Phase 3, Randomized, Double-Blind, Placebo-Controlled, 8-week Clinical Study to Assess the Efficacy, Safety, and Tolerability, of Intranasal Carbetocin (LV-101) in Prader-Willi Syndrome (PWS) With Long Term Follow-Up (CARE-PWS)
Phase: PHASE3
Conditions: Prader-Willi Syndrome
Sponsor: Levo Therapeutics, Inc.

Levo Therapeutics, Inc. 
Intranasal Carbetocin (LV-101) 
Protocol LV-101-3-01 v3.0/Amendment 4.0 
19 June 2019 
Page 1 of 93 
CONFIDENTIAL 
TITLE PAGE 
Protocol Title: 
Phase 3, Randomized, Double-Blind, Placebo-Controlled, 8-week Clinical Study to Assess the 
Efficacy, Safety, and Tolerability, of Intranasal Carbetocin (LV-101) in Prader-Willi Syndrome 
(PWS) with Long Term Follow-Up: CARE-PWS 
Protocol Number: 
LV-101-3-01
Protocol Version Number:
3.0
Amendment Number:
4
Compound Number:
LV-101
Study Phase:
Phase 3
Indication:
Prader-Willi syndrome
Name and Address of Sponsor:
Levo Therapeutics, Inc.
5215 Old Orchard Road
Skokie, IL 60077
Investigational New Drug Number: 
Medical Monitor Name and Contact  
Davis C. Ryman, MD, PhD 
Vice President, Clinical Development 
Levo Therapeutics, Inc. 
5215 Old Orchard Road 
Skokie, IL 60077 
Approval Date: 
19 June 2019 
This document contains data and/or information that Levo Therapeutics, Inc. considers confidential business 
information. No part of this document may be disclosed to third parties without prior notice to 
 Levo Therapeutics, Inc. 
NCT03649477

 
Levo Therapeutics, Inc. 
Intranasal Carbetocin (LV-101) 
Protocol LV-101-3-01 v3.0/Amendment 4.0 
19 June 2019 
Page 2 of 93 
 
CONFIDENTIAL 
APPROVAL 
CONTENT 
SIGNATURES 
By signing this document, I certify that I have reviewed and approve the above document. 
 
 
 
Davis C. Ryman, MD, PhD 
Vice President, Clinical Development 
Levo Therapeutics, Inc. 
 
 
Signature 
Date 
 
 
 
Jay Cormier, JD, PhD 
Vice President, Regulatory Affairs 
Levo Therapeutics, Inc. 
 
 
Signature 
Date 
 
 
 
Sara Cotter 
Chief Executive Officer 
Levo Therapeutics, Inc. 
 
 
Signature 
Date 
Clinical Document Title: 
Phase 3, Randomized, Double-Blind, Placebo-Controlled, 8-week 
Clinical Study to Assess the Efficacy, Safety, and Tolerability, of 
Intranasal Carbetocin (LV-101) in Prader Willi Syndrome (PWS) 
with Long Term Follow-Up:  CARE-PWS 
Clinical Document Version No.:  3.0/Amendment 4.0 
Version Date: 
19 June 2019 
Type of Document: 
Clinical Study Protocol 

 
Levo Therapeutics, Inc. 
Intranasal Carbetocin (LV-101) 
Protocol LV-101-3-01 v3.0/Amendment 4.0 
19 June 2019 
Page 3 of 93 
 
CONFIDENTIAL 
 
 
Ronald S. Pimentel, PhD 
Senior Biostatistician 
Innovative Analytics 
Signature 
Date 
 
Amendment 4 
Overall Rationale for the Amendment: 
The purpose of this amendment is to add an exploratory endpoint to assess changes in social 
behaviors 
 and to add an 
extension period to the study, allowing subjects to continue to receive the investigational 
product, if receiving benefit.  Additionally, the previous country-specific protocols for Canada 
and Australia (see Document History table below) have been incorporated into one harmonized 
document to serve all three participating countries (Canada, Australia, and United States). 
DOCUMENT HISTORY 
Document 
Date 
Amendment 4/v3.0  
19 Jun 2019 
Amendment 3 (AUS)/v2.2 
15 Mar 2019 
Amendment 2 (CAN)/v2.1 
20 Dec 2018 
Amendment 1/v2.0 
17 Sep 2018 
Original Protocol 
8 Aug 2018 
 
Please see protocol Section 13 for a summary of changes from the previous version of the 
protocol. 
 
 

 
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Intranasal Carbetocin (LV-101) 
Protocol LV-101-3-01 v3.0/Amendment 4.0 
19 June 2019 
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CONFIDENTIAL 
INVESTIGATOR STATEMENT 
• I confirm agreement to conduct the study in compliance with the protocol. 
• I confirm that I have read the Investigator’s Brochure. 
• I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study. 
I agree to ensure that all associates, colleagues, and employees assisting in the conduct of 
the study understand their obligations and will comply with the study protocol. 
Mechanisms are in place to ensure that site staff receives the appropriate training and 
information throughout the study. 
 
 
Principal Investigator Name (Printed) 
 
Signature 
 
 
 
 
 
Date 
 
Site 

 
Levo Therapeutics, Inc. 
Intranasal Carbetocin (LV-101) 
Protocol LV-101-3-01 v3.0/Amendment 4.0 
19 June 2019 
Page 5 of 93 
 
CONFIDENTIAL 
Synopsis 
Protocol Title:  
Phase 3, Randomized, Double-Blind, Placebo-Controlled, 8-week Clinical Study to Assess the 
Efficacy, Safety, and Tolerability of Intranasal Carbetocin (LV-101) in Prader-Willi Syndrome 
(PWS) with Long Term Follow-Up: CARE-PWS 
Sponsor: 
Levo Therapeutics, Inc. 
Number of Sites: 
Approximately 20 sites 
Planned Study Period: 
Enrollment time: Approximately 12 months 
Study Duration: Approximately 66 weeks per subject 
Objectives and Endpoints: 
 
Objectives 
Endpoints 
Primary 
 
• To assess the efficacy of 9.6 mg intranasal 
carbetocin (LV-101) 3 times per day 
versus placebo on PWS behavioral 
symptoms 
• Change in Hyperphagia Questionnaire for 
Clinical Trials (HQ-CT) total score from 
baseline to Week 8 
• Change in Children's Yale Brown 
Obsessive Compulsive Scale (CY-BOCS) 
Severity Rating total score from baseline 
to Week 8 
Secondary 
 
• To assess the efficacy of 3.2 mg intranasal 
carbetocin (LV-101) 3 times per day 
versus placebo on PWS behavioral 
symptoms 
• Change in HQ-CT total score from 
baseline to Week 8 
• Change in CY-BOCS Severity Rating 
total score from baseline to Week 8 
 
 
 

 
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Intranasal Carbetocin (LV-101) 
Protocol LV-101-3-01 v3.0/Amendment 4.0 
19 June 2019 
Page 6 of 93 
 
CONFIDENTIAL 
Objectives and Endpoints (continued): 
Objectives 
Endpoints 
• To assess the treatment effect of intranasal 
carbetocin (LV-101) versus placebo on a 
broader range of maladaptive behavioral 
symptoms, first assessing 9.6 mg/dose 
intranasal carbetocin (LV-101) then 
assessing 3.2 mg/dose intranasal 
carbetocin (LV-101) 
• Change in PWS Anxiety and Distress 
Questionnaire (PADQ) score from 
baseline to Week 8 
• Clinical Global Impression – Change 
(CGI-C) score at Week 8  
• To further characterize the treatment 
effect of intranasal carbetocin (LV-101) 
versus placebo on hyperphagia-related 
behavioral symptoms (as assessed by the 
caregiver), looking specifically at factors 
that may be less impacted by 
environmental controls (ie, food security), 
first assessing 9.6 mg/dose intranasal 
carbetocin (LV-101) then assessing 
3.2 mg/dose intranasal carbetocin 
(LV-101) 
• Change in score of a subset of HQ-CT 
items (Questions 1,2,5,6,8,9) from 
baseline to Week 8 
• Change in score of Question 9 of HQ-CT 
from baseline to Week 8 
Safety 
 
• To assess the safety and tolerability of 
intranasal carbetocin (LV-101) 
• Frequency, severity, and seriousness of 
adverse events during the study 
• Clinically significant changes in physical 
examinations, laboratory assessments, 
electrocardiograms, and vital signs during 
the study 
 
 
 

 
Levo Therapeutics, Inc. 
Intranasal Carbetocin (LV-101) 
Protocol LV-101-3-01 v3.0/Amendment 4.0 
19 June 2019 
Page 7 of 93 
 
CONFIDENTIAL 
Objectives and Endpoints (continued): 
 
Objectives 
Endpoints 
 

 
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Intranasal Carbetocin (LV-101) 
Protocol LV-101-3-01 v3.0/Amendment 4.0 
19 June 2019 
Page 8 of 93 
 
CONFIDENTIAL 
Study Design: 
This is a Phase 3 study to assess the efficacy, safety, and tolerability of intranasal carbetocin 
(LV-101) in subjects with PWS. A randomized, double-blind, placebo-controlled study with an 
8-week placebo-controlled period will be conducted in subjects who are 7 to 18 years of age with 
genetically confirmed PWS, documented Nutritional Phase 3 criteria, screening and baseline 
HQ-CT total scores ≥13, and screening and baseline CY-BOCS total scores ≥9. Approximately 
175 subjects will be randomized and dosed (1:1:1) to 3.2 mg intranasal carbetocin (LV-101) or 
9.6 mg intranasal carbetocin (LV-101) or placebo, administered 3 times per day before meals. 
Safety and tolerability will be assessed by adverse events, laboratory assessments, 
electrocardiograms, vital signs, and physical examinations (including nasal assessments). 
Efficacy will be assessed using both caregiver-reported and clinician-reported outcome measures 
as described above. Clinical study materials (carbetocin and placebo vials) will be blinded at the 
study level, ensuring the blind of the subject, caregiver, and study site. 
After the 8-week placebo-controlled period, there will be a long-term follow-up period of 
56 weeks during which all subjects will receive active treatment with intranasal carbetocin 
(LV-101). At Week 8, subjects who were randomized to placebo in the placebo-controlled period 
will be randomized (1:1) to 9.6 mg intranasal carbetocin (LV-101) or 3.2 mg intranasal 
carbetocin (LV-101) 3 times per day before meals. 
The study will also include an extension period, wherein subjects receiving benefit during the 
long-term follow-up period will have an opportunity to continue receiving intranasal carbetocin 
 
 
 
 
Number of Participants: 
The study will enroll and dose approximately 175 subjects.
 
 
 
 
Major Inclusion/Exclusion Criteria: 
Inclusion Criteria 
1. Age: 7 to 18 years old at screening 
2. Genetically confirmed PWS 
3. PWS Nutritional Phase 3  
  

 
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Intranasal Carbetocin (LV-101) 
Protocol LV-101-3-01 v3.0/Amendment 4.0 
19 June 2019 
Page 9 of 93 
 
CONFIDENTIAL 
7. Parent or guardian is capable of giving signed informed consent. 
8. Pediatric subjects capable of assent have indicated their willingness to participate in the 
study. 
Exclusion Criteria 
1. Living in a group home 
2. New food-related interventions, including environment or dietary restrictions, within 
1 month of screening 
3. Active upper respiratory infection at screening or baseline 
4. Genetically diagnosed Schaaf-Yang syndrome or other genetic, hormonal, or 
chromosomal cognitive impairment 
5. Presence of any cardiovascular disorders, epilepsy, frequent migraines, or severe 
asthma 
6. History of or active psychotic symptoms 
7. History of venous thrombosis or pulmonary embolism or any other history consistent 
with thrombophilia or hypercoagulable state that is considered clinically significant 
by the Investigator 
8. Dose of any allowed chronic concomitant medications or supplements that have not 
been stable for ≥3 months prior to the study or is not expected to remain stable while 
participating in the study; adjustments in growth hormone dose ≤10% are not 
exclusionary 
9. Major surgery within 6 months of screening or planned during the study 
10. Nasal surgery within 6 months of screening or planned during the study 
11. More than 3 episodes of sinusitis in the 12 months prior to Screening Visit 
12. Other nasal diseases that may affect deposition of intranasal medication 
13. Known hypersensitivity to any component of investigational product  
14. Diagnosis of cancer within the past 5 years, except managed basal cell carcinoma or 
squamous cell carcinoma of the skin are not exclusionary 

 
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Protocol LV-101-3-01 v3.0/Amendment 4.0 
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CONFIDENTIAL 
15. Unwilling to abstain from nasal saline, other nasal irrigation, or other intranasal 
medications for 2 weeks prior to the Baseline visit and during the 8-week, 
placebo-controlled period of the study 
 
 
 
17. Use of weight loss medication in the 6 months prior to screening 
18. Use of oxytocin or carbetocin in the 3 months prior to screening 
19. Use of vasopressin in the 3 months prior to screening 
20. Participation in an interventional research study involving another investigational 
medication or device in the 6 months prior to screening or during the study 
21. History of (within the 2 years prior to screening) or current abuse of/dependence on 
alcohol or illicit drugs 
22. Unwilling to follow protocol-specified contraception requirements 
23. Positive urine pregnancy test for female subjects at screening or baseline (pregnancy 
testing will only be conducted for females of childbearing potential, as judged by the 
Investigator) 
 
25. Based on the judgment of the Investigator, is unsuitable for the study for any reason, 
including but not limited to unstable medical condition, inability to comply with the 
protocol, or other risk to subject or to the integrity of the study 
Intervention Groups and Duration: 
Subjects who meet inclusion and exclusion criteria will be randomized to receive blinded 
investigational product to be administered intranasally 3 times per day before meals (ie, 
breakfast, lunch, and dinner) for 8 weeks. 
Group Number 
Treatment 
1 
9.6 mg/dose intranasal carbetocin (LV-101) 
2 
3.2 mg/dose intranasal carbetocin (LV-101) 
3 
Placebo 
After the 8-week, double-blind, placebo-controlled period, there will be a long-term follow-up 
period of 56 weeks during which all subjects will receive active treatment with intranasal 
carbetocin (LV-101). At Week 8, subjects who were randomized to placebo in the 
placebo-controlled period will be randomized (1:1) to 9.6 mg intranasal carbetocin (LV-101) or 
3.2 mg intranasal carbetocin (LV-101) 3 times per day before meals. 
The study will also include an extension period, wherein subjects receiving benefit during the 
long-term follow-up period will have an opportunity to continue receiving intranasal carbetocin 
 

 
Levo Therapeutics, Inc. 
Intranasal Carbetocin (LV-101) 
Protocol LV-101-3-01 v3.0/Amendment 4.0 
19 June 2019 
Page 11 of 93 
 
CONFIDENTIAL 
 
 
 
Statistical Analysis: 
The efficacy endpoints will be evaluated using the Full Analysis Set (ie, subjects who were 
randomized, completed baseline assessments, and received at least 1 dose of investigational 
product) unless indicated otherwise. 
 
