following assessments must be performed in person during Visit 15 (Week 36): 
 Review of concomitant medications 
 Review of AEs 
 Abbreviated, symptom directed physical examination 
 Drug Accountability. 
The following assessments can be performed remotely during Visit 16 (Week 38): 
 Review of concomitant medications 
 Review of AEs. 
5.9. 
Adjustments of Study Assessments for Visits Impacted by COVID-19 
The COVID-19 pandemic continues to affect the conduct of clinical studies around the world. 
For this reason, patients and/or Investigators may be unable to perform planned in-person 
assessments. Radius’ first priority is to protect the safety of study participants. Additional 
priorities include optimizing safety- and efficacy-related data acquisition and maintaining the 
integrity of the study. In accordance with FDA’s Guidance on Conduct of Clinical Trials of 
Medical Products During the COVID-19 Public Health Emergency, Radius will provide 
guidance (e.g. out of window visits, remote assessments, etc.) on a case by case basis. 


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5.9.1. 
Schedule of Assessments for the Screening, Tolerability, Dose Escalation, Maintenance, Taper, and Follow-Up 
Periods 
Table 6: 
Schedule of Assessments – Screening and Tolerability Periods 
Period 
Screening 
Tolerability 
Visit Number 
1 
2 
3 
4 
Study Time Point 
D -21 to 0 
(W -3 to 0) 
D 1 (W 1) 
D 15 (W 3) 
D 29 (W 5) 
Visit Window (Days) 
0 
±3 
±3 
±3 
Informed consent/assent (if appropriate) 
X 
 
 
 
Review of inclusion and exclusion criteria 
X 
 
 
 
Medical/surgical history including PWS genetic 
diagnosis, seizure history 
X 
 
 
 
Demographics 
X 
 
 
 
Review of prior/concomitant medications 
X 
X 
X 
X 
Start collection/recording of AEs 
X 
 
 
 
Review of AEs 
 
X 
X 
X 
Weight and heighta 
X 
X 
X 
X 
Record vital signsb 
X 
X 
X 
X 
Physical examc 
X 
 
 
 
HQ-CT Questionnaired 
X 
Xpre-dose 
X 
X 
Review of HQ-CT scores for eligibilitye 
 
X 
 
 
ABC Questionnaired 
X 
 
 
 
ESS-CHAD Questionnaired 
 
Xpre-dose 
 
 
CGI-S Hyperphagia Questionnaired 
 
Xpre-dose 
 
 
CaGI-S Hyperphagia Questionnaire 
X 
 
 
 
Skin Picking Questionnaired 
 
Xpre-dose 
 
 
C-SSRSd,f 
 
Xpre-dose 
 
 
Resting 12-lead ECG 
X 
 
 
 
Serum pregnancy testg 
X 
 
 
 
Urine drug screenh 
X 
 
 
 
Urinalysis 
X 
 
 
 
Chemistry panelsi 
X 
 
 
 
Hematologyj 
X 
 
 
 
HbA1c 
X 
 
 
 


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Period 
Screening 
Tolerability 
Visit Number 
1 
2 
3 
4 
Study Time Point 
D -21 to 0 
(W -3 to 0) 
D 1 (W 1) 
D 15 (W 3) 
D 29 (W 5) 
Visit Window (Days) 
0 
±3 
±3 
±3 
PT-INR 
X 
 
 
 
Serologies for HBV, HCV, and HIV 
X 
 
 
 
FSH for menopausal women onlyk 
X 
 
 
 
Appetite hormonesl 
X 
 
 
 
Biomarkersm 
X 
 
 
 
Review of eligibilityn 
X 
 
 
 
Placebo dispensing 
 
X 
 
 
Placebo dosingo 
 
X 
 
 
Drug accountability 
 
 
X 
X 
Food Diary Reminderp 
 
 
 
X 
Food Diary Distribution 
 
 
 
X 
Abbreviations: ABC = Aberrant Behavior Checklist questionnaire; AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
BMI = body mass index; BP = blood pressure; CBC = complete blood count; CGI-S = Clinical Global Impression of Change – Severity questionnaire; 
C-SSRS = Columbia-Suicide Severity Rating Scale; D = day; ECG = electrocardiogram; EDC = electronic data capture; ESS-CHAD = Epworth Daytime 
Sleepiness Scale; FSH = follicle-stimulating hormone; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; 
HbA1c = glycosylated hemoglobin; HQ-CT = Hyperphagia Questionnaire for Clinical Trials; HR = heart rate; MCH = mean corpuscular hemoglobin; 
MCHC = mean corpuscular hemoglobin concentration; MCV = mean corpuscular volume ; PT-INR = prothrombin time-international normalized ratio; 
PWS = Prader-Willi Syndrome; RBC = red blood cells; RDW = red cell distribution width; RR = respiratory rate; THC = tetrahydrocannabinol; WBC = white 
blood cells; W = week; WOCBP = women of childbearing potential. 
a Weight and height must be documented at every in-person visit as the EDC system will automatically calculated BMI (or BMI z-score) using both variables 
(Section 10.1.3). 
b Vital signs include BP, HR, RR, oxygen saturation, and temperature (Section 10.1.2). 
c A full physical exam should be performed at Screening Visit 1 (Section 10.1.4). Other physical exams should be abbreviated, symptom -directed. 
d If a caregiver is required to assist the patient in completing the questionnaire, the same caregiver should be available throughout the study. 
e The EDC system will automatically calculate mean HQ-CT score from Visit 1 and Visit 2. Patients with a mean HQ-CT score ≥13 will be eligible to continue 
in the Tolerability Period. Further details are described in Section 6.4. 
,f If the patient is the mental equivalent of 6 or younger then the children's version of the C-SSRS should be used. 
g For WOCBP only. 
h Drugs of abuse include THC. May be repeated at the Investigator’s discretion. 
i Chemistry panels include renal and liver function panels. Renal function panel includes sodium, potassium, chloride, calcium, bicarbonate, glucose, 
phosphorus, blood urea nitrogen, creatinine, and estimated glomerular filtration rate. Should be obtained after a 10-hour fast if possible. Liver function panel 
includes ALT, AST, albumin, alkaline phosphatase, direct bilirubin, total bilirubin, indirect bilirubin, and total protein (Table 9).  
j Hematology panel includes hematocrit, hemoglobin, MCV, MCH, MHCH, RDW, RBC, WBC, platelets, and differential (Table 9). 


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k FSH levels must be ≥30 mIU/mL with absence of menstruation for ≥1 year to be considered menopausal status (Section 10.1.11). 
l Includes insulin, ghrelin, and leptin (Table 9). Ghrelin samples will only be collected for Phase 3 patients at sites where proper collection is feasible.  
m Will only be performed in patients enrolled in the Phase 3 part of the study and be optional. Biomarker assessments will not be conducted in the Phase 2 part of 
the study. 
n Review of eligibility at Visit 1 includes all inclusion and exclusion criteria with the exception of HQ-CT. Eligibility related to HQ-CT scores will be assessed at 
Visit 2 and Visit 5 (Section 6.4). 
o Dosing should be completed at the site when patients are present for a study visit during Visit 2 and Visit 5 (Section 7.1) 
p Patients will be instructed to record the time of their evening and morning doses of study medication on the night prior to and the day of their next clinic visit 
with the type of meal administered. Patients should also be contacted approximately 1 week prior to their next visit to remind them to complete their food diary 
prior to their next visit (Section 10.1.14). 
 
 
 


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Table 7: Schedule of Assessments – Dose Escalation, Maintenance, Taper, and Follow-Up Periods 
 
DOUBLE-BLIND TREATMENT PHASEa 
TAPER 
PERIODb 
(2 weeks) 
FOLLOW-UP 
PERIODb 
(2 weeks) 
Period 
DOSE ESCALATION 
PERIODa 
(3 Weeks) 
MAINTENANCE PERIOD 
(24 Weeks) 
Visit Number 
5c,d 
6e 
7e,f 
8c  
9e 
10c  
11e,f 
12c  
13e,f 
14c,g,aa,bb 
15c 
16e 
Study Time Point 
D 43 
(W 7) 
D 50 
(W 8) 
(Remote) 
D 57 
(W 9) 
(Remote) 
D 64 
(W 10) 
D 99 
(W 15) 
(Remote) 
D 127 
(W 19) 
D 155 
(W 23) 
(Remote) 
D 183 
(W 27) 
D 204 
(W 30) 
(Remote) 
D 232 / 
ET/EOS 
(W 34) 
D 232  
(W 34) 
D 246c  
(W 36c) 
D 260e/ EOSe 
(W 38) 
(Remote) 
Visit Window (D) 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
Review of 
concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Review of AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Weight and heighth 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
Record vital signsi 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
Physical examj 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Xk 
 
HQ-CT 
Questionnairel,m 
Xpre-dose 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
Review of HQ-CT 
scores and I/E n,o  
X 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRSl,m,p 
Xpre-dose 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
Randomizationo 
Xq 
 
 
 
 
 
 
 
 
 
 
 
 
ABC 
Questionnairel,m  
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
ESS-CHAD 
Questionnairel,m 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
CGI-S Hyperphagia 
Questionnairel,m 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
CaGI-S Hyperphagia 
Questionnairel,m 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
CGI-C Hyperphagia 
Questionnairel,m 
 
 
 
 
 
 
 
 
 
X 
 
 
 
CaGI-C Irritability 
Questionnairel,m 
 
 
 
 
 
 
 
 
 
X 
 
 
 
CaGI-C 
Questionnairel,m 
 
 
 
 
 
 
 
 
 
X 
 
 
 


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DOUBLE-BLIND TREATMENT PHASEa 
TAPER 
PERIODb 
(2 weeks) 
FOLLOW-UP 
PERIODb 
(2 weeks) 
Period 
DOSE ESCALATION 
PERIODa 
(3 Weeks) 
MAINTENANCE PERIOD 
(24 Weeks) 
Visit Number 
5c,d 
6e 
7e,f 
8c  
9e 
10c  
11e,f 
12c  
13e,f 
14c,g,aa,bb 
15c 
16e 
Study Time Point 
D 43 
(W 7) 
D 50 
(W 8) 
(Remote) 
D 57 
(W 9) 
(Remote) 
D 64 
(W 10) 
D 99 
(W 15) 
(Remote) 
D 127 
(W 19) 
D 155 
(W 23) 
(Remote) 
D 183 
(W 27) 
D 204 
(W 30) 
(Remote) 
D 232 / 
ET/EOS 
(W 34) 
D 232  
(W 34) 
D 246c  
(W 36c) 
D 260e/ EOSe 
(W 38) 
(Remote) 
Visit Window (D) 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
Skin Picking 
Questionnairel,m 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
Resting 12-lead ECG 
X 
 
 
X 
 
X 
 
 
 
X 
 
 
 
Urinalysis 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
Urine dipstick 
pregnancy testr 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
Urine drug screens 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Chemistry panelst 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
Hematologyu 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
HbA1c 
 
 
 
X 
 
 
 
X 
 
X 
 
 
 
Appetite hormonesv 
X 
 
 
X 
 
 
 
X 
 
X 
 
 
 
Biomarkersw 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Pharmacokinetic 
X 
 
 
Xx 
 
 
 
X 
 
X 
 
 
 
Food Diary 
Collection 
X 
 
 
X 
 
 
 
X 
 
X 
 
 
 
Food Diary 
Reminderf 
 
 
X 
 
 
 
X 
 
X 
 
 
 
 
Food Diary 
Distribution 
 
 
Xcc 
 
 
 
Xcc 
 
Xcc 
 
 
 
 
Drug accountability 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
IP dispensing 
X 
 
 
X 
X 
X 
X 
X 
X 
 
X 
 
 
Dosingy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Seizure Patient 
Impression 
 
 
 
 
 
 
 
 
 
X 
 
 
 
DEXA scanz 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Tapering of IP over 
14 daysb 
 
 
 
 
 
 
 
 
 
 
Xb,g 
 
 
Abbreviations: ABC = Aberrant Behavior Checklist questionnaire; AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
BMI = body mass index; BP = blood pressure; CaGI-C = Caregiver Global Impression of Change; CBC = complete blood count; CGI-C= Clinical Global 


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Impression of Change; CGI-S= Clinical Global Impression of Change – Severity questionnaire; C-SSRS = Columbia-Suicide Severity Rating Scale; D = day; 
DEXA = dual-energy x-ray absorptiometry; DMC = Data Monitoring Committee; EDC = electronic data capture; ECG = electrocardiogram; 
ESS-CHAD = Epworth Daytime Sleepiness Scale; EOS = End of Study; HbA1c = glycosylated hemoglobin; HQ-CT = Hyperphagia Questionnaire for Clinical 
Trials; HR = heart rate; IP = investigational product (RAD011 or placebo); MCH = mean corpuscular hemoglobin; I/E = Inclusion/Exclusion Criteria; 
MCHC = mean corpuscular hemoglobin concentration; MCV = mean corpuscular volume; PK= Pharmacokinetic; PWS = Prader-Willi Syndrome; RBC = red 
blood cells; RDW = red cell distribution width; RR = respiratory rate; THC = tetrahydrocannabinol; W = week; WBC = white blood cells. 
a In the Phase 2 part of the study, all patients will be initiated on IP (RAD011 or placebo) 10 mg/kg/day (0.1 mL/kg/day) for a period of 1 week at Visit 5 
(Week 7). Patients randomized to low dose or low volume IP (10 mg/kg/day) will continue at a dose of 10 mg/kg/day (0.1 mL/kg/day) until the end of Week 9. 
Patients randomized to mid dose or mid volume IP (20 mg/kg/day) will have their dose increased to 20 mg/kg/day (0.2 mL/kg/day) at Visit 6 (Week 8) and will 
continue at that dose until the end of Week 9. Patients randomized to high dose or high volume IP (40 mg/kg/day) will have their dose increased to 
20 mg/kg/day (0.2 mL/kg/day) at Visit 6 (Week 8) and to 40 mg/kg/day at Visit 7 (Week 9). Details of the dose escalation schema are provided in Table 4. 
In the Phase 3 part of the study, all patients will be initiated on IP (RAD011 or placebo) 10 mg/kg/day IP (0.1 mL/kg/day) for a period of 1 week at Visit 5 
(Week 7). Dose escalation will occur similarly to the Phase 2 part of the study with the 1 or 2 doses recommended by the DMC following their review of safety 
and tolerability data from the Phase 2 part of the study. Details of the dose escalation schema are provided in Table 4.  
No dose decreases will be allowed during the Dose Escalation Period (Section 5.7.1).  
b The Taper and Follow Up Period visits (Visits 14 to 16) are only for patients who do not proceed to enroll in the active long-term extension study SCOUT-016 
and who are tapering off the IP. Patients will return to the site for assessment of concomitant medications, AEs, and to return and reconcile IP on Visit 15. 
Visit 16 may be done remotely (Section 5.8.6). 
c To be performed in person at the research site. 
d All assessments must be performed prior to dosing, unless specified otherwise. 
e Assessments may be conducted remotely via a phone call, video call, or other remote means of communication. Dispensing of IP may be done at the research 
site or remotely, using direct-to-patient shipping methods in accordance with all local laws and regulations. Sites may elect to conduct the entire visit in person. 
f At Week 9 (Visit 7), Week 23 (Visit 11), and Week 30 (Visit 13), patients will be instructed to record the time of their evening and morning doses of study 
medication on the night prior to and the day of their next clinic visit with the type of meal administered. Patients should also be contacted approximately 
1 week prior to their next visit to remind them to complete their food diary prior to their next visit (Section 10.1.14). 
g At visit 14, patients may be offered participation in the long-term extension study SCOUT-016. Patients eligible and electing to participate in the long-term 
extension study SCOUT-016 should continue treatment with IP as per the SCOUT-016 protocol. Patients who are not eligible or decide not to participate in the 
long-term extension study SCOUT-016 should proceed to the Taper and Follow-Up Periods (footnote b, Section 5.8.5.1).  
h Weight and height must be documented at every in-person visit (Section 10.1.3). 
i Vital signs include BP, HR, RR, oxygen saturation, and temperature (Section 10.1.2). 
j A full physical exam should be performed at Week 7 (Visit 5). Other physical exams should be abbreviated, symptom directed (Section 10.1.4). 
k To be performed at Visit 15 (Week 36) only. 
l If a caregiver is required to assist the patient in completing the questionnaire, the same caregiver should be available throughout the study. 
m When possible, study questionnaires should be completed prior collection of ECG and blood samples. 
n Patients meeting all inclusion and exclusion criteria should proceed to randomization.  
o The EDC system will automatically calculate mean HQ-CT score from Visit 3, Visit 4 and Visit 5 inclusively. Patients with a mean HQ-CT score ≥13 will be 
eligible for randomization. In addition, the EDC system will also automatically calculate the change in HQ-CT score from the Tolerability Period to the 
Screening Period. Patients must have a decrease in HQ-CT score ≤7 to be eligible for randomization. Further details are defined in Section 6.4.  
p If the patient is the mental equivalent of 6 or younger, then the children's version of the C-SSRS should be used. 


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q Randomization cannot be performed prior to evaluation and review of HQ-CT questionnaire scores for eligibility. Prior to assessing randomization eligibility, 
patients must complete the Visit 5 HQ-CT questionnaire (Section 6.4.2). 
r For WOCBP only. If positive, a quantitative serum pregnancy test must be sent to the central laboratory for confirmation. 
s Drugs of abuse include THC. May be repeated at the Investigator's discretion. 
t Chemistry panels include renal and liver function panels. Renal function panel includes sodium, potassium, chloride, calcium, bicarbonate, glucose, 
phosphorus, blood urea nitrogen, creatinine, and glomerular filtration rate. Should be obtained after a 10-hour fast if possible. Liver function panel includes 
ALT, AST, albumin, alkaline phosphatase, direct bilirubin, total bilirubin, indirect bilirubin, and total protein (Table 9). 
u Hematology panel includes hematocrit, hemoglobin, MCV, MCH, MHCH, RDW, RBC, WBC, platelets, and differential (Table 9). 
v Includes insulin, ghrelin, and leptin (Table 9). Ghrelin samples will only be collected for Phase 3 patients at sites where proper collection is feasible.  
w Will only be performed in patients enrolled in the Phase 3 part of the study and be optional. Biomarker assessments will not be conducted in the Phase 2 part of 
the study 
x Must be drawn 6 ± 2 hours after the previous IP dose. Patients may take their IP dose at home prior to presenting to the site for their visit in order to comply 
with the PK timing requirements. 
y Dosing should be completed at the site during Visit 2 and Visit 5. Dosing is not required to be done at the site when patients have remote or other visits 
(Section 7.1). 
z Can be performed before or after dosing. The DEXA scan can be performed within ± 7 days of the visit time point (Section 9.3.6). The DEXA scan will be 
performed at a certain number of US sites only. 
aa All assessments will be collected regardless of if the patient enters the taper period or completes the study and enter the long-term extension study. 
bb The two-week taper period does not have any visits associated with it. 
cc The food diary can be provided at the previous in-person visit. 


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5.10. 
Criteria for Study or Site Termination 
Throughout the course of the study, new information may become available to the Sponsor, its 
designee, or regulatory authorities indicating that the study or a study site should be terminated. 
Such decisions will be made after consultation between the Sponsor or its designee and the 
Investigator. The Sponsor or its designee has the right to terminate the participation of an 
individual site or the entire study at any time, for any reason, which may include: 
 The incidence or severity of AEs in this study or other studies indicate a potential safety 
hazard to patients 
 Unsatisfactory patient enrollment 
 Inadequate data recording 
 Non-adherence to protocol or applicable regulatory guidelines in study conduct. 
6. 
SELECTION AND WITHDRAWAL OF PATIENTS 
Patients will be male and non-pregnant female volunteers between 12 and 65 years of age 
inclusive (Phase 2) and between 8 and 65 years of age (Phase 3) at Screening with a genetically 
confirmed diagnosis of PWS, able to understand and provide written consent or assent, and who 
meet all the inclusion and none of the exclusion criteria. Eligibility for this study will be 
confirmed during the Screening and Tolerability Periods. 
6.1. 
Patient Inclusion Criteria 
To be eligible for this study, patients must meet all of the following inclusion criteria: 
1. Presence of a parent/legal guardian that is able to consent for their participation. 
Parent/caregiver/legal guardian can complete the required assessments throughout the 
study. Patient consent/assent will be obtained if the patient is 8 years of age or older and 
has the mental capacity to understand and sign a written consent/assent form and/or give 
verbal assent 
2. Males and females between: 
a. Phase 2: 12 and 65 years of age (inclusive) at time of consent/assent 
b. Phase 3: 8 and 65 years of age (inclusive) at time of consent/assent 
3. Documentation of genetically confirmed PWS diagnosis 
4. If a caregiver helps in completing the HQ-CT or other questionnaires, the same caregiver 
is available to complete the questionnaire throughout the duration of the study 
5. 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 up to 4 weeks after 
the last dose of RAD011 or placebo: 
a. Double barrier method (i.e., condom plus occlusive cap (diaphragm or 
cervical/vault caps), condom or occlusive cap plus spermicide), 


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b. Hormonal methods such as oral, implantable, injectable, vaginal ring, or 
transdermal contraceptives at a stable dose for a minimum of 1 full cycle (based 
on the patient’s usual menstrual cycle period) before IP administration 
c. Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS) 
d. If not using hormonal contraceptives or IUD or IUS, then all male partners 
throughout the study must have been vasectomized and have received medical 
assessment of the surgical success 
6. If male, is vasectomized and has received medical assessment of the surgical success or 
agrees to use an approved method of contraception (double barrier method as described 
in Inclusion Criterion 5, female partner’s use of an IUD or IUS [in place at least 12 weeks 
prior to dosing], oral contraceptives or female partner who is surgically sterile or 2 years 
postmenopausal) and agrees to use this method for 4 weeks after last administration of 
RAD011 or placebo 
7. If receiving growth hormone (GH), psychotropic therapy, metabolic treatments that could 
affect appetite (including metformin), and other treatment including thyroid hormone, 
must be on the same medication and stable dose for at least 90 days prior to 
consent/assent 
8. Any non-medical interventions (e.g., counseling, behavior modification) should be stable 
for at least 90 days prior to consent/assent 
9. HQ-CT eligibility automatically calculated in the electronic data capture (EDC) system: 
a. Visit 2 
i. Patients with a mean HQ-CT score ≥13 (from Visit 1 and Visit 2) will be 
eligible to continue in the Tolerability Period 
b. Visit 5 
i. Patients with a mean HQ-CT score ≥13 (from Visit 3, Visit 4 and Visit 5) 
will be eligible for randomization, and  
ii. Patients with a decrease in HQ-CT score (from Tolerability Period to the 
Screening Period) ≤7 will be eligible for randomization 
6.2. 
Patient Exclusion Criteria 
Patients meeting any of the following criteria will be excluded from the study: 
1. Hypersensitivity or intolerance to CBD, or any other excipients used in the RAD011 
preparation 
2. Known use of cannabis or cannabinoid containing products (including topical products) 
within 90 days prior to consent/assent 
3. History of chronic liver disease, such as cirrhosis or chronic hepatitis due to any cause 
4. Positive urine test for drugs of abuse, including tetrahydrocannabinol (THC), or known 
history of drug, alcohol, or substance abuse 
5. Use of prescription or over-the-counter weight loss agents within 90 days prior to 
consent/assent 
6. Implementation of new food restrictions or environmental restrictions within 90 days of 
consent/assent 


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7. Any significant comorbid condition or disease: 
a. Respiratory disease, heart disease, or psychiatric disorder which in the opinion of 
the Investigator would preclude the patient from participating or 
b. Uncontrolled type 1 or type 2 diabetes as determined by the Investigator or 
c. Clinically significant ECG abnormalities or other evidence of clinically 
significant heart disease as determined by the Investigator or 
d. Uncontrolled sleep apnea as determined by the Investigator or 
e. Neutropenia with neutrophil counts <1,000 /microL (grade 3 or grade 4 
neutropenia as defined by CTCAE v5.0) or 
f. History or presence of gastrointestinal disorders or any other condition known to 
interfere with the absorption, distribution, metabolism, or excretion of drugs taken 
orally as determined by the Investigator 
8. QT interval corrected for heart rate (HR) according to Fridericia's formula (QTcF) 
meeting the following criteria: 
a. For males and females aged 8 to <20 years: QTcF >439 msec  
b. For males aged 20 to 65 years: QTcF >450 msec  
c. For females aged 20 to 65 years; QTcF >470 msec 
9. At consent/assent, patients with age-matched hypertensive levels of systolic and/or 
diastolic blood pressure may be excluded at the Investigator’s discretion if deemed to be 
in the best interest of the patient. 
10. Pregnant (determined by a positive serum pregnancy test) or lactating female 
11. Unwillingness or inability to follow the procedures outlined in the protocol 
12. Estimated glomerular filtration rate <30 mL/min/1.73m2 or protein/creatinine ratio ≥0.4 
13. Bilirubin >1.5 × upper limit of normal (ULN), or aspartate aminotransferase (AST), 
alanine aminotransferase (ALT) >3 × ULN, or international normalized ratio (INR) 
>1.5 × ULN 
14. 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 
15. Other genetic, hormonal, chromosomal, cognitive, or behavioral impairment 
16. If living in a group home, patient spends less than 25 waking hours with their caregiver 
per week.  
17. Significant risk of committing suicide based on history, routine psychiatric examination, 
or based on the Investigator's judgment 
18. Participation in any other study involving an investigational product or device within 
4 weeks or 5 half-lives (whichever is longer) of consent/assent or longer as required by 
local regulations 
6.3. 
Patient Withdrawal Criteria 
A patient is free to withdraw consent/assent and/or discontinue participation in the study at any 
time, for any reason, without prejudice to further treatment. A patient may also be withdrawn 
from the study at any time at the discretion of the Investigator.  


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6.3.1. 
Discontinuation of Investigational Product 
The IP may be prematurely discontinued by the patient or the Investigator for reasons including, 
but not limited to: 
 Patient’s inability to comply with protocol requirements 
 The IP is no longer in the patient’s best interest, at the Investigator’s discretion 
 Patient’s decision to discontinue the IP 
 Discontinuation due to patient becoming pregnant 
 An unexpected, related SAE, or a SUSAR 
 Requirement for prohibited concomitant medication (Section 7.2). 
Patients who discontinue IP but do not withdraw consent/assent will continue to be followed 
according to the planned Schedule of Assessments but will not undergo drug dispensing or drug 
accountability. Patients who are unwilling or unable to complete planned assessments should 
undergo the End of Study Visit Assessments (Visit 14, Week 34). 
Patients who discontinue IP may have their IP tapered over up to 14 days, at the Investigator’s 
discretion. 
6.3.2. 
Drug-Induced Liver Injury 
Increase of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline 
phosphatase (ALP), or total bilirubin to >3 × ULN should be followed by repeat testing within 
48 to 72 hours of awareness of the increase, of ALT, AST, ALP, and total bilirubin to confirm 
the abnormalities and to determine if they are increasing or decreasing. Repeat laboratory testing 
can be done locally and/or centrally depending on clinical availability and turnaround time for 
prompt evaluation. There also should be an inquiry made about the symptoms. Repeat laboratory 
testing should also be done centrally as soon as possible, if not already tested centrally within 48-
72 hours of awareness of the increase. 
It is critical to initiate close observation immediately upon detection and confirmation of early 
signals of possible drug-induced liver injury, and not to wait until the next scheduled visit or 
monitoring interval. If additional testing, beyond that specified in the study protocol, is carried 
out, it is important that the patient’s information be added to the case report forms and database.  
Close observation includes: 
 Repeating liver enzyme and serum bilirubin tests two or three times weekly. Frequency 
of retesting can decrease to once a week or less if abnormalities stabilize or the IP has 
been discontinued and the patient is asymptomatic; 
 Obtaining a more detailed history of symptoms and prior or concurrent diseases; 
 Obtaining a history of concomitant drug use (including nonprescription medications and 
herbal and dietary supplement preparations), alcohol use, recreational drug use, and 
special diets; 


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 Ruling out acute viral hepatitis types A, B, C, D, and E; autoimmune or alcoholic 
hepatitis; nonalcoholic steatohepatitis; hypoxic/ischemic hepatopathy; and biliary tract 
disease; 
 Obtaining a history of exposure to environmental chemical agents; 
 Obtaining additional tests to evaluate liver function, as appropriate (e.g., international 
normalized ratio, direct bilirubin); 
 Considering gastroenterology or hepatology consultations.  
Discontinuation of IP should be considered if: 
 ALT or AST >8 × ULN; 
 ALT or AST >5 × ULN for more than 2 weeks; 
 ALT or AST >3 × ULN and (total bilirubin >2 × ULN or international normalized ratio 
>1.5); 
 ALT or AST >3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%). 
All study patients showing possible drug-induced liver injury should be followed until all 
abnormalities return to normal or to the baseline state. Drug-induced liver injury may develop or 
progress even after the causative drug has been stopped. Results should be recorded in the 
electronic case report form (eCRF) and in the database. Note that longer follow-up can 
sometimes reveal an off-drug repetition of what had appeared to be drug-induced liver injury, 
indicating that liver injury was related to underlying liver disease. 
All potential cases of drug-induced liver injury should be reviewed with the Medical Monitor. 
The IP should be discontinued at the Investigator’s discretion and the Sponsor notified at the 
earliest convenience.  
6.3.3. 
 Patient Withdrawal  
The Investigator should withdraw the patient from the study if they believe that participation is 
no longer in the patient’s best interest, or in the event of study termination by the Sponsor. If the 
patient elects to withdraw from the study, reason(s) for withdrawal should be documented. The 
Investigator will discuss with the patient procedures for withdrawal and any additional care or 
treatment alternatives available at that time. In addition, patients unable to tolerate the 
0.1 mL/kg/day dose level during the Tolerability Period or their assigned dose level(s) during the 
Dose Escalation Period will be withdrawn from the study.  
If a patient withdraws consent/assent from the study, the patient should be encouraged to 
complete all End of Study Visit assessments (Visit 14, Week 34) completed as described in the 
Schedule of Assessments (Table 7). At time of withdrawal of consent/assent, the patient will be 
withdrawn from all additional study procedures and follow-up. 
Data collected until patient withdrawal will be retained and included in the analysis of the study 
in accordance with local rules and regulations.  


