Conditions: Prader-Willi Syndrome Hyperphagia
Keywords: Prader-Willi Syndrome PWS
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 158
Healthy volunteers: no

Brief summary:
This Phase 2b/3 double-blind, placebo-controlled study will evaluate the safety, tolerability, and effects of livoletide on food-related behaviors in patients with Prader-Willi Syndrome (PWS).

Detailed description:
The protocol includes 2 consecutive parts:

1. The first part is a Phase 2b dose-response study consisting of a 3-month double-blind, placebo-controlled Core Period followed by a 9-month Extension Period.
2. The second part is a Phase 3 study consisting of a 6-month double-blind, placebo-controlled Core Period followed by a 6-month Extension Period. Phase 3 may be initiated following review of safety and efficacy results at the completion of the Phase 2b Core Period.

A total of approximately 50 patients per group (8 to 65 years of age) will be randomized (approximately 150 patients in total). In addition to this cohort of 150 patients, a separate cohort of patients 4 to 7 years of age will also be randomized.

Note: The 8-65 year old cohort has been fully enrolled. Enrollment into the 4-7 year age cohort remains ongoing.

Arms:
arm 1: Daily subcutaneous injection of \~ 60 mcg/kg for 3 month double-blind core period and 9 month open label extension period. arm 2: Daily subcutaneous injection of \~120 mcg/kg for 3 month double-blind core period and 9 month open label extension period. arm 3: Daily subcutaneous injection of 0.9% NaCl for the 3 month double-blind core period and then low-dose or high-dose livoletide for 9 month open label extension period.

Interventions: intervention 1: Livoletide intervention 2: Placebo
Intervention descriptions: intervention 1: Daily subcutaneous injection intervention 2: Daily subcutaneous injection

Protocol document:
Prot_001.pdf: 
Protocol Code Number: AZP01-CLI-003 
Confidential & Proprietary 
Page 1 of 172 
Version 1.2, July 31st, 2019 
 
 
 
Clinical Trial Protocol AZP01-CLI-003 
 
A Phase 2b/3 study to evaluate the safety, tolerability, and effects of 
Livoletide (AZP-531), an unacylated ghrelin analog, on food-related 
behaviors in patients with Prader-Willi syndrome 
 
Investigational Product: 
Livoletide (AZP-531) 
Study Name: 
ZEPHYR 
Protocol Code Number: 
AZP01-CLI-003 
Development Phase: 
Phase 2b/3 
EudraCT number: 
2018-003062-13 
IND number:  
130864 
NCT number: 
03790865 
Trial Sponsor: 
Millendo Therapeutics SAS 
 
15G Chemin du Saquin  
 
Ecully 69130, France  
Sponsor’s Medical Officer: 
Soraya Allas, MD, PhD 
 
Current Protocol Version: 
1.2 
Date: 
July 31st, 2019 
 
 
Confidentiality Statement 
This confidential document is the property of Millendo Therapeutics and it is provided for the use 
of the Investigator and other designated personnel solely in connection with the conduct of the 
study described herein. No information contained herein may be disclosed, except as necessary to 
obtain consent from persons who are considering participation in the study, without prior written 
approval of Millendo Therapeutics. 


Protocol Code Number: AZP01-CLI-003 
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Version 1.2, July 31st, 2019 
 
STATEMENT OF COMPLIANCE 
This trial will be carried out in accordance with guidelines of International Council for 
Harmonisation Good Clinical Practice E6 (ICH GCP), applicable United States (US) Code of 
Federal Regulations (CFR), and all applicable national and local regulatory requirements. The 
Principal Investigator will assure that no deviation from or changes to the protocol will take place 
without prior agreement from the Investigational New Drug (IND)/Clinical Trial Authorization 
(CTA) Sponsor, funding agency and documented approval from the Institutional Review Board 
(IRB)/Ethics Committee (EC), except where necessary to eliminate an immediate hazard(s) to the 
trial participants. All personnel involved in the conduct of this study have completed ICH GCP 
Training. 
The protocol, informed consent form(s), all recruitment materials, and all participant materials 
will be submitted to applicable IRB/EC for review and approval. Approval of both the protocol 
and the consent form must be obtained before any participant is enrolled. Any amendment to the 
protocol will require review and approval by the applicable IRB/EC before the changes are 
implemented to the study. All changes to the consent form will be IRB/EC approved; a 
determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form. 


Protocol Code Number: AZP01-CLI-003 
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Version 1.2, July 31st, 2019 
SPONSOR PROTOCOL APPROVAL 
 
Protocol Title: 
A Phase 2b/3 study to evaluate the safety, tolerability, and effects of 
Livoletide (AZP-531), an unacylated ghrelin analog, on food-related 
behaviors in patients with Prader-Willi syndrome 
 
Protocol Number: 
AZP01-CLI-003 
 
Current Version: 
1.2, July 31st, 2019 
 
 
 
 
I, the undersigned, have read this protocol and agree with its content and confirm that it contains all 
necessary information required to conduct the study.  
 
 
Approved by: 
 
Responsible Sponsor Medical Officer 
 
 
         
     
Signature: 
_________________________________ 
Date: July 31st, 2019 
 
 
Soraya Allas, MD, PhD 
 
 
Vice President, Clinical Development 
 


Protocol Code Number: AZP01-CLI-003 
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Version 1.2, July 31st, 2019 
INVESTIGATOR’S AGREEMENT 
Protocol Title: 
A Phase 2b/3 study to evaluate the safety, tolerability, and effects of 
Livoletide (AZP-531), an unacylated ghrelin analog, on food-related 
behaviors in patients with Prader-Willi syndrome 
 
Protocol Number: 
AZP01-CLI-003 
Current Version: 
1.2, July 31st, 2019 
I have carefully read Protocol AZP-CLI-003 entitled “A Phase 2b/3 study to evaluate the safety, 
tolerability, and effects of Livoletide (AZP-531), an unacylated ghrelin analog, on food-related 
behaviors in patients with Prader-Willi syndrome”. 
I confirm that I have read and agree to conduct the clinical study as outlined in the protocol and in 
compliance with Good Clinical Practice (GCP), the Declaration of Helsinki as amended, and all other 
applicable regulatory requirements. Furthermore, I understand that the Sponsor, Millendo 
Therapeutics SAS, and the Institutional Review Board/Research Ethics Board/Ethics Committee 
(IRB/REB/EC) must approve any changes to the protocol in writing before implementation. 
I agree on behalf of myself and all other personnel involved in the clinical study who are employed by 
me, to maintain confidentiality of all information received or developed in connection with this 
protocol. All data pertaining to this study will be provided to Millendo Therapeutics and any 
presentation or publication of study data will be reviewed by Millendo Therapeutics, before release. 
I have read and agree to the following Confidentiality Statement: 
Confidentiality Statement: This protocol and any related documents from Millendo Therapeutics, 
contain privileged information that is confidential and may not be disclosed unless such disclosure is 
required by federal laws or regulations. In any event, persons to whom the information is disclosed 
must be informed that it is privileged and/or confidential and may not be further disclosed by them. 
Information from this study may not be reproduced in any form without the written permission of 
Millendo Therapeutics. 
 
PRINCIPAL INVESTIGATOR: 
 
 
_______________________________________ 
 
__________________ 
Principal Investigator’s Signature 
Date 
 
 
______________________________________________________________________ 
Print Principal Investigator’s Address and Telephone Number 


Protocol Code Number: AZP01-CLI-003 
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Version 1.2, July 31st, 2019 
 
SPONSOR 
Millendo Therapeutics SAS  
 
Soraya Allas, MD, PhD 
Vice President, Clinical Development  
15G Chemin du Saquin 
69130 Ecully, France 
Phone: +33 472 18 09 24 
Fax: +33 478 33 36 29 
Email: allas@millendo.com  
 
Vivian Lin, MD (Millendo Therapeutics, Inc.) 
Senior Medical Director 
301 N. Main St., Ste. 100 
Ann Arbor, MI 48104 
Phone: +1 734 545 8150 
Fax: +1 888 637 1688 
Email: lin@millendo.com 
 
EUROPEAN COORDINATING PRINCIPAL INVESTIGATOR 
Pr. Maïthé Tauber, MD, PhD 
Hôpital des Enfants, Centre d’Endocrinologie, Maladies Osseuses, Génétique et Gynécologie 
Médicale 
CHU de Toulouse, 330 Avenue de Grande Bretagne 
31059 Toulouse Cedex 9, France 
Phone: +33 534 55 85 51 
Email: tauber.mt@chu-toulouse.fr 
 
KEY CONTACTS 


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MEDICAL MONITORING 
Michael S. Oldham, MD, MPH 
Medical Director 
Medpace 
5375 Medpace Way 
Cincinnati, Ohio 45227 
Phone: +1 513 579 9911, ext. 11080 
Mobile: +1 513 448 6925 
Fax: +1 513 579 0444 
Email: m.oldham@medpace.com 
 
Marco JD Tangelder, MD, PhD 
Senior Medical Director 
Medpace 
5375 Medpace Way 
Cincinnati, Ohio 45227 
Home office: Haarlem, the Netherlands 
Mobile: +31 620154282 
Email: m.tangelder@medpace.com 
 
STUDY MANAGEMENT AND MONITORING 
Clinical Research Organization (CRO): Medpace 
 
Guido Moesker 
Clinical Trial Manager 
Medpace 
Wallace House 
17-21 Maxwell Place  
Stirling, Scotland, FK8 1J, United Kingdom 
Phone: (+44) 1786 460 400, ext. 24475 
Mobile: +44(0)7741 887 832 
Email: g.moesker@medpace.com 
 
Shehnaz Moosa, MS, CCRC 
Clinical Trial Manager 
Medpace 
100 Decker Court, Suite 250 
Irving, Texas 75062 
Phone: +1 513 579 9911, ext. 25313 
Mobile: +1 513 203 5641 
Fax: +1 513 579 0444 
Email: s.moosa@medpace.com 


Protocol Code Number: AZP01-CLI-003 
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SERIOUS ADVERSE EVENTS REPORTING 
CRO Safety Department: Medpace Clinical Safety  
 
Medpace Serious Adverse Event (SAE) reporting line – United States:  
Phone: +1 513 579 9911, dial “3” 
Fax: +1 513 570 5196 
Email: medpace-safetynotification@medpace.com 
 
Medpace SAE reporting line – Europe:  
Phone: +49 89 89 55 718 44  
Fax: +49 89 89 55 718 104  
Email: medpace-safetynotification@medpace.com 


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Table of Contents 
KEY CONTACTS ......................................................................................................................................................... 5 
1 
PROTOCOL SUMMARY ................................................................................................................................. 13 
1.1 
Synopsis .......................................................................................................................................................... 13 
1.2 
Schedule of Activities .................................................................................................................................... 30 
1.2.1 
Schedule of Activities for Phase 2b Core Period ................................................................................... 30 
1.2.2 
Schedule of Activities for Phase 2b Extension Period ........................................................................... 33 
1.2.3 
Pharmacokinetic Schedule of Activities ................................................................................................. 35 
1.2.4 
Schedule of Activities for Phase 3 Core Period ..................................................................................... 36 
1.2.5 
Schedule of Activities for Phase 3 Extension Period ............................................................................. 39 
2 
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ..................... 41 
2.1 
Background Information .............................................................................................................................. 41 
2.1.1 
Overview of Prader-Willi Syndrome ...................................................................................................... 41 
2.1.2 
Hyperphagia Associated with Prader-Willi Syndrome .......................................................................... 41 
2.1.3 
Current Therapeutic Options for Hyperphagia associated with Prader-Willi Syndrome ...................... 42 
2.1.4 
Introduction to Ghrelin Biology............................................................................................................. 42 
2.2 
The Investigational Drug: Livoletide, an Unacylated Ghrelin Analog ..................................................... 45 
2.2.1 
Livoletide: General Description ............................................................................................................ 45 
2.2.2 
Chemistry and Description .................................................................................................................... 45 
2.3 
Summary of Relevant Nonclinical and Clinical Research ......................................................................... 46 
2.3.1 
Nonclinical Studies ................................................................................................................................ 46 
2.3.2 
Clinical Experience with Livoletide ....................................................................................................... 48 
2.4 
Rationale for Developing Livoletide in the Treatment of Hyperphagia in Patients with Prader-Willi 
Syndrome ................................................................................................................................................................. 50 
2.5 
Potential Risks and Benefits to Human Participants ................................................................................. 50 
2.5.1 
Known Potential Risks ........................................................................................................................... 50 
2.5.2 
Known Potential Benefits ....................................................................................................................... 52 
2.5.3 
Summary ................................................................................................................................................ 52 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................................... 52 
3.1 
Tabular Summary of Trial Objectives and Endpoints .............................................................................. 52 
3.1.1 
Phase 2b Tabular Summary of Trial Objectives and Endpoints ............................................................ 52 
3.1.2 
Phase 3 Tabular Summary of Trial Objectives and Endpoints .............................................................. 55 
3.2 
Justification for Core Period Primary and Secondary Endpoints ............................................................ 58 
3.2.1 
Phase 2b Justification for Core Period Primary and Secondary Endpoints.......................................... 58 
3.2.2 
Phase 3 Justification for Core Period Primary and Secondary Endpoints............................................ 58 


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4 
STUDY DESIGN ................................................................................................................................................ 59 
4.1 
Overall Study Design..................................................................................................................................... 59 
4.1.1 
Phase 2b Overall Study Design ............................................................................................................. 59 
4.1.2 
Phase 3 Overall Study Design ............................................................................................................... 60 
4.2 
Scientific Rationale and Discussion for Study Design ................................................................................ 62 
4.2.1 
Rationale for the Extension Period ........................................................................................................ 62 
4.2.2 
Rationale for the Control Arm ............................................................................................................... 62 
4.3 
Justification for Dose..................................................................................................................................... 62 
4.4 
Number of Patients ........................................................................................................................................ 62 
4.5 
Number of Study Sites .................................................................................................................................. 63 
4.6 
Definition of the End of the Study ................................................................................................................ 63 
5 
STUDY POPULATION..................................................................................................................................... 63 
5.1 
Phase 2b Patient Inclusion and Exclusion Criteria .................................................................................... 63 
5.1.1 
Phase 2b Patient Inclusion Criteria for the Core Period ...................................................................... 63 
5.1.2 
Phase 2b Patient Exclusion Criteria ...................................................................................................... 64 
5.1.3 
Phase 2b Patient Inclusion Criteria for the Extension Period ............................................................... 65 
5.2 
Phase 3 Patient Inclusion and Exclusion Criteria ...................................................................................... 66 
5.2.1 
Phase 3 Patient Inclusion Criteria for the Core Period ........................................................................ 66 
5.2.2 
Phase 3 Patient Exclusion Criteria ........................................................................................................ 67 
5.2.3 
Phase 3 Patient Inclusion Criteria for the Extension Period ................................................................. 68 
5.3 
Lifestyle Considerations ................................................................................................................................ 68 
5.3.1 
Contraception Requirements ................................................................................................................. 68 
5.3.2 
Other Requirements or Considerations ................................................................................................. 69 
5.4 
Screen Failures .............................................................................................................................................. 69 
5.5 
Justification for Inclusion of Vulnerable Participants ............................................................................... 69 
6 
STUDY DRUGS ................................................................................................................................................. 70 
6.1 
Study Drug Administration .......................................................................................................................... 70 
6.1.1 
Study Drug Description ......................................................................................................................... 70 
6.1.2 
Dosing and Administration .................................................................................................................... 70 
6.2 
Preparation/Handling/Storage/Accountability ........................................................................................... 71 
6.2.1 
Acquisition and Accountability .............................................................................................................. 71 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ............................................................................ 72 
6.2.3 
Product Storage and Stability ................................................................................................................ 72 
6.2.4 
Preparation ............................................................................................................................................ 72 
6.3 
Measures to Minimize Bias ........................................................................................................................... 73 
6.3.1 
Phase 2b Core Period Treatment Assignment and Blinding.................................................................. 73 


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6.3.2 
Phase 2b Extension Period Treatment Assignment and Blinding .......................................................... 73 
6.3.3 
Phase 3 Treatment Assignment and Blinding ........................................................................................ 74 
6.4 
Tracking of Dose and Assessment of Patient Compliance ......................................................................... 74 
6.5 
Concomitant Therapies ................................................................................................................................. 74 
6.6 
Rescue Medicine ............................................................................................................................................ 75 
7 
STUDY DRUG DISCONTINUATION AND PARTICIPANT DISCONTINUATION/WITHDRAWAL 75 
7.1 
Discontinuation of Study Treatment ........................................................................................................... 75 
7.2 
Participant Discontinuation/Withdrawal from the Study ......................................................................... 75 
7.2.1 
Handling of Participant Withdrawal or Termination ............................................................................ 76 
7.2.2 
Replacement of Patients ......................................................................................................................... 76 
7.3 
Lost to Follow-Up .......................................................................................................................................... 77 
7.4 
Premature Termination or Suspension of Study ........................................................................................ 77 
8 
STUDY ASSESSMENTS, PROCEDURES AND SCHEDULE ..................................................................... 77 
8.1 
Study Procedures/Evaluations ..................................................................................................................... 77 
8.1.1 
Study Specific Procedures ..................................................................................................................... 77 
8.1.2 
Laboratory Procedures/Evaluations ...................................................................................................... 78 
8.2 
Study Schedule............................................................................................................................................... 82 
8.2.1 
Phase 2b Study Schedule ....................................................................................................................... 82 
8.2.2 
Phase 3 Study Schedule ......................................................................................................................... 91 
8.2.3 
Early Termination Visit ....................................................................................................................... 101 
8.2.4 
Schedule of Activities Tables ............................................................................................................... 101 
9 
ASSESSMENT OF EFFICACY ..................................................................................................................... 101 
9.1 
Specifications of Primary and Secondary Efficacy Parameters .............................................................. 101 
9.1.1 
Hyperphagia Questionnaire for Clinical Trials ................................................................................... 102 
9.1.2 
Total Body Fat Mass ............................................................................................................................ 102 
9.1.3 
Waist Circumference............................................................................................................................ 103 
9.1.4 
Body Weight ......................................................................................................................................... 103 
10 
ASSESSMENT OF SAFETY .......................................................................................................................... 103 
10.1 
Specification of Safety Parameters ........................................................................................................ 103 
10.1.1 
Adverse Events ................................................................................................................................ 103 
10.1.2 
Vital Signs ....................................................................................................................................... 103 
10.1.3 
Height and Body Mass Index .......................................................................................................... 104 
10.1.4 
Physical Examination ..................................................................................................................... 104 
10.1.5 
Lean Body Mass and Bone Mineral Density ................................................................................... 104 
10.1.6 
Electrocardiograms ........................................................................................................................ 104 
10.1.7 
Safety Laboratory Parameters ........................................................................................................ 105 


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10.2 
Safety Measures for the Management of Hypoglycemia ..................................................................... 106 
10.3 
Adverse Events and Serious Adverse Events ....................................................................................... 106 
10.3.1 
Definition of Adverse Events, Adverse Drug Reactions, and Unexpected Adverse Drug Reactions
 
106 
10.3.2 
Definition of Serious Adverse Events .............................................................................................. 107 
10.4 
Classification of an Adverse Event ........................................................................................................ 108 
10.4.1 
Severity of Event ............................................................................................................................. 108 
10.4.2 
Relationship to Study Drug ............................................................................................................. 109 
10.5 
Reporting Procedures............................................................................................................................. 109 
10.5.1 
Reporting Adverse Events ............................................................................................................... 109 
10.5.2 
Reporting Serious Adverse Events .................................................................................................. 109 
10.5.3 
Reporting of Pregnancy .................................................................................................................. 111 
10.5.4 
Expedited Reporting ........................................................................................................................ 111 
10.5.5 
Special Situation Reports ................................................................................................................ 112 
10.6 
Safety Oversight ...................................................................................................................................... 112 
11 
ADDITIONAL STUDY ASSESSMENTS ...................................................................................................... 113 
11.1 
Fasting and Postprandial Glucose, Insulin, Acylated Ghrelin, and Unacylated Ghrelin Profile .... 115 
11.2 
Patient-reported Appetite Following Breakfast: Appetite-Numeric Rating Scale ............................ 115 
11.3 
Effects on Non-Food-Related Behavior: Developmental Behavior Checklist 2-Parent/Carer version
 
116 
11.4 
Effects on Patients’ Quality of Life: PedsQLTM 4.0 Generic Core Scales .......................................... 116 
11.5 
Effects on Caregiver Burden: Zarit Burden Interview ....................................................................... 116 
12 
CLINICAL MONITORING ........................................................................................................................... 116 
13 
STATISTICAL CONSIDERATIONS ............................................................................................................ 117 
13.1 
Statistical Hypotheses ............................................................................................................................. 117 
13.2 
Sample Size Determination .................................................................................................................... 118 
13.2.1 
Phase 2b .......................................................................................................................................... 118 
13.2.2 
Phase 3 ............................................................................................................................................ 118 
13.3 
Concept of Estimands and General Strategy for Analyses ................................................................. 118 
13.4 
Populations for Analyses ........................................................................................................................ 121 
13.4.1 
Full Analysis Set ............................................................................................................................. 121 
13.4.2 
Per Protocol .................................................................................................................................... 121 
13.4.3 
Safety Population ............................................................................................................................ 121 
13.4.4 
Pharmacokinetic Population ........................................................................................................... 121 
13.5 
Statistical Analyses ................................................................................................................................. 121 
13.5.1 
Phase 2b .......................................................................................................................................... 122 
13.5.2 
Phase 3 ............................................................................................................................................ 124 


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13.6 
Sub-group Analyses ................................................................................................................................ 124 
13.6.1 
Phase 2b .......................................................................................................................................... 124 
13.6.2 
Phase 3 ............................................................................................................................................ 124 
13.7 
Analyses of HQ-CT Measurement Properties ...................................................................................... 124 
13.8 
Analysis of Pharmacokinetic Samples .................................................................................................. 124 
14 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ............................................................................ 125 
15 
QUALITY CONTROL AND QUALITY ASSURANCE.............................................................................. 125 
16 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ............................... 126 
16.1 
Regulatory, Ethical, And Study Oversight Considerations ................................................................ 126 
16.2 
Institutional Review Board/Ethics Committee ..................................................................................... 126 
16.3 
Informed Consent Process ..................................................................................................................... 126 
16.4 
Participants’ and Data Confidentiality ................................................................................................. 127 
17 
DATA HANDLING AND RECORD KEEPING .......................................................................................... 128 
17.1 
Data Collection and Management Responsibilities ............................................................................. 128 
17.2 
Study Records Retention ........................................................................................................................ 128 
17.3 
Protocol Deviations ................................................................................................................................. 129 
17.4 
Protocol Amendments ............................................................................................................................ 130 
17.5 
Publication and Data Sharing Policy .................................................................................................... 130 
17.6 
Conflict of Interest Policy ...................................................................................................................... 130 
17.7 
Financing and Insurance ........................................................................................................................ 131 
18 
REFERENCES ................................................................................................................................................. 132 
19 
APPENDICES .................................................................................................................................................. 143 
19.1 
APPENDIX A: Declaration of Helsinki ................................................................................................ 143 
19.2 
APPENDIX B: Hyperphagia Questionnaire for Clinical Trials (HQ-CT) ........................................ 147 
19.3 
APPENDIX C: Numerical Rating Scale (NRS) for Appetite/Prospective Food Consumption ........ 149 
19.4 
APPENDIX D: Clinical Global Impression of Change – Hyperphagia (CGIC-H) Scale ................. 150 
19.5 
APPENDIX E: Caregiver Global Impression of Change - Hyperphagia (CgGIC-H) Scale ............ 151 
19.6 
APPENDIX F: Clinical Global Impression of Improvement (CGI-I) Scale ...................................... 152 
19.7 
APPENDIX G: Clinical Global Impression of Severity – Hyperphagia (CGIS-H) Scale ................ 153 
19.8 
APPENDIX H: Caregiver Global Impression of Severity - Hyperphagia (CgGIS-H) Scale ........... 154 
19.9 
APPENDIX I: Clinical Global Impression of Severity (CGI-S) Scale ............................................... 155 
19.10 
APPENDIX J: PEDSQLTM PARENT PROXY-REPORTS ................................................................ 156 
19.11 
APPENDIX K: Zarit Burden Interview ............................................................................................... 168 
19.12 
APPENDIX L: Protocol Versions ......................................................................................................... 172 


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1.1 
Synopsis 
Sponsor: 
Millendo Therapeutics SAS 
15G Chemin du Saquin 
Ecully 69130, France 
Name of 
Investigational 
Product: 
Livoletide (formerly known as AZP-531) 
Title of Study:  
A Phase 2b/3 study to evaluate the safety, tolerability, and effects of Livoletide (AZP-531), an 
unacylated ghrelin analog, on food-related behaviors in patients with Prader-Willi syndrome 
Study name: 
ZEPHYR 
Sponsor 
Protocol 
Number: 
AZP01-CLI-003 
Phase of 
Development:  
2b/3 
Study Centers: 
Approximately 40 sites in Europe, Australia and North America  
Indication: 
Hyperphagia and food-related behaviors in patients with Prader-Willi syndrome (PWS) 
Study Design: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This protocol includes 2 consecutive parts: 
1. The first part is a Phase 2b dose-response study consisting of a 3-month double-blind, 
placebo-controlled Core Period and a 9-month Extension Period. 
2. The second part is a Phase 3 study consisting of a 6-month double-blind, 
placebo-controlled Core Period followed by a 6-month Extension Period. Phase 3 may 
be initiated following review of safety and efficacy results at the completion of the 
Phase 2b Core Period. 
Patients who enrolled in the Phase 2b part will not be eligible for recruitment in the Phase 3 part. 
Phase 2b 
Phase 2b will include: 
 
A 3-month, double-blind, randomized, placebo-controlled treatment period (Phase 2b 
Core Period). After a screening period (up to 4 weeks), eligible patients will be 
randomized in a 1:1:1 ratio to one of two livoletide doses (8 mg/mL, low exposure or 
16 mg/mL, high exposure) or placebo. 
Randomization will be stratified based on age (≥4 and < 8 years of age, ≥8 and <18 years 
of age and ≥18 years of age) and body mass index (BMI) (patients 18 years of age: 
BMI <27 kg/m2 vs BMI 27 kg/m2; patients 4-17 years of age: BMI <90th percentile vs 
BMI 90th percentile for the same age and sex); 
 
A 9-month Extension Period (Phase 2b Extension Period). Patients randomized to 
livoletide for the Core Period will remain on the randomized dose (i.e. 8 mg/mL, low 
exposure or 16 mg/mL, high exposure) during the Extension Period. Patients randomized 
to placebo for the Core Period will cross-over to livoletide low or high exposure in a 
randomized (1:1) manner. The Interactive Response Technology (IRT) will manage 
treatment assignment so that the double-blind status can remain intact at the start of the 
Extension Period. 
1 
PROTOCOL SUMMARY 


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Study Design 
Continued: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PHASE 2b STUDY DESIGN
Core Period
Double Blind, Randomized,
Placebo-controlled Treatment Period
Extension Period
4 w.
9 months
3 months
AZP-531 low exposure
AZP-531 high exposure
Placebo
N=50
AZP-531 low
exposure
N=50
AZP-531 low exposure
AZP-531: 8 mg
N=50
AZP-531 high 
exposure
N=50
Randomization
AZP-531 high exposure
Screening
 
Abbreviations: AZP-531=livoletide; N=number of patients; w=weeks. 
Phase 3 
Phase 3 may commence after completion of the Phase 2b Core Period. Following review of data 
at the completion of the Phase 2b Core Period, the Phase 3 livoletide doses will be reassessed 
along with the statistical assumptions. Patients who enrolled in the Phase 2b part will not be 
eligible for recruitment in the Phase 3 part. 
Phase 3 will include: 
 
A 6-month, double-blind, randomized, placebo-controlled treatment period (Phase 3 
Core Period). After a screening period (up to 4 weeks), eligible patients will be 
randomized to livoletide or placebo; 
 
A 6-month Extension Period (Phase 3 Extension Period). Patients randomized to 
livoletide for the Core Period will remain on the randomized dose during the Extension 
Period. Patients randomized to placebo for the Core Period will cross-over to livoletide 
during the Extension Period. The IRT will manage treatment assignment so that the 
double-blind status can remain intact at the start of the Extension Period. 
 


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Study Design 
Continued: 
PHASE 3 STUDY DESIGN
Core Period
Double Blind, Randomized,
Placebo-controlled Treatment Period
Extension Period
4 w.
6 months
6 months
Placebo
AZP-531 dose(s) tbd
AZP-531 dose(s) tbd
Randomization
tbd: to be determined
AZP-531 dose(s) tbd
Screening
 
Abbreviations: AZP-531=livoletide; tbd=to be determined; w=weeks. 
Objectives: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Phase 2b 
PHASE 2b CORE PERIOD 
Primary efficacy objective: 
To demonstrate the efficacy of a 3-month treatment with livoletide as compared to placebo for 
reducing caregiver-observed food-related behavior as assessed by the Hyperphagia Questionnaire 
for Clinical Trials (HQ-CT). 
Secondary efficacy objectives: 
 
To demonstrate the efficacy of 3-month treatment with livoletide as compared to placebo 
for: 
 
Reducing total body fat mass in overweight/obese patients with PWS; 
 
Reducing waist circumference (WC) in overweight/obese patients with PWS; 
 
Reducing body weight (BW) in overweight/obese patients with PWS. 
Safety objective: 
 
To assess the safety and tolerability of livoletide as compared to placebo over a 3-month 
treatment period. 
Pharmacokinetic objective: 
 
To characterize the plasma pharmacokinetic (PK) of livoletide in patients with PWS; 
Additional assessments: 
 
To evaluate the effect of livoletide as compared to placebo on: 
 
Hyperphagia severity as assessed by the Caregiver and Clinical Global Impression of 
Severity - Hyperphagia scales (CgGIS-H and CGIS-H, respectively); 
 
Hyperphagia global impression of change as assessed by the Caregiver and Clinical 
Global Impression of Change - Hyperphagia scales (CgGIC-H and CGIC-H, 
respectively); 
 
Clinical global impression of change as assessed by the Clinical Global Impression 
of Improvement (CGI-I) scale; 


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Objectives 
Continued: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical global impression of severity as assessed by the Clinical Global Impression 
of - Severity (CGI-S) scale; 
 
Fasting (for approximately 8 hours) and postprandial glucose and insulin (profile); 
 
Patient-reported appetite following breakfast as assessed by a Numeric Rating Scale 
(NRS); 
 
Patients’ Non-Food-Related behavior as assessed by the Developmental Behavior 
Checklist 2-Parent/Carer version (DBC2-P); 
 
Patients’ Quality of Life (QoL) as assessed by the Pediatric Quality of Life 
inventoryTM (PedsQLTM) 4.0 Generic Core Scales; 
 
Caregivers’ disease burden as assessed by the Zarit Burden Interview (ZBI); 
 
Health state utilities as assessed by European Quality of Life Five Dimension Five 
Level Scale (EQ-5D-5L) Self-complete version and Proxy version 1; 
 
To evaluate the measurement properties of HQ-CT in the study population (test-retest 
reliability, construct validity and ability to detect change); 
 
To derive the responder threshold for meaningful change in the HQ-CT; 
 
To compare the percentage of HQ-CT responders between groups. 
PHASE 2b EXTENSION PERIOD 
Efficacy objectives: 
 
To assess the maintenance of efficacy of livoletide treatment on caregiver-observed 
food-related behavior as assessed by the HQ-CT; 
 
To assess the maintenance of efficacy of livoletide treatment on total body fat mass, WC, 
and BW in overweight/obese patients with PWS. 
Safety objective: 
 
To assess the long-term safety and tolerability of livoletide over a 12-month treatment 
period. 
Pharmacokinetic objective: 
 
To characterize the plasma PK of livoletide in patients with PWS; 
 
To characterize the plasma PK profile of livoletide in a subset of patients with PWS. 
Additional assessments: 
 
To evaluate the long-term effects of livoletide on: 
 
Hyperphagia severity as assessed by the CgGIS-H and CGIS-H; 
 
Hyperphagia global impression of change as assessed by the CgGIC-H and CGIC-H; 
 
Clinical global impression of change as assessed by the CGI-I; 
 
Clinical global severity as assessed by the CGI-S; 
 
Fasting (for approximately 8 hours) glucose and insulin; 
 
Patients’ Non-Food-Related behavior as assessed by the DBC2-P version; 
 
Patients’ QoL as assessed by the PedsQLTM 4.0 Generic Core Scales; 
 
Caregiver disease burden as assessed by the ZBI; 
 
Health state utilities as assessed by EQ-5D-5L Self-complete version and Proxy 
version 1. 


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Objectives 
Continued: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Phase 3: 
PHASE 3 CORE PERIOD 
Primary efficacy objective: 
To demonstrate the efficacy of a 6-month treatment with livoletide as compared to placebo for 
reducing caregiver-observed food-related behavior as assessed by HQ-CT.  
Secondary efficacy objectives:  
 
To demonstrate the efficacy of 6-month treatment with livoletide as compared to placebo 
for: 
 
Reducing total body fat mass in overweight/obese patients with PWS; 
 
Reducing WC in overweight/obese patients with PWS; 
 
Reducing BW in overweight/obese patients with PWS. 
Safety objective: 
 
To assess the safety and tolerability of livoletide as compared to placebo over a 6-month 
treatment period.  
Additional assessments: 
 
To evaluate the effect of livoletide as compared to placebo on: 
 
Hyperphagia severity as assessed by the CgGIS-H and CGIS-H; 
 
Hyperphagia global impression of change as assessed by the CgGIC-H and CGIC-H; 
 
Clinical global impression of change as assessed by the CGI-I; 
 
Clinical global impression of severity as assessed by the CGI-S; 
 
Fasting (for approximately 8 hours) and postprandial glucose and insulin (profile); 
 
Patient-reported appetite following breakfast as assessed by NRS; 
 
Patients’ Non-Food-Related behavior as assessed by the DBC2-P; 
 
Patients’ QoL as assessed by the PedsQLTM 4.0 Generic Core Scales; 
 
Caregivers’ disease burden as assessed by the ZBI; 
 
Health state utilities as assessed by EQ-5D-5L Self-complete version and Proxy 
version 1; 
 
To compare the percentage of HQ-CT responders between groups. 
PHASE 3 EXTENSION PERIOD 
Efficacy objectives: 
 
To assess the maintenance of efficacy of livoletide treatment on caregiver-observed 
food-related behavior as assessed by the HQ-CT; 
 
To assess the maintenance of efficacy of livoletide treatment on total body fat mass, WC, 
and BC in overweight/obese patients with PWS. 
Safety objective: 
 
To assess the long-term safety and tolerability of livoletide over a 12-month treatment 
period. 
 


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Objectives 
Continued: 
 
 
Additional assessments: 
 
To evaluate the long-term effects of livoletide on: 
 
Hyperphagia severity as assessed by the CgGIS-H and CGIS-H; 
 
Hyperphagia global impression of change as assessed by the CgGIC-H and CGIC-H; 
 
Clinical global impression of change as assessed by the CGI-I; 
 
Clinical global severity as assessed by the CGI-S; 
 
Fasting (for approximately 8 hours) glucose and insulin; 
 
Patients’ Non-Food-Related behavior as assessed by the DBC2-P version; 
 
Patients’ QoL as assessed by the PedsQLTM 4.0 Generic Core Scales; 
 
Caregiver disease burden as assessed by the ZBI; 
 
Health state utilities as assessed by EQ-5D-5L Self-complete version and Proxy 
version 1. 
Number of 
patients 
(planned):  
For Phase 2b, a total of approximately 50 patients per group (8 to 65 years of age) will need to be 
randomized (approximately 150 patients in total). In addition to this cohort of 150 patients, a 
separate cohort of patients 4 to 7 years of age will also be randomized to one of the 3 arms. 
For Phase 3, the total number of required patients to be randomized is estimated to be 50 patients 
per group. Final sample size will be determined following analysis of data at the completion of 
the Phase 2b Core Period. 
Duration of 
Study 
Participation: 
The overall study duration for each patient in both Phase 2b and Phase 3, inclusive of screening 
and follow-up, will be approximately 14 months. 
Diagnosis and 
Main Eligibility 
Criteria for 
Inclusion:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Phase 2b 
PHASE 2b INCLUSION CRITERIA (CORE PERIOD) 
To be enrolled in the study, patients must meet all the following criteria at screening: 
1. A confirmed genetic diagnosis of PWS. Documentation of PWS subtype (chromosome 
15 micro-deletion versus non-deletion) is also required for the study. If the PWS subtype 
is not known, a sample for testing may be obtained and the patient may continue on to be 
enrolled into the study if he or she meets all the other inclusion criteria and none of the 
exclusion criteria.  
2. Male and female patients 4 to 65 years of age, inclusive, 12 to 65 years of age for 
Australian sites 201 and 202. 
3. Have evidence of increased appetite or hyperphagia, as judged by the investigator, and a 
total HQ-CT score ≥10 (scale of 0-36). 
4. Patients willing to comply with the following lifestyle considerations: 
a. 
Be on a stable diet regimen. 
b. Be on a stable physical activity regimen. Patients should agree to refrain from 
changing their usual level of physical activity. 
5. Each patient must have a single primary caregiver who will be able to evaluate and score 
that patient’s behaviors and perform any study-related activities as defined in the 
protocol throughout the study. That person must have been caring for the patient for at 
least 6 months prior to screening, spend, on average, approximately 4 (or more) waking 
hours per day with the patient, and should be available for the duration of the study. 


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Diagnosis and 
Main Eligibility 
Criteria for 
Inclusion: 
Continued: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a. 
During the Extension Period, the time spent by the caregiver with the patient 
may be reduced, as long as the caregiver spends, on average, approximately 4 
(or more) waking hours per day with the patient at least 2 weeks before each 
visit. 
6. BMI ≤65 kg/m2 for adult patients. 
7. Women of Child Bearing Potential (WCBP) must have a negative pregnancy test. 
8. All WCBP, sexually active male patients, and all opposite sex partners of patients should 
agree to use medically-approved effective methods of birth control (e.g. diaphragm, 
condoms with spermicide) throughout the study and for 30 days after the last dose of 
study drug. 
a. 
WCBP or male patients who agree with a true abstinence (when in line with the 
preferred or usual lifestyle of the patient) can be included.  
9. Adequate renal function, defined as serum creatinine 1.5  upper limit of normal 
(ULN). 
10. Adequate hepatic function, defined as total bilirubin 1.5  ULN and aspartate 
aminotransferase (AST) and alanine aminotransferase (ALT) levels 3  ULN. 
11. Diabetes medications will be permitted if doses have been stable for at least 3 months 
prior to screening. Insulin doses are considered to have been stable if the prescribed total 
daily insulin doses are within approximately 20% of those at screening. 
12. Growth hormone treatment will be permitted if doses have been stable for at least 
1 month prior to screening. 
13. Psychotropic treatment (e.g. modafinil, topiramate, zonisamide, fluoxetine, aripiprazole, 
risperidone, quetiapine, and benzodiazepines) will be permitted if doses have been stable 
for at least 2 months prior to screening. 
14. Any other medication that is likely to affect behavior, body composition, or lipids (in the 
opinion of the investigator) must be stable for at least 2 months prior to screening, except 
as noted below: 
a. 
Thyroid hormone: changes within approximately 13 µg/day are acceptable 
b. Sex steroids: patients on sex steroids must have been taking them for at least 2 
months at screening; dose changes within approximately 25% of the screening 
dose are acceptable as are changes within a class (e.g., from one oral 
contraceptive to another, or from one selective estrogen receptor to another). 
15. Approved informed consent (Assent form for patients under the age of majority), signed 
by the patient, parent, or legal guardian, as appropriate, at the screening visit before any 
study procedures. 
16. For patients from France only: Is either affiliated with or a beneficiary of “sécurité 
sociale”. 
 
PHASE 2b EXCLUSION CRITERIA (CORE PERIOD) 
A patient will be excluded if they meet any of the following criteria at screening: 
1. History of chronic liver disease, such as cirrhosis or chronic hepatitis due to any cause, 
or suspected alcohol abuse. 
2. History of significant cardiovascular disease including history of congestive heart failure 
(CHF, New York Heart Association [NYHA] Class 3 or 4), angina pectoris, or 
myocardial infarction (MI) within 6 months prior to screening. 


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Diagnosis and 
Main Eligibility 
Criteria for 
Inclusion: 
Continued: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3. Type 1 diabetes mellitus. 
4. Glycated hemoglobin (HbA1c) >10%. 
5. History of frequent hypoglycemia. 
6. Blood pressure systolic 160 mmHg, diastolic 90 mmHg (adult patients) and blood 
pressure systolic >140 mmHg, diastolic >90 mmHg (patients 4 to 17 years of age).  
7. Use of weight loss agents and medications taken to affect appetite (e.g. Orlistat®, 
Lorcaserin, Qsymia®, Contrave®/Mysimba®, glucagon-like-peptide 1 [GLP-1] analogs, 
as well as any over-the counter medication and herbal agent) within 2 months prior to 
screening. 
8. Co-morbid condition or disease (such as respiratory disease or psychiatric disorder) 
diagnosed less than 1 month prior to screening. 
9. Co-morbid condition or disease or abnormal laboratory finding that would in the 
investigator’s judgment increase the patient risk to participating in this study or that will 
not allow the patient to complete the study. 
10. Known history of hepatitis B, hepatitis C, or human immunodeficiency virus (HIV). 
11. Participation in a clinical trial with an investigational agent within 3 months prior to 
screening. 
12. Clinically significant abnormalities on electrocardiogram (ECG) at screening, as follows: 
a. 
Patients 4 years of age: males QT interval corrected for heart rate by Bazett’s 
formula (QTcB) >448 ms, females QTcB >442 ms. 
b. Patients 5 to 7 years of age: males QTcB >443 ms, females QTcB >449 ms. 
c. 
Patients 8 to 11 years of age: males QTcB >440 ms, females QTcB >447 ms. 
d. Patients 12 to 15 years of age: males QTcB >449 ms, females QTcB >457 ms. 
e. 
Patients 16 years of age: males QTcB >450 ms, females QTcB >470 ms. 
13. Pregnant or lactating woman. 
14. History of hypersensitivity to drugs with a similar chemical structure or class as 
livoletide (acylated ghrelin [AG] and unacylated ghrelin [UAG]). 
15. Unwillingness or inability to follow the procedures outlined in the protocol. 
16. Patients living in a group home 50% of the time. 
17. Patients with body weight <20 kg. 
EXTENSION PERIOD: 
In order to be able to participate in the Extension Period, patients will be required to have 
completed the Core Period.  
Phase 3 
PHASE 3 INCLUSION CRITERIA (CORE PERIOD) 
To be enrolled in the study, patients must meet all the following criteria at screening: 
1. A confirmed genetic diagnosis of PWS. Documentation of PWS subtype (chromosome 
15 micro-deletion versus non-deletion) is also required for the study. If PWS subtype is 
not known, a sample for testing may be obtained and the patient may continue on to be 
enrolled into the study if he or she meets all the other inclusion criteria and none of the 
exclusion criteria.   
2. Male and female patients 8 to 65 years of age, inclusive. 


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Diagnosis and 
Main Eligibility 
Criteria for 
Inclusion: 
Continued: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3. Have evidence of increased appetite or hyperphagia, as judged by the investigator, and a 
total HQ-CT score ≥10 (scale of 0-36). 
4. Patients willing to comply with the following lifestyle considerations: 
a. 
Be on a stable diet regimen. 
b. Be on a stable physical activity regimen. Patients should agree to refrain from 
changing their usual level of physical activity. 
5. Each patient must have a single primary caregiver who will be able to evaluate and score 
that patient’s behaviors and perform any study-related activities as defined in the 
protocol throughout the study. That person must have been caring for the patient for at 
least 6 months prior to screening, spend, on average, approximately 4 (or more) waking 
hours per day with the patient, and should be available for the duration of the study. 
a. 
During the Extension Period, the time spent by the caregiver with the patient 
may be reduced, as long as the caregiver spends, on average, approximately 4 
(or more) waking hours per day with the patient at least 2 weeks before each 
visit. 
6. BMI ≤65 kg/m2 for adult patients. 
7. WCBP must have a negative pregnancy test. 
8. All WCBP, sexually active male patients, and all opposite sex partners of patients should 
agree to use medically-approved effective methods of birth control (e.g. diaphragm, 
condoms with spermicide) throughout the study and for 30 days after the last dose of 
study drug. 
a. 
WCBP or male patients who agree with a true abstinence (when in line with the 
preferred or usual lifestyle of the patient) can be included.  
9. Adequate renal function, defined as serum creatinine 1.5  ULN. 
10. Adequate hepatic function, defined as total bilirubin 1.5  ULN and AST and ALT 
levels 3  ULN. 
11. Diabetes medications will be permitted if doses have been stable for at least 3 months 
prior to screening. Insulin doses are considered to have been stable if the prescribed total 
daily insulin doses are within approximately 20% of those at screening. 
12. Growth hormone treatment will be permitted if doses have been stable for at least 
1 month prior to screening. 
13. Psychotropic treatment (e.g. modafinil, topiramate, zonisamide, fluoxetine, aripiprazole, 
risperidone, quetiapine, and benzodiazepines) will be permitted if doses have been stable 
for at least 2 months prior to screening. 
14. Any other medication that is likely to affect behavior, body composition, or lipids (in the 
opinion of the investigator) must be stable for at least 2 months prior to screening, except 
as noted below: 
a. 
Thyroid hormone: changes within approximately 13 µg/day are acceptable 
b. Sex steroids: patients on sex steroids must have been taking them for at least 2 
months at screening; dose changes within approximately 25% of the screening 
dose are acceptable as are changes within a class (e.g., from one oral 
contraceptive to another, or from one selective estrogen receptor to another). 
15. Approved informed consent (Assent form for patients under the age of majority) signed 
by the patient, parent, or legal guardian, as appropriate, at the screening visit before any 
study procedures. 


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Diagnosis and 
Main Eligibility 
Criteria for 
Inclusion: 
Continued: 
16. For patients from France only: Is either affiliated with or a beneficiary of “sécurité 
sociale”. 
PHASE 3 EXCLUSION CRITERIA (CORE PERIOD) 
A patient who enrolled in the Phase 2b part is not eligible for recruitment in the Phase 3 
part. 
A patient will be excluded if they meet any of the following criteria at screening: 
1. History of chronic liver disease, such as cirrhosis or chronic hepatitis due to any cause, 
or suspected alcohol abuse. 
2. History of significant cardiovascular disease including history of CHF (NYHA Class 3 
or 4), angina pectoris, or MI within 6 months prior to screening. 
3. Type 1 diabetes mellitus. 
4. HbA1c >10%. 
5. History of frequent hypoglycemia. 
6. Blood pressure systolic 160 mmHg, diastolic 90 mmHg (adult patients), and blood 
pressure systolic >140 mmHg, diastolic >90 mmHg (patients 8 to 17 years of age). 
7. Use of weight loss agents and medications taken to affect appetite (e.g. Orlistat®, 
Lorcaserin, Qsymia®, Contrave®/Mysimba®, GLP-1 analogs, as well as any over-the 
counter medication and herbal agent) within 2 months prior to screening. 
8. Co-morbid condition or disease (such as respiratory disease or psychiatric disorder) 
diagnosed less than 1 month prior to screening. 
9. Co-morbid condition or disease or abnormal laboratory finding that would in the 
investigator’s judgment increase the patient risk to participating in this study or that will 
not allow the patient to complete the study. 
10. Known history of hepatitis B, hepatitis C, or HIV. 
11. Participation in a clinical trial with an investigational agent within 3 months prior to 
screening. 
12. Patients who participated in the Phase 2b part of the study. 
13. Clinically significant abnormalities on ECG at screening, as follows: 
a. 
Patients 8 to 11 years of age: males QTcB >440 ms, females QTcB >447 ms. 
b. Patients 12 to 15 years of age: males QTcB >449 ms, females QTcB >457 ms. 
c. 
Patients 16 years of age: males QTcB >450 ms, females QTcB >470 ms. 
14. Pregnant or lactating woman. 
15. History of hypersensitivity to drugs with a similar chemical structure or class as 
livoletide (AG and UAG). 
16. Unwillingness or inability to follow the procedures outlined in the protocol. 
17. Patients living in a group home 50% of the time. 
18. Patients with body weight <20 kg. 
EXTENSION PERIOD: 
In order to be able to participate in the Extension Period, patients will be required to have 
completed the Core Period. 
Based on results from Phase 2b, some inclusion criteria for the Phase 3 Core and Extension 
Periods may be adjusted. 


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Dosage, Form, 
and Route of 
Administration 
for Livoletide:  
Livoletide will be administered by subcutaneous (SC) injection at rotating sites on the abdomen. 
Livoletide must be kept refrigerated at 2 to 8°C (36 to 46°F).  
The inclusion criterion age range of 4 to 65 years is expected to correspond to a BW range of ~20 
to 140 kg. Therefore, livoletide will be dosed according to BW on a µg/kg basis and will be 
provided as a sterile liquid formulation (in 0.9% sodium chloride [NaCl] solution) in single-use 
clear glass vials. Two concentrations of livoletide will be available for this study, 8 mg/mL and 
16 mg/mL. The volume of dosing will be adjusted according to BW (see table below) to achieve 
targeted livoletide exposure levels of approximately 60 µg/kg and 120 µg/kg (i.e. 8 mg/mL, low 
exposure or 16 mg/mL, high exposure).  
 
Low exposure 
(8 mg/mL) 
High exposure 
(16 mg/mL) 
Body weight range (kg) 
Daily injection volume (mL) 
Daily injection volume (mL) 
20.0 to 29.0 
0.125 
0.125 
30.0 to 49.0 
0.250 
0.250 
50.0 to 70.0 
0.375 
0.375 
>70.0 
0.500 
0.500 
The exposure dosing will be adjusted if there is any weight change at the 3-month visit at the end 
of the Core Period in Phase 2b or at the 6-month visit at the end of the Core Period in Phase 3. 


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Reference 
Therapy, 
Dosage, and 
Mode of 
Administration:  
Matching placebo to the livoletide study drug will be a 0.9% NaCl solution and will be provided 
as a sterile liquid formulation in single-use clear glass vials. Placebo will be administered at the 
same volume as livoletide by SC injection at rotating sites on the abdomen. Placebo must be kept 
refrigerated at 2 to 8°C (36 to 46°F). 
Criteria for 
Evaluation: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Phase 2b 
PHASE 2b CORE PERIOD 
Primary endpoint: 
Change from baseline to the end of the 3-month Core Period for HQ-CT total score. 
Secondary Endpoints: 
 
Percentage change from baseline to the end of the 3-month Core Period in total body fat 
mass in overweight/obese patients with PWS;  
 
Change from baseline to the end of the 3-month Core Period in WC in overweight/obese 
patients with PWS; 
 
Percentage change from baseline to the end of the 3-month Core Period in BW in 
overweight/obese patients with PWS. 
Safety Endpoints: 
 
Incidence of adverse events (AEs); 
 
Vital signs; 
 
Height and BMI; 
 
Physical examinations; 
 
Lean body mass and bone mineral density; 
 
ECG; 
 
Safety laboratory parameters (clinical chemistry including lipids, coagulation, 
hematology, urinalysis, HbA1c, ghrelin, anti-drug antibodies [ADA], and insulin-like 
growth factor-1 [IGF-1]). 
Pharmacokinetic Endpoints: 
The PK endpoints will be described in details in the SAP and will include as the data allow: Cmax, 
Tmax, AUC0-4, and other PK parameters of livoletide  
Additional Endpoints: 
 
Change from baseline in: 
 
CgGIS-H and CGIS-H scores; 
 
CgGIC-H and CGIC-H scores; 
 
CGI-I score; 
 
CGI-S score; 
 
Fasting (for approximately 8 hours) and postprandial glucose and insulin 
measurement (profile); 
 
Appetite-NRS score; 
 
DBC2-P score; 


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Criteria for 
Evaluation 
Continued: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PedsQLTM Parent-Proxy age-appropriate Reports score; 
 
ZBI score; 
 
EQ-5D-5L Self score and EQ-5D-5L Proxy version 1 score; 
 
Evaluation of the measurement properties and interpretation of clinically meaningful 
HQ-CT change in the study population using blinded study data and according to a 
psychometric analysis plan; 
 
Responder definition using anchor-based methods supplemented with both cumulative 
distribution function (CDF) and probability density function (PDF) to derive the 
responder threshold for meaningful change; 
 
Percentage of HQ-CT responders as defined by anchor-based and distribution-based 
methods. 
PHASE 2b EXTENSION PERIOD 
Efficacy Endpoints: 
 
Change from baseline to the end of the 9-month Extension Period and change from the 
end of the 3-month Core Period to the end of the 9-month Extension Period in HQ-CT 
total score; 
 
Percentage change from baseline to the end of the 9-month Extension Period and change 
from the end of the 3-month Core Period to the end of the 9-month Extension Period in 
total body fat mass in overweight/obese patients with PWS;  
 
Change from baseline to the end of the 9-month Extension Period and change from the 
end of the 3-month Core Period to the end of the 9-month Extension Period in WC in 
overweight/obese patients with PWS; 
 
Percentage change from baseline to the end of the 9-month Extension Period and change 
from the end of the 3-month Core Period to the end of the 9-month Extension Period in 
BW in overweight/obese patients with PWS. 
Safety Endpoints: 
 
Incidence of AEs; 
 
Vital signs; 
 
Height and BMI; 
 
Physical examinations; 
 
Lean body mass and bone mineral density; 
 
ECG; 
 
Safety laboratory parameters (clinical chemistry including lipids, coagulation, 
hematology, urinalysis, HbA1c, ghrelin, ADA, and IGF-1). 
Pharmacokinetic endpoints: 
Plasma livoletide PK parameters will be derived using non-compartmental methods. 
Where possible, the following PK parameters will be determined. Additional parameters may 
also be calculated as appropriate. 
Maximum concentration (Cmax); time of Cmax (tmax); observed minimum concentration (Cmin); 
time of Cmin (tmin); average concentration during the dosing interval (Cavg); fluctuation index over 
the dosing interval (FI); area under the concentration-time curve during the dosing interval 
(AUC(0-tau)); apparent terminal rate constant (λz); apparent terminal half-life (t1/2); apparent total 


Protocol Code Number: AZP01-CLI-003 
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Version 1.2, July 31st, 2019 
Criteria for 
Evaluation 
Continued: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
body clearance (CL/F); apparent volume of distribution (Vz/F); accumulation ratio for AUC(0-tau) 
(RAUC(0-tau)); accumulation ratio for Cmax (RCmax); and linearity index (LI) as appropriate. 
 