 
Adverse events, clinical laboratory assessments, electrocardiogram, vital signs, and physical 
examination findings will be summarized. 
A detailed description of the study statistical methods will be provided in the Statistical Analysis 
Plan. 
Data Monitoring Committee: 
A Data Monitoring Committee will be convened for the study. 

 
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Intranasal Carbetocin (LV-101) 
Protocol LV-101-3-01 v3.0/Amendment 4.0 
19 June 2019 
Page 12 of 93 
 
CONFIDENTIAL 
Schedule of Assessments 
The schedule of assessments for the placebo-controlled period is provided in Table 1, the 
schedule of assessments for the long-term follow-up period is provided in Table 2, and the 
schedule of assessments for the extension period is provided in Table 5. The schedule of 
assessments for questionnaires is provided in Table 3 for the placebo-controlled period and in 
Table 4 for the long-term follow-up period. 
 
 

 
Levo Therapeutics, Inc. 
Intranasal Carbetocin (LV-101) 
Protocol LV-101-3-01 v3.0/Amendment 4.0 
19 June 2019 
Page 13 of 93 
 
CONFIDENTIAL 
 
Table 1. 
Schedule of Assessments for the Placebo-Controlled Period 
Procedure 
Screening 
(14 to 28 days 
prior to 
Baseline) 
Baseline 
Site Visit 
Week 2 
Site Visit 
(±2 days) 
Week 8 
Site Visit 
(±2 days) 
Informed consent (ICF)/assent 
X 
 
 
 
Inclusion and exclusion criteria 
X 
X 
 
 
Demography 
X 
 
 
 
Medical history  
X 
X 
 
 
Physical examination 
X 
X 
X 
X 
Nasal assessment 
X 
X 
X 
X 
Vital signs (including weight) 
X 
X 
X 
X 
Height 
X 
 
 
 
Pregnancy testa 
X 
X 
X 
X 
Laboratory assessments (chemistry, 
hematology, coagulation, urinalysis) 
X 
X 
X 
X 
12-lead electrocardiogram 
X 
X 
 
X 
Randomization, if subject qualifies 
 
X 
 
Xb 
Training on investigational product 
administration 
 
X 
 
 
Study drug dosing 
 
X 
ongoing 
ongoing 
Adverse event review 
 
X 
X 
X 
Serious adverse event review 
X 
X 
X 
X 
Concomitant medication review 
(including all supplements) 
X 
X 
X 
X 
Caregiver training on clinical outcomes 
assessments 
X 
X 
 
 
Structured interview, including clinical 
outcomes assessments by caregiver and 
clinicianc 
X 
X 
X 
X 
Archive blood/plasma samplese 
 
X 
X 
X 
a Pregnancy testing will be conducted only for females of childbearing potential, as judged by the Investigator. 
b At Week 8, subjects who were randomized to placebo in the placebo-controlled period will be randomized (1:1) to 9.6 mg/dose 
intranasal carbetocin (LV-101) 3 times per day before meals or 3.2 mg/dose intranasal carbetocin (LV-101) 3 times per day 
before meals.  
 
 
 
 
 
 
 
 
 

 
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Protocol LV-101-3-01 v3.0/Amendment 4.0 
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CONFIDENTIAL 
Table 2. 
Schedule of Assessments for the Long-Term Follow-Up Period 
Procedure 
Week 10 
(±2 Days) 
Week 16 
(±1 Week) 
Week 28 
(±1 Week) 
Week 40 
(±1 Week) 
Week 52 
(±1 Week) 
Week 64 
(±1 Week) 
Early 
Term 
(if 
required) 
Physical examination 
X 
X 
X 
X 
X 
X 
X 
Nasal assessment 
X 
X 
X 
X 
X 
X 
X 
Vital signs (including 
weight) 
X 
X 
X 
X 
X 
X 
X 
Height 
 
 
 
 
 
X 
X 
Pregnancy testa 
X 
X 
X 
X 
X 
X 
X 
Laboratory assessments 
(chemistry, hematology, 
coagulation, urinalysis) 
X 
X 
X 
X 
X 
X 
X 
12-lead electrocardiogram 
 
X 
 
 
 
X 
X 
Study drug dosing 
ongoing 
ongoing 
ongoing 
ongoing 
ongoing 
X 
 
Extension period 
determination 
 
 
 
 
 
X 
 
Adverse event review 
X 
X 
X 
X 
X 
X 
X 
Serious adverse event 
review 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication 
review (including all 
supplements) 
X 
X 
X 
X 
X 
X 
X 
Structured interview, 
including clinical outcomes 
assessments by caregiver 
and clinicianb 
X 
X 
X 
X 
X 
X 
X 
Archive blood/plasma 
samplesd 
X 
X 
X 
X 
X 
X 
X 
 
a
 

 
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Protocol LV-101-3-01 v3.0/Amendment 4.0 
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CONFIDENTIAL 
 
Table 3. 
Schedule for the Questionnaires During the Placebo-Controlled Period 
Instrument 
Screening 
(14 to 28 
days prior to 
Baseline) 
Baseline 
Site Visit 
Week 2 
Site Visit 
(±2 days) 
Week 8 
Site Visit 
(±2 days) 
PWS Nutritional Phase Assessment 
X 
X 
 
 
Hyperphagia Questionnaire for Clinical Trials (HQ-CT) 
X  
X 
X 
X 
Children’s Yale Brown Obsessive Compulsive Scale 
(CY-BOCS)  
X 
X 
X 
X 
PWS Anxiety and Distress Questionnaire (PADQ) 
X 
X 
X 
X 
Clinical Global Impression 
Xa 
Xa 
Xa 
Xa 
 
PWS = Prader Willi Syndrome 
a Screening and baseline assessments will include only Severity. Post-baseline assessments will include Severity and Change. 
 
 

 
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Protocol LV-101-3-01 v3.0/Amendment 4.0 
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CONFIDENTIAL 
Table 4. 
Schedule for the Questionnaires During the Long-Term Follow-Up Period 
Instrument 
Week 10 
(±2 Days) 
Week 16 
(±1 Week) 
Week 28 
(±1 Week) 
Week 40 
(±1 Week) 
Week 52 
(±1 Week) 
Week 64 
(±1 Week) 
Early 
Term 
(if 
required) 
PWS Nutritional Phase 
Assessment 
 
 
 
 
 
X 
X 
Hyperphagia Questionnaire 
for Clinical Trials (HQ-CT) 
X 
X 
X 
X 
X 
X 
X 
Children’s Yale Brown 
Obsessive Compulsive Scale 
(CY-BOCS)  
X 
X 
X 
X 
X 
X 
X 
PWS Anxiety and Distress 
Questionnaire (PADQ) 
X 
X 
X 
X 
X 
X 
X 
Clinical Global Impression 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
 
PWS = Prader Willi Syndrome; Term = termination 
a Screening and baseline assessments will include only Severity. Post-baseline assessments will include Severity and Change. 
 
Table 5. 
Schedule of Assessments for the Extension Period 
Procedure 
Week 64b 
(±1 Week) 
Quarterly 
(±3 Weeks) 
End of Study (EOS)/Early 
Term (ET) 
Physical examination 
X 
 
X 
Nasal assessment 
X 
 
X 
Vital signs (including 
weight) 
X 
 
X 
Height 
X 
 
X 
Pregnancy testa 
X 
 
X 
Laboratory assessments 
(chemistry, hematology, 
coagulation, urinalysis) 
X 
 
X 
12-lead electrocardiogram 
X 
 
 
Study drug dosing 
ongoing 
ongoing 
 
Extension period ICF/assent 
X 
 
 

 
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Protocol LV-101-3-01 v3.0/Amendment 4.0 
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CONFIDENTIAL 
Procedure 
Week 64b 
(±1 Week) 
Quarterly 
(±3 Weeks) 
End of Study (EOS)/Early 
Term (ET) 
Extension period 
Enrollment 
X 
 
 
Safety Phone call 
 
X 
 
Adverse event review 
X 
X 
X 
Serious adverse event 
review 
X 
X 
X 
Concomitant medication 
review (including all 
supplements) 
X 
X 
X 
Structured interview, 
including clinical outcomes 
assessments by caregiver 
and clinician 
X 
 
 
Archive blood/plasma 
samples 
X 
 
 
 
a Pregnancy testing will be conducted only for females of childbearing potential, as judged by the Investigator. 
b Week 64 Visit of long-term follow-up period will serve as first visit of extension period 
 

 
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CONFIDENTIAL 
Table of Contents 
1. 
Introduction ...................................................................................................................22 
1.1. 
Background .....................................................................................................................23 
1.1.1. 
Nonclinical Information ..................................................................................................23 
1.1.2. 
Clinical Pharmacokinetics ..............................................................................................24 
1.1.3. 
Clinical Efficacy .............................................................................................................25 
1.1.4. 
Clinical Safety and Tolerability ......................................................................................25 
1.2. 
Study Rationale ...............................................................................................................26 
 
 
2. 
Objectives and Endpoints ............................................................................................28 
3. 
Study Design ..................................................................................................................30 
3.1. 
Overall Design ................................................................................................................30 
3.2. 
Scientific Rationale for Study Design ............................................................................30 
3.3. 
Justification for Dose ......................................................................................................31 
4. 
Study Population ...........................................................................................................32 
4.1. 
Inclusion Criteria ............................................................................................................32 
4.2. 
Exclusion Criteria ...........................................................................................................32 
4.3. 
Lifestyle Considerations .................................................................................................33 
5. 
Treatments .....................................................................................................................34 
5.1. 
Treatments Administered ................................................................................................34 
5.1.1. 
Investigational Product ...................................................................................................34 
5.1.2. 
Placebo ............................................................................................................................35 
5.1.3. 
Spray Pumps ...................................................................................................................35 
5.2. 
Preparation/Handling/Storage/Accountability ................................................................35 
5.2.1. 
First Dose of Investigational Product on Day 1 (Baseline Visit) ....................................35 
5.2.2. 
Subsequent Doses of Investigational Product .................................................................36 
5.3. 
Randomization and Blinding ..........................................................................................37 
5.4. 
Treatment Compliance ....................................................................................................37 
5.5. 
Concomitant Therapy .....................................................................................................38 
5.6. 
Prohibited Therapies .......................................................................................................38 
6. 
Discontinuation of Treatment and Withdrawal from Study ....................................40 
7. 
Study Assessments and Procedures.............................................................................41 
7.1. 
Efficacy and Pharmacokinetic Assessments ...................................................................41 
7.1.1. 
Hyperphagia Questionnaire for Clinical Trials (HQ-CT) ...............................................41 
7.1.2. 
Children’s Yale Brown Obsessive Compulsive Scale (CY-
BOCS) .............................................................................................................................41 
7.1.3. 
PWS Anxiety and Distress Questionnaire (PADQ) ........................................................42 
7.1.4. 
Clinical Global Impression – Severity (CGI-S) and Clinical 
Global Impression - Change (CGI-C) .............................................................................42 
 
 
 
 

 
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CONFIDENTIAL 
 
 
 