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6.3.4. 
Lost to Follow-Up 
A patient will be considered lost to follow-up if they repeatedly fail to return for scheduled visits 
and are unable to be contacted by the study site.  
The following actions must be taken if a patient fails to return to the clinic for a required study 
visit: 
 Attempt to contact the patient and reschedule the missed visit(s) as soon as possible and 
counsel the patient on the importance of maintaining the assigned visit schedule 
 Make every effort to regain contact with the patient (where possible, 3 telephone calls 
and, if necessary, a certified letter to the patient’s last known mailing address) and 
document these efforts in the patient’s medical record 
 Ascertain if the patient wishes to and/or should continue in the study 
 Consider the patient lost to follow-up once the aforementioned steps have been taken, 
contact with the patient has not been regained and document the reason for loss to 
follow-up if known. 
6.4. 
Evaluation of Eligibility at the End of the Screening and Tolerability 
Periods 
6.4.1. 
Screening Period 
During the Screening Period, Investigators will have to review a patient’s eligibility to proceed 
to the Tolerability Period. This will include review of inclusion/exclusion criteria, laboratory 
assessments, a review of PWS diagnosis, and ECG reading.  
In addition, at the end of the Screening Period (Visit 2) and prior to initiating dosing of patients 
at Visit 2, patients/caregivers must first complete the HQ-CT.  
The EDC system will automatically calculate a mean HQ-CT score from Visit 1 and Visit 2. 
Patients must have a mean HQ-CT score ≥13 to be eligible to continue in the Tolerability Period. 
Patients with a mean score <13 will not be eligible to continue in the Tolerability Period and will 
be discontinued from the study. 
6.4.2. 
Tolerability Period 
At the end of the Tolerability Period (Visit 5), Investigators will review a patient’s eligibility to 
be randomized and proceed to the Dose Escalation Period.  
Patients/caregivers must first complete the HQ-CT. The EDC system will automatically calculate 
a mean HQ-CT score from Visit 3, Visit 4 and Visit 5. Patients must have a mean HQ-CT score 
≥13 to be eligible to be randomized and proceed to the Dose Escalation Period. Patients with a 
mean score <13 will not be eligible for randomization and will not have the opportunity to 
participate in the long-term extension study (SCOUT-016). 
In addition, the EDC system will also automatically calculate the change in HQ-CT score from 
the Tolerability Period to the Screening Period. This change is calculated as: 
Mean HQ-CT score (Visit 3, Visit 4, Visit 5) – Mean HQ-CT score (Visit 1, Visit 2) 


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Patients with a decrease HQ-CT score ≤7 will be eligible for randomization. Patients with a 
decrease in HQ-CT score >7 will not be eligible for randomization and unable to proceed to the 
Dose Escalation Period. 
7. 
TREATMENT OF PATIENTS 
7.1. 
Investigational Product Administration 
The IP (RAD011 or placebo) will be administered orally twice daily with food, approximately 12 
hours apart. Patients must take the IP with food throughout the study.  
When patients are seen at the research site, dosing should be performed at the research site at the 
time points indicated in Table 7, during the Visit 2 and Visit 5 assessments. The dose prior to 
Visit 8 (Week 10) should be taken approximately 4 to 6 hours prior to the visit to allow for PK 
collection approximately 6 ± 2 hours after the dose (Section 10.1.14). When patients have a 
remote visit, dosing does not need to be performed at the research site.  
7.1.1. 
Tapering of Investigational Product for Patients Entering the Taper and Follow-
Up Periods 
For patients not participating in the long-term extension study (SCOUT-016) and entering the 
Taper and Follow-Up Periods, the IP will be tapered over 14 days. Following completion of Visit 
14 (End of Study/Week 34 Visit), the IP should be decreased by 50% during the first 7 days, 
followed by an additional 50% taper during the following 7 days and then discontinued. The 
taper schedule may be modified at the discretion of the Investigator but cannot occur over a 
longer time than 14 days. A final safety follow-up will be conducted 14 days after the IP is 
discontinued for patients who do not elect to continue into the long-term extension study. 
7.2. 
Concomitant Medications 
Growth hormone, psychotropic medications, and other therapies such as thyroid hormones 
(including homeopathic or naturally sourced thyroid supplements), started prior to enrollment 
and at stable doses for at least 90 days prior to enrollment are permitted in this study. Doses of 
psychotropic medications, thyroid hormones, and GH may be adjusted during the study if 
clinically required, at the discretion of the Investigator. However, change in such medications 
must be documented in the EDC. 
7.2.1. 
RAD011 Drug-Drug Interactions Overview 
The major biotransformation pathway for CBD is similar to that of other cannabinoids and is 
mediated by hydroxylation by CYP enzymes. Its interactions with human drug metabolizing 
enzymes (as a substrate, inhibitor, or inducer) were recently reviewed (Forster, 2021). 
Cannabidiol is metabolized primarily in the liver by CYP3A4 and to a lesser extent by 
CYP2C19. Specifically, CBD inhibits CYP3A4, CYP3A5, and CYP1A1 in vitro. It also appears 
to inhibit CYP2C9 and the transport protein P-glycoprotein. Thus, Cannabidiol may inhibit these 
two isozymes (CYP3A4 and CYP 2C19), as well as having small effects on CYP3A5, CYP2D6, 
CYP1A1, CYP1A2, and CYP2C9 (see Investigator’s Brochure for more information). 


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Medications that are strong inhibitors/inducers/sensitive substrates with a narrow therapeutic 
index for those CYP enzymes, although not prohibited, may require that the patient is monitored 
with special care to identify any AEs arising due to the potential for altered drug metabolism. 
Thus, the Investigator and study center staff should monitor patients who are taking concomitant 
medications that are metabolized by CYP3A4/5, CYP2C19, CYP1A1/2, CYP2C8/9, CYP2D6, 
or by P-glycoprotein with special care. 
Patients who experience adverse events due to significant drug/ drug interactions may have 
treatment discontinued while remaining on the study, at the Investigator’s discretion. 
7.3. 
RAD011 Precautions 
The following precautions should be communicated to patients or observed during the course of 
the study: 
 Somnolence and sedation: monitor for somnolence and sedation and advise patients not 
to drive or operate machinery until they have gained sufficient experience on RAD011. 
Concomitant use of RAD011 with other central nervous system depressants (including 
alcohol) may increase the risk of sedation and somnolence 
 Hypersensitivity reactions: advise patients to seek immediate medical care. Discontinue 
and do not restart RAD011 if hypersensitivity occurs.  
 Withdrawal of antiepileptic drugs: should be gradually withdrawn to minimize the risk of 
increased seizure frequency and status epilepticus.  
7.4. 
Treatment Adherence 
Importance of adherence to regimen will be reviewed with patients and study staff should ensure 
that patients remain compliant with the IP and study assessments. In addition, drug 
accountability will be completed at each study visit as detailed in the Pharmacy Manual. 
7.5. 
Randomization and Blinding 
Randomization will occur at Visit 5 (Week 7) after review of all eligibility criteria by the 
Investigator.  
Both Investigators and patients will be blinded to the randomization assigned treatment. During 
the Tolerability Period, all patients will receive 0.1 mL/kg/day of placebo. To maintain the blind, 
multiple placebo groups were created to mimic the RAD011 groups: low volume 
(0.1 mL/kg/day), mid volume (0.2 mL/kg/day), and high volume (0.4 mL/kg/day). During the 
dose escalation period, the volume of blinded therapy for the mid volume and high volume 
placebo groups will increase in the same manner as the mid dose and high dose RAD001 groups, 
further ensuring blinding between RAD011 and placebo 
The matching (appearance, smell and taste) placebo and RAD011 product will utilize the same 
MCT vehicle. 
Phase 2 of the study 
Patients who meet eligibility criteria will be randomized in a 2:2:2:1:1:1 manner to receive 
double-blind treatment with IP, defined as either low dose (10 mg/kg/day, [0.1 mL/kg/day]) 


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RAD011, mid dose (20 mg/kg/day, [0.2 mL/kg/day]) RAD011, high dose (40 mg/kg/day 
[0.4 mL/kg/day]) RAD011, low volume (0.1 mL/kg/day) placebo, mid volume (0.2 mL/kg/day) 
placebo, or high volume (0.4 mL/kg/day) placebo using a centralized randomization system. 
Randomization will be stratified according to current use of GH treatment (yes/no) and age 
(≥16 or <16 years old). 
Phase 3 of the study 
Following review by the DMC (Section 10.4), 1 or 2 dose levels will be recommended for 
continued development and assessment in Phase 3 of the study. Therefore, following the 
Tolerability Period, patients meeting randomization eligibility criteria will be randomized using a 
centralized randomization system in a way to obtain a balanced number of patients on RAD011 
and placebo to receive double-blind treatment with IP at dose levels recommended by the DMC.  
If 1 dose is recommended for continued development and assessment in Phase 3 of the study, 
randomization will be 1:1 (RAD011: placebo). 
If 2 doses are recommended for continued development and assessment in the Phase 3 part of the 
study, randomization will be 2:2:1:1 (RAD011 dose 1: RAD011 dose 2: placebo: placebo). 
Patients aged 8 to <12 years may be allowed to participate in the Phase 3 part of the study and 
will be randomized in a way to obtain a balanced number of patients on RAD011 (at dose levels 
recommended by the DMC) and placebo.  
7.5.1. 
Breaking the Blind 
Breaking the treatment blind for a patient should be done only in the event of a medical 
emergency where the identity of the IP is necessary to appropriately treat the patient. The 
Investigator may unblind the treatment received by the patient through the interactive response 
technology (IRT). The IRT will automatically document and record any such unblinding and 
notify the Sponsor Medical Monitor of the unblinding event. If possible, the Sponsor and/or 
designee should be contacted prior to unblinding of the treatment. The study monitor will not be 
apprised of the actual treatment assignment.  
7.6. 
Treatment After the End of the Study 
All patients completing the End of Study Visit (Visit 14, Week 34) may be offered enrollment in 
the long-term extension study (SCOUT-016).  
8. 
STUDY DRUG MATERIALS AND MANAGEMENT 
8.1. 
Description of Investigational Product 
RAD011 is an oral CBD solution in which CBD is solubilized in MCTs. Cannabidiol is 
classified as a phytocannabinoid with a low affinity for the cannabinoid receptors CB1 and CB2. 
Although CBD has a low affinity for CB1 receptors (Petitet, 1998; Thomas, 1998), it has 
demonstrated antagonism for CB1 receptor agonists (Pertwee, 2002; Zuardi, 1981). Table 8 
presents an overview of the IP. Cannabidiol Oral Solution 100 mg/mL formulation contains 
vitamin E (DL-alpha-tocopherol) as an antioxidant, saccharin as a sweetener, strawberry flavor, 
and MCTs. 


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Refer to the Investigator’s Brochure for a detailed description of RAD011. Refer to the 
Pharmacy Manual for detailed instructions on preparation, handling, storage, and accountability 
of RAD011. 
 
Table 8: 
Investigational Product 
 
Investigational Product 
Product Name: 
RAD011 
Placebo 
Dosage Form: 
Oral solution 
Oral solution 
Unit Dose 
30 mL vial at a concentration of 
100 mg/mL 
30 mL vial with vehicle 
Route of Administration 
Orally 
Orally 
Physical Description 
Clear, colorless to pale yellow to 
pinkish brown solution, free of visible 
particles. Medium chain triglycerides 
(Miglyol 812N) are used as the vehicle 
to dissolve cannabidiol 
Saccharin concentration of 0.24 mg/mL 
Clear, colorless to pale yellow to 
pinkish brown solution, free of visible 
particles. Medium chain triglycerides 
(Miglyol 812N) are used to formulate 
the placebo formulation 
Saccharin concentration of 0.24 mg/mL 
Manufacturer 
Benuvia Manufacturing 
Benuvia Manufacturing 
 
8.2. 
Study Drug Packaging and Labeling 
RAD011 (100 mg/mL) finished drug product is filled into 30 mL amber-colored screwcap glass 
bottles and capped with a 20-mm child resistant white polypropylene cap. The placebo will be 
provided in identical, amber-colored screwcap, child-resistant glass bottles. 
Investigational product will be released to the site upon receipt of all required essential 
documents. All medication provided to the study site will be prepared, packaged, and labeled by 
the Sponsor according to Standard Operating Procedures (SOP), Good Manufacturing Practices 
(GMP), and applicable local laws and regulations. 
8.3. 
Study Drug Storage 
The IP is shipped to the site at 2 to 8°C (36 to 46°F). While at the site, IP must always be stored 
in a refrigerated (2 to 8°C [36 to 46°F]) secure location with limited access. To ensure adequate 
storage in the home setting, IP is recommended to be stored in the caregiver’s refrigerator.  
Additional information on stability is provided in the Pharmacy Manual. 


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8.4. 
Study Drug Preparation 
Investigational product will be obtained from the vial using a plastic syringe provided by the 
Sponsor. The dose will be ejected from the plastic syringe into a dosing cup. Investigational 
product must be administered orally directly and not mixed with food or other liquids prior to 
administration. Patients should take the IP with food. 
8.5. 
Study Drug Accountability 
The Investigator is required to maintain adequate records of the disposition of the IP, including 
kit numbers, the date and quantity of drug received, the time, date, and volume to whom it was 
dispensed, and a detailed accounting of any drug accidentally or deliberately destroyed.  
Drug accountability will be measured at every in-person visit by weighing and counting the 
number of bottles returned by the patient at each visit. Patients will be required to retain and 
return all empty and partially filled bottles at each study visit. Additional details on drug 
accountability are provided in the Pharmacy Manual. 
Records for storage, preparation, and dispensing of IP must be available for inspection by the 
Sponsor throughout the study.  
8.6. 
Study Drug Handling and Disposal 
Unused IP will be returned to the Sponsor at the conclusion of the study, or destroyed according 
to the site’s SOPs, as mutually agreed between the Sponsor and the Site.  
Bottles of IP returned by patients may be destroyed per the site’s SOPs once accountability has 
been completed.  
9. 
ASSESSMENT OF EFFICACY 
Questionnaires completed by the patients, or their caregivers are used to assess primary, 
secondary, and other endpoints. The same caregiver should complete the questionnaires with the 
patient every time the questionnaires are administered.  
9.1. 
Primary Efficacy Endpoint (HQ-CT Questionnaire) 
The primary efficacy endpoint for this study is the change in HQ-CT scores from Baseline 
through End of Study/Week 34 Visit for RAD011 compared to placebo. The HQ-CT 
questionnaire is a tool that was developed specifically for use in patients with PWS and was 
validated in this population as a 13-item questionnaire (Dykens, 2007). The original tool was 
further refined and validated and now consists of 9 items, with a 2-week recall period. Each 
question is rated on a scale of 0 to 4, therefore providing a maximum score of 36. An HQ-CT 
score of 13 is associated with moderate to severe hyperphagia (Fehnel, 2015). 
The HQ-CT questionnaire was selected as the primary endpoint since it has been validated in 
patients with PWS and is the gold standard outcome measure in studies evaluating 
hyperphagia-related behavior (Allas, 2018; McCandless, 2017). Additionally, this tool has 
recently been reported to have a strong correlation to caregiver burden, further supporting the 
clinical relevance of the HQ-CT questionnaire in this study (Kayadjanian, 2021). 


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9.2. 
Secondary Efficacy Endpoints 
9.2.1. 
Change in Irritability (Irritability subscale of the ABC Questionnaire) 
A secondary endpoint of this study is to evaluate the change in PWS-associated irritability from 
Baseline through End of Study/Week 34 Visit using the irritability subscale of the ABC 
questionnaire. In patients with PWS, anxiety manifests as irritability. The ABC questionnaire is 
an informant-rated questionnaire assessing severity of behavioral symptoms, is one of the few 
empirically developed scales designed to measure psychiatric symptoms and behavioral 
disturbance exhibited by individuals with developmental disabilities (intellectual disability, 
autism spectrum disorder, cerebral palsy, epilepsy). According to factor analyses, there are five 
subscales: (a) irritability and agitation, (b) lethargy and social withdrawal, (c) stereotypic 
behavior, (d) hyperactivity and noncompliance, and I inappropriate speech (Aman, 1987). The 
ABC originally was developed to assess the effectiveness of psychotropic medication, and has 
been used extensively in pediatric, as well as adult behavioral and psychiatric research due to its 
high reliability and validity. The Irritability subscale of the ABC covers symptoms such as 
agitation, aggression, meltdowns, and self-harm. An extensive psychometric assessment of the 
ABC has indicated that the subscales have high internal consistency, good reliability, and 
established validity. For this reason, the Irritability subscale of the ABC questionnaire is being 
proposed to evaluate PWS-associated anxiety, manifesting as irritability, as a secondary 
outcome. Anxiety and irritability associated with PWS is of significant concern to patients and to 
their caregivers and represents an unmet medical need (Aman, 1995; Aman, 1987; Aman, 1985; 
Aman, 1985).  
Overall, the ABC contains 58 items divided in 5 subscales, and the Irritability subscale contains 
15 items. Each item is scored as 0 (never a problem), 1 (slight problem), 2 (moderately serious 
problem), or 3 (severe problem). Items load onto one of five empirically derived subscales: 
Irritability, Agitation, & Crying (15 items); Lethargy/Social Withdrawal (16 items); Stereotypic 
Behavior (7 items); Hyperactivity/Noncompliance (16 items); and Inappropriate Speech (4 
items). In addition, a Total Score can be calculated. The ABC questionnaire has a recall period of 
1 month, and has also successfully been used in patients with PWS (Clarke, 1996; Consoli, 2019; 
Ishii, 2017; Salehi, 2018). 
9.2.2. 
Change in Clinician Global Impression of Change in Hyperphagia (CGI-C 
Questionnaire) 
A secondary endpoint of this study is to evaluate the change in hyperphagia as defined by the 
CGI-C in Hyperphagia response through End of Study/Week 34 Visit. The CGI scales have been 
found to be valid as an external criterion in symptom improvement and to correlate significantly 
with self-rated and other valid scales of symptom severity (Khan, 2002; Leon, 1993). Clinical 
Global Impression scales have also been used successfully in evaluating therapeutic responses in 
patients with PWS (Avrahamy, 2015; Consoli, 2019; Dykens, 2018).  
9.2.3. 
Change in Clinician Global Impression of Severity of Hyperphagia (CGI-S 
Questionnaire) 
A secondary endpoint of this study is to evaluate the change in severity of hyperphagia as 
defined by the CGI-S response from Baseline through End of Study/Week 34 Visit.   


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9.3. 
Other Endpoints 
9.3.1. 
Change in Caregiver Global Impression of Change in Hyperphagia, Change in 
Caregiver Global Impression of Severity of Hyperphagia, Change in Caregiver 
Global Impression of Change in Irritability  
Caregiver global impression scales of severity and change specific to hyperphagia and change in 
irritability will be other endpoints in this study. They will be assessed through the End of 
Study/Week 34 visit. 
9.3.2. 
Change in Overall Behavior (ABC) 
Change in overall behavior from Baseline through End of Study/Week 34 Visit in response to 
RAD011 compared to placebo will also be considered an endpoint in this study. The remaining 
ABC subscales (described in Section 9.2.1) will be used to assess overall behavior. 
9.3.3. 
Change in Sleep (ESS-CHAD Questionnaire) 
An other endpoint is the change in the ESS-CHAD questionnaire from Baseline through End of 
Study/Week 34 Visit. The ESS-CHAD is an 8-question scale with a 1-month recall period that 
has been validated in school-attending children and adolescents to evaluate daytime sleepiness 
(Janssen, 2017). Each question is rated on a 0 to 3 scale, with a maximum score of 24, and a 
score above 10 is considered to represent mild excessive daytime sleepiness.  
9.3.4. 
Change in Body Mass Index and Weight 
Changes in BMI and weight through End of Study/Week 34 Visit will be evaluated as an other 
endpoint. Change in age-normalized BMI z-scores (USPSTF, 2017; Wei, 2020) will be used for 
patients aged 8 to 19 years inclusively, whereas percent change in weight will be used for 
patients aged 20 to 65 years.  
9.3.5. 
Change in Skin-Picking Behavior 
An other endpoint in this study is to evaluate the change in skin-picking behavior between scale 
values across time points using the Skin Picking questionnaire from Baseline through End of 
Study/Week 34. The Skin Picking questionnaire is a 6-item questionnaire of skin picking 
symptoms, with scores ranging from 0 to 24 (Keuthen, 2001). A score of ≥7 is considered highly 
suspicious for a skin picking disorder. 
9.3.6. 
Change in Muscle/Fat Composition (DEXA Scan) 
Change in muscle/fat composition using a DEXA scan from Visit 5 through End of 
Study/Week 34 visit will also be an other endpoint. The assessment of change in muscle/fat 
composition will be performed at a selected number of US sites only. All attempts should be 
made to have both DEXA scans performed at the same site using the same DEXA scanner, and 
DEXA scans of children and adolescents should be interpreted only by providers experienced in 
scoring DEXA scan in this patient population. Results of the DEXA scan will be reported as 
percentage body fat. The DEXA scan may be performed within ± 7 days of Visits 5 and 14. 


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9.4. 
Pharmacokinetic Endpoints 
Throughout the study, plasma samples will be collected to establish the PK profile of CBD and 
2 metabolites, 7-OH-CBD and 7-COOH-CBD in patients with PWS. Furthermore, an 
exposure-response analysis using CBD and 7-OH-CBD concentrations as well as a population 
PK model will be derived from the data. Details on sample collection are provided 
in Section 10.1.13 and in the Laboratory Manual. 
9.5. 
Biomarkers assessments (Phase 3 exploratory) 
For Phase 3 patients: If the patient/legal guardian consents, samples will be collected for 
exploratory assessment of biomarkers. Blood samples will be collected at Visit 1 and Visit 14 
and stored for potential exploratory analysis of biomarkers (including but not limited to 
inflammation). Details on sample collection are provided in the Laboratory Manual. No genetic 
or DNA analysis will be conducted on the samples. 
10. 
ASSESSMENT OF SAFETY 
10.1. 
Safety Parameters 
10.1.1. 
Demographics and Medical/Surgical/Seizure History 
Demographic characteristics will be collected during the Screening Visit (Visit 1). A full 
medical/surgical history (including seizure history) will also be documented at the Screening 
Visit (Visit 1). Evaluation of seizure history and Seizure Patient Impression are provided in 
Appendix 2. 
10.1.1.1 
Seizure Patient Impression 
Patients with a history of seizure who are randomized will be evaluated for potential changes in 
seizure activity at the End of Study/Week 34 Visit as detailed in Appendix 2. 
10.1.2. 
Vital Signs 
Vital signs to be collected include BP, HR, RR, oxygen saturation, and temperature. Blood 
pressure and pulse measurements may be assessed using an automated device or by manual 
techniques. Vital signs should be collected after the patient has rested (per standard of care) and 
prior to blood draws for laboratory tests. 
10.1.3. 
 Weight and Height 
Height and weight will be collected as identified in the Schedule of Assessments tables (Table 6 
and Table 7). Both height and weight must be collected per the Schedule of Assessments as BMI 
Z-scores will be computed for children and change from baseline will be computed for adults 
(see the SAP for additional information). Efforts should be made to use the same scale 
throughout the project when possible.  


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10.1.4. 
Physical Examination 
A full physical examination will be performed at Screening Visit 1 (Visit 1) and at Visit 5 
(Week 7). All other physical examinations should be abbreviated, symptom directed physical 
examinations. The Investigator is responsible for conducting the exams, determining findings, 
assessing abnormalities, and evaluating clinical significance. 
10.1.5. 
Electrocardiogram 
A 12-lead ECG will be performed after the patient has rested in a supine position.  
10.1.6. 
Columbia Suicide-Severity Rating Scale 
The C-SSRS is a broadly validated scale aimed at assessing suicidal risk in a variety of children 
and adult populations. The scale includes suggested questions to solicit the type of information 
needed to determine if suicidal ideation and/or behavior occurred. Administration of the C-SSRS 
should occur after nonleading AE collection, and findings from the C-SSRS should not be 
included as an AE unless it leads to study discontinuation. The first time the C-SSRS 
questionnaire is administered, on Visit 5 (Week 7), the Baseline/Screening questionnaire 
(Posner, 2008) should be used, and the “Since Last Visit” questionnaire should be used for all 
subsequent assessments. 
The standard C-SSRS scale should be used for patients aged 6 and over and the Children’s C-
SSRS scale should be used in patients aged less than 6 years. However, the Children’s version 
may be used in patients aged 6 years or older when the Investigator or designee determines that 
the patient is unable to understand the first couple of questions in the standard version. The same 
C-SSRS scale should be used for a given patient throughout the study.  
If a suicidal behavior is identified during the study, the Investigator must provide immediate care 
and refer the patient to additional care as needed.  
10.1.7. 
Laboratory Assessments 
Laboratory assessments will be performed per the Schedule of Assessments (Table 6 and 
Table 7). All laboratory assessments are to be performed centrally unless otherwise specified. 
The Investigator must review results from these laboratory assessments (performed locally and 
centrally) and determine the clinical significance of any results outside the reference range. This 
review must be documented, and laboratory values considered clinically significant during this 
study be recorded as an AE. On the days where a dose of IP is administered, all laboratory 
assessments should be performed prior to dosing unless otherwise specified. A list of analytes is 
presented in Table 9. 
10.1.8. 
Hepatic Function Testing 
Patients presenting with elevated liver function tests should be closely monitored. Any patient 
with an elevation of ALT or AST ≥3 × ULN, alkaline phosphatase ≥2 × ULN, or total 
bilirubin ≥2 × ULN should have their liver function tests repeated within 3 days. If the repeat 
results remain above these thresholds or higher, the Investigator should conduct additional 
testing and consult the Sponsor Medical Monitor. Monitoring of liver function tests should 
continue until results stabilize or return approximately to their level prior the initial elevation.  


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10.1.9. 
Estimated Glomerular Filtration Rate 
Estimated glomerular filtration rate will be calculated by the central laboratory using the Chronic 
Kidney Disease Epidemiology Collaboration (CKD-EPI) formula (Levey, 2009) for patients 
aged ≥18 years. For patients aged ≤17 years, the “Bedside Schwartz” equation (Schwartz, 2009) 
will be used to calculate eGFR. 
10.1.10. 
Urine Drug Screen 
Urine drug screen for drugs of abuse will be performed locally via dipstick testing on urine and 
may be repeated at the Investigator’s discretion. Testing kits will be provided by the central 
laboratory. Urine drug screens should test for the following drugs of abuse: THC, cocaine, 
opiates, methamphetamine, amphetamines, phencyclidine (PCP), benzodiazepine, barbiturates, 
methadone, tricyclic antidepressants, ecstasy, and oxycodone. 
10.1.11. 
Follicle-Stimulating Hormone 
Menopausal status of women must be confirmed by testing for FSH levels at the Screening Visit 
(Visit 1). To be considered menopausal, FSH level must be ≥30 mIU/mL and the patient must 
not have had a menstrual period in ≥1 year. Follicle-stimulating hormone testing must only be 
performed in women reporting menopause. 
10.1.12. 
Pregnancy Screen 
A serum pregnancy test will be performed centrally at Screening (Visit 1) in women of 
childbearing potential (WOCBP). All other pregnancy tests will be performed locally using 
dipstick testing on urine in women of childbearing potential only. Testing kits will be provided 
by the study site. A positive urine pregnancy test must be confirmed by sending a serum sample 
to the central laboratory. Women with a confirmed positive serum pregnancy test should be 
withdrawn from the study. The Investigator should refer the patient for appropriate care. Details 
on reporting and following pregnancies are provided in (Section 10.2.9). 
10.1.13. 
Pharmacokinetic Sampling 
On Visits 5 (Week 7), 8 (Week 10), 12 (Week 27), and 14 (End of Study [EOS]/Week 34), 
patients will have a blood sample collected for PK at the same time as their laboratory blood 
samples. The time of sampling will be recorded, with the exception of Visit 8 (Week 10). 
Pharmacokinetic sampling on Visit 8 should occur within 6 ± 2 hours of dose. The dose 
preceding Visit 8 PK sampling may be taken at home in order to comply with the PK sampling 
window. Pharmacokinetic samples at Visits 5, 12, and 14 can occur without regards to the time 
of dosing, as long as dosing and PK sampling times are accurately recorded. 


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Table 9: 
Laboratory Analytes 
Renal Panel (10-hour fastinga) 
Hematology 
HbA1c 
Sodium 
Hematocrit 
 
Potassium 
Hemoglobin 
Coagulation 
Chloride 
MCV 
PT-INR 
Calcium 
MCH 
Appetite Hormones 
Bicarbonate 
MCHC 
Insulin 
Glucose 
RDW 
Circulating ghrelinb 
Phosphorus 
RBC 
Leptin 
BUN 
WBC 
Urinalysis 
Creatinine 
Platelets 
Color 
eGFR 
Differential (% and absolute 
Appearance 
Liver Function Panel 
Count) 
pH 
ALT 
 
Neutrophils 
Specific gravity 
AST 
 
Eosinophils 
Protein 
Albumin 
 
Basophils 
Glucose 
Alkaline phosphatase 
 
Lymphocytes 
Ketones 
Direct and indirect bilirubin 
 
Monocytes 
Bilirubin 
Total bilirubin 
Urine tests 
Blood 
Total protein 
Drug screen including THCc,d  
Urobilinogen 
Serologies 
Pregnancy testc,e,f  
Nitrites  
HIV 
Other test 
Microscopic examination if  
Hepatitis B surface antigen 
FSHg 
blood, protein, or leukocyte  
Hepatitis C antibody 
Quantitative serum pregnancy testh 
esterase is abnormal in urine 
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; 
eGFR = estimated glomerular filtration rate; FSH = follicle stimulating hormone; HbA1c = glycosylated 
hemoglobin; HIV = human immunodeficiency virus; INR = international normalized ratio; MCH = mean 
corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin concentration; MCV = mean corpuscular volume; 
PT = prothrombin time; RBC = red blood cells; RDW = red cell distribution width; THC = tetrahydrocannabinol; 
WBC = white blood cells. 
All tests to be performed centrally unless otherwise specified 
a Fasting is preferred, if possible. If obtained in a non-fasting state, will not be considered a protocol deviation. 
b Includes acylated ghrelin and des-acyl ghrelin 
c Performed locally via dipstick testing and provided by the central laboratory. Must include testing for THC, 
cocaine, opiates, methamphetamine, amphetamines, PCP, benzodiazepine, barbiturates, methadone, tricyclic 
antidepressants, ecstasy, and oxycodone 
d May be repeated at any time at the Investigator’s discretion 
e To be performed in females of childbearing potential only. Testing kits to be provided by the study site 
f If positive, a confirmatory pregnancy test at the central laboratory is required 
g To be performed in postmenopausal females only 
h To be performed centrally at Screening (Visit 1) and if a local urine pregnancy test is positive. 


