Clinical trial NCT03649477
Conditions: Prader-Willi Syndrome
Keywords: PWS Prader-Willi syndrome carbetocin
Sponsor: Levo Therapeutics, Inc.
Start date: 2018-11-20; Completion date: 2022-07-09
Enrollment: 130 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This Phase 3 study is designed to test the effectiveness of intranasal carbetocin (LV-101) in participants with Prader-Willi syndrome (PWS). Carbetocin is an oxytocin analog (a man-made chemical that is like oxytocin). This study will also evaluate the safety and tolerability of LV-101.

Detailed description:
This is a Phase 3 randomized, double-blind study with an 8-week, placebo-controlled period designed to test the effectiveness, safety, and tolerability of LV-101 in participants with PWS.

Effectiveness will be measured using both caregiver-reported and clinician-reported measures of hyperphagia (extreme hunger), obsessive and compulsive behaviors, and anxiety. Safety and tolerability will be measured by adverse events, laboratory tests, and physical exams.

After the 8-week placebo-controlled period, there will be a long-term follow-up period of 56 weeks and an optional extension period after study week 64 during which all participants will receive active treatment with LV-101. At Week 8, participants who were randomized to placebo in the placebo-controlled period will be randomized to one of the two LV-101 doses, administered three times per day before meals.

Arms: arm 1: matched placebo during first 8-weeks; prospectively randomized 1:1 to either one of the two doses of carbetocin during 56-week follow-up and optional extension periods arm 2: 3.2 mg of LV-101 during first 8-weeks; remain on same dose during 56-week follow-up and optional extension periods arm 3: 9.6 mg of LV-101 during first 8-weeks; remain on same dose during 56-week follow-up and optional extension periods
Interventions: intervention 1: 3.2 mg intranasal carbetocin intervention 2: 9.6 mg intranasal carbetocin intervention 3: placebo
Intervention descriptions: intervention 1: three times per day with meals intervention 2: three times per day with meals intervention 3: three times per day with meals

Protocol documents:
Prot_000.pdf: 
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. 
 
 


 
Levo Therapeutics, Inc. 
Intranasal Carbetocin (LV-101) 
Protocol LV-101-3-01 v3.0/Amendment 4.0 
19 June 2019 
Page 4 of 93 
 
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 
 
 
 


 
Levo Therapeutics, Inc. 
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 
 


 
Levo Therapeutics, Inc. 
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  
  


 
Levo Therapeutics, Inc. 
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 


 
Levo Therapeutics, Inc. 
Intranasal Carbetocin (LV-101) 
Protocol LV-101-3-01 v3.0/Amendment 4.0 
19 June 2019 
Page 10 of 93 
 
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. 


 
Levo Therapeutics, Inc. 
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.  
 
 
 
 
 
 
 
 
 


 
Levo Therapeutics, Inc. 
Intranasal Carbetocin (LV-101) 
Protocol LV-101-3-01 v3.0/Amendment 4.0 
19 June 2019 
Page 14 of 93 
 
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
 


 
Levo Therapeutics, Inc. 
Intranasal Carbetocin (LV-101) 
Protocol LV-101-3-01 v3.0/Amendment 4.0 
19 June 2019 
Page 15 of 93 
 
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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Intranasal Carbetocin (LV-101) 
Protocol LV-101-3-01 v3.0/Amendment 4.0 
19 June 2019 
Page 16 of 93 
 
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 
 
 


 
Levo Therapeutics, Inc. 
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Protocol LV-101-3-01 v3.0/Amendment 4.0 
19 June 2019 
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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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Protocol LV-101-3-01 v3.0/Amendment 4.0 
19 June 2019 
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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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Protocol LV-101-3-01 v3.0/Amendment 4.0 
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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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SAP_001.pdf: 
Statistical Analysis Plan 
v. 1.1
Levo Therapeutics, Inc.  Protocol LV-101-3-01 
08 July 2020 
STATISTICAL ANALYSIS PLAN 
Protocol Number 
LV-101-3-01
Trial Phase  
Phase 3 
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 Version 
Version 3.0, Amendment 4, 19 June 2019 
Compound Name or Number 
Intranasal Carbetocin (LV-101) 
Indication 
Prader-Willi Syndrome 
Sponsor 
Levo Therapeutics, Inc. 
5215 Old Orchard Road 
Skokie, IL 60077 USA 
Document Type 
Statistical Analysis Plan 
Prepared by 
Brent A. Blumenstein, PhD 
Trial Architecture Consulting 
Version Number (Release Date) 
v. 1.1 (08 July 2020)
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


Statistical Analysis Plan 
 
v. 1.1 
Levo Therapeutics, Inc.  Protocol LV-101-3-01 
 
08 July 2020 
 
CONFIDENTIAL 
Page 2 of 62 
 
 
STATISTICAL ANALYSIS PLAN 
 
v. 1.1 (08 July 2020) 
 
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 
 
 
AUTHOR 
 
 
 
 
 
Brent A. Blumenstein, PhD 
Lead Biostatistician 
Trial Architecture Consulting 
 
Date 
 
 
APPROVAL SIGNATURES 
 
 
 
 
 
Davis C. Ryman, MD, PhD 
Vice President, Clinical Development 
Levo Therapeutics, Inc. 
 
Date 
 
 
 
 
 
Jay Cormier, JD, PhD 
Senior Vice President 
Levo Therapeutics, Inc. 
 
Date 
 
 
 
 
 
Sara Cotter 
Chief Executive Officer 
Levo Therapeutics, Inc. 
 
Date 


Statistical Analysis Plan 
 
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Levo Therapeutics, Inc.  Protocol LV-101-3-01 
 
08 July 2020 
 
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REVISION HISTORY 
 
Version 
Date 
Summary of Revision(s) 
1.0 
18 June 2020 
New Document 
1.1 
08 July 2020 
An addition to the analyses of global impression of 
change scales was made to include a proportional 
odds cumulative logit model.  This addition is 
reflected in Sections 6.3 and 6.4. 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
Abbreviation/Term 
Definition 
 
 
 
 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of Covariance 
AST 
Aspartate Aminotransferase 
ATC 
Anatomic Therapeutic Chemical 
AUC 
Area Under the Concentration-time Curve 
Cmax 
Maximum Concentration 
CGI-C 
Clinical Global Impression – Change 
CGI-S 
Clinical Global Impression – Severity 
cLDA 
Constrained Longitudinal Data Analysis 
COVID-19 
Coronavirus Disease 2019 
CY-BOCS 
Children's Yale Brown Obsessive Compulsive Scale 
ECG 
Electrocardiogram 
EoP 
End-of-Period 
EoS 
End-of-Study 
ET 
Early Termination 
FAS 
Full Analysis Set 
 
 
 
 
HQ-CT 
Hyperphagia Questionnaire for Clinical Trials 
IP 
Investigational Product 
IWRS 
Interactive Web Response System 
LS Mean 
Least Square Mean 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Model Repeated Measures 
 
 
 
 
PADQ 
PWS Anxiety and Distress Behaviors Questionnaire 
PAS 
Primary Analysis Set 


Statistical Analysis Plan 
 
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Abbreviation/Term 
Definition 
 
 
PT 
Preferred Term 
PWS 
Prader-Willi syndrome 
SAE 
Serious Adverse Event 
SD 
Standard deviation 
SE 
Standard Error 
SOC 
System Organ Class 
SOP 
Standard Operating Procedures 
 
 
Tmax 
Time to Maximum Concentration 
TEAE 
Treatment Emergent Adverse Event 
TLF 
Tables, Listings, and Figures 
WHODrug Global 
World Health Organization Drug Global 
 
 


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TABLE OF CONTENTS 
1 
STUDY OVERVIEW ............................................................................................................. 9 
2 
STUDY OBJECTIVES AND ENDPOINTS .......................................................................... 9 
3 
STUDY DESIGN.................................................................................................................. 11 
3.1 
Sample Size and Randomization .......................................................................... 11 
3.2 
Data Monitoring Committee ................................................................................. 12 
3.3 
Primary Analysis ................................................................................................... 12 
4 
GENERAL METHODS........................................................................................................ 13 
4.1 
Presentation of Data .............................................................................................. 13 
4.2 
Arms ...................................................................................................................... 13 
4.3 
Study Day.............................................................................................................. 14 
4.4 
Definition of Baseline, End-of-Period, and End-of-Study Values ....................... 14 
4.5 
Scheduled and Unscheduled Visits ....................................................................... 14 
4.6 
Handling of Dropouts or Missing Data ................................................................. 14 
4.7 
Invalid Questionnaire Data ................................................................................... 15 
 
 
4.9 
Analysis Sets ......................................................................................................... 15 
4.9.1 
Full Analysis Set ................................................................................................... 15 
4.9.2 
Primary Analysis Set............................................................................................. 16 
4.9.3 
Per-Protocol Analysis Set ..................................................................................... 16 
4.9.4 
Safety Analysis Set ............................................................................................... 17 
5 
STUDY DESCRIPTORS ..................................................................................................... 17 
5.1 
Eligibility and Informed Consent.......................................................................... 17 
5.2 
Missed Visits and Assessments ............................................................................ 18 
5.3 
Protocol Deviations ............................................................................................... 18 
5.4 
Demographics and Baseline Characteristics ......................................................... 18 
5.5 
General Medical History ....................................................................................... 18 
5.6 
Pre-Treatment and Concomitant Medications ...................................................... 18 
5.7 
IP Administration .................................................................................................. 19 
5.7.1 
Treatment Duration ............................................................................................... 19 
5.7.2 
IP Compliance ....................................................................................................... 19 
5.8 
Patient Study Progress .......................................................................................... 20 


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5.9 
Patient Disposition ................................................................................................ 20 
6 
PRIMARY EFFICACY ANALYSES .................................................................................. 20 
6.1 
Primary Efficacy Endpoints .................................................................................. 21 
6.1.1 
Sensitivity Analyses .............................................................................................. 23 
6.2 
Secondary Efficacy Endpoints .............................................................................. 24 
6.2.1 
Sensitivity Analyses .............................................................................................. 25 
 
 
 
 
7 
EFFICACY ASSESSMENTS DURING THE LONG-TERM FOLLOW-UP PERIOD ..... 28 
7.1.1 
PWS Nutritional Phase ......................................................................................... 28 
7.1.2 
Hyperphagia Questionnaire for Clinical Trials (HQ-CT) ..................................... 28 
7.1.3 
Children’s Yale Brown Obsessive Compulsive Scale (CY-BOCS) ..................... 28 
7.1.4 
PWS Anxiety and Distress Behaviors Questionnaire (PADQ) ............................ 28 
7.1.5 
Clinical Global Impression – Severity (CGI-S) and Clinical Global 
Impression – Change (CGI-C) .............................................................................................. 28 
 
 
 
 
 
 
8 
SAFETY ANALYSES.......................................................................................................... 29 
8.1 
Adverse Events (AEs) ........................................................................................... 29 
8.1.1 
Pre-Treatment Serious Adverse Events (SAEs) ................................................... 29 
8.1.2 
Treatment-Emergent AEs ..................................................................................... 30 
8.2 
Pregnancy Reporting ............................................................................................. 30 
8.3 
Intranasal Spray Pump Incidents (Including Malfunctions) ................................. 30 
8.4 
Clinical Safety Laboratory Assessments .............................................................. 30 
8.4.1 
Hematology, Coagulation, D-dimer, Chemistry, and Urinalysis .......................... 30 
8.4.2 
Pregnancy Testing ................................................................................................. 31 
8.5 
Physical Examination............................................................................................ 31 
8.6 
Nasal Assessment.................................................................................................. 31 
8.7 
Vital Signs and Weight ......................................................................................... 32 
8.8 
12-Lead Electrocardiograms ................................................................................. 32 
 
 
10 DEVIATIONS FROM STATISTICAL METHODS IN THE PROTOCOL ....................... 32 


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11 REFERENCES ..................................................................................................................... 32 
 
