Clinical trial NCT02527200
Conditions: Metabolism and Nutrition Disorder Obesity
Sponsor: Novo Nordisk A/S
Start date: 2015-11-09; Completion date: 2020-11-19
Enrollment: 56 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This trial is conducted globally. The aim of this trial is to investigate the effect of liraglutide for weight management in paediatric subjects with Prader-Willi Syndrome.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: liraglutide intervention 2: placebo
Intervention descriptions: intervention 1: Injected s.c./ subcutaneously (under the skin) This trial consists of a part A and a part B. Part A of the trial is conducted in obese adolescents with PWS. Part B of the trial is conducted in obese children with PWS. Entry into part A and part B of the trial will be sequential. intervention 2: Injected s.c./ subcutaneously (under the skin) This trial consists of a part A and a part B. Part A of the trial is conducted in obese adolescents with PWS. Part B of the trial is conducted in obese children with PWS. Entry into part A and part B of the trial will be sequential.

Protocol documents:
Prot_000.pdf: 
Cover Page for Protocol 
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT02527200 
Sponsor trial ID: 
NN8022-4179 
Official title of study: 
Effect of liraglutide for weight management in paediatric 
subjects with Prader-Willi Syndrome 
Document date* 
25 March 2021 
*Document date refers to the date on which the document was most recently updated. 
Note: The date in the header of Page 2 is the date of compilation of the documents and not of an update to content. 


Link
Link
Link
Link
Link
List of contents
Protocol ...............................................................................................................................................
Appendix A .........................................................................................................................................
Appendix B..........................................................................................................................................
Appendix C .........................................................................................................................................
Attachment I and II............................................................................................................................
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
Liraglutide 3.0 mg
Trial ID: NN8022-4179
Clinical Trial Report
Appendix 16.1.1
25 March 2021
1.0
Final
16.1.1 Protocol and protocol amendments
CONFIDENTIAL
 
 
 
 
 
Redacted protocol 
Includes redaction of personal identifiable information only. 
 
 
 
. 
 
 


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
1 of 125
Protocol – amended edition
Trial ID: NN8022-4179
Effect of liraglutide for weight management in paediatric subjects 
with Prader-Willi Syndrome
A randomised, placebo controlled, parallel group, multi-centre, multi-national trial 
with a 16-week double-blind period and 36-week open-label period
Trial phase: 3a
Applicable to all countries
Protocol originator
, Senior Trial Manager
1569, TrialOps Obesity & Metabolism 1
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
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CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
2 of 125
Protocol amendment summary of changes table
DOCUMENT HISTORY
Document version
Date
Applicable in country(-ies) and/or 
site(s) 
Protocol version 5.0
16 July 2020
All countries
Protocol version 4.0
16 March 2020
All countries
Protocol version 3.0
22 December 2017
All countries
Protocol version 2.0
28 August 2015
All countries
Original protocol version 1.0
30 April 2015
All countries
1. Protocol version 5 (16 July 2020)
This amendment is considered to be non-substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union65.
2. Overall rationale for preparing protocol, version 5.0:
The protocol is amended to align the number of subjects among protocol sections 1 (Summary), 6.1 
(Number of subjects), 6.6 (Subject replacement) and 17.1 (Sample size calculation).
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
3 of 125
Section # and name
Description of change
Brief rationale
1 – Summary 
The number of subjects is updated as 
following:
x
Approximately 57 subjects to be 
randomised, 33 in part A and 24 in 
part B
x
Evaluable subjects part A: at least 
28
x
Evaluable subjects part B: at least 
17
To update protocol section 1 
with the Paediatric 
Investigational Plan 
modification approved in 04-
Dec-2019 and to provide a 
consistent accurate estimate of 
the number of randomised and 
evaluable subjects, across all 
protocol sections, as required 
by the Italian Health Authority
6.1 – Number of 
subjects
The number of subjects planned to be 
randomised is updated to 57 in total, 
divided into 33 for part A and 24 for 
part B. The number of maximum 
subjects to be randomised is removed.
To align the protocol section 
6.1 – the number of planned 
randomised subjects – with the 
statistical calculation for 
sample size described in 
protocol section 17.1
6.6 – Subject 
replacement
The split of the number of evaluable 
subjects per age group is updated as 
following:
x
Part A:  evaluable number of 
subjects is increased
x
Part B: evaluable number of 
subjects is reduced
To update protocol section 6.6 
with the Paediatric 
Investigational Plan 
modification approved in 04-
Dec-2019 and to provide a 
consistent accurate estimate of 
the number of evaluable 
subjects across all protocol 
sections, as required by the 
Italian Health Authority
17.1 – Sample size 
calculation
The planned number of randomised 
subjects is updated, as well as the 
respective treatment difference. Table 
17-2 (Overview of randomised subjects) 
is also updated with more accurate 
numbers.
To update the protocol section 
17.1 with the Paediatric 
Investigational Plan 
modification approved in 04-
Dec-2019 and to provide a 
consistent accurate estimate of 
the number of randomised and 
evaluable subjects across all 
protocol sections, as required 
by the Italian Health Authority
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
4 of 125
Table of Contents
Page
Protocol amendment summary of changes table...........................................................................................2 
Table of Contents..............................................................................................................................................4 
Table of Figures................................................................................................................................................8 
Table of Tables..................................................................................................................................................8 
List of abbreviations.........................................................................................................................................9 
1 
Summary..................................................................................................................................................12 
2 
Flow chart ................................................................................................................................................16 
3 
Background information and rationale for the trial............................................................................22 
3.1 
Background information..............................................................................................................22 
3.2 
Rationale for the trial ...................................................................................................................24 
4 
Objectives and endpoints........................................................................................................................25 
4.1 
Objectives ....................................................................................................................................25 
4.2 
Endpoints .....................................................................................................................................25 
4.2.1 
Primary endpoints......................................................................................................25 
4.2.2 
Secondary endpoints..................................................................................................25 
4.2.2.1 
Supportive secondary efficacy endpoints............................................25 
4.2.2.2 
Supportive secondary PK endpoint .....................................................26 
4.2.2.3 
Supportive secondary safety endpoints ...............................................26 
5 
Trial design ..............................................................................................................................................28 
5.1 
Type of trial..................................................................................................................................28 
5.2 
Rationale for trial design..............................................................................................................30 
5.3 
Treatment of subjects...................................................................................................................31 
5.3.1 
Dose escalation ..........................................................................................................32 
5.3.1.1 
Dose escalation part A.........................................................................32 
5.3.1.2 
Dose escalation part B.........................................................................32 
5.3.2 
Maintenance...............................................................................................................33 
5.3.3 
Treatment of subjects who develop type 2 diabetes mellitus during the trial............34 
5.4 
Treatment after discontinuation of trial product ..........................................................................34 
5.5 
Rationale for treatment ................................................................................................................34 
6 
Trial population.......................................................................................................................................36 
6.1 
Number of subjects ......................................................................................................................36 
6.2 
Inclusion criteria ..........................................................................................................................36 
6.3 
Exclusion criteria .........................................................................................................................36 
6.4 
Discontinuation of trial product criteria.......................................................................................38 
6.5 
Withdrawal criteria ......................................................................................................................38 
6.6 
Subject replacement.....................................................................................................................38 
6.7 
Rationale for trial population.......................................................................................................39 
7 
Milestones.................................................................................................................................................40 
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
5 of 125
7.1 
Part A...........................................................................................................................................40 
7.2 
Part B ...........................................................................................................................................40 
7.3 
Recruitment..................................................................................................................................40 
7.4 
Trial registration...........................................................................................................................41 
8 
Methods and assessments .......................................................................................................................42 
8.1 
Visit procedures ...........................................................................................................................42 
8.1.1 
Screening, visit 1........................................................................................................42 
8.1.1.1 
Adrenal insufficiency test at screening, visit 1....................................42 
8.1.2 
Visits attended fasting................................................................................................43 
8.1.3 
Screening, visit 2........................................................................................................43 
8.1.4 
Screening failures.......................................................................................................43 
8.1.5 
Re-screening ..............................................................................................................43 
8.1.6 
Randomisation, visit 3 ...............................................................................................43 
8.1.7 
Dose escalation, visit 4-7 ...........................................................................................44 
8.1.8 
Discontinuation of trial product.................................................................................44 
8.1.9 
Withdrawal of informed consent/assent.....................................................................44 
8.1.10 
Home visits ................................................................................................................45 
8.2 
Laboratory assessments ...............................................................................................................45 
8.2.1 
Total blood volume for laboratory assessments.........................................................46 
8.2.2 
Laboratory reports......................................................................................................46 
8.3 
Subject related information..........................................................................................................47 
8.3.1 
Demography...............................................................................................................47 
8.3.2 
Concomitant illness and medical history ...................................................................47 
8.3.2.1 
History of psychiatric disorders ..........................................................47 
8.3.3 
Concomitant medication............................................................................................48 
8.3.4 
Tobacco use ...............................................................................................................48 
8.4 
Assessments for efficacy..............................................................................................................48 
8.4.1 
Body measurements...................................................................................................48 
8.4.1.1 
Body weight ........................................................................................48 
8.4.1.2 
Hip and waist circumference...............................................................49 
8.4.2 
Hyperphagia questionnaire ........................................................................................49 
8.4.3 
Systolic and diastolic blood pressure.........................................................................50 
8.4.4 
Blood samples for efficacy assessments ....................................................................50 
8.5 
Assessments for safety.................................................................................................................51 
8.5.1 
Height.........................................................................................................................51 
8.5.2 
Hypoglycaemic episodes ...........................................................................................51 
8.5.2.1 
Self-measured blood glucose (SMBG)................................................53 
8.5.3 
Pulse...........................................................................................................................53 
8.5.4 
Electrocardiogram – 12 lead ......................................................................................54 
8.5.5 
Pregnancy tests...........................................................................................................54 
8.5.5.1 
Blood samples .....................................................................................54 
8.5.5.2 
Urine-sticks .........................................................................................54 
8.5.5.3 
Recording of menstrual periods ..........................................................55 
8.5.6 
Physical examination .................................................................................................55 
8.5.7 
Blood samples for safety assessments .......................................................................55 
8.5.8 
Anti-liraglutide antibodies .........................................................................................57 
8.5.9 
Tanner staging............................................................................................................58 
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
6 of 125
8.5.10 
Mental health questionnaires (part A only)................................................................58 
8.5.10.1 
C-SSRS................................................................................................58 
8.5.10.2 
PHQ-9..................................................................................................59 
8.5.10.3 
Referral to mental health professional.................................................59 
8.6 
Additional safety assessments......................................................................................................60 
8.6.1 
In case of elevated calcitonin.....................................................................................60 
8.6.2 
Suspicion of acute pancreatitis...................................................................................60 
8.6.3 
Adverse events requiring specific event forms in the eCRF......................................60 
8.6.3.1 
Gallstone disease.................................................................................60 
8.6.3.2 
Neoplasms ...........................................................................................61 
8.6.3.3 
Pancreatitis ..........................................................................................61 
8.7 
Other assessments........................................................................................................................62 
8.7.1 
Plasma concentration of liraglutide for pharmacokinetics.........................................62 
8.7.2 
Dietary and physical activity counselling..................................................................62 
8.7.2.1 
Dietary counselling..............................................................................62 
8.7.2.2 
Counselling in physical activity ..........................................................63 
8.7.3 
Subject diary ..............................................................................................................63 
8.7.3.1 
Dosing diary ........................................................................................63 
8.7.3.2 
Hypoglycaemic episode diary .............................................................64 
8.7.3.3 
Menstrual period diary ........................................................................64 
8.8 
Subject compliance......................................................................................................................64 
9 
Trial supplies ...........................................................................................................................................65 
9.1 
Trial products...............................................................................................................................65 
9.2 
Labelling ......................................................................................................................................65 
9.3 
Storage .........................................................................................................................................66 
9.4 
Drug accountability and destruction ............................................................................................66 
9.5 
Auxiliary supplies........................................................................................................................67 
10 Interactive voice/web response system ..................................................................................................68 
11 Randomisation procedure and breaking of blinded codes ..................................................................69 
11.1 
Breaking of blinded codes ...........................................................................................................69 
11.2 
Laboratory access to blinded data................................................................................................70 
12 Adverse events, technical complaints and pregnancies........................................................................71 
12.1 
Definitions....................................................................................................................................71 
12.2 
Reporting of adverse events.........................................................................................................74 
12.3 
Follow-up of adverse events ........................................................................................................77 
12.4 
Technical complaints and technical complaint samples ..............................................................78 
12.4.1 
Reporting of technical complaints .............................................................................78 
12.4.2 
Collection, storage and shipment of technical complaint samples.............................79 
12.5 
Pregnancies ..................................................................................................................................79 
12.5.1 
Pregnancies in female subjects ..................................................................................79 
12.5.2 
Pregnancies in female partners of male trial subjects (Applicable for US only) .......81 
12.6 
Precautions and/or overdose ........................................................................................................82 
12.7 
Committees related to safety........................................................................................................82 
12.7.1 
Novo Nordisk safety committee ................................................................................82 
12.7.2 
Data monitoring committee .......................................................................................82 
13 Case report forms....................................................................................................................................83 
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
7 of 125
13.1 
Corrections to case report forms ..................................................................................................83 
13.2 
Case report form flow..................................................................................................................84 
14 Monitoring procedures ...........................................................................................................................85 
15 Data management....................................................................................................................................87 
16 Computerised systems.............................................................................................................................88 
17 Statistical considerations ........................................................................................................................89 
17.1 
Sample size calculation................................................................................................................89 
17.2 
Definition of analysis sets............................................................................................................91 
17.3 
Primary endpoints........................................................................................................................91 
17.4 
Secondary endpoints....................................................................................................................95 
17.4.1 
Supportive secondary endpoints ................................................................................95 
17.4.1.1 
Efficacy endpoints...............................................................................95 
17.4.1.2 
Safety endpoints ..................................................................................97 
17.4.1.3 
Pharmacokinetic endpoints................................................................101 
17.5 
Interim analysis..........................................................................................................................101 
17.6 
Pharmacokinetic and/or pharmacodynamic modelling..............................................................101 
17.7 
Health economics and/or patient reported outcomes .................................................................102 
18 Ethics ......................................................................................................................................................103 
18.1 
Benefit-risk assessment of the trial............................................................................................103 
18.2 
Informed consent .......................................................................................................................106 
18.3 
Data handling.............................................................................................................................107 
18.4 
Information to subject during trial .............................................................................................107 
18.5 
Premature termination of the trial and/or trial site.....................................................................108 
19 Protocol compliance..............................................................................................................................109 
20 Audits and inspections ..........................................................................................................................110 
21 Critical documents ................................................................................................................................111 
22 Responsibilities ......................................................................................................................................113 
23 Reports and publications......................................................................................................................114 
23.1 
Communication of results..........................................................................................................114 
23.1.1 
Authorship ...............................................................................................................115 
23.1.2 
Site-specific publication(s) by investigator(s) .........................................................115 
23.2 
Investigator access to data and review of results .......................................................................115 
24 Retention of clinical trial documentation and human biospecimens.................................................116 
24.1 
Retention of clinical trial documentation...................................................................................116 
24.2 
Retention of human biospecimens .............................................................................................116 
25 Institutional Review Boards/Independent Ethics Committees and regulatory authorities............118 
26 Indemnity statement .............................................................................................................................119 
27 References ..............................................................................................................................................120 
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
8 of 125
Table of Figures 
Page
Figure 5–1 
Trial diagram (Part A and part B (for children with body weight Ӌ 45 kg))...........................28 
Figure 5–2 
Trial diagram (Part B for children with body weight < 45 kg)...............................................29 
Figure 12–1 
Initial reporting of AEs...........................................................................................................76 
Figure 17–1 
ADA classification of hypoglycaemia...................................................................................99 
Table of Tables
Page
Table 8–1 
Volume of blood during the trial ............................................................................................46 
Table 9–1 
Trial products..........................................................................................................................65 
Table 9–2 
Storage....................................................................................................................................66 
Table 17–1 
Sample size calculations for different scenarios; total number of subjects ............................90 
Table 17–2 
Overview of randomised subjects...........................................................................................91 
Attachment I 
Global list of key staff and relevant departments and suppliers
Attachment II
Country list of key staff and relevant departments
Appendix A 
Body mass index for age
Appendix B
Blood pressure ranges for children
Appendix C
Calcitonin Monitoring
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
9 of 125
List of abbreviations
ACTH
adrenocorticotropic hormone 
ADA
American Diabetes Association
AE
adverse event
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
AUC
area under the curve 
BG
blood glucose
BMI
body mass index 
BOCF
baseline observation carried forward
CEA
carcinoembryonic antigen
CLAE
clinical laboratory adverse event
CL/F
apparent clearance
CPK
creatine kinase
CRF
case report form
C-SSRS
columbia suicidality severity rating scale 
DHEAS
dehydroepiandrosterone sulfate 
DMC
data monitoring committee
DUN
dispensing unit number
ECG
electrocardiogram
eCRF
electronic case report form
EOS
end-of-study
EOT
end-of-treatment
EMA
European Medicines Agency
FAS
full analysis set
FDA
Food and Drug Administration
FPFV
first patient first visit
FPG
fasting plasma glucose
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
10 of 125
FSH
follicle stimulating hormone
FU
follow up
GCP
Good Clinical Practice
GH
Growth 
GLP-1
glucagon-like peptide-1
HbA1c
glycosylated haemoglobin
hCG
human chorionic gonadotrophin
HDL
high density lipoprotein
IB
Investigator’s Brochure
hsCRP
high sensitivity C reactive protein 
ICMJE
International Committee of Medical Journal Editors
IEC
independent ethics committee
IGF-1
insulin-like growth factor-1
IMP
investigational medicinal product
IRB
Institutional Review Board
ITT
intention-to-treat
IV/WRS
interactive voice/web response system
LAR
legally acceptable representative 
LDL
low density lipoprotein
LH
luteinizing hormone
LOCF
last observation carried forward
LPFV
last patient first visit
LPLV
last patient last visit
MAP
modelling analysis plan
MedDRA
Medical Dictionary for Regulatory Activities
MHP
mental health professional 
MESI
medical event of special interest
MI
multiple imputation 
MMRM
mixed model for repeated measurements
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
11 of 125
MTD
maximum tolerated dose
NRS
numerical rating scale
PD
pharmacodynamic
PDCO
paediatric committee
PHQ-9
patient health questionnaire 9 
PG
plasma glucose
PK
pharmacokinetics
PRO
patient reported outcome
PWS
Prader-Willi Syndrome
SAE
serious adverse event
s.c.
subcutaneous(ly)
SDS
standard deviation score 
SDV
source data verification
SIF
safety information form
SMBG
self-measured blood glucose
SUSAR
suspected unexpected serious adverse reaction
T1DM
type 1 diabetes mellitus
T2DM
type 2 diabetes mellitus
TMM
trial materials manual
TPD
trial product discontinuation
TSH
thyroid stimulating hormone
UTN
universal trial number
V
visit
V/F
apparent distribution volume
WD
withdrawal
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
12 of 125
1
Summary
Objectives and endpoints:
Primary objective
To compare the efficacy of liraglutide versus placebo on weight loss in paediatric subjects with 
obesity and PWS at 16 weeks and versus no treatment at 52 weeks.
Secondary objectives
x
To compare the efficacy of liraglutide versus placebo on glycaemic control in children and 
adolescents with obesity and PWS at 16 weeks and versus no treatment at 52 weeks. 
x
To estimate the liraglutide steady state exposure in children and adolescents with obesity and 
PWS after 16 weeks of treatment.
x
To compare the safety of liraglutide versus placebo in children and adolescents with obesity and 
PWS at 16 weeks and versus no treatment at 52 weeks.
Primary endpoints
There are two co-primary endpoints:
x
Change in body mass index (BMI) standard deviation score (SDS) from baseline to 16 weeks
x
Change in body mass index (BMI) standard deviation score (SDS) from baseline to 52 weeks
Key supportive secondary efficacy endpoints
x
Percent of subjects achieving ≥ 5% reduction in baseline BMI at weeks 16 and 52
x
Percent of subjects achieving ≥ 10% reduction in baseline BMI at weeks 16 and 52
Change from baseline to 16 and 52 weeks in:
x
BMI
x
Body weight (kilogram (kg), pounds (lb) and percent (%))
x
Hyperphagia score:
–
total score and
–
hyperphagic behaviour, drive and severity score 
x
Systolic and diastolic blood pressure
x
Glucose metabolism: glycosylated haemoglobin (HbA1c), fasting plasma glucose (FPG)
Trial design:
This is a multi-centre, multi-national randomised, parallel group, placebo-controlled trial with a 16-
week double-blind period and a 36-week open-label period. This trial consists of a part A and a part 
B. Part A of the trial is conducted in adolescents (≥ 12 and < 18 years, Tanner stage 2−5) with 
obesity and PWS. Part B of the trial is conducted in children (≥ 6 and < 12 years, Tanner stage 
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
13 of 125
below 2 (defined as Tanner stage 1 with or without premature adrenarche)) with obesity and PWS. 
Entry into part A and part B of the trial will be sequential. The randomisation will be stratified 
according to pubertal status (part A) and by presence/absence of dysglycaemia (Parts A and B).
After all subjects in part A have completed the 16 week double-blind period, an independent 
external Data Monitoring Committee (DMC) will review the PK data and safety data from part A. 
The DMC will recommend to the Novo Nordisk safety committee whether children in part B should 
be randomised, and exposed to liraglutide/liraglutide placebo. In addition, the tolerability/safety and 
PK data from trial NN8022-4181 in children with obesity 7-11 years (both inclusive) will be 
reviewed to allow adjustments in part B.
At least 30% of subjects will be from areas with lifestyle and nutrition comparable to that in the 
European Union (EU).
Trial population:
Approximately 57 subjects will be randomised 2:1 to receive liraglutide or liraglutide placebo. 
Approximately 33 subjects will be randomised in part A and 24 in part B.
The trial will continue until at least 45 evaluable subjects are included in total, divided as:
x
Part A, at least 28 evaluable subjects
x
Part B, at least 17 evaluable subjects
–
and of these subjects at least 5 need to be below 9 years of age.
Key inclusion criteria:
x
Informed consent obtained before any trial-related activities. Trial-related activities are any 
procedures that are carried out as part of the trial, including activities to determine suitability for 
the trial
x
Confirmed diagnosis of PWS (by genetic testing)
x
Male or female, age at the time of signing informed consent: 
–
Part A: ≥ 12 and < 18 years
–
Part B: ≥ 6 and < 12 years 
x
Tanner stage 2−5 pubertal development for part A, and Tanner stage below 2 (defined as Tanner 
stage 1 with or without premature adrenarche) for part B
x
BMI corresponding to ≥ 30 kg/m2 for adults by international cut-off points1 and ≥ the 95th 
percentile for age and sex (for diagnosis of obesity)
x
Stable body weight during the previous 90 days before screening (< 10 kg self-reported weight
change)
x
Testing has been performed to evaluate for adrenal insufficiency and documented in medical 
record
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
14 of 125
Key exclusion criteria
x
Type 1 diabetes mellitus (T1DM)2
x
Type 2 diabetes mellitus (T2DM)2
x
Calcitonin ≥ 50 ng/L
x
No change in treatment plan with growth hormone (GH) from randomisation to the end of the 
open-label period patients on growth hormone to stay on, patients off GH to stay off during this 
period. Adjustments in doses of growth hormone will be permitted)
x
Family or personal history of Multiple Endocrine Neoplasia Type 2 (MEN2) or Medullary 
Thyroids Carcinoma (MTC)
x
History of pancreatitis (acute or chronic)
x
Treatment with any medication prescribed for weight loss within 90 days before screening (e.g. 
orlistat, zonisamide, topiramate/phentermine, lorcaserin, phentermine, bupropion/naltrexone, 
liraglutide, metformin)
x
Untreated adrenal insufficiency
x
Suggestive history of, or significant risk of gastroparesis (e.g. marked abdominal bloating post 
meal, history of vomiting, severe constipation), as judged by the Investigator
Assessments:
Efficacy
x
Height
x
Body weight
x
Hyperphagia questionnaire
x
Systolic and diastolic blood pressure
x
HbA1c and FPG
Pharmacokinetic
Area under the liraglutide plasma concentration - time curve (AUC)
Safety
x
Adverse events
x
Hypoglycaemia
x
Anti-liraglutide antibodies
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
15 of 125
Trial product(s):
Liraglutide and liraglutide placebo are investigational trial products:
x
Liraglutide 6.0 mg/ml, 3.0 ml, for s.c. injection with FlexPen®.
x
Liraglutide placebo, 3.0 ml, for s.c. injection with FlexPen®.
3URWRFROSURWRFROYHUVLRQ_
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CONFIDENTIAL


Protocol: Liraglutide
UTN: U1111-1162-7884
Date:
16 July 2020
Status:
Final
Novo Nordisk
Trial ID: NN8022-4179
EudraCT no.: 2014-004415-37
Version:
5.0
Page:
16 of 125
2
Flow chart
Trial Periods
Screening
Screening
Randomisation
Dose escalation
Double blind 
treatment
Open-label treatment
End of treatment
Follow-up
TPD 
16
week 
FU
TPD 
52
week 
FU
Visit number
11
21
3
4
5
6
7
8
9
102
11
123
13
143
153
16
173
183
19
20
10x
19x
Timing of visit (weeks)
-2
0
1
2
3
4
8
12
16
20
24
28
32
36
40
44
48
52
54
16
52
Visit window (days)
±2
±2
±2
±2
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
-5
±5
±5
SUBJECT RELATED
INFO/ASSESSMENTS
Informed consent and 
assents 18.2
x
In/exclusion criteria 6.2 6.3
x12
x
x
Discontinuation of trial 
product 6.4 8.1.8
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Withdrawal criteria 6.5
8.1.9
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Demography 8.3.1
x
Medical history and 
Concomitant illness4 8.3.2
x
History of psychiatric 
disorders 8.3.2.1
x
Concomitant medication 
8.3.3
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Tobacco use 8.3.4
x
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Protocol: Liraglutide
UTN: U1111-1162-7884
Date:
16 July 2020
Status:
Final
Novo Nordisk
Trial ID: NN8022-4179
EudraCT no.: 2014-004415-37
Version:
5.0
Page:
17 of 125
Trial Periods
Screening
Screening
Randomisation
Dose escalation
Double blind 
treatment
Open-label treatment
End of treatment
Follow-up
TPD 
16
week 
FU
TPD 
52
week 
FU
Visit number
11
21
3
4
5
6
7
8
9
102
11
123
13
143
153
16
173
183
19
20
10x
19x
Timing of visit (weeks)
-2
0
1
2
3
4
8
12
16
20
24
28
32
36
40
44
48
52
54
16
52
Visit window (days)
±2
±2
±2
±2
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
-5
±5
±5
Physical activity 
counselling 8.7.2.2
x
x
x
x
x
x5
x5
x
x5
x5
x5
x5
x5
x5
x5
x5
x
x
x
x
Dietary counselling 8.7.2.1
x
x
x
x
x
x5
x5
x
x5
x5
x5
x5
x5
x5
x5
x5
x
x
x
x
Dietary compliance 8.7.2.1
x
x
x
x
x5
x5
x
x5
x5
x5
x5
x5
x5
x5
x5
x
x
EFFICACY
Body weight 8.4.1.1
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Waist and hip 
circumference 8.4.1.2
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Hyperphagia questionnaire 
8.4.2
x
x
x
Systolic and diastolic blood 
pressure 8.4.3
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Lipids 8.4.4
x
x
x
x
x
hsCRP 8.4.4
x
x
x
x
x
Glucose metabolism 8.4.4
x
x
x
x
x
x
SAFETY
Height 8.5.1
x
x
x
x
x
x
x
x
Adverse events 12
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Hypoglycaemic 
episodes8.5.2 and SMBG 
8.5.2.1
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
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11
RI