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10.1.14. 
Food Diary 
A food diary will be distributed to all patients on Visits 4, 7, 11 and 14 but can be distributed at 
the site’s or patient’s convenience. This food diary will be collected as per Table 7. The food 
diary will collect time of food consumption, type and amount of food consumed, date and time of 
evening and morning dose, and support the pharmacokinetic analysis.  
10.2. 
Adverse and Serious Adverse Events 
10.2.1. 
Evaluation of Safety 
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of patients and is mandated by Regulatory Agencies worldwide. All 
clinical studies sponsored by Radius will be conducted in accordance with SOPs that have been 
established to conform to regulatory requirements worldwide to ensure appropriate reporting of 
safety information. 
Where possible, a diagnosis rather than a list of symptoms should be recorded. All AEs should 
be captured on the appropriate AE pages in the electronic case report form (eCRF) and in source 
documents. 
All AEs will be collected from the time of consent/assent until the following time points: 
 For patients who are not enrolled: until time of screen failure 
 For enrolled patients:  
 For patients continuing in the long-term extension study SCOUT-016: through 
Visit 14 (Week 34) inclusively 
 For patients entering the follow-up period with IP tapering: through Visit 16 
(Week 38). 
Investigators are not obligated to actively seek AEs or SAEs after the participant has concluded 
study participation. However, if the investigator learns of any SAE, including a death, at any 
time after a participant has completed the study or 30 days after the last dose of IP, and he/she 
considers the event to be reasonably related to the study intervention, the investigator must 
promptly report the SAE.  
All patients will be queried using non-leading questions about the occurrences of AEs at each 
study visit. Adverse events spontaneously reported by the patient and/or in response to an open 
question from the study personnel or revealed by observation will be recorded during the study at 
the investigational site. When possible, a constellation of signs and/or symptoms should be 
identified as one overall event or diagnosis. All AEs for enrolled patients will be recorded in the 
eCRF and the patient’s source documents. Any AEs for patients who are screened but not 
subsequently enrolled in the study will be recorded only in the patient’s source documents. The 
following data should be documented for each AE by the Investigator: 
 Description of the event term as diagnosis, in standard medical terminology when 
possible 
 Classification of “serious” or “not serious” 


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 Date and time of the onset and resolution (if applicable) 
 Severity 
 Causal relationship to study drug 
 Action taken with study drug 
 Outcome (as applicable) 
 Concomitant medication or other treatment given 
 Whether or not it caused the patient to discontinue the study. 
10.2.1.1 
Definition of Adverse Events 
An AE is any untoward medical occurrence in a clinical investigation patient administered a 
pharmaceutical product, which does not necessarily have a causal relationship with the treatment. 
An AE can therefore be any unfavorable and unintended diagnosis, symptom, sign (including an 
abnormal laboratory finding), syndrome or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product (ICH, 1995). This includes any newly occurring event which occurs during the study, 
having been absent at Screening, or any previous condition, if present at Screening, that appears 
to worsen (i.e., increased in severity or frequency) after the administration of study drug. 
Study assessments including laboratory tests, ECGs, physical examinations, and vital signs 
should be performed and those deemed a clinically significant worsening from Screening will be 
documented as an AE. When possible, a clinical diagnosis for the study assessment should be 
provided rather than the abnormal test result alone (e.g., urinary tract infection, anemia). In the 
absence of a diagnosis, the abnormal study assessment itself should be listed as the AE (e.g., 
bacteria in urine or decreased hemoglobin). 
Investigators will be requested to evaluate abnormal study assessments for clinical significance. 


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This would include: 
 Worsening from Screening (change in nature, severity, or frequency) of conditions 
present at Screening 
 Concomitant signs or symptoms related to the abnormal study assessment 
 Intercurrent illnesses 
 Drug interactions 
 Events related to or possibly related to concomitant medications 
 Further diagnostic testing or medical/surgical intervention is required 
 Abnormal laboratory values (this includes significant shifts from Screening within the 
range of normal that the Investigator considers to be clinically significant) 
o An abnormal laboratory value will not be assessed as an AE unless it requires a 
therapeutic intervention or is considered by the Investigator to be clinically 
significant 
 Clinically significant abnormalities in physical exam, vital signs, or weight 
 A change in the dose of study drug, if study drug is withheld, or discontinuation from 
study drug occurs. 
Hyperphagia or decreased appetite will not be considered an AE in this study unless it 
significantly worsens or warrants reporting in the opinion of the Investigator. 
10.2.1.2 
Determination of Clinical Significance Must be Made by the Investigator. 
Events that do not meet the definition of an AE or SAE include: 
 Planned hospital admissions or surgical procedures that are elective or for a condition 
that existed before the patient signed the ICF are not considered an AE unless the 
condition deteriorates in an unexpected manner during the study (e.g., surgery had to 
be performed earlier than planned) 
 Anticipated day-to-day fluctuations of pre-existing disease(s), condition(s), and signs 
or symptoms present or detected prior to the start of the study that are not more severe 
than expected for the patient’s condition. 
10.2.1.3 
Definition of a Serious Adverse Event 
An SAE is defined (21CFR 312.32) as any adverse experience that suggests a significant hazard, 
contraindication, side effect, or untoward medical occurrence that, in the view of the Investigator 
or Sponsor, results in any of the following criteria: 
 Death 
 Is immediately life threatening 
o An AE or suspected adverse reaction that places the patient, in the view of either 
the Investigator or the Sponsor, at immediate risk of death. It does not include an 


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AE or suspected adverse reaction that, had it occurred in a more severe form, 
might have caused death 
 Requires in-patient hospitalization or prolongation of existing hospitalization 
o Admittance to an emergency room for observation without being admitted to the 
hospital may be considered to be an AE but is not considered as an SAE unless 
other serious criteria is met. In addition, complications that occur during 
hospitalization are AEs, and if a complication prolongs hospitalization the event is 
considered serious 
 Results in persistent or significant disability or incapacity 
o Defined as a substantial disruption in a person’s ability to conduct normal life 
functions 
 Results in a congenital abnormality or birth defect 
o A congenital anomaly/birth defect that occurs in the offspring of a patient exposed 
to the IP 
 Other medically important event 
o An AE that may not result in death, be life threatening, or require hospitalization 
may be considered an SAE when, based upon appropriate medical judgement, the 
event may jeopardize the patient or may require medical intervention to prevent 
one of the outcomes listed in the definition of an SAE 
o Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias, or 
convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
Clarification should be made between the terms “serious” and “severe” since they are not 
synonymous. The term “severe” is often used to describe the intensity (synonym: severity) of a 
specific event (as in mild, moderate, or severe myocardial infarction); the event itself may be of 
relatively minor medical significance (such as a severe headache). This is not the same as 
“serious”, which is based on patient/event outcome or action criteria described above and are 
usually associated with events that pose a threat to a patient’s life or functioning. A severe AE 
does not necessarily need to be considered serious. Seriousness (not severity) serves as a guide 
for defining regulatory reporting obligations. 
In cases of events meeting serious criteria due to hospitalization, the onset date is the date of 
admission into the hospital and the stop date is the date the patient was discharged. Note that a 
SAE can meet more than one serious criterion (ie, medically important event) and therefore, 
event onset date and event stop date may not be the same as hospitalization dates, based on the 
Investigator’s assessment of the event(s). 
10.2.1.4 
Unexpected Adverse Events 
An AE or suspected adverse reaction is considered “unexpected” if it is not listed in the 
investigator brochure within the section “Reference Safety Information” for Assessment of 
Expectedness of Serious Adverse Reactions. 


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10.2.1.5 
Adverse Events of Special Interest (AESI) 
An AESI is an adverse event (AE) that is designated to be of special medical or scientific interest 
to the Sponsor. All AEs within the category of AESIs should be reported promptly, following the 
reporting procedures for abnormal laboratory, AEs or SAEs as appropriate. 
1. Suicide ideation and behavior AESI 
Included in this AESI are adverse events following administration of RAD011 that are assessed 
by the Investigator to be any of the following: suicidal ideation, suicidal behavior, suicide 
attempt, and completed suicide. 
2. Hepatic dysfunction AESI 
Included in this AESI are abnormal laboratory findings or adverse events suggestive of hepatic 
dysfunction following administration of RAD011 such as greater or moderate elevation of liver 
enzymes (AST, ALT, ALP, gamma-glutamyl transferase [GGT]) and bilirubin; or adverse events 
of right upper quadrant abdominal pain, chronic fatigue, loss of appetite, unexplained nausea and 
vomiting, yellowing of skin or eyes, itching, dark urine, and light-colored stools.  
10.2.2. 
Collection and Recording of Adverse Events 
All patients will be monitored closely for AEs/SAEs during study participation. Sources for 
AE/SAE notification include patient self-reports, abnormalities found on physical assessments, 
imaging, or other clinical investigations, clinical laboratory exam results, and other sources 
relating to the patient’s health that becomes available to the Investigator. The Investigator should 
take all appropriate measures to ensure the safety of patients and should follow up the outcome 
of all AEs (clinical, laboratory values, or other, etc.) until the return to normal or until the 
patient’s condition has stabilized. In the event of an SAE, the Investigator should follow up for 
the outcome until the clinical recovery is complete and laboratory results have returned to normal 
or until progression has been stabilized. 
All AEs/SAEs will be entered into the electronic database. All AEs/SAEs will be collected from 
the time of ICF signature up to completion of the EOS/Week 34 Visit for patients enrolling in the 
long-term extension study (SCOUT-016) or up to Week 38Visit for patients entering the Taper 
and Follow Up Periods. Patients who discontinue prematurely from the study will be encouraged 
to return for assessment of safety. Follow up safety information may also be obtained from a 
patient’s physician or medical records. 
All AEs/SAEs spontaneously reported by the patient and/or in response to an open question from 
study personnel or revealed by observation, physical examination, or other diagnostic procedures 
must be recorded in the source document and on the appropriate page of the eCRF. Any 
clinically relevant deterioration in laboratory assessments or other clinical findings is considered 
an AE and must be recorded on the appropriate pages of the eCRF. When possible, signs and 
symptoms indicating a common underlying pathology should be noted as one comprehensive 
event. Documentation of time of onset, time of resolution, seriousness assessment, maximal 
severity assessment, relationship assessment, action taken, treatments administered, and 
outcomes must be provided on the AE CRF and SAE form. 
All SAEs that occur during the course of the study, as defined by the protocol, must be reported 
by the Investigator to Radius by completing and emailing the SAE Form within 24 hours of the 


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Investigator or site’s study staff first becoming aware of the SAE to 
 (see 
Section 10.3 for additional details). In addition, all SAEs including deaths, which occur up to and 
including 30 days after administration of the last dose of study drug, must be reported to Radius 
within 24 hours of the first awareness. All SAEs and deaths must be reported whether or not 
considered causally related to the study drug. SAE forms will be provided to the clinical study 
site. The information collected will include a minimum of the following: 
 Patient number 
 A narrative description of the event 
 An assessment by the Investigator as to the relatedness to study drug 
 Intensity of the event. 
Note: Any SAE that occurs at any time after the completion of the study which the Investigator 
considers to be related to study drug, must be reported to the Sponsor or its designee. 
Planned or elective hospital admissions for treatment/procedures for a condition/disease that 
existed prior to signing the ICF and did not worsen from Screening will not be captured as SAEs. 
However, complications that occur during hospitalization are AEs, and if a complication 
prolongs hospitalization the event is considered serious. 
10.2.3. 
Follow-up of Adverse Events 
All AEs/SAEs will be followed up with appropriate medical management until resolved or 
before study end (database lock).  
Follow-up information on the SAE may be requested by the Contract Research Organization 
(CRO) or the Sponsor Medical Monitor. Contact information for reporting SAEs to the Medical 
Monitor will be provided in a separate document. 
Reasonable attempts should be made by the Investigator to obtain follow up and outcome 
information for unresolved AEs. The Sponsor may request additional information at the end of 
the study if necessary for unresolved AEs. 
For patients whose status is unclear or “lost to follow-up” because they fail to appear for study 
visits without stating an intention to discontinue or withdraw, the Investigator should show “due 
diligence” by documenting in the source documents steps taken to contact the patient, e.g., dates 
of telephone calls, registered letters, etc. A patient should not be formally considered lost to 
follow-up until his scheduled end of study visit would have occurred. 
10.2.4. 
Intensity 
For both SAEs and non-SAEs, the Investigator must determine both the intensity of the event 
and the relationship of the event to study drug administration. 
Intensity for each AE will be defined according to the following criteria as noted in Table 10. If 
the intensity of an AE changes within a day, the maximum intensity should be recorded. If the 
intensity changes over a longer period of time, the changes should be recorded as separate events 
(having separate onset and stop dates for each intensity). 


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Table 10: 
Intensity Classification and Definition of Adverse Events 
Intensity 
Definition 
Mild 
Awareness of sign or symptom, but easily tolerated 
Moderate 
Discomfort enough to cause interference with normal daily activities 
Severe 
Inability to perform normal daily activities 
10.2.5. 
Relationship to Study Drug 
Every effort should be made by the Investigator to assess the relationship (causality) of the AE, 
if any, to the IP.  
Investigators should use their knowledge of the patient, the circumstances surrounding the event, 
and an evaluation of any potential alternative causes to determine whether or not an AE is 
considered to be related to study drug, indicating on the eCRF that an AE is either related or not 
related. The following guidance should be taken into consideration when determining the 
relationship of an AE to study drug: 
 Temporal relationship of event onset to initiation of study drug 
 Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (where applicable) 
 Known association of the event with study drug or with similar treatments 
 Known association of the event with the disease under study 
 Presence of risk factors in the patient or environment, or use of concomitant 
medications known to be associated with the event 
 Presence of treatment-unrelated factors that are known to be associated with the 
occurrence of the event 
 Whether there is a reasonable alternative explanation for the event 
10.2.6. 
Study Drug Action taken 
The Investigator will determine the study drug action taken with regard to the AE. The action 
taken should be classified according to the categories shown in Table 11. 


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Table 11: 
Classification for Study Drug Action Taken with Regards to an Adverse 
Event 
Classification 
Definition 
Dose Not Changed 
Study drug dose or frequency not changed in response to the AE 
Dose Reduced 
Study drug dose or frequency reduced in response to the AE 
Drug Interrupted 
Study drug administration interrupted in response to the AE 
Drug Withdrawn 
Study drug administration permanently discontinued in response to the AE 
Not Applicable  
Action taken regarding study drug administration does not apply. 
“Not applicable” should be used in circumstances such as death or when the 
investigational treatment had ended before the AE began or the event occurred 
prior to investigational product administration. 
10.2.7. 
Adverse Event Outcome 
The outcome of an AE describes the status of the AE. An AE should be followed until the 
Investigator has determined and provided the outcome. The outcome should be classified 
according to the categories shown in Table 12. Resolution of AEs will be monitored throughout 
the study, and will be classified as resolved, resolved with sequelae, or ongoing. 
Table 12: 
Classifications for Outcome of an Adverse Event 
Classification 
Definition 
Recovered/Resolved 
Resolution of an AE with no residual signs or symptoms 
Recovered/Resolved with Sequelae 
Resolution of an AE with residual signs or symptoms 
Recovering/Resolving (Ongoing) 
Improvement of an AE 
Not Recovered/Not Resolved 
(Ongoing) 
Either incomplete improvement or no improvement of an AE, 
such that it remains ongoing. 
Fatal * 
Outcome of an AE is death. “Fatal” should be used when death is 
at least possibly related to the AE.  
Unknown 
Outcome of an AE is not known (e.g., patient lost to follow-up). 
*Only event(s) resulting in the fatal outcome, should report “fatal” as an outcome. All other events that were 
ongoing at the time of death should be reported as “not resolved.” 
10.2.8. 
Abuse, Misuse, and Overdose  
Abuse, misuse, and overdose (as defined below) must be assessed by the investigator and should 
be reported regardless of resulting in an adverse event. Any adverse event that meets seriousness 
criteria, as defined by the protocol, must also be reported by the Investigator to Radius by 
completing and emailing the SAE Form within 24 hours of the Investigator first becoming aware 
of the SAE to 
 (see Section 10.3 for additional details).  
 Abuse: Persistent or sporadic intentional intake of investigational medicinal product at a 
higher dose than prescribed per protocol (e.g., but below the dose defined for overdose) 
or when used for non-medical purpose (e.g., altering one’s state of consciousness) 


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 Misuse: Intentional or unintentional use of investigational medicinal product other than 
as directed or indicated at any dose. Note: this includes a situation where the test article is 
not used as directed at the dose prescribed by the protocol 
 Overdose: Administration of a quantity of a medicinal product greater than the dose 
defined in the protocol for the investigation product.  
10.2.9. 
Pregnancy 
Any pregnancy that occurs in a study participant during the study or within 30 days after the last 
study dose must be reported within 24 hours to the Radius Pharmacovigilance Department using 
the Pregnancy Report Form. Every effort should be made to gather information regarding the 
pregnancy course and outcome. It is the responsibility of the Investigator to obtain this 
information within 30 calendar days after the initial notification and approximately 30 days 
postpartum. 
Pregnancy is neither an AE nor an SAE, unless a complication relating to the pregnancy occurs. 
All reports of congenital abnormalities/birth defects are SAEs. Spontaneous miscarriages should 
also be reported and handled as SAEs. Elective abortions without complications should not be 
handled as AEs. The course of all pregnancies, including perinatal and neonatal outcome, 
regardless of whether the patient has discontinued participation in the study, will be followed 
until resolution, including follow up of the health status of the newborn to 6 weeks of age. 
Congenital abnormalities/birth defects in the offspring of patients should be reported as an SAE 
if conception occurred during this study.  
The effects of administration of the IP in pregnant females is unknown. Fetal development 
studies in female mice exposed to CBD suggest that perinatal CBD exposure in males may 
interfere with long term androgen mediated processes of differentiation, testicular function 
including spermatogenic and steroidogenic components, and endocrine functions. Therefore, 
women of childbearing potential are required to use effective contraception from Screening 
through 30 days after IP administration. 
In patients who have partners of child-bearing potential, the patient and his partner should use 
contraceptive approaches as mentioned in Inclusion Criterion 5 and Inclusion Criterion 6, and for 
at least 30 days after the last dose of IP. 
10.2.10. 
Study Completion and Post-Investigational Product Treatment 
The Investigator must provide follow-up medical care for all patients who are prematurely 
withdrawn from the study due to an AE or must refer them for appropriate ongoing care. 
10.3. 
Reporting of Serious Adverse Events 
Prompt notification of SAEs by the Investigator is essential so that legal obligations and ethical 
responsibilities toward the safety of patients are met. Documentation of submissions for all 
unexpected events must be retained in the site study file. 
All SAEs must be reported to the Sponsor within 24 hours of the Investigator’s awareness of the 
event. The Investigator must complete, sign and date the SAE Report Form and verify the 
accuracy of the information recorded on the SAE form with the corresponding source 


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documents. The event should also be entered onto the AE CRF in the EDC. E-mail the 
completed SAE form to:  
 Email: 
  
o Report the SAEs to Radius by completing an SAE Report Form. All sections on 
the form are to be completed. Information that is not available at the time of initial 
reporting should be submitted as a follow up within 24 hours of the investigator’s 
awareness. The date of receipt of an initial SAE Report Form will be considered 
as Day 0 for the purpose of determining the time for regulatory reporting of an 
expedited event and timelines of further study related activities 
o Do not attach documents (e.g., discharge summary, autopsy report, diagnostic test 
results, examinations, etc.) unless requested. All relevant information should be 
provided on the SAE form in English. 
It is the PI’s responsibility to notify the Institutional Review Board (IRB) or Institutional Ethics 
Committee (IEC) of all SAEs or other AEs that require reporting that occur at his or her site. 
The Sponsor is responsible for notifying the relevant regulatory authorities of all suspected 
unexpected, serious, adverse reactions (SUSAR, 7/15 Day Safety Reports) that occur during the 
clinical study. Each site is then responsible for notifying its IRB or IEC of these additional SAEs. 
A copy of such SUSAR will be sent to the clinical CRO who will be responsible for notifying all 
clinical sites, central IRBs (if applicable), and IECs. 
Any SAEs that occur at any time after completion of the study, which are considered by the 
Investigator to be related to IP, must be reported to the Sponsor or its designee via email 
.  
An investigator who receives a safety report describing an SAE or other specific safety 
information from RADIUS will file it in their Investigator Site File (ISF) and will notify their 
IRB and independent EC, if appropriate according to local requirements. 
10.4. 
Data Monitoring Committee 
A DMC, composed of individuals not affiliated with the study and selected based on their 
scientific and clinical background and expertise in clinical studies, will be formed. The roles, 
responsibilities and additional details on DMC operations are provided in the DMC Charter.  
After approximately 45 patients complete 4 weeks of the Maintenance Period of the Phase 2 part 
of the study, the DMC will meet to review the safety and tolerability data and to recommend 1 or 
2 RAD011 dose level(s) for evaluation in the Phase 3 part of the study.  
The DMC will also be available to assist in the review of aggregate safety events as requested by 
the Sponsor at any time during the study. 
11. 
STATISTICAL CONSIDERATIONS 
Statistical methods to assess study endpoints will be detailed in the final version of the Statistical 
Analysis Plan (SAP). The SAP will be finalized prior to database lock and unblinding. All 


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analyses and tabulations will be performed using SAS® Version 9.4 or higher (SAS Institute, 
Cary, NC).  
Efficacy analyses will be conducted on the ITT, mITT, and PP populations, safety analyses will 
be conducted on the Safety Population, and PK analyses will be performed on the PK Evaluable 
Population.  
Data will be presented using tables by treatment group, unless otherwise specified. Continuous 
variable summaries will be summarized using the number of patients (n), mean, standard 
deviation, median, minimum, and maximum. Categorical variable summaries will be 
summarized as frequency counts and percentages. Figures and listings may be used to support 
the presentation of selected data.  
Handling of missing and partial data will be described in the SAP.  
11.1. 
Sample Size Determination 
DMC Recommendation of Two RAD011 Doses 
For the primary efficacy analysis, a total of 150 patients (50 patients per treatment group) aged 
12 to 65 years will provide 90% power to compare each dose group vs. placebo with a two-sided 
alpha of 0.025. The study is powered to detect a difference in the HQ-CT from Baseline to 
Week 34 of 5 points with a standard deviation of 7 points. The 0.05 Type 1 error is split equally 
between groups (low dose and high dose). The low and high volume placebo groups will be 
combined for all comparisons to placebo. Assuming a 15% post-randomization dropout rate, 
approximately 180 patients (~60 patients per treatment group) will be evaluated for the primary 
efficacy analysis.  
Thus, if the DMC recommends two RAD011 doses for Phase 3 of the study, approximately a 
total of 191 patients aged 12 to 65 years (approximate target of 200 patients) will be randomized 
in this study. The 191 reflects 176 patients required for primary efficacy analysis plus 15 patients 
randomized in the Phase 2 part of the study to the dose not selected for Phase 3 of the study. 
Assuming a 20% pre-randomization eligibility failure rate (including HQ-CT eligibility criteria), 
approximately 240 patients will be enrolled into the Screening Period. An additional 10 patients 
per treatment group aged 8 to <12 years may be allowed to participate in Phase 3 of the study 
and will be randomized in a way to obtain a balanced number of patients on RAD011 (at dose 
levels recommended by the DMC) and placebo. Patients aged 8 to <12 will not be included in the 
primary efficacy analysis.  
DMC Recommendation of One RAD011 Dose 
For the primary efficacy analysis, a total of 100 patients (50 patients per treatment group) aged 
12 to 65 years will provide 94% power to compare active vs. placebo with a two-sided alpha of 
0.05. The study is powered to detect a difference in the HQ-CT from Baseline to Week 34 of 5 
points with a standard deviation of 7 points. Assuming a 15% post-randomization dropout rate, 
approximately 118 patients (~59 patients per treatment group) will be evaluated for the primary 
efficacy analysis.  
Thus, if the DMC recommends one RAD011 dose for Phase 3 of the study, approximately 148 
patients aged 12 to 65 years (target approximately 150 patients) will be randomized in this study. 


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The 148 reflects 118 patients required for primary efficacy analysis plus 30 patients randomized 
in the Phase 2 part of the study to the two doses not selected for Phase 3 of the study. 
Assuming a 20% pre-randomization eligibility failure rate (including HQ-CT eligibility criteria), 
approximately 185 patients will be enrolled into the Screening Period. An additional 10 patients 
per treatment group aged 8 to <12 years may be allowed to participate in Phase 3 of the study 
and will be randomized in a way to obtain a balanced number of patients on RAD011 (at dose 
level recommended by the DMC) and placebo. Patients aged 8 to <12 will not be included in the 
primary efficacy analysis.  
11.2. 
Hyperphagia Questionnaire for Clinical Trials and Prader-Willi 
Syndrome Mean Score 
In order to assess patient eligibility at the end of the Screening Period (Visit 2) and prior to 
initiating dosing of patients at Visit 2, patients/caregiver must complete the HQ-CT.  
The EDC system will automatically calculate a mean HQ-CT score from Visit 1 and Visit 2. 
Patients must have a mean HQ-CT score ≥13 to be eligible to continue in the Tolerability Period. 
Patients with a mean score <13 will not be eligible to continue in the Tolerability Period and will 
be discontinued from the study.  
At the end of the Tolerability Period (Visit 5), Investigators will review a patient’s HQ-CT 
eligibility to be randomized and proceed to the Dose Escalation Period.  
Patients/caregivers must first complete the HQ-CT. The EDC system will automatically calculate 
a mean HQ-CT score from Visit 3, Visit 4 and Visit 5. Patients must have a mean HQ-CT score 
≥13 to be eligible to be randomized and proceed to the Dose Escalation Period. Patients with a 
mean score <13 will not be eligible for randomization and will not have the opportunity to 
participate in the long-term extension study (SCOUT-016). 
11.3. 
Change in Hyperphagia Questionnaire for Clinical Trials During 
Tolerability Period Response Evaluation 
In addition to the mean HQ-CT score requirement described in Section 11.2, the EDC system 
will also automatically calculate the change in HQ-CT score from the Tolerability Period to the 
Screening Period. This change is calculated as 
Mean HQ-CT score (Visit 3, Visit 4, Visit 5) – Mean HQ-CT score (Visit 1, Visit 2) 
Patients must also have a decrease in HQ-CT score ≤7 to be eligible for randomization and able 
to proceed to the Dose Escalation Period. Patients with a decrease HQ-CT score >7 will not be 
eligible for randomization.  
11.4. 
Statistical Analyses 
11.4.1. 
Populations for Analyses 
The following patient populations will be defined for analysis: 
 Safety Population: the Safety Population will include all randomized patients who were 
treated with at least one dose of IP 


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 Intent to Treat (ITT) Population: the ITT Population will include all randomized patients 
 Modified ITT (mITT) Population: the mITT Population will include all patients aged 
≥12 years who were randomized, received at least 1 dose of IP, had at least 1 
post-randomization HQ-CT questionnaire completed, and were randomized to receive the 
dose level(s) recommended for development in Phase 3 of the study, including patients in 
the Phase 2 part of the study who received the chosen dose level(s) 
 Per Protocol (PP) Population: the PP Population will include all patients aged ≥12 years 
who were randomized, received at least 1 dose of IP, completed Week 34 without 
significant protocol deviations that were prospectively defined to impact efficacy (see 
SAP) and received the dose level(s) recommended for development in Phase 3 of the 
study, including patients in Phase 2 of the study who received the chosen dose level(s) 
 Pharmacokinetic Evaluable Population: the PK Evaluable Population will include all 
patients who received at least 1 dose of IP and underwent at least 1 PK sample collection.  
11.4.2. 
Primary Endpoint 
The primary endpoint, change in HQCT score from Baseline to End of Study (Week 34) will be 
analyzed for the mITT population based on the treatment policy estimand using a mixed model 
for repeated measures (MMRM) with change in HQCT score as the response variable and 
randomization assignment, Baseline HQ-CT score and stratification variables (age [≥16 or <16 
years] at randomization and GH treatment at randomization [yes/no]) and time × treatment 
interaction as fixed effects. Patient will be included as a random effect with an unstructured 
covariance matrix. A multiple imputation will be used for missing data. Baseline will be defined 
as the mean HQ-CT score (Visit 1, Visit 2). 
For the primary endpoint analysis at Week 34, multiple imputation will be used to assign a value 
to those cases with missing data. The full conditional specification method with predictive means 
matching as described in Berglund & Heeringa (Berglund, 2014) will be used. This method uses 
all of a patient’s known primary outcome measures at Baseline, Weeks 10, 19, 27, and/or 34 
weeks to impute any missing values for Week 34. 
DMC Recommendation of two RAD011 Doses 
The primary comparison will be mean change in HQ-CT as calculated via least square means 
comparing RAD011 low dose vs. placebo and RAD011 high dose vs. placebo at Week 34. Low 
dose and high dose groups will be compared to placebo at the two-sided 0.025 level so overall 
type 1 error is maintained at two-sided 0.05 level. 
DMC Recommendation of one RAD011 Dose 
The primary comparison will be mean change in HQ-CT as calculated via least square means 
comparing RAD011 vs. placebo at Week 34. RAD011 will be compared to placebo at the 
two-sided 0.05 level. 
11.4.3. 
Secondary and Other Endpoints 
All analyses of the secondary and other endpoints for continuous measures will be conducted 
analogous to the primary endpoint analysis, using, the baseline value of the relevant variable as a 


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covariate, and patient as a random effect. All analyses of the secondary and other endpoints will 
be described in the SAP. 
11.4.4. 
Pharmacokinetic Analyses 
All PK analyses will be described in the pharmacokinetic analysis plan prior to performing 
statistical analyses. A pharmacodynamic analysis may be completed to evaluate exposure with 
efficacy and safety. 
11.4.5. 
Safety Analyses 
The Safety Population will be used for all safety assessments. Safety assessments will be based 
on AEs, C-SSRS, vital signs, ECGs, and laboratory assessments. All analyses of safety will be 
described in the SAP. 
All safety assessments will be descriptive, and no inferential statistics will be performed. All data 
listings will be provided for protocol specified safety data. The Medical Dictionary for 
Regulatory Activities will be used to classify all AEs with respect to System Organ Class (SOC) 
and preferred term. Adverse event summaries will include only treatment-emergent adverse 
events (TEAEs) by treatment group. Assessment of severity and relationship will also be 
presented. Adverse events leading to study discontinuation will also be summarized by SOC, PT, 
severity, and relationship. 
The Columbia Suicide Severity Rating Scale will be used to evaluate suicidal ideation and 
intensity of ideation. Ideation and intensity will be grouped by categories, with separate 
groupings for the Baseline/Screening and the “Since Last Visit” questionnaires. 
Clinical laboratory and vital signs will be summarized for the Safety Population for observed 
values and change from Baseline. Shifts from Baseline according to normal range criteria will 
also be presented for all patients in the Safety Population.  
12. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
12.1. 
Study Monitoring 
Monitoring and auditing procedures approved by the Sponsor will be followed, in order to 
comply with Good Clinical Practices (GCP) guidelines (ICH E6[R2]). 
The study will be monitored by the Sponsor or its designee. Monitoring will be done by personal 
or remote visits from a representative or designee of the sponsor (site monitor) and will include 
review of the eCRFs for completeness and clarity, cross checking with source documents, and 
clarification of administrative matters will be performed. The review of medical records will be 
performed in a manner to ensure that patient confidentiality is maintained. Remote visits may 
require remote access to the patient’s electronic medical record and other systems at the study 
sites. Deidentified and redacted source documentation may need to be provided to the Sponsor or 
its designee to complete remote monitoring activities.  
The site monitor will ensure that the investigation is conducted according to protocol design and 
regulatory requirements by frequent communications (letter, email, telephone, and fax). 


