Conditions: Hyperphagia in Prader-Willi Syndrome
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 38
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the safety and effectiveness of intranasal FE 992097 in children and adults with Prader-Willi Syndrome.

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: FE 992097 intervention 2: Placebo
Intervention descriptions: intervention 1: Each spray pump actuation delivered a 50 μL volume of solution that contained 1.6 mg carbetocin (FE 992097); each dose consisted of 3 spray pump actuations in each nostril that delivered a total of 9.6 mg carbetocin.

Parents were instructed to administer 3 intranasal spray actuations in each nostril 3 times daily before meals for 14 days. intervention 2: Each spray pump actuation delivered a 50 μL volume of sterile sodium chloride solution 0.9%; each dose consisted of 3 spray pump actuations in each nostril.

Parents were instructed to administer 3 intranasal spray actuations in each nostril 3 times daily before meals for 14 days.

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
Protocol  
 
Title of trial:  
A Prospective, Randomized, Double-Blind, Placebo-Controlled Study to 
Evaluate the Safety and Effectiveness of Intranasal Carbetocin in Subjects 
with Prader-Willi Syndrome (PWS) 
NCT number: 
NCT01968187 
Sponsor trial code: 
000114  
Date:  
10-Feb-2014  
 
 
 
 
 


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CONFIDENTIAL
CLINICAL TRIAL PROTOCOL
A Prospective, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and 
Effectiveness of Intranasal Carbetocin in Subjects with Prader-Willi Syndrome (PWS)
Trial Code 000114
IND Number:
112,521
Investigational Medicinal Product:
Carbetocin (FE 992097)
Indication:
Treatment of hyperphagia behavioral symptoms in children 
and adults diagnosed with PWS
Phase:
2a
Name and Address of Sponsor:
Ferring International Pharmascience Center U.S., Inc.
4 Gatehall Drive, 3rd Floor
Parsippany, NJ  07054
Phone: 973-796-1600 
Fax: 973-796-1663
GCP Statement:
This trial will be performed in compliance with GCP.
The information in this document is confidential and is proprietary to Ferring Pharmaceuticals A/S or another company 
within the Ferring Group. It is understood that information in this document shall not be disclosed to any third party, in any 
form, without prior written consent of an authorized officer of Ferring Pharmaceuticals A/S or another company within the 
Ferring Group.


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SYNOPSIS
TITLE OF TRIAL
A Prospective, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Effectiveness of Intranasal 
Carbetocin in Subjects with Prader Willi Syndrome (PWS)
SIGNATORY INVESTIGATOR(S)
No signatory investigator(s) will be appointed for this trial.
TRIAL SITE(S)
The trial will be conducted at approximately 3 sites in the United States.
PLANNED TRIAL PERIOD
Enrollment time: Approximately 6 months
Trial duration: Approximately 8 months
CLINICAL PHASE
2a
OBJECTIVES
Primary objective 

To assess the effect of intranasal carbetocin (FE 992097) on hyperphagia behavioral symptoms in subjects with 
Prader-Willi Syndrome (PWS), measured by the Hyperphagia in Prader-Willi Syndrome Questionnaire-
Responsiveness (HPWSQ-R) scale – completed by the subject’s parent/caregiver
Secondary objectives

To assess the effect of intranasal carbetocin (FE 992097) on hyperphagia behavioral symptoms in subjects with 
Prader-Willi Syndrome (PWS), measured by the Hyperphagia in Prader-Willi Syndrome Questionnaire-
Responsiveness – Clinician (HPWSQ-R-C) scale – administered by the clinician

To assess improvement of PWS symptoms, assessed by the Clinical Global Impression (CGI) scale

To assess safety and tolerability of intranasal carbetocin

To assess a population pharmacokinetic model for the patient population utilizing sparse data sampling 

To assess the effects of intranasal carbetocin on PWS maladaptive behaviors, assessed by the Children’s 
Yale-Brown Obsessive Compulsive Scale (CY-BOCS)

To assess the sensitivity of Food Domain of the Reiss Profile


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ENDPOINTS
Primary endpoint 
Change in HPWSQ-R total score from Visit 2 to Visit 4
Secondary endpoints
1.
Clinical Global Impression-Improvement after treatment (CGI-I) at Visit 4
2.
Change from Visit 2 to Visit 4 for the following measurements:

HPWSQ-R hyperphagia behavior, drive, and severity domain scores

HPWSQ-R-C total score

HPWSQ-R-C hyperphagia behavior, drive, and severity domain scores
3.
Change from Visit 1 to Visit 4 for the following measurements:

CY-BOCS score

Food Domain of the Reiss Profile
4.
Population PK/PD relationships for carbetocin
Safety endpoints:

Frequency, severity and seriousness of adverse events

Clinically significant changes in vital signs

Clinically significant findings during physical and laboratory assessments

Physical examinations, including focused nasal examinations and nasal irritation, graded 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


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METHODOLOGY
This is a prospective, double-blind, placebo-controlled, parallel trial in subjects with PWS between 10 and 18 years of age 
with genetically confirmed diagnosis of PWS and a documented nutritional phase 3 based on the criteria of Miller et al, 
2011. Since PWS is a rare condition, and individuals with PWS are generally treated at a few centers of excellence 
throughout the country, it is expected that a significant proportion of eligible subjects will reside at a considerable 
geographic distance from the investigational site(s), requiring ground or air transportation to complete trial visits. The trial
design considers both the geographic challenges, as well as the need to ensure subjects’ home-life “normalcy” during the 
trial in order to accurately assess treatment effect. The trial includes a Screening Period, a 14-day Treatment Period, and a 
Follow-Up Period. Subjects, along with their parent/caregiver, will be required to visit the investigational site 4 times over 
the course of the trial and participate in 2 phone call assessments. 

Visit 1: Screening Period (Day -7 to Day 0)

Visit 2: Baseline 1st day dosing on site (Day 1)

Visit 3:  2nd day dosing on site (Day 2)

Phone call assessment (Day 8±1)

Visit 4: End-of-Treatment Visit (Day 15)

Follow-up phone call (Day 19±3)
Following appropriate informed consent procedures, subjects will undergo screening evaluations to determine eligibility 
before randomization. Screening evaluations include a physical examination, vital signs, 12-lead electrocardiogram (ECG), 
and laboratory assessments - hematology, clinical chemistry, hemostasis, and urinalysis. After randomization, efficacy 
measures and other assessments, including physical examination, vital signs, and collection of blood samples for clinical 
laboratory and pharmacokinetic evaluation, will be performed at selected visits according to the Trial Flow Chart (Table 1). 
Subjects will be closely monitored for adverse events throughout the trial.
Prior to first dosing at the investigational site, parents/caregivers will be trained on the proper use of the nasal spray device 
and procedures for investigational medicinal product (IMP) home delivery. Parents/caregivers will be instructed to 
administer 3 intranasal spray pumps of blinded IMP per nostril 3 times daily before meals within the following intervals:
Morning dose:
06:00 a.m. – 09:00 a.m.
Midday dose:
11:00 a.m. – 1:00 p.m.
Evening dose:
4:30 p.m. – 6:00 p.m.
Initial IMP dosing at Visit 2 (Day 1) and Visit 3 (Day 2) will take place under observation of the site staff at the 
investigational site. Subject vital signs will be monitored prior to and after IMP dosing at 30-minute intervals for 2 hours 
after each dose. IMP will be shipped by central pharmacy directly to the subject’s residence on regular intervals as needed 
for the duration of the Treatment Period.  IMP will be administered by parents/caregivers 3 times per day before meals 
within the above-specified dosing intervals. The IMP will require refrigeration during shipment to and during storage until 
administered. 
NUMBER OF SUBJECTS
Approximately 38 male or female subjects 10-18 years of age, with genetically confirmed diagnosis of PWS and
documented nutritional phase 3 PWS criteria (based on Miller et al, 2011), will be randomized.


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MAIN CRITERIA FOR INCLUSION / EXCLUSION
Inclusion Criteria: 
1.
Signed informed consent by parent/caregiver
2.
Signed assent by subject (if applicable)
3.
Male or female 10-18 years of age (both inclusive)
4.
Genetically confirmed diagnosis of PWS 
5.
Nutritional phase 3 PWS criteria based on Miller et al, 2011
6.
HPWSQ-R score  greater than 13 at screening (Visit 1)
7.
Willingness and ability of the parent/caregiver to comply with the protocol and trial requirements
8.
Negative urine drug and alcohol screen at screening (Visit 1)
9.
Negative urine pregnancy test for female subjects of childbearing potential at screening (Visit 1). 
10. Willing to use an adequate barrier method or hormonal method of contraception from informed consent to 1 week 
after the end of dosing of trial medication, if deemed appropriate by the investigator
11. Ability of the subject to perform procedures and assessment required of this trial, based on the investigator's 
judgment
Exclusion Criteria: 
1.
Known genetic, hormonal, or chromosomal cause of cognitive impairment other than PWS
2.
Presence of currently active psychotic symptoms
3.
Presence of any cardiovascular disorders, epilepsy, frequent migraines or severe asthma
4.
Previous diagnosis of autism spectrum disorder by a qualified healthcare provider
5.
Prior or concomitant use of a selective serotonin reuptake inhibitor (SSRI) or selective norepinephrine reuptake 
inhibitor (SNRI), antipsychotic medication, wakefulness-promoting drug, or thyroid hormone that does not comply 
with the criteria in Section 4.3.1
6.
Use of any of the prohibited medications or therapies listed in Section 4.3.2
7.
Major surgery within 6 months of screening (Visit 1)
8.
Nasal or sinus surgery within 1 year of screening (Visit 1)
9.
Chronic sinusitis - more than 3 episodes per year 
10. Other nasal diseases that may affect deposition of intranasal medication
11. Serum sodium < 135 mmol/L at screening (Visit 1)
12. Known hypersensitivity to any component of carbetocin or saline solution
13. History of long-term daily use of any intranasal medication
14. Cancer within the last 5 years except for adequately managed basal cell carcinoma or squamous cell carcinoma of 
the skin
15. History within the last 2 years or current abuse of alcohol or drugs
16. Intake of an IMP within the last 12 weeks preceding screening or longer, if judged by the investigator to possibly 
influence the outcome of the current trial
17. Mental incapacity or language barrier of the primary parent/caregiver precluding adequate understanding or 
cooperation
18. Considered by the investigator to be unsuitable to participate in the trial for any other reason


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MEDICINAL PRODUCTS
The IMPs to be used in this trial are:
Carbetocin intranasal spray – Carbetocin dissolved in sterile sodium chloride solution 0.9%

Carbetocin Powder for Solution for Nasal Spray, 160 mg

Sodium chloride solution 0.9%, sterile

The preweighed carbetocin powder to be reconstituted with the sodium chloride solution and subsequently 
transferred to a nasal spray device

Each spray pump actuation will deliver a 50 µL volume of solution containing 1.6 mg carbetocin; each dose 
will consist of 3 spray pump actuations in each nostril to deliver a total of 9.6 mg carbetocin
Placebo intranasal spray – sterile sodium chloride solution 0.9%

Sterile sodium chloride solution 0.9% to be transferred to a nasal spray device

Each spray pump actuation will deliver 50 µL volume of solution; each dose will consist of 3 spray pump 
actuations in each nostril
DURATION OF TREATMENT
For each subject, there will be 14 days of treatment with either intranasal carbetocin or placebo.
STATISTICAL METHODS
Sample Size: 
Based on the available literature (Dykens et al 2007), the baseline HPWSQ-R total score is assumed to be normally 
distributed with a standard deviation of 6.12, and the standard deviation of the change between baseline (Visit 2) and Visit 4 
is estimated to be between 5 and 6.  With 30 subjects eligible for the primary efficacy assessment, the trial has at least 80% 
power to detect a borderline statistically significant difference (1-sided 10% significance) between 2 groups when the true 
treatment group difference is -5 under the standard deviation of 5 to 6.  Subjects are randomized in a 1:1 ratio to either 
placebo or carbetocin.  
The efficacy of carbetocin will be assessed by change in HPWSQ-R total score from Visit 2 (baseline) to Visit 4. Assuming 
a dropout rate of approximately 20%, at least 19 subjects per treatment arm will need to be randomized to have a total of 30 
subjects eligible for the primary efficacy assessment.
Primary Analysis:
The primary endpoint will be analyzed using an analysis of covariance model with treatment and site as fixed effects and 
HPWSQ-R total score at Visit 2 (baseline) as a covariate. The last observation carried forward method will be used to carry 
forward non-missing values of HPWSQ-R total score during the phone call assessment (Day 8±1) to impute missing values 
of HPWSQ-R total score at Visit 4. The treatment group difference in total score between placebo and carbetocin will be 
calculated by subtracting the mean change from baseline in placebo from that in the carbetocin group.  A borderline 
statistically significant difference at the 10% significant level will be achieved if the upper limit of the 90% 1-sided 
confidence interval for the treatment difference is less than zero.
The secondary endpoints will be analyzed using a similar model to that of the primary endpoint.


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TABLE OF CONTENTS
Page
1
INTRODUCTION ................................................................................................................................... 13
1.1
Background................................................................................................................................... 13
1.2
Scientific Justification for Conducting the Trial........................................................................... 13
1.3
Benefit / Risk Aspects................................................................................................................... 14
2
TRIAL OBJECTIVES AND ENDPOINTS........................................................................................... 15
2.1
Objectives ..................................................................................................................................... 15
2.2
Endpoints ...................................................................................................................................... 15
3
INVESTIGATIONAL PLAN ................................................................................................................. 17
3.1
Overall Trial Design...................................................................................................................... 17
3.1.1
Overall Design and Control Methods .............................................................................. 17
3.1.2
Trial Schedule.................................................................................................................. 18
3.2
Planned Number of Trial Sites and Subjects................................................................................. 18
3.3
Interim Analysis............................................................................................................................ 18
3.4
Data Monitoring Committee (DMC) ............................................................................................ 18
3.5
Discussion of Overall Trial Design and Choice of Control Groups ............................................. 18
3.5.1
Trial Design ..................................................................................................................... 18
3.5.2
Selection of Endpoints ..................................................................................................... 19
3.5.3
Blinding ........................................................................................................................... 20
3.5.4
Selection of Doses in the Trial......................................................................................... 21
3.5.5
Selection and Timing of Dose for Each Subject.............................................................. 22
3.5.6
Withdrawal Criteria ......................................................................................................... 22
3.5.7
Follow-up Procedures ...................................................................................................... 22
4
SELECTION OF TRIAL POPULATION ............................................................................................ 23
4.1
Trial Population ............................................................................................................................ 23
4.1.1
Inclusion Criteria ............................................................................................................. 23
4.1.2
Exclusion Criteria ............................................................................................................ 23
4.2
Method of Assigning Subjects to Treatment Groups.................................................................... 24
4.3
Restrictions ................................................................................................................................... 25
4.3.1
Prior and Concomitant Therapies .................................................................................... 25
4.3.2
Prohibited Therapy........................................................................................................... 26
5
TREATMENTS ....................................................................................................................................... 27
5.1
Treatments Administered.............................................................................................................. 27
5.2
Characteristics and Source of Supply ........................................................................................... 27
5.3
Packaging and Labeling................................................................................................................ 28
5.4
Blinding / Unblinding ................................................................................................................... 28
5.4.1
Blinding ........................................................................................................................... 28
5.4.2
Unblinding of Individual Subject Treatment ................................................................... 28
5.5
Conditions for Storage and Use .................................................................................................... 29


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5.6
Treatment Compliance.................................................................................................................. 29
5.6.1
Preparation....................................................................................................................... 29
5.6.2
Dispensing and Accountability ........................................................................................ 29
5.6.3
Assessment of Compliance.............................................................................................. 30
5.7
Return and Destruction of Medicinal Products............................................................................. 30
6
TRIAL PROCEDURES .......................................................................................................................... 31
6.1
Trial Flow Chart............................................................................................................................ 31
6.1.1
Screening (Visit 1: Days -7 through 0)............................................................................ 32
6.1.2
Treatment Period.............................................................................................................. 33
6.1.3
Follow-up......................................................................................................................... 34
7
TRIAL ASSESSMENTS ......................................................................................................................... 36
7.1
Assessments Related to Endpoints................................................................................................ 36
7.1.1
Clinical Global Impression Scales ................................................................................... 36
7.1.2
Hyperphagia in PWS Questionnaires............................................................................... 36
7.1.3
Children’s Yale-Brown Obsessive-Compulsive Scale (CY-BOCS)................................ 36
7.1.4
Food Domain From the Reiss Profile .............................................................................. 36
7.2
Safety and Other Assessments ...................................................................................................... 36
7.2.1
Medical History ............................................................................................................... 36
7.2.2
Physical Examination....................................................................................................... 37
7.2.3
Nasal Examination........................................................................................................... 37
7.2.4
Height, Weight and Vital Signs ....................................................................................... 37
7.2.5
12-Lead Electrocardiogram.............................................................................................. 38
7.2.6
Clinical Laboratory Tests................................................................................................. 38
8
ADVERSE EVENTS ............................................................................................................................... 40
8.1
Adverse Event Definition.............................................................................................................. 40
8.2
Collection and Recording of Adverse Events............................................................................... 40
8.2.1
Collection of Adverse Events .......................................................................................... 40
8.2.2
Recording of Adverse Events .......................................................................................... 41
8.3
Pregnancy and Pregnancy Outcome ............................................................................................. 44
8.4
Serious Adverse Events ................................................................................................................ 45
8.4.1
Serious Adverse Event Definition.................................................................................... 45
8.4.2
Collection, Recording and Reporting of Serious Adverse Events ................................... 46
8.5
Follow-up of Adverse Events and Serious Adverse Events.......................................................... 47
8.5.1
Follow-up of Adverse Events with Onset during the Trial.............................................. 47
8.5.2
Collection of Serious Adverse Events with Onset after Last Trial Visit ......................... 47
9
STATISTICAL METHODS ................................................................................................................... 48
9.1
Determination of Sample Size ...................................................................................................... 48
9.2
Subject Disposition ....................................................................................................................... 48
9.3
Protocol Deviations....................................................................................................................... 48
9.4
Analysis Sets................................................................................................................................. 48
9.4.1
Safety Population............................................................................................................. 48