Endpoints for Additional Assessments: 
 
Change from baseline in: 
 
CgGIS-H and CGIS-H scores; 
 
CgGIC-H and CGIC-H scores; 
 
CGI-I score; 
 
CGI-S score; 
 
Fasting (for approximately 8 hours) glucose and insulin measurement; 
 
DBC2-P score; 
 
PedsQLTM Parent-Proxy age-appropriate Reports score; 
 
ZBI score; 
 
EQ-5D-5L Self score and EQ-5D-5L Proxy version 1 score; 
 
Percentage of HQ-CT responders as defined by anchor-based and distribution-based 
methods. 
Phase 3 
PHASE 3 CORE PERIOD 
Primary endpoint: 
Change from baseline to the end of the 6-month Core Period for HQ-CT total score. 
Secondary Endpoints: 
 
Percentage change from baseline to the end of the 6-month Core Period in total body fat 
mass in overweight/obese patients with PWS;  
 
Change from baseline to the end of the 6-month Core Period in WC in overweight/obese 
patients with PWS; 
 
Percentage change from baseline to the end of the 6-month Core Period in BW in 
overweight/obese patients with PWS. 
Safety Endpoints: 
 
Incidence of AEs; 
 
Vital signs; 
 
Height and BMI; 
 
Physical examinations; 
 
Lean body mass and bone mineral density; 
 
ECG; 
 
Safety laboratory parameters (clinical chemistry including lipids, coagulation, 
hematology, urinalysis, HbA1c, ghrelin, ADA, and IGF-1). 
 
 


Protocol Code Number: AZP01-CLI-003 
Confidential & Proprietary 
Page 27 of 172 
Version 1.2, July 31st, 2019 
Criteria for 
Evaluation 
Continued: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Additional Endpoints: 
 
Change from baseline in: 
 
CgGIS-H and CGIS-H scores; 
 
CgGIC-H and CGIC-H scores; 
 
CGI-I score; 
 
CGI-S score; 
 
Fasting (for approximately 8 hours) and postprandial glucose and insulin 
measurement (profile); 
 
Appetite-NRS score; 
 
DBC2-P score; 
 
PedsQLTM Parent-Proxy age-appropriate Reports score; 
 
ZBI score; 
 
EQ-5D-5L Self score and EQ-5D-5L Proxy version 1 score; 
 
Percentage of HQ-CT responders as defined by anchor-based and distribution-based 
methods. 
PHASE 3 EXTENSION PERIOD 
Efficacy Endpoints: 
 
Change from baseline to the end of the 6-month Extension Period and change from the 
end of the 6-month Core Period to the end of the 6-month Extension Period in HQ-CT 
total score; 
 
Percentage change from baseline to the end of the 6-month Extension Period and change 
from the end of the 6-month Core Period to the end of the 6-month Extension Period in 
total body fat mass in overweight/obese patients with PWS;  
 
Change from baseline to the end of the 6-month Extension Period and change from the 
end of the 6-month Core Period to the end of the 6-month Extension Period in WC in 
overweight/obese patients with PWS; 
 
Percentage change from baseline to the end of the 6-month Extension Period and change 
from the end of the 6-month Core Period to the end of the 6-month Extension Period in 
BW in overweight/obese patients with PWS. 
Safety Endpoints: 
 
Incidence of AEs; 
 
Vital signs; 
 
Height and BMI; 
 
Physical examinations; 
 
Lean body mass and bone mineral density; 
 
ECG; 
 
Safety laboratory parameters (clinical chemistry including lipids, coagulation, 
hematology, urinalysis, HbA1c, ghrelin, ADA, and IGF-1). 
 


Protocol Code Number: AZP01-CLI-003 
Confidential & Proprietary 
Page 28 of 172 
Version 1.2, July 31st, 2019 
Criteria for 
Evaluation 
Continued: 
 
 
Endpoints for Additional Assessments: 
 
Change from baseline in: 
 
CgGIS-H and CGIS-H scores; 
 
CgGIC-H and CGIC-H scores; 
 
CGI-I score; 
 
CGI-S score; 
 
Fasting (for approximately 8 hours) glucose and insulin measurement; 
 
DBC2-P score; 
 
PedsQLTM Parent-Proxy age-appropriate Reports score; 
 
ZBI score; 
 
EQ-5D-5L Self score and EQ-5D-5L Proxy version 1 score; 
 
Percentage of HQ-CT responders as defined by anchor-based and distribution-based 
methods. 
Data Analysis: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Phase 2b 
PHASE 2b CORE PERIOD 
Efficacy: The primary analysis for the primary efficacy endpoint will be done using a mixed 
model repeated measures analysis (MMRM) on the change-from-baseline HQ-CT total score 
within the first 3 months. As a supportive analysis, an analysis of covariance (ANCOVA) on the 
change-from-baseline HQ-CT total score at 3months will be performed.  
Safety: All safety data will be listed by treatment group, variable, visit, and time point (if 
applicable) for individual patients. Adverse events will be tabulated and summarized according 
to the Medical Dictionary for Regulatory Activities (MedDRA). Safety laboratory evaluations, 
12-lead ECG parameters, vital signs, physical examinations, and the other safety assessments 
(e.g. BMI, lipid profiles, HbA1c, lean body mass, etc.) will be summarized descriptively. 
PHASE 2b EXTENSION PERIOD 
Efficacy: An MMRM approach will be used to compare the change from baseline to the end of 
the 9-month Extension Period and the change from the end of the 3-month Core Period to the end 
of the 9-month Extension Period in HQ-CT total score. Similar statistical approaches will be 
used for the analyses of the secondary endpoints and additional assessments. 
Safety: All safety data will be listed by treatment group, variable, visit, and time point (if 
applicable) for individual patients. Adverse events will be tabulated and summarized according 
to MedDRA. Safety laboratory evaluations, 12-lead ECG parameters, vital signs, physical 
examinations, and the other safety assessments (e.g. BMI, lipid profiles, HbA1c, lean body mass, 
etc.) will be summarized descriptively. 
Phase 3 
Data analysis will be comparable to Phase 2b. 
PHASE 3 CORE PERIOD 
Efficacy: The primary analysis for the primary efficacy endpoint will be done using a mixed 
model repeated measures analysis (MMRM) on the change-from-baseline HQ-CT total score 
within the first 3 months. As a supportive analysis, an ANCOVA on the change-from-baseline 
HQ-CT total score at 6 months will be performed.  
Safety: All safety data will be listed by treatment group, variable, visit, and time point (if 
applicable) for individual patients. Adverse events will be tabulated and summarized according 


Protocol Code Number: AZP01-CLI-003 
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Page 29 of 172 
Version 1.2, July 31st, 2019 
 
Data Analysis 
Continued: 
 
 
 
 
to MedDRA. Safety laboratory evaluations, 12-lead ECG parameters, vital signs, physical 
examinations, and the other safety assessments (e.g. BMI, lipid profiles, HbA1c, lean body mass, 
etc.) will be summarized descriptively. 
PHASE 3 EXTENSION PERIOD 
Efficacy: An MMRM approach will be used to compare the change from baseline to the end of 
the 6-month Extension Period and the change from the end of the 6-month Core Period to the end 
of the 6-month Extension Period in HQ-CT total score. Similar statistical approaches will be 
used for the analyses of the secondary endpoints and additional assessments. 
Safety: All safety data will be listed by treatment group, variable, visit, and time point (if 
applicable) for individual patients. Adverse events will be tabulated and summarized according 
to MedDRA. Safety laboratory evaluations, 12-lead ECG parameters, vital signs, physical 
examinations, and the other safety assessments (e.g. BMI, lipid profiles, HbA1c, lean body mass, 
etc.) will be summarized descriptively. 
Safety 
Endpoints for 
the DMC 
review: 
Safety data review will be performed at a regular basis during the trials by an external Data 
Monitoring Committee (DMC) operating independently of the Sponsor. The DMC will make 
recommendations for the conduct of the study based on safety data. 
 
 
 
 
 


Protocol Code Number: AZP01-CLI-003 
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Version 1.2, July 31st, 2019 
1.2 
Schedule of Activities 
1.2.1 
Schedule of Activities for Phase 2b Core Period 
Study Stage 
Phase 2b Core Period 
Screening1 
Double-blind Treatment Period 
Visit# 
 
Randomization2 
 
 
End of Core 
Period/ 
/ET 
Discontinuation 
V1 
V2 
V3 
V4 
V5 
Study Week(s) 
-4 to -1 
1 
5 
9 
13 
Treatment Duration (weeks/months) 
- 
- 
4/1 
8/2 
12/3 
Study Day(s) 
-28 to -1 
1 
29 
57 
85 
Visit Window (±X days) 
0 
0 
3 
3 
3 
Informed consent and assign a study specific 
patient number 
X 
 
 
 
 
Demography 
X 
 
 
 
 
Medical history3 
X 
 
 
 
 
Disease history4 
X 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
IQ test5 
X 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
Physical examination6 
X (C) 
X (C) 
X (A) 
X (A) 
X (C) 
Vital signs7 
X 
X 
X 
X 
X 
WC, BW, and BMI8 
X 
X 
X 
X 
X 
Height9 
X 
X 
X 
X 
X 
12-lead ECG10 
X 
X10 
 
 
X 
DXA (total body fat mass, lean body mass, bone 
mineral density)11 
 
X 
 
 
X 
                                                 
1 The screening period is up to 4 weeks. 
2 The randomization visit will occur a minimum of 2 weeks after the screening visit. 
3 Complete medical history will be obtained at screening and any clinically significant changes from the screening visit will be reported as AEs. 
4 A confirmed genetic diagnosis of PWS. Documentation of PWS subtype (chromosome 15 micro-deletion versus non-deletion) is also required 
for the study. If the PWS subtype is not known, a sample for testing may be obtained and the patient may continue on to be enrolled into the 
study if he or she meets all the other inclusion criteria and none of the exclusion criteria.   
5 Collect IQ scores and dates of completion if available in patient’s medical record. 
6 “C” for complete physical examination, “A” for abbreviated physical examination. See Section 10.1.4 for assessments to be performed during a 
physical examination. 
7 Vital signs (respiration rate, pulse rate, and blood pressure) will be measured sitting after the patient has rested comfortably for 5 minutes. See 
Section 10.1.2. 
8 Before breakfast. See Section 9.1.3 and Section 9.1.4. 
9 Before breakfast. See Section 10.1.3.  
10 See Section 10.1.6. 
11 DXA can be obtained within 2 weeks prior to randomization (Visit 2) and the End of Core Period visit (Visit 5). See Section 9.1.2 and 
Section 10.1.5. 


Protocol Code Number: AZP01-CLI-003 
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Version 1.2, July 31st, 2019 
Study Stage 
Phase 2b Core Period 
Screening1 
Double-blind Treatment Period 
Visit# 
 
Randomization2 
 
 
End of Core 
Period/ 
/ET 
Discontinuation 
V1 
V2 
V3 
V4 
V5 
Study Week(s) 
-4 to -1 
1 
5 
9 
13 
Treatment Duration (weeks/months) 
- 
- 
4/1 
8/2 
12/3 
Study Day(s) 
-28 to -1 
1 
29 
57 
85 
Visit Window (±X days) 
0 
0 
3 
3 
3 
Pregnancy test12 
X 
X 
X 
X 
X 
Safety laboratory evaluations in the fasting 
condition13 
X 
X 
X 
 
X 
Blood samples for PK analysis14 
 
 
X 
 
 
Blood samples for HbA1c 
X 
X 
 
 
X 
Blood samples for glucose and insulin profiles15 
 
X 
X 
 
X 
Blood samples for AG and UAG profiles15 
 
X 
X 
 
X 
Blood samples for IGF-1 
 
X 
 
 
X 
Blood samples for ADA analysis 
 
X 
X 
 
X 
Review and completion of questionnaires on 
eDevice 16 
X 
X 
X 
X 
X 
Isocaloric breakfast taken on site and report any 
food not consumed17 
 
X 
X 
 
X 
Appetite-NRS17 
X 
X 
X 
 
X 
HQ-CT  
X 
X 
X 
X 
X 
Quality of Life: PedsQLTM Parent-Proxy Report 
 
X 
 
 
X 
CgGIS-H 
 
X 
X 
X 
X 
CGIS-H 
 
X 
X 
X 
X 
CgGIC-H 
 
 
X 
X 
X 
CGIC-H 
 
 
X 
X 
X 
CGI-I  
 
 
X 
X 
X 
CGI-S  
 
X 
X 
X 
X 
Caregiver Disease Burden: ZBI 
 
X 
 
 
X 
EQ-5D-5L Self-complete version and Proxy 
version 1 
 
X 
 
 
X 
DBC2-P 
 
X 
 
 
X 
                                                 
12 Pregnancy tests will be performed for women of childbearing potential only. See Section 8.1.2.2.3. 
13 Blood samples will be collected after fasting for approximately 8 hours. Clinical serum chemistries, hematology, coagulation, and urinalysis 
parameters are described in Section 8.1.2. Clinical laboratory evaluations will be performed centrally.  
14 PK samples (3-timepoint sampling) will be collected at the same time as glucose/insulin/AG/UAG profiles  as outlined in the Pharmacokinetic 
Schedule of Activities provided in Section 1.2.3. 
15 Blood samples for glucose, insulin, AG, and UAG profiles will be collected after fasting for approximately 8 hours (all patients) and 30 minutes 
and 180 minutes post-start of an isocaloric breakfast (only patients 8 to 65 years of age).  
16 The eDevice will be used to collect data from all questionnaires and the appetite-NRS. Data from the questionnaires and appetite-NRS will be 
completed on the eDevice while on site, either by the caregiver, the patient (for the NRS), or by the investigator. The eDevice will not be 
dispensed to the patients. 
17 Appetite-NRS should be administered (only to patients 8 to 65 years of age) before (after fasting for approximately 8 hours), at the end, and 
120 minutes post-start of an isocaloric breakfast, except at the screening visit, where NRS will be administered for training and acclimation 
purposes (no profile). Food not consumed when administered the isocaloric breakfast needs to be recorded. On-site consumption of isocaloric 
breakfast is not required for patients 4 to 7 years old. 


Protocol Code Number: AZP01-CLI-003 
Confidential & Proprietary 
Page 32 of 172 
Version 1.2, July 31st, 2019 
Study Stage 
Phase 2b Core Period 
Screening1 
Double-blind Treatment Period 
Visit# 
 
Randomization2 
 
 
End of Core 
Period/ 
/ET 
Discontinuation 
V1 
V2 
V3 
V4 
V5 
Study Week(s) 
-4 to -1 
1 
5 
9 
13 
Treatment Duration (weeks/months) 
- 
- 
4/1 
8/2 
12/3 
Study Day(s) 
-28 to -1 
1 
29 
57 
85 
Visit Window (±X days) 
0 
0 
3 
3 
3 
Review/record AEs 
X-------------------------------------------------------------------------------------------------------------
------------------------X 
Randomization via IRT18 
 
X 
 
 
 
Dispensation of glucometer kit19 
 
X 
 
 
 
Dispensation of study drug 
 
X 
X 
X 
X 
Drug accountability  
 
 
X 
X 
X 
On-site study drug administration 
(during treatment period only) 
 
X 
X 
X 
X 
Abbreviations: ADA=anti-drug antibodies; AEs=adverse events; AG=acylated ghrelin; BMI=body mass index; BW=body weight; CgGIC-
H=Caregiver Global Impression of Change – Hyperphagia; CgGIS-H=Caregiver Global Impression of Severity – Hyperphagia; CGIC-
H=Clinical Global Impression of Change – Hyperphagia; CGI-I=Clinical Global Impression of Improvement; CGI-S=Clinical Global Impression 
of Severity; CGIS-H=Clinical Global Impression of Severity – Hyperphagia; DBC2-P=Developmental Behavior Checklist 2-Parent/Carer 
version; DXA= dual energy X-ray absorptiometry; DNA=deoxyribonucleic acid; ECG=electrocardiogram; eDevice=electronic device; EQ-5D-
5L=European Quality of Life Five Dimension Five Level Scale; ET=Early Treatment; HbA1c=glycated hemoglobin; HQ-CT=Hyperphagia 
Questionnaire for Clinical Trials; IGF-1=insulin-like growth factor-1; IQ=Intelligence Quotient; IRT=Interactive Response Technology; 
NRS=Numerical Rating Scale; PedsQLTM=Pediatric Quality of Life inventoryTM; T2D=type 2 diabetes mellitus; UAG=unacylated ghrelin; 
V=visit; 
WC=waist 
circumference; 
ZBI= 
Zarit 
Burden 
Interview.
                                                 
18 Randomization via IRT should be performed on the first day of the double-blind treatment period. 
19 Glucometer will be provided to patients with T2D if necessary (i.e. if they do not have one). 


Protocol Code Number: AZP01-CLI-003 
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Version 1.2, July 31st, 2019 
 
1.2.2 
Schedule of Activities for Phase 2b Extension Period 
Study Stage 
Phase 2b Extension Period 
End of 
Study 
 
 
 
 
End of Extension Period/ 
Early Treatment 
Discontinuation 
Telephone 
Follow-up 
Visit # 
V6 
V7 
V8 
V9 
V10 
Study Week(s) 
18 
27 
40 
53 
57 
Treatment Duration (weeks/months)  
17/4 
26/6 
39/9 
52/12 
- 
Study Day(s) 
120 
183 
274 
365 
393 
Visit Window (±X days) 
4 
7 
7 
7 
7 
Concomitant medications 
X 
X 
X 
X 
X 
Physical Examination1 
X (C) 
X (C) 
X (A) 
X (C) 
 
Vital Signs2 
X 
X 
X 
X 
 
WC, BW, and BMI3 
X 
X 
X 
X 
 
Height4 
X 
X 
X 
X 
 
12-lead ECG5 
 
X6 
 
X 
 
DXA (total body fat mass, lean body 
mass, bone mineral density)6 
 
X 
 
X 
 
Pregnancy test7 
X 
X 
X 
X 
 
Safety laboratory evaluations in the 
fasting condition8 
X 
X 
X 
X 
 
Blood samples for HbA1c 
 
X 
X 
X 
 
Blood samples for fasting glucose and 
insulin9 
 
X 
X 
X 
 
Blood samples for fasting AG and UAG 
analyses9 
 
X 
 
X 
 
Blood sample for IGF-1 
 
X 
 
X 
 
Blood sample for ADA analysis 
 
X 
 
X 
 
                                                 
1 “C” for complete physical examination, “A” for abbreviated physical examination. See Section 10.1.4 for assessments to be performed during a 
physical examination. 
2 Vital signs (respiration rate, pulse rate, and blood pressure) will be measured sitting after the patient has rested comfortably for 5 minutes. See 
Section 10.1.2. 
3 Before breakfast. See Section 9.1.3 and Section 9.1.4. 
4 Before breakfast. See Section 10.1.3. 
5 See Section 10.1.6. 
6 DXA can be obtained within 2 weeks prior to visit 7 and the End of Extension Period visit (Visit 9). See Section 9.1.2 and Section 10.1.5 
7 Pregnancy tests will be performed for women of childbearing potential only. See Section 8.1.2.2.3. 
8 Blood samples will be collected after fasting for approximately 8 hours. Clinical serum chemistries, hematology, coagulation, and urinalysis 
parameters are described in Section 8.1.2. Clinical laboratory evaluations will be performed centrally.  
9 Blood samples will be collected after fasting for approximately 8 hours.  
 


Protocol Code Number: AZP01-CLI-003 
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Version 1.2, July 31st, 2019 
Study Stage 
Phase 2b Extension Period 
End of 
Study 
 
 
 
 
End of Extension Period/ 
Early Treatment 
Discontinuation 
Telephone 
Follow-up 
Visit # 
V6 
V7 
V8 
V9 
V10 
Study Week(s) 
18 
27 
40 
53 
57 
Treatment Duration (weeks/months)  
17/4 
26/6 
39/9 
52/12 
- 
Study Day(s) 
120 
183 
274 
365 
393 
Visit Window (±X days) 
4 
7 
7 
7 
7 
Blood samples for PK analysis10 
X 
X 
 
 
 
Review and completion of questionnaires 
on eDevice  
X 
X 
X 
X 
 
HQ-CT 
X 
X 
X 
X 
 
Quality of Life: PedsQLTM Parent-Proxy 
Report 
 
X 
 
X 
 
CgGIS-H 
X 
X 
X 
X 
 
CGIS-H 
X 
X 
X 
X 
 
CgGIC-H 
X 
X 
X 
X 
 
CGIC-H 
X 
X 
X 
X 
 
CGI-I  
X 
X 
X 
X 
 
CGI-S  
X 
X 
X 
X 
 
Caregiver Disease Burden: ZBI 
 
X 
 
X 
 
EQ-5D-5L Self-complete version and 
Proxy version 1 
 
X 
 
X 
 
DBC2-P 
 
X 
 
X 
 
Review/record AEs 
X------------------------------------------------------------------------------------------------------------------------
---------------------X 
Dispensation of study drug (livoletide)  
X 
X 
X 
 
 
Drug accountability 
X 
X 
X 
X 
 
On-site livoletide administration  
X 
X 
X 
X 
 
Abbreviations: ADA=anti-drug antibodies; AEs=adverse events; AG=acylated ghrelin; BMI=body mass index; BW=body weight; CgGIC-H=Caregiver 
Global Impression of Change – Hyperphagia; CgGIS-H=Caregiver Global Impression of Severity – Hyperphagia; CGIC-H=Clinical Global Impression of 
Change – Hyperphagia; CGI-I=Clinical Global Impression of Improvement; CGI-S=Clinical Global Impression of Severity; CGIS-H=Clinical Global 
Impression of Severity – Hyperphagia; DBC2-P=Developmental Behavior Checklist 2-Parent/Carer version; DXA= dual energy X-ray absorptiometry; 
ECG=electrocardiogram; eDevice=electronic device; EQ-5D-5L=European Quality of Life Five Dimension Five Level Scale; HbA1c=glycated 
hemoglobin; HQ-CT=Hyperphagia Questionnaire for Clinical Trials; IGF-1=insulin-like growth factor-1; PedsQLTM=Pediatric Quality of Life 
inventoryTM; PK=pharmacokinetic; UAG=unacylated ghrelin; V=visit; WC=waist circumference; ZBI= Zarit Burden Interview. 
 
 
 
                                                 
10 PK samples (profile or sparse sampling) will be collected as outlined in the Pharmacokinetic Schedule of Activities provided in Section 1.2.3. 


Protocol Code Number: AZP01-CLI-003 
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Version 1.2, July 31st, 2019 
1.2.3 
Pharmacokinetic Schedule of Activities 
Pharmacokinetic sampling –  
Visit 3 (Week 5/Day 
29) 
3-timepoint Sampling (all patients) 
Blood samples should be drawn at the same time as 
glucose/insulin/AG/UAG profiles  
Pre-dose 
30 min post start of breakfast  
180 min post start of breakfast 
 
Visit 6 (Week 18/Day 
120) 
Profile Sampling (up to 20 patients per dose group) 
Pre-dose  
0.5 (± 2 min), 1 (± 5 min), 2 (± 5 min), 4 (± 5 min), 7 (± 60 min) 
hours post-dose 
 
Sparse Sampling (all patients not included in profile sampling) 
Pre-dose 
1.5 hours (± 30 min) post-dose  
3.5 hours (± 30 min) post-dose 
Visit 7 (Week 27/Day 
183) 
Sparse Sampling (all patients) 
Pre-dose 
1.5 hours (± 30 min) post-dose  
3.5 hours (± 30 min) post-dose 
Abbreviations: min=minutes. 
 


Protocol Code Number: AZP01-CLI-003 
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Version 1.2, July 31st, 2019 
1.2.4 
Schedule of Activities for Phase 3 Core Period 
Study Stage 
Phase 3 Core Period 
Screening1 
Double-blind Treatment Period 
Visit# 
 
Randomizati
on2 
 
 
 
 
End of Core 
Period 
/ET 
Discontinuation 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
Study Week(s) 
-4 to -1 
1 
5 
9 
13 
18 
27 
Treatment Duration (weeks/months) 
- 
- 
4/1 
8/2 
12/3 
17/4 
26/6 
Study Day(s) 
-28 to -1 
1 
29 
57 
85 
120 
183 
Visit Window (±X days) 
0 
0 
3 
3 
3 
3 
3 
Informed Consent and assign a study 
specific patient number 
X 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
Medical History3 
X 
 
 
 
 
 
 
Disease History4 
X 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
X 
 
 
 
 
 
 
IQ test5 
X 
 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
Physical Examination6 
X (C) 
X (C) 
X (C) 
X (A) 
X (C) 
X (A) 
X (C) 
Vital Signs7 
X 
X 
X 
X 
X 
X 
X 
WC, BW, and BMI8 
X 
X 
X 
X 
X 
X 
X 
Height9 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG10 
X 
X 
 
 
 
 
X 
DXA (total body fat mass, lean body mass, 
bone mineral density)11 
 
X 
 
 
X 
 
X 
Pregnancy test12 
X 
X 
X 
X 
X 
X 
X 
Safety laboratory evaluations in the fasting 
condition 13 
X 
X 
X 
X 
X 
X 
X 
Blood samples for HbA1c 
X 
X 
 
 
X 
 
X 
Blood samples for glucose and insulin 
profile14 
 
X 
X 
 
X 
 
X 
                                                 
1 The screening period is up to 4 weeks. 
2 The randomization visit will occur a minimum of 2 weeks after the screening visit. 
3 Complete medical history will be obtained at screening and any clinically significant changes from the screening visit will be reported as 
AEs. 
4 Diagnosis of PWS confirmed by DNA testing. Documentation of PWS subtype (chromosome 15 micro-deletion versus non-deletion) is also 
required for the study. If the PWS subtype is not known, a sample for testing may be obtained and the patient may continue on to be enrolled 
into the study if he or she meets all the other inclusion criteria and none of the exclusion criteria.   
5 Collect IQ scores and dates of completion if available in patient’s medical record. 
6 “C” for complete physical examination, “A” for abbreviated physical examination. See Section 10.1.4 for assessments to be performed 
during a physical examination. 
7 Vital signs (respiration rate, pulse rate, and blood pressure) will be measured sitting after the patient has rested comfortably for 5 minutes. 
See Section 10.1.2. 
8 Before breakfast. See Section 9.1.3 and Section 9.1.4. 
9 Before breakfast. See Section 10.1.3.  
10 See Section 10.1.6. 
11 DXA can be obtained within 2 weeks prior to the randomization (Visit 2), to Visit 5 and to End of Core Period visit (Visit 7). See Section 
9.1.2 and Section 10.1.5. 
12 Pregnancy tests will be performed for women of childbearing potential only. See Section 8.1.2.2.3. 
13 Blood samples will be collected after fasting for approximately 8 hours. Clinical serum chemistries, hematology, coagulation, urinalysis 
parameters are described in Section 8.1.2. Clinical laboratory evaluations will be performed centrally.  


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Study Stage 
Phase 3 Core Period 
Screening1 
Double-blind Treatment Period 
Visit# 
 
Randomizati
on2 
 
 
 
 
End of Core 
Period 
/ET 
Discontinuation 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
Study Week(s) 
-4 to -1 
1 
5 
9 
13 
18 
27 
Treatment Duration (weeks/months) 
- 
- 
4/1 
8/2 
12/3 
17/4 
26/6 
Study Day(s) 
-28 to -1 
1 
29 
57 
85 
120 
183 
Visit Window (±X days) 
0 
0 
3 
3 
3 
3 
3 
Blood samples for AG and UAG profile14 
 
X 
X 
 
X 
 
X 
Blood samples for IGF-1 
 
X 
 
 
X 
 
X 
Blood samples for ADA analysis 
 
X 
 
 
X 
 
X 
Isocaloric breakfast on site and report any 
food not consumed 
 
X 
X 
 
X 
 
X 
Review and completion of questionnaires 
on eDevice15 
X 
X 
X 
X 
X 
X 
X 
Appetite-NRS16 
X 
X 
X 
 
X 
 
X 
HQ-CT  
X 
X 
X 
X 
X 
X 
X 
Quality of Life: PedsQLTM Parent-Proxy 
Report 
 
X 
 
 
X 
 
X 
CgGIS-H 
 
X 
X 
X 
X 
X 
X 
CGIS-H 
 
X 
X 
X 
X 
X 
X 
CgGIC-H 
 
 
X 
X 
X 
X 
X 
CGIC-H 
 
 
X 
X 
X 
X 
X 
CGI-I  
 
 
X 
X 
X 
X 
X 
CGI-S  
 
X 
X 
X 
X 
X 
X 
Caregiver Disease Burden: ZBI 
 
X 
 
 
X 
 
X 
EQ-5D-5L Self-complete version and 
Proxy version 1 
 
X 
 
 
X 
 
X 
DBC2-P 
 
X 
 
 
X 
 
X 
Review/record AEs 
X----------------------------------------------------------------------------------------------------------------
----------------------X 
Randomization via IRT17 
 
X 
 
 
 
 
 
Dispensation of glucometer kit18 
 
X 
 
 
 
 
 
Dispensation of study drug 
 
X 
X 
X 
X 
X 
X 
Drug accountability  
 
 
X 
X 
X 
X 
X 
On-site 
placebo 
or 
livoletide 
administration 
 
X 
X 
X 
X 
X 
X 
                                                                                                                                                                  
14 Blood samples for glucose, insulin, AG, and UAG profiles will be collected after fasting for approximately 8 hours and 30 minutes and 180 
minutes post-start of an isocaloric breakfast. 
15 The eDevice will be used to collect data from all questionnaires and the appetite-NRS. Data from the questionnaires and appetite-NRS will 
be completed on the eDevice while on site, either by the caregiver, the patient (for the NRS), or by the investigator. The eDevice will not be 
dispensed to the patients. 
16 Appetite-NRS should be administered to patients before (after fasting for approximately 8 hours), at the end, and 120 minutes post-start of 
an isocaloric breakfast, except at the screening visit where NRS will be administered for training and acclimation purposes (no profile). 
Food not consumed when administered the isocaloric breakfast needs to be recorded. 
17 Randomization via IRT should be performed on the first day of the double-blind treatment period. 
18 Glucometer will be provided to patients with T2D if necessary (i.e. if they do not have one). 


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Abbreviations: ADA=anti-drug antibodies; AEs=adverse events; AG=acylated ghrelin; BMI=body mass index; BW=body weight; CgGIC-
H=Caregiver Global Impression of Change – Hyperphagia; CgGIS-H=Caregiver Global Impression of Severity – Hyperphagia; CGIC-H=Clinical 
Global Impression of Change – Hyperphagia; CGI-I=Clinical Global Impression of Improvement; CGI-S=Clinical Global Impression of Severity; 
CGIS-H=Clinical Global Impression of Severity – Hyperphagia; DBC2-P=Developmental Behavior Checklist 2-Parent/Carer version; DXA= dual 
energy X-ray absorptiometry; DNA=deoxyribonucleic acid; ECG=electrocardiogram; eDevice=electronic device; EQ-5D-5L=European Quality of 
Life Five Dimension Five Level Scale; ET=Early Treatment; HbA1c=glycated hemoglobin; HQ-CT=Hyperphagia Questionnaire for Clinical Trials; 
IGF-1=insulin-like growth factor-1; IQ=Intelligence Quotient; IRT=Interactive Response Technology; NRS=Numerical Rating Scale; 
PedsQLTM=Pediatric Quality of Life inventoryTM; T2D=type 2 diabetes mellitus; UAG=unacylated ghrelin; V=visit; WC=waist circumference; ZBI= 
Zarit 
Burden 
Interview.


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1.2.5 
Schedule of Activities for Phase 3 Extension Period 
Study Stage 
Phase 3 Extension Period 
End of Study 
Visit# 
 
 
End of Extension 
Period/ 
Early Treatment 
Discontinuation  
Telephone follow-up 
V8 
V9 
V10 
V11 
Study Week(s) 
31 
40 
53 
57 
Treatment Duration (weeks/months)  
30/7 
39/9 
52/12 
- 
Study Day(s) 
211 
274 
365 
393 
Visit Window (±X days) 
7 
7 
7 
7 
Concomitant medications 
X 
X 
X 
X 
Physical examination1 
X (A) 
X (C) 
X (C) 
 
Vital signs2 
X 
X 
X 
 
WC, BW, and BMI3 
X 
X 
X 
 
Height4 
X 
X 
X 
 
12-lead ECG5 
 
X 
X 
 
DXA (total body fat mass, lean body 
mass, bone mineral density)6 
 
X 
X 
 
Pregnancy test7 
X 
X 
X 
 
Safety laboratory evaluations in the 
fasting condition8 
X 
 
X 
 
Blood samples for HbA1c 
 
X 
X 
 
Blood samples for fasting glucose and 
insulin9 
 
 
X 
 
Blood samples for fasting AG and UAG 
analyses10 
 
 
X 
 
Blood sample for IGF-1 
 
 
X 
 
Blood sample for ADA analysis 
 
 
X 
 
Review 
and 
completion 
of 
questionnaires on eDevice  
X 
X 
X 
 
HQ-CT 
X 
X 
X 
 
Quality of Life: PedsQLTM Parent-
Proxy Report 
 
 
X 
 
CgGIS-H 
X 
X 
X 
 
CGIS-H 
X 
X 
X 
 
CgGIC-H 
X 
X 
X 
 
CGIC-H 
X 
X 
X 
 
CGI-I  
X 
X 
X 
 
                                                 
1 “C” for complete physical examination, “A” for abbreviated physical examination. See Section 10.1.4 for assessments to be performed 
during a physical examination. 
2 Vital signs (respiration rate, pulse rate, and blood pressure) will be measured sitting after the patient has rested comfortably for 
5 minutes. See Section 10.1.2. 
3 Before breakfast. See Section 9.1.3 and Section 9.1.4. 
4 Before breakfast. See Section 10.1.3.  
5 See Section 10.1.6. 
6 DXA can be obtained with 2 weeks prior to Visit 9 and End of Extension Period visit (Visit 10). See Section 9.1.2 and Section 10.1.5. 
7 Pregnancy tests will be performed women of childbearing potential only. See Section 8.1.2.2.3. 
8 Blood samples will be collected after fasting for approximately 8 hours. Clinical serum chemistries, hematology, coagulation, urinalysis 
parameters are described in Section 8.1.2. Clinical laboratory evaluations will be performed centrally.  
9 Blood samples will be collected after fasting for approximately 8 hours.  


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Study Stage 
Phase 3 Extension Period 
End of Study 
Visit# 
 
 
End of Extension 
Period/ 
Early Treatment 
Discontinuation  
Telephone follow-up 
V8 
V9 
V10 
V11 
Study Week(s) 
31 
40 
53 
57 
Treatment Duration (weeks/months)  
30/7 
39/9 
52/12 
- 
Study Day(s) 
211 
274 
365 
393 
Visit Window (±X days) 
7 
7 
7 
7 
CGI-S  
X 
X 
X 
 
Caregiver Disease Burden: ZBI 
 
 
X 
 
EQ-5D-5L Self-complete version and 
Proxy version 1 
 
 
X 
 
DBC2-P 
 
 
X 
 
Review/record AEs 
X----------------------------------------------------------------------------------------------------------------
----------------X 
Dispensation of livoletide 
X 
X 
 
 
Drug accountability 
X 
X 
X 
 
On-site livoletide administration 
X 
X 
X 
 
Abbreviations: ADA=anti-drug antibodies; AEs=adverse events; AG=acylated ghrelin; BMI=body mass index; BW=body weight; CgGIC-
H=Caregiver Global Impression of Change – Hyperphagia; CgGIS-H=Caregiver Global Impression of Severity – Hyperphagia; CGIC-
H=Clinical Global Impression of Change – Hyperphagia; CGI-I=Clinical Global Impression of Improvement; CGI-S=Clinical Global 
Impression of Severity; CGIS-H=Clinical Global Impression of Severity – Hyperphagia; DBC2-P=Developmental Behavior Checklist 2-
Parent/Carer version; DXA= dual energy X-ray absorptiometry; ECG=electrocardiogram; eDevice=electronic device; EQ-5D-5L=European 
Quality of Life Five Dimension Five Level Scale; HbA1c=glycated hemoglobin; HQ-CT=Hyperphagia Questionnaire for Clinical Trials; 
IGF-1=insulin-like growth factor-1; NRS=Numerical Rating Scale; PedsQLTM=Pediatric Quality of Life inventoryTM; UAG=unacylated ghrelin; 
V=visit; WC=waist circumference; ZBI= Zarit Burden Interview. 
 
 
 


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AZP-531 is an 8-amino acid, cyclic, peptide analog of unacylated ghrelin (UAG). This study will 
evaluate AZP-531 for the treatment of hyperphagia and food-related behaviors in patients with 
Prader-Willi syndrome (PWS). All relevant information concerning the compound is available in 
the latest version of the Investigator’s Brochure (IB). 
2.1 
Background Information 
2.1.1 
Overview of Prader-Willi Syndrome 
Prader-Willi syndrome is a rare disease (in Europe, the prevalence ranges between 1 and 9 per 
100,000 – source Orphanet, last consultation March 06, 2018). It is a neurodevelopmental and 
hypothalamic disorder, equally affecting both sexes, due to genetic abnormalities that result in 
the absence of expression of genes at the locus q11-q13 on chromosome 15 (1). Approximately 
60-65% of affected individuals have a deletion of the paternal chromosome 15q11-q13 while 
most of the remaining patients display a maternal uniparental disomy for chromosome 15. A 
small percentage of patients may have abnormalities of the imprinting center or translocation 
involving chromosome 15.  
Prader-Willi syndrome is associated with dysmorphic features, short stature, growth hormone 
deficiency, hypogonadism, low calorie expenditure, and abnormal body composition with 
reduced fat free mass and increased fat mass. Cognitive impairments, behavioral disturbances, as 
well as psychiatric disorders are also part of the syndrome (2).  
The growing understanding of the natural history of PWS has recently led to the identification of 
several successive nutritional and eating behavior phases proceeding from poor feeding, through 
normal eating without and with obesity, to hyperphagia and life-threatening obesity (3).  
2.1.2 
Hyperphagia Associated with Prader-Willi Syndrome 
Hyperphagia is a significant, salient, and constant feature of the syndrome and is associated with 
abnormal and extreme behaviors towards food including obsessive food seeking, food storage, 
foraging, and hoarding (see Figure 1); all of these representing a lifelong source of distress and 
severely and negatively affecting social adaptation, occupational performance, and quality of life 
(QoL) (4, 5). Hyperphagia and abnormal food-related behaviors may result in life-threatening 
complications such as choking or gastric necrosis and rupture (6-8). This condition is associated 
with significant morbidity resulting from obesity, type 2 diabetes (T2D), and related 
complications that altogether contribute to reduced life expectancy (8-10). 
In addition to the direct impact that hyperphagia has on individuals suffering from PWS, the 
health-related quality of life (HRQoL) both for individuals and for their caregivers (5) and their 
families (11) is also affected.  
2 
INTRODUCTION: 
BACKGROUND 
INFORMATION 
AND 
SCIENTIFIC 
RATIONALE 


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Figure 1: Complications associated with hyperphagia in patients with Prader-Willi syndrome 
 
2.1.3 
Current Therapeutic Options for Hyperphagia associated with Prader-Willi 
Syndrome  
Currently, there are no effective pharmacological treatment options for hyperphagia and 
excessive eating behaviors associated with PWS. Management of food-related behaviors and 
obesity is problematic and represents one of the highest priority medical needs in PWS. Data 
from a recent survey performed by the United States (US) and Canadian Foundation for 
Prader-Willi Research in 779 parents revealed that 74% of them would look at reduction of 
hunger as most important for an ideal treatment for PWS (12). 
To date, continuous lifelong supervision, strict control over access to food, dietary restriction, 
and regular exercise are still the only available options. Growth hormone, which has been used 
since the early 2000’s for improvement in growth velocity and body composition, does not 
ameliorate 
PWS-associated 
hyperphagia 
(13, 
14). 
Similarly, 
anorexigenic 
agents, 
endocannabinoid antagonists, and gastric banding or bypass, have been proven ineffective in 
reducing hyperphagia or were associated with safety issues (15-17).  
Over the past few years, PWS's orphan indication and the significant unmet medical need has led 
a number of pharmaceutical companies to initiate clinical investigation programs in PWS; 
however, to date there are no therapies approved for the treatment of hyperphagia in PWS. 
2.1.4 
Introduction to Ghrelin Biology 
Ghrelin is a 28-amino acid peptide hormone produced predominantly by the stomach and 
expressed in lower amounts in a variety of organs including the gastrointestinal tract, pancreas, 
brain, pituitary gland, kidney, lung, and heart (18). 


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In the circulation, ghrelin is present in 2 forms (19): 1) the acylated ghrelin (AG) that has 
orexigenic, obesogenic, and diabetogenic properties (20-28) and 2) the UAG, also known as 
des-acyl ghrelin, that has been shown to inhibit AG effects (29-36). 
Unacylated ghrelin is acylated by ghrelin O-acyltransferase (GOAT) on the serine-3 residue (37) 
to yield AG as shown in Figure 2 below: 
 
Figure 2: Unacylated ghrelin (UAG) acylation by ghrelin O-acyltransferase (GOAT) 
 
Acylated Ghrelin 
Acylated ghrelin, commonly referred to as ghrelin, is a pleiotropic hormone, discovered for its 
property to activate the growth hormone secretagogue receptor (GHSR) (18) that contributes to 
the regulation of key endocrine and non-endocrine functions including glucose and lipid 
metabolism. Acylated ghrelin is one of the most powerful orexigenic agents and the only one 
acting in the periphery in animals and humans (20-23). The effect on appetite is mainly achieved 
through GHSR of hypothalamic neurons co-expressing Neuropeptide Y and agouti-related 
protein (AgRP) (25). Plasma AG levels peak before meals, normalize after feeding, and appear 
to be regulated by the nutritional status (24). In addition to induction of food intake, 
administration of AG is adipogenic, hyperglycemic, and induces insulin resistance (26-28).  
Unacylated Ghrelin 
Unacylated ghrelin is devoid of the acyl moiety and is unable to bind the GHSR at physiological 
concentrations (18, 38). Because it does not bind to GHSR, UAG was first considered as a 
degradation product with no biological activities. Data accumulated over the years has provided 
insights that UAG counteracts the metabolic effects of AG and the effects of AG on food 
consumption. In animals, administration of UAG improved glucose intolerance, inhibited fat 
mass deposition, and reduced body weight (BW) gain (39-42). UAG overexpression in 
transgenic mice also resulted in improvement of glucose tolerance and insulin sensitivity as well 
as reduced fat mass and resistance to high fat diet-induced obesity (43, 44). In humans, co-
administration of AG and UAG counteracted the increase in glucose and decrease in insulin, 
while administration of UAG alone had no effect (29). In addition, UAG has intrinsic direct 
activities for protection of various tissues including beta islets, muscle, vessels, heart, and brain 
(45-50).  
In animal models, where increased food intake is induced by exogenous administration of AG, 
administration of UAG has been shown to counteract this effect (31, 35, 36). In the rodent 
models, data suggest that UAG inhibits AG-induced hypothalamic neuronal activity through 
AG-independent neuronal pathways, possibly involving nesfatin-1 immunopositive neurons (31) 


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and/or melanocortin receptors (increased melanocortin-4 receptor [MC4R] and decreased 
melanocortin-3 receptor [MC3R]) in the hypothalamus (35).  
Acylated Ghrelin and Unacylated Acylated Ghrelin Levels in Prader-Willi Syndrome 
Although the basis for the excessive eating behavior observed in PWS is not yet completely 
understood, evidence supports involvement of appetite hormone disturbances and dysregulation 
of the hypothalamus area controlling appetite. 
Several studies have consistently documented increased fasting and postprandial circulating 
levels of total ghrelin in patients with PWS at all ages, as compared to control lean and obese 
subjects (51-54). In addition, in adults with PWS, plasma total ghrelin levels were also shown to 
positively correlate with ratings of hunger, which suggests that ghrelin may be responsible, at 
least in part, for the hyperphagia observed in PWS (54). 
In an observational study that included 138 children and adults with PWS, Kuppens and 
colleagues (55) showed that AG levels were globally elevated in patients with PWS as compared 
to those of healthy controls and obese subjects, while UAG levels were similar (Figure 3A). 
When looking specifically at AG and UAG levels according to the PWS nutritional phases 
(Figure 3B), UAG levels were showed to be significantly higher than AG levels in early 
nutritional phases. This is also documented by a recent study from Beauloye and colleagues that 
was conducted in infants with PWS (37 control and 100 infants with PWS from 1 month to 4 
years of age) (56). In the Kuppens study, the onset of hyperphagia and obesity (Phase 2a) is 
associated with a drastic drop in UAG levels, yet no change in AG levels. As a result, the 
AU/UAG ratio increased with progression of nutritional phases and severity of hyperphagia. It is 
hypothesized that this considerable change in the AG/UAG ratio drives the switch to 
hyperphagia and obesity. Altogether, these results indicate that PWS hyperphagia is associated 
with high levels of orexigenic AG and a relative UAG deficiency. 
 
 
 
 
 
 
 
 
 
Figure 3: AG and UAG levels in PWS, control, and obese subjects (A) and evolution of AG and 
UAG levels in nutritional phases in PWS (B). Adapted from Kuppens et al., 2015 
 
Abbreviations: AG=acylated ghrelin; PWS=Prader-Willi syndrome; UAG=unacylated ghrelin. 
 


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2.2 
The Investigational Drug: Livoletide, an Unacylated Ghrelin Analog 
2.2.1 
Livoletide: General Description 
Since its discovery, the ghrelin system has emerged as a pharmacological target for the treatment 
of a broad variety of diseases. In particular, various pharmacological tools including GHSR 
antagonists, AG-blocking agents, and GOAT inhibitors, have been designed with the objective of 
antagonizing or blocking the effects of AG on food intake, fat mass, and/or glucose. None of the 
designed GHSR antagonist and AG-blocking drug candidates has moved to clinical testing, to 
our knowledge, because of lack of efficacy and unwanted effects observed in animal models 
(37). Unacylated ghrelin pharmacological profile that includes both direct protective effects on 
tissues and a unique potency to functionally counteract AG metabolic activities and AG effect on 
food intake has provided the rationale for opening a new therapeutic class for the treatment of 
metabolic diseases and specifically PWS. 
However, UAG itself is subject to rapid proteolytic cleavage resulting in short duration of action. 
Thus, for pharmaceutical development purposes, a series of UAG analogs were designed. Analog 
UAG 6-13 (AZP-502), that does not contain serine 3, was found to be the smallest and most 
effective fragment able to mimic effect of full length UAG and was shown, as UAG, to prevent 
diabetes in streptozotocin-treated rats (57). 
Cyclization of the UAG 6-13 fragment improved in vitro plasma stability and in vivo half-life in 
animals and humans and resulted in livoletide (also known as AZP-531), a peptide analog of 
8 amino acids suitable for daily subcutaneous (SC) injection (58, 59). Livoletide has shown a 
comparable pharmacological profile to UAG and AZP-502, its linear counterpart, in both in vitro 
and in vivo models (40, 50, 57), including a rat model where livoletide counteracts AG-induced 
food intake. On the basis of this pharmacological profile, livoletide has been selected as a drug 
candidate for clinical development. The structures of UAG, AZP-502, and livoletide are 
presented below (Figure 4). 
 
Figure 4: Structure of unacylated ghrelin (UAG), AZP-502, and livoletide (AZP-531) 
 
2.2.2 
Chemistry and Description 
Livoletide is the acetate salt of cyclo human UAG (6-13). The chemical name is 
Glutamyl-Histidyl-Glutaminyl-Arginyl-Valyl-Glutaminyl-Seryl-Propyl, 
Cyclic 
1-8, 
acetate 
counter ion, abbreviated as follows: 
 
 
 
 
Glu-His-Gln-Arg-Val-Gln-Ser-Pro 


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The structural formula of livoletide is presented in Figure 5 below.  
NH
O
H
O
O
N
O
N
H
O
N
H
N
H
O
OH
O
NH2
O
N
H
N
H
N
H2
NH
O
N
H
N
H2
O
O
N
H
N
N
H
O
 
Figure 5: Structural formula of livoletide (AZP-531) 
 
The peptide is synthesized using N-(Fluorenyl-9-MethOxyCarbonyl) chemistry on solid phase in 
compliance with Good Manufacturing Practice (GMP). 
2.3 
Summary of Relevant Nonclinical and Clinical Research 
All nonclinical and clinical data that are relevant to the trial and that provide background for the 
trial are extensively described and available in the latest version of the IB. The following 
sections provide a summary of key significant nonclinical and clinical findings. 
2.3.1 
Nonclinical Studies 
Efficacy Results 
Proof-of-concept for the use of livoletide in PWS has been performed using a published rat 
model of inhibition of AG-induced food intake by UAG (31). In this model, livoletide was 
shown to significantly inhibit the effect of AG on cumulative food intake over a 2-hour feeding 
period. 
Pharmacology 
In vitro stability of livoletide was investigated in human plasma (58). Compared to AZP-502, the 
UAG 6-13 linear fragment, livoletide has increased stability. No degradation of livoletide was 
noted after 3 days of incubation at 37°C while its linear counterpart was degraded very quickly. 
When administered subcutaneously or intravenously to animals, livoletide was measured for up 
to 4 hours (in rats) and 8 hours (in dogs). Subcutaneous bioavailability of livoletide was 96% and 
85% in rats and dogs, respectively. Livoletide half-life was about 30 minutes in the rat and 
1 hour in the dog. 
Tissue distribution after SC administration of [3H] radiolabeled livoletide was assessed in a 
whole-body autoradiography study in male and female rats. In both genders, distribution was 
rapid and widespread, with the highest concentration of total radioactivity observed in the 
kidney. Concentrations of radioactivity in the spinal cord and brain were low throughout the 
study period, indicating that drug-related radioactivity was not crossing the blood-brain barrier to 
any significant extent. 


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Safety 
Core safety pharmacology studies with livoletide were performed in an Organization for 
Economic Co-operation and Development (OECD) member country in accordance with the 
OECD Test Guidelines and Principles of Good Laboratory Practice (GLP). No treatment related 
effects on major physiological systems including the cardiovascular system, respiratory system, 
and central nervous system were reported with livoletide. 
Results of GLP repeat dose toxicology studies indicate that livoletide administered by SC 
injection for 14 days was associated with no systemic toxicity at doses up to 2 x 18 mg/kg/day 
and 2 x 5.5 mg/kg/day in rats and dogs, respectively. 
Livoletide treatment caused minimal to moderate granulomatous SC inflammation associated 
with accumulation of foreign material, likely to be the test item, at some injection sites of a few 
treated animals (dogs) from all dose level groups. No anti-livoletide antibodies were noted at the 
end of the 14-day treatment period in either species. 
Good Laboratory Practice chronic 13-week toxicology studies were conducted. Results showed 
no systemic toxicity at doses up to 75 mg/kg/day and 30 mg/kg/day in rats and dogs, 
respectively. These doses provide a group mean area under the concentration-time curve (AUC) 
value of equal or greater than 50-fold the intended clinical systemic exposure. In the dog study, 
minimal granulomatous inflammation comparable to what was observed in the 14-week study 
was noted at one injection site of one control and one low dose group (10 mg/kg/day). No 
anti-livoletide antibodies were noted at the end of the 13-week treatment period in either species. 
Good Laboratory Practice chronic 26-week (rats) and 39-week (dogs) toxicology studies were 
conducted. Daily subcutaneous administration of livoletide at doses of 15, 30 and 45 mg/kg/day 
in the Wistar rat (for 26 consecutive weeks) or 3, 10 and 30 mg/kg/day in Beagle dogs (for 39 
consecutive weeks) was not associated with any evidence of overt systemic toxicity. 
Consequently, the high doses tested (45 mg/kg/day and 30 mg/kg/day respectively) could be 
considered as the NOAELs. Corresponding mean toxicokinetic values for Cmax and AUC0-24h 
(males/females) in rats were respectively 54.5/51.5 μg/mL and 129/112 μg.h/mL. Corresponding 
mean toxicokinetic values for Cmax and AUC (males/females) in dogs were respectively 
42.5/44.7 µg/mL and 119/113 µg.h/mL. 
Good Laboratory Practice preliminary embryo-fetal and development studies in rats and rabbits 
have been completed and data show that livoletide doses up to 75 mg/kg/day (rat) and 120 
mg/kg/day (rabbit) was not associated with embryo-fetal toxicity or teratogenic potential.  
To support the inclusion of patients 4-to-7-year-old in the study, a Good Laboratory Practice rat 
juvenile study has been conducted. Livoletide given daily by subcutaneous administration at 
doses of 10, 25 and 75 mg/kg/day to the juvenile Wistar rat from the age of weaning (i.e., at 21 
days of age) up to at least 12 weeks of age was well tolerated and was not associated with any 
evidence of overt systemic toxicity. In this study, toxicokinetic profiles were comparable to adult 
rats. This indicates comparable exposures for the same dose independent of age.  