 
Appendix B: SCHEDULE OF ASSESSMENTS ......................................................................... 34 
Appendix C: LIST OF TABLES FOR THE PLACEBO-CONTROLLED PERIOD .................. 40 
14.1 Demographic Data Summary Tables ............................................................................ 40 
14.2 Efficacy Data Summary Tables .................................................................................... 41 
14.3 Safety Data Summary Tables........................................................................................ 49 
Appendix D: LIST OF TABLES AND LISTINGS FOR THE LONG-TERM FOLLOW-UP 
PERIOD ........................................................................................................................................ 51 
14.1 Demographic Data Summary Tables ............................................................................ 51 
14.2 Efficacy Data Summary Tables .................................................................................... 52 
14.3 Safety Data Summary Tables........................................................................................ 56 
Appendix E: LIST OF PATIENT LISTINGS .............................................................................. 58 
16.2.1 Discontinued Patients................................................................................................. 58 
16.2.2 Protocol Deviations .................................................................................................... 58 
16.2.3 Patients Excluded from the Efficacy Analysis........................................................... 58 
16.2.4 Demographic and Baseline Characteristics ............................................................... 58 
16.2.5 Compliance and/or Drug Concentration Data ............................................................ 58 
16.2.6 Individual Efficacy Response Data ............................................................................ 59 
16.2.7 Adverse Event Data ................................................................................................... 61 
16.2.8 Listing of Individual Laboratory Measurements ....................................................... 62 
16.2.9 Other Data Listings .................................................................................................... 62 
 
 
 


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1 STUDY OVERVIEW 
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. 
It is essential that the user of this document also be familiar with the contents of the CARE-PWS 
study protocol.  The protocol is the designated place where background, operational, and 
procedural details necessary for the understanding of this trial can be found. 
This is a randomized and double-blind phase 3 study to assess the efficacy, safety, and 
tolerability of intranasal carbetocin (LV-101) in patients with PWS.  Clinical study drug 
(carbetocin and placebo vials) will be blinded at the study level, ensuring the blind of the 
sponsor, patient, caregiver, and study site.  While approximately 175 patients were originally 
intended to be enrolled, due to the Coronavirus Disease 2019 (COVID-19) pandemic, 130 
patients were randomized to receive 9.6 mg LV-101 or 3.2 mg LV-101 or placebo (1:1:1) during 
the placebo-controlled period.  Efficacy will be assessed using both caregiver-reported and 
clinician-reported outcome measures as listed in Appendix B. 
The initial 8-week, placebo-controlled period is the primary focus of the efficacy analyses.  After 
the 8-week double-blind, placebo-controlled period, there will be a long-term follow-up period 
of 56 weeks during which all patients will receive active treatment with LV-101.  The study 
provides for optional continued safety data collection during an extension period after Week 64 
with possible switch of carbetocin dose depending on the outcome of the primary efficacy 
analyses. 
2 STUDY OBJECTIVES AND ENDPOINTS 
Objectives and endpoints for the study are summarized in Table 1.  The primary efficacy 
estimand is the arm- and visit-specific mean of the changes from Baseline to the visit for the arm, 
and the analyses of this estimand will be performed in the context of a statistical model of 
repeated measures on the same patient. 
The efficacy objectives are primarily focused on analyses of data from the 8-week placebo-
controlled period.  Objectives for data collected after Week 64 are focused on descriptive 
analyses of long-term safety events. 


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Table 1. 
Study Protocol Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
• 
To assess the efficacy of 9.6 mg/dose 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/dose 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 LV-101 versus 
placebo on a broader range of maladaptive 
behavioral symptoms, first assessing 9.6 mg/dose 
LV-101 then assessing 3.2 mg/dose LV-101 
• 
Change in PADQ score from Baseline to Week 8 
• 
CGI-C score at Week 8  
• 
To further characterize the treatment effect of 
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 (i.e., 
food security), first assessing 9.6 mg/dose LV-101 
then assessing 3.2 mg/dose 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 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 


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The study contains three distinct periods: the placebo-controlled period (Baseline through the 
Week 8 visit), the long-term follow-up period (from the Week 8 visit to the Week 64 visit), and 
the extension period (following the Week 64 visit).  Analyses of efficacy and safety will be 
conducted for the placebo-controlled period, and descriptive statistics will be provided for 
efficacy and safety data collected in the long-term follow-up and extension periods.  The 
statistical objectives and methodology for the evaluation of study data are described in more 
detail below. 
3 STUDY DESIGN 
3.1 Sample Size and Randomization 
The study was originally designed to enroll approximately 175 patients. 
 
 
  
The results from the Phase 2 study of LV-101 served as the basis for powering this phase 3 
study.  The primary endpoint in the phase 2 study was HPWSQ-R, an 11-item questionnaire that 
was subsequently revised and validated, resulting in a 9-item questionnaire now called HQ-CT.  
These nine questions are a subset of the larger HPWSQ-R questionnaire. 
 
 
 
As a result, the subset of questions contained in the HQ-CT (9 vs. 11 questions) were used as the 
basis for power calculations 
, along with the CY-
BOCS results from the Phase 2 study 
 
To account for a possible diminution of effect from Phase 2 to Phase 3, the mean differences in 
both the HQ-CT and CY-BOCS were reduced by 
 while maintaining the same standard 
deviations for the purposes of powering the study 
 
  A variety of statistical models were then applied (e.g., ANCOVA, 
simple t-test).  Based on these models, the study was designed to have at least 90% power to 
detect a treatment arm difference in HQ-CT total score change from Baseline to Week 8 and at 
least 99% power to detect a treatment arm difference in CY-BOCS total score change from 
Baseline to Week 8. 
Due to the COVID-19 pandemic, however, the sample size will be reduced to 130 patients. 
Patients will be randomized (1:1:2:2) to one of four planned treatment arms: 
a. Placebo during the 8-week controlled period followed by 9.6 mg/dose LV-101 after the 
8-week placebo-controlled period 
b. Placebo during the 8-week controlled period followed by 3.2 mg/dose LV-101 after the 
8-week placebo-controlled period 
c. 9.6 mg/dose LV-101 throughout the study 
d. 3.2 mg/dose LV-101 throughout the study 
Because there is no study intervention difference between the two placebo arms during the 
placebo-controlled period, the data from these arms will be pooled in all analyses focused on the 


Statistical Analysis Plan 
 
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outcome from the placebo-controlled period, thereby creating a single placebo arm for all such 
analyses. 
Patients will be randomized on the day prior to the Baseline visit (with Baseline visit 
representing Day 1, the first dose day) using an Interactive Web Response System (IWRS).  The 
IWRS will provide a patient number and a unit number to be dispensed.  This randomization is 
performed prior to the Baseline visit to allow for refrigerated thawing of investigational product 
vials prior to initiation of study intervention.  The pharmacist will not know the identity of the 
intervention in the vials moved from freezing to refrigeration.  Therefore, this randomization 
prior to the Baseline visit does not unblind any clinical site worker (i.e., pharmacist, 
Investigator), caregiver, or patient. 
During the long-term follow-up and extension periods, all patients will receive LV-101.  Patients 
randomized to initially receive placebo in the placebo-controlled period will receive intranasal 
carbetocin at either 9.6 mg/dose or 3.2 mg/dose in the long-term follow-up and extension periods 
according to the identity of the placebo arm to which randomized.  Patients randomized to 
9.6 mg/dose or 3.2 mg/dose LV-101 in the placebo-controlled period will continue on that same 
dose throughout the long-term follow-up and extension periods. 
 
 
 
3.2 Data Monitoring Committee 
The Data Monitoring Committee (DMC) is an independent multidisciplinary group consisting of 
clinicians and a biostatistician that, collectively, has experience in the management of subjects 
with Prader-Willi syndrome and in the conduct and monitoring of randomized clinical trials with 
interim analyses, and will act as an independent group to evaluate data to assure patient safety 
and study integrity.  The objectives, roles, and responsibilities of the DMC and the format and 
frequency of the DMC meetings are documented in the DMC Charter. 
The DMC will review all adverse events that are deemed severe, serious, or IP-related, as well as 
clinically significant vital signs, ECGs, and laboratory test results.  The committee may also 
review specific study conduct related items, such as protocol deviations, in order to determine if 
these deviations are critical to the evaluation of safety during the clinical trial. 
3.3 Primary Analysis 
The primary analyses will be performed after all patients randomized for the placebo-controlled 
period have completed the Week 8 site visit assessments or have withdrawn from the study prior 
to completing the Week 8 visit.  Following completion of the Week 8 visit by the last patient, all 
data through Week 8 in the database will be locked, and treatment assignments will be unblinded 
for the purpose of analyses of study endpoints.  Unblinded information will not be disclosed to 
Investigators, caregivers, or patients. 
The list of tables that will be generated for the locked data are specified in Appendix C.  
Additional tables and listings will be generated at the time of interim lock that may include data 
that is not yet locked (i.e., data in the long-term follow-up period).  Those tables and listings are 
specified in Appendix D. 


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4 GENERAL METHODS 
4.1 Presentation of Data 
The data from the placebo-controlled period will be summarized separately from the long-term 
follow-up and extension periods.  The data from the long-term follow-up period may be 
summarized together with the data from the extension period. 
Data with qualifiers (e.g., “<”) will be listed with the qualifier but summarized without the 
qualifier.  Patient data listings will include data collected for all patients.  Listings will be sorted 
by treatment arm, site, patient number, nominal visit, date and time (as applicable), unless 
otherwise indicated. 
Categorical analyses will be summarized using counts and percentages.  Percentages will be 
based on the number of patients in the analysis set for whom there are non-missing data, unless 
otherwise specified.  Continuous variables, including change from Baseline, will be summarized 
using descriptive statistics [n, mean, standard deviation (SD), minimum, Q1, median, Q3, 
maximum].  For modeling results, least square (LS) means and standard errors (SEs) will be 
presented. 
All statistical comparisons will be performed using two-sided tests at an α = 0.05 significance 
level, unless specifically stated otherwise.  P-values will be presented to four decimal places.  
P-values < 0.0001 will be presented as “< 0.0001.” 
All analyses will be performed using SAS v 9.3 or higher (SAS Institute, Inc, Cary, North 
Carolina, USA).  Validation and quality control of the tables, listings, and figures (TLFs) will 
follow the appropriate Innovative Analytics standard operating procedures (SOPs). 
4.2 Arms 
There are four treatment arms, as indicated by the randomization scheme in Section 3.1.  
Treatment arm designations are defined separately for each study period, according to the 
following table. 
Table 2.  
Treatment Arms by Period  
Randomization Arm 
Planned Treatment 
Placebo-Controlled 
Period 
Arm Designation 
Long-Term Follow-Up 
and Extension Period 
Arm Designation 
Long-Term Follow-Up 
and Extension Period 
Pooled Arm 
Designation 
Placebo to 9.6 mg/dose 
Pooled placebo 
Placebo to 9.6 mg/dose 
Pooled 9.6 mg/dose 
Placebo to 3.2 mg/dose 
Pooled placebo 
Placebo to 3.2 mg/dose 
Pooled 3.2 mg/dose 
9.6 mg/dose 
9.6 mg/dose 
9.6 mg/dose 
Pooled 9.6 mg/dose 
3.2 mg/dose 
3.2 mg/dose 
3.2 mg/dose 
Pooled 3.2 mg/dose 


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4.3 Study Day 
The day of first IP administration is defined as Day 1.  All other study days will be labeled 
relative to Day 1.  Thus, study day for a particular event date on or after Day 1 is calculated as: 
(Date of event – Date of first IP administration + 1).  An event that occurs prior to Day 1 is 
calculated as: (Date of event – Date of IP administration). Day 0 will not be used. 
The duration of AE events will be calculated as (Event end date – Event start date + 1). 
4.4 Definition of Baseline, End-of-Period, and End-of-Study Values 
The Baseline value for each patient is the value obtained during the Baseline visit, unless 
otherwise indicated. 
For the primary analyses, the End-of-Period (EoP) value per patient is the last post-Baseline 
value during the placebo-controlled period.  For the long-term analyses, the End-of-Study (EoS) 
value per patient is the last post-Baseline value, which may be relative to the EoP value for the 
placebo controlled period (for example, time to first AE of placebo patients starting long-term 
follow-up). 
4.5 Scheduled and Unscheduled Visits 
For the purposes of statistical analyses, the nominal visit designations as assigned by the 
investigator will be used. 
4.6 Handling of Dropouts or Missing Data 
Patient-level listings will present data as reported.  Missing or partially missing dates that are 
required for date-dependent definitions (e.g., treatment-emergent adverse events, concomitant 
medications) will be assumed to be the most conservative date possible. 
For the efficacy endpoints, no imputation will be performed, and, as described further in 
Section 6.1, the mixed model repeated measures (MMRM) analysis will use all available data to 
estimate the mean treatment effect. 
An adverse event (AE) with a completely missing start date will be considered treatment-
emergent; similarly, an AE that started the same month and year as IP administration but with 
missing start day will be considered treatment-emergent. 
AEs with missing seriousness will be counted as “serious” in tables and missing in listings; 
likewise, AEs with missing severity will be counted as “severe” in tables and missing in listings 
and AEs with missing relatedness to the IP will be counted as “possibly related” and missing in 
listings. 
Medical history with missing stop dates will be considered ongoing.  Medications with missing 
stop dates will be considered in concurrent use during the study and will be counted in the 
summary table of concomitant medications. 