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9.4.2
Full Analysis Set (FAS) Population................................................................................. 48
9.4.3
Pharmacokinetic Population ............................................................................................ 49
9.5
Trial Population ............................................................................................................................ 49
9.5.1
Demographics and other Baseline Characteristics........................................................... 49
9.5.2
Medical History, Concomitant Medication and Other Safety Evaluations...................... 49
9.6
Endpoint Assessments................................................................................................................... 49
9.6.1
Efficacy Analyses ............................................................................................................ 49
9.7
Extent of Exposure........................................................................................................................ 49
9.8
Safety ............................................................................................................................................ 49
9.8.1
General Considerations.................................................................................................... 49
9.8.2
Adverse Events ................................................................................................................ 50
9.8.3
Safety Laboratory Variables ............................................................................................ 50
9.8.4
Other Safety Variables..................................................................................................... 50
9.9
Population Pharmacokinetic Modeling......................................................................................... 50
10
DATA HANDLING ................................................................................................................................. 51
10.1
Source Data and Source Documents............................................................................................. 51
10.2
eCRF ............................................................................................................................................. 51
10.3
Data Management ......................................................................................................................... 52
10.4
Provision of Additional Information............................................................................................. 52
11
MONITORING PROCEDURES ........................................................................................................... 53
11.1
Periodic Monitoring...................................................................................................................... 53
11.2
Audit and Inspection..................................................................................................................... 53
11.3
Confidentiality of Subject Data..................................................................................................... 53
12
CHANGES IN THE CONDUCT OF THE TRIAL.............................................................................. 54
12.1
Protocol Amendments................................................................................................................... 54
12.2
Deviations from the Protocol ........................................................................................................ 54
12.3
Premature Trial Termination......................................................................................................... 54
13
REPORTING AND PUBLICATION .................................................................................................... 55
13.1
Clinical Trial Report ..................................................................................................................... 55
13.2
Confidentiality and Ownership of Trial Data................................................................................ 55
13.3
Publications and Public Disclosure............................................................................................... 55
13.3.1 Publication Policy ............................................................................................................ 55
13.3.2 Public Disclosure Policy.................................................................................................. 55
14
ETHICAL AND REGULATORY ASPECTS....................................................................................... 56
14.1
Independent Ethics Committee (IEC) or Institutional Review Board (IRB) ................................ 56
14.2
Regulatory Authority(ies) Authorization / Approval / Notification.............................................. 56
14.3
End-of-Trial and End-of-Trial Notification .................................................................................. 56
14.4
Ethical Conduct of the Trial.......................................................................................................... 56
14.5
Subject Information and Consent.................................................................................................. 56
14.6
Compliance Reference Documents............................................................................................... 57
15
LIABILITIES AND INSURANCE ........................................................................................................ 58


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15.1
ICH-GCP Responsibilities............................................................................................................ 58
15.2
Liabilities and Insurance............................................................................................................... 58
16
ARCHIVING............................................................................................................................................ 59
16.1
Investigator File ............................................................................................................................ 59
16.2
Trial Master File ........................................................................................................................... 59
17
REFERENCE........................................................................................................................................... 60
APPENDICES..................................................................................................................................................... 62
LIST OF TABLES 
Table 1
Schedule of Activities.......................................................................................................... 31


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
Abbreviation
Definition
ANCOVA
Analysis of covariance 
CGI
Clinical Global Impression
CGI-I
Clinical Global Impression-Improvement after treatment
CGI-S
Clinical Global Impression Severity
CI
confidence interval
CL/F
apparent total clearance
Ctrough
plasma concentration observed immediately prior to first dose of the day
CRF
case report form
CRO
contract research organization
CY-BOCS
Children’s Yale-Brown Obsessive Compulsive Scale
DMC
Data Monitoring Committee
ECG
electrocardiogram
FAS
FDA
Full Analysis Set
Food and Drug Administration
F/U
follow-up
GCP
Good Clinical Practice
HPWSQ-R
HPWSQ-R-C
Hyperphagia in Prader-Willi Syndrome Questionnaire-Responsiveness – completed
by the parent/caregiver
Hyperphagia in Prader-Willi Syndrome Questionnaire-Responsiveness-Clinician –
administered by the clinician
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IMP
investigational medicinal product
IRB
Institutional Review Board


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Abbreviation
Definition
LOCF
Last observation carried forward
MedDRA
Medical Dictionary for Regulatory Activities
PK
pharmacokinetic
PWS
Prader-Willi syndrome
SAE
serious adverse event
SNRI
selective norepinephrine reuptake inhibitor
SSRI
selective serotonin reuptake inhibitor
VzF
apparent volume of distribution


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1
INTRODUCTION
1.1
Background
Prader-Willi syndrome (PWS) is a genetic disorder that occurs in approximately 1 out of every 16,000 
births (1). This rare, complex, and multisystem genetic disorder is caused by the lack of expression of 
paternally inherited imprinted genes on chromosome 15q11-q13 that can occur via 1 of 3 main 
mechanisms: paternal microdeletion, maternal uniparental disomy, and imprinting defect (2,3).
The course and natural history of PWS have classically been described as consisting of 2 distinct 
clinical stages. The first stage occurs during the neonatal and early infancy period, characterized by 
varying degrees of hypotonia, weak cry, poor suck reflex, feeding difficulties (failure to thrive), 
developmental delay, temperature instability, and underdeveloped sex organs (hypogonadism). Motor 
and language development delays are also notable during this first stage. The neonatal symptoms 
typically improve by 9-25 months of age, muscle tone improves, the child becomes more alert, appetite 
increases, and weight begins to normalize. 
The second stage of PWS (beginning ~2-4 years of age) is characterized by weight gain, onset and 
escalation of hyperphagia, and continued growth and developmental delays. In addition, as 
hyperphagia emerges, a separate and distinctly negative constellation of maladaptive or problematic 
behaviors is observed. These maladaptive (or problematic) behaviors include temper tantrums, 
depression, stubbornness, obsessive compulsivity, and sudden acts of violence. By the time persons 
with PWS reach chronological adolescence, unless obesity is life-threatening, behavioral 
difficultiesoften severebecome the central issue for individuals with the syndrome and their families
(4).  
More recently, Miller et al described the much more gradual and complex progression of the nutritional 
phases of PWS than that of the traditional 2 stages described in the literature (5). Miller characterized 
the PWS nutritional phases by assessing growth, metabolic, and laboratory changes. Miller’s reporting 
of the progression of PWS nutritional phases is considered to be a foundation for family counseling, 
patient management, and development of rational therapies. 
1.2
Scientific Justification for Conducting the Trial
Development of rational therapies for PWS is challenging and there are no approved drug products to 
treat the complex behavioral symptoms, including hyperphagia. Both children and adults with PWS 
can be particularly difficult to trial. Shortened attention spans and reduced tolerance for things that are 
difficult for the individual, combined with expressive language difficulties and slower than normal 
processing speeds frequently lead to behavioral refusals to complete testing protocols. Therefore, in 
addition to expert clinical assessment, contributory proxy or caregiver information is necessary for 
both clinical management and research trials. 


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The neurohypophyseal hormone, oxytocin, previously thought to only be responsible for milk ejection 
and uterine contraction during labor, has recently been identified as an important neurotransmitter and 
key modulator of behavior. Numerous non-clinical and clinical studies, including a small, single-dose, 
pilot study in PWS subjects suggest that oxytocin delivered via the nasal route will provide therapeutic 
benefit in treating both hyperphagia and negative behaviors in PWS (6).
Although there may be some positive clinical data, nasal oxytocin does not represent an ideal therapy. 
Oxytocin is not receptor-selective and, due to its considerable vasopressin V2 receptor activity, it 
carries the risk of prolonged antidiuresis and hyponatremia (7,8,9). Since some subjects with PWS are 
known to have polydipsia and low baseline serum sodium levels (10) adding an anti-diuretic increases 
the risk of serious complications due to hyponatremia. Therefore, a receptor-selective compound would 
be preferable to avoid these potential side-effects.
Carbetocin (FE 992097) is a selective oxytocin receptor agonist that has 2 amino acid substitutions 
from the native ligand, oxytocin. Due to the improved selectivity profile and established safety in 
humans, Ferring has initiated development of this molecule for the treatment of children and adults 
with PWS. 
1.3
Benefit / Risk Aspects
Carbetocin injection was first approved in Canada in June 1997. As of March 2013, the cumulative 
patient exposure for carbetocin is estimated to be more than 3.5 million patients in 71 countries outside 
the United States, where carbetocin is approved as DURATOBAL, DURATOCIN, LONACTENE, and 
PABAL for 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. No important safety concerns have been identified in non-clinical 
safety studies designed for the trial population and the route of administration or with the use of 
carbetocin in clinical trials or in post-marketing exposure. 


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2
TRIAL OBJECTIVES AND ENDPOINTS
2.1
Objectives
Primary objective

To assess the effect of intranasal carbetocin (FE 992097) on hyperphagia behavioral symptoms 
in subjects with PWS, measured by the Hyperphagia in Prader-Willi Syndrome Questionnaire-
Responsiveness (HPWSQ-R) scale – completed by the subject’s parent/caregiver
Secondary objectives

To assess the effect of intranasal carbetocin (FE 992097) on hyperphagia behavioral symptoms 
in subjects with PWS, measured by the Hyperphagia in Prader-Willi Syndrome Questionnaire-
Responsiveness-Clinician (HPWSQ-R-C) scale – administered by the clinician

To assess improvement of PWS symptoms, assessed by the Clinical Global Impression (CGI) 
scale

To assess safety and tolerability of intranasal carbetocin

To assess a population pharmacokinetic model for the patient population utilizing sparse data 
sampling 

To assess the effects of intranasal carbetocin on PWS maladaptive behaviors, assessed by the 
Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS)

To assess the sensitivity of Food Domain of the Reiss Profile
2.2
Endpoints
Primary endpoint

Change in HPWSQ-R total score from Visit 2 to Visit 4
Secondary endpoints
1. Clinical Global Impression-Improvement after treatment (CGI-I) score at Visit 4
2. Change from Visit 2 to Visit 4 for the following measurements:

HPWSQ-R hyperphagia behavior, drive, and severity domain scores

HPWSQ-R-C total score

HPWSQ-R-C hyperphagia behavior, drive, and severity domain scores
3. Change from Visit 2 to Visit 4 for the following measurements:

CY-BOCS score


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
Food Domain of the Reiss Profile
4. Population PK/PD relationships for carbetocin
Safety endpoints

Frequency, severity and seriousness of adverse events

Clinically significant changes in vital signs

Clinically significant findings during physical and laboratory assessments

Physical examinations, including focused nasal examinations and nasal irritation, graded 
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


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3
INVESTIGATIONAL PLAN
3.1
Overall Trial Design
3.1.1
Overall Design and Control Methods
This is a prospective, randomized, double-blind, placebo-controlled parallel trial in subjects with PWS 
between the ages of 10 and 18 years of age with genetically confirmed diagnosis of PWS and a 
documented nutritional phase 3 symptom criteria as defined by Miller et al 2011.[5]  The trial includes 
a Screening Period, a 14-day Treatment Period, and a Follow-Up Period. Subjects, along with their 
parent/caregiver, will be required to visit the investigational site 4 times over the course of the trial, 
and participate in 2 phone call assessments. 

Visit 1: Screening Period (Day -7 to Day 0)

Visit 2: Baseline 1st day dosing on site (Day 1)

Visit 3:  2nd day dosing on site (Day 2)

Phone call assessment (Day 8)

Visit 4: End-of-Treatment Visit (Day 15)

Follow-up phone call (Day 19±3)
Following appropriate informed consent procedures, subjects will undergo screening evaluations to 
determine eligibility before randomization. Screening evaluations include a physical examination,  
vital signs, height, weight, 12-lead electrocardiogram (ECG), nasal examination, and laboratory 
assessments - hematology, clinical chemistry, hemostasis, and urinalysis. Approximately 38 eligible 
male or female subjects will be randomized at Visit 2 to 1 of 2 treatment groups for 14 days:

Carbetocin: each spray pump actuation will deliver a 50 µL volume of solution containing 
1.6 mg carbetocin; each dose will consist of 3 spray pump actuations in each nostril to deliver a 
total of 9.6 mg carbetocin

Placebo:  each spray pump actuation will deliver a 50 µL volume of sterile sodium chloride 
solution 0.9%; each dose will consist of 3 spray pump actuations in each nostril
After randomization, efficacy measures and other assessments, including physical examination, vital 
signs, nasal examination, and collection of blood samples for clinical laboratory and pharmacokinetic 
(PK) evaluation, will be performed at selected visits according to Table 1. Subjects will be closely 
monitored for adverse events throughout the trial following informed consent.


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Prior to first dosing at the investigational site, parents/caregivers will be trained on the proper use of 
the nasal spray device and procedures for IMP home delivery. Parents/caregivers will be instructed to 
administer 3 intranasal spray pumps of blinded IMP per nostril 3 times daily before meals within the 
following intervals:
Morning dose:     06:00 a.m. – 09:00 a.m.
Midday dose:      11:00 a.m. – 1:00 p.m.
Evening dose:      4:30 p.m. – 6:00 p.m.
Initial IMP dosing at Visit 2 (Day 1) and Visit 3 (Day 2) will take place under observation of the site 
staff at the investigational site. Subject vital signs will be monitored prior to and after IMP dosing at 
30-minute intervals for 2 hours after each dose. IMP will be shipped by central pharmacy directly to 
the subject’s residence on regular intervals as needed for the duration of the Treatment Period.  IMP 
will be administered by parents/caregivers 3 times per day before meals within the above specified 
dosing intervals. The IMP will require refrigeration during shipment to and during storage at the 
investigational site or subject’s residence until administered. 
3.1.2
Trial Schedule
For each subject, there will be a Screening period and a 14-day Treatment period. An End-of-
Treatment Visit will be conducted on Day 15 and a Follow-up phone call will be conducted 4 days (3 
days) after the End-of-Treatment Visit. 
3.2
Planned Number of Trial Sites and Subjects
Approximately 38 male or female subjects 10-18 years of age with genetically confirmed diagnosis of 
PWS and documented nutritional phase 3 PWS symptom criteria will be randomized at approximately 
3 sites. It is expected that 30 subjects will complete the trial.
3.3
Interim Analysis
No interim analysis is planned.
3.4
Data Monitoring Committee (DMC)
No DMC will be established for this trial.
3.5
Discussion of Overall Trial Design and Choice of Control Groups
3.5.1
Trial Design
Placebo is a standard control used to ensure unbiased estimates for the effects of active treatment. The 
14-day duration of treatment was considered sufficient to observe the onset of efficacy for an active 
treatment of PWS. 


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Since PWS is a rare condition, and subjects with PWS are generally treated at a few centers of 
excellence throughout the country, it is expected that a significant proportion of eligible subjects will 
reside at a considerable geographic distance from the investigational site(s), requiring ground or air 
transportation to complete trial visits. The trial design considers both the geographic challenges, as 
well as the need to ensure subjects’ home-life “normalcy” during the trial in order to accurately assess 
treatment effect. 
3.5.2
Selection of Endpoints
HPWSQ-Responsiveness (HPWSQ-R)
The Hyperphagia in Prader-Willi Syndrome questionnaire (HPWSQ) is an informant-based measure 
originally developed by Elisabeth Dykens (Vanderbilt) as a comprehensive tool to examine the 
psychological, developmental and neurobiological correlates of hyperphagia in PWS (11). HPWSQ-R 
represents all 11 items from the original HPWSQ, structured to include a 1-week recall period. The 
HPWSQ-R is designed to be used for repeated measures to evaluate the change in hyperphagia severity 
after intervention.
CGI
CGI rating scales are commonly used measures of symptom severity, treatment response and the 
efficacy of treatments in treatment studies of subjects with psychiatric, neurological or behavioral 
disorders (12). CGI is an overall clinician-determined summary measure that takes into account all 
available information including knowledge of the subject’s history, psychosocial circumstances, 
symptoms, behavior, and the impact of the symptoms on the subject’s ability to function (13). The CGI 
measures 3 components: 1) severity of illness, 2) global improvement, and 3) efficacy index 
(comparison of subject's baseline condition with a ratio of current therapeutic benefit to severity of side 
effects).
The rationale for using CGI in an interventional trial of subjects with PWS is supported by a body of 
evidence and its usefulness in determining baseline functioning prior to starting a treatment and in 
evaluating treatment effect with the CGI-Improvement score (CGI-I).  Given its ease of use and ability 
to capture behavior that has occurred in the last 7 days, it is an effective tool for clinicians.  It also 
allows for sizable amounts of information to be summarized and yields an easily understood score as 
well as the potential for benchmarking PWS against several pediatric maladaptive behavioral type 
indications. 
Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS)
People with PWS often have obsessive compulsive symptoms, both food and non-food related, 
including repeated questioning, insistence on sameness, re-arranging items until they are “just right” 
and hoarding. The CY-BOCS is a clinician rated, semi-structured inventory of specific symptoms and 


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symptom severity in pediatric obsessive-compulsive disorder (OCD) (14). 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). CY-BOCS is well researched in psychometric studies with reported treatment 
sensitivity (14,15,16,17,18).
Food Domain of the Reiss Profile
Several indications may encompass hyperphagic behavior as part of the constellation of 
maladaptive behaviors encountered. However, unlike PWS, these indications are not considered 
“hyperphagia centric”. In unpublished pilot work, Dykens used the Food Domain of the Reiss 
Profile to simply document the frequency distribution of the 5 items in 64 people with PWS.  The 
mean BMI of the subjects was 30.82 (SD, 10.31; range: 16.6-64.4), and mean age was 17.33 (SD, 
10.79; range: 4.25-48.6). The majority of participants (from 81% to 97%) enjoyed eating, always 
thought about food, became upset if meals were delayed, and had hearty appetites. Parents 
endorsed the “always eating” item less frequently (55%), due to the needs for food limits, diets 
and supervision around food in PWS. In a second, published study by Dykens and Rosner [19], 
the 5 items that comprise the Food Domain from the Reiss Profile was used to evaluate 94 
subjects with PWS, Williams syndrome or Down syndrome. Subjects were evaluated at 3 time 
points, tested 2 years apart. The results showed that persons with PWS had significantly higher 
scores in the Reiss Profile food domain than either score for subjects with Williams syndrome or 
Down syndrome at all measurement time points.
3.5.3
Blinding
Blinding
The trial treatment(s) will be allocated according to computer-generated randomization codes prepared 
for all trial sites. The randomization assignment will be available to the unblinded pharmacist (at the 
site and central pharmacy), but not to any other person involved in the conduct and evaluation of the 
trial, until the trial database is locked.
Prior to the start of the trial, the investigator will assign a pharmacist to act as the unblinded site 
pharmacist. This person will be the only person unblinded to the subject’s treatment group at the site
and will be responsible for randomization, mixing, and distribution of the trial drug at Visits 2 & 3.
A central pharmacy will be utilized by Ferring to prepare and distribute unmixed drug kits to trial sites 
(to be mixed and administered by the site during Visit 2 & 3) and to provide pre-mixed trial drug to 
subjects and their parent/caregiver once the at-home portion of the trial commences.  