 
7.2. 
Safety Assessments .........................................................................................................44 
7.2.1. 
Medical History ..............................................................................................................44 
7.2.2. 
Physical Examinations ....................................................................................................44 
7.2.3. 
Nasal Assessment............................................................................................................45 
7.2.4. 
Vital Signs .......................................................................................................................45 
7.2.5. 
Electrocardiograms .........................................................................................................45 
7.2.6. 
Clinical Safety Laboratory Assessments ........................................................................45 
7.2.7. 
Extension Period Determination .....................................................................................46 
7.2.8. 
Safety Phone Call ............................................................................................................46 
7.3. 
Adverse Events and Serious Adverse Events .................................................................46 
7.3.1. 
Adverse Event Definition ...............................................................................................46 
7.3.2. 
Collection and Recording of Adverse Events .................................................................47 
7.3.3. 
Evaluation of Adverse Events .........................................................................................47 
7.3.4. 
Follow-up of Adverse Events and Serious Adverse Events ...........................................50 
7.3.5. 
Reporting Requirements for Serious Adverse Events ....................................................51 
7.3.6. 
Pregnancy ........................................................................................................................52 
7.4. 
Intranasal Spray Pump Incidents (Including Malfunctions) ...........................................52 
7.4.1. 
Time Period for Detecting Medical Device Incidents ....................................................53 
7.4.2. 
Follow-up of Medical Device Incidents .........................................................................53 
7.4.3. 
Prompt Reporting of Medical Device Incidents to the Sponsor .....................................54 
7.4.4. 
Regulatory Reporting Requirements for Medical Device 
Incidents ..........................................................................................................................54 
7.5. 
Treatment of Overdose ...................................................................................................54 
8. 
Statistical Considerations .............................................................................................55 
8.1. 
General Considerations ...................................................................................................55 
8.2. 
Sample Size Determination ............................................................................................55 
8.3. 
Analysis Sets ...................................................................................................................55 
8.4. 
Statistical Analyses .........................................................................................................55 
8.4.1. 
Efficacy Analyses ...........................................................................................................55 
8.4.2. 
Safety Analyses ...............................................................................................................57 
8.5. 
Interim Analyses .............................................................................................................58 
8.6. 
Data Monitoring Committee ...........................................................................................58 
9. 
Supporting Documentation and Operational Considerations ..................................59 
9.1. 
Data Handling .................................................................................................................59 
9.1.1. 
Source Data and Source Documents ...............................................................................59 
9.1.2. 
Electronic Case Report Form ..........................................................................................59 
9.1.3. 
Data Management ...........................................................................................................60 
9.2. 
Monitoring Procedures ...................................................................................................60 
9.2.1. 
Periodic Monitoring ........................................................................................................60 
9.2.2. 
Audit and Inspection .......................................................................................................60 
9.2.3. 
Confidentiality of Subject Data ......................................................................................60 

 
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9.3. 
Changes in the Conduct of the Study..............................................................................60 
9.3.1. 
Protocol Amendment ......................................................................................................60 
9.3.2. 
Deviations from the Protocol ..........................................................................................61 
9.3.3. 
Early Termination of the Study .......................................................................................61 
9.4. 
Publication Policy ...........................................................................................................61 
10. 
Regulatory and Ethical Considerations ......................................................................62 
10.1. 
Ethical Conduct of the Study ..........................................................................................62 
10.2. 
Informed Consent/Assent ...............................................................................................62 
10.3. 
Institutional Review Board/Ethics Committee (EC) ......................................................63 
10.4. 
Financial Disclosure .......................................................................................................63 
11. 
References ......................................................................................................................64 
12. 
Questionnaires ...............................................................................................................66 
12.1. 
Hyperphagia Questionnaire for Clinical Trials (HQ-CT) ...............................................66 
12.2. 
Children’s Yale Brown Obsessive Compulsive Scale (CY-
BOCS) .............................................................................................................................68 
 
 
12.4. 
Clinical Global Impression – Severity (CGI-S) and Clinical 
Global Impression   Change (CGI-C) .............................................................................74 
 
 
 
 
 
 
 
 
 
List of Tables 
Table 1. 
Schedule of Assessments for the Placebo-Controlled Period ........................... 13 
Table 2. 
Schedule of Assessments for the Long-Term Follow-Up Period ..................... 14 
Table 3. 
Schedule for the Questionnaires During the Placebo-Controlled Period .......... 15 
Table 4. 
Schedule for the Questionnaires During the Long-Term Follow-Up Period .... 16 
Table 5. 
Objectives and Endpoints .................................................................................. 28 
Table 6. 
Investigational Product ...................................................................................... 35 
 
 
Table 8. 
Definition of Serious Adverse Event ................................................................ 50 
 

 
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List of Abbreviations 
 
Abbreviation 
Definition 
CGI-C 
Clinical Global Impression – Change 
CGI-I 
Clinical Global Impression – Improvement 
CGI-S 
Clinical Global Impression – Severity 
CRO 
contract research organization 
CY-BOCS 
Children’s Yale-Brown Obsessive Compulsive Scale 
eCRF 
EC 
EOS 
ET 
electronic case report form 
ethics committee 
end of study 
early termination 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
hERG 
human-ether-a-go-go-related gene 
HPWSQ-R 
Hyperphagia in Prader-Willi Syndrome Questionnaire-Responsiveness 
HQ-CT 
ICF 
Hyperphagia Questionnaire for Clinical Trials 
informed consent form 
ICH 
International Conference on Harmonisation 
IRB 
Institutional Review Board 
IWRS 
Interactive Web Response System  
PADQ 
PWS Anxiety and Distress Questionnaire 
PWS 
 
Prader-Willi syndrome 
 
TEAE 
treatment-emergent adverse event 
WHO-DD 
World Health Organization drug dictionary 
Abbreviations that appear only in tables or figures are defined with the relevant tables and figures. 

 
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1. 
Introduction 
Prader-Willi syndrome (PWS) is a rare, serious, and life-threatening neurodevelopmental 
disorder that is caused by a defect on chromosome 15. In healthy individuals, several relevant 
genes in the 15q11-13 locus are expressed only from the paternal allele. The corresponding 
maternal allele is silenced (or “imprinted”), resulting in a complete reliance on the copy inherited 
from the father. When an individual lacks expression of these paternal genes, he/she develops 
PWS.   
Following birth, neonates with PWS show profound hypotonia and failure to thrive, often 
requiring the use of feeding tubes during the first year. Developmental delays and mild to 
moderate intellectual disability become apparent in the early years. Following the 
failure-to-thrive period, young children with PWS show rising levels of interest in food and 
food-related items. By 7 or 8 years of age, patients with PWS are typically fixated on food and 
become hyperphagic (suffering from an unrelenting hunger and excessive drive to eat). 
Hyperphagia in PWS is associated with the lack of a normal satiety response, in addition to a low 
basal metabolic rate. Despite adequate energy reserves, these patients are subjected to a false 
state of starvation. 
If left unsupervised, patients with hyperphagia are known to eat to the point of gastric rupture. 
Due to irregular swallowing and rapid food consumption, patients with PWS also have a greater 
propensity to choke while eating. Thus, hyperphagic patients require constant supervision. 
Patients with PWS also show high levels of anxiety, repetitive thinking/questioning, and 
obsessive and compulsive symptoms; these symptoms can be food-related as well as non-food 
related.   
Today, the only therapy currently approved by the United States Food and Drug Administration 
(FDA) to treat PWS is human growth hormone, which is used to increase linear growth. There 
are no therapies approved to treat the hallmark features of PWS, specifically hyperphagia, 
anxiety, and obsessive and compulsive symptoms. Prader-Willi syndrome is a uniquely complex, 
serious, and life-threatening syndrome with significant unmet medical need. 
While better known for its role in reproductive health and social-emotional behaviors, oxytocin 
is a potent anorectic hormone. Low doses of oxytocin injected intraperitoneally or 
intracerebroventricularly reduce food intake and the propensity to initiate feeding in wild-type 
rats in a dose-dependent manner [Arletti 1989]. Mice that are null for either oxytocin or the 
oxytocin receptor develop adult-onset obesity [Sabatier 2013]. Additionally, clinicians have 
identified an instructive group of patients that display a PWS-like phenotype and are deficient in 
oxytocin. These individuals have mutations in SIM1, a gene expressing a transcription factor 
important for developing oxytocin-producing neurons [Holder 2000]. In the corresponding 
SIM1-deficiency animal models, replacement of oxytocin rescues the hyperphagic phenotype. 
Postmortem studies in individuals with PWS have revealed significantly decreased numbers of 
oxytocin-secreting neurons in the paraventricular nucleus of the hypothalamus, suggesting that 
defects in the normal function of oxytocin may contribute to the severe hyperphagia and other 
behavioral symptoms characteristic of PWS [Swaab 1995]. In the aggregate, these data 

 
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demonstrate the anorexigenic properties of oxytocin and point to the potential utility of oxytocin 
and similar compounds in the treatment of PWS. 
Intranasal oxytocin has demonstrated excellent safety and tolerability in clinical studies of 
patients with PWS [Miller 2017, Tauber 2017, Kuppens 2016, Einfeld 2014, Tauber 2011]. No 
serious adverse events occurred in any of these studies. However, efficacy results with oxytocin 
have been mixed, and higher doses of oxytocin have been associated with temper tantrums. The 
off-target effects of oxytocin on vasopressin receptors may be limiting its therapeutic window. 
Specifically, excessive activation of the vasopressin V1a receptor, which is implicated in anxiety 
and depression, may exacerbate PWS behavioral symptoms. Additionally, excessive activation 
of the vasopressin V2 receptor by oxytocin may be associated with increased risks of antidiuresis 
and hyponatremia. 
Carbetocin, an 8 amino acid analog of oxytocin, is an oxytocin receptor agonist, which has 
similar potency to endogenous oxytocin, but possesses greater oxytocin receptor selectivity and 
longer duration of action [Engstrøm 1998]. Because carbetocin has greatly improved receptor 
selectivity compared to oxytocin, the potential side effects of oxytocin resulting from excessive 
activation of vasopressin receptors could be avoided. 
Carbetocin is approved in multiple countries outside the United States for the prevention of 
uterine atony and excessive bleeding following delivery of the infant by caesarean section under 
epidural or spinal anesthesia, for which it is administered as a 100 µg intravenous injection over 
1 minute. Since its approval in 1997, over 10 million women have been treated with carbetocin 
without significant safety concerns. 
The route of administration of carbetocin currently approved outside the United States is delivery 
by intravenous injection. However, this route of delivery would be challenging when dosing 
chronically 3 times per day before meals. In contrast, intranasal administration of carbetocin 
appears to be a suitable route of delivery for chronic use.   
1.1. 
Background 
A brief overview of nonclinical and clinical findings for carbetocin is provided below. Further 
details are provided in the Investigator’s Brochure. 
1.1.1. 
Nonclinical Information 
 
 
 
 
 
 
 

 
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1.1.2. 
Clinical Pharmacokinetics 
 
 
 
 
 
 

 
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1.1.3. 
Clinical Efficacy 
A prospective, randomized, double-blind, placebo-controlled, parallel-group, Phase 2 study 
(Study 000114) of 14 days of treatment with 9.6 mg/dose of intranasal carbetocin (LV-101) 
3 times per day before meals was conducted in 37 subjects with genetically confirmed PWS, 
between the ages of 10 to 18 years, and with documented Nutritional Phase 3 criteria. Intranasal 
carbetocin (LV-101) was well tolerated and improved hyperphagia and behavioral symptoms of 
PWS in this study [Dykens 2018]. The primary efficacy endpoint was the change in Hyperphagia 
in Prader-Willi Syndrome Questionnaire-Responsiveness (HPWSQ-R) total score from baseline 
to Day 15. The HPWSQ-R was completed by the caregiver. A decrease in the HPWSQ-R total 
score indicates improvement in hyperphagia. 
A statistically significantly greater decrease in the HPWSQ-R total score from baseline to 
Day 15 was observed for intranasal carbetocin (LV-101) compared to placebo. The least squares 
mean change from baseline to Day 15 for the intranasal carbetocin (LV-101) and placebo groups 
was -15.6 and -8.9, respectively (1-sided p=0.029). 
Treatment group differences for the behavior, drive, and severity domain scores of the 
HPWSQ-R were directionally consistent with the total score, indicating that the effect of 
intranasal carbetocin (LV-101) was evident across a range of hyperphagic symptoms. The 
remaining secondary efficacy results (Clinical Global Impression – Improvement [CGI-I]; 
clinician-rated version of the HPWSQ-R total and domain scores; Children’s Yale-Brown 
Obsessive Compulsive Scale [CY-BOCS]; and food domain of Reiss Profile) also indicated a 
statistically significant improvement of symptoms for the subjects in the intranasal carbetocin 
(LV-101) group when compared to the placebo group. 
1.1.4. 
Clinical Safety and Tolerability 
In the Phase 2 study (Study 000114) in subjects with PWS, there were no deaths, serious 
treatment-emergent adverse events (TEAEs), or severe TEAEs. One subject in the placebo group 
had an adverse event that led to withdrawal. A similar percentage of subjects in the intranasal 
carbetocin (LV-101) and placebo groups experienced at least 1 treatment-related TEAE (35.3% 
and 30.0%, respectively). 
Headache was the only TEAE reported for more than 2 subjects in the intranasal carbetocin 
(LV-101) group (5 [29.4%] subjects). In the placebo group, headache (6 [30.0%] subjects) and 

 
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medication error (2 [10.0%] subjects) were reported for 2 or more subjects. There were no 
clinically important treatment group differences (>1 subject) for any individual TEAE. 
 