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Regulatory authorities, the IRB/IEC and other appropriate institutional regulatory bodies, and/or 
the sponsor’s clinical quality assurance group may request access to all source documents, 
eCRFs, and other study documentation for on-site audit or inspection. Direct access to these 
documents must be guaranteed by the investigator, who must provide support at all times for 
these activities. 
To ensure compliance with GCP and all applicable regulatory requirements, the Sponsor or its 
designee may conduct a quality assurance audit. 
12.2. 
Audits and Inspections 
Authorized representatives of the Sponsor, a regulatory authority, an IEC, or an IRB may visit 
the site to perform audits or inspections, including source data verification. The purpose of a 
Sponsor audit or inspection is to systematically and independently examine all study-related 
activities and documents to determine whether these activities were conducted, and data were 
recorded, analyzed, and accurately reported according to the protocol, ICH-GCP, and any 
applicable regulatory requirements. The Investigator should contact the Sponsor immediately if 
contacted by a regulatory agency about an inspection. 
12.3. 
Institutional Review Board and Independent Ethics Committee 
The PI must obtain IRB/IEC approval for the investigation. Initial IRB/IEC approval, and all 
materials approved by the IRB/IEC for this study including the patient consent/assent 
form/process must be maintained by the Investigator and made available for inspection. 
13. 
ETHICAL AND REGULATORY CONSIDERATIONS 
13.1. 
Ethics Review 
This protocol was designed and will be conducted, recorded, and reported in compliance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, 1996; Guidelines for Clinical 
Safety Data Management, 1994; European Regulations and appropriate Ethics Committee, the 
Code of Federal Regulations (CFR 21 parts 50, 56, and 312) and any country specific regulations 
or laws. 
The final study protocol, including the final version of the ICF, must be approved or given a 
favorable opinion in writing by an IRB or IEC, as appropriate. If the Investigator directly 
submitted the protocol to an IRB or an IRC, he or she must submit written approval to the 
Sponsor or its designee before he or she can enroll any patient into the study. If the study 
protocol was submitted on behalf of the Sponsor or Investigator to local or central IRB or IEC, 
the Investigator must confirm IRB and/or IEC approval prior to enrolling patients in the study, in 
accordance with local laws and regulations. 
The Investigator, or a Sponsor designee, will be responsible for submitting any amendment to the 
protocol or to the ICF to the IRB or IEC in accordance with local laws and regulations. In 
addition, the IRB or IEC must approve all advertising used to recruit patients for the study and 
any written information to be provided to patients (e.g., food diaries). The protocol must be 


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re-approved by the IRB or IEC upon receipt of amendments and at the frequency required by 
local laws and regulations. 
Initial IRB or IEC approval, and all materials approved by the IRB or IEC for this study, 
including the ICF and recruitment materials, must be maintained by the investigator and made 
available for inspection. 
The PI at each study site is also responsible for providing the IRB or IEC with reports of any 
reportable serious adverse drug reactions from any other study conducted with the IP. The 
Sponsor or its designee will provide this information to the PI. 
Progress reports will be provided to the IRB or IEC according to local laws and regulations. 
13.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/GCP and applicable regulatory 
requirements. 
The Investigator will be thoroughly familiar with the appropriate use of the IP as described in the 
protocol and Investigator's Brochure. Essential clinical documents will be maintained to 
demonstrate the validity of the study and the integrity of the data collected. A TMF will be 
established at the beginning of the study, maintained for the duration of the study, and retained 
according to appropriate regulations. 
13.3. 
Patient Confidentiality 
Individual patient medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited. Such medical information may be given 
only after approval of the patient to the patient’s physician or to other appropriate medical 
personnel responsible for the patient’s well-being. 
Sponsor shall not disclose any confidential information on patients obtained during the 
performance of their duties in the clinical study without justifiable reasons. 
Sponsor affirms the patient’s right to protection against invasion of privacy. Only a patient 
identification number and/or initials (where allowed by local or national regulations) will 
identify patient data retrieved by Sponsor. However, Sponsor requires the Investigator to permit 
Sponsor, designated representative(s), the IRB/IEC and when necessary, representatives of the 
regulatory health authorities to review and/or to copy any medical records relevant to the study. 
Sponsor will ensure that the use and disclosure of protected health information or of personal 
data obtained during a research study complies with the local federal and/or regional legislation 
related to the privacy and protection of personal information. 
13.4. 
Written Informed Consent/Assent 
Investigator(s) at each site will explain the nature of the study, answer all questions regarding the 
study, and ensure that the patient or their legally authorized representative is given full and 
adequate oral and written information about the nature, purpose, possible risk, and benefit of the 
study, in accordance with local regulations and GCP guidelines. Patients must also be notified 


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that they are free to discontinue from the study at any time. The patient should be given the 
opportunity to ask questions and allowed time to consider the information provided.  
The patient or their legally authorized representative and the authorized person obtaining the 
informed consent must sign the ICF. The patient’s signed and dated ICF must be obtained before 
conducting any study procedures. The investigator(s) must maintain the original, signed and 
dated ICF, and provide a copy the signed and dated ICF to the patient or their legally authorized 
representative. 
Patients must be re-consented to the most current version of the ICF(s) during their participation 
in the study, as appropriate.  
Investigators must document in the patient’s medical record a statement that written informed 
consent was obtained before the patient was enrolled in the study, that no study procedures were 
performed prior to the patient signing the ICF, and the date the written consent was obtained. 
Investigators will also document in the patient’s medical record a statement that patients were 
reconsented with new ICFs, and the time reconsent occurred, when reconsenting is required.  
The Investigator obligations in this section are also be respected for patients providing assent. 
13.5. 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
14. 
DATA HANDLING AND RECORDKEEPING 
14.1. 
Case Report Form Completion 
The Sponsor or its designee will provide the clinical sites with access to the eCRFs for each 
patient. The PI is responsible for ensuring the accuracy, completeness, and timeliness of the data 
reported in a patient’s eCRF. Source documentation supporting the eCRF data should indicate 
the patient’s participation in the study and should document the dates and details of study 
procedures, AEs, and patient status. 
The investigator or designated representative should complete the eCRFs as soon as possible 
after information is collected. The Investigator must sign and date the eCRF to endorse the 
recorded data. 
14.2. 
Inspection of Records 
The Sponsor or its designee will be allowed to conduct site visits to the investigation facilities for 
the purpose of monitoring any aspect of the study. The PI agrees to allow the monitor to inspect 
the drug storage area, IP stocks, drug accountability records, patient charts and study source 
documents, and other records relative to study conduct. 


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14.3. 
Retention of Records 
The PI must maintain all documentation relating to the study for a period of 2 years after the last 
marketing application approval, or if not approved 2 years following the discontinuance of the 
test article for investigation or according to applicable regulatory requirements.  
If the Investigator withdraws from the responsibility of keeping the study records, custody must 
be transferred to a person willing to accept the responsibility. The Sponsor must be notified in 
writing if a custodial change occurs. 
14.4. 
Substantial Amendments to the Protocol 
A substantial amendment must be agreed to in writing by Sponsor and submitted to and 
approved by the respective regulatory authority and IRB/IEC before the amendment can be 
implemented. Written approval of a protocol amendment is not required prior to implementation 
of changes to the protocol which eliminate an immediate hazard to the study patient; however, 
approval must be obtained as soon as possible thereafter. Any amendments must also be signed 
by the PI. 
15. 
PUBLICATION POLICY 
All information regarding the IP is privileged and confidential information. The Investigator 
agrees to use this information to conduct the study and will not use it for other purposes without 
consent from the Sponsor. It is understood that there is an obligation to provide the Sponsor with 
complete data obtained during the study. The information obtained from the clinical study may 
be disclosed to regulatory authority(ies), other Investigators, corporate partners, or consultants as 
required. 
It is anticipated that the results of this study will be presented at scientific meetings and/or 
published in a peer reviewed scientific or medical journal. A Publications Committee of 
Investigators participating in the study and representatives from the Sponsor may be formed to 
oversee the publication and presentation of the study results, which will reflect the experience of 
all participating clinical sites.  
No publication or disclosure of study results will be permitted except under the terms and 
conditions of a separate written agreement between the Sponsor and the Investigator and/or the 
Investigator's institution. 
The Sponsor has full rights over any invention, discovery, or innovation, patentable or not, that 
may occur when performing the study.  
16. 
DISSEMINATION OF STUDY DATA 
Study results will be posted on the National Institutes of Health Protocol Registration and 
Results System website, ClinicalTrials.gov, to meet the FDAAA 801 and/or International 
Committee of Medical Journal Editors ICMJE requirements.  


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natural cannabinoids: evidence for partial agonist activity of delta9-tetrahydrocannabinol and 
antagonist activity of cannabidiol on rat brain cannabinoid receptors. Life Sci. 1998;63:PL1-6. 
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rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in 
overweight or obese patients: RIO-North America: a randomized controlled trial. JAMA. 
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Posner K, Brent D, Lucas C, Gould M, Stanley B, Brown G, et al. Columbia-suicide severity 
rating scale (C-SSRS). New York, NY: Columbia University Medical Center. 2008;10. 
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mice. Br J Pharmacol. 2009;156:1154-66. 
Salehi P, Herzig L, Capone G, Lu A, Oron AP, Kim SJ. Comparison of Aberrant Behavior 
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Schwartz GJ, Work DF. Measurement and estimation of GFR in children and adolescents. Clin J 
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18. 
APPENDICES 


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APPENDIX 1. SUMMARY OF PROTOCOL CHANGES 
Table 13: 
Summary of Protocol Changes 
Protocol Version 
(Date Issued) 
Changes 
Rationale 
Version 1.0 
(20 August 2021) 
Original Protocol 
Not applicable 
Version 2.0 
(13 September 
2021) 
Changed name of Sponsor from Radius Health, 
Inc. to Radius Pharmaceuticals, Inc. 
To be in Alignment with the Radius 
IND filing 
 
Maintenance Period updated from 23 Weeks to 24 
Weeks. 
To align with study design. 
 
Arrow added to study schematic in both Phases 
between Tolerability Period and SCOUT-016 LTE 
study 
Reflect potential participation of 
patients not eligible for 
randomization in the SCOUT-016 
LTE study 
 
Section 5.7.2: added clarification of weeks during 
which dose reductions could be conducted 
Clarify time frame for dose 
reductions during the Maintenance 
Period 
 
Section 5.8.4.1: added drug accountability 
assessment at Visit 5 
dispensed during the Tolerability 
Period is returned to the site. 
 
Section 5.8.6: Modified Visits in Taper and 
Follow-Up Periods 
Clarify and simplify assessments at 
visit time points 
 
Table 7: Changed visits in the Follow-Up Period to 
reflect changes in Section 5.7.2 and added 
assessments 
Provide enhanced clarity on 
assessments to be performed 
 
Table 7: food diary reminder changed from Visit 4 
to Visits 4, 7, 11, and 13. 
To assist in proper food diary 
completion and collection. 
 
Table 7: added Drug accountability assessment at 
Visit 5 
Confirm that all unused placebo 
dispensed during the Tolerability 
Period is returned to the site. 
 
Table 7: added Drug accountability assessment at 
Visit 15 
Ensure that all IP is returned to site 
 
Section 7.1: updated language for IP 
administration to: “administered orally twice daily 
with food”, and removed “, within approximately 
1 hour after a meal”  
Clarify timing of administration of IP 
with regards to food 
 
Section 7.5: corrected dose administered during 
Tolerability Period.  
Reflect dose to be administered of 
0.1 mL/kg/day 
 
Section 8.3: Study Drug Storage updated to 2 - 
8°C and added sentence to clarify additional 
information is provided in the Pharmacy Manual. 
To ensure proper refrigerated storage 
at the site and recommend 
refrigeration in the home setting. 
 
Section 10.1: general formatting updates 
 


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Protocol Version 
(Date Issued) 
Changes 
Rationale 
 
Section 10.2.2: changed start of AE collection 
from Visit 2 to Visit 1 
Ensure full AE documentation 
Version 3.0 
(25Oct2021) 
Section 5.8.2.1, specified that HQ-CT and ABC 
questionnaires must be completed a minimum of 
14 days prior to visit 2 
Clarify the exact time point 
 
Section 5.8.4.1, ABC-I will not be done at visit 5 
Replaced by full ABC questionnaire 
 
Section 5.8.5.1, ABC will now be completed at 
visit 14 
Replacing ABC-I questionnaire 
 
Sections 5.1, 5.8.3, 5.8.4.1, 6.4.1, 6.4.2, 11.2, 
specified that patient/caregiver completes HQ-CT  
Consistency with other sections 
 
Section 6.1, Inclusion criterion 1 updated to read 
“Presence of a parent/legal guardian that is able to 
consent for their participation. 
Parent/caregiver/legal guardian can complete the 
required assessments throughout the study. Patient 
Consent/Assent will be obtained if the patient is 8 
years of age or older and has the mental capacity 
to understand and sign a written consent/assent 
form and/or give verbal assent.” 
Clarify that a caregiver and/or legal 
guardian can assist in the 
consent/assent process 
 
Section 6.1, Inclusion criterion 2 updated to refer 
to age at time of consent 
Age to be calculated at date of 
consent rather than screening 
 
Section 6.1, Inclusion criterion 5, updated 
timescale from “30 days” to “4 weeks” after the 
last dose 
Consistency with other criteria 
 
Section 6.1, Inclusion criterion 6, updated IUD 
timescale to 12 weeks prior to dosing and 
continued used of approved contraceptive method 
to 4 weeks after last dose  
Consistency with other criteria 
 
Section 6.1, Inclusion criterion 7, added 
“metabolic treatments that could affect appetite 
(including metformin), to list. Updated timescale 
from “at least 6 weeks prior to screening” to “at 
least 4 weeks prior to consent/ascent” 
Clarify types of interventions and 
time frame 
 
Section 6.2, Exclusion criterion 2, within 4 weeks 
prior to consent/assent instead of screening 
Clarify that time frame starts from 
the time of consent/assent 
 
Section 6.2, Exclusion criterion 5, removed 
reference to “drugs known to affect appetite or 
gastric emptying”, update timing to within 4 weeks 
prior to consent/assent.  
Clarify indication for weight loss and 
harmonized timelines with other 
criteria 
 
Section 6.2, Exclusion criterion 6, updated 
timescale to within 4 weeks of consent/assent 
Harmonize timelines with other 
criteria 


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Protocol Version 
(Date Issued) 
Changes 
Rationale 
 
Section 6.2, Exclusion criterion 7, added “any 
significant”, bullet a timeline updated to 4 weeks 
prior to consent /assent, bullet e updated to specify 
drugs taken orally 
Clarify that comorbid conditions had 
to be clinically significant in the 
opinion of the investigator and 
harmonized timelines with other 
criteria 
 
Section 6.2, Exclusion criterion 9 updated to “At 
Screening, patients with age-matched hypertensive 
levels of systolic and/or diastolic blood pressure 
may be excluded at the Investigator’s discretion if 
deemed to be in the best interest of the patient.” 
Clarify that blood pressure 
measurements should be evaluated 
using age-specific reference ranges, 
as needed 
 
Section 6.2, added Exclusion criterion 18 : 
“Participation in any other study involving an 
investigational product or device within 4 
weeks or 5 half-lives (whichever is longer) of 
consent/assent or longer as required by local 
regulations” 
Prevent patients from participating in 
multiple interventional studies at 
once 
 
Section 7.2.1, removed paragraph about 
concomitant treatment with valproate, valproic 
acid, or divalproex-containing products.  
Final paragraph updated to “patients who 
experience adverse events due to significant 
drug/drug interactions may have treatment 
discontinued while remaining on study” 
Provide more general guidance to 
investigators 
 
Section 7.5, updated to read “To maintain the 
blind, multiple placebo groups were created to 
mimic the RAD011 groups: low volume 
(0.1 mL/kg/day), mid volume (0.2 mL/kg/day), 
and high volume (0.4 mL/kg/day). During the dose 
escalation period, the volume of blinded therapy 
for the mid volume and high volume placebo 
groups will increase in the same manner as the mid 
dose and high dose RAD001 groups, further 
ensuring blinding between RAD011 and placebo” 
Clarify that only mid and high 
volume placebo groups would 
increase the administered volume 
 
Section 8.4, now specifies that IP should be taken 
with food 
Clarify timing of administration of IP 
with regards to food 
 
Section 9.2.1, updated to refer to the irritability 
subscale of the ABC Questionnaire  
To specify that the irritability 
measure is a subscale of the ABC and 
not a separate instrument 
 
Section 9.3.4, removed the sentence 
“Interpretation of DEXA scan results should 
include age, gender, and race-matched Z scores.” 
Interpretation to be performed per 
standard of care 
 
Section 10.1.9, cutoff age for the formulas updated 
to 17 years. 
Alignment with central laboratory 
requirements 
 
Section 10.1.13.1, date and time of dosing will 
now be recorded in food diary.  
Specify additional information to be 
documented 


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Protocol Version 
(Date Issued) 
Changes 
Rationale 
 
Section 10.2.1, AEs will be collected from time of 
consent/assent 
Clarify the start of AE collection 
 
Section 13.4, title changed to “Written Informed 
Consent/Assent”, added “The Investigator 
obligations in this section are also be respected for 
patients providing assent.” 
Clarify that the Investigator 
obligations that apply to consent also 
apply to assent. 
 
Table 6, footnote f added  
Specify when the children’s version 
of the C-SSRS should be used 
 
Table 7, footnote p added  
Specify when the children’s version 
of the C-SSRS should be used 
Version 4.0 
(10Feb2022) 
Change logo of Radius and updated document 
version and date 
Administrative change 
 
Synopsis  
Consistency with other sections 
 
Section 4.1.2 edited secondary and other 
objectives to include CGI-S and CGI-C 
Updated per FDA Comments of 26-
Jan-2022 and 31-Jan-2022 
 
Section 5.1, 5.8.3, 5.8.4.1,  
Removed “However, patients not eligible for 
randomization for reasons other than a mean HQ 
CT score <13 may be offered participation in the 
long-term extension study (SCOUT 016)” 
SCOUT-016 protocol requires 
patients complete SCOUT-015 to be 
eligible for participation in order to 
demonstrate long-terms safety for 
RAD011 and potential maintenance 
of efficacy 
 
Section 5.1, changed caretaker to caregiver 
Administrative change 
 
Section 5.8.2.1, 5.8.5.1, added CGI-S Irritability  
Updated per FDA Comments of 26-
Jan-2022 and 31-Jan-2022 
 
Section 5.8.2.1, 5.8.4.1, added “Ghrelin samples 
will only be collected for Phase 3 patients at sites 
where proper collection is feasible” 
DMC recommendation on dose will 
be made in Ph3. This allows testing 
of Ghrelin when it could potentially 
link to efficacy. It also accounts for 
operational complexity in obtaining 
samples at all sites. 
 
Section 5.8.2.1, 5.8.5.1, 9.5 added biomarker 
assessment 
This will help to assess the potential 
anti-inflammatory effect of RAD011 
on low grade inflammation (LGI) 
often present in subjects with PWS. 
 
Section 5.8.2.2, 6, removed method of diagnosis 
Administrative change for clarity, 
updated to focus on the diagnosis 
 
Section 5.8.3.1, 5.8.5.1, added CGI-S Hyperphagia 
Updated per FDA Comments of 26-
Jan-2022 and 31-Jan-2022 
 
Section 5.8.5.1, added CGI-C Hyperphagia, CGI-C 
Irritability, and CaGI-C questionnaires 
Updated per FDA Comments of 26-
Jan-2022 and 31-Jan-2022 
 
Section 5.9, added COVID-19 impact assessment 
Include flexibility for sites to conduct 
the trial during a pandemic 
 
Updated Table 6 and Table 7 and footnotes 
Consistency with other sections 


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Protocol Version 
(Date Issued) 
Changes 
Rationale 
 
Section 6, removed abstinence and added double-
barrier contraception 
Updated per FDA Comments of 26-
Jan-2022 and 31-Jan-2022 
 
Section 6.2, added neutropenia to exclusion 
Updated per FDA Comments of 26-
Jan-2022 and 31-Jan-2022 
 
Section 6.2, edited group home criteria 
To allow patients living in a group 
home an opportunity to be eligible 
for participation while preserving the 
need for a consistent caregiver 
 
Section 6.3.2, added drug-induced liver injury 
Updated per FDA Comments of 26-
Jan-2022 and 31-Jan-2022 
 
Section 7.2, changed 6 weeks to 4 weeks for stable 
medication  
Administrative change to correct 
typo 
 
Section 7.5.1, added breaking the blind  
To ensure consistency with 
instructions provided to investigators 
within the Pharmacy Manual 
 
Section 9, 9.2.2, 9.3, 11.4.3, edited secondary and 
other objectives to include CGI-S and CGI-C. 
Editorial changes made for document consistency.  
Updated per FDA Comments of 26-
Jan-2022 and 31-Jan-2022. 
Administrative change 
 
Section 10.1.6, added clarity to C-SSRS scale for 
patients aged 6 and over.  
Updated per FDA Comments of 26-
Jan-2022 and 31-Jan-2022 
 
Section 10.2.1.5, added AESI for hepatic 
dysfunction and suicide ideation and behavior 
Updated per FDA Comments of 26-
Jan-2022 and 31-Jan-2022 
 
Section 10.2.9, added follow up for AE/SAE 
occurred during the course of all pregnancies.  
To further substantiate safety follow-
up in the event that a pregnancy 
occurs during the study 
 
Section 11.4.1 added “randomized” 
Updated per FDA Comments of 26-
Jan-2022 and 31-Jan-2022 
 
Section 11.4.2 specified the mITT will be analyzed 
based on the treatment policy estimand 
Updated per FDA Comments of 26-
Jan-2022 and 31-Jan-2022 
Version 5.0 
(10Mar2022) 
Change of version and date 
Administrative change 
 
Synopsis  
Consistency with other sections 


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Protocol Version 
(Date Issued) 
Changes 
Rationale 
 
Section 4.1.2.2 
Added the following secondary objectives:  
 
Effect of RAD011 on Clinician Global 
Impression of Change (CGI-C) in 
Hyperphagia 
 
Effect of RAD011 on Clinician Global 
Impression of Severity (CGI-S) of 
Hyperphagia Scale 
Removed the following secondary objective: 
 
Effect of RAD011 on Caregiver Global 
Impression of Change (CaGI-C) 
Updated per FDA Comments of 24-
Feb-2022 
 
Section 4.1.2.3 
Added the following other objective: 
 
Effect of RAD011 on Caregiver Global 
Impression of Change (CaGI-C) in 
Hyperphagia 
Modified the Global Impression of change and 
severity in hyperphagia and irritability from 
clinical to caregiver assessments 
Removed the following other objective: 
 
Effect of RAD011 on Clinical Global 
Impression of Change (CGI-C) in 
Hyperphagia Scale 
Updated per FDA Comments of 24-
Feb-2022 
 
Figures 2 and 3: updated figure to remove dotted 
line leading from the Tolerability Period to the 
SCOUT-016 LTE study 
Patients who do not complete the 
Maintenance Period are no longer 
eligible to participate in the 
SCOUT-016 LTE study 
 
Sections 5.8.2.1, 5.8.4.1: changed CGI-S 
Irritability to CaGI-S Hyperphagia 
Align with change in endpoints 
 
Section 5.8.5.1: changed CGI-S Irritability to 
CaGI-S Hyperphagia and CGI-C Irritability to 
CaGI-C Irritability 
Align with change in endpoints 
 
Tables 6 and 7: updated Schedules of Assessments 
to reflect changes in endpoints and associated 
assessments 
Align with change in endpoints 
 
Section 6.1, Inclusion criterion 7: changed stability 
period for GH, psychotropic therapy, metabolic 
treatments that could affect appetite, and other 
treatments including thyroid hormone from 
4 weeks to 90 days 
Updated per FDA Comments of 24-
Feb-2022 
 
Section 6.1, Inclusion criterion 8: changed stability 
period for non-medical interventions from 4 weeks 
to 90 days 
Updated per FDA Comments of 24-
Feb-2022 
 
Section 6.2, Exclusion criteria 2, 5, and 6: changed 
exclusion period from 4 weeks to 90 days 
Updated per FDA Comments of 24-
Feb-2022 


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Protocol Version 
(Date Issued) 
Changes 
Rationale 
 
Section 6.2, Exclusion criterion 7a): removed the 
4-week time prior to consent/assent period for 
diagnosis of a new respiratory, heart, or 
psychiatric disease 
These comorbid conditions might 
interfere with patient care and patient 
assessments, regardless of the time of 
diagnosis 
 
Section 7.2: changed stability period from 4 weeks 
to 90 days 
To align with inclusion criterion 7 
 
Section 9.2.2: updated wording in change in 
hyperphagia and changed CGI-C to CaGI-C. 
Removed text detailing CGI 7-point scale. 
To align with change in endpoints 
 
Section 9.2.3: Moved CGI-S description to Section 
9.2.3 
To align with change in endpoints 
 
Section 9.3.1: updated wording for caregiver 
impression of change and severity scales 
To align with change in endpoints 
 
Overall: formatting and administrative changes 
To align with other protocol changes 
and ensure consistency 


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APPENDIX 2. EVALUATION OF SEIZURE HISTORY AND SEIZURE 
PATIENT HISTORY 
Medical History Questionnaire 
As part of the Medical History assessments, the following questions must be asked and 
documented in the eCRF: 
 During the last 12 months did you experience any seizure that was medically 
documented? Yes/No 
 What was/were the type/s of seizure you experienced during the last 12 months? Please 
list all types. 
 Was/were the seizure(s) treated? Yes/No 
 Are you currently receiving any seizure medications? Please list all. 
 Has the dose for your anti-seizure medication changed during the last 6 months? 
 
Seizure Patient Impression 
At the End of Study/Week 34 Visit (Visit 14), patients with a seizure history must be asked the 
following questions and documented in the eCRF: 
 Based on your study experience, has your impression of seizures changed in any way 
(occurrence, severity, etc.): 
o No change 
o Became better 
o Became worse 
 


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SAP_001.pdf: 
Radius SCOUT-015 Statistical Analysis Plan v1.0 
CONFIDENTIAL 
Page 1 of 56 
A Phase 2/3, Randomized, Double-Blind, Placebo-Controlled Study of RAD011 (Cannabidiol 
Oral Solution) for the Treatment of Patients with Prader-Willi Syndrome 
Protocol Number: 
SCOUT-015 
Protocol Version: 
5.0 
Protocol Date: 
10 March 2022 
STATISTICAL ANALYSIS PLAN 
Version 1.0 
The effective date of the document is the last date of approval of the document 
NCT #: NCT05098509


 
Radius SCOUT-015 Statistical Analysis Plan v1.0 
CONFIDENTIAL 
Page 2 of 56 
 
 
A Phase 2/3, Randomized, Double-Blind, Placebo-Controlled Study of RAD011 
(Cannabidiol Oral Solution) for the Treatment of Patients with Prader-Willi Syndrome 
 
STATISTICAL ANALYSIS PLAN 
Version 1.0 
 
 
 
Author: 
 
 CTI 
 
 
 
 
 
CTI Biostatistics 
Reviewer: 
 
 CTI 
 
 
 
 
 
 
Sponsor Approval: 
 
 
Radius Health, Inc. 