Protocol: Liraglutide
UTN: U1111-1162-7884
Date:
16 July 2020
Status:
Final
Novo Nordisk
Trial ID: NN8022-4179
EudraCT no.: 2014-004415-37
Version:
5.0
Page:
18 of 125
Trial Periods
Screening
Screening
Randomisation
Dose escalation
Double blind 
treatment
Open-label treatment
End of treatment
Follow-up
TPD 
16
week 
FU
TPD 
52
week 
FU
Visit number
11
21
3
4
5
6
7
8
9
102
11
123
13
143
153
16
173
183
19
20
10x
19x
Timing of visit (weeks)
-2
0
1
2
3
4
8
12
16
20
24
28
32
36
40
44
48
52
54
16
52
Visit window (days)
±2
±2
±2
±2
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
-5
±5
±5
Pulse 8.5.3
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
ECG 8.5.4
x
x
x
Pregnancy test6 8.5.5
x6
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x6
First day of menstrual 
period 8.5.5.3
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Physical examination 8.5.6
x
x
x
x
x
Biochemistry 8.5.7
x
x
x
x
x
Haematology  8.5.7
x
x
x
x
x
Hormones7 8.5.7
x
x
x
x
x
Calcitonin 8.5.7
x
x
x
x
x
Anti-liraglutide antibodies 
8.5.8
x
x8
x8,9
x9,11
Tanner staging 8.5.9
x
x10
x10
PHQ-9 and C-SSRS 
(part A only) 8.5.10
x
x
x
OTHER ASSESSMENTS
Liraglutide plasma 
concentration  8.7.1
x8
x8
x8
x8
x8
x8
X9
TRIAL MATERIAL
Dispensing visit 9
x
x
x
x
x
x9
x9
x9
x9
x9
x9
x9
x9
Drug accountability 9.4
x
x
x
x
x9
x9
x9
x9
x9
x9
x9
x9
x9
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11
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Protocol: Liraglutide
UTN: U1111-1162-7884
Date:
16 July 2020
Status:
Final
Novo Nordisk
Trial ID: NN8022-4179
EudraCT no.: 2014-004415-37
Version:
5.0
Page:
19 of 125
Trial Periods
Screening
Screening
Randomisation
Dose escalation
Double blind 
treatment
Open-label treatment
End of treatment
Follow-up
TPD 
16
week 
FU
TPD 
52
week 
FU
Visit number
11
21
3
4
5
6
7
8
9
102
11
123
13
143
153
16
173
183
19
20
10x
19x
Timing of visit (weeks)
-2
0
1
2
3
4
8
12
16
20
24
28
32
36
40
44
48
52
54
16
52
Visit window (days)
±2
±2
±2
±2
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
-5
±5
±5
IV/IWRS session 10
x
x
x
x
x
x
x9
x9
x9
x9
x9
x9
x9
x9
x9
New dose of trial product 
8.1.7
x
x
x
x
REMINDERS
Training in trial product & 
pen handling (including 
injection technique) 8.1.6
x
x
x
x
x
x
x
x
x9
x9
x9
x9
x9
x9
x9
x9
Hand-out and instruct in 
BG meter 8.5.2.1
x
BG meter finger prick test 
8.5.2.1
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Dispense dosing diary 
8.7.3.1
x
Collect dosing diary
x
x
x
x
x
x
Dispense hypoglycaemic 
episode diary 8.7.3.2
x
Collect hypoglycaemic 
episode diary
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Dispense menstrual period 
diary 8.7.3.3
x
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11
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Protocol: Liraglutide
UTN: U1111-1162-7884
Date:
16 July 2020
Status:
Final
Novo Nordisk
Trial ID: NN8022-4179
EudraCT no.: 2014-004415-37
Version:
5.0
Page:
20 of 125
Trial Periods
Screening
Screening
Randomisation
Dose escalation
Double blind 
treatment
Open-label treatment
End of treatment
Follow-up
TPD 
16
week 
FU
TPD 
52
week 
FU
Visit number
11
21
3
4
5
6
7
8
9
102
11
123
13
143
153
16
173
183
19
20
10x
19x
Timing of visit (weeks)
-2
0
1
2
3
4
8
12
16
20
24
28
32
36
40
44
48
52
54
16
52
Visit window (days)
±2
±2
±2
±2
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
-5
±5
±5
Collect menstrual period 
diary
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Attend visit fasting 8.1.3
x
x
x
x
x
x
x11
Abbreviation list: TPD = trial product discontinuation, FU = follow up, SMBG = self-measured blood glucose, PHQ-9 = Patient Health Questionnaire 9, 
C-SSRS = Columbia Suicidality Severity Rating Scale, V = visit, BG = blood glucose, IV/WRS = interactive voice/web response system, ECG = electrocardiogram, 
hsCRP = high sensitivity C reactive protein.
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Protocol: Liraglutide
UTN: U1111-1162-7884
Date:
16 July 2020
Status:
Final
Novo Nordisk
Trial ID: NN8022-4179
EudraCT no.: 2014-004415-37
Version:
5.0
Page:
21 of 125
Footer
Description
1
Maximum two weeks between V1 and V3. V2 must be at least 1 day after V1, and V2 must be at least 5 days before V3, to ensure 
blood samples are available for randomisation.
2
All assessments at V10 should be performed prior to trial medication dispensing, as the trial medication dispensing session in IV/WRS 
as V10 will un-blind subject's treatment.
3
Home visits possible for subjects treated with liraglutide placebo only.
4
At V2 all pre-existing conditions should be reported as medical history or concomitant illness.
5
Visit can be performed as phone/video conference visit.
6
Only for females of childbearing potential. At V2 and V19 performed as serum pregnancy test and from V3-V18 urine-stick pregnancy 
test, if applicable 8.5.5.
7
Estradiol for female subjects only and testosterone for male subjects only.
8
Subjects must be instructed to withhold their trial product dose until blood sampling is performed.
9
Only for subjects on open-label liraglutide treatment.
10
Tanner staging can be performed up to 2 weeks before V10 and V19.
11
No 8 hour fasting needed before V20. Minimum 2 hours after the last meal, the anti-liraglutide antibody sample at V20 is to be taken.
12
Please review inclusion criterion 7 and exclusion criterion 27 and evaluate whether a local testing for adrenal insufficiency is needed at 
V1
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Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
22 of 125
3
Background information and rationale for the trial
The trial will be conducted in compliance with this protocol, ICH GCP3 and applicable regulatory 
requirements, and in accordance with the Declaration of Helsinki4.
In this document, the term investigator refers to the individual responsible for the overall conduct of 
the clinical trial at a trial site.
3.1
Background information
Prader Willi syndrome
Prader-Willi syndrome (PWS) is a genetic disorder characterised by hypotonia with poor sucking 
reflex, feeding difficulties, and poor weight gain during infancy, hypogonadism, growth hormone 
insufficiency causing short stature, mild to moderate mental retardation, early childhood-onset 
hyperphagia and obesity5. Birth incidence has been estimated at around 1: 30,000 and population 
prevalence at about 1: 50,0006.
Obesity typically manifests in early childhood and is a major cause of morbidity and mortality and 
is strongly associated with multiple comorbid conditions, including cardiopulmonary compromise, 
type 2 diabetes mellitus (T2DM), hypertension, thrombophlebitis, chronic leg oedema, and sleep 
apnoea7. Food-seeking behaviour is common in patients with PWS. Left unchecked and untreated, 
lack of appetite control can lead to morbid obesity8, typically manifesting in early childhood. 
Therefore improvement in weight control remains the most important goal of any PWS treatment 
programme.
A study by Brambilla et al. investigated metabolic syndrome in 109 children with PWS aged 2−18 
years (50 with obesity and 59  without obesity) and 96 controls with obesity without PWS. 16% of 
the subjects with obesity and PWS had metabolic syndrome (very close to that observed in the 
controls with obesity), whereas none of the subjects with PWS without obesity had metabolic 
syndrome, suggesting that obesity status play a key role in the development of metabolic 
syndrome.9
For treatment and prevention of obesity in PWS, low calorie and well-balanced diets with rigorous 
supervision and restriction of food access combined with regularly scheduled meals and physical 
activities are recommended.10,11 The treatment of obesity in PWS is difficult and requires a 
comprehensive multidisciplinary approach with establishment of rigid structures to limit food intake 
and promote supervised physical activity.12 Bariatric surgery is not recommended for children with 
PWS.13
The role of pharmacotherapy in PWS is uncertain. No medication has shown long-term 
effectiveness in controlling appetite.14 In one study, adult patients with PWS were found to have 
elevated ghrelin concentrations compared to the reference population, raising the possibility that 
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
23 of 125
ghrelin may contribute to the food-seeking behaviour observed in these subjects.15 A 56-week study 
by de Waele et al. found that octreotide (long-acting somatostatin analogue) significantly decreased 
fasting ghrelin concentrations, but did not significantly affect weight, behaviour, or appetite in 
9 adolescents (10.8−18.9 years) with PWS.12 Another study found that topiramate (anticonvulsant, 
one of the two components of the obesity medication Qsymia®)  had no significant effect on 
appetite and body mass index (BMI).16 In a pilot study in adult patients with PWS and obesity and 
control patients with obesity, a single dose of 10 μg of the GLP-1 receptor agonist (GLP1-RA) 
exenatide increased satiety independently of measured appetite hormones, lowered glucose before 
and during a control meal and, increased insulin secretion rate in both groups. Side effects were 
absent in PWS.17 In a recent case report of 6 patients by Fintini et al., the effect of long-term 
treatment with liraglutide (4 patients, 1.2−1.8 mg/day) or exenatide (2 patients, 20 μg/day) was 
evaluated in adult PWS patients with T2DM. During the 24 months of treatment, a tendency 
towards decreased BMI, HbA1c, and waist circumference and a significantly decreased mean 
glycaemia during continuous glycaemic monitoring was detected, especially during the first 12 
months.18
As children with PWS often suffer from short stature and excessive body fat, growth hormone (GH) 
has been used to improve linear growth and body composition.19,20 In one study reported by Bakker 
et al., 8 years of GH treatment of 60 children with PWS completely normalised height standard 
deviation score (SDS). BMI SDS was significantly lower compared to baseline. Although percent 
fat SDS improved significantly during the first year of GH treatment, it had returned to baseline 
level after 8 years of GH treatment. One explanation for this could be, that the gradual increase in 
percent fat SDS seen over the years during the clinical course of PWS, cannot be fully restrained by 
GH treatment.21
Liraglutide
Liraglutide is a once-daily glucagon-like peptide-1 (GLP-1) analogue classified as a ‘GLP-1
receptor agonist’, with 97% homology to human GLP-1. Liraglutide has unique therapeutic 
potential for the treatment of obesity, due to its combined effects not only on body weight but also 
on glycaemic control and other weight-related comorbidities. Liraglutide regulates appetite by 
increasing feelings of fullness and satiety, while lowering feelings of hunger and prospective food 
consumption.22,23 Liraglutide is a once-daily GLP-1 analogue, obtained by derivatising GLP-1 with 
a fatty acid, providing a compound with protracted pharmacokinetic properties suitable for once-
daily injection. 
Liraglutide at once-daily doses up to 1.8 mg has been approved in approximately 90 countries for 
the treatment of adults with type 2 diabetes mellitus (T2DM) (under the trade name Victoza®). The 
moderate dose-dependent weight loss observed in clinical trials with liraglutide in T2DM, together 
with the reductions in glycosylated haemoglobin A1c (HbA1c) and improvements in beta-cell 
function and cardiometabolic risk factors such as systolic blood pressure led to investigations into 
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
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its potential therapeutic use for weight management.24 The liraglutide 3.0 mg daily dose was 
recently approved in the US as an adjunct to diet and exercise for weight management in adults, 
under the trade name Saxenda® (approval granted 23 December 2014), followed by Health Canada 
approval end of February 2015, and in Europe by 23 March 2015.
Four phase 3 clinical trials assessing the effect of liraglutide 3.0 mg on body weight reduction have 
been completed in adult subjects with obesity or overweight with or without T2DM. In general, a 
5−10% mean body weight reduction was observed in subjects treated with liraglutide 3.0 mg in 
these trials, Detailed results from these trials can be found in the Investigator Brochure or the latest 
version thereof25.
To date, two short-term (5 to 6-week) randomised, controlled trials with liraglutide in paediatric 
subjects have been completed. In the first trial (NN2211-1800), liraglutide at doses up to 1.8 mg 
was generally well tolerated in paediatric subjects with T2DM aged 10−17 years.26 Liraglutide’s 
safety/tolerability and pharmacokinetic profiles in adolescents were similar to those observed in 
adults with T2DM. In the second trial (NN8022-3967), liraglutide at doses up to 3.0 mg was well 
tolerated in adolescents with obesity without T2DM (aged 12−17 years); no unexpected safety or 
tolerability issues were detected. As in adults, liraglutide exposure increased with increasing drug 
dose. Since no safety/tolerability concerns were raised in the NN8022-3967 trial, a large, long-term 
trial (NN8022-4180) will investigate the efficacy and safety of liraglutide (doses up to 3.0 mg) for 
chronic weight management in adolescents with obesity (≥ 12 and < 18 years) and without diabetes 
type 1.
For an assessment of benefits and risks of the trial, see section 18.1, in which a description of 
preclinical findings includes a dose-dependent delay in sexual maturation in juvenile rats, which 
was more pronounced in females.
3.2
Rationale for the trial
Currently, there are no approved weight management pharmacotherapies for children and 
adolescents within Europe, and in the US the only medication approved by the FDA for children 
≥12 years of age is orlistat. Obesity is a major cause of morbidity and mortality in PWS. It is 
challenging to achieve weight loss with diet and physical activity alone due to food-seeking 
behaviour and lack of appetite control in patients with PWS. Therefore there is an unmet medical 
need for anti-obesity medication as an adjunct to lifestyle interventions in this patient population.
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
25 of 125
4
Objectives and endpoints
4.1
Objectives
Primary objective
To compare the efficacy of liraglutide versus placebo on weight loss in paediatric subjects with 
obesity and PWS at 16 weeks and versus no treatment at 52 weeks.
Secondary objectives 
x
To compare the efficacy of liraglutide versus placebo on glycaemic control in children and 
adolescents with obesity and PWS at 16 weeks and versus no treatment at 52 weeks. 
x
To estimate the liraglutide steady state exposure in children and adolescents with obesity and 
PWS after 16 weeks of treatment.
x
To compare the safety of liraglutide versus placebo in children and adolescents with obesity and 
PWS at 16 weeks and versus no treatment at 52 weeks.
4.2
Endpoints
4.2.1
Primary endpoints
There are two co-primary endpoints:
x
Change in body mass index (BMI) standard deviation score (SDS) from baseline to 16 weeks
x
Change in body mass index (BMI) standard deviation score (SDS) from baseline to 52 weeks
4.2.2
Secondary endpoints
4.2.2.1
Supportive secondary efficacy endpoints
x
Percent of subjects achieving ≥ 5% reduction in baseline BMI at weeks 16 and 52*
x
Percent of subjects achieving ≥ 10% reduction in baseline BMI at weeks 16 and 52*
x
Percent of subjects with no increase in BMI SDS at weeks 16 and 52
Change from baseline to 16 and 52 weeks in:
x
BMI* 
x
Body weight (kilogram (kg), pounds (lb) and percent (%))*
x
Waist circumference
x
Waist to hip circumference ratio
x
Hyperphagia score:
–
total score and* 
–
hyperphagic behaviour, drive and severity score*
x
Cardiovascular risk factors:
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
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–
High sensitivity C reactive protein (hsCRP)
–
Fasting lipids: total cholesterol (TC), low density lipoprotein cholesterol (LDL-cholesterol), 
high density lipoprotein cholesterol (HDL-cholesterol), non-HDL cholesterol, very low 
density lipoprotein cholesterol (VLDL-cholesterol), triglycerides (TG), and free fatty acids 
(FFA)
x
Systolic and diastolic blood pressure*
x
Glucose metabolism: glycosylated haemoglobin (HbA1c)*, fasting plasma glucose (FPG)*, 
fasting insulin, fasting C-peptide, glycaemic category, homeostasis model assessment of beta-
cell function and insulin resistance parameters (HOMA-B and HOMA-IR)
4.2.2.2
Supportive secondary PK endpoint
Model-derived area under the curve (AUC) over the dosing interval in steady state.
4.2.2.3
Supportive secondary safety endpoints
x
Number of treatment-emergent adverse events during the trial
x
Number of severe treatment emergent episodes of hypoglycaemia
x
Number of blood glucose confirmed symptomatic episodes of hypoglycaemia
x
Occurrence of anti-liraglutide antibodies
Change from baseline to 16 and 52 weeks in:
x
Electrocardiogram (ECG)
x
Pulse
x
Laboratory parameters:
–
Haematology: haemoglobin, haematocrit, thrombocytes, erythrocytes, leukocytes, 
differential count (eosinophils, neutrophils, basophils, lymphocytes, monocytes)
–
Biochemistry: creatinine, creatine kinase (CPK), urea, albumin, bilirubin (total), alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, sodium, 
potassium, calcium total, calcium albumin corrected, amylase, lipase, and carcinoembryonic 
antigen (CEA)
–
Hormone levels including: calcitonin, insulin-like growth factor-1 (IGF-1), thyroid 
stimulating hormone (TSH), free thyroxine (free T4),  prolactin, adrenocorticotropic 
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
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hormone (ACTH), cortisol, dehydroepiandrosterone sulfate (DHEAS), luteinising hormone 
(LH), follicle stimulating hormone (FSH), estradiol (females), testosterone (males) 
x
Pubertal status
x
Physical examination including height
x
Part A only: Mental health assessed by Columbia Suicidality Severity Rating Scale (C-SSRS) 
and Patient Reported Health Questionnaire-9 (PHQ-9)
*Key supportive secondary endpoint prospectively selected for posting on clinicaltrials.gov
and EudraCT)
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
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5
Trial design
5.1
Type of trial
This is a multi-centre, multi-national, randomised, parallel group, placebo-controlled trial with a 
16-week double-blind period and a 36-week open-label period. This trial consists of a part A and a 
part B. Part A of the trial is conducted in adolescents (≥ 12 and < 18 years, Tanner stage 2−5) with 
obesity and PWS. Part B of the trial is conducted in children (≥ 6 and ˂ 12 years, Tanner stage 
below 2 (defined as Tanner stage 1 with or without premature adrenarche)) with obesity and PWS. 
Both part A and part B (for children with body weight ≥ 45 kg) will follow the trial diagram (Figure 
5–1). Part B for children with body weight < 45 kg will follow the trial diagram (Figure 5–2). Entry 
into part A and part B of the trial will be sequential. After all subjects in part A have completed the 
16-week double-blind period, an independent external Data Monitoring Committee (DMC) will 
review the PK data and safety data from part A. The DMC will recommend to the Novo Nordisk 
safety committee whether children in part B should be randomised, and exposed to 
liraglutide/liraglutide placebo. In addition, the tolerability/safety and PK data from trial NN8022-
4181 in children with obesity 7-11 years (both inclusive) will be reviewed to allow adjustments in 
part B, as needed (conclusion after part A; see above).
Figure 5–1
Trial diagram (Part A and part B (for children with body weight ≥ 45 kg))
Dose escalation can be prolonged to 8 weeks. Abbreviations: EOT = end-of-treatment; EOS = end-of-study; MTD = 
maximum tolerated dose. 
* Placebo injections will end at week 16 for subjects allocated to the placebo arm.
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
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Figure 5–2
Trial diagram (Part B for children with body weight < 45 kg)
Dose escalation can be prolonged to 8 weeks. Abbreviations: EOT = end-of-treatment; EOS = end-of-study; MTD = 
maximum tolerated dose. 
* Placebo injections will end at week 16 for subjects allocated to the placebo arm.
Subjects will be randomised 2:1 to receive liraglutide or liraglutide placebo. Part A has four strata 
as subjects are stratified according to Tanner stage 2−3 and 4−5 and by presence/absence of 
dysglycaemia. Part B includes subjects with Tanner below 2 (defined as Tanner stage 1 with or 
without premature adrenarche) and has two strata for presence/absence of dysglycaemia, see section 
11.
Dysglycaemia is defined as pre-diabetes with FPG 5.6 – 6.9 mmol/L (both inclusive) (100-125
mg/dL) (both inclusive) and/or HbA1c 5.7 – 6.4 % (both inclusive). The HbA1c and FPG results 
from V2 must be used.
At least 30% of subjects will be from areas with lifestyle and nutrition comparable to that in the 
European Union (EU). All subjects and/or their legally acceptable representative (LAR) will 
undergo counselling for weight loss and must be prescribed a structured programme for diet and 
physical activity throughout the trial (from randomisation to the end of the trial). Placebo injections 
will be stopped at week 16, at the end of the double-blind period.
Subjects treated with growth hormone therapy may enter the trial and will have no change in 
treatment plan with growth hormone from randomisation to the end of the open-label period 
(subjects on growth hormone will stay on, and subjects off growth hormone will stay off during this 
period. Adjustments to doses of growth hormone are permitted).
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
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5.2
Rationale for trial design
This trial is designed in accordance with regulatory requirements (FDA 21 CFR 314.126)27 and 
recommendations from the literature.2,28
The design has been chosen in accordance with the trial objectives and with input from the 
Paediatric Committee (PDCO) of the European Medicines Agency’s (EMA). 
The co-primary efficacy endpoints are change in BMI SDS from baseline to 16 weeks and 52 
weeks. Change in BMI SDS is selected based on the EMA recommendation regarding the 
assessment of efficacy of new medicinal products for the treatment of obesity in children.29 The first 
16 weeks will be placebo-controlled and double-blinded to evaluate the effect of liraglutide versus 
placebo, as an adjunct to a structured program for diet and physical activity. The 36-week open-
label period will provide supportive evidence to evaluate the continued efficacy and safety of 
liraglutide. Placebo injections will be stopped at the end of the double-blind period to avoid 
inconvenience to the subjects.
The rationale for choosing a treatment duration of 16 weeks for the primary efficacy endpoint is that 
this time period is considered adequate to show effect of liraglutide treatments on the endpoint, and 
to minimise the duration of placebo injections. The 36-week open-label period will allow additional 
time to evaluate the full effect of liraglutide on other efficacy endpoints including BMI, body 
weight, waist to hip circumference, cardiovascular risk factors (hsCRP and lipid profile), blood 
pressure and glucose metabolism and safety assessments. Furthermore, a 52-week total trial period 
is regarded to be sufficient to characterise the safety and tolerability profiles of liraglutide.
A 2:1 randomisation was chosen to ensure more subjects will receive active treatment with limited 
number of subjects enrolled in the trial, and therefore more safety data on liraglutide treatment is 
obtained.
The PK properties of liraglutide (i.e. exposure) in children and adolescents with PWS will be 
evaluated by population PK modelling, allowing for sparse PK sampling. The sparse sampling is 
implemented to reduce the burden on trial subjects and their LAR. The number of samples per 
subject has been chosen to allow for an adequate precision on the individual estimate for apparent 
clearance, CL/F. This parameter is used to derive exposure (AUC), thus allowing for a comparison 
with other relevant populations (such as adults with obesity, children with obesity and adolescents 
with obesity without PWS). Although sampling during the whole dosing interval will give adequate 
information on CL/F, the timing of sampling in the dosing interval has been optimized (mostly 
through samples) to improve precision of the CL/F estimate.
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
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5.3
Treatment of subjects
Liraglutide or liraglutide placebo will be administered by once-daily subcutaneous (s.c.) injections
either in the abdomen, thigh, or upper arm; injection site consistency is not required throughout the 
trial. During the 16-week double-blind period, subjects randomised to receive liraglutide placebo 
will receive placebo s.c. injections with injection volumes equivalent to the corresponding 
liraglutide dose. Liraglutide placebo contains the same excipients as liraglutide, but no active trial 
product. Injections can be administered at any time of day irrespective of meals. It is recommended 
that the time of injection is consistent throughout the trial. Subjects will be instructed to perform an 
air shot before the use of a new pre-filled pen. At the end-of the double-blind period, subjects 
randomised to receive placebo will stop injections once the investigator and subject are un-blinded 
to treatment allocation. During the 36-week open-label period, subjects in the liraglutide group will 
continue to receive liraglutide treatment. The maximum duration of treatment of a single subject, 
from first trial product administration to last trial product administration will be 52 weeks, and the 
maximum dose will be 3.0 mg/day in part A and for children in part B with a body weight ≥ 45 kg. 
For children in part B with a body weight of < 45 kg the maximum dose will be 2.4 mg/day. 
At the first visit subjects and their LAR will be instructed in symptoms and treatment of 
hypoglycaemia, and in blood glucose measurements. The liraglutide dose will not be escalated if the 
subject experiences SMBG < 3.1 mmol/L (56 mg/dL) or < 3.9 mmol/L (70 mg/dL) in the presence 
of symptoms of hypoglycaemia, during the week prior to the dose escalation visit. 
The following medications should not be used: orlistat, zonisamide, topiramate/phentermine, 
lorcaserin, phentermine and bupropion/naltrexone. Except for liraglutide as trial medication, GLP-1
receptor agonists cannot be prescribed during the trial. Metformin can only be used if the subject 
develops T2DM requiring an anti-diabetic agent as described in section 5.3.3.
Dosing in part B will be determined based on the results (including model-estimated steady state 
exposure) of the NN8022-4181 trial, a PK trial in children with obesity (Tanner stage below 2
(defined as Tanner stage 1 with or without premature adrenarche)), 7-11 years of age (both 
inclusive), and on the DMC review of PK data and safety data from the 16-week double-blind 
period from part A of this trial. If the dosing is different than for part A an amendment will be 
prepared.
Subjects in part A must have Tanner stage 2-5 pubertal development according to inclusion 
criterion 4. Pubertal development may have been hormonally induced with medical treatment.
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
32 of 125
5.3.1
Dose escalation
5.3.1.1
Dose escalation part A
Dose escalation will be based on tolerability as assessed by the investigator. 
Based on the results of the NN8022-3967 PK trial in pubertal adolescents with obesity (aged 12 to < 
18 years) including model-estimated steady state exposure, treatment is planned to be initiated in 
part A with liraglutide/placebo 0.6 mg daily for one week and increased in weekly steps of 0.6 mg 
until a maximum tolerated dose (MTD) (as judged by the investigator) or a dose of 3.0 mg 
liraglutide/placebo is reached. 
The trial product dose will be escalated only if the current dose is tolerated. If a subject has 
tolerability issues with the higher dose level (as judged by the investigator), it is allowed to lower to 
the previous dose level. 
If a trial product dose is poorly tolerated, subjects are allowed to remain at a dose level for a 
maximum of 2 weeks. This extended time of one additional week is allowed at each dose level, i.e. 
the dose escalation process may take up to 8 weeks in total. It is at the discretion of the investigator 
to judge when the subject has reached MTD.
Escalation of the liraglutide/placebo dose is not allowed if the subject has a SMBG < 3.1 mmol/L 
(56 mg/dL) or < 3.9 mmol/L (70 mg/dL) in the presence of symptoms of hypoglycaemia during the 
week prior to the dose escalation visits. Hypoglycaemic episodes must be reported according to 
section 8.5.2.
Visits to the clinic occur weekly during the 4 weeks of dose escalation at V4-V7. Ideally, subjects 
will reach maximum dose of 3.0 mg at V7.
In those cases where more than one week is needed at any dose escalation step, the subject must 
still follow the visit schedule (V4-V7). For the remaining dose escalation step(s) after V7 it is at the 
discretion of the investigator to be in frequent contact (e.g. by phone/video conference) with the 
subject to ensure correct dose settings. The dose-escalation process must be completed no later than 
V8. Contacts regarding dose escalation must be documented in the subject’s medical record and 
information about all dose levels must be recorded in the electronic case report form (eCRF).
5.3.1.2
Dose escalation part B
Based on result of the safety and PK data of NN8022-4181 and part A of NN8022-4179, the 
recommendation for part B - PWS children (aged 6 to < 12 years) with obesity is to initiate 
treatment with liraglutide/placebo based on weight. 
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
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For children with a body weight ≥ 45 kg, dosing will be initiated with liraglutide/placebo 0.6 mg 
daily for one week and increased in weekly steps of 0.6 mg until a maximum tolerated dose (MTD) 
(as judged by the investigator) or a dose of 3.0 mg liraglutide/placebo is reached.
For children with a body weight < 45 kg, dosing will be initiated with liraglutide/placebo 0.3 mg 
daily for one week and increased to 0.6 mg after the first week, thereafter the dose is increased in 
weekly steps of 0.6 mg until a MTD (as judged by the investigator) or a dose of 2.4 mg 
liraglutide/placebo is reached. 
Escalation of the liraglutide/placebo dose is not allowed if the subject has a SMBG < 3.1 mmol/L 
(56 mg/dL) or < 3.9 mmol/L (70 mg/dL) in the presence of symptoms of hypoglycaemia during the 
week prior to the dose escalation visits. 
Hypoglycaemic episodes must be reported according to Section 8.5.2.
Dose escalation will be based on tolerability as assessed by the investigator. The trial product dose 
will be escalated only if the current dose is tolerated. If a subject has tolerability issues with the 
higher dose level (as judged by the investigator), it is allowed to lower to the previous dose level. 
If a trial product dose is poorly tolerated during the dose escalation period, subjects are allowed to 
remain at a dose level for an additional week, i.e. four times in total, thus the dose escalation will 
last for eight weeks in total as a maximum. 
Visits and phone contacts to the clinic occur weekly during dose escalation. 
Trial Product dose at V8 will be defined as MTD.
5.3.2
Maintenance
In the event that a subject experiences unacceptable intolerance as judged by the investigator, the 
liraglutide dose may be lowered to the next, lower dose level as needed:
x
Part A and part B (children with a body weight ≥ 45 kg) (from 3.0 mg to 2.4 mg, from 2.4 
mg to 1.8 mg, from 1.8 mg to 1.2 mg, and from 1.2 mg to 0.6 mg).
x
Part B (children with a body weight < 45 kg) (from 2.4 mg to 1.8 mg, from 1.8 mg to 1.2 
mg, and from 1.2 mg to 0.6 mg and from 0.6 mg to 0.3 mg). 
The reason for de-escalation of the liraglutide dose must be documented in the subject’s medical 
record and transferred to the eCRF.
If the intolerance is due to intermittent illness or otherwise transient as judged by the investigator, 
the subject is allowed to return to the previous dose.
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
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If a subject treated with the individual weight-based starting dose experiences unacceptable 
intolerance as judged by the investigator the subject must be discontinued from trial product 
(Section 8.1.8).
5.3.3
Treatment of subjects who develop type 2 diabetes mellitus during the trial
If a subject develops T2DM during the course of the trial, he/she will be allowed to remain in the 
trial if glycaemic control can be achieved through diet and physical activity according to local 
standard of care. Furthermore, additional treatment with metformin is allowed at the discretion of 
the investigator.
If anti-diabetes treatment other than diet, physical activity and metformin is required for glycaemic 
control the trial product must be discontinued (sections 6.4 and 8.1.8)
5.4
Treatment after discontinuation of trial product
As liraglutide is not currently approved for treatment of obesity in the paediatric population, it will 
not be available to the subjects once the trial period ends. When subjects withdraw from or 
complete the trial, they should continue present or be switched to other suitable dietary and physical 
activity program at the discretion of the investigator. 
5.5
Rationale for treatment
The rationale for the dose-escalating design is to mitigate gastrointestinal adverse events. A 
corresponding tolerability/PK/PD trial (NN2211-1800) in paediatric subjects with T2DM, age 
10−17 years, with maximum dose of 1.8 mg liraglutide has been conducted as part of the Paediatric 
Investigation Plan (PIP) for Victoza® T2DM. In addition, a PK/PD trial NN8022-3967 in pubertal 
adolescents with obesity (aged 12 to < 18 years) has been completed as part of the PIP for 
liraglutide 3.0 mg for treatment of obesity. In trial (NN8022-4181), liraglutide, at doses up to 3.0 
mg, was generally well tolerated in children with obesity without T2DM (aged 7-11 years); no 
unexpected safety or tolerability issues were detected. As in adults, liraglutide exposure increased 
with increasing drug dose. 
The starting dose of 0.6 mg applied for part A of the current trial in adolescents with obesity and 
PWS is based on the tolerability results in trial NN2211-1800 and NN8022-3967. The maximum 
dose of 3.0 mg is the approved dose for the adult population with obesity, based on efficacy and 
safety evaluation from the phase 2 dose finding trial (NN8022-1807) and the phase 3a programme 
in adults. 
The weight-based starting dose of 0.6 mg for children with body weight ≥ 45 kg and 0.3 mg for 
children with body weight < 45 kg applied for part B is based on the limited data in patients below 
45 kg with liraglutide treatment. As a precautionary measure and to ensure comparable exposure at 
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
35 of 125
the start of treatment the 0.3 mg starting dose with a cap of 2.4 mg/day as a maximum dose for 
subjects < 45 kg is introduced.
The treatment duration of 16 weeks is considered adequate for evaluation of the effect of liraglutide 
on the primary efficacy endpoint during the double-blind period. The 36-week open-label period 
will provide supportive information on the effect of liraglutide on other efficacy endpoints and 
establish the safety profile of liraglutide in this patient population. A placebo group is included in 
the trial to compare safety between placebo and liraglutide treatment. The s.c. injection is the route 
of administration intended for clinical use of liraglutide.
For more information, see the latest edition of the Investigator’s Brochure for: Liraglutide 
(NN8022) in Weight Management or any updates hereof25.
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
36 of 125
6
Trial population
6.1
Number of subjects 
Number of subjects planned to be screened: 
64 (part A: 38; part B: 26)
Number of subjects planned to be randomised: 
57 (part A: 33; part B: 24)
Number of subjects expected to complete the trial: 45 (part A: 28; part B: 17)
6.2
Inclusion criteria
For an eligible subject, all inclusion criteria must be answered “yes”. 
1. Informed consent obtained before any trial-related activities. Trial-related activities are any 
procedures that are carried out as part of the trial, including activities to determine suitability for 
the trial
2. Confirmed diagnosis of Prader-Willi Syndrome (by genetic testing)
3. Male or female, age at the time of signing informed consent: 
–
Part A: ≥ 12 and < 18 years
–
Part B: ≥ 6 and < 12 years 
4. Tanner stage 2−5 pubertal development for part A, and Tanner stage below 2 (defined as Tanner 
stage 1 with or without premature adrenarche) for part B
5. BMI corresponding to ≥ 30 kg/m2 for adults by international cut-off points 30 and ≥ the 95th 
percentile for age and sex (for diagnosis of obesity) (please refer to Appendix A)
6. Stable body weight during the previous 90 days before screening (< 10 kg self-reported weight
change)
7. Testing has been performed to evaluate for adrenal insufficiency and documented in medical 
record
6.3
Exclusion criteria
For an eligible subject, all exclusion criteria must be answered "no".
1. Type 1 diabetes mellitus (T1DM)2
2. Type 2 diabetes mellitus (T2DM)2
3. No change in treatment plan with growth hormone (GH) from randomisation to the end of the 
open-label period (patients on growth hormone to stay on, patients off GH to stay off during this 
period. Adjustments in doses of growth hormone will be permitted)
4. Calcitonin ≥ 50 ng/L (please refer to Appendix C)
5. Family or personal history of Multiple Endocrine Neoplasia Type 2 (MEN2) or Medullary 
Thyroid Carcinoma (MTC)
6. History of pancreatitis (acute or chronic)
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
37 of 125
7. Treatment with any medication prescribed for weight loss within 90 days before screening (e.g. 
Orlistat, zonisamide, topiramate/phentermine, lorcaserin, phentermine, bupropion/naltrexone, 
liraglutide, metformin)
8. Diet attempts using herbal supplements or over-the-counter medications within 90 days before 
screening
9. Participation in an organised weight reduction programme (e.g. Weight Watchers®) within 
90 days before screening
10. Previous surgical treatment for obesity (excluding liposuction if performed > 1 year before 
screening)
11. History of major depressive disorder within 2 years before randomisation
12. History of other severe psychiatric disorder (e.g. schizophrenia, bipolar disorder)
13. Part A only: PHQ-9 score of ≥ 15 at screening
14. Part A only: Any suicidal ideation of type 4 or 5 in the last 30 days prior to screening based on 
the C-SSRS questionnaire
15. Any lifetime history of suicidal attempt
16. Any suicidal behaviour within 30 days before randomisation
17. Surgery scheduled for the trial duration period except for minor surgical procedures, at the 
discretion of the investigator 
18. Subjects with confirmed bulimia nervosa disorder 
19. Uncontrolled treated or untreated hypertension >99th percentile for age and gender in children 
(please refer to Appendix B). If white-coat hypertension is suspected at the screening V2 a 
repeated measurement at V3 prior to other trial related activities is allowed (last measurement 
being conclusive)
20. Diagnosis of malignant neoplasms within the last 5 years (except basal and squamous cell skin 
cancer, polyps and in-situ carcinomas)
21. Known or suspected abuse of alcohol or narcotics
22. Known or suspected hypersensitivity to trial product(s) or related products
23. Previous participation in this trial. Participation is defined as being randomised
24. Receipt of any investigational medicinal product within 30 days before screening or 
participation in another trial within 30 days before screening 
25. Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing 
potential not using adequate contraceptive methods (adequate contraceptive measures as 
required by local regulation or practice). 
26. Any condition which, in the opinion of the investigator might jeopardise subject’s safety or 
compliance with the protocol
27. Untreated adrenal insufficiency (please refer to Section 8.1.1.1)
28. Suggestive history of, or significant risk of gastroparesis (e.g. marked abdominal bloating post 
meal, history of vomiting, severe constipation), as judged by the Investigator
The inclusion and exclusion criteria will be checked prior to subject randomisation.
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
38 of 125
6.4
Discontinuation of trial product criteria
The subject must discontinue trial product if the following applies: 
1. Due to a safety concern at the discretion of the investigator
2. Non-compliant with trial procedures at the discretion of the investigator.
3. Pregnancy
4. Intention of becoming pregnant
5. Participation in another clinical trial throughout the trial
6. Included in the trial in violation of the inclusion and/or exclusion criteria
7. Diagnosis of acute pancreatitis (section 8.6.3.3 and 8.6.2)
8. Diagnosis of medullary thyroid carcinoma 
9. Weight loss attempts other than what is agreed with the dietitian as part of the trial intervention
10. If diabetes treatment other than diet, physical activity and metformin addition is initiated.
11. Initiation of treatment that based on the investigator’s judgement may cause significant weight 
change. This should also include treatment with any of the following medications: orlistat, 
zonisamide, topiramate, lorcaserin, phenteremine, bupropion, naltrexone or GLP-1 receptor 
agonists
12. Inadequate psycho- and/or pharmaco therapeutic treatment of a subject’s psychiatric disorder 
(section 8.5.10.3)
13. The subject and/or the subject’s LAR refuse referral to a mental health professional (MHP) and 
it in investigator’s opinion, it is unsafe for the subject to continue in the trial (section 8.5.10.3)
14. Due to safety reasons if at the recommendation of the external DMC and endorsed by the safety 
committee.
15. If a subject treated with the individual weight-based starting dose experiences unacceptable 
intolerance as judged by the investigator, the subject must be discontinued from trial product 
(Section 8.1.8)
See section 8.1.8 for how to handle discontinuation of trial product.
6.5
Withdrawal criteria
1. The subject may withdraw at will at any time either by the subject or by the subject’s parent or 
the subject’s legally acceptable representative. The subject’s request to discontinue must always 
be respected
See section 8.1.9 for how to handle withdrawals.
6.6
Subject replacement
Subject replacement will be initiated if the actual withdrawal rate is higher than assumed (10% at 
week 16 and 20% at week 52) to ensure the number of evaluable subjects required by PDCO will be 
met.
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
39 of 125
The trial will continue until at least 45 evaluable subjects are included in total, divided as:
x
Part A, at least 28 evaluable subjects
x
Part B, at least 17 evaluable subjects
–
and of these subjects at least 5 need to be below 9 years of age.
6.7
Rationale for trial population 
PWS is a rare genetic disease with an estimated incidence of 1:15,000 to 1:25,000 live births10,
therefore the number of subjects planned for this trial is relatively small.
Obesity is the major cause of morbidity and mortality in patients with PWS. The diagnosis of 
obesity in adolescents and children is based on BMI corresponding to ≥ 30 kg/m2 for adults by 
international cut-off points1 and ≥ 95th percentile for age and sex for children.
Subjects are required to have had testing performed to evaluate for adrenal insufficiency. This must 
be documented in their medical records to confirm adrenal sufficiency, see section 8.1.1.1.
Hypogonadism and growth hormone insufficiency (causing short stature) are commonly seen in 
patients with PWS31, suggesting that pituitary hormones are affected by the disease. The secretion 
of cortisol, the main adrenal glucocorticoid in humans is under the control of pituitary 
adrenocorticotropic hormone (ACTH). Adrenal insufficiency has been reported, and although 
uncommon in patients with PWS, the clinical manifestations are serious.10 Therefore it is important 
to ensure patients enrolled in the trial have had testing performed to evaluate for adrenal 
insufficiency, and that those who have this condition are under treatment.
As previously mentioned, subjects may enter the trial on GH therapy as short stature associated with 
PWS is an approved indication for GH therapy. It has been reported that in children with PWS, 8 
years of GH treatment resulted in completely normalised height and head circumference, and a 
significant increase in lean body mass during the first year, and remained stable for 7 years at a 
level above baseline.21 It is well known that growth hormone may affect glucose metabolism, and 
may increase fasting plasma glucose.32,33 Therefore, no change in GH treatment plan should be 
made during the trial, and subjects not using GH therapy will stay off during the trial. Adjustments 
in doses of growth hormone are permitted.
As mentioned previously in section 3.1, there is limited information on the safety and effectiveness 
of pharmacotherapy in controlling appetite and obesity in PWS patients, especially in children and 
adolescents with PWS. There is a knowledge gap and lack of treatment options for weight 
loss/improvement in the weight-related symptoms and risk factors in PWS population. Therefore 
the current trial has been mandated by PDCO and will provide useful information on using 
liraglutide as a therapeutic option for weight management in this patient population.
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
40 of 125
7
Milestones
7.1
Part A
Planned duration of recruitment period (FPFV– LPFV):
72 weeks
Planned date for first patient first visit (FPFV):
09-Nov-2015
Planned date for first patient first treatment: (FPFT)
23-Nov-2015
Planned date for last patient first visit (LPFV):
27-Mar-2017
Planned date for last patient first treatment (LPFT):
10-Apr-2017
Planned date for last patient last visit (LPLV): 
07-May-2018
7.2
Part B
Planned duration of recruitment period (FPFV– LPFV):
64 weeks
Planned date for first patient first visit (FPFV):
09-Apr-2018
Planned date for first patient first treatment: (FPFT)
23-Apr-2018
Planned date for last patient first visit (LPFV):
01-Jul-2019
Planned date for last patient first treatment (LPFT):
15-Jul-2019
Planned date for last patient last visit (LPLV): 
10-Aug-2020
End of trial is defined as LPLV for part B.
7.3
Recruitment
A global recruitment strategy will be developed in cooperation with the participating countries to 
ensure that a sufficient number of subjects are randomised. Prior to FPFV, all sites should have a 
site-specific recruitment strategy in place detailing how many subjects they can recruit within a 
certain period.
The screening and randomisation rate will be followed closely via the interactive voice/web 
response system (IV/WRS) in order to estimate when to stop screening. All investigators will be 
notified immediately when the recruitment period ends, after which no additional subjects may be 
screened and the IV/WRS will be closed for further screening. All subjects included in the 
screening period and eligible for randomisation can be randomised.
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
41 of 125
7.4
Trial registration
Information of the trial will be disclosed at clinicaltrials.gov and novonordisk-trials.com. According 
to the Novo Nordisk Code of Conduct for Clinical Trial Disclosure34, it will also be disclosed 
according to other applicable requirements such as those of the International Committee of Medical 
Journal Editors (ICMJE)35, the Food and Drug Administration Amendment Act (FDAAA)8,
European Commission Requirements36-38 and other relevant recommendations or regulations. If a 
subject requests to be included in the trial via the Novo Nordisk e-mail contact at these web sites, 
Novo Nordisk may disclose the investigator’s contact details to the subject. As a result of increasing 
requirements for transparency, some countries require public disclosure of investigator names and 
their affiliations.
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
42 of 125
8
Methods and assessments
The following sections describe the assessments and procedures. These are also included in the flow 
chart (section 2).
8.1
Visit procedures
It is the responsibility of the investigator to ensure that all site visits and phone/video conference 
contacts occur according to the flowchart. In order to secure consistency in data over time it is 
encouraged that assessments are performed consistently (e.g. using the same equipment and site 
staff with alike qualifications) throughout the trial.
All trial procedures must be performed as described in the protocol. Any discrepancies will result in 
protocol deviations and appropriate actions must be taken to avoid recurrence of the detected 
discrepancies. 
8.1.1
Screening, visit 1
Prior to any other trial related procedures, the investigator must obtain informed assent from each 
subject if applicable (based on age and local regulations) and informed consent from the subject’s 
LAR(s) (section 2). For information on informed assent and consent procedure see section 18.2.
All subjects and subject’s LAR(s) must be provided with a copy of their own signed and dated 
informed assent form and informed consent form.
A screening session must be made in the IW/VRS. During the session each subject will be assigned 
a unique 6-digit subject number which will remain the same throughout the trial. 
The investigator must keep a subject screening log, a subject identification code list and a subject 
enrolment log. The subject screening log and subject enrolment log may be combined in one list. 
At screening, subjects will be provided with a card stating that they are participating in a trial and 
given contact address(es) and telephone number(s) of relevant trial site staff. Subjects should be 
instructed to return the card to the investigator at the last trial visit. 
All subjects should be reminded to attend V2 in a fasting state. V2 must take place at least 1 day 
after V1.
8.1.1.1
Adrenal insufficiency test at screening, visit 1
If the testing for adrenal insufficiency has not been performed prior to screening V1 (inclusion 
criterion 7), the investigator may perform a test (of their choosing) locally to evaluate for adrenal 
insufficiency after screening and before randomisation. The results must be available and reviewed 
and the subject must have initiated treatment before the randomisation visit, if applicable.
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
43 of 125
8.1.2
Visits attended fasting
Fasting visits are specified in section 2. Fasting is defined as having consumed no food and drink 
except for water for the last 8 hours.
Any medication which should be taken with or after a meal should be withheld on the day of the 
visit until blood sampling and body weight measurements have been performed. Trial product can 
be taken as usual in relation to fasting visits.
In case a subject attends a fasting visit in a non-fasting state, all non-fasting measurements should 
be performed. The subject should return to the site in a fasting state to have fasting measurements 
done within the visit window for the relevant visit.
8.1.3
Screening, visit 2
All screening assessments as described in section 2 must be performed. V2 must be at least 1 day 
after V1, and V2 must be at least 5 days before V3.
8.1.4
Screening failures
For screening failures the screening failure form in the case report form (CRF) must be completed 
with the reason for not continuing in the trial. Serious and non-serious adverse events from 
screening failures must be transcribed by the investigator into the CRF. Follow-up of serious 
adverse events (SAEs) must be carried out according to section 12.
A screening failure session must be made in the IV/WRS. The case book must be signed. 
8.1.5
Re-screening
Re-screening of screening failures is allowed however there must be at least 90 days from screen 
failure date to re-screening. In case of re-screening, a new informed consent and assent must be 
obtained, a new screening number must be allocated and samples and assessments must be 
performed once more according to the screening procedures. For more information see section 10.
8.1.6
Randomisation, visit 3
Subject eligibility must be evaluated according to the inclusion and exclusion criteria. To randomise 
a subject a randomisation session must be performed in IV/WRS. The Tanner stage, HbA1c and 
FPG result from V2 must be entered in IV/WRS (section 11).
The subject must be instructed in handling of the pen and the trial product (section 9) including 
training in injection site (section 5.3) and injection technique. The subject should be instructed to 
perform an air shot before the use of a new pre-filled pen. At all subsequent visits, subjects should 
be trained at the investigators discretion. 
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
44 of 125
The first dose of trial product must be injected by the subject or their LAR at the site. 
For training in recognition of hypoglycaemia, see section 8.5.2 and for instruction in handling of the 
blood glucose (BG) meter including auxiliaries and self-measured blood glucose (SMBG), see 
sections 8.5.2.1.
8.1.7
Dose escalation, visit 4-7
At each visit during the dose escalation period, a measurement of the subject’s plasma glucose level 
by self-monitored blood glucose (section 8.5.2.1) must be performed before instructing the subject 
in dose escalation. For dose escalation see section 5.3.1.
8.1.8
Discontinuation of trial product
See section 6.4 for discontinuation of trial product criteria. For subjects with discontinuation of trial 
product, the investigator must at a minimum aim to:
x
undertake procedures for the end of treatment visit (V19) as soon as possible and
x
schedule a follow up visit (V20) two weeks later.
Depending on when the discontinuation of trial product takes place during the trial:
x
If trial product is discontinued between V3 and V9, the subject should attend V10x (16 weeks 
after V3) and V19x (52 weeks (± 5 days) after V3)
x
If trial product is discontinued between V11 and V19, the subject should attend V19x (52 weeks 
(± 5 days) after V3)
The end-of-trial form must be completed, and final drug accountability must be performed. A 
treatment discontinuation session must be made in the IV/WRS. The case book must be signed.
8.1.9
Withdrawal of informed consent/assent
See section 6.5 for withdrawal criteria. If a subject and/or their LAR withdraw informed 
consent/assent the investigator must aim to undertake procedures similar to those for the end of 
treatment (V19) as soon as possible and the follow up visit (V20) two weeks later. 
The end-of-trial form must be completed, and final drug accountability must be performed even if 
the subject is not able to come to the trial site. A treatment discontinuation session must be made in 
the IV/WRS. The case book must be signed. 
Although a subject is not obliged to give his/her reason(s) for withdrawing from a trial, the 
investigator must make a reasonable effort to ascertain the reason(s), while fully respecting the 
subject’s rights. Where the reasons are obtained, the primary reason for not completing the trial 
must be specified on the end-of-trial form in the CRF.
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
45 of 125
8.1.10
Home visits
Selected site visits as indicated in the flow chart (section 2) can be converted to home visits during 
the open-label period for subjects in the liraglutide placebo group. The selected visits have no 
scheduled drug dispensing, blood sampling, ECG measurement, or physical examination. 
Site staff must bring the following equipment during the home visit: 
x
Calibrated transportable scale
x
Calibrated blood pressure monitor 
x
Measuring tape for measurement of waist and hips
x
Urine sticks (applicable when females of childbearing potential are visited only)
x
Equipment for pulse measurement
x
BG meter for finger prick test (in case subject’s own BG meter is not available)
x
PHQ-9 questionnaire (self-completed by subjects)
x
C-SSRS questionnaire:
–
questionnaire to be completed at home (if home visit is conducted by site staff certified as 
C-SSRS interviewer) or
–
set-up of telephone/video conference interview (if home visit is not conducted by site staff 
certified as C-SSRS interviewer)
Documentation for remaining assessments as per the flowchart (concomitant medication, adverse 
event, review and collection of menstrual information diary information etc.) must be obtained 
during the home visit. The site dietitian must be informed that the site visit is converted to a home 
visit so a telephone/video conference contact to the subject can be established.
8.2
Laboratory assessments
Laboratory assessments are performed by a central laboratory except for assessments for liraglutide 
plasma concentration and anti-liraglutide antibodies that are analysed by special laboratories.
Descriptions of laboratory supplies and procedures for obtaining samples, handling and storage of 
samples including reporting of results and information regarding who will perform the assessments 
are described in a trial-specific laboratory manual provided by the central laboratory.
For a list of blood samples for efficacy assessment, see section 8.4.4 and for a list of blood samples 