 
 
 
 
1.2. 
Study Rationale 
There are no therapies currently approved by the FDA to treat the hallmark features of PWS, 
specifically hyperphagia, anxiety, and obsessive and compulsive symptoms. Intranasal oxytocin 
has demonstrated excellent safety and tolerability in clinical studies of patients with PWS 
[Miller 2017, Tauber 2017, Kuppens 2016, Einfeld 2014, Tauber 2011]. No serious adverse 
events occurred in any of these studies. However, efficacy results with oxytocin have been 
mixed, and higher doses have been associated with temper tantrums in some cases. The off-target 
vasopressin effects of oxytocin may be limiting its therapeutic window. Specifically, activation 
of the vasopressin V1a receptor, which is implicated in anxiety and depression, may exacerbate 
PWS behavioral symptoms. Additionally, oxytocin activation of the vasopressin V2 receptor is 
associated with increased risks of antidiuresis and hyponatremia. 
Carbetocin, an 8 amino acid analog of oxytocin, is an oxytocin receptor agonist which has 
similar potency to endogenous oxytocin, but possesses greater oxytocin receptor selectivity and 
longer duration of action [Engstrøm 1998]. Because carbetocin has greatly improved receptor 
selectivity compared to oxytocin itself, it may avoid the potential side effects of oxytocin related 
to off-target excessive activation of vasopressin receptors, creating a strong rationale for further 
development of carbetocin as a potential therapy for PWS.  
As further described in Section 1.1.3 and Section 1.1.4, a Phase 2 study in subjects with PWS 
demonstrated that 14 days of treatment with intranasal carbetocin (LV-101) was safe and well 
tolerated, and was associated with encouraging evidence of improvement in hyperphagia and 
obsessive-compulsive symptoms.   
For further evaluation of efficacy and safety across a range of dose levels, the current study will 
evaluate the safety and efficacy of 9.6 mg/dose and 3.2 mg/dose intranasal carbetocin (LV-101). 
This Phase 3 study is designed to assess the efficacy and safety of intranasal carbetocin (LV-101) 
through 8 weeks of double-blind treatment compared to placebo, and to further assess efficacy, 
safety, and tolerability during longer-term treatment with active carbetocin for 56 weeks. 
The study will also include an extension period, wherein subjects receiving benefit during the 
long-term follow-up period will have an opportunity to continue receiving intranasal carbetocin 
 

 
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2. 
Objectives and Endpoints 
Objectives and endpoints for the study are summarized in Table 5. 
Table 5. 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
• 
To assess the efficacy of 9.6 mg intranasal 
carbetocin (LV-101) 3 times per day versus 
placebo on PWS behavioral symptoms 
• 
Change in HQ-CT total score from baseline to 
Week 8 
• 
Change in CY-BOCS Severity Rating total 
score from baseline to Week 8 
Secondary 
 
• 
To assess the efficacy of 3.2 mg intranasal 
carbetocin (LV-101) 3 times per day versus 
placebo on PWS behavioral symptoms 
• 
Change in HQ-CT total score from baseline to 
Week 8 
• 
Change in CY-BOCS Severity Rating total 
score from baseline to Week 8 
• 
To assess the treatment effect of intranasal 
carbetocin (LV-101) versus placebo on a 
broader range of maladaptive behavioral 
symptoms, first assessing 9.6 mg/dose 
intranasal carbetocin (LV-101) then assessing 
3.2 mg/dose intranasal carbetocin (LV-101) 
• 
Change in PADQ score from baseline to 
Week 8 
• 
CGI-C score at Week 8  
• 
To further characterize the treatment effect of 
intranasal carbetocin (LV-101) versus placebo 
on hyperphagia-related behavioral symptoms 
(as assessed by the caregiver), looking 
specifically at factors that may be less 
impacted by environmental controls (ie, food 
security), first assessing 9.6 mg/dose 
intranasal carbetocin (LV-101) then assessing 
3.2 mg/dose intranasal carbetocin (LV-101) 
• 
Change in score of a subset of HQ-CT items 
(Questions 1,2,5,6,8,9) from baseline to 
Week 8 
• 
Change in score of Question 9 of HQ-CT 
from baseline to Week 8 
 
 
 

 
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Table 5. 
Objectives and Endpoints (Continued) 
Objectives 
Endpoints 
Safety 
 
• 
To assess the safety and tolerability of 
intranasal carbetocin (LV-101) 
• 
Frequency, severity, and seriousness of 
adverse events during the study 
• 
Clinically significant changes in physical 
examinations, laboratory assessments, 
electrocardiograms, and vital signs during the 
study 
CGI-C = Clinical Global Impression – Change; CGI-S = Clinical Global Impression – Severity; 
 
 CY-BOCS = Children's Yale Brown Obsessive Compulsive Scale; 
 
HQ-CT = Hyperphagia Questionnaire for Clinical Trials;
 PADQ = PWS Anxiety and 
Distress Questionnaire; PWS = Prader-Willi syndrome

 
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3. 
Study Design 
3.1. 
Overall Design 
This is a Phase 3 study to assess the efficacy, safety, and tolerability of intranasal carbetocin 
(LV-101) in subjects with PWS. A randomized, double-blind, placebo-controlled study with an 
8-week, placebo-controlled period will be conducted in subjects who are 7 to 18 years of age 
with genetically confirmed PWS, documented Nutritional Phase 3 criteria
 
Approximately 175 subjects will be randomized and dosed (1:1:1) to 3.2 mg intranasal 
carbetocin (LV-101) or 9.6 mg intranasal carbetocin (LV-101) or placebo, administered 3 times 
per day before meals. Safety and tolerability will be assessed by adverse events, laboratory 
assessments, electrocardiograms, vital signs, and physical examinations (including nasal 
assessments). Efficacy will be assessed using both caregiver-reported and clinician-reported 
outcome measures as described in Section 2. Clinical study materials (carbetocin and placebo 
vials) will be blinded at the study level, ensuring the blind of the subject, caregiver, and study 
site. 
After the 8-week double-blind, placebo-controlled period, there will be a long-term follow-up 
period of 56 weeks during which all subjects will receive active treatment with intranasal 
carbetocin (LV-101). At Week 8, subjects who were randomized to placebo in the 
placebo-controlled period will be randomized (1:1) to 9.6 mg intranasal carbetocin (LV-101) or 
3.2 mg intranasal carbetocin (LV-101) 3 times per day before meals. 
The study will also include an extension period, wherein subjects receiving benefit during the 
long-term follow-up period will have an opportunity to continue receiving intranasal carbetocin 
 
 
 
3.2. 
Scientific Rationale for Study Design 
A randomized, double-blind, placebo-controlled, parallel-group study design is considered the 
gold standard for clinical research because it can provide unbiased estimates of efficacy and 
safety.  
The inclusion criteria for age at enrollment (7 to 18 years of age), genetic confirmation of PWS, 
and PWS Nutritional Phase 3 assure that an appropriate population of hyperphagic subjects with 
PWS will be enrolled.
 
 
Exclusion criteria serve to assure subject safety and to 
exclude potentially confounding baseline factors. 
A duration of 8 weeks of double-blind treatment with intranasal carbetocin (LV-101) versus 
placebo, followed by longer-term follow-up of subjects receiving active intranasal carbetocin 

 
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(LV-101) for a total of 56 weeks, is considered sufficient to demonstrate the efficacy, safety, and 
tolerability of intranasal carbetocin (LV-101). 
3.3. 
Justification for Dose 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
In Phase 2 Study 000114, intranasal carbetocin (LV-101) 9.6 mg/dose was administered 3 times 
per day before meals for 14 days. A statistically significantly greater decrease in the HPWSQ-R 
total score from baseline to Day 15 was observed for intranasal carbetocin (LV-101) compared to 
placebo. Treatment group differences for the behavior, drive, and severity domain scores of the 
HPWSQ-R were directionally consistent with the total score, indicating that the effect of 
carbetocin was evident across a range of hyperphagic symptoms. The remaining secondary 
efficacy results (CGI-I; clinician-rated version of the HPWSQ-R total and domain scores; 
CY-BOCS; and food domain of Reiss Profile) also indicated a statistically significant 
improvement of symptoms for the subjects in the intranasal carbetocin (LV-101) group when 
compared to the placebo group. There were no deaths, serious TEAEs, or severe TEAEs in the 
study. There was some variability in drug exposure between subjects, as well as in the rate and 
extent of absorption within subjects from one dosing occasion to another. Neither subject’s body 
weight, age, nor sex appeared to influence the systemic disposition of carbetocin in the studied 
population. 
 
 
 
 
 
 

 
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4. 
Study Population 
4.1. 
Inclusion Criteria 
Eligible subjects must meet ALL of the following inclusion criteria: 
1. Age: 7 to 18 years old at screening 
2. Genetically confirmed PWS 
3. PWS Nutritional Phase 3  
7. Parent or guardian is capable of giving signed informed consent 
8. Pediatric subjects capable of assent have indicated their willingness to participate in the 
study. 
4.2. 
Exclusion Criteria  
Subjects who meet ANY of the following exclusion criteria are NOT eligible: 
1. Living in a group home 
2. New food-related interventions, including environment or dietary restrictions, within 
1 month of screening 
3. Active upper respiratory infection at screening or baseline 
4. Genetically diagnosed Schaaf-Yang syndrome or other genetic, hormonal, or 
chromosomal cognitive impairment 
5. Presence of any cardiovascular disorders, epilepsy, frequent migraines, or severe asthma 
 
 
 
8. Dose of any allowed chronic concomitant medications or supplements that have not been 
stable for ≥3 months prior to the study or is not expected to remain stable while 

 
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participating in the study; adjustments in growth hormone dose ≤10% are not 
exclusionary  
9. Major surgery within 6 months of screening or planned during the study 
10. Nasal surgery within 6 months of screening or planned during the study 
11. More than 3 episodes of sinusitis in the 12 months prior to Screening Visit 
12. Other nasal diseases that may affect deposition of intranasal medication 
13. Known hypersensitivity to any component of investigational product  
14. Diagnosis of cancer within the past 5 years, except managed basal cell carcinoma or 
squamous cell carcinoma of the skin are not exclusionary 
15. Unwilling to abstain from nasal saline, other nasal irrigation, or other intranasal 
medications for 2 weeks prior to the Baseline visit and during the 8-week, 
placebo-controlled period of the study 
 
 
17. Use of weight loss medication in the 6 months prior to screening 
18. Use of oxytocin or carbetocin in the 3 months prior to screening 
19. Use of vasopressin in the 3 months prior to screening 
20. Participation in an interventional research study involving another investigational 
medication or device in the 6 months prior to screening or during the study 
21. History of (within the 2 years prior to screening) or current abuse of/dependence on 
alcohol or illicit drugs 
22. Unwilling to follow protocol-specified contraception requirements 
23. Positive urine pregnancy test for female subjects at screening or baseline (pregnancy 
testing will only be conducted for females of childbearing potential, as judged by the 
Investigator) 
 
25. Based on the judgment of the Investigator, is unsuitable for the study for any reason, 
including but not limited to unstable medical condition, inability to comply with the 
protocol, or other risk to subject or to the integrity of the study 
4.3. 
Lifestyle Considerations 
There should be no new food-related interventions or restrictions from 1 month before screening 
until the end of the study.  
All medications the subject is receiving (including over-the-counter therapies such as vitamins, 
herbal, and nutritional supplements) during the study will be recorded in the medical source data 
and the electronic case report form (eCRF). 

 
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5. 
Treatments 
5.1. 
Treatments Administered 
Subjects who meet inclusion and exclusion criteria will be randomized to receive blinded 
investigational product to be administered intranasally 3 times per day before meals (ie, 
breakfast, lunch, and dinner) for 8 weeks. 
Group Number 
Treatment 
1 
9.6 mg/dose intranasal carbetocin (LV-101) 
2 
3.2 mg/dose intranasal carbetocin (LV-101) 
3 
Placebo 
After the 8-week, double-blind, placebo-controlled period, there will be a long-term follow-up 
period of 56 weeks during which all subjects will receive active treatment with intranasal 
carbetocin (LV-101). At Week 8, subjects who were randomized to placebo in the 
placebo-controlled period will be randomized (1:1) to 9.6 mg intranasal carbetocin (LV-101) or 
3.2 mg intranasal carbetocin (LV-101) administered 3 times per day before meals. 
Study drug should be administered with a minimum of 2.5 hours between each dose. 
The study will also include an extension period, wherein subjects receiving benefit during the 
long-term follow-up period will have an opportunity to continue receiving intranasal carbetocin 
 
 
 
 
5.1.1. 
Investigational Product 
Blinded investigational product, intranasal carbetocin or placebo, will be supplied 
 
Each vial will provide 3 doses of investigational product for use in a 24-hour period. 
 
 
 
 
 
The blinded doses of investigational product are described in Table 6. 

 
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Table 6. 
Investigational Product 
Blinded Dose Group  
9.6 mg/dose 
3.2 mg/dose 
Placebo 
 
 
 
 
 
 
 
 
 
 
5.1.2. 
Placebo 
Matching placebo will be provided for dosing during the 8-week placebo-controlled period. 
Placebo formulation will be identical to carbetocin formulations with the exceptions that 
carbetocin will not be present and the formulation will be adjusted to be isotonic (buffer will be 
increased to account for lack of carbetocin in the formulation). 
5.1.3. 
Spray Pumps 
Spray pumps 
 will also be provided for investigational product 
dosing. Instructions for spray pump use are provided in Section 5.2. 
Spray pump incidents, including those resulting from malfunctions of the spray pump, must be 
detected, documented, and reported by the Investigator throughout the study (see Section 7.4). 
5.2. 
Preparation/Handling/Storage/Accountability 
5.2.1. 
First Dose of Investigational Product on Day 1 (Baseline Visit) 
Starter packs (containing vials and spray pumps) will be provided to the study site. 
 