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The coordinator will instruct each subject’s parent/caregiver as to the proper administration and the 
timing of the drug administration. This person will be available to answer the subject’s and 
parent’s/caregiver’s questions regarding the trial drug and its administration.
Unblinding of Individual Subject Treatment
In case of an emergency, the emergency decoding envelope will be available to the investigator and the 
sponsor's medical officer. Breaking of the blind in individual subjects is only permitted in case of a 
serious, unexpected or other important adverse event, when the knowledge of the investigational 
medicinal product in question is required for therapeutic decisions for the management of the subject.
As far as the emergency permits, the need to break the blind will be agreed by the investigator and the 
sponsor. The investigator should document why, when and by whom the blind is broken.
In case of accidental unblinding, the same documentation as for emergency unblinding must be 
obtained, i.e., the code envelope must be opened and why, when, and by whom must be noted both on 
the code envelope and the subject’s medical records.
It may be necessary to unblind an individual subject’s treatment for the purposes of expedited reporting 
to the authorities and/or IRBs. In that situation, every effort will be made to maintain blinding of 
sponsor personnel involved in trial conduct, data analysis and interpretation. Only those individuals 
within Ferring Pharmaceuticals whose responsibility it is to report this information will know the 
identity of the IMP. Every attempt will be made to ensure that all other trial and site personnel will 
continue to remain blinded throughout the course of the trial. Information on whether the blind has 
been broken for any subjects must be collected before the database is declared clean and is released to 
the statistician.
3.5.4
Selection of Doses in the Trial
A non-clinical program designed to address the safety of the pediatric trial population and the route of 
administration, comprising chronic 6 months juvenile repeated dose toxicity studies after intranasal 
administration in both rat and dog, and reproductive toxicity studies investigating fertility and embryo-
fetal development, demonstrated satisfactory exposure margins and was considered sufficient to 
support commencement of the planned Phase 2a trial.A placebo-controlled combined single ascending 
dose and multiple-dose trial, with a crossover intravenous and nasal administration portion, in healthy 
adult human subjects to determine the pharmacokinetics, safety, tolerability and absolute 
bioavailability of nasal carbetocin was completed in December 2012. The absolute bioavailability was 
2.5%. No safety signals were observed up to the highest dose tested (9.6 mg) in either the single 
ascending dose or multiple-dose part. Pharmacokinetic data indicate linear pharmacokinetics over the 
dose range with respect to area under the concentration-time curve and maximum observed plasma 
concentration tested. 


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Thus, the existing non-clinical and clinical safety documentation with carbetocin and the results from 
the Phase 1 trial supports the choice of dose and dose regimen for the proposed Phase 2a trial.
3.5.5
Selection and Timing of Dose for Each Subject
Prior to first dosing at the investigational site, parents/caregivers will be trained on the proper use of 
the nasal spray device and procedures for IMP home delivery. Parents/caregivers will be instructed to 
administer 3 intranasal spray pumps of blinded IMP per nostril 3 times daily before meals within the 
following intervals:
Morning dose:      06:00 a.m. – 09:00 a.m.
Midday dose:      11:00 a.m. – 1:00 p.m.
Evening dose:      4:30 p.m. – 6:00 p.m.
Initial IMP dosing at Visit 2 (Day 1) and Visit 3 (Day 2) will take place under observation of the site 
staff at the investigational site. Subject vital signs will be monitored prior to and after IMP dosing at 
30-minute intervals for 2 hours after each dose. Subsequent IMP will be administered by 
parents/caregivers 3 times per day before meals within the above specified dosing intervals. 
3.5.6
Withdrawal Criteria
Every subject has the right to refuse further participation in the trial at any time and without providing 
reasons. A subject's participation is to terminate 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 the IMP has already been administered, the subject must be advised 
to agree to follow-up safety investigations, which will include all procedures outlined for the End-of-
Treatment Visit (Visit 4) – before withdrawal/discontinuation of the trial.
The subject may be withdrawn from the trial 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 trial, develop conditions, which would 
have prevented his/her entry into the trial according to the exclusion criteria, the subject must be 
withdrawn immediately. 
The withdrawal of subjects from the trial will be agreed upon by the investigator and the sponsor. 
3.5.7
Follow-up Procedures
There will be a follow-up/End-of-Treatment visit at Visit 4 (Day 15) and a follow-up phone call on 
Day 19 (3 days) (Table 1).


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4
SELECTION OF TRIAL POPULATION
4.1
Trial Population
4.1.1
Inclusion Criteria
Subjects who meet all of the following criteria will be eligible for the trial:
1. Signed informed consent by parent/caregiver
2. Signed assent by subject (if applicable)
3. Male or female 10-18 years of age (both inclusive)
4. Genetically confirmed diagnosis of PWS 
5. Nutritional phase 3 PWS criteria based on Miller et al, 2011 (5) (see Appendix VI)
6. HPWSQ-R score greater than 13 at screening, Visit 1 (see Appendix II )
7. Willingness and ability of the parent/caregiver to comply with the protocol
8. Negative urine drug and alcohol screen at screening (Visit 1)
9. Negative urine pregnancy test for female subjects of childbearing potential at screening 
(Visit 1).
10. Willing to use an adequate barrier method or hormonal method of contraception from informed 
consent to 1 week after the end of dosing of trial medication, if deemed appropriate by the 
investigator
11. Ability of the subject to perform procedures and assessment required of this trial, based on the 
investigator's judgment
4.1.2
Exclusion Criteria
The presence of any of the following excludes a subject from trial enrollment:
1. Known genetic, hormonal, or chromosomal cause of cognitive impairment other than PWS
2. Presence of currently active psychotic symptoms
3. Presence of any cardiovascular disorders, epilepsy, frequent migraines or severe asthma


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4. Previous diagnosis of autism spectrum disorder by a qualified healthcare provider
5. Prior or concomitant use of a selective serotonin reuptake inhibitor (SSRI) or selective 
norepinephrine reuptake inhibitor (SNRI), antipsychotic medication, wakefulness-promoting 
drug, or thyroid hormone that does not comply with the criteria in Section 4.3.1
6. Use of any of the prohibited medications or therapies listed in Section 4.3.2
7. Major surgery within 6 months of screening (Visit 1)
8. Nasal or sinus surgery within 1 year of screening (Visit 1)
9. Chronic sinusitis - more than 3 episodes per year 
10. Other nasal diseases that may affect deposition of intranasal medication
11. Serum sodium < 135 mmol/L at screening (Visit 1)
12. Known hypersensitivity to any component of carbetocin or saline solution
13. History of long-term daily use of any intranasal medication
14. Cancer within the last 5 years except for adequately managed basal cell carcinoma or squamous 
cell carcinoma of the skin
15. History within the last 2 years or current abuse of alcohol or drugs
16. Intake of an IMP within the last 12 weeks preceding screening or longer, if judged by the 
investigator to possibly influence the outcome of the current trial
17. Mental incapacity or language barrier of the primary parent/caregiver precluding adequate 
understanding or cooperation
18. Considered by the investigator to be unsuitable to participate in the trial for any other reason
4.2
Method of Assigning Subjects to Treatment Groups
Approximately 38 subjects meeting the eligibility requirements will be randomized in this trial. At 
each trial site, subjects will be assigned sequentially, in the order in which they are enrolled, to receive 
their allocated treatment according to a computer-generated randomization schedule prepared by 
Ferring or designee prior to trial initiation.


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Eligible subjects will be assigned to 1 of 2 treatments (carbetocin or placebo) in a sequential order,
based on their expected arrival to the trial site for the baseline Visit 2 (Day 1)
4.3
Restrictions
4.3.1
Prior and Concomitant Therapies
Use of any concomitant therapy will be recorded in the medical source data and the eCRF by trial staff,
following the subject interview at each visit. Required information includes the drug name, strength, 
formulation, route of administration, dosing frequency, indication for use, start and stop date, times. 
Any changes (including new therapies) must be recorded at each subsequent trial visit.
Prior and concomitant use of growth hormone is permitted.
Prior and concomitant use of the following types of medications is permitted only if the prescribed 
dosage of the medication has been stable for ≥ 6 months at time of screening:

A single selective serotonin reuptake inhibitor (SSRI) or selective norepinephrine
reuptake inhibitor (SNRI)

An antipsychotic medication

A wakefulness-promoting drug

A thyroid hormone
The table below lists examples of some common SSRIs, SNRIs, antipsychotics, wake promoting 
agents, and hypothyroid medications.
Class of Drug
Examples of Common Drugs in each Class
SSRIs
Citalopram
Sertraline
Paroxetine
Fluoxitene
SNRIs
Duloxetine
Venlafaxine
Desvenlafaxine
Antipsychotics
Respiridone
Wakefulness-promoting 
drugs
Amphetamine
Modafinil (Provigil)
Armodafinil (Nuvigil)
Thyroid hormones
Levothyroxine
Lyothyronine


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4.3.2
Prohibited Therapy
Concomitant use of any intranasal therapies, including nasal saline is prohibited. 
Concomitant use of any products containing prostaglandins (for a complete list see Appendix VII) is
prohibited. 
Occasional use of over-the-counter medications may be permitted with prior approval from the 
investigator and sponsor.


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5
TREATMENTS
5.1
Treatments Administered
The 2 treatments are:

Carbetocin: each spray pump actuation will deliver a 50 µL volume of solution containing 
1.6 mg carbetocin; each dose will consist of 3 spray pump actuations in each nostril to deliver a 
total of 9.6 mg carbetocin

Placebo:  each spray pump actuation will deliver a 50 µL volume of sterile sodium chloride 
solution 0.9%; each dose will consist of 3 spray pump actuations in each nostril
Carbetocin is a peptide comprising 8 amino acids. All amino acids, except glycine, which is achiral, are 
present as L-enantiomers. The 2 amino acids, L-O-methyl tyrosine and L 1-carboxypropylcysteine, are 
unnatural. The drug product for nasal administration is a solution consisting of the drug substance 
carbetocin dissolved in 5 mL of sterile 0.9% sodium chloride. 
Placebo will be a sterile sodium chloride solution 0.9% to be transferred to a nasal spray device.
Carbetocin Powder for Solution for Nasal Spray, 160 mg is preweighed in a glass vial for 
reconstitution with sterile sodium chloride solution 0.9%, and subsequent transfer to a nasal spray 
device.
5.2
Characteristics and Source of Supply
All medicinal drug products are provided by Ferring Pharmaceuticals/Ferring entity and will be 
handled according to the principles of Good Manufacturing Practice (GMP).
The IMP components will be delivered to the central pharmacy as pre-weighed carbetocin in vials and 
sterile 0.9% sodium chloride solution for reconstitution. After reconstitution, the IMP will be 
transferred to the glass container of the metered-dose nasal spray device, and the spray pump will be 
attached.
A central pharmacy will prepare/ship intranasal IMP kits for onsite mixing/dosing followed by 
preparing/shipping reconstituted IMP for off-site dosing.
IMP kits for mixing and dosing will be delivered to the investigational site for dosing on Visit 2 
(Day 1), Visit 3 (Day 2), and to provide IMP for off-site dosing on Day 3.
Reconstituted IMP shipments to the subject’s home for subsequent dosing will be made via special 
courier arrangements to ensure regular and timely shipment of blinded IMP to the subject’s home for 
use over the remainder of the treatment period. 


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5.3
Packaging and Labeling
Packaging and labeling of the medicinal products will be performed under the responsibility of the 
IMP Department at Ferring Pharmaceuticals A/S in accordance with GMP and national and local
regulatory requirements.
The content on the labels will be in accordance with Annex 13, Eudralex, volume 4 and national regulatory 
requirements.
Date and Clock time (example: 01Jan2013, 9:00 am EST) will be provided on reconstituted drug labels to 
indicate time of expiration.
5.4
Blinding / Unblinding
5.4.1
Blinding
The randomization list will not be available to any person involved in the conduct and evaluation of the 
trial until the trial database is declared clean and is released to the statistician.
The randomization list will be available only to the unblinded pharmacist(s) preparing the diluted 
solutions in the spray vial.
5.4.2
Unblinding of Individual Subject Treatment
An emergency decoding envelope will be available to the investigator and designated persons at 
Ferring. 
Breaking of the blind for individual subjects in emergency situations is only permitted in case of a 
suspected unexpected serious adverse reaction (SUSAR) or in case of an important adverse event 
where the knowledge of the IMP in question is required for therapeutic decisions for the management 
of the subject.
As far as the emergency permits, the need to break the blind will be agreed by the investigator and
Ferring. The person who opens a code envelope must record the reason and the date of opening, and 
then sign and date the opened envelope. The investigator must record the event of unblinding in the 
subject’s medical record, including the reason for unblinding, but not the treatment allocation if this 
can be avoided.
In case of accidental unblinding, the same documentation as for emergency unblinding must be 
obtained, i.e. the code envelope must be opened and why, when and by whom must be noted.


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It may be necessary to unblind an individual subject’s treatment for the purposes of expedited reporting 
to the authorities and Institutional Review Boards (IRBs). In that situation, every effort will be made to 
maintain blinding of sponsor personnel involved in data analysis and interpretation. Other personnel 
may be unblinded for SUSARs, including trial site staff as well as staff acting on behalf of Ferring.
Information on whether the blind has been broken for any subjects must be collected before the 
database is declared clean and is released to the statistician.
5.5
Conditions for Storage and Use
The IMP will require refrigeration during shipment to and during storage at the investigational site or 
subject’s residence for the duration of the trial. 
The investigator will ensure that IMP is stored in appropriate conditions in a reasonably secure, 
substantially constructed locked cabinet with controlled access. The substance (powder form) is stable 
for 24 months when stored at 2 - 8°C. The sterile sodium chloride solution 0.9% should be stored at 2 -
8°C. The expiry date is documented on the package. The temperature in the storage compartment shall 
be regularly monitored with a min/max thermometer and the values documented.
The shelf life of the nasal spray solutions and the placebo for carbetocin nasal solution after 
reconstitution/transfer to the nasal spray is 48 hours. After reconstitution the solution must be stored at 
2 - 8°C when it is not used for administration. 
5.6
Treatment Compliance
5.6.1
Preparation
The IMP will be shipped from an External Packaging Facility / central pharmacy as follows:

IMP kits will be sent to site(s) to be prepared on-site for dosing during on-site Visit 2 (Day 1) 
and Visit 3 (Day 2), and for off-site dosing on Day 3

Fully reconstituted IMP in the nasal spray device will be sent directly to subject’s residence for 
remainder of dosing period
5.6.2
Dispensing and Accountability
The investigator or parent/caregiver will dispense the medication only to the identified subjects of this 
trial, following the procedures described in this trial protocol and dispensing instructions. Subject 
dosing will be documented in a subject dispensing log. 
Drug inventory/dispensing will be documented in the source documents for each subject and the drug 
accountability binder. The investigator is responsible for all drug supplies. Written documentation is 
mandatory. After completion of the trial, all unused IMP will be returned to the sponsor. 


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5.6.3
Assessment of Compliance
The IMP will be dispensed only to subjects who meet the eligibility criteria and are randomized to a 
treatment in the trial. The investigator or his/her designated personnel (e.g., trial nurse) and 
parent/caregiver will maintain a drug dispensing log detailing the dates and quantities of IMPs 
dispensed to, and used by, each subject, as well as the batch numbers. The monitor will verify drug 
accountability during the trial.
Subjects will be asked to return used IMP containers. Treatment compliance will be verified by 
reviewing the containers, any unused nasal spray bottles, and/or subject’s statements documented in 
the source documents, in case the nasal spray device is lost.
5.7
Return and Destruction of Medicinal Products
After completion of the trial, all used and unused investigational product (and Temperature Monitoring 
Devices) will be returned to the sponsor.


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6
TRIAL PROCEDURES
6.1
Trial Flow Chart
The schedule of activities for the trial is presented in Table 1.
Table 1
Schedule of Activities
Period: Screening
Treatment
F/U
Baseline
1-Week 
Assessment
End of 
Treatment 
Visit / Early 
termination 
visit
F/U 
phone 
call
Visit: 
1
2
3
4
Days:
-7 to 0
1
2
3-7
8 (+/-1)
9-14
15
19 (+/-3)
IMP Dosing:
NA
On site
On site
Off site
On site
NA
Assessments
Written informed consent and assent
X
Inclusion/exclusion criteria
X
Prior/concomitant medication
X
X
X
X
X
Physical examination
X
X
Nasal examinationa
X
X
X
X
Medical history
X
Demographics
X
Urine drug and alcohol screen
X
X
Urine pregnancy test
X
X
Height and Weight 
X
X
Vital signsb
X
X
X
X
Electrocardiogramc
X
X
X
X
Blood samples for clinical chemistry, 
hematology, hemostasis, and urinalysis
X
X
X
Blood samples for pharmacokineticsd
X
X
Nutritional phase assessment
X
Randomizatione
Xe
HPWSQ-R and HPWSQ-R-C
X
X
X
X
CGI-S
X
CGI-I
X
X
CY-BOCS
X
X
X
Food Domain of Reiss Profile
X
X
X
IMP administration training
X
Dispense IMP
X
X
X
X
X
Return IMP
X
IMP dosing
X
X
X
X
X
Adverse events
X
X
X
X
X
X


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CGI-I=Clinical Global Impression-Improvement after treatment; CGI-S=Clinical Global Impression-Severity; CY-BOCS= Children’s 
Yale-Brown Obsessive-Compulsive scale; F/U=follow-up; HPWSQ-R=Hyperphagia in Prader-Willi Syndrome Questionnaire-
Responsiveness; HPWSQ-R-C=Hyperphagia in Prader-Willi Syndrome Questionnaire-Clinician ; IMP=investigational medicinal product
a
Nasal examinations to be done at Visit 1 (anytime), within 1 hour prior to each dose at Visit 2 and Visit 3, and at Visit 4 (anytime).
b    Includes pulse, respiration rate, blood pressure and body temperature. At Visit 2 and 3, vital signs will be monitored prior to and after 
IMP dosing at 30-minute intervals for 2 hours after each dose.
c     ECG to be done within 1 hour after morning dose at Visit 2 and 3.
d
Three blood samples to be collected at Visit 2 and Visit 3, according to the schedule specified in section 7.2.6 Clinical Laboratory 
Tests/Pharmacokinetic Assessments. All PK labs are to be done prior to subsequent dose.
e
Randomization will be done within 24 hours prior to the Visit 2, morning dose.
6.1.1
Screening (Visit 1: Days -7 through 0)
Prior to or at the Screening Visit, the parent or caregiver must receive a detailed explanation of the trial
and must sign the Informed Consent Form after having sufficient time to consider his/her child’s 
participation in the trial. After the parent or caregiver has signed the Informed Consent Form and the 
subject has signed the Assent Form (if applicable), the following will be collected and/or performed:

Inclusion/exclusion criteria

Use of prior/concomitant medication up to 14 days prior to first dose of trial medication

Parent/caregiver training on completion of HPWSQ-R

HPWSQ-R followed by HPWSQ-R-C

CY-BOCS (Symptoms Checklist & Severity Rating Scale)

Food Domain of Reiss Profile

Physical examination

Nasal examination (See scale listed in 7.2.3)

Medical history and demographic data

Urine drug and alcohol screen

Urine pregnancy test for females of childbearing potential

Vital signs (pulse, respiration rate, blood pressure, and body temperature)

Height and Weight

ECG

Clinical safety laboratory assessment:  chemistry, hematology, hemostasis, urinalysis

Nutritional phase assessment

Adverse events


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6.1.2
Treatment Period
Baseline 1st day of Dosing On Site (Visit 2:  Day 1)
The following will be collected and/or performed at Visit 2:

Record use of concomitant medications

Nasal examinations to be done within 1 hour prior to each dose (See scale listed in 7.2.3)

Vital signs (pulse, respiration rate, blood pressure, and body temperature) will be monitored 
prior to and after IMP dosing at 30-minute intervals for 2 hours after each dose.