Radius SCOUT-015 Statistical Analysis Plan v1.0 
CONFIDENTIAL 
Page 3 of 56 
Table of Contents 
LIST OF ABBREVIATIONS ...................................................................................................................... 5 
1.
INTRODUCTION ................................................................................................................................ 7 
2.
OBJECTIVES AND ENDPOINTS..................................................................................................... 7 
2.1 
OBJECTIVES .................................................................................................................................... 7 
2.1.1 Primary Objective ...................................................................................................................... 7 
2.1.2 Secondary Objectives ................................................................................................................. 7 
2.1.3 Other Objectives......................................................................................................................... 7 
2.2 
ENDPOINTS ..................................................................................................................................... 8 
2.2.1 Primary Efficacy Endpoint ......................................................................................................... 8 
2.2.2 Secondary Efficacy Endpoints .................................................................................................... 8 
2.2.3 Other Endpoints ......................................................................................................................... 8 
2.2.4 Pharmacokinetic (PK) Endpoints ............................................................................................... 9 
2.2.5 Safety Endpoints ......................................................................................................................... 9 
3.
INVESTIGATIONAL PLAN .............................................................................................................. 9 
3.1 
STUDY DESIGN ............................................................................................................................... 9 
3.2 
TREATMENT ................................................................................................................................. 13 
3.2.1 Randomization Scheme and Treatment Arm Assignment ......................................................... 13 
3.2.2 Blinding .................................................................................................................................... 14 
3.2.3 Dosing Schedule ....................................................................................................................... 14 
3.2.4 Patient Withdrawal and Study Termination ............................................................................. 15 
4.
GENERAL CONSIDERATIONS FOR DATA ANALYSIS .......................................................... 16 
4.1 
DATA QUALITY CONTROL PROCEDURES ..................................................................................... 16 
4.2 
ANALYSIS POPULATIONS.............................................................................................................. 17 
4.3 
ASSESSMENT WINDOWS............................................................................................................... 17 
4.4 
HANDLING OF DROPOUTS OR MISSING DATA .............................................................................. 18 
4.5 
MULTIPLE COMPARISONS ............................................................................................................ 18 
4.6 
DATA DERIVATIONS AND TRANSFORMATIONS ............................................................................ 20 
5.
STUDY PATIENTS ........................................................................................................................... 20 
5.1 
DISPOSITION OF PATIENTS ........................................................................................................... 20 
5.2 
PROTOCOL DEVIATIONS ............................................................................................................... 20 
5.3 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ..................................................................... 20 
5.4 
MEDICAL HISTORY ....................................................................................................................... 21 
5.5 
PRIOR AND CONCOMITANT MEDICATIONS .................................................................................. 21 
6.
EFFICACY ANALYSES ................................................................................................................... 21 
6.1 
PRIMARY EFFICACY ENDPOINT AND ANALYSIS .......................................................................... 21 
6.1.1 Sensitivity Analyses for the Primary Efficacy Endpoint ........................................................... 23 
6.1.2 Subgroup Analyses for the Primary Efficacy Endpoint ............................................................ 23 
6.1.3 Clinical Meaningfulness of Primary Efficacy Endpoint ........................................................... 24 


 
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Page 4 of 56 
 
 
6.2 
SECONDARY EFFICACY ENDPOINTS AND ANALYSES................................................................... 25 
6.3 
OTHER EFFICACY ENDPOINTS AND ANALYSES............................................................................ 27 
7. 
SAFETY ANALYSIS ......................................................................................................................... 32 
7.1 
EXTENT OF EXPOSURE AND COMPLIANCE ................................................................................... 32 
7.2 
ADVERSE EVENTS ........................................................................................................................ 33 
7.2.1 Treatment-emergent Adverse Events ........................................................................................ 34 
7.2.2 Adverse Event Intensity ............................................................................................................ 34 
7.2.3 Adverse Event Relationship to Study Drug .............................................................................. 34 
7.2.4 Serious Adverse Events ............................................................................................................ 34 
7.2.5 Adverse Events of Special Interest (AESI) ............................................................................... 35 
7.2.6 Adverse Event Summaries ........................................................................................................ 35 
7.3 
CLINICAL LABORATORY ASSESSMENTS ...................................................................................... 37 
7.4 
VITAL SIGNS................................................................................................................................. 37 
7.5 
ECG .............................................................................................................................................. 38 
7.6 
COLUMBIA SUICIDE-SEVERITY RATING SCALE (C-SSRS) .......................................................... 38 
7.7 
OTHER SAFETY MEASURES .......................................................................................................... 39 
8. 
INTERIM ANALYSES ..................................................................................................................... 39 
9. 
SAMPLE SIZE AND POWER CALCULATIONS ........................................................................ 40 
10. 
CHANGE FROM PROTOCOL ................................................................................................... 41 
11. 
REFERENCES ............................................................................................................................... 41 
12. 
APPENDICES ................................................................................................................................ 42 
12.1 
APPENDIX A PART 1: SCHEDULE OF ASSESSMENTS – SCREENING AND TOLERABILITY PERIODS 
42 
12.2 
APPENDIX A PART 2: SCHEDULE OF ASSESSMENTS - DOSE ESCALATION, MAINTENANCE, 
TAPER, AND FOLLOW-UP PERIODS .......................................................................................................... 45 
12.3 
APPENDIX B: MISSING OR INCOMPLETE DATES IMPUTATION RULES .......................................... 50 
12.4 
APPENDIX C: LIST OF PREFERRED TERMS FOR AESI ................................................................... 52 
12.5 
APPENDIX D: MARKED LAB ABNORMALITIES ........................................................................... 56 
12.5.1 
Hematology .......................................................................................................................... 56 


 
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LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
ABC 
Aberrant Behavior Checklist 
ABC-I 
Aberrant Behavior Checklist - Irritability subscale 
AE 
Adverse event 
AESI 
Adverse event of Special Interest 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
ATC 
Anatomical, Therapeutic, and Chemical 
AUS 
Australia 
BMI 
Body mass index 
CBD 
Cannabidiol 
CaGI-C 
Caregiver Global Impression of Change 
CaGI-S 
Caregiver Global Impression of Severity 
CGI-C 
Clinician Global Impression of Change 
CGI-S 
Clinical Global Impression of Change – Severity Scale 
CI 
Confidence interval 
CMH 
Cochran-Mantel-Haenszel 
CS 
Compound symmetry 
CSH 
Heterogeneous compound symmetry 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DEXA 
Dual-energy X-ray absorptiometry 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
ESS-CHAD 
Sleepiness Scale for Children and Adolescents 
EU 
Europe 
FCS 
Fully conditional specification 
GH 
Growth hormone 


 
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Abbreviation 
Definition 
HbA1c 
Glycosylated hemoglobin 
HQ-CT 
Hyperphagia Questionnaire for Clinical Trials 
IP 
Investigational product 
IRT 
Interactive Response Technology 
ITT 
Intent-to-Treat 
LS 
Least-squares 
MAR 
Missing at random 
MCID 
Minimal Clinically Important Difference 
MCT 
Medium Chain Triglycerides 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple imputation 
mITT 
Modified Intent-to-Treat 
MMRM 
Mixed Model for Repeated Measures 
MNAR 
Missing not at random 
NA 
North America 
PP 
Per Protocol 
PK 
Pharmacokinetics 
PMM 
Predictive means matching 
PT 
Preferred term 
PWS 
Prader-Willi Syndrome 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
TEAE 
Treatment-Emergent Adverse Event 
ULN 
Upper limit of normal 
WHO 
World Health Organization 


 
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1. INTRODUCTION 
 
This statistical analysis plan (SAP) is based on Protocol SCOUT-015 V5.0, titled “A Phase 2/3, 
Randomized, Double-Blind, Placebo-Controlled Study of RAD011 (Cannabidiol Oral Solution) 
for the Treatment of Patients with Prader-Willi Syndrome.” See the study protocol for full details. 
This document details the statistical methods planned to perform the Data Monitoring Committee 
(DMC) analysis for Phase 2 part of the study, and the final analysis at the end of Phase 3 part of 
the study. The DMC will review the safety and tolerability data and recommend 1 or 2 RAD011 
dose level(s) for evaluation in the Phase 3 part of the study. 
 
2. OBJECTIVES AND ENDPOINTS 
 
2.1 
Objectives 
 
2.1.1 
Primary Objective 
Phase 2 
The primary objective of the Phase 2 part of this study is to assess the safety and tolerability of 
multiple doses levels of RAD011 in order to select 1 or 2 dose level(s) to further evaluate in the 
Phase 3 part of the study. 
Phase 3 
The primary objective* of the Phase 3 part of this study is to assess the effect of RAD011 on 
hyperphagia-related behavior in patients with Prader-Willi Syndrome (PWS). 
*The Phase 3 part of the study will include all patients from the Phase 2 part of the study who were 
treated with dose level(s) selected for development in the Phase 3 part of the study. 
 
2.1.2 
Secondary Objectives 
Phase 3 
The secondary objectives* for the Phase 3 part of this study are to assess the following: 
• Effect of RAD011 on irritability 
• Effect of RAD011 on Clinician Global Impression of Change (CGI-C) in Hyperphagia 
• Effect of RAD011 on Clinician Global Impression of Severity (CGI-S) in Hyperphagia 
• Safety and tolerability of RAD011. 
 
*The Phase 3 part of the study will include all patients from the Phase 2 part of the study who were treated 
with dose level(s) selected for development in the Phase 3 part of the study. 
 
2.1.3 
Other Objectives 
Phase 3 
The other objectives* for the Phase 3 part of this study are to access the following: 
• Effect of RAD011 on Caregiver Global Impression of Change (CaGI-C) in Hyperphagia 
• Effect of RAD011 on Caregiver Global Impression of Severity (CaGI-S) of Hyperphagia 


 
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• Effect of RAD011 on Caregiver Global Impression of Change (CaGI-C) in Irritability 
• Effect of RAD011 on overall behavior 
• Effect of RAD011 on sleep 
• Effect of RAD011 on body mass index (BMI) and weight 
• Effect of RAD011 on skin-picking behavior 
• Effect of RAD011 on total muscle/fat composition (performed at selected US sites). 
 
*The Phase 3 part of the study will include all patients from the Phase 2 part of the study who were treated 
with dose level(s) selected for development in the Phase 3 part of the study. 
 
2.2 
Endpoints 
 
2.2.1 
Primary Efficacy Endpoint 
• Change in Hyperphagia Questionnaire for Clinical Trials (HQ-CT) scores from Baseline 
through End of Study/Week 34 Visit for RAD011 compared to placebo 
 
2.2.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints include the following: 
• Change in PWS-associated Irritability from Baseline through End of Study/Week 34 Visit 
using the Aberrant Behavior Checklist (ABC) questionnaire – Irritability subscale (ABC- 
I) for RAD011 compared to placebo 
• Change in hyperphagia as defined by the CGI-C in Hyperphagia through End of 
Study/Week 34 Visit 
• Change in severity of hyperphagia as defined by the CGI-S response from Baseline through 
End of Study/Week 34 Visit 
 
2.2.3 
Other Endpoints 
The other endpoints include the following: 
• Change in hyperphagia as defined by the CaGI-C in Hyperphagia response through End of 
Study/Week 34 Visit for RAD011 compared to placebo 
• Change in CaGI-S of Hyperphagia from Baseline through End of Study/Week 34 Visit 
• Change in irritability as defined by the CaGI-C in Irritability through End of Study/Week 
34 Visit 
• Change in overall behavior from Baseline through End of Study/Week 34 Visit using the 
ABC questionnaire subscales for RAD011 compared to placebo 
• Change in sleep from Baseline through End of Study/Week 34 Visit using the Epworth 
Sleepiness Scale for Children and Adolescents (ESS-CHAD) for RAD011 compared to 
placebo 
• Change in Weight and BMI from Baseline through End of Study/Week 34 Visit for RAD011 
compared to placebo 


 
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• Change in skin picking behavior using the Skin Picking Questionnaire from Baseline 
through End of Study/Week 34 for RAD011 compared to placebo 
• Change in muscle/fat composition using a dual-energy X-ray absorptiometry (DEXA) scan 
from Randomization through End of Study/Week 34 visit for RAD011 compared to 
placebo 
 
2.2.4 
Pharmacokinetic (PK) Endpoints 
Throughout the study, plasma samples will be collected to establish the PK profile of cannabidiol 
(CBD) and 2 metabolites, 7-OH-CBD and 7-COOH-CBD in patients with PWS. Furthermore, an 
exposure response analysis using CBD and 7-OH-CBD concentrations as well as a population PK 
model will be derived from the data. Data for the PK Analyses will be collected by ACM, samples 
analyzed by World Wide Clinical Trials (WWCT) and reported by Allucent. Allucent will provide 
details of the PK analyses in a separate analysis plan. 
 
2.2.5 
Safety Endpoints 
The safety endpoints include: 
• Treatment-emergent adverse events (TEAEs) 
• Vital signs (blood pressure, heart rate, body temperature, respiratory rate, oxygen 
saturation) 
• Electrocardiogram (ECG) 
• Columbia-Suicide Severity Rating Scale (C-SSRS) 
• Laboratory tests (chemistry, hematology, and urinalysis) 
 
3. INVESTIGATIONAL PLAN 
 
3.1 
Study Design 
This is a seamless Phase 2/3, double blind, randomized, placebo-controlled clinical study in 
patients diagnosed with PWS. The study will consist of six similar periods for the Phase 2 and 
Phase 3 parts of the study: 
• Screening Period (3 weeks): Review of eligibility prior to proceeding to the Tolerability 
Period 
• Tolerability Period (6 weeks): Determination of randomization eligibility 
• Dose Escalation Period (3 weeks) 
• Maintenance Period (24 weeks) 
• Taper Period (2 weeks) 
• Follow-Up Period (2 weeks). 
Patients who do not meet criteria for randomization eligibility will not be randomized to study 
SCOUT-015. All patients participating in the Maintenance Period may be offered participation in 
the long-term extension study (SCOUT-016). Patients who do not enroll in the SCOUT-016 study 


 
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will have their investigational product (RAD011 or placebo) tapered over 2 weeks (14 days), 
followed by a 2-week (14-day) safety follow-up. 
After approximately 45 patients complete 4 weeks of the Maintenance Period of the Phase 2 part 
of the study, the DMC will meet to review safety and tolerability data and to recommend 1 or 2 
RAD011 dose level(s) for evaluation in the Phase 3 part of the study. 
Screening Period (3 weeks, Visit 1 [Weeks -3 to 0]): 
Phase 2 and Phase 3 Parts of the study 
All patients with a signed informed consent/assent will undergo Screening assessments. Screening 
assessments will include a full medical history and physical exam, a review of documentation of 
PWS diagnosis, an ECG, laboratory assessments, and questionnaires (including the HQ-CT) as 
described in Appendix A Part 1. To be eligible for the Tolerability Period, patients must meet the 
following criterion: 
• Mean HQ-CT score ≥13 obtained from HQ-CT scores as defined in Protocol Section 6.4.1. 
The EDC system will automatically calculate a mean HQ-CT score from Visit 1 and Visit 
2. Patients must have a mean HQ-CT score ≥13 to be eligible to continue in the Tolerability 
Period. Patients with a mean score <13 will not be eligible to continue in the Tolerability 
Period and will be discontinued from the study. 
 
Patients not meeting Inclusion/Exclusion criteria defined in Protocol Section 6.1 and 6.2 for entry 
in the study will not be eligible for the study and may not be screened again. Caregivers will be 
required either to assist the patient or complete the questionnaires on behalf of the patient. The 
same caregiver should be available throughout the study to help in completing the questionnaires 
for purposes of consistency. 
Tolerability Period (6 weeks, Visits 2 to 5 [Weeks 1 to 7]) 
Phase 2 and Phase 3 of the study 
Patients who meet the eligibility criteria will undergo a 6-week Tolerability Period. During this 
Period, all patients will receive placebo at a dose of 0.1 mL/kg/day to assess tolerability of the 
formulation without active CBD and give patients time to adjust to study procedures and future 
Investigational Product (IP) administration. Patients unable to tolerate the 0.1 mL/kg/day dose 
level will be withdrawn from the study. 
Patients/caregivers will also complete serial HQ-CT questionnaires at 2-week intervals. At the end 
of the 6-week Tolerability Period and prior to randomization, patient randomization eligibility 
based on tolerability and HQ-CT scores will be evaluated. To be eligible for randomization, 
patients must meet both of the following criteria: 
• Mean HQ-CT score ≥13 obtained from prior HQ-CT scores as defined in Protocol Section 
6.4.2. The EDC system will automatically calculate a mean HQ-CT score from Visit 3, Visit 4 
and Visit 5. Patients must have a mean HQ-CT score ≥13 to be eligible to be randomized and 
proceed to the Dose Escalation Period. Patients with a mean score <13 will not be eligible for 
randomization and will not have the opportunity to participate in the long-term extension study 
(SCOUT-016). 
• Decrease from the Tolerability Period to the Screening Period in HQ-CT score ≤7 points as 
defined in Protocol Section 6.4.2. The EDC system will automatically calculate the change in 


 
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HQ-CT score from the Tolerability Period to the Screening Period. This change is calculated 
as: 
Mean HQ-CT score (Visit 3, Visit 4, Visit 5) – Mean HQ-CT score (Visit 1, Visit 2) 
Patients with a decrease HQ-CT score ≤7 will be eligible for randomization. Patients with a 
decrease in HQ-CT score >7 will not be eligible for randomization and unable to proceed to the 
Dose Escalation Period. 
Randomization 
 
Phase 2 of the study 
Following the Tolerability Period, patients meeting randomization eligibility criteria will be 
randomized to 1 of 6 groups (3 active to 3 placebo with the ratio of 2:2:2:1:1:1): low dose (10 
mg/kg/day [0.1 mL/kg/day]) RAD011, mid dose (20 mg/kg/day [0.2 mL/kg/day]) RAD011, high 
dose (40 mg/kg/day [0.4 mL/kg/day]) RAD011, low volume (0.1 mL/kg/day) placebo, mid volume 
(0.2 mL/kg/day) placebo, or high volume (0.4 mL/kg/day) placebo divided in two daily doses 
taken with food approximately 12 hours apart. 
Phase 3 of the study 
Following review of the Phase 2 safety and tolerability data by the DMC, 1 or 2 dose level(s) will 
be recommended for further development and assessment in Phase 3 of the study. 
Dose Escalation Period (3 weeks, Visits 5 to 7 [Weeks 7 to 9]) 
Phase 2 of the study 
After completing the Screening and Tolerability Periods, all randomized patients will be initiated 
on the IP 10 mg/kg/day (0.1 mL/kg/day) for a period of 1 week at Visit 5 (Week 7). Patients 
randomized to low dose or low volume IP (10 mg/kg/day) will continue at a dose of 10 mg/kg/day 
(0.1 mL/kg/day) until the end of Visit 7 (Week 9). Patients randomized to mid dose or mid volume 
IP (20 mg/kg/day) will have their dose increased to 20 mg/kg/day (0.2 mL/kg/day) at Visit 6 (Week 
8) and will continue at that dose until the end of Visit 7 (Week 9). Patients randomized to high 
dose or high volume IP (40 mg/kg/day) will have their dose increased to 20 mg/kg/day (0.2 
mL/kg/day) at Visit 6 (Week 8) and to 40 mg/kg/day (0.4 mL/kg/day) at Visit 7 (Week 9). 
The Investigator, or designee, will contact patients/caregivers by phone call, video call, email, or 
other remote means of communication at Visits 6 (Week 8) and 7 (Week 9) to determine if the 
patient’s dose may be escalated to the next dose level. Dose reductions will not be allowed during 
the Dose Escalation Period. Patients unable to tolerate their assigned dose level(s) during the Dose 
Escalation Period will be withdrawn from the study. 
Phase 3 of the study 
After completing the Screening and Tolerability Periods, all patients will be initiated on 10 
mg/kg/day IP (0.1 mL/kg/day) for a period of 1 week at Visit 5 (Week 7). Dose escalation will 
occur as in the Phase 2 of the study, according to the DMC-recommended Phase 3 dose level(s). 
The Investigator, or designee, will contact patients/caregivers by phone call, video call, email, or 
other remote means of communication at Visits 6 (Week 8) and 7 (Week 9) to determine if the 
patient’s dose may be escalated to the next dose level. Dose reductions will not be allowed during 
the Dose Escalation Period. If a patient cannot be escalated to the next dose level, the patient will 


 
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be discontinued from the study. 
Details of the dose escalation schema for Phase 2 and Phase 3 of the study are provided in Table 
1: 
Table 1. Dose Escalation Regimen 
 
Group for 
Analysis 
Dosing Group 
Target dose 
Visit 5 
Week 7 
Visit 6 
Week 8 
Visit 7 
Week 9 
RAD011 low 
dose 
RAD011 low dose 
(10 mg/kg/day = 0.1 mL/kg/day) 
10 mg/kg/day 
0.1 mL/kg/day 
10 mg/kg/day 
0.1 mL/kg/day 
10 mg/kg/day 
0.1 mL/kg/day 
RAD011 mid 
dose 
RAD011 mid dose 
(20 mg/kg/day = 0.2 mL/kg/day) 
10 mg/kg/day 
0.1 mL/kg/day 
20 mg/kg/day 
0.2 mL/kg/day 
20 mg/kg/day 
0.2 mL/kg/day 
RAD011 high 
dose 
RAD011 high dose 
(40 mg/kg/day = 0.4 mL/kg/day) 
10 mg/kg/day 
0.1 mL/kg/day 
20 mg/kg/day 
0.2 mL/kg/day 
40 mg/kg/day 
0.4 mL/kg/day 
Placebo 
Placebo low volume 
(0.1 mL/kg/day) 
0.1 mL/kg/day 
0.1 mL/kg/day 
0.1 mL/kg/day 
Placebo mid volume 
(0.2 mL/kg/day) 
0.1 mL/kg/day 
0.2 mL/kg/day 
0.2 mL/kg/day 
Placebo high volume 
(0.4 mL/kg/day) 
0.1 mL/kg/day 
0.2 mL/kg/day 
0.4 mL/kg/day 
 
Maintenance Period (24 weeks, Visits 8 to 14 [Weeks 10 to 34]) 
Phase 2 and Phase 3 of the study 
After completing the 3-week Dose Escalation Period, patients will enter the 24-week Maintenance 
Period. 
Some patients may have their dose adjusted based on tolerability during the Maintenance Period. 
After completion of the Maintenance Period, patients may be offered the opportunity to enroll in 
the long-term extension study (SCOUT-016). Patients who do not elect to enroll will be tapered 
off the IP. 
Taper Period (14 days, Visit 14 [Week 34]) and Follow-up Period (14 days, Visits 15 and 16 
[Weeks 36 and 38]) 
Patients who do not enroll in the long-term extension study (SCOUT-016) will have their IP 
tapered off over 14 days according to the following schedule: the IP should be decreased by 50% 
during the first 7 days, followed by an additional 50% during the following 7 days, and then 
discontinued. The taper schedule may be modified at the discretion of the Investigator but cannot 
be extended to a total period lasting more than 14 days. A final follow up will be conducted 2 
weeks after the last dose of IP for patients who are tapered off. 
A schematic representation of the Phase 2 and Phase 3 of the study is provided in the figures below: 


 
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Study Design Schematic – Phase 2 of the Study 
* Patients assigned to placebo will include low, mid, and high volume placebo to match active drug and will be 
combined for statistical analysis. 
Study Design Schematic – Phase 3 of the Study 
 
Abbreviations: FU = follow-up; LTE = long-term extension; RAND = randomization. 
* Patients assigned to placebo will be further broken down to achieve balanced exposure between placebo and 
RAD011 patients. Patients in the placebo group (matching volume) will be combined for statistical analysis. 
Final doses are to be determined based on the DMC decision. Schematic shows the scenario where 2 doses are 
chosen for Phase 3. 
 
3.2 
Treatment 
 
3.2.1 
Randomization Scheme and Treatment Arm Assignment 
Phase 2 of the study 
Patients who meet eligibility criteria will be randomized in a 2:2:2:1:1:1 manner to receive double- 
blind treatment with IP, defined as either low dose (10 mg/kg/day, [0.1 mL/kg/day]) RAD011, mid 
dose (20 mg/kg/day, [0.2 mL/kg/day]) RAD011, high dose (40 mg/kg/day [0.4 mL/kg/day]) 


 
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RAD011, low volume (0.1 mL/kg/day) placebo, mid volume (0.2 mL/kg/day) placebo, or high 
volume (0.4 mL/kg/day) placebo using a centralized randomization system. Randomization will 
be stratified according to current use of Growth Hormone (GH) treatment at the time of 
randomization (yes/no) and age (≥16 or <16 years old). 
A central randomization system, Medidata Rave Randomization & Trial Supply Management 
(RTSM)®, will be used for this study. 
Phase 3 of the study 
Following review by the DMC, 1 or 2 dose levels will be recommended for continued development 
and assessment in Phase 3 of the study. Therefore, following the Tolerability Period, patients 
meeting randomization eligibility criteria will be randomized using a centralized randomization 
system RTSM in a way to obtain a balanced number of patients on RAD011 and placebo to receive 
double-blind treatment with IP at dose levels recommended by the DMC. 
If 1 dose is recommended for continued development and assessment in Phase 3 of the study, 
randomization will be 1:1 (RAD011: placebo). 
If 2 doses are recommended for continued development and assessment in the Phase 3 part of the 
study, randomization will be 2:2:1:1 (RAD011 dose 1: RAD011 dose 2: placebo: placebo). 
Patients aged 8 to <12 years may be allowed to participate in the Phase 3 part of the study and will 
be randomized in a way to obtain a balanced number of patients on RAD011 (at dose levels 
recommended by the DMC) and placebo. Patients aged 8 to <12 will not be included in the primary 
efficacy analysis. 
 
3.2.2 
Blinding 
Both Investigators and patients will be blinded to the randomization assigned treatment. During 
the Tolerability Period, all patients will receive 0.1 mL/kg/day of placebo. To maintain the blind, 
multiple placebo groups were created to mimic the RAD011 groups: low volume (0.1 mL/kg/day), 
mid volume (0.2 mL/kg/day), and high volume (0.4 mL/kg/day). During the dose escalation 
period, the volume of blinded therapy for the mid volume and high volume placebo groups will 
increase in the same manner as the mid dose and high dose RAD001 groups, further ensuring 
blinding between RAD011 and placebo. 
The matching (appearance, smell and taste) placebo and RAD011 product will utilize the same 
medium chain triglycerides (MCT) vehicle. 
The assigned unblinded statistician will have access to unblinded data for DMC meeting purposes. 
Breaking the treatment blind for a patient should be done only in the event of a medical emergency 
where the identity of the IP is necessary to appropriately treat the patient. The Investigator may 
unblind the treatment received by the patient through the interactive response technology (IRT). 
The IRT will automatically document and record any such unblinding and notify the Sponsor 
Medical Monitor of the unblinding event. If possible, the Sponsor and/or designee should be 
contacted prior to unblinding of the treatment. The study monitor will not be apprised of the actual 
treatment assignment. 
 
3.2.3 
Dosing Schedule 
The IP (RAD011 or placebo) will be administered orally twice daily with food, approximately 12 


 
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hours apart. Patients must take the IP with food throughout the study. All patients will receive a 
dose on a mg/kg/day basis, and dose reductions will be allowed per the details below. 
1. During Dose Escalation Period, dose reductions for tolerability are not allowed. Patients 
unable to tolerate their assigned dose level(s) during the Dose Escalation Period will be 
withdrawn from the study. 
2. In the event that a patient does not tolerate their assigned dose level on a mg/kg/day basis 
during the Maintenance Period, the Investigator may decrease the patient’s dose by 25% at 
any time during the Maintenance Period after consultation with the Sponsor as shown in 
Table 2. Patients undergoing a dose reduction may not have their dose increased back to 
their originally assigned dose. If a second dose reduction is required for tolerability during 
the Maintenance Period, the patient should be discontinued from the study in consultation 
with the Sponsor. 
Table 2. Dose Level (mg/kg/day) Reduction for Tolerability during the Maintenance Period 
 
Dose Prior to Performing Dose Reduction 
Dose Following Dose Reduction (25% Decrease) 
10 mg/kg/day 
0.1 mL/kg/day 
7.5 mg/kg/day 
0.075 mL/kg/day 
20 mg/kg/day 
0.2 mL/kg/day 
15 mg/kg/day 
0.15 mL/kg/day 
40 mg/kg/day 
0.4 mL/kg/day 
30 mg/kg/day 
0.3 mL/kg/day 
 
During the Maintenance Period, all patients will be dosed using their actual body weight at Visit 
5 (Week 7), and this dose will be maintained through the course of the study. 
 
3.2.4 
Patient Withdrawal and Study Termination 
The Investigator should withdraw the patient from the study if they believe that participation is no 
longer in the patient’s best interest, or in the event of study termination by the Sponsor. If the 
patient elects to withdraw from the study, reason(s) for withdrawal should be documented. The 
Investigator will discuss with the patient procedures for withdrawal and any additional care or 
treatment alternatives available at that time. In addition, patients unable to tolerate the 0.1 
mL/kg/day dose level during the Tolerability Period or their assigned dose level(s) during the Dose 
Escalation Period will be withdrawn from the study. 
If a patient withdraws consent/assent from the study, the patient should be encouraged to complete 
all End of Study Visit assessments (Visit 14, Week 34) completed as described in the Schedule of 
Assessments (Appendix A, Part 2). At time of withdrawal of consent/assent, the patient will be 
withdrawn from all additional study procedures and follow-up. 
Data collected until patient withdrawal or lost to follow-up will be retained and included in the 
analysis of the study in accordance with local rules and regulations. 


 
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4. GENERAL CONSIDERATIONS FOR DATA ANALYSIS 
 
Unless otherwise specified, continuous variables will be summarized using descriptive statistics 
(the number of non-missing observations [n], mean, standard deviation [SD], median, minimum, 
and maximum). Categorical variables will be summarized by showing the number and percentage 
of patients within each category. 
Summary results will be provided for the RAD011 and placebo groups. The low, mid, and high 
volume placebo groups will be combined for summary analysis for the purposes of the DMC 
analysis. If 2 doses are selected for the Phase 3 part of the study, the 2 corresponding volume 
placebo groups will be combined for all Phase 3 statistical analyses and the other placebo group 
will be presented in its own column. All tabulations will be based on pooled data across centers. 
If the DMC recommends two RAD011 doses for Phase 3 of the study, all statistical comparisons 
will be performed using two-sided tests at an α = 0.025 significance level for each RAD011 dose 
group and placebo comparison. If the DMC recommends one RAD011 dose for Phase 3 of the 
study, all statistical comparisons will be performed using two-sided tests at an α = 0.05 significance 
level. 
All p-values will be displayed to four decimal places, with p-values less than 0.0001 presented as 
'<0.0001'. Minimum and maximum values will be reported with the same number of decimal 
places as in the units of collection with 3 decimals being maximum value; the mean will be 
presented with 1 decimal place more and the standard deviation 2 decimal places more than the 
units of collection. 
All analyses will be performed using SAS for Windows statistical software, version 9.4 or higher 
(SAS, Cary, NC), except where other software may be deemed more appropriate. 
CTI will perform all efficacy and safety analyses described in this SAP. PK samples will be 
collected by ACM, samples analyzed by WWCT, and analyzed and reported by Allucent. The PK 
analysis methods will be covered in a separate analysis plan provided by Allucent. 
Data with qualifiers (e.g., “<”) will be listed with the qualifier but summarized without the 
qualifier, unless otherwise specified. 
Patient data will be listed, sorted by treatment group (RAD011 followed by placebo), 
investigational center, and patient number. Demographic listing will also include Study Part 
enrolled (Phase 2/3). When applicable, listings will be additionally sorted by nominal visit and 
assessment date/time. 
 