Spray pumps will be stored 
at room temperature. 
The first dose of investigational product will be dispensed by the study site for observed dosing 
on Day 1. The Investigator, or trained and qualified designee, will train the caregiver on the 
process of assembly, priming, dosing, and storage.  
 
 
   
Assembly: Just prior to dosing, the crimp seal and stopper must be removed from the 
 
vial. The spray pump must be snapped into place, using the vial holder provided to prevent 
spilling. The Investigator or designee can demonstrate assembly using the first vial and the 
caregiver can assemble the second vial. 
Priming: Once assembled, the spray pump must be primed by holding the vial upright and 
spraying it 
 into the bag provided or a plastic bag with a paper towel inside. After 
priming, close the bag and throw the bag away. The spray pump does not require additional 
priming before the second and third doses. 

 
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Dosing: Prior to dosing, the subject should blow his or her nose. Following priming, each dose of 
investigational product will be administered via 2 sprays into each nostril, administered 
alternating between nostrils (ie, left nostril, then right nostril, then left nostril, then right nostril), 
for a total of 4 sprays. 
Study drug should be administered before meals with a minimum of 2.5 hours between each 
dose. 
The Investigator, caregiver, or designee will record the dose of investigational product 
administered to the subject on a paper dosing diary. Caregivers will be trained that completed 
dosing diaries must be returned to the site staff at study visits. 
 
   
 
 The clinical site is required to maintain current drug 
storage, dispensation, and accountability logs throughout the study. 
5.2.2. 
Subsequent Doses of Investigational Product 
Subsequent supplies of investigational product may be shipped to the caregiver’s home or 
dispensed by the study site. 
 
 
   
 
 
 
 
 
 
 
 
 
Assembly:  Prior to dosing, the crimp seal and stopper must be removed from the 
 vial. 
The spray pump must be snapped into place, using the vial holder provided to prevent spilling.   
Priming:  Once assembled, the spray pump must be primed by holding the vial upright and 
spraying it 
 into the bag provided or a plastic bag with a paper towel inside. After 
priming, close the bag throw the bag away. The spray pump does not require additional priming 
before the second and third doses. 

 
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Dosing: Prior to dosing, the subject should blow his or her nose. Following priming, each dose of 
investigational product will be administered via 2 sprays into each nostril, administered 
alternating between nostrils (ie, left nostril, then right nostril, then left nostril, then right nostril), 
for a total of 4 sprays. 
Study drug should be administered before meals with a minimum of 2.5 hours between each 
dose. 
The caregiver or designee will record all doses of investigational product administered to the 
subject on a paper dosing diary. Completed dosing diaries must be returned to the site staff at 
study visits. 
 
 
 
5.3. 
Randomization and Blinding 
Investigational product will be labelled with a unit number, such that the investigational product 
is blinded at the study level, preserving the blind for the Investigator, caregiver, and subject.   
Subjects will be randomized (1:1:1) to 9.6 mg/dose intranasal carbetocin (LV-101), 3.2 mg/dose 
intranasal carbetocin (LV-101), or placebo. Subjects will be randomized on the day prior to 
Day 1 (first dose day) using the Interactive Web Response System (IWRS) according to 
instructions provided to the study site. The IWRS will provide a subject number and a unit 
number to be dispensed, maintaining the study blind for the Investigator, caregiver, and subject 
during the 8-week placebo-controlled period.   
Subjects randomized to placebo in the placebo-controlled period will be randomized (1:1) to 
intranasal carbetocin at the 9.6 mg/dose or 3.2 mg/dose in the long-term follow-up period. 
Subjects will be randomized at the Week 8 site visit using the IWRS according to instructions 
provided to the study site. Subjects randomized to 9.6 mg/dose or 3.2 mg/dose intranasal 
carbetocin (LV-101) in the placebo-controlled period will continue on that same dose throughout 
the long-term follow-up period. Thus, all subjects will receive intranasal carbetocin (LV-101) 
during the long-term follow-up period; however, the actual investigational product dose will 
remain blinded to the Investigator, caregiver, and subject throughout the long-term follow-up 
period. 
After all subjects complete Week 8, the database will be locked and treatment assignments will 
be unblinded for the purpose of analysis of study endpoints. Unblinded information will not be 
disclosed to investigators, caregivers, or patients during or following the Week 8 analysis. 
5.4. 
Treatment Compliance 
The investigational product will be dispensed only for subjects who meet the eligibility criteria 
and are randomized to a treatment in the study. The Investigator or his/her designated personnel 

 
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(eg, study nurse) will maintain a drug dispensing log detailing the dates and quantities of 
investigational products dispensed to, and used by, each subject, as well as the batch numbers.  
The caregiver or designee will record all doses of investigational product administered to the 
subject on a paper dosing diary. Completed dosing diaries must be returned to the site staff at 
study visits. 
Caregivers will be asked to return all used and unused investigational product containers to the 
study site or clinical study material management company. 
5.5. 
Concomitant Therapy 
At screening, use of any intranasal therapies (including nasal saline) during the preceding 
6 months, any use of oxytocin or carbetocin, and all medications (including over-the-counter 
therapies such as vitamins, herbal, and nutritional supplements) within the preceding 30 days 
will be recorded in the medical source data and the eCRF. 
Use of any concomitant therapy will be recorded in the medical source data and the eCRF, 
following the subject interview at each visit. Required information includes the drug name, 
strength, formulation, route of administration, dosing frequency, indication for use, start date, 
and stop date. Any changes (including new therapies) must be recorded at each subsequent study 
visit. 
Every effort should be made to maintain concomitant medications at stable doses, if clinically 
possible. During the placebo-controlled period, if any change of dose of concomitant medication 
is judged medically necessary in the opinion of the Investigator, this should be discussed with 
Sponsor’s medical monitor. During the active treatment period, changes to concomitant 
medications should be recorded in the medical source data and the eCRF.   
During the active treatment period, if nasal saline, other nasal irrigation, or other intranasal 
medications are resumed, these treatments should be administered 1 hour before or after 
intranasal carbetocin (LV-101) administration. For once-daily administration of these treatments, 
bedtime dosing is recommended to separate dosing of nasal saline, other nasal irrigation, or other 
intranasal medications from intranasal carbetocin (LV-101) administration. 
5.6. 
Prohibited Therapies 
Prohibited therapies per exclusion criteria include: 
• New food-related interventions, including environment or dietary restrictions, within 
1 month of screening 
• Unwilling to abstain from nasal saline, other nasal irrigation, or intranasal medications 
for 2 weeks prior to the Baseline visit and during the 8-week placebo-controlled period of 
the study 

 
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• Use of weight loss medication 
• Use of oxytocin or carbetocin in the 3 months prior to screening 
• Use of vasopressin 

 
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6. 
Discontinuation of Treatment and Withdrawal from Study 
Every subject has the right to refuse further participation in the study at any time and without 
providing reasons. A subject's participation will be terminated immediately upon his/her request. 
The Investigator should obtain and document the reason for the subject’s withdrawal, if possible. 
If, at the time of refusal, a dose of investigational product has already been administered, the 
subject will be advised to agree to follow-up safety investigations, which will include all 
procedures outlined for the early termination visit, before withdrawal from the study. All adverse 
events will be monitored to resolution, and the subject will be monitored for new adverse events 
that may be related to withdrawal or are otherwise clinically important. 
The subject may be withdrawn from the study at any time at the discretion of the Investigator; 
the reason should be discussed with the Sponsor prior to discontinuing the subject and fully 
documented in the site source documents. Should the subject, during the course of the study, 
develop conditions, which would have prevented his/her entry into the study according to the 
exclusion criteria, the Investigator should discuss with the Sponsor the risks and benefits to 
remaining in the study.  
Subjects who withdraw from the study will not be replaced. 
Lost to Follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and the caregiver is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the caregiver and reschedule the missed visit as soon as 
possible, counsel the caregiver on the importance of maintaining the assigned visit 
schedule, and ascertain whether or not the family wishes to and/or should continue in the 
study. 
• Before a subject is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the caregiver (where possible, 3 telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the subject’s 
medical record. 
• Should the caregiver continue to be unreachable, the subject will be considered to have 
withdrawn from the study. 

 
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7. 
Study Assessments and Procedures 
The schedule of assessments for the 8-week, placebo-controlled period is provided in Table 1,  
the schedule of assessments for the long-term follow-up period is provided in Table 2, and the 
schedule of assessments for the extension period is provided in Table 5. The schedule of 
assessments for questionnaires during the placebo-controlled period is provided in Table 3 and 
during the long-term follow period in Table 4. 
During the first 16 weeks of the study, the visit window is ±2 days, measured from the baseline 
visit (not as measured from the previous visit). From Week 16 until the end of the study, the visit 
window is ±1 week (±7 days) as measured from the baseline visit (not as measured from the 
previous visit).  During the extension period, the visit window is ±3 weeks (±21 days) as 
measured from the baseline visit (not as measured from the previous visit). 
7.1. 
Efficacy and Pharmacokinetic Assessments 
7.1.1. 
Hyperphagia Questionnaire for Clinical Trials (HQ-CT) 
The HQ-CT is a 9-item questionnaire designed to be completed by caregivers of subjects with 
PWS. It is a revision of the 11-item HPWSQ-R and has been further validated. The Foundation 
for Prader-Willi Research has made the HQ-CT available for clinical studies in PWS. As a result, 
it is the consensus instrument within the PWS research community. The HQ-CT is useful in 
measuring observable behaviors that stem from subjects’ excessive drive to eat, but it is limited 
in its ability to assess the other important psychiatric symptoms and distress experienced in 
PWS. Given that some questions may be more sensitive to environmental controls, subsets of 
questions will also be analyzed. 
The HQ-CT should be completed by the same caregiver throughout the study. A copy of the 
HQ-CT is provided in Section 12.1. 
7.1.2. 
Children’s Yale Brown Obsessive Compulsive Scale (CY-BOCS) 
The CY-BOCS is a validated, clinician rated, semi-structured inventory of specific symptoms 
and symptom severity in pediatric obsessive-compulsive disorder [Scahill 1997]. It is also 
commonly used in related disorders and performed well in the Phase 2 study of intranasal 
carbetocin (LV-101) in PWS. It includes 2 primary components: the symptom checklist and 
severity scale. The 10 severity items are summed to produce an obsessions severity score 
(5 items), compulsions severity score (5 items), and total score (sum of all 10 severity items). 
The symptom checklist contains common obsessions and compulsions seen in classical 
obsessive-compulsive disorder, but it also offers flexibility with the “other” write-in fields to 
enable the clinician to capture the unique obsessive and compulsive symptoms seen in PWS. 
The scale will be administered by the Investigator or a designated rater (trained and qualified). 
For a given subject, the same person should perform this task around the same time throughout 
the study. A copy of the CY-BOCS is provided in Section 12.2. 

 
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7.1.3. 
PWS Anxiety and Distress Questionnaire (PADQ) 
The PADQ is a caregiver-reported instrument designed to capture observable signs of anxiety 
and distress common among subjects with PWS. It has been developed in collaboration with a 
working group of 3 experienced researchers who are also parents of individuals with PWS.
 
 
The PADQ should be completed by the same caregiver throughout the study. 
 
 
7.1.4. 
Clinical Global Impression – Severity (CGI-S) and Clinical Global 
Impression - Change (CGI-C) 
The CGI-S is a rating scale which records a clinician’s global impression of the current severity 
of illness on a 7-point scale, using a range of responses from 1 (normal) to 7 (among the most 
severely ill patients). The CGI-C is a similar rating scale which records a clinician’s global 
impression of change in severity of illness, using a range of responses from 1 (very much 
improved) to 7 (very much worse) [Guy 1976]. 
The scale will be administered by the Investigator or a designated rater (trained and qualified). 
For a given subject, the same person should perform this task throughout the study. A copy of 
the CGI-S and CGI-C is provided in Section 12.4. 
 
 
 
 
 

 
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7.2. 
Safety Assessments 
7.2.1. 
Medical History 
A complete medical history will be obtained and documented. The history will include current 
conditions, and substance usage.  
7.2.2. 
Physical Examinations 
A complete physical examination including general appearance, head, eyes, ears, nose, and 
throat, neck, cardiovascular, thorax/lungs, breasts, abdomen, genitourinary, musculoskeletal, 
lymph nodes, skin, neurological and mental status examination, will be performed by the 
Investigator or a delegated Sub-Investigator (a medically licensed, qualified study team 
member). A thorough examination of the lower extremities for potential signs of deep venous 
thrombosis should be performed with each physical examination. 
At screening and baseline, each category will be evaluated as normal, abnormal not clinically 
significant, or abnormal clinically significant. Abnormal clinically significant changes from 
baseline will be recorded as adverse events. Tanner staging will be recorded at the Screening 
Visit and the Week 64 or Early Termination visit. 