ECG (to be done within 1 hour after morning dose)

Laboratory samples for:
o
Pharmacokinetic sampling (3 blood samples according with the schedule specified in  
section 7.2.6 Clinical Laboratory Tests/Pharmacokinetic Assessments)

Randomization (done within 24 hours prior to Visit 2 morning dose)

HPWSQ-R followed by HPWSQ-R-C (prior to dose)

CGI-S (prior to dose)

IMP administration training

Dispense IMP

Blinded, randomized IMP dosed 3 times daily (before meals)

Adverse events
Visit 3: 2nd day of Dosing On Site (Visit 3:  Day 2)
The following will be collected and/or performed at Visit 3:

Record use of concomitant medications

Nasal examinations to be done within 1 hour prior to each dose (See scale listed in 7.2.3)

Vital signs (pulse, respiration rate, blood pressure, and body temperature) will be monitored 
prior to and after IMP dosing at 30-minute intervals for 2 hours after each dose.

ECG (to be done within 1 hour after morning dose)

Laboratory samples for:
o
Clinical safety laboratory assessment (chemistry, hematology, hemostasis, urinalysis) to 
be drawn post-morning dose (pre-meal)
o
Pharmacokinetic sampling (3 blood samples according with the schedule specified in  
section 7.2.6 Clinical Laboratory Tests/Pharmacokinetic Assessments)

Dispense IMP

IMP dosed 3 times daily

Adverse events


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3rd through 7th day of Dosing Off Site (Day 3 through Day 7)
The following will be performed on Day 3 through Day 7 by the parent/caregiver:

Receive/Dispense IMP

IMP dosed 3 times daily (before meals)
1-Week Assessment: 8th day (±1 day) of Dosing Off Site (Phone Call, Day 8)
The following will be collected and/or performed on Day 8:

Record use of concomitant medications

HPWSQ-R, followed by HPWSQ-R-C CGI-I

CY-BOCS Severity Rating Scale

Food Domain of Reiss Profile

Receive/Dispense IMP (not part of phone call)

IMP dosed 3 times daily (not part of phone call)

Adverse events
9th through 14th day of Dosing Off Site (Day 9 through Day 14)
The following will be performed on Day 9 through Day 14:

Receive/Dispense IMP

IMP dosed 3 times daily (before meals)
6.1.3
Follow-up
End-of-Treatment Visit (Visit 4:  Day 15)
The following will be collected and/or performed at Visit 4:

Record use of concomitant medications 

HPWSQ-R, followed by HPWSQ-R-C

CGI-I

CY-BOCS Severity Rating Scale

Food Domain of Reiss Profile

Physical examination

Nasal examination (See scale listed in 7.2.3)

Height and Weight

Vital signs (pulse, respiration rate, blood pressure, and body temperature)

ECG

Urine drug and alcohol screen


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
Urine pregnancy test for females of childbearing potential

Clinical safety laboratory assessment:  chemistry, hematology, hemostasis, urinalysis

Return IMP

Adverse events
Follow-up Phone Call (Day 19 ±3 days)
Each subject will be contacted by telephone on Day 19 (±3 days) and assessed for adverse events.


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7
TRIAL ASSESSMENTS
7.1
Assessments Related to Endpoints
7.1.1
Clinical Global Impression Scales
The CGI scale (Appendix I) is a 7-point clinician rating of illness severity (0 = no illness, 
6 = extremely ill), at the beginning of the trial and a 7-point clinician rating of improvement of patient 
condition, during and at the end of the trial (13). The scales will be administered by the Investigator or 
a delegated Sub-Investigator (trained and qualified by Investigator).
The CGI scales should be administered around the same time, by the same person, throughout the trial.
7.1.2
Hyperphagia in PWS Questionnaires
The HPWSQ-R (Appendix II ) consists of 11 questions that rate the food-seeking behavior of subjects 
with PWS (11). The scale will be administered by the parent/caregiver. HPWSQ-R-C (Appendix III) 
consists of the same 11 questions that rate the food-seeking behavior of subjects with PWS,
administered by the Investigator or a delegated Sub-Investigator (trained and qualified by Investigator).
The HPWSQ-R-scale should be administered by the same parent/caregiver throughout the trial.  The 
HPWSQ-R-C-scale should be administered by the same clinician throughout the trial.
7.1.3
Children’s Yale-Brown Obsessive-Compulsive Scale (CY-BOCS)
The CY-BOCS (Appendix IV) is a clinician rated, semi-structured inventory of specific symptoms and
symptom severity in pediatric obsessive-compulsive disorder (OCD) (14). 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 scale will be administered by the Investigator or a delegated Sub-
Investigator (trained and qualified by Investigator). Same person should perform this task around the 
same time, throughout the trial.
7.1.4
Food Domain From the Reiss Profile
The food domain of the Reiss Profile (Appendix V) consists of 7 questions that pertain to food seeking 
behavior. The scale will be administered by the Investigator or a delegated Sub-Investigator (trained 
and qualified by Investigator), around the same time throughout the trial. It should be administered by 
the same person.
7.2
Safety and Other Assessments
7.2.1
Medical History
A complete medical history will be obtained and documented at screening.


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7.2.2
Physical Examination
A complete physical examination including general appearance, head, eyes, ears, nose, and throat
(HEENT), 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 trial team member) at Visits 1 and 4.
At screening, each category will be evaluated as normal, abnormal not clinically significant or 
abnormal clinically significant. Abnormal clinically significant findings at screening must be reported 
on the Medical History Log.
At end-of-trial, potential changes from screening to end-of-trial will be evaluated for each category. In 
case of changes, these will be evaluated as normal, abnormal not clinically significant or abnormal 
clinically significant. Abnormal clinically significant changes from screening to end-of trial must be 
recorded as AEs.
7.2.3
Nasal Examination
Nasal examinations will be done at Visit 1, within 1 hour prior to each dose at Visit 2 and Visit 3, and 
at Visit 4 (anytime).
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
*Note: After randomization, grading of 3 or 4 will be documented as an adverse event.  If deemed 
appropriate, additional follow-up examinations will be performed at the discretion of the Investigator.
7.2.4
Height, Weight and Vital Signs
Height and weight will be measured at Visit 1 and Visit 4. 


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Pulse, respiration rate, blood pressure, and body temperature will be measured at each visit (or at early 
termination) under resting conditions while the subject is seated. All blood pressure measurements 
should be made using the same arm while the subject is in supine position after resting for 3 minutes, 
and prior to any scheduled blood draws. At Visit 2 and Visit 3 - vital signs will be monitored prior to 
and after IMP dosing at 30-minute intervals for 2 hours after each dose.
7.2.5
12-Lead Electrocardiogram
After at least a 5-minute rest in a supine position, a 12-lead ECG will be obtained at each visit (or at 
early termination). Additional ECGs may be obtained if clinically indicated. 
7.2.6
Clinical Laboratory Tests
Hematology, Hemostasis, Serum Chemistry, and Urinalysis
The following safety laboratory tests will be performed at the times specified in Table 1. A 10-hour 
overnight fast is required prior to collecting the blood samples. Specific instructions for blood 
collection will be provided in a laboratory manual to the trial site. 
Hematology: red blood cell count, white blood cell count, hematocrit, hemoglobin, platelet count, and 
differential count. 
Hemostasis: prothrombin time, activated partial thromboplastin time, thrombin time, and fibrinogen
Serum chemistry: glucose, blood urea nitrogen, creatinine, potassium, sodium, chloride, calcium, total 
protein, albumin, total bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine 
aminotransferase, and gamma glutamyl transferase. 
Urinalysis: blood, pH, specific gravity, protein, glucose, urobilinogen, and microscopic if positive for 
blood or protein.
The investigator is to review laboratory results for abnormalities and clinical significance. 
Pharmacokinetic Assessments
Blood samples for PK testing will be obtained according with the following schedule:
At a Given Site
Visit 2 (Day 1) morning dose
Visit 3 (Day 2) midday dose
1st randomized patient and every third 
thereafter (1, 4, 7, 10, etc.)
Pre-dose, 15, and 60 min
5, 20, and 120 min
2nd randomized patient and every third 
thereafter (2, 5, 8, 11, etc.)
10, 30, and 180 min
Pre-dose, 15, and 60 min
3rd randomized patient and every third 
thereafter (3, 6, 9, 12, etc.)
5, 20, and 120 min
10, 30, and 180 min


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All PK samples must be drawn prior to thenext dose.:

Visit 2 (Day 1) morning dose PK samples must be drawn prior to midday dose 

Visit 3 (Day 2) midday dose PK samples must be drawn prior to evening dose 
Specific instructions for blood collection will be provided to the trial site. 
Drug and Alcohol Screen
At screening and End of Treatment/Early Termination visit, a urine drug screen and alcohol test will be 
performed. 
Pregnancy Testing
Urine pregnancy tests will be performed on females of childbearing potential at Screening (Visit 1) and 
End of Treatment/Early Termination visit (Visit 4). Negative results are required for trial admission 
and/or administration of IMP.


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8
ADVERSE EVENTS
8.1
Adverse Event Definition
An adverse event is any untoward medical occurrence in a subject participating in a clinical trial. It 
includes:

Any unfavorable and unintended sign, symptom or disease temporally associated with the use 
of the IMP, whether or not considered to be caused by the IMP.

Adverse events commonly observed and adverse events anticipated based on the 
pharmacological effect of the IMP.

Any laboratory abnormality, vital sign or finding from physical (or gynecological) examination 
assessed as clinically significant by the investigator (note: findings from assessments and 
examinations done during screening are not adverse events, but are recorded as medical 
history).

Accidental injuries, reasons for any change in medication (drug and/or dose), reasons for any 
medical, nursing or pharmacy consultation, or reasons for admission to hospital or surgical 
procedures.

Overdoses and medication errors with and without clinical consequences.
An adverse drug reaction is an adverse event evaluated by the investigator as being probably or 
possibly causally related to treatment with the IMP. 
A serious adverse drug reaction is a serious adverse event (SAE) evaluated by the investigator and/or 
by Ferring as having a reasonable possibility of causal association with IMP.
An unexpected adverse event is an adverse event not identified in nature, severity, or frequency in the 
section “Undesirable Effects” in the sponsor’s current Investigator’s Brochure.
A treatment-emergent adverse event is any adverse event that begins during the Treatment Period or 
worsening of a pre-existing medical condition. The Treatment Period is the period during which a 
subject receives IMP.
8.2
Collection and Recording of Adverse Events
8.2.1
Collection of Adverse Events
The investigator must monitor the condition of the subject throughout the trial from the time of 
obtaining informed consent until the Day 19 follow-up phone call.


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The sources of adverse events cover:

The subject’s response to questions about his/her health (a standard non-leading question such 
as “How have you been feeling since your last visit?” is asked at each visit).

Symptoms spontaneously reported by the subject.

Investigations and examinations where the findings are assessed by the investigator to be 
clinically significant changes or abnormalities.

Other information relating to the subject’s health becoming known to the investigator 
(e.g., hospitalization).
8.2.2
Recording of Adverse Events
The investigator must record all adverse events in the Adverse Event Log provided in each subject’s 
eCRF with information about:

Adverse event

Date and time of onset (time can be omitted, if applicable)

Intensity

Causal relationship to IMP

Action taken to IMP

Other action taken

Date and time of outcome (time can be omitted, if applicable)

Outcome

Seriousness
Each of the items in the Adverse Event Log is described in detail in the following sections.
Adverse Event
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 changes in intensity, a 


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worst-case approach should be used when recording the event, i.e. the highest intensity and the longest 
duration of the event.a
Pre-existing conditions are not AEs, but become AEs if worsening occurs after IMP administration 
during the trial. Pre-existing clinically significant conditions diagnosed or observed as a result of the 
screening procedures must be recorded as medical history. 
Note: 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).
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. 
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 work or perform usual activities (unacceptable).
                                                
a
Exception: if an adverse event with onset before the first IMP administration (i.e., 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. 


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Causal Relationship to IMP
The possibility of whether the IMP caused the adverse event must be classified as one of the following:
Reasonable possibility: 
There is evidence or argument to suggest a causal relationship between the IMP and the adverse event. 
The adverse event may occur as part of the pharmacological action of the IMP or may be unpredictable 
in its occurrence.
Examples: 

Adverse events that are uncommon but are known to be strongly associated with IMP exposure.

Adverse events that are not commonly associated with IMP 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.
No reasonable possibility:
There is no reasonable evidence or argument to suggest a causal relationship between the IMP and the 
adverse event.
Examples:

Known consequences of the underlying disease or condition under investigation.

Adverse events common in the trial population, which are also anticipated to occur with some 
frequency during the course of the trial, regardless of IMP exposure.
Action Taken to IMP
The action taken to the IMP in response to an adverse event must be classified as one of the following:

No change (medication schedule maintained or no action taken)

Withdrawn

Interrupted

Dose reduced

Dose increased


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Other Action Taken
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 entered in the 
Concomitant Medication Log.
Date and Time of Outcome
The date the subject recovered or died.
Outcome
The outcome of an adverse event must be classified as one of the following:

Recovered (fully recovered or the condition has returned to the level observed at initiation of 
trial treatment)

Recovered with sequelae (resulted in persistent or significant disability/incapacity)

Recovering

Not yet recovered

Fatal
8.3
Pregnancy and Pregnancy Outcome
If a pregnancy occurs, the IMP should be immediately stopped and Pharmacovigilance at Ferring 
Pharmaceuticals must be informed and a SAE form completed. 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. If a pregnancy results in an abnormal outcome (birth defect/congenital anomaly), this must be 
reported as an SAE to Pharmacovigilance at Ferring Pharmaceuticals.
In cases in which a fetus may have been exposed through transmission of the IMP via semen following 
paternal exposure and the pregnancy results in an abnormal outcome (birth defect/congenital anomaly),
this must be reported as a serious adverse event to Pharmacovigilance at Ferring Pharmaceuticals.


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8.4
Serious Adverse Events
8.4.1
Serious Adverse Event Definition
Serious Adverse Events during the Trial
An event is defined a serious adverse 
event if it:
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 IMP. The death of a subject enrolled in a trial 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. Over-night stay for observation, stay at emergency room or treatment on 
an out-patient basis do not constitute a hospitalization. However, medical judgment must 
always be exercised and when in doubt the case should be considered serious (i.e. if case 
fulfills the criterion for a medically important event). Hospitalizations for administrative 
or social purposes do not constitute a serious adverse event (SAE). Hospital admissions 
and/or surgical operations planned before trial inclusion are not considered adverse events, 
if the illness or disease existed before the subject was enrolled in the trial, provided that 
the condition did not deteriorate during the trial.
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 IMP.
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 (e.g. 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.


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8.4.2
Collection, Recording and Reporting of Serious Adverse Events
SAE Reporting by the Investigator
All SAEs must be reported immediately to Ferring Pharmacovigilance as soon as it becomes known to 
the investigator and not later than within 24 hours of their knowledge of the occurrence of an SAE.
The investigator is responsible for submitting the completed SAE Report Form with the fullest possible 
details within 24 hours of his/her knowledge of the SAE.
The SAE Report Form must be completed and submitted according to the instructions provided on the 
form, using the contact details below:
Pharmacovigilance, Ferring Pharmaceuticals Inc.
Fax: 1-973-796-1791
Email:  Safety.fax@ferring.com  
Completion of the Demographics, Adverse Event Log, Medical History Log and Concomitant 
Medication Log 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 SAE such as hospital records, results from investigations, e.g., 
laboratory parameters, invasive procedures, scans and x-rays, and autopsy results can be faxed or 
scanned and e-mailed to Ferring Pharmacovigilance using the contact details in the section above. In 
any case this information must be supplied by the investigator upon request from Ferring. On any 
copies provided, such details such as subject’s name, address, and hospital ID number should be 
concealed and instead subject number should be provided.
The investigator will supply Ferring and the IRB with any additional requested information such as 
results of post-mortem examinations and hospital records.


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Expedited Reporting by Ferring
Ferring will report all adverse events that are serious, unexpected (according to the Investigator 
Brochure) and with a reasonable possible causality to the IMP as judged by either the investigator 
or Ferring to the relevant parties within the stipulated timelines.  Ferring will submit serious, 
unexpected, causally-related adverse event reports to the US Food and Drug Administration and other 
applicable Health Authorities according to local reporting requirements.  
Serious adverse events will be considered reportable regardless of whether or not the IMP was used in 
accordance with the provisions in the protocol, Investigator’s Brochure and labeling.
8.5
Follow-up of Adverse Events and Serious Adverse Events 
8.5.1
Follow-up of Adverse Events with Onset during the Trial
During the trial, the investigator must follow-up on each adverse event until it is resolved or until the 
medical condition of the subject is stable.
After the subject’s last visit, the investigator must follow-up on any adverse event classified as serious 
or considered to have a reasonable possible causality to the IMP until it is resolved or until the medical 
condition of the subject is stable. All such relevant follow-up information must be reported to Ferring. 
If the event is a chronic condition, the investigator and Ferring may agree that further follow-up is not 
required.
8.5.2
Collection of Serious Adverse Events with Onset after Last Trial Visit
If an investigator becomes aware of an SAE after the subject’s last visit and he/she assesses the SAE to 
have a reasonable possible causality to the IMP, the case will have to be reported to Ferring, regardless 
how long after the end of the trial this takes place.