for safety assessments, see section 8.5.7. For description of samples for liraglutide plasma 
concentration samples, see section 8.7.1 and for anti-liraglutide antibodies, see section 8.5.8.
No additional central laboratory assessments than those described in the protocol (section 2) are 
allowed.
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
46 of 125
All laboratory samples except for the liraglutide plasma concentration samples and the anti-
liraglutide antibody samples are sent to the central laboratory, analysed and reported to the 
investigator on an ongoing basis. 
Blood samples for liraglutide plasma concentration and anti-liraglutide antibodies are sent for 
storage only at the central laboratory and later sent to the special laboratory for analysis at specific 
time intervals. Furthermore, selected blood samples for anti-liraglutide antibodies are sent from the 
special laboratory to Novo Nordisk A/S for further characterisation, see section 8.5.8
The antibody samples are analysed before LPLV but results will not be reported to the investigator 
as these results will not be used for any clinical evaluation during the course of the trial. The results 
of the antibody samples will only be reported to the investigator upon request at the end of trial. 
Laboratory samples are destroyed on an ongoing basis or at the latest at the completion of the 
clinical trial report, except for antibody samples.
Antibody samples may be retained until approval of the paediatric indication by FDA and/or EMA 
or up to a period of 15 years. The retained antibody samples may be used for further 
characterisation of antibody responses towards drug if required by health authorities or for safety 
reasons, see section 24.2.
8.2.1
Total blood volume for laboratory assessments
Approximately 150 mL blood in total is collected from each subject during the entire trial period. 
Blood collection is performed in accordance with the guidelines in the EU Directive 2001/20/EC39.
Table 8–1
Volume of blood during the trial
Visit number
All visits
V2 V3
V4 V5 V6 V8 V9 V10 V13 V16 V19 V20
Total volume* 7.5 23.0 2.0 2.0 2.0 2.0 2.0 29.0 22.0 22.0 27.0 7.0
147.5 ml
*Precise volume at time of protocol preparation, minor variations may occur
8.2.2
Laboratory reports
The central laboratory provides results to the trial sites in the units preferred by the trial sites while 
the results that are transferred to the trial database will always be in SI units.
Review of laboratory reports must be documented by the investigator (signed and dated) on the 
document. The evaluation of screening results must be dated and signed prior to randomisation (V3) 
and for the subsequent visits on the day of evaluation. For any laboratory result outside the 
reference range, it must be specified whether the value is clinically significant or not. 
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
47 of 125
The laboratory equipment at the central laboratory may provide analyses not requested in the 
protocol but produced automatically in connection with the requested analyses according to 
specifications in the laboratory standard operating procedures. Such data will not be transferred to 
the trial database, but abnormal values must be reported to the investigator. The investigator must 
review all laboratory results for concomitant illnesses and AEs and report these according to this 
protocol.
The laboratory reports and evaluations must be retained as source documentation.
8.3
Subject related information
8.3.1
Demography
The following information must be collected (according to local regulation):
x
Date of birth 
x
Sex
x
Race
x
Ethnicity
8.3.2
Concomitant illness and medical history
A concomitant illness is any illness that is present at the start of the trial (V1) or found as a result 
of a screening procedure. All concomitant illnesses should be reported.
Any change to a concomitant illness should be recorded during the trial. A clinically significant 
worsening of a concomitant illness must be reported as an AE. 
Medical history is a medical event that the subject has experienced in the past. Only relevant and 
significant medical history as judged by the investigator should be reported. The following medical 
history should be reported as a minimum if applicable: cardiovascular diseases, gallstone diseases 
(e.g. cholecystitis), pancreatitis and psychiatric disorders. 
The information collected for concomitant illness and medical history should include diagnosis, 
date of onset and date of resolution or continuation, as applicable.
8.3.2.1
History of psychiatric disorders
Information related to psychiatric disorders (specifically history of depression, suicidal behaviour, 
anxiety, mood disorders, insomnia, or sleep disorders) must in addition to the medical history form 
also be recorded in the eCRF on a separate form.
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Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
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8.3.3
Concomitant medication
A concomitant medication is any medication, other than the trial product, which is taken during 
the trial, including the screening and follow-up periods.
Details of any concomitant medication must be recorded at V2. Changes in concomitant medication 
must be recorded at each visit as they occur. 
The information collected for each concomitant medication includes trade name or generic name, 
indication, start date and stop date or continuation. In addition, dose and route of administration for 
concomitant medication treatment for weight-related co-morbidities (diabetes mellitus, 
hypertension and dyslipidaemia) must be recorded.
If a change is due to an AE, then this must be reported according to section 12. If the change 
influences the subject’s eligibility to continue in the trial, the monitor must be informed.
8.3.4
Tobacco use
Details of tobacco use must be recorded at V2. 
Smoking is defined as smoking at least one cigarette, cigar or pipe daily. The collected information 
should include whether or not the subject smokes or has smoked. 
If the subject smokes or has smoked, record approximately when the subject started smoking and, if 
applicable, when the subject stopped smoking.
8.4
Assessments for efficacy
The timing of the assessments are outlined in the flow chart (section 2).
8.4.1
Body measurements
8.4.1.1
Body weight
Body weight must be measured to the nearest 0.1 kg or 0.1 pounds. Fasting body weight must be 
measured at the fasting visits (section 8.1.2). If the weight is not measured fasting at fasting visits, 
the subject must be called in for a new visit within the visit window to have the fasting weight 
measured. At the remaining visits the measurement is performed in a non-fasting state. 
The same scale should be used throughout the trial. The scale must be calibrated according to the 
directions for use and as a minimum once a year.
Body weight should be measured without shoes and only wearing light clothing and the subject 
should have an empty bladder.
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Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
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UTN: U1111-1162-7884
Status:
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Body weight measured at V2 is used for the calculation of BMI to evaluate inclusion criteria. Body 
weight measured at V3 is used as baseline for assessment of change in body weight.
BMI is calculated in the eCRF.
8.4.1.2
Hip and waist circumference
The hip circumference is defined as the widest circumference around the buttocks.
The waist circumference is defined as the minimal abdominal circumference located midway 
between the lower rib margin and the iliac crest. 
Three consecutive measurements each of hip and waist circumference must be performed. They 
should be measured in the horizontal plane and rounded up or down to the nearest 0.5 cm or 0.2 
inches using a non-stretchable measuring tape.
The circumference should be measured when the subject is in a standing position wearing light 
clothing. At fasting visits the subject should be measured with an empty bladder. The subject should 
be standing, feet together with arms down their side and waist and hip accessible. The tape should 
touch the skin but not compress soft tissue and twists in the tape should be avoided. The subject 
should be asked to breathe normally and the measurement should be taken when the subject is 
breathing out gently.
The measurements should be performed in the following order: waist, hip, waist, hip, waist and hip. 
All three measurements must be recorded in the eCRF.
8.4.2
Hyperphagia questionnaire
Hyperphagia, a characteristic of patients with PWS, will be assessed using the hyperphagia 
questionnaire. The hyperphagia questionnaire has been developed for use in adults and children as 
young as 4 years of age with PWS, and has been recommended for use in this population by the 
2014 2nd International Conference on Hyperphagia. 
Hyperphagia is a significant source of stress for patients with PWS and their families, and can lead 
to complications including choking, and in extreme cases gastric rupture.
Liraglutide may influence hyperphagia through regulation of appetite. Liraglutide is known to 
increase feelings of fullness and satiety, while lowering feelings of hunger and prospective food 
consumption40,41)
The subject’s LAR must fill out the PWS hyperphagia questionnaire according to flow chart (2).
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
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UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
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8.4.3
Systolic and diastolic blood pressure
For blood pressure at V2, three measurements must be performed. The mean value is calculated by 
the eCRF and must be used to evaluate eligibility of the subject (exclusion criterion 19 and 
Appendix B). For the subsequent visits, only one measurement needs to be performed.
The method for measuring systolic and diastolic blood pressure should follow the standard clinical 
practice at site, but as a minimum, the following guideline must be adhered to: 
x
Caffeine, smoking and exercise at least 30 minutes prior to measuring the blood pressure should 
be avoided 
x
Blood pressure should be measured in a sitting position, with the legs uncrossed, the back and 
arms supported 
x
The subject should be sitting for at least 5 minutes before the first measurement is taken
x
The subject should not talk during the measurement
x
The same arm and cuff size should be used for blood pressure measurements at subsequent 
visits
Any “abnormal, clinically significant” findings at screening must be recorded as medical 
history/concomitant illness in the eCRF and in the subject’s medical record.
Any clinically significant worsening or new clinically significant findings after V2 must be reported
as an AE in accordance with section 12.
If the investigator suspects white coat hypertension at V2, a re-assessment (three measurements) of 
the systolic and diastolic blood pressure is allowed, as described in exclusion criterion 19.
8.4.4
Blood samples for efficacy assessments
Any “abnormal, clinically significant” findings at V2 must be recorded as medical 
history/concomitant illness in the eCRF. The following blood samples must be drawn (for 
frequency see section 2):
Lipids (fasting):
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
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x
Total cholesterol
x
LDL-cholesterol
x
VLDL-cholesterol
x
HDL-cholesterol
x
Triglycerides
x
Free fatty acids
x
Non-HDL cholesterol
Biochemistry:
x
High sensitivity C reactive protein (hsCRP)
Glucose metabolism:
x
HbA1c
x
FPG
x
Fasting insulin
x
Fasting C-peptide
8.5
Assessments for safety
The timing of the assessments are outlined in the flow chart (section 2).
8.5.1
Height
Height should be measured (centimetres or inches, one decimal) without shoes as two individual 
measurements performed by a single observer using identical technique with a Harpenden or other 
wall mounted stadiometer. The subject should be repositioned between the two measurements.
8.5.2
Hypoglycaemic episodes
At V3, all subjects and their LAR must be instructed in symptom recognition and handling of 
hypoglycaemia.
Blood glucose should always be measured and recorded when a hypoglycaemic episode is 
suspected. 
All plasma glucose values:
x
≤ 3.9 mmol/L (70 mg/dL) or 
x
> 3.9 mmol/L (70 mg/dL) when they occur in conjunction with hypoglycaemic symptoms 
should be recorded by the subject or their LAR. These must be transcribed into the eCRF 
(hypoglycaemic episode form) throughout the trial from visit 3 to visit 18. 
The record should include the following information:
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
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x
Date and time of hypoglycaemic episode 
x
The plasma glucose level before treating the episode (if available) 
x
Whether the episode was symptomatic 
x
Whether the subject was able to treat him/herself 
x
Date and time of last trial product administration prior to episode 
x
Type and dose of last trial product administration prior to episode 
x
Date and time of last main meal prior to episode
x
Whether the episode occurred in relation to physical activity
x
Any sign of fever or other disease 
x
Whether the subject was asleep when the episode occurred
–
If yes, whether the symptoms of the episode woke up the subject
The answer to the question: "Was subject able to treat him/herself?" must be answered "No" for an 
episode requiring assistance of another person to actively administer carbohydrate, glucagon, or 
take other corrective actions. Plasma glucose concentrations may not be available during an event, 
but neurological recovery following the return of plasma glucose to normal is considered sufficient 
evidence that the event was induced by a low plasma glucose concentration10.
Oral carbohydrates should not be given if the subject is unconscious.
If the question "Was subject able to treat him/herself?" is answered "No", the following information 
should be recorded:
x
Who assisted in the treatment of the hypoglycaemic episode (i.e. family/friend/co-worker or 
similar, paramedic, doctor or other, please specify)
x
Where the treatment was administered (i.e. at home/at friends/at work or similar, in an 
ambulance, emergency room/hospital or other, please specify)
x
Type of treatment provided by other person (i.e. oral carbohydrates, glucagon, IV glucose or 
other, please specify)
x
Were symptoms alleviated after administration of treatment?
x
Factors contributing to the episode (i.e. physical activity, missed meal, diet changed, medication 
error (i.e. overdose, mix-up between products), miscalculation of insulin dose, other factors not 
listed, please specify or none)
x
Did the subject experience seizure?
x
Was the subject unconscious/comatose?
x
Did the subject experience any of the following symptoms11?
–
Autonomic: sweating, trembling, hunger or palpitations
–
Neuroglycopenic: confusion, drowsiness, speech difficulty, visual disturbances, odd 
behaviour, impaired balance or incoordination
–
General malaise: headache or malaise
x
Did the subject experience other symptoms? Please specify
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
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x
Description of the episode, if applicable 
A hypoglycaemic episode form must be filled in for each hypoglycaemic episode. If the 
hypoglycaemic episode fulfils the criteria for an SAE then an AE form and a safety information 
form (SIF) must also be filled in, see section 12.
8.5.2.1
Self-measured blood glucose (SMBG)
At V3, subjects are provided with a blood glucose (BG) meter including BG meter auxiliaries and 
instructions for use. The subjects or their LAR will be instructed in how to use and calibrate the 
device, according to the manufacturer’s instructions. Instruction will be repeated as necessary 
during the trial.
The BG meters use test strips calibrated to plasma values. Therefore, all measurements performed 
with capillary blood are automatically calibrated to plasma equivalent glucose values, which will be 
shown on the display.
At each visit, the subject or subject’s LAR must demonstrate how to use the BG meter device by 
measuring the subject’s blood glucose value, preferably by using be the subject’s own BG meter. 
The SMBG value must be documented in the subject’s medical record.
During dose escalation the SMBG measurement must be done before instructing the subject in dose 
escalation (section 8.1.7). In case the value fulfils the criteria of a hypoglycaemic episode this must 
be recorded in the eCRF (section 8.5.2).
Subjects or their LAR must be instructed to do a SMBG in between visits in case a hypoglycaemic 
episode is suspected (section 8.5.2). The subjects must be instructed to contact the investigator in 
case of low SMBGs.
Subjects or their LAR should be instructed in how to record the results of the SMBGs in the diaries. 
The record of each SMBG should include date, time and value (section 8.7.3.2). All hypoglycaemic 
episodes from the diary must be transcribed into the eCRF.   
8.5.3
Pulse
Pulse (beats per minute) must be recorded after resting for 5 minutes in a sitting position.
Any “abnormal, clinically significant” findings at screening must be recorded as medical 
history/concomitant illness in the eCRF and in the subject’s medical record.
Any clinically significant worsening or new clinically significant findings after V2 must be reported 
as an AE in accordance with section 12.
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
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8.5.4
Electrocardiogram – 12 lead
A 12-lead ECG must be performed and interpreted locally by the investigator. ECG print-outs must 
be evaluated, signed and dated by the investigator.
The evaluation of ECGs must follow the categories:
x
Normal
x
Abnormal, clinically significant yes/no
ECG performed for any reason unrelated to this trial within 12 weeks prior to V2 is acceptable 
provided no clinical symptoms suggestive of cardiac disease have been identified or occurred prior 
to enrolment. If an ECG is performed before the subject has signed the informed consent form, it 
must be documented in the subject’s medical records that the reason for performing the procedure is 
not related to this trial. It is allowed to perform the screening ECG after V2 but prior to V3. 
Any “abnormal, clinically significant” findings at screening must be recorded as medical 
history/concomitant illness in the eCRF and in the subject’s medical record.
ECGs performed within 30 days prior to the subsequent visits where an ECG is scheduled is 
acceptable (section 2).
Any clinically significant worsening or new clinically significant findings after V2 must be reported 
as an AE in accordance with section 12.
8.5.5
Pregnancy tests
All females of childbearing potential must have pregnancy tests performed as described below. For 
documentation of menstrual periods see section 8.7.3.3.
8.5.5.1
Blood samples
At V2 and V19, a serum pregnancy test must be performed.
If a female subject becomes of childbearing potential during the trial, a serum pregnancy test must 
be performed as soon as possible or at the latest at the next visit. 
8.5.5.2
Urine-sticks 
At V3-V18, urine-stick pregnancy tests will be performed at the site if: 
x
Pregnancy is suspected 
x
A menstrual period is missed (unless this is a part of the mode of action of the contraceptive 
method) 
x
According to local requirements
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
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The result of the urine-stick pregnancy test must be documented in the medical record.
8.5.5.3
Recording of menstrual periods
Documentation of the first date of the last menstrual period (if applicable) before V2 must be 
recorded in subject’s medical record. 
First date of all menstrual periods since last visit must be collected from all female subjects (section 
8.7.3.3) and recorded in the eCRF.
8.5.6
Physical examination
Physical examination must include:
x
General appearance 
x
Head, ears, eyes, nose, throat, neck
x
Respiratory system
x
Cardiovascular system
x
Gastrointestinal system including mouth
x
Musculoskeletal system
x
Central and peripheral nervous system
x
Skin
x
Thyroid gland
x
Lymph node palpation
Any “abnormal, clinically significant” findings at screening V2 must be recorded as medical 
history/concomitant illness in the eCRF and in the subject’s medical record.
Any clinically significant worsening or new clinically significant findings after V2 must be reported 
as an AE in accordance with section 12.
8.5.7
Blood samples for safety assessments
Any “abnormal, clinically significant” findings at V2 must be recorded as medical 
history/concomitant illness in the eCRF. The following blood samples must be drawn (for 
frequency see section 2):
Biochemistry:
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
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x
Creatinine
x
Creatine kinase (CPK)
x
Urea
x
Albumin
x
Bilirubin, total
x
Alanine aminotransferase (ALT)
x
Aspartate aminotransferase (AST)
x
Alkaline phosphatase
x
Sodium
x
Potassium
x
Calcium, total
x
Calcium, albumin corrected
x
Amylase
x
Lipase
Haematology:
x
Haemoglobin
x
Haematocrit
x
Thrombocytes
x
Erythrocytes
x
Leucocytes
x
Differential count: 
–
basophils
–
eosinophils 
–
lymphocyte 
–
monocytes 
–
neutrophils
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
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Hormones:
x
Calcitonin (refer to Appendix C for actions taken if calcitonin is ≥ 20 ng/L)
x
Prolactin
x
Follicle stimulating hormone (FSH)
x
Estradiol (females)
x
Luteinizing hormone (LH)
x
Testosterone (males)
x
Thyroid stimulating hormone (TSH)
x
Free T4
x
Adrenocorticotropic hormone (ACTH)
x
Cortisol
x
Dehydroepiandrosterone sulfate (DHEAS)
x
Carcinoembryonic antigen (CEA)
x
Insulin-like growth factor-1 (IGF-1)
Pregnancy test:
Beta-human chorionic gonadotropin (beta-hCG) 
8.5.8
Anti-liraglutide antibodies
Blood samples for determination of anti-liraglutide antibodies are collected from all subjects at 
randomisation (V3) and at the end of the 16-week double-blind period, see section 2. Only samples 
from subjects treated with liraglutide are analysed for anti-liraglutide antibody development. 
Depending on the number of subjects in the liraglutide treatment arm, baseline (randomisation V3) 
from subjects in the placebo group may be analysed for the purpose of determination of the assay 
cut points. At V19 and V20 antibody samples are collected and analysed from subjects treated with 
liraglutide only.
Blood samples for the determination of anti-liraglutide antibody must be drawn in a fasting state 
and prior to administrating trial product (see section 2). The anti-liraglutide antibody sample at V20 
is to be taken minimum 2 hours after the last meal.
Samples are analysed by the special laboratory for anti-liraglutide antibody formation including 
cross reactivity to endogenous GLP-1. Furthermore samples from the follow up visit (V20) that are 
found to be positive for anti-liraglutide antibodies will be analysed for neutralising effect against 
liraglutide. Anti-liraglutide antibody positive samples from V20 that are also found to cross react 
with endogenous GLP-1 will in addition be analysed for neutralising effect against endogenous 
GLP-1. The neutralising antibody analyses will be performed by Novo Nordisk A/S. Baseline 
antibody samples collected at the randomisation visit will be included in the neutralising antibody 
analyses for assessment of assay cut points. See further information in sections 8.2 and 24.2.
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Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
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UTN: U1111-1162-7884
Status:
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8.5.9
Tanner staging
Pubertal development must be assessed by Tanner staging in accordance with stages 1-542
according to flow chart 2. The assessments must be conducted by site staff trained in pubertal 
assessments. Assessment of testicular volume (by orchidometer) for boys must be included.
Tanner staging can be performed up to 2 weeks before V10 and V19. 
Evidence of accelerated pubertal development as judged by the investigator at V2 must be recorded 
as medical history/concomitant illness in the eCRF and in the subject’s medical record.
Acceleration of pubertal development after V3 as judged by the investigator must be reported as an 
AE in accordance with section 12.
Tanner staging is not required once the subject reaches the Tanner stage 5, as judged by the 
investigator.
8.5.10
Mental health questionnaires (part A only)
The mental health of subjects will be assessed by the following questionnaires to meet the 
regulatory requirements (section 2):
x
Columbia Suicide Severity Rating Scale (C-SSRS) Pediatric/Cognitively Impaired 
questionnaire43
x
Patient Health Questionnaire 9 (PHQ-9) for children and adolescents44. The questionnaires will 
be available in a linguistically validated paper version.
Drugs for weight loss are one of the non-psychiatric drugs for which treatment-emergent suicidal 
ideation and behaviour as well as depression must be surveyed. Even though liraglutide has not 
been associated with suicidality or depression the two mental health questionnaires, C-SSRS and 
PHQ-9 have been included in part A of the present trial. 
The questionnaires must be filled in and data must be entered into the eCRF. In case questionnaires 
cannot be completed because of mental incapacity, this must be documented in the subject’s 
medical record and the eCRF. 
8.5.10.1
C-SSRS
The investigator or delegated staff must complete the C-SSRS based on an interview with the 
subject. The investigator or delegated staff interviewing the subject must complete an online 
interviewer training prior to first interview.
The questionnaires completed at V2 must be used to exclude subjects from the trial with any 
suicidal ideation of type 4 (active suicidal ideation with some intent to act, without specific plan) or 
type 5 (active suicidal ideation with specific plan and intent). 
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Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
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Trial ID: NN8022-4179
Version:
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UTN: U1111-1162-7884
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8.5.10.2
PHQ-9
The PHQ-9 should be completed by the subject without interruption. 
The questionnaires completed at V2 must be used to exclude subjects with a PHQ-9 score ≥ 15 
from the trial.
The investigator or delegated staff must review questionnaires for completeness and adverse events 
immediately following administration. The review must be documented in the subject’s medical 
record. If clarification of entries or discrepancies in the questionnaire is needed, the subject must be 
questioned and a conclusion made in the subject’s medical record. Care must be taken not to bias 
the subject.
8.5.10.3
Referral to mental health professional
If a subject has a PHQ-9 score from 10-14 both inclusive on any questionnaire the subject should be 
referred to a mental health professional (MHP) if judged relevant by the investigator. If referral is 
not deemed relevant, this must be documented in the subject's medical record.
A subject must be referred to a MHP if the subject has:
x
a PHQ-9 score ≥ 15 or
x
any suicidal behaviour or
x
any suicidal ideation of type 4 or type 5 on any C-SSRS assessment
x
if the opinion of the investigator it is necessary for the safety of the subject
If one or more of the above referral criteria are met the investigator should explain to the subject 
and/or the subject’s LAR why the referral and psychiatric evaluation by a MHP is needed. If the 
subject and/or the subject’s LAR refuses to be referred to a MHP, the decision should be 
documented in the medical record and the investigator must assess, if it is safe for the subject to 
continue in the trial, or if the subject should be discontinued from trial product (section 6.4 and 
8.1.8).
If a subject’s psychiatric disorder can be adequately treated with psycho- and/or pharmacotherapy, 
then the subject, at the discretion of the investigator (in agreement with the MHP), may continue in 
the trial. Otherwise, the trial product must be discontinued (section 6.4 and 8.1.8).
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
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8.6
Additional safety assessments
8.6.1
In case of elevated calcitonin
If any calcitonin value post randomisation is above upper normal limit a repeated measurement of 
calcitonin should be taken within 4 weeks. All cases ≥ 20 ng/L will be reviewed by an external 
expert who will provide recommendations to the investigator whether further evaluation is 
indicated. For details, refer to appendix C.
8.6.2
Suspicion of acute pancreatitis
In case of acute, severe persistent abdominal pain leading to a suspicion of acute pancreatitis, the 
trial product should promptly be interrupted until the diagnosis of pancreatitis can be excluded. 
Appropriate additional examinations must be performed. Measurement of serum amylase and lipase 
activity levels must be done locally. If acute pancreatitis is ruled out, trial product should be re-
initiated on same dose as when trial product was interrupted. 
Pancreatitis is confirmed if as a minimum 2 of 3 criteria are met: 
x
Severe acute abdominal pain
x
Serum amylase and/or lipase >3× upper normal limit
x
Characteristic findings on relevant imaging e.g. computerised axial tomography/magnetic 
resonance imaging/ultrasound
If diagnosis of pancreatitis is confirmed the trial product must be discontinued (sections 6.4 and 
8.6.3.3) and appropriate treatment(s) and careful monitoring of the subject should be initiated.
8.6.3
Adverse events requiring specific event forms in the eCRF
For some AEs the investigator must complete a specific event form in the eCRF in addition to the 
AE form. The AEs that require specific event forms are: 
x
Gallstone disease
x
Neoplasms
x
Pancreatitis
In case any of these events fulfil the criteria for a serious adverse event, please report accordingly 
(section 12.1).
8.6.3.1
Gallstone disease
If an event of acute gallstone disease or clinical suspicion of this is observed during the trial, this 
must be recorded as an AE and on a specific gallstone event form in the eCRF. The following 
information should be obtained, if available as part of standard of care: 
x
Signs and symptoms of acute gallstone disease
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Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
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x
Specific laboratory test supporting a diagnosis of gallstone disease:
–
White blood cell count (WBC)
–
C-reactive protein (CRP)
–
Direct, indirect and total bilirubin
–
ALT and AST
–
Alkaline Phosphatase (ALP)
–
Amylase
–
Lipase
x
Imaging performed and consistency with gallstone disease
x
Treatment given for the condition
x
Relevant risk factors for gallstone disease including:
–
History of gallstones
–
Family history of gallstones
–
Relevant surgery
8.6.3.2
Neoplasms
All events of benign, pre-malignant/carcinoma in-situ and malignant neoplasms must be reported 
during the trial. This must be recorded as an AE and on a specific neoplasm event form in the 
eCRF. The following information should be obtained if available as part of standard of care: 
x
Type of neoplasm
x
Symptoms leading to identification of event
x
Diagnostic imaging
x
Pathological examination results
x
Treatment for the event
x
Participation in screening programs
x
Risk factors associated to the event
x
New diagnosis or recurrence/relapse of the neoplasm
8.6.3.3
Pancreatitis
If an event of pancreatitis is observed during the trial, this must be recorded as an AE and on a 
specific pancreatitis event form in the eCRF. The following information should be obtained if 
available as part of standard of care: 
x
Signs and symptoms of pancreatitis
x
Specific laboratory test supporting a diagnosis of pancreatitis:
–
Amylase
–
Lipase
–
ALT and AST
–
Bilirubin
–
Alkaline Phosphatase
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
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x
Imaging performed and consistency with pancreatic disease
x
Treatment and complications to the event
x
Relevant risk factors for pancreatic disease including:
–
History of gallstones
–
History of pancreatitis
–
Family history of pancreatitis
–
Trauma
8.7
Other assessments
8.7.1
Plasma concentration of liraglutide for pharmacokinetics
Blood samples for assessment of liraglutide plasma concentration are drawn from all subjects 
during the 16-week double-blind trial period as per section 2.
Subjects and subjects’ LAR must be instructed to withhold their trial product dose in the morning 
until blood sampling is performed on the visit.
The subjects and subjects’ LAR must be instructed to complete the dosing diary for liraglutide 
plasma concentration assessment (section 2) and the dose, date and exact time for sampling the 
blood must be recorded in the eCRF. 
The blood sample taken at V20 for liraglutide plasma concentration assessment from subjects 
treated with liraglutide only is not part of the pharmacokinetic/pharmacodynamic modelling plan 
(section 17.5). The purpose of this assessment is to preclude any false negative antibody results. 
Hence recordings in the subject’s dosing diary and eCRF are not requested for this sample. 
Quality controlled data must be available for review by Development Bioanalysis prior to database 
lock (DBL).
8.7.2
Dietary and physical activity counselling
8.7.2.1
Dietary counselling 
Subjects and subjects’ LAR must receive individualised dietary counselling with the goal of 
obtaining a weight loss. The counselling must be performed by a certified dietitian according to 
local standard. Individuals with Prader-Willi Syndrome have a different body composition with less 
muscle mass and a higher percentage of body fat even if they are at a normal body weight. As a 
result, their caloric needs are significantly lower and caloric intake should be restricted.
If a BMI corresponding to < 25 kg/m2 for adults by international cut-off points45 is reached subjects 
should be assigned a maintenance diet. 
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
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Dietary counselling can be done in person or by phone/video conference according to the flowchart 
and must be documented in subject’s medical record.
Dietary counselling should preferably take place within the visit window for the relevant visit.
Dietary compliance must be evaluated at every visit by the dietitian, using a numerical rating scale 
(NRS), and results must be provided to the investigator. The investigator or delegated staff must 
translate the NRS into a number and record the data into the eCRF.
8.7.2.2
Counselling in physical activity
At every site, there must be a qualified person (site staff trained in physical activity counselling) to 
provide instructions and advise on physical activity. An increase in physical activity is encouraged 
and reinforced at every visit.
8.7.3
Subject diary
Subjects will be provided with a paper diary to be completed at home. Only the subjects and/or the 
LAR must enter data in the diary. Subjects will be instructed by the investigator in when and how to 
complete the diary. It is important to explain to the subjects the necessity of accurate diary 
recording. 
Review of diaries must be documented by the investigator, either on the documents and/or in the 
subject’s medical record. If clarification of entries or discrepancies in the diary is needed, the 
subject must be questioned and a conclusion made in the subject’s medical record. Care must be 
taken not to bias the subject and it is important to explain to the subjects the necessity of accurate 
diary recording.
All data from the diary must be transcribed into the eCRF.
The diary will include three different sections as specified in sections 8.7.3.1, 8.7.3.2 and 8.7.3.3
8.7.3.1
Dosing diary
Dosing diary should be completed by the subject on the last three days before a visit including a 
blood sampling for liraglutide plasma concentration (section 8.7.1 and section 2).
The last 3 doses of liraglutide must be recorded with:
x
Dose 
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
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x
Date
x
Exact time
8.7.3.2
Hypoglycaemic episode diary
The hypoglycaemic episode diary should be completed if the subject recognises a hypoglycaemic 
episode, i.e. a hypoglycaemic form for each episode (section 8.5.2)
8.7.3.3
Menstrual period diary
The menstrual period diary forms should be completed by all female subjects of childbearing 
potential during the trial. The first day of all menstrual periods, if applicable, should be recorded in 
the diary.
8.8
Subject compliance
To ensure subject trial compliance, the investigator and/or delegated staff should remind the 
subjects to follow the trial procedures and requirements throughout the trial. If a subject is found to 
be non-compliant, the investigator and/or delegated staff should remind the subject of the 
importance of following the instructions given including taking the trial products as prescribed.
Subject treatment compliance is assessed by monitoring of drug accountability. Prior to visits where 
drug accountability is performed, the subject should be asked to return all used, partly used and 
unused trial product. The investigator must assess the amount of trial product returned compared to 
what was dispensed at the last dispensing visit and, in case of discrepancies, question the subject 
(section 9.4)
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
65 of 125
9
Trial supplies
Trial supplies comprise trial products and auxiliary supplies. Additional details regarding trial 
supplies can be found in the Trial Materials Manual (TMM). 
Trial products must not be dispensed to any person not included in the trial. 
Liraglutide or liraglutide placebo must not be used, if it does not appear clear and colourless or 
almost colourless.
9.1
Trial products
The following trial products will be provided by Novo Nordisk A/S, Denmark:
Table 9–1
Trial products
Trial product
Investigational medicinal 
product (IMP)
Strength
Dosage form
Route of 
administration
Delivery device
Liraglutide 6.0 mg/mL
3 mL cartridge
6.0 mg/mL
Solution for 
injection
Subcutaneous 
injection (s.c.)
3 mL FlexPen®
Liraglutide placebo
3 ml cartridge
N/A
Liraglutide and liraglutide placebo are visually identical.
9.2
Labelling
The trial products will be labelled in accordance with Annex 1346, local regulations and trial 
requirements.
Each trial site will be supplied with sufficient trial products for the trial on an on-going basis 
controlled by the IV/WRS. Dispensing unit numbers (DUNs) will be distributed to the trial sites 
according to enrolment and randomisation. 
The investigator must document that direction for use is given to the subject orally and in writing at 
the first dispensing visit (V3). At all subsequent drug dispensing visits, directions for use should be 
handed out to subjects, if needed. 
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
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9.3
Storage 
Table 9–2
Storage
Trial product
Storage conditions
(not-in-use)
In-use conditions
In-use time*
Liraglutide 6.0mg/mL 
Store in a refrigerator  
between 2°C to 8°C 
(36°F to 46°F)
Protect from light
Do not freeze
At temperatures 
below 30°C or in a 
refrigerator between 
2°C to 8°C
US: At room 
temperature (59°F to 
86°F) or in a 
refrigerator (36°F to 
46°F)
Protect from light
Do not freeze
Use within one 
month
US: Use within 
30 days
Liraglutide placebo
* In-use time starts when first dose is taken or used as spare pen. 
The investigator must ensure the availability of proper storage conditions, and also record and 
evaluate the temperature. The investigator must inform Novo Nordisk immediately if any trial 
product has been stored outside specified conditions (e.g. outside temperature range).
Trial product that has been stored improperly must not be dispensed to any subject before it has 
been evaluated and approved for further use by Novo Nordisk. The investigator must take 
appropriate action to ensure correct storage.
9.4
Drug accountability and destruction
Drug accountability is the responsibility of the investigator.
Subjects must be instructed to return all used, partly used and unused trial products including empty 
packaging material at each dispensing visit.
Returned trial product (used/partly used or unused including empty packaging material) can be 
stored at room temperature and must be stored separately from  non-allocated trial product.
Drug accountability is performed by using the IV/WRS drug accountability module. Only dispensed 
DUNs (= Dispensing Unit Numbers) returned by the subject (used/partly used or unused) are 
accounted for.
Destruction will be done according to local procedures after accountability is finalised and verified 
by the monitor. Destruction of products must be documented.
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
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9.5
Auxiliary supplies
The following will be provided by Novo Nordisk in accordance with the TMM:
x
Direction for Use for the FlexPen®
x
Needles for the device with a maximum needle length of 8 mm
x
Blood glucose meters (BG meters) and BG-meter auxiliaries
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
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10  Interactive voice/web response system
A trial-specific IV/WRS will be set up which can be accessed at any time via the internet or 
telephone. Access to the IV/WRS must be restricted to and controlled by authorised persons. 
IV/WRS is used for:
x
Screening
x
Screening failure
x
Randomisation
x
Medication arrival
x
Dispensing
x
Treatment discontinuation
x
Completion
x
Code break
x
Drug accountability
x
Data change
IV/WRS user manuals will be provided to each trial site.
DUNs will be allocated using IV/WRS. It is important to dispense the exact allocated DUNs to a 
subject. The subject’s treatment allocation will be revealed using the IV/WRS at V10.
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
69 of 125
11 Randomisation procedure and breaking of blinded codes
Randomisation will be stratified according to pubertal status and by presence/absence of 
dysglycaemia. Stratification will be controlled by the IV/WRS. The stratification factors are:
Pubertal status:
x
Tanner below 2 (defined as Tanner stage 1 with or without premature adrenarche) (part B only)
x
Tanner 2 or 3 (part A only)
x
Tanner 4 or 5 (part A only)
Glycaemic status:
x
dysglycaemia yes
x
dysglycaemia no
Dysglycaemia is defined as pre-diabetes with FPG 5.6 – 6.9 mmol/L (both inclusive) (100 - 125
mg/dL) (both inclusive) and/or HbA1c 5.7 – 6.4 % (both inclusive). The HbA1c and FPG results 
from V2 must be used.
At randomisation, the subjects will be randomised to one of two parallel treatment groups: 
liraglutide or placebo. The randomisation will be carried out in a 2:1 manner using the IV/WRS. 
The trial is a double-blind trial for the first 16 weeks followed by a 36 weeks open-label treatment 
period. Only subjects treated with liraglutide will receive trial treatment in the 36-weeks open-label 
treatment period. The subject’s treatment allocation will be un-blinded on an on-going basis after 
the double blind period at week 16 (V10).
11.1
Breaking of blinded codes
The IV/WRS will notify Novo Nordisk (monitor and the Global Safety department) immediately 
after the code is broken.
The code for a particular subject may be broken in a medical emergency if knowing the actual 
treatment would influence the treatment of the subject. Whenever a code is broken the person 
breaking the code must print the Code Break Confirmation Notification generated by the IV/WRS, 
record the reason, and sign and date the document.
When the code is broken, the treatment allocation will be accessible to the investigator and the 
Novo Nordisk Global Safety department. If IV/WRS is not accessible at the time of code break the 
IV/WRS helpdesk should be contacted. Contact details are listed in Attachment I.
If the code has been broken the subject is allowed to continue in the trial. If the subject must be 
withdrawn from the trial, a withdrawal session must be completed in IV/WRS.
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
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11.2
Laboratory access to blinded data
The special laboratories analysing the samples for anti-liraglutide antibodies and concentration of 
liraglutide will be provided with a randomisation list. This procedure will be described in a blinding 
plan.
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
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12 Adverse events, technical complaints and pregnancies
12.1
Definitions
Adverse event 
An adverse event (AE) is any untoward medical occurrence in a subject administered a product, and 
which does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom or disease temporally associated with the use of a product, whether or not
considered related to the product. 
An AE includes:
x
A clinically significant worsening of a concomitant illness.
x
A clinical laboratory adverse event (CLAE): a clinical laboratory abnormality which is 
clinically significant, i.e. an abnormality that suggests a disease and/or organ toxicity and is of a 
severity that requires active management. Active management includes active treatment or 
further investigations, for example change of medicine dose or more frequent follow-up due to 
the abnormality.
The following should not be reported as AEs:
x
Pre-existing conditions, including those found as a result of screening procedures (pre-existing 
conditions should be reported as medical history or concomitant illness).
x
Pre-planned procedures unless the condition for which the procedure was planned has worsened 
from the first trial related activity after the subject has signed the informed consent.
The following three definitions are used when assessing an AE:
x
Severity 
–
Mild - no or transient symptoms, no interference with the subject's daily activities.
–
Moderate - marked symptoms, moderate interference with the subject's daily activities.
–
Severe - considerable interference with the subject's daily activities; unacceptable.
x
Causality 
Relationship between an AE and the relevant trial product(s): 
–
Probable - Good reason and sufficient documentation to assume a causal relationship.
–
Possible - A causal relationship is conceivable and cannot be dismissed.
–
Unlikely - The event is most likely related to aetiology other than the trial product.
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
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x
Final outcome
–
Recovered/resolved - The subject has fully recovered, or by medical or surgical treatment 
the condition has returned to the level observed at the first trial-related activity after the 
subject signed the informed consent.
–
Recovering/resolving - The condition is improving and the subject is expected to recover 
from the event. This term is only applicable if the subject has completed the trial or has died 
from another AE.
–
Recovered/resolved with sequelae - The subject has recovered from the condition, but 
with lasting effect due to a disease, injury, treatment or procedure. If a sequela meets an 
SAE criterion, the AE must be reported as an SAE.
–
Not recovered/not resolved - The condition of the subject has not improved and the 
symptoms are unchanged, or the outcome is not known.
–
Fatal - This term is only applicable if the subject died from a condition related to the 
reported AE. Outcomes of other reported AEs in a subject before he/she died should be 
assessed as "recovered/resolved", "recovering/resolving", "recovered/resolved with 
sequelae" or "not recovered/not resolved". An AE with fatal outcome must be reported as an 
SAE.
–
Unknown - This term is only applicable if the subject is lost to follow-up.
Serious adverse event
A serious adverse event (SAE) is an experience that at any dose results in any of the following:
x
Death.
x
A life-threateninga experience.
x
In-patient hospitalisationb or prolongation of existing hospitalisation.
x
A persistent or significant disability or incapacityc.
x
A congenital anomaly or birth defect.
x
Important medical events that may not result in death, be life threateninga or require 
hospitalisationb may be considered an SAE when - based on appropriate medical judgement -
they may jeopardise the subject and may require medical or surgical intervention to prevent one 
of the outcomes listed in the definition of SAEd.
a.
The term "life threatening" in the definition of SAE refers to an event in which the subject was 
at risk of death at the time of the event. It does not refer to an event which hypothetically might 
have caused death if it was more severe.
b.
The term "hospitalisation" is used when a subject: 
–
Is admitted to a hospital or in-patient, irrespective of the duration of physical stay, or 
–
Stays at the hospital for treatment or observation for more than 24 hours
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
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Medical judgement must always be exercised, and when in doubt, the hospital contact should be 
regarded as a hospitalisation. Hospitalisations for administrative, trial related and social 
purposes do not constitute AEs and should therefore not be reported as AEs or SAEs. Hospital 
admissions for surgical procedures, planned before trial inclusion, are not considered AEs or 
SAEs.
c.
A substantial disruption of a subject's ability to conduct normal life functions (e.g. following the 
event or clinical investigation the subject has significant, persistent or permanent change, 
impairment, damage or disruption in his/her body function or structure, physical activity and/or 
quality of life).
d.
For example intensive treatment in an emergency room or at home of allergic bronchospasm, 
blood dyscrasiasis or convulsions that do not result in hospitalisation, or development of drug 
dependency or drug abuse.
The following AEs must always be reported as an SAE using the important medical event criterion 
if no other seriousness criteria are applicable:
x
suspicion of transmission of infectious agents via the trial product
x
risk of liver injury defined as alanine aminotransferase (ALT) or aspartate aminotransferase 
(AST) >3 x ULN and total bilirubin >2 x ULN, where no alternative aetiology exists (Hy's 
law).
Non-serious adverse event
A non-serious AE is any AE which does not fulfil the definition of an SAE.
Medical event of special interest
A medical event of special interest (MESI) is an event which, in the evaluation of safety, has a 
special focus. A MESI is an AE (SAE or non-serious AE) which fulfils one or more of the below
defined MESI criteria.
1. Medication errors concerning trial products:
–
Administration of wrong drug or use of wrong device. 
–
Note: Use of wrong DUN is not considered a medication error.
–
Wrong route of administration, such as intramuscular instead of subcutaneous.
–
Administration of an overdose with the intention to cause harm (e.g. suicide attempt).
–
Accidental administration of a lower or higher dose than intended. These are doses lower or 
higher than 0.6, 1.2, 1.8, 2.4 and 3.0 mg respectively for subjects in part A and part B 
(children with a body weight ≥ 45 kg) and doses lower than 0.3, 0.6, 1.2, 1.8 and 2.4 mg 
respectively for subjects in part B (children with a body weight < 45 kg) (within 24 hours). 
However the administered dose must deviate from the intended dose to an extent where 
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Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
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clinical consequences for the trial subject were likely to happen as judged by the 
investigator, although they did not necessarily occur.
When reporting a MESI, the following forms must be completed: the AE form, SIF and specific 
MESI form, as described in section 12.2 and illustrated in Figure 12–1.
Adverse events with additional data collection 
AEs with additional data collection are AEs (SAE or non-serious AE) defined as important for the 
evaluation of product safety. These include:
x
Gallstone disease
x
Neoplasms
x
Pancreatitis
A detailed description of additional data collection is described in section 8.6.3. When reporting 
adverse events with additional data collection, the following forms must be completed: the AE 
form, specific event form and if the event is serious the SIF as described in section 12.2 and 
illustrated in Figure 12–1.
Technical complaint
A technical complaint is any written, electronic, or oral communication that alleges product 
(medicine or device) defects. The technical complaint may be associated with an AE, but does not 
concern the AE itself.
Examples of technical complaints:
x
The physical or chemical appearance of trial products (e.g. discoloration, particles or 
contamination)
x
The packaging material (e.g. leakage, cracks, rubber membrane issues or errors in labelling text)
x
Problems related to devices (e.g. to the injection mechanism, dose setting mechanism, push 
button or interface between the pen and the needle)
12.2
Reporting of adverse events
All events meeting the definition of an AE must be collected and reported. This includes events 
from the first trial-related activity after the subject has signed the informed consent until the end of 
the post-treatment follow-up period (section 2). The events must be recorded in the applicable CRF 
forms in a timely manner, see timelines below and Figure 12–1
During each contact with the trial site staff, the subject must be asked about AEs and technical 
complaints, for example by asking: "Have you experienced any problems since the last contact?"
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
75 of 125
All AEs, either observed by the investigator or subject, must be reported by the investigator and 
evaluated. Novo Nordisk assessment of expectedness is performed according to the following 
reference documents: Liraglutide (NN8022) Weight Management Investigator’s Brochure (IB) or 
any updates hereof. 
All AEs must be recorded by the investigator on an AE form. The investigator should report the 
diagnosis, if available. If no diagnosis is available, the investigator should record each sign and 
symptom as individual AEs using separate AE forms.
For SAEs, a SIF must be completed in addition to the AE form. If several symptoms or diagnoses 
occur as part of the same clinical picture, one safety information form can be used to describe all 
the SAEs. 
MESIs, regardless of seriousness, must be reported using both the AE form and the SIF  and a 
MESI form. The MESI form is a form tailored to collect specific information related to the 
individual MESI.
AEs (SAE or non-serious AE) requiring additional data collection must be reported using both the 
AE form and the specific event form. The specific event form is a form tailored to collect specific 
information related to the individual event.
The AE form for a non-serious AE not fulfilling the MESI criteria should be signed when the event 
is resolved or at the end of the trial.
Timelines for initial reporting of AEs:
The investigator must complete the following forms in the eCRF within the specified timelines:
x
SAEs: The AE form within 24 hours and the SIF within 5 calendar days of the investigator's 
first knowledge of the SAE.
Both forms must be signed within 7 calendar days from the date the information was entered in 
the eCRF.
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
76 of 125
x
SAEs fulfilling the MESI criteria: In addition to above, the MESI form within 14 calendar 
days of the investigator's first knowledge of the AE.
x
SAEs with additional data collection: In addition to above, the specific event form within 14 
calendar days of investigator’s first knowledge of the event.
x
Non-serious AE fulfilling the MESI criteria: The AE form, SIF and MESI form within 14 
calendar days of the investigator's first knowledge of the event.
x
Non-serious AEs with additional data collection: The AE form and specific event form within 
14 calendar days of the investigator's first knowledge of the event.
If the eCRF is unavailable, the concerned AE information must be reported on paper forms and sent 
to Novo Nordisk by fax, e-mail or courier within the same timelines as stated above. When the 
eCRF becomes available again, the investigator must enter the information on the appropriate forms 
in the eCRF.
Contact details (fax, telephone, e-mail and address) are provided in the investigator trial master file. 
Figure 12–1
Initial reporting of AEs
An AE is 
observed and 
reported 
It is an SAE
complete:
x
AE form ≤ 24 hours
x
SIF ≤ 5 calendars days
It is a non-serious AE
complete:
x
AE form
Fulfilling 
seriousness 
criteria?
Complete ≤ 14 calendar 
days:
x
Medication Error form 
Complete ≤ 14 calendar 
days: 
x
Medication Error form 
and SIF 
Yes
No
AE: Adverse Event
SIF: Safety Information Form
MESI: Medical Event of Special Interest
Specific event form: Acute gallstone disease, Neoplasm and 
Pancreatitis (described in section 8.6)
*: If the answer to this question is no, no additional forms have to be 
completed 
All timelines are from the investigator’s first knowledge of the event
Requring additional 
data collection?*
Is the MESI criteria 
fulfilled?*
Complete ≤ 14 calendar 
days:
x
Specific event form
 