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4.7 Invalid Questionnaire Data 
For the study, Levo and qualified consultants have engaged with designated raters and 
Investigators to train such individuals on the proper administration of all observer-reported and 
clinician-rated outcome measures used in the study.  Despite these best efforts, it is possible that 
the administration of such measures may be improperly conducted or that circumstances beyond 
the control of the study site may cause the collected data to be invalid. 
Any CY-BOCS, HQ-CT, PADQ, or other efficacy measures judged to be invalid in the opinion 
of the designated rater or Investigator prior to database lock will not be included in the efficacy 
analyses.  The following criteria indicates that the time point is suspect and may be considered 
invalid: 
• A scale or questionnaire is administered improperly (e.g., due to inadequate 
administration). 
• An unexpected or unforeseen circumstance limits the ability of the respondent (caregiver) 
or designated rater to focus properly on completing the assessment or otherwise calls into 
question the reliability of the data collected. 
Any instances of questionnaire invalidity will be appropriately documented prior to unblinding 
of study data and will be deemed missing from all efficacy analyses. 
 
 
 
 
 
 
4.9 Analysis Sets 
Final decisions regarding assignment of patients to the Safety and Per-Protocol Analysis Sets 
will be made during the Data Review Committee (DRC) meeting and documented in the DRC 
report prior to database lock and unblinding for the primary efficacy and final analyses.  The 
DRC will be comprised, at a minimum, of Levo representatives and the Lead Statistician from 
Innovative Analytics (IA). 
A summary of the number and percentage of patients in each analysis set will be provided.  A 
listing of patient assignment into each analysis set will also be displayed. 
4.9.1 
Full Analysis Set 
The Full Analysis Set (FAS) includes all patients who are both randomized and dosed.  Patients 
will be analyzed according to the arm to which they are randomized.  The FAS will be used in 
lieu of an Intent-to-Treat Set as a result of the logistical requirement in the CARE-PWS study to 
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confirmation that they indeed meet entry criteria.  This results in patients that are “randomized 
but not dosed” when they do not meet entry criteria at Baseline. 
The justification for the use of the FAS in lieu of a traditional Intent-to-Treat is based on the fact 
that the FAS will be free of bias because no unblinding occurs as a result of randomization and 
therefore not initiating study intervention cannot be related to assigned arm.  The use of the FAS 
with the specified justification is consistent with ICH E9, “Statistical Principles for Clinical 
Trials.” 
4.9.2 
Primary Analysis Set 
The Primary Analysis Set (PAS) is a subset of the FAS that includes all patients with at least one 
post-Baseline visit (i.e., Week 2 or Week 8) completed prior to March 1, 2020 and excludes all 
efficacy data collected on or after March 1, 2020.  Patients who withdrew from the study prior to 
March 1, 2020 will be included even if no post-Baseline visits are recorded.  Patients will be 
analyzed according to the arm to which they are randomized. 
The PAS will be used as the definitive analysis for all alpha-controlled analyses (analyses 
associated with primary and secondary objectives). 
 
 
Sensitivity analyses will be conducted that include all data in the FAS. 
4.9.3 
Per-Protocol Analysis Set 
The Per-Protocol Analysis Set (PPS) includes patients in the PAS who have no protocol 
deviations during the placebo-controlled period that could significantly impact the completeness, 
accuracy, and/or reliability of the trial data.  Identification of all patients and measures to be 
included in the PPS analyses will be determined before the database lock and unblinding for the 
interim analysis. 
The PPS will be used as an additional sensitivity analysis for the efficacy endpoints.  PPS 
patients will be analyzed according to the arm to which they are randomized. 
4.9.3.1 
Important Protocol Deviations Leading to Exclusion from the PPS Analysis 
Only those deviations considered to have a major effect on efficacy will lead to complete 
exclusion of a patient from the PPS.  For the purposes of this study, the following criteria have 
been identified as protocol deviations potentially warranting exclusion from the PPS, as it is 
considered that the occurrences of any of these criteria might have an important influence on the 
primary efficacy endpoint.  Other deviations not specifically identified here may result in 
exclusion from the PPS analysis and will be identified prior to final database lock and 
unblinding. 


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Table 3.  
Important Protocol Deviations Leading to Exclusion from PPS 
Type 
Deviation 
Method of 
Identification 
Missing Data 
Primary efficacy questionnaires incomplete or absent for 
the Basline, Week 2, or Week 8 visit 
Programmatic 
Visit Out of Window 
Week 8 study visit is greater than two weeks from the 
scheduled visit date (visit date ± 2 weeks) 
Programmatic 
Concomitant Medications 
Patient is administered an exclusionary concomitant 
medication or dosing change that may, in the 
determination of the Sponsor, alter efficacy of the 
investigational product during the placebo-controlled 
period 
Manual 
Study Drug Compliance 
Patient misses greater than 20% of doses of 
investigational product during the placebo-controlled 
period of the study 
Manual 
Study Drug Compliance  
Incorrect study drug or incorrect dose administered 
during the placebo-controlled period of the study 
Manual 
Patient Eligibility 
Patient is inappropriately entered into the study or is 
later found to have violated an inclusion or exclusion 
criteria which may affect study efficacy measures 
Manual 
4.9.4 
Safety Analysis Set 
The Safety Analysis Set includes all patients who receive at least 1 dose of IP.  Patients will be 
analyzed according to the treatment actually received.  All safety analyses will be based on the 
Safety Analysis Set. 
5 
STUDY DESCRIPTORS 
The study descriptors to be listed and summarized are described below.  The FAS and PAS will 
be used for the listings and summaries, unless otherwise stated, as some of the summaries may 
also be prepared for other analysis sets, such as the PPS analysis set, defined in Section 4.9.  All 
summaries will be presented by treatment arm and overall (i.e., all LV-101 patients), unless 
otherwise stated. 
5.1 Eligibility and Informed Consent 
Eligibility and informed consent parameters will be listed for all screened patients and will 
include date of informed consent/assent, protocol version at study entry, Screening and Baseline 
eligibility criteria, and randomization date. 
The number and percentage of patients meeting all Screening and Baseline eligibility criteria and 
the number and percentage of patients with screen failure will be summarized.  Reason for screen 
failure (as applicable) will be summarized for all screened patients. 


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5.2 Missed Visits and Assessments 
A patient listing of missed visits will be presented. 
5.3 Protocol Deviations 
The number and percentage of patients with a protocol deviation will be displayed by protocol 
deviation category.  Protocol deviations will be listed and tabulated for the placebo-controlled, 
long-term follow-up, and extension periods.  Protocol deviations due to COVID-19, such as 
remote visits and missed assessments due to remote visits, will be listed. 
5.4 Demographics and Baseline Characteristics 
Demographic and Baseline characteristics will be listed and summarized for both the placebo-
controlled and long-term follow-up periods by treatment arm and overall (as applicable).  The 
demographic characteristics will consist of age, sex, genetic subtype of PWS, ethnicity, race, and 
prior use of oxytocin and carbetocin.  A patient’s age in years is calculated using the date of 
informed consent/assent, birth month, and birth year using the following formula: 
Age = INT ቈ[(year(ICDATE)*12 + month(ICDATE)] – [year(BIRTH)*12 + month(BIRTH)]
12
቉ 
where ICDATE = Informed Consent Date. 
Baseline characteristics to be summarized include Baseline PWS nutritional phase, Baseline 
weight (expressed in kilograms where 2.2 pounds are equal to 1 kilogram), calculated Baseline 
BMI (using Baseline weight and screening height), calculated Baseline weight z-scores, and 
Baseline growth hormone use (receiving or not).  Baseline values, as defined in Section 4.4, will 
be used for these Baseline characteristics. 
5.5 General Medical History 
General medical history will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA) coding system (Version 23.0) and will be listed and summarized for the placebo-
controlled and long-term follow-up periods.  The summary will be presented by MedDRA 
System Organ Class (SOC) and Preferred Term (PT).  At each level of patient summarization, a 
patient will be counted only once within that level. 
5.6 Pre-Treatment and 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 
Global dictionary (WHODrug Global) version September 1, 2018. 
Medications that were stopped before the start of the initial IP administration will be considered 
“pre-treatment.”  All other medications will be considered “concomitant.” 
Pre-treatment medications will be presented separately from concomitant medications.  Pre-
treatment medications will be summarized and listed.  Concomitant medications will be 
summarized and listed for the placebo-controlled, long-term follow-up, and extension periods. 


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For frequency tables, medications will be summarized by WHODrug Global Anatomic 
Therapeutic Chemical (ATC) Level 2 and Preferred Term.  At each level of patient 
summarization, patients who reported one or more medications within that level are only counted 
once for that level. 
5.7 IP Administration 
Details of IP administration will be listed for the Safety Analysis Set and will include for each 
visit: the kit number, date of first and last dose dispensed from the kit, number of missed doses, 
and number of unrecorded doses for the placebo-controlled, long-term follow-up, and extension 
periods. 
5.7.1 
Treatment Duration 
Overall treatment duration in days will be calculated using the following formula: 
 
Overall treatment duration = last IP administration date – first IP administration date + 1 
Summary statistics for overall treatment duration (days) will be presented by treatment arm and 
overall (as applicable) for the placebo-controlled, long-term follow-up, and extension periods.  A 
frequency table of treatment duration will also be presented for the following duration 
categories: 
• ≤ 56 days 
• > 56 and < 120 days 
• ≥ 120 and < 180 days 
• ≥ 180 and < 270 days 
• ≥ 270 and < 360 days 
• ≥ 360 days 
5.7.2 
IP Compliance 
IP compliance for each patient will be calculated using the following formula: 
IP Compliance (%) = Number of doses administered during the period
Number of planned doses during the period
 x 100 
The number of doses administered will be calculated based on the number of days between visits 
(multiplied by 3 planned doses per day) less the number of missed doses and number of 
unrecorded doses, accounting for instances where less than three doses are planned to be 
administered on the first day of each study period (i.e., if the Baseline or Week 8 visit occurs at 
the lunchtime dose). 
Where necessary to account for dose type, dose types are defined as follows. 
Dose Type 
Dose Time Interval 
Pre-breakfast 
06:00 – 10:29 
Pre-lunch 
10:30 – 15:59 


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Dose Type 
Dose Time Interval 
Pre-dinner 
16:00 – 20:00 
Query for data entry error 
20:01 – 05:59 
IP compliance will be summarized by treatment arm for each visit in the placebo-controlled and 
long-term follow-up periods, as well as overall for each study period.  A frequency table will 
also be presented by treatment arm, which will include the number of patients who received at 
least 1 dose, the total number of doses administered, the number of patients who missed at least 
one dose, the total number of missed doses, the number of patients with at least 1 missing data 
dose, and the total number of missing data doses. 
5.8 Patient Study Progress 
A listing of patient study progress will be presented, displaying the following dates by patient: 
Screening, informed consent, randomization, first IP administration, last IP administration, and 
study visits.  The number of patients that completed each study visit will be summarized. 
5.9 Patient Disposition 
Patient disposition will be listed and summarized for all screened patients.  The following will be 
summarized: 
• the number of patients randomized; 
• the number of patients who received IP; 
• the number of patients who completed Week 8 of the study; 
• the number of patients who discontinued from the study prior to Week 8 and the primary 
reason for discontinuation; 
• the number of patients who discontinued from the study after Week 8 but prior to 
Week 64 and the primary reason for discontinuation; 
• the number of patients still active in the study, if any; 
• the number of patients who completed Week 64;  
• the number of patients who chose to continue in the extention period; and  
• the number of patients who discontinued from the study during the extention period. 
6 PRIMARY EFFICACY ANALYSES 
Listings and summaries of the efficacy parameters will be presented for the Primary Analysis Set 
(PAS), unless indicated otherwise.  Efficacy parameters are described below, and unless 
otherwise indicated, all efficacy analyses will use study site as a covariate, where low enrolling 
sites will be pooled.  Low enrolling sites are defined as sites that did not enroll at least one 
subject in each of the three placebo-controlled treatment arms.  Therefore, site pooling may 
differ for each analysis set. 