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2.3.2 
Clinical Experience with Livoletide 
Table 1 below summarizes all completed clinical studies on livoletide to date. 
PHASE 
STUDY NB 
PUBLICATION 
PART 
OBJECTIVES 
STUDY DESIGN 
TEST PRODUCT/ 
ROUTE 
DURATION 
OF 
TREATMENT 
STUDY 
POPULATION 
NB SUBJECTS 
(AZP-531) 
Phase 1 
AZP01-CLI-
001 
Allas et al., 
2016(59) 
Part A 
Safety 
PK 
PD 
Randomized 
placebo-
controlled 
SAD 
0.3, 3, 15, 30, 60, 
120 µg/kg AZP-531 or 
placebo 
once a day/ 
SC 
Single-dose 
Male healthy 
subjects 
Age: 20-50 years 
BMI: 20.2-27.3 
kg/m² 
44 (33) 
Part B 
Safety 
PK 
PD 
Randomized 
placebo-
controlled 
 
MAD 
3, 15, 30, 60 µg/kg 
AZP-531 or placebo 
once a day/ 
SC 
14 days 
Overweight/obese 
subjects 
Age: 21-61 years 
BMI: 28- 37 kg/m² 
32 (24) 
Part C 
Safety 
PK 
PD 
Randomized 
placebo-
controlled 
 
MAD 
15, 60 µg/kg AZP-531 
once a day, 
30 µg/kg AZP-531 BID 
or placebo/ 
SC 
14 days 
Subjects with T2D 
Age: 34-64 years 
BMI: 24-39 kg/m² 
36 (27) 
Phase 2a 
AZP01-CLI-
002 
Allas et al., 
2017(60) 
 
Not 
applicable 
Safety 
PD 
Efficacy 
Randomized 
placebo-
controlled 
 50-70 kg BW: 
3 mg AZP-531 
 70 kg BW: 
4 mg AZP-531 
or placebo 
once a day/ 
SC 
14 days 
Adult and adolescent 
patients with PWS 
Age: 13-46 years 
BMI: 20.6-67.4 
kg/m² 
47 (23) 
Table 1: Tabular summary of completed clinical studies on livoletide (AZP-531) 
Abbreviations: AZP-531=livoletide; BID=twice daily; BMI=body mass index; BW=body weight; MAD=multiple ascending dose; NB=number; 
PD=pharmacodynamics; PK=pharmacokinetics; PWS=Prader-Willi syndrome; SAD=single ascending dose; SC=subcutaneous; T2D=type 2 
diabetes. 
 
Phase 1 Study (AZP01-CLI-001) 
Livoletide has been tested in a 3-part, Phase 1, first-in-human, placebo-controlled study 
conducted in a single phase 1 unit (59). Part A was a single ascending dose (SAD) study 
conducted to evaluate safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) 
of livoletide in healthy male adult volunteers at the doses of 0.3, 3, 15, 30, 60, and 120 µg/kg. 
Part B was a multiple ascending dose (MAD) study conducted to evaluate tolerability, PK, and 
PD in male and female obese/overweight subjects following repeated daily administration of 
livoletide for 14 days at doses of 3, 15, 30, and 60 µg/kg. Part C was a MAD study conducted to 
evaluate tolerability, PK, and PD in male and female subjects with imperfectly controlled T2D 
following repeated daily administration of livoletide for 14 days at doses of 15, 2 x 30, and 
60 µg/kg.  
This study showed that livoletide was well tolerated at the doses tested. There were neither 
serious nor severe adverse events (AEs) in any part of the study. There were no significant 


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findings with respect to clinical laboratory safety tests, vital signs, electrocardiogram (ECG; 
performed in all parts), and telemetry (performed in SAD only).  
Pharmacokinetics 
Livoletide PK parameters were comparable overall at the same doses in the 3 study parts. In 
Part B and C, single and multiple-dose PK parameters were similar. Livoletide was rapidly 
absorbed reaching peak concentrations within approximately 1 hour. The half-life ranged 
between 2 and 3 hours. Maximum concentration (Cmax) and AUC were dose-related and 
increased proportionally with the dose administered. Daily SC administration resulted in 24-hour 
exposure to livoletide at doses above 30 µg/kg. Accumulations in maximum and total exposures 
were negligible following repeated dosing for 14 days. 
Pharmacodynamics 
In Part B, PD findings included reductions in blood and interstitial glucose levels as well as 
reductions in BW after 14 days of administration of livoletide to subjects at doses ranging from 
15 µg/kg to 60 µg/kg (-2.6 kg vs -0.8 kg for placebo). Insulin levels were unchanged, consistent 
with an insulin-sensitizing effect. In Part C, glucose parameters improved in all groups including 
placebo, suggesting a study effect in uncontrolled patients at baseline. Notwithstanding, 
livoletide at the dose of 60 µg/kg reduced glycated hemoglobin (HbA1c) by 0.4% (vs 0.2% for 
placebo) and BW by -2.1 kg (vs -1.4 kg for placebo). 
Phase 2a Study (AZP01-CLI-002) 
A randomized, double-blind, placebo-controlled Phase 2a clinical trial was conducted to assess 
the safety, tolerability, and preliminary efficacy on food-related behavior of daily SC 
administrations of livoletide to patients with PWS. The study was performed in 47 male and 
female patients with genetically confirmed PWS and evidence of increased appetite and 
hyperphagia. This study was carried out in 7 sites across France, Spain, and Italy. Doses of 3 to 
4 mg of livoletide were administered SC daily for a total of 14 days.  
In this study, livoletide was well tolerated with no serious or severe AEs and no clinically 
significant changes with respect to safety laboratory tests. Results show a significant 
improvement in caregiver-observed food-related behavior in patients treated with livoletide, as 
assessed by the Hyperphagia Questionnaire (HQ) (61), with a particular improvement in the 
Hyperphagic Severity domain score of the HQ. The highest improvement was observed in 
livoletide subjects with the highest hyperphagia score at baseline. These findings were supported 
by a reduction in patient-reported appetite following breakfast in patients treated with livoletide, 
as assessed by a patient-reported appetite-Numeric Rating Scale (NRS). Body weight did not 
change in both groups while a significant reduction in waist circumference (WC) and fat mass 
was observed only with livoletide. Livoletide significantly decreased postprandial glucose levels 
in a baseline glucose dependent fashion. 


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2.4 
Rationale for Developing Livoletide in the Treatment of Hyperphagia in Patients 
with Prader-Willi Syndrome 
The development of livoletide in the treatment of hyperphagia in patients with PWS was based 
on the following observations: 
1. Plasma levels of AG are elevated in patients with PWS (with a relative deficit in UAG 
levels) and are hypothesized to contribute to the pathophysiology of hyperphagia. 
2. In animal models, where increased food intake is induced by exogenous administration of 
AG, administration of livoletide (similar to UAG) has been shown to inhibit this effect. 
3. Administration of livoletide to animals has been shown to prevent glucose intolerance, 
insulin resistance, and fat accumulation. 
It has been hypothesized that administration of livoletide in patients with PWS improves 
hyperphagia and food related behaviors and provides additional metabolic benefits including 
inhibition of fat deposition and weight gain as well as improvement of insulin sensitivity. 
Phase 1 data have indicated that livoletide administered for up to 14 days to obese subjects and 
patients with T2D at doses up to 60 µg/kg/day was well tolerated and resulted in improvement in 
metabolic parameters including BW and glucose control. Phase 2a results showed that a 14-day 
treatment with livoletide at doses up to 4 mg/day in patients with PWS was well tolerated and 
was associated with a significant improvement in food-related behaviors, as assessed by the HQ, 
supported by a reduction in patient-reported appetite, along with glucose control improvement, a 
reduction in WC, and a reduction in fat mass. 
Altogether, these observations provide initial safety and efficacy of livoletide and support the 
conduct of larger and long term clinical trials in patients with PWS. 
The single, pivotal Phase 2b/3 protocol provides greater efficiency than two separate studies as 
considerable site resources are required during study start-up and close-out activities. This is 
especially important in an orphan indication where the number of high quality investigator sites 
is limited. By combining the Phase 2b and Phase 3 studies into a single protocol, with nearly 
identical study design elements for both phases, sites may shift resource to protocol execution 
and patient care. 
2.5 
Potential Risks and Benefits to Human Participants 
2.5.1 
Known Potential Risks 
Please refer to the IB for livoletide for an expanded risk/benefit assessment. 
Animal Toxicology 
Non-clinical repeated-dose toxicity studies in rats and dogs, which may be relevant to human 
safety, revealed the following: 
 
In dogs, livoletide treatment caused minimal to moderate granulomatous SC inflammation 
associated with accumulation of foreign material, likely to be the test item, at some 
injection sites of a few treated animals from all dose level groups (5 out of 18 animals); 
 
No anti-livoletide antibodies were noted at the end of the 14-day treatment period in either 
species.  
Good Laboratory Practice chronic 13-week toxicology studies were conducted. Results show no 
systemic toxicity at doses up to 75 mg/kg/day and 30 mg/kg/day in rats and dogs, respectively. 


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These doses provide a group mean AUC value of greater than 50-fold the intended clinical 
systemic exposure. In the dog study, minimal granulomatous inflammation comparable to what 
was observed in the 14-week study was noted at one injection site of one control and one low 
dose group (10 mg/kg/day). No anti-livoletide antibodies were noted at the end of the 13-week 
treatment period in either species. 
Good Laboratory Practice chronic 26-week (rats) and 39-week (dogs) toxicology studies were 
conducted and were not associated with any evidence of overt systemic toxicity. Good 
Laboratory Practice preliminary embryo-fetal and development studies in rats and rabbits have 
been completed and data show that livoletide doses up to 75 mg/kg/day (rat) and 120 mg/kg/day 
(rabbit) were not associated with embryo-fetal toxicity or of a teratogenic potential.  
In addition, to support the inclusion of patients 4-to-7-year-old in the study, a Good Laboratory 
Practice rat juvenile study has been conducted. Livoletide given daily by subcutaneous 
administration at doses of 10, 25 and 75 mg/kg/day to the juvenile Wistar rat from the age of 
weaning (i.e., at 21 days of age) up to at least 12 weeks of age was well tolerated and was not 
associated with any evidence of overt systemic toxicity. In this study, toxicokinetic profiles were 
comparable to adult rats. This indicates comparable exposures for the same dose independent of 
age. 
 
Anticipated Safety Profile 
In a 3-part Phase I, randomized, placebo-controlled study (refer to Section 2.3.2 for details on 
study design), administration of livoletide was well tolerated, without serious or severe AEs.  
In healthy volunteers (Part A), the most common treatment-emergent AE (TEAE) reported was 
injection site erythema in 4 subjects at 120 µg/kg livoletide (in one or both injection sites) and in 
1 subject on placebo. In obese subjects (Part B), the most common TEAE reported was injection 
site reaction (4/24 subjects receiving livoletide and 1/8 subjects in the placebo group) followed 
by diarrhea (2/24 subjects receiving livoletide). In patients with T2D (Part C), the most common 
TEAE reported was diarrhea (5/27 subjects receiving livoletide and 1/9 receiving placebo), 
hematoma (4/24 subjects receiving livoletide), headache (2/9 subjects receiving placebo), and 
musculoskeletal pain (2/9 subjects receiving placebo). 
No hypoglycemia event occurred in any study part. No clinically significant findings were noted 
with respect to hematology, coagulation, blood chemistry, urinalysis, or vital signs in any study 
part. Cardiac assessments (telemetry in Part A and ECG in Part B and C) revealed no significant 
findings at the end of the treatment period. 
In patients with PWS (refer to Section 2.3.2 for details on study design), administration of 
livoletide for 14 days was well tolerated. There were transient injection site reactions which were 
seen at a higher frequency in the placebo group. There were no serious adverse events (SAEs) or 
AEs leading to study or treatment discontinuation, and no hypoglycemia events. There were no 
significant findings with respect to vital sign parameters and safety laboratory tests. 
Systemic side-effects following long-term treatment that may occur in patients with PWS cannot 
be reliably predicted. As granulomatous inflammation was observed locally at the injection sites 
in the dog toxicology study and injection site reactions possibly related to livoletide were noted 
during the Phase I study, patients in this study will be monitored for injection site reactions. 


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Although pre-clinical and clinical studies with livoletide have not indicated or revealed any 
hypoglycemia event to date at the doses tested, a theoretical slight possibility of hypoglycemia 
still exists. In this study, blood glucose in patients with T2D will be monitored daily, fasting, 
during the study period using a glucometer.  
No anti-livoletide antibodies were observed in both the rat and dog 3-month toxicology studies. 
In the Phase 1 and 2 clinical trials, samples for antibody analysis were collected but not analyzed 
as administration of livoletide was well tolerated with no significant drug reactions. In this study, 
samples for analysis of antibodies will be collected and analyzed.  
Safety and efficacy of livoletide during pregnancy have not been established. Although fertility 
is extremely rare in PWS and only a few cases of pregnancy have been reported in the literature 
(62), all post-menarchal female patients who will be included in the study must have a negative 
pregnancy test at randomization. In addition, Women of Child Bearing Potential (WCBP), 
sexually active male patients, and all male partners of female patients should agree to use 
adequate methods of birth control throughout the study and for 30 days after the last dose of 
study drug. 
2.5.2 
Known Potential Benefits 
Phase 2a results showed a significant improvement in caregiver-observed food-related behavior 
in patients treated with livoletide, as assessed by the HQ, which was supported by a reduction in 
patient-reported appetite following breakfast, as assessed by a patient-reported appetite-NRS. 
Over the 14-day treatment, BW did not change in both groups while a significant reduction in 
WC and fat mass was observed in patients treated with livoletide. Livoletide significantly 
decreased postprandial glucose levels in a baseline glucose dependent fashion 
It is therefore hypothesized that significant improvement in food related behavior will be 
observed after a long-term treatment period with livoletide as well as the potential for 
improvement across multiple metabolic parameters including body composition and glycemic 
parameters. 
2.5.3 
Summary 
Given the non-clinical safety profile of livoletide and available safety and initial efficacy data of 
livoletide in clinical studies conducted so far in healthy volunteers, obese subjects, patients with 
T2D, and patients with PWS, and in view of the unmet need in these patients, there is an 
appropriate potential benefit to risk consideration to study livoletide in hyperphagic patients with 
PWS. 
3.1 
Tabular Summary of Trial Objectives and Endpoints 
3.1.1 
Phase 2b Tabular Summary of Trial Objectives and Endpoints 
 
OBJECTIVES 
ENDPOINTS 
PHASE 2B CORE PERIOD 
Primary Efficacy 
 To demonstrate the efficacy of a 3-month treatment with 
livoletide as compared to placebo for reducing caregiver-
observed food-related behavior as assessed by the HQ-CT. 
 Change from baseline to the end of the 3-month Core 
Period in HQ-CT total score. 
3 
OBJECTIVES AND ENDPOINTS


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Secondary Efficacy 
 To demonstrate the efficacy of 3-month treatment with 
livoletide as compared to placebo for: 
 
o 
Reducing total body fat mass in overweight/obese 
patients with PWS; 
o Percentage change from baseline to the end of the 
3-month Core Period in total body fat mass in 
overweight/obese patients with PWS; 
o 
Reducing WC in overweight/obese patients with PWS; 
o Change from baseline to the end of the 3-month Core 
Period in WC in overweight/obese patients with PWS; 
o 
Reducing BW in overweight/obese patients with PWS. 
o Percentage change from baseline to the end of the 
3-month Core Period in BW in overweight/obese 
patients with PWS. 
Safety  
 To assess the safety and tolerability of livoletide as compared 
to placebo over a 3-month treatment period. 
 Incidence of AEs; 
 Vital signs; 
 Height and BMI; 
 Physical examination; 
 Lean body mass and bone mineral density; 
 ECG; 
 Safety laboratory parameters (clinical chemistry including 
lipids, 
coagulation, 
hematology, 
urinalysis, 
HbA1c, 
ghrelin, ADA, and IGF-1).  
Pharmacokinetics  
 To characterize plasma PK of livoletide in patients with 
PWS. 
 The PK endpoints will be described in details in the SAP 
and will include as the data allow: Cmax, Tmax, AUC0-4, and 
other PK parameters of livoletide 
Additional Assessments 
 To evaluate the effect of livoletide as compared to placebo 
on: 
 Change from baseline in: 
o Hyperphagia severity as assessed by the CgGIS-H and 
CGIS-H; 
o CgGIS-H and CGIS-H scores; 
o Hyperphagia global impression of change as assessed by 
the CgGIC-H and CGIC-H; 
o CgGIC-H and CGIC-H scores; 
o Clinical global impression of change as assessed by the 
CGI-I; 
o CGI-I score; 
o Clinical global impression of severity as assessed by the 
CGI-S; 
o CGI-S score; 
o Fasting (for approximately 8 hours) and postprandial 
glucose and insulin (profile); 
o Fasting (for approximately 8 hours) and postprandial 
glucose and insulin measurement (profile); 
o Patient-reported appetite following breakfast as assessed by 
an NRS; 
o Appetite-NRS score; 
o Patients’ Non-Food-Related behaviors as assessed by the 
DBC2-P; 
o DBC2-P score; 
o Patients’ Quality of Life as assessed by the PedsQLTM 4.0 
Generic Core Scales; 
o PedsQLTM 4.0 Parent-Proxy age-appropriate Reports 
score; 
o Caregivers’ disease burden as assessed by the ZBI; 
o Health 
state 
utilities 
as 
assessed 
by 
EQ-5D-5L 
Self-complete version and Proxy version 1; 
o ZBI score; 
o EQ-5D-5L Self score and EQ-5D-5L Proxy version 1 
score; 
 To evaluate the measurement properties of HQ-CT in the 
study population (test-retest reliability, construct validity and 
ability to detect change); 
 Evaluation 
of 
the 
measurement 
properties 
and 
interpretation of clinically meaningful HQ-CT change in 
the study population using blinded study data and 
according to a psychometric analysis plan; 
 
 To derive the responder threshold for meaningful change in 
the HQ-CT; 
 Responder 
definition 
using 
anchor-based 
methods 
supplemented with both CDF and PDF to derive the 
responder threshold for meaningful change; 
 To compare the number of HQ-CT responders between 
groups 
 Percentage 
of 
HQ-CT 
responders 
as 
defined 
by 
anchor-based and distribution-based methods. 
PHASE 2B EXTENSION PERIOD 


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Efficacy 
 To assess the maintenance of efficacy of livoletide treatment 
on caregiver-observed food-related behavior as assessed by 
the HQ-CT; 
 Change from baseline to the end of the 9-month Extension 
Period and change from the end of the 3-month Core 
Period to the end of the 9-month Extension Period in 
HQ-CT total score; 
 To assess the maintenance of efficacy of livoletide treatment 
on total body fat mass, WC, and BW in overweight/obese 
patients with PWS. 
 Percentage change from baseline to the end of the 9-month 
Extension Period and change from the end of the 3-month 
Core Period to the end of the 9-month Extension Period in 
total body fat mass in overweight/obese patients with PWS; 
 
 Change from baseline to the end of the 9-month Extension 
Period and change from the end of the 3-month Core 
Period to the end of the 9-month Extension Period in WC 
in overweight/obese patients with PWS; 
 
 Percentage change from baseline to the end of the 9-month 
Extension Period and change from the end of the 3-month 
Core Period to the end of the 9-month Extension Period in 
BW in overweight/obese patients with PWS. 
Safety  
 To assess the long-term safety and tolerability of livoletide 
over a 12-month treatment period. 
 Incidence of AEs; 
 Vital signs; 
 Height and BMI; 
 Physical examination; 
 Lean body mass and bone mineral density; 
 ECG; 
 Safety laboratory parameters (clinical chemistry including 
lipids, 
coagulation, 
hematology, 
urinalysis, 
HbA1c, 
ghrelin, ADA, and IGF-1).  
Pharmacokinetics 
 To characterize the plasma PK of livoletide in patients with 
PWS; 
 To characterize the plasma PK profile of livoletide in a subset 
of patients with PWS  
Plasma livoletide PK parameters will be derived using non-
compartmental methods. 
Where possible, the following PK parameters will be 
determined. Additional parameters may also be calculated as 
appropriate. 
Cmax; tmax; Cmin; tmin; Cavg; FI; AUC(0-tau); λz; t1/2; CL/F; Vz/F; 
RAUC(0-tau); RCmax; and LI as appropriate. 
Additional Assessments 
 To evaluate the long-term effect of livoletide on: 
 Change from baseline in: 
o Hyperphagia severity as assessed by the CgGIS-H and 
CGIS-H, respectively; 
o CgGIS-H and CGIS-H scores; 
o Hyperphagia global impression of change as assessed by 
the CgGIC-H and CGIC-H, respectively; 
o CgGIC-H and CGIC-H scores; 
o Clinical global impression of change as assessed by the 
CGI-I; 
o CGI-I score; 
o Clinical global severity as assessed by the CGI-S; 
o CGI-S score; 
o Fasting (for approximately 8 hours) glucose and insulin; 
o Fasting (for approximately 8 hours) glucose and insulin 
measurement; 
o Patients’ Non-Food-Related behaviors as assessed by the 
DBC2-P version; 
o DBC2-P score; 
o Patients’ Quality of Life as assessed by the PedsQLTM 4.0 
Generic Core Scales; 
o PedsQLTM Parent-Proxy age-appropriate Reports score; 
o Caregiver disease burden as assessed by the ZBI; 
o Health 
state 
utilities 
as 
assessed 
by 
EQ-5D-5L 
Self-complete version and Proxy version 1. 
o ZBI score; 
o EQ-5D-5L Self score and EQ-5D-5L Proxy version 1 
score; 
 
 Percentage 
of 
HQ-CT 
responders 
as 
defined 
by 
anchor-based and distribution-based methods. 
Table 2: Phase 2b  Description of the study objectives and endpoints for the Core Period and the 
Extension Period 


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Abbreviations: λz=apparent terminal rate constant; ADA=anti-drug antibodies; AEs=adverse events; AUC(0-tau)=area under the concentration-time 
curve during the dosing interval; BMI=body mass index; BW=body weight; Cavg=average concentration during the dosing interval; 
CDF=cumulative distribution function; CgGIC-H=Caregiver Global Impression of Change – Hyperphagia; CgGIS-H=Caregiver Global 
Impression of Severity – Hyperphagia; CGIC-H=Clinical Global Impression of Change – Hyperphagia; CGI-I=Clinical Global Impression of 
Improvement; CGI-S=Clinical Global Impression of Severity; CGIS-H=Clinical Global Impression of Severity – Hyperphagia; CL/F=apparent 
total body clearance; Cmax=maximum concentration; Cmin=observed minimum concentration; DBC2-P=Developmental Behavior Checklist 
2-Parent/Carer version; ECG=electrocardiogram; EQ-5D-5L=European Quality of Life Five Dimension Five Level Scale; FI=fluctuation index 
over the dosing interval; HbA1c=glycated hemoglobin; HQ-CT=Hyperphagia Questionnaire for Clinical Trials; IGF-1=insulin-like growth 
factor-1; LI=linearity index; NRS=Numerical Rating Scale; PDF=probability density function; PK=pharmacokinetic; PedsQLTM=Pediatric 
Quality of Life inventoryTM; PWS=Prader-Willi syndrome; RAUC(0-tau)=accumulation ratio for AUC(0-tau); RCmax=accumulation ratio for Cmax; 
t1/2=apparent terminal half-life; tmax=time of Cmax; tmin=time of Cmin; Vz/F=apparent volume of distribution; WC=waist circumference; 
ZBI=Zarit Burden Interview. 
 
 
3.1.2 
Phase 3 Tabular Summary of Trial Objectives and Endpoints 
 
OBJECTIVES 
ENDPOINTS 
PHASE 3 CORE PERIOD 
Primary Efficacy 
 To demonstrate the efficacy of a 6-month treatment with 
livoletide 
as 
compared 
to 
placebo 
for 
reducing 
caregiver-observed food-related behavior as assessed by the 
HQ-CT. 
 Change from baseline to the end of the 6-month Core 
Period in HQ-CT total score. 
Secondary Efficacy 
 To demonstrate the efficacy of 6-month treatment with 
livoletide as compared to placebo for: 
 
o Reducing total body fat mass in overweight/obese patients 
with PWS; 
o Percentage change from baseline to the end of the 
6-month Core Period in total body fat mass in 
overweight/obese patients with PWS; 
o Reducing WC in overweight/obese patients with PWS; 
o Change from baseline to the end of the 6-month Core 
Period in WC in overweight/obese patients with PWS; 
o Reducing BW in overweight/obese patients with PWS. 
o Percentage change from baseline to the end of the 
6-month Core Period in BW in overweight/obese 
patients with PWS. 
Safety  
 To assess the safety and tolerability of livoletide as compared 
to placebo over a 6-month treatment period. 
  Incidence of AEs; 
 Vital signs; 
 Height and BMI; 
 Physical examination; 
 Lean body mass and bone mineral density; 
 ECG; 
 Safety laboratory parameters (clinical chemistry including 
lipids, coagulation, hematology, urinalysis, HbA1c, 
ghrelin, ADA, and IGF-1). 
Additional Assessments 
 To evaluate the effect of livoletide as compared to placebo on: 
 Change from baseline in: 
o Hyperphagia severity as assessed by the CgGIS-H and 
CGIS-H; 
o CgGIS-H and CGIS-H scores; 
o Hyperphagia global impression of change as assessed by the 
CgGIC-H and CGIC-H; 
o CgGIC-H and CGIC-H scores; 
o Clinical global impression of change as assessed by the CGI-
I; 
o CGI-I score; 
o Clinical global impression of severity as assessed by the 
CGI-S; 
o CGI-S score; 
o Fasting (for approximately 8 hours) and postprandial glucose 
and insulin (profile); 
o Fasting (for approximately 8 hours) and postprandial 
glucose and insulin measurement (profile); 
o Patient-reported appetite following breakfast as assessed by 
o Appetite-NRS score; 


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OBJECTIVES 
ENDPOINTS 
an NRS; 
o Patients’ Non-Food-Related behaviors as assessed by the 
DBC2-P; 
o DBC2-P score; 
o Patients’ Quality of Life as assessed by the PedsQLTM 4.0 
Generic Core Scales; 
o PedsQLTM 4.0 Parent-Proxy age-appropriate Reports 
score; 
o Caregivers’ disease burden as assessed by the ZBI; 
o Health state utilities as assessed by EQ-5D-5L Self-complete 
version and Proxy version 1; 
o ZBI score; 
o EQ-5D-5L Self score and EQ-5D-5L Proxy version 1 
score; 
 To compare the number of HQ-CT responders between groups 
 Percentage of HQ-CT responders as defined by 
anchor-based and distribution-based methods. 


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OBJECTIVES 
ENDPOINTS 
PHASE 3 EXTENSION PERIOD 
Efficacy 
 To assess the maintenance of efficacy of livoletide treatment 
on caregiver-observed food-related behavior as assessed by the 
HQ-CT; 
 Change from baseline to the end of the 6-month 
Extension Period and change from the end of the 6-month 
Core Period to the end of the 6-month Extension Period 
in HQ-CT total score; 
 To assess the maintenance of efficacy of livoletide treatment 
on total body fat mass, WC, and BW in overweight/obese 
patients with PWS. 
 Percentage change from baseline to the end of the 
6-month Extension Period and change from the end of the 
6-month Core Period to the end of the 6-month Extension 
Period in total body fat mass in overweight/obese patients 
with PWS; 
 
 Change from baseline to the end of the 6-month 
Extension Period and change from the end of the 6-month 
Core Period to the end of the 6-month Extension Period 
in WC in overweight/obese patients with PWS; 
 
 Percentage change from baseline to the end of the 
6-month Extension Period and change from the end of the 
6-month Core Period to the end of the 6-month Extension 
Period in BW in overweight/obese patients with PWS. 
Safety  
 To assess the long-term safety and tolerability of livoletide 
over a 12-month treatment period. 
 Incidence of AEs; 
 Vital signs; 
 Height and BMI; 
 Physical examination; 
 Lean body mass and bone mineral density; 
 ECG; 
 Safety laboratory parameters (clinical chemistry including 
lipids, coagulation, hematology, urinalysis, HbA1c, 
ghrelin, ADA, and IGF-1). 
Additional Assessments 
  To evaluate the long-term effect of livoletide on: 
 Change from baseline in: 
o Hyperphagia severity as assessed by the CgGIS-H and 
CGIS-H, respectively; 
o CgGIS-H and CGIS-H scores; 
o Hyperphagia global impression of change as assessed by the 
CgGIC-H and CGIC-H, respectively; 
o CgGIC-H and CGIC-H scores; 
o Clinical global impression of change as assessed by the 
CGI-I; 
o CGI-I score; 
o Clinical global severity as assessed by the CGI-S; 
o CGI-S score; 
o Fasting (for approximately 8 hours) glucose and insulin; 
o Fasting (for approximately 8 hours) glucose and insulin 
measurement; 
o Patients’ Non-Food-Related behaviors as assessed by the 
DBC2-P version; 
o DBC2-P score; 
o Patients’ Quality of Life as assessed by the PedsQLTM 4.0 
Generic Core Scales; 
o PedsQLTM Parent-Proxy age-appropriate Reports score; 
o Caregiver disease burden as assessed by the ZBI; 
o Health state utilities as assessed by EQ-5D-5L Self-complete 
version and Proxy version 1. 
o ZBI score; 
o EQ-5D-5L Self score and EQ-5D-5L Proxy version 1 
score; 
 
 Percentage of HQ-CT responders as defined by 
anchor-based and distribution-based methods. 
Table 3: Phase 3  Description of the study objectives and endpoints for the Core Period and the 
Extension Period 
Abbreviations: ADA=anti-drug antibodies; AEs=adverse events; BMI=body mass index; BW=body weight; CgGIC-H=Caregiver Global 
Impression of Change – Hyperphagia; CgGIS-H=Caregiver Global Impression of Severity – Hyperphagia; CGIC-H=Clinical Global Impression 
of Change – Hyperphagia; CGI-I=Clinical Global Impression of Improvement; CGI-S=Clinical Global Impression of Severity; CGIS-H=Clinical 
Global Impression of Severity – Hyperphagia; DBC2-P=Developmental Behavior Checklist 2-Parent/Carer version; ECG=electrocardiogram; 
EQ-5D-5L=European Quality of Life Five Dimension Five Level Scale; HbA1c=glycated hemoglobin; HQ-CT=Hyperphagia Questionnaire for 


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Clinical Trials; IGF-1=insulin-like growth factor-1; NRS=Numerical Rating Scale; PedsQLTM=Pediatric Quality of Life inventoryTM; 
PWS=Prader-Willi syndrome; WC=waist circumference; ZBI=Zarit Burden Interview. 
3.2 
Justification for Core Period Primary and Secondary Endpoints  
3.2.1 
Phase 2b Justification for Core Period Primary and Secondary Endpoints 
In Phase 2b, the 3-month time point provides a reasonable balance between observing a 
treatment effect in food-related behavior and minimizing dropouts. 
3.2.1.1 
Phase 2b Primary Endpoint 
The primary endpoint proposed for Phase 2b with livoletide is the change from baseline to the 
end of the 3-month Core Period for Hyperphagia Questionnaire for Clinical Trials (HQ-CT) total 
score (see Section 19.2 Appendix B for HQ-CT content). 
The HQ-CT is derived from the HQ, a 13-item disease-specific questionnaire that was designed 
to assess food-related behaviors in patients with PWS as reported by caregivers as patients with 
PWS are unable to consistently and reliably report the severity of their hyperphagia and 
preoccupation with food, and food related behaviors (61).  
The HQ-CT is a 9-item instrument that has been developed and validated for use in clinical trials 
(content validity and measurement properties) based on industry standard and regulatory 
guidance (63). The HQ-CT was initially developed in US English and has been subsequently 
culturally adapted in 10 European languages (64). All items on the HQ-CT are rated on a 
five-point scale and are summed to generate a total score (0 to 36).  
Change in the HQ-CT total score is considered by the Food and Drug Administration (FDA) and 
European Medicine Agency (EMA) as a valid primary endpoint for use in clinical trials to 
demonstrate efficacy of a study drug in hyperphagia associated with PWS (based on discussions 
the Sponsor had at pre-IND and scientific advice meetings with FDA and EMA, respectively).  
3.2.1.2 
Phase 2b Secondary Endpoints (Core Period) 
The secondary endpoints proposed for Phase 2b Core Period are: 
 
Percentage change from baseline to the end of the 3-month Core Period in total body fat 
mass in overweight/obese patients with PWS;  
 
Change from baseline to the end of the 3-month Core Period in WC in overweight/obese 
patients with PWS; 
 
Percentage change from baseline to the end of the 3-month Core Period in BW in 
overweight/obese patients with PWS. 
Overweight and obesity is defined here as: 
 
For adults: Body mass index (BMI) is ≥27 kg/m2; 
 
For patients ≥ 4 and <18 years of age: ≥90th percentile for the same age and sex. 
All parameters are relevant in clinical practice on weight management. Waist circumference is 
used as an indirect measure of visceral fat content and cardiovascular risk.  
3.2.2 
Phase 3 Justification for Core Period Primary and Secondary Endpoints 
The Phase 3 Core Period primary and secondary endpoints are the same as for Phase 2b but will 
be determined at 6 months. The 6-month time point allows for an assessment of longer-term, 


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placebo-controlled endpoints that may require more than 3 months to observe a clinically 
meaningful effect. For example, some metabolic endpoints such as body composition and 
glycemic parameters may require a longer exposure period to observe maximal effects. 
4.1 
Overall Study Design 
The proposed Phase 2b/3 study will evaluate the safety, tolerability, and effects of livoletide on 
food-related behaviors in patients with PWS. 
This protocol includes 2 consecutive parts: 
1. The first part is a Phase 2b dose-response study consisting of a 3-month double-blind, 
placebo-controlled Core Period and a 9-month Extension Period. 
2. The second part is a Phase 3 study consisting of a 6-month double-blind, 
placebo-controlled Core Period followed by a 6-month Extension Period. Phase 3 may be 
initiated following review of safety and efficacy results at the completion of the Phase 2b 
Core Period. 
Patients who enrolled in the Phase 2b part will not be eligible for recruitment in the Phase 3 part. 
The overall study duration for each patient, inclusive of screening and follow-up will be 
approximately 14 months (same duration for Phase 2b and Phase 3). 
4.1.1 
Phase 2b Overall Study Design 
The Phase 2b part of the study will include adult and pediatric patients (4-65 years of age) with 
genetically confirmed PWS and evidence of hyperphagia as judged by the investigator and 
HQ-CT total score 10. 
Phase 2b will include: 
 
Phase 2b Core Period: A 3-month, double-blind, randomized, placebo-controlled 
treatment period (Phase 2b Core Period). After a screening period (up to 4 weeks), eligible 
patients will be randomized in a 1:1:1 ratio to one of two livoletide doses (8 mg/mL, low 
exposure or 16 mg/mL, high exposure) or placebo. 
Randomization will be stratified based on age (≥ 4 and < 8 years of age, ≥ 8 and <18 years 
of age and ≥18 years of age) and BMI (patients 18 years of age: BMI <27 kg/m2 vs BMI 
27 kg/m2; patients 4-17 years of age: BMI <90th percentile vs BMI 90th percentile for the 
same age and sex). For details on the stratification, please refer to Section 13.6; 
 
Phase 2b Extension Period: A 9-month Extension Period. Patients randomized to 
livoletide for the Core Period will remain on the randomized dose (i.e. 8 mg/mL, low 
exposure or 16 mg/mL, high exposure) during the Extension Period. Patients randomized 
to placebo for the Core Period will cross-over to livoletide low or high exposure in a 
randomized (1:1) manner. The Interactive Response Technology (IRT) will manage 
treatment assignment so that the double-blind status can remain intact at the start of the 
Extension Period.  
The overall study design and timelines for Phase 2b are presented in Figure 6. 
 
4 
STUDY DESIGN 


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PHASE 2b STUDY DESIGN
Core Period
Double Blind, Randomized,
Placebo-controlled Treatment Period
Extension Period
4 w.
9 months
3 months
AZP-531 low exposure
AZP-531 high exposure
Placebo
N=50
AZP-531 low
exposure
N=50
AZP-531 low exposure
AZP-531: 8 mg
N=50
AZP-531 high 
exposure
N=50
Randomization
AZP-531 high exposure
Screening
 
Figure 6: Phase 2b Core and Extension PeriodsStudy Schematic 
Abbreviations: AZP-531=livoletide; N=number of patients; w=weeks. 
 
4.1.2 
Phase 3 Overall Study Design 
Phase 3 may commence after completion of Phase 2b Core Period. Following review of data at 
the completion of the Phase 2b Core Period, the Phase 3 livoletide doses will be reassessed along 
with the statistical assumptions. Patients who enrolled in the Phase 2b part will not be eligible for 
recruitment in the Phase 3 part. 
The Phase 3 part of the study will include adult and pediatric patients (8-65 years of age, 4-7 
years of age may also be included) with genetically confirmed PWS and evidence of hyperphagia 
as judged by the investigator and HQ-CT total score 10.  


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Phase 3 will include: 
 
Phase 3 Core Period: A 6-month, double-blind, randomized, placebo-controlled treatment 
period. After a screening period (up to 4 weeks), eligible patients will be randomized to 
livoletide or placebo; 
 
Phase 3 Extension Period: A 6-month Extension Period. Patients randomized to livoletide 
for the Core Period will remain on the randomized dose during the Extension Period. 
Patients randomized to placebo for the Core Period will cross-over to livoletide during the 
Extension Period. The IRT will manage treatment assignment so that the double-blind 
status can remain intact at the start of the Extension Period.  
The overall study design and timelines for Phase 3 are presented in Figure 7. 
 
PHASE 3 STUDY DESIGN
Core Period
Double Blind, Randomized,
Placebo-controlled Treatment Period
Extension Period
4 w.
6 months
6 months
Placebo
AZP-531 dose(s) tbd
AZP-531 dose(s) tbd
Randomization
tbd: to be determined
AZP-531 dose(s) tbd
Screening
 
Figure 7: Phase 3 Core and Extension PeriodsStudy Schematic 
Abbreviations: AZP-531=livoletide; tbd=to be determined; w=weeks. 
 


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4.2 
Scientific Rationale and Discussion for Study Design 
4.2.1 
Rationale for the Extension Period  
Prader-Willi syndrome is a life-long disease. Therefore, it is critical to assess whether an effect 
on food behavior is maintained and that no compensatory mechanism that would decrease 
efficacy over time appears. 
In order to assess the maintenance of efficacy of livoletide treatment, Phase 2b will include a 
9-month Extension Period following the 3-month Core Period and Phase 3 will include a 
6-month Extension Period following the 6-month Core Period. For both Phase 2b and Phase 3 
the combined Core Period and Extension Period will allow collection of safety data over 
12 months of treatment.  
4.2.2 
Rationale for the Control Arm 
The control arm that has been selected for both the Phase 2b Core Period and Phase 3 Core 
Period is placebo. A placebo-controlled study was chosen because there is no approved 
medication for the pharmacological treatment of hyperphagia in patients with PWS that could 
have been used as an active comparator. 
4.3 
Justification for Dose 
The low exposure (8 mg/mL, 60 µg/kg/day targeted exposure) and high exposure (16 mg/mL, 
120 µg/kg/day targeted exposure) daily doses have been selected for Phase 2b in order to assess 
dose effect relationship. 
The selection of the doses is supported by the following observations: 
 
Cumulative nonclinical data available to date indicate that livoletide has a wide safety 
margin. In rats and dogs, the highest chronic dose (13 weeks) tested was considered the No 
Observed Adverse Effect Level (NOAEL) and provided a group mean AUC value of 
greater than or equal to 50-fold of the high clinical exposure; 
 
Administration of livoletide was well tolerated in humans following a single administration 
at doses up to 120 µg/kg and following repeated administration for 14 days at doses up to 
60 µg/kg/day; 
 
PK characteristics of livoletide were comparable overall at the same doses in 3 study 
populations including healthy subjects, obese subjects, and patients with T2D. Following 
repeated administration up to 60µg/kg/day, Cmax, and AUCs were dose-related and 
increased proportionally with the dose administered; 
 
Phase 2a clinical data obtained in patients with PWS demonstrated efficacy and a good 
safety profile when livoletide was administered once a day for 14 days (60 µg/kg/day 
targeted exposure). 
Following review of data at the completion of the Phase 2b Core Period, the Phase 3 livoletide 
doses will be reassessed along with the statistical assumptions. 
4.4 
Number of Patients 
For Phase 2b, approximately one hundred and fifty (150) patients (8 to 65 years of age) will be 
randomized in a 1:1:1 ratio to one of the 3 arms (livoletide low exposure [8 mg/mL], livoletide 


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high exposure [16 mg/mL], or placebo). In addition to this cohort of 150 patients, a separate 
cohort of patients 4 to 7 years of age will be randomized similarly (1:1:1 ratio). Please refer to 
Section 13.2 for details about the determination of the number of patients. 
For Phase 3, the total number of required patients to be randomized is estimated to be 50 patients 
per group. Final sample size will be determined following analysis of data at the completion of 
the Phase 2b Core Period. 
4.5 
Number of Study Sites 
This study will be conducted at multiple centers worldwide, at approximately 40 centers in 
Europe, Australia and North America. Participating sites will be specialized in the management 
of patients with PWS. 
4.6 
Definition of the End of the Study 
The end of study is defined as the last visit of the last patient (LPLV) in the trial globally. 
5.1 
Phase 2b Patient Inclusion and Exclusion Criteria 
5.1.1 
Phase 2b Patient Inclusion Criteria for the Core Period 
A patient must meet ALL of the following inclusion criteria at screening in order to be eligible to 
participate in the study: 
1. A confirmed genetic diagnosis of PWS. Documentation of PWS subtype (chromosome 15 
micro-deletion versus non-deletion) is also required for the study. If the PWS subtype is 
not known, a sample for testing may be obtained and the patient may continue on to be 
enrolled into the study if he or she meets all the other inclusion criteria and none of the 
exclusion criteria. 
2. Male and female patients 4 to 65 years of age, inclusive, 12 to 65 years for Australian sites 
201 and 202. 
3. Have evidence of increased appetite or hyperphagia, as judged by the investigator, and a 
total HQ-CT score ≥10 (scale of 0-36). 
4. Patients willing to comply with the following lifestyle considerations: 
a. 
Be on a stable diet regimen. 
b. 
Be on a stable physical activity regimen. Patients should agree to refrain from 
changing their usual level of physical activity. 
5. Each patient must have a single primary caregiver who will be able to evaluate and score 
that patient’s behaviors and perform any study-related activities as defined in the protocol 
throughout the study. That person must have been caring for the patient for at least 
6 months prior to screening, spend, on average, approximately 4 (or more) waking hours 
per day with the patient, and should be available for the duration of the study. 
a. During the Extension Period, the time spent by the caregiver with the patient may 
be reduced, as long as the caregiver spends, on average, approximately 4 (or 
more) waking hours per day with the patient at least 2 weeks before each visit.  
5 
STUDY POPULATION 


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6. BMI ≤65 kg/m2 for adult patients. 
7. WCBP must have a negative pregnancy test. 
8. All WCBP, sexually active male patients, and all opposite sex partners of patients should 
agree to use medically-approved effective methods of birth control (e.g. diaphragm, 
condoms with spermicide) throughout the study and for 30 days after the last dose of study 
drug. 
a. WCBP or male patients who agree with a true abstinence (when in line with the 
preferred or usual lifestyle of the patient) can be included. 
9. Adequate renal function, defined as serum creatinine 1.5  upper limit of normal (ULN). 
10. Adequate hepatic function, defined as total bilirubin 1.5  ULN and aspartate 
aminotransferase (AST) and alanine aminotransferase (ALT) levels 3  ULN. 
11. Diabetes medications will be permitted if doses have been stable for at least 3 months prior 
to screening. Insulin doses are considered to have been stable if the prescribed total daily 
insulin doses are within approximately 20% of those at screening. 
12. Growth hormone treatment will be permitted if doses have been stable for at least 1 month 
prior to screening. 
13. Psychotropic treatment (e.g. modafinil, topiramate, zonisamide, fluoxetine, aripiprazole, 
risperidone, quetiapine, and benzodiazepines) will be permitted if doses have been stable 
for at least 2 months prior to screening. 
14. Any other medication that is likely to affect behavior, body composition, or lipids (in the 
opinion of the investigator) (must be stable for at least 2 months prior to screening, except 
as noted below: 
a. Thyroid hormone: changes within approximately 13 µg/day are acceptable 
b. Sex steroids: patients on sex steroids must have been taking them for at least 2 
months at screening; dose changes within approximately 25% of the screening 
dose are acceptable as are changes within a class (e.g., from one oral 
contraceptive to another, or from one selective estrogen receptor to another). 
15. Approved informed consent (Assent form for patients under the age of majority) signed by 
the patient, parent, or legal guardian, as appropriate, at the screening visit before any study 
procedures. 
16. For patients from France only: Is either affiliated with or a beneficiary of “sécurité 
sociale”. 
5.1.2 
Phase 2b Patient Exclusion Criteria 
All patients meeting any of the following exclusion criteria at screening will be excluded from 
participation in this study: 
1. History of chronic liver disease, such as cirrhosis or chronic hepatitis due to any cause, or 
suspected alcohol abuse. 


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2. History of significant cardiovascular disease including history of congestive heart failure 
(CHF, New York Heart Association [NYHA] Class 3 or 4), angina pectoris, or myocardial 
infarction (MI) within 6 months prior to screening. 
3. Type 1 diabetes mellitus. 
4. HbA1c >10%. 
5. History of frequent hypoglycemia. 
6. Blood pressure systolic 160 mmHg, diastolic 90 mmHg (adult patients) and blood 
pressure systolic 140 mmHg, diastolic 90 mmHg (patients 4 to 17 years of age). 
7. Use of weight loss agents and medications taken to affect appetite (e.g. Orlistat®, Lorcaserin, 
Qsymia®, Contrave®/Mysimba®, glucagon-like-peptide 1 [GLP-1] analogs, as well as any 
over-the counter medication and herbal agent) within 2 months prior to screening. 
8. Co-morbid condition or disease (such as respiratory disease or psychiatric disorder) 
diagnosed less than 1 month prior to screening. 
9. Co-morbid condition or disease or abnormal laboratory finding that would in the 
investigator’s judgment increase the patient risk to participating in this study or that will 
not allow the patient to complete the study. 
10. Known history of hepatitis B, hepatitis C, or human immunodeficiency virus (HIV). 
11. Participation in a clinical trial with an investigational agent within 3 months prior to 
screening. 
12. Clinically significant abnormalities on ECG at screening, as follows: 
a. Patients 4 years of age: males QT interval corrected for heart rate by Bazett’s formula 
(QTcB) >448 ms, females QTcB >442 ms. 
b. Patients 5 to 7 years of age: males QTcB >443 ms, females QTcB >449 ms. 
c. Patients 8 to 11 years of age: males (QTcB) >440 ms, females QTcB >447 ms. 
d. Patients 12 to 15 years of age: males QTcB >449 ms, females QTcB >457 ms. 
e. Patients 16 years of age: males QTcB >450 ms, females QTcB >470 ms. 
13. Pregnant or lactating woman. 
14. History of hypersensitivity to drugs with a similar chemical structure or class as livoletide 
(AG and UAG). 
15. Unwillingness or inability to follow the procedures outlined in the protocol. 
16. Patients living in a group home 50% of the time. 
17. Patients with body weight <20 kg. 
5.1.3 
Phase 2b Patient Inclusion Criteria for the Extension Period 
In order to be able to participate in the Extension Period, patients will be required to have 
completed the Core Period. 


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5.2 
Phase 3 Patient Inclusion and Exclusion Criteria 
Based on results from Phase 2b, some inclusion criteria for the Phase 3 Core and Extension 
Periods may be adjusted. 
5.2.1 
Phase 3 Patient Inclusion Criteria for the Core Period 
A patient must meet ALL of the following inclusion criteria at screening in order to be eligible to 
participate in the study: 
1. A confirmed genetic diagnosis of PWS. Documentation of PWS subtype (chromosome 15 
micro-deletion versus non-deletion) is also required for the study. If the PWS subtype is 
not known, a sample for testing may be obtained and the patient may continue on to be 
enrolled into the study if he or she meets all the other inclusion criteria and none of the 
exclusion criteria. 
2. Male and female patients 8 to 65 years of age, inclusive. 
3. Have evidence of increased appetite or hyperphagia, as judged by the investigator, and a 
total HQ-CT score ≥10 (scale of 0-36). 
4. Patients willing to comply with the following lifestyle considerations: 
a. Be on a stable diet regimen. 
b. Be on a stable physical activity regimen. Patients should agree to refrain from 
changing their usual level of physical activity. 
5. Each patient must have a single primary caregiver who will be able to evaluate and score 
that patient’s behaviors and perform any study-related activities as defined in the protocol 
throughout the study. That person must have been caring for the patient for at least 
6 months prior to screening, spend, on average, approximately 4 (or more) waking hours 
per day with the patient, and should be available for the duration of the study. 
a. During the Extension Period, the time spent by the caregiver with the patient may 
be reduced as long as the caregiver spends, on average, approximately 4 (or more) 
waking hours per day with the patient at least 2 weeks before each visit. 
6. BMI ≤65 kg/m2 for adult patients. 
7. WCBP must have a negative pregnancy test. 
8. All WCBP, sexually active male patients, and all opposite sex partners of patients should 
agree to use medically-approved effective methods of birth control (diaphragm, condoms 
with spermicide) throughout the study and for 30 days after the last dose of study drug. 
a. WCBP or male patients who agree with a true abstinence (when in line with the 
preferred or usual lifestyle of the patient) can be included. 
9. Adequate renal function, defined as serum creatinine 1.5  ULN. 
10. Adequate hepatic function, defined as total bilirubin 1.5  ULN and AST and ALT levels 
3  ULN. 
11. Diabetes medications will be permitted if doses have been stable for at least 3 months prior 
to screening. Insulin doses are considered to have been stable if the prescribed total daily 
insulin doses are within approximately 20% of those at screening. 


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12. Growth hormone treatment will be permitted if doses have been stable for at least 1 month 
prior to screening. 
13. Psychotropic treatment (e.g. modafinil, topiramate, zonisamide, fluoxetine, aripiprazole, 
risperidone, quetiapine, and benzodiazepines) will be permitted if doses have been stable 
for at least 2 months prior to screening. 
14. Any other medication that is likely to affect behavior, body composition, or lipids (in the 
opinion of the investigator) must be stable for at least 2 months prior to screening, except 
as noted below: 
a. Thyroid hormone: changes within approximately 13 µg/day are acceptable 
b. Sex steroids: patients on sex steroids must have been taking them for at least 2 
months at screening; dose changes within approximately 25% of the screening 
dose are acceptable as are changes within a class (e.g., from one oral 
contraceptive to another, or from one selective estrogen receptor to another). 
15. Approved informed consent (Assent form for patients under the age of majority) signed by 
the patient, parent, or legal guardian, as appropriate, at the screening visit before any study 
procedures. 
16. For patients from France only: Is either affiliated with or a beneficiary of “sécurité 
sociale”. 
5.2.2 
Phase 3 Patient Exclusion Criteria 
A patient who enrolled in the Phase 2b part is not eligible for recruitment in the Phase 3 part. 
All patients meeting any of the following exclusion criteria at screening will be excluded from 
participation in this study: 
1. History of chronic liver disease, such as cirrhosis or chronic hepatitis due to any cause, or 
suspected alcohol abuse. 
2. History of significant cardiovascular disease including history of CHF (NYHA Class 3 or 
4), angina pectoris, or MI within 6 months prior to screening. 
3. Type 1 diabetes mellitus. 
4. HbA1c >10%. 
5. History of frequent hypoglycemia. 
6. Blood pressure systolic 160 mmHg, diastolic 90 mmHg (adult patients) and blood 
pressure systolic 140 mmHg, diastolic 90 mmHg (patients 8 to 17 years of age). 
7. Use of weight loss agents and medications taken to affect appetite (e.g. Orlistat®, 
Lorcaserin, Qsymia®, Contrave®/Mysimba®, GLP-1 analogs, as well as any over-the 
counter medication and herbal agent) within 2 months prior to screening. 
8. Co-morbid condition or disease (such as respiratory disease or psychiatric disorder) 
diagnosed less than 1 month prior to screening. 


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9. Co-morbid condition or disease or abnormal laboratory finding that would in the 
investigator’s judgment increase the patient risk to participating in this study or that will 
not allow the patient to complete the study. 
10. Known history of hepatitis B, hepatitis C, or HIV. 
11. Participation in a clinical trial with an investigational agent within 3 months prior to 
screening. 
12. Patients who participated in the Phase 2b part of the study. 
13. Clinically significant abnormalities on ECG at screening, as follows: 
a. Patients 8 to 11 years of age: males QTcB >440 ms, females QTcB >447 ms. 
b. Patients 12 to 15 years of age: males QTcB >449 ms, females QTcB >457 ms. 
c. Patients 16 years of age: males QTcB >450 ms, females QTcB >470 ms. 
14. Pregnant or lactating woman. 
15. History of hypersensitivity to drugs with a similar chemical structure or class as livoletide 
(AG and UAG). 
16. Unwillingness or inability to follow the procedures outlined in the protocol. 
17. Patients living in a group home 50% of the time.  
18. Patients with body weight <20 kg. 
5.2.3 
Phase 3 Patient Inclusion Criteria for the Extension Period 
In order to be able to participate in the Extension Period, patients will be required to have 
completed the Core Period. 
5.3 
Lifestyle Considerations 
5.3.1 
Contraception Requirements 
All patients of childbearing potential, if not abstinent, must be willing to practice effective 
contraception from the time of signing the informed consent form (ICF), during study treatment, 
and for 30 days after the final dose of study treatment. This includes sexually active male 
patients and all opposite sex partners of patients. Pediatric/adolescent patients must initiate 
contraception at menarche/spermarche or must discontinue study drug. 
Please refer to Section 8.1.2.2 for the definition of childbearing potential. 