Is the MESI criteria 
fulfilled?*
Requring additional 
data collection?*
Complete ≤ 14 calendar 
days:
x
Specific event form
 
Yes
Yes
Yes
Yes
Reporting of trial product-related SUSARs by Novo Nordisk:
Novo Nordisk will notify the investigator of trial product-related suspected unexpected serious 
adverse reactions (SUSARs) in accordance with local requirements and GCP47. In addition, the 
investigator will be informed of any trial-related SAEs that may warrant a change in any trial 
procedure.
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
77 of 125
In accordance with regulatory requirements, Novo Nordisk will inform the regulatory authorities, 
including EMA, of trial product-related SUSARs. In addition, Novo Nordisk will inform the 
IRBs/IECs of trial product-related SUSARs in accordance with local requirement and GCP47, unless 
locally this is an obligation of the investigator.
Novo Nordisk products used as concomitant medication:
If a SAE and/or MESI is considered to have a causal relationship with a Novo Nordisk marketed 
product used as concomitant medication in the trial, it is important that the suspected relationship is 
reported to Novo Nordisk, e.g. in the alternative aetiology section on the safety information form. 
Novo Nordisk may need to report this adverse event to relevant regulatory authorities.
12.3
Follow-up of adverse events
The investigator must record follow-up information by updating the forms in the eCRF. Follow up 
information should only include new (updated and/or additional) information that reflects the 
situation at the time of the investigator’s signature.
Follow up information must be reported to Novo Nordisk according to the following:
x
SAEs: The investigator must record follow-up information on all SAEs by updating the 
applicable form(s) in the eCRF (AE form, safety information form, specific event form and/or 
MESI form). All SAEs must be followed until the outcome of the event is “recovered/resolved”, 
“recovered/resolved with sequelae” or “fatal”, and until all queries have been resolved. Cases of 
chronic conditions, cancer or AEs ongoing at time of death (where death is due to another AE) 
may be closed with the outcome “recovering/resolving” or “not recovered/not resolved”. Cases 
can be closed with the outcome of “recovering/resolving” when the subject has completed the 
follow-up period and is expected by the investigator to recover.
The SAE follow-up information should only include new (e.g. corrections or additional) 
information and must be reported within 24 hours of the investigator's first knowledge of the 
information. This is also the case for previously non-serious AEs which subsequently become
SAEs. 
x
Non-serious AEs: The investigator must record follow-up information on non-serious AEs by 
updating the applicable form(s) in the eCRF (the AE form and/or the specific event form). Non-
serious AEs must be followed until the outcome of the event is “recovering/resolving”, 
“recovered/resolved” or “recovered/resolved with sequelae” or until the end of the follow-up
period stated in the protocol, whichever comes first, and until all queries related to these AEs 
have been resolved. Cases of chronic conditions, cancer or AEs ongoing at time of death (where 
death is due to another AE) may be closed with the outcome “recovering/resolving” or “not 
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
78 of 125
recovered/not resolved”. Cases can be closed with the outcome of “recovering/resolving” when 
the subject has completed the follow-up period and is expected by the investigator to recover.
x
Non-serious AE fulfilling the MESI criteria: Non-serious AE fulfilling the MESI criteria 
must be followed as specified for non-serious AEs by updating the applicable form(s) in the 
eCRF (AE form, safety information form and/or MESI form). Follow-up information on MESIs 
should only include new (e.g. corrections or additional) information and must be reported 
within 14 calendar days of the investigator’s first knowledge of the information. This is also 
the case for previously reported non-serious AEs which subsequently fulfil the MESI criteria. 
The investigator must ensure that the worst case severity and seriousness of an event is kept 
throughout the trial. A worsening of an unresolved AE must be reported as follow up with re-
assessment of severity and/or seriousness of the event.
Queries or follow-up requests from Novo Nordisk must be responded to within 14 calendar days
from the date of receipt of the request, unless otherwise specified in the follow-up request.
12.4
Technical complaints and technical complaint samples
12.4.1
Reporting of technical complaints
All technical complaints on any of the following products: 
x
Liraglutide FlexPen®
x
Placebo FlexPen® 
x
Needles
which occur from the time of first usage of the product until the time of the last usage of the 
product, must be collected and reported to Customer Complaint Center, Novo Nordisk.
Contact details (fax, e-mail and address) are provided in Attachment I to the protocol.
The investigator must assess whether the technical complaint is related to any AEs, SAEs, and/or 
MESI.
Technical complaints must be reported on a separate technical complaint form. A technical 
complaint form for each coded batch  number or for each DUN must be completed.
The investigator must complete the technical complaint form in the eCRF within the following 
timelines of the trial site obtaining knowledge of the technical complaint:
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
79 of 125
x
Technical complaint assessed as related to an SAE within 24 hours
x
All other technical complaints within 5 calendar days
If the eCRF is unavailable or when reporting a technical complaint that is not subject related, the 
information must be provided on a paper form by fax, e-mail or courier to Customer Complaint 
Center, Novo Nordisk, within the same timelines as stated above. When the eCRF becomes 
available again, the investigator must enter the information on the technical complaint form in the 
eCRF.
12.4.2
Collection, storage and shipment of technical complaint samples
The investigator must collect the technical complaint sample and notify the monitor within 5 
calendar days of obtaining the sample at trial site. The monitor must coordinate the shipment to 
Customer Complaint Center, Novo Nordisk (the address is provided in Attachment I) and ensure 
that the sample is sent as soon as possible. A print or copy of the technical complaint form must be 
sent with the sample.
The investigator must ensure that the technical complaint sample contains the coded batch number 
and, if available, the DUN.
If the technical complaint sample is unobtainable, the investigator must specify on the technical 
complaint form why it is unobtainable. 
Storage of the technical complaint sample must be done in accordance with the conditions 
prescribed for the product. The shipment of the technical complaint sample should be done in 
accordance with the same conditions as for storage (section 9).
12.5
Pregnancies
12.5.1
Pregnancies in female subjects
Female subjects must be instructed to notify the investigator immediately if they become pregnant 
during the trial. The investigator must report any pregnancy in subjects who have received trial 
products.
The investigator must follow the pregnancy until the pregnancy outcome and the newborn infant is 
one month of age.
The investigator must report information about the pregnancy, pregnancy outcome, and health of 
the newborn infant(s), as well as AEs in connection with the pregnancy, and AEs in the foetus and 
newborn infant.
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
80 of 125
The following must be collected and reported by the investigator to Novo Nordisk - electronically 
(e.g. in PDF format), or by fax or courier:
1. Reporting of pregnancy information
Information about the pregnancy and pregnancy outcome/health of the newborn infant(s) has to 
be reported on Maternal Form 1A and 1B, respectively. 
When the pregnancy outcome is abnormal (i.e. congenital anomalies, foetal death including 
spontaneous abortion and/or any anomalies of the foetus observed at gross examination or 
during autopsy), and/or when a congenital anomaly is diagnosed within the first month, further 
information has to be reported for the female subject on Maternal Form 2. In addition, 
information from the male partner has to be reported on the Paternal Form, after an informed 
consent has been obtained from the male partner. 
Initial reporting and follow-up information must be reported within 14 calendar days of the 
investigator's first knowledge of initial or follow-up information. 
2. Reporting of AE information
The investigator has to report AEs in connection with the pregnancy as well as in the foetus and 
newborn infant(s). The SAEs that must be reported include abnormal outcome, such as foetal 
death (including spontaneous abortion), and congenital anomalies (including those observed at 
gross examination or during autopsy of the foetus), as well as other pregnancy complications 
fulfilling the criteria of an SAE.
Forms and timelines for reporting AEs:
Non-serious AEs: 
–
Paper AE form* within 14 calendar days of the investigator's first knowledge of the initial 
or follow-up information to the non-serious AE.
SAEs: 
–
Paper AE form* within 24 hours of the investigator's first knowledge of the SAE.
–
Paper safety information form within 5 calendar days of the investigator's first knowledge 
of the SAE.
–
SAE follow-up information to the AE form and/or safety information form within 24 
hours of the investigator's first knowledge of the follow-up information.
*
It must be clearly stated in the AE diagnosis field on the AE form if the event occurred in 
the subject, foetus or newborn infant.
Any queries or follow-up requests from Novo Nordisk to non-serious AEs, SAEs and pregnancy 
forms must be responded to by the investigator within 14 calendar days from the date of receipt of 
the request, unless otherwise specified in the follow-up request.
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
81 of 125
12.5.2
Pregnancies in female partners of male trial subjects (Applicable for US only)
Male subjects must be instructed to notify the investigator if their female partner becomes pregnant 
during the trial, except in the screening period. At the last scheduled visit, male subjects must be 
asked if their female partner has become pregnant.
If a female partner has become pregnant during the trial, the investigator must follow-up on the 
pregnancy outcome and until the newborn infant is one month of age, irrespective of whether the 
trial is completed or not. The investigator must ask the male subject and assess, if the pregnancy 
outcome is normal or abnormal. 
When the pregnancy outcome is normal this information is recorded in the subject's medical record 
only, no further information is collected and reported to Novo Nordisk. When the pregnancy 
outcome is abnormal (i.e. congenital anomalies, foetal death including spontaneous abortion and/or 
any anomalies of the foetus observed at gross examination or during autopsy), the following must 
be reported by the investigator to Novo Nordisk electronically (e.g. in PDF format) or by fax:
1. Reporting of pregnancy information
Information from the male subject has to be reported on the Paternal Form. Furthermore, 
information from the female partner (including information about the pregnancy outcome and 
health status of the infant until the age of one month) has to be reported on the Maternal Forms 
1A, 1B and 2, after an informed consent has been obtained from the female partner. 
Initial reporting and follow-up information must be reported within 14 calendar days of the 
investigator's first knowledge of initial or follow-up information. 
2. Reporting of AE information
The following AEs in the foetus and newborn infant have to be reported:
–
Non-serious AEs evaluated as possible/probably related to the father's treatment with the 
trial product(s). 
–
SAEs in the foetus and newborn infant - whether or not related to the father's treatment with 
the trial product(s). This includes an abnormal outcome - such as foetal death (including 
spontaneous abortion) and congenital anomalies (including those observed at gross 
examination or during autopsy of the foetus).
Forms and timelines for reporting AEs:
See section 12.5.1, point 2, "Forms and timelines for reporting AEs:". 
Any queries or follow-up requests from Novo Nordisk to non-serious AEs, SAEs and pregnancy 
forms must be responded to by the investigator within 14 calendar days from the date of receipt of 
the request, unless otherwise specified in the follow-up request.
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11
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
82 of 125
12.6
Precautions and/or overdose
From clinical trials and marketed use of liraglutide overdoses have been reported up to 24 times the 
recommended dose (72 mg). Generally, the patients reported severe nausea, vomiting and diarrhoea, 
but recovered without complications. Severe hypoglycaemia has also been observed.   
12.7
Committees related to safety
12.7.1
Novo Nordisk safety committee
Novo Nordisk will constitute an internal liraglutide safety committee to perform ongoing safety 
surveillance. The liraglutide safety committee may recommend unblinding of any data for further 
analysis, and in this case an independent ad hoc group will be established in order to maintain the 
blinding of the trial personnel.
12.7.2
Data monitoring committee
The independent data monitoring committee (DMC) is established to review and evaluate 
accumulating data from an ongoing clinical trial in order to protect the safety of the subjects and to 
evaluate the evolving risk-benefit if required.
The DMC is composed of permanent members who are independent of Novo Nordisk and will 
cover relevant specialities (specialists in paediatrics, statistics and endocrinology) and they may 
request assistance from a number of additional ad hoc members, if needed.
The DMC is established to review PK data and unblinded safety data from the 16-week double-
blind period of part A and recommend if the trial can proceed to part B. The DMC will also monitor 
safety throughout the trial on an ongoing basis, and recommend to Novo Nordisk whether to 
continue, modify, or terminate the trial as necessary. The composition of the DMC, objectives of 
the surveillance, meeting frequency and type, data to be analysed at the meetings and 
responsibilities with regard to information (such as meeting minutes) will be described in a DMC 
charter.
The DMC members will have direct contact with the Novo Nordisk Global Safety, and will have no 
direct interaction with trial management. The DMC recommendations should be addressed directly 
to Novo Nordisk Global Safety and the internal Novo Nordisk safety committee. It is the 
responsibility of the internal Novo Nordisk safety committee to take action for subject safety based 
on the DMC recommendations. DMC concerns relating to trial processes will be communicated to 
trial management via Novo Nordisk Global Safety.
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11
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
83 of 125
13 Case report forms 
In this trial a combination of electronic case report forms (eCRF) and paper CRFs will be used.
Novo Nordisk will provide a system for the eCRF. This system and support services to the system 
will be provided by an external supplier.
Ensure that all relevant questions are answered, and that no empty data field exists. If a test or an 
assessment has not been done and will not be available, or if the question is irrelevant (e.g. is not 
applicable), indicate this according to the data entry instructions.
The following will be provided as paper CRFs:
x
Pregnancy forms
x
Technical complaint forms (only to be used as back-up for electronic reporting)
x
AE forms (only to be used as back-up for electronic reporting)
x
Safety information forms (only to be used as back-up for electronic reporting)
The paper version of the technical complaint form, AE form, safety information forms and special 
forms must only be used to ensure timely reporting when/if the electronic CRF is unavailable. The 
technical complaint form must be used for complaints that are not subject related.
On the paper CRF forms print legibly, using a ballpoint pen. Ensure that all questions are answered, 
and that no empty data blocks exist. Ensure that no information is recorded outside the data blocks. 
If a test/assessment has not been done and will not be available, indicate this by writing "ND" (not 
done) in the appropriate answer field in the CRF. If the question is irrelevant (e.g. is not applicable) 
indicate this by writing "NA" (not applicable) in the appropriate answer field. Further guidance can 
be obtained from the instructions in the CRF.
The investigator must ensure that all information is consistent with the source documentation. By 
electronically signing the case book in the eCRF, the investigator confirms that the information in 
the eCRF and related forms is complete and correct.
13.1
Corrections to case report forms 
Corrections to the CRF data may be made by the investigator or the investigator's delegated staff. 
An audit trail will be maintained in the CRF application containing as a minimum: the old and the 
new data, identification of the person entering the data, date and time of the entry and reason for the 
correction.
If corrections are made by the investigator's delegated staff after the date the investigator has signed 
the case book, the case book must be signed and dated again by the investigator.
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11
RI
CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
84 of 125
13.2
Case report form flow 
The investigator must ensure that data is recorded in the eCRF as soon as possible, preferably 
within 5 days after the visit. Once data has been entered, it will be available to Novo Nordisk for 
data verification and validation purposes.
Site specific eCRF data (in an electronic readable format) will be provided to the trial site before 
access to the eCRF is revoked. This data must be retained at the trial site.
3URWRFROSURWRFROYHUVLRQ_
11
RI
CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
85 of 125
14 Monitoring procedures 
During the course of the trial, the monitor will visit the trial site to ensure that the protocol is 
adhered to, that all issues have been recorded, to perform source data verification and to monitor 
drug accountability. The first monitoring visit will be performed as soon as possible after FPFV at 
the trial site and no later than 4 weeks after. The monitoring visit intervals will depend on the 
outcome of the remote monitoring of the CRFs, the trial site's recruitment rate and the compliance 
of the trial site to the protocol and GCP47, but will not exceed 12 weeks for trial sites with active 
subjects (defined as subjects in screening, treatment, or follow-up).
The monitor must be given direct access to source documents (original documents, data and 
records). Direct access includes permission to examine, analyse, verify and reproduce any record(s) 
and report(s) that are important to the evaluation of the trial. If the electronic medical record does 
not have a visible audit trail, the investigator must provide the monitor with signed and dated 
printouts. In addition the relevant trial site staff should be available for discussions at monitoring 
visits and between monitoring visits (e.g. by telephone).
All data must be verifiable in source documentation other than the CRF.
For all data recorded the source document must be defined in a source document agreement at each 
trial site. There must only be one source defined at any time for any data element.
The investigator must make a reasonable effort to obtain additional information from external
sources e.g. primary physician and other hospitals/departments to collect information required to 
evaluate all inclusion and exclusion criteria if not available in the subject’s medical record at the 
trial site and if not part of the screening assessments performed.
Considering the electronic source data environment, it is accepted that the earliest practically 
retainable record should be considered as the location of the source data and therefore transcription 
to the diary from the glucometer is considered the source document for recordings of glucometer.
Source data generated by the trial site can be corrected by another person than the person entering 
the source data if accepted by local regulations; any correction must be explained, signed and dated 
by the person making the correction.
The original diaries and PROs must not be removed from the trial site, unless they form part of the 
CRF and a copy is kept at the site.
The monitor will ensure that the CRFs are completed.
The following data will be source data verified for screening failures: 
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11
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
86 of 125
x
Date for obtaining informed consent.
x
Screen failure reason.
x
SAEs
Monitors must review the subject's medical records and other source data to ensure consistency 
and/or identify omissions compared to the CRF. If discrepancies are found, the investigator must be 
questioned about these.
A follow-up letter (paper or electronic) will be sent to the investigator following each monitoring 
visit. This should address any action to be taken.
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11
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
87 of 125
15 Data management
Data management is the responsibility of Novo Nordisk. Data management may be delegated under 
an agreement of transfer of responsibilities to a contract research organisation (CRO). 
Appropriate measures, including encryption of data files containing person identifiable data, will be 
used to ensure confidentiality of subject data, when they are transmitted over open networks. 
Data from central laboratories will be transferred electronically. In cases where data is transferred 
via non-secure electronic networks, data will be encrypted during transfer.
The subject and any biological material obtained from the subject will be identified by subject 
number and trial ID. Appropriate measures such as encryption or leaving out certain identifiers will 
be enforced to protect the identity of subjects in all presentations and publications as required by 
local, regional and national requirements.
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
88 of 125
16 Computerised systems
Novo Nordisk will capture and process clinical data using computerised systems that are described 
in Novo Nordisk Standard Operating Procedures and IT architecture documentation. The use and 
control of these systems are documented.
Investigators working on the trial may use their own electronic systems to capture source data. 
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
89 of 125
17 Statistical considerations
If necessary, a statistical analysis plan (SAP) may be written in addition to the protocol, including a 
more technical and detailed elaboration of the statistical analyses. 
Results from the statistical analysis will generally be presented by two-sided confidence intervals
(CIs) with a confidence level of 95%. Superiority will be claimed if the two-sided p-value is less 
than 5% and the treatment estimate favours liraglutide. 
The full analysis set (FAS) will be used in the analysis of the efficacy endpoints. For the safety
endpoints, the safety analysis set (SAS) will be used. The definition of the analysis sets is given in 
Section 17.2.
For safety endpoints, summaries will be presented separately for the periods “in trial” and “on 
treatment” as defined in Section 17.4.1.2.
The baseline value will be defined as the last measured and available value from V3 
(randomisation) and V2 (screening). 
Laboratory values below the lower limit of quantification (LLOQ) will be set to ½LLOQ.
17.1
Sample size calculation
This is a superiority trial comparing liraglutide to placebo. Based on previous experience the 
treatment effect after 52 weeks is expected to be considerable larger than after 16 weeks. Therefore 
the sample size calculation below focuses alone on the first co-primary endpoint.
It is difficult to assess the anticipated effect of liraglutide in BMI SDS48 in children and adolescents 
with PWS. It is anticipated that the effect is similar to the effect for adults. 
The standard deviation (SD) is assessed based on publications49, and trial NN8022-3967 in
adolescents with obesity aged 12−17 years. For the sample size scenarios, SDs of 0.15, 0.25 and 
0.35 were investigated.
The effect of withdrawals is accounted for as a reduction of the anticipated treatment difference and 
increase of the SD. Since a conservative imputation method is planned for the main analysis of the 
primary endpoint, it is assumed that withdrawn subjects respond as if treated with placebo for the 
entire trial. The assumed withdrawal percentage at week 16 is 10% and 20% at week 52. This is 
lower than what was seen for trial NN8022-1839 in adults with obesity and adults with overweight. 
Since patients with Prader-Willi Syndrome are under close supervision by parents or institutional 
staff and for the lack of other therapeutic options, this assumption is considered reasonable. Let 
݌ௐ஽denote the probability of withdrawal. The adjustment for withdrawals is made by correcting the 
treatment difference Δ and variance σ2 as
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
90 of 125
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ߪ௖௢௥௥
ଶ
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The total number of subjects is shown for the investigated scenarios in the table below for 80%, 
85% and 90% power.
Table 17–1
Sample size calculations for different scenarios; total number of subjects
Power
Treatment difference (completers)
SD
0.15
0.25
0.35
80%
-0.22
27
63
117
-0.225
27
60
111
-0.23
24
57
108
85%
-0.22
30
72
132
-0.225
30
69
126
-0.23
27
66
123
90%
-0.22
33
81
156
-0.225
33
78
147
-0.23
33
75
141
It seems realistic and conservative to assume a SD of 0.25 and a withdrawal rate of 10% after 16 
weeks and 20% after 52 weeks. A withdrawal rate of 10% gives 57 subjects randomised. With this 
setting, a treatment difference of -0.23 corresponding to approximately a 5-6% decrease in BMI can 
be detected with a power of 80%. Assuming a withdrawal rate at 20% at week 52 a trial completion 
of 45 subjects, which is a regulatory requirement, is obtainable.
The distribution of the 57 subjects for randomisation on part A and B and the two treatment groups 
are shown in the table below. 
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
91 of 125
Table 17–2
Overview of randomised subjects
Liraglutide
Placeb
o
Total Liraglutide and 
Placebo
Expected 
number of 
subjects to 
complete 
treatment (at 
least 80%)
Minimum 
PIP 
requirement 
of subjects to 
complete 
treatment 
Part A
22
11
33
28
28
Part B
16
8
24
19
17
Total 
38
19
57
47
45
17.2
Definition of analysis sets
The following analysis sets are defined in accordance with the ICH-E9 guideline. 
FAS: Includes all randomised subjects who have received at least one dose of trial product and have 
any post-randomisation data. The statistical evaluation of the FAS will follow the intention-to-treat 
(ITT) principle and subjects will contribute to the evaluation “as randomised”.
SAS: Includes all subjects exposed to at least one dose of trial product. Subjects in the SAS will 
contribute to the evaluation “as treated”.
Data from nominal visits (V10x and V19x) will be used prior to imputation of remaining missing 
data unless otherwise stated. 
Before data are locked for statistical analysis, a blind review of all data will take place. Any 
decision to exclude a subject or single observations from the statistical analysis is the joint 
responsibility of the trial statistician, the ITM and the medical specialist. Exclusion of data from 
analyses will be used restrictively and normally no data should be excluded from the FAS. The 
subjects or observations to be excluded, and the reasons for their exclusion must be documented and 
signed by those responsible before database lock. The subjects and observations excluded from 
analysis sets, and the reason for this, will be described in the clinical trial report.
17.3
Primary endpoints
The two co-primary endpoints are: 
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
92 of 125
x
Change from baseline in BMI SDS48 after 16 weeks of treatment
x
Change from baseline in BMI SDS after 52 weeks of treatment
The hypotheses of equality between liraglutide and placebo for each of the two endpoints are tested 
in a hierarchical manner in the order in which the endpoints are presented. The implication is that 
liraglutide will only be considered statistically significantly better than placebo at 52 weeks if it is 
considered statistically significantly better with respect to the first primary endpoint.
The primary analysis will include subjects from all strata, i.e. both from part A and part B (provided 
that the external DMC recommends that part B will be conducted).
BMI SDS will be summarised using descriptive statistics according to the stratification factor for 
Tanner stage and stratification factor for glycaemic category. In case there are a very low number of 
subjects within one glycaemic category, the description may be done according to stratification 
factor for Tanner stage alone. 
The analysis of each of the co-primary endpoints will use the same approach and is described 
below. 
The objective is to show that liraglutide is superior to placebo in obtaining weight loss. 
Let μliraglutide and μplacebo denote mean change in BMI SDS for liraglutide and placebo respectively. 
The null-hypothesis and the alternative hypothesis are:
H0: μliraglutide = μplacebo against the alternative HA: μliraglutide ≠ μplacebo
The null-hypothesis will be rejected on a 5% level if the two-sided 95% confidence interval of the 
treatment difference μliraglutide - μplacebo excludes 0. If the upper limit is below 0 superiority of 
liraglutide against placebo can be concluded.
The hypothesis will be tested using an analysis of covariance (ANCOVA) with treatment, sex, 
region, baseline glycaemic category, stratification factor for Tanner stage and interaction between 
baseline glycaemic category and stratification factor for Tanner stage as fixed effects and baseline 
BMI SDS and baseline age as covariates. Part A of the trial includes Tanner stage 2-5 or 
hormonally-induced puberty, and part B includes Tanner stage below 2 and subjects with premature 
adrenarche. The stratification factor for Tanner stage includes three levels; stage below 2 (defined 
as Tanner stage 1 with or without premature adrenarche) (corresponding to part B), stage 2 and 3 
together, and stage 4 and 5 together (the last two corresponds to part A). The baseline glycaemic 
category includes two levels; presence and absence of dysglycaemia.
Missing data will in the main analysis be handled by the following multiple imputation (MI) 
method. A pattern mixture model approach is applied where withdrawn subjects with missing 
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11
RI
CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
93 of 125
values are assumed to respond as if treated with placebo for the entire trial. Multiple copies (N = 
1000) of the full dataset will be generated by imputing missing values based on estimated 
parameters for the placebo group. This will be done as follows.
x
In the first step, N = 1000 copies of the dataset will be generated.
x
In the second step, an enriched ANCOVA model with sex, region, stratification factor for 
Tanner stage, baseline glycaemic category and interaction between baseline glycaemic category 
and stratification factor for Tanner stage as fixed effects and baseline BMI SDS, as covariate is 
fitted to the change from baseline in BMI SDS at 16 weeks (or 52 weeks) for the completers in 
the placebo group only.
x
For each of the N copies of the dataset, the estimated parameters and their variances from this
model are used to impute missing values at 16 weeks (or 52 weeks) for subjects in both 
treatment arms, based on their factor levels and the values of the covariates.
x
For each of the N complete datasets, the change from baseline in BMI SDS at 16 weeks (or 52
weeks) is analysed using the main ANCOVA model with treatment, sex, region, baseline 
glycaemic category, stratification factor for Tanner stage and interaction between baseline 
glycaemic category and stratification factor for Tanner stage as fixed effects, and baseline BMI 
SDS and baseline age as covariates. 
x
The estimates and SDs for the N data sets are pooled to one estimate mMI and associated SDMI 
using Rubin’s formula:
݉ெூൌ
ͳ
ͳͲͲ ෍݉௜
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௜ୀଵ
ǡ
ܵܦெூൌඩͳ
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where mi and SDi are the estimated means and standard deviations for the N copies of the dataset. 
From mMI and SDMI , the 95% CI for the treatment difference and the associated p-value are 
calculated.
If N = 1000 copies are insufficient to obtain stable results, a higher number will be used.
The MI method assumes that withdrawn subjects with missing values in the placebo arm have a 
response similar to the completers in the in the placebo arm given similar baseline characteristics. In 
the active arm the assumption is that withdrawn subjects with missing values behave as if they have 
been in the placebo arm during entire trial regardless of the time of withdrawal. In this way the 
assumptions are differential and conservative for estimating the treatment effect. The estimate in the 
primary analysis can be said to be an intention to treat (ITT) estimator or an effectiveness estimand 
of the add-on effect of liraglutide to dietary and physical activity counselling. 
If the imputation ANCOVA model cannot be estimated due to too few placebo subjects with 
available data, explanatory variables will be removed in the following order until the model is 
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11
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
94 of 125
estimable: region, sex, baseline BMI SDS, Tanner stage, baseline glycaemic category and 
interaction between baseline glycaemic category and stratification factor for Tanner stage.
Sensitivity analysis
To investigate the sensitivity of the results of the main analysis of the primary endpoint with regard 
to the handling of missing data, the following sensitivity analyses will be performed:
x
An ANCOVA will be performed with imputation of missing values according to the last 
observation carried forward (LOCF) method. The model will include terms for treatment, sex, 
region, baseline glycaemic category, stratification factor for Tanner stage and interaction 
between baseline glycaemic category and stratification factor for Tanner stage, and baseline 
BMI SDS and baseline age as covariates. The response variable will be the last available 
measurement of BMI SDS obtained within the 16-week double-blind period of the trial. Data 
from nominal visits (V10x and V19x) will not be used for this analysis.
x
The same type of ANCOVA as above will be performed, but using an imputation of missing 
values according to the baseline observation carried forward (BOCF) method. Missing 
measurements of BMI SDS at 16 weeks will with this method be imputed by the corresponding 
baseline values.
x
The same type of ANCOVA as above will be performed without imputation by only including 
subjects who completed the 16-week double-blind period. 
x
A mixed model for repeated measurements (MMRM) will be applied where all post baseline 
BMI SDS measurements obtained at planned visits during the 16-week double-blind period will 
enter as the dependent variables, and visit, treatment, sex, region, baseline glycaemic category, 
stratification factor for Tanner stage and interaction between baseline glycaemic category and 
stratification factor for Tanner stage will be included as fixed effects, and baseline BMI SDS 
and baseline age as covariates. All these factors and covariates will be nested under visit, which 
is technically the same as introducing the corresponding interaction terms in the model. An 
unstructured covariance matrix for the BMI SDS measurements within subject will be 
employed.
The sensitivity analyses will be repeated for the week 52 co-primary endpoint.
The ANCOVA model with LOCF assumes that post treatment discontinuation, the body weight is 
on average stable in both treatment arms. If the assumption holds, the treatment effect (effectiveness 
estimand) in each arm and the treatment difference can be estimated from this analysis unbiased. If 
the withdrawal and the development in both arms are similar, the treatment difference can be 
estimated from this analysis unbiased. If the development in body weight after treatment 
discontinuation differs between active and placebo, this analysis might provide an optimistic or 
over-conservative estimate, depending on the actual circumstances. The analysis is included to be 
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
95 of 125
able to compare the results with legacy obesity programs, where this analysis was the main analysis
of the primary endpoints.
The ANCOVA model with BOCF assumes that post treatment withdrawn subjects  with missing 
values returns to a body weight in the proximity of their baseline body weight regardless of the 
timing of withdrawal. This analysis is expected to provide a conservative estimate (effectiveness 
estimand) of the treatment effect (in each arm). The impact of this assumption on the treatment 
difference depends on withdrawal pattern over time and development of body weight post 
withdrawal and reason for withdrawal. The analysis is typically expected to provide a conservative 
estimate of the treatment difference (effectiveness estimand).
The MMRM model assumes that withdrawn subjects, had they completed the trial, would not have
behaved differently than completing subjects from the same treatment arm with the same baseline
characteristics and change in body weight at time of withdrawal. This analysis estimates the
treatment difference had all subjects stayed on the randomised treatment (efficacy
estimand).
The ANCOVA analysis in completers is expected to give more positive results than the primary 
analysis. However, this analysis has its own clinical interpretation and will serve as a benchmark 
and provide an estimate of the efficacy estimand in the population that tolerate the trial product and 
endure the diet and exercise counselling program.
17.4
Secondary endpoints
17.4.1
Supportive secondary endpoints
The planned secondary endpoints will be analysed as outlined in this section.
17.4.1.1
Efficacy endpoints
BMI
The changes in BMI from baseline at 16 and 52 weeks will be analysed separately with the same 
type of ANCOVA with MI as used for the main analysis of the primary endpoint, but with the 
baseline BMI as covariate instead of the baseline BMI SDS.
In addition, the following categorical endpoints related to BMI will be evaluated:
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
96 of 125
x
Percentage of subjects achieving ≥ 5% reduction in baseline BMI at 16 weeks
x
Percentage of subjects achieving ≥ 5% reduction in baseline BMI at 52 weeks
x
Percentage of subjects achieving ≥ 10% reduction in baseline BMI at 16 weeks
x
Percentage of subjects achieving ≥ 10% reduction in baseline BMI at 52 weeks
These endpoints will be analysed separately using a logistic regression model. The response will be 
a binary outcome (yes/no) indicating for each subject whether the respective minimum reduction in 
BMI has been achieved. The model will include treatment, sex, region, baseline glycaemic 
category, stratification factor for Tanner stage and interaction between baseline glycaemic category 
and stratification factor for Tanner stage as fixed effects, and baseline BMI and baseline age as 
covariates. The treatment differences will be presented as odds ratios together with the associated 
95% CIs.
For the analysis of the categorical endpoints, missing BMI values will be imputed using the 100 
complete datasets from the MI performed for the corresponding analysis on the continuous change 
in BMI. The logistic regression will be performed on each of these datasets. Rubin’s formula will 
then be applied on the 100 estimates of the log odds ratio and the associated SDs to produce a 
pooled estimate and SD. These pooled values will lastly be used to calculate the 95% CI for the 
odds ratio.
BMI SDS: No increase
The percentage of subjects with no increase in BMI SDS at 16 and 52 weeks will be analysed using 
the same statistical method as the one used for the categorical endpoints related to BMI, but with 
the baseline BMI SDS as covariate instead of the baseline BMI.
Hyperphagia questionnaire outcome
The questionnaire on hyperphagia will be evaluated similarly to the primary endpoint. That is, the 
change in hyperphagia score (hyperphagia total score and hyperphagic behaviour, drive and severity 
score respectively), from baseline at 16 and 52 weeks will be analysed separately using the same 
type of ANCOVA with MI as used for the main analysis of the primary endpoint, but with the 
corresponding baseline hyperphagia score instead of the baseline BMI SDS as covariate. 
Glycaemic category
The change in glycaemic category (normoglycaemia, pre-diabetes, T2DM) from baseline at 16 and 
52 weeks will be summarised using descriptive statistics. 
Furthermore, two separate analyses will be performed on the binary variable normoglycaemia 
(yes/no) at 16 and 52 weeks, using a logistic regression model with the factors treatment, sex, 
region, baseline glycaemic category, stratification factor for Tanner stage and interaction between 
baseline glycaemic category and stratification factor for Tanner stage , and baseline age as 
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
97 of 125
covariate. Missing data will be handled by a MI method similar to the one used for the main 
analysis of the primary endpoint, but adapted to the logistic regression model. The treatment 
differences will be presented as odds ratios together with the associated 95% CIs.
Other efficacy endpoints
The following other efficacy variables will be evaluated:
x
Body weight
x
Waist circumference
x
Waist to hip circumference ratio
x
CV biomarker (hsCRP)
x
Fasting lipids (TC, LDL-cholesterol, HDL-cholesterol, non-HDL cholesterol, VLDL 
cholesterol, TG and FFA)
x
Systolic and diastolic blood pressure
x
Quantitative glucose metabolism parameters (HbA1c, FPG, fasting insulin, C-peptide, HOMA-B
and HOMA-IR)
The changes in these variables from baseline at 16 and 52 weeks will be analysed using the same 
type of ANCOVA with MI as used for the main analysis of the primary endpoint, but with the 
baseline value of the corresponding variable instead of the baseline BMI SDS as covariate. Each 
endpoint will be analysed separately. For hsCRP, fasting lipids, fasting insulin, C-peptide, HOMA 
B and HOMA IR, the response and baseline values will be log transformed prior to the analysis.
17.4.1.2
Safety endpoints
Adverse events
AEs will be summarised for the safety analysis set separately for two periods: 
x
In trial: defined as events with onset date on or after the first day of trial product administration 
and no later than the last study visit.
x
On treatment: defined as events with onset date on or after the first day of trial product 
administration and no later than whatever comes first: a) 14 days after the last day on trial 
product, b) FU visit (subjects with trial product discontinued), or c) last study visit (early 
withdrawn subjects without FU visit).
x
A treatment emergent adverse event (TEAE) is defined as an event that occurs in the ‘on 
treatment’ period .  
The AEs will be coded using the most recent version of the Medical Dictionary for regulatory 
Activities (MedDRA). They will be presented in terms of the number and percentage of subjects 
with at least one event, the number of events and the event rate per 1000 years. AEs in the screening 
period will be presented in listings.
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
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Hypoglycaemic episodes
The hypoglycaemic episodes will be summarised descriptively by severity and treatment in terms of 
the number and percentage of subjects with at least one event and the total number of events. In the 
same way as for AEs, there will be separate summaries for the “in trial” and “on treatment” periods. 
Hypoglycaemic episodes in the screening period will be presented in listings.
Classification of Hypoglycaemia: 
Treatment emergent: Hypoglycaemic episodes will be defined as treatment emergent if the onset of 
the episode occurs on or after the first day of trial product administration, and no later than 14 days 
after the last day on trial product.
Nocturnal hypoglycaemic episodes: Are episodes occurring between 00:01 and 05.59 both 
inclusive.
Hypoglycaemic episodes are classified according to the Novo Nordisk classification of 
hypoglycaemia and the American Diabetes Association (ADA) classification of hypoglycaemia (see 
Figure 17–1).
Novo Nordisk classification of hypoglycaemia
In normal physiology, symptoms of hypoglycaemia occur below a plasma glucose level of 3.1 
mmol/L (56 mg/dL)50. Therefore, Novo Nordisk has included hypoglycaemia with plasma glucose 
levels below this cut-off point in the definition of blood glucose (BG) confirmed hypoglycaemia.
Novo Nordisk uses the following classification in addition to the ADA classification: 
x
Severe hypoglycaemia according to the ADA classification51.
x
Symptomatic BG confirmed hypoglycaemia: An episode that is BG confirmed by plasma 
glucose value < 3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia.
x
Asymptomatic BG confirmed hypoglycaemia: An episode that is BG confirmed by plasma 
glucose value < 3.1 mmol/L (56 mg/dL) without symptoms consistent with hypoglycaemia.
x
Severe or BG confirmed symptomatic hypoglycaemia: An episode that is severe according to 
the ADA classification51 or BG confirmed by a plasma glucose value < 3.1 mmol/L (56 mg/dL) 
with symptoms consistent with hypoglycaemia. 
x
BG confirmed hypoglycaemia: An episode that is BG confirmed by a plasma glucose value <3.1 
mmol/L (56 mg/dL) with or without symptoms consistent with hypoglycaemia. 
x
Severe or BG confirmed hypoglycaemia: An episode that is severe according to the ADA 
classification51 or BG confirmed by a plasma glucose value < 3.1 mmol/L (56 mg/dL) with or 
without symptoms consistent with hypoglycaemia. 
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Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
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ADA classification2 of hypoglycaemia 
x
Severe hypoglycaemia: An episode requiring assistance of another person to actively administer 
carbohydrate, glucagon, or take other corrective actions. Plasma glucose concentrations may not 
be available during an event, but neurological recovery following the return of plasma glucose 
to normal is considered sufficient evidence that the event was induced by a low plasma glucose 
concentration.
x
Asymptomatic hypoglycaemia: An episode not accompanied by typical symptoms of 
hypoglycaemia, but with a measured plasma glucose concentration ≤ 3.9 mmol/L (70 mg/dL).
x
Documented symptomatic hypoglycaemia: An episode during which typical symptoms of 
hypoglycaemia are accompanied by a measured plasma glucose concentration ≤ 3.9 mmol/L (70 
mg/dL).
x
Pseudo-hypoglycaemia: An episode during which the person with diabetes reports any of the 
typical symptoms of hypoglycaemia with a measured plasma glucose concentration > 3.9 
mmol/L (70 mg/dL) but approaching that level.
x
Probable symptomatic hypoglycaemia: An episode during which symptoms of hypoglycaemia 
are not accompanied by a plasma glucose determination but that was presumably caused by a 
plasma glucose concentration ≤ 3.9 mmol/L (70 mg/dL).
Hypoglycaemic 
episode 
PG ≤ 3.9 mmol/L 
(70 mg/dL) 
or 
Alleviation of 
symptoms 
or
Seizure, coma or 
fatal 
SMBG
measurement
Asymptomatic 
hypoglycaemia
Documented 
symptomatic 
hypoglycaemia
Pseudo- 
hypoglycaemia
Probable 
symptomatic 
hypoglycaemia
No
Yes
No measurement 
with symptoms
PG > 3.9 mmol/L 
(70 mg/dL)
with symptoms
PG ≤ 3.9 mmol/L 
(70 mg/dL)
with symptoms
PG ≤ 3.9 mmol/L 
(70 mg/dL)
without symptoms
No
Yes
Note: Glucose measurements are performed with capillary blood calibrated to plasma equivalent glucose values
Subject 
able to 
treat him/
herself
Severe 
hypoglycaemia 
(ADA 2013)
 