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6.1 Primary Efficacy Endpoints 
As discussed during Levo’s 
 meeting with FDA, there are two primary efficacy 
endpoints in this study focusing specifically on the 9.6 mg/dose LV-101 versus placebo: 
1. the HQ-CT total score change from Baseline to Week 8 
and 
2. the CY-BOCS total score change from Baseline to Week 8. 
 
 
 
 
 
 
 
 
 
 
 
 


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In accordance with FDA’s draft guidance, “Multiple Endpoints in Clinical Trials, Guidance for 
Industry,” and as agreed to with FDA during the 
 meeting, these primary efficacy 
endpoints will be evaluated using the Hochberg multi-step, step-up procedure (Hochberg, 1988; 
Huang and Hsu, 2007) at an overall 2-sided 0.05 level of significance. The hypotheses to be 
tested are as follows: 
HQ-CT: 𝐻𝐻𝑜𝑜: 𝜇𝜇𝐻𝐻−𝜇𝜇𝑃𝑃= 0 𝑣𝑣𝑣𝑣. 𝐻𝐻𝑎𝑎: 𝜇𝜇𝐻𝐻−𝜇𝜇𝑃𝑃≠0 
CY-BOCS: 𝐻𝐻𝑜𝑜: 𝜇𝜇𝐻𝐻−𝜇𝜇𝑃𝑃= 0 𝑣𝑣𝑣𝑣. 𝐻𝐻𝑎𝑎: 𝜇𝜇𝐻𝐻−𝜇𝜇𝑃𝑃≠0 
Where 𝐻𝐻𝑜𝑜 is the null hypothesis, 𝐻𝐻𝑎𝑎 is the alternative hypothesis, and µH and µP are the 
population mean changes from Baseline to Week 8 in 9.6 mg/dose LV-101 and placebo-treated 
patients, respectively.  Change from Baseline is defined as the Week 8 value minus the Baseline 
value for each patient. 
The overall Type I error probability is specified to be two-sided 0.05 (overall two-sided alpha).  
Protection for the overall two-sided alpha against multiplicity across the two primary outcomes 
will be implemented using the Hochberg procedure.  If the largest of the two-sided p-values is 
≤ 0.05 (the specified level of significance), then both comparisons will be identified as having 
met statistical criterion.  If the largest of the two-sided p-values is > 0.05, but the smallest of the 
two-sided p-values for the two comparisons is ≤ 0.025 (half the specified level of significance), 
then the associated comparison with the smaller p-value will be identified as having met 
statistical criterion.  If neither of the two-sided p-values for the two primary comparisons is 
≤ 0.025 (= 0.05/2), then neither of the primary objectives will be identified as having met 
statistical criterion. 
The process for the Hochberg multi-step procedure is illustrated in Figure 1. 
 
 
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Figure 1. Process for Hochberg multi-step, step-up procedure 
 
6.1.1 
Sensitivity Analyses 
The primary efficacy analyses will be repeated using the FAS replacing the PAS, then using the 
PPS replacing the PAS. 
The primary efficacy analyses will also be repeated by replacing the primary model with an 
MMRM where Baseline values are not included as dependent variables but instead are used as an 
additional covariate.  This analysis will then be repeated using the FAS replacing the PAS.  
 
 


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An effect modifier analysis will be used to assess departures from homogeneity of effect across 
subsets defined by Baseline attributes.  Baseline attributes may include, but are not limited to 
gender, age (tertiles), gender by age (tertiles), 
 and 
site.  Low-enrolling sites, as defined in Section 6, will be pooled.  The effect modifier analysis 
will first be performed for the PAS, then subsequently for the FAS. 
The sensitivity of the primary analysis to missing data may be evaluated using multiple 
imputation on the PAS and FAS.  These planned multiple imputation sensitivity analyses may 
use the pattern mixture methodology to impute with 500 replicates.  Two imputations are 
planned:  
1. replace experimental arm missing data with random sampling from non-missing 
experimental arm data and replace missing control arm missing data with random 
sampling from non-missing control arm data 
and 
2. replace experimental arm missing data with random sampling from non-missing 
control arm data and replace missing control arm missing data with random 
sampling from non-missing experimental arm data.  
Additional multiple imputations will be done if deemed beneficial, based on data-driven results, 
when it is obvious that such data-driven analyses challenge the original analyses planned.  The 
motivation will be to illustrate the nature and extent of imputations necessary to challenge 
favorable outcomes by nearly reversing or reversing to an unfavorable outcome. 
Sensitivity analyses will be performed removing study visit data where either the caregiver or 
clinician rater differ from the caregiver or clinician rater during the Baseline visit. 
6.2 Secondary Efficacy Endpoints 
If at least one of the two primary efficacy endpoints meet statistical significance using the 
Hochberg procedure, the secondary endpoints will then be tested for the PAS.  
 


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The first secondary efficacy evaluation will repeat the primary efficacy Hochberg procedure, 
using the 3.2 mg/dose LV-101 (instead of 9.6 mg/dose LV-101).  Specifically, this is an analysis 
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/dose LV-101 arm versus placebo, using the same 
Hochberg procedure as described in Section 6.1 and the appropriate level of significance 
remaining from the primary analyses.  This first secondary efficacy analysis will act as a 
gatekeeper to subsequent secondary evaluations. 
If the first secondary evaluation fails (i.e., neither HQ-CT nor CY-BOCS meet significance using 
the Hochberg approach for the 3.2 mg/dose), all subsequent analyses will become descriptive. 
Otherwise, if the first secondary evaluation succeeds (i.e., either HQ-CT or CY-BOCS meet 
significance using the Hochberg approach for the 3.2 mg/dose), then a fixed-sequence test 
procedure will be performed to assess the following additional secondary efficacy endpoints in 
the order specified (hierarchical alpha protection). 
• PADQ total score change from Baseline to Week 8 
• CGI-C score through Week 8 
• HQ-CT total score for Questions 1, 2, 5, 6, 8, and 9 change from Baseline to Week 8 
• HQ-CT score for Question 9 change from Baseline to Week 8 
The previously described cLDA analysis will be performed when appropriate, with the 
comparison of 9.6 mg/dose LV-101 versus placebo tested first for each endpoint sequentially, 
followed by 3.2 mg/dose LV-101 versus placebo.  For the analysis of CGI-C, the secondary 
MMRM model will be used instead of the cLDA model, with the Baseline CGI-S as the 
covariate. 
Once one test fails to meet significance, then all subsequent statistical tests will provide only 
nominal p-values; all subsequent analyses will be considered descriptive. 
6.2.1 
Sensitivity Analyses 
The secondary efficacy analyses will be repeated using the FAS replacing the PAS, then the PPS 
replacing the PAS. 
The secondary sensitivity analysis will also repeat the primary sensitivity analyses as described 
in Section 6.1.1, instead using the 3.2 mg/dose LV-101 (vs. 9.6 mg/dose LV-101), including the 
application of the secondary MMRM model for both the PAS and FAS. 
Effect modifier analyses will be performed on the first two secondary endpoints (i.e., 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/dose LV-101 arm versus placebo) for the PAS and FAS. 


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7 EFFICACY ASSESSMENTS DURING THE LONG-TERM FOLLOW-
UP PERIOD 
Listings and tables for the efficacy assessments during the long-term follow-up period will be 
presented for the PAS and FAS, unless indicated otherwise.  All presentations of change in 
values will be presented as change from Baseline and change from Week 8. 
7.1.1 
PWS Nutritional Phase 
Observed values will be listed.  A frequency table will be presented by treatment arm and 
overall. 
7.1.2 
Hyperphagia Questionnaire for Clinical Trials (HQ-CT) 
Observed values will be listed. 
Observed totals of the individual raw scores, changes from the placebo-controlled period 
Baseline total scores, and changes from Week 8 total scores will be summarized by treatment 
arm and overall for Weeks 10, 16, 28, 40, 52, 64, and at EoS. 
Observed totals for each subset and changes of the prospectively identified HQ-CT subsets 
(Questions 1, 2, 5, 6, 8, and 9, and Question 9 alone) will also be summarized by treatment arm 
and overall for Weeks 10, 16, 28, 40, 52, 64, and at EoS. 
7.1.3 
Children’s Yale Brown Obsessive Compulsive Scale (CY-BOCS) 
Results of the clinician-completed symptom checklists will be listed.  Observed values, changes 
from the placebo-controlled period Baseline values, and changes from Week 8 values will be 
summarized by treatment arm and overall for Weeks 10, 16, 28, 40, 52, 64, and at EoS.  These 
summaries will be presented for total scores, obsessions severity subscores, and compulsions 
severity subscores. 
7.1.4 
PWS Anxiety and Distress Behaviors Questionnaire (PADQ) 
Results of the caregiver-completed questionnaire will be listed.  PADQ total scores are 
calculated as the sum of the first 14 items of the questionnaire.  Observed values, changes from 
the placebo-controlled Baseline values, and changes from Week 8 values will be summarized by 
treatment arm and overall for Weeks 10, 16, 28, 40, 52, 64, and at EoS. 
7.1.5 
Clinical Global Impression – Severity (CGI-S) and Clinical Global 
Impression – Change (CGI-C) 
Clinician global impressions of the current severity of illness and changes in severity of illness 
will be listed.  Observed values for CGI-S and CGI-C will be summarized by treatment arm and 
overall for Weeks 10, 16, 28, 40, 52, 64, and at EoS. 