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5.3.2 
Other Requirements or Considerations 
During this study, patients are: 
 
Required to fast for approximately 8 hours before visits requiring blood sampling; 
 
Patients 8 to 65 years are required to take an isocaloric breakfast prepared at the study 
center at selected site visits. 
5.4 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently randomly assigned to the study drug or entered in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure 
participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any SAE. 
In accordance with HQ-CT administration guidelines, individuals who do not meet the criterion 
for participation in the Phase 2b part of the protocol (screen failure) because of their HQ-CT 
score must not be rescreened for Phase 2b. However, given the length of time anticipated 
between closure of screening for Phase 2b and start of screening for Phase 3, such a patient may 
be eligible to screen for participation in Phase 3. 
5.5 
Justification for Inclusion of Vulnerable Participants 
Although the research will include adults, both legally competent and under guardianship, we 
believe there is a clear clinical and methodological rationale for the inclusion of minors and 
patients under guardianship in this study: 
1. Hyperphagia and abnormal food behavior start at an early age and are particularly critical 
in the management of patients with PWS.  
Considering i) the serious nature of hyperphagia, ii) the implementation of measures when 
hyperphagia starts to develop may be critical, and iii) safety and efficacy results from 
previous clinical studies, there is a reasonable likelihood that pediatric patients (children 
and adolescents) stand to benefit from the results of the research. 
2. PWS is rare genetic disease with a limited population. Legal guardianship and assisted 
living are usually required to ensure a safe living environment, since individuals with PWS 
typically make poor decisions related to living arrangements and food (65, 66). A 
significant proportion of adult patients with PWS are under guardianship. For example, in 
France, 52.8% of patients with PWS are under guardianship (67). 
Considering the challenging number of available patients in this rare disease, and in order 
have reliable results, patients under guardianship measures will also be enrolled in this 
study. 
Overall, based on clinical results from the Phase 2a study, patients participating in this study may 
benefit from the study treatment. It is reasonable to assume that the research is necessary to 
promote the health of the population represented and this research cannot instead be performed 
only on legally competent persons. 


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6.1 
Study Drug Administration 
6.1.1 
Study Drug Description 
Information on the study drugs (livoletide and placebo product) can be obtained from the IB for 
livoletide. 
6.1.2 
Dosing and Administration 
Study drug must be dispensed or administered only to patients enrolled in the study and in 
accordance with the protocol.  
Study drug doses will be administered by the site staff during site visits. Otherwise, other doses 
(doses in between site visits) will be administered at the patient’s home (or other location 
convenient to the patient). Injections will be performed each study morning before breakfast at 
approximately the same time. At the randomization visit the injection will be performed when all 
the assessments have been completed. At selected site visits, an isocaloric breakfast will be 
served 30 minutes following injection. 
Study drug will be administered by SC injection at rotating sites on the abdomen. Study drug 
must be kept refrigerated at 2 to 8°C (36 to 46°F).  
The inclusion criterion age range of 4 to 65 years is expected to correspond to a BW range of 
~20 to 140 kg. Therefore, livoletide will be dosed according to BW on a µg/kg basis and will be 
provided as a sterile liquid formulation (in 0.9% sodium chloride [NaCl] solution) in single-use 
clear glass vials. Two concentrations of livoletide will be available for this study, 8 mg/mL and 
16 mg/mL. The volume of dosing will be adjusted according to BW (Table 4) to achieve targeted 
livoletide exposure levels of approximately 60 µg/kg and 120 µg/kg (i.e. a low exposure and a 
high exposure). Both livoletide concentrations as well as matching placebo are identical in 
appearance to maintain the study blind. Placebo will be administered at the same volumes as 
livoletide. 
 
 
Low exposure 
(8 mg/mL) 
High exposure 
(16 mg/mL) 
Body weight 
range (kg) 
Daily injection volume (mL) 
Daily injection volume (mL) 
20.0 to 29.0 
0.125 
0.125 
30.0 to 49.0 
0.250 
0.250 
50.0 to 70.0 
0.375 
0.375 
>70.0 
0.500 
0.500 
Table 4: Adjustment of livoletide dosing according to body weight 
 
The exposure dosing will be adjusted if there is any weight change at the 3-month visit at the end 
of the Core Period in Phase 2b or at the 6-month visit at the end of the Core Period in Phase 3. 
Detailed instructions on study drug administration will be provided to the caregivers and site in a 
specific document. 
6 
STUDY DRUGS 


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6.1.2.1 
Route of Administration 
The study drug will be administered subcutaneously as a single injection under a full skin fold of 
the anterior abdominal region, at rotating sites, every day during the treatment period. 
6.1.2.2 
Starting Dose and Dose Escalation Schedule 
Two exposure levels per dose (i.e. 60 µg/kg and 120 µg/kg) will be targeted in the study with 
each serving as starting dose. No dose escalation will be permitted during the study.  
Following review of data at the completion of the Phase 2b Core Period, the Phase 3 livoletide 
doses will be reassessed along with the statistical assumptions. 
6.1.2.3 
Dose Adjustments/Modifications/Delays  
If a dose is missed, it should not be taken if it is less than 8 hours until the next dose. 
6.2 
Preparation/Handling/Storage/Accountability 
6.2.1 
Acquisition and Accountability 
6.2.1.1 
Acquisition 
Study drug will be dispensed to the study center in a blinded fashion as treatment kits. The 
allocation of study drug to patients must only be carried out by the IRT. For further information 
on this procedure, please refer to the dedicated manual. 
Drug administration supplies will also be provided. 
6.2.1.2 
Accountability 
The investigator has the ultimate responsibility for the study drug accountability at the study site. 
Each investigator/designated individual (e.g. pharmacist or any other appropriate person) is 
responsible for taking an inventory of each shipment of study drug received. The 
investigator/designee will acknowledge receipt of study drug, using IRT to confirm shipment 
condition and content.  
Study drug must be used only as directed in this protocol. The investigator/designee must keep 
accurate records of all study drug received from Millendo Therapeutics/designee. Additionally, 
the investigator/designee must keep accurate records of the study drug throughout the study 
including the use by each patient, the reconciliation of all delivered and received study drug, and 
the return of used and unused study drug (as applicable) as specified in the dedicated manual. All 
study drugs must be accounted for and all discrepancies investigated and documented 
appropriately.  
Study drug stock may not be removed from the investigative site where originally shipped 
without prior knowledge and consent of Millendo Therapeutics or their delegated Clinical 
Research Organization (CRO). When authorized, all applicable local, state, and national laws 
must be adhered to for the transfer.  
At the end of the study, all used and unused vials of study drug will be destroyed by the 
investigative site or sent to a designated contractor for disposal on behalf of Millendo 
Therapeutics, per the instructions at that time.  


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6.2.2 
Formulation, Appearance, Packaging, and Labeling 
6.2.2.1 
Pharmaceutical Formulation and Appearance 
Livoletide and placebo will be manufactured by: 
BAG Health Care GmbH 
Amtsgerichtsstrasse 1-5  
35423 Lich 
Germany 
Livoletide and placebo will be dispensed in same sized 2-mL clear single-use glass vials. Each 
livoletide vial will contain 0.6 mL of either the low concentration (8 mg/mL) or the high 
concentration (16 mg/mL) of sterile livoletide in 0.9% NaCl solution for injection. To ensure 
adequate blinding, all livoletide and placebo vials will be of comparable aspect at visual 
inspection.  
6.2.2.2 
Labeling and Packaging 
All packaging, labeling, and the preparation of livoletide and placebo will be in compliance with 
GMP, as described in Annex 13 of Volume 4 to European Union GMP guidelines, and any other 
or local applicable regulations.  
CSM Clinical Supplies Management Europe GmbH 
Am Kronberger Hang 3 
65824 Schwalbach a.Ts. 
Germany 
Study drug labels will include all appropriate local labeling requirements on the vial and external 
label. Sample labels will be submitted to health authorities, per local country submission 
requirements. 
6.2.3 
Product Storage and Stability 
Treatment kits should be stored refrigerated (between +2°C and +8°C [(+36°F and +46°F]) either 
at the study center (locked environment with restricted access) or at patient’s home, as 
applicable, prior to use. 
No special procedures for the safe handling of study drug are required. A Sponsor representative 
or designee will be permitted, upon request, to audit the supplies, storage, dispensing procedures, 
and records. 
Study drug supplied for this study may not be administered to any person not enrolled in the 
study. 
6.2.4 
Preparation 
No preparation is required, the volume of the livoletide or placebo vial should be injected as it is. 
Instructions will be provided in a separate document. 


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6.3 
Measures to Minimize Bias 
6.3.1 
Phase 2b Core Period Treatment Assignment and Blinding 
Patients will be assigned to one of the 3 treatment groups in a randomized fashion. A 
computer-generated randomization schedule will be prepared prior to the start of the study. An 
IRT will be used to assign randomization number and kit number according to the randomization 
schedule.  
Randomization will be 1:1:1 among treatment arms. Stratification will be performed based on 
age (≥ 4 and <8 years of age, ≥ 8 and <18 years of age, and ≥18 years of age) and BMI (patients 
>18 years of age: BMI <27 kg/m2 vs BMI ≥27 kg/m2; patients 4-17 years of age: BMI <90th 
percentile vs BMI 90th percentile for the same age and sex). A minimum of 25 
overweight/obese subjects will be randomized per treatment group. Further details are described 
in Section 13.2.1. 
Patients, investigational staff, and persons performing the assessments and data analysis will 
remain blinded to the identity of study treatment from the time of randomization until database 
lock. 
The randomized code may be broken if an emergency situation arises that in the investigator’s 
opinion requires the knowledge of the code (for example, life threatening situation or necessity 
to know the product administered to provide with the best medical care). The investigator must 
do his/her very best to contact the Sponsor or representative before unblinding the code through 
the IRT system. Date, time, and reason(s) for breaking the code must be recorded by the 
investigator.  
Randomization data will be kept strictly confidential, accessible only to authorized persons, until 
the time of unblinding. It is the responsibility of the investigator to maintain the blind throughout 
the study. At the conclusion of the trial, the occurrence of any emergency code breaks will be 
verified after return of all code break reports and unused drug supplies to the packaging supplier. 
The drug codes will be broken and made available (unblinding) for data analysis only when the 
clinical database is locked, and the protocol violations are determined.  
The Sponsor reserves the right to break the blind for SAEs that are considered to be related to the 
study drug and unexpected, which could require an expedited report to the regulatory authorities. 
6.3.2 
Phase 2b Extension Period Treatment Assignment and Blinding  
The IRT will manage treatment assignment for the Extension Period so that the double-blind 
status can remain intact at the start of the Extension Period. Thus, the Extension Period will 
remain double-blinded for a long as feasible to ensure as robust a dataset as possible. Change 
from baseline assessments within a given treatment arm, as well as comparisons between 
treatment arms, can still provide extremely valuable and meaningful data, especially if the blind 
in maintained. Patients randomized to livoletide for the Core Period will remain on the 
randomized dose during the Extension Period (i.e. a patient randomized to livoletide low 
exposure during the Core Period will remain on low exposure for the duration of the Extension 
Period, no changes are allowed). Patients randomized to placebo for the Core Period will cross-
over to livoletide (low exposure [8 mg/mL] or high exposure [16 mg/mL] in a 1:1 randomized 
manner) during the Extension Period. 


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6.3.3 
Phase 3 Treatment Assignment and Blinding 
The same procedures used for Phase 2b will be used for Phase 3. Patients will be assigned to one 
of the treatment groups in a randomized fashion. A computer-generated randomization schedule 
will be prepared prior to the start of the study. An IRT will be used to assign randomization 
number and kit number according to the randomization schedule. Randomization and blinding 
procedures described for Phase 2b apply for Phase 3. 
Stratification variables will be reassessed following review of data at the completion of the 
Phase 2b Core Period. 
6.4 
Tracking of Dose and Assessment of Patient Compliance 
Compliance with study drug administration is dependent on administration of SC injections and 
attendance by the patient at the clinic for scheduled assessment visits. Compliance with study 
drug administration will be verified through observation by study staff, documented through the 
completion of a patient diary, and reported on the electronic case report forms (eCRFs).  
6.5 
Concomitant Therapies 
All concomitant prescription medications taken during study participation will be recorded on 
the eCRFs. For this protocol, a prescription medication is defined as a medication that can be 
prescribed only by a properly authorized/licensed clinician. Medications to be reported in the 
eCRF 
are 
concomitant 
prescription 
medications, 
over-the-counter 
medications, 
and 
non-prescription medications  
For Phase 2b and 3, as described in Section 5.1 and Section 5.2, the following medications are 
allowed under specific conditions: 
 
Diabetes Treatment: Diabetes medication will be permitted if doses have been stable for 
at least 3 months prior to screening. Insulin doses are considered to have been stable if the 
prescribed total daily insulin doses are within approximately 20% of those at screening; 
 
Growth Hormone Treatment: Growth hormone treatment will be permitted if doses have 
been stable for at least 1 month prior to screening; 
 
Psychotropic Treatment: Psychotropic treatment (e.g. modafinil, topiramate, zonisamide, 
fluoxetine, aripiprazole, risperidone, quetiapine, and benzodiazepines) will be permitted if 
doses have been stable for at least 2 months prior to screening. 
Any other medication that is likely to affect behavior, body composition, or lipids (in the opinion 
of the investigator) must be stable for at least 2 months prior to screening, except as noted below: 
 Thyroid hormone: changes within approximately 3 µg/day are acceptable 
 Sex steroids: patients on sex steroids must have been taking them of at least 2 months at 
screening; dose changes within approximately 25% of the screening dose are acceptable 
as are changes within class (e.g., from one oral contraceptive to another, or from one 
selective estrogen receptor to another). 
 
 


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The following medications are NOT allowed for Phase 2b or Phase 3: 
 
Weight loss agents and medications taken to affect appetite (e.g. Orlistat®, Lorcaserin, 
Qsymia®, Contrave®/Mysimba®, GLP-1 analogs as well as any over-the counter 
medication and herbal agent). 
In the interest of patients’ safety and acceptable standards of medical care, the investigator will 
be permitted to prescribe treatments. All prescribed treatments should be maintained at constant 
dose if possible and must be recorded in the patient’ eCRFs. 
6.6 
Rescue Medicine 
This section is not applicable. 
Participants may withdraw voluntarily from the study or the Principal Investigator (PI) in 
accordance with the Sponsor may terminate a participant from the study. 
7.1 
Discontinuation of Study Treatment 
Patients (or legally authorized representatives) can decline to continue receiving the study drug 
and/or other protocol-required procedures at any time during the study.  
If a clinically significant finding is identified (including, but not limited to changes from 
baseline) after enrollment, the investigator or qualified designee will determine if any change in 
participant management is needed. Any new clinically relevant finding will be reported as an 
AE. 
7.2 
Participant Discontinuation/Withdrawal from the Study 
Patients have the right to withdraw from the study at any time and for any reason without 
prejudice to future medical care by the physician or institution. 
Reasons for removal from protocol-required treatment or procedures might include the 
following: 
 
Study withdrawal: Participants are free to withdraw from participation in the study at any 
time upon request.  
o For the Netherlands, if patients show resistance (refuse to cooperate) during the 
study, the investigator will follow the guidelines listed below and will have to 
stop the study immediately: 
 Code of Conduct relating to expressions of abjection by minors 
participating in medical research; 
 Code of conduct relating to the expression of objection by people with 
mental disabilities in the context of the Medical Research in Human 
Subjects Act (WMO); 
 
Pregnancy: Withdraw the patient from the clinical trial and follow the procedure described 
in Section 8.1.2.2; 
7 
STUDY 
DRUG 
DISCONTINUATION 
AND 
PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 


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 
Adverse Events: Any clinical AE, laboratory abnormality, or other medical condition or 
situation occurs such that continued participation in the study would not be in the best 
interest of the participant. Complete an Adverse Event Form; 
 
Eligibility: The participant meets an exclusion criterion (either newly developed or not 
previously recognized) that precludes further study participation; 
 
Protocol violation: Lack of compliance to protocol requirements and/or procedures; 
 
Lost to follow-up: Refer to Section 7.3; 
 
Death; 
 
Other: This category is to be used for a patient who discontinues due to a reason other than 
those specified in the predefined categories above (e.g. including but not limited to 
administrative deviations that preclude satisfactory completion of protocol assessments). 
The eCRF will be completed following instructions provided to the site. 
Any patient who discontinues early from the study should be strongly encouraged to come back 
to the study site to conduct all study assessment described under Early Termination Visit in the 
Schedule of Assessments. Minimum assessments include HQ-CT administration, safety 
assessments, Caregiver Global Impression of Severity - Hyperphagia (CgGIS-H) and Clinical 
Global Impression of Severity - Hyperphagia (CGIS-H). 
7.2.1 
Handling of Participant Withdrawal or Termination 
Before interrupting or discontinuing study drug, the investigator should contact the Sponsor or 
designee (except in the case of an emergency) in order to discuss the proposed reason. It has to 
be documented whether or not each patient completes the study. If any patient study treatment or 
observations are discontinued, the reason must be recorded in the patient medical file and in the 
eCRF. Patients will be instructed by the investigator to immediately contact their personal 
primary care physician to resume to their entire PWS treatment. 
The investigator is to discuss with the patient appropriate processes for discontinuation and the 
options for procedures that may continue such as collection of data, including endpoints and 
AEs.  
The investigator must document the agreement in the procedures that the patient will continue 
with and the level of follow-up that is agreed to by the patient (e.g. in person, by telephone/mail, 
through family/friends, in correspondence/communication with other physicians, from review of 
the medical records.). 
If a patient withdraws due to an AE at any time during the study, the investigator should arrange 
for the patient to have appropriate follow-up until the AE has resolved or stabilized.  
7.2.2 
Replacement of Patients 
Patients who withdraw from the study after randomization will not be replaced.  
For Phase 2b, the total number of randomized patients 8 to 65 years of age is estimated to be 
approximately 50 patients per group. 
For Phase 3, the total number of randomized patients is estimated to be approximately 
50 patients per group but will be determined following analysis of data at the completion of the 
Phase 2b Core Period. 


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7.3 
Lost to Follow-Up 
A participant will be considered lost to follow-up if he or she fails to return for 2 consecutive 
scheduled visits and is unable to be contacted by the study site staff.  
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
 
The site will attempt to contact the participant and reschedule the missed visit and counsel 
the participant on the importance of maintaining the assigned visit schedule and ascertain if 
the participant wishes to and/or should continue in the study; 
 
Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, a 
certified letter to the participant’s last known mailing address or local equivalent methods). 
These contact attempts should be documented in the participant’s medical record or study 
file as instructed by the Sponsor/representative; 
 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
7.4 
Premature Termination or Suspension of Study 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to the investigator, and 
regulatory authorities. If the study is prematurely terminated or suspended, the PI will promptly 
inform the Institutional Review Board (IRB)/Ethics Committee (EC) and will provide the 
reason(s) for the termination or suspension.  
Circumstances that may warrant termination or suspension include, but are not limited to:  
 
Determination of unexpected, significant, or unacceptable risk to participants;  
 
Demonstration of efficacy that would warrant stopping;  
 
Insufficient compliance with protocol requirements; 
 
Data that are not sufficiently complete and/or evaluable; 
 
Determination of futility. 
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed and satisfy the Sponsor, IRB/EC, and/or Regulatory Authorities. 
8.1 
Study Procedures/Evaluations 
8.1.1 
Study Specific Procedures 
The following is a list of study specific procedures (i.e. not part of Standard Clinical Care) and 
their description: 
8 
STUDY ASSESSMENTS, PROCEDURES AND SCHEDULE 


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 
Dual energy X-ray absorptiometry (DXA) scan: Pertinent variables of body 
composition, including total body fat mass, lean body mass, and bone mineral density will 
be measured by DXA. Also see Section 9.1.2 and Section 10.1.5; 
 
ECG (12-lead): Also see Section 10.1.6; 
 
PK: Blood samples for PK analysis must be drawn per the Schedule of Activities tables 
available in Section 1.2. A Manual detailing the PK sample collection, preparation, storage 
and shipping process will be provided. Also see Section 8.1.2.3.1; 
 
HQ-CT, CgGIS-H/CGIS-H, Caregiver Global Impression of Change - Hyperphagia 
(CgGIC-H)/Clinical Global Impression of Change – Hyperphagia (CGIC-H), Clinical 
Global Impression of Improvement (CGI-I), Clinical Global Impression of Severity 
(CGI-S), Appetite-NRS, Pediatric Quality of Life inventoryTM (PedsQLTM) Parent-
Proxy age-appropriate Report, Developmental Behavior Checklist 2-Parent/Carer 
version (DBC2-P) Questionnaires, Zarit Burden Interview (ZBI), and European 
Quality of Life Five Dimension Five Level Scale (EQ-5D-5L) Self-complete version 
and Proxy version 1: Administration guidelines for these questionnaires will be provided. 
Also see Section 11.2, Section 11.3, Section 11.4 and Section 11.5. 
Caregivers will receive instructions on questionnaires completion and will complete the 
assessment on site throughout the clinical trial. 
Questionnaires completed by the investigator: each questionnaire should be completed by 
the same investigator for a given patient if possible. If this is not possible, an overlapping 
assessment should be performed between the previous and the new investigator; 
 
Intelligence Quotient (IQ) testing: IQ test scores and dates of completion will be 
collected if available in the patient’s medical records; 
 
Clinical Laboratory Testing: All laboratory evaluations are described in Section 8.1.2 
below. 
8.1.2 
Laboratory Procedures/Evaluations 
8.1.2.1 
Clinical Laboratory Evaluations 
Patients will be required to fast for approximately 8 hours before visits requiring fasted blood 
sampling. 
All clinical laboratory assays (except urine pregnancy test) will be performed at central 
laboratories according to the laboratory’s normal procedures. Reference ranges will be supplied 
by the laboratory and used to assess the laboratory data for clinical significance and out of range 
pathological changes. Abnormal laboratory values which are unexpected or not explained by the 
clinical condition should be repeated until confirmed, explained, or resolved.  
The investigator will be copied on all laboratory reports and will review and assess all out of 
range results to evaluate clinical significance. Any abnormal laboratory values, assessed as 
clinically significant on blood samples performed at screening, will be recorded in the medical 
history. Any abnormal laboratory value changes (safety laboratory evaluations) starting from the 
time of signing the ICF assessed as clinically significant will be recorded as an AE as appropriate 
(refer to Section 10.3). 


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Clinical laboratory evaluations will include: 
 
Safety laboratory evaluations in fasting condition (fasting for approximately 8 hours) as 
summarized in Table 5; 
 
Blood glucose and insulin (fasting for approximately 8 hours and postprandial during the 
Core Period/fasting for approximately 8 hours only during the Extension Period); 
 
Plasma ghrelin (AG and UAG) (fasting for approximately 8 hours and postprandial during 
the Core Period/fasting for approximately 8 hours only during the Extension Period); 
 
HbA1C; 
 
Anti-livoletide antibodies (anti-drug antibodies [ADA]). Any patient who tests positive for 
ADA will be followed until the serum titers revert to baseline; 
 
Insulin-like growth factor-1 (IGF-1); 
 
Follicle stimulating hormone (FSH)/luteinizing hormone (LH) when needed. 
Dipsticks for pregnancy test will be provided. 
See also Section 10.1.7. 
 
Clinical chemistry: 
Sodium 
Potassium 
Calcium 
Chloride 
Bicarbonate 
Urea nitrogen 
Creatinine 
Glucose 
Total bilirubin 
Total protein 
Aspartate aminotransferase (AST) 
Albumin 
Uric acid 
Lactate dehydrogenase (LDH) 
Alanine aminotransferase (ALT) 
Alkaline phosphatase (ALP) 
Total cholesterol 
Triglycerides 
Low density lipoprotein (LDL) 
High density lipoprotein (HDL) 
Coagulation: 
Prothrombin time 
Activated partial thromboplastin time 
 
Hematology:  
Hemoglobin 
Hematocrit 
Red blood cell count 
Platelets 
White blood cell count (including differentials) 
Urinalysis: 
 
pH 
Protein 
Glucose 
Ketones 
Bilirubin 
Specific gravity 
Leukocyte esterase 
Blood (free hemoglobin) 
Nitrite 
Urobilinogen 
Table 5: Summary table of clinical laboratory parameters assessed during the study. 
 
In the Phase 2b study Core and Extension Periods, the estimated blood volume taken from 
patients will be approximately 145 ml for patients 4 to 7 years of age and approximately 189 mL 
for patients 8-65 years of age. This volume does not include any blood samples that would be 


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needed for retest. For patients 4-15 years of age, the scheduled blood volumes to be drawn for 
the study are 2.5% of estimated total blood volume per single draw and 5% of estimated total 
blood volume per 30-day period as per pediatric guidelines. 
In the Phase 3 study Core and Extension Periods, the estimated blood volume taken from patients 
will be approximately 184 mL. This volume does not include any blood samples that would be 
needed for retest. For patients 8-15 years of age, the scheduled blood volumes to be drawn for 
the study are 2.5% of estimated total blood volume per single draw and 5% of estimated total 
blood volume per 30-day period as per pediatric guidelines. 
8.1.2.2 
Pregnancy 
8.1.2.2.1 
Definition of Childbearing Potential: Female Patients 
A female patient is considered of childbearing potential if she: 
 
Is anatomically and physiologically capable of becoming pregnant; and 
 
Will be or could possibly be sexually active with a male while undergoing study treatment 
with the possibility of posing harm to a fetus. 
A female patient is considered to be of non-childbearing potential (i.e. physiologically incapable 
of becoming pregnant) if she: 
 
Is prepubertal or pre-menarchal; or 
 
Is post-menopausal (at least 12 months consecutively amenorrhoeic, at least 45 years of 
age, and has a LH and FSH levels in the local post-menopausal ranges); or 
 
Is surgically sterilized (i.e. bilateral tubal ligation, total hysterectomy, or bilateral 
oophorectomy) with surgery at least 1 month before the first dose of study treatment; or 
 
Has a documented congenital or acquired disorder that is incompatible with pregnancy. 
8.1.2.2.2 
Definition of Childbearing Potential: Male Patients 
A male patient is considered of childbearing potential if he: 
 
Is anatomically and physiologically capable of causing a pregnancy in a female partner; 
and 
 
Will be or could possibly be sexually active with a female (who is or may become 
pregnant) while undergoing study treatment with the possibility of posing harm to a fetus. 
A male patient is considered to be of non-childbearing potential if he: 
 
Is prepubertal or pre-spermarchal; or 
 
Has a documented successful vasectomy (with confirmed azoospermia). 
8.1.2.2.3 
Pregnancy Testing 
All female patients of childbearing potential must have a negative pregnancy test (urine) at all 
visits when the test is performed. 
Pregnancy tests will be performed for WCBP only. A urine pregnancy test will be performed at 
screening, or after the onset of menarche if the patient was pre-menarchal at screening, and urine 


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pregnancy tests will be performed thereafter at each study visit and any time pregnancy is 
suspected. 
Positive urine tests performed using dipsticks at the study site are to be confirmed by serum 
testing. Serum testing will be performed at a central laboratory. 
The results of the pregnancy test must be known before study drug administration. 
8.1.2.2.4 
Reporting 
Pregnancy is rarely observed in PWS. If a patient becomes pregnant during the study treatment 
period or within 14 days after the last dose of study drug the Sponsor or designee must be 
notified. If the pregnancy occurs during the treatment period, the study drug will be 
discontinued, and Early Termination study procedures will be performed. 
A pregnancy must be reported by the investigator to the Sponsor or designee within 24 hours of 
awareness. Pregnancies must be reported to Medpace Clinical Safety within 24 hours of 
knowledge of the event. Medpace Clinical Safety will then provide the investigator/site the 
Exposure In Utero (EIU) form for completion. The investigator/site must complete the EIU form 
and fax/email it back to Medpace Clinical Safety.  
The pregnancy should be followed by the investigator until the outcome of the pregnancy, 
whenever possible. Once the outcome of the pregnancy is known, the follow-up EIU form should 
be completed and faxed/emailed to Medpace Clinical Safety. If the outcome of the pregnancy 
meets the criteria for immediate classification as an SAE (e.g., congenital anomaly), the 
investigator should follow the procedures for reporting an SAE.  
8.1.2.3 
Other Assays or Procedures 
8.1.2.3.1 
Pharmacokinetics 
During the Core period, all patients will have blood samples collected at three timepoints at Visit 
3 (Week 5/Day 29). During the Extension period, a subset of patients (Up to N=20/livoletide 
group; 40 patients in total) at selected study sites will undergo PK profile sampling at Visit 6 
(Week 18/Day 120). In patients from whom profile samples are not collected (i.e. sparse 
sampling), three samples will be collected. At Visit 7 (Week 27/Day 183) an additional set of 
sparse samples will be collected from all patients. All timepoints are detailed in the 
Pharmacokinetic Schedule of Activities Section 1.2.3.  
For all samples, the date as well as the nominal and actual time of each sample collection will be 
recorded on the medical record and then reported in the eCRF, together with the time of the 
study drug injection at the same visit. 
Whole blood will be collected in tubes of up to 3 mL containing spray-dried K3 
ethylenediaminetetraacetic acid as anti-coagulant for the analysis of livoletide. Additional details 
will be provided in a separate manual. 
8.1.2.4 
Specimen Preparation, Handling and Storage and Shipment 
A Manual detailing the sample collection, preparation, handling, storage, and shipping process 
for PK and safety evaluations and other laboratory assessments will be provided prior to site 
initiation. 


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8.2 
Study Schedule 
All required study procedures are outlined in the Schedule of Activities tables available in 
Section 1.2. All information required by the protocol must be recorded. 
As indicated in the Schedule of Activities tables, a window of 3 days for visits during the 
double-blind treatment period and 7 days for visits during the Extension Period (except Visit 6 
for Phase 2b, which has a window of 4 days) is allowable for study procedures, as long as the 
proper order of procedures and assessments, as described in the sections below, is maintained. 
These windows are not applicable during the baseline period and other periods for which specific 
time limits have been defined and cannot be exceeded (e.g. screening period: Day -28 to -1).  
Patients will be required to fast for approximately 8 hours before visits requiring blood sampling. 
During the Core Period, patients will be required to consume an isocaloric breakfast prepared at 
the study center at visits when samples are taken for insulin and glucose profiles, AG and UAG 
profiles and when the appetite-NRS is administered. 
8.2.1 
Phase 2b Study Schedule 
8.2.1.1 
Phase 2b Visit 1: Screening and Enrollment (Week -4 to -1/Day -28 to -1) 
The following procedures will be performed during the screening visit: 
 
Obtain signed informed consent and assent from potential patients and/or parents or legal 
guardians, as appropriate; 
 
Assign a study specific patient number; 
 
Contact the IRT to register the patient in the study; 
 
Obtain demographics, medical and disease history, prior and concomitant medications 
(Note: Tanner staging will be included as part of the medical history if performed in the 
past 2 months. Patient will be staged if staging not available);  
 
Assess inclusion and exclusion criteria to determine eligibility; 
 
Collect IQ test scores and dates of completion if available in the patient’s medical record; 
 
Perform a 12-lead ECG;  
 
Perform medical examinations (complete physical examination, vital signs); 
 
Obtain height, WC, BW, and BMI before breakfast; 
 
Perform a urine pregnancy test (WCBP only). A positive urine pregnancy test should be 
confirmed with a serum sample; 
 
Perform safety laboratory evaluations in fasting condition (after fasting for approximately 
8 hours); 
 
Collect blood sample for HbA1c analysis; 
 
Review/record of AEs that occurred since the signature of the ICF. For AEs classification, 
refer to Section 10.4; 
 
Review and completion of questionnaires on electronic device (eDevice) on site and ensure 
all questionnaires have been completed before the patient leaves the site:  


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o For patients 8 to 65 years of age, administer appetite-NRS to patients for training and 
acclimation purposes;  
o Administer HQ-CT to primary caregiver. 
Note: Whenever the 12-lead ECGs, vital signs, and blood draws are scheduled for the same 
nominal time, it is preferred that the assessments occur in the following order: 12-lead ECG, 
vital signs, and blood draws 
8.2.1.2 
Phase 2b Visit 2: Randomization (Week 1/Day 1) 
The randomization visit will occur a minimum of 2 weeks after the screening visit. 
The patient should have been fasting for approximately 8 hours when they attend this visit. 
The following procedures will be performed: 
 
Review of concomitant medications;  
 
Review/record of AEs that occurred since the last visit on site; 
 
Contact the IRT to randomize the patient and obtain study drug assignment. 
In addition, the following activities will be performed for baseline evaluations: 
 
For patients 8 to 65 years of age, perform 12-lead ECG before administering study drug 
and 1 hour post-dose; 
 
Perform medical examinations (complete physical examination, vital signs); 
 
Record height (patients <18 years of age only), WC, BW, and BMI before breakfast; 
 
Perform a DXA scan (can be obtained within 2 weeks prior to Visit 2); 
 
Perform a urine pregnancy test (WCBP only). A positive urine pregnancy test should be 
confirmed with a serum sample; 
 
Perform safety laboratory evaluations in fasting condition; 
 
For patients 8 to 65 years of age, collect blood samples at selected time points for the 
following analyses: 
o Glucose and insulin profiles (before, 30 minutes and 180 minutes post-start of 
breakfast); 
o AG and UAG profiles (before, 30 minutes and 180 minutes post-start of breakfast); 
 
For patients 4 to 7 years of age, collect blood samples for glucose, insulin, AG and UAG 
(fasting) 
 
Collect blood samples for the following analyses: 
o HbA1c;  
o IGF-1; 
o ADA; 
 
For patients 8 to 65 years of age, isocaloric breakfast taken on site and record any food not 
consumed; 


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 
Review and completion of questionnaires on eDevice on site and ensure all questionnaires 
have been completed before the patient leaves the site: 
o For patients 8 to 65 years of age, administer appetite-NRS to patients, under the 
supervision of the study personnel, at selected time points (before, at the end, and 
120 minutes post-start of breakfast); 
o Administer HQ-CT to primary caregiver; 
o Administer age-appropriate PedsQLTM Parent Proxy-Report to primary caregiver; 
o Administer CgGIS-H to primary caregiver; 
o Investigator to complete CGIS-H and CGI-S; 
o Administer ZBI to primary caregiver; 
o Administer EQ-5D-5L Self-complete version and Proxy version 1 to the primary 
caregiver; 
o Administer DBC2-P questionnaire to primary caregiver; 
 
Dispense glucometer kit to the patients with T2D if needed (i.e. if they do not have one); 
 
Dispense study drug and supplies for treatment until next visit; 
 
For patients 8 to 65 years of age, administer first dose of the study drug after the last 
sample has been taken for the glucose, insulin, AG, and UAG profiles; 
 
For patients 4 to 7 years of age, administer first dose of the study drug after all the patient 
assessments were completed;  
 
Ask and remind caregiver to administer study drug daily and at approximately the same 
time before breakfast. 
Note: Whenever the 12-lead ECGs, vital signs, and blood draws are scheduled for the same 
nominal time, it is preferred that the assessments occur in the following order: 12-lead ECG, 
vital signs, and blood draws. 
Note: An isocaloric breakfast will be administered at this visit. Any food not consumed should be 
recorded and reported in the eCRF. Breakfast should not last more than 30 minutes. The NRS 
should be administered before any blood sampling and study drug administration in order for 
patients to complete the questionnaire while they are relaxed.  
8.2.1.3 
Phase 2b Visit 3: Core Period (Week 5/Day 29) 
The patient should have been fasting for approximately 8 hours when they attend this visit. 
The following activities will be performed: 
 
Review of concomitant medications; 
 
Review/Record of AEs that occurred since the last visit on site; 
 
Perform medical examinations (abbreviated physical examination, vital signs); 
 
Record height (patients <18 years of age only), WC, BW, and BMI before breakfast; 


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 
Perform a urine pregnancy test (WCBP only). A positive urine pregnancy test should be 
confirmed with a serum sample; 
 
Perform safety laboratory evaluations in fasting condition; 
 
For patients 8 to 65 years of age, collect blood samples at selected time points for the 
following analyses: 
o Glucose and insulin profiles (before, 30 minutes and 180 minutes post-start of 
breakfast); 
o AG and UAG profiles (before, 30 minutes and 180 minutes post-start of breakfast); 
• 
For patients 4 to 7 years of age, collect blood samples for glucose, insulin, AG and UAG 
(fasting) 
• 
Collect blood sample for ADA; 
• 
Collect blood samples for PK (3-timepoint sampling: before, 30 minutes and 180 minutes 
post-start of breakfast) 
• 
Isocaloric breakfast taken on site and record any food not consumed; 
 
Review and completion of questionnaires on eDevice on site and ensure all questionnaires 
have been completed before the patient leaves the site: 
o For patients 8 to 65 years of age, administer appetite-NRS to patients, under the 
supervision of the study personnel, at selected time points (before, at the end, and 
120 minutes post-start of breakfast); 
o Administer HQ-CT to primary caregiver; 
o Administer CgGIS-H and CgGIC-H to primary caregiver; 
o Investigator to complete CGIS-H, CGIC-H, CGI-I, and CGI-S; 
 
Contact IRT for study drug assignment and dispense study drug and supplies for treatment 
until next visit; 
 
Check drug accountability and compliance, collect all returned study drug; 
 
Administer study drug 30 minutes before starting breakfast; 
 
Ask and remind caregiver to administer study drug daily and at approximately at the same 
time before breakfast. 
Note: An isocaloric breakfast will be administered at this visit. Any food not consumed should be 
recorded and reported in the eCRF. Breakfast should not last more than 30 minutes. The NRS 
should be administered before any blood sampling and study drug administration in order for 
patients to complete the questionnaire while they are relaxed.  
8.2.1.4 
Phase 2b Visit 4: Core Period (Week 9/Day 57) 
The patient should have been fasting for approximately 8 hours when they attend this visit. 
The following activities will be performed: 
 
Review of concomitant medications; 


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 
Review/Record of AEs that occurred since the last visit on site; 
 
Perform medical examinations (abbreviated physical examination, vital signs); 
 
Record height (patients <18 years of age only), WC, BW, and BMI before breakfast; 
 
Perform a urine pregnancy test (WCBP only). A positive urine pregnancy test should be 
confirmed with a serum sample; 
 
Review and completion of questionnaires on eDevice on site and ensure all questionnaires 
have been completed before the patient leaves the site: 
o Administer HQ-CT to primary caregiver; 
o Administer CgGIS-H and CgGIC-H to primary caregiver; 
o Investigator to complete CGIS-H, CGIC-H, CGI-I, and CGI-S; 
 
Contact the IRT to obtain study drug assignment and dispense study drug and supplies for 
treatment until next visit; 
 
Check drug accountability and compliance, collect all returned study drug; 
 
Administer study drug; 
 
Ask and remind caregiver to administer study drug daily and at approximately at the same 
time before breakfast. 
8.2.1.5 
Phase 2b Visit 5: End of Core Period/Core Period Early Treatment 
Discontinuation and Primary Endpoint Evaluation (Week 13/Day 85) 
The patient should have been fasting for approximately 8 hours when they attend this visit. 
The following activities will be performed: 
 
Review of concomitant medications;  
 
Review/record of AEs that occurred since the last visit on site; 
 
For patients 8 to 65 years of age, perform 12-lead ECG before administering study drug 
and 1 hour post-dose; 
 
For patient 4 to 7 years of age, perform 12-lead ECG only before administering the study 
drug; 
 
Perform medical examinations (complete physical examination, vital signs); 
 
Record height (patients <18 years of age only), WC, BW, and BMI before breakfast; 
 
Perform a DXA scan (can be obtained within 2 weeks prior to Visit 5); 
 
Perform a urine pregnancy test (WCBP only). A positive urine pregnancy test should be 
confirmed with a serum sample; 
 
Perform safety laboratory evaluations in fasting condition; 
 
For patients 8 to 65 years of age, collect blood samples at selected time points for the 
following analyses: 


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o Glucose and insulin profiles (before, 30 minutes and 180 minutes post-start of 
breakfast); 
o AG and UAG profiles (before, 30 minutes and 180 minutes post-start of breakfast); 
• 
For patients 4 to 7 years, collect blood samples for glucose, insulin, AG and UAG (fasting) 
 
Collect blood samples for the following analyses: 
o HbA1c; 
o IGF-1; 
o ADA; 
 
For patients 8 to 65 years of age, isocaloric breakfast taken on site and record any food not 
consumed; 
 
Review and completion of questionnaires on eDevice on site and ensure all questionnaires 
have been completed before the patient leaves the site: 
o For patients 8 to 65 years of age, administer appetite-NRS to patients, under the 
supervision of the study personnel, at selected time points (before, at the end, and 
120 minutes post-start of breakfast); 
o Administer HQ-CT to primary caregiver; 
o Administer age-appropriate PedsQLTM Parent Proxy-Report to primary caregiver; 
o Administer CgGIS-H and CgGIC-H to primary caregiver; 
o Investigator to complete CGIS-H, CGIC-H, CGI-I, and CGI-S; 
o Administer ZBI to primary caregiver; 
o Administer EQ-5D-5L Self-complete version and Proxy version 1 to the primary 
caregiver; 
o Administer DBC2-P questionnaire to primary caregiver; 
 
Administer last dose of the Core Period 30 minutes before starting breakfast; 
 
Check drug accountability and compliance, collect all returned study drug; 
 
Contact IRT for study drug assignment and dispense livoletide and supplies for treatment 
until next visit; 
 
Check patient BW and adjust dose volume accordingly for the extension phase; 
 
Ask and remind caregiver to administer study drug daily and at approximately at the same 
time before breakfast. 
Note: An isocaloric breakfast will be administered at this visit. Any food not consumed should be 
recorded and reported in the eCRF. Breakfast should not last more than 30 minutes. The NRS 
should be administered before any blood sampling and study drug administration in order for 
patients to complete the questionnaire while they are relaxed.  
Note: Whenever the 12-lead ECGs, vital signs, and blood draws are scheduled for the same 
nominal time, it is preferred that the assessments occur in the following order: 12-lead ECG, 
vital signs, and blood draws. 


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8.2.1.6 
Phase 2b Visit 6: Extension Period (Week 18/Day 120) 
The patient should have been fasting for approximately 8 hours when they attend this visit. 
The following activities will be performed: 
 
Review of concomitant medications;  
 
Review/record of AEs that occurred since the last visit on site; 
 
Perform medical examinations (complete physical examination, vital signs); 
 
Record height (patients <18 years of age only), WC, BW, and BMI before breakfast; 
 
Perform a urine pregnancy test (WCBP only). A positive urine pregnancy test should be 
confirmed with a serum sample; 
 
Perform safety laboratory evaluations in fasting condition; 
 
Review and completion of questionnaires on eDevice on site and ensure all questionnaires 
have been completed before the patient leaves the site: 
o Administer HQ-CT to primary caregiver; 
o Administer CgGIS-H and CgGIC-H to primary caregiver; 
o Investigator to complete CGIS-H, CGIC-H, CGI-I, and CGI-S; 
 
Collect blood samples for PK (either profile or sparse sampling); 
 
Contact IRT for study drug assignment and dispense livoletide and supplies for treatment 
until next visit; 
 
Check drug accountability and compliance, collect all returned study drug; 
 
Administer livoletide; 
 
Ask and remind caregiver to administer study drug daily and at approximately at the same 
time before breakfast. 
8.2.1.7 
Phase 2b Visit 7: Extension Period (Week 27/Day 183) 
The patient should have been fasting for approximately 8 hours when they attend this visit. 
The following activities will be performed: 
 
Review of concomitant medications;  
 
Review/record of AEs that occurred since the last visit on site; 
 
For patients 8 to 65 years of age, perform a 12-lead ECG before administering study drug 
and 1 hour post-dose; 
 
Perform medical examinations (complete physical examination, vital signs);  
 
Record height (patients <18 years of age only), WC, BW, and BMI before breakfast; 
 
Perform a DXA scan (can be obtained within 2 weeks prior to Visit 7); 
 
Perform a urine pregnancy test (WCBP only). A positive urine pregnancy test should be 
confirmed with a serum sample; 


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 
Perform safety laboratory evaluations in fasting condition; 
 
Collect blood samples for the following analyses: 
o HbA1c;  
o Fasting glucose and insulin; 
o Fasting AG and UAG; 
o IGF-1; 
o ADA; 
 
Collect blood samples for PK (sparse sampling) 
 
Review and completion of questionnaires on eDevice on site and ensure all questionnaires 
have been completed before the patient leaves the site: 
o Administer HQ-CT to primary caregiver; 
o Administer age-appropriate PedsQLTM Parent Proxy-Report to primary caregiver; 
o Administer CgGIS-H and CgGIC-H to primary caregiver; 
o Investigator to complete CGIS-H, CGIC-H, CGI-I, and CGI-S; 
o Administer ZBI to primary caregiver;  
o  Administer EQ-5D-5L Self-complete version and Proxy version 1 to the primary 
caregiver; 
o Administer DBC2-P questionnaire to primary caregiver; 
 
Contact IRT for study drug assignment and dispense livoletide and supplies for treatment 
until next visit; 
 
Check drug accountability and compliance, collect all returned study drug;  
 
Administer livoletide; 
 
Ask and remind caregiver to administer study drug daily and at approximately at the same 
time before breakfast. 
Note: Whenever the 12-lead ECGs, vital signs, and blood draws are scheduled for the same 
nominal time, it is preferred that the assessments occur in the following order: 12-lead ECG, 
vital signs, and blood draws. 
8.2.1.8 
Phase 2b Visit 8: Extension Period (Week 40/Day 274) 
The patient should have been fasting for approximately 8 hours when they attend this visit. 
The following activities will be performed: 
 
Review of concomitant medications;  
 
Review/record of AEs that occurred since the last visit on site; 
 
Perform medical examinations (abbreviated physical examination, vital signs); 
 
Record height (patients <18 years of age only), WC, BW, and BMI before breakfast; 


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 
Perform a urine pregnancy test (WCBP only). A positive urine pregnancy test should be 
confirmed with a serum sample; 
 
Perform safety laboratory evaluations in fasting condition; 
 
Collect blood samples for the following analyses: 
o HbA1c;  
o Fasting glucose and insulin; 
 
Review and completion of questionnaires on eDevice on site and ensure all questionnaires 
have been completed before the patient leaves the site: 
o Administer HQ-CT to primary caregiver; 
o Administer CgGIS-H and CgGIC-H to primary caregiver; 
o Investigator to complete CGIS-H, CGIC-H, CGI-I, and CGI-S; 
 
Contact IRT for study drug assignment and dispense livoletide and supplies for treatment 
until next visit; 
 
Check drug accountability and compliance, collect all returned study drug; 
 
Administer livoletide; 
 
Ask and remind caregiver to administer study drug daily and at approximately at the same 
time before breakfast. 
8.2.1.9 
Phase 2b Visit 9: End of Extension Period/Extension Period Early Treatment 
Discontinuation (Week 53/Day 365) 
The patient should have been fasting for approximately 8 hours when they attend this visit. 
The following activities will be performed: 
 
Review of concomitant medications;  
 
Review/record of AEs that occurred since the last visit on site; 
 
For patients 8 to 65 years of age, perform a 12-lead ECG before administering study drug 
and 1 hour post dose; 
 
For patients 4 to 7 years of age, perform 12-lead ECG only before administering study 
drug; 
 
Perform medical examinations (complete physical examination, vital signs); 
 
Record height (patients <18 years of age only), WC, BW, and BMI before breakfast; 
 
Perform a DXA scan (can be obtained within 2 weeks prior to Visit 9); 
 
Perform a urine pregnancy test (WCBP only). A positive urine pregnancy test should be 
confirmed with a serum sample; 
 
Perform safety laboratory evaluations in fasting condition; 


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 
Collect blood samples for the following analyses: 
o HbA1c;  
o Fasting glucose and insulin; 
o Fasting AG and UAG; 
o IGF-1; 
o ADA; 
 
Review and completion of questionnaires on eDevice on site and ensure all questionnaires 
have been completed before the patient leaves the site: 
o Administer HQ-CT to primary caregiver; 
o Administer age-appropriate PedsQLTM Parent Proxy-Report to primary caregiver; 
o Administer CgGIS-H and CgGIC-H to primary caregiver; 
o Investigator to complete CGIS-H, CGIC-H, CGI-I, and CGI-S; 
o Administer ZBI to primary caregiver;  
o Administer EQ-5D-5L Self-complete version and Proxy version 1 to the primary 
caregiver; 
o Administer DBC2-P questionnaire to primary caregiver; 
 
Check drug accountability and compliance, collect all returned study drug; 
 
Administer livoletide. 
Note: Whenever the 12-lead ECGs, vital signs, and blood draws are scheduled for the same 
nominal time, it is preferred that the assessments occur in the following order: 12-lead ECG, 
vital signs, and blood draws. 
8.2.1.10 
Phase 2b Visit 10: End of Study Telephone Follow-up (Week 57/Day 393) 
Patients will be contacted by telephone to collect information about AEs and concomitant 
medications related to AEs. 
8.2.2 
Phase 3 Study Schedule 
8.2.2.1 
Phase 3 Visit 1: Screening and Enrollment (Week -4 to -1/Day -28 to -1) 
The following procedures will be performed during the screening visit: 
 
Obtain signed informed consent and assent from potential patients and/or parents or legal 
guardians, as appropriate; 
 
Assign a study specific patient number; 
 
Contact the IRT to register the patient in the study; 
 
Obtain demographics, medical and disease history, prior and concomitant medications 
(Note: Tanner staging will be included as part of the medical history if performed in the 
past 2 months. Patient will be staged if staging not available);  
 
Assess inclusion and exclusion criteria to determine eligibility; 


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 
Collect IQ test scores and dates of completion if available in the patient’s medical record; 
 
Perform a 12-lead ECG;  
 
Perform medical examinations (complete physical examination, vital signs); 
 
Obtain height, WC, BW, and BMI before breakfast; 
 
Perform a urine pregnancy test (WCBP only). A positive urine pregnancy test should be 
confirmed with a serum sample; 
 
Perform safety laboratory evaluations in fasting condition; 
 
Collect blood sample for HbA1c analysis; 
 
Review/record of AEs that occurred since the signature of the ICF. For AEs classification, 
refer to Section 10.4; 
 
Review and completion of questionnaires on eDevice on site and ensure all questionnaires 
have been completed before the patient leaves the site:  
o Administer appetite-NRS to patients for training and acclimation purposes;  
o Administer HQ-CT to primary caregiver. 
Note: Whenever the 12-lead ECGs, vital signs, and blood draws are scheduled for the same 
nominal time, the assessments should occur in the following order: 12-lead ECG, vital signs, and 
blood draws, considering the blood draws to be done in fasting conditions. 
8.2.2.2 
Phase 3 Visit 2: Randomization (Week 1/Day 1) 
The randomization visit will occur a minimum of 2 weeks after the screening visit. 
The patient should have been fasting for approximately 8 hours when they attend this visit. 
The following procedures will be performed: 
 
Review of concomitant medications;  
 
Review/record of AEs that occurred since the last visit on site; 
 
Contact the IRT to randomize the patient and obtain study drug assignment. 
In addition, the following activities will be performed for baseline evaluations: 
 
Perform 12-lead ECG before administering study drug and 1 hour post-dose; 
 
Perform medical examinations (complete physical examination, vital signs); 
 
Record height (patients aged <18 years only), WC, BW, and BMI before breakfast; 
 
Perform a DXA scan (can be obtained within 2 weeks prior to Visit 2); 
 
Perform a urine pregnancy test (WCBP only). A positive urine pregnancy test should be 
confirmed with a serum sample; 
 
Perform safety laboratory evaluations in fasting condition; 
 
Collect blood samples at selected time points for the following analyses: 


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o Glucose and insulin profiles (before, 30 minutes and 180 minutes post-start of 
breakfast); 
o AG and UAG profiles (before, 30 minutes and 180 minutes post-start of breakfast); 
 
Collect blood samples for the following analyses: 
o HbA1c;  
o IGF-1; 
o ADA; 
 
Isocaloric breakfast taken on site and record any food not consumed; 
 
Review and completion of questionnaires on eDevice on site and ensure all questionnaires 
have been completed before the patient leaves the site: 
o Administer appetite-NRS to patients, under the supervision of the study personnel, at 
selected time points (before, at the end, and 120 minutes post-start of breakfast); 
o Administer HQ-CT to primary caregiver; 
o Administer age-appropriate PedsQLTM Parent Proxy-Report to primary caregiver; 
o Administer CgGIS-H to primary caregiver; 
o Investigator to complete CGIS-H and CGI-S; 
o Administer ZBI to primary caregiver; 
o Administer EQ-5D-5L Self-complete version and Proxy version 1 to the primary 
caregiver; 
o Administer DBC2-P questionnaire to primary caregiver; 
 
Dispense glucometer kit to the patients with T2D if needed (i.e. if they do not have one); 
 
Dispense study drug and supplies for treatment until next visit; 
 
Administer first dose of the study drug after the last sample has been taken for the glucose, 
insulin, AG, and AUG profiles; 
 
Ask and remind caregiver to administer study drug daily and at approximately at the same 
time before breakfast. 
Note: Whenever the 12-lead ECGs, vital signs, and blood draws are scheduled for the same 
nominal time, the assessments should occur in the following order: 12-lead ECG, vital signs, and 
blood draws, considering the blood draws to be done in fasting conditions. 
Note: An isocaloric breakfast will be administered at this visit. Any food not consumed should be 
recorded and reported in the eCRF. Breakfast should not last more than 30 minutes. The NRS 
should be administered before any blood sampling and study drug administration in order for 
patients to complete the questionnaire while they are relaxed.  