4.1 
Data Quality Control Procedures 
Once all the source verification is complete, all queries are resolved, and the database has been 
updated appropriately, the database will be locked and made available to CTI Biostatistics for final 
analysis. 
Safety data will be pulled by CTI Biostatistics for the DMC analysis at a time when source 
verification and query resolution is ongoing, however, all critical data needed for DMC analysis 
will be entered and fully source data verified for this data-cut. 


 
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4.2 
Analysis Populations 
The following populations will be defined for analysis: 
 
1. Intent-to-Treat (ITT) Population: the ITT Population will include all randomized patients. 
2. Modified ITT (mITT) Population: the mITT Population will include all patients aged ≥ 12 
years who were randomized, received at least 1 dose of IP, had at least 1 post-randomization 
HQ-CT questionnaire completed, and were randomized to receive the dose level(s) 
recommended for development in Phase 3 part of the study, including patients in the Phase 2 
part of the study who received the chosen dose level(s). 
3. Safety Population: the Safety Population will include all randomized patients who were treated 
with at least 1 dose of IP. 
4. Per Protocol (PP) Population: the PP Population will include all patients aged ≥12 years who 
were randomized, received at least 1 dose of IP, completed Week 34 without significant 
protocol deviations that were prospectively defined to impact efficacy and received the dose 
level(s) recommended for development in the Phase 3 part of the study, including patients in 
Phase 2 of the study who received the chosen dose level(s). 
Prior to database lock and unblinding, patients who had a significant protocol deviation leading 
to exclusion from the PP population will be identified in a blinded manner by the study team. 
5. PK Evaluable Population: the PK Evaluable Population will include all patients who received 
at least 1 dose of IP and underwent at least 1 PK sample collection. 
 
4.3 
Assessment Windows 
Data will be summarized by nominal study visit recorded in the database except the early 
termination visit which will be re-assigned to an applicable visit for summary purpose. 
To re-assign the early termination visit, the protocol specified visit windows will be extended to 
the midpoint between visits so that there is no gap between the visits (Table 3). If a re-assigned 
early termination visit falls into an existing scheduled visit where data already exists, the data 
collected from the scheduled visit will be used for the summary analysis. The re-mapped early 
termination visit will be presented in the summary tables only if there is no data already existing 
for the visit. The early termination visit recorded in the database together with the calculated study 
days will be displayed in the data listings. 
Table 3. Early Termination Visit Re-mapping Windows 
 
Visit Number 
Study Time Point 
Minimum Window Day 
Maximum Window Day 
5 
Day 43 
40 
46 
6 
Day 50 
47 
53 
7 
Day 57 
54 
60 
8 
Day 64 
61 
81 
9 
Day 99 
82 
113 
10 
Day 127 
114 
141 


 
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11 
Day 155 
142 
169 
12 
Day 183 
170 
193 
13 
Day 204 
194 
218 
14 
Day 232 
219 
235 
 
The analysis of exposure and compliance by analysis period and the safety analyses on TEAEs 
based on the adverse event (AE) onset date during an analysis period are described as below in 
Table 4. 
Table 4. Analysis Period 
 
Analysis Period 
Protocol Defined Study 
Windows 
(Start – Stop) 
Window Start Time 
Window Stop Time 
Tolerability 
Day 1 - Day 42 
1st placebo dosing 
date 
Date at Visit 5 - 1 
Dose Escalation 
Day 43 - Day 63 
Date at Visit 5 
Date at Visit 8 - 1 
Maintenance 
Day 64 - Day 232 
Date at Visit 8 
Date at Visit 14 
Taper* 
Day 233 - Day 246 
Date at Visit 14 + 1 
Date at Visit 15 
Follow-Up* 
Day 247 - Day 260 
Date at Visit 15+1 
Date at Visit 16 
* Taper and Follow-up periods only apply to the patients who do not participate in long term 
extension study (SCOUT-016). 
 
4.4 
Handling of Dropouts or Missing Data 
Missing data on demographic, baseline information and safety will be treated as missing. Patient- 
level listings will present data as reported. Missing or partially missing dates that are required for 
date-dependent definitions (e.g., treatment-emergent adverse events, concomitant medications) 
will be assumed to be the most conservative date possible. See Appendix B for the details of 
imputation rules. 
Details of any missing data imputation for primary and secondary efficacy analyses will be 
specified in Section 6.1 and 6.2. No imputations will be performed for the other efficacy endpoints. 
 
4.5 
Multiple Comparisons 
A hierarchical, serial gatekeeper testing strategy will be used to protect the overall two-sided 
significance level of α = 0.05 when testing the primary and secondary efficacy outcome measures. 
DMC Recommendation of two RAD011 Doses 
The primary efficacy analysis will be performed using two-sided tests at an α = 0.025 significance 
level for each RAD011 dose group and placebo comparison (RAD011 low dose vs. placebo and 
RAD011 high dose vs. placebo) so overall Type 1 error is maintained at two-sided 0.05 level. 
The primary endpoint for each RAD011 dose group and placebo comparison will serve as a 


 
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gatekeeper for the secondary efficacy endpoints with the same dose. Thus, if and only if the change 
in HQ-CT score from Baseline to End of Study/Week 34 visit is significantly different from 
placebo in a RAD011 dose group, then statistical significance will also be assessed for the 
secondary efficacy endpoints for the same dose group comparison. 
The secondary endpoints will be tested sequentially in a hierarchical order as specified below to 
protect the overall significance level at 5% (two-sided): 
1. Change in hyperphagia as defined by the CGI-C in Hyperphagia response through End of 
Study/Week 34 Visit 
2. Change in severity of hyperphagia as defined by the CGI-S of Hyperphagia response from 
Baseline through End of Study/Week 34 Visit 
3. Change in ABC-I from Baseline through End of Study/Week 34 Visit 
Error! Reference source not found. presents the complete gatekeeping strategy for this study. 
Each family from the secondary endpoints will be tested at α = 0.025 level (two-sided) provided 
all analyses in the preceding families were significant within the same dose. 
 
If the DMC recommends one RAD011 dose for Phase 3 of the study, the same gatekeeper strategy 


 
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described above applies to both primary and secondary efficacy analyses using the two-sided α = 
0.05 significance level for the comparison between RAD011 and placebo. 
No adjustment for multiplicity will be performed for testing the other endpoints. 
 
4.6 
Data Derivations and Transformations 
The following derivations will be used in this study: 
The day of first IP administration in Tolerability Period at Visit 2 is defined as Day 1. All other 
study days will be presented relative to Day 1. 
Study Day: 
• Date of assessment – date of first IP administration + 1 for assessments done on or after 
Day 1 
• Date of assessment – date of first IP administration for assessments done prior to Day 1 
Baseline Observation: Unless otherwise specified, the baseline value is the last non-missing value 
prior to the first IP administration. 
Baseline HQ-CT is defined as the mean HQ-CT score from Visit 1 and Visit 2. 
Baseline DEXA scan is defined as the assessment done at Visit 5. 
Duration: 
• Duration in days = end date – start date + 1 
 
5. STUDY PATIENTS 
 
5.1 
Disposition of Patients 
Patient disposition will be listed and summarized for all screened patients. The frequency counts 
and percentages of all patients in the ITT, mITT, Safety, and PP Population will be provided. 
Patient disposition including study completion status and reasons for early termination, together 
with whether they continue into the long-term extension study (SCOUT-016) will be tabulated by 
treatment group and overall. 
 
5.2 
Protocol Deviations 
The number and percentage of patients in the ITT Population that have minor, major and 
significant protocol deviations, including the type of deviation within each category, will be 
tabulated for the treatment groups. Significant protocol deviations may include randomized 
patients that didn’t meet I/E criteria, patients who developed withdrawal criteria but were not 
withdrawn, patients where the patient/site staff where unproperly unblinded, and received wrong 
treatment, are a subset of major deviations, and are defined as affecting efficacy or safety 
conclusions of the study. Significant protocol deviations will be identified prior to unbinding. 
A listing of all protocol deviations will be provided. 
 
5.3 
Demographic and Baseline Characteristics 
Demographic and Baseline characteristics will be listed and summarized descriptively for the ITT 


 
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Population. The demographic and baseline characteristics will consist of age and age group (≥16 
years, ≥12 and ≤15 years, and ≥8 and ≤11 years), gender, race, ethnicity, region (NA, EU, AUS), 
baseline height, baseline weight, baseline Body Mass Index [BMI], calculated age-normalized 
baseline BMI z-scores for patients aged 8 to 19 years inclusively, growth hormone use (Yes/No) 
at randomization, and whether experienced any seizure during past 12 months (Yes/No). 
The summary analysis will be repeated for the mITT, Per Protocol, and Safety populations. The 
analysis on Safety population will be based on the treatment actually received. If a patient was 
randomized to placebo but received an active kit by accident, then the patient’s “actual” treatment 
would be the corresponding RAD011 volume (e.g. if randomized to mid volume placebo but 
receives active kit, then actual treatment is mid dose RAD011). 
In addition, the seizure history, coagulation, and serology results will be presented in a listing. 
 
5.4 
Medical History 
All medical conditions and surgical procedures will be classified by system organ class (SOC) and 
preferred term (PT) using the Medical Dictionary for Regulatory Activities (MedDRA v24.1 or 
later). The number and percentage of patients with each medical condition and surgical procedure 
will be presented for each SOC and PT for the ITT population. 
 
5.5 
Prior and Concomitant Medications 
All prior and concomitant medications collected will be coded using the World Health 
Organization (WHO) Drug Dictionary version September 2021 B3 Global WHO-Drug or later. 
The number and percentage of patients in the ITT population using prior and concomitant 
medications will be tabulated by Anatomical, Therapeutic, and Chemical (ATC) level 2 and 
preferred name. 
Prior medications will be summarized separately from concomitant medications. 
Prior medications are defined as medications that ended prior to the date of first IP administration. 
Concomitant medications are defined as medications that started at any time but ended on or after 
the date of first IP administration, including those that are ongoing at study completion. In the case 
of a missing or partial end date/time, in order to determine whether a medication is prior or 
concomitant, the imputation rules described in Appendix B will be used. Note, the imputed 
date/time will only be used to determine whether a medication is prior or concomitant. The actual 
date/time reported on the eCRFs will be presented in the listings. 
 
6. EFFICACY ANALYSES 
 
6.1 
Primary Efficacy Endpoint and Analysis 
The primary efficacy endpoint for this study is the change in HQ‑ CT scores from Baseline 
through End of Study/Week 34 Visit for RAD011 compared to placebo in the mITT population 
based on the treatment policy estimand. 
The HQ-CT questionnaire consists of 9 items, with a 2-week recall period. Each question is rated 
on a scale of 0 to 4, providing a maximum score of 36. The HQ-CT total score will be used to 
demonstrate improvements in hyperphagia-related behavior (extreme uncontrollable hunger) 
between RAD011 and placebo groups. An HQ-CT score of 13 is associated with moderate to 


 
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severe hyperphagia[1] (Fehnel 2015). 
After approximately 45 patients complete 4 weeks of the Maintenance Period of the Phase 2 part 
of the study, the DMC will meet to review safety and tolerability data and to determine 1 or 2 
RAD011 dose level(s) for evaluation in the Phase 3 part of the study. If DMC recommends 2 
RAD011 doses, the primary comparison will be mean change in HQ-CT as calculated via least 
square means comparing RAD011 low dose vs. placebo and RAD011 high dose vs. placebo at 
Week 34. Low dose and high dose groups will be compared to placebo at the two-sided 0.025 level 
so overall type 1 error is maintained at two-sided 0.05 level. If the DMC recommendation is one 
RAD011 dose, the primary comparison will be mean change in HQ-CT as calculated via least 
square means comparing RAD011 vs. placebo at Week 34 at the two-sided 0.05 level. 
Change in HQ‑ CT total score from Baseline through End of Study/Week 34 Visit will be 
evaluated by fitting a linear mixed model for repeated measures (MMRM). The model will include 
change from baseline in HQ-CT score as the response variable; randomization treatment 
assignment (as a class variable), visit (as a class variable), stratification variables (age category at 
randomization [>=16 or <16 years] and GH treatment at randomization [yes/no]), and treatment- 
by-visit interaction as fixed effects; baseline HQ-CT score as a covariate. Patient will be included 
as a random effect. 
An unstructured covariance matrix will be used to model the within-subject error. Parameters will 
be estimated using restricted maximum likelihood with the Kenward-Roger method for calculating 
the denominator degrees of freedom. In case the model will not converge with the unstructured 
covariance structure, the heterogeneous compound symmetry (CSH) will be used instead. 
Furthermore, if the model fails to converge with CSH, the compound symmetry (CS) structure will 
be used. In each case of CSH and CS, the sandwich estimator (SAS option: EMIPRICAL) will 
be used with the SAS option BETWITHIN for the denominator degrees of freedom. Data collected 
at Baseline (Visits 1 and 2), Weeks 10, 19, 27, and/or 34 will be included in the analysis. Baseline 
is defined as the mean HQ-CT score from Visit 1 and Visit 2. 
For the primary endpoint analysis at Week 34, multiple imputation (MI) will be used to assign a 
value to those cases with missing data based on the missing at random (MAR) assumption. The 
SAS fully conditional specification (FCS) method with predictive means matching (PMM) as 
described in Berglund & Heeringa [2] will be used. This method uses all of a patient’s known 
primary outcome measures at Baseline, Weeks 10, 19, 27, and/or 34 weeks to impute any missing 
values through Week 34. The model will include randomization treatment assignment and 
stratification variables (age category at randomization [>=16 or <16 years] and GH treatment at 
randomization [yes/no]). The SAS FCS REGPMM method will be used in the PROC MI. The MI 
procedure will be repeated 50 times and each derived imputation will be analyzed separately using 
the MMRM as described above, and then pooled with PROC MIANALYZE. 
The output from the MIANALYZE procedure including the least-squares (LS) means and 97.5% 
or 95% confidence intervals (CIs) for each treatment group based on number of doses chosen for 
Phase 3, the treatment difference in the LS means, the 97.5% or 95% CI for the difference based 
on number of doses chosen for Phase 3, and the associated p-value will be reported on Weeks 10, 
19, 27 and 34. If 2 doses are chosen for Phase 3, then 97.5% CIs will be presented. If 1 dose is 
chosen for Phase 3, then 95% CIs will be presented. 


 
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6.1.1 
Sensitivity Analyses for the Primary Efficacy Endpoint 
The primary endpoint analysis will be repeated using the PP population if different from the mITT 
population. 
Descriptive statistics on primary endpoint for patients aged 8 to <12 may be calculated if the 
sample size for this age group warrants a meaningful summary analysis. Otherwise, a listing for 
this age group would be sufficient. 
To explore the uncertainty in parameter estimation due to missing data, the following sensitivity 
analyses will be performed using the mITT population: 
• Repeat the MMRM analysis without imputation 
• RAD011 patients who discontinued from the study due to an AE will be treated as missing 
not at random (MNAR) and the imputation for these patients’ missing data will be based 
on the observed data in the placebo group. This can be done by assigning these patients to 
placebo in the SAS MI procedure so that the missing data imputed for these patients will 
be based on the placebo group. After generating a set of imputation datasets, these patients 
will be assigned back to RAD011 for the MMRM analysis. 
• Repeat the primary endpoint analysis using the actual stratifications, if ≥10% are different 
from the randomized stratifications. 
• An additional sensitivity analysis using the tipping-point approach will be conducted to 
assess the robustness of the primary analysis approach only if the primary analysis is 
significant. This is particularly important if a significant treatment effect is found from the 
primary analysis based on the MAR assumption. In which case, the validity of the result 
should be examined to explore the impact of MNAR on the outcome. 
Tipping point analysis is a means of exploring the influence of missingness on the overall 
conclusion from statistical inference by positing a wide spectrum of assumptions regarding 
the missingness mechanism (from less conservative to more conservative). The analysis 
finds a (tipping) point in this spectrum of assumptions, at which conclusions change from 
being favorable to the experimental treatment to being unfavorable. After such a tipping 
point is determined, clinical judgment can be applied as to the plausibility of the 
assumptions underlying this tipping point. 
The tipping point imputation analysis will use a specified sequence of shift parameters (k), 
which adjust the imputed values for observations in the active treatment group. This can 
be done in the SAS MI procedure with the MNAR statement using the imputed datasets 
from the MAR described above in Section 6.1. Each derived imputation from a shift 
parameter will be analyzed separately using the MMRM method, and then pooled with 
PROC MIANALYZE. A p-value for the treatment effect will be produced for each value 
of k. The smallest value of k where the treatment effect is no longer significant is identified 
as the tipping point. 
 
6.1.2 
Subgroup Analyses for the Primary Efficacy Endpoint 
Subgroup analyses by randomized age group stratification (>=16; <16 years), randomized GH 
group stratification (Yes/No), gender, Race (White; non-White), Region (NA, EU, AUS), 
Ethnicity (Hispanic or Latino; Not Hispanic or Latino), patients with DEXA performed and BMI 


 
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group (normal/overweight/obese based on age and race defined categorization in Table 5) will be 
performed on the primary efficacy endpoint using the method specified in Section 6.1. The 
imputed dataset created from the primary analysis will be used rather than re-imputing based on 
the subgroups. The results for Week 34 will be presented graphically using Forest Plot with LS 
Means and 97.5% or 95% CI based on number of doses chosen for Phase 3 on X-axis and 
subgroups on Y-axis. The BMI group will be defined based on the following categories in Table 
5: 
Table 5. BMI (kg/m2) Categories and Ranges 
 
Age (yrs) 
Normal Weight 
(kg/m2) 
Overweight 
(kg/m2) 
Obese 
(kg/m2) 
≥20, Non-Asian 
18.5-<25.0 
25-<30.0 
≥30 
≥20, Asian 
18.5-<23.0 
23-<27.5 
≥27.5 
≤19 
≥5th percentile and 
<85th percentile 
≥85th percentile and 
<95th percentile 
≥95th percentile 
 
6.1.3 
Clinical Meaningfulness of Primary Efficacy Endpoint 
Separate plots of the cumulative distribution function of the change from baseline in HQ-CT to 
Week 34 for all patients in the mITT Population in each treatment group used in the primary 
efficacy analysis for the CaGI-S of Hyperphagia and CaGI-C in Hyperphagia at Week 34. The 
change from baseline will be calculated based on the data collected in the database without 
imputation. The minimal clinically important difference (MCID) for the change from baseline in 
HQ-CT at Week 34 will be examined using anchor-based methods for patients meeting the 
following criteria: 
• Improved vs. Not Improved based on the CaGI-C in Hyperphagia where Improved will be 
defined as any patient with a CaGI-C in Hyperphagia response of 'Much better’, 
‘Moderately better’, or ‘A little better’ and Not Improved will be defined as a response of 
‘No difference’, ‘A little worse’, ‘Moderately worse’, or ‘Much worse’. 
• No Severity vs. Any Severity based on the CaGI-S of Hyperphagia where No Severity will 
be defined as having a CaGI-S response of ‘None’ and Any Severity will be defined as 
having a response of ‘Mild’, ‘Moderate’, ‘Severe’, or ‘Very Severe’. 
The mean change from baseline in HQ-CT at Week 34 will be presented for all patients in each 
group (Improved/Not Improved or No Severity/Any Severity) along with the difference in means 
between the categories in each questionnaire. The primary assessment of clinical meaningfulness 
will be based on the mean change from baseline in HQ-CT for all patients in the Improved group 
(ie all patients with a score of ‘Much better’, ‘Moderately better’, or ‘A littler better’). 
In addition, a responder analysis will be performed based on the cut-off point using the mean 
change from baseline in HQ-CT at Week 34 within the Improved group. The proportion of 
patients with change from baseline values at Week 34 ≥ the cut-off point in each RAD011 group 
will be compared to placebo using the CMH method, stratified by age category at randomization 


 
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[>=16 or <16 years] and GH treatment at randomization [yes/no]. The p-value for row mean 
scores differ statistic will be reported. 
 
6.2 
Secondary Efficacy Endpoints and Analyses 
The following secondary endpoints comparing RAD011 with placebo will be analyzed using a 
hierarchical testing, serial gatekeeping strategy as described above in Section 4.5 based on the 
mITT population. The fixed-sequence test procedure will be performed in the order specified as 
below: 
• Change in hyperphagia as defined by the CGI-C in Hyperphagia through End of 
Study/Week 34 Visit 
• Change in severity of hyperphagia as defined by the CGI-S of Hyperphagia response from 
Baseline through End of Study/Week 34 Visit 
• Change in PWS-associated Irritability from Baseline through End of Study/Week 34 Visit 
using the ABC-I subscale for RAD011 compared to placebo 
These three secondary efficacy endpoints will be tested for the same dose only if the primary 
efficacy endpoint for that dose meets statistical significance (α=0.025 if 2 RAD011 dose levels 
continue into Phase 3; α=0.05 if 1 RAD011 dose level continues into Phase 3), thus maintaining 
the overall significance level at two-sided 5%. If the first secondary endpoint for a dose level fails 
to meet significance (α=0.025 if 2 RAD011 dose levels; α=0.05 if 1 RAD011 dose level), then the 
subsequent analyses will be considered descriptive, and the statistical tests will provide only 
nominal p-values. 
As a sensitivity analysis, each of the secondary endpoints will also be analyzed using the PP 
population, assuming there are differences between the mITT and PP populations. 
Change in hyperphagia as defined by CGI-C in Hyperphagia through End of Study/Week 
34 Visit 
The CGI-C of hyperphagia is a single-item, clinician-rated measure, assessing the clinician’s 
impression about changes in the patient’s hyperphagia condition since the start of taking the study 
medication at the initiation of the Tolerability Period. The CGI-C of hyperphagia utilizes a 5-point 
response scale: 1=Much better; 2=A little better; 3=No change; 4=A little worse; 5=Much worse. 
Data will be collected at End of Study/Week 34 visit. 
The analysis of CGI-C in hyperphagia assessed at Week 34 will be conducted using the Cochran- 
Mantel-Haenszel (CMH) method, stratified by age category at randomization [>=16 or <16 years] 
and GH treatment at randomization [yes/no]. The p-value for row mean scores differ statistic, 
together with the descriptive summary (frequency count and percentage) for each CGI-C response 
and for categories of Improved (response scales of 1 and 2), No change (response scale of 3), and 
Worse (response scales of 4 and 5) will be presented. Missing data will remain as missing, and no 
imputation is planned. 
In addition, the 5-point response scale will be dichotomized into two categories (responder and 
non-responder). The responder category will include the response scales of 1 and 2, and the non- 
responder category will include the response scales of 3 to 5. The binary results will be analyzed 
using the CMH method, stratified by age category at randomization [>=16 or <16 years] and GH 
treatment at randomization [yes/no]. The p-value for row mean scores differ statistic will be 


 
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reported and will serve as the primary test of the change in CGI-C in Hyperphagia. 
Change in CGI-S of Hyperphagia Scale from Baseline through End of Study/Week 34 Visit 
The CGI-S of hyperphagia is a single-item, clinician-rated measure, assessing the clinician’s 
impression of the severity of a patient’s hyperphagia condition. The CGI-S of hyperphagia utilizes 
a 5-point response scale: 1=None; 2=Mild; 3=Moderate; 4=Severe; 5=Very Severe. 
The analysis of change in CGI-S of hyperphagia from Baseline through Week 34 will be conducted 
using the CMH method, stratified by age category at randomization [>=16 or <16 years] and GH 
treatment at randomization [yes/no]. The p-value for row mean scores differ statistic at each post- 
Baseline visit (Weeks 10, 19, 27, and/or 34), together with the descriptive summary (frequency 
count and percentage) for each CGI-S response at each visit will be presented. Missing data will 
remain as missing, and no imputation is planned. 
Change in ABC-I subscale score from Baseline through End of Study/Week 34 Visit 
The ABC questionnaire is an informant-rated questionnaire assessing severity of behavioral 
symptoms and is one of the few empirically developed scales designed to measure psychiatric 
symptoms and behavioral disturbance exhibited by individuals with developmental disabilities 
(intellectual disability, autism spectrum disorder, cerebral palsy, epilepsy). 
Overall, the ABC contains 58 items divided in five subscales: (a) irritability and agitation (15 
items), (b) lethargy and social withdrawal (16 items), (c) stereotypic behavior (7 items), (d) 
hyperactivity and noncompliance (16 items), and (e) inappropriate speech (4 items). 
Each item is scored as 0 (never a problem), 1 (slight problem), 2 (moderately serious problem), or 
3 (severe problem). If a caregiver is required to assist the patient in completing the questionnaire, 
the same caregiver should be available throughout the study. 
The ABC-I (irritability and agitation) subscale score will not be calculated if ≥4 items are missing 
in that subscale. In this case, the missing ABC-I subscale score will remain missing, and no 
imputation is planned for this analysis. If there are less than 4 missing items in the irritability 
subscale, then the subscale score will be calculated as follows: (# of items in the subscale/# of 
completed items) * the sum of the completed items for that subscale. 
Change in ABC-I subscale score from Baseline through End of Study/Week 34 Visit will be 
evaluated by using MMRM. The model will include change from baseline in ABC-I subscale score 
as the response variable; randomization treatment assignment (as a class variable), visit (as a class 
variable), stratification variables (age category at randomization [>=16 or <16 years] and GH 
treatment at randomization [yes/no]), and treatment-by-visit interaction as fixed effects; baseline 
ABC-I subscale score as a covariate. Patient will be included as a random effect. 
An unstructured covariance matrix will be used to model the within-subject error. Parameters will 
be estimated using restricted maximum likelihood with the Kenward-Roger method for calculating 
the denominator degrees of freedom. In case the model will not converge with the unstructured 
covariance structure, the CSH will be used instead. Furthermore, if the model fails to converge 
with the CSH, the CS structure will be used. In each case of CSH and CS, the sandwich estimator 
(SAS option: EMIPRICAL) will be used with the SAS option BETWITHIN for the denominator 
degrees of freedom. ABC-I subscale scores collected at Baseline (Visit 1), Weeks 10, 19, 27, 
and/or 34 will be included in the analysis. 
From this model, the LS means and CIs for each treatment group, the treatment difference in the 


 
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LS means, the CI for the difference, and the associated p-value will be reported on Weeks 10, 19, 
27 and 34. If 2 doses are chosen for Phase 3, then 97.5% CIs will be presented. If 1 dose is chosen 
for Phase 3, then 95% CIs will be presented. 
A plot of the cumulative distribution function of the change from baseline in ABC-I to Week 34 
for all patients in the mITT Population in each treatment group used in the primary efficacy 
analysis for the CaGI-C in Irritability at Week 34. The MCID will be examined using anchor- 
based methods based on the mean change from baseline in ABC-I at Week 34 will be compared 
for patients meeting the following criteria: 
• Improved vs. Not Improved based on the CaGI-C in Irritability where Improved will be 
defined as any patient with a CaGI-C response of 'Much better’, ‘Moderately better’, or ‘A 
little better’, and Not Improved will be defined as a response of ‘No difference’, ‘A little 
worse’, ‘Moderately worse’, or ‘Much worse’. 
The mean change from baseline in ABC-I to Week 34 will be presented for each group of 
patients (Improved/Not Improved) along with the difference in means between the categories. 
Additionally, the clinical meaningfulness will be assessed on a distribution-based approach in 
accordance with the ABC-2 Community/Residential Manual which states “we regard half- 
standard deviation changes on the ABC subscales to be meaningful”. 
 
6.3 
Other Efficacy Endpoints and Analyses 
The following other efficacy endpoints comparing RAD011 with placebo will be analyzed based 
on the mITT population. Missing data from all other efficacy endpoints will remain as missing and 
no imputations are planned. 
Change in hyperphagia as defined by CaGI-C in Hyperphagia response through End of 
Study/Week 34 Visit 
The CaGI-C is a single-item, caregiver-rated measure, assessing the caregiver’s impression about 
changes in the patient’s food-related behavior compared to before the beginning of the trial. The 
CaGI-C utilizes a 7-point response scale (1=Much better; 2=Moderately better; 3=A little better; 
4=No difference; 5=A little worse; 6=Moderately worse; 7=Much worse). Data will be collected 
at End of Study/Week 34 visit. 
The analysis of CaGI-C assessed at Week 34 will be conducted using the CMH method, stratified 
by age category at randomization [>=16 or <16 years] and GH treatment at randomization [yes/no]. 
The p-value for row mean scores differ statistic, together with the descriptive summary (frequency 
count and percentage) for each CaGI-C response and for categories of Improved (response scales 
of 1 to 3), No change (response scale of 4), and Worse (response scales of 5 to 7) will be presented. 
In addition, the 7-point response scale will be dichotomized into two categories (Improved and 
Not Improved). The Improved category will include the response scales of 1 to 3; and the Not 
Improved category will include the response scales of 4 to 7. The binary results will be analyzed 
using the CMH method, stratified by age category at randomization [>=16 or <16 years] and GH 
treatment at randomization [yes/no]. The p-value for row mean scores differ statistic will be 
reported. 