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8 SAFETY ANALYSES 
Listings and tables of the safety parameters will be presented for the Safety Analysis Set, with  
separate tables for the placebo-controlled, long-term follow-up, and extension periods.  The data 
from the long-term follow-up period may be summarized together with the data from the 
extension period, where applicable.  Note that the study remains blinded with respect to 
carbetocin dose even after the placebo-controlled period and therefore between-arm comparisons 
are free of confounding with the exception of the loss due to study departures and deviations 
related to intervention used.  Safety parameters are described below. 
All presentations of change in values for the long-term follow-up period will be presented as 
change from Baseline and change from Week 8.  For the purposes of Baseline and Week 8 
values for safety and laboratory assessments, the values will be the values obtained on the date of 
the Baseline and Week 8 visit, or, if missing, the last non-missing value prior to the visit (the last 
observation will be carried forward). 
8.1 Adverse Events (AEs) 
Adverse events will be coded using MedDRA Version 23.0. 
For the placebo-controlled period, summaries will include AEs with a start date from the start 
date of the first dose of IP in the placebo-controlled period to the patient’s last placebo-
controlled period visit, but summaries will exclude any events with a start date that is on or after 
the start date of the first dose of IP in the long-term follow-up period. 
Combined long-term follow-up/extension period summaries will include events with a start date 
from the start date of the first dose of IP in the long-term follow-up period to study termination. 
8.1.1 
Pre-Treatment Serious Adverse Events (SAEs) 
Pre-treatment SAEs are defined as any SAE that started before the patient’s first exposure to the 
IP in the placebo-controlled period.  An SAE that is ongoing at the time of initial IP exposure 


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and subsequently worsens after IP exposure is considered treatment-emergent and will be 
recorded as a separate SAE.  Pre-treatment SAEs will be listed only. 
8.1.2 
Treatment-Emergent AEs 
The following AEs are defined as treatment-emergent AEs (TEAEs). 
- 
AEs that begin or worsen after the first administration of investigational product 
- 
AEs with a completely missing start date or AEs with missing start day that started the 
same month and year as investigational product administration 
Patient listings of all treatment-emergent adverse events as reported will be presented. 
An overall summary table will be presented by treatment arm for all TEAEs, TEAEs by 
maximum severity, TEAEs by greatest degree of relationship to IP, serious TEAEs, TEAEs 
leading to drug interruption, TEAEs leading to study discontinuation, and deaths. 
Serious TEAEs, deaths, and TEAEs that resulted in study discontinuation will be listed and 
summarized. 
 
 
All adverse event tables will include summaries by MedDRA System Organ Class and Preferred 
Term, with patients who have the same adverse event more than once counted only once for that 
event and with patients who have more than one adverse event within a System Organ Class 
counted only once in that System Organ Class.  The numbers and percentages of patients 
reporting an event will be presented in these summaries. 
8.2 Pregnancy Reporting 
If observed, pregnancy related information from a female patient or a male participant’s female 
partner who becomes pregnant while the male participant is in the study will be listed. 
8.3 Intranasal Spray Pump Incidents (Including Malfunctions) 
All medical device incidents or malfunctions of the device that resulted in an incident will be 
listed. Incidents reported by the site and by the sponsor will be listed separately. 
8.4 Clinical Safety Laboratory Assessments  
Clinical safety laboratory assessments will be summarized separately for the placebo-controlled 
period and the long-term follow-up period. Laboratory assessments are not performed in the 
extension period. 
8.4.1 
Hematology, Coagulation, D-dimer, Chemistry, and Urinalysis 
• Hematology:  Platelet count, red blood cell count, hemoglobin, hematocrit, white 
blood cell count with differential (neutrophils, lymphocytes, monocytes, 
eosinophils, and basophils) 


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• Coagulation:  Prothrombin time, activated partial thromboplastin time, thrombin 
time, fibrinogen 
• D-dimer (during placebo-controlled period only) 
• Chemistry: Calcium, chloride, sodium, potassium, glucose, aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), 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) 
 
For hematology, coagulation, D-dimer, chemistry, and urinalysis quantitative tests, summary 
statistics will be presented for the observed values at each visit.  Summary statistics will also be 
presented for the change from Baseline values to each post-Baseline visit, including EoP/EoS. 
The shift from Baseline to EoP/EoS (as applicable) will also be presented for the hematology, 
coagulation, D-dimer, and chemistry panel parameters with results classified as low (L), Normal 
(N), and high (H) according to the laboratory-supplied normal ranges.  A summary of shift to 
low and high will be presented for each parameter, displaying the number of patients whose 
values shifted as a percentage of the number of patients at risk for shifting, defined as follows: 
• The patients at risk for shifting to high are those with normal or low values at Baseline. 
• The patients at risk for shifting to low are those with normal or high values at Baseline. 
For all tests, results will be displayed in patient listings, with those values falling outside the 
laboratory reference range flagged.  Laboratory reference ranges will be provided by the 
laboratory site(s) and included in an appendix of the clinical study report. 
8.4.2 
Pregnancy Testing 
Urine pregnancy tests performed on females of childbearing potential will be listed. 
8.5 Physical Examination 
Physical examination results will be listed and summarized for both the placebo-controlled and 
long-term follow-up periods.  Physical examinations are not performed in the extension period.  
Observed status (e.g., normal, abnormal-not clinically significant, abnormal-clinically 
significant, not done) will be summarized for each body system by visit. 
Observed status of Tanner staging (e.g., Stage 1 – Stage 5) will also be summarized. 
8.6 Nasal Assessment 
Nasal assessment results will be listed and summarized for both the placebo-controlled and long-
term follow-up periods.  Nasal assessments are not performed in the extension period.  Observed 
protocol-specified grades (e.g., Grade 0, Grade 1A, Grade 1B, Grade 2, Grade 3 and Grade 4) by 
visit will be summarized. 


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8.7 Vital Signs and Weight 
Vital signs include systolic and diastolic blood pressure, pulse, respiration rate, and body 
temperature.  Observed values of vital signs, height, weight, and BMI will be displayed in patient 
listings.  BMI scores, weight Z-scores, and BMI Z-scores will be calculated, where applicable, 
and listed.  Observed values and changes from Baseline (for all parameters except height) will be 
summarized at each post-Baseline visit, including EoP/EoS separately for the placebo-controlled 
and long-term follow-up periods.  Vital signs are not collected in the extension period. 
8.8 
12-Lead Electrocardiograms 
Overall interpretation of 12-lead Electrocardiograms (ECGs) will be listed and summarized 
separately for the placebo-controlled and long-term follow-up period.  A summary of shift to 
normal, abnormal (not clinically significant), and abnormal (clinically significant) will be 
presented for each parameter, displaying the number of patients whose values shifted as a 
percentage of the number of patients at risk for shifting, defined as follows: 
• The patients at risk for shifting to abnormal are those with normal values at Baseline. 
• The patients at risk for shifting to normal are those with abnormal values at Baseline. 
 
10 DEVIATIONS FROM STATISTICAL METHODS IN THE PROTOCOL 
There were no changes to the conduct of the study since the last protocol amendment.  Analyses 
planned but not performed and the rationales for the changes are as follows. 
<Deviations to be added later if necessary> 
11 REFERENCES 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX B: SCHEDULE OF ASSESSMENTS 
The schedule of assessments for the placebo-controlled period is provided in Table 4, the 
schedule of assessments for the long-term follow-up period is provided in Table 5, and the 
schedule of assessments for the extension period is provided in Table 8. The schedule of 
assessments for questionnaires is provided in Table 6 for the placebo-controlled period and in 
Table 7 for the long-term follow-up period. 
 
 


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Table 4. 
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/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 patient 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 
Plasma collection for pharmacokinetics 
 
 
Xd 
 
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, patients 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.  
c See Table 6. Appropriate training and procedures will be instituted (including structured interviews) to ensure familiarity with 
the instruments, administer instruments consistently (reducing measurement error), and enable honest feedback. 
d Obtain blood sample at 25 to 35 minutes after observed dosing of study drug. 
e Archive samples may be tested for immunogenicity (presence and characterization of anti-drug antibodies), genetic testing 
(including genome sequencing) and biochemical analyses of hormones or other analytes of relevance to Prader-Willi syndrome. 
 
 


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Table 5. 
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, 
urinalysis) 
X 
X 
X 
X 
X 
X 
X 
12-lead electrocardiogram 
 
X 
 
 
 
X 
X 
Study drug dosing 
ongoing 
ongoing 
ongoing 
ongoing 
ongoing 
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 Pregnancy testing will be conducted only for females of childbearing potential, as judged by the Investigator. 
b See Table 7. Appropriate training and procedures will be instituted (including structured interviews) to ensure familiarity with 
the instruments, administer instruments consistently (reducing measurement error), and enable honest feedback. 
c Obtain at 5 to 10 minutes, 25 to 35 minutes, 1.5 hours ±15 minutes, and 2.5 hours ±15 minutes after observed dosing. 
d Archive samples may be tested for immunogenicity (presence and characterization of anti-drug antibodies), genetic testing 
(including genome sequencing) and biochemical analyses of hormones or other analytes of relevance to Prader-Willi syndrome. 
 
 


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Table 6. 
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 Behaviors Questionnaire 
(PADQ) 
X 
X 
X 
X 
Clinical Global Impression 
Xa 
Xa 
Xa 
Xa 
A = anxiety; CGI = clinical global impression; CareGI = caregiver global impression; H = hyperphagia; 
OC = obsessive-compulsive; 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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Table 7. 
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 
Behaviors Questionnaire 
(PADQ) 
X 
X 
X 
X 
X 
X 
X 
Clinical Global Impression 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
A = anxiety; CGI = clinical global impression; CareGI = caregiver global impression; H = hyperphagia; 
OC = obsessive-compulsive; PWS = Prader Willi Syndrome; Term = termination 
a Screening and Baseline assessments will include only Severity. Post-Baseline assessments will include Severity and Change. 


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Table 8. 
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, 
urinalysis) 
X 
 
X 
12-lead electrocardiogram 
X 
 
 
Study drug dosing 
ongoing 
ongoing 
 
Extension period ICF/assent 
X 
 
 
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 clinicianb 
X 
 
 
Archive blood/plasma samplesd 
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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APPENDIX C: LIST OF TABLES FOR THE PLACEBO-CONTROLLED 
PERIOD 
The statistical tables will appear in Section 14 of the clinical study report.  The statistical tables, 
therefore, have a prefix of “14.” 
14.1 Demographic Data Summary Tables 
14.1A Demographic Data Summary Tables for the Placebo-Controlled Period 
Table 14.1A.1: 
Patient Eligibility by Treatment Arm 
Table 14.1A.2: 
Patient Disposition by Treatment Arm 
Table 14.1A.3.1: 
Patient Study Visit Occurrence by Treatment Arm – Placebo-Controlled 
Period (Primary Analysis Set) 
Table 14.1A.3.2: 
Patient Study Visit Occurrence by Treatment Arm – Placebo-Controlled 
Period (Full Analysis Set) 
Table 14.1A.4.1: 
Important Protocol Deviations by Treatment Arm – Placebo-Controlled 
Period (Primary Analysis Set) 
Table 14.1A.4.2: 
Important Protocol Deviations by Treatment Arm – Placebo-Controlled 
Period (Full Analysis Set) 
Table 14.1A.5: 
Analysis Sets by Treatment Arm – Placebo-Controlled Period 
Table 14.1A.6.1: 
Summary of Demographic and Baseline Characteristics by Treatment Arm 
– Placebo-Controlled Period (Primary Analysis Set) 
Table 14.1A.6.2: 
Summary of Demographic and Baseline Characteristics by Treatment Arm 
– Placebo-Controlled Period (Full Analysis Set) 
Table 14.1A.7.1: 
Medical History by Treatment Arm – Placebo-Controlled Period (Primary 
Analysis Set) 
Table 14.1A.7.2: 
Medical History by Treatment Arm – Placebo-Controlled Period (Full 
Analysis Set) 
Table 14.1A.8.1: 
Pre-Treatment Medications by Treatment Arm (Primary Analysis Set) 
Table 14.1A.8.2: 
Pre-Treatment Medications by Treatment Arm (Full Analysis Set) 
Table 14.1A.9.1: 
Concomitant Medications by Treatment Arm – Placebo-Controlled Period 
(Primary Analysis Set) 
Table 14.1A.9.2: 
Concomitant Medications by Treatment Arm – Placebo-Controlled Period 
(Full Analysis Set) 
Table 14.1A.10: 
Summary of Treatment Duration by Treatment Arm – Placebo-Controlled 
Period 