 
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7.2.3. 
Nasal Assessment 
Grading will be conducted according to the following scale:  
Grade 0 = no abnormal findings  
Grade 1A = focal nasal mucosal inflammation, erythema, or hyperemia  
Grade 1B = superficial nasal mucosal erosion  
Grade 2 = moderate nasal mucosal erosion  
Grade 3 = nasal mucosal ulceration  
Grade 4 = nasal septum perforation 
After randomization, Grades 3 and 4 will be documented as adverse events. If deemed 
appropriate, additional follow-up examinations will be performed at the discretion of the 
Investigator. 
7.2.4. 
Vital Signs 
Pulse, respiration rate, and body temperature will be measured under resting conditions while the 
subject is seated. All blood pressure measurements should be made using the same arm while the 
subject is in the supine position after resting for 3 minutes, and prior to any scheduled blood 
draws. Weight should be measured consistently for each subject with regard to time of day and 
time since last meal. Subjects should wear a hospital gown or underwear for weight and height 
measurements. 
7.2.5. 
Electrocardiograms 
A 12-lead electrocardiogram will be obtained after at least a 5-minute rest in a supine position, 
and prior to any scheduled blood draws. The baseline electrocardiogram must be measured prior 
to administration of investigational product. 
7.2.6. 
Clinical Safety Laboratory Assessments 
Samples may be drawn non-fasting and can be repeated fasting if judged necessary by the 
Investigator. Specific instructions for blood collection will be provided in a central laboratory 
manual to the study site for the United States and Canada.  Clinical safety laboratory samples 
will be processed by each site’s local laboratory in Australia. 
Hematology, Coagulation, Serum Chemistry, and Urinalysis 
Hematology:  Platelet count, red blood cell count, hemoglobin, hematocrit, white blood cell 
count with differential (neutrophils, lymphocytes, monocytes, eosinophils, and basophils)  
Coagulation:  Prothrombin time, activated partial thromboplastin time, thrombin time, fibrinogen  
Note: d-dimer (during placebo-controlled period only) 

 
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Serum chemistry: Calcium, chloride, sodium, potassium, glucose, aspartate aminotransferase, 
alanine aminotransferase, total and direct bilirubin (reflex to direct), creatinine, blood urea 
nitrogen, total protein, alkaline phosphatase, and albumin  
Urinalysis: specific gravity, pH, glucose, protein, blood, urobilinogen by dipstick, and 
microscopic examination (if blood or protein is abnormal) 
The Investigator will review laboratory results for abnormalities and clinical significance. 
Pregnancy Testing 
Urine pregnancy tests (ß-human chorionic gonadotropin) will be performed on females of 
childbearing potential, as assessed by the Investigator or a Sub-Investigator. 
7.2.7. 
Extension Period Determination 
During the Week 64 Visit and following consultation with the subject and caregiver, the 
investigator will make a determination whether continuing on intranasal carbetocin (LV-101) 
would be in the subject’s best health interest by weighing the subject’s documented clinical  
benefit against any safety concerns.  Subjects for whom the investigator determines continuation 
would be appropriate will complete the extension period informed consent process and will be 
enrolled into the extension period to continue intranasal carbetocin (LV-101) treatment. 
7.2.8. 
Safety Phone Call 
Caregivers will be contacted by phone at least quarterly during the extension period.  Clinical 
sites will document discussion of any adverse events and/or serious adverse events, concomitant 
medications, and any missed doses. 
7.3. 
Adverse Events and Serious Adverse Events 
7.3.1. 
Adverse Event Definition 
An adverse event is any untoward medical occurrence in a subject participating in a clinical 
study.  
A TEAE is any adverse event that begins or worsens after the first administration of 
investigational product. An unexpected adverse event is an adverse event not identified in nature, 
severity, or frequency in the Sponsor’s current Investigator’s Brochure. 
Adverse events should be recorded as diagnoses, if available. If not, separate signs and 
symptoms should be recorded. One diagnosis/symptom should be entered per record. 
If a subject suffers from the same adverse event more than once and the subject recovers in 
between the events, the adverse events should be recorded separately. If an adverse event 

 
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changes in intensity, a worst-case approach should be used when recording the event (ie, record 
the highest intensity and the longest duration of the event. However, if an adverse event with 
onset before the first investigational product administration (ie, a pre-treatment adverse event) 
changes in intensity, this must be recorded as 2 separate events. The initial adverse event should 
be recorded with outcome “not yet recovered” and the date and time of outcome is when the 
intensity changed. The second adverse event should be recorded with date and time of onset 
when the intensity changed. 
Pre-existing conditions are not adverse events, but become adverse events if worsening occurs 
after investigational product administration during the study. Pre-existing clinically significant 
conditions diagnosed or observed as a result of the screening procedures must be recorded as 
medical history.  
A procedure is not an adverse event; the reason for conducting the procedure is. Hospitalization 
is not an adverse event; the reason for hospitalization is. Death is not an adverse event, but the 
cause of death is (an exception is sudden death of unknown cause, which is an adverse event). 
7.3.2. 
Collection and Recording of Adverse Events 
The Investigator must monitor the condition of the subject throughout the study from the time of 
obtaining informed consent until 30 days after the last dose of study medication.  
All serious adverse events will be collected from the signing of the informed consent form until 
30 days after the last dose of study medication. Other adverse events will be collected from the 
Baseline Visit until 30 days after the last dose of study medication. 
Investigators are not obligated to actively seek adverse events or serious adverse events after 
conclusion of study participation. However, if the Investigator learns of any serious adverse 
event, including a death, at any time after a participant has been discharged from the study, and 
the event is considered to be reasonably related to the study intervention or study participation, 
the Investigator must promptly notify the Sponsor. 
7.3.3. 
Evaluation of Adverse Events 
The Investigator must record all adverse events in the eCRF with information about: 
• Date and time of onset (time can be omitted, if applicable) 
• Severity/intensity 
• Causal relationship to investigational product 
• Action taken  
• Outcome 
• Date and time of outcome (time can be omitted, if applicable) 
• Seriousness 

 
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7.3.3.1. 
Date and Time of Onset 
The date of onset is the date when the first sign(s) or symptom(s) were first noted. If the adverse 
event is an abnormal clinically significant laboratory test or outcome of an examination, the 
onset date is the date the sample was taken or the examination was performed. 
7.3.3.2. 
Severity/Intensity 
The intensity of an adverse event must be classified using the following 3-point scale: 
Mild:  
Awareness of signs or symptoms, but no disruption of usual activity 
Moderate: 
Event sufficient to affect usual activity (disturbing) 
Severe: 
Inability to perform usual activities (unacceptable) 
7.3.3.3. 
Relationship to Investigational Product 
The possibility of whether the investigational product caused the adverse event must be 
classified as one of the following: 
Possibly related: There is evidence or argument to suggest a causal relationship between the 
investigational product and the adverse event. The adverse event may occur as part of the 
pharmacological action of the investigational product or may be unpredictable in its occurrence. 
Examples may include: 
• Adverse events that are uncommon but are known to be strongly associated with 
investigational product exposure 
• Adverse events that are not commonly associated with investigational product exposure, 
but the event occurs in association with other factors strongly suggesting causation, such 
as a strong temporal association or the event recurs on rechallenge 
Not related: There is no reasonable evidence or argument to suggest a causal relationship 
between the investigational product and the adverse event. Examples may include:  
• Known consequences of the underlying disease or condition under investigation 
• Adverse events common in the study population, which are also anticipated to occur with 
some frequency during the course of the study, regardless of investigational product 
exposure 
7.3.3.4. 
Action Taken 
The action taken with the investigational product in response to an adverse event must be 
classified as one of the following: 
• No change (medication schedule maintained or no action taken) 
• Study medication temporarily held 
• Study medication discontinued 

 
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Adverse events requiring therapy must be treated with recognized standards of medical care to 
protect the health and well-being of the subject. Appropriate resuscitation equipment and 
medicines must be available to ensure the best possible treatment of an emergency situation. 
If medication is administered to treat the adverse event, this medication should be recorded 
(Section 5.5). 
7.3.3.5. 
Outcome 
The outcome of an adverse event will be classified as one of the following: 
• Recovered (fully recovered or the condition has returned to the level observed at 
initiation of study treatment) 
• Recovered with sequelae (resulted in persistent or significant disability/incapacity) 
• Not yet recovered 
• Fatal 
7.3.3.6. 
Date and Time of Outcome 
The date that the subject recovered or died will be recorded. If the subject has not recovered or 
died at the time of study completion, the date of last adverse event follow-up will be recorded. 
7.3.3.7. 
Serious Adverse Events 
A serious adverse event is defined as an adverse event meeting any of the criteria in Table 8. 

 
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Table 8. 
Definition of Serious Adverse Event 
Serious Adverse Event Criteria 
Guidance 
Results in death 
Any event resulting in a fatal outcome must be fully documented and reported, 
including deaths occurring within 4 weeks after the treatment ends and 
irrespective of the causal relationship to the investigational product. The death 
of a subject enrolled in a study is per se not an event, but an outcome. 
Is life-threatening 
The term life-threatening refers to an adverse event in which the subject was at 
immediate risk of death at the time of the event. It does not refer to an event, 
which may have caused death if it were more severe. 
Requires in-patient hospitalization 
or prolongation of existing 
hospitalization 
The term hospitalization means that the subject was admitted to hospital or 
that existing hospitalization was extended as a result of an event. 
Hospitalization describes a period of at least 24 hours. Overnight stay for 
observation, stay at emergency room, or treatment on an outpatient basis do 
not constitute a hospitalization. However, medical judgment must always be 
exercised and when in doubt the case should be considered serious (ie, if case 
fulfills the criterion for a medically important event). Hospitalizations for 
administrative or social purposes do not constitute a serious adverse event. 
Hospital admissions and/or surgical operations planned before study inclusion 
are not considered adverse events, if the illness or disease existed before the 
subject was enrolled in the study, provided that the condition did not 
deteriorate during the study. 
Results in persistent or significant 
disability/incapacity 
Disability/incapacity means a substantial disruption of a person’s ability to 
conduct normal life functions. In doubt, the decision should be left to medical 
judgment by the Investigator. 
Is a congenital anomaly/birth defect Congenital anomaly/birth defect observed in any offspring of the subject 
conceived during treatment with the investigational product. 
Is an important medical event 
Important medical events are events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require intervention to prevent one of the other outcomes listed 
in the definition above. Examples of important medical events include adverse 
events that suggest a significant hazard, contraindication or precaution, 
occurrence of malignancy or development of drug dependency or drug abuse. 
Medical and scientific judgment should be exercised in deciding whether 
events qualify as medically important. 
Important medical events include any suspected transmission of an infectious 
agent via a medicinal product. Any organism virus or infectious particle 
(eg, prion protein transmitting transmissible spongiform encephalopathy), 
pathogenic or non-pathogenic, is considered an infectious agent. A 
transmission of an infectious agent may be suspected from clinical symptoms 
or laboratory findings indicating an infection in a subject exposed to a 
medicinal product. 
 
7.3.4. 
Follow-up of Adverse Events and Serious Adverse Events 
During the study, the Investigator must follow each adverse event until it is resolved or until the 
medical condition of the subject is stable. 

 
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After the subject’s last visit, the Investigator must follow any adverse event classified as serious 
or considered to have a reasonable possible causality to the investigational product until it is 
resolved or until the medical condition of the subject is stable. All such relevant follow-up 
information must be reported to the Sponsor. If the event is a chronic condition, the Investigator 
and the Sponsor may agree that further follow-up is not required. 
7.3.5. 
Reporting Requirements for Serious Adverse Events 
All serious adverse events must be reported immediately to Levo Therapeutics, Inc. as soon as it 
becomes known to the Investigator and not later than within 24 hours of their knowledge of the 
occurrence of a serious adverse event. 
The Investigator is responsible for submitting the completed Serious Adverse Event Report Form 
with the fullest possible details within 24 hours of his/her knowledge of the serious adverse 
event. The site will notify the Institutional Review Board (IRB)/Ethics Committee (EC) 
according to its guidelines. 
The Serious Adverse Event Report Form must be completed and submitted according to the 
instructions provided on the form, using the email address below: 
 
Demographic characteristics, adverse event information, medical history, and concomitant 
medication information are mandatory for initial reports and for follow-up reports if any relevant 
changes have been made since the initial report.  
Additional information relevant to the serious adverse event such as hospital records, results 
from investigations (eg, laboratory parameters, invasive procedures, scans and x rays, and 
autopsy results) can sent to Levo Therapeutics, Inc. using the contact details above. In any case 
this information must be supplied by the Investigator upon request from Levo Therapeutics, Inc. 
On any copies provided, such details such as subject’s name, address, and hospital identification 
number should be concealed and instead subject number should be provided. 
The Investigator will supply Levo Therapeutics, Inc. and the IRB with any additional requested 
information, such as results of post-mortem examinations and hospital records. 
Expedited Reporting by Levo Therapeutics, Inc. 
Levo Therapeutics, Inc. will report to the relevant parties within the stipulated timelines all 
adverse events that are serious, unexpected (according to the Investigator’s Brochure) and with a 
reasonable possible causality to the investigational product as judged by either the Investigator or 
Levo Therapeutics, Inc. Levo Therapeutics, Inc. will submit serious, unexpected, causally-related 
adverse event reports to Health Canada, the Australian Therapeutic Goods Administration 
(TGA), and the FDA within the timelines required by each regulatory authority.   
Serious adverse events will be considered reportable regardless of whether or not the 
investigational product was used in accordance with the provisions in the protocol and 
Investigator’s Brochure. 