Figure 17–1
ADA classification of hypoglycaemia
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
100 of 125
Anti-liraglutide antibodies
Anti-liraglutide antibodies will be summarised in terms of the number and percentage of subjects at 
each visit that are antibody-positive and antibody-negative. Similarly, subjects with cross-reactivity 
against endogenous GLP-1 and in vitro neutralising effect will be summarised.
In addition, a comparison of the change in HbA1c and body weight between antibody-positive and 
antibody-negative subjects will be performed using descriptive statistics and graphs. Listings with 
the individual antibody results will also contain information about the HbA1c levels and body 
weight measurements. The impact of anti-liraglutide antibodies on safety will be similarly assessed 
by descriptive comparisons between antibody-positive and antibody-negative subjects.
ECG
Summary statistics and the frequencies of shifts in ECG status from baseline at 16 and 52 weeks 
will be tabulated for each treatment group.
Pulse
Summary statistics and the frequencies of shifts from baseline to 16 and 52 weeks will be tabulated 
for each treatment group. In addition, statistical analyses similar to those made for blood pressure 
will be performed.
Laboratory parameters
Summary statistics will be tabulated for each laboratory parameter. The distributions will also be 
presented graphically using box plots by treatment and week.
For each laboratory parameter, the values will be compared to the relevant reference range. The 
results will be presented as follows:
x
Shifts from baseline at 16 and 52 weeks will be tabulated. The shift tables will include the 
number of subjects below, within and above the reference range at each visit
x
The proportion of subjects with laboratory values outside the reference range will be tabulated 
per visit and treatment group
x
Individual values outside the reference range (abnormal values) will be listed by treatment and 
subject
For amylase and lipase two statistical analyses will be applied, respectively.  The relative change 
(100*value/baseline) will be analysed with an MMRM model as described under sensitivity 
analysis in section 17.3. The response and baseline values will be log transformed prior to the 
analysis. Subjects having a measurement above 3UNR anytime during treatment (yes/no) will be 
analysed using a logistic regression. For the evaluation of the response, all measurements obtained 
during treatment will be included and these measurements are defined as any scheduled or un-
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
101 of 125
scheduled measurements obtained from, but not including, baseline and until, and including, end of 
treatment (visit 19). The model will include treatment, sex, region, baseline glycaemic category, 
stratification factor for Tanner stage and interaction between baseline glycaemic category and 
stratification factor for Tanner stage as fixed effects, and baseline value of the variable and baseline 
age as covariates. Separate analyses will be made for amylase and lipase. The treatment differences 
will be presented as odds ratios together with the associated 95% CIs.
Pubertal status
Tanner stage at screening as well as changes in Tanner stage at 16 and 52 weeks will be 
summarised using descriptive statistics.
Physical examination
Physical examination at screening and changes in physical examination will be summarised.
Mental health questionnaires
Results from the mental health questionnaires PHQ-9 and C-SSRS from part A will be summarised 
using descriptive statistics and the frequencies of shifts from baseline to 16 and 52 weeks will be 
tabulated for each treatment group.
17.4.1.3
Pharmacokinetic endpoints
See section 4.2.2.2.
17.5
Interim analysis
No interim analysis is planned for the efficacy data in this trial. PK data from part A will be 
included in a population PK analysis also including historical data for other populations to aid dose 
selection for part B. Modelling results and safety data will be reviewed by the DMC before subjects 
in Part B will be enrolled in the trial. Before the randomisation code break, modelling results will 
only be communicated to DMC and to individuals involved in dose selection for part B.
17.6
Pharmacokinetic and/or pharmacodynamic modelling
The population PK analysis will be performed by Quantitative Clinical Pharmacology, Novo
Nordisk A/S. A more technical and detailed elaboration of the population PK analysis will be done 
in the modelling analysis plan (MAP), which will be finalised before DBL. The population PK 
analysis will be reported in a modelling analysis report separate from the CTR. The model-derived 
AUC and CL/F will be summarized in the CTR, referring to the modelling analysis report, which 
will be included as an appendix to the CTR. 
The objective of this modelling analysis is to study the liraglutide exposure in paediatric subjects 
with PWS and to investigate the effects on liraglutide plasma concentrations of pre-specified 
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
102 of 125
covariates for these subjects. The analyses will be based on sparse liraglutide plasma concentration
samples from all subjects, dosing history, body measurements and demographic data. Data from 
pre-defined historical trials in relevant populations (for example adults with obesity) might be 
included in the analysis to allow for the comparison with relevant populations. No pre-defined time 
of day is specified for the sampling, but the exact date and time of sampling will be recorded by the 
investigator.
The pharmacokinetics of liraglutide will be evaluated using population PK analysis methods to aim 
for the estimation of the apparent clearance (CL/F) and apparent distribution volume (V/F). 
AUC (0-24hr, ss) and t½ will be derived from the model parameter estimates. Due to the sparseness of 
the data, V/F might not be estimable, and hence, t½ cannot be derived. In case, CL/F will be 
estimated, while other model parameters may be set to prior pre-defined estimates (based on data 
from other trials). The number and timing of samples has been optimised to allow for the estimation 
of CL/F. 
The individual estimates of AUC (0-24hr, ss) will be derived from CL/F, and used to verify adequate 
exposure in patients in part A and B.
The pre-specified analysis will explore the effects of covariates on liraglutide exposure. The 
covariates of interest, such as body weight, sex and age group, will be tested on CL/F. 
Exposure-response analysis
The PK and PD data may be included in exploratory analyses of PK and exposure-response 
relationships, which may also include data from other trials.
17.7
Health economics and/or patient reported outcomes
The questionnaire of hyperphagia score will be evaluated as described in Section 17.4.1.1 The 
evaluation of the mental health questionnaires PHQ-9 and C-SSRS is described in Section 17.4.1.2.
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
103 of 125
18 Ethics
18.1
Benefit-risk assessment of the trial
The trial will be conducted in compliance with ICH GCP47, applicable regulatory requirements and 
in accordance with the Declaration of Helsinki.4
Current treatment options for paediatrics with obesity are limited and include lifestyle modifications 
and orlistat. Both treatment options are associated with suboptimal adherence, which in the case of 
orlistat is due to gastrointestinal adverse reactions52-56. In a head-to-head comparison of liraglutide 
3.0 mg and orlistat in adults with obesity, liraglutide effected significantly greater mean weight loss 
after one year (3.8 kg more than orlistat, p<0.0001) and enabled a greater proportion of subjects to 
lose >5% of baseline body weight57.
The present trial design will be conducted in children only after the safety has been confirmed in 
adolescents with obesity who have a documented history of failing to lose weight with lifestyle 
modifications. Trial subjects will have access to experimental intensified treatment, liraglutide, 
which has been shown to induce weight loss and improve cardio metabolic and quality of life 
parameters in adults with obesity at a dose of liraglutide 3.0 mg. 
To date, two randomised, controlled PK/PD trials with liraglutide have been completed in paediatric 
subjects; trial NN2211-1800 (liraglutide 1.8 mg in subjects with T2DM (10 to ˂ 18 years, duration 
of 5-6 weeks) and trial NN8022-3967 (liraglutide 3.0 mg in subjects with obesity and without 
T2DM (12 to ˂ 18 years), duration of 5-6 weeks). In both trials, liraglutide was generally well 
tolerated, and there were no unexpected safety or tolerability issues identified. 
The safety and efficacy experience with liraglutide in adult and paediatric subjects is described in 
details in the current version of the Investigator’s Brochure58 and any updates hereof.
Identified and expected risks
With respect to the key risks of liraglutide, the most frequently reported adverse events in subjects 
treated with liraglutide 3.0 mg were gastrointestinal (nausea and diarrhoea), with onset in weeks 
1-4; these were mild to moderate, and transient. Other gastrointestinal adverse events included: 
dyspepsia, vomiting, constipation, and abdominal pain. During the post-marketing safety 
surveillance of post-marketing reports from marketed liraglutide (Victoza®), Novo Nordisk A/S 
identified reports containing events related to altered renal function using the standardised 
MedDRA query (SMQ) Acute renal failure. These events are mainly transient and related to 
dehydration and were more frequent in patients with pre-existing renal impairment. Based on the 
known risk associated with subcutaneous administration of proteins and peptides, reported adverse 
events related to allergic reactions and due to the potential severity of these events, allergic 
reactions is an identified risk.
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
104 of 125
An association between the use of GLP-1RAs and pancreatitis has been suggested based on case 
reports received in clinical trials and during the post-marketing experience with liraglutide (in 
T2DM) and other GLP-1RAs. Few events of pancreatitis have been reported in clinical trials with 
liraglutide in weight management. Cases of gallstones (cholelithiasis) and inflammation of the 
gallbladder (cholecystitis) were reported more commonly in adult subjects treated with liraglutide
3.0 mg compared to placebo. From literature, it is well-known that obesity carries an increased risk 
of cholelithiasis and that an association between rapid and or marked weight loss and the 
development of cholelithiasis is present59-62.
Potential risks
There is currently no evidence in humans supporting a causal relationship between liraglutide 
treatment and any of the following potential risks. 
C-cell tumours induced in mice and rats following dosing of liraglutide are believed to be caused by 
a non-genotoxic, specific GLP-1 receptor-mediated mechanism to which mice and rats are 
particularly sensitive. The relevance for humans is likely to be low. No reports of MTC have been 
identified as having a clear causal relationship to liraglutide. Data from the intensive monitoring of 
calcitonin (a marker for MTC) in plasma in the liraglutide clinical development programmes do not 
support an effect of liraglutide effect on calcitonin levels in humans.
Subjects with obesity and subjects with overweight have an increased risk of certain types of 
cancer. In the weight management programme, the reporting rate of neoplasm events confirmed by 
external independent event adjudication was similar with liraglutide and placebo. Based on a 
limited number of reports in the weight management programme, a numerical imbalance was 
observed for events of breast neoplasms in females and colorectal adenomas in males.
In the clinical development programme, mean increase in resting pulse (by 2-3 beats per minute) as 
well as a decrease in systolic blood pressure has been observed. The long-term clinical effects of the 
increase in resting pulse have not been established. There was no indication that the effect on 
resting pulse was dose dependent. However, as the long-term clinical effects of the increase in 
resting pulse have not been established, cardiovascular disorders are an important potential risk also 
for liraglutide in weight management.
Trial-specific risk mitigation
Adrenal insufficiency has been reported in patients with PWS. Although uncommon, the clinical 
manifestations are serious63. Therefore it is important to ensure patients enrolled in the trial do not 
have this condition. As an inclusion criterion, subjects are required to have had testing performed to 
evaluate for adrenal insufficiency before enrolment in the trial, see Section 8.1.1.1.
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
105 of 125
All participating subjects will be monitored closely through frequent site visits and telephone/video 
conference contact. Blood sampling frequency and volume will be minimised for subjects’ safety 
and convenience. The duration of the double-blind trial period is set to 16 weeks in an effort to limit 
the duration of placebo injections and reduce unnecessary subject discomfort/inconvenience 
(Section 5.2).
In order to improve gastrointestinal tolerability of liraglutide, a weekly dose-escalation scheme will 
be used during the initial 4-8 weeks. In contrast to the scheme used for adult subjects, for children 
with PWS subjects, the liraglutide dose will be escalated only if the previous dose is tolerated (as 
judged by the investigator). Furthermore, to resolve tolerability issues, the investigator is allowed to 
down-titrate to the previously given dose or to prolong a dose step for one additional week (see 
section 5.3 for details). Subjects treated with liraglutide should be advised of the potential risk of 
dehydration, renal impairment and acute renal failure, in relation to gastrointestinal AEs and take 
precautions to avoid fluid depletion. Subjects with PWS will not necessarily present with 
gastrointestinal symptoms but are at risk of delayed gastric emptying and treatment with liraglutide 
may exacerbate this. With the potential risk of gastric rupture, the Investigator must pay special 
attention to subjects who vomit or have persistent, severe abdominal pain.
Hypoglycaemic episodes will be assessed in this trial as part of routine safety monitoring. If a 
subject develops T2DM during the trial, he/she will be allowed to remain in the trial if glycaemic 
control can be achieved diet and exercise with additional metformin.
Subjects with a history of acute or chronic pancreatitis will be excluded from trial participation. 
Trial participants will be informed of the characteristic symptoms of acute pancreatitis. 
Furthermore, serum lipase and amylase activity levels will be monitored on a regular basis during 
the course of the trial. If pancreatitis is suspected, liraglutide/liraglutide placebo will be 
discontinued until confirmatory tests have been conducted and appropriate treatment should be 
initiated. Subjects that are diagnosed with acute pancreatitis must have their trial product 
withdrawn.
Subjects with a personal or family history of MTC and subjects with Multiple Endocrine Neoplasia 
Syndrome type 2 are excluded from this trial. In addition, subjects with a screening calcitonin (a 
specific biomarker for C-cell activation) level > 50 ng/L will be excluded from the trial, as hormone 
concentrations above this threshold are indicative of C-cell neoplasia64. During the trial, calcitonin 
levels will be measured at pre-specified trial visits and levels above upper normal range will be 
flagged by the laboratory, and reported to the investigator and Novo Nordisk. 
It is assumed that the benefits and risks associated with long-term liraglutide treatment will be the 
same for the paediatric population with PWS as for the adult populations with the exception of any 
unforeseen effects on growth and pubertal development. In non-clinical studies, dosing liraglutide 
from post-natal day 21 to 91 in juvenile rats caused a dose-dependent delay in sexual maturation,
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11
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
106 of 125
defined in females as age of animals for vaginal opening, and for males as preputial separation 
(both onset and end) that was most pronounced in females. A delay in age of sexual maturation is 
known to occur in rats and humans under caloric restriction/increased energy expenditure7. Estrous 
cycle length was slightly extended among high-dose female rats during treatment but returned to 
normal after two weeks of recovery.
Pubertal and growth related hormonal levels, biochemical parameters of bone metabolism and 
growth and pubertal development will be monitored in the present trial. An external independent 
DMC will be established to review and evaluate accumulative data from an ongoing clinical trial in 
order to protect the safety of the subjects and to evaluate the evolving risk-benefit profile of 
liraglutide. Additionally an expert in paediatric calcitonin will review abnormal levels as described 
in Appendix C.
Conclusion
Given the scarcity and limitations of available treatment options for paediatric obesity, and obesity 
associated with PWS, the potential weight loss and cardio-metabolic benefits of liraglutide and its 
acceptable safety/tolerability profile noted in the short-term paediatric trials, it is concluded that the 
potential benefits from participating in the present trial outweigh the potential risks. Based on the
tolerability seen and model-estimated steady-state liraglutide exposure in the previous PK/PD trials 
in children 10 to less than 18 years with T2DM and 12 to less than 18 years with obesity, a starting 
dose of 0.6 mg has been chosen in children ≥ 12 and ˂ 18 years. Dosing in children ≥ 6 and ˂ 12 
years of age will be determined based on the results of the NN8022-4181 trial and on the DMC 
review of PK and safety data from the 16-week double-blind period of part A of this trial.
18.2
Informed consent
In seeking and documenting informed consent, the investigator must comply with applicable 
regulatory requirement(s) and adhere to ICH GCP47 and the requirements in the Declaration of 
Helsinki4.
Before any trial-related activity, the investigator must give the subject and/or the subject’s legally 
acceptable representative (LAR) verbal and written information about the trial and the procedures 
involved in a form that the subject or the subject’s LAR can read and understand. This includes the 
use of an impartial witness where required according to local requirements.
The subjects or the subject’s LAR must be fully informed of their rights and responsibilities while 
participating in the trial as well as possible disadvantages of being treated with the trial products. In 
addition to the information given to the subject’s LAR, the child or adolescent must be given 
information according to his/her capacity to understand, always taking into consideration the 
subject’s presumed willingness to participate in a clinical trial.
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11
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
107 of 125
The investigator must ensure the subject ample time to come to a decision whether or not to 
participate in the trial. The informed consent/assent must be signed at least one day prior to V2 as 
the subject must attend this visit fasting. 
A voluntary, signed and personally dated informed consent must be obtained from the subject 
and/or the subject’s LAR before any trial-related activity.
If the minor reaches legal age while participating in the trial and has only signed an age specific 
informed consent/child assent form, the subject has to re-consent to the informed consent form 
signed by the subject’s LAR.
The responsibility for seeking informed consent must remain with the investigator, but the 
investigator may delegate the task to a medically qualified person, in accordance with local 
requirements. The written informed consent must be signed and personally dated by the person who 
seeks the informed consent before any trial-related activity.
If information becomes available that may be relevant to the subject’s willingness to continue 
participating in the trial, the investigator must inform the subject and/or the subject’s LAR in a 
timely manner, and a revised written subject information must be provided and a new informed 
consent must be obtained.
18.3
Data handling
If the subject is withdrawn from the trial or lost to follow up, then the subject’s data will be handled 
as follows:
x
Data already collected and data collected at the end-of-trial visit will be retained by Novo 
Nordisk, entered into the database and used for the trial report. 
x
Safety events will be reported to Novo Nordisk and regulatory authorities according to 
local/national requirements.
If data is used, it will always be in accordance with local regulations and IRBs/IECs.
18.4
Information to subject during trial
The site will be offered a communication package to the subject during the conduct of the trial. The 
package content is issued by Novo Nordisk. The communication package will contain the letters 
intended for distribution to the subjects. The letters will be translated and adjusted to local 
requirements and distributed to the subject by discretion of the investigator. The subject may 
receive a “welcome to the trial letter” and a “thank you for your participation letter” after 
completion of the trial. Further the subject may receive letters during the trial.
All written information to subjects must be sent to IRB/IEC for approval/favourable opinion and to 
regulatory authorities for approval or notification according to local regulations.
3URWRFROSURWRFROYHUVLRQ_
11
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
108 of 125
18.5
Premature termination of the trial and/or trial site
Novo Nordisk, the DMC, the IRBs/IECs or a regulatory authority may decide to stop the trial, part 
of the trial or a trial site at any time, but agreement on procedures to be followed must be obtained.
If a trial is suspended or prematurely terminated, the investigator must inform the subjects promptly 
and ensure appropriate therapy and follow-up. The investigator and/or Novo Nordisk must also 
promptly inform the regulatory authorities and IRBs/IECs and provide a detailed written 
explanation. 
If, after the termination of the trial, the benefit-risk analysis changes, the new evaluation must be 
provided to the IRBs/IECs in case it has an impact on the planned follow-up of subjects who have 
participated in the trial. If it has an impact, the actions needed to inform and protect the subjects 
should be described.
3URWRFROSURWRFROYHUVLRQ_
11
RI
CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
109 of 125
19 Protocol compliance
Deviations from the protocol should be avoided.
If deviations do occur, the investigator must inform the monitor and the implications of the 
deviation must be reviewed and discussed.
Deviations must be documented and explained in a protocol deviation by stating the reason, date, 
and the action(s) taken. Some deviations, for which corrections are not possible, can be 
acknowledged and confirmed via edit checks in the eCRF or via listings from the clinical database. 
Documentation on protocol deviations must be kept in the investigator's trial master file and 
sponsor trial master file.
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11
RI
CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
110 of 125
20 Audits and inspections
Any aspect of the clinical trial may be subject to audits conducted by Novo Nordisk or inspections 
from domestic or foreign regulatory authorities or from IRBs/IECs. Audits and inspections may 
take place during or after the trial. The investigator and the site staff as well as Novo Nordisk staff 
have an obligation to cooperate and assist in audits and inspections. This includes giving auditors 
and inspectors direct access to all source documents and other documents at the trial site relevant to 
the clinical trial. This includes permission to examine, analyse, verify and reproduce any record(s) 
and report(s) that are relevant to the evaluation of the trial.
3URWRFROSURWRFROYHUVLRQ_
11
RI
CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
111 of 125
21  Critical documents
Before a trial site is allowed to start screening subjects, the following documents must be available 
to Novo Nordisk:
x
Regulatory approval and/or acknowledgement of notification as required 
x
Approval/favourable opinion from IRBs/IECs clearly identifying the documents reviewed as 
follows: protocol, any protocol amendments, subject information/informed consent form, any 
other written information to be provided to the subject and subject recruitment materials
x
List of IRB/IEC members and/or constitution (or a general assurance number/statement of 
compliance)
x
Curricula vitae of investigator and sub-investigator(s) (current, dated and signed - must include 
documented GCP training or a certificate)
x
Signed receipt of Investigator's Brochure 
x
Signed and dated Agreement on Protocol
x
Signed and dated agreement on protocol amendment, if applicable
x
Contract, signed by the investigator and/or appropriate parties on behalf of the investigator’s site 
and Novo Nordisk
x
Source document agreement
x
Central laboratory certification and normal ranges
x
Insurance statement, if applicable
x
Financial disclosure form from investigator and sub-investigator(s)
x
For US trial sites: FDA form 1572 must be completed and signed by the investigator at each site
FDA form 1572:
For US sites:
x
Intended for US sites
x
Conducted for US sites
x
All investigators, as described above, wil sign FDA form 1572
For sites outside the US:
x
Intended for participating sites outside of the US
x
Not conducted under the IND
x
All investigators outside of the US will not sign FDA form 1572
Novo Nordisk will analyse and report data from all sites together if more than one site is involved in 
the trial.
By signing the protocol, each investigator agrees to comply fully with ICH GCP47, applicable
regulatory requirements and the Declaration of Helsinki4.
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11
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
112 of 125
By signing the protocol, each investigator also agrees to allow Novo Nordisk to make investigator's 
name and information about site name and address publically available if this is required by 
national or international regulations.
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11
RI
CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
113 of 125
22 Responsibilities
The investigator is accountable for the conduct of the trial at his/her site. If any tasks are delegated, 
the investigator must maintain a log of appropriately qualified persons to whom he/she has 
delegated specified trial-related duties. The investigator must ensure that there is adequate training 
for all staff participating in the conduct of the trial. It is the investigator's responsibility to supervise 
the conduct of the trial and to protect the rights, safety, and well-being of the subjects.
A qualified physician, who is an investigator or a sub-investigator for the trial, must be responsible 
for all trial-related medical decisions.
The investigator must ensure adequate supervision of the conduct of the trial at the trial site. 
The investigator will follow instructions from Novo Nordisk when processing data.
The investigator is responsible for filing essential documents (i.e. those documents which 
individually and collectively permit evaluation of the conduct of a trial and the quality of the data 
produced) in the investigator trial master file. The documents including the subject identification 
code list should be kept in a secure locked facility, so no unauthorised persons can get access to the 
data.
The investigator will take all necessary technical and organisational safety measures to prevent 
accidental or wrongful destruction, loss or deterioration of data. The investigator will prevent any 
unauthorised access to data or any other processing of data against applicable law. The investigator 
must be able to provide the necessary information or otherwise demonstrate to Novo Nordisk that 
such technical and organisational safety measures have been taken.
During any period of unavailability, the investigator must delegate responsibility for medical care of 
subjects to a specific qualified physician who will be readily available to subjects during that time.
If the investigator is no longer able to fulfil the role as investigator (e.g. if he/she moves or retires), 
a new investigator will be appointed in consultation with Novo Nordisk. 
The investigator and other site personnel must have sufficient English skills according to their 
assigned task(s).
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
114 of 125
23 Reports and publications
The information obtained during the conduct of this trial is considered confidential, and may be 
used by or on behalf of Novo Nordisk for regulatory purposes as well as for the general 
development of the trial product. All information supplied by Novo Nordisk in connection with this 
trial shall remain the sole property of Novo Nordisk and is to be considered confidential 
information. 
No confidential information shall be disclosed to others without prior written consent from Novo 
Nordisk. Such information shall not be used except in the performance of this trial. The information 
obtained during this trial may be made available to other physicians who are conducting other 
clinical trials with the trial product, if deemed necessary by Novo Nordisk. Provided that certain 
conditions are fulfilled, Novo Nordisk may grant access to information obtained during this trial to 
researchers who require access for research projects studying the same disease and/or trial product 
studied in this trial.
Novo Nordisk may publish on its clinical trials website a redacted clinical trial report for this trial.
One investigator will be appointed by Novo Nordisk to review and sign the clinical trial report 
(signatory investigator) on behalf of all participating investigators. The signatory investigator will 
be appointed based upon the criteria defined by the International Committee of Medical Journal 
Editors for research publications35.
23.1
Communication of results
Novo Nordisk commits to communicating, and otherwise making available for public disclosure, 
results of trials regardless of outcome. Public disclosure includes publication of a paper in a 
scientific journal, abstract submission with a poster or oral presentation at a scientific meeting, or 
disclosure by other means.
The results of this trial will be subject to public disclosure on external web sites according to 
international and national regulations, as reflected in the Novo Nordisk Code of Conduct for 
Clinical Trial Disclosure34.
Novo Nordisk reserves the right to defer the release of data until specified milestones are reached, 
for example when the clinical trial report is available. This includes the right not to release the 
results of interim analyses, because the release of such information may influence the results of the 
entire trial.
At the end of the trial, one or more scientific publications may be prepared collaboratively by the 
investigator(s) and Novo Nordisk. Novo Nordisk reserves the right to postpone publication and/or 
communication for up to 60 days to protect intellectual property.
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
115 of 125
In all cases the trial results will be reported in an objective, accurate, balanced and complete 
manner, with a discussion of the strengths and limitations. All authors will be given the relevant 
statistical tables, figures, and reports needed to evaluate the planned publication. In the event of any 
disagreement on the content of any publication, both the investigators' and Novo Nordisk opinions 
will be fairly and sufficiently represented in the publication.
Where required by the journal, the investigator from each trial site will be named in an 
acknowledgement or in the supplementary material, as specified by the journal. 
Novo Nordisk maintains the right to be informed of plans by any investigator to publish and to 
review any scientific paper, presentation, communication or other information concerning the
investigation described in this protocol. Any such communication must be submitted in writing to 
Novo Nordisk before submission for comments. Comments will be given within four weeks from 
receipt of the planned communication.
23.1.1
Authorship
Authorship of publications should be in accordance with the Uniform Requirements of the 
International Committee of Medical Journal Editors35 (sometimes referred to as the Vancouver 
Criteria).
23.1.2
Site-specific publication(s) by investigator(s)
For a multi-centre clinical trial, analyses based on single-site data usually have significant statistical 
limitations and frequently do not provide meaningful information for healthcare professionals or 
subjects, and therefore may not be supported by Novo Nordisk. It is a Novo Nordisk policy that 
such individual reports do not precede the primary manuscript and should always reference the 
primary manuscript of the trial.
Novo Nordisk reserves the right to prior review of such publications. Further to allow for the 
primary manuscript to be published as the first, Novo Nordisk asks for deferment of publication of 
individual site results until the primary manuscript is accepted for publication. As Novo Nordisk 
wants to live up to the industry publication policy, submission of a primary publication will take 
place no later than 18 months after trial completion. 
23.2
Investigator access to data and review of results
As owner of the trial database, Novo Nordisk has the discretion to determine who will have access 
to the database. 
Individual investigators will have their own research subjects' data, and will be provided with the 
randomisation code after results are available.
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
116 of 125
24 Retention of clinical trial documentation and human biospecimens
24.1
Retention of clinical trial documentation
Subject's medical records must be kept for the maximum period permitted by the hospital, 
institution or private practice.
The investigator must agree to archive the documentation (this includes both electronic and paper-
based records) pertaining to the trial in an archive after completion or discontinuation of the trial if 
not otherwise notified. The investigator should not destroy any documents without prior permission 
from Novo Nordisk. If the investigator cannot archive the documents at the trial site, Novo Nordisk 
can refer the investigator to an independent archive provider that has a system in place to allow only 
the investigator to access the files.
The investigator must be able to access his/her trial documents without involving Novo Nordisk in 
any way. Site-specific CRFs and other subject data (in an electronic readable format or as paper 
copies or prints) will be provided to the investigator before access is revoked to the systems and/or 
electronic devices supplied by Novo Nordisk. These data must be retained by the trial site. If the 
provided data (e.g. the CD-ROM) is not readable during the entire storage period, the investigator 
can request a new copy. A copy of all data will be stored by Novo Nordisk.
Novo Nordisk will maintain Novo Nordisk documentation pertaining to the trial for as long as the 
product is on the market plus 20 years. 
The files from the trial site/institution must be retained for 15 years after the completion of the trial, 
or longer if required by local regulations or Novo Nordisk. In any case trial files cannot be 
destroyed until the trial site/institution is notified by Novo Nordisk. The deletion process must 
ensure confidentiality of data and must be done in accordance with local regulatory requirements.
24.2
Retention of human biospecimens
Anti-liraglutide antibody samples are taken during the trial (section 2). The samples are sent via
central lab to a special lab, where they are analysed. Samples from V19 that are anti-drug antibody 
positive as well as a number of anti-drug antibody negative baseline samples will be sent from the 
special lab to Novo Nordisk for further analysis. Only personnel from the special lab and Novo 
Nordisk will have access to the samples. The samples may be stored until marketing authorisation 
by regulatory authorities (USA and EU) but no longer than 15 years after end of trial as further 
characterisation of the antibody response may be requested by the health authorities.
None of the data will be identified by name. Antibody samples will be identified only by a subject 
number, a visit number and a trial identification number. In the event that the collected antibody 
samples will be used in the future, the investigator will be informed by Novo Nordisk about the 
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
117 of 125
results if the findings are deemed clinically relevant. In this case, a written summary of the findings, 
including listings of subject specific values, will be provided once a firm conclusion from the 
results has been drawn by Novo Nordisk.
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
118 of 125
25 Institutional Review Boards/Independent Ethics Committees and 
regulatory authorities
IRB/IEC:
Written approval or favourable opinion must be obtained from IRB/IEC prior to commencement of 
the trial.
During the trial, the investigator or Novo Nordisk, as applicable, must promptly report the 
following to the IRB/IEC, in accordance with local requirements: updates to Investigator's 
Brochure, unexpected SAEs where a causal relationship cannot be ruled out, protocol amendments 
according to local requirements, deviations to the protocol implemented to eliminate immediate 
hazards to the subjects, new information that may affect adversely the safety of the subjects or the 
conduct of the trial (including new benefit-risk analysis in case it will have an impact on the 
planned follow-up of the subjects), annually written summaries of the trial status, and other 
documents as required by the local IRB/IEC.
The investigator must ensure submission of the clinical trial report synopsis to the IRB/IEC.
Protocol amendments must not be implemented before approval or favourable opinion according to 
local regulations, unless necessary to eliminate immediate hazards to the subjects.
The investigator must maintain an accurate and complete record of all submissions made to the 
IRB/IEC. The records must be filed in the investigator trial master file and copies must be sent to 
Novo Nordisk.
Regulatory Authorities:
Regulatory authorities will receive the clinical trial application, protocol amendments, reports on 
SAEs, and the clinical trial report according to national requirements.
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
119 of 125
26 Indemnity statement
Novo Nordisk carries product liability for its products, and liability as assumed under the special
laws, acts and/or guidelines for conducting clinical trials in any country, unless others have shown 
negligence.
Novo Nordisk assumes no liability in the event of negligence, or any other liability of the sites or 
investigators conducting the trial, or by persons for whom the said site or investigator are 
responsible.
Novo Nordisk accepts liability in accordance with:
France: The French Public Health Code article L 1121-10 (law n° 2004-806 of 9 August 2004 art. 
88 I, IX Journal Officiel of 11 August 2004. "The sponsor is responsible for identification of the 
harmful consequences of the biomedical research for the person lending himself thereto and for 
indemnification of his beneficiaries, except in case of proof, incumbent on it, that the prejudice is 
not attributable to his fault of or the fault of any intervening party, without the sponsor's being 
entitled to call on acts by a third party or the voluntary withdrawal of the person who had initially 
consented to cooperating in the research.
Netherlands: Wetgeving betreffende geneesmiddelen; geneesmiddelenwet 1 juli 2007 (Medicines 
Law, 1 July 2007). De Wet Medisch-wetenschappelijk Onderzoek met mensen (WMO), 1 maart 
2006 (Medical Research Involving Human Subjects Act, 1 March 2006). Besluit verplichte 
verzekering bij medisch-wetenschappelijk onderzoek met mensen 2015, 24 november 2014 (Decree 
compulsory insurance in medical research involving human subjects 2015, 24 November 2014). 
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
120 of 125
27 References
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Published July 2013.  2013. 
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
121 of 125
14 Chen C, Visootsak J, Dills S, Graham JM, Jr. Prader-Willi syndrome: an update and review 
for the primary pediatrician. Clin Pediatr (Phila) 2007; 46(7):580-591.
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22 Secher A, Jelsing J, Baquero AF, Hecksher-Sorensen J, Cowley MA, Dalboge LS et al. The 
arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss. J Clin 
Invest 2014; 124(10):4473-4488.
23 van CJ, Sloth B, Jensen CB, Flint A, Blaak EE, Saris WH. Effects of the once-daily GLP-1
analog liraglutide on gastric emptying, glycemic parameters, appetite and energy metabolism 
in obese, non-diabetic adults. Int J Obes (Lond) 2014; 38(6):784-793.
24 Blonde L, Russell-Jones D. The safety and efficacy of liraglutide with or without oral 
antidiabetic drug therapy in type 2 diabetes: an overview of the LEAD 1-5 studies. Diabetes 
Obes Metab 2009; 11 Suppl 3:26-34.
25 Novo Nordisk A/S. Investigator's Brochure: Liraglutide in Weight Management (edition 7) or 
any updates hereof. Novo Nordisk A/S, editor.  2015. 
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
122 of 125
26 Wadden TA, Hollander P, Klein S, Niswender K, Woo V, Hale PM et al. Weight maintenance 
and additional weight loss with liraglutide after low-calorie-diet-induced weight loss: the 
SCALE Maintenance randomized study. Int J Obes (Lond) 2013; 37(11):1443-1451.
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28 Guidelines on clinical evaluation of medicinal products used in weight control 
(CPMP/EWP/281/96 Rev. 1). Addendum on weight control in 
children.EMEA/CHMP/EWP/517497/2007. London 24 July. 2008.
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products used in weight control (CPMP/EWP/281/96 Rev.1). Addendum on weight control in 
children. EMEA/CHMP/EWP/517497/2007. London, 24 July 2008.  
30 Cole TJ, Bellizzi MC, Flegal KM, Dietz WH. Establishing a standard definition for child 
overweight and obesity worldwide: international survey. BMJ 2000; 320(7244):1240-1243.
31 Cassidy SB, Driscoll DJ. Prader-Willi syndrome. Eur J Hum Genet 2009; 17(1):3-13.
32 Colmenares A, Pinto G, Taupin P, Giuseppe A, Odent T, Trivin C et al. Effects on growth and 
metabolism of growth hormone treatment for 3 years in 36 children with Prader-Willi 
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33 Crino A, Di GG, Manco M, Grugni G, Maggioni A. Effects of growth hormone therapy on 
glucose metabolism and insulin sensitivity indices in prepubertal children with Prader-Willi 
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34 Novo Nordisk: http://novonordisk-trials.com/website/content/how-we-disclose-trial-
information.aspx.
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37 The European Parliament and the Council of the European Council. Regulation (EC) No 
726/2004 of the European Parliament and of the Council of 31 March 2004 laying down 
Community procedures for the authorisation and supervision of medicinal products for human 
and veterinary use and establishing a European Medicines Agency, article 57. Official Journal 
of the European Communities April 2001.
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
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38 The European Parliament and the Council of the European Council. Regulation (EC) No
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40 Secher A, Jelsing J, Baquero AF, Hecksher-Sorensen J, Cowley MA, Dalboge LS. The acurate 
nucleus mediates GLP-1 receptor agnist liraglutide-dependent weight loss. J Clin Invest 2014; 
124(10):4473-4488.
41 van CJ, Sloth B, Jensen CB, Flint A, Blaak EE SW. Effects of the once-daily GLP-1 analog 
liraglutide on gastric emptying, glycemic parameters, appetite and energy metabolism in 
obese, non-diabetic adults. Int J Obes (Lond) 2014; 38(6):784-793.
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Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
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50 Schwartz NS, Clutter WE, Shah SD, Cryer PE. Glycemic thresholds for activation of glucose 
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79(3):777-781.
51 Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L et al. Hypoglycemia and 
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52 Han JC, Lawlor DA, Kimm SY. Childhood obesity. Lancet 2010; 375(9727):1737-1748.
53 Kohn M, Rees JM, Brill S, Fonseca V, Jacobson M, Katzman DK. Preventing and treating 
adolescent obesity: a position paper of the society for adolescent medicine. J Adolesc Health 
2006; 38(6):784-787.
54 Miller JL, Silverstein JH. Management approaches for pediatric obesity. NAT CLIN PRACT 
ENDOCRINOL METAB 2007; 3(12):810-818.
55 Barlow SE. Expert committee recommendations regarding the prevention, assessment, and 
treatment of child and adolescent overweight and obesity: Summary report. Pediatrics 2007; 
120:S164-S192.
56 Viner RM, Hsia Y, Tomsic T, Wong IC. Efficacy and safety of anti-obesity drugs in children 
and adolescents: systematic review and meta-analysis. Obes Rev 2010; 11(8):593-602.
57 Astrup A, Rossner S, Van Gaal L, Rissanen A, Niskanen L, Al Hakim M et al. Effects of 
liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study. 
Lancet 2009; 374:1606-1616.
58 Investigator's Brochure, Liraglutide, NN8022, 7th Edition. Novo Nordisk A/S. 28 Jan 2015.
59 Shaffer EA. Epidemiology and risk factors for gallstone disease: has the paradigm changed in 
the 21st century? Curr Gastroenterol Rep 2005; 7(2):132-140.
60 Erlinger S. Gallstones in obesity and weight loss. Eur J Gastroenterol Hepatol 2000; 
12(12):1347-1352.
61 Amaral JF, Thompson WR. Gallbladder disease in the morbidly obese. Am J Surg 1985; 
149(4):551-557.
62 Tsai CJ, Leitzmann MF, Willett WC, Giovannucci EL. Prospective study of abdominal 
adiposity and gallstone disease in US men. Am J Clin Nutr 2004; 80(1):38-44.
63 Cataletto M, Angula M, Hertz G WB. Prader-Willi syndrome A primer for clinicians. Int J 
Pediatr Endocrinol 2011;(1):12.
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11
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CONFIDENTIAL