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Table 14.1A.12: 
Frequency Table of Study Drug Compliance by Visit and Treatment Arm 
– Placebo-Controlled Period 
Table 14.1A.13: 
Frequency Table of Administered Doses by Treatment Arm – Placebo-
Controlled Period 
14.2 Efficacy Data Summary Tables  
14.2A Efficacy Data Summary Tables for the Placebo-Controlled Period 
14.2A.1 Hyperphagia Questionnaire for Clinical Trials (HQ-CT) Summary Tables 
Table 14.2A.1.1.1: 
Summary of Observed Values and Change from Baseline in HQ-CT Total 
Score by Treatment Arm – Placebo-Controlled Period (Primary Analysis 
Set) 
Table 14.2A.1.1.2: 
Summary of Observed Values and Change from Baseline in HQ-CT Total 
Score by Treatment Arm – Placebo-Controlled Period (Full Analysis Set) 
Table 14.2A.1.2.1: 
HQ-CT Total Score – Constrained Longitudinal Data Analysis – Placebo-
Controlled Period (Primary Analysis Set) 
Table 14.2A.1.2.2: 
HQ-CT Total Score – Constrained Longitudinal Data Analysis – Placebo-
Controlled Period (Full Analysis Set) 
Table 14.2A.1.2.3: 
HQ-CT Total Score – Constrained Longitudinal Data Analysis – Placebo-
Controlled Period (Per-Protocol Analysis Set) 
Table 14.2A.1.3.1: 
HQ-CT Total Score – Repeated Measures Analysis – Placebo-Controlled 
Period (Primary Analysis Set) 
Table 14.2A.1.3.2: 
HQ-CT Total Score – Repeated Measures Analysis – Placebo-Controlled 
Period (Full Analysis Set) 
Table 14.2A.1.4.1: 
HQ-CT Total Score by Gender – Effect Modifier Analysis – Placebo-
Controlled Period (Primary Analysis Set) 
Table 14.2A.1.4.2: 
HQ-CT Total Score by Age Tertile – Effect Modifier Analysis – Placebo-
Controlled Period (Primary Analysis Set) 
Table 14.2A.1.4.3: 
HQ-CT Total Score by Gender and Age Tertile– Effect Modifier Analysis 
– Placebo-Controlled Period (Primary Analysis Set) 
Table 14.2A.1.4.5: 
HQ-CT Total Score by Site – Effect Modifier Analysis – Placebo-
Controlled Period (Primary Analysis Set) 
Table 14.2A.1.5.1: 
HQ-CT Total Score by Gender – Effect Modifier Analysis – Placebo-
Controlled Period (Full Analysis Set) 


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Table 14.2A.1.5.2: 
HQ-CT Total Score by Age Tertile – Effect Modifier Analysis – Placebo-
Controlled Period (Full Analysis Set) 
Table 14.2A.1.5.3: 
HQ-CT Total Score by Gender and Age Tertile– Effect Modifier Analysis 
– Placebo-Controlled Period (Full Analysis Set) 
Table 14.2A.1.5.5: 
HQ-CT Total Score by Site – Effect Modifier Analysis – Placebo-
Controlled Period (Full Analysis Set) 
Table 14.2A.1.6.1: 
Summary of Observed Values and Change from Baseline in Total Score of 
a Subset of HQ-CT by Treatment Arm – Placebo-Controlled Period 
(Primary Analysis Set) 
Table 14.2A.1.6.2: 
Summary of Observed Values and Change from Baseline in Total Score of 
a Subset of HQ-CT by Treatment Arm – Placebo-Controlled Period (Full 
Analysis Set) 
Table 14.2A.1.7.1: 
Total Score of a Subset of HQ-CT – Constrained Longitudinal Data 
Analysis – Placebo-Controlled Period (Primary Analysis Set) 
Table 14.2A.1.7.2: 
Total Score of a Subset of HQ-CT – Constrained Longitudinal Data 
Analysis – Placebo-Controlled Period (Full Analysis Set) 
Table 14.2A.1.7.3: 
Total Score of a Subset of HQ-CT – Constrained Longitudinal Data 
Analysis – Placebo-Controlled Period (Per-Protocol Analysis Set) 
Table 14.2A.1.8.1: 
Total Score of a Subset of HQ-CT – Repeated Measures Analysis – 
Placebo-Controlled Period (Primary Analysis Set) 
Table 14.2A.1.8.2: 
Total Score of a Subset of HQ-CT – Repeated Measures Data Analysis – 
Placebo-Controlled Period (Full Analysis Set) 
Table 14.2A.1.9.1: 
Summary of Observed Values and Change from Baseline in HQ-CT 
Question 9 Score by Treatment Arm – Placebo-Controlled Period 
(Primary Analysis Set) 
Table 14.2A.1.9.2: 
Summary of Observed Values and Change from Baseline in HQ-CT 
Question 9 Score by Treatment Arm – Placebo-Controlled Period (Full 
Analysis Set) 
Table 14.2A.1.10.1: HQ-CT Question 9 Score – Constrained Longitudinal Data Analysis – 
Placebo-Controlled Period (Primary Analysis Set) 
Table 14.2A.1.10.2: HQ-CT Question 9 Score – Constrained Longitudinal Data Analysis – 
Placebo-Controlled Period (Full Analysis Set) 


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Table 14.2A.1.10.3: HQ-CT Question 9 Score – Constrained Longitudinal Data Analysis – 
Placebo-Controlled Period (Per-Protocol Analysis Set) 
Table 14.2A.1.11.1: HQ-CT Question 9 Score – Repeated Measures Analysis – Placebo-
Controlled Period (Primary Analysis Set) 
Table 14.2A.1.11.2: HQ-CT Question 9 Score – Repeated Measures Analysis – Placebo-
Controlled Period (Full Analysis Set) 
14.2A.2 Children’s Yale Brown Obsessive Compulsive Scale (CY-BOCS) Summary Tables 
Table 14.2A.2.1.1: 
Summary of Observed Values and Change from Baseline in CY-BOCS 
Severity Rating Total Score by Treatment Arm – Placebo-Controlled 
Period (Primary Analysis Set) 
Table 14.2A.2.1.2: 
Summary of Observed Values and Change from Baseline in CY-BOCS 
Severity Rating Total Score by Treatment Arm – Placebo-Controlled 
Period (Full Analysis Set) 
Table 14.2A.2.2.1: 
CY-BOCS Severity Rating Total Score – Constrained Longitudinal Data 
Analysis – Placebo-Controlled Period (Primary Analysis Set) 
Table 14.2A.2.2.2: 
CY-BOCS Severity Rating Total Score – Constrained Longitudinal Data 
Analysis – Placebo-Controlled Period (Full Analysis Set) 
Table 14.2A.2.2.3: 
CY-BOCS Severity Rating Total Score – Constrained Longitudinal Data 
Analysis – Placebo-Controlled Period (Per-Protocol Analysis Set) 
Table 14.2A.2.3.1: 
CY-BOCS Severity Rating Total Score – Repeated Measures Analysis – 
Placebo-Controlled Period (Primary Analysis Set) 
Table 14.2A.2.3.2: 
CY-BOCS Severity Rating Total Score – Repeated Measures Analysis – 
Placebo-Controlled Period (Full Analysis Set) 
Table 14.2A.2.4.1: 
CY-BOCS Severity Rating Total Score by Gender – Effect Modifier 
Analysis – Placebo-Controlled Period (Primary Analysis Set) 
Table 14.2A.2.4.2: 
CY-BOCS Severity Rating Total Score by Age Tertile – Effect Modifier 
Analysis – Placebo-Controlled Period (Primary Analysis Set) 
Table 14.2A.2.4.3: 
CY-BOCS Severity Rating Total Score by Gender and Age Tertile – 
Effect Modifier Analysis – Placebo-Controlled Period (Primary Analysis 
Set) 
Table 14.2A.2.4.5: 
CY-BOCS Severity Rating Total Score by Site – Effect Modifier Analysis 
– Placebo-Controlled Period (Primary Analysis Set) 


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Table 14.2A.2.5.1: 
CY-BOCS Severity Rating Total Score by Gender – Effect Modifier 
Analysis – Placebo-Controlled Period (Full Analysis Set) 
Table 14.2A.2.5.2: 
CY-BOCS Severity Rating Total Score by Age Tertile – Effect Modifier 
Analysis – Placebo-Controlled Period (Full Analysis Set) 
Table 14.2A.2.5.3: 
CY-BOCS Severity Rating Total Score by Gender and Age Tertile – 
Effect Modifier Analysis – Placebo-Controlled Period (Full Analysis Set) 
Table 14.2A.2.5.5: 
CY-BOCS Severity Rating Total Score by Site – Effect Modifier Analysis 
– Placebo-Controlled Period (Full Analysis Set) 
Table 14.2A.2.6.1: 
Summary of Observed Values and Change from Baseline in CY-BOCS 
Obsessions Severity Rating Score by Treatment Arm – Placebo-Controlled 
Period (Primary Analysis Set) 
Table 14.2A.2.6.2: 
Summary of Observed Values and Change from Baseline in CY-BOCS 
Obsessions Severity Rating Score by Treatment Arm – Placebo-Controlled 
Period (Full Analysis Set) 
Table 14.2A.2.7.1: 
CY-BOCS Obsessions Severity Rating Score – Constrained Longitudinal 
Data Analysis – Placebo-Controlled Period (Primary Analysis Set) 
Table 14.2A.2.7.2: 
CY-BOCS Obsessions Severity Rating Score – Constrained Longitudinal 
Data Analysis – Placebo-Controlled Period (Full Analysis Set) 
Table 14.2A.2.8.1: 
Summary of Observed Values and Change from Baseline in CY-BOCS 
Compulsions Severity Rating Score by Treatment Arm – Placebo-
Controlled Period (Primary Analysis Set) 
Table 14.2A.2.8.2: 
Summary of Observed Values and Change from Baseline in CY-BOCS 
Compulsions Severity Rating Score by Treatment Arm – Placebo-
Controlled Period (Full Analysis Set) 
Table 14.2A.2.9.1: 
CY-BOCS Compulsions Severity Rating Score – Constrained 
Longitudinal Data Analysis – Placebo-Controlled Period (Primary 
Analysis Set) 
Table 14.2A.2.9.2: 
CY-BOCS Compulsions Severity Rating Score – Constrained 
Longitudinal Data Analysis – Placebo-Controlled Period (Full Analysis 
Set) 
14.2A.3 PWS Anxiety and Distress Behaviors Questionnaire (PADQ) Summary Tables 
Table 14.2A.3.1.1: 
Summary of Observed Values and Change from Baseline in PADQ Score 
by Treatment Arm – Placebo-Controlled Period (Primary Analysis Set) 


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Table 14.2A.3.1.2: 
Summary of Observed Values and Change from Baseline in PADQ Score 
by Treatment Arm – Placebo-Controlled Period (Full Analysis Set) 
Table 14.2A.3.2.1: 
PADQ Score – Constrained Longitudinal Data Analysis– Placebo-
Controlled Period (Primary Analysis Set) 
Table 14.2A.3.2.2: 
PADQ Score – Constrained Longitudinal Data Analysis– Placebo-
Controlled Period (Full Analysis Set) 
Table 14.2A.3.2.3: 
PADQ Score – Constrained Longitudinal Data Analysis– Placebo-
Controlled Period (Per-Protocol Analysis Set) 
Table 14.2A.3.3.1: 
PADQ Score – Repeated Measures Analysis– Placebo-Controlled Period 
(Primary Analysis Set) 
Table 14.2A.3.3.2: 
PADQ Score – Repeated Measures Analysis– Placebo-Controlled Period 
(Full Analysis Set) 
14.2A.4 Overall PWS Clinical Global Impression (CGI) Summary Tables 
Table 14.2A.4.1.1: 
Summary of Observed Values and Change from Baseline in CGI-S Score 
by Treatment Arm – Placebo-Controlled Period (Primary Analysis Set) 
Table 14.2A.4.1.2: 
Summary of Observed Values and Change from Baseline in CGI-S Score 
by Treatment Arm – Placebo-Controlled Period (Full Analysis Set) 
Table 14.2A.4.2.1: 
CGI-S Score – Constrained Longitudinal Data Analysis – Placebo-
Controlled Period (Primary Analysis Set) 
Table 14.2A.4.2.2: 
CGI-S Score – Constrained Longitudinal Data Analysis – Placebo-
Controlled Period (Full Analysis Set) 
Table 14.2A.4.3.1: 
Summary of Observed CGI-C Score by Treatment Arm – Placebo-
Controlled Period (Primary Analysis Set) 
Table 14.2A.4.3.2: 
Summary of Observed CGI-C Score by Treatment Arm – Placebo-
Controlled Period (Full Analysis Set) 
Table 14.2A.4.4.1: 
CGI-C Score – Repeated Measures Analysis – Placebo-Controlled Period 
(Primary Analysis Set) 
Table 14.2A.4.4.2: 
CGI-C Score – Repeated Measures Data Analysis – Placebo-Controlled 
Period (Full Analysis Set) 
Table 14.2A.4.4.3: 
CGI-C Score – Repeated Measures Data Analysis – Placebo-Controlled 
Period (Per-Protocol Analysis Set) 