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8.2.2.3 
Phase 3 Visit 3: Core Period (Week 5/Day 29) 
The patient should have been fasting for approximately 8 hours when they attend this visit. 
The following activities will be performed: 
 
Review of concomitant medications; 
 
Review/Record of AEs that occurred since the last visit on site; 
 
Perform medical examinations (complete physical examination, vital signs); 
 
Record height (patients aged <18 years only), WC, BW, and BMI before breakfast; 
 
Perform a urine pregnancy test (WCBP only). A positive urine pregnancy test should be 
confirmed with a serum sample; 
 
Perform safety laboratory evaluations in fasting condition; 
 
Collect blood samples at selected time points for the following analyses: 
o Glucose and insulin profiles (before, 30 minutes and 180 minutes post-start of 
breakfast); 
o AG and UAG profiles (before, 30 minutes and 180 minutes post-start of breakfast); 
 
Isocaloric breakfast taken on site and record any food not consumed; 
 
Review and completion of questionnaires on eDevice on site and ensure all questionnaires 
have been completed before the patient leaves the site: 
o Administer appetite-NRS to patients, under the supervision of the study personnel, at 
selected time points (before, at the end, and 120 minutes post-start of breakfast); 
o Administer HQ-CT to primary caregiver; 
o Administer CgGIS-H and CgGIC-H to primary caregiver; 
o Investigator to complete CGIS-H, CGIC-H, CGI-I, and CGI-S; 
 
Contact IRT for study drug assignments and dispense study drug and supplies for treatment 
until next visit; 
 
Check drug accountability and compliance, collect all returned study drug; 
 
Administer study drug 30 minutes before starting breakfast; 
 
Ask and remind caregiver to administer study drug daily and at approximately at the same 
time before breakfast. 
Note: An isocaloric breakfast will be administered at this visit. Any food not consumed should be 
recorded and reported in the eCRF. Breakfast should not last more than 30 minutes. The NRS 
should be administered before any blood sampling and study drug administration in order for 
patients to complete the questionnaire while they are relaxed.  
8.2.2.4 
Phase 3 Visit 4: Core Period (Week 9/Day 57) 
The patient should have been fasting for approximately 8 hours when they attend this visit. 
The following activities will be performed: 


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 
Review of concomitant medications; 
 
Review/Record of AEs that occurred since the last visit on site; 
 
Perform medical examinations (abbreviated physical examination, vital signs); 
 
Record height (patients aged <18 years only), WC, BW, and BMI before breakfast; 
 
Perform a urine pregnancy test (WCBP only). A positive urine pregnancy test should be 
confirmed with a serum sample; 
 
Perform safety laboratory evaluations in fasting condition; 
 
Review and completion of questionnaires on eDevice on site and ensure all questionnaires 
have been completed before the patient leaves the site: 
o Administer HQ-CT to primary caregiver; 
o Administer CgGIS-H and CgGIC-H to primary caregiver; 
o Investigator to complete CGIS-H, CGIC-H, CGI-I, and CGI-S; 
 
Contact the IRT to obtain study drug assignment and dispense study drug and supplies for 
treatment until next visit; 
 
Check drug accountability and compliance, collect all returned study drug; 
 
Administer study drug; 
 
Ask and remind caregiver to administer study drug daily and at approximately at the same 
time before breakfast. 
8.2.2.5 
Phase 3 Visit 5: Core Period (Week 13/Day 85) 
The patient should have been fasting for approximately 8 hours when they attend this visit. 
The following activities will be performed: 
 
Review of concomitant medications;  
 
Review/record of AEs that occurred since the last visit on site; 
 
Perform medical examinations (complete physical examination, vital signs); 
 
Record height (patients aged <18 years only), WC, BW, and BMI before breakfast; 
 
Perform a DXA scan (can be obtained within 2 weeks prior to Visit 5); 
 
Perform a urine pregnancy test (WCBP only). A positive urine pregnancy test should be 
confirmed with a serum sample; 
 
Perform safety laboratory evaluations in fasting condition; 
 
Collect blood samples at selected time points for the following analyses: 
o Glucose and insulin profiles (before, 30 minutes and 180 minutes post-start of 
breakfast); 
o AG and UAG profiles (before, 30 minutes and 180 minutes post-start of breakfast); 
 
Collect blood samples for the following analyses: 


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o HbA1c; 
o IGF-1; 
o ADA; 
 
Isocaloric breakfast taken on site and record any food not consumed; 
 
Review and completion of questionnaires on eDevice on site and ensure all questionnaires 
have been completed before the patient leaves the site: 
o Administer appetite-NRS to patients, under the supervision of the study personnel, at 
selected time points (before, at the end, and 120 minutes post-start of breakfast); 
o Administer HQ-CT to primary caregiver; 
o Administer age-appropriate PedsQLTM Parent Proxy-Report to primary caregiver; 
o Administer CgGIS-H and CgGIC-H to primary caregiver; 
o Investigator to complete CGIS-H, CGIC-H, CGI-I, and CGI-S; 
o Administer ZBI to primary caregiver; 
o Administer EQ-5D-5L Self-complete version and Proxy version 1 to the primary 
caregiver; 
o Administer DBC2-P questionnaire to primary caregiver; 
 
Contact IRT for study drug assignment and dispense study drug and supplies for treatment 
until next visit; 
 
Check drug accountability and compliance, collect all returned study drug; 
 
Administer study drug 30 minutes before starting breakfast; 
 
Ask and remind caregiver to administer study drug daily and at approximately at the same 
time before breakfast. 
Note: An isocaloric breakfast will be administered at this visit. Any food not consumed should be 
recorded and reported in the eCRF. Breakfast should not last more than 30 minutes. The NRS 
should be administered before any blood sampling and study drug administration in order for 
patients to complete the questionnaire while they are relaxed.  
8.2.2.6 
Phase 3 Visit 6: Core Period (Week 18/Day 120) 
The patient should have been fasting for approximately 8 hours when they attend this visit. 
The following activities will be performed: 
 
Review of concomitant medications;  
 
Review/record of AEs that occurred since the last visit on site; 
 
Perform medical examinations (abbreviated physical examination, vital signs); 
 
Record height (patients aged <18 years only), WC, BW, and BMI before breakfast; 
 
Perform a urine pregnancy test (WCBP only). A positive urine pregnancy test should be 
confirmed with a serum sample; 


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 
Perform safety laboratory evaluations in fasting condition; 
 
Review and completion of questionnaires on eDevice on site and ensure all questionnaires 
have been completed before the patient leaves the site: 
o Administer HQ-CT to primary caregiver; 
o Administer CgGIS-H and CgGIC-H to primary caregiver; 
o Investigator to complete CGIS-H, CGIC-H, CGI-I, and CGI-S; 
 
Contact IRT for study drug assignment and dispense study drug and supplies for treatment 
until next visit; 
 
Check drug accountability and compliance, collect all returned study drug; 
 
Administer study drug; 
 
Ask and remind caregiver to administer study drug daily and at approximately at the same 
time before breakfast. 
8.2.2.7 
Phase 3 Visit 7: End of Core Period/Core Period Early Discontinuation 
(Week 27/Day 183) 
The patient should have been fasting for approximately 8 hours when they attend this visit. 
The following activities will be performed: 
 
Review of concomitant medications;  
 
Review/record of AEs that occurred since the last visit on site; 
 
Perform a 12-lead ECG; 
 
Perform medical examinations (complete physical examination, vital signs); 
 
Record height (patients aged <18 years only), WC, BW, and BMI before breakfast; 
 
Perform a DXA scan (can be obtained within 2 weeks prior to Visit 7); 
 
Perform a urine pregnancy test (WCBP only). A positive urine pregnancy test should be 
confirmed with a serum sample; 
 
Perform safety laboratory evaluations in fasting condition; 
 
Collect blood samples at selected time points for the following analyses: 
o Glucose and insulin profiles (before, 30 minutes and 180 minutes post-start of 
breakfast); 
o AG and UAG profiles (before, 30 minutes and 180 minutes post-start of breakfast); 
 
Collect blood samples for the following analyses: 
o HbA1c; 
o IGF-1; 
o ADA; 
 
Isocaloric breakfast taken on site and record any food not consumed; 


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 
Review and completion of questionnaires on eDevice on site and ensure all questionnaires 
have been completed before the patient leaves the site: 
o Administer appetite-NRS to patients, under the supervision of the study personnel, at 
selected time points (before, at the end, and 120 minutes post-start of breakfast); 
o Administer HQ-CT to primary caregiver; 
o Administer age-appropriate PedsQLTM Parent Proxy-Report to primary caregiver; 
o Administer CgGIS-H and CgGIC-H to primary caregiver; 
o Investigator to complete CGIS-H, CGIC-H, CGI-I, and CGI-S; 
o Administer ZBI to primary caregiver;  
o  Administer EQ-5D-5L Self-complete version and Proxy version 1 to the primary 
caregiver; 
o Administer DBC2-P questionnaire to primary caregiver; 
 
Contact IRT for study drug assignment and dispense livoletide and supplies for treatment 
until next visit; 
 
Check drug accountability and compliance, collect all returned study drug; 
 
Check patient BW and adjust dose volume accordingly for the extension phase; 
 
Administer livoletide; 
 
Ask and remind caregiver to administer study drug daily and at approximately at the same 
time before breakfast. 
Note: Whenever the 12-lead ECGs, vital signs, and blood draws are scheduled for the same 
nominal time, the assessments should occur in the following order: 12-lead ECG, vital signs, and 
blood draws, considering the blood draws to be done in fasting conditions. 
Note: An isocaloric breakfast will be administered at this visit. Any food not consumed should be 
recorded and reported in the eCRF. Breakfast should not last more than 30 minutes. The NRS 
should be administered before any blood sampling and study drug administration in order for 
patients to complete the questionnaire while they are relaxed.  
8.2.2.8 
Phase 3 Visit 8: Extension Period (Week 30/Day 211) 
The patient should have been fasting for approximately 8 hours when they attend this visit. 
The following activities will be performed: 
 
Review of concomitant medications;  
 
Review/record of AEs that occurred since the last visit on site; 
 
Perform medical examinations (abbreviated physical examination, vital signs); 
 
Record height (patients aged <18 years only), WC, BW, and BMI before breakfast; 
 
Perform a urine pregnancy test (WCBP only). A positive urine pregnancy test should be 
confirmed with a serum sample; 
 
Perform safety laboratory evaluations in fasting condition; 


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 
Review and completion of questionnaires on eDevice on site and ensure all questionnaires 
have been completed before the patient leaves the site: 
o Administer HQ-CT to primary caregiver; 
o Administer CgGIS-H and CgGIC-H to primary caregiver; 
o Investigator to complete CGIS-H, CGIC-H, CGI-I, and CGI-S; 
 
Contact IRT for study drug assignment and dispense livoletide and supplies for treatment 
until next visit; 
 
Check drug accountability and compliance, collect all returned study drug; 
 
Administer livoletide; 
 
Ask and remind caregiver to administer study drug daily and at approximately at the same 
time before breakfast. 
8.2.2.9 
Phase 3 Visit 9: Extension Period (Week 40/Day 274) 
The patient should have been fasting for approximately 8 hours when they attend this visit. 
The following activities will be performed: 
 
Review of concomitant medications;  
 
Review/record of AEs that occurred since the last visit on site; 
 
Perform a 12-lead ECG; 
 
Perform medical examinations (complete physical examination, vital signs); 
 
Record height (patients aged <18 years only), WC, BW, and BMI before breakfast; 
 
Perform a DXA scan (can be obtained within 2 weeks prior to Visit 9); 
 
Perform a urine pregnancy test (WCBP only). A positive urine pregnancy test should be 
confirmed with a serum sample; 
 
Collect blood sample for Hb1Ac analysis; 
 
Review and completion of questionnaires on eDevice on site and ensure all questionnaires 
have been completed before the patient leaves the site: 
o Administer HQ-CT to primary caregiver; 
o Administer CgGIS-H and CgGIC-H to primary caregiver; 
o Investigator to complete CGIS-H, CGIC-H, CGI-I, and CGI-S; 
 
Contact IRT for study drug assignment and dispense livoletide and supplies for treatment 
until next visit; 
 
Check drug accountability and compliance, collect all returned study drug; 
 
Administer livoletide; 
 
Ask and remind caregiver to administer study drug daily and at approximately at the same 
time before breakfast. 


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Note: Whenever the 12-lead ECGs, vital signs, and blood draws are scheduled for the same 
nominal time, the assessments should occur in the following order: 12-lead ECG, vital signs, and 
blood draws, considering the blood draws to be done in fasting conditions. 
8.2.2.10 
Phase 3 Visit 10: End of Extension Period/Extension Period Early Treatment 
Discontinuation (Week 53/Day 365) 
The patient should have been fasting for approximately 8 hours when they attend this visit. 
The following activities will be performed: 
 
Review of concomitant medications;  
 
Review/record of AEs that occurred since the last visit on site; 
 
Perform a 12-lead ECG; 
 
Perform medical examinations (complete physical examination, vital signs); 
 
Record height (patients aged <18 years only), WC, BW, and BMI before breakfast; 
 
Perform a DXA scan (can be obtained within 2 weeks prior to Visit 10); 
 
Perform a urine pregnancy test (WCBP only). A positive urine pregnancy test should be 
confirmed with a serum sample; 
 
Perform safety laboratory evaluations in fasting condition; 
 
Collect blood samples for the following analyses: 
o HbA1c;  
o Fasting insulin ; 
o Fasting AG and UAG ; 
o IGF-1; 
o ADA; 
 
Review and completion of questionnaires on eDevice on site and ensure all questionnaires 
have been completed before the patient leaves the site: 
o Administer HQ-CT to primary caregiver; 
o Administer age-appropriate PedsQLTM Parent Proxy-Report to primary caregiver; 
o Administer CgGIS-H and CgGIC-H to primary caregiver; 
o Investigator to complete CGIS-H, CGIC-H, CGI-I, and CGI-S; 
o Administer ZBI to primary caregiver;  
o Administer EQ-5D-5L Self-complete version and Proxy version 1 to the primary 
caregiver; 
o Administer DBC2-P questionnaire to primary caregiver; 
 
Check drug accountability and compliance, collect all returned study drug; 
 
Administer livoletide. 


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Note: Whenever the 12-lead ECGs, vital signs, and blood draws are scheduled for the same 
nominal time, the assessments should occur in the following order: 12-lead ECG, vital signs, and 
blood draws, considering the blood draws to be done in fasting conditions. 
8.2.2.11 
 hase 3 Visit 11: End of Study Telephone Follow-up (Week 57/Day 393) 
Patients will be contacted by telephone to collect information about AEs and concomitant 
medications related to AEs. 
8.2.3 
Early Termination Visit 
For those patients who terminate the study early, every effort will be made to determine their 
reason for dropping out, and to complete the Early Treatment Discontinuation Visit assessments 
described in Section 7.2.1 and in the Schedule of Activities tables available in Section 1.2. 
For details of the Early Treatment Discontinuation Visit activities to be performed, please refer 
to the following sections: 
 
Phase 2b Core Period, Section 8.2.1.5; 
 
Phase 2b Extension Period, Section 8.2.1.9; 
 
Phase 3 Core Period, Section 8.2.2.7; 
 
Phase 3 Extension Period, Section 8.2.2.10. 
8.2.4 
Schedule of Activities Tables 
Please refer to the following sections for the Schedule of Activities tables: 
 
Phase 2b Core Period, Section 1.2.1; 
 
Phase 2b Extension Period, Section 1.2.2; 
 
Phase 3 Core Period, Section 1.2.4; 
 
Phase 3 Extension Period, Section 1.2.5. 
9.1 
Specifications of Primary and Secondary Efficacy Parameters 
Phase 2b 
Efficacy assessments in the Phase 2b Core Period will include the following: 
 
HQ-CT (primary endpoint): Change from baseline to the end of the 3-month Core Period 
in food-related behaviors, as assessed by the HQ-CT total score (see Section 19.2 
Appendix B for HQ-CT content); 
 
Total body fat mass, WC, and BW: Change from baseline to the end of the 3-month Core 
Period. 
Efficacy assessments in the Phase 2b Extension Period will include the following: 
 
HQ-CT: Change from baseline to the end of the 9-month Extension Period and change 
from the end of the 3-month Core Period to the end of the 9-month Extension Period in 
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food-related behaviors, as assessed by the HQ-CT total score (see Section 19.2 Appendix B 
for HQ-CT content); 
 
Total body fat mass, WC, and BW: Change from baseline to the end of the 9-month 
Extension Period and change from the end of the 3-month Core Period to the end of the 
9-month Extension Period. 
Phase 3 
Efficacy assessments in the Phase 3 Core Period will include the following: 
 
HQ-CT (primary endpoint): Change from baseline to the end of the 6-month Core Period 
in food-related behaviors, as assessed by the HQ-CT total score (see Section 19.2 
Appendix B for HQ-CT content); 
 
Total body fat mass, WC, and BW: Change from baseline to the end of the 6-month Core 
Period. 
Efficacy assessments in the Phase 3 Extension Period will include the following: 
 
HQ-CT: Change from baseline to the end of the 6-month Extension Period and change 
from the end of the 6-month Core Period to the end of the 6-month Extension Period in 
food-related behaviors, as assessed by the HQ-CT total score (see Section 19.2 Appendix B 
for HQ-CT content); 
 
Total body fat mass, WC, and BW: Change from baseline to the end of the 6-month 
Extension Period and change from the end of the 6-month Core Period to the end of the 
6-month Extension Period. 
9.1.1 
Hyperphagia Questionnaire for Clinical Trials 
Food-related behavior will be assessed through the HQ-CT questionnaire, a validated 9-item 
caregiver-reported outcomes measure. HQ-CT (and other study questionnaires) will be provided 
on eDevice. 
In order to optimize the consistency with which the HQ-CT will be administered and to 
maximize data accuracy across sites and studies, sites will be provided with administration 
guidelines upon study initiation. 
9.1.2 
Total Body Fat Mass 
Total body fat mass will be assessed by DXA. 
Dual energy X-ray absorptiometry enables quantification of fat, lean, and bone tissues. The two 
low-energy levels used in DXA and their differential attenuation through the body allow the 
discrimination of total body adipose and soft tissue, in addition to bone mineral content and bone 
mineral density. Dual energy X-ray absorptiometry is fast and user-friendly for the patient and 
the operator. A typical whole-body scan takes approximately 10 to 20 minutes and exposes the 
patient to low levels of radiation.  
DXAs will be conducted at each local facility using standardized procedures and settings. DXA 
images will be read by an independent central reader, blinded to the patient’s treatment 
assignment: 
 


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Emily Lay, MS 
Project Manager 
Medpace Core Laboratories 
5375 Medpace Way 
Cincinnati, Ohio 45227 
Tel: +1.513.579.9911, ext. 12626 
Fax: +1.513.579.0444 
E-mail: e.lay@medpace.com 
 
Only GE Healthcare or Hologic systems capable of measuring total body composition will be 
used in this study and must be approved by the core laboratory. 
Specific acquisition guidelines will be provided in a separate DXA Acquisition Manual. 
Patients will be scanned in light clothing, in supine position, and the entire body will be scanned 
from the top of the head down to the feet in a rectilinear manner. Measurements should be made 
for four different regions (head, arms, trunk, and legs) and for the body as a whole. 
9.1.3 
Waist Circumference 
The WC should be measured before breakfast at the superior border of iliac crest, according to 
recommendations from the Anthropometry Procedures Manual of the National Health and 
Nutrition Examination Survey, Revised 2007. A separate document describing the procedure will 
be provided to sites. 
9.1.4 
Body Weight 
Before breakfast, patients will be weighed clothed (underwear, light gown or light clothing), 
without footwear (shoes or sandals) or heavy jewelry, using a calibrated scale. The same scale 
should be used throughout the study if possible. The conditions under which patients are 
weighed should be kept consistent if possible.  
10.1 
Specification of Safety Parameters 
Please refer to Schedules of Activities in Section 1.2. 
10.1.1 
Adverse Events 
All AEs must be collected beginning from the time the patient signs the ICF until the last study 
visit or 30 days (by phone only) after the last dose of study drug, whichever is longer. Please 
refer to Section 10.3, Section 10.4, and Section 10.5 for the detailed definition of AEs and 
reporting procedures. 
10.1.2 
Vital Signs 
Vital signs include respiration rate, pulse rate, and blood pressure (systolic blood pressure [SBP] 
and diastolic blood pressure [DBP]), measured sitting after the patient has rested comfortably for 
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5 minutes. Each patient’s blood pressure should be taken using the same arm. Temperature will 
be recorded in Celsius or Fahrenheit. Pulse rate will be counted for a full minute and recorded in 
beats per minute. Respirations will be counted for a full minute and recorded in breaths per 
minute. 
For the safety of the patient, additional vital signs may be obtained at the discretion of the 
investigator. 
10.1.3 
Height and Body Mass Index 
Height will be measured before breakfast, with a wall-mounted or portable stadiometer, to the 
nearest 0.1 cm and without shoes. Height will be measured for adults once at screening, and at 
each visit for patients <18 years of age.  
Body mass index will be calculated at each visit. 
10.1.4 
Physical Examination 
A complete or abbreviated physical examination will be obtained at selected visits. At any time, 
targeted physical examination may be performed if needed based on AEs and positives from 
review of systems. 
The examination of the following will be performed for a complete physical examination: heart, 
peripheral vasculature, lungs, musculoskeletal system, abdomen, neurologic function, endocrine 
system, genito-urinary system, skin, lymph nodes, and any areas pertinent to any AEs and 
positives from review of systems. 
The following systems will be examined for an abbreviated physical examination: heart, lungs, 
abdomen, and any areas pertinent to any AEs and positives from review of systems. 
Significant findings that are observed at screening must be recorded as Medical History. 
Clinically significant changes from the screening visit which meet the definition of an AE must 
be recorded as an AE. 
10.1.5 
Lean Body Mass and Bone Mineral Density 
Lean body mass and bone mineral density will be assessed by DXA as described in 
Section 9.1.2. 
10.1.6 
Electrocardiograms 
For patients 8 to 65 years of age, ECG will be performed in triplicate pre-dose and 1 hour post 
dose (except at the screening visit). For patients 4 to 7 years of age, ECG will be performed in 
triplicate pre-dose only, at screening visit, end of Core Period visit and end of study visit.  
Twelve-lead digital ECGs will be obtained after 10 minutes in a supine position. Whenever vital 
signs, 12-lead ECGs, and blood draws are scheduled for the same nominal time, it is preferred 
that the assessments occur in the following order: 12-lead ECG, vital signs, and blood draws. 
Skin preparation should be thorough and electrodes should be placed according to standard 
12-lead ECG placement. 
ECGs will be digitally recorded and printed on paper. The printed paper ECGs will be used for 
“real time” bedside ECG assessment by the investigator (or designee) who will be responsible 
for the overall interpretation and determination of the clinical significance of any potential ECG 
findings. Digital ECGs will be submitted to the ECG core laboratory, which will perform the 


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digital ECG analysis and interpretation in this study using standard methodology. If the central 
reader identifies an abnormality, per the study alert criteria, the investigator will be notified who 
will review the ECG and report any AEs as necessary. 
The following variables will be reported: HR, RR interval, PR interval, QRS complex duration, 
QT interval, QTCB, and QT interval corrected for HR by Fridericia’s formula (QTCF). The 
investigator may add additional 12-lead ECG safety assessments if there are any abnormal 
findings or if the Investigator considers it is required for any other safety reason. 
Sites will be provided with ECG machines.  
Instruction for ECG acquisition will be provided in a separate manual. ECG recordings will be 
read by an independent central reader, blinded to the patient’s treatment assignment: 
Emily Lay, MS 
Project Manager 
Medpace Core Laboratories 
5375 Medpace Way 
Cincinnati, Ohio 45227 
Tel: +1.513.579.9911, ext. 12626 
Fax: +1.513.579.0444 
E-mail: e.lay@medpace.com 
10.1.7 
Safety Laboratory Parameters 
Safety laboratory parameters include safety laboratory evaluations (clinical chemistry including 
lipids, coagulation, hematology, and urinalysis) described in Section 8.1.2 (Table 5), as well as 
HbA1c, ghrelin, ADA, and IGF-1. 
Any patient that tests positive for ADA will be followed until the serum titers revert to baseline. 
Details on sample collection, processing, and shipping will be provided in a Laboratory Manual. 
All samples will be shipped to a central laboratory: 
Europe 
Tatiana Afrikanova, PhD  
Project Manager  
Medpace Reference Laboratories 
Technologielaan 19 
3001 Leuven, Belgium 
Tel: +32 16 40 77 75 ext. 23626 
E-mail: t.afrikanova@medpacelab.com 
 


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United States 
Dana Lee 
Project Manager  
Medpace Reference Laboratories 
5365 Medpace Way 
Cincinnati, Ohio 45227 
Tel: +1.513.366.3270, ext. 11279 
Mobile: +1.513.760.2060 
Fax: +1.513.366.3273 
E-mail: d.lee1@medpacelab.com 
 
10.2 
Safety Measures for the Management of Hypoglycemia  
The clinical sites in this study are expected to be experienced in the management of diabetes 
mellitus, including common complications such as hypoglycemia. At the clinical site, in case of 
symptomatic hypoglycemia, sugar, glucose drinks, or other sources of carbohydrates appropriate 
for the treatment of hypoglycemia will be available. If there is no adequate response to oral 
treatment or the patient is unable to eat or drink, intravenous dextrose and intramuscular 
glucagon will also be available. 
Patients with T2D, as well as their caregiver (as applicable), will be instructed to monitor fasting 
glucose levels (according to their usual practice) during the treatment periods using a glucometer. 
In addition, patients and their caregiver (as applicable) will be educated to recognize symptoms 
of hypoglycemia and will be instructed to take or give sugar if fasting glucose value is below 
70 mg/dL (3.9 mmol/L) and to repeat glucose check in the next 30 minutes and the next hour. 
They will be instructed to call the study center if one of the repeat values is below 70 mg/dL 
(3.9 mmol/L) for further investigation and management. 
10.3 
Adverse Events and Serious Adverse Events 
10.3.1 
Definition of Adverse Events, Adverse Drug Reactions, and Unexpected 
Adverse Drug Reactions 
Adverse Event: Any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug-related.  
 
All AEs, regardless of relationship to study drug, should be collected beginning from the 
time the patient signs the ICF until the last study visit or 30 days after the last dose of study 
drug, whichever is later. (Any SAE judged by the investigator to be related to the study 
treatment should be reported to the Sponsor regardless of the length of time that has passed 
since study completion.) Adverse events in study subjects include any change in the 
subject’s condition. This includes symptoms, physical findings, or clinical syndromes; 
 
Wherever possible, a specific disease or syndrome, rather than individual associated signs 
and symptoms, should be identified by the investigator and recorded. However, if an 
observed or reported sign or symptom is not considered a component of a specific disease 


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or syndrome by the investigator, it should be recorded as a separate AE. Additionally, the 
condition that led to a medical or surgical procedure (e.g. surgery, endoscopy, tooth 
extraction, or transfusion) should be recorded as an AE, not the procedure. Any medical 
condition already present at screening should not be reported as an AE unless the medical 
condition or signs or symptoms present at baseline worsens in severity or seriousness at 
any time during the study. Clinically significant examination (e.g. ECG) findings that are 
detected during the study or are present at screening and worsen during the study should be 
reported as an AE. 
o An abnormal laboratory value may be considered an AE if the identified laboratory 
abnormality leads to any type of intervention, whether prescribed in the protocol or 
not. It is up to the investigator to determine whether an abnormal laboratory value 
constitutes an AE. If an abnormal laboratory value is caused by a disease process, the 
disease process and not the laboratory abnormality should be listed as the AE (e.g. if 
new onset viral hepatitis is causing elevated ALT, the specific hepatitis and not the 
elevated ALT should be listed as the AE); 
o Examples of laboratory abnormalities that should be considered AEs include those 
that result in withdrawal of the study treatment or additional concomitant treatment. 
All laboratory abnormalities considered to constitute an AE should be recorded on the 
appropriate AE page of the eCRF. Laboratory abnormalities do not need to be listed 
as separate AEs if they are considered to be part of a clinical syndrome that is being 
reported as an AE. It is the responsibility of the investigator to review all safety 
laboratory findings in all patients. Abnormal values should be commented upon as to 
clinical relevance or importance on the eCRF or the laboratory report as appropriate. 
Medical and scientific judgment should be exercised in deciding whether an isolated 
laboratory abnormality should be classified as an AE; 
 
Every effort must be made by the investigator to categorize each AE according to its 
severity and its relationship to study drug; 
 
Patients who develop toxicity on study will be followed until the event resolves, stabilizes, 
or returns to baseline. 
Adverse Reaction: All noxious and unintended responses to study drug at any dose should be 
considered to be adverse reactions. “Responses to study drug” means that there is a causal 
relationship between the study drug and the responses. “Suspected adverse reaction” implies a 
lesser degree of certainty about causality than “adverse reaction.” 
Unexpected Adverse Reaction: An unexpected adverse reaction is defined as an adverse 
reaction, the nature or severity of which is not consistent with the applicable product 
information. For the study drug, the reference safety information (RSI) is included in the version 
of the livoletide IB currently in force. 
10.3.2 
Definition of Serious Adverse Events 
An SAE is any untoward medical occurrence that: 
 
Results in death; 
 
Is life-threatening (Note: The term “life-threatening” in the definition of “serious” refers to 
an event in which, in view of either the investigator or Sponsor, the patient was at 


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immediate risk of death at the time of the event; it does not refer to an event that 
hypothetically might have caused death if it were more severe.); 
 
Requires inpatient hospitalization or prolongation of an existing hospitalization 
Notes:  
Any hospital admission with at least one overnight stay will be considered an inpatient 
hospitalization. An emergency room visit without hospital admission will not be recorded 
as an SAE under this criterion, nor will hospitalization for a procedure scheduled or 
planned before signing of informed consent. However, unexpected complications and/or 
prolongation of hospitalizations that occur during elective surgery should be recorded as 
AEs and assessed for seriousness. 
The following hospitalizations are not considered to be SAEs because there is no AE 
(i.e. no untoward medical occurrence) associated with the hospitalization: 
o Hospitalizations for respite/hospice care; 
o Hospitalization planned prior to informed consent (where the condition requiring the 
hospitalization has not changed post study drug administration); 
 
Results in persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions; 
 
Is a congenital anomaly/birth defect; or 
 
Is determined to be an important medical event (at the discretion of the Investigator). 
Note: Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient and may require medical or surgical intervention 
to prevent one of the other outcomes listed in the SAE definition. 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. 
10.4 
Classification of an Adverse Event 
10.4.1 
Severity of Event 
The assessment of severity must be provided by the investigator and based on the investigator’s 
clinical judgment. Maximum severity should be assigned to one of the following categories: 
 
Mild: An AE that is easily tolerated by the patient, causing minimal discomfort and not 
interfering with everyday activities; 
 
Moderate: An AE that is sufficiently discomforting to interfere with normal everyday 
activities; 
 
Severe: An AE that prevents normal everyday activities. 
An AE that is assessed as severe should not be confused with an SAE. Refer to Section 10.3.2 
for the definition of an SAE. 


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10.4.2 
Relationship to Study Drug 
The investigator will categorize each AE as to its potential relationship to study drug: unrelated, 
unlikely related, possibly related, probably related, and definitely related. Items to be 
considered when assessing the relationship of an AE to the study treatment are as follows:  
 
Temporal relationship of the onset of the event to the initiation of the study treatment; 
 
The course of the event, considering especially the effect of discontinuation of study 
treatment or reintroduction of study treatment, as applicable; 
 
Whether the event is known to be associated with the study treatment or with other similar 
treatments; 
 
The presence of risk factors in the study patient known to increase the occurrence of the 
event; 
 
The presence of non-study treatment-related factors that are known to be associated with 
the occurrence of the event. 
The relationship categories of unrelated and unlikely related will be summarized for reporting 
purposes as Not Related. For Not Related events, the time course between the administration of 
study drug and the occurrence or worsening of the AE rules out a causal relationship with study 
drug, and another cause of the AE (concomitant drugs, therapies, complications, etc.) is 
suspected. 
The relationship categories of possibly, probably, and definitely related will be summarized for 
reporting purposes as Related. Only AEs thought to be caused by the study drug should be 
classified as “related to study drug.” For Related events, the time course between the 
administration of study drug and the occurrence or worsening of the AE is consistent with a 
causal relationship, and no other cause (concomitant drugs, therapies, complications, etc.) can be 
identified. The definition implies a reasonable possibility of a causal relationship between the 
event and the study drug. This means that there are facts (evidence) or arguments to suggest a 
causal relationship. 
10.5 
Reporting Procedures 
10.5.1 
Reporting Adverse Events  
Adverse events, whether reported by the patient or observed by the investigator/study personnel, 
must be documented in the patient’s medical record and reported by recording all pertinent 
information on the appropriate eCRF Form in the electronic data capture (EDC) system. 
Adverse events, regardless of causality assessment, must be collected beginning from the time 
the patient signs the ICF until the last study visit or 30 days after the last dose of study drug, 
whichever is longer.  
All AEs must be followed until resolution, or if resolution is unlikely until stabilization. 
10.5.2 
Reporting Serious Adverse Events  
10.5.2.1 
Initial Serious Adverse Event Reports 
All information regarding SAEs, whether reported by the patient or observed by the 
investigator/study personnel, must be documented in the patient’s medical record and reported 
by recording all pertinent information on the SAE Forms in the EDC system. 


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Serious AEs, regardless of causality assessment, must be collected beginning from the time the 
patient signs the ICF until the last study visit or 30 days after the last dose of study drug, 
whichever is longer. Any SAE judged by the investigator to be related to the study treatment 
should be reported to the Sponsor regardless of the length of time that has passed since study 
completion. 
Study site personnel should complete the eCRF SAE Form in the EDC system and the 
investigator should assess the causality within 24 hours (without delay, for France only) of 
knowledge of the event (this refers to any AE that meets any of the aforementioned seriousness 
criteria). When the form is completed, Medpace Clinical Safety personnel will be notified 
electronically by the EDC system and will retrieve the form. If the EDC system is unavailable, 
the SAE will be reported to Medpace Clinical Safety via email or telephone (see safety contact 
information below) and the completed form will be sent to Medpace by fax/email (see safety 
contact information below) within 24 hours of awareness (without delay, for France only). When 
the EDC system becomes available, the SAE information must be entered within 24 hours 
(without delay, for France only) of the system becoming available. 
The minimum information required for the initial SAE report is covered by the eCRF SAE Form. 
If requested by Clinical Safety, SAE reports should be followed as soon as possible by detailed 
descriptions including copies of hospital case reports, autopsy reports, and other documents (see 
Follow-up Reports, below).  
Safety contact information for this study is as follows: 
Medpace SAE reporting line – USA 
Phone: +1-513-579-9911, dial “3” 
Fax: +1-513-570-5196 
Email: medpace-safetynotification@medpace.com 
Medpace SAE reporting line – Europe 
Phone: +49 89 89 55 718 44 
Fax: +49 89 89 55 718 104 
Email: medpace-safetynotification@medpace.com 
For urgent safety issues, call the Medical Monitor: 
Michael S. Oldham, MD, MPH 
Medical Director 
Medpace 
5375 Medpace Way 
Cincinnati, Ohio 45227 
Phone: +1 513 579 9911, ext. 11080 
Mobile: +1 513 448 6925 
Fax: +1 513 579 0444 
Email: m.oldham@medpace.com 


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Marco JD Tangelder, MD, PhD 
Senior Medical Director 
Medpace 
5375 Medpace Way 
Cincinnati, Ohio 45227 
Home office: Haarlem, the Netherlands 
Mobile: +31 620154282 
Email: m.tangelder@medpace.com 
10.5.2.2 
Follow-up Serious Adverse Event Reports 
The investigator must continue to follow the subject until the SAE has subsided or until the 
condition becomes chronic in nature, stabilizes (in the case of persistent impairment), or the 
subject dies. 
Within 24 hours (without delay, for France only) of receipt of follow-up information, the 
investigator must update the eCRF SAE Form within the EDC system. Any requested supporting 
documentation (e.g. patient discharge summary or autopsy reports) should be submitted via 
e-mail at (medpace-safetynotification@medpace.com) or fax (+1-513-570-5196 or +49 89 89 55 
718 104). If it is not possible to access the EDC system, refer to the procedures outlined above 
(Section 10.5.2) for initial reporting of SAEs. All personal data must be redacted prior to 
submission; instead, please provide the study number and the patient identification number (ID) 
on each document. If the follow-up information changes the investigator’s assessment of 
causality, this should also be updated in the eCRF SAE form. 
The investigator should notify the IRB/EC of the occurrence of the SAE, in writing, in 
accordance with local requirements. A copy of this communication must be filed in the 
investigator’s files for this study. 
10.5.3 
Reporting of Pregnancy 
Please refer to Section 8.1.2.2 for the detailed procedures for pregnancy testing, prevention, and 
reporting. 
10.5.4 
Expedited Reporting  
The RSI is provided in Section 6.9 of the IB. The RSI is used for assessing whether an adverse 
reaction is a suspected unexpected serious adverse reaction (SUSAR).  
The Sponsor/designee will report all relevant information about SUSARs that are fatal or life-
threatening as soon as possible to the FDA, applicable competent authorities in all the Member 
States concerned, and to the Central EC and in any case no later than 7 days after knowledge by 
the Sponsor/designee of such a case. Relevant follow-up information will subsequently be 
communicated within an additional eight days.  
All other SUSARs will be reported to the FDA, applicable competent authorities concerned and 
to the Central EC concerned as soon as possible but within a maximum of 15 days of first 
knowledge by the sponsor/designee.  
The Sponsor/designee will also report any additional expedited safety reports required in 
accordance with the timelines outlined in country-specific legislation. 
The Sponsor/designee will also inform all investigators as required per local regulation. 


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10.5.5 
Special Situation Reports  
Special situation reports include reports of overdose, misuse, abuse, medication error and reports 
of adverse reactions associated with product complaints. 
 
Overdose: refers to the administration of a quantity of a medicinal product given per 
administration or cumulatively (accidentally or intentionally), which is above the 
maximum recommended dose according to the protocol. Clinical judgement should always 
be applied.  
In cases of a discrepancy in the drug accountability, overdose will be established only 
when it is clear that the patient has taken additional dose(s) or the investigator has reason 
to suspect that the patient has taken additional dose (s); 
 
Misuse: refers to situations where the medicinal product is intentionally and 
inappropriately used not in a way that is not in accordance with the protocol instructions or 
local prescribing information and may be accompanied by harmful physical and/or 
psychological effects; 
 
Abuse: is defined as persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects; 
 
Medication Error: Medication error is any unintentional error in the prescribing, 
dispensing or administration of a medicinal product by a healthcare professional, patient or 
consumer, respectively. The administration or consumption of the unassigned treatment 
and administration of an expired product are always reportable as medication errors, cases 
of patients missing doses of investigational product are not considered reportable as 
medication error; 
 
Product Complaint: is defined as any written, electronic, or oral communication that 
alleges deficiencies related to the identity, quality, durability, reliability, safety, 
effectiveness, or performance of a drug or device after it is released for distribution. A 
special situations form will only be completed if a complaint is associated with an adverse 
drug reaction.  
All special situation events as described above must be reported on the Special Situations Report 
form and faxed/emailed to Medpace Clinical Safety (see contact information listed above in 
Section 10.5.2) within 24 hours (without delay, for France only) of knowledge of the event. All 
AEs associated with these Special Situation reports should be reported as AEs or SAEs as well as 
recorded on the AE eCRF and/or the SAE report form. Details of the symptoms and signs, 
clinical management and outcome should be provided, when available.  
10.6 
Safety Oversight 
A Data Monitoring Committee (DMC) will be utilized in this study to ensure external objective 
medical and/or statistical review of safety data of the study. 
The DMC will be composed of independent experts external to the study and will review safety 
data on a regular basis. 
The DMC will operate under the rules of an approved charter that will define the roles and 
responsibilities of its members. Following each meeting, the DMC will provide its input to 
Millendo Therapeutics. 


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Phase 2b 
Additional assessments in the Phase 2b Core Period will include the following: 
 
Change from baseline in: 
o CgGIS-H score (see Section 19.8 Appendix H) and CGIS-H score (see Section 19.7 
Appendix G); 
o CgGIC-H score (see Section 19.5 Appendix E) and CGIC-H score (see Section 19.4 
Appendix D); 
o CGI-I score (see Section 19.6 Appendix F); 
o CGI-S score (see Section 19.9 Appendix I); 
o Fasting and postprandial glucose and insulin measurement (profile); 
o Appetite-NRS score; 
o DBC2-P score; 
o PedsQLTM Parent-Proxy age-appropriate Reports score; 
o ZBI score; 
o EQ-5D-5L Self score and EQ-5D-5L Proxy version 1 score; 
o BMI; 
o BMI Z-score 
 
 
Evaluation of the measurement properties and interpretation of clinically meaningful 
HQ-CT (see Section 9.1.1) change in the study population using blinded study data and 
according to a psychometric analysis plan; 
 
Responder definition using anchor-based methods supplemented with both cumulative 
distribution function (CDF) and probability density function (PDF) to derive the responder 
threshold for meaningful change; 
 
Percentage of HQ-CT responders as defined by anchor-based and distribution-based 
methods.  
 
Percentage change from baseline in BMI 
 
Percentage of patients with ≥5% and ≥10% reduction in BMI 
 
 
11 
ADDITIONAL STUDY ASSESSMENTS


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Additional assessments in the Phase 2b Extension Period will include the following: 
 
Change from baseline in: 
o CgGIS-H score (see Section 19.8 Appendix H) and CGIS-H score (see Section 19.7 
Appendix G); 
o CgGIC-H score (see Section 19.5 Appendix E) and CGIC-H score (see Section 19.4 
Appendix D); 
o CGI-I score (see Section 19.6 Appendix F); 
o CGI-S score (see Section 19.9 Appendix I); 
o Fasting glucose and insulin measurement; 
o DBC2-P score; 
o PedsQLTM Parent-Proxy age-appropriate Reports score; 
o ZBI score;  
o EQ-5D-5L Self score and EQ-5D-5L Proxy version 1 score; 
o BMI; 
o BMI Z-score 
 
 
Percentage of HQ-CT responders as defined by anchor-based and distribution-based 
methods.  
 
Percentage change from baseline in BMI 
 
Percentage of patients with ≥5% and ≥10% reduction in BMI 
 
Phase 3 
Additional assessments in the Phase 3 Core Period will include the following: 
 
Change from baseline in: 
o CgGIS-H score (see Section 19.8 Appendix H) and CGIS-H score (see Section 19.7 
Appendix G); 
o CgGIC-H score (see Section 19.5 Appendix E) and CGIC-H score (see Section 19.4 
Appendix D); 
o CGI-I score (see Section 19.6 Appendix F); 
o CGI-S score (see Section 19.9 Appendix I); 
o Fasting and postprandial glucose and insulin measurement (profile); 
o Appetite-NRS score; 
o DBC2-P score; 
o PedsQLTM Parent-Proxy age-appropriate Reports score; 


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o ZBI score;  
o EQ-5D-5L Self score and EQ-5D-5L Proxy version 1 score; 
 
Percentage of HQ-CT responders as defined by anchor-based and distribution-based 
methods. 
Additional assessments in the Phase 3 Extension Period will include the following: 
 
Change from baseline in: 
o CgGIS-H score (see Section 19.8 Appendix H) and CGIS-H score (see Section 19.7 
Appendix G); 
o CgGIC-H score (see Section 19.5 Appendix E) and CGIC-H score (see Section 19.4 
Appendix D); 
o CGI-I score (see Section 19.6 Appendix F); 
o CGI-S score (see Section 19.9 Appendix I); 
o Fasting glucose and insulin measurement; 
o DBC2-P score; 
o PedsQLTM Parent-Proxy age-appropriate Reports score; 
o ZBI score;  
o EQ-5D-5L Self score and EQ-5D-5L Proxy version 1 score; 
 
Percentage of HQ-CT responders as defined by anchor-based and distribution-based 
methods. 
11.1 
Fasting and Postprandial Glucose, Insulin, Acylated Ghrelin, and Unacylated 
Ghrelin Profile 
Patients will be required to fast for approximately 8 hours before visits requiring fasted blood 
sampling. 
During the Phase 2b Core Period and Phase 3 Core Period, blood levels of glucose, insulin, 
ghrelin, and UAG will be measured for patients 8 to 65 years of age at the following timepoints: 
 
Before isocaloric breakfast (and before dosing); 
 
30 minutes post-start of breakfast; 
 
180 minutes post-start of breakfast. 
During the Phase 2b Core Period (patients 4 to 7 years of age), Phase 2b Extension Period and 
Phase 3 Extension Period, blood levels of fasting glucose, insulin, ghrelin, and UAG will be 
measured. 
11.2 
Patient-reported Appetite Following Breakfast: Appetite-Numeric Rating Scale 
During the Core Period only, and for patients 8 to 65 years of age only, isocaloric breakfast will 
be provided, and patients will be asked to rate appetite/prospective food consumption using an 
appetite-NRS that has been specifically designed for the population of patients with PWS (see 
Section 19.3 Appendix C).  


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Completion of this scale will be performed under the supervision of the study personnel 
(assessments at the study center) before breakfast (after fasting for approximately 8 hours, and 
before dosing/before any blood sampling when applicable), at the end of breakfast, and 
120 minutes post-start of an isocaloric breakfast (see below), except at the screening visit, where 
the NRS will be administered for training and acclimation purposes (no profile). 
With the exception of the randomization visit (visit 2), when the NRS is to be administered, the 
study drug should be administered 30 minutes before breakfast. 
At visits when appetite-NRS assessment will be performed, patients will be given an isocaloric 
breakfast of 300 to 350 kcal (for patients 8 to 12 years of age) or 350-400 kcal (for patients 
>12 years of age). This breakfast will be composed of 60% carbohydrates; 25% lipids; 15% 
proteins. Breakfast must have the same number of calories and must be comparable in 
composition between days. Patients are encouraged to finish the entire breakfast. Any food not 
consumed needs to be recorded and reported in the eCRF. Breakfast should not last more than 
30 minutes.  
The appetite-NRS administration guidelines will be provided in a separate document. 
11.3 
Effects on Non-Food-Related Behavior: Developmental Behavior Checklist 
2-Parent/Carer version 
The DBC2-P is a 96-item instrument completed by parents or other primary caregivers, used for 
the assessment of behavioral and emotional problems in people with developmental and 
intellectual disabilities. The DBC2-P will be completed by the patients’ primary caregiver. 
11.4 
Effects on Patients’ Quality of Life: PedsQLTM 4.0 Generic Core Scales 
The QoL of participants will be assessed through the parent-proxy PedsQLTM 4.0 report (68-73) 
(Section 19.10 Appendix J). The PedsQLTM measurement model is a brief, standardized 
assessment instrument that systematically assesses HRQoL through child self-reports. In this 
study, considering that patients with PWS have cognitive impairment, the parent proxy report 
scale will be used, in accordance with PedsQLTM 4.0 administration guidelines. The PedsQLTM 
4.0 Generic Core Scale consists of 23 items applicable to a healthy school and community 
populations, as well as pediatric populations with acute and chronic health conditions. It 
encompasses: 1) physical functioning (eight items); 2) emotional functioning (five items); 
3) social functioning (five items); and 4) work/studies functioning (five items). 
PedsQLTM 4.0 Parent-Proxy age-appropriate Reports will be used for all patients and will be 
completed by the patients’ primary caregiver. 
11.5 
Effects on Caregiver Burden: Zarit Burden Interview 
The ZBI is a self-reported outcome that was designed to assess the level of burden experienced 
by the principal caregiver of individuals with disabilities (Section 19.11 Appendix K). This 
questionnaire will be completed by the patients’ primary caregiver. 
Clinical site monitoring is conducted to ensure that the rights and well-being of human patients 
are protected, that the reported trial data are accurate, complete, and verifiable, and that the 
conduct of the trial is in compliance with the currently approved protocol/amendment(s), with 
Good Clinical Practice (GCP), and with applicable regulatory requirement(s). 
12 
CLINICAL MONITORING


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 
Monitoring for this study will be performed by Millendo Therapeutics or its designee; 
 
At the monitoring visits, the progress of the study will be discussed with the investigator, 
or his/her representative. The ICFs will be reviewed for signatures and the eCRFs checked 
for completeness and accuracy. Patient source data must be available for review. The 
investigator and his/her staff are expected to cooperate with the study monitor and be 
available during at least a portion of the monitoring visit to review the eCRFs and any 
queries/resolutions, answer questions, and provide any missing information; 
 
The study monitor will record the date of each visit together with a summary of the status 
and progress of the study. Proposed actions will be confirmed with the investigator in 
writing; 
 
Telephone contact will be made with the investigator as necessary during the data 
collection period and during the data and report writing periods; 
 
Details of clinical site monitoring are documented in a Clinical Monitoring Plan (CMP). 
The CMP describes in detail who will conduct the monitoring, at what frequency 
monitoring will be done, at what level of detail monitoring will be performed, and the 
distribution of monitoring reports.  
Complete details of the analysis plan will be provided in the Statistical Analysis Plan (SAP) 
related to each Phase and Period (Phase 2b Core Period, Phase 2b Extension Period, Phase 3 
Core Period, and Phase 3 Extension Period). 
Any deviations from, or additions to, the original analysis plan in this protocol will be 
documented in the SAPs and the clinical study report(s). 
13.1 
Statistical Hypotheses 
Safety data will be presented descriptively, thus no formal hypothesis for safety will be tested. 
Efficacy endpoints will be tested with hypothesis of the form:  
 
H0: µTest = µPlacebo 
H1: µTest ≠ µPlacebo  
for continuous variables 
 
H0: πTest = πPlacebo 
H1: πTest ≠ πPlacebo 
for categorical variables 
 
where µ is the mean in the population and π is the proportion in the population. 
 
13 
STATISTICAL CONSIDERATIONS


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13.2 
Sample Size Determination 
13.2.1 
Phase 2b 
In the completed Phase 2a study (2 weeks of treatment), the change from baseline to Day 14 in 
the 9-item score of the HQ was -4.3 units for livoletide and -1.6 units for placebo, with a 
difference between groups of 2.7 units.  
For the Phase 2b Core Period (N=150, 8- to 65-year-olds), a between group difference of 4 units 
in the change from baseline in the HQ-CT score has been selected for sample size calculation 
based on the following:  
1. It is considered reasonable to achieve this difference as a 3 months treatment period is 
expected to produce a higher effect as compared to short-term treatment (2 weeks). 
2. It is in line with the HQ-CT distribution-based estimates of meaningful change observed in 
a landmark Phase 3 clinical trial (74) that included 107 obese individuals with PWS 12 to 
65 years of age (half-standard deviation [SD]=3.3, standard error of the mean [SEM]=4.4). 
In addition, the distribution-based estimates were found to be approximately the magnitude 
of the difference between the mean change of the “A little better” and “No change” in the 
CGIC subgroups. 
Assuming a 2-sided parametric test, alpha of 2.5% (Bonferroni adjustment for 2 comparisons) 
and a SD of 5, forty-one (41) patients per group will allow to detect a difference between groups 
of at least 4 units in the primary endpoint 9-item score of the HQ-CT. This is considered a 
conservative approach as higher is the difference between groups, lower is the sample size. 
Assuming a drop-out rate at 3 months of about 18%, a total of 50 patients (8 to 65 years of age) 
per group will need to be randomized.  
There is no formal sample size calculation done for patients in the 4 to 7 year of age cohort since 
data for subjects in this cohort will be considered supportive (i.e. this cohort will not be included 
in the Phase 2b primary endpoint analysis).  
Randomization will be stratified to ensure there are at least 25 patients (8 to 65 years of age) who 
are overweight/obese per treatment group. 
13.2.2 
Phase 3 
For Phase 3, the total number of required patients to be randomized is estimated to be 50 patients 
per group. Final sample size will be determined following analysis of data at the completion of 
the Phase 2b Core Period. 
13.3 
Concept of Estimands and General Strategy for Analyses 
As per the ICH E9 Addendum, an estimand defines in detail what needs to be estimated to 
address a specific scientific question of interest. In this study, the specific question or objective is 
to demonstrate the efficacy of a 3-month (or 6-month) treatment with livoletide as compared to 
placebo for reducing caregiver-observed food-related behavior. As described in Figure 8 below, 
a description of an estimand includes four attributes:  
A. 
the population, that is, the patients targeted by the scientific question; 
B. 
the variable (or endpoint), to be obtained for each patient, that is required to 
address the scientific question; 


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C. 
the specification of how to account for intercurrent events to reflect the scientific 
question of interest. 
D. 
the population-level summary for the variable which provides, as required, a basis 
for a comparison between treatment conditions. 
In this study, the main two intercurrent events identified are the missing observations caused par 
patients dropping out before their 3 months (for the phase 2b) or their 6 months (for the phase 3) 
evaluation and the younger age group of 4-7 years old who might not behave similarly to the 
older group. 
The main estimator will be based on the 8-65 years old group using an MMRM approach to 
handle the missing observations.  Sensitivity analyses will present the results in the subgroup of 
4-7 years old patients separately, as well as combined with the 8-65 years old patients. Moreover, 
additional sensitivity analyses will be performed on observed cases at 3 months (for the phase 
2b) or 6 months (for the phase 3) to evaluate the robustness of the missing observations strategy 
using the MMRM approach in the 8-65 years old group. 
Supplementary analyses will consist of the analyses of the key secondary endpoints in a manner 
similar to the main estimator (i.e. MMRM in the 8-65 years old group). They will also consist of 
the statistical analyses of all additional study assessments as described in section 11. These 
supplementary analyses will all be supportive in providing additional insights into the 
understanding of the treatment effect. 
 