Protocol: Liraglutide
CONFIDENTIAL
Date:
16 July 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
5.0
UTN: U1111-1162-7884
Status:
Final
EudraCT no.: 2014-004415-37
Page:
125 of 125
64 Fitch A, Fox C, Bauer K, Gross A, Heim C, Judge-Diets J et al. Institute for Clinical System 
Improvement. Prevention and Management of Obesity for Children and Adolescents. Institute 
for Clinical System Improvement 2013; 2013(2013). 
65   The European Parliament and the Council of the European Council. Directive 2001/20/EC of 
the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, 
regulations and administrative provisions of the member states relating to the implementation 
of good clinical practice in the conduct of clinical trials on medicinal products for human use. 
2001.
3URWRFROSURWRFROYHUVLRQ_
11
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CONFIDENTIAL


Global and country key Novo Nordisk staff 
Attachments I and II (if applicable) to the protocol are located in the Trial Master File. 
Content: Global key staff and Country key staff 
VV-CLIN-109705
2.0
.
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
Liraglutide 3.0 mg
Trial ID: NN8022-4179
Clinical Trial Report
Appendix 16.1.1
25 March 2021
1.0
Final
CONFIDENTIAL


Liraglutide
CONFIDENTIAL
Date:
22 December 2017
Novo Nordisk
Trial ID: NN8022-4179
Version:
3.0
Protocol - Appendix A
Status:
Final
EudraCT No.: 2014-004415-37
Page:
1 of 17
Appendix A
Liraglutide
NN8022-4179
Body mass index for age
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties
3URWRFRODSS[DY_
11
RI
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Liraglutide
CONFIDENTIAL
Date:
22 December 2017
Novo Nordisk
Trial ID: NN8022-4179
Version:
3.0
Protocol - Appendix A
Status:
Final
EudraCT No.: 2014-004415-37
Page:
2 of 17
Table of Contents
Page
Table of Contents........................................................................................................................................2
List of in-text tables ....................................................................................................................................3
1
Introduction .........................................................................................................................................4
2
International BMI cut of points...........................................................................................................5
3
Determination of a subject’s BMI > 95th percentile...........................................................................6
4
References ..........................................................................................................................................17
3URWRFRODSS[DY_
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RI
CONFIDENTIAL


Liraglutide
CONFIDENTIAL
Date:
22 December 2017
Novo Nordisk
Trial ID: NN8022-4179
Version:
3.0
Protocol - Appendix A
Status:
Final
EudraCT No.: 2014-004415-37
Page:
3 of 17
List of in-text tables
Page
Table 1
International cut off points for body mass index for obesity by sex for children between 6 
and 18 years, defined to pass through BMI of 30 kg/m2 at age 18. Obtained by averaging 
data from Brazil, Great Britain, Hong Kong, Netherlands, Singapore, and United States1...........5
Table 2
International cut off points for body mass index for obesity by sex for children between 6 
and 18 years, defined to pass through BMI of 25 kg/m2 at age 18. Obtained by averaging 
data from Brazil, Great Britain, Hong Kong, Netherlands, Singapore, and United States ...........6
Table 3
BMI-for-age GIRLS 6 to 18 years (percentiles) .........................................................................7
Table 4
BMI-for-age-BOYS2 6 to 18 years (percentiles) ......................................................................12
3URWRFRODSS[DY_
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RI
CONFIDENTIAL


Liraglutide
CONFIDENTIAL
Date:
22 December 2017
Novo Nordisk
Trial ID: NN8022-4179
Version:
3.0
Protocol - Appendix A
Status:
Final
EudraCT No.: 2014-004415-37
Page:
4 of 17
1
Introduction
According to protocol inclusion criterion no. 5subjects must have a BMI corresponding to ≥ 30
kg/m2for adults by international cut-off points and ≥ the 95th percentile for age and sex. Table 1, 
table 3 and table 4must be used to determine subjecteligibility.
Table 2 should be used if subjects are assigned a maintenance diet.
3URWRFRODSS[DY_
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RI
CONFIDENTIAL


Liraglutide
CONFIDENTIAL
Date:
22 December 2017
Novo Nordisk
Trial ID: NN8022-4179
Version:
3.0
Protocol - Appendix A
Status:
Final
EudraCT No.: 2014-004415-37
Page:
5 of 17
2
International BMI cut of points
Table 1
International cut off points for body mass index for obesity by sex for children 
between 6 and 18 years, defined to pass through BMI of 30 kg/m2 at age 18.
Obtained by averaging data from Brazil, Great Britain, Hong Kong, Netherlands, 
Singapore, and United States1
Age : Years
Body mass index 30 kg/m2
Males
Body mass index 30 kg/m2
Females
6
19.78
19.65
6.5
20.23
20.08
7
20.63
20.51
7.5
21.09
21.01
8
21.60
21.57
8.5
22.17
22.18
9
22.77
22.81
9.5
23.39
23.46
10
24.00
24.11
10.5
24.57
24.77
11
25.10
25.42
11.5
25.58
26.05
12
26.02
26.67
12.5
26.43
27.24
13
26.84
27.76
13.5
27.25
28.20
14
27.63
28.57
14.5
27.98
28.87
15
28.30
29.11
15.5
28.60
29.29
16
28.88
29.43
16.5
29.14
29.56
17
29.41
29.69
17.5
29.70
29.84
18
30
30
3URWRFRODSS[DY_
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RI
CONFIDENTIAL


Liraglutide
CONFIDENTIAL
Date:
22 December 2017
Novo Nordisk
Trial ID: NN8022-4179
Version:
3.0
Protocol - Appendix A
Status:
Final
EudraCT No.: 2014-004415-37
Page:
6 of 17
Table 2
International cut off points for body mass index for obesity by sex for children 
between 6 and 18 years, defined to pass through BMI of 25 kg/m2 at age 18.
Obtained by averaging data from Brazil, Great Britain, Hong Kong, Netherlands, 
Singapore, and United States1
Age : Years
Body mass index 25 kg/m2
Males
Body mass index 25 kg/m2
Females
6
17.55
17.34
6.5
17.71
17.53
7
17.92
17.75
7.5
18.16
18.03
8
18.44
18.35
8.5
18.76
18.69
9
19.10
19.07
9.5
19.46
19.45
10
19.84
19.86
10.5
20.20
20.29
11
20.55
20.74
11.5
20.89
21.20
12
21.22
21.68
12.5
21.56
22.14
13
21.91
22.58
13.5
22.27
22.98
14
22.62
23.34
14.5
22.96
23.66
15
23.29
23.94
15.5
23.60
24.17
16
23.90
24.37
16.5
24.19
24.54
17
24.46
24.70
17.5
24.73
24.85
18
25
25
3URWRFRODSS[DY_
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RI
CONFIDENTIAL


Liraglutide
CONFIDENTIAL
Date:
22 December 2017
Novo Nordisk
Trial ID: NN8022-4179
Version:
3.0
Protocol - Appendix A
Status:
Final
EudraCT No.: 2014-004415-37
Page:
7 of 17
Determination of a subject’s BMI > 95th percentile2
Table 3
BMI-for-age GIRLS
6 to 18 years (percentiles) 
Year: Month
Month
95th percentile
(BMI in kg/m2)
6:0
72
18.4
6:1
73
18.4
6:2
74
18.4
6:3
75
18.5
6:4
76
18.5
6:5
77
18.5
6:6
78
18.6
6:7
79
18.6
6:8
80
18.6
6:9
81
18.7
6:10
82
18.7
6:11
83
18.8
7:0
84
18.8
7:1
85
18.9
7:2
86
18.9
7:3
87
19.0
7:4
88
19.0
7:5
89
19.1
7:6
90
19.1
7:7
91
19.2
7:8
92
19.2
7:9
93
19.3
7:10
94
19.3
7:11
95
19.4
8:0
96
19.4
8:1
97
19.5
8:2
98
19.6
8:3
99
19.6
3URWRFRODSS[DY_
11
RI
CONFIDENTIAL


Liraglutide
CONFIDENTIAL
Date:
22 December 2017
Novo Nordisk
Trial ID: NN8022-4179
Version:
3.0
Protocol - Appendix A
Status:
Final
EudraCT No.: 2014-004415-37
Page:
8 of 17
Year: Month
Month
95th percentile
(BMI in kg/m2)
8:4
100
19.7
8:5
101
19.8
8:6
102
19.8
8:7
103
19.9
8:8
104
20.0
8:9
105
20.0
9:10
106
20.1
9:11
107
20.2
9:0
108
20.2
9:1
109
20.3
9:2
110
20.4
9:3
111
20.5
9:4
112
20.5
9:5
113
20.6
9:6
114
20.7
9:7
115
20.7
9:8
116
20.8
9:9
117
20.9
9:10
118
21.0
9:11
119
21.1
10:0
120
21.1
10:1
121
21.2
10:2
122
21.3
10:3
123
21.4
10:4
124
21.5
10:5
125
21.5
10:6
126
21.6
10:7
127
21.7
10:8
128
21.8
10:9
129
21.9
10:10
130
22.0
3URWRFRODSS[DY_
11
RI
CONFIDENTIAL


Liraglutide
CONFIDENTIAL
Date:
22 December 2017
Novo Nordisk
Trial ID: NN8022-4179
Version:
3.0
Protocol - Appendix A
Status:
Final
EudraCT No.: 2014-004415-37
Page:
9 of 17
Year: Month
Month
95th percentile
(BMI in kg/m2)
10:11
131
22.1
11:0
132
22.2
11:1
133
22.2
11:2
134
22.3
11:3
135
22.4
11:4
136
22.5
11:5
137
22.6
11:6
138
22.7
11:7
139
22.8
11:8
140
22.9
11:9
141
23.0
11:10
142
23.1
11:11
143
23.2
12:0
144
23.3
12:1
145
23.4
12:2
146
23.5
12:3
147
23.6
12:4
148
23.7
12:5
149
23.8
12:6
150
23.9
12:7
151
23.9
12:8
152
24.0
12:9
153
24.1
12:10
154
24.2
12:11
155
24.3
13:0
156
24.4
13:1
157
24.5
13:2
158
24.6
13:3
159
24.7
13:4
160
24.8
13:5
161
24.9
3URWRFRODSS[DY_
11
RI
CONFIDENTIAL


Liraglutide
CONFIDENTIAL
Date:
22 December 2017
Novo Nordisk
Trial ID: NN8022-4179
Version:
3.0
Protocol - Appendix A
Status:
Final
EudraCT No.: 2014-004415-37
Page:
10 of 17
Year: Month
Month
95th percentile
(BMI in kg/m2)
13:6
162
25.0
13:7
163
25.1
13:8
164
25.1
13:9
165
25.2
13:10
166
25.3
13:11
167
25.4
14:0
168
25.5
14:1
169
25.6
14:2
170
25.6
14:3
171
25.7
14:4
172
25.8
14:5
173
25.9
14:6
174
25.9
14:7
175
26.0
14:8
176
26.1
14:9
177
26.1
14:10
178
26.2
14:11
179
26.3
15:0
180
26.3
15:1
181
26.4
15:2
182
26.5
15:3
183
26.5
15:4
184
26.6
15:5
185
26.6
15:6
186
26.7
15:7
187
26.7
15:8
188
26.8
15:9
189
26.8
15:10
190
26.9
15:11
191
26.9
16:0
192
27.0
3URWRFRODSS[DY_
11
RI
CONFIDENTIAL


Liraglutide
CONFIDENTIAL
Date:
22 December 2017
Novo Nordisk
Trial ID: NN8022-4179
Version:
3.0
Protocol - Appendix A
Status:
Final
EudraCT No.: 2014-004415-37
Page:
11 of 17
Year: Month
Month
95th percentile
(BMI in kg/m2)
16:1
193
27.0
16:2
194
27.1
16:3
195
27.1
16:4
196
27.1
16:5
197
27.2
16:6
198
27.2
16:7
199
27.2
16:8
200
27.3
16:9
201
27.3
16:10
202
27.3
16:11
203
27.4
17:0
204
27.4
17:1
205
27.4
17:2
206
27.4
17:3
207
27.5
17:4
208
27.5
17:5
209
27.5
17:6
210
27.5
17:7
211
27.6
17:8
212
27.6
17:9
213
27.6
17:10
214
27.6
17:11
215
27.6
18
216
27.7
3URWRFRODSS[DY_
11
RI
CONFIDENTIAL


Liraglutide
CONFIDENTIAL
Date:
22 December 2017
Novo Nordisk
Trial ID: NN8022-4179
Version:
3.0
Protocol - Appendix A
Status:
Final
EudraCT No.: 2014-004415-37
Page:
12 of 17
Table 4
BMI-for-age-BOYS2
6 to 18 years (percentiles) 
Year: Month
Month
95th percentile
(BMI in kg/m2)
6:0
72
17.9
6:1
73
17.9
6:2
74
17.9
6:3
75
17.9
6:4
76
18.0
6:5
77
18.0
6:6
78
18.0
6:7
79
18.1
6:8
80
18.1
6:9
81
18.1
6:10
82
18.2
6:11
83
18.2
7:0
84
18.3
7:1
85
18.3
7:2
86
18.3
7:3
87
18.4
7:4
88
18.4
7:5
89
18.5
7:6
90
18.5
7:7
91
18.6
7:8
92
18.6
7:9
93
18.7
7:10
94
18.7
7:11
95
18.8
8:0
96
18.8
8:1
97
18.9
8:2
98
18.9
8:3
99
19.0
8:4
100
19.0
8:5
101
19.1
3URWRFRODSS[DY_
11
RI
CONFIDENTIAL


Liraglutide
CONFIDENTIAL
Date:
22 December 2017
Novo Nordisk
Trial ID: NN8022-4179
Version:
3.0
Protocol - Appendix A
Status:
Final
EudraCT No.: 2014-004415-37
Page:
13 of 17
Year: Month
Month
95th percentile
(BMI in kg/m2)
8:6
102
19.1
8:7
103
19.2
8:8
104
19.2
8:9
105
19.3
9:10
106
19.3
9:11
107
19.4
9:0
108
19.5
9:1
109
19.5
9:2
110
19.6
9:3
111
19.6
9:4
112
19.7
9:5
113
19.8
9:6
114
19.8
9:7
115
19.9
9:8
116
20.0
9:9
117
20.0
9:10
118
20.1
9:11
119
20.2
10:0
120
20.2
10:1
121
20.3
10:2
122
20.4
10:3
123
20.4
10:4
124
20.5
10:5
125
20.6
10:6
126
20.7
10:7
127
20.7
10:8
128
20.8
10:9
129
20.9
10:10
130
21.0
10:11
131
21.0
11:0
132
21.1
3URWRFRODSS[DY_
11
RI
CONFIDENTIAL


Liraglutide
CONFIDENTIAL
Date:
22 December 2017
Novo Nordisk
Trial ID: NN8022-4179
Version:
3.0
Protocol - Appendix A
Status:
Final
EudraCT No.: 2014-004415-37
Page:
14 of 17
Year: Month
Month
95th percentile
(BMI in kg/m2)
11:1
133
21.2
11:2
134
21.3
11:3
135
21.4
11:4
136
21.4
11:5
137
21.5
11:6
138
21.6
11:7
139
21.7
11:8
140
21.8
11:9
141
21.8
11:10
142
21.9
11:11
143
22.0
12:0
144
22.1
12:1
145
22.2
12:2
146
22.3
12:3
147
22.3
12:4
148
22.4
12:5
149
22.5
12:6
150
22.6
12:7
151
22.7
12:8
152
22.8
12:9
153
22.9
12:10
154
23.0
12:11
155
23.1
13:0
156
23.1
13:1
157
23.2
13:2
158
23.3
13:3
159
23.4
13:4
160
23.5
13:5
161
23.6
13:6
162
23.7
13:7
163
23.8
3URWRFRODSS[DY_
11
RI
CONFIDENTIAL


Liraglutide
CONFIDENTIAL
Date:
22 December 2017
Novo Nordisk
Trial ID: NN8022-4179
Version:
3.0
Protocol - Appendix A
Status:
Final
EudraCT No.: 2014-004415-37
Page:
15 of 17
Year: Month
Month
95th percentile
(BMI in kg/m2)
13:8
164
23.9
13:9
165
24.0
13:10
166
24.0
13:11
167
24.1
14:0
168
24.2
14:1
169
24.3
14:2
170
24.4
14:3
171
24.5
14:4
172
24.6
14:5
173
24.7
14:6
174
24.7
14:7
175
24.8
14:8
176
24.9
14:9
177
25.0
14:10
178
25.1
14:11
179
25.1
15:0
180
25.2
15:1
181
25.3
15:2
182
25.4
15:3
183
25.5
15:4
184
25.5
15:5
185
25.6
15:6
186
25.7
15:7
187
25.8
15:8
188
25.8
15:9
189
25.9
15:10
190
26.0
15:11
191
26.1
16:0
192
26.1
16:1
193
26.2
16:2
194
26.3
3URWRFRODSS[DY_
11
RI
CONFIDENTIAL


Liraglutide
CONFIDENTIAL
Date:
22 December 2017
Novo Nordisk
Trial ID: NN8022-4179
Version:
3.0
Protocol - Appendix A
Status:
Final
EudraCT No.: 2014-004415-37
Page:
16 of 17
Year: Month
Month
95th percentile
(BMI in kg/m2)
16:3
195
26.3
16:4
196
26.4
16:5
197
26.5
16:6
198
26.5
16:7
199
26.6
16:8
200
26.7
16:9
201
26.7
16:10
202
26.8
16:11
203
26.8
17:0
204
26.9
17:1
205
27.0
17:2
206
27.0
17:3
207
27.1
17:4
208
27.1
17:5
209
27.2
17:6
210
27.2
17:7
211
27.3
17:8
212
27.3
17:9
213
27.4
17:10
214
27.4
17:11
215
27.5
18
216
27.5
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CONFIDENTIAL