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9
STATISTICAL METHODS
Details of the statistical methodology will be provided in a separate Statistical Analysis Plan. All 
individual subject data will be listed by domain.
9.1
Determination of Sample Size
Based on available literature (Dykens et al 2007), the HPWSQ-R total score at baseline (Visit 2) is
assumed to be normally distributed with a standard deviation of 6.12, and the standard deviation of the 
change between baseline (Visit 2) and Visit 4 is estimated to be between 5 and 6 (11).  With 30 
subjects eligible for the primary efficacy assessment, the trial has at least 80% power to detect a 
borderline statistically significant difference (1-sided 10% significance) between 2 groups when the 
true treatment group difference is -5 under the standard deviation of 5 to 6.  Subjects are randomized in 
a 1:1 ratio to either placebo or carbetocin.  
The efficacy of carbetocin will be assessed by change in HPWSQ-R total score from Visit 2 to Visit 4. 
Assuming a dropout rate of approximately 20%, at least 19 subjects per treatment arm will need to be 
randomized to have a total of 30 subjects eligible for the primary efficacy assessment.
9.2
Subject Disposition
The number of subjects randomized into the trial will be summarized overall. Subjects who discontinue 
IMP or are removed from the trial permanently will also be reported by the treatment received 
immediately prior to discontinuation. Randomization errors, reasons for trial discontinuation, and time 
of withdrawal from the trial will be reported. No formal statistical analysis will be performed.
9.3
Protocol Deviations
Major or minor protocol deviations will be defined and documented prior to database lock.
9.4
Analysis Sets
9.4.1
Safety Population
All subjects who received at least 1 dose of IMP will be included in the safety population.
9.4.2
Full Analysis Set (FAS) Population
The FAS population will include all subjects in the safety population who have the primary efficacy 
endpoint measured.


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9.4.3
Pharmacokinetic Population
The PK population will include all subjects in the safety population who have sufficient plasma
carbetocin concentrations for inclusion in population PK modeling.
9.5
Trial Population
9.5.1
Demographics and other Baseline Characteristics
Subject characteristics at trial entry will be summarized overall in frequency tables for qualitative 
variables, and descriptive statistics will be provided for quantitative variables. No formal statistical 
analysis will be performed.
9.5.2
Medical History, Concomitant Medication and Other Safety Evaluations
Medical history obtained at screening will be listed by subject. Physical examination results, including 
nasal examinations and nasal irritation, will be listed by subject. Concomitant medications will be 
listed by subject.
9.6
Endpoint Assessments
9.6.1
Efficacy Analyses
The primary endpoint will be analyzed in the FAS population using an analysis of covariance 
(ANCOVA) model with treatment and site as fixed effects and HPWSQ-R (completed by the
parent/caregiver) total score at Visit 2 (baseline) as a covariate. The last observation carried forward
(LOCF) method will be used to carry forward non-missing values of HPWSQ-R total score during the
phone call assessment (Day 8±1) to impute missing values of HPWSQ-R total score at Visit 4. The 
treatment group difference in total score between placebo and carbetocin will be calculated by 
subtracting the mean change from baseline in placebo from that in the carbetocin group.  A borderline 
statistically significant difference at the 10% significant level will be achieved if the upper limit of the 
90% 1-sided confidence interval for the treatment difference is less than zero.
The secondary endpoints will be analyzed using a similar model to that of the primary endpoint.
9.7
Extent of Exposure 
The total trial treatment exposure will be summarized and listed by treatment group for the safety 
population.
9.8
Safety
9.8.1
General Considerations
Safety parameters will be evaluated for the safety analysis data set.


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Complete listings and summary tables for all safety information, including adverse events, clinical 
laboratory safety data, physical examination, nasal examination, vital signs, and ECG will be 
presented. No formal statistical analysis will be performed.
9.8.2
Adverse Events
All adverse events will be listed by subject using the most current version of the Medical Dictionary 
for Regulatory Activities (MedDRA) dictionary for system organ class and preferred term. 
Treatment-emergent adverse events will be listed by subject, and the incidence of treatment-emergent 
adverse events will be presented by treatment. In addition, treatment-emergent adverse events will be 
presented by causality (relationship to the trial medication) and intensity (severity) and seriousness. 
Deaths, serious adverse events, and adverse events leading to discontinuation will be listed.
9.8.3
Safety Laboratory Variables
Clinical safety laboratory values for each subject will be listed by test, and all values outside the 
normal range will be identified. Mean laboratory values will be summarized by treatment group and 
visit using descriptive statistics: sample size, mean, median, standard deviation, minimum, and 
maximum values.
9.8.4
Other Safety Variables
Vital Signs
Vital signs will be summarized by treatment and visit using descriptive statistics: sample size, mean, 
median, standard deviation, minimum, and maximum values. 
Electrocardiograms
Subjects with clinically significant deteriorations in ECG findings will be identified. 
9.9
Population Pharmacokinetic Modeling
Plasma carbetocin PK parameters will be estimated from serum carbetocin concentrations using 
population analysis. The following carbetocin PK parameters will be estimated:
Ctrough:
Observed plasma concentration prior to dosing
CL/F:
Apparent total clearance
Vz/F:
Apparent volume of distribution


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10
DATA HANDLING
10.1
Source Data and Source Documents
Source Data – ICH Definition
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 trial necessary for the reconstruction and 
evaluation of the trial. Source data are contained in source documents (original records or certified 
copies).
Source Documents - ICH Definition
Source documents are defined as original documents, data, and records (e.g. 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 trial).
Trial-specific Source Data Requirements – Ferring
An 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, 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 Food and Drug Administration (FDA) is notified. For each 
subject enrolled, the investigator will indicate in the source record(s) that the subject participates in this 
trial, and will record all trial 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. 
10.2
eCRF
An eCRF system provided by an independent third-party contract research organization (CRO) will be 
used for data capture. The system is validated and access at all levels to the system is granted/revoked 
following Ferring 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. 


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The eCRF system and the database will be hosted at the independent third party CRO. After the trial, 
the database is declared clean and released to the statistician, a final copy of the database will be stored 
at Ferring. The investigator will also receive a copy of the trial site’s final and locked data (including 
audit trail, electronic signature and queries) as write-protected PDF-files produced by the independent 
third party CRO. The PDF-files will be stored on a CD and will be provided to the investigator before 
access to the eCRF is revoked.
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.
10.3
Data Management 
A data management plan will be created under the responsibility of Ferring’s Biometrics Department. 
The data management plan will be issued before data collection begins and will describe all functions, 
processes, and specifications for data collection, cleaning, and validation.
The data management plan will describe captured methods, 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.
10.4
Provision of Additional Information
On request, the investigator will provide the sponsor with additional data relating to the trial, or copies 
of relevant source records, duly anonymized. This is important when errors in data transcription are 
encountered. In case of particular issues or governmental queries, it may be necessary to have access to 
the complete trial documents, provided that the subjects' confidentiality is maintained and protected in 
accordance with applicable requirements.


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11
MONITORING PROCEDURES
11.1
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 trial-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 a subject is enrolled at the site. 
11.2
Audit and Inspection
The investigator will make all the trial-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.
11.3
Confidentiality of Subject Data
The investigator will ensure that the confidentiality of the subjects' 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 trial. Documents not 
intended for submission to the sponsor (e.g., the confidential subject identification code and the signed 
informed consent forms) will be maintained by the investigator in strict confidence.


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12
CHANGES IN THE CONDUCT OF THE TRIAL
12.1
Protocol Amendments
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. 
Significant amendments will be submitted for consideration to the approving IRB(s) and regulatory 
authorities, in accordance with local regulations. 
An approval is required for a significant amendment, e.g., one that could affect the safety of the 
subjects, or that entails a significant change of the scope/design of the trial.
12.2
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 must be reported to the IRB. Any paper documentation must be kept in the 
Investigator’s File and in the Trial Master File.
12.3
Premature Trial Termination
Both the investigator (with regard to his/her participation) and the sponsor reserve the right to 
terminate the trial at any time. Should this become necessary, the procedures will be agreed upon after 
consultation between the 2 parties. In terminating the trial, 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) will be informed.


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13
REPORTING AND PUBLICATION
13.1
Clinical Trial Report
The data and information collected during this trial will be reported in a trial report prepared by the 
sponsor. The final report may be used for the further development of the IMP as considered necessary 
by the sponsor.
13.2
Confidentiality and Ownership of Trial Data
Any confidential information relating to the IMP or the trial, including any data and results from the 
trial, will be the exclusive property of the sponsor. The investigator and any other persons involved in 
the trial will protect the confidentiality of this proprietary information belonging to Ferring 
Pharmaceuticals, Inc.
13.3
Publications and Public Disclosure
13.3.1
Publication Policy
Submission of data for journal publication and/or presentation of data to scientific audiences may be 
considered by Ferring Pharmaceuticals Inc. and the investigator(s). Submission of a manuscript for 
publication will be considered based on the merits of the trial results. 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. The investigator(s) agrees that the sponsor will have the opportunity to 
review all manuscripts and abstracts (at least 30 days) related to this trial prior to any submission for 
presentation or publication. Likewise, if the sponsor prepares a publication based on the results of this 
trial, a copy of the manuscript will be provided to the investigator(s) prior to publication.
Any external contract research organization or laboratory involved in the conduct of this trial has no 
publication rights regarding this trial.
13.3.2
Public Disclosure Policy 
ICMJE member journals have adopted a trials-registration policy as a condition for publication. This 
policy requires that all clinical trials be registered in a public, clinical trials registry. Thus, it is the 
responsibility of Ferring to register the trial in an appropriate registry, i.e. clinicaltrials.gov, which is 
sponsored by the National Institutes of Health.


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14
ETHICAL AND REGULATORY ASPECTS
14.1
Independent Ethics Committee (IEC) or Institutional Review Board (IRB)
An IRB will review the trial protocol and any amendments and advertisements used for recruitment. 
The IRB will review the informed consent form, their updates (if any), and any written materials given 
to the subjects. A list of all IRBs consulted and the name of the committee chair(s) will be included in 
the trial report.
14.2
Regulatory Authority(ies) Authorization / Approval / Notification
The regulatory permission to perform the trial will be obtained in accordance with applicable 
regulatory requirements. All ethical and regulatory approvals must be available before a subject is 
exposed to any trial-related procedure, including screening tests for eligibility.
14.3
End-of-Trial and End-of-Trial Notification
At the end of the trial, the IRB will be notified in writing. 
14.4
Ethical Conduct of the Trial
This trial 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.
14.5
Subject Information and Consent
The investigator or designee will obtain a freely given written informed consent from each subject’s 
parent or 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 trial that are 
relevant to the subject's decision to participate. The consent form must be signed and dated by the 
parent or caregiver before the subject is exposed to any trial-related procedure, including screening 
tests for eligibility.
The investigator or designee will explain that the subjects are completely free to refuse to enter the trial
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 parent or caregiver will receive a copy of any available subject information and her 
signed consent. 


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The subject and parent or caregiver should be informed if new information becomes available that may 
be relevant to their willingness to continue participation in the trial. 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 parent or 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 parent or caregiver in accordance with national regulations. If such subjects can 
understand the risks and benefits of the trial, they should also be informed and provide their written 
consent.
14.6
Compliance Reference Documents
The Helsinki Declaration, the consolidated ICH-GCP, and the national law in the United States of 
America shall constitute the main reference guidelines for ethical and regulatory conduct.


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15
LIABILITIES AND INSURANCE
15.1
ICH-GCP Responsibilities
The responsibilities of Ferring, the monitor and the investigator will be as defined in the ICH-GCP 
consolidated guideline, and applicable regulatory requirements in the country where the trial takes 
place. The investigator is responsible for adhering to the ICH-GCP responsibilities of investigators, for 
dispensing the IMP in accordance with the approved protocol or an approved amendment, and for its 
secure storage and safe handling throughout the trial.
15.2
Liabilities and Insurance
In case of any damage or injury occurring to a subject in association with the IMP or the participation 
in the trial, Ferring has contracted an insurance which covers the liability of Ferring, the investigator 
and other persons involved in the trial in compliance with the laws in the countries involved.


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16
ARCHIVING
16.1
Investigator File
To enable evaluations and/or audits from regulatory authorities or Ferring Pharmaceuticals, the 
investigator agrees to keep records, including the identity of all participating subjects (sufficient 
information to link records, eCRFs and hospital records), all original signed informed consent forms, 
copies of all eCRFs, and detailed records of treatment disposition. The records shall be retained 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, 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 FDA is notified. 
If the investigator relocates, retires, or for any reason withdraws from the trial, the trial records may be 
transferred to an acceptable designee, such as another investigator, another institution, or to Ferring. 
The investigator must obtain Ferring Pharmaceutical’s written permission before disposing of any 
records.
No trial site document may be destroyed without prior written agreement between the investigator and 
the sponsor. Should the investigator elect to assign the trial documents to another party or move them 
to another location, the sponsor must be notified. 
16.2
Trial Master File
Ferring will archive the trial master file in accordance with ICH-GCP and applicable regulatory 
requirements.


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17
REFERENCE
1
Burd L, Vesely B, Martsolf J, Kerbeshian J. Prevalence study of Prader-Willi syndrome in 
North Dakota. Am J Med Genet. 1990; 37:97-9.
2
Jin DK. Systematic review of the clinical and genetic aspects of Prader-Willi syndrome. Korean 
J Pediatr. 2011;54:55-63.
3
Cassidy SB, Driscoll DJ. Prader-Willi syndrome. Eur J of Human Genet. 2009;17:3-13.
4
Greenswag LR. Adults with Prader-Willi syndrome: a survey of 232 cases. Dev Med Child 
Neurol. 1987;29(2):145-52.
5
Miller JL, Lynn CH, Driscoll DC, et al. Nutritional phases in Prader-Willi syndrome. Am J 
Med Genet A. 2011;155:1040-9.
6
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.
7
Seifer DB, Sandberg EC, Ueland K, Sladen RN. Water intoxication and hyponatremic 
encephalopathy from the use of an oxytocin nasal spray. A case report. J Reprod Med. 
1985;30:225-8.
8
Ansseau M, Legros JJ, Mormont C, et al. Intranasal oxytocin in obsessive-compulsive disorder. 
Psychoneuroendocrinology. 1987;12:231-6.
9
Mayer-Hubner B. Pseudotumour cerebri from intranasal oxytocin and excessive fluid intake. 
Lancet. 1996;347(9001):623.
10
Akefeldt A. Water intake and risk of hyponatremia in Prader-Willi Syndrome. J Intellect 
Disabil Res. 2009;53:521-28.
11
Dykens EM, Maxwell MA, Pantino E, Kossler R, Roof E. Assessment of hyperphagia in 
Prader-Willi syndrome. Obesity. 2007;15:1816-26.
12
Guy W. Early Clinical Drug Evaluation (ECDEU) Assessment Manual for 
Psychopharmacology, revised. National Institute of Mental Health, Rockville, MD. 1976.


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13
Busner, J. and S. D. Targum. “The clinical global impressions scale: applying a research tool in 
clinical practice.” Psychiatry (Edgmont) 2007; 4(7): 28-37.
14
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.
15
Storch EA, Murphy TK, Geffken GR, et al. Psychometric evaluation of the Children’s Yale-
Brown Obsessive Compulsive Scale. Psychiatry Res. 2004;129:91–8.
16
Yucelen AG, Rodopman-Arman A, Topcuoglu V, Yazgan MY, Fisek G. Interrater reliability 
and clinical efficacy of Children’s Yale-Brown Obsessive–Compulsive Scale in an outpatient 
setting. Compr Psychiatry. 2006;47:48–53.
17
Pediatric OCD Treatment Study (POTS) Team. Cognitive-behavior therapy, sertraline, and their 
combination for children and adolescents with obsessive-compulsive disorder: the Pediatric 
OCD Treatment Study (POTS) randomized controlled trial. JAMA. 2004;292(16):1969-76.
18
Storch EA, Gefffken GR, Merlo LJ, et al. Family-based cognitive-behavioral therapy for 
pediatric obsessive-compulsive disorder: Comparison of intensive and weekly approaches. 
J Am Acad Child Adolesc Psychiatry. 2007;46:469–78.
19
Dykens and Rosner 1999 Dykens, EM and B. Rosner.  Refining behavioral phenotypes: 
personality-motivation in Williams and Prader-Willi syndromes.  Am J Ment Retard 1999; 
104(2): 158-69.