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14.3 Safety Data Summary Tables 
14.3A Safety Data Summary Tables During the Placebo-Controlled Period 
14.3A.1 Displays of Adverse Events During the Placebo-Controlled Period 
Table 14.3A.1.1: 
Overall Summary Table of Treatment-Emergent Adverse Events – 
Placebo-Controlled Period 
Table 14.3A.1.2: 
Frequency Table of Treatment-Emergent Adverse Events by SOC, PT, 
and Treatment Arm – Placebo-Controlled Period 
Table 14.3A.1.3: 
Frequency Table of Treatment-Emergent Adverse Events Leading to 
Study Drug Interruption by SOC, PT, and Treatment Arm – Placebo-
Controlled Period 
Table 14.3A.1.4: 
Frequency Table of Treatment-Emergent Adverse Events Leading to 
Study Drug Discontinuation by SOC, PT, and Treatment Arm – Placebo-
Controlled Period 
Table 14.3A.1.5: 
Frequency Table of Treatment-Emergent Adverse Events by SOC, PT, 
Maximum Severity, and Treatment Arm – Placebo-Controlled Period 
Table 14.3A.1.6: 
Frequency Table of Treatment-Emergent Adverse Events Possibly Related 
to Study Drug by SOC, PT, and Treatment Arm – Placebo-Controlled 
Period 


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14.3A.2 Deaths and Serious Adverse Events During the Placebo-Controlled Period 
Table 14.3A.2.1: 
Frequency Table of Treatment-Emergent Serious Adverse Events by SOC, 
PT, and Treatment Arm – Placebo-Controlled Period 
Table 14.3A.2.2: 
Frequency Table of Treatment-Emergent Serious Adverse Events Possibly 
Related to Study Drug by SOC, PT, and Treatment Arm – Placebo-
Controlled Period 
14.3A.4 Laboratory Data During the Placebo-Controlled Period 
Table 14.3A.4.1: 
Summary of Hematology Results by Visit and Treatment Arm – Placebo-
Controlled Period 
Table 14.3A.4.2: 
Shift Table of Hematology Results by Treatment Arm – Placebo-
Controlled Period 
Table 14.3A.4.3: 
Summary of Serum Chemistry Results by Visit and Treatment Arm – 
Placebo-Controlled Period 
Table 14.3A.4.4: 
Shift Table of Serum Chemistry Results by Treatment Arm – Placebo-
Controlled Period 
Table 14.3A.4.5: 
Summary of Urinalysis Results by Visit and Treatment Arm – Placebo-
Controlled Period 
Table 14.3A.4.6: 
Summary of Coagulation Results by Visit and Treatment Arm – Placebo-
Controlled Period 
Table 14.3A.4.7: 
Shift Table of Coagulation Results by Treatment Arm – Placebo-
Controlled Period 
Table 14.3A.4.9: 
Frequency Table of ECG Global Assessments by Visit and Treatment Arm 
– Placebo-Controlled Period 
Table 14.3A.4.10: 
Shift Table of ECG Results by Treatment Arm – Placebo-Controlled 
Period 
Table 14.3A.4.11: 
Summary of Vital Sign Parameter by Visit and Treatment Arm – Placebo-
Controlled Period 
 
 


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APPENDIX D: LIST OF TABLES AND LISTINGS FOR THE LONG-
TERM FOLLOW-UP PERIOD 
The statistical tables will appear in Section 14 of the clinical study report.  The statistical tables, 
therefore, have a prefix of “14.” 
14.1 Demographic Data Summary Tables 
14.1B Demographic Data Summary Tables for the Long-Term Follow-Up Period 
Table 14.1B.3.1: 
Patient Study Visit Occurrence by Treatment Arm – Long-Term Follow-
Up Period (Primary Analysis Set) 
Table 14.1B.3.2: 
Patient Study Visit Occurrence by Treatment Arm – Long-Term Follow-
Up Period (Full Analysis Set) 
Table 14.1B.4.1: 
Important Protocol Deviations by Treatment Arm – Long-Term Follow-
Up and Extension Periods (Primary Analysis Set) 
Table 14.1B.4.2: 
Important Protocol Deviations by Treatment Arm – Long-Term Follow-
Up and Extension Periods (Full Analysis Set) 
Table 14.1B.5: 
Analysis Sets by Treatment Arm – Long-Term Follow-Up and Extension 
Periods 
Table 14.1B.6.1: 
Summary of Demographic and Baseline Characteristics by Treatment Arm 
– Long-Term Follow-Up and Extension Periods (Primary Analysis Set) 
Table 14.1B.6.2: 
Summary of Demographic and Baseline Characteristics by Treatment Arm 
– Long-Term Follow-Up and Extension Periods (Full Analysis Set) 
Table 14.1B.7.1: 
Medical History by Treatment Arm – Long-Term Follow-Up and 
Extension Periods (Primary Analysis Set) 
Table 14.1B.7.2: 
Medical History by Treatment Arm – Long-Term Follow-Up and 
Extension Periods (Full Analysis Set) 
Table 14.1B.9.1: 
Concomitant Medications by Treatment Arm – Long-Term Follow-Up and 
Extension Periods (Primary Analysis Set) 
Table 14.1B.9.2: 
Concomitant Medications by Treatment Arm – Long-Term Follow-Up and 
Extension Periods (Full Analysis Set) 
Table 14.1B.10: 
Summary of Treatment Duration by Treatment Arm – Long-Term Follow-
Up and Extension Periods 
Table 14.1B.11: 
Frequency Table of Treatment Duration by Treatment Arm 
Table 14.1B.12: 
Frequency Table of Study Drug Compliance by Visit and Treatment Arm 
– Long-Term Follow-Up and Extension Periods 


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Table 14.1B.13: 
Frequency Table of Administered Doses by Treatment Arm – Long-Term 
Follow-Up and Extension Periods 
14.2 Efficacy Data Summary Tables  
14.2B Efficacy Data Summary Tables for the Long-Term Follow-Up Period 
14.2B.1 Hyperphagia Questionnaire for Clinical Trials (HQ-CT) Summary Tables 
Table 14.2B.1.1.1: 
Summary of Observed Values and Change from Baseline in HQ-CT Total 
Score by Treatment Arm – Long-Term Follow-Up Period (Primary 
Analysis Set) 
Table 14.2B.1.1.2: 
Summary of Observed Values and Change from Baseline in HQ-CT Total 
Score by Treatment Arm – Long-Term Follow-Up Period (Full Analysis 
Set) 
Table 14.2B.1.6.1: 
Summary of Observed Values and Change from Baseline in Total Score of 
a Subset of HQ-CT by Treatment Arm – Long-Term Follow-Up Period 
(Primary Analysis Set) 
Table 14.2B.1.6.2: 
Summary of Observed Values and Change from Baseline in Total Score of 
a Subset of HQ-CT by Treatment Arm – Long-Term Follow-Up Period 
(Full Analysis Set) 
Table 14.2B.1.9.1: 
Summary of Observed Values and Change from Baseline in HQ-CT 
Question 9 Score by Treatment Arm – Long-Term Follow-Up Period 
(Primary Analysis Set) 
Table 14.2B.1.9.2: 
Summary of Observed Values and Change from Baseline in HQ-CT 
Question 9 Score by Treatment Arm – Long-Term Follow-Up Period (Full 
Analysis Set) 
14.2B.2 Children’s Yale Brown Obsessive Compulsive Scale (CY-BOCS) Summary Tables 
Table 14.2B.2.1.1: 
Summary of Observed Values and Change from Baseline in CY-BOCS 
Severity Rating Total Score by Treatment Arm – Long-Term Follow-Up 
Period (Primary Analysis Set) 
Table 14.2B.2.1.2: 
Summary of Observed Values and Change from Baseline in CY-BOCS 
Severity Rating Total Score by Treatment Arm – Long-Term Follow-Up 
Period (Full Analysis Set) 
Table 14.2B.2.6.1: 
Summary of Observed Values and Change from Baseline in CY-BOCS 
Obsessions Severity Rating Score by Treatment Arm – Long-Term 
Follow-Up Period (Primary Analysis Set) 
Table 14.2B.2.6.2: 
Summary of Observed Values and Change from Baseline in CY-BOCS 
Obsessions Severity Rating Score by Treatment Arm – Long-Term 
Follow-Up Period (Full Analysis Set) 


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Table 14.2B.2.8.1: 
Summary of Observed Values and Change from Baseline in CY-BOCS 
Compulsions Severity Rating Score by Treatment Arm – Long-Term 
Follow-Up Period (Primary Analysis Set) 
Table 14.2B.2.8.2: 
Summary of Observed Values and Change from Baseline in CY-BOCS 
Compulsions Severity Rating Score by Treatment Arm – Long-Term 
Follow-Up Period (Full Analysis Set) 
14.2B.3 PWS Anxiety and Distress Behaviors Questionnaire (PADQ) Summary Tables 
Table 14.2B.3.1.1: 
Summary of Observed Values and Change from Baseline in PADQ Score 
by Treatment Arm – Long-Term Follow-Up Period (Primary Analysis Set) 
Table 14.2B.3.1.2: 
Summary of Observed Values and Change from Baseline in PADQ Score 
by Treatment Arm – Long-Term Follow-Up Period (Full Analysis Set) 
14.2B.4 Overall PWS Clinical Global Impression (CGI) Summary Tables 
Table 14.2B.4.1.1: 
Summary of Observed Values and Change from Baseline in CGI-S Score 
by Treatment Arm – Long-Term Follow-Up Period (Primary Analysis Set) 
Table 14.2B.4.1.2: 
Summary of Observed Values and Change from Baseline in CGI-S Score 
by Treatment Arm – Long-Term Follow-Up Period (Full Analysis Set) 
Table 14.2B.4.3.1: 
Summary of Observed CGI-C Score by Treatment Arm – Long-Term 
Follow-Up Period (Primary Analysis Set) 
Table 14.2B.4.3.2: 
Summary of Observed CGI-C Score by Treatment Arm – Long-Term 
Follow-Up Period (Full Analysis Set) 


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14.2B.9 Other Efficacy Summary Tables 
Table 14.2B.9.1.1: 
PWS Nutritional Phase by Treatment Arm (Primary Analysis Set) 
Table 14.2B.9.1.2: 
PWS Nutritional Phase by Treatment Arm (Full Analysis Set) 