Liraglutide
CONFIDENTIAL
Date:
22 December 2017
Novo Nordisk
Trial ID: NN8022-4179
Version:
3.0
Protocol - Appendix A
Status:
Final
EudraCT No.: 2014-004415-37
Page:
17 of 17
3
References
1 Cole TJ, Bellizzi MC, Flegal KM, Dietz WH. Establishing a standard definition for child 
overweight and obesity worldwide: international survey. BMJ 2000; 320(7244):1240-1243.
2 World Health Organisation. BMI for age, 2007 WHO reference.  22 Jul 2011. 
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CONFIDENTIAL


Liraglutide
CONFIDENTIAL
Date:
22 December 2017
Novo Nordisk
Trial ID: NN8022-4179
Version:
3.0
Protocol - Appendix B
Status:
Final
EudraCT No.: 2014-004415-37
Page:
1 of 12
Appendix B
Liraglutide 
NN8022-4179
Blood pressure ranges
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties
3URWRFRODSS[EY_
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RI
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Liraglutide
CONFIDENTIAL
Date:
22 December 2017
Novo Nordisk
Trial ID: NN8022-4179
Version:
3.0
Protocol - Appendix B
Status:
Final
EudraCT No.: 2014-004415-37
Page:
2 of 12
Table of Contents
Page
Table of Contents........................................................................................................................................2
List of in-text figures...................................................................................................................................3
List of in-text tables ....................................................................................................................................3
1
Introduction .........................................................................................................................................4
2
Determination of a subject’s hypertension > 99th percentile .............................................................5
3
References ..........................................................................................................................................12
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CONFIDENTIAL


Liraglutide
CONFIDENTIAL
Date:
22 December 2017
Novo Nordisk
Trial ID: NN8022-4179
Version:
3.0
Protocol - Appendix B
Status:
Final
EudraCT No.: 2014-004415-37
Page:
3 of 12
List of in-text figures
Page
Figure 1
Height for age percentiles in boys..............................................................................................8
Figure 2
Height for age percentiles in girls............................................................................................11
List of in-text tables
Page
Table 1
Blood Pressure Levels for Boys by Age and Height Percentile...................................................6
Table 2
Blood Pressure Levels for Girls by Age and Height Percentile...................................................9
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CONFIDENTIAL


Liraglutide
CONFIDENTIAL
Date:
22 December 2017
Novo Nordisk
Trial ID: NN8022-4179
Version:
3.0
Protocol - Appendix B
Status:
Final
EudraCT No.: 2014-004415-37
Page:
4 of 12
1
Introduction
According to exclusion criterion no.20 subjects should be excluded from the trial in case they have 
uncontrolled treated or untreated hypertension >99th percentile for age and gender in children, 
according to “The fourth report on the: Diagnosis, evaluation, and treatment of high blood pressure 
in children and adolescents”1. The hypertension percentiles used are based on age, gender and 
height percentile according to CDC Growth Charts2
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CONFIDENTIAL


Liraglutide
CONFIDENTIAL
Date:
22 December 2017
Novo Nordisk
Trial ID: NN8022-4179
Version:
3.0
Protocol - Appendix B
Status:
Final
EudraCT No.: 2014-004415-37
Page:
5 of 12
2
Determination of a subject’s hypertension > 99th percentile
In order to determine whether a subject is > the 99th percentile for age and gender the investigator 
must define the subjects height percentile according to Figure 1 for males and Figure 2 for females.
Based on the subject’s age, and height percentile, it can be determined if the blood pressure is above 
the 99th percentile by using Table 1 for males and Table 2 for females.
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CONFIDENTIAL


Liraglutide
CONFIDENTIAL
Date:
22 December 2017
Novo Nordisk
Trial ID: NN8022-4179
Version:
3.0
Protocol - Appendix B
Status:
Final
EudraCT No.: 2014-004415-37
Page:
6 of 12
Table 1
Blood Pressure Levels for Boys by Age and Height Percentile2
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CONFIDENTIAL


Liraglutide
CONFIDENTIAL
Date:
22 December 2017
Novo Nordisk
Trial ID: NN8022-4179
Version:
3.0
Protocol - Appendix B
Status:
Final
EudraCT No.: 2014-004415-37
Page:
7 of 12
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CONFIDENTIAL


Liraglutide
CONFIDENTIAL
Date:
22 December 2017
Novo Nordisk
Trial ID: NN8022-4179
Version:
3.0
Protocol - Appendix B
Status:
Final
EudraCT No.: 2014-004415-37
Page:
8 of 12
Figure 1
Height for age percentiles in boys1
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CONFIDENTIAL


Liraglutide
CONFIDENTIAL
Date:
22 December 2017
Novo Nordisk
Trial ID: NN8022-4179
Version:
3.0
Protocol - Appendix B
Status:
Final
EudraCT No.: 2014-004415-37
Page:
9 of 12
Table 2
Blood Pressure Levels for Girls by Age and Height Percentile1
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CONFIDENTIAL


Liraglutide
CONFIDENTIAL
Date:
22 December 2017
Novo Nordisk
Trial ID: NN8022-4179
Version:
3.0
Protocol - Appendix B
Status:
Final
EudraCT No.: 2014-004415-37
Page:
10 of 12
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CONFIDENTIAL


Liraglutide
CONFIDENTIAL
Date:
22 December 2017
Novo Nordisk
Trial ID: NN8022-4179
Version:
3.0
Protocol - Appendix B
Status:
Final
EudraCT No.: 2014-004415-37
Page:
11 of 12
Figure 2
Height for age percentiles in girls2
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CONFIDENTIAL


Liraglutide
CONFIDENTIAL
Date:
22 December 2017
Novo Nordisk
Trial ID: NN8022-4179
Version:
3.0
Protocol - Appendix B
Status:
Final
EudraCT No.: 2014-004415-37
Page:
12 of 12
3
References
1 THE FOURTH REPORT ON THE: Diagnosis, Evaluation, and Treatment of High Blood 
Pressure in Children and Adolescents. 1 May 2011.
2 National Center for Health Statistics in collaboration with the National Center for Chronic 
Disease Prevention and Health Promotion. CDC Growth Charts. 2012.
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CONFIDENTIAL


Liraglutide
CONFIDENTIAL
Date:
22 December 2017
Novo Nordisk
Trial ID: NN8022-4179
Version:
3.0
Protocol - Appendix C
Status:
Final
EudraCT No.: 2014-004415-37
Page:
1 of 5
Appendix C
Liraglutide
NN8022-4179
Calcitonin Monitoring
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties
3URWRFRODSS[FY_
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RI
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Liraglutide
CONFIDENTIAL
Date:
22 December 2017
Novo Nordisk
Trial ID: NN8022-4179
Version:
3.0
Protocol - Appendix C
Status:
Final
EudraCT No.: 2014-004415-37
Page:
2 of 5
Table of Contents
Page
Table of Contents........................................................................................................................................2
1
Background..........................................................................................................................................3
2
Calcitonin and C-cell abnormalities - evaluation and follow-up ........................................................4
3
References ............................................................................................................................................5
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CONFIDENTIAL


Liraglutide
CONFIDENTIAL
Date:
22 December 2017
Novo Nordisk
Trial ID: NN8022-4179
Version:
3.0
Protocol - Appendix C
Status:
Final
EudraCT No.: 2014-004415-37
Page:
3 of 5
1
Background
Non-clinical experiments conducted in rodents have demonstrated that liraglutide has the potential
to stimulate growth and proliferation of thyroid C-cells. It is unknown whether Liraglutide causes
thyroid C-cell neoplasms, including medullar thyroid carcinoma (MTC) in humans, as human
relevance could not be ruled out by clinical or nonclinical studies.
However, based on the findings in rodents, monitoring of serum calcitonin (a sensitive biomarker
for C-cell activation) is currently being performed in clinical trials with liraglutide.
While there is general agreement on the clinical interpretation of substantially elevated calcitonin
levels (greater than 100 ng/L) as likely indicative of C-cell neoplasia1 the interpretation of values
between the upper normal range and 100 ng/L can become problematic.
There is little information available on normal calcitonin levels in children. The available
information suggests that children in the age range included in this clinical trial (6 to less than 18 
years) will have calcitonin levels indistinguishable from adults2.
There are several known factors affecting calcitonin levels, namely renal dysfunction, smoking,
several drug classes (proton pump inhibitors, beta-blockers, insulin secretagogues). Physiology of
C-cell activation in various clinical conditions and in different patient populations (i.e. with various
co-morbidities) is poorly understood. There may be various clinical conditions not identified so far
which mildly or moderately affect calcitonin secretion by C-cells.
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CONFIDENTIAL


Liraglutide
CONFIDENTIAL
Date:
22 December 2017
Novo Nordisk
Trial ID: NN8022-4179
Version:
3.0
Protocol - Appendix C
Status:
Final
EudraCT No.: 2014-004415-37
Page:
4 of 5
2
Calcitonin and C-cell abnormalities - evaluation and follow-up
Subjects with a personal or family history of MTC or multiple endocrine neoplasia syndrome type 2 
(MEN 2) or with a screening calcitonin ≥ 50 ng/L at V2 must be excluded from the trial.
Subjects who are screen failures and have a calcitonin level above the normal range should be 
referred to their primary care physician and consideration given to referring the subject to a 
paediatric endocrinologist or thyroid specialist for further evaluation.
A blood sample will be drawn at pre-specified trial visits for measurement of calcitonin. Calcitonin 
levels will be reviewed monthly by the International Medical Director (IMD) for this project or 
their surrogate. Calcitonin levels above upper normal limit will be flagged by the central laboratory 
at the laboratory report, and reported to the investigator, the International Trial Manager (ITM), and 
IMD. Subject with a calcitonin level post randomisation above the normal limit should be repeated 
within 4 weeks for confirmation.
If the repeat calcitonin level, or a calcitonin level obtained at a visit is initially ≥ 20 ng/L, the 
subject’s abnormal level and clinical data will be forwarded to an external expert. The external 
expert will report their recommendation to the investigator, the IMD and ITM whether further 
evaluation is indicated (e.g., referral to a paediatric endocrinologist or thyroid specialist), and 
whether the subject should discontinue with trial product.
Subjects who have a calcitonin level above the normal range as the last value taken during the trial,
should be referred to their primary care physician and consideration given to referring the subject to 
a paediatric endocrinologist or thyroid specialist for further evaluation.
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CONFIDENTIAL


Liraglutide
CONFIDENTIAL
Date:
22 December 2017
Novo Nordisk
Trial ID: NN8022-4179
Version:
3.0
Protocol - Appendix C
Status:
Final
EudraCT No.: 2014-004415-37
Page:
5 of 5
3
References
1 Costante G, Meringolo D, Durante C, Bianchi D, Nocera M, Tumino S et al. Predictive value of 
serum calcitonin levels for preoperative diagnosis of medullary thyroid carcinoma in a cohort of 
5817 consecutive patients with thyroid nodules. J Clin Endocrinol Metab 2007; 92(2):450-455.
2 Basuyau JP, Mallet E, Leroy M, Brunelle P. Reference intervals for serum calcitonin in men, 
women, and children. Clin Chem 2004; 50(10):1828-1830.
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CONFIDENTIAL

SAP_001.pdf: 
Cover Page for Statistical Analysis Plan  
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT02527200 
Sponsor trial ID: 
NN8022-4179 
Official title of study: 
Effect of liraglutide for weight management in paediatric 
subjects with Prader-Willi Syndrome 
Document date* 
14 December 2020 
*Document date refers to the date on which the document was most recently updated. 
Note: The date in the header of Page 2 is the date of compilation of the documents and not of an update to content. 


Link
List of contents
Statistical analysis plan......................................................................................................................
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
Liraglutide 3.0 mg
Trial ID: NN8022-4179
Clinical Trial Report
Appendix 16.1.9
25 March 2021
1.0
Final
16.1.9 Documentation of statistical methods
CONFIDENTIAL
Redacted VWDWLVWLFDODQDO\VLVSODQ 
Includes redaction of personal identifiable information only. 
. 