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APPENDICES
Appendix I – Clinical Global Impressions Scales
Clinical Global Impression-Severity Rating
Subject Number_______ Rater__________________
Age______ Genetic subtype of PWS__________ Date of visit_____________
The CGI is usually rated relative to the past seven days (including the day of the visit up to and 
through the visit).
CGI-Severity (CGI-S) Considering your total clinical experience with Prader-Willi
syndrome population; how ill is this patient at this time? (Which is rated on a 7
point scale-circle one answer)
1=Normal, Not at all ill
2=Borderline ill
3=Mildly ill
4=Moderately ill
5=Markedly ill
6=Severely ill
7=Among the most extremely ill patients
CGI-Improvement (CGI-I) Compared to the patient’s condition at baseline visit,
this patient’s condition is: (circle one) Minimal amount of improvement needed for clinical
meaningfulness.
1=Very Much Improved since baseline (initiation of treatment)
2=Much Improved
3=Minimally Improved
4=No Change from baseline
5=Minimally worse
6=Much Worse
7=Very Much Worse from baseline


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Appendix II – Hyperphagia in Prader-Willi Syndrome Questionnaire-Responsiveness (HPWSQ-
R) Scale – completed by the parent/caregiver
This survey will help keep track of how things have been with your child in the past week.  
For each one of the survey items, please mark an 
in the one box that best describes your answer.
1. These questions are about how things have been with your child during the past week?  For each question, please 
give the one answer that comes closest to the way to describe the situation-
Not at all
A little bit
Moderate
Quite a bit 
Extremely





a  How upset did your child
   generally become when denied 
   a desired food?...................................................
1 ................
2 .................
3 .................
4 .................
5
b  How persistent was your child in 
   asking or looking for food after 
   being told “no” or “no more”? ..........................
1…………..
2 .................
3 .................
4 .................
5
c  How distressed did your child become 
   when stopped from talking about food
   or engaging in food-related behaviors? .............
1…………..
2 .................
3 .................
4 .................
5
d  How “clever” or “fast” was your child
   in obtaining food? .............................................
1…………..
2 .................
3 .................
4 .................
5
e  To what extent did food-related thoughts, 
   talk, or behavior interfere with your child’s
   normal daily routines, 
   self-care, school, or work?.................................
1…………..
2 .................
3 .................
4 .................
5


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2. How much of the time during the past week did your child …
None of
the time
A little of the 
time
Some of the 
time
Most of the 
time
All of the 
time





a  Try to bargain or manipulate 
   to get more food ................................................
1.................
2.................
3..................
4................
5
b  Forage through the trash for food.....................
1.................
2.................
3..................
4................
5
c  Get up at night to food seek? ............................
1.................
2.................
3..................
4................
5
d  Talk about food or engaged 
   in food-related behaviors, outside of 
   normal meal times .............................................
1.................
2.................
3..................
4................
5
e   Try to steal food...............................................
1.................
2.................
3..................
4................
5
3. During the past week, once your child had food on his/her mind, how easy was it for you or others to re-direct your 
child away from food to other things?
Extremely easy
Very easy
Somewhat hard
Very hard
Extremely hard





  
1
  
2
  
3
  
4
  
5


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Appendix III – Hyperphagia in Prader-Willi Syndrome Questionnaire-Responsiveness (HPWSQ-
R-C) Scale – administered by the clinician
This survey will help keep track of how things have been with the patient in the past week.  
For each one of the survey items, please mark an 
in the one box that best describes your answer.
1. These questions are about how things have been with the patient during the past week?  For each question, please 
give the one answer that comes closest to the way to describe the situation-
Not at all
A little bit
Moderate
Quite a bit 
Extremely





a  How upset did the patient 
   generally become when denied 
   a desired food?...................................................
1 ................
2 .................
3 .................
4 .................
5
b  How persistent was the patient in 
   asking or looking for food after 
   being told “no” or “no more”? ..........................
1…………..
2 .................
3 .................
4 .................
5
c  How distressed did the patient become 
   when stopped from talking about food
   or engaging in food-related behaviors? .............
1…………..
2 .................
3 .................
4 .................
5
d  How “clever” or “fast” was the patient 
   in obtaining food? .............................................
1…………..
2 .................
3 .................
4 .................
5
e  To what extent did food-related thoughts, 
   talk, or behavior interfere with the patient’s 
   normal daily routines, 
   self-care, school, or work?.................................
1…………..
2 .................
3 .................
4 .................
5


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2. How much of the time during the past week did the patient …
None of
the time
A little of the 
time
Some of the 
time
Most of the 
time
All of the 
time





a  Try to bargain or manipulate 
   to get more food ................................................
1.................
2.................
3..................
4................
5
b  Forage through the trash for food.....................
1.................
2.................
3..................
4................
5
c  Get up at night to food seek? ............................
1.................
2.................
3..................
4................
5
d  Talk about food or engaged 
   in food-related behaviors, outside of 
   normal meal times .............................................
1.................
2.................
3..................
4................
5
e   Try to steal food...............................................
1.................
2.................
3..................
4................
5
3. During the past week, once the patient had food on his/her mind, how easy was it to re-direct the patient away from 
food to other things?
Extremely easy
Very easy
Somewhat hard
Very hard
Extremely hard





  
1
  
2
  
3
  
4
  
5


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Appendix IV – Children’s Yale-Brown Obsessive Compulsive Scale
CY-BOCS Symptom Checklist
Children’s Yale-Brown Obsessive Compulsive Scale
Administering the CY-BOCS Symptom Checklist and CY-BOCS Severity Ratings
1. Establish the diagnosis of obsessive compulsive disorder.
2. Using the CY-BOCS Symptom Checklist (below), ascertain current and past symptoms.
3. Next, administer the 10 item severity ratings (other form) to assess the severity of the OCD 
during the last week.
4. Re-administer the CY-BOCS Severity Rating Scale to monitor progress.
Patient ______________________________________ Date _______________


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CY-BOCS Obsessions Checklist 
Check all symptoms that apply (Items marked “*” may or may not be OCD Phenomena) 
Current
Past
Contamination Obsessions
Current
Past
Sexual Obsessions
□
□
Concern with dirt, germs, certain 
illnesses 
(e.g., AIDS)
□
□
Forbidden or perverse sexual 
thoughts, images, impulses
□
□
Concerns or disgust with bodily waste or 
secretions (e.g. urine, feces, saliva)
□
□
Content involves homosexuality
□
□
Excessive concern with environmental 
contaminants (e.g., asbestos, radiation, 
toxic waste)
□
□
Sexual behavior towards others 
(aggressive)
□
□
Excessive concern with household items 
(e.g., cleaners, solvents)
□
□
Other (describe) 
______________________
□
□
Excessive concern about animals / 
insects
Hoarding / Saving Obsessions
□
□
Excessively bothered by sticky 
substances or residues
□
□
Fear of losing things
□
□
Concerned will get ill because of 
contaminant
□
□
Other (describe) 
______________________
□
□
Concerned will get others ill by 
spreading contaminant (aggressive)
□
□
Magical Thoughts / Superstitious 
Obsessions
□
□
No concern with consequences of 
contamination other than how it might 
feel *
□
□
Lucky / unlucky numbers, colors, 
words
□
□
Other (describe) 
_________________________
□
□
Other (describe) 
______________________
Aggressive Obsessions
Somatic Obsessions
□
□
Fear might harm self 
□
□
Excessive concern with illness or 
disease *
□
□
Fear might harm others 
□
□
Excessive concern with body part or 
aspect of appearance (e.g. 
dismorphophobia)
□
□
Fear harm will come to self 
□
□
Other (describe) 
______________________
□
□
Fear harm will come to others (maybe 
because of something child did or did 
not do)
Religious Obsessions
□
□
Violent or horrific images
□
□
Excessive concern or fear of 
offending religious objects
□
□
Fear of blurting out obscenities or insults 
□
□
Excessive concern with right / wrong 
morality
□
□
Fear of doing something embarrassing * 
□
□
Other (describe) 
______________________
□
□
Fear will act on unwanted impulses (e.g., 
to stab a family member)
Miscellaneous Obsessions
□
□
Fear will steal things
□
□
The need to know or remember
□
□
Fear will be responsible for something 
else terrible happening (e.g. ,fire, 
burglary, flood)
□
□
Fear of saying certain things


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Target Symptoms List for Obsessions
OBSESSIONS (describe, listing by order of severity, with #1 being most severe, #2 second most severe, etc):
1. ________________________________________________________________________
2. ________________________________________________________________________
3. ________________________________________________________________________
4. ________________________________________________________________________
□
□
Other (describe)
______________________
□
□
Fear of not saying just the right thing
□
□
Intrusive (non – violent) images
□
□
Intrusive sounds, words, music, or 
numbers
□
□
Other (describe) 
______________________


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CY-BOCS Symptom Checklist
Children’s Yale-Brown Obsessive Compulsive Scale
CY-BOCS Compulsions Checklist
Check all symptoms that apply (Items marked “*” may or may not be OCD phenomena)
Current
Past
Washing  / Cleaning Compulsions
Current
Past
Hoarding / Saving Compulsions
□
□
Excessive or ritualized hand washing
Distinguish from hobbies and concern 
for objects of monetary or sentimental 
value
□
□
Excessive or ritualized showering, 
bathing, tooth brushing, grooming, toilet 
routine
□
□
Difficulty throwing things away, 
saving bits of paper, string, etc.
□
□
Excessive cleaning of items, such as 
personal clothes or important objects
□
□
Other (describe) 
____________________
□
□
Other measures to prevent or remove 
contact with contaminants
Excessive Games / Superstitious 
Behaviors 
□
□
Other (describe) 
______________________
□
□
Distinguish from age appropriate 
magical games (e.g. array of behavior, 
such as sleeping over certain spots on 
a floor, touching an object / self a 
certain number of times to prevent 
something bad from happening)
Checking Compulsions
□
□
Other (describe) 
____________________
□
□
Checking locks, toys, school books / 
items, etc.
□
□
Rituals Involving Other Persons
□
□
Checking associated with getting 
washed, dressed, or undressed
□
□
The need to involve another person 
(usually a parent) in ritual (e.g. asking 
a parent to repeatedly answer the same 
question, making mother perform 
certain mealtime rituals involving 
specific utensils)
□
□
Checking that did not / will not harm 
others
□
□
Other (describe) 
____________________
□
□
Checking that did not / will not harm 
self
□
□
Miscellaneous Compulsions
□
□
Checking that nothing terrible did / will 
happen
□
□
Mental rituals other than checking / 
counting
□
□
Checking that did not make mistake
□
□
Need to tell, ask, or confess
□
□
Checking tied to somatic obsessions
□
□
Measures, not checking, to prevent:
□
□
Other (describe) 
______________________
□
□
harm to self
Repeating Rituals
□
□
harm to others
□
□
Rereading, erasing, or rewriting
□
□
terrible consequences
□
□
Need to repeat activities (e.g. in / out of 
doorway, up / down from chair)
□
□
Ritualized eating behaviors*


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□
□
Other (describe) 
______________________
□
□
Excessive list making*
Counting Compulsions
□
□
Need to touch, tap, rub*
□
□
Objects, certain numbers, words, etc.
□
□
Need to do things (e.g. touch or 
arrange until it feels just right)
□
□
Other (describe) 
______________________
□
□
Rituals involving blinking or staring
Ordering / Arranging
□
□
Trichotillomania (hair pulling)
□
□
Need for symmetry / evening up (e.g. 
lining items up in a certain way or 
arranging personal items in specific 
patterns)
□
□
Other self-damaging or self-mutilating 
behaviors
□
□
Other (describe) 
____________________
Target Symptoms List for Compulsions
COMPULSIONS (describe, listing by order of severity, with #1 being the most severe, #2 second most severe, etc.)
1. ________________________________________________________________________
2. ________________________________________________________________________
3. ________________________________________________________________________
4. ________________________________________________________________________


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Appendix V – Food Domain of the Reiss Profile
REISS PROFILE OF FUNDAMENTAL GOALS
AND MOTIVATION SENSITIVITIES
FOR PERSONS WITH MENTAL RETARDATION
(*Food Domain Only)
Information on Person You are Rating
Be sure that you have known the person you are rating for at least four months
State of residence:
__________________
Approximate IQ (check one):
Age
__________________
50 and above 
Gender:
Male
Female
35 – 50
Racial Background: __________________
less than 35
Does this person have psychiatric diagnosis or behavior problem?   yes   no
If yes, please indicate the diagnosis or the nature of the behavior problem as best you can.
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
__________________________________________


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Instructions:  Please indicate if you agree or disagree that each of the following phrases is true of the 
person you are rating.  If the phrase is a valid description of the person, indicate if you agree or 
strongly agree.  If the phrase is an invalid description of the person, indicate if you disagree or strongly 
disagree.  Use the neutral rating if you have no opinion, do not know, or feel that the description is not 
applicable.  Each rating should be made without consulting others.  Thank you for your assistance.
SD
(Strongly Disagree):
this phrase is not at all characteristic of the person
D
(Disagree):
this phrase does not characterize the person well
N
(Neutral):
do not know, not applicable
A
(Agree):
this phrase somewhat characterizes the person
SA
(Strongly Agree):
this phrase is definitely characteristic of the person
1.
More than most people, enjoys eating……………………….……….……SD
D
N
A
SA
2.
Always thinking about food………………………………………………….…. SD
D
N
A
SA
3.
Always eating……………………………………………………………………….…. SD
D
N
A
SA
4.
Very hearty appetite………………………………………..……………………... SD
D
N
A
SA
5.
Eating is more important than it is for most people……………….… SD
D
N
A
SA
6.
More than most people, becomes upset if meals are delayed.... SD
D
N
A
SA
7.
Often asks about /plans next meal (What’s for lunch?)………….... SD
D
N
A
SA


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Appendix VI – Nutritional Phase Assessment
Phase 0 Decreased fetal movements and lower birth weight
Full-term birth weight and BMI are about 15–20% less than the siblings
Typically normal gestational age
85% have decreased fetal movements
Phase 1a Hypotonia with difficulty feeding (0–9 months)
Weak, uncoordinated suck. Usually cannot breastfeed
Needs assistance with feeding either through feeding tubes (nasal/oral gastric tube or 
gastrostomy tube) or orally with special, widened nipples. Many would die without assisted 
feeding
Oral feeds are very slow
Severely decreased appetite. Shows little or no evidence of being hungry
Does not cry for food or get excited at feeding time
If feeding just occurred when baby ‘‘acted hungry’’ then would have severe ‘‘failure-to-thrive’’
Weak cry
Phase 1b No difficulty feeding and growing appropriately on growth curve (9–25 months)
No longer needs assisted feeding
Growing steadily along growth curve with normal feeding
Normal appetite
Phase 2a Weight increasing without an increase in appetite or excessive calories (2.1–4.5 years)
Infant starts crossing growth curve centile lines
No increase in appetite
Appetite appropriate for age
Will become obese if given the recommended daily allowance (RDA) for calories or if eating a 
‘‘typical’’ toddler diet of 70% carbohydrates
Typically needs to be restricted to 60–80% of RDA to prevent obesity
Phase 2b Weight increasing with an increase in appetite (4.5–8 years)
Increased interest in food. Frequently asking ‘‘food related’’ questions
Preoccupied with food. Very concerned about the next meal/snack (e.g., ‘‘Did you remember to 
pack my lunch?’’)
Increased appetite
Will eat more food than a typical child if allowed
Will eat food within their line of sight if unattended
Will become obese if allowed to eat what they want
Can be fairly easily redirected about food
Can feel full
Will stop eating voluntarily
Phase 3 Hyperphagic, rarely feels full (8 years - adulthood)
Constantly thinking about food
While eating one meal they are already thinking about the next meal
Will awaken from sleep early thinking about food


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Will continue eating if portion size is not limited
Rarely (truly) feels full
Will steal food or money to pay for food
Can eat food from garbage and other unsavory/inedible sources (e.g., dog food, frozen food, 
crayons, etc.)
Typically are not truthful about what they have eaten (i.e. amount and types of food)
Will gain considerable amount of weight over a short period of time if not supervised (e.g., 
some individuals are known to have gained up to 20 pounds in one weekend)
Food typically needs to be locked up. Frequently the child will ask the parent to lock the food if 
the parent has forgotten
Will break into neighbors’ houses for food
Temper tantrums and ‘‘meltdowns’’ frequently related to food
Needs to be placed on a diet that is approximately 50–70% of the RDA to maintain a healthy 
weight
Phase 4 Appetite is no longer insatiable (adulthood)
Appetite may still be increased or may be normal or less than normal
Previously in phase 3, but now a noticeable improvement in their appetite control
Can feel full
Appetite can fluctuate in this phase, but the key component is noticeable improvement in 
control of appetite compared to when they were younger
Not as preoccupied with food
Absence of major temper tantrums and ‘‘meltdowns’’ related to food
Onset in adulthood. Could be as early as 20s or as late as 40–50s
Most adults have not gone into this phase and maybe some (most?) never will
Miller et al 2011 (5)


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Appendix VII – List of Drugs Containing Prostaglandins
1. Apo-Misoprostol 
2. Arthotec 
3. Arthotec Akut 
4. Arthotec Forte 
5. Arthrotec 
6. Artotec 
7. Artrenac Pro 
8. Artrene SR 
9. Corrigast 
10. Cyprostol 
11. Cytolog 
12. Cytotec 
13. Glefos 
14. Gymiso 
15. Menpros 
16. Mirolut 
17. Misodex 
18. Misopess 
19. Misoprost 
20. Misoprostol
21. Misotrol 
22. Mizoprostol 
23. Novo-Misoprostol 
24. PMS-Misoprostol 
25. Symbol


 
 
 
 
 
 
 
 
Statistical Analysis Plan  
 
 
Title of trial:  
A Prospective, Randomized, Double-Blind, Placebo-Controlled Study to 
Evaluate the Safety and Effectiveness of Intranasal Carbetocin in Subjects 
with Prader-Willi Syndrome (PWS) 
NCT number: 
NCT01968187 
Sponsor trial code: 
000114 
Date:  
 - 
 
 
 
 
 


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[TemplateI for]
STATISTICAL ANALYSIS PLAN
A Prospective, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety 
and Effectiveness of Intranasal Carbetocin in Subjects with Prader-Willi Syndrome (PWS)
Trial Code 000114
Investigational Product:
Carbetocin (FE 992097)
Indication:
Treatment of hyperphagia behavioral symptoms in children
                                                              and adults diagnosed with PWS
Phase:
2a
Author:
Ph.D.
Date of issue:
24 July 2014
Version:
1.0
The information in this document is confidential and is proprietary to Ferring Pharmaceuticals A/S or another 
company within the Ferring Group. It is understood that information in this document shall not be disclosed to any 
third party, in any form, without prior written consent of an authorised officer of Ferring Pharmaceuticals A/S or 
another company within the Ferring Group
                                                
PPD


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Change log
Version
No.
Effective
Date
Reason for the Change / Revision
Supersedes


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SignedII agreement on Statistical Analysis Plan
Author:  
_______________________________ 
________________
              
 Ph.D.                   
Date (dd/mm/yyyy)
             
 Biostatistics
             
C
Review:
_______________________________
________________
 M.D.
               