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Figure 8: General concept of estimands in the Phase 2b and Phase 3 studies 
 
 
Sensitivity Estimator 2 
Difference in mean changes 
from baseline at 3 (or 6) months 
in 
HQ-CT 
(livoletide 
vs. 
Placebo) using the observed 
case. 
Supplementary Estimators 
Difference in mean changes 
from baseline at 3 (or 6) months 
in: 
   -Fat mass 
   -Waist circumference 
   -Body weight 
Supplementary Estimates 
Main Estimator 
Difference in mean changes from baseline 
through 3 (or 6) months in HQ-CT (livoletide 
vs. Placebo) using MMRM in the 8-65 years 
old group. 
Sensitivity Estimators 1 
Difference in mean changes 
from baseline through 3 (or 6) 
months in HQ-CT using MMRM 
in the 4-7 years old group. 
Combined age groups using 
MMRM 
Main Estimate 
Sensitivity Estimates 
Trial Objective: to demonstrate the efficacy of a 
3-month (or 6-month) treatment with livoletide as 
compared to placebo for reducing caregiver-
observed food-related behavior.  
*** 
i. population 
ii. variable 
iii. intercurrent events 
iv. population summary 
Estimand*** 
i. 
Patient with PWS Hyperphagia Questionnaire for 
Clinical Trials (HQ-CT) evaluated over the last 3 (or 6) 
months 
ii. 
4-7 years of age, discontinuation prior to the 3 (or 6) 
months evaluation  
iii. 
Change from baseline at 3 (or 6) months in HQ-CT 


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13.4 
Populations for Analyses 
Populations will be derived for each Phase and Period (Phase 2b Core Period, Phase 2b 
Extension Period, Phase 3 Core Period, and Phase 3 Extension Period) with the exception of the 
PK population, which will be defined for the Phase 2b Core and Extension Periods. 
13.4.1 
Full Analysis Set 
All randomized patients will be included in the Full Analysis Set (FAS). The initial 
randomization will be preserved for this analysis set in order to comply with the Intent-To-Treat 
(ITT) principle. 
13.4.2 
Per Protocol 
The Per Protocol set (PP) will include all randomized patients who: 
 
Completed the period of treatment (i.e. 3 months [Phase 2b Core Period], 6 months 
[Phase 3 Core and Extension Periods] or 9 months [Phase 2b Extension Period]); 
 
Have non-missing observation at baseline and at the end of the period for the primary 
efficacy endpoint; 
 
Have no major protocol violations including the violation of inclusion/non-inclusion 
criteria. 
The treatment actually received by the patient will be used in this set. Prior to database lock, 
major protocol violations will be defined and reviewed by Millendo Therapeutics and the CRO 
in charge of the study follow-up in a blinded fashion. Patients with major protocol violations will 
be excluded from the PP population(s). 
13.4.3 
Safety Population 
All randomized patients who received at least one dose of study drug will be included in the 
Safety population. Patients will be analyzed as per the treatment they received. 
13.4.4 
 Pharmacokinetic Population 
All randomized patients who received at least one dose of study drug and for whom robust PK 
data can be obtained will be included in the PK population. 
13.5 
Statistical Analyses 
All continuous variables will be summarized by presenting the number of patients, mean, SD, 
median, minimum, and maximum. Categorical variables will be presented as frequencies and 
percentages. 
Efficacy analyses will be performed on the FAS as main analyses and on PP population, as 
supportive analyses. Safety analyses will be performed on the Safety population. 
Methods to control for the overall type 1 error for multiple testing will be described in detail in 
the SAPs. 
For efficacy endpoints, handling of missing observations will be done using the mixed model 
repeat measures (MMRM) approach. No imputation of missing observations will be done for 
safety parameters. 


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For all statistical efficacy analyses, the distribution of efficacy the residuals will be visually 
examined to determine whether substantial departures from normality and homogeneity of 
variance are apparent. If the data are inconsistent with the assumption of normality and 
homogeneity of variance, alternative non-parametric models may be presented instead. 
All details regarding the efficacy and safety variable definitions, analyses strategy, statistical 
justification, and techniques for handling missing values will be presented in separate SAPs that 
will be prepared before the database is locked and any analyses are undertaken. 
13.5.1 
Phase 2b 
13.5.1.1 
Analysis of the Efficacy Endpoints 
Core Period 
The primary analysis for the primary efficacy endpoint will be done using a mixed model 
repeated measures analysis (MMRM) on the change-from-baseline HQ-CT total score within the 
first 3-months. The model will include treatment, visit, stratification variables, and treatment by 
visit interaction as fixed effects and baseline score as a covariate. An unstructured covariance 
will be used to model the correlation. In the case where convergence issues arise, the 
autoregressive (AR (1)) structure will be used.  Contrasts will be defined in the mixed model to 
test for treatment differences at different time points, but the primary comparison will be done at 
3-months. 
As supportive analysis, an analysis of covariance (ANCOVA) on the change-from-baseline HQ-
CT total score at 3 months will be performed. The model will include treatment and the 
stratification variables as fixed effects, and HQ-CT total score at baseline as a covariate.  
The key secondary endpoints percentage change from baseline in total body fat mass, change 
from baseline in WC, and percentage change from baseline in BW on overweight/obese patients 
will be analyzed using the same approach as for the primary efficacy endpoint. In addition, as 
exploratory analyses, the analyses will also be performed based on all patients, including BMI 
(categorical variable) in the statistical models. 
Sensitivity analyses will be performed on the 4-7 years old group separately and combined with 
the 8-65 years old group, using MMRM models. 
Extension Period 
The change from baseline to the end of the 9-month Extension Period in HQ-CT total score and 
the change from the end of the 3-month Core Period to the end of the 9-month Extension Period 
in HQ-CT total score will be compared using an MMRM approach. The dependent variable will 
be HQ-CT total score. The model will include treatment, stratification variables, and treatment 
by visit interaction. An unstructured variance-covariance matrix will be used to model the 
intra-patient correlation. In the case where convergence issues arise, the autoregressive (AR (1)) 
structure will be used. Contrasts will be defined in the mixed model to test 12 months vs 
3 months and 12 months vs baseline, per treatment. 
Percentage change from baseline in total body fat mass, change from baseline in WC, and 
percentage change from baseline in BW will be analyzed using the same approach as described 
above on overweight/obese patients. 


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13.5.1.2 
Analysis of the Additional Assessments 
Similar statistical approaches as described in Section 13.5.1.1 will be used for the analyses of the 
additional assessments being continuous variables. Responders will be analyzed using a 
Pearson-Chi Squared test. 
13.5.1.3 
Safety Analyses 
Results from the Core and the Extension Periods will be presented separately. 
Adverse Events: 
Adverse events will be collected from the time of signing of informed consent. Adverse events 
will be classified as TEAEs or pre-treatment AEs. An AE with an unknown/unreported onset 
date will also be counted as a TEAE. Unless otherwise stated, all references to Aes in this study 
protocol refer to TEAEs. An increase of intensity or frequency of a pre-treatment AE will also be 
considered as a TEAE. 
The number and percentage of patients, who experience TEAEs, will be presented by System 
Organ Class (SOC) and by Preferred Term (PT) within SOC for each treatment group. TEAEs 
will be similarly presented by severity and by relationship to study drug. TEAEs will be 
presented for each group. The total number of TEAEs, as well as the total number of patients 
with TEAEs, will also be presented. Treatment-emergent SAEs (TESAEs) will be presented 
similarly as TEAEs. 
A patient experiencing the same TEAE multiple times will be counted only once for the 
corresponding PT. Similarly, if a patient experiences multiple Aes within the same SOC, the 
patient will be counted only once for that SOC. If a patient experiences more than one AE within 
different severity or relationship categories within the same SOC/PT, only the worst case (worst 
severity and related AE) will be reported. Aes will be sorted alphabetically by SOC and within 
each SOC the PT will be presented by decreasing order of total frequency. Aes will be coded to 
SOC and PT using the Medical Dictionary for Regulatory Activities (MedDRA). 
A listing of SAEs and discontinuations due to Aes will be presented. Patient deaths will be listed 
separately. SAEs and discontinuations due to Aes will be described by case narratives. All Aes 
will be presented by investigative site and by treatment group in a listing, which will include the 
patient identifier, PT, reported term, severity, seriousness, action taken, outcome, relationship, 
date of onset, duration, end date, and study treatment at the time of the event of most recent 
study treatment taken. Separate listings will be provided for pre-treatment and post-treatment 
events. 
Safety Laboratory Evaluations 
Descriptive statistics (n, mean, SD, median, and range) for each clinical laboratory test will be 
presented by treatment group and available visit. Change from baseline to each available 
post dose visit will also be summarized. 
According to the laboratory normal ranges, laboratory test results will be categorized as low 
(< lower normal limit), normal (within normal range), and high (> upper normal limit). Shift 
tables comparing the distributions of these three categories at baseline versus each available 
post-dose visit will be presented by treatment group for key safety laboratory evaluations. 


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Moreover, a summary of newly occurring or notable worsening laboratory abnormalities will be 
presented. The criteria to identify these laboratory abnormalities will be defined in the SAP(s). 
Vital Signs and Electrocardiograms 
Descriptive statistics (n, mean, SD, median, and range) will be presented by treatment group and 
available visits. Change from baseline to each available post-dose visit will also be summarized. 
Physical Examinations 
Physical exam will be summarized by visit in terms of n (%) of patients with normal/abnormal 
results per body system and treatment group. Moreover, shift tables from baseline to the end of 
each period will be presented. 
Lean Body Mass and Bone Mineral Density 
Descriptive statistics (n, mean, SD, median, and range) will be presented by treatment group and 
available visits for lean body mass and bone mineral density results. Change and percent change 
(for lean body mass) from baseline to each available post-dose visit will also be summarized. 
13.5.1.4 
Planned Interim Analyses (if applicable) 
No interim analysis is planned in Phase 2b. 
13.5.2 
Phase 3 
Statistical analyses to be performed in Phase 3 (Core and Extension Periods) will be comparable 
to those performed in Phase 2b and will be further described at a later stage. 
13.6 
Sub-group Analyses 
13.6.1 
Phase 2b 
Primary efficacy endpoint HQ-CT total score will also be analyzed by subgroups of age (4 to 7 
years of age, 8 to 17 years of age, and ≥18 years of age) and BMI (patients 18 years of age: 
BMI <27 kg/m2 vs BMI 27 kg/m2; patients 4-17 years of age: BMI <90th percentile vs 
BMI 90th percentile for the same age and sex). 
Analyses on blood glucose and insulin will be performed on all population and on patients with 
elevated postprandial glucose (EPG). EPG is defined as 1-hour post-meal glucose concentration 
≥8.0 mmol/L (144 mg/dL). 
13.6.2 
Phase 3 
Sub-group analysis to be performed in Phase 3 (Core and Extension Periods) will be further 
described at a later stage. 
13.7 
Analyses of HQ-CT Measurement Properties 
The analyses of HQ-CT measurement properties will be described in a specific separate 
document. 
13.8 
Analysis of Pharmacokinetic Samples 
Plasma livoletide PK parameters will be derived using non-compartmental methods. 
Where possible, the following PK parameters will be determined. Additional parameters may 
also be calculated as appropriate. 


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Maximum concentration (Cmax); time of Cmax (tmax); observed minimum concentration (Cmin); 
time of Cmin (tmin); average concentration during the dosing interval (Cavg); fluctuation index over 
the dosing interval (FI); area under the concentration-time curve during the dosing interval 
(AUC(0-tau)); apparent terminal rate constant (λz); apparent terminal half-life (t1/2); apparent total 
body clearance (CL/F); apparent volume of distribution (Vz/F); accumulation ratio for AUC(0-tau) 
(RAUC(0-tau)); accumulation ratio for Cmax (RCmax); and linearity index (LI) as appropriate. 
The linear up/log down trapezoidal method will be used for calculation of all PK areas under the 
curve. Further details of the PK analyses will be described in a separate PK SAP. The plasma 
concentrations obtained during this study may be used for a stand-alone population-PK model 
that will be reported separately. 
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with International Council for Harmonisation (ICH GCP) Guidelines and regulatory 
and institutional requirements for the protection of confidentiality of participants.  
The study monitor or other authorized representatives of the Sponsor may inspect all documents 
and records required to be maintained by the investigator, including but not limited to, medical 
records (office, clinic, or hospital) and pharmacy records for the patients in this study. The 
clinical study site will permit access to such records.  
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Examples 
of these original documents and data records include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, participant’s memory aids or evaluation 
checklists, pharmacy dispensing records, recorded audio tapes of counseling sessions, recorded 
data from automated instruments, copies or transcriptions certified after verification as being 
accurate and complete, microfiches, photographic negatives, microfilm or magnetic media, 
x-rays, and participant files and records kept at the pharmacy, at the laboratories, and 
medico-technical departments involved in the clinical trial. 
It is not acceptable for the eCRF to be the only record of a patient’s participation in the study. 
This is to ensure that anyone who accesses the patient medical record is adequately informed that 
the patient is participating in a clinical trial. 
This study will be conducted in compliance with the protocol, current GCP rules, and the 
applicable regulatory requirements.  
Quality Control comprises the operational techniques and activities undertaken within the quality 
assurance system to verify that the requirements for quality of the trial-related activities have 
been fulfilled.  
Monitoring is the act of overseeing the progress of a clinical trial, and of ensuring that it is 
conducted, recorded, and reported in accordance with the protocol, Standard Operating 
Procedures (SOPs), GCP, and the applicable regulatory requirement(s). As part of the 
supervision of the study progress, the Sponsor personnel or the CRO may, on request, 
14 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
15 
QUALITY CONTROL AND QUALITY ASSURANCE 


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accompany the monitor on visits to the study site. The investigator and the study investigator 
collaborators commit to cooperate with the monitor to resolve any problems, corrections, or 
possible misunderstandings concerning the findings or protocol violations detected in the course 
of these monitoring visits.  
Protocol violations will be sorted in significant and non-significant violations before the blind 
data review. A significant violation is any violation identified during monitoring that requires 
immediate information to the Sponsor for possible action (for example, withdrawal of the patient 
from the study).  
During the data review and before unblinding, protocol violations will be sorted in major and 
minor violations. A major violation is any violation having an impact on the classification of the 
population sets (for example, impacting the main evaluation criteria).  
Site personnel will be trained on the condition to be treated, the protocol, and all study-specific 
procedures. They will be provided with specific instructions. 
16.1 
Regulatory, Ethical, And Study Oversight Considerations 
The investigator will ensure that this study is conducted in full conformity with ICH GCP E6 
principles, the Declaration of Helsinki (1964) and all subsequent amendments as amended (see 
Section 19.1 Appendix A), and all other applicable regulatory requirements.  
16.2 
Institutional Review Board/Ethics Committee 
It is the responsibility of the investigator to submit this protocol, the informed consent document 
(approved by the Sponsor or its designate), relevant supporting information, and patient 
recruitment materials to the IRB/EC for review. All must be approved prior to site initiation. 
Prior to implementing changes in the study, the Sponsor and the IRB/EC must also approve any 
revised ICFs and/or protocol amendments. 
On the IRB/EC approval letter, the study reference number the date of review and actions taken 
should be clearly stated. 
Study drug will not be released to the site and recruitment of patients will not begin until the 
IRB/EC written approval has been received by the Sponsor or its designee. 
The investigator is responsible for keeping the IRB/EC apprised of the progress of the study and 
of any changes made to the protocol and/or ICF. The investigator must also keep the IRB/EC 
informed of any serious and significant AEs, as per country regulation. 
16.3 
Informed Consent Process 
According to local requirements and GCP, prior to participation in the study, the investigator 
must fully explain orally to each patient and legally authorized representative the nature of the 
study, its purpose, the procedures involved, the expected duration, the potential risks and benefits 
involved, and any discomfort or constraint it may entail. The patient and legally authorized 
representative should be given ample time and opportunity to inquire about details of the trial 
and to decide whether or not to participate in the trial. Each patient must be informed that 
participation in the study is voluntary and that he or she may withdraw from the study at any 
16 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS


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time and that withdrawal of consent will not affect his/her subsequent medical treatment or 
relationship with the treating physician.  
The ICF is documented by means of a written, signed, and dated patient/legally authorized 
representative consent form (or age-appropriate assent form) per local requirements, prior to the 
start of the study. Age-appropriate assent forms will be completed for minor patients. The 
Informed Consent/Assent Form will be written in a language and in a form understandable to the 
patient/legally authorized representative. This assent form will be dated and signed by the patient 
insofar as possible. In all cases, the first name and last name will be asked to be mentioned by 
the patient. 
One signed and dated copy of the ICF will be given to the patient/parent and one signed and 
dated original copy will be maintained by the investigator in the study file in compliance with 
ICH E6 and local regulations. 
The investigator should clearly indicate the patient’s participation in a clinical trial in his/her 
medical chart. No patient can have a study-related procedure performed before informed consent 
has been obtained. The assistance of the legally acceptable representative will also be 
documented in the patient medical chart.  
The Informed Consent/Assent Form is part of the protocol and must be submitted for IRB/EC 
approval. Millendo Therapeutics or designee will supply a proposed Informed Consent/Assent 
Form, that complies with regulatory requirements and is considered appropriate for the study. 
Any changes to the proposed consent/assent form suggested by the investigator must be agreed 
to by Millendo Therapeutics or designee before submission to the IRB/EC and a copy of the 
approval version must be provided to Millendo Therapeutics or designee after IRB/EC approval. 
In addition, any change that may affect patients’ participation and/or safety will necessitate 
patients to re-consent.  
16.4 
Participants’ and Data Confidentiality 
Patient confidentiality is strictly held in trust by the Sponsor and/or their designee(s), 
participating investigators, and any staff. This confidentiality includes the clinical information 
relating to participating patients, as well as any genetic or biological testing. 
Any research information obtained about the patient in this study will be kept confidential in 
accordance with all relevant national and international laws governing data privacy and security. 
A patient will not be identified by name, only by his/her initials. The patient’s name or any other 
identifying information will not appear in any reports published as a result of this study. 
The study protocol, documentation, data, and all other information generated will be held in 
strict confidence. However, information obtained from individual patient’s participation in the 
study may be disclosed with his/her express written consent to the health care providers for the 
purpose of obtaining appropriate medical care. The patient’s medical records/charts and tests 
with his/her name on them may be made available to the appropriate CRO, the Sponsor, its 
potential eventual partners, and any other regulatory authorities. This is for the purpose of 
verifying information obtained for this study. Confidentiality will be maintained throughout the 
study within the limits of the law. 
A patient’s name will not be given to anyone except the researchers conducting the study, who 
have pledged an oath of confidentiality. All identifying information will be kept behind locked 


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doors, under the supervision of the study investigator, and will not be transferred outside of the 
investigator site 
The study monitors or other authorized representatives of the Sponsor may inspect all documents 
and records required to be maintained by the investigator, including but not limited to, medical 
records (office, clinic, or hospital) and pharmacy records for the patients in this study. The study 
site will permit access to such records. 
A patient may take away his/her permission to collect, use, and share information about him/her 
at any time. If this situation occurs, the patient will not be able to remain in the study. No new 
information that identifies the patient will be gathered after that date. However, the information 
about the patient that has already been gathered and transferred may still be used and given to 
others as described above in order to preserve the scientific integrity and quality of the study. 
17.1 
Data Collection and Management Responsibilities 
The Sponsor or its designee will instruct the study center regarding data capture procedures on 
eCRF.  
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site PI. The investigator is responsible for ensuring the accuracy, completeness, legibility, 
and timeliness of the data reported. 
Source documentation supporting the data should indicate the patient’s participation in the study 
and should document the dates and details of study procedures, AEs, and patient status.  
All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data. Black ink is required to ensure clarity of reproduced copies. When making 
changes or corrections, cross out the original entry with a single line, and initial and date the 
change. DO NOT ERASE, OVERWRITE, OR USE CORRECTION FLUID OR TAPE ON 
THE ORIGINAL. 
The investigator, or designated representative, should complete data entry as soon as possible 
after information is collected, preferably on the same day that a study patient is seen for an 
examination, treatment, or any other study procedure. Data reported in the eCRF derived from 
source documents should be consistent with the source documents or the discrepancies should be 
explained and captured in a progress note and maintained in the participant’s official electronic 
study record.  
Clinical data (including AEs, concomitant medications, and expected adverse reactions data) and 
selected clinical laboratory data will be entered into Clintrak EDC, a 21 Code of Federal 
Regulations (CFR) Part 11-compliant data capture system provided by the Clintrak EDC. The 
data system includes password protection and internal quality checks, such as automatic range 
checks, to identify data that appear inconsistent, incomplete, or inaccurate. Clinical data will be 
entered directly from the source documents. 
17.2 
Study Records Retention 
To enable evaluations and/or audits from the regulatory authorities, the appropriate CRO, or the 
Sponsor, the investigator agrees to keep records, including the identity of all participating 
17 
DATA HANDLING AND RECORD KEEPING 


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patients (sufficient information to link records, eCRFs, and hospital records), all original signed 
ICFs, copies of all eCRFs, source documents, and detailed records of treatment disposition. The 
investigator must maintain confidential all study documentation, and take measures to prevent 
accidental or premature destruction of these documents.  
If the investigator relocates, retires, or for any reason withdraws from the study, then the Sponsor 
should be prospectively notified. The study records must be transferred to an acceptable 
designee, such as another investigator, another institution, or to the Sponsor. The investigator 
must obtain written permission from the Sponsor before disposing of any records. 
It is recommended that the Sponsor or designee retain the study documents at least fifteen (15) 
years after the completion or discontinuation of the Clinical Trial, or a minimum of 2 years after 
the last approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region, or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product. 
However, applicable regulatory requirements should be taken into account in the event that a 
longer period is required.  
If the Sponsor’s situation is such that archiving cannot be ensured, Sponsor shall transfer his 
responsibility for archiving to a mutually agreed designee.  
17.3 
Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, ICH GCP, or Manual 
of Procedures requirements. The noncompliance may be either on the part of the participant, the 
investigator, or the study site staff. As a result of deviations, corrective actions are to be 
developed by the site and implemented promptly.  
These practices are consistent with ICH GCP:  
 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, 4.5.3, and 4.5.4;  
 
5.1 Quality Assurance and Quality Control, section 5.1.1;  
 
5.20 Noncompliance, sections 5.20.1, and 5.20.2. 
No deviation may be made from the protocol unless an amendment has been agreed to in writing 
by both the investigator and the Sponsor and approved by the IRB/EC, except for patient safety 
as noted below. Investigative sites will contact the medical monitor to request clarifications 
regarding any aspect of the clinical study or eligibility of patients. 
When an emergency occurs that requires a deviation from the protocol for an individual patient, 
the deviation will be only for that patient. The investigator or other physician in attendance in 
such an emergency will, if circumstances and time permit, contact the Sponsor or their 
representative(s), immediately by telephone. Such contacts will be made as soon as possible to 
permit a decision as to whether or not the patient (for whom the protocol deviation was affected) 
is to continue in the study. The source documentation will completely describe the protocol 
deviation and state the reasons for such deviation. In addition, the IRB/EC will be notified in 
writing of such protocol deviation, as appropriate. 


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17.4 
Protocol Amendments 
Any change or addition to this protocol requires a written protocol amendment that must be 
approved by Millendo Therapeutics and the Coordinating PI before implementation.  
Amendments significantly affecting the safety of patients, the scope of the investigation, or the 
scientific quality of the study require additional approval by the IRB/EC, and, when applicable, 
by the regulatory authority. A copy of the written approval of the IRB/EC, which becomes part 
of the protocol, must be given to Millendo Therapeutics.  
These requirements for approval should in no way prevent any immediate action from being 
taken by the investigator or by Millendo Therapeutics in the interest of preserving the safety of 
all patients included in the trial.  
Amendments affecting only administrative aspects of the study do not require formal protocol 
amendments or IRB/EC approval but the IRB/EC of each center must be kept informed of such 
administrative changes (e.g. correcting for typographical errors, rewording for clarity, changes in 
study personnel). 
17.5 
Publication and Data Sharing Policy 
Any formal presentation or publication of data collected as a direct or indirect result of this trial 
will be considered a joint publication by the investigators and the appropriate personnel of 
Millendo Therapeutics. It is mandatory that the first publication is based on all data obtained 
from all analyzed patients as stipulated in the protocol. Participating investigators must agree not 
to present data gathered individually or by a subgroup of centers before the full, initial 
publication. Authorship will be determined according to Millendo Therapeutics publication 
policy and in agreement with the coordinating PI. The latter will be the last author and 
co-authorship will be based on substantial contributions to study conception and design and/or 
analysis and interpretation of data in accordance with the Vancouver protocol, as well as on 
recruitment performance when applicable.  
Millendo Therapeutics will manage the process of preparing abstracts, posters, and manuscripts 
for the joint publications that include data from all centers. For any other intended 
communication on the data from this study, Millendo Therapeutics requests to receive copies in 
advance (at least 15 working days for an abstract or oral presentation and 45 working days for a 
manuscript). This is to allow Millendo Therapeutics to review the communications for accuracy 
(thus avoiding potential discrepancies with submissions to regulatory authorities), to verify that 
confidential information is not being inadvertently divulged, to provide any relevant 
supplementary information, and to allow establishment of co-authorship. 
The detailed obligations regarding the publication of any data, material results, or other 
information, generated or created in relation to the study shall be set out in the agreement 
between each investigator and the Sponsor. 
A summary of the study results will be made publicly available within 12 months of reaching the 
end of the study, defined as the date of the LPLV. A full clinical study report will be made 
publicly available no later than 18 months after the end of the study. 
17.6 
Conflict of Interest Policy 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who have 


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a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed 
and managed. Furthermore, persons who have a perceived conflict of interest will be required to 
have such conflicts managed in a way that is appropriate to their participation in the design and 
conduct of this trial.  
17.7 
Financing and Insurance 
In accordance with the provisions of the law and the GCP principles, the Sponsor will subscribe 
to an insurance policy covering, in its terms and conditions, its legal liability for certain injuries 
to participating persons arising out of this research performed strictly in accordance with the 
scientific protocol as well as with applicable law and professional standards. 


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59. 
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LIST OF TABLES 
Table 1: Tabular summary of completed clinical studies on livoletide (AZP-531) ...................... 48 
Table 2: Phase 2b  Description of the study objectives and endpoints for the Core Period and the 
Extension Period ........................................................................................................................... 54 
Table 3: Phase 3  Description of the study objectives and endpoints for the Core Period and the 
Extension Period ........................................................................................................................... 57 
Table 4: Adjustment of livoletide dosing according to body weight ............................................ 70 
Table 5: Summary table of clinical laboratory parameters assessed during the study. ................. 79 
 
LIST OF FIGURES 
Figure 1: Complications associated with hyperphagia in patients with Prader-Willi syndrome .. 42 
Figure 2: Unacylated ghrelin (UAG) acylation by ghrelin O-acyltransferase (GOAT) ............... 43 
Figure 3: AG and UAG levels in PWS, control, and obese subjects (A) and evolution of AG and 
UAG levels in nutritional phases in PWS (B). Adapted from Kuppens et al., 2015 .................... 44 
Figure 4: Structure of unacylated ghrelin (UAG), AZP-502, and livoletide (AZP-531) .............. 45 
Figure 5: Structural formula of livoletide (AZP-531) ................................................................... 46 
Figure 6: Phase 2b Core and Extension PeriodsStudy Schematic .............................................. 60 
Figure 7: Phase 3 Core and Extension PeriodsStudy Schematic ................................................ 61 
Figure 8: General concept of estimands in the Phase 2b and Phase 3 studies ............................ 120 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation  
Definition 
or Term 
°C 
 
 
Celsius degree 
°F 
 
 
Fahrenheit degree 
µg 
 
 
microgram 
ADA 
 
 
anti-drug antibodies 
AE 
 
 
adverse event 
AG 
 
 
acylated ghrelin 
AgRP 
 
 
agouti-related protein 
ALT 
 
 
alanine aminotransferase 
ANCOVA 
 
analysis of covariance 
AST 
 
 
aspartate aminotransferase 
AUC 
 
 
area under the concentration-time curve 
AUC(0-tau) 
area under the concentration-time curve during the dosing interval 
AZP-531 
 
livoletide 
BID 
 
 
twice daily 
BMI 
 
 
body mass index 
BW 
 
 
body weight 
Cavg 
 
 
average concentration during the dosing interval 
Cmax 
 
 
maximum concentration 
Cmin 
 
 
observed minimum concentration 
CDF 
 
 
cumulative distribution function 
CGI-I 
 
 
Clinical Global Impression of Improvement 
CGI-S  
 
Clinical Global Impression of Severity 
CgGIS-H 
 
Caregiver Global Impression of Severity - Hyperphagia 
CGIS-H  
 
Clinical Global Impression of Severity - Hyperphagia 
CgGIC-H 
 
Caregiver Global Impression of Change - Hyperphagia 
CGIC-H  
 
Clinical Global Impression of Change – Hyperphagia 
CHF 
 
 
congestive heart failure 
CL/F 
 
 
apparent total body clearance 


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CMP 
 
 
Clinical Monitoring Plan 
CONSORT 
 
Consolidated Standards of Reporting Trials 
CRO 
 
 
Clinical Research Organization 
CTA 
 
 
Clinical Trial Authorization 
CFR 
 
 
Code of Federal Regulations 
DBC2-P  
 
Developmental Behavior Checklist 2-Parent/Carer version 
DBP 
 
 
diastolic blood pressure 
DXA 
 
 
dual energy X-ray absorptiometry 
dL 
 
 
deciLiter 
DMC 
 
 
Data Monitoring Committee 
DNA 
 
 
deoxyribonucleic acid 
EC 
 
 
Ethics Committee 
ECG 
 
 
electrocardiogram 
eCRF 
 
 
electronic Case Report Form 
EDC 
 
 
electronic data capture 
eDevice  
 
electronic device 
EIU 
 
 
Exposure In Utero 
e.g. 
 
 
exempli gratia 
EMA 
 
 
European Medicine Agency 
EPG 
 
 
Elevated Postprandial Glucose 
EQ-5D-5L 
 
European Quality of Life Five Dimension Five Level Scale 
FAS 
 
 
Full Analysis Set 
FDA 
 
 
Food and Drug Administration 
FI 
 
 
fluctuation index over the dosing interval 
FISH 
 
 
fluorescence in situ hybridization 
FSH 
 
 
follicle stimulating hormone 
g 
 
 
gram 
GCP 
 
 
Good Clinical Practice 
GHSR  
 
Growth Hormone Secretagogue Receptor 
GLP 
 
 
Good Laboratory Practice 
GLP-1  
 
glucagon-like-peptide 1 
GMP 
 
 
Good Manufacturing Practice 
GOAT  
 
ghrelin O-acyltransferase 


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HbA1c  
 
glycated hemoglobin 
HDL 
 
 
high density lipoprotein 
HIV 
 
 
human immunodeficiency virus 
HQ 
 
 
Hyperphagia Questionnaire 
HQ-CT  
 
Hyperphagia Questionnaire for Clinical Trials 
HR 
 
 
heart rate 
HRQoL  
 
health-related quality of life 
IB 
 
 
Investigator’s Brochure 
ICF 
 
 
informed consent form 
ICH 
 
 
International Council for Harmonisation 
ID 
 
 
identification number 
i.e. 
 
 
id est 
IGF-1   
 
insulin-like growth factor-1 
IND 
 
 
Investigational New Drug 
IQ 
 
 
Intelligence Quotient 
IRB 
 
 
Institutional Review Board 
ITT 
 
 
Intent-To-Treat 
IRT 
 
 
Interactive Response Technology 
kg 
 
 
kilogram 
λz 
 
 
apparent terminal rate constant 
L 
 
 
Liter 
LDH 
 
 
lactate dehydrogenase 
LDL 
 
 
low density lipoprotein 
LH 
 
 
luteinizing hormone 
LI 
 
 
linearity index 
LPLV 
 
 
last visit of the last patient 
MAD 
 
 
multiple ascending dose 
MC3R  
 
melanocortin-3 receptor 
MC4R  
 
melanocortin-4 receptor 
MD 
 
 
Doctor of Medicine 
MedDRA 
 
Medical Dictionary for Regulatory Activities 
MI 
 
 
myocardial infarction 


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mg 
 
 
milligram 
mmHg  
 
milliliter of mercury 
MMRM  
 
mixed-effect model repeat measurement 
mL 
 
 
milliliter 
N 
 
 
number of patients 
NaCl 
 
 
sodium chloride 
NOAEL  
 
No Observed Adverse Effect Level 
NRS 
 
 
Numerical Rating Scale 
NYHA  
 
New York Heart Association 
OECD  
 
Organization for Economic Co-operation and Development 
PedsQLTM  
 
Pediatric Quality of Life inventoryTM 
PD 
 
 
pharmacodynamic 
PDF 
 
 
probability density function 
PI 
 
 
Principal Investigator 
PK 
 
 
pharmacokinetics 
PP 
 
 
Per Protocol 
PT 
 
 
Preferred Term 
PWS 
 
 
Prader-Willi Syndrome 
QoL 
 
 
Quality of Life 
QTCB 
 
 
QT interval corrected for HR by Bazett’s formula 
QTCF 
 
 
QT interval corrected for HR by Fridericia’s formula 
RAUC(0-tau) 
 
accumulation ratio for AUC(0-tau) 
RCmax 
 
 
accumulation ratio for Cmax 
REB 
 
 
Research Ethics Board 
RSI 
 
 
reference safety information 
SAD 
 
 
single ascending dose 
SAE 
 
 
serious adverse event 
SAP 
 
 
Statistical Analysis Plan 
SBP 
 
 
systolic blood pressure 
SC 
 
 
subcutaneous 
SD 
 
 
standard deviation 
SEM 
 
 
standard error of the mean 
SOC 
 
 
System Organ Class 


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SOP 
 
 
Standard Operating Procedure 
SUSARs 
 
suspected unexpected serious adverse reactions 
t1/2 
 
 
apparent terminal half-life 
tmax 
 
 
time of Cmax  
tmin 
 
 
time of Cmin 
T2D 
 
 
type 2 diabetes  
tbc 
 
 
to be confirmed 
TEAE  
 
treatment-emergent adverse event 
UAG 
 
 
unacylated ghrelin 
ULN 
 
 
upper limit of normal 
US 
 
 
United States 
V 
 
 
visit 
Vz/F 
 
 
apparent volume of distribution 
vs 
 
 
versus 
WC 
 
 
waist circumference 
WCBP  
 
Women of Child Bearing Potential 
ZBI 
 
 
Zarit Burden Interview 
 


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19.1 
APPENDIX A: Declaration of Helsinki 
Recommendations guiding physicians in biomedical research involving human subjects. 
Adopted by the 18th World Medical Assembly, Helsinki, Finland, June 1964, and all subsequent 
amendments. 
Introduction 
It is the mission of the physician to safeguard the health of the people. His or her knowledge and 
conscience are dedicated to the fulfillment of this mission. 
The Declaration of Geneva of The World Medical Association binds the physician with the 
words, “The health of my patient will be my first consideration,” and the International Code of 
Medical Ethics declares that, “A physician shall act only in the patient’s interest when providing 
medical care which might have the effect of weakening the physical and mental condition of the 
patient.” 
The purpose of biomedical research involving human subjects must be to improve diagnostic, 
therapeutic and prophylactic procedures and the understanding of the etiology and pathogenesis 
of disease. 
In current medical practice most diagnostic, therapeutic or prophylactic procedures involve 
hazards. This applies especially to biomedical research. 
Medical progress is based on research which ultimately must rest in part on experimentation 
involving human subjects. 
In the field of biomedical research a fundamental distinction must be recognized between 
medical research in which the aim is essentially diagnostic or therapeutic for a patient, and 
medical research, the essential object of which is purely scientific and without implying direct 
diagnostic or therapeutic value to the person subjected to the research. 
Special caution must be exercised in the conduct of research which may affect the environment, 
and the welfare of animals used for research must be respected. 
Because it is essential that the results of laboratory experiments be applied to human beings to 
further scientific knowledge and to help suffering humanity, the World Medical Association has 
prepared the following recommendations as a guide to every physician in biomedical research 
involving human subjects. They should be kept under review in the future. It must be stressed 
that the standards as drafted are only a guide to physicians all over the world. Physicians are not 
relieved from criminal, civil and ethical responsibilities under the laws of their own countries. 
 
19 
APPENDICES 


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I.  
Basic principles 
1. 
Biomedical research involving human subjects must conform to generally accepted 
scientific principles and should be based on adequately performed laboratory and animal 
experimentation and on a thorough knowledge of the scientific literature. 
2. 
The design and performance of each experimental procedure involving human subjects 
should be clearly formulated in an experimental protocol which should be transmitted 
for consideration, comment and guidance to a specially appointed committee 
independent of the investigator and the Sponsor provided that this independent 
committee is in conformity with the laws and regulations of the country in which the 
research experiment is performed. 
3. 
Biomedical research involving human subjects should be conducted only by 
scientifically qualified persons and under the supervision of a clinically competent 
medical person. The responsibility for the human subject must always rest with a 
medically qualified person and never rest on the subject of the research, even though the 
subject has given his or her consent. 
4. 
Biomedical research involving human subjects cannot legitimately be carried out unless 
the importance of the objective is in proportion to the inherent risk to the subject. 
5. 
Every biomedical research project involving human subjects should be preceded by 
careful assessment of predictable risks in comparison with foreseeable benefits to the 
subject or to others. Concern for the interests of the subject must always prevail over the 
interests of science and society. 
6. 
The right of the research subject to safeguard his or her integrity must always be 
respected. Every precaution should be taken to respect the privacy of the subject and to 
minimize the impact of the study on the subject’s physical and mental integrity and on 
the personality of the subject. 
7. 
Physicians should abstain from engaging in research projects involving human subjects 
unless they are satisfied that the hazards involved are believed to be predictable. 
Physicians should cease any investigation if the hazards are found to outweigh the 
potential benefits. 
8. 
In publication of the results of his or her research, the physician is obliged to preserve 
the accuracy of the results. Reports of experimentation not in accordance with the 
principles laid down in this Declaration should not be accepted for publication. 
9. 
In any research on human beings, each potential subject must be adequately informed of 
the aims, methods, anticipated benefits and potential hazards of the study and the 
discomfort it may entail. He or she should be informed that he or she is at liberty to 


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abstain from participation in the study and that he or she is free to withdraw his or her 
consent to participation at any time. The physician should then obtain the subject’s 
freely-given informed consent, preferably in writing. 
10. When obtaining informed consent for the research project the physician should be 
particularly cautious if the subject is in a dependent relationship to him or her or may 
consent under duress. In that case the informed consent should be obtained by a 
physician who is not engaged in the investigation and who is completely independent of 
this official relationship. 
11. In case of legal incompetence, informed consent should be obtained from the legal 
guardian in accordance with national legislation. Where physical or mental incapacity 
makes it impossible to obtain informed consent, or when the subject is a minor, 
permission from the responsible relative replaces that of the subject in accordance with 
national legislation. 
 
Whenever the minor child is in fact able to give consent, the minor’s consent must be 
obtained in addition to the consent of the minor’s legal guardian. 
12. The research protocol should always contain a statement of the ethical considerations 
involved and should indicate that the principles enunciated in the present Declaration are 
complied with. 
II. 
Medical research combined with professional care (clinical research) 
1. 
In the treatment of the sick person, the physician must be free to use a new diagnostic 
and therapeutic measure, if in his or her judgment it offers hope of saving life, re-
establishing health or alleviating suffering. 
2. 
The potential benefits, hazards and discomfort of a new method should be weighed 
against the advantages of the best current diagnostic and therapeutic methods. 
3. 
In any medical study, every patient – including those of a control group, if any – should 
be assured of the best proven diagnostic and therapeutic method. This does not exclude 
the use of inert placebo studies where no proven diagnostic or therapeutic method exists. 
4. 
The refusal of the patient to participate in a study must never interfere with the 
physician-patient relationship. 
5. 
If the physician considers it essential not to obtain informed consent, the specific reasons 
for this proposal should be stated in the experimental protocol for transmission to the 
independent committee (I,2). 


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6. 
The physician can combine medical research with professional care, the objective being 
the acquisition of new medical knowledge, only to the extent that medical research is 
justified by its potential diagnostic or therapeutic value for the patient. 
III. Non-therapeutic biomedical re-search involving human subjects (non-clinical 
biomedical research) 
1. 
In the purely scientific application of medical research carried out on a human being, it 
is the duty of the physician to remain the protector of the life and health of that person 
on whom biomedical research is being carried out. 
2. 
The subjects should be volunteers – either healthy persons or patients for whom the 
experimental design is not related to the patient’s illness. 
3. 
The investigator or the investigating team should discontinue the research if in his/her or 
their judgment it may, if continued, be harmful to the individual. 
4. 
In research on man, the interest of science and society should never take precedence 
over considerations related to the well-being of the subject. 
 


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19.2 
APPENDIX B: Hyperphagia Questionnaire for Clinical Trials (HQ-CT) 
Hyperphagia Questionnaire for Clinical Trials (HQ-CT) 
Instructions: 
The following items refer to the person in your care and assessment of his/her food-related behavior 
during the past 2 weeks.     
 
(1) During the past 2 weeks, how upset did the person generally become when denied a desired food? 
□ Not at all upset  
□ A little upset 
□ Moderately upset 
□ Very upset 
□ Extremely upset 
 
(2) During the past 2 weeks, how often did the person try to bargain or manipulate to get more food at 
meals? 
□ Never 
□ Up to 2 times a week 
□ 3 to 6 times a week 
□ Every day 
□ Several times a day 
 
(3) During the past 2 weeks, how often did the person forage through trash for food? 
□ Never 
□ 1 time 
□ 2 times 
□ 3 times 
□ 4 or more times 
 
(4) During the past 2 weeks, how often did the person get up at night to food seek? 
□ Never 
□ 1 time 
□ 2 times 
□ 3 times 
□ 4 or more times 
 


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(5) During the past 2 weeks, how persistent was the person in asking or looking for food after being told 
“no” or “no more”? 
□ Not at all persistent 
□ A little persistent 
□ Moderately persistent 
□ Very persistent 
□ Extremely persistent 
 
(6) During the past 2 weeks, outside of normal meal times, how much time did the person generally spend 
asking or talking about food? 
□ Less than 5 minutes a day 
□ 5 to 15 minutes a day 
□ 15 to 30 minutes a day 
□ 30 minutes to 1 hour a day 
□ More than 1 hour a day 
 (7) During the past 2 weeks, how often did the person try to sneak or steal food (that you are aware of)? 
□ Never 
□ 1 time 
□ 2 times 
□ 3 times 
□ 4 or more times 
 
(8) During the past 2 weeks, when others tried to stop the person from asking about food, how distressed 
did he or she generally appear?  
□ Not at all distressed  
□ A little distressed 
□ Moderately distressed 
□ Very distressed 
□ Extremely distressed 
 
(9) During the past 2 weeks, how often did food-related behavior interfere with the person’s normal daily 
activities, such as self-care, recreation, school, or work? 
□ Never 
□ Up to 2 times a week 
□ 3 to 6 times a week 
□ Every day 
□ Several times a day 


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19.3 
APPENDIX C: Numerical Rating Scale (NRS) for Appetite/Prospective Food 
Consumption 
The paper version of the questionnaire will be adapted for assessment using the eDevice. 
 
Patient number: _̲_______  ____ 
Test date: 
Meal:  Breakfast   Lunch  
Time of the test:  Before   After  2
 
Indicate how much food you could eat right now,  
by checking the appropriate box 
 
 
 
 
 
Nothing at 
all 
 
A small amount 
 
A medium amount 
 
A large amount 
 
A very 
large amount 
☐ 
 
☐ 
 
☐ 
 
☐ 
 
☐ 
 
 


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19.4 
APPENDIX D: Clinical Global Impression of Change – Hyperphagia (CGIC-H) 
Scale  
 
The paper version of the questionnaire will be adapted for assessment using the eDevice. 
 
Clinical Global Impression of Change – Hyperphagia (CGIC-H) 
Scale 
 
Overall, how would you rate the person’s hyperphagia now as compared to before the 
beginning of the study? 
 
 = Much better  
 = Moderately better  
 = A little better 
 = No difference 
 = A little worse 
 = Moderately worse 
 = Much worse  
 
 


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19.5 
APPENDIX E: Caregiver Global Impression of Change - Hyperphagia (CgGIC-H) 
Scale  
 
The paper version of the questionnaire will be adapted for assessment using the eDevice. 
 
Caregiver Global Impression of Change - Hyperphagia (CgGIC-H) 
Scale 
 
 
Overall, based on your observations, how would you rate the person’s hyperphagia now as 
compared to before the beginning of the study? 
 
 = Much better  
 = Moderately better  
 = A little better 
 = No difference 
 = A little worse 
 = Moderately worse 
 = Much worse


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19.6 
APPENDIX F: Clinical Global Impression of Improvement (CGI-I) Scale 
 
Clinical Global Impression of Improvement (CGI-I) Scale 
 
The paper version of the questionnaire will be adapted for assessment using the eDevice. 
 
Overall, how would you rate the person’s general condition now as compared to before the 
beginning of the study? 
 
 = Much better  
 = Moderately better  
 = A little better 
 = No difference 
 = A little worse 
 = Moderately worse 
 = Much worse  
 
 
 
 


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19.7 
APPENDIX G: Clinical Global Impression of Severity – Hyperphagia (CGIS-H) 
Scale  
 
The paper version of the questionnaire will be adapted for assessment using the eDevice. 
 
 
Clinical Global Impression of Severity – Hyperphagia (CGIS-H) 
Scale 
 
 
Overall, how would you rate the severity of the person’s hyperphagia now? 
 
 = Normal, not at all hyperphagic 
 = Borderline hyperphagic 
 = Mildly hyperphagic 
 = Moderately hyperphagic 
 = Markedly hyperphagic 
 = Severely hyperphagic 
 = Among the most extremely hyperphagic patients


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19.8 
APPENDIX H: Caregiver Global Impression of Severity - Hyperphagia (CgGIS-H) 
Scale  
 
The paper version of the questionnaire will be adapted for assessment using the eDevice. 
 
Caregiver Global Impression of Severity - Hyperphagia (CgGIS-H) 
Scale 
 
 
Overall, based on your observations, how would you rate the person’s hyperphagia now? 
 
 = None 
 = Mild 
 = Moderate 
 = Severe 


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19.9 
APPENDIX I: Clinical Global Impression of Severity (CGI-S) Scale 
 
Clinical Global Impression of Severity (CGI-S) Scale  
 
The paper version of the questionnaire will be adapted for assessment using the eDevice. 
 
 
Considering your total clinical experience with this particular population, how would you 
rate the severity of the person’s disease? 
 
 = Normal, not at all ill 
 = Borderline ill 
 = Mildly ill 
 = Moderately ill 
 = Markedly ill 
 = Severely ill 
 = Extremely ill 
 


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19.10 APPENDIX J: PEDSQLTM PARENT PROXY-REPORTS 
The paper version of the questionnaire will be adapted for assessment using the eDevice. 
PedsQL™ contact information and permission to use: Mapi Research Trust, Lyon, France– Internet: 
https://eprovide.mapi-trust.org and www.pedsql.org/index.html 
 
 
 
 
PedsQL ™ 
Adult Quality of Life 
Inventory 
Version 4.0 
PARENT REPORT for ADULTS 
 
DIRECTIONS 
 
On the following page is a list of things that might be a problem for your child. 
Please tell us how much of a problem each one has been for your child 
during the past ONE month by circling: 
 
0 if it is never a problem 
1 if it is almost never a problem 
2 if it is sometimes a problem 
3 if it is often a problem 
4 if it is almost always a problem 
 
There are no right or wrong answers. 
If you do not understand a question, please ask for help. 
 
 
ID#__________________________ 
 
Date:________________________ 


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In the past ONE month, how much of a problem has your child had with … 
 
Physical Functioning (PROBLEMS WITH…) 
Never 
Almost 
Never 
Some-
times 
Often 
Almost 
Always 
1.  Walking more than one block 
0 
1 
2 
3 
4 
2.  Running 
0 
1 
2 
3 
4 
3.  Participating in sports activity or exercise  
0 
1 
2 
3 
4 
4.  Lifting something heavy 
0 
1 
2 
3 
4 
5.  Taking a bath or shower by him or herself  
0 
1 
2 
3 
4 
6.  Doing chores around the house  
0 
1 
2 
3 
4 
7.  Having hurts or aches 
0 
1 
2 
3 
4 
8.  Low energy level 
0 
1 
2 
3 
4 
 
Emotional Functioning (PROBLEMS WITH…) 
Never 
Almost 
Never 
Some-
times 
Often 
Almost 
Always 
1.  Feeling afraid or scared 
0 
1 
2 
3 
4 
2.  Feeling sad or blue 
0 
1 
2 
3 
4 
3.  Feeling angry 
0 
1 
2 
3 
4 
4.  Trouble sleeping 
0 
1 
2 
3 
4 
5.  Worrying about what will happen to him or her 
0 
1 
2 
3 
4 
 
Social Functioning (PROBLEMS WITH…) 
Never 
Almost 
Never 
Some-
times 
Often 
Almost 
Always 
1.  Getting along with other adults 
0 
1 
2 
3 
4 
2.  Other adults not wanting to be his or her friend 
0 
1 
2 
3 
4 
3.  Getting teased by other adults 
0 
1 
2 
3 
4 
4.  Not able to do things that others his or her age 
can do  
0 
1 
2 
3 
4 
5.  Keeping up with other adults 
0 
1 
2 
3 
4 
 
Work/Studies Functioning (PROBLEMS WITH…) 
Never 
Almost 
Never 
Some-
times 
Often 
Almost 
Always 
1.  Paying attention at work or school 
0 
1 
2 
3 
4 
2.  Forgetting things 
0 
1 
2 
3 
4 
3.  Keeping up with work or studies 
0 
1 
2 
3 
4 
4.  Missing work or school because of not feeling 
well  
0 
1 
2 
3 
4 
5.  Missing work or school to go to the doctor or 
hospital 
0 
1 
2 
3 
4 
 


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PedsQL ™ 
Adult Quality of Life 
Inventory 
Version 4.0 
PARENT REPORT for YOUNG ADULTS (ages 18-25) 
 
 
 
 
 
 
ID#__________________________ 
 
Date:________________________ 
 
DIRECTIONS 
 
On the following page is a list of things that might be a problem for your child. 
Please tell us how much of a problem each one has been for your child 
during the past ONE month by circling: 
 
0 if it is never a problem 
1 if it is almost never a problem 
2 if it is sometimes a problem 
3 if it is often a problem 
4 if it is almost always a problem 
 
There are no right or wrong answers. 
If you do not understand a question, please ask for help. 
 


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In the past ONE month, how much of a problem has your child had with … 
 
Physical Functioning (PROBLEMS WITH…) 
Never 
Almost 
Never 
Some-
times 
Often 
Almost 
Always 
1.  Walking more than one block 
0 
1 
2 
3 
4 
2.  Running 
0 
1 
2 
3 
4 
3.  Participating in sports activity or exercise  
0 
1 
2 
3 
4 
4.  Lifting something heavy 
0 
1 
2 
3 
4 
5.  Taking a bath or shower by him or herself  
0 
1 
2 
3 
4 
6.  Doing chores around the house  
0 
1 
2 
3 
4 
7.  Having hurts or aches 
0 
1 
2 
3 
4 
8.  Low energy level 
0 
1 
2 
3 
4 
 
Emotional Functioning (PROBLEMS WITH…) 
Never 
Almost 
Never 
Some-
times 
Often 
Almost 
Always 
1.  Feeling afraid or scared 
0 
1 
2 
3 
4 
2.  Feeling sad or blue 
0 
1 
2 
3 
4 
3.  Feeling angry 
0 
1 
2 
3 
4 
4.  Trouble sleeping 
0 
1 
2 
3 
4 
5.  Worrying about what will happen to him or her 
0 
1 
2 
3 
4 
 
Social Functioning (PROBLEMS WITH…) 
Never 
Almost 
Never 
Some-
times 
Often 
Almost 
Always 
1.  Getting along with other young adults 
0 
1 
2 
3 
4 
2.  Other young adults not wanting to be his or her 
friend 
0 
1 
2 
3 
4 
3.  Getting teased by other young adults 
0 
1 
2 
3 
4 
4.  Not able to do things that others his or her age 
can do  
0 
1 
2 
3 
4 
5.  Keeping up with other young adults 
0 
1 
2 
3 
4 
 
Work/Studies Functioning (PROBLEMS WITH…) 
Never 
Almost 
Never 
Some-
times 
Often 
Almost 
Always 
1.  Paying attention at work or school 
0 
1 
2 
3 
4 
2.  Forgetting things 
0 
1 
2 
3 
4 
3.  Keeping up with work or studies 
0 
1 
2 
3 
4 
4.  Missing work or school because of not feeling 
well  
0 
1 
2 
3 
4 
5.  Missing work or school to go to the doctor or 
hospital 
0 
1 
2 
3 
4 


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PedsQL ™ 
Adult Quality of Life 
Inventory 
Version 4.0 
PARENT REPORT for TEENS (ages 13-18) 
 
 
 
 
 
 
ID#__________________________ 
 
Date:________________________ 
 
DIRECTIONS 
 
On the following page is a list of things that might be a problem for your teen. 
Please tell us how much of a problem each one has been for your teen 
during the past ONE month by circling: 
 
0 if it is never a problem 
1 if it is almost never a problem 
2 if it is sometimes a problem 
3 if it is often a problem 
4 if it is almost always a problem 
 
There are no right or wrong answers. 
If you do not understand a question, please ask for help. 
 