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14.3 Safety Data Summary Tables 
14.3B Safety Data Summary Tables During the Long-Term Follow-Up Period 
14.3B.1 Displays of Adverse Events During the Long-Term Follow-Up Period 
Table 14.3B.1.1: 
Overall Summary Table of Treatment-Emergent Adverse Events – Long-
Term Follow-Up and Extension Periods 
Table 14.3B.1.2: 
Frequency Table of Treatment-Emergent Adverse Events by SOC, PT, 
and Treatment Arm – Long-Term Follow-Up and Extension Periods 
Table 14.3B.1.3: 
Frequency Table of Treatment-Emergent Adverse Events Leading to 
Study Drug Interruption by SOC, PT, and Treatment Arm – Long-Term 
Follow-Up and Extension Periods 
Table 14.3B.1.4: 
Frequency Table of Treatment-Emergent Adverse Events Leading to 
Study Drug Discontinuation by SOC, PT, and Treatment Arm – Long-
Term Follow-Up and Extension Periods 
Table 14.3B.1.5: 
Frequency Table of Treatment-Emergent Adverse Events by SOC, PT, 
Maximum Severity, and Treatment Arm – Long-Term Follow-Up and 
Extension Periods 
Table 14.3B.1.6: 
Frequency Table of Treatment-Emergent Adverse Events Possibly Related 
to Study Drug by SOC, PT, and Treatment Arm – Long-Term Follow-Up 
and Extension Periods 
14.3B.2 Deaths and Serious Adverse Events During the Long-Term Follow-Up Period 
Table 14.3B.2.1: 
Frequency Table of Treatment-Emergent Serious Adverse Events by SOC, 
PT, and Treatment Arm – Long-Term Follow-Up and Extension Periods 
Table 14.3B.2.2: 
Frequency Table of Treatment-Emergent Serious Adverse Events Possibly 
Related to Study Drug by SOC, PT, and Treatment Arm – Long-Term 
Follow-Up and Extension Periods 


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14.3B.4 Laboratory Data During the Long-Term Follow-Up Period 
Table 14.3B.4.1: 
Summary of Hematology Results by Visit and Treatment Arm – Long-
Term Follow-Up Period 
Table 14.3B.4.2: 
Shift Table of Hematology Results by Treatment Arm – Long-Term 
Follow-Up Period 
Table 14.3B.4.3: 
Summary of Serum Chemistry Results by Visit and Treatment Arm – 
Long-Term Follow-Up Period 
Table 14.3B.4.4: 
Shift Table of Serum Chemistry Results by Treatment Arm – Long-Term 
Follow-Up Period 
Table 14.3B.4.5: 
Summary of Urinalysis Results by Visit and Treatment Arm – Long-Term 
Follow-Up Period 
Table 14.3B.4.6: 
Summary of Coagulation Results by Visit and Treatment Arm – Long-
Term Follow-Up Period 
Table 14.3B.4.7: 
Shift Table of Coagulation Results by Treatment Arm – Long-Term 
Follow-Up Period 
Table 14.3B.4.8: 
Frequency Table of Tanner Staging by Visit and Treatment Arm – Long-
Term Follow-Up Period 
Table 14.3B.4.9: 
Frequency Table of ECG Global Assessments by Visit and Treatment Arm 
– Long-Term Follow-Up Period 
Table 14.3B.4.10: 
Shift Table of ECG Results by Treatment Arm – Long-Term Follow-Up 
Period 
Table 14.3B.4.11: 
Summary of Vital Sign Parameter by Visit and Treatment Arm – Long-
Term Follow-Up Period 
 
 


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APPENDIX E: LIST OF PATIENT LISTINGS 
The patient listings will appear in Appendix 16.2 of the clinical study report.  The patient 
listings, therefore, have a prefix of “16.2.” 
16.2.1 Discontinued Patients 
Listing 16.2.1.1: 
Informed Consent and Protocol Version 
Listing 16.2.1.2: 
Patient Disposition and Reasons for Discontinuation from Study 
16.2.2 Protocol Deviations 
Listing 16.2.2.1: 
Important Protocol Deviations by Patient 
Listing 16.2.2.2: 
Protocol Deviations – Remote Visits Due to COVID-19 by Patient 
Listing 16.2.2.3: 
Missed Assessments for Remote Visits Due to COVID-19 by Patient 
Listing 16.2.2.4: 
Missed Visits by Patient 
Listing 16.2.2.5: 
Study Visit Occurrence by Patient 
Listing 16.2.2.6: 
Analysis Sets by Patient 
16.2.3 Patients Excluded from the Efficacy Analysis 
Listing 16.2.3.1: 
Data Points Excluded from the Primary Analysis Set 
Listing 16.2.3.2: 
Patients Excluded from the Per-Protocol Analysis Set 
16.2.4 Demographic and Baseline Characteristics 
Listing 16.2.4.1: 
Demographic and Baseline Characteristics by Patient 
Listing 16.2.4.2: 
Medical History by Patient 
Listing 16.2.4.3: 
Substance Use by Patient 
Listing 16.2.4.4: 
Prior Oxytocin or Carbetocin Use by Patient 
Listing 16.2.4.5: 
Pre-Treatment Medications by Patient (Part 1) 
Listing 16.2.4.6: 
Pre-Treatment Medications by Patient (Part 2) 
Listing 16.2.4.7: 
Concomitant Medications by Patient (Part 1) 
Listing 16.2.4.8: 
Concomitant Medications by Patient (Part 2) 
Listing 16.2.4.9: 
Pre-Treatment Treatments and Procedures by Patient 
Listing 16.2.4.10: 
Concomitant Treatments and Procedures by Patient 
16.2.5 Compliance and/or Drug Concentration Data 
Listing 16.2.5.1: 
Study Drug Dispensation by Patient 
Listing 16.2.5.2: 
Study Drug Administration by Patient 


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Listing 16.2.5.3: 
Missed and Missing Doses by Patient 
16.2.6 Individual Efficacy Response Data 
Listing 16.2.6.1.1: 
Hyperphagia Questionnaire for Clinical Trials (HQ-CT) Scores by Patient 
(Part 1) 
Listing 16.2.6.1.2: 
Hyperphagia Questionnaire for Clinical Trials (HQ-CT) Scores by Patient 
(Part 2) 
Listing 16.2.6.1.3: 
Hyperphagia Questionnaire for Clinical Trials (HQ-CT) Scores by Patient 
(Part 3) 
Listing 16.2.6.2.1: 
Children’s Yale Brown Obsessive Compulsive Scale (CY-BOCS) 
Obsessions – Contamination, Aggressive, Sexual, and Hoarding / Saving 
Obsessions by Patient 
Listing 16.2.6.2.2: 
Children’s Yale Brown Obsessive Compulsive Scale (CY-BOCS) 
Obsessions – Magical/Superstitious, Somatic, Religious, and 
Miscellaneous Obsessions by Patient  
Listing 16.2.6.2.3: 
Children’s Yale Brown Obsessive Compulsive Scale (CY-BOCS) 
Obsessions – Target Symptoms by Patient 
 
Listing 16.2.6.2.4: 
Children’s Yale Brown Obsessive Compulsive Scale (CY-BOCS) 
Compulsions – Washing / Cleaning, Checking, Repeating, and Counting 
Compulsions by Patient 
Listing 16.2.6.2.5: 
Children’s Yale Brown Obsessive Compulsive Scale (CY-BOCS) 
Compulsions – Ordering / Arranging, Hoarding / Saving, and  Excessive 
Games / Superstitious Compulsions by Patient 
Listing 16.2.6.2.6: 
Children’s Yale Brown Obsessive Compulsive Scale (CY-BOCS) 
Compulsions – Rituals Involving Other Persons and Miscellaneous 
Compulsions by Patient 
Listing 16.2.6.2.7: 
Children’s Yale Brown Obsessive Compulsive Scale (CY-BOCS) 
Compulsions – Target Symptoms by Patient 
Listing 16.2.6.2.8: 
Children’s Yale Brown Obsessive Compulsive Scale (CY-BOCS) 
Obsessions Severity Ratings by Patient 
Listing 16.2.6.2.9: 
Children’s Yale Brown Obsessive Compulsive Scale (CY-BOCS) 
Compulsions Severity Ratings by Patient 
Listing 16.2.6.2.10: 
Children’s Yale Brown Obsessive Compulsive Scale (CY-BOCS) 
Subtotals and Total Scores by Patient 
Listing 16.2.6.3.1: 
PWS Anxiety and Distress Behaviors Questionnaire (PADQ) Scores by 
Patient (Part 1) 


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Listing 16.2.6.3.2: 
PWS Anxiety and Distress Behaviors Questionnaire (PADQ) Scores by 
Patient (Part 2) 
Listing 16.2.6.3.3: 
PWS Anxiety and Distress Behaviors Questionnaire (PADQ) Scores by 
Patient (Part 3) 
Listing 16.2.6.4: 
Clinical Global Impressions of Severity and Change by Patient 
Listing 16.2.6.12: 
PWS Nutritional Phase by Patient 


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16.2.7 Adverse Event Data 
Listing 16.2.7.1: 
Treatment-Emergent Adverse Events by Patient (Part 1) 
Listing 16.2.7.2: 
Treatment-Emergent Adverse Events by Patient (Part 2) 
Listing 16.2.7.3: 
Treatment-Emergent Adverse Events Possibly Related to Study Drug by 
Patient (Part 1) 
Listing 16.2.7.4: 
Treatment-Emergent Adverse Events Possibly Related to Study Drug by 
Patient (Part 2) 
Listing 16.2.7.7: 
Pre-Treatment Serious Adverse Events by Patient (Part 1) 
Listing 16.2.7.8: 
Pre-Treatment Serious Adverse Events by Patient (Part 2) 
Listing 16.2.7.9: 
Pre-Treatment Serious Adverse Events by Patient (Part 3) 
Listing 16.2.7.10: 
Treatment-Emergent Serious Adverse Events by Patient (Part 1) 
Listing 16.2.7.11: 
Treatment-Emergent Serious Adverse Events by Patient (Part 2) 
Listing 16.2.7.12: 
Treatment-Emergent Serious Adverse Events by Patient (Part 3) 
Listing 16.2.7.13: 
Treatment-Emergent Adverse Events Leading to Study Drug Interruption 
by Patient (Part 1) 
Listing 16.2.7.14: 
Treatment-Emergent Adverse Events Leading to Study Drug Interruption 
by Patient (Part 2) 


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Listing 16.2.7.15: 
Treatment-Emergent Adverse Events Leading to Study Drug 
Discontinuation by Patient (Part 1) 
Listing 16.2.7.16: 
Treatment-Emergent Adverse Events Leading to Study Drug 
Discontinuation by Patient (Part 2) 
Listing 16.2.7.17: 
Treatment-Emergent Serious Adverse Events Leading to Death (Part 1) 
Listing 16.2.7.18: 
Treatment-Emergent Serious Adverse Events Leading to Death (Part 2) 
Listing 16.2.7.19: 
Treatment-Emergent Serious Adverse Events Leading to Death (Part 3) 
Listing 16.2.7.20: 
Investigator Narratives of Adverse Events 
Listing 16.2.7.21: 
Investigator Narratives of CY-BOCS Results 
16.2.8 Listing of Individual Laboratory Measurements 
Listing 16.2.8.1: 
Hematology Results by Patient 
Listing 16.2.8.2: 
Serum Chemistry Results by Patient 
Listing 16.2.8.3: 
Urinalysis Results by Patient 
Listing 16.2.8.4: 
Coagulation Results by Patient 
Listing 16.2.8.5: 
Physical Exam Results by Patient 
Listing 16.2.8.6: 
Tanner Staging by Patient 
Listing 16.2.8.7: 
Nasal Assessment Results by Patient 
Listing 16.2.8.8: 
ECG Results by Patient 
Listing 16.2.8.9: 
Vital Sign Results by Patient 
Listing 16.2.8.10: 
Urine Pregnancy Test Results by Patient 
16.2.9 Other Data Listings 
Listing 16.2.9.1: 
Intranasal Spray Pump Incidents Reported by Site 
Listing 16.2.9.2: 
Intranasal Spray Pump Incidents Reported by Sponsor (Part 1) 
Listing 16.2.9.3: 
Intranasal Spray Pump Incidents Reported by Sponsor (Part 2)