Date (dd/mm/yyyy)
 Gastroenterology
aScience Center U.S., Inc.
_______________________________
________________
MD, MBA
                             
Date (dd/mm/yyyy)
Ferring International PhamaScience Center U.S., Inc.
_______________________________
________________
                    
Date (dd/mm/yyyy)
ance Marketed Products
_______________________________
________________
                             
Date (dd/mm/yyyy)
 Clinical Operations
nternational PhamaScience Center U.S., Inc.
_______________________________
________________
 MSc.                                     
Date (dd/mm/yyyy)
 Biostatistics / Project Statistician
rnational PhamaScience Center U.S., Inc.
_______________________________
________________
                                             
Date (dd/mm/yyyy)
 Pharmacokineticist
Ferring International PhamaScience
Approval:
________________________________
________________
 Ph.D.
Date (dd/mm/yyyy)
 Biometrics
 A/S
                                                
II Can be replaced by a list of reviewers/approvers if sign off can be performed in the REAL system
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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TABLE OF CONTENTS
1
Introduction.......................................................................................................................................... 6
1.1
Definitions/ Abbreviations...................................................................................................... 6
1.1.1
Definition of Terms.................................................................................................... 6
1.1.2
Abbreviations ............................................................................................................. 6
2
Trial Objectives and Endpoints.......................................................................................................... 8
2.1
Objectives................................................................................................................................. 8
2.2
Endpoints................................................................................................................................. 8
3
Trial design......................................................................................................................................... 10
3.1
General Design Considerations............................................................................................ 10
3.2
Determination of Sample Size.............................................................................................. 11
4
Subject Disposition ............................................................................................................................ 12
5
Protocol Deviations............................................................................................................................ 13
6
Analysis sets........................................................................................................................................ 14
6.1
Intention-To-Treat Analysis Set .......................................................................................... 14
6.2
Full-Analysis Set.................................................................................................................... 14
6.3
Per Protocol Analysis Set ..................................................................................................... 14
6.4
Safety Analysis Set ................................................................................................................ 14
6.5
Pharmacokinetic Analysis Set.............................................................................................. 14
7
Trial population ................................................................................................................................. 15
7.1
Demographics and Other Baseline Characteristics ........................................................... 15
7.1.1
Demographics........................................................................................................... 15
7.1.2
Vital Signs at Baseline ............................................................................................. 15
7.1.3
Trial-specific Baseline Variables or History of Disease........................................ 15
7.1.4
Laboratory Efficacy/Pharmacodynamic Parameters at Baseline ....................... 15
7.2
Medical History..................................................................................................................... 15
7.3
Prior and Concomitant Medication..................................................................................... 16
7.4
Physical Examination ........................................................................................................... 16
8
Exposure and Treatment Compliance ............................................................................................. 17
8.1.1
Extent of Exposure................................................................................................... 17
8.1.2
Treatment Compliance............................................................................................ 17
9
Efficacy ............................................................................................................................................... 18


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9.1
General Considerations........................................................................................................ 18
9.2
Primary Endpoint(s)............................................................................................................. 18
9.2.1
Primary Variable(s) Analysis.................................................................................. 19
9.2.2
Sensitivity Analyses.................................................................................................. 19
9.3
Secondary Endpoint(s) ......................................................................................................... 20
9.4
Exploratory Analyses............................................................................................................ 21
10
Safety................................................................................................................................................... 22
10.1
General Considerations........................................................................................................ 22
10.2
Adverse Events...................................................................................................................... 22
10.2.1 Overview of Treatment-Emergent Adverse Events.............................................. 22
10.2.2 Incidence of Adverse Events ................................................................................... 23
10.3
Safety Laboratory Variables................................................................................................ 23
10.3.1 Summary Statistics .................................................................................................. 23
10.3.2 Laboratory Variable Changes Relative to Normal Range ................................... 23
10.3.3 Markedly Abnormal Changes................................................................................. 24
10.3.4 Data Listings............................................................................................................. 24
10.4
Vital Signs and ECG............................................................................................................. 24
10.4.1 Vital Signs................................................................................................................. 24
10.4.1.1
Summary Statistics...............................................................................................................................24
10.4.1.2
Markedly Abnormal Changes ..............................................................................................................24
10.4.1.3
Data Listings ........................................................................................................................................25
10.4.2 ECGs ......................................................................................................................... 25
10.4.2.1
Summary Statistics...............................................................................................................................25
10.4.2.2
Markedly Abnormal Changes ..............................................................................................................25
10.4.2.3
Data Listings ........................................................................................................................................25
10.5
Other Safety Variables ......................................................................................................... 25
10.5.1 Nasal examination.................................................................................................... 25
11
Interim analyses ................................................................................................................................. 26
12
Deviations from protocol analysis .................................................................................................... 27
13
References........................................................................................................................................... 28
14
Tables, Listings and Figures ............................................................................................................. 29
Appendix 1
Markedly Abnormal Laboratory Safety Values, Vital Signs............................................ 30


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1
Introduction
This Statistical Analysis Plan (SAP) describes the planned statistical analyses for Trial 000114 
based on the protocol amendment (version 4, dated 10 February 2014) “A Prospective, 
Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Effectiveness of 
Intranasal Carbetocin in Subjects with Prader Willi Syndrome (PWS)”.
The SAP provides a more technical and detailed elaboration of the statistical analyses of efficacy 
and safety as outlined and/or specified in the protocol as well as data handling rules and exploratory 
analyses not mentioned in the protocol.
1.1
Definitions/ Abbreviations
1.1.1
Definition of Terms
Terms
Definitions
Enrolled
When subject and Investigator signed the Informed Consent Form
Randomised
Subject randomised to trial treatment
Screened
Subject who enters the screening phase
1.1.2
Abbreviations
Abbreviations
Meaning of abbreviations in document
AE
Adverse Event
ANCOVA
Analysis of Covariance 
ATC
Anatomical Therapeutic Chemical
BMI
Body Mass Index
CI
Confidence Interval
CGI
Clinical Global Impression
CGI-I
Clinical Global Impression-Improvement 
CGI-S
Clinical Global Impression-Severity
CRF
Clinical Report Form
CS
Clinical Significant
CY-BOCS
Children’s Yale-Brown Obsessive Compulsive Scale
ECG
Electrocardiogram
FAS
Full Analysis Set
F/U
Follow-up
HPWSQ-R
Hyperphagia in Prader-Willi Syndrome Questionnaire-
Responsiveness – completed by the parent/caregiver
HPWSQ-R-C
Hyperphagia in Prader-Willi Syndrome Questionnaire-
Responsiveness-Clinician – administered by the clinician
IMP
Investigational Medicinal Product


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Abbreviations
Meaning of abbreviations in document
LOCF
Last observation carried forward
MedDRA
Medical Dictionary for Regulatory Activities
NCS
Not Clinical Significant
OCD
Obsessive-Compulsive Disorder
PK
Pharmacokinetic
PWS
Prader Willi Syndrome
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SOC
System Organ Class
TEAE
Treatment Emergent Adverse Event
WHODrug
World Health Organisation Drug Dictionary


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2
Trial Objectives and Endpoints
2.1
Objectives
Primary objective

To assess the effect of intranasal carbetocin (FE 992097) on hyperphagia behavioral 
symptoms in subjects with PWS, measured by the Hyperphagia in Prader-Willi Syndrome 
Questionnaire-Responsiveness (HPWSQ-R) scale – completed by the subject’s 
parent/caregiver
Secondary objectives

To assess the effect of intranasal carbetocin (FE 992097) on hyperphagia behavioral 
symptoms in subjects with PWS, measured by the Hyperphagia in Prader-Willi Syndrome 
Questionnaire-Responsiveness-Clinician (HPWSQ-R-C) scale – administered by the 
clinician

To assess improvement of PWS symptoms, assessed by the Clinical Global Impression 
(CGI) scale

To assess safety and tolerability of intranasal carbetocin

To assess a population pharmacokinetic model for the patient population utilizing sparse 
data sampling 

To assess the effects of intranasal carbetocin on PWS maladaptive behaviors, assessed by 
the Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS)

To assess the sensitivity of Food Domain of the Reiss Profile
2.2
Endpoints
Primary endpoint

Change in HPWSQ-R total score from Visit 2/Baseline to Visit 4
Secondary endpoints
1. Clinical Global Impression-Improvement after treatment (CGI-I) score at Day 8 and Visit 4
2. Change from Visit 2/Baseline to Day 8 and Visit 4 for the following measurements:

HPWSQ-R hyperphagia behavior, drive, and severity domain scores

HPWSQ-R-C total score

HPWSQ-R-C hyperphagia behavior, drive, and severity domain scores
3. Change from Visit 1/Baseline to Day 8 and Visit 4 for the following measurements:


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
CY-BOCS score

Food Domain of the Reiss Profile
4. Population PK/PD relationships for carbetocin
Safety endpoints

Frequency, severity and seriousness of adverse events

Clinically significant changes in vital signs

Clinically significant findings during physical and laboratory assessments

Physical examinations, including focused nasal examinations and nasal irritation, graded 
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


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3
Trial design
3.1
General Design Considerations
This is a prospective, randomized, double-blind, placebo-controlled, multi-center, parallel trial in 
subjects with PWS between 10 and 18 years of age with genetically confirmed diagnosis of PWS 
and a documented nutritional phase 3 based on the criteria defined by Miller et al 2011. The trial 
includes a Screening Period, a 14-day Treatment Period, and a Follow-Up Period. Subjects, along 
with their parent or caregiver, will be required to visit the investigational site 4 times over the 
course of the trial, and participate in 2 phone call assessments.

Visit 1: Screening Period (Day -7 to Day 0)

Visit 2: Baseline 1st day dosing on site (Day 1)

Visit 3:  2nd day dosing on site (Day 2)

Phone call assessment (Day 8)

Visit 4: End-of-Treatment Visit (Day 15)

Follow-up phone call (Day 19±3)
Following appropriate informed consent procedures, subjects will undergo screening evaluations to 
determine eligibility before randomization. Screening evaluations include a physical examination, 
vital signs, height, weight, 12-lead electrocardiogram (ECG), nasal examination, and laboratory 
assessments - hematology, clinical chemistry, hemostasis, and urinalysis. Approximately 38 eligible 
male or female subjects will be randomized at Visit 2 to 1 of 2 treatment groups for 14 days:

Carbetocin: each spray pump actuation will deliver a 50 µL volume of solution containing 
1.6 mg carbetocin; each dose will consist of 3 spray pump actuations in each nostril to 
deliver a total of 9.6 mg carbetocin

Placebo:  each spray pump actuation will deliver a 50 µL volume of sterile sodium chloride 
solution 0.9%; each dose will consist of 3 spray pump actuations in each nostril
After randomization, efficacy measures and other assessments, including physical examination, 
vital signs, nasal examination, and collection of blood samples for clinical laboratory and 
pharmacokinetic (PK) evaluation, will be performed at selected visits according to Schedule of 
Activities in the Protocol. Subjects will be closely monitored for adverse events throughout the trial
following informed consent.
Prior to first dosing at the investigational site, parents/caregivers will be trained on the proper use 
of the nasal spray device and procedures for Investigational Medicinal Product (IMP) home 
delivery. Parents/caregivers will be instructed to administer 3 intranasal spray pumps of blinded 
IMP per nostril 3 times daily before meals within the following intervals:


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Morning dose:      06:00 a.m. – 09:00 a.m.
Midday dose:      11:00 a.m. – 1:00 p.m.
Evening dose:      4:30 p.m. – 6:00 p.m.
Initial IMP dosing at Visit 2 (Day 1) and Visit 3 (Day 2) will take place under observation of the 
site staff at the investigational site. Subject vital signs will be monitored prior to and after IMP 
dosing at 30-minute intervals for 2 hours after each dose. IMP will be shipped by central pharmacy 
directly to the subject’s residence on regular intervals as needed for the duration of the Treatment 
Period.  IMP will be administered by parents/caregivers 3 times per day before meals within the 
above specified dosing intervals. The IMP will require refrigeration during shipment to and during 
storage at the investigational site or subject’s residence until administered.
3.2
Determination of Sample Size
Based on available literature (Dykens et al 2007), the HPWSQ-R total score at baseline (Visit 2) is
assumed to be normally distributed with a standard deviation of 6.12, and the standard deviation of 
the change between baseline (Visit 2) and Visit 4 is estimated to be between 5 and 6. With 30 
subjects eligible for the primary efficacy assessment, the trial has at least 80% power to detect a 
borderline statistically significant difference (1-sided 10% significance) between 2 groups when the 
true treatment group difference is -5 under the standard deviation of 5 to 6.  Subjects are 
randomized in a 1:1 ratio to either placebo or carbetocin.  
The efficacy of carbetocin will be assessed by change in HPWSQ-R total score from Visit 
2/Baseline to Visit 4. Assuming a dropout rate of approximately 20%, at least 19 subjects per 
treatment arm will need to be randomized to have a total of 30 subjects eligible for the primary 
efficacy assessment.


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4
Subject Disposition
The number of subjects who enrolled and/or randomized into the trial will be summarized overall. 
Subjects who discontinue IMP or are removed from the trial permanently will also be reported by 
the treatment received immediately prior to discontinuation. Reasons for trial discontinuation will 
be summarized by treatment as well as randomization errors and time of withdrawal from the trial, 
if appropriate. No formal statistical analysis will be performed.
The number of subjects screened but not randomized/allocated to treatment will be presented with 
the reason(s) for screen failure in a data listing.


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5
Protocol Deviations
Rating of protocol deviations as ‘minor’ and ‘major’ will be decided by the Ferring clinical team on 
the basis of a blinded review of data before declaration of clean file and lock of database. Major 
protocol deviations will lead to exclusion of data from the Per Protocol analyses. Minor protocol 
deviations will not lead to exclusion of data from any analyses. 
The full list of major protocol deviations will be detailed and documented in the clean file 
document prior to treatment unblinding. 
Major protocol deviations include, but are not restricted to, the following: 

Violation of inclusion or exclusion criteria that may affect the efficacy analysis such as:
o
Inclusion criterion 4, genetically confirmed diagnosis of PWS
o
Inclusion criterion 5, Nutritional phase 3 PWS criteria based on Miller et al, 2011; 
o
Inclusion criterion 6, HPWSQ-R score greater than 13 at screening, Visit 1
o
Exclusion criterion 5, Prior or concomitant use of a selective serotonin reuptake 
inhibitor (SSRI) or selective norepinephrine reuptake inhibitor (SNRI), antipsychotic 
medication, wakefulness-promoting drug, or thyroid hormone that does not comply 
with the criteria in Section 4.3.1 of the Protocol; 
o
Exclusion criterion 6, Use of any of the prohibited medications or therapies listed in 
Section 4.3.2 of Protocol 

Actual treatment not in accordance with randomized treatment.

Less 80% compliance with treatment and/or missing more than 4 consecutive doses

HPWSQ-R assessment not completed on Day 15 


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6
Analysis sets
6.1
Intention-To-Treat Analysis Set
The intention-to-treat (ITT) analysis set comprises of all randomized (as planned) subjects.
6.2
Full-Analysis Set
The full analysis set (FAS) population will include all subjects in the safety population who have 
the primary efficacy endpoint measured (Baseline and Day 8±1 or Day 15). Analyses for the FAS 
will be conducted according to the randomized treatment. The primary endpoint will be analyzed in 
the FAS population.
6.3
Per Protocol Analysis Set
Subjects in the FAS population with major protocol deviations will be excluded from the PP (per-
protocol) analysis set. These subjects will be identified prior to breaking the study blind. Analyses 
for the PP will be conducted according to the randomized treatment.
6.4
Safety Analysis Set 
All subjects who received any amount of IMP will be included in the safety population. Analyses 
for the safety population will be conducted according to the actual treatment received.
6.5
Pharmacokinetic Analysis Set
The pharmacokinetic (PK) population will include all subjects in the safety population who have 
sufficient plasma carbetocin concentrations for inclusion in population PK modeling.  PK analysis 
will be addressed in a separate document.


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7
Trial population
7.1
Demographics and Other Baseline Characteristics
Categorical data will be summarized using numbers and percentages. The percentages are based on 
the total number of subjects with a corresponding assessment. Continuous data will be presented, 
for example, using the number of subjects (n), mean and standard deviation, median, minimum and 
maximum. Summary will be conducted for the safety population or FAS population if specified. All 
baseline characteristics will be listed.
Missing values concerning demographics and baseline characteristics will not be imputed. 
7.1.1
Demographics
Baseline demographics variables include age, sex, race and ethnicity, height, weight and Body 
Mass Index (BMI). Age will be calculated as (Date of Informed Consent – Date of Birth)/365.25, 
rounded down to the nearest integer. BMI will be calculated as body weight (kg)/(height (m))2, 
rounded to one decimal place.
Descriptive statistics of the demographics variables will be summarized based on FAS population 
by treatment randomized as well as based on safety population by actual treatment. No formal 
statistical analysis will be performed.
7.1.2
Vital Signs at Baseline
Baseline vital signs (blood pressure, pulse, body temperature, and respiration rate) will be 
summarized by treatment.
7.1.3
Trial-specific Baseline Variables or History of Disease
Descriptive statistics will be summarized by treatment for urine drug screen and alcohol test, and 
nutritional phase assessment.
Other baseline assessments will be presented and summarized in by-visit tables or in listings.
7.1.4
Laboratory Efficacy/Pharmacodynamic Parameters at Baseline
PK analysis will be addressed in a separate document.
7.2
Medical History
Medical and surgical history recorded at screening visit will be coded using Medical Dictionary for 
Regulatory Activities (MedDRA) version 16.1. Medical and surgical history will be listed by 
treatment and subject as well as summarized by system organ class (SOC) and preferred term (PT).


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7.3
Prior and Concomitant Medication
Prior and concomitant medications will be coded using World Health Organisation Drug 
(WHODrug) Dictionary version 01SEP2013. Medications will be listed by treatment and subject as 
well as summarized by Anatomical Therapeutic Chemical (ATC) classification 1st level 
(alphabetically), ATC classification 2nd level (in decreasing order of frequency) and treatment 
group. These medications will be tabulated separately for:
1) Prior medication; i.e. medication taken exclusively prior to first IMP administration
2) Concomitant medication, i.e. medication taken after IMP administration 
If the timing of the dose of a concomitant medication cannot be established in relation to the 
administration of IMP, it will be considered as concomitant medication.
7.4
Physical Examination
Physical examination results will be listed by treatment and subject. Subjects with abnormalities at 
any screening, baseline, or post-baseline visit will be listed with all physical examination 
evaluations by body system for the Safety analysis set.


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8
Exposure and Treatment Compliance
8.1.1
Extent of Exposure 
The total trial treatment exposure will be summarized by treatment group for the safety population.  
Summary statistics are provided for the duration of exposure (number of days) of study medication 
(last known date patient took study medication - first dose date + 1).
8.1.2
Treatment Compliance 
Treatment administration collected in the clinical report form (CRF) will be listed by treatment and 
subject. Treatment compliance will be calculated as (the number of actual doses intake / the number 
of planned doses)*100% where an actual dose consists of a total of six sprays between the two 
nostrils. The number of planned doses is 42 (=14*3) per study design. 
The number of subjects who had at least 80% treatment compliance and missed no more than 4 
consecutive dosing time-points will be summarized. The calculated treatment compliance will be 
listed as well.