 
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Change in CaGI-S of Hyperphagia from Baseline through End of Study/Week 34 Visit 
The CaGI-S of hyperphagia is a single-item, caregiver-rated measure, assessing the caregiver’s 
impression of the severity of a patient’s hyperphagia condition. The CaGI-S of hyperphagia 
utilizes a 5-point response scale: 1=None; 2=Mild; 3=Moderate; 4=Severe; 5=Very Severe. 
The analysis of change in CaGI-S of hyperphagia from baseline through Week 34 will be 
conducted using the CMH method, stratified by age category at randomization [>=16 or <16 years] 
and GH treatment at randomization [yes/no]. The p-value for row mean scores differ statistic at 
each post-Baseline visit (Weeks 10, 19, 27, and/or 34), together with the descriptive summary 
(frequency count and percentage) for each CaGI-S response at each visit will be presented. 
Change in irritability as defined by CaGI-C in Irritability 
The CaGI-C of irritability is a single-item, caregiver-rated measure, assessing the caregiver’s 
impression about changes in the patient’s irritability condition since the start of taking the study 
medication at the initiation of the Tolerability Period. The CaGI-C of irritability utilizes a 7-point 
response scale: 1=Much better; 2=Moderately better; 3=A little better; 4=No difference; 5=A little 
worse; 6=Moderately worse; 7=Much worse. Data will be collected at End of Study/Week 34 visit. 
The analysis of CaGI-C in irritability assessed at Week 34 will be conducted using the CMH 
method, stratified by age category at randomization [>=16 or <16 years] and GH treatment at 
randomization [yes/no]. The p-value for row mean scores differ statistic, together with the 
descriptive summary (frequency count and percentage) for each CaGI-C response and for 
categories of Improved (response scales of 1 to 3), No change (response scale of 4), and Worse 
(response scales of 5 to 7) will be presented. 
In addition, the 7-point response scale will be dichotomized into two categories (Improved and 
Not Improved). The Improved category will include the response scales of 1 to 3; and the Not 
Improved category will include the response scales of 4 to 7. The binary results will be analyzed 
using the CMH method, stratified by age category at randomization [>=16 or <16 years] and GH 
treatment at randomization [yes/no]. The p-value for row mean scores differ statistic will be 
reported. 
Change in overall behavior from Baseline through End of Study/Week 34 Visit using the 
ABC questionnaire subscales 
The ABC questionnaire was detailed in Section 6.2 above for the analysis of irritability subscale 
scores. The list below outlines the scenarios when the score cannot be calculated for the other 
subscales: 
• For Lethargy/social withdrawal and Hyperactivity/Noncompliance subscales, the score 
will not be calculated if ≥4 items are missing in that subscale. 
• For Stereotypic behavior subscale, the score will not be calculated if ≥3 items are missing 
in that subscale. 
• For Inappropriate speech subscale, the score will not be calculated if ≥2 items are missing 
in that subscale. 
In these cases, the missing ABC subscale scores will remain missing, and no imputation is planned 
for this analysis. If missing items are present in a subscale, but the score can be calculated, then 
the subscale score will be calculated as follows: (# of items in the subscale/# of completed items) 


 
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* the sum of the completed items for that subscale. 
Change in each of the ABC subscale scores from Baseline through End of Study/Week 34 Visit 
will be evaluated by using MMRM. For each subscale, the model will include change from 
baseline in the subscale score as the response variable; randomization treatment assignment (as a 
class variable), visit (as a class variable), stratification variables (age category at randomization 
[>=16 or <16 years] and GH treatment at randomization [yes/no]), and treatment-by-visit 
interaction as fixed effects; baseline ABC subscale score as a covariate. Patient will be included 
as a random effect. 
An unstructured covariance matrix will be used to model the within-subject error. Parameters will 
be estimated using restricted maximum likelihood with the Kenward-Roger method for calculating 
the denominator degrees of freedom. In case the model will not converge with the unstructured 
covariance structure, the CSH will be used instead. Furthermore, if the model fails to converge 
with CSH, the CS structure will be used. In each case of CSH and CS, the sandwich estimator 
(SAS option: EMIPRICAL) will be used with the SAS option BETWITHIN for the denominator 
degrees of freedom. ABC subscale scores collected at Baseline (Visit 1), Weeks 10, 19, 27, and/or 
34 will be included in the analysis. 
From this model, the LS means and CIs for each treatment group, the treatment difference in the 
LS means, the CI for the difference, and the associated p-value will be reported on Weeks 10, 19, 
27 and 34. If 2 doses are chosen for Phase 3, then 97.5% CIs will be presented. If 1 dose is chosen 
for Phase 3, then 95% CIs will be presented. 
Change in sleep from Baseline through End of Study/Week 34 Visit using the ESS-CHAD 
The ESS-CHAD is an 8-question scale with a 1-month recall period that has been validated in 
school-attending children and adolescents to evaluate daytime sleepiness. Each question is rated 
on a 0 to 3 scale, with a maximum score of 24, and a score above 10 is considered to represent 
mild excessive daytime sleepiness 
Change in ESS-CHAD score from Baseline through End of Study/Week 34 Visit will be evaluated 
by using MMRM. The model will include change from baseline in ESS-CHAD score as the 
response variable; randomization treatment assignment (as a class variable), visit (as a class 
variable), stratification variables (age category at randomization [>=16 or <16 years] and GH 
treatment at randomization [yes/no]), and treatment-by-visit interaction as fixed effects; baseline 
ESS-CHAD score as a covariate. Patient will be included as a random effect. 
An unstructured covariance matrix will be used to model the within-subject error. Parameters will 
be estimated using restricted maximum likelihood with the Kenward-Roger method for calculating 
the denominator degrees of freedom. In case the model will not converge with the unstructured 
covariance structure, the CSH will be used instead. Furthermore, if the model fails to converge 
with CSH, the CS structure will be used. In each case of CSH and CS, the sandwich estimator 
(SAS option: EMIPRICAL) will be used with the SAS option BETWITHIN for the denominator 
degrees of freedom. ESS-CHAD score collected at Baseline (Visit 2), Weeks 19 and/or 34 will be 
included in the analysis. 
From this model, the LS means and CIs for each treatment group, the treatment difference in the 
LS means, the CI for the difference, and the associated p-value will be reported on Weeks 19 and 
34. If 2 doses are chosen for Phase 3, then 97.5% CIs will be presented. If 1 dose is chosen for 
Phase 3, then 95% CIs will be presented. 


 
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Change in weight and BMI from Baseline through End of Study/Week 34 Visit 
Change in age-normalized BMI z-scores [3] will be used for patients aged 8 to 19 years inclusively, 
whereas percent change in weight will be used for patients aged 20 to 65 years. 
The BMI Z-scores, also called BMI standard deviation scores, are measures of relative weight 
adjusted for child age and sex. BMI Z-score can be determined based on the age, sex, BMI, and 
the CDC reference standard. The CDC growth charts contain 10 smoothed percentiles (between 
the 3rd and 97th) of BMI for 24- to 240-month-old children and adolescents. These smoothed 
estimates were subsequently used to derive lambda (L, the power transformation to achieve 
normality), mu (M, mean or median) and sigma (S, coefficient of variation) parameters for Cole's 
LMS method [4, 5]. Estimates of these 3 parameters allow the BMI of any children to be expressed 
as a z-score and percentile relative to children of the same sex and age in the CDC growth charts. 
To calculate the z-score for any BMI value (BMIz) with the LMS method, the following formula 
is used: 
 
𝐵𝑀𝐼𝑧 = [( 
𝐵𝑀𝐼 𝐿 ) 
𝑀 
− 1] ÷ (𝐿 × 𝑆) 
Values for the L, M, and S are available on the CDC website for each sex and month of age. 
For BMI values at or above the 95th percentile, the BMI z-score will be re-calculated using the 
methods described in Rong Wei’s paper [3], in which the half normal distributions are used to 
model the distribution of BMI ≥ 95th percentile. These values combined with the CDC BMI z- 
scores (below 95th percentile) will be used for the analysis. 
For mITT patients aged ≥20 years, the percent change in weight from Baseline through End of 
Study/Week 34 Visit will be evaluated by using MMRM. The model will include percent change 
from baseline in weight as the response variable; randomization treatment assignment (as a class 
variable), visit (as a class variable), stratification variable (GH treatment at randomization 
[yes/no]), and treatment-by-visit interaction as fixed effects; baseline weight as a covariate. Patient 
will be included as a random effect. 
In addition, for mITT patients aged ≥18 years, the percent change in BMI from Baseline through 
End of Study/Week 34 Visit will be evaluated by using MMRM as described above for the analysis 
of percent change in weight. 
For mITT patients aged <20 years, the change in age-normalized BMI z-scores from Baseline 
through End of Study/Week 34 Visit will be evaluated by using MMRM. The model will include 
change from baseline in BMI z-score as the response variable; randomization treatment assignment 
(as a class variable), visit (as a class variable), stratification variable (GH treatment at 
randomization [yes/no]), and treatment-by-visit interaction as fixed effects; baseline BMI z-score 
as a covariate. Patient will be included as a random effect. 
For both MMRM analyses, an unstructured covariance matrix will be used to model the within- 
subject error. Parameters will be estimated using restricted maximum likelihood with the 
Kenward-Roger method for calculating the denominator degrees of freedom. In case the model 
will not converge with the unstructured covariance structure, the CSH will be used instead. 
Furthermore, if the model fails to converge with CSH, the CS structure will be used. In each case 
of CSH and CS, the sandwich estimator (SAS option: EMIPRICAL) will be used with the SAS 
option BETWITHIN for the denominator degrees of freedom. Weight, BMI and BMI z-scores 


 
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collected at Baseline (Visit 2), Weeks 10, 19, 27 and/or 34 will be included in the analysis. 
From this model, the LS means and CIs for each treatment group, the treatment difference in the 
LS means, the CI for the difference, and the associated p-value will be reported on Weeks 10, 19, 
27 and 34. If 2 doses are chosen for Phase 3, then 97.5% CIs will be presented. If 1 dose is chosen 
for Phase 3, then 95% CIs will be presented. 
Change in skin picking behavior using the Skin Picking Questionnaire from Baseline 
through End of Study/Week 34 Visit 
The Skin Picking questionnaire is a 6-item questionnaire of skin picking symptoms, with scores 
from 0 to 24. Each item utilizes a 4-point scale with 0 indicating none or minimal and 4 indicating 
extreme. A score of ≥7 is considered highly suspicious for a skin picking disorder. 
Change in skin picking score from Baseline through End of Study/Week 34 Visit will be evaluated 
by using MMRM. The model will include change from baseline in skin picking score as the 
response variable; randomization treatment assignment (as a class variable), visit (as a class 
variable), stratification variables (age category at randomization [>=16 or <16 years] and GH 
treatment at randomization [yes/no]), and treatment-by-visit interaction as fixed effects; baseline 
skin picking score as a covariate. Patient will be included as a random effect. 
An unstructured covariance matrix will be used to model the within-subject error. Parameters will 
be estimated using restricted maximum likelihood with the Kenward-Roger method for calculating 
the denominator degrees of freedom. In case the model will not converge with the unstructured 
covariance structure, the CSH will be used instead. Furthermore, if the model fails to converge 
with CSH, the CS structure will be used. In each case of CSH and CS, the sandwich estimator 
(SAS option: EMIPRICAL) will be used with the SAS option BETWITHIN for the denominator 
degrees of freedom. Skin picking score collected at Baseline (Visit 2), Weeks 19 and/or 34 will be 
included in the analysis. 
From this model, the LS means and CIs for each treatment group, the treatment difference in the 
LS means, the CI for the difference, and the associated p-value will be reported on Weeks 19 and 
34. If 2 doses are chosen for Phase 3, then 97.5% CIs will be presented. If 1 dose is chosen for 
Phase 3, then 95% CIs will be presented. 
Change in muscle/fat composition using a DEXA scan from Randomization through End of 
Study/Week 34 Visit 
The assessment of change in muscle/fat composition using DEXA scan will be performed at a 
selected number of US sites only. Results of the DEXA scan will be reported as total mass, fat 
mass, lean mass, percentage body fat, and bone mineral content. Data will be collected at 
randomization (Visit 5) and End of Study/Week 34 visit. 
The analysis of change from baseline in each DEXA scan parameter at Week 34 will be performed 
using an analysis of covariance (ANCOVA) model. The model will include change from baseline 
in each DEXA scan parameter as the response variable; randomization treatment assignment (as a 
class variable) and stratification variables (age category at randomization [>=16 or <16 years] and 
GH treatment at randomization [yes/no]) as fixed effects; DEXA scan parameter at baseline as a 
covariate. From this model, the LS means and CIs for each treatment group, the treatment 
difference in the LS means, the CI for the difference, and the associated p-value will be presented. 
If 2 doses are chosen for Phase 3, then 97.5% CIs will be presented. If 1 dose is chosen for Phase 


 
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3, then 95% CIs will be presented. 
Change in Appetite Hormones from Baseline through End of Study/Week 34 Visit 
Appetite hormones including insulin and leptin as well as HbA1c and insulin resistance will be 
collected at the time points presented in Appendix A. Insulin resistance will be calculated as insulin 
(mU/L) x glucose (nmol/L)/22.5. Change in each parameter from Baseline through End of 
Study/Week 34 Visit will be evaluated by using MMRM. The model will include change from 
baseline in each parameter as the response variable; randomization treatment assignment (as a 
class variable), visit (as a class variable), stratification variables (age category at randomization 
[>=16 or <16 years] and GH treatment at randomization [yes/no]), and treatment-by-visit 
interaction as fixed effects; baseline parameter value as a covariate. Patient will be included as a 
random effect. 
An unstructured covariance matrix will be used to model the within-subject error. Parameters will 
be estimated using restricted maximum likelihood with the Kenward-Roger method for calculating 
the denominator degrees of freedom. In case the model will not converge with the unstructured 
covariance structure, the CSH will be used instead. Furthermore, if the model fails to converge 
with CSH, the CS structure will be used. In each case of CSH and CS, the sandwich estimator 
(SAS option: EMIPRICAL) will be used with the SAS option BETWITHIN for the denominator 
degrees of freedom. Appetite hormones collected at Baseline (Visit 1), Weeks 10, 27, and/or 34 
will be included in the analysis. 
From this model, the LS means and CIs for each treatment group, the treatment difference in the 
LS means, the CI for the difference, and the associated p-value will be reported on Weeks 10, 27, 
and 34. If 2 doses are chosen for Phase 3, then 97.5% CIs will be presented. If 1 dose is chosen for 
Phase 3, then 95% CIs will be presented. 
 
7. SAFETY ANALYSIS 
 
Safety assessments will include assessment of AEs, C-SSRS, vital signs, ECGs, and laboratory 
assessments. All safety analyses will be conducted using the Safety Population. No formal 
hypothesis testing will be performed to compare differences between treatment groups. 
 
7.1 
Extent of Exposure and Compliance 
The duration of exposure (days), total dose administered (mg/kg) will be summarized by period: 
Tolerability, Dose Escalation, Maintenance, and Taper periods. Additionally, the number of 
patients with a dose level reduction during Maintenance Period will be presented. 
Duration of exposure will be calculated as: 
For each period (defined in Table 4 for start and stop dates): Duration of exposure (days) 
= The last study drug administration date - The first study drug administration date – 1 
Total dose administered (mg/kg) will be calculated as: 
For each period: Total dose administered (mg/kg) = [(sum of dispensed weights in grams 
– sum of returned weights in grams)* (2800/69.5)]/patient weight in kg 
Note: 1) The dispensed weight and returned weight are based on the “Study Drug 
Accountability” eCRF for the total initial kit weight and returned kit weight respectively. 


 
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Bottles that are not returned will be assumed to have not been used. 2) For calculation 
during the Tolerability period, the patient weight (kg) will be based on the assessment on 
Visit 2; for all other periods, the patient weight (kg) will be based on the assessment on 
Visit 5. 
In addition, the treatment compliance (%) will be calculated as follows and summarized for the 
Maintenance Period. Additionally, number of patients with treatment compliance in each 
category of <80%, ≥80% to ≤120%, and >120% will be presented. 
Treatment compliance (%) = ([Total dose administered (mg/kg)]/(Total Expected Dose 
(mg/kg)) x 100. 
Note: 
1) Total dose administered (mg/kg) = [(sum of dispensed weights in grams – sum of 
returned weights in grams) * (2800/69.5)]/ patient weight in kg 
2) Total expected dose (mg/kg) = Treatment duration in days * Dose Level of 10/20/40 
on patient level, where treatment duration is based on the patient actual treatment 
days in the Maintenance period. If a patient has a dose reduction, then the 25% dose 
reduction will be considered for the expected dose calculations by using Total 
expected dose (mg/kg) = Treatment duration in the Maintenance period prior to 
dose reduction * dose Level of 10/20/40 plus remaining treatment duration during 
the Maintenance Period * reduced dose level; the start date of dose reduction is the 
visit date when the first dose reduction is recorded as “Yes” on the Study Drug 
Dispensation eCRF page during the maintenance period. 
Details of IP administration based on the information collected on the “Study Drug 
Accountability” eCRF page will be listed and will include: the kit number, date dispensed, total 
initial kit weight (g), date of kit returned, returned kit weight (g), number of bottles returned, and 
any comments. 
A separate listing will be provided to include treatment start and stop date, the duration of exposure 
(days), total dose administered (mg/kg), the visit the dose level was reduced during Maintenance 
Period, and treatment compliance for each treatment period. 
 
7.2 
Adverse Events 
An AE is any untoward medical occurrence in a clinical investigation patient administered a 
pharmaceutical product, which does not necessarily have a causal relationship with the treatment. 
This includes any newly occurring event which occurs during the study, having been absent at 
Screening, or any previous condition, if present at Screening, that appears to worsen (i.e., increased 
in severity or frequency) after the administration of study drug. 
All AEs will be collected from the time of consent/assent until the following time points: 
• For patients who are not randomized: until time of screen failure 
• For randomized patients: 
• 
For patients continuing in the long-term extension study SCOUT-016: through 
Visit 14 (Week 34) inclusively 
• 
For patients entering the follow-up period with IP tapering: through Visit 16 (Week 


 
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38). 
Investigators are not obligated to actively seek AEs or serious adverse events (SAEs) after the 
participant has concluded study participation. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has completed the study or 30 days after the last 
dose of IP, and he/she considers the event to be reasonably related to the study intervention, the 
investigator must promptly report the SAE. 
 
7.2.1 
Treatment-emergent Adverse Events 
A treatment-emergent adverse event (TEAE) is defined as an AE that first occurs or worsens in 
intensity after the first dose of study drug. For adverse events with missing or partially missing 
start/stop dates, the imputation of missing dates will be performed as described in Appendix B. 
 
7.2.2 
Adverse Event Intensity 
For both SAEs and non-SAEs, the Investigator must determine both the intensity of the event and 
the relationship of the event to study drug administration. 
Intensity for each AE will be defined according to the following criteria as noted in Table 6. If the 
intensity of an AE changes within a day, the maximum intensity should be recorded. If the intensity 
changes over a longer period of time, the changes should be recorded as separate events (having 
separate onset and stop dates for each intensity). 
Table 6:    Intensity Classification and Definition of Adverse Events 
 
Intensity 
Definition 
Mild 
Awareness of sign or symptom, but easily tolerated 
Moderate 
Discomfort enough to cause interference with normal daily activities 
Severe 
Inability to perform normal daily activities 
 
7.2.3 
Adverse Event Relationship to Study Drug 
Every effort should be made by the Investigator to assess the relationship (causality) of the AE, if 
any, to the IP. 
Investigators should use their knowledge of the patient, the circumstances surrounding the event, 
and an evaluation of any potential alternative causes to determine whether or not an AE is 
considered to be related to study drug, indicating on the eCRF that an AE is either Related or Not 
Related. 
 
7.2.4 
Serious Adverse Events 
An SAE is defined as any adverse experience that suggests a significant hazard, contraindication, 
side effect, or untoward medical occurrence that, in the view of the Investigator or Sponsor, results 
in any of the following criteria: 
1. Death 
2. Is immediately life threatening 
3. Requires in-patient hospitalization or prolongation of existing hospitalization 


 
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4. Results in persistent or significant disability or incapacity 
5. Results in a congenital abnormality or birth defect 
6. Other medically important event 
 
7.2.5 
Adverse Events of Special Interest (AESI) 
An AESI is an AE that is designated to be of special medical or scientific interest to the Sponsor. 
All AEs within the category of AESIs should be reported promptly, following the reporting 
procedures for abnormal laboratory, AEs or SAEs as appropriate. 
• Suicide ideation and behavior AESI 
Included in this AESI are AEs following administration of RAD011 that are assessed by the 
Investigator to be any of the following: suicidal ideation, suicidal behavior, suicide attempt, and 
completed suicide. 
• Hepatic dysfunction AESI 
Included in this AESI are abnormal laboratory findings or AEs suggestive of hepatic dysfunction 
following administration of RAD011 such as greater or moderate elevation of liver enzymes (AST, 
ALT, ALP, gamma-glutamyl transferase [GGT]) and bilirubin; or AEs of right upper quadrant 
abdominal pain, chronic fatigue, loss of appetite, unexplained nausea and vomiting, yellowing of 
skin or eyes, itching, dark urine, and light-colored stools. 
The preferred terms for AESI are listed in Appendix C. 
 
7.2.6 
Adverse Event Summaries 
All AEs (serious and non-serious) occurring after the first dose of study drug administration and 
before the end of study, regardless of relationship to study drug, will be included and classified by 
SOC and PT using MedDRA, v24.1 or later. 
For treatment-emergent AEs (TEAEs), the following will be summarized and presented for the 
Safety Population: 
i. 
An overall summary of TEAEs will be provided for treatment period AEs defined as AEs 
with onset dates during Dose Escalation, Maintenance, Taper, and Follow-up periods. The 
table will include: 
a. the number and percentage of patients experiencing a TEAE 
b. the number and percentage of patients experiencing a TEAE by strongest 
relationship to study drug 
c. the number and percentage of patients experiencing a TEAE by maximum severity 
d. the number and percentage of patients experiencing a SAE during the study 
e. the number and percentage of patients experiencing a treatment-emergent SAE 
(TESAE) 
f. the number and percentage of patients experiencing a TEAE leading to study drug 
discontinuation 
g. the number of percentages of patients experiencing an AE leading to death during 


 
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the study 
h. the number and percentage of patients experiencing a TEAE leading to death 
i. the number of percentage of patients experiencing an AESI 
ii. 
the number and percentage of patients and number of events for patients experiencing a 
TEAE by SOC and PT for the treatment period and by period (Tolerability, Dose 
Escalation, Maintenance, Taper, and Follow-up) 
iii. 
the number and percentage of patients and number of events for patients experiencing a 
related TEAE by SOC and PT for Dose Escalation and Maintenance periods each 
separately 
iv. 
the number and percentage of patients experiencing a TEAE by SOC, PT and the strongest 
relationship to study drug for Dose Escalation and Maintenance periods each separately 
v. 
the number and percentage of patients experiencing a TEAE by SOC and PT and the 
maximum severity for Dose Escalation and Maintenance periods each separately 
vi. 
the number and percentage of patients experiencing a TESAE by SOC and PT for the 
treatment period, Dose Escalation, and Maintenance periods each separately 
vii. 
the number and percentage of patients experiencing a TEAE leading to study drug 
discontinuation by SOC and PT for the treatment period, Dose Escalation, and 
Maintenance periods each separately 
viii. 
the number and percentage of patients experiencing an AESI by SOC and PT for the 
treatment period 
In the overall summary of TEAEs table (i), besides tabulating the number and percentage of 
patients, the total number of events will also be provided. If a patient has repeated episodes of a 
particular TEAE, all events will be counted in the summary table. In the remaining summary tables, 
the incidence of TEAEs will be calculated by dividing the number of patients who have 
experienced the event by the total number of patients in the Safety Population. Thus, the incidence 
of TEAEs is shown in terms of the total number of patients and not in terms of the total number of 
events. If a patient has repeated events of a particular TEAE, only the most severe episode, or the 
event with the strongest causal relationship to study drug, will be counted in the summary tables. 
A patient with more than one type of TEAE in a particular SOC or PT will be counted only once 
in the total of patients experiencing TEAEs in that particular SOC or PT. 
All occurrences of all AEs and SAEs will be listed for each patient, grouped by treatment group. 
The listing will contain the following information: treatment group, verbatim term, SOC, PT, 
severity, relationship to study drug, date and day of onset, date and day of resolution, action taken 
with regard to study drug, the outcome, whether the event was an SAE, whether it led to study 
discontinuation, and whether it is a TEAE. Listings will be sorted by treatment group, patient 
identification number, onset date, SOC, and PT. If the onset date is completely missing, then these 
events will be presented first. If the onset date is missing a month or a day, then these events will 
be presented before any complete dates. 
A separate listing will be presented for AESI. 
Percent of patients by AE Onset Date in each period experiencing an AE with a PT with ≥10% 
incidence will be presented in a line graph. The X axis will represent the AE onset period in the 


 
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Tolerability, Dose Escalation, Maintenance, Taper, and Follow-up periods. The Y axis will 
represent the percentage of patients within each onset period by treatment group. Each treatment 
group will be distinguished by different color. 
 
7.3 
Clinical Laboratory Assessments 
Clinical laboratory tests will be obtained at the time points presented in Appendix A. For 
continuous laboratory variables summary statistics of the actual values and change from Baseline 
values will be presented by treatment group at each treatment visit separated by panel (chemistry, 
hematology, and urinalysis). In addition, summary statistics for the actual value and change from 
Baseline are to be presented by treatment group for the last visit, minimum, and maximum post- 
Baseline values during the defined treatment period. Shifts from Baseline for the last visit, 
minimum, and maximum post-Baseline values during the defined treatment period (Visit 5 through 
Visit 16) according to normal range criteria will also be presented. Repeated or unscheduled 
laboratory assessments during the study will not be presented in by-visit summaries, but will be 
considered when determining the last visit, minimum, and maximum post-Baseline values during 
the defined treatment period. 
Marked laboratory abnormalities are detailed in Appendix D for selected hematology parameters. 
The number and percentage of patients with treatment-emergent marked abnormalities 
(Low/High) will be presented in a summary table for each lab parameter specified in Appendix D 
by visit and treatment group. Summary for the last visit including unscheduled assessments will 
also be presented. 
The number of patients meeting the criteria for Hy’s Law along with number of patients meeting 
the individual lab thresholds (ALT ≥ 3×Upper limit of normal [ULN], AST ≥ 3×ULN, or total 
bilirubin ≥ 2×ULN) will be summarized. An eDISH plot will be generated for maximum total 
bilirubin (Y-axis) vs. maximum ALT or AST (x-axis). The criteria of Hy’s Law are as follows: 
• (ALT or AST ≥ 3×ULN) and total bilirubin ≥ 2×ULN 
To meet the above criteria, a patient must experience the elevation in total bilirubin and ALT or 
AST at the same visit. For example, a patient who experiences a >=2 x ULN elevation of total 
bilirubin at one visit and a 3 x ULN elevation in ALT (or AST) at a subsequent visit has not 
fulfilled the Hy’s Law criteria. A patient with ALT and AST values missing or a patient with total 
bilirubin value missing has not fulfilled the Hy’s Law criteria 
All laboratory data from all (scheduled or unscheduled) visits will be listed. 
 
7.4 
Vital Signs 
Descriptive summaries of the vital signs (both actual and change from baseline values) including 
systolic and diastolic blood pressure, heart rate, respiratory rate, oxygen saturation, and 
temperature will be prepared for each study treatment by visit. 
Unscheduled visits will be excluded from the summaries but will be included in the data listings. 
Marked abnormalities for vital signs are shown as below in Table 7. 


 
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Table 7 Marked Vital Signs Abnormalities 
 
Parameter 
Abnormality Criteria: Low 
Abnormality Criteria: High 
Systolic blood 
pressure (mmHg) 
<=90 and >=20 decrease from 
baseline 
>=180 and >=20 increase from 
baseline 
Diastolic blood 
pressure (mmHg) 
<=50 and >=15 decrease from 
baseline 
>=105 and >=15 increase from 
baseline 
Heart rate 
(beats/min) 
<=50 and >=15 decrease from 
baseline 
>=120 and >=15 increase from 
baseline 
 
The number and percentage of patients with treatment-emergent marked abnormalities 
(Low/High) for systolic/diastolic blood pressure and heart rate will be presented in a summary 
table by visit and treatment group. Summary for the last visit including unscheduled assessments 
will also be presented. 
 
7.5 
ECG 
Electrocardiogram measurements (RR interval, PR interval, QRS duration, QT interval, and QTcF 
interval) will be summarized by presenting descriptive statistics of actual data and change from 
baseline values at each visit. The findings (normal; abnormal, not clinically significant; Abnormal, 
clinically significant) will be included in the data listing. 
A summary table will be presented for the number and percentage of patients with QTcF >450 
(ms), >480 (ms), >500 (ms), as well as with change from baseline in QTcF >30 ms and >60 ms by 
visit. The summary for change from baseline in QTcF >30 ms and >60 ms will also be presented 
for any post-baseline visit. 
 
7.6 
Columbia Suicide-Severity Rating Scale (C-SSRS) 
The C-SSRS is a broadly validated scale aimed at assessing suicidal risk in a variety of children 
and adult populations. The scale includes suggested questions to solicit the type of information 
needed to determine if suicidal ideation and/or behavior occurred. The first time the C-SSRS 
questionnaire is administered, on Visit 5 (Week 7), the Baseline/Screening questionnaire [6] should 
be used, and the “Since Last Visit” questionnaire should be used for all subsequent assessments. 
The standard C-SSRS scale should be used for patients aged 6 and over and the Children’s C-SSRS 
scale should be used in patients aged less than 6 years. However, the Children’s version may be 
used in patients aged 6 years or older when the Investigator or designee determines that the patient 
is unable to understand the first couple of questions in the standard version. The same C-SSRS 
scale should be used for a given patient throughout the study. 
The C-SSRS outcomes include the following categories and have binary responses (yes/no) [7]: 
1. Wish to be Dead 
2. Non-specific Active Suicidal Thoughts 
3. Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
4. Active Suicidal Ideation with Some Intent to Act, without Specific Plan 


 
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5. Active Suicidal Ideation with Specific Plan and Intent 
6. Preparatory acts or Behavior 
7. Aborted Attempt 
8. Interrupted Attempt 
9. Actual Attempt (non-fatal) 
10. Completed Suicide 
11. Self-Injurious Behavior (Non-suicidal and/or intent unknown) 
The following outcome is a numerical score to assess the intensity of ideation: 
• Suicidal Ideation Score: The maximum suicidal ideation category (1-5 on the C-SSRS, 
with 1 being the least severe and 5 being the most severe) present at the assessment. A 
score of 0 will be assigned if no ideation is present. 
The number and percentage of patients with an event in each of the 11 categories listed above will 
be presented by visit. 
A shift table will be provided for change in C-SSRS categories from Baseline (Tolerability) to the 
End of Study/Week 34 by visit. The C-SSRS categories for this shift table will include: No suicidal 
ideation or behavior, Suicidal Ideation, and Suicidal Behavior. Suicidal Ideation includes any one 
of the five suicidal ideation events (Categories 1-5 as shown above). Suicidal behavior includes 
any one of the six suicidal behavior events (Categories 6-11 as shown above). Each patient will be 
counted only once in one of the 3 categories, so patients who have both Suicidal Ideation and 
Suicidal Behavior are included in the Suicidal Behavior category. 
In addition, a separate shift table for change in maximum C-SSRS suicidal ideation scores (0-5) 
from Baseline to End of Study/Week 34 by visit will also be presented. 
A by-patient data listing will be provided. 
 