 
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7.3.6. 
Pregnancy 
Because of the young age of study subjects and the nature of the syndrome, it is considered likely 
that the majority of study subjects will not be sexually active.  In the event that a subject is 
sexually active, the Investigator will confirm that the subject will, throughout participation in the 
study and at least 30 days following the last dose of study drug, either (1) remain abstinent from 
sexual intercourse or (2) use an effective barrier method or hormonal method of contraception.  
In such cases, the Investigator will discuss use of effective contraception with the subject and 
caregiver and the study medical monitor. 
If a pregnancy occurs, the investigational product should be immediately stopped and the 
Sponsor must be informed. The mother and the fetus must be followed at least until the birth of 
the infant and 1 month after the birth of the infant. In general, the follow-up will include the 
course, duration, and the outcome of the pregnancy, as well as neonatal health.  
While pregnancy itself is not considered to be an adverse event or serious adverse event, any 
pregnancy complication or elective termination of a pregnancy will be reported as an adverse 
event or serious adverse event. A spontaneous abortion is always considered to be a serious 
adverse event and will be reported as such. If a pregnancy results in an abnormal outcome (birth 
defect/congenital anomaly), this must be reported as a serious adverse event. 
The Investigator will attempt to collect pregnancy information on any male participant’s female 
partner who becomes pregnant while the male participant is in this study. After obtaining signed 
informed consent from the pregnant female partner, the female partner will also be followed to 
determine the outcome of the pregnancy. Any termination of the pregnancy will be reported 
regardless of fetal status (presence or absence of anomalies) or indication for the procedure. A 
spontaneous abortion is always considered to be a serious adverse event and will be reported as 
such. If the pregnancy results in an abnormal outcome (birth defect/congenital anomaly this must 
be reported as a serious adverse event. 
7.4. 
Intranasal Spray Pump Incidents (Including Malfunctions) 
Intranasal spray pumps are being provided for use in this study for administration of 
investigational product. In order to fulfill regulatory reporting obligations worldwide, the 
Investigator is responsible for the detection and documentation of events meeting the definitions 
of incident or malfunction that occur during the study with the spray pumps. 
A medical device incident is any malfunction or deterioration in the characteristics and/or 
performance of a device as well as any inadequacy in the labeling or the instructions for use 
which, directly or indirectly, might lead to or might have led to the death of a 
participant/user/other person or to a serious deterioration in his/her state of health. Not all 
incidents lead to death or serious deterioration in health. The nonoccurrence of such a result 
might have been due to other fortunate circumstances or to the intervention of health care 
personnel. 
A serious deterioration in state of health can include any of the following: 
• life-threatening illness 

 
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• permanent impairment of body function or permanent damage to body structure 
• condition necessitating medical or surgical intervention to prevent one of the above 
• fetal distress, fetal death, or any congenital abnormality or birth defect 
Examples of medical device incidents include: 
• A participant, user, caregiver, or healthcare professional is injured as a result of a medical 
device failure or its misuse. 
• A participant’s study intervention is interrupted or compromised by a medical device 
failure. 
• A misdiagnosis due to medical device failure leads to inappropriate treatment. 
• A participant’s health deteriorates due to medical device failure. 
NOTE: Incidents fulfilling the definition of an adverse event/serious adverse event will also 
follow the processes outlined in Section 7.3. 
7.4.1. 
Time Period for Detecting Medical Device Incidents 
Medical device incidents or malfunctions of the device that result in an incident will be detected, 
documented, and reported during all periods of the study in which the medical device is used. If 
the Investigator learns of any incident at any time after a participant has been discharged from 
the study, and such incident is considered reasonably related to a medical device provided for the 
study, the Investigator will promptly notify the Sponsor. 
Documenting of medical device incidents include: 
• Any medical device incident occurring during the study will be documented in the 
participant’s medical records, in accordance with the Investigator’s normal clinical 
practice, and on the appropriate form of the eCRF. 
• For incidents fulfilling the definition of an adverse event or a serious adverse event, the 
appropriate adverse event/serious adverse event eCRF page will be completed. 
• It is very important that the investigator provides his/her assessment of causality 
(relationship to the medical device provided by the Sponsor) at the time of the initial 
adverse event or serious adverse event report and describes any corrective or remedial 
actions taken to prevent recurrence of the incident. 
• A remedial action is any action other than routine maintenance or servicing of a medical 
device where such action is necessary to prevent recurrence of an incident. This includes 
any amendment to the device design to prevent recurrence. 
7.4.2. 
Follow-up of Medical Device Incidents 
All medical device incidents involving an adverse event will be followed and reported in the 
same manner as other adverse events (see Section 7.3). This applies to all participants, including 
those who discontinue study intervention. 

 
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The Investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality of the incident. New or 
updated information will be provided by the Investigator. 
7.4.3. 
Prompt Reporting of Medical Device Incidents to the Sponsor 
Medical device incidents will be reported to the Sponsor within 24 hours after the Investigator 
determines that the event meets the protocol definition of a medical device incident. Information 
regarding the medical device incident will be collected using a Spray Pump Incident Report 
Form. Medical device incidents should be emailed to:  
 
7.4.4. 
Regulatory Reporting Requirements for Medical Device Incidents 
The Investigator will promptly report all incidents occurring with any medical device provided 
for use in the study in order for the Sponsor to fulfill the legal responsibility to notify appropriate 
regulatory authorities and other entities about certain safety information relating to medical 
devices being used in clinical studies. The Investigator, or designee, will comply with the 
applicable local regulatory requirements relating to the reporting of medical device incidents to 
the IRB/EC. 
7.5. 
Treatment of Overdose 
No specific antidote is available. In the case of severe pharmacologic effects, intravenous 
infusion of hypotonic solutions should be avoided. 
The size of the vial provided in this study helps to limit risk of overdose. If an overdose occurs, 
contact the Investigator and/or study coordinator. The subject should be monitored for seizures 
and behavioral changes (eg, aggressive behavior, temper tantrums, or other behavioral change). 

 
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8. 
Statistical Considerations 
8.1. 
General Considerations 
The objectives of this study are to evaluate the efficacy, safety and tolerability of intranasal 
carbetocin (LV-101) administered 3 times per day before meals in patients with PWS. The 
detailed description of the study statistical methods is provided in the Statistical Analysis Plan. 
Any deviations from the Statistical Analysis Plan will be described and justified in the final 
clinical study report. 
8.2. 
Sample Size Determination 
The study will enroll and dose approximately 175 subjects. The study alpha is specified to be 2-
sided 0.05 with multiplicity control for the primary outcomes, thereby leading to study success if 
either outcome meets the statistical criterion. 
 
 
 
 
 
  
8.3. 
Analysis Sets 
The following analysis sets will be defined for the study: 
Intent-to-Treat Analysis Set: Subjects who were randomized. Subjects will be 
summarized in the treatment in which they were randomized. 
Safety Analysis Set: Subjects who received at least 1 dose of investigational product. 
Subjects will be summarized according to the treatment actually received. 
Full Analysis Set (FAS): Subjects in the Safety Analysis Set who completed baseline 
assessments. 
 
8.4. 
Statistical Analyses 
8.4.1. 
Efficacy Analyses 
The efficacy endpoints will be evaluated using the FAS dataset unless indicated otherwise. 
8.4.1.1. 
Primary Efficacy Endpoints 
The primary efficacy endpoints are the HQ-CT total score change from baseline to Week 8 and 
the CY-BOCS total score change from baseline to Week 8 for 9.6 mg intranasal carbetocin 
(LV-101) versus placebo. 

 
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8.4.1.2. 
Secondary Efficacy Endpoints 
The first secondary efficacy evaluation will be an analysis of the primary outcomes of HQ-CT 
total score change from baseline to Week 8 and the CY-BOCS total score change from baseline 
to Week 8 for the 3.2 mg intranasal carbetocin (low dose LV-101) group versus placebo, using 
the same model in Section 8.4.1.1. This first secondary efficacy assessment will act as a 
gatekeeper to subsequent secondary evaluations. If the first secondary evaluation fails, then 
subsequent secondary evaluations will become descriptive. 
A fixed-sequence test procedure will then be performed to assess the following additional 
secondary efficacy endpoints in the order specified (hierarchical alpha protection).  
• PADQ score change from baseline at Week 8 
• CGI-C score at Week 8 
• HQ-CT total score for Questions 1,2,5,6,8, and 9 change from baseline at Week 8 
• HQ-CT score for Question 9 change from baseline at Week 8. 
The previously described mixed model repeated measures analysis will be used when 
appropriate, with the comparison 9.6 mg intranasal carbetocin (LV-101) versus placebo tested 
first for each endpoint, followed by 3.2 mg intranasal carbetocin (LV-101) versus placebo. 

 
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8.4.2. 
Safety Analyses 
Safety parameters will be listed and summarized for the safety population. 
8.4.2.1. 
Adverse Events 
Directly observed and spontaneously reported adverse events will be recorded from time of 
signing informed consent (serious adverse events only) through 30 days after the last dose of 
study medication. Adverse events will be coded using Medical Dictionary for Regulatory 
Activities, in which each reported event is mapped to a preferred term and a system organ class. 
A TEAE will be defined as an adverse event that was not present prior to the first investigational 
product administration or was present but worsened in intensity or frequency. All reported 
adverse events will be listed. Both TEAEs and non-TEAEs will be summarized, overall and by 
severity and seriousness. For each system organ class and preferred term within system organ 
classes, the numbers and percentages of subjects reporting an event, as well as the number of 
events that were reported, will be calculated. Deaths, adverse events that resulted in study 
discontinuation, severe adverse events, and serious adverse events will be listed and summarized 
separately. 

 
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8.4.2.2. 
Concomitant Medications 
Prescription, over-the-counter, and alternative medication use will be coded to drug class, 
preferred drug name, and generic/trade drug name using the World Health Organization drug 
dictionary (WHO-DD). Medications that were stopped before the start of the investigational 
product administration procedure will be considered “pre-treatment.” All other medications will 
be considered “concomitant.” Medications that were started or ongoing at the time the 
investigational product administration procedure was started will be considered “baseline” (a 
subset of “concomitant”). All reported medications will be listed. Frequencies and percentages of 
subjects reporting or receiving each medication will be summarized by WHO-DD drug class and 
preferred name within drug class. Pre-treatment and baseline medications will be summarized 
separately. 
8.4.2.3. 
Clinical Laboratory Assessment 
Laboratory assessments will be listed and summarized by visit within each panel (eg, chemistry, 
hematology, etc.). Summary tables will show means of observed values and changes from 
baseline for observations on a continuous scale and distributions of categorical observations. 
Shift tables will be produced that will show frequencies and percentages of subjects who shift 
from one out-of-range category at baseline to another out-of-range category at subsequent visits. 
8.4.2.4. 
Physical Examination 
Observed status (eg, normal, abnormal) and changes from baseline in body system-specific 
physical examination findings will be summarized by visit within each body system. 
8.4.2.5. 
Electrocardiogram, Vital Signs, and Weight 
Observed values and changes from baseline will be summarized by visit. 
8.5. 
Interim Analyses 
After all subjects have completed the Week 8 visit (excluding drop-outs), the database will be 
locked and treatment assignments through Week 8 will be unblinded.   
8.6. 
Data Monitoring Committee 
A Data Monitoring Committee will be convened for the study. 

 
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9. 
Supporting Documentation and Operational Considerations 
9.1. 
Data Handling 
9.1.1. 
Source Data and Source Documents 
Source data are defined as all information in original records and certified copies of original 
records of clinical findings, observations, or other activities in a clinical study necessary for the 
reconstruction and evaluation of the study. Source data are contained in source documents 
(original records or certified copies). 
Source documents are defined as original documents, data, and records (eg, hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate copies, microfiches, photographic negatives, 
microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the 
laboratories and at medico-technical departments involved in the clinical study). 
The Investigator shall retain the source records for a period of 5 years following the date a 
marketing application is approved for the drug for the indication for which it is being 
investigated; or such longer period as required by regulatory authorities such as Health Canada, 
TGA, or FDA; or, if no application is to be filed or if the application is not approved for such 
indication, until 5 years after the investigation is discontinued and the FDA is notified. For each 
subject enrolled, the Investigator will indicate in the source record(s) that the subject participates 
in this study and will record all study-specific information including: any adverse event, any 
concomitant therapy, primary response variable(s), date of informed consent/assent, progress 
notes and status at treatment end, and the end of the subject’s participation. 
9.1.2. 
Electronic Case Report Form 
An eCRF system provided by an independent third-party CRO will be used for data capture. The 
system is validated and access at all levels to the system is granted/revoked following Levo 
Therapeutics, Inc. and vendor procedures, in accordance with regulatory and system 
requirements. 
Data should be entered into the system within 5 days after the subject has attended a visit or after 
the data become available, as applicable. Data entry of serious adverse events will be within 
24 hours of the Investigator becoming aware. Also, applicable data (demographics, medical 
history, concomitant medication, etc.) must be entered at the time of entry of serious adverse 
event. The Investigator will approve/authorize the eCRF entries for each subject with an 
electronic signature which is equivalent to a handwritten signature.  
Errors occurring in the eCRF will be corrected electronically. Such corrections/modifications 
will be automatically tracked by an audit trail detailing the date and time of the correction and 
the name of the person making the correction. 