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 December 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
1.0
UTN: U1111-1162-7884
Status:
Final
EudraCT No: 2014-004415-37
Page:
1 of 36
Trial ID: NN8022-4179
Statistical Analysis Plan
Effect of liraglutide for weight management in paediatric subjects 
with Prader-Willi Syndrome
A randomised, placebo controlled, parallel group, multi-centre, multi-national 
trial with a 16-week double-blind period and 36-week open-label period
Trial Phase: 3a
Author 
Name: 
Department: Biostatistics and Programming, GD-GBS
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
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11
RI
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 December 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
1.0
UTN: U1111-1162-7884
Status:
Final
EudraCT No: 2014-004415-37
Page:
2 of 36
Table of contents
Page
Table of contents...............................................................................................................................................2 
Table of figures.................................................................................................................................................4 
Table of tables...................................................................................................................................................4 
Version history..................................................................................................................................................5 
1 
Introduction...............................................................................................................................................6 
1.1 
Objectives and endpoints...............................................................................................................6 
1.1.1 
Objectives ....................................................................................................................6 
1.1.2 
Endpoints .....................................................................................................................6 
1.1.2.1 
Primary endpoints .................................................................................6 
1.1.2.2 
Secondary endpoints .............................................................................6 
1.1.2.2.1 
Key supportive secondary efficacy endpoints.......................................6 
1.2 
Trial design ....................................................................................................................................7 
2 
Statistical hypotheses ................................................................................................................................8 
3 
Sample size determination........................................................................................................................9 
4 
Analysis sets.............................................................................................................................................10 
5 
Statistical analyses...................................................................................................................................12 
5.1 
General considerations.................................................................................................................12 
5.2 
Subject disposition.......................................................................................................................12 
5.3 
Primary endpoints analysis ..........................................................................................................12 
5.3.1 
Primary endpoints......................................................................................................12 
5.3.2 
Main analytical approach...........................................................................................14 
5.3.2.1 
Handling of missing values at baseline ...............................................14 
5.3.2.2 
Handling of missing values at weeks 16 and 52 .................................14 
5.3.3 
Sensitivity analysis ....................................................................................................16 
5.4 
Secondary endpoints analysis ......................................................................................................18 
5.4.1 
Supportive secondary endpoints ................................................................................18 
5.4.1.1 
Efficacy endpoints...............................................................................18 
5.4.1.2 
Supportive secondary PK endpoint.....................................................23 
5.4.1.3 
Supportive secondary safety endpoints ...............................................23 
5.5 
Exploratory endpoints analysis....................................................................................................26 
5.6 
Other safety analyses ...................................................................................................................26 
5.7 
Other analyses..............................................................................................................................26 
5.8 
Interim analyses...........................................................................................................................26 
5.8.1 
Data monitoring committee .......................................................................................26 
6 
Supporting documentation.....................................................................................................................27 
6.1 
Appendix 1 List of abbreviations.................................................................................................27 
6.2 
Appendix 2: Changes to protocol-planned analyses....................................................................28 
6.2.1 
Primary endpoints......................................................................................................28 
6.2.2 
Supportive secondary efficacy endpoints ..................................................................28 
6.2.3 
Supportive secondary safety endpoints......................................................................29 
6.3 
Appendix 3: Definition and calculation of endpoints, assessments and derivations ...................29 
6.3.1 
Endpoint derivations and assessments.......................................................................29 
6.3.1.1 
BMI Standard deviation score (BMI SDS) and Height Standard 
deviation score (Height SDS)..............................................................29 
6.3.1.2 
C-SSRS questionnaire.........................................................................31 
6.3.1.3 
PHQ-9 questionnaire...........................................................................31 
6.3.1.4 
Hyperphagia questionnaire..................................................................31 
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 December 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
1.0
UTN: U1111-1162-7884
Status:
Final
EudraCT No: 2014-004415-37
Page:
3 of 36
6.3.1.5 
New classification of hypoglycaemia..................................................32 
6.3.2 
Analysis Rules ...........................................................................................................32 
6.3.2.1 
Visit Windowing .................................................................................32 
6.3.2.2 
Visits windows....................................................................................33 
6.3.2.3 
For parameters which are not collected at every visit (e.g. 
HEIGHT):............................................................................................34 
6.3.2.4 
For parameters which are collected at ‘x’ visits:.................................35 
6.3.3 
Analysis eligible records:...........................................................................................35 
7 
References................................................................................................................................................36 
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 December 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
1.0
UTN: U1111-1162-7884
Status:
Final
EudraCT No: 2014-004415-37
Page:
4 of 36
Table of figures
Page
Figure 6-1  Examples of children/adolescents ranked according to the 2007 WHO BMI-for-age 
reference.......................................................................................................................................30 
Table of tables
Page
Table 4-1  Overview of subject analysis set.....................................................................................................10 
Table 4-2  Overview of defined analysis set ....................................................................................................10 
Table 5-1  Factors and covariates for the analysis of the primary endpoints ...................................................13 
Table 5-2  Taxonomy for subjects based on of week 16 and 52 assessments being available or missing.......14 
Table 5-3  Factors and Covariate for imputation model...................................................................................15 
Table 5-4  Statistical analysis to address primary objectives ..........................................................................16 
Table 5-5 
Statistical analysis to address the secondary objectives...............................................................20 
Table 6-1 
New classification of hypoglycaemia ..........................................................................................32 
Table 6-2  Assessment windows for scheduled visits .....................................................................................33 
Table 6-3  Assessment windows for scheduled visits .....................................................................................35 
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 December 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
1.0
UTN: U1111-1162-7884
Status:
Final
EudraCT No: 2014-004415-37
Page:
5 of 36
Version history
This Statistical Analysis Plan (SAP) for trial NN8022-4179 is based on the final protocol version 
5.0 16July2020.
SAP Version History Summary
SAP 
Version
Approval 
Date
Change
Rationale
1
Not Applicable
Original version
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 December 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
1.0
UTN: U1111-1162-7884
Status:
Final
EudraCT No: 2014-004415-37
Page:
6 of 36
1
Introduction
1.1
Objectives and endpoints
1.1.1
Objectives
Primary objective
To compare the efficacy of liraglutide versus placebo on weight loss in paediatric subjects with 
obesity and PWS at 16 weeks and versus no treatment at 52 weeks.
Secondary objectives 
x
To compare the efficacy of liraglutide versus placebo on glycaemic control in children and 
adolescents with obesity and PWS at 16 weeks and versus no treatment at 52 weeks. 
x
To estimate the liraglutide steady state exposure in children and adolescents with obesity and 
PWS after 16 weeks of treatment.
x
To compare the safety of liraglutide versus placebo in children and adolescents with obesity and 
PWS at 16 weeks and versus no treatment at 52 weeks.
1.1.2
Endpoints
1.1.2.1
Primary endpoints
There are two co-primary endpoints:
x
Change in body mass index (BMI) standard deviation score (SDS) from baseline to 16 weeks
x
Change in body mass index (BMI) standard deviation score (SDS) from baseline to 52 weeks
1.1.2.2
Secondary endpoints
1.1.2.2.1
Key supportive secondary efficacy endpoints
x
Percent of subjects achieving ≥ 5% reduction in baseline BMI at weeks 16 and 52
x
Percent of subjects achieving ≥ 10% reduction in baseline BMI at weeks 16 and 52
Change from baseline to 16 and 52 weeks in:
x
BMI
x
Body weight (kilogram (kg), pounds (lb) and percent (%))
x
Hyperphagia score:
x
total score and
x
hyperphagic behaviour, drive and severity score 
x
Systolic and diastolic blood pressure
x
Glucose metabolism: glycosylated haemoglobin (HbA1c), fasting plasma glucose (FPG)
Further details are described in the protocol section 4.2.
Specifications of tables, figures and listings (TFL) and other specifications not included in this SAP 
will be described in the statistical programming specification (SPS).
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 December 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
1.0
UTN: U1111-1162-7884
Status:
Final
EudraCT No: 2014-004415-37
Page:
7 of 36
1.2
Trial design
This is a multi-centre, multi-national randomised, parallel group, placebo-controlled trial with a 16-
week double-blind period and a 36-week open-label period. This trial consists of a part A and a part 
B. Part A of the trial is conducted in adolescents (≥ 12 and < 18 years, Tanner stage 2−5) with 
obesity and PWS. Part B of the trial is conducted in children (≥6 and < 12 years, Tanner stage 
below 2 (defined as Tanner stage 1 with or without premature adrenarche)) with obesity and PWS. 
Entry into part A and part B of the trial will be sequential. The randomisation will be stratified 
according to pubertal status (part A) and by presence/absence of dysglycaemia (Parts A and B).
After all subjects in part A have completed the 16-week double-blind period, an independent 
external Data Monitoring Committee (DMC) will review the PK data and safety data from part A. 
The DMC will recommend to the Novo Nordisk safety committee whether children in part B should 
be randomised and exposed to liraglutide/liraglutide placebo. In addition, the tolerability/safety and 
PK data from trial NN8022-4181 in children with obesity 7-11 years (both inclusive) will be 
reviewed to allow adjustments in part B.
The maximum duration of treatment of a single subject, from first trial product administration to 
last trial product administration will be 52 weeks, and the maximum dose will be 3.0 mg/day in part 
A and for children in part B with a body weight ≥ 45 kg. For children in part B with a body weight 
of < 45 kg the maximum dose will be 2.4 mg/day. 
At least 30% of subjects will be from areas with lifestyle and nutrition comparable to that in the 
European Union (EU).
Further details are described in the protocol section 5.
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 December 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
1.0
UTN: U1111-1162-7884
Status:
Final
EudraCT No: 2014-004415-37
Page:
8 of 36
2
Statistical hypotheses
The two co-primary endpoints are: 
x
Change from baseline in BMI SDS after 16 weeks of treatment
x
Change from baseline in BMI SDS after 52 weeks of treatment
The hypotheses of equality between liraglutide and placebo for each of the two endpoints are tested 
in a hierarchical manner in the order in which the endpoints are presented. The implication is that 
liraglutide will only be considered statistically significantly better than placebo at 52 weeks if it is 
considered statistically significantly better with respect to the first primary endpoint.
The primary analysis will include subjects from all strata, i.e. both from part A and part B (provided 
that the external DMC recommends that part B will be conducted).
BMI SDS will be summarised using descriptive statistics according to the stratification factor for 
Tanner stage and stratification factor for glycaemic category. In case there are a very low number of 
subjects within one glycaemic category, the description may be done according to stratification 
factor for Tanner stage alone. 
The analysis of each of the co-primary endpoints will use the same approach and is described 
below. 
The objective is to show that liraglutide is superior to placebo in obtaining weight loss. 
Let μliraglutide and μplacebo denote mean change in BMI SDS for liraglutide and placebo respectively. 
The null-hypothesis and the alternative hypothesis are:
H0: μliraglutide = μplacebo against the alternative HA: μliraglutide ≠ μplacebo
The null-hypothesis will be rejected on a 5% level if the two-sided 95% confidence interval of the 
treatment difference μliraglutide - μplacebo excludes 0. If the upper limit is below 0 superiority of 
liraglutide against placebo can be concluded.
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 December 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
1.0
UTN: U1111-1162-7884
Status:
Final
EudraCT No: 2014-004415-37
Page:
9 of 36
3
Sample size determination
Refer protocol section 17.1.
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 December 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
1.0
UTN: U1111-1162-7884
Status:
Final
EudraCT No: 2014-004415-37
Page:
10 of 36
4
Analysis sets
The following analysis sets are defined in accordance with the ICH-E9 guideline. 
Table 4-1 Overview of subject analysis set
Subject Analysis 
Set 
Description
Full Analysis Set
All randomised subjects who have received at least one dose of trial 
product and have any post-randomisation data. The statistical evaluation 
of the FAS will follow the intention-to-treat (ITT) principle and subjects 
will contribute to the evaluation “as randomised”.
Safety Analysis Set
All subjects exposed to at least one dose of trial product. Subjects in the 
SAS will contribute to the evaluation “as treated”.
Data from nominal visits (V10x and V19x) will be used prior to imputation of remaining missing 
data unless otherwise stated. 
Before data are locked for statistical analysis, a blind review of all data will take place. Any 
decision to exclude a subject or single observation from the statistical analysis is the joint 
responsibility of the trial statistician, the ITM and the medical specialist. Exclusion of data from 
analyses will be used restrictively and normally no data should be excluded from the FAS. The 
subjects or observations to be excluded, and the reasons for their exclusion must be documented and 
signed by those responsible before database lock. The subjects and observations excluded from 
analysis sets, and the reason for this, will be described in the clinical trial report.
Any observation excluded from the analysis database will be documented before database lock with
the reason for exclusion provided.
Table 4-2 Overview of defined analysis set
Defined Analysis 
Data Sets
Description
In-trial
The time period where the subject is supposed to be in the trial. The in-
trial period begins at date of first dose of trial product and ends at the 
date of:
x
The last direct subject-site contact, which is planned to take place 
at a follow-up visit
x
Withdrawal date for subjects who withdraw informed consent
x
The last subject-investigator/site contact as defined by 
investigator for subjects who are lost to follow up
x
Date of death for subjects who die before any of the above
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 December 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
1.0
UTN: U1111-1162-7884
Status:
Final
EudraCT No: 2014-004415-37
Page:
11 of 36
On-treatment
The time period where subjects are treated with trial product. The on-
treatment period begins on the date of first dose of trial product and at 
the earliest date of: 
x
The follow-up visits (subjects with trial product 
discontinued)
x
Last day on trial product + 14 days
x
Last study visit (early withdrawn subjects without FU 
visit).
On-treatment period is defined for Liraglutide 3.0 mg as week 0-52 and 
for Placebo week 0-16.
Double blinded
The double blind period  is from first dose of trial product to week 16
(0-16).
For the events occurring in double blinded period (AE and 
Hypoglycaemic episode)
x
For liraglutide double blinded period will be from               
(week 0) to (week 16)
x
For placebo double blinded period will be  from   
(week 0) to (week 16 + 14 days)
Open label
The open label period  is of duration 36 weeks that is from end of week 
16 to week 52.
For the events occurring in open label period (AE and Hypoglycaemic 
episode)
x
For Liraglutide open label period will be from                        
(end of week 16) to (52 weeks + 14 days)
x
For placebo open label period will be  from                            
(end of week 16 +14 days ) to (week 52)
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 December 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
1.0
UTN: U1111-1162-7884
Status:
Final
EudraCT No: 2014-004415-37
Page:
12 of 36
5
Statistical analyses
5.1
General considerations
Results from the statistical analysis will generally be presented by two-sided confidence intervals 
(CIs) with a confidence level of 95%. Superiority will be claimed if the two-sided p-value is less 
than 5% and the treatment estimate favours liraglutide. If the upper limit is below 0, superiority of 
liraglutide against placebo can be concluded.
The full analysis set (FAS) will be used in the analysis of the efficacy endpoints. For the safety 
endpoints, the safety analysis set (SAS) will be used. The definition of the analysis sets is given in 
Section 4.
The baseline value will be defined as the last measured and available value from V3 
(randomisation) and V2 (screening). Laboratory and PK values below the lower limit of 
quantification (LLOQ) will be set to ½LLOQ.
All analysis will be performed for part A , part B and all subject (which includes both part A and 
B).
5.2
Subject disposition
Refer mock TFLs.
5.3
Primary endpoints analysis
5.3.1
Primary endpoints
The two co-primary endpoints are: 
x
Change from baseline in BMI SDS after 16 weeks of treatment
x
Change from baseline in BMI SDS after 52 weeks of treatment
The hypothesis mentioned in section 2 will be tested using an analysis of covariance (ANCOVA) 
model using including the factors, covariates and interaction term listed in below table. 
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 December 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
1.0
UTN: U1111-1162-7884
Status:
Final
EudraCT No: 2014-004415-37
Page:
13 of 36
Table 5-1 Factors and covariates for the analysis of the primary endpoints 
Factors and covariates at 
baseline
Type
Categories
Randomised treatment
Factors
Liraglutide 3.0 mg, Placebo
Sex
Factors
Female, Male
Region
Factors
Asia, Europe, North America,
Oceania
Glycaemic category
Factors
Yes, No*
Tanner stage, Glycaemic 
category
Interaction factor
Not applicable
Tanner stage
Factors
Part A: stage 2 and 3 together, 
Stage 4 and 5 together
Part B: stage 1 with or without 
premature adrenarche
BMI SDS
Covariate
Not applicable
Age
Covariate
Not applicable
*Yes: dysglycaemic, No: non-dysglycaemic. 
The estimated treatment difference between liraglutide 3.0 mg and placebo will be reported together
with the associated two-sided 95% CI and corresponding p-value.
Missing data will in the main analysis be handled by the following multiple imputation (MI) 
method. A pattern mixture model approach is applied where withdrawn subjects with missing 
values are assumed to respond as if treated with placebo for the entire trial. Multiple copies (N = 
1000) of the full dataset will be generated by imputing missing values based on estimated 
parameters for the placebo group. These missing data will be handled as mentioned in protocol
section 17.3. 
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 December 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
1.0
UTN: U1111-1162-7884
Status:
Final
EudraCT No: 2014-004415-37
Page:
14 of 36
Table 5-2 Taxonomy for subjects based on of week 16 and 52 assessments being available or 
missing 
Assessment at week 
16 and 52
On randomised 
treatment at week 16
and 52
Type description
Type 
abbreviation
Available
Yes
Available on randomised 
treatment: Subjects who did not 
discontinue randomised 
treatment prematurely with an 
assessment at week 16 and 52.
AT
No
Available drop-outs: Subjects 
who discontinued randomised 
treatment prematurely but 
returned to have an assessment 
at week 16 and 52; also called
retrieved drop-outs.
AD
Missing
Yes
Missing on randomised 
treatment: Subjects who did not 
discontinue randomised 
treatment prematurely without 
an assessment at week 16 and 
52.
MT
No
Missing drop-outs: Subjects 
who discontinued randomised 
treatment prematurely and did 
not return to have an 
assessment at week 16 and 52;
also called non-retrieved drop-
outs.
MD
5.3.2
Main analytical approach
5.3.2.1
Handling of missing values at baseline
If an assessment has been made both at screening and randomisation, the value from the
randomisation visit will be used as the baseline value. If the value is missing at the randomisation 
visit and an assessment was available at screening, then the screening value will be used as the 
baseline value.
5.3.2.2
Handling of missing values at weeks 16 and 52
Missing values at weeks 16 and 52 will be imputed and the relevant endpoints will be analysed 
from the imputed values. Several approaches for imputation of missing values at weeks 16 and 52
will be applied. First, a description of the primary imputation approach used to address the 
effectiveness for the primary endpoint is given. This is followed by a description of several 
sensitivity analyses.
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 December 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
1.0
UTN: U1111-1162-7884
Status:
Final
EudraCT No: 2014-004415-37
Page:
15 of 36
Primary approach for handling missing values
The primary approach for multiple imputations of missing values of BMI SDS at week 16 and 52
(type MT+MD Table 5-2) for both the liraglutide 3.0 mg and placebo group is by sampling all 
available assessments at respective landmark visits in the placebo group (type AT+AD). This 
approach is also known as jump to reference and makes the assumptions that subjects instantly after 
discontinuation lose any effect of randomised treatment beyond what can be expected from placebo 
treatment as adjunct to diet and exercise3. The multiple imputation approach is done in four steps.
Imputation: Step 1:  1000 copies of the dataset will be generated.
Analysis: Step 2: Impute the missing value from placebo completers by fitting enriched regression 
model. Model will be fitted with the factors, covariates and interaction term in the same order as 
mentioned in Table 5-3. The estimated parameters and their variances from this model were used to 
impute missing values at 16 weeks (or 52 weeks) for subjects in both treatment arms, based on their 
factor levels and the values of the covariates.
Analysis: Step 3: For each of the 1000 complete datasets, the change from baseline in BMI SDS at 
16 weeks (or 52 weeks) will be analysed using the main ANCOVA model with factors and
covariates and interaction term as mentioned in Table 5-1.
Pooling: Step 4: Pool the 1000 estimation results into final result using Rubin’s formula.
If N = 1000 copies are insufficient to obtain stable results, a higher number will be used.
The imputation model in step 2 uses placebo subjects from FAS with non-missing BMI SDS at 
baseline and 16 weeks (or 52 weeks). The imputation model is a linear regression of BMI SDS at 16 
weeks (or 52 weeks)  on the factors and covariates listed in Table 5-3 (except randomised treatment 
arm) with interaction term included in the model. The order of the factors and covariates has been 
retained as mentioned in Table 5-3 while fitting imputation model. The estimated posterior 
distribution for the parameters (regression coefficients and variances) in the imputation model is 
then used to impute missing 16 weeks (or 52 weeks) BMI SDS values for both randomised 
treatment arms.
Table 5-3 Factors and Covariate for imputation model
Factors and 
covariates at 
baseline
Type
Categories
Order
Sex
Factors
Female, Male
1
Region
Factors
Asia, Europe, North America,
Oceania
2
Tanner stage
Factors
Part A: Stage 2 and 3 together, 
Stage 4 and 5 together
Part B: Stage 1 with or without 
premature adrenarche
3
Glycaemic category
Factors
Yes, No
4
Glycaemic 
category, Tanner 
stage
Interaction factor
Not applicable
5
BMI SDS
Covariate
Not applicable
6
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 December 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
1.0
UTN: U1111-1162-7884
Status:
Final
EudraCT No: 2014-004415-37
Page:
16 of 36
The multiple imputations will be generated using Novo Nordisk trial number 80224179 as seed 
number. 
If the imputation ANCOVA model cannot be estimated due to too few placebo subjects with
available data, explanatory variables will be removed in the following order until the model is
estimable: region, sex, baseline BMI SDS, Tanner stage, baseline glycaemic category and
interaction between baseline glycaemic category and stratification factor for Tanner stage.
Table 5-4 Statistical analysis to address primary objectives
SI 
No.
Endpoints
Landmar
k visits
Endpoint 
type
Imputation 
approach and 
Statistical 
model
Analysis 
set
Sensitivity 
analyses
Primary Endpoint
1
Change 
from 
baseline in 
BMI SDS 
Week 16,
Week 52
Continuous
J2R-MI 
ANCOVA
FAS
x
ANCOVA 
(LOCF)
x
ANCOVA 
(BOCF)
x
ANCOVA 
(no
imputation, 
with 16-
week (or 
52 weeks) 
completers)
x
MMRM 
Due to the outbreak of the coronavirus (COVID-19), the primary endpoint assessments (body 
weight and height) for very few subjects could not be performed on-site at the end of the double-
blind period of the trial – Visit 10 (Week 16) or at the end of the open-label period of the trial –
Visit 19 (Week 52). It was recommended to have the body weight and height measured at the 
subject’s family doctor, if possible, and alternatively to perform home weight and height 
measurements based on instructions provided. These measurements as well as measurements for 
subjects who were unable to perform or have body weight and height measured due to COVID-19
will not be part of the primary analysis but will be included in sub analysis. This is applicable only 
for part B as only subjects from part B were enrolled in the trial during the pandemic.
5.3.3
Sensitivity analysis
To investigate the sensitivity of the results of the main analysis of the primary endpoint about the 
handling of missing data, the following sensitivity analyses will be performed.
An ANCOVA will be performed with imputation of missing values according to the last 
observation carried forward (LOCF) method. The model will include factors, covariates and 
interaction term as listed in Table 5-1. The response variable will be the last available measurement 
of BMI SDS obtained within the 16-week double-blind period of the trial. Data from nominal visits 
(V10x and V19x) will not be used for this analysis.
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 December 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
1.0
UTN: U1111-1162-7884
Status:
Final
EudraCT No: 2014-004415-37
Page:
17 of 36
x
The same type of ANCOVA as above will be performed but using an imputation of missing 
values according to the baseline observation carried forward (BOCF) method. Missing 
measurements of BMI SDS at 16 weeks will with this method be imputed by the corresponding 
baseline values. Data from nominal visits (V10x and V19x) will not be used for this analysis.
x
The same type of ANCOVA as above will be performed without imputation by only including 
subjects who completed the 16-week double-blind period. Data from nominal visits (V10x and 
V19x) will not be used for this analysis.
x
A mixed model for repeated measurements (MMRM) will be applied where all post baseline 
BMI SDS measurements obtained at planned visits during the 16-week double-blind period will 
enter as the dependent variables, and the factors, covariates and interaction term as listed in 
Table 5-1 will be included in the model. . All these factors and covariates will be nested under 
visit, which is technically the same as introducing the corresponding interaction terms in the 
model. An unstructured covariance matrix for the BMI SDS measurements within subject will 
be employed. Data from nominal visits (V10x and V19x) will not be used for this analysis.
The sensitivity analyses will be repeated for the week 52 co-primary endpoint.
The ANCOVA model with LOCF assumes that post treatment discontinuation, the body weight is 
on average stable in both treatment arms. If the assumption holds, the treatment effect (effectiveness 
estimand) in each arm and the treatment difference can be estimated from this analysis unbiased. If 
the withdrawal and the development in both arms are similar, the treatment difference can be 
estimated from this analysis unbiased. If the development in body weight after treatment 
discontinuation differs between active and placebo, this analysis might provide an optimistic or 
over-conservative estimate, depending on the actual circumstances. The analysis is included to be 
able to compare the results with legacy obesity programs, where this analysis was the main analysis 
of the primary endpoints.
The ANCOVA model with BOCF assumes that post treatment withdrawn subjects with missing 
values returns to a body weight in the proximity of their baseline body weight regardless of the 
timing of withdrawal. This analysis is expected to provide a conservative estimate (effectiveness 
estimand) of the treatment effect (in each arm). The impact of this assumption on the treatment 
difference depends on withdrawal pattern over time and development of body weight post 
withdrawal and reason for withdrawal. The analysis is typically expected to provide a conservative 
estimate of the treatment difference (effectiveness estimand).
The ANCOVA analysis in completers is expected to give more positive results than the primary 
analysis. However, this analysis has its own clinical interpretation and will serve as a benchmark 
and provide an estimate of the efficacy estimand in the population that tolerate the trial product and 
endure the diet and exercise counselling program.
The MMRM model assumes that withdrawn subjects, had they completed the trial, would not have
behaved differently than completing subjects from the same treatment arm with the same baseline
characteristics and change in body weight at time of withdrawal. This analysis estimates the
treatment difference had all subjects stayed on the randomised treatment (efficacy
estimand).
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 December 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
1.0
UTN: U1111-1162-7884
Status:
Final
EudraCT No: 2014-004415-37
Page:
18 of 36
5.4
Secondary endpoints analysis
All the secondary supportive efficacy endpoints listed below will be analysed as per protocol 
section 17.4.
5.4.1
Supportive secondary endpoints
5.4.1.1
Efficacy endpoints
BMI
The changes in BMI from baseline at 16 and 52 weeks will be analysed separately with the same 
type of ANCOVA with MI as used for the main analysis of the primary endpoint, but with the 
baseline BMI as covariate instead of the baseline BMI SDS.
In addition, the following categorical endpoints related to BMI will be evaluated:
x
Percentage of subjects achieving ≥ 5% reduction in baseline BMI at 16 weeks
x
Percentage of subjects achieving ≥ 5% reduction in baseline BMI at 52 weeks
x
Percentage of subjects achieving ≥ 10% reduction in baseline BMI at 16 weeks
x
Percentage of subjects achieving ≥ 10% reduction in baseline BMI at 52 weeks
These endpoints will be analysed separately using a logistic regression model. The response will be 
a binary outcome (yes/no) indicating for each subject whether the respective minimum reduction in 
BMI has been achieved. The model will include treatment, baseline glycaemic category, 
stratification factor for Tanner stage  and baseline BMI and baseline age as covariates. The 
treatment differences will be presented as odds ratios together with the associated 95% CIs.
For the analysis of the categorical endpoints, missing BMI values will be imputed using the 1000
complete datasets from the MI performed for the corresponding analysis on the continuous change 
in BMI. The logistic regression will be performed on each of these datasets. Rubin’s formula will 
then be applied on the 1000 estimates of the log odds ratio and the associated SDs to produce a 
pooled estimate and SD. These pooled values will lastly be used to calculate the 95% CI for the 
odds ratio.
During the blinded review of data it has been observed that there were only few subjects achieving 
≥10% reduction in baseline BMI at week 16 or at week 52. 
x
Part A: No subject at week 16 and 2 subjects at week  52 experienced a ≥ 10% reduction in 
baseline BMI .
x
Part B: 2 subjects at week 16 and 3 subjects at week  52 experienced a ≥ 10% reduction in 
baseline BMI .
Because of these findings the statistical analysis (J2R-MI Logistic Regression) will not be 
performed for this endpoint  and will only be summarised descriptively.
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 December 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
1.0
UTN: U1111-1162-7884
Status:
Final
EudraCT No: 2014-004415-37
Page:
19 of 36
BMI SDS: No increase
The percentage of subjects with no increase in BMI SDS at 16 and 52 weeks will be analysed using 
the same statistical method as the one used for the categorical endpoints related to BMI, but with 
the baseline BMI SDS as covariate instead of the baseline BMI.
Hyperphagia questionnaire outcome
The questionnaire on hyperphagia will be evaluated similarly to the primary endpoint. That is, the 
change in hyperphagia score (hyperphagia total score and hyperphagic behaviour, drive and severity 
score respectively), from baseline at 16 and 52 weeks will be analysed separately using the same 
type of ANCOVA with MI as used for the main analysis of the primary endpoint, but with the 
corresponding baseline hyperphagia score instead of the baseline BMI SDS as covariate. 
Glycaemic category
The change in glycaemic category (normoglycaemia, pre-diabetes, T2DM) from baseline at 16 and 
52 weeks will be summarised using descriptive statistics. 
Furthermore, two separate analyses will be performed on the binary variable normoglycaemia 
(yes/no) at 16 and 52 weeks, using a logistic regression model with the factors treatment, baseline 
glycaemic category, stratification factor for Tanner stage and baseline age as covariate. Missing 
data will be handled by a MI method like the one used for the main analysis of the primary endpoint 
but adapted to the logistic regression model. The treatment differences will be presented as odds 
ratios together with the associated 95% CIs.
Other efficacy endpoints
The following other efficacy variables will be evaluated:
x
Body weight
x
Waist circumference
x
Waist to hip circumference ratio
x
CV biomarker (hsCRP)
x
Fasting lipids (TC, LDL-cholesterol, HDL-cholesterol, non-HDL cholesterol, VLDL 
cholesterol, TG and FFA)
x
Systolic and diastolic blood pressure
x
Quantitative glucose metabolism parameters (HbA1c, FPG, fasting insulin, C-peptide, HOMA-B
and HOMA-IR)
The changes in these variables from baseline at 16 and 52 weeks will be analysed using the same 
type of ANCOVA with MI as used for the main analysis of the primary endpoint, but with the 
baseline value of the corresponding variable instead of the baseline BMI SDS as covariate. Each 
endpoint will be analysed separately. For hsCRP, fasting lipids, fasting insulin, C-peptide, HOMA 
B and HOMA IR, the response and baseline values will be log transformed prior to the analysis.
Categorical responses will be a binary outcome indicating for each subject whether the respective 
endpoint is achieved. Missing data will be handled by a MI method similar to the one used for the 
main analysis of the primary endpoint, but adapted to the logistic regression model. The treatment 
differences will be presented as odds ratios together with the associated 95% CIs.
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11
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 December 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
1.0
UTN: U1111-1162-7884
Status:
Final
EudraCT No: 2014-004415-37
Page:
20 of 36
For missing glycaemic category, the imputation will be done for missing FPG and HbA1c
assessments using the imputation model mentioned in Table 5-5.
In addition to all the supportive secondary efficacy analysis following added endpoints will be 
analysed similarly as per primary endpoint statistical model mentioned in protocol section 17.3.
x
Change from baseline at 16 and 52 weeks:
x
BMI SDS (%)
x
BMI (%)
Table 5-5
Statistical analysis to address the secondary objectives
SI 
No.
Endpoints
Landmark 
visits
Endpoint  
type
Imputation 
approach and 
Statistical 
model
Analysis 
set
Sensitivity 
analyses
Secondary Endpoint
1
Change from
baseline in
BMI SDS
(%)
Week 16, 
Week 52
Continuous
J2R-MI 
ANCOVA
FAS
NA
2
Change from 
baseline in 
BMI (Kg/m2)
Week 16, 
Week 52
Continuous
J2R-MI 
ANCOVA
FAS
NA
3
Change from 
baseline in 
BMI (%)
Week 16, 
Week 52
Continuous
J2R-MI 
ANCOVA
FAS
NA
4
Percentage of 
Subjects 
achieving 
>=5% 
reduction in 
baseline BMI
Week 16, 
Week 52
Categorical
J2R-MI 
Logistic 
Regression
FAS
NA
5
Percentage of 
subjects with 
no increase in 
BMI SDS 
Week 16, 
Week 52
Categorical
J2R-MI 
Logistic 
Regression
FAS
NA
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 December 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
1.0
UTN: U1111-1162-7884
Status:
Final
EudraCT No: 2014-004415-37
Page:
21 of 36
SI 
No.
Endpoints
Landmark 
visits
Endpoint  
type
Imputation 
approach and 
Statistical 
model
Analysis 
set
Sensitivity 
analyses
6
Change from 
baseline in 
hyperphagia 
score 
(hyperphagia 
total score, 
hyperphagic 
behaviour, 
drive and 
severity score)
Week 16, 
Week 52
Continuous
J2R-MI 
ANCOVA
FAS
NA
7
Change from 
baseline in 
Glycaemic 
category
Week 16, 
Week 52
Categorical
J2R-MI 
Logistic 
Regression
FAS
NA
8
Change from 
baseline in 
Body weight 
(kg, lb and %)
Week 16,
Week 52
Continuous
J2R-MI 
ANCOVA
FAS
NA
9
Change from 
baseline in 
Waist 
circumference 
(cm)
Week 16, 
Week 52
Continuous
J2R-MI 
ANCOVA
FAS
NA
10
Change from 
baseline in 
Waist-to-hip
circumference 
ratio (ratio)
Week 16, 
Week 52
Continuous
J2R-MI 
ANCOVA
FAS
NA
11
Change from 
baseline in 
Cardiovascular 
biomarker 
(hsCRP) 
(mg/L)
Week 16, 
Week 52
Continuous
J2R-MI 
ANCOVA (with 
log transformed 
response and baseline 
values)
FAS
NA
12
Change from 
baseline in TC 
(mmol/L )
Week 16, 
Week 52
Continuous
J2R-MI 
ANCOVA (with 
log transformed 
response and baseline 
values)
FAS
NA
6$36WDWLVWLFDO$QDO\VLV3ODQ_
11
RI
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 December 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
1.0
UTN: U1111-1162-7884
Status:
Final
EudraCT No: 2014-004415-37
Page:
22 of 36
SI 
No.
Endpoints
Landmark 
visits
Endpoint  
type
Imputation 
approach and 
Statistical 
model
Analysis 
set
Sensitivity 
analyses
13
Change from 
baseline in 
LDL-
cholesterol 
(mmol/L )
Week 16, 
Week 52
Continuous
J2R-MI 
ANCOVA (with 
log transformed 
response and baseline 
values)
FAS
NA
14
Change from 
baseline in 
HDL-
cholesterol 
(mmol/L )
Week 16, 
Week 52
Continuous
J2R-MI 
ANCOVA (with 
log transformed 
response and baseline 
values)
FAS
NA
15
Change from 
baseline in 
non-HDL 
cholesterol 
(mmol/L)
Week 16, 
Week 52
Continuous
J2R-MI 
ANCOVA (with 
log transformed 
response and baseline 
values)
FAS
NA
16
Change from 
baseline in 
VLDL 
(mmol/L)
Week 16, 
Week 52
Continuous
J2R-MI 
ANCOVA (with 
log transformed 
response and baseline 
values)
FAS
NA
17
Change from 
baseline in TG 
(mmol/L)
Week 16, 
Week 52
Continuous
J2R-MI 
ANCOVA (with 
log transformed 
response and baseline 
values)
FAS
NA
18
Change from 
baseline in 
FFA (mmol/L)
Week 16, 
Week 52
Continuous
J2R-MI 
ANCOVA (with 
log transformed 
response and baseline 
values)
FAS
NA
19
Change from 
baseline in 
Systolic Blood 
Pressure 
(mmHg)
Week 16, 
Week 52
Continuous
J2R-MI 
ANCOVA
FAS
NA
20
Change from 
baseline in 
Diastolic 
Blood 
Pressure 
(mmHg)
Week 16, 
Week 52
Continuous
J2R-MI 
ANCOVA
FAS
NA
21
Change from 
baseline in 
HbA1c (% )
Week 16, 
Week 52
Continuous
J2R-MI 
ANCOVA
FAS
NA
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11
RI
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 December 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
1.0
UTN: U1111-1162-7884
Status:
Final
EudraCT No: 2014-004415-37
Page:
23 of 36
SI 
No.
Endpoints
Landmark 
visits
Endpoint  
type
Imputation 
approach and 
Statistical 
model
Analysis 
set
Sensitivity 
analyses
22
Change from 
baseline in 
FPG (mmol/L)
Week 16, 
Week 52
Continuous
J2R-MI 
ANCOVA 
FAS
NA
23
Change from 
baseline in 
fasting insulin 
(pmol/L)
Week 16, 
Week 52
Continuous
J2R-MI 
ANCOVA (with 
log transformed 
response and baseline 
values)
FAS
NA
24
Change from 
baseline in C-
peptide 
(nmol/L)
Week 16, 
Week 52
Continuous
J2R-MI 
ANCOVA (with 
log transformed 
response and baseline 
values)
FAS
NA
25
Change from 
baseline in 
HOMA-B
Week 16, 
Week 52
Continuous
J2R-MI 
ANCOVA (with 
log transformed 
response and baseline 
values)
FAS
NA
26
Change from 
baseline in 
HOMA-IR
Week 16, 
Week 52
Continuous
J2R-MI 
ANCOVA (with 
log transformed 
response and baseline 
values)
FAS
NA
27
Change from 
baseline in 
Pulse 
(beats/min)
Week 16, 
Week 52
Continuous
J2R-MI 
ANCOVA
SAS
NA
28
Relative 
change from 
baseline in 
Amylase
Week 16, 
Week 52
Continuous
MMRM (with log 
transformed response 
and baseline values)
SAS
NA
29
Relative 
change from 
baseline in 
Lipase
Week 16, 
Week 52
Continuous
MMRM (with log 
transformed response 
and baseline values)
SAS
NA
5.4.1.2
Supportive secondary PK endpoint
Model-derived area under the curve (AUC) over the dosing interval in steady state.
5.4.1.3
Supportive secondary safety endpoints
Adverse events
AEs will be summarised by System organ class (SOC) and Preferred term (PT) level for the safety 
analysis set separately for two periods: 
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11
RI
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 December 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
1.0
UTN: U1111-1162-7884
Status:
Final
EudraCT No: 2014-004415-37
Page:
24 of 36
x
In trial: defined as events with onset date on or after the first day of trial product administration 
and no later than the last study visit.
x
On treatment: defined as events with onset date on or after the first day of trial product 
administration and no later than whatever comes first: a) 14 days after the last day on trial 
product, b) FU visit (subjects with trial product discontinued), or c) last study visit (early 
withdrawn subjects without FU visit).
x
A treatment emergent adverse event (TEAE) is defined as an event that occurs in the ‘on 
treatment’ period.  
In addition, the TEAEs will be summarised for the double blinded (0-16 week) and open label (end 
of week 16 to week 52.
The AEs will be coded using the most recent version of the Medical Dictionary for regulatory 
Activities (MedDRA). They will be presented in terms of the number and percentage of subjects 
with at least one event, the number of events and the event rate per 1000 years. AEs in the screening 
period will be presented in listings.
Hypoglycaemic episodes
The hypoglycaemic episodes will be summarised descriptively by severity and treatment in terms of 
the number and percentage of subjects with at least one event and the total number of events. In the 
same way as for AEs, there will be separate summaries for the “in trial” and “on treatment” periods. 
Hypoglycaemic episodes in the screening period will be presented in listings.
Hypoglycaemic episodes will also be summarised based on newer classification recommended by 
International Hypoglycaemia Study Group (IHSG) 201712, ADA 201813 and ISPAD 201814 for 
clinically significant hypoglycaemia (PG confirmed <3.0 mmol/L) (see Appendix 3 for the new 
classification)
The hypoglycaemic episodes will be summarised for the double blinded period (0-16 week) and 
open label period (end of week 16 to week 52).
Anti-liraglutide antibodies
Anti-liraglutide antibodies will be summarised in terms of the number and percentage of subjects at 
each visit that are antibody-positive and antibody-negative. Similarly, subjects with cross-reactivity 
against endogenous GLP-1 and in vitro neutralising effect will be summarised.
In addition, a comparison of the change in HbA1c and body weight between antibody-positive and 
antibody-negative subjects will be performed using descriptive statistics and graphs. Listings with 
the individual antibody results will also contain information about the HbA1c levels and body 
weight measurements. The impact of anti-liraglutide antibodies on safety will be similarly assessed 
by descriptive comparisons between antibody-positive and antibody-negative subjects.
ECG
Summary statistics and the frequencies of shifts in ECG status from baseline at 16 and 52 weeks 
will be tabulated for each treatment group.
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11
RI
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 December 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
1.0
UTN: U1111-1162-7884
Status:
Final
EudraCT No: 2014-004415-37
Page:
25 of 36
Pulse
Summary statistics and the frequencies of shifts from baseline to 16 and 52 weeks will be tabulated 
for each treatment group. In addition, statistical analyses similar to those made for blood pressure 
will be performed considering safety analysis set.
Laboratory parameters
Summary statistics will be tabulated for each laboratory parameter. The distributions will also be
presented graphically using box plots by treatment and week.
For each laboratory parameter, the values will be compared to the relevant reference range. The 
results will be presented as follows:
x
Shifts from baseline at 16 and 52 weeks will be tabulated. The shift tables will include the 
number of subjects below, within and above the reference range at each visit
x
The proportion of subjects with laboratory values outside the reference range will be tabulated 
per visit and treatment group
x
Individual values outside the reference range (abnormal values) will be listed by treatment and 
subject
For amylase and lipase  the relative change (100*value/baseline) will be analysed with an MMRM 
model as described under sensitivity analysis in section 5.3.3. The response and baseline values will 
be log transformed prior to the analysis. Safety analysis set will be considered. All lab parameters 
will be reported in standard units. However for the parameters like Total Cholesterol, LDL, HDL, 
Triglycerides, Total bilirubin, Creatinine, calcium, HbA1C, Fasting plasma glucose conventional 
units will also be provided along with standard units in the descriptive statistics output.
Box plots will be provided for lab parameters like Calcitonin, Lipase, Amylase, ALT, AST and 
Prolactin
Pubertal status
Tanner stage at screening as well as changes in Tanner stage at 16 and 52 weeks will be 
summarised using descriptive statistics.
Physical examination
Physical examination at screening and changes in physical examination will be summarised.
Mental health questionnaires
Results from the mental health questionnaires PHQ-9 and C-SSRS from part A will be summarised 
using descriptive statistics and the frequencies of shifts from baseline to 16 and 52 weeks will be 
tabulated for each treatment group.
In addition to all the supportive secondary safety endpoints, following  endpoints is added.
x
Height) velocity in cm/year (if subject is still growing)
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11
RI
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 December 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
1.0
UTN: U1111-1162-7884
Status:
Final
EudraCT No: 2014-004415-37
Page:
26 of 36
Height velocity
Height velocity is the change in height per year and is measured in cm/year.
The height velocity is calculated as the difference between current height and baseline divided by
time duration in days between those measurement time points and multiplied by 365 days.
5.5
Exploratory endpoints analysis
Not applicable
5.6
Other safety analyses
Not applicable
5.7
Other analyses
Not applicable
5.8
Interim analyses
No interim analysis is planned for the efficacy data in this trial. PK data from part A will be 
included in a population PK analysis also including historical data for other populations to aid dose 
selection for part B. Modelling results and safety data will be reviewed by the DMC before subjects 
in Part B will be enrolled in the trial. Before the randomisation code break for part A, modelling 
results will only be communicated to DMC and to individuals involved in dose selection for part B.
5.8.1
Data monitoring committee
Refer section 12.7.2 from Protocol.
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11
RI
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 December 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
1.0
UTN: U1111-1162-7884
Status:
Final
EudraCT No: 2014-004415-37
Page:
27 of 36
6
Supporting documentation
6.1
Appendix 1 List of abbreviations
AE
adverse event
ALT
alanine aminotransferase
AD
available drop-out
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
AUC
area under the curve 
AT 
available on treatment
BMI
body mass index
BMI SDS
body mass index standard deviation score
BOCF
baseline observation carried forward
CI
confidence interval
CRF
case report form
C-SSRS
columbia suicidality severity rating scale 
CV
coefficient of variance
FAS
full analysis set
DMC
data monitoring committee
HbA1c
glycosylated haemoglobin
hCG
human chorionic gonadotrophin
HDL
high density lipoprotein
hsCRP
high sensitivity C reactive protein 
LDL
low density lipoprotein
LOCF
last observation carried forward
MD
missing drop-out
MedDRA
Medical Dictionary for Regulatory Activities
MI
multiple imputation 
MMRM
mixed model for repeated measurements
MT
missing on treatment
PD
pharmacodynamics
PHQ-9
patient health questionnaire 9 
PK
pharmacokinetics
SAE
serious adverse event
SAP
statistical analysis plan
SAS
safety analysis set
LAR
legally acceptable representative
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11
RI
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 December 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
1.0
UTN: U1111-1162-7884
Status:
Final
EudraCT No: 2014-004415-37
Page:
28 of 36
6.2
Appendix 2: Changes to protocol-planned analyses
In this SAP the following changes is been made to the statistical consideration in the protocol are as
elaborated below for:
6.2.1
Primary endpoints
x
Due to the COVID-19 pandemic, the primary endpoint assessments (body weight and height) 
for very few subjects in part B could not be performed at the end of the double-blind period of 
the trial – Visit 10 (Week 16) or at the end of the open-label period of the trial – Visit 19 (Week 
52). These measurements (missing or performed at home) will not be part of the primary 
analysis. An additional analysis will be performed by including the subjects impacted by 
COVID-19 at week16 and 52 for the change from baseline in BMI SDS.
x
For the sensitivity analysis using LOCF method the protocol mentions that data from nominal 
visits (V10x and V19x) will not be used .Similarly for sensitivity analysis using BOCF, MMRM 
and week 16/52 completer analysis, data from nominal visits (10x and 19x) will be excluded.
6.2.2
Supportive secondary efficacy endpoints
x
Additional analysis for changes from baseline at 16 and 52 weeks 
x
BMI SDS (%)
x
BMI (%)
It will be analysed with the same type of ANCOVA with MI as used for the main analysis of the 
primary endpoint, with the corresponding baseline covariate.
x
During the blinded review of data it has been observed that there were only few subjects 
achieving ≥ 10% reduction in baseline BMI at week 16  or at week 52 (as mentioned in 
section 5.4.1). Therefore the statistical analysis (J2R-MI Logistic Regression) will not be 
performed for this endpoint  and will be summarised descriptively.
x
For the analysis of categorical endpoints , the protocol mentions to include treatment, sex, 
region, baseline glycaemic category, stratification factor for Tanner stage and interaction 
between baseline glycaemic category and stratification factor for Tanner stage as fixed effects, 
and baseline BMI/BMI SDS (wherever applicable) and baseline age as covariates. During the 
blinded review of data for the categorical endpoints it has been observed that due to the small
number of subjects in the trial the model cannot be estimated. To avoid the risk of over fitting 
and to make the model estimable the following explanatory variables will be removed from the 
analysis model.: sex, region ,interaction between baseline glycaemic category and stratification 
factor for Tanner stage.
x
During the blinded review of data it has been observed that no subject reported an amylase 
measurement above 3UNR and only one subject reported a lipase measurement above 3UNR.
Due to the few number of subjects having a measurement above 3UNR,for these parameters at
any time during treatment, the statistical analysis (Logistic Regression) will not be performed.
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11
RI
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 December 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
1.0
UTN: U1111-1162-7884
Status:
Final
EudraCT No: 2014-004415-37
Page:
29 of 36
6.2.3
Supportive secondary safety endpoints
x
Additional safety endpoints, is been added as below.
x
Height velocity in cm/year (if subject is still growing)
x
The testosterone analysis (change from baseline values at week 16 and 52) for part B could not 
be performed as originally planned due to an unforeseen change in the assay used by the central 
laboratory to measure testosterone during the trial. On 05 Dec 2018, Q2 laboratories moved 
from the Siemens ADVIA Centaur Testosterone “TSTO” assay to the new “TSTII” assay. The 
upgraded assay adheres more closely to the LC-MS reference values. This change in 
methodology prevented a direct comparison of values measured at different time points during 
the trial. As a result, the changes from baseline for individual subjects at week 16 and 52 are not 
provided for part B. Testosterone analysis for part A will be performed as mentioned in 
protocol. A listing of various hormones (LH, FSH and testosterone) analysed at different 
timepoints during the trial will be provided with reference ranges. Summary statistics for the 
testosterone analysis using the two different assays will be provided.
x
Safety analysis set will be used to analyse change from baseline pulse values at week 16 and 52.
Also to analyse MMRM model for relative change from baseline for amylase and lipase values 
at week 16 and 52.
x
C-SSRS will only be summarised using summary statistics (frequency count, percentage) for
baseline, week 16 and week 52 and the shift from baseline to 16 and 52 week will not be 
produced.
6.3
Appendix 3: Definition and calculation of endpoints, assessments and derivations
6.3.1
Endpoint derivations and assessments
6.3.1.1
BMI Standard deviation score (BMI SDS) and Height Standard deviation score 
(Height SDS)
BMI SDS and height SDS score will be calculated using external reference data on BMI and height 
from WHO4
The following procedure is recommended to calculate a z-score for an individual child with 
measurement y at age t:
1: Calculate 
zind =
ሾ௬Ȁெሺ௧ሻሿ௅ሺ௧ሻିଵ
ௌሺ௧ሻ௅ሺ௧ሻ
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11
RI
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 December 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
1.0
UTN: U1111-1162-7884
Status:
Final
EudraCT No: 2014-004415-37
Page:
30 of 36
2: Compute the final z-score (Z*ind) of the child for the indicator as:
Where:
x
L(t), M(t) and S(t): Box-cox power, median and CV respectively
x
y: Individual BMI or height value
x
SD3pos: is the cut-off 3 SD calculated at t (age) by LMS method:
SD3pos=M(t)[1+L(t)*S(t)*(3)]1/L(t)
x
SD3neg: is the cut-off -3 SD calculated at t by the LMS method:
SD3neg=M(t)[1+L(t)*S(t)*(-3)]1/L(t)
x
SD23pos: is the difference between the cut-offs 3 SD and 2 SD calculated at t by LMS 
method:
SD23pos=M(t)[1+L(t)*S(t)*(3)]1/L(t) – M(t)[1+L(t)*S(t)*(2)]1/L(t)
x
SD23neg: is the difference between the cut-offs -2 SD and -3 SD calculated at t by LMS 
method:
SD23neg = M(t)[1+L(t)*S(t)*(-2)]1/L(t) – M(t)[1+L(t)*S(t)*(-3)]1/L(t)
To illustrate the procedure, an example with BMI-for-age for boys is provided below and displayed
in Figure 6-1.
Figure 6-1 Examples of children/adolescents ranked according to the 2007 WHO BMI-for-
age reference.
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11
RI
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 December 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
1.0
UTN: U1111-1162-7884
Status:
Final
EudraCT No: 2014-004415-37
Page:
31 of 36
Child 1: 11-year-old boy with BMI=30
L=1.7862 M=16.9392 S=0.11070
Z=
ሾଷ଴Ǥ଴Ȁଵ଺Ǥଽଷଽଶሿ̰ሺሺିଵǤ଻଼଺ଶሻሻሺିଵሻ
଴Ǥଵଵ଴଻଴כሺିଵǤ଻଼଺ଶሻ
ൌ͵ǤʹͶ > 3
SD3=16.9392*[1+(-1.7862)*0.11070*(3)]1/(-1.7862) = 28.03
SD2=16.9392*[1+(-1.7862)*0.11071*(2)]1/(-1.7862) = 22.45
SD23 = 28.03 – 22.45 = 5.58
Z*ind= 3+ሺ͵Ͳ െʹͺǤͲ͵ȀͷǤͷͺሻൌ͵Ǥ͵ͷ (BMI SDS)
Similar calculation will be done for height SDS.
6.3.1.2
C-SSRS questionnaire
The Columbia-Suicide Severity Rating Scale questionnaire is used for part A to assess the subject’s 
mental state. It contains two sets of questions; one meant for the screening/randomisation visit (C-
SSRS-01; baseline) and the other for the rest of the visits (C-SSRS-02; since last visit). At 
screening/randomisation, the questionnaire is part of the exclusion criteria (suicidal behavior,
previous suicide attempts). During the trial, the questionnaire is used to evaluate the subject’s 
mental status between visits. The first part of the questionnaire is to build up around ‘yes/no’ 
questions, which depending on the answers trigger other parts of the questionnaire
6.3.1.3
PHQ-9 questionnaire
The Patient Health Questionnaire 9 is used for part A to assess the mental health of the subject. 
PHQ-9 is done throughout the trial period. It contains 9 questions which are answered with a 
categorical rating (not at all, several days, more than half the days, nearly every day) translated 
directly into a number (0-3). The numbers are summed at the bottom of the questionnaire by the 
investigator. Similar to C-SSRS-01, this questionnaire is used at screening/randomisation as part of 
the exclusion criteria, i.e., if the total score is ≥15 then the subject should be excluded from the trial. 
6.3.1.4
Hyperphagia questionnaire
Hyperphagia, a characteristic of patients with PWS, will be assessed using the hyperphagia 
questionnaire. It contains 13 questions. Out of 13 questions 11 questions are categorised into 3
domains (behaviour, drive and severity) scores. 2 questions will be considered as additional 
questions. The Total score is the sum of all the 3 domain scores. 
12 questions out of 13 are answered with a categorical rating, translated directly into a number (1-
5). There is one question, “how old was your child when they first showed an increased interest in 
food?” which will be answered in to number directly.
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11
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 December 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
1.0
UTN: U1111-1162-7884
Status:
Final
EudraCT No: 2014-004415-37
Page:
32 of 36
6.3.1.5
New classification of hypoglycaemia
Treatment emergent hypoglycaemic episodes will also be summarised by International 
Hypoglycaemia Study Group (IHSG) 201712, ADA 201813 and ISPAD 201814 for clinically 
significant hypoglycaemia (PG confirmed <3.0 mmol/L) (see Table 6-1 for the new classification). 
Table 6-1
New classification of hypoglycaemia
Level
Glycaemic criteria
Description
Hypoglycaemia alert 
value (level 1)
< 3.9 mmol/L (70 mg/dL) 
and ≥3.0 mmol/L (54 
mg/dL)  
Sufficiently low for treatment with fast-
acting carbohydrate and dose adjustment of 
glucose-lowering therapy
Clinically significant 
hypoglycaemia (level 
2)
< 3.0 mmol/L (54 mg/dL)
Sufficiently low to indicate serious, 
clinically important hypoglycaemia
Severe hypoglycaemia 
(level 3)
No specific glucose 
threshold
Hypoglycaemia associated with severe 
cognitive impairment requiring external 
assistance for recovery
Unclassifiable
Unclassifiable
Episodes which could not be classified 
according to the above new classifications
Notes: The above terms ‘hypoglycaemia alert value’ for level 1 and ‘clinically significant hypoglycaemia’ for level 2
were adapted by Novo Nordisk from IHSG 2017, ADA 2018, ISPAD 2018 recommendations for hypoglycaemia. 
‘Severe hypoglycaemia’ (level 3) term was as defined by ADA 2013 and ISPAD 2018.
6.3.2
Analysis Rules
6.3.2.1
Visit Windowing
Primary and secondary endpoints analysis is performed at Visit 10 (week 16) and Visit 19 (week 
52).
For subjects who prematurely discontinues trial product or subject and/or the subject’s LAR(s) 
withdraw consent, the investigator must aim to undertake procedures similar to those for the end of 
treatment (V19) as soon as possible and the follow up visit (V20) two weeks later.
The subjects were asked to attend additional visits depending on when the trial product
discontinuation takes place during the trial:
x
If trial product is discontinued between V3 and V9, the subject should attend V10x (16 weeks 
after V3) and V19x (52 weeks (± 5 days) after V3).
x
If trial product is discontinued between V11 and V19, the subject should attend V19x (52 weeks 
(± 5 days) after V3).
The end of double-blind treatment (V10) and end of treatment (V19) collected for prematurely 
discontinued subject and withdrawn subjects did not exactly taken place in respective endpoint 
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 December 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
1.0
UTN: U1111-1162-7884
Status:
Final
EudraCT No: 2014-004415-37
Page:
33 of 36
weeks (i.e., at week 16 and week 52). Hence these records will be reallocated to the respective 
weeks based on analysis day on when the assessments are done by visit windowing concept.
6.3.2.2
Visits windows
Generally, visit-windows will be used for the data that is summarized by visit; they are based on the 
study evaluation schedule and comprise a set of days around the nominal visit day. For any 
assessment, there are the protocol defined scheduled visits around which visit windows were 
created to cover the complete range of days within the study.  
In 4179 the visit windowing will be done only for V10 and V19 visits for prematurely 
discontinued/withdrawn subjects.
The visit windows are shown in Table 6-2.
In this table, the days are counted since the date of randomization for both safety and efficacy 
assessments. These visit windows apply to measurements taken at every visit. For assessments 
collected less often different visit windows will be applied as detailed below.
When visit windows are used, all visits will be re-aligned, i.e., they will be mapped into one of the 
visit windows. For example, if the Week 4 visit of a subject is delayed and occurs on Day 46 
instead of on Day 29, it will be re-aligned to visit window Week 8. In the case of major deviations 
from the visit schedule, or due to unscheduled visits, several assessments of a subject may fall in a 
particular visit window (either scheduled or unscheduled). Statistical approaches to handle multiple 
assessments in a given visit window are specified below.
In general, if two consecutive visits Vt and Vs are x days apart, the upper limit of the visit window 
for Vt will be Vt+x/2 and the lower limit for the visit Vs will be Vs-x/2 (if x is even, the lower limit
for Vs will be Vs-x/2+1, and the upper limit for Vt will be Vt+x/2). The algorithm needs to ensure 
that visit windows are not overlapping and that there are no gaps, such that each assessment can be 
uniquely allocated to one visit window, e.g., if Week 8 visit is scheduled for day 57, Week 12 is
scheduled at Day 85 and Week 16 is scheduled at Day 113, then the visit window for week 12 
extends from Day 79 to Day 106.
Note: The lower limit of first visit will be assigned with -999 which accommodate all assessments 
occurred before the scheduled day.
The upper limit of last visit will be assigned with 999 which accommodate all assessments occurred 
after the scheduled day.
Table 6-2 Assessment windows for scheduled visits
Analysis Visit
Week
Scheduled 
Day
Visit Window
Visit 1 (screening)
week -2
-15
Day -15 to -8
Visit 2 (screening)
week -1
-8
Day -7 to -3
Visit 3 (week 0)
Randomisation
1
Day -2 to 4
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 December 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
1.0
UTN: U1111-1162-7884
Status:
Final
EudraCT No: 2014-004415-37
Page:
34 of 36
Analysis Visit
Week
Scheduled 
Day
Visit Window
Visit 4 (week 1)
week 1
8
Day 5 to 11
Visit 5 (week 2)
week 2
15
Day 12 to 18
Visit 6 (week 3)
week 3
22
Day 19 to 25
Visit 7 (week 4)
week 4
29
Day 26 to 50
Visit 8 (week 8)
week 8
57
Day 51 to 78
Visit 9 (week 12)
week 12
85
Day 79 to 106
Visit 10 (week 16)
week 16
113
Day 107 to 134
Visit 10x (week 16 follow-up)
week 16
113
Day 107 to 134
Visit 11 (week 20)
week 20
141
Day 135 to 162
Visit 12 (week 24)
week 24
169
Day 163 to 190
Visit 13 (week 28)
week 28
197
Day 191 to 218
Visit 14 (week 32)
week 32
225
Day 219 to 246
Visit 15 (week 36)
week 36
253
Day 247 to 274
Visit 16 (week 40)
week 40
281
Day 275 to 302
Visit 17 (week 44)
week 44
309
Day 303 to 330
Visit 18 (week 48)
week 48
337
Day 331 to 358
Visit 19 (week 52)
week 52
365
Day 359 to 371
Visit 19x (week 52 follow-up)
week 52
365
Day 359 to 371
Visit 20 (week 54)
week 54
379
Day 372 to 999
6.3.2.3
For parameters which are not collected at every visit (e.g. HEIGHT): 
Visit windows defined in Table 6-2 will be combined. For example Table 6-3 show visit windows 
for HEIGHT.
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 December 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
1.0
UTN: U1111-1162-7884
Status:
Final
EudraCT No: 2014-004415-37
Page:
35 of 36
Table 6-3 Assessment windows for scheduled visits 
Analysis Visit
Week
Scheduled 
Day
Visit Window
Visit 2 (screening)
week -1
-8
Day -7 to -3
Visit 3 (week 0)
Randomisation
1
Day -2 to 106
Visit 10 (week 16)
week 16
113
Day 107 to 190
Visit 10x (week 16 follow-up)
week 16
113
Day 107 to 190
Visit 13 (week 28)
week 28
197
Day 191 to 274
Visit 16 (week 40)
week 40
281
Day 275 to 358
Visit 19 (week 52)
week 52
365
Day 359 to 371
Visit 19x (week 52 follow-up)
week 52
365
Day 359 to 371
6.3.2.4
For parameters which are collected at ‘x’ visits:
For premature discontinued subjects a parameter such as ‘BODY WEIGHT’, ‘HEIGHT’ is 
collected at additional visits like 10x and 19x, hence if the visit reallocation for these parameters 
and related parameters such as ‘BMI’, ‘BMI SDS’  are reallocated to x visit instead of normal visit 
(i.e., visits 10 and 19). Other parameters are reallocated to normal visits.
Note: Withdrawal subjects are reallocated to normal visits.
6.3.3
Analysis eligible records:
If the records are reallocated to the visit which is already collected, then the collected visit record is 
used for analysis instead of record which is reallocated to that visit. 
if the subjects have records for both normal visit (Visit 10 (week 16) and x visit Visit 10x (week 16)
then the records which are reallocated are not eligible for analysis.
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 December 2020
Novo Nordisk
Trial ID: NN8022-4179
Version:
1.0
UTN: U1111-1162-7884
Status:
Final
EudraCT No: 2014-004415-37
Page:
36 of 36
7
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CONFIDENTIAL