7.7 
Other Safety Measures 
Data listings will be provided for food diary and patient impression of seizures (No change; 
Became better; Became worse). In addition, a descriptive summary of patient impression of 
seizures will be provided. 
 
8. INTERIM ANALYSES 
 
After approximately 45 patients complete 4 weeks of the Maintenance Period of the Phase 2 part 
of the study, an interim analysis for DMC will be performed. The DMC will meet to review the 
safety and tolerability data and recommend 1 or 2 RAD011 dose level(s) for evaluation in the 
Phase 3 part of the study. 
The DMC will also be available to assist in the review of aggregate safety events as requested by 
the Sponsor at any time during the study. 


 
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9. SAMPLE SIZE AND POWER CALCULATIONS 
 
The DMC will recommend one RAD011 Dose or two RAD011 Doses after Phase 2 part of the 
study. The sample size and power calculation will vary based on the DMC recommendation. 
DMC Recommendation of Two RAD011 Doses 
For the primary efficacy analysis, a total of 150 patients (50 patients per treatment group) aged 12 
to 65 years will provide 90% power to compare each dose group vs. placebo with a two-sided 
alpha of 0.025. The study is powered to detect a difference in the HQ-CT from Baseline to Week 
34 of 5 points with a standard deviation of 7 points. The 0.05 Type 1 error is split equally between 
groups (low dose and high dose). The low and high volume placebo groups will be combined for 
all comparisons to placebo. Assuming a 15% post-randomization dropout rate, approximately 180 
patients (~60 patients per treatment group) will be evaluated for the primary efficacy analysis. 
Thus, if the DMC recommends two RAD011 doses for Phase 3 of the study, approximately a total 
of 191 patients aged 12 to 65 years (approximate target of 200 patients) will be randomized in this 
study. The 191 reflects 176 patients required for primary efficacy analysis plus 15 patients 
randomized in the Phase 2 part of the study to the dose not selected for Phase 3 of the study. 
Assuming a 20% pre-randomization eligibility failure rate (including HQ-CT eligibility criteria), 
approximately 240 patients will be enrolled into the Screening Period. An additional 10 patients 
per treatment group aged 8 to <12 years may be allowed to participate in Phase 3 of the study and 
will be randomized in a way to obtain a balanced number of patients on RAD011 (at dose levels 
recommended by the DMC) and placebo. Patients aged 8 to <12 will not be included in the primary 
efficacy analysis. 
DMC Recommendation of One RAD011 Dose 
For the primary efficacy analysis, a total of 100 patients (50 patients per treatment group) aged 12 
to 65 years will provide 94% power to compare active vs. placebo with a two-sided alpha of 0.05. 
The study is powered to detect a difference in the HQ-CT from Baseline to Week 34 of 5 points 
with a standard deviation of 7 points. Assuming a 15% post-randomization dropout rate, 
approximately 118 patients (~59 patients per treatment group) will be evaluated for the primary 
efficacy analysis. 
Thus, if the DMC recommends one RAD011 dose for Phase 3 of the study, approximately 148 
patients aged 12 to 65 years (target approximately 150 patients) will be randomized in this study. 
The 148 reflects 118 patients required for primary efficacy analysis plus 30 patients randomized 
in the Phase 2 part of the study to the two doses not selected for Phase 3 of the study. 
Assuming a 20% pre-randomization eligibility failure rate (including HQ-CT eligibility criteria), 
approximately 185 patients will be enrolled into the Screening Period. An additional 10 patients 
per treatment group aged 8 to <12 years may be allowed to participate in Phase 3 of the study and 
will be randomized in a way to obtain a balanced number of patients on RAD011 (at dose level 
recommended by the DMC) and placebo. Patients aged 8 to <12 will not be included in the primary 
efficacy analysis. 


 
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10. CHANGE FROM PROTOCOL 
 
Protocol: 
Change: 
Coagulation analysis is included in the Safety Removed 
the 
summary 
analysis 
for 
and 
Tolerability 
endpoints 
section 
for coagulation  since  it  is  only  collected  at 
laboratory tests. 
Screening. Only listing will be provided. 
 
11. REFERENCES 
 
1. Fehnel S, Brown TM, Nelson L, Chen A, Roof E, Kim DD, et al. Development Of The 
Hyperphagia Questionnaire For Use In Prader-Willi Syndrome Clinical Trials. Race/ethnicity. 
2015;6:100.0. 
2. Berglund P, Heeringa SG. Multiple imputation of missing data using SAS: SAS Institute; 2014. 
3. Wei R, Ogden CL, Parsons VL, Freedman DS, Hales CM. A method for calculating BMI z- 
scores and percentiles above the 95(th) percentile of the CDC growth charts. Ann Hum Biol. 
2020; 47:514-21. 
4. Cole TJ, Green PJ. Smoothing reference centile curves: the LMS method and penalized 
likelihood. Stat Med. 1992; 11:1305–19. 
5. Cole TJ. The LMS method for constructing normalized growth standards. Eur J Clin Nutr. 
1990/01/01. 1990; 44:45–60. 
6. Posner K, Brent D, Lucas C, Gould M, Stanley B, Brown G, et al. Columbia-suicide severity 
rating scale (C-SSRS). New York, NY: Columbia University Medical Center. 2008;10. 
7. Mary E. Nilsson, et al. Columbia-Suicide Severity Rating Scale Scoring and Data Analysis 
Guide, version 2.0, 2013. 


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12. APPENDICES 
 
12.1 
Appendix A Part 1: Schedule of Assessments – Screening and Tolerability Periods 
 
Period 
Screening 
Tolerability 
Visit Number 
1 
2 
3 
4 
Study Time Point 
D -21 to 0 
(W -3 to 0) 
D 1 (W 1) 
D 15 (W 3) 
D 29 (W 5) 
Visit Window (Days) 
0 
±3 
±3 
±3 
Informed consent/assent (if appropriate) 
X 
Review of inclusion and exclusion criteria 
X 
Medical/surgical history including PWS genetic 
diagnosis, seizure history 
X 
Demographics 
X 
Review of prior/concomitant medications 
X 
X 
X 
X 
Start collection/recording of AEs 
X 
Review of AEs 
X 
X 
X 
Weight and heighta 
X 
X 
X 
X 
Record vital signsb 
X 
X 
X 
X 
Physical examc 
X 
HQ-CT Questionnaired 
X 
Xpre-dose 
X 
X 
Review of HQ-CT scores for eligibilitye 
X 
ABC Questionnaired 
X 
ESS-CHAD Questionnaired 
Xpre-dose 
CGI-S Hyperphagia Questionnaired 
Xpre-dose 
CaGI-S Hyperphagia Questionnaire 
X 
Skin Picking Questionnaired 
Xpre-dose 
C-SSRSd,f 
Xpre-dose 
Resting 12-lead ECG 
X 
Serum pregnancy testg 
X 
Urine drug screenh 
X 
Urinalysis 
X 
Chemistry panelsi 
X 
Hematologyj 
X 
HbA1c 
X 


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Period 
Screening 
Tolerability 
Visit Number 
1 
2 
3 
4 
Study Time Point 
D -21 to 0 
(W -3 to 0) 
D 1 (W 1) 
D 15 (W 3) 
D 29 (W 5) 
Visit Window (Days) 
0 
±3 
±3 
±3 
PT-INR 
X 
Serologies for HBV, HCV, and HIV 
X 
FSH for menopausal women onlyk 
X 
Appetite hormonesl 
X 
Biomarkersm 
X 
Review of eligibilityn 
X 
Placebo dispensing 
X 
Placebo dosingo 
X 
Drug accountability 
X 
X 
Food Diary Reminderp 
X 
Food Diary Distribution 
X 
Abbreviations: ABC = Aberrant Behavior Checklist questionnaire; AE = adverse event; ALT = alanine aminotransferase; AST = 
aspartate aminotransferase; BMI = body mass index; BP = blood pressure; CBC = complete blood count; CGI-S = Clinical Global 
Impression of Change – Severity questionnaire; C-SSRS = Columbia-Suicide Severity Rating Scale; D = day; ECG = electrocardiogram; 
EDC = electronic data capture; ESS-CHAD = Epworth Daytime Sleepiness Scale; FSH = follicle-stimulating hormone; HBV = hepatitis 
B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; HbA1c = glycosylated hemoglobin; HQ-CT = Hyperphagia 
Questionnaire for Clinical Trials; HR = heart rate; MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin 
concentration; MCV = mean corpuscular volume ; PT-INR = prothrombin time-international normalized ratio; PWS = Prader-Willi 
Syndrome; RBC = red blood cells; RDW = red cell distribution width; RR = respiratory rate; THC = tetrahydrocannabinol; WBC = 
white blood cells; W = week; WOCBP = women of childbearing potential. 
a Weight and height must be documented at every in-person visit as the EDC system will automatically calculated BMI (or BMI z-score) 
using both variables (Protocol Section 10.1.3). 
b Vital signs include BP, HR, RR, oxygen saturation, and temperature (Protocol Section 10.1.2). 
c A full physical exam should be performed at Screening Visit 1 (Protocol Section 10.1.4). Other physical exams should be abbreviated, 
symptom -directed. 
d If a caregiver is required to assist the patient in completing the questionnaire, the same caregiver should be available throughout the 
study. 
e The EDC system will automatically calculate mean HQ-CT score from Visit 1 and Visit 2. Patients with a mean HQ-CT score ≥13 will 
be eligible to continue in the Tolerability Period. Further details are described in Protocol Section 6.4. 
f If the patient is the mental equivalent of 6 or younger then the children's version of the C-SSRS should be used. 


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g For WOCBP only. 
h Drugs of abuse include THC. May be repeated at the Investigator’s discretion. 
i Chemistry panels include renal and liver function panels. Renal function panel includes sodium, potassium, chloride, calcium, 
bicarbonate, glucose, phosphorus, blood urea nitrogen, creatinine, and estimated glomerular filtration rate. Should be obtained after a 
10-hour fast if possible. Liver function panel includes ALT, AST, albumin, alkaline phosphatase, direct bilirubin, total bilirubin, indirect 
bilirubin, and total protein (Protocol Table 9) 
j Hematology panel includes hematocrit, hemoglobin, MCV, MCH, MHCH, RDW, RBC, WBC, platelets, and differential (Protocol 
Table 9). 
k FSH levels must be ≥30 mIU/mL with absence of menstruation for ≥1 year to be considered menopausal status (Protocol Section 
10.1.11). 
l Includes insulin, ghrelin, and leptin (Protocol Table 9). Ghrelin samples will only be collected for Phase 3 patients at sites where proper 
collection is feasible. 
m Will only be performed in patients enrolled in the Phase 3 part of the study and be optional. Biomarker assessments will not be 
conducted in the Phase 2 part of the study. 
n Review of eligibility at Visit 1 includes all inclusion and exclusion criteria with the exception of HQ-CT. Eligibility related to HQ-CT 
scores will be assessed at Visit 2 and Visit 5 (Protocol Section 6.4). 
o Dosing should be completed at the site when patients are present for a study visit during Visit 2 and Visit 5 (Protocol Section 7.1) 
p Patients will be instructed to record the time of their evening and morning doses of study medication on the night prior to and the day 
of their next clinic visit with the type of meal administered. Patients should also be contacted approximately 1 week prior to their next 
visit to remind them to complete their food diary prior to their next visit (Protocol Section 10.1.14). 


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12.2 
Appendix A Part 2: Schedule of Assessments - Dose Escalation, Maintenance, Taper, and Follow-Up Periods 
 
DOUBLE-BLIND TREATMENT PHASEa 
TAPER 
PERIODb 
(2 weeks) 
FOLLOW-UP 
PERIODb 
(2 weeks) 
Period 
DOSE ESCALATION 
PERIODa 
(3 Weeks) 
MAINTENANCE PERIOD 
(24 Weeks) 
Visit Number 
5c,d 
6e 
7e,f 
8c 
9e 
10c 
11e,f 
12c 
13e,f 
14c,g,aa,bb 
15c 
16e 
Study Time Point 
D 43 
(W 7) 
D 50 
(W 8) 
(Remote) 
D 57 
(W 9) 
(Remote) 
D 64 
(W 10) 
D 99 
(W 15) 
(Remote) 
D 127 
(W 19) 
D 155 
(W 23) 
(Remote) 
D 183 
(W 27) 
D 204 
(W 30) 
(Remote) 
D 232 / 
ET/EOS 
(W 34) 
D 232 
(W 34) 
D 246c 
(W 36c) 
D 260e/ EOSe 
(W 38) 
(Remote) 
Visit Window (D) 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
Review of 
concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review of AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight and heighth 
X 
X 
X 
X 
X 
Record vital signsi 
X 
X 
X 
X 
X 
Physical examj 
X 
X 
X 
X 
X 
Xk 
HQ-CT 
Questionnairel,m 
Xpre-dose 
X 
X 
X 
X 
Review of HQ-CT 
scores and I/E n,o 
X 
C-SSRSl,m,p 
Xpre-dose 
X 
X 
X 
X 
Randomizationo 
Xq 
ABC 
Questionnairel,m 
X 
X 
X 
X 
X 
ESS-CHAD 
Questionnairel,m 
X 
X 
X 
CGI-S Hyperphagia 
Questionnairel,m 
X 
X 
X 
X 
X 
CaGI-S Hyperphagia 
Questionnairel,m 
X 
X 
X 
X 
X 
CGI-C Hyperphagia 
Questionnairel,m 
X 
CaGI-C Irritability 
Questionnairel,m 
X 
CaGI-C 
Questionnairel,m 
X 


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DOUBLE-BLIND TREATMENT PHASEa 
TAPER 
PERIODb 
(2 weeks) 
FOLLOW-UP 
PERIODb 
(2 weeks) 
Period 
DOSE ESCALATION 
PERIODa 
(3 Weeks) 
MAINTENANCE PERIOD 
(24 Weeks) 
Visit Number 
5c,d 
6e 
7e,f 
8c 
9e 
10c 
11e,f 
12c 
13e,f 
14c,g,aa,bb 
15c 
16e 
Study Time Point 
D 43 
(W 7) 
D 50 
(W 8) 
(Remote) 
D 57 
(W 9) 
(Remote) 
D 64 
(W 10) 
D 99 
(W 15) 
(Remote) 
D 127 
(W 19) 
D 155 
(W 23) 
(Remote) 
D 183 
(W 27) 
D 204 
(W 30) 
(Remote) 
D 232 / 
ET/EOS 
(W 34) 
D 232 
(W 34) 
D 246c 
(W 36c) 
D 260e/ EOSe 
(W 38) 
(Remote) 
Visit Window (D) 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
Skin Picking 
Questionnairel,m 
X 
X 
X 
Resting 12-lead ECG 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
Urine dipstick 
pregnancy testr 
X 
X 
X 
X 
X 
Urine drug screens 
X 
Chemistry panelst 
X 
X 
X 
X 
X 
Hematologyu 
X 
X 
X 
X 
X 
HbA1c 
X 
X 
X 
Appetite hormonesv 
X 
X 
X 
X 
Biomarkersw 
X 
Pharmacokinetic 
X 
Xx 
X 
X 
Food Diary 
Collection 
X 
X 
X 
X 
Food Diary 
Reminderf 
X 
X 
X 
Food Diary 
Distribution 
Xcc 
Xcc 
Xcc 
Drug accountability 
X 
X 
X 
X 
X 
X 
IP dispensing 
X 
X 
X 
X 
X 
X 
X 
X 
Dosingy 
X 
Seizure Patient 
Impression 
X 
DEXA scanz 
X 
X 
Tapering of IP over 
14 daysb 
Xb,g 
Abbreviations: ABC = Aberrant Behavior Checklist questionnaire; AE = adverse event; ALT = alanine aminotransferase; AST = 


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aspartate aminotransferase;BMI = body mass index; BP = blood pressure; CaGI-C = Caregiver Global Impression of Change; CBC = 
complete blood count; CGI-C= Clinical Global Impression of Change; CGI-S= Clinical Global Impression of Change – Severity 
questionnaire; C-SSRS = Columbia-Suicide Severity Rating Scale; D = day; DEXA = dual-energy x-ray absorptiometry; DMC = Data 
Monitoring Committee; EDC = electronic data capture; ECG = electrocardiogram; ESS-CHAD = Epworth Daytime Sleepiness Scale; 
EOS = End of Study; HbA1c = glycosylated hemoglobin; HQ-CT = Hyperphagia Questionnaire for ClinicalTrials; HR = heart rate; IP 
= investigational product (RAD011 or placebo); MCH = mean corpuscular hemoglobin; I/E = Inclusion/Exclusion Criteria; MCHC = 
mean corpuscular hemoglobin concentration; MCV = mean corpuscular volume; PK= Pharmacokinetic; PWS = Prader-Willi Syndrome; 
RBC = redblood cells; RDW = red cell distribution width; RR = respiratory rate; THC = tetrahydrocannabinol; W = week; WBC = white 
blood cells. 
a In the Phase 2 part of the study, all patients will be initiated on IP (RAD011 or placebo) 10 mg/kg/day (0.1 mL/kg/day) for a period of 
1 week at Visit 5 (Week 7). Patients randomized to low dose or low volume IP (10 mg/kg/day) will continue at a dose of 10 mg/kg/day 
(0.1 mL/kg/day) until the end of Week 9. Patients randomized to mid dose or mid volume IP (20 mg/kg/day) will have their dose 
increased to 20 mg/kg/day (0.2 mL/kg/day) at Visit 6 (Week 8) and will continue at that dose until the end of Week 9. Patients 
randomized to high dose or high volume IP (40 mg/kg/day) will have their dose increased to 20 mg/kg/day (0.2 mL/kg/day) at Visit 6 
(Week 8) and to 40 mg/kg/day at Visit 7 (Week 9). Details of the dose escalation schema are provided in Protocol Table 4. 
In the Phase 3 part of the study, all patients will be initiated on IP (RAD011 or placebo) 10 mg/kg/day IP (0.1 mL/kg/day) for a period 
of 1 week at Visit 5 (Week 7). Dose escalation will occur similarly to the Phase 2 part of the study with the 1 or 2 doses recommended 
by the DMC following their review of safety and tolerability data from the Phase 2 part of the study. Details of the dose escalation 
schema are provided in Protocol Table 4. 
No dose decreases will be allowed during the Dose Escalation Period (Protocol Section 5.7.1). 
b The Taper and Follow Up Period visits (Visits 14 to 16) are only for patients who do not proceed to enroll in the active long-term 
extension study SCOUT-016 and who are tapering off the IP. Patients will return to the site for assessment of concomitant medications, 
AEs, and to return and reconcile IP on Visit 15. Visit 16 may be done remotely (Protocol Section 5.8.6). 
c To be performed in person at the research site. 
d All assessments must be performed prior to dosing, unless specified otherwise. 
e Assessments may be conducted remotely via a phone call, video call, or other remote means of communication. Dispensing of IP may 
be done at the research site or remotely, using direct-to-patient shipping methods in accordance with all local laws and regulations. Sites 
may elect to conduct the entire visit in person. 
f At Week 9 (Visit 7), Week 23 (Visit 11), and Week 30 (Visit 13), patients will be instructed to record the time of their evening and 
morning doses of study medication on the night prior to and the day of their next clinic visit with the type of meal administered. Patients 
should also be contacted approximately 1 week prior to their next visit to remind them to complete their food diary prior to their next 
visit (Protocol Section 10.1.14). 
g At visit 14, patients may be offered participation in the long-term extension study SCOUT-016. Patients eligible and electing to 


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participate in the long-term extension study SCOUT-016 should continue treatment with IP as per the SCOUT-016 protocol. Patients 
who are not eligible or decide not to participate in the long-term extension study SCOUT-016 should proceed to the Taper and Follow- 
Up Periods (Protocol Section 5.8.5.1). 
h Weight and height must be documented at every in-person visit (Protocol Section 10.1.3). 
i Vital signs include BP, HR, RR, oxygen saturation, and temperature (Protocol Section 10.1.2). 
j A full physical exam should be performed at Week 7 (Visit 5). Other physical exams should be abbreviated, symptom directed (Protocol 
Section 10.1.4). 
k To be performed at Visit 15 (Week 36) only. 
l If a caregiver is required to assist the patient in completing the questionnaire, the same caregiver should be available throughout the 
study. 
m When possible, study questionnaires should be completed prior collection of ECG and blood samples. 
n Patients meeting all inclusion and exclusion criteria should proceed to randomization. 
o The EDC system will automatically calculate mean HQ-CT score from Visit 3, Visit 4 and Visit 5 inclusively. Patients with a mean 
HQ-CT score ≥13 will be eligible for randomization. In addition, the EDC system will also automatically calculate the change in HQ- 
CT score from the Tolerability Period to the Screening Period. Patients must have a decrease in HQ-CT score ≤7 to be eligible for 
randomization. Further details are defined in Protocol Section 6.4. 
p If the patient is the mental equivalent of 6 or younger then the children's version of the C-SSRS should be used. 
q Randomization cannot be performed prior to evaluation and review of HQ-CT questionnaire scores for eligibility. Prior to assessing 
randomization eligibility, patients must complete the Visit 5 HQ-CT questionnaire (Protocol Section 6.4.2). 
r For WOCBP only. If positive, a quantitative serum pregnancy test must be sent to the central laboratory for confirmation. 
s Drugs of abuse include THC. May be repeated at the Investigator's discretion. 
t Chemistry panels include renal and liver function panels. Renal function panel includes sodium, potassium, chloride, calcium, 
bicarbonate, glucose, phosphorus, blood urea nitrogen, creatinine, and glomerular filtration rate. Should be obtained after a 10-hour fast 
if possible. Liver function panel includes ALT, AST, albumin, alkaline phosphatase, direct bilirubin, total bilirubin, indirect bilirubin, 
and total protein (Protocol Table 9). 
u Hematology panel includes hematocrit, hemoglobin, MCV, MCH, MHCH, RDW, RBC, WBC, platelets, and differential (Protocol 
Table 9). 
v Includes insulin, ghrelin, and leptin (Protocol Table 9). Ghrelin samples will only be collected for Phase 3 patients at sites where proper 
collection is feasible. 
w Will only be performed in patients enrolled in the Phase 3 part of the study and be optional. Biomarker assessments will not be 
conducted in the Phase 2 part of the study 
x Must be drawn 6 ± 2 hours after the previous IP dose. Patients may take their IP dose at home prior to presenting to the site for their 
visit in order to comply with the PK timing requirements. 


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y Dosing should be completed at the site during Visit 2 and Visit 5. Dosing is not required to be done at the site when patients have 
remote or other visits (Protocol Section 7.1). 
z Can be performed before or after dosing. The DEXA scan can be performed within ± 7 days of the visit time point (Protocol Section 
9.3.6). The DEXA scan will be performed at a certain number of US sites only. 
aa All assessments will be collected regardless of if the patient enters the taper period or completes the study and enter the long-term 
extension study. 
bb The two-week taper period does not have any visits associated with it. 
cc The food diary can be provided at the previous in-person visit. 


 
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12.3 
Appendix B: Missing or Incomplete Dates Imputation Rules 
Imputation of Partial or Completely Missing Start Dates for AEs and Concomitant 
Medications 
• If only the month and year are specified and the month and year of first dose is not the 
same as the month and year of the start date, then use the 1st of the month. 
• If only the month and year are specified and the month and year of first dose is the same 
as the month and year of the start, then use the date of first dose. 
• If only the year is specified, and the year of first dose is not the same as the year of the start 
date, then use January 1 of the year of the start date. 
• If only the year is specified, and the year of first dose is the same as the year of the start 
date, then use the date of first dose. 
• If the start date is completely unknown, and the stop date is unknown or not prior to the 
date of first dose, then use the date of first dose. 
Imputation of Partial or Completely Missing Stop Dates for AEs and Concomitant 
Medications 
• If only the month and year are specified, then use the last day of the month. 
• If only the year is specified, then use December 31 of that year. 
• If the stop date is completely unknown, do not impute the stop date. 
o If an AE was resolved and the resolution date is completely unknown, then do not 
impute the resolution date. 
Imputation for Missing Study Medication Start and Stop Dates 
No imputation should be performed for missing study medication start dates. This field on the 
eCRF should not be partial or missing. 
For partial or missing date of last dose of study medication, the following imputation rules will be 
applied for the purpose of calculating overall exposure: 
If the day is missing (but month and year available), impute the last dose date as the minimum of 
the last day of the month or the date of last contact reported on the trial termination eCRF; if day 
and month are both missing (only year available), impute the last dose date as the minimum of the 
last day of the year or the date of last contact on the trial termination eCRF. 
If a patient died and has a partial or missing last administration date, the date is to set to the date 
of death. If there is a partial date of last dose and the month/year are prior to the month and year 
of the date of death, follow partial date imputation rules. 
If the last dose date is completely missing and no information could be obtained from data cleaning 
exercises, the last dose date should be imputed as the date of last contact according to the study 
termination eCRF. A review of the data for patients with completely missing last dose dates should 
be performed to ensure that the imputation does not result in an unrealistic value for duration of 
exposure. 
Imputed date of last dose dates should only be used for calculation of the duration of exposure. 


 
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The date as recorded on the eCRF should be presented in patient data listings (no imputed dates 
should be included in patient data listings). 


 
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12.4 
Appendix C: List of Preferred Terms for AESI 
PT for Hepatic dysfunction AESI 
PT 
Acquired factor V deficiency 
Alanine aminotransferase abnormal 
Alanine aminotransferase increased 
Ammonia abnormal 
Ammonia increased 
Ascites 
Aspartate aminotransferase abnormal 
Aspartate aminotransferase increased 
AST/ALT ratio abnormal 
Bacterascites 
Bile output abnormal 
Bile output decreased 
Biliary ascites 
Bilirubin conjugated abnormal 
Bilirubin conjugated increased 
Bilirubin urine present 
Biopsy liver abnormal 
Blood bilirubin abnormal 
Blood bilirubin increased 
Blood bilirubin unconjugated increased 
Bromosulphthalein test abnormal 
Child-Pugh-Turcotte score abnormal 
Child-Pugh-Turcotte score increased 
Computerised tomogram liver abnormal 
Congestive hepatopathy 
Foetor hepaticus 
Galactose elimination capacity test abnormal 
Galactose elimination capacity test decreased 
Gamma-glutamyltransferase abnormal 
Gamma-glutamyltransferase increased 
Guanase increased 
Hepaplastin abnormal 
Hepaplastin decreased 
Hepatic artery flow decreased 
Hepatic enzyme abnormal 
Hepatic enzyme decreased 
Hepatic enzyme increased 
Hepatic function abnormal 
Hepatic hydrothorax 


 
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PT 
Hepatic hypertrophy 
Hepatic hypoperfusion 
Hepatic mass 
Hepatic pain 
Hepatic sequestration 
Hepatic vascular resistance increased 
Hepatic venous pressure gradient abnormal 
Hepatic venous pressure gradient increased 
Hepatobiliary scan abnormal 
Hepatomegaly 
Hepatosplenomegaly 
Hyperammonaemia 
Hyperbilirubinaemia 
Hypercholia 
Hypertransaminasaemia 
Kayser-Fleischer ring 
Liver function test abnormal 
Liver function test decreased 
Liver function test increased 
Liver induration 
Liver palpable 
Liver scan abnormal 
Liver tenderness 
Drug-Induced Liver Injury 
Magnetic resonance imaging hepatobiliary abnormal 
Magnetic resonance proton density fat fraction measurement 
Mitochondrial aspartate aminotransferase increased 
Molar ratio of total branched-chain amino acid to tyrosine 
Oedema due to hepatic disease 
Perihepatic discomfort 
Retrograde portal vein flow 
Total bile acids increased 
Transaminases abnormal 
Transaminases increased 
Ultrasound liver abnormal 
Urine bilirubin increased 
White nipple sign 
X-ray hepatobiliary abnormal 
5'nucleotidase increased 
AST to platelet ratio index increased 
Blood alkaline phosphatase abnormal 
Blood alkaline phosphatase increased 


 
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PT 
Blood cholinesterase abnormal 
Blood cholinesterase decreased 
Cytokeratin 18 increased 
Deficiency of bile secretion 
Glutamate dehydrogenase increased 
Glycocholic acid increased 
Haemorrhagic ascites 
Hepatic fibrosis marker abnormal 
Hepatic fibrosis marker increased 
Hepatic lymphocytic infiltration 
Hepatitis A immunity confirmed 
Hepatitis B immunity confirmed 
Hepatitis E immunity confirmed 
Hypoalbuminaemia 
Leucine aminopeptidase increased 
Liver iron concentration abnormal 
Liver iron concentration increased 
Liver opacity 
Model for end stage liver disease score abnormal 
Model for end stage liver disease score increased 
Osteopontin increased 
Periportal oedema 
Peritoneal fluid protein abnormal 
Peritoneal fluid protein decreased 
Peritoneal fluid protein increased 
Pneumobilia 
Portal vein flow decreased 
Portal vein pressure increased 
Retinol binding protein decreased 
Urobilinogen urine decreased 
Urobilinogen urine increased 
 
PT for Suicide ideation and behavior AESI 
 
Assisted Suicide 
Columbia suicide severity rating scale abnormal 
Completed suicide 
Depression suicidal 
Intentional overdose 
Intentional self-injury 
Poisoning deliberate 
PT 


 
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PT 
 
Self-injurious ideation 
Suicidal behaviour 
Suicidal ideation 
Suicide attempt 
Suicide threat 
Suspected suicide 
Suspected suicide attempt 


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12.5 
APPENDIX D: Marked Lab abnormalities 
12.5.1 Hematology 
PARAMETER 
AGE 
RANGE 
UNIT 
(conventional) 
ABNORMALITY 
CRITERIA 
(conventional) 
UNIT 
(standard) 
ABNORMALITY 
CRITERIA 
(standard) 
Hemoglobin 
All 
g/dL 
≤10.0 
>110% of ULN
g/L 
≤100 
>110% of ULN
WBC/Leukocytes 
All 
109/L 
≤3.0 
g/L 
≤3.0 
Neutrophils 
Absolute 
>1m
109/L 
<1.5 
g/L 
<1.5 
RBC/ 
Erythrocytes 
All 
1012/L 
<90% of LLN 
g/L 
<90% of LLN 
Note: Criteria for abnormality are defined either from Common Terminology Criteria for Adverse Events v5.0 
Grade 1 if it exits or applies a >=110% or a <=90% rule.