 
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9.1.3. 
Data Management 
A data management plan will be created and issued before data collection begins and will 
describe all functions, processes, and specifications for data collection, cleaning, and validation. 
The data management plan will include who is authorized to enter the data, decisions about 
ownership of data, source data storage, which data will be transferred (including timing of 
transfers), the origin and destination of the data, and who will have access to the data at all times. 
9.2. 
Monitoring Procedures 
9.2.1. 
Periodic Monitoring 
The monitor will contact and visit the Investigator periodically to ensure adherence to the 
protocol, International Conference on Harmonisation (ICH)-Good Clinical Practice (GCP), 
standard operating procedures and applicable regulatory requirements, maintenance of 
study-related source records, and completeness, accuracy and verifiability of all eCRF entries 
compared to source data. The Investigator will cooperate with the monitor to ensure that any 
discrepancies that may be identified are resolved. A monitoring visit will take place shortly after 
the first subject is enrolled at the site. 
9.2.2. 
Audit and Inspection 
The Investigator will make all the study-related source data and records, both paper and 
electronic, available to a quality assurance auditor mandated by the Sponsor, or to domestic or 
foreign regulatory inspectors, after reasonable notice. The main purposes of an audit or 
inspection are to confirm that the rights and well-being of the subjects have been adequately 
protected, the protocol and standard operating procedures have been adhered to, and that all data 
relevant for the evaluation of the investigational product have been processed and reported in 
compliance with ICH-GCP and applicable regulatory requirements. 
The Investigator should notify the Sponsor without any delay of an announced inspection by a 
regulatory authority. 
9.2.3. 
Confidentiality of Subject Data 
The Investigator will ensure that the confidentiality of the subject data will be preserved. In the 
eCRF or any other documents submitted to the Sponsor, the subjects will not be identified by 
their names, but by an identification system consisting of their initials and assigned number in 
the study. Documents not intended for submission to the Sponsor (eg, the confidential subject 
identification code and the signed informed consent forms) will be maintained by the 
Investigator in strict confidence. 
9.3. 
Changes in the Conduct of the Study 
9.3.1. 
Protocol Amendment 
Any change to this protocol will be documented in a protocol amendment, issued by the Sponsor, 
and agreed upon by the Investigator and the Sponsor prior to its implementation.  

 
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Significant amendments will be submitted for consideration to the approving IRB(s)/ECs, and 
regulatory authorities, in accordance with local regulations.  
An approval is required for a significant amendment (eg, one that could affect the safety of the 
subjects, or that entails a significant change of the scope/design of the study). 
9.3.2. 
Deviations from the Protocol 
Deviations from the protocol are discouraged. If deviations do occur, the Investigator must 
inform the monitor, and the implications of the deviation must be reviewed and discussed. Any 
deviation must be documented with the visit number and type of violation. Any significant 
violations as determined by the Sponsor and/or IRB/EC must be reported to the IRB/EC. Any 
paper documentation must be kept in the Investigator’s file and in the Trial Master File. 
9.3.3. 
Early Termination of the Study 
Both the Investigator (with regard to his/her participation) and the Sponsor reserve the right to 
terminate the study at any time. Should this become necessary, the procedures will be agreed 
upon after consultation between the 2 parties. In terminating the study, the Sponsor and the 
Investigator will ensure that adequate consideration is given to the protection of the best interests 
of the subjects. Regulatory authorities and IRB(s)/ECs will be informed. 
9.4. 
Publication Policy 
Submission of data for journal publication and/or presentation of data to scientific audiences may 
be considered by Levo Therapeutics, Inc. The details of specific journal authorship will be 
discussed by the Investigator(s) and the Sponsor, with the final decision at the discretion of the 
Sponsor. If the Sponsor prepares a publication based on the results of this study, a copy of the 
manuscript will be provided to the Investigator(s) prior to publication. Investigator(s) may not 
separately publish data from the study without written authorization from the Sponsor. 
Any external CRO or laboratory involved in the conduct of this study has no publication rights 
regarding this study. 
 

 
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10. 
Regulatory and Ethical Considerations 
The responsibilities of Levo Therapeutics, Inc., the monitor, and the Investigator will be as 
defined in the ICH-GCP consolidated guideline, and applicable regulatory requirements in the 
country where the study takes place. The Investigator is responsible for adhering to the 
ICH-GCP responsibilities of Investigators, for dispensing the investigational product in 
accordance with the approved protocol or an approved amendment, and for its secure storage and 
safe handling throughout the study. 
10.1. 
Ethical Conduct of the Study 
This study will be conducted in accordance with the ethical principles that have their origins in 
the Declaration of Helsinki, in compliance with the approved protocol, ICH-GCP, and applicable 
regulatory requirements.  
The regulatory permission to perform the study will be obtained in accordance with applicable 
regulatory requirements. All ethical and regulatory approvals must be available before a subject 
is exposed to any study-related procedure, including screening tests for eligibility. 
10.2. 
Informed Consent/Assent 
The Investigator or designee will obtain a freely given written informed consent from each 
subject’s caregiver, and signed assent by the subject (if applicable) after an appropriate 
explanation of the aims, methods, anticipated benefits, potential hazards, and any other aspects 
of the study that are relevant to the subject's decision to participate. The consent form must be 
signed and dated by the caregiver before the subject is exposed to any study-related procedure, 
including screening tests for eligibility. The assent form (if applicable) must also be signed and 
dated by the subject before exposure to any study-related procedure, including screening tests for 
eligibility. 
The Investigator or designee will explain that the subjects are completely free to refuse to enter 
the study or to withdraw from it at any time, without any consequences for their further care and 
without the need to justify their decision. 
The subject and caregiver will receive a copy of any available subject information and signed 
consent/assent.  
The subject and caregiver should be informed if new information becomes available that may be 
relevant to their willingness to continue participation in the study. The communication of this 
information should be documented and a new version of the informed consent and subject 
information form be prepared, if applicable. 
Each subject and caregiver will be informed that the monitor, a quality assurance auditor 
mandated by the Sponsor, or a health authority inspector, in accordance with applicable 
regulatory requirements, may review his/her source records and data. Data protection will be 
handled in compliance with local and national regulations. 
For subjects not qualified to give their legal consent, the written informed consent must be 
obtained from the legal caregiver in accordance with national regulations. If such subjects can 

 
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understand the risks and benefits of the study, they should also be informed and provide their 
written consent. 
10.3. 
Institutional Review Board/Ethics Committee (EC) 
An IRB or EC will review the protocol and any amendments and advertisements used for 
recruitment. The IRB/EC will review the informed consent/assent form, their updates (if any), 
and any written materials given to the subjects. A list of all IRBs/ECs consulted and the name of 
the committee chair(s) will be included in the study report. 
At the end of the study the IRB/EC will be notified in writing. 
10.4. 
Financial Disclosure 
Investigators and Sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
 
 

 
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11. 
References 
First Author, Year 
Publication 
Arletti, 1989 
Arletti R, Benelli A, Bertolini A. Influence of oxytocin on feeding 
behavior in the rat. Peptides. 1989;10(1):89-93. 
Dykens, 2018 
Dykens EM, Miller J, Angulo M, et al. Intranasal carbetocin reduces 
hyperphagia in individuals with Prader-Willi syndrome. JCI Insight. 
2018 Jun 21;3(12). pii: 98333. doi: 10.1172/jci.insight.98333.  
Einfeld, 2014 
Einfeld SL, Smith E, McGregor IS, et al. A double-blind randomized 
controlled trial of oxytocin nasal spray in Prader Willi syndrome. Am J 
Med Genet A. 2014;164A(9):2232-9. 
Engstrøm, 1998 
Engstrøm T, Barth T, Melin P, Vilhardt H. Oxytocin receptor binding 
and uterotonic activity of carbetocin and its metabolites following 
enzymatic degradation. Eur J Pharmacol. 1998;355:203-10. 
Guy, 1976 
Guy W. Early Clinical Drug Evaluation (ECDEU) Assessment Manual 
for Psychopharmacology, revised. National Institute of Mental Health, 
Rockville, MD. 1976. 
Holder, 2000 
Holder JL Jr, Butte NF, Zinn AR. Profound obesity associated with a 
balanced translocation that disrupts the SIM1 gene. Hum Mol Genet. 
2000;9(1):101-8. 
Kuppens, 2016 
Kuppens RJ, Donze SH, Hokken-Koelega AC. Promising effects of 
oxytocin on social and food-related behaviour in young children with 
Prader–Willi syndrome: a randomized, double-blind, controlled 
crossover trial. Clin Endocrinol (Oxf). 2016;85(6):979-87. 
Miller, 2017 
Miller JL, Tamura R, Butler MG, et al. Oxytocin treatment in children 
with Prader-Willi syndrome: a double-blind, placebo-controlled, 
crossover study. Am J Med Genet A. 2017;173(5):1243-50. 
Sabatier, 2013 
Sabatier N, Leng G, Menzies J. Oxytocin, feeding, and satiety. Front 
Endocrinol (Lausanne). 2013;4:35. 
Scahill, 1997 
Scahill L, Riddle MA, McSwiggin-Hardin M, et al. Children’s 
Yale-Brown Obsessive Compulsive Scale: reliability and validity. 
J Am Acad Child Adolesc Psychiatry. 1997;36:844–52. 

 
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Swaab, 1995 
Swaab DF, Purba JS, Hofman MA. Alterations in the hypothalamic 
paraventricular nucleus and its oxytocin neurons (putative satiety cells) 
in Prader-Willi syndrome: a study of five cases. J Clin Endocrinol 
Metab. 1995;80(2):573-9. 
Tauber, 2017 
Tauber M, Boulanouar K, Diene G, et al. The use of oxytocin to 
improve feeding and social skills in infants with Prader-Willi 
syndrome. Pediatrics. 2017;139(2). 
Tauber, 2011 
Tauber M, Mantoulan C, Copet P, et al. Oxytocin may be useful to 
increase trust in others and decrease disruptive behaviours in patients 
with Prader-Willi syndrome: a randomised placebo-controlled trial in 
24 patients. Orphanet J Rare Dis. 2011;6:47. 
 

 
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12. 
Questionnaires 
12.1. 
Hyperphagia Questionnaire for Clinical Trials (HQ-CT) 
 
 
 

 
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12.2. 
Children’s Yale Brown Obsessive Compulsive Scale (CY-BOCS) 
 

 
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12.4. 
Clinical Global Impression – Severity (CGI-S) and Clinical Global 
Impression   Change (CGI-C) 
 
 
 

 
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Protocol LV-101-3-01 v3.0/Amendment 4.0 
19 June 2019 
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Intranasal Carbetocin (LV-101) 
Protocol LV-101-3-01 v3.0/Amendment 4.0 
19 June 2019 
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Levo Therapeutics, Inc. 
Intranasal Carbetocin (LV-101) 
Protocol LV-101-3-01 v3.0/Amendment 4.0 
19 June 2019 
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Levo Therapeutics, Inc. 
Intranasal Carbetocin (LV-101) 
Protocol LV-101-3-01 v3.0/Amendment 4.0 
19 June 2019 
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Intranasal Carbetocin (LV-101) 
Protocol LV-101-3-01 v3.0/Amendment 4.0 
19 June 2019 
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Levo Therapeutics, Inc. 
Intranasal Carbetocin (LV-101) 
Protocol LV-101-3-01 v3.0/Amendment 4.0 
19 June 2019 
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Levo Therapeutics, Inc. 
Intranasal Carbetocin (LV-101) 
Protocol LV-101-3-01 v3.0/Amendment 4.0 
19 June 2019 
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Levo Therapeutics, Inc. 
Intranasal Carbetocin (LV-101) 
Protocol LV-101-3-01 v3.0/Amendment 4.0 
19 June 2019 
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Levo Therapeutics, Inc. 
Intranasal Carbetocin (LV-101) 
Protocol LV-101-3-01 v3.0/Amendment 4.0 
19 June 2019 
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Intranasal Carbetocin (LV-101) 
Protocol LV-101-3-01 v3.0/Amendment 4.0 
19 June 2019 
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Intranasal Carbetocin (LV-101) 
Protocol LV-101-3-01 v3.0/Amendment 4.0 
19 June 2019 
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Levo Therapeutics, Inc. 
Intranasal Carbetocin (LV-101) 
Protocol LV-101-3-01 v3.0/Amendment 4.0 
19 June 2019 
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Levo Therapeutics, Inc. 
Intranasal Carbetocin (LV-101) 
Protocol LV-101-3-01 v3.0/Amendment 4.0 
19 June 2019 
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Levo Therapeutics, Inc. 
Intranasal Carbetocin (LV-101) 
Protocol LV-101-3-01 v3.0/Amendment 4.0 
19 June 2019 
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Levo Therapeutics, Inc. 
Intranasal Carbetocin (LV-101) 
Protocol LV-101-3-01 v3.0/Amendment 4.0 
19 June 2019 
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Levo Therapeutics, Inc. 
Intranasal Carbetocin (LV-101) 
Protocol LV-101-3-01 v3.0/Amendment 4.0 
19 June 2019 
Page 93 of 93 
CONFIDENTIAL