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In the past ONE month, how much of a problem has your teen had with … 
 
Physical Functioning (PROBLEMS WITH…) 
Never 
Almost 
Never 
Some-
times 
Often 
Almost 
Always 
1.  Walking more than one block 
0 
1 
2 
3 
4 
2.  Running 
0 
1 
2 
3 
4 
3.  Participating in sports activity or exercise  
0 
1 
2 
3 
4 
4.  Lifting something heavy 
0 
1 
2 
3 
4 
5.  Taking a bath or shower by him or herself  
0 
1 
2 
3 
4 
6.  Doing chores around the house  
0 
1 
2 
3 
4 
7.  Having hurts or aches 
0 
1 
2 
3 
4 
8.  Low energy level 
0 
1 
2 
3 
4 
 
Emotional Functioning (PROBLEMS WITH…) 
Never 
Almost 
Never 
Some-
times 
Often 
Almost 
Always 
1.  Feeling afraid or scared 
0 
1 
2 
3 
4 
2.  Feeling sad or blue 
0 
1 
2 
3 
4 
3.  Feeling angry 
0 
1 
2 
3 
4 
4.  Trouble sleeping 
0 
1 
2 
3 
4 
5.  Worrying about what will happen to him or her 
0 
1 
2 
3 
4 
 
Social Functioning (PROBLEMS WITH…) 
Never 
Almost 
Never 
Some-
times 
Often 
Almost 
Always 
1.  Getting along with other teens 
0 
1 
2 
3 
4 
2.  Other teens not wanting to be his or her friend 
0 
1 
2 
3 
4 
3.  Getting teased by other teens 
0 
1 
2 
3 
4 
4.  Not able to do things that others his or her age 
can do  
0 
1 
2 
3 
4 
5.  Keeping up with other teens 
0 
1 
2 
3 
4 
 
Work/Studies Functioning (PROBLEMS WITH…) 
Never 
Almost 
Never 
Some-
times 
Often 
Almost 
Always 
1.  Paying attention in class 
0 
1 
2 
3 
4 
2.  Forgetting things 
0 
1 
2 
3 
4 
3.  Keeping up with schoolwork 
0 
1 
2 
3 
4 
4.  Missing school because of not feeling well  
0 
1 
2 
3 
4 
5.  Missing school to go to the doctor or hospital 
0 
1 
2 
3 
4 


Protocol Code Number: AZP01-CLI-003 
Confidential & Proprietary 
Page 162 of 172 
Version 1.2, July 31st, 2019 
 
 
 
 
PedsQL ™ 
Adult Quality of Life 
Inventory 
Version 4.0 
PARENT REPORT for CHILDREN (ages 8-12) 
 
 
 
 
 
 
ID#__________________________ 
 
Date:________________________ 
 
DIRECTIONS 
 
On the following page is a list of things that might be a problem for your child. 
Please tell us how much of a problem each one has been for your child 
during the past ONE month by circling: 
 
0 if it is never a problem 
1 if it is almost never a problem 
2 if it is sometimes a problem 
3 if it is often a problem 
4 if it is almost always a problem 
 
There are no right or wrong answers. 
If you do not understand a question, please ask for help. 
 


Protocol Code Number: AZP01-CLI-003 
Confidential & Proprietary 
Page 163 of 172 
Version 1.2, July 31st, 2019 
In the past ONE month, how much of a problem has your child had with … 
 
Physical Functioning (PROBLEMS WITH…) 
Never 
Almost 
Never 
Some-
times 
Often 
Almost 
Always 
1.  Walking more than one block 
0 
1 
2 
3 
4 
2.  Running 
0 
1 
2 
3 
4 
3.  Participating in sports activity or exercise  
0 
1 
2 
3 
4 
4.  Lifting something heavy 
0 
1 
2 
3 
4 
5.  Taking a bath or shower by him or herself  
0 
1 
2 
3 
4 
6.  Doing chores around the house  
0 
1 
2 
3 
4 
7.  Having hurts or aches 
0 
1 
2 
3 
4 
8.  Low energy level 
0 
1 
2 
3 
4 
 
Emotional Functioning (PROBLEMS WITH…) 
Never 
Almost 
Never 
Some-
times 
Often 
Almost 
Always 
1.  Feeling afraid or scared 
0 
1 
2 
3 
4 
2.  Feeling sad or blue 
0 
1 
2 
3 
4 
3.  Feeling angry 
0 
1 
2 
3 
4 
4.  Trouble sleeping 
0 
1 
2 
3 
4 
5.  Worrying about what will happen to him or her 
0 
1 
2 
3 
4 
 
Social Functioning (PROBLEMS WITH…) 
Never 
Almost 
Never 
Some-
times 
Often 
Almost 
Always 
1.  Getting along with other children 
0 
1 
2 
3 
4 
2.  Other kids not wanting to be his or her friend 
0 
1 
2 
3 
4 
3.  Getting teased by other children 
0 
1 
2 
3 
4 
4.  Not able to do things that other children his or 
her age can do  
0 
1 
2 
3 
4 
5.  Keeping up with other children 
0 
1 
2 
3 
4 
 
Work/Studies Functioning (PROBLEMS WITH…) 
Never 
Almost 
Never 
Some-
times 
Often 
Almost 
Always 
1.  Paying attention in class 
0 
1 
2 
3 
4 
2.  Forgetting things 
0 
1 
2 
3 
4 
3.  Keeping up with schoolwork 
0 
1 
2 
3 
4 
4.  Missing school because of not feeling well  
0 
1 
2 
3 
4 
5.  Missing school to go to the doctor or hospital 
0 
1 
2 
3 
4 
 


Protocol Code Number: AZP01-CLI-003 
Confidential & Proprietary 
Page 164 of 172 
Version 1.2, July 31st, 2019 
 
 
 
 
 
 
PedsQL ™ 
Pediatric Quality of Life Inventory  
Version 4.0 
PARENT REPORT for YOUNG CHILDREN (ages 5-7) 
 
DIRECTIONS 
 
On the following page is a list of things that might be a problem for your child. 
Please tell us how much of a problem each one has been for your child 
during the past ONE month by circling: 
 
0 if it is never a problem 
1 if it is almost never a problem 
2 if it is sometimes a problem 
3 if it is often a problem 
4 if it is almost always a problem 
 
There are no right or wrong answers. 
If you do not understand a question, please ask for help. 
 
 
 
ID#__________________________ 
 
Date:________________________ 


Protocol Code Number: AZP01-CLI-003 
Confidential & Proprietary 
Page 165 of 172 
Version 1.2, July 31st, 2019 
In the past ONE month, how much of a problem has your child had with … 
 
Physical Functioning (PROBLEMS WITH…) 
Never 
Almost 
Never 
Some-
times 
Often 
Almost 
Always 
1.  Walking more than one block 
0 
1 
2 
3 
4 
2.  Running 
0 
1 
2 
3 
4 
3.  Participating in sports activity or exercise  
0 
1 
2 
3 
4 
4.  Lifting something heavy 
0 
1 
2 
3 
4 
5.  Taking a bath or shower by him or herself  
0 
1 
2 
3 
4 
6.  Doing chores, like picking up his or her toys  
0 
1 
2 
3 
4 
7.  Having hurts or aches 
0 
1 
2 
3 
4 
8.  Low energy level 
0 
1 
2 
3 
4 
 
Emotional Functioning (PROBLEMS WITH…) 
Never 
Almost 
Never 
Some-
times 
Often 
Almost 
Always 
1.  Feeling afraid or scared 
0 
1 
2 
3 
4 
2.  Feeling sad or blue 
0 
1 
2 
3 
4 
3.  Feeling angry 
0 
1 
2 
3 
4 
4.  Trouble sleeping 
0 
1 
2 
3 
4 
5.  Worrying about what will happen to him or her 
0 
1 
2 
3 
4 
 
Social Functioning (problems with…) 
Never 
Almost 
Never 
Some-
times 
Often 
Almost 
Always 
1.  Getting along with other children 
0 
1 
2 
3 
4 
2.  Other kids not wanting to be his or her friend 
0 
1 
2 
3 
4 
3.  Getting teased by other children 
0 
1 
2 
3 
4 
4.  Not able to do things that other children his or 
     her age can do  
0 
1 
2 
3 
4 
5.  Keeping up when playing with other children 
0 
1 
2 
3 
4 
 
School Functioning (problems with…) 
Never 
Almost 
Never 
Some-
times 
Often 
Almost 
Always 
1.  Paying attention in class 
0 
1 
2 
3 
4 
2.  Forgetting things 
0 
1 
2 
3 
4 
3.  Keeping up with school activities 
0 
1 
2 
3 
4 
4.  Missing school because of not feeling well  
0 
1 
2 
3 
4 
5.  Missing school to go to the doctor or hospital 
0 
1 
2 
3 
4 


Protocol Code Number: AZP01-CLI-003 
Confidential & Proprietary 
Page 166 of 172 
Version 1.2, July 31st, 2019 
 
 
 
 
PedsQL ™ 
Pediatric Quality of Life  
Inventory  
 
Version 4.0 
 
 
PARENT REPORT for TODDLERS (ages 2-4) 
 
 
20 
DIRECTIONS 
 
     On the following page is a list of things that might be a problem for your child. 
     Please tell us how much of a problem each one has been for your child 
     during the past  ONE  month by circling: 
 
0 if it is never a problem  
1 if it is almost never a problem  
2 if it is sometimes a problem 
3 if it is often a problem 
4 if it is almost always a problem 
 
     There are no right or wrong answers.   
     If you do not understand a question, please ask for help. 
 
ID#__________________________ 
 
Date:________________________ 


Protocol Code Number: AZP01-CLI-003 
Confidential & Proprietary 
Page 167 of 172 
Version 1.2, July 31st, 2019 
In the past ONE month, how much of a problem has your child had with … 
Physical Functioning (PROBLEMS WITH…) 
Never 
Almost 
Never 
Some-
times 
Often 
Almost 
Always 
1.  Walking  
0 
1 
2 
3 
4 
2.  Running 
0 
1 
2 
3 
4 
3.  Participating in active play or exercise  
0 
1 
2 
3 
4 
4.  Lifting something heavy 
0 
1 
2 
3 
4 
5.  Bathing  
0 
1 
2 
3 
4 
6.  Helping to pick up his or her toys  
0 
1 
2 
3 
4 
7.  Having hurts or aches 
0 
1 
2 
3 
4 
8.  Low energy level 
0 
1 
2 
3 
4 
 
Emotional Functioning (problems with…) 
Never 
Almost 
Never 
Some-
times 
Often 
Almost 
Always 
1.  Feeling afraid or scared 
0 
1 
2 
3 
4 
2.  Feeling sad or blue 
0 
1 
2 
3 
4 
3.  Feeling angry 
0 
1 
2 
3 
4 
4.  Trouble sleeping 
0 
1 
2 
3 
4 
5.  Worrying  
0 
1 
2 
3 
4 
 
Social Functioning (problems with…) 
Never 
Almost 
Never 
Some-
times 
Often 
Almost 
Always 
1.  Playing with other children 
0 
1 
2 
3 
4 
2.  Other kids not wanting to play with him or her 
0 
1 
2 
3 
4 
3.  Getting teased by other children 
0 
1 
2 
3 
4 
4.  Not able to do things that other children his or 
her age can do 
0 
1 
2 
3 
4 
5.  Keeping up when playing with other children 
0 
1 
2 
3 
4 
 
*Please complete this section if your child attends school or daycare 
School Functioning (problems with…) 
Never 
Almost 
Never 
Some-
times 
Often 
Almost 
Always 
1.  Doing the same school activities as peers 
0 
1 
2 
3 
4 
2.  Missing school/daycare because of not feeling 
well 
0 
1 
2 
3 
4 
3.  Missing school/daycare to go to the doctor or 
     hospital 
0 
1 
2 
3 
4 
 


Protocol Code Number: AZP01-CLI-003 
Confidential & Proprietary 
Page 168 of 172 
Version 1.2, July 31st, 2019 
 
20.1 
APPENDIX K: Zarit Burden Interview  
The paper version of the questionnaire will be adapted for assessment using the eDevice. 
 
BURDEN INTERVIEW 
 
INSTRUCTIONS:  The following is a list of statements, which reflect how people sometimes 
feel when taking care of another person.  After each statement, indicate how often you feel that 
way; never, rarely, sometimes, quite frequently, or nearly always.  There are no right or wrong 
answers. 
 
1. 
Do you feel that your relative asks for more help than he/she needs? 
 
0.  Never 
1.  Rarely 
2.  Sometimes 3.  Quite Frequently 4.  Nearly Always 
 
2. 
Do you feel that because of the time you spend with your relative that you don’t have 
enough time for yourself? 
 
0.  Never 
1.  Rarely 
2.  Sometimes 3.  Quite Frequently 4.  Nearly Always 
 
3. 
Do you feel stressed between caring for your relative and trying to meet other 
responsibilities for your family or work? 
 
0.  Never 
1.  Rarely 
2.  Sometimes 3.  Quite Frequently 4.  Nearly Always 
 
4. 
Do you feel embarrassed over your relative’s behavior? 
 
0.  Never 
1.  Rarely 
2.  Sometimes 3.  Quite Frequently 4.  Nearly Always 
 
5. 
Do you feel angry when you are around your relative? 
 
0.  Never 
1.  Rarely 
2.  Sometimes 3.  Quite Frequently 4.  Nearly Always 
 


Protocol Code Number: AZP01-CLI-003 
Confidential & Proprietary 
Page 169 of 172 
Version 1.2, July 31st, 2019 
6. 
Do you feel that your relative currently affects your relationship with other family 
members or friends in a negative way? 
 
0.  Never 
1.  Rarely 
2.  Sometimes 3.  Quite Frequently 4.  Nearly Always 
 
7. 
Are you afraid what the future holds for your relative? 
 
0.  Never 
1.  Rarely 
2.  Sometimes 3.  Quite Frequently 4.  Nearly Always 
 
8. 
Do you feel your relative is dependent upon you? 
 
0.  Never 
1.  Rarely 
2.  Sometimes 3.  Quite Frequently 4.  Nearly Always 
 
9. 
Do you feel strained when you are around your relative? 
 
0.  Never 
1.  Rarely 
2.  Sometimes 3.  Quite Frequently 4.  Nearly Always 
 
10. 
Do you feel your health has suffered because of your involvement with your relative? 
 
0.  Never 
1.  Rarely 
2.  Sometimes 3.  Quite Frequently 4.  Nearly Always 
 
11. 
Do you feel that you don’t have as much privacy as you would like, because of your 
relative? 
 
0.  Never 
1.  Rarely 
2.  Sometimes 3.  Quite Frequently 4.  Nearly Always 
 
12. 
Do you feel that your social life has suffered because you are caring for your relative? 
 
0.  Never 
1.  Rarely 
2.  Sometimes 3.  Quite Frequently 4.  Nearly Always 
 
13. 
Do you feel uncomfortable about having friends over, because of your relative? 
 
0.  Never 
1.  Rarely 
2.  Sometimes 3.  Quite Frequently 4.  Nearly Always 


Protocol Code Number: AZP01-CLI-003 
Confidential & Proprietary 
Page 170 of 172 
Version 1.2, July 31st, 2019 
 
14. 
Do you feel that your relative seems to expect you to take care of him/her, as if you were 
the only one he/she could depend on? 
 
0.  Never 
1.  Rarely 
2.  Sometimes 3.  Quite Frequently 4.  Nearly Always 
 
15. 
Do you feel that you don’t have enough money to care for your relative, in addition to the 
rest of your expenses? 
 
0.  Never 
1.  Rarely 
2.  Sometimes 3.  Quite Frequently 4.  Nearly Always 
 
16. 
Do you feel that you will be unable to take care of your relative much longer? 
 
0.  Never 
1.  Rarely 
2.  Sometimes 3.  Quite Frequently 4.  Nearly Always 
 
17. 
Do you feel you have lost control of your life since your relative’s illness? 
 
0.  Never 
1.  Rarely 
2.  Sometimes 3.  Quite Frequently 4.  Nearly Always 
 
18. 
Do you wish you could just leave the care of your relative to someone else? 
 
0.  Never 
1.  Rarely 
2.  Sometimes 3.  Quite Frequently 4.  Nearly Always 
 
19. 
Do you feel uncertain about what to do about your relative? 
 
0.  Never 
1.  Rarely 
2.  Sometimes 3.  Quite Frequently 4.  Nearly Always 
 
20. 
Do you feel you should be doing more for your relative? 
 
0.  Never 
1.  Rarely 
2.  Sometimes 3.  Quite Frequently 4.  Nearly Always 
 


Protocol Code Number: AZP01-CLI-003 
Confidential & Proprietary 
Page 171 of 172 
Version 1.2, July 31st, 2019 
21. 
Do you feel you could do a better job in caring for your relative? 
 
0.  Never 
1.  Rarely 
2.  Sometimes 3.  Quite Frequently 4.  Nearly Always 
 
22. 
Overall, how burdened do you feel in caring for your relative? 
 
0.  Not at all 
1.  A little 
2.  Moderately 3.  Quite a bit 
4.  Extremely  
 
 
 
 
Copyright 1983, 1990, Steven H. Zarit and Judy M. Zarit 


Protocol Code Number: AZP01-CLI-003 
Confidential & Proprietary 
Page 172 of 172 
Version 1.2, July 31st, 2019 
 
20.2 
APPENDIX L: Protocol Versions 
 
Protocol Version 
Date 
Significant Revision 
1.0 
September 5, 2018 
N/A – Initial version 
1.1 
November 13, 2018 
PK design and Screening 
period duration 
1.2 
July 31st, 2019 
Inclusion of patients 4 to7 
years of age to the study 
 
 

SAP_000.pdf: 
23-Mar-2020
Version: Final 1.1 
Page 1 of 53 
Statistical Analysis Plan 
Phase 2b – Core Period 
Title: 
A Phase 2b/3 study to evaluate the safety, tolerability, 
and effects of livoletide (AZP-531), an unacylated 
ghrelin analog, on food-related behaviors in patients 
with Prader-Willi syndrome 
Protocol Number: 
AZP01-CLI-003 
Product: 
AZP-531 
Sponsor: 
Millendo Therapeutics SAS 
15G Chemin du Saquin 
Ecully 69130, France 
Date: 
23-Mar-2020
Version: 
Final 1.1 
Prepared by: 
Excelsus Statistics, Inc. 
4278 Av. Hampton 
Montreal (Qc), H4A 2K9 
Canada 


Signature Page
Title: 
A Phase 2bl3 study to evaluate the safety, tolerability, and effects of
livoletide (AZP-531), an unacylated ghrelin analog, on food-related
behaviors in patients with Prader-Willi syndrome
ProtocolNumber: AZP0I-CLI-003
Prepared hyl
Josee Morin, MSc
Senior Bj
ExcelsuJ
Approved byr
lliane Potvin, MSc
President
Excelsus Statistics
Vivian Lin, MI)
Vice President
Clinical Developrnent
Millendo T"herapeutics
(rye
M
_'B
-d.4fl-M
c3
#: E i4,,$&f eA*
Date
23MAR2020
Date
Signature
23-Mar-2020
Version: Final l"l
Page ? *f 53
\
\
Date


 
23-Mar-2020 
Version: Final 1.1 
Page 3 of 53 
 
 
 
Modification History 
 
Version 
Date of the 
Document Version 
Author 
Significant Changes from 
Previous Authorized Version 
Draft 1.0 
05-APR-2018 
Josée Morin 
N/A 
Final 1.0 
22-Nov-2019 
Diane Potvin 
Updated according to FDA review 
and protocol updates  
Final 1.1 
23-Mar-2020 
Diane Potvin 
Updated according to some of the 
FDA comments and the ZEPHYR 
(AZP01-CLI-003) 
protocol 
amendment. 
As 
additional 
change, 
the 
gatekeeper strategy was removed 
for the key secondary endpoints 
and Holm’s method was proposed 
to control the overall type 1 error 
for the two comparisons on the 
primary endpoint. 
 


 
AZP01-CLI-003 
Statistical Analysis Plan 
 
 
 
23-Mar-2020 
Version: Final 1.1 
Page 4 of 53 
 
 
Table of Contents 
1.0 
INTRODUCTION........................................................................................................9 
2.0 
STUDY OBJECTIVES ................................................................................................9 
2.1 
Primary Objective ............................................................................................9 
2.2 
Secondary Objectives.......................................................................................9 
2.3 
Additional Assessments .................................................................................10 
2.4 
Safety Objectives ............................................................................................11 
3.0 
STUDY DESIGN ........................................................................................................11 
3.1 
General Description .......................................................................................11 
3.2 
Schedule of Events .........................................................................................12 
4.0 
PLANNED ANALYSES ............................................................................................17 
4.1 
Data Monitoring Committee (DMC) ............................................................17 
4.2 
Interim Analysis .............................................................................................17 
4.3 
Final Analysis .................................................................................................17 
5.0 
ANALYSIS SETS.......................................................................................................17 
5.1 
Full Analysis Set [FAS] ..................................................................................17 
5.2 
Per Protocol Analysis Set [PP] ......................................................................17 
5.3 
Safety Analysis Set [SAF] ..............................................................................18 
6.0 
STATISTICAL CONSIDERATIONS .....................................................................18 
6.1 
Sample Size Determination ...........................................................................18 
6.2 
Database Lock and Unblinding Procedure..................................................19 
6.3 
Reference Start Date and Analysis Day .......................................................19 
6.4 
Baseline ...........................................................................................................20 
6.5 
Retests, Unscheduled Visits and Early Termination Data .........................22 
6.6 
Definitions .......................................................................................................22 
6.7 
Windowing Conventions ...............................................................................23 
6.8 
Software Version ............................................................................................24 
6.9 
Concept of Estimands and General Strategy for Analyses ........................24 
6.10 
General Presentation .....................................................................................27 
6.11 
Multicenter Studies ........................................................................................27 
6.12 
Missing data ....................................................................................................28 
6.13 
Multiple Comparisons/Multiplicity ..............................................................29 
6.14 
Examination of Subgroups ............................................................................29 
6.15 
Examination of Cohort of Patients 4-7 Years of Age..................................30 


 
AZP01-CLI-003 
Statistical Analysis Plan 
 
 
 
23-Mar-2020 
Version: Final 1.1 
Page 5 of 53 
 
 
7.0 
DISPOSITION AND WITHDRAWALS .................................................................30 
8.0 
PROTOCOL DEVIATIONS ....................................................................................30 
9.0 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ................30 
10.0 
SURGICAL AND MEDICAL HISTORY ...............................................................31 
11.0 
PRIOR AND CONCOMITANT MEDICATIONS.................................................31 
12.0 
STUDY DRUG EXPOSURE AND COMPLIANCE ..............................................32 
12.1 
Derivations ......................................................................................................32 
13.0 
EFFICACY OUTCOMES.........................................................................................32 
13.1 
Primary Efficacy Variable ............................................................................33 
13.1.1 
Primary Efficacy Variable & Derivation .......................................33 
13.1.2 
Missing Data Methods for Primary Efficacy Variable ..................33 
13.1.3 
Primary Analysis of Primary Efficacy Variable ............................33 
13.1.4 
Sensitivity Analyses .......................................................................34 
13.1.4.1 
Analysis of Covariance at 3 Months ............................34 
13.1.4.2 
Subgroup Analyses ......................................................34 
13.1.4.3 
Analysis of Cohort of Patients 4-7 Years of 
Age and All Age Groups Combined ............................35 
13.2 
Secondary Efficacy Variables .......................................................................35 
13.2.1 
Secondary Efficacy Variables & Derivations ................................35 
13.2.2 
Missing Data Methods for Secondary Efficacy 
Variables ........................................................................................36 
13.2.3 
Analysis of Secondary Efficacy Variables ....................................36 
13.2.4 
Analysis of the Cohort of Patients 4-7 Years of Age and 
All Age Groups Combined ............................................................37 
13.3 
Additional Assessments .................................................................................37 
13.3.1 
Additional Assessments & Derivations .........................................37 
13.3.2 
Analysis of Additional Assessments ..............................................40 
13.3.2.1 
Analysis of the Cohort of Patients 8-65 
Years of Age ................................................................40 
13.3.2.2 
Analysis of the Cohort of Patients 4-7 Years 
of Age and All Age Groups Combined........................44 
14.0 
SAFETY OUTCOMES .............................................................................................46 
14.1 
Adverse Events ...............................................................................................46 
14.1.1 
All TEAEs ......................................................................................48 
14.1.1.1 
Severity ........................................................................48 


 
AZP01-CLI-003 
Statistical Analysis Plan 
 
 
 
23-Mar-2020 
Version: Final 1.1 
Page 6 of 53 
 
 
14.1.1.2 
Relationship to Study Drug ..........................................48 
14.1.2 
TEAEs Leading to Discontinuation of Study Drug .......................48 
14.1.3 
Serious Adverse Events .................................................................48 
14.2 
Deaths ..............................................................................................................49 
14.3 
Vital Signs and Height ...................................................................................49 
14.4 
Physical Examination ....................................................................................49 
14.5 
Bone Mineral Density ....................................................................................49 
14.6 
12-Lead ECG ..................................................................................................49 
14.7 
Safety Laboratory Parameters .....................................................................50 
14.8 
IGF-1 Evaluation ...........................................................................................51 
15.0 
CHANGES FROM PROTOCOL .............................................................................51 
16.0 
REFERENCES ...........................................................................................................51 
APPENDIX 1 ..........................................................................................................................53 
Algorithm for Treatment Emergence of Adverse Events ......................................53 
Algorithm for Concomitant Medications .................................................................53 
 
 


 
AZP01-CLI-003 
Statistical Analysis Plan 
 
 
 
23-Mar-2020 
Version: Final 1.1 
Page 7 of 53 
 
 
 
Abbreviations 
 
AE 
Adverse Event 
AG 
Acylated Ghrelin 
ANCOVA 
Analysis of covariance 
ANOVA  
Analysis of variance  
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index 
BW 
Body Weight 
CGI 
Clinical Global Impression 
CGI-I 
Clinical Global Impression-Improvement 
CGI-S 
Clinical Global Impression of Severity 
CgGIS-H 
Caregiver Global Impression of Severity – Hyperphagia 
CGIS-H 
Clinician Global Impression of Severity – Hyperphagia 
CgGIC-H 
Caregiver Global Impression of Change – Hyperphagia 
CGIC-H 
Clinician Global Impression of Change - Hyperphagia 
CRO 
Contractual Research Organization 
CSR 
Clinical Study Report 
DBC-P 
Developmental Behavior Checklist for Pediatric patients 
DMC 
Data Monitoring Committee 
ECG  
Electrocardiogram  
eCRF 
Electronic Case Report Form  
EPG 
Elevated Postprandial Glucose 
EQ-5D-5L 
European Quality of Life Five Dimension Five Level Scale 
FAS 
Full Analysis Set 
HOMA-IR 
Homeostatic Model Assessment for Insulin Resistance 
HQ-CT 
Hyperphagia Questionnaire for Clinical Trials 
IGF-1 
Insulin-like growth factor 1 
IGT 
Impaired Glucose Tolerance 
IQ 
Intelligence Quotient 
ITT 
Intent To Treat 
IWRS 
Interactive Web Response System 
kg 
Kilogram 
KR 
Kenward-Rogers 
MedDRA  
Medical Dictionary for Regulatory Activities  
MMRM 
Mixed Model Repeated Measures 
MNAR 
Missing-Not-At-Random 
NDA 
New Drug Application 
NRS 
Numerical Rating Scales 
PK 
Pharmacokinetic 
PP 
Per Protocol 
PPMS 
Pattern-Mixture Models 
PT 
Preferred Term 
PWS 
Prader-Willi Syndrome 


 
AZP01-CLI-003 
Statistical Analysis Plan 
 
 
 
23-Mar-2020 
Version: Final 1.1 
Page 8 of 53 
 
 
REML 
Restricted Maximum Likelihood 
SAE  
Serious Adverse Event  
SAP  
Statistical Analysis Plan  
SD  
Standard Deviation  
SI 
Système International 
SOC 
System Organ Class 
TEAE 
Treatment-Emergent Adverse Event  
TOEPH 
Toeplitz 
T2D 
Type 2 Diabetes Mellitus 
UAG 
Unacylated Ghrelin 
WC 
Waist Circumference 
WHO-DD  
World Health Organization-Drug Dictionary  
ZBI 
Zarit Burden Interview 
 
 


 
AZP01-CLI-003 
Statistical Analysis Plan 
 
 
 
23-Mar-2020 
Version: Final 1.1 
Page 9 of 53 
 
 
1.0 
INTRODUCTION 
This Statistical Analysis Plan (SAP) describes the planned analysis and reporting for Millendo 
Therapeutics clinical protocol AZP01-CLI-003 (version 1.3 dated March 23, 2020) and 
subsequent amendments. The protocol includes two parts: (i) a Phase 2b dose-response study 
(3-month double-blind, placebo-controlled Core Period and a 9-month Extension Period) and 
(ii) a Phase 3 study (6-month double-blind, placebo-controlled Core Period and a 6-month 
Extension Period). This document refers only to the Phase 2b Core Period. Statistical analyses 
pertaining to the extension period and to the Phase 3 part are presented in separate documents. 
The investigational product is livoletide, formerly known as AZP-531. 
This SAP has been developed prior to database lock and final analysis for the Phase 2b Core 
Period. All final analyses will be conducted after the clinical trial data are entered into the 
database, any discrepancies in the data are resolved, and the database is locked (closed to 
changes). 
The derivation of the responder threshold for the Hyperphagia Questionnaire for Clinical Trials 
(HQ-CT) and analyses of the measurement properties of the HQ-CT are not covered in this 
SAP but will be described in a stand-alone Psychometric Analysis Plan. 
The pharmacokinetic (PK) endpoints and related statistical analyses will be described in detail 
in a separate Pharmacokinetic Analysis Plan. 
2.0 
STUDY OBJECTIVES 
2.1 Primary Objective 
Core Period 
• To demonstrate the efficacy of 3-month treatment with livoletide as compared to 
placebo for reducing caregiver-observed food-related behavior as assessed by the HQ-
CT. 
2.2 Secondary Objectives 
Core Period 
• To demonstrate the efficacy of 3-month treatment with livoletide as compared to 
placebo for: 
- 
Reducing total body fat mass in overweight/obese patients with Prader-Willi 
Syndrome (PWS); 


 
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- 
Reducing waist circumference (WC) in overweight/obese patients with PWS; 
- 
Reducing body weight (BW) in overweight/obese patients with PWS; 
 
where  
Overweight/obese is defined as: 
For patients ≥ 18 years of age: Body mass index (BMI) ≥ 27 kg/m2 
For patients 4-17 years of age: BMI ≥ 90th percentile for the same age and sex 
2.3 Additional Assessments 
Core Period 
• 
To evaluate the effect of livoletide as compared to placebo on: 
− Hyperphagia severity as assessed by the Caregiver and Clinical Global Impression 
of Severity - Hyperphagia scales (CgGIS-H and CGIS-H, respectively); 
− Hyperphagia global impression of change as assessed by the Caregiver and Clinical 
Global Impression of Change - Hyperphagia scales (CgGIC-H and CGIC-H, 
respectively); 
− Clinical global impression of change as assessed by the Clinical Global Impression 
of Improvement (CGI-I) scale; 
− Clinical global impression of severity as assessed by the Clinical Global Impression 
of - Severity (CGI-S) scale; 
− Fasting (for approximately 8 hours) and postprandial glucose and insulin (profile); 
− HOMA-IR; 
− HbA1c; 
− Lipids; 
− Lean body mass; 
− Patient-reported appetite following breakfast as assessed by a Numeric Rating Scale 
(NRS); 
− Patients’ Non-Food-Related behavior as assessed by the Developmental Behavior 
Checklist 2-Parent/Carer version (DBC2-P); 
− Patients’ Quality of Life (QoL) as assessed by the Pediatric Quality of Life 
inventoryTM (PedsQLTM) 4.0 Generic Core Scales; 
− Caregivers’ disease burden as assessed by the Zarit Burden Interview (ZBI); 
− Health state utilities as assessed by European Quality of Life Five Dimension Five 
Level Scale (EQ-5D-5L) Self-complete version and Proxy version 1; 
− BMI and BMI Z-score (the latter for patients 4-17 years of age only); 
• 
To evaluate the measurement properties of the HQ-CT in the study population (test-
retest reliability, construct validity and ability to detect change); 
• 
To derive the responder threshold for meaningful change in the HQ-CT; 


 
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• 
To compare the percentage of HQ-CT responders between groups, where HQ-CT 
responders will be defined as per the stand-alone Psychometric Analysis Plan. 
2.4 Safety Objectives 
To assess the safety and tolerability of livoletide as compared to placebo over a 3-month 
treatment period. 
3.0 
STUDY DESIGN 
3.1 General Description 
The Phase 2b part of the study will include adult and pediatric patients (4-65 years of age) with 
genetically confirmed PWS and evidence of hyperphagia as judged by the investigator and 
HQ-CT total score ≥ 10. For Phase 2b, a total of approximately 150 patients 8 to 65 years of 
age will need to be randomized. In addition to this cohort of 150 patients, a separate cohort of 
patients 4 to 7 years of age will also be randomized. Phase 2b will include a Core Period and 
an Extension Period. The patients will be randomized in approximately 40 sites in Europe, 
Australia and North America. 
 
The Phase 2b Core Period will consist of a 3-month, randomized, double-blind, placebo-
controlled treatment period. After a screening period (up to 4 weeks), approximately one 
hundred and fifty (150) patients 8 to 65 years of age will be randomized in a 1:1:1 ratio to one 
of the 3 arms (livoletide 60 µg/kg - low exposure [8 mg/mL], livoletide 120 µg/kg - high 
exposure [16 mg/mL], or placebo). In addition to this cohort of 150 patients, a separate cohort 
of patients 4 to 7 years of age will be randomized similarly (1:1:1 ratio). Randomization will 
be stratified based on age (age ≥4 and < 8 years, ≥8 and <18 years vs ≥18 years) and BMI 
(patients ≥ 18 years of age: BMI <27 kg/m2 vs BMI ≥ 27 kg/m2; patients 4-17 years of age: 
BMI <90th percentile vs BMI ≥ 90th percentile for the same age and sex). A minimum of 25 
overweight/obese patients will be randomized per treatment group. 
 
Patients randomized to livoletide for the Core Period will remain on the randomized dose (i.e., 
60 µg/kg or 120 µg/kg) during the Extension Period. Patients randomized to placebo for the 
Core Period will cross-over to livoletide 60 µg/kg or 120 µg/kg in a randomized (1:1) manner. 
The Interactive Response Technology (IRT) will manage treatment assignment so that the 
double-blind status can remain intact at the start of the Extension Period. 
 
 
 
 


 
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Figure 1: Phase 2b Study Design 
 
 
Abbreviations: AZP-531=livoletide; N=number of patients; pts=patients; w=weeks 
 
3.2 Schedule of Events 
Schedule of events is presented in Table 1. 
 
 
Core Period
Double Blind, Randomized,
Placebo-controlled Treatment Period
Extension Period
4 w.
9 months
3 months
AZP-531 low exposure
AZP-531 high exposure
Placebo
N=50
AZP-531 low
exposure
N=50
AZP-531 low exposure
AZP-531: 8 mg
N=50
AZP-531 high 
exposure
N=50
Randomization
AZP-531 high exposure
Screening


 
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Table 1: Schedule of Events – Phase 2b Core Period 
Study Stage 
Phase 2b Core Period 
Screening1 
Double-blind Treatment Period 
Visit# 
 
Randomization2 
 
 
End of Core Period 
/ET Discontinuation 
V1 
V2 
V3 
V4 
V5 
Study Week(s) 
-4 to -1 
1 
5 
9 
13 
Treatment Duration (weeks/months) 
- 
- 
4/1 
8/2 
12/3 
Study Day(s) 
-28 to -1 
1 
29 
57 
85 
Visit Window (±X days) 
0 
0 
3 
3 
3 
Informed consent and assign a study specific patient 
number 
X 
 
 
 
 
Demography 
X 
 
 
 
 
Medical history3 
X 
 
 
 
 
Disease history4 
X 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
IQ test5 
X 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
Physical examination6 
X (C) 
X (C) 
X (A) 
X (A) 
X (C) 
Vital signs7 
X 
X 
X 
X 
X 
 
1 The screening period is up to 4 weeks. 
2 The randomization visit will occur a minimum of 2 weeks after the screening visit. 
3 Complete medical history will be obtained at screening and any clinically significant changes from the screening visit will be reported as AEs. 
4 A confirmed genetic diagnosis of PWS. Documentation of PWS subtype (chromosome 15 micro-deletion versus non-deletion) is also required for the study. If the PWS subtype is not 
known, a sample for testing may be obtained and the patient may continue on to be enrolled into the study if he or she meets all the other inclusion criteria and none of the 
exclusion criteria. 
5Collect IQ scores and dates of completion if available in patient’s medical record. 
6 “C” for complete physical examination, “A” for abbreviated physical examination. See Section Error! Reference source not found. of the protocol for assessments to be performed 
during a physical examination. 
7 Vital signs (respiration rate, pulse rate, and blood pressure) will be measured sitting after the patient has rested comfortably for 5 minutes. See Section Error! Reference source not 
found. of the protocol. 


 
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Study Stage 
Phase 2b Core Period 
Screening1 
Double-blind Treatment Period 
Visit# 
 
Randomization2 
 
 
End of Core Period 
/ET Discontinuation 
V1 
V2 
V3 
V4 
V5 
Study Week(s) 
-4 to -1 
1 
5 
9 
13 
Treatment Duration (weeks/months) 
- 
- 
4/1 
8/2 
12/3 
Study Day(s) 
-28 to -1 
1 
29 
57 
85 
Visit Window (±X days) 
0 
0 
3 
3 
3 
WC, BW, and BMI8 
X 
X 
X 
X 
X 
Height9 
X 
X 
X 
X 
X 
12-lead ECG10 
X 
X10 
 
 
X 
DXA (total body fat mass, lean body mass, bone mineral 
density)11 
 
X 
 
 
X 
Pregnancy test12 
X 
X 
X 
X 
X 
Safety laboratory evaluations in the fasting condition13 
X 
X 
X 
 
X 
Blood samples for PK analysis14 
 
 
X 
 
 
Blood samples for HbA1c 
X 
X 
 
 
X 
Blood samples for glucose and insulin profiles15 
 
X 
X 
 
X 
Blood samples for AG and UAG profiles15 
 
X 
X 
 
X 
 
8 Before breakfast. See Section Error! Reference source not found. and Section Error! Reference source not found. of the protocol. 
9 Before breakfast. See Section Error! Reference source not found. of the protocol. 
10 See Section Error! Reference source not found. of the protocol. 
11 DXA can be obtained within 2 weeks prior to randomization (Visit 2) and the End of Core Period visit (Visit 5). See Section Error! Reference source not found. and Section Error! 
Reference source not found. of the protocol. 
12 Pregnancy tests will be performed for women of childbearing potential only. See Section Error! Reference source not found. of the protocol. 
13 Blood samples will be collected after fasting for approximately 8 hours. Clinical serum chemistries, hematology, coagulation, and urinalysis parameters are described in Section 
Error! Reference source not found. of the protocol. Clinical laboratory evaluations will be performed centrally.  
14 PK samples (3-timepoint sampling) will be collected at the same time as glucose/insulin/AG/UAG profiles  as outlined in the Pharmacokinetic Schedule of Activities provided in 
Section Error! Reference source not found. of the protocol. 
15 Blood samples for glucose, insulin, AG, and UAG profiles will be collected after fasting for approximately 8 hours (all patients) and 30 minutes and 180 minutes post-start of an 
isocaloric breakfast (only patients 8 to 65 years).  


 
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Study Stage 
Phase 2b Core Period 
Screening1 
Double-blind Treatment Period 
Visit# 
 
Randomization2 
 
 
End of Core Period 
/ET Discontinuation 
V1 
V2 
V3 
V4 
V5 
Study Week(s) 
-4 to -1 
1 
5 
9 
13 
Treatment Duration (weeks/months) 
- 
- 
4/1 
8/2 
12/3 
Study Day(s) 
-28 to -1 
1 
29 
57 
85 
Visit Window (±X days) 
0 
0 
3 
3 
3 
Blood samples for IGF-1 
 
X 
 
 
X 
Blood samples for ADA analysis 
 
X 
X 
 
X 
 
 
 
 
 
 
Review and completion of questionnaires on eDevice 16 
X 
X 
X 
X 
X 
Isocaloric breakfast taken on site and report any food not 
consumed 17 
 
X 
X 
 
X 
Appetite-NRS17 
X 
X 
X 
 
X 
HQ-CT  
X 
X 
X 
X 
X 
Quality of Life: PedsQLTM Parent-Proxy Report 
 
X 
 
 
X 
CgGIS-H 
 
X 
X 
X 
X 
CGIS-H 
 
X 
X 
X 
X 
CgGIC-H 
 
 
X 
X 
X 
CGIC-H 
 
 
X 
X 
X 
CGI-I  
 
 
X 
X 
X 
CGI-S  
 
X 
X 
X 
X 
Caregiver Disease Burden: ZBI 
 
X 
 
 
X 
EQ-5D-5L Self-complete version and Proxy version 1 
 
X 
 
 
X 
 
16 The eDevice will be used to collect data from all questionnaires and the appetite-NRS. Data from the questionnaires and appetite-NRS will be completed on the eDevice while on site, 
either by the caregiver, the patient (for the NRS), or by the investigator. The eDevice will not be dispensed to the patients. 
17 Appetite-NRS should be administered (only to patients 8 to 65 years) before (after fasting for approximately 8 hours), at the end, and 120 minutes post-start of an isocaloric breakfast, 
except at screening visit, where NRS will be administer for training and acclimation purposes (no profile). Food not consumed when administered the isocaloric breakfast needs to be 
recorded. One-site consumption of isocaloric breakfast is not required for patients 4 to 7 years old. 


 
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Study Stage 
Phase 2b Core Period 
Screening1 
Double-blind Treatment Period 
Visit# 
 
Randomization2 
 
 
End of Core Period 
/ET Discontinuation 
V1 
V2 
V3 
V4 
V5 
Study Week(s) 
-4 to -1 
1 
5 
9 
13 
Treatment Duration (weeks/months) 
- 
- 
4/1 
8/2 
12/3 
Study Day(s) 
-28 to -1 
1 
29 
57 
85 
Visit Window (±X days) 
0 
0 
3 
3 
3 
DBC2-P 
 
X 
 
 
X 
Review/record AEs 
X-------------------------------------------------------------------------------------------------------------------------------------X 
Randomization via IRT18 
 
X 
 
 
 
Dispensation of glucometer kit19 
 
X 
 
 
 
Dispensation of study drug 
 
X 
X 
X 
X 
Drug accountability  
 
 
X 
X 
X 
On-site study drug administration 
(during treatment period only) 
 
X 
X 
X 
X 
 
18 Randomization via IRT should be performed on the first day of the double-blind treatment period. 
19 Glucometer will be provided to patients with T2D if necessary (i.e. if they do not have one). 


 
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4.0 
PLANNED ANALYSES 
4.1 Data Monitoring Committee (DMC) 
Safety data review will be performed at a regular basis during the trial by an external Data 
Monitoring Committee (DMC) operating independently of the Sponsor to make recommendations 
for the conduct of the study based on safety data. The DMC will operate under the rules of an 
approved charter defining the roles and responsibilities of its members. 
4.2 Interim Analysis 
No interim analysis is planned in the Core Period of the Phase 2b study. 
4.3 Final Analysis 
All analyses per age cohort (8-65 years old and 4-7 years old as described in section 3.1) will be 
performed following the signature of the analysis plan and the lock of the database for that age 
cohort for the Phase 2b Core Period of the study. Once database lock is performed for all age 
cohorts, statistical analyses will also be performed on all age cohorts combined. For more details, 
please refer to section 6.2. 
5.0 
ANALYSIS SETS 
5.1 Full Analysis Set [FAS] 
The Full Analysis Set (FAS) will include all randomized patients. The initial randomization will 
be preserved for this analysis set in order to comply with the Intent-to-Treat (ITT) principle. 
5.2 Per Protocol Analysis Set [PP] 
The Per Protocol Set (PP) will include all randomized patients who: 
- 
Completed their first 3 months of treatment. 
- 
Have non-missing observations at Baseline and Day 85 for the primary efficacy endpoint 
(HQ-CT total score). 
- 
Have a baseline value for the primary efficacy endpoint (HQ-CT total score) ≥ 10. 
- 
Have no major CSR-reportable protocol deviations defined as those that may have 
impacted the primary efficacy assessment. 
Prior to the database lock of the Core Period, major CSR-reportable protocol deviations will be 
defined and reviewed by Millendo Therapeutics and the CRO in charge of the study follow-up in 


 
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a blinded fashion. Patients with major CSR-reportable protocol deviations will be excluded from 
the PP set.  
5.3 Safety Analysis Set [SAF] 
The Safety Analysis Set (SAF) will include all randomized patients who received at least one dose 
of the study drug. The treatment actually received by the subject will be used in this set. 
6.0 
STATISTICAL CONSIDERATIONS 
6.1 Sample Size Determination 
In the completed Phase 2a study (2 weeks of treatment), the change from baseline to Day 14 in the 
9-item score of the HQ was -4.3 units for livoletide and -1.6 units for placebo, with a difference 
between groups of 2.7 units.  
For the Phase 2b Core Period (N=150, patients 8 to 65 years of age), a between group difference 
of 4 units in the change from baseline in the HQ-CT score has been selected for sample size 
calculation based on the following:  
1. It is considered reasonable to achieve this difference as a 3 months treatment period is 
expected to produce a higher effect as compared to short-term treatment (2 weeks). 
2. It is in line with the HQ-CT distribution-based estimates of meaningful change observed in 
a landmark Phase 3 clinical trial1 that included 107 obese individuals with PWS, 12 to 65 
years of age (half-standard deviation [SD]=3.3, standard error of the mean [SEM]=4.4). In 
addition, the distribution-based estimates were found to be approximately the magnitude of 
the difference between the mean change of the “A little better” and “No change” in the CGIC 
subgroups. 
Assuming a 2-sided parametric test, alpha of 2.5% (Bonferroni adjustment for 2 comparisons) and 
a SD of 5, forty-one (41) patients per group will allow to detect a difference between groups of at 
least 4 units in the primary endpoint 9-item score of the HQ-CT. This is considered a conservative 
approach since the higher the difference between groups, the lower the sample size. 
Assuming a drop-out rate at 3 months of about 18%, a total of 50 patients (8 to 65 years of age) 
per group will need to be randomized with a minimum of 25 overweight/obese patients per 
treatment group. 
There is no formal sample size calculation done for patients in the 4 to 7 years of age cohort since 
analysis of this cohort is supportive (i.e. they will not be included in the Phase 2b primary endpoint 
analysis). 
 


 
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6.2 Database Lock and Unblinding Procedure 
During Phase 2b, there will be two database lock events: one at the conclusion of the Core Period 
and one at the end of the Extension Period, therefore requiring two unblinding procedures.  Also, 
since the cohort of patients 4 to 7 years of age will take longer to recruit than the cohort of patients 
8 to 65 years of age, there will be a rolling lock at the end of both periods (i.e., a first lock for the 
cohort of patients 8 to 65 years of age; and a second lock for all patients, to include the cohort of 
patients 4 to 7 years of age). 
Per age cohort, once data checks have been resolved, and the analysis sets and the SAP have been 
finalized and signed, the clinical database related to the Phase 2b Core Period will be locked in 
order to proceed with the statistical analyses. As the cohort of the 4- to 7-year-old patients will 
take longer to recruit, the statistical analyses will be performed first with the 8- to 65-year-old 
patients and then with the cohort of the 4- to 7-year-old patients and all age cohorts combined. 
6.3 Reference Start Date and Analysis Day 
Analysis Day will be calculated from the reference start date and will be used to show start/stop 
day or study day of assessments and events. 
Reference start date is defined as the day of the first dose of study drug (i.e., Day 1 of the Core 
Period). 
• 
If the date of the event is on or after the reference date then:  
Analysis Day = (date of event – reference date) + 1. 
• 
If the date of the event is prior to the reference date then:  
Analysis Day = (date of event – reference date). 
In the situation where the event date is partial or missing, Analysis Day and any corresponding 
durations will appear partial or missing in the listings. 
 
 


 
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6.4 Baseline 
The baseline is defined for each parameter as in Table 2 below: 
Table 2: Baseline Definitions 
Endpoint 
V1 V2 
Baseline Definitions 
Additional Information 
HQ-CT 
X 
X 
Mean of V1 and V2 
Include all unscheduled 
assessments between V1 and V2 in 
the Mean. 
Total Body Fat 
Mass 
 
X 
V2 value 
 
Waist 
Circumference 
X 
X 
Mean of V1 and V2 
Include all unscheduled 
assessments between V1 and V2 in 
the Mean. 
Body Weight 
X 
X 
Mean of V1 and V2 
Include all unscheduled 
assessments between V1 and V2 in 
the Mean. 
CgGIS-H 
 
X 
V2 
 
CGIS-H 
 
X 
V2 
 
CgGIC-H 
 
 
N/A 
 
CGIC-H 
 
 
N/A 
 
CGI-I 
 
 
N/A 
 
CGI-S 
 
X 
V2 
 
Fasting & 
Postprandial 
Glucose 
 
X 
V2 (time point specific) 
Take the nominal time point into 
account:  after fasting (all patients) 
and 30 minutes and 180 minutes 
post-start of an isocaloric breakfast 
(only patients 8 to 65 years of 
age). 
Insulin 
 
X 
V2 (time point specific) 
Take the nominal time point into 
account:  after fasting (all patients) 
and 30 minutes and 180 minutes 
post-start of an isocaloric breakfast 
(only patients 8 to 65 years of 
age). 


 
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HOMA-IR 
 
X 
V2 
 
HbA1c 
X 
X 
Mean of V1 and V2 
Include all unscheduled 
assessments between V1 and V2 in 
the Mean. 
Lipids 
X 
X 
Mean of V1 and V2 
Include all unscheduled 
assessments between V1 and V2 in 
the Mean. 
Lean Body Mass 
 
X 
V2 
Include values from 3 weeks 
before to one week after V2. 
including unscheduled 
assessments. 
Appetite-NRS 
X 
X 
V2 
 
DBC2-P 
 
X 
V2 
 
PedsQL 
 
X 
V2 
 
ZBI 
 
X 
V2 
 
EQ-5D-5L 
 
X 
V2 
 
BMI 
X 
X 
Mean of V1 and V2 
Include all unscheduled 
assessments between V1 and V2 in 
the Mean. 
Vital Signs 
X 
X 
Last pre-dose 
assessment on or prior 
to V2 
Including unscheduled 
assessments. 
Height 
X 
X 
Last assessment on or 
prior to V2  
Including unscheduled 
assessments. 
PE 
X 
X 
Last assessment on or 
prior to V2 
Including unscheduled 
assessments. 
Bone Mineral 
Density 
 
X 
Last assessment on or 
prior to V2 
Include values from 3 weeks 
before to one week after V2, 
including unscheduled 
assessments. 
ECG 
X 
X 
Last pre-dose 
assessment on or prior 
to V2 
Including unscheduled 
assessments. 


 
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Safety Labs 
X 
X 
Last pre-dose 
assessment on or prior 
to V2 
Including unscheduled 
assessments. 
AG, UAG, 
AG/UAG 
 
X 
V2 (time point specific) 
Take the nominal time point into 
account:  after fasting (all patients) 
and 30 minutes and 180 minutes 
post-start of an isocaloric breakfast 
(only patients 8 to 65 years of 
age). 
IGF-1 
 
X 
Last pre-dose 
assessment on or prior 
to V2 
 
ADA 
 
X 
Last pre-dose 
assessment on or prior 
to V2 
 
 
Adverse events (AEs) commencing on the reference start date will be considered to be treatment-
emergent adverse events (TEAEs). Medications taken during the treatment core period will be 
considered to be concomitant medications. 
6.5 Retests, Unscheduled Visits and Early Termination Data 
Unscheduled and retest measurements will be provided in data listings. Those values might be 
used in the summary statistics for pre-dose measurements (see section 6.4), but they will not be 
used in by-visit summaries for post-dose measurements, unless there are no scheduled data 
available for a planned visit. If only unscheduled data are available for a planned visit (as per the 
schedule of assessments, using the statistical windowing), those data will be used in by-visit 
summaries for post-dose measurements as well. 
For early termination visits, data will be mapped using the windowing conventions presented in 
section 6.7. 
6.6 Definitions  
• BMI (kg/ m2) = weight (kg)/ height (m)2 
• Overweight/obese patients 
o patients ≥18 years of age: BMI ≥27 kg/m2 
o patients 4-17 years of age: BMI ≥90th percentile for the same age and sex  
• Non overweight/obese patients 


 
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o patients ≥18 years of age: BMI <27 kg/m2  
o patients 4-17 years of age: BMI <90th percentile for the same age and sex  
• T2D patients are defined as those with any ongoing medical history with MedDRA 
preferred term = "diabetes mellitus" or "diabetes mellitus inadequate control" or "diabetes 
with hyperosmolarity" or "insulin resistant diabetes" or "insulin-requiring type 2 diabetes 
mellitus" or "type 2 diabetes mellitus", since patients with type 1 diabetes mellitus are 
excluded from the study. 
• Prediabetic patients are defined as those not having ongoing medical history of T2D (as 
defined above), and meeting any of the following: HbA1c 5.7-6.4% at V1 and V2, fasting 
plasma glucose at V2 5.6-6.9 mmol/L, ongoing medical history with preferred term = 
"glucose tolerance impaired" or "impaired fasting glucose".  
• Dyslipidemia at baseline is defined as (LDL-c >= 3.0 mmol/liter at V1 and V2) and/or 
(triglycerides >= 2.0 mmol/liter at V1 and V2). 
• Elevated postprandial glucose (EPG) is defined as 3-hr post-start of breakfast glucose 
concentration ≥ 8.0 mmol/L (144 mg/dL) at V2. 
6.7 Windowing Conventions 
The following table describes assignment of visit windows for purposes of analysis for the Phase 
2b Core Period. Windowing will be applied to the data prior to any missing data calculations. 
These windows will be used to report efficacy variables, vital signs, 12-lead ECG and safety 
laboratory evaluations. The windowing will also be applied to flags used for study completion 
(e.g., completion of the 3-month Core Period). 
Table 3: Analysis Visit Windows 
Visit/Study Week 
Target 
Day 
Visit Window 
As per protocol 
Visit Window 
Statistical Analyses 
Baseline 
Day 1 
Not Applicable 
See section 6.4. 
Visit 3 / Week 5 
Day 29 
Day 26 – Day 32 
Day 2 – Day 43  
Visit 4 / Week 9 
Day 57 
Day 54 – Day 60 
Day 44 – Day 71 
Visit 5 / Week 13 
Day 85 
Day 82 – 88 
Day 72 – Day 103 a, b 
  
a This should be prior to the first dose of study drug in the Extension Period, except for DXA. 
b For DXA, measures taken within 3 weeks prior to or within 7 days after the V5 date will be considered as V5 
values. 
 