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9
Efficacy
9.1
General Considerations
Efficacy analysis will be conducted for the FAS population unless otherwise specified. All 
statistical tests will be performed using a one-sided test at a 10% significance level. No adjustments 
will be made for multiple tests. Baseline for all efficacy analyses will be the values obtained at the 
last assessment prior to the first dose of IMP.
Handling of missing scores of questionnaire
A subscore or domain score of the HPWSQ-R questionnaire is defined as the sum of all items 
scores in the domain. The average value of completed items in a domain will be used an estimate of 
missing items. If more than 50 percent of the items from a domain are missing, the corresponding 
domain score will be set to missing. Total score is the sum of these three subscores. Total score will 
be missing if any subscore is missing.
The last observation carried forward (LOCF) method will be used to carry forward non-missing 
values of HPWSQ-R total score during the phone call assessment (Day 8±1) to impute missing 
values of HPWSQ-R total score at Visit 4 (i.e. exactly on Day 15). Any assessments not within the 
window Day 8±1 and prior to Day 15 will not be used for LOCF imputation.  For subjects who 
discontinued IMP prior to Day 12, if they have HPWSQ-R assessments on Day 15, then the 
assessments are considered invalid for primary endpoint analysis. LOCF values at Day 15 will be 
populated with non-missing values of HPWSQ-R total score during the phone call assessment (Day 
8±1).
Similarly, HPWSQ-R-C will be handled in the same way as HPWSQ-R. The analyses of HPWSQ-
R and HPWSQ-R-C will be conducted based on LOCF values unless otherwise specified.
No imputation will be applied to the domain score of HPWSQ-R and HPWSQ-R-C, and other 
questionnaires (Clinical Global Impression, CY-BOCS and Food Domain of the Reiss Profile). 
9.2
Primary Endpoint(s)
The Hyperphagia in Prader-Willi Syndrome questionnaire (HPWSQ-R) is an informant-based tool 
for examining the psychological, developmental, and neurobiological correlates of hyperphagia in 
PWS. The items measure hyperphagic symptoms are reported by caregivers and are rated on a five-
point scale (1: not at all/none of the tim/extremely easy to 5: extremely/all of the time/extremely 
hard). HPWSQ-R Questionnaire is classified into 3 domains; behavior, drive, and severity.
Subdomain
Question
Hyperphagic Behavior
1d. How “clever” or “fast” was your child in obtaining food?
2a. Try to bargain or manipulate to get more food
2b. Forage through the trash for food


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2c. Get up at night to food seek
2e. Try to steal food
Hyperphagic Drive
1a. How upset did your child generally become when denied a desired food?
1b. How persistent was your child in asking or looking for food after being told 
      “no” or “no more”?
1c. How distressed did your child become when stopped from talking about 
      food or engaging in food-related behaviors?
3. Once food on mind, how easy to redirect away from food
Hyperphagic Severity
1e. To what extent did food-related thoughts, talk, or behaviour interfere with 
      your child’s normal daily routines, self-care, school, or work                           
2d. Talk about food or engaged in food-related behaviors, outside of normal 
      meal times
The subscore for a domain is defined as the sum of all item scores in the domain. Total score is the 
sum of these three subscores. Total score will be missing if any subscore is missing. Missing item 
scores and total score will be handled as described in the section 9.1.
9.2.1
Primary Variable(s) Analysis
The primary variable is change in HPWSQ-R total score from baseline to Visit 4 (Day 15) and will 
be analyzed in the FAS population using an analysis of covariance (ANCOVA) model with 
treatment and site as fixed effects and HPWSQ-R total score at baseline as a covariate. The 
treatment group difference in total score between placebo and carbetocin will be calculated by 
subtracting the mean change from baseline in placebo from that in the carbetocin group.  A 
borderline statistically significant difference at the 10% significant level will be achieved if the 
upper limit of the 90% 1-sided confidence interval (CI) for the treatment difference is less than 
zero. The corresponding p-value will be reported as well.
Summary of HPWSQ-R total score will be presented as well as a box-and-whisker plot of change in 
HPWSQ-R total score by visit.
9.2.2
Sensitivity Analyses 
The analysis of the primary endpoint in the section 9.2.1 will be also conducted based on the 
subjects in the PP population and ITT population.
In addition, the primary endpoint will be analyzed using repeated measures analysis with treatment, 
site, visit and treatment-by-visit interaction as fixed effects and HPWSQ-R total score at baseline as
a covariate. An unstructured working correlation matrix will be used for the analysis. LOCF will 
not be used to impute missing values because it would affect the correlation of observations 
between weeks. The two treatment groups will be compared at Visit 4 (Day 15). The LS means, the 
LS mean difference, and 90% 1-sided confidence interval (CI) for the treatment difference will be 
presented will be presented at each visit as well.


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9.3
Secondary Endpoint(s) 
Secondary endpoints include Clinical Global Impression-Improvement after treatment (CGI-I) 
score at Day 8 and Visit 4, change from Visit 2/Baseline to Day 8 and Visit 4 for the following 
measurements:

HPWSQ-R hyperphagia behavior, drive, and severity domain scores

HPWSQ-R-C total score

HPWSQ-R-C hyperphagia behavior, drive, and severity domain scores
and change from Visit 1/Baseline to Day 8 and Visit 4 for the following measurements:

CY-BOCS total score

Food Domain of the Reiss Profile
The improvement of PWS symptoms will be assessed by the Clinical Global Impression (CGI). The 
CGI scale is a 7-point clinician rating of illness severity (1 = no illness, 7 = extremely ill), at the 
beginning of the trial and a 7-point clinician rating of improvement of patient condition (1 = very 
much improved, 7 = very much worse), during and at the end of the trial.
HPWSQ-R-C scale consists of the same 11 questions and has the same scoring as HPWSQ-R. 
HPWSQ-R-C is administered by the same clinician throughout the trial while the HPWSQ-R scale 
is administered by the parent or caregiver.
The CY-BOCS is a clinician rated, semi-structured inventory of specific symptoms and symptom 
severity (0 = none, 4 = extreme) in pediatric obsessive-compulsive disorder (OCD). It includes 2
primary components: the Symptom Checklists 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 food domain of the Reiss Profile consists of 7 questions that pertain to food seeking behaviour. 
For analysis purpose, the scales of Food Domain of the Reiss Profile will be scores as follows:
Scales of Food Domain of the Reiss Profile
Score
Strongly Disagree
-2
Disagree
-1
Neutral
0
Agree
1
Strongly Agree
2
Total score of Food Domain of the Reiss Profile is defined as the sum of all individual item scores.
The secondary endpoints will be analyzed in a similar fashion as the primary endpoint. All analysis 
of secondary endpoints will be conducted using ANCOVA model treatment and site as fixed effects 


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and baseline score as a covariate. Clinical Global Impression - Severity (CGI-S) will be used as 
baseline covariate for CGI-I analysis.
9.4
Exploratory Analyses
The relation between the primary endpoint and the secondary endpoints will be explored by visit 
for the FAS population using the Pearson correlation coefficients. An ad-hoc analysis might be 
performed to further explore the relation between the primary endpoint and the secondary 
endpoints.


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10
Safety
10.1
General Considerations
Safety parameters will be evaluated for the safety analysis set. Complete listings and summary 
tables for all safety information, including adverse events, clinical laboratory safety data, physical 
examination, nasal examination, vital signs, and ECG will be presented.  No formal statistical 
analysis will be performed.
Unscheduled assessments prior to the first IMP administration will be included to derive baseline 
while post-baseline unscheduled assessments will not be included in the data analysis unless 
specified.
10.2
Adverse Events
Adverse events (AEs) are classified according to the MedDRA version 16.1 give a system organ 
class and preferred term for each event.
A treatment-emergent adverse event (TEAE) is any adverse event that begins during the treatment 
period or worsening of a pre-existing medical condition. The Treatment Period is the period during 
which a subject receives IMP (including the residual time of drug effect). More specially, for 
subjects who completing all doses as planned on Day 14, the Treatment Period is Day 1 to Day 15. 
For subjects who discontinued IMP, the Treatment Period is Day 1 to the dose date + 1.
TEAEs will be listed by treatment and subject, and the incidence of TEAEs will be presented by 
treatment. In addition, TEAEs will be presented by causality (relationship to the trial medication) 
and intensity (severity) and seriousness. Serious adverse events (SAEs) and adverse events leading 
to discontinuation will be listed.
If a subject has an AE with unknown intensity, then the subject is counted in the category of 
“Severe”. If an AE with unknown relationship to IMP, then the AE is considered to be related to 
IMP.
10.2.1
Overview of Treatment-Emergent Adverse Events
A TEAE overview summary table will be prepared including the number of subjects reporting a
TEAE, the percentage of subjects (%) with a TEAE, and the number of events (E) reported, for the 
following categories: 

Treatment-emergent adverse events

Treatment-emergent adverse events leading to Deaths

Treatment-emergent adverse events by intensity

Serious treatment-emergent adverse events 


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
Treatment-emergent adverse events leading to withdrawal 

Adverse drug reactions
10.2.2
Incidence of Adverse Events
TEAEs will be summarized in a table by treatment, system organ class (SOC) and preferred term 
(PT). The table will display the total number of subjects reporting a TEAE, the percentage of 
subjects (%) with a TEAE, and/or the number of events (E) reported. TEAEs will be presented by 
SOC sorted alphabetically and PT sorted in decreasing frequency of occurrence.
Summary tables will be prepared for:

All TEAEs

TEAEs with an incidence [≥ 5%] of subjects in any treatment group

TEAEs by causality (related/unrelated)

TEAEs by intensity
Supporting data listings will be provided for:

All adverse events

Serious adverse events 

Adverse events leading to withdrawal. 
10.3
Safety Laboratory Variables
Baseline for all laboratory analyses will be the values obtained at the last assessment prior to the 
first dose of IMP. End of trial will include the last post-baseline observation during the trial. 
10.3.1
Summary Statistics
All chemistry, haematology, haemostasis, and urinalysis laboratory continuous data will be 
summarized for the baseline and post-baseline evaluations, as well as change from baseline, using 
descriptive statistics: sample size, mean, median, standard deviation, minimum, and maximum 
values.
10.3.2
Laboratory Variable Changes Relative to Normal Range
Changes relative to normal ranges are presented with shift tables with total number of subjects, and 
number and percent of subjects who experienced a shift.
The following categories for shift tables are defined:

Low: 
Values which are below the lower reference range limit;

Normal: 
Values which are within the lower and upper reference range;


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
High: 
Values which are above the upper reference range limit.

Absent: 
No value for measured variable (for urinalysis only)

Present: 
Any value obtained for measured variable (for urinalysis only)
For all haematology, haemostasis and clinical chemistry laboratory variables, shift tables will be 
prepared to compare baseline values to the worst value at post-baseline (including unscheduled 
values). More specifically, for haematology, haemostasis and clinical chemistry, tables presenting 
the changes from Low or Normal to High and from High or Normal to Low will be provided.  For 
urinalysis variables, shift tables will summarize the number (%) of subjects who had “absent” 
values at baseline and “present” values at post-baseline.
10.3.3
Markedly Abnormal Changes
A summary table will be prepared that displays for each laboratory variable the number and 
percentage of subjects in each treatment group with normal baseline values who had at least one 
pre-specified markedly abnormal value anytime during the treatment period. Pre-specified 
markedly abnormal criteria for laboratory tests are given in Appendix 1.
10.3.4
Data Listings
Clinical safety laboratory values will be listed by treatment, subject and test. All values outside the 
normal range will be identified.
Subjects with any markedly abnormal changes at any time-point will be also listed with all values
of the corresponding laboratory tests. The laboratory values with markedly abnormal changes will 
be flagged out.
10.4
Vital Signs and ECG
10.4.1
Vital Signs
Baseline for all vital signs (blood pressure, pulse, body temperature, and respiration rate) analyses 
will be the values obtained at the last assessment prior to the first dose of IMP. End of trial will 
include the last post-baseline observation during the trial.
10.4.1.1
Summary Statistics
All vital signs data will be summarized for the baseline and post-baseline evaluations, as well as 
change from baseline, using descriptive statistics: sample size, mean, median, standard deviation, 
minimum, and maximum values. 
10.4.1.2
Markedly Abnormal Changes
A summary table will be prepared that displays for each vital signs parameter the number and 
percentage of subjects in each treatment group with normal baseline values who had one or more 


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pre-specified markedly abnormal treatment-emergent values, according to the definition in 
Appendix 1. The markedly abnormal criteria will be used to define normal baseline as well.
10.4.1.3
Data Listings
Vital signs values will be listed by treatment and subject.
Subjects with any markedly abnormal changes at any time-point will be also listed with all values
of the corresponding vital signs. The vital signs values with markedly abnormal changes will be 
flagged out.
10.4.2
ECGs
Baseline for all ECG analyses will be the values obtained at the last assessment prior to the first 
dose of IMP. End of trial will include the last post-baseline observation during the trial.
10.4.2.1
Summary Statistics 
ECG qualitative data will be summarized in number (%) for “normal”, “abnormal – not clinically 
significant (NCS)” and “abnormal –clinically significant (CS)” collected in CRF. 
10.4.2.2
Markedly Abnormal Changes
Not applicable since no quantitative data will be collected for this study.
10.4.2.3
Data Listings
ECG data will be listed by treatment and subject.
10.5
Other Safety Variables
The remainder of the data collected in the CRF (e.g., pregnancy test, nasal examination) will be 
listed by treatment and subject. Nasal examination will be also summarized as described in the 
following section.
10.5.1
Nasal examination
Baseline for nasal examination analyses will be the values obtained at the last assessment prior to 
the first dose of IMP. End of trial will include the last post-baseline observation during the trial.
Number (%) of subjects with each grade of nasal examination result will be summarized by 
treatment, visit and timepoint. In addition, the changes in nasal examination result by treatment, 
visit and timepoint are presented with shift tables with total number of subjects, and number and 
percent of subjects who experienced a shift.


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11
Interim analyses
No interim analysis is planned.


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12
Deviations from protocol analysis
There are no deviations from the analyses planned in the protocol.


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13
References
[1]
Dykens EM, Maxwell MA, Pantino E, Kossler R, Roof E. Assessment of hyperphagia in 
Prader-Willi syndrome. Obesity. 2007;15:1816-26.
[2]
Miller JL, Lynn CH, Driscoll DC, et al. Nutritional phases in Prader-Willi syndrome. 
Am J Med Genet A. 2011;155:1040-9.


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14
Tables, Listings and Figures
The document with tables, figures and listings (TLF) shells presented in a separate document.


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Appendix 1
Markedly Abnormal Laboratory Safety Values, Vital 
Signs
Table 1:
Markedly abnormal Criteria for Laboratory Tests
HAEMATOLOGY
Variable
Units
Age
Markedly Abnormal Criteria
Low
High
Hemoglobin
g/dL
6 mo-18 yr
≤ 8
NA
RBC
x106/mm3
6 mo-18 yr
≤ 3.5
NA
Hematocrit
%
6 mo-18 yr
≤ 30
≥ 50
Leukocytes
x103/mm3
6 mo to 18 
yr
≤ 2.8
≥ 20
Neutrophils
x103/mm3
6 mo-18 yr
≤ 1
≥ 10
Lymphocytes
x103/mm3
2-18 yr
< 1
≥ 10
Eosinophils
%*
All ages
NA
≥ 10
Monocytes
%*
6 mo-18 yr
NA
≥ 15
Basophils
%*
6 mo-18 yr
NA
≥ 5
Platelets
x103/mm3
6 mo-18 yr
≤ 50
≥ 750
*The percentage indicates the relative number of each type of leucocytes in the blood. The absolute count is calculated 
by multiply the relative value (%) by the total leukocyte count/100.
HEMOSTASIS AND COAGULATION
Variable
Units
Age
Markedly Abnormal Criteria
Low
High
Fibrinogen
g/L
All
NA
≥ 5
Prothrombin 
Time (PT)
seconds
All 
NA
≥ 20
Partial 
Thromboplastin 
Time (APTT)
seconds
6 mo-18 yr
≤20
≥ 50


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CHEMISTRY
Variable
Units
Age
Markedly Abnormal Criteria
Low
High
ALT
U/L
1-19yr  
Not applicable
≥ 3x ULN
AST
U/L
10-19yr 
Not applicable
≥ 3x ULN
Total protein
g/L
> 1yr 
≤ 40
≥90
Albumin
g/L
All 
≤ 25
> 60
Alkaline 
phosphatase
U/L
All 
Not applicable
≥ 3x ULN
Total 
bilirubin
μmol/L
10-18yr
Not applicable
≥1.5xULN
Creatinine
μmol/L
All
Not applicable
≥120
Glucose
mmol/L
24m-11yr
12-18yr
≤ 2.5
≤2.8
> 8
> 10
GGT
U/L
All 
Not applicable
≥ 3x ULN
Urea nitrogen
mmol/L
All
Not applicable
≥ 8.0
Potassium 
mmol/L
> 2m
≤3
≥6
Sodium
mmol/L
All
≤ 130
≥ 150
Calcium total
mmol/L
All
≤1.8
≥ 3
Chloride
mmol/L
All
≤90
≥115


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Table 2:
Markedly abnormal Criteria for Vital Signs
Markedly abnormal Criteria for Pulse Rate
Age
Low
High
9 years ≤ x < 11 years
≤66
≥114
11 years ≤ x < 13 years girls
11 years ≤ x < 13 years boys
≤66
≤61
≥114
≥109
13 years ≤ x < 15 years girls
13 years ≤ x < 15 years boys
≤61
≤56
≥109
≥104
15 years ≤ x < 17 years girls
15 years ≤ x < 17 years boys
≤56
≤51
≥104
≥99
17 years ≤ x < 19 years girls
17 years ≤ x < 19 years boys
≤51
≤46
≥99
≥94
Markedly abnormal Respiratory rate (breaths/min)
Age
Low
High
5 years <= x < 12 years
≤10
≥40
12 years <= x < 16 years
≤7
≥40
16 years <= x 
≤7
≥30
Markedly abnormal blood pressure levels for BOYS by age
Age
(years)
Unit
SBP
Lower 
limit (≤)
SBP
Upper 
limit (≥)
DBP
Lower 
limit (≤)
DBP
Upper 
limit (≥)
10 years <= x < 11 years
mmHg
77
127
34
88
11 years <= x < 12 years
mmHg
79
129
35
89
12 years <= x < 13 years
mmHg
81
131
35
89
13 years <= x < 14 years
mmHg
84
134
36
90
14 years <= x < 15 years
mmHg
86
136
36
90
15 years <= x < 16 years
mmHg
89
139
37
91
16 years <= x < 17 years
mmHg
92
141
39
93
17 years <= x < 18 years
mmHg
94
144
41
95
18 years <= x < 19 years
mmHg
94
144
41
95


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Markedly abnormal blood pressure levels for GIRLS by age
Age
(years)
Unit
SBP
Lower 
limit (≤)
SBP
Upper 
limit (≥)
DBP
Lower 
limit (≤)
DBP
Upper 
limit (≥)
10 years <= x < 11 years
mmHg
78
126
35
86
11 years <= x < 12 years
mmHg
80
128
36
87
12 years <= x < 13 years
mmHg
81
130
37
88
13 years <= x < 14 years
mmHg
83
132
38
89
14 years <= x < 15 years
mmHg
85
134
39
90
15 years <= x < 16 years
mmHg
86
135
40
91
16 years <= x < 17 years
mmHg
87
136
41
92
17 years <= x < 18 years
mmHg
87
136
41
92
18 years <= x < 19 years
mmHg
87
136
41
92