If more than one evaluation falls into the same time window, the evaluation nearest to the target 
day will be considered as the analysis value. If two evaluations are equally distant from the target 
day, the evaluation occurring after the target day will be retained. 


 
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6.8 Software Version 
All analysis will be performed using SAS® software version 9.4 or higher. 
6.9 Concept of Estimands and General Strategy for Analyses 
As per ICH E9 Addendum2, an estimand defines in detail what needs to be estimated to address a 
specific scientific question of interest. In this study, the specific question or objective is to 
demonstrate the efficacy of a 3-month (or 6-month) treatment with livoletide as compared to 
placebo for reducing caregiver-observed food-related behavior. As described in Figure 2 below, a 
description of an estimand includes four attributes:  
A. the population, that is, the patients targeted by the scientific question; 
B. the variable (or endpoint), to be obtained for each patient, that is required to address the 
scientific question; 
C. the specification of how to account for intercurrent events to reflect the scientific question 
of interest. 
D. the population-level summary for the variable which provides, as required, a basis for a 
comparison between treatment conditions. 
The main estimand in this study will follow a treatment policy strategy. As per protocol section 
7.2.1, a patient might continue in the study, but off drug (thus adhering to the Treatment policy 
strategy). Because it is not anticipated that patients will be followed for very long once they stop 
study drug, since patients typically do not want to be “off drug on study”, we had identified the 
main intercurrent event as discontinuation of study treatment. Since the patient will most likely 
not be followed-up after treatment discontinuation, this would result in missing data for the main 
estimand efficacy assessment at 3 months (for the phase 2b part) or 6 months (for the phase 3 part).  
The main estimand will be based on the 8-65 years of age cohort. 
The main estimator of the main estimand will be based on the cohort of patients 8-65 years of age 
using a mixed model repeated measures (MMRM) approach to handle the missing observations.  
Sensitivity analyses will be performed on observed cases at 3 months (for the phase 2b part) or 6 
months (for the phase 3 part) to evaluate the robustness of the missing observations strategy using 
the MMRM approach in the cohort of patients 8-65 years of age. If missing observations are not 
at random or if the drop-out rate is more than 10%, additional imputation methods for missing 
observations will be performed by using a pattern-mixture models (PMMs) with PROC MI in SAS. 
PMMs are a straightforward and transparent way of modeling a wide variety of assumptions about 
missing data, and are particularly suited to implementing missing-not-at-random (MNAR) 
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Supplementary analyses will consist of the analyses of the key secondary endpoints in a manner 
similar to the main estimator of the main estimand. They will also consist of the statistical analyses 
of all additional study assessments as described in section 2.3. These supplementary analyses will 
all be supportive in providing additional insights into the understanding of the treatment effect. 
Exploratory analyses for the main estimand will present the results in the cohort of patients 4-7 
years of age separately, as well as combined with the patients 8-65 years of age in a same MMRM 
model. 
 


 
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Figure 2: General concept of estimands in phase 2b and phase 3 studies 
 


 
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6.10   General Presentation 
All data presentations are limited to the Core Period, which includes the scheduled Core 
Period visits and unscheduled visits that occur prior to the end of the Core Period/withdrawal 
during the Core Period. AEs are limited to only those that start during the Core Period, and 
concomitant medications are limited to only those that started prior to the end of the Core 
Period (i.e., start date <= end of Core Period data). The first study drug administration refers 
to the first administration during the Core Period. The last drug administration refers to the 
last administration during the Core Period. The last contact date refers to the last contact 
during the Core Period. 
 
All continuous variables will be summarized by presenting the number of patients, mean, 
standard deviation, median, minimum, and maximum. Categorical variables (including level 
of scales) will be presented as frequencies and percentages. Summary tables will be presented 
by treatment group (60 µg/kg, 120 µg/kg and Placebo), visit, and time point, when applicable. 
An overall alpha of 5% will be used. Details related to multiplicity are presented in Section 
6.13. 
6.11 Multicenter Studies 
This study will be conducted at multiple sites worldwide, at approximately 40 sites in Europe, 
Australia and USA. To obtain a sufficient and better-balanced number of patients among study 
sites, pooling of sites will be applied prior to performing the statistical analyses and unblinding 
of treatments. Sites without at least 5 patients in the FAS will be incorporated into pooled sites 
as described below. European sites will be pooled together and USA sites will be pooled 
together. 
Sites in USA 
1) Sites with fewer than 5 patients in the FAS will be pooled with the geographically 
closest sites in a common geographical area (i.e., state). Within a geographical area: 
a. Sites with fewer than 5 patients will be ordered from lowest to highest in terms 
of number of FAS patients. In case of ties, the ordering for tied sites will be 
determined according to the site identification number (from smallest to 
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b. Sites will be combined beginning at the smallest until the resulting pooled site 
contains at least 5 FAS patients. The sites pooled in this way will be considered 
as a single site in the statistical analyses. 
c. The process described above will resume for the remaining sites not meeting 
the criterion of having at least 5 FAS patients. If the final set of pooled sites 
does not meet the criterion of having at least 5 FAS patients, the final set will 
be pooled with the preceding pooled site. 
In the case where fewer than 5 FAS patients are available in one geographical area, the 
patients will be pooled with the closest geographical area (i.e., with the closest state). If 
there is more than one closest geographical area, the one with the smallest site identification 
number will be chosen. 
 
Sites in Europe (for each Country) and Australia 
1) Sites with fewer than 5 patients will be ordered from lowest to highest in terms of 
number of FAS patients. In case of ties, the ordering for tied sites will be determined 
according to the site identification number (from smallest to largest). 
2) Sites will be combined beginning at the smallest until the resulting pooled site contains 
at least 5 FAS patients. The sites pooled in this way will be considered as a single site 
in the statistical analyses. 
3) The process described above will resume for the remaining sites not meeting the 
criterion of having at least 5 FAS patients. If the final set of pooled sites does not meet 
the criterion of having at least 5 FAS patients, the final set will be pooled with the 
preceding pooled site. 
In the case where fewer than 5 FAS patients are available in one country, the patients will 
be pooled as described in points 1) a to c (with countries instead of states). 
6.12 Missing data 
Unless otherwise specified, missing safety data will not be imputed. Missing efficacy 
endpoints will be handled as described in Section 13 of this analysis plan. 
See Error! Reference source not found.Appendix 1 for handling of completely or partially 
missing dates for prior and concomitant medications and adverse events. In general, the 
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Event Start Date Imputation 
• Imputation of event end date should be done before imputation of event start date.  
• Completely missing: Impute to the first study drug administration date. 
• Missing day and month: Impute to January 1st, unless year is the same as year of first 
study drug administration then impute to the first study drug administration date. 
• Missing day: Impute to the 1st of the month, unless month and year are the same as 
month and year of first study drug administration then impute to the first study drug 
administration date. 
• If imputed event start date is after event end date (imputed or not), set the event start 
date to the event end date. 
Event End Date Imputation 
• Completely missing (and not flagged as “ongoing”): Impute to the last contact date. 
• Missing day and month: Impute to December 31st, unless year is the same as last 
contact date then impute to the last contact date. 
• Missing day: Impute to the last day of the month, unless year and month are the same 
as year and month of last contact date, then impute to the last contact date. 
6.13 Multiple Comparisons/Multiplicity 
In order to control for the overall type 1 error at 5% for the primary endpoint, Holm’s method 
will be used for the two comparisons of interest (i.e., livoletide 60 µg/kg vs. placebo and 
livoletide 120 µg/kg vs. placebo). Using Holm’s method, the comparison of interest with the 
smallest p-value will first be tested at alpha of 2.5% (2-sided). If not statistically significant, 
both comparisons will be declared not statistically significant. If statistically significant, that 
comparison will be declared statistically significant and the second comparison of interest 
(with the larger p-value) will be tested at alpha of 5% (2-sided).  
With Holm’s method, the study will be considered positive in terms of efficacy, if at least one 
of the comparisons is declared statistically significant. This strategy, which is a step-down 
version of the Bonferroni test, will control the overall type 1 error to no more than 5%. 
The key secondary and other efficacy parameters will be tested at a nominal alpha of 5% for 
all comparisons, without control for multiplicity of testing. 
6.14 Examination of Subgroups 
For the cohort of patients 8-65 years of age, the following subgroups will be assessed in regards 
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• 
Age (8-17 and ≥18 years of age) 
• 
BMI (not overweight/obese, overweight/obese)   
In addition, analyses of blood glucose, insulin, HOMA-IR and HbA1c will be performed on 
patients with elevated postprandial glucose (EPG) and also based on prediabetic/T2D patients. 
Lipid data will be presented for patients with dyslipidemia at baseline. 
6.15 Examination of Cohort of Patients 4-7 Years of Age 
The cohort of patients 4-7 years of age will be presented separately as well as combined with 
the cohort of patients 8-65 years of age. 
7.0 
DISPOSITION AND WITHDRAWALS 
All patients who provide informed consent will be accounted for. The number of patients 
randomized, treated, completing and discontinuing from the Phase 2b Core Period as well as 
the number of patients in each analysis population will be summarized by treatment group. For 
patients who did not complete the Phase 2b Core Period, the reasons for withdrawal will be 
presented. The reasons for which a patient is excluded from the analysis populations will be 
presented. The number of patients screened for inclusion will also be presented. Reasons for 
screen failures will be reported. 
 
Summaries will be presented for the patients age 8-65 years of age, for the cohort of patients 
4-7 years of age and for all patients (4-65 years of age) combined. 
8.0 
PROTOCOL DEVIATIONS 
Clinical study report (CSR)-reportable-protocol deviations (as identified by the Sponsor prior 
to the database lock) will be summarized for all randomized patients by treatment group, and 
all CSR-reportable protocol deviations will be presented in a by-subject listing. Summaries 
will be presented for the cohort of patients 8-65 years of age, for the cohort of patients 4-7 
years of age and for all patients (4-65 years of age) combined. 
9.0 
DEMOGRAPHIC AND OTHER BASELINE 
CHARACTERISTICS 
Baseline measures and demographic information will be summarized by treatment group for 
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limited to: sex, age, age group (4-7, 8-17 and ≥ 18 years), genetic subtype (chromosome 15 
micro-deletion, maternal uniparental disomy, imprinting center defect, non-deletion), body 
weight, height, body mass index (BMI), BMI category (not overweight/obese or 
overweight/obese), waist circumference, waist circumference by BMI category, total body fat 
mass, total body fat mass by BMI category, HQ-CT, CgGIS-H, CGIS-H, ZBI, use of growth 
hormone medication (yes/no), fasting AG, fasting UAG, AG/UAG ratio, HbA1c, fasting 
glucose, fasting insulin (for patients not on insulin at V2 (WHODrug ATC3=A10A)), 
prediabetes or T2D (yes/no), EPG (yes/no), dyslipidemia (yes/no) and HOMA-IR (for patients 
not on insulin at V2 (ATC3=A10A)).  
Summaries will be presented for the patients 8-65 years of age, for the cohort of patients 4-7 
years of age and for all patients (4-65 years of age) combined. 
Individual patient data listings will be provided for all demographic and baseline 
characteristics. IQ will be listed only. 
10.0 SURGICAL AND MEDICAL HISTORY 
Medical history will be presented for the Safety analysis set. Medical history will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA) dictionary, version 22.0. A 
summary table of medical history will be presented by treatment group and all treatments 
combined. Summaries will be presented for the patients 8-65 years of age, for the cohort of 
patients 4-7 years of age and for all patients (4-65 years of age) combined. A by-patient listing 
of all medical history will be presented. 
11.0 PRIOR AND CONCOMITANT MEDICATIONS 
Prior medications are defined as any medications started prior to the first dose of study drug. 
Concomitant medications are defined as any medications taken during the treatment period of 
the study, including those that started prior to the first dose date of study drug and continued 
past that date. All medications will be coded using the World Health Organization Drug 
Dictionary (WHO DD), March 2019. 
Incidence of concomitant medications will be tabulated by treatment group and all treatments 
combined by Anatomical Therapeutic Chemical (ATC) Classification System levels 1 to 4. 
Summaries will be presented for the patients 8-65 years of age, for the cohort of patients 4-7 
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medications will be presented with an indication of whether the medication is considered 
concomitant or not and prior or not. 
12.0 STUDY DRUG EXPOSURE AND COMPLIANCE 
The total extent of exposure, number of injections and compliance during the treatment period 
will be summarized by treatment group for the FAS, Safety, and PP sets. Summaries will be 
presented for the patients 8-65 years of age, for the cohort of patients 4-7 years of age and for 
all patients (4-65 years of age) combined. A by-patient listing of all exposure and compliance 
data will be presented. 
12.1 Derivations 
The number of injections performed is calculated as: 
Date of last dose of study drug – Date of first dose of study drug – any missed doses 
+ 1 
The total extent of exposure (expressed as a number of days) will be defined as: 
Date of last dose of study drug - Date of first dose of study drug + 1  
Compliance (as a percentage) will be calculated as follows: 
100 ∗(Number of injections performed)/(Total extent of exposure (in days) ) 
13.0 EFFICACY OUTCOMES 
Efficacy analyses will be performed on the FAS as main analyses and on the PP set as 
supportive analyses (when applicable). 
Actual change and percentage change (when applicable) from baseline results for all variables, 
including each item of the HQ-CT, will be summarized by treatment group and visit, using 
descriptive statistics, including n, arithmetic mean, standard deviation (SD), 95% confidence 
interval to the mean, median, minimum, Q1, Q3, and maximum values. Descriptive summaries 
will be presented for the patients 8-65 years of age, for the cohort of patients 4-7 years of age 
and for all patients (4-65 years of age) combined. 
For each inferential analysis, the distribution of efficacy residuals will be visually examined to 
determine whether substantial departures from normality and homogeneity of variance are 
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variance, alternative transformation of the dependent variable or non-parametric models may 
be presented instead. 
Individual patient data listings will be provided for all efficacy outcomes. 
13.1 Primary Efficacy Variable 
13.1.1 Primary Efficacy Variable & Derivation 
The primary efficacy endpoint is the change from baseline to the end of the 3-month Core 
Period (i.e., V5/Week 13) in HQ-CT total score. The HQ-CT is derived from the Hyperphagia 
Questionnaire and is a 9-item instrument that has been developed and validated for use in 
clinical trials.  
All items on the HQ-CT are rated on a five-point scale (0 = not a problem to 4 = severe and/or 
frequent problem) and are summed to generate a total score from 0 to 36. The HQ-CT 
questionnaire is completed at screening, randomization (V2), V3, V4 and V5 during the Core 
Period.  
13.1.2 Missing Data Methods for Primary Efficacy Variable 
Missing observations for the primary endpoint will be addressed by using the mixed-effect 
model repeated measures (MMRM) approach with an unstructured (UN) variance-covariance 
pattern across the visits. Details are presented in section 13.1.3. 
If missing observations are not at random, additional imputation methods for missing 
observations will be performed by using PROC MI in SAS. 
13.1.3 Primary Analysis of Primary Efficacy Variable 
The primary analysis for the primary efficacy endpoint will be done using an MMRM analysis 
on the change from baseline in HQ-CT total score within the first 3 months in the cohort of 
patients 8-65 years of age. The model will include treatment, visit, stratification variables (age 
group 8-17 years,  ≥ 18 years), BMI category (overweight/obese, not overweight/obese), and 
treatment-by-visit interaction as fixed effects and screening HQ-CT total score and V2 minus 
screening HQ-CT total scores as covariates. An unstructured covariance matrix will be used to 
model the correlation. The method of estimation will be REML and the method for 
approximating the degrees of freedom of the denominator will be Kenward-Rogers (KR). If 
convergence issues arise, the heterogeneous Toeplitz (TOEPH) structure will be used.  If 
TOEPH is used, a sensitivity analysis of the MMRM results will be performed by requesting 
the empirical sandwich estimator (option EMPIRICAL) and by allowing SAS to use the default 
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in the mixed model to test for treatment differences at different time points, but the primary 
comparison will be done at 3 months (i.e., V5/Week 13). This analysis will be performed on 
both FAS (primary analysis) and PP. 
As a supportive statistical analysis, MMRM on the change from baseline in HQ-CT total score 
will be done with treatment, visit, stratification variables, pooled sites, treatment by visit 
interaction, pooled sites-by-visit interaction, pooled sites-by-treatment interaction and pooled 
sites-by-treatment-by-visit interaction as fixed effects and baseline HQ-CT total score and 
screening HQ-CT total score as covariates. An unstructured covariance will be used to model 
the correlation. If convergence issues arise, TOEPH structure will be used. If pooled sites-by-
visit interaction, pooled sites-by-treatment interaction or pooled sites-by-treatment-by-visit 
interaction are not statistically significant (p<0.05), they will be removed from the model. 
Contrasts will be defined in the mixed model to test for treatment differences at different time 
points. This analysis will be performed on FAS only. 
As exploratory statistical analyses, every item of the HQ-CT global score will be analyzed as 
described in the first paragraph, but by using each item as dependent variable in a separate 
statistical model. These analyses will be performed on FAS only. 
13.1.4 Sensitivity Analyses 
13.1.4.1 
Analysis of Covariance at 3 Months 
As a sensitivity analysis, an analysis of covariance (ANCOVA) on the change-from-baseline 
HQ-CT total score at 3 months will be performed (with no imputation of missing values) in 
the cohort of patients 8-65 years of age. The model will include treatment and the stratification 
variables as fixed effects, and screening HQ-CT total score and V2 minus screening HQ-CT 
total scores as covariates. The treatment differences in least-squares means and corresponding 
95% CIs will be presented. This analysis will be performed on FAS only. 
13.1.4.2 
 Subgroup Analyses  
In addition to the primary analysis which will present the effect of treatment with Age (8-65 
years) and BMI combined, subgroup analyses will be performed to explore the treatment effect 
within each level of age group and each level of BMI category. 
A sensitivity analysis will be performed on the change from baseline in HQ-CT total score 
within the first 3-month treatment period with subgroups of age (age 8 to 17 and age ≥18 years) 
included in the statistical model. The MMRM model will be used with treatment, age group, 
BMI category, visit, and the interactions treatment-by-age group, treatment-by-visit and 
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CT total scores as covariates. Contrasts will be defined to test for treatment differences for 
each level of age group and visit. The differences in least-squares means and corresponding 
95% CIs will be presented. Additionally, the treatment differences in least-squares means and 
corresponding 95% CIs will be presented by visit for all ages combined. 
Similar analyses will be done on the change from baseline in HQ-CT total score within the 
first 3-month treatment period with subgroups of BMI (not overweight/obese and. 
overweight/obese) included in the statistical model. The MMRM model will be used with 
treatment, age group, BMI category, visit, and the interactions treatment-by-BMI category, 
treatment-by-visit and treatment-by-visit-by-BMI category as fixed effects and screening and 
V2 minus screening HQ-CT total scores as covariates. Contrasts will be defined to test for 
treatment differences for each level of BMI category and visit. The differences in least-squares 
means and corresponding 95% CIs will be presented. Additionally, the treatment differences 
in least-squares means and corresponding 95% CIs will be presented by visit for all BMI 
combined.   
Results will also be presented graphically (Forest Plot) using the FAS.  
13.1.4.3 
Analysis of Cohort of Patients 4-7 Years of Age and All Age 
Groups Combined 
In addition to descriptively summarizing the HQ-CT scores for the cohort of patients 4 to 7 
years of age (See section 13.0), the analysis of section 13.1.4.2 will be repeated with age group 
separated in three categories: age 4-7 years, age 8 to 17 years, and age ≥18 years. The MMRM 
model will be used with treatment, age group, BMI category, visit, and the interactions 
treatment-by-age group, treatment-by-visit and treatment-by-visit-by-age group as fixed 
effects and screening and V2 minus screening HQ-CT total scores as covariates. Contrasts will 
be defined to test for treatment differences for each level of age and visit. The differences in 
least-squares means and corresponding 95% CIs will be presented. Additionally, the treatment 
differences in least-squares means and corresponding 95% CIs will be presented by visit for 
all age groups combined. These analyses will be done on FAS. 
13.2 Secondary Efficacy Variables 
13.2.1 Secondary Efficacy Variables & Derivations 
The key secondary efficacy endpoints include the percentage change from baseline to the end 
of the 3-month Core Period in total body fat mass, the change from baseline to the end of the 
3-month Core Period in waist circumference and the percentage change from baseline to the 
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assessed in overweight/obese patients as main analyses and in not overweight/obese patients 
and on all patients as supportive analyses. 
Before breakfast, patients will be weighed clothed (underwear, light gown or light clothing 
only), without footwear (no shoes or sandals) or heavy jewelry, using a calibrated scale. The 
same scale should be used throughout the study if possible. The conditions under which 
patients are weighed should be kept consistent if possible. Total body fat mass will be assessed 
by Dual Energy X-ray Absorptiometry (DXA). Waist circumference and body weight are 
measured at screening, randomization (V2), V3, V4 and V5 during the Core Period and fat 
mass is measured at V2 and V5 during the Core Period. 
13.2.2 Missing Data Methods for Secondary Efficacy Variables 
Missing observations for the secondary endpoints of body weight and waist circumference will 
be handled the same way as for the primary endpoint (i.e., using the MMRM approach with an 
unstructured (UN) variance-covariance pattern across the visits). Details are presented in 
section 13.1.3. For total body fat mass, since this parameter is only measured at randomization 
and at week 13, no missing observations will be imputed.  
13.2.3 Analysis of Secondary Efficacy Variables 
The primary and supportive analyses described in section 13.1.3 will be performed on the 
change from baseline in waist circumference and percentage change from baseline in body 
weight based on overweight/obese patients. The stratification variable related to the BMI will 
not be included in the different statistical models.  
For the percentage change from baseline in total body fat mass, an ANCOVA on the percentage 
change from baseline in total body fat mass at 3 months will be performed (with no imputation 
of missing values). The model will include treatment and the stratification variable age group 
(age 8 to 17 years and age ≥18 years) as fixed effects and total body fat mass at baseline as 
covariate. The treatment differences in least-squares means and corresponding 95% CIs will 
be presented. The analysis will be done on both FAS and PP. A supportive analysis including 
pooled sites and pooled sites by treatment will also be performed. The pooled sites-by-
treatment interaction will be removed from the statistical model if not statistically significant 
(p<0.05). The analysis will be done on FAS in overweight/obese patients only. 
A second supportive ANCOVA will be done on the change from baseline in total body fat 
mass using a similar model as for the percentage change-from-baseline in total body fat mass. 
The analysis will be done on FAS. 


 
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The statistical analyses described above will be done in overweight/obese patients as main 
analyses and in not overweight/obese patients and on all patients as exploratory analyses (in 
FAS only). The analyses on all patients will include BMI category as covariate. 
13.2.4 Analysis of the Cohort of Patients 4-7 Years of Age and All Age Groups 
Combined 
In addition to descriptively summarizing the key secondary efficacy variables for the cohort of 
patients 4-7 years of age (See section 13.0), the following statistical analyses will be 
performed: 
• The sensitivity analysis including the 4- to 7-year-old age group described in section 
13.1.4.3 will be performed on the change from baseline in waist circumference and 
percentage change from baseline in body weight based on overweight/obese patients. 
The stratification variable related to the BMI will not be included in the different 
statistical models. 
• For the percentage change from baseline and the change from baseline in total body fat 
mass, an ANCOVA at 3 months will be performed (with no imputation of missing 
values). The model will include treatment and the stratification variable age group (age 
4-7 years, age 8-17 years, and age ≥18 years) as fixed effects, the interaction age group-
by-treatment and total body fat mass at baseline as covariate. Contrasts will be defined 
to test for treatment differences for each level of age. The differences in least-squares 
means and corresponding 95% CIs will be presented. Additionally, the treatment 
differences in least-squares means and corresponding 95% CIs will be presented for all 
age groups combined.  
The statistical analyses described above will be done in overweight/obese patients as main 
analyses and in not overweight/obese patients and on all patients as exploratory analyses 
(in FAS only). The analyses on all patients will include BMI category as covariate. 
13.3 Additional Assessments 
13.3.1 Additional Assessments & Derivations 
The additional assessments include the following:  
Change from baseline to the end of the 3-Month Core Period in: 
• Caregiver and Clinician Global Impression of Severity - Hyperphagia (CgGIS-H and 
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• Clinical Global Impression of Severity (CGI-S) score 
• Fasting/postprandial glucose and insulin 
• HOMA-IR 
• HbA1c 
• Lipids (total cholesterol, triglycerides, low density lipoprotein-cholesterol (LDL-c), 
high density lipoprotein-cholesterol (HDL-c)) 
• Lean body mass 
• Appetite-Numeric Rating Scale (NRS) scores 
• Developmental Behavior Checklist Parent/Carer (DBC-P) score 
• PedsQLTM Parent-Proxy age-appropriate Reports scores 
• Zarit Burden Interview (ZBI) scores 
• Health state utilities as assessed by EQ-5D-5L 
• BMI 
• BMI Z-score (patients <18 years of age only) 
Actual end of the 3-Month Core Period assessment in: 
• Caregiver and Clinician Global Impression of Change - Hyperphagia (CgGIC-H and 
CGIC-H) scores 
• Clinical Global Impression of General Improvement (CGI-I) score 
In addition, the percentage of HQ-CT responders at 3 months as defined by anchor-based and 
distribution-based methods will be determined as specified in the Psychometric and Responder 
Analysis Plan and results will be presented in the corresponding report, which will be included 
in an appendix to the clinical study report. 
Glucose and insulin are collected after fasting for approximately 8 hours (all patients) and 30 
minutes and 180 minutes post-start of an isocaloric breakfast (only patients 8 to 65 years of 
age) at V2, V3 and V5. 
HOMA-IR is defined as fasting insulin (µU/L) x fasting plasma glucose (nmol/L)/22.5 
(obtained at V2; calculated only for patients not currently on insulin (ATC3=A10A)). HOMA-
IR will be derived at V2, V3 and V5. 
HbA1c is measured at screening, V2 and V5. 
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Lean body mass is measured at V2 and V5. 
Clinical Global Impression scales have been developed as research tools for clinical practice 
and have been since extensively used in clinical trials. They evaluate either severity of illness 
or clinical global improvement. Scales for severity of hyperphagia (CGIS-H, CgGIS-H and 
CGI-S) and hyperphagia improvement (CGIC-H, CgGIC-H and CGI-I) have been adapted 
from these tools. CGIS-H, CgGIS-H and CGI-S are measured at V2, V3, V4 and V5.  CGIC-
H, CgGIC-H and CGI-I are measured at V3, V4 and V5. 
Patients are asked to rate appetite/prospective food consumption using 6-point NRS (“nothing 
at all” to “A very very large amount”) specifically designed for the PWS patient population. 
NRS is measured at screening (only to patients 8 to 65 years), V2, V3 and V5. NRS will be 
measured before (after fasting for approximately 8 hours), at the end, and 120 minutes post-
start of an isocaloric breakfast, except at screening visit, where NRS will be administer for 
training and acclimation purposes (no profile). 
The DBC-P is a 96-item instrument completed by parents or other primary caregivers, used for 
the assessment of behavioral and emotional problems in people with developmental and 
intellectual disabilities. For each item that does describe the patient, number 2 would be circled 
if the item is very true or often true. Number 1 would be circled if the item is somewhat or 
sometimes true. If the item is not true, then 0 would be circled. If the patient is unable to behave 
in the way referred to in an item, 0 will be selected. All items for DPC-P are summed to 
generate a total score. DBC-P is measured at V2 and V5. 
The PedsQLTM generic core scale consists of 23 items related to physical functioning (eight 
items), emotional functioning (five items), social functioning (five items) and 
school/work/studies functioning (five items). All items are rated on a five-point scale (0 = 
Never to 4 = Almost Always) and are summed to generate a total score from 0 to 92.  
The ZBI assess the level of burden experienced by the principal caregiver of study participants. 
It is a 20-item questionnaire rated on a five-point scale (0 = Never to 4 = Nearly Always) and 
summed to generate a total score from 0 to 80. PedsQLTM is measured at V2 and V5. 
The EQ-5D-5L consists of 2 pages: the EQ-5D-5L descriptive system and the EQ Visual 
Analogue scale (EQ VAS). The descriptive system comprises 5 dimensions of health (mobility, 
self-care, usual activities, pain/discomfort, anxiety/depression). For each dimension, 
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of increasing levels of severity (no problems, slight problems, moderate problems, severe 
problems, and extreme problems). This will result in a 1-digit number which will express the 
level selected for that dimension: ‘1’ (no problems); ‘2’ (slight problems); ‘3’ (moderate 
problems); ‘4’ (severe problems) and ‘5’ (extreme problems). A unique EQ-5D health state is 
referred to by a 5-digit code. For example, state 11111 indicates no problems on any of the 5 
dimensions. These data will be converted into a weighted health state index by applying scores 
from EQ-5D value sets elicited from general population samples.  
In addition to the descriptive system, respondents also assess their health on the day of 
assessment on a visual analogue scale, ranging from 0 (worst imaginable health) to 100 (best 
imaginable health). EQ-5D-5L is measured at V2 and V5. 
The BMI Z-scores, also called BMI standard deviation scores, are measures of relative weight 
adjusted for child age and sex. BMI Z-score will be determined based on the age, sex, BMI, 
and the CDC reference standard3 for 4- to 17-year-old patients. BMI is measured at screening, 
V2, V3, V4 and V5.  BMI Z-score will be derived at those visits as well. 
13.3.2 Analysis of Additional Assessments 
13.3.2.1 
Analysis of the Cohort of Patients 8-65 Years of Age 
CgGIS-H/CGIS-H and CGI-S scores 
Analysis will be done using a mixed model repeated measures analysis (MMRM) on the 
change-from-baseline in CgGIS-H/CGIS-H and CGI-S scores. The model will include 
treatment, visit, age group (8-17 years, ≥18 years), BMI category, and treatment by visit 
interaction as fixed effects and baseline result as a covariate. An unstructured covariance will 
be used to model the correlation. If convergence issues arise, TOEPH structure will be used.  
Contrasts will be defined in the mixed model to test for treatment differences at different time 
points. The differences in least-squares means and corresponding 95% CIs will be presented. 
Analysis will be performed on the FAS set. 
DBC-P, PedsQLTM and ZBI scores 
Analysis will be done using an ANCOVA on the change-from-baseline in DBC-P, PedsQLTM 
and ZBI scores. The model will include treatment, age group (8-17 years, ≥18 years) and BMI 
category as fixed effects and baseline result as a covariate. The treatment differences in least-
squares means and corresponding 95% CIs will be presented. Analysis will be performed on 
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Glucose (Fasting/Postprandial), Insulin (Fasting/Postprandial), HOMA-IR and HbA1c 
The analysis will be done using a mixed model repeated measures analysis (MMRM) to model 
the change from baseline glucose/insulin/HOMA-IR at visits 3 and 5. The model will include 
treatment, time (before breakfast, and 30 min and 180 min post-start of breakfast), visit, age 
group (8-17 years, ≥18 years), BMI category, time-by-treatment, treatment-by-visit, time-by-
visit and time-by-treatment-by-visit interactions as fixed effects and corresponding timepoint 
baseline glucose/insulin/HOMA-IR as covariate. Unstructured covariance will be used to 
model the correlation. If convergence issues arise, TOEPH structure will be used.  Contrasts 
will be defined in the mixed model to test for treatment differences at the different time points. 
The differences in least-squares means and corresponding 95% CIs will be presented.  
For HbA1c, an ANCOVA on the change-from-baseline HbA1c at 3 months will be performed 
(with no imputation of missing values). The model will include treatment, age group (8-17 
years, ≥18 years) and BMI category as fixed effects and screening and V2 minus screening 
HbA1c as covariates. The treatment differences in least-squares means and corresponding 95% 
CIs will be presented. Moreover, HbA1c will be descriptively presented by visit and treatment 
in terms of n (%) in the following categories: <5.7%, 5.7-5.9%, 6.0-6.4% and >6.4%. A 
Cochran-Mantel-Hansel test will be performed at month 3 to test the treatment effect, 
controlling for age group. A shift table from worst post-dose HbA1c category from baseline 
will also be descriptively presented. 
All analyses will be performed on FAS. 
In addition, the same models described above on glucose, insulin, HOMA-IR and HbA1c will 
be performed on patients with EPG, and on patients with prediabetes/T2D.  
All analyses performed on insulin and HOMA-IR will not include patients who were on insulin 
(ATC3=A10A).  
Analyses performed on glucose will also be performed without patients who were on insulin. 
Lipids 
The analysis will be done using a mixed model repeated measures analysis (MMRM) to model 
the percentage change and change from baseline in total cholesterol, triglycerides, LDL-c and 
HDL-c at visits 3 and 5. The model will include treatment, visit, age group (8-17 years, ≥18 
years), BMI category, time-by-treatment, treatment-by-visit, time-by-visit and time-by-
treatment-by-visit interactions as fixed effects and corresponding timepoint screening and V2 
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covariance will be used to model the correlation. If convergence issues arise, TOEPH structure 
will be used.  Contrasts will be defined in the mixed model to test for treatment differences at 
the different time points. The differences in least-squares means and corresponding 95% CIs 
will be presented. The analyses will be done on all patients and on patients with dyslipidemia 
at baseline. All analyses will be performed on FAS. 
Lean body mass 
For the change from baseline in lean body mass, an ANCOVA on the change from baseline in 
lean body mass at 3 months will be performed (with no imputation of missing values). The 
model will include treatment and the stratification variable age group (age 8 to 17 years and 
age ≥18 years) as fixed effects and lean body mass at baseline as covariate. The treatment 
differences in least-squares means and corresponding 95% CIs will be presented. The analysis 
will be done on FAS. 
These statistical analyses will be done in overweight/obese patients, in not overweight/obese 
patients and on all patients. The analyses on all patients will include BMI category as 
covariate. 
Appetite-NRS 
This analysis will be done using an MMRM analysis to model the change from baseline 
Appetite-NRS score at visits 3 and 5. The model will include treatment, time (end of breakfast 
and 120 min. post-start of breakfast), visit, age group (8-17 years, ≥18 years), BMI category, 
time-by-treatment, 
treatment-by-visit, 
time-by-visit 
and 
time-by-treatment-by-visit 
interactions as fixed effects and corresponding timepoint baseline (V2) Appetite-NRS score as 
covariate. An unstructured covariance will be used to model the correlation. If convergence 
issues arise, TOEPH structure will be used.  Contrasts will be defined in the mixed model to 
test for treatment differences at the different time points. The differences in least-squares 
means and corresponding 95% CIs will be presented. Analysis will be performed on the FAS 
set. 
 
CgGIC-H/CGIC-H and CGI-I 
An MMRM analysis will be used to model the post dose CgGIC-H/CGIC-H and CGI-I at visits 
3, 4 and 5. The model will include treatment, visit, age group (8-17 years, ≥18 years) and BMI 
category as fixed effects, and treatment-by-visit interaction. Unstructured covariance will be 
used to model the correlation. If convergence issues arise, TOEPH structure will be used. 
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points. The differences in least-squares means and corresponding 95% CIs will be presented. 
Analysis will be performed on the FAS set. 
EQ-5D-5L and VAS 
Frequency count and percentage for each level of each dimension will be presented by 
treatment group and visit. Actual and change from baseline results in EQ-5D-5L derived utility 
index and VAS will be summarized by treatment group and visit, using descriptive statistics, 
including n, arithmetic mean, standard deviation (SD), 95% confidence interval to the mean, 
median, minimum, Q1, Q3, and maximum values. 
An ANCOVA will be performed on the change from baseline EQ-5D-5L utility index and 
VAS at 3-month. The model will include treatment, age group (8-17 years, ≥18 years), and 
BMI category as fixed effects and the baseline EQ-5D-5L utility index/visual analogue scale 
as covariate. The treatment differences in least-squares means and corresponding 95% CIs will 
be presented. 
Analysis will be performed on the FAS set. 
HQ-CT responders 
The analysis of HQ-CT responders at 3 months will be described in the Psychometric and 
Responder Analysis plan and results presented in the corresponding report, which will be 
included as an appendix to the Clinical Study Report. 
BMI and BMI Z-Score 
BMI will be analysed for patients 18-65 years of age.  
BMI Z-scores will be analysed for patients 8-17 years of age.  
The analysis will be done using an MMRM analysis to model the percentage change from 
baseline in BMI and the change from baseline in BMI at visits 3, 4 and 5. The model will 
include treatment, visit, age group (8-17 years, ≥18 years) and BMI category as fixed effects, 
treatment-by-visit interaction and corresponding timepoint screening and V2 minus screening 
BMI as covariates. Unstructured covariance will be used to model the correlation. If 
convergence issues arise, TOEPH structure will be used.  Contrasts will be defined in the mixed 
model to test for treatment differences at the different time points. The differences in least-
squares means and corresponding 95% CIs will be presented. 
For change from baseline in BMI Z-score, a similar model will be used, but without the 
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The number and proportion of patients with decreases of ≥5% vs. <5% and ≥10% vs. <10% in 
BMI will be presented descriptively by age group, visit and treatment. Cochran-Mantel-Hansel 
tests will be performed at each visit to test the treatment effect, controlling for age group. 
The change-from-baseline BMI z-score will be descriptively presented, per visit, as n (%) in 
the following categories: 
• 
>1.0 
• 
0.6 to 1.0 
• 
0.1 to 0.5 
• 
-0.5 to -0.0 
• 
-1.0 to -0.6 
• 
<-1.0 
As well as in the following categories for the BMI z-score at each visit: 
• 
>4.0 
• 
3.1 to 4.0 
• 
2.1 to 3.0 
• 
1.1 to 2.0 
• 
-1.0 to 1.0 
• 
< -1.0 
All analyses will be performed on FAS. 
13.3.2.2 
Analysis of the Cohort of Patients 4-7 Years of Age and All Age 
Groups Combined 
Descriptive summaries for the additional assessments will be presented for the 4- to 7-year of 
age-old cohort (See section 13.0). 
For CgGIS-H/CGIS-H and CGI-S, a sensitivity analysis including the 4- to 7-year-old cohort 
will be performed. The MMRM model will be used with treatment, age group (4-7, 8-17, ≥18 
years), BMI category, visit, and the interactions treatment-by-age group, treatment-by-visit and 
treatment-by-visit-by-age group as fixed effects and baseline result as a covariate. Contrasts 
will be defined to test for treatment differences for each level of age and visit. The differences 
in least-squares means and corresponding 95% CIs will be presented. Additionally, the 
treatment differences in least-squares means and corresponding 95% CIs will be presented by 
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For DBC-P, PedsQLTM, ZBI scores, an ANCOVA on the change from baseline in DBC-P, 
PedsQLTM and ZBI at 3 months will be performed (with no imputation of missing values) in 
the 4- to 65-year-old patients. The model will include treatment and the stratification variable 
age group (4-7, 8-17,  ≥18 years) and BMI category as fixed effect, the interaction treatment-
by-age group, and the corresponding value at baseline as a covariate. Contrasts will be defined 
to test for treatment differences for each level of age. The differences in least-squares means 
and corresponding 95% CIs will be presented. Additionally, the treatment differences in least-
squares means and corresponding 95% CIs will be presented for all age groups combined. 
For glucose (fasting), insulin (fasting) and HOMA-IR, the analysis will be done using an 
MMRM analysis to model the change from baseline glucose/insulin/HOMA-IR at visits 3 and 
5. The model will include treatment, age group (4-7, 8-17,  ≥18 years), BMI category and visit 
as fixed effects, the interactions treatment-by-age group, treatment-by-visit and treatment-by-
visit-by-age group and corresponding baseline glucose/insulin/HOMA-IR as covariate. 
Unstructured covariance will be used to model the correlation. If convergence issues arise, 
TOEPH structure will be used.  Contrasts will be defined to test for treatment differences for 
each level of age group and visit. The differences in least-squares means and corresponding 
95% CIs will be presented. Additionally, the treatment differences in least-squares means and 
corresponding 95% CIs will be presented by visit for all age groups combined. 
For HbA1c, an ANCOVA model similar to the one described for DBC-P, PedsQLTM and ZBI 
scores will be performed.  
In addition, the same models described above on glucose, insulin, HOMA-IR and HbA1c will 
be performed on patients with EPG, and on patients with prediabetes/T2D.  
All analyses performed on insulin and HOMA-IR will not include patients who were on insulin 
(ATC3=A10A) at V2. 
Analyses performed on glucose will also be performed without patients who were on insulin. 
For lipids, a similar model as described for glucose will be performed, but with screening and 
V2 minus screening scores as covariates. The analyses will be done on all patients and on 
patients with dyslipidemia at baseline. 
For lean body mass, a similar model as described in section 13.2.4 for total body fat mass will 
be performed. 
For CgGIC-H/CGIC-H and CGI-I, an MMRM analysis will be used to model the post dose 
CgGIC-H/CGIC-H and CGI-I at visits 3, 4 and 5. The model will include treatment, visit, age 


 
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group (4-7, 8-17, ≥18 years) and BMI category as fixed effects and the interactions treatment-
by-age group, treatment-by-visit and treatment-by-visit-by-age group. Unstructured 
covariance will be used to model the correlation. If convergence issues arise, TOEPH structure 
will be used. Contrasts will be defined to test for treatment differences for each level of age 
group and visit. The differences in least-squares means and corresponding 95% CIs will be 
presented. Additionally, the treatment differences in least-squares means and corresponding 
95% CIs will be presented by visit for all age groups combined. 
For EQ-5D-5L and VAS, descriptive statistics will be presented as described in section 
13.3.2.1, for age group 4-7 years and for all ages combined. Moreover, the ANCOVA will be 
performed on the change from baseline EQ-5D-5L utility index and VAS at 3 months. The 
model will include treatment, age group (4-7, 8-17, ≥18 years) as fixed effects, treatment-by-
age group interaction and the baseline EQ-5D-5L utility index/visual analogue scale as 
covariate. Contrasts will be defined to test for treatment differences for each level of age. The 
differences in least-squares means and corresponding 95% CIs will be presented. Additionally, 
the treatment differences in least-squares means and corresponding 95% CIs will be presented 
for all age groups combined. 
HQ-CT responder analyses, as described in section 13.3.2.1, will be repeated for the age group 
of 4- to 7-year-olds and for all age groups combined. 
For BMI Z-Score (calculated for patients 4-17 years of age), a similar MMRM model as 
described for glucose will be performed but with screening and V2 minus screening scores as 
covariates. The factor age group has two categories (4-7 years of age and 8-17 years of age).  
14.0 SAFETY OUTCOMES 
Safety analyses will be performed on the Safety Analysis Set. Individual patient data listings 
will be provided for all safety outcomes. The safety summaries will first be presented for the 
cohort of patients 8-65 years of age and will be repeated for the cohort of patients 4-7 years of 
age, as well as for all patients (4-65 years of age) combined.  
14.1 Adverse Events 
An adverse event (AE) is defined as any untoward medical occurrence associated with the use 
of a drug in humans, whether or not considered drug-related. 


 
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Only AEs during the Core Period are considered in this SAP.  An AE will be considered as 
part of the Core Period if its start date is earlier than or the same as the last contact date in the 
Core Period. 
All AEs, regardless of relationship to study drug, should be collected beginning from the time 
the subject signs the informed consent form until the last study visit or 30 days after the last 
dose of study drug, whichever is later. Any serious adverse event (SAE) judged by the 
Investigator to be related to the study treatment should be reported to the Sponsor regardless 
of the length of time that has passed since study completion. AEs in study patients include any 
change in the subject’s condition. This includes symptoms, physical findings, or clinical 
syndromes. All AEs and SAEs must be followed to resolution or, if resolution is unlikely, to 
stabilization. 
All AEs will be coded to body system and preferred term using the Medical Dictionary for 
Regulatory Activities (MedDRA) dictionary, version 22.0. 
AEs will be classified as treatment-emergent AEs (TEAEs) or pre-treatment AEs. A TEAE is 
defined as any event that started on the same day as or after the first dose of study drug. A pre-
treatment AE is defined as any event that started prior to the day of first dose of study drug (at 
or after informed consent date and prior to first dose date). An increase of intensity or 
frequency of a pre-treatment AE will also be considered as a TEAE. See Appendix 1 for 
handling of partial dates for AEs.  In the case where it is not possible to define an AE as 
treatment emergent or not, the AE will be classified by the worst case, i.e., treatment emergent. 
An AE with an unknown/unreported onset date will also be counted as a treatment-emergent 
AE. 
For general presentation of summary tables by System Organ Class (SOC) and Preferred Term 
(PT), a patient experiencing the same TEAE multiple times will be counted only once at each 
level of summarization. The summary tables will be sorted alphabetically by SOC and within 
each SOC the PT will be presented by decreasing order of total frequency. 
An overall summary table of AEs will be presented. The number and percentage of patients 
who experienced TEAEs, related TEAEs, treatment-emergent SAEs, related treatment-
emergent SAEs and TEAEs leading to treatment discontinuation will be presented. The number 
of events will also be presented. 
All AEs will be presented in a listing, by treatment group and patient number, and will include 
the following information: patient identifier, SOC, PT, reported term, severity, seriousness, 
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be provided for SAEs, TEAEs leading to study drug discontinuation, and TEAEs leading to 
death. 
14.1.1 All TEAEs 
The number and percentage of patients who experience TEAEs and the number of events will 
be presented by SOC and by PT within SOC for each treatment group. TEAEs will also be 
presented by PT in descending order. 
14.1.1.1 
Severity 
The number and percentage of patients who experience TEAEs will be presented by SOC, PT 
within SOC, and Severity (mild/moderate/severe) for each treatment group. If a patient 
experiences more than one TEAE with different severity within the same SOC/PT, only the 
worst case (worst severity) will be reported. A TEAE with an unknown severity will be 
considered as severe.  
14.1.1.2 
Relationship to Study Drug 
Related AEs are defined as any AEs assessed by the Investigator as “Definitely Related”, 
“Probably Related” or “Possibly Related”. AEs assessed as “Unlikely Related” or “Unrelated” 
will be defined as not related. Adverse events with an unknown relationship will be considered 
as related. 
The number and percentage of patients who experience TEAEs will be presented by System 
Organ Class (SOC), Preferred Term (PT) within SOC and Relationship for each treatment 
group. If a patient experiences more than one TEAE with different relationship within the same 
SOC/PT, only the TEAE with the greatest degree of relationship to study drug will be reported.  
14.1.2 TEAEs Leading to Discontinuation of Study Drug 
The number and percentage of patients who experience TEAEs leading to discontinuation of 
the study drug will be presented by SOC and by PT within SOC for each treatment group. 
14.1.3 Serious Adverse Events 
The number and percentage of patients who experience treatment-emergent SAEs will be 
presented by SOC and by PT within SOC for each treatment group. Treatment-emergent SAEs 
will also be summarized by Severity and Relationship, as described in sections 14.1.1.1 and 
14.1.1.2 above. 


 
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14.2 Deaths 
If any patients die during the study, the information will be presented in a data listing. 
14.3 Vital Signs and Height 
Descriptive statistics for each vital sign measurement and height will be presented by treatment 
group and available visit. Change from baseline to each available post-dose visit will also be 
summarized. These statistics will also be presented for all patients 8-17 years of age, patients 
8-17 years of age who are not on growth hormone (WHODrug ATC code=H01AC), and 
patients 8-17 years of age who are on growth hormone (WHODrug ATC code=H01AC). 
14.4 Physical Examination 
Physical Exam will be summarized by visit in terms of number and percentage of patients with 
normal/abnormal (not clinically significant)/abnormal (clinically significant) results per body 
system and treatment group.  
14.5 Bone Mineral Density 
Descriptive statistics for bone mineral density measurements will be presented by treatment 
group and available visit. Change from baseline to each available post-dose visit will also be 
summarized. 
14.6 12-Lead ECG 
Descriptive statistics for ECG measurements will be presented by treatment group and 
available visit and time point. Change from baseline to each available post-dose visit and time 
point will also be summarized. Overall assessment of ECG will also be summarized by visit 
and time point in terms of number and percentages of patients with normal/abnormal (not 
clinically significant)/abnormal (clinically significant) results. For quantitative measures 
reported in triplicate, the mean of the triplicates will be reported in the tables. For qualitative 
assessments reported in triplicate, the worst assessment will be reported in the tables. 
Qualitative assessment will be presented for both central and local readings, but quantitative 
results will be presented only from central readings. 
In addition, abnormal quantitative ECG measurements will be identified and summarized by 
visit, time point,  and treatment group in accordance with the following predefined criteria: 
• Absolute values for QT, QTc interval and QTcF will be classified as: 
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> 480 msec  
> 500 msec 
 
• Change from Baseline for QT interval, QTc interval and QTcF will be classified as: 
>30 msec increase from baseline 
>60 msec increase from baseline 
14.7 Safety Laboratory Parameters 
Results of all clinical laboratory assays (except urine pregnancy test) will be performed at 
central laboratories and will be included in the reporting of this study for Blood Chemistry, 
Coagulation, Hematology and Urinalysis. A list of laboratory assessments to be included in 
the outputs is included in Section 8.1.2 of the protocol (Version 1.2, dated 31 July 2019). 
Presentations will use both Système International (SI) units and conventional units where these 
differ. Quantitative laboratory measurements reported as “< X”, i.e., below the lower limit of 
quantification (BLQ), or “> X”, i.e., above the upper limit of quantification (ULQ), will be 
converted to X for the purpose of quantitative summaries, but will be presented as recorded, 
i.e., as “< X” or “> X” in the listings. 
Descriptive statistics for each clinical laboratory test will be presented by treatment group and 
available visit. Change from baseline to each available post-dose visit will also be summarized. 
According to the laboratory normal ranges, laboratory test results will be categorized as low 
(< lower normal limit), normal (within normal range), and high (> upper normal limit). Shift 
tables for selected laboratory values comparing the distributions of these three categories at 
baseline versus each available post-dose visit will be presented by treatment group. 
The selected laboratory parameters are: 
Chemistry 
• Serum creatinine (<LLN, normal, >ULN, missing, total) 
• AST, ALT (Low or Normal, >1 – 3x ULN, >3 – 5x ULN, >5x ULN, missing, total) 
• Total bilirubin (Low or Normal, >1 – 1.5x ULN, >1.5 – 2x ULN, >2x ULN, missing, 
total) 
• Alkaline phosphatase (Low or Normal, >1 – 1.5x ULN, >1.5 – 2x ULN, >2x ULN, 
Missing, total) 


 
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Listings of all clinical laboratory data for each patient will be provided with values outside the 
normal ranges indicated as well as the change from baseline. A listing of all abnormal 
laboratory findings will also be provided. 
The blood levels for AG, UAG and AG/UAG ratio will be presented descriptively by visit and 
treatment group. Change from baseline to each available post-dose visit will also be 
summarized. 
Results from anti-livoletide antibodies (ADA: Anti-Drug Antibodies) testing will also be 
summarized if data are available. 
14.8 IGF-1 Evaluation 
IGF-1 levels and change in IGF-1 levels will be summarized in patients 8-17 years of age who 
are: 
• On growth hormone (WHODrug ATC code=H01AC), and for which the growth 
hormone dose did not change between V1 and V5. 
• Not on growth hormone. 
• For all patients 8-17 years of age. 
15.0 Changes from Protocol 
• Some subgroup analyses were added: analysis on HbA1c and HOMA-IR in patients 
with elevated postprandial glucose (EPG), analyses on blood glucose, insulin, HOMA-
IR and HbA1c based on prediabetes/T2D patients (as per the information in the medical 
history), and analysis on lipids in patients with dyslipidemia at baseline. 
• IGF-1 evaluation was added in section 14.8 in order to investigate the effect of 
livoletide on IGF-1 levels in patients on growth hormone. 
16.0 REFERENCES 
1. McCandless SE, Yanovski JA, Miller J, Fu C, Bird LM, Salehi P, Chan CL, Stafford 
D, Abuzzahab MJ, Viskochil D, Barlow SE, Angulo M, Myers SE, Whitman BY, Styne 
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Diabetes Obes Metab. 2017 Dec;19(12):1751-1761. 


 
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2. ICH E9 (R1) addendum on estimands and sensitivity analysis in clinical trials to the 
guideline on statistical principles for clinical trials. Final version. 20 November 2019. 
ICH Expert Working Group. 
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Examination Statistics. May 2002. 
 
 
 


 
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Statistical Analysis Plan 
 
 
 
 
 
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Version: Final 1.1 
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APPENDIX 1 
Algorithm for Treatment Emergence of Adverse Events 
If part of the date/time of an AE is missing, but the existing parts allow determination of timing 
of AE onset/end relative to start and stop date of the study drug, then the AE will be classified 
(treatment-emergent or not treatment-emergent) per review of the existing parts of the 
date/time field. If timing of the AE onset/end relative to start and stop date of the study drug 
cannot be made, then the AE will be assumed to be a treatment-emergent adverse event 
(TEAE). 
Algorithm for Concomitant Medications 
For the purposes of determining whether a medication was taken during the treatment period 
of the study, any missing or partial start or stop dates for which a definitive determination 
cannot be made will result in that medication being assumed to be concomitant.